CN103222964B - Orlistat oral preparation and preparation method thereof - Google Patents
Orlistat oral preparation and preparation method thereof Download PDFInfo
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- CN103222964B CN103222964B CN201310032613.9A CN201310032613A CN103222964B CN 103222964 B CN103222964 B CN 103222964B CN 201310032613 A CN201310032613 A CN 201310032613A CN 103222964 B CN103222964 B CN 103222964B
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- orlistat
- acrylic resin
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Abstract
The invention discloses an orlistat oral preparation and a preparation method thereof. The orlistat oral preparation is an orlistat tablet. The orlistat tablet comprises an orlistat acrylic resin solid dispersion, a disintegrating agent and pharmaceutically acceptable auxiliary materials. The orlistat acrylic resin solid dispersion is prepared by rapid expansion of supercritical solution and has D90 less than 10 microns. The raw materials of the orlistat oral preparation are micronized by a supercritical technology and an inert material layer is coated on the orlistat surface so that the problems of a low dissolution rate of the preparation obtained by the prior art, and sticking in tabletting are solved.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, in particular to a kind of orlistat oral formulations and preparation method thereof.
Background technology
Orlistat is long-acting and potent specificity gastrointestinal tract lipase inhibitor, it by with harmonization of the stomach small intestinal lumen in the active ser position of gastric lipase and pancreatic lipase form covalent bond and make enzyme deactivation.Fat in food can not be decomposed into free fatty, thereby fat can not be absorbed, utilize, thereby reduces energy intake, controls body weight.This medicine is without bringing into play drug effect by systemic Absorption, and seldom through gastrointestinal absorption, thereby its blood drug level is extremely low.Use this product therapeutic dose to have no body accumulation.Site of metabolism is at gastrointestinal tract wall, and the elimination half-life is about 14～19 hours.This product of approximately 97%, with defecate, wherein 83% is discharged with original shape.Can be applicable to clinically obesity and hyperlipemia.
The chemical name of orlistat: N-formyl-L-Leu (s)-1[(2s, 3s) 3-hexyl-4 oxygen base-2-glycidyl methyl] ten diester, also claim ORLISTAT (THL), be a kind of semisynthetic lipstatin derivant, structural formula is as follows:
Orlistat is that white is to off-white color crystalline powder; Odorless very easily dissolves in methanol, ethanol, acetonitrile, chloroform, almost insoluble in water, almost insoluble in 0.1mol/L hydrochloric acid solution.Fusing point is 40～48 ℃.Because the fusing point of orlistat is low, at humid air or in higher than the dry air of 35 ℃, easily there is hydrolytic degradation and thermal degradation, problems such as being prone to adhesion in technical process, boning and reassociating; And orlistat is more fluffy, poor fluidity, even smoothly filled capsules or tabletting.The dissolution of prepared preparation is low, can not meet treatment requirement.
CN102552168A discloses a kind of pharmaceutical composition that contains orlistat and preparation method thereof, orlistat is mixed in-45 ℃～-15 ℃ cryogrindings with hydrophilicity condiment, obtain hybrid particles, and then mix homogeneously with the acceptable adjuvant 0-100 of pharmacy part, make capsule, tablet or granule.Solve the adhesion and bonding phenomenon and the low defect of dissolution that in orlistat preparation process, are prone to, guaranteed the good dissolution of orlistat preparation, improved product quality.But the method needs cryogrinding equipment, although can be pulverized and mixed, but still cannot guarantee the sticking problem in tabletting or capsule charge process, large production technology controllability is not high.
CN102362863A discloses a kind of preparation containing orlistat and preparation method thereof, by orlistat fused solution, coating, on blank or blank piller surface, has solved the sticking problem causing because of orlistat thawing in production process, and preparation has kept good stability and dissolution simultaneously.Although avoided sticking problem, after coating, unilateral or piller rough surface, rough, tablet or the piller surface orlistat raw material that easily comes off.
CN101791296B discloses a kind of orlistat tablets and preparation method thereof to be passed through orlistat, cyclodextrin after enclose, be pressed into tablet with pharmaceutically acceptable adjuvant again, this tablet has solved the sticking problem of orlistat with common process tabletting, chemistry and the physical stability of orlistat have been significantly improved, covered the unpleasant taste of orlistat, improve the compliance that is difficult to swallow patient's oral administration, there is good dissolution, improved the curative effect of orlistat.But this technique needs loaded down with trivial details enclose process, and technique is more complicated.
The compositions > > (application number 98800369.4) that the Chinese patent < < of Yuan Yan enterprise Roche application contains Tetrahydrolipstatin discloses a kind of compositions that contains orlistat, by orlistat, stabilizing agent (polyvidone, lactose, hypromellose, hyprolose) and pharmaceutical excipient (surfactant, diluent, disintegrating agent, Pulvis Talci), employing is extruded spheronization and is prepared piller, control the particle diameter of these microgranules in 0.25mm～2mm scope, be prepared into again suitable oral solid formulation-capsule, tablet or packed dosage form, to solve in technical process, there is adhesion and adhesion problem.In production, need to extrude, rolling circle equipment, and in capsule charge process, because frictional heating causes the free orlistat in surface, melt adhesion.
US7393545 discloses a kind of soluble fiber element sheet of lipase inhibitor, have problems as follows: adopted a large amount of methylcellulose as carrier, cause sheet heavy very large, increased patient's medication difficulty, if taken after dissolving, mouthfeel is bad again, does not fundamentally solve sticking problem in tabletting process, just, by increasing sheet weight, reduced the content of orlistat.
WO2009050720 discloses the pharmaceutical composition containing orlistat, has improved dissolution and the bioavailability of medicine, adopts fluid unit, and process is as follows: the aqueous solution of the water soluble polymer material that (a) preparation contains surfactant; (b) orlistat powder is dispersed in this solution; (c) orlistat suspension is sprayed on to pharmaceutically acceptable pharmaceutic adjuvant surface, is finally processed into dosage form.But, this suspension is sprayed in the process on graininess adjuvant surface, it is coated that orlistat raw material surface that can not be all is all aggregated thing, will inevitably some orlistat be attached to the outer surface of granule, equally can be because of drift heating sticking in tabletting process.
In addition, orlistat sheet prepared by above technology, its dissolution determination test all adds surfactant in dissolution medium, to improve dissolution in vitro, yet human gastrointestinal tract is interior and surfactant-free, and the dissolution of tablet prepared by above technology is still to be improved.
Summary of the invention
In view of the deficiencies in the prior art, the object of the invention is to study by the physicochemical properties to orlistat, and screen formulation and technology by lot of experiments, a kind of smooth surface, orlistat solid orally ingestible that dissolution is good and preparation method thereof are provided.
Particle diameter and the crystal formation of drug-eluting speed and medicine are in close relations, and the little stripping of particle diameter is fast, unformed fast compared with crystal formation dissolving.Therefore, heat of the present invention is planned orlistat and is made unformed micronization form, yet because orlistat fusing point is low, conventional pulverizing is difficult to realize, and pulverize at low temperature is difficult to again industrialization.In order to realize object of the present invention, inventor studies by lot of experiments, has finally obtained following technical scheme:
A kind of orlistat tablets, this tablet is comprised of orlistat acrylic resin solid dispersion, disintegrating agent and other pharmaceutically acceptable adjuvants, described orlistat acrylic resin solid dispersion adopts using supercritical fluid quick expansion method to be prepared from, D90 < 10 μ m.
Preferably, described orlistat tablets, wherein the weight ratio of orlistat and acrylic resin is 1: 0.5-3.
Further preferably, described orlistat tablets, wherein the weight ratio of orlistat and acrylic resin is 1: 1-2.
Again further preferably, described orlistat tablets, wherein the weight ratio of orlistat and acrylic resin is 1: 1.5.
Described disintegrating agent is selected from one or more in carboxymethyl starch sodium, polyvinylpolypyrrolidone, hydroxypropyl cellulose, starch and cross-linking sodium carboxymethyl cellulose.
Described disintegrating agent is preferably polyvinylpolypyrrolidone.
Described pharmaceutically acceptable adjuvant is selected from one or more in microcrystalline Cellulose, lactose, mannitol, polyvidone, pregelatinized Starch, silicon dioxide, Pulvis Talci and magnesium stearate.
A method of preparing above-mentioned orlistat tablets, comprises the following steps:
(1) acrylic resin, orlistat are dissolved in ethanol;
(2) by supercritical CO
2with the nozzle that the solution of step (1) is 10 microns by aperture reduces pressure, decompression time 10
-5second, form the orlistat acrylic resin solid dispersion fine powder that granularity is less than 10 μ m;
(3) by the solid dispersion fine powder of step (2) gained and microcrystalline Cellulose, polyvinylpolypyrrolidone mix homogeneously, granulate, dry, add magnesium stearate, mix tabletting and get final product.
The present invention selects supercritical technology to carry out micronization raw material, simultaneously by orlistat surface-coated one deck inert material, has successfully solved the lower problem of preparation dissolution prepared by prior art, and has solved sticking problem in tabletting process.That is: the inventor creatively combines using supercritical fluid quick expansion legal system for powder material and solid dispersions technique, adopt using supercritical fluid quick expansion legal system for orlistat acrylic resin solid dispersion, orlistat is prepared into the unformed shape of micropowder, then this solid dispersion is mixed homogeneously with pharmaceutically acceptable adjuvant, granulate, dry, tabletting, can obtain not adding in dissolution medium surfactant can stripping rapidly, the orlistat tablets of any surface finish, obtained beyond thought effect.
Accompanying drawing explanation
Fig. 1 is the DSC collection of illustrative plates of orlistat raw material.
Fig. 2 is the DSC collection of illustrative plates of acrylic resin.
Fig. 3 is the DSC collection of illustrative plates of 1: 1 mixture of orlistat acrylic resin.
Fig. 4 is the DSC collection of illustrative plates of 1: 1 solid dispersion of orlistat acrylic resin.
Specific embodiment
Be below specific embodiments of the invention, technical scheme of the present invention is done to further description, but protection scope of the present invention is not limited to these embodiment.Every do not deviate from the change of the present invention design or be equal to substitute include within protection scope of the present invention.
Embodiment 1
1. solid dispersion preparation
Orlistat 120g
Acrylic resin 60g
Dehydrated alcohol 600g
The orlistat of recipe quantity, acrylic resin are dissolved in dehydrated alcohol, and on supercritical fluid equipment, by supercritical fluid CO2, the nozzle that is 10 microns by aperture fast reduces pressure, decompression time 10
-5second, utilize using supercritical fluid quick expansion legal system for orlistat acrylic resin solid dispersion, dispersion D90 < 10 μ m.
2. orlistat sheet preparation
Solid dispersion is mixed homogeneously with microcrystalline Cellulose, polyvinylpolypyrrolidone, add pure water appropriate, granulate, dry, dry granule is crossed 20 mesh sieves, then mix homogeneously with the magnesium stearate of recipe quantity, and tabletting and get final product.
Embodiment 2
1. solid dispersion preparation
Orlistat 120g
Acrylic resin 360g
Dehydrated alcohol 2000g
The orlistat of recipe quantity, acrylic resin are dissolved in dehydrated alcohol, and on supercritical fluid equipment, by supercritical fluid CO2, the nozzle that is 10 microns by aperture fast reduces pressure, decompression time 10
-5second, utilize using supercritical fluid quick expansion legal system for orlistat acrylic resin solid dispersion, dispersion D90 < 10 μ m.
2. orlistat sheet preparation
Solid dispersion is mixed homogeneously with microcrystalline Cellulose, polyvinylpolypyrrolidone, add pure water appropriate, granulate, dry, dry granule is crossed 20 mesh sieves, then mix homogeneously with the magnesium stearate of recipe quantity, and tabletting and get final product.
Embodiment 3
1. solid dispersion preparation
Orlistat 120g
Acrylic resin 180g
Dehydrated alcohol 1000g
The orlistat of recipe quantity, acrylic resin are dissolved in dehydrated alcohol, and on supercritical fluid equipment, by supercritical fluid CO2, the nozzle that is 10 microns by aperture fast reduces pressure, decompression time 10
-5second, utilize using supercritical fluid quick expansion legal system for orlistat acrylic resin solid dispersion, dispersion D90 < 10 μ m.
2. orlistat sheet preparation
Solid dispersion is mixed homogeneously with microcrystalline Cellulose, polyvinylpolypyrrolidone, add pure water appropriate, granulate, dry, dry granule is crossed 20 mesh sieves, then mix homogeneously with the magnesium stearate of recipe quantity, and tabletting and get final product.
Comparative example
1. orlistat raw material is processed
Orlistat 120g
Dehydrated alcohol 1000g
The orlistat of recipe quantity is dissolved in dehydrated alcohol, on supercritical fluid equipment, by supercritical fluid CO2, is the nozzle of 10 microns by aperture fast, D90 < 10 μ m.
2. orlistat sheet preparation
After processing, orlistat raw material is mixed homogeneously with microcrystalline Cellulose, polyvinylpolypyrrolidone, adds pure water appropriate, granulates, and is dried, and dry granule is crossed 20 mesh sieves, then mix homogeneously with the magnesium stearate of recipe quantity, and tabletting and get final product.
Checking embodiment
(1) confirmation of orlistat crystal formation
The preparation of 1: 1 solid dispersion of orlistat acrylic resin
Orlistat 120g
Acrylic resin 120g
Dehydrated alcohol 100g
The orlistat of recipe quantity, acrylic resin are dissolved in dehydrated alcohol, and on supercritical fluid equipment, by supercritical fluid CO2, the nozzle that is 10 microns by aperture fast reduces pressure, decompression time 10
-5second, utilize using supercritical fluid quick expansion legal system for orlistat acrylic resin solid dispersion, dispersion D90 < 10 μ m.
Utilize the crystal formation of DSC checking orlistat.Collection of illustrative plates is referring to accompanying drawing 1-4.As can be seen from the figure: orlistat and acrylic resin form after solid dispersion, and on DSC collection of illustrative plates, orlistat endothermic peak disappears, this explanation dispersion forms; And orlistat endothermic peak still exists in mixture.
(2) dissolution method (2010 editions two appendix XC the second methods of Chinese Pharmacopoeia), take pH as 1.2 hydrochloric acid solution 900ml be dissolution medium, rotating speed is 75 revs/min, through 45 minutes, sampling and measuring.Get solution 10ml and filter, according to high performance liquid chromatography (2010 editions two appendix VD of Chinese Pharmacopoeia measure).
| Embodiment | 10min dissolution | 45min dissolution |
| Embodiment 1 | 78.2％ | 98.2％ |
| Embodiment 2 | 82.3％ | 99.6％ |
| Embodiment 3 | 81.0％ | 98.9％ |
| Comparative example 1 | 5.1％ | 5.2％ |
It can be seen from the table, the tablet that utilizes the present invention to prepare, in gastric acid, stripping is very fast; Although comparative example's 1 energy micropowder is below 10 μ m, owing to not adopting solid dispersions technique, orlistat raw material is crystal formation state, and stripping is poor.
Claims (7)
1. an orlistat tablets, it is characterized in that: this tablet is comprised of orlistat acrylic resin solid dispersion, disintegrating agent and other pharmaceutically acceptable adjuvants, described orlistat acrylic resin solid dispersion adopts using supercritical fluid quick expansion method to be prepared from, D90 < 10 μ m.
2. orlistat tablets according to claim 1, is characterized in that: the weight ratio of orlistat and acrylic resin is 1: 1-2.
3. orlistat tablets according to claim 1, is characterized in that: the weight ratio of orlistat and acrylic resin is 1: 1.5.
4. orlistat tablets according to claim 1, is characterized in that: described disintegrating agent is selected from one or more in carboxymethyl starch sodium, polyvinylpolypyrrolidone, hydroxypropyl cellulose, starch and cross-linking sodium carboxymethyl cellulose.
5. orlistat tablets according to claim 1, is characterized in that: described disintegrating agent is polyvinylpolypyrrolidone.
6. orlistat tablets according to claim 1, is characterized in that: described pharmaceutically acceptable adjuvant is selected from one or more in microcrystalline Cellulose, lactose, mannitol, polyvidone, pregelatinized Starch, silicon dioxide, Pulvis Talci and magnesium stearate.
7. a method of preparing orlistat tablets claimed in claim 1, is characterized in that: comprise the following steps:
(1) acrylic resin, orlistat are dissolved in ethanol;
(2) by supercritical CO
2with the nozzle that the solution of step (1) is 10 microns by aperture reduces pressure, decompression time 10-5 second, form the orlistat acrylic resin solid dispersion fine powder that granularity is less than 10 μ m;
(3) by the solid dispersion fine powder of step (2) gained and microcrystalline Cellulose, polyvinylpolypyrrolidone mix homogeneously, granulate, dry, add magnesium stearate, mix tabletting and get final product.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310032613.9A CN103222964B (en) | 2013-01-29 | 2013-01-29 | Orlistat oral preparation and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310032613.9A CN103222964B (en) | 2013-01-29 | 2013-01-29 | Orlistat oral preparation and preparation method thereof |
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| CN103222964A CN103222964A (en) | 2013-07-31 |
| CN103222964B true CN103222964B (en) | 2014-10-08 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105796567B (en) * | 2014-12-29 | 2020-03-17 | 北京福元医药股份有限公司 | Cetilistat solid dispersion and pharmaceutical preparation thereof |
| CN109364033B (en) * | 2018-11-23 | 2021-10-01 | 南京泽恒医药技术开发有限公司 | Mercaptopurine quartering chewable tablet and preparation method thereof |
| WO2021072773A1 (en) * | 2019-10-18 | 2021-04-22 | 山东新时代药业有限公司 | Orlistat capsule and preparation method therefor |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999052504A1 (en) * | 1998-04-09 | 1999-10-21 | F. Hoffmann-La Roche Ag | Process for the manufacture of (sub)micron sized particles by dissolving in compressed gas and surfactants |
| CN1438880A (en) * | 2000-06-27 | 2003-08-27 | 霍夫曼-拉罗奇有限公司 | Method for preparing a composition |
| WO2009039157A2 (en) * | 2007-09-17 | 2009-03-26 | Dr. Reddy's Laboratories Ltd. | Orlistat pharmaceutical formulations |
| WO2010111238A2 (en) * | 2009-03-23 | 2010-09-30 | Micell Technologies, Inc. | Improved biodegradable polymers |
-
2013
- 2013-01-29 CN CN201310032613.9A patent/CN103222964B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999052504A1 (en) * | 1998-04-09 | 1999-10-21 | F. Hoffmann-La Roche Ag | Process for the manufacture of (sub)micron sized particles by dissolving in compressed gas and surfactants |
| CN1295466A (en) * | 1998-04-09 | 2001-05-16 | 弗·哈夫曼-拉罗切有限公司 | Process for manufacture of (sub) micron sized particles by dissolving in compressed gas and surfactants |
| CN1438880A (en) * | 2000-06-27 | 2003-08-27 | 霍夫曼-拉罗奇有限公司 | Method for preparing a composition |
| WO2009039157A2 (en) * | 2007-09-17 | 2009-03-26 | Dr. Reddy's Laboratories Ltd. | Orlistat pharmaceutical formulations |
| WO2010111238A2 (en) * | 2009-03-23 | 2010-09-30 | Micell Technologies, Inc. | Improved biodegradable polymers |
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Application publication date: 20130731 Assignee: Guangzhou Ren Heng Pharmaceutical Technology Co., Ltd Assignor: Qingdao University Contract record no.: 2015440000162 Denomination of invention: Orlistat oral preparation and preparation method thereof Granted publication date: 20141008 License type: Exclusive License Record date: 20150526 |
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