CA2152780A1 - Transdermal hormone replacement therapy - Google Patents
Transdermal hormone replacement therapyInfo
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- CA2152780A1 CA2152780A1 CA002152780A CA2152780A CA2152780A1 CA 2152780 A1 CA2152780 A1 CA 2152780A1 CA 002152780 A CA002152780 A CA 002152780A CA 2152780 A CA2152780 A CA 2152780A CA 2152780 A1 CA2152780 A1 CA 2152780A1
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- progestin
- dominant
- estrogen
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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
-
- 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
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
The present invention provides a method of treating a female in need of hormone replacement therapy comprising transdermally administering to said female a series of alternating phases of from about one to about four days of estrogen dominant activity and phases of from about one to about four days of progestin dominant activity, with the estrogen dominant activity phase consisting of administering a transdermal estrogen substance alone or administering a transdermal estrogen substance and a transdermal progestin substance and the progestin dominant activity phase consisting of administering a transdermal progestin substance and a transdermal estrogen substance, the amount of progesting substance being alternatively increased in the progesting dominant activity phase and decreased in the estrogen dominant activity phase to provide the required dominant activity.
Description
Wo 94/14450 21 5 2 7 8 0 PCT/CA93/00564 Transdermal, mult~phas~c hor~one replace~ent therapy.
llLCII~ICAUL FlEI~D
This invention relates to hormone replacement therapy tor menopausal or castrate women. In particular. this invention relates to a t`orm of a preparation 5 and method which involves transdermal delivery.
BACKGROUND ART
Estrogen replacement therapy is warranted in menopausal women for several reasons. Estrogen replacement is known to relieve hot flushes and this reiief of flushes and night sweats improves sleep patterns and contributes to the 10 patient's general feeling of well-being. Estrogen replacement protects against postmenopausal loss of calcium from the skeleton, especially from vertebral bodies, preventing crush fractures and loss ot body height. Several studies havenow reported that long-term estrogen therapy is also associated with a reductionin the incidence of classical osteoporotic fractures of the torearm and hip.
15 Another beneficial effect of long-term estrogen use is the reduction of the risk of death from ischemic heart disease probably rnedi~ted by changés in blood lipoprotein conc~nl,~tions. Estrogen repl~rement has also been shown to improve the vascularity and health of the vaginal mucosa and urinary tract. The only major risk tactor associated with estrogen administration in the doses '0 required to relieve menopausal symptoms. is hyperstimulation of the endometrium and an increased risk of endometrial cancer. The addition ot a progestin tor 13 days each month has been demonstrated to protect the endometrium from these stimulatory effects of estrogen.
Progestin protects the endometrium by reducing nuclear estradiol ~5 receptor concentration and thereby decreasing nuclear estrogen bioavailability resulting in an antimitotic effect and lowering DNA synthesis. Progestins also increase the activity of endometrial estradiol-17,Bdehydrogenase. an enzyme which metabolizes estradiol to estrone. a less potent estrogen. However.
21S~780 concerns have been expressed about the potential adverse effects of progestin insuppressing high density lipoprotein cholesterol concentrations. This cholesterol fraction appears to have a protective eft'ect against ischemic heart disease andatherosclerosis. The lowering of HDL cholesterol by progestin could negate the S long-term beneficial effects of estrogen in reducing the incidence of myocardial infraction. Other side effects ot' progestins include acne, breast tenderness, depression and irritability. Since the side effects of p~oges~ins appear to be dose dependent. the dose ot' progestin used with postmenopausal estrogen replacement should be the minimum nececc~ry to achieve endometrial 1 0 protection.
Current hormonal replacement consists of continuous (daily or cyclic) (example days 1-25 of each month) estrogen ~-~minictration with the addition ot'a progestin for 10-13 days each month (example days 13-25 of each month).
This type of replacement regimen is eft'ective in preventing menopausal 15 symptoms and at the same time, prolec~ the endo.,lc,-h~ against the development of hyperplasia or ;~n~c~rcinollla. However, the cyclic ~,~mjnictratjon of a progei,lin leads to a scheduled withdrawal bleed or period in 65-75% of women. This withdrawal bleeding is usually not welcomed by the patient and can lead to problems with compliance. Also because the progcjlin '0 administration is preceded by up to 13-16 days of unopposed estrogen therapy with endometrial proliferation and estrogen and progestin receptor induction, itis possible that a high dose of progc~lin is required to antagonize these et'fects resulting in a greater chance of side effects and adverse metabolic effects.
While newer continuous low dose estrogen and progestin regimens for hormonal ~5 replacement may avoid the problem of withdrawal bleeding, daily ~dminictration of a proge~lin in these regimens induces depletion of both estrogen and proge~lin recepto,~ resulting in endometrial atrophy which may be associated with breakthrough bleeding. Since abnormal bleeding in a postmenopausal Wo 94/14450 21 S 2 7 8 0 PCT/CA93/00564 woman is known to be associaled with endometrial carcinoma it must be investigated by endometrial sampling tor hypertrophy usually by D&C. Daily administration of a progestin also raises the concern that the t`avourable effects of estrogen on HDL cholesterol metabolism will be adversely affected with a S tall in HDL cholesterol.
Thus. in U.S. Patent No. S. 108.995 the present applicant has described a regimen which is better able to protect the endometrium against the estrogen related risk ot endometrial hyperplasia and adenocarcinoma with a lower dose ot progestin by ~minictering progestin for a short period of time alternating 10 with a short period of absent or reduced progestin. Tlle formulation administers a low dose of progestin intermittently throughout the month~ and as a result thetollowing are achieved: the substantial elimination ot withdrawal bleeding;
intermittent increases in estrogen activity; and stimul~tion of endometrial growth and progestin rec~pto,s. Consequently the endometrium is more sensitive to 15 subsequent progei,lin activity which limits growth by decreasing estrogen recep~o,~ and increasing 17~hydroxysteroid dehydlogenase. Interaction of progesLin with p~ogeslh~ receptors induces secreto~y changes in the endometrium which results in a denser stroma and endometrial stability. A return to relatively dominant estrogenic activity then again stimulates estrogen and 20 proge~lin receptors and renews endometrial sensitivity to proge;.lin. This push/pull activity keeps endometrial activity within a low range depending on the number of days ot estrogenic and progestagenic activity and m~int~inc a stable endometrium resulting in the substantial absence of breakthrough or withdrawal bleeding. This formulation allows better progestational effects with 25 less progestin. The dose of progestin is significantly decreased compared with a prepafation com~ining a constant daily dosage of a progestin. A total steroid dosage can be achieved which is similar to or even lower than that of the present cyclic method of administering estrogen and progestin for hormonal 215278~
replacement therapy ot ovarian tailure. A reduction in progestin dosage results in less negative impact on HDL cholesterol levels.
Transdermal drug delivery systems are known in the art. Some patents in this area are concerned with the transdermal delivery of hormone 5 tormulations tor various purposes. Examples of such patents are as tollows:
U.S. Patent No. 4.816.258 issued March 28~ 1989 to Nedberge et al discloses a drug tormulation of ethinyl estradiol and levo-norgestrel tor transdermal administration which comprises a matrix containing the steroids and a skin permeation enhancing amount of glycerol mono-oleate.
U.S. Patent No. 5,122.382 issued June 16. 1992 to Gail et al discloses a composition tor transdermal administration comprising an estrogen and ST-1435. The tormulation delivers certain qll~mi~ies per day of the steroids andincludes a skin permeation enhancer.
U.S. Patent No. 5.023.084 issued June 11, 1991 and U.S. Patent No.
4.906,169 issued March 6, 1992, both to Chien et al describe a combination of estrogen and progc;,lin in a contraceptive tormulation with a transdermal unit comprising a b~rl~ing layer, a polymer layer cont~ining the hormones and an adhesive layer.
U.S. Patents Nos. 4,624.665. issued November 25, 1986, 4,687.481 '0 issued August 18. 1987. 4.834.978 issued May 30. 1989, 4.810.499 issued March 7. 1989 and 4.927.687 issued May 22. 1990 describe a transdermal delivery system which is said to prevent dose dumping of the drug to be delivered caused by accidental rupture of a ret~ining member and ensures effective and prolon~ed delivery of the drug, particularly con1laceptive steroids.
25 Suitable steroids include norethindrone. norgejllel~ estradiol. Ievo-nor~esllel and mestranol.
DISCLOSURE OF INVENTION
The benefits ot transdermal delivery systems are perceived to exist Wo 94tl4450 215 2 7 8 0 PCT/CA93/00564 primarily in the ability to bypass the liver on the "first pass" of the hormonesthrough the body, by not delivering them orally. Gastrointestinal absorption requires transit through the liver. and metabolism ot the drug occurs there, before the first complete circulatory loop. takes the drug to the target organs S (i.e., uterus, heart. bones~ central nervous system. etc.). The advantaQe of avoiding the liver is that lower amounts of the drug can be given to a patient in order to achieve the same degree of efficacy in target tissues, thereby ~iminiching the untoward metabolic etfects (e.g., changes in coagulation tactors, glucose metabolism, lipids. etc.) that would be encountered via the oral 10 route. (See Transdermal Hormone Replacement, M.l. Whitehead and L.
Schenkel, 1990.) It is also thought that avoidance of the stomach could prevent some ot the nausea and gastrointestin~l distress that is associated with estrogen therapy when taken orally. (See Transdermal Aflminictration of Oestrogen/~oge~in Hormone Replacement Therapy, M.l. Whitehead et al. The Lancet, 310-312, Feb. 10, 1990.) It is believed that a conlinuous transdermal delivery system generally provides more constant steady-state plasma levels of ho.".ones, devoid of peaks and valleys, than does a once daily oral lminictration. The "first pass"
phenomenon could also be argued to underlie the perceived disadvantage of the '0 transdermal delivery route. This perceived disadvantage is that estrogens actually induce some ~avourable changes in the lipoprotein profile (stimulating increases in HDL cholesterol, t`or example) and these effects are likely the result of induction of liver enzymes. Diminichin~ hepatic exposure to the drug could be predicted to diminish the beneficial effects of these drugs.
~5 Nevertheless. there are a number of factors to be weighed in determining whether a patient should be treated with hormone therapy orally versus transdermally, and generally, the factors in tavour of transdermal include a patient who is very sensitive to pharmacological agents in general. a Wo 94/14450 ; PCT/CA93/00564 2~5278Q
noncompliant or t'orgettul patient who may have difficulty with daily dosing regimens, gastrointestinal disturbances from oral estrogen therapy and a lack ot`
response to the oral route. In contrast~ the selection of the oral t'orm might be pret'erable in the case where a patient is perceived to have a high risk t'or 5 cardiovascular disease. hyperlipidemia. a tendency to dermal sensitivity and dermatologic disorders.
It is believed that the use ot a transdermal delivery system tor the regimen of U.S. Patent No. 5,108,995 would enhance the benefits ot' the basic regimen on its own because of the perceived advantages of the transdermal 10 route. In addition. it has also been t'ound that the transdermal delivery system works best with a particular selection of hormones which are most suitable tor this deliverv route.
In one t'orm. the invention provides a method of treating a t'emale in need of hormone replacement therapy comprising transdermally ~dminictering to IS said female, a pharm~reutic~l patch regimen series arranged in alternating phases of dominant hormone activity of from about one day to about t'our days, said phases being selected from estrogen dominant activity phases and progestin dominant activity phases, each of said phases comprising at least one patch which is applied and removed in accordance with the particular dominant phase ~0 activity, wherein the estrogen dominant activity phase contains an amount of a substance exhibiting eaLrogen activity sufficient to promote the development of progesth~ receptors in the endometrium of said female, or an amount of a substance exhibiting estrogen activity sut`ficient to promote the development ofprogestin receptor~ in the endometrium of said female and an amount of a ~5 substance exhibiting ,l~logei.Lin activity; and wherein the plogeslin dominant activity phases contain an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity sufficient to antagonize the et'fect of estrogen on the endometrium ot' said t'emale, and the estrogen and wo 94/14450 21 5 2 7 8 0 PCT/CA93/00564 progestin are selected from transdermally administrable hormones.
The present invention provides a method ot` treating a female in need ot`
hormone replacement therapy comprising transdermallv administering, to said temale a pharmaceutical patch regimen series arranged in alternating phases of S dominant hormone activity ot` from about one dav to about four days, said ' ' phases being selected from estrogen dominant activity phases and progestin dominanl activity phases, each ot said phases comprising at least one patch which is applied and removed in accordance with the particular dominant phase activity. said estrogen dominant activity phase consisting ot` administering a lO transdermal estrogen substance alone or administering a transdermal estrogen substance and a transdermal progestin substance. and said progestin dominant activity phase consisting ot ~lminictering a transdermal progestin substance anda transdermal estrogen subsr~nre, the amount ot progestin substance being alternatelv incleased in the progestin dominant activity phase and decreased in 15 the estrogen dominant activity phase to provide the required dominant activity.
In another aspect the invention provides a pharm~reu~ic~l preparation for admini~tration to a temale in need of hormone replacement therapy comprising a patch regimen series arranged in alle~na[ing phases of dominant hormone activity of from about one day to about four days, each of said phases being ~0 selected from estrogen dominant activity phases and progestin dominant activity phases, each ot said phases comprising at least one patch which is applied and removed in accordance with the particular dominant phase activity, said estrogen dominant activity phase consisting of a transdermal estrogen substance alone or a transdermal estrogen substance and a transdermal progeslin ~5 substance. and said progestin dominant activity phase consisting of a transdermal progestin substance and a transdermal es~logen subst~n~e, the amount of progestin substance being alternately increased in the progestin dominant activity phase and decreased in the estrogen dominant activity phase to W O 94/14450 ~CT/CA93/00564 21~27~0 ~ "
provide the required dominant activity.
In another form the invention provides a package comprising a pharmaceutical transdermal patch regimen tor ~minictratjon to a t`emale in need of hormone replacement therapy wherein the package consists ot a 5 pharmaceutical patch regimen series arranged in alternating phases of dominanthormone activity ot from about one day to about four days. each ot` said phases being selected trom estrogen dominant activity phases and progestin dominant activity phases, each ot said phases comprising at least one patch which is applied and removed in accordance with the particular dominant phase activity, 10 said estrogen dominant activity phase consisting ot a transdermal estro en substance alone or a transdermal estrogen substance and a transdermal progestin substance, and said progestin dominant activity phase consisting ot a transdermal progestin subst~nre and a transdermal estrogen substance. the amount ot progeslin substance being alternately increased in the progestin 15 dominant activity phase and decreased in the estrogen dominant activity phase to provide the required dominant activity.
In a preter,ed form ot the invention the estrogen and progestin are selected from transdermal eslrogens and progeslins which provide levels of activity, equivalent to a transdermal delivery rate of from about 25 ~g/day to ~0 about 150 ~g/day. more preterably about 100 ~g/day of 17-,B estradiol and from about 250 ~g/day to about S00 ~g/day of piperazine estrone sulphate and from about 15 ~g/day, more preferably about 25 ~g/day to about 1000 ,~ g/day ot norethindrone acetate or from about 5 ~g/day to about 150 ~g/day of 3-keto-desogestrel~ with the proviso that the progestin is increased in the S progestin dominant phase relative to the estrogen dominant phase to produce the required dominance.
In a pret`erred form of the present invention, a first patch, for example either an adhesive matrix type or a drug reservoir type (ethanolic gel) is Wo 94/14450 215 2 7 8 0 PCT/CA93/00~64 prepared cont~ining sufficient 17-~ estradiol to provide a transdermal delivery rate of from about 25 ~Lg/day to about 100 ~g/day. A second patch is prepared~
either adhesive matrix or drug reservoir (ethanolic gel) type containin~
sufficient 17-,(3 estradiol to glve the above release rate and sufficient 5 norethindrone acetate (NETA) tO provide a transdermal delivery rate ot' from about 25 ~g/day to about 1000 ~g/day of NETA, more pret'erably from about 75 ~g/day to about 500 ~g/day. most preferably 75 ~g/day to about 300 ,ug/day. In the case of the combination of 17-,B estradiol and 3-keto-desogestrel, the amount of 17-~3 estradiol remains the same as set out 10 above, while the amount of 3-keto-desogestrel is sut'ficient to provide a transdermal delivery rate of from about 5 ~g/day to about 150 ~g/day. more preferably 25 ~Lg/day to about 150 ~g/day. It is the application of these patches in the required sequence which provides the advantage of the present invention.
The estrogens which may be employed as a co---;)onenl in the regimens of this invention may be any of those conver.lionally available which can be absorbed through the skin. Typically, the estrogen may be selectP~ from the group comprising synthetic and natural estrogens. The synthetic estrogens may be selected from, for example, ethinyl estradiol, micronized estradiol, 17-~
20 estradiol, mestranol. estradiol valerate. I l-nitrato estradiol.
7-a-methy~ nitrato-estradiol. piperazine estrone sulfate and quinestranol. Of particular interest are 17a-ethinylestradiol and esters and ethers thereot'. Thepl e~'~r. ed estrogen is 17-~ estradiol .
The progestin component may be any proges~ionally active compound.
25 Thus, the progeslin may be selected from proge~lerone, 1 7-hydroxyprogesterone, d ihydroproge-~lerone . medroxyprogesterone acetate .
norethindrone, norethindrone acetate, norethynodrel, ethynodioldiacet~r~
norgestrel, levo-norgestrel, gestodene. delta-15-levonorge~lleh norgestimate~
wo 94/14450 2 lS 2~ 8 0 PCT/CA93/00564 17-deacetyl norgestimate, nomegesterol, nesterone. desogestrel and 3-keto-desogestrel. Preterred progestins are norethindrone acetate and 3-keto-desogestrel.
The selection of hormones most suited tor transdermal deliverv may be 5 determined by conventional tests used in the art to determine skin permeability.
The most common is the In Vitro Skin Permeation Cllamber using hairless mouse skin or human cadaver skin. The literature contains much int`ormation on these tests and the t`ollowing references are typical:
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), pp 105-lO8, 1989;
c) Liu P, Higuchi Wl, Song W~ Kurihara-Bergstrom T, Good WR.
Qll~ntit~ive Evaluation of Ethanol Effects on Diffusion and Metabolism of ~Estradiol in Hairless Mouse Skin. Pharm Res 8(7), pp 865-872, 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 hor",ones. skin permeation and hence transdermal delivery rates are important, but also, the stability ot the hormones in the tormulation can be a tactor. Stability can be ~ccecced or measured in two basic wavs: visual inspection and in vitro dissolution.
'5 Visual inspection is generally conducted on both a macroscopic and a microscopic level t`or crystal tormation. As tor in vitro dissolution, there aretests tor in vitro release rates which are standard in the art. Generally when these criteria are met, the transdermal delivery rates required are readily WO 94/14450 " PCT/CA93/00564 achieved.
The phases may comprise from one to tour days, but these days need not be exactly twenty-four hour days. Obviously there are limits as to the flexibility available given that absence ot hormone for too long would likely result hl S withdrawal bleeding, but for exampl~. for a three day phase. the total number ot hours might be 66 or 78. as opposed to 72. A preferred regimen uses phases comprising about three and about tour days. Other combinations such as two and three or one and three, or three and three. or two and tour, or one and tourmay be used.
Generally hormone replacement therapy is delivered without interruption.
But. there may be instances where interruption could be desirable in which case, patches cont~ining placebo or any other hormone-free agent may be included in a package. Examples ot suitable alternative hormone-free agents include vitamins, such as iron supplements.
Generally, the quantities of es~rogen and progestin inco,l,orated in the t`ormulation of the invention are dependent on the activity of the estrogen or progestin selected. In the present formulation, estrogen is administered continuously. in other words, it is always present in the t`ormulation, while the proge~ level is adjusted up or down to produce the required estrogen or '0 progestin dominance. The selection of quantities is dependent on the type of estrogen or progeslin since each hormone has its own specific activity.
Typically in the formulations described in U.S. Patent No. 5.108,995. the amount ot estrogen activity per unit dose may be equivalent in estrogenic activity to a range of from a minimum of about 0.3 mg of piperazine estrone 25 sulphate to a maximum of about 2.5 mg of piperazine estrone sulphate. The amount ot progestin activity per unit dose may be equivalent in progestagenic activity to a range of from a minimum of 0 mg to a maximum of about 5 mg ot norethindrone.
WO 94t14450 215 2 ~ 8 0 - PCT/CA93/00564 Some preferred combinations include the t`ollowing:
1. Three units doses of 0.75 mg piperazine estrone sulphate alternatin with three unit doses of 0.75 mg ot' piperazine estrone sulphate with 0.35 mg ot' norethindrone.
S ~. Three unit doses of 0.75 mg piperazine estrone sulphate and 0.15 mg of norethindrone alternating with three unit doses of 0.75 mg ot' piperazine estrone sulphate and 0.35 mg of norethindrone.
Equivalent dosages t'or transdermal can be determined from hormone blood level measurements. Generally, it is thought that t'or the delivery rates 10 contemplated t'or the patch formulations of the present invention, the amounts ot' hormones may be characterized as t'ollows. Firstly, each phase would generally constitute a single patch, though a series of patches could be used to make up aphase. Patch size is dependent on, among other parameters. the length of the phase, and the potency of the hormone. For example, patches of 17-~ estradiol 15 are currently available which provide transdelll,al delivery rates of about 50 ~g/day. In such inssnce, the amount of 17-¦3 estradiol is 4 mg and the size of the patch is about 18 cm' with the actual reservoir being about 10 cm`. In the case of a patch consining the two ho",lones, such as 17-~13 estradiol and norethindrone aceste. the amounts of same would be 10 mg and 30 mg, ~0 re~peclively and the patch surface area would be 26 cm- to provide transdermal delivery rates of about 50 ~Lg/day for 17-,B estradiol and about 250 ,ugiday fornorethindrone acetate. 3-Keto-desogestrel is a more potent progestin and the amount inco",o,dt~d in a patch might range from about 4 mg to about 30 mg to provide the required daily transdermal delivery rates. Tlle range for 17-¦3 25 estradiol may be from about I mg to about 10 mg (in adhesive matrix reservoir, this could change in another type of pauh), and t'or norethindrone acetate, the range may be from about 10 mg to about 100 mg.
The above combinations may also be grouped into three's and four's.
Wo 94/14450 21~ 2 7 8 0 ` PCT/CA93/00564 starting with either three or four day groups and ending with the other.
There are a number of transdermal patches available commercially which may be used in the present method. Most important to remember is that the sequence of administration is critical to the present invention and the 5 arrangement of the patches or their application in the predetermined order must be effected for the benefits of the invention to be obtained. Two such patches are described here for purposes of exemplification only, but others may be employed.
In one known system, a matrix of a solid adhesive of acrylic copolymer base 10 cont~ining hormones in dissolved form is employed. The system involves the use of a flexible b~cking foil which may comprise for example polyethylene terephth~i~te. A release liner forms another layer (in contact with the adhesive). A swellable polysaccharide, galactom~nn~n is added to the adhesive matrix to improve the adhesion between the surtace of the patch and hydrated 15 skin, over the whole application, and to reduce irritation phenomena caused by occlusion effects. Preferably, a three layer l~min~te is produced of the b~ckingfoil, drug matrix and release liner. Currently, a commercial product of this nature is sold under the trade mark SYSTEN TTS.
Another commercial product is that available under the trade mark ~0 ESTRADERM. ESTRADERMT~ is an estradiol transdermal system designed to release estradiol through a rate-limiting membrane continuously upon applicationto intact skin. The ESTRADERMT" system co~ ises five layers: a backing layer, a drug reservoir, a control membrane, an adhesive layer and a protective layer in that order from outside to inside. The qualitative composition of the ~5 ESTRADERM drug reservoir is estradiol, alcohol and hydroxy propylcellulose.
For transdermal administration, as has already been stated. any suitable torm ot patch may be selected. Another which is known to be useful in the administration of hormone formulations is described in detail in U.S. Patent No.
Wo 94/14450 PCT/CA93/00564 21527'801 4.668,23' issued May 26. 1987 to Cordes and Wolff, the disclosure ot` which is incorporated herein by reference. In this U.S. patent, the system described is atour layer system comprising an impermeable backing or covering layer: a reservoir layer adjacent to the backing or covering layer: an adhesive layer S permeable to the hormones and a protective layer which is removed before application of the patch. As described earlier. a three layer system may be used which comprises a backing layer, a drug matrix adhesive layer and a release liner.
An estrogen patch tor the present invention may be prepared using an 10 ethanolic gel type of drug reservoir. The weight ot hormone, pret`erably 17-~estradiol may comprise 4 mg. The patch mav have a surtace area of about 18 cm-. In appearance it may be round with the reservoir co~ "ising about 10 cm` of the patch. This generally provides a transdermal delivery rate of about 10 ~g/day tor 17-~ estradiol.
An estrogen/proge~lin patch may be prepared using an ethanolic gel type of drug reservoir with the amounts of hormones comprising 10 mg of 17-,B
estradiol and 30 mg of norethindrone acetate, for example. The total contact area of such a patch would be about 20 cm- and have the appedrdnce of eyeglasses with two joined reservoirs with each reservoir cont~ining both drugs.This generally provides a transdermal delivery rate of about 50 ~g/day of 17-,B
estradiol and about 250 ~g/day of norethindrone acetate.
Typically, this preparation is tor administration to post menopausal patients and/or those who are actively symptomatic.
The patches may be packaged, for example. in cartons containing a number of transdermal 17-13estradiol patches and a number ot transdermal 17-,B
estradiol and norethindrone acetate patches. Each patch may be individually sealed in a proteclive pouch.
In this example a tirst 17-~ estradiol patch may be applied for the required wo 94/14450 ~ PCT/CA93/00564 ~5~780 number of days (although it is not essential to start witll this phase), this patcl is removed and one ot` the 17-¦3 estradiol and norethindrone acetate patches is applied for the required number of days. The second patch is then removed and another 17-~ estradiol patch is applied. and so on. The treatment is normally S continued without interruption. The individual patches are usually changed every three or four days dependin~ on the particular regimen. although the patches may be prepared for application tor any combination ot days within the one to tour days limitation tor the regimen.
Each new patch is applied to a ditferent site. Preferred application sites are 10 clean, dry and intact areas of skin, below the waistline on the trunk of the bodv. Preterably the buttock. hip or abdomen area is chosen since these areas of skin wrinkle least during body movement.
MODES FOR CARRYING OUT THE INVENTION
In the t`ollowing examples, specific embodiments ot the present invention are IS set forth. These are meant to be illustrative of the invention and are not meant to limit it in any way. All parts and percentages are by weight, unless indic~d otherwise.
A three-day phase transdermal patch of 17-~3estradiol (100 ~Lg/day) is ~O administered and alternated with a three-day phase transdermal patch of 17-,~estradiol (100 ~g/day) and norethindrone (.35 mg/day). These patches are applied alternately and without interruption.
A three-day phase transdermal patch of 17-,Bestradiol (100 ~g/day) is 'S administered and alternated with a three-day phase transdermal patch of 17-~estradiol (100 ~g/day) and norethindrone acetate (0.35 mg/day). These patches are applied alternately and without interruption.
WO 94/14450 21~ 2 7 8 0 ` - PCT/CA93/00564 A three-day phase transdermal patch ot 17-~3 estradiol (50 ~g/day) is administered and alternated witll a three-day phase transdermal patch ot 17-~
estradiol (50 ~g/day) and norethindrone acetate (0.15 mg/day). These patches S are applied alternately and without interruption.
A three-day phase transdermal patch of 17-,B estradiol (25 llg/day) is administered and alternated with a tl-ree-day phase transdermal patch of 17-~3 estradiol (25 ~g/day) and norethindrone acetate (0.50 mg/day). These patches are applied alternately and without interruption.
E,YAMPLE S
An estrogen patch using an ethanolic gel type of drug reservoir incorporating about 4 mg. of 17-,B estradiol is prepared having a surtace area ot about 18 cm'. In appear~nce it is round with the reservoir COI"~l ising about 10 cm' of the patch. This generally provides a transdermal delivery rate of about 10 ~g/day tor 17-,B estradiol.
An estrogen/progestin patch is prepared using an ethanolic gel type of drug reservoir with the amounts of hormones comprising 10 mg of 17-~ estradiol and 30 mg of norethindrone acetate. The total contact area of such a patch is about 20 cm~. The patches have the appearance of eyeglasses with two joined reservoirs with each reservoir containing both drugs. These patches generally provide a transdermal delivery rate of 50 ~g/day of 17-~ estradiol and 250 ~g/day of norethindrone acetate.
The patches are packaged in cartons containing a number ot transdermal 17-13 estradiol patches and a number ot transdermal 17-13 estradiol and norethindrone acetate patches. Each patch is individually sealed in a protectivepouch.
A first 17-~3 estradiol patch is applied for the required three days (although it Wo 94/14450 215 2 7 8 0 PCT/CA93/00564 is not essential to start with this phase), this patch is removed and one of the17-,B estradiol and norethindrone acetate patches is applied tor four days. The second patch is then removed and another 17-~ estradiol patch is applied~ and so on. The treatment is continued without interruption. Each new patch is 5 applied to a different site. Preferred application sites are clean. dry and intact areas of skin, below the waistline on the trunk of the body. Preferably the buttock, hip or abdomen area is chosen since these areas of skin wrinkle least during body movement.
While the present invention has been described with reterence to specific 10 embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition~ many modifications may be made to adapt a particular situation, material or composition of matter, process. process step or steps, or then present objective15 to the spirit of this invention without departing from its eccenti~l te~r~hingc.
INDUSIl~IAL APPLlCABILlTY
The benefits of transdermal delivery systems are perceived to exist primarily inthe ability to bypass the liver on the "first pass" of the hormones through the body, by not delivering them orally. The advantage of avoiding the liver is that20 iower amounts ot the drug can be given to a patient in order to achieve the same degree of efficacy in target tissues. thereby diminishing the untoward metabolic effects (e.g., changes in coagulation tactors. glucose metabolism, lipids, etc.) that would be encout"ered via the oral route. It is also thought that avoidance of the stomach could prevent some of the nausea and gastrointestinal 25 distress that is associated with estrogen therapy when taken orally. It is believed that a continuous transdermal delivery system generally provides more constant steady-state plasma levels of hormones. devoid of peaks and valleys, than does a once daily oral administration. Estrogen replacement therapy is W O 94/14450 2 1 5 ~ 7 8 0 PCTICA93/00564 known to relieve hot tlushes and this relief ot flushes and night sweats improves sleep patterns and contributes to the patient's general teeling of well-being.
Estrogen replacement protects against postmenopausal loss ot calcium from the skeleton especially from vertebral bodies. preventing crush fractures and loss 5 of body height. Several studies have now reported that long-term estrogen therapy is also associated with a reduction in the incidence of classical osteoporotic fractures of the forearm and hip. Another beneficial effect of long-term estrogen use is the reduction of the risk of death trom ischemic heartdisease probably medi~ted by changes in blood lipoprotein concentrations.
10 Estrogen replacement has also been shown to improve the vascularity and health of the vaginal mucosa and urinary tract.
llLCII~ICAUL FlEI~D
This invention relates to hormone replacement therapy tor menopausal or castrate women. In particular. this invention relates to a t`orm of a preparation 5 and method which involves transdermal delivery.
BACKGROUND ART
Estrogen replacement therapy is warranted in menopausal women for several reasons. Estrogen replacement is known to relieve hot flushes and this reiief of flushes and night sweats improves sleep patterns and contributes to the 10 patient's general feeling of well-being. Estrogen replacement protects against postmenopausal loss of calcium from the skeleton, especially from vertebral bodies, preventing crush fractures and loss ot body height. Several studies havenow reported that long-term estrogen therapy is also associated with a reductionin the incidence of classical osteoporotic fractures of the torearm and hip.
15 Another beneficial effect of long-term estrogen use is the reduction of the risk of death from ischemic heart disease probably rnedi~ted by changés in blood lipoprotein conc~nl,~tions. Estrogen repl~rement has also been shown to improve the vascularity and health of the vaginal mucosa and urinary tract. The only major risk tactor associated with estrogen administration in the doses '0 required to relieve menopausal symptoms. is hyperstimulation of the endometrium and an increased risk of endometrial cancer. The addition ot a progestin tor 13 days each month has been demonstrated to protect the endometrium from these stimulatory effects of estrogen.
Progestin protects the endometrium by reducing nuclear estradiol ~5 receptor concentration and thereby decreasing nuclear estrogen bioavailability resulting in an antimitotic effect and lowering DNA synthesis. Progestins also increase the activity of endometrial estradiol-17,Bdehydrogenase. an enzyme which metabolizes estradiol to estrone. a less potent estrogen. However.
21S~780 concerns have been expressed about the potential adverse effects of progestin insuppressing high density lipoprotein cholesterol concentrations. This cholesterol fraction appears to have a protective eft'ect against ischemic heart disease andatherosclerosis. The lowering of HDL cholesterol by progestin could negate the S long-term beneficial effects of estrogen in reducing the incidence of myocardial infraction. Other side effects ot' progestins include acne, breast tenderness, depression and irritability. Since the side effects of p~oges~ins appear to be dose dependent. the dose ot' progestin used with postmenopausal estrogen replacement should be the minimum nececc~ry to achieve endometrial 1 0 protection.
Current hormonal replacement consists of continuous (daily or cyclic) (example days 1-25 of each month) estrogen ~-~minictration with the addition ot'a progestin for 10-13 days each month (example days 13-25 of each month).
This type of replacement regimen is eft'ective in preventing menopausal 15 symptoms and at the same time, prolec~ the endo.,lc,-h~ against the development of hyperplasia or ;~n~c~rcinollla. However, the cyclic ~,~mjnictratjon of a progei,lin leads to a scheduled withdrawal bleed or period in 65-75% of women. This withdrawal bleeding is usually not welcomed by the patient and can lead to problems with compliance. Also because the progcjlin '0 administration is preceded by up to 13-16 days of unopposed estrogen therapy with endometrial proliferation and estrogen and progestin receptor induction, itis possible that a high dose of progc~lin is required to antagonize these et'fects resulting in a greater chance of side effects and adverse metabolic effects.
While newer continuous low dose estrogen and progestin regimens for hormonal ~5 replacement may avoid the problem of withdrawal bleeding, daily ~dminictration of a proge~lin in these regimens induces depletion of both estrogen and proge~lin recepto,~ resulting in endometrial atrophy which may be associated with breakthrough bleeding. Since abnormal bleeding in a postmenopausal Wo 94/14450 21 S 2 7 8 0 PCT/CA93/00564 woman is known to be associaled with endometrial carcinoma it must be investigated by endometrial sampling tor hypertrophy usually by D&C. Daily administration of a progestin also raises the concern that the t`avourable effects of estrogen on HDL cholesterol metabolism will be adversely affected with a S tall in HDL cholesterol.
Thus. in U.S. Patent No. S. 108.995 the present applicant has described a regimen which is better able to protect the endometrium against the estrogen related risk ot endometrial hyperplasia and adenocarcinoma with a lower dose ot progestin by ~minictering progestin for a short period of time alternating 10 with a short period of absent or reduced progestin. Tlle formulation administers a low dose of progestin intermittently throughout the month~ and as a result thetollowing are achieved: the substantial elimination ot withdrawal bleeding;
intermittent increases in estrogen activity; and stimul~tion of endometrial growth and progestin rec~pto,s. Consequently the endometrium is more sensitive to 15 subsequent progei,lin activity which limits growth by decreasing estrogen recep~o,~ and increasing 17~hydroxysteroid dehydlogenase. Interaction of progesLin with p~ogeslh~ receptors induces secreto~y changes in the endometrium which results in a denser stroma and endometrial stability. A return to relatively dominant estrogenic activity then again stimulates estrogen and 20 proge~lin receptors and renews endometrial sensitivity to proge;.lin. This push/pull activity keeps endometrial activity within a low range depending on the number of days ot estrogenic and progestagenic activity and m~int~inc a stable endometrium resulting in the substantial absence of breakthrough or withdrawal bleeding. This formulation allows better progestational effects with 25 less progestin. The dose of progestin is significantly decreased compared with a prepafation com~ining a constant daily dosage of a progestin. A total steroid dosage can be achieved which is similar to or even lower than that of the present cyclic method of administering estrogen and progestin for hormonal 215278~
replacement therapy ot ovarian tailure. A reduction in progestin dosage results in less negative impact on HDL cholesterol levels.
Transdermal drug delivery systems are known in the art. Some patents in this area are concerned with the transdermal delivery of hormone 5 tormulations tor various purposes. Examples of such patents are as tollows:
U.S. Patent No. 4.816.258 issued March 28~ 1989 to Nedberge et al discloses a drug tormulation of ethinyl estradiol and levo-norgestrel tor transdermal administration which comprises a matrix containing the steroids and a skin permeation enhancing amount of glycerol mono-oleate.
U.S. Patent No. 5,122.382 issued June 16. 1992 to Gail et al discloses a composition tor transdermal administration comprising an estrogen and ST-1435. The tormulation delivers certain qll~mi~ies per day of the steroids andincludes a skin permeation enhancer.
U.S. Patent No. 5.023.084 issued June 11, 1991 and U.S. Patent No.
4.906,169 issued March 6, 1992, both to Chien et al describe a combination of estrogen and progc;,lin in a contraceptive tormulation with a transdermal unit comprising a b~rl~ing layer, a polymer layer cont~ining the hormones and an adhesive layer.
U.S. Patents Nos. 4,624.665. issued November 25, 1986, 4,687.481 '0 issued August 18. 1987. 4.834.978 issued May 30. 1989, 4.810.499 issued March 7. 1989 and 4.927.687 issued May 22. 1990 describe a transdermal delivery system which is said to prevent dose dumping of the drug to be delivered caused by accidental rupture of a ret~ining member and ensures effective and prolon~ed delivery of the drug, particularly con1laceptive steroids.
25 Suitable steroids include norethindrone. norgejllel~ estradiol. Ievo-nor~esllel and mestranol.
DISCLOSURE OF INVENTION
The benefits ot transdermal delivery systems are perceived to exist Wo 94tl4450 215 2 7 8 0 PCT/CA93/00564 primarily in the ability to bypass the liver on the "first pass" of the hormonesthrough the body, by not delivering them orally. Gastrointestinal absorption requires transit through the liver. and metabolism ot the drug occurs there, before the first complete circulatory loop. takes the drug to the target organs S (i.e., uterus, heart. bones~ central nervous system. etc.). The advantaQe of avoiding the liver is that lower amounts of the drug can be given to a patient in order to achieve the same degree of efficacy in target tissues, thereby ~iminiching the untoward metabolic etfects (e.g., changes in coagulation tactors, glucose metabolism, lipids. etc.) that would be encountered via the oral 10 route. (See Transdermal Hormone Replacement, M.l. Whitehead and L.
Schenkel, 1990.) It is also thought that avoidance of the stomach could prevent some ot the nausea and gastrointestin~l distress that is associated with estrogen therapy when taken orally. (See Transdermal Aflminictration of Oestrogen/~oge~in Hormone Replacement Therapy, M.l. Whitehead et al. The Lancet, 310-312, Feb. 10, 1990.) It is believed that a conlinuous transdermal delivery system generally provides more constant steady-state plasma levels of ho.".ones, devoid of peaks and valleys, than does a once daily oral lminictration. The "first pass"
phenomenon could also be argued to underlie the perceived disadvantage of the '0 transdermal delivery route. This perceived disadvantage is that estrogens actually induce some ~avourable changes in the lipoprotein profile (stimulating increases in HDL cholesterol, t`or example) and these effects are likely the result of induction of liver enzymes. Diminichin~ hepatic exposure to the drug could be predicted to diminish the beneficial effects of these drugs.
~5 Nevertheless. there are a number of factors to be weighed in determining whether a patient should be treated with hormone therapy orally versus transdermally, and generally, the factors in tavour of transdermal include a patient who is very sensitive to pharmacological agents in general. a Wo 94/14450 ; PCT/CA93/00564 2~5278Q
noncompliant or t'orgettul patient who may have difficulty with daily dosing regimens, gastrointestinal disturbances from oral estrogen therapy and a lack ot`
response to the oral route. In contrast~ the selection of the oral t'orm might be pret'erable in the case where a patient is perceived to have a high risk t'or 5 cardiovascular disease. hyperlipidemia. a tendency to dermal sensitivity and dermatologic disorders.
It is believed that the use ot a transdermal delivery system tor the regimen of U.S. Patent No. 5,108,995 would enhance the benefits ot' the basic regimen on its own because of the perceived advantages of the transdermal 10 route. In addition. it has also been t'ound that the transdermal delivery system works best with a particular selection of hormones which are most suitable tor this deliverv route.
In one t'orm. the invention provides a method of treating a t'emale in need of hormone replacement therapy comprising transdermally ~dminictering to IS said female, a pharm~reutic~l patch regimen series arranged in alternating phases of dominant hormone activity of from about one day to about t'our days, said phases being selected from estrogen dominant activity phases and progestin dominant activity phases, each of said phases comprising at least one patch which is applied and removed in accordance with the particular dominant phase ~0 activity, wherein the estrogen dominant activity phase contains an amount of a substance exhibiting eaLrogen activity sufficient to promote the development of progesth~ receptors in the endometrium of said female, or an amount of a substance exhibiting estrogen activity sut`ficient to promote the development ofprogestin receptor~ in the endometrium of said female and an amount of a ~5 substance exhibiting ,l~logei.Lin activity; and wherein the plogeslin dominant activity phases contain an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity sufficient to antagonize the et'fect of estrogen on the endometrium ot' said t'emale, and the estrogen and wo 94/14450 21 5 2 7 8 0 PCT/CA93/00564 progestin are selected from transdermally administrable hormones.
The present invention provides a method ot` treating a female in need ot`
hormone replacement therapy comprising transdermallv administering, to said temale a pharmaceutical patch regimen series arranged in alternating phases of S dominant hormone activity ot` from about one dav to about four days, said ' ' phases being selected from estrogen dominant activity phases and progestin dominanl activity phases, each ot said phases comprising at least one patch which is applied and removed in accordance with the particular dominant phase activity. said estrogen dominant activity phase consisting ot` administering a lO transdermal estrogen substance alone or administering a transdermal estrogen substance and a transdermal progestin substance. and said progestin dominant activity phase consisting ot ~lminictering a transdermal progestin substance anda transdermal estrogen subsr~nre, the amount ot progestin substance being alternatelv incleased in the progestin dominant activity phase and decreased in 15 the estrogen dominant activity phase to provide the required dominant activity.
In another aspect the invention provides a pharm~reu~ic~l preparation for admini~tration to a temale in need of hormone replacement therapy comprising a patch regimen series arranged in alle~na[ing phases of dominant hormone activity of from about one day to about four days, each of said phases being ~0 selected from estrogen dominant activity phases and progestin dominant activity phases, each ot said phases comprising at least one patch which is applied and removed in accordance with the particular dominant phase activity, said estrogen dominant activity phase consisting of a transdermal estrogen substance alone or a transdermal estrogen substance and a transdermal progeslin ~5 substance. and said progestin dominant activity phase consisting of a transdermal progestin substance and a transdermal es~logen subst~n~e, the amount of progestin substance being alternately increased in the progestin dominant activity phase and decreased in the estrogen dominant activity phase to W O 94/14450 ~CT/CA93/00564 21~27~0 ~ "
provide the required dominant activity.
In another form the invention provides a package comprising a pharmaceutical transdermal patch regimen tor ~minictratjon to a t`emale in need of hormone replacement therapy wherein the package consists ot a 5 pharmaceutical patch regimen series arranged in alternating phases of dominanthormone activity ot from about one day to about four days. each ot` said phases being selected trom estrogen dominant activity phases and progestin dominant activity phases, each ot said phases comprising at least one patch which is applied and removed in accordance with the particular dominant phase activity, 10 said estrogen dominant activity phase consisting ot a transdermal estro en substance alone or a transdermal estrogen substance and a transdermal progestin substance, and said progestin dominant activity phase consisting ot a transdermal progestin subst~nre and a transdermal estrogen substance. the amount ot progeslin substance being alternately increased in the progestin 15 dominant activity phase and decreased in the estrogen dominant activity phase to provide the required dominant activity.
In a preter,ed form ot the invention the estrogen and progestin are selected from transdermal eslrogens and progeslins which provide levels of activity, equivalent to a transdermal delivery rate of from about 25 ~g/day to ~0 about 150 ~g/day. more preterably about 100 ~g/day of 17-,B estradiol and from about 250 ~g/day to about S00 ~g/day of piperazine estrone sulphate and from about 15 ~g/day, more preferably about 25 ~g/day to about 1000 ,~ g/day ot norethindrone acetate or from about 5 ~g/day to about 150 ~g/day of 3-keto-desogestrel~ with the proviso that the progestin is increased in the S progestin dominant phase relative to the estrogen dominant phase to produce the required dominance.
In a pret`erred form of the present invention, a first patch, for example either an adhesive matrix type or a drug reservoir type (ethanolic gel) is Wo 94/14450 215 2 7 8 0 PCT/CA93/00~64 prepared cont~ining sufficient 17-~ estradiol to provide a transdermal delivery rate of from about 25 ~Lg/day to about 100 ~g/day. A second patch is prepared~
either adhesive matrix or drug reservoir (ethanolic gel) type containin~
sufficient 17-,(3 estradiol to glve the above release rate and sufficient 5 norethindrone acetate (NETA) tO provide a transdermal delivery rate ot' from about 25 ~g/day to about 1000 ~g/day of NETA, more pret'erably from about 75 ~g/day to about 500 ~g/day. most preferably 75 ~g/day to about 300 ,ug/day. In the case of the combination of 17-,B estradiol and 3-keto-desogestrel, the amount of 17-~3 estradiol remains the same as set out 10 above, while the amount of 3-keto-desogestrel is sut'ficient to provide a transdermal delivery rate of from about 5 ~g/day to about 150 ~g/day. more preferably 25 ~Lg/day to about 150 ~g/day. It is the application of these patches in the required sequence which provides the advantage of the present invention.
The estrogens which may be employed as a co---;)onenl in the regimens of this invention may be any of those conver.lionally available which can be absorbed through the skin. Typically, the estrogen may be selectP~ from the group comprising synthetic and natural estrogens. The synthetic estrogens may be selected from, for example, ethinyl estradiol, micronized estradiol, 17-~
20 estradiol, mestranol. estradiol valerate. I l-nitrato estradiol.
7-a-methy~ nitrato-estradiol. piperazine estrone sulfate and quinestranol. Of particular interest are 17a-ethinylestradiol and esters and ethers thereot'. Thepl e~'~r. ed estrogen is 17-~ estradiol .
The progestin component may be any proges~ionally active compound.
25 Thus, the progeslin may be selected from proge~lerone, 1 7-hydroxyprogesterone, d ihydroproge-~lerone . medroxyprogesterone acetate .
norethindrone, norethindrone acetate, norethynodrel, ethynodioldiacet~r~
norgestrel, levo-norgestrel, gestodene. delta-15-levonorge~lleh norgestimate~
wo 94/14450 2 lS 2~ 8 0 PCT/CA93/00564 17-deacetyl norgestimate, nomegesterol, nesterone. desogestrel and 3-keto-desogestrel. Preterred progestins are norethindrone acetate and 3-keto-desogestrel.
The selection of hormones most suited tor transdermal deliverv may be 5 determined by conventional tests used in the art to determine skin permeability.
The most common is the In Vitro Skin Permeation Cllamber using hairless mouse skin or human cadaver skin. The literature contains much int`ormation on these tests and the t`ollowing references are typical:
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), pp 105-lO8, 1989;
c) Liu P, Higuchi Wl, Song W~ Kurihara-Bergstrom T, Good WR.
Qll~ntit~ive Evaluation of Ethanol Effects on Diffusion and Metabolism of ~Estradiol in Hairless Mouse Skin. Pharm Res 8(7), pp 865-872, 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 hor",ones. skin permeation and hence transdermal delivery rates are important, but also, the stability ot the hormones in the tormulation can be a tactor. Stability can be ~ccecced or measured in two basic wavs: visual inspection and in vitro dissolution.
'5 Visual inspection is generally conducted on both a macroscopic and a microscopic level t`or crystal tormation. As tor in vitro dissolution, there aretests tor in vitro release rates which are standard in the art. Generally when these criteria are met, the transdermal delivery rates required are readily WO 94/14450 " PCT/CA93/00564 achieved.
The phases may comprise from one to tour days, but these days need not be exactly twenty-four hour days. Obviously there are limits as to the flexibility available given that absence ot hormone for too long would likely result hl S withdrawal bleeding, but for exampl~. for a three day phase. the total number ot hours might be 66 or 78. as opposed to 72. A preferred regimen uses phases comprising about three and about tour days. Other combinations such as two and three or one and three, or three and three. or two and tour, or one and tourmay be used.
Generally hormone replacement therapy is delivered without interruption.
But. there may be instances where interruption could be desirable in which case, patches cont~ining placebo or any other hormone-free agent may be included in a package. Examples ot suitable alternative hormone-free agents include vitamins, such as iron supplements.
Generally, the quantities of es~rogen and progestin inco,l,orated in the t`ormulation of the invention are dependent on the activity of the estrogen or progestin selected. In the present formulation, estrogen is administered continuously. in other words, it is always present in the t`ormulation, while the proge~ level is adjusted up or down to produce the required estrogen or '0 progestin dominance. The selection of quantities is dependent on the type of estrogen or progeslin since each hormone has its own specific activity.
Typically in the formulations described in U.S. Patent No. 5.108,995. the amount ot estrogen activity per unit dose may be equivalent in estrogenic activity to a range of from a minimum of about 0.3 mg of piperazine estrone 25 sulphate to a maximum of about 2.5 mg of piperazine estrone sulphate. The amount ot progestin activity per unit dose may be equivalent in progestagenic activity to a range of from a minimum of 0 mg to a maximum of about 5 mg ot norethindrone.
WO 94t14450 215 2 ~ 8 0 - PCT/CA93/00564 Some preferred combinations include the t`ollowing:
1. Three units doses of 0.75 mg piperazine estrone sulphate alternatin with three unit doses of 0.75 mg ot' piperazine estrone sulphate with 0.35 mg ot' norethindrone.
S ~. Three unit doses of 0.75 mg piperazine estrone sulphate and 0.15 mg of norethindrone alternating with three unit doses of 0.75 mg ot' piperazine estrone sulphate and 0.35 mg of norethindrone.
Equivalent dosages t'or transdermal can be determined from hormone blood level measurements. Generally, it is thought that t'or the delivery rates 10 contemplated t'or the patch formulations of the present invention, the amounts ot' hormones may be characterized as t'ollows. Firstly, each phase would generally constitute a single patch, though a series of patches could be used to make up aphase. Patch size is dependent on, among other parameters. the length of the phase, and the potency of the hormone. For example, patches of 17-~ estradiol 15 are currently available which provide transdelll,al delivery rates of about 50 ~g/day. In such inssnce, the amount of 17-¦3 estradiol is 4 mg and the size of the patch is about 18 cm' with the actual reservoir being about 10 cm`. In the case of a patch consining the two ho",lones, such as 17-~13 estradiol and norethindrone aceste. the amounts of same would be 10 mg and 30 mg, ~0 re~peclively and the patch surface area would be 26 cm- to provide transdermal delivery rates of about 50 ~Lg/day for 17-,B estradiol and about 250 ,ugiday fornorethindrone acetate. 3-Keto-desogestrel is a more potent progestin and the amount inco",o,dt~d in a patch might range from about 4 mg to about 30 mg to provide the required daily transdermal delivery rates. Tlle range for 17-¦3 25 estradiol may be from about I mg to about 10 mg (in adhesive matrix reservoir, this could change in another type of pauh), and t'or norethindrone acetate, the range may be from about 10 mg to about 100 mg.
The above combinations may also be grouped into three's and four's.
Wo 94/14450 21~ 2 7 8 0 ` PCT/CA93/00564 starting with either three or four day groups and ending with the other.
There are a number of transdermal patches available commercially which may be used in the present method. Most important to remember is that the sequence of administration is critical to the present invention and the 5 arrangement of the patches or their application in the predetermined order must be effected for the benefits of the invention to be obtained. Two such patches are described here for purposes of exemplification only, but others may be employed.
In one known system, a matrix of a solid adhesive of acrylic copolymer base 10 cont~ining hormones in dissolved form is employed. The system involves the use of a flexible b~cking foil which may comprise for example polyethylene terephth~i~te. A release liner forms another layer (in contact with the adhesive). A swellable polysaccharide, galactom~nn~n is added to the adhesive matrix to improve the adhesion between the surtace of the patch and hydrated 15 skin, over the whole application, and to reduce irritation phenomena caused by occlusion effects. Preferably, a three layer l~min~te is produced of the b~ckingfoil, drug matrix and release liner. Currently, a commercial product of this nature is sold under the trade mark SYSTEN TTS.
Another commercial product is that available under the trade mark ~0 ESTRADERM. ESTRADERMT~ is an estradiol transdermal system designed to release estradiol through a rate-limiting membrane continuously upon applicationto intact skin. The ESTRADERMT" system co~ ises five layers: a backing layer, a drug reservoir, a control membrane, an adhesive layer and a protective layer in that order from outside to inside. The qualitative composition of the ~5 ESTRADERM drug reservoir is estradiol, alcohol and hydroxy propylcellulose.
For transdermal administration, as has already been stated. any suitable torm ot patch may be selected. Another which is known to be useful in the administration of hormone formulations is described in detail in U.S. Patent No.
Wo 94/14450 PCT/CA93/00564 21527'801 4.668,23' issued May 26. 1987 to Cordes and Wolff, the disclosure ot` which is incorporated herein by reference. In this U.S. patent, the system described is atour layer system comprising an impermeable backing or covering layer: a reservoir layer adjacent to the backing or covering layer: an adhesive layer S permeable to the hormones and a protective layer which is removed before application of the patch. As described earlier. a three layer system may be used which comprises a backing layer, a drug matrix adhesive layer and a release liner.
An estrogen patch tor the present invention may be prepared using an 10 ethanolic gel type of drug reservoir. The weight ot hormone, pret`erably 17-~estradiol may comprise 4 mg. The patch mav have a surtace area of about 18 cm-. In appearance it may be round with the reservoir co~ "ising about 10 cm` of the patch. This generally provides a transdermal delivery rate of about 10 ~g/day tor 17-~ estradiol.
An estrogen/proge~lin patch may be prepared using an ethanolic gel type of drug reservoir with the amounts of hormones comprising 10 mg of 17-,B
estradiol and 30 mg of norethindrone acetate, for example. The total contact area of such a patch would be about 20 cm- and have the appedrdnce of eyeglasses with two joined reservoirs with each reservoir cont~ining both drugs.This generally provides a transdermal delivery rate of about 50 ~g/day of 17-,B
estradiol and about 250 ~g/day of norethindrone acetate.
Typically, this preparation is tor administration to post menopausal patients and/or those who are actively symptomatic.
The patches may be packaged, for example. in cartons containing a number of transdermal 17-13estradiol patches and a number ot transdermal 17-,B
estradiol and norethindrone acetate patches. Each patch may be individually sealed in a proteclive pouch.
In this example a tirst 17-~ estradiol patch may be applied for the required wo 94/14450 ~ PCT/CA93/00564 ~5~780 number of days (although it is not essential to start witll this phase), this patcl is removed and one ot` the 17-¦3 estradiol and norethindrone acetate patches is applied for the required number of days. The second patch is then removed and another 17-~ estradiol patch is applied. and so on. The treatment is normally S continued without interruption. The individual patches are usually changed every three or four days dependin~ on the particular regimen. although the patches may be prepared for application tor any combination ot days within the one to tour days limitation tor the regimen.
Each new patch is applied to a ditferent site. Preferred application sites are 10 clean, dry and intact areas of skin, below the waistline on the trunk of the bodv. Preterably the buttock. hip or abdomen area is chosen since these areas of skin wrinkle least during body movement.
MODES FOR CARRYING OUT THE INVENTION
In the t`ollowing examples, specific embodiments ot the present invention are IS set forth. These are meant to be illustrative of the invention and are not meant to limit it in any way. All parts and percentages are by weight, unless indic~d otherwise.
A three-day phase transdermal patch of 17-~3estradiol (100 ~Lg/day) is ~O administered and alternated with a three-day phase transdermal patch of 17-,~estradiol (100 ~g/day) and norethindrone (.35 mg/day). These patches are applied alternately and without interruption.
A three-day phase transdermal patch of 17-,Bestradiol (100 ~g/day) is 'S administered and alternated with a three-day phase transdermal patch of 17-~estradiol (100 ~g/day) and norethindrone acetate (0.35 mg/day). These patches are applied alternately and without interruption.
WO 94/14450 21~ 2 7 8 0 ` - PCT/CA93/00564 A three-day phase transdermal patch ot 17-~3 estradiol (50 ~g/day) is administered and alternated witll a three-day phase transdermal patch ot 17-~
estradiol (50 ~g/day) and norethindrone acetate (0.15 mg/day). These patches S are applied alternately and without interruption.
A three-day phase transdermal patch of 17-,B estradiol (25 llg/day) is administered and alternated with a tl-ree-day phase transdermal patch of 17-~3 estradiol (25 ~g/day) and norethindrone acetate (0.50 mg/day). These patches are applied alternately and without interruption.
E,YAMPLE S
An estrogen patch using an ethanolic gel type of drug reservoir incorporating about 4 mg. of 17-,B estradiol is prepared having a surtace area ot about 18 cm'. In appear~nce it is round with the reservoir COI"~l ising about 10 cm' of the patch. This generally provides a transdermal delivery rate of about 10 ~g/day tor 17-,B estradiol.
An estrogen/progestin patch is prepared using an ethanolic gel type of drug reservoir with the amounts of hormones comprising 10 mg of 17-~ estradiol and 30 mg of norethindrone acetate. The total contact area of such a patch is about 20 cm~. The patches have the appearance of eyeglasses with two joined reservoirs with each reservoir containing both drugs. These patches generally provide a transdermal delivery rate of 50 ~g/day of 17-~ estradiol and 250 ~g/day of norethindrone acetate.
The patches are packaged in cartons containing a number ot transdermal 17-13 estradiol patches and a number ot transdermal 17-13 estradiol and norethindrone acetate patches. Each patch is individually sealed in a protectivepouch.
A first 17-~3 estradiol patch is applied for the required three days (although it Wo 94/14450 215 2 7 8 0 PCT/CA93/00564 is not essential to start with this phase), this patch is removed and one of the17-,B estradiol and norethindrone acetate patches is applied tor four days. The second patch is then removed and another 17-~ estradiol patch is applied~ and so on. The treatment is continued without interruption. Each new patch is 5 applied to a different site. Preferred application sites are clean. dry and intact areas of skin, below the waistline on the trunk of the body. Preferably the buttock, hip or abdomen area is chosen since these areas of skin wrinkle least during body movement.
While the present invention has been described with reterence to specific 10 embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition~ many modifications may be made to adapt a particular situation, material or composition of matter, process. process step or steps, or then present objective15 to the spirit of this invention without departing from its eccenti~l te~r~hingc.
INDUSIl~IAL APPLlCABILlTY
The benefits of transdermal delivery systems are perceived to exist primarily inthe ability to bypass the liver on the "first pass" of the hormones through the body, by not delivering them orally. The advantage of avoiding the liver is that20 iower amounts ot the drug can be given to a patient in order to achieve the same degree of efficacy in target tissues. thereby diminishing the untoward metabolic effects (e.g., changes in coagulation tactors. glucose metabolism, lipids, etc.) that would be encout"ered via the oral route. It is also thought that avoidance of the stomach could prevent some of the nausea and gastrointestinal 25 distress that is associated with estrogen therapy when taken orally. It is believed that a continuous transdermal delivery system generally provides more constant steady-state plasma levels of hormones. devoid of peaks and valleys, than does a once daily oral administration. Estrogen replacement therapy is W O 94/14450 2 1 5 ~ 7 8 0 PCTICA93/00564 known to relieve hot tlushes and this relief ot flushes and night sweats improves sleep patterns and contributes to the patient's general teeling of well-being.
Estrogen replacement protects against postmenopausal loss ot calcium from the skeleton especially from vertebral bodies. preventing crush fractures and loss 5 of body height. Several studies have now reported that long-term estrogen therapy is also associated with a reduction in the incidence of classical osteoporotic fractures of the forearm and hip. Another beneficial effect of long-term estrogen use is the reduction of the risk of death trom ischemic heartdisease probably medi~ted by changes in blood lipoprotein concentrations.
10 Estrogen replacement has also been shown to improve the vascularity and health of the vaginal mucosa and urinary tract.
Claims (63)
1. A method of treating a female in need of hormone replacement therapy comprising transdermally administering to said female a pharmaceutical patch regimen series arranged in alternating phases of dominant hormone activity of from about one day to about four days, said phases being selected from estrogen dominant activity phases and progestin dominant activity phases, each of said phases comprising at least one patch which is applied and removed in accordance with the particular dominant phase activity, said estrogen dominant activity phase consisting of administering a transdermal estrogen substance alone or administering a transdermal estrogen substance and a transdermal progestin substance, and said progestin dominant activity phase consisting of administering a transdermal progestin substance and a transdermal estrogen substance, the amount of progestin substance being alternately increased in the progestin dominant activity phase and decreased in the estrogen dominant activity phase to provide the required dominant activity.
2. A method as claimed in Claim 1 wherein each phase is administered by a single patch.
3. A method as claimed in Claim 1 wherein each phase is administered by a plurality of patches.
4. A method as claimed in Claim 1 wherein the phases are administered without interruption.
5. A method as claimed in Claim 1 wherein the estrogen and progestin are selected from estrogens and progestins which provide levels of activity, equivalent to a transdermal delivery rate of from about 25 µg/day to about 100 µg/day of 17-.beta. estradiol and from about 25 µg/day to about 1000 µg/day of norethindrone acetate or from about 5 µg/day to about 150 µg/day of 3-keto-desogestrel, with the proviso that the progestin is increased in the progestin dominant phase relative to the estrogen dominant phase to produce the required dominance.
6. A method as claimed in Claim 1 wherein the estrogen dominant phase comprises an amount of 17-.beta. estradiol sufficient to provide a transdermal delivery rate of from about 25 µg/day to about 100 µg/day and the progestin dominant phase comprises an amount of 17-.beta. estradiol sufficient to provide a transdermal delivery rate of from about 25 µg/day to about 100 µg/day and an amount of norethindrone acetate sufficient to provide a transdermal delivery rate of from about 25 µg/day to about 1000 µg/day.
7. A method as claimed in Claim 6 wherein the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days.
8. A method as claimed in Claim 6 wherein the estrogen dominant phase comprises about four days and the progestin dominant phase comprises about three days.
9. A method as claimed in Claim 6 wherein the amount of norethindrone acetate is sufficient to provide a transdermal delivery rate of from about 75 µg/day to about 500 µg/day.
10. A method as claimed in Claim 6 wherein the amount of norethindrone acetate is sufficient to provide a transdermal delivery rate of from about 75 µg/day to about 300 µg/day.
11. A method as claimed in Claim 1 wherein the estrogen dominant phase comprises an amount of 17-.beta.estradiol sufficient to provide a transdermal delivery rate of from about 25 µg/day to about 100 µg/day and the progestin dominant phase comprises an amount of 17-.beta.estradiol sufficient to provide atransdermal delivery rate of from about 25 µg/day to about 100 µg/day and an amount of 3-keto-desogestrel sufficient to provide a transdermal delivery rate of from about 5 µg/day to about 150 µg/day.
12. A method as claimed in Claim 11 wherein the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days.
13. A method as claimed in Claim 11 wherein the estrogen dominant phase comprises the equivalent of about four days and the progestin dominant phase comprises about three days.
14. A method as claimed in Claim 11 wherein the amount of 3-keto-desogestrel is sufficient to provide a transdermal delivery rate of from about 25 µg/day to about 150 µg/day.
15. A method as claimed in Claim 1 wherein the estrogen dominant phase comprises an amount of 17-.beta.estradiol sufficient to provide a transdermal delivery rate of about 50 µg/day and the progestin dominant phase comprises an amount of 17-.beta.estradiol sufficient to provide a transdermal delivery rate of about 50 µg/day and an amount of norethindrone acetate sufficient to provide a transdermal delivery rate of about 300 µg/day.
16. A method as claimed in Claim 15 wherein the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days.
17. A method as claimed in Claim 15 wherein the estrogen dominant phase comprises about tour days and the progestin dominant phase comprises about three days.
18. A method as claimed in Claim 1 wherein the estrogen dominant phase comprises an amount of 17-.beta.estradiol sufficient to provide a transdermal delivery rate of about 50 µg/day and the progestin dominant phase comprises an amount of 17-.beta.estradiol sufficient to provide a transdermal delivery rate of about 50 µg/day and an amount of norethindrone acetate sufficient to provide a transdermal delivery rate of about 150 µg/day.
19. A method as claimed in Claim 18 wherein the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days.
20. A method as claimed in Claim 18 wherein the estrogen dominant phase comprises about four days and the progestin dominant phase comprises about three days.
21. A pharmaceutical package comprising a transdermal patch regimen for administration to a female in need of hormone replacement therapy wherein the package consists of a pharmaceutical patch regimen series arranged in alternating phases of dominant hormone activity of from about one day to about four days, each of said phases being selected from estrogen dominant activity phases and progestin dominant activity phases, each of said phases comprising at least one patch which is applied and removed in accordance with the particular dominant phase activity, said estrogen dominant activity phase consisting of a transdermal estrogen substance alone or a transdermal estrogen substance and a transdermal progestin substance, and said progestin dominant activity phase consisting of a transdermal progestin substance and a transdermalestrogen substance, the amount of progestin substance being alternately increased in the progestin dominant activity phase and decreased in the estrogendominant activity phase to provide the required dominant activity.
22. A package as claimed in Claim 21 wherein each phase is administered by a single patch.
23. A package as claimed in Claim 21 wherein each phase is administered by a plurality of patches.
24. A package as claimed in Claim 21 wherein the phases are administered without interruption.
25. A package as claimed in Claim 21 wherein the estrogen and progestin are selected from estrogens provide levels of activity equivalent to a transdermal delivery rate of from about 25 µg/day to about 100 µg/day of 17-.beta.estradiol and from about 25 µg/day to about 1000 µg/day of norethindrone acetate or fromabout 50 µg/day to about 150 µg/day of 3-keto-desogestrel, with the proviso that the progestin is increased in the progestin dominant phase relative to the estrogen dominant phase to produce the required dominance.
26. A package as claimed in Claim 21 wherein the estrogen dominant phase comprises an amount of 17-.beta. estradiol sufficient to provide a transdermal delivery rate of from about 25 µg/day to about 100 µg/day and the progestin dominant phase comprises an amount of 17-.beta. estradiol sufficient to provide a transdermal delivery rate of from about 25 µg/day to about 100 µg/day and an amount of norethindrone acetate sufficient to provide a transdermal delivery rate of from about 25 µg/day to about 1000 µg/day.
27. A package as claimed in claim 26 wherein the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days.
28. A package as claimed in Claim 26 wherein the estrogen dominant phase comprises about four days and the progestin dominant phase comprises about three days.
29. A package as claimed in Claim 26 wherein the amount of norethindrone acetate is sufficient to provide a transdermal delivery rate of from about 75 µg/day to about 500 µg/day.
30. A package as claimed in Claim 26 wherein the amount of norethindrone acetate is sufficient to provide a transdermal delivery rate of from about 75 µg/day to about 300 µg/day.
31. A package as claimed in Claim 21 wherein the estrogen dominant phase comprises an amount of 17-.beta. estradiol sufficient to provide a transdermal delivery rate of from about 25 µg/day to about 100 µg/day and the progestin dominant phase comprises an amount of 17-.beta. estradiol sufficient to provide a transdermal delivery rate of from about 25 µg/day to about 100 µg/day and an amount of 3-keto-desogestrel sufficient to provide a transdermal delivery rate of from about 5 µg/day to about 150 µg/day.
32. A package as claimed in Claim 31 wherein the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days.
33. A package as claimed in Claim 31 wherein the estrogen dominant phase comprises the equivalent of about four days and the progestin dominant phase comprises the equivalent of about three days.
34. A package as claimed in Claim 31 wherein the amount of 3-keto-desogestrel is sufficient to provide a transdermal delivery rate of from about 25 µg/day to about 150 µg/day.
35. A package as claimed in Claim 21 wherein the estrogen dominant phase comprises an amount of 17-.beta. estradiol sufficient to provide a transdermal delivery rate of about 50 µg/day and the progestin dominant phase comprises an amount of 17-.beta. estradiol sufficient to provide a transdermal delivery rate of about 50 µg/day and an amount of norethindrone acetate sufficient to provide a transdermal delivery rate of about 300 µg/day.
36. A package as claimed in Claim 31 wherein the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days.
37. A package as claimed in Claim 31 wherein the estrogen dominant phase comprises about four days and the progestin dominant phase comprises about three days.
38. A package as claimed in Claim 21 wherein the estrogen dominant phase comprises an amount of 17-.beta. estradiol sufficient to provide a transdermal delivery rate of about 50 µg/day and the progestin dominant phase comprises an amount of 17-.beta. estradiol sufficient to provide a transdermal delivery rate of about 50 µg/day and an amount of norethindrone acetate sufficient to provide a transdermal delivery rate of about 150 µg/day.
39. A package as claimed in Claim 38 wherein the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days.
40. A package as claimed in Claim 38 wherein the estrogen dominant phase comprises about four days and the progestin dominant phase comprises about three days.
41. A package as claimed in Claim 21 wherein each phase comprises a single patch.
42. A package as claimed in Claim 21 wherein each phase comprises a plurality of patches.
43. A pharmaceutical preparation for administration to a female in need of hormone replacement therapy comprising a patch regimen series arranged in alternating phases of dominant hormone activity of from about one day to about four days each of said phases being selected from estrogen dominant activity phases and progestin dominant activity phases, each of said phases comprising at least one patch which is applied and removed in accordance with the particular dominant phase activity said estrogen dominant activity phase consisting of a transdermal estrogen substance alone or a transdermal estrogen substance and a transdermal progestin substance and said progestin dominant activity phase consisting of a transdermal progestin substance and a transdermalestrogen substance, the amount of progestin substance being alternately increased in the progestin dominant activity phase and decreased in the estrogendominant activity phase to provide the required dominant activity.
44. The use of a pharmaceutical patch regimen in the preparation of a medicament for the treatment of a female in need of hormone replacement therapy without interuption,the patch regimen comprising a series of patches arranged in alternating phases of dominant hormone activity of from about one day to about four days said phases being selected from estrogen dominant activity phases and progestin dominant activity phases each of said phases comprising at least one patch which is applied and removed in accordance with the particular dominant phase activity said estrogen dominant activity phase consisting of administering a transdermal estrogen substance alone or administering a transdermal estrogen substance and a transdermal progestin substance and said progestin dominant activity phase consisting of administering a transdermal progestin substance and a transdermal estrogen substance the amount of progestin substance being alternately increased in the progestin dominant activity phase and decreased in the estrogen dominant activity phase to provide the required dominant activity.
45. The use as claimed in Claim 44 wherein each phase is administered by a single patch.
46. The use as claimed in Claim 44 wherein each phase is administered by a plurality of patches.
47. The use as claimed in Claim 44 wherein the phases are administered without interruption.
48. The use as claimed in Claim 44 wherein the estrogen and progestin are selected from estrogens and progestins which provide levels of activity, equivalent to a transdermal delivery rate of from about 25 µg/day to about 100 µg/day of 17-.beta.estradiol and from about 25 µg/day to about 1000 µg/day of norethindrone acetate or from about 5 µg/day to about 150 µg/day of 3-keto-desogestrel, with the proviso that the progestin is increased in the progestin dominant phase relative to the estrogen dominant phase to produce the required dominance.
49. The use as claimed in Claim 44 wherein the estrogen dominant phase comprises an amount of 17-.beta.estradiol sufficient to provide a transdermal delivery rate of from about 25 µg/day to about 100 µg/day and the progestin dominant phase comprises an amount of 17-.beta.estradiol sufficient to provide atransdermal delivery rate of from about 25 µg/day to about 100 µg/day and an amount of norethindrone acetate sufficient to provide a transdermal delivery rate of from about 25 µg/day to about 1000 µg/day.
50. The use as claimed in Claim 54 wherein the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days.
51. The use as claimed in Claim 54 wherein the estrogen dominant phase comprises about tour days and the progestin dominant phase comprises about three days.
52. The use as claimed in Claim 54 wherein the amount of norethindrone acetate is sufficient to provide a transdermal delivery rate of from about 75 µg/day to about 500 µg/day.
53. The use as claimed in Claim 54 wherein the amount of norethindrone acetate is sufficient to provide a transdermal delivery rate of from about 75 µg/day to about 300 µg/day.
54. The use as claimed in Claim 44 wherein the estrogen dominant phase comprises an amount of 17-.beta.estradiol sufficient to provide a transdermal delivery rate of from about 25 µg/day to about 100 µg/day and the progestin dominant phase comprises an amount of 17-.beta.estradiol sufficient to provide atransdermal delivery rate of from about 25 µg/day to about 100 µg/day and an amount of 3-keto-desogestrel sufficient to provide a transdermal delivery rate of from about 5 µg/day to about 150 µg/day.
55. The use as claimed in Claim 54 wherein the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days.
56. The use as claimed in Claim 54 wherein the estrogen dominant phase comprises the equivalent of about four days and the progestin dominant phase comprises about three days.
57. The use as claimed in Claim 54 wherein the amount of 3-keto-desogestrel is sufficient to provide a transdermal delivery rate of from about 25 µg/day to about 150 µg/day.
58. The use as claimed in Claim 44 wherein the estrogen dominant phase comprises an amount of 17-.beta.estradiol sufficient to provide a transdermal delivery rate of about 50 µg/day and the progestin dominant phase comprises an amount of 17-.beta.estradiol sufficient to provide a transdermal delivery rate of about 50 µg/day and an amount of norethindrone acetate sufficient to provide a transdermal delivery rate of about 300 µg/day.
59. The use as claimed in Claim 58 wherein the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days.
60. The use as claimed in Claim 58 wherein the estrogen dominant phase comprises about four days and the progestin dominant phase comprises about three days.
61. The use as claimed in Claim 44 wherein the estrogen dominant phase comprises an amount of 17-.beta.estradiol sufficient to provide a transdermal delivery rate of about 50 µg/day and the progestin dominant phase comprises an amount of 17-.beta.estradiol sufficient to provide a transdermal delivery rate of about 50 µg/day and an amount of norethindrone acetate sufficient to provide a transdermal delivery rate of about 150 µg/day.
62. The use as claimed in Claim 61 wherein the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days.
63. The use as claimed in Claim 61 wherein the estrogen dominant phase comprises about four days and the progestin dominant phase comprises about three days.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US99682092A | 1992-12-28 | 1992-12-28 | |
| US07/996,820 | 1992-12-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2152780A1 true CA2152780A1 (en) | 1994-07-07 |
Family
ID=25543344
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002152780A Abandoned CA2152780A1 (en) | 1992-12-28 | 1993-12-24 | Transdermal hormone replacement therapy |
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 |
| HU214598B (en) * | 1987-09-24 | 1998-04-28 | Jencap Research Ltd | Process for producing contraceptive compositions containing estragen and progestin and applicable for hormonal therapy |
-
1993
- 1993-12-24 WO PCT/CA1993/000564 patent/WO1994014450A1/en not_active Application Discontinuation
- 1993-12-24 CA CA002152780A patent/CA2152780A1/en not_active Abandoned
- 1993-12-24 EP EP94904111A patent/EP0675720A1/en not_active Withdrawn
- 1993-12-27 IL IL10818393A patent/IL108183A0/en unknown
- 1993-12-27 SI SI9300687A patent/SI9300687A/en unknown
- 1993-12-27 ZA ZA939686A patent/ZA939686B/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 |
|---|---|
| EP0675720A1 (en) | 1995-10-11 |
| CN1097987A (en) | 1995-02-01 |
| ZA939686B (en) | 1994-08-29 |
| SI9300687A (en) | 1994-09-30 |
| IL108183A0 (en) | 1994-04-12 |
| WO1994014450A1 (en) | 1994-07-07 |
| MXPA94000108A (en) | 2004-08-20 |
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Legal Events
| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |