CN102406605A - Ethosome preparation of male hormone medicaments and its preparation method - Google Patents
Ethosome preparation of male hormone medicaments and its preparation method Download PDFInfo
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- CN102406605A CN102406605A CN2011101077806A CN201110107780A CN102406605A CN 102406605 A CN102406605 A CN 102406605A CN 2011101077806 A CN2011101077806 A CN 2011101077806A CN 201110107780 A CN201110107780 A CN 201110107780A CN 102406605 A CN102406605 A CN 102406605A
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Abstract
The invention provides an ethosome preparation of male hormone medicaments and its preparation method, and specifically relates to a new preparation form ethosome of medicaments for treating a series of diseases caused by male hormone deletion, such as delayed pubertas, male sterility, endocrine erectile dysfunction (impotence), male climacteric syndrome etc. and adding male hormones, as well as a preparation technology thereof. The invention aims to provide an ethosome preparation which makes use of the novel transdermal drug delivery carrier ethosome for improving transdermal transport of male hormone medicaments and enhancing their curative effects.
Description
Technical field
The present invention relates to ethosome preparation of male sex hormone drug and preparation method thereof; Relate in particular to treatment because a series of diseases that androgen disappearance causes, such as: adolescence delay, the novel form and the preparation technology of the medicine ethosome of the additional androgen of diseases such as male infertility, incretion erection disturbance (sexual impotence), male climacteric syndrome.
Background technology
Give birth to testosterone in the male and can not cause a lot of clinical problems completely, as adolescence delay, diseases such as male infertility, incretion erection disturbance (sexual impotence), male climacteric syndrome.And testosterone is very important to male's all one's life, and its biological action is except that to the reproductive system, and is almost omnipresent to the influence of non-reproductive system, and exercises its biological effect widely through different approaches and mechanism
[6], the low male of testosterone levels also is prone to suffer from multiple internal disease for this reason, therefore gives exogenous testosterone to replenish the deficiency of self secretion level, and (testosterone supplement therapy TST) is very important promptly to adopt the testosterone alternative medicine.Big quantity research confirms that TST has benefit widely, can be applicable to the treatment of former or Secondary cases (testis) hypofunction and the low disease of male menopause testosterone levels; Can improve the dementia patients cognition, correct the dysthymic disorder, improve sleep; Can improve bone density, the prevention fracture; Can alleviate insulin resistant, reduce type ii diabetes patient blood sugar level, alleviate visceral adiposity; Lipid metabolism there is positive impact; Can help coronary heart disease, anginal control, alleviate symptoms of heart failure; Promote anabolism, change health and form, improve physical ability etc.
At present, testosterone preparation can be divided into two big types basically: great majority are 17 α-testosterone esters, and minority is the alkanes T preparation at C-1,7,17 methylates (CH3).Be absorbed into blood after alkyl compound is oral very soon, peaking behind 90～120min, needs repeatedly oral at the half-life short (being about 150min).Because its toxic and side effects, as cause hepatic injury, jaundice, even bring out hepatocarcinoma, so clinically abandon.The ketone ester compounds comprises Testosterone Propionate (TP), testosterone enanthatas (TE), testosterone undecanoate (TU), normal-butyl cyclohexane carboxylic acid testosterone (TB) etc.; Because of various LCFA is arranged on its side chain; Lipotropy strengthens; Its half-life in blood also increases, thereby makes it be successfully used to clinical treatment.TP need inject weekly 1 time and the plasma testosterone instability; TB is the most long-acting testosterone ester of developing at present, sustainable 3-4 month action time, but because of its prescription and solubility, clinical trial at present temporarily stops, and TU is because it is insoluble in water, and oral absolute bioavailability is merely about 7%.Two kinds of dosage forms of injection and soft capsule are arranged at present; Injection needs injection in 3 months 1 time; Cumbersome, commercially available soft capsule
is an imported product, is that TU is dissolved in the oleic acid oral administration; Though improved bioavailability; But life-time service causes gastrointestinal reaction easily, and product needs cryopreservation, very inconvenience.The Androderm that the patch of clinical practice has produced in usa Tai Side (Testoderm) and Germany to produce, both active component all are testosterones, the former is affixed on scrotum, discharges medicine 4～6mg every day; The latter is non-scrotum paster, and use 2.5mg juvenile every day, and per day for adults is used 7.5mg, can be affixed on health everywhere on the skin.But with the pressure sensitive adhesive be the patch of carrier because breathability is poor, local skin is uncomfortable and cost an arm and a leg, domestic patient is difficult to accept.
Because these medicine majorities are fat-soluble medicine, dissolubility is low and because the fine and close horny layer structure of skin makes these hormone medicines be difficult to see through skin performance drug effect, clinical efficacy is poor.
Summary of the invention
The object of the present invention is to provide ethosome preparation of male sex hormone drug and preparation method thereof, utilize this novel percutaneous dosing carrier of ethosome, improve the male sex hormone drug transport through skin, improve its curative effect.The present invention has strong to skin nonirritant, transdermal penetration ability, as effectively to improve testosterone in body concentration characteristics.
Mainly consisting of of the ethosome preparation of male sex hormone drug provided by the invention
The ethosome outward appearance is regular circular or ellipse in the preparation of the present invention, particle diameter between 50～500nm, preferred 50～200nm.
Phospholipid is that medicinal phospholipid adopts soybean lecithin, lecithin, two palmityl phospholipid in the preparation of the present invention.
Androgen medicine in the preparation of the present invention adopts: testosterone, Testosterone Propionate, testosterone undecanoate etc.
Surfactant in the preparation of the present invention adopts one or more in dodecyl sodium sulfate, CTAB, TWEEN-80, sodium cholate, the poloxamer-188.
Cosolvent is isopropyl myristate, oleic acid, PEG400 etc. in the preparation of the present invention
The alcohol of the small-molecular weight in the preparation of the present invention is selected ethanol or propylene glycol, preferred alcohol for use.
A kind of method for preparing is a film dispersion method in the preparation of the present invention, at first above-mentioned fat-soluble component is placed the pyriform bottle, is dissolved in chloroform or the ether by above-mentioned percentage by weight; On Rotary Evaporators; 30～60 ℃ of water bath with thermostatic control decompression rotary evaporations are removed organic solvent and are formed uniform lipid membrane, and after the continuation evacuation made solvent thoroughly wave to the greatest extent, adding concentration was no more than 50% ethanol water and is rotated hydration; Form medicine ethosome dispersion; After cryogenic probe is ultrasonic,, make the ethosome preparation of the uniform male sex hormone drug of particle diameter through the filtering with microporous membrane of 0.45um.
A kind of method for preparing is to adopt injection method in the preparation of the present invention, at first with above-mentioned fat-soluble component, is dissolved in the ethanol by above-mentioned percentage by weight, in being full of N
2Hermetic container in 40 ℃ of insulated and stirred it is dissolved fully; With water with the streams shape slowly join ethanol mutually in; After continuing to mix 10～30min under 40 ℃ of conditions, stop to stir, treat the sample cool to room temperature after; Behind the 0.45um filtering with microporous membrane, obtain the ethosome preparation of the uniform male sex hormone drug of particle diameter.
Beneficial effect of the present invention:
Ethosome be in recent years in the drug delivery system a kind of have high morphotropism, high envelop rate, can complete transdermal novel lipide carrier; Be that a kind of softness, toughness are very strong and can strengthen the carrier of medicine skin-communication, especially be suitable as topical administration and transdermal administration carrier.In recent years, increasing research shows that ethosome has the unrivaled topical carrier property of liposome, because the dissolubility of most medicines in ethanol is high, the envelop rate of ethosome Chinese medicine is significantly improved, and percolation ratio reduces; Simultaneously the ethosome carrier also can transmit for hydrophilic and lipophilic drugs provide in the effective cell, its good biocompatibility can be much self can't transdermal pharmaceutical pack be wrapped in wherein, carry entering skin, formation drug depot and bring into play local drug effect lastingly.
(1) the androgens medicine has been processed stable ethosome through adding surfactant and cosolvent,, increased the transmitance of medicine through the transdermal penetration administration; Improve drug bioavailability; Avoid the first pass effect of medicine, keep stable blood drug level, thereby improved curative effect.
(2) ethosome is a kind of vesicle drug administration carrier of being made up of phospholipid, alcohol, water etc.; Just the alcohol by small-molecular weight replaces cholesterol; Alcohol gives ethosome mobile and super deformed property, and under skin hydration pressure, ethosome can carry himself aperture of little 1/5～1/10 of medicine tranmittance; Can get into deep skin soon and absorbed and the performance drug effect, so ethosome has become the drug delivery carrier that development potentiality is arranged in the transdermal delivery system very much by subcutaneous blood capillary.
(3) dissolubility of the alcohol extraction fat-solubility medicine of small-molecular weight, thereby the drug loading and the envelop rate of raising ethosome.
(4) ethosome of the present invention is formed simply, technology is easy, preparation stabilization good, envelop rate is high, to the skin nonirritant, is prone to suitability for industrialized production, has bigger promotional value.
(5) ethosome of the present invention can directly apply to clinically, can be carrier with other pharmaceutic adjuvant further also, processes the product of various dosage forms, comprises gel, ointment, patch etc.
The specific embodiment
Provide embodiment below so that the present invention is described further, but it is to be noted that following examples can not be interpreted as the restriction to protection domain of the present invention.Content still belongs to protection scope of the present invention to some nonessential improvement and the adjustment that the present invention makes to those skilled in the art according to the present invention.
Embodiment 1
Present embodiment adopts injection method to prepare the testosterone ethosome
Preparation: precision takes by weighing isopropyl myristate, testosterone and soybean lecithin and is dissolved in the dehydrated alcohol, and 40 ℃, 700rmin-1 magnetic agitation dissolve it fully in the hermetic container that is full of N2.With dodecyl sodium sulfate be dissolved in the water with the streams shape slowly with water join ethanol mutually in; After under 40 ℃, 700r/min condition, continuing to mix 10～30min; Stop to stir; After treating the sample cool to room temperature,, get entrapment efficiency at the testosterone ethosome more than 90% through the 0.45um filtering with microporous membrane.
Embodiment 2
Present embodiment adopts injection method to prepare the Testosterone Propionate ethosome
Preparation: precision takes by weighing oleic acid, Testosterone Propionate and soybean lecithin and is dissolved in the dehydrated alcohol, and 40 ℃, 700rmin-1 magnetic agitation dissolve it fully in the hermetic container that is full of N2.With dodecyl sodium sulfate be dissolved in the water with the streams shape slowly with water join ethanol mutually in; After under 40 ℃, 700r/min condition, continuing to mix 10～30min; Stop to stir; After treating the sample cool to room temperature, filter, get entrapment efficiency at the Testosterone Propionate ethosome more than 90% through microporous filter membrane (0.45um).
Embodiment 3
Present embodiment adopts injection method to prepare the testosterone undecanoate ethosome
Preparation: above-mentioned testosterone undecanoate, lecithin, isopropyl myristate are dissolved in the chloroform, and on Rotary Evaporators, 40 ℃ of water bath with thermostatic control decompression rotary evaporations are removed organic solvent and formed uniform lipid membrane; The continuation evacuation is dissolved in CTAB in 35% alcoholic solution after making solvent thoroughly wave to the greatest extent, and the dissolving back adds; Be rotated hydration, form medicine ethosome dispersion, after cryogenic probe is ultrasonic; Through the filtering with microporous membrane of 0.45um, make the ethosome of the uniform testosterone undecanoate of particle diameter.
Embodiment 4
Present embodiment adopts injection method to prepare the testosterone ethosome
Preparation: precision takes by weighing isopropyl myristate, testosterone, TWEEN-80 and two palmityl phospholipid and is dissolved in the dehydrated alcohol, in being full of N
2Hermetic container in 40 ℃, 700rmin-1 magnetic agitation it is dissolved fully.With water with the streams shape slowly join ethanol mutually in; After under 40 ℃, 700r/min condition, continuing to mix 10～30min, stop to stir, treat the sample cool to room temperature after; Through the 0.45um filtering with microporous membrane, get entrapment efficiency at the testosterone ethosome more than 90%.
Embodiment 5
Present embodiment adopts injection method to prepare the Testosterone Propionate ethosome
Preparation: precision takes by weighing PEG400, Testosterone Propionate and soybean lecithin and is dissolved in the dehydrated alcohol, and 40 ℃, 700rmin-1 magnetic agitation dissolve it fully in the hermetic container that is full of N2.With CTAB be dissolved in the water with the streams shape slowly with water join ethanol mutually in; After under 40 ℃, 700r/min condition, continuing to mix 10～30min, stop to stir, treat the sample cool to room temperature after; Filter through microporous filter membrane (0.45um), get the Testosterone Propionate ethosome.
Claims (9)
1. the ethosome preparation of male sex hormone drug is characterized in that: ethosome is made up of the alcohol of medicine (testosterone, Testosterone Propionate, testosterone undecanoate etc.), phospholipid, small-molecular weight, surfactant, cosolvent etc.It is characterized in that: in ethosome, it is composed of the following components by weight percentage with drug encapsulation:
Male sex hormone drug 0.1%～2%
Phosphatidase 11 %～5%
The alcohol 20%～45% of small-molecular weight
Surfactant 0.1%～2%
Cosolvent 0.2%～2%
Water: 44%～78.6%
2. the ethosome preparation of male sex hormone drug is characterized in that: described androgen medicine employing: testosterone or Testosterone Propionate or testosterone undecanoate.
3. the ethosome preparation of male sex hormone drug according to claim 1 is characterized in that: described phospholipid employing soybean lecithin or lecithin or two palmityl phospholipid.
4. the ethosome preparation of male sex hormone drug according to claim 1; It is characterized in that: described surfactant adopts one or more in dodecyl sodium sulfate, CTAB, TWEEN-80, sodium cholate, the poloxamer-188, and described cosolvent is isopropyl myristate, oleic acid etc.
5. the ethosome preparation of male sex hormone drug according to claim 1, it is characterized in that: the alcohol of described small-molecular weight is selected ethanol or propylene glycol for use.
6. the ethosome preparation of male sex hormone drug according to claim 1, it is characterized in that: the ethosome outward appearance is regular circular or ellipse, and particle diameter is between 50～500nm.
7. the method for preparing of the ethosome preparation of male sex hormone drug is characterized in that: adopt film dispersion method, at first above-mentioned fat-soluble component is placed the pyriform bottle; Be dissolved in chloroform or the ether by above-mentioned percentage by weight, on Rotary Evaporators, 30～60 ℃ of water bath with thermostatic control decompression rotary evaporations are removed organic solvent and are formed uniform lipid membrane; After the continuation evacuation makes solvent thoroughly wave to the greatest extent; Adding concentration is no more than 50% ethanol water and is rotated hydration, forms medicine ethosome dispersion, after cryogenic probe is ultrasonic; Through the filtering with microporous membrane of 0.45um, make the ethosome preparation of the uniform male sex hormone drug of particle diameter.
8. the method for preparing of the ethosome preparation of male sex hormone drug is characterized in that: adopt injection method, at first with above-mentioned fat-soluble component, be dissolved in the ethanol by above-mentioned percentage by weight, in being full of N
2Hermetic container in 40 ℃ of insulated and stirred it is dissolved fully; With water with the streams shape slowly join ethanol mutually in; After continuing to mix 10～30min under 40 ℃ of conditions, stop to stir, treat the sample cool to room temperature after; Behind the 0.45um filtering with microporous membrane, obtain the ethosome preparation of the uniform male sex hormone drug of particle diameter.
9. according to the method for preparing of the ethosome preparation of claim 7 or 8 described male sex hormone drugs; It is characterized in that: the ethosome preparation of said preparation; Directly apply to clinical or be carrier further with other pharmaceutic adjuvant; Process the product of various dosage forms, comprise gel, ointment, patch.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011101077806A CN102406605A (en) | 2011-04-28 | 2011-04-28 | Ethosome preparation of male hormone medicaments and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011101077806A CN102406605A (en) | 2011-04-28 | 2011-04-28 | Ethosome preparation of male hormone medicaments and its preparation method |
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| CN2011101077806A Pending CN102406605A (en) | 2011-04-28 | 2011-04-28 | Ethosome preparation of male hormone medicaments and its preparation method |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102813624A (en) * | 2012-08-13 | 2012-12-12 | 中国人民解放军第三军医大学 | Lidocaine ethosome and preparation method thereof |
| CN109700764A (en) * | 2019-02-20 | 2019-05-03 | 广东食品药品职业学院 | Protona in-situ gel spray and preparation method thereof |
| CN110664806A (en) * | 2019-10-17 | 2020-01-10 | 广东省农业科学院动物卫生研究所 | Fipronil and methoprene glycol plastid and preparation method and application thereof |
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| US5716638A (en) * | 1994-06-22 | 1998-02-10 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Composition for applying active substances to or through the skin |
| CN101273971A (en) * | 2008-05-09 | 2008-10-01 | 绍兴文理学院 | Ethosomes preparation of antimycotics pharmaceutical and method for preparing the same |
| CN101574373A (en) * | 2008-05-09 | 2009-11-11 | 北京因科瑞斯医药科技有限公司 | Toad venom alcohol plastid and preparation method thereof |
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2011
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Patent Citations (3)
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| US5716638A (en) * | 1994-06-22 | 1998-02-10 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Composition for applying active substances to or through the skin |
| CN101273971A (en) * | 2008-05-09 | 2008-10-01 | 绍兴文理学院 | Ethosomes preparation of antimycotics pharmaceutical and method for preparing the same |
| CN101574373A (en) * | 2008-05-09 | 2009-11-11 | 北京因科瑞斯医药科技有限公司 | Toad venom alcohol plastid and preparation method thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102813624A (en) * | 2012-08-13 | 2012-12-12 | 中国人民解放军第三军医大学 | Lidocaine ethosome and preparation method thereof |
| CN102813624B (en) * | 2012-08-13 | 2013-10-30 | 中国人民解放军第三军医大学 | Lidocaine ethosome and preparation method thereof |
| CN109700764A (en) * | 2019-02-20 | 2019-05-03 | 广东食品药品职业学院 | Protona in-situ gel spray and preparation method thereof |
| CN109700764B (en) * | 2019-02-20 | 2021-07-06 | 广东食品药品职业学院 | Dihydrotestosterone in-situ gel spray and preparation method thereof |
| CN110664806A (en) * | 2019-10-17 | 2020-01-10 | 广东省农业科学院动物卫生研究所 | Fipronil and methoprene glycol plastid and preparation method and application thereof |
| CN110664806B (en) * | 2019-10-17 | 2023-02-28 | 广东省农业科学院动物卫生研究所 | Fipronil and methoprene dihydric alcohol plastid and preparation method and application thereof |
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Application publication date: 20120411 |