CN1097987A - The Hormone Replacement Therapy of transdermal - Google Patents
The Hormone Replacement Therapy of transdermal Download PDFInfo
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- CN1097987A CN1097987A CN93121739A CN93121739A CN1097987A CN 1097987 A CN1097987 A CN 1097987A CN 93121739 A CN93121739 A CN 93121739A CN 93121739 A CN93121739 A CN 93121739A CN 1097987 A CN1097987 A CN 1097987A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
Abstract
The invention provides a kind of method that the women who needs hormone replacement therapy is treated, this method comprise to above-mentioned women's transdermal administration a series of alternative with about one to the leading hormonal activity stage of about four days estrogen and about one to the leading active stage of about four days progestogen, the leading active stage of above-mentioned estrogen is by using a kind of transdermal estrogen material separately or using a kind of transdermal estrogen material and transdermal progestogen material is formed, and the leading active stage of above-mentioned progestogen is formed by using a kind of transdermal progestogen material and a kind of transdermal estrogen material, for required leading activity is provided, make the progestogen amount of substance alternately increase and alternately reduce in the leading active stage of estrogen in the leading active stage of progestogen.
Description
This application is the part continuation application of the U. S. application (application number 07/974182) of proposition on November 10th, 1992, the latter is that the application number that proposed on April 27th, 1992 is the division of 07/874016 application, application number is that 07/874016 application then is that the application number that proposes April 26 nineteen ninety is the existing United States Patent (USP) 5108995 of 07/515691() continuation application, the latter then is again that application number that JIUYUE in 1988 proposed on the 22nd is 07/247861 continuation application.
The present invention relates to Hormone Replacement Therapy to menopause or OO women.Especially, the present invention relates to a kind of dosage form relevant and method with transdermal release.
In the women of menopause, the get the nod reason of several aspects of controversies in hormone replacement in the elderly.It is excited that known controversies in hormone replacement in the elderly slows down heat, and slowing down of this excitement and night sweat improves sleep pattern and be of value to the good emotion of patient's tool.The estrogen replacement method prevents the disappearance of calcium in the postclimacteric skeleton (especially spinal column), and the prevention impact is fractured and lost weight.Now existing several the long-term estrin treatments of research report are also relevant with the minimizing of the osteoporotic fracture incidence rate of the forearm of classics and hip.The estrogenic beneficial effect of another kind of life-time service is that to reduce perhaps be the lethal danger of ischemic heart disease by the concentration change mediation of blood lipoprotein.The estrogen replacement method also demonstrates the health that can improve vascularity and vaginal mucosa and urethra.Taking estrogenic unique principal risk factor of slowing down the symptoms of menopause required dosage is the danger of endometrial overstimulation and the carcinoma of endometrium of increasing.Added in every month and showed in 13 days with progestogen and can make endometrium avoid estrogenic stimulation.
Progestogen are protected endometrium by the estradiol receptor concentration that reduces nuclear, and therefore reduce the estrogen bioavailability that causes the resisting mitosis effect and reduce the synthetic nuclear of DNA.Progestogen can also increase the activity of endometrial oestradiol-17-dehydrogenase, and it is estrone that this enzyme makes estradiol metabolite, and estrone is a kind of low estrogen of rendeing a service.Yet, demonstrated care to the potential side effect of progestogen in suppressing HDL-C concentration.This cholesterol moiety demonstrates protective effect to ischemic heart disease and atherosclerosis.Reduce the HDL cholesterol by progestogen and can offset the long-term beneficial effect that estrogen reduces myocardium not normal disease incidence rate.Other side effect of progestogen comprises acne, uncomfortable in chest, oppressive and irritability.Because the side effect of progestogen is dose dependents, therefore the dosage of the progestogen that use with postclimacteric controversies in hormone replacement in the elderly should be to obtain the required lowest dose level of endometrium protective effect.
Present Hormone Replacement Therapy is added with progestogen by successive (every day or cycle) (as every month 1-25 days) estrogen administration and every month 10-13 days (as every month 13-25 days) and constitutes.This alternative medicine instructions about how to take medicine effectively prevent symptoms of menopause and protect endometrium to exempt the development of hypertrophy or adenocarcinoma simultaneously.Yet the cyclic application progestogen cause regular retirement hemorrhage or intermittent hemorrhage in the women of 65-75%.This retirement is hemorrhage not to be subjected to the patient to welcome also may cause some problem.Also owing to take progestogen, so side effect and metabolic these effects of pair of needing the progestogen of high dose to come antagonism to produce higher chance are possible 13-16 days of the estrin treatment of no antagonism with endometrial hyperplasia and estrogen and progesterone receptor inducing action.Though the newer continuous low dose estrogen and the Hormone Replacement Therapy of progestogen instructions about how to take medicine can avoid retirement property hemorrhage, in these therapies, use every day progestogen can induce consume the estrogen cause atrophy of endometrium and progesterone receptor the two, this atrophy of endometrium is relevant with break-through bleeding.Because known postmenopausal women's abnormal bleeding is relevant with carcinoma of endometrium, must use D﹠amp usually; C sees the loose situation of looking into the endometrium print.
Using progestogen every day also makes people be concerned about estrogen the advantageous effect of HDL cholesterol metabolism will be had a negative impact to the minimizing of HDL cholesterol.
In United States Patent (USP) 5108995; the applicant has described a kind of instructions about how to take medicine; this instructions about how to take medicine be by short-term take progestogen and alternately short-term need not or reduce the progestogen consumption; thereby can protect endometrium preferably with the low dosage progestogen, make it avoid the endometrial hyperplasia relevant and the danger of adenocarcinoma with estrogen.This prescription is intermittently used the progestogen of low dosage in the whole middle of the month, and obtained following result: it is hemorrhage to have eliminated retirement in fact; Estrogen activity discontinuity increases; And stimulate the endometrium growth and excite progesterone receptor.Consequently endometrium is responsive more to progestin subsequently, and progestin subsequently comes limiting growth by reducing estrogen receptor and increasing by 17 beta-hydroxysteroid dehydrogenases.The interaction of progestogen and progesterone receptor induces endometrial secretion to change, and this variation produces denser substrate and uterine veil stability.Answer to leading relatively estrogen activity then excites estrogen and progesterone receptor once more and recovers the sensitivity of endometrium to progestogen.This push-and-pull activity estrogen that depends on natural law and progestin among a small circle in keep endometrium active and kept and in fact do not produce stable endometrium breakthrough or that retirement is hemorrhage.This prescription has produced progestogen action preferably with a spot of progestogen.The dosage of these progestogen is compared obvious minimizing with the preparation that contains constant daily dose progestogen.For the Hormone Replacement Therapy of ovarian disease, total steroid dosage can be similar or lower than it with the dosage of progestogen circulation instructions of taking to this estrogen.The minimizing of progestin dosage produces less adverse effect to the HDL cholesterol levels.
The transdermal drug delivery systme is known in the art.Some patent in this field relates to the hormone prescription that is used for various purpose transdermal release.This class patent is exemplified below:
United States Patent (USP) 4816258(1989 March 28 of people such as Nedberge is open) a kind of ethinyl estradiol of transdermal administration and the pharmaceutical formulation of left-handed-18-methylnorethindron disclosed, it contain a kind of substrate that contains steroid and a kind of promote the dermal osmosis amount-olein.
United States Patent (USP) 5122382(1992 June 16 of people such as Gail is open) a kind of compositions of transdermal administration is disclosed, it contains a kind of estrogen and ST-1435.This prescription discharges a certain amount of steroid and contains a kind of dermal osmosis accelerator every day.
United States Patent (USP) 5023084(1991 June 11 of people such as Chien is open) and United States Patent (USP) 4906169(1992 open March 6) described during contraception that estrogen and progestogen are incorporated into a transdermal unit dose fills a prescription, this unit dose contains a supporting film, promptly a kind of polymeric film that contains hormone and adhered layer.
United States Patent (USP) 4624665(1986 November 25 is open), 4687481(1987 is open August 18), 4834978(1989 is open May 30), 4810499(1989 is open March 7) and 4927687(1990 May 22 openly) a kind of transdermal release system described, it is said that it can prevent because of the break dosage of the release medicine that causes of the chance of reserve part inclines and releases, and guarantee that medicine effectively and the release of prolong drug (especially Bi Yun steroid).Suitable steroid comprises norethindrone, 18-methylnorethindron, estradiol, levogyrate-18 methyl polysulfide promise ketone and 17a-ethynylestradiol-3-methyl ester, mestranol.
The benefit of having found the main existence of transdermal release system be its not oral administration discharge, hormone can be walked around liver when " at first by " whole machine body.Gastrointestinal absorption needs through the liver transhipment, and medicine carries out metabolism at liver, before circulating fully for the first time, brings medicine into target organ (that is: uterus, heart, skeleton, central nervous system etc.).The benefit of avoiding medicine to enter liver is to use than the medicine of low dosage to obtain the curative effect of same degree at target tissue to the patient, lowers the metabolic effect (as the variation of coagulation factor, glucose metabolism, fat etc.) that does not comply with one's wishes that oral route will produce thus.(see Transdermal Hormone Replaoement, M.I.Whitehead and L.Sohenkel, 1990.) also consider feel sick and gastrointestinal upset relevant in the time of can avoiding oral without stomach with estrin treatment.(see Transdermal Administration of Oestrogen/Progestin Hormone Replacement Therapy, M.I.Whitehead et al, The Lancet 310-312, Feb, 10,1990.）
It is believed that to continue that the transdermal release system is more oral than the every day usually once to provide more constant stable state hormone plasma concentration, and do not have peak and paddy concentration.May show also that this " first by " phenomenon is the impercipient basis of transdermal release approach.This deficiency of finding is exactly the useful variation (increasing as stimulating the HDL cholesterol) that in fact estrogen induced some lipoprotein, and these effects may be the inductive results of liver enzyme.Can foretell the beneficial effect that can reduce these medicines that contacts that reduces liver and medicine.
Yet, whether adopt oral or transdermal to carry out to consider in the hormone therapy factor aspect several the decision patient, in general, the useful factor of transdermal means is comprised usually medicament patient hypersensitive, is not obedient to or forgetful patient, they have any problem to taking medicine every day, and the oral estrogen treatment has gastrointestinal upset and oral route is replied deficiency.On the contrary, find that the patient has that high-risk cardiovascular disease, blood fat are too high, under the situation of skin allergy and dermatopathy, selecting oral form may be preferably.
It is believed that instructions about how to take medicine, adopt the transdermal release system will improve the advantage of basic instructions about how to take medicine self because of the benefit of the transdermal route of precognition by United States Patent (USP) 5108995.In addition, find that also the transdermal release system work of the hormone that is suitable for this delivery pathways most of selection gets best especially.
Under a kind of form, the invention provides a kind of method that the women who needs hormone replacement therapy is treated, it comprises to above-mentioned women with about one to four day leading hormonal activity alternating phases, a kind of medicine patch therapeutic scheme series (Pharmaceutical Patchregimen series) that transdermal administration is arranged, the described stage is selected from leading active stage of estrogen and leading active stage of progestogen, above-mentioned each stage includes a kind of according to active patch that use and that take off of specific dominated stage at least, wherein the leading active stage of estrogen is contained a certain amount of material that is enough to promote the demonstration estrogen activity of progesterone receptor development in above-mentioned women's endometrium, or contains a certain amount of be enough to the promote material of the demonstration estrogen activity of progesterone receptor development in above-mentioned women's endometrium and the material of a certain amount of demonstration progestin; And wherein the leading active stage of progestogen is contained material and a certain amount of material that is enough to antagonism estrogen to the demonstration progestin of above-mentioned women's endometrium effect of a certain amount of demonstration estrogen activity, but and estrogen and progestogen be selected from the hormone of applied dermally.
The invention provides a kind of method that the women who needs hormone replacement therapy is treated, it comprises to above-mentioned women's transdermal administration therapeutic scheme medicine series patch, this patch is with about one to four day alternative arrangement and use of leading hormonal activity stage, the described stage is selected from leading active stage of estrogen and leading active stage of progestogen, above-mentioned each stage includes a kind of patch of using and take off according to specific dominated stage activity at least, the leading active stage of described estrogen is by using a kind of transdermal estrogen material separately or using a kind of transdermal estrogen material and a kind of transdermal progestogen material is formed, and the leading active stage of described progestogen is by using a kind of transdermal progestogen material and a kind of transdermal estrogen material is formed, the progestogen amount of substance alternately the leading active stage of progestogen increase and in the leading active stage reduction of estrogen so that required leading activity to be provided.
On the other hand, the invention provides and a kind ofly carry out the pharmaceutical preparation that the women of hormone replacement therapy uses to needs, it comprises a kind of patch therapeutic scheme series, this patch is with about one to four day alternative arrangement and use of leading hormonal activity stage, described each stage is selected from leading active stage of estrogen and leading active stage of progestogen, above-mentioned each stage includes a kind of according to active patch that use and that take off of specific dominated stage at least, the leading active stage of described estrogen is made up of the estrogen substance of independent a kind of transdermal or a kind of estrogen substance of transdermal and a kind of progestogen material of transdermal, and the leading active stage of described progestogen is made up of a kind of transdermal progestogen material and a kind of transdermal estrogen material, and the progestogen amount of substance alternately increases and reduces so that required leading activity to be provided in the leading active stage of estrogen in the leading active stage of progestogen.
The present invention provides a kind of packing that comprises the drug transdermal patch therapeutic scheme that is applied to the women that need carry out hormone replacement therapy with another kind of form, wherein should packing form by medicine patch therapeutic scheme series, this patch is with about one to four day alternative arrangement and use of leading hormonal activity stage, described each stage is selected from leading active stage of estrogen and leading active stage of progestogen, above-mentioned each stage includes a kind of patch of using and taking off according to specific dominated stage activity at least, described estrogen is leading, and the stage of living is made up of the estrogen substance of independent a kind of transdermal or a kind of estrogen substance of transdermal and a kind of progestogen material of transdermal, and the leading active stage of described progestogen is made up of a kind of transdermal progestogen material and a kind of transdermal estrogen material, and the progestogen amount of substance alternately increases and reduces so that required leading activity to be provided in the leading active stage of estrogen in the leading active stage of progestogen.
In a preferred form of the invention, estrogen and progestogen are selected from transdermal estrogen and progestogen, it is about 25 μ g/ days to about 150 μ g/ days that the activity level that they provide is equivalent to transdermal release speed, more preferably from about 100 μ g/ days 17-β estradiol and about 250 μ g/ days to about 500 μ g/ days piperazine estrone sulfate and about 15 μ g/ days, 3-ketone-Desogestrel (3-Keto-desogestrel) of 25 μ g/ days to about 1000 μ g/ days norethindrone acetate or about 5 μ g/ days to about 150 μ g/ days more preferably from about, condition is with respect to the progestogen of estrogen dominated stage in the dominated stage, and progestogen increase to produce required advantage.
In a preferred form of the invention, first kind of patch for example is prepared into coherent matrix type or drug reservoir (reservoir) type (ethanol glue), and the 17-β estradiol that it contains capacity is to provide about 25 μ g/ days to about 100 μ g/ days transdermal release rate.Prepare second kind of patch, coherent matrix or drug reservoir (ethanol glue) type, the 17-β estradiol that it contains capacity with the norethindrone acetate (NETA) that provides above-mentioned rate of release and capacity with transdermal release speed that about 25 μ g/ days to about 1000 μ g/ days NETA is provided, more preferably from about 75 μ g/ days to about 500 μ g/ days, most preferably from about 75 μ g/ days to about 300 μ g/ days.Under 17-β estradiol and the bonded situation of 3-ketone-Desogestrel, the amount of 17-β estradiol maintains the same amount of listing as above-mentioned, and the amount of 3-ketone-Desogestrel is enough to provide about 5 μ g/ days to about 150 μ g/ days, more preferably 25 μ g/ days to about 150 μ g/ days transdermal release speed.So that being provided, the required order of advantage of the present invention uses these patches.
The estrogen that can be used as a composition in the instructions about how to take medicine of the present invention can be the available estrogen that can be absorbed by percutaneous of any classics.Typically, estrogen can be selected from synthetic and natural estrogen.Synthetic estrogen can be selected from, as alkynyl estradiol, micronized estradiol, 17-β estradiol, 1,17a-ethynylestradiol-3-methyl ester, mestranol, estradiol valerate, 11-nitroso-group estradiol, 7-Alpha-Methyl-11-nitroso-group-estradiol, piperazine estrone sulfate and quinestrol (quinestranol).Make us the interested 17-of having α alkynyl estradiol and ester and ether especially.Preferred estrogen is 17-β estradiol.
The progestogen component can be the reactive compound of any progestogenic.Therefore, progestogen can be selected from progesterone, 17-hydroxyprogesterone, dihydroprogesterone, medroxyprogesterone acetate, norethindrone, norethindrone acetate, Norethynodrel, ethynodiol diacetate (ethynodioldiacetate), methylnorethindron, l-norgestrel, gestodene (gestodene), δ-15-l-norgestrel, norgestimate, 17-and remove acetyl norgestimate, nomegesterol, nesterone, Desogestrel (desogestrel) and 3-ketone-Desogestrel.Preferred progestogen are norethindrone acetate and 3-ketone-Desogestrel.
The conventionally test method of the mensuration percutaneous permeability that can adopt by this area is determined the selection of the hormone of optimum transdermal release.The most frequently used vitro skin permeate chamber that is to use hairless mouse skin or people's corpse skin.Comprise many data about these tests in the document, main literature is as follows:
a） Kao J，Hall J.Skin Absorption and Cutaneous First Pass Metabolism of Topical Steroids：In Vitro Studies with Mouse Skin in Organ Culture.J Pharmacol Exp Ther 241（2），pp 482-487，1987;
b） Tojo K，Lee C.A Method for Predicting Steady-state Rate of Skin Penetration In Vivo.J Invest Derm 92（1），pp105-108，1989;
c） Liu P，Higuchi WI，Song W，Kurihara-Bergstrom T，Good WR Quantitative Evaluation of Ethanol Effects on Diffusion and Metabolism of β-Estradiol in Hairless Mouse Skin.Pharm Res 8（7），pp865-872，1991;and
d） Roy S，Gutierrez M，Chiang C.Permeation of Norethindrone， Norethindrone Acetate and Norethindrone Diacetate Through Cadaver Skin.Pharm Res Suppl 6，p 1168，1989.
In selecting suitable hormone, dermal osmosis and transdermal release rate therefore are important, and the stability of hormone also is a factor in the prescription.Can estimate or measure stability with two kinds of basic modes: promptly visual sight is looked into and dissolution in vitro.
Usually the two all carries out visual inspection to crystal formation both macro and micro level.Because in dissolution in vitro, test be the release in vitro rate of this area standard.In general, when meeting these standards, just obtain required transdermal release rate easily.
Each stage can comprise about one to four day, but does not need twenty four hours really these days.Significantly, the available time retractility that provides is limited because there is not the oversize retirement property that will cause of the time of hormone hemorrhage, for example, a stage of three days, hour sum can be 66 or 78(relative with 72 hours).Preferred instructions about how to take medicine adopt and comprise about three days and about four days stage.Other combination, as two and three or one and three, or three and three, or two and four, or one and four also can be used.
In general, hormone replacement therapy does not interruptedly carry out.Yet, the also example that might need interrupt, in this case, the plaster agent contains in placebo or the packing can include any other non-hormone agents.The example of suitable selectable non-hormone agents comprises vitamin, for example iron supplement agent.
In general, the amount that is incorporated into estrogen in the prescription of the present invention and progestogen depends on the activity of selected estrogen and progestogen.In prescription of the present invention, estrogen is continuous administration, in other words, always contains estrogen in the prescription, and in order to produce required estrogen or progestogen advantage, adjust estrogenic level up or down.The type of estrogen or progestogen is depended in the selection of amount, because every kind of hormone all has himself specific activity.
Typically, the estrogen activity amount (in estrogenic activity) of per unit dosage is equivalent to the scope of minimum about 0.3mg piperazine estrone sulfate to the most about 2.5mg piperazine estrone sulfate in the prescription of describing in the United States Patent (USP) 5108995.Per unit dosage progestin amount (in the activity of progestogen) is equivalent to minimum about 0mg and arrives the norethindrone of the most about 5mg.
Some is preferably as follows in conjunction with comprising:
1. the norethindrone of the 0.75mg piperazine estrone sulfate of the 0.75mg piperazine estrone sulfate of three unit dose and three unit dose and 0.35mg alternately.
2. the norethindrone of the 0.75mg piperazine estrone sulfate of the norethindrone of the 0.75mg piperazine estrone sulfate of three unit dose and 1.5mg and three unit dose and 0.35mg alternately.
Can determine that the grade of transdermal works as dosage by the blood levels measurement of hormone.In general, consider the release rate of patch prescription of the present invention, think that the measurer of hormone has following feature.At first, each stage is made up of a single card usually, although also available several patches are formed a stage.In other parameter, the size of patch depends on the length in this stage and the effectiveness of hormone.For example, the transdermal release speed that provides of the patch of present available 17-β estradiol is about 50 μ g/ days.In this embodiment, the amount of 17-β estradiol is 4mg, and the size of patch is about 18cm
2, the actual storage powder (reservoir) that it has is about 10cm
2, containing under two kinds of hormones plaster situation of (as containing 17-β estradiol and norethindrone acetate) at potion, the amount of the two will be respectively 10mg and 30mg, and the surface area of this patch will be 26cm
2, the transdermal release speed that provides is 17-β estradiol 50 μ g/ days and norethindrone acetate 250 μ g/ days.3-ketone-Desogestrel is more effective progestogen, and the amount that it is incorporated in the patch can be that about 4mg is to about 30mg, so that required transdermal release speed every day to be provided.The scope of 17-β estradiol can from about 1mg to about 10mg(the coherent matrix storehouse, this amount can change in the patch of another type), can be about 10mg to about 100mg for this scope of norethindrone acetate.
Above-mentioned combination also can be formed the group of three days or four days, serves as beginning and is end with another group with three days groups or four days groups.
Commercially available transdermal patch has many, and they can be used for this method.For purposes of the invention, should remember the most important thing is that the order of using is strict, and the application that the arrangement of this patch or its pre-determine order can influence gained advantage of the present invention surely.Two these class examples as herein described are only presented for purposes of illustration, also can use other patch.
In a kind of known system, use the acrylic copolymer based matter of the solid-state adhesion of the hormone that contains dissolved form.This system comprises uses one deck elasticity support foil, and this paper tinsel can contain just like polyethylene terephthalate.Discharge lining and form another layer (linking to each other) with this adhesion coating.With a kind of inflatable polysaccharide, galactomannan is added to the adhesiveness of improving in the coherent matrix between the skin of patch surface and aquation during the whole application, and alleviates the stimulation that closure function causes.Preferably, support foil, drug matrices and release lining are made a trilaminar thin slice.At present, the trade mark of the commodity of this commercially available class character is SYSTEN TIS.
Another kind of available goods marks is ESTRADERM.
ESTRADERM
TMBe a kind of estradiol transdermal system of using with contact skin, this System Design is for to discharge estradiol continuously by a kind of speed limit film.This ESTRADERM
TMSystem comprises five layers: with outside in order is supporting layer, drug reservoir, controlling diaphragm, adhesion layer and protective layer.The qualitative composition of this ESTRADERM drug reservoir is estradiol, ethanol and hydroxypropyl cellulose.
As explain already art, select the patch of any suitable form to be used for transdermal administration.The United States Patent (USP) 4668232 of Cordes and Wolff is described the another kind of known patch that is used for the hormone prescription administration in detail, and the disclosure text is incorporated herein by reference.In this piece United States Patent (USP), described system is one or four coating systems, and it comprises an impermeable supporting layer, or cover layer; One with the drug reservoir layer of supporting layer or cover layer adjacency; A permeable adhesion coating of hormone and a protective layer of before using this medicament, taking off.As previously mentioned, also can use three coating systems that comprise a supporting layer, a drug matrices adhesion coating and a release lining.
The drug reservoir of available ethanol glue type prepares estrogen patch of the present invention.The amount of hormone (preferred 17-β estradiol) is 4mg.The surface area of this patch is about 18cm
2In appearance, it can be to have to comprise about 10cm
2The circle of the drug reservoir of patch.The transdermal release speed of the 17-β estradiol that this patch generally provides is about 10 μ g/ days.
For example, ethanol glue type drug reservoir that can a certain amount of with containing (the 17-β estradiol and the 30mg norethindrone acetate that comprise 10mg) prepares a kind of estrogenic/progestogenic patch.Total contact area of this kind patch will be about 20cm
2, and its outward appearance is the shape of glasses that two continuous Drug Storages are arranged, and contains two kinds of medicines in each storehouse.The transdermal release speed that this patch generally provides is about 50 μ g/ days 17-β estradiol and about 250 μ g/ days norethindrone acetates.
Typically, said preparation is applied to postclimacteric patient and/or those have the people of activity symptom.
These patches can be packaged in as in the carton, comprise the Menorest of a certain amount of transdermal and the 17-β estradiol and the norethindrone acetate patch of a certain amount of transdermal in the carton.Each patch can be enclosed in the protectiveness groove separately.
In this embodiment, the first Menorest that pastes can use a couple of days (although be not must from this stage) as required, takes this patch off and uses a 17-β estradiol as required and norethindrone patch a couple of days.Take second kind of patch then off and use another Menorest, the rest may be inferred.Treat normally successive and do not interrupt.Use although these subsides can be prepared into, changed each patch in per three or four days according to specific use usually with any natural law combination in any one to four day time limit.
Use each new patch at different parts.The advantageous applications position is cleaning, drying and the unmarred skin surface of the following body trunk portion of stringcourse.Preferred buttock, hip or abdominal part, because during body kinematics, the skin wrinkle at these positions are minimum.
In the following example, listed specific embodiments of the present invention.These example intentions are set forth the present invention and are limited the present invention never in any form.Except as otherwise noted, all umber and percentage number average are by weight.
Embodiment 1
Use 17-β estradiol (the 100 μ g/ days) transdermal patch of three day phase and alternately use with the 17-β estradiol (100 μ g/ days) and the transdermal patch of norethindrone (0.35mg/ days) of three day phase.Alternately and use these patches incessantly.
Embodiment 2
Use 17-β estradiol (the 100 μ g/ days) transdermal patch of three day phase and alternately use with the 17-β estradiol (100 μ g/ days) and the transdermal patch of norethindrone acetate (0.35mg/ days) of three day phase.Alternately and use these patches incessantly.
Embodiment 3
Use 17-β estradiol (the 50 μ g/ days) transdermal patch of three day phase and alternately use with the 17-β estradiol (50 μ g/ days) and the transdermal patch of norethindrone acetate (0.15mg/ days) of three day phase.Alternately and use these patches incessantly.
Embodiment 4
Use 17-β estradiol (the 25 μ g/ days) transdermal patch of three day phase and alternately use with the 17-β estradiol (25 μ g/ days) and the transdermal patch of norethindrone acetate (0.50mg/ days) of three day phase.Alternately and use these patches incessantly.
Embodiment 5
The ethanol glue type drug reservoir that employing comprises the 4mg17-β estradiol of having an appointment prepares and has about 18cm
2The estrogen patch of surface area.Its outward appearance is to have to comprise about 10cm
2The annulus of the drug reservoir of patch.The transdermal release speed of the 17-β estradiol that this patch generally provides is about 10 μ g/ days.
The ethanol glue type drug reservoir that employing contains a certain amount of hormone (comprising 10mg17-β estradiol and 30mg norethindrone acetate) prepares the estrogenic/progestogenic patch.Total contact surface of this patch is 20cm
2The outward appearance of this patch is the shape of glasses with two continuous drug reservoir, and each drug reservoir contains two kinds of medicines.The transdermal release speed that this class patch generally provides is 50 μ g/ days 17-β estradiol and 250 μ g/ days norethindrone acetates.
This patch is packaged in the carton, includes the Menorest of a certain amount of transdermal and the 17-β estradiol and the norethindrone acetate patch of a certain amount of transdermal in the carton.Each patch is sealed in the protectiveness groove separately.
Use and firstly pasted Menorest three days (though be not must from this stage) as required, take off this patch, use one and pasted 17-β estradiol and norethindrone acetate patch four days.Take off second kind of patch then, use another Menorest again, the rest may be inferred.Treat continuously and uninterruptedly.Use each new patch at different parts.The advantageous applications position is cleaning, drying and the unmarred skin surface of the following body trunk of stringcourse.Preferred buttock, hip or abdominal part, because during body kinematics, the skin wrinkle at these positions are minimum.
Though described the present invention according to specific embodiments, this area professional is appreciated that and is not deviating under the spirit and scope of the present invention that various changes can be made and corresponding substituting.In addition, can carry out many adjustment for adapting to particular case, material or component, method, process or step, perhaps these adjustment have embodied spirit of the present invention truly and have not deviated from it and instruct substantially.
Claims (58)
1, a kind of method that the women who needs hormone replacement therapy is treated, this method comprises a kind of medicine patch therapeutic scheme series of being arranged with about one to four day leading hormonal activity alternating phases transdermal administration to above-mentioned women, the above-mentioned stage is selected from leading active stage of estrogen and leading active stage of progestogen, above-mentioned each stage is contained at least a patch, use or take off this patch according to specific dominated stage activity, the leading active stage of above-mentioned estrogen is by using a kind of transdermal estrogen material separately or using a kind of transdermal estrogen material and a kind of transdermal progestogen material is formed, and the leading active stage of above-mentioned progestogen is by using a kind of transdermal progestogen material and a kind of transdermal estrogen material is formed, for required leading activity is provided, make the progestogen amount of substance alternately increase and reduce in the leading active stage of estrogen in the leading active stage of progestogen.
2, method as claimed in claim 1, wherein each stage is used single patch.
3, method as claimed in claim 1, wherein each stage is used a plurality of patches.
4, method as claimed in claim 1, estrogen wherein and progestogen are selected from such estrogen and progestogen, the activity level that it provided is equivalent to the transdermal release speed of the vinegar alkynes promise of about 25 μ g/ days to about 100 μ g/ days 17-β estradiol and about 25 μ g/ days to about 1000 μ g/ days, condition is with respect to the estrogen dominated stage, progestogen increased in the progestogen dominated stage, to produce required advantage.
5, method as claimed in claim 1, the estrogen dominated stage is wherein contained a certain amount of 17-β estradiol that is enough to provide about 25 μ g/ days to about 100 μ g/ days transdermal release speed, and this progestogen dominated stage is contained and a certain amount ofly is enough to provide about 25 μ g/ days to the 17-β estradiol of about 100 μ g/ days transdermal release speed and a certain amount of norethindrone acetate that is enough to provide about 25 μ g/ days to about 1000 μ g/ days transdermal release speed.
6, method as claimed in claim 5, the estrogen dominated stage wherein comprises about three days and the leading active stage of progestogen comprises about four days.
7, method as claimed in claim 5, the estrogen dominated stage wherein comprises about four days and the progestogen dominated stage comprises about three days.
8, method as claimed in claim 5, wherein the amount of vinegar acetylenic ketone is enough to provide about 75 μ g/ days to about 500 μ g/ days transdermal release speed.
9, method as claimed in claim 5, wherein the amount of norethindrone acetate is enough to provide about 75 μ g/ days to about 300 μ g/ days transdermal release speed.
10, method as claimed in claim 1, the estrogen dominated stage is wherein contained a certain amount of 17-β estradiol that is enough to provide about 25 μ g/ days to about 100 μ g/ days transdermal release speed, and this progestogen dominated stage is contained and a certain amount ofly is enough to provide about 25 μ g/ days to the 17-β estradiol of about 100 μ g/ days transdermal release speed with a certain amount ofly be enough to provide the 3-ketone-Desogestrel that arrived about 150 μ g/ days transdermal release speed in about 5 μ g/ days.
11, as the method for claim 10, wherein the estrogen dominated stage comprises about three days and the progestogen dominated stage comprises about four days.
12, as the method for claim 10, wherein the estrogen dominated stage comprises and being equivalent to about four days and the progestogen dominated stage comprises about three days.
13, as the method for claim 10, wherein the amount of 3-ketone-Desogestrel is enough to provide about 25 μ g/ days to about 150 μ g/ days transdermal release speed.
14, method as claimed in claim 1, the estrogen dominated stage is wherein contained a certain amount of 17-β estradiol that is enough to provide about 50 μ g/ days transdermal release speed, and this progestogen dominated stage is contained a certain amount of 17-β estradiol and a certain amount of vinegar acetylenic ketone that is enough to provide about 300 μ g/ days transdermal release speed that is enough to provide about 50 μ g/ days transdermal release speed.
15, as the method for claim 14, the estrogen dominated stage wherein comprises about three days and the progestogen dominated stage comprises about four days.
16, as the method for claim 14, the estrogen dominated stage wherein comprises about four days and the progestogen dominated stage comprises about three days.
17, method as claimed in claim 1, the estrogen dominated stage is wherein contained a certain amount of 17-β estradiol that is enough to provide about 50 μ g/ days transdermal release speed, and this progestogen dominated stage is contained a certain amount of 17-β estradiol and a certain amount of norethindrone acetate that is enough to provide about 150 μ g/ days transdermal release speed that is enough to provide about 50 μ g/ days transdermal release speed.
18, as the method for claim 17, the estrogen dominated stage wherein comprises about three days and the progestogen dominated stage comprises about four days.
19, as the method for claim 17, the estrogen dominated stage wherein comprises about four days and the progestogen dominated stage comprises about three days.
20, a kind of drug packages that comprises the transdermal patch usage that is applied to the women who needs hormone replacement therapy, wherein should packing by at about one day to four days leading hormonal activity alternating phases.Middle plaster agent therapeutic scheme series of arranging is formed, the above-mentioned stage is selected from leading active stage of estrogen and leading active stage of progestogen, above-mentioned each stage is contained at least a patch, use or take off this patch according to specific dominated stage activity, the leading active stage of above-mentioned estrogen is made of independent a kind of transdermal estrogen material or a kind of transdermal estrogen material and transdermal progestogen material, and the leading active stage of above-mentioned progestogen is made up of a kind of transdermal progestogen material and a kind of transdermal estrogen material, for required leading activity is provided, make the progestogen amount of substance alternately increase and reduce in the leading active stage of estrogen in the leading active stage of progestogen.
21, as the packing of claim 20, estrogen wherein and progestogen are selected from such estrogen and progestogen, the activity level that it provided is equivalent to the about 25 μ g/ days transdermal release speed to the 3-ketone-Desogestrel of the norethindrone acetate of the transdermal release speed of about 100 μ g/ days 17-β estradiol and about 25 μ g/ days to about 1000 μ g/ days or about 5 μ g/ days to about 150 μ g/ days, condition is with respect to the estrogen dominated stage, progestogen increased in the progestogen dominated stage, to produce required advantage.
22, packing as claimed in claim 1, the estrogen dominated stage is wherein contained a certain amount of 17-β estradiol that is enough to provide about 25 μ g/ days to about 100 μ g/ days transdermal release speed, and this progestogen dominated stage is contained and a certain amount ofly is enough to provide about 25 μ g/ days to the 17-β estradiol of about 100 μ g/ days transdermal release speed with a certain amount ofly be enough to provide the norethindrone acetate that arrived about 1000 μ g/ days transdermal release speed in about 5 μ g/ days.
23, as the packing of claim 22, wherein the estrogen dominated stage comprises about three days and the progestogen dominated stage comprises about four days.
24, as the packing of claim 22, wherein the estrogen dominated stage comprises about four days and the progestogen dominated stage comprises about three days.
25, as the packing of claim 22, wherein the amount of norethindrone acetate is enough to provide about 75 μ g/ days to about 500 μ g/ days transdermal release speed.
26, as the packing of claim 22, wherein the amount of norethindrone acetate is enough to provide about 75 μ g/ days to about 300 μ g/ days transdermal release speed.
27, as the packing of claim 20, wherein the estrogen dominated stage is contained a certain amount of 17-β estradiol that is enough to provide about 25 μ g/ days to about 100 μ g/ days transdermal release speed, and the progestogen dominated stage is contained and a certain amount ofly is enough to provide about 25 μ g/ days to the 17-β estradiol of about 100 μ g/ days transdermal release speed with a certain amount ofly be enough to provide the 3-ketone-Desogestrel that arrived about 150 μ g/ days transdermal release speed in about 5 μ g/ days.
28, as the packing of claim 27, wherein the estrogen dominated stage comprises about three days and the progestogen dominated stage comprises about four days.
29, as the packing of claim 27, wherein the estrogen dominated stage comprises and being equivalent to about four days and the progestogen dominated stage comprises and is equivalent to about three days.
30, as the packing of claim 27, wherein the amount of 3-ketone-Desogestrel is enough to provide about 25 μ g/ days to about 150 transdermal release speed.
31, as the packing of claim 20, wherein the estrogen dominated stage is contained a certain amount of 17-β estradiol that is enough to provide about 50 μ g/ days transdermal release speed, and this progestogen dominated stage is contained a certain amount of 17-β estradiol and a certain amount of norethindrone acetate that is enough to provide about 300 μ g/ days transdermal release speed that is enough to provide about 50 μ g/ days transdermal release speed.
32, as the packing of claim 31, wherein the estrogen dominated stage comprises about three days and the progestogen dominated stage comprises about four days.
33, as the packing of claim 31, wherein the estrogen dominated stage comprises about four days and the progestogen dominated stage comprises about three days.
34, as the packing of claim 20, wherein the estrogen dominated stage is contained a certain amount of 17-β estradiol that is enough to provide about 50 μ g/ days transdermal release speed, and this progestogen dominated stage is contained a certain amount of 17-β estradiol and a certain amount of norethindrone acetate that is enough to provide about 150 μ g/ days transdermal release speed that is enough to provide about 50 μ g/ days transdermal release speed.
35, as the packing of claim 34, wherein the estrogen dominated stage comprises about three days and the progestogen dominated stage comprises about four days.
36, the packing of claim 34, wherein the estrogen dominated stage comprises four days and the progestogen dominated stage comprises about three days.
37, as the packing of claim 20, wherein each stage comprises single patch.
38, as the packing of claim 20, wherein each stage comprises a plurality of patches.
39, a kind of pharmaceutical preparation that is applied to the women who needs hormone replacement therapy, it comprises with the about one patch therapeutic scheme series to about four days leading hormonal activity alternating phases arrangement, above-mentioned each stage is selected from leading active stage of estrogen and leading active stage of progestogen, above-mentioned each stage is contained at least a patch, use or take off this patch according to specific dominated stage activity, the leading active stage of above-mentioned estrogen is made up of independent a kind of transdermal estrogen material or a kind of transdermal estrogen material and a kind of transdermal progestogen material, and the leading active stage of above-mentioned progestogen is made up of a kind of transdermal progestogen material and a kind of transdermal estrogen material, for required leading activity is provided, make the progestogen amount of substance alternately increase and reduce in the leading active stage of estrogen in the leading active stage of progestogen.
40, the purposes of a kind of medicine patch therapeutic scheme in preparing the medicament for the treatment of the women that need carry out hormone replacement therapy incessantly, this patch therapeutic scheme comprises with the about one a series of patches to about four days leading hormonal activity alternating phases use, the above-mentioned stage is selected from leading active stage of estrogen and leading active stage of progestogen, above-mentioned each stage is contained at least a patch, use or take off this patch according to specific dominated stage activity, the leading active stage of above-mentioned estrogen is by using the transdermal estrogen material separately or using a kind of estrogen substance and transdermal progestogen material is formed, and the leading active stage of above-mentioned progestogen is by using a kind of transdermal progestogen material and a kind of transdermal estrogen material is formed, for required leading activity is provided, make the progestogen amount of substance alternately increase and reduce in the leading active stage of estrogen in the leading active stage of progestogen.
41, as the purposes of claim 40, each stage is wherein used single patch.
42, as the purposes of claim 40, each stage is used a plurality of patches.
43, as the purposes of claim 40, estrogen wherein and progestogen are selected from such estrogen and progestogen, the activity level that it provided be equivalent to about 25 μ g/ days to about 100 μ g/ days 17-β estradiol and about 25 μ g/ days to about 1000 μ g/ days norethindrone acetates or about 5 μ g/ days transdermal release speed to about 150 μ g/ days 3-ketone-Desogestrel, its condition is with respect to the estrogen dominated stage, progestogen increased in the progestogen dominated stage, to produce required advantage.
44, as the purposes of claim 40, the estrogen dominated stage is wherein contained a certain amount of 17-β estradiol that is enough to provide about 25 μ g/ days to about 100 μ g/ days transdermal release speed, and this progestogen dominated stage is contained and a certain amount ofly is enough to provide about 25 μ g/ days to the 17-β estradiol of about 100 μ g/ days transdermal release speed with a certain amount ofly be enough to provide the norethindrone acetate that arrived about 1000 μ g/ days transdermal release speed in about 25 μ g/ days.
45, as the purposes of claim 44, wherein the estrogen dominated stage comprises about three days and the progestogen dominated stage comprises about four days.
46, as the purposes of claim 44, wherein the estrogen dominated stage comprises four days and the progestogen dominated stage comprises about three days.
47, as the purposes of claim 44, wherein the amount of norethindrone acetate is enough to provide about 75 μ g/ days to about 500 μ g/ days transdermal release speed.
48, as the purposes of claim 44, wherein the amount of norethindrone acetate is enough to provide about 75 μ g/ days to about 300 μ g/ days transdermal release speed.
49, as the purposes of claim 41, wherein the estrogen dominated stage is contained a certain amount of 17-β estradiol that is enough to provide about 25 μ g/ days to about 100 μ g/ days transdermal release speed, and this progestogen dominated stage, a certain amount of about 25 μ g/ days 17-β estradiol and a certain amount of 3-ketone-Desogestrels that are enough to provide about 5 μ g/ days about 150 μ g/ days transdermal release speed to about 100 μ g/ days transdermal release speed that are enough to provide were provided.
50, as the purposes of claim 49, wherein the estrogen dominated stage comprises about three days and the progestogen dominated stage comprises about four days.
51, as the purposes of claim 49, wherein the estrogen dominated stage comprises about four days and the progestogen dominated stage comprises about three days.
52, as the purposes of claim 49, wherein the amount of 3-ketone-Desogestrel is enough to provide about 25 μ g/ days to about 150 μ g/ days transdermal release speed.
53, as the purposes of claim 41, wherein the estrogen dominated stage is contained a certain amount of 17-β estradiol that is enough to provide about 50 μ g/ days transdermal release speed, and this progestogen dominated stage is contained a certain amount of 17-β estradiol and a certain amount of norethindrone acetate that is enough to provide about 300 μ g/ days transdermal release speed that is enough to provide about 50 μ g/ days transdermal release speed.
54, as the purposes of claim 53, wherein the leading active stage of estrogen comprises about three days and the leading active stage of progestogen comprises about four days.
55, as the purposes of claim 53, wherein the leading active stage of estrogen comprises about four days and the leading active stage of progestogen comprises about three days.
56, as the purposes of claim 41, wherein the leading active stage of estrogen is contained a certain amount of 17-β estradiol that is enough to provide about 50 μ g/ days transdermal release speed, and this progestogen dominated stage is contained a certain amount of 17-β estradiol and a certain amount of norethindrone acetate that is enough to provide about 150 μ g/ days transdermal release speed that is enough to provide about 50 μ g/ days transdermal release speed.
57, as the purposes of claim 56, wherein the estrogen dominated stage comprises about three days and the progestogen dominated stage comprises about four days.
58, as the purposes of claim 56, wherein the estrogen dominated stage comprises about four days and the progestogen dominated stage comprises about three days.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US99682092A | 1992-12-28 | 1992-12-28 | |
| US996,820 | 1992-12-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1097987A true CN1097987A (en) | 1995-02-01 |
Family
ID=25543344
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93121739A Pending CN1097987A (en) | 1992-12-28 | 1993-12-28 | The Hormone Replacement Therapy of transdermal |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0675720A1 (en) |
| CN (1) | CN1097987A (en) |
| CA (1) | CA2152780A1 (en) |
| IL (1) | IL108183A0 (en) |
| MX (1) | MXPA94000108A (en) |
| SI (1) | SI9300687A (en) |
| WO (1) | WO1994014450A1 (en) |
| ZA (1) | ZA939686B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5855920A (en) * | 1996-12-13 | 1999-01-05 | Chein; Edmund Y. M. | Total hormone replacement therapy |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5108995A (en) * | 1987-09-24 | 1992-04-28 | Jencap Research Ltd. | Hormone preparation and method |
| DE3888269T2 (en) * | 1987-09-24 | 1994-07-07 | Jencap Research Ltd | Hormone composition and application. |
-
1993
- 1993-12-24 CA CA002152780A patent/CA2152780A1/en not_active Abandoned
- 1993-12-24 EP EP94904111A patent/EP0675720A1/en not_active Withdrawn
- 1993-12-24 WO PCT/CA1993/000564 patent/WO1994014450A1/en not_active Application Discontinuation
- 1993-12-27 SI SI9300687A patent/SI9300687A/en unknown
- 1993-12-27 ZA ZA939686A patent/ZA939686B/en unknown
- 1993-12-27 IL IL10818393A patent/IL108183A0/en unknown
- 1993-12-28 CN CN93121739A patent/CN1097987A/en active Pending
-
1994
- 1994-01-03 MX MXPA94000108A patent/MXPA94000108A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA94000108A (en) | 2004-08-20 |
| EP0675720A1 (en) | 1995-10-11 |
| IL108183A0 (en) | 1994-04-12 |
| CA2152780A1 (en) | 1994-07-07 |
| WO1994014450A1 (en) | 1994-07-07 |
| SI9300687A (en) | 1994-09-30 |
| ZA939686B (en) | 1994-08-29 |
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| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |