MX2008007383A - Complex formulation comprising amlodipine camsylate and simvastatin and method for preparation thereof - Google Patents

Abstract

The present invention relates to a complex formulation for oral administration comprisingamlodipine camsylateand simvastatin, and a preparation method thereof. Thecomplex formulation of the present invention comprising amlodipine camsylate,simvastatin and a stabilizing agent can be used advantageously for preventingand treating diseases such as hyperlipidemia, atherosclerosis, hypertension,and cardiovascular disease.

Description

COMPLEX FORMULATION COMPRISING AMLODIPINE CAMSILATE AND SIMVASTATIN AND METHOD FOR THE PREPARATION OF THE SAME Field of the Invention The present invention relates to a complex formulation for oral administration comprising amlodipine camsylate and simvastatin, and a method for the preparation thereof.

Background of the Invention Hyperhpidemia or elevation of serum lipid level is related to the occurrence of cardiovascular diseases and arteriesclerosis Hyperhpidemia includes hypercholesterolemia, familial dysbetalipoprotenemia, diabetic dishpidemia, nephritic dyslipidemia and familial combined hyperlipidemia Hypercholesterolemia, a representative example of hyperlipidemia, is caused by levels high cholesterol-LDL (low density protein) and total cholesterol in serum, and the treatment of hypercholesterolemia by reducing the level of serum lipids, especially the LDL-cholesterol level, makes it possible to reduce the risk of cardiovascular diseases , which leads to the delayed progression of arteriesclerosis (American diabetes association, Diabetic care, 23 (suppl), S57- S65, 2000). Therefore, many studies have been conducted on lipid reduction therapy to delay the progress of arteriosclerosis or relieving the arteri Osterosis in order to reduce the risk of cardiovascular diseases, for example, coronary heart disease, in a patient diagnosed with hyperlipidemia or hypercholestrolemia. Hypertension is accompanied by hyperlipidemia in many cases, which can cause cardiac conditions such as angina. Therefore, it is very important to control hypertension along with the cholesterol level when a patient is suffering from coronary heart disease, so that the risk or fatality that arise from cardiovascular diseases can be reduced. For example, Kramsch et al. have disclosed that a calcium channel blocking agent such as amlodipine, an antihypertensive agent, can be administered together with a lipid reducing agent to improve the therapeutic effects against atherosclerosis (Kramsch et al., Journal of Human Hypertension, Suppl. 1, 53-59, 1995), and Lichtlen PR et al. have reported that an early atherosclerotic disease in humans can be effectively treated by co-administration of a calcium channel blocking agent (Lichtlen PR et al, Lancet, 335, 1109-1139, 1990; and Waters D. et al. , Circulation, 82, 1940-1953, 1990). In addition, U.S. Patent No. 4,681,893 discloses that some statin drugs that include atrovastatin are useful for treating atherosclerosis, and it has been reported that in the case of the administration of a statin drug (pravastatin or lovastatin) together with a calcium channel blocking agent (amlodipine), atherosclerotic diseases can receive better treatment through the synergistic effects of the two drugs (Jukema et al., Circulation, Suppl. 1, 1-197, 1995; and Orekhov et al., Cardiovescular Drug and Theraphy, 11, 350, 1997). However, Caduet * '(Pfizer), a commercially available atrovastatin-besylate complex formulation of amlodipine in which astrovastatin is an inhibitor of HMG-CoA reductase and amlodipine besylate is a therapeutic for hypertension, has the problem of that the photostability of amlodipine besylate is poor, implying that amlodipine besylate can degrade very easily during storage of the complex formulation. The inventors of the present application have found that a complex formulation for oral administration comprising amlodipine camsylate, which has a photostability higher than that of amlodipine besylate, exhibits improved stability.

Brief Description of the Invention Accordingly, it is an object of the present invention to provide a complex formulation comprising amlodipine camsylate and simvastatin, which are therapeutic for hypertension and hyper pidia, respectively, and dp method for the preparation thereof In accordance with an aspect of the present invention, there is provided a complex formulation for oral administration comprising amlodipine camsylate simvastatin, and a stabilizing agent 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 show respectively Figure 1 is a schematic diagram of the formulation of complex of the invention comprising amlodipmo camsylate and simvastatin Figure 2 is a graph showing the changes in the contents of amlodipine besylate and amlodipine camsylate when exposed to sunlight, Figure 3 the amounts of the products of degradation of amlodipmo besylate and amlodipine camsylate when exposed to sunlight, Figure 4 shows the amounts of degradation products of amlodipine besylate and amlodipine camsylate when exposed to incandescent light, Figure 5: changes in the content of amlodipine when the solid dispersions prepared in Comparative Example 1 and the Examples 1 to 4 were subjected to stability tests; Figure 6: Amounts of the amlodipine degradation products generated when the solid dispersions prepared in Comparative Example 1 and Examples 1 to 4 were subjected to stability tests; Figure 7: the change in amlodipine content during the stability test of the complex formulations prepared in Comparative Example 2 and Examples 5 to 7; Figure 8: the amounts of the degradation products of amlodipine during the stability tests of the complex formulations prepared in Comparative Example 2 and Examples 5 to 7; Figure 9: changes in the amlodipine content during the stability tests of the complex formulations prepared in Example 7 and Comparative Example 3; Figure 10: the amount of the degradation product of amlodipine during the stability tests for the complex formulations prepared in Example 7 and Comparative Example 3; Figure 11: changes in simvastatin contents during stability tests of the complex formulations prepared in Comparative Examples 2 and 3, and Examples 5 to 7; Figure 12: changes in the content of amlodipine through the comparative stability tests of the complex formulation prepared in Example 7 and a control formulation, Caduet ^; and Figure 13: Amounts of the degradation products of amlodipine during the comparative stability test for the complex formulation prepared in Example 7 and a control formulation, Caduet'3.

Detailed description of the invention The complex formulation of the present invention is characterized in that it comprises amlodipine camsylate and simvastatin, which are therapeutics for hypertension and hyperlipidemia, respectively, as shown in Figure 1. Each ingredient of the formulation of the invention is described in detail below. invention: 1) Pharmacologically active ingredient The pharmaceutically active ingredient of the complex formulation according to the present invention comprises amlodipine camsylate, which is a calcium channel block agent, used to treat hypertension; and simvastatin (US Pat. Nos. 4,448,784 and 4,450,171), which is an inhibitor of HMG-CoA reductase, used to treat hyperlipidemia and arterysclerosis by reducing the level of lipoprotein or blood lipid. Amlodipmo camsylate has a photostability superior to the amlodipine besylate known as the most appropriate amlodipine salt up to now Amlodipine camsylate can be used in an amount ranging from 0 5 to 20% by weight, preferably from 1 to 10% by weight based on the total weight of the complex formulation When the amount is less than 0 5% by weight, its therapeutic effect can not be expected, and when it is greater than 20% by weight, a safety problem may arise due to exceeding the allowable daily dose. Simvastatin may be employed in an amount ranging from 0 5 to 50% by weight preferably from 1 to 40% by weight based on the total weight of the formulation of complex When the amount is less than 0 5% by weight, its therapeutic effect can not be expected, and when it is greater than 50% by weight, a safety problem may arise due to exceeding the allowable daily dose 2) Stabilization agent The complex formulation according to the present invention comprises a stabilizing agent that prevents oxidation of amlodipine camsylate and simvastatin used as a pharmaceutically active ingredient. The stabilizing agent used in the present invention can be any of the known stabilizing agents. , and illustrative stabilizing agents include butylated hydroxy toluene (BHT), butylated hydroxy apisol (BHA), erythorbic acid, ascorbic acid, tocopherol and the like. In the present invention, stabilizing agent can be employed in an amount ranging from 0.001 to 100% by weight, preferably 0.002 to 50% by weight based on the weight of amlodipine camsylate. When the amount is less than 0.001% by weight of amlodipine camsylate, it is difficult to obtain the expected drug stability, and when it is greater than the amlodipine camsylate weight, a safety problem can arise due to exceeding the allowable daily dose. 3) Pharmaceutically acceptable additive The sustained release formulation of the present invention may further comprise at least one of the known pharmaceutically acceptable additives such as a dispersing agent, binder, lubricating agent, sweetening agent, excipient and the like, in order to prepare a solid formulation suitable for oral administration. Representative Examples of the pharmaceutically acceptable additive can include any binder generally used in pharmacy. such as polyvinylpyrrolidone (PVP), gelatin, hydroxypropyl cellulose and Copovidone, and any lubricating agent generally used in pharmacy, such as fatty acid ester of sucrose, talcum, light anhydrous silicic acid, zinc and magnesium salts of stearic acid and the like . The complex formulation of the invention for oral administration comprising said ingredients can be prepared by means of the following steps: 1) dissolving amlodipine camsylate and a stabilizing agent in an organic solvent to obtain a solution and "remove the solvent organic from the solution in order to obtain a solid dispersion; and 2) mixing the solid dispersion obtained in step 1 with simvastatin and a pharmaceutically acceptable additive to obtain a mixture, and granulating the mixture by wet milling in order to obtain granules, followed by the formulation of the granules. In step 1), the organic solvent can be methanol, ethanol, dichloromethane, chloroform and the like, and the solid dispersion can be prepared by a conventional method such as spray dewatering, solvent evaporation, micropulverization-wetting, melting, and freeze drying. In step 2), a solvent such as water, ethanol and dichloromethane can be used to form a binder solution during the preparation of the granules comprising the pharmaceutically active ingredients of the complex formulation, amlodipine camsylate and simvastatin.

In addition, the above method according to the present invention may further comprise the step of coating the obtained complex formulation with a film layer to protect the formulation from degenerative factors such as light and moisture as well as to improve compliance of the patient ( for example, by blocking a bitter taste). The outer film layer can be a layer of light protective film, moisture proof film layer or sugar film layer. The preferred film layer may comprise at least one of the water-soluble film-forming materials such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), cellulose acetate phthalate (CAP), ethylcellulose (EC), methylcellulose (MC), polymethacrylate, Kollicoat1 * (BASF, Germany) and Opadry® (Colorcon, USA). The water soluble film layer can be used in an amount ranging from 0.5 to 20% by weight, preferably 1 to 10% by weight based on the weight of the complex formulation of the invention. When the amount is less than 0.5% by weight, the film becomes unstable, and when it is greater than 20% by weight, it adversely affects the release of the drug. In addition, the water soluble film layer may comprise plasticizers such as polyethyleneglycol (PEG), glycerol triacetate and acetylated monoglyceride. The amlodipine-simvastatin camsylate complex formulation of the present invention prepared by the above method has an improved effect of the pharmaceutically active ingredients upon rapid release and has an improved stability of amlodipine camsylate and simvastatin since it comprises the stabilization. The complex formulation of the invention can be used effectively to prevent and treat hyperlipidemia, arteriosclerosis, hypertension, cardiovascular disease and the disease combined therewith when administered orally once a day in an individual dose. The following Examples are intended to further illustrate the present invention without limiting its scope.

Examples 1 to 4 and Comparative Example 1: Preparation of solid dispersion comprising amlodipine camsylate and a stabilizing agent The amlodipine camsylate. an active ingredient, and BHT (UENO Fine Chemical, USA), a stabilizing agent, were dissolved in 100 MI of a mixture of etapol and dichloromethane (2: 8, w / w) according to the amounts described in Table 1 , respectively, and each of the resulting mixtures was subjected to spray dehydration to obtain a solid dispersion. Table 1 The conditions for the spray dehydration process 1) Buchi Mini Spray Dryer B-191 2) Affluent temperature 80 ° C, effluent 52 ° C 3) Air flow 500 Nl / h 4) Pump (%) 12% (spray in an amount of approximately 120 Mld per hour) Examples 5 to 7 and Comparative Example 2 Preparation of an amlodipine-simvastatin camsylate complex formulation for oral administration The complex formulations for oral administration were prepared using the components described in Table 2. Each of the solid dispersions prepared in Examples 1 to 4 and Comparative Example 1 was mixed with simvastatin, an active ingredient to treat hyperhpidemia, microcpstalin cellulose. , mannitol, dibasic calcium phosphate and sodium starch glycolate Then, a binder solution prepared by dissolving 3 mg of Povidone (BASF, Germany) in about 50 MI of purified water were added to the mixture, which was granulated by of wet milling to obtain the granules. The granules were dried and passed through a 750 μm sieve. Magnesium stearate as a lubricating agent was added to the granules and an amlodipine-simvastatin camsylate complex formulation for oral administration was prepared by any conventional tabletting method.

Table 2 Comparative Example 3: Preparation of amlodipine-simvastatin camsylate complex formulation for oral administration A complex formulation was prepared for oral administration using the components listed in Table 3. Simvastatin, microcrystalline cellulose, mannitol, dibasic calcium phosphate and sodium starch glycoate were mixed together, and a binder solution prepared by dissolving the solution was added. mg of Povidone (BASF, Germany) in approximately 50 MI of purified water. The resulting mixture was granulated through wet grinding to obtain the granules. The granules were dried and passed through a 750 μm sieve. The solid dispersion comprising amlodipine camsylate and BHT, prepared by the methods of Examples 1 to 4, was added to the screened granules. Then, the magnesium stearate, a lubricating agent, was added to the resulting mixture, and an amlodipine-simvastatin camsylate complex formulation was prepared for oral administration via any conventional tabletting method.

Table 3 Reference Example; the comparative test for the stability of amlodipine besylate and amlodipine camsylate The amlodipine camsylate and the amlodipine besylate were exposed to sunlight or an incandescent light (220 V, 100 W) at 40 ° C under a relative humidity of 75%. The change in the amlodipine content and the amount of the degradation product of amlodipine, the compound of the formula (I), were measured under the conditions described in Table 4. The results are shown in Figures 2 to 4. 0) Table 4 Figure 2 shows the time-dependent degradation rate of amlodipine besylate and amlodipine camsylate by the action of sunlight; Figure 3 shows the amount of the impurity generation rate from amlodipine by the action of sunlight; and Figure 4, the rate of generation of impurity from amlodipine caused by exposure to incandescent light. The above results imply that amlodipine camsylate has a higher photostability compared to amlodipine besylate.

Test Example 1: Stability test of an amlodipine-stabilization stabilizer dispersion of solid Each of the solid dispersions of Comparative Example 1 and Examples 1 to 3 were exposed to sunlight or incandescent light (220 V, 100 V), and changes in the content of amlodipine and the compound of the formula (I ), a degradation product of amlodipine, were analyzed under the conditions described in Table 4. The results are shown in Figures 5 and 6. As shown in Figures 5 and 6, the stability of amlodipine improves as the increases the amount of BHT, a stabilizing agent.

Test Example 2: Stability test of a solid dispersion of amlodipine-simvastatin camsylate The complex formulations of Comparative Example 2 and 3, and Examples 5 to 7 wherein each is placed in an HDPE bottle containing approximately 5 g of silica gel and changes in the contents of simvastatin, amlodipine, and the product of degradation of amlodipine (impurities of the formula (I)) were analyzed at 60 ° C under a relative humidity of 75%. The amounts of amlodipine and the degradation product were determined by the method of Test Example 1 and the content of simvastatin was analyzed according to the method described under the topic "simvastatin tablets" in U.S. pharmacopoeia (28tn amendment). Figure 7 and Figure 8 show the changes in the contents of amlodipine and its degradation product, respectively, which shows that the amlodipine camsylate stability is increased with the amount of BHT, the stabilizing agent. Furthermore, as can be seen in Figures 9 and 10, the stability of amlodipine is poor when a granule containing simvastatin was first prepared and then the amlodipine camsylate was mixed with the granule (Comparative Example 3). This is because of the increased likelihood that the amlodipine camsylate contacts directly with the magnesium stearate, the lubricating agent, and affects its stability. On the other hand, the stability of amlodipine is satisfactory when the amlodipine camsylate and the simvastatin are subjected together to the granulation as described in Example 7, for a reduced chance that the amlodipine camsylate contacts the magnesium stearate. Figure 11 shows the change in the content of simvastatin, which shows that BHT increases the stability of simvastatin.

Test Example 3: Comparative stability test of a complex formulation as compared to a control formulation The amlodipine-simvastatin camsylate complex formulation of Example 7 and the amlodipine-atorvastatin besylate complex formulation, Caduet® (Pfizer), which is currently sold in the United States of America, were each placed in a bottle HDPE containing approximately 5 g of silica gel and stored at 40 C under a relative humidity of 75% for 6 months. Then, the changes in the contents of amlodipine and its degradation product were analyzed by the method of Test Example 2. The results are shown in Figures 12 and 13. As can be seen in Figures 12 and 13, the stability of amlodipyone in the complex formulation of the present invention was greatly improved compared to the control formulation. While the invention has been described with respect to the above specific embodiments, it will be recognized that those skilled in the art can make various modifications and changes to the invention which are also within the scope of the invention as defined by the appended claims. .

Claims (1)

CLAIMS 1 A complex formulation for oral administration comprising amlodipine camsylate, simvastatin and a stabilizing agent 2 The complex formulation according to claim 1, characterized in that the amount of amlodipine camsylate ranges from 0 5 to 20% by weight based on the weight of the complex formulation 3 The complex formulation according to claim 1, characterized in that the amount of simvastatin ranges from 0 5 to 50% by weight based on the weight of the complex formulation. A complex according to claim 1, characterized in that the stabilizing agent is selected from the group comprising butylated hydroxy toluene (BHT), butylated hydroxy anisole (BHA), eptorobic acid, ascorbic acid, tocopherol, and a mixture thereof. The complex formulation according to claim 1, characterized in that the amount of the stabilizing agent The formulation ranges from 0,001 to 100% by weight based on the weight of amlodipine camsylate 6 The complex formulation according to claim 1, further comprising a pharmaceutically acceptable additive selected from the group consisting of microcrystalline cellulose. dibasic calcium phosphate, sodium starch glycolate, magnesium stearate and a mixture thereof. A process for the preparation of the complex formulation according to claim 1, comprising: 1) dissolving amlodipine camsylate and the stabilizing agent in an organic solvent, and removing the organic solvent from the resulting solution to obtain a solid dispersion; and 2) mixing the solid dispersion obtained in step 1 with simvastatin and a pharmaceutically acceptable additive to obtain a mixture, and granulating the mixture by wet milling to obtain the granules, followed by the formulation of the granules. 8. The method according to claim 7, characterized in that the removal of the organic solvent in the stage

1) is carried out by means of spray drying, solvent evaporation, micropulverization-wetting, melting or freeze-drying methods. The method according to claim 7, further comprising the step of coating the outer surface of the complex formulation with a film layer. The method according to claim 9, characterized in that the film layer is made of a water-soluble material selected from the group comprising hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), cellulose acetate phthalate (CAP), ethyl cellulose (EC), methyl cellulose (MC), polymethacrylate, Kollicoat'5 '(BASF, Germany) and Opadry® (Colorcon, USA). The method according to claim 9, characterized in that the film layer is a layer of light protective film, a layer of moisture proof film, or a layer of sugar film. The method according to claim 9, characterized in that the amount of the film layer varies from 0.5 to 20% by weight based on the weight of the complex formulation.