Composition for increasing of the effectiveness of UV-B therapy, process for the preparation thereof, and its use

Abstract

A light-therapeutic composition is disclosed, which can modify the optical characteristics of the skin, thereby increase the effectiveness of the UV-B therapy. The composition according to the invention includes one or more material, which sets the minimum value of wavelength of the light transmitted, one or more material, which is suitable to modify the above-mentioned wavelength value, and increase the transmittance of the skin in a certain wavelength-range, furthermore, optionally an excipient. The composition according to the invention blocks the UV radiation in the wavelength ranging from 280 to 300 nm, and helps the incorporation of the UV radiation by the skin in the wavelength ranging from 310 to 320 nm.

Claims

1. A composition for modulating the optical transmittance of the skin within the ultraviolet spectrum comprising a) one or more materials for setting a minimum value of wavelength of the light transmitted, wherein the one or more materials are selected from the group consisting of carbomer interpolymer type A, carbomer homopolymer type C, zinc-hyaluronate, glycerin, isopropyl myristate, caprylic/capric triglyceride, PEG 200, PEG 300, PEG 600, carbomer homopolymer type A, propylene glycol, and PEG 400; b) a material for modifying the value of wavelength set by the one or more materials according to a) and enhancing the optical transmittance of the skin in a given range of wavelengths, wherein the material is nicotinic acid; and c) an excipient, which allows the light to penetrate into the skin in a wavelength range above the value relevant for the use, where the excipient is selected from the group consisting of triethanolamine, a combination of phenoxyethanol, caprylyl glycol and chlorphenesin, and distilled water.

2. The composition according to claim 1, wherein the composition comprises one or more of the following components in the given quantities: TABLE-US-00008 Propylene glycol from 0.1 to 10 percent by mass (0.1-10 wt %), carbomer homopolymer from 0.1 to 0.5 percent by mass (0.1-0.5 wt %), type A carbomer interpolymer from 0.1 to 5 percent by mass (0.1-5 wt %), type A carbomer homopolymer from 0.1 to 5 percent by mass (0.1-5 wt %), type C Zinc hyaluronate from 0.01 to 3 percent by mass (0.01-3 wt %), Glycerin from 0.1 to 30 percent by mass (0.1-30 wt %), Isopropyl myristate from 1 to 10 percent by mass (1-10 wt %), caprylic/capric from 1 to 30 percent by mass (1-30 wt %), triglyceride PEG 200 from 10 to 90 percent by mass (10-90 wt %), PEG 300 from 10 to 90 percent by mass (10-90 wt %) PEG 400 from 10 to 90 percent by mass (10-90 wt %), PEG 600 from 10 to 90 percent by mass (10-90 wt %), Benzaldehyde from 0.001 to 1 percent by mass (0.001-1 wt %) and/or Nicotinic acid from 0.01 to 1 percent by mass (0.01-1 wt %).

3. The composition according to claim 1, wherein the composition blocks the ultraviolet radiation in the wavelength range of 280-300 nm and facilitates its transmission into the skin in a wavelength range of 310-320 nm.

4. The composition according to claim 1, wherein the dosage form of the composition is solution, gel, ointment, cream, foam, spray, emulsion, or tonic.

5. A composition for modulating the optical transmittance of the skin within the ultraviolet spectrum comprising a) a material for setting a minimum value of wavelength of the light transmitted, wherein the material is PEG 400; b) a material for modifying the value of wavelength set by the materials according to a) and enhancing the optical transmittance of the skin in a given range of wavelengths, wherein the material is nicotinic acid, wherein the composition comprises in an amount of from 0.01 to 0.10 gram nicotinic acid per 100 grams of the composition and PEG 400.

6. The composition according to claim 1, wherein the composition comprises carbomer homopolymer type A 1% aqueous gel in an amount of 10 to 50 grams, propylene glycol in an amount of 0.1 to 10 grams, triethanolamine in an amount of 0.1 to 0.5 gram, the combination of phenoxyethanol, caprylyl glycol and chlorphenesin in an amount of 1 to 5 grams per 100 grams of the composition and distilled water.

7. A method for enhancing the effectiveness of ultraviolet light therapy, said method comprising delivering to a target skin surface of a patient in need of such therapy a composition comprising a) one or more materials for setting a minimum value of wavelength of the light transmitted, wherein the one or more materials are selected from the group consisting of carbomer interpolymer type A, carbomer homopolymer type C, zinc-hyaluronate, glycerin, isopropyl myristate, caprylic/capric triglyceride, PEG 200, PEG 300, PEG 600, carbomer homopolymer type A, propylene glycol, and PEG 400; b) a material for modifying the value of wavelength set by the one or more materials according to a) and enhancing the optical transmittance of the skin in a given range of wavelengths, wherein the material is nicotinic acid; and c) an excipient, which allows the light to penetrate into the skin in a wavelength range above the value relevant for the use, wherein the excipient is selected from the group consisting of triethanolamine, a combination of phenoxyethanol, caprylyl glycol and chlorphenesin, and distilled water and performing ultraviolet light therapy on said patient.

8. The composition according to claim 1, wherein the composition comprises in an amount of 0.0405 gram nicotinic acid per 100 grams of the composition and PEG 400.

9. The composition according to claim 1, wherein the composition comprises carbomer homopolymer type A 1% aqueous gel in an amount of 13.8 grams, propylene glycol in an amount of 10 grams, triethanolamine in an amount of 0.1 gram, and the combination of phenoxyethanol, caprylyl glycol and chlorphenesin in an amount of 1 gram per 100 grams of the composition and distilled water.

10. The method of claim 7, wherein the target skin surface comprises a psoriatic plaque.

11. The method of claim 10, further comprising applying a common sunscreen on symptom-free skin outside of the target skin surface.

12. The method of claim 7, wherein said composition comprises the combination of phenoxyethanol, caprylyl glycol and chlorphenesin.

Description

EXAMPLES

(1) In this section, our invention will be described through examples both for implementation and efficacy, with reference to figures listed and attached below.

(2) FIG. 1 shows the penetration of ultraviolet B radiation into the skin without pre-treatment and after pre-treatment with the composition according to the present invention.

(3) FIG. 2 shows optical transmittance spectrum of the spray formulation of the composition according to the present invention.

(4) FIG. 3 shows optical transmittance spectrum of the gel formulation of the composition according to the present invention.

(5) FIG. 4 shows optical transmittance spectrum of Macrogol 400 (PEG 400).

(6) FIG. 5 shows optical transmittance spectrum of propylene glycol.

(7) FIG. 6 shows optical transmittance spectrum of Carbopol 971P.

(8) FIG. 7 shows optical transmittance spectrum of Carbopol Ultrez 10.

(9) FIG. 8 shows optical transmittance spectrum of Carbopol 980 NF.

(10) FIG. 9 shows optical transmittance spectrum of zinc hyaluronate.

(11) FIG. 10 shows optical transmittance spectrum of glycerin.

(12) FIG. 11 shows optical transmittance spectrum of isopropyl myristate.

(13) FIG. 12 shows optical transmittance spectrum of Migliol 810.

(14) FIG. 13 shows optical transmittance spectrum of Macrogol 200.

(15) FIG. 14 shows optical transmittance spectrum of Macrogol 300.

(16) FIG. 15 shows optical transmittance spectrum of Macrogol 600.

(17) FIG. 16 shows optical transmittance spectrum of sodium hyaluronate.

(18) FIG. 17 shows optical transmittance spectrum of nicotinic acid.

(19) FIG. 18 shows optical transmittance spectrum of lactic acid.

(20) FIG. 19 shows optical transmittance spectrum of methenamine.

(21) FIG. 20 shows optical transmittance spectrum of transcutol.

(22) FIG. 21 shows optical transmittance spectrum of polyaminopropyl biguanide (Cosmocil CQ).

(23) FIG. 22 shows ultraviolet transmittance spectra of 0.6 ml and 3.6 ml volumes of the spray formulation of the composition, respectively, measured by Lab sphere UV Transmittance Analyzer. Layer thickness was 0.24 mm and 1.44 mm, respectively (evenly spread on a polymethyl methacrylate [PMMA] disc of 50×50 mm) Wavelength range: 250-450 nm. Measuring points (9) and points determined by template (5).

(24) The goal of the inventors was to develop such compositions, which do not transmit light with a wavelength shorter than 290-300 nm but feature a markedly higher transmittance for radiation with a wavelength above this value. Dermal application required the constitution of a composition suitable for patients' use. In addition to therapeutic goals, the primary intention of the inventors was to create a non-greasy, non-shiny composition, which is well tolerated by patients.

(25) After measuring in vivo transmission of several agents inventors found that Macrogol 400 (FIG. 4) and sodium hyaluronate/Carbopol (FIG. 3) exhibit almost 100% transmission in the therapeutic wavelength range. Furthermore, a sharp decrease of transmittance was detectable around 300 nm wavelength and it fell to zero below this value. For nicotinic acid this effect is more pronounced (FIG. 17).

(26) I. Composition of Samples Prepared for Clinical Trials

(27) From among the numerous compositions tested, two samples have been selected for further development and in-depth clinical investigation.

(28) Composition in Spray Form

(29) Components of the sample:

(30) TABLE-US-00002 Nicotinic acid 0.0405 g Macrogol 400 (PEG 400) ad 100.0 g
Composition in Gel Form

(31) Components of the sample:

(32) TABLE-US-00003 Sodium hyaluronate 1% aqueous gel 20.0 g Carbopol 971P 1% aqueous gel 13.8 g Propylene glycol 10.0 g Triethanolamine 0.10 g Microkill COS 1.0 g Distilled water ad 100.0 g

(33) For the spray formulation, nicotinic acid was dissolved in Macrogol 400 at room temperature. For the gel formulation, first Microkill COS was mixed with propylene glycol, and both hydrogels, i.e. with sodium hyaluronate 1% aqueous gel, and Carbopol 971P 1% aqueous gel, respectively, and finally distilled water was added up to 100 grams.

(34) Compositions suitable for therapeutic purposes were selected by the measurement of optical transmittance. Measurements were performed using a Helios a spectrophotometer in the wavelength range of 200-600 nm. FIGS. 4 and 2 show optical transmittance spectra of Macrogol 400 and the spray formulation of the composition, respectively. FIG. 3 illustrates the optical transmittance spectrum of the gel formulation of the composition.

(35) II. Clinically Tested Samples

(36) Initial In Vitro Tests

(37) In vitro tests were performed in accordance with the COLIPA SPF test method. Above 300 nm wavelength, the transmittance was almost 100%, while a sharp decrease was observed below 300 nm (FIGS. 2, 3 and 22). In the case of lower wavelength the transmittance decreased with increasing thickness of the layer on the disc (FIG. 22).

(38) Initial In Vivo Tests I

(39) It was assessed whether the spray or gel formulation of the composition has any effect on the minimal erythema dose (MED) during ultraviolet light therapy in the therapeutic range of wavelengths. MED was determined on skin surfaces with and without pre-treatment. Light source for the experiments was a selective ultraviolet B phototherapy (SUP) lamp with the following properties: (292.5-335 nm), and a TH-1 Skintester (280-320 nm). During the test 50 mJ/cm.sup.2-1000 mJ/cm.sup.2 light was applied. At the given wavelength there was no significant difference in MED between untreated and pre-treated skin areas for either light source.

(40) In the following in vivo SPF values were measured according to COLIPA standards (light source was an SPF Solar Simulator Model 16S 150W, Solar Light Co.). In the wide range of wavelengths defined above SPF was <2, which means that due to their selective transmittance properties shown in the ultraviolet B spectrum, both the solution and the gel formulations of the composition have different mechanism of action than a common sunscreen. In subjects with dry skin both the solution and the gel formulation of the composition facilitated the penetration of ultraviolet B radiation into the skin and MED values were therefore a bit higher than in subjects with normal or oily skin.

(41) Study Participants

(42) 20 patients with chronic plaque psoriasis (15 males, 5 females) between 18 and 65 years of age (mean age: 47.6 years) were enrolled into the study. At baseline, mean body surface area (BSA) affected by psoriasis was 12.9%. Patients for whom ultraviolet B light therapy was contraindicated were excluded from the study. Four patients received oral acitretin (25 mg/day) and 18 patients were treated by narrow-band ultraviolet B light therapy. One patient was subject to XeCl excimer laser therapy and another patient received oral PUVA therapy.

(43) Light Therapy

(44) Light therapy was performed using a Waldmann UV5000 cabinet equipped with Waldmann F85/100W-UV01 tubes, a Waldmann UV7001K cabinet equipped with Waldmann F85/100W-PUVA tubes, and a Photomedex Xtrac 308 nm XeCl excimer laser, respectively.

(45) Patients were randomized into 2 treatment groups. Pre-treatment prior to light therapy was accomplished with the solution formulation of the composition in 10 patients and with the gel formulation of the composition in the remaining 10 patients. In both groups left and right sides of the body were compared to each other. For each patient one or two symmetrical plaque pairs were identified as target lesions for assessment. Regarding all 20 patients enrolled into the study, altogether 40 plaque pairs were identified. Target plaques were located on the upper or lower extremities or on the chest. One side of the body was randomly assigned for pre-treatment with the solution or gel formulation of the composition, while the other side of the body was pre-treated with liquid paraffin. Patients were blinded for the pre-treatment protocol. Before pre-treatment all plaques were assessed for size, infiltration and the severity of erythema according to a scale with the following values: 0=none; 1=mild; 2=moderate; 3=severe; 4=very severe. Scores were then summarized. A blinded investigator, who was not familiar with the pre-treatment protocol, performed the clinical assessment of plaques at baseline and in every two weeks thereafter. Pre-treatment was conducted by a qualified nurse a few minutes before each light therapy session. The trial was completed when the score for a particular plaque became equal to zero. Patients received treatments 2 to 3 times a week. At the end of the light therapy period, patients were asked about their preference for pre-treatment type.

(46) Statistical Analysis

(47) For each plaque pair comparison between sides pre-treated with liquid paraffin and the solution or gel formulation was performed by Spearman's rank correlation test (SPSS 15.0 software).

(48) Results

(49) Composition in Spray Form

(50) In the group randomized for pre-treatment with the solution formulation of the composition, the trial was completed in the case of 9 patients. One subject dropped out from the trial due to the rapid progression of psoriasis that required systemic therapy. Mean plaque severity score was 6.64 for the body side pre-treated with the solution and gel formulation of the composition as we intended to choose comparable plaques. However, it was uncertain whether there is a significant difference in the improvement (target plaque score) between the sides pre-treated with liquid paraffin and the solution formulation of the composition. Assessments were done at week 4 in two patients and at week 6 in eight patients. Table 1 shows mean PASI scores for body sides pre-treated with liquid paraffin and the solution formulation of the composition at weeks 0, 2, 4 and 8.

(51) TABLE-US-00004 TABLE 1 Week 0 Week 2 Week 4 Week 6 liquid liquid liquid liquid paraffin solution paraffin solution paraffin solution paraffin solution Plaque 6.65 ± 6.65 ± 4.76 ± 4.82 ± 4.00 ± 3.65 ± 1.38 ± 0.85 ± score 1.32 1.32 1.20 1.18 2.45 2.64 1.19 0.80

(52) As shown in Table 2, there is at least a moderately strong positive correlation between scores for plaques pre-treated with liquid paraffin and those for plaques pre-treated with the solution or the gel formulation and all values significantly differ from zero. Therefore, liquid paraffin and the solution formulation of the composition seem to be interchangeable with each other.

(53) TABLE-US-00005 TABLE 2 Week 0 Week 2 Week 4 Week 6 Spearman's R Spearman's R Spearman's R Spearman's R Erythema 1.000 1.000 0.882 0.795 Size 1.000 0.835 1.000 1.000 Infiltration 1.000 0.704 0.853 0.589 Altogether 1.000 0.706 0.932 0.657
Composition in Gel Form

(54) In the group assigned for pre-treatment with the gel formulation of the composition, the trial was completed in the case of all 10 patients. Mean plaque severity score was 6.91 for the body side pre-treated with the gel formulation of the composition and 6.83 for the body side pre-treated with liquid paraffin. Similarly to patients in the solution pre-treatment group, we selected target plaques suitable for comparison. However, it was uncertain whether there is a significant difference in the improvement (target plaque score) between sides pre-treated with liquid paraffin and the gel formulation of the composition. Assessments were done at week 4 in one patient, at week 6 in six patients and at week 8 in three patients. Table 3 shows mean PASI scores for body sides pre-treated with liquid paraffin and the gel formulation of the composition at weeks 0, 2, 4 and 8.

(55) TABLE-US-00006 TABLE 3 Week 0 Week 2 Week 4 Week 6 Week 8 liquid liquid liquid liquid liquid paraffin gel paraffin gel paraffin gel paraffin gel paraffin gel plaque 6.83 ± 6.91 ± 4.35 ± 4.83 ± 2.70 ± 3.35 ± 1.52 ± 1.52 ± 1.77 ± 1.55 ± score 1.11 1.12 0.88 1.11 1.92 1.90 1.57 1.63 1.72 1.59

(56) As shown in Table 4, there is at least a moderately strong positive correlation between scores for plaques pre-treated with liquid paraffin and those for plaques pre-treated with the solution or the gel formulation and all values significantly differ from zero. Therefore, liquid paraffin and the solution formulation of the composition seem to be interchangeable with each other.

(57) TABLE-US-00007 TABLE 4 Week 0 Week 2 Week 4 Week 6 Spearman's R* Spearman's R Spearman's R Spearman's R Erythema 1.000 0.942 0.937 0.961 Size 0.920 0.550 0.456 1.000 Infiltration 0.936 0.377 0.701 0.771 Altogether 0.903 0.620 0.770 0.946 *Spearman's rank correlation coefficient
Tolerability

(58) After completing the treatments patients were asked about their preference for the pre-treatment, i.e. which pre-treatment regimen they found the least unpleasant. The question was as follows: “Which pre-treatment did you find to be cosmetically more acceptable? The pre-treatment on the left side or on the right side of your body?” During the study data were also collected on the patients' subjective attitude to the pre-treatment. According to their reports, patients did not experience any adverse effects. Preference rates in the different groups were 7:2 (solution vs. liquid paraffin; 1 patient reported no difference between sides) and 9:1 (gel vs. liquid paraffin), respectively.

(59) Safety

(60) One subject dropped out from the trial due to the rapid progression of psoriasis that required systemic therapy. However, relation between aggravation of psoriasis and the trial was improbable. No adverse events were reported either in the solution or in the gel group.

(61) Initial In Vivo Tests II

(62) In our trial conducted in August 2011, 60 patients suffering from chronic plaque psoriasis were enrolled. Patients were treated by heliotherapy applying a common sunscreen with SPF 30 on symptom-free skin and the gel formulation of the composition on psoriatic plaques, immediately before sunbathing. The two-part study kit included therefore a common sunscreen with SPF 30 and the gel formulation of the composition.

(63) Depending on the number of days with sunshine, patients received the study treatment 4 to 5 times a week, for 4 weeks.

(64) From among the 60 patients enrolled into the study, psoriatic symptoms were improved by >90% in 38 subjects, while 75-90% improvement were detected in 16 patients and 50-75% improvement in 6 patients, respectively. Worsening of psoriatic plaques or sunburn on symptom-free skin was not occurred in any of the patients. Patient found the administration of the two different compositions (one for the symptom-free skin surface and one for the psoriatic plaques) convenient and comfortable.

(65) Results led to conclude that the combination treatment scheme, i.e. pre-treatment of psoriatic lesions with the gel formulation of the composition and the application of a common sunscreen on the symptom-free skin at the same time is a favourable regimen for heliotherapy.

INDUSTRIAL APPLICABILITY

(66) Favourable effects of ultraviolet B radiation are utilized in the treatment of several dermatological disorders. However, due to certain physiological and pathophysiological features of the psoriatic skin (disintegration of stratum corneum, parakeratosis) its upper layer is characterized by an increased reflection and scattering of incident light. Therefore, effectiveness of light therapy does not reach the desired level while higher doses of radiation may increase the risk of adverse effects. Optical enhancement of skin transmittance may result in higher effectiveness of light therapy but only a specific part of the ultraviolet B spectrum is suitable for therapeutic purposes. Ultraviolet B radiation ranging from 280 to 320 nm wavelength has only a lower therapeutic effect but causes more severe skin inflammation while the spectral range between 310-320 nm demonstrates higher therapeutic effectiveness and a reduced pro-inflammatory potential.

(67) The advantage of the present invention is thus, on the one hand, to facilitate the penetration of the therapeutically effective part of the ultraviolet B radiation into the skin and, on the other hand, to protect against the unwanted ranges of ultraviolet B spectrum which enables to use higher doses of ultraviolet B radiation during light therapy. By means of the present invention the effectiveness of light therapy will be enhanced while harmful side effects avoided.

(68) The composition according to the present invention is photostable, non-photosensitizing and does not absorb the therapeutically active spectrum of ultraviolet B radiation. Further advantage of the composition according to the present invention is that it is cosmetically acceptable for the treated subjects. All components of the composition according to the present invention are well-tolerated and safe and neither of them alone nor as a mixture render the skin oily or fatty or stain clothing.

(69) The above properties enable the composition according to the present invention to amend heliotherapy with an effective protection against the harmful part of ultraviolet radiation in various skin disorders. Several psoriatic patients prefer natural sunlight as treatment. In order to avoid sunburn, appropriate sunscreen should be applied on normal uninvolved skin. Application of a sunscreen is, however, not recommended on psoriatic skin as it may block the penetration of light into the plaques. In addition, the scaly, hyperkeratotic surface of the lesions can also reflect light. Different compositions can reduce this negative effect. Several investigations have demonstrated that the various emollients exert a sun protective effect. Compositions developed by the inventors enable a proper pre-treatment before sunbathing as they have the appropriate transmission spectrum, filter unnecessary wavelengths of ultraviolet radiation and are cosmetically well tolerated.