CN102579403B - Duloxetine hydrochloride drug composition - Google Patents
Duloxetine hydrochloride drug composition Download PDFInfo
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- CN102579403B CN102579403B CN 201110441614 CN201110441614A CN102579403B CN 102579403 B CN102579403 B CN 102579403B CN 201110441614 CN201110441614 CN 201110441614 CN 201110441614 A CN201110441614 A CN 201110441614A CN 102579403 B CN102579403 B CN 102579403B
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- 229960002496 duloxetine hydrochloride Drugs 0.000 title claims abstract description 128
- JFTURWWGPMTABQ-UHFFFAOYSA-N n,n-dimethyl-3-naphthalen-1-yloxy-3-thiophen-2-ylpropan-1-amine Chemical compound C=1C=CC2=CC=CC=C2C=1OC(CCN(C)C)C1=CC=CS1 JFTURWWGPMTABQ-UHFFFAOYSA-N 0.000 title claims abstract description 128
- 239000000203 mixture Substances 0.000 title claims abstract description 33
- 239000003814 drug Substances 0.000 title abstract description 29
- 229940079593 drug Drugs 0.000 title abstract description 10
- 238000013268 sustained release Methods 0.000 claims abstract description 28
- 239000012730 sustained-release form Substances 0.000 claims abstract description 28
- 239000002775 capsule Substances 0.000 claims abstract description 13
- 238000000576 coating method Methods 0.000 claims description 53
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 46
- 238000002360 preparation method Methods 0.000 claims description 43
- 239000008194 pharmaceutical composition Substances 0.000 claims description 41
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- 229920003081 Povidone K 30 Polymers 0.000 claims description 30
- 238000001035 drying Methods 0.000 claims description 30
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 28
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a sustained-release duloxetine hydrochloride drug composition, which is characterized in that the drug composition is a duloxetine hydrochloride sustained-release capsule, and consists of duloxetine hydrochloride sustained-release pellets and duloxetine hydrochloride sustained-release pellets which are released by a time delay of 4h according to a ratio of 1:1. The duloxetine hydrochloride drug composition has good stability, and also has the more obvious advantages of improving the product yield, lowering the cost, realizing the industrialization and being better applied clinically.
Description
Technical field
The present invention relates to the medicine in the field of medicaments, especially relate to duloxetine hydrochloride pharmaceutical composition of a kind of sustainable release and preparation method thereof.
Background technology
Duloxetine hydrochloride is 5-hydroxy tryptamine and the NRI of EliLilly company exploitation.5-hydroxy tryptamine and norepinephrine all belong to central neurotransmitter, are regulating and control emotion and are playing an important role aspect the sensitivity of pain.Duloxetine can suppress neuron to the reuptake of 5-hydroxy tryptamine and norepinephrine, improve the concentration of these two kinds of central neurotransmitters in brain and spinal cord thus, so can be used for treating some mental state disease such as depression and anxiety neurosis and alleviate central pain such as diabetes peripheral nervous characteristic of disease pain and women's fibromyalgia etc.Duloxetine also can act on 5-hydroxy tryptamine and the norepinephrine receptor in the urethra, thereby strengthens neurogenic tonus degree and the contractility of sphincter of urethra, so also effective to the treatment of women's stress urinary incontinence disease.Duloxetine is the oral enteric capsule preparations, in August, 2004 first after the U.S. gets the Green Light, country's listing surplus 70 now.In August, 2004, duloxetine also European Union get permission to treat 18 years old women in to severe stress urinary incontinence disease; In June, 2008, U.S. FDA is ratified duloxetine again and be used for to be alleviated this chronic, severe depression that is difficult to treat of adult's fibromyalgia, generalized anxiety disorder, women's stress urinary incontinence disease and diabetes-alleviating peripheral nervous characteristic of disease pain and these 5 kinds of neurological's relevant diseases of fibromyalgia.In duloxetine safety and toleration, determined curative effect and produce effects are fast in addition, and therapeutic regimen is easy again, and side reaction is few, so obtain that clinical rapidly and accept extensively market potential is huge, are worth clinical and market is paid close attention to.
Common name: duloxetine hydrochloride;
English name: Duloxetine Hydrochloride;
Chemical name: (S)-(+)-N-methyl-3-(1-naphthoxy)-the 3-(2-thiophene)-propylamin hydrochloride;
Chemical structural formula:
Molecular formula: C
18H
19ONSHCl;
Molecular weight: 333.88;
Physicochemical property: white is to slightly brown white solid, slightly soluble in the water.
The pharmacology type: duloxetine hydrochloride is selectivity 5-hydroxy tryptamine and NRI.
Indication: be used for the treatment of major depression disease (MDD); Treat the neuralgia relevant with diabetic peripheral neuropathy.
Application number be CN200610022051.X disclosure of the Invention duloxetine hydrochloride sustained release medicine, formed jointly by acceptable adjunct ingredient in duloxetine hydrochloride and the oral drugs, wherein duloxetine hydrochloride is 15% ~ 65% of medicine gross weight, at least include the macromolecular scaffold slow-release material in the said adjunct ingredient, rate of release is regulated composition and enteric solubility external cladding material, and the macromolecular scaffold slow-release material is 1% ~ 80%, rate of release is adjusted to and is divided into 0.1% ~ 50%, and the enteric solubility external cladding material is 1.5% ~ 10%.This medicine has the matrix type slow-release function of intestinal corrosion, and is rapid-action, strong drug action, prolong action time, significantly reduce the untoward reaction of the back dose abrupt release of taking medicine, make blood drug level and drug effect more steady lasting, strengthen patient's medication compliance and clinical therapeutic efficacy.
Application number be CN200410067160.4 disclosure of the Invention a kind of enteric coated table of duloxetine and preparation method thereof.The present invention can arrive small intestinal smoothly for guaranteeing the principal agent duloxetine, avoids discharging under one's belt and destroys its pharmaceutically active, therefore will wrap one deck enteric coating to reach this requirement in plain sheet outside.The present invention simultaneously adopts solid dispersion technology, increases the principal agent dissolubility, improves final burst size, thereby reaches the raising bioavailability.Enteric coated table of duloxetine of the present invention, preparation are stable in acid, enter behind the small intestinal because preparation process, and the rapid dissolubility of medicine satisfies the needs of clinical application.
Application number be CN200410067161.9 disclosure of the Invention a kind of duloxetine enteric coated tiny pill capsule and preparation method thereof.Described micropill is made up of the celphere coatings outer with being wrapped in celphere; Said coatings comprises the principal agent layer that contains principal agent and adjuvant, is wrapped in the outer sealing coat of principal agent layer and is wrapped in the outer enteric layer of sealing coat.Product of the present invention, behind preparation process, principal agent does not originally discharge and discharges rapidly after entering small intestinal at acidic group, has avoided principal agent by stomach acids destroy, and obtains large increase by the solid dispersion technology dissolubility, can satisfy people's needs.
Application number be CN200980101718.7 disclosure of the Invention pharmaceutical composition, it comprises duloxetine or the acceptable salt of its medicine and one or more pharmaceutically-acceptable excipients, the D90 granularity that it is characterized in that duloxetine is 2 μ m to 40 μ m.。
Application number be CN200810207877.2 disclosure of the Invention a kind of duloxetine enteric-coated preparation and core and preparation method, this duloxetine enteric-coated preparation core is made up of active constituents of medicine duloxetine or its salt and acceptable accessories, wherein, contain the water-soluble hot melt material in the acceptable accessories, and the content of water-soluble hot melt material is 10% ~ 40%, the content of active constituents of medicine duloxetine or its salt is 15 ~ 60%, all the other are other acceptable accessories, and described percentage ratio accounts for the mass percent of core total amount for it.The present invention adopts hot melting process to prepare the core of the enteric coated preparation of duloxetine or its salt, simplified preparation process, avoid the introducing of moisture in the preparation process or organic solvent, reduced the degraded of dissolvent residual and principal agent, improved its preparation stability in preparation and storage process; The drug content height, dissolution is good.
Application number is that the invention of CN200610102204.1 relates to and contains duloxetine hydrochloride enteric coated tablet and preparation method thereof.The duloxetine hydrochloride enteric coatel tablets are made up of label, stomach dissolution type sealing coat, enteric layer three parts.The technical solution adopted in the present invention effectively avoids medicine to influence the release of medicine with enteric material generation cross reaction in dispose procedure, has effectively improved stability of drug, and preparation method is simple to operation, be suitable for suitability for industrialized production.
Application number be CN200910215411.1 disclosure of the Invention a kind of enteric-coated sustained release preparation and core and preparation method of duloxetine.This core is made up of active constituents of medicine duloxetine or its salt and acceptable accessories, wherein, contain hot melt material in the described acceptable accessories, this hot melt material comprises a kind of water-soluble hot melt material and a kind of hydrophobicity hot melt material at least, and the content of hot melt material is 20% ~ 35%, the content 50% ~ 75% of duloxetine or its salt, all the other are other acceptable accessories, described percentage ratio accounts for the mass percent of core total amount for it.The present invention adopts hot melting process to prepare the core of the enteric-coated sustained release preparation of duloxetine, avoided the introducing of moisture in the preparation or organic solvent, reduced degraded and the dissolvent residual of principal agent; Suitably postponed the release of duloxetine in intestinal, 4 hours burst sizes are more than 70% of total amount in the pH6.8 phosphate buffer, are conducive to reduce patient's untoward reaction.
Duloxetine hydrochloride is the off-white color crystalline powder, to photo-labile, dissolubility is relatively poor and unstable under sour environment in water, be easy to degraded, in order to guarantee that medicine does not react with acidic materials, Given this therefore the suitable enteric coated preparation of making of duloxetine hydrochloride needs a kind of medicine dissolution that can increase can guarantee not slow releasing preparation that reacts with acid and preparation method thereof again.
The inventor is through studying for a long period of time, and unexpected the discovery used special adjuvant, the duloxetine hydrochloride pharmaceutical composition of special process preparation, and light resistance is good, good stability, bioavailability height.Not only successfully solved the problem of the poor stability of duloxetine hydrochloride, improved bioavailability, reduced production costs, easy to implement, can realize industrialization, remarkable in economical benefits.
Summary of the invention
First purpose of the present invention is to provide a kind of duloxetine hydrochloride pharmaceutical composition, and this duloxetine hydrochloride pharmaceutical composition is stable to light, good stability, to improving product yield, reduce cost, realize industrialization, better application has more obvious advantage in clinical.
Second purpose of the present invention is to provide duloxetine hydrochloride preparation of drug combination method of the present invention, and this method is simple, and prepared duloxetine hydrochloride pharmaceutical composition is stable to light, good stability.
For realizing first purpose of the present invention, the present invention adopts following technical scheme:
A kind of duloxetine hydrochloride pharmaceutical composition, per 1000 described duloxetine hydrochloride pharmaceutical compositions, its prescription consists of:
Duloxetine hydrochloride 20-60g
HYDROXYPROPYL BETA-CYCLODEXTRIN 20-60g
Sodium lauryl sulphate 10-30g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 6-18g
Triethyl citrate 1-3g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of.
Be preferably, per 1000 described duloxetine hydrochloride pharmaceutical compositions, its prescription consists of:
Duloxetine hydrochloride 20g
HYDROXYPROPYL BETA-CYCLODEXTRIN 20g
Sodium lauryl sulphate 10g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 6g
Triethyl citrate 1g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of.
Be preferably, per 1000 described duloxetine hydrochloride pharmaceutical compositions, its prescription consists of:
Duloxetine hydrochloride 30g
HYDROXYPROPYL BETA-CYCLODEXTRIN 30g
Sodium lauryl sulphate 15g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 12g
Triethyl citrate 2g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of.
Be preferably, per 1000 described duloxetine hydrochloride pharmaceutical compositions, its prescription consists of:
Duloxetine hydrochloride 60g
HYDROXYPROPYL BETA-CYCLODEXTRIN 60g
Sodium lauryl sulphate 30g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 18g
Triethyl citrate 3g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of.
Duloxetine hydrochloride pharmaceutical composition of the present invention is to adopt following method preparation:
1) with starch, dextrin, sodium chloride fine powder mix homogeneously, cross 80 mesh sieves, be that binding agent is made piller with 8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution, round as a ball to the 28-20 order, drying obtains blank piller;
2) duloxetine hydrochloride, HYDROXYPROPYL BETA-CYCLODEXTRIN and sodium lauryl sulphate are mixed, cross 80 mesh sieves, get blank piller surface that step 1) makes with the 30 alcoholic solution moistenings of 8% 30 POVIDONE K 30 BP/USP, to evenly be bonded on the blank piller will dividing of mix homogeneously then, drying is chosen 30-20 purpose duloxetine hydrochloride piller;
3) take by weighing EudragitS100, be dissolved in the alcoholic solution, add triethyl citrate, mixing is mixed with concentration and counts 4% solution for EudragitS100 weight;
4) use the fluidized bed coating operation, the solution that step 3) is made is to step 2) half recipe quantity piller carry out coating, drying, coatings thickness is 2-4um, makes the duloxetine hydrochloride sustained release piller;
5) use the fluidized bed coating operation, the solution that step 3) is made is to other step 2) half recipe quantity piller carry out coating, drying, coatings thickness is 6-8um, makes time-delay in 4 hours and discharges the duloxetine hydrochloride piller;
6) step 4) duloxetine hydrochloride sustained release piller and step 5) time-delay in 4 hours are discharged the duloxetine hydrochloride sustained release piller according to the 1:1 mix homogeneously;
7) dress capsule;
8) packing, namely.
For realizing first purpose of the present invention, the present invention adopts following technical scheme:
Duloxetine hydrochloride preparation of drug combination method of the present invention, wherein, this method comprises the steps:
1) with starch, dextrin, sodium chloride fine powder mix homogeneously, cross 80 mesh sieves, be that binding agent is made piller with 8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution, round as a ball to the 28-20 order, drying obtains blank piller;
2) duloxetine hydrochloride, HYDROXYPROPYL BETA-CYCLODEXTRIN and sodium lauryl sulphate are mixed, cross 80 mesh sieves, get blank piller surface that step 1) makes with the 30 alcoholic solution moistenings of 8% 30 POVIDONE K 30 BP/USP, to evenly be bonded on the blank piller will dividing of mix homogeneously then, drying is chosen 30-20 purpose duloxetine hydrochloride piller;
3) take by weighing EudragitS100, be dissolved in the alcoholic solution, add triethyl citrate, mixing is mixed with concentration and counts 4% solution for EudragitS100 weight;
4) use the fluidized bed coating operation, the solution that step 3) is made is to step 2) half recipe quantity piller carry out coating, drying, coatings thickness is 2-4um, makes the duloxetine hydrochloride sustained release piller;
5) use the fluidized bed coating operation, the solution that step 3) is made is to other step 2) half recipe quantity piller carry out coating, drying, coatings thickness is 6-8um, makes time-delay in 4 hours and discharges the duloxetine hydrochloride piller;
6) step 4) duloxetine hydrochloride sustained release piller and step 5) time-delay in 4 hours are discharged the duloxetine hydrochloride sustained release piller according to the 1:1 mix homogeneously;
7) dress capsule;
8) packing, namely.
Below to the more detailed elaboration of the present invention:
One aspect of the present invention provides a kind of duloxetine hydrochloride pharmaceutical composition, per 1000 described duloxetine hydrochloride pharmaceutical compositions, and its prescription consists of:
Duloxetine hydrochloride 20g
HYDROXYPROPYL BETA-CYCLODEXTRIN 20g
Sodium lauryl sulphate 10g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 6g
Triethyl citrate 1g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of.
One aspect of the present invention provides a kind of duloxetine hydrochloride pharmaceutical composition, per 1000 described duloxetine hydrochloride pharmaceutical compositions, and its prescription consists of:
Duloxetine hydrochloride 30g
HYDROXYPROPYL BETA-CYCLODEXTRIN 30g
Sodium lauryl sulphate 15g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 12g
Triethyl citrate 2g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of.
One aspect of the present invention provides a kind of duloxetine hydrochloride pharmaceutical composition, per 1000 described duloxetine hydrochloride pharmaceutical compositions, and its prescription consists of:
Duloxetine hydrochloride 60g
HYDROXYPROPYL BETA-CYCLODEXTRIN 60g
Sodium lauryl sulphate 30g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 18g
Triethyl citrate 3g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of.
Traditional duloxetine hydrochloride pharmaceutical composition, photostability is poor, easily degraded, bioavailability is low, and quality can't guarantee.
Among the present invention, in to duloxetine hydrochloride pharmaceutical composition supplementary material Study on Compatibility process, find to add HYDROXYPROPYL BETA-CYCLODEXTRIN and sodium lauryl sulphate basic auxiliary, can effectively increase the external stripping rate of release of duloxetine hydrochloride, through the screening of tens of times test recipes and the summary of test data, optimized its recipe quantity, not only solved the problem to poor stability, and effectively improve its external stripping rate of release, constant product quality.
Among the present invention, according to the clinical usage and dosage of duloxetine hydrochloride, optimize prescription, select suitable preparation technology, optimum release profiles makes it be applied to both evade discharging in gastric acid in clinical destroy active component, this medicine held stationary is discharged, and the clinical practice side effect is little.
The inventor finds through great deal of experimental, when the duloxetine hydrochloride pharmaceutical composition is above-mentioned prescription, and described pharmaceutical composition the best in quality, stability is best.
Another aspect of the present invention provides duloxetine hydrochloride preparation of drug combination method of the present invention, and this method is simple, prepared duloxetine hydrochloride pharmaceutical composition good stability, bioavailability height.
Preparation method provided by the present invention comprises:
1) with starch, dextrin, sodium chloride fine powder mix homogeneously, cross 80 mesh sieves, be that binding agent is made piller with 8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution, round as a ball to the 28-20 order, drying obtains blank piller;
2) duloxetine hydrochloride, HYDROXYPROPYL BETA-CYCLODEXTRIN and sodium lauryl sulphate are mixed, cross 80 mesh sieves, get blank piller surface that step 1) makes with the 30 alcoholic solution moistenings of 8% 30 POVIDONE K 30 BP/USP, to evenly be bonded on the blank piller will dividing of mix homogeneously then, drying is chosen 30-20 purpose duloxetine hydrochloride piller;
3) take by weighing EudragitS100, be dissolved in the alcoholic solution, add triethyl citrate, mixing is mixed with concentration and counts 4% solution for EudragitS100 weight;
4) use the fluidized bed coating operation, the solution that step 3) is made is to step 2) half recipe quantity piller carry out coating, drying, coatings thickness is 2-4um, makes the duloxetine hydrochloride sustained release piller;
5) use the fluidized bed coating operation, the solution that step 3) is made is to other step 2) half recipe quantity piller carry out coating, drying, coatings thickness is 6-8um, makes time-delay in 4 hours and discharges the duloxetine hydrochloride piller;
6) step 4) duloxetine hydrochloride sustained release piller and step 5) time-delay in 4 hours are discharged the duloxetine hydrochloride sustained release piller according to the 1:1 mix homogeneously;
7) dress capsule;
8) packing, namely.
The duloxetine hydrochloride pharmaceutical composition that makes according to the inventive method proves that through industrial amplification production and study on the stability product is stable, through pharmacology, toxicological test, human body is not had injury.
Below by test data beneficial effect of the present invention is described.
Compare stability test with the product of the embodiment of the invention 1 and prior art comparative example 4 product, the result is as follows:
Embodiment 1 accelerated test result
Comparative example 4 accelerated test results
Last table shows that the sample comparison of the embodiment of the invention 1 is more stable from the prescription analysis angle than the sample of embodiment 4; On release mechanism, embodiment 1 more is better than comparative example 4, can long-acting lasting release, and the release amount is stable, reduces medicining times, has improved the compliance of clinical application greatly.
The invention has the advantages that, overcome problem in the prior art, product can be maintained a long-term stability.
The solution of the present invention design and test data are as follows:
Raw material research:
With raw material, remove medicinal composite film packaging, sample is directly put in the weighing botle, spreads out into≤thin layer that 5mm is thick, places 10 days under 60 ℃ ± 2 ℃ high temperature, illumination 4500lx ± 500lx, 25 ℃ of relative humidity 92.5% ± 5% conditions, in sampling in the 10th day, measures.
Influence factor's result of the test of raw material
Shown by above result of the test: at 60 ℃ ± 2 ℃ high temperature, relative humidity 92.5% ± 5%(25 ℃), under illumination 4500lx ± 500lx condition, investigated through 10 days, related substance slightly increases.
Adjuvant research:
From raw material mix research and document, consider to add different types of basic auxiliary and mix according to a certain percentage with raw material, place the influence factor, continue to investigate its related substance situation of change:
Meglumine
Molecular formula: CH
2OH(CHOH)
4CH
2NH CH
3
Molecular weight: 195.22
Character:For white to light yellow crystalline powder, odorless or little smelly.Being a kind of organic base, mainly is to do the pH regulator agent, with acid effect salify.
Sodium lauryl sulphate
Molecular formula:C
12H
25NaO
4S
Molecular weight:288.38
Character:White powder, water-soluble.As soluble lubricant, can promote disintegrate and the medicine dissolution rate of tablet.
Choose duloxetine hydrochloride and adjuvant meglumine, sodium lauryl sulphate by the prescription mixed, get a certain amount of, test method according to influence factor in the medicine stability guideline, respectively under 4500LX ± 500LX illumination condition, in the calorstat of 60 ℃ of high temperature and 25 ℃ of relative humidity 92.5% ± 5%(KNO3 saturated solutions) calorstat placed 10 days, investigate appearance character and related substance, result of the test sees Table 4:
Table 4 supplementary material Study on Compatibility result
Shown that by above result of the test added observation from the related substance detection, adjuvant sodium lauryl sulphate and duloxetine compatibility have more advantages of excellent stability.
At the prescription design initial stage, consider that the duloxetine hydrochloride GI irritation is bigger, so slow release method is adopted in the prescription design, purpose is in order to allow the duloxetine hydrochloride long-acting release of delaying time, to detect so design prescription 1 carries out each index, the result is as follows:
Prescription 1
Duloxetine hydrochloride 60g
Sodium lauryl sulphate 30g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 18g
Triethyl citrate 3g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of.
Preparation technology
1) with starch, dextrin, sodium chloride fine powder mix homogeneously, cross 80 mesh sieves, be that binding agent is made piller with 8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution, round as a ball to the 28-20 order, drying obtains blank piller;
2) duloxetine hydrochloride, sodium lauryl sulphate are mixed, cross 80 mesh sieves, get blank piller surface that step 1) makes with the 30 alcoholic solution moistenings of 8% 30 POVIDONE K 30 BP/USP, to evenly be bonded on the blank piller will dividing of mix homogeneously then, drying is chosen 30-20 purpose duloxetine hydrochloride piller;
3) take by weighing EudragitS100, be dissolved in the alcoholic solution, add triethyl citrate, mixing is mixed with concentration and counts 4% solution for EudragitS100 weight;
4) use the fluidized bed coating operation, the solution that step 3) is made is to step 2) half recipe quantity piller carry out coating, drying, coatings thickness is 2-4um, makes the duloxetine hydrochloride sustained release piller;
5) use the fluidized bed coating operation, the solution that step 3) is made is to other step 2) half recipe quantity piller carry out coating, drying, coatings thickness is 6-8um, makes time-delay in 4 hours and discharges the duloxetine hydrochloride piller;
6) step 4) duloxetine hydrochloride sustained release piller and step 5) time-delay in 4 hours are discharged the duloxetine hydrochloride sustained release piller according to the 1:1 mix homogeneously;
7) dress capsule;
8) packing, namely.
The preparation result investigates:
The 1 burst size measurement result of writing out a prescription
Above result of the test shows: this prescription did not reach maximum and discharges in 12 hours, considered to add certain special adjuvant, improved its rate of release.
Adjuvant research:
Cyclodextrin is starch derivatives, mainly as oral and injection medicine preparation, and the most frequently used is α-, β-, gamma-cyclodextrin has 6,7,8 glucose units respectively.Cyclodextrin is the ring molecule of the cavity by rigid structure and center thereof " tubbiness " or " coniform " that constitute, its size is according to the difference of the type of cyclodextrin and difference, the cavity inner surface is hydrophobicity, and the outside of ring is hydrophilic, this is by due to the arrangement in the polyhydroxylated molecule, this arrangement makes cyclodextrin hold enclosed molecule in the cavity again, forms clathrate.Cyclodextrin can be used to prepare the clathrate of multiple drug molecule, mainly plays and improves the effect that improves release and bioavailability, and this is attributable to the increase of dissolubility, and the raising of chemistry and physical stability.The clathrate of cyclodextrin also is used for covering the disagreeable taste of active substance and liquid substance is converted into solid material.
It is oral nontoxic that HYDROXYPROPYL BETA-CYCLODEXTRIN is considered to, so safety when using in solid preparation.
According to above experimental phenomena, the following prescription of design, further investigate:
Prescription 2
Duloxetine hydrochloride 60g
HYDROXYPROPYL BETA-CYCLODEXTRIN 60g
Sodium lauryl sulphate 30g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 18g
Triethyl citrate 3g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of.
Preparation technology:
1) with starch, dextrin, sodium chloride fine powder mix homogeneously, cross 80 mesh sieves, be that binding agent is made piller with 8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution, round as a ball to the 28-20 order, drying obtains blank piller;
2) duloxetine hydrochloride, HYDROXYPROPYL BETA-CYCLODEXTRIN and sodium lauryl sulphate are mixed, cross 80 mesh sieves, get blank piller surface that step 1) makes with the 30 alcoholic solution moistenings of 8% 30 POVIDONE K 30 BP/USP, to evenly be bonded on the blank piller will dividing of mix homogeneously then, drying is chosen 30-20 purpose duloxetine hydrochloride piller;
3) take by weighing EudragitS100, be dissolved in the alcoholic solution, add triethyl citrate, mixing is mixed with concentration and counts 4% solution for EudragitS100 weight;
4) use the fluidized bed coating operation, the solution that step 3) is made is to step 2) half recipe quantity piller carry out coating, drying, coatings thickness is 2-4um, makes the duloxetine hydrochloride sustained release piller;
5) use the fluidized bed coating operation, the solution that step 3) is made is to other step 2) half recipe quantity piller carry out coating, drying, coatings thickness is 6-8um, makes time-delay in 4 hours and discharges the duloxetine hydrochloride piller;
6) step 4) duloxetine hydrochloride sustained release piller and step 5) time-delay in 4 hours are discharged the duloxetine hydrochloride sustained release piller according to the 1:1 mix homogeneously;
7) dress capsule;
8) packing, namely.
The preparation result investigates:
The 2 burst size measurement results of writing out a prescription
Above result of the test shows: this prescription reached maximum and discharges in 12 hours, add special adjuvant, and special process obviously improves its rate of release.
Above result of the test shows: this prescription is better than other prescription.
Compared with prior art, the present invention has following advantage:
1) new duloxetine hydrochloride compositions provided by the present invention has thoroughly solved the stability problem of duloxetine hydrochloride.
2) duloxetine hydrochloride pharmaceutical composition provided by the present invention is for the market risk of the yield that improves this product, reduction product, and better application has very big help in clinical treatment.
3) new duloxetine hydrochloride compositions provided by the present invention proves constant product quality through industrialized great production and study on the stability, through pharmacology, toxicological test, human body is not had injury.
4) new duloxetine hydrochloride preparation of compositions method provided by the present invention, this method is simple, prepared duloxetine hydrochloride pharmaceutical composition good stability, bioavailability height.
The specific embodiment
Be described in further detail below in conjunction with the present invention of embodiment
Embodiment 1
Per 1000 described duloxetine hydrochloride pharmaceutical compositions, its prescription consists of:
Duloxetine hydrochloride 20g
HYDROXYPROPYL BETA-CYCLODEXTRIN 20g
Sodium lauryl sulphate 10g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 6g
Triethyl citrate 1g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of
Preparation technology:
1) with starch, dextrin, sodium chloride fine powder mix homogeneously, cross 80 mesh sieves, be that binding agent is made piller with 8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution, round as a ball to the 28-20 order, drying obtains blank piller;
2) duloxetine hydrochloride, HYDROXYPROPYL BETA-CYCLODEXTRIN and sodium lauryl sulphate are mixed, cross 80 mesh sieves, get blank piller surface that step 1) makes with the 30 alcoholic solution moistenings of 8% 30 POVIDONE K 30 BP/USP, to evenly be bonded on the blank piller will dividing of mix homogeneously then, drying is chosen 30-20 purpose duloxetine hydrochloride piller;
3) take by weighing EudragitS100, be dissolved in the alcoholic solution, add triethyl citrate, mixing is mixed with concentration and counts 4% solution for EudragitS100 weight;
4) use the fluidized bed coating operation, the solution that step 3) is made is to step 2) half recipe quantity piller carry out coating, drying, coatings thickness is 2-4um, makes the duloxetine hydrochloride sustained release piller;
5) use the fluidized bed coating operation, the solution that step 3) is made is to other step 2) half recipe quantity piller carry out coating, drying, coatings thickness is 6-8um, makes time-delay in 4 hours and discharges the duloxetine hydrochloride piller;
6) step 4) duloxetine hydrochloride sustained release piller and step 5) time-delay in 4 hours are discharged the duloxetine hydrochloride sustained release piller according to the 1:1 mix homogeneously;
7) dress capsule;
8) packing, namely.
Embodiment 2
Per 1000 described duloxetine hydrochloride pharmaceutical compositions, its prescription consists of:
Duloxetine hydrochloride 30g
HYDROXYPROPYL BETA-CYCLODEXTRIN 30g
Sodium lauryl sulphate 15g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 12g
Triethyl citrate 2g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of
Preparation technology: with embodiment 1.
Embodiment 3
Per 1000 described duloxetine hydrochloride pharmaceutical compositions, its prescription consists of:
Duloxetine hydrochloride 60g
HYDROXYPROPYL BETA-CYCLODEXTRIN 60g
Sodium lauryl sulphate 30g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 18g
Triethyl citrate 3g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of
Preparation technology: with embodiment 1.
Comparing embodiment 1
Patent CN200410067161.9 embodiment 5
Preparation technology: poloxamer is dissolved in the adequate amount of ethanol solution, adds the duloxetine of recipe quantity, treat that its dissolving back adds dextran and galactose, mix, sieve, in baking oven, dry, namely get the solid dispersion of duloxetine, it is standby that it was pulverized 200 mesh sieves.A step coating pelletizing machine is used in the celphere medicine-feeding.The hypromellose of recipe quantity is dissolved in few water of trying one's best, then liquid slowly is sprayed onto on the micropill that is rolling, the colleague is duloxetine solid dispersion powder and Pulvis Talci adhering on the micropill intermittently, after coating is finished 55 ℃ of dryings 1 hour.
Sealing coat coating solution preparation: half water of recipe quantity is heated to 70 ℃, pours hypromellose into, stir to make and be uniformly dispersed, add sucrose and stir standby at a slow speed.Pulvis Talci and titanium dioxide add in second half the water, with high-shear homogenate machine homogenate number minute, in the solution of the hypromellose that the step prepared before suspension slowly poured into, stir half an hour at a slow speed, under the lasting stirring of magnetic stirrer, carry out coating with fluid bed.
Enteric layer coating solution preparation: take by weighing needed S100, be dissolved in the general alcoholic solution of recipe quantity, add triethyl citrate, Pulvis Talci is poured in second half the ethanol, high-shear homogenate machine homogenate number minute is slowly poured this suspension in the solution of S100 into then, continues to stir to get final product half an hour, the same fluidized bed coating that is suitable for is operated under the lasting stirring of magnetic agitation, after coating finishes, tablet is taken out, put 40 ℃ of baking ovens, solidify a few hours, wrap complete layer again.
Complete layer coating solution compound method and vegetation technology and sealing coat are similar, the interior fluidized drying of fluid bed taking-up in 10 minutes again after coating is finished, and the 3# capsule for the treatment of to pack into after it cools off namely gets duloxetine enteric-coated coated micropill capsule.
Test example 1
This test example is to investigate the stability of duloxetine hydrochloride compositions provided by the present invention.
The accelerated test of duloxetine hydrochloride pharmaceutical composition
Method according to embodiment of the invention 1-3 prepares three batches of duloxetine hydrochloride pharmaceutical compositions (lot number is respectively SR1003101, SR1003102, SR1003103) according to commercially available back, at 40 ℃ ± 2 ℃, the condition of RH75% ± 5% was placed 6 months, during this time respectively at sampling in the 1st, 2,3,6 month, detect according to stable inspection item, and compare with 0 day data.
1, investigation project
High spot reviews: character, release, related substance and content.
2, test data sees the following form
Accelerated test result
Above conclusion (of pressure testing) is as can be seen: this product is placed 6 months every detection indexs and was compared no significant difference, good stability with 0 month under long term test and accelerated test condition.
Comparative test example 1
According to result of the test as can be known, embodiment 1 and comparative example 1 compare by 0 day data, and embodiment 1 possesses the slow release releasing effect, the related substance testing result, and it is more stable that SR1003101 criticizes (embodiment 1), and the present invention has tangible quality stability.
Claims (6)
1. duloxetine hydrochloride pharmaceutical composition, it is characterized in that, this pharmaceutical composition is the duloxetine hydrochloride sustained release capsule, discharges the duloxetine hydrochloride piller by duloxetine hydrochloride sustained release piller and time-delay in 4 hours and forms by 1:1, and per 1000 its prescriptions consist of:
Duloxetine hydrochloride 20-60g
Betacyclodextrin 20-60g
Sodium lauryl sulphate 10-30g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 6-18g
Triethyl citrate 1-3g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of.
2. pharmaceutical composition according to claim 1 is characterized in that, wherein the weight ratio of duloxetine hydrochloride and betacyclodextrin, sodium lauryl sulphate is 1:1:0.5.
3. pharmaceutical composition according to claim 1 and 2 is characterized in that, its described duloxetine hydrochloride pharmaceutical composition, and per 1000 its prescriptions consist of:
Duloxetine hydrochloride 20g
Betacyclodextrin 20g
Sodium lauryl sulphate 10g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 6g
Triethyl citrate 1g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of.
4. pharmaceutical composition according to claim 1 and 2 is characterized in that, its described duloxetine hydrochloride pharmaceutical composition, and per 1000 its prescriptions consist of:
Duloxetine hydrochloride 30g
Betacyclodextrin 30g
Sodium lauryl sulphate 15g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 12g
Triethyl citrate 2g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of.
5. pharmaceutical composition according to claim 1 and 2 is characterized in that, its described duloxetine hydrochloride pharmaceutical composition, and per 1000 its prescriptions consist of:
Duloxetine hydrochloride 60g
Betacyclodextrin 60g
Sodium lauryl sulphate 30g
Starch 100g
Sodium chloride fine powder 40g
Dextrin 20g
EudragitS100 18g
Triethyl citrate 3g
8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of.
6. according to any described duloxetine hydrochloride preparation of drug combination method of claim 1-5, it is characterized in that this method comprises the steps:
1) with starch, dextrin, sodium chloride fine powder mix homogeneously, cross 80 mesh sieves, be that binding agent is made piller with 8% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution, round as a ball to the 28-20 order, drying obtains blank piller;
2) duloxetine hydrochloride, betacyclodextrin and sodium lauryl sulphate are mixed, cross 80 mesh sieves, get blank piller surface that step 1) makes with the 30 alcoholic solution moistenings of 8% 30 POVIDONE K 30 BP/USP, the medicated powder of mix homogeneously evenly is bonded on the blank piller then, drying is chosen 30-20 purpose duloxetine hydrochloride piller;
3) take by weighing EudragitS100, be dissolved in the alcoholic solution, add triethyl citrate, mixing is mixed with concentration and counts 4% solution for EudragitS100 weight;
4) use the fluidized bed coating operation, the solution that step 3) is made is to step 2) half recipe quantity piller carry out coating, drying, coatings thickness is 2-4um, makes the duloxetine hydrochloride sustained release piller;
5) use the fluidized bed coating operation, the solution that step 3) is made is to other step 2) half recipe quantity piller carry out coating, drying, coatings thickness is 6-8um, makes time-delay in 4 hours and discharges the duloxetine hydrochloride piller;
6) step 4) duloxetine hydrochloride sustained release piller and step 5) time-delay in 4 hours are discharged the duloxetine hydrochloride sustained release piller according to the 1:1 mix homogeneously;
7) dress capsule;
8) packing, namely.
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| CN1759829A (en) * | 2004-10-14 | 2006-04-19 | 上海医药工业研究院 | Duloxetine enteric coated tiny pill capsule, and preparation method |
| WO2009092129A1 (en) * | 2008-01-25 | 2009-07-30 | Alpharma Pty Ltd | Delayed release pharmaceutical composition of duloxetine |
| CN101686947A (en) * | 2007-06-23 | 2010-03-31 | 箭锋国际有限公司 | duloxetine formulation |
| CN101756960A (en) * | 2008-12-26 | 2010-06-30 | 上海中西制药有限公司 | Duloxetine enteric-coated preparation and core material and preparation method thereof |
| WO2010150219A1 (en) * | 2009-06-25 | 2010-12-29 | Wockhardt Research Centre | Pharmaceutical composition of duloxetine or pharmaceutically acceptable salts thereof |
-
2011
- 2011-12-26 CN CN 201110441614 patent/CN102579403B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1759830A (en) * | 2004-10-14 | 2006-04-19 | 上海医药工业研究院 | Enteric coated table of duloxetine, and preparation method |
| CN1759829A (en) * | 2004-10-14 | 2006-04-19 | 上海医药工业研究院 | Duloxetine enteric coated tiny pill capsule, and preparation method |
| CN101686947A (en) * | 2007-06-23 | 2010-03-31 | 箭锋国际有限公司 | duloxetine formulation |
| WO2009092129A1 (en) * | 2008-01-25 | 2009-07-30 | Alpharma Pty Ltd | Delayed release pharmaceutical composition of duloxetine |
| CN101756960A (en) * | 2008-12-26 | 2010-06-30 | 上海中西制药有限公司 | Duloxetine enteric-coated preparation and core material and preparation method thereof |
| WO2010150219A1 (en) * | 2009-06-25 | 2010-12-29 | Wockhardt Research Centre | Pharmaceutical composition of duloxetine or pharmaceutically acceptable salts thereof |
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| CN102579403A (en) | 2012-07-18 |
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