DE19852981A1 - Use of botulinum toxin and its derivatives in topical treatment compositions to influence acetylcholine-dependent body functions - Google Patents

Abstract

A botulinum toxin and its derivatives useful for the treatment of hyperhydrosis, are applied to and absorbed via the skin and act on acetylcholinergic structures.

Description

1. Field of the invention

The present invention offers a novel method of acetylcholine-dependent bodies functions and states topically epicutane (i.e. by local application to the skin and subsequent subsequent completely or partial absorption (absorption) in and / or through the skin) through botulinum toxins (in German use also "botulinum toxins", plural / "Botulinum toxin", singular), its derivatives, analogs and molecular fragments (also manufactured and / or modified by laboratory chemistry).

As a further important point of the invention, the botulinum toxin can be used with a Skin-promoting substance physically mixed, molecularly chemically linked or chemophysically packaged (e.g. liposomes, micelle formation) and / or it other measures can be taken to improve skin absorption e.g. B. occlusive dressing / plaster with drug delivery).

The body functions and states to be influenced are primarily the sweat glands secretion, further exemplary muscular tension and contractures, Muscle strains, joint diseases (including those caused by muscle dysfunction Pain) and skin folds, especially in the facial area.

If the sweat gland function is affected, the toxin acts after penetration into the Skin / subcutaneous tissue on the sweat glands located there by inhibiting the acetylcholinergic gene Functional structures. If the muscular function is affected, the toxin has an effect Penetration through the skin at the underlying acetylcholinergic muscle function structures by inhibiting the transmission of excitation.

2. Background of the Invention a. Affected acetylcholinergic excitation structure

Acetylcholine acts in the organism, among other things, as an excitation agent for certain Nerve structures (transmitters). The arousal that causes the affected muscle to contract is achieved by the so-called motor end plate through transmitter release. The Sweat gland secretion is also controlled by this acetylcholine transmitter, whereby Acetylcholine increases sweat gland secretion.

By blocking / reducing these acetylcholine-controlled functions, one can Reduce the above functions.

b. Botulinum toxins

Botulinum toxins are neurotoxins (nerve toxins). In particular botulinum toxin type A, has been used for some time to treat muscular disorders of the physical condition (Muscle tension, contractures, muscular related skeletal deformities, disorders of muscle functions in the gastrointestinal tract), body secretion disorders (increased Saliva and sweat formation, ophthalmology) and facial skin wrinkle formation.

Naturally, botulinum toxin is made by the anaerobic and spore-forming family Bacteria Clostridium botulinum are formed under certain environmental conditions. Generally Several types of toxin (= poison) are known, designated by the letters A to G, the The toxicity of the individual toxin types is different. The strongest toxin is  Type A, a polypeptide / protein with a molecular weight of approximately 150,000 daltons, the minimal lethal dose with a single human intake at approximately 0.00003 µg / kg body weight. The intoxication especially can be done through food absorption, through skin wounds, inhalation and through mucosal absorption / absorption.

The toxicity is caused by the rapid, strong and irreversible binding of the toxin to the presynaptic cholinergic nerve endings and the resulting inhibition of the Exocytosis (simplified: release) of acetylcholine by reducing the Acetylcholine release frequency. Since the binding of the toxin is irreversible, its effect only reduced or eliminated by the formation of new nerve endings, which is why the effect duration lasts correspondingly long (months / type A) (if the intoxicated individual survives). Death occurs mainly due to paralysis of the respiratory muscles with full consciousness (Inhibition of excitation transmission by acetylcholine on the motor end plate).

The toxin itself can be molecularly divided into a larger (approx. 100,000 Dalton) and a smaller (approx. 50,000 Dalton) polypeptide chain can be divided, which are interconnected by disulfide bridges bond are linked. The larger chain is said to be responsible for the binding property of the molecule the presynaptic structure, the smaller one being responsible for the toxic property.

The commercially available botulinum toxin is manufactured using special techniques. The amounts that are used therapeutically are below that for humans lethal dose. The effectiveness (pharmacological: Potency) of the is measured Therapeutic purposes used toxin in units, one unit being the lethal dose for 50% of a group of 18 to 20 female Swiss Webster laboratory mice with approx Represents 20 g body weight per mouse (i.e., when one unit is fed, half of the mice are dead), which is pharmacologically called LD 50. The dose used for human therapy depends on the severity the disease and is approximately between 0.01 and 1000 units.

For the reduction of sweat gland secretion in the armpits are used per body half z. B. about 0.2 to 2 units intracutaneously, distributed over several puncture sites, injected.

Botulinum toxin A is available from Porton (trade name Dysport) and from from Allergan / USA or Merz / Germany (trade name Botox). The toxin is removed neither in a suitable solution before, or as a dry substance, which before use with the appropriate solvent.

The other types of toxins (B to G) have different toxicity and duration of action.

To date, treatment with botulinum toxin is not a standard treatment method, in particular the treatment of facial wrinkles and lately the blockage of the sweat glands has been known.

c. Substances that improve the skin absorption of substances

The skin has the character of a lipid membrane and preferably leaves lipophilic substances happen. Hydrophilic and higher molecular weight substances are very little or not at all taken. Compared to mucous membranes, absorption through the skin is essential less. The main obstacle is the thickness of the horny epithelial layer (stratum corneum) with its relatively low water content of 5-10% compared to 70% in lower ones Skin layers (corium).

An improvement in the skin absorption of a substance can e.g. B. can be achieved by a Shortening the diffusion path (e.g. in deepithelization, combustion of the Skin surface), covering the skin and the applied fabric with occlusive dressing (Patches, fatty ointment, increasing the water content of the upper skin layer),  hyperaemic substances (e.g. benzyl nicotinate) or by tractor substances (Carrier, e.g. dimethyl sulfoxide = DMSO).

3. Differentiation from other patents

Almost all inventions relating to botulinum toxin are owned by Allergan, Inc. 2525 Dupont Drive, P.O. Box 19534, Irvine, California, whereby a patent (PCT / US94 / 14 717, Int. Publ. WO 95/17 904) deals particularly intensively with the possible uses. It should be emphasized that this patent expressly states the injection for the application of the Toxins describes, although alternative ways of use are mentioned, but by way of example only other types of injection (e.g. subcutaneously instead of intramuscularly or the Placement of the toxin in / on certain internal body structures).

The topical, local application on the skin and the associated penetration of the toxin in or through the skin was not mentioned, but only the injection as an active act of the therapist to place the toxin at the appropriate active site by removing the skin of the Patients were punctured with an injection needle.

The application to mucous membranes, e.g. B. eye, conjunctiva, intestine, through which the toxin is naturally absorbed (ophthalmology). Listed above Although the patent describes the use as an intestinal enema for intestinal spasms, the Mucosal absorption was not explicitly highlighted.

Even if other patents describe transcutaneous absorption using local application should not be "mixed" with a substance that facilitates the skin absorption of the toxin as a second innovation of the present invention.

Delimitation summary

• - Application and absorption by application to the skin, not mucous membrane.
• - No injection or other mechanotraumatic delivery method.
• - In addition, "mixing" with a substance that facilitates skin absorption.

4. Detailed description

Botulinum toxin, e.g. B. from Merz, is mixed with appropriate solvents and, if necessary, mixed with appropriate additional substances for stabilization. In addition, additives to achieve a certain viscosity, tonicity, adhesiveness, Consistency or the like can be added.

In addition, a substance to facilitate skin penetration, e.g. B. dimethyl sulfoxide (DSMO) added.

The preparation can take all forms, material designs and mixtures ingest e.g. B. the common dermatological forms of preparation (ointments, creams, pastes, Gels, emulsions, solids (similar to deodorants), solutions, suspensions, powders, baths, Partial baths ect.).

The preparation forms can also be kept in all conceivable containers and / or application (e.g. tube, bottle, roller dispenser, dispenser, feed container). The container can also use a system to prepare the required amount of preparation / toxin Release or deploy or hold application unit.  

If necessary (e.g. for reasons of shelf life of the toxin), the active ingredient can be combined with the Additives and the skin penetration easier in any order before use be mixed, also in functional vessels.

The amount of toxin to be used can vary within the therapeutic doses, there can be different strengths (units of toxin) according to the necessary Therapy request can be used. The added substances can also be of type and Amount as well as ratio can be arbitrary, according to one or more effects.

Botulinum toxin A or any other botulinum toxin can be used, too chemically modified, derivatives, analogs, chain fragments, molecular modified or added.

The admixtures can be any, the method for improving penetration is also in or not limited by the skin surface.

It can ect directly on the botulinum toxin molecule or on the aforementioned derivatives. on Penetration enhancers can be tacked by binding, the drug molecule can also (Toxin / derivative, ect.) In certain cases to improve penetration (e.g. lipophilic Envelopes / "liposomes", micelles, ect.) "Packed".

Measures to improve skin penetration and Apply the active ingredient (toxin / derivative ect.).

In addition, any substances such. B. side agents, diagnostics, color and Fragrances are introduced.

Applications of the aforementioned forms of preparation for the treatment of muscular Dysfunction, pain and facial wrinkle treatment ect. includes present Invention.

5. Application example a. Hyperhidrosis a.a.

A patient, male 39 years with axillary hyperhidrosis, is treated with one Preparation from a total of 10 units of botulinum toxin A dissolved in 5 ml of solvent with 5 ml 50% DMSO solution. The patient was treated 5 days in the evening (hidrosis on least) axillary 1 ml per body side of this preparation on the with the Minor sweat test applied to previously marked, depilated areas of skin. After graduation during treatment, axillary sweat production was reduced by approximately 80%. The effect lasted about 3-4 months.

from.

A form of preparation can be used for patients with appropriate compliance Self-application can be left, or there can be sufficient ready-made products Potency and consistency appropriate to the patient z. B. be prescribed by the doctor who the patient with pathological hyperhidrosis is used at certain intervals.  

a. c.

Treatment of palmar and / or plantar hyperhidrosis by the aforementioned Preparations. With palmar hyperhidrosis (increased sweating of the palms) z. B. special gloves coated with active ingredient / preparation on the inside / filled find the z. B. worn overnight (similar occlusive dressing) to the active ingredient to get penetrated.

b. Sweat blockade as a deodorant measure in Euhidrosis

In a low dose and therefore reduced risk of side effects, the preparation in deodorant products e.g. B. Deodorant sticks / rollers are introduced and z. B. effective daily use and for the first time "safe" before e.g. B. axillary sweat production protect.

Claims (6)

1. a. Botulinum toxin or its changes, as described above, is due to the Applied to the skin and acts on the acetylcholine gene by absorption into / through the skin Structures. 2 B. Botulinum toxin or its changes, as described above, is described in Used in conjunction with a skin absorption enhancer. 3. c. Other additions are made as in point b. described, individually or in Combination used. 4. d. Formulations z. B. dermatological and / or cosmetic type of the points a. to c. Described, also for long-term use in Euhidrosis, as described, for. B. at axillary, palmar, plantar and facial perspiration. 5. e. A special occlusive dressing in the form of special gloves or footwear, in which inside the active ingredient is / has been introduced, e.g. B. for the therapy of the palmar and plantar hydrosis (e.g. overnight) and to protect against the effects of unwanted Fabrics related especially to the palms of the hands during therapy Skin absorption enhancers, e.g. B. when touching other substances with the palm of your hand. 6. f. The under point e. described products, but without limitation to certain Ingredients, as under points a. to e. described. For example, others can Active ingredients such as cosmetics alone or only Vaseline for skin care may be included. (A separate patent application may have to be made for this product (if not already patented) be formulated.)