CN101797235B - Oral disintegrating tablet of sodium carbosulfonate and preparation method thereof - Google Patents

Abstract

The invention discloses a carbazochrome sodium sulfonate orally disintegrating tablet and a preparation method thereof, wherein the orally disintegrating tablet comprises the following components in percentage by mass: 1 to 15 percent of carbazochrome sodium sulfonate, 50 to 90 percent of filler, 5 to 40 percent of disintegrant, 1 to 8 percent of adhesive, 0.1 to 5 percent of lubricant and 0.1 to 5 percent of flavoring agent; the oral liquid has the advantages of smooth and attractive surface, proper hardness, rapid disintegration without water in the oral cavity, rapid absorption, quick effect, small first pass effect of the liver, high bioavailability, small irritation to the gastrointestinal tract, good taste and convenient taking, and is particularly suitable for the old, children, patients lying in bed or having difficulty in swallowing, especially patients who have inconvenience in drinking water due to hemorrhage in or after surgery; the orally disintegrating tablet is prepared by a wet granulation tabletting method, has simple production process, stable and easily controlled preparation quality and low cost, and is suitable for industrial large-scale production.

Description

Oral disintegrating tablet of sodium carbosulfonate and preparation method thereof

technical field

The invention relates to a pharmaceutical preparation, in particular to an orally disintegrating tablet of sodium carbosulfonate, and also relates to a preparation method of the orally disintegrating tablet.

Background technique

Tablet has the advantages of stable quality, accurate dosage, convenient taking and carrying, high degree of production mechanization, and low production cost. It is one of the most commonly used pharmaceutical dosage forms at present. But at the same time, due to its slow disintegration, low bioavailability, and difficulty in swallowing for some patients, its application is limited to a certain extent. In recent years, new types of tablets such as orally disintegrating tablets, dispersible tablets and sublingual tablets have emerged. Orally disintegrating tablet is a tablet that can disintegrate or dissolve quickly without water in the oral cavity. Convenient and other advantages, especially suitable for the elderly, children, patients who are bedridden, have difficulty swallowing or have inconvenient drinking water.

Carbazochrome Sodium Sulfonate, the chemical name is 1-methyl-6-oxo-2,3,5,6-tetrahydroindole-5-semicarbazone-2-sulfonate sodium salt trihydrate It is a new generation of hemostatic drug developed by Mitsubishi Tanabe Pharmaceutical Co., Ltd. in Japan. It has the advantages of good hemostatic effect, rapid onset, long-lasting effect, and small side effects. It is mainly used in the urinary system, upper gastrointestinal tract, respiratory tract and gynecology. For obstetric hemorrhage, it has a more significant effect on the urinary system, and can also be used for the prevention and treatment of surgical bleeding.

Sodium carbosulfonate

The types of preparations that have been marketed for sodium carbosulfonate mainly include ordinary tablets, capsules, powders, granules, injections and powder injections for injection, etc. At present, there are no orally disintegrating tablets on the market, and no relevant research reports have been seen.

Contents of the invention

In view of this, one of the objectives of the present invention is to provide an orally disintegrating tablet of sodium carbene sulfonate, and the second objective is to provide a preparation method of the orally disintegrating tablet of sodium carbene sulfonate.

To achieve the above object, the present invention adopts the following technical solutions:

1. Orally disintegrating tablets of carbosulfonate sodium, composed of the following components by mass percentage: 1% to 15% of carbosulfonate sodium, 50% to 90% of filler, 5% to 40% of disintegrant, binder 1% to 8% of lubricants, 0.1% to 5% of lubricants and 0.1% to 5% of flavoring agents.

Further, it consists of the following components in terms of mass percentage: 1% to 10% of sodium carbosulfonate, 65% to 85% of filler, 5% to 20% of disintegrant, 2% to 6% of binder, lubricant 0.1%~1% and flavoring agent 0.4%~1.5%;

Further, it is composed of the following components in terms of mass percentage: 8% to 9% of sodium carbosulfonate, 74% to 80% of filler, 6% to 12% of disintegrant, 3% to 5% of binder, lubricant 0.4%~0.5% and flavoring agent 0.4%~1.0%;

Further, the filler is one or more of starch, pregelatinized starch, dextrin, powdered sugar, lactose, mannitol, xylitol, erythritol and microcrystalline cellulose; the disintegrant It is one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose sodium starch, crospovidone and effervescent disintegrant, effervescent disintegrant Composed of tartaric acid, citric acid or fumaric acid and sodium bicarbonate or sodium carbonate; the binder is one or more of starch, methylcellulose, ethylcellulose and hydroxypropylmethylcellulose; The lubricant is one or more of magnesium stearate, talcum powder and micronized silica gel; the flavoring agent is one or more of saccharin sodium, aspartame, stevia and menthol;

Further, the filler is one or more of starch, mannitol and microcrystalline cellulose; the disintegrant is crospovidone and/or effervescent disintegrant; the binder is hydroxyl Propylmethylcellulose; The lubricant is magnesium stearate; The flavoring agent is Menthol and/or Aspartame;

Further, the filler is starch, mannitol and microcrystalline cellulose; the disintegrant is crospovidone or crospovidone and an effervescent disintegrant, and the effervescent disintegrant consists of citric acid and carbonic acid Composed of sodium hydrogen; the flavoring agent is menthol or menthol and aspartame.

2. The preparation method of the orally disintegrating tablet of sodium carbosulfonate adopts wet granulation and tabletting method, comprising the following steps:

a. Pulverization: respectively pulverize fillers, disintegrants, binders, lubricants and flavoring agents into fine powders with a fineness above 100 mesh;

b. Granulation: mix sodium carbosulfonate with part of the filler, pulverize and pass through an 80-mesh sieve; Mesh sieve; add wetting agent to make soft material, granulate with 20-40 mesh sieve, dry at 60±5°C, pass through 20-60 mesh sieve for granulation;

c. Tablet compression: mix the dry granules sized in step b with additional disintegrants, lubricants, and additional flavoring agents, and then compress into tablets to obtain orally disintegrating tablets of sodium carbosulfonate.

Further, the wetting agent in the step b is an aqueous ethanol solution with a volume fraction of 60%;

Further, in the step b, a 24-mesh sieve is used for granulation, and the dry granules are passed through a 24-mesh sieve for granulation.

The beneficial effect of the present invention is that: the orally disintegrating tablet of carbosulfonate of the present invention has a smooth and beautiful surface, and suitable hardness; it does not need to be taken with water, and saliva can make it disintegrate rapidly in the oral cavity, which is convenient to take, and is especially suitable for the elderly , children, patients who are bedridden or who have difficulty swallowing, especially those who suffer from bleeding during or after surgery and have difficulty drinking water; the taste is cool, sweet and delicate, easy for patients to accept, and the drug compliance is good; after disintegration, except for part of the drug, it follows the swallowing action After entering the gastrointestinal tract, a considerable part is directly absorbed through the oral cavity, with quick onset, small first-pass effect of the liver, and high bioavailability; the drug entering the gastrointestinal tract is uniformly dispersed fine particles, which are distributed in a large area in the gastrointestinal tract. The absorption point is increased, and the local irritation to the gastrointestinal tract is reduced; the present invention adopts the wet granulation and tabletting method to prepare orally disintegrating tablets of sodium carbosulfonate, the production process is simple, the preparation quality is stable and easy to control, and the cost is low, which is suitable for large-scale industrialization Production.

The invention is a research project of "Chongqing Veterinary Medicine Engineering Technology Research Center".

Detailed ways

In order to make the object, technical solution and advantages of the present invention clearer, preferred embodiments of the present invention will be described in detail below.

The orally disintegrating tablet of sodium carbosulfonate of the present invention consists of the following components in terms of mass percentage:

Sodium carbosulfonate: 1% to 15%, preferably 1% to 10%, more preferably 8% to 9%;

Filler: 50% to 90%, preferably 65% to 85%, more preferably 74% to 80%;

Disintegrant: 5% to 40%, preferably 5% to 20%, more preferably 6% to 12%;

Binder: 1% to 8%, preferably 2% to 6%, more preferably 3% to 5%;

Lubricant: 0.1% to 5%, preferably 0.1% to 1%, more preferably 0.4% to 0.5%;

Flavoring agent: 0.1% to 5%, preferably 0.4% to 1.5%, more preferably 0.4% to 1.0%.

The filler is selected from one or more of starch, pregelatinized starch, dextrin, powdered sugar, lactose, mannitol, xylitol, erythritol and microcrystalline cellulose, preferably starch, mannitol and microcrystalline cellulose. One or more of crystalline cellulose, more preferably mannitol, starch and microcrystalline cellulose. Starch is very stable in nature, cheap in price, low in hygroscopicity, strong in water absorption and has a certain swelling property, and is suitable for water-insoluble or slightly soluble drugs. Mannitol is easily soluble in water, stable in nature, non-hygroscopic, and its sweetness is about 70% that of sucrose. Because it absorbs heat when it dissolves, it has a cool feeling when it melts in the mouth. Microcrystalline cellulose is insoluble in water, has good fluidity and compressibility, in addition to being used as a filler, it also has lubricating and disintegrating functions, and low-substituted hydroxypropyl cellulose and cross-linked carboxymethyl cellulose with strong swelling properties When cellulose sodium, croscarmellose sodium, and crospovidone are used in combination, the porosity of the tablet can be increased, capillary action can be enhanced, and the tablet can be quickly disintegrated in a small amount of water.

The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl starch, cross-linked povidone and effervescent disintegrants , preferably crospovidone and/or effervescent disintegrant, more preferably crospovidone or crospovidone and effervescent disintegrant. Crospovidone has high capillary activity and hydration ability, and can quickly absorb water into the tablet. When the internal pressure, that is, the swelling force exceeds the strength of the tablet, the tablet will disintegrate. It is a high-efficiency tablet disintegrating agent. The effervescent disintegrant is composed of organic acid and weak base. The acid and base react with water to generate carbon dioxide gas, which makes the tablet disintegrate rapidly. In the present invention, the effervescent disintegrant preferably consists of tartaric acid, citric acid or fumaric acid and sodium bicarbonate or sodium carbonate, more preferably citric acid and sodium bicarbonate.

The binder is selected from one or more of starch, methylcellulose, ethylcellulose and hydroxypropylmethylcellulose, preferably hydroxypropylmethylcellulose.

The lubricant is selected from one or more of magnesium stearate, talcum powder and micronized silica gel, preferably magnesium stearate.

Since orally disintegrating tablets disintegrate or dissolve in the oral cavity, special attention should be paid to the mouthfeel when preparing orally disintegrating tablets. A flavoring agent is added to the orally disintegrating tablet of the present invention, and the flavoring agent is selected from one or more of saccharin sodium, aspartame, stevia and menthol, preferably aspartame and/or peppermint Brain, more preferably menthol or aspartame and menthol.

The orally disintegrating tablet of sodium carbosulfonate of the present invention is prepared by a wet granulation tableting method, comprising the following steps:

a. Pulverization: respectively pulverize fillers, disintegrants, binders, lubricants and flavoring agents into fine powders with a fineness above 100 mesh;

b. Granulation: mix sodium carbosulfonate with part of the filler, pulverize and pass through an 80-mesh sieve; Mesh sieve; add wetting agent to make soft material, granulate with 20-40 mesh sieve, dry at 60±5°C, pass through 20-60 mesh sieve for granulation;

c. Tablet compression: mix the dry granules sized in step b with additional disintegrants, lubricants, and additional flavoring agents, and then compress into tablets to obtain orally disintegrating tablets of sodium carbosulfonate.

The following points should be paid attention to during wet granulation and tabletting: (1) Since the water content of the main drug carbosulfonate is about 15%, it is easy to stick to the machine when it is crushed alone, and a small amount of sticks into strips, which is not easy to sieve Simultaneously, the water content of filler starch is also higher (generally 10%～15%), it is more difficult to mix and pulverize with the main ingredient, and it is not easy to sieve; therefore, starch should be dried in advance at 100～105°C before use in the present invention , so that the water content is below 8%; at the same time, the sodium carbosulfonate is firstly mixed with dry starch, crushed, sieved, and then mixed with other auxiliary materials. (2) There are three conventional methods of adding disintegrants: ①Internal addition: the disintegrant is mixed evenly with other ingredients and then granulated, so that the disintegrant exists inside the granules. Although the disintegration is slow, once disintegrated into fine particles, which is conducive to dissolution; ②External addition method: the disintegrating agent is added to the dry granules after granulation, so that the disintegrating agent exists outside the granules and between the granules. After the water penetrates, the disintegration is rapid. , but because there is no disintegrant in the granules, it is not easy to disintegrate into fine particles, and the dissolution is slightly poor; ③ Internal and external addition: Divide the disintegrating agent into two parts, one part is added by internal addition, and the other is added by external addition. Through the single factor test, it was found that when the disintegrating agent was added by internal and external addition, it was more conducive to the rapid disintegration of orally disintegrating tablets. Therefore, the present invention uses internal and external addition to add disintegrants. Among them, the method of adding the effervescent disintegrating agent is: mix one of the acid and the alkali with other ingredients and then granulate, and add the other to the dry granules after granulation, so as to avoid acid and alkali in wet granulation. Alkali reacts with water. (3) Due to the volatility of flavoring agents such as menthol, the present invention selects to add volatile flavoring agents before granulation to minimize its volatilization loss, and the remaining non-volatile flavoring agents are added after granulation , so that the outer layer of the prepared tablet is sweet, and it is easier to be accepted by patients in terms of mouthfeel.

The study found that the orally disintegrating tablets of carbosulfonium sodium prepared by using the above-mentioned raw materials and methods have a smooth, beautiful surface and appropriate hardness. They can completely disintegrate in 30 seconds in 37±1°C water and pass through a 30-mesh sieve, which meets the requirements of the oral cavity. Disintegrating Tablet Requirements.

Example 1

prescription

Preparation method: Grind all the components in the prescription except sodium carbosulfonate into fine powder with a fineness of more than 100 mesh; dry the starch at 100-105°C to keep the water content below 8%; Sodium sulfonate and dry starch are mixed, pulverized, and passed through an 80-mesh sieve; then mixed with prescription quantities of mannitol, microcrystalline cellulose, hydroxypropyl methylcellulose and menthol and 1/2 prescription quantities of crospovidone Mix and pass through a 80-mesh sieve; then add an appropriate amount of ethanol water solution with a volume fraction of 60% to make soft materials, granulate with a 24-mesh sieve, dry at 60±5°C, pass the dry granules through a 24-mesh sieve for granulation; then add the remaining Crospovidone and the prescribed amount of magnesium stearate were mixed evenly and tabletted to make 1000 orally disintegrating tablets of sodium carbosulfonate, each containing 10 mg of sodium carbosulfonate.

Quality The obtained orally disintegrating tablet has a smooth and beautiful surface; the hardness is 22-27 Newtons; it disintegrates completely in 24 seconds in water at 37±1°C and passes through a 30-mesh sieve; the taste is sweet, cool, delicate, and has no gritty feeling.

Example 2

prescription

Preparation method: Grind all the components in the prescription except sodium carbosulfonate into fine powder with a fineness of more than 100 mesh; dry the starch at 100-105°C to keep the water content below 8%; Sodium sulfonate and dry starch are mixed, pulverized, and passed through an 80-mesh sieve; then cross-linked with mannitol, microcrystalline cellulose, citric acid, hydroxypropyl methylcellulose and menthol and 1/2 of the prescription amount Mix povidone and pass through a 80-mesh sieve; then add an appropriate amount of ethanol aqueous solution with a volume fraction of 60% to make soft materials, granulate with a 24-mesh sieve, dry at 60±5°C, and pass the dry granules through a 24-mesh sieve for granulation; Add the sodium bicarbonate and magnesium stearate of remaining crospovidone and prescription quantity in, mix, tabletting, make 1000 tablets of orally disintegrating sodium carbosulfonate altogether, each contains sodium carbosulfonate 10mg.

Quality The obtained orally disintegrating tablet has a smooth and beautiful surface; the hardness is 21-28 Newtons; it disintegrates completely in 23 seconds in water at 37±1°C and passes through a 30-mesh sieve; the taste is cool, sweet, delicate, and free of grit.

Example 3

prescription

Preparation method: Grind all the components in the prescription except sodium carbosulfonate into fine powder with a fineness of more than 100 mesh; dry the starch at 100-105°C to keep the water content below 8%; Sodium sulfonate and dry starch are mixed, pulverized, and passed through an 80-mesh sieve; then mixed with prescription quantities of mannitol, microcrystalline cellulose, hydroxypropyl methylcellulose and menthol and 1/2 prescription quantities of crospovidone Mix and pass through a 80-mesh sieve; then add an appropriate amount of ethanol water solution with a volume fraction of 60% to make soft materials, granulate with a 24-mesh sieve, dry at 60±5°C, pass the dry granules through a 24-mesh sieve for granulation; then add the remaining Cross-linked povidone, magnesium stearate and aspartame in the prescribed amount were mixed evenly, and tabletted to make 1000 orally disintegrating tablets of sodium carbosulfonate, each containing 10 mg of sodium carbosulfonate.

Quality The obtained orally disintegrating tablet has a smooth and beautiful surface; the hardness is 22-27 Newtons; it disintegrates completely in 25 seconds in 37±1°C water and passes through a 30-mesh sieve; the taste is cool, sweet, fine and smooth, without gritty feeling.

Example 4

prescription

Preparation method: Grind all the components in the prescription except sodium carbosulfonate into fine powder with a fineness of more than 100 mesh; dry the starch at 100-105°C to keep the water content below 8%; Sodium sulfonate and dry starch are mixed, pulverized, and passed through an 80-mesh sieve; then cross-linked with mannitol, microcrystalline cellulose, citric acid, hydroxypropylmethylcellulose and menthol and 1/2 of the prescription amount Mix povidone and pass through a 80-mesh sieve; then add an appropriate amount of ethanol aqueous solution with a volume fraction of 60% to make soft materials, granulate with a 24-mesh sieve, dry at 60±5°C, and pass the dry granules through a 24-mesh sieve for granulation; Add the remaining crospovidone and the prescribed amount of sodium bicarbonate, magnesium stearate and aspartame, mix well, and press into tablets to make 1000 orally disintegrating tablets of sodium carbosulfonate, each containing calorie Sodium Sulfate 10mg.

Quality The obtained orally disintegrating tablet has a smooth and beautiful surface; the hardness is 17-27 Newtons; it disintegrates completely in 28 seconds in water at 37±1°C and passes through a 30-mesh sieve; the taste is cool, sweet, delicate, and has no gritty feeling.

Example 5

prescription

Preparation method: Grind all the components in the prescription except sodium carbosulfonate into fine powder with a fineness of more than 100 mesh; dry the starch at 100-105°C to keep the water content below 8%; Sodium sulfonate and dry starch are mixed, pulverized, and passed through an 80-mesh sieve; then cross-linked with mannitol, microcrystalline cellulose, citric acid, hydroxypropylmethylcellulose and menthol and 1/2 of the prescription amount Mix povidone and pass through a 80-mesh sieve; then add an appropriate amount of ethanol aqueous solution with a volume fraction of 60% to make soft materials, granulate with a 24-mesh sieve, dry at 60±5°C, and pass the dry granules through a 24-mesh sieve for granulation; Add the remaining crospovidone and the prescribed amount of sodium bicarbonate, magnesium stearate and aspartame, mix well, and press into tablets to make 1000 orally disintegrating tablets of sodium carbosulfonate, each containing calorie Sodium Sulfate 10mg.

Quality The obtained orally disintegrating tablet has a smooth and beautiful surface; the hardness is 23-28 Newtons; it disintegrates completely in 30 seconds in water at 37±1°C and passes through a 30-mesh sieve; the taste is cool, sweet, delicate, and free of grit.

Example 6

prescription

Preparation method: Grind all the components in the prescription except sodium carbosulfonate into fine powder with a fineness of more than 100 mesh; dry the starch at 100-105°C to keep the water content below 8%; Sodium sulfonate and dry starch are mixed, pulverized, and passed through an 80-mesh sieve; then cross-linked with mannitol, microcrystalline cellulose, citric acid, hydroxypropylmethylcellulose and menthol and 1/2 of the prescription amount Mix povidone and pass through a 80-mesh sieve; then add an appropriate amount of ethanol aqueous solution with a volume fraction of 60% to make soft materials, granulate with a 24-mesh sieve, dry at 60±5°C, and pass the dry granules through a 24-mesh sieve for granulation; Add the remaining crospovidone and the prescribed amount of sodium bicarbonate, magnesium stearate and aspartame, mix well, and press into tablets to make 1000 orally disintegrating tablets of sodium carbosulfonate, each containing calorie Sodium Sulfate 10mg.

Quality The obtained orally disintegrating tablet has a smooth and beautiful surface; the hardness is 25-28 Newtons; it disintegrates completely in 28 seconds in 37±1°C water and passes through a 30-mesh sieve; the taste is cool, sweet, delicate, and free of grit.

Dissolution comparison of the orally disintegrating tablets of sodium carbosulfonate of the present invention and commercially available sodium carbosulfonate ordinary tablets

Method: get respectively the orally disintegrating tablets of sodium carbosulfonate prepared by each embodiment of the present invention and commercially available ordinary tablets of sodium carbosulfonate, take water 900mL as the dissolution medium, and the rotating speed is 50 revolutions per minute, according to Chinese Pharmacopoeia 2005 edition two Part Appendix XC second method operation, respectively at 1, 5, 10, 15, 20, 25, 30, 45 minutes, take 5mL of the solution, filter, take the subsequent filtrate as the test solution, and measure the absorption at a wavelength of 363nm According to the absorption coefficient (E ^{1% 1} _cm ) of C ₁₀ H ₁₁ N ₄ O ₅ SNa is 862 to calculate the dissolution rate. The results are shown in the table below. As can be seen from the table, compared with commercially available sodium carbosulfonate ordinary tablets, the orally disintegrating tablet of sodium carbosulfonate of the present invention has the characteristics of fast disintegration, fast dissolution and high dissolution rate.

Comparison of Dissolution Rates between Orally Disintegrating Tablets of Epicarbosulfonate Sodium and Common Tablets of Epicarbosulfonate Sodium

Finally, it is noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described with reference to the preferred embodiments of the present invention, those skilled in the art should understand that it can be described in the form Various changes may be made in matter and details thereof without departing from the spirit and scope of the invention as defined in the appended claims.

Claims (4)

1. Sodium carbosulfonate orally disintegrating tablet, characterized in that: it is composed of the following components in terms of mass percentage: 8% to 9% of sodium carbosulfonate, 74% to 80% of filler, and 6% to 12% of disintegrating agent %, binder 3%-5%, lubricant 0.4%-0.5% and flavoring agent 0.4%-1%; the filler is starch, mannitol and microcrystalline cellulose; the disintegrant is crosslinked Povidone or crospovidone and an effervescent disintegrant, the effervescent disintegrator is composed of citric acid and sodium bicarbonate; the binder is hydroxypropylmethylcellulose; the lubricant is stearin Magnesium acid; the flavoring agent is menthol or menthol and aspartame. 2. the preparation method of the orally disintegrating tablet of sodium carbosulfonate as claimed in claim 1 is characterized in that: adopt wet granulation tabletting method, comprise the following steps: a. Pulverization: respectively pulverize fillers, disintegrants, binders, lubricants and flavoring agents into fine powders with a fineness above 100 mesh; b. Granulation: mix sodium carbosulfonate with part of the filler, pulverize and pass through an 80-mesh sieve; Mesh sieve; add wetting agent to make soft material, granulate with 20-40 mesh sieve, dry at 60±5°C, pass through 20-60 mesh sieve for granulation; c. Tablet compression: mix the dry granules sized in step b with additional disintegrants, lubricants, and additional flavoring agents, and then compress into tablets to obtain orally disintegrating tablets of sodium carbosulfonate. 3. The preparation method of sodium carbosulfonate orally disintegrating tablet according to claim 2, characterized in that: the wetting agent in the step b is an aqueous ethanol solution with a volume fraction of 60%. 4. The preparation method of the orally disintegrating tablet of carbosulfonate sodium according to claim 2, characterized in that: in the step b, a 24-mesh sieve is used for granulation, and the dry granules are passed through a 24-mesh sieve for granulation.