CN109498544A - Stable Olanzapine composition and preparation method thereof - Google Patents
Stable Olanzapine composition and preparation method thereof Download PDFInfo
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- CN109498544A CN109498544A CN201710830001.2A CN201710830001A CN109498544A CN 109498544 A CN109498544 A CN 109498544A CN 201710830001 A CN201710830001 A CN 201710830001A CN 109498544 A CN109498544 A CN 109498544A
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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
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- 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
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- 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
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Abstract
This application discloses a kind of stable pharmaceutical compositions and preparation method thereof containing Olanzapine.The composition contains Olanzapine and other pharmaceutically acceptable auxiliary materials, using special preparation method, can effectively improve the stability of Olanzapine in the composition, the treatment for spirit classification disease.
Description
Technical field
The application belongs to technical field of medicine, and in particular to contains the pharmaceutical composition of Olanzapine and its preparation side
Method.
Background technique
World Health Organization's estimation, the schizoid lifetime prevalence in the whole world are about 3.8 ‰~8.4 ‰.The U.S.
Research, lifetime prevalence are up to 13 ‰.Annual new cases, i.e. annual morbidity are 0.22 ‰ or so.Although 2/3 patient needs
Hospitalization, but only the schizophreniac of half is treated.
Entitled 2- methyl-1 0- (4- methyl-1-the piperazine)-4H- thieno [2,3- of chemistry of Olanzapine (Olanzapine)
B] [1,5] benzodiazepine as a kind of 5-HT2 and D2 receptor antagonist is treatment schizophrenia fiest-tire medication, curative effect
It is excellent, the positive symptom, negative symptoms and affective symptom of schizophrenic patients can be improved；It is first to be approved for schizophrenia
The atypical antipsychotic of new generation of disease long-term treatment is used at least 84 countries；It is currently the only one right
There are few the anti-smart drug dispensing objects of the atypia of adverse reaction for heart.Olanzapine is a kind of novel mental researched and developed by Lilly Co., Eli.
Medication, trade name Zyprexa®, listed in 1996 in USA and EU, import China in 1999 now lists dosage form both at home and abroad
There are tablet, freeze-drying oral disintegrating tablet, long-acting injection and short-acting freeze drying powder injection.
Olanzapine itself is more unstable, can be oxidized generate impurity C(2-Methyl-4- (4- under oxidative conditions
Methylpiperazin-1-yl) 4 '-N-oxide of -10H-benzo [b] thieno [2,3-e] [1,4] diazepine).It is miscellaneous
Quality Control system is the important component of drug quality, to the limit of impurity C in the olanzapine orally-disintegrating tablet quality standard of United States Pharmacopeia
Carry out strict control.Therefore when preparing Olanzapine related preparations, the generation of the impurity is avoided to the maximum extent, is conducive to improve difficult to understand
The product quality and safety of the flat related preparations of nitrogen are of great importance to patient clinical drug safety is improved.
Summary of the invention
The application's is designed to provide a kind of preferable Olanzapine composition of stability and preparation method.Due to Olanzapine
It can be oxidized to (2-Methyl-4- (4-methylpiperazin-1-yl) -10H-benzo [b] under oxidative conditions
4 '-N-oxide of thieno [2,3-e] [Isosorbide-5-Nitrae] diazepine), i.e. impurity C, and containing with oxidation work in many auxiliary materials
Impurity (such as peroxide and fumed metal oxide), so as to cause the generation of impurity C in preparation, therefore the application is using special
Different preparation process is first individually made the auxiliary material (such as crospovidone) containing oxidation impurity using adhesive appropriate
Grain, then mixed with bulk pharmaceutical chemicals and other auxiliary materials, the area that Olanzapine and the auxiliary material with oxidative impurities directly contact is reduced, from
And reduce the generation of impurity C；The available control compared with limits of impurity C in finally obtained Olanzapine composition.
Olanzapine composition provided herein, containing Olanzapine, filler, disintegrating agent, corrigent, lubricant and its
His pharmaceutically acceptable auxiliary material；The ratio of Olanzapine is 2.5 ~ 10% in Olanzapine composition provided herein, filler
Ratio be 50 ~ 80%, the ratio of disintegrating agent is 10 ~ 30%, and the ratio of corrigent is 0 ~ 5%, and the ratio of lubricant is 0.5 ~ 5%；
Or, the ratio of Olanzapine is about 5%, the ratio of filler is 60 ~ 70%, and the ratio of disintegrating agent is 15 ~ 25%, the ratio of corrigent
For 2-3%, the ratio of lubricant is 1 ~ 3%；
Olanzapine composition provided herein, wherein filler is lactose, mannitol, microcrystalline cellulose, xylitol, pre- glue
Change one or more of starch；Disintegrating agent is crospovidone, one kind or several of croscarmellose sodium, dried starch
Kind；Corrigent is one or more of aspartame, acesulfame potassium, stevioside, menthol；Lubricant is magnesium stearate, talcum
One or more of powder, sodium stearyl fumarate.
Olanzapine composition provided herein the preparation method is as follows:
(1a) weighs recipe quantity disintegrating agent, partially filled agent and/or adhesive and is uniformly mixed；
(2) Olanzapine and remaining filler, corrigent for weighing recipe quantity, are sufficiently mixed with material I, obtain material II；
(3) recipe quantity lubricant is weighed, is added in material II, Olanzapine composition is obtained after mixing.
The preparation method of Olanzapine composition provided herein, further includes:
(1b) carries out wet granulation using adhesive appropriate and/or wetting agent；Dry to obtain material I.
In Olanzapine preparation method of composition described herein, the type of adhesive is hydroxypropyl cellulose, hydroxypropyl first
One or more of cellulose；The adding manner of adhesive is that dry method is added, and/or is configured to certain density solution；Object
The fine powder amount of material I is controlled 30% hereinafter, to avoid Olanzapine from contacting with the auxiliary material containing oxidizing substance, reduces impurity C's
It generates.
The Olanzapine composition obtained according to above-mentioned preparation method: the ratio of Olanzapine is 2.5 ~ 10%, the ratio of filler
It is 50 ~ 80%, the ratio of disintegrating agent is 10 ~ 30%, and the ratio of corrigent is 0 ~ 5%, and the ratio of lubricant is 0.5 ~ 5%；Or, nitrogen difficult to understand
Flat ratio is about 5%, and the ratio of filler is 60 ~ 70%, and the ratio of disintegrating agent is 15 ~ 25%, and the ratio of corrigent is 2-3%,
The ratio of lubricant is 1 ~ 3%.
Above-mentioned Olanzapine composition, can be used for preparing tablet, oral disintegrating tablet, dispersible tablet, granule and dry suspensoid agent.
Olanzapine composition provided by the present application, wherein the content of impurity C is lower than 0.20%, preferably shorter than 0.10%, preferably
Lower than 0.05%, and after shelf-stability test, preparation stability is good.
Specific embodiment
Following embodiment further describes beneficial effects of the present invention, and embodiment is only used for the purpose of illustration, does not limit this
The range of invention, at the same those of ordinary skill in the art made according to the present invention it is obvious change and modification be also contained in
Within the scope of the invention.
(1) preparation of Olanzapine composition
Embodiment 1
Preparation process
(1) recipe quantity crospovidone, microcrystalline cellulose are weighed, 60 meshes is crossed and is uniformly mixed；
(2) hydroxypropyl methylcellulose being configured to 3% aqueous solution, above-mentioned material is added, the granulation of 24 meshes is dried, 24 mesh sieves,
Obtain material I, fine powder amount 21%；
(3) yield is converted, Olanzapine, lactose and the material I after conversion are sufficiently mixed, material II is obtained；
(4) conversion amount magnesium stearate is weighed, is added in material II, Olanzapine composition is obtained after mixing.
Embodiment 2
Preparation process
(1) recipe quantity crospovidone, microcrystalline cellulose, hydroxypropyl methylcellulose are weighed, 60 meshes is crossed and is uniformly mixed；
(2) by 20% alcohol solution, above-mentioned material is added, the granulation of 24 meshes is dried, and 24 mesh sieves obtain material I, and fine powder amount is
18.2%；
(3) yield is converted, Olanzapine, mannitol, aspartame and the material I after conversion are sufficiently mixed, material II is obtained；
(4) conversion amount magnesium stearate is weighed, is added in material II, Olanzapine composition is obtained after mixing.
Embodiment 3
Preparation process
(1) recipe quantity croscarmellose sodium, microcrystalline cellulose, hydroxypropyl methylcellulose are weighed, 60 meshes is crossed and is uniformly mixed；
(2) by 20% alcohol solution, above-mentioned material is added, the granulation of 24 meshes is dried, and 24 mesh sieves obtain material I, and fine powder amount is
15.3%；
(3) yield is converted, Olanzapine, xylitol, stevioside and the material I after conversion are sufficiently mixed, material II is obtained；
(4) conversion amount magnesium stearate is weighed, is added in material II, Olanzapine composition is obtained after mixing.
Embodiment 4
Preparation process
(1) recipe quantity croscarmellose sodium, microcrystalline cellulose are weighed, 60 meshes is crossed and is uniformly mixed；
(2) hydroxypropyl methylcellulose being configured to 5% aqueous solution, above-mentioned material is added, the granulation of 20 meshes is dried, 20 mesh sieves,
Obtain material I, fine powder amount 12.9%；
(3) yield is converted, Olanzapine, lactose and the material I after conversion are sufficiently mixed, material II is obtained；
(4) conversion amount talcum powder is weighed, is added in material II, Olanzapine composition is obtained after mixing.
Embodiment 5
Preparation process
(1) recipe quantity crospovidone, microcrystalline cellulose are weighed, 60 meshes is crossed and is uniformly mixed；
(2) hydroxypropyl methylcellulose being configured to 2% aqueous solution, above-mentioned material is added, the granulation of 24 meshes is dried, 24 mesh sieves,
Obtain material I, fine powder amount 27.3%；
(3) yield is converted, Olanzapine, lactose, menthol and the material I after conversion are sufficiently mixed, material II is obtained；
(4) conversion amount talcum powder is weighed, is added in material II, Olanzapine composition is obtained after mixing.
Embodiment 6
Preparation process
(1) recipe quantity crospovidone, microcrystalline cellulose, hydroxypropyl methylcellulose are weighed, 60 meshes is crossed and is uniformly mixed；
(2) hydroxypropyl methylcellulose being configured to 2% aqueous solution, above-mentioned material is added, the granulation of 20 meshes is dried, 20 mesh sieves,
Obtain material I, fine powder amount 9.2%；
(3) yield is converted, Olanzapine, lactose, aspartame and the material I after conversion are sufficiently mixed, material II is obtained；
(4) conversion amount sodium stearyl fumarate is weighed, is added in material II, Olanzapine composition is obtained after mixing.
Comparative example
Preparation process
(1) recipe quantity Olanzapine, lactose, microcrystalline cellulose, crospovidone are weighed, 60 meshes is crossed and is uniformly mixed, obtain material I；
(2) hydroxypropyl methylcellulose being configured to 3% aqueous solution, above-mentioned material is added, the granulation of 20 meshes is dried, 20 mesh sieves,
Obtain material II；
(3) yield is converted, the aspartame after conversion is sufficiently mixed with material II, obtains material III；
(4) conversion amount magnesium stearate is weighed, is added in material III, Olanzapine composition is obtained after mixing.
(2) criteria of quality evaluation
The content of impurity C in the Olanzapine composition being prepared using USP standard test the above various embodiments.
Impurity C content (%) in different embodiments
。
Compared by 0 day and 10 days results of influence factor of comparative example and the impurity C content of embodiment 1 ~ 6 it is found that
The auxiliary material that oxidative impurities will be present individually is pelletized, and is reduced the contact area of Olanzapine and such auxiliary material, can fundamentally be dropped
Low Olanzapine oxidation impurities, the i.e. generation of impurity C；Stabilization of the Olanzapine composition under intense environment is effectively raised simultaneously
Property, impurity increases less；Impurity C in Olanzapine composition can effectively be controlled using preparation method described herein
Content is lower than 0.20%；.
Embodiment described above is only to absolutely prove preferred embodiment that is of the invention and being lifted, protection model of the invention
It encloses without being limited thereto.Those skilled in the art's made equivalent substitute or transformation on the basis of the present invention, in the present invention
Protection scope within.Protection scope of the present invention is subject to claims.
Claims (10)
1. the pharmaceutical composition containing Olanzapine: containing Olanzapine, filler, disintegrating agent, corrigent, lubricant and other pharmacy
Upper acceptable auxiliary material.
2. according to Olanzapine composition described in claim 1: the ratio of Olanzapine is 2.5 ~ 10%, the ratio of filler is 50 ~
80%, the ratio of disintegrating agent is 10 ~ 30%, and the ratio of corrigent is 0 ~ 5%, and the ratio of lubricant is 0.5 ~ 5%；
Or, the ratio of Olanzapine is about 5%, the ratio of filler is 60 ~ 70%, and the ratio of disintegrating agent is 15 ~ 25%, corrigent
Ratio is 2-3%, and the ratio of lubricant is 1 ~ 3%.
3. according to Olanzapine composition of any of claims 1 or 2: preparation method is as follows:
(1a) weighs recipe quantity disintegrating agent, partially filled agent and/or adhesive and is uniformly mixed；
The Olanzapine and remaining filler, corrigent for weighing recipe quantity, are sufficiently mixed with material I, obtain material II；
(3) recipe quantity lubricant is weighed, is added in material II, Olanzapine composition is obtained after mixing.
4. preparation method according to claim 3, further includes:
(1b) carries out wet granulation using adhesive appropriate and/or wetting agent；Dry to obtain material I.
5. preparation method according to claim 3 or 4: the type of adhesive is hydroxypropyl cellulose, hydroxypropyl methylcellulose
One or more of.
6. preparation method according to claim 3 or 4: the adding manner of adhesive is that dry method is added, and/or is configured to one
Determine the solution of concentration.
7. preparation method according to claim 3 or 4: the fine powder amount of material I is 30% or less.
8. the Olanzapine composition that preparation method according to claim 3 or 4 obtains: the ratio of Olanzapine is 2.5 ~ 10%,
The ratio of filler is 50 ~ 80%, and the ratio of disintegrating agent is 10 ~ 30%, and the ratio of corrigent is 0 ~ 5%, and the ratio of lubricant is
0.5~5%；
Or, the ratio of Olanzapine is about 5%, the ratio of filler is 60 ~ 70%, and the ratio of disintegrating agent is 15 ~ 25%, corrigent
Ratio is 2-3%, and the ratio of lubricant is 1 ~ 3%.
9. Olanzapine composition according to claim 8: can be used for preparing tablet, oral disintegrating tablet, dispersible tablet, granule and do
The preparations such as suspension.
10. Olanzapine composition or preparation according to claim 8 or claim 9: wherein the content of impurity C is lower than 0.20%, preferably
Lower than 0.10%, preferably shorter than 0.05%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710830001.2A CN109498544A (en) | 2017-09-15 | 2017-09-15 | Stable Olanzapine composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710830001.2A CN109498544A (en) | 2017-09-15 | 2017-09-15 | Stable Olanzapine composition and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109498544A true CN109498544A (en) | 2019-03-22 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710830001.2A Pending CN109498544A (en) | 2017-09-15 | 2017-09-15 | Stable Olanzapine composition and preparation method thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006074951A2 (en) * | 2005-01-14 | 2006-07-20 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Orally disintegrating composition of olanzapine or donepezil |
| CN101904824A (en) * | 2009-06-04 | 2010-12-08 | 齐鲁制药有限公司 | Olanzapine orally-disintegrating tablet preparation and preparation method thereof |
-
2017
- 2017-09-15 CN CN201710830001.2A patent/CN109498544A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006074951A2 (en) * | 2005-01-14 | 2006-07-20 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Orally disintegrating composition of olanzapine or donepezil |
| CN101904824A (en) * | 2009-06-04 | 2010-12-08 | 齐鲁制药有限公司 | Olanzapine orally-disintegrating tablet preparation and preparation method thereof |
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Application publication date: 20190322 |