Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof

Related Applications This application is filed on May 8, 2012, US Provisional Application No. 61 / 644,105; US Provisional Application No. 61 / 657,239 filed on June 8, 2012; filed on August 23, 2012. US Provisional Application No. 61 / 692,487, US Provisional Application No. 61 / 763,770 filed on February 12, 2013; and US Provisional Application No. 61 / 788,519 filed on March 15, 2013, and 2013. Claims the priorities and interests of US Non-Provisional Application No. 13 / 735,973 filed on January 7. The contents of each of these applications are incorporated herein by reference in their entirety.

Tech. Provide a method of manufacture.

Background Technology Fluticasone propionate [(6α, 11β, 16α, 17α) -6,9, -difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopropoxy) Androsta-1,4- Dien-17-carbothioic acid, S-fluoromethyl ester], synthetic fluticosteroid. This corticosteroid consists primarily of a class of synthetic steroids used as anti-inflammatory and antipruritic agents. Fluticasone propionate (FP) has been commercialized as a corticosteroid for treating inflammation-related diseases such as allergic rhinitis, asthma and atopic dermatitis. The PK / PD properties of this molecule are well established by its long-term use in humans.

Chemically, fluticasone propionate is C₂₅H₃₁F₃0₅It is S. Fluticasone propionate has a molecular weight of 500.6. Fluticasone propionate is a white to off-white powder that is insoluble in water. Like other topical corticosteroids, fluticasone propionate is anti-inflammatory and has the properties of stopping itching and causing vasoconstriction. The mechanism of anti-inflammatory activity of this topical steroid is generally unclear. However, corticosteroids are phospholipase A, which is collectively called lipocortin.₂It is believed to act by inducing inhibitory proteins. These proteins are presumed to regulate the biosynthesis of potent transmitters of inflammation, such as prostaglandins and leukotrienes, by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is phospholipase A₂Is released from membrane phospholipids. This compound has strong anti-inflammatory activity and is particularly useful for the treatment of respiratory disorders, especially asthma. In vitro assays using human lung cytosole preparations show that fluticasone propionate has an affinity of more than 18 times that of dexamethasone, and almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of budesonide. Established as a human glucocorticoid receptor agonist with an affinity for.

Adverse reactions due to the currently commercially available forms of fluticazone propionate include lymphatic signs and symptoms; cardiovascular agitation; hypersensitivity reactions (vascular edema, skin rash, facial and tongue edema, itching, urticaria, Bronchial spasm, tingling, difficulty breathing, and anaphylactic / anaphylactic reactions); middle ear inflammation; tonsillitis; nasal leakage / posterior nasal leakage / nasal juice; ear pain; cough; laryngitis; Nasal signs and symptoms; Unspecified oropharyngeal plaques; Ear, nose and throat polyps; Sucking; Paranasal pain; Rashitis; Throat contractions; Allergic ear disorders, nasal disorders and pharyngeal disorders; Taste and / Or changes or disappearance of odor sensation; nasal septum; bleeding to nasal mucosa; nasal rash; voice changes; fluid turbulence; weight gain; thyroidoma; uric acid metabolism disorders; appetite disorders; eye irritation; hazy eyes; Glaucoma; increased intraocular pressure and cataracts; keratitis and conjunctivitis; palpebral conjunctivitis; nausea and vomiting; abdominal pain; viral gastroenteritis; gastroenteritis / colitis; gastrointestinal infections; abdominal discomfort; diarrhea; constipation; rash inflammation; digestion Poor and gastric disorders; abnormal liver function; trauma; fever; rash; tooth problems; mouth irritation; mouth and tongue disorders; cholecystitis; lower airway infections; pneumonia; joint pain and rheumatoid arthritis; muscle spasms and Spasm; Fracture; Wound and laceration; Contusion and hematoma; Burn; Musculoskeletal inflammation; Bone and cartilage disorders; Joint pain; Contusion / strain; Neck disorder / Symptoms; Muscle tingling / pain; Pain and pain; Pain; dizziness / dizziness; tremor; sleep onset; compression nerve syndrome; sleep disorder; cerebral nerve palsy; migraine; nervousness; bronchitis; chest congestion and / or symptoms; malaise and fatigue; pain; edema and swelling Bacterial infections; Fungal infections; Movement disorders; cysts, humps and masses; Mood disorders; Acute nasopharyngeal inflammation; Difficulty breathing; Inhalant irritation; Urticaria; Rash / rash; Sweat and sebaceous disorders; Sweat; Photodermatitis; dermatitis and dermatosis; viral skin infections; eczema; fungal skin infections; itching; acne and folliculitis; burns; polychosis; increased erythema; urticaria; folliculitis Pigment deficiency; Peri-mouth dermatitis; Skin atrophy; Skin streaks; Sweat rash;Pustular psoriasis; urinary infections; bacterial reproductive infections; dysmenorrhea; vaginal candidiasis; pelvic peritonitis; vaginitis / external vaginitis; and irregular menstrual cycles.

The mechanism of action of fluticasone in all commercial and research products is equal; the penetration of the cell's progenitor membrane and subsequent binding of the molecule to the glucocorticoid receptor of the cytosol (two transcribed by a single gene). Represented by separate receptors GR-α and GR-β). Of the two receptors, GR-α is involved in the production of anti-inflammatory responses. Another mechanism that regulates inflammation is protein-mediated-protein sequestration occurs via binding to other pro-inflammatory transcription factors, such as activated protein (AP-1), which is the transcription of inflammatory genes. Brings inhibition. The GC-GR complex can also act indirectly through the induction of an inhibitory protein, eg, ΙκΒ, which suppresses NF-κB activity. In this way, anti-inflammatory effects also affect immunological pathways, resulting in immunosuppression, one of the side effects observed with drugs. Other related side effects include eye effects such as increased intraocular pressure (glaucoma) and increased cataracts. However, these side effects correlate with drug concentration and route of administration.

There is a need for a topical preparation of fluticasone suitable for ocular use.

<p><patcit num="1"><text>U.S. Pat. No. 6406718</text></patcit></p>

<p> Outline of the Invention The present invention is based on the discovery of a method for preparing stable sterile nanocrystals of hydrophobic drugs, such as fluticasone propionate nanocrystals or triamcinolone acetonide nanocrystals. The method of the invention comprises suspending a suspension of hydrophobic drugs (eg, fluticasone propionate and triamcinolone acetonide) nanocrystals while maintaining size, purity, shape (rod or plate), pH, and weight osmolal concentration. Allows for a concentrated form of 0.0001% to 10%. This process allowed the production of topical formulations at higher tolerable concentrations than previously achieved for the treatment of inflammatory disorders of the eye and skin. The process also allows the production of more crystalline hydrophobic drugs and the control of nanocrystal size and size distribution of hydrophobic drugs. Control of size and size distribution is controlled by specific conditions of the process, such as temperature, pH and / or viscosity of component solution for the process, stabilizer type, molecular weight and / or viscosity, annealing duration, sonication output energy. , Batch size, as well as flow rate, etc. can be selected.</p><p> In one aspect, the invention provides a fixed form (form A) of fluticasone propionate characterized by a powder X-ray diffraction pattern containing peaks at about 7.8, 15.7, 20.8, 23.7, 24.5, and 32.5 degrees 2θ. ..</p><p> The present invention also provides multiple nanoplates of fluticasone propionate having an average size of about 10-10000 nm, (eg, 100-1000 nm or 300-600 nm).</p><p> The present invention is 0.35 g / cm³Above (for example, 0.40 g / cm³Above, 0.45g / cm³Above, 0.50g / cm³Above, or 0.55 g / cm³Further provided is a purified fluticasone propionate in crystalline form, characterized by a tap density (above).</p><p> The stereomorphic, crystalline, and / or nanocrystals described herein may include one or more of the following features:</p><p> The stereotype is further characterized by a powder X-ray diffraction pattern further including peaks at about 9.9, 13.0, 14.6, 16.0, 16.9, 18.1 and 34.3 degrees 2θ.</p><p> The stereotype is characterized by a powder X-ray diffraction pattern that is substantially similar to the pattern shown in FIG. 31A.</p><p> The stereotype has a purity greater than 80% by weight (eg,&gt; 85% by weight,&gt; 90% by weight,&gt; 95% by weight,&gt; 97% by weight,&gt; 98% by weight, or&gt; 99% by weight).</p><p> The standard form is 0.35 g / cm³Above (for example, 0.40 g / cm³Above, 0.45g / cm³Above, 0.50g / cm³Above, or 0.55 g / cm³The tap density of (above) is further characterized.</p><p> The stereotype is further characterized by a melting range of 10 ° C and a melting point of 299.5 ° C.</p><p> The stereotype is further characterized by a dissolution rate in water of about 1 μg / g / day in water at room temperature.</p><p> The stereotypes include fluticasone propionate nanoplates with an average size of about 10-10000 nm, (eg, 100-1000 nm, 300-600 nm, 400-800 nm, or 500-700 nm).</p><p> The stereotypes include fluticasone propionate nanoplates with a narrow range of size distributions. In other words, the nanoplates are substantially uniform in size.</p><p> The fixed form is 50 ~ 100nm, 100 ~ 300nm, 300 ~ 600nm, 400 ~ 600nm, 400 ~ 800nm, 800 ~ 2000nm, 1000 ~ 2000nm, 1000 ~ 5000nm, 2000 ~ 5000nm, 2000 ~ 3000nm, 3000 ~ 5000nm, or 5000. Includes fluticasone propionate nanoplates with a size distribution of ~ 10000 nm.</p><p> Each nanoplate has a thickness between 5 nm and 500 nm (eg, 5 to 400 nm, 5 to 200 nm, 10 to 150 nm or 30 to 100 nm).</p><p> The nanoplate has a [001] crystal axis that is substantially perpendicular to the surface that defines the thickness of the nanoplate.</p><p> Multiple nanoplates are 0.35 g / cm³Above (for example, 0.40 g / cm³Above, 0.45g / cm³Above, 0.50g / cm³Above, or 0.55 g / cm³It is characterized by the tap density of (above).</p><p> Multiple nanoplates feature a melting point of 299.5 ° C with a melting range of 10 ° C.</p><p> Multiple nanoplates are characterized by a rate of dissolution in water at room temperature of approximately 1 μg / g / day.</p><p> Multiple nanoplates feature a powder X-ray diffraction pattern containing peaks at about 7.8, 15.7, 20.8, 23.7, 24.5, and 32.5 degrees 2θ.</p><p> The plurality of nanoplates is further characterized by a powder X-ray diffraction pattern further including peaks at about 9.9, 13.0, 14.6, 16.0, 16.9, 18.1 and 34.3 degrees 2θ.</p><p> The plurality of nanoplates are characterized by a powder X-ray diffraction pattern that is substantially similar to the pattern shown in FIG. 31A.</p><p> Multiple nanoplates have a purity greater than 80% by weight (eg,&gt; 85% by weight,&gt; 90% by weight,&gt; 95% by weight,&gt; 97% by weight,&gt; 98% by weight, or&gt; 99% by weight).</p><p> The crystalline morphology is further characterized by a melting range of 10 ° C and a melting point of 299.5 ° C.</p><p> The crystalline morphology is further characterized by a dissolution rate in water of about 1 μg / g / day in water at room temperature.</p><p> The crystal morphology is further characterized by a powder X-ray diffraction pattern containing peaks at about 7.8, 15.7, 20.8, 23.7, 24.5, and 32.5 degrees 2θ.</p><p> The crystal morphology is further characterized by a powder X-ray diffraction pattern, further comprising peaks at about 9.9, 13.0, 14.6, 16.0, 16.9, 18.1 and 34.3 degrees 2θ.</p><p> The crystal morphology is characterized by a powder X-ray diffraction pattern that is substantially similar to the pattern shown in FIG. 31A.</p><p> The crystalline form has a purity greater than 80% by weight (eg,&gt; 85% by weight,&gt; 90% by weight,&gt; 95% by weight,&gt; 97% by weight,&gt; 98% by weight, or&gt; 99% by weight).</p><p> In another aspect, the invention provides a novel fixed form of triamcinolone acetonide, ie, form B, which form B at about 11.9, 13.5, 14.6, 15.0, 16.0, 17.7, and 24.8 degrees 2θ. It features a powder X-ray diffraction pattern containing peaks.</p><p> Form B is further characterized by a powder X-ray diffraction pattern containing additional peaks at about 7.5, 12.4, 13.8, 17.2, 18.1, 19.9, 27.0 and 30.3 degrees 2θ.</p><p> Form B features a powder X-ray diffraction pattern that is substantially similar to the red profile in FIG.</p><p> Form B is substantially free of impurities.</p><p> Form B has a purity greater than 85%, greater than 90%, greater than 92%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%.</p><p> The present invention also provides a method for producing the plurality of nanoplates. The method includes: preparing a phase I solution (eg, a sterile solution) containing fluticazone propionate and a solvent for fluticazone propionate, at least one surface stabilizer and a poor solvent for fluticazone propionate. In the step of preparing a phase II solution (for example, a sterile solution) containing the above, in which at least one surface stabilizer contains a cellulose-based surface stabilizer, the phase I solution and the phase II solution are mixed. A step of obtaining a phase III mixture, in which ultrasonic treatment is applied when mixing the two solutions, and the mixing is carried out at a first temperature of 25 ° C. or less, and a step. Period (T₁), For example, the step of annealing the phase III mixture at a second temperature above the first temperature during the period for producing a phase III suspension containing multiple nanoplates of fluticasone propionate.</p><p> In another aspect, the invention provides a method of producing purified, stable sterile nanocrystals of a hydrophobic therapeutic agent. The method includes: preparing a Phase I solution (eg, a sterile solution) containing a hydrophobic therapeutic agent and a solvent for the hydrophobic therapeutic agent, a poor solvent for at least one surface stabilizer and the hydrophobic therapeutic agent. A step of preparing a phase II solution (for example, a sterile solution) containing the above, a step of mixing the phase I solution and the phase II solution to obtain a phase III mixture, and the mixing is 25 ° C or less. Steps performed at the first temperature, and for a period of time (T)₁), For example, the step of annealing the phase III mixture at a second temperature above the first temperature during the period for producing a phase III suspension containing multiple nanocrystals of the hydrophobic therapeutic agent.</p><p> The methods described herein may include one or more of the following features:</p><p> Hydrophobic therapeutic agents are steroid drugs such as corticosteroids.</p><p> The hydrophobic therapeutic agent is fluticasone or an ester thereof or triamcinolone acetonide.</p><p> The hydrophobic therapeutic agent is fluticasone propionate.</p><p> Sonication (eg, 10-75 W or about 50-70 W power) is applied when mixing the Phase I sterile solution with the Phase II sterile solution.</p><p> The first temperature is between -10 ° C and 30 ° C, between -10 ° C and 25 ° C (eg, 22 ° C or 20 ° C or less), or between -5 ° C and 10 ° C. The temperature is between 0 ° C and 5 ° C, or between 0 ° C and 2 ° C, or between 2 ° C and 4 ° C, or between 2 ° C and 8 ° C.</p><p> The second temperature is between 4 ° C and 60 ° C, or between 10 ° C and 40 ° C, or between 15 ° C and 25 ° C.</p><p> T₁Is at least 8 hours.</p><p> At least one surface stabilizer in the phase II solution contains a cellulosic surface stabilizer.</p><p> The cellulosic surface stabilizer is methyl cellulose having a molecular weight of 100 kDa or less.</p><p> Methyl cellulose has a concentration of about 0.1% to 0.5% in a phase III suspension.</p><p> The cellulosic surface stabilizer used in the phase II solution is an aqueous solution.</p><p> An aqueous solution of a cellulosic surface stabilizer has a viscosity of 4000 cP or less (for example, 2000 cP or less, 1000 cP or less, 500 cP or less, 100 cP or less, 50 cP or less, 30 cP or less, or 15 cP or less).</p><p> The aqueous solution of the cellulosic surface stabilizer has a viscosity of about 4cP to 50cP, and the cellulosic surface stabilizer is methylcellulose.</p><p> Poor solvents include water (eg distilled water).</p><p> At least one surface stabilizer in the phase II solution further comprises benzalkonium chloride.</p><p> The concentration of benzalkonium chloride in the phase II solution is about 0.005% to 0.15% (eg, about 0.01% to 0.12% or 0.02% to 0.08%).</p><p> The pH value of the phase II solution is 6.5 or less, 6.0 or less, or 5.5 or less.</p><p> The solvent of the phase I solution contains a polyether.</p><p> The polyether is selected from polyethylene glycol (PEG), polypropylene glycol (PPG), and mixtures thereof.</p><p> The polyether is selected from PEG400, PPG400, and mixtures thereof.</p><p> PEG400 has a concentration of about 20-35% in Phase I solution.</p><p> PPG400 has a concentration of about 65% to 75% in Phase I solution.</p><p> Solvents for Phase I solutions include one or more polyols, such as monomeric polyols (eg, glycerol, propylene glycol, and ethylene glycol) and polymeric polyols (eg, polyethylene glycol).</p><p> The Phase I solution further contains a surface stabilizer.</p><p> The surface stabilizer in the phase I solution is, for example, Tween80 at a concentration of about 7.0% to 15% in the phase I solution.</p><p> Volume ratios of Phase I and Phase II solutions range from 1: 10 to 10: 1 (eg 1: 3 to 3: 1 or 1: 2 to 2: 1 or about 1: 1). Is.</p><p> Cellulose-based surface stabilizers are methylcellulose with a molecular weight of 100 kDa or less, the first temperature is between 0 ° C and 5 ° C, and the second temperature is between 10 ° C and 40 ° C. Temperature, T₁Is at least 8 hours.</p><p> The method further comprises purification of multiple nanocrystals of the hydrophobic therapeutic agent by tangential flow filtration or continuous flow centrifugation. The method may further comprise drying a plurality of nanocrystals of the hydrophobic therapeutic agent, for example by filtration, vacuum drying, or centrifugation. In this method, for example, the nanocrystals are purified by centrifugation, and then the purified nanocrystals are used as an appropriate aqueous solution (adding an additional additive to the final preparation that meets the FDA standard for administration to the eye or skin). Mixing with (which can be formed) can be further compared. For example, mixing is carried out in a mixer (eg, Silverson Lab Mixer) at room temperature at 6000 RPM for about 60 minutes or longer.</p><p> A phase I sterilized solution of fluticazone and a phase II sterilized solution containing distilled water to produce a phase III suspension containing a suspension of benzalkonium chloride, methylcellulose, and, for example, fluticazone nanocrystals. Purified, stable sterile nanocrystals of fluticazone by mixing. Nanocrystals are between 400 and 800 nm. Fruticazone nanocrystals are washed and replaced with a suitable aqueous solution for purification, i.e., to remove crystallization solvents from Phase I and Phase II solutions, and / or to reduce their concentrations. This replacement is performed, for example, by using tangential flow filtration (TFF) or hollow fiber filter cartridges. In some embodiments, the nanocrystals are exchanged for a formulation that meets FDA criteria for administration to the eye or skin. Alternatively, the nanocrystals are replaced with a sterile aqueous solution and additional additives are added to this aqueous solution to form the final formulation that meets the FDA criteria for administration to the eye or skin. The fluticasone concentration in the final aqueous buffer is between about 0.0001% and 10% (w / v). In some embodiments, the annealing step is performed prior to the buffer replacement step. The annealing step is performed at about 25-40 ° C and for a duration of about 30 minutes to 24 hours.</p><p> Preferably, the fluticasone in the phase I solution has a concentration of about 0.4% to 1.0% w / v. More preferably, the fluticasone in the phase I solution has a concentration of about 0.45% w / v.</p><p> In some embodiments, the phase I solution further comprises Tween80, polyethylene glycol (PEG) 400 and polypropylene glycol (PPG) 400. Tween80 has a concentration of about 7.0% to 15% w / v. PEG400 has a concentration of about 20-35% (w / v). PPG400 has a concentration of about 65% to 75% (w / v). In a preferred embodiment, the Phase I solution is fluticasone at a concentration of about 0.45% w / v, Tween80 at a concentration of about 7.44%, PEG400 at a concentration of about 23% (w / v), and PPG400 at a concentration of about 69.11. It is contained at a concentration of% (w / v).</p><p> Mixing Phase I and Phase II is carried out at temperatures below 8 ° C (eg 0-2 ° C, 2-4 ° C or 2-8 ° C). The volume ratio between Phase I and Phase II is 0.15 to 0.3 or 1: 1 to 1: 3. The phase I solution mixes with the phase II solution at a flow rate of 0.5 to 1.4 ml / min, in which case the phase II solution is stationary. See, for example, Figure 3. In other embodiments, the phase III is 0.5-900 ml / min (eg, 0.5-2.0 ml / min, 10-900 ml / min, 12-700 ml / min, 50-400 ml / min, 100-250 ml / min, Or a phase I solution with a flow rate of 110-130 ml / min) and 2.5-2100 ml / min (eg 2.5-10 ml / min, 10-900 ml / min, 12-700 ml / min, 50-400 ml / min, 100- It is formed by combining with a phase II solution at a flow rate of 250 ml / min, or 110-130 ml / min) in a flow reactor. See, for example, Figure 4. In some embodiments, the flow rate of Phase I and the flow rate of Phase II solution are substantially the same. In other embodiments, the flow rate of Phase I is lower than the flow rate of Phase II, for example, the volume ratio of Phase I solution to Phase II solution is about 1: 2 or 1: 3. In some embodiments, the flow rate of the Phase III suspension leaving the flow reactor is about 20-2800 ml / min (eg, about 100-800 ml / min or 200-400 ml / min). In some cases, the phase III mixture is sonicated.</p><p> In some embodiments, the final aqueous buffer containing methylcellulose, permeation enhancer and wetting agent. Methyl cellulose has a concentration of, for example, about 0.5% (w / v).</p><p> Similarly, the present invention includes a plurality of nanocrystals produced by the method of the present invention and a composition containing the nanocrystals (for example, a pharmaceutical composition). The composition is substantially free of organic solvents. Nanocrystals have an average size in the range of 400-800 nm (eg, 300-600 nm, 400-600 nm or 500-700 nm). Nanocrystals do not aggregate and do not increase in size over a 24-hour period. Nanocrystals are nanoplates, eg, fluticasone propionate nanoplates with a [001] crystal axis that is substantially perpendicular to the surface that defines the thickness of the nanoplate. Nanoplates can have thicknesses in the range of about 5 nm to 100 nm. In some cases, the nanocrystals are coated with methylcellulose.</p><p> Further provided by the present invention are topical sterile nanos containing a fluticasone nanocrystal suspension of the invention between 0.0001% and 10% w / v and a pharmaceutically acceptable aqueous additive. It is a crystalline fluticasone preparation. In some embodiments, the pharmaceutical product has a viscosity between 10 and 20 cP at 20 ° C. The weight osmolal concentration of this product is about 280-350 mOsm / kg. The pH of the pharmaceutical product is about 6 to 7.5.</p><p> In another aspect, the invention is directed to the eye, for example, by topically administering an effective amount of a formulation of the invention (eg, a topical formulation) to the eyelid margin, skin or surface of the eye of the subject in need thereof. Provides a method of treating or alleviating the symptoms of the disorder (eg, blepharitis, meibomian gland dysfunction, postoperative pain or postoperative eye inflammation, dry eye, eye allergy or vegetative inflammation). The pharmaceutical product is administered using, for example, an applicator (eg, a brush or a swab). In one embodiment, a therapeutically effective amount of the formulation is used to treat blepharitis, eg, via an applicator (eg, a brush such as a Latisse® brush or a swab such as a 25-3317-U swab). It is administered to subjects who need it. In some embodiments, the pharmaceuticals are pharmaceuticals with a suspension of the FP nanocrystals of the invention (eg, 0.01-1%, or about 0.25%, 0.1% or 0.05%) between 0.001% and 5%. It is a fluticasone preparation for topical sterile nanocrystal propionate containing an acceptable aqueous additive. In some embodiments, the formulation further contains about 0.002 to 0.01% (eg, 50 ppm + 15%) of benzalconium chloride (BKC). In some embodiments, the formulation is one or more coating dispersants (eg, tyloxapol, polysorbate 80, and PEG stearate, eg, PEG40 steerate), one or more tissue wetting agents (eg, glycerin),. One or more polymer stabilizers (eg, methylcellulose 4000cP), one or more buffers (eg, dibasic sodium phosphate Na)₂HP0₄And monosodium phosphate NaH₂P0₄, And / or one or more isotonicity modifiers (eg, sodium chloride). In some embodiments, the formulation has a viscosity between 40-50 cP at 20 ° C. In some embodiments, the weight osmolal concentration of the formulation is about 280-350 (eg, about 285-305) mOsm / kg. In some embodiments, the pH of the formulation is about 6.8-7.2. In some embodiments, the formulation has a viscosity between 40-50 cP at 20 ° C. In some embodiments, the FP nanocrystals in the formulation have a median size of 300-600 nm, an average size of 500-700 nm, a D50 value of 300-600 nm, and / or a D90 of less than 2 μm (eg, less than 1.5 μm). Has a value.</p><p> In yet another aspect, the invention is directed to a respiratory disease (eg, asthma or chronic obstructive pulmonary disease (COPD)) by administering an effective amount of the pharmaceutical composition of the invention to a subject in need thereof. , Provide methods for treating or alleviating rhinitis, dermatitis or esophagitis.</p><p> Also provided is a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or additives and nanocrystals of a hydrophobic drug produced by the method of the invention (eg, fluticasone propionate). Is. The composition can be in the form of a dry powder / inhaler, an ophthalmic preparation, a spray, an ointment, a cream, a pill, etc. In a further embodiment, the invention is the fluticasone nanocrystal of the invention. Provided is a semi-flexible polyurethane coater containing a pharmaceutically acceptable aqueous additive.</p><p> In yet another aspect, the invention presents a surgical or implantable device (eg, a stent, angioplastic balloon, catheter, shunt, access device, guidewire, etc.) coated or impregnated with a fluticazone crystal propionate of the invention. Provided are graft systems, intravascular imaging devices, vascular system closure devices, endoscopy accessories, or other devices disclosed herein). In some embodiments, fluticasone propionate crystals are coated or embedded in a surgical or implantable device to alter the release time of the drug. For example, coating or embedding fluticasone propionate crystals in a surgical or implantable device increases drug release time.</p><p> Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Methods and materials similar to or equivalent to those described herein can be used in the practice of the invention, but suitable methods and materials are described below. All publications, patent applications, patents and other references described herein are expressly incorporated by reference in their entirety. In the event of inconsistency, the specification of the invention, including the definition, will prevail. Moreover, the materials, methods and examples described herein are exemplary only and are not intended to be limiting.</p><p> As an advantage of the method of the invention, this product (eg, nanocrystals of hydrophobic drug) is purer (or at least not pure), more crystalline, and / or more than stock material of the drug. It is stable. Also advantages are the controllable size and size distribution of the product, the ability to make the size of the product substantially uniform (which can result in better control of drug release in vivo), and the methods of the invention. May cause little or no degradation to the drug.</p><p> Other features and advantages of the invention will become apparent and embraced by the description and claims detailed below.</p>

<figref num="1">An overview of the physical and chemical properties of fluticasone propionate.</figref><figref num="2">An HPLC chromatogram of fluticasone propionate and its common impurities.</figref><figref num="3">It is a scheme of one embodiment (referred to as "batch process") of the process of the present invention.</figref><figref num="4">It is a scheme of another embodiment (referred to as "flow process") of the process of the present invention.</figref><figref num="5">It is a figure which shows that the average size of a fluticasone nanocrystal of propionate can be controlled by changing a specific composition of a phase II solution.</figref><figref num="6">It is a figure which shows the particle size of fluticasone propionate produced by the top-down technique such as microsolution formation, jet grinding, sonication (wet grinding) and homogenization.</figref><figref num="7">It is a figure which shows the effect of the pH of a phase II solution on the particle size of fluticasone propionate.</figref><figref num="8">It is a figure which shows the effect of various stabilizers in a phase II solution on the particle size of fluticasone propionate.</figref><figref num="9">It is a figure which shows the effect of the pH of a phase III mixture on the particle size of fluticasone propionate.</figref><figref num="10">It is a figure which shows that the purified fluticasone propionate nanocrystals do not aggregate with time.</figref><figref num="11">It is a figure which shows the effect on the particle size of fluticasone propionate at the time of mixing a phase I solution and a phase II solution.</figref><figref num="12">It is a figure which shows the effect of the annealing temperature on the particle size of fluticasone propionate at a concentration of 0.1% in a phase III suspension.</figref><figref num="13">It is a figure which shows the effect of the annealing temperature on the particle size of fluticasone propionate at a concentration of 10% in a phase III suspension.</figref><figref num="14">It is a figure which shows the effect of the type of a filter on the loss of a drug crystal.</figref><figref num="15">It is a figure which shows the effect of the pore size of a filter on the loss of a drug crystal.</figref><figref num="16">It is a figure which shows the dispersibility of a pharmaceutical product as a function of a batch scale (from left to right: 20 g, 100 g, 250 g, 1000 g and 2000 g).</figref><figref num="17">It is a figure which shows the dispersibility of a pharmaceutical product as a function of FP concentration (from left to right: 10%, 5%, 1%, 0.1%, 0.05%, 0.01% and 0.005%).</figref><figref num="18">It is a figure which shows the uniformity of a pharmaceutical product as a function of time.</figref><figref num="19">It is a schematic diagram of a flow reactor.</figref><figref num="20">It is a figure which shows the effect of the flow rate on the particle size of fluticasone propionate in a flow process.</figref><figref num="21">21A-C are diagrams showing the particle size distribution of FP nanocrystals produced by the batch process, FP particles produced by homogenization, and FP stock received from the manufacturer.</figref><figref num="22">A group of figures showing particle size stability of fluticasone propionate nanosuspension at 25 ° C and 40 ° C for up to 75 days.</figref><figref num="23">It is a figure which shows the dissolution rate of the homogenized fluticasone propionate (1-5 micron, represented by a gray square dot), and the fluticasone propionate crystal (400-600 nm, represented by a black diamond dot) produced by a batch process. ..</figref><figref num="24">FIGS. 24A and 24B are chromatograms of the fluticasone propionate stock material and the nanocrystals produced by the batch process, respectively.</figref><figref num="25">25A and 25B are optical micrographs (Model: OMAX, 1600 ×) of dried fluticasone propionate crystals and FP stock materials prepared by batch process, respectively.</figref><figref num="26">26A and 26B are scanning electron micrographs of dried fluticasone propionate crystals prepared by batch process.</figref><figref num="27">27A and 27B are scanning electron micrographs of dried fluticasone propionate stock material and FP crystals prepared by homogenization, respectively.</figref><figref num="28-1">FIGS. 28A and 28B are combinations of fluticasone propionate nanocrystals prepared by batch process and DSC / TGA of FP stock material, respectively.</figref><figref num="28-2">FIGS. 28A and 28B are combinations of fluticasone propionate nanocrystals prepared by batch process and DSC / TGA of FP stock material, respectively.</figref><figref num="29">It is a Fourier transform infrared spectroscopy scan of the FP nanocrystal produced by the batch process of the present invention.</figref><figref num="30">A Fourier transform infrared spectroscopy scan of the FP stock material.</figref><figref num="31-1">FIG. 31A is an XRPD pattern (black) of fluticasone nanocrystals produced by the batch process.</figref><figref num="31-2">Figure 31B shows the XRPD of fluticasone nanocrystals of propionate produced by the batch process, in which the calculated XRPD pattern of polymorph 1 (red) and the superimposed XRPD pattern of polymorph 2 (blue) are superimposed. It is a pattern (black). Blue arrows indicate some differences in the XRPD pattern.</figref><figref num="32">It is a figure which shows the size distribution of the triamcinolone acetonide crystal produced by the method of this invention.</figref><figref num="33">DSC scan of triamcinolone acetonide stock material.</figref><figref num="34">DSC scan of triamcinolone acetonide crystals produced by the method of the present invention.</figref><figref num="35">Thermogravimetric analysis of triamcinolone acetonide stock material.</figref><figref num="36">It is a thermogravimetric analysis of the triamcinolone acetonide crystal produced by the method of this invention.</figref><figref num="37-1">Figures 37A-E are scanning electron micrographs of triamcinolone acetonide stock materials at various magnifications and triamcinolone acetonide crystals produced by the methods of the invention: A and B-magnifications of 100x and 5000x, respectively. Triamcinolone acetonide stock material; C, D, and E-triamcinolone acetonide crystals produced by the methods of the invention at 100x, 5000x, and 10000x, respectively.</figref><figref num="37-2">Figures 37A-E are scanning electron micrographs of triamcinolone acetonide stock materials at various magnifications and triamcinolone acetonide crystals produced by the methods of the invention: C, D, and E-magnification 100x each. , 5000 ×, and 10000 × triamcinolone acetonide crystals produced by the method of the present invention.</figref><figref num="38">It is a schematic diagram which shows one embodiment of the process of this invention for the process of production and purification for fluticasone propionate nanocrystals.</figref><figref num="39">The XRPD pattern (red) of the triamcinolone acetonide nanocrystals prepared by the method of the present invention, superimposed on the XRPD pattern (blue) of the triamcinolone acetonide stock material. Arrows indicate some differences in the XRPD pattern.</figref>

Detailed Description of the Invention The present invention is sterile nanocrystals (possibly nano) of a hydrophobic therapeutic agent (eg, fluticasone propionate) optimized to meet pharmaceutical specifications for administration (eg, topical or intranasal). A method and composition for producing a suspension) are described. The compositions produced by this method are ideally suitable for the topical treatment of inflammatory disorders, such as eye disorders and skin disorders. The composition produced by this method is also ideally used, for example, for inflammatory disorders, respiratory disorders, autoimmune diseases and cancer, where the hydrophobic drugs in the composition are used. Suitable for systemic or non-systemic procedures.

When the drug nanocrystals produced by the method of the present invention are administered to a subject in need thereof, a specific administration route, for example, eye drops, gels, ointments, dry powders, gels, aerosols, etc. Alternatively, it can be in various forms suitable for the form of colloidal suspensions (eg, liquid suspensions). For example, drug nanocrystals are "dispersed" phases suspended within another phase, which is the "continuous" phase. A nanosuspension can be defined as a colloidal dispersion of nano-sized drug particles that is produced in a suitable manner and stabilized with a suitable stabilizer or surface stabilizer. Unless otherwise stated, the terms "stabilizer," "surface stabilizer," and "steric stabilizer" are used interchangeably herein. In one embodiment, the drug is delivered or formulated for delivery via a systemic or local route. For example, the drug is delivered or formulated for direct delivery or delivery via an applicator (eg, brush or swab). For example, the drug is delivered or formulated for delivery via a local route to tissues such as eye tissue and / or appendages. The drug is delivered or formulated for delivery via intraocular, intravitreal, subretinal, intracapsular, intrachoroidal, subconjunctival, subconjunctival, intraluminal, intraorbital, posterior cardesac, or periball injection. can do. The drug can also be delivered or formulated for delivery via topical application to tissues such as ocular tissue and / or appendages. The drug can also be delivered or formulated for delivery via a implantable or surgical (eg, drug delivery) device.

Nanosuspension of insoluble drugs, such as nanocrystal suspensions, can dramatically reduce their effective concentration by enhancing bioavailability. By "bioavailable" is meant a lysed drug that is molecularly available for absorption by cells.

Fluticasone propionate has a solubility of 0.14 micrograms / ml and is almost insoluble in water. Since most ophthalmic suspensions are aqueous, the particle size of the insoluble drug determines its rate of dissolution in the dissolved drug (or bio-available drug) at any given time point. One way to enhance bioavailability is to ensure a completely dissolved drug solution. A method for enhancing the bioavailability of water-insoluble drugs with respect to insoluble drugs is the use of micronized or nano-sized dosage forms. In the case of fluticasone propionate, the dissolution rate is dramatically increased by reducing the particle size. The emission rate of fluticasone propionate particles with a size of 800 to 900 nm is several times that of particles larger than 10 microns. Thus, nanosuspension of fluticasone propionate has the potential to produce potent pharmaceuticals that are effective at concentrations that do not cause harmful side effects. At higher concentrations, fluticasone propionate can cause an increase in intraocular pressure that results in glaucoma and cataracts. An effective formulation of fluticasone propionate can be envisioned at lower concentrations if the drug is in the form of nanoparticles, or more water soluble. For fluticasone propionate, the effective concentrations of commercialized drug products range from 0.005% (Cutivate) and 0.5% (Flonase). Thus, making a drug "effective" at previously unanticipated concentrations for its indication is a surprising and unexpected result. Similarly, for another hydrophobic drug, triamcinolone acetonide (17.5 μg / mL water soluble at 28 ° C), the drug is, for example, in the form of nanoparticles produced via the method of the invention. If so, an effective formulation of TA can be unexpectedly obtained at lower concentrations of TA that were not previously envisioned for a particular indication.

Thus, in the design of topical medications that require immediate and then sustained resolution, bioadhesive nanocrystaline suspensions simultaneously increase bioavailability while reducing drug residence time. It is presumed to support strengthening. In the examples described in the present invention, a fluticasone propionate suspension has been developed for the treatment of blepharitis characterized by inflammation and infection of the eyelids. However, the fluticasone propionate compositions described herein can also be utilized for the prevention or treatment of other inflammatory conditions in the eye. For example, the compositions described in the present invention can be used for post-surgical post-operative care. For example, the compositions of the invention can be used to control post-surgery pain and thus inflammation after surgery, argon laser trabeculoplasty and photorefractive surgery. In addition, the fluticazone propionate composition can be used to treat other eye disorders such as eye allergies, allergic conjunctivitis, cystoid macular edema uveitis, or meibomian gland dysfunction. In addition, the fluticasone propionate composition can be used to treat skin disorders such as atopic dermatitis, skin lesions, eczema, psoriasis, or rashes.

Difficulties in Producing Stable Nanocrystals of Hydrophobic Drugs Successful production of nanosuspensions presents two major challenges. The first challenge is the production of particles of the desired size. For most drugs that are insoluble in water, the desired particle size is submicron (10-990 nm) ranging from low nm to high nm. The second step is to maintain the particle size over the long term. Both steps are difficult.

Drug suspensions are usually prepared by a "top-down" technique, which mechanically disrupts the dispersion into smaller particles. Techniques such as wet milling, sonication, microsolutionization and high pressure homogenization are examples of this technique for producing micronized and nano-sized particles. In high pressure homogenization, the nanocrystal size produced from this process depends not only on the hardness of the drug material, but also on the homogenization pressure and the number of cycles. However, high pressure homogenization does not depend on the type of stabilizer. Thus, the efficiency of the stabilizer, i.e. whether the stabilizer can prevent particle agglutination, is indicated after processing and during storage. Therefore, it is very important to understand the phenomena involved in particle formation in the particular process used.

During milling or mechanical particle size reduction, two contradictory processes interact within the milling vessel: fragmentation of the material into smaller particles and particle growth through interparticle collisions. The appearance of these two opposite phenomena depends on the process parameters. Often after a certain time point, the particle size reaches a certain level and continued milling does not further reduce the particle size. In some cases, an increase in grinding time may achieve a reduction in particle size by reducing the milling rate, while also resulting in a slow increase in the particle size and heterogeneity of the material. Changes in physical morphology or amorphization can also occur during milling. Mechanical pressures above a critical pressure value increase lattice vibrations and destabilize the crystal lattice. The number of defects increases and the conversion to the amorphous state occurs above the significant defect concentration. The high stress imposed on the drug crystals during the particle reduction technique results in destabilization of the crystal structure, loss of crystallinity, and sometimes a shift to less stable polymorphic forms. The formation of amorphous regions in the crystal structure results in a slow increase in particle size as the suspension shifts back to a stable, crystalline form.

Another challenge to nanocrystal production is the slow increase in particle size, also known as "Ostwald ripening". Crystal growth in colloidal suspensions is commonly known as Ostwald ripening and is involved in changes in particle size and size distribution. Ostwald ripening results from these dissolution dependences on particle size. According to the Ostwald-Freundlich equation, small crystals have higher saturation solubility than larger crystals, creating a drug concentration gradient between the smaller and larger crystals. As a result, the molecule diffuses from the higher concentration around the smaller crystal to the region around the larger crystal with the lower drug concentration. This creates a supersaturated solution state around the large crystals, resulting in drug crystallization into the large crystals. This diffusion process leaves an unsaturated solution around the small crystals, causing the small crystals to dissolve the drug molecules into the medium. This diffusion process continues until all the small crystals have melted. Ostwald ripening is basically the process by which large particle crystals sacrifice small crystals. This subsequently shifts the crystal size and size distribution of the colloidal suspension to a higher range. Dispersions with drugs dissolved in the continuous phase also always result in instability in particle size.

Another challenge with nanocrystals is agglomeration or swarming of particles. Stabilizers play a decisive role in stabilizing the dispersion. Stabilizers must achieve orderly and proper stabilization by adsorbing the particle surface. In addition, the adsorption should be strong enough to last for a long time. Stabilizer adsorption can occur by ionic interactions, hydrogen bonds, van der Waals or ionic dipole interactions, or by hydrophobic effects.

Possible interactions between stabilizer functional groups and drug materials should always be considered before selecting a drug / stabilizer pair. Many drugs have structures containing functional groups such as phenols, amines, hydroxyl groups, ethers or carboxylic acid groups, which are capable of interacting. Strong ionic interactions, hydrogen bonds, dipole-induced forces, and weak van der Waals or London interactions can enhance or disrupt particle formation. The concentration level of the stabilizer is also important. Adsorption / region is a surface property that is usually independent of particle size. This means that the total amount of stabilizer is directly related to the crystal size, as the amount adsorbed correlates with the surface area. Adsorption of polymer molecules to the crystal surface occurs as the reduction in free energy due to adsorption compensates for the associated entropy loss. Since steric stabilization is based on the adsorption / desorption process, process variables such as stabilizer concentration, particle size, solvent, etc. are important factors for the effectiveness of the stabilizer.

Another method of stabilizing crystal size is the technique used to produce aerosolized microparticles of fluticasone propionate, which is the spray-drying of particulate suspensions in the presence of specific stabilizers. be. A combination of top-down methods has also been used to produce particles of the desired size. Another way to stabilize the particle size is to freeze-dry the particulate suspension.

Another commonly used method for producing nanosuspensions is the anti-solvent precipitation method, in which the drug solution is precipitated as nanocrystals in the anti-solvent. This technique is called the "bottom-up" crystallization technique, in which the nanocrystals are produced in situ. Precipitation of the drug as nanocrystals usually occurs with homogenization or sonication. If the drug is dissolved in an organic solvent such as acetone prior to precipitation, the organic solvent must be removed after the formation of the particles. This is usually done by evaporation of the solvent. This evaporation step presents a challenge to this method of particle formation. This is because the evaporation process can change the dynamics of particle stabilization, often with a rapid increase in grain size. In addition, residual levels of organic solvent often remain bound to the additives used in the pharmaceutical. Therefore, although this method has been explored, it has its challenges and is generally unfavorable.

Nanocrystals of hydrophobic drugs produced by the process defined in the present invention do not use toxic organic solvents that need to be removed and do not exhibit the particle instability defined in the above section.

Central features of the present invention The present invention provides an ultrasonic crystallization / purification process capable of producing nanocrystals of a drug (eg, hydrophobic drugs) or suspensions containing the nanocrystals. This process (a) incorporates sterile filtration of all components prior to the formation of nanocrystals, (b) produces crystals of the desired size, and (c) a particular sterically stabilized composition at a particular temperature. When used in combination with annealing, it stabilizes the nanocrystals and (d) provides the prescriber with the flexibility to purify the particles by replacing the original continuous phase with another continuous phase. d) Provide flexibility to achieve the desired final concentration of drug in the final pharmaceutical vehicle. In step (d), the significance of the purification step is that the composition that produces and stabilizes the particles in the desired size has special implications for and depends on the parameters of ionic strength, polymer molecular weight and structure and pH. Can be the main and important aspects of the invention. The composition used to produce the particles is usually not the composition envisioned by the prescriber as the final formulation or concentrate of the final drug. This is addressed by spray drying or lyophilization. The nanocrystals produced by this process are in the range of 100 nm to 500 nm, 500 to 900 nm, 400 to 800 nm and 900 nm to 10000 nm. Preferably, the nanocrystals have a size in the range of 400 to 800 nm (eg, 400 to 600 nm). The size and size distribution of the nanocrystals of the present invention can be determined by conventional methods such as dynamic light scattering (DLS), scanning electron microscope (SEM), transmission electron microscope (TEM), and X-ray power diffraction (XRPD). Can be determined by. In the present invention, the nanocrystals are purified by exchanging with a final biocompatible, histocompatible buffer.

Two-part process: This process is characterized by being a two-part process for preparing nanocrystals, defined as Step 1 and Step 2. In some cases, this process is one step, in which case the final formulation is prepared in one step (step 1 only). In contrast to this two-step process (step 1, followed by step 2), the first part of this process is the production of nanocrystals of the desired size (step 1). The second part of this process is the purification of highly pure nanocrystals suspended at the desired drug concentration and nanocrystals to produce an additive composition optimized for the final formulation. (Step 2).

Drug Concentration: In a preferred embodiment, the initial nanocrystal concentration (after step 1) is 0.1% drug (eg corticosteroid, eg FP), but the final formulation may be as high as 10% (step 2). rear). The initial concentration of the suspension may be less than 0.1% (step 1) and can be concentrated to 10% during the purification process using the same or different medium compositions (step 2). The initial concentration of the suspension may be 0.1% or less than 0.1%, preferably 0.06%. Initial suspensions may be purified to lower concentrations using the same or different vehicle compositions (step 2). Among the preferred compositions, the initial suspension may be formed at 0.06% (step 1) and purified to 0.06% or less using the same initial medium composition or different medium compositions (step 1). 2). The initial concentration of the nanosuspension is 1%, 1% to 0.5%, 0.5% to 0.1%, 0.1% to 0.05%, 0.05% to 0.01%, 0.01% to 0.005%, 0.005% to 0.001%, 0.001%. It may be ~ 0.0005%, 0.0005% ~ 0.0001%, 0.0001% ~ 0.00001%.

Step 1 involves dissolving the drug in an FDA-approved additive to create Phase I. The solution (Phase I) is then sterile filtered through a 0.22 micron PVDF (polyvinylidene fluoride) filter. Prepare a solution containing a particular composition of tranquilizer at a certain viscosity, pH and ionic strength. This is Phase II. In one embodiment, the drug is a steroidal drug. In a preferred embodiment, the drug is fluticasone propionate. In another preferred embodiment, the drug is fluticasone flocate. In another embodiment, the drug is any salt form of fluticasone propionate.

In one embodiment, step 1 comprises: preparing a phase I solution (eg, a sterile solution) containing a hydrophobic therapeutic agent and a solvent for the hydrophobic therapeutic agent; at least one surface stabilizer and hydrophobicity. A step of preparing a phase II solution (eg, a sterile solution) containing a poor solvent for the therapeutic agent; a step of mixing the phase I solution and the phase II solution to obtain a phase III mixture, which is the mixing. Steps performed at the first temperature below 25 ° C; for a period of time (T)₁), For example, the step of annealing the phase III mixture at a second temperature above the first temperature during the period for producing a phase III suspension containing multiple nanocrystals of the hydrophobic therapeutic agent. And, for example, the step of optionally purifying nanocrystals by tangential flow filtration, hollow fiber cartridge filtration, or centrifugation (eg, continuous flow centrifugation).

In some cases, centrifugation is performed at about 39,000 xg, about 1.6 L / min.

Optionally, step 1 comprises diluting with solution after the annealing step and before the purification step. For example, this dilution step involves redispersing the nanocrystals in solution. The solution used for dilution is about 0.002 to 0.01% (eg 50 ppm ± 15%) benzalconium chloride, 0.01 to 1% polysorbate 80 (eg about 0.2%), 0.01 to 1% PEG40 stearate. (Eg about 0.2%), buffers (eg citrate buffers, pH 6.25), and water can be included. Pellets formed during purification (eg during centrifugation) are redistributed into the final formulation (see eg Figure 38). By adding the pellets to a suitable aqueous solution, the nanocrystals contained in the mixer (eg, Silverson Lab Mixer) can be redistributed. By performing the redispersion at 6000 RPM at room temperature for about 45 minutes or longer (eg, about 60 minutes or longer), the final product that meets the FDA criteria for ocular or skin administration can be obtained. The pharmaceutical product may contain one or more pharmaceutically acceptable additives.

For example, the hydrophobic remedy is a steroid.

For example, the hydrophobic remedy is fluticasone propionate or triamcinolone acetonide.

For example, at least one surface stabilizer comprises a cellulosic surface stabilizer, such as methylcellulose.

For example, methylcellulose has a molecular weight of 100 kDa or less.

For example, cellulosic stabilizers used in Phase II solutions (eg, methylcellulose) have viscosities between 4cP and 50cP, eg, 15-45cP.

For example, the first temperature is, for example, 20 ° C or less, 8 ° C or less, such as &lt;4 ° C, &lt;2 ° C, or 0-4 ° C.

For example, the second temperature, the annealing temperature, is between 20 ° C and 60 ° C.

For example, the annealing step is necessary to reduce the particle size of the nanocrystals and / or to cure the nanocrystals (eg, to increase the hardness of the nanocrystals).

For example, continuous flow centrifugation is performed at about 39,000xg, about 1.6 L / min.

For example, nanocrystals produced by the methods described herein are between 10 nm and 10000 nm (eg, 50-5000 nm, 80-3000 nm, 100-5000 nm, 100-2000 nm, 100-1000 nm, or 100- Has an average size of 800 nm).

For example, the nanocrystals produced by the methods described herein have a suitable particle size for delivery by microneedles (ie, 27-41 gauge). For example, when injected into the space of the upper choroid of the eye, the nanocrystals can be efficiently delivered to the posterior part of the eye, or the drug can be delivered to the anterior tissue of the eye, such as the lens, the body of the ciliary body. Minimize eye side effects, such as the formation of high intraocular pressure (IOP) or cataracts, by dissolving more slowly so as to treat the target tissue without clinging to the vitreous or the like.

For example, nanocrystals produced by the methods described herein have a narrow range of size distributions. In other words, the nanocrystals are substantially uniform in size.

For example, the ratio of D90 to D10 values for nanocrystals is lower than 10, eg, lower than 5, lower than 4, lower than 3, lower than 2, or lower than 1.5. For example, nanocrystals are 50 to 100 nm, 100 to 300 nm, 300 to 600 nm, 400 to 600 nm, 400 to 800 nm, 800 to 2000 nm, 1000 to 2000 nm, 1000 to 5000 nm, 2000 to 5000 nm, 2000 to 3000 nm, 3000 to 5000 nm, Or it has a size distribution of 5000 to 10000 nm.

For example, nanocrystals produced by the methods described herein are 5000 nm or less (eg, 4000 nm or less, 3000 nm or less, 2000 nm or less, 1000 nm or less, 900 nm or less, 800 nm or less, 700 nm or less, 700 nm or less, 600 nm or less. , 500 nm or less, 400 nm or less, 300 nm or less, 200 nm or less, 100 nm or less, or 80 nm or less) has a D90 value.

For example, the nanocrystals produced by the methods described herein are coated with methylcellulose.

For example, the methylcellulose coated nanocrystals produced by the methods described herein are stable, eg, they do not aggregate.

For example, the nanocrystals produced by the methods described herein are fluticasone propionate nanocrystals with a size distribution of 400-600 nm.

For example, the nanocrystals produced by the methods described herein are triamcinolone acetonide nanocrystals with a size distribution of 300-400 nm.

For example, the nanocrystals produced by the methods described herein are in the form of either liquid suspensions or dry powders.

For example, nanocrystals produced by the methods described herein are 0.0001% to 10%, 20%, 30%, 40%, 50%, 60%, 70%, etc. It has concentrations up to 80%, 90%, 99%, or 99.99%.

For example, sonication is applied when mixing a phase I solution with a phase II solution.

For example, methylcellulose is in the concentration range of 0.1% to 0.5% (eg, 0.2 to 0.4%) in a phase II solution.

For example, the phase II solution further comprises a second stabilizer, such as benzalkonium chloride, in a concentration range of 0.005% to 0.1% (eg, 0.01 to 0.02%).

For example, if the hydrophobic drug is fluticasone propionate, the phase II solution has a pH of 5.5.

For example, if the hydrophobic drug is triamcinolone acetonide, the phase II solution has a pH of about 4.

For example, the solvent of the phase I solution contains a polyether.

For example, the polyether is selected from polyethylene glycol (PEG), polypropylene glycol (PPG), and mixtures thereof.

For example, the polyether is selected from PEG400, PPG400, PEG40 stearate, and mixtures thereof.

For example, PEG400 has a concentration of about 20-35% in Phase I solution.

For example, PPG400 has a concentration of about 65% to 75% in Phase I solution.

For example, the solvent for the Phase I solution comprises one or more polyols, such as monomeric polyols (eg, glycerol, propylene glycol, and ethylene glycol) and polymeric polyols (eg, polyethylene glycol).

For example, the solvent for the Phase I solution comprises one or more monomeric polyols.

For example, Phase I solutions further contain surface stabilizers.

For example, the surface stabilizer in the Phase I solution is, for example, Tween80 at a concentration of about 7.0% to 15% in the Phase I solution.

For example, the concentration of hydrophobic drug in Phase I solution is about 0.1-10%, eg 0.1-5.0%, 0.2-2.5% or 0.4-10%.

For example, when the hydrophobic drug is FP, the concentration of FP in the phase I solution is about 0.1-10%, for example 0.4-1.0%.

For example, the volume ratio of Phase I solution to Phase II solution is 1: 10 to 10: 1 (eg 1: 3 to 3: 1 or 1: 2 to 2: 1 or about 1: 1). Is the range of.

For example, a cellulosic surface stabilizer is methylcellulose having a molecular weight of 100 kDa or less, the first temperature is between 0 ° C and 5 ° C, and the second temperature is between 10 ° C and 40 ° C. The temperature between, T₁Is at least 8 hours.

The method of the present invention allows the production of drug crystals with a narrow particle size distribution (PSD) range from very small sizes (eg &lt;75 nm) to larger sizes (eg 5,000 nm), allowing particles of a particular size to be produced alone. , Or in combination with smaller or larger size particles of the same drug crystal made via the methods described herein, or in different forms of drug (eg, stock material obtained by homogenization). Or other additives (eg, solvents, mucilages, mucosal adhesives) or to control release, distribution, metabolism or elimination, or to enhance tissue penetration or tissue retention time of such drugs. ) Can be used in combination.

In one embodiment, the drug suspension is in a static batch reactor using sonication (eg, sonication) or ultrahomogenization to disperse the drug that precipitates in a poor solvent. Prepare. In one embodiment, the sonication process is performed by placing it in an ultrasonic treatment tank and providing ultrasonic energy to the entire fluid. In another embodiment, the sonication process is performed using a sonot load of probe. In yet another embodiment, the dispersion step in the precipitation of the drug into a poor solvent is high pressure homogenization.

In another embodiment, the drug suspension is prepared in a flow reactor during sonication or ultrahomogenization. The temperature of the solution may be 0-4 degrees Celsius or 2-8 degrees Celsius. In another embodiment, the temperature of the solution may be 22-30 degrees Celsius. The flow reactor may be jacketed for temperature control.

The drug solution (Phase I) is weighed into the reactor using a syringe pump. In another embodiment, the drug suspension is weighed into the reactor using another automated pump device. The flow rate of Phase I may be in the range of 0.1 ml / min to 40 ml / min. Within the flow-through reactor (or flow reactor), the flow rate of Phase I is 0.1 ml / min-40 ml / min or 0.5-900 ml / min (eg 0.5-2.0 ml / min, 10-900 ml / min, It may be in the range of 12 to 700 ml / min, 50 to 400 ml / min, 100 to 250 ml / min, or 110 to 130 ml / min). In the flow-through reactor, the flow rate of Phase II is 0.1 ml / min-40 ml / min or 2.5-2100 ml / min (eg 2.5-900 ml / min, 2.5-2.0 ml / min, 10-900 ml / min, It may be in the range of 12 to 700 ml / min, 50 to 400 ml / min, 100 to 250 ml / min, or 110 to 130 ml / min).

Phase I and Phase II components of Step 1: Additives used to dissolve the drug to produce the solution in Phase I are miscible and soluble in Phase II. Is selected. The phase II component is a component in which this phase acts as a poor solvent only for the drug. When Phase I is added to Phase II in the presence of sonication, the drug precipitates into nanocrystals. Phase II is sterile filtered through a 0.22 micron PVDF filter and placed in a retention vessel maintained at 0-4 ° C or 2-8 ° C. Phase II is weighed and placed in a cell equipped with a sonot load or sonicated probe. Next, the phase I solution is weighed and dropped into the cell while being sonicated to form the phase II solution. The nanocrystals produced in step 1 can be retained in the retention tank at 2-8 ° C, 22-25 ° C or 30-40 ° C. This "retaining" process is called annealing and stabilizes the nanocrystals produced in step 1.

The annealing, or physical aging, of the nanosuspension produced in step 1 allows the drug molecule to "relax" and align to its most stable thermodynamic state. The choice of annealing temperature depends on the physiochemical characteristics of the drug. The duration of annealing is also important. In one embodiment, the duration of annealing is 30 minutes. In another embodiment, the duration of annealing is between 30 and 90 minutes. In another embodiment, the duration of annealing is between 90 minutes and 12 hours. In another embodiment, the duration of annealing is between 12 and 24 hours.

The components of Phase I and Phase II have a low viscosity, which allows each phase to be sterilized and filtered through a 0.22 micron filter. Alternatively, sterilization filtration can be performed by other sterilizing means, such as autoclaving, gamma irradiation, ethylene oxide (ETO) irradiation.

Solvents for creating Phase I for early nanosuspension are not limited to these, but are limited to PEG400, PEG300, PEG100, PEG1000, PEG-steerate, PEG40-steerate, PEG-Laureate, lecithin, phosphatidylcholine. , PEG-oleate, PEG-glycerol, Tweens, span, polypropylene glycol, DMSO, ethanol, isopropanol, NMP, DMF, acetone, methylene chloride, sorbitol.

The steric stabilizing solutions used as Phase II for the initial nanosuspension are, but are not limited to, methylcellulose, PVP, PVA, HPMC, cellulose, Pluronic F127, Pluronic. F68, carbomer, hydroxyethyl cellulose, hydroxypropyl cellulose, PEG, lecithin, phosphatidylcholine, polyquaternium-1, polylysine, polyarginine, polyhistidine, guar gum, xanthan gum, chitosan, alginate, hyaluronic acid, chondroitin sulfate, tween20, tween80, You can choose from spun, sorbitol, and aqueous amino acids. In a preferred embodiment, the steric stabilizer is methylcellulose with a viscosity of 15 cP. In another embodiment, the phase II tranquilizer is methylcellulose with a viscosity of 4cP. In another embodiment, the steric stabilizer is methylcellulose with a viscosity of 50 cP. In another embodiment, the steric stabilizer is methylcellulose with a viscosity of 4000 cP. In another embodiment, the steric stabilizer is methylcellulose with a viscosity of 100,000 cP. The concentration of methylcellulose is 0.10% to 0.20%, 0.20% to 0.40% and 0.40% to 0.50%. In a preferred embodiment, the concentration of methylcellulose in Phase II is 0.20%. In another preferred embodiment, the concentration of methylcellulose in Phase II is 0.39%. In one embodiment, the steric stabilizer in Phase II is carbomer 940 at concentrations of 0.1-1%, 1% -10%. In another embodiment, the steric stabilizer in Phase II is carboxymethyl cellulose at concentrations between 0.1% and 1% and between 1% and 10%. In another embodiment, the steric stabilizer in Phase II is carboxymethyl cellulose in combination with Carbomer 940. In another embodiment, the steric stabilizer in Phase II is PVA at concentrations between 0.1% and 1% and between 1 and 10%. In another embodiment, the steric stabilizer in Phase II is PVP at a concentration between 0.1% and 10%.

The steric stabilizer can also be cationic. Examples of useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulose-based, alginates, phospholipids, and non-polymeric compounds such as amphoteric ion stabilizers, poly-n. -Methylpyridinium, anthrylpyridinium chloride, cationic phospholipid, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylatetrimethylammonium bromide bromide (PMMTMABr), hexyldecyltrimethylammonium bromide (HDMAB), polyvinylpyrrolidone-2-dimethylamino Ethylmethacrylate dimethylsulfate, 1,2 dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- [amino (polyethylene glycol) 2000] (sodium salt) (also known as DPPE-PEG (2000) -amine Na) , Poly (2-methacryloxyethyltrimethylammonium bromide), Poloxamine (eg, Tetronic 908®, Poloxamine) Also known as 908®), lysozyme, long chain polymers such as alginic acid and carrageenan. Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quaternary ammonium compounds such as stearyltrimethylammonium chloride, benzyl-di (2-chloroethyl) ethylammonium bromide. Coconut trimethylammonium chloride or coconut trimethylammonium bromide, coconutmethyldihydroxyethylammonium chloride or coconutmethyldihirodoxyethylammonium bromide, decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride or decyldimethylhydroxyethylammonium bromide, C_12~15Dimethylhydroxyethylammonium chloride or C_12~15Dimethylhydroxyethylammonium bromide, coconut dimethylhydroxyethylammonium chloride or coconut dimethylhydroxyethylammonium bromide, myristyltrimethylammoniummethylsulfate, lauryldimethylbenzylammonium chloride or lauryldimethylbenzylammonium bromide, lauryldimethyl (ethenoxy)₄Ammonium chloride or lauryldimethyl (ethenoxy)₄Ammonium bromide, N-alkyl (C_12~18) Dimethylbenzylammonium chloride, N-alkyl (C)_14~18) Dimethyl-benzylammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyldidecylammonium chloride, N-alkyl and (C)₁_2~14) Dimethyl 1-naphthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salt and dialkyldimethylammonium salt, lauryltrimethylammonium chloride, ethoxylated alkylamide alkyldialkylammonium salt and / or ethoxylated trialkyl Ammonium salt, dialkylbenzenedialkylammonium chloride, N-didecyldimethylammonium chloride, N-tetradecyldimethylbenzylammonium, chloride monohydrate, N-alkyl (C)_12~14) Dimethyl 1-naphthylmethylammonium chloride and dodecyldimethylbenzylammonium chloride, dialkylbenzenealkylammonium chloride, lauryltrimethylammonium chloride, alkylbenzylmethylammonium chloride, alkylbenzyldimethylammonium bromide, C₁₂, C₁₅, C₁₇Trimethylammonium bromide, dodecylbenzyltriethylammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethylammonium chloride, alkyldimethylammonium halogenide, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethyl Ammonium bromide, methyltrioctyl ammonium chloride (ALIQUAT 336 ), POLYQUAT 10 , Tetrabutylammonium bromide, benzyltrimethylammonium bromide, choline ester (eg, choline ester of fatty acid), benzalconium chloride, stearalconium chloride compound (eg, stearyltrimonium chloride and distearyldimonium chloride). , Cetylpyridinium bromide or cetylpyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL and ALKAQUAT , alkylpyridinium salts; amines such as alkylamines, dialkylamines, alkanolamines, Amine salts such as polyethylene polyamines, N, N-dialkylaminoalkyl acrylates, and vinylpyridines, such as laurylamine acetate, stearylamine acetate, alkylpyridinium salts, and alkylimidazolium salts, and amine oxides; imideazolinium salts. Protonized quaternary acrylamides; methylated quaternary polymers such as poly [diallyldimethylammonium chloride] and poly- [N-methylvinylpyridinium chloride]; and cationic guars.

Ingredients of Step 2: Ingredients of Step 2 are selected to perform the task of purifying the nanocrystals prepared in the previous step. The purification process is tangential flow filtration (TFF), or vertical flow filtration (NFF), dialysis filtration or microfiltration to perform ultrafiltration. In another embodiment, step 2 is performed by centrifugation. The choice of filter depends on the size of the nanocrystals produced. The pore size of the filter can be 0.1 μm, 0.2 μm, 0.5 μm, 0.8 μm, 1 μm, 10 μm or 20 μm. When the size distribution of nanoparticles peaks at 0.5 μm, the pore size of the PVDF filter is 0.1 μm. Preferably, the nanoparticles have a peak size of 0.5 μm. In this step, the nanocrystal suspension is purified so that the initial continuous steps are completely replaced by the new continuous phase. The new continuous phase is selected to have the lowest solubility in the drug. This minimizes or eliminates Ostwald ripening.

The components of the purification process can be selected from the group containing aqueous solutions of HPMC, MC, carbomer, cellulose, PEG, chitosan, alginate, PVP, F127, F68, hyaluronic acid, polyacrylic acid, but not limited to these. can.

The component of step 2 may have a tissue adhesive component that enhances the residence time of the nanocrystals at the site and subsequently prolongs the effectiveness of the treatment. The tissue adhesive component may be cationic or anionic. Cationic tissue adhesive molecules are polyquad-1, polyethyleneimine, PAMAM dendrimer, PEI dendrimer, chitosan, alginate and derivatives thereof.

The drug nanocrystals (possibly nanosuspensions) produced by the defined process can be immunomodulators for treating the inflammatory condition of the eye. Immunomodulators have proven to be effective in various inflammatory conditions that are resistant to steroids, or when chronic use of steroids is associated with steroids. Currently available agents act as cytotoxic agents that block the proliferation of lymphocytes or as immunomodulators that block the synthesis of lymphocytes. Cyclosporin A is a preferred immunomodulator that can be prepared using the processes defined in the present invention.

The drug nanosuspension can be a combination of two drugs formulated using the same process. Thus, it can be envisioned that both drugs are simultaneously dissolved in a common additive and then precipitated using the techniques specified in the present invention.

Hydrophobic Therapeutic Agents As used herein, the term "hydrophobic therapeutic agent" or "hydrophobic drug" is poorly soluble in water, eg, less than about 10 mg / mL (eg, less than 1 mg / mL,). Refers to a therapeutic agent having a water solubility of less than 0.1 mg / mL or less than 0.01 mg / mL).

The methods of the invention can be applied to the production of nanocrystals and / or new defined forms of hydrophobic drugs. Examples of hydrophobic drugs include, but are not limited to, ROCK inhibitors, SYK-specific inhibitors, JAK-specific inhibitors, SYK / JAK or multi-kinase inhibitors, MTORs, STAT3 inhibitors, VEGFR / PDGFR inhibitors. , C-Met inhibitor, ALK inhibitor, mTOR inhibitor, PI3Kδ inhibitor, PI3K / mTOR inhibitor, p38 / MAPK inhibitor, NSAID, steroid, antibiotic, antiviral agent, antifungal, antiparsitic ), Antihypertensive agents, cancer drugs or antineoplastic agents, immunomodulatory drugs (eg, immunosuppressants), psychiatric drugs, dermatological drugs, lipid-lowering agents, antisuppressants, antidiabetic agents, antiepileptic drugs Agents, anti-gout agents, anti-hypertensive agents, anti-malaria agents, anti-mitiginal pain agents, anti-muscarinic agents, anti-thyroid agents, anti-anxiety agents, sedatives, sleeping agents, nerve relaxants, β-blockers, cardiotonics, corticosteroids , Diuretics, anti-Parkinson agents, gastrointestinal agents, histamine H-receptor antagonists, lipid regulators, nitrates and other anti-angina agents, nutritional agents, opioid analgesics, sex hormones, and stimulants.

A suitable hydrophobic drug for the method of the invention can be a steroid. As steroids, for example, fluticazone, hydrocortisone, hydrocortisone acetate, cortisone acetate, thixocortor pivalate, prednisolone, methylprednisolone, prednisolone, triamsinolone acetonide, triamsinolone alcohol, mometamethasone, amcinonide, budesonide, dexamethasone, fluorionide. Acetonide, flunisolide, fluoromethasone, clobetazole propionate, roteprednisolone, medrizone, limexolone, difluprednisolone, halcinonide, bechrometasone, betamethasone, betamethasone sodium phosphate, cyclesonide, dexamethasone, sodium phosphate dexamethasone, dexamethasone acetate. Hydrocortisone-17-butyrate, hydrocortisone-17-valerate, achrometazone dipropionic acid, betamethasone oxamethasone, betamethasone dipropionate, prednisolone, clobetazone-17-butyrate, clobetazol-17-propionate, fluoricate caproate, pivalic acid Fluocortron, fluprednidene acetate, prednisolone acetate, prednisolone sodium phosphate, fluoromethalone, fluoromethalone acetate, roteprednol etabonate, and betamethasone phosphate (these esters and pharmaceutically acceptable) (Including prednisolone).

Suitable hydrophobic drugs for the methods of the invention are nonsteroidal anti-inflammatory drugs such as bromfenac, diclofenac sodium, flurbiprofen, ketrolactromethamine, maplacolato, naproxen, oxaprozin, ibuprofen, and nepafenac (these). Includes esters and pharmaceutically acceptable salts).

As another hydrophobic drug suitable for the method of the present invention, besifloxacin, DE-110 (Santen). Inc.), levamipide, androgen (DHEA, testosterone, poorly water-soluble analogs and derivatives), estrogen (estradiol, estrone, and derivatives of estrone, poorly water-soluble compounds; for example, estradiol, levonorgestrel. ), Its analogs, isomers or derivatives), poorly water-soluble progesterone and progestin (1st to 4th generation) (eg, norethisterone, its analogs and derivatives, medroxyprogesterone, or tagaproget) ), And pregnenolone. Examples of various generations of progestins include: 1st generation (estran) eg noretindron, norethinodorel, norethindrone acetate, and ethinodiol diacetate; 2nd generation (gonane) such as levonorgestrel, norethisterone, and norgestrel. 3rd generation (gonane), eg desogestodene, gestodene, norethisterone, and drospirenone; and 4th generation, eg dienogest, drospirenone, nestron, nomegestrol acetate and trimegeanone.

Other examples of hydrophobic drugs include, for example, 10-alkoxy-9-nitrocamptothecin, 17b-estradiol, 3'-azido-3'-deoxythymidine palmitate, 5-aminolevulinic acid, ABT-963, asecrophenac, acracino. Mycin In, piroxicam, podophylrotoxin, porcine pancreatic lipase and colipase, probucol, pyrazinamide, quercetin, laroxifen, lisveratrol, rain, rifampicin, ritonavir, losbustatin, saquinavir, silymarin, silolims, spironolactone, stavudine, sulfisoxazole , Tachlorimus, tadalafil, tancinone, tea polyphenols, theophylline, thiaprofenic acid, tipranavir, torbutamid, tortellodin tartrate, tranilast, tretinoin, triamcinolone acetonide, tryptride, troglycazone, balaccyclovir, verapamil, vincristine , Warfarin, and XK469. As a further example, for example, amhotericin B, gentamicin and other aminoglycoside antibiotics, ceftriaxone and other cephalosporins, tetracycline, cyclosporin A, alloxypurine, auranofin, azapropazone, benolylate, diflunisal, etodrac, fenoprofen, pheno. Profencalcium, meclophenamic acid, mefanamic acid, nabmeton, oxyphenbutazone, phenylbutazone, slindac, benznidazole, cryoquinol, decoquinate, diiodohydroxyquinoline, diloxanidefloate, dinitrmid, fluzolidone, metronidazole, nimorazole , Nitroflazone, ornidazole, and tinidazole. Included are Last, Tretinoin, Triamcinolone Acetonide, Tryptride, Troglitazone, Baracyclovir, Bellapamil, Vincristine, Vinorelbine Tartrate Hydrogen Salt, Vinposetin, Vitamin-E, Warfarin, and XK469. As a further example, for example, amhotericin B, gentamicin and other aminoglycoside antibiotics, ceftriaxone and other cephalosporins, tetracycline, cyclosporin A, alloxypurine, auranofin, azapropazone, benolylate, diflunisal, etodrac, fenoprofen, pheno. Profencalcium, meclophenamic acid, mefanamic acid, nabmeton, oxyphenbutazone, phenylbutazone, slindac, benznidazole, cryoquinol, decoquinate, diiodohydroxyquinoline, diloxanidefloate, dinitrmid, fluzolidone, metronidazole, nimorazole , Nitroflazone, ornidazole, and tinidazole. Included are Last, Tretinoin, Triamcinolone Acetonide, Tryptride, Troglitazone, Baracyclovir, Bellapamil, Vincristine, Vinorelbine Tartrate Hydrogen Salt, Vinposetin, Vitamin-E, Warfarin, and XK469. As a further example, for example, amhotericin B, gentamicin and other aminoglycoside antibiotics, ceftriaxone and other cephalosporins, tetracycline, cyclosporin A, alloxypurine, auranofin, azapropazone, benolylate, diflunisal, etodrac, fenoprofen, pheno. Profencalcium, meclophenamic acid, mefanamic acid, nabmeton, oxyphenbutazone, phenylbutazone, slindac, benznidazole, cryoquinol, decoquinate, diiodohydroxyquinoline, diloxanidefloate, dinitrmid, fluzolidone, metronidazole, nimorazole , Nitroflazone, ornidazole, and tinidazole.

Suitable hydrophobic drugs for the methods of the invention can also be FDA-approved drugs with a cLogP of 5 or greater, such as those listed in the table below.

<tables num="1-1"><img file="JP6972255B2_D0001.tif" /></tables>

<tables num="1-2"><img file="JP6972255B2_D0002.tif" /></tables>

<tables num="1-3"><img file="JP6972255B2_D0003.tif" /></tables>

<tables num="1-4"><img file="JP6972255B2_D0004.tif" /></tables>

<tables num="1-5"><img file="JP6972255B2_D0005.tif" /></tables>

Suitable hydrophobic drugs for the methods of the invention can also be FDA-approved drugs with ALogP of 5 or higher, such as those listed in the table below.

<tables num="2-1"><img file="JP6972255B2_D0006.tif" /></tables>

<tables num="2-2"><img file="JP6972255B2_D0007.tif" /></tables>

<tables num="2-3"><img file="JP6972255B2_D0008.tif" /></tables>

<tables num="2-4"><img file="JP6972255B2_D0009.tif" /></tables>

<tables num="2-5"><img file="JP6972255B2_D0010.tif" /></tables>

Other suitable drugs for the methods of the invention include long-acting bronchial dilators (eg salmetherol xinafoate and formosterol), anti-inflammatory agents (statins such as atorvastatin, simvastatin, lovastatin and rosuvastatin), macrolide antibiotics. Substances (eg azithromycin), anti-vomiting agents, drugs highly metabolized by initial transit metabolism (eg imipramine, morphine, buprenorfin, propranolol, diazepam and midazolam), protein therapeutics (eg ranibizmab, bebasizumab, affrivastatin) , Lilonacept, and those listed in the table below.

<tables num="3-1"><img file="JP6972255B2_D0011.tif" /></tables>

<tables num="3-2"><img file="JP6972255B2_D0012.tif" /></tables>

Additional examples of hydrophobic drugs are also described, for example, in Therapeutic systems Research Laboratory, Inc., Ann Arbor, MI (www.tsrlinc), the contents of each of which are incorporated herein by reference in their entirety. Biopharmaceutics Classification System (BCS) database by .com) (http://69.20.123.154/services/bcs/search.cfm); M Linderberg et al., "Classification of Orally Administered Drugs on the WHO Model List of Essential Medicines According to the Biopharmaceutics Classification System, Eur J Pharm &amp; Biopharm, Vol. 58: pp. 265-278 (2004); NA Kasim et al., "Molecular" properties of WHO Essential Drugs &amp; Provisional Biopharmaceutical Classification Molec Pharm ,, Volume 1 (No. 1): pp. 85-96 (2004); A Dahan &amp; GL Amidon, Provisional BCS Classification of the Leading Oral Drugs on the Global Market in Burger's Medicinal Chemistry, Drug Discovery &amp; Development, 2010; Elgart A et al., Lipospheres and pro-nano lipospheres for delivery of poorly water soluble compounds. Chem.Phys.Lipids. May 2012; Volume 165 (4): 438 ~ Page 53; Parhi R et al., Preparation and characterization of solid lipid nanoparticles-a review.Curr Drug Discov Technol. March 2012; Volume 9 (No. 1): pp. 2-16; Linn M et al., Soluplus® as an effective absorption enhancer of poorly soluble drugs in vitro and in vivo.Eur J Pharm Sci. February 14, 2012; Volume 45 (No. 3): pp. 336-43; Salustio PJ et al., Advanced technologies for oral controlled release: cyclodextrins for oral controlled release. AAPS Pharm SciTech. December 2011; Volume 12 (No. 4): pp. 1276-92. PMCID: PMC3225529; Kawabata Y et al., Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications. Int J Pharm. November 25, 2011; Volume 420 (No. 1): pp. 1-10; van Hoogevest P et al., Drug delivery strategies for poorly water-soluble drugs: the industrial perspective. Expert Opin Drug Deliv .November 2011; Volume 8 (No. 11): pp. 1481-500; Bikiaris DN.Solid dispersions, part I: recent evolutions and future opportunities in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs.Expert Opin Drug Deliv .November 2011; Volume 8 (No. 11): 1501 ~ 19; Singh A et al., Oral formulation strategies to improve solubility of poorly water-soluble drugs. Expert Opin Drug Deliv. October 2011; Volume 8 (No. 10): 1361-78; Tran PH-L et al., Controlled release systems containing solid dispersions : strategiesgies and mechanisms.Pharm Res. October 2011; Vol. 28 (No. 10): pp. 2353-78; Srinarong P et al., Improved dissolution behavior of lipophilic drugs by solid dispersions: the production process as starting point for formulation considerations. Expert Opin Drug Deliv. September 2011; Volume 8 (No. 9): 1121-40; Chen H et al., Nanonization strategies for poorly water-soluble drugs. Drug Discov.Today. April 2011; Volume 16 (No. 7-8) : 354-60; Kleberg K et al., Characterising the behavior of poorly water soluble drugs in the intestine: application of biorelevant media for solubility, dispersion and transport studies. J.Pharm.Pharmacol. November 2010; Volume 62 (No. 11) ): 1656 ~ 68; and He CX et al., Microemulsions as drug delivery systems to improve the solubility and the bioavailability of Poorly water-soluble drugs. Expert Opin Drug Deliv. April 2010; Volume 7 (No. 4): pp. 445-60;

The nanocrystals of hydrophobic drugs produced by this method are ideally systemic for disorders in which the hydrophobic drugs are used, such as inflammatory disorders, respiratory disorders, autoimmune diseases, cardiovascular diseases and cancer. Suitable for sexual or non-systemic procedures. For example, the nanocrystals of the invention can be rheumatoid arthritis, lupus (including, for example, lupus nephritis and systemic lupus erythematosus), allergic asthma, lymphoma (eg, including non-hodgkin lymphoma and chronic lymphocytic leukemia), immune platelets. Decreasing purpura, psoriasis, psoriasis arthritis, dermatitis, tonic spondylitis, Crohn's disease, ulcerative colitis, gout, atopic dermatitis, multiple sclerosis, bullous pemphigoid (including bullous pemphigoid) , Autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, Gillan Valley syndrome, Wegner's granulomatosis, and / or can be used to treat glomerulonephritis. The nanocrystals of the invention can also be used in the major prevention of major cardiac adverse events in patients with coronary artery disease.

New Prescribed Form One unexpected advantage of the method of the invention is that the hydrophobic drug nanocrystals produced via the method are novel and different from commercially available stock material forms or known forms of hydrophobic drugs. To have a morphology. New forms with higher tap densities and / or additional crystallinity may be more stable (eg, thermally stable).

In one aspect, the invention provides a novel stereotype of fluticasone propionate, i.e., form A, which is a powder containing peaks at about 7.8, 15.7, 20.8, 23.7, 24.5, and 32.5 degrees 2θ. It features an X-ray diffraction pattern.

For example, Form A is further characterized by a powder X-ray diffraction pattern containing additional peaks at about 9.9, 13.0, 14.6, 16.0, 16.9, 18.1 and 34.3 degrees 2θ.

For example, Form A is characterized by a powder X-ray diffraction pattern containing the peaks listed in Table A below.

<tables num="4"><img file="JP6972255B2_D0013.tif" /></tables>

For example, Form A is characterized by nanocrystals in the form of long plates or blades.

For example, Form A is substantially free of impurities.

For example, Form A has a purity greater than 90%, greater than 92%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%.

For example, form A is 0.5786 g / cm.³Has a tap density of. In contrast, the tap density of fluticasone propionate stock is 0.3278 g / cm.³Is.

For example, the heat of fusion for form A is significantly higher (54.21 J / g), the former form A is a more crystalline material, and more energy is used to break intermolecular bonds, such as ionic and hydrogen bonds. Indicates that you need it.

For example, Form A has a melting range of 10 ° C and also exhibits a highly ordered microstructure. In contrast, the fluticasone propionate stock material melts over a slightly wider range (11.1 ° C).

For example, Form A dissolves more slowly than stock or homogenized material. Form A reaches saturated lysis after 6 weeks of incubation in an aqueous solvent, whereas stock or homogenized materials reach saturated lysis within 2 weeks of incubation in an aqueous medium.

For example, Form A is characterized by a rate of dissolution in water at room temperature of about 1 μg / g / day in an aqueous medium (eg, water or aqueous solution).

For example, the unit cell structure of Form A is monoclinic, P21, a = 7.7116 Å, b = 14.170 Å, c = l1.306 Å, beta = 98.285, capacity 1222.6.

For example, Form A has a melting point of 299.5 ° C, as opposed to a melting point of 297.3 ° C for the stock material (polymorph 1).

For example, Form A is characterized by a nanoplate having an average size of about 10 to 10000 nm, (eg, 100 to 1000 nm or 300 to 600 nm).

For example, Form A features a fluticasone propionate nanoplate with a narrow range of size distributions. For example, Form A has 50 to 100 nm, 100 to 300 nm, 300 to 600 nm, 400 to 600 nm, 400 to 800 nm, 800 to 2000 nm, 1000 to 2000 nm, 1000 to 5000 nm, 2000 to 5000 nm, 2000 to 3000 nm, 3000 to 5000 nm, Alternatively, it features a fluticasone propionate nanoplate with a size distribution of 5000-10000 nm.

For example, the nanoplates each have a thickness between 5 nm and 200 nm (eg, 10 to 150 nm or 30 to 100 nm).

For example, the nanoplate has a [001] crystal axis that is substantially perpendicular to the surface that defines the thickness of the nanoplate.

In another aspect, the invention provides a novel fixed form of triamcinolone acetonide, form B, which peaks at about 11.9, 13.5, 14.6, 15.0, 16.0, 17.7, and 24.8 degrees 2θ. It features a powder X-ray diffraction pattern containing.

For example, Form B is further characterized by a powder X-ray diffraction pattern containing additional peaks at about 7.5, 12.4, 13.8, 17.2, 18.1, 19.9, 27.0 and 30.3 degrees 2θ.

For example, form B is characterized by a powder X-ray diffraction pattern containing the peaks listed in Table B below.

<tables num="5"><img file="JP6972255B2_D0014.tif" /></tables>

For example, Form B features a powder X-ray diffraction pattern that is substantially similar to the red profile in FIG.

For example, Form B is substantially free of impurities.

For example, Form B has a purity greater than 90%, greater than 92%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%.

Pharmaceutical Compositions The present invention also presents disorders in which hydrophobic drugs are used, such as inflammatory disorders, such as eye disorders and skin disorders, respiratory disorders such as asthma or COPD, or cancers such as lymphoma systemic. A pharmaceutical composition comprising an effective amount of nanocrystals of a hydrophobic drug described herein and a pharmaceutically acceptable carrier useful for sexual or non-systemic treatment or alleviation. ..

In one embodiment, the invention is a nanocrystal of a hydrophobic drug (eg, fluticazone) useful for the treatment or alleviation of signs or symptoms of blepharitis and / or meibomian gland dysfunction (MGD), and their prevention. It is characterized by a novel topical pharmaceutical composition comprising an effective amount and a pharmaceutically acceptable carrier. Effective amounts of the formulations of the present invention can be used to reduce inflammation of the palpebral margin, thereby treating blepharitis and / or MGD.

For example, the compositions described in the present invention can be used for post-surgical post-operative care. For example, the compositions of the present invention can be used for postoperative pain control, surgery, argon laser trabeculoplasty and postoperative inflammation control. In addition, the composition can be used to treat other eye disorders such as eye allergies, allergic conjunctivitis, cystoid macular edema or meibomian gland dysfunction.

In addition, the compositions described in the present invention include systemic or non-systemic treatments or alleviations of skin disorders such as atopic dermatitis, skin lesions, eczema, psoriasis, or signs or symptoms of rash. Can be used for the prevention of.

Signs and symptoms associated with blepharitis include, for example, redness of the eyelids, swelling of the eyelids, discomfort of the eyelids, pruritus of the eyelids, detachment of the skin of the eyelids and redness of the eyes.

Signs and symptoms of abnormal tarsal secretions include, but are not limited to, increased tarsal secretion viscosity, opacity, color, and increased time (refractory) between glandular secretions. Signs and symptoms of disease associated with abnormal meibomian gland (eg, MGD) secretions include, but are not limited to, dry eye, redness of the eyes, itching and / or irritation of the eyelid margins and / or edema, physical discomfort, and. Tangled eyelashes can be mentioned.

The activator component improves, treats, alleviates, inhibits, prevents, or otherwise reduces the signs and symptoms of blepharitis and / or MGD. The compositions of the present invention are pleasing to application to the subject's eye, eyelid, eyelashes, or eyelid margin and can be used for the resolution of acute or chronic blepharitis and / or MGD, in particular. Suitable for both intermittent and long-term use.

Also, the compositions described in the present invention are systemic or non-systemic for respiratory disorders (eg, asthma or COPD), autoimmune diseases (eg, lupus or psoriasis), and cancer (eg, lymphoma). It can be used for treatment, alleviation of these signs or symptoms and prevention of these.

Fluticasone containing an ester and its pharmaceutically acceptable salt. Fluticasone propionate is the preferred pharmaceutically acceptable salt. Fluticasone propionate is used as S-fluoromethyl-6-α-9-difluoro-11-β-hydroxy-16-α-methyl-3-oxoandrosta-1,4-diene-17-β-carbothioate. Also known, 17-propionate is a synthetic, trifluoroylated, chemical formula C.₂₅H₃₁F₃O₅It is a corticosteroid with S. It is a white to off-white powder with a molecular weight of 500.6 g / mol. Fluticasone propionate is substantially insoluble in water (0.14 μg / ml), is freely soluble in dimethyl sulfoxide and dimethyl-formamide, and is slightly soluble in methanol and 95% ethanol.

Pharmaceutical eye formulations typically treat or prevent eye and skin disorders in appropriate effective amounts for short-term or long-term use, eg, about 0.0001% to about 10% wt / vol, preferably. It contains about 0.001% to about 5%, more preferably about 0.01% to about 3%, even more preferably about 0.01% to about 1% of an ocular drug (eg, fluticasone). The amount of eye drug (eg, fluticasone) will vary with the particular formulation and indicated use.

Preferably, the effective amount of nanocrystals of the hydrophobic drug (eg, fluticasone) present in the formulation should be sufficient to treat or prevent inflammatory disorders, respiratory disorders or cancer.

In certain embodiments, the compositions described herein are sustained release compositions. In another embodiment, the composition described herein is a fast-release composition. Without wishing to be constrained by theory, the rate of drug release of the compositions of the invention can be controlled by selecting a particular morphology or size of the drug particles. For example, the composition can contain fluticasone propionate in the form of form A only, or can include a mixture of form A and polymorph 1 and / or polymorph 2 of FP. As another example, the composition is composed of nanocrystals of drugs of different sizes and / or size dispersions, eg, nanocrystals of 300-600 nm (ie D10-D90) and nanocrystals of about 800-900 nm (ie D10-D90). Combinations with crystals can be included.

The pharmaceutical compositions of the invention described can be administered alone or in combination with other therapies. For example, the pharmaceutical composition of the present invention is not limited to these, but is limited to vasoconstrictors, antiallergens, anesthetics, painkillers, dry eye agents (eg, secretagogues, mucilage mimetics, polymers, lipids, oxidation). Other active ingredients (possibly in the form of nanocrystals via the methods of the invention), including, but not limited to, vasoconstrictors, antiallergenic agents, etc. Administered with (simultaneously or sequentially) pharmaceutical compositions containing other active ingredients, including anesthetics, analgesics, dry eye agents (eg, secretagogues, mucilage mimetics, polymers, lipids, antioxidants), etc. You may.

The pharmaceutical composition of the present invention comprises a disorder in which a hydrophobic drug is used, such as an inflammatory disorder, such as an eye disorder and a skin disorder, a respiratory disorder such as asthma, or a systemic cancer such as lymphoma. It can be formulated in various dosage forms suitable for sexual or non-systemic treatment or alleviation. The compositions described herein are for a particular route of administration, such as topical, oral (including, for example, oral inhalation), intranasal, enteral or parenteral (injection into the circulatory system). It can be formulated in an appropriate form.

In certain embodiments, the formulations described herein are sustained release formulations. In other embodiments, the formulations described herein are immediate release formulations.

In certain embodiments, the topical compositions according to the invention are liquids, suspensions, ointments, emulsions, gels, eye drops, and other suitable for topical administration to the eye and skin. Formulate as a dosage form. In other embodiments, the compositions according to the invention are as dry powers, aerosols, liquids, suspensions, ointments, emulsions, gels and other dosage forms suitable for intranasal or oral administration. To formulate.

Preferably, the topical composition of the eye is prepared for administration to the ocular membrane, eyelashes, eyelid margin, skin, or surface of the eye. In addition, modifications such as sustained release, stabilization, and easy absorption properties may be further applied to such preparations. These dosage forms are sterilized by, for example, filtration through a microbial separation filter, heat sterilization, or the like.

Aqueous solutions are generally preferred because of the ease of formulation and the ease with which such compositions can be administered by the patient by applying the formulation to the eyelids, eyelashes and eyelid margins. Applications include applicators, eg patient fingers, Wek-Cel, Q-tip, cotton swabs, polyurethane swabs, polyester swabs, 25-3318-U swabs, 25-3318-H swabs, 25-3317-U swabs, 25-803 2PD swabs, 25-8061-PAR swabs, brushes (eg Latissie® brushes) or formulations may be performed using other devices capable of delivering to the ocular lid, eyelashes or eyelid margins. can.

However, the composition may also be a suspension, a viscous or semi-viscous gel, or another type of solid or semi-solid composition. In one embodiment, the formulation of the invention (eg, fluticasone formulation) is an aqueous formulation. The aqueous formulations of the present invention are typically more than 50% by weight, preferably more than 75% by weight, most preferably more than 90% by weight. In another embodiment, the formulation is a lyophilized formulation.

In certain embodiments, the pharmaceuticals of the invention are formulated as suspensions. Such formulations generally have a particle size of 800 nm or less. Further, the suspension preparation of the present invention can prevent particle aggregation by containing a suspending agent and a dispersant.

In certain embodiments, the carrier is non-aqueous. Non-aqueous carriers include oils such as castor oil, olive oil, peanut oil, macadamia nut oil, walnut oil, almond oil, pumpkin seed oil, cottonseed oil, sesame oil, corn oil, soybean oil, avocado oil, palm oil, palm oil, Includes sunflower oil, benibana oil, flaxseed oil, grape seed oil, canola oil, low viscosity silicone oil, light oil, or any combination thereof.

In embodiments where the formulation is an ointment, the preferred ointment base used to prepare the ophthalmic ointment of the present invention may be those that have been used in conventional ophthalmic ointments. In particular, the bases are liquid paraffin, white vaseline, purified lanolin, gelled hydrocarbon, polyethylene glycol, hydrophilic ointment base, white ointment base, absorbent ointment base, macrogol (trade name) ointment base. , Single ointment base and the like. For example, without limitation, the ointment formulations of the present invention contain fluticasone propionate, petrolatum and mineral oil.

In embodiments where the formulation is gelement, the preferred gelement base used to prepare the ophthalmic ointment of the present invention may be those used in conventional ocular gelments, such as Gental Gel. ..

In embodiments where the formulation is a cream, the preferred cream base used to prepare the eye creams of the present invention may be those that have been used in conventional eye creams. For example, without limitation, the cream formulations of the present invention contain fluticasone propionate, PEG400, oils and surfactants.

Topical formulations may further require the presence of a solubilizer, especially if the active or inert ingredients tend to form suspensions or emulsions. Suitable solubilizers for the compositions related to the above are, for example, tyroxapol, fatty acid glycerol polyethylene glycol ester, fatty acid polyethylene glycol ester, polyethylene glycol, glycerol ether, cyclodextrin (eg alpha-, beta- or gamma-cyclo). Dextrins such as alkylated, hydroxyalkylated, carboxyalkylated or alkyloxycarbonyl-alkylated derivatives, or mono-or diglycosyl-alpha-,-beta-or-gamma-cyclodextrin, mono- or dimaltosyl-alpha-, beta. -Or gamma-cyclodextrin or panosyl-cyclodextrin), polysorbate 20, polysorbate 80 or a mixture of these compounds. Specific examples of particularly preferred solubilizers are reaction products of castor oil and ethylene oxide, such as Cremophor EL® or Cremophor. Products such as RH40 (registered trademark). The reaction product of castor oil and ethylene oxide has proven to be a particularly good solubilizer that is extremely well tolerated by the eye. Another preferred solubilizer is selected from tyroxapol and cyclodextrin. The concentration used depends in particular on the concentration of the active ingredient. The amount added is typically sufficient to solubilize the active ingredient. For example, the concentration of the solubilizer is 0.1 to 5000 times the concentration of the active ingredient.

Other compounds can also be added to the formulations of the invention to adjust (eg, increase) the viscosity of the carrier. Examples of viscosity enhancers include, but are not limited to: polysaccharides such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran, various polymers of the cellulose family; vinyl polymers; and acrylic acid polymers.

In another embodiment, the topical formulations of the present invention do not contain preservatives. Such formulations may be more desirable to limit exposure to preservatives, patients wearing contact lenses, or using some topical eye drops, and / or already on the surface of the eye. Useful for patients with defects (eg dry eye).

Any of the various carriers can be used in the formulations of the present invention. The viscosity of the carrier is about 1cP ~ about 4,000,000cP, about 1cP ~ about 3,000,000, about 1cP ~ about 2,000,000cP, about 1cP ~ about 1,000,000cP, about 1cP ~ about 500,000cP, about 1cP ~ about 400,000cP, about 1cP ~ about. 300,000cP, about 1cP ~ about 200,000cP, about 1cP ~ about 100,000cP, about 1cP ~ about 50,000cP, about 1cP ~ about 40,000cP, about 1cP ~ about 30,000cP, about 1cP ~ about 20,000cP, about 1cP ~ about 10,000 cP, about 50cP ~ about 10,000cP, about 50cP ~ about 5,000cP, about 50cP ~ about 2500cP, about 50cP ~ about 1,000cP, about 50cP ~ about 500cP, about 50cP ~ about 400cP, about 50cP ~ about 300cP, about 50cP ~ About 200cP, about 50cP ~ about 100cP, about 10cP ~ about 1000cP, about 10cP ~ about 900cP, about 10cP ~ about 800cP, about 10cP ~ about 700cP, about 10cP ~ about 600cP, about 10cP ~ about 500cP, about 10cP ~ about 400cP , About 10cP to about 300cP, about 10cP to about 200cP, or about 10cP to about 100cP.

Viscosity is Brookfield Cone with CP40 or equivalent spindle and plate viscometer model VDV-III Ultra with shear rate of about 22.50 +/- about 10 (1 / sec).⁺, Or using the Brookfield viscometer model LVDV-E with SC4-18 or equivalent spindle, with a shear rate of about 26 +/- about 10 (1 / sec), temperature 20 ° C +/- 1 ° C Can be measured with. Alternatively, the viscosity is Brookfield Cone with CP40 or equivalent spindle and plate viscometer model VDV-III Ultra with a shear rate of about 22.50 +/- about 10 (1 / sec).⁺, Or at 25 ° C +/- 1 ° C using the Brookfield viscometer model LVDV-E with SC4-18 or equivalent spindle, which has a shear rate of about 26 +/- about 10 (1 / sec). It can also be measured.

Other compounds can also be added to the formulations of the invention to adjust (eg, increase) the viscosity of the carrier. Examples of viscosity enhancers include, but are not limited to, polysaccharides such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran, various polymers of the cellulose family; vinyl polymers; and acrylic acid polymers.

The crystals of the invention (eg, fluticasone propionate crystals) can be coated or impregnated into surgical or implantable devices. In some embodiments, coating or embedding crystals (eg, fluticasone propionate crystals) in a surgical or implantable device prolongs drug release time while providing highly localized drug delivery. .. The advantage of this mode of administration is that more accurate concentrations and minor side effects can be achieved. In one embodiment, the implantable device is an eye implantable device for drug delivery. In another embodiment, the implantable device is a retractable transplant that is surgically implantable. In another embodiment, the implantable device is biodegradable, eg, biodegradable microparticles. In a further embodiment, the implantable device is made of silicon, eg, nanostructured porous silicon. Exemplary surgical devices include, but are not limited to, stents (eg, self-expandable stents, balloon-expandable coil stents, balloon-expandable tubular stents and balloon-expandable hybrid stents), angiogenic balloons, catheters (eg, eg, self-expandable stents). Microcatheter, stent delivery catheter), shunt, access device, guide wire, graft system, intravascular imaging device, vascular closure device, endoscopy accessories. For example, the device used in the method or composition of the invention is an iScience device, iVeena device, Clearside device, or Ocusert device. Coating onto surgical devices shall be performed using standard methods known in the art, such as those referenced in US20070048433A1, whose contents are incorporated herein by reference. Can be done.

Additives In some embodiments, the pharmaceutical product of the present invention comprises one or more pharmaceutically acceptable additives. The term additive, as used herein, broadly refers to a biologically inert substance used in combination with an activator of a pharmaceutical product. Additives can be, for example, as solubilizers, stabilizers, surfactants, palliatives, viscosity agents, diluents, inert carriers, preservatives, binders, disintegrants, coatings, flavors or colorants. Can be used. Preferably, at least one additive is selected to provide one or more advantageous physical properties for the formulation, such as increased stability and / or solubility of the active agent. "Pharmaceutically acceptable" additives are those approved by state or federal regulators for animal use, preferably for human use, or for animal use. Preferably for human use, it is listed in the United States Pharmacopeia, the European Pharmacopoeia or another generally recognized pharmacopoeia.

Examples of carriers that can be used in the formulations of the present invention are water, a mixture of water and a water-miscible solvent, such as C.₁~ C₇-Vegetable oils or mineral oils (including 0.5-5% non-toxic water-soluble polymers) such as alkanol, natural products such as gelatin, alginate, pectin, tragant, Indian gum, xanthan gum, carrageenin, agar and acacia, etc. Preferred crosslinked polyacrylic acids such as starch derivatives such as starch acetate and hydroxypropyl starch, as well as other synthetic products such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinylmethyl ether, polyethylene oxide, eg neutral carbs. Examples include poles, or mixtures of these polymers. The concentration of the carrier is typically 1 to 100,000 times the concentration of the active ingredient.

Further examples of additives include certain inert proteins such as albumin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as aspartic acid (or instead sometimes referred to as asparagate), glutamic acid (instead of glutamic acid). (Sometimes referred to as salts), lysine, arginine, glycine, and histidine; fatty acids and phospholipids, such as alkyl sulfonates and caprylates; surfactants, such as sodium dodecyl sulfate and polysorbate; nonionic surfactants. Activators, such as TWEEN®, represented by PLURONICS® or polyethylene glycol (PEG), 200, 300, 400, or 600; Carbowax, 1000, 1500, 4000, 6000, and 10000. Represented by; carbohydrates such as glucose, sucrose, mannose, maltose, trehalose, and dextrin (including cyclodextrin); polyols such as mannitol and sorbitol; chelating agents such as EDTA; and salt forming pairs. Ions, such as sodium, may be mentioned.

In certain embodiments, the carrier is a polymeric, mucosally adherent vehicle. Examples of mucoadhesive vehicles suitable for use in the methods or formulations of the invention are, but are not limited to, dextran, polyethylene glycol, polyvinylpyrrolidone, polysaccharide gels, Gelrite®, cellulose, without limitation. Included are based polymers and aqueous polymeric suspending agents comprising one or more polymeric suspending agents, including carboxy-containing polymer systems. In certain embodiments, the polymeric suspending agent comprises a polymer (eg, polycarbophil) containing crosslinked carboxy. In another particular embodiment, the polymeric suspending agent comprises polyethylene glycol (PEG). Examples of polymer systems containing crosslinked carboxys suitable for use in topical stable ocular formulations of the invention are, but are not limited to, Noveon AA-1, Carbopol®, and / or DuraSite ( Registered trademark) (In Site Vision).

In other specific embodiments, the formulations of the invention include one or more additives selected from the following: tear substitutes, tonicity enhancers, preservatives, solubilizers, viscosity enhancers. , Viscous lubricants, emulsifiers, wetting agents, sequestering agents, and fillers. The amount and type of additive added generally ranges from about 0.0001% to 90% by weight, depending on the specific needs of the formulation.

Tear substitute According to some embodiments, the formulation may include an artificial tear substitute. The terms "substitute tears" or "wetting agents" lubricate, "moisten", approach the consistency of endogenous tears, aid in the accumulation of natural tears, or otherwise to the eye. Refers to a molecule or composition that provides a temporary solution to the signs or symptoms and conditions of dry eye upon administration. Various tear substitutes are known in the art and include, but are not limited to: monomeric polyols such as glycerol, propylene glycol, and ethylene glycol; polymeric polyols such as polyethylene glycol; Cellular esters such as hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl cellulose; dextran, such as dextran 70; water-soluble proteins such as gelatin; vinyl polymers such as polyvinyl alcohol, polyvinylpyrrolidone, and povidone; And carbomer, such as carbomer 934P, carbomer 941, carbomer 940 and carbomer 974P. Many such substitute tear fluids are commercially available and are not limited to, but include:Cellulous esters such as Bion Tears®, Celluvisc®, Gental®, OccuCoat®, Refresh®, Systane®, Teargen II®. , Tears Naturale®, Tears Natural II®, Tears Naturale Free®, and Thera Tears®; and polyvinyl alcohol, eg Akwa Tears®, Hypo Tears®, Moisture Eyes®, Murine Lubricating®, and Visites Tears®, Soothe®, etc. Tear substitutes may also contain paraffin, eg, a commercially available Lacri-Lube @ ointment. Other commercially available ointments used as tear substitutes include Lubrifresh PM®, Moisture Eyes PM® and Refresh PM®.

In a preferred embodiment of the invention, the tear substitute comprises hydroxypropylmethyl cellulose (hypromellose or HPMC). According to certain embodiments, the concentration of HPMC is in the range of about 0.1% to about 2% w / v or any particular value within said range. According to certain embodiments, the concentration of HPMC is in the range of about 0.5% to about 1.5% w / v or any particular value within said range. According to certain embodiments, the concentration of HPMC is in the range of about 0.1% to about 1% w / v or any particular value within said range. According to certain embodiments, the concentration of HPMC is in the range of about 0.6% to about 1% w / v, or any particular value within said range. In a preferred embodiment, the concentration of HPMC is in the range of about 0.1% to about 1.0% w / v, or any particular value within said range (ie, 0.1 to 0.2%, 0.2 to 0.3%, 0.3 to 0.4%). , 0.4 ~ 0.5%, 0.5 ~ 0.6%, 0.6 ~ 0.7%, 0.7 ~ 0.8%, 0.8-0.9%, 0.9 ~ 1.0%; about 0.2%, about 0.21%, about 0.22%, about 0.23%, about 0.24% , About 0.25%, about 0.26%, about 0.27%, about 0.28%, about 0.29%, about 0.30%, about 0.70%, about 0.71%, about 0.72%, about 0.73%, about 0.74%, about 0.75%, about 0.76%, about 0.77%, about 0.78%, about 0.79%, about 0.80%, about 0.81%, about 0.82%, about 0.83%, about 0.84%, about 0.85%, about 0.86%, about 0.87%, about 0.88% , About 0.89%, or about 0.90%).

For example, without limitation, tear substitutes containing hydroxypropylmethylcellulose are GenTeal® lubricating eye drops. GenTeal® (Ciba Vision-Novartis) is a sterile lubricating eye drop containing 3 mg / g of hydroxypropylmethylcellulose and is maintained on sodium perborate. Another example of HPMC-based tear fluid is provided.

In another preferred embodiment, the tear substitute comprises sodium carboxymethyl cellulose. For example, an unrestricted tear substitute containing sodium carboxymethyl cellulose is Refresh® Tears. Refresh® Tears is a gentle, non-sensitizing preservative, Stabilized Oxychloro, a lubricant similar to normal tears that eventually transforms into a natural tear component upon use. Contains a complex (Purite ).

In some embodiments, the tear substitute or one or more of its components is pH 5.0-9.0, preferably pH 5.5-7.5, more preferably pH 6 with a suitable salt (eg, phosphate salt). Buffer to .0 to 7.0 (or any particular value within the above range). In some embodiments, the tear substitute further comprises one or more components, which include, without limitation, glycerol, propylene glycerol, glycerin, sodium borate, magnesium chloride and zinc chloride. included.

Salts, Buffers, and Preservatives The formulations of the present invention may also contain pharmaceutically acceptable salts, buffers or preservatives. Examples of such salts include those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, citric acid, boron, formic acid, malonic acid, Succinic acid etc. Such salts can also be prepared as alkali metal salts or alkaline earth metal salts, such as sodium salts, potassium salts or calcium salts. Examples of buffers include phosphoric acid, citric acid, acetic acid, and 2- (N-morpholino) ethanesulfonic acid (MES).

The pharmaceutical product of the present invention can include a buffer system. When used in this application, the term "buffer" or "buffer system" is usually combined with at least one other compound to provide a buffering capacity, i.e., a relatively small change from the original pH. Alternatively, it means a compound that provides a buffer system in solution that exhibits the ability to neutralize either an acid or a base (alkali) within limits without causing change. According to some embodiments, the buffer component is present in an amount of 0.05% to 2.5% (w / v) or 0.1% to 1.5% (w / v).

Preferred buffers include borate buffer, phosphate buffer, calcium buffer, and combinations and mixtures thereof. Boric acid buffers include, for example, boric acid and salts thereof, such as sodium borate or potassium borate. Boric acid buffers also include, for example, compounds such as potassium tetraborate or potassium metaborate that produce boric acid or salts thereof in solution.

The phosphate buffer system preferably includes one or more monobasic phosphates, dibasic phosphates and the like. Particularly useful phosphate buffers are those selected from alkali metal and / or alkaline earth metal phosphates. An example of a suitable phosphate buffer is dibasic sodium phosphate (Na).₂HPO₄), Monobasic sodium phosphate (NaH)₂PO₄) And monobasic potassium phosphate (KH)₂PO₄) One or more. Phosphate buffer components are often used in amounts of 0.01% or 0.5% (w / v) calculated as phosphate ions.

Preferred buffer systems are based on borate / borate, monobasic and / or dibasic phosphate / phosphate, or combined borate / phosphate buffer systems. For example, the combined borate / phosphate buffer system can be formulated from a mixture of sodium borate and phosphate, or a combination of sodium borate and monobasic phosphate.

In a combined boric acid / phosphate buffer system, the solution comprises from about 0.05 to 2.5% (w / v) phosphate or a salt thereof and from 0.1 to 5.0% (w / v) boric acid or a salt thereof. Phosphate buffer is used at a concentration of 0.004 to 0.2 M (molar), preferably 0.04 to 0.1 M (in total). The borate buffer (in total) is used at a concentration of 0.02 to 0.8 M, preferably 0.07 to 0.2 M.

Other known buffer compounds such as citrate, sodium bicarbonate, TRIS and the like can optionally be added to the lens care composition. Other components in solution have other functions, but these can also affect buffer capacity. For example, EDTA is often used as a complexing agent, but EDTA can have a significant effect on the buffering capacity of a solution.

According to some embodiments, the pH of the aqueous solution for the eye is a physiological pH or a pH close to it. Preferably, the pH of the aqueous solution for the eye is between about 5.5 and about 8.0 or any particular value within the above range. According to some embodiments, the pH of the aqueous solution for the eye is between about 6.5 and 7.5 or any particular value within the above range (eg, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5). According to some embodiments, the pH of the aqueous solution for the eye is about 7. Those involved will recognize that the pH can be further adjusted to the optimum pH depending on the stability of the active ingredient contained in the pharmaceutical product. According to some embodiments, the pH is adjusted with a base (eg 1N sodium hydroxide) or an acid (eg 1N hydrochloric acid).

Buffers can be particularly useful for pH adjustments, preferably physiological pH adjustments. The pH of the solution of the invention should be maintained in the range of 5.5 to 8.0, more preferably about 6.0 to 7.5, more preferably about 6.5 to 7.0 (or any particular value within the above range). Suitable buffers such as borate, sodium borate, potassium citrate, citric acid, sodium hydrogencarbonate, TRIS, and various mixed phosphate buffers (Na).₂HPO₄, NaH₂PO₄And KH₂PO₄Includes combinations of), as well as mixtures thereof. Borate buffers are preferred. Generally, the buffer is used in an amount ranging from about 0.05 to 2.5 weight percent, preferably 0.1 to 1.5 weight percent.

According to a preferred embodiment, the pharmaceutical product of the present invention does not contain a preservative. In certain embodiments, the ophthalmic formulation further comprises a preservative. The preservative can typically be selected from quaternary ammonium compounds such as benzalkonium chloride, benzoxonium chloride and the like. Benzyl benzoium chloride is N-benzyl-N- (C)₈~ C₁₈Alkyl) -N, N-Didecylammonium chloride is described in more detail. Further examples of preservatives include antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium; amino acids cysteine and methionine; citric acid and sodium citrate; and synthetic preservatives such as thimerosal. , And alkylparabens and the like (including, for example, methylparaben and propylparaben). Other preservatives include octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzethonium chloride, phenol, catechol, resorcinol, cyclohexanol, 3-pentanol, m-cresol, phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate. Sodium perborate, sodium chlorite, alcohols such as chlorobutanol, butyl alcohol or benzyl alcohol or phenylethanol, guanidine derivatives such as chlorohexidine or polyhexamethylene biguanide, sodium perborate, German®. ) II, sorbic acid and stabilized oxychloro complex (eg, Purite®). Preferred preservatives are quaternary ammonium compounds, especially benzalconium chloride or derivatives thereof, such as Polyquad (see US Pat. No. 4,407,791), alkylmercury salts, parabens and stabilized oxychloro complexes (eg, Purite®). )). Where appropriate, sufficient preservatives should be added to the ocular composition to ensure protection against secondary contamination in use caused by bacteria and fungi.

In certain embodiments, the formulations of the invention include a preservative selected from the following: benzalkonium chloride, 0.001 to 0.05%; benzethonium chloride, up to 0.02%; sorbic acid, 0.01% to 0.5%; Polyhexamethylene biguanide, 0.1ppm ~ 300ppm; Polyquaternium-1 (Omamer M) -0.1ppm ~ 200ppm; Hypochlorite compound, perchlorite compound or chlorite compound, 500ppm or less, preferably 10 (Between ~ 200ppm); Hydrogen source resulting in 0.0001 ~ 0.1% weight% hydrogen with a stabilized hydrogen solution, suitable stabilizer; alkyl ester of p-hydroxybenzoic acid and its Mixtures, preferably methylparaben and propylparaben, 0.01% to 0.5%; chlorhexidine, 0.005% to 0.01%; chlorobutanol, up to 0.5%; and stabilized oxychloro complex (Purite®) 0.001% to 0.5%.

In another embodiment, the ophthalmic preparation of the present invention does not contain a preservative. Such formulations may be more desirable to limit exposure to preservatives, patients wearing contact lenses, or patients using some topical eye drops and / or already defective on the surface of the eye. It is useful for some patients (eg dry eye).

Viscosity enhancer and viscous lubricant In certain embodiments, the viscosity enhancer may be added to the formulation of the invention. Examples of such agents include polysaccharides such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran, various polymers of the cellulose family, vinyl polymers, and acrylic acid polymers.

Various viscosity enhancers are known in the art and include, but are not limited to, polyols such as glycerol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, propylene glycol, and ethylene glycol. , Polyvinyl alcohol, povidone, and polyvinylpyrrolidone; cellulose derivatives such as hydroxypropylmethyl cellulose (also known as hypromellose and HPMC), sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, and methyl cellulose; dextran, such as dextran 70; water-soluble. Sex proteins such as gelatin; carbomer such as carbomer 934P, carbomer 941, carbomer 940 and carbomer 974P; and gums such as HP-guar or a combination thereof. Other compounds can also be added to the formulations of the invention to increase carrier viscosity. Examples of viscosity enhancers include, but are not limited to, polysaccharides such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran, various polymers of the cellulose family; vinyl polymers; and acrylic acid polymers. .. Combinations and mixtures of the above agents are also suitable.

According to some embodiments, the concentration of the viscosity enhancer or combination of agents is in the range of about 0.5% to about 2% w / v, or any particular value within said range. According to some embodiments, the concentration of the viscosity enhancer or combination of agents is in the range of about 0.5% to about 1.5% w / v, or any particular value within said range. According to some embodiments, the concentration of the viscosity enhancer or combination of agents is in the range of about 0.5% to about 1% w / v, or any particular value within said range. According to some embodiments, the concentration of the viscosity enhancer or combination of agents is in the range of about 0.6% to about 1% w / v, or any particular value within said range. According to some embodiments, the concentration of the viscosity enhancer or combination of agents ranges from about 0.7% to about 0.9% w / v, or any particular value within said range (ie, about 0.70%, about. 0.71%, about 0.72%, about 0.73%, about 0.74%, about 0.75%, about 0.76%, about 0.77%, about 0.78%, about 0.79%, about 0.80%, about 0.81%, about 0.82%, about 0.83% , About 0.84%, about 0.85%, about 0.86%, about 0.87%, about 0.88%, about 0.89%, or about 0.90%).

In certain embodiments, the formulations of the invention include an ocular mucolytic agent and / or a viscosity-enhancing polymer selected from one or more of the following: cellulose derivatives such as carboxymethyl cellulose (0.01). ~ 5%), hydroxyethyl cellulose (0.01% ~ 5%), hydroxypropylmethyl cellulose or hypromellose (0.01% ~ 5%), and methyl cellulose (methylcelluose) (0.02% ~ 5%); dextran 40/70 (0.01% ~ 1) %); Gelatin (0.01% ~ 0.1%); Polymers, such as glycerin (0.01% ~ 5%), polyethylene glycol 300 (0.02% ~ 5%), polyethylene glycol 400 (0.02% ~ 5%), polysorbate 80 (. 0.02% ~ 3%), propylene glycol (0.02% ~ 3%), polyvinyl alcohol (0.02% ~ 5%), and povidone (0.02% ~ 3%); hypromellose (0.01% ~ 2%); and chondroitin sulfate (0.01% ~ 2%).

In one preferred embodiment of the invention, the viscosity enhancing component comprises hydroxypropylmethyl cellulose (hypromellose or HPMC). HPMC provides the desired level of viscosity and functions to provide viscous activity. According to some embodiments, the concentration of HPMC is in the range of about 0% to about 2% w / v, or any particular value within said range. According to some embodiments, the concentration of HPMC is in the range of about 0% to about 1.5% w / v, or any particular value within said range. According to some embodiments, the concentration of HPMC is in the range of about 0% to about 0.5% w / v, or any particular value within said range.

In another preferred embodiment, the viscosity enhancing component comprises sodium carboxymethyl cellulose.

The viscosity of the ophthalmic preparation of the present invention can be measured by using a standard method known in the art, for example, a viscometer or a rheometer. Those skilled in the art will recognize that factors such as temperature and shear rate can perform viscosity measurements. In certain embodiments, the viscosities of the ophthalmic formulations of the present invention are Brookfield Cone with CP40 or equivalent spindle and plate viscometer model VDV-, with a shear rate of about 22.50 +/- about 10 (1/sec). III Ultra⁺, Or at 20 ° C +/- 1 ° C using the Brookfield viscometer model LVDV-E with SC4-18 or equivalent spindle, with a shear rate of about 26 +/- about 10 (1/sec). taking measurement.

Tonicity enhancer Tonicity is typically adjusted with a tonicity enhancer, if necessary. Such agents may be, for example, ionic and / or nonionic types. Examples of ionic tonicity enhancers are alkali metal or alkaline earth metal halides, such as CaCl.₂, KBr, KCl, LiCl, Nal, NaBr or NaCl, Na₂SO₄Or there is boric acid. Nonionic tonicity enhancers are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol or dextrose. The aqueous solution of the present invention is typically adjusted with an isotonic agent to bring it closer to the normal osmotic pressure of tears, which corresponds to a 0.9% solution of sodium chloride or a 2.5% solution of glycerol. A weight osmol concentration of about 200-1000 mOsm / kg is preferred, more preferably 200-500 mOsm / kg, or any particular value within the above range (eg, 200 mOsm / kg, 210 mOsm / kg, 220 mOsm / kg, 230 mOsm / kg). , 240mOsm / kg, 250mOsm / kg, 260mOsm / kg, 270mOsm / kg, 280mOsm / kg, 290mOsm / kg, 300mOsm / kg, 310mOsm / kg, 320mOsm / kg, 330mOsm / kg, 340mOsm / kg, 350mOsm / kg / kg, 370mOsm / kg, 380mOsm / kg, 390mOsm / kg or 400mOsm / kg). In certain embodiments, the ophthalmic formulations of the present invention are adjusted with an isotonic agent to a weight osmolal concentration in the range of about 240-360 mOsm / kg (eg, 300 mOsm / kg).

The pharmaceutical product of the present invention may further contain an isotonic agent or a combination of isotonic agents. According to some embodiments, the pharmaceutical product of the present invention may contain an effective amount of tonicity adjusting component. Among them, suitable tonicity adjusting ingredients that can be used are, for example, various inorganic salts customarily used in contact lens care products. Polyols and polysaccharides can also be used to adjust tonicity. A weight osmolal concentration of 200 mOsmol / kg to 1000 mOsmol / kg, or an amount of tonicity adjusting component that provides any particular value within the above range is effective.

Preferably, the tonicity component comprises a physiological equilibrium salt solution that mimics the mineral composition of tears. According to some embodiments, the tonicity can be adjusted, for example, with a tonicity enhancer, including agents of the ionic and / or nonionic type. Examples of ionic tonicity enhancers are alkali metal or alkaline earth metal halides such as CaCl.₂, KBr, KCl, LiCl, Nal, NaBr or NaCl, Na₂SO₄Or boric acid. Nonionic tonicity enhancers are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol or dextrose.

According to some embodiments, the tonicity components are NaCl, KCl, ZnCl.₂, CaCl₂And MgCl₂Two or more of them are included in a ratio that gives the above-mentioned weight osmolal concentration range. According to some embodiments, the weight osmolal concentration range of the pharmaceutical product of the present invention is from about 100 to about 1000 mOsm / kg, preferably from about 500 to about 1000 mOsm / kg. According to some embodiments, the tonicity components are NaCl, KCl, ZnCl.₂, CaCl₂And MgCl₂Three or more of them are included in a ratio that gives a weight osmolal concentration range of about 100 to about 1000 mOsm / kg, preferably about 500 to about 1000 mOsm / kg. According to some embodiments, the tonicity components are NaCl, KCl, ZnCl.₂, CaCl₂And MgCl₂Four or more of them are included in a ratio that gives a weight osmolal concentration range of about 100 to about 1000 mOsm / kg, preferably about 500 to about 1000 mOsm / kg. According to some embodiments, the tonicity components are NaCl, KCl, ZnCl.₂, CaCl₂And MgCl₂Is included in a ratio that provides a weight osmolal concentration range of about 100 to about 1000 mOsm / kg, preferably about 500 to about 1000 mOsm / kg.

According to some embodiments, NaCl is in the range of about 0.1 to about 1% w / v, preferably about 0.2 to about 0.8% w / v, more preferably about 0.39% w / v. According to some embodiments, KCl is in the range of about 0.02 to about 0.5% w / v, preferably about 0.05 to about 0.3% w / v, more preferably about 0.14% w / v. According to some embodiments, CaCl₂Is in the range of about 0.0005 to about 0.1% w / v, preferably about 0.005 to about 0.08% w / v, more preferably about 0.06% w / v. According to some embodiments, MgCl₂Is in the range of about 0.0005 to about 0.1% w / v, preferably about 0.005 to about 0.08% w / v, more preferably about 0.06% W / V. According to some embodiments, ZnCl₂Is in the range of about 0.0005 to about 0.1% w / v, preferably about 0.005 to about 0.08% w / v, more preferably about 0.06% W / V.

According to some embodiments, the ophthalmic formulations of the present invention approach the osmotic pressure of normal tears, which corresponds to a 0.9% solution of sodium chloride or a 2.5% solution of glycerol, by adjusting with an isotonic agent. Can be made to. A weight osmolal concentration of about 225 to 400 mOsm / kg is preferred, more preferably 280 to 320 mOsm.

Solubilizer Topical formulations may further require the presence of a solubilizer, especially if one or more of the constituents tend to form a suspension or emulsion. Suitable solubilizers include, for example, tyroxapol, fatty acid glycerol polyethylene glycol ester, fatty acid polyethylene glycol ester, polyethylene glycol, glycerol ether, cyclodextrin (eg alpha-, beta- or gamma-cyclodextrin, eg alkylation, hydroxyalkyl. Compounds, carboxyalkylated or alkyloxycarbonyl-alkylated derivatives, or mono-or diglycosyl-alpha-, beta-or gamma-cyclodextrin, mono-or dimaltosyl-alpha-, beta-or gamma-cyclodextrin or panosyl-cyclo Dextrin), polysorbate 20, polysorbate 80 or mixtures thereof. In a preferred embodiment, the solubilizer is a reaction product of castor oil and ethylene oxide, such as Cremophor EL® or Cremophor. Products such as RH40 (registered trademark). The reaction product of castor oil and ethylene oxide has proven to be a particularly good solubilizer that is extremely well tolerated by the eye. In another embodiment, the solubilizer is tyroxapol or cyclodextrin. The concentration used depends particularly on the concentration of the active ingredient. The amount added is typically sufficient to solubilize the active ingredient. For example, the concentration of the solubilizer is 0.1 to 5000 times the concentration of the active ingredient.

Antispasmodic The antispasmodic used in the present invention is an effective amount (ie, "slippery amount") sufficient to obtain a viscous effect, that is, to lubricate the mucosal surface and relieve dryness and irritation. Used in. Examples of suitable slimming agents include polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, but specifically exclude other components such as polyethylene oxide and polyacrylic acid. In yet other embodiments, other or additional mucilages can be used in combination with glycerin and propylene glycol. For example, polyvinylpyrrolidone and polyvinyl alcohol can also be used.

The specific amount of the mucilage used in the present invention will vary depending on the application; however, typically a range of some mucilages is provided: glycerin: about 0.2. ~ About 1.5%, preferably about 1% (w / w); Propylene glycol: about 0.2 ~ about 1.5%, preferably about 1% (w / w); Cellulose derivative: about 0.2 ~ about It is 3%, but preferably about 0.5% (w / w). When additional mucilages are used, they are typically used in the amounts specified in the over-the-counter monographs cited above. A preferred cellulose derivative is pharmaceutical grade hydroxypropylmethylcellulose (HPMC).

Stability The formulations of the present invention provide the chemical stability of the formulated hydrophobic drugs (eg, steroids) and other optionally active agents of the formulations. In this context, "stability" and "stable" are the chemical degradation and physical changes of hydrophobic drugs (eg, steroids) and other active agents, such as given manufacturing conditions, preparation conditions, transport conditions. And resistance to sedimentation or sedimentation under storage conditions. The "stable" formulations of the invention are also preferably at least 90%, 95%, 98%, 99 of starting or reference amounts under given manufacturing, preparation, transport and / or storage conditions. Hold% or 99.5%. Amounts of hydrophobic drugs (eg, steroids) and otherwise active agents use any of the art approved methods, such as UV-Vis spectrophotometry and high performance liquid chromatography (HPLC). Can be decided.

In certain embodiments, the formulation is stable at temperatures in the range of about 20-30 ° C for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, or at least 7 weeks. Is. In other embodiments, the formulation is prepared at a temperature in the range of about 20-30 ° C for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, It is stable for at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months. In one embodiment, the pharmaceutical product is stable at 20-25 ° C for at least 3 months.

In other embodiments, the formulation is prepared at a temperature in the range of about 2-8 ° C for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months. Stable for at least 12 months, at least 14 months, at least 16 months, at least 18 months, at least 20 months, at least 22 months, or at least 24 months. In one embodiment, the pharmaceutical product is stable at 2-8 ° C for at least 2 months.

In other embodiments, the formulation is at a temperature of about -20 ° C for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 It is stable for months, at least 14 months, at least 16 months, at least 18 months, at least 20 months, at least 22 months, or at least 24 months. In one embodiment, the formulation is stable at -20 ° C for at least 6-12 months.

In certain embodiments, the hydrophobic drug formulations of the present invention are stable at temperatures up to 0.10% at temperatures of about 20-30 ° C for at least 3 months. In another embodiment, the formulation is stable at a temperature of about 2-8 ° C, at concentrations up to 0.10%, for at least 6 months.

In some embodiments, the formulation is a suspension of the FP nanocrystals of the invention between 0.001% and 5% (eg, 0.01-1%, or about 0.25%, 0.1% or 0.05%), and the pharmaceutical. A sterile, topical nanocrystalline fluticasone propionate formulation containing an acceptable aqueous additive.

In some embodiments, the pharmaceutical product further contains about 0.002 to 0.01% (eg, 50 ppm + 15%) of benzalconium chloride (BKC).

In some embodiments, the formulation is one or more coating dispersants (eg, tyloxapol, polysorbate 80, and PEG stearate, such as PEG40 stearate), one or more tissue wetting agents (eg, glycerin). , One or more polymer stabilizers (eg, methylcellulose 4000cP), one or more buffers (eg, dibasic sodium phosphate Na)₂HPO₄And monosodium phosphate NaH₂PO₄, And / or one or more isotonicity modifiers (eg, sodium chloride).

In one embodiment, the pharmaceutical product is the FP nanocrystals of the invention between 0.01% and 1% (eg, about 0.25%, 0.1% or 0.05%), benzalconium chloride (eg, 0.002 to 0.01% or about 0.005). %), Polysorbate 80 (eg 0.01-1% or about 0.2%), PEG40 stearate (eg 0.01-1% or about 0.2%), Glycerin (eg 0.1-10% or about 1%), Methylcellulose 4000cP (Eg 0.05-5% or 0.5%), sodium chloride (eg 0.05-5% or 0.5%), sodium dibasic sodium phosphate Na₂HPO₄And monosodium phosphate NaH₂PO₄And water, the formulation has a pH of about 6.8-7.2. In another embodiment, the formulation is the FP nanocrystals of the invention between 0.01% and 1% (eg, about 0.25%, 0.1% or 0.05%), benzalconium chloride (eg, 0.002 to 0.01% or about). 0.005%), tyrosapol (eg 0.01-1% or about 0.2%), glycerin (eg 0.1-10% or about 1%), methylcellulose 4000cP (eg 0.05-5% or 0.5%), sodium chloride (eg 0.05-5% or 0.5%) , 0.05 ~ 5% or 0.5%), Sodium dibasic sodium phosphate Na₂HPO₄And monosodium phosphate NaH₂PO₄, And water, the formulation has a pH of about 6.8-7.2.

In some embodiments, the formulation has a viscosity between 40-50 cP at 20 ° C. In some embodiments, the weight osmolal concentration of the formulation is about 280-350 (eg, about 285-305) mOsm / kg. In some embodiments, the pH of the formulation is about 6.8-7.2. In some embodiments, the formulation has a viscosity between 40-50 cP at 20 ° C.

In some embodiments, the FP nanocrystals in the formulation have a median size of 300-600 nm, an average size of 500-700 nm, a D50 value of 300-600 nm, and / or a D90 value of less than 2 μm.

In some embodiments, the formulation has a therapeutically effective amount for treating blepharitis, eg, a brush (eg, a brush, eg, a Latisse® brush or swab, eg, a 25-3317-U swab). Administered via. In one embodiment, two drops (about 40 μL in diameter) of the formulation are filled in an applicator, (eg, a brush or swab), and then, for example, the applicator is slid over the lower eyelid (once or twice). Then, by sliding it on the upper eyelid (once or twice), it is delivered to the subject in need, and if necessary, the above steps are repeated for the other eye using a new applicator.

Usage The present invention also provides for the prevention or alleviation of disorders in which hydrophobic drugs are used, such as systemic or non-systemic treatment of inflammatory disorders, respiratory disorders, autoimmune diseases or cancer symptoms. Provided are the use of the formulations described herein.

In embodiments, fluticasone propionate is used, depending on the mode of administration, for example, respiratory related diseases such as asthma, pulmonary emphysema, respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), chronic bronchitis, Cystic fibrosis, acquired immunodeficiency syndrome (including AIDS-related pneumonia), seasonal or perennial rhinitis, seasonal or perennial allergic and non-allergic (vasomotor) rhinitis, or topical corticosteroids Can treat skin conditions that can be treated with steroids. Like other topical corticosteroids, fluticasone propionate has properties that cause anti-inflammatory, anti-itch and vasoconstriction.

When administered as an aerosol, fluticasone propionate acts locally in the lungs; therefore, no therapeutic effect is expected from plasma levels. Experiments with conventional oral doses of fluticasone propionate, labeled and unlabeled, show that oral systemic bioavailability of fluticasone propionate is predominantly incomplete absorption and pre-systemic circulation in the intestine and liver. It was demonstrated by metabolism to be negligible (&lt;1%).

The degree of percutaneous absorption of topical corticosteroids is determined by a number of factors, including the integrity of the vehicle and epidermal barrier. Closed bandages increase penetration. Topical corticosteroids can be absorbed through normal, intact skin. Inflammation and / or other disease processes in the skin increase percutaneous absorption.

Routes of Delivery In certain embodiments, the methods of treatment disclosed in the present invention include all local (non-systemic) routes of delivery to ocular tissue and appendages. Delivery routes are not limited to these, but topical formulations such as eye drops, gels or ointments and any intraocular, intravitreal, subretinal, intracapsular, superior choroid, subconjunctival, subconjunctival, intraluminal. Includes intraorbital, posterior and periball injections or implantable or surgical devices.

Fluticasone propionate is in the crystalline form named Form 1 by dissolving the crude product in ethyl acetate (eg, obtained as described in British Patent No. 2088877) and then recrystallizing. Obtained. It has also been shown that standard spray-drying techniques result in only known form 1 of fluticasone propionate. See U.S. Pat. No. 6,406,718 by Cooper et al. A second polymorphic form of fluticasone propionate, prepared using supercritical fluid technology, has been described by Cooper et al.

Cooper et al. Describe a method for forming a particulate propionic acid fluticazone product, which comprises the simultaneous introduction of a supercritical fluid in solution or suspension and a vehicle containing at least fluticazone propionate into a particle forming vessel. The temperature and pressure in this vessel are controlled so that the dispersion and extraction of the vehicle occur substantially simultaneously with the action of the supercritical fluid. Chemicals described as useful as supercritical fluids include carbon dioxide, nitric oxide, sulfur hexafluoride, xenone, ethylene, chlorotrifluoromethane, ethane and trifluoromethane. The supercritical fluid optionally contains one or more modifiers, such as methanol, ethanol, ethyl acetate, acetone, acetonitrile or any mixture thereof. A supercritical fluid modifier (or co-solvent) is a chemical that, when added to a supercritical fluid, alters the intrinsic properties of the supercritical fluid at or around the critical point. According to Cooper et al., Fluticasone propionate particles produced using supercritical fluids have a particle size in the range of 1-10 microns, preferably 1-5 microns.

There are some drawbacks associated with the fluticasone composition of Cooper et al. First, particle sizes less than 1 micron are desirable. This is because smaller particle sizes can be accompanied by more rapid dissolution upon administration, resulting in a faster onset of action, as well as greater bioavailability. In addition, tiny fluticasone particles, i.e. less than about 150 nm in diameter, are desirable, which allows the composition to be sterile filtered. In addition, the fluticasone particles of Cooper et al. May contain supercritical fluid residues, which are undesirable because they have no pharmaceutical properties and can potentially cause adverse reactions.

Fluticasone propionate is commercially available in several different commercial forms. ADVAIR DISKUS® (GlaxoSmithKline, Research Triangle Park, NC) is an inhalation powder of a combination of ultrafine fluticasone propionate and salmeterol xinafoate, which is a highly selective beta.₂-An adrenergic bronchodilator. Dosage forms are commercially available in three doses of fluticasone propionate: 100 mcg, 250 mcg, and 500 mcg.

After administration of ADVAIR® DISKUS® to healthy subjects, peak plasma levels of fluticasone propionate were achieved in 1-2 hours. Physicians' Desk Reference, 57th Edition, 1433 (Thompson) See PDR, NJ 2003). Whether to provide 500 mcg of fluticasone propionate powder and 50 mcg of salmeterol powder at the same time when ADVAIR® DISKUS® 500/50 (containing 500 mcg of fluticasone propionate and 50 mcg of salmeterol xinafoate) is administered. , Or when fluticasone propionate powder 500 mcg was provided alone, the steady-state mean peak plasma concentrations of fluticasone propionate were 57, 73 and 70 pg / mL, respectively. (The same document). Peak plasma concentrations of fluticasone propionate in an adult patient (n = 11) are undetectable after 500 mcg of fluticasone propionate inhalation powder twice daily using a DISKUS® device. It ranged from to 266 pg / mL. The average plasma concentration of fluticasone propionate was 110 pg / mL. The systemic bioavailability of fluticasone propionate inhalation powder in healthy volunteers using DISKUS® devices averaged 18%. ADVAIR DISKUS® is indicated for long-term, twice-daily asthma maintenance therapy.

FLOVENT® DISKUS® (GlaxoSmithKline) is an oral inhalation powder of ultrafine fluticasone propionate (50mcg, 100mcg, and 250mcg) in lactose. Under standardized in vitro test conditions, FLOVENT® DISKUS® delivers 47, 94 or 235 mcg of fluticasone propionate from FLOVENT® DISKUS® 50 mcg, 100 mcg and 250 mcg, respectively. do. In healthy adult volunteers, the systemic bioavailability of fluticasone propionate from DISKUS® devices averages about 18%. FLOVENT® DISKUS® is indicated for maintenance therapy of asthma as a prophylactic treatment and for patients requiring oral corticosteroid treatment for asthma.

FLOVENT® ROTADISK® (GlaxoSmithKline) is an oral inhalation powder of ultrafine fluticasone propionate (50 mcg, 100 mcg and 250 mcg) blended with lactose. Under standardized in vitro test conditions, FLOVENT® ROTADISK® from FLOVENT® ROTADISK® 50 mcg, 100 mcg or 250 mcg to 44, 88 or 220 mcg of fluticasone propionate, respectively. Deliver. (The same document). In healthy adult volunteers, the systemic bioavailability of fluticasone propionate from ROTADISK® devices averages about 13.5%. (The same document). FLOVENT® ROTADISK® is indicated for maintenance therapy of asthma as a prophylactic treatment and for patients requiring oral corticosteroid treatment for asthma.

FLOVENT® (GlaxoSmithKline) is a microcrystalline suspension of fluticasone propionate (44mcg, 110mcg or 220mcg) in a mixture of two chlorofluorocarbon sprays (trichlorofluoromethane and dichlorodifluoromethane) and lecithin. An oral inhalation aerosol of the agent. When the inhaler is activated, 50, 125 or 250 mcg of fluticasone propionate is delivered from the valve and 44, 110 or 220 mcg of fluticasone propionate is delivered from the actuator, respectively. In healthy volunteers, the systemic bioavailability of fluticasone propionate inhalation aerosol is, on average, about 30% of the dose delivered from the actuator. Peak plasma concentrations after inhalation of doses of 880-mcg ranged from 0.1 to 1.0 ng / ml. (The same document). FLOVENT® is indicated for asthma maintenance therapy as a prophylactic treatment.

FLONASE® (GlaxoSmithKline) is a nasal spray of an aqueous suspension of ultrafine fluticasone propionate (50 mcg / dose) administered using a metered spray pump. The dosage form also contains microcrystalline cellulose, sodium carboxymethyl cellulose, dextrose, 0.02% w / w benzalconium chloride, polysorbate 80 and 0.25% w / w phenylethyl alcohol. Indirect calculations have shown that fluticasone propionate delivered by the intranasal route has an average of less than 2% absolute bioavailability. Fluticasone propionate plasma levels after 3 weeks of intranasal treatment in patients with allergic rhinitis were detected only when the recommended dose was exceeded and then only in samples where plasma levels were accidentally low. The level (50 pg / mL) was exceeded. Due to the low bioavailability of the intranasal route, most of the pharmacokinetic data was obtained via other routes of administration. Experiments with oral dosing of radiolabeled drugs have demonstrated that fluticasone propionate is highly extracted from plasma and is poorly absorbed. Oral bioavailability is negligible and most of the circulating radioactivity is due to inactive metabolites. Experiments comparing the effects of oral and nasal dosing demonstrated that the therapeutic effect of FLONASE® may be due to the topical effect of fluticasone propionate applied to the nasal mucosa. FLONASE® nasal drops are indicated for the management of nasal symptoms of seasonal and perennial allergic and non-allergic rhinitis.

CUTIVATE® (GlaxoSmithKline) is a fluticasone propionic acid cream or ointment (0.05% and 0.005% concentration) for topical skin diseases. Creams and ointments are moderately potent corticosteroids that are indicated for the resolution of the inflammatory and pruritic appearance of corticosteroid-reactive skin diseases. Plasma levels were generally below quantified levels (0.05 ng / ml) in 12 healthy male human experiments receiving 12.5 g of 0.05% fluticasone propionate cream twice daily for 3 weeks. Met. In another experiment of 6 healthy men who received 25 g of fluticasone propionate cream at 25 g for 5 days under occlusion, plasma levels of fluticasone ranged from 0.07 to 0.39 ng / ml. Plasma levels of fluticasone were 0.08 to 0.22 in an experiment of 6 healthy volunteers who applied fluticasone ointment 0.005% propionate under occlusion to the torso and legs twice daily for up to 5 days. It was in the range of ng / mL.

The present invention features methods of treating, preventing or alleviating eye disorders in a subject, such as blepharitis and / or symptoms such as MGD, including the use of the novel formulations described above. For example, a method for treating or preventing an eye disorder (eg, blepharitis or MGD) is to administer a preparation containing the above-mentioned novel preparation to the eye, eyelid, eyelashes or eyelid margin of the subject in need thereof. May include.

The present invention is further characterized by a method of treating a skin disorder in a subject, including the use of the novel formulations described herein.

The present invention describes a method of treating a respiratory disease (eg, asthma or COPD), rhinitis, dermatitis or esophagitis by administering the formulations described herein to a subject in need thereof. Further features.

The present invention also comprises a method of treating a cancer (eg, lymphoma) by administering the formulations described herein to a subject in need thereof.

The present invention also comprises a method of treating an autoimmune disease (eg, lupus or psoriasis) by administering the formulation described herein to a subject in need thereof.

The effective amount of the active agent contained in a given formulation, and the efficacy of the formulation for treating, preventing or alleviating the symptoms of targeted disorders such as blepharitis and / or MGD, depend on one or more of the following: Can be assessed: slit lamp assessment, fluorescein staining, tear film destruction time and meibomian gland secretion quality assessment (secretion viscosity, gland color, glandular alignment, vascular distribution pattern, vascular distribution redness, hyper Assess one or more of keratinization, posterior lid edges, eyelids, skin-mucosal junctions, peri-gland redness, glandular shape and gland height).

The effective amount of the active agent (s) in the formulation will depend on the rate of absorption, inactivation, and excretion of the drug, as well as the rate of delivery of the active agent (s) from the formulation. Note that dose values can also vary depending on the severity of the condition to be alleviated. For any particular subject, the specific dosing regimen should be adjusted over time by the individual needs and the professional judgment of the person managing or instructing the administration of the composition. Please understand further. Typically, dosing will be determined using techniques known to those of skill in the art.

The dose of any compound of the invention is the patient's symptoms, age and other physical characteristics, the nature and severity of the disorder to be treated or prevented, the degree of comfort desired, the route of administration, and the form of the supplement. It will fluctuate according to. Any of the target formulations may be administered in a single dose or a divided dose. The dose for the pharmaceutical product of the present invention can be easily determined by a technique known to those skilled in the art or as taught herein. In an embodiment, about 1-100 μg (eg 10-100 μg) of FP nanoparticles is administered to each eyelid to treat blepharitis. In one embodiment, two drops of the pharmaceutical product containing FP nanocrystals (eg 0.01-1%, or about 0.25%, 0.1% or about 0.05%) (total volume about 80 μL) are applied to each eye. For example, two drops of the formulation are first filled in an applicator (eg, a brush or swab), then, for example, the applicator is slid onto the lower eyelid (once or twice) and then on the upper eyelid (once). Or twice) to deliver it to the subject in need by sliding, and if necessary, repeat the above steps for the other eye using a new applicator.

Any possible effect on the effective dose or amount and the timing of administration of the formulation needs to be identified for any particular formulation of the invention. This can be accomplished by routine experimentation as described herein. The efficacy of any formulation and method of treatment or prevention is one or more related to the efficacy of the composition and the degree of comfort to the patient as described herein by administering the formulation. The effect of administration is evaluated by measuring the indicators, and the treated values of these indicators are compared with the values of the same indicators before treatment, or the treated values of these indicators are different formulations. It can be assessed by comparing it with the value of the same index used.

The exact time and amount of administration of any particular formulation that will result in the most effective treatment in a given patient is the activity, pharmacokinetics, and bioavailability of the particular compound, the patient's physiological status. Depends on age, gender, type and stage of disease, general health, responsiveness to a given dose and type of drug), route of administration, etc. The guidelines presented herein can be used to optimize treatment, eg, optimal time and / or dosage, which is subject monitoring and dose and / or timing. It only performs a conventional test consisting of adjustments.

By using a combination of several active agents formulated into the compositions of the present invention, the dose required for any individual ingredient can be reduced. This is because the onset and duration of the effects of different ingredients can be favored. In such combination therapies, the different active agents may be delivered together or separately, simultaneously or at different times of the day.

Packaging The formulations of the invention can be packaged as either single-dose or multi-dose products. Single dose products are sterile prior to opening the package and all of the composition in the package is intended to be consumed in a single application to the patient's one or both eyes. The use of antibacterial preservatives to maintain the sterility of the composition after opening the package is generally not required. When the preparation is an ointment preparation, it can be packaged for an ointment, if necessary, as known to those skilled in the art.

Multi-dose products are also sterile before opening the package. However, multiple doses of the product ensure that the composition is microbially as a result of repeated opening and handling of the container, as the container of the composition can be opened multiple times before consuming all of the composition in the container. It must have sufficient antibacterial activity so that it is not contaminated. The level of antibacterial activity required for this purpose is well known to those of skill in the art and is addressed by official publications such as the United States Pharmacopeia (USP) and other publications by the Food and Drug Administration, as well as other countries. It is specified in the publications to be published. A detailed description of the specifications for the preservation of ophthalmic drugs against microbial contamination and the procedure for assessing the efficacy of preservatives of a particular formulation is provided by these publications. In the United States, the standard of preservative efficacy is commonly referred to as the "USP PET" requirement (the acronym "PET" stands for "preservative efficacy test").

The use of single-dose packaging arrangements eliminates the need to include antibacterial preservatives in the composition, which is a significant advantage from a medical point of view. This is because conventional antibacterial agents used to store eye compositions (eg, benzalconium chloride) cause eye irritation, especially in patients suffering from dry eye conditions or pre-existing eye irritation. Because you get it. However, currently available single-dose packaging arrangements, such as small plastic vials prepared using a process known as "bag-filling packaging," have some drawbacks to manufacturers and consumers. Has. The main drawbacks of single dose packaging systems are the huge amount of packaging material required (wasteful and expensive) and the inconvenience to consumers. Also, the consumer does not discard the single dose container after applying one or two drops to the eye as instructed, instead of any remaining in the opened container and container for later use. There is a risk of preserving the composition. This improper use of single-dose products creates a risk of microbial contamination of single-dose products and the associated risk of eye infections when the contaminated composition is applied to the eye.

While the formulations of the present invention are preferably formulated as "ready-to-use" aqueous solutions, alternative formulations are envisioned within the scope of the invention. Thus, for example, active ingredients, surfactants, salts, chelating agents or other ingredients of ophthalmic solutions, or mixtures thereof, are lyophilized or otherwise in water (eg, deionized water or distillation). It can be provided as a dry powder or tablet ready for dissolution (in water). No sterile water is needed due to the self-preservation of the solution.

Ophthalmic ointments can be produced as follows: Preservatives, surfactants, stabilizers, alcohols, esters or oils, as needed, in ointment bases such as dairy pots or ointment mixing equipment. A mixture is formed by blending with liquid paraffin or white petrolatum placed therein. The ointment thus prepared is filled in an ointment bottle or tube.

Kits In yet another embodiment, the invention is to implement a kit for packaging and / or storing and / or using the formulations described herein, as well as the methods described herein. Kits are provided. Thus, for example, a kit may include one or more containers containing one or more ophthalmic solutions, ointment suspensions or formulations, tablets or capsules of the invention. The kit can be intended to facilitate one or more aspects of shipping, use and storage.

The kit may optionally include a topical applicator that facilitates administration of the formulations provided herein. In some embodiments, the formulation is prefilled in a topical applicator. Topical applicators include, for example, swabs or rods.

The kit may optionally include documentation of instructions containing instructions that disclose (ie, protocol) the means of using the formulations provided herein. The kit may optionally include a topical applicator to facilitate administration of the formulations provided herein. The documentation of the instructions typically includes, but is not limited to, written or printed matter. Any medium capable of storing such instruction manuals and communicating them to the end user is envisioned by the present invention. Examples of such media include, but are not limited to, electronic storage media (eg, magnetic disks, tapes, cartridges, chips), optical media (eg, CDROM), and the like. Such media may include the address of an internet site from which such documentation is available.

All publications and patents described herein are referenced in their entirety, as if each individual publication or patent was incorporated by reference, as if specifically and individually adapted. Incorporated herein by. In the event of a conflict, this application, including any definition herein, will prevail. All percentages and ratios used herein are by weight unless otherwise noted. All averages used herein are number averages unless otherwise noted. For example, the average size of nanocrystals described herein is the average size of numbers. Further, the molecular weight of the polymers described herein is the number average molar mass of the polymers, unless otherwise indicated. As used herein, the range / distribution of particle size or thickness of nanoparticles is the range defined by the D10 and D90 values, excluding the range of average sizes of nanoparticles.

Definition The term "D10" or "D10 value" refers to a value in which 10% of the population is below this value. Similarly, "D90" or "D90 value" means a value where 90 percent of the population is below this D90, and "D50" or "D50 value" means that 50 percent of the population is below D50. Refers to the value to be located.

The term "statistical mode" or "mode" refers to the most frequently occurring values in a set of data. It is not uncommon to have more than one mode for a dataset. A distribution with two modes is called bimodal. A distribution with three modes is called trimodal. The distribution mode with continuous random variables is the maximum value of the function. Similar to the discrete distribution, there can be more than one mode.

The term "median" or "statistical median" is a number that separates the upper half of a data sample, population, or potential distribution from the lower half.

The term "abnormal meibomian gland secretion" refers to meibomian gland secretion with increased viscosity, opacity, color and / or increased time (refractory period) between glandular secretions.

The term "aqueous" refers to an aqueous composition in which the carrier is typically water in the range&gt; 50%, more preferably&gt; 75%, and particularly&gt; 90%, based on weight.

The term "eyelid inflammation" refers to disorders including inflammation of the eyelids, where inflammation results in redness of the eyelids, swelling of the eyelids, discomfort of the eyelids, itching of the eyelids, peeling of the skin of the eyelids, and redness of the eyes. Abnormal meibomian gland secretion plays a role, with keratinization of the eyelids, rounding of the eyelid margins, grayline obsculation, increased transparency of the eyelid margins, and increased vascular distribution. The terms meibomian gland dysfunction (MGD) and meibomian gland inflammation are commonly referred to by most researchers as blepharitis, but these are different diseases associated with abnormal meibomian glands (ie, meibomian gland secretions). It is important to note that this term is incompatible. Blepharitis can cause chronic meibomian gland dysfunction. Second, when meibomians act as the outermost layer of the tear film and act to slow the evaporation of tears, the poor quality causes MGD to cause dry eye symptoms.

The term "comfortable" as used herein contrasts with pain, burns, stinging sensations, itching, physical sensations of irritation, or other symptoms associated with physical discomfort. In addition, it refers to a feeling of physical satisfaction or relief.

The term "comfortable ocular formulation", as used herein, provides a physical resolution from signs or symptoms associated with eyelid inflammation and / or eye discomfort and, when injected into the eye, Refers to an ocular formulation that produces only acceptable levels of pain, burns, stinging sensations, itching, irritation, or other symptoms associated with eye discomfort.

The phrase "effective amount" is an approved term in the art and, when incorporated into the pharmaceutical compositions of the present invention, is partly desired at a reasonable profit / loss ratio applicable to any medical procedure. Refers to the amount of drug that produces the effect of. In certain embodiments, the term is necessary or sufficient to eliminate, reduce, or maintain the symptoms of eyelid margin irritation (eg, prevent diffusion), or prevent or treat eyelid margin inflammation. Point to. Effective amounts may vary depending on factors such as the disease or condition being treated, the particular composition being administered, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular drug without the need for undue testing.

The phrase "pharmaceutically acceptable" is approved in the art and, within sound medical judgment, may cause excessive toxicity, irritation, allergic reactions, or other problems or complications. Refers to compositions, polymers and other materials and / or salts and / or dosage forms thereof that are suitable for use in contact with human and animal tissues, rather than in proportion to a reasonable profit / loss ratio.

The phrase "pharmaceutically acceptable carrier" is approved in the art and is, for example, a pharmaceutically acceptable material, composition or medium, such as a liquid (aqueous or non-aqueous) or solid. Refers to fillers, diluents, additives, solvents or encapsulation materials of any supplement or composition, or components thereof, from one organ or part of the body, to another organ of the body, or. It is involved in retaining or transporting parts or delivering the drug to the surface of the eye. Each carrier must be "acceptable" in the sense that it is compatible with the other components of the composition and is not harmful to the patient. In certain embodiments, the pharmaceutically acceptable carrier is non-pyrogenic. Examples of some of the materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch. And potato starch and the like; (3) cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacant; (5) malt; (6) gelatin; (7) talc; (8) Additives such as cocoa butter and suppository wax; (9) oils such as castor oil, olive oil, peanut oil, macadamia nut oil, walnut oil, almond oil, pumpkin seed oil, cottonseed oil, sesame oil, corn oil, soybean oil. , Avocado oil, palm oil, palm oil, sunflower oil, Benibana oil, flaxseed oil, grape seed oil, canola oil, low viscosity silicone oil, light oil, or any combination thereof; (10) Glycol, eg propylene glycol, etc. (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide And aluminum hydroxide, etc .; (15) alginic acid; (16) oil without exothermic substances;

The term "pharmaceutically acceptable salt" has been approved in the art and, without limitation, any of the compositions of the invention or any of its components, including therapeutic agents, additives, other materials and the like. Refers to the addition salts of relatively non-toxic inorganic and organic acids. Examples of pharmaceutically acceptable salts include salts derived from mineral acids such as hydrochloric acid and sulfuric acid, and salts derived from organic acids such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Can be mentioned. Pharmaceutically acceptable salts include conventional non-toxic salts, or quaternary ammonium salts of the formed parent compound, for example derived from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and organic acids such as acetic acid, flonic acid. (fuoric), propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartrate acid, citric acid, ascorbic acid, pamon acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamate acid, benzoic acid, salicylic acid, sulfanyl Includes salts prepared from acids such as 2-acetoxybenzoic acid, fumaric acid, tolunesulfonic, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid.

The term "topical" refers to the route of administration, i.e., the administration of a drug to the surface of the body, such as the skin, tissue or mucous membrane of the subject in need of it. For example, topical medications can be administered to the lid, eyelashes, eyelid margins, skin, or eye (eg, eye drops applied to the surface of the eye, eg conjunctiva). Topical medications may also be those by inhalation, such as asthma medications, or medications applied to the tooth surface.

The term "intraocular" as used herein refers to any location within the eye.

The term "intravitreal" as used herein refers to the interior of the gel behind the eye. For example, Lucentis injections are administered intravitreal.

The term "subretinal" as used herein refers to the area between the retina and the choroid. For example, the iScience device is administered subretinal.

The term "intracapsule" as used herein refers to the inside of a lens capsule. For example, the iVeena device is administered intrasac.

The term "upper choroid" as used herein refers to the region between the choroid and the sclera. For example, the Clearside device is administered to the superior choroid.

The term "sub-tenon sac" as used herein refers to the area posterior to the orbital septum, outside the sclera, and below the sac. For example, triamcinolone injections are given sub-Tenon's sac.

The term "subconjunctival" as used herein refers to the region between the conjunctiva and the sclera. For example, Macusight rapamycin injection is given to the subconjunctival area.

The term "intracavitary" as used herein refers to "entering the cavity" of the eye, eg, into the anterior or posterior cavity of the eye. For example, any injection during cataract surgery is administered intracavitarily.

The term "intraorbital" as used herein refers to insertion into the eyelid. For example, Botox injections are administered intraorbitally.

The term "cardesac" as used herein refers to the space between the eyelid and the sphere. For example, the Ocusert device is administered to Caldesac.

The term "posterior eyeball" as used herein refers to the posterior of the orbit of the eye. The term "peripheral" as used herein refers to intraorbital or adjacent to the eye. For example, anesthetic blockage prior to eye surgery is administered to the posterior or peri-ball space.

As used herein, "subject in need" is a disorder for which the hydrophobic drugs described herein are intended for treatment, such as an inflammatory disorder. , Respiratory disorders, autoimmune diseases or subjects with cancer. "Subjects" include mammals. Mammals may be, for example, humans or suitable non-human mammals such as primates, mice, rats, dogs, cats, cows, horses, goats, camels, sheep or pigs. The subject may also be a bird or poultry. In one embodiment, the mammal is a human.

The term "prevent" is approved in the art when used with respect to conditions such as blepharitis and reduces the frequency of the subject's medical condition compared to the subject not given the composition. , Or the administration of a composition that delays the onset, signs and / or symptoms.

The term "treat" is an approved term in the art that refers to the cure and amelioration of at least one symptom of any condition or disease.

<p> (Example 1) Method for preparing 0.1% fluticasone propionate nanoparticles: An HPLC method for determining the concentration of fluticasone propionate was developed and details were provided to A.</p><p> The specific composition of Phase I depends on the solubility of the drug in this phase. Solubility of fluticasone propionate in FDA-approved solvents and excipients was determined by dissolving 10 mg of the drug in each solvent, vigorously vortexing and equilibrating at 25 ° C overnight. The suspension was centrifuged at 10000 rpm and the supernatant was analyzed by RP-HPLC at 239 nm. The solubility and compatibility of fluticasone propionate in each solvent was evaluated.</p><p> A. Development of HPLC method All USP methods for analyzing fluticasone propionate (creams, ointments) have excipients capable of degrading or blocking columns, low resolution for peak separation, and peak height. Since there is a high possibility that there is no such substance, the method of extracting with hexane before diluting with the mobile phase is used. Extraction methods result in the loss of degradation products, especially those that have not been previously characterized. It seemed necessary to develop methods that would result in the quantification of degradation products that could result from APIs and potential incompatibility with excipients.</p><p> Sample preparation method 1. 400 μl (1 mg / ml drug suspension) of the sample was combined with 1.6 ml of the mobile phase and mixed by vortex (the sample is currently 0.2 mg / ml). 2. 2 ml of the sample was collected in a 5 ml syringe. Then, it was filtered by hand pressure through a syringe Millex GV filter (Millipore, diameter 33 mm, 0.22um, Durapore (PVDF), catalog number: SLGV033RB, yellow). This effort requires a moderate amount of manual pressure. 3. The filtered sample was injected directly onto the HPLC using an isocratic method.</p><p> Column wash: Using a new dilution / filtration method, the column pressure was slightly increased from 222 bar to 230 bar after several injections of the sample containing the treated formulation. Washing the column with a mobile phase, or in combination with methanol and a 0.1 M ammonium acetate solution at pH = 7, was found to be useful in reducing the column pressure to about 222 bar of the original pressure. With a current column flow rate of 1.5 ml / min and a column length of 250 mm, the pressure is expected to be lower and higher than similar methods with shorter column lengths. HPLC has a cutoff pressure of 400 bar. Column pressure monitoring is essential in determining when column washes are required for the HPLC method to record pressure, in turn with scans. Injection of additional diluents containing no pharmaceuticals is also added more frequently to wash the column and prevent excessive pressurization, inadequate peak shape, and loss of height.</p><p> Sample Preparation The sequence for flowing the pharmaceutical product of multiple samples should include the injection of blanks to prevent an increase in column pressure. When the precision sample was run on HPLC, the pressure was increased from 221 bar to 230 bar and the vehicle was injected 12 times. Then, after these injections, the sample without any vehicle was continued 8 times and the pressure was reduced to 228 bar. Further washing was performed after the order of reducing the pressure to lower levels. Based on these results, the mobile phase should be injected 2 to 4 times after a total of 6 to 8 injections of the formulation prepared as described. Further column washing should be considered, if necessary, prior to another formulation sequence.</p><p> Chromatography conditions: Instrument: Agilent1200HPLC with autosampler and DAD detector. Mobile phase: Isocratic, 50% methanol, 35% 0.01M ammonium phosphate pH = 3.5, 15% acetonitrile. Flow velocity: 1.5 ml / min Analysis time: 20 min Column: Phenomenex Luna C18 5 micron 100A 250-4.6mm P / N 00G-4041-EO Column temperature: 40 ° C Sample tray: Room temperature Injection volume: 50 microliters DAD detection: Preparation of 239nm sample: Blanks were run in order between experimental sets to ensure no carryover. Preparation of standard: A 5 mg / ml standard stock solution of fluticasone was prepared by weighing a solid fluticasone and dissolving it in 100% acetonitrile. Dilution of this stock was performed in sample diluent (50% acetonitrile / water) for calibration curve samples. Sample diluent: 50% acetonitrile / water.</p><p> Methods of Development Specificity The peak shape and height of the FP and its impurities, as well as the retention time, should be similar to the sample containing the mobile phase as a vehicle or diluent. Table 1 below shows a comparison of peak areas and heights for HPLC samples containing only vehicle or mobile phase, as shown in Figure 2.</p><p><tables num="6"><img file="JP6972255B2_D0015.tif" /></tables></p><p> There is a very good fit between the sample with and without the pharmaceutical vehicle. Table 2 shows the area and height of these samples.</p><p><tables num="7"><img file="JP6972255B2_D0016.tif" /></tables></p><p> Impurities B, C and D: Impurities B, C and D from vehicle injection were also compared to the same impurities from the vehicle-free sample. Table 3 below shows the equivalents between the two samples. The diluent is the mobile phase.</p><p><tables num="8"><img file="JP6972255B2_D0017.tif" /></tables></p><p> Retention time The retention times for fluticasone propionate and impurities B, C and D are as follows.</p><p><tables num="9"><img file="JP6972255B2_D0018.tif" /></tables></p><p> Linearity The linearity of the new sample preparation was evaluated by spiked a blank vehicle sample with a known amount of fluticasone propionate dissolved in acetonitrile. 5.11 mg / ml fluticasone propionate 300 μl, 400 μl and 500 μl spikes were dissolved in 2 grams of vehicle and diluted to 10 ml in mobile phase (MP). The mobile phase was 50% methanol, 35% 0.01M ammonium phosphate with pH = 3.5, and 15% acetonitrile. The results are shown in Table 5 below. The unit of the x-axis is mg / ml of FP. A method is considered linear if the correlation coefficient or R2 value is greater than or equal to 0.999.</p><p><tables num="10"><img file="JP6972255B2_D0019.tif" /></tables></p><p> The same spike was also performed using the 100% mobile phase. The linearity of these samples is shown in Table 6 below. The x-axis in this case is mg / ml of fluticasone propionate.</p><p><tables num="11"><img file="JP6972255B2_D0020.tif" /></tables></p><p> Chromatograms of the above samples from samples of vehicles and diluents of the same concentration are superimposed and show the same peak shape and height for fluticasone propionate and impurities B, C and D.</p><p> Accuracy The accuracy was evaluated by injecting a 0.2 mg / ml sample prepared from the suspension sample 10 times. The results are provided in Table 7 below.</p><p><tables num="12"><img file="JP6972255B2_D0021.tif" /></tables></p><p> The relative standard deviation (RSD) of the target for assessing accuracy is 1.0%. All values were well within this range.</p><p> Accuracy The accuracy of the three levels of method in new sample preparation was assessed by spiked a known amount of fluticasone propionate into about 2 grams of vehicle and comparing the calculated values with actual results. Table 8 below shows the recovery rate using the calibration curve shown in Table 5.</p><p><tables num="13"><img file="JP6972255B2_D0022.tif" /></tables></p><p> The acceptance criteria for this case are spike recovery rates of 99% to 101%. In this case, there is a good correlation between the measured value and the calculated value.</p><p> LOD and LLOQ From the blank of this method, the noise is approximately 0.1 absorption units, which is the same for the LOD and LLOQ calculations in Part A of this report. LLOQ and LOD should be 10x and 3x of this height, respectively. Since the peak heights are very similar with and without the vehicle, LOD and LLOQ were prepared in the same concentration range as Part A of this report, but in this case spike enrichment was prepared in the mobile phase and the vehicle. Spikes into 2 grams and diluted to 10 ml in mobile phase relative to LOD and LLOQ concentrations. 2 × injection of sample, the average is shown below. The 511 ng / ml sample provided a reproducible area / height, 31.4 / 1.7 (LLOQ). For LOD, a sample of 153.3 ng / ml provided an area / height of 8.1 / 0.44. The heights of both LLOQ and LOD were approximately calculated based on the measured noise.</p><p> B. Determining the solubility of fluticasone propionate Table 9 shows the solubility of fluticasone propionate. The specific composition of Phase I depends on the solubility of the drug in this phase. Solubility of fluticasone propionate in FDA-approved solvents and excipients was determined by dissolving 10 mg of the drug in each solvent, vigorously vortexing and equilibrating at 25 ° C overnight. The suspension was centrifuged at 10000 rpm and the supernatant was analyzed by RP-HPLC at 239 nm. The solubility and compatibility of fluticasone propionate in each solvent was evaluated.</p><p><tables num="14"><img file="JP6972255B2_D0023.tif" /></tables></p><p> C. Preparation of nanocrystals by anti-solvent crystallization during sonication (1 step process) The process is as shown in Figure 3 and there is no purification step. For fluticasone propionate, the drug was dissolved in the following composition: fluticasone propionate (0.45%), Tween80 (7.44%), PEG400 (23%), polypropylene glycol 400 (69.11%). This composition was Phase I. The solubility of fluticasone propionate was maximized in each of these solvents. The composition of Phase I was reached using Table 9. The final composition (after adding Phase I to Phase II) contained 0.1% w / w drug and excipients at concentrations approved for ophthalmic use.</p><p> Both Phase I and Phase II were sterile filtered through a 0.22 micron PVDF filter and then mixed. In an experiment investigating the kinetics of drug binding to a filter of fluticasone propionate in Phase I, it was found that FP had little or no binding to a PVDF filter.</p><p> The sterilized Phase I was added dropwise to the sterilized continuous phase (Phase II solution) while sonicating. 4.3 g of Phase I was added dropwise to 15.76 g of Phase II. Sonication was performed on Sonic Rupture 400 (Omni International, Inc.). The sonication conditions were as follows: (a) Chip size (12.7 mm), temperature 2-4 ° C, output 10 W, duration: 1.5 minutes, batch size 20 ml. This was accomplished using a 50 ml beaker. The rate at which Phase I is added to Phase II determines the particle size of the crystals formed. In the 20 ml batch, the rate of adding Phase I to Phase II was 2.15 ml / min.</p><p> Since the constituents of Phase II act as a stabilizing phase for droplets when nanocrystals are formed, there are particularly subtle differences in the specific composition of this phase. The effectiveness of the stabilizer depends on the molecular weight and chemical structure of the stabilizing polymer, the adhesion of the stabilizer to the drug surface, and the ability to reduce the surface energy of the nanocrystals. In addition, the concentration of polymer in the continuous phase is believed to affect the particle size of the suspension. The function of the stabilizing phase is also to prevent droplet adhesion before nanoparticles form. For a preparation of fluticasone 0.1% propionate, the final composition of Phase II is 0.013% benzalkonium chloride. Chloride), 0.25% methyl cellol, and 99.7% water. For fluticasone propionate, the suspension obtained at the end of step 1 contains a regulated amount of excipient acceptable for FDA-approved ophthalmic agents. The 0.1% fluticasone propionate nanoparticle suspension contains 0.1% drug, 3.23% Tween80, 4.97% PEG400, 14.95% PPG400, 0.010% benzalkonium chloride, 0.38% methylcellulose, and a sufficient amount of purification. Contains water. The particle size range for this step is 400-800 nm. The pH was 5.8 and the molar osmotic concentration was 546 mOsm / Kg.</p><p> High osmotic solutions are acceptable for the treatment of blepharitis, but isotonic suspensions are always desirable as they are applied at the interface between the eyelids and the surface of the eye.</p><p> At a drug concentration of 0.06%, the vehicle composition is isotonic (316 mOsm / kg). At this drug concentration, the respective concentrations of excipient in the continuous phase are 2.57% Tween80, 2.99% PEG400, 8.97% PPG400, 0.010% benzalconium chloride, and purified water (sufficient amount). The pH of this solution is 6.5. NaOH may be added to adjust the pH to a neutral pH. It can then be diluted to reduce the concentration of fluticasone nanocrystals suspended in the vehicle. Table 10 shows the preparations of fluticasone propionate prepared at a concentration of 0.06% to 0.001%.</p><p><tables num="15"><img file="JP6972255B2_D0024.tif" /></tables></p><p> The solution meets ophthalmic criteria for pH, excipient composition, and molar osmolality. Formulations with concentrations above 0.06% have a molar osmolality value&gt; 350 mOsm / kg. One of the problems with this formulation is "Ostwald ripening", that is, the growth of particle size. In the presence of dissolved fluticasone propionate, particle size growth is observed. The excipient present in the formulation dissolves some of the drug in the continuous phase. This results in particle instability over long-term storage.</p><p> Effect of Phase II Polymer Composition on Initial Particle Size Phase II composition is extremely significant and unpredictable to those of skill in the art. The step of forming particles is a collaborative phenomenon between the dispersion and adhesion of droplets before precipitation. In addition, the properties of the drug need to be compatible with the properties of the particle stabilizing polymer.</p><p> As shown in Figure 5, the use of HPMC, PVA, PVP, Pluronic, and mixtures thereof produced particles with an average diameter greater than 1 micron. The combination of 2% tween20 and 0.5% CMC in water as the Phase II solvent appeared to produce smaller (0.4-0.6 micron) particles. These particles, however, grew to a size of 1.2 microns over time. The use of high viscosity polymers such as 0.5% xanthan gum produced very large (&gt; 20 micron) particles.</p><p> Phase III (Phase I + Phase II combination): In Phase II, the combination of 0.12% benzalkonium chloride / 0.25% methylcellulose (15cP) / water reproducibly produces the smallest particles (400-600nm, 15 batches) seemed to produce a composition. The combination of Phase I and Phase II results in Phase III, in which nanocrystals are formed during sonication.</p><p> This phase III composition was also chemically stable at 40 ° C for more than 4 weeks. This combination of polymers also maintains the particle size to its original size for 5-14 days.</p><p> b. Batch particle size obtained by top-down technology We compared particles produced by top-down technology such as microsolution, jet crushing, sonication (wet grinding), and homogenization. As shown in Figure 6, the batches produced by these techniques all produce fine particles larger than 2 microns. Some particles were 8 microns in size. The particles under the microscope were destroyed and looked like debris.</p><p> c. Effect of Phase II pH on initial particle size As shown in Figure 7, pH is thought to play a crucial role in initial particle size. Initial particle size was consistently high (1.0-1.3 microns) when Phase II was pH adjusted to pH 7-7.2 with 0.1% w / w phosphate buffer. When left unadjusted, the particle size was consistently between 500 and 800 nm. FIG. 7 shows the average particle size of the pH-balanced and pH-balanced batches produced. The pH disproportionate batch (n = 3) was 5.5 for 0.1% fluticasone propionate and 6.5 for 0.06% fluticasone propionate (n = 3). The effect of pH on particle size was unexpected and unpredictable to those of skill in the art.</p><p> d. Effect of the molecular weight of the sterically stabilized polymer in Phase II on the particle size The molecular weight of the sterically stabilized polymer in Phase II plays a crucial role in the particle size of the nanocrystals, as shown in FIG. For example, 4000 centipores hydroxypropylmethylcellulose (HPMC) consistently produces particles that are larger than those produced when using 45 cmpores HPMC.</p><p> e. Effect of pH on particle size stability The stability of nanocrystals is controlled by the pH of Phase III formed by the combination of Phase I and Phase II. 20 gram batches of nanocrystals were generated at pH 5.5 and placed on stability at 25 ° C. Another 20 gram batch was generated at pH 7.5 and stability was determined at 25 ° C for 30 days. Surprisingly, the 7.5 particles rapidly grew to an average particle size above 1 micron. See Figure 9. This phenomenon was verified for batches on a 50 gram scale.</p><p> f. Final Composition of Phase III Product (Phase I + Phase II) The composition of Phase III is 0.1% fluticasone propionate, 1.63% Tween80, 5% PEG400, 15% PPG400, 0.01%. Benzalconium chloride, 0.2% methylcellulose, and 77.95% water. The pH of this phase is 5.5.</p><p> g. Purification of fluticasone propionate nanocrystals The fluticasone propionate nanocrystals were purified by exchanging continuous phases by either tangential flow filtration or hollow fiber cartridge filtration. A high flow membrane is used for filtration. Filters such as PVDF and PES with a hole size of 0.22 microns or less are suitable for this purpose. A tangential flow device from Millipore (Pellicon XL 50 system) can be used for this purpose.</p><p> For a batch size of 250 g, nanocrystal suspension (Phase III) was poured into a 500 ml container at a pump speed of 3 at a pressure never exceeding 30 psi. After rinsing the nanosuspension to 10 ml, the cleaning solution was added. The cleaning solution was 0.1% tween80 and was delivered into a container at 30 ° C. The cleaning solution was changed twice to ensure that the buffer was completely replaced. The concentrate was then assayed for drug concentration. Based on the assay results, the volume of reconstruction was adjusted to achieve the desired concentration. In addition, methylcellulose, sodium chloride and phosphate were added to reach a weight molar osmolality composition.</p><p> As shown in FIG. 10, the purified fluticasone propionate nanocrystals showed no agglomeration over time.</p><p> (Example 2) Illustrative nanocrystal production process Processes for producing purified, stable, sterile nanocrystals of fluticasone propionate with a size range of 400-600 nm include: A sterilized Phase I solution of fluticazone propionate in PEG400, PPG400, and Tween80 under ultrasound at a flow rate of 1 to 1.4 ml / min, methylcellulose between 15cP and 45cP, benzalconium chloride, and An in-situ crystallization step, as well as a phase III, to produce a sterilized phase III suspension by mixing with a sterilized phase II solution containing purified water with a ratio of 0.2 to 1 and a pH of 5 to 6. The annealing step of maintaining the phase propionic acid fluticazone nanocrystals in a holding tank at a temperature in the range of 25-40 ° C for a duration of 30 minutes to 24 hours, as well as 0.1 ~ of propionic acid fluticazone nanocrystals. Washing with a sterile aqueous solution containing 0.5% Tween 80 by exchange filtration through a membrane with a pore size of 0.1-0.22 micron, a purification step, and concentration of fluticazone nanocrystals propionate to a range between 0.0001% and 10%. Concentration step, as well Additional excipients are added to the sterile form to meet FDA and drug production criteria for weight molar osmolality, pH, viscosity, biocompatibility and permeability that are considered suitable for specific products and clinical indications. , The final compounding step.</p><p> (Example 3) Nanocrystal production process-batch process The process described in this example was applied to generate FP crystals with a size range of 400 to 600 nm. Particle size optimization using this process is a function of phase I and phase II composition, sonication output energy, phase I flow velocity, and phase I and phase II temperature. The flow rate of Phase I for all batches (20-2000 g) was 1.43 ml / min.</p><p> Phase I composition: FP: 0.45% w / w; Tween80: 7.67% w / w; PEG400: 23.18% w / w, PPG400 (PPG = polypropylene glycol): 68.70% w / w. Phase II composition: benzalkonium chloride: 0.020% w / w, methylcellulose 15cp 0.40% w / w, water (enough to make 100%). Composition of Phase III dispersion: FP: 0.225% w / w, Tween80: 3.796% w / w, PEG400: 11.577% w / w, PPG400: 34.41% w / w, benzalkonium chloride 0.01%, methylcellulose (MC15cP) ): 0.2% w / w, enough to make 100% water. The volume ratio of Phase I to Phase II was 1: 1 in this batch process.</p><p> The temperature of each of Phase I and Phase II was 0 to 1 ° C (ice water slurry). The ultrasonic output energy was 25% with a 3/4 probe and Omni Cellruptor Sonicator. The pH of Phase II was 5.5. The higher the pH, the larger the particles. pH &lt;5. The particle size was between 150 and 220 nm, but it was also observed that the drug began to decompose at low pH.</p><p> As in Example 1, it was found that the size of the FP crystal was controlled by selecting the appropriate stabilizer and pH value for the phase II solution. See, for example, Figures 7 and 8.</p><p> Particle sizes in the 400-600 nm range were achieved at lower temperatures (Figure 11). The particles produced at room temperature were large, aggregated and showed flexible amorphous regions.</p><p> Fluticasone propionate crystals were prepared by ultrasonic crystallization, and then the dispersion (Phase III) was annealed at 25 ° C. The particles were equilibrated to a stable particle size after an annealing time of at least 8 hours (FIGS. 12 and 13). This annealing step surprisingly reduced the particle size. As shown in FIGS. 12 and 13, the equilibrated particle size leveled off at 8 hours and there is no statistical difference between the different annealing temperatures, ie 4 ° C, 25 ° C and 40 ° C. .. In addition, the annealing effect is consistent for FP at concentrations of 0.1% and 10%.</p><p> The crystals produced by the above process were purified by either tangential flow filtration or continuous centrifugation. Filtration conditions were developed using a laboratory-scale Pellicon XL50 filtration device. The purpose of this step was to purify the crystals produced in the previous step. 14 and 15 show that drug loss with a PVDF filter with a pore size of 0.1 micron was minimal. Purification by centrifugation was performed by exchanging the liquid with a 0.1% w / w solution.</p><p> The final composition of fluticasone propionate was 0.0001-10% w / w, methylcellulose 0.2% w / w (4000cP), benzalkonium chloride 0.01%, and water (sufficient amount). The final formulation is flexible in that additional excipients can be added to the formulation depending on the indication.</p><p> (Example 4) Dispersion of nanocrystals from batch process It was observed that the final composition or formulation of FP produced in Example 3 was still dispersed for more than at least 8 hours. In particular, 5 ml of nanosuspension was placed in a 10 ml glass screw capped vial, all of which contained 0.1% FP nanosuspension in the final composition. Each vial was shaken upside down 10 times to fully disperse the sample. After shaking, each vial was stored at 25 ° C and sampled over time for up to 24 hours.</p><p> Each sample was redistributed after 24 hours and sampled again (indicated by the blue arrows in FIGS. 16 and 17). Sample collection was performed by collecting 0.5 ml of the sample from the central part of the pharmaceutical product. Samples were analyzed by HPLC assay. As shown in FIGS. 16 and 17, the final product was still dispersed for at least 8 hours and was fully redispersed upon shaking. In addition, all FPs at 0.005% to 10% concentrations were sufficiently redispersed, and the redispersibility was reproducible over the batch scale (20 g to 2000 g). All concentrations were dispersed over 80% at RT in 24 hours. All concentrations were redistributed by shaking the vial, indicating a fluffy, robust suspension. It was concluded that the higher the concentration, the faster the rate of fixation.</p><p> (Example 5) Nanocrystal stability from batch process The final composition or formulation of FP was also observed to be stable over all concentrations tested, ie 0.005%, 0.01%, 0.1% and 10%. .. Samples were placed in stability chambers at 4 ° C, 25 ° C and 40 ° C. Time points for stability: T = 0d, T = 1 week, T = 2 weeks, T = 4 weeks.</p><p> Assays by HPLC showed 99-101% at 4 ° C, 25 ° C, and 106% at 40 ° C. There was no change in impurities B, C and D in the samples tested from T = 0d. The pH (6.5 to 6.8) of the pharmaceutical product tested did not change from T = 0d. Furthermore, the FP particle size (505 to 620 nm) did not change from T = 0d.</p><p> (Example 6) Uniformity of nanocrystal composition A new suspension formulation for fluticazone propionate (FP) containing sodium chloride, phosphate, methylcellulose, tween80, benzalconium chloride, and water is added to the top of the suspension solution. The content uniformity over time was tested by sampling the central and bottom parts. The purpose was to determine the length of time that the particles of the suspension were still equally dispersed in the solution after shaking.</p><p> Approximately 20 ml of 0.07% FP suspension was placed in a vial and shaken up and down 10 times to suspend the FP particles. 200 μl of top, center and bottom samples were taken at 0 hours, 0.5 hours, 1 hour, 3 hours, 6.5 hours and 23 hours. All samples were analyzed by HPLC using a calibration curve. Samples were taken directly into HPLC vials and diluted with 800 μl of diluent (75/25 acetonitrile / water). Weights of 200 μl of sample and 800 μl of diluent were recorded and used in the final calculation of the amount of FP in each sample.</p><p> The results showed that in the first 6.5 hours, there was little or no difference between the top, center and bottom samples. However, the 23-hour sample was macroscopically colonized and supported by HPLC results.</p><p> Based on the above dilutions, a 3-point calibration range was selected from 0.056 to 0.45 mg / ml. See Table 11 below. Three standard solutions of FP were prepared from stock standard 0.5787 mg / ml.</p><p><tables num="16"><img file="JP6972255B2_D0025.tif" /></tables></p><p> A calibration curve was prepared using the three known concentrations of stock solution described above and 200 ul of blank vehicle and corrected for any matrix effect that the vehicle could have against the standard.</p><p> The calculation for the concentration was based on the following formula: (stock weight) x (stock standard) / (total sample weight) The calibration curve is shown in Table 12 below. All standards are in mg of FP per gram of solution.</p><p><tables num="17"><img file="JP6972255B2_D0026.tif" /></tables></p><p> Using the calibration curve in Table 12, time point samples were analyzed using gradients and intercepts. Table 13 below shows the data obtained from sample analysis at time points.</p><p><tables num="18"><img file="JP6972255B2_D0027.tif" /></tables></p><p> The data are also graphed over a range of time points and are shown in FIG.</p><p> (Example 7) Nanocrystal production process-FLOW PROCESS Nanosuspension of fluticasone propionate with a particle size range of 400 to 600 nm was also prepared using the flow process scheme.</p><p> Fluticasone propionic acid nanosuspension was prepared using the flow reactor shown in FIG. Phase I and Phase II were weighed into the flow reactor as shown in the flow diagram in FIG.</p><p> The particle size of these nanosuspensions was measured with a Malvern Zetasizer S90. Both Phase I and Phase II solutions used to make the nanosuspension were continuously pumped into the flow system of the sonicator. Twenty-five batches of sample were prepared under various conditions. The effects of the flow velocities of both phases, the annealing temperature of Phase III, and the amplitude of the sonicator on particle size were analyzed. Most aspects of the "batch process variables" described in Examples 1 and 3 (eg, the temperature at which the two phases are mixed, the type and viscosity / molecular weight of the cellulose-based stabilizer in Phase II, the pH of Phase II, And the annealing temperature and time) were also true.</p><p> Materials and equipment (A) Raw components listed in Table 14 below (B) Malvern Nanosizer S90 (C) Flow reactor (D) Sonicator probe, size 25 mm. 1 (E) Pump I (NE-9000, New Era Pump Systems Inc.) (F) Pump II (Console Drive, Cole-Palmer) with probe extender.</p><p><tables num="19"><img file="JP6972255B2_D0028.tif" /></tables></p><p> Both Phase I and Phase II solutions were prepared in advance and then pumped into the flow system in a 1: 1 ratio. Details of the preparation and the composition of both phases are described below, taking a 500 g batch as an example.</p><p> Phase I preparation (500 g batch) 2.28 g of fluticasone propionate was added slowly into a solution of 38.34 g of tween80, 116 g of PEG400, and 344 g of PPG400. All components of the solution were vortexed and sonicated using a standard sonic bath until all solids were in solution.</p><p><tables num="20"><img file="JP6972255B2_D0029.tif" /></tables></p><p> Phase II preparation (500 g batch) 1 g of 10% benzalkonium chloride solution was added to a mixture of 299 g of water and 200 g of 1% methylcellulose (15cP). The mixture was vortexed. The composition of Phase II was as follows: benzalkonium chloride 0.020%, methylcellulose 15cp 0.4%, water 99.58%.</p><p> Phase I and Phase II mixing conditions (500g for each phase, Phase III total 1000g) The conditions for the mixing step are listed below: Phase I and Phase II mixture temperature: 0-5 ° C Sound wave tip size: 25 mm in diameter Sound wave amplitude: 25-75% (depending on specific experiment) Phase I flow velocity: 12-700 ml / min (depending on specific experiment) Phase II Flow rate: 12-700 ml / min Cooler temperature: 0--10 ° C Cooling air: 5 psi Experiment duration: 2-8 min Mixing procedure (500 g batch for each phase).</p><p> Phase II 250g was mounted in the sonicator. The cooling device (0 ~ -10 ° C) and cooling air (5psi) were then switched on. Phase I 500 g was added to a 1000 ml beaker in an ice / water mixing bath. The remaining 250 g of Phase II was added to another 1000 ml beaker in an ice / water mixing bath. The temperature of each phase was stabilized for at least 30 minutes. The flow rate of each two-phase pump was set to 12-700 ml / min. The sonicator was then switched on and the amplitude was adjusted. I turned on the pump. Once both phases were pumped, the ultrasound, pump and air generator were shut down.</p><p> Twenty-five batches of sample were prepared under various conditions. Most batches have a peak average particle size of less than 1 micron, except for three batches prepared at relatively high flow rates (eg 700 ml / min for each phase and 250 ml / min for each phase).</p><p> Effect of both phases on particle size Both phases were pumped at the same actual flow rate (Phase I: Phase II ratio was 1). In FIG. 20, the particle size (represented by the square dots in FIG. 20) was plotted against the final flow velocity in Phase III (represented by the vertical bar in FIG. 20). Three samples prepared at 200 ml / min have a minimum particle size of about 400-600 nm.</p><p> These experiments demonstrated that fluticasone nanocrystals of propionic acid can be prepared using the schematic diagram of the flow process shown in FIG. Microscopic examination demonstrated a planar-like morphology with respect to the crystal. Preliminary stability tests (4 week stability at 25 ° C and 40 ° C) on formulations prepared using the flow process demonstrated particle size stability and chemical integrity.</p><p> Overall, a trend was noted regarding the process variables that control particle size. Controlling the temperatures of Phase I and Phase II to &lt;2 ° C results in consistent and robust production of uniformly sized particles. Other variables were the output energy of sonication, as well as the phase I and phase II flow velocities. Flow velocity appeared to be a regulatory variable in producing a uniform range of particle sizes. With current sonicator probe designs, the highest flow rates to achieve particle sizes in the 400-600 nm range were approximately 200 ml / min / pump, or 400 ml / min for Phase III.</p><p> (Example 8) Further characterization of nanocrystals produced by batch process Nanocrystals of FP were prepared using a 1000 g batch process similar to that described in Example 1 or Example 3. The suspension was collected in solids by centrifugation and dried in a vacuum oven for 12 hours. Two additional batches (ie b and c) were prepared using the same process.</p><p> Uniformized FP particles were prepared using Polytron (Kinematica) with a velocity setting of 4 in the aqueous dispersion. The samples were washed using a centrifugation process and dried in a vacuum oven.</p><p> The fluticasone propionate stock solution received from the manufacturer was used.</p><p> Particle size evaluation The particle size of FP nanocrystals prepared by the batch process was measured by Malvern ZetaSizer S90. The particle sizes of batches (b) and (c) were measured by Malvern MasterSizer S. As shown in Figure 21, nanocrystals produced by the batch process produced narrowly distributed crystals within the size range of 400-600 nm, whereas FP stock materials and homogenized FP materials have a wide particle size distribution. (Fig. 21B and Fig. 21C, respectively).</p><p> Fluticasone propionate crystal suspension is highly stable Nanocrystals prepared by batch process are tested for stability to assess whether the particle size distribution is still in the narrow range of 400-600 nm. bottom. Nanoparticles, 0.1% w / v FP, 0.90% w / v sodium chloride, 0.51% w / v methylcellulose (MC4000cP), 0.10% w / v sodium phosphate, 0.20% w / v Tween80, Formulated in a final vehicle containing 0.01% w / v benzalconium chloride and 98.18% w / v water. The pharmaceuticals were placed in stability incubators at 25 ° C and 40 ° C.</p><p> Samples were measured for particle size, pH, molar osmolality and assay. All samples maintained pH, molar osmolality, particle size and assay [FP] at 25 ° C and 40 ° C for 75 days. Figure 22 shows the stability of particle size over 75 days even at 40 ° C.</p><p> This data shows that the fluticasone propionate prepared by the process of the present invention contains highly crystalline crystals and has a stable morphological microstructure evidenced by the absence of crystal growth (Ostwald ripening) over time. It suggests that it is included.</p><p> Saturation Solubility and Saturation Rate The saturation solubility of FP was measured by HPLC on the nanocrystals, homogenized FP, and FP stock materials produced by the batch process of the invention. Saturated solubility for all three materials was 40-45 μg / ml. In another test, the dissolution rates of nanocrystals (size range 400-600 nm) were compared to batches containing suspended and micronized fluticasone propionate in the size range 1-5 microns. The comparative dissolution rate is shown in FIG.</p><p> The purity of the fluticasone propionate nanocrystals was evaluated and compared to the purity of the FP stock material received from the manufacturer. Shown in FIG. 24A is a chromatogram of the fluticasone propionate drug substance (retention time: 13.388 minutes) and its known impurities (retention times 6.457 minutes and 9.720 minutes). Shown in FIG. 24B is a chromatogram of fluticasone propionate nanocrystals produced by the batch process. Compared to the stock drug substance, the fluticasone nanocrystals produced by the batch process were more pure and markedly absent of impurities at 6.457 and 9.720 minutes. Note that the scale for HPLC chromatograms for fluticasone propionate crystals produced by the batch process was 0-500 mAU, compared to 0-1200 mAU for stock materials. Therefore, it can be concluded that the nanocrystallization and purification process of the present invention produces purer nanocrystals of fluticasone propionate.</p><p> Morphology of FP Nanocrystals Shown in FIGS. 25A and 25B are light micrographs (Model: OMAX, 1600 ×) of dried fluticasone propionate crystals prepared by batch process and compared to FP in stock material. The appearance of FP crystals produced by the nanocrystallization process is clearly distinct from the stock material fluticasone propionate drug substance. As can be seen in FIG. 25A, the fluticasone propionate nanocrystals are rod-shaped and have well-defined directional shape dimensions. In contrast, fluticasone propionate stock material is not considered to support any particular shape or dimension.</p><p> The external appearance and morphology of the FP crystals prepared by the batch process was compared to the FP of the stock material. Scanning electron micrographs were collected at 10000 × magnification using a Hitachi SEM device. Experiments were performed at Microvision, Inc., Chelmsford, MA.</p><p> Visually, the difference between the crystals produced by the batch process and other samples is noticeable. Fluticasone propionate crystals prepared by the batch process were blade-like planes or rod-shaped with well-defined directional shape dimensions (FIGS. 26A and 26B). In contrast, the morphology of the fluticasone propionate stock crystals appeared round rather than planar, or had angled edges like the fluticasone propionate crystals produced by the batch process. (Fig. 27A).</p><p> FIG. 27B is a scanning electron micrograph of homogenized FP particles (top-down process). Visually, these particles look like stock materials.</p><p> Thermal Properties To measure the thermal properties of fluticasone propionate for each sample, approximately 10 mg from each sample was collected and placed in a clean alumina crucible. The table below outlines the test conditions and parameters for the simultaneous thermal analysis test. The samples were (a) fluticasone propionate nanocrystals and (b) fluticasone propionate stock material. Specimens were tested at a heating rate of 10 ° C / min, starting at 30 ° C and reaching a final temperature of 350 ° C. This process was repeated for each sample. Experiments were performed at EBATCO, LLC, Eden Prairie, MN.</p><p><tables num="21"><img file="JP6972255B2_D0030.tif" /></tables></p><p> The results of the thermal analysis test are shown for each sample in Table 16 below. The temperature at which the material softens, also known as the glass transition temperature, was significantly lower in the fluticasone propionate stock material than in the fluticasone propionate crystals produced by the batch process (57.6 ° C). In addition, the heat of fusion for the fluticazone propionate crystals produced by the new process is significantly higher (54.21J / g) than the FP stock material (48.44J / g), and the fluticazone propionate crystals produced by the new process It was pointed out that it is a more crystalline material and requires more energy to break intermolecular bonds such as ionic and hydrogen bonds.</p><p><tables num="22"><img file="JP6972255B2_D0031.tif" /></tables></p><p> FIG. 28A shows the DSC / TGA combination of fluticasone propionate crystals produced by the batch process. Compared to the thermal properties of the fluticasone propionate stock material (Fig. 28B), the initiation of melting of the FP nanocrystals was higher than the initiation of melting of the fluticasone propionate stock: initiation._Melting(FP nanocrystals from batch process) 299.5 ° C&gt; Start_Melting(FP, stock) 297.3 ° C. In addition, as evidenced by thermogravimetric analysis (TGA), the starting temperature_{Mass ejection}(FP nanocrystals from batch process) 299 ° C is the starting temperature_{Mass ejection}(FP, current situation) It was higher than 250 ° C. The data suggest that the fluticasone propionate crystals produced by the batch process have thermal behavior indicating that they are more crystalline and ordered material than the fluticasone propionate stock material.</p><p> Fluticazone propionate crystals prepared by the batch process are neither solvates nor hydrates In theory, when the solvent is trapped in the crystal structure, they are called "solvate compounds". When the specific solvent is water, the crystals are called "hydrates". Solvation compounds and hydrates in a particular crystalline form exhibit various properties such as dissolution, density and the like. Differential scanning calorimetry (DSC) can be used to detect the presence of trapped solvents that can be induced to deviate from the crystal lattice when heated. Crystals prepared using the batch process do not have additional melt transition (DSC) or polyphasic mass release (TGA) (Fig. 28A), the crystals are pure crystals, solvate compounds or water. It means that it is not Japanese. The fluticasone propionic acid stock material is neither a solvate nor a hydrate, but as expected, it has a crystalline structure (Fig. 28B).</p><p> Fluticasone propionate crystals produced by the batch process have a higher bulk tap density than the fluticasone propionate stock material. The tap density of the dried fluticasone propionate crystals prepared by the batch process is 0.5786 g / cm.³Met. In contrast, the tap density of fluticasone propionic acid stock is 0.3278 g / cm.³Met. The data suggest that the fluticasone propionate crystals produced by the batch process have a higher filling than the fluticasone stock propionate.</p><p> Fruticazone propionate crystals produced by the batch process are neither amorphous nor partially amorphous The fluticazone propionate crystals produced by the batch process are "cold crystallization", i.e. crystallization before melting or Note that it does not show an amorphous phase. The presence of a single, sharp melt transition at 299.5 ° C suggests that the material is free of amorphous or amorphic phases. The sharpness of the melt transition (melt range 10 ° C) also means a highly ordered microstructure. In contrast, the fluticasone propionate stock material melted over a slightly wider range (11.1 ° C).</p><p> Fluticasone propionate crystals and fluticasone propionate stock materials produced by the batch process were compared to each other for their infrared frequency of vibration (FTIR) using a Nicolet Fourier Transform Infrared Spectrophotometer. Since certain bonds and functional groups oscillate at known frequencies, FTIR is used to verify / verify the identity of known organics. The FTIR spectra of fluticasone propionate crystals produced by the batch process did not show the presence of any additional vibrational frequencies when compared to the known FITR spectra of fluticasone propionate (Fig. 30).</p><p> Fluticasone propionate vs. two known forms of fluticasone propionate crystal structure produced by the process of the present polymorphism 1 and 2 are the two previously published crystal forms of fluticasone propionate. For example, US Pat. No. 6,406,718B1 (Patent Document 1), and J. Cejka, B. Kratochvil, and A. Jegorov., 2005, "Crystal Structure of Fluticasone Propionate", Z. Kristallogr. NCS 220 (2005). See pages 143 to 144. From the published literature, polymorph 1 is the most stable and known form of fluticasone propionate in that it is the most abundant. Polymorph 1 is formed by free crystallization from moderately polar solvents (acetone, ethyl acetate, and dichlorimethane). Polymorph 2 crystallizes from a supercritical fluid and is only described in US Pat. No. 6,406,718B1, with no other published articles.</p><p> The crystal structure of polymorph 1 is provided by Cejka et al. And has the following unit cell features: C₂₅H₃₁F₃O₅S, monoclinic, P12₁1 (no.4), a = 7.6496 Å, b = 14.138 Å, c = 10.9833 Å.</p><p> The crystal structure of polymorph 2 is provided in US Pat. No. 6,406,718B1, and Kariuki et al., 1999, Chem.Commun., 16771678. The unit cell parameters are a = 23.2434 Å, b = 13.9783 Å, and c = 7.65 Å. The unit cell was described as orthorhombic. As noted by Kariuki et al., There was a marked similarity between the two crystal structures. For reference, the calculated XRPD powder patterns for polymorph 1 (red) and polymorph 2 (blue) are shown in Figure 31B.</p><p> A pattern of powder X-ray diffraction (XRPD) of both materials in the first set of tests to determine the crystal structure of the fluticazone nanocrystals of propionate prepared by the batch process and compare it to the crystal structure of the fluticazone stock material of propionate. Was collected by an X-ray diffractometer (Shimadzu XRD6000 diffractometer) operated at 40 KV and 30 mA. The sample was divided for analysis and finely ground. Samples were scanned in 2 theta 0.02 ° steps from 10 ° to 65 ° in 2 seconds per step. Diffracted X-rays were paralleled using a 0.05 ° light receiving slit and detected by a solid state scintillation detector. Peak intensity and resolution calibration was verified using solid quartz standard 640d. These tests were performed on XRD Laboratories, IL.</p><p> The XRPD patterns of both fluticasone propionate crystals and fluticasone propionate stock materials prepared by the batch process were compared to the XRPD patterns calculated from the published polymorph 1 and 2 crystal structures. Overlaying the XRPD pattern of fluticasone propionate stock and fluticasone polymorph 1 propionate pointed out that the FP stock material exists as the most abundant and stable polymorph, polymorph 1.</p><p> Overlaying XRPD patterns of FP crystals (an example of a "top-down" process) and FP stock materials by homogenization demonstrates a good "peak-to-peak" match between patterns and even between intensities. rice field. It can be concluded that the homogenized sample of fluticasone propionate is of the same polymorph as the fluticasone propionate stock (polymorph 1). In contrast, the XRPD pattern of fluticasone propionate crystals (batch process) is overlaid (black) on published polymorph 1 (red) and polymorph 2 (blue), as shown in Figure 31B. There was a clear difference in the diffraction pattern. Further experiments conducted at Triclinic Labs, Inc. determined the differences in the unit cell structure of the crystals produced by the batch process and the microstructure from the standard polymorph 1. The data suggest that the fluticasone propionate crystals produced by the new process had a newer and more distinct microstructure than the standard polymorph 1.</p><p> Unit lattice structure of fluticasone nanocrystals prepared by batch process All samples were prepared by filling the voids of the sample holder with powder and gently pressing the sample to provide a flat reference surface. All excess material was removed and returned to the original container. All measured datasets were preprocessed to remove background and evaluated by a common area of 100,000 counts over the normal measurement range. Indexing is the determination of the crystal unit cell using the measured diffraction peak positions. The peak position for the provided XRPD data file was first determined using Winplot R.</p><p> To model the difference in peak intensity between XRPD datasets (Batch process and FP of polymorph 1), a crystalline harmonic preferred orientation function is added to the description of the crystal structure and the FP. The (batch process) tested the hypothesis that it is a novel crystalline crystal habit. Using the harmonic term 8 in expansion, the permissible harmonic symmetry was 2 / m and "fiber". Adding the selective orientation function to the description of the crystal structure of the standard polymorph 1, the XRPD patterns of the standard polymorph 1 and the fluticasone propionate crystals produced by the batch process could be consistent. This proved that FP (batch process) is a crystal habit of a novel polymorph 1 crystal.</p><p> By definition, known polymorphic crystal habits have different microstructures, such as planes of orientation that can result in different shapes and appearances (Miller index), while having the same unit crystal lattice structure and type. In the case of fluticasone propionate produced by the batch process, the crystals had a different appearance than the stock material (FIG. 27) (shown by SEM in FIG. 26).</p><p> Differences between the miniaturization of FP crystals and the XRPD data collected for our batches were essentially different in diffraction peak intensity. Peaks with a non-zero Miller index of "1" showed a significant increase in strength against in-house materials. Rietveld modeling of our own material confirmed that the FP nanocrystals from the batch process were strongly aligned in the [001] (c-axis) in the diffractive powder sample in the crystallographic direction perpendicular to the sample surface. Was done. This suggests that well-defined crystal habits are produced by our own method of generation, and that habits are likely to be planar or cutlery-like in nature. Due to the consistent habit, the in-house material was filled differently in the XRPD sample holder, resulting in the observation of preferred orientation (PO). Stock materials, on the other hand, did not exhibit any significant selective orientation (PO).</p><p> The effective crystal structure derived from the in-house material further suggests a knife-like or planar-like habit in which the crystallographic ab plane lies almost parallel to the surface to which it is maximally exposed. Effective crystal structures can be used to investigate API functional groups exposed by the maximum crystal plane of the blade habit.</p><p> The unit cell structure of the fluticasone propionate crystal produced by the batch process is monoclinic, P21, a = 7.7116 Å, b = 14.170 Å, c = 11.306 Å, beta = 98.285, volume 1222.6. By comparison, the crystal structure of polymorph 1 is provided by Cejka et al. And has the following unit cell characteristics: C₂₅H₃₁F₃0₅S, monoclinic, P12₁1 (no.4), a = 7.6496 Å, b = 14.138 Å, c = 10.9833 Å.</p><p> Thus, fluticasone propionate (by batch process) is a novel crystal habit that occupies a unit cell type, similar to polymorph 1 which is the most stable and most abundant crystalline state ever published. Can be stated. Since the most stable polymorph has the highest melting point in theory, the novel crystal habit (fluticasone propionate by the process of the present invention) may be the most stable crystal structure of the drug substance ever invented. Can be estimated. As mentioned above, as shown in FIGS. 28A and 28B, the melting point of the new crystal was 299.5 ° C, whereas it was 297.3 ° C for the stock material (polymorph 1). In addition, the presence of novel crystal habits in the FP nanocrystals produced by the process of the present invention was reproducible.</p><p> MAUD can generate a "pole map" for a particular crystallographic orientation based on the selective orientation parameters derived during Rietveld modeling. For each selected crystallographic axis, the pole figure illustrates the angular distribution of that crystal axis around the surface of the reflective sample holder. In an ideal powder, all crystallographic axes are randomly oriented, resulting in a pole figure with uniform color. In single crystal samples, each crystallographic axis is oriented in a single direction. If the direction is perpendicular to the sample surface, the pole figure shows a single high intensity point in the center of the plot. Extreme point diagrams derived from XRPD data collected for FP nanocrystals by batch process showed a single high intensity central pole with respect to the crystallographic axis of [001]. This indicates a strong selective orientation in which the crystallographic c-axis is perpendicular to the surface of the powder sample. One possible propulsion force for this strong selective orientation occurs when the crystal habit is planar or cutlery. When filled in a reflective holder and pressed flat, the flat surface of the crystal tends to align parallel to the sample surface (like a few sheets of paper). This suggests that in FP nanocrystals from the batch process, the crystallographic c-axis is near vertical through the largest flat crystal plane. In contrast, the pole figure calculated for the FP stock material showed a general distribution of crystallographic orientations that was more characteristic of the associated randomly oriented samples.</p><p> (Example 9) Triamcinolone acetonide (TA) crystal manufacturing process-Batch process Triamcinolone acetonide is used to treat various skin conditions and reduce the discomfort of oral ulcers (mouth sores), in the form of nasal drops. It is a synthetic corticosteroid used as a popular drug in allergic and perennial allergic rhinitis. It is a more potent derivative of triamcinolone, about eight times more potent than prednisone. This IUPAC name is (4aS, 4bR, 5S, 6aS, 6bS, 9aR, 10aS, 10bS) -4b-fluoro-6b-glycoroyl-5-hydroxy-4a, 6a,8,8-tetramethyl-4a, 4b, 5 , 6,6a, 6b, 9a, 10,10a, 10b, 11,12-Dodecahydro-2H-Naft [2', 1': 4,5] Indeno [1,2-d] [1,3] Dioxol- 2-on, molecular formula C₂₄H₃₁FO₆, Molecular weight 434.5g mol^-1Is.</p><p> Solubility of Triamcinolone Acetonide Triamcinolone Acetonide (TA) used stock received from the manufacturer. The solubility of triamcinolone acetonide (TA) was measured in propylene glycol, polypropylene glycol, Tween20, Tween80, PEG400.</p><p> First, 5 mg of TA was added to 10 g of solvent and the mixture was vortexed for 5 minutes and sonicated in a water bath for 10 minutes. When the first amount was completely dissolved in the solvent (a clear solution of TA in the solvent), 1-5 mg of TA was added. This process was continued until saturated solubility was reached. The solvent with the highest solubility was selected for further development as Phase I.</p><p> To prepare Phase I, the solubility of TA was evaluated in various pure non-aqueous systems. TA is actually insoluble in water. The solubility of TA in propylene glycol, polypropylene glycol, PEG400, Tween20, and Tween80 was evaluated. First, 5 mg of TA was added to these solvents, the suspension was vortexed and sonicated in a 37 ° C water bath for 15 minutes. Once the API (ie TA) was dissolved, 1 mg of drug was added to the vial. This process was continued until preliminary estimates of the drug in all solvents were achieved. The solubility of TA in propylene glycol, polypropylene glycol, PEG400, Tween20, and Tween80 was 14, 8, 7, 5.5 and 4 mg / mL, respectively.</p><p> Preparation of TA Nanocrystals Phase I This is the phase in which the drug is dissolved. Phase I was prepared with the highest concentration API in the selected solvent. Propylene glycol was shown as a better solvent and was chosen for further development. Final composition of Phase I: TA: 1.4% w / w, PG (PG = propylene glycol). The batch size was 50 grams.</p><p> Phase II Phase II composition: benzalkonium chloride 0.0125% w / w, methylcellulose 15cp 0.257% w / w, water (appropriate amount up to 100%). Since TA decomposes at higher pH (eg, Ungphaiboon S et al., Am J Health Syst Pharm., March 1, 2005; Vol. 62 (5): pp. 485-91), add 0.1% citric acid. The pH of the solvent was lowered. The final pH of Phase II was 3.91. The batch size was 100 grams. Phase II was cooled to 0 ° C in an ice-water slurry.</p><p> Phase III production and annealing This procedure produces 150 grams of Phase III. The combination of Phase I and Phase II produces nanocrystals of API dispersed in the vehicle. This dispersion is Phase III.</p><p> Phase III was prepared by measuring 50 g of Phase I in 100 g of Phase II.</p><p> Phase I 50 grams was filled into a 60 ml syringe fitted with needle-mounted 6-inch long and 18-gauge needles. Phase II 100 g was poured into a 250 ml beaker and cooled to 0 ° C with an ice-water slurry. Sonic Ruptor Ultrasonic Homogenizer (Omni International) was set to an intensity of 20% and sonicated using a 3/4 inch diameter titanium probe. The flow rate of Phase I was maintained at 1.43 ml / min. Phase III was recovered in a 250 ml Pyrex beaker. The obtained Phase III was a milky white dispersion system. The dispersion was annealed at 25 ° C for 4 hours in a 250 ml beaker covered with parafilm. The composition of the phase III dispersion system: TA: 0.41% w / w, PG: 32.86% w / w, benzalconium chloride 0.01%, methyl cellulose (MC15cP): 0.2% w / w, water 66.93% w / w.</p><p> Purification The slurry was subsequently centrifuged at 10000 rpm and 4 ° C (3 ×). The following steps were performed: The slurry was divided into 6 25 ml, 50 ml polypropylene centrifuge tubes, respectively. 25 ml of "wash" solution was added to each tube. The wash solution contained 0.01 w / w% benzalconium chloride and 0.2% w / w Tween 80 in distilled water. Therefore, the dilution was 1: 1. Dilute the slurry with Thermo-Scientific IEC CL31R Centrifugation was performed at 4 ° C. and 10000 rpm for 90 minutes using Multi-Speed. After pelleting, the pellet was redistributed with a wash solution and filled to the mark of 50 ml. The dispersion was centrifuged as described above. After washing twice, the pellet was combined in two 1.5 ml centrifuge tubes and redistributed with approximately 1 ml wash solution. The dispersion was centrifuged again at 12000 RPM for 12 minutes using an Eppendorf centrifuge 5415D. The pellet was collected, combined in a 50 ml centrifuge tube and redistributed in 40 ml of wash solution. Dispersion was achieved by vortexing and then sonicating in a water bath for 15 minutes at room temperature. The dispersion was centrifuged at 10000 RPM for 10 minutes. The supernatant was decanted and the pellet was dried in a vacuum oven (VWR International, Oregon, USA) at room temperature for 72 hours.</p><p> (Example 10) The characterization particles of the TA crystals produced by the process of the process flow were sized after annealing with respect to the phase III dispersion system prepared in Example 9 above. A Malvern dynamic light scattering device (Model S90) was used to determine the size and size distribution of nanocrystals. To measure particle size, 40 microliters of suspension was pipetted into 2960 microliters of 0.1% benzalconium chloride (BKC). 5x10⁴~1×10⁶Count / s strength has been achieved. The particle size distribution of the pharmaceutical product was measured 3 times each. The average size of TA particles from Example 9 was in the size range of 300-400 nm (n = 3). See Figure 32.</p><p> Thermal Properties of TA Nanocrystals vs. TA Stock Materials The thermal properties of TA particles from Example 9 were investigated using Shimadzu DSC-60 and TGA-50.</p><p> Approximately 10 mg of sample was analyzed in an aluminum open pan at 10 ° C / min from room temperature to 320 ° C.^-1Heated at the scan rate of. Figure 33 shows a differential thermal measurement scan of the TA API. The peak of heat of fusion is 289.42 ° C, ΔH_mIt was 83.5J / g. By comparison, the peak heat of fusion for the nanocrystals produced by the process described in Example 9 is 275.78 ° C, ΔH._m= 108.45J / g (Fig. 34). The data suggest that TA nanocrystals are significantly more crystalline, as evidenced by the higher heat of fusion. In addition, nanocrystals have a large shift in melting point (compared to API), suggesting differences in internal crystal structure.</p><p> 35 and 36 are TGA scans of TA stock materials and TA nanocrystals, respectively. By comparison, it is clear that both of these materials have very similar weight loss profiles when heated, and it is pointed out that heating the material breaks the same molecular binding. However, as with the DSC profile, there are significant differences in the initiation of weight loss of each phase between materials, suggesting differences in crystal structure and morphology.</p><p> Morphology of TA nanocrystals vs. TA stock materials The morphology of TA nanocrystals created in Example 9 was investigated with a Spirit EDS / imaging system of the Amray 1000A upgraded with a scanning electron microscope (SEM) (PGT (Princeton Gamma Tech)). The sample was argon sputter coated with gold (approximately 200 Å) (Hummer V from Anatech). The sample was mounted on double-sided tape. Figures 37A and 37B are SEM images of TA stock materials at two different magnifications. 37C-E are SEM images of TA nanocrystals. As seen in the SEM images, the morphology of the nanocrystals prepared by the process of the present invention is significantly different from the morphology of the stock material from the manufacturer.</p><p> TA nanocrystals prepared by the process of the present invention are the only modifications made by adapting the measurement of triamcinolone acetonide, which maintains its purity and completeness, from Matysova et al. (2003), "Determination of methylparaben, propylparaben, triamcinolone". Was an increase in uptime to compensate for our longer columns used in the assay. Low concentrations of samples were run in an attempt to amplify peak-to-TA peaks for all contaminants (effect seen in fluticasone analysis). The resulting chromatogram was very clean, with TA peak elution at 28.9 minutes. The conditions were as follows: HPLC system: Agilent 1100 Chemstation software column: Phenomenex Luna; C18, pore size 5 μm, 100 Å, dimensions: 250 × 4.60 mm mobile phase: 40 / 60v / v acetonitrile and HPLC grade. Water injection volume: 20 μL Analysis time: 30 minutes Detection wavelength: 240 nm The HPLC traces of TA nanocrystals were compared to the HPLC traces of TA stock materials, demonstrating that the nanocrystals produced by the process of the invention do not decompose as a result of the process of the invention.</p><p> Crystal structure of triamcinolone acetonide vs. stock material triamcinolone acetonide produced by the process of the present invention Triamcinolone acetonide crystals (ie, Form B) prepared by the method of the present invention are demonstrated by the different XRPD patterns in FIG. As you can see, it has a different crystal habit from the stock material. In other words, the triamcinolone molecules are packed in the unit cell differently from those of the stock material. Like the fluticasone nanocrystals (form A), this new stereomorphic form of triamcinolone can have different physical properties compared to the stock material of triamcinolone.</p><p> (Example 11) Nanocrystal production process-Modified flow and purification process (a) Reproducibly produces nanocrystals with an average cumrant size of approximately 500 nm (± 200 nm), (b) Stability is chemical stability and The experiments were designed to produce stable crystals, as defined by physical stability, with good reproducibility, and (c) to produce process conditions that maintain crystal size with good reproducibility after purification with high centrifugal force.</p><p> Some modifications were made to the flow process described in Example 7. In particular, a mixing step was added between crystal formation and annealing. Other steps added include (a) dilution with "wash solution" between annealing and centrifugation steps, (b) redispersion of pellets in wash solution for further purification, (c) pellets. Includes recovery and redispersion of the pellet into the final pharmaceutical composition. This modified flow process can be used to produce 0.09% drug nanosuspensions at 3500 g / min to produce commercially relevant volumes of nanosuspensions. The flow reactor was fitted with sanitary equipment designed for high pressure steam sterilization. The steps specified in Figure 38 resulted in the final formation of highly pure drug crystals with a cumulant average size of 500 nm (± 200 nm).</p><p> The role of probe design For scale-up experiments aimed at increasing efficiency, standard 1 sonication probes with a single active tip at the bottom of the probe, and multiple sonication tips on the cane Performed with both "bump-stick" probes.</p><p> Standard probe experiments Various combinations of fluticasone propionate percent, flow rate, temperature and sonication amplitude were tested to determine these effects on the average crystal size. The percentage value of fluticasone propionate ranged from 0.224% to 0.229%. Phase I flow rates ranged from 0 to 825 mL / min. The flow rate of Phase II was 10 to 900 mL / min. Phase III flow rates ranged from 25 to 1400 mL / min. The range of the phase II / phase I flow velocity ratio was 1. The temperature was 0 to 22 ° C for Phase I, 0 to 22 ° C for Phase II, and 10 to 40 ° C for Phase III. The average temperature in Phase III ranged from 12.5 ° C to 40 ° C. The amplitude of sonication ranged from 25% to 75% output. The average size of the crystals obtained (eg, d50, i.e., median mass diameter) ranged from 0.413 μm to 7 μm.</p><p> The highest flow rates for Phase I and Phase II producing d50 sized particles at about 500 nm were 250 ml / min at all output energies (25% output, 75% output). Higher flow rates of 700 ml / min for Phase I and Phase II (Phase II / Phase I ratio = 1) resulted in large particle sizes of&gt; 7 μm.</p><p> Experiments with the powerhead probe have demonstrated that higher flow rates in Phase I and Phase II can be achieved, thus increasing the effectiveness of the flow process many times. When used with other parameter variables such as buffer selection, phase II pH, or sonication output energy, a particle size of d50 500 nm could be achieved. All other experiments described in this example were performed with a powerhead probe.</p><p> The role of buffer and pH in Phase II Phase II pH affected particle size. The pH of Phase II was about 8, and after mixing Phase I and Phase II, the pH was about 7. Ascorbic acid buffers and citrate buffers at pH 4 and pH 5 were investigated as buffers for Phase II. Particle size was measured using a Malvern S90. Malvern S90 measures particle size by dynamic light scattering (DLS). For needle-shaped crystals as their own fluticasone propionate crystals produced by this process, the most relevant value for particle size measured by DLS is the peak average or cumulant average. Therefore, all particle size values are reported as cumulant averages. An example is shown in Table 17.</p><p><tables num="23"><img file="JP6972255B2_D0032.tif" /></tables></p><p> Both 25 ° C and 40 ° C are suitable annealing temperatures. Further temperatures may also be suitable for annealing. The ascorbic acid buffer used in Phase II, pH 5, produced particles between 500 and 800 nm (d50). Citric acid buffers at pH 4 and pH 5 were investigated as buffering agents in Phase II in multiple flow reactor batches. Typical examples are shown in Tables 18-19.</p><p><tables num="24"><img file="JP6972255B2_D0033.tif" /></tables></p><p><tables num="25"><img file="JP6972255B2_D0034.tif" /></tables></p><p> Overall, both citrate and ascorbic acid buffers were appropriate, with no statistical differences. Since citric acid buffer is present in many pharmaceutical formulations, it was selected as the optimal buffer. A slight increase in impurities was shown in the nanosuspension prepared at pH 4 and annealed at 25 ° C, so pH 5 was selected as the optimum pH for Phase II. The nanosuspension prepared at pH 5 in Phase II showed no increase in impurities in the citrate buffer during annealing.</p><p> The role of sonication output energy The sonication output energy was investigated as a variable in the production of particle-sized nanocrystals with a cumulant average of 500 nm (± 200 nm). Horiba LA-950 Laser Diffraction / Scattering, which provides the statistical mean, median and mode of each batch analyzed to obtain detailed, statistically meaningful data for particle size. An equation particle size distribution measuring device (Laser Diffraction Particle Sizer) was used.</p><p> Table 21 is an example of a batch prepared with an output energy of 40% and a phase I: phase II ratio of 1: 4. The composition of Phase II was citrate buffer, 0.4% 15 cm poise methyl cellulose (MC), 0.005% benzalconium chloride, 0.1% PEG40 stearate, and distilled water at pH 5. The data shown in Tables 22-24 are representative of batches produced at 50%, 60% and 70% output energies, all other parameters being identical or as similar as possible. Therefore, the compositions of Phase I, Phase II and Phase III are the same, and the temperature of each phase and the annealing temperature in each batch are similar. The annealing temperature of the incubator ranges from 25 to 28 ° C and the relative humidity is 65% to 75%. The phase III flow rate for each batch was 3250 g / min (± 200 g / min). After forming the nanocrystals, each batch was mixed at room temperature with a 250 RPM Scilogix mixer. The batch size was approximately 3500 grams. The composition of Phase III of each batch is shown in Table 20.</p><p><tables num="26"><img file="JP6972255B2_D0035.tif" /></tables></p><p> Particle size data were provided for mean, median and mode. By definition, the mode of particle size means the maximum number of particles at that size, the median particle size means the number of particles in the "center" of the distribution, and the average particle size is. , The average of all sizes for the entire distribution. In a fully monomodal Gaussian distribution, the mean, median and mode are all similar. In a distorted distribution, these values vary widely. After at least 24 hours of annealing, the mean, median, and mode values are all in the 250 nm range.</p><p><tables num="27"><img file="JP6972255B2_D0036.tif" /></tables></p><p><tables num="28"><img file="JP6972255B2_D0037.tif" /></tables></p><p><tables num="29"><img file="JP6972255B2_D0038.tif" /></tables></p><p><tables num="30"><img file="JP6972255B2_D0039.tif" /></tables></p><p><tables num="31"><img file="JP6972255B2_D0040.tif" /></tables></p><p> Thus, the initial particle size (T = 0 value) produced by crystallization in the presence of sonication correlates almost directly with the output energy, i.e., the higher the output energy, the more statistically significant. The mode (the most frequently occurring size) is small.</p><p> Annealing allows the particles to settle into a lower energy state. The particles have high surface energy as the output energy increases, resulting in particle agglutination. This is demonstrated in Table 24, which describes the dynamics of the particle size of a batch produced at 70% output energy. At T = 0, the batch has an average particle size of 2.93 microns and a mode (most frequent value) of 0.3631 microns, with large particles distorting the average even though most particles are &lt;500 nm. It is pointed out that it was present in some distribution. At 25 ° C annealing T = 96 hours, the mean, median and mode were within 250 nm of each other, demonstrating that the large particles distorting the mean were agglomerates. Annealing the batch reduced the surface energy to an equilibrium ground state, thus de-aggregating the particles.</p><p> Particle size decreases with annealing Annealing has been shown to be a crucial part of the batch process, as shown in the previous data. Annealing the crystals produced by the continuous flow process has also proven to be an important part of the process, as discussed in the previous section.</p><p> The importance of annealing kinetics was also demonstrated above. In various experiments, the particle sizes of the batches annealed at 25 ° C, 40 ° C and 60 ° C appeared not to be significantly different from each other in terms of particle size. However, annealing has another purpose. Crystallization is "completed" by annealing, thus allowing the crystal to be "cured". From this point of view, the higher the temperature at which the particles are annealed without decomposition, the more crystalline the particles become.</p><p> Table 26 shows batches prepared at pH 5, Phase II buffered with ascorbic acid salt, annealed at two different temperatures. These batches were prepared with ascorbic acid buffer, pH 5, Phase I: Phase II: 1: 3, output energy 60%. Particle size was measured by Malvern S90. Particles in the same batch annealed at two different temperatures show different average peak sizes as measured by this device. However, both sets show a reduction in particle size with annealing.</p><p><tables num="32"><img file="JP6972255B2_D0041.tif" /></tables></p><p><tables num="33"><img file="JP6972255B2_D0042.tif" /></tables></p><p> The role of mixing head design Mixing head design is important for mixing nanosuspension immediately after crystallization in a flow reactor. The mixing head was tested in multiple experiments. Silverson mixing head was evaluated. Medium and low shear mixing heads (coaxial and paddle) provided the best particle size. A paddle mixer was selected as the optimum mixing head for all batches.</p><p> Role of benzalconium chloride Benzalconium chloride is required to produce particles with a statistical mode of about 500 nm.</p><p> Table 28 is representative of batches prepared in Phase II without benzalconium chloride. The mean, median and mode variances were within 250 nm. The mode was 1.07 micron. Since particle sizes of about 1 micron and above were obtained for all batches produced without benzalconium chloride, the statistical mode was to produce particles with a size of about 500 nm. The presence of benzalconium chloride in Phase II appears to be necessary. The batches shown in Table 28, Table 29, Table 30A and Table 30B were analyzed by the Horiba LA-950 laser diffraction / scattering particle size distribution measuring device.</p><p><tables num="34"><img file="JP6972255B2_D0043.tif" /></tables></p><p> Table 29 is a representative batch prepared with 20 ppm (0.002%) benzalkonium chloride in Phase II. Phase II was also buffered with citrate, pH 5. The flow velocity in Phase III was 3250 ± 200 nm. The batch was a 1: 4 ratio batch. Therefore, the BAK concentration in Phase III was 16 ppm. This batch meets the T = 0 particle size standard with a statistical mode &lt;500 nm (± 200 nm).</p><p><tables num="35"><img file="JP6972255B2_D0044.tif" /></tables></p><p> Tables 30A and 30B are representative batches prepared with 50 ppm (0.005%) benzalconium chloride in Phase II. Phase II was also buffered with citrate, pH 5. The flow velocity in Phase III was 3250 ± 200 nm. The batch was a 1: 4 ratio batch. Therefore, the BAK concentration in Phase III was 40 ppm. The batch meets the T = 0 particle size standard with a statistical mode &lt;500 nm (± 200 nm). These batches also contained PEG40-stearate as a stabilizing molecule.</p><p><tables num="36"><img file="JP6972255B2_D0045.tif" /></tables></p><p><tables num="37"><img file="JP6972255B2_D0046.tif" /></tables></p><p> Role of PEG40-Stearate 0.01% PEG40-Stearate was used as the only stabilizer in citrate buffer phase II, 1: 3 phase I / phase II ratio, 60% AMP. This data was analyzed by Malvern S90. The particle sizes shown are cumulant averages. As shown in Table 31, the standard of particle size satisfying the cumulant average of 500 nm was satisfied. The level of PEG40-stearate varies depending on whether a benzalconium chloride-free batch is prepared.</p><p><tables num="38"><img file="JP6972255B2_D0047.tif" /></tables></p><p> We demonstrated continuous flow centrifugation as a preferred means of purifying fluticasone nanocrystals of propionic acid purified by continuous flow centrifugation. By purification, the continuous phase of Phase III was removed by centrifugation. The pellet is redistributed as a concentrate in the wash solution and the dispersion is centrifuged again. Continuous centrifugation can be performed with a Sorvall centrifuge, or Beckman Coulter's JI-30 can be used with the JCF-Z rotor.</p><p> Overall, the nanosuspension was annealed overnight and then the batch was diluted 1: 1 with 0.1% PEG40-stearate, 0.1% Tween80, and 50 ppm benzalkonium chloride. Dilution of the nanosuspension can reduce the viscosity of Phase III and facilitate centrifugation.</p><p> The Beckman centrifuge was cooled to 4 ° C and the suspension was centrifuged at 39000 G, 1.6 L / min. The supernatant was clear and appeared to be particle-free. The particle size distribution is shown in Table 32. This batch was prepared without benzalconium chloride. Therefore, the particle size is larger than the usual 500 nm statistical mode. Surprisingly, after purification, the mode shifts to &lt;500 nm. This indicates that the aggregated particles are decomposed by centrifugation. This is a way to eliminate large particles.</p><p><tables num="39"><img file="JP6972255B2_D0048.tif" /></tables></p><p> Flow process variables that play a role in particle size are for Phase I and Phase II temperatures, Phase II pH, Phase II composition, output energy, probe design, flow velocity, and Phase II Phase I. Ratio, annealing temperature, mixing conditions after particle formation, and composition of wash solution before purification. These results demonstrate, for the first time, that the flow process of production produces a commercial volume of fluticasone nanosuspension crystals of propionate, which can be purified using high flow continuous centrifugation. ..</p><p> (Example 12) Formulation and evaluation of FP nanocrystals Fluticasone nanocrystals with propionic acid have various FP contents (eg, 0.25% ± 0.0375% (0.21 to 0.29%), 0.1% ± 0.015% (0.085 to 0.115%), and A preparation containing 0.05% ± 0.0075% (0.043 to 0.058%)) was prepared and evaluated. The following parameters of each formulation were evaluated: formulation spread over the skin (preferably with minimal contact angle), chemical compatibility with FP (of other ingredients), dosage uniformity and redispersion. Sex, particle stability (preferably the particle size does not change), and droplet size (a function of viscosity and intermolecular surface tension that maximizes the preferred droplet size).</p><p> Tables 33 and 34 below list the components of two different pharmaceutical formulations (each containing 0.25% FP) prepared for use in treating blepharitis and the like.</p><p><tables num="40"><img file="JP6972255B2_D0049.tif" /></tables></p><p><tables num="41"><img file="JP6972255B2_D0050.tif" /></tables></p><p> The components of the product I are listed in Table 33 above, and the product I was evaluated and had the following properties: viscosity = 45 + 4.1cP; pH = 6.8 ~ 7.2; weight molar osmotic concentration = 290 ~ 305 mOsm / kg; particle size: statistical mode: 400 nm, median: 514 nm, average value: 700 nm, d50: 400 nm, d90: 1.4 μm; and droplet size = 40 ± 2 μL. In addition, Formula I is redispersible upon shaking, exhibits a uniform dose for at least 1 hour after shaking, and the particle size is stable at temperatures between 25 ° C and 40 ° C for at least 21 days. rice field.</p><p> The components of the product II are listed in Table 34 above, and the product II was evaluated and had the following properties: Viscosity = 46 ± 3.2 cP; pH = 6.8 to 7.2; / kg; Particle size: Statistical mode: 410 nm, median: 520 nm, mean: 700 nm, d50: 520 nm, d90: 1.4 μm; and droplet size = 40 ± 2.3 μL. In addition, Pharmaceutical II is redispersible upon shaking, shows a uniform dose for at least 1 hour after shaking, and the particle size is stable at temperatures between 25 ° C and 40 ° C for at least 18 days. rice field.</p><p> The average drop size of other formulations with different FP contents (ie about 0.25%, 0.1%, 0.05% and 0%) is tested and summarized in Table 35 below. The test was performed using a 7 mL drop tip eye drop bottle filled with 5 mL and with the drop tip pointing vertically downwards. The amount of FP per drop was determined by HPLC.</p><p><tables num="42"><img file="JP6972255B2_D0051.tif" /></tables></p><p> As shown in Table 35 above, the size of the droplets was constant across all the formulations tested.</p><p> To test the drug delivery efficiency of various coaters, the 0.25% FP formulation I mentioned above is equipped with various coaters such as swabs and brushes (eg Foamec-1 swab, polyurethane swab, polyester swab). , 25-3318-U Swab, 25-3318-H Swab, 25-3317-U Swab, 25-803 2PD Swab, 25-806 1-PAR Swab, Cotton Swab, and Latisse® Brush), then Each applicator equipped with FP was smashed against the polypropylene membrane to determine the amount of FP transferred onto the membrane.</p><p> More specifically, for each applicator, two drops of the pharmaceutical product I were mounted on the applicator, and then the applicator was banged twice on the polypropylene membrane. The FP transferred onto the membrane was then extracted with the mobile phase used for HPLC analysis to determine the amount of FP transferred onto the membrane. The same measurement was repeated 3-8 times for each type of applicator. It was observed that the Latisse® brush demonstrated better drug delivery to the polypropylene membrane than other applicators (ie, transferred about 56% FP on average). The second ranked was the 25-3317-U swab (ie, about 34% of FP was transferred on average). The average percentage of FP delivered to the polypropylene membrane by each of the other applicators tested is listed in Table 36 below.</p><p><tables num="43"><img file="JP6972255B2_D0052.tif" /></tables></p><p> It was also observed that the polyester swab and the cotton swab quickly absorbed the droplets of the pharmaceutical product, and when the membrane was smashed, the FP hardly transferred. Polyurethane swabs, on the other hand, "beaded" the droplets, and the droplets fell. The Latisse® brush took 2 seconds to absorb the first droplet and the 25-3317-U swab took 1.3 seconds to absorb the first droplet. In terms of ease of use, the Latisse® brush is easier to use than the other applicators tested.</p><p> Equivalents One of ordinary skill in the art will be able to recognize or confirm many equivalents for a particular embodiment of the invention described herein using only routine experiments. Although specific embodiments of the present invention have been discussed, the above specification is descriptive and not limiting. Many variations of the invention will be apparent to those of skill in the art upon review of the specification. The complete scope of the invention should be determined by reference to the claims, along with the full scope of the equivalent, and the specification with such modifications. Such equivalents are to be incorporated by the following claims.</p>