MX2008002251A - Pharmaceutical formulation with high stability and dissolution and manufacturing process - Google Patents
Pharmaceutical formulation with high stability and dissolution and manufacturing processInfo
- Publication number
- MX2008002251A MX2008002251A MXMX/A/2008/002251A MX2008002251A MX2008002251A MX 2008002251 A MX2008002251 A MX 2008002251A MX 2008002251 A MX2008002251 A MX 2008002251A MX 2008002251 A MX2008002251 A MX 2008002251A
- Authority
- MX
- Mexico
- Prior art keywords
- pharmaceutical formulation
- weight
- acid
- cellulose
- parts
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 34
- 238000004090 dissolution Methods 0.000 title claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 title 1
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- 239000002904 solvent Substances 0.000 claims abstract description 36
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- -1 ketostearyl alcohol Chemical compound 0.000 claims description 25
- AHLBNYSZXLDEJQ-FWEHEUNISA-N Orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 claims description 23
- 229960001243 orlistat Drugs 0.000 claims description 23
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- LVGKNOAMLMIIKO-QXMHVHEDSA-N Ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 4
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- 150000002338 glycosides Chemical class 0.000 claims description 4
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- 238000000465 moulding Methods 0.000 claims description 4
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- VBICKXHEKHSIBG-UHFFFAOYSA-N rac-1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 4
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 3
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- 235000010409 propane-1,2-diol alginate Nutrition 0.000 claims description 3
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- ONBWNNUYXGJKKD-UHFFFAOYSA-N 1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonic acid;sodium Chemical group [Na].CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC ONBWNNUYXGJKKD-UHFFFAOYSA-N 0.000 claims description 2
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 claims description 2
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 claims description 2
- BVDRUCCQKHGCRX-UHFFFAOYSA-N 2,3-dihydroxypropyl formate Chemical compound OCC(O)COC=O BVDRUCCQKHGCRX-UHFFFAOYSA-N 0.000 claims description 2
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 claims description 2
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N 3-Mercaptopropane-1,2-diol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 2
- CWSZBVAUYPTXTG-UHFFFAOYSA-N 5-[6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxy-5-[4-hydroxy-3-(2-hydroxyethoxy)-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)OCCO)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 CWSZBVAUYPTXTG-UHFFFAOYSA-N 0.000 claims description 2
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- PZZYQPZGQPZBDN-UHFFFAOYSA-N Aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 claims description 2
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- 241000416162 Astragalus gummifer Species 0.000 claims description 2
- 229940043253 Butylated Hydroxyanisole Drugs 0.000 claims description 2
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- CZBZUDVBLSSABA-UHFFFAOYSA-N Butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
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- ZBCBWPMODOFKDW-UHFFFAOYSA-N Diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 2
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- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- 229960002598 Fumaric acid Drugs 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 229940031574 HYDROXYMETHYL CELLULOSE Drugs 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- AXISYYRBXTVTFY-UHFFFAOYSA-N Isopropyl myristate Chemical compound CCCCCCCCCCCCCC(=O)OC(C)C AXISYYRBXTVTFY-UHFFFAOYSA-N 0.000 claims description 2
- TYQCGQRIZGCHNB-JLAZNSOCSA-N L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 claims description 2
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- RWPGFSMJFRPDDP-UHFFFAOYSA-L Potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 claims description 2
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
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- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 claims description 2
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- 210000000496 Pancreas Anatomy 0.000 description 1
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- 229940068968 Polysorbate 80 Drugs 0.000 description 1
- 241000048284 Potato virus P Species 0.000 description 1
- 229940100515 SORBITAN Drugs 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
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- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
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- 229960001367 tartaric acid Drugs 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
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- WHGYBXFWUBPSRW-FOUAGVGXSA-N β-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
Abstract
Disclosed herein are a pharmaceutical formulation with high stability and dissolution, and a method for preparing the pharmaceutical formulation. The pharmaceutical formulation comprises a pharmacologically active substance, a solvent, a solubilizer, a surfactant, an antioxidant, and an adsorbent. According to the pharmaceutical formulation and the method, the pharmacologically active substance is mixed with the solvent, the solubilizer agent and the surfactant for improving the solubility of the pharmacologically active substance to obtain an amorphous liquid or semi-solid state, the antioxidant is melted together with the mixture to solve poor chemical stability of the pharmacologically active substance in an amorphous or liquid state, and the adsorbent is strongly adsorbed to the molten mixture so as to be transformed into a powder form so that the resulting molecules are reconstituted into very tiny crystal forms within the adsorbent to ensure chemical stability.
Description
PHARMACEUTICAL FORMULATION WITH HIGH STABILITY AND DISSOLUTION AND PREPARATION PROCESS
Technical Field The present invention relates to a pharmaceutical formulation with high stability and dissolution, and a method for preparing the pharmaceutical formulation. More specifically, the present invention relates to a pharmaceutical formulation comprising a pharmacologically active substance, a solvent, a solubilizer, a surfactant, an antioxidant and an adsorbent, wherein the pharmacologically active substance is mixed with the solvent, the solubilizing agent and the surfactant to improve the solubility of the pharmacologically active substance to obtain an amorphous or semi-solid liquid state, the antioxidant is melted together with the mixture to solve the poor chemical stability of the pharmacologically active substance in an amorphous or liquid state, and the adsorbent is strongly adsorbs the molten mixture to transform into a powder form so that the resulting molecules are reconstituted in very small crystalline forms within the adsorbent to ensure chemical stability, the characteristic porous or cellulose structure of the adsorbent blocks and protects the drug substance active agent against factors, for example, air and moisture, causing the chemical instability of the pharmacologically active substance, and the final pharmaceutical formulation to stabilize within a pH of 4.5 to 5.5.
Previous Art In most cases, the solubility of drugs depends on the crystalline forms of the drug's ingredients. It is a generally known fact that the high crystallinity of drugs leads to poor solubility and low bioavailability of the drugs. Therefore, the interruption of the stability of poorly soluble drugs and the transformation of crystallinity into an amorphous state are of the greatest importance for the improvement of the bioavailability of drugs.
In this regard, several methods have been known or suggested, for example: 1) a method for preparing a mixture of a pharmacologically active substance and a dispersant by simultaneously dissolving the pharmacologically active substance and the dispersant in an organic solvent to obtain a mixed solution; injecting the solution at a high velocity to rapidly evaporate the organic solvent, thereby preventing recrystallization of the pharmacologically active substance; 2) a method for preparing an amorphous copolymer by melting a pharmacologically active substance having a low melting point together with a polymer compound having a melting point similar to that of the pharmacologically active substance, and rapidly cooling the molten mixture; 3) a method for preventing recrystallization of a pharmacologically active substance having a low molecular weight by dissolving the pharmacologically active substance in a solvent, and capturing the molecules of the pharmacologically active substance within beta-cyclodextrin cavities; 4) a method for preparing a liquid formulation or a soft capsule using a mixed solution of a pharmacologically active substance, a solubilizer and a surfactant; 5) a method for preparing a liquid or powder formulation of a pharmacologically active substance using lecithin liposomes, taking advantage of the physicochemical characteristics of lecithin to form a hydrophilic and lipophilic spheroid layer; 6) a method for preparing a microemulsion, such as a W / O, O / W, O / W / O, W / O / W emulsion, of a pharmacologically active substance; and 7) a method for preparing a mixture of a polymer compound and a crystalline pharmacologically active substance at an optimum temperature in the form of nanopowder while stirring at a high rate to induce a solid diffusion, as described in the Patent Application Korean No. 10-2004-0044474.
The crystalline forms of some drugs, particularly low-melting drugs, play an important role in stabilizing drugs. Amorphous forms of unstable compounds under general sto conditions may promote denaturation of unstable compounds. Accordingly, it is required that the pharmaceutical formulations have a crystalline form to solve the problems arising from their low melting point and possible degradation under sto conditions, and conversely, they must be able to solve the problem of the poor solubility that results from their crystallinity. There is thus a need to develop a pharmaceutical formulation that meets the requirements. For example, orlistat (tetrahydrolipstatin) as an inhibitor of lipase or its structurally related compounds are molecules that can degrade during sto by various mechanisms. It is well known that the rate of degradation of active compounds depends largely on the physicochemical states of the active compound. Lipase inhibitors or their structurally related compounds retain their crystalline forms to ensure stability during sto, but accompany solubility difficulties resulting from their crystallinity. Therefore, stability and solubility have to be considered in drugs for oral administration. Factors that damage the chemical stability of drugs under general sto conditions are oxidation and reduction reactions. Therefore, it is necessary to design pharmaceutical formulations that are stable against air and moisture. The invention of the international patent application PCT / EP2002 / 005958 is based on the results that the eutectic temperature of a mixture of orlistat, a fatty acid or a salt of fatty acid and water is lower than body temperature and that a dry powder of the mixture is present in powder form under sto conditions. According to this invention, degradation of orlistat is delayed by previously providing an ester of fatty acids, which is a degradation product of orlistat, to help maintain the equilibrium of chemical degradation. However, since the final state of the composition is amorphous
as clearly indicated in the patent publication, the chemical stability of the composition is incompletely ensured, the preparation involves complicated steps, and the stability is not continuously guaranteed. International patent application No. PCT / EP2001 / 06834 describes a porous formulation that expands into solutions and dispersions. However, the disadvantage of the formulation is that the preparation process is very complicated.
DESCRIPTION OF THE INVENTION
Technical Problem Therefore, the present invention has been developed in view of the above problems, and it is an object of the present invention to provide a pharmaceutical formulation having a crystalline form to solve the problems arising from its low melting point. and possible degradation under storage conditions, and conversely, it can solve the problem of poor solubility resulting from its crystallinity.
Technical Solution In accordance with one aspect of the present invention to achieve the above-mentioned object, a pharmaceutical formulation is provided comprising a pharmacologically active substance, at least one solvent, at least one solubilizer, at least one surfactant, at least an antioxidant, at least an antioxidant synergist, and an adsorbent, wherein the pharmacologically active substance is melted together with the solvent, the solubilizing agent and the surfactant, the antioxidant and the antioxidant synergist are added to ensure chemical stability, the adsorbent it is adsorbed in the molten mixture to improve the possible chemical instability of the pharmacologically active substance in a liquid state and to induce the state of the mixture to a powder form, and the adsorbed mixture is dispersed uniformly so that the
active substance is recrystallized very finely within the adsorbende due to a very strong surface tension of adsorption.
BEST MODE FOR CARRYING OUT THE INVENTION The pharmacologically active substance is a poorly soluble substance, is unstable under storage conditions, resulting in degradation, and can degrade rapidly in an amorphous or liquid state. The pharmacologically active substance is preferably a lipase inhibitor, and preferably orlistat (tetrahydrolipstatin) or its analog, for example, 2-oxy-4H-3,1-benzoxazine-4-one.
Orlistat is a lipase inhibitor represented by Formula 1 which follows:
The term "lipase inhibitor" refers to a compound that is capable of inhibiting the action of lipase in the stomach and pancreas. Orlistat is a drug that has a melting point as low as 43 ° C, and is commercially available in powder form. The dissolution rate of orlistat that does not undergo any denaturation under good storage conditions is about 60%. This low rate of dissolution of orlistat does not satisfy the required level of bioavailability. In addition, when orlistat raw materials are exposed to high temperature during transport, the orlistat dust particles are added quickly. Subsequently, the aggregates remain until they cool down, causing damage to the orlistat solution. As a result, the rate of orlistat dissolution is sharply reduced to 40% or less.
The solubilizer is an acceptable pharmaceutical solvent for the purpose of increasing the bioavailability of the pharmacologically active substance. Examples of suitable solubilizers include solvents, such as almond oil, castor oil, corn oil, cottonseed oil, ethyl oleate, glycerin, glyceryl monostearate, olive oil, peanut oil, polyethylene glycol, propylene glycol, oil of soy. Solubilizers are also included that one of their functional groups is linked to the hydrophobic pharmacologically active substance and whose hydrophilic groups are not linked to the pharmacologically active substance, after which the solubilizers dissolve rapidly in the water through the hydrophilic groups when they come in contact with water, to solubilize the poorly soluble active substance, and their examples include gum arabic, ketostearyl alcohol, cholesterol, diethanolamine, ethyl oleate, ethylene glycol palmito-stearate, glycerin, glyceryl monostearate, hydroxypropyl cellulose, isopropyl myristate, lecithin, medium chain glyceride, monoethanolamine, oleic acid, propylene glycol, polyoxyethylene alkyl ether, polyoxyethylene castor oil glucoside, fatty acids of polyethylene sorbitan, polyoxyethylene stearate, propylene glycol alginate, sorbitan fatty acid ester, stearic acid, sunflower oil and triethanolamine. These solubilizers can be used alone or as a mixture thereof. The solubilizers are preferably present in a liquid state at room temperature. The most preferred are polyethylene glycol and the glycoside of polyoxyethylene castor oil. The surfactant serves to control the surface tension of lipophilic materials to increase the solubility of the lipophilic materials in water, and is also involved in the dispersion of the pharmacologically active substance in the liquid phase. Exemplary surfactants include sodium docusate, glyceryl mono oleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester (polysorbate = Tween), sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester. The surfactant is preferably provided in an oily state, and is preferably
polysorbate An auxiliary surfactant powder can also be used. As the preferred auxiliary surfactant, sodium lauryl sulfate is used. The antioxidant plays a fundamental role in preventing the oxidation of the pharmacologically active substance to ensure the storage stability of the drug. In addition, it is known that antioxidants prevent recrystallization and reaggregation of drugs in gastric acid after oral ingestion (see, Korean Patent Application No. 10-2004-0044475). Examples of such antioxidants are tocopherol, ascorbic acid and its glycosides, butylated hydroxyanisole, citric acid, edetic acid, fumaric acid, malic acid, monothioglycerin, phosphoric acid, potassium metabisulfite, propionic acid, propyl gellite and tartaric acid. The antioxidant preferably exists in a liquid state at room temperature, and preferably the tocopherol-related materials which are the most acceptable in pharmaceutical formulations. The antioxidant synergist refers to a material that further improves the antioxidant potency of the antioxidant. For example, when tocopherol is used as an antioxidant, citric acid can be added as an antioxidant synergist. In most cases, two or more antioxidants are used to create synergistic effects. Accordingly, the use of at least one antioxidant and at least one antioxidant synergist is included within the scope of the present invention. Dispersants and adsorbents differ greatly in terms of their functions. That is, the adsorbents work to disperse other materials by means of their absorption, while the dispersants function to uniformly disperse other materials within a matrix instead of adsorbing the materials. The adsorbent used in the present invention has a porous structure, and specifically refers to a material that is present in a colloidal amorphous form or a porous polymeric material. Examples of such adsorbents include: porous mineral materials, such as silicon dioxide, kaolin and magnesium aluminum silicate; polymers that fundamentally adsorb low molecular weight matepales within their structure,
such as cyclodextrins and their derivatives, alginic acid and alginate propylene glycol; gums, such as cellulose powder, microcrystalline cellulose, ethyl cellulose, methyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose; polymers that have an important function to disperse other materials, such as poloxamers, povidone and its derivatives, sodium starch glycolate and carbomers. In addition to these dispersants, dextrin, gelatin, medium chain triglyceride, tragacanth and the like, are good adsorbents and dispersants. These adsorbents can be used alone to perform adsorption / dispersion functions, but mixtures of two or more adsorbents are preferably used to create synergistic effects. A mixture of a porous colloidal adsorbent and a cellulose type adsorbent is preferred. In addition, a mixture with a polymeric adsorbent is very useful. More preferably, colloidal silicon dioxide and microcrystalline cellulose are used as adsorbents, and preferably polyvinyl pyrrolidone and sodium starch glycolate are used as dispersants. The crystallinity required in maintaining the good chemical stability of orlistat and its related materials is disadvantageous in terms of bioavailability. However, transformation of a crystalline form into an amorphous form to increase bioavailability results in damage to chemical stability. An important point of the present invention is to provide solutions to satisfy the contradictory requirements. For this purpose, the present invention suggests the following solutions: reduction of excessive crystallinity, use of a solubilized composition, improvement of the antioxidant capacity, use of porous type adsorbents and cellulose to solve the problems of instability, for example, hydrolysis , and determination of an adequate pH value to achieve maximum chemical stability. A method for preparing the pharmaceutical formulation according to the present invention consists of the steps of:
mix 0.01-20 parts by weight of the solvent, 0.01-20 parts by weight of the solubilizer, 0.01-10 parts by weight of the surfactant and 0.01-2 parts by weight of the antioxidant with heating of 40-60 ° C; mix the mixture with 1 part by weight of the pharmacologically active substance; adsorb the mixture obtained in the previous step to 0.1-20 parts by weight of the adsorbent; mixing the mixture obtained in the previous step with a pharmaceutically acceptable excipient suitable for molding; and molding the mixture obtained in the previous step in a tablet followed by the coating or capsule. In the step of mixing with the pharmacologically active substance, the solubilization is carried out as quickly as possible to ensure the stability of the pharmacologically active substance. In the adsorption step to the adsorbent, a mixture of the adsorbent and a dispersing powder are supplied to a vessel in which high speed agitation and dispersion can be performed, and then the above solution is poured into the vessel with very rapid stirring to induce adsorption and rapid cooling. In this stage, the agitation is carried out at a very high speed for a sufficient time to allow very rapid adsorption and uniform dispersion of the solution. As an excipient, at least one material selected from Tween 80 (polysorbate 80), PVP K-30 (polyvinyl pyrrolidone), and talc (Mg 3 (OH) 2 Si 4 O 0) can be used.
Mode for the invention. Below, the pharmaceutical formulation of the present invention will be explained in more detail with reference to the following examples.
EXAMPLES
Example 1: 10g of polyethylene glycol 400, 10g of polyoxyethylene castor oil (Cremofor), 10g of polysorbate and 5g of tocopherol acetate were heated to 40-60 ° C, and then 120g of orlistat was added thereto. The mixture was homogeneously whipped to prepare a pale yellow transparent liquid formulation. The liquid state was transformed into an opaque coagulated state at room temperature. Some portions were used to carry out a test for liquid stability. The other portions were adsorbed to an adsorbent, and then an excipient was added to them. The resulting mixture was pressurized to produce tablets, followed by coating with a film to obtain 800 tablet samples. 1) the liquid samples were cooled to form a coagulated material. The coagulated material had a uniform shape and composition, and showed no phase separation and reaggregation. A series of storage at a low temperature of 4 ° C and storage at a high temperature of 40 ° C was repeated several times, and after that, a dissolution test was carried out. As a result, a high dissolution rate of 99.1% was obtained. However, the degradation of the liquid was observed after six weeks of storage under accelerated storage conditions. In addition, a 15% reduction in content was observed. Obscure particles were observed as degradation products and layers in which the dark particles were dispersed. 2) The tablet samples were stored under accelerated conditions (temperature: 40 ° C, relative humidity: 70%). Table 1 shows changes in the dissolution index and content of the tablet samples after six months of storage.
Table 1
Example 2: 10g of polyoxyethylene castor oil (Cremofor) were heated at 40-60 ° C to obtain a clear liquid, and then 10g of polysorbate was added thereto with gentle agitation. 120 g of orlistat were added to the mixture and stirred homogeneously to form a clear, pale yellow liquid formulation. The liquid state was transformed into an opaque coagulated state at room temperature. Some portions were taken to observe the state of the liquid, and other portions were adsorbed to produce tablets, followed by a coating to obtain 800 samples of tablets. 1) No phase separation and no reaggregation was observed in the liquid samples. By the procedure of Example 1, a series of storage at a low temperature and storage at a high temperature was repeated several times, and after that, a dissolution test was carried out. As a result, a dissolution rate of about 59% was obtained. These observations indirectly show that the solvent selected in the present invention was convenient and unavoidable to maximize the efficiency of the solubilizer, the surfactant and the antioxidant. After 2 weeks of storage under accelerated conditions, the degradation products and their layers were observed. 2) The dissolution of the tablet samples was tested, and as a result satisfactory results were not obtained.
Example 3: When 10g of polyethylene glycol, 10g of polysorbate and 5g of tocopheryl acetate were mixed with heating to obtain a clear liquid, 120g of orlistat was added to the mixture. The resulting mixture was stirred homogeneously to prepare a pale yellow clear liquid formulation. The liquid state was transformed into an opaque semi-coagulated state at room temperature. By the procedure of Example 1, some portions were separated, adsorbed rapidly and pressed to produce tablets. 1) During coagulation, phase separation, reaggregation and recrystallization of the separated liquid samples were observed. By the procedure of example 1, a series of storage at low temperature and storage at high temperature were repeated several times, and subsequently, a dissolution test was carried out. As a result, a dissolution index of about 23% was obtained. These observations demonstrate that the solubilizer is an inevitable ingredient for the stable dissolution of the formulation. After 2 weeks of storage under accelerated conditions, the degradation products and their layers were observed. 2) The dissolution rate of the tablet samples was tested, and as a result, the dissolution rates of the tablet samples were not significantly erent from those of the liquid samples.
Example 4: 10g of polyethylene glycol, 10g of the polyoxyethylene castor oil (Cremofor) and 5g of the tocopherol acetate were mixed and stirred homogeneously with heating to prepare a clear solution, and then they were added
120g of orlistat to the solution. The mixture was stirred homogeneously to prepare a pale yellow transparent liquid formulation. 1) The liquid state was transformed into an opaque semi-coagulated state at room temperature. No phase separation or reaggregation was observed.
A series of low-temperature storage was repeated several times.
storage at high temperature, and subsequently, a dissolution test was carried out. As a result, a dissolution rate of 88% was obtained. However, a reduction in content was observed after four weeks of storage under accelerated storage conditions. The degradation products and their layers were observed. 2) An adsorbed powder was subjected to pressure to produce tablets, then covered to obtain samples of tablets. The tablet samples were stored under accelerated conditions for 6 months. Table 2 shows the changes in the rate of dissolution and content of the tablet samples during storage.
Table 2
The data shown in Table 2 show that the surfactant contributed significantly to the dissolution of the pharmacologically active substance.
Example 5: 10g of polyethylene glycol and 10g of polyoxyethylene castor oil (Cremofor) were mixed and stirred homogeneously with heating to prepare a clear solution, and then 120g of orlistat was added to the solution. The mixture was stirred homogeneously to prepare a pale yellow transparent liquid formulation. 1) The liquid state was transformed into an opaque coagulated state at room temperature. No separation, recrystallization and reaggregation of the phase was observed. These observations demonstrate that the antioxidant was involved in recrystallization and reaggregation to prevent phase separation during aggregation from occurring. A series of storage at low
Temperature and storage at high temperature was repeated several times, and subsequently, a dissolution test was carried out. As a result, a high dissolution rate of 95% was obtained. This suggests that phase separation and reaggregation during coagulation did not lead to a reduction in the rate of dissolution, and that optimal mixing of the solvent, the solubilizer and the surfactant leads to an effective solution. However, a reduction in liquid content was observed after four weeks of storage under accelerated storage conditions. The degradation products and their layers were also observed. 2) An adsorbed powder was subjected to pressure to produce tablets, then coated to obtain samples of coated tablets. The tablet samples were stored under accelerated conditions for 6 months. Table 3 shows changes in the dissolution index and the content of the tablet samples during storage.
Table 3
As can be seen from the data shown in Table 3, tocopherol was significantly involved in the stability of the drug (ie, orlistat). Table 4 shows the content of the ingredients in each of the tablets produced in Examples 1 to 5.
Table 4
Surprisingly, the present inventors have found that when a pharmacologically active substance is mixed with a solvent, a solubilizing agent and a surfactant to improve the solubility of the pharmacologically active substance to obtain an amorphous liquid or a semi-solid state, an antioxidant is fused together with the mixture to solve the poor chemical stability of the pharmacologically active substance in an amorphous or liquid state, and an adsorbent is strongly adsorbed to the molten mixture to be transformed into powder form, the resulting very small molecules are reconstituted into crystalline forms inside the adsorbent to ensure chemical stability, the porous or cellulose structure characteristic of the adsorbent
blocks and protects the pharmacologically active substance from factors, for example, air and moisture, causing chemical instability of the pharmacologically active substance, and the final pharmaceutical formulation to stabilize within a pH (as measured using an aqueous solution of 1g of the pharmaceutical formulation in 100 ml of water) from 4.5 to 5.5. The present invention has been achieved based on these findings.
INDUSTRIAL APPLICABILITY As is evident from the foregoing description, the pharmaceutical formulation of the present invention overcomes difficulties in the preparation of an active ingredient with a low melting point in a solid formulation, the poor solubility of an active ingredient, and the danger of chemical modifications during storage. In addition, according to the pharmaceutical formulation of the present invention, a drug can be stably dissolved despite changes in body environments. Furthermore, since the pharmaceutical formulation of the present invention advantageously takes advantage of the low melting point and the lipophilicity of a drug, it is economically advantageous. Moreover, the pharmaceutical formulation of the present invention has an advantage in that the hazards of chemical changes resulting from a high-energy state of a liquid phase can be reliably avoided. Although the preferred embodiments of the present invention have been described for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions may be possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims. .
Claims (8)
1. A pharmaceutical formulation with high stability and dissolution, said pharmaceutical formulation comprising 1 part by weight of orlistat, a lipase inhibitor, or its analog as a pharmacologically active substance that is poorly soluble and has a low melting point, 0.01 to 20 parts by weight of a solvent, 0.01 to 20 parts by weight of a solubilizer, 0.01 to 10 parts by weight of a surfactant, 0.01 to 2 parts by weight of an antioxidant, and 0.1 to 20 parts by weight of an adsorbent or dispersant.
2. The pharmaceutical formulation according to claim 1, wherein the solvent is selected from almond oil, castor oil, corn oil, cottonseed oil, ethyl oleate, glycerin, glyceryl monostearate, olive oil, peanut oil. , polyethylene glycol, propylene glycol, soybean oil, and their mixtures.
3. The pharmaceutical formulation according to claim 1, wherein the solubilizer is selected from gum arabic, ketostearyl alcohol, cholesterol, diethanolamine, ethyl oleate, ethylene glycol palmito stearate, glycerin, glyceryl monostearate, hydroxypropyl cellulose, isopropyl myristate, lecithin. , medium chain glyceride, monoethanolamine, oleic acid, propylene glycol, polyoxyethylene alkyl ether, polyoxyethylene castor oil glycoside, polyethylene sorbitan fatty acid ester, polyoxyethylene stearate, propylene glycol alginate, fatty acid ester of sorbitan, stearic acid, sunflower oil, triethanolamine and mixtures thereof. The pharmaceutical formulation according to claim 1, wherein the surfactant is selected from sodium docusate, glyceryl mono oleate, alkyl polyethylene ether, sorbitan fatty acid ester polyoxyethylene (polysorbate = Tween), sodium lauryl sulfate, sorbic acid , ester of sorbitan fatty acids and mixtures thereof. 5. The pharmaceutical formulation according to claim 1, wherein the antioxidant is selected from tocopherol, ascorbic acid and its glycosides, butylated hydroxyanisole, citric acid, edetic acid, fumaric acid, malic acid, monothioglycerin, phosphoric acid, potassium metabisulfite, propionic acid, propyl gellite, tar acid and mixtures thereof. The pharmaceutical formulation according to claim 1, wherein the adsorbent or dispersant is selected from silicon dioxide, kaolin, magnesium aluminum silicate, cyclodextrins and their derivatives, alginic acid, propylene glycol alginate, gums, including gum arabic and xanthan gum, celluloses, including cellulose powder, microcrystalline cellulose, ethyl cellulose, methyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose, poloxamers, povidone and its derivatives, glycolate of sodium starch, carbomeros, dextrin, gelatin, medium chain triglyceride, tragacanth and mixtures thereof. 7. The pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation has a pH of 4.5 to 5.5. 8. A method for preparing a pharmaceutical formulation with high stability and dissolution, said method comprising the steps of: mixing 0.01-20 parts by weight of a solvent, 0.01-20 parts by weight of a solubilizer, 0.01-10 parts by weight of a surfactant and 0.01-2 parts by weight of an antioxidant with heating at 40-60 ° C (step S1); mixing the mixture obtained in step S1 with 1 part by weight of a pharmacologically active substance (step S2); adsorbing the mixture obtained in step S2 to 0.1-20 parts by weight of an adsorbent (step S3); mixing the mixture obtained in step S3 with a pharmaceutically acceptable excipient suitable for molding (step S4); and molding the mixture obtained in step S4 in a tablet followed by a coating or encapsulation (step S5).
Applications Claiming Priority (1)
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KR1020050075266 | 2005-08-17 |
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