CN1254246C - Oral disintegration tablet of silaenafil and its pharmaceutically receptible salt and its preparing method - Google Patents

Abstract

The present invention relates to sildenafil (5-[2-ethoxyl-5-(4-methyl-1-piperazine sulfonyl) phenyl]-1-methyl-3-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d] pyrimidine-7-ketone), a pharmaceutically acceptable salt orally disintegrating tablet of sildenafil and a preparation process thereof. The present invention aims at making up for the preparation insufficiency of existing sildenafil and pharmaceutically acceptable salt preparation of sildenafil, and providing sildenafil, a pharmaceutically acceptable salt orally disintegrating tablet of sildenafil and a preparation process thereof for all patients and medical workers; sildenafil and pharmaceutically acceptable salt orally disintegrating tablet of sildenafil have the advantages of convenient use and rapid absorption and effect-taking. Sildenafil and pharmaceutically acceptable salt are used as raw materials; filling agents, disintegrating agents, corrigents, flow aid, lubricating agents, etc. are used as auxiliary materials; adhesives or coating materials can also be used according to different situations; appropriate quantity of effervescent agents can be added on specific situation; the orally disintegrating tablet is prepared by a specific preparation method and obtained after tabletting by tabletting machines. The orally disintegrating tablet of the present invention has the characteristics of good friability, rapid disintegration, good taste, no gravel feel, no need of specific production condition, low production cost, convenient carry, storage, transportation and use, etc.; most of all, the orally disintegrating tablet can be taken without water and takes effect quickly, and therefore, the present invention improves the patient's compliance and enhances the curative effect of the medicine.

Description

Oral cavity disintegration tablet of sldenafil and pharmaceutically acceptable salt thereof and preparation method thereof

[technical field]

The present invention relates to a kind of sldenafil and pharmaceutically acceptable salt preparation thereof that is used for the treatment of male sexual disorder, relate in particular to a kind of sldenafil and pharmaceutically acceptable salt orally disintegrating tablet preparation thereof with rapid release effect.

[background technology]

Libido can make neurocyte secretion nitric oxide (NO), see through the spongy body vascular smooth muscle cell through diffusion, activate guanylate cyclase, but guanylate cyclase catalysis GTP generates cGMP, cGMP is the second message,second messenger of cellular signal transduction, can make the penis smooth muscle relaxation, finally make erection.CGMP can generate 5GMP through the catalysis of 5 type phosphodiesterases (PDE-5), loses second message,second messenger's effect.Sldenafil is the special inhibitor of 5 type phosphodiesterases (PDE-5), suppresses cGMP and is converted into 5GMP, and the cGMP in the smooth muscle cell is increased, thereby obtains and keep erection.Libido can make neurocyte secretion nitric oxide (NO), see through the spongy body vascular smooth muscle cell through diffusion, activate guanylate cyclase, but guanylate cyclase catalysis GTP generates cGMP, cGMP is the second message,second messenger of cellular signal transduction, can make the penis smooth muscle relaxation, finally make erection.CGMP can generate 5GMP through the catalysis of 5 type phosphodiesterases (PDE-5), loses second message,second messenger's effect.Sldenafil is the special inhibitor of 5 type phosphodiesterases (PDE-5), suppresses cGMP and is converted into 5GMP, and the cGMP in the smooth muscle cell is increased, thereby obtains and keep erection.

[summary of the invention]

The objective of the invention is to improve existing sldenafil and pharmaceutically acceptable salt thereof aspect peroral dosage form deficiency, provide a kind of taking convenience, absorption is rapid-action, bioavailability is high sldenafil and pharmaceutically acceptable salt orally disintegrating tablet preparation thereof to extensive patients and medical personnel.Needn't drink water when the present invention relates to take, in the oral cavity, only need tens seconds can rapid disintegrate or dissolving, the sldenafil that can finish to take medicine with saliva hypopharynx and pharmaceutically acceptable salt oral cavity disintegration tablet thereof and preparation method thereof.

One, prescription

Sldenafil and the pharmaceutically acceptable salt oral cavity disintegration tablet thereof that reaches of the present invention, comprise material medicine sldenafil and pharmaceutically acceptable salt thereof, need following former, the auxiliary material of 9 classes altogether, wherein: when not making Cotton seeds, then do not use coating material, effervescent also can for selecting adjuvant for use as one sees fit.Sldenafil and pharmaceutically acceptable salt thereof (5-50) %, binding agent (0-5) %, filler (10-80) %, disintegrating agent (2-35) %, correctives (1-40) %, coating material (0-40) %, effervescent (0-30) %, fluidizer (0.01-5) %, lubricant (0.3-3) %.

Wherein:

Binding agent includes but are not limited to starch, pregelatinized Starch, dextrin, maltodextrin, sucrose, arabic gum, gelatin, methylcellulose, carboxymethyl cellulose, ethyl cellulose, polyvinyl alcohol, Polyethylene Glycol, polyvinylpyrrolidone (PVP), alginic acid and alginate, xanthan gum, hydroxypropyl cellulose and hydroxypropyl emthylcellulose (HPMC), can use use also capable of being combined separately.

Filler include but are not limited to mannitol (granular or powdery), xylitol, sorbitol, maltose, Chi alcohol, microcrystalline Cellulose, PROSOLV  SMCC, polymerization sugar (EMDEX ), coupling sugar, glucose, lactose, sucrose, dextrin and starch etc., can use separately, also can applied in any combination, consumption is generally (10-80) %.

Disintegrating agent includes but are not limited to crospolyvinylpyrrolidone (PVPP), carboxymethyl starch sodium (CMS-Na), low substituted hydroxy-propyl methylcellulose (L-HPC), cross-linking sodium carboxymethyl cellulose (CCNa) and soybean polysaccharide (EMCOSOY ) etc., can use use also capable of being combined separately.

Correctives includes but are not limited to mannitol, xylitol, stevioside, lactose, fructose, sucrose, protein sugar, maltose alcohol, glycyrrhizin, Sodium Cyclamate, gelatin, aspartame, flavoring banana essence, flavoring pineapple essence, vanillin, fragrant citrus essence, flavoring orange essence, Herba Menthae essence, ginseng essence, strawberry essence, citric acid, citric acid etc., can use use also capable of being combined separately.

Coating material includes but are not limited to gelatin, arabic gum, alginate, chitosan, carboxymethyl cellulose salt, cellulose acetate phthalate ester, ethyl cellulose, methylcellulose, hypromellose, crylic acid resin (homemade acrylic resin I, II, III, IV, Eudragit  series), polyvinyl alcohol, polyvinylpyrrolidone, Polyethylene Glycol etc., can use use also capable of being combined separately.

Fluidizer includes but are not limited to micropowder silica gel, Pulvis Talci, Cab-O-sil, Arosil, hydrated sodium aluminosilicate etc., can use use also capable of being combined separately.

Lubricant includes but are not limited to magnesium stearate, calcium stearate, zinc stearate, glyceryl monostearate, Polyethylene Glycol, hydrogenated vegetable oil, sodium stearyl fumarate, polyoxyethylene monostearate, single Laurel sucrose acid ester, sodium laurylsulfate, lauryl alcohol sulphuric acid younger sister, Stepanol MG and Pulvis Talci etc., can use use also capable of being combined separately.

Effervescent includes but are not limited to the mixture of malic acid, citric acid or citric acid and sodium bicarbonate or sodium carbonate.

Two, preparation method

Sldenafil and the pharmaceutically acceptable salt oral cavity disintegration tablet thereof that reaches of the present invention, its preparation method is a direct compression process, the manufacturer with preparation conventional tablet all can adopt.

Sldenafil and pharmaceutically acceptable salt mildly bitter flavor thereof, the present invention can adopt two kinds of distinct methods to carry out flavoring or taste masking: 1. adopt the direct flavoring of correctives; 2. in advance sldenafil and pharmaceutically acceptable salt thereof are carried out powder coating with taste masking.

Concrete preparation method is as follows:

The preprocess method of first step sldenafil and pharmaceutically acceptable salt thereof:

1. direct flavoring method---this law is granulated to sldenafil and pharmaceutically acceptable salt raw material thereof or is not dealt with, and directly enters for second step;

2. powder coating taste masking---get selected coating material, with the dissolving of the solvent that adapts with it and to be diluted to debita spissitudo standby, getting sldenafil and pharmaceutically acceptable salt thereof again places ebullated bed to make boiling, spray into above-mentioned solution with suitable speed then and carry out powder coating, get sldenafil and pharmaceutically acceptable salt powder coating granule thereof, dry back sieving for standby;

Second step took by weighing correctives and sldenafil and pharmaceutically acceptable salt thereof or the feed particles after first step taste masking processing according to quantity, and mix homogeneously is standby;

The 3rd step took by weighing filler, disintegrating agent, effervescent, fluidizer and mix homogeneously according to quantity, made evenly again with through second mixing of materials that goes on foot gained, and adding lubricant mixing is standby;

The 4th step gained material detects through intermediate, determine that sheet is heavy after, send into the tablet machine tabletting promptly.

[beneficial effect]

Tablet is a kind of conventional dosage forms, because of its steady quality, dosage accurately, take, easy to carry, mechanization degree is high, low one of the at present the most frequently used dosage form that becomes of production cost, but because of the tablet extrusion forming, disintegrate is slow, bioavailability is lower, and part patient swallows comparatively difficult, thereby promoting the use of to a certain extent of tablet is restricted.The oral administration solid quick releasing formulation becomes a focus, particularly oral cavity disintegration tablet of new drug development in recent years for this reason, because of its taking convenience, rapid-action, bioavailability is high, the good emphasis that becomes tablet exploitation of mouthfeel.

Oral cavity disintegration tablet is meant not to be needed water or only needs low amounts of water, need not to chew, and tablet places lingual surface, meets after saliva separates rapidly or collapse, and borrows and swallows power, and medicine can be gone into the tablet of stomach onset.The characteristics of oral cavity disintegration tablet are that absorption is fast, bioavailability is high, and intestinal is residual few, and side effect is low, avoids liver first-pass effect etc.

According to the requirement of " formulation characteristic of oral cavity disintegration tablet and quality control meeting summary ", oral cavity disintegration tablet has essential leap than the disintegration rate of drop pill and ordinary tablet, and the disintegrate of oral cavity disintegration tablet generally in 30 seconds, is no more than 1 minute at most.And the dissolve scattered time limit of drop pill Chinese Pharmacopoeia regulation is in 30 minutes, and be all molten loosing about 15 minutes the disintegration of conventional tablet Chinese Pharmacopoeia regulation.

[specific embodiment]

For the preparation method of sldenafil of the present invention and pharmaceutically acceptable salt oral cavity disintegration tablet thereof better is described, in conjunction with directly flavoring method and powder coating taste masking method are as follows for an embodiment respectively:

Embodiment one direct flavoring method

One. prescription

1. raw material---sildenafil citrate 25.0g;

2. binding agent---polyvinylpyrrolidone K-300.5g;

3. filler---mannitol 53.5g;

PROSOLVSMCC 5.0g；

4. correctives---aspartame 1.0g;

Herba Menthae essence 1.0g;

5. disintegrating agent---crospolyvinylpyrrolidone 8.0g;

L-HPC 4.0g；

6. fluidizer---micropowder silica gel 1.0g;

7. lubricant---sodium stearyl fumarate 1.0g.

Gross weight 100g makes 1000, specification: the 25mg/ sheet altogether.

Two. preparation method

1) get the sildenafil citrate raw material pulverizing, granulate, cross 26 mesh sieves with polyvinylpyrrolidone K-30, standby;

2) with micropowder silica gel, Herba Menthae essence, PROSOLV  SMCC and aspartame, cross 40 mesh sieves respectively, mix homogeneously adds the sldenafil and the pharmaceutically acceptable salt granule thereof of having granulated again, and mix homogeneously is standby;

3) get mannitol, L-HPC and crospolyvinylpyrrolidone and cross 40 mesh sieves respectively, mix homogeneously will add and mix homogeneously through the raw material of flavoring again, adds sodium stearyl fumarate and mix homogeneously at last;

4) intermediate content detection, determine that sheet is heavy after, send into the tablet machine tabletting promptly.

Embodiment two powder coating taste masking methods

One. prescription

1. raw material---sildenafil citrate 50.0g;

2. coating material---Eudragit  E10010.0g;

3. filler---mannitol 95.5g;

PROSOLVSMCC 15.0g；

4. correctives---aspartame 2.0g;

Herba Menthae essence 2.0g;

5. disintegrating agent---crospolyvinylpyrrolidone 12.0g;

L-HPC 8.0g；

6. fluidizer---micropowder silica gel 3.5g;

7. lubricant---sodium stearyl fumarate 2.0g.

Gross weight 200g makes 1000, specification: the 50mg/ sheet altogether.

Two. preparation method

1) gets Eudragit  E100 with the dissolving of the medicinal industrial alcohol more than 95% and to be diluted to finite concentration standby;

2) get sldenafil and pharmaceutically acceptable salt thereof and place ebullated bed to seethe with excitement, spray into above-mentioned solution by certain speed and carry out powder coating, make sldenafil and pharmaceutically acceptable salt powder coating granule thereof, dry back is standby;

3) with mannitol, PROSOLV  SMCC, micropowder silica gel, PVPP, L-HPC, aspartame, sodium stearyl fumarate and Herba Menthae essence mix homogeneously, again and sieve after the coated granule mixing standby;

4) intermediate content detection, determine that sheet is heavy after, send into the tablet machine tabletting promptly.

Embodiment three effervescent flavoring methods

One. prescription

1. raw material---sildenafil citrate 100.0g;

2. binding agent---polyvinylpyrrolidone K-302.0g;

3. effervescent---citric acid 50.0g;

Sodium bicarbonate 40.0g;

4. filler---mannitol 112.0g;

PROSOLVSMCC 20.0g；

5. correctives---aspartame 4.0g;

Fragrant citrus essence 4.0g;

6. disintegrating agent---crospolyvinylpyrrolidone 40.0g;

L-HPC 20.0g；

7. fluidizer---micropowder silica gel 4.0g;

8. lubricant---sodium stearyl fumarate 4.0g.

Gross weight 400g makes 1000, specification: the 100mg/ sheet altogether.

Two. preparation method

1) get sildenafil citrate and citric acid raw material and mix the back pulverizing, granulate, cross 26 mesh sieves with polyvinylpyrrolidone K-30, standby;

2) get sodium bicarbonate and pulverize, granulate, cross 26 mesh sieves with polyvinylpyrrolidone K-30, standby;

3) adjuvant that all the other are all is crossed mix homogeneously behind 40 mesh sieves respectively, adds the granule of having granulated again, and mix homogeneously is standby;

4) intermediate content detection, determine that sheet is heavy after, send into the tablet machine tabletting promptly.

Disintegration that the sample of the foregoing description is measured and slice, thin piece hardness are as follows:

Disintegration of the foregoing description and slice, thin piece hardness numerical value are as follows:

Embodiment	Disintegration (second)	Slice, thin piece hardness (newton)
			1 2 3	9-22 15-33 17-35	16-25 15-28 17-27

Claims (3)

1. sldenafil and salt oral disintegration tablet thereof, it is characterized in that its weight consists of sldenafil and salt 5～50% thereof, clothing sheet material polyacrylic resin 5～40%, disintegrating agent crospolyvinylpyrrolidone and low-substituted hydroxypropyl methylcellulose amount to 2～35%, filler 10-80%, correctives 1～40%, fluidizer 0.01～5%, lubricant 0.3～3% is formed, wherein filler is selected from mannitol, microcrystalline Cellulose, dextrin, lactose, starch, in maltodextrin and the pregelatinized Starch one or more, correctives is selected from mannitol, lactose, stevioside, gelatin, aspartame, cyclamate, glycyrrhizin, fragrant citrus essence, flavoring orange essence, Herba Menthae essence, ginseng essence, strawberry essence, citric acid, in the citric acid one or more, fluidizer is selected from micropowder silica gel, Pulvis Talci, Cab-O-sil, Arosil, in the hydrated sodium aluminosilicate one or more, lubricant is selected from magnesium stearate, glyceryl monostearate, Stepanol MG, in the Pulvis Talci one or more; After wherein sldenafil and salt thereof being carried out powder coating with coating material, the gained granule is pressed into disintegrating tablet with other adjuvant.

2. sldenafil oral cavity disintegration tablet as claimed in claim 1, it is characterized in that its weight consists of: 50 parts of sildenafil citrates, 10 parts of polyacrylic resins, 95.5 parts in mannitol, 15 parts of silicified microcrystalline fibers, 2 parts of aspartames, 2 parts in Herba Menthae essence, 12 parts of crospolyvinylpyrrolidone, 8 parts of low-substituted hydroxypropyl methylcellulose, 3.5 parts of micropowder silica gels, 2 parts of sodium stearyl fumarates.

3. the preparation method of sldenafil as claimed in claim 1 or 2 and salt oral disintegration tablet thereof is characterized in that being made up of following steps:

The pretreatment of first step sldenafil and salt thereof; Get selected coating material, with the dissolving of the solvent that adapts with it and to be diluted to debita spissitudo standby, getting sldenafil and salt thereof again places fluid bed to make boiling, spray into above-mentioned solution with suitable speed then and carry out powder coating, get sldenafil and salt powder coating granule thereof, dry back sieving for standby;

Second step took by weighing correctives and sldenafil and salt particle thereof or the feed particles after first step taste masking processing according to quantity, and mix homogeneously is standby;

The 3rd step took by weighing filler, disintegrating agent, fluidizer and mix homogeneously according to quantity, made evenly again with through second mixing of materials that goes on foot gained, added the lubricant mixing, and is standby;

The 4th step gained material detects through intermediate, determine that sheet is heavy after, send into the tablet machine tabletting promptly.