CN103156860A - Olanzapine composition and preparation method thereof - Google Patents
Olanzapine composition and preparation method thereof Download PDFInfo
- Publication number
- CN103156860A CN103156860A CN 201110413864 CN201110413864A CN103156860A CN 103156860 A CN103156860 A CN 103156860A CN 201110413864 CN201110413864 CN 201110413864 CN 201110413864 A CN201110413864 A CN 201110413864A CN 103156860 A CN103156860 A CN 103156860A
- Authority
- CN
- China
- Prior art keywords
- olanzapine
- preparation
- mean size
- particle mean
- equal
- 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
Abstract
The invention provides a composition comprising olanzapine crystalline particles with an average particle size equal to or smaller than 30 [mu]m and a pharmaceutically acceptable carrier. The olanzapine crystalline particles with the average particle size equal to or smaller than 30 [mu]m are basically bioequivalent. The composition can be used for treating mental diseases such as schizophrenia.
Description
Technical field
The invention belongs to oral Preparation this field, the present invention relates to contain the olanzapine pharmaceutical preparations composition of the olanzapine crystalline particle with full-size cutoff, the invention still further relates to a kind of olanzapine solid preparation and preparation method thereof.
Background technology
Olanzapine (Olanzapine) chemistry 2-methyl-4-(4-methyl-4-chloromethyl-1-piperazinyl) by name-10H-thieno [2,3-b] [1,5]-benzodiazepine, be a kind of known compound and can use MS5, in 229,382, disclosed operation is synthesized.Be used for the treatment of schizophrenia and show that it can be used for preventing to suffer from the recurrence of amphicheirality patient with phychlogical problems manic episode.This product has advantages of that long-term efficacy reaches side effect well little as antipsychotic agent, and the dosage form of going on the market at present has conventional tablet, oral cavity dispersible tablet, oral cavity disintegration tablet and intramuscular injection agent; Domestic only have an ordinary tablet.Yet this compound water soluble is lower, and this is disadvantageous to bioavailability.
Bioavailability is the applicable degree of target tissue after drug administration.Many factors affect bioavailability, comprise dosage form and various character, for example the dissolution rate of medicine.Bioavailability is poor is the outstanding problem that runs in the exploitation of Pharmaceutical composition, particularly contains those compositionss of active component poorly soluble in water.
The dissolution rate of known drug particles can be with the increase of surface area, i.e. reducing of granularity and increasing.So, studied and prepared the method for segmenting medicine, and size and the size range of controlling Pharmaceutical composition Chinese medicine granule have been made effort.The U.S. Patent numbers such as Liversidge 5,145,684 disclose has drug particles that is adsorbed on its lip-deep non-crosslinked surface stabilizer and preparation method thereof.This patent does not propose the microparticle compositions of olanzapine.
The method for preparing nanoparticle composition has description in following patent, for example U.S. Patent number 5,518, and 187 and 5,862,999, both titles are " method of grinding medical substance "; U.S. Patent number 5,718,388, " grinding the continuation method of medical substance "; And U.S. Patent number 5,510,118, " preparation contains the method for the therapeutic combination of nano-particle ".WO02/098565 " system and method for the raw material of milling " has described the nanoparticle active pharmaceutical compositions in addition; U.S. Patent number 5,776,496 " improving ultrasonic backscattered extra small porous particle ".These patents are not described preparation microgranule olanzapine.
From the preparation viewpoint, for how improving this type of the stripping of insoluble chemical compound of olanzapine, pharmaceutics area research personnel seek the solubility property that various technology are improved medicine always, the special preparation excipient that typical solution route has (1) to use to increase dissolubility is surfactant for example, and/or (2) are long-pending to promote its quick dissolving by increasing medical surfaces with the preparation of granule medicine.But the preparation difficulty that a kind of rear method obtains is large and increased cost, and quality control is difficult simultaneously.
Summary of the invention
The invention provides a kind of particle mean size and be less than or equal to the olanzapine crystal grain of 30 μ m and the pharmaceutical composition of pharmaceutically acceptable diluent or carrier.Herein and the granularity of stipulating in claims refer to the granularity determined with the Malvern light scattering.
Determine now: for the compositions that contains the olanzapine crystal grain, when its particle mean size is less than or equal to 30 μ m, show good dissolution properties under the physiological pH condition, and containing the preparation that granularity is less than or equal to the olanzapine crystal of 30 μ m is bioequivalent basically, and this explanation granularity has nothing to do with the bioequivalent factor that affect olanzapine less than the granule of 30 μ m.
The present invention also provides a kind of antipsychotic method, comprise: use the compositions of effective dose to the patient of needs treatment, compositions contains olanzapine crystal or the pharmaceutically acceptable carrier that useful Malvern determination of light scattering particle mean size is less than or equal to 30 μ m.
As mentioned above, owing to showing good solubility property under the physiological pH condition, preparation of the present invention is particularly advantageous, but research find dissolution in vitro speed not with granular relevant.That is to say, usually particle size reduction and/or specific surface area increase can make the rate of dissolution than low solubility drug increase, but when being equal to or less than 30 μ m for the granularity of olanzapine, its rate of dissolution in water-bearing media does not change with the variation of granularity basically, therefore seems basically irrelevant with granularity.Therefore, use common galenic pharmacy method and apparatus, can be easy to obtain the compositions of reasonable granularity, olanzapine is added in said composition, do not need to take again further step or special technology to reach more small granule and dissolve with promotion.
When external when carrying out the solubility test of preparation of the present invention, the dissolution characteristics that said preparation preferably shows is, when containing 900ml water, be equipped with in the MSP-2 device of paddle agitator, under the speed with 50rpm/min stirs, have at least 85% olanzapine dissolved in 15min.Usually, this test result is the meansigma methods of predetermined dose number (as capsule, tablet, suspensoid or other preparation), predetermined number wherein normally 6.Usually make the temperature of dissolve medium maintain 37 ℃ during test.As hereinafter described, usually determine the amount of olanzapine dissolving with HPLC.
Term " granule " refers to individual particle, and no matter these granules are individualisms or exist with coherent condition.Like this, the compositions that contains the olanzapine crystal grain may contain polymer, and the granularity of these polymer is considerably beyond the boundary of 30 μ m of appointment herein.If contain each average particle size of main drug substance granule (being olanzapine) of polymer less than 30 μ m, this aggregation itself is considered to satisfy the particle size restrictions of definition herein, and therefore such compositions belongs to scope of the present invention.
" bioequivalence " described herein refers to: for containing olanzapine crystal grain with given particle mean size and the dosage form of pharmaceutically acceptable carrier, (generally include one group of experimenter of at least 10 or more people) when with crossing research, it being tested; Be that 5 μ m are that the equivalent preparation is taken medicine to same group of experimenter with granularity simultaneously, for each intersection group, area under the former averaged curve (AMC) and/C
maxAt least be the corresponding average A MC of the latter and/or C
max80%.
For containing the olanzapine of particle mean size less than 30 μ m, routine be can be prepared into, be generally dry pharmaceutical dosage forms such as tablet, powder, unit dose bag and the oral capsule of oral suspensions are used for, can prepare such dosage form with conventional method.
In addition, the present invention also provides a kind of preparation method of oral cavity disintegration tablet of the olanzapine group compound that contains the olanzapine crystal grain.Except containing olanzapine, said composition also can contain conventional pharmaceutically acceptable excipient, such as: filler and diluent such as lactose, starch, mannitol etc.; Binding agent such as carboxymethyl cellulose and other cellulose derivative, polyvinylpyrrolidone etc.; Disintegrating agent such as cross-linking sodium carboxymethyl cellulose, crosslinked starch sodium, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose etc. lubricant such as magnesium stearate, silicon dioxide etc., some excipient can have several functions, and for example disintegrating agent also can be used as filler.
In preferred preparation method embodiment, can adopt legacy equipment and conventional method (as wet granulation) preparation tablet.
In containing the tablet of the present composition, the content of olanzapine is generally 5-20mg, twice of general oral administration every day, but the content outside this scope and therewith different administration frequency be also feasible in treatment, as noted earlier, such dosage form for the treatment psychosis be have useful especially, as the psychosis for the treatment of schizophrenia type.
In order to assess the dissolution properties of dosage form, by dissolving, it is tested in the MSP-2 device, as previously mentioned, this device contains the 900ml aqueous medium.Test period, dissolve medium maintain 37 ℃ usually.In aqueous medium, if having 85% at least in 15min, be preferably 85% olanzapine dissolving, this dosage form belongs to scope of the present invention.
The amount of the olanzapine of dissolving can be measured by HPLC method routinely.Utilize the canonical plotting of the concentration of concentration known-reference material peak height (or peak area), the HPLC peak height (or peak area) that sample is obtained compares with peak height (or peak area) in canonical plotting, can easily carry out quantitative assay, common, olanzapine normal concentration used is chosen in the range of linearity of uv absorption of concentration-UV-detector used.
The specific embodiment:
Further describe the present invention below in conjunction with specific embodiment, advantage and disadvantage of the present invention will be more clear along with description.But these embodiment are only exemplary, scope of the present invention are not consisted of any restriction.It will be understood by those skilled in the art that lower without departing from the spirit and scope of the present invention and can modify or replace details and the form of technical solution of the present invention, but these modifications and replacement all fall within the scope of protection of the present invention.
Lower series preparation is the representative formulation that represents in the scope of the invention, and all formulation application particle mean sizes are that the olanzapine of 5-30 μ m prepares tablet according to the method for routine.
Embodiment 1:
In 100, be the olanzapine of 5 μ m and 2.05g mannitol, the 4.95g microcrystalline Cellulose mix homogeneously that sieves with the 0.50g particle mean size, do binding agent with the HPMC of 1%-3%, 16 mesh sieves are granulated, 40 ℃ of-60 ℃ of dryings, 24 mesh sieve granulate; Add 2.27g low-substituted hydroxypropyl cellulose, 0.1g magnesium stearate in the granule of gained, 0.1g stevioside, 0.03g Mentholum, the mixing of sieving is determined the heavy rear tabletting of sheet and get final product.
Embodiment 2:
In 100, be the olanzapine of 12 μ m and 2.55g mannitol, the 4.45g polyvinylpolypyrrolidone mix homogeneously that sieves with the 0.50g particle mean size, do binding agent with the HPMC of 1%-3%, 16 mesh sieves are granulated, 40 ℃ of-60 ℃ of dryings, 24 mesh sieve granulate; Add 2.20g low-substituted hydroxypropyl cellulose, 0.1g magnesium stearate in the granule of gained, the 0.2g stevioside, the mixing of sieving is determined the heavy rear tabletting of sheet and get final product.
Embodiment 3:
In 100, be the olanzapine of 21 μ m and 2.35g mannitol, the 4.65g polyvinylpolypyrrolidone mix homogeneously that sieves with the 0.50g particle mean size, do binding agent with the HPMC of 1%-3%, 16 mesh sieves are granulated, 40 ℃ of-60 ℃ of dryings, 24 mesh sieve granulate; Add 2.22g polyvinylpolypyrrolidone, 0.1g magnesium stearate in the granule of gained, 0.15g stevioside, 0.03g Mentholum, the mixing of sieving is determined the heavy rear tabletting of sheet and get final product.
Embodiment 4:
In 100, be the olanzapine of 29 μ m and 2.05g mannitol, the 4.65g polyvinylpolypyrrolidone mix homogeneously that sieves with the 0.50g particle mean size, do binding agent with the HPMC of 1%-3%, 16 mesh sieves are granulated, 40 ℃ of-60 ℃ of dryings, 24 mesh sieve granulate; Add 2.52g crosslinked starch sodium, 0.05g magnesium stearate in the granule of gained, 0.13g stevioside, 0.1g Mentholum, the mixing of sieving is determined the heavy rear tabletting of sheet and get final product.
For further illustrating the present invention, will carry out examination of the inside with outside to the preparation of embodiment 1-4.
Dissolution properties for four kinds of varigrained olanzapine orally-disintegrating tablets assessing embodiment 1-4, in containing 900ml water, the MSP-2 device of paddle agitator be housed, under the speed with 50rpm/min stirs, by dissolving, it to be tested, this device contains the 900ml aqueous medium.Test period, dissolve medium maintain 37 ℃ usually.Usually, this test result is the meansigma methods of predetermined dose number (as capsule, tablet, suspensoid or other preparation), predetermined number wherein normally 6.
Get respectively each 6 of the oral cavity disintegration tablets of four kinds of varigrained olanzapine crystal of embodiment 1-4, put into said apparatus, the amount of the olanzapine of dissolving is measured by HPLC method routinely.Utilize the canonical plotting of the concentration of concentration known-reference material peak height (or peak area), the HPLC peak height (or peak area) that sample is obtained compares with peak height (or peak area) in canonical plotting, common, olanzapine normal concentration used is chosen in the range of linearity of uv absorption of concentration-UV-detector used.
Four kinds of average accumulated dissolutions that contain the oral cavity disintegration tablet of varigrained olanzapine crystal see Table 1 when 15min.
The average accumulated dissolution of table 1 embodiment 1-4 preparation
Therefore, use the 5mg tablet than coarsegrain (less than 30 μ m) preparation, can obtain the dissolution properties suitable with the tablet for preparing with small grain size 5 μ m.
For the present invention is described, open, random, minute 3 phases, four groups and without people's pharmacokinetics crossing research of eliminating under phase hidden danger attitude condition, wherein use four kinds of olanzapine orally-disintegrating tablets (identical compositions), every kind of tablet contains the 5mg olanzapine, but the granularity of olanzapine is different, and particle mean size is respectively 5 μ m, 12 μ m, 21 μ m and 29 μ m, these four kinds of tablets take altogether for 20 routine health volunteers, and the men and women does not limit.Experimenter's oral drugs every day 2 times (1 * 10mg/ sheet, interval 12 hours) early or after dinner taking immediately, are taken 50ml water simultaneously when taking medicine.Early take immediately after the meal 1 * 10mg tablet, by following decimation in time blood sample: 0 (taking medicine front), 0.5,1,2,3,4,6,8,10 and 12 hour.At the 1st, 2,4,5,7 and the 8th days, obtain other blood serum sample before taking medicine morning.Adopt high phase liquid-phase chromatographic analysis determine this medicine the time discharge curve under area (AMC
0-mf) and the maximum serum-concentration (C of olanzapine
max).Range estimation data show: reached steady-state system exposure (expos μ re) on the 3rd day.The Tmax value was from 0-12 hour, and then meansigma methods is 5-8 hour in all tested group, and four test group do not observe the significant difference (p=0.63) of significant Tmax.
Table 2 embodiment 1-4 intersects pharmacokinetic
Therefore, use the 5mg tablet than coarsegrain (less than 30 μ m) preparation, can obtain system's exposure suitable with the tablet for preparing with small grain size 5 μ m.
Claims (7)
1. compositions contains and has olanzapine crystal grain and the pharmaceutically acceptable diluent or carrier that particle mean size is equal to or less than 30 μ m, it is characterized in that particle mean size is equal to or less than the equal bioequivalence of preparation of the olanzapine of 30 μ m.
2. compositions according to claim 1, have particle mean size and be equal to or less than the olanzapine crystal grain of 30 μ m except comprising, its pharmaceutically acceptable diluent or carrier comprises such as filler and diluent such as lactose, starch, mannitol, microcrystalline Cellulose etc.; The alcohol-water solution of binding agent such as carboxymethyl cellulose and other cellulose derivative, polyvinylpyrrolidone, variable concentrations etc.; Disintegrating agent such as cross-linking sodium carboxymethyl cellulose, crosslinked starch sodium, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone etc.; Lubricant such as magnesium stearate, silicon dioxide, stearic acid etc.
3. compositions according to claim 2, wherein said particle mean size is 5-30 μ m.
4. compositions according to claim 1, adopt wet granulation in preparation oral cavity disintegration tablet process.
5. compositions according to claim 1, the average A MC of the said composition of its demonstration and/or C
maxBe at least another kind and be equal to preparation average A MC and/or C
max80%.The olanzapine particle mean size identical but contained with described compositions of another kind of preparation herein is 5 μ m.
6. compositions according to claim 1, wherein in containing the water of 900ml, the MSP-2 device of paddle agitator be housed, when being equivalent to 30mg or during still less olanzapine dosage form amount adds this device under 50rpm/min stirs, have at least 85% olanzapine to dissolve in 15min.
7. antipsychotic method, the method comprises: compositions from the claim 1 of effective dose to the patient of the described treatment of needs that use.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110413864 CN103156860A (en) | 2011-12-13 | 2011-12-13 | Olanzapine composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110413864 CN103156860A (en) | 2011-12-13 | 2011-12-13 | Olanzapine composition and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103156860A true CN103156860A (en) | 2013-06-19 |
Family
ID=48580726
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110413864 Pending CN103156860A (en) | 2011-12-13 | 2011-12-13 | Olanzapine composition and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103156860A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104523631A (en) * | 2015-02-02 | 2015-04-22 | 刘平 | Preparation method of olanzapine orally disintegrating tablet for treating depression |
| CN104887634A (en) * | 2015-05-07 | 2015-09-09 | 河北龙海药业有限公司 | Olanzapine orally disintegrating tablets and preparation method thereof |
| CN105078893A (en) * | 2014-05-22 | 2015-11-25 | 广东东阳光药业有限公司 | Olanzapine with specific particle size and solid composition containing olanzapine with same particle size |
| CN105106141A (en) * | 2015-09-22 | 2015-12-02 | 成都欣捷高新技术开发有限公司 | Freeze-drying oral preparation containing olanzapine and preparation method of freeze-drying oral preparation |
| CN111643506A (en) * | 2020-06-15 | 2020-09-11 | 重庆医药高等专科学校 | Olanzapine fluoxetine compound capsule preparation and preparation method thereof |
| CN111836615A (en) * | 2018-01-05 | 2020-10-27 | 英倍尔药业股份有限公司 | Intranasal delivery of olanzapine by precision nasal device |
| CN113143878A (en) * | 2021-03-19 | 2021-07-23 | 杭州新诺华医药有限公司 | Olanzapine composition and preparation method thereof |
-
2011
- 2011-12-13 CN CN 201110413864 patent/CN103156860A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105078893A (en) * | 2014-05-22 | 2015-11-25 | 广东东阳光药业有限公司 | Olanzapine with specific particle size and solid composition containing olanzapine with same particle size |
| CN104523631A (en) * | 2015-02-02 | 2015-04-22 | 刘平 | Preparation method of olanzapine orally disintegrating tablet for treating depression |
| CN104523631B (en) * | 2015-02-02 | 2017-04-19 | 刘新刚 | Preparation method of olanzapine orally disintegrating tablet for treating depression |
| CN104887634A (en) * | 2015-05-07 | 2015-09-09 | 河北龙海药业有限公司 | Olanzapine orally disintegrating tablets and preparation method thereof |
| CN104887634B (en) * | 2015-05-07 | 2017-12-26 | 河北龙海药业有限公司 | Olanzapine oral disnitegration tablet and preparation method thereof |
| CN105106141A (en) * | 2015-09-22 | 2015-12-02 | 成都欣捷高新技术开发有限公司 | Freeze-drying oral preparation containing olanzapine and preparation method of freeze-drying oral preparation |
| CN111836615A (en) * | 2018-01-05 | 2020-10-27 | 英倍尔药业股份有限公司 | Intranasal delivery of olanzapine by precision nasal device |
| US11752100B2 (en) | 2018-01-05 | 2023-09-12 | Impel Pharmaceuticals Inc. | Intranasal delivery of olanzapine by precision olfactory device |
| CN111643506A (en) * | 2020-06-15 | 2020-09-11 | 重庆医药高等专科学校 | Olanzapine fluoxetine compound capsule preparation and preparation method thereof |
| CN113143878A (en) * | 2021-03-19 | 2021-07-23 | 杭州新诺华医药有限公司 | Olanzapine composition and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6932746B2 (en) | Enzalutamide preparation | |
| CN101600419B (en) | Revaprazan-containing solid dispersion and process for the preparation thereof | |
| CN103156860A (en) | Olanzapine composition and preparation method thereof | |
| EP1847257B1 (en) | Solid preparation comprising enteric solid dispersion | |
| CN109602713A (en) | Tablet or capsule comprising pharmaceutical composition | |
| US8663698B2 (en) | Solid dispersion preparation | |
| CN102596953A (en) | Propane-i-sulfonic acid {3-[5-(4-chloro-phenyl)-1h-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compositions and uses thereof | |
| CN106102716A (en) | The solid composite medicament of androgen receptor antagonists | |
| JP2001163769A (en) | Cilostazol preparation | |
| Braig et al. | Enhanced dissolution of naproxen from pure-drug, crystalline nanoparticles: A case study formulated into spray-dried granules and compressed tablets | |
| CN102143738A (en) | Pharmaceutical solid preparation | |
| CN103479643A (en) | Preparation method of compound preparation for treating high blood pressure | |
| WO2007072218A2 (en) | Formulations containing glimepiride and/or its salts | |
| CN106511348A (en) | Huperzine-A framework particles, orally disintegrating tablets and preparation methods thereof | |
| CN103717209A (en) | Prasugrel-containing immediate release stable oral pharmaceutical compositions | |
| CN100589801C (en) | Spray-dried granules containing pranlukast and processes for the preparation thereof | |
| JP2013047258A (en) | Solid preparation containing enteric solid dispersion | |
| JP3007387B2 (en) | Base powder for sustained release formulation | |
| TW201609108A (en) | Pharmaceutical dosage forms | |
| JPH0776516A (en) | Production of slightly soluble medicine-containing preparation | |
| CN114712359A (en) | Alvatripopa maleate pharmaceutical preparation and preparation method and application thereof | |
| WO2010082855A1 (en) | Pharmaceutical compositions comprising ziprasidone free base or ziprasidone hydrochloride and the method for their preparation | |
| Charan et al. | Immediate drug release dosage form: A review | |
| JP2007131587A (en) | Pharmaceutical composition comprising quinoline derivative as active ingredient and method for producing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C05 | Deemed withdrawal (patent law before 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130619 |