Large, porous particles produced by controlling humidity during a spray draying process

ES 2 318 007 T3

DESCRIPTION

Large porous particles produced by controlling humidity during a spray drying process.

Foundation of the invention

A number of techniques and mechanisms are commonly available to deliver drugs to the respiratory system. Among them, metered dose inhalers (MDI) or dry powder inhalers (DPI) can be used to deliver drug formulations in solid powder form. Several properties of the powder have been identified that improve delivery to the pulmonary system. For example, it has been found that particles having a vibrated dust density of less than 0.4 g / cm³ and an aerodynamic diameter that is between about 1 and 3 microns, they are well suited for delivery to alveoli or distal pulmonary areas. If delivery to the central or upper airways is desired, particles having larger aerodynamic diameters are preferred, ranging for example from about 3 to about 5 microns. Furthermore, particles having a geometric diameter greater than about 5 microns are believed to more successfully prevent phagocytic involvement by alveolar macrophages and clearance of the lungs.

WO 01/00312 and WO 01/23821 describe procedures comprising:

a) controlling the moisture content of a drying gas;

b) atomizing a liquid feed to form liquid droplets; Y

c) contacting the liquid droplets with the drying gas, thereby drying the liquid droplets to form spray dry particles.

WO 01/013892 describes a method for making particles suitable for inhalation using spray drying a solution in a gas that is hot.

Methods for producing particles having desired characteristics that can be adapted and optimized for delivery to selective sites in the pulmonary system, and in particular to the distal areas of the lung, continue to be needed.

Summary of the invention

The invention generally relates to producing spray-dried particles having certain properties or characteristics. Properties discussed in this document include vibrated powder density, volume median geometric diameter (VMGD), and mass median aerodynamic diameter (MMAD). The relationships between these properties are discussed further below. Particles having a low MMAD, coupled with a large VMGD, are preferred for particle delivery in alveoli or distal pulmonary areas.

In one embodiment, the invention relates to a method of producing dry spray particles having targeted aerodynamic properties, eg, vibrated powder density and / or aerodynamic diameter. The method includes atomizing a liquid feed and controlling the moisture content of a drying gas to a selected level to form particles having the directed aerodynamic diameter or the directed vibrated powder density.

In another embodiment, the invention relates to a method of producing particles that includes atomizing a liquid feed to produce liquid droplets and contacting the liquid droplets with a drying gas having a dew point between 0 ° C h - 40 ° C, thus producing the particles. In a preferred embodiment, the particles have a vibrated powder density of less than about 0.4 g / cm³. In another preferred embodiment, the particles have a VMGD greater than about 5 microns (microns or pin) and a MMAD between 1 pm and 5 pm.

In other embodiments, the invention relates to methods of forming particles having one or more targeted or desired properties, eg, a targeted or desired vibrated powder density, VMGD and / or MMAD. The methods include atomizing a liquid feed to produce liquid droplets and contacting the liquid droplets with a drying gas having a dew point that corresponds to forming particles having the directed property (s). In preferred embodiments, the values ​​for the vibrated powder density, VMGD and / or MMAD for a particular powder formulation, are measured as a function of the dew points of the drying gas. From this correlation, a dew point that corresponds to a desired or targeted value of the vibrated powder density, VMGD and / or MMAD, is then selected for the particular formulation.

The invention is advantageous in the production of particles having specific characteristics. For example, in inhalation applications, the particles can be tailored to enhance delivery to a specific site in the pulmonary system. The spray-dried particles produced by the methods of the invention have improved aerosolization and aerodynamic properties, lowered particle agglomeration, and improved powder flowability. The particles are well adapted for use in powder inhaler mechanisms and show less deposition in the mouth, throat and inhaler mechanism.

ES 2 318 007 T3

The methods of the invention are simple, inexpensive and reproducible. By practicing the invention, production can be optimized by forming particles that have desired properties. Process steps and waste materials can be reduced and the throughput of manufacturing particles having specific characteristics can be maximized.

Other advantages of the invention include quick drying and ease of production.

Brief description of the drawings

Figure 1 is a schematic diagram of one embodiment of the apparatus that can be used to carry out the invention.

Figure 2 is a curve showing the correlation between process gas dew point and vibrated powder density of spray dry particles including DPPC (60% by weight), lactose (20% by weight) and albumin ( 20% by weight).

Figure 3 is a curve showing the correlation between mass median aerodynamic diameter (MMAD) and process gas dew point for spray dry particles including DPPC (60% by weight), lactose (20% by weight ) and albumin (20% by weight).

Figure 4 is a curve showing MMAD as a function of dew point for a formulation of estradiol (90% by weight) and DPPC (10% by weight).

Detailed description of the invention

The features and other details of the invention, either as steps of the invention or as a combination of parts of the invention, will now be described more particularly with reference to the accompanying drawing and will be pointed out in the claims. The drawing is not necessarily to scale, an emphasis instead on illustrating the principles of the invention. The same number present in different figures represents the same point or an equivalent point. It will be understood that particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The main feature of this invention can be employed in various embodiments without departing from the scope of the invention.

Shown in Figure 1 is apparatus 10, including spray dryer 12. Spray dryer 12 preferably employs a centrifugal atomization mechanism that includes a rotating disk or wheel to break the liquid feed into droplets. The rotating disk typically operates within the range of 10,000 to 55,000 rotations per minute (rpm). Alternatively, hydraulic pressure nozzle atomization, pneumatic two-fluid atomization, sonic atomization, and other atomization techniques, as are known in the art, may also be employed. In a preferred embodiment, a spray dryer 12 on a Mobile Minor, Model EX manufactured by Niro, Columbia, MD. Other commercially available spray dryers from suppliers such as Niro, APV Systems, Denmark (for example, the APV Anhydro model) and Swenson, Harvey, IL, may also be employed, as may augmented spray dryers suitable for industrial capacity production lines. . Commercially available spray dryers generally have water evaporation capacities ranging from 1 to 120 kg / hr. For example, a Niro Mobile Minor ™ spray dryer has a water evaporation capacity of approximately 7 kg / hr.

The apparatus 10 further includes a supply container 14 that contains the liquid feed. The liquid feed can be supplied to container 14 or can be prepared on-site, from its components. A batch or continuous mode of producing liquid feed may be employed, as is known in the art. Apparatus 10 may be provided with additional supply containers, not shown in Figure 1.

From supply container 14, liquid feed is directed to spray dryer 12, for example by means of liquid pump 16. The flow rate at which feed liquid is being fed to spray dryer 12 can be controlled and / or or be monitored by flowmeter 18. In one embodiment, the liquid feed is directed to spray dryer 12 at a flow rate ranging from about 10 millimeters (ml) / min to about 120 ml / min and preferably at a flow rate ranging from about 40 ml / min to about 100 ml / min. Other feed rates can be employed, as is known in the art. For example, in larger models of spray dryers, liquid feed is directed to spray dryer 12 at a flow rate ranging from about 5 to about 10 liters / min.

The liquid feed includes a solvent that can be aqueous, organic, or an aqueous-organic cosolvent. Aqueous solvents include, for example, water and buffered solutions. Examples of organic solvents include, but are not limited to, alcohols such as, for example, ethanol, methanol, propanol, isopropanol, and butanotes. Other organic solvents include but are not limited to perfluorocarbons, dichloromethanes, chloroform, ether, ethyl acetate, methyl tert-butyl ether, and others. In a preferred embodiment, the organic solvent is ethanol. If a co-solvent is used, the amount of organic solvent may be present in the co-solvent in an amount ranging from 10 to 90% by volume. In a preferred embodiment, the organic solvent is present in the co-solvent in an amount ranging from 30 to 85% by volume.

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Liquid feed can have a neutral, acidic or alkaline pH. Optionally, a pH buffer can be added to the solvent or cosolvent or to the formed mixture. Preferably, the pH can range from 3 to 10.

In one embodiment of the invention, the liquid feed also includes a biologically active (bioactive) compound, eg, a therapeutic, prophylactic, or diagnostic agent. Bioactive compounds or agents are also referred to herein as drugs or medicaments. The amount of bioactive agent present in the liquid feed generally ranges from 0.1% by weight to 100% by weight, preferably from 1.0% by weight to 100% by weight.

Examples of biologically active agents include synthetic organic and inorganic compounds, proteins, peptides, polypeptides, DNA and RNA nucleic acid sequences that have therapeutic, prophylactic or diagnostic activities. Nucleic acid sequences include genes, antisense molecules that bind to complementary DNA or RNA and inhibit transcription, and ribozymes. The agents to be incorporated can have a variety of biological activities, such as vasoactive agents, neuroactive agents, hormones, anticoagulants, immunomodulatory agents, cytotoxic agents, prophylactic agents, antibiotics, antivirals, antisense, antigens, and antibiotics. Compounds with a wide range of molecular weight can be used, for example between 100 and 500,000 grams or more per mole.

The liquid diet may include a therapeutic agent for local delivery within the lung, such as agents for the treatment of asthma, chronic obstructive pulmonary disease (COPD), emphysema, or cystic fibrosis, or for systemic treatment. For example, genes for the treatment of diseases such as cystic fibrosis can be administered, as can beta-agonist steroids, anticholinergics and leukotriene modifiers for asthma. Other specific therapeutic agents include, but are not limited to, human growth hormone, insulin, calcitonin, gonadotropin releasing hormone, luteinizing hormone releasing hormone (LHRH), granulocyte colony stimulating factor ("G -CSF ”), parathyroid hormone and PTH-related peptide, somatostatin, testosterone, progesterone, estradiol, nicotine, fentanyl, norestisterone, clonidine, scopolamine, salicylate, cromolyn sodium, salmeterol, formeterol, albuterol, epinephrine, L-dopa, and diazepam, as well as medications that primarily target the central nervous system, kidneys, heart, and other organs.

Diagnostic agents include, but are not limited to, imaging agents including commercially available agents used in positron emission tomography (PET), computer assisted tomography (CAT), single photon emission computed tomography, X-ray, fluoroscopy, and magnetic resonance imaging (MRI).

Examples of suitable materials for use as contrast agents in MRI include, but are not limited to, the commonly available gadolinium chelates, such as diethylene-triamine-pentacetic acid (DTPA) and dimeglumine gadopentotate, in addition to iron, magnesium, manganese. , copper and chromium.

Examples of useful materials for CAT and X-rays include iodine-based materials for intravenous administration, such as ionic monomers typified by diatrizoate and iotalamate, non-ionic monomers such as iopamidol, isohexol, and ioversol, non-ionic dimers, such as iotrol and iodixanol, and ionic dimers, eg ioxagalt.

The liquid feed may include additional component (s). In a preferred embodiment, the liquid feed includes one or more phospholipids, such as, for example, a phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, or a combination thereof. In one embodiment, the phospholipids are endogenous to the lung. Specific examples of phospholipids are shown in Table 1. Combinations of phospholipids can also be employed.

(Table goes to next page)

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TABLE 1

<td>Dilaurylolyphosphatidylcholine (C12; 0)</td><td>DLPC</td>

<td>Dimyristoylphosphatidylcholine (C14; 0)</td><td>DMPC</td>

<td>Dipalmitoylphosphatidylcholine (C16: 0)</td><td>DPPC</td>

<td>Distearoylphosphatidylcholine (C18: 0)</td><td>DSPC</td>

<td>Dioleoylphosphatidylcholine (C18: 1)</td><td>DOPC</td>

<td>Dilaurylolylphosphatidylglycerol</td><td>DLPG</td>

<td>Dimyristoylphosphatidylglycerol</td><td>DMPG</td>

<td>Dipalmitoylphosphatidylglycerol</td><td>DPPG</td>

<td>Distearoylphosphatidylglycerol</td><td>DSPG</td>

<td>Dioleoylphosphatidylglycerol</td><td>DOPG</td>

<td>Dimyristoylphosphatidic acid</td><td>DMPA</td>

<td>Dimyristoylphosphatidic acid</td><td>DMPA</td>

<td>Dipalmitoylphosphatidic acid</td><td>DPPA</td>

<td>Dipalmitoylphosphatidic acid</td><td>DPPA</td>

<td>Dimyristoyl-phosphatidylethanolamine</td><td>DMPE</td>

<td>Dipalmitoyl-phosphatidylethanolamine</td><td>DPPE</td>

<td>Dimyristoylphosphatidylserine</td><td>DMPS</td>

<td>Dipalimitoylphosphatidylserine</td><td>DPPS</td>

<td>Dipalmitoyl-sphingomyelin</td><td>DPSP</td>

<td>Distearoyl-sphingomyelin</td><td>DSSP</td>

Charged phospholipids can also be used. Examples of charged phospholipids are described in US Patent Application entitled "Particles for Inhalation Having Sustained Release Properties" 09 / 752,106, filed December 29, 2000, and US Patent Application Serial No. 09 / 752,109 entitled "Particles for Inhalation Having Sustained Release Properties," filed December 29, 2000.

Phospholipids can be present in the liquid feed in an amount ranging from 5 percent by weight (%) to about 95% by weight. Preferably, it may be present in the particles in an amount ranging from 20% by weight to 80% by weight.

The phospholipids or combinations thereof can be selected to impart controlled release properties to the spray dried particles produced by the methods of the invention. Particles having controlled release properties and methods for modulating the release of a biologically active agent are described in US Provisional Patent Application no. 60 / 150,742 entitled "Modulation of Release From Dry Powder Formulations by Controlling Matrix Transition", filed August 25, 1999, and US Non-Provisional Patent Application 09 / 644,736, filed August 23, 2000, with the title "Modulation of Release From Dry Powder Formulations".

In another embodiment of the invention, the liquid feed includes a surfactant. As used herein, the term "surfactant" refers to any agent that preferentially absorbs an interface between two immiscible phases, such as the interface between water and an organic polymer solution, a water / air interface, or a solvent interface. organic / air. Surfactants generally possess a hydrophilic moiety and a lipophilic moiety, so that by absorbing the microparticles, they tend to present residues to the external environment that do not attract similarly coated particles, thus reducing particle agglomeration. Surfactants can also promote the absorption of a therapeutic or diagnostic agent and increase the bioavailability of the agent.

In addition to lung surfactants, such as, for example, the phospholipids discussed above, suitable surfactants include but are not limited to hexadecanol; fatty alcohols such as polyethylene glycol (PEG);

ES 2 318 007 T3 polyoxyethylene-9-lauryl ether, a surface active fatty acid, such as palmitic acid or oleic acid; glycocholate; surfactin; a poloxamer; a fatty acid ester of sorbitan such as sorbitan trioleate (Span 85), Tween 80 (Polyoxyethylene sorbitan Monooleate); and tyloxapol.

The surfactant can be present in the liquid feed in an amount ranging from 0.01% by weight to 5% by weight. Preferably, it may be present in the particles in an amount ranging from 0.1% by weight to 1.0% by weight.

Methods for preparing and administering particles that include surfactants, and in particular phospholipids, are described in US Patent No. 5,855,913, filed January 5, 1999 to Hanes et al and in US Patent No. 5,985,309 filed November 16, 1999 to Edwards et al.

In another embodiment of the invention, the liquid feed includes an amino acid. Hydrophobic amino acids are preferred. Suitable amino acids include hydrophobic amino acids that occur naturally or unnaturally.

Examples of amino acids that may be employed include, but are not limited to: glycine, proline, alanine, cysteine, methionine, valine, leucine, tyrosine, isoleucine, phenylalanine, tryptophan. Preferred hydrophobic amino acids include, but are not limited to, leucine, isoleucine, alanine, valine, phenylalanine, glycine, and tryptophan. Amino acids including hydrophobic amino acid combinations can also be employed. Non-naturally occurring amino acids include, for example, beta-amino acids. Both the D, L and racemic configurations of hydrophobic amino acids can be employed. Suitable hydrophobic amino acids can further include amino acid analogs. As used herein, an analogous amino acid includes the D or L configuration of an amino acid having the following formula: -NH-CHR-CO-, where R is an aliphatic group, a substituted aliphatic group, a benzyl group , a substituted benzyl group, an aromatic group or a substituted aromatic group and in which R does not correspond to the side chain of a naturally occurring amino acid. As used herein, aliphatic groups include C1-C8 cyclic, branched, or straight chain hydrocarbons, which are fully saturated, contain one or two heteroatoms such as nitrogen, oxygen, or sulfur, and / or contain one or more units. of establishment. Aromatic groups include carbocyclic aromatic groups, such as phenyl and naphthyl, and heterocyclic aromatic groups such as imidazolyl, indolyl, thienyl, furanyl, pyridyl, pyranyl, oxazolyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, and acridintyl.

Suitable substituents on an aliphatic, aromatic, or benzyl group include -OH, halogen (-Br, Cl, I, and F) -O (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl, or substituted aryl group), -CN, -NO₂, -COOH, NH₂, NH (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group, -N (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group) 2, -COO (aliphatic, substituted aliphatic, benzyl group) , substituted benzyl, aryl or substituted aryl), -CONH2, -CO-NH (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group)), -SH, -S (aliphatic, substituted aliphatic group, benzyl, substituted benzyl, aromatic or substituted aromatic group) and -NH-C (= NH) -NH₂. A substituted benzyl or aromatic group can also have a substituted aliphatic or aliphatic group as a substituent. A substituted aliphatic group can also have a benzyl, substituted benzyl, aryl, or substituted aryl group as a substituent. A substituted aliphatic, substituted aromatic, or substituted benzyl group can have one or more substituents. Modifying an amino acid substituent can increase, for example, the lipophilicity or hydrophobicity of natural amino acids that are hydrophilic.

A number of suitable amino acids, amino acid analogs and salts thereof can be obtained commercially. Others can be synthesized by methods known in the art. Synthetic techniques are described, for example, in Green and Wuts, "Protecting Groups in Organic Synthesis", John Wiley and Sons, Chapters 5 and 7, 1991.

Hydrophobicity is generally defined with respect to the partition of an amino acid between a nonpolar solvent and water. Hydrophobic amino acids are those acids that show a preference for the non-polar solvent. The relative hydrophobicity of amino acids can be expressed on a hydrophobicity scale where glycine has the value 0.5. On this scale, amino acids that have a preference for water have values ​​below 0.5 and those that have a preference for nonpolar solvents have a value above 0.5. As used herein, the term hydrophobic amino acid refers to an amino acid that, on the hydrophobicity scale, has a value greater than or equal to 0.5, in other words, it has a tendency to partition into the non-polar acid that is at least equal to that of glycine.

Combinations of hydrophobic amino acids can also be used. Furthermore, combinations of hydrophobic and hydrophilic amino acids (preferably distributed in water) can also be used, where the total combination is hydrophobic. Combinations of one or more amino acids and one or more phospholipids or surfactants can also be employed.

The amino acid can be present in the liquid feed in an amount from 0% by weight to 60% by weight. Preferably, the amino acid can be present in the liquid feed in an amount ranging from 5% by weight to 30% by weight. The salt of a hydrophobic amino acid can be present in the liquid feed in an amount of 0% by weight to 60% by weight. Preferably, the amino acid salt is present in the liquid feed in an amount ranging from 5% by weight to 30% by weight. Methods of formation and partitioning of particles that include an amino acid are described in US Patent Application No. 09 / 382,959, filed on 25

ES 2 318 007 T3 of August 1999, entitled "Use of Simple Amino Acids to Form Porous Particles During Spray Drying", and in US Patent Application 09 / 644,320 filed August 23, 2000, entitled " Use of Simple Amino Acids to Form Porous Particles ”.

In another embodiment of the invention, the liquid feed includes a carboxylate moiety and a multivalent metal salt. One or more phospholipids can also be included. Such compositions are described in US Provisional Application 60 / 150,662, filed August 25, 1999, entitled "Formulation for Spray-Drying Large Porous Particles," and US Patent Application 09 / 644,105. filed August 23, 2000, titled "Formulation for Spray-Drying Large Porous Particles." In a preferred embodiment, the liquid feed includes sodium citrate and calcium chloride.

Biocompatible, and preferably biodegradable, polymers can also be included in the liquid feed. Particles including such polymeric materials are described in US Patent No. 5,874,064, issued February 23, 1999, to Edwards et al., The teachings of which are incorporated herein by reference in their entirety, and in U.S. Patent 6,136,295, issued October 24, 2000 to Edwards et al.

The liquid feed can further include a material such as, for example, dextran, polysaccharides, lactose, trehalose, cyclodextrins, proteins, peptides, polypeptides, fatty acids, inorganic compounds, phosphates.

The total solids concentration in the liquid feed ranges from 0.1% to 0.5% and higher. Solids can include biologically active agents, excipient, phospholipid, surfactants, salts, buffers, metals, and other compounds.

Also directed to the spray dryer 12 is a drying gas. The term "drying gas" is used herein interchangeably with the term "process gas". In a preferred embodiment, the humidity level of the drying gas is controlled. Examples of gases suitable in carrying out the methods of the invention include, but are not limited to, air, nitrogen, argon, carbon dioxide, helium, combinations or mixtures thereof or others. Nitrogen gas is preferred.

Drying gas having a specified moisture level can be formed by adding moisture to a gas stream by steam injection, spray tanks, conventional gas mixing techniques, and other techniques or equipment known in the art.

In a preferred embodiment of the invention, a first gas stream, from a gas source not shown in Figure 1, is humidified by bubbling it through water, for example by passing it through a pressure chamber 20, then than it is combined with a second gas stream that is not humidified. The second gas stream can be obtained, for example, directly from the gas source, without passing it through water.

External spray dryers or other equipment, including an atomizer and heater, are often present in manufacturing facilities in the pharmaceutical industry. In another embodiment of the invention, the dried gas leaving said external spray dryer or other apparatus including atomizer and heater, not shown in Figure 1, is directed, like the humidified drying gas, to the spray dryer. 12. Optionally, additional drying and / or heating of the gas exiting the external spray dryer or other equipment may be required prior to introducing it into the spray dryer 12.

The flow rate of one or both streams can be regulated, as is known in the art, to obtain a drying gas having a desired moisture content. For example, valve 22 in addition to additional valves, not shown in Figure 1, can be provided to control and vary the gas flow rate and thus the humidity levels in the drying gas. In one embodiment of the invention, the humidity of the drying gas is controlled with a precision of at least 1.0 ° C and is preferably less than +/- 0.1 ° C at the dew point. In Figure 1, the dew point of the drying gas is monitored by the hygrometer 24.

The dew point is the temperature to which the drying gas must cool, at constant pressure and constant water vapor content, for saturation to occur. If the dew point is below 0 ° C, it is often referred to as the "freezing point". Tables for the conversion between dew and freezing points are available in meteorological applications and can often be obtained from hygrometer manufacturers. The relationship between dew point, relative humidity, absolute humidity and temperature of dry bulb thermometers is expressed in psychrometric charts, as described in Perry's Chemical Engineering Handbook, Perry, McGraw Hill.

A preferred method of measuring the dew point of the drying gas directed to the spray dryer 12 includes cooling a mirror surface. An LED light source shines on the mirror surface and reflects off an optical sensor. A platinum resistance thermometer embedded below the mirror surface allows direct monitoring of the mirror temperature. As the drying gas flows, a dew layer forms on the mirror surface. A specific example of such a hygrometer is Dew Prime ™ 12000, manufactured by Edge Tech of Milford, MA. The measuring range for this hygrometer is between about -50 ° C to about 100 ° C. A suitable refrigerator that can be used to cool the mirror is provided by Polyscience of Niles, IL as Model 1162.

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Another suitable hygrometer that can be used in carrying out the invention is Super-Dew^TM Provided by Shaw Moisture Meters, Ltd., Bradford, UK This hygrometer uses a molecular sieve adsorber with a 24K gold outer conductor and can measure dew points as low as -100 ° C.

Other means of expressing the humidity levels in the drying gas, such as, for example, absolute humidity, mole fraction, partial pressure, weight of water vapor per unit volume of gas mixture, and parts per million (PPM) , can also be used. How they are calculated, measured, or converted into one another is known in the art.

Similarly, the invention can be practiced with solvents other than water. A common solvent is ethanol. Other non-aqueous solvents, as known in the art, can also be employed. In such cases, instead of using a drying gas having a specific moisture content, the drying gas employed has a specific concentration of the non-aqueous solvent vapor. The vapor concentration of the solvent in the drying gas can be expressed, as is known in the art, and essentially as described above for water. Said drying gas can be prepared essentially as described above.

The flow rate of the drying gas directed to the spray dryer 12 is monitored by the flow meter 26. The valve 28 may be provided to adjust the flow rate, as is known in the art. In one embodiment, the flow rate of the drying gas directed to the spray dryer 12 ranges from 50 hg / hr to 130 kg / hr, preferably from 70 kg / hr to 110 kg / hr. Other flow rates can be employed, as is known in the art.

The drying gas is heated by the heater 30. Other methods of heating the drying gas can be employed, as is known in the art. The inlet temperature of the drying gas is controlled and / or monitored by a thermocouple 32. Generally, the drying gas is supplied to the spray dryer at a temperature between 80 ° C and 200 ° C, preferably between 85 ° C and 175 ° C. ° C.

General principles and techniques of spray drying are known in the art. For example, spray drying is discussed by K. Masters in "Spray Drying Handbook", John Wiley &amp; Sons, New York, 1984, the contents of which are incorporated herein by reference in their entirety.

During spray drying, the liquid feed directed to spray dryer 12 is atomized. The resulting droplets are contacted with hot drying gas having a controlled moisture content, as discussed above, thereby removing the solvent from the droplets and forming dry spray particles. The drying gas outlet temperature is measured by thermocouple 34. Generally, this temperature ranges between 35 ° C and 80 ° C, preferably between 40 ° C and 70 ° C.

Apparatus 10 also includes cyclone 36. Cyclone 36 typically uses centrifugal action to separate spray dried product from exhaust gases, for example, spent drying gas and solvent vapors, which are removed from cyclone 36 by means of from outlet conduit 38. Spray drying particles are directed from cyclone 36 to dust collection container 40. The collected spray dried particles can be stored under controlled temperature and relative humidity conditions, eg, 22 ° C and 15% RH.

In a preferred embodiment, the spray dried particles of the invention have a vibrated powder density of less than about 0.4 g / cm³. Particles that have a vibrated dust density of less than about 0.4 g / cm³ they are referred to herein as "aerodynamically light particles". More preferred are particles that have a vibrated powder density of less than about 0.1 g / cm.³. Vibrated powder density can be measured using instruments known to those skilled in the art such as, but not limited to the Dual Platform Microprocessor Controlled Vibrated Powder Density Test Apparatus (Vankel Technology, Cary, NC) or a GeoPyc instrument.^TM (Micrometrics Instrument Corp., Norcross, GA 30093). Vibrated powder density is a standard measure of cover mass density. The density of vibrated powder can be determined using the USP Charge Density and Vibrated Density method, United States Pharmacopeia convention, Rockville, MD, 10th Supplement, 4950-4951, 1999. Characteristics that can contribute to a low density of vibrated powder they include uneven surface texture and porous structure.

The cover mass density of an isotropic particle is defined as the mass of the particle divided by the minimum volume of cover in sphere within which it can be enclosed. In one embodiment of the invention, the particles have a cover mass density of less than about 0.4 g / cm³.

Aerodynamically light particles have a preferred size, for example, a volume median geometric diameter (VMGD) of at least about 5 µm. In one embodiment, the VMGD is from 5 pm to 30 pm. In another embodiment of the invention, the particles have a VMGD ranging from 10 pm to 30 pm. In other embodiments, the particles have a mean diameter, mass median diameter (MMD), a mass median coverage diameter (MMED), or a mass median geometric diameter (MMGD) of at least 5 pm, for example 5 pm to 30 pm.

The diameter of the spray dried particles, for example the VMGD, can be measured using an electrical zone sensing instrument such as a Multisizer Ile (Coulter Electronic, Luton, Beds, England), or a laser diffraction instrument (for example , Helos, manufactured by Sympatec, Princeton, NJ). Other instruments for measuring particle diameter are well known in the art. The diameter of particles in a sample will vary depending

ES 2 318 007 T3 of factors such as particle composition and synthesis methods. The particle size distribution in a sample can be selected to allow optimal deposition to marked sites within the respiratory tract.

Aerodynamically light particles preferably have "mass median aerodynamic diameter" (MMAD), also referred to herein as "aerodynamic diameter", between about 1 pm and about 5 pm. In another embodiment of the invention, the MMAD is between about 1 pm and about 3 pm. In a further embodiment, the MMAD is between about 3 pm and about 5 pm.

Experimentally, the aerodynamic diameter can be determined using a gravitational decantation method, whereby the time for a set of particles to decant a certain distance is used to directly infer the aerodynamic diameter of the particles. An indirect method of measuring mass median aerodynamic diameter (MMAD) is the multi-stage liquid impactor (MSLI). Alternative instruments that may be used to determine aerodynamic diameters include those known under the name Aerosizer ™ (TSI, Inc., Amherst, MA) or under the name Anderson Cascade Impactor (Anderson Inst., Sunyra, GA).

The aerodynamic diameter, d_aer can be calculated from the equation:

aer vibrated where d_g is the geometric diameter, for example the MMGD, and p_vibrated is the density of vibrated powder.

Particles that have a vibrated dust density less than about 0.4 g / cm³, median diameters of at least about 5 pm and an aerodynamic diameter of between about 1 pm and about 5 pm, preferably between about 1 pm and about 3 pm, are better able to escape inertial and gravitational deposition in the oropharyngeal region, and they target the airways, particularly the distal areas of the lung. The use of larger, more porous particles is advantageous in that they are capable of aerosolizing more effectively than smaller, more dense aerosol particles, such as those commonly used for inhalation therapy.

In another embodiment of the invention, the particles have a cover mass density, also referred to as a "bulk density" of less than about 0.4 g / cm.³. Particles further having a mean diameter of between about 5 pm and about 30 pm are preferred. Bulk density and the relationship between bulk density, mean diameter, and aerodynamic diameter are discussed in US application no. 08 / 655,570, filed May 24, 1996. In a preferred embodiment, the aerodynamic diameter of particles having a mass density less than about 0.4 g / cm³ and a mean diameter between 5 pm and 30 pm, the mass mean aerodynamic diameter is between 1 pm and 5 pm.

Compared to relatively denser smaller particles, larger aerodynamically light particles, preferably having a mean diameter of at least about 5 pm, can further potentially more successfully prevent phagocytic engulfment by alveolar macrophages and clearing of the lungs, due to to the exclusion by particle size of the cytosolic space of phagocytes. Phagocytosis of particles by alveolar macrophages reduces dramatically as the particle diameter increases beyond about 3 pm. Kawaguchi, H., et al., Biomaterials 7: 61-66 (1986); Krenis, LJ and Strauss, B., Proc. Soc. Exp. Med., 107: 748-750 (1961); and Rudt, S. and Muller, RH, J. Contr. Rel, 22: 263-272 (1992). For particles of statistically isotropic shape, such as spheres with rough surfaces, the covered volume of particle is approximately equivalent to the volume of cytosolic space required within a macrophage for complete phagocytosis of the particle.

The particles must be manufactured with the appropriate vibrated powder material, surface roughness, diameter and density for localized delivery to selected regions of the respiratory tract such as the distal areas of the lung or the central or upper airways. For example, higher densities or larger particles can be used for delivery to the upper respiratory tract, or a mixture of particles of varying size in a sample, provided that the same or different therapeutic agent can be administered to target different regions of the lung in an administration. Particles having an aerodynamic diameter ranging from about 3 to about 5 pm are preferred for delivery to the central and upper airways. Particles having an aerodynamic diameter ranging from about 1 to about 3 pm are preferred for delivery to the lung distal areas.

Inertial impact and gravitational deposition of aerosols are predominant deposition mechanisms in the upper airways and acini of the lungs during normal breathing conditions. Edwards, DA, J. Aerosol Sci., 26: 293-317 (1995). The importance of both mechanisms of deposition increases in proportion to the mass of aerosols and not to the volume (or cover) of the particle. As the site of aerosol deposition in the lungs is determined by the mass of the aerosol (at least for particles of mean aerodynamic diameter greater than about 1 pm), decrease the density of vibrated dust by increasing irregularities of the particle surface and the porosity of the particle allows the distribution of cover volumes of larger particles in the lungs, the other physical parameters being the same.

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The low density of vibrated powder has a small aerodynamic diameter compared to the current diameter of the covering sphere. The aerodynamic diameter, d_aer, is related to the diameter of the coverage sphere, d (Gonda, I., "Physicochemical principles in aerosol delivery", in Topics in Pharmaceutical Sciences 1991 (editors DJA Crommein and KK Midha), pp. 95-117, Stuttgart: Medpharm Scientific Publishers, 1992)), using the formula:

^daer - ^d \ i^p where the cover mass ρ is in units of g / cm³. The maximum deposition of monodispersed aerosol particles in the alveolar region of the human lung (~ 60%) is given for an aerodynamic diameter of approximately d_aer - 3 jum. Heyder, J. et al, J. Aerosol Sci., 17: 811-825 (1986). Due to its small cover mass density, the actual diameter d of the aerodynamically light particles comprising a monodisperse inhaled powder that will exhibit maximum deposition in the lung distal areas is:

d - 3 / fip pm (where ρ &lt;1 g / cm³);

where d is always greater than 3 jum. For example, aerodynamically light particles that have a covering mass density, ρ - 0.1 g / cm³, will show a maximum deposition for particles having coverage diameters as large as 9.5 jum. The increased particle size decreases the interparticle adhesion forces. Visser, J., Powder Technology, 58: 1-10. Thus, the large particle size increases the efficiency of aerosolization to the lung distal areas for particles of low cover mass density, in addition to contributing to lower phagocytic losses.

The aerodynamic diameter can be calculated to provide maximum deposition within the lungs. Previously this was achieved by using very small particles less than about five microns in diameter, preferably between about one and about three microns, which are then susceptible to phagocytosis. Selection of particles that are larger in diameter, but light enough (hence the "aerodynamically light" characterization), results in a distribution equivalent to the lungs, although larger particles are not engulfed.

The methods of the invention include controlling the properties of the spray dried particles by manipulating the moisture content of the drying gas. For example, it has been found that the moisture present in the drying gas can be optimized to produce particles that combine large geometric dimensions, for example, VMGD, and low vibrated dust density and that have aerodynamic properties that promote distribution to the alveoli or distal lung areas. On the other hand, using a drying gas that has too high or too low a moisture content, when compared to the optimized moisture level, results in an increase in vibrated powder density, and MMAD and an increase in VMGD. . The latter particles can be adapted, for example, for preferential delivery to the central airways.

For a given formulation, the relationship between the aerodynamic properties of the particles and the moisture content of the drying gas, expressed, for example, in terms of the set or set dew point, can be determined experimentally as follows. The particles can be spray dried using a process gas that has specified dew points. For each dew point value, the properties of the spray dried particles, eg vibrated powder density, VMGD, MMAD, can be measured. A correlation between the dew point and the density of vibrated dust, VMGD or MMAD can be generated over the range of the dew point used. The correlation can then be used to select a dew point that results in the formation of particles having desired properties.

In one embodiment of the invention, the spray dried particles are formed using a drying gas having a dew point ranging from about 0 ° C to about -40 ° C. For example, for improved delivery to lung distal areas, a dew point of -40 ° C is preferred in spray dry particles having a 50/50 weight percent DPPC / human growth hormone or hGH. A dew point of about -20 ° C is preferred for a formulation that includes 38/38/16/8 percent by weight of DSPC / DPPC / leucine / albuterol sulfate. DSPC / Leucine / Salmeterol 74.5 / 24.0 / 1.5 weight percent formulations can be spray dried using a drying gas with a dew point of about -20 ° C. A dew point of -30 ° C is preferred in spray drying formulations that include a monoclonal antibody such as a humanized monoclonal antibody IgG1 and DPPC (60/40 monoclonal antibody / DPPC by weight percent).

The particles produced by the methods of the invention and which include a medicament, for example one or more of the bioactive agents described above, can be administered to the respiratory tract of a patient in need of treatment, prophylaxis or diagnosis. Administration of particles to the respiratory system can be by means such as those known in the art. For example, the particles are distributed from an inhalation mechanism. In a preferred embodiment, the particles are delivered via a dry powder inhaler (DPI). Metered dose inhalers (MDI), or instillation techniques can also be employed.

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Various suitable inhalation mechanisms and methods that can be used to deliver particles to the respiratory tract of the patient are known in the art. For example, suitable inhalers are described in US Patent No. 4,069,819, issued August 5, 1976 to Valentini, et al., US Patent No. 4,995,385 issued February 26, 1991 to Valentini, et al., And US Patent No. 5,997,848 issued December 7, 1999 to Patton, et al. Other examples of suitable inhalers include, but are not limited to, the Spinhaler® (Fisons, Loughborough, UK), Rotahaler® (Glaxo-Wellcome, Research Triangle Technology Park, North Carolina), FlowCaps® (Hovione, Loures, Portugal) , Inhalator® (Boehringer-Ingelheim, Germany), and the Aerolizer^® (Novartis, Switzerland), the Diskhaler^® (Glaxo-Wellcome, RTP, NC) and others, such as those known to those of skill in the art.

Preferably, the particles delivered to the respiratory tract travel through the upper airways (oropharynx and larynx), the lower airways including the trachea followed by bifurcations in the bronchi and bronchioles and through the terminal bronchioles that are successively divided into respiratory bronchioles that then lead to the last respiratory tract, alveoli, or distal lung areas. In a preferred embodiment of the invention, the majority of the particle mass is deposited in the distal areas of the lung. In another embodiment of the invention, delivery is primarily in the central airways. Delivery to the upper respiratory tract can also be obtained.

In one embodiment of the invention, delivery to the pulmonary system of particles is in a single step acting by respiration, as described in US Non-Provisional Patent Application, "High Efficient Delivery of a Large Therapeutic Mass Aerosol ”, Application No. 09 / 591,307, filed June 9, 2000. In another embodiment of the invention, at least 50% of the mass of the particles stored in the inhaler canister is delivered to the respiratory system of a subject in a single breath-activated step. In a further embodiment, at least 5 milligrams and preferably at least 10 milligrams of a drug are delivered by delivering in a single breath, to the respiratory tract of a subject, particles enclosed in the receptacle. Amounts as large as 15, 20, 25, 30, 35, 40, and 50 milligrams can be dispensed.

As used herein, the term "effective amount" means the amount necessary to achieve the desired therapeutic or diagnostic effect or efficacy. Actual effective amounts of drug may vary depending on the specific drug or combination thereof being used, the particular composition formulated, the mode of administration, and the age, weight, disease of the patient, and severity of the symptoms or disease to be treated. . Dosages for a particular patient can be determined by one of ordinary skill in the art using conventional considerations (eg by means of an appropriate conventional pharmacological protocol). In one example, effective amounts of albuterol sulfate range from 100 micrograms (pg) to 1.0 milligrams (mg).

Dosage, formulations and aerosol delivery systems can also be selected for a particular therapeutic application, as described, for example, in Gonda, I. "Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract", in Critical Reviews in Therapeutic Drugs Carrier Systems, 6: 273-313, 1990, and in Moren, "Aerosol dosage forms and formulations", in: Aerosols in Medicine. Principles, Diagnosis and Therapy, Moren, et al., Editors, Esevier, Amsterdam, 1985.

The particles of the invention can be used in compositions suitable for drug delivery to the pulmonary system. For example, such compositions can include the particles and a pharmaceutically acceptable carrier for administration to a patient, preferably for administration via inhalation. The particles can be administered alone or in any appropriate pharmaceutically acceptable vehicle, such as a liquid, for example saline, or in a powder, for administration to the respiratory system. They can co-partition with larger transport particles, which do not include a therapeutic agent, having the latter mass median diameters for example in the range between 50 pm and 100 pm.

The present invention will be further understood by reference to the following non-limiting examples.

Exemplification

The liquid pump used in these experiments was a Masterflex, Model 2000, from Cole-Parmer Instrument Company. The liquid mass flow meter was Promass 64, while the gaseous mass flow meter was a Promass F. Both were manufactured by Endress and Hauser, Switzerland. The Hygrometer / Freezer used was a Dew Prime I, Model 2000 (Edge Tech, Milford, MA) / Model 1162 (Polyscience, Niles, IL). The spray dryer was a Mobile Minor, Model EX, from Niro Inc., Columbia MD. The atomizer used was SL24-50 / M-02 / B with straight blades, also from Niro, Columbia, MD. The collection container was a 1 L glass container (Niro, Columbia, ND).

Example 1

A formulation including 60/20/20 weight percent DPPC, lactose, and albumin was prepared as follows.

DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), obtained from Avanti Polar Labs, Alabaster, AL and albumin, bovine, fraction V, obtained from Sigma, St. Louis, MO, were removed from cold storage. and allowed to warm to room temperature, typically for at least about 20 minutes. 600 mg of DPPC was dissolved in 850 ml

ES 2 318 007 T3 of ethyl alcohol, 200 alcoholic strength, USP. 200 mg of B-lactose anhydrate, USP grade, from Spectrum Laboratories, Laguna Hills, CA, was dissolved in 150 ml of USP sterile water. After the solution was clear, 200 mg of albumin was dissolved in the above aqueous solution. The pH of the aqueous solution, measured by a pH / ion analyzer, model # 355, from Corning Inc., Corning, NY, was adjusted to 8.1 ± 0.1 using 1.0N sodium hydroxide solution.

The aqueous phase was slowly poured into the ethanolic phase with continuous stirring until the solution cleared. 850 ml of ethyl alcohol, 200 strength, USP, was placed in the 1L glass jar with stir bar. 150 ml of USP sterile water was mixed with the ethanolic phase by slowly pouring the water into the ethanolic phase, with stirring until the solution was clear.

Spray drying was carried out using a liquid feed rate of 48 ml / minute and a process gas rate of 88 kg / hour. The rotary atomizer pressure was adjusted to obtain a wheel speed of approximately 18800 rotations per minute (rpm).

The other spray drying parameters are shown in Table 2 and the dew points employed are shown in Table 2. Also shown in Table 2 are the vibrated powder densities, VMGD and MMAD of the spray dried particles.

TABLE 2

<td>Gear n °</td><td>T input (° C)</td><td>T output (° C)</td><td>Dew point (° C)</td><td>vibrated p (g / cm³)</td><td>VMGD (p.m)</td><td>MMAD (p.m)</td>

<td> 1</td><td> 110</td><td> 58</td><td> -22</td><td> 0,104</td><td> 7,61</td><td> 2,96</td>

<td> 2</td><td> 110</td><td> 59</td><td> -15</td><td> 0,124</td><td> 7,47</td><td> 2,92</td>

<td> 3</td><td> 110</td><td> 60</td><td> -6,4</td><td> 0,24</td><td> 6,4</td><td> 3,15</td>

<td> 4</td><td> 110</td><td> 60</td><td> 0</td><td> 0,28</td><td> 6,15</td><td> 3,29</td>

<td> 5</td><td> 110</td><td> 58</td><td> -39</td><td> 0,169</td><td> 7,2</td><td> 3,23</td>

A curve showing the correlation or relationship between the dew point (in degrees C) of the process gas and the vibrated powder density of the resulting spray dry particles is shown in Figure 2. Figure 3 is a curve showing the relationship between MMAD and the dew point (in degrees C) of the process gas.

As can be seen from Table 2 and Figures 2 and 3, for this formulation, the optimal dew point range to produce particles that have minimized vibrated dust density, higher VMGD, and lower MMAD can be produced using a drying gas that has a dew point ranging from -15 ° C to -22 ° C. Dew point values ​​outside of this range can be selected to form particles that have higher densities of vibrated dust and higher MMAD.

Example 2

A formulation including 10% by weight of DPPC, obtained from Avanti Polar Labs, Alabaster, AL and 90% by weight of estradiol, obtained from Spectrum Quality Products, New Brunswick, NJ, was spray dried using a 70/30 volume / volume of ethanol / water solvent. The solid concentration was 3 g / l. The process gas used was air. The spray drying parameters used and the MMAD of the spray dried particles formed using process gas at different dew point values ​​are shown in Table 3 and Figure 4. As seen from Table 3 and Figure 4, MMAD was minimized when the process air had a dew point of approximately -5 ° C. Higher or lower dew points can be selected to form particles having a 90/10 estradiol / DPPC formulation and higher MMAD values.

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TABLE 3

<td>March</td><td>T input (° C)</td><td>T output (° C)</td><td>Atomization (rpm)</td><td>Process gas (kg / hr)</td><td>Liquid feeding (ml / min)</td><td>Dew point (° C)</td><td>MMAD (p.m)</td>

<td> 1</td><td> 110</td><td> 58</td><td> 14600</td><td> 85</td><td> 40</td><td> -1</td><td> 3,05</td>

<td> 2</td><td> 110</td><td> 58</td><td> 14600</td><td> 85</td><td> 40</td><td> -5</td><td> 2,75</td>

<td> 3</td><td> 110</td><td> 60</td><td> 14600</td><td> 85</td><td> 40</td><td> 4</td><td> 3,12</td>

<td> 4</td><td> 110</td><td> 59</td><td> 14600</td><td> 85</td><td> 40</td><td> -18</td><td> 3,62</td>

<td> 5</td><td> 110</td><td> 59</td><td> 14600</td><td> 85</td><td> 40</td><td> 8</td><td> 3,16</td>