CN101978953A - Solid dosage forms based on hygroscopic excipients - Google Patents

Abstract

A solid preparation based on hygroscopic excipients in the technical field of pharmaceutical preparation, the components and content of which are: active ingredient 1-10%, hygroscopic excipients 0.1-60%, antioxidant 0.1-2.0%, excipients 40-75%, disintegrant 2-10%, binder 1-10% and lubricant 0.5-3%. The present invention can solve this problem by adding hygroscopic adjuvants, reducing the contact between hygroscopic drugs and water, thereby reducing the hydrolysis of easily hydrolyzable drugs in solid preparations.

Description

Solid dosage forms based on hygroscopic excipients

technical field

The invention relates to a preparation in the technical field of pharmaceutical preparation, in particular to a solid preparation based on a hygroscopic auxiliary material.

Background technique

The basic requirements of pharmaceutical preparations should be safe, effective and stable. Stability refers to the stability of a drug in vitro. If the drug decomposes and deteriorates, it will not only reduce the efficacy of the drug, but some drugs may even produce toxic and side effects. Therefore, the stability of the drug preparation is very important to ensure the safety and effectiveness of the drug preparation. Drugs have different degradation reactions due to different chemical structures. Hydrolysis and oxidation are the two main pathways for drug degradation. Other reactions such as isomerization, polymerization, and decarboxylation also occur in some drugs.

Hydrolysis is the main way of drug degradation, and the drugs that belong to this type of degradation mainly include esters (including lactones), amides (including lactams) and so on. The hydrolysis of procaine hydrochloride, acetylsalicylic acid, tetracaine hydrochloride, propensine, and atropine sulfate belongs to the hydrolysis of ester drugs; the hydrolysis of simvastatin and pilocarpine nitrate belongs to the hydrolysis of lactones. The oxygen in the ester molecule is more electronegative than carbon, so the acyl group is polarized, and the nucleophilic reagent OH ^- reacts to make the reaction happen.

The hydrolysis of barbiturates and acetaminophen belongs to the hydrolysis of amide drugs, which generate acids and amines after hydrolysis.

As a kind of pharmaceutical preparation, solid preparation has its own characteristics: system inhomogeneity, such as tablets and capsules, the content of each tablet is not exactly the same, so it is difficult to reproduce the analysis results; these dosage forms are also multi-phase systems, often Comprising gas phases (air and water), liquid phases (adsorbed moisture), and solid phases, the composition and state of these phases can all change as experiments are performed. In particular, the presence of moisture causes great difficulties to the experiment, because moisture has a great influence on stability. These characteristics are more unfavorable for the stability of solid dosage forms containing easily hydrolyzable drugs.

After searching the prior art documents, it was found that the Chinese patent announcement number is CN1951501A, and the announcement date is September 29, 2006, which records a kind of "Meclofenoxate hydrochloride pharmaceutical composition that can prevent hydrolysis", which includes active Composition of meclofenoxate hydrochloride, pharmaceutical excipients, lubricant and stabilizer, the stabilizer can keep the medicine weakly acidic. However, if the above-mentioned method for preventing the hydrolysis of meclofenoxate hydrochloride is extended to other solid preparations, there will be the following problems: under acidic conditions, the hydrolysis of some drugs will be accelerated, because the acid has a catalytic effect on the hydrolysis, and it will not be able to prevent the hydrolysis of the solid preparations. Hydrolysis The effect of drug hydrolysis. The Chinese patent announcement number is CN 1994296A, and the announcement date is July 11, 2007. The patent name is: a pharmaceutical preparation containing simvastatin. The patent mentions the following content: a pharmaceutical preparation containing simvastatin, passed Adding an organic acid accounting for 9%-12% of the total amount of the preparation as an acidic pH regulator can make the pH of the aqueous solution of the pharmaceutical preparation preferably in the range of 2.5-3.2. The oxidation process of simvastatin can be effectively inhibited through combined application with other auxiliary materials such as antioxidants, and a pharmaceutical preparation with better stability than existing preparations can be prepared. However, there are still at least three deficiencies in the preparation of the above-mentioned simvastatin preparation: ① the content drop of the drug due to hydrolysis is not considered; However, the raw material of simvastatin is unstable to heat, and the use of this process will cause a decrease in content; ③ a large amount of organic solvents are used in the granulation process, and the volatilization of organic solvents may affect the stability of the drug.

Contents of the invention

Aiming at the above-mentioned deficiencies in the prior art, the present invention provides a solid preparation based on hygroscopic excipients. This problem can be solved by adding hygroscopic excipients, reducing the contact between hygroscopic drugs and moisture, thereby reducing the solid preparation. Hydrolysis of readily hydrolyzable drugs in formulations.

The present invention is realized through the following technical solutions. The components and contents of the present invention are: 1-10% of active ingredients, 0.1-60% of hygroscopic auxiliary materials, 0.1-2.0% of antioxidants, and 40-75% of excipients , disintegrant 2-10%, binder 1-10% and lubricant 0.5-3%.

The active ingredients include: procaine hydrochloride, acetylsalicylic acid, tetracaine hydrochloride, simvastatin, propensine, atropine sulfate, chloramphenicol, penicillin, barbiturate, acetaminophen, Vitamin B or stability and so on.

The hygroscopic auxiliary materials are mannitol, sorbitol, cross-linked sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, polyethylene glycol, One or more of povidone, sodium alginate or citric acid; preferably one or more of sorbitol, croscarmellose sodium or citric acid.

Described excipient is lactose, white sugar, maltose, mannitol, maltitol, erythritol, corn starch, rice starch, wheat starch, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, One or a combination of low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, talc, light silicic anhydride or calcium phosphate; preferably selected from sugar, starch, cellulose, One or a combination of lactose, white sugar, corn starch, crystalline cellulose, croscarmellose sodium, carboxymethylcellulose or low-substituted hydroxypropyl cellulose.

The disintegrating agent is crystalline cellulose, powdered cellulose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose calcium, corn starch, alpha starch, partially alpha One or a combination of starch, hydroxypropyl starch, sodium hydroxymethyl starch or cross-linked polyvinylpyrrolidone.

The binder is methyl cellulose, carboxymethyl cellulose, carboxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, crystalline fiber, alpha starch, polyvinyl alcohol, polyester One or a combination of vinylpyrrolidone, pullulan, dextrin, gum arabic or gelatin.

The lubricant is one of magnesium stearate, calcium stearate, hardened oil, sucrose fatty acid ester or polyethylene glycol or a combination thereof.

The solid preparation is tablet, powder, granule or capsule.

Adding one or more of the hygroscopic adjuvants under this dosage condition can have a significant protective effect on the hygroscopic drug in the solid preparation, and significantly reduce the hydrolysis of the hygroscopic drug in the solid preparation.

Detailed ways

The embodiments of the present invention are described in detail below. This embodiment is implemented on the premise of the technical solution of the present invention, and detailed implementation methods and specific operating procedures are provided, but the protection scope of the present invention is not limited to the following implementation example.

Example 1

The components of this example and their mass percentages are: 5% simvastatin, 0.5% BHA, 60.5% lactose, 28% microcrystalline cellulose, 5% croscarmellose sodium and 1% magnesium stearate .

Wherein: the amount of simvastatin is 5mg, 10mg, 20mg or 40mg.

The preparation method of this embodiment comprises the following steps:

(1) Weigh BHA into a glass mortar, gradually add lactose and mix evenly by doubling the grinding method, and pass through a 60-mesh sieve to obtain the mixture ①;

(2) Then weigh the simvastatin of the prescribed amount and put it into a glass mortar, then add the above-mentioned mixture ① and mix by double grinding method to obtain the mixture ②;

(3) Weigh lactose equal to the above-mentioned mixture ②, mix with the mixture ② evenly, and pass through a 20-mesh sieve to obtain the mixture ③;

(4) Mix the mixture ③ with the remaining lactose, microcrystalline cellulose, and croscarmellose sodium in a mixer, then add magnesium stearate, mix evenly, and press into tablets.

Example 2

The components and their mass percentages in this example are: 5.1% simvastatin, 0.3% BHA, 59.7% lactose, 30.8% microcrystalline cellulose, 5.2% sorbitol and 0.9% magnesium stearate.

Wherein: the amount of simvastatin is 5mg, 10mg, 20mg or 40mg.

The preparation method of this embodiment comprises the following steps:

(1) Weigh BHA into a glass mortar, gradually add lactose and mix evenly by doubling the grinding method, and pass through a 60-mesh sieve to obtain the mixture ①;

(2) Then weigh the simvastatin of the prescribed amount and put it into a glass mortar, then add the above-mentioned mixture ① and mix by double grinding method to obtain the mixture ②;

(3) Weigh lactose equal to the above-mentioned mixture ②, mix with the mixture ② evenly, and pass through a 20-mesh sieve to obtain the mixture ③;

(4) Mix the mixture ③ with the remaining lactose, microcrystalline cellulose, and sorbitol in a mixer, then add magnesium stearate, mix evenly, and press into tablets.

Example 3

The components and their mass percentages of this example are: 4.8% simvastatin, 0.4% BHA, 58.6% lactose, 30% microcrystalline cellulose, 30% microcrystalline cellulose, 5.2% citric acid and magnesium stearate 1 %.

Wherein: the amount of simvastatin is 5mg, 10mg, 20mg or 40mg.

The preparation method of this embodiment comprises the following steps:

(1) Weigh BHA into a glass mortar, gradually add lactose and mix evenly by doubling the grinding method, and pass through a 60-mesh sieve to obtain the mixture ①;

(2) Then weigh the simvastatin of the prescribed amount and put it into a glass mortar, then add the above-mentioned mixture ① and mix by double grinding method to obtain the mixture ②;

(3) Weigh lactose equal to the above-mentioned mixture ②, mix with the mixture ② evenly, and pass through a 20-mesh sieve to obtain the mixture ③;

(4) Mix the mixture ③ with the remaining lactose, microcrystalline cellulose, and citric acid in a mixer, then add magnesium stearate, mix evenly, and press into tablets.

Example 4

The components and their mass percentages in this example are: 4.9% simvastatin, 0.5% BHA, 58.5% lactose, 25.1% microcrystalline cellulose, 2% citric acid, 8% sorbitol and 1% magnesium stearate.

Wherein: the amount of simvastatin is 5mg, 10mg, 20mg or 40mg.

The preparation method of this embodiment comprises the following steps:

(1) Weigh BHA into a glass mortar, gradually add lactose and mix evenly by doubling the grinding method, and pass through a 60-mesh sieve to obtain the mixture ①;

(2) Then weigh the simvastatin of the prescribed amount and put it into a glass mortar, then add the above-mentioned mixture ① and mix by double grinding method to obtain the mixture ②;

(3) Weigh lactose equal to the above-mentioned mixture ②, mix with the mixture ② evenly, and pass through a 20-mesh sieve to obtain the mixture ③;

(4) Mix the mixture ③ with the remaining lactose, microcrystalline cellulose, citric acid and sorbitol in a mixer, then add magnesium stearate, mix evenly, and press into tablets.

Example 5

The components of this example and their mass percentages are: 5.1% simvastatin, 0.3% BHA, 60.3% lactose, 25% microcrystalline cellulose, 5.1% croscarmellose sodium, 3.3% sorbitol and hard Magnesium fatty acid 0.9%.

Wherein: the amount of simvastatin is 5mg, 10mg, 20mg or 40mg.

The preparation method of this embodiment comprises the following steps:

(1) Weigh BHA into a glass mortar, gradually add lactose and mix evenly by doubling the grinding method, and pass through a 60-mesh sieve to obtain the mixture ①;

(2) Then weigh the simvastatin of the prescribed amount and put it into a glass mortar, then add the above-mentioned mixture ① and mix by double grinding method to obtain the mixture ②;

(3) Weigh lactose equal to the above-mentioned mixture ②, mix with the mixture ② evenly, and pass through a 20-mesh sieve to obtain the mixture ③;

(4) Mix the mixture ③ with the remaining lactose, microcrystalline cellulose, croscarmellose sodium and sorbitol in a mixer, then add magnesium stearate, mix evenly, and press into tablets.

comparative example

The components and their mass percentages of this embodiment are: 5% simvastatin, 0.5% BHA, 65.5% lactose, 28% microcrystalline cellulose and 1% magnesium stearate.

Wherein: the amount of simvastatin is 5mg, 10mg, 20mg or 40mg.

The preparation method of this embodiment comprises the following steps:

(1) Weigh BHA into a glass mortar, gradually add lactose and mix evenly by doubling the grinding method, and pass through a 60-mesh sieve to obtain the mixture ①;

(2) Then weigh the simvastatin of the prescribed amount and put it into a glass mortar, then add the above-mentioned mixture ① and mix by double grinding method to obtain the mixture ②;

(3) Weigh lactose equal to the above-mentioned mixture ②, mix with the mixture ② evenly, and pass through a 20-mesh sieve to obtain the mixture ③;

(4) Mix the mixture ③ with the remaining lactose and microcrystalline cellulose in a mixer, then add magnesium stearate, mix evenly, and press into tablets.

Test case

Take the simvastatin tablets in Examples 1, 2, 4 and Comparative Example 1, and place the weighing bottle in a desiccator for ten days at 25°C with a relative humidity of 90 ± 1%. , on day 1, day 5, and day 10, the content of simvastatin hydrolyzate simvastatin acid in simvastatin tablets was detected by high performance liquid chromatography.

(1) On the 1st day and the 5th day of the experiment, the simvastatin tablet of embodiment 1, 2, 4 is compared with comparative example 1 and the simvastatin hydrolyzate simvastatin acid content difference is very little (＜0.05%) ;

(2) Compared with comparative example 1 in the simvastatin tablet of embodiment 1,2,4 on the 10th day, the simvastatin acid content obviously reduces, especially in the simvastatin tablet of embodiment 4 and 2 The content of simvastatin acid compared with the content of simvastatin acid in Comparative Example 1 has reduced by 25% and 29%. content was reduced by 10%.

Illustrate by test example 1: add one or more in the hygroscopic adjuvant under the dosage condition of the method of the present invention, can produce obvious protective effect to the hygroscopic medicine in the solid preparation, make the hygroscopic medicine in the solid preparation Hydrolysis was significantly reduced.

Claims (10)

1. A solid preparation based on hygroscopic auxiliary materials, characterized in that its components and contents are: active ingredient 1-10%, hygroscopic auxiliary materials 0.1-60%, antioxidant 0.1-2.0%, excipient 40-75% of agent, 2-10% of disintegrant, 1-10% of binder and 0.5-3% of lubricant. 2. The solid preparation based on hygroscopic adjuvants according to claim 1, wherein the active ingredients include: procaine hydrochloride, acetylsalicylic acid, tetracaine hydrochloride, simvastatin, Rubensine, atropine sulfate, chloramphenicol, penicillin, barbiturates, acetaminophen, B vitamins, or diazepam. 3. the solid preparation based on hygroscopicity auxiliary material according to claim 1, is characterized in that, described hygroscopicity auxiliary material is mannitol, sorbitol, cross-linked sodium carboxymethyl starch, cross-linked carboxymethyl fiber One or more of plain sodium, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, polyethylene glycol, povidone, sodium alginate or citric acid. 4. The solid preparation based on the hygroscopicity auxiliary material according to claim 1 or 3, wherein the hygroscopicity auxiliary material is one of sorbitol, croscarmellose sodium or citric acid or more. 5. The solid preparation based on easily hygroscopic adjuvants according to claim 1, wherein the excipients are lactose, white sugar, maltose, mannitol, maltitol, erythritol, corn starch, rice starch , wheat starch, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, talc, light silicic anhydride Or one or a combination of calcium phosphates. 6. The solid preparation based on easily hygroscopic adjuvants according to claim 1 or 5, characterized in that, the excipients are sugar, starch, cellulose, lactose, white sugar, cornstarch, crystalline cellulose, One or a combination of sodium carboxymethyl cellulose, carboxymethyl cellulose or low-substituted hydroxypropyl cellulose. 7. The solid preparation based on easily hygroscopic adjuvants according to claim 1, wherein the disintegrating agent is crystalline cellulose, powdered cellulose, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxyl Propyl cellulose, hydroxypropyl cellulose calcium, corn starch, pregelatinized starch, partially pregelatinized starch, hydroxypropyl starch, sodium hydroxymethyl starch or cross-linked polyvinylpyrrolidone or a combination thereof. 8. The solid preparation based on hygroscopic adjuvants according to claim 1, characterized in that, the binder is methyl cellulose, carboxymethyl cellulose, carboxypropyl cellulose, hydroxypropyl cellulose One or a combination of cellulose, hydroxypropyl methylcellulose, crystalline fiber, alpha starch, polyvinyl alcohol, polyvinylpyrrolidone, pullulan, dextrin, gum arabic or gelatin. 9. The solid preparation based on easily hygroscopic adjuvants according to claim 1, wherein the lubricant is magnesium stearate, calcium stearate, hardened oil, sucrose fatty acid ester or polyethylene glycol one or a combination of them. 10. The solid preparation based on easily hygroscopic excipients according to claim 1, characterized in that, the solid preparation is tablet, powder, granule or capsule.