CN100548309C - Stavudine sustained release tablet - Google Patents
Stavudine sustained release tablet Download PDFInfo
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- CN100548309C CN100548309C CNB2004100876587A CN200410087658A CN100548309C CN 100548309 C CN100548309 C CN 100548309C CN B2004100876587 A CNB2004100876587 A CN B2004100876587A CN 200410087658 A CN200410087658 A CN 200410087658A CN 100548309 C CN100548309 C CN 100548309C
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- stavudine
- pharmaceutic adjuvant
- sustained release
- hypromellose
- adjuvant
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Abstract
The present invention relates to a kind of efabirenz, specifically relate to stavudine sustained release tablet and preparation method thereof.It is characterized in that the composition in outer slow release film-coat forms by stavudine with as the gel skeleton label of pharmaceutic adjuvant, the gel skeleton label weight ratio of wherein contained stavudine and pharmaceutic adjuvant is 1: 0.68-2.32.Its preparation method comprises film-making core, coating etc.; The objective of the invention is to solve existing stavudine sustained release dosage form manufacturing equipment, complex process, general preparation factory such as is difficult at the existing problem in aspect.This tablet manufacture method is that gel skeleton slow release method known in the field and film coating slow release method have been carried out combination, and the defective that exists separately when avoiding single the use has improved patient's drug safety.
Description
One, technical field;
The present invention relates to a kind of efabirenz, specifically relate to stavudine sustained release tablet and preparation method thereof.
Two, background technology;
(Stavudine D4T) is a kind of efabirenz that has obtained multinational approval listing to stavudine, and independent or drug combination is used for the treatment of the relevant syndrome of HIV (human immunodeficiency virus) (HIV) infection and acquired immune deficiency syndrome (AIDS) or acquired immune deficiency syndrome (AIDS).Its chemical name and structural formula are as follows:
Chemical name: 2, the two dehydrogenations of 3--3-deoxyribosylthymine, structural formula:
Molecular formula: C
10H
12N
2O
4, molecular weight: 224.21.
Common stavudine preparation is a kind of capsule, and by patient's body weight difference, every day, dosage 30～100mg took at twice.Present stage treating AIDS comparison effective method is a therapeuticcocktail of anti-retrovirals, and promptly the anti HIV-1 virus medicine of the multiple different mechanisms of action is united use.Simplify therapeutic regimen as much as possible, can improve the compliance of patient's medication.Stavudine has good absorption at gastrointestinal tract, and this also is the prerequisite of its slow releasing preparation of preparation.
U.S. Bristol Myers Squibb Pharma Co. " sustained-release micro-spheres that contains stavudine " has applied for patent (CN14207774A) in China, and it is to adopt a kind of hard capsule preparation of extruding balling-up method preparation, and about 24 hours blood drug level can be provided.The lasting release microsphere of describing in the patent comprises that micropill is extruded, the preparation process of round as a ball, screening, must have special appointed condition could implement, so generally preparation factory is difficult to carry out this work.
Three, summary of the invention;
The invention provides a kind of stavudine sustained release tablet that adopts pharmaceutical factory's tablet common apparatus to prepare, its purpose is to solve existing stavudine sustained release dosage form manufacturing equipment, complex process, and general preparation factory such as is difficult at the existing problem in aspect.
A kind of stavudine sustained release tablet, it includes stavudine and outer slow release film-coat, it is characterized in that the composition in outer slow release film-coat forms by stavudine with as the gel skeleton label of pharmaceutic adjuvant, the gel skeleton label weight ratio of wherein contained stavudine and pharmaceutic adjuvant is 1: 0.68-2.32.
Described pharmaceutic adjuvant rises the adjuvant of slow releasing function except that the solubility that comprises hypromellose and/or ethyl cellulose and/or polycarboxy ethene and/or alginic acid and/or insoluble salt and/or other, also comprise tablet molding adjuvant, as filler, binding agent, lubricant, membrane material, wherein filler is lactose, microcrystalline Cellulose, starch, sucrose, mannitol, Pulvis Talci, silicon dioxide; Binding agent is the ethanol-water solution of polyvinylpyrrolidone, hypromellose, starch slurry, water, dehydrated alcohol, various concentration; Lubricant is stearic acid, magnesium stearate, Pulvis Talci, starch, paraffin; Membrane material is polyvinyl alcohol or contains hypromellose or organic solutions such as the ethanol of hymetellose or ethyl cellulose or acetone, or the aqueous dispersion of making by above-mentioned material, as Aquacoat (Aquacoat, Sulease), acrylic resin aqueous dispersion (EudrgitNE30D, Eudragit RS, Eudragit RL).
Pharmaceutic adjuvant also is included as and improves the necessary various plasticizers of membrane material filming performance, as Polyethylene Glycol, dimethyl phthalate, dibutyl sebacate.
The preferred hypromellose of one of described pharmaceutic adjuvant, its consumption is the 20-70% of stavudine weight; The preferred lactose of two filleies and the microcrystalline Cellulose of pharmaceutic adjuvant, its consumption is respectively the 20-75% of stavudine weight; Three of pharmaceutic adjuvant, the preferred magnesium stearate of lubricant, its consumption is the 1%-3% of stavudine weight; Four of pharmaceutic adjuvant, binding agent preferred starch, its consumption are stavudine weight 5%-10%.
One of described slow release film-coat preferred material is a hypromellose; Two of preferred material is an ethyl cellulose; Three of preferred material is a dibutyl sebacate; Four of preferred material is that volumetric concentration is 85% ethanol; Its weight ratio is 1: 1.8-2.2: 0.35-0.4: 37.4-40.
A kind of preparation method of stavudine sustained release tablet is characterized in that adopting following operating procedure:
(1) film-making core;
1. stavudine is pulverized the back and is crossed 100 mesh sieves; Lactose, microcrystalline Cellulose, magnesium stearate, direct mistake 80 mesh sieves of hydroxypropyl emthylcellulose are standby;
2. starch is made 4% starch slurry;
3. take by weighing recipe quantity stavudine, lactose, microcrystalline Cellulose, put in the fluidized granulation machine, open blower fan, material is suitable fluidized state, sprays into the starch slurry fluidized granulation;
4. dried granule adds recipe quantity hydroxypropyl emthylcellulose, magnesium stearate, behind the 20 mesh sieve granulate, and tabletting;
5. label after the assay was approved, it is standby to put 40 ℃ of baking oven preheatings 2 hours;
(2) coating;
1. get hydroxypropyl emthylcellulose, ethyl cellulose, dibutyl sebacate, join in 85% ethanol under stirring, continue stir about 2 hours;
2. get the label of preheating and put in the coating pan, with the 1. made coating solution spray coating of step, regulate inlet temperature and pot rotating speed, spray velocity and pressure, make film forming even, weightening finish is more than 8%.
This tablet manufacture method is that gel skeleton slow release method known in the field and film coating slow release method have been carried out combination, the defective that exists separately when avoiding single the use.For medicine soluble in water,, also be difficult to reach being released in about 24 hours of control medicine such as the gel skeleton slow release even the use amount of slow-release material reaches more than 50%; In case and the greatest problem of film coating slow release is to have certain local coating film forming inhomogeneous (this is to be difficult to be avoided) to occur in suitability for industrialized production, just will causes " prominent the releasing " of medicine, even cause serious adverse effects.And slow releasing tablet of the present invention can provide effective stavudine blood drug level in about 24 hours, and the stability experiment examination also shows sample steady quality under defined terms of preparation.
Adopt the tablet of process preparation of the present invention, can guarantee stavudine stablizing in pelletization, and need not add adjuvant in addition.Compare with sustained-release micro-spheres, the greatest problem that sustained release film coat exists is exactly " prominent releasing ", and it is excessive that " prominent releasing " can produce dose, causes toxic and side effects, and particularly for the medicine of the such good water solubility of stavudine, this danger is just bigger.The present invention is owing to added a certain amount of hydrophilic gel material---hypromellose (HPMC) in label, can make label meet the gel state that water forms, under common disintegrate test condition, keep more than 3 hours, significantly reduced probability, improved patient's drug safety because of the uneven medicine of coating film forming " prominent releasing ".
Four, the specific embodiment;
Embodiment 1
1. label is write out a prescription
2. label preparation technology
(1) stavudine is pulverized the back and cross 100 mesh sieves.Lactose, microcrystalline Cellulose, magnesium stearate, direct mistake 80 mesh sieves of hypromellose are standby.
(2) it is standby starch to be made 4% starch slurry.
(3) take by weighing recipe quantity stavudine, lactose, microcrystalline Cellulose, put in the fluidized granulation machine.Open blower fan and make material be suitable fluidized state, spray into the starch slurry fluidized granulation.
(4) dried granule adds recipe quantity hypromellose, magnesium stearate, 20 mesh sieve granulate, tabletting.
(5) label after the assay was approved, it is standby to put 40 ℃ of baking oven preheating 2h.
3. coating is write out a prescription
Raw material inventory weight ratio
Hypromellose 4.7g 1
Ethyl cellulose 8.8g 1.87
Dibutyl sebacate 1.75g 0.37
85% ethanol 180g 38.3
4. art for coating
(1) gets hypromellose, ethyl cellulose, dibutyl sebacate, join in 85% ethanol under stirring, continue stir about 2 hours.
(2) label of getting preheating is put in the coating pan, with 7 made coating solution spray coatings, regulates inlet temperature and pot rotating speed, spray velocity and pressure, makes film forming even, and weightening finish is 8%.
(3) coating finishes, and takes out coated tablet, puts and continues dry 4h in 40 ℃ of baking ovens.Check back packing.
Embodiment 2
1. label is write out a prescription
2. label preparation technology: 2 in concrete steps such as the example 1.
3. coating is write out a prescription
Raw material inventory weight ratio
Hypromellose 4.7g 1
Ethyl cellulose 8.46g 1.80
Dibutyl sebacate 1.64g 0.35
85% ethanol 176g 37.4
4. art for coating: 4 in concrete steps such as the example 1.
Embodiment 3
1. label is write out a prescription
2. label preparation technology
In concrete steps such as the example 12.
3. coating is write out a prescription
Raw material inventory weight ratio
Hypromellose 4.7g 1
Ethyl cellulose 10.34g 2.2
Dibutyl sebacate 1.88g 0.4
85% ethanol 188g 40
4. art for coating
In concrete steps such as the example 14.
Embodiment 4
Other conditions are with example 1, and difference is that label raw material lactose is by cane sugar substitution.
Embodiment 5
Other conditions are with example 1, and difference is that coating raw material hypromellose is substituted by hydroxypropyl cellulose.
Embodiment 6
Other conditions are with example 2, and difference is that (1) sheet core raw material microcrystalline Cellulose is by starch in replace;
(2) coating feed ethanol/water is substituted by acetone.
Stavudine sustained release sheet to the present invention preparation has carried out the test of tablet indexs such as outward appearance, friability, and the release of sample, stability etc. have been carried out The effects, and its result is as follows:
(tabulation vides infra)
Be not difficult to find out from The above results: press embodiments of the invention and implement, the stavudine sustained release sheet of preparation, release is preferably all arranged, under common study on the stability condition, active component does not have significant change, its catabolite one related substance item does not obviously increase yet, and meets correlated quality standard-required (it is below 2% that impurity is limited the quantity of).
The slow releasing tablet and the conventional release capsule preparation of embodiment 1 preparation have been carried out the animal body giving drugs into nose respectively for dynamics research, its result shows: the stavudine sustained release tablet of the present invention's preparation can continue to discharge in 24 hours, bioavailability with respect to conventional release capsule preparation is 108.06%, through variance analysis and two one-sided detection, both bioequivalences.There were significant differences for maximum plasma concentration Cmax and peak time Tmax.
Claims (5)
1, a kind of stavudine sustained release tablet, it includes stavudine and outer slow release film-coat, it is characterized in that the composition in outer slow release film-coat forms by stavudine with as the gel skeleton label of pharmaceutic adjuvant, wherein contained stavudine is 1 with gel skeleton label weight ratio as pharmaceutic adjuvant: 0.68-2.32.
2, stavudine sustained release tablet according to claim 1, it is characterized in that: described pharmaceutic adjuvant rises the adjuvant of slow releasing function except that the solubility that comprises hypromellose and/or ethyl cellulose and/or polycarboxy ethene and/or alginic acid and/or insoluble salt and/or other, also comprise tablet molding adjuvant, tablet molding adjuvant comprises filler, binding agent, lubricant and membrane material, and wherein filler is selected from lactose, microcrystalline Cellulose, starch, sucrose, mannitol, Pulvis Talci, silicon dioxide; Binding agent is selected from the ethanol-water solution of polyvinylpyrrolidone, hypromellose, starch slurry, water, dehydrated alcohol, various concentration; Lubricant is selected from stearic acid, magnesium stearate, Pulvis Talci, starch, paraffin; Membrane material is selected from polyvinyl alcohol or contains hypromellose or the ethanol of hymetellose or ethyl cellulose or acetone organic solution, or the aqueous dispersion of making by above-mentioned material, aqueous dispersion is selected from Aquacoat, acrylic resin aqueous dispersion.
3, stavudine sustained release tablet according to claim 2 is characterized in that: pharmaceutic adjuvant also is included as and improves the necessary various plasticizers of membrane material filming performance, and plasticizer is selected from Polyethylene Glycol, dimethyl phthalate, dibutyl sebacate.
4, stavudine sustained release tablet according to claim 2 is characterized in that: one of pharmaceutic adjuvant of described slow releasing function is selected hypromellose for use, and its consumption is the 20-70% of stavudine weight; Two filleies of pharmaceutic adjuvant are selected lactose and microcrystalline Cellulose for use, and its consumption is respectively the 20-75% of stavudine weight; Three of pharmaceutic adjuvant, lubricant is selected magnesium stearate for use, and its consumption is the 1%-3% of stavudine weight; Four of pharmaceutic adjuvant, binding agent is selected starch for use, and its consumption is stavudine weight 5%-10%.
5, stavudine sustained release tablet according to claim 3 is characterized in that: one of described slow release film-coat the selection of material is a hypromellose; Two of the selection of material is an ethyl cellulose; Three of the selection of material is a dibutyl sebacate; Four of the selection of material is that volumetric concentration is 85% ethanol; Its weight ratio hypromellose: ethyl cellulose: dibutyl sebacate: ethanol is 1: 1.8-2.2: 0.35-0.4: 37.4-40.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100876587A CN100548309C (en) | 2004-11-24 | 2004-11-24 | Stavudine sustained release tablet |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100876587A CN100548309C (en) | 2004-11-24 | 2004-11-24 | Stavudine sustained release tablet |
Publications (2)
| Publication Number | Publication Date |
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| CN1634116A CN1634116A (en) | 2005-07-06 |
| CN100548309C true CN100548309C (en) | 2009-10-14 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB2004100876587A Expired - Fee Related CN100548309C (en) | 2004-11-24 | 2004-11-24 | Stavudine sustained release tablet |
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004112756A1 (en) | 2003-06-26 | 2004-12-29 | Isa Odidi | Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient |
| US10624858B2 (en) | 2004-08-23 | 2020-04-21 | Intellipharmaceutics Corp | Controlled release composition using transition coating, and method of preparing same |
| US10064828B1 (en) | 2005-12-23 | 2018-09-04 | Intellipharmaceutics Corp. | Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems |
| US9561188B2 (en) | 2006-04-03 | 2017-02-07 | Intellipharmaceutics Corporation | Controlled release delivery device comprising an organosol coat |
| US10960077B2 (en) | 2006-05-12 | 2021-03-30 | Intellipharmaceutics Corp. | Abuse and alcohol resistant drug composition |
| CN104306340B (en) * | 2014-10-27 | 2017-07-04 | 哈尔滨商业大学 | Slow controlled release microparticle of a kind of Allopurinol and preparation method thereof |
| CN107875133A (en) * | 2017-12-11 | 2018-04-06 | 湖南省湘中制药有限公司 | A kind of slow-releasing magnesium propylvalerate tablet and its preparation technology |
| CN109481420B (en) * | 2018-12-03 | 2020-11-10 | 江苏四环生物制药有限公司 | Mecobalamin sustained-release capsule |
Citations (4)
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| CN86107734A (en) * | 1985-11-18 | 1987-05-20 | 霍夫曼-拉罗奇有限公司 | The preparation of medicine |
| US4919938A (en) * | 1986-07-09 | 1990-04-24 | Merck Sharp & Dohme Ltd. | Sustained release pharmaceutical compositions in oral dosage form |
| US5594030A (en) * | 1993-07-22 | 1997-01-14 | Laboratorio Farmaceutico C.T. S.R.L. | Controlled release pharmaceutical compositions based on one or more pharmaceutically acceptable salts of gamma hydroxy-butyric acid |
| CN1420774A (en) * | 2000-03-30 | 2003-05-28 | 布里斯托尔-迈尔斯斯奎布公司 | Sustained release beadlets conty. stavudine |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86107734A (en) * | 1985-11-18 | 1987-05-20 | 霍夫曼-拉罗奇有限公司 | The preparation of medicine |
| US4919938A (en) * | 1986-07-09 | 1990-04-24 | Merck Sharp & Dohme Ltd. | Sustained release pharmaceutical compositions in oral dosage form |
| US5594030A (en) * | 1993-07-22 | 1997-01-14 | Laboratorio Farmaceutico C.T. S.R.L. | Controlled release pharmaceutical compositions based on one or more pharmaceutically acceptable salts of gamma hydroxy-butyric acid |
| CN1420774A (en) * | 2000-03-30 | 2003-05-28 | 布里斯托尔-迈尔斯斯奎布公司 | Sustained release beadlets conty. stavudine |
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