CN103565762A - Blonanserin pharmaceutical composition with improved oral absorptivity - Google Patents
Blonanserin pharmaceutical composition with improved oral absorptivity Download PDFInfo
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- CN103565762A CN103565762A CN201210257496.1A CN201210257496A CN103565762A CN 103565762 A CN103565762 A CN 103565762A CN 201210257496 A CN201210257496 A CN 201210257496A CN 103565762 A CN103565762 A CN 103565762A
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- blonanserin
- pharmaceutical composition
- cyclodextrin
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Abstract
A bonanserin pharmaceutical composition with improved oral absorptivity is characterized by comprising the components by weight: a first part: 4 g of bonanserin and 25 g of alpha cyclodextrin; and a second part: 20 g of cospovidone, 50 g of microcrystalline cellulose, 60 g of lactose, 20 g of pregelatinized starch, 1 g of powdered steatile, 1 g of magnesium stearate and proper amount of a povidone anhydrous-alcohol solution with a ratio of 5%.
Description
Technical field
The present invention relates to blonanserin pharmaceutical composition and preparation method thereof a kind of.Blonanserin is scattered in α cyclodextrin, can improves largely vitro release, thereby improve bioavailability.
Background technology
Schizophrenia is with cognitive power and the emotion degree of depth, to be split into a kind of disease of feature, shows as the most basic behavior of men and is affected, such as language, thought, consciousness and self-perception etc.The included scope of the symptom of this disease is wider, and modal is the obstacle of spiritual aspect, such as hallucinating, paranoea and illusion etc.
According to statistics, schizophrenia is 0.5%～1.5% at global prevalence rate, and in all patients that receive treatment, only has 5% finally can be returned to one's perfect health.In addition; because schizophrenia can cause complication conventionally; such as anxiety disorder, depression or mental drug abuse etc.; an investigation according to Datamonitor shows, will suffer the puzzlement of the diseases such as at least one or more concurrent psychosis or cognitive disorder over the schizophrenic of 1 ∕ 3 (38%).Therefore, TB Ustun is in the investigation statistics carrying out in the global burden for mental disorder for 1999, classify schizophrenia as global the third-largest disabling condition, the forward hemiplegia and blind that even surpassed of its rank, from then on, schizophrenia also becomes one and makes us the complexion changed of what is said or talked about, the too late disease of keeping away.
Treatment schizophrenia drug is since early 1950s is found the antipsycholic action of chlorpromazine, and schizophrenia be take Drug therapy as main always.At present conventional antipsychotic drug is divided into typical case and the large class of atypia two by receptor blocking effect difference: it is representative that classical antipsychotic be take chlorpromazine, haloperidol. and Main Function mechanism is to block dopamine receptor, to the schizoid positive symptom, (hallucination, vain hope, excited restless, impulsive behavior etc.) have good therapeutic effect for they. and the extrapyramidal symptoms (EPS) is common simultaneously, and to negative symptoms (apathy, the poverty of thought, hypobulia etc.) weak curative effect; The anti-essence of atypia is divided medicine, treatment spectrum is wider, negative symptoms successful is better than to conventional medicament, safe, side effect is slighter, and taking dose is less, has also occurred a lot of more advanced dosage forms, greatly improved patient's compliance, represented that medicine has clozapine, risperidone, olanzapine, cis-N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl etc.
Blonanserin is 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-, six hydrogen cycloocta-[b] pyridines are atypia antischizophrinic things of new generation, are that European patent EP 0385237 is open the earliest, illustrated its superior medical treatment public tender that, disclose it and be used for the treatment of schizophrenia.This product is domestic without import at present, also without producing said preparation.Spain and the U.S. are in II clinical trial phase.2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9, the blonanserin general by name (Blonanserin) of 10-six hydrogen cycloocta-[b] pyridines, molecular formula: C
23h
30fN
3, molecular weight: 367.5.It belongs to the medicine of the single-minded 5-HT2 of acting on receptor and D2 receptor, is close to the medicine of selectively acting in current atypical antipsychotic market.Obviously improve schizoid positive shape (as hallucination, illusion etc.) and negative symptoms (as feel down in spirits, hypokinesia etc.), reduce extrapyramidal system rate of side effects (parkinson's syndrome, acute dystonia, cathisophobia etc.) and other untoward reaction, safety toleration is obviously better than Traditional antipsychotics.The appearance that can say it is the much progress in schizophrenia drug treatment history.As treatment, schizoid line medication. China will have broad application prospects.
Therefore be necessary to prepare a kind of being easy to carry, the oral formulations of taking convenience fills the domestic gaps.
Chinese patent CN101766626A discloses a kind of schizophrenia for the treatment of containing the oral formulations of blonanserin, it is with 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5, 6, 7, 8, 9, 10-six hydrogen cycloocta-[b] pyridines are raw material, comprise one or more pharmaceutically useful excipient, its preparation method is by 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5, 6, 7, 8, 9, 10-six hydrogen cycloocta-[b] pyridine and selectable diluent, binding agent, disintegrating agent, antitack agent and lubricant, add appropriate wetting agent and make soft material, sieve and make wet granular, by wet grain drying, granulate sieves, be made into oral formulations, wherein to account for weight of formulation percentage ratio be 0.1-30% to blonanserin.
Chinese patent CN101530412 discloses a kind of chemistry comprising [2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5 by name, 6,7,8,9,10-six hydrogen cycloocta-[b] pyridines] or the composition and method of making the same of its officinal salt, its contain be no less than 10% weight alkaline matter as stabilizing agent.Compositions of the present invention, has good stability, and energy blocking 5-hydroxytryptamine-2 receptor and Dopamine-2 receptor, can be used for treating schizophrenia.
The conventional preparation method of prior art is prepared blonanserin preparation, because of the physicochemical property of blonanserin material, easily causes that to prepare in tablet mobility of particle bad, sticking, and tablet appearance is defective, and release is lower.Can not large-scale industrialized production.
In order to improve production quality, overcome the problem of can not industrialization producing, we have carried out the design and researchp of a large amount of technical schemes, choose optimum prescription and technique, have solved above-mentioned technological deficiency.
Blonanserin Pharmaceutical composition prepared by the present invention, employing is scattered in blonanserin in α cyclodextrin, obviously overcomes and in production technology, adopts conventional preparation method, the low and shortcoming that is difficult for making of release, the method has improved its vitro release greatly, and then improves its bioavailability.
Therefore, the inventor has solved this conventional formulation relevant issues, and successfully develops a kind of blonanserin pharmaceutical composition with the oral absorptivity of improvement.There is higher stability and higher bioavailability.
Summary of the invention
The object of this invention is to provide a kind of blonanserin pharmaceutical composition with the oral absorptivity of improvement, it has the performance characteristic of high expectations aspect raising bioavailability and high stability.
Another object of the present invention is to provide a kind of method of utilizing described compositions to prepare blonanserin pharmaceutical composition.
According to an aspect of the present invention, provide blonanserin pharmaceutical composition, its blonanserin is scattered in α cyclodextrin, formulated by following weight ratio:
Form 1
Blonanserin 4g
α cyclodextrin 25g
Form 2
Crospovidone 20g
Microcrystalline Cellulose 50g
Lactose 60g
Pregelatinized Starch 20g
Pulvis Talci 1g
Magnesium stearate 1g
5% polyvidone ethanol solution is appropriate
Another aspect of the present invention, has the preparation method of blonanserin pharmaceutical composition of the oral absorptivity of improvement, it is characterized in that, through following steps:
1) the aqueous solution spraying of blonanserin and α cyclodextrin is dry, obtain spray-dired granule, this spray-dried granules and water-soluble diluent are mixed to get to a pre-composition, this pre-composition and mix lubricant are finally obtained to mixture, direct compression;
2) by microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, Pulvis Talci, magnesium stearate is sieved respectively, adopts 5% polyvidone ethanol solution, mix, make 30-40 order granule, at 50 ℃ of following being dried, granulate, add lubricant, mix homogeneously, direct compression;
3) will contain the tablet of first and second portion, direct compression, obtains final pharmaceutical composition.
Below data declaration beneficial effect of the present invention by experiment.
With the product of prior art embodiment 1 of the present invention and embodiment 2, carried out constant temperature accelerated stability test and the room temperature stability test that keeps sample, result is as follows:
Above result of the test explanation, embodiment 2 is in acceleration and long-term put procedure, and sample related substance is not significantly increased, and dissolution is qualified, and quality is comparatively stable; Adopting embodiment 1 prepared by prior art is only 45% detection stripping in 0 day, and product is defective.
Advantage of the present invention is technical maturity, simple to operate, is applicable to industrial large-scale production.
Advantage of the present invention is also to adopt blonanserin is scattered in α cyclodextrin, obviously overcome and in production technology, adopt conventional preparation method, low and the poor fluidity of release such as is difficult for making at the shortcoming, and the method has improved its vitro release greatly, and then improves its bioavailability.
Cyclodextrin is starch derivatives, mainly as oral and injection medicine preparation, and the most frequently used is α-, β-, gamma-cyclodextrin, has respectively 6,7,8 glucose units.Cyclodextrin is the ring molecule of the cavity by rigid structure and center thereof " tubbiness " or " coniform " that form, its size is according to the difference of the type of cyclodextrin and difference, cavity inner surface is hydrophobicity, and the outside of ring is hydrophilic, this is due to the arrangement in polyhydroxylated molecule, this arrangement makes cyclodextrin in cavity, hold enclosed molecule again, forms clathrate.Cyclodextrin can be used to prepare the clathrate of multi-medicament 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 is also used for covering the disagreeable taste of active substance and liquid substance is converted into solid material.
That alpha-cyclodextrin is considered to is oral nontoxic, so safety while using in solid preparation.
Following Formulation and optimization Test are used for illustrating the present invention:
The physicochemical property of blonanserin: this product is white crystalline powder, has special odor.The general preparation principle of following tablet, we have designed pre-prescription:
(1) prescription
Blonanserin 4g
Crospovidone 10g
Microcrystalline Cellulose 50g
Lactose 60g
Pregelatinized Starch 20g
Pulvis Talci 1g
Magnesium stearate 1g
5% polyvidone dehydrated alcohol is appropriate
Make 1000
(2) preparation method
1) the aqueous solution spraying of blonanserin and α cyclodextrin is dry, obtain spray-dired granule, this spray-dried granules and water-soluble diluent are mixed to get to a pre-composition, this pre-composition and mix lubricant are finally obtained to mixture, direct compression;
2) by microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, Pulvis Talci, magnesium stearate is sieved respectively, adopts 5% polyvidone ethanol solution, mix, make 30-40 order granule, at 50 ℃ of following being dried, granulate, add lubricant, mix homogeneously, direct compression;
3) will contain the tablet of first and second portion, direct compression, obtains final pharmaceutical composition.
to write out a prescription in advance and carry out stripping curve mensuration:
| Time | 5min | 10min | 30min | 45min |
| Pre-prescription | 8.5% | 15.8% | 25.5% | 45.1% |
?by above result of the test, shown: the stripping of said preparation prescription does not reach maximum stripping for 45 minutes, and we consider that adjusting process and prescription further screen:
| Prescription forms | 1 | 2 |
| Blonanserin | 4g | 4g |
| α cyclodextrin | 25g | 10g |
| Microcrystalline Cellulose | 50g | 50g |
| Lactose | 60g | 60g |
| Pregelatinized Starch | 20g | 20g |
| Crospovidone | 20g | 20g |
| 5% polyvidone ethanol solution | In right amount | In right amount |
| Magnesium stearate | 1g | 1g |
| Pulvis Talci | 1g | 1g |
technique:
1) the aqueous solution spraying of blonanserin and α cyclodextrin is dry, obtain spray-dired granule, this spray-dried granules and water-soluble diluent are mixed to get to a pre-composition, this pre-composition and mix lubricant are finally obtained to mixture, direct compression;
2) by microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, Pulvis Talci, magnesium stearate is sieved respectively, adopts 5% polyvidone ethanol solution, mix, make 30-40 order granule, at 50 ℃ of following being dried, granulate, add lubricant, mix homogeneously, direct compression;
3) will contain the tablet of first and second portion, direct compression, obtains final pharmaceutical composition.
Result of the test shows, prescription prepared by the 1 employing clathrate process of writing out a prescription, without sticking problem, obtains good outward appearance and hardness, and dissolution is also all qualified, and we finally determine best prescription and technique.
(1) prescription
Form 1
Blonanserin 4g
α cyclodextrin 25g
Form 2
Crospovidone 20g
Microcrystalline Cellulose 50g
Lactose 60g
Pregelatinized Starch 20g
Pulvis Talci 1g
Magnesium stearate 1g
5% polyvidone ethanol solution is appropriate
Make 1000
(2) preparation method
1) the aqueous solution spraying of blonanserin and α cyclodextrin is dry, obtain spray-dired granule, this spray-dried granules and water-soluble diluent are mixed to get to a pre-composition, this pre-composition and mix lubricant are finally obtained to mixture, direct compression;
2) by microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, Pulvis Talci, magnesium stearate is sieved respectively, adopts 5% polyvidone ethanol solution, mix, make 30-40 order granule, at 50 ℃ of following being dried, granulate, add lubricant, mix homogeneously, direct compression;
3) will contain the tablet of first and second portion, direct compression, obtains final pharmaceutical composition.
The specific embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but should understands the non-scope that only limits to these embodiment of scope of the present invention.
embodiment 1(prior art)
(1) prescription
Blonanserin 4g
Crospovidone 10g
Microcrystalline Cellulose 50g
Lactose 60g
Pregelatinized Starch 20g
Pulvis Talci 1g
Magnesium stearate 1g
5% polyvidone dehydrated alcohol is appropriate
Make 1000
(2) preparation method
5) blonanserin is pulverized, sieved, standby; By microcrystalline Cellulose, lactose, crospovidone, pregelatinized Starch, magnesium stearate, Pulvis Talci sieves respectively, standby;
6) by recipe quantity, take supplementary material respectively, standby;
7) get mix homogeneously supplementary material and adopt respectively 50% alcoholic solution to granulate with 20 eye mesh screens, 50 ℃ are dry, and 20
Eye mesh screen granulate;
8) according to content, adjust loading amount tabletting.
embodiment 2
(1) prescription
Form 1
Blonanserin 4g
α cyclodextrin 25g
Form 2
Crospovidone 20g
Microcrystalline Cellulose 50g
Lactose 60g
Pregelatinized Starch 20g
Pulvis Talci 1g
Magnesium stearate 1g
5% polyvidone ethanol solution is appropriate
Make 1000
(2) preparation method
1) the aqueous solution spraying of blonanserin and α cyclodextrin is dry, obtain spray-dired granule, this spray-dried granules and water-soluble diluent are mixed to get to a pre-composition, this pre-composition and mix lubricant are finally obtained to mixture, direct compression;
2) by microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, Pulvis Talci, magnesium stearate is sieved respectively, adopts 5% polyvidone ethanol solution, mix, make 30-40 order granule, at 50 ℃ of following being dried, granulate, add lubricant, mix homogeneously, direct compression;
3) will contain the tablet of first and second portion, direct compression, obtains final pharmaceutical composition.
Claims (3)
1. the pharmaceutical composition with the oral absorptivity of improvement, is characterized in that containing and has the first of pharmaceutical active and the second portion of pharmaceutic adjuvant, and wherein first comprises blonanserin 4g and alpha-cyclodextrin 25g and other pharmaceutically acceptable auxiliaries.
2. pharmaceutical composition according to claim 1, its second portion comprise crospovidone 20g, microcrystalline Cellulose 50g,
Lactose 60g, pregelatinized Starch 20g, Pulvis Talci 1g, magnesium stearate 1g and 5% appropriate polyvidone ethanol solution.
3. the preparation method of blonanserin pharmaceutical composition according to claim 1 with the oral absorptivity of improvement, is characterized in that, through following steps:
1) the aqueous solution spraying of blonanserin and α cyclodextrin is dry, obtain spray-dired granule, this spray-dried granules and water-soluble diluent are mixed to get to a pre-composition, this pre-composition and mix lubricant are finally obtained to mixture, direct compression;
2) by microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, Pulvis Talci, magnesium stearate is sieved respectively, adopts 5% polyvidone ethanol solution, mix, make 30-40 order granule, at 50 ℃ of following being dried, granulate, add lubricant, mix homogeneously, direct compression;
3) will contain the tablet of first and second portion, direct compression, obtains final pharmaceutical composition.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210257496.1A CN103565762A (en) | 2012-07-25 | 2012-07-25 | Blonanserin pharmaceutical composition with improved oral absorptivity |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018203706A (en) * | 2017-06-08 | 2018-12-27 | 高田製薬株式会社 | Tablet containing blonanserin |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102038685A (en) * | 2010-11-29 | 2011-05-04 | 天津市汉康医药生物技术有限公司 | Blonanserin medicine composition with capacity of improving oral absorbability |
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- 2012-07-25 CN CN201210257496.1A patent/CN103565762A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102038685A (en) * | 2010-11-29 | 2011-05-04 | 天津市汉康医药生物技术有限公司 | Blonanserin medicine composition with capacity of improving oral absorbability |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018203706A (en) * | 2017-06-08 | 2018-12-27 | 高田製薬株式会社 | Tablet containing blonanserin |
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Application publication date: 20140212 |