KR100791256B1 - Pharmaceutically available and stable atorvastatin solid dispersion and composition comprising the same - Google Patents

Abstract

The present invention relates to [R- (R ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-[( Phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid and a solid dispersion comprising a pharmaceutically usable water-soluble polymer, and a pharmaceutical composition comprising the same, wherein the solid dispersion according to the present invention It is excellent in solubility and stability, and can improve the bioavailability of the compound.

Atorvastatin, Water Soluble Polymer, Solid Dispersion

Description

Pharmaceutically useful and stable atorvastatin solid dispersions and compositions comprising same {PHARMACEUTICALLY AVAILABLE AND STABLE ATORVASTATIN SOLID DISPERSION AND COMPOSITION COMPRISING THE SAME}

1 is a conceptual diagram of atorvastatin solid dispersion.

2 is a scanning electron microscope (SEM) photograph of the atorvastatin solid dispersion prepared in Example 1. FIG.

3 is XRD (X-ray powder diffraction) data of the atorvastatin solid dispersion prepared in Example 2. FIG.

[R- (R ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3 having the structure of formula Amorphous solid dispersion comprising -phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid (hereinafter referred to as "atorvastatin acid") and a water-soluble polymer and a pharmaceutical comprising the same It relates to a composition.

 The present invention also relates to a method for preparing amorphous solid dispersion by dissolving atorvastatin acid and water-soluble polymer in ethanol or a mixed solvent of ethanol and purified water using a fluidized bed granulator or a spray dryer.

Atorvastatin acid (Formula 1) is part of a group of drugs called statins. Statin drugs are currently the most effective drugs for lowering the concentration of low density lipoprotein (LDL) particles in the bloodstream of patients at risk of developing cardiovascular disease. High levels of LDL in the bloodstream form coronary lesions that impede blood flow, rupture blood vessels, and promote the development of thrombosis (Goodman and Gilman, The pharmacological Basis of Therapeutics, p879, 9 ^th , 1996).

The mechanism of action of statin drugs has been elucidated in some detail. The drug inhibits the synthesis of cholesterol and other sterols by competitively inhibiting 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase. HMG-CoA reductase catalyzes the conversion of HMG to mevalonate, a step in determining the rate of cholesterol biosynthesis. Decreasing the amount of cholesterol synthesis increases the number of LDL receptors and decreases the concentration of LDL particles in the bloodstream. Thus, atorvastatin acid and its pharmaceutically acceptable salts are known as potent lipid lowering agents as effective therapeutic agents for hyperlipidemia, hypercholesterolemia, arteriosclerosis, osteoporosis, prostatic hyperplasia, Alzheimer's disease, and primary hypercholesterolemia.

However, since atorvastatin acid is generally known to be transformed into a lactone compound (Formula 2) by dehydration, it cannot be used as a pharmaceutical raw material because it is pharmacologically unstable [Reference] Drug Metabolism and Disposition by The American Society for Pharmacology and Exerimental Therapeutics, 28: 1369-1378, 2000]. In particular, it has the disadvantage of easily changing in acidic solution. [References Albert S. Kearney et al. Pharmaceutical Research, Vol. 10, 1993, pages 1461-1465.

In this regard, according to PCT Patent Publication No. WO05 / 026116 filed by Pfizer in 2005, Form A of atorvastatin acid was prepared from atorvastatin calcium crystalline Form I (US Patent No. 5969156), Again form A to P ₂ O ₅ After 72 hours of storage, Form B is converted to Form B, and it is disclosed that Forms A and B thus prepared are stable. However, this publication does not describe data on the pharmaceutical stability of atorvastatin acid crystalline forms A and B and that the atorvastatin acid raw material can be formulated and commercialized. Therefore, it was confirmed that there is no precedent of successful commercialization using the atorvastatin acid raw material.

However, although Lipitor ^R is currently commercially available as an atorvastatin preparation, the raw material for preparing Lipitor ^R is atorvastatin hemicalcium having a structure of Formula 3 below. Methods for preparing atorvastatin hemi calcium are described in U.S. Patent Nos. 4,681,893; No. 5,003,080; 5,097,045; 5,097,045; 5,103,024; 5,103,024; 5,124,482; 5,124,482; 5,149,837; 5,149,837; 5,155,251; 5,155,251; 5,216,174; 5,245,047; 5,273,995; 5,273,995; 5,397,792; 5,397,792; 5,342,952 and in PLBrower et al. Tetrahedron Letters (1992), vol. 33, pages 2279-2282, KLBaumann et al., Tetrahedron Letters (1992), vol. 33, pages 2283-2284 and A. Graul e al., Drugs Future (1997), vol. 22, pages 956-968.

The atorvastatin calcium salt is well known in the art, it is known to be useful in the manufacture of pharmaceutical formulations for oral administration such as tablets, capsules, or powders. Also, the atorvastatin calcium salt is known to be amorphous or crystalline, which is disclosed in WO97 / 3958, WO / 97/3959, WO / 01/03384, WO / 02/041834, WO / 02/043732, WO / 02/051804, WO / 02/057229, WO / 03/004470, WO / 03050085, WO / 03/068739, WO / 03070702 , WO / 03/082816, WO / 04/32920, WO / 04/043918, WO / 04/050618, WO / 04/85391, and the like.

However, atorvastatin crystalline calcium salts are known to have the disadvantage of low stability and bioavailability, while having better stability than amorphous [Reference Konno T., Chem . Pharm . Bull., 1990, 38: 2003-2007 ]. Further, according to the patent documents WO00 / 35425, US5686104, US6126971, atorvastatin amorphous calcium salts have high solubility and bioavailability, but it is described that a large amount of excipients of alkali metal salts and alkaline earth metal salts are required to stabilize. . In order to overcome the disadvantages of the atorvastatin calcium form (crystalline, amorphous) in the present invention without using the excipients of alkali metals and alkaline earth metals in the present invention using the atorvastatin acid using a fluidized bed granulator or spray dryer Combinations of possible organic polymers and organic excipients have led to the production of stable amorphous solid dispersions.

It is an object of the present invention to provide an atorvastatin solid dispersion and a preparation method thereof. The atorvastatin solid dispersion according to the present invention has a particle size of 1 μm to 150 μm and exhibits excellent solubility and stability, so that it may be easily prepared in various dosage forms of oral dosage forms such as tablets, powders, and granules. In addition, it is possible to improve the bioavailability by controlling the dissolution rate and rate of atorvastatin by changing the content and composition ratio of the composition.

It is another object of the present invention to provide a method for preparing a stable amorphous solid dispersion by combining atorvastatin acid with a pharmaceutically available organic polymer and an organic excipient by a conventional method using a fluidized bed granulator or a spray dryer.

The present invention relates to an amorphous solid dispersion comprising an atorvastatin acid having a structure of Formula 1 and a water-soluble polymer and a composition comprising the same.

The present invention also relates to a method for preparing amorphous solid dispersion by dissolving atorvastatin acid and water-soluble polymer in ethanol or a mixed solvent of ethanol and purified water using a fluidized bed granulator or a spray dryer.

The atorvastatin acid used in the present invention can be prepared by known methods. See, for example, US Pat. No. 4,827,93 and PLBrower et al., Tetrahedron Letters (1992), vol. 33, pages 2279-2282 , KLBaumann et al., Tetrahedron Letters (1992), vol. 33, pages 2283-2284 and A. Graul et al ., Drugs Future (1997), vol. 22, pages 956-968 prepared by ring-opening reaction from atorvastatin lactone according to the known method disclosed in the literature, or as disclosed in Bi2005, WO2005 / 033078, (6- {2- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl] -ethyl} -2-phenyl- [1,3,2] dioxaborinane- 4-yl) acetic acid t-butyl ester.

Preferred water-soluble polymers according to the invention are methacrylate (Eudragit), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyvinyl acetaldiethylaminoacetate (trade name: AEA), polyethylene glycol and At least one selected from the group consisting of polyvinyl alcohol esters (trade name: Kollicoat IR), and plasmon. More preferred water-soluble polymers are at least one selected from the group consisting of polybutyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate, and polyvinyl acetal diethylamino acetate.

 In the solid dispersion according to the present invention, the weight ratio of the atorvastatin acid and the water-soluble polymer is preferably 1: 0.05-10, more preferably 1: 0.1-5. If the weight ratio of the water-soluble polymer to 1 part by weight of atorvastatin acid is less than 0.05, there is a problem in stabilizing the atorvastatin acid, and if it exceeds 10, it is not preferable to tablet the formulation.

In addition, the size of the atorvastatin particles in the solid dispersion according to the present invention is preferably 1 μm to 150 μm. In this case, when the size of the particles is smaller than 1 μm, it is difficult to formulate due to the scattering and adhesion of the particles.

The present invention also relates to a pharmaceutical composition for inhibiting 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, comprising the solid dispersion according to the present invention and a pharmaceutically acceptable carrier. will be.

The pharmaceutically acceptable carrier may be used one or more selected from the group consisting of excipients, disintegrants, binders, surfactants, dissolution aids, and lubricants. Such a carrier can control the bioavailability of the drug by controlling the dissolution rate and rate of the solid dispersion. In the above, the surfactant or the dissolution aid may be used for the purpose of controlling the dissolution rate, and the lubricant may be used to control the size of the fluidity and particle size of the solid dispersion.

Preferably, excipients include starch, lactose, glucose, white sugar, mannitol, sucrose, microcrystalline cellulose, sodium hydrogen phosphate, calcium dihydrogen phosphate, lactose, glucose, mannitol, sucrose, maltodextrin (trade names: Glucidex, Roquette), Dextrin (Dextrin, Chemos), cyclodextrin (CyD, ISP), galactose and the like can be used, most preferably glucose, lactose, or mannitol.

The disintegrant may preferably be a starch derivative such as sodium starch glycolate, carboxymethyl cellulose calcium, a carboxymethylcellulose derivative such as crosslinked carboxymethylcellulose, crosslinked polyvinylpyrrolidone, croscarmellose sodium (AcDiSol), or the like. Most preferably croscarmellose sodium (AcDiSol).

The binder is preferably methyl cellulose, hydroxypropyl methyl cellulose, cellulose derivatives such as carboxymethyl cellulose sodium, polyvinylpyrrolidone, gelatin and the like.

As the surfactant, sodium lauryl sulfate and its derivatives, poloxamer and its derivatives, saturated polyglycoglycerides, various polysorbates such as Tween 20, Tween 40, Tween 60, Tween 80, etc. can be used. And most preferably Tween 80 or Poloxamer 407 can be used.

As the dissolution aid, hydroxypropyl cellulose, betacyclodextrin, or the like is preferably used.

As the lubricant, stearic acid and its pharmaceutically acceptable alkali metal salts, colloidal silicon dioxide, silicates, talc, aerosils, microcrystalline cellulose and the like can be used, and most preferably aerosil, croscarmell Rossodium or microcrystalline cellulose can be used.

The composition ratio of the solid dispersion which can control the dissolution rate and rate of atorvastatin acid is 0.05 to 10 parts by weight of polymer, 0.5 parts by weight or less of excipient, 0.3 parts by weight or less of surfactant, and 1 part by weight of atorvastatin acid, and It is suitable to use with 0.3 weight part or less of other additives.

The invention also relates to a process for preparing amorphous solid dispersions by dissolving atorvastatin acid and water soluble polymers in a solvent.

At this time, a conventional organic solvent can be used for a solvent. As a solvent usable in the present invention, one or more selected from the group consisting of ethanol, purified water, acetylacetate, dichloromethane, toluene, and isopropyl alcohol, which are solvents capable of dissolving both excipients and drugs, may be used, but is not limited thereto. .

In the above method for dissolving the atorvastatin acid and the water-soluble polymer in a solvent may be used a conventional method known in the art, preferably a fluidized bed granulator or spray dryer. More preferably, the particle size can be easily adjusted to a particle size range of 1 μm to 150 μm, and a spray dryer capable of mass production may be used. In this case, it is preferable to adjust the amount of hydrophilic polymer to 3-20 (weight or W / V)% relative to the amount of solvent for optimum spraying conditions. More preferably, the amount of hydrophilic polymer relative to the amount of solvent is 5-10 (weight or W /%). The V)% range is most preferred.

The atorvastatin solid dispersion prepared in the above method is stabilized by inclusion of an organic polymer in the form of FIG. 1, and forms an amorphous solid dispersion having a particle size of 1 μm to 150 μm as shown in FIG. 2.

The solid dispersion according to the present invention can be manufactured in various oral dosage forms such as tablets, powders, and granules by conventional methods, and thus has very useful characteristics in product development.

Such a present invention will be described in more detail based on the following Examples and Test Examples, but the present invention is not limited thereto.

Example

Example 1. atorvastatin acid + Eudragit (weight ratio 1: 0.1) The composition of the solid dispersion prepared

Eudragit E100 (4.0 g) was dissolved in 1.5 L of EtOH, and chromatographed atorvastatin acid (40.0 g) was added thereto, followed by stirring for 30 minutes to disperse in the mixed solution. The mixed solution prepared by using the spray dryer (Dynamic N-D101) was spray-dried at an injection temperature of 100 ± 5 ^o C, exhaust temperature of 60 ± 5 ^o C, and an atomizer speed of 10,000 ± 100 rpm, yielding 42.24 g of amorphous solid dispersion (manufacturing yield). : 96%).

Particle Analysis (Model: CILAS 1064): Average = 40.11 μm, 10% = 21.08 μm, 90% = 66.86 μm

Example 2 Preparation of Solid Dispersion with Atovastatin Acid + Eudragit (Weight Ratio 1: 0.5) Composition

Eudragit E100 (20.0 g) was dissolved in 1.5 L of EtOH, and atorvastatin acid (40.0 g) was added thereto, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was performed in the same manner as in Example 1 to obtain 57.0 g of an amorphous solid dispersion (95% yield).

Particle Analysis (Model: CILAS 1064): Average = 36.35 μm, 10% = 17.08 μm, 90% = 56.67 μm

XRD analysis: shown in FIG.

Example 3 Preparation of Solid Dispersion with Atovastatin Acid + Eudragit (Weight Ratio 1: 1) Composition

Eudragit E100 (40.0 g) was dissolved in 1.5 L of EtOH, and chromatographed atorvastatin acid (40.0 g) was added thereto, followed by stirring for 30 minutes to disperse in the mixed solution. 77 g of amorphous solid dispersion was spray-dried at the spray temperature of 90 ± 5 ^o C, the exhaust temperature of 55 ± 5 ^o C, and the sprayer speed of 10,000 ± 100 rpm using a spray dryer (Dynamic N-D101). 96%).

Particle Analysis (Model: CILAS 1064): Average = 40.11 μm, 10% = 21.08 μm, 90% = 66.86 μm

Example 4 Preparation of Solid Dispersion with Atovastatin Acid + Eudragit (Weight Ratio 1: 2) Composition

Eudragit E100 (40.0 g) was dissolved in 1.5 L of EtOH and atorvastatin acid (20.0 g) was added thereto, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was performed in the same manner as in Example 1 to obtain 57.0 g of an amorphous solid dispersion (95% yield).

Particle Analysis (Model: CILAS 1064): Average = 36.35 μm, 10% = 17.08 μm, 90% = 56.67 μm

Example 5 Atorvastatin acid + Eudragit (weight ratio 1: 5) of the solid dispersion composition prepared

Eudragit E100 (100.0 g) was dissolved in 1.5 L of EtOH and atorvastatin acid (20.0 g) was added thereto, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was performed in the same manner as in Example 1 to obtain 57.0 g of an amorphous solid dispersion (95% yield).

Particle Analysis (Model: CILAS 1064): Average = 36.35 μm, 10% = 17.08 μm, 90% = 56.67 μm

Example 6 Preparation of Solid Dispersion with Atovastatin Acid + Eudragit + Aerosil (Weight Ratio 1: 0.5: 0.5) Composition

Eudragit E100 (15.0 g) and atorvastatin acid (30.0 g) were dissolved in 1.5 L of EtOH, and Aerosil 200 (15.0 g) was added, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was performed in the same manner as in Example 1, to obtain 56.0 g of an amorphous solid dispersion (93% yield).

Particle Analysis (Model: CILAS 1064): Average = 42.41 μm, 10% = 22.18 μm, 90% = 69.66 μm

Example 7 Preparation of Solid Dispersion with Atovastatin Acid + Eudragit + Aerosil (Weight Ratio 1: 1: 0.5) Composition

Eudragit E100 (40.0 g) was dissolved in 1.5 L of EtOH, atorvastatin acid (40.0 g) and Aerosil 200 (20.0 g) were added, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was performed in the same manner as in Example 1 to obtain 85.0 g of an amorphous solid dispersion (manufacturing yield: 96%).

Particle Analysis (Model: CILAS 1064): Average = 43.12 μm, 10% = 21.82 μm, 90% = 67.56 μm

Example 8 Preparation of Solid Dispersion with Atovastatin Acid + AEA ^™ + Aerosil (Weight Ratio 1: 0.5: 0.5) Composition

Polyvinyl acetal diethylamino acetate (Sankyo, AEA ^TM ) (20.0 g) was dissolved in 1.5 L of EtOH, atorvastatin acid (40.0 g) and aerosil 200 (20.0 g) were added, followed by stirring for 30 minutes. Dispersed in. Spray drying was performed in the same manner as in Example 1 to obtain 77.0 g of an amorphous solid dispersion (manufacturing yield: 96%).

Particle Analysis (Model: CILAS 1064): Average = 41.33 μm, 10% = 23.10 μm, 90% = 68.06 μm

Example 9 Preparation of Solid Dispersion of Atovastatin Acid + Eudragit + Betacyclodextrin (Weight Ratio 1: 0.5: 0.25) Composition

After dissolving Eudragit E100 (20.0g) in 2.0L of EtOH and betacyclodextrin (10.0g) in 1.0L of purified water, atortostatin acid (40.0g) was added and stirred for 30 minutes to the mixed solution. Dispersed. Spray drying was performed in the same manner as in Example 1 to obtain 66.0 g of an amorphous solid dispersion (yield: 94%).

Particle Analysis (Model: CILAS 1064): Average = 42.21 μm, 10% = 20.29 μm, 90% = 65.64 μm

Example 10 Preparation of Solid Dispersion with Atovastatin Acid + Eudragit + Poloxamer 407 (Weight Ratio 1: 0.5: 0.25) Composition

Dissolve Eudragit E100 (20.0g) and Poloxamer 407 (10.0g) in 2.0 liters of EtOH, mix in 1.0 liter of purified water, add atorvastatin acid (40.0 g), and stir for 30 minutes to disperse in the mixed solution. I was. Spray drying was performed in the same manner as in Example 1 to obtain 67.0 g of an amorphous solid dispersion (manufacturing yield: 96%).

Particle Analysis (Model: CILAS 1064): Average = 41.23 μm, 10% = 20.12 μm, 90% = 63.63 μm

Example 11 Preparation of Solid Dispersion with Atovastatin Acid + Eudragit + Tween 80 (Weight Ratio 1: 0.5: 0.1) Composition

Eudragit E100 (20 g) and Tween 80 (4 g) were dissolved in 2.0 L of EtOH, and mixed with 1.0 L of purified water. Atovastatin acid (40.0 g) was added thereto, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was performed in the same manner as in Example 1 to obtain 64.0 g of an amorphous solid dispersion (manufacturing yield: 94%).

Particle Analysis (Model: CILAS 1064): Average = 43.12 μm, 10% = 21.82 μm, 90% = 67.56 μm

Example 12 Preparation of Solid Dispersion with Atovastatin Acid + Eudragit + HPMC5cps (Weight Ratio 1: 0.5: 0.25) Composition

Eudragit E100 (20g) and HPMC5cps (10g) were dissolved in 2.0L of EtOH, and mixed with 1.0L of purified water. Then, atorvastatin acid (40.0g) was added, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was carried out in the same manner as in Example 1 to obtain 63.0 g of an amorphous solid dispersion (manufacturing yield: 90%).

Particle Analysis (Model: CILAS 1064): Average = 43.12 μm, 10% = 21.82 μm, 90% = 67.56 μm

Example 13 Preparation of Solid Dispersion with Atovastatin Acid + Eudragit + Glucose (Weight Ratio 1: 0.5: 0.25) Composition

Eudragit E100 (20 g) and glucose (10 g) were dissolved in 2.0 L of EtOH, and mixed with 1.0 L of purified water. Atovastatin acid (40.0 g) was added thereto, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was carried out in the same manner as in Example 1 to obtain 65.0 g of an amorphous solid dispersion (93% yield).

Particle Analysis (Model: CILAS 1064): Average = 43.12 μm, 10% = 21.82 μm, 90% = 67.56 μm

Example 14 Preparation of Solid Dispersion with Atovastatin Acid + Eudragit + Lactose (Weight Ratio 1: 0.5: 0.25) Composition

Eudragit E100 (20 g) and lactose (10 g) were dissolved in 2.0 L of EtOH, and mixed with 1.0 L of purified water. Atovastatin acid (40.0 g) was added thereto, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was performed in the same manner as in Example 1 to obtain 65.0 g of an amorphous solid dispersion (manufacturing yield: 93%).

Particle Analysis (Model: CILAS 1064): Average = 43.12 μm, 10% = 21.82 μm, 90% = 67.56 μm

Example 15 Preparation of Solid Dispersion with Atovastatin Acid + Eudragit + Mannitol (Weight Ratio 1: 0.5: 0.25) Composition

Eudragit E100 (20 g) and mannitol (10 g) were dissolved in 2.0 L of EtOH, mixed in 1.0 L of purified water, and then atorvastatin acid (40.0 g) was added thereto, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was performed in the same manner as in Example 1 to obtain 67.0 g of an amorphous solid dispersion (manufacturing yield: 96%).

Particle Analysis (Model: CILAS 1064): Average = 41.31 μm, 10% = 20.11 μm, 90% = 63.04 μm

Example 16 Preparation of Solid Dispersion with Atovastatin Acid + Eudragit + Chromemellose Sodium (Weight Ratio 1: 0.5: 0.25) Composition

Eudragit E100 (20.0 g) and croscarmellose sodium (10.0 g) were dissolved in 2.0 liters of EtOH, and atorvastatin acid (40.0 g) was added thereto, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was performed in the same manner as in Example 1 to obtain 66.0 g of an amorphous solid dispersion (94% yield).

Particle Analysis (Model: CILAS 1064): Average = 43.13 μm, 10% = 21.92 μm, 90% = 66.69 μm

Example 17 Preparation of Solid Dispersion with Atovastatin Acid + Eudragit + Arginine (Weight Ratio 1: 0.5: 0.1) Composition

Eudragit E100 (20.0 g) was dissolved in 2.0 liters of EtOH, arginine (4.0 g) dissolved in 1.0 L of purified water was added, followed by addition of atorvastatin acid (40.0 g), followed by stirring for 30 minutes to disperse in the mixed solution. . Spray drying was performed in the same manner as in Example 1 to obtain 63.0 g of an amorphous solid dispersion (manufacturing yield: 94%).

Particle Analysis (Model: CILAS 1064): Average = 42.13 μm, 10% = 21.21 μm, 90% = 66.90 μm

Example 18 Preparation of Solid Dispersion with Atovastatin Acid + HPMC 5cps + Glucose (Weight Ratio 1: 0.5: 0.25) Composition

HPMC 5cps (20.0g) was dissolved in 2.0L of EtOH, glucose (20.0g) dissolved in 1.0L of purified water was mixed, and then added to atorvastatin acid (40.0g), followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was performed in the same manner as in Example 1 to obtain 61.0 g of an amorphous solid dispersion (95% yield).

Particle Analysis (Model: CILAS 1064): Average = 42.21 μm, 10% = 20.29 μm, 90% = 65.64 μm

Example 19 Preparation of Solid Dispersion with Atovastatin Acid + AEA ^™ + Mannitol (Weight Ratio 1: 0.5: 0.5) Composition

AEA ^TM (20.0 g) was dissolved in 2.0 L of EtOH, and mannitol (20.0 g) dissolved in 1.0 L of purified water was added, followed by addition of atorvastatin acid (40.0 g), followed by stirring for 30 minutes to disperse the mixed solution. Spray drying was performed in the same manner as in Example 1 to obtain 75.0 g of an amorphous solid dispersion (manufacturing yield: 93%).

Particle Analysis (Model: CILAS 1064): Average = 40.87 μm, 10% = 21.42 μm, 90% = 64.32 μm

Example 20 Preparation of Solid Dispersion with Atovastatin Acid + AEA ^™ (Weight Ratio 1: 0.5) Composition

AEA ^™ (20.0 g) was dissolved in 2.0 L of EtOH, and atorvastatin acid (40.0 g) was added thereto, followed by stirring for 30 minutes to disperse the mixture. Spray drying was performed in the same manner as in Example 1, to obtain 56.0 g of an amorphous solid dispersion (93% yield).

Particle Analysis (Model: CILAS 1064): Average = 41.70 μm, 10% = 22.23 μm, 90% = 65.93 μm

Example 21 Preparation of Solid Dispersion with Atovastatin Acid + HPMC 5cps (Weight Ratio 1: 0.5) Composition

HPMC 5cps (20.0g) was dissolved in 2.0L of EtOH, and atorvastatin acid (40.0g) was added thereto, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was performed in the same manner as in Example 1 to obtain 57.0 g of an amorphous solid dispersion (95% yield).

Particle Analysis (Model: CILAS 1064): Average = 40.08 μm, 10% = 21.03 μm, 90% = 64.32 μm

Example 22 Preparation of Solid Dispersion with Atovastatin Acid + PVPk30 (Weight Ratio 1: 0.5) Composition

PVPk30 (20.0 g) was dissolved in 2.0 L of EtOH, and atorvastatin acid (40.0 g) was added thereto, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was performed in the same manner as in Example 1, to obtain 56.0 g of an amorphous solid dispersion (93% yield).

Particle Analysis (Model: CILAS 1064): Average = 41.70 μm, 10% = 22.23 μm, 90% = 65.93 μm

Example 23 Preparation of Solid Dispersion with Atovastatin Acid + Plasdon630 (Weight Ratio 1: 0.5) Composition

Plasdon630 (20.0 g) was dissolved in 2.0 L of EtOH, and atorvastatin acid (40.0 g) was added thereto, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was performed in the same manner as in Example 1 to obtain 57.0 g of an amorphous solid dispersion (95% yield).

Particle Analysis (Model: CILAS 1064): Average = 40.10 μm, 10% = 21.23 μm, 90% = 64.03 μm

Example 24 Preparation of Solid Dispersion with Atovastatin Acid + PEG4000 (Weight Ratio 1: 0.5) Composition

PEG4000 (20.0 g) was dissolved in 2.0 L of EtOH, and atorvastatin acid (40.0 g) was added thereto, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was performed in the same manner as in Example 1, to obtain 56.0 g of an amorphous solid dispersion (93% yield).

Particle Analysis (Model: CILAS 1064): Average = 41.34 μm, 10% = 20.22 μm, 90% = 63.92 μm

Example 25 Preparation of Solid Dispersion with Atovastatin Acid + AEA ^™ + Arginine (Weight Ratio 1: 0.5: 0.1) Composition

AEA ^TM (20.0 g) was dissolved in 2.0 L of EtOH, and L-arginine (4.0 g) dissolved in 1.0 L of purified water was added, followed by addition of atorvastatin acid (40.0 g), followed by stirring for 30 minutes to disperse in the mixed solution. . Spray drying was performed in the same manner as in Example 1 to obtain 61.0 g of an amorphous solid dispersion (95% yield).

Particle Analysis (Model: CILAS 1064): Average = 41.07 μm, 10% = 20.42 μm, 90% = 64.02 μm

Example 26 Preparation of Solid Dispersion with Atovastatin Acid + AEA ^™ + Eudragit (Weight Ratio 1: 0.5: 0.5) Composition

AEA ^TM (20.0 g) and Eudragit (20 g) were dissolved in 3.0 L of EtOH, and atorvastatin acid (40.0 g) was added, followed by stirring for 30 minutes to disperse in the mixed solution. Spray drying was carried out in the same manner as in Example 1 to obtain 76.0 g of an amorphous solid dispersion (95% yield).

Particle Analysis (Model: CILAS 1064): Average = 41.70 μm, 10% = 22.23 μm, 90% = 65.93 μm

Example 27 Preparation of Solid Dispersion with Atovastatin Acid + AEA ^TM (Weight Ratio 1: 1) Composition

AEA ^TM (40.0 g) was dissolved in 3.0 L of EtOH, and atorvastatin acid (40.0 g) was added thereto, followed by stirring for 30 minutes to disperse the mixture. Spray drying was carried out in the same manner as in Example 1 to obtain 75.0 g of an amorphous solid dispersion (manufacturing yield: 94%).

Particle Analysis (Model: CILAS 1064): Average = 41.03 μm, 10% = 21.53 μm, 90% = 64.37 μm

Test Example 1. Preparation test of tablets (300mg per tablet)

The solid dispersion prepared in Example 1-27 (atorvastatin acid: polymer = 1: 0.1 to 5), 30 mg of sodium hydrogen phosphate, and 4 mg of sodium laurisulfate were mixed and sieved to 50 mesh. However, since the mixing ratio of the polymer of Example 1-24 and atorvastatin acid was different, the solid dispersion weight ratio was added or subtracted from the microcrystalline cellulose.

After passing through the mixture, microcrystalline cellulose, 15 mg of croscarmellose sodium, 15 mg of crospovidone and 4 mg of magnesium stearate were added to tablets.

Tablets were prepared by tableting to 300 mg (20 mg of atorvastatin acid) per tablet. In tablets (300 mg per tablet), 10 mg of polyvinyl alcohol, 2.88 mg of titanium oxide, 1.8 mg of talc, 0.18 mg of lecithin, and 0.04 mg of xanthan gum were coated with water.

Test Example 2 Solubility Test

The solubility of atorvastatin acid was measured using the solid dispersion prepared in Example, and the stability test of the solid dispersion was carried out for one month under exposure.

How to measure:

1) Specimen: atorvastatin calcium salt (Lot No .: IM41246, manufacturer: Cipla)

              Atorvastatin

              Atorvastatin Solid Dispersion (Examples 2, 9, 10, 16, 20)

2) Preparation of the sample solution: Each sample was accurately taken as 100 mg as the main component (atorvastatin) and placed in a 50 mL flask. The sample was adjusted to exactly 20 mL using the first solution (pH 1.2). The solution was extracted by ultrasonic shaking for 30 minutes and then stirred for 30 minutes. The solution was centrifuged (3000 rpm, 20 minutes), and then 10 mL of the supernatant was filtered through a 0.45 탆 membrane filter. The first 2 mL was discarded and 5 mL of the filtrate was taken and diluted 10 times with water. This solution was filtered through a 0.45 탆 membrane filter to discard the first 2 mL, and the filtrate was used as the sample solution.

3) Preparation of standard solution: 20 mg of atorvastatin commercial standard was accurately taken into a 100 mL volumetric flask and adjusted to exactly 100 mL with 50% acetonitrile. The solution was extracted by ultrasonic shaking for 30 minutes and then stirred for 30 minutes. The solution was diluted 10-fold, 50-fold, and 100-fold with 50% acetonitrile, respectively, and filtered through a 0.45 µm membrane filter to discard the first 2 mL, and the rest as a standard solution.

4) Calculation: After the standard solution was injected and the calibration curve was drawn with the standard solution, the concentration of each sample was obtained by substituting the calibration curve.

5) Operating conditions: The test was conducted under the following conditions.

Method: Liquid Chromatograph

Detector: ultraviolet absorption photometer (wavelength 244 nm)

Column: Capcell Pak C18 (4.6 × 150mm, 5um)

Temperature: 35 ℃

Mobile phase: Acetonitrile and 0.05 M / L ammonium acetate buffer (pH 4.0) mixture (55:45)

Flow rate: 1.0mL / min

Sample weight: 100 mg of solid dispersion raw material or calcium salt as atorvastatin

The results are shown in Table 1 below.

TABLE 1

Test Example 3 Tablet Dissolution Test

The dissolution rate of the tablet was measured using the solid dispersion prepared in Example. Eight specimens were tested according to the dissolution test method 2 of the reference and test methods of Lipitor, the reference drug.

1) Preparation of Standard Solution: 50 mg of atorvastatin calcium standard (containing 45.9 mg of atorvastatin) was placed in a 50 ml flask, labeled with 50% acetonitrile, and stirred until the standard was completely dissolved. 5.0 mL of this solution was taken into a 20 mL volumetric flask, labeled with water, filtered through a membrane filter, and the first 2 mL was discarded. The filtrate was used as a standard solution.

2) Operation and Calculation: The dissolution test was carried out by measuring the absorbance after the dissolution test under the following conditions using water as the reference solution and the standard solution.

Analysis method: ultraviolet absorption spectrophotometry

Instrument: UV-VIS Spectrophotometer

Wave length: 244nm

Eluent: Water 900Ml

Rotational Speed: 50 times / min

Elution temperature: 37.0 ℃ ± 0.5 ℃

Elution time: 30 minutes

The results are shown in Table 2.

TABLE 2

Test Example 4 X-ray Diffraction Spectroscopy

The crystallinity of the solid dispersion prepared according to Example 1 was evaluated using an X-ray diffractometer (Mac Science, Japan, Model: M18XHF-SRA). Figure 3 shows the XRD spectrum data (powder diffraction pattern) of the atorvastatin solid dispersion prepared according to Example 2, this data is 40 kilovolts using an X-ray powder diffractometer Data measured with a CuK-α beam at a voltage of and a current of 300 milliamps. In view of the pattern of FIG. 3, it can be seen that the solid dispersion of the present invention is amorphous because the relative intensity of the diffraction angle and the diffraction peak is very low.

Test Example 5. Stability Test

Obtain optimal formulations (Examples 1, 2, 5, 6, 12, 13, 17, 20, 22, and 26) based on physicochemical properties (solubility, appearance, dissolution rate) in tablets prepared by various examples The stability test was carried out. The stability test was carried out in accordance with the content and lead test method for a total of six months in 1, 2, 4, 6 months in aluminum packaging under accelerated conditions (40 ℃ / 75% relative humidity), the results are shown in Table 3 and same.

<Testing method of contents and lead substance>

1) Preparation of standard solution: 20 mg of commercially available atorvastatin standard was precisely weighed, placed in a 200 mL volumetric flask, and dissolved in a diluted solution (0.05 M ammonium phosphate buffer solution (pH 7.4) / acetonitrile = 50/50). The solution was filtered through a membrane filter to discard the first 2 mL to make the filtrate the standard solution.

2) Preparation of sample solution: 20 tablets or more of the tablets prepared in Example were each weighed precisely, and the average weight of one tablet was obtained to obtain powder. Accurately weigh 10 mg of the equivalent of atorvastatin, add diluted solution (0.05 M ammonium phosphate buffer (pH7.4) / acetonitrile = 50/50) to exactly 100 mL, extract for 10 minutes in an ultrasonic water bath, and stir for 10 minutes. . The solution was filtered through a membrane filter to discard the first 2 mL to make the filtrate a sample solution.

3) Calculation: The test solution and the standard solution were tested by liquid chromatograph method in the pharmacopoeia general test method and then calculated based on the peak area of the standard solution.

4) Operating conditions: The test was conducted under the following conditions.

Analysis method: liquid chromatograph method

Instrument: UV-VIS Spectrophotometer

Wave length: 244nm

Column: Connect two Capcellpak C18 MG (4.6 × 250mm, 5㎛).

Mobile phase: Acetonitrile / tetrahydrofuran / 0.05M ammonium phosphate buffer (pH 4.0) = 37/20/43

Flow rate: 0.7 ml / min

TABLE 3

Since the solid dispersion according to the present invention has better solubility and stability in water than known atorvastatin calcium salts, it is easy to prepare into various oral dosage forms such as tablets, powders, and granules by conventional methods. In addition, the dissolution rate and rate can be adjusted by changing the content and composition of the solid dispersion, characterized in that to improve the bioavailability of atorvastatin.

Claims (15)

At least one water-soluble selected from the group consisting of atorvastatin acid having a structure of Formula 1 and polybutyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate, and polyvinyl acetal diethylamino acetate An amorphous solid dispersion comprising a polymer. [Formula 1]

delete delete The solid dispersion according to claim 1, wherein the weight ratio of atorvastatin acid and the water-soluble polymer is 1: 0.05-10. The solid dispersion according to claim 1, wherein the particles of the solid dispersion have a size of 1 µm to 150 µm. Hyperlipidemia, hypercholesterolemia, arteriosclerosis, osteoporosis, enlarged prostate, Alzheimer's disease, and primary hypertension, comprising the solid dispersion according to any one of claims 1, 4 or 5 and a pharmaceutically acceptable carrier. A pharmaceutical composition for treating or preventing a disease selected from the group consisting of cholesterol. 7. The composition of claim 6, wherein the pharmaceutically acceptable carrier is at least one selected from the group consisting of excipients, disintegrants, binders, surfactants, dissolution aids, and glidants. 8. A pharmaceutically acceptable carrier according to claim 7, wherein the pharmaceutically acceptable carrier consists of aerosil, microcrystalline cellulose, poloxamer, polysorbate, hydroxylpropylmethylcellulose, betacyclodextrin, croscarmellose sodium, starch, lactose and mannitol. At least one composition selected from the group. The method according to claim 7, wherein, based on 1 part by weight of atorvastatin acid, 0.05 to 10 parts by weight of polymer, 0.5 parts by weight or less of excipient, 0.3 parts by weight or less of surfactant, and 0.3 weight of disintegrant, binder, dissolution aid and lubricant A composition, characterized by being used in parts or less. delete delete delete delete delete delete

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