Combination of lipoic acid and taurine as osmoprotective agent

Abstract

The present invention relates to a combination of lipoic acid and taurine for use as an osmoprotective agent for the prevention and treatment of ailments of the skin and of the mucous membranes associated with osmotic imbalance. It also relates to a method for preventing and treating ailments of the skin and of the mucous membranes associated with osmotic imbalance, in which an appropriate amount of a combination of lipoic acid and taurine is applied to the skin or the mucous membranes of a patient who is in need thereof. The invention also relates to a pharmaceutical or cosmetic composition suitable for topical application or an oph-thalmic composition which comprises a combination oflipoic acid and taurine.

Claims

1. A pharmaceutical or cosmetic composition for topical application comprising a combination of lipoic acid and taurine and a pharmaceutically or cosmetically acceptable carrier, wherein said composition comprises from 0.001 to 0.1 wt % lipoic acid and from 0.2 to 1.0 wt % taurine relative to the total weight of the composition and wherein the lipoic acid:taurine weight ratio ranges from 0.004 to 0.05.

2. The composition of claim 1, wherein said composition is suitable for application to the skin, and wherein said composition is selected from the group consisting of creams, salves, gels, lotions, solutions, emulsions and ointments.

3. The composition of claim 2, wherein said composition comprises from 0.005 to 0.05 wt % lipoic acid relative to the total weight of the composition.

4. The composition of claim 1, that is an ophthalmic composition suitable for application to the eye.

5. A method for treatment of a skin condition in which dry skin appears in a patient in need thereof, comprising applying the composition according to claim 1 to skin of said patient.

6. The method of claim 5, wherein said composition is suitable for application to the skin, and further wherein said compositions is selected from the group consisting of creams, salves, gels, lotions, solutions, emulsions and ointments.

7. The method of claim 5, wherein the skin condition is selected from the group consisting of atopic dermatitis, ichthyosis, eczema and psoriasis.

8. A method for treatment of an eye condition related to dry eye in a patient in need thereof, comprising applying the composition according to claim 1 to an eye of said patient.

9. The method of claim 8, wherein the composition comprises from 0.5 wt % taurine relative to the total weight of the composition.

10. The method of claim 8, wherein the eye condition related to dry eye is a sign of Meibomian gland dysfunction, hyperevaporative syndrome or lacrimal insufficiency.

11. A method for the treatment of ocular edema, optionally in corneal edema, in a patient in need thereof, comprising applying the composition according to claim 1 to the eye of said patient.

12. The composition according to claim 1, wherein the composition is substantially free of preservatives.

13. The composition of claim 1, wherein the lipoic acid:taurine weight ratio ranges from 0.01 to 0.05.

14. The composition of claim 1, wherein the lipoic acid:taurine weight ratio is 0.02.

15. The composition of claim 2, comprising 0.01 wt % lipoic acid relative to the total weight of the composition.

16. The composition of claim 2, comprising 0.5 wt % taurine relative to the total weight of the composition.

17. The composition of claim 1, wherein dry matter content is between 0.001 and 0.05 wt. %.

18. The composition of claim 1, wherein said composition is an osmoprotectant used to prevent and treat ailments of the skin and mucus membranes associated with osmotic imbalance.

19. A pharmaceutical or cosmetic composition for topical application comprising a combination of lipoic acid and taurine and a pharmaceutically or cosmetically acceptable carrier, wherein said composition comprises from 0.005 to 0.02 wt % lipoic acid and 0.5 wt % taurine relative to the total weight of the composition, and wherein the lipoic acid:taurine weight ratio is 0.01 to 0.04.

Description

DESCRIPTION OF THE FIGURES

(1) FIGS. 1 to 4 represent cell viability results after osmotic stress for various concentrations of lipoic acid, alone or combined with glycerin and/or taurine.

EXAMPLES

(2) The compositions given in the following examples are prepared according to the usual methods of the technical field. Specific sanitary precautions are taken for the preparation and packaging of preservative-free compositions so as to avoid contamination.

Example 1: Dermatological Composition

(3) TABLE-US-00001 Components Amount Caprylic/capric triglyceride 20.00% Tribehenin PEG-20 esters 3.00% Niacinamide 3.00% Taurine 0.50% Glycerin 0.50% Allantoin 0.20% Sodium lipoate 0.01% Ceramide 3 0.10% Sodium hyaluronate 0.20% Sodium lipoate 0.01% Sodium hydroxide (10% solution) 1.50% Reverse-osmosis water q.s. 100%

Example 2: Dermatological Composition

(4) TABLE-US-00002 Components Amount Cocamidopropyl betaine 10.00% Decyl glucoside 5.00% Glycerin 5.00% Niacinamide 2.00% Trisodium citrate dihydrate 1.45% Xanthan gum 0.75% Taurine 0.50% Allantoin 0.20% Sodium hyaluronate 0.10% Citric acid 0.025% Lipoic acid 0.005% Water q.s. 100%

Example 3: Dermatological Composition

(5) TABLE-US-00003 Components Amount Caprylic/capric triglyceride 25.00% Niacinamide 4.00% Tribehenin PEG-20 esters 3.50% Glycerin 3.00% Trisodium citrate 1.45% Xanthan gum 0.80% Taurine 0.50% Allantoin 0.50% Sodium hyaluronate 0.10% Ceramide NP 0.10% Citric acid 0.05% Lipoic acid 0.05% Water q.s. 100%

Example 4: Dermatological Composition

(6) TABLE-US-00004 Components Amount Caprylic/capric triglyceride 20.00% Tribehenin PEG-20 esters 3.00% Glycerin 3.00% Trisodium citrate 1.45% Xanthan gum 0.80% Sodium hyaluronate 0.50% Taurine 0.50% Allantoin 0.20% Helianthus annuus (sunflower oil), 0.10% Retinyl palmitate Citric acid 0.05% Lipoic acid 0.01% Water q.s. 100%

Example 5: Ophthalmic Composition

(7) TABLE-US-00005 Components Amount Sodium hyaluronate 0.20% Taurine 0.5% Sodium lipoate 0.001% Caprylic/capric triglyceride 0.05% Soy lecithin 0.15% Sodium carboxymethylcellulose 0.15% Trisodium citrate dihydrate 0.05% Citric acid 0.02% NaOH (1N) q.s. pH 6.7 Sodium chloride q.s. 150 mOsmol/L Water for injection q.s. 100%

Example 6: Ophthalmic Composition

(8) TABLE-US-00006 Components Amount Sodium chloride 5.00% Sodium hyaluronate 0.18% Taurine 0.1% Lipoic acid 0.001% Sodium carboxymethylcellulose 0.3% Disodium citrate dihydrate 1.5% Citric acid monohydrate q.s. pH 7 Purified water q.s. 100%

Example 4—Osmoprotective Activity of Lipoic Acid and Taurine Alone or in Mixtures

(9) A study was carried out to determine the osmoprotective capacity of sodium lipoate (A) during hyperosmolar stress on human conjunctival (WKD) and corneal (HCE) cells.

(10) In a second phase, tests were carried out to compare the effect of lipoic acid, glycerin (B), and taurine (C), individually and when the molecules were combined, on HCE cells under hyperosmolar stress conditions.

(11) The osmoprotective activity of A, then A with B and C, was evaluated by measuring cell viability in particular. To that end, cells were preincubated for 17 h with the test substance(s). Next, the medium was removed and the cells were subjected to hyperosmolar stress by addition of sodium chloride (100 mM NaCl) to the culture medium (M199 for the WKD cells and KSFM for the HCE cells). Cell-growth control cells were contacted with isotonic medium. Cell viability was analyzed pre-osmotic stress (0 h) in order to measure the effect of the molecules remaining in contact with the cells during the 17 h of incubation, then at 4 h, 8 h and 24 h post-induction of osmotic stress. The cell viability measurement was carried out via an XTT assay.

(12) Various concentrations of A were tested for the “molecule alone” tests: 0.0005%, 0.001%, 0.005%, 0.01% and 0.05% w/v. For the molecule mixture tests, the following concentrations were tested: for A: 0.001%, 0.005%, and 0.01% w/v; for B: 0.25% w/v; and for C: 0.5% and 1% w/v.

(13) To ensure the validity and the significance of the data, the results obtained were analyzed statistically. The results presented below result from the mean of 3 independent repetitions, carried out on different days.

Cell Viability Measurements for Various Concentrations of Lipoic Acid (Sodium Lipoate) with WKD Cells

(14) TABLE-US-00007 0 h 4 h 8 h 24 h At 0.0005% 99.90% 62.70% 38.50% 18.80% At 0.001% 98.50% 69.60% 42.40% 18.50% At 0.005% 102.80% 109.40% 76.10% 12.60% At 0.01% 98.10% 119.90% 82.90% 8.90% At 0.05% 56.30% 46.00% 27.80% 2.70% NaCl 98.80% 50.70% 33.50% 25.80% HIDC 92.30% 68.80% 50.40% 56.40%

(15) Cell viability measurements for various concentrations of lipoic acid (sodium lipoate) with HCE cells are shown in FIG. 1.

(16) Lipoic acid has high osmoprotective activity against osmotic stress at 0.005% and 0.001% (w/v) at 4 h and 8 h post-stress.

(17) FIGS. 2 to 4 represent the viability results obtained with various mixtures of A with B, C and B+C.

(18) An enhanced osmoprotective effect of lipoic acid is observed when it is combined with glycerin (B) and with taurine (C), or with both. This enhancement is expressed as higher cell viability than that observed with lipoic acid alone, with glycerin alone or with taurine alone. It is particularly marked for the combination lipoic acid+taurine (FIG. 3), which increases said osmoprotective action over time, up to 24 h post-stress.

Example 5—Osmoprotective Activity of Mixtures of Lipoic Acid and Taurine

(19) The protocol of Example 4 is repeated with 11 mixtures (M1 to M11) of sodium lipoate (A) and taurine (B). The cell viability results obtained confirm the increase in osmoprotective action over time observed for the mixtures of Example 4.

Cell Viability Measurements for Various Concentrations of Lipoic Acid (Sodium Lipoate—A) and Taurine (B) with WKD Cells

(20) TABLE-US-00008 A % C % A/C t = 0 h t = 4 h t = 8 h t = 24 h M1 0.0001 0.10 0.001 81% 63% 50% 33% M2 0.0002 0.10 0.002 84% 66% 51% 32% M3 0.0050 1.00 0.005 84% 70% 67% 54% M4 0.0050 0.50 0.010 93% 72% 66% 52% M5 0.0050 0.25 0.020 96% 78% 65% 46% M6 0.0100 0.50 0.020 96% 73% 69% 51% M7 0.0200 1.00 0.020 82% 63% 58% 50% M8 0.0200 1.00 0.020 90% 64% 57% 40% M9 0.0050 0.10 0.050 92% 74% 58% 36% M10 0.0500 0.25 0.200 61% 49% 40% 21% M11 0.0500 0.10 0.500 73% 52% 27% 19% Control (NaCl) 94% 68% 46% 22%

(21) The improved osmoprotective effect appears even more marked for the preferred lipoic acid:taurine weight ratio, which ranges from about 0.004 to about 0.05 (mixtures M3 to M9).

REFERENCES

(22) U.S. Pat. No. 5,817,630 U.S. Pat. No. 6,162,393 US 2004/265345 US 2005/192229 US 2006/188492 WO 01/93824 WO 02098345 DE10229995 BR PI0 800 818 CN 103 860 625 JP 2013 241398 Masami Kojima et al., Japanese Journal of Ophthalmology, January 2007, Volume 51, Issue 1, pp 10-13