CN101259112A - Sagrelate hydrochloride monolayer osmotic pump controlled-release preparation and preparation method thereof - Google Patents

Abstract

The invention relates to the medicine technical filed, in particular to a monolayer osmotic pump controlled release preparation of sarpogrelate hydrochloride and a preparation method thereof, which is characterized by lasting drug effect, constant curative effect, slight toxic and side effect. The monolayer osmotic pump controlled release preparation of sarpogrelate hydrochloride comprises by weight percentage of 1 to 40 percent of sarpogrelate hydrochloride, 30 to 90 percent of auxiliary material that can promote osmosis, 1 to 40 percent of membrane material that performs controlled release and the rest is other auxiliary material; the diameter of a small drug release hole is 0.1 to 2.0 mm. The preparation method comprises: a certain amount of drug according to the prescription is mixed with an adhesive, a bulking agent and a co-penetrant which are respectively ground and screened, prepared into soft material and palletized, dried and particle finished and then added with a lube and pressed to obtain tablet core. Coating liquid is prepared and the tablet core coated, after coating, drying is done to solidify the coating membrane, and then one side of coated tablet is provided with the small drug release hole, thus obtaining an osmotic pump controlled release tablet. The monolayer osmotic pump controlled release preparation of sarpogrelate hydrochloride of the invention has the advantages of reducing times of dosage, promoting the compliance of sufferers and satisfying the requirements of clinical medication.

Description

Sagrelate hydrochloride monolayer osmotic pump controlled-release preparation and preparation method thereof

technical field

The invention relates to the technical field of medicine, specifically a drug for improving ischemic symptoms such as ulcers, pain and coldness caused by chronic arterial occlusive disease-sargrelate hydrochloride monolayer osmotic pump controlled release preparation and its preparation method .

Background technique

Sarpogrelate hydrochloride (English name: sarpogrelate hydrochloride) is a 5-HT receptor blocker originally developed by Mitsubishi Corporation, a cardiovascular drug. Launched in 1993, it is clinically used to improve ischemic symptoms such as ulcers, pain and cold sensation caused by chronic arterial occlusive disease.

Its pharmacological characteristics are as follows: ①Inhibition of platelet aggregation: This product selectively antagonizes the 5-hydroxytryptamine (5-HT) receptors of platelets and blood vessels, and inhibits platelet aggregation. This product inhibits platelet aggregation caused by collagen alone, and its IC50 is 4.5 μmol/L. When collagen and 5-HT are added, it will inhibit platelet aggregation more strongly, with IC50 being 0.1 μmol/L. Oral administration of ordinary tablets of sargrelate hydrochloride can significantly inhibit the platelet aggregation induced by adding 5-HT and collagen. This inhibitory effect on agglutination occurs relatively quickly, reaching the peak within 1.5 hours after taking the drug, and can last for 4 to 6 hours. After 12 hours, the agglutination tended to recover. ② This product inhibits the vasoconstriction caused by 5-HT and platelet aggregation: low concentration of 5-HT can cause the vasoconstriction reaction, and also cause the vasoconstriction reaction when platelet aggregation occurs. This product has a vasoconstriction effect on 5-HT and platelet aggregation that increases with the increase of drug concentration, and at the same time, this product can also inhibit the contraction of vascular smooth muscle caused by platelet aggregation. ③Antithrombotic effect: Clinical trials have shown that this product can inhibit the animal model of arterial occlusive disease in rats caused by arterial injection of lauric acid. ④Improve systemic circulation: This product has a good improvement effect on the reduction of blood flow in collateral circulation of lower extremities caused by 5-HT, and it will be enhanced with the increase of dose.

Osmotic pump preparations belong to slow/controlled release preparations in pharmaceutical preparations, and are a type of preparations made by the principle of osmotic pressure. Oral osmotic pump tablets have attracted widespread attention for their unique drug release mode and stable drug release rate, and are the most ideal sustained/controlled release preparations among oral controlled release preparations so far. The release principle of osmotic pump tablets: the size and shape of osmotic pump tablets are the same as those of ordinary tablets. The solid drug and excipients are pressed into the core of the drug, and a layer of water-permeable insoluble polymer film coating is applied outside the film. Or mechanical force to open a small hole (or add water-soluble porogen) to make. When the drug enters the gastrointestinal tract, the coating selectively allows water to penetrate into the dissolved drug, making the internal osmotic pressure of the tablet higher than the external gastrointestinal fluid, and the drug cannot be released through the coating, and the drug solution can only slowly pass through the pores. let go. Therefore, the osmotic pump preparation has the function of continuously and slowly controlling drug release, and the drug release rate is constant, not affected by the pH environment of the gastrointestinal tract, gastrointestinal peristalsis, etc., and the drug absorption rate is mainly limited by the drug release rate. The concentration fluctuation range is small, avoiding the peak and valley phenomenon of blood drug concentration, and can reduce the side effects of the drug.

Oral osmotic pump preparations that have been researched and developed include single-chamber and multi-chamber osmotic pump preparations. Single-chamber osmotic pump tablets include ordinary type, semi-permeable and enteric mixed coating material type, multi-layer coating film type with different permeability, and multi-layer composite material coating type; multi-chamber osmotic pump formulations include Osmotic pumps with piston-like additive components, dual-chamber osmotic pumps with flexible diaphragms, miniature osmotic pumps, and more. Oral slow/controlled release osmotic pump preparations are favored by people because they are convenient to take, can reduce the number of medications, have long-lasting curative effect, and are safe and reliable.

Cardiovascular disease is generally a chronic disease that requires long-term medication. The currently marketed dosage form of sargrelate hydrochloride is a common tablet, the specification is 100mg/tablet, and the dosing regimen is 3 times/day. Patients take frequent doses every day, easily forgetting or omissions, resulting in missing the time of taking the medicine or reducing the frequency of taking the medicine, the blood drug concentration in the blood fluctuates greatly, the drug is easy to accumulate, and the patient's drug compliance is poor. Therefore, this single-layer osmotic pump controlled-release preparation of sagrelate hydrochloride will allow patients to be administered once a day, and the drug dosage design and drug release speed design will be carried out according to the design principles of osmotic pump preparations. It reduces the individual differences of patients and prolongs the release of active substances, which is different from ordinary preparations.

Contents of the invention

The object of the present invention is to provide a single-layer osmotic pump controlled-release tablet of sagrelate hydrochloride which is convenient for administration, long-lasting in effect, stable in curative effect and less in toxic and side effects.

The purpose of the present invention is achieved like this:

Preparation of the present invention contains following components by weight percentage:

Sagrelate Hydrochloride 1-40%

Excipients that promote penetration 30-90%

Coating material for controlled release 1-40%

Other accessories Balance

Drug release hole diameter 0.1-2.0mm

Wherein the pharmaceutically acceptable salt of sargrelate hydrochloride is hydrochloride, and the adjuvant that promotes penetration is sodium chloride and/or potassium chloride and/or citric acid and/or sodium citrate and/or lactose and/or mannitol and /or fructose and/or sucrose and/or disodium hydrogen phosphate and/or polyoxyethylene and/or gum arabic and/or hypromellose and/or sodium methyl starch and/or low-substituted hydroxypropyl cellulose and/or croscarmellose sodium and/or crospovidone and/or polyvinylpyrrolidone and/or carbopol.

The film material for controlled release is cellulose acetate and/or ethyl cellulose and/or acrylic resin and/or hydroxypropyl methyl cellulose and/or polyethylene and/or polyethylene glycols.

The drug release holes on one or both sides of the coated tablet are laser perforated or mechanically perforated, and the diameter of the drug release pores can be 0.1-2.0mm.

The above-mentioned auxiliary materials are drug carriers, swelling materials, suspending agents, penetration aids, porogens, adhesives, lubricants, anti-sticking agents, semi-permeable membrane materials, plasticizers, light-shielding agents, and solvents. Drug carriers, swelling materials, and suspending agents can be polyoxyethylene, gum arabic, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, carbopol wait. Penetration aids can be citric acid, sodium citrate, sodium chloride, potassium chloride, lactose, mannitol, fructose, sucrose, etc.; adhesives can be polyvinylpyrrolidone, hypromellose, etc.; wetting agents can be Use water, absolute ethanol, ethanol-water solution of various concentrations; Lubricant can adopt stearic acid, magnesium stearate, talcum powder, micropowder silica gel etc.; Porogen can be sucrose, mannitol, polyethylene glycol ( Polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000), urea, etc.; plasticizers can be methyl phthalate and/or citric acid ester, ethyl phthalate, triester citrate, polyethylene glycol; opacifying agent can be titanium dioxide, talc, silicon dioxide, etc.; film material can be cellulose acetate, polyethylene, ethyl cellulose, acrylic acid Resins, etc.; solvents can be acetone, absolute ethanol, ethanol, water, etc.

The dosage form of the above-mentioned preparation can be tablet, coated type, capsule, soft capsule. The preparation method of the osmotic pump preparation of the present invention includes: crushing and sieving the medicine, binder, filler and penetration enhancer of the prescription amount respectively, after mixing evenly, softening with binder, sieving and granulating, oven drying Dry, sieve and granulate, add lubricant, mix evenly, and compress into tablets to obtain tablet cores. Dissolve the film-forming material and plasticizer in a solvent as a coating solution, put the tablet core in a coating pan, and coat it. After coating, dry it in a drying oven to solidify the coating film, and then coat it A suitable small hole for drug release is prepared on one side of the tablet by laser or mechanical means to obtain a single-layer osmotic pump controlled release tablet of sagrexate hydrochloride.

The advantages of the invention are: compared with common preparations, the preparation only needs to be administered once a day, has long-lasting effect, stable curative effect, and less toxic and side effects. The controlled-release preparation of the invention will be clinically used to improve ischemic symptoms such as ulcer, pain and cold sensation caused by chronic arterial occlusion.

Description of drawings:

Fig. 1 is the drug release curve of the sargrelate hydrochloride single-layer core controlled-release tablet prepared according to Example 1

Fig. 2 is the drug release curve of the sargrelate hydrochloride single-layer core controlled-release tablet prepared according to Example 2

Detailed ways:

Example 1:

Chip composition:

Sagrelate Hydrochloride 25%

Polyoxyethylene (molecular weight: 300,000) 42.5%

Citric acid 32.0%

Magnesium Stearate 0.5%

Composition of semi-permeable membrane coating solution:

Cellulose acetate 2.0%

Macrogol 400 0.16%

Acetone Solvent

Preparation method: crush the prescription amount of medicine, citric acid and polyoxyethylene respectively, pass through a 100-mesh sieve, mix well, soften with starch slurry, pass through 18-mesh granulation, oven-dried at 60°C, pass through a 20-mesh sieve Granules, add lubricant, mix evenly, and directly compress into tablets to obtain tablet cores. Dissolve cellulose acetate and plasticizer PEG400 in acetone solution as a coating solution, put the tablet core in a coating pan, and coat at a coating temperature of 40-60°C. After coating, coat the tablet at 40 Dry in a drying oven at ℃ to solidify the coating film, and then prepare a 0.5mm drug release hole on one side of the coating tablet by laser or mechanical means to obtain a single-layer osmotic pump controlled release tablet of sagrelate hydrochloride.

Example 2:

Chip composition:

Sagrelate Hydrochloride 20%

Polyoxyethylene (molecular weight: 300,000) 15%

Citric Acid 64.5%

Magnesium Stearate 0.5%

Composition of semi-permeable membrane coating solution:

Cellulose acetate 2.5%

Macrogol 400 0.25%

Acetone Solvent

Preparation method: crush the prescription amount of medicine, citric acid and polyoxyethylene respectively, pass through a 100-mesh sieve, mix well, soften with starch slurry, pass through 18-mesh granulation, oven-dried at 60°C, pass through a 20-mesh sieve Granules, add lubricant, mix evenly, and directly compress into tablets to obtain tablet cores. Dissolve cellulose acetate and plasticizer PEG400 in acetone solution as a coating solution, put the tablet core in a coating pan, and coat at a coating temperature of 40-60°C. After coating, coat the tablet at 40 Dry in a drying oven at ℃ to solidify the coating film, and then prepare a 0.5mm drug release hole on one side of the coating tablet by laser or mechanical means to obtain a single-layer osmotic pump controlled release tablet of sagrelate hydrochloride.

Example 3:

Chip composition:

Sagrelate Hydrochloride 30%

Polyoxyethylene (molecular weight: 300,000) 50%

Lactose 19.5%

Magnesium Stearate 0.5%

Composition of semi-permeable membrane coating solution:

Cellulose acetate 3.0%

Macrogol 400 0.3%

Acetone: Isopropanol (4:1) Solvent

Preparation method: respectively pulverize the prescribed amount of medicine, lactose and polyoxyethylene through a 100-mesh sieve, mix uniformly, then add lubricant, mix uniformly, and directly compress into tablets to obtain tablet cores. Dissolve cellulose acetate and plasticizer PEG 400 in acetone solution as a coating solution, put the tablet core in a coating pan, and coat at a coating temperature of 40-60°C. After coating, coat the tablet in Dry in a drying oven at 40°C to solidify the coating film, and then prepare a 0.5mm drug release hole on one side of the coating tablet by laser or mechanical means to obtain a single-layer osmotic pump controlled release tablet of sagrexate hydrochloride.

Example 4:

Chip composition:

Sagrelate Hydrochloride 20%

Citric Acid 79.5%

Magnesium Stearate 0.5%

Composition of semi-permeable membrane coating solution:

Cellulose acetate 3.0%

Macrogol 400 0.3%

Acetone: Isopropanol (4:1) Solvent

Preparation method: crush the prescription amount of medicine, citric acid and polyoxyethylene respectively, pass through a 100-mesh sieve, mix well, soften with starch slurry, pass through 18-mesh granulation, oven-dried at 60°C, pass through a 20-mesh sieve Granules, add lubricant, mix evenly, and directly compress into tablets to obtain tablet cores. Dissolve cellulose acetate and plasticizer PEG400 in acetone solution as a coating solution, put the tablet core in a coating pan, and coat at a coating temperature of 40-60°C. After coating, coat the tablet at 40 Dry in a drying oven at ℃ to solidify the coating film, and then prepare a 0.5mm drug release hole on one side of the coating tablet by laser or mechanical means to obtain a single-layer osmotic pump controlled release tablet of sagrelate hydrochloride.

Claims (6)

1. The single-layer osmotic pump tablet of sarcogrelate hydrochloride is characterized in that: the preparation contains the following ingredients by weight percentage: Sagrelate Hydrochloride 1-40% 30-90% of excipients that promote penetration Membrane material for controlled release 1-40% Other accessories Balance Drug release hole diameter 0.1-2.0mm 2. The sarcogrelate hydrochloride single-layer core osmotic pump controlled-release tablet according to claim 1, characterized in that: the medicinal salt of sarcogrelate hydrochloride is hydrochloride. 3. sagrelate hydrochloride single-layer osmotic pump controlled-release tablet according to claim 1, is characterized in that: the adjuvant that plays osmotic effect is sodium chloride and/or potassium chloride and/or citric acid and/or lemon sodium phosphate and/or lactose and/or mannitol and/or fructose and/or sucrose and/or disodium hydrogen phosphate and/or polyoxyethylene and/or gum arabic and/or hypromellose and/or methyl starch Sodium and/or low-substituted hydroxypropylcellulose and/or croscarmellose sodium and/or crospovidone and/or polyvinylpyrrolidone and/or carbopol. 4. according to the sargrelate hydrochloride monolayer osmotic pump controlled-release tablet described in claim 1, it is characterized in that: the membrane material that plays controlled release is cellulose acetate and/or ethyl cellulose and/or acrylic resin and /or hydroxypropylmethylcellulose and/or polyethylene and/or polyethylene glycols. 5. The sargrelate hydrochloride single-layer osmotic pump controlled-release tablet according to claim 1 is characterized in that: the drug release holes on one or both sides of the coated tablet are laser perforated or mechanically perforated, and the drug release holes The aperture may be 0.1-2.0mm. 6. The sargrelate hydrochloride single-layer osmotic pump controlled-release tablet according to claim 1, is characterized in that: the medicine of prescription quantity and binding agent, filler, penetration enhancer are pulverized and sieved respectively, after mixing uniformly , soften with binder, granulate through sieving, oven-dried, granulate through sieving, add lubricant, mix evenly, and compress into tablets to obtain tablet cores. Dissolve the film-forming material and plasticizer in a solvent as a coating solution, put the tablet core in a coating pan, and coat it. After coating, dry it in a drying oven to solidify the coating film, and then coat it A suitable small hole for drug release is prepared on one side of the tablet by laser or mechanical means to obtain a single-layer osmotic pump controlled release tablet of sagrexate hydrochloride.

Images