WO2008018110A2

WO2008018110A2 - Use of nifedipine in anti -wrinkle compositions

Info

Publication number: WO2008018110A2
Application number: PCT/IT2007/000577
Authority: WO
Inventors: Carmine Antropoli
Original assignee: Carmine Antropoli
Priority date: 2006-08-10
Filing date: 2007-08-08
Publication date: 2008-02-14
Also published as: WO2008018110A3; ITRM20060440A1

Abstract

Nifedipine, a well-known calcium antagonist of the dihydropyridine type already used in the care of and treatment of many disorders, applied topically, is capable of relaxing the muscles responsible for the formation of wrinkles. The invention also includes nif edipine-based preparations for anti-wrinkle treatment.

Description

USE OF NIFEDIPINE IN .WCI-WRINKLE COMPOSITIONS .

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BRIEF SUMMARY OF THE INVENTION

The invention relates to the cosmeceuticals sector and, more particularly, to the topical use of nifedipine for anti-wrinkle treatment. According to the invention, the local use of nifedipine on dry, clean skin reduces excessive stimulation of the mimic muscles, relaxing facial tension after only a few days. The invention also relates to nifedipine-based preparations for anti- wrinkle treatment.

FIELD OF THE INVENTION

By the term cosmeceuticals is meant that sector of cosmetics-drugs which is involved in the care not of a disease but of a person's own image: those conditions which, last century, were not part of what was thought of as health, - baldness, wrinkles, ageing skin, sun spots, and so on - but which are now being transformed into real and actual diseases or at least into conditions to be treated such as would be the case for diabetes or an ulcer.

Particularly commonly referred to is the problem of wrinkles, the appearance of which is a sign of the ageing of the skin and of damage from the sun's rays.

The contraction of the muscles of the face is the main and predominant factor in the formation of wrinkles. With the result that, over time, the chronic contraction of the muscles of the face forms visible folds on the face, even when it is relaxed, and with the passage of time " the wrinkles tend to remain even when the face is ^λλat rest"

Every wrinkle of the face, therefore, begins with chronic contraction of a mimic muscle: glabellar line^'s: are caused by the contraction of the procerus and corrugator muscles of the eyebrow; the wrinkles of the forehead: are caused by the contraction of the frontal muscle; crow's feet: are caused by the contraction of the orbicular muscle of the eyes; peribuccal wrinkles: are due to the contraction of the orbicular muscle of the mouth.

In the dermis and subcutaneous layer a series of changes start consisting mainly of: a reduction in the concentration of hyaluronic acid with the subsequent loss of water in the tissues; a reduction in the production of sebum (in women) with advancing age and subsequent dryness of the skin; greater production of inelastic and harder type III collagen, to the detriment of type I or "young" collagen which gives elasticity and plasticity to the tissues; a reduction in elastic fibres; flattening of the dermo-epidermal junction with a reduction in its ability to resist mechanical stimuli; a reduction in the thickness of the dermis.

In addition to these changes, in the peribuccal area there is also: thinning of the lips; muscular hypotonia with subsequent flattening of the labial line; a reduction in the volume of the mascellar and mandibular bone crests with subsequent abundance of the soft tissues in relation to the supporting bones.

In addition to these changes there are a number of subjective factors which can accelerate the appearance of the wrinkles of the face such as: cigarette smoke; exposure to the sun; orthodontic problems; excessive facial expressions; stress and tiredness.

To significantly reduce these wrinkles and have smoother skin again, it is necessary to act on the main mechanism responsible for the formation of wrinkles and promote decontraction of the skin. Currently the only approved drug for the treatment of glabellar lines is botulinum toxin type A. Since it first appeared the drug has been very popular in America, being the most requested beauty treatment since 2003. Botulinum toxin acts on the peripheral nervous system, blocking the release of acetylcholine from the vesicles of the neuromuscular synapse, causing the blocking of muscle stimulation and therefore flaccid muscle paralysis. Before being approved for aesthetic use botulinum toxin underwent a long bureaucratic journey: indeed in 1989 the American FDA (Food and Drug Administration) approved and registered this drug for the treatment of strabismus and blepharospasm, then only in 2002 was it approved for aesthetic use too. This approval came ten years after the first publication in an international scientific review on the use of botulinum toxin to reduce glabellar lines (Drs. Jean and Alastair Carruthers; J Derm Surg Oncol: 1992) .

In Italy it was only from March 2004 that the Ministry of Health authorised the aesthetic use of this drug limited to a single type (Vistabex) and only for the treatment of glabellar lines in patients under 65 years of age, and only if injected by a doctor specialising in plastic or maxillo-facial surgery, dermatologists or eye specialists. Authorisation was granted on the basis of what was demonstrated by many clinical trials which attest to its safety and reliability.

The aesthetic use of botulinum toxin type A serum does not give rise to particular contraindications and the only known side-effects are due to reduced distribution of the toxin to "healthy" terminals around the area to be treated with subsequent mild paralysis.

The real unsolved problem in this type of aesthetic procedure is the fact that the paralysis induced by the toxin is reversible in times which vary depending on the muscle treated, the dose, the patient and other unknown factors, on account of which after 2- 6 months after the treatment of skeletal terminals and 8-12 months after the treatment of autonomic terminals the patient must be treated again. In a number of cases repeated treatments cause mild desensitisation, but the more serious problem occurs following the treatment of large muscles, which must be treated with significant quantities of neurotoxin. In these cases immunisation may occur with the production by the patient of type A anti-toxin antibodies with neutralising action. Furthermore, a number of rare subjects are resistant to the botulinum neurotoxin type A, initially caused by the contraction of the orbicular muscle of the eyes. Today there are also alternatives for reducing wrinkles - although their mechanism has not been scientifically defined - which supplement the botulinum injections. These substances, which are described as "Botox-like", do not contain botulinum toxin, in that it is very large and cannot be absorbed by the skin, but a particular protein (hexapeptide) .

The main active principles used in these cosmetics are:

Argireline (Acetyl Hexapeptide 3) : is a protein complex which inhibits muscle contraction;

Adenoxine : is a combination of adenosine and magnesium which reduces the concentration of calcium necessary for muscle contraction;

Boswellic acid: acts on the cells of the dermis preventing the development of contractile action.

These active principles nevertheless present two problems: difficulty in crossing the skin barrier and the ability to act only on the superficial muscles, the "muscle coat", and not on the large muscles. The type of skin also greatly affects the result; thinner and more easily dehydrating skins derive more immediate effects, greasy and oily skin require more applications to see the first benefits because the product is absorbed to a lesser extent. These products have no contraindications, except for subjects who are allergic to the active principles and to the emollients, and can be used as supplementary treatment to the infiltration of botulinum toxin, in that the action of these cosmetics is superficial, because they do not manage to act on the deep layers nor do they inhibit the physiological and pathological processes of the skin.

The aim of this invention is to overcome the disadvantages and the limits of the anti-wrinkle products available so far, proposing a new medicinal product based on nifedipine as an alternative to botulinum toxin. Indeed it has been shown that nifedipine, a well-known calcium antagonist of the dihydropyridine type, already used for the care of and treatment of many disorders, and applied for topical use, is capable of relaxing the muscles responsible for the formation of wrinkles.

Indeed in the muscles nifedipine acts by blocking the calcium channels which play a key role in the contraction of the sarcomerus. The contraction of the muscles, released from a nerve impulse, opens the calcium channels, which are normally closed, sited on the membranes of the sarcoplasmatic reticulum and therefore causes the ion to exit with an increase in the concentration of Ca++ in the cytoplasm of the muscle fibres. At high concentrations of Ca++, troponin binds the ion, causing the displacement of tropomyosin (sited on the actin filament) from the sites to attack the myosin. The actin-myosin complex forms which activates the cyclical contraction of the myosin bridges, enabling the cell to contract. Then, with the interruption of the nerve impulse, the calcium-dependent ATPase pump sited on the membrane of the sarcoplasmatic reticulum rapidly removes the calcium from the cytoplasmatic site stopping the muscle contraction. Based on this principle a galenic preparation based on nifedipine (named ANTROX) between 0.3 and 10% of the total weight has been developed, which, used topically, reduces the contraction of the muscles responsible for facial expressions, and which in the long term lead to the formation of wrinkles.

In order to be better able to increase the absorption of nifedipine topically into the skin, it is prepared with the addition of oils and emollients: jojoba oil, macadamia oil, Karate butter, palmitic acid, retinoic acid, etc.

Absorption by the skin is in fact affected by various factors which include: the condition of the skin (abrasions, ulcerative lesions, burns, etc.); the degree of vascularisation; age; different areas of the body surface. In a test carried out on 20 people, (with daily application in the evening of the nifedipine-based product) , there was relaxation of the muscle tension as soon as after 6 days in 70% of people, with a smoothing out of the wrinkles in 60% of the people after 20 days and in more than 80% of the people after 4 weeks; the increase in the degree of hydration seen in all the patients was constant.

2 weeks after suspension of the treatment 95% of the patients still displayed noticeable results. The tolerability of the product was 100%. CONCLUSIONS

Nifedipine is a well-known calcium-antagonist drug which has been used since the 80' s for cardiovascular disorders and only via the oral route. It acts as a muscle relaxant by inhibiting the flow of Ca++ into the sarcoplasm of the smooth muscle, with subsequent saving of oxygen as well as a reduction in the mechanical contraction of the muscle fibres. Studies which have examined the topical use of nifedipine on the tone of the mimic muscles of the face, have shown that the local use of nifedipine applied every evening to dry, clean skin reduces excessive stimulation of the mimic muscles, relaxing facial tension as soon as after 6 days .

An improvement was obtained in more than 75% of the subjects and after 4 weeks the features were relaxed and the wrinkles had visibly reduced. In particular from the results obtained in these studies it can be suggested that the pharmacological approach with the nifedipine-based drug would at least be able to delay the advance of wrinkles and avoid the need to resort to expensive and more painful inoculations of botulinum toxin, in addition to this there is also the simplicity of home use.

Another advantage of the anti-wrinkle preparation according to this invention consists of the fact that, while Botox can only be injected into the upper part of the face, this preparation can be spread over the whole of the surface of the face; moreover without the direct involvement of the doctor.

This makes it possible to treat not only the glabellar lines, as in the case of botulinum toxin, but all the mimic muscles, including the orbicular muscle of the eyes, thus constituting a valid therapeutic tool against the disorder of palpebral ptosis making it possible to avoid surgical procedures such as blepharoplastic surgery.

Claims

CLAIMS :

1) Use of nifedipine for the preparation of a pharmacological product for anti-wrinkle treatment.

2) Topical use of nifedipine for the cosmetic treatment of wrinkles. 3) Preparation for topical use for anti-wrinkle treatment containing nifedipine as the active principle.

4) Preparation for topical use for anti-wrinkle treatment as in the preceding claim but also containing oils and emollients capable of increasing the absorption of nifedipine into the skin.

5) Preparation for topical use for anti-wrinkle treatment as in the preceding claim characterised in that the oils and emollients contain jojoba oil, macadamia oil, Karate butter, palmitic acid and retinoic acid.

6) Preparation for topical use as in any of the claims from 3 onwards characterised in that nifedipine is present in a percentage of between 0.3 and 10% of its total weight.

7) Preparation for topical use as in any one of the claims from 3 onwards characterised in that it is in the form of a gel, cream, ointment, emulsion or oil.