CA2185616C - Hormonal agent for skin treatment - Google Patents
Hormonal agent for skin treatment Download PDFInfo
- Publication number
- CA2185616C CA2185616C CA002185616A CA2185616A CA2185616C CA 2185616 C CA2185616 C CA 2185616C CA 002185616 A CA002185616 A CA 002185616A CA 2185616 A CA2185616 A CA 2185616A CA 2185616 C CA2185616 C CA 2185616C
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- CA
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- Prior art keywords
- dienogest
- skin
- pharmaceutical preparation
- active ingredient
- hair
- 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.)
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Classifications
-
- 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
- A61K31/567—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 substituted in position 17 alpha, e.g. mestranol, norethandrolone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/63—Steroids; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q5/00—Preparations for care of the hair
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
Abstract
The pharmaceutical composition, especially for treating skin with seborrhea, Acne vulgaris and androgonically conditioned alopecia, contains a hormonal agent including the gestogen, dienogest, or a combination of dienogest and an estrogen, as active ingredient. Methods for treatment of this type of skin condition include topical application of the composition including the dienogest which results in an outstanding sebosuppression, a drastic reduction of androstandiol glucuronide and a moderate competitive blockage of androgen receptor sites. Galenic formulations are described which limit and/or prevent the permeation of the active ingredient through the skin. The pharmaceutical preparation including the dienogest and conventional dermatologically acceptable carrier and auxiliary substances in the described galenic formulation advantageously provides a drastic reduction in androstandiol glucuronide and moderate androgen receptor blockage without passing through the skin barrier so that systemic effects including side reactions are substantially prevented.
Description
. 21856~6 BE IT KNOWN that WE, Siegfried GOLBS, Michael OE~TEL, Michael DITTGEN, Thomas GR~SER and Christoph LUDERSCHMIDT, citizens of Germany, whose post office addresses and residencies are, respectively, Brambacher Strasse 55, Leipzig, Germany 04207; Beethovenstrasse 30, Jena, Germany 07743; Heiden~erg 35/37, Apolda, Germany 99510; Heinrich-Hertz Strasse 7, Erfurt, Germany 99095; and Orthstrasse 22, Milnchen, Germany 81245, have invented a new and improved _ - T- AGENT FOR 8~IN ~R~MT!NT
of whlch the following is a complete specification thereof:
~ 21856t6 B~ckground o~ the Invention The present invention relates to a h~ -1 agent or composition for skin treatment, especially seborrhea, Acne Vl-7 a~ris, androgenically conditioned alopecia and androgenic symptoms of women.
In central Europe the incidence of hormonally conditioned skin diseases, such as acne, seborrhea and hirsutism, is estimated at 35 to 50 %. These illnesses appear primarily in young men and women after puberty who are exposed to considerable suffering because of them (H.
Hagen, et al, ~lini~rh~ Erfassumg antiandrogener Effekte von Dienogest {Clinical Determination of antiandrogenic effects of dienogest}, pp. 223 -230 in "Dienogest-Praklinik und Klinik eines neuen Gestagens", A. T~ hr-nn, ed, Walter de Gruyter Verlag, Berlin, New York, 1995).
The sebaceous gland activity is considerably influenced by hormones. Testosterone and dihydrotestosterones are responsible for the sebocyte proliferation and sebogenesis and provide, as a result, the driving force for sebo-genesis. An interaction with androgen receptors, which are localized in human skin (acne areas, such as the face, upper breast portions, the V-shaped region of the back and the outer sides of the upper arms), especially the sebaceous gland and sebaceous gland follicle, is, among other things, a prerequisite for this (R. Choudhry, et al, "Localization of ~_r 2 1 ~ 5 6 1 6 androgen receptors in human skin by i ..h; F:tochemistrY:
implications for the h~ -1 regulation of hair growth, sebaceous gland and sweat glands", in J. Endocr. 133, pp.
467-475(1992); M.E. Sawaya, "Purification o~ androgen receptors in human sebocytes and hair", in J. Invest.
Dermat. 98, pp. 92-96(1992).
Continuous sebum production increases in acne patients ~r~n(1 i n~ on the androgen secretions and the peripheral response of the end organs and reaches its highest value in Acne conqlobata.
A hormonal agent or composition which is described in German Patent DE-PS 43 21 957 is used ~or acne therapy. This hormonal agent is a composition which i5 taken orally.
Because of its systemic action undesirable effects and material ~ tion occur in acne patients. Besides the hormonal treatment of acne it is also known to stimulate hair growth. In German Patent Document DE 36 15 396 a combination preparation comprising a hair tonic including cyproteron acetate in hair tonic is used as a combined pr~paration for treating the scalp skin and for promotion of hair growth.
The action of cyproteron acetate and chlorr-~lin~n acetate during therapeutic application is based on a centrally mediated antigonadotropic ef fect. Because of that an acne therapy and/or treatment of alopecia in humans is not possible with these active ingredients. Further-m-ore cyproteronic acetate and chlormadinon acetate causes a peripheral competitive androgen receptor blockage in acne of women (Ch. Luderschmidt, "Die Akne der Frau~The Acne of Women}" in Gynakol. Prax., 19, pp. 479-488, 1995).
~lummary of the Invention It is an object of the present invention to provide a pharmaceutical composition, especially for the treatment of acne, seborrhea or alopecia, in which the systemic effect of the hormonal agent acting as active ingredient is prevented and a direct peripheral effect is produced at the place of occurrence on the skin (seborrhea, acne areas, alopecia, androgenic symptoms of women) and which may be used in both women as well as men.
It is another object of the invention to still further limit and/or to hinder the permeation of the active ingredient through the skin by suitable galenic measures.
Because of these measures the penetration of the skin by the active ingredient is promoted instead of hindered. However the permeation by the substances is controlled by the formulation so that the active material is not available or only slightly available systemically in order to avoid or m;n;m; 7e undesirable effects in the organism.
It is an additional object of the invention to provide a manufacturing or production process for the pharmaceutical composition in which the active ingredient is stable and prepared ~h~ - yLIamically active so that, after it is applied to the skin, it penetrates the skin very rapidly and to a great extent, however slightly or only in a very much reduced extent by the most diverse penetration paths, e.g. transfollicularly, transglandularly and transepidermally. This process should further guarantee that the active ingredient does not come into contact with water, reactive solvents or surfactants or light for a long period of time.
Particularly it is an object of the present invention to include defatting or deoiling substances, like those described in German Patent Document DE 42 29 820, which promote the penetration of hormonal active ingredients in the skin, for a local, but nonsystemically effective, application. The use of defatting or deoiling 6ubstances 6hould prevent or hinder the stimulation of the skin to overproduce oil or fat because of oil or fat removal.
The method of applying the pharmaceutical composition topically after it is prepared by the preparative methods according to the invention releases the active ingredient as fast as possible and as completely as possible, promotes its passage into the skin tissue while avoiding absorption and thus introduces no undesirable reciprocal action (interactions) with the biological tissue, as are known, for example, for certain solvents and surfactants.
218561~
According to the invention these objects are attained by a method of topical treatment of Acne vulqaris, seborrhea, androgonically conditioned alopecia and androgenic symptoms of women comprising the step of applying locally on the skin a pharmaceutical composition containing the antiandrogenieally acting gestogen, dienogest, and/or a eombination of dienogest and an estrogen or phytestrogen.
Brief Description of the Drawing The o~jeets, features and advantages of the invention will now be explained in greater detail in the following deseription of preferred ~embodiments, with reference to the accompany drawing, in which Figure 1 is a bar graph illustration showing the drastic reduetion in androstandiol glueuronide concentration in serum occurring after topical treatment using the pharmaceutical composition aeeording to the invention;
Figure 2 is a graphieal illustration of the relationship of serum coneentration of dienogest and time when the dienogest is taken orally, intravenously or applied topieally;
Figure 3 is a eross-seetional view through a reaetion vessel for produetion of the pharmaceutical composition aeeording to the invention; and 21B5S1~
Figure 4 is a graphical illustration comparing dienogest concentration-time curves in serum for different preparations according to~ the invention.
Description of tha Praferrad ~-ho~ir- t~
The dienogest produces an outstanding sebosuppression when it is applied topically. Because of that, as shown in Figure 1, appended hereinbelow, a drastic reduction of androstandiol glucuronide concentration in serum and a moderate competitive inhibition of androgen receptors occurs. Androstandiol glucuronidé is regarded as a marker of the peripheral conversion of testosterone into dihydrotestosterone. It has been shown that dienogest acts at the level of a stronger antiandrogen such as cyproteron acetate in LNcaP cells in Yitro. In combination with an estrogen, such as 17a-estradiol or estriol, the suppressive effects of the hormonal agent according to the invention are increased. At the beginning of the topical treatment particularly there is a direct action of the estrogen on sebogenesis to reduce the sebum influence. A definite reduction in sebaceous gland surface area has also been proven. Androgen receptors in the shrunken sebaceous gland may be detected only rarely or not at all. The acne improves after three to four weeks of treatment. The topical application of a combination of dienogest and an estrogen in a suitable galenic form is advantageous with significant acne .
In contrast to the two gestogens, cyproteron acetate and chlorr-~;n~n acetate, dienogest in the galenic preparation described in this patent, does not penetrate through the skin and acts directly on end organs. Because of this dienogest, also in combination with an estrogen, has the maj or advantage that it acts directly on skin end organs in topical application in male and female patients.
Concentration-time experimentally tl~tF~rmin~d curves show that 10 mg of dienogest, delivered tr~n~ ly, in contrast to the results or oral and/or i.v. application (2 mg of dienogest), do not penetrate the skin barrier. The concentration-time curves illustrated in Fig. 2, described hereinbelow, clearly show that this is the situation. ~he dienogest concentration values in serum vary in the vicinity of predetf~rminl~-l limits (1 ng/ml) after tri~n~:df~
distribution. A systemic effect of dienogest is not expected until its concentration in serum reaches 10 ng/ml.
A systemic action of dienogest is however prevented, since the active ingredient in the proposed galenic formulation does not penetrate the skin barrier and thus can not cause systemic effects. Because of that undesirable systemic side-effects, which, among other things, can occur on oral application, are prevented in this type of topical application . In the galenic preparation (salve, cream, lotion, facial tonic, hair tonic or hair balm) the gestogen, ~-- 21856t 6 dienogest, is contained or present advantageously ih an amount between o. 01 to 4 percent by weight in the preparation .
According to the invention the effective ingredient in the galenic preparation is present in a hydrophilic or deoiling foundation in a thP yllamic state suitable for the preparation. The effective ingredient is thus prepared so that it is distributed molecularly dispersed in the deoiling or hydrophilic foundation. In the case of a hydrophilic preparation (aqueous solution, hydrogel, lotion or O/W emulsion) it is sufficient that the gestogen i5 dissolved in ethanol or a similar vehicle and added in this form. In the case of the deoiling preparation (lipogel or a preparation containing at least one partly fatty or similar substance, e.g. a W/o emulsion) the active ingredient is combined with a hydrophilic component (H) and generally molecularly dispersed in it. Advantageously sugar or sugar-like substances, such as saccharose, lactose, mannitol, sugar alcohol, urea or other N-containing compounds can be used as the hydrophilic ingredient(E~).
On contact with skin liquids (e.g. sweat) the hydrophilic ingredient sees to it that the effective ingredient very rapidly goes into solution and penetrates the skin.
It has also proven to be advantageous to mix the solution of the active ingredient with a permeation promotor and/or a stabilizer. The permeation promotor additionally promotes the absorption of the active ingredient in the skin. A nitrogen-containing eompound, e.g. an acid amide, an amine or an alkaloid, may be used as permeation promotor.
Urea is particularly suitable as permeation promotor.
The stabilizer provides the active ingredient with a sufficient stability, especially in the case of the solution. The antioxidants known from basic principles, such as tocopherol, can be used as the stabilizer, however also complex formers, reducing agents and/or W-absorbers may also be considered. The permeation of the effeetive ingredient by the skin is limited and/or hindered by the preparation aeeording to the invention and a eomparatively high availability of the aetive ingredient on the skin is provided. When the preparation according to the invention based on a deoiling foundation is used in addition the stimulation of oil overproduction is countered, since a certain controlled amount of oil required for reconstituting the skin is provided.
For example, oils(e.g. peanut oil and/or castor oil), waxes(e.g. bees wax, hard wax, fluid wax), hydrogels, ethanol, water, benzyl benzoate, isopropyl myristate, lecithin, glycerol, lanol~in, boric acid, sodium tetraborate, lactie aeid, viseous fluid paraffin, propylene glyeol, deionized water or a mixture of these eompounds ean be used as the earrier/auxiliary substanees for the loeally applied preparation including dienogest. With the help of this preparation the eutaneous pharmaeologieal aetion of the 2~85616 antiandrogenically acting gestogen, dienogest, also in combination with an estrogen, the reduction of sebogenesis ~estrogen effect) to sufficient extent in the skin is guaranteed. Because of that sebosuppression occurs, which leads to a reduction of sebaceous gland surface and elimination of comedones. A disadvantgeous action of the dienogest is not present because of the gelenic preparation.
Damage to the treated skin (horny skin, hair follicules) does not occur.
Allergic and toxic reactions are not to be expected because of the active ingredient, the combination of the active ingredient with es~rogen and also the additive and auxiliary materials.
A closed system is suitable for making the pharmaceutical preparation according to the invention. The active ingredient, protected from light, is combined in a predetormi n~d weight ratio with a permeation promotor and a stabilizer in the closed system and is in the same process at most briefly heated and can be dispersed with the aid of a high speed mixer in a lipophilic or hydrophilic vehicle.
To make the pharmaceutical preparation according to the invention advantageously the apparatus shown in Figure 3 is used, which comprises a closed vessel 1 which is equipped with a first stirring apparatus 3, a second stirring apparatus 5, a wiper apparatus 4 and laterally with a heatable or coolable jacket 6. The vessel 1 is provided with an upper filling connector pipe 2 and a lower filling connector pipe 7. Drive devices 8 and 9 are provided for the respective apparatuses 3 and 4.
The method of making the preparation according to the invention is now described for the pharmaceutical preparation with the gestogen, dienogest, as active ingredient. A mixture of conventional additive materials often used in dermatological compositions (see the example) is present in vessel 1. The additive materials are introduced in liquid or solid form through the upper filling connector pipe 2 . The f irst slowly running stirring apparatus 3 is put into rotation by operating the drive device 8. At the same time a wiper apparatus 4 is activated so that a minimum amount of material adheres to the edges of the vessel 1. In a hydrophilic preparation the gestogen, dienogest, is introduced through the lower filling connector pipe 7 as a pure substance or dissolved in a hydrophilic vehicle. A permeation promotor and/or stabilizer is added j ointly with the gestogen or after the active ingredient is completely dispersed in the mixture with the additive materials. After that, the entire mixture is homogenized with the help of the comparatively more rapidly running stirring apparatus 5. D.or-n~l;n~ on the rigidity of the mixture usually brief heating occurs. Usually however at the beginning of the homogenization a cooling must be performed.
2~85616 The cooling interval is essential for the stabilization of the thP - :y--amic state of the gestogen in the preparation. The cooling and stirring speeds are decisive for the effectiveness of the gestogen in the resulting preparation with a given recipe and concentrations of homogenizer/ stabilizer. Furthermore the stability of the gestogen in the preparation essentially depends on the temperatures existing during the making of the preparation.
It has proven particularly advantageous when the temperature in the vessel and similarly the rotation speed of the stirring devices are regulated stepwise and are related in a definite manner to the heating/cooling rate of the jacket ~iu~ ul~ding the vessel. Air or liquid (water) can flow through the j acket .
In the method of making the pharmaceutical preparation based on a deoiling foundation the ~h~-ceutically active ingredient is mixed in a separate vessel with a hydrophilic component or ingredient. This mixture is heated to at least partially melt it while excluding water, other solvents and/or surfactants and subsequently is dispersed with rapid cooling in a gas. The in~ te product arising therefrom is now added to another mixture of auxiliary materials commonly used in dermatological preparations which was prepared in an additional vessel and is dispersed uniformly in the galenic preparation. Either jointly with .
.
the active material or after the active material has been completely dispersed, a permeation promotor and/or stabilizer is added. The temperature is increased so that a creamy mixture is guaranteed. Besides a first stirring device with a comparatively lower rotation speed a second stirring device with a comparatively higher rotation speed is used as homogenizer. The temperature o~ the preparation is now continuously lowered. The cooling rate is advantageously about 1 C/min.
The making of a galenic preparation is possible with the process according to the invention without bringing the active ingredient into contact with reactive solvents or surfactants and without exposing it to light for a substantial time.
Besides gestogens, such as dienogest, additional active ingredients, especially hormones such as natural and/or synthetic antiandrogens (chlormadinon acetate), estrogens and corticoidal steroids, may be applied locally in a galenic preparation based on the above-described process. The pharmaceutical preparation thus made does not produce systemic effects or only produces slight systemic effects.
The rh~ outical preparations according to the invention with dienogest or a combination of dienogest and an estrogen and/or other natural and/or synthetic antiandrogens as 2 1 856 ~ 6 .
active ingredient may be used for local treatment of a plurality of androgen caused maladies or diseases. Hair tonic, hair balm and/or hair cream based on the pharmaceutical preparation according to the invention can be used for treatment of hair loss or promotion of hair growth and as a palliative for and/or for elimination of vasomotor scalp pains. Thus, among Qther things, it is possible to prevent hair loss in women with androgen symptoms, especially in the post menopause phase, by direct application of the preparation according to the invention to the scalp skin, and/or to promote hair growth.
The invention will nQw be illustrated with the following examples, whose~ details should not be construed as limiting the appended claims.
EX~IIPLES
ExamPle 1: Faci~l LotiQn SQlutiQr~
0 . 2 5 g dienogest 0.40 g castor oil~
0. 60 g benzyl benzoate ad lO0. 0 g ethanol (96 96) s. dye compound, perfumes lO0. 00 g Prep ration:
Dienogest and benzyl benzoate are dissolved in a given amount of ethanol (9696). The mixture is heated briefly to 50 C. After that the mixture must be rapidly cooled to 20 C.
Subsequently the required dyes and perfume materials 21856t6 .
dissolved in the given quantity of castor oil are added to the solution.
Examl~le 2: Fac; ~ l LQt~ior~ solu~iQn 0 . 25 g dienogest 0. 40 g peanut oil 2 . 5 g lecithin 2 . 0 g isopropyl myristate ad lO0. 0 g ethanol (96 96) q.s, dye compound, perfumes 100 . 00 g Pr~paration:
Dienogest and isopropyl myristate are dissolved in the given amount of 96 % ethanol. Thus the mixture is briefly heated to 50 C. Subsequently it is rapidly cooled to 20 C.
Finally the required dyes: and aromatic materials which are previously dissolved with lecithin in the peanut oil, are added as a mixture with the oil and lecithin to the solution .
Exam~le 3: Sk; n Cr~;~m Part A
of whlch the following is a complete specification thereof:
~ 21856t6 B~ckground o~ the Invention The present invention relates to a h~ -1 agent or composition for skin treatment, especially seborrhea, Acne Vl-7 a~ris, androgenically conditioned alopecia and androgenic symptoms of women.
In central Europe the incidence of hormonally conditioned skin diseases, such as acne, seborrhea and hirsutism, is estimated at 35 to 50 %. These illnesses appear primarily in young men and women after puberty who are exposed to considerable suffering because of them (H.
Hagen, et al, ~lini~rh~ Erfassumg antiandrogener Effekte von Dienogest {Clinical Determination of antiandrogenic effects of dienogest}, pp. 223 -230 in "Dienogest-Praklinik und Klinik eines neuen Gestagens", A. T~ hr-nn, ed, Walter de Gruyter Verlag, Berlin, New York, 1995).
The sebaceous gland activity is considerably influenced by hormones. Testosterone and dihydrotestosterones are responsible for the sebocyte proliferation and sebogenesis and provide, as a result, the driving force for sebo-genesis. An interaction with androgen receptors, which are localized in human skin (acne areas, such as the face, upper breast portions, the V-shaped region of the back and the outer sides of the upper arms), especially the sebaceous gland and sebaceous gland follicle, is, among other things, a prerequisite for this (R. Choudhry, et al, "Localization of ~_r 2 1 ~ 5 6 1 6 androgen receptors in human skin by i ..h; F:tochemistrY:
implications for the h~ -1 regulation of hair growth, sebaceous gland and sweat glands", in J. Endocr. 133, pp.
467-475(1992); M.E. Sawaya, "Purification o~ androgen receptors in human sebocytes and hair", in J. Invest.
Dermat. 98, pp. 92-96(1992).
Continuous sebum production increases in acne patients ~r~n(1 i n~ on the androgen secretions and the peripheral response of the end organs and reaches its highest value in Acne conqlobata.
A hormonal agent or composition which is described in German Patent DE-PS 43 21 957 is used ~or acne therapy. This hormonal agent is a composition which i5 taken orally.
Because of its systemic action undesirable effects and material ~ tion occur in acne patients. Besides the hormonal treatment of acne it is also known to stimulate hair growth. In German Patent Document DE 36 15 396 a combination preparation comprising a hair tonic including cyproteron acetate in hair tonic is used as a combined pr~paration for treating the scalp skin and for promotion of hair growth.
The action of cyproteron acetate and chlorr-~lin~n acetate during therapeutic application is based on a centrally mediated antigonadotropic ef fect. Because of that an acne therapy and/or treatment of alopecia in humans is not possible with these active ingredients. Further-m-ore cyproteronic acetate and chlormadinon acetate causes a peripheral competitive androgen receptor blockage in acne of women (Ch. Luderschmidt, "Die Akne der Frau~The Acne of Women}" in Gynakol. Prax., 19, pp. 479-488, 1995).
~lummary of the Invention It is an object of the present invention to provide a pharmaceutical composition, especially for the treatment of acne, seborrhea or alopecia, in which the systemic effect of the hormonal agent acting as active ingredient is prevented and a direct peripheral effect is produced at the place of occurrence on the skin (seborrhea, acne areas, alopecia, androgenic symptoms of women) and which may be used in both women as well as men.
It is another object of the invention to still further limit and/or to hinder the permeation of the active ingredient through the skin by suitable galenic measures.
Because of these measures the penetration of the skin by the active ingredient is promoted instead of hindered. However the permeation by the substances is controlled by the formulation so that the active material is not available or only slightly available systemically in order to avoid or m;n;m; 7e undesirable effects in the organism.
It is an additional object of the invention to provide a manufacturing or production process for the pharmaceutical composition in which the active ingredient is stable and prepared ~h~ - yLIamically active so that, after it is applied to the skin, it penetrates the skin very rapidly and to a great extent, however slightly or only in a very much reduced extent by the most diverse penetration paths, e.g. transfollicularly, transglandularly and transepidermally. This process should further guarantee that the active ingredient does not come into contact with water, reactive solvents or surfactants or light for a long period of time.
Particularly it is an object of the present invention to include defatting or deoiling substances, like those described in German Patent Document DE 42 29 820, which promote the penetration of hormonal active ingredients in the skin, for a local, but nonsystemically effective, application. The use of defatting or deoiling 6ubstances 6hould prevent or hinder the stimulation of the skin to overproduce oil or fat because of oil or fat removal.
The method of applying the pharmaceutical composition topically after it is prepared by the preparative methods according to the invention releases the active ingredient as fast as possible and as completely as possible, promotes its passage into the skin tissue while avoiding absorption and thus introduces no undesirable reciprocal action (interactions) with the biological tissue, as are known, for example, for certain solvents and surfactants.
218561~
According to the invention these objects are attained by a method of topical treatment of Acne vulqaris, seborrhea, androgonically conditioned alopecia and androgenic symptoms of women comprising the step of applying locally on the skin a pharmaceutical composition containing the antiandrogenieally acting gestogen, dienogest, and/or a eombination of dienogest and an estrogen or phytestrogen.
Brief Description of the Drawing The o~jeets, features and advantages of the invention will now be explained in greater detail in the following deseription of preferred ~embodiments, with reference to the accompany drawing, in which Figure 1 is a bar graph illustration showing the drastic reduetion in androstandiol glueuronide concentration in serum occurring after topical treatment using the pharmaceutical composition aeeording to the invention;
Figure 2 is a graphieal illustration of the relationship of serum coneentration of dienogest and time when the dienogest is taken orally, intravenously or applied topieally;
Figure 3 is a eross-seetional view through a reaetion vessel for produetion of the pharmaceutical composition aeeording to the invention; and 21B5S1~
Figure 4 is a graphical illustration comparing dienogest concentration-time curves in serum for different preparations according to~ the invention.
Description of tha Praferrad ~-ho~ir- t~
The dienogest produces an outstanding sebosuppression when it is applied topically. Because of that, as shown in Figure 1, appended hereinbelow, a drastic reduction of androstandiol glucuronide concentration in serum and a moderate competitive inhibition of androgen receptors occurs. Androstandiol glucuronidé is regarded as a marker of the peripheral conversion of testosterone into dihydrotestosterone. It has been shown that dienogest acts at the level of a stronger antiandrogen such as cyproteron acetate in LNcaP cells in Yitro. In combination with an estrogen, such as 17a-estradiol or estriol, the suppressive effects of the hormonal agent according to the invention are increased. At the beginning of the topical treatment particularly there is a direct action of the estrogen on sebogenesis to reduce the sebum influence. A definite reduction in sebaceous gland surface area has also been proven. Androgen receptors in the shrunken sebaceous gland may be detected only rarely or not at all. The acne improves after three to four weeks of treatment. The topical application of a combination of dienogest and an estrogen in a suitable galenic form is advantageous with significant acne .
In contrast to the two gestogens, cyproteron acetate and chlorr-~;n~n acetate, dienogest in the galenic preparation described in this patent, does not penetrate through the skin and acts directly on end organs. Because of this dienogest, also in combination with an estrogen, has the maj or advantage that it acts directly on skin end organs in topical application in male and female patients.
Concentration-time experimentally tl~tF~rmin~d curves show that 10 mg of dienogest, delivered tr~n~ ly, in contrast to the results or oral and/or i.v. application (2 mg of dienogest), do not penetrate the skin barrier. The concentration-time curves illustrated in Fig. 2, described hereinbelow, clearly show that this is the situation. ~he dienogest concentration values in serum vary in the vicinity of predetf~rminl~-l limits (1 ng/ml) after tri~n~:df~
distribution. A systemic effect of dienogest is not expected until its concentration in serum reaches 10 ng/ml.
A systemic action of dienogest is however prevented, since the active ingredient in the proposed galenic formulation does not penetrate the skin barrier and thus can not cause systemic effects. Because of that undesirable systemic side-effects, which, among other things, can occur on oral application, are prevented in this type of topical application . In the galenic preparation (salve, cream, lotion, facial tonic, hair tonic or hair balm) the gestogen, ~-- 21856t 6 dienogest, is contained or present advantageously ih an amount between o. 01 to 4 percent by weight in the preparation .
According to the invention the effective ingredient in the galenic preparation is present in a hydrophilic or deoiling foundation in a thP yllamic state suitable for the preparation. The effective ingredient is thus prepared so that it is distributed molecularly dispersed in the deoiling or hydrophilic foundation. In the case of a hydrophilic preparation (aqueous solution, hydrogel, lotion or O/W emulsion) it is sufficient that the gestogen i5 dissolved in ethanol or a similar vehicle and added in this form. In the case of the deoiling preparation (lipogel or a preparation containing at least one partly fatty or similar substance, e.g. a W/o emulsion) the active ingredient is combined with a hydrophilic component (H) and generally molecularly dispersed in it. Advantageously sugar or sugar-like substances, such as saccharose, lactose, mannitol, sugar alcohol, urea or other N-containing compounds can be used as the hydrophilic ingredient(E~).
On contact with skin liquids (e.g. sweat) the hydrophilic ingredient sees to it that the effective ingredient very rapidly goes into solution and penetrates the skin.
It has also proven to be advantageous to mix the solution of the active ingredient with a permeation promotor and/or a stabilizer. The permeation promotor additionally promotes the absorption of the active ingredient in the skin. A nitrogen-containing eompound, e.g. an acid amide, an amine or an alkaloid, may be used as permeation promotor.
Urea is particularly suitable as permeation promotor.
The stabilizer provides the active ingredient with a sufficient stability, especially in the case of the solution. The antioxidants known from basic principles, such as tocopherol, can be used as the stabilizer, however also complex formers, reducing agents and/or W-absorbers may also be considered. The permeation of the effeetive ingredient by the skin is limited and/or hindered by the preparation aeeording to the invention and a eomparatively high availability of the aetive ingredient on the skin is provided. When the preparation according to the invention based on a deoiling foundation is used in addition the stimulation of oil overproduction is countered, since a certain controlled amount of oil required for reconstituting the skin is provided.
For example, oils(e.g. peanut oil and/or castor oil), waxes(e.g. bees wax, hard wax, fluid wax), hydrogels, ethanol, water, benzyl benzoate, isopropyl myristate, lecithin, glycerol, lanol~in, boric acid, sodium tetraborate, lactie aeid, viseous fluid paraffin, propylene glyeol, deionized water or a mixture of these eompounds ean be used as the earrier/auxiliary substanees for the loeally applied preparation including dienogest. With the help of this preparation the eutaneous pharmaeologieal aetion of the 2~85616 antiandrogenically acting gestogen, dienogest, also in combination with an estrogen, the reduction of sebogenesis ~estrogen effect) to sufficient extent in the skin is guaranteed. Because of that sebosuppression occurs, which leads to a reduction of sebaceous gland surface and elimination of comedones. A disadvantgeous action of the dienogest is not present because of the gelenic preparation.
Damage to the treated skin (horny skin, hair follicules) does not occur.
Allergic and toxic reactions are not to be expected because of the active ingredient, the combination of the active ingredient with es~rogen and also the additive and auxiliary materials.
A closed system is suitable for making the pharmaceutical preparation according to the invention. The active ingredient, protected from light, is combined in a predetormi n~d weight ratio with a permeation promotor and a stabilizer in the closed system and is in the same process at most briefly heated and can be dispersed with the aid of a high speed mixer in a lipophilic or hydrophilic vehicle.
To make the pharmaceutical preparation according to the invention advantageously the apparatus shown in Figure 3 is used, which comprises a closed vessel 1 which is equipped with a first stirring apparatus 3, a second stirring apparatus 5, a wiper apparatus 4 and laterally with a heatable or coolable jacket 6. The vessel 1 is provided with an upper filling connector pipe 2 and a lower filling connector pipe 7. Drive devices 8 and 9 are provided for the respective apparatuses 3 and 4.
The method of making the preparation according to the invention is now described for the pharmaceutical preparation with the gestogen, dienogest, as active ingredient. A mixture of conventional additive materials often used in dermatological compositions (see the example) is present in vessel 1. The additive materials are introduced in liquid or solid form through the upper filling connector pipe 2 . The f irst slowly running stirring apparatus 3 is put into rotation by operating the drive device 8. At the same time a wiper apparatus 4 is activated so that a minimum amount of material adheres to the edges of the vessel 1. In a hydrophilic preparation the gestogen, dienogest, is introduced through the lower filling connector pipe 7 as a pure substance or dissolved in a hydrophilic vehicle. A permeation promotor and/or stabilizer is added j ointly with the gestogen or after the active ingredient is completely dispersed in the mixture with the additive materials. After that, the entire mixture is homogenized with the help of the comparatively more rapidly running stirring apparatus 5. D.or-n~l;n~ on the rigidity of the mixture usually brief heating occurs. Usually however at the beginning of the homogenization a cooling must be performed.
2~85616 The cooling interval is essential for the stabilization of the thP - :y--amic state of the gestogen in the preparation. The cooling and stirring speeds are decisive for the effectiveness of the gestogen in the resulting preparation with a given recipe and concentrations of homogenizer/ stabilizer. Furthermore the stability of the gestogen in the preparation essentially depends on the temperatures existing during the making of the preparation.
It has proven particularly advantageous when the temperature in the vessel and similarly the rotation speed of the stirring devices are regulated stepwise and are related in a definite manner to the heating/cooling rate of the jacket ~iu~ ul~ding the vessel. Air or liquid (water) can flow through the j acket .
In the method of making the pharmaceutical preparation based on a deoiling foundation the ~h~-ceutically active ingredient is mixed in a separate vessel with a hydrophilic component or ingredient. This mixture is heated to at least partially melt it while excluding water, other solvents and/or surfactants and subsequently is dispersed with rapid cooling in a gas. The in~ te product arising therefrom is now added to another mixture of auxiliary materials commonly used in dermatological preparations which was prepared in an additional vessel and is dispersed uniformly in the galenic preparation. Either jointly with .
.
the active material or after the active material has been completely dispersed, a permeation promotor and/or stabilizer is added. The temperature is increased so that a creamy mixture is guaranteed. Besides a first stirring device with a comparatively lower rotation speed a second stirring device with a comparatively higher rotation speed is used as homogenizer. The temperature o~ the preparation is now continuously lowered. The cooling rate is advantageously about 1 C/min.
The making of a galenic preparation is possible with the process according to the invention without bringing the active ingredient into contact with reactive solvents or surfactants and without exposing it to light for a substantial time.
Besides gestogens, such as dienogest, additional active ingredients, especially hormones such as natural and/or synthetic antiandrogens (chlormadinon acetate), estrogens and corticoidal steroids, may be applied locally in a galenic preparation based on the above-described process. The pharmaceutical preparation thus made does not produce systemic effects or only produces slight systemic effects.
The rh~ outical preparations according to the invention with dienogest or a combination of dienogest and an estrogen and/or other natural and/or synthetic antiandrogens as 2 1 856 ~ 6 .
active ingredient may be used for local treatment of a plurality of androgen caused maladies or diseases. Hair tonic, hair balm and/or hair cream based on the pharmaceutical preparation according to the invention can be used for treatment of hair loss or promotion of hair growth and as a palliative for and/or for elimination of vasomotor scalp pains. Thus, among Qther things, it is possible to prevent hair loss in women with androgen symptoms, especially in the post menopause phase, by direct application of the preparation according to the invention to the scalp skin, and/or to promote hair growth.
The invention will nQw be illustrated with the following examples, whose~ details should not be construed as limiting the appended claims.
EX~IIPLES
ExamPle 1: Faci~l LotiQn SQlutiQr~
0 . 2 5 g dienogest 0.40 g castor oil~
0. 60 g benzyl benzoate ad lO0. 0 g ethanol (96 96) s. dye compound, perfumes lO0. 00 g Prep ration:
Dienogest and benzyl benzoate are dissolved in a given amount of ethanol (9696). The mixture is heated briefly to 50 C. After that the mixture must be rapidly cooled to 20 C.
Subsequently the required dyes and perfume materials 21856t6 .
dissolved in the given quantity of castor oil are added to the solution.
Examl~le 2: Fac; ~ l LQt~ior~ solu~iQn 0 . 25 g dienogest 0. 40 g peanut oil 2 . 5 g lecithin 2 . 0 g isopropyl myristate ad lO0. 0 g ethanol (96 96) q.s, dye compound, perfumes 100 . 00 g Pr~paration:
Dienogest and isopropyl myristate are dissolved in the given amount of 96 % ethanol. Thus the mixture is briefly heated to 50 C. Subsequently it is rapidly cooled to 20 C.
Finally the required dyes: and aromatic materials which are previously dissolved with lecithin in the peanut oil, are added as a mixture with the oil and lecithin to the solution .
Exam~le 3: Sk; n Cr~;~m Part A
4 . 5 g Bees wax 9 . 5 g hard wax 3 . 5 g lanolin 8 . 0 g isopropyl myristate 8. 0 g liquid wax 4 . 0 q glycerol 37 . 5 g total for part A
Part B
2 . 2 g dienogest 4, 4 q sacchrose 6 . 6 g total for part B
2~856~6 .
Part C
55. 6 g deionized water o . 2 g sodium tetraborate 1. 5 g boric acid 0 . 7 a lactic acid 62 . 2 g total for part C
Part D
q. s . preservative materials and perfumes .
Prepar~l tion:
The materials of part A are heated to 90 C, melted and mixed. A solid dispersion (part s) made according to the method already described from dienogest and saccharose 1:2 is homogeneously dispersed in the melt. This is processed in the above-described reactor vessel according to the invention with the following conditions:
vessel temperature after adding the solid dispersion: 40 C
rotation speed of the wiper 1 rpm rotation speed of the slo~rer stirrer 50 rpm rotation speed of the homogenizer 3450 rpm cooling rate 1 C/min Exam~le 4: Skin Salve Part A
4. 0 g Bees wax 9 . 5 g glycerol monostearate 4 . o g lanolin 8. 0 g isopropyl myristate 8. 0 g paraffin(viscous liquid) 4 . 0 q propylene glycol 37 . 5 g total for part A
Part B
20. 0 g deionized water 0 . 2 a sodium tetraborate 20.2 g total for part B
~ 2185616 Part C
0 .16 g dienogest 19 . 84 q ethanol 20 . oo g total for part C
Part D
q. s . preservative materials and perfumes .
Preparation:
The A portion was heated to 90 C, melted and mixed. The melt is mixed(partially saponified) with the borax solution which was also first heated to 90 C. Subsequently the mixture of parts A and B is cooled to below 50'C, before the ethanolic dienogest solutiontpart C) is mixed with it.
Finally the preservative and perfume containing part D is added to the mixture of parts A, B and C. Then the product is cooled at 20 C with stirring.
ExamPle 5: Skin Lotion Part A
0 . 50 kg dienogest 9 . 45 kg ethanol 0 . 05 kg glycerol lO . 00 kg Part B
1. 0 kg sorbitan monostearate 1. 5 kg macrogol stearate 2 . 5 kg medium chain length triglyceride o . 05 kg potassium sorbate o. 025 kg water-free citric acid water ad 40.00 kg Preparation:
The solution (part A) is homogeneously distributed in the mixture B. The preparation then proceeds according to the general method described hereinabove with the following conditions:
Vessel temperature on addition of solution A: 30 C
Rotation speed of the wiper: 1 rpm Rotation speed of the slower stirrer: 90 rpm Rotation speed of the homogenizer 3850 rpm Cooling rate: l C
ExamPle 6: LiPoqel 5. o g dienogest 1000. 0 g wool wax alcohol salve Preparation:
The micronized dienogest is uniformly distributed in the stated amount in the wool wax alcohol salve.
ExamPle 7: LiPoqel + EI with Diçnoqest 5 . 0 g dienogest 45 . 0 g lactose wool wax alcohol salve to 1000 . 0 g Preparation:
A solid dispersion of dienogest and lactose 1:9 is f irst prepared according to the above-described methods .
This solid dispersion is uniformly distributed in the wool wax alcohol salve according to DAB 10. In an analogous smaller vessel, as described earlier in the description above, this is processed under the following conditions:
! 2 ~ 856 t 6 vessel temperature after adding the solid dispersion: 40 C
rotation speed of the wiper 2 rpm rotation speed of the slower stirrer 10 rpm rotation speed of the homogenizer 2050 rpm cool ing rate : 1 C~min r le 8: HYdroqel with Dienoqest 5. 0 g dienogest 400. 0 g ethanol 30. 0 g methylhydroxyethyl cellulose pure water to 1000 . 0 g Prep~r~tion:
The stated amount of dienogest is dissolved in the ethanol and uniformly mixed with the aqueous methyl~lyd, ~xyt:~hyl cellulose gel as described above.
Exam~le 9: Hyd~Qqel with ~ienQqest and 17~-Estradiol 5. 0 g dienogest 5 . O mg 17a-estradiol 400.0 g ethanol 30. 0 g methylhydroxyethyl cellulose pure water to 1000 . 0 g PreparYtion:
The stated amounts of dienogest and 17a-estradiol are dissolved in ethanol and uniformly mixed with the aqueous methylhydroxyethyl cellulose gel as described above.
ExamQle 10: LipQqel: DienQqest Plus Estriol 5.0 g dienogest 0 . 0 mg estriol wool wax alcohol salve to 1000. 0 g 2~85616 .
Pr~3p~r~tion:
The dienogest and estriol are uniformly mixed in the stated amount in the wool wax alcohol salve.
Example 11: ~Iair Ton1ç or l~;r SpXav o. 2 g dienogest 0 . 4 g castor oil o. 6 g benzyl benzoate q. s . Dye compounds, perfumes ethanol 9 6 96 ad 100 . 0 g Preparation:
Dienogest and benzylbenzoate or isopropyl myristate are dissolved in the stated amount of ethanol. The mixture is briefly heated at 50 C . After that it is rapidly cooled to 20 C. Finally the required dye compounds and perfumes dissolved in the stated amount of castor oil are added to the resulting solution.
Example 12 ~ i r Tonic or 1~; r SPrav 0 . 2 g chloxmadinon acetate o . 4 g peanut oil 2 . 5 g lecithin o. 6 g benzylbenzoate q. s . dye, , ~, perfumes ethanol 9 6 % ad 100 . 0 g Preparation:
The chlorr-c9;n~1n acetate and benzylbenzoate are dissolved in the stated amount of ethanol. Then the mixture is briefly heated at 50 C. After that it is rapidly cooled to 20 C. Finally the required dye compounds and perfumes dissolved in the stated amount of peanut oil are added to the resulting solution.
Example 13: Dienogest-Hair Balm with Hair-fixing Action (Conditioner) Part A
2.0 g cetyl lactate 2.0 g isopropyl myristate 4.0 g glycerol monostearate 1.0 g polyethyleneglycol (PEG)-40-stearate 2.0 g cetyl stearyl alcohol 1.0 g cetyl alcohol _____ 12.0 g total Part B
30.0 g aloe vera as colorless gel 33.9 g deionized water 0.3 g hydroxypropylmethyl cellulose (HPMC) 3.4 g Quat's mixture of Quat-22 and Quat-26(2:5) 0.3 g lactic acid ______ 67.9 g total Part C
0.23 g dienogest 19.75 g ethanol _______ 19.98 g total Part D
q.s. Dye compounds, preservatives and perfumes Preparation:
A glutinous mixture is made from the HPMC and water.
The ingredients of Part B are added to the glutinous mixture. The resultant mixture is homogenized and after that 2~856~6 .~
heated to 80 C(water bath). Part B is prepared by mixing the above-stated ingredients of it at 80 C (water bath) . Part B
is then mixed with the same heating with Part A. The mixture of parts A and B is cooled with stirring at 50 C. The ethanolic solution (Part C) is added with stirring to the mixture of parts A and B cooled below 50 C. The resultant mixture is cooled further. Finally the required dye compounds, preservatives and perfumes are added to the mixture of parts A, B and C. The resultant mixture I then coolçd with stirring to 20 C.
Exam~le 14: ChlQrma~9;non Aççtate Hair Cr~m(GrQominq Cream) Part A
4 . 0 g bees wax 10. 0 g glycerol monostearate 3 . 5 g lanolin 8 . 0 g isopropyl myristate 8 . 0 g viscous paraffin 4, o q propylene glycol 37 . 5 g total Part B
20. 0 g deionized water 0 . 2 q sodium tetraborate 2 0 . 2 g total Part C
0 . l9 g chlomadinon acetate l9 . 81 q ethanol 20 . 00 g total Part D
q. s. Dye compounds, preservatives and perfumes 2~85616 Preparation:
The substances of Pa-rt A are heated at 90 C, then melted and mixed. The melt is mixed(partially saponified) with the borax solution(Part C) also heated at 90 C. The resultant mixture is subsequently cooled with stirring to under 50 C, before the ethanolic chl~ l;n~ln acetate solution (Part C) is added. Finally, the required dye compounds, preservatives and perfumes of Part D are added to the resulting mixture of parts A, B and C and the resulting mixture is cooled at 20'C with stirring.
Exam~le 15: Dienoaest ~T~;r Crf~ ~m Part A
4 . 0 g bees wax 10 . 0 g hard wax 3 . 5 g lanolin 8 . 0 g isopropyl myristate 8 . 0 g liquid wax 4 . 0 q glycerol 37 . 5 g total Part B
0 . 2 g dienogest (micronized) Part C
60 . 0 g deionized water~
0 . 2 g sodium tetraborate 1. 5 g boric acid 0 . 7 a lactic acid 62 . 4 g total Part D
q. s . Dye compounds, preservatives and perfumes Preparation:
The ingredients of Part A are heated at 90 C, then melted and mixed. The micronized dienogest (Part B), protected from light, is mixed in this melt. The resultant mixture is subsequently cooled with stirring to under 50 C.
The water phase C is added with stirring to the cooled mixture of parts A and B. The resulting mixture is cooled further below 50 C. Finally, the required dye compounds, preservatives and perfumes of Part D are added to the resulting mixture o~ parts A, B and C and the resulting mixture is cooled at 20 C with stirring.
The purpose of these ph7~ tical preparations, above all, is the penetration of the active ingredient into the skin while limiting or preventing resorption and the penetration of the active ingredient through the skin.
~1; n; cal Tests To test the performance of the formulae or compositions of the above-described examples, portions of hydrogel (Hydrogel, Example 8) and a Lipogel without (Lipogel, Example 6) and with a hydrophilic additive according to the invention (Lipogel + ~., Example 7) were applied to three human test subjects respectively under the following conditions: application amount, 2 g(10 mg dienogest);
~ 6 surface, forehead; and acting time 3 h.
After that the dienogest serum level was detPrmi nPrl by means of RIA. As 6hown in Fig. 4 while a comparatively large amount of dienogest is found in the serum from a pharmaceutically ordinary lipogel, this is not the situation when the hydrogel and the lipogel with hydrophilic additive are used. The serum level of both the latter preparations does not differ significantly from each other. Both serum levels of these preparations differ significantly from the serum level of dienogest resulting from application of the lipogel without the additional additive. That means that with these latter preparations significantly more dienogest remains in the skin and as a result systemic side effects are largely prevented. The serum concentration of dienogest usually required for systemic side effects amounts to 40 to 50 ng/ml. The dienogest serum level after application of the preparation according to the invention amounts to about a factor of 20 lower than this threshold for side effects.
All forms of acne and increased sebum production(seborrhea) are treatable by topical application of the dienogest-containing formulations(facial lotions, skin salves, skin creams, lotions). The sebaceous gland activity has a typical time course in women during aging.
Approximately every second women, beginning with the age of puberty, has a more or less remarkably increased sebaceous gland secretion which can lead to oily skin.
.~
In a study of penetration by dienogest of intact skin in 9 human test subjects it was proven that the effective ingredient (hydrogel formulation) did not penetration into the body. No active ingredients were found in the blood plasma of 5 acne patients 12 and 24 hours after being treated twice with the compositions according to the invention (10 mg dienogest in 2 g skin salve~.
The effect of a 2.2 g dienogest-containing skin cream (example 2) was tested in acne patients and patients with seborrhea during activity studies in 24 women of ages between 18 and 45 years and 18 men of ages between 24 and 46 years. In all patients the dienogest-containing skin cream was applied to the right half of the forehead. The left half of the forehead acted as control. The skin cream was applied twice daily (morning and evening) to the skin area to be treated. The experiment duration was 8 weeks. In all patients a considerable reduction of the sebum generation was observed already after 8 treatment days. A remarkable reduction of skin surface lipids of about 42 to 47 % was observed in both male and female test subjects after 14 to 21 days. Particularly a decline of the wax components was observed. These waxes are of greater significance in the production of acne and ~:~ ~1nn~s. A definite improvement in the acne conditions present in the patients was observed in 4 to 8 weeks of treatment. In 52 % of the acne patients after 4 treatment weeks no symptoms r~ i n~d. After 8 weeks .~
of therapy only 12 96 of the acne patients had any noticeable acne present and in these cases exceptionally pronounced acne had been present at the start of the treatment. Also in these patients a clearly positive course of the treatment was observed during the eight weeks of treatment .
The dienogest-containing preparations (facial lotion, skin salve, skin cream, lotion~ according to the invention are used so that the increased sebaceous gland secretions (seborrhea) and the noninflammed acne are successfully prevented with the help of a sufficient amount of the respective preparations. It is rec~ -ntl~-l that the topical formulation be used on the skin with various concentrations according to the individual case ~f~pPnfl i n~ on the strength of the disease being treated. Prior to the beginning of therapy of androgenic conditions skin changes a det~-rm;n~d of the individual hormone status is re~ -n~led in fertile females.
The treatment with the dienogest-containing skin agent extends to the diseased portions of the skin(seborrhea, acne areas, alopecia, androgenizing symptoms in women). It is rec~ -n~d that daily applications or applications several times a day be made during treatment of these skin diseases.
~85616 .--Clinical Tests of Acne and Sebor~hea Treatments The tests 1 to 5 hereinbelow exemplify the application of the compositions according to the invention for the treatment of acne and seborrhea.
Test 1:
A O . 25 % dienogest-containing facial lotion was used for treatment of seborrhea. With increased sPh~eollc gland production a twice daily application to the affected areas is rf~ mmF~n~ with increased sebaceous gland production in the facial area. This hormonal agent was used over a period of eight weeks and provided an outstanding sebum 6uppression .
Test 2:
For acne therapy a 3 9~ dienogest-containing skin cream was applied twice daily to the skin areas infected with acne in an acne therapy program. The cream was applied over a 3 month test interval and a very good therapeutic action was observed already after 4 treatment weeks in sever cases of acne .
2~ 856 ~ 6 Test 3:
A o . 2 ~6 dienogest-containing skin salve was applied at least once per day for treatment of excessive sebum production o the sebaceous gland o the skin. Within a few minutes the salve was absorbed by the skin. The performance observed was similar to the outstanding performance observed during test l.
Test- 4:
An o . 5 % dienogest-containing lotion was used a prepar.ation for acne therapy. The lotion was applied to the areas having acne twice daily. A very good therapeutic action was observed for this preparation because of the rapid penetration into the skin. The results were similar to those of test 2.
Test 5:
An O . 5 % dienogest-containing hydrogel which contained 5 mg of 17a-estradiol in lOOO g gel, was applied for treatment of acne. The gel was applied once a day for a 3 month test period. Already after 4 treatment weeks a definite sebosuppression effect was observed with partial eliminated of ~_, ?c~..n.~c.
2185~1b .--The following tests 6 to 8 shows the application of the compositions according to the invention for the treatment of hair loss and the promotion of hair waxes.
Test 6:
For treatment of the entire scalp skin use of a 0. 2 %
hair tonic/hair spray is rec -n~ed~ in which a total dose of 20 ml per week should not be ~Y~ d.
Test 7:
A 0 . 5 9~ hair tonic/spray is r-l -n~ l for treatment of postmenopausal androgenically conditioned hair loss at a maximum dosage up to 20 ml per week.
Test 8:
For a locally limitea androgenically conditioned hair loss only the scalp region (peaks areas, forehead surfaces, rear scalp surfaces) involved should be treated with balm and/or hair cream or hair spray daily or at least 3 times in one week.
A successful therapeutic result in the form of increased hair growth was observed in tests 6 to 8 after 3 treatment months.
The invention described and claimed herein is also described in German Patent Application 195 34 209.7-41 filed in Germany on September 16, 1995. Priority rights based on 2~8561~
the aforesaid German Patent Application are being claimed.
The disclosure in the priority document, German Patent Application 195 34 209.7-41, is incorporated in this specification by reference.
While the invention has been illustrated and described as embodied in a pharmaceutical composition including a hormonal agent and method for skin treatment, especially of seborrhea, acne and the like, and a method of making the pharmaceutical composition, it is not intended to be limited to the details shown, since various modifications and changes may be made without departing in any way from the spirit of the present invention.
Without further analysis, the foregoing will so fully reveal the gist of the present invention that others can, by applying current knowledge, readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this invention .
What is claimed is new and is set forth in the following appended claims.
Part B
2 . 2 g dienogest 4, 4 q sacchrose 6 . 6 g total for part B
2~856~6 .
Part C
55. 6 g deionized water o . 2 g sodium tetraborate 1. 5 g boric acid 0 . 7 a lactic acid 62 . 2 g total for part C
Part D
q. s . preservative materials and perfumes .
Prepar~l tion:
The materials of part A are heated to 90 C, melted and mixed. A solid dispersion (part s) made according to the method already described from dienogest and saccharose 1:2 is homogeneously dispersed in the melt. This is processed in the above-described reactor vessel according to the invention with the following conditions:
vessel temperature after adding the solid dispersion: 40 C
rotation speed of the wiper 1 rpm rotation speed of the slo~rer stirrer 50 rpm rotation speed of the homogenizer 3450 rpm cooling rate 1 C/min Exam~le 4: Skin Salve Part A
4. 0 g Bees wax 9 . 5 g glycerol monostearate 4 . o g lanolin 8. 0 g isopropyl myristate 8. 0 g paraffin(viscous liquid) 4 . 0 q propylene glycol 37 . 5 g total for part A
Part B
20. 0 g deionized water 0 . 2 a sodium tetraborate 20.2 g total for part B
~ 2185616 Part C
0 .16 g dienogest 19 . 84 q ethanol 20 . oo g total for part C
Part D
q. s . preservative materials and perfumes .
Preparation:
The A portion was heated to 90 C, melted and mixed. The melt is mixed(partially saponified) with the borax solution which was also first heated to 90 C. Subsequently the mixture of parts A and B is cooled to below 50'C, before the ethanolic dienogest solutiontpart C) is mixed with it.
Finally the preservative and perfume containing part D is added to the mixture of parts A, B and C. Then the product is cooled at 20 C with stirring.
ExamPle 5: Skin Lotion Part A
0 . 50 kg dienogest 9 . 45 kg ethanol 0 . 05 kg glycerol lO . 00 kg Part B
1. 0 kg sorbitan monostearate 1. 5 kg macrogol stearate 2 . 5 kg medium chain length triglyceride o . 05 kg potassium sorbate o. 025 kg water-free citric acid water ad 40.00 kg Preparation:
The solution (part A) is homogeneously distributed in the mixture B. The preparation then proceeds according to the general method described hereinabove with the following conditions:
Vessel temperature on addition of solution A: 30 C
Rotation speed of the wiper: 1 rpm Rotation speed of the slower stirrer: 90 rpm Rotation speed of the homogenizer 3850 rpm Cooling rate: l C
ExamPle 6: LiPoqel 5. o g dienogest 1000. 0 g wool wax alcohol salve Preparation:
The micronized dienogest is uniformly distributed in the stated amount in the wool wax alcohol salve.
ExamPle 7: LiPoqel + EI with Diçnoqest 5 . 0 g dienogest 45 . 0 g lactose wool wax alcohol salve to 1000 . 0 g Preparation:
A solid dispersion of dienogest and lactose 1:9 is f irst prepared according to the above-described methods .
This solid dispersion is uniformly distributed in the wool wax alcohol salve according to DAB 10. In an analogous smaller vessel, as described earlier in the description above, this is processed under the following conditions:
! 2 ~ 856 t 6 vessel temperature after adding the solid dispersion: 40 C
rotation speed of the wiper 2 rpm rotation speed of the slower stirrer 10 rpm rotation speed of the homogenizer 2050 rpm cool ing rate : 1 C~min r le 8: HYdroqel with Dienoqest 5. 0 g dienogest 400. 0 g ethanol 30. 0 g methylhydroxyethyl cellulose pure water to 1000 . 0 g Prep~r~tion:
The stated amount of dienogest is dissolved in the ethanol and uniformly mixed with the aqueous methyl~lyd, ~xyt:~hyl cellulose gel as described above.
Exam~le 9: Hyd~Qqel with ~ienQqest and 17~-Estradiol 5. 0 g dienogest 5 . O mg 17a-estradiol 400.0 g ethanol 30. 0 g methylhydroxyethyl cellulose pure water to 1000 . 0 g PreparYtion:
The stated amounts of dienogest and 17a-estradiol are dissolved in ethanol and uniformly mixed with the aqueous methylhydroxyethyl cellulose gel as described above.
ExamQle 10: LipQqel: DienQqest Plus Estriol 5.0 g dienogest 0 . 0 mg estriol wool wax alcohol salve to 1000. 0 g 2~85616 .
Pr~3p~r~tion:
The dienogest and estriol are uniformly mixed in the stated amount in the wool wax alcohol salve.
Example 11: ~Iair Ton1ç or l~;r SpXav o. 2 g dienogest 0 . 4 g castor oil o. 6 g benzyl benzoate q. s . Dye compounds, perfumes ethanol 9 6 96 ad 100 . 0 g Preparation:
Dienogest and benzylbenzoate or isopropyl myristate are dissolved in the stated amount of ethanol. The mixture is briefly heated at 50 C . After that it is rapidly cooled to 20 C. Finally the required dye compounds and perfumes dissolved in the stated amount of castor oil are added to the resulting solution.
Example 12 ~ i r Tonic or 1~; r SPrav 0 . 2 g chloxmadinon acetate o . 4 g peanut oil 2 . 5 g lecithin o. 6 g benzylbenzoate q. s . dye, , ~, perfumes ethanol 9 6 % ad 100 . 0 g Preparation:
The chlorr-c9;n~1n acetate and benzylbenzoate are dissolved in the stated amount of ethanol. Then the mixture is briefly heated at 50 C. After that it is rapidly cooled to 20 C. Finally the required dye compounds and perfumes dissolved in the stated amount of peanut oil are added to the resulting solution.
Example 13: Dienogest-Hair Balm with Hair-fixing Action (Conditioner) Part A
2.0 g cetyl lactate 2.0 g isopropyl myristate 4.0 g glycerol monostearate 1.0 g polyethyleneglycol (PEG)-40-stearate 2.0 g cetyl stearyl alcohol 1.0 g cetyl alcohol _____ 12.0 g total Part B
30.0 g aloe vera as colorless gel 33.9 g deionized water 0.3 g hydroxypropylmethyl cellulose (HPMC) 3.4 g Quat's mixture of Quat-22 and Quat-26(2:5) 0.3 g lactic acid ______ 67.9 g total Part C
0.23 g dienogest 19.75 g ethanol _______ 19.98 g total Part D
q.s. Dye compounds, preservatives and perfumes Preparation:
A glutinous mixture is made from the HPMC and water.
The ingredients of Part B are added to the glutinous mixture. The resultant mixture is homogenized and after that 2~856~6 .~
heated to 80 C(water bath). Part B is prepared by mixing the above-stated ingredients of it at 80 C (water bath) . Part B
is then mixed with the same heating with Part A. The mixture of parts A and B is cooled with stirring at 50 C. The ethanolic solution (Part C) is added with stirring to the mixture of parts A and B cooled below 50 C. The resultant mixture is cooled further. Finally the required dye compounds, preservatives and perfumes are added to the mixture of parts A, B and C. The resultant mixture I then coolçd with stirring to 20 C.
Exam~le 14: ChlQrma~9;non Aççtate Hair Cr~m(GrQominq Cream) Part A
4 . 0 g bees wax 10. 0 g glycerol monostearate 3 . 5 g lanolin 8 . 0 g isopropyl myristate 8 . 0 g viscous paraffin 4, o q propylene glycol 37 . 5 g total Part B
20. 0 g deionized water 0 . 2 q sodium tetraborate 2 0 . 2 g total Part C
0 . l9 g chlomadinon acetate l9 . 81 q ethanol 20 . 00 g total Part D
q. s. Dye compounds, preservatives and perfumes 2~85616 Preparation:
The substances of Pa-rt A are heated at 90 C, then melted and mixed. The melt is mixed(partially saponified) with the borax solution(Part C) also heated at 90 C. The resultant mixture is subsequently cooled with stirring to under 50 C, before the ethanolic chl~ l;n~ln acetate solution (Part C) is added. Finally, the required dye compounds, preservatives and perfumes of Part D are added to the resulting mixture of parts A, B and C and the resulting mixture is cooled at 20'C with stirring.
Exam~le 15: Dienoaest ~T~;r Crf~ ~m Part A
4 . 0 g bees wax 10 . 0 g hard wax 3 . 5 g lanolin 8 . 0 g isopropyl myristate 8 . 0 g liquid wax 4 . 0 q glycerol 37 . 5 g total Part B
0 . 2 g dienogest (micronized) Part C
60 . 0 g deionized water~
0 . 2 g sodium tetraborate 1. 5 g boric acid 0 . 7 a lactic acid 62 . 4 g total Part D
q. s . Dye compounds, preservatives and perfumes Preparation:
The ingredients of Part A are heated at 90 C, then melted and mixed. The micronized dienogest (Part B), protected from light, is mixed in this melt. The resultant mixture is subsequently cooled with stirring to under 50 C.
The water phase C is added with stirring to the cooled mixture of parts A and B. The resulting mixture is cooled further below 50 C. Finally, the required dye compounds, preservatives and perfumes of Part D are added to the resulting mixture o~ parts A, B and C and the resulting mixture is cooled at 20 C with stirring.
The purpose of these ph7~ tical preparations, above all, is the penetration of the active ingredient into the skin while limiting or preventing resorption and the penetration of the active ingredient through the skin.
~1; n; cal Tests To test the performance of the formulae or compositions of the above-described examples, portions of hydrogel (Hydrogel, Example 8) and a Lipogel without (Lipogel, Example 6) and with a hydrophilic additive according to the invention (Lipogel + ~., Example 7) were applied to three human test subjects respectively under the following conditions: application amount, 2 g(10 mg dienogest);
~ 6 surface, forehead; and acting time 3 h.
After that the dienogest serum level was detPrmi nPrl by means of RIA. As 6hown in Fig. 4 while a comparatively large amount of dienogest is found in the serum from a pharmaceutically ordinary lipogel, this is not the situation when the hydrogel and the lipogel with hydrophilic additive are used. The serum level of both the latter preparations does not differ significantly from each other. Both serum levels of these preparations differ significantly from the serum level of dienogest resulting from application of the lipogel without the additional additive. That means that with these latter preparations significantly more dienogest remains in the skin and as a result systemic side effects are largely prevented. The serum concentration of dienogest usually required for systemic side effects amounts to 40 to 50 ng/ml. The dienogest serum level after application of the preparation according to the invention amounts to about a factor of 20 lower than this threshold for side effects.
All forms of acne and increased sebum production(seborrhea) are treatable by topical application of the dienogest-containing formulations(facial lotions, skin salves, skin creams, lotions). The sebaceous gland activity has a typical time course in women during aging.
Approximately every second women, beginning with the age of puberty, has a more or less remarkably increased sebaceous gland secretion which can lead to oily skin.
.~
In a study of penetration by dienogest of intact skin in 9 human test subjects it was proven that the effective ingredient (hydrogel formulation) did not penetration into the body. No active ingredients were found in the blood plasma of 5 acne patients 12 and 24 hours after being treated twice with the compositions according to the invention (10 mg dienogest in 2 g skin salve~.
The effect of a 2.2 g dienogest-containing skin cream (example 2) was tested in acne patients and patients with seborrhea during activity studies in 24 women of ages between 18 and 45 years and 18 men of ages between 24 and 46 years. In all patients the dienogest-containing skin cream was applied to the right half of the forehead. The left half of the forehead acted as control. The skin cream was applied twice daily (morning and evening) to the skin area to be treated. The experiment duration was 8 weeks. In all patients a considerable reduction of the sebum generation was observed already after 8 treatment days. A remarkable reduction of skin surface lipids of about 42 to 47 % was observed in both male and female test subjects after 14 to 21 days. Particularly a decline of the wax components was observed. These waxes are of greater significance in the production of acne and ~:~ ~1nn~s. A definite improvement in the acne conditions present in the patients was observed in 4 to 8 weeks of treatment. In 52 % of the acne patients after 4 treatment weeks no symptoms r~ i n~d. After 8 weeks .~
of therapy only 12 96 of the acne patients had any noticeable acne present and in these cases exceptionally pronounced acne had been present at the start of the treatment. Also in these patients a clearly positive course of the treatment was observed during the eight weeks of treatment .
The dienogest-containing preparations (facial lotion, skin salve, skin cream, lotion~ according to the invention are used so that the increased sebaceous gland secretions (seborrhea) and the noninflammed acne are successfully prevented with the help of a sufficient amount of the respective preparations. It is rec~ -ntl~-l that the topical formulation be used on the skin with various concentrations according to the individual case ~f~pPnfl i n~ on the strength of the disease being treated. Prior to the beginning of therapy of androgenic conditions skin changes a det~-rm;n~d of the individual hormone status is re~ -n~led in fertile females.
The treatment with the dienogest-containing skin agent extends to the diseased portions of the skin(seborrhea, acne areas, alopecia, androgenizing symptoms in women). It is rec~ -n~d that daily applications or applications several times a day be made during treatment of these skin diseases.
~85616 .--Clinical Tests of Acne and Sebor~hea Treatments The tests 1 to 5 hereinbelow exemplify the application of the compositions according to the invention for the treatment of acne and seborrhea.
Test 1:
A O . 25 % dienogest-containing facial lotion was used for treatment of seborrhea. With increased sPh~eollc gland production a twice daily application to the affected areas is rf~ mmF~n~ with increased sebaceous gland production in the facial area. This hormonal agent was used over a period of eight weeks and provided an outstanding sebum 6uppression .
Test 2:
For acne therapy a 3 9~ dienogest-containing skin cream was applied twice daily to the skin areas infected with acne in an acne therapy program. The cream was applied over a 3 month test interval and a very good therapeutic action was observed already after 4 treatment weeks in sever cases of acne .
2~ 856 ~ 6 Test 3:
A o . 2 ~6 dienogest-containing skin salve was applied at least once per day for treatment of excessive sebum production o the sebaceous gland o the skin. Within a few minutes the salve was absorbed by the skin. The performance observed was similar to the outstanding performance observed during test l.
Test- 4:
An o . 5 % dienogest-containing lotion was used a prepar.ation for acne therapy. The lotion was applied to the areas having acne twice daily. A very good therapeutic action was observed for this preparation because of the rapid penetration into the skin. The results were similar to those of test 2.
Test 5:
An O . 5 % dienogest-containing hydrogel which contained 5 mg of 17a-estradiol in lOOO g gel, was applied for treatment of acne. The gel was applied once a day for a 3 month test period. Already after 4 treatment weeks a definite sebosuppression effect was observed with partial eliminated of ~_, ?c~..n.~c.
2185~1b .--The following tests 6 to 8 shows the application of the compositions according to the invention for the treatment of hair loss and the promotion of hair waxes.
Test 6:
For treatment of the entire scalp skin use of a 0. 2 %
hair tonic/hair spray is rec -n~ed~ in which a total dose of 20 ml per week should not be ~Y~ d.
Test 7:
A 0 . 5 9~ hair tonic/spray is r-l -n~ l for treatment of postmenopausal androgenically conditioned hair loss at a maximum dosage up to 20 ml per week.
Test 8:
For a locally limitea androgenically conditioned hair loss only the scalp region (peaks areas, forehead surfaces, rear scalp surfaces) involved should be treated with balm and/or hair cream or hair spray daily or at least 3 times in one week.
A successful therapeutic result in the form of increased hair growth was observed in tests 6 to 8 after 3 treatment months.
The invention described and claimed herein is also described in German Patent Application 195 34 209.7-41 filed in Germany on September 16, 1995. Priority rights based on 2~8561~
the aforesaid German Patent Application are being claimed.
The disclosure in the priority document, German Patent Application 195 34 209.7-41, is incorporated in this specification by reference.
While the invention has been illustrated and described as embodied in a pharmaceutical composition including a hormonal agent and method for skin treatment, especially of seborrhea, acne and the like, and a method of making the pharmaceutical composition, it is not intended to be limited to the details shown, since various modifications and changes may be made without departing in any way from the spirit of the present invention.
Without further analysis, the foregoing will so fully reveal the gist of the present invention that others can, by applying current knowledge, readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this invention .
What is claimed is new and is set forth in the following appended claims.
Claims (30)
1. A pharmaceutical composition for treating skin comprising an active ingredient and at least one carrier and auxiliary substance, wherein said active ingredient is selected from the group consisting of an antiandrogenically acting gestogen, a first combination and a second combination;
wherein said antiandrogenically acting gestogen consists of dienogest, said first combination consists of a combination of said dienogest and a synthetic or natural estrogen and said second combination consists of a combination of said dienogest and phytestrogen.
wherein said antiandrogenically acting gestogen consists of dienogest, said first combination consists of a combination of said dienogest and a synthetic or natural estrogen and said second combination consists of a combination of said dienogest and phytestrogen.
2. The pharmaceutical composition as defined in claim 1, containing from 0.01 to 4 percent by weight of said dienogest.
3. The pharmaceutical composition as defined in claim 1, wherein said active ingredient is dispersed molecularly in a hydrophilic foundation.
4. The pharmaceutical composition as defined in claim 1, wherein said active ingredient is dispersed molecularly in a deoiling foundation in combination with a hydrophilic ingredient.
5. The pharmaceutical composition as defined in claim 4, wherein the hydrophilic ingredient is a sugar.
6. The pharmaceutical composition as defined in claim 4, wherein the hydrophilic ingredient is a sugar-like compound selected from the group consisting of saccharose, lactose, mannitol, sugar alcohols, urea and nitrogen-containing compounds.
7. The pharmaceutical composition as defined in claim 1, further comprising a permeation promoting substance.
8. The pharmaceutical composition as defined in claim 7, wherein said permeation promoting substance consists of at least one nitrogen-containing compound.
9. The pharmaceutical composition as defined in claim 8, wherein said at least one nitrogen-containing compound is selected from the group consisting of acid amides, amines and alkaloids.
10. The pharmaceutical composition as defined in claim 1, further comprising a stabilizing substance.
11. The pharmaceutical composition as defined in claim 10, wherein said stabilizing substance is at least one member selected from the group consisting of antioxidants, complex formers, reducing agents and UV-absorbers.
12. The pharmaceutical composition as defined in claim 11, wherein said antioxidants include tocopherol.
13. The pharmaceutical composition as defined in claim 1, in the form of a skin cream, a skin salve, a lotion, a liniment, a facial lotion, a hair tonic, a hair balm or a hair cream.
14. The pharmaceutical composition as defined in claim 1, further comprising at least one member selected from the group consisting of dye compounds, preservative compounds and perfumes.
15. A use of a pharmaceutical preparation for treating local areas of skin containing Acne vulgaris, wherein the pharmaceutical preparation contains dienogest or a combination of dienogest and an estrogen as an active ingredient.
16. The use as defined in claim 15, wherein the pharmaceutical preparation is in such a form of a facial lotion, a skin salve, a skin cream or a lotion that the pharmaceutical preparation is allowed to penetrate the local areas of skin.
17. A use of a pharmaceutical preparation for treating local areas of skin containing seborrhea, wherein the pharmaceutical preparation contains dienogest or a combination of dienogest and an estrogen as an active ingredient.
18. The use as defined in claim 17, wherein the pharmaceutical preparation is in such a form of a facial lotion, a skin salve, a skin cream or a lotion that the pharmaceutical preparation is allowed to penetrate the local areas of skin.
19. A method of treating hair loss which comprises applying an effective amount of a pharmaceutical preparation to local areas of skin exhibiting hair loss, wherein the pharmaceutical preparation contains dienogest or a combination of dienogest and an estrogen as an active ingredient for treating hair loss.
20. The method as defined in claim 19, wherein the pharmaceutical preparation is in the form of a hair cream, a hair balm or a hair tonic; and the pharmaceutical preparation is applied at least once a day during the treating so that the pharmaceutical preparation is allowed to penetrate the local areas.
21. A method of promoting hair growth which comprises applying an effective amount of a pharmaceutical preparation to local areas of skin on which hair growth is to be promoted, wherein the pharmaceutical preparation contains dienogest or a combination of dienogest and an estrogen as an active ingredient for promotion of hair growth.
22. The method as defined in claim 21, wherein the pharmaceutical preparation is in the form of a hair cream, a hair balm or a hair tonic; and the pharmaceutical preparation is applied at least once a day during the treatment so that the pharmaceutical preparation is allowed to penetrate the local areas.
23. A use of a pharmaceutical preparation for alleviating vasomotor scalp pain, wherein the pharmaceutical preparation contains dienogest or a combination of dienogest and an estrogen as an active ingredient for alleviating the vasomotor scalp pain.
24. The use as defined in claim 23, wherein the pharmaceutical preparation is in such a form of a facial lotion, a skin salve, a skin cream, a lotion, a hair cream, a hair balm or a hair tonic that the pharmaceutical preparation is allowed to penetrate local areas of skin.
25. A process of making a pharmaceutical composition, said process comprising the steps of:
a) dissolving a pharmaceutically active ingredient in a hydrophilic foundation to form a solution;
b) providing an opaque reaction vessel having walls and means for stirring, means for heating contents of the reaction vessel and means for removing deposits from the walls of the vessel comprising a rotatable wiper movable over the walls of the vessel;
c) mixing the solution formed in step a) with at least one liquid or solid dermatologically acceptable auxiliary substance to form a reaction mixture in the opaque reaction vessel:
d) stirring the reaction mixture with the means for stirring, heating the reaction mixture with the means for heating and removing deposits from said walls of said reaction vessel by operating said rotatable wiper to form a creamy galenic preparation; and e) continuously cooling said galenic preparation with additional stirring.
a) dissolving a pharmaceutically active ingredient in a hydrophilic foundation to form a solution;
b) providing an opaque reaction vessel having walls and means for stirring, means for heating contents of the reaction vessel and means for removing deposits from the walls of the vessel comprising a rotatable wiper movable over the walls of the vessel;
c) mixing the solution formed in step a) with at least one liquid or solid dermatologically acceptable auxiliary substance to form a reaction mixture in the opaque reaction vessel:
d) stirring the reaction mixture with the means for stirring, heating the reaction mixture with the means for heating and removing deposits from said walls of said reaction vessel by operating said rotatable wiper to form a creamy galenic preparation; and e) continuously cooling said galenic preparation with additional stirring.
26. The process as defined in claim 25, wherein the at least one auxiliary substance added during the mixing includes at least one member selected-from the group consisting of permeation promotor substances and stabilizing substances.
27. The process as defined in claim 25, wherein said pharmaceutically active ingredient is dienogest or a combination of dienogest and an estrogen.
28. A process of making a pharmaceutical composition, said process comprising the steps of:
a) mixing a pharmaceutically active ingredient with a hydrophilic component in a first vessel to form a mixture:
b) heating the mixture in the first vessel to at least partially melt said mixture while excluding water, other solvents and surfactants to form a resultant product;
c) dispersing the resultant product with cooling in a gas to form a dispersed product;
d) providing an opaque reaction vessel having means for stirring, means for heating contents of the reaction vessel and means for removing deposits from walls of the vessel comprising a rotatable wiper movable over the walls of the vessel;
e) mixing the dispersed product formed in step c) with at least one liquid or solid dermatologically acceptable auxiliary substance to form a reaction mixture in the opaque reaction vessel;
d) stirring the reaction mixture with the means for stirring, heating the reaction mixture with the means for heating and removing deposits from said walls of said reaction vessel by operating said rotatable wiper to form a creamy galenic preparation; and e) continuously cooling said galenic preparation with stirring.
a) mixing a pharmaceutically active ingredient with a hydrophilic component in a first vessel to form a mixture:
b) heating the mixture in the first vessel to at least partially melt said mixture while excluding water, other solvents and surfactants to form a resultant product;
c) dispersing the resultant product with cooling in a gas to form a dispersed product;
d) providing an opaque reaction vessel having means for stirring, means for heating contents of the reaction vessel and means for removing deposits from walls of the vessel comprising a rotatable wiper movable over the walls of the vessel;
e) mixing the dispersed product formed in step c) with at least one liquid or solid dermatologically acceptable auxiliary substance to form a reaction mixture in the opaque reaction vessel;
d) stirring the reaction mixture with the means for stirring, heating the reaction mixture with the means for heating and removing deposits from said walls of said reaction vessel by operating said rotatable wiper to form a creamy galenic preparation; and e) continuously cooling said galenic preparation with stirring.
29. The process as defined in claim 28, wherein the at least one auxiliary substance added during the mixing includes at least one member selected from the group consisting of permeation promotor substances and stabilizing substances.
30. The process as defined in claim 28, wherein said pharmaceutically active ingredient is dienogest or a combination of dienogest and an estrogen.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19534209A DE19534209A1 (en) | 1995-09-15 | 1995-09-15 | Hormonal agent for the treatment of the skin |
| DE19534209.7 | 1995-09-16 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2185616A1 CA2185616A1 (en) | 1997-03-17 |
| CA2185616C true CA2185616C (en) | 2001-02-27 |
Family
ID=7772237
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002185616A Expired - Fee Related CA2185616C (en) | 1995-09-15 | 1996-09-16 | Hormonal agent for skin treatment |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US5910493A (en) |
| EP (1) | EP0765663A3 (en) |
| CA (1) | CA2185616C (en) |
| DE (1) | DE19534209A1 (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999008654A1 (en) * | 1997-08-21 | 1999-02-25 | Johnson & Johnson Consumer Companies, Inc. | USE OF 17-α-ESTRADIOL FOR THE TREATMENT OF AGED OR SUNDAMAGED SKIN AND/OR SKIN ATROPHY |
| US6488940B2 (en) | 1997-08-21 | 2002-12-03 | Johnson & Johnson Consumer Companies, Inc. | Use of 17-α-estradiol for the treatment of aged or sundamaged skin and/or skin atrophy |
| AU6434999A (en) * | 1998-09-28 | 2000-04-17 | Gavin Deon Petersen | Hair growth stimulant |
| DE19916384A1 (en) * | 1999-03-31 | 2000-10-05 | Schering Ag | Microparticles useful in treatment of androgen-dependent disorders include biodegradable, synthetic polymers of e.g. polyesters of hydroxycarboxylic acids |
| DE19918644A1 (en) * | 1999-04-16 | 2000-10-26 | Jenapharm Gmbh | Intradermal composition for local treatment of skin aging or wrinkles, comprising matrix containing estrogen and structure former to minimize systemic side-effects |
| JP2003527310A (en) * | 1999-04-16 | 2003-09-16 | イエナフアルム ゲーエムベーハー ウント ツェーオー． カーゲー | Pharmaceutical or cosmetic composition for local intradermal administration of estrogen |
| DE10141443B4 (en) * | 2001-08-23 | 2007-02-01 | Christos C. Prof. Dr. Zouboulis | Use of molecular biologically produced, non-viral agents for the treatment of acne |
| DE50213170D1 (en) * | 2002-09-04 | 2009-02-12 | Fraunhofer Ges Forschung | Use of a means for the treatment of cardiac hypertrophy |
| EP1716110A1 (en) * | 2004-02-13 | 2006-11-02 | Warner-Lambert Company LLC | Androgen receptor modulators |
| WO2005100305A1 (en) * | 2004-04-13 | 2005-10-27 | Warner-Lambert Company Llc | Androgen modulators |
| EP1740533A1 (en) * | 2004-04-22 | 2007-01-10 | Warner-Lambert Company LLC | Androgen modulators |
| MXPA06015169A (en) * | 2004-07-08 | 2007-08-21 | Warner Lambert Co | Androgen modulators. |
| BRPI0514469A (en) * | 2004-08-18 | 2008-06-10 | Warner Lambert Co | androgen modulators |
| US20060118002A1 (en) * | 2004-12-03 | 2006-06-08 | Sud-Chemie Inc. | Organoclay composition containing quat mixtures |
| TW200724139A (en) * | 2005-05-05 | 2007-07-01 | Warner Lambert Co | Androgen modulators |
| US20090170886A1 (en) * | 2005-08-08 | 2009-07-02 | Pfizer Inc | Androgen modulators |
| US8288366B2 (en) | 2006-06-20 | 2012-10-16 | Chochinov Ronald H | Formulation for hair growth |
| DE102006062120A1 (en) | 2006-12-22 | 2008-06-26 | Grünenthal GmbH | Pharmaceutical composition for acne treatment |
| US8846063B2 (en) * | 2008-12-16 | 2014-09-30 | Kimberly-Clark Worldwide, Inc. | Personal care composition containing a volatile and a terpene alcohol |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2257223A1 (en) * | 1972-11-22 | 1974-06-12 | Fouad Dr Med Talabani | Hair growth and anti- hairloss compsn. - contg. mixts of androgen, oestrogen, corticoid and carriers |
| DE4229820C2 (en) * | 1992-09-07 | 1998-12-03 | Jenapharm Gmbh | Progestogen-based pharmaceutical preparation |
| DE4308406C1 (en) * | 1993-03-12 | 1994-06-16 | Jenapharm Gmbh | Contraceptive compsn. with reduced hormone dose and reduced side-effects - contg. synergistic mixt. of biogenic, synthetic oestrogen and gestagen |
| DE4313926A1 (en) * | 1993-04-28 | 1994-11-03 | Jenapharm Gmbh | Multiphase pharmaceutical product for hormonal contraception |
| DE4321957C2 (en) * | 1993-07-01 | 1995-09-28 | Marika Dr Med Ehrlich | Use of a hormonal agent to treat acne |
| DE4406462C2 (en) * | 1994-02-24 | 1997-05-28 | Jenapharm Gmbh | Process and apparatus for the preparation of solid dispersions |
-
1995
- 1995-09-15 DE DE19534209A patent/DE19534209A1/en not_active Withdrawn
-
1996
- 1996-09-12 EP EP96114619A patent/EP0765663A3/en not_active Withdrawn
- 1996-09-16 CA CA002185616A patent/CA2185616C/en not_active Expired - Fee Related
- 1996-09-16 US US08/714,463 patent/US5910493A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US5910493A (en) | 1999-06-08 |
| EP0765663A3 (en) | 1997-11-12 |
| CA2185616A1 (en) | 1997-03-17 |
| DE19534209A1 (en) | 1997-03-20 |
| EP0765663A2 (en) | 1997-04-02 |
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