CN104523653B - Acarbose capsules agent pharmaceutical composition - Google Patents
Acarbose capsules agent pharmaceutical composition Download PDFInfo
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- CN104523653B CN104523653B CN201510061944.4A CN201510061944A CN104523653B CN 104523653 B CN104523653 B CN 104523653B CN 201510061944 A CN201510061944 A CN 201510061944A CN 104523653 B CN104523653 B CN 104523653B
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- acarbose
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The present invention relates to Acarbose capsules agent pharmaceutical composition.Specifically, described capsule includes capsule shells and is wrapped in the capsule shells and in powder or granular implant.The capsule shells capsule shells, capsule shells, capsule shells, capsule shells made by with pectin as key component or capsule shells made by with carboxymethyl cellulose as key component made by with Sargassum polysaccharides as key component made by with hydroxypropyl methyl cellulose as key component made by with gelatin as key component.The implant includes active substance, diluent, lubricant, fluidizer.The active substance is Acarbose.The capsule of the present invention has excellent pharmaceutical properties.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a pharmaceutical composition, in particular to a pharmaceutical preparation in the form of hard capsules, and specifically relates to an acarbose capsule pharmaceutical composition. The invention also relates to a method for producing the same.
Background
Diabetes Mellitus (DM) is a group of metabolic diseases characterized by elevated levels of chronic blood glucose (abbreviated as blood glucose) due to defects in insulin secretion and/or action. Long-term disorders of carbohydrate, fat and protein metabolism can cause multiple system damage, resulting in chronic progressive lesions, hypofunction and failure of tissues and organs such as eyes, kidneys, nerves, heart, blood vessels and the like. Serious metabolic disorders, such as Diabetic Ketoacidosis (DKA), hyperglycemia, etc., may occur in severe conditions or under stress. The disease causes the reduction of the life quality of patients, shortens the life span and increases the fatality rate, and becomes the third most non-infectious disease seriously harming human health after cardiovascular and cerebrovascular diseases and cancers in developed countries. It is expected that the prevalence of diabetes will increase from 1.73 to 3.66 billion in 2000 by 2030. Accordingly, diabetes will spread to 5% of the general population worldwide. The number of diabetics in China is increasing, and the diabetes mellitus is the second major diabetes mellitus country after India. Diabetes is a chronic disease, and needs to be taken for a long time and scientifically treated. Among diabetic patients, type ii diabetic patients account for more than 90%, and among the therapeutic measures for type ii diabetic patients, oral hypoglycemic agents are the main therapeutic means.
Acarbose (Acarbose) is a drug developed in 70 th middle-age Bayer company in Germany for treating type II diabetes, and is the first brand drug of oral hypoglycemic drugs, wherein the chemical name is O-4,6-dideoxy-4- [ (1S,4R,5S,6S) -4,5,6-trihydroxy-3- (hydroxymethyl) -2-cyclohexenyl-1-amino ] -alpha-D-glucopyranosyl- (1 → 4) -O-alpha-D-glucopyranosyl- (1 → 4) -D-glucopyranosyl, the chemical name is O-4,6-dideoxy-4- [ [ (1S,4R,5S,6S) -4,5,6-trihydroxy-3- (hydroxymethy) -2-cyclohexen-1-yl ] amino ] α -D-glucopyranosyl- (1 → 4) -O- α -D-glucopyranosyl- (1 → 4) -D-glucose. Acarbose was first marketed in germany in 1990, was approved by the FDA in 1996 and was marketed in the united states in 1998, and entered china under the trade name "bgrasp".
Acarbose has the molecular formula of C25H43NO18, molecular weight of 645.60, and chemical structural formula:
acarbose is an oral hypoglycemic different from sulfonylureas and biguanides prepared by biosynthesis, is an alpha-glucosidase inhibitor, and has strong affinity to amylase and alpha-glucosidase on the upper edge of intestinal cells. When the acarbose is taken at a meal, the hydrolysis of food polysaccharides in the digestive tract can be interfered, and the absorption of glucose and fructose is delayed, so that the peak value of postprandial blood sugar rise is obviously reduced. Since this inhibition is reversible, acarbose can only delay complex carbohydrate digestion, rather than completely block glucose absorption. Clinical tests on healthy adults show that acarbose can reduce postprandial hyperglycemia and plasma insulin concentration, delay the concentration of glucose entering blood, level the postprandial blood glucose peak and slow down the decline of the peak value of glucose. The blood sugar tends to be stable day and night. The acarbose is more beneficial to patients who are easy to have hypoglycemia at night. Animal experiments show that acarbose also has the effect of reducing the concentration of blood triglyceride, blood cholesterol and free fatty acid.
Chinese patent application publication CN101019874A (200710020560.3) discloses an acarbose pharmaceutical composition and a preparation method thereof, which is prepared by mixing acarbose and a lubricant acting as a glidant, adding a filler after mixing, adding a lubricant, mixing, and tabletting. The method has the following disadvantages: acarbose has poor flowability, the flowability cannot be well improved even though a lubricant is added, the main drug and the auxiliary materials are uniformly mixed and then tabletted, the acarbose raw material is lighter, the auxiliary materials are directly mixed and then tabletted, the difference in the tablet is large, even unqualified phenomenon occurs, powder spraying can occur in the tabletting process, and the qualification of the tablet weight cannot be guaranteed.
Chinese patent CN101411715B (200710156138.0) relates to a pharmaceutical composition containing acarbose, which is prepared by screening various adjuvants and dosages, and comprises the following components in percentage by weight: 8-32% of acarbose, 50-70% of a filler, 2-12% of a disintegrating agent, 5-20% of a disintegrating aid and 0.5-5% of a lubricant; wherein the filler is selected from one or more of microcrystalline cellulose, mannitol, and copovidone; the disintegrant is one or more of crospovidone, carboxymethyl starch sodium and croscarmellose sodium; the disintegration assistant is organic acid and sodium bicarbonate; the lubricant is micropowder silica gel and/or magnesium stearate; wherein the pharmaceutical composition containing the acarbose is used for preparing orally disintegrating tablets. The acarbose preparation can be rapidly disintegrated in oral cavity, does not need water and is easier to take.
Chinese patent CN101336904B (200810063335.2) discloses an acarbose chewable tablet, which consists of a filler and a lubricant. The concrete composition is as follows: acarbose: 5-30% of a filler: 60-90% of a lubricant: 0.1-10%, wetting agent: 0-10% of a flavoring agent: 0 to 10 percent; wherein the filler is mannitol, sorbitol, mannitol and microcrystalline cellulose, sorbitol and microcrystalline cellulose, mannitol and sorbitol and microcrystalline cellulose; wherein the lubricant is one or more of the following: stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium dodecyl sulfate, magnesium dodecyl sulfate, polyethylene glycol, talcum powder or superfine silica powder. The invention is believed to overcome the obstacle that acarbose is not easy to be made into chewable tablets by optimizing the specific auxiliary materials, and simultaneously overcome the defects that the acarbose common tablets are easy to absorb moisture and have sandy sense when being taken, thereby greatly improving the compliance of patients while ensuring the drug effect. The invention also discloses a preparation method of the acarbose chewable tablet, which is stable and feasible, simple in preparation process, controllable in product quality and suitable for industrial production.
Chinese patent CN101496790B (200910096314.5) discloses a chewable tablet with acarbose as active ingredient. The acarbose is used as a medicinal active component, and is mixed with pharmaceutically acceptable auxiliary materials to form a medicinal composition. Specifically, the tablet comprises the following components in percentage by weight: acarbose: 1% -50/455 × 100%, avicel cl 611: 300/455 100-600/654 100%, flavoring agent: 0-60%, lubricant: 0-10 percent, and the sum of the percentage contents of the components is 100 percent. Acarbose has the defect of easy moisture absorption and hardening, and the novel compound auxiliary material Avicel CL611 is believed to have the advantages of simple process, direct tabletting, time and labor saving, and simultaneously overcomes the defect that the common chewable tablet is easy to absorb moisture.
Chinese patent application CN102905687A (201180020548.7) discloses an Orally Disintegrating Tablet (ODT) for acarbose, a glycosidase inhibitor, comprising 1-30% acarbose, 40-90% water soluble carrier, 1-50% water insoluble carrier. The preparation method of the tablet comprises the following steps: precompression of acarbose having a moisture content of 0 to 5%, mixing with a water-insoluble carrier, mixing with a water-soluble carrier, tabletting.
Chinese patent application CN103315971A (201310232803.5) discloses an acarbose tablet and a preparation method thereof, wherein acarbose, microcrystalline cellulose and starch and 2/3 carboxymethyl starch sodium are uniformly mixed to obtain a premix; granulating and finishing the mixture by a dry method to obtain particles; and uniformly mixing the granules, 1/3 sodium carboxymethyl starch, magnesium stearate and silicon dioxide, and tabletting by a tabletting machine to obtain the acarbose tablets. The tablet prepared by adopting the dry granulation and tabletting method effectively improves the hardness and stability of the tablet, solves the problems of unqualified disintegration time limit and unqualified microorganism, improves the product quality, has simple process flow, saves energy and cost, and is suitable for industrial production.
However, the present inventors have found that there still remain some technical problems to be overcome in the process of preparing acarbose capsules in order to obtain acarbose capsules with excellent formulation quality.
Disclosure of Invention
The object of the present invention is to provide an acarbose capsule having excellent formulation quality properties, and another object of the present invention is to provide a method for preparing the acarbose capsule. It has been surprisingly found that the acarbose capsules prepared according to the invention have excellent properties. The present invention has been completed based on this finding.
To this end, the present invention provides, in a first aspect, a capsule comprising a capsule shell and a filler in powder or granular form enclosed within the capsule shell. Typically, the capsule is a hard capsule.
It is well known to those skilled in the pharmaceutical arts that capsules, particularly hard capsules, have a capsule shell filled with the above-described fill material, also referred to as "contents".
The capsule according to any embodiment of the first aspect of the present invention, wherein the capsule shell is selected from the group consisting of: the capsule shell is prepared from gelatin as main component, hydroxypropyl methylcellulose as main component, algal polysaccharide as main component, pectin as main component, or carboxymethyl cellulose as main component. In the present invention, the term "capsule shell" may also be referred to as "empty capsule" or similar terms. As is well known, a hollow capsule generally consists of a capsule body and a capsule cap, which are sealed together after being filled with a medicament to form a capsule. In the present invention, all references to "capsules" refer to hard capsules.
The capsule according to any one of the embodiments of the first aspect of the present invention, wherein the capsule shell is a capsule shell made of gelatin as a main component. It may be a conventional gelatin hollow capsule that dissolves under a wide range of pH conditions or an enteric gelatin hollow capsule that dissolves in intestinal fluids. In the present invention, reference to "gelatin hollow capsules" is intended to refer to ordinary gelatin hollow capsules that are soluble under a wide range of pH conditions, unless otherwise indicated. The modification of the enteric-coated gelatin capsule refers to the enteric-coated gelatin hollow capsule. In one embodiment, the capsule shell is not a capsule shell of an enteric gelatin hollow capsule.
The gelatin hollow capsules referred to in the present invention have typically been received in the 2010 version, department two of the chinese pharmacopoeia, and many products have been approved by the national food and drug administration for marketing, such as gelatin hollow capsules of the national standard F20020020009 (shaoxing and), the national standard F20020020035 (di sheng zhejiang), and the national standard F20030004 (changshu long standing grain), which in the present invention may be referred to as common gelatin hollow capsules or similar designations to distinguish them from the following enteric gelatin hollow capsules. Furthermore, by dipping with formaldehyde in the preparation of ordinary gelatin hollow capsules, enteric gelatin hollow capsules which are insoluble in the stomach but soluble in the intestine, such as enteric gelatin hollow capsules of the national standard F20020030 (shaoxing kange) and the national standard F20070003 (new changkongping), can be obtained.
The capsule shell (which can also be generally called as hypromellose empty capsule) which is prepared by taking hydroxypropyl methylcellulose as a main component, the capsule shell (which can also be generally called as algal polysaccharide empty capsule) which is prepared by taking algal polysaccharide as a main component are approved by the national food and drug administration and marketing, such as the hypromellose empty capsule with the national drug standard F20090002 (Suzhou capsule), the hypromellose empty capsule with the national drug standard F20120001 (Shaoxing kanke) and the algal polysaccharide empty capsule with the national drug standard F20050002 (Qinhandao medical capsule).
The capsule shell (which is also commonly called as a pectin empty capsule) prepared by taking pectin as a main component and related to the invention has been developed and is primarily applied to certain fields (for example, the capsule shell is sold by Nanjing Yibaier science and technology company; for example, the empty capsule containing 60-85% of pectin is described in Chinese patent application No. 200910185990.X, and is prepared by referring to the method of example 1 on page 2 of the specification of the patent document when the capsule shell is used in the invention, and can be called as #990.X pectin capsule or the like for short).
The capsule shell (which is also commonly referred to as carboxymethyl cellulose empty capsule, or CMC capsule or the like) mainly composed of carboxymethyl cellulose according to the present invention has been developed and primarily applied to some fields (for example, the empty capsule containing 80 to 90% carboxymethyl cellulose described in chinese patent application No. 200910116242.6 is prepared by referring to the method of example 1 on page 3 of the specification of the patent document, and may be referred to as #242.6CMC capsule or the like) when used in the present invention.
A capsule according to any embodiment of the first aspect of the invention, wherein the filling comprises an active substance, a diluent, a lubricant, a glidant.
A capsule according to any one of the embodiments of the first aspect of the invention, wherein the active substance is acarbose.
The capsule according to any of the embodiments of the first aspect of the present invention, wherein the diluent is selected from the group consisting of starch, dextrin, carboxymethyl starch, hydroxypropyl starch, modified pregelatinized starch, lactose, powdered sugar, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, calcium carbonate, and the like, and combinations thereof.
The capsule according to any one of the embodiments of the first aspect of the present invention, wherein the diluent is selected from the group consisting of starch (e.g. corn starch, potato starch, rice starch, wheat starch, tapioca starch, etc. are all possible), dextrin, carboxymethyl starch, hydroxypropyl starch, modified pregelatinized starch, microcrystalline cellulose, and combinations thereof.
A capsule according to any one of the embodiments of the first aspect of the present invention, wherein the diluent is microcrystalline cellulose in combination with a component selected from the group consisting of: starches (e.g., corn starch, potato starch, rice starch, wheat starch, tapioca starch, etc. are all possible), dextrin, carboxymethyl starch, hydroxypropyl starch, modified pregelatinized starch, lactose, powdered sugar, calcium phosphate, calcium hydrogen phosphate, calcium carbonate.
The capsule according to any one of the embodiments of the first aspect of the present invention, wherein the diluent is selected from the group consisting of starch, microcrystalline cellulose, modified pregelatinized starch, and combinations thereof.
A capsule according to any one of the embodiments of the first aspect of the present invention, wherein the lubricant is selected from the group consisting of: magnesium stearate, stearic acid, polyethylene glycol having a molecular weight of 4000-.
The capsule according to any embodiment of the first aspect of the present invention, wherein the glidant is selected from the group consisting of: talc, silica gel micropowder, and the like, and combinations thereof.
The capsule according to any embodiment of the first aspect of the present invention, wherein the filling comprises acarbose, microcrystalline cellulose, starch, modified pregelatinized starch, a lubricant, a glidant.
The capsule according to any one of the embodiments of the first aspect of the present invention, wherein the filler comprises 50 parts by weight of acarbose, 5-50 parts by weight of microcrystalline cellulose, 50-200 parts by weight of starch, 10-100 parts by weight of modified pregelatinized starch, 0.5-5 parts by weight of lubricant, and 0.3-3 parts by weight of glidant.
The capsule according to any one of the embodiments of the first aspect of the present invention, wherein the filler comprises 50 parts by weight of acarbose, 10-40 parts by weight of microcrystalline cellulose, 60-150 parts by weight of starch, 20-75 parts by weight of modified pregelatinized starch, 1-2.5 parts by weight of lubricant, and 0.5-1.5 parts by weight of glidant.
The capsule according to any one of the embodiments of the first aspect of the present invention, wherein the filler comprises 50 parts by weight of acarbose, 15-30 parts by weight of microcrystalline cellulose, 75-100 parts by weight of starch, 25-50 parts by weight of modified pregelatinized starch, 1.2-2 parts by weight of lubricant, and 0.5-1.2 parts by weight of glidant.
A capsule according to any embodiment of the first aspect of the invention, wherein the filling comprises 50 parts by weight acarbose, 20 parts by weight microcrystalline cellulose, 90 parts by weight starch, 40 parts by weight modified pregelatinized starch, 1.5 parts by weight lubricant, 1 part by weight glidant.
A capsule according to any embodiment of the first aspect of the invention, wherein the filling comprises 50 parts by weight acarbose, 20 parts by weight microcrystalline cellulose, 87.5 parts by weight starch, 40 parts by weight modified pregelatinized starch, 1.5 parts by weight lubricant, 1 part by weight glidant.
A capsule according to any embodiment of the first aspect of the present invention, wherein the filling has a formulation as described in any of the examples herein below.
The capsule according to any one of the embodiments of the first aspect of the present invention is prepared by the following method:
(i) preparing a filler in powder or granular form;
(ii) filling the obtained filler into capsule shell, and sealing the capsule.
A capsule according to any one of the embodiments of the first aspect of the present invention, wherein the filling is prepared by the method comprising the following steps:
(1) uniformly mixing acarbose and microcrystalline cellulose in a prescription amount, and crushing the acarbose and the microcrystalline cellulose together into fine powder which is sieved by a 80-mesh sieve;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) and (3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as the filling of the capsule.
A capsule according to any one of the embodiments of the first aspect of the present invention, wherein the filling is prepared by the method comprising the following steps:
(1) uniformly mixing acarbose and microcrystalline cellulose according to the prescription amount, spraying ethanol with the concentration of more than 98% (the weight ratio of acarbose to the ethanol is 50: 2-5) into the mixed powder in a high-speed mixing state, pre-pressing the obtained mixture into a sheet by using an extruder, crushing the sheet into particles, drying to remove the ethanol, and crushing the particles into fine powder which is sieved by a 80-mesh sieve;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) and (3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as the filling of the capsule.
A capsule according to any one of the embodiments of the first aspect of the present invention, wherein the filling material is filled into the capsule shell, further comprising the step of measuring the content of the active substance in the filling material and calculating the filling amount of each capsule.
It has surprisingly been found that after the resulting filling has been filled into empty capsules after the acarbose and microcrystalline cellulose have been previously treated by the process of the invention, capsules are produced which have excellent physical stability, e.g. which can be maintained after long-term storage.
Further, the present invention provides in a second aspect a process for the preparation of a capsule, for example a capsule according to any of the embodiments of the first aspect of the present invention, comprising the steps of:
(i) preparing a filler in powder or granular form;
(ii) filling the obtained filler into capsule shell, and sealing the capsule.
The method according to any embodiment of the second aspect of the invention, wherein the capsule is a hard capsule.
The method according to any embodiment of the second aspect of the invention, wherein the capsule shell is selected from the group consisting of: the capsule shell is prepared from gelatin as main component, hydroxypropyl methylcellulose as main component, algal polysaccharide as main component, pectin as main component, or carboxymethyl cellulose as main component. In the present invention, the term "capsule shell" may also be referred to as "empty capsule" or similar terms. As is well known, a hollow capsule generally consists of a capsule body and a capsule cap, which are sealed together after being filled with a medicament to form a capsule. In the present invention, all references to "capsules" refer to hard capsules.
The process according to any one of the embodiments of the second aspect of the present invention, wherein the capsule shell is a capsule shell made of gelatin as a main component. It may be a conventional gelatin hollow capsule that dissolves under a wide range of pH conditions or an enteric gelatin hollow capsule that dissolves in intestinal fluids. In the present invention, reference to "gelatin hollow capsules" is intended to refer to ordinary gelatin hollow capsules that are soluble under a wide range of pH conditions, unless otherwise indicated. The modification of the enteric-coated gelatin capsule refers to the enteric-coated gelatin hollow capsule. In one embodiment, the capsule shell is not a capsule shell of an enteric gelatin hollow capsule.
The gelatin hollow capsules referred to in the present invention have typically been received in the 2010 version, department two of the chinese pharmacopoeia, and many products have been approved by the national food and drug administration for marketing, such as gelatin hollow capsules of the national standard F20020020009 (shaoxing and), the national standard F20020020035 (di sheng zhejiang), and the national standard F20030004 (changshu long standing grain), which in the present invention may be referred to as common gelatin hollow capsules or similar designations to distinguish them from the following enteric gelatin hollow capsules. Furthermore, by dipping with formaldehyde in the preparation of ordinary gelatin hollow capsules, enteric gelatin hollow capsules which are insoluble in the stomach but soluble in the intestine, such as enteric gelatin hollow capsules of the national standard F20020030 (shaoxing kange) and the national standard F20070003 (new changkongping), can be obtained.
The capsule shell (which can also be generally called as hypromellose empty capsule) which is prepared by taking hydroxypropyl methylcellulose as a main component, the capsule shell (which can also be generally called as algal polysaccharide empty capsule) which is prepared by taking algal polysaccharide as a main component are approved by the national food and drug administration and marketing, such as the hypromellose empty capsule with the national drug standard F20090002 (Suzhou capsule), the hypromellose empty capsule with the national drug standard F20120001 (Shaoxing kanke) and the algal polysaccharide empty capsule with the national drug standard F20050002 (Qinhandao medical capsule).
The capsule shell (which is also commonly called as a pectin empty capsule) prepared by taking pectin as a main component and related to the invention has been developed and is primarily applied to certain fields (for example, the capsule shell is sold by Nanjing Yibaier science and technology company; for example, the empty capsule containing 60-85% of pectin is described in Chinese patent application No. 200910185990.X, and is prepared by referring to the method of example 1 on page 2 of the specification of the patent document when the capsule shell is used in the invention, and can be called as #990.X pectin capsule or the like for short).
The capsule shell (which is also commonly referred to as carboxymethyl cellulose empty capsule, or CMC capsule or the like) mainly composed of carboxymethyl cellulose according to the present invention has been developed and primarily applied to some fields (for example, the empty capsule containing 80 to 90% carboxymethyl cellulose described in chinese patent application No. 200910116242.6 is prepared by referring to the method of example 1 on page 3 of the specification of the patent document, and may be referred to as #242.6CMC capsule or the like) when used in the present invention.
The method according to any embodiment of the second aspect of the invention, wherein the filling comprises an active substance, a diluent, a lubricant, a glidant.
The method according to any of the embodiments of the second aspect of the present invention, wherein the active substance is acarbose.
The method according to any embodiment of the second aspect of the present invention, wherein the diluent is selected from the group consisting of starch, dextrin, carboxymethyl starch, hydroxypropyl starch, modified pregelatinized starch, lactose, powdered sugar, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, calcium carbonate, and the like, and combinations thereof.
The method according to any embodiment of the second aspect of the present invention, wherein the diluent is microcrystalline cellulose in combination with a component selected from the group consisting of: starch, dextrin, carboxymethyl starch, hydroxypropyl starch, modified pregelatinized starch, lactose, powdered sugar, calcium phosphate, calcium hydrogen phosphate, and calcium carbonate.
The method according to any embodiment of the second aspect of the present invention, wherein the diluent is selected from the group consisting of starch (e.g. corn starch, potato starch, rice starch, wheat starch, tapioca starch, etc. are all possible), dextrin, carboxymethyl starch, hydroxypropyl starch, modified pregelatinized starch, microcrystalline cellulose, and combinations thereof.
The method according to any embodiment of the second aspect of the present invention, wherein the diluent is selected from the group consisting of starch, microcrystalline cellulose, modified pregelatinized starch, and combinations thereof.
The method according to any embodiment of the second aspect of the invention, wherein the lubricant is selected from the group consisting of: magnesium stearate, stearic acid, polyethylene glycol having a molecular weight of 4000-.
The method according to any embodiment of the second aspect of the invention, wherein the glidant is selected from the group consisting of: talc, silica gel micropowder, and the like, and combinations thereof.
The method according to any embodiment of the second aspect of the invention, wherein the filling comprises acarbose, microcrystalline cellulose, starch, modified pregelatinized starch, a lubricant, a glidant.
The method according to any embodiment of the second aspect of the present invention, wherein the filler comprises 50 parts by weight of acarbose, 5-50 parts by weight of microcrystalline cellulose, 50-200 parts by weight of starch, 10-100 parts by weight of modified pregelatinized starch, 0.5-5 parts by weight of lubricant, and 0.3-3 parts by weight of glidant.
The method according to any embodiment of the second aspect of the present invention, wherein the filler comprises 50 parts by weight of acarbose, 10-40 parts by weight of microcrystalline cellulose, 60-150 parts by weight of starch, 20-75 parts by weight of modified pregelatinized starch, 1-2.5 parts by weight of lubricant and 0.5-1.5 parts by weight of glidant.
The method according to any embodiment of the second aspect of the present invention, wherein the filler comprises 50 parts by weight of acarbose, 15-30 parts by weight of microcrystalline cellulose, 75-100 parts by weight of starch, 25-50 parts by weight of modified pregelatinized starch, 1.2-2 parts by weight of lubricant, and 0.5-1.2 parts by weight of glidant.
The method according to any embodiment of the second aspect of the invention, wherein the filling comprises 50 parts by weight acarbose, 20 parts by weight microcrystalline cellulose, 90 parts by weight starch, 40 parts by weight modified pregelatinized starch, 1.5 parts by weight lubricant, 1 part by weight glidant.
The method according to any embodiment of the second aspect of the invention, wherein the filling comprises 50 parts by weight acarbose, 20 parts by weight microcrystalline cellulose, 87.5 parts by weight starch, 40 parts by weight modified pregelatinized starch, 1.5 parts by weight lubricant, 1 part by weight glidant.
The method according to any embodiment of the second aspect of the present invention, wherein the filler has a formulation as described in any of the examples herein below.
The method according to any embodiment of the second aspect of the present invention, wherein the filler is prepared by the method comprising the following steps:
(1) uniformly mixing acarbose and microcrystalline cellulose in a prescription amount, and crushing the acarbose and the microcrystalline cellulose together into fine powder which is sieved by a 80-mesh sieve;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) and (3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as the filling of the capsule.
The method according to any embodiment of the second aspect of the present invention, wherein the filler is prepared by the method comprising the following steps:
(1) uniformly mixing acarbose and microcrystalline cellulose according to the prescription amount, spraying ethanol with the concentration of more than 98% (the weight ratio of acarbose to the ethanol is 50: 2-5) into the mixed powder in a high-speed mixing state, pre-pressing the obtained mixture into a sheet by using an extruder, crushing the sheet into particles, drying to remove the ethanol, and crushing the particles into fine powder which is sieved by a 80-mesh sieve;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) and (3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as the filling of the capsule.
The method according to any embodiment of the second aspect of the present invention, wherein the filling material is filled into the capsule shell, further comprising the step of measuring the content of the active substance in the filling material and calculating the filling amount of each capsule.
Any technical feature possessed by any one aspect of the invention or any embodiment of that aspect is equally applicable to any other embodiment or any embodiment of any other aspect, so long as they are not mutually inconsistent, although appropriate modifications to the respective features may be made as necessary when applicable to each other. Various aspects and features of the disclosure are described further below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
In the present invention, references to% are weight/weight percentages, as not otherwise specified.
The various materials used in the present invention, including the various adjuvants used, are well known to those skilled in the art and are readily commercially available, for example, the modified pregelatinized starch is available from Hebei Macro Source starch company, Qufudanli pharmaceutic adjuvant company, and the like.
Acarbose (Acarbose) tablets are commercially available under the trade name bgrasp and are indicated for type 2 diabetes in conjunction with dietary management. Lowering postprandial blood glucose in impaired glucose tolerance.
Acarbose is usually administered in whole tablet form immediately before meal consumption or by chewing together with the first few mouths of food; the generally recommended dosages are: the initial dose is 50mg at a time (1 tablet at a time), 3 times a day, and gradually increased to 0.1g at a time (2 tablets at a time), 3 times a day, in individual cases to 0.2g at a time (4 tablets at a time), 3 times a day, or following a physician; 3. if the curative effect of the patient is not obvious after taking the medicine for 4-8 weeks, the dosage can be increased. If the patient is untimely after maintaining strict diabetic diet, the dosage can not be increased, and sometimes the dosage needs to be reduced properly, wherein the average dosage is 0.1g once and 3 times a day.
Drug interaction during treatment with acarbose, sucrose or sucrose-containing foods often cause abdominal discomfort and even diarrhea due to increased carbohydrate glycolysis in the colon. The product has antihyperglycemic effect, but does not cause hypoglycemia. If the product is used with sulfonylurea drugs, metformin or insulin, hypoglycemia may occur, so it is necessary to reduce the dose of sulfonylurea drugs, metformin or insulin. Otherwise, hypoglycemic coma may occur in individual cases. In individual cases, acarbose may affect the bioavailability of digoxin, and thus the dosage of digoxin may need to be adjusted. During taking the product, the simultaneous taking of the cholestyramide, the intestinal adsorbent and the digestive enzyme preparation is avoided, so that the curative effect of the product is not influenced. No interaction with dimethicone was found.
Since the 70 s in the 20 th century, the number of people who have suffered from glucose metabolism diseases such as diabetic hyperglycemia has increased rapidly, and diabetes is now classified as the third most fatal disease after cardiovascular tumors, which seriously threatens human health. The influence of diabetes on the quality of life and huge medical expenses promote the attention of the whole society to diabetes and the deep research on various treatment means of diabetes.
Acarbose (Acarbose) is a clinically common alpha-glucosidase inhibitor, belongs to one of common medicines for type 2 diabetes, is a biosynthetic pseudotetrasaccharide, and can inhibit the activity of alpha-glucosidase of cells on the intestinal wall, so that the degradation of oligosaccharide disaccharide or polysaccharide in intestinal tracts is delayed, and the degradation and absorption of glucose and fructose are delayed, thereby achieving the effect of reducing postprandial blood sugar. Because of its good pharmacokinetic properties and low toxicity, acarbose is an ideal hypoglycemic agent.
In the research aspect of fermentation process of acarbose, the acarbose is relatively complicated in chemical structure, so that the industrial scale production is mainly obtained by microbial fermentation at present. Acarbose can be extracted from fermentation liquor of actinoplanes, and the research on anabolism paths and fermentation processes of acarbose in microorganisms is one of the research hotspots of acarbose.
In the research of the separation process of acarbose, the research on the extraction process of acarbose has been increasingly reported in recent years. In the nineties, resin is generally used for separation and extraction abroad, and the characteristic of weak alkalinity of one-NH-group in an acarbose structure is utilized, so that the acarbose can be separated and purified by ion exchange resin. It is reported that the characteristic of acarbose precipitation in ethanol is utilized, after the preliminary separation is carried out by an alcohol precipitation method, the purification and the refining are carried out by using a strong acid cation exchange resin and an affinity chromatography, and the finally obtained acarbose has the purity as high as 98 percent.
In addition, in the aspect of research on acarbose derivatives, both ends of a carbon side chain of acarbose are modified by using enzymes, so that acarbose derivatives with stronger carbohydrate hydrolase inhibition capability can be obtained.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible.
In the following specific examples section, where not otherwise mentioned, the formulation of the capsule filling is provided in terms of the amount of each material in each capsule; in the actual preparation, the capsules were dosed in an amount of 50000 capsules per batch. In the following specific examples section, as not mentioned otherwise, the hard capsule shell used in preparing the capsule is a capsule shell made of gelatin as a main component, and an appropriate size is selected to fill the amount of the filling indicated by the prescription.
Example 1: preparation of acarbose capsules
The formula is as follows:
| acarbose | 50mg |
| Microcrystalline cellulose | 20mg |
| Corn starch | 90mg |
| Modified pregelatinized starch | 40mg |
| Silicon dioxide | 1mg |
| Magnesium stearate | 1.5mg |
The preparation method comprises the following steps:
(1) uniformly mixing acarbose and microcrystalline cellulose according to the prescription amount, spraying ethanol with the concentration of more than 98% (the weight ratio of acarbose to the ethanol is 50: 4) into the mixed powder in a high-speed mixing state, pre-pressing the obtained mixture into a sheet by using an extruder, crushing the sheet into particles, drying to remove the ethanol, and crushing the particles into fine powder which is sieved by a 80-mesh sieve;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as a filling of the capsule;
(4) detecting the content of the active substance in the filling material, and calculating the filling amount of the filling material in each capsule;
(5) filling the obtained filler into capsule shell, and sealing the capsule.
Example 2: preparation of acarbose capsules
The formula is as follows:
| acarbose | 50mg |
| Microcrystalline cellulose | 20mg |
| Cassava starch | 87.5mg |
| Modified pregelatinized starch | 40mg |
| Silicon dioxide | 1mg |
| Magnesium stearate | 1.5mg |
The preparation method comprises the following steps:
(1) uniformly mixing acarbose and microcrystalline cellulose according to the prescription amount, spraying ethanol with the concentration of more than 98% (the weight ratio of acarbose to the ethanol is 50: 3) into the mixed powder in a high-speed mixing state, pre-pressing the obtained mixture into a sheet by using an extruder, crushing the sheet into particles, drying to remove the ethanol, and crushing the particles into fine powder which is sieved by a 80-mesh sieve;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as a filling of the capsule;
(4) detecting the content of the active substance in the filling material, and calculating the filling amount of the filling material in each capsule;
(5) filling the obtained filler into capsule shell, and sealing the capsule.
Example 3: preparation of acarbose capsules
The formula is as follows:
| acarbose | 50mg |
| Microcrystalline cellulose | 15mg |
| Potato starch | 95mg |
| Modified pregelatinized starch | 45mg |
| Silicon dioxide | 0.5mg |
| Magnesium stearate | 1.2mg |
The preparation method comprises the following steps:
(1) uniformly mixing acarbose and microcrystalline cellulose according to the prescription amount, spraying ethanol with the concentration of more than 98% (the weight ratio of acarbose to the ethanol is 50: 2) into the mixed powder in a high-speed mixing state, pre-pressing the obtained mixture into a sheet by using an extruder, crushing the sheet into particles, drying to remove the ethanol, and crushing the particles into fine powder which is sieved by a 80-mesh sieve;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as a filling of the capsule;
(4) detecting the content of the active substance in the filling material, and calculating the filling amount of the filling material in each capsule;
(5) filling the obtained filler into capsule shell, and sealing the capsule.
Example 4: preparation of acarbose capsules
The formula is as follows:
| acarbose | 50mg |
| Microcrystalline cellulose | 30mg |
| Rice starch | 85mg |
| Modified pregelatinized starch | 35mg |
| Silicon dioxide | 1.2mg |
| Polyethylene glycol 6000 | 2mg |
The preparation method comprises the following steps:
(1) uniformly mixing acarbose and microcrystalline cellulose according to the prescription amount, spraying ethanol with the concentration of more than 98% (the weight ratio of acarbose to the ethanol is 50: 5) into the mixed powder in a high-speed mixing state, pre-pressing the obtained mixture into a sheet by using an extruder, crushing the sheet into particles, drying to remove the ethanol, and crushing the particles into fine powder which is sieved by a 80-mesh sieve;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as a filling of the capsule;
(4) detecting the content of the active substance in the filling material, and calculating the filling amount of the filling material in each capsule;
(5) filling the obtained filler into capsule shell, and sealing the capsule.
Example 5: preparation of acarbose capsules
The formula is as follows:
| acarbose | 50mg |
| Microcrystalline cellulose | 10mg |
| Potato starch | 100mg |
| Modification ofPregelatinized starch | 50mg |
| Talcum powder | 1.5mg |
| Zinc stearate | 1mg |
The preparation method comprises the following steps:
(1) uniformly mixing acarbose and microcrystalline cellulose according to the prescription amount, spraying ethanol with the concentration of more than 98% (the weight ratio of acarbose to the ethanol is 50: 3) into the mixed powder in a high-speed mixing state, pre-pressing the obtained mixture into a sheet by using an extruder, crushing the sheet into particles, drying to remove the ethanol, and crushing the particles into fine powder which is sieved by a 80-mesh sieve;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as a filling of the capsule;
(4) detecting the content of the active substance in the filling material, and calculating the filling amount of the filling material in each capsule;
(5) filling the obtained filler into capsule shell, and sealing the capsule.
Example 6: preparation of acarbose capsules
The formula is as follows:
| acarbose | 50mg |
| Microcrystalline cellulose | 40mg |
| Wheat starch | 75mg |
| Modified pregelatinized starch | 25mg |
| Silica gel micropowder | 0.5mg |
| Calcium stearate | 2.5mg |
The preparation method comprises the following steps:
(1) uniformly mixing acarbose and microcrystalline cellulose according to the prescription amount, spraying ethanol with the concentration of more than 98% (the weight ratio of acarbose to the ethanol is 50: 4) into the mixed powder in a high-speed mixing state, pre-pressing the obtained mixture into a sheet by using an extruder, crushing the sheet into particles, drying to remove the ethanol, and crushing the particles into fine powder which is sieved by a 80-mesh sieve;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as a filling of the capsule;
(4) detecting the content of the active substance in the filling material, and calculating the filling amount of the filling material in each capsule;
(5) filling the obtained filler into capsule shell, and sealing the capsule.
Example 7: preparation of acarbose capsules
The formula is as follows:
| acarbose | 50mg |
| Microcrystalline cellulose | 20mg |
| Corn starch | 90mg |
| Modified pregelatinized starch | 40mg |
| Silicon dioxide | 1mg |
| Magnesium stearate | 1.5mg |
The preparation method comprises the following steps:
(1) uniformly mixing acarbose which is crushed in advance and sieved by a 80-mesh sieve with the microcrystalline cellulose according to the prescription amount;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as a filling of the capsule;
(4) detecting the content of the active substance in the filling material, and calculating the filling amount of the filling material in each capsule;
(5) filling the obtained filler into capsule shell, and sealing the capsule.
Example 8: preparation of acarbose capsules
The formula is as follows:
| acarbose | 50mg |
| Microcrystalline cellulose | 20mg |
| Cassava starch | 87.5mg |
| Modified pregelatinized starch | 40mg |
| Silicon dioxide | 1mg |
| Magnesium stearate | 1.5mg |
The preparation method comprises the following steps:
(1) uniformly mixing acarbose which is crushed in advance and sieved by a 80-mesh sieve with the microcrystalline cellulose according to the prescription amount;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as a filling of the capsule;
(4) detecting the content of the active substance in the filling material, and calculating the filling amount of the filling material in each capsule;
(5) filling the obtained filler into capsule shell, and sealing the capsule.
Example 9: preparation of acarbose capsules
The formula is as follows:
| acarbose | 50mg |
| Microcrystalline cellulose | 15mg |
| Potato starch | 95mg |
| Modified pregelatinized starch | 45mg |
| Silicon dioxide | 0.5mg |
| Magnesium stearate | 1.2mg |
The preparation method comprises the following steps:
(1) uniformly mixing acarbose which is crushed in advance and sieved by a 80-mesh sieve with the microcrystalline cellulose according to the prescription amount;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as a filling of the capsule;
(4) detecting the content of the active substance in the filling material, and calculating the filling amount of the filling material in each capsule;
(5) filling the obtained filler into capsule shell, and sealing the capsule.
Example 10: preparation of acarbose capsules
The formula is as follows:
| acarbose | 50mg |
| Microcrystalline cellulose | 30mg |
| Rice starch | 85mg |
| Modified pregelatinized starch | 35mg |
| Silicon dioxide | 1.2mg |
| Magnesium stearate | 2mg |
The preparation method comprises the following steps:
(1) uniformly mixing acarbose which is crushed in advance and sieved by a 80-mesh sieve with the microcrystalline cellulose according to the prescription amount;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as a filling of the capsule;
(4) detecting the content of the active substance in the filling material, and calculating the filling amount of the filling material in each capsule;
(5) filling the obtained filler into capsule shell, and sealing the capsule.
Example 11: preparation of acarbose capsules
The formula is as follows:
| acarbose | 50mg |
| Microcrystalline cellulose | 10mg |
| Potato starch | 100mg |
| Modified pregelatinized starch | 50mg |
| Talcum powder | 1.5mg |
| Zinc stearate | 1mg |
The preparation method comprises the following steps:
(1) uniformly mixing acarbose which is crushed in advance and sieved by a 80-mesh sieve with the microcrystalline cellulose according to the prescription amount;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as a filling of the capsule;
(4) detecting the content of the active substance in the filling material, and calculating the filling amount of the filling material in each capsule;
(5) filling the obtained filler into capsule shell, and sealing the capsule.
Example 12: preparation of acarbose capsules
The formula is as follows:
| acarbose | 50mg |
| Microcrystalline cellulose | 40mg |
| Wheat starch | 75mg |
| Modified pregelatinized starch | 25mg |
| Silica gel micropowder | 0.5mg |
| Calcium stearate | 2.5mg |
The preparation method comprises the following steps:
(1) uniformly mixing acarbose which is crushed in advance and sieved by a 80-mesh sieve with the microcrystalline cellulose according to the prescription amount;
(2) uniformly mixing other diluents which are crushed in advance and sieved by a 80-mesh sieve with the mixed powder obtained in the step (1);
(3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as a filling of the capsule;
(4) detecting the content of the active substance in the filling material, and calculating the filling amount of the filling material in each capsule;
(5) filling the obtained filler into capsule shell, and sealing the capsule.
Example 13: preparation of acarbose Capsule (#971)
The formula is as follows:
| acarbose | 50mg |
| Microcrystalline cellulose | 13mg |
| Starch | 63mg |
| Sodium starch glycolate | 4.2mg |
| Silicon dioxide | 7mg |
| Magnesium stearate | 0.7mg |
The preparation method comprises the following steps: respectively crushing acarbose, microcrystalline cellulose, starch, sodium carboxymethyl starch, silicon dioxide and magnesium stearate, and sieving with a 100-mesh sieve for later use; placing acarbose, microcrystalline cellulose, starch and 2/3 sodium carboxymethyl starch in a mixer, and starting the mixer to mix uniformly to obtain a premix; putting the premix into a GZL series dry rolling granulator, wherein the roller pressure is 40Pa, the roller rotating speed is 20 r/min, the mixture conveying speed is 60 r/min, starting the granulator, sieving with a 20-mesh sieve after finishing granules, and discharging to obtain particles; and (3) adding the granules, magnesium stearate, silicon dioxide and the rest sodium carboxymethyl starch into a multi-directional mixer, mixing for 30 minutes, filling the obtained mixed material into a capsule shell, and sealing the capsule to obtain the capsule.
Example 14: preparation of acarbose Capsule (#874)
The formula is as follows:
| acarbose | 50mg |
| Microcrystalline cellulose | 20mg |
| Starch | 25mg |
| Compressible starch | 30mg |
| Silicon dioxide | 0.05mg |
| Magnesium stearate | 0.05mg |
The preparation method comprises the following steps: firstly, mixing acarbose and microcrystalline cellulose in the prescription amount for 5 minutes, adding starch and compressible starch in the prescription amount for mixing for 5 minutes, adding magnesium stearate and silicon dioxide in the prescription amount into a mixer for mixing for 1 minute, filling the obtained mixed material into a capsule shell, and sealing the capsule to obtain the oral liquid.
Example 15: preparation of acarbose Capsule (#874)
The formula is as follows:
| acarbose | 50mg |
| Microcrystalline cellulose | 20mg |
| Starch | 25mg |
| Compressible starch | 30mg |
| Silicon dioxide | 0.05mg |
| Magnesium stearate | 0.05mg |
The preparation method comprises the following steps: firstly, mixing acarbose and silicon dioxide according to the prescription amount for 3 minutes, adding microcrystalline cellulose for mixing for 5 minutes, then adding starch and compressible starch according to the prescription amount for mixing for 5 minutes, finally adding magnesium stearate according to the prescription amount for mixing for 1 minute, filling the obtained mixed material into a capsule shell, and sealing the capsule to obtain the finished product.
Test example 1: examination of Capsule Properties
The capsules prepared in the above examples have good appearance and no adhesion, deformation, leakage or capsule shell rupture. Taking a batch of intact capsules with the weight of about 100g (the capsules of different batches have different grain numbers due to different contents), placing the capsules in a tablet friability tester in the XG tablet friability inspection method in the appendix of the second part of the pharmacopoeia of the people's republic of China, 2010 edition, rotating 100 times according to the method, taking out the capsules, placing the capsules in a 20-mesh sieve, sieving to remove powder, weighing the weight of the rest capsules, and calculating the weight loss percentage, namely the weight loss percentage, of the processed capsules of the batch. This percentage weight loss would be close to 0 if the capsules did not exhibit deformation, leakage or capsule shell rupture, which is desirable; however, if the capsule is not deformed, leaking or the capsule shell is broken, the weight loss percentage is increased. The algorithm for weight loss percentage is as follows: the difference obtained by subtracting the weight of the capsules after being processed by the friability apparatus and being sieved is divided by the percentage obtained by dividing the initial weight of the capsules. The results show that the weight loss percentage of all the capsules obtained in examples 1-15 was < 0.24%, and was in the range of 0.03% to 0.24%.
The capsules of each batch prepared above are hermetically packaged by adopting a water-proof and gas-proof aluminum plastic composite film bag (simulating the sealing package on the market), the hermetically packaged capsules are placed under the constant temperature condition of 40 ℃ for 5 months to be treated at high temperature, the weight loss percentage of each batch of capsules after being treated at high temperature is measured according to the method, and the result shows that: in examples 1-6, the weight loss percentage of each capsule is less than 0.37%, and is within the range of 0.15% -0.37%, and the capsule leakage or capsule shell rupture phenomenon does not occur in each batch of capsules; in examples 7-15, the weight loss percentage of each capsule was in the range of 2.21% to 3.74%, and 2-8 capsules of each batch were leaky or ruptured. In supplementary experiments, capsules were obtained by replacing the capsule shells used in examples 1 to 12 with four capsule shells, one made of hydroxypropyl methylcellulose as a main component, one made of algal polysaccharide as a main component, one made of pectin as a main component, and one made of carboxymethyl cellulose as a main component, respectively; the weight loss percentage of these capsules in the initial state and after high temperature treatment was then determined with reference to the above; the results showed that the weight loss percentage of each capsule obtained by filling four capsule shells with each of the fillings of examples 1-6 was < 0.41%, and was in the range of 0.13% to 0.41%, and no capsule leakage or capsule shell rupture occurred in each batch of capsules; examples 7-12 the weight loss percentage of each capsule obtained by filling four capsule shells with each filling was in the range of 2.04% to 4.17%, and 3-14 capsules of each batch exhibited leakage or capsule shell rupture. The capsule of the invention is applicable to various capsule shells.
Test example 2: examination of Capsule Properties
1. Determination of content
Measuring by high performance liquid chromatography (appendix V D of second part of Chinese pharmacopoeia 2010 edition);
chromatographic conditions and system applicability test: using amino-bonded silica gel as a packing material (Welch ULtimate XB-NH2 column, 50mm × 4.6mm × 5 μm application, or a chromatography column with equivalent performance); phosphate buffer solution (taking 600mg of monopotassium phosphate and 279mg of anhydrous disodium hydrogen phosphate, adding water for dissolving and diluting to 1000ml) -acetonitrile (25: 75) is taken as a mobile phase; the flow rate was 2.0ml per minute; the detection wavelength is 210 nm; the column temperature is 35 ℃;
taking about 200mg of acarbose, placing the acarbose into a 10ml measuring flask, adding a small amount of water to dissolve the acarbose, adding 1ml of 0.1mol/L sodium hydroxide solution, uniformly mixing, standing at room temperature for 1 hour, adding 1ml of 0.1mol/L hydrochloric acid solution, diluting with water to scale, shaking up, taking 10 μ L of the solution as a system applicable solution, injecting the solution into a liquid chromatograph, recording a chromatogram, wherein the retention time of the degraded impurity A relative to a main peak is about 0.9, the ratio (Hp/Hv) of the peak height (Hp from a base line to the highest point of the peak of the impurity A) of the impurity A to the peak valley (Hv from the base line to the lowest point) between the two peaks of the impurity A and the acarbose is not less than 2.0; the number of theoretical plates is not less than 2000 calculated according to acarbose peak;
the determination method comprises the following steps: taking a proper amount of contents under the condition of different capsule filling amounts, uniformly mixing, precisely weighing a proper amount (about equivalent to 50mg of acarbose), putting into a 50ml measuring flask, adding a proper amount of water, ultrasonically dissolving acarbose, diluting with water to a scale, shaking uniformly, filtering, precisely measuring 10 mu l of subsequent filtrate, injecting into a liquid chromatograph, and recording a chromatogram; taking a proper amount of acarbose reference substance, precisely weighing, adding water to dissolve, quantitatively diluting to obtain a solution containing about 1mg of acarbose per 1ml, and measuring by the same method. Calculating according to the peak area by an external standard method to obtain the product.
Acarbose (C) was measured in each of the capsules of examples 1-1525H43NO18) Should be in the range of 98.0% -102.0% of the marked amount, indicating that each batch of capsules has good content property.
2. Dissolution rate
Taking acarbose capsules, taking 900ml of water as a dissolution medium according to a dissolution rate determination method (first method of appendix XC of the second part of the 2010 edition of Chinese pharmacopoeia), rotating at 50 revolutions per minute, operating according to the method, filtering 10ml of solution after 30 minutes, determining according to the chromatographic conditions (the proportion of a mobile phase is adjusted to ensure that the peak emergence time of a main peak is between 5 and 10 minutes) under the content determination item, precisely measuring 30 mu l of subsequent filtrate, injecting into a liquid chromatograph, and recording a chromatogram; taking a proper amount of acarbose reference substance, precisely weighing, adding water to dissolve, quantitatively diluting to obtain a solution containing 50 μ g of acarbose per 1ml, and determining by the same method; and calculating the elution amount of each particle by peak area according to an external standard method. The dissolution amount of each batch of capsules in examples 1-15 is determined to be in the range of 88% -94%, and all the capsules meet the specification.
3. And (3) related substance inspection:
taking a proper amount of capsule contents (about equivalent to 500mg of acarbose), putting into a 25ml measuring flask, adding a proper amount of water, shaking to dissolve acarbose, diluting with water to scale, shaking up, filtering, and taking the subsequent filtrate as a test solution; precisely measuring 1ml of a test solution, placing the test solution into a 100ml measuring flask, and diluting the test solution to a scale with water to obtain a control solution; taking a proper amount of the control solution, and diluting the control solution with water to prepare a solution containing about 10 mu g of acarbose per 1ml as a sensitivity solution; injecting 10 μ l of the sensitive solution into a liquid chromatograph according to the chromatographic conditions under the content determination item, and recording the chromatogram, wherein the signal-to-noise ratio of the acarbose peak is more than 10; injecting 10 μ l of the control solution into a liquid chromatograph, and adjusting the detection sensitivity to make the peak height of the main component chromatographic peak about 10% of the full scale; precisely measuring 10 μ l of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram until the retention time of the main component peak is 2.5 times; and calculating each impurity peak of the chromatogram of the test solution according to an area normalization method. The results show that each of the capsules of examples 1-15 was substantially identical to the commercial product of the bgrasp tablet, indicating that the capsules of the present invention have superior performance.
Claims (20)
1. A capsule comprising a capsule shell and a filler in powder or granular form enclosed within the capsule shell; the filler comprises 50 parts by weight of acarbose, 5-50 parts by weight of microcrystalline cellulose, 50-200 parts by weight of starch, 10-100 parts by weight of modified pregelatinized starch, 0.5-5 parts by weight of lubricant and 0.3-3 parts by weight of glidant; the filler is prepared by the following steps:
(1) uniformly mixing acarbose and microcrystalline cellulose with a formula amount, and spraying ethanol with the concentration of more than 98% into the mixed powder under a high-speed mixing state, wherein the weight ratio of the acarbose to the ethanol is 50: 2-5, pre-pressing the obtained mixture into a sheet by using an extruder, crushing the sheet into particles, drying to remove ethanol, and crushing the particles into fine powder which is sieved by a sieve of 80 meshes;
(2) uniformly mixing starch and modified pregelatinized starch which are crushed in advance and sieved by a sieve of 80 meshes with the fine powder obtained in the step (1) to obtain mixed powder;
(3) and (3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as the filling of the capsule.
2. The capsule according to claim 1, wherein the capsule shell is selected from the group consisting of: the capsule shell is prepared from gelatin as main component, hydroxypropyl methylcellulose as main component, algal polysaccharide as main component, pectin as main component, or carboxymethyl cellulose as main component.
3. The capsule according to claim 1, wherein the starch is selected from the group consisting of corn starch, potato starch, rice starch, wheat starch, tapioca starch.
4. A capsule according to claim 1, said lubricant being selected from: magnesium stearate, stearic acid, polyethylene glycol having a molecular weight of 4000-.
5. A capsule according to claim 1, wherein the glidant is selected from the group consisting of: talc powder, silica fume and combinations thereof.
6. The capsule according to claim 1, wherein the filler comprises 50 parts by weight of acarbose, 10-40 parts by weight of microcrystalline cellulose, 60-150 parts by weight of starch, 20-75 parts by weight of modified pregelatinized starch, 1-2.5 parts by weight of lubricant and 0.5-1.5 parts by weight of glidant.
7. The capsule according to claim 1, wherein the filler comprises 50 parts by weight of acarbose, 15-30 parts by weight of microcrystalline cellulose, 75-100 parts by weight of starch, 25-50 parts by weight of modified pregelatinized starch, 1.2-2 parts by weight of lubricant and 0.5-1.2 parts by weight of glidant.
8. The capsule according to claim 1, wherein the filling comprises 50 parts by weight of acarbose, 20 parts by weight of microcrystalline cellulose, 90 parts by weight of starch, 40 parts by weight of modified pregelatinized starch, 1.5 parts by weight of lubricant and 1 part by weight of glidant.
9. The capsule according to claim 1, wherein the filling comprises 50 parts by weight of acarbose, 20 parts by weight of microcrystalline cellulose, 87.5 parts by weight of starch, 40 parts by weight of modified pregelatinized starch, 1.5 parts by weight of lubricant, and 1 part by weight of glidant.
10. A capsule according to claim 1, wherein the filling has the composition of any one of the following formulations 1 to 6:
formula 1: 50mg of acarbose, 20mg of microcrystalline cellulose, 90mg of corn starch, 40mg of modified pregelatinized starch, 1mg of silicon dioxide and 1.5mg of magnesium stearate;
and (2) formula: 50mg of acarbose, 20mg of microcrystalline cellulose, 87.5mg of cassava starch, 40mg of modified pregelatinized starch, 1mg of silicon dioxide and 1.5mg of magnesium stearate;
and (3) formula: 50mg of acarbose, 15mg of microcrystalline cellulose, 95mg of potato starch, 45mg of modified pregelatinized starch, 0.5mg of silicon dioxide and 1.2mg of magnesium stearate;
and (4) formula: 50mg of acarbose, 30mg of microcrystalline cellulose, 85mg of rice starch, 35mg of modified pregelatinized starch, 1.2mg of silicon dioxide and 2mg of polyethylene glycol 6000;
and (5) formula: 50mg of acarbose, 10mg of microcrystalline cellulose, 100mg of potato starch, 50mg of modified pregelatinized starch, 1.5mg of talcum powder and 1mg of zinc stearate;
and (6) formula: 50mg of acarbose, 40mg of microcrystalline cellulose, 75mg of wheat starch, 25mg of modified pregelatinized starch, 0.5mg of micropowder silica gel and 2.5mg of calcium stearate.
11. A process for preparing a capsule comprising a capsule shell and a fill in powder or granular form enclosed within the capsule shell, the process comprising the steps of:
(i) preparing a filler in powder or granular form;
(ii) filling the obtained filler into capsule shell, sealing the capsule to obtain the final product,
wherein,
the filler comprises 50 parts by weight of acarbose, 5-50 parts by weight of microcrystalline cellulose, 50-200 parts by weight of starch, 10-100 parts by weight of modified pregelatinized starch, 0.5-5 parts by weight of lubricant and 0.3-3 parts by weight of glidant;
the filler is prepared by the following steps:
(1) uniformly mixing acarbose and microcrystalline cellulose with a formula amount, and spraying ethanol with the concentration of more than 98% into the mixed powder under a high-speed mixing state, wherein the weight ratio of the acarbose to the ethanol is 50: 2-5, pre-pressing the obtained mixture into a sheet by using an extruder, crushing the sheet into particles, drying to remove ethanol, and crushing the particles into fine powder which is sieved by a sieve of 80 meshes;
(2) uniformly mixing starch and modified pregelatinized starch which are crushed in advance and sieved by a sieve of 80 meshes with the fine powder obtained in the step (1) to obtain mixed powder;
(3) and (3) mixing the glidant and the lubricant with the mixed powder obtained in the step (2) in a three-dimensional mixer for 5-10 minutes to obtain a uniform total mixture which is used as the filling of the capsule.
12. The method according to claim 11, the capsule shell being selected from the group consisting of: the capsule shell is prepared from gelatin as main component, hydroxypropyl methylcellulose as main component, algal polysaccharide as main component, pectin as main component, or carboxymethyl cellulose as main component.
13. The method according to claim 11, said starch being selected from the group consisting of corn starch, potato starch, rice starch, wheat starch, tapioca starch.
14. The method of claim 11, said lubricant being selected from the group consisting of: magnesium stearate, stearic acid, polyethylene glycol having a molecular weight of 4000-.
15. The method according to claim 11, the glidant is selected from the group consisting of: talc powder, silica fume and combinations thereof.
16. The method according to claim 11, wherein the filler comprises 50 parts by weight of acarbose, 10-40 parts by weight of microcrystalline cellulose, 60-150 parts by weight of starch, 20-75 parts by weight of modified pregelatinized starch, 1-2.5 parts by weight of a lubricant, and 0.5-1.5 parts by weight of a glidant.
17. The method according to claim 11, wherein the filler comprises 50 parts by weight of acarbose, 15-30 parts by weight of microcrystalline cellulose, 75-100 parts by weight of starch, 25-50 parts by weight of modified pregelatinized starch, 1.2-2 parts by weight of a lubricant, and 0.5-1.2 parts by weight of a glidant.
18. The method according to claim 11, the filling comprising 50 parts by weight acarbose, 20 parts by weight microcrystalline cellulose, 90 parts by weight starch, 40 parts by weight modified pregelatinized starch, 1.5 parts by weight lubricant, 1 part by weight glidant.
19. The method according to claim 11, the filling comprising 50 parts by weight acarbose, 20 parts by weight microcrystalline cellulose, 87.5 parts by weight starch, 40 parts by weight modified pregelatinized starch, 1.5 parts by weight lubricant, 1 part by weight glidant.
20. The method according to claim 11, wherein the fill mass is prior to filling into the capsule shell, further comprising the step of measuring the active content of the fill mass and calculating the fill volume per capsule.
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| CN103599188A (en) * | 2013-12-02 | 2014-02-26 | 李兴惠 | Heat-clearing phlegm-reducing detoxifying capsule |
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| CN1736379A (en) * | 2004-08-11 | 2006-02-22 | 深圳市天一时科技开发有限公司 | Moxifloxaci gelatin capsule and preparation process thereof |
| CN101606921A (en) * | 2009-07-08 | 2009-12-23 | 青岛黄海制药有限责任公司 | Acarbose solid sustained-release preparation and preparation method thereof |
| CN102688252A (en) * | 2012-06-12 | 2012-09-26 | 北京韩美药品有限公司 | Acarbose oral solid preparation composition and preparation method thereof |
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