Use of chitosans for the treatment of nail inflammatory diseases

Abstract

Chitosan-based nail formulations are useful to treat nail inflammatory diseases such as psoriasis, atopic dermatitis and lichen planus. The chitosan is normally in the form of an amino-polysaccharide derivative, preferably water soluble, such as hydroxypropyl chitosan. The formulation may be a nail lacquer, a spray, a cream, an ointment, a gel, a lotion or a foam and may comprise chitosan, a chitosan derivative or a salt thereof in an amount from 0.1 to 25 wt. % with respect to the total weight of the formulation.

Claims

1. A method of treating a nail inflammatory disease in a human or animal subject in need thereof, the method comprising administering to the nail of the subject, a therapeutically effective amount of a composition comprising hydroxypropyl chitosan and one or more active principles selected from betamethasone, budesonide, clobetasol and salts thereof, salicylic acid, benzoic acid and salts thereof, an extract from Equisetum arvense, an extract from Harpagophyton procumbens, diclofenac, aspirin, ketoprofen, calcipotriol, calcitriol, tretinoin, acitretin, tazarotene, and cyclosporine.

2. The method of claim 1, wherein the nail inflammatory disease is selected from nail psoriasis, lichen planus, atopic dermatitis, and alopecia areata.

3. The method of claim 1, wherein the composition is administered topically.

4. The method of claim 3, wherein the composition is applied to the nail surface freely, under semi-occlusive or occlusive medication.

5. The method of claim 3, wherein the composition is administered by means of a topical formulation.

6. The method of claim 5, wherein the topical formulation is a nail lacquer, a spray, a cream, an ointment, a gel, a lotion, or a foam.

7. The method of claim 5, wherein the topical formulation comprises hydroxypropyl chitosan in an amount from 0.1 to 25 wt. % with respect to the total weight of the formulation.

8. The method of claim 5, wherein the topical formulation comprises hydroxypropyl chitosan in an amount from 0.3 to 10 wt. % with respect to the total weight of the formulation.

Description

EXAMPLE 1

(1) A nail lacquer having the following composition wt./wt. % is prepared:

(2) TABLE-US-00001 1. purified water 21.0% 2. ethanol 73.0% 3. ethyl acetate 4.0% 4. hydroxypropyl chitosan (HPCH) 1.0% 5. cetostearyl alcohol 1.0%
Preparation

(3) The formulation is prepared by using a closed vessel with a stirrer. To this vessel are added ethanol, deionized water and ethyl acetate to form a mixture. Thereafter, cetostearyl alcohol is added. Finally, hydroxypropyl chitosan is added and the resulting mixture is stirred for 24 hours or until dissolution.

(4) The obtained composition has a clear and homogenous appearance even after prolonged storage. Moreover, when applied on the nails, the liquid is able to form a matte, non-sticky and elastic film which could strongly adhere to the nail surface.

EXAMPLE 2

(5) A nail lacquer having the following composition wt./wt. % is prepared:

(6) TABLE-US-00002 1. purified water 29.375% 2. ethanol 96 70.0% 3. budesonide 0.025% 4. hydroxypropyl chitosan (HPCH) 0.5% 5. Peg-40 Hydrogenated castor oil 0.1%
Preparation

(7) The formulation is prepared as per the Examples 1 and 3, by adding hydroxypropyl chitosan as the final ingredient and stirring for 24 hours or until dissolution.

EXAMPLE 3

(8) A nail lacquer having the following composition wt./wt. % is prepared:

(9) TABLE-US-00003 1. propylene glycol 13.0% 2. isopropanol 82.497% 3. calcitriol 0.003% 4. ethyl acetate 4.0% 5. chitosan 0.5%
Preparation

(10) Chitosan is dissolved in propylene glycol, then calcitriol previously dissolved in isopropanol is added. Then ethyl acetate is added and the resulting mixture is stirred until dissolution.

EXAMPLE 4

(11) A nail lacquer having the following composition wt./wt. % was prepared:

(12) TABLE-US-00004 1. purified water 29.35% 2. ethanol 96 70.00% 3. hydroxypropyl chitosan (HPCH) 0.50% 4. betamethasone-17-valerate 0.05% 4. PEG-40 hydrogenated castor oil 1.00%
Preparation

(13) The formulation was prepared by using a suitable closed vessel provided with a stirrer. To this vessel were added ethanol, betamethasone-17-valerate and PEG-40 hydrogenated castor oil. The mixture was stirred and then water was added. After short stirring hydroxypropyl chitosan was added. The mixture was stirred for 24 hours until complete dispersion of hydroxypropyl chitosan. The resulting composition is limpid, colourless liquid, with typical alcoholic odour.

EXAMPLE 5

(14) A nail lacquer having the following composition wt./wt. % was prepared:

(15) TABLE-US-00005 1. purified water 29.0% 2. ethanol 96 60.0% 3. hydroxypropyl chitosan (HPCH) 0.5% 4. cyclosporine 5.0% 5. urea 5.0% 6. Polyethylenlycol 400 0.5%
Preparation

(16) The formulation was prepared by using a suitable closed vessel provided with a stirrer. To this vessel were added water, ethanol, and after short stirring cyclosporine. The complete dissolution was immediate. Then urea was added, and, after dissolution, Polyethylenglycol 400 was added. After 10 min stirring hydroxypropyl chitosan was added. The mixture was stirred for 8 hours until complete dissolution of hydroxypropyl chitosan. The resulting composition was a limpid, colourless liquid, even after prolonged storage.

(17) Moreover, the liquid was able to form a matte, non-sticky and elastic film which could strongly adhere to the nail surface.

EXAMPLE 6

(18) A nail lacquer having the following composition wt./wt. % was prepared:

(19) TABLE-US-00006 1. purified water 19.45% 2. propylene glycol 10.00% 2. isopropanol 70.00% 3. chitosan 0.50% 4. bechlometasone dipropionate 0.05%
Preparation

(20) The formulation was prepared by dissolving chitosan and bechlometasone dipropionate in propylene glycol, then adding the other ingredients, and stirring the mixture until dissolution. The resulting liquid was able to form an elastic film which could strongly adhere to the skin surface.

EXAMPLE 7

(21) A nail lacquer having the following composition wt./wt. % was prepared:

(22) TABLE-US-00007 1. purified water 52.0% 2. ethanol 36.5% 3. diethylenglycole monomethyleter 0.5% 4. methylsulphonylmethane (DMSO.sub.2) 5.0% 5. hydroxypropyl chitosan (HPCH) 1.0% 6. Equisetum arvense glycolic extract 5.0%
Preparation

(23) The formulation was prepared by using a suitable closed vessel provided with a stirrer. To this vessel were added ethanol, deionized water and diethyleneglycol-monomethylether to form a mixture. Thereafter, after dissolution thereof, Equiselum arvense glycolic extract and methylsulphonyl methane were added. Finally, hydroxypropyl chitosan was added and the resulting mixture was stirred for 24 hours or until dissolution.

(24) The obtained nail lacquer composition had a clear and homogeneous appearance and a yellowish color even after prolonged storage. Moreover, the lacquer was able to form a matte, non-sticky and plastic film which could strongly adhere to the nails. When applied, the moisture and air permeable lacquer did not burn or cause irritation on the adjacent skin or the periungual bed.

EXAMPLE 8

(25) An open, controlled clinical study was performed to assess the efficacy and the safety profile of the nail lacquer according to the Example 7 on patients with nail psoriasis. The involved patients were 20 women and 10 men, aged between 18 and 75 years (mean 46.5 yrs) affected by nail psoriasis, with symmetric lesions of both sides. The nail alterations were manifest from 6 months-2 years prior to the inclusion into the study, with the following clinical characteristics: presence of pitting=15%; presence of onycholysis=9%; presence of leuchonychia=6%. The severity of the nail psoriasis, measured by the NAPSI score (Nail psoriasis severity index, according to Baran R., Br J Dermatol, 2004, 150:568-569; Parrish at al., J Am Acad Dermatol, 2005, 53:745-476), was between 2 and 5. The nail lacquer according to the Example 7 was applied once daily by the patients on the fingernails of the left hand for 24 consecutive weeks.

(26) No other systemic or topical antipsoriatic treatment was taken by the patients during the whole treatment period. At the end, the therapeutic efficacy was judged by the investigator by a clinical examination at cold light, and compared to the fingernails of the right hand. At the end of 24 treatment week, the result of the treated fingernails was judged as excellent in 18 cases, good in 5 cases and none in 5 cases, while the untreated hands were unmodified compared to baseline. The remaining 2 cases were lost to follow up. The quality of life of patients, measured by Dermatology Life Quality Index (DLQI) is a simple 10-question validated Quality of Life questionnaire (Finlay & Khan: Clinical and Experimental Dermatology, 1994, 19:210-216 related to the treated hand, also resulted as much improved at the end of treatment compared to baseline (FIG. 1).

(27) During the study, no adverse events occurred, and tolerability of the product according to the Example 7 was judged as optimal by 100% of patients. The judgement of the patients was always very satisfactory both for the treatment easiness and for the organoleptic characteristics of the product.

EXAMPLE 9

(28) A liquid formulation having the following w/w % composition was prepared:

(29) TABLE-US-00008 1. Calcipotriol anhydrous 0.005% 2. Isopropyl alcohol 51.00% 3. Diethylene glycole monoethyl ether.sup.1 3.00% 4. Hydroxypropyl chitosan 0.50% 5. Purified water 45.495% .sup.1TRANSCUTOL P
Preparation

(30) Calcipotriol Anhydrous was dissolved in the minimum suitable volume of Isopropyl alcohol and added to the remaining quantity of Isopropyl alcohol under stirring condition. Diethylene glycole monoethyl ether was added and dissolved, then, purified water was added and stirred until well mixed. Hydroxypropyl chitosan was added in little portions and stirred until dissolution not less than 8 hours. The obtained solution was filtered with a 316 stainless steel 5 m pore size filter.

EXAMPLE 10

(31) A liquid formulation having the following w/w % composition was prepared:

(32) TABLE-US-00009 1. Cyclosporine 5.00% 2. Ethyl alcohol 96% 84.00% 3. Urea 5.00% 4. Macrogol 400 0.50% 5. Hydroxypropyl chitosan 0.50% 6. Purified water 5.00%
Preparation

(33) Ethyl alcohol and purified water were mixed and cyclosporine was added to the obtained solution and dissolved.

(34) Macrogol 400 was added and mixed until dissolution and then, urea was added and dissolved. Hydroxypropyl chitosan was added in little portions and stirred until dissolution not less than 8 hours. The obtained solution was filtered with a 316 stainless steel 5 m pore size filter.

EXAMPLE 11

(35) A randomized, double-blind, placebo-controlled, parallel-group clinical trial was performed on 77 patients, affected by mild to moderate nail psoriasis in at least one fingernail. The subject gave their written informed consent before starting any trial procedure. One of the formulations according to the Examples 9 or 10 was randomly applied once daily (at bed-time, 6 hours before washing) for 24 weeks to all fingernails. A third group applied a placebo, namely the vehicle of the composition as per the Example 9, but devoid of the active ingredient calcipotriol.

(36) Another 12 weeks of observation (follow-up period) were planned after the treatment period. Severity of the nail psoriasis was assessed every 4 weeks during the treatment period and at the end of the follow-up on all affected fingernails by means of the NAPSI (Nail Psoriasis Severity Index) score (Rich P., Scher R. K. Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis. Journal Am. Acad. Dermatology August 2003). The Intent to Treat population of the study included 34 patients applied the formulation as per Example 9, 30 as per Example 10 and 15 the placebo.

(37) The data of parameter NAPSI are reported in the following Table 1 as baseline value (meansstandard deviations) and as changes from baseline at week 24 (end of treatment) and week 36 (end of follow up). The NAPSI score, indicating the disease severity, was homogeneously distributed among the three groups at baseline and in the group treated with the composition as per Example 9 decreased by about 33% and 37% of the baseline value at the weeks 24 and 36, respectively. A lower decrease of the score was recorded in the group treated with the composition as per the Example 10 by about 10% and 15% at the weeks 24 and 36. In placebo group, the score decreased by about 5 and 7%, respectively.

(38) TABLE-US-00010 TABLE 1 Composition as Composition as Visit PLACEBO per Example 9 per Example 10 Visit 1 Baseline Mean 22.29 20.25 23.87 value SD 14.49 14.26 17.76 Change from baseline Visit 6 (Week 24) Mean 1.11 6.78 2.42 SD 5.13 9.52 9.29 Visit 7 (Week 36) Mean 1.71 7.43 3.50 SD 7.72 10.55 8.37

(39) The results show that the presence of active compounds commonly used in the treatment of psoriasis like immunosuppressive agent (cyclosporine) as per Example 10 and even more antipsoriatic vitamin D3 analogues like calcipotriol as per Example 9, according to the present invention improved the efficacy of the solution of hydroxypropyl chitosan in decreasing the severity of nail psoriasis.