CN1586471A - Silibinin meglumine salt oral disintegration tablet preparation and its preparing method - Google Patents

Abstract

The invention relates to a method that can protect liver cells from damage, stimulate the biosynthesis of proteins in liver cells, promote the recovery of damaged liver cells, have direct and indirect anti-fibrosis effects, capture oxygen free radicals, prevent and remove fat deposition in the liver and infiltration of silybin meglumine salt orally disintegrating tablets. The purpose of the present invention is to make up for the deficiency of the existing silybin meglumine salt formulation, to provide patients and medical workers with a drug with clear chemical composition, fast absorption and high bioavailability, which can avoid the liver first-pass effect , and convenient to take silybin meglumine salt orally disintegrating tablet and its preparation process. Using silibinin meglumine salt as raw material, fillers, disintegrants, flavoring agents, glidants, lubricants, etc. as auxiliary materials, adhesives or coating materials can be used according to different situations, and can also be added as appropriate An appropriate amount of effervescent agent is prepared by a specific preparation method and compressed into tablets by a tablet machine. The orally disintegrating tablet of the present invention has good friability, rapid disintegration, good taste, no gritty feeling, and does not require special production conditions; it has the characteristics of low production cost, convenient carrying, storage, transportation and taking; it is especially suitable for swallowing Difficult patients or taking it under anhydrous conditions can improve patient compliance and improve the efficacy of the drug.

Description

Silybin meglumine salt orally disintegrating tablet preparation and preparation method thereof

[technical field]

The invention relates to a silibinin meglumine salt preparation which has the obvious effect of protecting and stabilizing liver cells and is used for treating acute and chronic hepatitis, liver cirrhosis, liver poisoning and other diseases, especially relates to a kind of silibinin meglumine salt preparation with quick release effect Orally disintegrating tablet preparation of silybin meglumine salt.

[Background technique]

Silybin meglumine salt is a combination of silybin and meglumine (1-methylamino-1-deoxysorbitol), and silybin meglumine salt is more soluble than silybin In water, so the absorption speed and curative effect are better than silybin.

Silybin meglumine salt and silybin have the same indications and clinical efficacy.

The bioavailability of silibinin meglumine salt is low due to its poor solubility. At present, the dosage forms of silybin meglumine salt preparation mainly include common tablet and capsule dosage forms. There is no orally disintegrating tablet preparation or related literature of silybin meglumine salt. The silibinin meglumine salt is made into an orally disintegrating tablet, which is convenient for patients to carry and take, and helps to improve the patient's compliance, thereby ensuring the curative effect of the silybin meglumine salt.

[Content of the invention]

The purpose of the present invention is to improve the deficiencies of the existing silybin meglumine salt in the oral dosage form, and provide patients and medical workers with a silybin meglumine salt that is convenient to take, fast to absorb and act, and has high bioavailability. Oral disintegrating tablet preparation of thisbin meglumine salt. The invention relates to a silibinin meglumine salt orally disintegrating tablet and a preparation method thereof, which can be rapidly disintegrated or dissolved in the oral cavity without drinking water, and can be swallowed with saliva to complete the administration.

1. Prescription

The orally disintegrating tablets of silibinin meglumine salt mentioned in the present invention, including the raw drug silybin meglumine salt, require the following 9 types of raw materials and auxiliary materials. No coating material is used, and the effervescent agent can choose auxiliary materials as appropriate, or not.

Silibinin meglumine salt (5-50)%, binder (0-5)%, filler (10-80)%, disintegrant (2-35)%, flavoring agent (1- 40)%, coating material (0-40)%, effervescent agent (0-30)%, glidant (0.01-5)%, lubricant (0.3-3)%.

in:

Binders include but are not limited to starch, pregelatinized starch, dextrin, maltodextrin, sucrose, acacia, methylcellulose, carboxymethylcellulose, ethylcellulose, polyvinyl alcohol, polyethylene glycol , polyvinylpyrrolidone (PVP), alginic acid and alginate, xanthan gum and hydroxypropyl methylcellulose (HPMC), can be used alone or in combination.

Bulking agents include, but are not limited to, mannitol (granulated or powdered), xylitol, sorbitol, maltose, microcrystalline cellulose, ^PROSOLV® SMCC, polymeric sugars ( ^EMDEX® ), glucose, lactose, sucrose, dextrin, and starch etc., can be used alone or in combination, and the dosage is usually (10-80)%.

Disintegrants include but not limited to microcrystalline cellulose, ^PROSOLV® SMCC, cross-linked polyvinylpyrrolidone (PVPP), sodium carboxymethyl starch (CMS-Na), low-substituted hydroxypropylmethylcellulose (L-HPC) , croscarmellose sodium (CCNa) and soybean polysaccharide (EMCOSOY ^® ), etc., can be used alone or in combination.

Flavoring agents include but not limited to mannitol, xylitol, stevioside, lactose, fructose, sucrose, protein sugar, maltitol, glycyrrhizin, sodium cyclamate, gelatin, aspartame, banana flavor, Pineapple essence, vanillin, orange essence, orange essence, mint essence, ginseng essence, strawberry essence, citric acid, citric acid, etc. can be used alone or in combination.

Coating materials include, but are not limited to, gelatin, gum arabic, alginate, chitosan, carboxymethylcellulose salt, cellulose acetate phthalate, ethylcellulose, methylcellulose, hypromellose, Acrylic resins (domestic acrylic resins I, II, III, IV, ^Eudragit® series), polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, etc. can be used alone or in combination.

Glidants include but are not limited to micronized silica gel, talc, Cab-O-sil, Arosil, hydrated sodium aluminosilicate, etc., which can be used alone or in combination.

Lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, glyceryl monostearate, polyethylene glycol, hydrogenated vegetable oil, sodium stearyl fumarate, polyoxyethylene monostearate Esters, monolauric sucrose, sodium lauryl sulfate, magnesium lauryl sulfate, magnesium lauryl sulfate and talc, etc. can be used alone or in combination.

Effervescent agents include, but are not limited to, malic acid, citric acid, or a mixture of citric acid and sodium bicarbonate or sodium carbonate.

2. Preparation method

The preparation method of the orally disintegrating tablet of silybin meglumine salt mentioned in the present invention is a direct compression method, which can be used by manufacturers who have the ability to prepare conventional tablets.

The taste of silibinin meglumine salt is slightly bitter, and the present invention can use two different methods for flavor correction or taste masking: ① using a flavoring agent to directly taste; ② powder-packing silybin meglumine salt in advance Clothes to cover up the smell.

The specific preparation method is as follows:

The first step The pretreatment method of silybin meglumine salt:

① Direct flavoring method - this method granulates or does not process the raw material of silybin meglumine salt, and directly enters the second step;

②Powder coating taste masking—take the selected coating material, dissolve it with a suitable solvent and dilute it to an appropriate concentration for later use, then take silibinin meglumine salt and place it in an ebullating bed to make it boil, and then Spray the above solution at an appropriate speed for powder coating to obtain silybin meglumine salt powder-coated granules, which are dried and sieved for later use;

The second step is to weigh the flavoring agent and silybin meglumine salt or the raw material granules after the first taste-masking treatment, and mix them uniformly for later use;

The third step is to weigh and mix the filler, disintegrant, effervescent agent, and glidant according to the amount, and then mix it with the material obtained in the second step to make it even, add a lubricant and mix it for later use;

The fourth step The obtained material is tested by the intermediate, and after the weight of the tablet is determined, it is sent to the tablet press for tableting.

[beneficial effect]

Tablet is a traditional dosage form. It is one of the most commonly used dosage forms at present because of its stable quality, accurate dosage, convenient administration, easy carrying, high degree of mechanization, and low production cost. However, it disintegrates slowly due to compression molding , bioavailability is low, and some patients are difficult to swallow, so the popularization and use of tablets is limited to a certain extent. For this reason, oral solid immediate-release preparations have become a hot spot in the research and development of new drugs in recent years, especially orally disintegrating tablets, which have become the focus of tablet development because of their convenience, rapid onset of action, high bioavailability, and good taste.

Orally disintegrating tablets refer to tablets that do not require water or only need a small amount of water, and do not need to be chewed. The tablet is placed on the tongue, and after being rapidly disintegrated or disintegrated by saliva, the drug can enter the stomach and take effect by virtue of swallowing power. Orally disintegrating tablets are characterized by fast absorption, high bioavailability, less intestinal residue, low side effects, and avoiding the liver first-pass effect.

According to the requirements of the "Dosage Form Characteristics and Quality Control Meeting Minutes of Orally Disintegrating Tablets", the disintegration speed of orally disintegrating tablets is substantially faster than that of dripping pills and ordinary tablets. The disintegration of orally disintegrating tablets generally takes less than 30 seconds. No more than 1 minute.

[specific example]

In order to better illustrate the preparation method of the silybin meglumine salt orally disintegrating tablet of the present invention, an example is given in combination with the direct flavoring method and the powder coating taste-masking method as follows:

Embodiment one direct flavoring method

1. Prescription

1. Raw material - silybin meglumine salt 100.0g;

2. Adhesive - polyvinylpyrrolidone K-30 1.0g;

3. Filling agent - mannitol 154.0g;

4. Flavoring agent - aspartame 3.0g;

Orange essence 6.0g;

5. Disintegrant—cross-linked polyvinylpyrrolidone 14.0g;

Croscarmellose sodium 16.0g;

6. Glidant—micronized silica gel 3.0g;

7. Lubricant—sodium stearyl fumarate 3.0 g.

The total weight is 300g, and a total of 2000 pieces are made.

2. Preparation method

1) The raw material of silibinin meglumine salt is crushed, granulated with polyvinylpyrrolidone K-30, water or ethanol is used as a wetting agent, passed through a 26-mesh sieve, dried, and set aside;

2) Pass the cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, micropowder silica gel, sodium stearyl fumarate, orange flavor and aspartame through a 40-mesh sieve, mix well, and then add the granulated silybin meglumine salt granules, mix well and set aside;

3) add mannitol and mix evenly;

4) Intermediate content detection, after determining the weight of the tablet, it is sent to a tablet press for tableting.

Embodiment two powder coating taste masking method

1. Prescription

1. Raw material - silybin meglumine salt 100.0g;

2. Coating material - ^Eudragit® E100 20.0g;

3. Filling agent - mannitol 132.0g;

4. Flavoring agent - aspartame 3.0g;

Orange essence 6.0g;

5. Disintegrant—cross-linked polyvinylpyrrolidone 14.0g;

Croscarmellose sodium 16.0g;

6. Glidant—micronized silica gel 6.0g;

7. Lubricant—sodium stearyl fumarate 3.0 g.

The total weight is 300g, and a total of 2000 pieces are made.

2. Preparation method

1) Dissolve ^Eudragit® E100 with more than 95% pharmaceutical industrial ethanol and dilute to a certain concentration for later use;

2) Take silibinin meglumine salt and place it in an ebullating bed for boiling, spray the above solution at a certain speed for powder coating to obtain silibinin meglumine salt powder-coated granules, dry and set aside;

3) Mix mannitol, micronized silica gel, PVPP, L-HPC, aspartame, sodium stearyl fumarate and orange flavor evenly, and then mix with sieved coating particles for later use;

4) Intermediate content detection, after determining the weight of the tablet, it is sent to a tablet press for tableting.

Claims (8)

1. A pharmaceutical preparation silibinin meglumine salt orally disintegrating tablet with the effects of treating and preventing acute and chronic hepatitis and persistent hepatitis and lowering blood fat, consisting of silibinin meglumine salt, filler, Raw and auxiliary materials such as disintegrants, flavoring agents, glidants, lubricants, etc., can also be added with binders, effervescent agents or coating materials according to the situation, and prepared by specific methods in an appropriate proportion. It is characterized in that its prescription is composed as follows: silibinin meglumine salt (5-50)%, binder (0-5)%, filler (10-80)%, disintegrant (2-35)% , flavoring agent (1-40)%, coating material (0-40)%, effervescent agent (0-30)%, glidant (0.01-5)%, lubricant (0.3-3)%. 2. According to the various auxiliary materials described in claim 1, it is characterized in that the selection types are as follows: Binders – including but not limited to starch, pregelatinized starch, dextrin, maltodextrin, sucrose, acacia, methylcellulose, carboxymethylcellulose, ethylcellulose, polyvinyl alcohol, polyethylene Glycol, polyvinylpyrrolidone (PVP), alginic acid and alginate, xanthan gum and hydroxypropylmethylcellulose (HPMC), can be used alone or in combination. Bulking agents – including but not limited to mannitol (granulated or powdered), xylitol, sorbitol, maltose, microcrystalline cellulose, ^PROSOLV® SMCC, polymeric sugars ( ^EMDEX® ), glucose, lactose, sucrose, dextrin and starch, etc., can be used alone or in combination, and the dosage is usually (10-80)%. Disintegrants—including but not limited to cross-linked polyvinylpyrrolidone (PVPP), sodium carboxymethyl starch (CMS-Na), low-substituted hydroxypropyl methylcellulose (L-HPC), cross-linked carboxymethyl cellulose Vegetarian sodium (CCNa) and soybean polysaccharide (EMCOSOY ^® ), etc., can be used alone or in combination. Flavoring agents - including but not limited to mannitol, xylitol, stevioside, lactose, fructose, sucrose, protein sugar, maltitol, glycyrrhizin, sodium cyclamate, gelatin, aspartame, banana Essence, pineapple essence, vanillin, orange essence, orange essence, mint essence, ginseng essence, strawberry essence, citric acid, citric acid, etc. can be used alone or in combination. Coating materials – including but not limited to gelatin, gum arabic, alginates, chitosan, carboxymethylcellulose salts, cellulose acetate phthalate, ethylcellulose, methylcellulose, hypromellose Acrylic resins, acrylic resins (domestic acrylic resins I, II, III, IV, ^Eudragit® series), polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, etc. can be used alone or in combination. Glidants—including but not limited to micronized silica gel, talc, Cab-O-sil, Arosil, hydrated sodium aluminosilicate, etc., can be used alone or in combination. Lubricants – including but not limited to magnesium stearate, calcium stearate, zinc stearate, glyceryl monostearate, polyethylene glycol, hydrogenated vegetable oil, sodium stearyl fumarate, polyoxyethylene monostearate Fatty acid esters, monolauric sucrose, sodium lauryl sulfate, magnesium lauryl sulfate, magnesium lauryl sulfate, talc, etc. can be used alone or in combination. 3. A preparation method for the silybin meglumine salt orally disintegrating tablet for claim 1, characterized in that it consists of the following steps: The first step of pretreatment of silibinin meglumine salt: (1) Direct taste correction - this method granulates or does not process the raw material of silybin meglumine salt, and directly enters the second step; (2) Taste masking by powder coating - take the selected coating material, dissolve it with a suitable solvent and dilute it to an appropriate concentration for later use, then take silibinin meglumine salt and place it in a boiling bed to make it boil , and then spray the above solution at an appropriate speed for powder coating to obtain silybin meglumine salt powder-coated granules, which are dried and sieved for subsequent use; In the second step, the flavoring agent and silybin meglumine salt or the raw material granules after the taste-masking treatment in the first step are weighed, and mixed uniformly for later use; The third step is to weigh the filler, disintegrating agent, effervescent agent and glidant according to the amount and mix them evenly, then mix them with the materials obtained in the second step to make them even, add the lubricant and mix well for later use; The material obtained in the fourth step is tested by intermediates, and after the weight of the tablet is determined, it is sent to a tablet press for tableting. 4. According to the preparation method described in claim 3, it is characterized in that: the method (2) of the first step needs to use coating material to carry out taste-masking treatment to silybin meglumine salt in advance. 5. according to the preparation method described in claim 4, it is characterized in that: the coating material that is used for taste-masking treatment is gelatin, gum arabic, alginate, chitosan, carboxymethyl cellulose salt, cellulose acetate Phthalate esters, ethyl cellulose, methyl cellulose, hypromellose, acrylic resins (domestic acrylic resins I, II, III, IV, Eudragit® ^series ), polyvinyl alcohol, polyvinylpyrrolidone, polyethylene Any one or a mixture of two or more such as diols. 6. According to any one of the preparation methods described in claim 3, it is characterized in that: according to the situation, the auxiliary material effervescent agent can also be added. 7. According to the effervescent agent described in claim 6, it is characterized in that: the auxiliary material is malic acid, citric acid or a mixture of citric acid and sodium bicarbonate or sodium carbonate. 8. A preparation method for the silibinin meglumine salt orally disintegrating tablet as claimed in claim 1, characterized in that the hardness of the obtained tablet is between 10 and 45 Newtons, and the disintegration time is between 10 and 45 Newtons. 1-60 seconds.