CN102846566A - A duloxetine enteric-coated tablet and its preparation method - Google Patents
A duloxetine enteric-coated tablet and its preparation method Download PDFInfo
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- CN102846566A CN102846566A CN2011101822423A CN201110182242A CN102846566A CN 102846566 A CN102846566 A CN 102846566A CN 2011101822423 A CN2011101822423 A CN 2011101822423A CN 201110182242 A CN201110182242 A CN 201110182242A CN 102846566 A CN102846566 A CN 102846566A
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Abstract
The invention discloses a duloxetine enteric-coated tablet, comprising duloxetine and/or pharmaceutically acceptable salt thereof and adjuvants, the adjuvants including pH regulator and/or buffer pair and stabilizer. The pH regulator is selected from one or more of sodium citrate, sodium bisulfite, cysteine, sodium hydroxide, hydrochloric acid. The invention also discloses a preparation method for the duloxetine enteric-coated preparation. The duloxetine enteric-coated preparation prepared by the preparation method can maintain the related substrates in a low level during long-term storage, and has good dissolution property and stability and high bioavailability.
Description
Technical field
The invention belongs to drug world, relate to the solid pharmaceutical preparation of a kind of duloxetine or its pharmaceutically acceptable salt, and preparation method thereof.
Background technology
Duloxetine chemistry (S)-(+) by name-N-methyl-3-(1-naphthoxy)-3-(2-thienyl)-propylamine in the Drug therapy field, uses with the form of hydrochlorate usually, and the structural formula of duloxetine hydrochloride is as follows:
Duloxetine hydrochloride is a kind of selective serotonin and norepinephrine double-absorption inhibitor (SNRIs), present duloxetine hydrochloride pharmaceutical dosage form both domestic and external is mainly enteric coated tablet and enteric coated capsule, can be used for the treatment of depression, stress incontinence and diabete peripheral herve pains and other diseases.
Because duloxetine at sour environment, as unstable in the gastric juice, is degraded easily, usually duloxetine is prepared into enteric coated pharmaceutical preparation, such as enteric coatel tablets or enteric coated capsule, thereby postpone the release of medicine, the protection duloxetine is avoided the degraded of gastric acid.Duloxetine stable not ideal, have bibliographical information its with some pharmaceutic adjuvant compatibility after produce easily new impurity (related substance), in long term storage, impurity (related substance) also can continue to increase.And contain secondary amino group in the duloxetine structure, chemical property is comparatively active, easily react with fat, acid and anhydride etc., and duloxetine can form dissolving slowly with many enteric materials reactions that contain carboxyl or basic insoluble coating.There is technical literature to propose to select selectively enteric material, perhaps between enteric layer and medicine, adds and contain migration and the interaction that glucide and talcous sealing coat alleviate enteric coating material and duloxetine.Disclosed in the Chinese patent " LY-248686's enteric coated pill, ZL95108414.3 " such as Eli Lilly Company and adopted HPMC-AS-AS as the preparation method of the duloxetine hydrochloride enteric coated pill of enteric layer.The Chinese patent of Teva Pharmaceutical Industries Ltd " duloxetine hydrochloride delayed release formulations CN 101448493A " discloses the methacrylic acid copolymer enteric coating scheme that comprises sealing coat that adopts.The Chinese patent of Alphapharm Pty Ltd. " the sustained release pharmaceutical composition CN 101939004A of duloxetine " discloses the technical scheme that adopts control duloxetine granularity to prepare duloxetine enteric-coated preparation.
Summary of the invention
Because there is the aforementioned stable problem in duloxetine formulation, the object of the invention is to except duloxetine being made enteric coated preparation to resist the destruction of gastric juice to medicine, also should guarantee the stability of duloxetine formulation in preparation and storage, provide that a kind of release is good, bioavailability is high, the enteric coated tablet of dulouxetine agent of good stability.Said preparation can reduce as far as possible or avoid in storing process duloxetine produce degraded or and preparation in adjuvant interact, ensure drug quality.Described enteric coated duloxetine sheet does not dissolve in acid medium, active component does not discharge, and can dissolve fast release in neutrality to alkaline medium, and in the longer-term storage process, its impurity (related substance) maintains a reduced levels, and good stability is arranged.
For solving the problems of the technologies described above, the inventor adopts special preparation process to prepare enteric coated tablet of dulouxetine.Concrete, the present invention relates to following technical proposals:
The present invention relates to a kind of method for preparing enteric coated tablet of dulouxetine, it comprises: contain duloxetine and its esters label, be coated on the sealing coat on the label and be coated on the outer enteric layer of sealing coat.
Wherein said label comprises principal agent, binding agent, excipient, lubricant and stabilizing agent etc.Described principal agent is duloxetine or its esters, preferred duloxetine hydrochloride, and its concentration range in preparation is 8%～30% of label weight.Because duloxetine is slightly soluble in water, and the specification of its oral formulations is generally 20mg/ grain (sheet), 30mg/ grain (sheet), 40mg/ grain (sheet) and 60mg/ grain (sheet), for making it reach in vivo good release, find through test, the particle size range of control duloxetine raw material is: D[4,3]=2 μ m～40 μ m; D50=2 μ m～40 μ m; During D90=10 μ m～80 μ m, can guarantee effectively that in the intestinal juice environment medicine can discharge fully substantially in 45 minutes, improve dissolubility and the bioavailability of medicine.
Because duloxetine has unstable at sour environment, has simultaneously the chemical characteristic to some pharmaceutic adjuvant sensitivity.Through experimentation, discovery in label, add have the pH regulator effect chemical compound/buffering is right, perhaps one or more in the medicinal inorganic salt, perhaps micropowder silica gel is as stabilizing agent, can increase the chemical stability of preparation in the long-term storage process, control its related substance one in a small amount, reduce preparation to requirement and the dependence of inner packing.Find through overtesting, when adopting wet granulation technology technology well known in the art to prepare label, in binding agent or wetting agent, add pH in 6.2～7.8 pH adjusting agent or buffering to improving the stability of duloxetine formulation.Described binding agent or wetting agent are pharmaceutically acceptable solution, such as ethanol water of water, ethanol, ethanol water, polyvidone k30 etc.Described pH adjusting agent and buffering be to can be from routine, can play in the medicinal materials of pH regulator effect and choose, and it is right to cushion such as the pH adjusting agent such as sodium citrate, sodium sulfite, cysteine, sodium hydroxide, hydrochloric acid and salt thereof or soda acid.Described pH adjusting agent can be single pH adjusting agent, and it is right also to can be compound pH adjusting agent and buffering that two or more one-tenth are grouped into, preferably is selected from sodium citrate and sodium hydroxide, and its consumption is 0.1%～5.0% of label weight.
Except pH adjusting agent, stabilizing agent also can be selected from one or more of pharmaceutically acceptable inorganic salt, preferably is selected from calcium carbonate, and its consumption is 10%～60% of duloxetine weight.
The excipient that duloxetine enteric-coated preparation label among the present invention is selected can be the adjuvant of this area routine, but the principal agent of should getting along well reacts or affects its stability, as selecting mannitol, lactose, starch, sucrose, microcrystalline Cellulose etc. as main excipient.
Lubricant can select this area to commonly use adjuvant, such as in magnesium stearate, Pulvis Talci, stearic acid, calcium stearate, Polyethylene Glycol, sodium stearyl fumarate, micropowder silica gel, the docosane acid glyceride etc. one or more, preferred magnesium stearate, micropowder silica gel.What wherein the content of lubricant was better is to account for 0.5%～3.0% of label weight.
In the preparation of sheet slug particle, also can add disintegrating agent among the present invention, such as hyprolose, methylcellulose; Polyvinylpolypyrrolidone, carboxymethylstach sodium etc.
The preparation of label can be taked diverse ways as required, wet granulation such as routine, described wet granulation can carry out according to conventional steps and condition that this area belongs to the various method of granulating of wet granulation category, granulates (such as wobbler extruding, screw extrusion and rotary squeezing etc.), stirs and granulate and fluidized-bed spray granulation etc. such as extruding.Principal agent with after pharmaceutic adjuvant mixes, is added binding agent or wetting agent and granulates.
Among the present invention, the sealing coat filmogen can be selected the insolated layer materials of this area routine, better be selected from a kind of in hypromellose or hyprolose or the methylcellulose, also can add a certain proportion of filler, opacifier and plasticizer etc. simultaneously, can strengthen buffer action such as pharmaceutically useful sugar or sugar alcohol and Pulvis Talci, add titanium dioxide and can play interception.Preparation and the technique of sealing coat coating solution are generally, and with film former, are distributed in the water such as hypromellose, add filler and opacifier etc., cross 60 mesh sieves after stirring, and are prepared into the sealing coat coating solution.Label is set high in the effect coating pan, and the sheet bed tempertaure is about 30～60 ℃, evenly sprays into the coating solution coating.
Enteric layer among the present invention can be comprised of field of pharmaceutical preparations several enteric materials commonly used, plasticizer etc.Enteric material is preferentially selected one or more in acrylic resin, hypromellose acid esters succinate, the Hydroxypropyl methyl cellulose phtalate.Plasticizer can be selected one or both in triethyl citrate, the Polyethylene Glycol.Preparation and the technique of enteric layer coating solution are generally, and with enteric material, are distributed in the water such as acrylic resin, add plasticizer etc., and stirring, homogenize 5～10 minutes are prepared into the enteric layer coating solution.The label of wrapping sealing coat is set high in the effect coating pan, and the sheet bed tempertaure is about 30～50 ℃, evenly sprays into the coating solution coating.
Further, the invention provides a kind of duloxetine pharmaceutical preparation that is made by said method.
Among the present invention, above-mentioned each optimum condition, can be on the basis that meets this area general knowledge combination in any, get final product to get the preferred embodiments of the invention.
Among the present invention, agents useful for same and raw material be commercially available getting all.
Positive progressive effect of the present invention is:
(1) amount of related substance can obviously reduce in the duloxetine pharmaceutical preparation that obtains of preparation method of the present invention.(2) dissolution characteristic and the good stability of the duloxetine pharmaceutical preparation that obtains of preparation method of the present invention, bioavailability is high.(3) preparation method of the present invention is easy and simple to handle, cost is low, need not special installation, easily is applied to suitability for industrialized production.
The specific embodiment
The below further specifies the present invention with embodiment, but the present invention is not limited.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
Comparative example's 1 duloxetine hydrochloride (20mg/ sheet) prescription and preparation method:
Embodiment 1 duloxetine hydrochloride (20mg/ sheet) prescription and preparation method:
Embodiment 2 duloxetine hydrochlorides (20mg/ sheet) prescription and preparation method:
Embodiment 3 duloxetine hydrochlorides (20mg/ sheet) prescription and preparation method:
Embodiment 4 duloxetine hydrochlorides (20mg/ sheet) prescription and preparation method
Embodiment 5 duloxetine hydrochlorides (20mg/ sheet) prescription and preparation method
Embodiment 6 duloxetine hydrochlorides (40mg/ sheet) prescription and preparation method
Embodiment 7 duloxetine hydrochlorides (20mg/ sheet) prescription and preparation method
Effect embodiment 1:
Enteric coated preparation drug release determination method according to Chinese Pharmacopoeia two appendix in 2010, through behind the simulated gastric fluid, take phosphate buffer (pH6.8) 900ml as release medium, rotating speed is that per minute 100 turns, measure the release of the duloxetine hydrochloride of comparative example 1 and embodiment 1, the stripping quantity that calculates every is recorded in following table:
Effect embodiment 2:
Duloxetine hydrochloride is set high in the density polyethylene plastic bottle, and sealing is put into and is accelerated to investigate case, in 40.0 ℃ ± 2.0 ℃ of temperature, places six months under relative humidity 75% ± 5% condition, and its stability is investigated in contrast.
Assay method: take phosphate buffer (pH value 5.8)-acetonitrile (63: 37) as mobile phase, the detection wavelength is 230nm, precision is measured sample solution injection liquid chromatography, and the record chromatogram is to 2 times of main constituent peak retention time, and its result data sees the following form:
Claims (8)
1. the preparation method of an enteric coated tablet of dulouxetine agent is characterized in that comprising:
(a) particle size range of duloxetine and its esters is D50=2 μ m～40 μ m;
(b) adjuvant in the label comprise pH adjusting agent, buffering to one or more of stabilizing agent;
(c) between label and the enteric layer sealing coat is arranged;
(d) at sealing coat and cushion outside enteric layer is arranged.
2. enteric coated tablet as claimed in claim 1, it is characterized in that containing in the label pH adjusting agent or cushion right.
3. enteric coated tablet as claimed in claim 1 is characterized in that the stabilizing agent that contains in the label is calcium carbonate.
4. enteric coated tablet as claimed in claim 2, it is right to it is characterized in that pH adjusting agent is selected from the pH adjusting agent such as sodium citrate, sodium sulfite, cysteine, sodium hydroxide, hydrochloric acid and salt or soda acid buffering thereof.
5. enteric coated tablet as claimed in claim 2 is characterized in that its pH adjusting agent is selected from sodium citrate, sodium sulfite and sodium hydroxide.
6. enteric coated tablet as claimed in claim 2, it is characterized in that pH adjusting agent or cushioning right pH scope is 6.2～7.8.
7. enteric coated tablet as claimed in claim 3, the consumption of calcium carbonate accounts for 10%～60% of duloxetine weight.
8. the duloxetine medicinal tablet that is made by each described preparation method among the claim 1-7.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101822423A CN102846566A (en) | 2011-06-30 | 2011-06-30 | A duloxetine enteric-coated tablet and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011101822423A CN102846566A (en) | 2011-06-30 | 2011-06-30 | A duloxetine enteric-coated tablet and its preparation method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103127023A (en) * | 2013-03-01 | 2013-06-05 | 南京正宽医药科技有限公司 | Duloxetine hydrochloride enteric-coated tablet and preparation method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1883473A (en) * | 2005-06-22 | 2006-12-27 | 北京德众万全医药科技有限公司 | An enteric coated tablet of dulouxetine |
| CN101190208A (en) * | 2006-11-30 | 2008-06-04 | 石药集团中奇制药技术（石家庄）有限公司 | Medicinal preparations containing duloxetine hydrochloride and preparation method thereof |
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2011
- 2011-06-30 CN CN2011101822423A patent/CN102846566A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1883473A (en) * | 2005-06-22 | 2006-12-27 | 北京德众万全医药科技有限公司 | An enteric coated tablet of dulouxetine |
| CN101190208A (en) * | 2006-11-30 | 2008-06-04 | 石药集团中奇制药技术（石家庄）有限公司 | Medicinal preparations containing duloxetine hydrochloride and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103127023A (en) * | 2013-03-01 | 2013-06-05 | 南京正宽医药科技有限公司 | Duloxetine hydrochloride enteric-coated tablet and preparation method |
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Application publication date: 20130102 |