Title of Invention | "A METHOD FOR PREPARING THE SUSTAINED RELEASE FORMULATION " |
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Abstract | A method for preparing the sustained release formulation as claimed in claim 1, comprising the steps of mixing the HMG-CoA reductase inhibitor, the solubilizing agent, and the stabilizing agent in a solvent selected from water, ethanol and methylene chloride to obtain the solid dispersant; homogeneously mixing the mixture of sodium alginate and xanthan gum as the sustained release composite carrier and the mixture of propylene glycol ester alginate and hydroxypropyl methyl cellulose as the gel hydration accelerator with the solid dispersant to form a first mixture; adding a pharmaceutically acceptable additive to the first mixture to form a second mixture; "and dry-mixing and formulating the second mixture into the sustained release formulation, wherein the solubilizing agent is selected from the group consisting of d-a-tocopheryl polyethylene glycol 1000 succinate, polyoxyethylene stearic acid ester, polyethylene glycol and polyoxypropylene-polyoxypropylene block copolymer, the stabilizing agent is selected from the group consisting of butylated hydroxy toluene, butylated hydroxy anisol, erythorbic acid and ascorbic acid, the pharmaceutically acceptable additive is selected from the group consisting of binder, lubricating agent, sweetening agent and excipient, the solubilizing agent is 0.05 to 20 weight part; the stabilizing agent is 0.01 to 0.1 weight part; the sustained release composite carrier is 3 to 30 weight part; and the gel hydration accelerator is 0.1 to 5 weight part based on 1 weight part of the HMG-CoA reductase inhibitor. |
Full Text | SUSTAINED RELEASE FORMULATION FOR ORAL ADMINISTRATION OF HMG-COA REDUCTASE INHIBITOR AND METHOD FOR THE PREPARATION THEREOF Field of the Invention The present invention relates to a sustained release formulation for oral administration of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor which comprises a solid dispersant, a sustained release composite carrier, and a gel hydration accelerator, wherein the solid dispersant comprises the HMG-CoA reductase inhibitor, a solubilizing agent, and a stabilizing agent; and a method for the preparation thereof. Background of the Invention Hyperlipidemia or increased blood lipid level is a major cause for cardiovascular diseases and arteriosclerosis. Representative examples of hyperlipidemia are hypercholesterolemia, familial dysbetalipoproteinemia, diabetic dyslipidemia, nephrotic dyslipidemia and familial combined hyperlipidemia. Several types of agents for lowering the blood lipid level have been developed to treat hyperlipidemia or hypercholesterolemia. Typically, these agents reduce the synthesis of lipoproteins or lipids in serum, or facilitate the removal of lipoproteins or lipids from serum or plasma. Among these agents, inhibitors of HMG-CoA reductase, a rate-limiting enzyme in the biosynthetic pathway of cholesterol, have been developed to lower the concentration of lipoproteins or lipids in serum. Exemplary HMG-CoA reductase inhibitors are: mevastatin (U.S. Patent No: 3,983,140), lovastatin also called mevinolin (U.S. Patent No: 4,231,938), pravastatin (U.S. Patent Nos: 4,346,227 and 4,410,629), lactone of pravastatin (U.S. Patent No: 4,448,979), velostatin and simvastatin, also referred to as synvinolin (U.S. Patent Nos: 4,448,784 and 4,450,171), rivastatin, fluvastatin, atorvastatin and cerivastatin. The HMG-CoA reductase inhibitors have been widely used for treating hyperlipidemia for several decades to lower total in vivo concentration of cholesterol and LDL-cholesterol (Grundi, S.M, et al., N. Engl. J. Med. 319(1): 24-32, 25-26 and 31, 1998). The synthesis of mevalonate by the action of HMG-CoA is an early step in the biosynthetic pathway of cholesterol, and the HMG-CoA reductase inhibitor lowers total concentration of cholesterol and LDL-cholesterol hi serum by inhibiting the synthesis of mevalonate (Grundi, S.M. et al., AT. Engl. J. Med. 319(1): 24-32,25-26 and 31,1998). However, most of such HMG-CoA reductase inhibitors are administered in the form of rapid release formulations, which causes side effects such as hepatoxicity, muscular disorder and rabdomyolysis (Garnet, W.R. et al., Am. J. Cordial. 78: 20-25, 1996; The lovastatin pravastatin study group, Am. J. Cordial. 71: 810-815, 1993; Duzovne, C.A. et al., Am. J. Med. 91: 25S-30S, 1991; and Mantel, G.M. etsl.,Am. J. Cardiol 66: 11B-15B, 1990). Accordingly, there has been a need to develop a sustained release formulation of the HMG-CoA reductase inhibitor to prevent or alleviate the side effects induced by the rapid release of HMG-CoA reductase inhibitor. Many studies on the sustained release formulation of HMG-CoA reductase inhibitor have suggested that most of the HMG-CoA reductase inhibitors absorbed in the body are metabolized in the liver (85% and more) while only 5% or less account for those transferred to the systemic circulation system. Thus, a bioavailability of the HMG-CoA reductase inhibitor to the systemic circulation system is poor. Also, as the HMG-CoA reductase inhibitor exerts its enzymatic activity mainly in the Ever, it is important to understand the pharmacokinetics in the liver as well as its bioavailability. The rapid release formulation of HMG-CoA reductase inhibitor shows the dose-dependent nonlinear pharmacokinetics, but cannot maintain its therapeutic effect for a long time because of the prolonged clearance half-life caused by saturation (capacity-limited) phenomenon present during a hepatic metabolism. However, when administering the sustained release formulation of HMG-CoA reductase inhibitor,, although the blood concentration of HMG-CoA reductase inhibitor may be lower than that of the rapid release formulation due to the hepatic metabolism, there is no occurrence of the saturation due to its low blood concentration. According to the latest studies, it has been reported that the sustained release formulation of HMG-CoA reductase inhibitor shows equal or slightly lower bioavailbility than the rapid release formulation in both acidic and lacton types. However, its drug delivering efficiency to a target site is shown to be superior to that of the rapid release formulation (John R, Amer. /. Cardio. 89: 15, 2002). Accordingly, the sustained release formulation is capable of more effectively lowering the LDL-cholesterol level in blood than the rapid release formulation (Monique ?,Am. J. DrugDeliv. 1(4): 287-290, 2003). The present inventors have therefore endeavored to solve the problems of the rapid release formulation of HMG-CoA reducatse inhibitor previously reported and developed a new sustained release formulation of HMG-CoA reductase inhibitor having an improved bioavailability with minimal side effects by keeping the amount of HMG-CoA reductase inhibitor at a constant level in blood through a slow and uniform release mechanism thereof. Summary of the Invention Accordingly, it is an object of the present invention to provide a sustained release formulation for oral administration of an HMG-CoA reductase inhibitor for treating hyperlipidemia which is capable of slowly releasing the HMG-CoA reductase inhibitor at a uniform rate for a long time. It is another object of the present invention to provide a method for the preparation of said formulation. In accordance with one aspect of the present invention, there is provided a sustained release formulation for oral administration of an HMG-CoA reductase inhibitor which comprises a solid dispersant containing the HMG-CoA reductase inhibitor, a solubilizing agent and a stabilizing agent; a sustained release composite carrier, and a gel hydration accelerator. In accordance with another aspect of the present invention, there is provided a method for preparing the sustained release formulation for oral administration of the HMG-CoA reductase inhibitor, which comprises the steps of: (1) mixing the HMG-CoA reductase inhibitor, the solubilizing agent, and the stabilizing agent in a solvent to obtain the solid dispersant; (2) homogeneously mixing the sustained release composite carrier and the gel hydration accelerator with the solid dispersant to form a first mixture; (3) adding at least one pharmaceutically acceptable additive to the first mixture to form a second mixture; and (4) dry-mixing and formulating the second mixture into a solid formulation. Brief Description of the Drawings The above and other objects and features of the present invention will become apparent from the following description of the invention, when taken in conjunction with the accompanying drawings which respectively show: Fig. 1 shows a diagram comparing solubilities of the solid dispersants prepared in Examples 1 to 3; Fig. 2 illustrates graphs representing elution rates of the sustained release formulations prepared in Example 4, the graphs being shown for each rotational speed; Fig. 3 presents a diagram comparing elution rates of the sustained release formulations prepared in Examples 4 to 6 depending on the amount of xantan gum; Fig. 4 depicts a diagram comparing elution rates of the sustained release formulations prepared in Examples 7 to 9 depending on the amount of HPMC 2208; Fig. 5 offers a diagram representing the change in blood simvastatm level after oral administration of the sustained release formulation prepared in Example 5; Fig. 6 illustrates a diagram representing distribution and excretion patterns of simvastatin into bile juice after oral administration of the sustained release formulation prepared in Example 5. Detailed Description of the Invention The present invention provides a sustained release formulation for oral administration of an HMG-CoA reductase inhibitor which comprises a solid dispersant containing the HMG-CoA reductase inhibitor, a solubilizing agent and a stabilizing agent; a sustained release composite carrier; and a gel hydration accelerator The sustained release formulation of the present invention may be prepared by the following steps: 1) mixing the HMG-CoA reductase inhibitor, the solubilizing agent, and the stabilizing agent in a solvent to obtain the solid dispersant; 2) homogeneously mixing the sustained release composite carrier and the gel hydration accelerator with the solid dispersant to form a first mixture; 3) adding at least one pharmaceutically acceptable additive to the first mixture to form a second mixture; and 4) dry-mixing and formulating the second mixture into a solid formulation. Since the sustained release formulation for oral administration of the present invention slowly releases the HMG-CoA reductase inhibitor into blood at a uniform rate, it is capable of maintaining a constant drug level in blood. Accordingly, the sustained release formulation for oral administration can be effectively used for preventing and treating hyperlipidemia and arteriosclerosis by orally administering once per day at a single dose. Hereinafter, the components of the sustained release formulation of the present invention are described in detail as follows: (i) Pharmacologically active ingredient The HMG-CoA reductase inhibitor is a drug used for treating hyperlipidemia and arteriosclerosis by lowering lipoprotein or lipid level in blood. Representative examples thereof may include mevastatin (U.S. Patent No: 3,983,140), lovastatin (U.S. Patent No: 4,231,938), pravastatin (U.S. Patent Nos: 4,346,227 and 4,410,629), lactone of pravastatin (U.S. Patent No: 4,448,979), velostatin, simvastatin (U.S. Patent Nos: 4,448,784 and 4,450,171), xivastatin, fluvastatin, atorvastatin, cerivastatin, and a pharmaceutically acceptable salt thereof. Among the above-mentioned HMG-CoA reductase inhibitors, simvastatin or a pharmaceutically acceptable salt thereof is preferred. (ii) Solubilizing agent Since poorly water-soluble drug's bioavailabiliry is decreased in proportion to the decrease in its solubility, the study for solubilizing die drug and increasing its solubility is essential for developing a sustained-release formulation of a poorly water-soluble drug. Since most HMG-CoA reductase inhibitors are poorly water-soluble compounds, the solubilizing agent serves to increase the drug's solubility in the present invention. Representative examples of the solubilizing agent may include vitamin E TPGS (d-a-tocopheryl polyethylene glycol 1000 succinate: Eastman), polyoxyethylene stearic acid ester (e.g., Myrj: ICI), polyethylene glycol, polyoxypropylene-polyoxypropylene block copolymer (e.g., Poloxamer: BASF) and the like. The sustained release formulation of the present invention comprises the solubilizing agent in an amount ranging from 0.05 to 20 weight part, preferably 0.1 to 10 weight part based on 1 weight part of a pharmacologically active ingredient. (iii) Stabilizing agent The stabilizing agent for use in the present invention may be any one of the conventional stabilizing agents, which prevents a drug from oxidizing. Exemplary stabilizing agents are butylated hydroxy toluene (BHT), butylated liydroxy anisol (BHA), erythorbic acid, ascorbic acid and the like. The inventive sustained release formulation of the present invention comprises the stabilizing agent in an amount ranging from 0.01 to 0.5 weight part, preferably O.02 to 0.1 weight part based on 1 weight part of a pharmacologically active ingredient. The present invention prepares the solid dispersant having an improved solubility by mixing the pharmacologically active ingredient, the solubilizing agent and the stabilizing agent according to a conventional method such as a spray-drying method, a solvent evaporating method, a finely pulverizing-wetting method, a melting method and a freeze-drying method. In case of formulating via the spray-drying method, the solid dispersant of the present invention may further comprise a pharmaceutically acceptable solubilizing carrier. The pharmaceutically acceptable solubilizing carrier makes the solid dispersant with smaller particle sizes homogeneously distributed, to improve the solubility thereof. Representative examples of the solubilizing carrier may include starch and a derivative thereof (e.g., dextrin, carboxymethyl starch); cellulose and a derivative thereof (methylcellulose, hydroxypropyl methylcellulose); saccharaids (lactose, sugar, glucose); silicic acid and silicates (natural aluminum silicic acid, magnesium silicic acid); carbonate (calcium carbonate, magnesium carbonate, sodium hydrogen carbonate); polyoxyethylene derivative; glycerin monostearate and the like. (iv) Sustained release composite carrier In the present invention, the sustained release composite carrier served to form a liydrogel is preferably a mixture of sodium alginate (Keltone® HVCR, Keltone® LVF, Kelcosol®, Kelset®: ISP, USA) and xantan gum (Keltrol® F; Kelco®, USA), and the mixture may further comprise locust bean gum (Cesagum® LN1, LR 200; Cesalprnia, Italy). Generally, the effects of the components are as follows: the sodium alginate suppresses the occurrence of an initial burst effect; the xantan gum contributes to configuration fixation, which mrnirnizes the difference in elution rates due to physical force such as gastrointestinal motility; and the locust bean gum can more strongly fix the configuration in combination with the xantan gum. If the above-mentioned carrier ingredients are used in the mixture at a certain mixed ratio, the initial burst effect and the difference in elution rates due to the physical force can be reduced. In the sustained release formulation of the present invention, the sustained release composite carrier may be used in an amount ranging from 3 to 30 weight part, preferably 5 to 25 weight part based on 1 weight part of a pharmacologically active ingredient. In case of using the mixture of sodium alginate and xantan gum as the sustained release composite carrier, the xantan gum is used in an amount ranging from 0.1 to 10 weight part, preferably 3 to 6 weight part based on 1 weight part of the sodium alginate. Further, in case of using the mixture of sodium, alginate, xantan gum and locust bean gum as the sustained release composite carrier, the xantan gum is used in an amount ranging from 0.2 to 10 weight part, preferably 3 to 6 weight part, and the locust bean gum is used in an amount ranging from 0.1 to 5 weight part, preferably 0.5 to 5 weight part based on 1 weight part of the sodium alginate. (v) Gel hydration accelerator The gel hydration accelerator used in the present invention plays a key role in forming a single homogeneous gelated core without forming a non-gelated core. When the sustained release formulation of the present invention is brought into contact with in vivo aqueous medium, the gel hydration accelerator induces its rapid hydration and infiltrates water into an internal core of the formulation in an equal and rapid fashion. In the present invention, the gel hydration accelerator is preferably a mixture of propylene glycol ester alginate and hydroxypropyl methylcellulose (HPMC). In the above mixture, it is preferable that HPMC has a viscosity ranging from 4,000 to 100,000 cps, and the propylene glycol ester alginate is used in an amount ranging from 0.05 to 2O weight part, preferably 0.1 to 10 weight part based on 1 weight part of HPMC. In the sustained release formulation of the present invention, the gel hydration accelerator is used in an amount ranging from 0.1 to 20 weight part., preferably, 0.5 to 15 weight part based on 1 weight part of a pharmacologically active ingredient. Besides, the sustained release formulation of the present invention may further comprise at least one pharmaceutically acceptable additive for preparing a solid formulation for oral administration. Representative examples of the pharmaceutically acceptable additive are a binder, a lubricating agent, a sweetening agent, an excipient and the like. The binder for use in the preparation of the solid formulation may be any one of the pharmaceutically acceptable binders such as polyvinylpyrrolidone (PVP), gelatin, hydroxypropyl cellulose, kofovidone (Kollidon VA64: BASF, Germany) and the like. The lubricating agent for use in the present invention may be any one of the pharmaceutically acceptable lubricating agents, which increases fluidity. Representative examples thereof may include light anhydrous silicic acid, zinc or magnesium salt of stearate, and the like. Further, the present invention provides a method for preparing the sustained release formulation for oral administration of the HMG-CoA reductase inhibitor. The method of the present invention comprises the following steps (1) mixing the HMG-CoA reductase inhibitor, the solubilizing agent, and the stabilizing agent in a solvent to obtain the solid dispersant; (2) homogeneously mixing the sustained release composite carrier and the gel hydration accelerator with the solid dispersant to form a first mixture; (3) adding at least one pharmaceutically acceptable additive to the first mixture to form a second mixture; and (4) dry-mixing and formulating the second mixture into a solid formulation. Additionally, the method of the present invention may further comprise the step of coating the surface of the solid formulation prepared in step (4) with any one of the pharmaceutically acceptable coating agents. Representative examples of the coating agent may include hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol and the like. In step (1), the solid dispersant may be prepared by a conventional method such as a spray-drying method, a solvent evaporating method, a finely pulverizing-wetting method, a melting method and a freeze-drying method, and it is preferable to have a particle size ranging from 5 to 200 (M in diameter. The solvent used for 'dissolving the HMG-CoA reductase inhibitor, the solubilizing agent, and the stabilizing agent is preferably water, ethanol or methylene chloride. The dried mixture obtained in step 4) may be formulated into soft and hard capsules in accordance with the conventional procedures. In a preferred embodiment of the present invention, the second mixture of step (4) may be compressed into a tablet according to a direct tablet-forming method or formulated into a tablet after compressing and pulverizing. A typical daily dose of the sustained release formulation for oral administration of the HMG-CoA reductase inhibitor can be in the form of a single dose or in divided doses. The following Examples are intended to further illustrate the present invention without limiting its scope. Examples 1 to 3; Preparation of solid dispersants Simvastatin (Hanmi Fine Chemical Co., Ltd., Korea), vitamin E TPGS (Eastman, USA), BHT (UENO Fine Chemical, USA) and HPMC 2910 (Shin-Etsu, Japan) were dissolved in ethanol according to the following amount as described in Table 1 (Examples 1 to 3; experimental groups), and each of the resulting mixtures was subjected to spray-drying, to obtain a sold dispersant having an average particle size of 100 (M and below. As a comparative group, the solid dispersant was prepared by mixing only simvastatin and HPMC 2910 in ethanol (Comparative Example 1). Simvastatin, vitamin E TPGS, Myrj, BHT and HPMC 2910 were mixed to prepare solid dispersants according to "the same method as described hi Best View in Resolution of 1024x768 or later. Enable Javascript for Better Performance. |
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6445-delnp-2006-Abstract-(22-07-2011).pdf
6445-delnp-2006-Abstract-(30-12-2011).pdf
6445-delnp-2006-Assignment-(21-07-2011).pdf
6445-delnp-2006-assignments.pdf
6445-delnp-2006-Claims-(22-07-2011).pdf
6445-delnp-2006-Claims-(30-12-2011).pdf
6445-delnp-2006-Correspodence Others-(22-07-2011).pdf
6445-DELNP-2006-Correspondence Others-(04-08-2011).pdf
6445-delnp-2006-Correspondence Others-(21-07-2011).pdf
6445-delnp-2006-Correspondence Others-(30-12-2011).pdf
6445-DELNP-2006-Correspondence-Others-(04-01-2011).pdf
6445-delnp-2006-correspondence-others-1.pdf
6445-DELNP-2006-Correspondence-Others.pdf
6445-delnp-2006-description (complete).pdf
6445-DELNP-2006-Drawings-(04-08-2011).pdf
6445-delnp-2006-Form-1-(21-07-2011).pdf
6445-delnp-2006-Form-1-(22-07-2011).pdf
6445-delnp-2006-Form-2-(21-07-2011).pdf
6445-delnp-2006-Form-2-(22-07-2011).pdf
6445-DELNP-2006-GPA-(04-01-2011).pdf
6445-delnp-2006-GPA-(21-07-2011).pdf
6445-delnp-2006-pct-notification.pdf
6445-delnp-2006-pct-request form.pdf
6445-delnp-2006-pct-search report.pdf
Patent Number | 251909 | |||||||||||||||||||||
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Indian Patent Application Number | 6445/DELNP/2006 | |||||||||||||||||||||
PG Journal Number | 16/2012 | |||||||||||||||||||||
Publication Date | 20-Apr-2012 | |||||||||||||||||||||
Grant Date | 17-Apr-2012 | |||||||||||||||||||||
Date of Filing | 01-Nov-2006 | |||||||||||||||||||||
Name of Patentee | HANMI HOLDINGS CO., LTD. | |||||||||||||||||||||
Applicant Address | #45, BANGI-DONG, SONGPA, SEOUL 138-828, REPUBLIC OF KOREA | |||||||||||||||||||||
Inventors:
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PCT International Classification Number | A61K 47/00 | |||||||||||||||||||||
PCT International Application Number | PCT/KR2005/001021 | |||||||||||||||||||||
PCT International Filing date | 2005-04-08 | |||||||||||||||||||||
PCT Conventions:
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