CN104546714A - Enzalutamide micelle preparation and preparation method thereof - Google Patents
Enzalutamide micelle preparation and preparation method thereof Download PDFInfo
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- CN104546714A CN104546714A CN201510074058.5A CN201510074058A CN104546714A CN 104546714 A CN104546714 A CN 104546714A CN 201510074058 A CN201510074058 A CN 201510074058A CN 104546714 A CN104546714 A CN 104546714A
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- shandong amine
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Abstract
The invention discloses an enzalutamide micelle preparation and a preparation method thereof. The enzalutamide micelle preparation disclosed by the invention is prepared from enzalutamide and an amphiphilic block copolymer. The preparation method disclosed by the invention comprises the following steps of: mixing enzalutamide with the amphiphilic block copolymer to dissolve in an organic solvent, rotatably evaporating to remove the organic solvent so as to obtain an enzalutamide-containing film skeleton, drying, adding deionized water, ultrasonically dispersing, oscillating at constant temperature to obtain micelle solution, and adjusting the speed and centrifuging to obtain supernate, namely the enzalutamide nano-micelle preparation. The enzalutamide micelle preparation prepared by the invention has the characteristics of being high in encapsulation efficiency, drug loading ratio and the like; the enzalutamide nano-micelle is prepared by adopting an improved film dispersion method; therefore, the solubleness of enzalutamide in water is increased; the drug loading capacity of the preparation is 6% or above; and the enzalutamide micelle preparation is steady in structure, small in particle size and easy to store.
Description
Technical field
The present invention relates to a kind of advanced prostate cancer new drug grace to mix Shandong amine micellar preparation its preparation method, belong to pharmaceutical engineering applied technical field.
Background technology
Grace Shandong amine (Enzalutamide) of mixing develops androgen antagonist medicine of new generation cooperatively by Medivation company of the U.S. and Japanese Astellas (Astellas) company, can be used for treating late period (transitivity) the male castration-resistant prostate cancer (Castration-Resistant Prostate Ccancer) having spread or recurred.Approval listing in Nikkei FDA (Food and Drug Adminstration) August 31 in 2012 (FDA).The U.S. mainly provides patient to use with grace Shandong amine capsule product of mixing, and is a kind of androgen receptor inhibitor, is applicable to treat advanced prostate cancer patients, and its grace Shandong amine chemical constitution of mixing is:
Formula 1: grace is mixed Shandong amine chemical structural formula
Micelle is a kind of thermodynamic stable system, is that the lipophilic tail end of surfactant molecule gathers in micelle inner, avoids contacting with the hydrone of polarity; The polar hydrophilic head end of molecule is then exposed to outside, has an effect with the hydrone of polarity, and produces protective effect to the hydrophobic group of micelle inside.The solubilising of micelle for a long time for insoluble drug in pharmacy, micelle can improve the stability of medicine as pharmaceutical carrier, improves drug effect, reduces the effects such as toxicity.
Polylactic acid (Polylactic Acid, PLA) be a kind of new bio degradable material, the starch material using reproducible plant resources to propose, obtains glucose by saccharifying, obtain lactic acid by biofermentation again, then obtain polylactic acid by polyreaction.Polylactic acid has degradability and biocompatibility, has obtained U.S. FDA approval in excipient substance, has had a good application prospect as pharmaceutical carrier.
Polymethoxy Polyethylene Glycol (MPEG), is obtained by polyreaction for raw material with methanol and oxirane.The biocompatibility that polymethoxy Polyethylene Glycol is good, hydrophilic, nontoxic, non-immunogenicity, non-stimulated to human body, gentle.With polylactic acid and polymethoxy Polyethylene Glycol for raw material can prepare MPEG-PLA, this polymer can be used as pharmaceutical carrier and enters clinical practice.To mix Shandong amine micelle by preparing grace with the MPEG-PLA material of biodegradable, high medicine carrying reason, grace can be increased and to mix Shandong amine solvent degree, improve grace and to mix the stability of Shandong amine and bioavailability.
Polyoxyethylene ether (PEO), also known as polyethylene glycol oxide or poly(ethylene oxide), is a kind of non-ionic surface active agent.Polyoxyethylene (PEO)-polylactic acid (PLA) prepares with polyoxyethylene ether and polylactic acid, polyoxyethylene-polylactic acid has good life phase capacitive, medicinal macromolecule carrier etc. is widely used at field of medicaments, to mix Shandong amine micelle for the preparation of grace, grace can be increased equally to mix Shandong amine solvent degree, improve grace and to mix the stability of Shandong amine and bioavailability.
Certainly, also there are other to be suitable for medicinal macromolecule carrier etc. in amphipathic nature block polymer, mix Shandong amine micelle for the preparation of grace, grace can be increased equally and to mix Shandong amine solvent degree, improve grace and to mix the stability of Shandong amine and bioavailability.
Summary of the invention
Object: be solve the deficiencies in the prior art, the invention provides a kind of grace and to mix Shandong amine micellar preparation and preparation method thereof, easy to prepare, the good effect of preparation, stable, toxic and side effects is low.
Technical scheme: for solving the problems of the technologies described above, the technical solution used in the present invention is:
A kind of grace is mixed Shandong amine micellar preparation, it is characterized in that, comprises by the raw material of following mass fraction: grace is mixed Shandong amine 1-50 part, amphipathic nature block polymer 10-100 part; The mix mass ratio of Shandong amine and amphipathic nature block polymer of described grace is 1:2-1:100.
Described amphipathic nature block polymer is the one in MPEG-PLA, polyoxyethylene-polylactic acid (PLA), polyethylene glycol-benzyl aspartic acid, polyoxyethylene (PEO)-poly-benzyl aspartic acid.
Described a kind of grace is mixed Shandong amine micellar preparation, it is characterized in that: described grace is mixed Shandong amine micellar preparation, is take amphipathic nature block polymer as carrier, adopts film dispersion method to be prepared from.
Above-mentioned a kind of grace is mixed the preparation method of Shandong amine micellar preparation, prepared by employing film dispersion method: in reaction vessel, proportionally add amphipathic nature block polymer and grace to mix Shandong amine, add organic solvent again and carry out stirring and dissolving, then water-bath removing organic solvent, drying, obtain dry transparent medicine membrane bone frame, add deionized water, ultrasonic disperse, co oscillation in parallel, centrifugal, remove non-encapsulated particle, obtain grace and to mix Shandong amine micellar preparation.
Described a kind of grace is mixed the preparation method of Shandong amine micellar preparation, it is characterized in that: described organic solvent is one or more in ethanol, oxolane, ethyl acetate, dichloromethane, acetone.
Preferably, described a kind of grace is mixed the preparation method of Shandong amine micellar preparation, it is characterized in that: described bath temperature is 30-40 DEG C.
Preferably, described a kind of grace is mixed the preparation method of Shandong amine micellar preparation, it is characterized in that: described drying is for dry in vacuum drying oven.
Preferably, described a kind of grace is mixed the preparation method of Shandong amine micellar preparation, and it is characterized in that: ultrasonic disperse under room temperature, and combine 37 DEG C of constant temperature oscillations, 12000rpm is centrifugal.
Beneficial effect: a kind of grace provided by the invention is mixed Shandong amine micellar preparation and preparation method thereof, by be MPEG-PLA with the amphipathic nature block polymer of biodegradable, high medicine carrying reason, the material such as polyoxyethylene-polylactic acid, polyethylene glycol-benzyl aspartic acid, polyoxyethylene-poly-benzyl aspartic acid prepares grace and to mix Shandong amine nano-micelle, grace can be increased to mix Shandong amine solvent degree, improve grace and to mix the stability of Shandong amine and bioavailability.The present invention uses amphipathic nature block polymer to be micellar fractions, MPEG-PLA, polyoxyethylene-polylactic acid, polyethylene glycol-benzyl aspartic acid, polyoxyethylene-poly-benzyl aspartic acid etc. is a kind of amphipathic nature block polymer, in aqueous can spontaneous formation hydrophobic section cohesion, hydrophilic section is to external micelle; Grace prepared by the present invention Shandong amine micellar preparation of mixing has envelop rate and carrying drug ratio high; The present invention adopts the film dispersion method of improvement to prepare grace and to mix Shandong amine nano-micelle, and improve grace and to mix the dissolubility of An Enza Shandong, Shandong amine in water, preparation drug loading can reach more than 6%, its Stability Analysis of Structures, and particle diameter is little, is easy to preserve.
Detailed description of the invention
Below in conjunction with instantiation, the present invention is illustrated:
Embodiment 1:
In round-bottomed flask, add MPEG-PLA 200.0mg and grace to mix Shandong amine 20.0mg, add appropriate ethanol stirring and dissolving, rotate under 30-40 DEG C of water-bath and steam except ethanol, vacuum drying 4 hours, obtains dry transparent medicine membrane bone frame.Add 10ml deionized water again, ultrasonic disperse 20min under room temperature, vibrate 20min at 37 DEG C, with centrifugal under 12000rpm centrifugal 20min, remove non-encapsulated or large particle, the grace that supernatant is clear is mixed Shandong amine micellar preparation.
Obtained grace is mixed in the amine micellar preparation of Shandong, grace mix Shandong amine envelop rate this 87.5%, drug loading 9.06%.
Separate out without drug precipitation under preserving at 4 DEG C.
Embodiment 2:
In round-bottomed flask, add MPEG-PLA 200.0mg and grace to mix Shandong amine 16.0mg, after adding appropriate dichloromethane stirring and dissolving, under 30-40 DEG C of water-bath, rotate and steam except dichloromethane, vacuum drying 24 hours, obtain dry transparent medicine membrane bone frame, add 15.0ml deionized water, at ambient temperature ultrasonic disperse 25min, then use constant temperature oscillation 30min, (remove non-encapsulated crystalline drug) after the centrifugal 15min of 12000rpm, supernatant is transparent micellar preparation.
Obtained grace is mixed in the amine micellar preparation of Shandong, and envelop rate is 82.5%, drug loading 7.57%.
Separate out without drug precipitation under preserving at 4 DEG C.
Embodiment 3:
In round-bottomed flask, add polyoxyethylene-polylactic acid 200.0mg and grace to mix Shandong amine 15.0mg, after adding appropriate acetone stirring and dissolving, under 30-40 DEG C of water-bath, rotate and steam except acetone, vacuum drying 24 hours, obtain dry transparent medicine membrane bone frame, add 12.0ml deionized water, at ambient temperature ultrasonic disperse 25min, then use constant temperature oscillation 30min, (remove non-encapsulated crystalline drug) after the centrifugal 20min of 12000rpm, supernatant is transparent micellar preparation.
Obtained grace is mixed in the amine micellar preparation of Shandong, and envelop rate is 80.1%, drug loading 6.54%.
Separate out without drug precipitation under preserving at 4 DEG C.
Embodiment 4:
In round-bottomed flask, add polyoxyethylene-polylactic acid 200.0mg and grace to mix Shandong amine 50.0mg, after adding appropriate oxolane, ethyl acetate mixed solvent stirring and dissolving, under 30-40 DEG C of water-bath, rotate and steam except oxolane, ethyl acetate, vacuum drying 24 hours, obtain dry transparent medicine membrane bone frame, add 13.0ml deionized water, ultrasonic disperse 25min at ambient temperature, use constant temperature oscillation 30min again, (remove non-encapsulated crystalline drug) after the centrifugal 20min of 12000rpm, supernatant is transparent micellar preparation.
Obtained grace is mixed in the amine micellar preparation of Shandong, and envelop rate is 83.5%, drug loading 7.03%.
Separate out without drug precipitation under preserving at 4 DEG C.
Embodiment 5:
In round-bottomed flask, add polyethylene glycol-benzyl aspartic acid 200.0mg and grace to mix Shandong amine 100.0mg, after adding appropriate oxolane stirring and dissolving, under 30-40 DEG C of water-bath, rotate and steam except oxolane, vacuum drying 24 hours, obtain dry transparent medicine membrane bone frame, add 11.0ml deionized water, ultrasonic disperse 25min at ambient temperature, use constant temperature oscillation 30min again, (remove non-encapsulated crystalline drug) after the centrifugal 20min of 12000rpm, supernatant is transparent micellar preparation.
Obtained grace is mixed in the amine micellar preparation of Shandong, and envelop rate is 81.3%, drug loading 7.93%.
Separate out without drug precipitation under preserving at 4 DEG C.
Embodiment 6:
In round-bottomed flask, add polyoxyethylene-poly-benzyl aspartic acid 200.0mg and grace to mix Shandong amine 10.0mg, after adding appropriate ethyl acetate stirring and dissolving, under 30-40 DEG C of water-bath, rotate and steam except ethyl acetate, vacuum drying 24 hours, obtain dry transparent medicine membrane bone frame, add 10.0ml deionized water, ultrasonic disperse 25min at ambient temperature, use constant temperature oscillation 30min again, (remove non-encapsulated crystalline drug) after the centrifugal 20min of 12000rpm, supernatant is transparent micellar preparation.
Obtained grace is mixed in the amine micellar preparation of Shandong, and envelop rate is 87.4%, drug loading 7.79%.
Separate out without drug precipitation under preserving at 4 DEG C.
Below disclose the present invention with preferred embodiment, so it is not intended to limiting the invention, and all employings are equal to replacement or the technical scheme that obtains of equivalent transformation mode, all drop within protection scope of the present invention.
Claims (8)
1. grace is mixed a Shandong amine micellar preparation, it is characterized in that, comprises by the raw material of following mass fraction: grace is mixed Shandong amine 1-50 part, amphipathic nature block polymer 10-100 part; The mix mass ratio of Shandong amine and amphipathic nature block polymer of described grace is 1:2-1:100.
2. a kind of grace according to claim 1 is mixed Shandong amine micellar preparation, it is characterized in that: described amphipathic nature block polymer is the one in MPEG-PLA, polyoxyethylene-polylactic acid, polyethylene glycol-benzyl aspartic acid, polyoxyethylene-poly-benzyl aspartic acid.
3. a kind of grace according to claim 1 is mixed Shandong amine micellar preparation, it is characterized in that: described grace is mixed Shandong amine micellar preparation, is take amphipathic nature block polymer as carrier, adopts film dispersion method to be prepared from.
4. a kind of grace according to any one of claim 1-3 is mixed the preparation method of Shandong amine micellar preparation, prepared by employing film dispersion method: in reaction vessel, proportionally add amphipathic nature block polymer and grace to mix Shandong amine, add organic solvent again and carry out stirring and dissolving, then water-bath removing organic solvent, drying, obtain dry transparent medicine membrane bone frame, add deionized water, ultrasonic disperse, co oscillation in parallel, centrifugal, remove non-encapsulated particle, obtain grace and to mix Shandong amine micellar preparation.
5. a kind of grace according to claim 4 is mixed the preparation method of Shandong amine micellar preparation, it is characterized in that: described organic solvent is one or more in ethanol, oxolane, ethyl acetate, dichloromethane, acetone.
6. a kind of grace according to claim 4 is mixed the preparation method of Shandong amine micellar preparation, it is characterized in that: described bath temperature is 30-40 DEG C.
7. a kind of grace according to claim 4 is mixed the preparation method of Shandong amine micellar preparation, it is characterized in that: described drying is for dry in vacuum drying oven.
8. a kind of grace according to claim 4 is mixed the preparation method of Shandong amine micellar preparation, and it is characterized in that: ultrasonic disperse under room temperature, and combine 37 DEG C of constant temperature oscillations, 12000rpm is centrifugal.
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| CN201510074058.5A CN104546714A (en) | 2015-02-11 | 2015-02-11 | Enzalutamide micelle preparation and preparation method thereof |
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| CN201510074058.5A CN104546714A (en) | 2015-02-11 | 2015-02-11 | Enzalutamide micelle preparation and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018037310A1 (en) | 2016-08-20 | 2018-03-01 | Ftf Pharma Private Limited | Pharmaceutical composition comprising an androgen receptor inhibitor |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102218027A (en) * | 2011-04-22 | 2011-10-19 | 上海谊众生物技术有限公司 | Polymer micelle lyophilized agent encapsulating insoluble antitumor drug |
| CN102274163A (en) * | 2011-08-12 | 2011-12-14 | 山东大学 | Curcumin nano micelle preparation and preparation method thereof |
| WO2014043208A1 (en) * | 2012-09-11 | 2014-03-20 | Medivation Prostate Therapeutics, Inc. | Formulations of enzalutamide |
| CN103772686A (en) * | 2012-10-26 | 2014-05-07 | 苏州雷纳药物研发有限公司 | Amphiphilic block copolymer and preparation method thereof, micelle drug delivery system formed by copolymer and anti-tumor drug |
| WO2015022349A1 (en) * | 2013-08-14 | 2015-02-19 | Ratiopharm Gmbh | Dosage form comprising enzalutamide |
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2015
- 2015-02-11 CN CN201510074058.5A patent/CN104546714A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102218027A (en) * | 2011-04-22 | 2011-10-19 | 上海谊众生物技术有限公司 | Polymer micelle lyophilized agent encapsulating insoluble antitumor drug |
| CN102274163A (en) * | 2011-08-12 | 2011-12-14 | 山东大学 | Curcumin nano micelle preparation and preparation method thereof |
| WO2014043208A1 (en) * | 2012-09-11 | 2014-03-20 | Medivation Prostate Therapeutics, Inc. | Formulations of enzalutamide |
| CN103772686A (en) * | 2012-10-26 | 2014-05-07 | 苏州雷纳药物研发有限公司 | Amphiphilic block copolymer and preparation method thereof, micelle drug delivery system formed by copolymer and anti-tumor drug |
| WO2015022349A1 (en) * | 2013-08-14 | 2015-02-19 | Ratiopharm Gmbh | Dosage form comprising enzalutamide |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018037310A1 (en) | 2016-08-20 | 2018-03-01 | Ftf Pharma Private Limited | Pharmaceutical composition comprising an androgen receptor inhibitor |
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Application publication date: 20150429 |