IL91067A - Sustained-release transdermal pharmaceutical compositions comprising estrogens - Google Patents

Description

91067/3 SUSTAINED-RELEASE TOPICAL PHARMACEUTICAL COMPOSITIONS COMPRISING ESTROGENS.

FIELD OF THE INVENTION : This invention refers to new compositions of matter for the topical application to humans of 17 - beta estradiol (Estradiol )and of compounds having a similar activity such as progesterone, medroxyprogesterone acetate, norethindrone, norethindrone acetate, dydrogesterone, ethinodiol acetate, hydroxyprogesterone caproate, norgestel , megestrol acetate and the like, in a controlled manner so that the concentration of the drug is kept within levels desir-r able for optimum clinical efficacy.

BACKGROUND OF THE INVENTION : The knowledge of the endocrinological role of estradiol dates from the early part of this century. Its relation to the menstrual cycle was established in the 1920 ' s and its chemical structure was elucidated in the 1930's.

When the ovaries do not function properly due to age (menopause ) or other reasons, or have been removed, the consequent lack of endogenous estradiol may produce a number of symptoms such as hot flushes, pain and increased hypocalcemia eventually leading to osteoporosis.

One way of avoiding or alleviating these symptoms is by administering to the patient a compensatory dose of estrogen. This treatment is not without danger. Thus it has been, establiehed by various researchers that in women taking exogenous estrogens there is an increased risk of endometrial cancer, estimated to be between 4.5 to 11.9 times greater than in nonusers. The risk is related to dosage and duration of use.

Other side-effects due tp the intake of estradiol may be cholelithiasis (gall bladder disease) and thromboembolic disease due to increase in lipoproteins and triglycerides levels in the blood.

Following the increase in the average age of human population during the last decades there is a higher number of female patients suffering from menopause symptoms and osteoporosis, therefore there exists a growing need for a suitable form of therapy, but due to the sometimes dangerous side-effects mentioned above, treatment has to be with a very fine tuning of the dosage, i.e. the blood levels of the drug are kept at the minimum required for clinical efficacy.

The concentrations of estradiol required for clinical effectiveness have been shown to be between 50 and 120 picogram per milliliter of plasma. At 60 P9/ml a reduction of about 50 % of the hot flushes was observed arid these totally disappeared at about 120 pg/ml .

Various methods are in use or have been proposed for estradiol therapy, such as tablets, aqueous suspensions for injection, implants and patches for transdermal medication. The oral therapy, using tablets, is the most convenient for the patient but the effect is rather short, the half life of estradiol in the plasma being only about one hour, and up to 3 doses per day may be required to maintain their therapeutically effective levels. The first pass inacfcivation of Estradiol is very high, its oral availability being only about 30%. This leads to accumulation in the body of large quantities of estrone and other estrogens. The use of injections, implants or pellets, while avoiding the first pass loss, is much less convenient to the patients and use of these forms of therapy is therefore not popular.

Lately there has been an increased interest in transdermal forms :of estradigl therapy. Estradiol, like pther estrogens, is easily absorbed through the skin, and since as indicated above, very small concentrations (around 100 pg/ml) are required for clinical effect-ivity, this seems to be an ideal drug for transdermal application. Furthermore, it has been shown that transdermal absorption of estradiol from different body sites is comparable. The problem is how to control the flux of the estrogen so that an adequate amount is released into the body over a long period of time.

A patch containing estradiol has been described in U.S.4379454. It consists of a dilute ethanolic solution of Estradiol gelled by hydroxypropyl cellulose. This gel is contained between a polymeric membrane composed of an ethyl ene/vinyl acetate copolymer and a backing of aluminized polyethylene therephthalate. The device is attached to the skin by means of a contact adhesive on its rim. Delivery of the drug is regulated by the rate of diffusion of the estradiol through the copolymer membrane. Such a device containing 0.05 mg of the drug has been shown to produce serum 'levels between 25 and 50- pg/ml. The patch has to be changed once a week.

In U.S. 4383993 nasal preparations are described containing estradiol and/or progesterone. The estrogens are mixed with a surfactant (Tween 80) and diluted with isotonic saline.

Application is by spraying.

SUMMARY OF THE INVENTION : It is known from previous studies cited in the literature that Estradiol is absorbed easily through the human skin. It is non-irritating, and the plasma levels required for clinical efficacy are very small .

In U.S. Patent 4533!i40 we have described a topical polymeric system which delivers nitroglycerin through the skin at a slow rate, so that applications are effective for a period of 24 hours in controlling angina pectoris symptoms. The system works by creating a pliable, adherent, polymeric film on the skin from which the drug is transferred to the internal layers of the epidermic and is diffused from there into the circulatory system. No membrane is used in this transfer process, the drug-carrying film is in direct and intimate contact with the skin, and this provides a simpler and more efficient system.

Polyvinylpyrrolidone (PVP) is a polymer widely used in pharmaceutical applications under the general name "povidone" . It is soluble in water and in alcohol .

It is known from the literature (Resetaris D.E. et al . Int. J.

Pharmaceutics 2. 113 (1979) that PVP constitutes a good solubilizing moiety for estradiol, it is an excellent crystal growth retardant and as such slows the transformation of the drug from its high-energy state to the stable crystalline form. PVP by itself is not a suitable material for film forming on the skin. It is quite hygroscopic and with the body's moisture it produces a sticky layer which is cosmetically unsatisfactory. The copolymers of vinyl pyrrol idone herein described avoid these problems while maintaining to a degree, the solubilization properties of the PVP moiety.

In the case of estradiol we have found that using polymers of the general type described in the above patent but modified so as to be particularly good solvents for the drug, it is possible to retain it in the polymeric film from where it will be slowly released into the skin.

For the purpose of this invention, the solubilization parameters of the polymers used in the formulation should be such that they are as close as possible to those of the Estradiol so as to produce a film having a good retention of the drug, thus minimizing migration and delaying penetration into the skin. Thus, a prolonged effect is obtained and the drug levels in the plasma controlled within the desired levels of concentration.

DETAILED DESCRIPTION OF THE INVENTION : The invention relates to simple and very effective long acting topical formulations of estradiol or a similar compound such as progesterone, medroxyprogesterone acetate, norethindrone, norethindrone acetate, dydrogesterone, ethinodiol acetate, hydroxyprogesterone caproate, norgestel , megestrol acetate, and the like, based on suitable solubil-izing film-forming polymers. These formulations are applied directly to the skin and are self-adhesive and non-irritating. After depletion of the drug they can be easily removed by using soap and water or by rubbing with alcohol.

For the purposes of this invention we have found that the most suitable polymers are water insoluble polymers of vinyl pyrrol idone as described in our U.S. Patent 4533540.

Water-insoluble copolymers of N-vinylpyrrol idone(called for short vinyl pyrrol idone) which may be used in the practice of this invention, may be prepared by the copolymerization of N-vinyl pyrrol idone with one or more appropriate comonomers in the proportions which yield water-insoluble, uncrossl inked copolymers. Suitable comonomers include acrylic esters, methacrylic esters, vinyl esters, crotonic esters, vinyl ethers, maleic half esters and diesters, vinylene carbonate, styrene, allyl esters, allyl ethers, etc. Other comonomers which are capable of copolymerizating with vinyl pyrrol idone, which are well known to those skilled in the art, may also be used.

Toxicological considerations restrict the choice of monomers to those which yield copolymers having a demonstrated lack of toxicological side-effects, on topical application to the skin.

The acrylic, methacrylic, crotonic and maleic esters which may be used in the preparation of the water-insoluble vinyl pyrrol idone copolymers which are effective in the practice of the present invention, include the esters 'of .C- linear, branched or cyclic alkanols, aralkanols, phenols and substituted phenols. The copolymers of vinyl pyrrol idone and the acrylic, methacrylic, crotonic and maleic esters may be made by copolymerization of vinylpyrrol-idone with the appropriate esters or by esterif ication of copolymers of vinyl pyrrol idone and acrylic, methacrylic, crotonic and maleic acids or anhydrides, with the appropriate hydroxyl -containing compound.

The vinyl esters and allyl esters which may be used in the preparation of the water-insoluble vinyl pyrrol idone copolymers which are useful in the practice of this invention, include the esters of C-^-C^ linear, branched or cyclic aliphatic, araliphatic or aromatic carbo-xylic acids. The copolymers of vinyl'pyrrol idone and the vinyl esters may be prepared by copolymerization of vinyl pyrrol idone with the appropriate vinyl ester or by transesterif ication of copolymers of vinyl pyrrol idone and vinyl acetate or other vinyl esters or by esterif ication of hydrolyzed copolymers of vinyl pyrrol idone and vinyl acetate or other vinyl esters. The copolymers of vinyl-pyrrol idone and allyl esters may also be prepared either by direct copolymerization or by transesterif cation or esterif ication, analogous to the preparation of vinyl ester copolymers with vinyl-pyrrol idone.

Graft copolymers made by- grafting vinyl monomers onto polyvinylpyrrolidone may also be used, e.g. graft copolymers of polyvinylpyrrolidone with acrylic esters, methacrylic esters, styrene, vinyl acetate and the like.

The water-insoluble copolymers of vinyl pyrrol idone which may be used in the practice of the present invention may be prepared by any of the conventional methods known in the art, including bulk, solution, emulsion, suspension or dispersion polymerization, with appropriate free radical catalysts such as peroxygen compounds, azo compounds redox systems, radiation and other catalytic techniques for initiating free radical polymerization. Since the method of polymerization is not an integral part of the practice of the present invention, any suitable method known to those skilled in the art may be used.

The amount of one or more comonomers in the water-insoluble vinyl pyrrol idone copolymers which are useful in the practice of the present invention, may be varied from 0.1 to 90% weight.

The actual amount is determined by the nature of the comonomer and the concentration necessary to produce a water-insoluble copolymer, either before or after copolymerization.

The drug used in this invention may be 17-beta estradiol or its esters such as estradiol benzoate, cypionate, valerate or other derivatives such as ethyny] estradiol such as progesterone, medroxy-prohesterone acetate, noreth ndrone, norethindrone acetate, dy-drogesterone, ethinodiol acetate, hydroxyprogesterone caproate, norgestel , megestrol acetate and the like. However, the preferred-drug is 17-beta estradiol. The polymer is such that it constitutes a good solvent for the estrogen, thus retarding its penetration into the skin. The rate of penetration therefore becomes a function of the partition coefficient for the drug between the polymeric film and the skin, this ratio being also influenced by the concentration of the drug in the polymer and the solubility parameter of the polymer. By suitable changes in the polymer composition, concentration of drug and surface of application, it is possible to achieve an optimum dosage for the patient.

The invention is illustrated by the following examples, but not 1 imited to them.

Example 1. 66.7 parts of Vinyl pyrrol idone were mixed with 28.6 part of Lauryl methacrylate and 200 parts of water containing 5 parts of sodium stearate. The mixture was heated and polymerized, using hydrogen peroxide as catalyst. The emulsion obtained was dried to a fine white powder. Nitrogen content was 8.6%. A gel was prepared containing 20 parts of the above polymer, 6 parts of glycerine, 3 parts of high viscosity PVP, 6 parts of fumed silicon dioxide and 64 parts of anhydrous ethanol . One hundred parts of this base were mixed with respectively 0.1, 0.25, and 0.35 parts by weight of estradiol.

A smooth gel was obtained, which when applied to the skin, dried after 3 minutes leaving a soft pliable film from which estradiol is released.

Of the gel containing 0.1% estradiol, approximately 2.5 gr. were daily applied to the skin of a post-hysterectomy patient, for a period of 3 months. Initial estradiol content in the plasma was below 10 pg/ml , at the end of the 3 months it was 254 pg/ml .

A similar application was made with the 0.25% estradiol gel on a patient who after two days of treatment showed plasma levels of 338 pg/ml while the initial level was 61 pg/ml before treatment.

Example 2 : A 64/36 by weight ratio vinyl pyrrol idone/2-ethylhexyl acrylate copolymer was prepared in isopropanol solution using lauroyl peroxide as catalyst. The copolymer obtained was dried on a teflon sheet. This material was formulated in gel form with estradiol as per formulations below.

Example 3 : A gel was prepared having the following composition: polymer (as per example 1) 11 parts, cetyl alcohol 4 parts, propylene glycol 5.5 parts, isopropyl myri state 2.8 parts, magnesium stearate 1 part, sodium stearate 3.8 parts, fumed silica 68 parts, ethanol 68 parts. After vigorous mixing, a high-viscosity gel (30-40.000 cps) was obtained. One hundred parts of this part by weight were mixed respectively with 0.05, 0.1, 0.5 and 1 part of estradiol.

The resulting formulations were packed in aluminum tubes for clinical trial. Some of the results obtained were as follows: Gel-containing 0.05% estradiol, daily dosage of about 1.5 g. to menopausial patient. Initial estradiol in the plasma 22 pg/ml , after 3 days 46 pg/ml. Gel containing 0.35% estradiol, same conditions as above, initial estradiol below 10 pg/ml, after 3 days 64 pg/ml . The same type of patient (menopause) treated with a gel containing 0.5% estradiol has a plasma content of 67 pg/ml after 3 days and 70 pg/ml after 21 days from an initial content of 37 pg/ml. Another menopause patient treated with the 1% gel showed after 5 days 83 pg/ml from an initial level of 25 pg/ml . - . , glycerine 22 parts cetyl alcohol 19.8. Isopropyl . myris'tate 8.8 Magnesium stearate 11. Sodium stearate 3.7, Aerosil 3008.8, Medroxyprogesterone acetate 4.4 parts and ethanol 107 parts. The gel was used in clinical trials for treating menopausic oatients.

Example 5 : The following formulations were prepared for in vitro diffusion tests using human skin as the membrane: A base gel was prepared , as per example 1. To 100 gr of this base were added respectively: 0.5 gr of Estradiol benzoate and 0.01 gr of Ethinyl estradiol. These gels when tested on a diffusion cell showed a transfer rate of about 1/10 g as compared with the same drugs at the same concentration but in a standard macrogol gel.

This demonstrates the slower rate of release from a polymer-film.

Claims (18)

9 1 0 6 7 / 2 -11- CLAIMS :

1. A composition for the sustained transdermal administration of an estrogen selected from the group consisting of 17/3-estradiol, ethinylestradiol and 17/3-estradiol esters, comprising an ointment base, gel or film containing a mixture of the estrogen and an uncross-linked, water-insoluble vinylpyrrolidone copolymer containing at least 10% by weight vinylpyrrolidone and a comonomer which is copolymerizable therewith by free radical polymerization, wherein the estrogen concentration is within the range of about 0.01 % to about 1 % of the total weight of the composition.

2. A composition for the sustained transdermal administration of an estrogen selected from the group consisting of 17 J-estradiol, ethinylestradiol and 17 3-estradiol esters, comprising an ointment base, gel or film containing a mixture of the estrogen and an uncross-linked, water-insoluble vinylpyrrolidone copolymer which contains at least 10% by weight vinylpyrrolidone and units derived from an ester of an unsaturated acid selected from the group consisting of acrylic acid, methacrylic acid, crotonic acid, maleic acid and the corresponding anhydrides, wherein the estrogen concentration is within the range of about 0.01 % to about 1 % of the total weight of the composition.

3. The composition of claim 2, wherein the ester is selected from the group consisting of the acrylic and methacrylic esters of C\ to C40 linear and branched alkanols.

4. The composition of claim 2, wherein the ester is lauryl methacrylate.

5. The composition of claim 2, wherein the ester is 2-ethylhexyl acrylate. ,'

6. A composition for the sustained transdermal administration of an estrogen selected from the group consisting of 17 3-estradiol, ethinylestradiol and estradiol esters, comprising an ointment base, gel or film containing a mixture of the estrogen and an uncross-linked, water-insoluble vinylpyrrolidone copolymer which contains at least 10% by weight vinylpyrrol- 9 1 0 6 7 / 2 -12- idone and units derived from an ester of a saturated acid selected from the group consisting of the vinyl and allyl esters of Ci to C 0 carboxylic acids, wherein the estrogen concentration is within the range of about 0.01 % to about 1 % of the total weight of the composition.

7. The composition of claim 6, wherein the ester is vinyl acetate.

8. A composition for the sustained transdermal administration of an estrogen selected from the group consisting of 17 3-estradiol, ethinylestradiol and 17 3-estradiol esters, comprising an ointment base, gel or film containing a mixture of the estrogen and an uncross-linked, water-insoluble vinylpyrrolidone copolymer with styrene, wherein the copolymer contains at least 10% by weight vinylpyrrolidone, and wherein the estrogen concentration is within the range of about 0.01% to about 1 % of the total weight of the composition.

9. The composition of claim 6, wherein the water-insoluble vinylpyrrolidone copolymer contains units derived from an unsaturated acid selected from the group consisting of acrylic acid, methacrylic acid, cro-tonic acid, maleic acid and the corresponding anhydrides.

10. The composition of claim 1, wherein the estrogen and water-insoluble vinylpyrrolidone copolymer are combined with an ointment base.

11. The composition of claim 2, wherein the estrogen and water-insoluble vinylpyrrolidone copolymer are combined with an ointment base.

12. The composition of claim 6, wherein the estrogen and water-insoluble vinylpyrrolidone copolymer are combined with an ointment base.

13. A bandage, gauze or tape impregnated or coated with the composition of claim 10.

14. A bandage, gauze or tape impregnated or coated with the composition of claim 11.

15. A bandage, gauze or tape impregnated or coated with the composition of claim 12. -13- 9 1 0 6 7

16. The composition of claim 1, wherein the estrogen and water-insoluble vinylpyrrolidone copolymer are combined with a solvent and a thickener to generate a gelled composition.

17. The composition of claim 2, wherein the estrogen and water-insoluble vinylpyrrolidone copolymer are combined with a solvent and a thickener to generate a gelled composition.

18. The composition of claim 6, wherein the estrogen and water-insoluble vinylpyrrolidone copolymer are combined with a solvent and a thickener to generate a gelled composition. 0S8IEN ZEDEK & RAPAPORT p. 0. Bax 33116 , Tel-A v i v