Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)

The present invention relates to the field of modified release of pharmaceutically active ingredients except amoxicillin. In the disclosure herein, the expression "modified release" refers to the release of the active ingredient that begins as soon as the Galen pharmaceutical form is contacted with its lysis medium (in vivo or in vitro), or, for example, 0.5 to several hours. It optionally means the release of the active ingredient that does not initiate until after a scheduled period in the range of. From the point of view of the present invention, the time required to release 50% of the active ingredient is usually several hours and can be extended to, for example, 0.5 to 30 hours.

More specifically, the present invention relates to liquid pharmaceutical formulations for oral administration with a modified release of the active ingredient except amoxicillin. Each of these formulations consists of a suspension or dispersion of microcapsules formed from a nucleus containing amoxicillin and a coating that encloses the nucleus. According to the present invention, the microcapsules constituting the dispersed phase of the suspension are designed to allow modified release of the active ingredient except amoxicillin.

Furthermore, the present invention specifically relates to a "multi-microcapsule" aqueous suspension of the active ingredient except amoxicillin for oral administration, the suspension being stable throughout the treatment and the active ingredient (amoxicillin). Allows modified release of). These suspensions are especially useful in the following cases: --Forms for modified release of active ingredient at high therapeutic doses (eg, 500-1000 milligrams or more); --Liquid pediatric (paediatric) or geriatric (geriatric) forms for modified release of the active ingredient (eg, sachets, or recoverable oral suspensions in bottles); --Taste masking and / or protection of highly sensitive active ingredients.

The present invention further relates to specific methods for the preparation of microcapsules suspended in water.

Oral pharmaceutical formulations for the modified release of the active ingredient are well known. Some of these formulations consist of tablets containing therapeutically active nuclei covered with indigestible material of various thicknesses. More recently, microcapsules or microparticles containing active ingredient nuclei coated with layers of different permeability or solubility have appeared. These microcapsules / microparticles are placed, for example, in gelatin capsules that form the Galene pharmaceutical system for the modified release of the active ingredient.

The majority of released modified pharmaceutical forms, including coated active ingredient nuclei, are solid forms: tablets, gelatin capsules, microparticles or microcapsules.

For the description of the dry form of the microcapsules, a detailed description is given in Patent EP-B-0 709 087, which is a (pharmaceutical or nutritional) Galene pharmaceutical system, preferably in the form of tablets, advantageous. Describes the form of disintegrating tablets, or powders or gelatin capsules, in particular a reserved type containing at least one medicinal and / or nutritional active ingredient (AP) selected from antibiotics. It is characterized by containing microcapsules, intended for oral administration, and characterized by: --They consist of AP particles, each covered with a film coating of the following composition: 1-Insoluble in tube liquid, present in an amount of 50-90% by dry weight based on the total weight of the coating composition, at least one water-insoluble cellulose derivative such as ethyl cellulose and / or particularly preferably cellulose. At least one cellulosic polymer (P1) consisting of acetate; 2-Based on the total weight of the coating composition, present in an amount of 2-25% by dry weight, at least one polyacrylamide and / or poly-N-vinylamide and / or poly-N-vinyllactam, particularly preferred. Consists of polyacrylamide and / or polyvinylpyrrolidone, at least one nitrogen-containing polymer (P2); 3-Abundant in an amount of 2-20% by dry weight based on the total weight of the coating composition, the following compounds: glycerol ester, phthalate, citrate, sebacate, cetyl alcohol ester and castor oil, salicylic acid and chin, At least one plasticizer, particularly preferably consisting of at least one of castor oil; 4-Alkalimetal or alkali of fatty acids present in an amount of 2-20% by dry weight, preferably stearic acid and / or oleic acid, based on the total weight of the coating composition. Earth metal salts and / or nonionic surfactants: preferably polyethoxylated sorbitan esters and / or polyethoxylated castor oil derivatives and / or lubricants: eg stearates, preferably calcium, magnesium, aluminum, Alternatively, the agent can be selected from stearate of zinc, or stearyl fumarate, preferably stearyl fumarate sodium, and / or glycerol bihinate, and the agent can contain only one or a mixture of the above products. At least one surfactant and / or lubricant; --They have a particle size of 50-1000 microns; -And they are designed to be present in the small intestine for a period of at least about 5 hours, which allows absorption of APs for at least the time they stay in the small intestine.

The above document relates only to the microcapsule-based dry drug form and does not mention the microcapsule-based oral liquid drug form.

These released modified solid pharmaceutical formulations are not always convenient, especially when they are administered to very young children or very old patients who have difficulty swallowing.

This is the case when the active ingredient in question needs to be administered orally in high doses, eg metformin, eg 500-1000 milligrams or more. It is clear that such solid Galene pharmaceutical systems are inadequate because they are too bulky and therefore very difficult to swallow, especially for young children and the elderly. This can be a cause of worsening patient dosing rates and, as a result, jeopardizing the success of therapeutic treatment.

Similarly, for pediatric forms in which the therapeutic administration should be applied according to the weight of the child, the suspension of the invention is suitable for existing bottles provided with a kg graduated syringe, and thus new. No device development is required. Therefore, release-modified forms that were previously rarely used by children are now available due to the advantages of the present invention. The advantage of such a form is the reduction in the number of daily dosing units and the effectiveness of treatment between continuous dosing units (eg, antibiotics, anti-inflammatory, cardiovascular treatments, etc.) It is an optimization. Therefore, liquid pharmaceutical formulations with controlled release, which are easy to prepare, will make significant progress.

In this case, it is even more advantageous to use a release-modified Galen pharmaceutical system consisting of multiple microcapsules smaller than 1000 microns in diameter. In fact, in these systems, the dose of active ingredient to be administered is dispersed in a large number of microcapsules (typically 10,000 at a dose of 500 mg) and therefore has the following intrinsic advantages: A release profile with several release pulses, or a release profile that guarantees constant AP plasma concentration levels with appropriate control of different fractions, by using a mixture of microcapsules with different modified release profiles. Is given.

-Prevent tissue contact with high doses of AP (dumping). Each microcapsule actually contains only a very reduced dose of active ingredient, thus avoiding the risk of tissue damage due to local overconcentration of active active ingredient.

It is possible to combine several Galene pharmaceutical forms (in immediate release or modified release) containing one or more active ingredients within those "multi-microcapsule" systems.

It is known that liquid multiparticle gallen pharmaceutical forms, or more precisely colloidal suspensions, are preferred over solid forms for high dose active ingredients or pediatric applications for oral administration. ing.

Liquid suspensions for modified release of the active ingredient are difficult to prepare. The main difficulty that must be overcome is to avoid releasing the active ingredient into the liquid phase during storage of the suspension, while allowing a modified release as soon as it enters the gastrointestinal tract. Is. This objective is particularly difficult to achieve because the active ingredient is stored in the liquid for a very long time compared to the desired release time in the gastrointestinal tract fluid. Moreover, the modified release system must not be disrupted to the point of disrupting the release profile and release time of the active ingredient by prolonging retention in the fluid during storage.

Moreover, in order for these liquid formulations to be sufficiently effective, the following are important: Yes The microcapsules are very small (<1000 microns), Yes And the weight ratio of coating excipients is limited, this modality is only achieved due to their small size and the large specific surface area of the microcapsules that facilitate release. It's even more difficult.

French patent application FR-A-2 634 377 should first be mentioned as a prior art for oral liquid pharmaceutical formulations for the modified release of active ingredients; this document is coated with an ionic polymer. Disclosed is a novel release-modified pharmaceutical formulation that is based on a resin / active ingredient complex, the polarity of which is opposite to that of the resin, and is immobilized on it with an ionic bond. There is. The active ingredient is also ionic and has the opposite polarity to the resin. The resin may be sodium polystyrene sulfonate, and the ionic coating polymer is selected from acrylic acid and methacrylic acid ester polymers (EUDRAGIT®). The resin is impregnated with an aqueous solution of the active ingredient. The resin particles impregnated with the active ingredient are then coated with an organic solution of the ionic polymer. The resulting microcapsules are converted to an oral suspension (particularly Example 2). The possibility of using ionic resins and ionic coated polymers is limited to application to ionic active ingredients.

U.S. Pat. Nos. US-B-4,999,189 and US-B-5,186,930 relate to liquid pharmaceutical compositions containing an ion-exchange ionic resin / active ingredient complex suspended in a liquid phase. The particles of these resin / active ingredient complexes have a high melting point and a pharmaceutically acceptable first layer of wax, and a pharmaceutically acceptable water-insoluble polymer (ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, etc.). It is coated with an outer layer, a second layer of hydroxyethyl cellulose, Eudragit®, etc.). A plasticizer such as dibutyl sevacate can be introduced into this second layer, the outer layer. The active ingredient is fixed to the ion exchange resin by ionic bonding. The liquid phase consists of a high fructose content glucose syrup and some other components such as glycerol or propylene glycol.

US-B-5,186,930 differs from the first US patent in providing a sufficient amount of first layer (wax) to protect the particles of the resin / active ingredient complex from expansion and cracking.

These US patents do not provide any data that can assess the nature of the modified release of the active ingredient. Moreover, the use of an ion exchange resin as a carrier for the active ingredient is rather inconvenient, limiting the variety of active ingredients contained. Moreover, the Galen pharmaceutical system makes no conclusive proposals regarding the stability and preservation of the modified release properties of the active ingredient.

PCT patent application WO-A-87 / 07833 and patent US-B-4,902,513 disclose an aqueous suspension of microcapsules of active ingredient (eg, theophylline) by modified release of active ingredient (eg, 12 hours). are doing. These suspensions are prepared by saturating the aqueous phase with the active ingredient prior to introducing the active ingredient microcapsules into the aqueous phase. Compositions of coating agents for microcapsules that allow modified release of the active ingredient are not disclosed in the above document. Here, the coating composition is a critical factor that ensures the maintenance of the modified release of the microcapsules after storage in the aqueous phase. The technical proposal described is that after the microcapsules are stored in the liquid phase, the liquid phase suspension in the form of microcapsules with modified release without interfering with the stability of the modified release propofol of the active ingredient. It does not disclose any means to solve the dual problem of producing liquids.

European patent application EP-A-0 601 508 relates to an aqueous suspension for oral administration of naxopren with a modified release profile. This suspension contains a nasoprene-coated microgranule suspended in a syrup-like aqueous liquid phase. The technical problem underlying the invention is that it must provide a modified release form of nasoprene that contains a dose of 1000 mg and can be administered in a once-daily dosage form.

This fine granule consists of napoprene, polyvinylpyrrolidone, and lactose (90). ~ 300 μm). Their coating consists of four layers. The first contains diethyl cellulose / diethyl phthalate / polyethylene glycol. The second is based on EUDRAGIT (meth) acrylate / (meth) acrylic copolymers. The third contains glycerol stearate / wax / fatty acid alcohol and the fourth consists of an enteric coating based on cellulose acetate / phthalate. Naxoplen is modified for release over 24 hours.

Example 22 of the European Patent EP-A-0 601 508 includes proof of the stability of the release profile after storing the liquid suspension for 30 days.

One of the disadvantages of this suspension comes from the enteric layer, which is designed to disintegrate at neutral pH into a liquid, so that it is at neutral pH. Disables the use of suspension. Another disadvantage of this enteric layer is that it blocks the release of active ingredients in the stomach at acidic pH. For APs whose absorption windows are located in the upper part of the gastrointestinal tract, releasing the active ingredient in the stomach is often beneficial for increasing bioavailability. Moreover, the multi-layer solution in question is very complex and, in addition, naproxen-specific.

PCT patent application WO-A-96 / 01628 discloses a liquid pharmaceutical formulation for oral administration according to a modified release profile (12 hours) of the active ingredient consisting of moguisteine. Its purpose is to be easy to distribute and ingest, have a release time that avoids multiple dosing units, is stable over time in an aqueous suspension, and is pleasing to favor dosing rates. It is to propose a modified release liquid formulation of moguistain that is flavored and whose production does not involve the use of toxic substances such as solvents. To this end, the invention of PCT patent application WO-A-96 / 01628 is a hydrophilic first layer consisting of cellulose acetate / phthalate and diethyl phthalate, hydrophobicity consisting of glycerol stearate / wax / fatty acid alcohol. In a weakly hydroxylated liquid phase (basically based on sorbitol and glycerol) of moguistain granules (90-300 μm) coated in the second layer and the same hydrophilic third layer as the first layer. Suspension is presented. This multi-layered form is very complex to prepare and is also specific for moguistain.

In this technical context, a fundamental object of the present invention is to provide an aqueous suspension of microcapsules of active ingredient excluding amoxicillin for oral administration of active ingredient according to a modified release profile. The coating of the microcapsules is designed so that the release profile is not perturbed and does not depend on the liquefaction time of the microcapsules in the liquid phase (preferably water). Thus, the active ingredient contained in the microcapsules is prevented from leaking into the liquid phase throughout the storage of the suspension, but the modified release of the active ingredient is suitable for it to actuate the release. Immediately after suspension of the microcapsules in the solvent (preferably water) phase of the microcapsules in the environment, i.e., the gastrointestinal tract in vivo, pH 6.8, using a type II device according to the third edition of the European Pharmacopoeia It is immediately possible under the conditions of a dissolution test conducted in a phosphate buffer medium with a volume of 900 ml and a temperature of 37 ° C.

Another object of the present invention is to provide an aqueous solution suspension of microcapsules of active ingredients (excluding amoxicillin) containing a film coating formed of a single layer.

Another object of the present invention is the microcapsules of active ingredients (excluding amoxicillin) in which the dissolution ratio derived from the microcapsules is 15% or less, preferably 5% or less of the total weight of the active ingredients present in the microcapsules. To provide an aqueous suspension of capsules.

Another object of the present invention is a microcapsule of an active ingredient (excluding amoxicillin) in which a part of the active ingredient is in an immediate release form and the other part of the active ingredient is in a modified release form (microcapsules). To provide an aqueous liquid suspension.

Another basic object of the present invention is a modified release of the active ingredient (excluding amoxicillin) that allows the release of the active ingredient according to a release profile that is not altered by aging the suspension. Is to provide an aqueous suspension of microcapsules for.

Another basic object of the present invention consists of particles of the active ingredient (excluding amoxicillin), each coated with an release half-life t._1/2It is to provide an aqueous suspension of microcapsules that allows the release of the active ingredient according to an extended and / or optionally delayed profile such that is 0.5-30 hours.

Another object of the present invention is to provide an oral gallen pharmaceutical form that is liquid and consists of a large number of microcapsules (eg, approximately thousands), the multiplicity of the microcapsules being statistically good. It guarantees the reproducibility of the dynamics of APs through the gastrointestinal tract, thereby improving the control of bioavailability and therefore its effectiveness.

One basic object of the present invention is an oral liquid gallen pharmaceutical form consisting of a plurality of coated microcapsules, avoiding the use of large amounts of coating agent and having a weight ratio of coating agent comparable to that of an integral type. Is to provide.

Another basic object of the present invention is the mixing of several active ingredients, each of which is coated with an active ingredient (excluding amoxicillin) to form microcapsules, each having a different release time. Is possible to provide an aqueous suspension of modified release.

Another basic object of the present invention is the modification of the active ingredient as a method of treating human or veterinary disease, in which the modified release profile is also unaffected by the storage of microcapsules in liquid form in suspension. It is to provide the use of a suspension (preferably aqueous) of microcapsules consisting of particles of individually coated active ingredient (excluding amoxicillin) to determine the release.

Another basic object of the present invention is to individually coat the modified release profile to determine the modified release of the active ingredient, which is also unaffected by the storage of the microcapsules in liquid form in suspension. It is to provide an agent based on a suspension of preferably aqueous microcapsules consisting of particles of the active ingredient (excluding amoxicillin).

Of all the above objectives, in particular, we have succeeded in developing a multi-microcapsule Galene pharmaceutical system, preferably in the form of an aqueous suspension, for the modified release of the active ingredient except amoxicillin. And this is --With arbitrary delay, without breaking the modified release profile --Stable, easy to prepare, economical and efficient.

To do this, we --Selecting a highly specific coating composition for microcapsules, -And using a liquid phase saturated with the active ingredient (preferably aqueous) or a sufficient amount of solvent (preferably water) for a restricted but easy-to-swallow suspension. It is advocated to suspend the microcapsules in a liquid phase (preferably aqueous) that can be saturated with the active ingredient in contact with the capsules.

Accordingly, the present invention satisfying the above object is, in particular, a suspension of aqueous liquid phase microcapsules intended for oral administration, allowing modified release of at least one active ingredient (excluding amoxicillin). hand, Each contains multiple microcapsules consisting of a nucleus and film coating containing at least one active ingredient (excluding amoxicillin), the film coating being: Applicable to the nucleus -Controlling the modified release of the active ingredient, -Has a composition corresponding to one of the following three groups A, B and C: Group A 1A-Insoluble in the liquid in the tube, present in an amount of 50-90%, preferably 50-80% by dry weight, based on the total weight of the coating composition, consisting of at least one water-insoluble cellulose derivative. , At least one film-forming polymer (P1); Based on the total weight of the 2A-coating composition, it is present in an amount of 2-25%, preferably 5-15% by dry weight and at least one polyacrylamide and / or poly-N-vinylamide and / or poly. -At least one nitrogen-containing polymer (P2) consisting of N-vinyllactam; 3A-Present in an amount of 2-20%, preferably 4-15% by dry weight, based on the total weight of the coating composition, the following compounds: glycerol esters, phthalates, citrates, sebacates, cetyl alcohol esters and At least one plasticizer consisting of at least one of castor oil; 4A-Present in an amount of 2-20%, preferably 4-15% by dry weight, based on the total weight of the coating composition, anionic and / or nonionic surfactants and / Or at least one surfactant and / or lubricant selected from the lubricants, wherein the agent can contain only one or a mixture of the above products; Group B ~ 1B-At least one hydrophilic polymer having a group that is ionized at a neutral pH and preferably selected from cellulose derivatives; At least one hydrophobic compound different from ~ 2B-A; Group C 1C-At least one film-forming polymer that is insoluble in gastrointestinal fluid; 2C-At least one water-soluble polymer; 3C-At least one plasticizer; 4C-Arbitrarily, preferably at least one surfactant / lubricant selected from the following group of products: ~ Anionic surfactant; ~ And / or nonionic surfactants: And the liquid phase is saturated or saturated with the active ingredient in contact with the microcapsules. It is related to a suspension characterized by that.

With respect to the present disclosure, the expression "microcapsules of active ingredient" means microcapsules containing one or more active ingredients and optionally at least one excipient in the nucleus.

The suspensions of the present invention consist of individually coated microcapsules of the active ingredient and pose two major obstacles to the preparation of aqueous suspensions of microcapsules that allow modified release of the active ingredient. It is possible to overcome these two obstacles. a) Limit the proportion of active ingredient that can be released immediately from the microcapsules to a value less than 15%, preferably less than 5% of the total weight of active ingredient used in the microcapsules; b) Obtain a modified release system that is strong enough to avoid any change or disintegration of the release profile of the active ingredient during storage of the aqueous suspension :.

The suspension also makes it possible to facilitate oral administration of drugs with high therapeutic doses, especially in the elderly and children, which significantly increases the dosing rate and the success of the treatment.

Moreover, for APs with limited absorption windows, the modified release form of multiple microcapsules is particularly beneficial, as shown in the preface of the present disclosure.

In one preferred embodiment of the invention, the groups A, B and C from which the components of the coating composition are selected are: Group A 1A-Ethyl Cellulose and / or Cellulose Acetate; 2A-polyacrylamide and / or polyvinylpyrrolidone; 3A-castor oil; 4A-Alkale metal or alkaline earth metal salts of fatty acids, preferably stearic acid and / or oleic acid, adopted individually or as a mixture of each other, polyethoxylated sorbitan esters, polyethoxylated castor oil derivatives, Stearate, preferably stearate of calcium, magnesium, aluminum, or zinc, stearyl fumarate, preferably stearyl fumarate sodium, or glycerol bihinate; Group B 1B ~ Cellulose Acetate-Phthalate; ~ Hydroxypropyl Methyl Cellulose Phthalate; ~ Hydroxypropyl Methyl Cellulose Acetate-Succinate; ~ (Meta) Acrylic Acid / (Meta) Acrylic Acid Alkyl (Methyl) Ester Copolymer (EUDRAGIT® S or L); ~ And their mixture; 2B ~ Hydrogenated plant wax (Dynasan (registered trademark) P60, Dynasan (registered trademark) P116); ~ Triglycerides (tristearin, tripalmitin, Lubritab®, Cutina HR, etc.); ~ Animal and vegetable fats (Mitsuro, Carnauba wax, etc.); ~ And their mixtures; Group C 1C ~ Water-insoluble cellulose derivatives, especially ethyl cellulose and / or cellulose acetate; ~ Acrylic derivative; ~ Polyvinyl acetate; And their mixtures; 2C ~ Water-soluble cellulose derivative; ~ Polyacrylamide; ~ Poly-N-vinylamide; ~ Poly-N-Vinyl Lactam; ~ Polyvinyl alcohol (PVA); ~ Polyoxyethylene (POE); ~ Polyvinylpyrrolidone (PVP) (preferably); ~ And their mixtures; 3C ~ Glycerol and its esters, preferably from the following subgroups: acetylated glycerides, glycerol monostearate, glyceryl triacetate, and glycerol tributyrate; ~ Preferred the following subgroups of phthalates: dibutyl phthalate, diethyl phthalate, dimethyl phthalate, and dioctyl phthalate; ~ Preferred the following subgroups of cytorates: acetyltributylcytorate, acetyltriethylcytolate, tributylcytolate, and triethylcytorate; ~ Preferred the following subgroups of sebacates: diethyl sebacate and dibutyl sebacate; ~ Adipate; ~ Azelato; ~ Benzoate; ~ Vegetable oil; ~ Fumarate, preferably diethyl fumarate; ~ Malate, preferably diethyl malate; ~ Oxalate, preferably diethyl oxalate; ~ Succinate, preferably dibutyl phthalate; ~ Butyrate; ~ Cetyl alcohol ester; ~ Salicylic acid; ~ Triacetin; ~ Maronate, preferably diethyl malonate; ~ Kuching; ~ Castor oil (which is especially preferable); ~ And their mixtures; 4C ~ Alkali metal or alkaline earth metal salts of fatty acids, preferably stearic acid and / or oleic acid; ~ Polyethoxylated oil, preferably polyethoxylated hydrogenated castor oil; Polyoxyethylene / polyoxypropylene copolymer; Polyethoxylated sorbitan ester; Polyethoxylated castor oil derivative; Stearate, preferably calcium, magnesium, aluminum or zinc; Stearyl fumarate, preferably sodium stearyl fumarate; Glycerol undergone; And their mixtures.

Preferably, the film coating is composed of a single layer whose weight is presented at 1-50%, preferably 5-40% of the total weight of the microcapsules.

According to one preferred feature of the invention, the liquid phase is aqueous: more preferably at least 20% by weight water, particularly preferably at least 50% by weight water.

Suspensions according to the present invention are advantageous. --30-95% by weight, preferably 60-85% by weight liquid phase (preferably water); -And 5 to 70% by weight, preferably 15 to 40% by weight microcapsules, including.

Conveniently, the amount of solvent-liquid phase (preferably water) for the active ingredient is based on the proportion of the lysing active ingredient resulting from the microcapsules, based on the total weight of the active ingredient contained in the microcapsules. By weight% or less, preferably 5% by weight or less.

In a first aspect of the invention, the liquid phase is saturated with the active ingredient (excluding amoxicillin), at least partially, preferably entirely, after the introduction of the microcapsules into the liquid phase. In the essential dissolution, what is contained in the microcapsules and saturates the liquid phase is the active ingredient.

In a second aspect of the invention, the liquid phase is at least partially, preferably entirely, by the non-encapsulating active ingredient prior to introduction of the microcapsules into the liquid phase. Saturated with (excluding amoxicillin). This embodiment is of particular value for administration of amoxicillin in allowing the immediate release fraction to be combined with the modified release fraction.

In fact, this amount is to saturate the liquid phase with the active ingredient prior to the introduction of the microcapsules into the suspension, and therefore the active ingredient contained in the microcapsules is related to the saturation of the liquid phase. No, or little to do with it. Therefore, the diffusion of the active ingredient contained in the microcapsules is suppressed or almost suppressed.

According to one preferred feature of the invention that allows this liquid oral formulation to be fully effective, the microcapsules have a particle size of 1000 microns or less, preferably 200-800 microns, and particularly preferably 200-600 microns.

"Particle size" is understood in the context of the present invention as it means that at least 75% by weight of the microcapsules have a diameter limited to the sieve size in question.

Also, for the purpose of improving efficacy, the amount of coating agent for the microcapsules is advantageously corresponding to 1-50%, preferably 5-40% of the weight of the coated microcapsules. This advantageous feature, due to their small size, microcapsules have a large specific surface area and should be acquired to facilitate release.

In order to control the in vivo and in vitro release of the active ingredient, it is preferred to use a film coating for microcapsules belonging to Group A or C according to the present invention.

For more detailed qualitative and quantitative information on this Group A coating composition, refer to European Patent EP-B-0 709 087. The contents are incorporated herein by reference.

Another possible method of defining the liquid suspension of the present invention is in vitro obtained in a phosphate buffer medium at pH 6.8, 37 ° C. using the Type II apparatus described in the 3rd edition of the European Pharmacopoeia. To consider the release profile, this is The percentage PI of the active ingredient released during the initial 15 minutes of the dissolution test is PI 15 Preferably PI 5; The remaining active ingredient is AP (t)_1/2) 50% by weight release time is released over a period defined as: 0.5 t_1/230 Preferably 0.5 t_1/2≦20。

In addition, with respect to in vitro dissolution properties, the suspensions of the present invention --Immediately after suspending the microcapsules in the solvent (preferably water) phase, a phosphate buffer with a pH of 6.8, a volume of 900 ml and a temperature of 37 ° C using a type II device described in the Third Edition of the European Pharmacopoeia. Early in vitro release profile obtained in media Pfi, as well as, --10 days after suspending the microcapsules in the solvent (preferably water) phase, a phosphate buffer at pH 6.8 and temperature 37 ° C using the Type II apparatus described in the 3rd edition of the European Pharmacopoeia. In vitro release profile Pf obtained in media₁₀, However, it is characterized by being similar.

European Medicines Evaluation Unit-/ Committee for proprietary medicinal products (CPMP) --London, 29 July 1999, CPMP / QWP / 604/96: Guidance on the quality of modified release products Description for: A: Oral formulation form, B: Transdermal dosage form-Section I (Quality)-Attachment 3: Similar factor f2: Release profile yields a value of> 50 for similar factor f2, hence , The similarity is clear.

Due to these advantageous characteristics of the suspension according to the present invention, high doses of the active ingredient can be taken orally without difficulty and without altering or optionally delaying the release mode of the active ingredient. It is possible to administer.

According to another advantageous physicochemical feature, the pH of the liquid suspension of the present invention can be optionally acidic or neutral.

It is extremely valuable to add at least one rheological modifier to the suspension. In particular, it is commonly used in the pharmaceutical industry, especially in the Handbook of Pharmaceutical Excipients (3rd Edition, Am. Pharmaceutical Association, Arthur H. KIBBE, 2000, ISBN 0917330-96-X. Europe. It may be one or more "viscosifiers" selected from those described in 0-85369-381-1). Examples mentioned are: --Water-soluble cellulose derivatives (hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, etc.); --Polyethylene glycol; --Arginate and its derivatives; --Carrageenan; --Agar; --Gelatin; - Maltodextrin; --Polydextrose; --Gar, carob, acacia, xanthan, gueran and other rubbers; --Polyvinyl alcohol; --Povidone; --Pectin; --Silica gel; --Natural and modified starches and their derivatives; --Dextran; --Other Is.

It is also a good idea to introduce into the suspension at least one agent for modifying the solubility of the active ingredient in the liquid phase of the solvent (preferably water), such as salt, sugar, glycerol and the like. In fact, in the case of very well soluble active ingredients, their solutes can suppress the leakage of the active ingredient from the microcapsules by reducing the saturation concentration of the active ingredient in the aqueous phase.

Surfactants, colorants, dispersants, preservatives, taste improvers, to ensure that the suspension has all of the quality of oral gallen pharmaceutical forms that are easy to swallow, stable and tasty. It is beneficial to include at least one additive selected from the group containing flavorings, sweeteners, antioxidants and mixtures thereof.

Examples of these additives mentioned are commonly used in the pharmaceutical industry, and in particular, the Pharmaceutical Excipients Handbook (3rd Edition, Pharmaceutical Association, Arthur H. KIBBE, 2000, ISBN 0917330-96-X. Europe. It is disclosed in 0-85369-381-1), or in the case of emulsifiers, it is described on page 5, lines 14-29 of EP-A-0 273 890, and in the case of thickeners, EP-A-0. It is shown on page 5, lines 19 to 20 of 601 508.

The active ingredient used to prepare the controlled release suspension of the present invention can be selected from at least one of the following very diverse active agents: anti-ulceric agents, anti-diabetic agents, anti-coagulation agents. Drugs, antithrombotic drugs, antithrombotic drugs, antiarrhythmic drugs, vasodilators, antiangiopathic drugs, antihypertensive drugs, vasoprotectors, fertility promoters, Delivery inducers and inhibitors, contraceptives, antibiotics, antifungal drugs, antiviral drugs, anticancer drugs, antiinflammatory drugs, analgesics, antiepileptic drugs, anti-Parkinson's disease drugs, neuroleptics, hypnotics, anti- Anxiety drugs, psychostimulants, anti-biased drugs, antidepressants, antitussives, antihistamines, and antiallergic drugs.

The present invention is particularly limited to, but not limited to, for pharmaceutical active ingredients that need to be orally administered at high doses, such as 500-1000 milligrams or more, and for suspensions for pediatrics. Applies.

The active ingredient is preferably selected from the following compounds: pentoxyphyllin, prazocin, acyclovir, nifedipine, zirchiazem, naproxen, ibprofen, flurubiprofen, ketoprofen, phenoprofen, indomethacin, diclofenac, fentiazac, valerate. Estradiol, metopril, sulpylide, captopril, cimetidine, diclofenac, nifedipine, terphenazine, atenolol, salbutamoll, carbamazepine, lanitidine, enalapril, simbatatin, fluoroxetin, alprazolam, famotidine, gancyclovir, famciclov , Perindopril, morphin, pentazocin, metformin, acetaminophen, omeprazole, metoclopramide, atenolol, salbutamoll Morphine, verapamil, erythromycin, caffeine, frosemide, cephalosphorin, montelukast, valaciclovir, ascorbate, diazepam, theophylline, ciprofloxacin, vancomycin, aminoglycoside, penicillin (excluding amoxicillin) and them. Mixture of.

More specifically, the invention further comprises a kit for preparing a suspension as defined above with respect to a drug, more precisely a Galen pharmaceutical pack. --Substantially dry microcapsules containing the active ingredient to saturate the liquid phase with the active ingredient when the two solid and liquid phases are brought into contact; -And / or modified doses of active ingredient required for release are required to saturate the liquid phase with the active ingredient when the saturated dose of active ingredient is contacted with the liquid phase. A mixture of microcapsules in a substantially dry form, including a sufficient amount of immediate release uncoated active ingredient; -And at least a portion of the liquid phase and / or components useful in its preparation, and / or a protocol for the preparation of the suspension.

This type of aesthetic agent according to the present invention facilitates the patient to prepare a modified release suspension in a stable form, especially with respect to the modified release, for at least several days. be able to. Therefore, the patient is easy to administer orally and is guaranteed a perfectly effective drug from a therapeutic point of view.

The microcapsules constituting the solid phase of the suspension of the present invention can be prepared by microencapsulation techniques available to engineers in the field, and the main techniques are C. DUVERNEY and JP BENOIT. Outlined in an article by ("L'actualite chimique", 1986, December). More specifically, the technique in question is microencapsulation by film coating, which yields a personalized "reservoir" system as opposed to the matrix system. More specifically, the reference is patent EP-B-0 953 359 described above.

It is beneficial to use particles of the active ingredient of the desired size as a starting material to generate nuclei based on the active ingredient (excluding amoxicillin) of the microcapsules of the present invention. The particles are crystals of pure active ingredient and / or in the presence of at least one convenient small amount of binder and / or agent for altering the solubility properties inherent in the AP. It may be pretreated by one of the convenient techniques used in the field, eg granulation.

The present invention is provided solely for illustration purposes and will be more clearly understood in terms of its composition, properties and preparation with the help of the following examples showing variants and advantages of the present invention.

[Example 1] Preparation of acyclovir microcapsules: 1000 g of acyclovir and 30 g of povidone® were mixed dry for 5 minutes. The mixture was granulated with water. The granules were dried in a ventilation dryer at 40 ° C. and then categorized on a 500 μm sieve. Fractions of 200-500 μm were selected. 700 g of the granules obtained above dissolved in a 60/40 w / w acetone / isopropanol mixture, 27.3 g of ethyl cellulose, 3.7 g of castor oil, 3.7 g of magnesium stearate, and 2.9 g of povidone (R). And coated using the Glatt GPC-G1 fluidized air bed device. Product temperature: 40 ° C.

Suspension preparation: The 0.58 g microcapsules obtained above were placed in 37 ml, pH 6.8 phosphate buffer.

test: The suspension was stored at room temperature for 10 days. After 10 days, the suspension was subjected to blade stirring at 100 rpm in a phosphate buffer medium at pH 6.8, volume 900 ml, temperature 37 ° C, using a Type II device according to the third edition of the European Pharmacopoeia. ), The dissolution was analyzed by UV detection at 252 nm. The results are shown in Attached Figure 1.

This profile is clearly identical: similar factor f₂Is greater than 50. The microcapsules remained highly efficient in the aqueous suspension.

[Example 2] Preparation of Spironolactone Microcapsules: Step 1: Granules First, 45 g of spironolactone, 25 g of PEG40-hydrogenated castor oil and 30 g of povidone were solubilized in a water / acetone / isopropanol mixture (5/57/38 w / w). The solution was then sprayed onto 800 g of cellulose spheres (300-500 μm in diameter) using a Glatt GPC-G1 fluidized air bed device.

Step 2: Coating 1.44 g of ethyl cellulose, 0.16 g of castor oil, 0.64 g of poloxamer 188, and 0.96 g of povidone obtained by dissolving 50 g of the granules obtained above in an acetone / isopropanol mixture (60/40 w / w). And coated using the Glatt GPC-G1 fluidized air bed device.

Suspension preparation: The 0.07 g microcapsules obtained above were placed in 0.165 ml of phosphate buffer at pH 6.8.

test: The suspension was stored at room temperature for 19 days. After 19 days, the suspension was blade agitated at 100 rpm in a phosphate buffer medium at pH 6.8, volume 1000 ml, temperature 37 ° C, using a Type II device according to the third edition of the European Pharmacopoeia. ), The dissolution was analyzed by UV detection at 240 nm. The results are shown in Attached Figure 2.

The profile is clearly the same: similar factor f₂Is greater than 50. The microcapsules remained very efficiently in the aqueous suspension.

[Example 3] Preparation of Metformin Microcapsules: 192.4 g of ethyl cellulose, 26 g of castor oil, 26 g of magnesium stearate, and 20.8 g of povidone (R) in which 740 g of metformin crystals (200-500 μm fraction) were dissolved in a 60/40 w / w acetone / isopropanol mixture. And coated using the Glatt GPC-G1 fluidized air bed device. Product temperature: 40 ° C.

Preparation of suspensions (29% free and 71% encapsulated form): The 50 g microcapsules obtained above were dried and mixed with 15 g metformin crystals and 0.7 g xanthan gum in a 100 ml glass flask. 34.3 g of purified water was then added to the powder mixture. After manual agitation, a suspension is obtained that produces a sediment very slowly. The total metformin titer in suspension is 0.52 g / ml.

Stability test: The suspension was stored at room temperature for 12 days. After 12 days, the suspension was blade agitated at 100 rpm in a phosphate buffer medium at pH 6.8, volume 900 ml, temperature 37 ° C, using a Type II device according to the third edition of the European Pharmacopoeia. ), The dissolution was analyzed by UV detection at 232 nm. The results are shown in Attached Figure 3.

The profile is clearly the same: similar factor f₂Is greater than 50. The microcapsules remained very efficiently in the aqueous suspension.

Uniformity test: The suspension was manually agitated and then 6 5 ml samples were taken in a graduated syringe. The metformin content of each sample was measured by HPLC and shown below:<tables num="1"><img file="JP4732696B2_D0001.tif" /></tables>

The sample was very uniform and its dose was shown to match the expected value of 2.60 g for 5 ml.

Therefore, this preparation can be administered without the risk of overdose or underdose.

<figref num="1">The initial dissolution profile of the suspension of Example 1 and the dissolution profile after storage for 10 days are shown. Solubility (D)% is a function of time (hours).</figref><figref num="2">The initial dissolution profile of the suspension of Example 2 and the dissolution profile after storage for 19 days are shown. Solubility (D)% is a function of time (hours).</figref><figref num="3">The initial dissolution profile of the suspension of Example 3 and the dissolution profile after storage for 12 days are shown. Solubility (D)% is a function of time (hours). This suspension was combined with 29% free metformin and 71% encapsulated metformin.</figref>