DE2401453A1 - PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF SKIN PROLIFERATIONAL DISEASES - Google Patents

Description

Ka / Dl

'11. Jan. 1374

Our no. 19 087

John James Voorhees
Ann Arbor, Mich., V.St.A.

Pharmaceutical composition for the treatment of
Skin proliferation diseases.

The present invention relates to pharmaceutical compositions for the treatment of skin proliferation diseases, the active ingredient is a papaverine alkaloid the general formula

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v / orin X represents a carbonyl radical or C and η · Ο or 1, R. represents a hydroxy radical, a methoxy radical, an ethoxy radical or an ethyl radical, R ₂ , R, and R ₁ . Hydrogen atoms, hydroxy groups, methoxy groups or ethoxy groups, R ₁ - denotes a hydrogen atom or an ethoxy group, R / - denotes a hydrogen atom or a methyl group and R ₇ denotes a hydrogen atom or a methyl group, where, if R ₇ denotes a methyl group, those in the ring A are saturated double bonds, or contain the pharmaceutically acceptable acid addition salts thereof.

The compositions of the invention can be topical or administered by intralesional, interdermal, or subcutaneous injection. Treatment can be either be carried out therapeutically or prophylactically.

Skin proliferation diseases are widespread in the world spread and seek millions of people and their

Pets home. Methods for treatment are according to the invention such diseases and pharmaceutical compositions useful for alleviating these diseases are provided. The term "skin proliferation diseases" includes benign and malignant Skin proliferation diseases accelerated by Cell division in the epidermis, the skin or the skin appendages, associated with incomplete tissue differentiation are characterized, understood. Such diseases include psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and scaly skin cell carcinoma, lamellar ichthyosis, epidermoly-

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tic hyperkeratosis, premalignant, induced by the sun Keratosis, non-malignant keratosis, acne and seborrheic Dermatitis in humans and atopic dermatitis and mange in pets.

To date, skin proliferation disorders have generally been considered a perennial evil by mankind accepted that in different degrees of strength, which over time, with the inherited skin properties and external factors fluctuate, occurs, whereby these diseases however always as disfiguring, painful and were considered pathological. In the history of mankind there have been innumerable with fluctuating degrees of success Medicines and treatments suggested, tried and applied. However, none was previously devised Treatment or applied pharmaceutical composition in the wide range of special diseases, which by the expression "diseases of skin proliferation" can be circumscribed 'quite' successfully.

The current treatments of a commercial nature prescribed for the treatment of skin proliferative diseases and applied. Include three ways:

(1) topical applications: coal tar derivatives, 5-fluorouracil, Vitamin Α acid, glucocorticoids in high doses (which form an impermissible concentration), Bath oils and non-specific emollients being creams and ointments;

(2) systemic administration .: glucocorticoids and classic anti-cancer drugs, such as methothrexate, hydroxyurea, Azaribine and cyclophosphamide;

(3) physical treatments: ultraviolet light, x-ray radiation and, in severe cases, surgical Interventions.

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While these treatments in certain cases lead to one Leaving the original symptoms unchecked, every treatment suffers from a certain deficiency, e.g. temporary and incomplete relief of symptoms, rapid recurrence of the disease; when the mitigation is over, serious and sometimes irreversible damage (atrophy), wel- ■ before resulting from topical application for extended periods of time / glucocortxcoxdene, acute inhibition bone marrow formation and liver cirrhosis resulting from prolonged use of methothrexate, which can lead to the death "of the patient, and cancer formation as a result of the use of anti-cancer drugs, X-ray exposure or ultraviolet rays.

It has now been found that diseases of the skin proliferation be alleviated, i.e. that the symptoms of the disease are noticeably weakened or even undetectable if'man affected by the disease patient or the sick animal with one or more of the invention pharmaceutical compositions treated, which in the following are nlihlji * - ^ «^^^! * ^^^.

For the purposes of the present invention, it is a skin proliferation disease referred to as relieved when, when touched, there is an inconsistent decrease in the thickness of a pathological one Change, with or without residual redness, residual slightly dilated blood vessels, or one residual hyper- or hypopigmentation is detected. In this sense, a number of psoriasis are referred to as alleviated, if a pathological change due to dandruff-free psoriasis is noticeably reduced in thickness or noticeably but incompletely cleared ^ (cleared) or completely cleaned.

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The compositions according to the invention can be topical or administered by intradermal, intra- or perilesional or subcutaneous injection.

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The term "topical", as used herein, refers to the application of the active ingredient, which is incorporated into a suitable pharmaceutical carrier and applied to the site of the disease to exert a local effect. Accordingly, such topical compositions encompass those pharmaceutical forms in which the compound is applied externally by direct contact with the skin surface to be treated. Common pharmaceutical forms for this purpose include ointments, lotions, pastes, jellies, sprays, aerosols, bath oils, and the like.

The term "ointment" includes formulations (including creams) with oily, absorptive, water-soluble., _ ₌ And emulsion-like basic substances, such as vaseline, lanolin, polyethylene glycols and mixtures thereof ^ JSs was found that one ₌₌ tp ₌ @ ljfcGfee == = ^ ef ^f aSreichuhg under

that is larger than that to be treated

delnde area compared to a non-occluded topical Application gives better results, and the former is consequently the preferred method of opisciien treatment with the compositions according to the invention.

The percentage (weight / weight) of the =% en_activity used herein is ~ Wn * etWart) r3r % to about 15%> preferably from about 0.5 % to about 2 % of the pharmaceutical composition and in these compositions the " above-listed pharmaceutical carriers for topical application from a major amount of the composition. ^ = ^ - * "'

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The introduction is called an "intraderral" injection of the composition according to the invention into the dermis (high dermls) understood by injection with a needle or by injection with air under high pressure.

Under "intra- or perilesional" injection this is Introducing the composition according to the invention into the pathological change or understood in the tissue adjacent to the pathological change.

The compositions can be intramuscular, subcutaneous or so that the composition penetrates the bloodstream Injected intravenously or by application to non-diseased skin.

For parenteral administration, liquid dosage forms are prepared by adding the active ingredient or the Active ingredients and a sterile vehicle, with water being preferred, are used. The connection can, depending on Form and concentration used, either suspended or dissolved in the vehicle. In the preparation of Of solutions, a water-soluble form of the compound can be dissolved in water for injection and passed through a filter sterilized before filling into a suitable vial or ampoule and its closure. In the vehicle, the auxiliaries, v / ie for example local anesthetics, preservatives and Buffer dissolved; * earth. To increase the stability can the composition can be frozen after filling into the vial and the water removed under vacuum. The freeze-dried powder is then placed in the vial

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and a dedicated vial of water for injection may be supplied to restore fluid prior to use. Parenteral suspensions are used made in the same way as borrowed, with except that the compound is suspended in the vehicle, rather than dissolved, and that there is no sterilization can be achieved by filtration. The compound can be sterilized by grounding it prior to suspension exposes ethylene oxide in the sterile vehicle. Advantageously, a surfactant or a Wetting agents included in the composition to facilitate even distribution.

The percentage (weight / volume) of the active ingredient for injectable compositions ranges from about 0.1 % to about 5 %, and preferably from about 0.5 to 2 %.

The compositions according to the invention can be used in conjunction with glucocorticoids. Under the The term "glucocorticoids" is used as a naturally occurring one Product of the adrenal cortex or its synthetic analogue understood, which is an anti-inflammatory Efficacy and has minimal or no mineral corticoid or sex steroid efficacy. Of the natural glucocorticoids can be used, for example, hydrocortisone or synthetic glucocorticoids such as e.g. Use methylprednisolone acetate (prednisone) for oral administration or triamcinolone for topical therapy. The glucocorticoids should be used in small amounts or a "permissible dosage". Under the expression "permissible dosage" for glucocorticoids ·

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is understood to mean a quantity which minimally supplements the natural release of levuladic glucocorticoids in a normal person and which, when administered alone, has no noticeable effect on diseases of skin proliferation. ''

The following examples serve to illustrate the present invention.

example 1 Papaverine hydrochloride 0.9 g Cetyl alcohol 5.4: g Stearyl alcohol 5.4 g Na lauryl sulfate 1.35 g Vaseline 27, above Propylene glycol 9.0 g

distilled water ad 9.0 g

The oil phase was made by melting petroleum jelly, cetyl alcohol and stearyl alcohol together. The remaining ingredients were dissolved in water and added to the oil phase to form a cream.

The cream is useful in treating psoriasis by rubbing twice a day on the changes caused by psoriasis.

Example 2

The topical compositions listed below are useful in the treatment of psoriasis.

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ointment

Papaverine 0.1 g

Cetin '27 g

Beeswax 27 g

C'arbapol 934 ad 100 g

cream

Papaverine 1 g

Polyethylene glycol 400 37.5 g

1,2,6-hexanetriol 20 g

Polyethylene glycol 4000 ad 100 g

cream

Papaverine hydrochloride "5 g

Polyethylene glycol 400 37 g

Polyethylene Glycal 400 Monostearate 26 g

Polyethylene glycol 4000 ad 100 g

cream

Papaverine hydrochloride 5 g

Polyethylene glycol 400. 47.5 g

Cetyl alcohol 5g

Polyethylene glycol 4000 ad 100 g

ointment

Papaverine hydrochloride ■ 10 g

anhydrous lanolin 20 g

Mineral oil 25 g

Vaseline ad 100 g

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The ointments and creams listed above are at the Treatment of psoriasis by applying 3 times a day to the affected areas of the skin is useful.

Example 3

1,000 g of a topical cream was made up of the following ingredients manufactured:

Papaverine phosphate 100 g

Polysorbate 80 50 g self-emulsifying glyceryl monostearate ("Tegacid regular", commercial product of Goldschmidt Chemical Corporation,

New York, N.Y.) 150 g

Cetin x 100 g

Propylene glycol 50 g

Methyl paraben 1 g

Deionized water ad 1,000 g

The self-emulsifying glyceryl monostearate and the cetin were melted together at a temperature of 70 to 80 ° C. The methyl paraben was dissolved in approximately 500 grams of water and the propylene glycol, polysorbate 80 and papaverine phosphate were added successively while maintaining a temperature of 75 to 80 ° C. The methyl paraben mixture was slowly added to the melt of glyceryl monostearate and cetin with constant stirring. Of the Addition was continued for at least 30 minutes while continuing to stir until the temperature reached 40 to 45 ° C fell. Finally, enough water was added to bring the final weight to 1,000 g and the preparation was stirred to maintain homogeneity until it had cooled and solidified.

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The composition thus obtained is applied to human skin twice a day for the treatment of acne.

example k Parenteral solution

A sterile aqueous solution for injection made in 1 cm Containing 75 mg papaverine hydrochloride was prepared from the following ingredients:

Papaverine hydrochloride 50 g

Lidocaine hydrochloride 4 g

Methyl paraben 2.5 g

Propyl paraben x 0.17 g

Water for injection ad 1,000 cm

The ingredients were dissolved in water and the solution was sterilized by filtration. The sterile solution was filled into 2 cm vials and the vials were capped.

Example 5 Parenteral solution

A sterile aqueous solution for injection containing in 1 cm ^ 10 mg papaverine hydrochloride, ¹ was prepared from the following ingredients:

Papaverine hydrochloride 10 g

Sodium chloride q.s *

Water for injection ad. 1,000 cm

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The papaverine hydrochloride was added to the water and a sufficient amount of sodium chloride was added to to form an isotonic solution. The solution was sterilized by filtration. The sterile solution was Aseptically filled in sterile vials in quantities of 2 cm ^ and the vials were sealed.

The solution thus obtained was intradermal in amounts of 0.1 cm ^ injected into the area of changes caused by psoriasis.

Example 6

The procedure of Examples 1 to 5 was repeated with the exception that the papaverine used there by an equal amount of ethaverine, octaverine, l-benzyl-6,7-dimethoxyisoquinoline, 3-ethyl-1-benzyl-6,7-dimethoxyisoquinoline, papaveraldine, codamine, laudanine, laudanosine, paveril and Norlaudanosolin was replaced. In this way, compositions suitable for treatment from psoriasis are valuable.

The compositions prepared in Examples 1 to 6 can be prepared in a similar manner by treating

atopic dermatitis, unspecific dermatitis, primary Irritant contact dermatitis, allergic contact dermatitis, basal and scaly skin cell carcinoma., lamellar ichthyosis, epidermolytic.-hyperkeratosis., premalignant, sun-induced keratosis, non-malignant Keratosis, acne and seborrheic dermatitis atopic dermatitis in humans and mange in peddlers.

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Claims (4)

240H53 claims: 1. Pharmaceutical composition for the treatment of skin proliferation diseases, characterized in that that it is a compound of the formula where X is a carbonyl radical or G and η is 0 or 1, R _{1 is} a hydroxy radical, a methoxy radical, an ethoxy radical or an ethyl radical, Rp ,. R, and Rj. Hydrogen atoms, hydroxy groups, methoxy groups or ethoxy groups, R ₁ -a hydrogen atom or an ethoxy group, Rg a hydrogen atom or a methyl group and R "denotes a hydrogen atom or a methyl group, where, if R ₇ denotes a methyl group, those in the ring A shown double bonds are saturated, or contains a pharmaceutically .acceptable acid addition salt thereof as an active ingredient together with a pharmaceutically acceptable carrier. 2. Pharmaceutical composition according to claim l.in Form of a topical application form. 409829/1084 - l4 - 240M53 3. Pharmaceutical composition according to Claim 1, in Pbrm an injectable use form. 4. Pharmaceutical composition according to claim 1, characterized characterized in that it is papaverine or a pharmacologically acceptable acid addition salt thereof as the active ingredient contains. For John James Voorhees (Dr. H.J. Wolff) Lawyer 409829/1084