PT94787B - PREPARATION PROCESS OF PHARMACEUTICAL COMPOSITIONS FOR TRANSDERMIC ADMINISTRATION OF CORTICOSTEROIDS AND COMPOUNDS WITH SIMILAR PHYSIOLOGICAL ACTIVITY - Google Patents

Abstract

Preparation of compositions; topical transdermal application of corticosteroids; oestradiol type.

Description

INVENTION PATENT No. 94 787

NAME: IZHAK BLANK

EPxGRAFE: Process for preparing pharmaceutical compositions for transdermal administration of corticosteroids and compounds with similar physiological activity

INVENTORS:

Claim of the right of priority (under Article 4q of the Paris Convention of 20 March 1883):

Israel on July 21, 1989 under on ^fi . 91 0 67

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Patent No. 94787

Process for preparing pharmaceutical compositions for transdermal administration of corticosteroids and compounds with similar physiological activity ”so that

IZHAK BLANK, intends to obtain privilege of invention in Portugal.

SUMMARY The present invention relates to the process of preparing pharmaceutical compositions for topical transdermal application of estradlol-type corticosteroids, such as 17-beta-estradlol, and compounds having similar physiological activity, in which the drug is associated with a polymer skin trainer, capable of dissolving the drug and, when applied to the skin, adhering to it and releasing the drug, on the skin, at a slow rate.

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DESCRIPTIVE MEMORY

Field of the Invention The present invention relates to the process of preparing new compositions for topical transdermal application, to human, of 17-beta-estradiol (Estradiol) and compounds having a similar activity, such as progesterone, medroxy acetate. progesterone, norethindrone, norethindrone acetate, dldrogesterone, ethlnodiol acetate, hydroxyprogesterone caproate, norgestel, megestrol acetate and the like · The passage of the drug through the skin occurs in a controlled manner, so that the concentration of the drug is kept within desirable levels for optimal clinical efficacy.

Background of the Invention knowledge of the endocrinological role of estradiol dates from the beginning of this century * Its relationship with the menstrual cycle was established in the 1920s and its chemical structure was elucidated in the 1930s ·

When the ovaries do not function properly, due to (menopause) going or for other reasons, or have been removed, the consequent lack of endogenous estradiol can produce a number of symptoms such as hot flashes, pain and increased local hernia leading »eventually» to osteoporosis .

One way to avoid or alleviate these symptoms is to give the patient a compensating dose of estrogen. This treatment is not without danger * Thus »it has been established by several researchers that in women taking exogenous estrogens there is an increased risk of endometrial cancer, estimated to be 4.5 to 11.9 times higher than that of non-users. The risk is related to the dosage and duration of use *

Other side effects due to the administration of estradiol may be colelltiasis (gallbladder disease) and thromboembolic disease due to increased levels of lipoproteins and triglycerides in the blood. Following the increase in the average age of the human population, during the last decades, there are a higher number of female patients suffering from symptoms of menopause and osteoporosis, there is therefore an increasing need for an adequate form of therapy, but 71

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Due to the sometimes dangerous side effects mentioned above, treatment has to be done with a very accurate dosage adjustment, i.e. the levels of the drug in the blood are kept to the minimum required for clinical effectiveness.

The estradiol concentrations required for clinical efficacy have been shown to be between 50 and 120 picograms per ml of plasma. At 6th pg / ml, a reduction of about 50% of hot flashes was observed and these disappeared, totally, at about 120 pg / ml.

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

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

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-4 A US estradiol containing dressing has been described in U.S. 4,379,454. It consists of a diluted ethanol solution of Estradiol, gellfV each by hydroxypropylcellulose * This gel is contained between a polymeric membrane composed of an ethylene / vinyl acetate copolymer and an aluminum coated polyethylene terephthalate support. The device is attached to the skin by means of a contact adhesive on its rim * The distribution of the medication is regulated by the rate of diffusion of estradiol through the copolymer membrane * It has been shown that such a device containing 0.05 nig of the medication produces serum levels between 25 θ 50 pg / ml. The dressing has to be changed once a week. In the U.S

583 993 nasal preparations containing estradiol and / or progesterone are described · Estrogens are mixed with a surfactant (Tween 80) and diluted with laotonic saline. The application is by spraying.

Summary of the Invention

It is known from previous studies, cited in the literature, that Estradiol is easily absorbed through human skin. It is not irritating and the plasma levels required for clinical effectiveness are very low *

In the U * S Patent. 4,533,540 describe a topical polymeric system, which distributes introglycerin through the skin at a slow rate, so that applications are effective over a 24 hour period in controlling symptoms of angina pectorls. The system works by creating on the skin a polymeric film, adherent, flexible, from which the medicine is transferred to the inner layers of the epidermis and is diffused from there to the circulatory system * No membrane is used in this transfer process, the drug carrier film is in direct and intimate contact with the skin, and this provides a simpler and more effective system.

Polyvinylpyrrolidone (PVP) is a polymer widely used in pharmaceutical applications under the general name povldone.

It is soluble in water and alcohol.

It is known from the literature (Resetaris D.E., et al, Int. J. Phar maceutlcs 2. 113 (1979)) that PVP constitutes a good portion

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-5aolubilizer for estradlol, it is an excellent retardant of crystal growth and, as such, delays the transformation of the drug from its high energy state to a stable crystalline form. PVP per se is not a suitable material for film formation on the skin. It is quite hygroscopic and produces, with the moisture of the body, a sticky layer that is chemically undesirable. The vinylpyrrolidone copolymers described herein prevent these problems by maintaining, to a certain degree, the solubility properties of the PVP portion.

In the case of estradlol we 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 on the skin.

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

Detailed Description of the Invention Invention relates to the process of preparing long-acting, simple and very effective topical formulations of estrol or a similar compound such as progesterone, medroxyprogesterone acetate, norethindrone, norethindrone acetate, didrogesterone, acetate ethinodiol, hydroxy progesterone hydroxy caproate, norgestel, megestrol acetate and the like, based on suitable solubilizing film-forming polymers. These formulations are applied directly to the skin and are self-adhesive and non-irritating. After the medication is exhausted, 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 vinylpyrrolidone, as described in our U.S. Patent 4,553,540.

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The water-insoluble copolymers of N-vinylpyrrolidone (abbreviated vinylplyrolidone) that can be used in the practice of this invention can be prepared by the limerization cup of N-vinylpyrrolidone with one or more appropriate comonomers in the proportions that give rise to non-crosslinked, insoluble copolymers. in water. Suitable comonomers include acrylic esters, methacrylic esters, vinyl esters, crotonic esters, heml-esters and malodoric esters, vinylidene carbonate, styrene, allyl esters, allyl ethers, etc. Other comonomers that are also used capable of copolymerization with vinylpyrrolidone and which are well known to those skilled in the art.

Toxicological considerations restrict the choice of monomers to those that give rise to copolymers having a demonstrated lack of toxicological side effects in topical application to the skin. Acrylic, methacrylic, crotonic and maleic esters that can be used in the preparation of the water-insoluble vinylpyrrolidone copolymers that are effective in the practice of the present invention, include the linear alkanols, aralkanols, phenols and substituted esters Cj-Ο ^ θ , branched or cyclic. The vinylplrolidone copolymers and the acrylic, methacrylic, crotonic and malellic esters can be made by copolymerizing vinylplrolidone with the appropriate esters or by esterifying the vinylplrolidone copolymers and the acrylic, methacrylic, and acrylic acids or anhydrides, male and female, cros, 11 with the appropriate hydroxyl-containing compound. Vinyl esters and allyl esters that can be used in the preparation of water-soluble vinylplrolidone copolymers that are useful in the practice of this invention include linear, branched or cyclic, aliphatic, araliphatic carboxylic acid esters. or aromatics · Vinylplrolidone copolymers and vinyl esters can be prepared by copolymerizing vinylplrolidone with the appropriate vinyl ester or by transesterification of vinyl pyrrolidone copolymers and vinyl acetate or other vinyl esters or by esterification of vinyl copolymers vinyl pyrrolldone and vinyl acetate or other vinyl esters · The

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copolymer of vinylpyrrolidone and allyl esters can also be prepared either by direct copolymerization or by transesterification or esterification, analogous to the preparation of vinyl ester copolymers with vinylpyrrolidone *

Graft copolymers made by grafting vinyl monomers into polyvinylpyrrolidone, for example, polyvinylpyrrolidone graft copolymers with acrylic esters, methacrylic esters, styrene, vinyl acetate and the like can also be used.

The water-insoluble copolymers of vinyl pyrrolidone that can be used in the practice of the present invention can be prepared by any of the conventional processes known in the art, including solution, emulsion, suspension or dispersion mass polymerization, with appropriate free radical catalysts, such as as peroxygen compounds, azo compounds, redox systems, radiation and other catalytic techniques for the initiation of polymerization by free radicals. Any suitable process, known to those skilled in the art, can be used, since the polymerization process is not an integral part of the practice of the present invention *

The amount of one or more comonomers in the water-insoluble vinllpyrrolidone copolymers that are useful in the practice of the present invention, can vary from 0.1 to 90% by weight * The amount of real is determined by the nature of the comonomer and the concentration required to produce a water-insoluble copolymer, either before or after copolymerization *

The drug used in this invention can be 17-beta-estradiol or its esters, such as benzoate, clplonate, valerate or other estradiol derivatives such as ethyl estradiol, such as progesterone, medroxyprogesterone acetate, norethylone, acetate norethindrone, dldrogesterone, ethylenediol acetate, hydroxyprogesterone caproate, norgestel, megestrol acetate and the like. However, the preferred drug is 17-beta estradiol * The polymer is such that it is a good solvent for estrogen, thus slowing its penetration into the skin. Consequently, the penetration speed becomes a function of the drug's partition coefficient between the polymeric film

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and the skin, being * also * this speed Influenced by the concentration of the drug in the polymer and by the polymer solubility parameter. By appropriate changes in the composition of the polymer, in the concentration of the drug and in the application surface * it is possible to achieve an optimal dosage for the patient.

Invention is illustrated by the following examples, but is not limited to them ·

EXAMPLE 1

Emulsion copolymerization of 66.7 parts of N-vinylpyrrolidone / ~ V? _7 and 28 * 6 parts of lauryl methacrylate / ~ LM_7 was performed in 200 parts of water containing 5 parts of sodium stearate and 1.25 parts of hydrogen peroxide / conc · 3θ / 7 as catalyst ·

The mixture was heated with stirring and polymerization was performed at 75 ² C for about 10 hours. The conversion was 92%. The emulsion was spray dried at about 210 * C to a fine, off-white powder. The nitrogen content of the copolymer was 8.6%, indicating a PV content of 68%.

EXAMPLE 2

Copolymerization in a solution of 64 parts of N-vinylpyrrolidone and 36 parts of 2-ethylhexyl acrylate was carried out in 100 ml of isopropanol using a part of lauroyl peroxide as a catalyst. The polymerization was carried out under reflux, with stirring for a period of 12 hours. The conversion was 95% · The copolymer solution was poured on a teflon sheet and dried in an air oven at 6o ^and G · The nitrogen content of the copolymer was 8.4%, indicating a content of 66% in PV in finished material ·

EXAMPLE 3

An emulsion polymer was prepared using the following materials: water 23042, Alipal 00436 / emulsifier_7 46o, Ammonia / 25% solution _J7 75 * N-vinylpyrrolidone 9288, lauryl methacrylate 3981, hydrogen peroxide / conc. 30% _J7 339 and metabiates sodium sulfite 53, dissolved in 979 water. / All quantities are indicated in units of piece_ /. The reaction

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it took 11 hours to complete giving a conversion of 96.24%. Did the analysis show a content of 67.5% ⁱⁿ V? ^{in the} comonomer.

The emulsion was spray dried as in example 1 and gave a VP content of 66.1%. After drying in an air oven for 24 hours at a temperature of 9O ⁹ C content of free mono- mers was: 0 '03 in VH and 0.23% by LM.

EXAMPLE 4

Emulsion polymerization was performed using the following components, in parts by weight * ·

Water 22100, Stearic acid 440, Ammonia solution / ~ 25% __ 7 192, Isopropanol 112, N-vinylpyrrolidone monomer 8o64, lauryl methacrylate monomer 3456, Sodium metablssulfite / 6% solution _ / 425 and hydrogen peroxide / conc. 30% _7 156.

Polymerization was carried out in a stainless steel reactor provided with a heater, condenser and mechanical stirrer. It was carried out for a period of 5 hours, maintaining the temperature at 75 ² C during stirring, and then continued for another 4 hours, under the same conditions in order to complete the polymerization and minimize the free monomers. The emulsion was then cooled to room temperature. At this point it contained 32.5% solids / ~ 94% conversion_7 · It was then »diluted to a solids concentration of 20% and spray dried at 210 ^S C to give a fine, dirty, white powder that analyzed had 8.7% nitrogen, equivalent to a content of 69% in PV.

EXAMPLE 5

A gel was prepared by dissolving 20 parts of a VP / LM copolymer made as for example 1, in 64 parts of anhydrous ethanol · This was done at room temperature, with stirring · To the above solution 6 parts of glycerin were added , parts of polyvinylpyrrolidone / ~ Κ9θ_7 β 6 parts of silica fume (”fumed silica *) / ~ Aerosil 300 __ / · Gels containing estradol were prepared by mixing 100 parts of the gel base, 0.1 or 0 , 25 parts of pure 17- ^ -estradlol · The resulting soft gels were applied to patients' skin from a tube using a graduated cardboard ruler · They became

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-10 completely dry after 3 mi nu toe, producing flexible, soft films containing the medicine ·

EXAMPLE 6

A skin was applied to a patient / Ã_7 after a hysterectomy for a period of 3 months / daily application_7, approximately 2.5 cm of gel / equivalent to about 1.5e_7 containing 0.1% Estradiol · It was made a similar application of 1.5 g of gel containing 0.25% Estradiol to the skin of a similarly operated / b / 7 patient · Blood tests carried out on several

times showed the following results: B Patient THE Estradiol in gel 0.1% 0.25% Initial plasma estradiol level / pg / ml __ / <10 61 After two days - 338 After three months 254 -

EXAMPLE 7

A gel was prepared having the following composition: polymer / as for example 1_7 11 parts, cetyl alcohol 4 parts, propylene glycol 5 * 5 parts, isopropyl myristate 2.8 parts, magnesium stearate 1 part, sodium stearate 3.8 parts, smoked silica (fumed Bilica) 7 parts, ethanol 68 parts.

After vigorous mixing, a high viscosity gel / 30-40000 cps__7 was obtained.

EXAMPLE 8

One hundred parts / ~ 9 by weight_7 of the gel prepared as for example 7 were mixed with 0.05, 0.1, 0.5 · 1 part of 17- (3-E £ tradiol, respectively, by vigorously mixing in a closed container for 15 minutes The resulting materials were then packaged in aluminum tubes and used for clinical trials

EXAMPLE 9

A gel was prepared by vigorously mixing the following components / in% by weight __ /: ethanol 83.7, Klncel HF / a trademark for a class of hydroxypropyl cellulose_7 1, polymer,

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-11as for example 3 · · · »cetyl alcohol 1,9, propylene glycol 1, Isopropyl mlristate 1 * 4, magnesium stearate 0 * 5« sodium stearate 1 * 5 * aerosil 300 ·

One hundred parts of the homogeneous gel obtained was mixed 0 * 5 or 1 part of 17- (3-Stripe) The active gel was packed in aluminum tubes or plastic containers with a ball applicator and used for clinical trials.

Example 10

A gel prepared as for example 9, containing 1% Estradiol, was applied to a selected group of menopausal patients. · The application was made once a day using a graduated card rule. The dosage varied between 0 * 5 ® 1 * 5 S of gel per application · 08 initial and final levels of Estradiol in plasma / as pg / ml_J7 are shown below ·

Patient Applied quantity / κγ 7 Time / days 7 E2 1 ni ci al E2 fi 1 1.5 9 25 83 2 1.5 3 23 111 3 0.5 9 20 70 4 1.5 19 20 11 5 1.5 16 20 > 200 6 o, 5 - 1.5 5 25 47 7 o, 5 - 1.5 5 20 86 8 o, 5 - 1.5 5 22 98 EXAMPLE 11 Was prepared a gel like for example 7, using the

polymer as for example 2 and having various concentrations of Estradiol * from 0.05 to 1%. These were packed in aluminum tubes and applied using a graduated cardboard ruler.

The applications were made once a day and the amounts varied from 0 * 5 g to 1.5 g · The tested patients had very low levels of endogenous Estradiol *. The results obtained are shown below, as pg E2 in the plasma:

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Patient / X7 /> 7 rc ⁷ Estradlol in Gel,% 0.05 0.35 0.5 1.0 Plasma estradlol level, pg / ml Initial 22 / 10 37 25 After 3 days 46 64 67 - After 5 days - - - 83 After 21 days - - 70 - EXAMPLE i2 It was tested in patients Immediately after hlsterectomla

maie bilateral salplngoophorectomy * a gel prepared as for example 9 »containing 1% Eatradlol and packed in plastic containers with a ball applicator. The application of about 0.8 g of the gel was done once a day. Plasma estradlol levels are shown below in / ^ Pg / ml ^ /:

Patient Treatment Time (Years) E-2 E-2 Medlo 1. Menopause 2 50 - 100 80 2. Menopause surgical 2 yoo - 250 150 3 · Menopause surgical 1 60 - I50 120 4. Menopause 1 40 - I50 110 EXAMPLE 13 A gel base was prepared as for 0 example 5- sepa radically, it was done ointment end of macrogol by 65 g mixture

macrogol 300 with 35 g d® macrogol 4000 / macrogol is a trade name for polletilenogllcol · The numbers Indicate the approximate molecular weight_7 ·

Two compositions were made from the gel base above: A / containing 0.5% / ~ by weight_ / Estradlol benzoate, and b7 containing 0.01% ethinyl estradiol · Similar compositions C and D were made using, respectively, macrogol ointment ·

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-13 The diffusion rate of the steroids was measured in a standard diffusion cell, using isotonic saline as the receiving solution. Preparations A and B showed diffusion rates of an order of magnitude lower than that of equivalent preparations C and D.

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Claims (9)

- CLAIMS1 *. - Process of preparing a preparation for transdermal administration of estrogens or their functional derivatives or compounds with similar activity, characterized by the dissolution of a film-forming polymer, capable of dissolving the drug, and the drug, which when applied to the skin, adheres to it and releases it through the skin at a slow rate. 2-, - Process according to claim 1, characterized in that the dissolved active compound is progesterone, medroxyprogesterone acetate, norethindrone, norethleronine acetate, dldrogesterone, ethinodiol acetate, hydroxyprogesterone caproate, norgestel, megestrol acetate and similar. 3- · - Process for preparing a composition for sustained transdermal administration of 17-beta-estradiol, in the form of a solution, gel, ointment * dressing or film, containing the drug, characterized in that the drug is dissolved in a non-cross-linked copolymer and water-insoluble, of vinylpyrrolidone, with esters of unsaturated acids * crotonic and maleic * with the amount of vinylpyrrolidone not less than 10% of the total. 4 ?. Process according to claim 3, characterized in that the ester used is selected from the group consisting of linear and branched acrylic and methacrylic esters of C ^-C ^ g alkanols. ⁸ · 5 - Process according to claim 4, characterized in that the ester used is laurllo methacrylate " 6 *. Process according to claim 4, characterized in that the ester used is 2-ethyl-bexyl acrylate 7 ^! · - Process for preparing a composition for the sustained transdermal administration of estradlol * characterized by forming a film or solution containing a mixture of ethanol and a vinylpyrrolidone copolymer, non-crosslinked and insoluble in water, containing at least , 10% by weight of vinylplyrolone and units derived from a saturated acid ester, selected from the group consisting of vinyl and allyl esters 71 310 File: 5778/89 -15 "of C ^ -C ^ q carboxylic acids, with the estradlol concentration between 0.05 ® ® up to 5% with the total weight of the composition * 8 *. Process according to claim 7, characterized in that the ester is vinyl acetate * 9 *. - Process for the preparation of a composition for sustained transdermal administration of 17-beta-estradiol in the form of a solution, gel, ointment, dressing or film, characterized in that the drug is dissolved in a non-cross-linked, water-insoluble vinylpyrrolidone copolymer, composed of 50 to 8% vinyl_pyrrolidone and 50 to 2% lauryl methacrylate *