TOPICAL COMPOSITIONS COMPRISING DIAMINOOXIDASE FOR THE TREATMENT OR PREVENTION OF DISEASES ASSOCIATED WITH HIGH HISTAMINE LEVELS WHICH INVOLVE AN INCREASE IN PAIN

Abstract

The present invention relates to a pharmaceutical, cosmetic or dermo-cosmetic composition that comprises DAO, for use in the prevention or treatment of diseases or pathological conditions associated with high levels of histamine in blood which involve an increase in pain, preferably fibromyalgia, characterised in that the application of the composition is topical.

Claims

1. A method of preventing or treating fibromyalgia, comprising administering a pharmaceutical, cosmetic or dermo-cosmetic topical composition comprising DAO.

2. The method according to claim 1, wherein said composition is a cream, a serum, a gel, a hydrogel, an oil, a bioadhesive patch or a spray.

3. The method according to claim 1, wherein the DAO is in the form of a powder, a lyophilised powder, or encapsulated in a nanoparticle, microparticle or liposome.

4. The method according to claim 1, wherein the DAO is of biotechnological origin, or from a vegetable or animal extraction.

5. The method according to claim 1, wherein the DAO is from a vegetable or animal extraction.

6. The method according to claim 1, wherein the concentration of DAO in said topical composition ranges between 0.005% and 20% by weight.

7. The method according to claim 1, wherein the concentration of DAO in said topical composition ranges between 0.5% and 5% by weight.

8. The method according to claim 1, wherein said composition in the form of a patch is a flexible bioadhesive patch that comprises: a) a therapeutically effective quantity of DAO in powder form, b) a pharmaceutically acceptable solvent in a quantity ranging between approximately 5% and approximately 70% by weight with respect to the total weight of the composition, the solvent including approximately between 5% and 50% by weight of a plasticiser, and c) a pharmaceutically acceptable bioadhesive support at a concentration ranging between approximately 20% and 50% by weight with respect to the weight of the complete composition, where the composition is substantially water-free, substantially insoluble in water and bioadhesive.

9. The method according to claim 1, wherein said composition in the form of a cream, a serum, a gel, a hydrogel or an oil is applied to a medical device wherefrom it is released in a controlled manner to the area affected by pain.

10. The method according to claim 1, wherein said administration of the topical composition is carried out together with a diet low in histamine-rich and/or histamine releasing food.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention relates to a topical pharmaceutical, cosmetic or dermo-cosmetic composition that comprises DAO, to be used in the prevention or treatment of diseases or pathological conditions associated with high levels of histamine in blood which involve an increase in pain. In particular, said diseases or pathological conditions are migraine, fibromyalgia, spondylitis and muscle contractures, preferably fibromyalgia.

[0035] The present invention also relates to the use of a pharmaceutical, cosmetic or dermo-cosmetic composition that comprises DAO for the manufacturing of a medicament for the treatment or prevention of diseases or pathological conditions associated with high levels of histamine in blood which involve an increase in pain, characterised in that the application of said composition is topical. In particular, said diseases or pathological conditions are migraine, fibromyalgia, spondylitis and muscle contractures, preferably fibromyalgia.

[0036] In the present invention, prevention is understood to mean avoiding the onset of a disease or pathological condition associated with high levels of histamine in blood which involves an increase in pain, in particular migraine, fibromyalgia, spondylitis and muscle contractures, preferably fibromyalgia.

[0037] In the present invention, treatment is understood to mean the clinical intervention designed to alter the natural evolution of an individual and which is performed during the evolution of the clinical pathology. The desirable effects of the treatment include prevention of the reappearance of the disease, alleviation of the symptoms, alleviation of any direct or indirect pathological consequence of the disease, reduction in the rate of progression of the disease, improvement or partial cure of the pathological condition and remission or improved prognosis.

[0038] The DAO used in the present invention may be of both biotechnological origin and vegetable or animal extraction.

[0039] The topical compositions comprising DAO may have a great variety of dosage forms: creams of the two-phase oil-water (o/w) and water-oil (w/o) types, or the three-phase water-oil-water (w/o/w) and oil-water-oil (o/w/o) types, sera, gels, bioadhesive patches, sprays, ointments, hydrogels, etc. Hydrogels and creams are better in terms of absorption; in particular, hydrogels that contain carboxymethyl cellulose as a base and oil-in-water creams are the especially preferred types. Ointments in general include vaseline, bases for hydrophilic ointments, bases for the absorption of oils or Macrogol bases.

[0040] The concentration of DAO in the different topical compositions may range between 0.005% and 20% by weight, the preferred concentration range being between 0.5% and 5% by weight.

[0041] A suitable medium for dissolving DAO is phosphate buffer (pH 7.2), which serves to keep the pH of the preparation within a suitable pre-determined range for stability of the DAO itself and which is not aggressive for the physiological area of application of said composition.

[0042] The fats and oils to be used include higher hydrocarbons such as, for example, liquid paraffin, vaseline, squalene, etc.; higher alcohols such as, for example, cetyl alcohol, stearyl alcohol, etc.; higher esters such as, for example, tristearyl glyceride, tripalmitoyl glyceride, distearyl glyceride, monostearyl glyceride, cholesteryl stearate, isopropyl myristate, etc.; and waxes such as, for example, bee was, Japan wax, etc.

[0043] The emulsifier to be used includes non-ionic surface active agents, such as polyoxyethylene derivatives of fats and oils, polyglycerol esters, ethers of fats and oils, sugar esters, amphoteric-surface active agents, and similar agents.

[0044] Polyhydric alcohols such as glycerin, propylene glycol, ethylene glycol, 1,3-butylene glycol, sorbitol, etc., may also be used.

[0045] The creams may be prepared by the addition of DAO powder to a mixture of the excipients, the fats potentially being in the molten state, under stirring until an oil-in-water or a water-in-oil emulsion is formed.

[0046] Another type of topical compositions covered by the present invention are flexible bioadhesive compositions for localised topical application on the area affected by pain. These bioadhesive compositions comprise: a) a therapeutically effective quantity of DAO in powder form, b) a pharmaceutically acceptable solvent in a quantity ranging between approximately 5% and approximately 70% by weight with respect to the total weight of the composition, the solvent including approximately between 5 and 50% by weight of a plasticiser, and c) a pharmaceutically acceptable bioadhesive support at a concentration ranging between approximately 20% and 50% by weight with respect to the weight of the complete composition, where the composition is substantially water-free, substantially insoluble in water and bioadhesive. The solvents used must be pharmaceutically acceptable substances, preferably liquids, which do not have a substantial adverse effect on the system's adhesion or solubility properties. The preferred solvent is a polyhydric alcohol or a combination of polyhydric alcohols. Other suitable solvents include fatty acids such as oleic acid, linoleic acid, caprylic acid and similar acids, as well as fatty esters. Other further suitable solvents include non-volatile solvents generally used in dermal or transdermal compositions for the dissolution of similar compounds. The DAO is found in microdispersed form in the solvent and also on the support, i.e. there is an intimate dispersion of DAO at the molecular or ionic level. The final dosage form must be substantially occlusive to the permeabilisation of water in vivo. Suitable bioadhesive supports include any non-toxic polymer, particularly those used to support drugs designed for transdermal release, such as elastomers of natural or synthetic origin, such as, for example: polyisobutylene, styrene, butadiene, styrene copolymers, urethane acrylics, silicones, polyacrylates and polysaccharides such as, for example, gum karaya, gum tragacanth, pectin, cellulose and cellulose derivatives and similar, as well as other known substances capable of forming a colloidal solid that may adhere to the tissue, preferably for application on the dermis.

[0047] The topical compositions of the present invention may be applied directly on the areas affected by pain, such as the temples (hemicranial parietals) or the frontal or occipital areas, in the case of migraine pains; the inferior cervical area, the trapezius muscles, supraspinal areas, the second rib, the gluteal muscles or the knee, in the case of fibromyalgia; the back (spine) and joints in the case of spondylitis; and the affected areas in the case of muscle contractures.

[0048] The creams may also be applied to medical devices or sanitary products, such as, for example, the front ends of anti-migraine headbands, which are placed around the head on the area where the pain is focalised. Thus, for example, the front ends of anti-migraine headbands, protected in patent applications ES 2132037 and WO 2008/113871, may contain a cavity covered by a sponge-type, porous material adapted to house a given quantity of the cream or the gel of the present invention. In particular, the headband is placed around the patient's head, exerting pressure mainly on the parietal areas and releasing the DAO of the topical composition housed in the cavity of the front ends thereof. This produces a double therapeutic effect: the pressure on the temple area exerted by the headband cushions the force of the blood as it passes through the dilated artery and the increased level of DAO in blood leads to a degradation of the excess histamine that causes the arterial vasodilation which originates the vascular cephalalgia and the migraine pain.

[0049] The present invention also relates to a treatment method that comprises administering a topical composition comprising DAO according to any of the embodiments of the present invention in a therapeutically effective quantity to patients who present diseases or pathological conditions associated with high levels of histamine in blood which involve an increase in pain, or who present the risk of suffering therefrom.

[0050] In a further aspect, the administration of the topical composition of the present invention is carried out together with a diet low in histamine-rich and/or histamine releasing food.

EXAMPLES

Example 1

[0051] A topical pharmaceutical composition was prepared in the form of an oil/water (o/w) cream containing 2% of DAO.

TABLE-US-00001 Ingredients % (weight/weight) Disodium EDTA 0.3 Imidazolidinyl urea (Abiol) 0.2 Mixture of parabens in phenoxyethanol (Phenonip) 0.85 Potassium cetyl phosphate (Arlatone Map 160K) 3 Ethylhexyl cocoate (Waglinol 13088) 2.5 C.sub.12-C.sub.15 alkyl benzoate (Finsolv TN) 5.0 Cetearyl alcohol, cetearyl glucoside (Montanov 68) 5.0 Menthyl lactate (Frescolat) 0.3 Dimethicone (DC 200 silicone) 1.0 Tocopheryl acetate (Vitamin E acetate) 0.5 Polyacrylamide, water, C.sub.13-.sub.14 2.0 isoparaffin, Laureth-7 (Sepigel) Fragrance (perfume) 0.3 DAO 2 Water s.q.

Example 2

[0052] A topical pharmaceutical composition was prepared in the form of a water/oil (w/o) cream containing 3% of DAO.

TABLE-US-00002 Ingredients % (weight/weight) Disodium EDTA 0.3 Imidazolidinyl urea (Abiol) 0.2 Glycerin 3.0 Magnesium sulfate 1.0 Aloe Vera gel 1.0 Mineral oil 15.0 Ethylhexyl cocoate (Waglinol 13088) 10.0 Cera Alba (Permulgin 1550) 1.5 Mixture of parabens in phenoxyethanol (Phenonip) 0.85 Hydrogenated castor oil (Cutina HR) 0.75 Sorbitan sesquioleate (Arlacel 83) 3.0 BHT 0.05 Jojoba seed oil 0.5 Fragrance (perfume) 0.3 Magnesium sulfate 2.0 DAO 3 Water s.q.

Example 3

[0053] A topical pharmaceutical composition was prepared in the form of a serum containing 1.5% of DAO.

TABLE-US-00003 Ingredients % (weight/weight) Disodium EDTA 0.3 Imidazolidinyl urea (Abiol) 0.2 Mixture of parabens in phenoxyethanol (Phenonip) 0.85 Water, glycerin, glyceryl polyacrylate (Hispagel) 8.0 PEG-40 hydrogenated castor oil (Cremofor CO 40) 0.6 Carbomer (Ultrez 10) 0.5 Propylene glycol 3.0 Glycerin 5.0 Butylene glycol 1.0 Fragrance (perfume) 0.3 DAO 1.5 Water s.q.

Example 4

[0054] A topical pharmaceutical composition was prepared in the form of a gel containing 2% of DAO.

TABLE-US-00004 Ingredients % (weight/weight) Disodium EDTA 0.3 Imidazolidinyl urea (Abiol) 0.2 Mixture of parabens in phenoxyethanol (Phenonip) 0.85 Water, glycerin, glyceryl polyacrylate (Hispagel) 40.0 PEG-40 hydrogenated castor oil (Cremofor CO 40) 0.6 CI 42090 (1% FDC BLUE) 0.05 Fragrance (perfume) 0.3 DAO 2.0 Water s.q.

Example 5

[0055] A topical pharmaceutical composition was prepared in the form of a bioadhesive patch containing 10% of DAO, by mixing DAO with propylene glycol, lecithin and glycerin, under slight heating. It was cooled to 25 C. prior to the addition of gum karaya. After the gum karaya was added, the final composition was applied to a suitable support material, such as a non-woven polyester film, and heated in order to accelerate the formation of the gel in its final form.

TABLE-US-00005 Ingredient % (weight/weight) Adhesive (gum karaya) 35 Binding agent (lecithin) 20 Solvent (propylene glycol) 10 Solvent (glycerin) 25 DAO 10

Example 6

[0056] A topical pharmaceutical composition was prepared in the form of a cream containing 2% of DAO, following Example 1, and this cream was introduced into the cavities of the front ends of the MIGRACALM anti-migraine headband, which is placed around the head on the area where the pain is focalised.

Example 7

[0057] The topical compositions comprising DAO of the present invention were assayed on a total of 72 subjects, as outpatients (45 men and 27 women between 21 and 65 years of age), suffering from migraine without aura (35 subjects), fibromyalgia (10 subjects), spondylitis (9 subjects) and muscle contractures (18 subjects). The subjects included in the study came from a prior diagnosis of migraine (pain in the hemicranial area), fibromyalgia, spondylitis or muscle contractures, in both the back and the limbs.

[0058] The following tables show the results in relation to pain relief of the different compositions of the present invention, in the different types of pain studied.

TABLE-US-00006 TABLE 1 Results obtained with the cream composition of Example 1 Marked improvement or complete Typology of pain cessation of pain (% of the total) Migraine 28 of 35 (80%).sup. Fibromyalgia 7 of 10 (70%) Spondylitis 6 of 9 (66.6%) Muscle contractures 14 of 18 (77.7%)

TABLE-US-00007 TABLE 2 Results obtained with the cream composition of Example 2 Marked improvement or complete Typology of pain cessation of pain (% of the total) Migraine 26 of 35 (74.3%) Fibromyalgia 6 of 10 (60%) Spondylitis 4 of 9 (44.4%) Muscle contractures 15 of 18 (83.3%)

TABLE-US-00008 TABLE 3 Results obtained with the serum composition of Example 3 Marked improvement or complete Typology of pain cessation of pain (% of the total) Migraine 27 of 35 (77.1%) Fibromyalgia 6 of 10 (60%) Spondylitis 5 of 9 (55.5%) Muscle contractures 15 of 18 (83.3%)

TABLE-US-00009 TABLE 4 Results obtained with the gel composition of Example 4 Marked improvement or complete Typology of pain cessation of pain (% of the total) Migraine 26 of 35 (74.3%) Fibromyalgia 6 of 10 (60%) Spondylitis 5 of 9 (55.5%) Muscle contractures 15 of 18 (83.3%)

TABLE-US-00010 TABLE 5 Results obtained with the composition in bioadhesive patches of Example 5 Marked improvement or complete Typology of pain cessation of pain (% of the total) Spondylitis 6 of 9 (66.6%) Muscle contractures 16 of 18 (88.9%)

TABLE-US-00011 TABLE 6 Results obtained with the cream composition of Example 1 applied to the MIGRACALM anti-migraine headband, which was placed around the head on the area where the pain is focalised, in patients suffering from migraine attacks. Marked improvement or complete Typology of pain cessation of pain (% of the total) Migraine 32 of 35 (91.4%)