CN105640961A - A pharmaceutical composition containing ibrutinib - Google Patents
A pharmaceutical composition containing ibrutinib Download PDFInfo
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- CN105640961A CN105640961A CN201410659778.3A CN201410659778A CN105640961A CN 105640961 A CN105640961 A CN 105640961A CN 201410659778 A CN201410659778 A CN 201410659778A CN 105640961 A CN105640961 A CN 105640961A
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Abstract
The invention relates to a pharmaceutical composition containing ibrutinib. The active component of the composition is the ibrutinib. The composition is characterized in that medium- and long-chain saturated or unsaturated aliphatic acids, substituted carboxylic acids, and the like, which are pharmaceutical acids or a mixture of one or more acids therein or fish oil are adopted as lipophilic components, proper water is added to prepare a hydrophilic substrate or not added according to different requirements of each dosage form, and the composition is suitable for preparation of soft capsules, ointment, eye drops, oral liquids, injections, and other dosage forms.
Description
The present invention relates to a kind of pharmaceutical composition containing replacing Buddhist nun according to Shandong, its active ingredient is for Buddhist nun according to Shandong; Ethanol or propylene glycol or its mixture are as solvent or surfactant adjuvant; Hydrophilic surfactant active taking HLB value (hydrophilic-lipophilic balance) as 10 to 19 is for solubilizing agent; Be characterized in selecting that long-chain is saturated or unsaturated fatty acids, substituted carboxylic acid etc. can the mixture of pharmaceutically acceptable organic acid or wherein one or more acid or fish oil as lipophilic ingredients; Different requirements according to each formulation, can not add water or add suitable water and make hydrophilic matrix, and the formula of said composition is applicable in the preparation of the formulations such as soft capsule, ointment, oral liquid and injection.
More specifically, the present invention relates to the pharmaceutical composition replacing Buddhist nun's insoluble according to Shandong, the formula of said composition is applicable in the preparation of the formulations such as soft capsule, ointment, oral liquid and injection. Now each component in pharmaceutical composition of the present invention is illustrated respectively.
1. activeconstituents
Activeconstituents is for Buddhist nun according to Shandong, the earliest by because drawing " human genome map " and well-known Sai Laila gene engineering company of the U.S. (CeleraGenomics) develops, due to Celera fund and resource problem, within 2006, the development rights of this medicine are transferred the Pharmacyclics company of California by Celera, 2011, under Johnson & Johnson, Subsidiary Company Yang Sen pharmacy (Jassen) obtained and the right of Pharmacyclics company cooperative development. It is used for the treatment of lymphoma mantle cell (MCL) according to Shandong for Buddhist nun, it is common in person in middle and old age, be a kind of rare but be in progress non-Hodgkin��s B cell lymphoma (NHL) rapidly. In the U.S., its patient's number occupies the 6% of all non-Hodgkin lymphoma cases. Buddhist nun (Imbruvica) is replaced to be the third medicine getting permission to be used for the treatment of lymphoma mantle cell (MCL) according to Shandong. Breakthrough medicine qualification is authorized in February, 2013 by U.S. FDA for Buddhist nun (Ibrutinib) according to Shandong. Imbruvica is the 2nd medicine enjoying this treatment got permission since FDA releases breakthrough new drug new policies. Listing preparation according to Shandong for Buddhist nun at present is capsule. But owing to it belongs to low-solubility drug, preparing the solid dosage bioavailability concerns such as capsule is the main problem affecting this medicine effect always. In order to ensure bioavailability, before preparing solid preparation, often need that raw material is carried out micronization and reduce particle diameter, increase, to obtain, the object that solubleness improves bioavailability. But medicine is carried out micronization add production process, extend manufacture cycle, considerably increase production cost undoubtedly.
Insoluble drug is being carried out on the basis of solubilising by the present invention, the combination of many kinds of tensio-active agents, surfactivity auxiliary agent, solubilizing agent, oily components has been carried out long-term research, thus found original technology had not related to new according to Shandong for Buddhist nun's liquid composition.Said composition preparation technology is simple, has good stability, and bioavailability improves.
2. solvent or surfactivity auxiliary agent
In the present invention, need to the mixed solution of fat-soluble medicine is had better solvability ethanol or propylene glycol or ethanol and propylene glycol as activeconstituents solvent or surfactant adjuvant. Wherein, the ratio of ethanol and propylene glycol is 1: 0.1��10 (weight ratios), it is preferable that the ethanol of mixing solubility promoter and the ratio of propylene glycol are 1: 0.5��5 (weight ratios), and optimum proportion is 1: 1��3 (weight ratios).
3. hydrophilic surfactant active taking HLB value as 10 to 19 is for solubilizing agent.
In the composition of the present invention, select HLB value be 10 to 19 medicinal hydrophilic surfactant active be the solubilizing agent of fat-soluble medicine, to promote that hydrophilic in composition and oleophilic moiety reaches balance, form stable emulsification. This kind of HLB value is the tensio-active agent of 10��19 is castor oil derivatives, such as CremophorEL, CremophorRH40, Cremophor60 or Tweens, such as Tween80, Tween65, Tween20 or wheat pool class, such as Myj52. It particularly preferably is castor oil derivatives.
In the present composition, most is distinctive is select the mixture of saturated or the pharmaceutically acceptable organic acid such as unsaturated fatty acids, substituted carboxylic acid or wherein one or more acid or fish oil as lipophilic ingredients. The application of this kind of oil components so that this composition is more stable than other compositions of original invention, and more succinct. In the present invention, the carboxylic acid in the mixture of saturated or the pharmaceutically acceptable organic acid such as unsaturated fatty acids, substituted carboxylic acid or wherein one or more acid of middle long-chain or fish oil can exist with ester group state with the alcohol class in composition, it is also possible to exists with unbound state. Wherein saturated fatty acid as the middle long-chain in oily components is C8��28Carboxylic acid, for the unsaturated fatty acids of the middle long-chain in oily components is C10��24One, two, trienic acid. It is preferably C as the saturated of oily components and unsaturated fatty acids14��22One, two, trienic acid or its mixture.
5., according to the different requirements of each formulation, water can not be added or add suitable water and make hydrophilic matrix.
Another unique distinction of the present invention is, can not add water according to the different use of composition, it is possible to add a certain proportion of water, and wherein the ratio of active ingredient and water is 1: 0��1000 (weight ratios).
6., according to the different demands on clinical, the present invention can be prepared into soft capsule containing according to Shandong for the pharmaceutical composition of Buddhist nun, it is possible to makes the formulations such as ointment, oral liquid and injection liquid.
When the composition of the present invention is made various formulation, as required, the auxiliary material required for concrete formulation or additives can be added, such as oxidation inhibitor, seasonings, permeate promotor, pH adjusting agent, sanitas etc., not by the restriction of listed content. The preparation method of different dosage form, can carry out according to the conventional requirement of this formulation.
The present invention will be made a more detailed description by the following examples. It should be understood, however, that these embodiments are not used to first determine the present invention's.
Embodiment 1
Preparation method: ethanol, propylene glycol, polyoxyethylenated castor oil, oleic acid are mixed, then add according to Shandong for Buddhist nun's stirring and dissolving.
Embodiment 2:
Preparation method: ethanol, glycerine, polyoxyethylenated castor oil, olein are mixed, then add according to Shandong for Buddhist nun's stirring and dissolving.
Embodiment 3:
Preparation method: ethanol, polyoxyethylene glycol, polyoxyethylenated castor oil, medium chain triglycerides are mixed, then add according to Shandong for Buddhist nun's stirring and dissolving.
Composition 1.0g prepared by Example 1 (is equivalent to according to Shandong for Buddhist nun 140mg) filling with No. 0 gelatine capsule shell, with commercially available hard capsule (trade(brand)name: IMBRUVICATM, specification: 140mg) compare the dissolved corrosion in 0.1mol/L hydrochloric acid soln, pH4.5 acetate buffer and pH6.8 phosphate buffered saline buffer respectively, the results are shown in Table 1, table 2, table 3, and accompanying drawing 1, accompanying drawing 2, accompanying drawing 3.
Accompanying drawing explanation
Fig. 1 is that embodiment 1 compares figure with commercial preparation stripping curve in 0.1mol/L hydrochloric acid soln.
Fig. 2 is that embodiment 1 compares figure with commercial preparation stripping curve in pH4.5 acetate buffer.
Fig. 3 is that embodiment 1 compares figure with commercial preparation stripping curve in pH6.8 phosphate buffered saline buffer.
Table 1 embodiment 1 compares (%) with commercial preparation stripping curve in 0.1mol/L hydrochloric acid soln
| Time (min) | 10 | 20 | 30 | 45 | 60 |
| Embodiment 1 | 50.5 | 85.4 | 98.7 | 99.2 | 100.3 |
| Commercial preparation | 25.6 | 42.3 | 67.8 | 75.5 | 80.2 |
Table 2 embodiment 1 compares (%) with commercial preparation stripping curve in pH4.5 acetate buffer
| Time (min) | 10 | 20 | 30 | 45 | 60 |
| Embodiment 1 | 52.3 | 88.6 | 101.2 | 101.1 | 101.1 |
| Commercial preparation | 27.6 | 45.2 | 69.8 | 74.3 | 81.5 |
Table 3 embodiment 1 compares (%) with commercial preparation stripping curve in pH6.8 phosphate buffered saline buffer
| Time (min) | 10 | 20 | 30 | 45 | 60 |
| Embodiment 1 | 51.7 | 89.8 | 100.4 | 100.2 | 100.1 |
| Commercial preparation | 26.5 | 41.7 | 65.4 | 75.8 | 83.4 |
Claims (10)
1., containing the pharmaceutical composition replacing Buddhist nun according to Shandong, it comprises following main component:
(1) as the ciclosporin of active ingredient;
(2) as the ethanol of solvent or surfactant adjuvant or propylene glycol or its mixture.
(3) HLB value as solubilizing agent is the hydrophilic surfactant active of 10 to 19.
(4) middle long-chain as oily components is saturated or unsaturated fatty acids, substituted carboxylic acid etc. can the mixtures of pharmaceutically acceptable organic acid or one or more acid.
(5) according to the different requirements of each formulation, can not adding water or add suitable water and make hydrophilic matrix, said composition can be prepared into the formulations such as soft capsule, ointment, oral liquid and injection.
2. pharmaceutical composition according to claim 1 is wherein 1: 0.1��10 (weight ratios) as the ratio of the mixing ethanol of solubility promoter and propylene glycol.
3. pharmaceutical composition according to claim 1 is wherein 1: 0.5��5 (weight ratios) as the ratio of the mixing ethanol of solubility promoter and propylene glycol.
4. pharmaceutical composition according to claim 1, wherein HLB value to be the tensio-active agent of 10��19 be castor oil derivatives or Tweens or wheat pool class.
5. pharmaceutical composition according to claim 1, wherein middle long-chain unsaturated fatty acid as oily components is C5��28Carboxylic acid.
6. pharmaceutical composition according to claim 1, wherein middle long-chain unsaturated fatty acid as oily components is C10��24One, two, trienic acid.
7. pharmaceutical composition according to claim 6, wherein middle long-chain unsaturated fatty acid as oily components is C14��22One, two, trienic acid.
8. pharmaceutical composition according to claim 1, wherein substituted carboxylic acid as oily components is lactic acid.
9. pharmaceutical composition according to claim 1, wherein the ratio of active ingredient and water is 1: 0��1000 (weight ratios).
10. pharmaceutical composition according to claim 1, wherein said composition can be prepared into the formulations such as soft capsule, ointment, oral liquid and injection.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410659778.3A CN105640961A (en) | 2014-11-18 | 2014-11-18 | A pharmaceutical composition containing ibrutinib |
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| CN201410659778.3A CN105640961A (en) | 2014-11-18 | 2014-11-18 | A pharmaceutical composition containing ibrutinib |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106619643A (en) * | 2016-11-11 | 2017-05-10 | 上海雅本化学有限公司 | Pharmaceutical composition containing ibrutinib |
| US9655857B2 (en) | 2015-03-03 | 2017-05-23 | Pharmacyclics Llc | Pharmaceutical formulations of a Bruton's tyrosine kinase inhibitor |
| US9713617B2 (en) | 2012-06-04 | 2017-07-25 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| US20180028537A1 (en) | 2014-08-07 | 2018-02-01 | Pharmacyclics Llc | Novel Formulations of a Bruton's Tyrosine Kinase Inhibitor |
-
2014
- 2014-11-18 CN CN201410659778.3A patent/CN105640961A/en active Pending
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10106548B2 (en) | 2012-06-04 | 2018-10-23 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| US10294231B2 (en) | 2012-06-04 | 2019-05-21 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| US10961251B1 (en) | 2012-06-04 | 2021-03-30 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| US9725455B1 (en) | 2012-06-04 | 2017-08-08 | Pharmacyclics Llc | Crystalline forms of a bruton's tyrosine kinase inhibitor |
| US10125140B1 (en) | 2012-06-04 | 2018-11-13 | Pharmacyclics Llc | Crystalline forms of a bruton's tyrosine kinase inhibitor |
| US10752634B2 (en) | 2012-06-04 | 2020-08-25 | Pharmacyclics Llc | Crystalline forms of a brutons tyrosine kinase inhibitor |
| US10294232B2 (en) | 2012-06-04 | 2019-05-21 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| US10266540B2 (en) | 2012-06-04 | 2019-04-23 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| US9713617B2 (en) | 2012-06-04 | 2017-07-25 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| US9828383B1 (en) | 2012-06-04 | 2017-11-28 | Pharmacyclic s LLC | Crystalline forms of a bruton's tyrosine kinase inhibitor |
| US10065968B2 (en) | 2012-06-04 | 2018-09-04 | Pharmacyclics Llc | Crystalline forms of a bruton's tyrosine kinase inhibitor |
| US20180028537A1 (en) | 2014-08-07 | 2018-02-01 | Pharmacyclics Llc | Novel Formulations of a Bruton's Tyrosine Kinase Inhibitor |
| US10213386B2 (en) | 2015-03-03 | 2019-02-26 | Pharmacyclics Llc | Pharmaceutical formulations of a Bruton's tyrosine kinase inhibitor |
| US10010507B1 (en) | 2015-03-03 | 2018-07-03 | Pharmacyclics Llc | Pharmaceutical formulations of a bruton's tyrosine kinase inhibitor |
| US9655857B2 (en) | 2015-03-03 | 2017-05-23 | Pharmacyclics Llc | Pharmaceutical formulations of a Bruton's tyrosine kinase inhibitor |
| US10828259B2 (en) | 2015-03-03 | 2020-11-10 | Pharmacyclics Llc | Pharmaceutical formulations of a Bruton's tyrosine kinase inhibitor |
| CN106619643A (en) * | 2016-11-11 | 2017-05-10 | 上海雅本化学有限公司 | Pharmaceutical composition containing ibrutinib |
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Application publication date: 20160608 |