KR100481459B1 - Composition for transdermal administration of an estrogen, a progestin or a mixture thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical preparation in the form of a gel suitable for transdermal administration of an active agent of estrogens or progestins or a mixture of the two, wherein the chemical formula CH ₃ (CH ₂ ) _n CH ₂ OH (wherein n is a mixture comprising monoalkyl ether of aliphatic alcohol and diethylene glycol of 8 to 16); As a vehicle or carrier, a mixture of alkanols, glycols and water having 2 to 4 carbon atoms; Copolymers or polymers of acrylic acid as gelling agents; And quaternary amines as thickeners and neutralizing agents. By using the pharmaceutical preparation according to the present invention, it is possible to transdermally deliver the drug therapeutically.

Description

Composition for transdermal administration of an estrogen, a progestin or a mixture

The present invention relates to a pharmaceutical formulation of a novel composition for transdermal administration of estrogen, progestin or mixtures thereof, and more particularly, a pharmaceutical agent having excellent cosmetic properties and hypoallergenic properties, which is useful for the treatment of hormone replacement via transdermal route (HRT). To pharmaceutical preparations.

When the ovary fails to function properly due to age or disease such as menopause or removal of the ovaries, many symptoms, such as osteoporosis due to hot flushes, pain and an increase in calcium deficiency resulting in deficiency of endogenous estradiol. Indicates.

To alleviate and eliminate these symptoms, there is a method of hormone replacement treatment by prescribing a supplemental amount of estrogen.

The serum level of estradiol required for clinical efficacy is 40-60 pg / ml and was observed by Powers. The values in these ranges are the physiological serum levels of early follicles in premenopausal women.

There are a variety of methods or dosage forms provided or used for estradiol replacement therapy such as tablets, injections, implants and transdermal devices (patches or gels) and the like. Of these, oral treatment with tablets is easy to accept by the patient. However, estradiol is rapidly metabolized during inactive developing estrone through the liver for the first time. Therefore, high doses of estradiol are needed to achieve clinically suitable estradiol serum levels, and as a result high levels of estrone serum provide more than physiological values. Absorption through the gastrointestinal pathway increases the delivery of the estrogen circulation to the liver, and much of the liver is metabolized to inactive conjugates so that only a fraction of the active hormones participate in the general circulation. The liver responds to this increased delivery with increased protein and lipid metabolism and these activities can carry potential risks. Examples of such transformations include increased hepatic synthesis of renin substrates, sex hormone-binding globulins and changes in cholesterol and lipid lipoprotein metabolism.

Parenteral administration and the use of implants or pellets to avoid first-pass metabolism is much more inconvenient for patients and these dosage forms are less common.

Estradiol transdermal administration is a skin delivery device that circulates estradiol through the stratum corneum of the epidermis at a constant rate. Clinical studies have shown the effective benefits of transdermal estradiol on plasma. Gonadotropin, purulent vaginal epithelium, metabolic parameters of bone resorption and menopausal symptoms (fever, sleep disorders, urogenital discomfort, mood sticking) are comparable to those of oral and subcutaneous estrogens, whereas oral estrogens to hepatic metabolism Undesirable effects are avoided (Balfour 1990).

In general, physicians prescribe progestin-bound estrogen in postmenopausal women who have not had hysterectomy. Resistant estrogens cause anomalous vaginal bleeding, endometrial hyperplasia and hyperstimulation of the endometrium causing cancer. Only progestin addition can protect the endometrium while maintaining a beneficial effect on the skeleton and symptoms. According to the literature, the transdermal amount of noethin drone acetate required to resist endometrial estrogen hyperstimulation is about 200-300 mcg / day (Whitehead 1990).

Transdermal estradiol should be administered continuously or at intervals of three weeks without one week (free interval) during the 28-day cycle. Continuous treatment is particularly suitable for women who have undergone hysterectomy or have symptoms of estrogen deficiency during the free interval.

Patients with an intact uterus should receive additional progestin therapy continuously for 10 to 15 days each month. Whether estrogen therapy is cyclic or continuous, bleeding often stops at the end of every step of progestin therapy.

Continuous / binding therapy (continuous estrogen and continuous progeston) has the advantage of not causing hemostasis. Transdermal administration of the drug offers several therapeutic advantages over conventional routes of administration. However, the main disadvantage of this treatment is the limited amount of drug delivered through the skin. This limitation is due to several factors. Because skin is inherently a protective barrier, the rate of transport of most compounds through the skin is very slow. In general, it is difficult to apply to patch surface area of 50 to 100 sqcm or more. Thus, transdermal application of semisolid dosage forms such as gels, creams, ointments, liquids can increase patient compliance and extend the application of surface areas.

In order to overcome the barrier properties of the epidermal stratum corneum and to facilitate the absorption of the active agent into the skin, many compounds such as azone, glycol, pyrrolidone, aliphatic alcohol, fatty acids and esters thereof are used as penetration enhancers ["pharmaceutical skin penetration enhancement" Marcel Dekker, New York 1993, pages 229-242.

EPA 0 367 431 describes aliphatic alcohols such as isopropyl alcohol and isobutyl alcohol commonly used in topical transdermal formulations to increase the rate of transdermal delivery of steroid drugs.

EP 0 573 133 describes transdermal devices containing gestodems that bind one or more estrogens. It also describes the addition of transdermal penetration enhancers.

FR 0 518 879 claims a estradiol based medicament for postmenopausal treatment. This simple agent is a hydroalcoholic gel in which estradiol is dissolved in the above-mentioned vehicle and claims to be administered by transdermal route of estradiol.

EPA 0 279 977 describes transdermal devices administered by progestrone and estradiol esters themselves or combinations thereof, sucrose monococoate, glycerol monooleate, sucrose monolaurate, glycerol monolaurate A polymer matrix of a drug containing a penetration enhancer such as is used.

USP 5 023 084 claims a transdermal estrogen / progestin device consisting of a polymer adhesive such as polyacrylic, silicone or other suitable polymer adhesive and a polymer layer made of decyl alcohol as penetration enhancer.

GB 2 208 147 A describes a transdermal reservoir form comprising ethanol as a reagent for enhancing skin absorption and having a membrane controlled for the administration of estrogen and progestin.

WO 90/11 064 describes skin penetration enhancer compositions relating to estrogens and progestins or mixtures thereof. The composition comprises diethylene glycol monoethyl or monomethyl ether and propylene glycol monolaurate, methyl laurate and the like.

Although there are many patents and publications related to the transdermal administration of steroid drugs and the use of penetration enhancers, the inventors of the present invention have disclosed that semi-solid dosage vehicle compositions and adjuvant and transdermal compositions of estrogens, progestins or mixtures thereof, as disclosed herein, No relevant data could be found in the prior art.

The above mentioned patents or publications report on the study of diethylene glycol monoethyl ether with lauryl alcohol in ternary vehicle composites in semisolid dosage forms designed for simultaneous administration of estradiol and noethine drone acetate via transdermal route. none.

The present invention has been made to solve the above problems, and an object of the present invention is for many steroid compounds such as estradiol, noethyne drone or mixtures thereof, estrogen and progestin combined with a suitable penetration enhancer at a controlled rate. To provide a transdermal drug that can deliver.

It is a main object of the present invention to provide a gel dosage form which shows a suitable and effective transdermal penetration enhancing effect on estradiol, noethine drone acetate or mixtures thereof.

In order to achieve the above object, the present invention provides a penetration-enhanced pharmaceutical formulation suitable for transdermal administration of an active agent of estrogens or progestins or a mixture of both.

As used herein, “penetration enhancer” or “penetration enhancer” relates to increasing the skin penetrating capacity of an active agent pharmaceutically to increase the rate of absorption of the drug through the skin and penetration into the bloodstream. Through the use of such reinforcing agents, in particular, the increased penetration effect through the use of the reinforcing agent composition of the present invention is applied to animal skin or human skin using the diffusion cell apparatus described in the Examples herein to measure the rate of diffusion of the drug. Can be observed.

As used herein, "effective" or "proper" penetration enhancer means that the penetration enhancer will provide the desired increase in skin permeability, and will also provide an appropriate degree of penetration, rate of administration, and amount of delivery agent.

By the term "transdermal" delivery we mean transdermal and transmucosal administration, ie, the drug is delivered through the skin or mucous tissue and delivered into the bloodstream.

As used herein, "carrier" or "vehicle" means a transporter suitable for transdermal drug administration and includes materials such as liquids, gels, solvents, liquid thinners, stabilizers, and the like, used in the prior art, and are compositions in toxic environments. Does not interact with other components of and is not toxic. Examples of suitable vehicles used herein include water, alcohols, polyalcohols and glycols.

As used herein, "pharmaceutical active agent" or "drug" means a chemical or compound suitable for transdermal or mucosal administration that induces the desired systemic effect.

A “pharmaceutically effective” amount of a pharmaceutically active agent means a sufficient amount of the compound that is nontoxic but provides the desired therapeutic effect.

The term " closed condition " as used in this experiment using the apparatus described in FIG. 3 means that the diffusion chamber 2 is closed by the top plate 3, which blocks exchange from outside air. Means that. On the contrary, the term "non-closed condition" means that the top plate 3 has a hole which allows free interaction with external air which allows evaporation of the volatile solvent with the agent to be tested.

The present invention relates to a penetration enhancer of an active agent, substantially comprising a mixture of a monoalkyl ether of an aliphatic alcohol of general formula CH ₃ (CH ₂ ) _n CH ₂ OH, wherein n is 8 to 16; As a vehicle or carrier, a mixture of alkanols, glycols and water having 2 to 4 carbon atoms; Copolymers or polymers of acrylic acid as gelling agents; And gel form suitable for transdermal administration of estrogens or progestins or active agents of both mixtures, including quaternary amines as thickening and neutralizing agents.

In the skin penetration enhancer, the alkanol having 2 to 4 carbon atoms is preferably ethanol or polyalcohol, preferably in a vehicle or carrier composition consisting of propylene glycol and water, the first component is of the general formula CH _3- (CH ₂ ) a fatty acid represented by _n- CH ₂ OH, where n is an integer, 8 to 16, preferably 8 to 12, most preferably 10. And the second component is a monoalkyl ether of diethylene glycol, preferably diethylene glycol monoethyl ether or diethylene glycol monomethyl ether and most preferably diethylene glycol monoethyl ether.

The present invention provides a formulation in which the dosage form of 17-β-estradiol and noethynedrone acetate is administered at a rate of penetration that establishes the concentration of the therapeutically effective system is limited to a limited amount of chemical to provide a consistent penetration rate. Provide the substance. The chemicals are fatty alcohols such as lauryl alcohol, n-decanol, oleyl alcohol and the like and diethylene glycol monoethyl ether in ternary vehicles consisting of ethanol, propylene glycol and water.

(카르복시비닐 폴리머)를 사용하고 활성제로서 에스트라디올 및 노르에틴드론 아세테이트; 침투 강화제로서 라우릴 알콜 및 디에틸렌 글리콜 모노에틸 에테르를 포함하는 경피제제는 24시간을 통하여 두 호르몬의 치료학적으로 유효한 혈청 농도를 제공한다. 상기의 제제에 관한 생체이용률은 폐경기후의 여성을 대상으로 시행되었다.Acrylic acid polymers or copolymers, preferably carbomers, as gelling agents in ternary vehicle mixtures consisting of ethanol, propylene glycol and water

(Carboxyvinyl polymer) and used as activators estradiol and noethyne drone acetate; Transdermal formulations comprising lauryl alcohol and diethylene glycol monoethyl ether as penetration enhancers provide a therapeutically effective serum concentration of both hormones over 24 hours. Bioavailability for the above formulations was performed in postmenopausal women.

Although the action of the stratum corneum effect in the present invention has not been fully understood so far, it will be understood as the following matters.

Mainly fatty acids contribute to the stratum corneum due to lipid affinity and interaction with the stratum corneum lipids.

Diethylene glycol monoethyl ether dissolves both hydrophilic and lipid affinity actives and facilitates penetration of the actives into the skin.

Lower monohydric alcohols, such as ethanol, have the function of increasing the liquid flowability of the stratum corneum or the extraction of lipids from the stratum corneum.

Since a wide range of pharmaceutical vehicles, propylene glycol, acts as a cosolvent of the drug, it increases the solubility of the active agent in the formulation and solvates the intracellular keratin of the stratum corneum to increase the fluidity of the drug.

Water increases the solubility of the hydrophilic active agent in the formulation and accelerates the release of the lipid affinity active agent from the formulation and skin hydration.

Polymers or copolymers of acrylic acid, such as carbomer ^R (carboxyvinyl polymer), act as gelling agents and facilitate the release of lipid affinity activators to act as penetration enhancers.

Tertiary amines, such as triethanolamine, have the function of neutralizing and concentrating the system.

The present invention relates to a novel composition based on binding of an enhancer in a vehicle composition for transdermal administration of the steroid hormone itself or a mixture thereof. This is very important because transdermal permeability is mainly affected by the physicochemical properties of the penetrant and the interaction of the penetrant with the reinforcing agent. The formulations provide therapeutically useful concentrations of steroid hormones such as estradiol and noethine drone for the treatment of hormone replacement.

The present invention is directed to methods of providing novel compositions and controlled doses of estradiol and noethynedrone acetate applied through the human percutaneous. The novel composition comprises estradiol and noethetrone acetate or mixtures thereof in a gel dosage form that optimizes for proper penetration so that the concentration of drug in the patient's serum can be maintained at a desirable level to have a clinically appropriate effect. .

The therapeutically effective daily dose by the prior art (Powers 1985 and Whitehead 1990) is about 40-50 mcg / day of estrogen on the basis of 17-β-estradiol and 200-250 mcg / day of progestin on the noretin drone acetate.

The inventors have discovered that there is interference when estradiol and noethine drone acetate are combined during the infiltration process. There is no mention of this interference in the prior art of combined transdermal administration of estrogen and progestin.

It is not clear that specific synthetic progestins are effective in transdermal administration with or without a penetration enhancer in an amount sufficient to prevent estrogen endometrial hyperplasia.

The combination of two or more skin penetration enhancer compounds often results in excellent effects such as excellent transdermal absorption, but the combination of penetration enhancers has shown controlled and sustained transdermal absorption of hormones for 24 hours.

The scientific literature says that a true synergistic effect is achieved when the penetration enhancer combination has a greater effect than when used as an individual component itself.

(Besins Iscovesco)로부터의 침투 속도는 폐쇄조건에서 시험관내 침투 연구에서 높은 값을 나타내었다.It has also been found that the formulations disclosed herein exhibit high penetration rates in non-closed conditions. Conversely, oestrogel

Penetration rates from Besins Iscovesco were high in in vitro penetration studies at closed conditions.

It has also been found that lauryl alcohol acts as the most appropriate enhancer in the administration of noethine drone acetate. Thus high penetration of noethine drone acetate / estradiol is carried out using lauryl alcohol in the same concentration ratio of noethine drone acetate / estradiol in the formulation.

In addition, lauryl alcohol showed a high initial increase effect, while diethylene glycol monoethyl ether showed a latent increase in hormone penetration. Moreover, as mentioned in the bioavailability studies in postmenopausal women described herein, the mixture of penetration enhancers has allowed us to provide adequate and sustained hormone serum levels for 24 hours.

In a preferred embodiment of the present invention, estradiol 0.02 to 0.09% (w / w), preferably 0.04 to 0.07% (w / w), most preferably 0.06% (w / w) and noethine drone acetate 0.30 Estradiol and noethetrone acetate as pharmaceutically active agents containing from 1.50% (w / w), preferably 0.60-1.20% (w / w), most preferably 1.20% (w / w). Dissolve in the dosage form. The selected fatty acid lauryl alcohol comprises 0.40 to 6.00% (w / w), preferably 1.00 to 4.00% (w / w), most preferably 2.00% (w / w), and diethylene glycol mono Ethyl ether comprises 1.00 to 15.00% (w / w), preferably 2.50 to 10.00% (w / w), most preferably 5.00% (w / w).

Active agents and compounds that enhance hormone penetration rate include alkanes having 2 to 4 carbon atoms, preferably ethanol; Soluble in a three-way vehicle composite consisting of polyalcohol, preferably propylene glycol and purified water.

The final formulation is therefore 0.02 to 0.09% (w / w), preferably 0.04 to 0.07% (w / w), most preferably 0.06% (w / w) estradiol; 0.30-1.50% (w / w), preferably 0.60-1.20% (w / w), most preferably 1.20% (w / w) noethin drone acetate; 0.40 to 6.00% (w / w), preferably 1.00 to 4.00% (w / w), most preferably 2.00% (w / w) lauryl alcohol; 1.00 to 15.00% (w / w), preferably 2.50 to 10.00% (w / w), most preferably 5.00% (w / w) diethylene glycol monoethyl ether; 20.00 to 65.00% (w / w), preferably 30.00 to 55.00% (w / w), most preferably 44.49% (w / w) ethanol; 1.00 to 12.00% (w / w), preferably 3.00 to 9.00% (w / w), most preferably 6.00% (w / w) propylene glycol and 20.00 to 65.00% (w / w), preferably Comprises 30.00 to 55.00% (w / w), most preferably 39.45% (w / w) water. Other components to finally complete the formulation include carbomer (carboxyvinyl polymer) 0.50 to 4.00% (w / w), preferably 1.00 to 2.50% (w / w), most preferably 1.20% (w) / w); Triethanolamine 0.05 to 1.00% (w / w), preferably 0.10 to 0.60% (w / w), most preferably 0,40% (w / w) and flavoring agent 0.05 to 0.50% (w / w) , Preferably 0.10 to 0.30% (w / w), most preferably 0.20% (w / w).

Optionally, ethylenediaminotetraacetic acid (E.D.T.A) may be contained as an antioxidant up to 0.2% by weight of the total formulation weight.

Percentages are based on the total weight of the gel dosage form.

Penetration enhancers according to the invention can prove to be very suitable for hormones and at the same time do not increase the permeability of other hormones. This is described by Chien's book "Development Concepts and Practice in Transdermal Therapeutic System" in Transdermal Therapeutic Systemic Medications, Marcel Dekker Inc., New York, 1989, pages 25 -81].

There is no known reinforcing agent or combination thereof that shows a percutaneous penetration enhancing effect on the active agent or drug. By way of example, the results of the present invention are cited as exemplified herein below.

Enhancement of skin penetration of various drugs using other forms of strengthening

In addition, another benefit of the present invention was supported when the results reported by Chien were analyzed. Chien announced the dependence of reinforcing elements on skin penetration of progesterone on the length of alkyl chains of saturated fatty acids in "Dermal transdermal drugs". Chien discovered a major strengthening effect with capronic acid (C8), but also describes decanoic acid (C10) in USP 5 145 682 as a better strengthening agent for estradiol. The effect of a skin penetration enhancer on a particular active agent is the function of the form, the concentration and how much the penetration enhancer is released from the device. This conclusion is consistent with the conclusions of the present inventors, which were drawn from Chien's ["Dermal transdermal drug", Maarcel Dekker, New York 1987, pages 25-81].

The prior art indicated herein is clearly at least a steroid compound as shown in this patent application and is not a universal penetration enhancer composition and the proper penetration rate through the skin can only be determined by testing different types of compounds at different concentrations. . While the prior art is useful for the theoretical approach, the results must be carefully considered for various variables.

The following examples show examples of the invention and are not intended to limit the invention.

< Example 1>

Estrogen hormone is a naturally occurring estrogen 17-β-estradiol. Other estrogenic steroid hormones can be used with complete or partial replacement of 17-β-estradiol. For example, esters are biologically compatible and can be effectively transdermally absorbed. Estradiol esters include estradiol-3,17-diacetate; Estradiol-3-acetate; Estradiol-17 acetate; Estradiol-3,17-divalerate; Estradiol-3-valerate; Estradiol-17-valerate; 3-mono, 17-mono and 3,17-dipropionate esters, and corresponding cypionate, heptanoate, benzoate and other esters; Ethynyl estradiol; Estrone and other estrogenic steroids and derivatives thereof that can be administered via the transdermal route. It can be used in combination with the aforementioned steroids.

As progestin, noethynedrone acetate is currently preferred. Other progestins can be used from noethyne drones, norgestines, methoxyprogesterones, progesterones, progesterone acetates, norgestrels, chromadinanes, gestadens and the like.

Lauryl alcohol and diethylene glycol monoethyl ether are preferred as penetration enhancer compounds.

Other reinforcing agents may be used instead of lauryl alcohol. Other suitable reagents such as n-decanol, lauryl acid, oleyl alcohol, etc., proposed in the prior art described herein can be used.

Estradiol 0.06% (w / w), noethine drone acetate 1.20% (w / w) (the ratio of norietin drone acetate / estradiol is 20: 1), lauryl alcohol 2.00% (w / w), di Ethylene glycol monoethyl ether 5.00% (w / w), ethanol 44.53% (w / w), propylene glycol 5.99% (w / w), purified water 39.43% (w / w), carbomer (carboxyvinyl polymer) 1.20% (w / w), 0.39% (w / w) triethanolamine, and 0.20% (w / w) flavourant were prepared in a 250 ml container and agglomerated and air bubble obstructed by a 300 rpm mixer at room temperature. The mixture was stirred to disperse the carbomer (carboxyvinyl polymer) in the total amount of purified water. Slowly pour the carbomer (carboxyvinyl polymer) and sprinkle it in water. After 1 hour propylene glycol was added with continuous mixing to ensure uniformity. Meanwhile, estradiol, noethetrone acetate, lauryl alcohol, diethylene glycol monoethyl ether and flavoring agent are dissolved in the total amount of ethanol to prepare the ethanol phase in another vessel. The ethanol phase was then poured onto water and stirred at 300 rpm until homogeneous. Triethanolamine was added during the final stirring.

< Example 2>

Estradiol 0.04% (w / w), norethine drone acetate 0.60% (w / w) (the ratio of norietin drone acetate / estradiol is 15: 1), lauric acid 1.00% (w / w), di Ethylene glycol monoethyl ether 5.01% (w / w), ethanol 47.16% (w / w), propylene glycol 4.64% (w / w), purified water 40.12% (w / w), carbomer (carboxyvinyl polymer) 1.20% (w / w), a gel containing 0.23% (w / w) of triethanolamine was prepared according to the method described in Example 1.

< Example 3>

Estradiol 0.015% (w / w), norethine drone acetate 0.45% (w / w) (the ratio of norietin drone acetate / estradiol is 30: 1), lauric acid 1.00% (w / w), di Ethylene glycol monoethyl ether 5.07% (w / w), ethanol 43.54% (w / w), propylene glycol 4.99% (w / w), purified water 43.54% (w / w), carbomer (carboxyvinyl polymer) 1.20% (w / w), a gel containing 0.20% (w / w) of triethanolamine was prepared according to the method described in Example 1.

< Example 4>

Estradiol 0.015% (w / w), noethine drone acetate 0.45% (w / w) (the ratio of norietin drone acetate / estradiol is 30: 1), lauryl alcohol 1.00% (w / w), di Ethylene glycol monoethyl ether 5.07% (w / w), ethanol 43.52% (w / w), propylene glycol 4.99% (w / w), purified water 43.52% (w / w), carbomer (carboxyvinyl polymer) 1.20% (w / w), a gel containing 0.24% (w / w) triethanolamine (gel containing lauryl alcohol instead of lauryl acid) was prepared according to the method described in Example 1.

< Example 5>

Estradiol 0.06% (w / w), ethanol 48.80% (w / w), propylene glycol 6.06% (w / w), purified water 43.28% (w / w), carbomer (carboxyvinyl polymer) 1.20% (w / w), a gel containing 0.40% (w / w) of triethanolamine and 0.20% (w / w) of flavor was prepared according to the method described in Example 1.

< Example 6>

Noethyne drone acetate 1.20% (w / w), ethanol 48.22% (w / w), propylene glycol 6.06% (w / w), purified water 42.69% (w / w), carbomer (carboxyvinyl polymer) 1.20% ( w / w), triethanolamine 0.43% (w / w) and a flavoring agent 0.20% (w / w) were prepared according to the method described in Example 1.

< Example 7>

Estradiol 0.06% (w / w), norethine drone acetate 1.20% (w / w) (northine drone acetate / estradiol ratio is 20: 1), ethanol 48.19% (w / w), propylene glycol 5.98 % (w / w), purified water 42.72% (w / w), carbomer (carboxyvinyl polymer) 1.20% (w / w), triethanolamine 0.43% (w / w), flavor 0.22% (w / w) Gel) was prepared according to the method described in Example 1.

< Example 8>

Except for the addition of lauryl alcohol and diethylene glycol monoethyl ether as penetration enhancers, it basically comprises the same gel as the formulation of Example 5. The gel composition is as follows: estradiol 0.06% (w / w), lauryl alcohol 2.00% (w / w), diethylene glycol monoethyl ether 5.00% (w / w), ethanol 45.22% (w / w) , Propylene glycol 5.96% (w / w), purified water 39.96% (w / w), carbomer (carboxyvinyl polymer) 1.20% (w / w), triethanolamine 0.40% (w / w), flavor 0.20% ( gels containing w / w) were prepared according to the method described in Example 1.

< Example 9>

Except for the addition of lauryl alcohol and diethylene glycol monoethyl ether as penetration enhancers, basically the same gel as the formulation of Example 6 was included. The gel composition was as follows: 1.20% (w / w) noethyne drone acetate, 2.01% (w / w) lauryl alcohol, 5.02% (w / w) diethylene glycol monoethyl ether, 44.52% (w / w) ethanol w), propylene glycol 6.00% (w / w), purified water 39.46% (w / w), carbomer (carboxyvinyl polymer) 1.20% (w / w), triethanolamine 0.39% (w / w), flavor 0.20 Gels containing% (w / w) were prepared according to the method described in Example 1.

< Example 10>

Estradiol 0.06% (w / w), norethine drone acetate 1.20% (w / w) (northine drone acetate / estradiol ratio is 20: 1), lauryl alcohol 2.00% (w / w), ethanol 50.32% (w / w), purified water 44.61% (w / w), carbomer (carboxyvinyl polymer) 1.20% (w / w), triethanolamine 0.40% (w / w), flavor 0.21% (w / w) Gel) was prepared according to the method described in Example 1.

< Example 11>

Estradiol 0.06% (w / w), norethine drone acetate 1.20% (w / w) (northine drone acetate / estradiol ratio is 20: 1), diethylene glycol monoethyl ether 5.02% (w / w) ), Ethanol 48.60% (w / w), purified water 43.33% (w / w), carbomer (carboxyvinyl polymer) 1.20% (w / w), triethanolamine 0.38% (w / w), flavor 0.20% ( gels containing w / w) were prepared according to the method described in Example 1.

< Example 12>

Estradiol 0.03% (w / w), norethine drone acetate 0.60% (w / w) (the ratio of norethine drone acetate / estradiol is 20: 1), diethylene glycol monoethyl ether 5.00% (w / w ), Ethanol 45.83% (w / w), propylene glycol 6.11% (w / w), purified water 40.63% (w / w), carbomer (carboxyvinyl polymer) 1.20% (w / w), triethanolamine 0.40% ( w / w), a gel containing 0.22% (w / w) flavoring agent was prepared according to the method described in Example 1.

< Example 13>

Except for the addition of n-decanol (n-decyl alcohol) as penetration enhancer, it basically comprises the same gel as the formulation of Example 12. The gel composition is as follows. Estradiol 0.03% (w / w), norethine drone acetate 0.60% (w / w) (the ratio of norethine drone acetate / estradiol is 20: 1), n-decanol 1.00% (w / w), Diethylene glycol monoethyl ether 5.0% (w / w), ethanol 45.35% (w / w), propylene glycol 6.03% (w / w), purified water 40.21% (w / w), carbomer (carboxyvinyl polymer) 1.20 A gel containing% (w / w), triethanolamine 0.40% (w / w) and 0.17% (w / w) flavor was prepared according to the method described in Example 1.

< Example 14>

Except for the addition of oleyl alcohol as penetration enhancer, it basically comprises the same gel as the formulation of Example 12. The gel composition is as follows: estradiol 0.03% (w / w), noethyne drone acetate 0.60% (w / w) (norethine drone acetate / estradiol ratio is 20: 1), oleyl alcohol 1.00% (w / w), diethylene glycol monoethyl ether 5.00% (w / w), ethanol 45.95% (w / w), propylene glycol 5.01% (w / w), purified water 40.77% w / w), carbomer ( Carboxyvinyl polymer) A gel containing 1.22% (w / w), 0.22% (w / w) triethanolamine, and 0.20% (w / w) flavor was prepared according to the method described in Example 1.

< Example 15>

Except for the addition of lauryl alcohol as a penetration enhancer, it basically contains the same gel as the formulation of Example 12. The gel composition is as follows: estradiol 0.03% (w / w), noethine drone acetate 0.60% (w / w) (norethine drone acetate / estradiol ratio is 20: 1), lauryl alcohol 2.0% (w / w), diethylene glycol monoethyl ether 5.0% (w / w), ethanol 45.43% (w / w), propylene glycol 5.02% (w / w), purified water 40.29% w / w), carbomer ( Carboxyvinyl polymer) A gel containing 1.20% (w / w), triethanolamine 0.20% (w / w) and 0.21% (w / w) flavoring agent was prepared according to the method described in Example 1.

< Example 16>

Estradiol 0.06% (w / w), norethine drone 0.50% (w / w) (northine drone acetate / estradiol ratio is 8.3: 1), lauryl alcohol 1.99% (w / w), diethylene Glycol monoethyl ether 4.98% (w / w), ethanol 44.75% (w / w), propylene glycol 6.31% (w / w), purified water 39.62% (w / w), carbomer (carboxyvinyl polymer) 1.20% ( w / w), 0.40% (w / w) triethanolamine, and 0.19% (w / w) flavoring agent were prepared according to the method described in Example 1.

< Example 17>

Estradiol 0.061% (w / w), methoxyprogesterone acetate 0.297% (w / w) (the ratio of methoxyprogesterone acetate / estradiol is about 4.8: 1), lauryl alcohol 1.98% (w / w), Diethylene glycol monoethyl ether 5.10% (w / w), ethanol 44.98% (w / w), propylene glycol 5.96% (w / w), purified water 39.86% (w / w), carbomer (carboxyvinyl polymer) 1.20 A gel containing% (w / w), 0.39% (w / w) triethanolamine, and 0.18% (w / w) flavor was prepared according to the method described in Example 1.

Penetration studies in vitro

In addition, as shown in FIG. 3, an in vitro permeation experiment was conducted to the abdominal skin of guinea pigs using a diffusion chamber.

Pig's abdominal skin was shaved for 72 hours before guinea-san female pigs (8-16 months old) were sacrificed by cervical dislocation. Only intact animals were used. The entire thickness of the abdominal skin is surgically excised and one of the vertical diffuse cell sections with 1.77sqcm of epithelium facing upwards of the percutaneous surface is prepared. The pharmaceutical formulations of the amounts described in the above examples are sprayed onto the transdermal layer while the transdermal layer is contacted with lauryl sodium sulfate solution at 34 ° C. The behavior of hormones in the subcompartment (receptor phase) was sampled at a given time and monitored and measured using high performance liquid chromatography (HPLC).

The experiment was conducted under two different conditions; In order to prevent evaporation of the volatile solvent, it was carried out under closed conditions with a glass lid and under open conditions where evaporation was allowed.

The table below shows the results of in vitro penetration experiments.

TABLE 1

Table 1 summarizes the results obtained in Example 2 and Oestrogel (Becinth Iscobestos) under closed and non-closed conditions.

The results obtained with the oestrogels were about 90 times higher during the experiments under closed conditions. However, it was surprisingly found that the penetration values for 17-β-estradiol and noethyne drone acetate were extremely high even under the non-closed conditions in this example.

We have assumed that the behavior of the formulation is due to the addition of several phenomena. These elements are listed below:

The formulation can fill or inject general irregularities of the transdermal. Thus a reservoir of vehicle was generated and increased transdermal absorption of the compound even when all the ethanol evaporated.

It seems that this formulation has the advantage of super saturation. The effect was predicted in alcoholic lotions and gels, but in the more complex systems of this experiment, the loss of volatile solvents (alcohols) increases the thermodynamic activity in the residual vehicle due to the generation of supersaturated solutions (Davis and Hadgraft's "Pharmaceutical Increased skin penetration "Marcel Dekker, New York 1993).

Another phenomenon is the production of an invisible closed film that can reduce the hydration state of the stratum corneum or the transdermal water content and the transdermal water loss. Increasing the water content increased the permeability and elasticity of the stratum corneum, while decreasing the water content would have the opposite effect (Davis and Hadgraft's "Increasing Pharmaceutical Skin Penetration" Marcel Dekker, New York 1993).

TABLE 2

Table 2 shows the results obtained using lauryl alcohol and lauric acid as penetration enhancers.

Contrary to the prediction that lauric acid is more effective as an increasing agent than lauryl alcohol because of the results for filling naloxone in Brain and Walter's "Increased Pharmaceutical Skin Penetration" (Marcel Dekker, New York 1993), In the case of both of the reagents showed an increase effect, surprisingly, in the case of the noretin drone acetate lauryl alcohol was twice as high penetration rate. This result confirms our prediction that no universal strengthening agent is present.

Based on these results, it can be estimated that the formulation of the present invention comprising lauryl alcohol can be administered in vivo with higher penetration rate of noethine drone / estradiol with the same concentration ratio of noethine drone acetate / estradiol in the formulation. there was.

TABLE 3

Example 5 (Estradiol only), Example 6 (Norethine drone acetate only), Example 7 (Norethine drone acetate and estradiol) without a strengthening agent in Table 3 and Example 8 (Estradiol) Only), the results obtained in Example 9 (norethin drone acetate only) and Example 1 (norethin drone acetate and estradiol) are shown.

These results clearly show that there is interference between hormones in the infiltration process, since 17-β-estradiol penetrated from the binding gel is considerably less than 17-β-estradiol penetrated from the estradiol gel. Noretin drone acetate penetrated from the noretin drone acetate gel and the mixed gel did not show a significant difference when the agent was not included in the formulation, but surprisingly, when no penetration enhancer was included in the formulation in the noretin drone acetate penetrated from the binding gel Showed a significant increase.

TABLE 4

Table 4 shows the effect of the enhancer composition. Lauryl alcohol is an excellent penetration enhancer at the beginning (8 hours) and diethylene glycol monoethyl ether is an excellent penetration enhancer at the end (16 hours, 24 hours). Moreover, the preferred mixture of lauryl alcohol and diethylene glycol monoethyl ether of the present invention maintains the strengthening effect for 24 hours.

TABLE 5

Table 5 shows diethylene glycol monoethyl ether (Example 12), diethylene glycol monoethyl ether and n-decanol (Example 13), diethylene glycol monoethyl ether and oleyl alcohol (Example 14) and diethylene The results of in vitro penetration obtained as four formulations containing the adjuvant composition of Glycle monoethyl ether and lauryl alcohol (Example 15) are shown.

Comparing the results obtained in Examples 12 and 13, diethylene glycol monoethyl ether alone and diethylene glycol monoethyl ether added with n-decanol showed the same increasing effect for estradiol but with n-decanol It was greater for the rate of penetration of noethyne drone acetate obtained using

Comparing the results of Examples 14 and 15, diethylene glycol monoethyl ether with oleyl alcohol and diethylene glycol monoethyl ether with lauryl alcohol showed the same increasing effect with estradiol, It was larger for noethyne drone acetate with lauryl alcohol.

These results support our hypothesis that there is no universal reinforcement.

The results obtained in Examples 12, 13, 14 and 15 showed that oleyl alcohol is the highest potentiator for estradiol, as lauryl alcohol has the highest potent for noethine drone acetate.

TABLE 6

Table 6 shows the infiltration results in vitro obtained using Examples 16 and 17. This example uses estradiol, noethetrone and hydroxyprogesterone acetate as progestins, respectively.

Bioavailability of 17-β-estradiol and noethine drone acetate in postmenopausal women

Estradiol and noethetrone acetate penetration rates, consisting of the transdermal formulations or compositions shown herein, were applied to the estra of eight postmenopausal women by applying a daily dose of 5 g of the transdermal formulation described in Example 1 across the arms, forearms, and shoulders. Diol and noethine drone serum levels were assessed by measuring in vivo. The study period was three days and therefore three daily doses were administered. After the study began, blood samples were taken at 0 hours (baseline), 2, 6, 12, 24, 30, 36, 48, 54, 60 and 72 hours. Estradiol and noethine drone serum levels were determined through time-dependent fluorescence immunoassay and enzyme immunoassay, respectively.

Table 7 and Table 8, Figures 1 and 2 show the results.

TABLE 7

TABLE 8

Pharmaceutical preparations in semi-solid dosage forms for transdermal delivery of estrogens, synthetic progestins or mixtures thereof according to the invention can deliver therapeutically effective and sustained steroid hormones through the skin and can easily control the rate of penetration. .

Figure 1 shows the results of the estradiol serum level for the time obtained experimentally as shown in Table 7 results obtained using the transdermal preparation of Example 1.

Figure 2 shows the values of noethine drone serum levels for the experimentally obtained time as shown in Table 8 the results obtained using the transdermal preparation of Example 1.

Figure 3 schematically shows "Hansen P / N 57-VC" (vertical diffuse cells) where: 1 is a cell receptor, 2 is a donor (administration area), 3 is a top plate, 4 is a wiper, 5 Is a clamp, 6 is a membrane, 7 is a water jacket, 8 is a sample point, 9 is a spiral stirrer, 10 is a magnetic stirrer, 11 is a sample tube, 12 is a probe from a microette, 13 is a cell level line, 14 is a medium Replacement tube, typical cell dimensions are 15 mm in diameter and 7 ml in volume.

Claims (13)

As a penetration enhancer in the active agent substantially a mixture of a monoalkyl ether of an aliphatic alcohol of the general formula CH ₃ (CH ₂ ) _n CH ₂ OH, wherein n is 8 to 16) and diethylene glycol; As a vehicle or carrier, a mixture of alkanols, glycols and water having 2 to 4 carbon atoms; Copolymers or polymers of acrylic acid as gelling agents; And gel form suitable for transdermal administration of estrogens or progestins or active agents of both mixtures, including quaternary amines as thickening and neutralizing agents. The pharmaceutical preparation according to claim 1, wherein the active agent is taken alone in 17-β-estradiol and noethyne drone or in a mixture thereof. The pharmaceutical preparation according to claim 1, wherein the active agent is taken alone in 17-β-estradiol and noethyne drone acetate or in a mixture thereof. The alkanol of claim 1 or 2, wherein the aliphatic alcohol is lauryl alcohol and the monoalkyl ether of diethylene glycol is monomethyl- or monoethyl-ether, and the alkanol containing 2 to 4 carbon atoms is ethanol, glycol Pharmaceutical formulation wherein propylene glycol and quaternary amine are triethanolamines. The method of claim 1, wherein 17-β-estradiol 0.02 to 0.09% (w / w), norethine drone acetate 0.30 to 1.50% (w / w), lauryl alcohol 0.4 to 6.0% (w / w), di Ethylene glycol monoethyl ether 1-15% (w / w), ethanol 20-65% (w / w), propylene glycol 1-12% (w / w), water 20-65% (w / w), acrylic acid A pharmaceutical formulation containing 0.5 to 4% (w / w) of polymers or copolymers and 0.05 to 1% (w / w) of triethanolamine. The method of claim 1, wherein 17-β-estradiol 0.06% (w / w), noethyne drone acetate 1.20% (w / w), lauryl alcohol 2.00% (w / w), diethylene glycol monoethyl ether 5.00 % (w / w), ethanol 44.49% (w / w), propylene glycol 6.0% (w / w), water 39.45% (w / w), 1.20% (w / w) polymer or copolymer of acrylic acid, triethanol Pharmaceutical formulation containing 0.40% (w / w) amine and 0.20% (w / w) flavor. The pharmaceutical formulation according to claim 1, wherein the carboxyvinyl polymer is used as a polymer or copolymer of acrylic acid. The pharmaceutical formulation of claim 1, wherein the penetration enhancer contains lauryl acid, which is 1% (w / w) of the total formulation weight. The pharmaceutical preparation according to claim 1, wherein the weight ratio of 17-β-estradiol to noethyne drone acetate as an active agent is 1:20. 2. A pharmaceutical formulation according to claim 1 which contains n-decanol which is 1% of the total formulation weight as a penetration enhancer. 2. The pharmaceutical formulation of claim 1, wherein the penetration enhancer contains oleyl alcohol, which is 1% of the total formulation weight. The pharmaceutical formulation according to claim 1, wherein the weight ratio of 17-β-estradiol to noethyne drone as an active agent is 1: 8. 2. The pharmaceutical formulation of claim 1 wherein the weight ratio of 17-β-estradiol to hydroxyprogesterone acetate as an active agent is 1: 5.

Images