WO2008018106A1

WO2008018106A1 - Alpha lipoic acid combined with dimethylsulfoxide for tropical use

Info

Publication number: WO2008018106A1
Application number: PCT/IT2007/000566
Authority: WO
Inventors: Piergiorgio Carlo Anzaghi
Original assignee: River Pharma Srl
Priority date: 2006-08-08
Filing date: 2007-08-03
Publication date: 2008-02-14
Also published as: ITLO20060004A1

Abstract

The present invention has as its object a new pharmaceutical or cosmetic composition containing as active ingredients an antioxidant agent with molecular weight of between 100 Da and 300 Da and dimethylsulfoxide, capable of improving the absorption, the bioavailability and the effectiveness in formulations for topical use.

Description

TITLE

ALPHA LIPOIC ACID COMBINED WITH DIMETHYLSULFOXIDE FOR TROPICAL USE

BACKGROUND OF THE INVENTION

The invention concerns a pharmaceutical or cosmetic composition that comprises an antioxidant agent with molecular weight of between 100 Da and 300 Da, in particular alpha lipoic acid, also in reduced form of dihydrolipoic acid, and dimethylsulfoxide (DMSO), which can be associated with other compounds with functions of solvents, stabilisers and demulcents and with other excipients considered suitable for stable cosmetic and pharmaceutical formulations for external use.

Alpha lipoic acid or 6,8-thioctic acid in oxidised form is chemically a cyclic disulphide that can exist as RS racemic mixture, as R- or S- enantiomer, or in reduced form as dihydrolipoic acid with two free sulfhydryl groups. It has been demonstrated that lipoic acid, and in particular optical isomer R, is a powerful antioxidant in vitro and in vivo in both lipophile and hydrophile environments (I. Parker et al., Free Radic. Biol. Med., 1995; 19, 227-250).

At different stages and with various action mechanisms, it is able to inhibit free radicals reactive with oxygen known as ROS (reactive oxygen species), preserving the skin from oxidising damage that ranges from ageing to erythemas from ultraviolet rays right up to cancer. Lipoic acid also performs a scavenging action on the heavy metals, such as copper, mercury and cadmium (which amongst other things catalyse the formation of ROS) in this way eliminating potential risk factors for degenerative illnesses.

Lipoic acid (oxidised form) is reduced metabolically in the cells to dihydrolipoic acid (reduced form) that is even more active as antioxidant. Both forms thus function as a particularly effective "redox pair". This pair is indeed capable in the body of recovering other endogenous defence systems acting with respect to free radicals, such as vitamins C and E, tocopherols, and Coenzyme Q 10 and in particular of restoring the glutathione in reduced form inside the cells, with a metabolic process that involves cystine. Alpha lipoic acid is also provided with both the characteristics of lipophily and of hydrophily that allow it to exert its antioxidant activity both on the membranes and in the aqueous fluids of the body (K. Marangone et al., Free Rad. Biol. Med., 1999, 27, 1 1 14- 1 121 ). From what has been stated, it can be seen that there is a preference for alpha lipoic acid as powerful and universal antioxidant agent, antiradical and anti-inflammatory capable of working both inside and outside of human cells, due both to its lipophilic properties in the form of free acid, and to its hydrophilic properties when in the form of salt.

The use of alpha lipoic acid as topical antioxidant is known and is described for example by M. Podda et al., Current Problems Dermatol., 2001 , 29, 43-51 .

The chemical combination object of the present invention comprises dimethylsulfoxide as second active component. DMSO is an aprotic dipolar solvent, colourless and odourless, soluble in water, alcohol and in numerous aprotic organic solvents. It quickly penetrates into the skin and is therefore able to promote the absorption in the skin of active ingredients dissolved in it without damaging them. DMSO is also equipped with antiradical activity on ROS and in particular on radical OH (Jingsong Zhang et al., 40 ° Western Regional Meeting of the ACS, Anaheim, CA, Abstracts 22-25, January 2006). The antiradical action justifies its use as local analgesic, anti-inflammatory and antioxidant, for example in arthritis.

DMSO has been clinically used in the prevention of damage to soft tissues (G. Bertelli et al., Journal of Clinical Oncology, 1995, 13, 2851 -2855), in the treatment of interstitial cystitis and of dermatosclerosis. Use in the veterinary field in the reduction of swelling from trauma is made easier by effective cutaneous administration and by its low toxicity (K. H. Scheffer, Monatschefte fuer Veterinaermedizin, 1969, 24, 604-612). DESCRIPTION OF THE INVENTION

The present invention concerns a new pharmaceutical or cosmetic composition comprising an antioxidant agent with molecular weight of between 100 Da and 300 Da, preferably between 150 Da and 250 Da, and dimethylsulfoxide. The antioxidant agent is preferably alpha lipoic acid both as racemic mixture, or else more preferably in R form or reduced as dihydrolipoic acid, melatonin, allantoin, dimethyl sulfone MSM, Pycnogenol or trans-resveratrol. The presence of DMSO does not only solve obvious problems of dissolution and of promotion of cutaneous absorption of alpha lipoic acid, but also that of completing and enhancing its antioxidant action. The combination between the antioxidant with molecular weight of between 100 Da and 300 Da and the dimethylsulfoxide is surprisingly able to synergise the chemical- physical, biological and pharmacological action of the individual components in formulations for topical use.

Another aspect of the invention concerns the stability of alpha lipoic acid in formulations for cosmetic and pharmaceutical use. Indeed, it is known that said acid is not very stable, in particular as water-soluble salt. Therefore it is formulated with the addition of different stabilising anti-oxidants, such as dehydroascorbic acid (vitamin C), vitamin E, vitamin K, alpha-tocopherol, Pycnogenol and melatonin, allantoin, resveratrol and dimethyl sulfone MSM, without taking into account their redox potential. In the present combination the addition in low percentages of vitamin A is preferred, which is specifically the most effective in slowing down the degradation of alpha lipoic acid (A. Segall et al., J. Cosmetic Sci., 2004; 55, 449-461 ). In formulations for cosmetic and dermatological use it is foreseen to add antioxidant as stabiliser, preferably Vitamin A palmitate or acetate, in a percentage within the range between 0, 1 % p/p and 5% p/p, preferably between 0,2% p/p and 2% p/p, with respect to the total weight of the composition. In another aspect, the composition object of the invention can comprise a hydrophile excipient, such as an alcohol or a glycol. Amongst alcohols ethanol and sorbitol are preferred. Amongst the various known glycol derivatives, glycerol, diethyleneglycol, polypropylenglycol and polyoxyethyleneglycol are used in cosmetics or in pharmaceutics. In the topical formulations of the present invention glycerol is preferred due to the absence of toxicity and its emollient and demulcent properties, as well as a specific solvent action of the combination of active ingredients. The percentage of hydrophile excipient is within the range between 10% p/p and 70% p/p, preferably between 30% p/p and 60% p/p, with respect to the total weight of the composition. The presence of the hydrophilic excipient is synergic to the solvent action of DMSO, as well as clearly improving the comfort and the cutaneous tolerability of the preparation.

In another aspect, in the composition object of the present invention, the percentage of antioxidant agent is within the range of between 0, 1 % p/p and 30% p/p, preferably between 0,5% p/p and 10% p/p and even more preferably between 2% p/p and 5% p/p, with respect to the total weight of the composition.

The percentage of dimethylsulfoxide in the composition object of the present invention, is within the range between 5% p/p and 70% p/p, preferably between 10% p/p and 50% p/p, with respect to the total weight of the composition.

In a further aspect of the present invention, the aforementioned composition can have other components with synergic action associated with it, in order to broaden and improve the chemical- physical, biological and pharmacological characteristics. Amongst these Pycnogenol, melatonin, allantoin, transresveratrol and dimethyl sulfone MSM are preferred, due to their substantial antioxidant activity

The composition object of the present invention, based upon an antioxidant agent with molecular weight of between 100 Da and 300 Da and dimethylsulfoxide, is formulated for external use preferably as solution, as emulsions W/O and O/W, as mono and bi-phase gel, as anhydrous ointment, as cream, as salve, as soap, as lotion, as transdermal patch, foam or shampoo in mixture with excipients commonly used in pharmaceutics.

The composition obj ect of the present invention increases cellular vitality, counteracting the formation of inflammation mediators and promoting cytoprotection. The described formulations can be used effectively topically in the treatment of various types of dermatitis, acne and rosacea, of various types of alopecia (aerata, scarring, female), of erythemas and of psoriasis. In dermatological use, further specifically active ingredients can be added to the formulations, selected from antimycotic agents, antiseptics, antibiotics, disinfectants, cortisones and specific agents against acne, psoriasis and seborrea.

In the field of cosmetics the composition of the present invention is beneficial in different phenomena of ageing and of degradation of the appearance of the skin. It is equipped with hydrating, soothing, anti-ageing, elasticising, anti-wrinkle, firming, anti-cellulite and anti-blemish action. It also exerts a hair protection action and slows down baldness.

The following examples are useful for illustrating the invention without however any intention to limit it. EXAMPLES

Hereafter follows a legend explaining the commercial names used in the examples:

Simulgel NS - hydroxyethylacrylate, sodium acryloyldimethyltaurate copolymer, squalane and polysorbate.

Transcutol CG - monoethyl ether rectified diethylene glycol

Sepicide HP - phenoxyethanol, methylparaben, ethylparaben, propylparaben and butylparaben.

Aquaxil HP - xylitolglucosides, anhydroxyxylitol and xylitol.

Example 1

3% solution in alpha lipoic acid

Ingredients Amount by weight

Alpha lipoic acid g 3,0

Dimethylsulfoxide g 40,0

Vitamin A g 0,3

The alpha lipoic acid is dissolved in DMSO and the solution obtained is taken to the volume of 100 ml by the addition of glycerine, bottling in dark glass sealed vials.

Example 2

2% solution at in R alpha lipoic acid

Ingredients Amount by weight

R alpha lipoic acid g 2,0

Dimethylsulfoxide g 30,0

Vitamin A g 0,2

Glycerine as needed

The R alpha lipoic acid is dissolved in DMSO, the solution is taken to the volume of 100 with glycerine, bottling in dark glass sealed vials

Example 3

Lotion at 0,5 % in RS alpha lipoic acid

Ingredients Amount by weight

RS alpha lipoic acid g 0,5 Dimethylsulfoxide g 35,0

Vitamin A palmitate g 0, 1

The RS alpha lipoic acid is dissolved in DMSO, the Vitamin A palmitate is added and it is taken to the volume of 100 with glycerine.

Example 4

Gel at 2% in R-lipoic acid

Ingredients Amount by weight _f

R alpha lipoic acid g 2,0

Dimethylsulfoxide g 90,0

Vitamin A g 0,2

Carbopol 940 g 5,7

Triethanolamine (TEA) g 2,8

The lipoic acid is dissolved in DMSO and the Carbopol and the TEA are added under stirring and it is taken up to volume with distilled water.

Example 5

Cream at 2,5 % in R-lipoic acid

Ingredients Amount by weight

R-lipoic acid g 25,00

Dimethylsulfoxide g 300,00

Vitamin A g 10,00

Allantoin g 10,00

Melatonin g 4,00

Manuka oil g 40,00

Tamanu oil g 40,00

Bisabolol g 10,00

Simulgel NS g 24,40

Acquaxil HP g 20,00

Sepicide HP g 3,00

Imidazolidin urea g 1 ,70

Perfume g 5,00 Water as needed

The R-lipoic acid, the melatonin and the allantoin are added to the

DMSO cold and under stirring.

Separately, the gelling agents SimulgeL NS and Acquaxil are added to the water and admixed with the help of a turboemulsifier. Then manuka, tamanu, bisabolol, vitamin A, sepicide HP, imidazolidin urea and perfume are added, again under stirring,.

Finally, the solution of DMSO and R-lipoic acid, melatonin and allantoin obtained previously is added.

Example 6

Solution at 5 % in R-lipoic acid

Ingredients Amount by weight

R-lipoic acid g 50,00

Dimethylsulfoxide g 300,00

Vitamin A g 10,00

Allantoin g 5 ,00

Melatonin g 4,00

Resveratrol g 4,00

Manuka oil g 20,00

Tamanu oil g 20,00

Bisabolol g 50,00

Glycerine g 100,00

Glycol g 200,00

Transcutol GC g 229,00

Sepicide HP g 3,00

Perfume g 5,00

The R-lipoic acid, the melatonin, the allantoin and the transresveratrol are added to the DMSO cold and under stirring . Manuka, tamanu, bisabolol, vitamin A, Transcutol, sepicide HP and perfume are added, cold and under stirring to the clear solution thus obtained. EXPERIMENTAL PART

1. Assessment in the treatment of psoriasis and of seborrheic dermatitis

The formulation of example 2 has been used in roll-on form, to assess the clinical effectiveness in topical treatment of psoriasis and of seborrheic dermatitis.

16 patients of both male and female gender aged between 18 and 71 years old, suffering from patchy psoriasis or seborrheic dermatitis were selected. All of the people selected accepted to stop using other topical or systemic substances to cure psoriasis or seborrheic dermatitis at least 2 weeks before the start of the study and during the study period. All of the subjects signed up committed themselves to follow a controlled lifestyle for the days of the experiment; nobody indicated that they used either topical or systemic drugs. None of the patients withdrew from the study and the products were used daily. Performance of the test

The volunteers visited the medical study 5 times: 1 st visit

During the first visit psoriasis and seborrheic dermatitis patches were selected and photographed specifying their location, the clinical characteristics of gravity and of erythema, the presence of the subjective sensation of irritation and of cutaneous dryness. Then the product object of the study and a leaflet indicating the methods of treatment were handed over . Subsequent visits

After 2-7- 15 days of treatment a clinical control assessment was carried out and a questionnaire was proposed to assess the effectiveness of the product used. Final visit

After 30 days of treatment a clinical control assessment, an assessment of comfort and of acceptability of the product and a final photographic assessment were carried out.

Performance of the test

The difference in the parameters monitored before and after the use of the product is assessed.

Clinical assessments by the dermatologist:

- Reduction of psoriasis plaques (results shown in figures 1 and 2)

- Reduction of the areas suffering from seborrea (results shown in figures 3 and 4)

- Reduction of redness (erythema) (results shown in figure 5)

- Reduction of irritation (results shown in figure 6)

The assessments were carried out according to the score shown in table 1 at time [tθ] (baseline value) and during the period of use of the product: after 7, 15, and 30 days. Findings of the dermatologist with the collaboration of the patient:

- Relief (results shown in figure 7)

- Attenuation of irritation (results shown in figure 8)

- Attenuation of redness (results shown in figure 9)

The assessments were carried out according to the score shown in table 2 at time [tθ] (baseline value) and during the period of use of the product: after 2, 7, 15, and 30 days

Findings of the patient:

Tolerability of the product (results shown in figure 10)

Effectiveness of the product (results shown in figure 1 1 )

Practicality of application of the product (results shown in figure

12)

The assessments are carried out at the end of the monitored period.

The clinical score available to the volunteers to offer their personal judgement on the parameters of interest is a scale of values from 1 to 10 (1 is equivalent to a very bad judgement and 10 represents an excellent judgement, 6 is equivalent to sufficient, the judgements from 7 to 10 can be considered satisfactory). The number 1 indicates the clinical score (from 1 to 10) indicated by a certain patient for the parameter in question. The results are expressed as number of subjects that gave that score.

The recorded data is processed and displayed graphically.

Assessment and calculation of the results

The photographic assessment completes the clinical assessment of the dermatologist and the assessment of the patients according to the clinical score shown in the tables below.

A subjective assessment of tolerability was given by each patient through a specific questionnaire (numerical score from 1 to 10)

Table 1.

Degree of the parameter Score considered

Absent 0

Mild 2

Moderate 4

Clear 6

Serious 8

Table 2.

Judgement Score

Poor 0

Sufficient 2

Moderate 4

Good 6

Excellent 8

Results. The product in object was tolerated well by all of the volunteers that participated in the study, displays a high practicality of application and gives a feeling of relief reducing the state of dryness and irritation accompanied by a reduction in redness in the areas of application of the product.

The treatment brought about a reduction in redness and in irritation, recorded already at 7 days of treatment in most of the volunteers involved; there was a reduction in redness and irritation in all of the volunteers after 30 days of treatment, the irritation disappeared in 5 volunteers at the end of the period of treatment. The clearness of the psoriasis plaques, on the other hand, is mild for 2 volunteers out of 9 after 30 days of treatment, for 7 volunteers the reduction of the plaques becomes moderate after 30 days of treatment. As regards the areas suffering from seborrheic dermatitis, in 2 volunteers out of 7 it totally cleared up after 30 days of treatment whereas in 2 volunteers the remaining lesions were only mild, in the remaining 3 patients the lesions were only partially resolved and remain moderately evident.

The careful analysis of the results indicates that the product tested is effective on the two pathologies monitored. Indeed, at the end of the treatment period all of the volunteers record a positive evolution of different degrees of the cutaneous lesions. This result is satisfactory, given the relatively short period of treatment of such cutaneous lesions.

This fact leads us to presume that the treatment, extended for a longer period, would be of substantial help to people suffering from psoriasis and seborrheic dermatitis.

Moreover, from the practical point of view, the roll-on applicator is well accepted by most of the patients, since it is quick and easy to apply.

The assessed composition represents a non-pharmacological alternative for initial treatment of mild or moderate psoriasis, or a valid support for topical or systemic pharmacological therapy of the most serious forms.

2. Assessment in the treatment of skin with acneic tendency The formulation of example 1 was used to assess the clinical effectiveness in the treatment of skin with acneic tendency. In particular it is assessed that the product is decongesting for the skin reddened by the acneic inflammation and contributes to a quick positive evolution of acneic lesions (pimples, pustules and comedos).

10 subjects of male and female gender having acneic skin and aged between 18 and 40 years old were selected, according to the following inclusion criteria:

- good general state of health

- absence of cutaneous pathologies

- absence of pharmacological treatments in progress

- commitment to not vary their normal daily routine

- no history of allergy

The products were used daily as indicated by the client.

The skin area chosen for the test is the face.

The difference in the monitored parameters before and after use of the product is assessed. <

Instrumental assessments:

Images filed through digital videocamera.

Clinical assessments:

- Tolerability of the product (occurrence of irritation following use of the product, worsening of the initial clinical situation).

- Soothing effect on the redness present in the cutaneous area with acneic tendency

- Evolution of the acneic lesions (spots, microcysts, comedos, dyschromias or blotches)

The measurements are taken:

- At time [tθ] (baseline value). - During the period of use of the product: after 7, 15, and 30 days

The recorded data is processed and displayed graphically.

The photographic assessment is completed by the clinical assessment by the dermatologist according to the clinical score shown in tables 1 -3 below.

Table 1 - Redness of the cutaneous area treated

Table 2 - Initial state of the acneic lesions

Table 3 — Evolution of acneic lesions

Figure 13 shows the graphical display of the progression of the redness of the acneic skin during treatment, assessed at time zero (TO), and after 7, 15 and 30 days (T7, Tl 5 and T30 respectively). Figure 14 shows the graphical display of the progression of the resolution of acneic lesions during treatment, assessed at time zero (TO), and after 7, 15 and 30 days (T7, T15 and T30 respectively). From the results shown in the aforementioned figures it can be seen that there is a rapid improvement in acneic lesions that in 7 volunteers already partially resolve from the 7th day. On the 15th day 4 subjects have their acneic lesions completely resolved whereas on 3 of them they are partially resolved. On the _x30th day of treatment the subjects that record the disappearance of^* the acneic lesions are 7. The results demonstrate that constant use of the product promotes the normalisation of the skin, soothes the redness caused "by the acneic eruption", performs a mild exfoliating action thus promoting a faster evolution and solution of the acneic lesions.

Claims

1. A pharmaceutical or cosmetic composition comprising an antioxidant agent and dimethylsulfoxide, wherein the molecular weight of the antioxidant agent is between 100 Da and 300 Da.

2. A composition according to claim 1 , wherein the molecular weight of the antioxidant agent is between 150 Da and 250 Da.

3. A composition according to claim 1 wherein the antioxidant agent is alpha lipoic acid, the R optical isomer of alpha lipoic acid, dihydrolipoic acid, melatonin, allantoin, dimethyl sulfone MSM, Pycnogenol or trans-resveratrol.

4. A composition according to claim 1 , wherein the percentage of antioxidant agent is within the range of between 0, 1 % and 30%, preferably between 0,5% and 10% and even more preferably between 2% p/p and 5% p/p, with respect to the total weight of the composition.

5. A composition according to claim 1 , wherein the percentage of dimethylsulfoxide is within the range of between 5% and 70%, preferably between 10% and 50%, with respect to the total weight of the composition.

6. A composition according to claim 1 , which also comprises a stabiliser selected from alpha-tocopherol, resveratrol, Pycnogenol, melatonin, allantoin, dimethyl sulfone MSM, vitamin A, vitamin C, vitamin E and vitamin K and their pharmaceutically acceptable salts.

7. A composition according to claim 6, where the stabiliser is vitamin A acetate or Vitamin A palmitate.

8. A composition according to claim 6, where the percentage of stabiliser is within the range of between 0,1% and 5%, preferably between 0,2% and 2%, with respect to the total weight of the composition.

9. A composition according to claim 1 , which also comprises a hydrophilic excipient selected from ethanol, glycerol, propylene glycol, sorbitol, diethyleneglycol and polyoxyethyleneglycol

10. A composition according to claim 9, where the hydrophilic excipient is glycerol.

1 1. A composition according to claim 9, where the percentage of hydrophilic excipient is within the range of between 10% and 70%, preferably between 30%and 60%, with respect to the total weight of the composition.

12. A composition according to claim 1 , administered topically.

13.A composition according to claim 12, in the form of a solution, WVO and O/W emulsion, gel, anhydrous ointment, cream, salve, lotion, soap, transdermal patch, foam or shampoo.

14.A composition according to claim 1 , which also comprises an antimycotic, antiseptic, antibiotic, disinfectant, anti-acne, antipsoriasis or antiseborrheic active ingredient .

15. Use of a composition as defined in claims 1 to 14, for the production of a medicament for treating dermatitis, acne, alopecia, baldness, erythemas, rosacea and psoriasis.

16. Use of a composition as defined in claims 1 a 14, for the production of a cosmetic for soothing, hydrating, anti-age, elasticising, anti-wrinkle, firming, anti-cellulite and anti- couperose treatment of the skin.

17. Use of an antioxidant agent and dimethylsulfoxide, where the molecular weight of the antioxidant agent is between 100 Da and 300 Da, for treating dermatitis, acne, alopecia, baldness, erythemas, rosacea and psoriasis and for soothing, hydrating, anti-age, elasticising, anti-wrinkle, firming, anti-cellulite and anti-couperose treatment of the skin.

8. Use of an oxidant agent and dimethylsulfoxide according to claim 17, where the oxidant agent is selected from alpha lipoic acid, R optical isomer of alpha lipoic acid, dihydrolipoic acid, melatonin, allantoin, dimethyl sulfone MSM, Pycnogenol or trans-resveratrol.