DE2254296A1 - ACNE CONTROL MEDICINAL PRODUCTS - Google Patents

Description

PATENT LAWYERS

dr. W. Schalk dipl.-ing, P. Wirth dipl.-ing. G. Dannenberg DR. V. SCHMIED-KOWARZIK · DR. P. WEINHOLD · DR. D. GUDEL

6 FRANKFURT AM MAIN CR. ESCHENHEIMER STRASSE 39

SK / SK PA-516

Syntex Corporation Apartado Postal 7386 Panama / Panama

Medicines to fight acne

The present invention relates to medicaments for akrieba inoculation, especially to drugs that are suitable for the treatment of acne-prone patients.

There is extensive literature on the acne disease. Patients with severe Acne can preserve dermatological scars and psychological damage for a long time after the last symptoms have disappeared. Treatment for acne has largely focused on the use of "drying" lotions that are serve to hide the effects of the disease, namely visible damage, but not necessarily the cause.

The present invention overcomes the disadvantages of those previously used Preparations for treating acne; it provides a completely new concept that prevents the occurrence of the symptoms characteristic of acne due to the inhibitory

Prevents the effectiveness of a class of certain fatty acid amide compounds or preparations containing them as an essential active component ¹ .

309820/1055

225A29B

_ 2 -

The present invention further provides an effective method of combating acne which is characterized by being applied locally acne full skin area an effective amount of one of the group's compounds of dietary amides of straight-chain, saturated or unsaturated alkanoic acids with 12-18 carbon atoms or a durmatologically acceptable preparation, that contains such a compound as an essential component, on tr cig I.

The present invention further relates to υLn preparation, the one Connection to the above definition in a mixture with a dorniatulogically appealing Carrier included and free from components that irritate the skin, such as diethanolamine, is. This preparation is intended as a prophylactic. · ;; Preparation for local Use for the prevention of acne.

Without wishing to be bound by a theoretical explanation with regard to the urindurigsgernäf3en action mechanism ¹ , it is assumed that the use of the active compounds defined here achieves a fight against acne by removing those caused by Corynebacterium acnes and others on the surface of the skin; Organisms that produce lipolytic enzymes are inhibited, which are considered to be the main causes of acne oclur acne vulgaris disease. It is further assumed that the inhibition of the lipolytic enzyme found here prevents the hydrolytic cleavage of the normal scbuin triclycerilo, which in turn precedes the production of long-chain fatty acids, the presence of which presumably initiate the inflammations typical of acne damage. The unactive compounds according to the invention presumably also inhibit the growth of the microorganisms per se. The active compound according to the invention has a relieving effect on combating acne.

309820/1055
BATH ORIGINAL

225A 296

The active compounds according to the invention include, for example: lauric acid diethanolamide
Myristic acid diet nanolami
Palmitic acid diethanolamide.
Oleic acid diethanolartn ri
Stearic acid diethanolamide
Isostearic acid diethanolamide
Palmitoleic acid diethanolamide

Linseed oil diethanolamide (Linoleic acid diethanolamide) Linolenic acid diethanolamide and
Eleostearic acid diethanolamide.

The ethanolamides of oleic acid, palmitic acid, lauric acid, Isostearic acid and myristic acid.

As used herein, the term "effective amount" refers to the amount which is used to effectively combat acne in a patient. This amount can depending on many factors, such as the patient's age, response to treatment, disease severity, and various dermatological unrf

Environmental conditions, such as the activity of the sebum glands ("secaceous glands"), hygiene habits,
/ Occupational conditions or drug use, as well as diet, vary over a wide range. Usually, an effective amount of the compositions described herein at a concentration of about 0.1 wt _t f / o to about 30 wt..-Jyo or more, the latter concentrations are applied particularly in the early stages of treatment. Concentrations of about 1-10% by weight are particularly favorable.

309820 / 105S

As used herein, "acne-prone skin area" refers to the area of skin on a patient that is or may be affected by acne. This area is characterized by the strong presence of sebum glands that are particularly active at a young age, and includes the cheeks and forehead and, to a lesser extent, the neck, back, poll, and shoulders Chest. There are documented cases where acne has affected the entire trunk, legs, and arms. Acne cases have also been reported from childhood to adulthood.

The active compounds of the invention can be administered alone or suitably be formulated into a dermatologically acceptable preparation. Since they are generally extremely surface-active, non-ionic, in organic Solvent-soluble and water-dispersible, they are compatible with a wide variety of topical or cosmetic formulations. Suitable dermatological preparations include ointments, lotions, solutions, tinctures, creams, gels and aerosols. The special preparation and its formulation process are usually in the pharmacist's field and are determined by diagnosis, desired effect, patient's condition, suggestions of the Physician and the ability of pharmacist determined.

Many formulations have already been described, such as in "American Pharmacy "4th ed. (1955) by J.B. Lippincott Co. (especially Chapters 13, 14, 15, 1G and 17), "Textbook of Pharmaceutical Compounding and Dispensing", 2. Ed. (1955), J.B. Lippincott Co. (particularly Chapter 12), Remington's Pharmaceutical Sciences, 14th ed. (1970), Mark Publishing Co. (particularly Chapter 85) and U.S. Patent 3,592,930; these references will be hereby included in the present application.

309820/1055

BATH ORIGINAL

2254298

Ointments are soft, lubricious, semi-solid preparations that contain the active means usually contained in solubilized form or in suspension. Different ointment bases can be classified according to their composition will:

a) oleaginous bases derived from hydrophobic oils from

(i) mineral origin such as petrolatum, liquid petrolatum and paraffin

(ii) animal origin, such as lard, and
(iii) vegetable origin
exist

b) absorbent bases composed of hydrophilic oils such as wool fat and hydrophilic petrolatum;

c) washable bases, such as polyethylene glycol ointments and

d) emulsion bases, such as water-containing wool fat.

Lotions are liquid preparations and vary from simple solutions to aqueous or aqueous-alcoholic preparations containing finely divided substances contain. The carrier consists of suspending or dispersing agents such as cellulose derivatives (ethyl cellulose, methyl cellulose, etc.), gelatin and Gums that contain the active agent in those consisting of water, alcohol, glycerin, etc. Incorporate carrier.

Solutions are made from dermatologically acceptable organic solvents, where the active ingredient is solubilized. Some of the commonly used solvents are propylene glycol and water.

Tinctures consist of alcoholic or aqueous-alcoholic solutions of the active ingredients. Some of the alcohols commonly found in topical tinctures are ethanol and isopropanol.

309820/1055

Creams are opaque, soft solids or thick liquids made up of the active ingredient dissolved or suspended in the base. The different cream bases can be classified according to their composition: \

a) Oil-in-water type creams including preparations such as foundation creams, hand creams, shaving creams, etc .;

and

b) water-in-oil type creams comprising matte / smoothening creams; and

c) anhydrous creams (see e.g. U.S. Patent 3,592,930).

Gels are semi-solid preparations made by gelling a solution or Suspension of the active material in a carrier. The deceitful, the watery or can be anhydrous, can be achieved by using various gelling agents, such as carboxypolymethylene ("Carbopols" from D.F. Goodrich) and using alkalis such as sodium hydroxide and amines such as Polyethylene {15) coconut amine ("Ethomeen C / 25" from Armor Industrial Chemical Comp.) Neutralized to the appropriate gel consistency.

Aerosols consist of solutions or suspensions of the active ingredients in an inert carrier and are dispensed by a special spray device. Some commonly used carriers are trichloro monofluoromethane and dichlorodifluoromethane.

The method of the invention is administered topically and as needed applied. Usually 2 to 4 applications per day are appropriate.

The following examples illustrate the present invention without it to restrict.

309820 / 1Θ55

At s ρ each 1 1

A 1 cc aliquot of GlyceryltriolEat- (9.17) T was analyzed by thin layer chromatography separated on silica gel in hexane / ether / acetic acid (70: 30: 1), and the area corresponding to pure triolein was eulated. The radioactive material was mixed with 8.8639 g of cold, previously purified triolein in 500 ecm Benzene diluted. The solution obtained contains 20 millimoles of the said Connection in Triolein.

The crude enzyme produced by three days of ethanol / acetic acid precipitation Cultures of Coryrebacterium acnes (ATCC No. 6919] were sequentially passed through "Sephadex G-25" and "G-100" columns and the concentrate to Use diluted to 250 ecm in the experiment described below.

Example 2_

An emulsion was prepared by adding 5.70 ecm that obtained in Example 1 Benzene solution evaporated; then 6 ecm of 10% gum arabic were in Water and 3.4 ecm 0.05M phosphate buffer (pH 7.1.) Were added and the mixture Sonicated for 3 intervals of 20 seconds. 0.7 cc aliquots, containing 2 millimoles of emulsified triolein were added to each of the 10 1 / G "dram" vials were added for each compound to be tested.

Vial # 1 drained an additional 0.3 ecm of buffer at time 0 and served as 0 control.

Vials No. 2 through 9 received 0.1 ecm of the corresponding dilutions of the active in combination in water and 0.2 ecm enzyme solution at time 0.

The # 10 vial received 0.1 ml of buffer and 0.2 ml of enzyme and served as 100- $ dge control. . ι

3G9820 / 10KS

-B-

The hydrolysis was allowed to continue for 60 minutes, then the vials were transferred to a silicone oil bath and kept at 95 C. After 5 minutes they were removed on the bath and each became a 50 µl aliquot on one 5 × 20 cm silica gel thin-layer chromatography test plate transferred. Each plate was further wetted with a mixture of standard cold materials for easy identification and the plates were soaked in hexane / Ether / acetic acid (70: 30: 1) developed to a height of about 15 cm. The freer ones Areas corresponding to oleic acid (after visualization with iodine vapor) were scratched directly into scintillating vials and counted.

The counts obtained from 50 #ul by thin layer chromatography Free oleic acid per minute was calculated on semi-log paper as cpm plotted against log (active compound) and gave a curve from which the concentration given for each compound as follows was a 50% inhibition was determined:

Compound concentration, which is a 50- ^. Inhi

bation of triolein (2mM) hydrolysis results

Oleic acid diethanolamide 0.054 mM

Palminitic acid diethanolamide 0.086 mM

Lauric acid diethanol arid 0.11 mM

Isostearic acid diethanolamide 0.14 "M

Myristic acid diethanolamide 0.32 mM

9-acetamidostearic acid 0.46 mM

N-morpholinooleamide 0.70 mM

Undecylenediethanolamide 0.66 mM

Oleamide 4.0 mM

Oleic acid 7.2 mM

Diethanolamine V 20.0 mM

/ ♦ Unriecylenmonoäthanolamid 0.86 mM

30982Q / 1Q55

Example _ 3

Culture glasses were made, the 10 ecm freshly made Difco Fluid thioglycollate medium with agar and indicator contained. For every concentration each connection were 'duplicates' made by corresponding Aqueous solutions or dispersions into the culture glasses using a pipette filled, giving a final concentration of 50, 25, 12.5, 6.25 and found 0.1 µg / cc. Each jar was at 0.2 ecm of a 48 hour culture by C. acnes (ATCC No. 6919), then the jars were inoculated at intervals of Examined 24 hours. The incubation took place at 3? C. The results were as follows:

Compound inhibitor concentration, µg / ccm

■ after 72 hours ^/

Oleic acid diethanolamide · about 12.5

Palmitic acid diethanolamide -, about 6.5

Lauric acid diethanolamis about 12.5

Isostearic acid diethanolamide about 12.5

Myristic acid diethanolamide about 6.5

Undecylenediethanolamide> 300

Oleic acid growth stimulant

200 µg / cc

Triplet. Growth stimulant

200 µg / cc

The following examples show methods of making gel, ointment, tincture and solution formulations.
Example 4

Oleic acid diethanolamide was dissolved in ethanol with stirring. "Caropol 940" was dispersed in water. The two mixtures were combined with stirring, then "Ethomeen C-25" was added to form a gel formulation of the the following composition resulted:

309820/1055

Oleic acid diethanolamide 30.0 ^D / o (range 0.01-30)

Ethanol 50.0%

"Carbopol 940" $ 1.0

least. Water 1B ₁ 5 ⁰ J ₀

"Ethomeen C-25" 0.5 ° / ₀

10 ° / o

The above procedure was done with palmitic acid diethanolamiu and propylene glycol instead of oleic acid diethanolamide and ethanol repeated.

Example 5

Petrolatum was heated to about 60-70 C. Ölsäurediäthanolamid was added to the melt which was then mixed at room temperature to give an ointment formulation containing about 0.01-30 ° / ₀ Ölsäurediäthanolamid contained.

Example 6

Ölsäurediäthanolamid was dissolved in ethanol to a Tinkturformulierung that ETMB contained 0.01-30 i> Ölsäurediäthanolamid.

example 7)

Oleic acid diethanolamide was dissolved in propylene glycol and gave a solution formulation, which contained about 0.01-30% oleic acid diethanolamide.

309820/105

Claims (1)

r; ' -. ' 225429B Claims 1, - Acne control and prevention agent, consisting of one compound from a diethanol amide to a straight-chain, saturated or unsaturated one Alkanoic acid with 12-18 carbon atoms mixed with a dermatological acceptable carrier, the agent being free from skin irritating components is. 2, - Aknebekämpfungs- and -verhütungsmittel according to claim 1 _Λ characterized in that the connection ÖlsäurediäthanQlamid, Palmitinsäurediäthanol- amide, Isostearinsäurediäthanolamid, Laurinsäurediäthanolamid or myristic is säurediäthanolamid. - 3. Anti-acne and preventive agents according to claims 1 and 2 characterized in that the compound in a concentration of about 1-ID Ew .-% is present. The patent attorney: 309820 / 1Θ55