CN107412198A - Duloxetine hydrochloride enteric slow release granule and preparation method thereof - Google Patents
Duloxetine hydrochloride enteric slow release granule and preparation method thereof Download PDFInfo
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- CN107412198A CN107412198A CN201710186547.9A CN201710186547A CN107412198A CN 107412198 A CN107412198 A CN 107412198A CN 201710186547 A CN201710186547 A CN 201710186547A CN 107412198 A CN107412198 A CN 107412198A
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- Prior art keywords
- duloxetine hydrochloride
- enteric
- duloxetine
- slow release
- release
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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
- A61K9/5005—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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- 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
- A61K9/5005—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
Abstract
The invention discloses a kind of enteric slow release granule of hydrochloric Duloxetine and preparation method thereof.Duloxetine hydrochloride is first prepared into inclusion compound by the preparation of the present invention, is then prepared into enteric coated particles again.Collectively constituted including duloxetine hydrochloride inclusion compound and acceptable auxiliary material, polymeric alloy membrane, rate of release modifying ingredients and enteric solubility external sheath material are comprised at least in wherein described adjunct ingredient, the medicine discharges in enteron aisle corrosion, action time is lasting, substantially reduce the rate of side effects that dose discharges rapidly after taking medicine, blood concentration and medicine is set to act on more steady lasting, enhancing patient's medication compliance and clinical therapeutic efficacy.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, in particular to a kind of duloxetine hydrochloride enteric coated particles and its
Preparation method.
Background technology
Duloxetine hydrochloride (Duloxetine Hydrochloride) to serotonin (5-HT) and removes first kidney to be a kind of
The intake of upper parathyrine (NE) has the compound that double inhibition acts on.Existing research data it has been shown that the medicine to depression,
Pain caused by diabetic peripheral neuropathy and the tonicity urinary incontinence etc. have certain curative effect.
Duloxetine hydrochloride for white or off-white color crystalline powder, photostability is poor, in water dissolubility it is poor and
It is unstable under sour environment, it is easy to degrade.In consideration of it, in order to ensure that medicine does not react with acidic materials, salt acidity Lip river
Enteric coated preparations are suitably made in Xi Ting, it is therefore desirable to a kind of system that can increase drug solubility and can and ensure not react with acid
Agent and preparation method thereof.
CN1759829A discloses a kind of duloxetine enteric coated tiny pill capsule and preparation method thereof, and the micropill is by blank pill
Core and the coatings composition being wrapped in outside blank capsule core, described coatings include the main medicament layer containing main ingredient and auxiliary material, bag
The separation layer being rolled in outside main medicament layer and the enteric layer being wrapped in outside separation layer.The enteric-coated pellet capsule is although can reach in small intestine
The advantages of interior rapid release, but the requirement of enteric-coated micro-pill preparation technology parameter is strict, and also technique is cumbersome, preparation time length, no
Utilize industrialized production.
Duloxetine hydrochloride sustained release particle provided by the invention, the water solubility of medicine, and medicine are added using clathrate process
Thing rate of release is stable, drug release time length, avoids the compliance issues that multiple dosing is brought.
The content of the invention
It is an object of the invention to provide a kind of duloxetine hydrochloride enteric slow release particle, the enteric slow release particle preparation work
Skill is simple, facilitates patients, less times for spraying, improves the Compliance of patient.And can effectively control delays medicine to exist
Internal absorption, blood concentration is steady, persistent, and curative effect is stable.
The duloxetine hydrochloride enteric slow release particle, active ingredient are duloxetine hydrochloride, in addition to high molecular slow-release
The auxiliary material component of material, rate of release modifying ingredients and enteric solubility external sheath material.Wherein duloxetine hydrochloride is by salt acidity
Inclusion compound is made with inclusion material in duloxetine, and the weight ratio of duloxetine hydrochloride and inclusion material is 1:1~1:3, preferred scheme
It is 1:2.
Described polymeric alloy membrane is hydroxypropyl methyl cellulose, ethyl cellulose, polypropylene propylhomoserin resin and hard
At least one of resin acid.It is preferred that hydroxypropyl methyl cellulose and stearic acid, wherein duloxetine hydrochloride and high molecular slow-release material
It is 3.2 to expect weight ratio:1.5.
Described rate of release modifying ingredients be sodium carboxymethylcellulose, PVPP, low-substituted hydroxypropyl cellulose,
Microcrystalline cellulose is one or more of, preferably PVPP and microcrystalline cellulose, and wherein duloxetine hydrochloride is adjusted with rate of release
It is 2.7 to save weight ratio of constituents:7.5.
Described enteric-soluble coating material includes methacrylate copolymer, cellulose acetate, hydroxypropyl methylcellulose phthalein
Acid esters, polyvinyl acetate, polyacrylic resin one or more therein, preferred methacrylate copolymer and hydroxypropyl first
Cellulose phthalate, wherein duloxetine hydrochloride are 1.5 with enteric-soluble coating material weight ratio:1.
The preparation method of duloxetine hydrochloride enteric slow release particle of the present invention concretely comprises the following steps：
（1）Prepare medicinal inclusion compound：Duloxetine hydrochloride drug solution is prepared first, is then added hydroxypropylβ-cyclodextrin and is stirred
Mix, included, inclusion filters after terminating, and dries, produces inclusion particulate；
（2）It is prepared by particulate：Inclusion compound obtained above is mixed with high-molecular bone frame material and speed modifying ingredients, using wet method
Granulation obtains duloxetine hydrochloride sustained release particulate；
（3）Enteric slow release particle preparation：The above-mentioned sustained-release microparticle being prepared is coated using enteric material, produces hydrochloric acid
Duloxetine enteric-coated slow-releasing granules.
Duloxetine hydrochloride enteric slow release particle provided by the present invention, medicinal inclusion compound is prepared using clathrate process, and
Slow-releasing granules are prepared using wet granulation, have effectively achieved the slow releasing function of medicine, then particle is wrapped with enteric material
Clothing.Avoiding medicine from being degraded in stomach in sour environment, reduce medicining times, improve the Compliance of patient, cost is relatively low,
It is suitable for industrialized production.
Specific embodiment
This application provides a kind of duloxetine hydrochloride enteric slow release particle, its composition are as follows.
Embodiment
Duloxetine hydrochloride：Hydroxypropylβ-cyclodextrin is 1:2
Preparation technology：
Containing in 50% ethanol aqueous medium, in prescription ratio, duloxetine hydrochloride and hydroxypropylβ-cyclodextrin are reacted, gained is molten
Liquid, to clarifying, inclusion compound is isolated from mixture duloxetine hydrochloride inclusion compound is crossed into 100 mesh sieves through filtering with microporous membrane, will
Remaining auxiliary material crushed 80 mesh sieves；The accurate supplementary material for weighing recipe quantity, is well mixed, adds suitable quantity of water that mixture is made into wet thing
Material is pelletized on granulator with 18 mesh sieves, 60 DEG C of dryings, and obtained particle is coated in fluid bed by enteric material, produces intestines
Molten slow-releasing granules.
In this application, duloxetine hydrochloride inclusion compound enteric slow release particle is prepared from specific auxiliary material.Wherein described height
Molecule slow-release material is methacrylate copolymer and HP-55, and the two part by weight is 3.2:1.5；Release
Put speed modifying ingredients disintegrant is for PVPP and the composition of Ac-Di-Sol, the two part by weight
2.7:7.5；Enteric coating material is the composition of methacrylate copolymer and HP-55, the two weight ratio
Example is 1.5:1.
It is demonstrated experimentally that not any conventional auxiliary material is suitable for preparing duloxetine hydrochloride inclusion compound enteric slow release particle, choosing
With the duloxetine hydrochloride enteric coated particles that this specific auxiliary material is prepared dissolution velocity, stability, dissolution rate etc. effect
Fruit is far better than the duloxetine hydrochloride inclusion compound enteric slow release particle that other auxiliary materials are prepared.
Comparative example 1
Duloxetine hydrochloride：Hydroxypropylβ-cyclodextrin is 1:2
Preparation method is same as above.
Comparative example 2
Duloxetine hydrochloride：Hydroxypropylβ-cyclodextrin is 1:2
Preparation method is same as above.
Comparative example 3
Duloxetine hydrochloride：Hydroxypropylβ-cyclodextrin is 1:2
Preparation method is same as above.
Comparative example 4
Duloxetine hydrochloride：Hydroxypropylβ-cyclodextrin is 1:2
Preparation method is same as above.
Comparative example 5
Duloxetine hydrochloride：Hydroxypropylβ-cyclodextrin is 1:2
Preparation method is same as above.
Influence of the different enteric coating materials to duloxetine hydrochloride enteric slow release particle.
Test method：The duloxetine hydrochloride enteric slow release particle that different enteric coating materials are prepared is being simulated respectively
Measure dissolution rate in gastric juice environment and simulation intestinal environment, the results are shown in Table 1.
Prescription：
,
Table 1
。
Only using the group of methacrylate copolymer and HP-55 it can be seen from the data of table 1
Enteric coated particles of the compound as enteric coating material（That is embodiment）It is almost insoluble in simulate the gastric juice environment, in simulation intestinal environment
In almost can whole dissolutions；And the enteric coated particles that other enteric coating materials are prepared in simulate the gastric juice environment dissolution rate compared with
Greatly, it is impossible to make granule safety stomach and be disintegrated again to enteron aisle.Therefore, the enteric coated particles of the application are using specific
Enteric coating auxiliary material, other kinds of enteric coating auxiliary material are not suitable for being prepared into duloxetine hydrochloride enteric slow release particle.
Duloxetine hydrochloride enteric slow release granule stability is tested.
Shadow has been carried out to comparative example and the outward appearance of the enteric coated particles of embodiment 1 ~ 5, dissolution rate, content and dissolution time
The factor of sound is investigated.
Hot test：Take the sample of Comparative Examples Example 1 ~ 5 to be laid in right amount in culture dish, be placed in 60 DEG C of insulating box
Middle to place 10 days, the 0th, 5,10 day during this, separately sampled product measure, measurement result is shown in Table 2.
High wet test：Take sample to be laid in right amount in culture dish, placed under conditions of 25 DEG C of relative humidity RH90% ± 5%
10 days, the 0th, 5,10 day during this, separately sampled product measure, measurement result was shown in Table 2.
Strong illumination is tested, and is taken sample to be laid in right amount in culture dish, is placed in light cupboard in 4500Lx ± 500LX condition
Illumination 10 days, the 0th, 5,10 day during this, separately sampled product measure, measurement result is shown in Table 2.
Each embodiment enteric coated particles of table 2. are hot and humid and strong light stability inferior
Each component type selected in comparative example 1 does not change, but the two in the composition of polymeric alloy membrane
Part by weight is changed；The rate of release modifying ingredients type selected in comparative example 2 does not change, but composition
In the part by weight of the two changed；The hydroxypropyl methyl that polymeric alloy membrane is changed into single in comparative example 3 is fine
Dimension element；Rate of release modifying ingredients is changed into single PVPP in comparative example 4；It is macromolecular sustained in comparative example 5
Release material, rate of release modifying ingredients is changed to single hydroxypropyl methyl cellulose and single PVPP.By table 2
Experimental data can be seen that in the case where each Ingredient Amount is identical, and auxiliary material type does not change but changes component
Usage ratio, the duloxetine hydrochloride enteric slow release particle being prepared（Comparative example 1 ~ 5）Stability relative to implementation
Example significantly reduces.Above-mentioned description of test, the only herein described salt acidity being prepared by specific auxiliary material and specific dosage
Duloxetine enteric coated particles just have unexpected superior solubility speed, stability, dissolution rate.
Claims (6)
1. duloxetine hydrochloride enteric slow release particle, including active ingredient duloxetine hydrochloride, polymeric alloy membrane, release speed
Spend modifying ingredients and enteric solubility external sheath material.
2. duloxetine hydrochloride enteric slow release particle as claimed in claim 1, it is characterised in that the duloxetine hydrochloride is
Inclusion compound, inclusion material is hydroxypropylβ-cyclodextrin, and the weight ratio of duloxetine hydrochloride and inclusion material is 1:1~1:3.
3. duloxetine hydrochloride enteric slow release particle as claimed in claim 1, it is characterised in that described high molecular slow-release material
Expect for hydroxypropyl methyl cellulose, ethyl cellulose, the one or more in polypropylene propylhomoserin resin and stearic acid, preferably hydroxypropyl
Ylmethyl cellulose and stearic acid, duloxetine hydrochloride are 3.2 with polymeric alloy membrane weight ratio:1.5.
4. the duloxetine hydrochloride enteric slow release particle as described in claim 1, it is characterised in that described rate of release regulation
Composition is sodium carboxymethylcellulose, PVPP, low-substituted hydroxypropyl cellulose, microcrystalline cellulose are one or more of, preferably
PVPP and microcrystalline cellulose, duloxetine hydrochloride are 2.7 with rate of release modifying ingredients weight ratio:7.5.
5. the duloxetine hydrochloride enteric slow release particle as described in claim 1, it is characterised in that described enteric coatings material
Material includes methacrylate copolymer, cellulose acetate, HP-55, polyvinyl acetate, polyacrylic acid
Resin one or more therein, preferred methacrylate copolymer and HP-55, duloxetine hydrochloride
It is 1.5 with enteric-soluble coating material weight ratio:1.
6. the duloxetine hydrochloride enteric slow release particle according to claim 1 ~ 5 any one, its preparation method is included such as
Lower step：
（1）Prepare medicinal inclusion compound：Duloxetine hydrochloride drug solution is prepared first, is then added hydroxypropylβ-cyclodextrin and is stirred
Mix, included, inclusion filters after terminating, and dries, produces inclusion particulate；
（2）It is prepared by particulate：Inclusion compound obtained above is mixed with high-molecular bone frame material and speed modifying ingredients, using wet method
Granulation obtains duloxetine hydrochloride sustained release particulate；
（3）Enteric slow release particle preparation：The above-mentioned sustained-release microparticle being prepared is coated using enteric material, produces hydrochloric acid
Duloxetine enteric-coated slow-releasing granules.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710186547.9A CN107412198A (en) | 2017-03-27 | 2017-03-27 | Duloxetine hydrochloride enteric slow release granule and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710186547.9A CN107412198A (en) | 2017-03-27 | 2017-03-27 | Duloxetine hydrochloride enteric slow release granule and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
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| CN107412198A true CN107412198A (en) | 2017-12-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710186547.9A Pending CN107412198A (en) | 2017-03-27 | 2017-03-27 | Duloxetine hydrochloride enteric slow release granule and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114053218A (en) * | 2020-08-06 | 2022-02-18 | 武汉科福新药有限责任公司 | Nadolol sustained-release oral liquid and preparation method thereof |
| CN114099445A (en) * | 2021-11-12 | 2022-03-01 | 成都市坤宏优创生物科技有限公司 | Preparation method of sustained-release granules |
| CN116617189A (en) * | 2023-07-26 | 2023-08-22 | 四川尚锐生物医药有限公司 | Duloxetine hydrochloride sustained-release capsule and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101164532A (en) * | 2006-10-17 | 2008-04-23 | 重庆圣华曦药业有限公司 | Duloxetine hydrochloride sustained release medicine |
| CN101361703A (en) * | 2008-09-24 | 2009-02-11 | 宋洪涛 | Sirolimos sustained and controlled release preparation and preparation method thereof |
| US20100285123A1 (en) * | 2005-06-20 | 2010-11-11 | Rudresha Korlakunte Virupakshalah Prasad | Controlled Release Dosage Formulation of Duloxetine |
-
2017
- 2017-03-27 CN CN201710186547.9A patent/CN107412198A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100285123A1 (en) * | 2005-06-20 | 2010-11-11 | Rudresha Korlakunte Virupakshalah Prasad | Controlled Release Dosage Formulation of Duloxetine |
| CN101164532A (en) * | 2006-10-17 | 2008-04-23 | 重庆圣华曦药业有限公司 | Duloxetine hydrochloride sustained release medicine |
| CN101361703A (en) * | 2008-09-24 | 2009-02-11 | 宋洪涛 | Sirolimos sustained and controlled release preparation and preparation method thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114053218A (en) * | 2020-08-06 | 2022-02-18 | 武汉科福新药有限责任公司 | Nadolol sustained-release oral liquid and preparation method thereof |
| CN114053218B (en) * | 2020-08-06 | 2022-11-15 | 武汉科福新药有限责任公司 | Nadolol sustained-release oral liquid and preparation method thereof |
| CN114099445A (en) * | 2021-11-12 | 2022-03-01 | 成都市坤宏优创生物科技有限公司 | Preparation method of sustained-release granules |
| CN116617189A (en) * | 2023-07-26 | 2023-08-22 | 四川尚锐生物医药有限公司 | Duloxetine hydrochloride sustained-release capsule and preparation method thereof |
| CN116617189B (en) * | 2023-07-26 | 2023-09-26 | 四川尚锐生物医药有限公司 | Duloxetine hydrochloride sustained-release capsule and preparation method thereof |
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Application publication date: 20171201 |