CN101057850A - Sildenafil citrate sublingual tablet and its preparation method - Google Patents
Sildenafil citrate sublingual tablet and its preparation method Download PDFInfo
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- CN101057850A CN101057850A CN 200610009940 CN200610009940A CN101057850A CN 101057850 A CN101057850 A CN 101057850A CN 200610009940 CN200610009940 CN 200610009940 CN 200610009940 A CN200610009940 A CN 200610009940A CN 101057850 A CN101057850 A CN 101057850A
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Abstract
The invention discloses an acidum citricum hypoglossal tablet and the preparing method, relating to a tablet and the preparation method. The invention means to solve problems: current acidum citricum are all oral tablets and capsule, the content is large and increases liver injury, and it is easy to generate adverse effect. The comprised component and their weight proportion are as follows: acidum citricum 20 -30 units, manna sugar 45-65 units, lactin 65-105 units, sweetener 0. 5-1. 5 units, ethanol solution with concentration being 5%PVPK30 30 -40 units and dolomol 4-8 units. The preparation method comprises following steps: sifting sot material with nylon screen of 18-20 order to produce particular, drying at 55-65 Deg. C; sifting granular with screen of 14-16 order and placing for 5-7 hours for sheeting. The tablet is characterized by small content, increased biological utilization rate, low adverse effect rate, and the method is characterized by short and simple process.
Description
Technical field
The present invention relates to the manufacture method of a kind of medicine buccal tablet and this buccal tablet.
Background technology
Along with increasingly sharpening of social competition, environmental pollution is serious day by day, and the sickness rate of male erectile dysfunction has the trend of rising.Sildenafil citrate (Sildenafil; Trade name Viagra, viagra) be first oral formulations that obtains the treatment erection disturbance of FDA approval.During sexual stimulus, the nerve of penis sponge and endotheliocyte discharge nitric oxide (NO), NO activates guanylate cyclase (guanylatecyclase) thereby generates cyclic guanylic acid (aGMP), cause the smooth muscle cell diastole of tremulous pulse, small artery and penis sponge sinusoid, erectile tissue is congested and erect.AGMP is generally by the di-phosphate ester enzymatic degradation, and is higher with phosphodiesterase-5 (PDE-5) content in the genitals.The erection disturbance patient often can not produce enough aGMP.Sildenafil citrate can suppress the activity of PDE-5 specifically, and the level of aGMP is increased, thereby causes vasodilation and keep the erection of penis.Studies show that sildenafil citrate has curative effect preferably to ischemic heart desease, hypertension, diabetes, organic and psychogenic erection disturbance.At present, the sildenafil citrate that each manufacturer produces all is oral tablet and capsule, and content is bigger, and specification is 100mg and 50mg.Oral administration is traditional, safe administering mode through gastrointestinal absorption, but because the gastrointestinal factor makes bioavailability of medicament be affected, unnecessary dosage strengthens, and through first pass effect, increased the burden and the damage of liver, reduced absolute bioavailability.Unnecessary dosage strengthens, and can directly have influence on the generation of toxicity.The untoward reaction of sildenafil citrate has: 1, cardiovascular system: the cardiovascular system untoward reaction of sldenafil comprises serious cardiovascular event, as myocardium infarction, cardiac sudden death, arrhythmia, hypotension, hemorrhage, the property crossed an ischemic shock and the hypertension of cerebrovascular.2, digestive system: the digestive system untoward reaction comprises vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, xerostomia, abnormal liver function, hemorrhage of rectum, gingivitis etc.3, blood system: the blood system untoward reaction comprises anemia and leukopenia.4, endocrine/metabolism: thirsty, edema, gout, diabetes, hyperglycemia, PE, hyperuricemia, hypoglycemic reaction, hypernatremia etc. can occur.5, respiratory system: asthma, laryngitis, pharyngitis, sinusitis, bronchitis, abundant expectoration, cough etc. can occur.6, genitourinary system: cystitis, nocturia, frequent micturition, urinary incontinence, abnormal ejaculation, genitals edema can occur and lack orgasm etc.Also can cause erection time lengthening (above 4 hours), priapism (painful was erected above 6 hours) and hematuria.Surpass 4 hours as continuing to erect, the patient should go to a doctor immediately.Erection is handled at once as abnormity, and penile tissue may suffer damage and may cause nonvolatil erection function forfeiture.7, nervous system: nervous system untoward reaction can occur, and take sldenafil and get in touch if having time as epilepsy and anxiety.8, skeletal musculature: it is slow, insensitive etc. arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, osteodynia, myasthenia, synovitis, insomnia, drowsiness, dreaminess, reflection to occur.9, skin and appendages thereof: urticaria, herpes simplex, pruritus, perspiration, skin ulcer, contact dermatitis, exfoliative dermatitis etc. can occur.10, the special sense: platycoria, conjunctivitis, photophobia, tinnitus, ophthalmalgia, deafness, ophthalmorrhagia, cataract, eye can occur and do etc.Visual abnormality slight and a property crossed also can appear, mainly show as to look and look for lightly, but light sensation enhancing or blurred vision and diplopia, of short duration visual deprivation or visual deterioration, blood-shot eye illness or eye hyperemia, eye burn feeling, eye swelling and constriction, increased intraocular pressure, retinal vasculopathy or hemorrhage, untoward reaction such as vitreous body peels off, macula lutea peripheral edema are arranged also.11, other: other still general reaction can occur, as facial edema, photosensitivity reaction, shock, weak, pain, shiver with cold, accident fall, stomachache, anaphylaxis, chest pain, accidental injury etc.
Summary of the invention
The objective of the invention is for solving existing sildenafil citrate all is oral tablet and capsule, and content is bigger, and oral administration has increased the burden and the damage of liver, can reduce bioavailability, easily produces the problem of untoward reaction.A kind of sildenafil citrate sublingual tablet and preparation method thereof is provided.Sildenafil citrate sublingual tablet of the present invention have consumption little, reduce burden and damage to liver, improve bioavailability, the characteristics that untoward reaction is low; Manufacture method of the present invention has flow process weak point, technology characteristic of simple.Sildenafil citrate sublingual tablet of the present invention is 15%PVP by 20～30 parts of sildenafil citrates, 45～65 parts in mannitol, 65～105 parts of lactose, 0.5～1.5 part of sweetener, concentration by weight
K3030～40 parts of ethanol liquid and magnesium stearate are made for 4～8 parts.The manufacture method of sildenafil citrate sublingual tablet of the present invention is: one, getting 20～30 parts of sildenafil citrates, 45～65 parts in mannitol, 65～105 parts of lactose, 0.5～1.5 part of sweetener, concentration by weight is 15%PVP
K304～8 parts of 30～40 parts of ethanol liquid and magnesium stearate; Two, solid material was pulverized 110～130 mesh sieves; Three, the powder mixing of sildenafil citrate, lactose and mannitol is made dry mash; Four, the concentration of getting gross weight 45～55% is 15%PVP
K30Ethanol liquid, together joins in the dry mash mix homogeneously and makes compound after the sweetener dissolving with this ethanol liquid; Five, be 15%PVP with the remaining concentration that accounts for gross weight 45～55%
K30Ethanol liquid joins in the rapid compound of previous step and makes soft material; Six, soft material is made granule with 18～20 order nylon mesh, the granule of making aeration-drying under 55～65 ℃ of conditions; Seven, with 14～16 mesh sieve granulate; Eight, sift out the fine powder that the granulate process occurs with 60～70 mesh sieves, add magnesium stearate and the granule mixing of haveing suffered with 14～16 mesh sieves in fine powder, sealing was placed 5～7 hours; Nine, tabletting (every heavy 0.2 the gram, every contain sildenafil citrate 10～25mg), the packing (being the finished product buccal tablet).For showing the result of use of sildenafil citrate sublingual tablet of the present invention, according to " the medicine registration management way " of State Food and Drug Administration promulgation and the " pertinent regulations of clinical drug trial management regulation (GCP); select 30 examples to suffer from erection disturbance (the normal male subject of other physical signs; adopt self interleaved mode single dose to be tried sildenafil citrate sublingual tablet and oral reference sildenafil citrate tablet (Viagra that Pfizer Inc. produces; sheet weight 50mg);, to estimate its bioequivalence with its haemoconcentration of high effective liquid chromatography for measuring; calculate its pharmacokinetic parameters and relative bioavailability thereof.
1, case selection standard: through male patient 30 people that suffer from erection disturbance (annotate: other physiology indication is normally) that hospital outpatient is made a definite diagnosis, 33 years old of age minimum, oldest 51 years old, 40 years old mean age, on average sick time was 1 year.
2, the diagnostic criteria of disease: male erectile dysfunction (ED).
3, medication ingredient: every contains sildenafil citrate 10～25mg.
4, administrated method: buccal under the ten minutes tongue before the sexual intercourse, each half sheet or a slice (sildenafil citrate that is equivalent to 5～25mg).
5, the criterion of curative effect: the comparison of the Viagra oral tablet bioavailability that sildenafil citrate sublingual tablet of the present invention and Pfizer produce, accumulative total blood drug level and peak time.
6, efficacy result analysis: the peak time average out to 10.2 ± 5.3min of sildenafil citrate sublingual tablet, absolute bioavailability is 74.9%, sildenafil citrate tablet (the Viagra that Pfizer Inc. produces, the heavy 50mg of sheet) peak time average out to 46.7 ± 5.3min, absolute bioavailability is 42.2%.
7, sildenafil citrate sublingual tablet of the present invention aspect the treatment of male erectile dysfunction (ED) with the sildenafil citrate tablet (Viagra that Pfizer Inc. produces, the heavy 50mg of sheet) compares, the erection time that begins after sildenafil citrate sublingual tablet is taken medicine was respectively 7～15 minutes, sildenafil citrate tablet (the Viagra that Pfizer Inc. produces, the heavy 50mg of sheet) the erection time that begins after taking medicine was respectively 30～45 minutes, erection persistent period ratio after sildenafil citrate sublingual tablet is taken medicine is taken the sildenafil citrate tablet (Viagra that Pfizer Inc. produces, the heavy 50mg of sheet) long 3～15 minutes respectively erection persistent period, erection hardness and sexual intercourse mass ratio are taken sildenafil citrate tablet (Viagra that Pfizer Inc. produces, the heavy 50mg of sheet) and are all increased.Through 1 year follow up a case by regular visits to, do not find any untoward reaction that the sildenafil citrate buccal tablet brings.
Contribution of the present invention is, sildenafil citrate is prepared into sublingual lozenge, the experiment proved that it is effective route of administration.Human hypoglossis mucous membrane has abundant blood vessel, and has good permeability, because sublingual administration makes drug release even, absorb rapidly, bioavailability is than higher, medicine directly enters blood circulation, be not subjected to the influence of first pass effect, can reduce the intake of medicine, reduce toxic reaction, the patient gets final product medication under situation about need not drink water, more convenient.
Sildenafil citrate sublingual tablet of the present invention have consumption little, reduce burden and damage to liver, improve bioavailability, the advantage that has no adverse reaction; Manufacture method of the present invention has flow process weak point, advantage of simple technology.
The specific embodiment
The specific embodiment one: the sildenafil citrate sublingual tablet of present embodiment is 15%PVP by 20～30 parts of sildenafil citrates, 45～65 parts in mannitol, 65～105 parts of lactose, 0.5～1.5 part of sweetener, concentration by weight
K3030～40 parts of ethanol liquid and magnesium stearate are made for 4～8 parts.The manufacture method of present embodiment sildenafil citrate sublingual tablet is: one, getting 20～30 parts of sildenafil citrates, 45～65 parts in mannitol, 65～105 parts of lactose, 0.5～1.5 part of sweetener, concentration by weight is 15%PVP
K304～8 parts of 30～40 parts of ethanol liquid and magnesium stearate; Two, solid material was pulverized 110～130 mesh sieves; Three, the powder mixing of sildenafil citrate, lactose and mannitol is made dry mash; Four, the concentration of getting gross weight 45～55% is 15%PVP
K30Ethanol liquid, together joins in the dry mash mix homogeneously and makes compound after the sweetener dissolving with this ethanol liquid; Five, be 15%PVP with the remaining concentration that accounts for gross weight 45～55%
K30Ethanol liquid joins in the rapid compound of previous step and makes soft material; Six, soft material is made granule with 18～20 order nylon mesh, the granule of making aeration-drying under 55～65 ℃ of conditions; Seven, with 14～16 mesh sieve granulate; Eight, sift out the fine powder that the granulate process occurs with 60～70 mesh sieves, add magnesium stearate and the granule mixing of haveing suffered with 14～16 mesh sieves in fine powder, sealing was placed 5～7 hours; Nine, tabletting (every heavy 0.2 the gram, every contain sildenafil citrate 10～25mg), the packing (being the finished product buccal tablet).
The specific embodiment two: the sildenafil citrate sublingual tablet of present embodiment is 15%PVP by 21～29 parts of sildenafil citrates, 46～64 parts in mannitol, 67～103 parts of lactose, 0.6～1.4 part of sweetener, concentration by weight
K3031～39 parts of ethanol liquid and magnesium stearate are made for 4.5～7.5 parts.Other method is identical with the specific embodiment one.
The specific embodiment three: the sildenafil citrate sublingual tablet of present embodiment is 15%PVP by 22～28 parts of sildenafil citrates, 48～61 parts in mannitol, 69～100 parts of lactose, 0.7～1.3 part of sweetener, concentration by weight
K3033～37 parts of ethanol liquid and magnesium stearate are made for 5～7 parts.Other method is identical with the specific embodiment one.
The specific embodiment four: the sildenafil citrate sublingual tablet of present embodiment is 15%PVP by 25 parts of sildenafil citrates, 55 parts in mannitol, 85 parts of lactose, 1 part of sweetener, concentration by weight
K3036 parts of ethanol liquid and magnesium stearate are made for 6 parts.Other method is identical with the specific embodiment one.
The specific embodiment five: the sildenafil citrate sublingual tablet of present embodiment is 15%PVP by 20～30 parts of sildenafil citrates, 45～65 parts in mannitol, 65～105 parts of lactose, 0.5～1.5 part of sweetener, concentration by weight
K3030～40 parts of ethanol liquid, 35～45 parts of cocoa powder, 0.2～0.8 part of cacao essence and magnesium stearate are made for 4～8 parts.Cocoa powder was together pulverized 110～130 mesh sieves with solid material in second step, cacao essence is added and the granule mixing of haveing suffered with 14～16 mesh sieves simultaneously with magnesium stearate in the 8th step again, sealing was placed 5～7 hours.Other method is identical with the specific embodiment one.
The specific embodiment six: the sildenafil citrate sublingual tablet of present embodiment is 15%PVP by 20～30 parts of sildenafil citrates, 45～65 parts in mannitol, 65～105 parts of lactose, 0.5～1.5 part of sweetener, concentration by weight
K3030～40 parts of ethanol liquid, 0.1～0.3 part of carmine pigment, 0.2～0.7 part of almond essence and magnesium stearate are made for 4～8 parts.Sweetener in carmine pigment and the 4th step is together dissolved; Almond essence is added simultaneously with magnesium stearate in the 8th step, and again with the granule mixing of haveing suffered with 14～16 mesh sieves, sealing was placed 5～7 hours.Other method is identical with the specific embodiment one.
Cocoa powder and cacao essence that the specific embodiment five and the specific embodiment six are added; Carmine pigment and almond essence can make sildenafil citrate sublingual tablet have cocoa perfume (or spice) or almond flavor road, can correct the bitterness of sildenafil citrate effectively and change color and luster, reduce the sensation of mouthfeel discomfort, make ED patient acceptant.
Claims (7)
1, a kind of sildenafil citrate sublingual tablet is characterized in that sildenafil citrate sublingual tablet is 15%PVP by 20～30 parts of sildenafil citrates, 45～65 parts in mannitol, 65～105 parts of lactose, 0.5～1.5 part of sweetener, concentration by weight
K3030～40 parts of ethanol liquid and magnesium stearate are made for 4～8 parts.
2, sildenafil citrate sublingual tablet according to claim 1 is characterized in that 21～29 parts of sildenafil citrates, 46～64 parts in mannitol, 67～103 parts of lactose, 0.6～1.4 part of sweetener, concentration are 15%PVP
K3031～39 parts of ethanol liquid and magnesium stearate are made for 4.5～7.5 parts.
3, sildenafil citrate sublingual tablet according to claim 1 is characterized in that 22～28 parts of sildenafil citrates, 48～61 parts in mannitol, 69～100 parts of lactose, 0.7～1.3 part of sweetener, concentration are 15%PVP
K3033～37 parts of ethanol liquid and magnesium stearate are made for 5～7 parts.
4, sildenafil citrate sublingual tablet according to claim 1 is characterized in that sildenafil citrate sublingual tablet is 15%PVP by 25 parts of sildenafil citrates, 55 parts in mannitol, 85 parts of lactose, 1 part of sweetener, concentration by weight
K3036 parts of ethanol liquid and magnesium stearate are made for 6 parts.
5, the manufacture method of the described sildenafil citrate sublingual tablet of the arbitrary claim of a kind of claim 1～4 is characterized in that the manufacture method of sildenafil citrate sublingual tablet is: one, getting 20～30 parts of sildenafil citrates, 45～65 parts in mannitol, 65～105 parts of lactose, 0.5～1.5 part of sweetener, concentration by weight is 15%PVP
K304～8 parts of 30～40 parts of ethanol liquid and magnesium stearate; Two, solid material was pulverized 110～130 mesh sieves; Three, the powder mixing of sildenafil citrate, lactose and mannitol is made dry mash; Four, the concentration of getting gross weight 45～55% is 15%PVP
K30Ethanol liquid, together joins in the dry mash mix homogeneously and makes compound after the sweetener dissolving with this ethanol liquid; Five, be 15%PVP with the remaining concentration that accounts for gross weight 45～55%
K30Ethanol liquid joins in the rapid compound of previous step and makes soft material; Six, soft material is made granule with 18～20 order nylon mesh, the granule of making aeration-drying under 55～65 ℃ of conditions; Seven, with 14～16 mesh sieve granulate; Eight, sift out the fine powder that the granulate process occurs with 60～70 mesh sieves, add magnesium stearate and the granule mixing of haveing suffered with 14～16 mesh sieves in fine powder, sealing was placed 5～7 hours; Nine, tabletting, packing.
6, a kind of sildenafil citrate sublingual tablet is characterized in that 20～30 parts of sildenafil citrates, 45～65 parts in mannitol, 65～105 parts of lactose, 0.5～1.5 part of sweetener, concentration are 15%PVP
K3030～40 parts of ethanol liquid, 35～45 parts of cocoa powder, 0.2～0.8 part of cacao essence and magnesium stearate are made for 4～8 parts.
7, a kind of sildenafil citrate sublingual tablet is characterized in that sildenafil citrate sublingual tablet is 15%PVP by 20～30 parts of sildenafil citrates, 45～65 parts in mannitol, 65～105 parts of lactose, 0.5～1.5 part of sweetener, concentration by weight
K3030～40 parts of ethanol liquid, 0.1～0.3 part of carmine pigment, 0.2～0.7 part of almond essence and magnesium stearate are made for 4～8 parts.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2006100099402A CN100488509C (en) | 2006-04-19 | 2006-04-19 | Sildenafil citrate sublingual tablet and its preparation method |
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| CNB2006100099402A CN100488509C (en) | 2006-04-19 | 2006-04-19 | Sildenafil citrate sublingual tablet and its preparation method |
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| Publication Number | Publication Date |
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| CN101057850A true CN101057850A (en) | 2007-10-24 |
| CN100488509C CN100488509C (en) | 2009-05-20 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103893139A (en) * | 2012-12-28 | 2014-07-02 | 石药集团中奇制药技术（石家庄）有限公司 | Asenapine composition and preparation method thereof |
-
2006
- 2006-04-19 CN CNB2006100099402A patent/CN100488509C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103893139A (en) * | 2012-12-28 | 2014-07-02 | 石药集团中奇制药技术（石家庄）有限公司 | Asenapine composition and preparation method thereof |
| CN103893139B (en) * | 2012-12-28 | 2018-06-08 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of asenapine composition and preparation method thereof |
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| CN100488509C (en) | 2009-05-20 |
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