CN105534949A - Duloxetine hydrochloride enteric mini-pill preparation - Google Patents
Duloxetine hydrochloride enteric mini-pill preparation Download PDFInfo
- Publication number
- CN105534949A CN105534949A CN201610002251.2A CN201610002251A CN105534949A CN 105534949 A CN105534949 A CN 105534949A CN 201610002251 A CN201610002251 A CN 201610002251A CN 105534949 A CN105534949 A CN 105534949A
- Authority
- CN
- China
- Prior art keywords
- copolymer
- duloxetine hydrochloride
- pharmaceutically acceptable
- methacrylic acid
- enteric
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- 229960002496 duloxetine hydrochloride Drugs 0.000 title claims abstract description 36
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- QMBJSIBWORFWQT-DFXBJWIESA-N Chlormadinone acetate Chemical compound C1=C(Cl)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 QMBJSIBWORFWQT-DFXBJWIESA-N 0.000 title abstract 4
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- 125000004494 ethyl ester group Chemical group 0.000 claims description 4
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 claims description 4
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- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 abstract description 8
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- 229940034706 duloxetine 60 mg Drugs 0.000 description 4
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- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 4
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- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 2
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- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a duloxetine hydrochloride enteric mini-pill preparation. Mini-pills include medicine-carrying pill cores, isolation coating layers, enteric coating layers and dispensable modification layers. When a relatively common methyl acrylic copolymer is adopted as an enteric material in a prescription, the purpose that an in-vitro dissolution curve of active ingredients is consistent to positive control medicine Cymbalta is achieved by adding sorbitol into the isolation layers. The duloxetine hydrochloride enteric mini-pill preparation adopts medicinal acrylic resin which is marked with medicinal registration batch number and easy to obtain as an enteric material. An adopted conventional preparation method and a process are simple, the duloxetine hydrochloride enteric mini-pill preparation is suitable for industrial production, and a medicine reasonable in price and reliable in treating effect is provided for patients suffering from depression.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of enteric coated pellets formulation of duloxetine hydrochloride.
Background technology
Duloxetine hydrochloride (DuloxetineHydrochloride, API) an effective 5-hydroxy tryptamine and the norepinephrine double-absorption inhibitor of Cure of depression is used to, chemical name is: s-(+)-N-methyl-3-(1-naphthyl oxygen base)-3-(2-thienyl)-propylamin hydrochloride, and its structural formula is:
Duloxetine hydrochloride is white or off-white color crystalline powder or powder, is slightly soluble in water, unstable under acidic condition, is easy to degraded, so be suitable for making enteric coated preparation to resist the destruction of gastric juice to medicine.
Li Lai house journal US5508276 discloses a kind of enteric coated micropill of duloxetine, comprising medicated core a) be made up of duloxetine and pharmaceutically acceptable excipient; B) dispensable sealing coat; C) enteric coating layer containing hydroxypropylmethylcellulose acetate cellulose hemisuccinate ester (HPMCAS) and pharmaceutically useful excipient; D) dispensable decorative layer.Preferably add sugar in the isolation layer, can acid resistance be improved, the effect of diffusion barrier can also be played, to stop the migration being dissolved in medicated core in product moisture content or enteric coating layer component.This patent selects HPMCAS as enteric material, need below sub-cooled to 20 DEG C, and yield is lower when implementing with the form of suspension.In patent, public technology scheme is for carry out part neutralization with ammonia to material, can promote that HPMCAS dissolves, but adopts the mode of ammonia neutralization to be not easy to industrial production operation, and can cause certain pollution to environment.
Zhongqi Pharmaceutical Technology (Shijiazhuang) Co. Ltd. of Shiyao Group patent CN103505421A discloses a kind of enteric coated micropill of duloxetine, medicated core a) be made up of duloxetine and pharmaceutically acceptable excipient; B) dispensable sealing coat; C) containing methacrylic acid copolymer as enteric material.Add sugar alcohol in the isolation layer and prepare micropill, the In Vitro Dissolution curve of pellet preparations is consistent with positive control drug (glad hundred of Li Lai company reaches), reaches good result of extraction.Add in sealing coat sugar alcohol be selected from mannitol, xylitol, maltose alcohol one or more, wherein preferred mannitol.Sorbitol is not mentioned in its claim.And whether specific requirement is made to the particle diameter of crude drug.Wherein patent Example 1 is:
Duloxetine hydrochloride enteric coated preparation disclosed in patent US5508276 exists that production cost is high, technique is unfavorable for the problems such as commercial production, and HPMCAS is not easy to buy.And the open duloxetine hydrochloride enteric coated preparation technique of patent CN103505421A is relatively simpler than the technique of Li Lai company, be more suitable for suitability for industrialized production.Enteric material is methacrylic acid copolymer (trade name MAE-30-DP), and it is the copolymer (1: 1) of methacrylic acid-acrylic acid ethyl ester, a kind of low viscous milky aqueous dispersion.
Summary of the invention
There is many advantages in medicinal acrylic resin as enteric material, commercial have many types, if drug dissolution problem can be solved, cheap medicine can be provided, so the present invention adopts medicinal acrylic resin to develop Duloxetine hydrochloride enteric pellet preparation equally for patient.
The present inventor finds in development process, preparing micropill, reaching good result of extraction based on adding mannitol in patent CN103505421A sealing coat.Sealing coat adopts sorbitol (isomers of mannitol), when in prescription, enteric material is methacrylic acid copolymer, and the In Vitro Dissolution curve of the pellet preparations of preparation and the similar of positive control drug (glad hundred of Li Lai company reaches).And in June accelerated test, by comparing the content of related substance in the acceleration situation of change of 6 months, enteric coated micropill stability of the present invention is better than the pellet preparations of embodiment 1 in patent CN103505421A.
Therefore, the invention provides a kind of Duloxetine hydrochloride enteric pellet preparation, forming by carrying pill core, contagion gown layer, enteric coating layer and dispensable decorative layer.
Described duloxetine hydrochloride raw material granularity distribution D90 is less than 200 microns, more preferentially, is less than 40 microns, is preferably less than 25 microns further, be most preferably less than 15 microns.
The described pill core that carries is made up of celphere and the duloxetine hydrochloride be wrapped in outside celphere and pharmaceutically acceptable adjuvant.Wherein said celphere is sugar pill, starch ball, lactose ball, lactose/starch ball, sucrose/starch ball, silicon dioxide ball, microcrystalline Cellulose ball; Described pharmaceutically acceptable adjuvant be selected from hydroxypropyl emthylcellulose (HPMC), polyvinyl pyrrolidone one or both, one or both in preferred hydroxypropyl emthylcellulose, polyvinyl pyrrolidone (PVP).
Described contagion gown layer is wrapped in and carries outside pill core, plays the effect preventing medicine from contacting with the enteric coating layer containing acidic-group, ensures the stability of medicine.Described contagion gown layer compound mode has 2 kinds: contagion gown layer compound mode 1): sorbitol and pharmaceutically acceptable adjuvant composition; Contagion gown layer compound mode 2): sorbitol and the one or more combination thing in other sugar alcohol (mannitol, xylitol, maltose alcohol) and and pharmaceutically acceptable adjuvant composition.Contagion gown layer compound mode be sorbitol and pharmaceutically acceptable adjuvant composition most preferably.Described sorbitol can promote the release of duloxetine hydrochloride.Described pharmaceutically acceptable adjuvant comprises water-soluable gel material and antiplastering aid, wherein water-soluable gel material is selected from one or more in hydroxypropyl emthylcellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose (HPC), preferred hydroxypropyl emthylcellulose, antiplastering aid be selected from Talcum (Talc), micropowder silica gel one or both, preferably talc.
Described enteric coating layer is wrapped in outside contagion gown layer, is made up of, plays and prevent medicine from discharging under one's belt and causing medicine by the effect of stomach acids destroy medicinal acrylic resin and pharmaceutically acceptable adjuvant.The Antacid effectiveness of the thickness major effect medicine of enteric layer and dissolution rate.Medicinal acrylic resin is selected from the one or more combination thing of following kinds, concrete kind is: butyl methacrylate, Dimethylaminoethyl Methacrylate and methyl methacrylate (1: 2: 1) copolymer (especially strange E100, methacrylic acid aminoalkyl ester copolymer E type); Methacrylic acid and ethyl acrylate (1: 1) copolymer (methacrylic acid copolymer C type, EUDRAGIT L100-55 aqueous dispersion); Methacrylic acid and methyl methacrylate (1: 1) copolymer (methacrylic acid copolymer A type); Methacrylic acid and methyl methacrylate (1: 2) copolymer (methacrylic acid copolymer Type B); Ethyl acrylate, methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester (1: 2: 0.2) copolymer (ammonio methacrylate copolymer A type); Ethyl acrylate, methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester (1: 2: 0.1) copolymer (ammonio methacrylate copolymer Type B, ammonio methacrylate copolymer Type B); Ethyl acrylate and methyl methacrylate (2: 1) copolymer (EUDRAGIT NE 30 D EUDRAGIT NE 30D aqueous dispersion); Methacrylic acid, acrylic acid methyl ester. and methyl methacrylate (1: 1: 1) copolymer.Further preferable methyl acrylic acid and ethyl acrylate (1: 1) copolymer (EUDRAGIT L100-55 aqueous dispersion), trade name: especially strange L30D-55; MAE30DP.Most preferably especially strange L30D-55.Described pharmaceutically acceptable adjuvant comprises plasticizer and antiplastering aid, wherein the Main Function of plasticizer is the vitrification point reducing coating material, and increase its toughness, be selected from one or more in triethyl citrate (TEC), tributyl citrate, glycerol triacetate, tributyl 2-acetylcitrate, optimization citric acid triethyl (TEC), described antiplastering aid is selected from one or more in Talcum (Talc), micropowder silica gel, glyceryl monostearate, preferably talc (Talc).
Herein, except as otherwise noted, all percentage ratio, ratio, ratio etc. are all come in unit of weight.
The diameter of described celphere is 0.15 ~ 1.18mm, further preferred 0.3 ~ 0.8mm, and the diameter of described Duloxetine hydrochloride enteric pellet is 0.5 ~ 1.5mm.
Described contagion gown layer is weightening finish 10% ~ 50% on the basis of carrying pill core.
The weightening finish 15% ~ 40% on the basis of isolation ball core of described enteric coating layer.
The weightening finish 0% ~ 15% on the basis of isolation ball core of described decorative layer.
The preparation method of enteric coated pellets formulation of the present invention comprises the steps:
(1) pill core is carried in preparation: be suspended in pharmaceutically acceptable adjuvant by duloxetine hydrochloride, be wrapped on celphere, is prepared into and carries pill core;
(2) bag contagion gown layer: by sorbitol and pharmaceutically acceptable auxiliary materials and mixing, what be wrapped in prepared by step (1) carries on pill core, obtains isolating drug-loaded pellets;
(3) enteric-coating layer: methacrylic acid copolymer joined in the acceptable adjuvant of pharmacy and mix, is wrapped on isolation drug-loaded pellets prepared by step (2);
(4) dispensable decorative layer:
(5) dry.
The enteric coated pellets formulation of duloxetine hydrochloride provided by the invention adopts methacrylic acid copolymer as enteric material, this material is easily buied, cost is lower, and when contagion gown layer uses sorbitol, what its dissolution rate and preparation stability can reach gift to list a company glad hundred reaches consistent effect.Dissolution is high, while reducing costs, ensure that curative effect, and the present invention can take conventional preparation method, and technique is simple, is applicable to suitability for industrialized production, can provides reasonable price, curative effect reliable medicine for patients with depression.In June accelerated test, increase situation by the content comparing related substance, enteric coated micropill stability of the present invention is better than the pellet preparations of embodiment 1 in patent CN103505421A.Compared with patent CN103505421A, creative primary formulation stability of the present invention is significantly increased.
Accompanying drawing explanation
Fig. 1 is the comparison diagram of embodiment 1 and positive control drug (glad hundred reach) stripping curve;
Fig. 2 is the comparison diagram of embodiment 2 and positive control drug (glad hundred reach) stripping curve;
Fig. 3 is the comparison diagram of embodiment 3 and positive control drug (glad hundred reach) stripping curve;
Fig. 4 is the comparison diagram of comparative example 1 and positive control drug (glad hundred reach) stripping curve;
Fig. 5 is the comparison diagram of comparative example 2 and positive control drug (glad hundred reach) stripping curve;
Detailed description of the invention
The following examples give the concrete prescription of several enteric coated pellets formulation and preparation technology, but should as the restriction to content of the present invention.
In dissolved corrosion comparison, 2 kinds of comparative examples are given at this, be respectively the comparative example 1 that sealing coat does not add sorbitol, sealing coat adopts Polyethylene Glycol to substitute the comparative example 2 of sugar alcohol, when measuring embodiment and comparative example stripping curve, glad hundred to reach (every capsules is containing 60mg duloxetine) gone on the market is adopted as positive control drug, to be contrasted by dissolved corrosion.
In stability comparison, 1 kind of comparative example (comparative example 3) is given at this, adopt glad hundred to reach (every capsules is containing 60mg duloxetine) gone on the market to carry out stability as positive control drug and compare, the impurity content of enteric coated micropill is compared.
Dissolution determination method: get this product, according to drug release determination method (Chinese Pharmacopoeia version in 2010 two annex XD second method methods 2), adopt the device of dissolution method (Chinese Pharmacopoeia version in 2010 two annex XC first methods), first with 0.1mol/L hydrochloric acid solution (8.5 → 1000) 1000ml for dissolution medium, rotating speed is 100 turns per minute, operates in accordance with the law, samples after 2 hours, filter with 0.45um microporous filter membrane, get subsequent filtrate as need testing solution I; (sodium phosphate Na is got immediately with pH6.8 buffer solution
3hPO4.12H
2o, 19.01g with hydrochloric acid 6.375ml, add water to 1000ml, pH is adjusted to be 6.8 ± 0.05 with 5mol/L hydrochloric acid or 5mol/L sodium hydroxide) 1000ml is dissolution medium, rotating speed is constant, continues to operate in accordance with the law, respectively at 15,20,30,45,60,90min sampling, filter with 0.45um microporous filter membrane, get subsequent filtrate as need testing solution II; Adopt the content of duloxetine in high effective liquid chromatography for measuring test solution.
Related substance is studied, and precision measures system and uses liquid 10ul, and with intermixture, ((get Ammonium biphosphate 216mg potassium dihydrogen phosphate 4.5g, the 1000ml that adds water makes dissolving to phosphate buffer, both obtains.PH value should be 8.0 ± 0.3)-methanol (50: 50)) be diluted to every 1ml containing N-succinyl duloxetine and be about the solution of 0.03ug as volumetric soiutions.Precision measures need testing solution 10ul injection liquid chromatography.Record chromatogram is to 2.5 times of N-succinyl duloxetine peak retention time.Test sample is if any impurity peaks.Calculate by normalization method.
Be filler with octyl silane group silica gel, with phosphate buffer (potassium dihydrogen phosphate 3.4g and triethylamine 15ml, the 1000ml that adds water makes dissolving, pH value should be 5.5 ± 0.2)-methanol-oxolane (587: 323: 90) is mobile phase, determined wavelength 230nm, column temperature is 45 DEG C, mobile phase 1.5ml per minute, get duloxetine hydrochloride reference substance 11mg, alpha-Naphthol reference substance 5.0mg and N-succinyl Du Luoxi reference substance 2.5mg, as in same 100ml measuring bottle, adding methanol 1ml makes it dissolve, scale is diluted to mixed solvent, shake up, solution is suitable for as system.Determined wavelength is selected: scanned by DAD collection of illustrative plates, we determine determined wavelength is 230nm.
Embodiment 1
Table-1 embodiment 1 prescription (1000)
Preparation technology
1, carry the preparation of pill core: be suspended in by duloxetine hydrochloride in 5%HPMC aqueous solution, prepare drug-loaded pellets by the mode of spraying this suspension on blank sugar pill ball core.The inlet temperature 40-45 DEG C of setting bottom spraying type fluid bed, atomizing pressure 1.0-1.5bar, air quantity 40-50m
3/ h, controls temperature of charge 37-40 DEG C.
2, the preparation of contagion gown layer: after sorbitol, HPMC are dissolved, add Talc and be fully dispersed to evenly.What by bottom spraying type fluid bed, this suspension was sprayed to that step 1 prepares carries on pill core, obtains isolating drug-loaded pellets.The inlet temperature 40-45 DEG C of setting bottom spraying type fluid bed, atomizing pressure 1.0-1.5bar, air quantity 40-50m
3/ h, controls temperature of charge 37-40 DEG C.
3, the preparation of enteric coating layer: be dissolved in suitable quantity of water by plasticizer TEC, add Talc, be uniformly dispersed, then adds L30D-55 and stirs more than plasticising 30min, for subsequent use.Carry out enteric coating with bottom spraying type fluid bed to the piller having wrapped contagion gown layer, setup parameter is: inlet temperature 31-35 DEG C, atomizing pressure 1.0-1.5bar, air quantity 40-50m
3/ h, controls temperature of charge 28-32 DEG C.
4, after enteric coating terminates, piller is placed in the baking oven of 40 DEG C, standing and drying 2h.
5, measure content, calculate loading amount, encapsulated (by every capsules containing duloxetine 60mg).
Stripping curve is shown in Fig. 1, as can be seen from Fig. 1 and, the dissolved corrosion of the enteric coated pellets formulation of embodiment 1 is similar to positive control drug (glad hundred reach), can realize good stripping.
Embodiment 2
Table-2 embodiment 2 prescriptions (1000)
Preparation technology: with embodiment 1.
Stripping curve is shown in Fig. 2, can find out, the dissolved corrosion of the enteric coated pellets formulation of embodiment 2 is similar to positive control drug (glad hundred reach), can realize good stripping.
Embodiment 3
Table-3 embodiment 3 prescriptions (1000)
Preparation technology: with embodiment 1.
Stripping curve is shown in Fig. 3, and as seen from Figure 3, the dissolved corrosion of the enteric coated pellets formulation of embodiment 3 is similar to positive control drug (glad hundred reach), can realize good stripping.
Comparative example 1
Table-4 comparative example 1 prescriptions (1000)
Preparation technology: 1, carry the preparation method of pill core with embodiment 1.
2, after contagion gown layer: HPMC dissolves, add Talc and be fully dispersed to evenly.All the other operating procedures and parameter are with embodiment 1.
3, enteric coating layer preparation method is with embodiment 1.
4, after enteric coating terminates, piller is placed in the baking oven of 40 DEG C, standing and drying 2h.
5, measure content, calculate loading amount, encapsulated (by every capsules containing duloxetine 60mg).
Stripping curve is shown in Fig. 4, and as seen from Figure 4, the dissolved corrosion of the enteric coated pellets formulation of comparative example 1 is compared with positive control drug (glad hundred reach), and dissolution is on the low side.
Comparative example 2
Table-5 comparative example 2 prescriptions (1000)
Preparation technology: 1, carry the preparation method of pill core with embodiment 1.
2, contagion gown layer: add in PEG4000 solution after Talc fully falls apart and add HPMC solution, be fully dispersed to evenly.All the other operating procedures and parameter are with embodiment 1.
3, enteric coating layer preparation method is with embodiment 1.
4, after enteric coating terminates, piller is placed in the baking oven of 40 DEG C, standing and drying 2h.
5, measure content, calculate loading amount, encapsulated (by every capsules containing duloxetine 60mg).
Stripping curve is shown in Fig. 5, and as seen from Figure 5, the dissolved corrosion of the enteric coated pellets formulation of comparative example 2 is compared with positive control drug (glad hundred reach), and dissolution is on the low side.
To sum up, as can be seen from Fig. 1-3 and table-6 stripping curve evaluations, the dissolved corrosion of Duloxetine hydrochloride enteric pellet preparation of the present invention is similar to positive control drug (glad hundred reach), and dissolution is high, and dissolution rate is fast, can reach good result of extraction; And Fig. 4-5 and table-6 stripping curve evaluations can be found out, do not use sorbitol or sorbitol composition in the isolation layer and use Polyethylene Glycol to replace the comparative example of sugar alcohol, all can not reach the result of extraction as positive control drug (glad hundred reach).
Table-6 stripping curve evaluations
Comparative example 3
Table-7 comparative example 3 prescriptions (1000)
Preparation technology: 1, carry the preparation method of pill core with embodiment 1.
2, contagion gown layer: add in PEG4000 solution after Talc fully falls apart and add HPMC solution, be fully dispersed to evenly.All the other operating procedures and parameter are with embodiment 1.
3, enteric coating layer preparation method is with embodiment 1.
4, after enteric coating terminates, piller is placed in the baking oven of 40 DEG C, standing and drying 2h.
5, measure content, calculate loading amount, encapsulated (by every capsules containing duloxetine 60mg).
6 months accelerated test data: concrete operations are: by duloxetine hydrochloride enteric pellet filled capsules, aluminum-plastic packaged, by packaged aluminium-plastic panel, are placed in the stable experiment item of 40 DEG C/75%RH, investigate product stability, the results are shown in following table.Show-86 months Acceleration study related substance data summarization
As seen from the above table, CN103505421A embodiment, i.e. comparative example 3 of the present invention, at the end of June accelerated test, total impurities content is close to limit standard (0.4%), and embodiments of the invention 1 fundamental sum commercial preparation is similar.Can think that stripping and stability have concordance with commercial preparation (glad hundred reach) in placing to invention formulation formulation and technology in vitro.
Claims (10)
1. a Duloxetine hydrochloride enteric pellet preparation, forming by carrying pill core, contagion gown layer, enteric coating layer and dispensable decorative layer, it is characterized in that:
The described pill core that carries is made up of celphere and the duloxetine hydrochloride be wrapped in outside celphere and pharmaceutically acceptable adjuvant;
Described contagion gown layer is wrapped in and carries outside pill core, be made up of sorbitol and pharmaceutically acceptable adjuvant, or sorbitol forms with the one or more combination thing in other sugar alcohol (mannitol, xylitol, maltose alcohol) and pharmaceutically acceptable adjuvant;
Described enteric coating layer is wrapped in outside contagion gown layer, is made up of medicinal acrylic resin and pharmaceutically acceptable adjuvant.
Described dispensable decorative layer, outside enteric coating layer, is made up of pharmaceutically acceptable adjuvant.
2. Duloxetine hydrochloride enteric pellet preparation according to claim 1, it is characterized in that, the described duloxetine hydrochloride raw material granularity distribution D90 carrying pill core is less than 200 microns, is more preferentially less than 40 microns, preferably be less than 25 microns further, be most preferably less than 15 microns.
3. Duloxetine hydrochloride enteric pellet preparation according to claim 1, is characterized in that, the described celphere carrying pill core is sugar pill, starch ball, lactose ball, lactose/starch ball, sucrose/starch ball, silicon dioxide ball, microcrystalline Cellulose ball.
4. Duloxetine hydrochloride enteric pellet preparation according to claim 1, it is characterized in that, the described pharmaceutically acceptable adjuvant carrying pill core be selected from hydroxypropyl emthylcellulose, polyvinyl pyrrolidone one or both, one or both in preferred hydroxypropyl emthylcellulose, polyvinyl pyrrolidone.
5. Duloxetine hydrochloride enteric pellet preparation according to claim 1, is characterized in that, is describedly made up of sorbitol and pharmaceutically acceptable adjuvant.
6. Duloxetine hydrochloride enteric pellet preparation according to claim 1, it is characterized in that, sorbitol and the one or more combination thing in its other sugar alcohol mannitol, xylitol, maltose alcohol and pharmaceutically acceptable adjuvant composition, most preferably sorbitol and pharmaceutically acceptable adjuvant composition.
7. Duloxetine hydrochloride enteric pellet preparation according to claim 1, is characterized in that, described in state celphere diameter be 0.15 ~ 1.18mm, preferred 0.3 ~ 0.8mm further, the diameter of described Duloxetine hydrochloride enteric pellet is 0.5 ~ 1.5mm.
8. Duloxetine hydrochloride enteric pellet preparation according to claim 1, is characterized in that, the pharmaceutically acceptable adjuvant in described year pill core be selected from hydroxypropyl emthylcellulose, polyvinyl pyrrolidone one or both.
9. Duloxetine hydrochloride enteric pellet preparation according to claim 1, it is characterized in that, pharmaceutically acceptable adjuvant in described contagion gown layer comprises water-soluable gel material and antiplastering aid, wherein water-soluable gel material is selected from one or more in hydroxypropyl emthylcellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, antiplastering aid be selected from Talcum, micropowder silica gel one or both.
10. Duloxetine hydrochloride enteric pellet preparation according to claim 1, it is characterized in that, in described enteric coating layer, medicinal acrylic resin is selected from the one or more combination thing of following kinds, concrete kind is: butyl methacrylate, Dimethylaminoethyl Methacrylate and methyl methacrylate (1: 2: 1) copolymer (especially strange E100, methacrylic acid aminoalkyl ester copolymer E type); Methacrylic acid and ethyl acrylate (1: 1) copolymer (methacrylic acid copolymer C type, EUDRAGIT L100-55 aqueous dispersion); Methacrylic acid and methyl methacrylate (1: 1) copolymer (methacrylic acid copolymer A type); Methacrylic acid and methyl methacrylate (1: 2) copolymer (methacrylic acid copolymer Type B); Ethyl acrylate, methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester (1: 2: 0.2) copolymer (ammonio methacrylate copolymer A type); Ethyl acrylate, methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester (1: 2: 0.1) copolymer (ammonio methacrylate copolymer Type B, ammonio methacrylate copolymer Type B); Ethyl acrylate and methyl methacrylate (2: 1) copolymer (EUDRAGIT NE 30 D EUDRAGIT NE 30D aqueous dispersion); Methacrylic acid, acrylic acid methyl ester. and methyl methacrylate (1: 1: 1) copolymer.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106008788A (en) * | 2016-05-18 | 2016-10-12 | 张绍国 | Low-permeability sustained-release coating material and preparation method thereof |
| CN107281160A (en) * | 2017-07-28 | 2017-10-24 | 昆明邦宇制药有限公司 | A kind of berberine enteric-coated micro-pill and preparation method thereof, application |
| CN112043681A (en) * | 2019-06-06 | 2020-12-08 | 上海奥科达生物医药科技有限公司 | Lacosamide pharmaceutical composition and pharmaceutical preparation thereof |
| CN113116827A (en) * | 2019-12-30 | 2021-07-16 | 上海复星星泰医药科技有限公司 | Oseltamivir phosphate granules and preparation method thereof |
| CN113244197A (en) * | 2021-05-24 | 2021-08-13 | 天方药业有限公司 | Carbamazepine sustained-release capsule and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106008788A (en) * | 2016-05-18 | 2016-10-12 | 张绍国 | Low-permeability sustained-release coating material and preparation method thereof |
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| CN112043681A (en) * | 2019-06-06 | 2020-12-08 | 上海奥科达生物医药科技有限公司 | Lacosamide pharmaceutical composition and pharmaceutical preparation thereof |
| US11337943B2 (en) | 2019-06-06 | 2022-05-24 | Shanghai Aucta Pharmaceuticals Co., Ltd. | Lacosamide pharmaceutical composition and dosage form thereof |
| US11883374B2 (en) | 2019-06-06 | 2024-01-30 | Shanghai Aucta Pharmaceuticals Co., Ltd. | Lacosamide pharmaceutical composition and dosage form thereof |
| CN113116827A (en) * | 2019-12-30 | 2021-07-16 | 上海复星星泰医药科技有限公司 | Oseltamivir phosphate granules and preparation method thereof |
| CN113116827B (en) * | 2019-12-30 | 2022-09-23 | 上海复星星泰医药科技有限公司 | Oseltamivir phosphate granules and preparation method thereof |
| CN113244197A (en) * | 2021-05-24 | 2021-08-13 | 天方药业有限公司 | Carbamazepine sustained-release capsule and preparation method thereof |
| CN113244197B (en) * | 2021-05-24 | 2023-02-28 | 天方药业有限公司 | Carbamazepine sustained-release capsule and preparation method thereof |
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Application publication date: 20160504 |