CN103169712B - Improve dutasteride's preparation of bioavilability and preparation method thereof - Google Patents
Improve dutasteride's preparation of bioavilability and preparation method thereof Download PDFInfo
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- CN103169712B CN103169712B CN201110430444.5A CN201110430444A CN103169712B CN 103169712 B CN103169712 B CN 103169712B CN 201110430444 A CN201110430444 A CN 201110430444A CN 103169712 B CN103169712 B CN 103169712B
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- dutasteride
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Abstract
The invention provides a kind of pharmaceutical composition containing dutasteride for improving biological utilisation and preparation method thereof, the surfactant of the dutasteride containing 0.02%~0.5% (W/W), 30%~70% (W/W) oil medium and 25%~66% (W/W)；One or more of the surfactant in sapn, tween, lecithin, soybean lecithin or cholesterine.The made preparation of composition of the present invention significantly improves dutasteride's dissolution in vitro compared with prior art preparation, and bioavilability is up to 144%.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, and in particular to he is male for a kind of degree for improving dissolution rate and bioavilability
Amine preparation, the invention further relates to the preparation method of the pharmaceutical composition.
Background technology
Dutasteride (Dutasteride) is a kind of medicine for being used to treat hyperplasia of prostate.
Dutasteride's water-soluble is very poor, therefore bioavilability is low.The standby dutasteride's preparation of Ge Lan element company systems
AVODARTIt is to dissolve main ingredient dutasteride with pungent/glycerol decanoate, forms liquid post package in soft capsule, be prepared into soft
Capsule, it would be desirable to improve its bioavilability.But the product bioavilability is not still high, is only about 60% (referring to FDA
AVODARTDescribed in specification).
Therefore, it is necessary to be studied, new pharmaceutical formulation is developed, dutasteride's dissolubility is improved, obtained further
Improve dutasteride's preparation of bioavilability.
The content of the invention
Present invention aim to address dutasteride's dissolution rate it is low the problem of there is provided a kind of degree for improving biological utilisation he
Male amine composition.
The inventors discovered that, if making dutasteride form emulsifying systems, its dissolution rate can be effectively improved, and then improve
Its bioavilability.And add surfactant in dutasteride's preparation is prepared, then can make to be dissolved in oil medium moderate he
One self-emulsifying drug delivery systems of male amine formation, increase dissolubility, reach the purpose of invention.
Inventor by repetition test and exploration, screened the suitable oil medium of dutasteride's preparation, surfactant,
Cosurfactant etc., has obtained the species and respective Optimum of the above-mentioned assistant agent for being applied to dutasteride, by experiment
Confirm, the bioavilability of dutasteride in preparation can be significantly improved.Dutasteride is dissolved completely in oil medium in preparation
In, and in the presence of surfactant, form a self-emulsifying drug delivery systemses, not only dutasteride is effectively disperseed, also
Considerably increase its dissolubility.
Specific composition is as follows：
A kind of dutasteride's composition, contains dutasteride, 30%~70% (W/W) oil medium and 0%~0.3%
(W/W) antioxidant, it is characterized in that also containing 25%~66% (W/W) surfactant and helping for 0%~10% (W/W)
Surfactant；
Described oil medium need not be limited particularly, as long as it is acceptable to dissolve dutasteride and medicine, such as
Can be medium-chain fatty glyceride, long-chain fat acid glyceride or medium-chain fatty glyceride and long-chain fat acid glyceride
Mixture.
It is preferred that long-chain fat acid glyceride.Wherein, medium-chain fatty glyceride be selected from C8~C10 fatty acid glycerine list,
Double, three esters or its mixture, preferably octanoic acid glyceride or glycerol decanoate；Long-chain fat acid glyceride is selected from C12~C18 fat
Fat acid glycerol single, double, triple ester or its mixture, preferably glyceryl monooleate, olein, soybean oil, corn oil or sesame
Sesame oil；The content of oil medium is 30%~70% (W/W).
The cosurfactants of 10% (W/W) below are added in above-mentioned composition, self-emulsifying drug delivery systemses can be preferably formed.
One or more of the cosurfactant in ethanol, propane diols or glycerine.
The antioxidants of 0.3% (W/W) below are added in above-mentioned composition, the stability of preparation is more preferably；The antioxygen
One or more of the agent in dibutyl hydroxy toluene, butylated hydroxy anisole or tert-butylhydroquinone.
Depending on the content of dutasteride can need according to clinic in above-mentioned composition, it can such as contain 0.02%~0.5% (W/W)
Dutasteride.
Present invention also offers a kind of preparation method of above-mentioned dutasteride's composition：By dutasteride, oil medium and
Surfactant is mixed, and is dissolved by heating, and stirring makes uniformly, to produce.
As needed, cosurfactant and/or antioxidant can also be added before the mixing.
Above-mentioned dutasteride's composition, can be prepared into specific formulation according to the need for administering mode.
Such as it is prepared into soft capsule：Dutasteride, oil medium and surfactant (can be helped surface to live if necessary
Property agent and/or antioxidant) mixing, dissolve by heating, stirring makes uniform, soft capsule, that is, degree of obtaining prepared according still further to conventional method
His male amine soft capsule.
It is an advantage of the invention that：
1. significantly improve dutasteride's dissolution in vitro
Experiment confirmation is (see test example 1,2), dutasteride's composition and commercially available AVODART of the inventionSoft capsule is compared,
Dissolution in vitro is improved significantly.
2. significantly improve the bioavilability of dutasteride
Experiment confirmation is (see test example 3), dutasteride's composition and AVODART of the present inventionSoft capsule is compared, biological utilisation
Degree is significantly improved, and its relative bioavailability is up to 144%.
Brief description of the drawings
Fig. 1~Fig. 3 is the dutasteride's soft capsule of embodiment 1 and commercially available AVODARTThe effect of soft capsule compares, wherein：
Fig. 1 is the dissolution in vitro comparison diagram in water；Fig. 2 is the dissolution in vitro comparison diagram in hydrochloric acid；Fig. 3 is blood
Concentration/time comparison diagram.
Embodiment
It is only dutasteride's pharmaceutical formulation described in example below for example, but the present invention is not limited to embodiment
In used composition and content, can have multiple choices.
The preparation of the dutasteride's soft capsule of embodiment 1~5
1st, it is formulated：It is shown in Table 1；
The embodiment 1~5 of table 1 prepares the formula of dutasteride's soft capsule
2nd, preparation method：Each component is mixed, is dissolved by heating, is stirred until homogeneous, obtains decoction；Gelatin, appropriate amount of water separately are taken,
Vessel in heating is put, rubber liquid is obtained；Above-mentioned decoction and rubber liquid are taken, it is compressing with RGY6X15F type encapsulating machines, dry, obtain
Dutasteride's soft capsule 1000.
Dutasteride's soft capsule and commercially available AVODART that drug sample is embodiment 1 are tested in tests below example 1~3
Soft capsule
The soft capsule of the present invention of test example 1 and commercially available AVODARTDissolution in vitro contrast of the soft capsule in water
1st, test method：
Using《Chinese Pharmacopoeia》Basket method in 2010 editions annex X C dissolution methods, takes test specimen to be surveyed respectively
Fixed, dissolution medium is 900mL water, and rotating speed is 50 turns/min；
Respectively at 5,10,15,20,30,45,60,90min timing samplings 5mL；
The content of dutasteride in sampling sample is determined with HPLC methods (the μ L of sample size 100)；HPLC testing conditions are：Color
Compose post：Phenyl silane bonded silica gel column (205 × 4.6mm, 5 μm)；Mobile phase：Acetonitrile-methanol-water (40: 20: 35)；Detect ripple
It is long：240nm；Flow velocity：1.0ml/min.
2nd, result of the test：
AVODARTSoft capsule maximum dissolution rate is 10%；
Dutasteride's soft capsule of the embodiment of the present invention 1 reached 100% in 30 minutes dissolution rates, and dissolution rate is significantly improved.
Dissolution figure is shown in Fig. 1.
The soft capsule of the present invention of test example 2 and commercially available AVODARTDissolution in vitro contrast of the soft capsule in hydrochloric acid
1st, test method：
Dissolution medium is 900mL 0.1mol/L hydrochloric acid, and other are identical with test example 1.
2nd, result of the test：
AVODARTSoft capsule maximum dissolution rate is 12%；
Dutasteride's soft capsule of the embodiment of the present invention 1 reached 100% in 30 minutes dissolution rates, and dissolution rate is significantly improved,
Dissolution figure is shown in Fig. 2.
The soft capsule of the present invention of test example 3 and commercially available AVODARTPharmacokinetics contrast of the soft capsule in beasle dog body
1st, test method：
1) administration and blood specimen collection
Male beagle dogs 6 (11~13kg) are taken, by the order of administration of table 2, after period 1 administration is finished, by 1 week
The cleaning phase, then carry out second round administration；
Every dog dosage is 0.5mg.Fasting 12h before administration, 0.25 after medication, 0.50,0.75,1.00,1.50,
2.00th, 3.00,4.00,6.00,8.00,12.00 hours, blood 3mL is taken respectively at femoral vein；
Blood sample is placed in the centrifuge tube of liquaemin processing, after 4000 turns/min is centrifuged 15 minutes, takes blood plasma 1.0mL in -20
DEG C freezen protective.
The pharmacokinetic trial order of administration of table 2
Note：A represents to use commercially available AVODART in table 2Soft capsule be administered, B represent with the dutasteride's soft capsule of embodiment 1 to
Medicine；The cleaning phase is 1 week.
2) blood sample treatments and assay
Each gained blood plasma 0.5mL is respectively placed in centrifuge tube in taking 1), with ether-acetic acid acetate mixed solvent (volume ratio 1
: 1) 2mL vortexs 5min, 3000 turns/min are centrifuged 5 minutes, supernatant are taken, nitrogen stream volatilizes organic solvent, with 100 μ L acetonitriles-first
Alcohol-water (40: 20: 35) is dissolved, and takes 50 μ L sample introductions, and the content of dutasteride in each sample is determined with HPLC methods.
2nd, result of the test
According to HPLC measurement results, the average value of his male amine content of the sample moderate of identical medicine identical period is obtained；
According to average value, C is drawnmax(highest blood concentration), Tmax(time for reaching highest blood concentration)；
Drug-time curve is drawn, AUC (extent of drug absorption in 12 hours) is obtained with trapezoidal method.
Obtained Cmax、Tmax, the pharmacokinetic parameters such as AUC be shown in Table 3,
Drug-time curve (blood concentration/time) is shown in Fig. 3.
The calculation formula of wherein relative bioavailability is：
The pharmacokinetic trial result of table 3
The dutasteride's soft capsule of embodiment 1 and commercially available AVODART can be seen that according to table 3 and Fig. 3Soft capsule is compared：
1)TmaxIt is substantially reduced, reaches the time advance of highest blood concentration 1.5 hours；
2)CmaxSignificantly improve, i.e., highest blood concentration improves nearly 1 times；
3) bioavilability is significantly improved, and relative bioavailability is up to 144%.
Claims (3)
1. a kind of active component is the medicine of dutasteride, containing dutasteride, oil medium and antioxidant, it is characterized in that：
The formulation of medicine is soft capsule；
The cosurfactant of surfactant containing 25%~66% (W/W) and 0%~10% (W/W)；
The one kind or many of the antioxidant in dibutyl hydroxy toluene, butylated hydroxy anisole or tert-butylhydroquinone
Kind, content is 0%~0.3% percentage by weight；
The surfactant is selected from following any：
Soybean lecithin+cholesterine+lecithin；
Polysorbate65+soybean lecithin+cholesterine+lecithin；
Span 20+soybean lecithin+cholesterine+lecithin；
Span 20+cholesterine；
One or more of the cosurfactant in ethanol, propane diols or glycerine；
The oil medium is selected from glycerol caprylate, glycerol decanoate, glyceryl monooleate, olein, soybean oil, jade
One or more in rice bran oil or sesame oil, content is 30%~70% percentage by weight.
2. the composition of claim 1, the oil medium is selected from following any：
Tricaprylin+Capmul MCM C10+sesame oil；
Capmul MCM C10；
Soybean oil, soybean oil+corn oil；
Tricaprylin+Capmul MCM C10+glyceryl monooleate+sesame oil.
3. the composition described in claim 1 or 2, the content of dutasteride is 0.02%~0.5% (W/W).
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| CN201110430444.5A CN103169712B (en) | 2011-12-20 | 2011-12-20 | Improve dutasteride's preparation of bioavilability and preparation method thereof |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105395517B (en) * | 2015-12-11 | 2018-04-06 | 成都华宇制药有限公司 | A kind of dutasteride's soft capsule preparation and its preparation technology |
| CN109394723B (en) * | 2017-08-17 | 2020-11-24 | 海南皇隆制药股份有限公司 | Dutasteride soft capsule and preparation method thereof |
| WO2020122681A1 (en) * | 2018-12-14 | 2020-06-18 | Chong Kun Dang Pharmaceutical Corp. | Composition comprising dutasteride |
| CN109668982B (en) * | 2018-12-28 | 2021-06-01 | 重庆华邦制药有限公司 | Method for separating and measuring impurity A in dutasteride soft capsules by high performance liquid chromatography |
| EP3914234A4 (en) * | 2019-01-25 | 2022-09-14 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions |
| CN109674762A (en) * | 2019-03-05 | 2019-04-26 | 南京正大天晴制药有限公司 | A kind of composition capsule of dutasteride and hair growth |
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| CN1263461A (en) * | 1997-08-19 | 2000-08-16 | 葛兰素集团有限公司 | Pharmaceutical composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB9717444D0 (en) * | 1997-08-19 | 1997-10-22 | Glaxo Group Ltd | Pharmaceutical composition |
| WO2010092596A1 (en) * | 2009-02-10 | 2010-08-19 | Genepharm India Private Limited | An oral pharmaceutical composition of dutasteride |
| CN102145003B (en) * | 2010-02-08 | 2015-04-22 | 张立英 | Medicinal composition containing insoluble medicament |
| CN102247379A (en) * | 2011-01-12 | 2011-11-23 | 北京润德康医药技术有限公司 | Compound preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1263461A (en) * | 1997-08-19 | 2000-08-16 | 葛兰素集团有限公司 | Pharmaceutical composition |
Non-Patent Citations (1)
| Title |
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| 自微乳化释药系统（SMEDDS）的研究进展;张晓峰 等;《现代药物与临床》;20091231;第24卷(第5期);261-264 * |
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