CN1997357A - Uses and formulations for transdermal or transmucosal application of active agents - Google Patents
Uses and formulations for transdermal or transmucosal application of active agents Download PDFInfo
- Publication number
- CN1997357A CN1997357A CNA2004800051239A CN200480005123A CN1997357A CN 1997357 A CN1997357 A CN 1997357A CN A2004800051239 A CNA2004800051239 A CN A2004800051239A CN 200480005123 A CN200480005123 A CN 200480005123A CN 1997357 A CN1997357 A CN 1997357A
- Authority
- CN
- China
- Prior art keywords
- preparation
- activating agent
- treatment
- subjected
- testosterone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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- 238000009472 formulation Methods 0.000 title abstract description 7
- 239000013543 active substance Substances 0.000 title abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 82
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- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 claims description 14
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 claims description 14
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- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 10
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 claims description 10
- 206010027304 Menopausal symptoms Diseases 0.000 claims description 8
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 claims description 8
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 8
- 229960003387 progesterone Drugs 0.000 claims description 8
- 239000000186 progesterone Substances 0.000 claims description 8
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 claims description 7
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- 239000003963 antioxidant agent Substances 0.000 claims description 7
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- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 claims description 7
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- 239000002674 ointment Substances 0.000 claims description 7
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 claims description 6
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 claims description 6
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- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 claims description 6
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 claims description 6
- YNVGQYHLRCDXFQ-XGXHKTLJSA-N Lynestrenol Chemical compound C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 YNVGQYHLRCDXFQ-XGXHKTLJSA-N 0.000 claims description 6
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- 229960002568 ethinylestradiol Drugs 0.000 claims description 6
- ONKUMRGIYFNPJW-KIEAKMPYSA-N ethynodiol diacetate Chemical compound C1C[C@]2(C)[C@@](C#C)(OC(C)=O)CC[C@H]2[C@@H]2CCC3=C[C@@H](OC(=O)C)CC[C@@H]3[C@H]21 ONKUMRGIYFNPJW-KIEAKMPYSA-N 0.000 claims description 6
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 6
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- UYIFTLBWAOGQBI-BZDYCCQFSA-N Benzhormovarine Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4O)C)CC2=CC=3OC(=O)C1=CC=CC=C1 UYIFTLBWAOGQBI-BZDYCCQFSA-N 0.000 claims description 5
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- MTMZZIPTQITGCY-OLGWUGKESA-N Moxestrol Chemical compound OC1=CC=C2[C@H]3[C@@H](OC)C[C@]4(C)[C@@](C#C)(O)CC[C@H]4[C@@H]3CCC2=C1 MTMZZIPTQITGCY-OLGWUGKESA-N 0.000 claims description 5
- IMONTRJLAWHYGT-ZCPXKWAGSA-N Norethindrone Acetate Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@](C#C)(OC(=O)C)[C@@]1(C)CC2 IMONTRJLAWHYGT-ZCPXKWAGSA-N 0.000 claims description 5
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Images
Abstract
Uses and formulations for providing transdermal or transmucosal delivery of active agents to subjects in need thereof. The formulations and methods treat symptoms of hormonal disorders including hypogonadism, female sexual desire disorder, female menopausal disorder, and adrenal insufficiency.
Description
Background of invention
Invention field
The present invention relate generally to the activating agent transdermal or thoroughly mucosal delivery to the preparation and the method that are subjected to treatment target. Particularly, the present invention relates to preparation and the method for the symptom of therapeutic adenasthenia, women's menopausal symptom, female libido obstacle, hypothyroid sex dysfunction and adrenal insufficiency.
Background technology
The reduction of the endogenous steroid hormone level of people usually causes various bad clinical symptoms. For example, the inducible clinical symptoms of man's (hypogonadism) that testosterone levels is lower comprise impotence, lack sexual drive, myasthenia and osteoporosis. Equally, in the women, the reduction of testosterone and/or estrogen level can cause Female sexual dysfunction, and they clinical symptoms that comprise are as lacking sexual drive, lacking and arouse or pleasant sensation, deficient in energy, happy sensation reduce and osteoporosis. In addition, the reduction of women's estrogen and/or progesterone level, as by due to the menopause, the clinical symptoms that often cause comprise hectic fever, night sweat, vaginal atrophy, sexual hypoesthesia and osteoporosis.
Except aforesaid endogenous steroid hormone level reduces, the not golden reduction that also can cause man and women's dehydroepiandrosterone (DHEA) level of adrenal function. Adrenal gland also relates to the generation of many hormones in the body, comprises DHEA and sex hormone such as estrogen and testosterone. So adrenal insufficiency can cause DHEA and sex hormone level to reduce, this can cause above-mentioned clinical symptoms.
Although steroid hormone concentration can return to normal or near normal level by HRT, existing form of therapy (that is, oral, intramuscular, subcutaneous, transdermal patch and topical preparation) has some shortcomings. For example, the testosterone of oral administration is most degraded in liver, and is not a feasible selection for hormone replacement therefore, because it can not make testosterone arrive the body circulation. In addition, thus modified testosterone analogues (for example, methyltestosterone and Dianabol) and the dysfunction of liver that reduces degraded raises relevant such as the liver enzyme with combined with bilirubin. The injection testosterone can make testosterone concentration produce widely peak-change to-paddy, and can not simulate the testosterone normal fluctuation, thereby is difficult to keep the blood plasma physiological level. The testosterone injection also often increases relevant with anxious state of mind and serum lipids level. Injection needs larger pin to be used for intramuscular to send, and it causes the patient to be lowered because of the compliance due to the discomfort. Usually, the normal oral administration of estrogen. This method of administration causes the circulating hormone level not enough also with the complication relevant with hormone metabolism. In addition, use the being seen side effect of oral estrogen to comprise gall stone and blood clot. In order to overcome these problems, developed transdermal delivery means, thereby so that the more favourable mode of patient is obtained therapeutic action.
Advantageously, transdermal and/or method that thoroughly the mucosal delivery activating agent can provide a kind of convenience, do not have pain, Noninvasive is subjected to the treatment target activating agent. In addition, can avoid the well-verified oral problem relevant with " first pass effect " that activating agent runs into that give by skin or mucomembranous surface administering active agents.
Although transdermal and/or thoroughly the mucosal delivery activating agent can overcome with oral and give some relevant problem of activating agent, as above-mentioned those, they also have the shortcoming of oneself. Problem is, transdermal drug delivery system usually is limited to low-molecular-weight drug and has those of suitable lipophilic/hydrophil balance structure. The HMW medicine, or have the medicine of too high or too low hydrophil balance, usually can not be incorporated in the existing transdermal system by cuticular impermeable concentration to be high enough to overcoming them. Particularly, the polar medicine transdermal is too slow, and because most medicines all are nonpolar natures, therefore this restriction is significant.
In the art, made great efforts the barrier of skin is carried out chemical modification, thereby make some medicament can permeate (because diffusion is mainly by cuticula control), improve the validity of the medicament of sending, improve and send number of times, reduce dosage delivered, reduce the side effect of various delivering methods, reduce patient's reaction etc.
In this, penetration enhancer is for increasing the permeability of skin surface to medicine, and they usually are solvent such as dimethyl sulfoxide (DMSO) (DMSO) and the dimethylacetylamides of accepting proton. Other after deliberation and be reported as effective penetration enhancer and comprise 2-pyrrolidines, N, N-diethyl-meta-toluamide (Deet), 1-dodecyl-azacycloheptan-2-one, N, dinethylformamide, N-methyl-2-pyrrolidines, mercaptoethanol acid calcium, hexanol, aliphatic acid and ester, pyrrolidinone derivatives, 1,3-two alkane and 1, the derivative of 3-dioxolanes, 1-N-dodecyl-2-Pyrrolidone-5-carboxylic acid, 2-amyl group-2-oxo-pyrrolidine acetic acid, 2-dodecyl-2-OXo-1-pyrrolidine acetic acid, 1-azacyclo-heptan-2-ketone-2-dodecyl acetic acid and aminoalcohol derivative, derivative particularly including 1,3-, two alkane.
Yet the most frequently used penetration enhancer is poisonous, irritating, oiliness, odorous or causes irritated. Particularly, use also thinks that to transdermal delivery activating agent such as steroid hormone be essential penetration enhancer, be compound such as LCFA such as oleic acid, fatty alcohol such as laruyl alcohol and long-chain fat ester such as isopropyl myristate, trend comprises makes preparation become oiliness and cacodorous aliphatic group.
For example, US Patent No. 5,891,462 instructions use laruyl alcohol as the penetration enhancer of estradiol and norethindrone acetate. This preparation does not all have attraction to the user with near user's all other men. Although this specific patent disclosure do not have the estradiol of laruyl alcohol composition or three embodiment of norethindrone acetate preparation, but this preparation is comparing embodiment, and being used for illustrating long-chain fatty alcohol such as laruyl alcohol is that transdermal delivery norethindrone acetate and estradiol are to being subjected to the necessary viewpoint of holding for a long time for the treatment of target.
In addition, for example, known testosterone gel preparation FORTIGELAnd TOSTRELLE(Cellegy Pharma, South San Francisco, CA) all comprises ethanol, propyl alcohol, propane diols, carbomer, triethanolamine, purifies waste water and as the oleic acid of penetration enhancer, the latter causes excitant and the stench of these preparations. Equally, TESTIM(Auxilium Pharmaceuticals, Norristown, PA) be 1% testosterone gel and comprise pentadecane lactone (pentadecalactone), acrylate, glycerine, polyethylene glycol (PEG) and pentadecane lactone as penetration enhancer. It is a kind of very smelly compound. TESTIMNeither be desirable, because it contains the not glycerine of desired amount, they can not be by the fine tolerance of skin.
Summary of the invention
The present invention relate generally to transdermal or thoroughly at least a activating agent of mucosal delivery to being subjected to treatment target, i.e. mammal such as people's preparation and method. The invention still further relates to by transdermal or saturating mucous membrane and give the method that activating agent is treated the hormone disease.
One aspect of the present invention provides a kind of transdermal or saturating mucous membrane preparation that gives at least a activating agent. and said preparation comprises at least a activating agent and delivery vector, and described delivery vector contains alkanol, polyalcohol and presents in an amount at least sufficient to the enhanced activity agent by the penetration enhancer of mammal skin or mucomembranous surface infiltration. In this specific embodiments, activating agent not merely is testosterone, and when activating agent comprised estrogen or progestational hormone, said preparation did not comprise respectively estrogen or the progestational hormone for the treatment of effective dose. Advantageously, said preparation there is no long-chain fatty alcohol, LCFA or long-chain fat ester, thereby avoids the bad smell and the spread effect that are caused by this compounds in the said preparation use procedure.
In the present invention on the other hand, said preparation comprises activating agent and delivery vector, and described delivery vector contains alkanol, polyalcohol and penetration enhancer tetraethylene glycol furfural (tetraglycol furol). The amount of penetration enhancer is enough to improve activating agent by the infiltration of mammal skin or mucomembranous surface. Preferred penetration enhancer is glycol furfural (glycofurol).
The present invention provides the method for the hormone disease that a kind for the treatment of is subjected to treatment target on the other hand. The method comprises to the object of this treatment of needs uses a kind of preparation, said preparation comprises at least a activating agent and the delivery vector of effective dose, and described delivery vector contains alkanol, polyalcohol and presents in an amount at least sufficient to the enhanced activity agent by the penetration enhancer of mammal skin or mucomembranous surface infiltration. Advantageously, said preparation can reduce the frequency of at least a clinical symptoms of hormone disease such as hectic fever, night sweat, sexual hypoesthesia, vaginal atrophy and osteoporosis. In addition, described at least a activating agent can be selected from androgen, estrogen, progestational hormone or its combination. Said preparation can comprise the first and second activating agents of simultaneously administration.
In the present invention on the other hand, the method comprises to the object of needs treatment uses a kind of preparation, said preparation comprises at least a activating agent and delivery vector, and described delivery vector contains aliphatic alcohol, polyalcohol and presents in an amount at least sufficient to the enhanced activity agent by the penetration enhancer tetraethylene glycol furfural of skin or mucomembranous surface infiltration. Preferably, aliphatic alcohol accounts for the about 5-80% of delivery vector weight, and polyalcohol and penetration enhancer respectively account for the about 1%-30% of delivery vector, and to be that glycol furfural and water are optional be present in the carrier penetration enhancer.
In the present invention on the other hand, the method for the treatment of hormone disease comprises to the object of needs treatment uses a kind of preparation, said preparation comprises at least a activating agent, condition is that activating agent not merely is testosterone, and when activating agent is estrogen or progestational hormone, there is not respectively progestational hormone or the estrogen for the treatment of effective dose in the said preparation. Delivery vector comprises fat to be executed alcohol, polyalcohol and presents in an amount at least sufficient to the enhanced activity agent by the penetration enhancer of skin or mucomembranous surface infiltration. Said preparation there is no long-chain fatty alcohol, LCFA and long-chain fat ester, thereby avoids the bad smell, spread effect and the greasy quality that are caused by this compounds.
Another embodiment of the present invention comprises the method for using preparation for treating to be subjected to the hormone disease for the treatment of target, said preparation comprises at least a activating agent and the delivery vector of effective dose, described delivery vector contains alkanol, polyalcohol and penetration enhancer, and wherein the amount of penetration enhancer is enough to improve activating agent by the infiltration of mammal skin or mucomembranous surface. Any preparation disclosed herein all can be used in this method.
Another embodiment relates to penetration enhancer and strengthens at least a activating agent of effective dose by the purposes of mammal skin or mucomembranous surface infiltration, it is characterized in that penetration enhancer is joined in the delivery vector of said preparation. Effective dose is used for the treatment of the hormone disease that is subjected to treatment target, preferred penetration enhancer and preparation as disclosed herein those.
Another embodiment of the present invention relates to any preparation disclosed herein is subjected to the hormone disease for the treatment of target for the preparation for the treatment of the purposes of medicine.
Preparation of the present invention can be the forms such as gel, lotion, creme, spray, aerosol, ointment, emulsion, suspension, liposome system, lacquer, patch, bandage or impermeable plastic wound dressing.
The present invention also comprises a kind of kit, wherein comprise above-mentioned preparation with and operation instruction. This kit generally includes a container, and this container is equipped with preparation and has the distributor that discharges or use as required the described preparation of predetermined close or predetermined. Distributor also can discharge the composition of predetermined close or volume automatically after user's triggering is enabled.
The accompanying drawing summary
Can more clearly understand feature of the present invention and usefulness by the following for example the detailed description and the accompanying drawings of embodiment, wherein:
Fig. 1 is described in to use from the people to excise 10mg testosterone/cm in the skin that gets off and the load chamber2External model in, comprise testosterone medicine in time in the preparation of various amount laruyl alcohols (LA) and disengage (flux) (curve map of n=3-4 ± SD).
Fig. 2 is described in to use from the people to excise 50mg testosterone/cm in the skin that gets off and the load chamber2External model in, (the curve map of n=3-4 ± SD) that comprises that the testosterone medicine in time in the preparation of various amount laruyl alcohols (LA) disengages.
Fig. 3 A, B﹠C be respectively describe give the 1%T+0%LA gel after, the curve map of and testosterone serum-concentration intermediate value bioavailable total in the mesosome, free the 1st, 7,14 and 21 day sampling period.
Fig. 3 D, E﹠F describe the various dose scheme and with behind the 1%T+2%LA gel for treating, at the curve map of the 1st, 7,14 day sampling period testosterone serum-concentration average bioavailable and that dissociate in the mesosome.
Fig. 4 A is after describing the single dose administration of E2+0%LA gel, curve map (the a=0.75mg E2 of estradiol (E2) average serum concentration; B=1.50mg E2).
Fig. 4 B is after describing the repetitively administered of E2+0%LA gel, and E2 in time and curve map (the a=0.75mg E2 of the average rough concentration that changes; B=1.50mg E2).
Fig. 4 C be described in one be subjected to repeatedly to give the E2+0%LA gel in the treatment target after, the curve map (2.5g of the average rough concentration of E2 that changes in time; ± SD; 240.0H value is outside scale (28.0ng/dl)).
Fig. 4 D is after describing the E2+0%LA gel repetitively administered of two dosage, in time and the curve map of the individual E2 rough concentration that changes.
Fig. 4 E is curve map (the a=0.75mg E2 that describes E2 average serum concentration after the multidose administration of E2+0%LA gel; B=1.50mg E2).
Fig. 4 F is curve map (the a=0.75mg E2 that describes oestrone (E1) average serum concentration after the single dose administration of E2+0%LA gel; B=1.50mg E2).
Fig. 4 G is curve map (the a=0.75mg E2 of the average rough concentration of E1 behind the description E2+0%LA gel repetitively administered; B=1.50mg E2).
Fig. 4 H is curve map (the a=0.75mg E2 of E1 average serum concentration after the administration of description E2+0%LA gel multidose; B=1.50mg E2).
Fig. 4 I is curve map (the a=0.75mg E2 of OES (sulfuric acid E1) average serum concentration after the administration of description E2+0%LA gel single dose; B=1.50mg E2).
Fig. 4 J is curve map (the a=0.75mg E2 of the average rough concentration of sulfuric acid E1 after the administration of description E2+0%LA gel multidose; B=1.50mg E2).
Fig. 4 K is curve map (the a=0.75mg E2 of sulfuric acid E1 average serum concentration after the administration of description E2+0%LA gel multidose; B=1.50mg E2).
Fig. 5 A be describe give each dosage E2+0%LA gel after, every day the moderate-average change that severe hectic fever rate is compared with baseline curve map. (therapeutic interest effect colony (" ITT "); The method (" LOCF ") that observed for the last time by treatment target to early stage interruption.
Fig. 5 B be describe give the E2+0%LA gel of each dosage after, every day the moderate-average change that severe hectic fever rate is compared with baseline curve map (valuable-LOCF).
Fig. 5 C is after description gives the E2+0%LA gel of each dosage, the curve map (ITT-LOCF) of the average change that the average order of severity of hectic fever every day is compared with baseline.
Detailed description of the preferred embodiments
Preparation of the present invention can be clarify, can wash, sense of touch is nice and cool, the preparation of rapid-curing cutback, easy to apply and/or non-greasy, such as gel. In other side of the present invention, said preparation can be spray, ointment, aerosol, patch, suck and sublingual tablets, suppository, vagina formulation or other passive or transdermal device initiatively of absorbing by skin or mucomembranous surface. Preferred formulation of the present invention can be directly used on the skin, for example and nonrestrictive, and by gel, ointment or creme; Or indirectly by patch, bandage or other impermeable plastic wound dressing.
Advantageously, do not use the preparation of the pure and mild LCFA of long-chain fat not have the offensive odour of prior art preparation. Therefore, preparation of the present invention can produce larger patient compliance. Preparation of the present invention there is no this pure and mild aliphatic acid, so said preparation can not give out the smell relevant with those compounds. In this, " there is no " and refer to can not give the amount of preparation at 1 meter the interior perceptible smell of distance. This preparation also is considered to there is no smell. With regard to example and illustrational purpose, the preparation that contained fatty alcohol, aliphatic acid and/or fatty ester are less than weight of formulation about 0.04% there is no smell.
The present invention relates generally to provides activating agent to the preparation that is subjected to treatment target. The invention still further relates to the preparation that transdermal or saturating mucous membrane give activating agent, it there is no the pure and mild LCFA of long-chain fat of stench. It is shocking that preparation of the present invention can fully absorb, thereby the selected activating agent of effective dose is circulated in serum, and do not comprise the pure and mild LCFA of long-chain fat that uses up to now.
Preparation of the present invention can comprise the combination of at least a activating agent or activating agent. " activating agent " used herein refers to when giving organism (human or animal), induces pharmacology and/or the material of physiological role or the combination of preparation or material or preparation of expectation by part and/or general action.
Delivery vector of the present invention comprises aliphatic alcohol such as C2-C
4Alkanol, polyalcohol, penetration enhancer diethylene glycol (DEG) one alkyl ether or tetraethylene glycol furfural, its consumption are enough to improve activating agent by mammal skin or mucomembranous surface infiltration, and the optional water that comprises.
For example, diethylene glycol (DEG) one alkyl ether is diethylene glycol monomethyl ether or carbitol or its mixture. The tetraethylene glycol furfural is represented by following formula:
Preferred compound is known as the glycol furfural. In addition, for example, preferred polyalcohol comprises propane diols, dipropylene glycol or its mixture.
Preferably, polyalcohol accounts for the about 1%-30% of carrier; Penetration enhancer accounts for the about 0.2%-30 % of carrier. Preferably, the weight ratio of polyalcohol and penetration enhancer is 2: 1-1: 1, or 1.25: 1-1.2: 1.
With regard to illustrate with unrestriced purpose with regard to, aliphatic alcohol is selected from: C2-C
4Alkanol is such as ethanol, isopropyl alcohol and normal propyl alcohol. The alkanol preferred alcohol.
Preferably, alkanol accounts for the about 80%w/w of about 5-; The preferably about 65%w/w of about 15%-and more preferably 20-55%w/w.
As known in the art, can select the amount of pure constituents in the preparation, make activating agent reach maximum by skin diffusion and make simultaneously any negative effect to the desired characteristic of activating agent itself or preparation reach minimum.
The invention still further relates to being subjected in the treatment target of this treatment of needs, treat the method for its hormone disease, obstacle or situation. The method generally comprises the preparation that is subjected to treatment target to contain at least a activating agent of effective dosage and delivery vector.
In one of them preferred embodiment of the present invention, the method comprises that treatment is selected from the hormone disease of hypogonadism, Female sexual dysfunction, hypothyroid sex dysfunction and adrenal insufficiency, the method comprises to the object of this treatment of needs uses at least a activating agent that contains effective dosage and the preparation of delivery vector, and delivery vector contains alkanol, polyalcohol and presents in an amount at least sufficient to the enhanced activity agent by the penetration enhancer of mammal skin or mucomembranous surface infiltration. Give the frequency that said preparation can reduce at least a clinical symptoms of hormone disease for the treatment of. For example, give the frequency that said preparation helps to reduce symptom such as hectic fever, night sweat, sexual hypoesthesia and osteoporosis etc.
In another preferred embodiment, provide treatment to be subjected to the method for the hormone disease for the treatment of target, comprise need this treatment be subjected at least a activating agent for the treatment of target and delivery vector, delivery vector comprises aliphatic alcohol, polyalcohol and presents in an amount at least sufficient to the enhanced activity agent by the penetration enhancer tetraethylene glycol furfural of skin or mucomembranous surface infiltration. Preferably, the tetraethylene glycol furfural is the glycol furfural.
Preferably, be subjected to the preparation for the treatment of target to there is no long-chain fatty alcohol, LCFA and long-chain fatty alcohol, thereby avoid the bad smell and the spread effect that occur in the preparation use procedure.
The treatment target that is subjected to that need to treat can be sex. Therefore, select to be used for preparation and the activating agent type of methods for the treatment of and the effective dose of activating agent and depend in part on the sex that is subjected to treatment target and the type that will treat the hormone disease.
With regard to illustrate with non-limiting purpose with regard to, according to the present invention, for example, the women who treats can be that reproduction age or age are longer, its ovarioestrogen, progestational hormone and/or androgenic generation are interrupted, this or because natural menopause, operation technique, radiation, chemical ovary remove or extract or too early ovarian failure. Except natural menopause and aging, the global cycle androgen that causes testosterone to lack descend be attributable to suppress the adrenal androgen secretion situation (namely, gross stress reaction, anorexia nervosa, cushing's syndrome and hypophysis renal insufficiency), can reduce the situation (that is, the use of ovarian failure and pharmacological dose glucocorticoid) of ovarian androgens secretion and chronic disease such as muscular atrophy disease as acquired immunodeficiency syndrome (AIDS). Therefore, term used herein " hormone disease " refers to cause any situation that suppressed by the treatment target hormone secretion or descend.
Except the treatment women be subjected to treatment target because old and feeble and the women's menopausal symptom that above-mentioned other factors causes, women's androgen (and estrogen) level reduces can cause Female sexual dysfunction (FSD), clinical symptoms occur as lacking sexual drive, arousing or pleasant sensation; Deficient in energy, happy sensation reduces and osteoporosis. Use the preferred result of preparation for treating women FSD of the present invention can comprise following one or more: energy increases, happy sensation increases, bone calcium is lost minimizing and sexuality and nympholepsy.
In premenopausal women, total plasma testosterone concentration is generally 15-65ng/dL (free testosterone level in the pre-menopausal women is about 1.5-7pg/ml) and fluctuates within the menstrual cycle, the peak value of androgen concentration and cycle the preovulatory phase and pmgravid blood plasma estrogen concentrations peak value corresponding. In the those years of transition after leading to menopause, the circulation androgen levels begins to descend, and this is because the ovary minimizing relevant with the age with acth secretion. Research report, the normal 24 hourly average plasma testosterone levels of pre-menopausal women in the time of more than 40 year old are their half in the time of 20 years old. Yet, common accept be, total testosterone levels<25ng/dL (<50 years old) of hypoandrogenism women or<total testosterone levels of 20ng/dL (〉=50 years old) and oophorectomize women can<10ng/dL.
In this, the method can comprise and gave the testosterone that the women is subjected to the about 3mg treatment of the about 1mg-for the treatment of target effective dose in per 24 hours. Therefore, said preparation is preferably given and provided at least about (>30ng/dL) the testosterone total serum concentration of the about 55ng/dL of 15-, or the testosterone of the about 7pg/mL of the about 2-serum-concentration that dissociates by treatment target.
In addition, studies show that relatively independent ERT, testosterone substitutes associating controversies in hormone replacement in the elderly (" ERT ") can improve sexual function and happy parameter. The sexual intercourse rate descends relevant with the remarkable reduction of testosterone with sex fantasy minimizing and estradiol with the property thinking. Testosterone reduces also relevant with the coital frequence reduction. Can improve vasomotor symptoms, colpoxerosis and general health although the spay women is carried out independent estradiol treatment, sexual desire is improved very little. Injected testosterone enanthatas hysterectomize and the spay women in observe sexual drive, arouse and the sex fantasy frequency increases, surpass and carry out separately that ERT observes. Therefore, the method according to this invention, the treatment women is comprised by treatment target to contain the preparation that activating agent comprises the preferred testosterone of androgen and estrogen, and the treatment women is comprised by treatment target to give singly to contain estradiol as the preparation of activating agent.
Another that the nature of accepting insufficient ERT 〉=4 month or operation menopausal women are carried out studies show that, with placebo or carry out separately estrin treatment and compare, androgen/estrin treatment 4 and after 8 weeks is sexyly felt and sexual desire significantly improves. To studies show that of carrying out of operation menopausal women, androgen/estrin treatment can raise libido, arouses, fast happy energy level. Reported also that the postmenopausal women is carried out the subcutaneous estrogen implantation of subcutaneous testosterone implantation associating can improve sexual desire. In the women of experience oophorectomize and uterectomy, transdermal gives testosterone can improve sexual function and psychological happy. In order to obtain sound response aspect the sexual desire, the approximately at least upper end of the normal physiological scope that the plasma testosterone level is returned in youth ovulation women, observe.
Therefore, treat and to obtain ideally above-mentioned at least preferred result with containing estrogenic independent or same composition. It is about 30-100pg/mL that premenopausal women is subjected to the serum-concentration of the common estradiol for the treatment of target, and level is lower than 20pg/mL after the normal menopause.
In addition, the women reduces such as estrogen (and progestational hormone) level due to owing to aging can cause menopause, and then produces clinical symptoms such as hectic fever and night sweat, vaginal atrophy, sexual hypoesthesia, cardiopathic dangerous the increasing and osteoporosis. Use the preferred result of the present composition can comprise following one or more: the incidence of hectic fever and night sweat and the order of severity reduce, bone calcium is lost danger reduction, vagina mucosa and urethra dead due to minimizings, the ischemic heart disease vascularity and healthy raising and sexuality and desire increase. Therefore, in another preferred embodiment, the method comprise the women who needs treatment be subjected to treatment target contain estrogen associating progestational hormone both as the preparation of activating agent.
As mentioned above, described method comprises that the treatment male sex is subjected to the hormone disease for the treatment of target. For example, the treatment male sex's hypogonadism (testosterone levels is low). The clinical symptoms that man's hypogonadism causes comprise impotence, lack sexual drive, myasthenia and osteoporosis. Use the preferred result of present composition treatment man hypogonadism to comprise following one or more: the incidence of impotence and the order of severity reduce, bone calcium is lost minimizing, muscle strength increase and sexuality and desire increases.
The common testosterone total serum of normal male object concentration is about 300-1050ng/dL, and hypogonadism man's level is lower than 300ng/dL. Therefore, composition of the present invention can be used for for being subjected to treatment target that the testosterone of about 50mg/ days treatment effective doses is provided. Therefore, using said composition to be preferably provided at least about the free serum-concentration of the testosterone of 300-1000ng/dL by treatment target.
In another preferred embodiment, the method that provides a kind for the treatment of to be subjected to treatment target hormone disease, the method comprise and are subjected at least a activating agent for the treatment of target and delivery vector; Condition is that activating agent not merely is testosterone, and when activating agent is estrogen or progestational hormone, do not have respectively progestational hormone or the estrogen for the treatment of effective dose in the said preparation, this delivery vector contains aliphatic alcohol, polyalcohol and presents in an amount at least sufficient to the enhanced activity agent by the penetration enhancer of skin or mucomembranous surface infiltration; Wherein said preparation there is no long-chain fatty alcohol, LCFA and long-chain fat ester, thereby avoids bad smell and spread effect.
According to the inventive method, treatment is subjected to the adrenal insufficiency for the treatment of target, and described disease reduces men and women's dehydroepiandrosterone (DHEA) level. Adrenal gland relates to the generation of the many hormones of body, comprises DHEA and sex hormone such as estrogen and testosterone. Therefore, the reduction of DHEA level can cause above-mentioned symptom. Therefore, according to the present invention, the method comprises and is subjected to a kind of preparation that comprises effective dose DHEA and above-mentioned delivery vector for the treatment of target.
The free serum-concentration of the common DHEA of normal female object is about 550-980ng/dl, and the free serum-concentration of the DHEA of normal male object is about 750-1250ng/dl. Therefore, composition of the present invention can be used for for being subjected to treatment target that the dehydroepiandrosterone of about 50-200mg/ days treatment effective doses is provided. Therefore, use said composition to be preferably and be subjected to treatment target that at least 550 dehydroepiandrosterone serum-concentrations to as high as 1250ng/ml are provided, this depends on patient's sex.
Preferred dose unit can continue about 24 hours time and send the selected activating agent of effective dose, preferred steroids hormone. The activating agent of " effectively " or " treatment effectively " amount refers to provide the nontoxic of required effect but the medicament of capacity.
In other side of the present invention, provide the preparation that contains activating agent and delivery vector.
The activating agent of preparation can be selected from: androgen, progestational hormone, anti-estrogen, anti--progestational hormone, anti--androgen, 2-adrenergic agonist components, anodyne, sedative, acid amides, aryl piperazines, neurotic, antitumor agent, antiinflammatory, anticholinergic, anticonvulsant, antidepressant, Anti-epileptics, antihistaminic, rescinnamine, muscle relaxant, diuretics, bronchodilator and glucocorticoid. Optionally, according to the course for the treatment of that mammal is subjected to treatment target, can use any other suitable activating agent. Following activating agent only is used for illustrating, and should not be interpreted as limitation of the present invention.
Hormone. in one of them embodiment of the present invention, activating agent comprises steroids or on-steroidal hormone, their any or combination of precursor, derivative and analog, ester and salt, includes but not limited to: dehydroepiandrosterone (DHEA), androgen, estrogen and progesterone (being also referred to as progestational hormone). For example, the combination of hormone can comprise that androgen adds estrogen, androgen and adds progestational hormone or androgen and add estrogen and add progestational hormone.
The androgenic example that can be used among the present invention comprises testosterone (17-beta-hydroxy androstenone) and testosterone ester, such as testosterone enanthatas, testosterone propionate and depo-testosterone. Above-mentioned testosterone ester is that commercially available those skilled in the art's technology known or that pertinent literature is described of maybe can using is easy to preparation. Also can use testosterone and the pharmaceutically acceptable ester of 4-dihydrotestosterone, usually ester be hydroxyl from the C-17 position form (as, heptanoate, propionic ester, cipionate, phenylacetate, acetic acid esters, isobutyrate, buciclate, heptanoate, decylate, hendecane acid esters, decylate and isodecyl acid esters); Pharmaceutically acceptable derivates such as methyltestosterone, Testolactone, Oxymetholone and Fluoxymesterone with testosterone.
Other the suitable androgen medicament that can be used in the preparation of the present invention includes but not limited to: endogenous androgen, its precursor and derivative, comprise androsterone, acetic acid androsterone, propionic acid androsterone, benzoic acid androsterone, androstenediol, 3-acetic acid androstenediol, 17-acetic acid androstenediol, 3,17-two acetic acid androstenediols, 17-benzoic acid androstenediol, 3-acetic acid-17-benzoic acid androstenediol, androstenedione, dehydroepiandrosterone sulfate sodium, 4-dihydrotestosterone (dht), 5-dihydrotestosterone, dromostanolone, dromostanolone propionate, ethyl estrenol, Nandrolone Phenylpropionate, abolon, 19-Nortestosterone Frylpropionate, cyclohexane testobolin, benzoic acid nandrolone, cyclohexane-carboxylic acid nandrolone, oxandrolone, stanozolol.
The example that can be used for estrogen among the present invention and progestational hormone comprises estrogen such as 17-β-estradiol, estradiol, oestradiol benzoate, 17-β-cycloprovera, estriol, oestrone, ethinylestradiol, mestranol, moxestrol, mytatrienediol, Polyestradiol Phosphate, quinestradol, quinestrol; Progestational hormone such as Allylestrenol, anagestone, CA, delmadinone acetate, demegestone, Desogestrel, Dimethisterone, Dydrogesterone, lynenol, ethisterone, Etynodiol, ethynodiol diacetate, flurogestone acetate, gestodene, Gestonorone Caproate, Prohalone, 17-hydroxyl-16-methylene-progesterone, 17 Alpha-hydroxy progesterone, caproic acid 17 α-hydroxyprogesterone, lynestrenol, Medrogestone, Medroxyprogesterone, megestrol acetate, melengestrol, norethindrone, norethindrone acetate, norethynodrel, Norgesterone, norgestimate, norgestrel, Norgestrienone, 19-norprogesterone, Vinylnortestosterone, pentagestrone, progesterone, natural progesterone, Promegestone, Quingestrone, trengestone.
Other activating agent. other suitable activating agent includes but not limited to antiestrogenic such as TAM, 4-OH TAM; Antiprogestin and antiandrogen, alpha-adrenergic activator such as Budralazine, clonidine, adrenaline, fenoxazoline, naphazoline, phenylephrine, phenylpropanolamine, beta-adrenergic activator such as Formoterol, methoxyphenamine, alpha antiadrenergic agent such as Doxazosin, prazosin, terazosin hydrochloride, Trimazosin, corynine, beta-adrenergic blocking agent such as atenolol, bisoprolol, carteolol, Carvedilol, metoprolol, Nadolol, penbutolol, anodyne (anesthetic or non-narcotic dose) are such as buprenorphine, dihydromorphine, metazocine, methadone, morphine, morphine derivatives, nicomorphine, Oxymorphone.
Sedative. acid amides. aryl piperazines. other suitable activating agent comprises sedative and anxyolitics, for example benzodiazepine derivatives such as alprazolam, Bromazepam, flutazolam, Ketazolam, Lorazepam, prazepam; Acid amides such as Butoctamide, carbromide, neoprol, isovaleryl diethylamide, Niaprazine, tricetamide, Trimetozine, zolpidem, zopiclone; Aryl piperazines such as buspirone.
Neurotic. antitumor agent. antiinflammatory. other suitable activating agent comprises neurotic such as nicotine, citric acid nicotine and the tartaric acid nicotine for smoking cessation; Antitumor agent such as 5 FU 5 fluorouracil; Antiinflammatory; Anesthetic; The antianginal agent; Anticholinergic; Anticonvulsant; Antidepressant; Anti-epileptics; Antiestrogenic; Antihistaminic; The Antiparkinsonian agent; Bronchodilator; Diuretics; Glucocorticoid, muscle relaxant; Narcotic antagonist; Antithyroid hypofunction agent such as Levothyroxine, thyroid gland, thyroxine; Rescinnamine is benzothiadiazine derivatives such as captopril, Cilazapril, enalapril, lisinopril, Perindopril, Ramipril for example; Guanidine derivatives such as guanethidine; Quinazoline derivant such as Alfuzosin; Serfin derivative such as reserpine, sulphone amide derivative such as frusemide; Other is such as minoxidil, Amlodipine, Carclura, felodipine, moxonidine, Licardipine Hydrochloride, nifedipine, minipress etc. and calcium channel blocker such as aralkyl amine such as bepridil, Altiazem, Fendiline, Gallopamil, terodiline, Verapamil; Dihydrogen pyridine derivative such as felodipine, isradipine, nicardipine, nifedipine, Nilvadipine, Nimodipine, Nisoldipine, nitrendipine; Bridged piperazine derivatives such as flunarizine; Other is such as perhexiline; Calcium regulator such as calcifediol, calcitonin, calcitriol, clodronic acid pamidronic acid, dihydrotachysterol, Elcatonin, Etidronic Acid, Ipriflavone, pamidronic acid, parathyroid hormone, acetic acid teriparatide.
Described preparation also can contain thickener or gelling agent, presents in an amount at least sufficient to change preparation viscosity. Gelling agent can be selected from: carbomer, carboxylic hexenoic acid or polyacrylic acid such as Carbopol 980 or 940 NF, 981 or 941 NF, 1382 or 1342 NF, 5984 or 934 NF, ETD 2020,2050,934P NF, 971P NF, 974P NF, Noveon AA-1 USP; Cellulose derivative such as ethyl cellulose, hydroxypropyl methylcellulose (HPMC), ethylhydroxyethylcellulose (EHEC), carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC) (Klucel different brackets), hydroxyethylcellulose (HEC) (Natrosol level), HPMCP 55, Methocel level; Natural gum such as Arabic gum, xanthans, guar gum, alginates; Polyvinylpyrrolidone derivative such as Kollidon level; Poloxalkol such as Lutrol F level 68,127. Other gelling agent comprises shitosan, polyvinyl alcohol, pectin, veegum level.
Preferably, gelling agent is Lutrol F level and Carbopol level. Different according to polymer type, gelling agent accounts for the about 30.0%w/w of about 0.2-. More preferably, gelling agent contains the thickener of about 0.5-5 % by weight.
Can select the consumption of gelling agent in the preparation, thereby required product denseness and/or viscosity are provided, help to be used for skin.
Anticorrisive agent. said preparation also can contain anticorrisive agent, pricks ammonia ammonium and derivative, benzoic acid, phenmethylol and derivative, bronopol, p-hydroxybenzoate, centrimide, Chlorhexidine, cresols and derivative, miaow urea, phenol, phenoxetol, benzyl carbinol, phenylmercuric salts, thimerosal, sorbic acid and derivative such as, but not limited to benzene. According to the difference of type of compounds, anticorrisive agent accounts for the about 10.0%w/w of the about 0.01-of preparation.
Antioxidant. said preparation can be chosen wantonly and contain antioxidant, such as, but not limited to tocopherol and derivative, ascorbic acid and derivative, BHA, butylated hydroxytoluene, fumaric acid, malic acid, propyl gallate, inclined to one side disulfate and derivative. According to the difference of type of compounds, antioxidant accounts for the about 5.0%w/w of the about 0.001-of preparation.
Buffer solution. said preparation also can contain buffer solution such as carbonate buffer solution, citrate buffer, phosphate buffer, acetate buffer, hydrochloric acid, lactic acid, tartaric acid, diethylamine, triethylamine, diisopropylamine, amino methylamine. Certainly can comprise other buffer solution known in the art. Buffer solution can replace in the said preparation water yield up to 100%.
Wetting agent. said preparation also can contain wetting agent, as but be not limited to glycerine, propane diols, D-sorbite, glycerol triacetate. According to the difference of type of compounds, wetting agent accounts for the about 1-10 %w/w of preparation.
Chelating agent. said preparation also can contain chelating agent such as ethylenediamine tetra-acetic acid. According to the difference of type of compounds, chelating agent accounts for the about 5%w/w of the about 0.001-of preparation.
Surfactant. said preparation also can contain anion, nonionic or cationic surfactant. Different according to type of compounds, surfactant accounts for the about 30%w/w of the about 0.1%-of preparation.
PH adjusting agent. randomly, said preparation can contain pH adjusting agent, generally is nertralizer, and it can be chosen wantonly has crosslinked function. And unrestricted, pH adjusting agent can comprise tertiary amine as an example, such as triethanolamine, tromethamine amine, tetrahydroxypropyl ethylenediamine, NaOH solution. PH adjusting agent accounts for the about 2%w/w of the about 0.05-of preparation.
NMF and softening agent. randomly, said preparation can contain NMF and/or softening agent, thus softening skin and make skin smooth, or keep moistening. And unrestricted, NMF and softening agent can comprise cholesterol, lecithin, liquid paraffin,light, vaseline and urea as an example.
With regard to any particular formulations, can select activating agent and other composition, distribute and required infiltration capacity thereby obtain required drug delivery. Can determine that also best pH and its can be depending on for example character, matrix and the required degree of disengaging of hormone.
In particular preferred embodiment of the present invention, said preparation can have following prescription.
Table 1
Estradiol | 0.01%-2% |
Carbomer | 0.05%-4% |
Triethanolamine (being adjusted to pH5.9) |
0.05%-1 |
Ethanol | |
20%-65% | |
Propane diols | 1%-15% |
Carbitol | 1%-15% |
Add ion-exchange and purify the |
20%-65% |
Table 2
Testosterone | 0.01%-10% |
Carbomer | 0.05%-4% |
Triethanolamine (being adjusted to pH5.9) |
0.05%-1 |
Ethanol | |
20%-65% | |
Propane diols | 1%-15% |
Carbitol | 1%-15% |
Add ion-exchange and purify the |
20%-65% |
Table 3
Estradiol | 0.01%-1% |
Acritamer 940 | 1.2% |
Triethanolamine (being adjusted to pH5.9) | 0.4% |
Ethanol | 46.28% |
Propane diols |
6 |
Carbitol | |
5% | |
EDETATE SODIUM | 0.06% |
Add ion-exchange and purify the |
100% |
Table 4
Testosterone | 0.01%-10% |
Carbopol | 1.2% |
Triethanolamine (being adjusted to pH5.9) | 0.4% |
Ethanol | 46.28% |
Propane diols |
6 |
Carbitol | |
5% | |
EDETATE SODIUM | 0.06% |
Add ion-exchange and purify the |
100% |
Table 5
Testosterone | 1% |
Carbopol | 1.2% |
Triethanolamine (being adjusted to pH5.9) | 0.4% |
Ethanol | 47.5% |
Propane diols |
6 |
Carbitol | |
5% | |
EDETATE SODIUM | 0.06% |
Add ion-exchange and purify the |
100% |
At least owing to underlying cause, preparation of the present invention is favourable. At first, preparation of the present invention there is no long-chain fatty alcohol, LCFA and long-chain fat ester. It is shocking that said preparation demonstrates is enough to send the required activating agent of effective dose to user's dermal osmosis. This is a beyond thought usefulness, those skilled in the art can not find at an easy rate, this is to need long-chain fatty alcohol, LCFA and long-chain fat ester to improve dermal osmosis because of it has been generally acknowledged that, thereby makes the activating agent skin permeation of effective dose.
The second, because said preparation does not contain the aliphatic acid group that is generally comprised within the topical gels, such as aliphatic acid, so it does not have smell or the oiliness quality relevant with this composition in the present used gel. The 3rd, there is no that long-chain fatty alcohol, LCFA and long-chain fat ester mean that excitant chance lower and component interaction is less, have reduced the needs to antioxidant in the preparation or anticorrisive agent. See, Tanojo H.Boelsma E, Junginger HE, Ponec M, Bodde HE, " the local aliphatic acid that uses is in vivo to the adjusting of human skin barrier ",Skin Pharmacol Appl.Skin Physiol.In March, 1998-April; 11 (2) 87-97. Yet, should understand, if need this anticorrisive agent, the present invention comprises the preparation that contains antioxidant or anticorrisive agent. Be reduced to minute number at least reduce production costs and possible skin irritatin aspect be favourable. Numerous researchs recognize that unrighted acid such as oleic acid cause that the potential of stimulation may. In addition, be reduced to the storage stability that minute number can increase by reducing composition interactional chance before sending preparation. Yet, this not other composition of meaning person can not be included in the preparation and to be used for specific aesthetics and/or function. For example, said preparation can be chosen wantonly and contain one or more and make the moisture NMF of skin, or is used for softening skin or makes the softening agent of skin smooth. Glycerine is exactly the example of this suitable moisturizing additive.
But described preparation uses once every day, or uses repeatedly every day, and this depends on patient's situation. Preparation of the present invention can locally be used for any body part, such as thigh, belly, shoulder and upper arm. Therein in embodiment, the preparation of gel form is used for about 5 inches skins of taking advantage of 5 inches areas. But one after the other is used for the zones of different of body. For example, gel can be used for thigh when using for the first time, be used for upper arm when using for the second time, return thigh when using for the third time. This is favourable for alleviating skin to any sensitiveness that repeatedly contacts the said preparation component.
Thereby the present invention includes above-mentioned preparation for treating is subjected to treatment target to increase the purposes of activating agent cyclical level in the patient body.
The selected activating agent of effective dose can be sent by preferred dose unit during about 24 hours. The activating agent of " effectively " or " treatment effectively " amount refers to nontoxic but is enough to provide the dosing of required effect.
Yet, those skilled in the art will recognize that required dosage depends on concrete activating agent and other factors; The minimum effective dose of each activating agent certainly preferably makes and reduces to minimum with the relevant side effect of selected activating agent treatment. Preferably use said preparation with the regular time, the administration of activating agent is continuous basically like this.
Embodiment
The following example is used for illustrating, and should not be interpreted as limitation of the present invention.
One of them embodiment of embodiment 1. preparations of the present invention is a kind of topical gels, and it contains testosterone 1.25%w/w, propane diols 5.95%w/w, ethanol 45.46%w/w, distilled water 45.67%w/w, carbomer (Carbopol 980 NF) 1.21%w/w, triethanolamine 0.39%w/w, EDETATE SODIUM 0.06%w/w.
One of them embodiment of embodiment 2. preparations of the present invention is a kind of gel, and it consists of testosterone 1.00%w/w, carbitol 5.00%w/w, propane diols 6.00%w/w, ethanol 47.52%w/w, the 38.87%w/w that purifies waste water, carbomer (CARBOPOLTM980 NF) 1.20%w/w, triethanolamine 0.35%w/w, EDETATE SODIUM 0.06%w/w.
One of them embodiment of embodiment 3. preparations of the present invention is a kind of local water alcogel preparation, and it contains 1% testosterone as active component. The I/II phase multidose of said preparation, the clinical research of dosage escalation in the women, have been carried out. Carry out this and study validity to determine that said preparation is treated hypothyroid dysaphrodisia (" HSDD "), comprised by treatment target to have the operation menopausal women of low testosterone levels.
This studies show that the about 0.88g testosterone gel preparation of about 0.22g-every day (2.2-8.8mg/ days testosterones) can cause average total testosterone serum-concentration and free testosterone serum-concentration to drop on the interior or a little higher than normal range (NR) of normal range (NR) of pre-menopausal women in 7 days.
Embodiment 4. carries out in vitro study with the testosterone permeability in the application on human skin of determining excision and getting off, the testosterone preparation of table 5 (does not contain laruyl alcohol above wherein using, " 1%T+0%LA "), (" 1%T+1% or 2%LA ") compares with other testosterone preparation that contains 1% and 2% laruyl alcohol. The result of these researchs provides in the table 6,7 and 8 below.
In first research, the human skin fragment that excises is fixed among the Franz Vertical Diffusion Cells (Hansen Research Inc.). With about 10mg testosterone/cm2(1%T+0,1 or 2%LA) is contained in the load chamber on the skin, maintains 35 ℃. Behind the loading, accept the sampling of solution with selected interval. Testosterone in the penetration study disengages with cumulant and provides in the following Table 6.
Table 6
Disengage (μ g/hcm2) | Cum.(μg/cm 2)Amt.(SD) | |||||
Time (h) | 0%LA | 1%LA |
2 |
0%LA | 1%LA | 2%LA |
3 | 0.43 | 0.159 | 0.101 | 0.129 | 0.478 | 0.303 |
6 | 0.093 | 0.468 | 0.307 | 0.410 | 1.884 | 1.225 |
9 | 0.062 | 0.329 | 0.172 | 0.595 | 2.871 | 1.740 |
12 | 0.051 | 0.165 | 0.121 | 0.748 | 3.368 | 2.104 |
18 | 0.027 | 0.049 | 0.047 | 0.911 | 3.664 | 2.388 |
24 | 0.026 | 0.036 | 0.052 | 1.070 | 3.883 | 2.699 |
The testosterone of gel disengages with cumulant and provides in the table 7 and 8 below, and wherein this gel contains about 1.25% testosterone, 5.00%Transcutol, 5.95% propane diols, 43.09% ethanol, 43.07% distilled water, 1.20%Carbopol 980NF, 0.38% triethanolamine, 0.059%EDTA.
Table 7
Testosterone is external to disengage (μ g/h*cm 2) *Mean value+/-S.D. | |
Above-described embodiment 1 | 1.12+/-0.36 |
* (cumulant of the medicine of infiltration is to the slope of time between 12-24 hour)
Table 8
Testosterone cumulant (μ g/cm2) *Mean value+/-S.D. | |
Time (h) | Above-described embodiment 1 |
0 | 0 |
6 | 10.25+/-4.97 |
12 | 20.40+/-6,75 |
18 | 27.84+/-8.70 |
24 | 33.80+/-10.45 |
Fig. 1 is described in to use 10mg testosterone/cm in the application on human skin excise and the load chamber2External model in, contain testosterone medicine in time in the preparation of different amount laruyl alcohols (LA) and disengage curve map (n=3-4 ± SD). The curve of 1%T+0%LA is different from the preparation that contains laruyl alcohol. In 6 hours, curve hangs down about 4 times than the 2%LA preparation, but generally speaking more consistent. All curves all show infiltration after 6 hours testosterone disengage reduction, this may be because drug consumption.
Use said method to carry out another penetration study, difference is about 50mg testosterone/cm2Be contained in the load chamber on the skin. Behind the loading, hour accept the sampling of solution with selected interval. Testosterone in the penetration study disengages with cumulant and provides below.
Table 9
Disengage (μ g/hcm2) | Cum.(μ g/cm 2)Amt. (SD) | |||||
Time (h) | 0%LA | 1%LA |
2 |
0%LA | 1%LA | 2%LA |
3.0 | 0.448 | 0.872 | 0.900 | 1.345 | 2.617 | 2.700 |
6.0 | 0.521 | 1.216 | 1.336 | 2.908 | 5.732 | 6.709 |
9.0 | 0.504 | 0.914 | 0.801 | 4.421 | 8.473 | 9.112 |
Fig. 2 is described in to use 50mg testosterone/cm in the application on human skin excise and the load chamber2External model in, contain testosterone medicine in time in the preparation of different amount laruyl alcohols (LA) and disengage curve map (n=3-4 ± SD).
This studies show that 1%T+0%LA has lower permeability. Yet the penetration curve variation is less, makes its possibility better for the women, because testosterone levels must titration in narrow scope. Therefore, these in vitro study meetings those of ordinary skills are believed contain laruyl alcohol in the preparation be needs, with the hormone cyclical level that obtains to suit. Yet unexpected discovery of applicant need not to contain laruyl alcohol to obtain the circulation activating agent infiltration of effective dose in topical preparation. This is especially true for Female sexual dysfunction, and wherein required testosterone blood plasma level is lower than the viewed testosterone treatment of therapeutic adenasthenia blood plasma level.
The use experience of embodiment 5. gel preparations and transdermal patch usually shows the low incidence of the mild skin toxicity relevant with gel and the relevant extensive dermoreaction with patch, and this is probably relevant with the closure property of adhesive therefor or patch. For example, use the topical gels preparation of testosterone, small number of patients has dermoreaction, and nobody need to treat or discontinue medication. On the contrary, in the patient of the overwhelming majority with transdermal patch treatment, observe of short duration light to moderate erythema, and some patient has more serious reaction, comprise foaming, necrosis and ulcer. See, for example, Gelas B, Th é bault J, Roux I, Herbrecht F, Zartarian M., " new estradiol Tx 11323 (A) gel and the comparative studies of transdermal matrix system acceptability " Contraception, fertilit é, sexualit é 1997 Jun; 25 (6): 470-474).
The purpose of embodiment 6. these researchs is that security and the pharmacokinetics of estimating multidose 1%T+0%LA water alcogel in the postmenopausal women distribute. At front 7 days of research, be subjected to the treatment target local 0.22g of use every day to contain the preparation (2.2mg/ days testosterones) of 1%T+0%LA. At 8-14 days, the preparation (4.4mg/ days testosterones) that is subjected to treatment target to accept 0.44g to contain 1%T+0%LA, at 15-21 days, the preparation (8.8mg/ days testosterones) that is subjected to treatment target to accept 0.88g to contain 1%T+0%LA. Before each dosage escalation, do not remove the phase. Total, free pharmacokinetics result with testosterone bioavailable provides below.
The total testosterone of table 10. | ||||
Parameter | First day | The 7th day | The 14th day | The 31st day |
Every daily dose | 2.2mg | 2.2mg | 4.4mg | 8.8mg |
N | 7 | 7 | 7 | 7 |
C o(ng/dL) | 21.00(6.0) | 42.43(14.8) | 68.71(35.6) | 87.00(41.6) |
C avg(ng/dL) | 38.49(17.0) | 56.03(24.5) | 91.99(51.2) | 141.49(72.0) |
C max(ng/dL) | 69.86(33.0) | 113.57(92.9) | 165.57(113.8) | 203.86(128.3) |
C min(ng/Dl) | 19.00(6.2) | 31.14.(15.6) | 43.14(20.6) | 77.57(27.9) |
T max *(hr) | 20(20-24) | 16(1-24) | 16(1-24) | 20(3-24) |
T min *(hr) | 1(0-6) | 6(0-20) | 6(0-12) | 0(0-12) |
AUC(ng·hr/dL) | 923.79(408.3) | 1344.71(588.5) | 2207.79(1228.1) | 3395.64(1728.8) |
AR (ratio) | -- | 1.59(0.7) | 2.32(0.5) | 3.59(0.6) |
Free testosterone | ||||
Parameterleter | First day | The 7th day | The 14th day | The 21st day |
Every daily dose | 2.2mg | 2.2mg | 4.4mg | 8.8mg |
N | 7 | 7 | 7 | 7 |
C o(pg/mL) | 2.64(1.0) | 5.24(1.8) | 7.87(3.2) | 10.80(7.4) |
C avg(pg/mL) | 4.81(1.8) | 6.96(1.9) | 11.13(5.4) | 16.69(7.3) |
C max(pg/mL) | 8.84(3.6) | 15.79(14.3) | 21.31(19.5) | 25.80(16.0) |
C min(pg/mL) | 2.26(0.9) | 3.67(1.3) | 5.53(2.2) | 9.23(4.9) |
T max *(hr) | 20(20-24) | 20(3-24) | 16(1-24) | 20(3-24) |
T min *(hr) | 1(0-12) | 9(0-20) | 9(0-12) | 0(0-6) |
AUC(pg hr/mL) | -- | 1.57(0.6) | 2.28(0.5) | 3.43(0.8) |
Biology can utilize testosterone | ||||
Parameter l eter | First day | The 7th day | The 14th day | The 21st day |
Every daily dose | 2.2mg | 2.2mg | 4.4mg | 8.8mg |
N | 7 | 7 | 7 | 7 |
C o(ng/dL) | 4.01(2.1) | 7.94(3.7) | 12.56(5.8) | 16.27(12.1) |
C avg(ng/dL) | 7.48(3.4) | 10.81(3.6) | 16.47(8.1) | 25.04(11.5) |
C max(ng/dL) | 13.33(6.7) | 25.57(28.5) | 32.14(29.4) | 39.13(27.1) |
C min(ng/dL) | 3.69(1.7) | 5.84(2.7) | 8.43(3.6) | 13.84(7.7) |
T max *(hr) | 20(20-24) | 16(1-24) | 16(9-24) | 20(3-24) |
AUC(ng hr/dL) | 179.4(81.4) | 259.52(87.1) | 395.23(195.0) | 600.94(276.2) |
AR (ratio) | -- | 1.59(0.7) | 2.26(0.7) | 3.48(1.2) |
Fig. 3 A-C is after giving 1%T+0%LA in the Description respectively, between the 1st, 7,14 and 21 day sampling period, and total, free and the curve map available testosterone serum of biology concentration intermediate value.
The total testosterone of average baselining and free testosterone concentration are respectively 21.0ng/dL and 2.6pg/mL. Give the 1%T+0%LA1 of 0.22g every day after week, average total testosterone and free testosterone concentration are respectively 56.0ng/dL and 7.0pg/mL. Give every day 1 week of 0.44g 1%T+0%LA average total testosterone and free testosterone concentration to be increased to respectively 92.0ng/dL and 11.1pg/mL. Giving 0.88g 1%T+0%LA 7 days every day is subjected to the average testosterone for the treatment of target and free testosterone concentration to increase to 141.5ng/dL and 16.7pg/mL with 7.
Fig. 3 D-F is different dosing dosage and with after the 1%T+2%LA treatment in the Description respectively, and between the 1st, 7,14 day sampling period, average biology can utilize the curve map with free testosterone serum concentration. During more similar testosterone dosage, these data show that the testosterone level can not change owing to containing laruyl alcohol basically in body. Therefore, opposite with external discovery, laruyl alcohol is not that effectively the serum level is necessary in the acquisition body.
This studies confirm that can raise endogenous testosterone of 1%T+0%LA produces lower women's free testosterone concentration. The 0.22g dosage corresponding with the 2.2mg testosterone produces the average free testosterone concentration near Upper Limit of Normal Value. With regard to 0.44g dosage, average free testosterone concentration is 1.6 times of Upper Limit of Normal Value, and the average free testosterone concentration of 0.88g dosage is about 2.4 times of Upper Limit of Normal Value.
In addition, in studying an I/II phase, with 2.2,4.4 and testosterone dosage every day of 8.8mg give 1%T+0%LA preparation (dosage of 0.22g/ days, 0.44g/ days and 0.88g/ days used respectively 7 days separately). In this research, described preparation can be by fine tolerance. Do not report serious or significant adverse events. In any one treatment group, all do not detect the remarkable change of clinical labororatory's variable, vital sign, ECG parameter or physical examination result.
The primary and foremost purpose of 7. researchs of embodiment is to estimate two kinds of securities different, the repeatedly Estradilum of local dose, tolerance and pharmacokinetics to distribute, and comprises PK variables A UC and Cmax, be with or without with respect to postmenopausal women and proofreaied and correct by endogenous estradiol concentration. Every is subjected to treatment target to accept a kind of in two kinds of estradiol treatments, continuous 14 days, accepts 1.25g Estradilum 0.06% (0.75mg estradiol/sky) or accept 2.5g Estradilum 0.06% (1.5mg estradiol/sky).
Can keep 2.4ng/dl (24pg/ml) mean concentration (=AUC τ/24) in the 0.75mg E2/ of multidose days. Two multiple dose 1.5mg produced 5.3ng/dl (53pg/ml) mean concentration in E2/ days. This value and use transdermal patch such as EstradermAfter observe meet very much. When use had the patch of 25 μ g/ days nominal release rate, report 23pg/ml on average kept concentration. With regard to had 50 μ g/ days or the patch of 100 μ g/ days release rates with regard to, the mean concentration of report is respectively 40pg/ml and 75pg/ml. EstradermAt the European Economic Community and U.S. Register, effective to post menopausal diseases, comprise that hectic fever alleviates, and can be used for the prevention of osteoporosis. Therefore, prediction E2 gel preparation is safely and effectively for the treatment symptoms of menopause, comprises alleviating hectic fever, and is used for the prevention of osteoporosis.
Estradiol concentration time data (0-24 hour) behind the single dose (the 1st day). Fig. 4 A is after describing the single dose administration of E2+0%LA gel, curve map (the a=0.75mg E2 of estradiol (E2) average serum concentration; B=1.50mg E2). Give than low dosage (treatment group a) after, concentration time curve confirms to observe E2 concentration to be increased. On an average, E2 concentration increases to the 2.1ng/dl E2 of 24H from the baseline value of 0H 0.4ng/dl E2. After using higher dosage (treatment group b), observe the 3.0ng/dl E2 that increases to 24H from the 0.5ng/dl of 0H baseline E2.
Estradiol rough concentration data (1-20 days). Fig. 4 B be describe repeatedly give the E2+0%LA gel after, the curve map of the average rough concentration of E2 that changes in time. On an average, rough concentration increases until use rear about 24H (the 2nd day, before the administration). Afterwards, observe the concentration platform, level fluctuate in the 2.1ng/dl of 24H and after using final dose that day (336H=the 15th day, 2.4ng/dl E2 0H). Within this sampling interval, rough concentration be change and 1.3ng/dl E2 minimum of a value (before the administration in the 3rd day) that 48H observes to the 2.4ng/dl maximum of 336H (the 15th day, 0H) between fluctuation. After the last administration, average E2 concentration be down to 0.8ng/dl and at 456H (the 20th day, 0H discontinued medication rear 5 days) near baseline values (0.6ng/dl) before the administration.
Fig. 4 D is after description gives the E2+0%LA gel repeatedly with two kinds of dosage, change in time, individual E2 rough concentration. On an average, E2 concentration continues to increase, until about 240H (before the administration in the 11st day). and concentration increases to the 8.7ng/dl of 240H from the 0.5ng/dl of baseline (0H).
Also detected the trough intermediate value, and 96H (the 5th day, before the administration) reaches the platform of about 5.1ng/dl E2 after use. Afterwards, rough concentration be change and the minimum of a value of 4.2ng/dl E2 (intermediate value of 288H, the 13rd day, before the administration) to 336H (the 15th day, fluctuate between the maximum of 5.3ng/dl 0H). After the last administration, average E2 concentration is down to 0.8ng/dl, 456H (the 20th day, 0H; Discontinued medication rear 5 days) near baseline values (0.5ng/dl) before the administration. The detection of intermediate value rough concentration shows, with regard to E2 gel 1.25g and 2.5g dosage, the E2 concentration of stable state reaches when 4 days and 5 days respectively.
(the 14th day) estradiol concentration time data (0-24 hour) after 14 doses. Fig. 4 E is after describing the multidose administration of E2+0%LA gel, the curve map of E2 average serum concentration. The 14th day distribution confirms that stable state E2 concentration reached (312H) at the 14th day. The average E2 concentration of (treatment group a:2.4ng/dl E2, treatment group b:5.5ng/dl E2) was suitable when (treatment group a:2.0ng/dl E2, treatment group b:5.0ng/dl E2) and this sampling interval finished when this interval began. Average maximum E2 concentration is respectively 3.7ng/dl and 8.8ng/dl (the 14th day data).
The estradiol pharmacokinetics parameter of the 1st day and the 14th day. after using Bio-E-Gel with 1.25g and 2.5g single or multiple, the pharmacokinetics parameter of E2 is shown to provide among the 10a below. The general introduction of pharmacokinetics parameter (uncorrected and baseline-adjustment) provides in table 10c and 10d respectively.
After single uses 1.25g E2 gel, the 1st day Cmax (Cmax) be 2.3ng/dl. On an average, reach the time t of CmaxmaxReach at 17.67H. Be measured as 27.5ng/dl*H with contacting by AUC τ of E2. After repeatedly using, CmaxConcentration increased to 3.7ng/dl at the 14th day. tmaxEstimated value was about 16H in the time of the 14th day, with observed at the 1st day quite. At the 14th day, be 57.0ng/dl*H with contacting of E2, be higher than and observed at the 1st day, confirm Reusability after, E2 accumulates in serum.
After single uses 2.5g E2 gel, the 1st day Cmax (Cmax) be 3.7ng/dl. On an average, reach the time t of CmaxmaxReach at 18H. Be measured as 49.7ng/dl*H with contacting by AUC τ of E2. After repeatedly using, CmaxConcentration increased to 8.8ng/dl at the 14th day. In the time of the 14th day, tmaxEstimated value is about 18H, with observed in the 1st day quite. The 14th day is 128.2ng/dl*H with contacting of E2, is higher than to observe in the 1st day, confirm Reusability after, E2 accumulates in serum.
The ratio of E2 gel 2.5g/1.25g geometrical mean be used for to be estimated the dose ratio of E2 behind the E2 gel of these two dosage. After single dose was used, average AUC ratio (E2 gel 2.5g/1.25g) was to be 117.6/51.9=2.3 after 38.4/19.2=2.0 and the multidose administration, shows dose ratio.
The PK variable of table 10a:E2-dosage | |||||
Variable | Statistics | 1.25g Bio-E-Gel, single dose | 1.25g Bio-E-Gel, multi-agent | 2.5g Bio-E-Gel, single dose | 2.5g Bio-E-Gel, multi-agent |
AUC τ [ng/dl *H] | N average SD GeoM G_CV | 6 27.5 17.2 19.2 173.5 | 6 57.0 29.9 51.9 48.0 | 6 49.7 48.1 38.4 79.0 | 6 128.2 50.0 117.6 53.1 |
C max [ng/dl] | N average SD GeoM G_CV | 6 2.3 1.8 1.7 110.1 | 6 3.7 2.3 3.2 54.2 | 6 3.7 2.7 3.1 75.9 | 6 8.8 4.8 7.6 67.0 |
t max [H] | N average SD Min Med Max | 6 17.67 8.62 2.00 20.00 24.00 | 6 327.83 9.85 313.00 332.00 336.00 | 6 18.00 4.90 12.00 16.00 24.00 | 6 330.33 8.62 314.00 334.00 336.00 |
Baseline, C0 [ng/dl] | N average SD Min Med Max | 6 0.5 0.4 0.0 0.5 1.3 | 6 0.5 0.4 0.0 0.5 1.3 | 6 0.4 0.3 0.0 0.4 0.8 | 6 0.4 0.3 0.0 0.4 0.8 |
The estradiol pharmacokinetics parameter of adjusting with the 14th day base line in the 1st day. two groups E2 baseline concentrations is similar and as calculated, 1.25g and 2.5g E2 gel are respectively 0.5ng/dl and 0.4ng/dl. In order to proofread and correct endogenous E2 concentration, from the total concentration of using rear measurement, deduct baseline E2 concentration (E2 gel 1.25g: 0.5ng/dl and 2.5g: 0.4ng/dl), take the concentration of baseline adjustment as the basis, recomputate AUC τ and Cmax The result of the pharmacokinetics variable of baseline adjustment summarizes in table 10b. After single uses 1.25g and 2.5g E2 gel, the C that baseline is adjustedmaxEstimated value is respectively 1.8ng/dl and 3.4ng/dl. With regard to AUC τ, the baseline-adjusted value of 1.25g and 2.5g E2 gel is respectively 14.9ng/dL*H and 41.4ng/dl*H. Behind the Reusability, the C of 1.25g and 2.5g E2 gelmaxEstimated value increases to respectively 3.1ng/dl and 8.4ng/dl, and AUC τ estimated value increases to 44.2ng/dl*H and 119.6ng/dl*H. Medicine was accumulated in serum after these increased reflection Reusability gel.
Adjust concentration (312H is before the administration in the 14th day) by the baseline behind the last potion, the linear segment of the concentration time curve that transforms according to logarithm by the log-linear regression, calculates the eventually end of E2 and eliminates the half-life (t1/2). Independent and the mean estimates of half-life provides in table 10d behind use 1.25g and the 2.5g E2 gel. The intermediate value half-life of E2 gel 1.25g is that (scope: 13.11-76.71), that 2.5g is 35.58H (scope 26.60-51.59) to 22.15H. The half-life estimated value of two treatment groups is suitable.
Table 10b:E2-PK variable, baseline is adjusted | |||||
Variable | Statistics | 1.25g, single dose | 1.25g, multi-agent | 2.5g, single dose | 2.5g, multi-agent |
δAUC τ [ng/dl *H] | N average SD GeoM G CV | 14.9 13.3 9.8 147.3 | 44.2 22.2 39.7 56.1 | 41.4 51.1 25.2 139.6 | 119.6 51.2 108.9 53.5 |
δC max [ng/dl] | N average SD GeoM G CV | 6 1.8 1.8 1.2 132.8 | 6 3.1 2.0 2.7 56.4 | 6 3.4 2.9 2.4 118.5 | 6 8.4 4.7 7.3 68.5 |
t 1/2 [H] | N average SD Min Med Max | 4 33.53 29.16 13.11 22.15 76.71 | 4 37.34 12.41 26.60 35.58 51.59 |
Oestrone concentration time data (0-24 hour) behind the single dose (the 1st day). Fig. 4 F is after the description single dose gives the E2+0%LA gel, the curve map of oestrone (E1) average serum concentration. On an average, E1 concentration increases to the 3.4ng/dl E1 of 24H from the 2.4ng/dl E1 baseline value of 0H. After using more high dose (treatment group b), observe the 4.0ng/dl E1 that increases to 24H from the 2.4ng/dl E1 of baseline (0H).
Oestrone rough concentration data (1-20 days). after the curve map of Fig. 4 G is described and is repeatedly given the E2+0%LA gel, the average rough concentration of E1. On an average, rough concentration increases until use rear about 72H (the 4th day, before the administration). Afterwards, observe concentration and reach platform, (336H='s level the 5th day fluctuates between 5.2ng/dl E1 0H) that day at the 4.3ng/dl of 72H with after using last potion. Within this sampling interval, rough concentration changes, and fluctuation between the 5.3ng/dl maximum (the 13rd day, before the administration) of 4.1ng/dl E1 minimum of a value (the 5th day, before the administration) that 96H observes and 288H. After the last administration, average E1 concentration be down to 3.0ng/dl and 456H (the 20th day, 0H; Discontinued medication rear 5 days) near baseline values (2.4ng/dl) before the administration.
The average E1 rough concentration that repeatedly gives behind the Bio-E-Gel 2.5g also represents in Fig. 4 G. On an average, E1 concentration continues to increase, until about 240H (the 11st day, before the administration). Concentration increases to the 10.4ng/dl of 240H from the 2.4ng/dl of baseline (0H). Afterwards, rough concentration be change and the 7.8ng/dl of 9.1ng/dl E1 (288H=the 13rd day is before the administration) and 336H (the 15th day, 0H) between fluctuation. After the last administration, average E1 concentration be down to 3.1ng/dl and 456H (the 20th day, 0H; Discontinued medication rear 5 days) near baseline values (4.0ng/dl) before the administration. Inspection to average rough concentration shows that the stable state E1 concentration of Bio-E-Gel 2.5g and 1.25g dosage reached at 11 days and 13 days respectively.
The oestrone concentration time data (0-24 hour) of (the 14th day) after 14 doses. Fig. 4 H is after the description multi-agent gives the E2+0%LA gel, the curve map of E1 average serum concentration. The 14th day distribution confirms that stable state E1 concentration reached (312H) at the 14th day. E1 concentration (treatment group a:5.2ng/dl, treatment group b:7.8ng/dl) when the E1 concentration when this interval begins (treatment group a:4.8ng/dl, treatment group b:8.2ng/dl) and this sampling interval finish is comparable. The 14th day average maximum E1 concentration (312-336H) is respectively 6.0ng/dl and 9.2ng/dl.
The oestrone pharmacokinetics parameter of the 1st day and the 14th day. after single uses 1.25g E2 gel, the 1st day Cmax (Cmax) be 3.6ng/dl. On an average, reach the time t of CmaxmaxObtain at 12.67H. Be measured as 56.2ng/dl*H with contacting by AUC τ of E1. After repeatedly using, CmaxConcentration increased to 6.0ng/dl at the 14th day. The 14th day tmaxEstimated value be about 11H and with observed at the 1st day quite. In the time of the 14th day, be 111.4ng/dl*H with contacting of E1, be higher than and observed at the 1st day, confirm Reusability after, E1 accumulates in serum.
After single uses the 2.5gE2 gel, the 1st day Cmax (Cmax) be 4.1ng/dl. On an average, reach the time t of CmaxmaxObtain at 21H. Be measured as 62.2ng/dl*H with contacting by AUC τ of E1. After repeatedly using, CmaxConcentration increased to 9.2ng/dl at the 14th day. tmaxEstimated value was about 2H at the 14th day, was lower than to observe at the 1st day. At the 14th day, be 179.7ng/dl*H with contacting of E1, be higher than and observed at the 1st day, confirm Reusability after, E1 accumulates in serum.
The PK variable of table 10c:E1-dosage | |||||
Variable | Statistics | 1.25g single dose | 1.25g multi-agent | 2.5g single dose | 2.5g multi-agent |
AUC τ [ng/dl *H] | N average SD GeoM G_CV | 6 56.2 31.2 49.6 59.2 | 6 111.4 54.2 100.8 51.9 | 6 62.2 30.0 56.2 53.2 | 6 179.7 67.6 167.1 46.3 |
C max [ng/dl] | N average SD GeoM G_CV | 6 3.6 1.6 3.2 56.3 | 6 6.0 2.7 5.6 45.0 | 6 4.1 0.6 4.0 13.2 | 6 9.2 3.1 8.7 40.5 |
t max [H] | N average SD Min Med Max | 6 12.67 12.42 1.00 13.00 24.00 | 6 323.33 9.93 312.00 322.00 336.00 | 6 21.01 7.33 6.05 24.00 24.00 | 6 314.33 1.51 312.00 314.00 316.00 |
Baseline, C0 [ng/dl] | N average SD Min Med Max | 6 1.8 1.4 0.5 1.5 4.4 | 6 1.8 1.4 0.5 1.5 4.4 | 6 2.0 0.9 1.1 1.8 3.2 | 6 2.0 0.9 1.1 1.8 3.2 |
The 1st day and the 14th day, the oestrone pharmacokinetics parameter that baseline is adjusted. two groups E1 baseline concentration is similar, and 1.25g and 2.5gE2 gel are respectively 1.8ng/dl and 2.0ng/dl as calculated. In order to proofread and correct endogenous E1 concentration, from the total concentration of using rear measurement, deduct baseline E1 concentration (E2 gel 1.25g: 1.8ng/dl and E2 gel 2.5g: 2.0ng/dl), take the concentration of baseline adjustment as the basis, recomputate AUC τ and Cmax The result of the pharmacokinetics variable of baseline adjustment summarizes in table 10d. After single uses 1.25g and 2.5g E2 gel, the C that baseline is adjustedmaxEstimated value is respectively 1.8ng/dl and 2.0ng/dl. With regard to AUC τ, the baseline-adjusted value of 1.25g and 2.5g E2 gel is respectively 14.5ng/dL*H and 17.9ng/dl*H. Behind the Reusability, the C of 1.25g and 2.5g E2 gelmaxEstimated value increases to respectively 4.2ng/dl and 7.2ng/dl, and AUC τ estimated value increases to 67.1ng/dl*H and 131.2ng/dl*H. Medicine was accumulated in serum after these increased reflection Reusability gel.
Table 10d:E1-PK variable, baseline is adjusted | |||||
Variable | Statistics | 1.25g single dose | 1.25g multi-agent | 2.5g single dose | 2.5g multi-agent |
δAUC τ [ng/dl *H] | N average SD Med GeoM G_CV | 6 14.5 5.6 14.6 13.6 42.1 | 6 67.1 27.1 63.9 63.0 39.9 | 6 17.9 6.0 16.2 17.2 31.3 | 6 131.2 68.4 139.6 113.8 68.0 |
δC max [ng/dl] | N average SD Med GeoM G_CV | 6 1.8 0.8 1.7 1.6 47.2 | 6 4.2 1.7 3.6 4.0 34.7 | 6 2.0 0.5 2.0 2.0 30.6 | 6 7.2 3.2 8.0 6.4 57.5 |
OES concentration time data (0-24 hour) behind the single dose (the 1st day). Fig. 4 I is after the description single dose gives the E2+0%LA gel, curve map (the a=0.75mg E2 of OES (sulfuric acid E1) average serum concentration; B=1.50mg E2). On an average, E1-S concentration increases to the 79.0ng/dl E1-S of 24H from the baseline value of the 45.8ng/dl of 0H E1. After using more high dose (treatment group b), observe the 70.7ng/dl E1-S that increases to 24H from the baseline 34.7ng/dl E1-S of 0H.
OES rough concentration data (1-20 days). Fig. 4 J is after the description multidose gives the E2+0%LA gel, curve map (the a=0.75mg E2 of the average rough concentration of sulfuric acid E1; B=1.50mg E2). On an average, rough concentration continues along with Reusability to increase, and the mean value curve map shows approximately and changes in 192H (the 9th day, before the administration) increment rate as far as possible. E1-S serum concentration the 133.8ng/dl of 192H with use last potion after that day (336H; The 15th day, fluctuate between 117.8ng/dl E1-S 0H). After the last administration, average E1-S concentration is down to 77.0ng/dl, 456H (the 20th day, 0H; Discontinued medication rear 5 days) be higher than baseline values (45.8ng/dl) before the administration.
On an average, E1-S concentration continue to increase, until about 312H (the 14th day, before the administration), and the change of the increment rate of trying one's best clearly (the 11st day, before the administration) when about 240H. Concentration increases to the 193.5ng/dl of 240H from the 34.7ng/dl of baseline (0H). Afterwards, rough concentration changes, and 193.5ng/dl E1 (240H) and 336H (the 15th day, fluctuate between 155.7ng/dl 0H). After the last administration, average E1-S concentration be down to 60.3ng/dl and 456H (the 20th day, 0H; Discontinued medication rear 5 days) be higher than baseline values (34.7ng/dl) before the administration. The inspection of average rough concentration shows that the stable state sulfuric acid E1 concentration of E2 gel 1.25g and 2.5g dosage reached at 13 and 14 days respectively.
The concentration time data (0-24 hour) of OES after 14 doses (the 14th day). Fig. 4 K is after the description multidose gives the E2+0%LA gel, the curve map of sulfuric acid E1 average serum concentration. The 14th day distribution confirms that the E1-S concentration of stable state reached (312H) basically at the 14th day. (treatment group a:117.8ng/dl, treatment group b:155.7ng/dl) was slightly different when the average E1-S concentration (treatment group a:130.7ng/dl, treatment group b:200.3ng/dl) when this interval begins and this sampling interval finished. Yet the scope of value is overlapping, shows thus result's comparativity. The 14th day average maximum E1-S concentration of E2 gel 1.25g is 163.5ng/dl E1-S, and E2 gel 2.5g is 253.8ng/dl E1-S.
The OES pharmacokinetics parameter of the 1st day and the 14th day. the pharmacokinetics parameter of E1-S provides in table 10e with 1.25g and 2.5g single and after repeatedly using the E2 gel. Pharmacokinetics parameter (not corrected and baseline-adjusted) general introduction provides in table 10c and 10d respectively.
After single uses 1.25g E2 gel, the 1st day Cmax (Cmax) be 80.2ng/dl. On an average, reach the time t of CmaxmaxObtain at 20.67H. Be measured as 1359.2ng/dl*H with contacting by AUC τ of E1-S. After repeatedly using, CmaxConcentration increased to 163.5ng/dl at the 14th day. tmaxEstimated value was about 5H at the 14th day and is lower than to be observed on the 1st day. With E1-S contact the 14th day for 2834.1ng/dl*H, be higher than and observed in the 1st day, confirmed Reusability after, E1-S accumulates in serum.
After single uses 2.5g E2 gel, the 1st day Cmax (Cmax) be 74.7ng/dl. On an average, reach the time t of CmaxmaxObtain at 20H. Be measured as 1207.4ng/dl*H with contacting by AUC τ of E1-S. After repeatedly using, CmaxConcentration increased to 253.8ng/dl at the 14th day. The 14th day tmaxEstimated value is about 3H and is lower than to be observed on the 1st day. With E1-S contact the 14th day for 4079.2ng/dl*H, be higher than and observed in the 1st day, confirmed Reusability after, E1-S accumulates in serum.
Table 10e: the PK variable of sulfuric acid E1-dosage | |||||
Variable | Statistics | 1.25g single dose | 1.25g multi-agent | 2.5g single dose | 2.5g multi-agent |
AUC τ [ng/dl *H] | N average SD GeoM G_CV | 6 1359.2 407.8 1302.6 33.9 | 6 2834.1 1219.0 2611.1 47.2 | 6 1207.4 243.6 1184.3 22.6 | 6 4079.2 1674.5 3798.7 43.4 |
C max [ng/dl] | N average SD GeoM G_CV | 6 80.2 30.5 75.2 41.5 | 6 163.5 75.5 148.2 52.6 | 6 74.7 12.1 73.8 17.0 | 6 253.8 124.2 231.3 49.0 |
t max [H] | N average SD Min Med Max | 6 20.67 8.16 4.00 24.00 24.00 | 6 316.67 3.93 314.00 315.00 324.00 | 6 20.00 6.20 12.00 24.00 24.00 | 6 315.33 4.46 312.00 313.50 324.00 |
Baseline, C0 [ng/dl] | N average SD Min Med Max | 6 51.3 17.9 23.3 55.5 71.0 | 6 51.3 17.9 23.3 55.5 71.0 | 6 36.9 10.7 23.3 38.0 53.0 | 6 36.9 10.7 23.3 38.0 53.0 |
The 1st day and the 14th day, the OES pharmacokinetics parameter that baseline is adjusted. two groups E1-S baseline concentration is similar, is respectively 51.3ng/dl and 36.9ng/dl through measuring 1.25g and 2.5g E2 gel. In order to proofread and correct endogenous E1-S concentration, from the total concentration of using rear measurement, deduct baseline E1-S concentration (E2 gel 1.25g: 51.3ng/dl and Bio-E-Gel 2.5g: 36.9ng/dl), take the concentration of baseline adjustment as the basis, recomputate AUC τ and Cmax After single uses 1.25g and 2.5g E2 gel, the C that baseline is adjustedmaxEstimated value is respectively 28.8ng/dl and 37.7ng/dl. With regard to AUC τ, the baseline-adjusted value of 1.25g and 2.5g E2 gel is respectively 165.7ng/dL*H and 325.5ng/dl*H. Behind the Reusability, the C of 1.25g and 2.5g E2 gelmaxEstimated value increases to respectively 112.2ng/dl and 216.9ng/dl, and AUC τ estimated value increases to 1602.1ng/dl*H and 3192.5ng/dl*H. After these increases reflected the Reusability gel, medicine was accumulated in serum.
Table 10f: sulfuric acid E1-PK variable, baseline is adjusted | |||||
Variable | Statistics | 1.25g single dose | 1.25g multi-agent | 2.5g single dose | 2.5g multi-agent |
δAUC τ [ng/dl *H] | N average SD GeoM G_CV | 6 165.7 63.7 153.9 46.4 | 6 1602.1 878.6 1403.2 61.9 | 6 325.5 267.1 256.1 87.6 | 6 3192.5 1543.4 2893.6 51.8 |
δC max [ng/dl] | N average SD GeoM G_CV | 6 28.8 19.3 24.1 71.7 | 6 112.2 61.0 97.0 67.2 | 6 37.7 16.0 33.7 63.6 | 6 216.9 120.4 192.9 55.7 |
Sex hormone binding globulin (SHBG). except research approach, measure the SHBG concentration in the form subsequently, in particular for explaining that the accident of E2 in being subjected to treatment target 04 accumulate. In table 10g, data are tabulated. In general, average SHBG concentration increases in time, average 72.5nmol/l from 0H behind the E2 gel 1.25g increases to 84.00nmol/l through 80.17mol/l, and the average 72.5nmol/l from 0H behind the E2 gel 2.5g increases to 88.83nmol/l through 77.83nmol/l. The treatment target 04 that is subjected to of accepting E2 gel 2.5g shows similar pattern. SHBG-concentration is respectively 58nmol/l and 53nmol/l before processing. 192H (the 9th day, before the administration) SHBG concentration is 58nmol/l after using for the first time, and 360H (the 16th day, increase to 71nmol/l after 0H). Therefore, do not shown by treatment target 04 to be different from other to be subjected to treatment target and SHBG concentration can not explain E2 concentration excessive among this curer.
Table 10g:SHBG[nMol/l] | |||||
Treatment | Statistics | With respect to the scheduled time of using for the first time | |||
-16 | -10 | 192 | 360 | ||
The E2 gel, 1.25 | N average SD GeoM G CV | 6 72.33 23.73 69.12 34.09 | 6 72.50 24.83 69.02 35.54 | 6 80.17 28.53 75.94 37.59 | 6 84.00 29.18 79.73 36.85 |
The E2 gel, 2.5g | N average SD GeoM G CV | 6 74.00 29.64 68.91 43.88 | 6 72.50 30.34 67.20 45.10 | 6 77.83 32.17 72.20 45.01 | 6 88.83 38.97 81.17 50.71 |
The pharmacokinetics conclusion. calculate the pharmacokinetics feature, as estimating substituting of effect. Demonstrate multidose and give 0.75mg and 1.5mg E2 gel, produce respectively the average serum concentration of about 2.4ng/dl B2 and 5.3ng/dl E2. These values and the transdermal patch that utilizes E2/ days release rates of 25 and 50 μ g obtain is in the equal big or small order of magnitude, and is approved for disease after the menopause, comprises alleviating hectic fever.
The security conclusion. observe 8 adverse events; Having 7 in them, to be classified as (possibility) relevant with research treatment; After giving 1.25g and 2.5g E2 gel, 3 and 4 events are arranged respectively. Two kinds of therapeutic schemes all demonstrate splendid skin tolerance. Do not have serious, violent or significant adverse events generation. Nobody withdraws from. Vital sign, ECG, clinical labororatory's variable or physical examination result significantly do not change. The research medication is by fine tolerance. The not relevant difference of the security features of two kinds of treatments studying.
Average and the individual serum concentration time curve of E2, the E1 of conclusion .1.25g and 2.5g E2 gel and E1-S shows that two kinds are treated the drug concentration that the baseline values that is higher than measurement all can be provided. The pharmacokinetics of gel product confirms usually to reach the medicine levelling bench behind the repetitively administered. In addition, in case interrupt medicine, the medicine level was got back in 5 days or near baseline values. The pharmacokinetics prompting 1.25g of E2, E1 and E1-S and the dosage proportionality of 2.5g gel product. At the 1st day and the 14th day, the mean parameter estimated value of 2.5g treatment group was about the twice of 1.25g treatment group estimated value.
t
maxEstimated value in two treatment groups, all change. Under the 14th day stable state, tmaxSome estimated value when dosing interval begins, occur. In these cases, serum concentration may continue to raise after administration immediately, and this is owing to the medicine that derives from previous dosage exists. After two kinds for the treatment of administrations, the time that reaches Cmax all occurs in the 16-20 H after using for the first time.
The acquisition of stable state is mainly estimated by graphical method. The average rough concentration of E2 all highly changes in two treatment groups, but does not demonstrate the tendency of remarkable increase during studying. Intermediate value rough concentration curve map shows that two treatment groups all reached the E2 stable state at the 5th day. The t1/2 estimated value (about 33H) of the E2 that obtains in this research will reach stable state as basic after the about 9-10 of administration days, this result is consistent with graph-analytic result. Therefore, the pharmacokinetics that carried out in the 14th day in treatment is measured and should be represented stable state. Observe similar result for E1 and E1-S, although seem more variable and fluctuate larger for these two analyte concentrations.
Calculate the pharmacokinetics feature, as estimating substituting of effect. Show that multi-agent 0.75mg and 1.5mg E2 gel produce respectively the average serum concentration of about 2.4ng/dl E2 and 5.3ng/dl E2. The big or small order of magnitude of these values is to obtain after using the transdermal patch of 25 and 50 μ g/ days release rates, and has been approved for disease after the menopause, comprises alleviating hectic fever and osteoporosis. Therefore, it is safely and effectively that prediction E2 gel will be proved for treatment menopause symptom, comprises alleviating hectic fever and osteoporosis.
The E2 gel that contains 0.06% estradiol is water alcogel preparation, provides with the little bag form of single dose: E2 gel 0.625g/ days (0.375mg/ days E2), E2 gel 1.25g/ days (0.75mg/ days E2) or E2 gels 2.5g/ days (1.5mg/ days E2). Be subjected to treatment target with the E2 gel local thigh that is used for every day.
The parameter of estimating comprises: hectic fever incidence and the order of severity. Adverse events, the detection of safety experiment chamber, vital sign, body weight, health check-up, BE, skin irritatin effect have been estimated.
The elementary analysis result of common main effect terminal point shows that the E2 gel minimum effective dose of the angiokinesis symptom for the treatment of the postmenopausal women is E2 gel 2.5g/ days (1.5mg/ days E2). In 2.5g/ days treatment groups of E2 gel, when the 4th week, moderate is 2.7 to have clinical meaning (namely 〉=2.0) to severe hectic fever rate apart from the difference of the average change of baseline and placebo, has superiority (placebo-0.6 at the average change aspect apart from baseline aspect the average order of severity of hectic fever every day with respect to placebo; E2 gel 2.5g/ days ,-0.9). Other E2 gel administration group is compared with placebo, and the similar difference aspect every day hectic fever rate does not have clinical meaning (E2 gel 0.625g/ days, 0.7; E2 gel 1.25g/ days, 0.0).
Table 11
Every day, moderate was to severe hectic fever rate
The average change of comparing with baselinea
Estimate | Placebo (N=42) | E2 gel 0.625g/ days (N=41) | E2 gel 1.25g/ days (N=39) | E2 gel 2.5g/ days (N=38) |
Baseline (mean value ± SD)b | 16.0±9.88 | 12.5±5.60 | 12.3±7.26 | 13.0±5.97 |
The-1 week (placebo introducing) | -5.3 | -3.9 | -4.7 | -5.0 |
The 1st week | -7.3 | -5.8 | -5.9 | -7.5 |
The 2nd week | -7.9 | -7.5 | -7.2 | -9.4 |
The 3rd week | -8.5 | -8.5 | -7.4 | -10.5 |
The 4th week | -8.5 | -9.2 | -8.5 | -11.2 |
aFor 4 weeks of the-1 week to the, mean value is the least square mean value that derives from the ANCOVA model, and this model has the interactional factor in treatment, position and treatment-position, and baseline hectic fever rate is as covariant.bUnadjusted mean value and standard deviation. baseline was based on 7 days of the screening phase. |
In main efficiency analysis, with regard to the 4th every day in week moderate-severe hectic fever rate alleviate 〉=90% be subjected to the treatment target ratio, treatment group is compared, the validity (55% is subjected to treatment target) that shows 2.5g/ days groups of E2 gel, and other E2 gel dose group similar to placebo (27%-35%). In addition, during the 4th week, the intermediate value estradiol concentration (33pg/mL) of 2.5g/ days dosage groups of E2 gel is positioned at the low side of expection therapeutic domain, and the median concentration of other E2 gel dose group is lower than this scope (E2 gel 0.625g/ days, 12pg/mL; E2 gel 1.25g/ days, 23pg/mL).
Efficiency analysis. compare with placebo, the main effect evaluation of the clinical validity of E2 gel 0.625g/ days (0.375mg E2), 1.25g/ days (0.75mg E2) and E2 gel of E2 gel 2.5g/ days (1.5mg E2) is the change that the average order of severity of hectic fever every day was compared with baseline when change that (moderate-severe) hectic fever rate is compared with baseline every day was with the 4th week of estimating in ITT LOCF Data Set when measuring for the 4th week. The baseline measures that uses during these are analyzed is to analyze the data that obtain as the basis take the screening phase, does not comprise the baseline measures based on the data that obtain in the placebo introductory phase.
The elementary analysis of the change that the average order of severity of hectic fever every day is compared with baseline not adjust mean value as the basis, uses treatment group as factor by unidirectional ANOVA model. Yet, consider the difference of average baselining hectic fever every day rate between treatment group, and significantly treatment-position interacts, the elementary analysis of the change that every day, the hectic fever rate was compared with baseline be derive from the least square mean value of ANCOVA model be the basis, this model has the interactional factor in treatment, position and treatment-position, and baseline hectic fever rate is as covariant. These elementary analysis results only are discussed.
As the secondary efficacy analysis, the analysis of above-mentioned 2 common main terminal points is carried out at valuable treatment target LOCF Data Set. Other analysis comprise the 4th every day in when week moderate-severe hectic fever rate compare with baseline minimizing 〉=50%, 〉=60%, 〉=70%, 〉=80%, 〉=90%, 〉=95% or 100% be subjected to the treatment target ratio, it carries out for ITT LOCF and valuable treatment target LOCF Data Sets. With regard to ITT Data Set, the result of these proportion gradings provides in the text form.
The descriptive analysis of 2 common main terminal points was carried out for ITT observation case Data Set and valuable treatment target observation case Data Set in the 1st, 2,3,4 weeks. Because only there are 4 to be subjected to the too early TD for the treatment of target, therefore, the result of the observation analysis of cases that these data groups are carried out almost analyzes identically with LOCF, does not therefore discuss in detail in this report.
The average change that every day, moderate-severe hectic fever rate was compared with baseline. purpose treatment Data Set-LOCF analyzes. in the LOCF of ITT Data Set analyzes, all observe the average minimizing that moderate every day-severe hectic fever rate is compared with baseline for whole 4 treatment groups, observed more significant minimizing in 2.5g/ days in the dosage group at the E2 gel and (see Table 11a and Fig. 5 a).
Between 2.5g/ days groups of E2 gel and placebo, observe the 4th week clinical significant difference (namely 〉=2.0) (group difference=-2.7) that every day, the hectic fever rate on average alleviated, and two E2 gels than low dosage do not show and compare clinical significant difference with placebo. Therefore, two lower E2 gel doses are invalid, and 2.5g/ days dosage of E2 gel is proved to be the minimum effective dose for the treatment of moderate-severe hectic fever.
Fig. 5 A be describe give the estradiol of various dose after, every day the moderate-average change that severe hectic fever rate is compared with baseline curve map (ITT-LOCF).
Table 11a
The average change (ITT-LOCF) that every day, moderate was compared with baseline to severe hectic fever rate
Estimate | The average change of comparing with baseline | |||
Placebo (N=42) | E2 gel 0.625g/ days (N=41) | E2 gel 1.25g/ days (N=39)b | E2 gel 2.5g/ days (N=38)c | |
Baseline (mean value ± SD)d | 16.0±9.88 | 12.5±5.60 | 12.3±7.26 | 13.0±5.97 |
The-1 week (placebo introducing) | -5.3 | -3.9 | -4.7 | -5.0 |
The 1st week | -7.3 | -5.8 | -5.9 | -7.5 |
The 2nd week | -7.9 | -7.5 | -7.2 | -9.4 |
The 3rd week | -8.5 | -8.5 | -7.4 | -10.5 |
The 4th week | -8.5 | -9.2 | -8.5 | -11.2 |
aFrom 4 weeks of the-1 week to the, mean value is the least square mean value that derives from the ANCOVA model, and this model has the interactional factor in treatment, position and treatment-position, and baseline hectic fever rate is as covariant.bAlthough ITT Bio-E-Gel included 40 in 1.25g/ days and is subjected to treatment target in the treatment group, be not included in the hectic fever analysis by treatment target 102, this is because unmanageable base-line data.cWhen estimating in the 1st week, 2.5g/ days treatment group N=37 of E2 gel, this is because lost by the hectic fever record that treatment target 187 should week.dUnadjusted mean value and standard deviation. baseline was based on 7 days of the screening phase. |
The valuable treatment target Data set-LOCF that is subjected to analyzes. in the valuable LOCF that is subjected to treatment target Data set analyzes, all observe on average alleviating that moderate every day-severe hectic fever rate is compared with baseline for whole 4 treatment groups, observed more significant alleviating (seeing Table 11b and Fig. 5 b) in 2.5g/ days in the dosage group at the E2 gel. Between 2.5g/ days dosage groups of E2 gel and placebo, observe the 4th every day in week clinical significant difference that the hectic fever rate on average alleviates (namely, 〉=2.0) (group difference=-3.2), and two E2 gels than low dosage do not demonstrate and compare clinical significant difference with placebo.
Fig. 5 B be describe give the estradiol of various dose after, every day the moderate-average change that severe hectic fever rate is compared with baseline curve map (valuable-LOCF).
Table 11b
The average change that every day, moderate was compared with baseline to severe hectic fever rate (valuable-LOCF)
Estimate | The average change of comparing with baselinea | |||
Placebo (N=28) | E2 gel 0.625g/ days (N=38) | E2 gel 1.25g/ days (N=33) | E2 gel 2.5g/ days (N=30) | |
Baseline (mean value ± SD)b | 15.3±9.35 | 12.3±5.11 | 12.8±7.73 | 13.4±5.91 |
The-1 week (placebo introducing) | -4.8 | -3.7 | -5.0 | -4.8 |
The 1st week | -6.7 | -5.9 | -6.0 | -7.6 |
The 2nd week | -7.1 | -7.6 | -7.3 | -9.4 |
The 3rd week | -7.9 | -8.5 | -7.6 | -10.6 |
The 4th week | -8.0 | -9.1 | -9.0 | -11.2 |
aFrom 4 weeks of the-1 week to the, mean value is the least square mean value that derives from the ANCOVA model, and this model has the interactional factor in treatment, position and treatment-position, and baseline hectic fever rate is as covariant.bUnadjusted mean value and standard deviation. baseline was based on 7 days of the screening phase. |
The 4th every day in week moderate-severe hectic fever rate alleviate 〉=90% or 100% be subjected to the treatment target ratio. purpose treatment Data Set-LOCF analyzes. in the LOCF of ITT Data Set analyzes, great majority in 2.5g/ days dosage groups of E2 gel are subjected to treatment target (55%, 21/38) every day in the 4th week the alleviating of moderate-severe hectic fever rate 〉=90%, placebo and two low E2 gel dose groups are about 1/3 and are subjected to treatment target (seeing Table 11c) by contrast. In 2.5g/ days dosage groups of E2 gel 24 (24%) percent is subjected to treatment target to alleviate (that is, not having moderate to the severe hectic fever) having 100% the 4th week.
Table 11c
The 4th every day in when week moderate alleviate 〉=50%-100% to severe hectic fever rate
Be subjected to treatment target number and ratio (ITT-LOCF)
Estimate 〉=50% alleviate 〉=60% alleviate 〉=70% alleviate 〉=80% alleviate 〉=90% alleviate 〉=95% alleviate 100% and alleviate | Be subjected to treatment target number (%) | |||
Placebo (N=42) 32 (76%) 29 (69%) 24 (57%) 19 (45%) 13 (31%) 8 (19%) 4 (10%) | 0.625g/ days (N=41) 31 (76%) 29 (71%) 21 (51%) 15 (37%) 11 (27%) 7 (17%) 4 (10%) of E2 gel | E2 gel 1.25g/ days (N=39)a 32(82%) 28(72%) 23(59%) 17(44%) 14(36%) 12(31%) 8(21%) | 2.5g/ days (N=38) 33 (87%) 32 (84%) 29 (76%) 24 (63%) 21 (55%) 19 (50%) 9 (24%) of E2 gel | |
aBe subjected to treatment target although ITT E2 gel had 40 in 1.25g/ days in the treatment group, be not included in the hectic fever analysis by treatment target 102, this is because unmanageable base-line data. |
The average change of comparing with the baseline order of severity of hectic fever. purpose treatment Data Set-LOCF analyzes. in the LOCF of ITT Data set analyzes, all observed and on average alleviating that the average order of severity of baseline hectic fever every day is compared for whole 4 treatment groups, observe more significant alleviating in 2.5g/ days dosage groups of E2 gel, and 1.25g/ days dosage groups of E2 gel degree lower (seeing Table 11d and Fig. 5 c). In 2.5g/ days dosage groups of E2 gel the reduction in time of the average order of severity of hectic fever every day with see in the 4th week every day the hectic fever rate on average alleviate the clinical meaningful difference-complementary of comparing with placebo.
Fig. 5 C be describe give the various dose estradiol after, the curve map (ITT-LOCF) of the average change of comparing with baseline with the average order of severity of hectic fever every day.
Table 11d
The average change (ITT-LOCF) that the average order of severity of hectic fever every day is compared with baseline
Estimate | The average change of comparing with baselinea | |||
Placebo (N=42) | E2 gel 0.625g/ days (N=41) | E2 gel 1.25g/ days (N=39)b | E2 gel 2.5g/ days (N=38)c | |
Baseline (mean value ± SD)d | 2.3±0.31 | 2.2±0.30 | 2.3±0.33 | 2.2±0.33 |
The-1 week (placebo introducing) | -0.2 | -0.2 | -0.2 | -0.1 |
The 1st week | -0.5 | -0.2 | -0.3 | -0.3 |
The 2nd week | -0.6 | -0.3 | -0.5 | -0.6 |
The 3rd week | -0.6 | -0.4 | -0.6 | -0.7 |
The 4th week | -0.6 | -0.6 | -0.8 | -0.9 |
aOrder of severity grade: 1=is slight, 2=moderate, 3=severe.bBe subjected to treatment target although ITT Bio-E-Gel comprised 40 in 1.25g/ days in the treatment group, be not included in the hectic fever analysis by treatment target 102, this is because unmanageable base-line data.cWhen estimating in the 1st week, Bio-E-Gel 2.5g/ days treatment group N=37, this is because lost by the hectic fever record that treatment target 187 should week.dUnadjusted mean value and standard deviation. baseline was based on 7 days of the screening phase. |
Drug dose, drug concentration and with the relation of reaction. estradiol, oestrone and OES. before administration in the 1st day and research obtain trough serum sample after finishing, be used for measuring the concentration of estradiol, oestrone and OES. In order to summarize, all measurement result settings that will be lower than the 5pg/ml detectability equal detectability (that is, being assigned as the value of 5pg/mL). The 1st day and the 4th when week estradiol, oestrone and the rough concentration of OES in treatment group, alter a great deal (seeing Table 11e). Consider variability and moderate sample size, intermediate value will be discussed.
In all treatment groups, estradiol (5pg/mL), the 1st day intermediate value of oestrone (18.5-22.0pg/mL) and estradiol/oestrone are than (0.29-0.42) consistent with postclimacteric distribution (seeing Table 11e). Yet the treatment target that is subjected to of satisfied<20pg/mL estradiol inclusive criteria failed to satisfy this standard when it should be noted some screening at the 1st day. Except measuring intrinsic variability own, it infers that reason is the unstability that is subjected to the treatment target hormonal readiness that menopause occured in upper one year, hysterectomize and do not have ovariectomized treatment target age<50 year old of being subjected to, or may not report about during screening, using the non-compliance of estrogen product.
After using the treatment of E2 gel, the 4th all intermediate value estradiol, oestrone and OES concentration show separate (the seeing Table 11e) between the treatment group consistent with the administration of E2 gel dose. For E2 gel 0.625g/ days, 1.25g/ days and 2.5g/ days dosage groups, the estradiol intermediate value in the 4th week is respectively 12pg/mL, 23pg/mL and 33pg/mL.
The female cave of trough estradiol, oestrone and sulfuric acid (ITT) when table 11e the 1st day and the 4th week
Hormone | Estimate | Placebo | E2 gel 0.625g/ days | E2 gel 1.25g/ days | E2 gel 2.5g/ days | |
E2 (pg/mL) | ||||||
The 1st day mean value ± SD intermediate value scope the 4th all mean value ± SD intermediate value scope | (N=41) 12.2±18.5 5 5-110 (N=40) 11.4±15.4 5 5-85 | (N=41) 15.3±24.5 5 5-120 (N=41) 24.1±41.6 12 5-240 | (N=39) 10.3±13.5 5 5-64 (N=37) 34.8±33.0 23 5-170 | (N=38) 12.3±20.3 5 5-110 (N=37) 46.8±44.6 33 5-250 | ||
E1 (pg/mL) | The 1st day mean value ± SD intermediate value scope the 4th all mean value ± SD intermediate value scope | (N=41) 22.3±13.9 19.0 5-65 (N=40) 21.6±15.3 19.5 5-82 | (N=41) 29.9±28.1 22.0 6-160 (N=41) 36.3±15.7 35.0 5-78 | (N=39) 24.3±15.8 22.0 5-93 (N=37) 51.9±29.1 44.0 13-130 | (N=38) 22.4±13.9 18.5 5-67 (N=36) 72.3±43.8 60.5 17-200 | |
The E2/E1 ratio | The 1st day mean value ± SD intermediate value scope the 4th all mean value ± SD intermediate value scope | (N=41) 0.55±0.52 0.42 0.2-2.9 (N=40) 0.59±0.59 0.37 0.2-3.2 | (N=41) 0.49±0.36 0.31 0.0-1.6 (N=41) 0.55±0.56 0.35 0.2-3.3 | (N=39) 0.43±0.29 0.29 0.1-1.2 (N=37) 0.67±0.59 0.51 0.2-3.8 | (N=38) 0.47±0.33 0.39 0.2-2.0 (N=36) 0.64±0.33 0.54 0.2-1.7 |
E1-S (pg/mL) | The 1st day mean value ± SD intermediate value scope the 4th all mean value ± SD intermediate value scope | (N=41) 532.4± 350.2 410.0 150-2100 (N=40) 573±616.6 400.0 110-4020 | (N=41) 691.0± 815.5 480.0 170-4760 (N=40) 944.4± 579.1 740.0 300-2870 | (N=39) 457.4± 193.9 430 190-940 (N=38) 1562± 1610 995.0 280-8020 | (N=38) 523.2± 443.5 430.0 180-2650 (N=36) 2283± 1884 1765 330-7040 |
The security conclusion. in this postmenopausal women crowd every day use about 4 weeks of 0.625-2.5g E2 gel (0.375-1.5mg estradiol) be safety and can fine tolerance. Total incidence of the adverse events that treatment occurs in the E2 gel group does not increase (each dosage group about 50%) along with dosage level, and can compare with the incidence of placebo (40%). Compare with placebo (5%), reported more continually the adverse events relevant with the mammary gland disease with reproductive system (0.625g/ days, 1.25g/ days and 2.5g/ days E2 gel groups be respectively 10%, 18% and 13%) in the E2 gel group, just as to such medicine expection. These events that are subjected to report in the treatment target at 2 or more E2 gels comprise: breast tenderness, metrorrhagia (vagina drop), sore nipples, hysterotrismus and fluor vaginalis. Concern without obvious between the generation of these events and E2 gel dose or the estradiol level. Be not subjected to treatment target owing to these events are interrupted research.
Breast examination shows that the E2 gel is on being subjected to whole the treatment target do not affected when final the evaluation by treatment targets except one; The slight breast tenderness adverse events that the change that observed by treatment target (E2 gel 2.5g/ days) for this name is reported corresponding to an example disappears in a week after it in the end studies administration.
In research process, there are not death or serious adverse events to occur. Two (2) are subjected to treatment target (being the E2 gel 1.25g/ days) owing to adverse events interrupts the double blinding treatment, wherein only have one (dizziness) to be considered to and may to be correlated with; Two all recovered by treatment target.
When analyzing from baseline to the 4 all average changes of estimating, observe the E2 gel to not clinically significant impact of the result of clinical labororatory. In the 4th when week, compared from the treatment target ratio that is subjected to that normal baseline changes to unusual level, show that to change to the incidence that is higher than normal cholesterol levels in the E2 gel group higher, and clearly change to the incidence that is higher than normal BUN level and increase relevant with the E2 gel dose; Yet; every group only have an appointment 10 be subjected to treatment target be included in cholesterol relatively in (because most cholesterol levels that had by treatment target to be higher than normal baseline), and BUN changes with the clinical manifestation of the corresponding change of other renal function index or renal insufficiency irrelevant.
Do not observe the E2 gel to the clinical important function of vital sign, body weight, health check-up or skin irritatin evaluation of effect.
Conclusion. transdermal ET directly is delivered to estradiol in the body circulation via skin, and the head that has avoided thus oral ET to occur crosses hepatic metabolism, and has avoided oral ET to the effect of liver and gall system. For any liver function parameter, do not observe statistically significant or the clinical significant change of the average change of estimating from 4 weeks of baseline to the, recording. 0.625g/ days dosage groups of E2 gel wherein one be subjected to treatment target to experience the AST increase, the researcher feels it is clinical significant; And this name is raise (44u/L) at baseline ALT by treatment target, rises to 70u/L when final the evaluation. In 2.5g/ days dosage groups of E2 gel 1.25g/ days or E2 gel, not observing the liver functional test that is subjected to treatment target has clinical significant increase.
With the part use the relevant adverse events of the gel of studying seldom and more continually reported in the dosage group in 1.25g/ days at the E2 gel. The event of the frequent report relevant with using institute's drugs is to use the dry skin at position, is subjected to occur in the treatment target at two. These events are considered to slight, outbreak after using drugs to surpass for 2 weeks, and event continues to be no more than 7 days. Other skin dependent event of reporting comprises uses the position to burn or itch, and each event all is subjected to occur in the treatment target at one. Do not treat the erythema of drawing at the use position.
Oral ET has shown that the biliary cholesterol saturation index of sening as an envoy to increases, and increases relevant with the danger of gallstone disease; As if yet this impact is also not obvious in transdermal ET. In E2 gel dose group, be not subjected to treatment target to have the clinical remarkable change of bilirubin level, and do not have report to increase relevant adverse events, Bilirubinemia or gall stone with cholesterol.
Think at first and use transdermal ET can avoid using the being seen serum lipid of oral ET and lipoprotein to increase, but studies show that the change of serum lipid and lipoprotein has occured really, but outbreak and progress want slow than oral ET. In the research in this 4 week, in these parameters, do not observe clinically significant average change, although can not expect overall change in treatment duration in 4 weeks only. 2.5g/ days dosage groups of E2 gel wherein one be subjected to treatment target to have triglycerides from the clinical remarkable change of baseline; Yet this is drawn blood by the final laboratory for the treatment of target is not fasting. Incidentally, this baseline cholesterol that is subjected to treatment target is 287mg/dL, and LDL is 172mg/dL.
The result of this research confirms that to give 4 weeks of E2 gel be safe every day and can be by fine tolerance with 0.625-2.5g/ days dosage.
According to the present invention, said preparation can contain above-mentioned preparation with and the kit of operation instruction in provide. This kit generally includes a container, and this container is used for the storage preparation and has the distributor that discharges as required or use predetermined dosage or predetermined preparation. This distributor also can trigger through the user and start the composition that automatically discharges predetermined dosage or volume.
Kit of the present invention can comprise described preparation in bag, pipe, bottle or any other suitable container. Described kit can contain the preparation that is packaged in the single dose in the independent pouch, and the user opened pouch and used the composition that is included in the pouch as active component dosage every day like this. This kit also can contain the composition that is packaged in the multidose in the container. In the use procedure, can instruct be subjected to treatment target from container the composition of distribution provisions amount be used for skin (such as " amount of dime size " etc.). Composition of the present invention can be stored in the aluminum pipe, stores at least about 6 weeks under about 25 ℃ and 60% relative humidity and 40 ℃ and 75% relative humidity.
This container can comprise the metering distributor, so just can when each triggering distributor, be distributed the preparation of known volume or dosage by the user. In example, said preparation can provide in dosing pump bottle therein. The preparation that provides can be finite concentration, can distribute specific weight or volume (such as 0.87g), and repeatedly start pump when each Pressing pump like this, such as three times, can distribute the preparation of required dosage for being subjected to treatment target. In example, this kit comprises the gel preparation that is contained in container such as the Orion dosing pump bottle therein. Except can using pump bottle type container, also can use in addition other container such as the rod or roll and put formula container etc. on the skin. The implementation scheme of the invention described above is not limitation of the present invention, and those skilled in the art can determine at an easy rate that other embodiment of the present invention and feature drop within the scope of claim and equivalent thereof.
Although specification has been described implementation scheme of the present invention, those skilled in the art can design change of the present invention in the situation that does not deviate from the present invention's design. Therefore, invention scope described herein and required for protection is not subjected to the restriction of implementation scheme disclosed herein, because these embodiments are intended to as illustrating the some aspects of the present invention. Any embodiment intention that is equal to falls within the scope of the present invention. In fact, according to the description of front, those, various improvement of the present invention all are apparent to those skilled in the art except shown here and described. This improvement also falls within the scope of the claims.
Claims (70)
1. a transdermal or saturating mucous membrane are used the preparation of activating agent, comprise:
At least a activating agent, condition are that this activating agent not merely is testosterone, and when activating agent is estrogen or progestational hormone, do not have respectively progestational hormone or the estrogen for the treatment of effective dose in the said preparation; With
Delivery vector comprises alkanol, polyalcohol and presents in an amount at least sufficient to the enhanced activity agent by the penetration enhancer of mammal skin or mucomembranous surface infiltration;
Wherein said preparation there is no long-chain fatty alcohol, LCFA and long-chain fat ester, to avoid bad smell and the spread effect in the preparation use procedure.
2. preparation according to claim 1, wherein alkanol accounts for the about 5-80% of delivery vector weight, polyalcohol accounts for the about 1%-30% of delivery vector weight, penetration enhancer accounts for the about 0.2-30% of delivery vector weight, delivery vector promotes skin or mucomembranous surface to the absorption of described at least a activating agent like this, thereby makes preparation from the transfer on this class surface or remove and reduce to minimum.
3. preparation according to claim 2, wherein alkanol and water are combined to form water-alcohol mixture, and this water-alcohol mixture accounts for that the about 40-of delivery vector weight is about 98%, and alkanol accounts for the about 5%-80% of this mixture weight, and water accounts for the about 20%-95% of this mixture weight.
4. preparation according to claim 2, wherein activating agent is estradiol, it accounts for the about 0.01%-2% of said preparation; Alkanol accounts for the about 20-65% of said preparation; Polyalcohol is propane diols, and it accounts for the about 1%-15% of said preparation; Penetration enhancer is carbitol, and it is about 1%-15% that it accounts for said preparation, and wherein said preparation also contains the gelling agent that accounts for said preparation 0.05%-about 4%, accounts for the nertralizer of the about 0.05%-1% of said preparation and accounts for the water of the about 20-65% of said preparation.
5. preparation according to claim 4 also contains chelating agent.
6. preparation according to claim 2, wherein the weight ratio of polyalcohol and penetration enhancer is 2: 1-1: 1.
7. preparation according to claim 1, wherein alkanol is the C that is selected from ethanol, isopropyl alcohol and normal propyl alcohol2-C
4Alcohol, polyalcohol are polypropylene glycols, and penetration enhancer is tetraethylene glycol furfural or diethylene glycol (DEG) one alkyl ether.
8. preparation according to claim 1, wherein activating agent is androgen, estrogen, progestational hormone or its combination.
9. preparation according to claim 8, wherein androgen is selected from: testosterone, 17-β-hydroxy-androstane ketenes, testosterone ester, methyltestosterone, testis lactone, Oxymetholone, Fluoxymesterone, androsterone, acetic acid androsterone, propionic acid androsterone, benzoic acid androsterone, androstenediol, 3-acetic acid androstenediol, 17-acetic acid androstenediol, 3,17-two acetic acid androstenediols, 17-benzoic acid androstenediol, 3-acetic acid-17-benzoic acid androstenediol, androstenedione, dehydroepiandrosterone sulfate sodium, 4-dihydrotestosterone, 5-dihydrotestosterone, dromostanolone, dromostanolone propionate, ethyl estrenol, Nandrolone Phenylpropionate, abolon, 19-Nortestosterone Frylpropionate, cyclohexane testobolin, benzoic acid nandrolone, cyclohexane-carboxylic acid nandrolone, oxandrolone and stanozolol or its any combination.
10. preparation according to claim 8, wherein estrogen is selected from: 17-β-estradiol, estradiol, oestradiol benzoate, 17-β-cycloprovera, estriol, oestrone, ethinylestradiol, mestranol, moxestrol, mytatrienediol, Polyestradiol Phosphate, quinestradol and quinestrol or its any combination.
11. preparation according to claim 1, wherein said preparation also contains at least a in gelling agent, nertralizer, buffer, NMF, wetting agent, surfactant, antioxidant, softening agent or the buffer solution.
12. preparation according to claim 1, wherein said preparation is the form of gel, lotion, creme, spray, aerosol, ointment, emulsion, suspension, liposome system, lacquer, patch, bandage or impermeable plastic wound dressing.
13. a treatment is subjected to the method for the hormone disease for the treatment of target, the method comprises to the object of this treatment of needs uses a kind of preparation, described preparation comprises at least a activating agent and the delivery vector of effective dose, and this delivery vector contains alkanol, polyalcohol and presents in an amount at least sufficient to the enhanced activity agent by the penetration enhancer of mammal skin or mucomembranous surface infiltration; Wherein said hormone disease is selected from hypogonadism, women's menopausal symptom, Female sexual dysfunction, hypothyroid dysaphrodisia and adrenal insufficiency, and wherein the administration of said preparation can reduce the frequency of at least a clinical symptoms of described hormone disease.
14. method according to claim 13, wherein said preparation there is no long-chain fatty alcohol, LCFA and long-chain fat ester, thereby avoids the bad smell and the spread effect that occur in the said preparation use procedure.
15. method according to claim 13, wherein activating agent is androgen, estrogen, progestational hormone or its combination.
16. method according to claim 15, wherein androgen is selected from: testosterone, 17-β-hydroxy-androstane ketenes, testosterone ester, methyltestosterone, testis lactone, Oxymetholone, Fluoxymesterone, androsterone, acetic acid androsterone, propionic acid androsterone, benzoic acid androsterone, androstenediol, 3-acetic acid androstenediol, 17-acetic acid androstenediol, 3,17-two acetic acid androstenediols, 17-benzoic acid androstenediol, 3-acetic acid-17-benzoic acid androstenediol, androstenedione, dehydroepiandrosterone sulfate sodium, 4-dihydrotestosterone, 5-dihydrotestosterone, dromostanolone, dromostanolone propionate, ethyl estrenol, Nandrolone Phenylpropionate, abolon, 19-Nortestosterone Frylpropionate, cyclohexane testobolin, benzoic acid nandrolone, cyclohexane-carboxylic acid nandrolone, oxandrolone and stanozolol or its any combination.
17. method according to claim 16, wherein activating agent is testosterone, and it accounts for the about 0.05%-10% of said preparation; Alkanol accounts for the about 20-65% of said preparation; Polyalcohol is propane diols, and it accounts for the about 1%-15% of said preparation; Penetration enhancer is carbitol, and it accounts for about 1 %-15% of said preparation; And wherein said preparation also contains the gelling agent that accounts for said preparation 0.01%-about 4%, account for the nertralizer of the about 0.05%-1% of said preparation and account for the water of the about 20%-65% of said preparation.
18. method according to claim 17, wherein said preparation also contains chelating agent.
19. method according to claim 16, wherein being subjected to treatment target is that the women is subjected to treatment target, and activating agent is that the treatment effective dose of testosterone and testosterone is the per 24 hours about 0.88g of about 2.2mg-.
20. method according to claim 16, wherein being subjected to treatment target is that the women is subjected to treatment target, and activating agent is that testosterone and the method can increase the serum level of testosterone to about 142 nanogram/decilitres.
21. method according to claim 16, wherein being subjected to treatment target is that the women is subjected to treatment target, and activating agent is that testosterone and the method can increase the serum level of testosterone to about 17 pik/milliliters.
22. method according to claim 15, wherein estrogen is selected from 17-β-estradiol, estradiol, oestradiol benzoate, 17-β-cycloprovera, estriol, oestrone, ethinylestradiol, mestranol, moxestrol, mytatrienediol, Polyestradiol Phosphate, quinestradol and quinestrol or its any combination.
23. method according to claim 22, wherein being subjected to treatment target is that the women is subjected to treatment target, and activating agent is that the treatment effective dose of estradiol and estradiol is about 1.5 milligrams of per 24 hours about 0.375-.
24. method according to claim 22, wherein being subjected to treatment target is that the women is subjected to treatment target, and activating agent is that the free serum concentration of estradiol and estradiol increases to about 8.8 nanograms.
25. method according to claim 22, wherein being subjected to treatment target is that the women is subjected to treatment target, and activating agent is that estradiol and the method can increase the serum level of oestrone to about 10.4 nanogram/decilitres.
26. method according to claim 22, wherein being subjected to treatment target is that the women is subjected to treatment target, and activating agent is that estradiol and the method can increase the serum level of oestrone to about 193 nanogram/decilitres.
27. method according to claim 15, wherein progestational hormone is selected from: Allylestrenol, anagestone, CA, delmadinone acetate, demegestone, Desogestrel, Dimethisterone, Dydrogesterone, lynenol, ethisterone, Etynodiol, ethynodiol diacetate, flurogestone acetate, gestodene, Gestonorone Caproate, Prohalone, 17-hydroxyl-16-methylene-progesterone, 17 Alpha-hydroxy progesterone, caproic acid 17 Alpha-hydroxy progesterone, lynestrenol, Medrogestone, Medroxyprogesterone, megestrol acetate, melengestrol, norethindrone, norethindrone acetate, norethynodrel, Norgesterone, norgestimate, norgestrel, Norgestrienone, 19-norprogesterone, Vinylnortestosterone, pentagestrone, progesterone, natural progesterone, Promegestone, Quingestrone and trengestone or its any combination.
28. method according to claim 13, wherein activating agent is the combination of two kinds of different activities agent of simultaneously administration.
29. method according to claim 15, wherein treat the women and be subjected to hypogonadism, women's menopausal symptom or the Female sexual dysfunction for the treatment of target, and said preparation contains testosterone and unites other activating agent that is selected from oestrone, estradiol, 17 β estradiol, ethinylestradiol, styptanon, two caproic acid estriol and sulfamic acid estriol.
30. method according to claim 15 is wherein treated hypogonadism or women's menopausal symptom that the women is subjected to treatment target, and activating agent comprises estradiol associating progestational hormone.
31. method according to claim 16 is wherein treated the hypogonadism that the male sex is subjected to treatment target, and activating agent comprises at least a androgen.
32. method according to claim 31, wherein said at least a androgen comprise methyltestosterone associating methandrostenolate.
33. method according to claim 13, wherein the method comprises that treatment is subjected to the adrenal insufficiency for the treatment of target, and activating agent comprises dehydroepiandrosterone (DHEA).
34. method according to claim 13, wherein alkanol is selected from ethanol, isopropyl alcohol and normal propyl alcohol, and polyalcohol is propane diols, and penetration enhancer is diethylene glycol (DEG) one alkyl ether or tetraethylene glycol furfural, alkanol mixes with water, and this mixture accounts for the about 40-of delivery vector about 98%.
35. method according to claim 13, wherein said preparation is the form of gel, lotion, creme, spray, aerosol, ointment, emulsion, suspension, liposome system, lacquer, patch, bandage or impermeable plastic wound dressing.
36. a treatment is subjected to the method for the hormone disease for the treatment of target, the method comprises to the object of this treatment of needs uses a kind of preparation, said preparation comprises at least a activating agent, condition is that this activating agent not merely is testosterone, and when activating agent is estrogen or progestational hormone, there is not respectively progestational hormone or the estrogen for the treatment of effective dose in the said preparation; And delivery vector, this delivery vector comprises aliphatic alcohol, polyalcohol and presents in an amount at least sufficient to the enhanced activity agent by the penetration enhancer of skin or mucomembranous surface infiltration; Wherein said preparation there is no long-chain fatty alcohol, LCFA and long-chain fat ester, thereby avoids bad smell and spread effect.
37. method according to claim 36, wherein the amount of delivery vector is enough to reduce or prevents that preparation from transferring on clothes or other people, makes thus preparation that the pollution of clothes is reduced to minimum.
38. method according to claim 36, wherein polyalcohol accounts for the about 1%-30% of carrier, and aliphatic alcohol accounts for the about 5-80% of carrier weight, and penetration enhancer accounts for the about 1%-30% of carrier, and water is optional is present in the carrier.
39. a transdermal or saturating mucous membrane are used the preparation of activating agent, comprise:
At least a activating agent; With
Contain alkanol, polyalcohol and present in an amount at least sufficient to the enhanced activity agent by the delivery vector of the penetration enhancer tetraethylene glycol furfural of mammal skin or mucomembranous surface infiltration.
40. described preparation according to claim 39, wherein said preparation there is no long-chain fatty alcohol, LCFA and long-chain fat ester, thereby avoids the bad smell and the spread effect that occur in the said preparation use procedure.
41. described preparation according to claim 39, wherein alkanol accounts for the about 5-80% of delivery vector weight, polyalcohol accounts for the about 1%-30% of delivery vector weight, penetration enhancer is the glycol furfural, it accounts for the about 1-30% of delivery vector weight, delivery vector promotes described at least a activating agent to be absorbed by skin or mucomembranous surface like this, thereby makes preparation from the transfer on this class surface or remove and reduce to minimum.
42. described preparation according to claim 41, wherein alkanol and water are combined to form water-alcohol mixture, it is about 98% that this water-alcohol mixture accounts for the about 40-of delivery vector weight, and alkanol accounts for the about 5%-80% of this mixture weight, and water accounts for the about 20%-95% of this mixture weight.
43. described preparation according to claim 41, wherein the weight ratio of polyalcohol and penetration enhancer is 2: 1-1: 1.
44. described preparation according to claim 41, wherein alkanol is the C that is selected from ethanol, isopropyl alcohol and normal propyl alcohol2-C
4Alcohol, polyalcohol are polypropylene glycols.
45. described preparation according to claim 39, wherein activating agent is androgen, estrogen, progestational hormone or its combination.
46. described preparation according to claim 45, wherein androgen is selected from: testosterone, 17-β-hydroxy-androstane ketenes, testosterone ester, methyltestosterone, testis lactone, Oxymetholone, Fluoxymesterone, androsterone, acetic acid androsterone, propionic acid androsterone, benzoic acid androsterone, androstenediol, 3-acetic acid androstenediol, 17-acetic acid androstenediol, 3,17-two acetic acid androstenediols, 17-benzoic acid androstenediol, 3-acetic acid-17-benzoic acid androstenediol, androstenedione, dehydroepiandrosterone sulfate sodium, 4-dihydrotestosterone, 5-dihydrotestosterone, dromostanolone, dromostanolone propionate, ethyl estrenol, Nandrolone Phenylpropionate, abolon, 19-Nortestosterone Frylpropionate, cyclohexane testobolin, benzoic acid nandrolone, cyclohexane-carboxylic acid nandrolone, oxandrolone and stanozolol or its any combination.
47. described preparation according to claim 45, wherein estrogen is selected from: 17-β-estradiol, estradiol, oestradiol benzoate, 17-β-cycloprovera, estriol, oestrone, ethinylestradiol, mestranol, moxestrol, mytatrienediol, Polyestradiol Phosphate, quinestradol and quinestrol or its any combination.
48. described preparation according to claim 39, wherein said preparation also contains at least a in gelling agent, nertralizer, buffer, NMF, wetting agent, surfactant, antioxidant, softening agent or the buffer solution.
49. described preparation according to claim 39, wherein said preparation is the form of gel, lotion, creme, spray, aerosol, ointment, emulsion, suspension, liposome system, lacquer, patch, bandage or impermeable plastic wound dressing.
50. a treatment is subjected to the method for the hormone disease for the treatment of target, the method comprises to the object of this treatment of needs uses a kind of preparation, said preparation contains at least a activating agent and delivery vector, and described delivery vector contains aliphatic alcohol, polyalcohol and presents in an amount at least sufficient to the enhanced activity agent by the penetration enhancer tetraethylene glycol furfural of skin or mucomembranous surface infiltration.
51. described method according to claim 50, wherein said preparation there is no long-chain fatty alcohol, LCFA and long-chain fat ester, thereby avoids bad smell and spread effect.
52. described method according to claim 50, wherein activating agent is androgen, estrogen, progestational hormone or its combination.
53. described method according to claim 50, the administration of described preparation can reduce the frequency of at least a clinical symptoms of described hormone disease.
54. described method according to claim 50, wherein the hormone disease comprises hypogonadism, women's menopausal symptom, Female sexual dysfunction, hypothyroid dysaphrodisia and adrenal insufficiency.
55. 4 described methods according to claim 5, the administration of wherein said preparation can reduce the frequency of at least a clinical symptoms, comprising: hectic fever, night sweat, vaginal atrophy, sexual hypoesthesia and osteoporosis, impotence, myasthenia.
56. described method according to claim 50, wherein polyalcohol accounts for the about 1%-30% of carrier, and aliphatic alcohol accounts for the about 5-80% of carrier weight, and penetration enhancer is the glycol furfural, and it accounts for about 1 %-30% of carrier, and water is optional to be present in the carrier.
57. described method according to claim 50, wherein preparation is the form of creme, ointment, gel or lotion.
58. any one described preparation of claim 1-12 or 39-49 is subjected to the purposes of medicine of the hormone disease for the treatment of target for the preparation for the treatment of.
59. 8 described purposes according to claim 5, wherein the hormone disease is selected from hypogonadism, women's menopausal symptom, Female sexual dysfunction, hypothyroid dysaphrodisia and adrenal insufficiency.
60. 8 or 59 described purposes according to claim 5, wherein activating agent is androgen, estrogen, progestational hormone or its combination.
61. 0 described purposes according to claim 6, wherein androgen is selected from: testosterone, 17-β-hydroxy-androstane ketenes, testosterone ester, methyltestosterone, testis lactone, Oxymetholone, Fluoxymesterone, androsterone, acetic acid androsterone, propionic acid androsterone, benzoic acid androsterone, androstenediol, 3-acetic acid androstenediol, 17-acetic acid androstenediol, 3,17-two acetic acid androstenediols, 17-benzoic acid androstenediol, 3-acetic acid-17-benzoic acid androstenediol, androstenedione, dehydroepiandrosterone sulfate sodium, 4-dihydrotestosterone, 5-dihydrotestosterone, dromostanolone, dromostanolone propionate, ethyl estrenol, Nandrolone Phenylpropionate, abolon, 19-Nortestosterone Frylpropionate, cyclohexane testobolin, benzoic acid nandrolone, cyclohexane-carboxylic acid nandrolone, oxandrolone and stanozolol or its any combination.
62. 0 described purposes according to claim 6, wherein estrogen is selected from: 17-β-estradiol, estradiol, oestradiol benzoate, 17-β-cycloprovera, estriol, oestrone, ethinylestradiol, mestranol, moxestrol, mytatrienediol, Polyestradiol Phosphate, quinestradol and quinestrol or its any combination.
63. 0 described purposes according to claim 6, wherein progestational hormone is selected from: Allylestrenol, anagestone, CA, delmadinone acetate, demegestone, Desogestrel, Dimethisterone, Dydrogesterone, lynenol, ethisterone, Etynodiol, ethynodiol diacetate, flurogestone acetate, gestodene, Gestonorone Caproate, Prohalone, 17-hydroxyl-16-methylene-progesterone, 17 Alpha-hydroxy progesterone, caproic acid 17 Alpha-hydroxy progesterone, lynestrenol, Medrogestone, Medroxyprogesterone, megestrol acetate, melengestrol, norethindrone, norethindrone acetate, norethynodrel, Norgesterone, norgestimate, norgestrel, Norgestrienone, 19-norprogesterone, Vinylnortestosterone, pentagestrone, progesterone, natural progesterone, Promegestone, Quingestrone and trengestone or its any combination.
64. penetration enhancer strengthens at least a activating agent of effective dose by the purposes of mammal skin or mucomembranous surface infiltration, it is characterized in that penetration enhancer is joined in the delivery vector of preparation, wherein said carrier comprises alkanol and polyalcohol, and wherein said preparation is intended to treat the hormone disease that is subjected to treatment target; Wherein said hormone disease is selected from hypogonadism, women's menopausal symptom, Female sexual dysfunction, hypothyroid dysaphrodisia and adrenal insufficiency, and the administration of said preparation can reduce the frequency of at least a clinical symptoms of described hormone disease.
65. penetration enhancer strengthens at least a activating agent of effective dose by the purposes of mammal skin or mucomembranous surface infiltration, it is characterized in that penetration enhancer is joined in the delivery vector that contains alkanol and polyalcohol, wherein said preparation there is no long-chain fatty alcohol, LCFA and long-chain fat ester, thereby avoid bad smell and spread effect, and condition is that activating agent not merely is testosterone, and when activating agent is estrogen or progestational hormone, there is not respectively progestational hormone or the estrogen for the treatment of effective dose in the said preparation.
66. penetration enhancer strengthens at least a activating agent of effective dose by the purposes of mammal skin or mucomembranous surface infiltration, it is characterized in that penetration enhancer is joined in the delivery vector of preparation, wherein this carrier comprises alkanol and polyalcohol, and to be tetraethylene glycol furfural and its be present in the preparation to be enough to improve the amount of activating agent by skin or mucomembranous surface infiltration penetration enhancer.
67. a treatment is subjected to treatment target to be subjected to the kit of activating agent serum level in the treatment target with increase, comprise: contain at least a activating agent of effective dosage and the preparation of delivery vector, this delivery vector comprises alkanol, polyalcohol and presents in an amount at least sufficient to the enhanced activity agent by the penetration enhancer of mammal skin or mucomembranous surface infiltration, wherein said preparation there is no long-chain fatty alcohol, LCFA and long-chain fat ester, thereby avoids being derived from the said preparation use procedure bad smell and the spread effect of this class compound; With
Container, this container are equipped with described preparation and comprise the distributor that discharges as required or use the preparation of predetermined dosage or volume.
68. 7 described kits according to claim 6, wherein said distributor discharge predetermined dosage or volume after enabling automatically being triggered by the user.
69. 7 described kits according to claim 6, wherein said distributor is pump.
70. a transdermal or saturating mucous membrane are used the preparation of activating agent, comprise:
At least a activating agent that contains dehydroepiandrosterone (DHEA); With
Contain alkanol, polyalcohol and present in an amount at least sufficient to the enhanced activity agent by the delivery vector of the penetration enhancer of mammal skin or mucomembranous surface infiltration.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610168951.9A CN105853396A (en) | 2003-03-11 | 2004-03-11 | Methods and formulations for transdermal or transmucosal application of active agents |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US45360403P | 2003-03-11 | 2003-03-11 | |
US60/453,604 | 2003-03-11 | ||
US60/510,613 | 2003-10-10 | ||
US10/798,111 | 2004-03-10 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN201610168951.9A Division CN105853396A (en) | 2003-03-11 | 2004-03-11 | Methods and formulations for transdermal or transmucosal application of active agents |
Publications (1)
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CN1997357A true CN1997357A (en) | 2007-07-11 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CNA2004800051239A Pending CN1997357A (en) | 2003-03-11 | 2004-03-11 | Uses and formulations for transdermal or transmucosal application of active agents |
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CN (1) | CN1997357A (en) |
ZA (1) | ZA200505985B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102018671A (en) * | 2011-01-05 | 2011-04-20 | 浙江大学 | Estradiol transdermal spray and preparation method thereof |
CN103327962A (en) * | 2011-01-26 | 2013-09-25 | 辉凌公司 | Testosterone formulations |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0811381A1 (en) * | 1996-06-06 | 1997-12-10 | Permatec N.V. | A novel composition for transdermal administration of an estrogen, a progestin or a mixture thereof |
-
2004
- 2004-03-11 CN CNA2004800051239A patent/CN1997357A/en active Pending
-
2005
- 2005-07-26 ZA ZA200505985A patent/ZA200505985B/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0811381A1 (en) * | 1996-06-06 | 1997-12-10 | Permatec N.V. | A novel composition for transdermal administration of an estrogen, a progestin or a mixture thereof |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102018671A (en) * | 2011-01-05 | 2011-04-20 | 浙江大学 | Estradiol transdermal spray and preparation method thereof |
CN102018671B (en) * | 2011-01-05 | 2012-07-25 | 浙江大学 | Estradiol transdermal spray and preparation method thereof |
CN103327962A (en) * | 2011-01-26 | 2013-09-25 | 辉凌公司 | Testosterone formulations |
CN103327962B (en) * | 2011-01-26 | 2016-04-27 | 辉凌公司 | Testosterone preparation |
TWI564029B (en) * | 2011-01-26 | 2017-01-01 | 菲瑞茵公司 | Testosterone formulations |
Also Published As
Publication number | Publication date |
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ZA200505985B (en) | 2006-05-31 |
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