Method for producing pharmaceutical composition containing microparticles

Abstract

A pharmaceutical composition having a consistent desired release rate is prepared by controlling the final mixing time based on the molecular weight measured in the intermediate product. The pharmaceutical composition comprises microparticles containing a polyhydric alcohol, a salt, a water-soluble polymer, and a pharmaceutically active ingredient. The microparticles are dispersed in a matrix of a hydrophobic component and an amphiphilic component.

Description

[Technical field]

[0001] The present invention relates to a method for producing a pharmaceutical composition. More specifically, the present invention relates to a method for producing a pharmaceutical composition containing microparticles that can stably contain a water-labile active ingredient and remain at the administration site, thereby releasing such an active ingredient over a long period of time. [Background technology]

[0002] (Related Technology) Some active ingredients of pharmaceutical compositions, such as antibiotics and anti-inflammatory agents, are highly effective but unstable, and therefore their incorporation into pharmaceutical compositions is limited.For example, tetracycline and macrolide antibiotics are active ingredients with a broad antibacterial spectrum, but they are substances that are affected by water, heat, or additives, and are easily denatured when incorporated into a composition.Therefore, various techniques have been studied to stably incorporate these antibiotics into pharmaceutical compositions. For example, JP52-90616A discloses an aqueous solution for injection, which aims to stabilize tetracycline antibiotics such as oxytetracycline, doxycycline, tetracycline, chlortetracycline or their salts by chelating it with an alkaline earth metal compound such as a magnesium compound in an aqueous solution of 2-pyrrolidone. Furthermore, JP53-94028A discloses a pharmaceutical composition, which aims to stabilize oxytetracycline by incorporating alkaline earth metal ions, polyvinylpyrrolidone and an aliphatic amide into the composition and adjusting the pH of the composition to 5.0-7.5. Furthermore, U.S. Patent No. 3,335,055 discloses a method for stabilizing tetracycline using magnesium ions and a pyridine derivative such as isonicotinamide. Furthermore, JPH02-34325B and JPH07-29930B disclose pharmaceutical compositions that can stably contain minocycline, a tetracycline antibiotic, and that can exert the sustained effect of minocycline for a long period of time by blending minocycline with a magnesium compound, a water-soluble polymer, a polyhydric alcohol, a methacrylate copolymer, and a solubilizer.

[0003] When such pharmaceutical compositions are simply prepared according to a conventional procedure, water is mixed into the pharmaceutical composition, and this water binds to the highly hydratable components in the composition, so that it cannot be sufficiently removed by simply heating the composition at a high temperature for a long time. In addition, sometimes the molecular chains of the polymers in the composition are cut, and the components in the composition are denatured due to chemical reactions between the components. In the case of periodontal pharmaceutical compositions, when a pharmaceutical composition that does not remain at the administration site is administered to a periodontal disease site, such as a periodontal pocket, a high concentration of the active ingredient may temporarily remain in the periodontal pocket and a certain degree of therapeutic effect may be obtained, but the concentration of the active ingredient in the periodontal pocket cannot be maintained for a long period of time due to the flow of saliva, food, drink, etc. in the oral cavity. US20080248124 discloses a method for preparing a pharmaceutical composition containing a water-labile active ingredient and providing a sustained release for a long period of time. The method includes the steps of (i) mixing and heating a first phase prepared by mixing component (A) one or more polyhydric alcohols and (B) one or more salts under reduced pressure with a second phase containing component (C) one or more water-soluble polymers before evaporating substantially all of the water in the first phase by mixing and heating the mixture of the first and second phases under reduced pressure, or after evaporating substantially all of the water in the first phase by mixing and heating the first phase under reduced pressure; and (ii) adding component (D) a third phase containing one or more active ingredients to the mixture to obtain a pharmaceutical composition. The pharmaceutical composition prepared by this method can stably incorporate the water-labile active ingredient and remain at the administration site, thereby enabling the active ingredient to be sustainedly released for a long period of time. There is still interest in the manufacture of such pharmaceutical compositions that consistently exhibit a desirable release rate.

Summary of the Invention

[0004] A pharmaceutical composition containing microparticles dispersed in a matrix is i) obtaining a mixture containing component (A), component (B), and component (C) having a molecular weight M measured by gel permeation chromatography; and ii) mixing the mixture with a pharmaceutically active ingredient (D), a hydrophobic ingredient (E), and an amphiphilic ingredient (F) at a temperature in the range of about 30°C to 70°C for T minutes, thereby preparing a pharmaceutical composition, satisfying the formula I: 0.00136M - 230 < T < 0.00136M - 169; Component (A) is a polyhydric alcohol; Component (B) is an inorganic magnesium, calcium, or barium salt, or a hydrate thereof; Component (C) is a water-soluble polymer.

Brief Description of the Drawings

[0005]

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Modes for Carrying Out the Invention

[0006] In one embodiment, a method for preparing a pharmaceutical composition includes: (i) obtaining a first mixture comprising component (A), component (B), and component (C) having a molecular weight M as measured by gel permeation chromatography; and (ii) mixing the first mixture with a pharma- ceutical active component (D), a hydrophobic component (E), and an amphiphilic component (F). Component (A) is a polyhydric alcohol, preferably a water-soluble polymer. Examples of polyhydric alcohols include, but are not limited to, glycerin, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, hexylene glycol, 1,5-pentanediol, 1,3-butylene glycol, polyethylene glycol, and the like. The polyhydric alcohols may be used alone or in combination of two or more. In one embodiment, component (A) is glycerin, ethylene glycol, or diethylene glycol. Glycerin is particularly preferred because it has a high water content and is less irritating to the human body. Furthermore, pharmaceutical compositions produced using glycerin exhibit excellent properties.

[0007] In one embodiment, the amount of component (A) is about 50% to about 85% by weight based on the total weight of the pharmaceutical composition. Preferably, the amount of component (A) is about 65% or about 70% by weight or more and about 80% by weight or less based on the total weight of the pharmaceutical composition. When the term "about" is used herein in connection with a numerical value, it is intended that the associated numerical value includes a tolerance of ±10% around the stated numerical value. Component (B) is a salt, preferably an inorganic salt. Useful salts include, but are not limited to, alkaline earth metal salts including magnesium salts such as magnesium chloride, magnesium acetate, magnesium sulfate, magnesium nitrate, magnesium carbonate, magnesium gluconate, magnesium oxide, and magnesium hydroxide; calcium salts such as calcium chloride, calcium sulfate, calcium nitrate, calcium gluconate, calcium malate, calcium lactate, calcium oxide, and calcium hydroxide; and barium salts such as barium chloride, barium sulfate, and barium nitrate. Hydrates of the above salts can also be used. The salts and their hydrates may be used alone or in combination of two or more. Among these, magnesium salts such as magnesium chloride, magnesium gluconate, magnesium acetate, magnesium sulfate, and magnesium nitrate or their hydrates are preferred because they suitably stabilize the active ingredient (D), which is unstable in water. In one embodiment, component (B) is magnesium chloride, magnesium gluconate, or a hydrate thereof. Magnesium chloride or its hexahydrate, which is widely used in the pharmaceutical field, is particularly preferred.

[0008] The amount of component (B) is about 0.5% by mass to about 10% by mass based on the total mass of the pharmaceutical composition. Preferably, the amount of component (B) is about 2% by mass or about 3% by mass or more and about 7% by mass or less or about 6% by mass or less based on the total mass of the pharmaceutical composition. In one embodiment, the amount of component (B) is about 5% by mass based on the total mass of the pharmaceutical composition. Component (C) is a water-soluble polymer. Useful water-soluble polymers include, but are not limited to, hydroxyethyl cellulose, hydroxymethyl cellulose (referred to as HEC), methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl ethyl cellulose, sodium carboxymethyl cellulose, sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone, carrageenan, xanthan gum, locust bean gum, guar gum, tragacanth gum, starch, succinoglucan, and the like. The water-soluble polymers may be used alone or in combination of two or more. In one embodiment, water-soluble polymers having hydroxyl groups are preferred. Cellulose derivatives are more preferred, with hydroxyethyl cellulose being particularly preferred. In one embodiment, component (C) is hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, or polyvinylpyrrolidone. In other embodiments, component (C) is hydroxyethyl cellulose or polyvinylpyrrolidone.

[0009] In one embodiment, the viscosity of a 2% aqueous solution of HEC is preferably 200 to 500, and more preferably 250 to 400, when measured at 25° C. with a Brookfield viscometer. The amount of component (C) is about 0.1% by mass to about 20% by mass based on the total mass of the pharmaceutical composition. Preferably, the amount of component (C) is about 2% by mass or about 3% by mass or more and about 7% by mass or less or about 5% by mass or less based on the total mass of the pharmaceutical composition. In one embodiment, the amount of component (C) is about 4% by mass based on the total mass of the pharmaceutical composition. In another embodiment, the amount of component (C) is about 0.2 parts by weight to about 50 parts by weight, preferably about 1 part by weight to about 10 parts by weight, based on 100 parts by weight of component (A).

[0010] The active ingredient (D) includes a water-unstable active ingredient that becomes unstable in the presence of water. The phrase "water-unstable active ingredient" as used herein means a compound in which the proportion of undenatured components decreases to 95% or less, preferably 90% or less, when dissolved or mixed with purified water at room temperature and stored at 25°C for 7 days. Examples of water-unstable active ingredients include antibacterial agents such as tetracyclines, penicillins, carbapenems, cephems, monobactams, aminoglycosides, and macrolide antibiotics; antifungal agents such as polyenes, azoles, echinocandins, and pyrimidine antibiotics; and anti-inflammatory agents such as steroids and non-steroids. Pharmaceutically acceptable salts of the above compounds can also be used. The active ingredient or its pharma- ceutically acceptable salt may be used alone or in combination of two or more. In a preferred embodiment, one or more tetracycline antibiotics that are significantly stabilized by salts of divalent metal ions can be used, such as minocycline, doxycycline, tetracycline, oxytetracycline, chlortetracycline and their pharma- ceutical acceptable salts.In another preferred embodiment, minocycline or its pharma-ceutical acceptable salts, such as minocycline hydrochloride, can be used.Minocycline has a high affinity to the tooth surface, so it remains in that position after release.Therefore, the pharmaceutical composition containing minocycline can be used as a topical antibiotic agent for effectively treating moderate to severe chronic periodontal disease.

[0011] The amount of the active ingredient (D) may vary depending on the desired effect, and is usually about 0.1% by mass to about 10% by mass based on the total mass of the pharmaceutical composition. Preferably, the amount of the active ingredient (D) is about 0.5%, about 0.7%, or about 1% by mass or more, and about 5%, about 3%, or about 2.5% by mass or less, based on the total mass of the pharmaceutical composition. Component (E) is preferably a methacrylate copolymer. Examples of methacrylate copolymers include, but are not limited to, aminoalkyl methacrylate copolymers (copolymers of methyl methacrylate, butyl methacrylate, and dimethylaminoethyl methacrylate (e.g., Eudragit® E, Pharma Polymers)) and aminoalkyl methacrylate copolymers (copolymers of ethyl acrylate, methyl methacrylate, and methacrylate ethyl trimethyl ammonium chloride (e.g., Eudragit® RS, Pharma Polymers)). The methacrylate copolymers may be used alone or in combination of two or more.

[0012] The amount of component (E) is about 0.5% by mass to about 10% by mass based on the total mass of the pharmaceutical composition. When the amount of component (E) is less than about 0.5% by mass, it is difficult to achieve sustained release of the active ingredient (D). On the other hand, when the amount of component (E) is more than about 10% by mass, the viscoelasticity of the composition increases, making it difficult to manufacture the pharmaceutical composition. Preferably, the amount of component (E) is about 0.5% by mass or about 1% by mass or more, and about 5% by mass or about 3% by mass or less, based on the total mass of the pharmaceutical composition. In one embodiment, the amount of component (E) is about 2% by mass based on the total mass of the pharmaceutical composition. The amphiphilic component (F) is preferably an organic solvent. Examples of organic solvents include, but are not limited to, esters of lower polyhydric alcohols and lower fatty acids, such as triacetin, tributyrin, and ethylene glycol diacetate, and esters of lower alcohols and dicarboxylic acids, such as diethyl sebacate, diethyl phthalate, dibutyl phthalate, diisopropyl adipate, and dibutyl succinate. The organic solvents may be used alone or in combination of two or more. As used herein, the term "lower polyhydric alcohol" refers to a polyhydric alcohol containing 2 to 6 carbon atoms. The lower fatty acids and lower alcohols each contain 1 to 6 carbon atoms.

[0013] The amount of component (F) is preferably about 5% by mass to about 25% by mass based on the total mass of the pharmaceutical composition. When the amount of component (F) is within this range, a suitable pharmaceutical composition can be formed and the desired sustained release of the active ingredient (D) can be achieved. Preferably, the amount of component (F) is about 7% by mass or about 10% by mass or more and about 15% by mass or about 14% by mass or less based on the total mass of the pharmaceutical composition. In one embodiment, the amount of component (F) is about 12% by mass based on the total mass of the pharmaceutical composition. When the quantitative ranges of the above-mentioned components are defined in this specification, when the total amount of each component exceeds 100% by mass, it should be understood that this means that each component is added in an amount within the specified range so that the total amount of the components does not exceed 100% by mass. In the pharmaceutical composition described herein, it is believed that component (A) (e.g., polyhydric alcohol) dissolves component (B) (e.g., salt) to form microparticles containing active ingredient (D) (e.g., minocycline) and component (B) together with component (C) (e.g., water-soluble polymer). Component (B) is used to stabilize the water-unstable active ingredient (D) in the pharmaceutical composition. Component (E) (e.g., Eudragit) and component (F) (e.g., triacetin) are substantially immiscible with component (A) and are added to form a matrix for the microparticles and impart sustained release properties to the active ingredient stably contained in the microparticles. In particular, when the composition comes into contact with water or saliva, component (F) in the matrix is ​​gradually replaced by water. When the water penetrates the matrix and finally reaches the microparticles containing active ingredient (D), the active ingredient (D) dissolves in water and is released from the microparticles.

[0014] Next, a method for preparing the pharmaceutical composition will be described. In the first step of the method, component (A) and component (B) are mixed to obtain a first mixture. In one embodiment, the first mixture containing component (A) and component (B) is heated so that component (B) is completely dissolved in component (A). In another embodiment, substantially all of the water contained in the first mixture is removed, for example, by heating the mixture, preferably under reduced pressure. Any suitable mixing means can be used. In one embodiment, "mixing" is achieved by stirring. Typically, the first step is carried out at a temperature of about 80°C or higher, preferably about 90°C to about 100°C, and under a reduced pressure of about 100 mmHg or less, preferably about 80 mmHg or less. When the temperature is lower than about 80°C, not all of component (B) can be dissolved in component (A). On the other hand, when the pressure is not reduced to about 100 mmHg or less, it becomes difficult to remove substantially all of the water from the first mixture. As used herein, the phrase "removing substantially all water" means that the mixture contains no more than about 5% by weight, preferably no more than about 3% by weight, and more preferably no more than about 1% by weight, based on the total weight of the mixture.

[0015] Preferably, the amount of water contained in the first mixture may be calculated by measuring the amount of captured water removed, for example, by suction, and subtracting the measured amount from the amount of water contained in the first mixture before suction, thereby allowing the amount of water contained in the first mixture to be accurately calculated. In one embodiment, the blending ratio of component (B) is about 2 parts by mass to about 11 parts by mass, preferably about 4 parts by mass to about 9 parts by mass, and more preferably about 6 to 8 parts by mass per 100 parts by mass of component (A). Next, component (C) is mixed with the first mixture to obtain a second mixture. Depending on the type of component (A) contained in the first mixture, when component (C) is added alone, it may be difficult to uniformly mix with the first mixture even at high temperatures (e.g., 140°C or higher). In such cases, component (C) may be dispersed in a polyhydric alcohol at ambient temperature and then added to the first mixture. This polyhydric alcohol may be the same as or different from component (A) contained in the first mixture.

[0016] In one embodiment, the blending ratio of component (C) is about 2 parts by mass to about 11 parts by mass, preferably about 4 parts by mass to about 8 parts by mass, and more preferably about 5 parts by mass to about 6 parts by mass per 100 parts by mass of component (A). In another embodiment, the blending ratio of component (B) is about 0.3 parts by mass to about 3.5 parts by mass, preferably about 0.5 parts by mass to about 2.5 parts by mass, and more preferably about 0.7 to 1.5 parts by mass per part by mass of component (C). The second mixture containing components (A), (B) and (C) is then heated to about 95°C to about 180°C, preferably about 100°C to about 140°C. When the temperature of the second mixture is lower than about 95°C, it becomes difficult to completely dissolve component (C). On the other hand, when the temperature of the second mixture is higher than about 180°C, decomposition of component (C) occurs, which may make it impossible to stably incorporate active ingredient (D) into the pharmaceutical composition. In one embodiment, this step is carried out under atmospheric pressure or under reduced pressure. When mixing is carried out under atmospheric pressure, the conditions are milder than those under reduced pressure, so that denaturation of the components, such as decomposition of component (C), can be suppressed. On the other hand, when mixing is carried out under reduced pressure, water can be further removed from the mixture during mixing. Preferably, this step is carried out under atmospheric pressure and then under reduced pressure. This not only allows component (C) to be gently mixed with the first mixture under atmospheric pressure, but also allows air bubbles in the second mixture to be removed simultaneously with the removal of water under reduced pressure, thereby further improving the stability of the pharmaceutical composition.

[0017] In one embodiment, the second mixture is subjected to reduced pressure after the dissolution of component (C) is confirmed. The degree of reduced pressure may be set as appropriate, preferably about 100 mmHg or less, more preferably about 80 mmHg or less. Further, the reduced pressure may be started at an initial temperature of about 65°C or higher, preferably about 80°C or higher, and then the temperature may be lowered to about 75°C or lower, preferably 65°C or lower while reducing the pressure. In one embodiment, substantially all of the water in the second mixture is removed before mixing with the active ingredient (D). Further, from the viewpoint of the stability of component (C), it is preferable to carry out water removal under reduced pressure on the first mixture before mixing the first mixture and component (C). After confirming that component (C) is uniformly dissolved in the second mixture, the weight average molecular weight Mw of component (C) in the second mixture is measured by, for example, gel permeation chromatography. In one embodiment, the molecular weight of the water-soluble polymer in the second mixture is about 150,000 to about 300,000, more preferably about 170,000 to about 285,000. Typically, Mw of component (C) in the second mixture is 20 - 30% smaller than Mw of component (C) before being mixed with the first mixture due to the cleavage of component (C) caused by the increase in temperature.

[0018] Next, the temperature of the second mixture is maintained at about 75°C or lower, preferably about 70°C or lower, and more preferably about 65°C or lower, and about 30°C or higher, and more preferably about 35°C or higher. Then the second mixture is mixed with the active ingredient (D), the hydrophobic component (E), and the amphiphilic component (F) for T minutes. When the temperature is higher than about 75°C, decomposition of the active ingredient (D) may occur, and the efficacy of the pharmaceutical composition may decrease. In one embodiment, the mixture is preferably degassed under reduced pressure, preferably at about 100 mmHg or less, more preferably at about 80 mmHg or less. Further, when the mixture is not degassed, the stability of the pharmaceutical composition decreases. T refers to the mixing time when all of components (A) to (F) are present. In one embodiment, T satisfies the formula: 0.00136M - 287 < T < 0.00136M - 161. In other embodiments, T is the following formula I: 0.00136M - 230 < T < 0.00136M - 169, Formula I is satisfied. In one embodiment, T is in the range of about 30 minutes to about 180 minutes. In other embodiments, T is in the range of about 30 minutes to about 90 minutes.

[0019] Mixing can be carried out with any suitable device. In one embodiment, mixing is carried out in a circular pot equipped with a stirring device. The pot can have a diameter of about 350 mm and a depth of about 300 mm. The stirring device can be a stirring rod having one or more stirring blades at one end. The rotation speed can be about 5 - 60 rpm. In one embodiment, the active ingredient (D) is dissolved in a polyhydric alcohol which may be the same as or different from the component (A) used alone or in the first mixture, and then mixed with the second mixture at a temperature of about 60°C to about 70°C. Thereafter, the resulting mixture is cooled to about 30°C to about 35°C, and components (E) and (F) are added thereto. Preferably, component (E) is first dissolved in component (F) before addition. In one embodiment, the amount of component (B) is about 0.5 times to about 10 times the mass based on the mass of the active ingredient (D). When the amount of component (B) is within this range, the active ingredient (D) can be stably formulated into the pharmaceutical composition. Preferably, the amount of component (B) is about 1 time or about 2 times or more and about 8 times or about 5 times or less the mass based on the mass of the active ingredient (D). In one embodiment, the amount of component (B) is about 2.5 times the mass based on the mass of the active ingredient (D).

[0020] In certain embodiments, the mixing ratio of components (E) and (F) is about 1 part by mass to about 100 parts by mass per 100 parts by mass in total of components (A), (B), (C) and (D). Within this mixing ratio, the particle size of the fine particles can be controlled within a desired range. Preferably, the mixing ratio of components (E) and (F) is about 8 parts by mass or about 12 parts by mass or more and about 25 parts by mass or about 20 parts by mass or less per 100 parts by mass in total of components (A), (B), (C) and (D). In another embodiment, the compounding ratio of component (F) is preferably 1.5 to 10 times, more preferably 3.5 to 7 times, and most preferably 6 times, compared with component (E). When this compounding ratio increases, the particle size of the microparticles increases. Furthermore, the release rate of the active ingredient from the microparticles increases with increasing particle size. When the particle size of the microparticles increases, the viscoelasticity of the pharmaceutical composition decreases, and it is believed that the retention of the pharmaceutical composition at the administration site decreases. When the compounding ratio is not within the above range, the stability of the matrix deteriorates, making it difficult to sustained release of the active ingredient. In one embodiment, the resulting pharmaceutical composition comprises microparticles formed by components (A), (B), (C) and (D), which are dispersed in a matrix formed by components (E) and (F). In one embodiment, the microparticles have an average particle size of about 0.5 μm to about 1.2 μm. Preferably, the particle size is greater than about 0.7 μm or about 0.8 μm and less than about 1.0 μm or about 0.9 μm.

[0021] In other embodiments, the pharmaceutical composition described herein is substantially free of water.The amount of water contained in the pharmaceutical composition is preferably about 5% by weight or less, more preferably about 3% by weight or less, and more preferably about 1% by weight or less, based on the total weight of the pharmaceutical composition.When the amount of water is more than about 5% by weight, the efficacy of active ingredient (D) cannot be maintained for a long time. Furthermore, the pharmaceutical compositions described in this specification may contain, in addition to the above-mentioned components (A) to (F), other components that are conventionally used in pharmaceutical compositions, such as colorants, flavoring agents, surfactants, excipients, etc., so long as they do not impair the effects of the pharmaceutical composition. In one embodiment, the pharmaceutical composition has a viscoelasticity (tan δ) measured at 2 Hz of about 0.35 to about 0.60. Preferably, the viscoelasticity is greater than or equal to about 0.44 or about 0.45 and less than or equal to about 0.55 or about 0.53. In another embodiment, the pharmaceutical composition has a release rate of about 40% to about 90% in 7 hours, more preferably about 50% or about 55% or more and about 80% or about 70% or less in 7 hours.

[0022] The pharmaceutical composition described herein can be administered externally, particularly to mucous membranes. For example, when minocycline or a pharma- ceutical acceptable salt thereof is used as an active ingredient, it can be prepared into a dental pharmaceutical composition. The dental pharmaceutical composition can be prepared as a paste-like ointment pharmaceutical composition administered locally. In this case, it can be conveniently administered to the affected site such as a periodontal pocket using a syringe for use in periodontal disease. Furthermore, it can suppress systemic side effects that have been observed in oral administration in the past, such as digestive side effects such as anorexia, nausea, and diarrhea, biochemical side effects such as thrombocytopenia and eosinophilia, or the occurrence of superinfection, and can efficiently exert its medicinal effect. Furthermore, by releasing minocycline for a long period of time, it becomes unnecessary to re-administer the pharmaceutical composition to the patient within a short period of time, and the burden on the patient is reduced. The present invention will now be described in more detail with reference to examples, which are intended as illustrations and should not be construed as limiting the scope of the invention. All references cited herein and in the Examples below are expressly incorporated by reference in their entirety.

[0023] Example 22 (Formulation of Microparticles) 11.2 kg of glycerin was placed in a 20 L planetary mixer equipped with a vacuum pump, and 1 kg of magnesium chloride hexahydrate was dispersed therein. The mixer had a diameter of 350 mm, and a depth of 300 mm. The rotation speed was 55 rpm. The mixture was heated to 90-100 °C at 100 mmHg and stirred for 60 minutes to dissolve the magnesium chloride hexahydrate in the glycerin and to remove substantially all of the water contained in the glycerin and magnesium chloride hexahydrate. The removed water was captured in a trap and its amount was measured. After the mixture was returned to atmospheric pressure, another mixture of 0.8 kg of hydroxyethyl cellulose (HEC) dispersed in 2.8 kg of glycerin was added to the mixture. The mixture was heated to 135 °C and stirred for 30 minutes until the uniform dissolution of the hydroxyethyl cellulose was visually confirmed. The mixture was cooled and an aliquot was taken to measure the molecular weight Mw of the hydroxyethyl cellulose contained in the intermediate product. The measured molecular weight was 212251. The mixture was then degassed under a vacuum of 100 mmHg. After the temperature of the mixture reached 65°C, 0.4 kg of minocycline hydrochloride dispersed in glycerin (the total mass was equal to 1 kg, which is the total mass of the trapped water (the total mass was adjusted so that the total mass of the final product was 20 kg)) was added and then stirred. After confirming the uniform dissolution of minocycline hydrochloride by visual observation, a solution of 0.4 kg of Eudragit® RS dissolved in 2.4 kg of triacetin was added. The mixture was then degassed and uniformly stirred for 60 minutes to obtain a paste-like pharmaceutical composition (composition 1) containing minocycline hydrochloride as an active ingredient in fine particles.

[0024] Molecular weight determination by gel permeation chromatography. Measurement equipment: Agilent 1260 Infinity II HPLC system Preparation of mobile phase: 0.1M NaNO 3 was prepared and degassed by ultrasonic treatment for 30 minutes. Sample preparation: 1. Pullulan (standard) was prepared at concentrations between 0.1 and 0.2% (w / v). 2. 0.08 g of sample was diluted with 1 ml of mobile phase and mixed well by vortexing and sonication. 3. Filter the solution from step 2 through a Millex-HP 13 mm PESO 0.45 μm. 4. 0.02 g of hydroxyethyl cellulose (raw material) was dissolved in 5 ml of mobile phase, mixed and filtered as in steps 2 and 3. 5. Shodex STANDARD P-82 was used as the standard material for the calibration curve.

[0025] Molecular weight determination: The molecular weight was measured under the following conditions: Column: Shodex OHpakSB-806M HQ UV detector: 210 nm Flow rate: 0.5ml / min Temperature: 50℃ Injection: 40μl

[0026] Measurement of particle size distribution The particle size of composition 1 was measured by a laser diffraction particle size distribution measuring device (e.g., Shimadzu SALD-2200). Specifically, a blank measurement was first performed. Next, a small amount of the composition was placed on a slide glass, covered with a cover glass, and pressed lightly so that the composition spread thinly. The slide glass was set in the measurement section, and a neutral density (ND) filter was attached so that the absorbance was 1.0 or less and the maximum light intensity was about 30 to 60%. The measurement was performed under the following conditions. Flexural index: 1.60-0.10i, where i denotes the angle of incidence. Number of measurements: 1 Evaluation target particle size range: 0.03 to 280.00 μm The results are shown in Figure 1. As is clear from FIG. 1, the average particle size (D50%) of Composition 1 is 1.0969 μm.

[0027] Microscopic observation Composition 1 diluted with triacetin was observed under a fluorescence microscope. Luminescence of the microparticles due to minocycline hydrochloride was observed under fluorescent light. This confirmed the presence of minocycline hydrochloride in the microparticles (Figure 2).

[0028] Measurement of release rate by dissolution test According to the test method, dissolution method, and second method of the Japanese Pharmacopoeia, with some modifications, a dissolution test was conducted. That is, a cell (2) with an inner diameter of 30 mm and a depth of 0.5 mm was filled with approximately 500 mg of the sample (1) instead of a sinker, and the cell was immersed in a container (Figure 3). Next, 500 ml of water was added and mixed while rotating at 100 rpm and 37 °C. The dissolution concentration of minocycline hydrochloride was calculated by measuring the absorbance at 348 nm using a spectrophotometer (Shimadzu Corporation, UV-260). As is clear from the results shown in Figure 4, Composition 1 showed suitable release behavior, and it was demonstrated that the active ingredient could be sustainedly released at 20 - 40% in 3 hours and 50 - 60% in 7 hours.

[0029] Examples 1 - 21 and 23 - 25 As shown in Table 1, Examples 1 - 21 and 23 - 25 were prepared in the same manner as in Example 22, except that HEC raw materials with different molecular weights were used and appropriate fixed times were applied. A plot of the final mixing time against the molecular weight of HEC in the intermediate product is shown in Figure 5.

[0030]

Table 1

[0031] As shown in Figure 5, when the mixing time T satisfies the formula I: 0.00136M - 230 < T < 0.00136M - 169, a composition with a release rate of 55% - 70% in 7 hours can be obtained. Furthermore, T = 0.00136M - 207 generated by linear approximation had a correlation coefficient R of 0.923 and showed a strong positive correlation between M and T.

[0032] Examples 111 to 139 Examples 111-139 were prepared in the same manner as in Example 22, except that HEC starting materials with different molecular weights were used and corresponding fixation times were applied, as shown in Table 2.

[0033] Rheological tests The viscoelasticity (tan δ) was measured by frequency-dependent measurement at a frequency of 2 Hz and 25° C. using a rheometer (Anton Paar MCR102). Measuring instrument: Rheometer MCR-102 (Anton Paar) Measurement cell: Φ25mm parallel plate Measurement gap: 1mm Measurement points: 16 points Temperature: 25℃ Frequency: 0.02Hz to 20Hz Strain level 1%

[0034] The viscoelasticity and release rate of Examples 111-139 were measured and the results are summarized in Table 2. A plot of release rate vs. viscoelasticity of Examples 111-139 is shown in FIG.

[0035] [Table 2]

[0036] 6, when the viscoelasticity of the composition is within the range of 0.44 to 0.55, a composition having a release rate of 50% to 80% in 7 hours can be obtained. Furthermore, when the viscoelasticity of the composition is within the range of 0.45 to 0.53, a composition having a release rate of 55% to 70% in 7 hours can usually be obtained. Another aspect of the present invention may be as follows. 〔1〕A method for preparing a pharmaceutical composition, comprising: i) obtaining a mixture comprising component (A), component (B), and component (C) having a molecular weight M measured by gel permeation chromatography; and ii) mixing the mixture with a pharmaceutically active ingredient (D), a hydrophobic component (E), and an amphiphilic component (F) at a temperature in the range of about 30 °C to 70 °C for T minutes to produce a pharmaceutical composition comprising fine particles dispersed in a matrix, where T satisfies 0.00136M - 230 < T < 0.00136M - 169; component (A) is a polyhydric alcohol; component (B) is an inorganic salt of magnesium, calcium, or barium, or a hydrate thereof; component (C) is a water-soluble polymer, the method. 〔2〕(i) Component (A) is selected from the group consisting of glycerin, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, hexylene glycol, 1,5-pentanediol, 1,3-butylene glycol, and polyethylene glycol; (ii) Component (B) is selected from the group consisting of magnesium chloride, magnesium acetate, magnesium sulfate, magnesium nitrate, magnesium carbonate, magnesium gluconate, magnesium oxide, magnesium hydroxide, calcium chloride, calcium sulfate, calcium nitrate, calcium gluconate, calcium malate, calcium lactate, calcium oxide, calcium hydroxide, barium chloride, barium sulfate, barium nitrate, and hydrates thereof; (iii) Component (C) is selected from the group consisting of hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl ethyl cellulose, sodium carboxymethyl cellulose, sodium alginate, polyvinyl alcohol, polyvinyl pyrrolidone, carrageenan, xanthan gum, locust bean gum, guar gum, tragacanth gum, starch, and succinoglucan; (iv) Component (D) is selected from the group consisting of antibacterial agents, antifungal agents, anti-inflammatory agents, and pharmaceutically acceptable salts thereof; (v) Component (E) is a methacrylate copolymer; or (vi) The method according to the above-mentioned [1], wherein the component (F) is an ester of a lower polyhydric alcohol and a lower fatty acid, or an ester of a lower alcohol and a dicarboxylic acid. [3] (i) Component (A) is glycerin, ethylene glycol, or diethylene glycol; (ii) component (B) is a magnesium salt or a hydrate thereof; (iii) component (C) is hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or polyvinylpyrrolidone; (iv) component (D) is a tetracycline, penicillin, carbapenem, cephem, monobactam, aminoglycoside, or macrolide antibiotic; a polyene, azole, echinocandin, or pyrimidine antibiotic; a steroid or nonsteroidal anti-inflammatory drug, or a pharma- ceutically acceptable salt thereof; (v) component (E) is a copolymer of methyl methacrylate with butyl methacrylate and dimethylaminoethyl methacrylate, or a copolymer of ethyl acrylate with methyl methacrylate and methacrylateethyltrimethylammonium chloride; or (vi) The method according to the above-mentioned [1], wherein the component (F) is triacetin, tributyrin, ethylene glycol diacetate, diethyl sebacate, diethyl phthalate, dibutyl phthalate, diisopropyl adipate, or dibutyl succinate. [4] (i) Component (A) is glycerin; (ii) component (B) is magnesium chloride, magnesium gluconate, or a hydrate thereof; (iii) component (C) is hydroxyethyl cellulose or polyvinylpyrrolidone; (iv) component (D) is minocycline, doxycycline, tetracycline, oxytetracycline, chlortetracycline, or a pharma- ceutically acceptable salt thereof; (v) component (E) is a copolymer of ethyl acrylate with methyl methacrylate and methacrylate ethyltrimethylammonium chloride; or (vi) The method according to the above (1), wherein the component (F) is triacetin. [5] (i) Component A is about 50% by mass to about 85% by mass based on the total mass of the pharmaceutical composition; (ii) component B is about 0.5% by mass to about 10% by mass based on the total mass of the pharmaceutical composition; (iii) component C is about 0.1% by mass to about 20% by mass based on the total mass of the pharmaceutical composition; (iv) component D is about 0.1% by mass to about 10% by mass based on the total mass of the pharmaceutical composition; (v) component E is about 0.5% by mass to about 10% by mass based on the total mass of the pharmaceutical composition; (vi) The method according to [1] above, wherein component F is about 5% by mass to about 25% by mass based on the total mass of the pharmaceutical composition. [6] (i) the blending ratio of component (B) to component (A) is about 2 parts by mass to about 11 parts by mass per 100 parts by mass of component (A); (ii) the blending ratio of component (C) to component (A) is about 2 parts by mass to about 11 parts by mass per 100 parts by mass of component (A); (iii) the blending ratio of component (B) to component (C) is about 0.3 parts by mass to about 3.5 parts by mass per part by mass of component (C); (iv) the amount of component (B) is about 0.5 to about 10 times by mass based on the mass of component (D); (v) the amount of component (F) is about 1.5 to about 10 times by mass based on the mass of component (E); or (vi) The method according to the above [1], wherein the blending ratio of components (E) and (F) is about 1 part by mass to about 100 parts by mass per 100 parts by mass of components (A), (B), (C), and (D). [7] The method according to [1] above, wherein the mixture is a solution of components (B) and (C) dissolved in component (A). [8] The method according to [1], wherein the amount of water contained in the mixture is about 5% by mass or less based on the total mass of the mixture. [9] The method according to [1] above, wherein the mixing ii) is carried out at about 30°C to about 70°C.

[10] The mixture ii) is ii-1) mixing the mixture with component (D) to obtain an intermediate mixture; and ii-2) Mixing the intermediate mixture obtained in ii-1) with components E and F. The method according to claim 1, comprising:

[11] The method according to [1] above, wherein M is within the range of about 150,000 to about 300,000.

[12] The method according to [1] above, wherein T is within the range of about 30 minutes to about 90 minutes.

[13] The method according to [1], wherein the microparticles comprise components (A), (B), (C), and (D), and the matrix comprises components (E) and (F).

[14] The method according to [1], wherein the microparticles have an average diameter of about 0.5 μm to about 1.2 μm.

[15] The method according to [1] above, wherein the amount of water contained in the pharmaceutical composition is about 5% by mass or less, based on the total mass of the pharmaceutical composition.

[16] The method according to [1] above, wherein the pharmaceutical composition has an average release rate of about 55% to about 70% after 7 hours in a dissolution test.

[17] The method according to [1] above, wherein the pharmaceutical composition has a viscoelasticity of about 0.44 to about 0.55 as determined by frequency-dependent measurement.

Claims

1. 1. A method for preparing a pharmaceutical composition comprising the steps of: i) obtaining a mixture comprising component (A), component (B), and component (C), wherein component (C) has a weight average molecular weight M of about 150,000 to about 300,000 after dissolution in the mixture, as measured by gel permeation chromatography; and ii) mixing said mixture with a pharma- ceutical active ingredient (D), a hydrophobic component (E), and an amphiphilic component (F) at a temperature ranging from about 30°C to 70°C for T minutes, thereby producing a pharmaceutical composition comprising microparticles dispersed in a matrix; T satisfies 0.00136M-230<T<0.00136M-169; Component (A) is glycerin and is about 50% to about 85% by weight, based on the total weight of the pharmaceutical composition; Component (B) is magnesium chloride, magnesium gluconate, or a hydrate thereof, and is about 0.5% to about 10% by weight based on the total weight of the pharmaceutical composition; Component (C) is hydroxyethyl cellulose; Component (D) is minocycline, doxycycline, tetracycline, oxytetracycline, chlortetracycline or a pharma- ceutically acceptable salt thereof, and is present in an amount of about 0.1% to about 10% by weight based on the total weight of the pharmaceutical composition; Component (E) is a copolymer of ethyl acrylate with methyl methacrylate and methacrylate ethyltrimethylammonium chloride, in an amount of about 0.5% to about 10% by weight based on the total weight of the pharmaceutical composition; Component (F) is triacetin and is present in an amount of about 5% to about 25% by weight based on the total weight of the pharmaceutical composition; and The compounding ratio of component (C) to component (A) is about 4 parts by mass to about 8 parts by mass per 100 parts by mass of component (A).

2. (i) the blending ratio of component (B) to component (A) is about 2 parts by mass to about 11 parts by mass per 100 parts by mass of component (A); (ii) the blending ratio of component (C) to component (A) is about 5 parts by mass to about 6 parts by mass per 100 parts by mass of component (A); (iii) the blending ratio of component (B) to component (C) is about 0.3 parts by mass to about 3.5 parts by mass per 1 part by mass of component (C); (iv) the amount of component (B) is from about 0.5 to about 10 times by weight based on the weight of component (D); (v) the amount of component (F) is from about 1.5 to about 10 times by weight based on the weight of component (E); or (vi) The method according to claim 1, wherein the blending ratio of components (E) and (F) is from about 1 part by weight to about 100 parts by weight per 100 parts by weight of components (A), (B), (C), and (D).

3. 2. The method of claim 1, wherein the mixture is a solution of components (B) and (C) dissolved in component (A).

4. 2. The method of claim 1, wherein the mixture contains water in an amount of about 5% by weight or less, based on the total weight of the mixture.

5. The mixing in ii) ii-1) mixing the mixture with component (D) to obtain an intermediate mixture; and ii-2) mixing the intermediate mixture obtained in ii-1) with components (E) and (F); The method of claim 1 , comprising:

6. 2. The method of claim 1, wherein M is in the range of about 170,000 to about 285,000.

7. 2. The method of claim 1, wherein T is in the range of about 30 minutes to about 90 minutes.

8. 2. The method of claim 1, wherein the microparticles comprise components (A), (B), (C), and (D) and the matrix comprises components (E) and (F).

9. The method of claim 1 , wherein the microparticles have an average diameter of about 0.5 μm to about 1.2 μm.

10. The method according to claim 1 , wherein the amount of water contained in the pharmaceutical composition is about 5% by weight or less, based on the total weight of the pharmaceutical composition.

11. 10. The method of claim 1, wherein the pharmaceutical composition has an average release rate of about 55% to about 70% after 7 hours in a dissolution test.

12. 10. The method of claim 1, wherein the pharmaceutical composition has a viscoelasticity of about 0.44 to about 0.55 by frequency dependent measurement.

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