CA2004203A1 - Compositions for transdermal delivery of estradiol - Google Patents

Compositions for transdermal delivery of estradiol

Info

Publication number
CA2004203A1
CA2004203A1 CA002004203A CA2004203A CA2004203A1 CA 2004203 A1 CA2004203 A1 CA 2004203A1 CA 002004203 A CA002004203 A CA 002004203A CA 2004203 A CA2004203 A CA 2004203A CA 2004203 A1 CA2004203 A1 CA 2004203A1
Authority
CA
Canada
Prior art keywords
adhesive
estradiol
pyrol
oleic acid
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002004203A
Other languages
French (fr)
Inventor
Sharad K. Govil
Dale Sterner
Stephen Jones
Geraldine Kennedy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme Corp
Original Assignee
Schering Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Corp filed Critical Schering Corp
Publication of CA2004203A1 publication Critical patent/CA2004203A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Abstract

ABSTRACT
Solvent systems comprising oleic acid, linear alcohol lactate and either dipropylene glycol or N-methyl-2-pyrrolidine useful for preparing adhesive matrix and rsservoir-type transdermal delivery devices for estradiol are disclosed.

Description

2004;~0~

COMPOSITIONS FOR TRANSDERMAL DELIVERY OF ESTRADIOL

SUMMARY OF THE INVENTION
The present invention relates to transder~al delivery of estradiol using a ~olvent ~ystem comprising oleic acid, linear alcohol lactate and either dipropylene glycol or N-methyl-2-pyrrolidone. Said solvent system may be used to prepare an adhesive matrix transdermal device or a reservoir transdermal device.
In particular, adhesive matrices can be prepared from vinyl acetate, acrylic, silicone or synthetic or natural ru~ber latex pressure sensitive adhesives. Where the transdermal device comprises a reservoir, the solvent system may be used to prepare a solutio~ or a gel.

BACKGROUND
The use of estradiol in estro~en replace~ent therapy iæ well known, and in fact ~n estradiol transdermal system comprising estradiol and e~hanol gelled with hydroxypropyl cellulose in a reserYoir-type transdermal patch i~ co~mercially available ~rom CI~
Phar~aceutical Company (ESTRADERM).
Various patent~ and published applications al~o relate to transdermal estradiol ~ystem3. For instance, U.K. patent application 2,093,694 discloses co-administration of e~tr~diol and ~thanol to incr~asQ
dermal penetrat~on of the drug. Sev~r~l other publications relate in general to enhancing dermal penetration of drugs and also specifically name estradiol: U.S. Patent 4,658,343 to Leeper et al discloses the use of polyethylene glycol monolaurate a~ a penetration enhancer; U.X. patent application 2,158,355 to Sarpotdar et al disclose the si~ilar use of a combination of propylene glycol and glycerine in specified ratios; and European patent application 147,146 to Tsuk discloses menthol as a penetration enhancer.
Other patent publications discloses the use of a matrix or gel for transdermally delivering estradiol:
PC~ publication W087/07138 to Chien et al discloses estradiol microdispersed in a polymer (e.g. a cilicone polymer) matrix; U.S. patent 4,668,232 to Cordes et al discloses a drug in a reservoir comprised of a polymer matrix composed of a rubber, an adhesive resin ma~erial, and a water-swellable polymer (e.g. a polysaccharide);
UcS. patent 4,559,222 to Enscore et al discloses a mineral oil-polyisobutylene-colloidal silicon dioxide matrix useful for transdermal delivery of estradiol, among other drugs; German patent application 3,333~240 discloses estradiol dissolved in a gel, which gel i8 dispersed in a crosslinked ~ilicone elastomer; French patent application 2,547,502 and U.S. patent 4,291,014 to Keith et al both disclose a-transdermal ~atrix usable for estradiol which comprises a polar plasticizer (e.q.
polyethylene glycol), a polyvinyl alcohol and a polyvinyl pyrrolidone.
Still other patents relate to the ~ore mechanical aspects of transdermal devices suitable for estra~iol administration. European patent application 250,125 to Berry et al and U.X. patent application 2,185,187 to Campbell et al disclose drug-containinq X00~03 ~atria~s incorporating ~ibers, which fiber~ ~bsorb the active or i~part flexlbility to the devicQ, rèspectively; U.S. patent 4,666,441 to Andriol~ ~t al discloses a transdermal device with multiple compartments to prevent uneven settling of the active in the patch when stored; and U.S. patent 4,624,665 to Nuwayser discloses microparticles of drug dispersed in a viscous material.
Effective transdermal administration of nany drugs has been achieved using various skin penetration enhancers. Oleic acid has been reported to be a penetration enhancer: see Cooper, ~Increased Skin Permeability for Lipophilic Molecules~, J. Pharm. Sci., 73, 1153 (1984~, wherein the use of varying concentrations of oleic acid in a polar solvent such as a diol (especially propylene glycol) enhanced the penetration of salicylic acid. U.S. 4,305,936 discloses a solution for topical or local appl~ication of a corticosteroid comprising a glyceral ester of a fatty acid of 6 to 22 carbon atoms, an alkanol cosolvent (e.g., dipropylene glycol), and a ~suitable auxiliary adjuvant~, e.g., oleic acid. PCT Application No. US86/02584 discloses enhanced penetration of mouse s~in by estradiol in a carrier comprisina 2-ethyl-1,3-hexane diol and oleic acid.
Disclosures relating to skin penetration enhancement with N-methyl-2-pyrrolidone (m-pyrol) include Bennett et al., ~Optimization of bioavailability o~
topical steroids: non- w cluded penetration enhancers under ther~odynamic control~, J. Pharm. Pharma~ol., 37, 298 (1985), wherein both ~-pyrol and a combination o~
oleic acid and propylene glycol were reported to increase 6teroid (betamethasone 17-benzoate) bioavailability.
U.S. patent 4,557,934 to Cooper discloses a combination of Azone and m-pyrol or a C3-C4 diol to enhance 200~Z03 penetration of a vari~ty of drug~, ~lthough estradiol i8 not specifi~ally men~ioned.

DETAILED DESCRIPTION
We have ~urprisingly found that the USQ 0~
specific solvent systems not only serves to dissolve e~tradiol in ~ pressure ~ensitive poly~eric adhesive matrix fiuitable for a transder~al device, but also promotes diffusion of estradiol through and out of the matrix and acts as a skin penetration enhancer to provide optimum, controlled transdermal flux through human skin. The transdermal delivery devices of the present invention therefore include both adhesive matrix and reservoir transdermal devices comprising either of two specific solYent systems which have found to be especially useful for preparing the devices and for administering estradiol. One solvent system compris~s dipropylene glycol (DPG), oleic acid and linear alcohol lactate and the second solvent system-comprises m-pyrol, oleic acid and linear alcohol lactate. The DPG ~olvent system i~ preferred.
Adhesive drug matrices of the present invention may be prepared from a poly~er mixture (i.e. a polymer blend) compri~ing, in addition to estradiol, a pressure sensitive polymeric adhesive and the solvent components listed above, a crosslink~ng agent, a polymer thick¢ner -to ad~u~t viscosity, and one or more processing solv~nts such a~ water and an alcohol such as ethanol. The concentrations of the components depend on whether they are deter~ined before or after curing , ~ince during the drying ~nd curing processes the ~olvent~ largely evaporat~. The concentrations which follow are-calculated as a w/w percentage. on a ~wet~ ba~i~, the ~ adhesive concentration is about 60 to about 80%, prefer~bly about 70 to about 75~, the crosslinking agent 200~X03 _5_ i~ pres~nt at about 0.1 to about 0.5%, prefQrably about 0.3~, and the thickener i8 present at about O.S to about 1.5%, preferably about 1% or as necessary to ad~ust vi~c08ity. T~e processing solvents represent about 10 to about 20% of the wet mixture, with typically about S to about 10% being water and about 2 to about 10% being alcohol.
For the DPG solvent system, the concentration range (~wet~ basis) is about 1 to about 20~ DPG, about 1 to about 20% oleic acid and about 1 to about 10% linear alcohol lactate (a C12-C15 alcohol lactate, e.g.
Ceraphyl-41 from Van Dyk, Division of Mallinckrodt, Inc., Belleville, NJ~, preferably about 2 to about 10%, especially about 5% DPG, about 2 to about 5%, especially about 3% oleic acid, and about 2 to about 5%, especially about 3% linear alcohol lactate. The m-pyrol solvent system comprises about 1 to about 20% m-pyrol, about 1 to about 20% oleic acid and about 1 to about 10% linear alcohol lactate, pr~fer~bly about 2 to about 10%
especially about 5% m-pyrol, about 2 to about 5~, especially about 37 oleic acid and about 2 to about 5 especially about 3% linear alcohol lactate.
Concentration ranges of the components in a cured matrix (i.e., ~dry~ basis) are about 70 to about 90% pressure sensitive adhesive, about 0.1 to about 0.5%
crosslinker, about 1 to about 2% thickener, about 2.5 to about 5% linear alcohol lactate, about 2.5 to about 5%
oleic acid, and about 5 to about 10% DPG or m-pyrol.
~ or a reservoir-type device, concentration ranges similar to the 'wet~ basis range above may be used, ~ince the final transdermal device preferably comprises an adhesive layer with the same component~ a~
describad above, except that the adhesive layer i~
separated from the estradiol solution by a polymer membrane. If, however, a different type of device is zoo~zn~

used (e.g. the adhesive i~ applled only around the Qdge of a device, thereby using proportionately le88 adhesive), the concentration percentages for the estradiol solution components are calculated on a different basis since the adhesive, crosslinking agent, thickener, and processing solvents are not present.
Concentration ranges for the solvent system in an estradiol solution per se are about 20% to about 60% m-pyrol or DPG, preferably about 40% to about 50%, especially about 45% DPG or m-pyrol; about 10% to about 40% oleic acid, preferably about 15 to about 25%, especially about 23% oleic acid; and about 10 to about 40% linear alcohol lactate, preferably about 15 to about 25%, especially about 23% linear alcohol lactate.
As used herein in the specification, the term ~estradiol~ includes estradiol and the pharmaceutically acceptable esters thereof. The concentration of estradiol in an adhesive matrix of the present invention similarly depends on whether it is measured nwet~, i.e., in the polymer blend before curing, or ~dry~, i.e. after curing. When ~wet~, estradiol is present at about 0.5 to about 5~, preferably about 1%, and when ~dry~ at about 1 to about 10%, preferably about 2%. In a reservoir device comprising a preferred adhesive layer as described above, estradiol is present at a concentration of about 0.5 to about 5%, while estradiol concentration in the solvent syste~ alone is about 5% to about 10%, preferably about 8 to about 15%, especially about 9%.
Pressur~ sensitive polymeric adhesives suitable for preparing matrices of the present invention include pharmaceutically acceptable acrylic, vinyl acetate, silicone and synthetic or natural rubber adhesives. For example, acrylic adhesives such as RA 2484, RA 2333, RA
2397, RA~`301~ l~rom Monsanto Co. are appropriate~ Other acrylic adhesives, such as Durotak, zbo4203 manuf~ctured by Morton Thlokol, Inc., and N~ocryl XAS210 by PGlyvinyl Chemicals, ~td. may bo util~æed.
Vinyl acetate adhesive~ include Plexbon~ 149 and Flexbond 15Q from Air Produ~ts.
Numerous silicone based adhesives may be used, such as Q72929, Q27406, X72920 and 355, each manufactured by Dow-Corning.
Natural and syntheti~ rubbers include polyiso-butylenes, neoprenes, polybutadienes and polyisoprene~.
The adhesives may be used singly or combinçd for use in the patch.
A crosslinking agent ~ay be added to facilitate curing, for example Aerotex Resin 3730 (American Cyanamid) and a thickener may be added to adjust the viscosity of the polymer mixture to about 6000-10,000 cps for coating on a backing material (the initial viscosity is about 3000 cps). The thickener can be an acrylic polymer thickener such as AMSC0 6038A (Unocal).
- For adhesive-matrix devices, the the poly~er blend is applied to a suitable backing material impermeable to estradiol or the other components of the polymer blend. The backing materials, which are preferably water resistant and can be occlusive or non-occlusive, can be selected from such materials as foam, metal foil, polyester, low density polyethylene, copolymers of vinyl chloride and polyvinylidene chloride (e.g. Saran), and laminates thereof. A typical foa~ -backing is a polyethylene closed cell radiation cross-1~nked foam such as Volar (Voltek, Division of Sekisui America Corp., Lawrence, MA).
Whers the transdermal device i5 a reservoir-type device, either ~olvent system described above can be used to ~orm an estradiol solution to fill the reser~oir, or about 0.1 to about 2%, preferably ab~ut 0.5~ of a gelling agent such as hydroxypropyl cellulose can be - zoo~o`~

added to ~orm a gQl. The solution or g~l $g retain~d in the reservoir by a suitable rate-controlling membrane such as an ethylene-vinyl acetate (~VA) copoly~er membrane (e.g. 1-20% vinyl acetate), which me~brane preferably has a face layer of a pres~ure sensitive adhesive as described above. Backing ~aterials for reservoir-type patches are similar to those described above for adhesive matrix-type devices.
Both adhesive matrix and reservoir devices preferably contain a release liner impermeable to the drug and the solvent system in order to protect the adhesive layer until the patch is to be applied to the skin. Typical materials suitable for release liners are polyethylene and polyethylene-coated paper, preferably silicon-coated to ~acilitate removal.
Methods for prep_ring adhesive matrix transdermal devices are known in the art. A preferred method for preparing adhesive matrix transdermal devices of the present invention comprises casting a thin layer of the polymer blend onto the material to be used as the release liner, curing the polymer blend to form the polymer adhesive (including drying in an oven), and laminating the backing material to the resultant adhesive layer. Suitably sized patches may then be punched out automatically, and the patches are preferably sealed into protecti~e pouches.
The layer of polymer blend cast on the release liner according to the preferred method i8 preferably about 5 mils to about 10 mils thick~ The cast layer i8 preferably dried at a temperature of about 80C for a period of about 20 min. A specific example of a formulation is shown below.
Reservoir-type patches may al~o be made by known procedures. For example, a layer of~adhesive may be applied to the release liner, the rate-controlling zoo42n:~

~embrane may bQ laminatQd to the adh~lv~ ~ide, a portion of gelled e~tradiol solution m~y ke plac~d on the membrane, and the backing material m~y then be heat-sealed to the rate-controlling membrane around the edge~
of the patch.
The size of the transder~al device of the present invention depends on the dose requirements, with preferred patch area being about 5 to about 20 cm2, preferably 7.5 or 15 cm2. The preferred delivery rate of estradiol is 0.25 l 0.2 ug/cm2/hr, giving a preferred daily dosage of about 50 ~g. A patch is applied and left in place for several days, preferabl~ for 1 week, bu~
shorter time periods, e.g. 3 days or 1 day may slso be used. The exact dose is determined by the skilled clinician depending on such factors as the age, weight and condition of the patient.
~ The following Table I shows typical adhesive matrix formulations of the present invention.

TABLE I
GENERAL FORMUI,ATIONS

Acrylic Pn~wre ~ ive 72.9% -- 72.9%
Sensitive ~sive Vinyl Acetate Adhesive - 72.9%
Pn~re Sensitive Adhesive Purified Wbter USP Solvent 8.7% 8.7% 8.7~
Dipn~lene Glyool Solvent - 5.3% 2.5%
N-~etbyl- Sblvent 5.3% - -2~ o1idbne Es~diol Drug 1.1% 1.1% 1.1%
E~nol USP Pnxxssing 5.3% 5.3% 5.3%
Solvent z004~0~

~IE~ ~I~ F~ 1 ~llA 2 ~ 3 0~1-41 ~lv~t 2.7% 2.7S 3.75 - Oleic A~:id NF C~Solv~nt 2.7% 2.7% 3.75 Cro6slirdc~ Cro6slird~ 0.3~ 0.3% 0,3%

hi~ as r~ded as ~d (q.s-) to adjust to adjust - visco6i~. ~i~.

Eollawir~ is a specific exan~le of an adhesive matrix fnatian:
Ingredients P ~ /lOOg batch step I: 1) RA-2484 (or Fle~xx~ 149)72.9g 2) A~x~K Resin 3730 0.3 3) Purified Water USP 8.7 4) C~hyl 41 2.7 5) Diprcpylene Glyool s.3 step II: 1) Oleic Acid 2.7 2) E~Y~ 5 3 3) Esb~iol 1.1 4) Thi~h~r 1.0 100. Og 12-pk. poly~x~ted p~bx~ (release 1~Y~) Volar foam (~ad~

Add, in order, the ingredients for Step 1 and mix for 15 minutes. Separately combine, in order, the ingredients for Step II and mix until ~mooth. Combine the products of Steps I and II and mix until smooth.
Check Yiscosity, and if necessary, add thickener to increase viscosity of the polymer blend to the required level.
Cast a`5-10 mil layer of polymer blend onto the release liner. Dry the layer at 80-C for 20 ~in.

Laminate the backing material to the dry polymer fllm using conventional e~uipment.
Using an automatic punch machine, punch out the desired ~ize patches. Using a pouch machine, enclose the patche~ in pouches and heat-seal closed.

20()~

Alt~rnatively, in the above procQdur~ the dipropylene glycol and ethanol may b~ int~rchanged, i.e., ethanol i8 mixed with the ingredient~ of Step I and dipropylene glycol is mixed with the ingredients of Step II.
The following Table II shows the in-vitro diffusion rates (J8S = ~g/cm21hr) of estradiol (E2) from different transdermal patches through heat isolated human cadaver epidermis using single compartment diffusion cells.
IA~LE II
IN-VTTRO DIFFusIoN R~ OF E~DIOL
F~nulation:* Sh~
%E2 %mrp %DPG %C-41 %o~ A~ive ~ Jss (~g/Cm~/hr) 2 - - - - acrylic 1 0.03 ' 0.01 215 - - - acrylic 1 0.06 ' 0.03 2 - - 15 - a y lic 1 0.11 ~ 0.02 210 - 5 5 acrylic 1 - 0.13 ~ 0.02 210 - 5 5 2 0.12 l 0.04 210 - 5 5 3 0.10 1 0.02 210 - 5 5 4 0.17 ~ 0~02 27.5 - 7.5 5 acrylic 1 0.13 ~ 0.02 27-5 - 7.5 5 2 0.13 t 0.03 27.5 - 7.5 5 3 0.13 ~ 0.02 2 - 10 5 5 vin~lacetate 1 0.26 ' 0.03 2 - 10 5 5 2 0.30 ~ 0.17 2 - 10 5 5 3 0.21 ~ 0.05 2 - 10 5 5 4 0.30 l 0.04 2 - 10 5 5 5 0.33 ' 0.06 2 - 10 5 5 acrylic 1 0.29 ~ 0.02 2 - 10 5 5 2 0.27 ~ 0.03 * E2 5 e~l~diol; mrp = m~ol; C~41 = c~hyl-41;
o~ = oleic acid; DPG = d~x~lene glycol

Claims (13)

1. A pharmaceutical composition for transdermal delivery of estradiol or a pharmaceutically acceptable ester thereof comprising oleic acid, linear alcohol lactate and either dipropylene glycol or m-pyrol.
2. An adhesive-matrix composition of claim 1 further comprising a pharmaceutically acceptable pressure sensitive polymeric adhesive or adhesive mixture.
3. A composition of claim 2 wherein the adhesive is selected from the group consisting of vinyl acetate, acrylic, silicone, synthetic or natural rubber latex pressure sensitive adhesives and mixtures thereof.
4. A composition as defined in claim 2 or 3 comprising about 1 to about 10% estradiol or a pharmaceutically acceptable ester thereof, about 2.5 to about 5% oleic acid, about 2.5 to about 5% linear alcohol lactate, about 5 to about 10% dipropylene glycol or m-pyrol, and about 70 to about 90% pressure sensitive adhesive.
5. A composition of claim 4 further comprising about 0.1 to about 0.5% crosslinker and about 1 to about 2% thickener.
6. A polymer mixture suitable for preparing an adhesive matrix estradiol composition of claim 2 comprising about 0.5 to about 5% estradiol or a pharmaceutically acceptable ester thereof, about 1 to about 20% oleic acid, about 1 to about 10% linear alcohol lactate, about 1 to about 20% dipropylene glycol or m-pyrol, and about 60 to about 80% pressure sensitive adhesive or adhesive mixture.
7. A polymer mixture of claim 6 comprising about 2 to about 5% oleic acid, about 1 to about 10% linear alcohol lactate, about 1 to about 20% dipropylene glycol or m-pyrol, and about 60 to about 80% pressure sensitive adhesive or adhesive mixture.
8. A polymer mixture as defined in claim 6 or 7 further comprising about 0.1 to about 0.5% crosslinking agent, about 0.5 to about 1.5% thickener, about 5 to about 10% water, and about 2 to about 10% alcohol.
9. A mixture of claim 8 comprising 72.9% pressure sensitive adhesive; 1.1% estradiol; 2.7% linear alcohol lactate; 2.7% oleic acid; 0.3% crosslinking agent; 1.0%
thickener; 8.7% water; 5.3% ethanol; and 5.3% dipropylene glycol or m-pyrol.
10. A mixture of claim 9 wherein the pressure sensitive adhesive is a vinyl acetate adhesive or an acrylic adhesive.
11. A pharmaceutical composition of claim 1 for use in a reservoir-type transdermal device comprising about 20 to about 60% dipropylene glycol or m-pyrol; about 10 to about 40% oleic acid; about 10 to about 40% linear alcohol lactate; and about 5 to about 20% estradiol or a pharmaceutically acceptable ester thereof.
12. A composition of claim 11 further comprising about 0.1 to about 2% gelling agent.
13. A process for preparing an adhesive matrix transdermal device for administering estradiol or a pharmaceutically acceptable ester thereof, said process comprising applying a polymer mixture to a backing member and curing the polymer mixture, wherein said polymer mixture comprises about 0.5 to about 5% estradiol or a pharmaceutically acceptable ester thereof, about 1 to about 20% oleic, about 1 to about 10% linear alcohol lactate, about 1 to about 20% dipropylene glycol or m-pyrol, about 60 to about 80% pharmaceutically acceptable pressure sensitive adhesive or adhesive mixture, about 0.1 to about 0.5% crosslinking agent, about 0.5 to about 1.5% thickener, about 5 to about 10% water, and about 2 to about 10% ethanol.
CA002004203A 1988-12-01 1989-11-29 Compositions for transdermal delivery of estradiol Abandoned CA2004203A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US27862588A 1988-12-01 1988-12-01
US278,625 1988-12-01

Publications (1)

Publication Number Publication Date
CA2004203A1 true CA2004203A1 (en) 1990-06-01

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US (1) US5154922A (en)
EP (1) EP0371496A1 (en)
KR (1) KR900701242A (en)
AU (1) AU4745390A (en)
CA (1) CA2004203A1 (en)
IL (1) IL92496A0 (en)
WO (1) WO1990006120A1 (en)
ZA (1) ZA899112B (en)

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IL92496A0 (en) 1990-08-31
AU4745390A (en) 1990-06-26

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