DE2401449A1 - PHARMACEUTICAL COMPOSITION FOR THE RELIEF OF SKIN PROLIFERATIONAL DISEASES - Google Patents

Description

RECHTSANWÄLTE P / Dl DR. JUR. DIPL-CHER WALTER BEfI ALFREl) UOePPENER *> / η -i / / λ Ί1 lan 107J

DR. JUR. DIP'.-CHEM. H.-J. WOLW - 2 4 0 H 4 9 ^{ih J8n} ' ^{] 97} *

DR. JUR. HANS Ci-iR. AX FRANKFURT AM MAIN-HOCHS? AOELONSTiASSt 53

Our no. 19 092

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

Pharmaceutical composition for the relief of skin proliferation diseases

The present invention relates to pharmaceutical compositions for the relief of skin proliferation disorders such as psoriasis, atopic dermatitis and the like People or pets. Compositions according to the invention which are topically and / or parenterally and / or systemically can be administered contain a pharmaceutical carrier and at least one analog of the 3 »5-cyclic Adenosine monophosphate or at least an antiviral Means as an active ingredient.

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

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External factors fluctuate, occurs, but these diseases are always considered disfiguring, painful and were considered pathological. In the history of mankind there have been innumerable with fluctuating degrees of success Medicines and treatments proposed, tried and used. However, none was previously devised! Treatment or applied pharmaceutical composition in the wide range of special diseases, which can be delimited by the expression "diseases of skin proliferation", quite successfully.

The current treatments of a commercial nature, which Prescribed and used to treat skin proliferation disorders include three routes:

(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 agents, "such as methothrexate, hydroxyurea, Azaribine and cyclophosphamide;

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

While these treatments do result in some relief from the original symptoms in certain cases, every treatment suffers from a certain deficiency, e.g. a temporary and incomplete alleviation of Symptoms, rapid recurrence of the disease> when relief is over, severe

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and sometimes irreversible damage (atrophy) resulting from topical application during extended periods

from
Periods / glucocorticoids, acute inhibition of bone marrow formation and liver cirrhosis resulting from prolonged use of methothrexate which can lead to patient death, and cancer formation due to the use of anticancer agents, x-rays or ultraviolet rays.

It has now been found that diseases of skin proliferation are alleviated, i.e. the symptoms of the disease noticeably weakened or even undetectable when you look at the patient or treats the sick animal with one or more of the pharmaceutical compositions according to the invention, which are described in more detail below.

For the purposes of the present invention, it is a skin proliferation disease referred to as relieved if, when touched, a noticeable 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. With this in mind, psoriasis is considered relieved denotes when a pathological change due to a 'scale-free psoriasis is noticeably reduced in thickness or is noticeably but incompletely cleared or completely cleaned.

The compositions of the invention can be topical or administered by injection so that the composition penetrates the bloodstream, or they can

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administered intradermally, intra- or perilesional or subcutaneously will.

he
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 topically 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 base materials such as Vaseline, lanolin, polyethylene glycols and their mixtures. It it has been found that topical administration under occlusion of an area which is larger than that to be treated Area ^ versus a non-occluded topical Application gives better results and the former is consequently the preferred method of topical treatment with the compositions according to the invention.

An "intradermal" injection is the introduction of the composition according to the invention into the dermis (high dermis) by injection with a needle or understood by injection with air under high pressure.

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- R _

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 according to the invention can be injected in this way that they can stimulate the blood circulation intramuscularly, subcutaneously, through suppositories rectally, sublingually, intravenously, Reached orally, by inhalation, or by application to non-diseased 'skin.

The best mode of administration of the compounds of the invention is to treat the diseased animal or human such that continued release of the active ingredient at the diseased site or sites occurs at a selected, controlled rate which is maintained for an extended period of time. For example, epinephrine is released continuously and provides epinephrine activity which is maintained for 9 to 10 hours when an aqueous suspension of crystalline epinephrine in the ratio of 1: 200 in a sterile solution containing 0.5 % phenol, 0.5 Contains% sodium thioglycolate, 1 % sodium ascorbate and 25 % glycerin in water. This suspension can be administered subcutaneously in a dosage of 0.1 to 0.3 cm ^ of the suspension. Epinephrine activity is obtained essentially immediately from the epinephrine in solution, and continued release results from the crystalline epinephrine in suspension. There may be various modifications to the components of the suspension to match the particular active ingredient selected for injection

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_{tolerated, t} are made in order to obtain the desired, continued and sustained activity of the active ingredient at the site to be treated. Furthermore, the aforementioned components of the suspension can be expediently replaced in order to adapt the selected active ingredient for topical or systemic administration to the diseased patient, and similarly improved results are obtained from those applications in which the active ingredient is released over an extended period of time.

The compositions according to the invention contain a pharmaceutical carrier and about 0.1 to about 15 wt. # / Vol. Of at least one compound belonging to the following groups of compounds:
1. a compound having the general formula

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in which R _{1 is} a hydrogen atom or a methyl group; Rp is a hydrogen atom or a phenyl group; R, a propyl, isopropyl or phenyl group; R ^ is a hydrogen or bromine atom, a methylthio or benzyithio group and X is an oxygen atom or a methylene group;

2. a compound of the general formula

in which R ₁ and Rp are hydrogen atoms or hydroxyl groups; Y represents a hydrogen atom or an alkali metal; Z represents a hydrogen atom, a benzylthio or thiol group, a halogen atom, an alkylthio group in which the alkyl radical comprises 1 to 8 carbon atoms, or a hydroxyl group;

ti

and R ₂ J is a hydrogen atom, a group -C-NH-R, - in which R ₁ - is a phenyl, benzyl or alkyl group having 1 to 8 carbon atoms;

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3. a compound of the general formula

° \ N V

in which R _{1 is} one of the groups -CONH ₂ , -CSNH ₂ , -C (NH) NH ₂ , -C (NH) NHOH ₉ -CN, or -COOCH ₃ ; R ₁ and R _{2 represent} hydrogen atoms or hydroxyl groups, and Y represents a hydrogen atom or an alkali metal.

The compositions according to the invention can be used in conjunction with glucocorticoids. Under the The term "glucocorticoids" refers to a naturally occurring product of the adrenal cortex or its synthetic Analogous understood, which has anti-inflammatory effectiveness and minimal or no mineralcorticoids or has sex steroid activity. For example, from the natural glucocorticoids Hydrocortisone or synthetic glucocorticoids such as e.g.

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* "■" * 9 Λ Π 1 Δ Λ Q

Methylprednisolone Acetate (prednisone) for oral administration or use triamcinolone for topical therapy. The glueocorticoids should be in small amounts or an "allowable dosage" can be used. Under the term "permissible dosage" for glucocorticoids A lot is understood which affects the natural expulsion of adrenal glucocorticoids in one normal person minimally supplemented and which, when administered alone, have no noticeable effect on diseases of skin proliferation. Advantageously, according to the therapy of Examples 1 to 10, additional Advantages of oral administration of 20 mg prednisone twice a week at the same time as or following the or the compositions according to the invention are obtained.

The amount of the active ingredient to be used in the compositions according to the invention for topical, parenteral or systemic administration is in the case of topical administration from about 0.1 % to about 15% by weight / vol., In the case of parenteral administration from about 0.1 to about 10 wt .- # / vol. and for oral dosage forms, the percentage of active ingredient will be determined by the physical properties of the carrier in terms of manufacturing requirements and elegance.

The compositions of the invention are suitable for systemic administration. People and animals in Dosage unit forms such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions and oral solutions or suspensions and oil-water emulsions with a content of a suitable one Amount of one or more of the aforementioned active ingredients made available. "

For oral administration, both solid and liquid dosage unit forms can be prepared. To the

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Preparation of solid compositions, such as tablets, becomes the main active ingredient with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, Calcium sulfate, starch, lactose, acacia gum, methyl cellulose or functionally similar Substances mixed as pharmaceutical excipients or carriers. The tablets can be coated or can be otherwise formulated to give a dosage form having the benefit of an extended period or delayed effect or a previously determined successive effect of the included medication Offer. For example, a tablet can have an inner dosage component and an outer dosage component include, the latter being in the form of an envelope of the former.

However, a 2-component system can also be used for the production of tablets which contain 2 or more incompatible active ingredients. Wafers are made in the same way as tablets; they differ only in the form and through the inclusion of sucrose or other sweeteners and / or flavorings. In the simplest embodiment, capsules such as tablets are 'produced' by mixing the active ingredient or active ingredients with an inert pharmaceutical excipient and filling the mixture into a hard gelatin capsule of a suitable size. In another embodiment, capsules are produced by filling hard gelatine capsules with the active ingredient or the active ingredient-containing spheres coated with polymeric acids. Soft gelatin capsules are made by machine encapsulation of a slurry of the active ingredient or ingredients in a

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compatible vegetable oil, liquid paraffin oil or another inert oil.

Liquid dosage unit forms for oral administration, such as syrups. Elixirs and suspensions can can also be produced. The water-soluble forms can be in an aqueous vehicle together with sugar, Aromatic flavors and preservatives are dissolved to form a syrup. Becomes an elixir produced by using an aqueous-alcoholic (ethanol) vehicle with suitable sweeteners, such as sugar and saccharin, used together with an aromatic flavor.

Suspensions can be prepared from the insoluble forms with a syrupy vehicle using a suspending agent, such as acacia, tragacanth, methyl cellulose and the like.

By dispersing the active ingredient or the active ingredients in "a suitable ointment base, such as Vaseline, lanolin, polyethylene glycol or mixtures thereof, topical ointments can be made. Advantageously becomes the active ingredient or the active ingredients with the help of a colloid mill using paraffin oil finely divided as a trituration agent before dispersion in the ointment base. Topical creams and lotions are produced by the active ingredient or the active ingredients in the oil phase before emulsifying the same in Water dispersed.

For parenteral administration, the dosage forms are prepared by adding the active ingredient or the

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Active ingredients and a sterile vehicle, with water being preferred, are used. The compound, depending on the form and the concentration used, can either be suspended or dissolved in the vehicle. In the preparation of solutions, a water-soluble form of the compound can be dissolved in water for injection and sterilized through a filter before filling into a suitable vial or ampoule and its closure. The auxiliaries, such as, for example, local anesthetics, preservatives and buffers, can advantageously be dissolved in the vehicle. To increase stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The freeze-dried powder is then enclosed in the vial and an accompanying vial of water for injection may be supplied for reconstitution before use. Parenteral suspensions are prepared in essentially the same manner, except that the compound is suspended in the vehicle, rather than dissolved, and that sterilization by filtration cannot be achieved. The compound can be sterilized by exposure to ethylene oxide prior to suspension in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate even distribution.

For parenteral or systemic administration of the compositions according to the invention, the usual Dosages of the selected active ingredient or the selected active ingredients are applied. The invention Compositions can include one or more of the aforementioned active ingredients in a single composition

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contain; There can be a variety of compositions, each of which is a single or multiple active ingredient. contain, are administered. In some cases, the administration of compositions containing a single active ingredient or a mixture of active ingredients, in a variety of these administration forms may be considered, such as a combination of oral administration and / or injection and / or topical administration and the like.

In other cases it is advantageous to use the dosage forms combined in a time-spaced sequence, for example by systemic administration of one or more of the compositions applies for a period of time, and then one or more compositions administered topically or by injection while systemic administration continues, and the like.

The following examples explain the invention in more detail; they are examples of compositions which typical for the combination of selected active ingredients with a pharmaceutical carrier used for treatment of diseases of the skin proliferation can be used in the aforementioned manner.

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example 1 Capsules

1,000 two-part hard gelatin capsules for oral use, each _{containing 200 mg of 8-methylthio-3 J} 5-cyclic adenosine monophosphate (hereinafter referred to as 8-methylthio-cAMP), were made from the following substances:

8-methylthio-cAMP 200 g

Corn starch 150 g

Talc · 75 g

Magnesium stearate 2.5 g

The materials were mixed thoroughly and then encapsulated in the usual manner.

The aforementioned capsules are useful for the systemic treatment of psoriasis in adults by administering one capsule every 1 hour.

Following the above procedure, capsules were made in a similar manner produced, which contained 5, 100 or 500 mg of active ingredient by instead of 200 g of 8-methylthio-cAMP corresponding amounts of this active ingredient used.

Example 2

Capsules

1,000 two-part harp gelatine capsules for oral use each containing 200 mg of 8-methylthio-cAMP were made from the following ingredients:

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8-methylthio-cAMP 200 g

Corn starch 250 g

Talc 75 g

Magnesium stearate, 2.5 g '

The ingredients were mixed thoroughly and then encapsulated in the usual manner.

The capsules so produced are useful for the systemic treatment of psoriasis in adults; it one capsule is administered orally twice a day.

Example 3

Tablets

1,000 tablets for oral use each containing 500 mg of 8-methylthio-cAMP were made from the following Components manufactured:

8-methylthio-cAMP. 500 g

Lactose 125 g

Corn starch 65 g

Magnesium stearate 7 »5 g

Paraffin oil 3 g

The ingredients were carefully mixed and extruded. The blanks were crushed by taking them through a sieve with a mesh size of 0.99 mm (No. l6 screen) drove. The granules obtained were then compressed into tablets, each tablet being 500 mg 8-methylthio-cAMP.

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The tablets so produced are useful for the systemic treatment of psoriasis in adults; one tablet is given orally every 4 hours.

Example 4 Oral syrup

1,000 cnr of an aqueous suspension for oral use, in each case a dose of 5 cnr 200 mg 8-methylthio-cAMP was made from the following ingredients:

8-methylthio-cAMP Citric Acid Benzoic Acid Sucrose Tragacanth Lime Oil Deionized Water

Citric acid, benzoic acid, sucrose, tragacanth

in
and limonene oil were dispersed in enough water that a solution of 850 cm was obtained. The 8-methylthio-cAMP was stirred into the syrup until it was evenly distributed. Sufficient water was added to make 1,000 cnr.

The composition so prepared is for the systemic treatment of psoriasis in adults., At one dose of a teaspoon full 4 times a day ^ usable.

40 G 2 G 1 G 700 G 5 G 2 cnr ad 1,000 cnr

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Example 5 Parenteral solution

A sterile aqueous solution for intramuscular use, which in a cm 75 mg of 8-methylthio-cAMP was made from the following ingredients:

8-methylthio-cAMP 75 g

Lidocaine hydrochloride k g

Methyl paraben '2.5 g

Propyl paraben 0.17 g

Water for injection ad 1000 cnr

The ingredients were dissolved in the water, and the solution was sterilized by filtration. The sterile Solution was filled into vials and the vials sealed.

The composition is useful for the systemic treatment of psoriasis, taking it in a dose of 1 cm ^ * l times administered intramuscularly daily.

Example 6 Parenteral solution

A sterile aqueous solution for intradermal use, which contained 5 mg of 8-methylthio-cAMP in one cm ^, was made from the following components:

8-methylthio-cAMP x 5g

10% sodium chloride solution q.s.

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Injection water ad 1000 cm

The 8-methylthio-cAMP was added to the water and enough sodium chloride was added to make it isotonic Solution formed and the solution was sterilized by filtration.

The sterile solution is administered intradermally by high pressure injection for treatment / psoriasis.

Example 7 Topical ointment

1,000 g of a 0.25% ointment was made up of the following ingredients manufactured:

8-methylthio-cAMP '. 2.5 g

heavy paraffin oil 250 g

Wool fat 200 g

Vaseline - ad 1,000 g

The petroleum jelly and wool grease were melted and 100 g of the paraffin oil was added. To the rest The 8-methylthio-cAMP was added to paraffin oil, and the mixture was ground until the powder was finely divided and was evenly distributed.

The powder mixture was stirred into the petroleum jelly mixture and stirring was continued until until the ointment froze.

The ointment produced in this way is suitable for the treatment of mange if it is applied topically to the animal skin.

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Example 8

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

8-methylthio-cAMP 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

Polysorbate 80 x 5 g

Methyl paraben 1 g

Deionized water "ad 1,000 g

The glyceryl monostearate and cetin were melted together at a temperature of 70 to 80 ° C. The methyl paraben was "dissolved" in about 500 g of water, and the propylene glycol, polysorbate 80 and 8-methylthio-cAMP were in turn added, maintaining a temperature of 75 to 80 ^° C. The methyl paraben mixture slowly became the melt of the glyceryl monostearate and the Cetins were added with constant stirring The addition was continued for at least 30 minutes with continued stirring until the temperature dropped to 40 to 45 ° C. By adding 2.5 g of citric acid and 0.2 g of dibasic sodium phosphate dissolved in 50 g of water the pH of the final cream was adjusted to 3.5 and finally enough water was added to make the

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The final weight was brought to 1,000 g and the preparation was stirred to maintain homogeneity, until it cooled and froze.

The composition thus obtained is useful for treating psoriasis by applying it to the pathological ones Applying changes with an occlusion bandage.

Example 9

8-methylthio-cAMP 1,000 g

Cety! Alcohol 600 g

Stearyl alcohol 600 g

Aerosol OT 150 g

Petroleum jelly. 3,000 g

Propylene glycol 1,000 ml of distilled water to 10,000 g

The 8-methylthio-cAMP was mixed with the petrolatum and placed in a melt of the alcohols and propylene glycol stirred in. The aerosol OT was dissolved in 5,000 cm of water and the vaseline mixture turned into an emulsion formed by adding so much water that 3000 g were obtained.

The cream is applied to the areas pathologically changed by psoriasis with an occlusal bandage twice a day upset.

A composition that allows better penetration of the Active ingredient in the skin was optional

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obtained by following the procedure of the previous example by passing 2,000 g of water through 2,000 g of dimethylacetamide replaced.

Example 10

Following the procedures of Examples 1 to 8, wherein the 8-methylthio-cAMP is replaced by a therapeutic dosage amount of each of phenylethano-cAMP and methyl-1- (2,3,5 ~ tri-0-benzoyl-β-0-ribofuranosyl) -1, 2,4-triazolo-3-carboxylate Replaced, compositions have been made that are useful for treating psoriasis proven.

The compositions prepared in Examples 1 to 10 can be used in a similar manner for treating Ethiopian dermatitis, nonspecific 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 in humans as well as atopic dermatitis and mange in skin animals.

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Claims (3)

Re: patent application P 24 01 John James Voorhees - our no. 19 092 - claims 1. Pharmaceutical preparations for the relief of skin proliferation diseases ₉ containing a pharmaceutical carrier and one of the following compounds; 1) Compounds of the general formula wherein R _{1 represents} a hydrogen atom or a methyl group; R _{2 is} a hydrogen atom or a phenyl group; R ^ is a propyl, isopropyl or phenyl group; R ^ is a hydrogen or bromine atom, a methylthio or benzylthio group and X is an oxygen atom or a methylene group; 409830/1097 2) compounds of the general formula wherein R and Rp are hydrogen atoms or hydroxyl groups; Y represents a hydrogen atom or an alkali metal; Z represents a hydrogen atom, a benzylthio or thiol group, a halogen atom, an alkylthio group having 1 to 8 carbon atoms, or a hydroxyl group; Ru a water t! atom or the group -C-NH-R ₁ -, in which R ^ is a phenyl, benzyl or alkyl group having 1 to 8 carbon atoms; or 3) compounds of the general formula 409830/1097 -Vi - 240U49 wherein ₂ , C (NH) NH ₂ , ₂ hydrogen atoms ₁ one of the groups -CONH ₃ , -CSNH ₂ , -C (NH) NH -C (NH) NHOH, -CN, or -COOCH,; R ₁ and or hydroxyl groups, and Y denote a hydrogen atom or an alkali metal,
or mixtures of these compounds as active ingredients. 2. Composition according to claim 1, characterized in that the active ingredient is at least one compound the general formula 409830/1097 240H49 where R is a hydrogen atom or a methyl group, Rp is a hydrogen atom or a phenyl group, R, a propyl, isopropyl or phenyl group ·, R ₁ ^ is a hydrogen or bromine atom, or a methylthio or benzylthio group, and X is an oxygen atom or are a methylene group. 3. Composition according to claim 1, characterized in that the active ingredient is at least one compound of general formula A09830 / 1097 wherein R ₁ and R ~ are hydrogen atoms or hydroxyl groups; Y represents a hydrogen atom or an alkali metal; Z represents a hydrogen atom, a benzylthio or a thiol group, a halogen atom, an alkylthio group having 1 to 8 carbon atoms or a hydroxyl group; R ^ a hydrogen ti atom or the group -C-NH-R ₅ , in which R ₁ . is a phenyl, benzyl or C. to C.sub.6 alkyl group. H. Composition according to claim 1, characterized in that the active ingredient is at least one compound of the general formula 409830/1097 240H49 where R _{1 is} one of the groups -CONH ₂ , -CSNH ₂ , -C (NH) NHOH, -CN, or -COOCH ₅ ; R ₁ and R _{2 represent} hydrogen atoms or hydroxyl groups, Y represents a hydrogen atom or an alkali metal. For r John James Yborhees (Dr. H.J \ Wolff) Lawyer 409830/1097