CN104107169A - Duloxetine hydrochloride medicinal composition and a preparation method thereof - Google Patents
Duloxetine hydrochloride medicinal composition and a preparation method thereof Download PDFInfo
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- CN104107169A CN104107169A CN201410337195.9A CN201410337195A CN104107169A CN 104107169 A CN104107169 A CN 104107169A CN 201410337195 A CN201410337195 A CN 201410337195A CN 104107169 A CN104107169 A CN 104107169A
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Abstract
The invention discloses a duloxetine hydrochloride enteric medicinal composition. The composition comprises a drug-loaded pellet containing duloxetine hydrochloride (a), an isolation layer (b), an enteric layer (c) and a modified layer (d), wherein the isolation layer comprises a collapse layer and a separation layer. The invention further discloses a preparation method of the medicinal composition.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of Duloxetine hydrochloride drug composition and preparation method thereof.
Background technology
Duloxetine hydrochloride capsule (Duloxetine HCl) is 5-hydroxy tryptamine and NRI (SNRI) double inhibitor by Lilly Co., Eli. (Eli Lilly and Company) invention, be used for the treatment of severe depression, stress incontinence and diabete peripheral herve pain, specification is 20mg, 30mg and 60mg.Its commodity be called " glad hundred reach " (
).Duloxetine hydrochloride molecular formula is C
18h
19nOSHCl, molecular weight is 333.88, its molecular structural formula is as follows:
According to the application documents NDA.appl.No21427 of disclosed Li Lai company of united states drug food Surveillance Authority (FDA),
for containing the capsule of duloxetine hydrochloride enteric coated micropill, in its preparation prescription, contain active ingredient hydrochloric acid duloxetine (Duloxetine HCl) and non-active ingredient hydroxypropyl emthylcellulose, hydroxypropyl methylcellulose acetate succinate, sucrose, sugared ball, Pulvis Talci, titanium dioxide, triethyl citrate, sodium lauryl sulphate, gelatin, FD & C Blue No.2 and iron oxide yellow.
The former patent CN1106191C that grinds of China discloses LY-248686's enteric coated pill, and it comprises: medicated core a) being made up of duloxetine and pharmaceutically acceptable excipient; B) dispensable sealing coat; C) enteric layer that contains Hydroxypropyl Methyl Cellulose Phthalate and pharmaceutically acceptable excipient; D) dispensable decorative layer.Said preparation uses specific Hydroxypropyl Methyl Cellulose Phthalate as enteric layer, and in the situation that using acetic acid hypromellose succinic acid, need to pass through ammonia neutralization polymer.As everyone knows, ammonia has strong impulse, and ammonia is volatile simultaneously, is difficult to accurate weighing in production process.
Chinese patent CN100362996C provide a kind of duloxetine enteric coated tiny pill capsule and preparation method thereof, and this patent discloses a kind of enteric coated micropill, for ensureing duloxetine stripping, and the duloxetine hydrochloride medicine-feeding layer that this patent adopts solid dispersion technology to prepare.This technology adopts poloxamer to be dissolved in appropriate alcoholic solution, adds recipe quantity duloxetine, dextran, galactose to dry in baking oven and makes duloxetine solid dispersion.This preparation process adopts more complicated solid dispersions technique to prepare active layer, needs to use dehydrated alcohol organic solvent simultaneously.
Chinese patent CN101686947A provides a kind of duloxetine formulation, and this patent discloses a kind of duloxetine enteric-coated preparation of being prepared as enteric material by specific enteric material hydroxypropyl methylcellulose phthalate (HPMCP).
Chinese patent CN101448493A provides a kind of duloxetine hydrochloride delayed release (slow release) preparaton, adopt at least one specific enteric material to be selected from hydroxypropyl methylcellulose phthalate (HPMCP) and methacrylic acid copolymer enteric material is prepared from, wherein duloxetine and PVP need be dissolved in the coating of adding medicine to after 95% ethanol and purified water.Owing to using in process of production 95% ethanol, therefore in production process, need special antiknock device.
Therefore, we wish to develop a kind of duloxetine hydrochloride enteric coated pill core, it has been coated with coated special functional sealing coat on the ball core that contains duloxetine hydrochloride biological active substances, can adapt to enteric material arbitrarily, and do not need active substance duloxetine hydrochloride to adopt the method for special preparation to be processed, and in production process without using the organic solvent such as ethanol, produce widely adaptability and lower production cost thereby have, there is more preferably commercial significance.
Summary of the invention
Duloxetine hydrochloride enteric-coated composition provided by the present invention, comprise ball core, (b) that (a) contain duloxetine hydrochloride and surround duloxetine hydrochloride sealing coat, (c) enteric layer, (d) decorative layer containing pill core, wherein sealing coat comprises cave in layer and stratum disjunctum.
For duloxetine hydrochloride enteric coated preparation, there is beyond thought cross reaction in the enteric material of itself causing due to the acid labile of duloxetine hydrochloride and acidic-group, therefore between duloxetine hydrochloride and enteric layer, need a stratum disjunctum, this stratum disjunctum can effectively be isolated duloxetine hydrochloride and enteric layer, makes it to become effective enteric coated preparation.
According to duloxetine hydrochloride enteric-coated medicament combination provided by the present invention; wherein the sealing coat of duloxetine hydrochloride enteric coated micropill plays special dual structure effect; 1) play isolation enteric layer and medicated layer; prolection composition duloxetine hydrochloride is stable at enteric material arbitrarily; 2) work the effect of caving in, promote the release of duloxetine hydrochloride.
Duloxetine hydrochloride has the acid labile of height, and enteric dosage form is its best dosage form.But duloxetine hydrochloride reacts with the acidic-group in many known enteric materials, form to dissolve and even can not dissolve slowly coating.The patent US5508276 of Lilly Co., Eli. discloses duloxetine hydrochloride enteric coated pill, adopts Hydroxypropyl Methyl Cellulose Phthalate (HPMCAS) as enteric coating in ball.In order to reduce reacting between active substance and Hydroxypropyl Methyl Cellulose Phthalate (HPMCAS) acidic-group; select the special same type of material of succinyl group between 4-28% that have, therefore in production process, need to use the acid group of ammonia neutralization part.The inventor finds through research and development, when duloxetine hydrochloride is containing the special stratum disjunctum of pill core outsourcing, thereby ensure effective isolating active composition duloxetine and enteric material within the medicine storage life, reach the stability that improves duloxetine hydrochloride in duloxetine hydrochloride enteric coated capsule.
According to the present invention, " stratum disjunctum " refers to the separation duloxetine hydrochloride being mainly made up of water-soluble film forming agent and highly-water-soluble solid micro-powder excipient containing the inert layer between pill core and enteric layer, it can stop duloxetine hydrochloride and enteric material to produce cross reaction, produces the defect of drug release aspect.
Chinese patent CN100362996C provide a kind of duloxetine enteric coated tiny pill capsule and preparation method thereof, and this patent discloses a kind of enteric coated micropill, for ensureing duloxetine stripping, and the duloxetine hydrochloride medicine-feeding layer that this patent adopts solid dispersion technology to prepare.The inventor finds through research, employing cave in layer can impel the casing of duloxetine hydrochloride enteric coated preparation to dissolve fast and effectively, and then can solve the defect of duloxetine hydrochloride enteric coated preparation drug release aspect, and be applicable to commonly use arbitrarily enteric material, have and produce widely adaptability, be more suitable for commercially producing, its commercial significance is self-evident.
The inventor finds through research, duloxetine hydrochloride carries pill core and does not contain and cave in layer or contain the layer that caves in not containing stratum disjunctum containing stratum disjunctum, the drug release aspect of duloxetine hydrochloride enteric coated capsule is all partially slow, and duloxetine hydrochloride carries pill core and only comprises stratum disjunctum outward and cave in a layer rear guarantee duloxetine hydrochloride release.
According to the present invention, " layer caves in " refers to and directly sticks to the coatings that duloxetine hydrochloride is easily peeled off containing pill core outward, it is characterized in that its rete contains water-soluble film forming agent and highly-water-soluble solid micro-powder excipient in forming, wherein water-soluble film forming agent is low concentration, highly-water-soluble solid micro-powder excipient is high concentration, thereby there is a large amount of capillary tube holes, under capillary tube hydration, can dissolve rapidly and leave containing pill core, take away the enteric layer of surface coverage simultaneously, thus the impact of avoiding enteric layer to discharge carrying pill core.But in the layer that caves in, capillary tube hole also will cause duloxetine hydrochloride enteric coated preparation to occur the defect of drug release aspect, reason be small-molecule active substance duloxetine hydrochloride can move out capillary tube hole contact with active substance produce disadvantageous cross reaction, affect the release of duloxetine hydrochloride enteric coated preparation.
According to the present invention; term " stratum disjunctum " refers to the coatings that is enclosed in the layer outside that cave in; it is characterized in that in its rete formation, water-soluble film forming agent is high concentration; thereby have height compactness; form the protective layer of one deck densification in the outside of " layer caves in ", hinder active component and overflow and contact the defect that occurs drug release aspect with enteric layer by a large amount of capillary tube hole in " layer caves in ".Thereby ensure that from designing duloxetine hydrochloride enteric coated pill core can be with the preparation of enteric material arbitrarily.
According to the present invention, the water-soluble film forming agent of composition " sealing coat " is selected from hypromellose, hyprolose, polyvidone, polyvinyl alcohol.
According to the present invention, the highly-water-soluble solid micro-powder excipient of composition " sealing coat " is selected from one or more in mannitol, galactose, maltose, lactose and sucrose.
According to the present invention, the water-soluble film forming agent of composition " sealing coat " and highly-water-soluble solid micro-powder excipient are applied to duloxetine hydrochloride containing on pill core by being configured to coating soln using film coating procedure.This type of coating solution can be prepared, also can on market, obtain, and for example film coating pre-mix dose Opadry AMB, YS17006, OY-B-28920,03K19229, by Colorcon, Ltd.us (U.S.) manufactures.
According to the present invention, the water-soluble film forming agent that forms " layer caves in " is low concentration, and its concentration is the highest is no more than 25%, preferably not higher than 15%, most preferably not higher than 5%.
According to the present invention, the amount of " cave in layer " is the duloxetine hydrochloride amount 25%-45% (w/w) that contains pill core, is preferably 30%-40% (w/w).
According to the present invention, the water-soluble film forming agent that forms " stratum disjunctum " is high concentration, and its concentration is minimum is not less than 50%, is preferably not less than 70%, is most preferably not less than 90%.
According to the present invention, the amount of " stratum disjunctum " is layer 10%-40% (w/w) for amount that cave in, and is preferably 15%-35% (w/w).
According to the present invention, what " w/w " represented is mass ratio.
According to duloxetine hydrochloride enteric-coated composition provided by the present invention, its enteric coating is selected from enteric material arbitrarily, is preferably methacrylic resin, Hydroxypropyl Methyl Cellulose Phthalate, HP-55.This type of coating solution can be prepared, and also can on market, obtain, and for example L30D-55 is by Evonik Degussa., and that Ltd. (Germany) manufactures, 93A18925 is by Colorcon., and Ltd.us (U.S.) manufactures.
Therefore, in depth say, the object of the invention is to use the duloxetine hydrochloride enteric coated pill core of special insulation layer structure can adopt any enteric material to produce, production better adaptability, thereby be more suitable for commercially producing.
According to the preparation method of duloxetine hydrochloride enteric-coated medicament combination of the present invention, comprise following process:
A. on celphere, use the coating solution that contains duloxetine hydrochloride and binding agent to carry out coating, obtain containing duloxetine hydrochloride ball core;
B. on the medicine carrying micropill that contains duloxetine hydrochloride, use the coating solution that contains water-soluble film forming agent, excipient and antiplastering aid to carry out coating, obtain being surrounded by medicine layer and the medicine carrying micropill of the layer that caves in;
C. be surrounded by medicine layer and the medicine carrying micropill of the layer that caves on use the coating solution that contains water-soluble film forming agent, obtain being surrounded by medicine layer, layer and the medicine carrying micropill of stratum disjunctum cave in;
D. being surrounded by medicine layer, use the coating solution that contains enteric material to carry out coating on the ball core of cave in layer and stratum disjunctum, obtain duloxetine hydrochloride enteric coated pill core;
E. on duloxetine hydrochloride enteric coated pill core, use the stomach dissolution type coating solution with humidity resistance to carry out coating.
Detailed description of the invention
By following specific embodiment, can more specific description the present invention.But the present invention is not limited to following examples.
Embodiment
According to the application documents NDA.appl.No21427 of disclosed Lilly Co., Eli. of united states drug food Surveillance Authority (FDA), adopt following stripping assay method to evaluate above-mentioned preparation.
This result shows, duloxetine hydrochloride enteric coated micropill provided by the invention is applicable to enteric material arbitrarily, has splendid productibility.
Claims (10)
1. a duloxetine hydrochloride enteric-coated medicament combination, is characterized in that comprising the medicine carrying micropill that (a) contains duloxetine hydrochloride; (b) sealing coat; (c) enteric layer; (d) decorative layer, wherein sealing coat comprises cave in layer and stratum disjunctum.
2. duloxetine hydrochloride enteric-coated medicament combination according to claim 1, is characterized in that the described layer that caves in is mainly made up of water-soluble film forming agent, highly-water-soluble solid micro-powder excipient and antiplastering aid.
3. duloxetine hydrochloride enteric-coated medicament combination according to claim 2, is characterized in that the described water-soluble film forming agent caving in layer is low concentration, the highest 25% (w/w) that be no more than of its concentration.
4. duloxetine hydrochloride enteric-coated medicament combination according to claim 3, is characterized in that the consumption of the described layer that caves in is the 25%-45% (w/w) of duloxetine hydrochloride pastille micropill consumption.
5. duloxetine hydrochloride enteric-coated medicament combination according to claim 1, it is characterized in that surround cave in layer stratum disjunctum in water-soluble film forming agent be high concentration, its concentration is minimum is not less than 50%.
6. duloxetine hydrochloride enteric-coated medicament combination according to claim 1, it is characterized in that stratum disjunctum with respect to the weight ratio of the layer that caves in is 0.1: 1 to 0.4: 1.
7. according to the duloxetine hydrochloride enteric-coated medicament combination described in claim 2 and 5, it is characterized in that water-soluble film forming agent is selected from one or more in hypromellose, hyprolose, polyvidone, polyvinyl alcohol.
8. duloxetine hydrochloride enteric-coated medicament combination according to claim 2, is characterized in that highly-water-soluble solid micro-powder excipient is selected from one or more in mannitol, galactose, maltose, lactose and sucrose.
9. duloxetine hydrochloride enteric-coated medicament combination according to claim 1, is characterized in that described enteric layer is selected from the one in methacrylic resin, Hydroxypropyl Methyl Cellulose Phthalate, HP-55.
10. prepare a method for duloxetine hydrochloride enteric-coated medicament combination as claimed in claim 1, comprise following process:
A. on celphere, use the coating solution that contains duloxetine hydrochloride and binding agent to carry out coating, obtain containing duloxetine hydrochloride ball core;
B. on the medicine carrying micropill that contains duloxetine hydrochloride, use the coating solution that contains water-soluble film forming agent, excipient and antiplastering aid to carry out coating, obtain being surrounded by medicine layer and the medicine carrying micropill of the layer that caves in;
C. be surrounded by medicine layer and the medicine carrying micropill of the layer that caves on use the coating solution that contains water-soluble film forming agent, obtain being surrounded by medicine layer, layer and the medicine carrying micropill of stratum disjunctum cave in;
D. being surrounded by medicine layer, use the coating solution that contains enteric material to carry out coating on the ball core of cave in layer and stratum disjunctum, obtain duloxetine hydrochloride enteric coated pill core;
E. on duloxetine hydrochloride enteric coated pill core, use the stomach dissolution type coating solution with humidity resistance to carry out coating.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410337195.9A CN104107169A (en) | 2014-07-12 | 2014-07-12 | Duloxetine hydrochloride medicinal composition and a preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410337195.9A CN104107169A (en) | 2014-07-12 | 2014-07-12 | Duloxetine hydrochloride medicinal composition and a preparation method thereof |
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| CN104107169A true CN104107169A (en) | 2014-10-22 |
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| CN201410337195.9A Pending CN104107169A (en) | 2014-07-12 | 2014-07-12 | Duloxetine hydrochloride medicinal composition and a preparation method thereof |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080226711A1 (en) * | 2007-03-12 | 2008-09-18 | Torrent Pharmaceuticals Ltd. | Pharmaceutical compositions of duloxetine |
| WO2011006670A1 (en) * | 2009-07-17 | 2011-01-20 | Add Technologies Ltd. | Separating layers for pharmaceutical preparations to prevent interactions between medicinal drugs and pharmaceutical-technological adjuvants |
| CN102908331A (en) * | 2011-08-01 | 2013-02-06 | 浙江九洲药物科技有限公司 | Duloxetine hydrochloride enteric capsules and preparation method thereof |
| CN103211777A (en) * | 2013-03-31 | 2013-07-24 | 北京万全阳光医学技术有限公司 | Pharmaceutic preparation of duloxetine hydrochloride and preparation method thereof |
| CN103393615A (en) * | 2013-07-24 | 2013-11-20 | 海南华益泰康药业有限公司 | Duloxetine enteric pellet and preparation method thereof |
| CN103565749A (en) * | 2012-07-26 | 2014-02-12 | 重庆药友制药有限责任公司 | Duloxetine hydrochloride enteric pellet and preparation method thereof |
-
2014
- 2014-07-12 CN CN201410337195.9A patent/CN104107169A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080226711A1 (en) * | 2007-03-12 | 2008-09-18 | Torrent Pharmaceuticals Ltd. | Pharmaceutical compositions of duloxetine |
| WO2011006670A1 (en) * | 2009-07-17 | 2011-01-20 | Add Technologies Ltd. | Separating layers for pharmaceutical preparations to prevent interactions between medicinal drugs and pharmaceutical-technological adjuvants |
| CN102908331A (en) * | 2011-08-01 | 2013-02-06 | 浙江九洲药物科技有限公司 | Duloxetine hydrochloride enteric capsules and preparation method thereof |
| CN103565749A (en) * | 2012-07-26 | 2014-02-12 | 重庆药友制药有限责任公司 | Duloxetine hydrochloride enteric pellet and preparation method thereof |
| CN103211777A (en) * | 2013-03-31 | 2013-07-24 | 北京万全阳光医学技术有限公司 | Pharmaceutic preparation of duloxetine hydrochloride and preparation method thereof |
| CN103393615A (en) * | 2013-07-24 | 2013-11-20 | 海南华益泰康药业有限公司 | Duloxetine enteric pellet and preparation method thereof |
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Application publication date: 20141022 |