CN103222964A - Orlistat oral preparation and preparation method thereof - Google Patents
Orlistat oral preparation and preparation method thereof Download PDFInfo
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- CN103222964A CN103222964A CN2013100326139A CN201310032613A CN103222964A CN 103222964 A CN103222964 A CN 103222964A CN 2013100326139 A CN2013100326139 A CN 2013100326139A CN 201310032613 A CN201310032613 A CN 201310032613A CN 103222964 A CN103222964 A CN 103222964A
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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 the 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 the 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 the food can not be decomposed into free fatty, thereby fat can not be absorbed, utilize, and takes in controlling body weight thereby reduce heat.This medicine need not to absorb the performance drug effect by whole body, and seldom through gastrointestinal absorption, thereby its blood drug level is extremely low.Use this product therapeutic dose not see body accumulation.Site of metabolism is at gastrointestinal tract wall, and the elimination half-life is about 14～19 hours.This product of about 97% is with defecate, wherein 83% discharges with original shape.Can be applicable to obesity and hyperlipemia clinically.
The chemical name of orlistat: N-formyl-L-leucine (s)-1[(2s, 3s) 3-hexyl-4 oxygen base-2-glycidyl methyl] ten diester, also claim tetrahydrochysene lipstatin (THL), be a kind of semisynthetic lipstatin derivant, structural formula is as follows:
Orlistat is that white is to the off-white color crystalline powder; Odorless, very easily dissolving is almost insoluble in water in methanol, ethanol, acetonitrile, chloroform, and is almost insoluble in the 0.1mol/L hydrochloric acid solution.Fusing point is 40～48 ℃.Because the fusing point of orlistat is low, at humid air or be higher than in 35 ℃ the dry air, hydrolytic degradation and thermal degradation easily take place, problems such as being prone to adhesion in technical process, boning and reassociating; And orlistat is more fluffy, and is mobile poor, even filled capsules or tabletting smoothly.The dissolution of prepared preparation is low, can not satisfy the 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 with pharmacy acceptable auxiliary 0-100 part mix homogeneously, make capsule, tablet or granule.Solve the adhesion and bonding phenomenon and the low defective of dissolution that are prone in the orlistat preparation process, guaranteed orlistat preparation dissolution preferably, improved product quality.But this method needs cryogrinding equipment, although can pulverize mixing, but still can't guarantee sticking problem in tabletting or the capsule charge process, and big production technology controllability is not high.
CN102362863A discloses a kind of preparation that contains orlistat and preparation method thereof, with the orlistat fused solution, coating has solved the sticking problem that causes because of the orlistat thawing in the production process on blank or blank piller surface, and preparation has kept good stable and dissolution simultaneously.Although avoided the sticking problem, unilateral or piller rough surface is rough behind the coating, 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 through behind the enclose, be pressed into tablet with acceptable accessories again, this tablet has solved the sticking problem of orlistat with the common process tabletting, the 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, had good dissolution, improved the curative effect of orlistat.But the enclose process that this arts demand is loaded down with trivial details, technology are complicated.
The former Chinese patent " compositions that contains Tetrahydrolipstatin " (application number 98800369.4) that grinds the Luo Shi of enterprise application discloses a kind of compositions that contains orlistat, with orlistat, stabilizing agent (polyvidone, lactose, hypromellose, hyprolose) and pharmaceutical excipient (surfactant, diluent, disintegrating agent, Pulvis Talci), employing is extruded spheronization and is prepared piller, the particle diameter of controlling these microgranules is in 0.25mm～2mm scope, refabrication becomes suitable oral solid formulation-capsule, tablet or packed dosage form adhesion and adhesion problem occur to solve in the technical process.Need in the production to extrude, rolling circle equipment, and in the capsule charge process, melt adhesion because of frictional heating causes surperficial free orlistat.
US7393545 discloses a kind of plain sheet of soluble fiber of lipase inhibitor, it is as follows to have problems: adopted a large amount of methylcellulose as carrier, cause sheet heavy very big, increased patient's medication difficulty, if take after dissolving, mouthfeel is bad again, does not fundamentally solve sticking problem in the tabletting process, just weigh, reduced the content of orlistat by increasing sheet.
WO2009050720 discloses the pharmaceutical composition that contains orlistat, has improved the dissolution and the bioavailability of medicine, adopts fluid unit, and process is as follows: (a) preparation contains the aqueous solution of the water soluble polymer material of surfactant; (b) the orlistat powder is dispersed in this solution; (c) the orlistat suspension is sprayed on pharmaceutically acceptable pharmaceutic adjuvant surface, is processed into dosage form at last.But, this suspension is sprayed in the process on graininess adjuvant surface, orlistat raw material surface that can not be all is aggregated thing and coats, and will inevitably be attached to particulate outer surface by some orlistat, equally can be because of drift heating sticking in the tabletting process.
In addition, the orlistat sheet of above technology preparation, 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 the tablet of above technology preparation still remains to be improved.
Summary of the invention
In view of the deficiencies in the prior art, the objective of the invention is to study by physicochemical properties to orlistat, and by a large amount of experiment sieving formulation and technologies, provide a kind of smooth surface, orlistat solid orally ingestible that dissolution is good and preparation method thereof.
The particle diameter and the crystal formation of medicine dissolution rate and medicine are in close relations, and the little stripping of particle diameter is fast, and be unformed fast than the crystal formation dissolving.Therefore, heat of the present invention is planned orlistat and is made unformed micronization form, yet because the orlistat fusing point is low, the conventional pulverizing is difficult to realize that pulverize at low temperature is difficult to industrialization again.In order to realize purpose of the present invention, the inventor has finally obtained following technical scheme by a large amount of experimental studies:
A kind of orlistat tablets, this tablet is made up of orlistat acrylic resin solid dispersion, disintegrating agent and other acceptable accessories, described orlistat acrylic resin solid dispersion adopts the 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 the cross-linking sodium carboxymethyl cellulose.
Described disintegrating agent is preferably polyvinylpolypyrrolidone.
Described acceptable accessories is selected from one or more in microcrystalline Cellulose, lactose, mannitol, polyvidone, pregelatinized Starch, silicon dioxide, Pulvis Talci and the magnesium stearate.
A kind of method for preparing above-mentioned orlistat tablets may further comprise the steps:
(1) acrylic resin, orlistat are dissolved in the ethanol;
(2) with supercritical CO
2And the solution of step (1) is 10 microns nozzle decompression by the aperture, decompression time 10
-5Second, form the orlistat acrylic resin solid dispersion fine powder of granularity less than 10 μ m;
(3) with the solid dispersion fine powder of step (2) gained and microcrystalline Cellulose, polyvinylpolypyrrolidone mix homogeneously, granulate, drying adds magnesium stearate, and the mixing tabletting promptly.
The present invention selects for use supercritical technology to carry out the micronization raw material, simultaneously with orlistat surface-coated one deck inert material, has successfully solved the lower problem of preparation dissolution of prior art for preparing, and has solved sticking problem in the tabletting process.That is: the inventor creatively is equipped with powder material with the using supercritical fluid quick expansion legal system and solid dispersions technique combines, adopt the using supercritical fluid quick expansion legal system to be equipped with orlistat acrylic resin solid dispersion, orlistat is prepared into the unformed shape of micropowder, then that this solid dispersion and mixing acceptable accessories is even, granulate, dry, tabletting, can obtain not adding in the dissolution medium surfactant can stripping rapidly, the orlistat tablets of any surface finish, obtained beyond thought effect.
Description of drawings
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
Below be specific embodiments of the invention, technical scheme of the present invention is done further the 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
Orlistat, the acrylic resin of recipe quantity are dissolved in the dehydrated alcohol, on supercritical fluid equipment, by supercritical fluid CO2, are 10 microns nozzle decompression by the aperture fast, decompression time 10
-5Second, utilize the using supercritical fluid quick expansion legal system to be equipped with orlistat acrylic resin solid dispersion, dispersion D90＜10 μ m.
2. orlistat sheet preparation
With solid dispersion and microcrystalline Cellulose, polyvinylpolypyrrolidone mix homogeneously, it is an amount of to add pure water, granulate, and drying, dried granule is crossed 20 mesh sieves, and with the magnesium stearate mix homogeneously of recipe quantity, tabletting is promptly then.
Embodiment 2
1. solid dispersion preparation
Orlistat 120g
Acrylic resin 360g
Dehydrated alcohol 2000g
Orlistat, the acrylic resin of recipe quantity are dissolved in the dehydrated alcohol, on supercritical fluid equipment, by supercritical fluid CO2, are 10 microns nozzle decompression by the aperture fast, decompression time 10
-5Second, utilize the using supercritical fluid quick expansion legal system to be equipped with orlistat acrylic resin solid dispersion, dispersion D90＜10 μ m.
2. orlistat sheet preparation
With solid dispersion and microcrystalline Cellulose, polyvinylpolypyrrolidone mix homogeneously, it is an amount of to add pure water, granulate, and drying, dried granule is crossed 20 mesh sieves, and with the magnesium stearate mix homogeneously of recipe quantity, tabletting is promptly then.
Embodiment 3
1. solid dispersion preparation
Orlistat 120g
Acrylic resin 180g
Dehydrated alcohol 1000g
Orlistat, the acrylic resin of recipe quantity are dissolved in the dehydrated alcohol, on supercritical fluid equipment, by supercritical fluid CO2, are 10 microns nozzle decompression by the aperture fast, decompression time 10
-5Second, utilize the using supercritical fluid quick expansion legal system to be equipped with orlistat acrylic resin solid dispersion, dispersion D90＜10 μ m.
2. orlistat sheet preparation
With solid dispersion and microcrystalline Cellulose, polyvinylpolypyrrolidone mix homogeneously, it is an amount of to add pure water, granulate, and drying, dried granule is crossed 20 mesh sieves, and with the magnesium stearate mix homogeneously of recipe quantity, tabletting is promptly then.
The comparative example
1. the orlistat raw material is handled
Orlistat 120g
Dehydrated alcohol 1000g
The orlistat of recipe quantity is dissolved in the dehydrated alcohol, on supercritical fluid equipment, by supercritical fluid CO2, is 10 microns nozzle by the aperture fast, D90＜10 μ m.
2. orlistat sheet preparation
To handle back orlistat raw material and microcrystalline Cellulose, polyvinylpolypyrrolidone mix homogeneously, it is an amount of to add pure water, granulation, and drying, dried granule is crossed 20 mesh sieves, and with the magnesium stearate mix homogeneously of recipe quantity, tabletting is promptly then.
Checking embodiment
(1) conclusive evidence of orlistat crystal formation
The preparation of 1: 1 solid dispersion of orlistat acrylic resin
Orlistat 120g
Acrylic resin 120g
Dehydrated alcohol 100g
Orlistat, the acrylic resin of recipe quantity are dissolved in the dehydrated alcohol, on supercritical fluid equipment, by supercritical fluid CO2, are 10 microns nozzle decompression by the aperture fast, decompression time 10
-5Second, utilize the using supercritical fluid quick expansion legal system to be equipped with 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: after orlistat and acrylic resin formed solid dispersion, the orlistat endothermic peak disappeared on the DSC collection of illustrative plates, and this explanation dispersion forms; And the orlistat endothermic peak still exists in the mixture.
(2) dissolution method (2010 editions two appendix XC second methods of Chinese Pharmacopoeia) is that 1.2 hydrochloric acid solution 900ml are dissolution medium with pH, and rotating speed is 75 rev/mins, through 45 minutes, and sampling and measuring.Get solution 10ml and filter, according to high performance liquid chromatography (2010 editions two appendix VD of Chinese Pharmacopoeia measure).
| Embodiment | The 10min dissolution | The 45min dissolution |
| Embodiment 1 | 78.2％ | 98.2％ |
| Embodiment 2 | 82.3％ | 99.6％ |
| Embodiment 3 | 81.0％ | 98.9％ |
| The comparative example 1 | 5.1％ | 5.2％ |
It can be seen from the table, the tablet that utilizes the present invention to prepare, stripping is very fast in gastric acid; Although comparative example's 1 energy micropowder is below 10 μ m, owing to do not adopt solid dispersions technique, the orlistat raw material is the crystal formation attitude, and stripping is relatively poor.
Claims (8)
1. orlistat tablets, it is characterized in that: this tablet is made up of orlistat acrylic resin solid dispersion, disintegrating agent and other acceptable accessories, described orlistat acrylic resin solid dispersion adopts the 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: 0.5-3.
3. orlistat tablets according to claim 1 is characterized in that: the weight ratio of orlistat and acrylic resin is 1: 1-2.
4. orlistat tablets according to claim 1 is characterized in that: the weight ratio of orlistat and acrylic resin is 1: 1.5.
5. 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 the cross-linking sodium carboxymethyl cellulose.
6. orlistat tablets according to claim 1 is characterized in that: described disintegrating agent is a polyvinylpolypyrrolidone.
7. orlistat tablets according to claim 1 is characterized in that: described acceptable accessories is selected from one or more in microcrystalline Cellulose, lactose, mannitol, polyvidone, pregelatinized Starch, silicon dioxide, Pulvis Talci and the magnesium stearate.
8. method for preparing the described orlistat tablets of claim 1 is characterized in that: may further comprise the steps:
(1) acrylic resin, orlistat are dissolved in the ethanol;
(2) with supercritical CO
2And the solution of step (1) is 10 microns nozzle decompression by the aperture, decompression time 10
-5Second, form the orlistat acrylic resin solid dispersion fine powder of granularity less than 10 μ m;
(3) with the solid dispersion fine powder of step (2) gained and microcrystalline Cellulose, polyvinylpolypyrrolidone mix homogeneously, granulate, drying adds magnesium stearate, and the mixing tabletting promptly.
Priority Applications (1)
| 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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| 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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| CN103222964A true CN103222964A (en) | 2013-07-31 |
| CN103222964B CN103222964B (en) | 2014-10-08 |
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| CN201310032613.9A Expired - Fee Related CN103222964B (en) | 2013-01-29 | 2013-01-29 | Orlistat oral preparation and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105796567A (en) * | 2014-12-29 | 2016-07-27 | 北京万生药业有限责任公司 | Cetilistat solid dispersion and medicinal preparation prepared from the solid dispersion |
| CN109364033A (en) * | 2018-11-23 | 2019-02-22 | 南京泽恒医药技术开发有限公司 | A kind of mercaptopurine four divides chewable tablets 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 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105796567A (en) * | 2014-12-29 | 2016-07-27 | 北京万生药业有限责任公司 | Cetilistat solid dispersion and medicinal preparation prepared from the solid dispersion |
| 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 |
| CN109364033A (en) * | 2018-11-23 | 2019-02-22 | 南京泽恒医药技术开发有限公司 | A kind of mercaptopurine four divides chewable tablets 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 |
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| Publication number | Publication date |
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| CN103222964B (en) | 2014-10-08 |
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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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