WO2018192000A1 - Osmotic pump tablet of perindopril and salt thereof and preparation method of same - Google Patents

Abstract

A perindopril osmotic pump type controlled-release tablet, comprising a drug-containing tablet core and a semi-permeable membrane coating. There is a drug delivery orifice on the semi-permeable membrane coating layer. The tablet core contains 1.0-4.0 mg of perindopril or a pharmaceutically acceptable salt thereof, 20-50 mg of a filler, 20-60 mg of an osmotically active substance, 10-30 mg of a binder, 10-32 mg of a solubilizer, and 3-6 mg of a lubricant.

Description

Osmotic pump sheet of perindopril and its salt and preparation method thereof Technical field

The invention belongs to the technical field of medicine, and relates to a perindopril osmotic pump type controlled release tablet and a preparation method thereof. Background technique

The osmotic pump type controlled release preparation is based on osmotic pressure and has zero release kinetics as a release characteristic, and can release the drug at a constant speed within a certain time range. Compared with matrix type and depot sustained release technology, the release of drugs is largely independent of physiological parameters such as pH value, gastric emptying time, peristalsis, etc., and the correlation between the body and the outside is good, and the drug can be adjusted. The release characteristics optimize the pharmacodynamic effect of the system; the phenomenon that the blood drug concentration caused by the common oral preparation fluctuates greatly, the adverse reaction is alleviated, and the safety and effectiveness of the drug are greatly improved. At present, osmotic pump controlled release preparations such as nifedipine controlled release tablets, prazosin controlled release tablets, glipizide controlled release tablets, etc., which have been marketed abroad, have achieved good therapeutic and commercial effects. .

Osmotic pump type controlled release preparations mainly include oral osmotic pumps, microporous osmotic pumps, and implantable osmotic pumps. At present, the most widely used osmotic pump preparation is an oral osmotic pump, which generally consists of a core and a coating film. Oral osmotic pumps include single chamber osmotic pumps, multi-chamber osmotic pumps and liquid osmotic pumps. Among them, the single-chamber osmotic pump has the simplest structure and preparation process, and uses a conventional tablet preparation process to compress the drug and a suitable osmotic active substance into a tablet core, and then uses a water-insoluble polymer material such as cellulose acetate to the core. The coating is carried out to prepare a semi-permeable coating film, and then a small hole having a suitable pore diameter is formed by laser or mechanical means on the film. The moisture in the environmental medium can penetrate into the core through the semipermeable membrane to dissolve the osmotic active substance and the drug in the core, thereby forming a saturated solution of high osmotic pressure in the membrane. Depending on the constant osmotic pressure difference inside and outside the membrane, the drug is released from the drug release hole and absorbed by the gastrointestinal tract. During drug release, the drug concentration in the membrane is The osmotic pressure is maintained constant to ensure a constant release rate during this period.

Angiotesion Converting Enzyme Inhibitors (ACEI) is a new and widely used antihypertensive and anti-congestive heart failure drug developed in the 1980s. Perindopril is the third generation of potent, long-acting angiotensin-converting enzyme inhibitor (ACEI) that was developed in the early 1980s. Perindopril hydrolyzes in vivo and acts as an active metabolite, perindopril. Its antihypertensive mechanism is to block the conversion of angiotensin I into an active blood vessel.

Angiotensin II, reduce the release of norepinephrine and vascular endothelial cells from nerve endings, inhibit the degradation of bradykinin, and increase the formation of bradykinin and vasodilator prostaglandins. Perindopril has a significant antihypertensive effect and is well tolerated. It not only effectively lowers blood pressure, but also reverses vascular abnormalities associated with hypertension and reduces cardiovascular morbidity and mortality. Therefore, perindopril plays an important role in the treatment of hypertension and the prevention and treatment of cardiovascular diseases. However, the production of perindopril is affected by diet, and the food changes the bioavailability of its active metabolite, perindopril. Perindopril tablets must be taken before meals. Currently, the commercially available preparation is an ordinary matrix-type sustained-release preparation, which is administered once a day to reduce the frequency of drug administration and improve patient compliance. However, since the drug release of the matrix-type sustained-release tablet is easily affected by the gastrointestinal environment such as gastrointestinal motility and pH, especially in the case of gastrointestinal motility, the matrix is destroyed and loses the sustained release effect, and the sustained and stable drug concentration cannot be maintained. Not conducive to the treatment of the disease. Therefore, there is still a need for a controlled release formulation of perindopril which is simple in process, ideal in release, and effective in efficacy.

Summary of the invention

The object of the present invention is to overcome the deficiencies of the currently used clinically used perindopril tablets. The osmotic pump type controlled release tablets were prepared with perindopril as the main drug. The advantage of the preparation is that the zero-order release kinetics is the release characteristic, and the drug can be released slowly and at a constant speed for a certain period of time, which is beneficial to maintaining the long-term and high-efficiency blood concentration in the body and improving the therapeutic effect of the drug. The drug release rate is controlled by the prescription design, and the release rate is generally not Affected by gastrointestinal physiological factors such as peristalsis, pH, gastric emptying time and other variables, the correlation between internal and external is good.

The present invention provides an osmotic pump controlled release tablet of perindopril and a pharmaceutically acceptable salt thereof as a single chamber osmotic pump controlled release formulation comprising a single layer core, a semipermeable film coating and a drug delivery orifice. When moisture enters the core through the semi-permeable membrane, the osmotic active material swells and dissolves, producing a high osmotic pressure, and the drug solution is released from the orifice at a constant rate.

The core of the osmotic pump type controlled release preparation of the invention comprises 1.0-4.0 mg of the drug, 20-50 mg of the filler, 20-60 mg of the osmotic active substance, 10-30 mg of the binder, 10~32 mg of the solubilizing agent and the lubricant. 3 to 6 mg. The semipermeable coating film coating material is 10-30 mg, the plasticizer is 2-10 mg, and an appropriate amount of solvent.

The perindopril osmotic pump type controlled release tablet according to the present invention is selected from the group consisting of gum arabic, tragacanth, peach gum, carboxymethyl cellulose, dextrin, starch or a mixture thereof.

The perindopril osmotic pump type controlled release tablet of the present invention, the osmotic active substance used is selected from the group consisting of mannitol, glucose, lactose, sucrose, sodium chloride or a mixture thereof.

The perindopril osmotic pump type controlled release tablet of the present invention is selected from the group consisting of starch syrup, hypromellose, povidone, sodium carboxymethylcellulose or a mixture thereof.

The perindopril osmotic pump type controlled release tablet of the present invention uses a release rate adjusting agent selected from the group consisting of polyethylene glycol, propylene glycol, glycerin, dibutyl phthalate or a mixture thereof.

The perindopril osmotic pump type controlled release tablet according to the present invention is selected from the group consisting of magnesium stearate, calcium stearate, talc, micronized silica gel, sodium lauryl sulfate, and polyoxyethylene single hard. Glyceryl glycerides, waxes or mixtures thereof.

The perindopril osmotic pump type controlled release tablet of the present invention is used as a solubilizing agent, pluronic acid, sodium stearate, polyethylene glycol 4000 or a mixture thereof.

The perindopril osmotic pump type controlled release tablet according to the invention, the semipermeable film coating material is selected from the cellulose acetate fiber Wort or hypromellose phthalate, the plasticizer is selected from dibutyl sebacate or PEG 200, and the solvent is selected from acetone or ethanol.

The perindopril osmotic pump type controlled release tablet according to the present invention is characterized in that the preparation process is as follows:

(1) Mix the perindopril first with the solubilizer for 15-20 min, add the filler and the osmotic active substance in a mixer for 15-20 min, make the soft material with the binder aqueous solution, and sieve the granules through 20 mesh. Dry at 40-60 ° C for 6-8 h, sieve through 16 mesh sieves, mix and evenly compress.

(2) Dissolving the semi-permeable film coating material and other auxiliary materials in the coating layer with acetone or ethanol to prepare a semi-permeable film coating liquid, coating the coating coating, and curing at 40 to 50 ° C after the coating is completed. ~8h.

(3) After the coating is cured, a laser puncher can be used to punch 0.1-0.5 mm holes on the semi-permeable film coating layer.

DRAWINGS

Figure 1 is a graph showing the release profiles of Perindopril osmotic pump type controlled release tablets of Examples 1 to 4 in phosphate buffer pH 7.4. As can be seen from the figure, the release of the drug exhibits a significant zero-order release characteristic, indicating that the osmotic pump-controlled release tablets prepared by perindopril can release the drug at a constant rate, thereby maintaining a stable blood concentration and efficiently exerting the drug. Therapeutic effect.

detailed description

Example 1

prescription

Preparation process: Perindopril and solubilizer were mixed uniformly for 15 min, mixed with filler and osmotic active substance in a mixer for 15 min, made of soft material with 1% binder aqueous solution, granulated by 20 mesh sieve, 40 ° C Dry for 6h, pass through 16 mesh sieve, and mix and evenly compress. The coating material and other excipients in the coating layer were dissolved in acetone, coated with a coating pan, and cured at 40 ° C for 6 h after the coating was completed. After the coating is cured, a 0.5 mm hole can be punched on the coating layer with a laser puncher.

Example 2

prescription

Preparation process: Perindopril and solubilizer were mixed uniformly for 15 min, mixed with filler and osmotic active substance in a mixer for 15 min, made of soft material with 1% binder aqueous solution, and sieved through 20 mesh sieve, 50 ° C Dry for 7h, pass through 16 mesh sieve, and mix and evenly compress. The coating material and other excipients in the coating layer were dissolved in acetone, coated in a coating pan, and cured at 50 ° C for 7 h after the coating was completed. After the coating is cured, a 0.4 mm hole can be punched on the coating layer with a laser puncher.

Example 3

prescription

Preparation process: Perindopril and solubilizer were mixed uniformly for 15 min, mixed with filler and osmotic active substance in a mixer for 20 min, made of soft material with 2% binder aqueous solution, and sieved by 20 mesh sieve, 40 ° C Dry for 8 h, sieve through 16 mesh sieves, mix and evenly compress. The coating material and other excipients in the coating layer were dissolved in ethanol, coated in a coating pan, and cured at 40 ° C for 8 h after the coating was completed. After the coating is cured, the laser puncher is used. Apply 0.2mm holes to the coating layer.

Example 4

prescription

Preparation process: Perindopril and solubilizer were mixed uniformly for 20 min, mixed with filler and osmotic active substance in a mixer for 15 min, made of soft material with 2% binder aqueous solution, granulated by 20 mesh sieve, 50 ° C Dry for 6h, pass through 16 mesh sieve, and mix and evenly compress. The coating material and other excipients in the coating layer were dissolved in acetone, coated with a coating pan, and cured at 50 ° C for 8 h after the coating was completed. After the coating is cured, a 0.1 mm hole can be punched on the coating layer with a laser puncher.

Claims (9)

A perindopril osmotic pump type controlled release tablet comprising a tablet core and a semipermeable film coating, and a semipermeable film coating layer having a drug releasing pore, wherein the tablet core contains perindopril and its pharmacy The acceptable salt is 1.0 to 4.0 mg, the filler is 20 to 50 mg, the osmotic pressure active material is 20 to 60 mg, the binder is 10 to 30 mg, the solubilizing agent is 10 to 32 mg, and the lubricant is 3 to 6 mg. The perindopril osmotic pump type controlled release tablet according to claim 1, wherein the pharmaceutically acceptable salt of perindopril is perindopril tert-butylamine salt and perindopril arginine salt. The perindopril osmotic pump type controlled release tablet according to claim 1, wherein the filler used is selected from the group consisting of sodium alginate, gum arabic, tragacanth, peach gum, carbomer, dextran, carboxymethyl cellulose, --cyclodextrin, dextrin, starch or a mixture thereof. A perindopril osmotic pump type controlled release tablet according to claim 1, wherein the osmotic active substance is selected from the group consisting of mannitol, sorbitol, glucose, lactose, fructose, sucrose or a mixture thereof. A perindopril osmotic pump type controlled release tablet according to claim 1, wherein the binder is selected from the group consisting of starch syrup, hypromellose, povidone, sodium carboxymethylcellulose or a mixture thereof. A perindopril osmotic pump type controlled release tablet according to claim 1, wherein the lubricant used is selected from the group consisting of magnesium stearate, calcium stearate, talc, micronized silica gel, sodium lauryl sulfate, and polyoxyethylene single hard. Glyceryl glycerides, waxes or mixtures thereof. The perindopril osmotic pump type controlled release tablet according to claim 1, wherein the solubilizing agent is pluronic, sodium stearate, polyethylene glycol 4000 or a mixture thereof. The perindopril osmotic pump type controlled release tablet according to claim 1, wherein the composition of the semipermeable film coating is 10 to 30 mg of a coating material, 2 to 10 mg of a plasticizer, and an appropriate amount of a solvent. The coating material is selected from cellulose acetate or hypromellose phthalate, the plasticizer is selected from dibutyl sebacate or PEG 200, and the solvent is selected from acetone or ethanol. The perindopril osmotic pump type controlled release tablet according to any one of claims 1 to 8, characterized in that the preparation process as follows: (1) Mixing perindopril with filler, solubilizer, binder and osmotic active substance in a mixer, making soft material, granulating through 20 mesh, drying at 40-60 ° C for 6-8 h, adding Lubricant, mix and evenly compress. (2) Dissolving the semipermeable membrane coating material and other excipients in the coating layer with acetone or ethanol to prepare a semipermeable membrane coating liquid. (3) Coating the core, waving the coating solvent in the coated tablet, and punching the semipermeable film coating layer with a laser punch.

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