Topical semisolid composition containing an antimicrobial agent and pirfenidone for the treatment of chronic skin damage

Abstract

The invention provides topical pharmaceutical gel compositions for the treatment of chronic skin damage, specifically for damage caused by neuropathic ulcers and preferably for the treatment of diabetic foot, and in the treatment of vascular ulcers wherein said compositions comprise a combination of Modified Diallyl Disulfide Oxide (M-DDO) (as an antiseptic/antibiotic agent) and 5-methyl-1-phenyl-2(1H)-pyridone. Furthermore, the invention describes methods of treatment, applications and/or pharmaceutical uses in the preparation of medicaments for eliminating, reducing or preventing chronic skin lesions and the damages caused by neuropathic ulcers and particularly in the treatment of diabetic foot and in the treatment of vascular ulcers.

Claims

1. A method of treating chronic skin damage in a subject in need thereof, the method comprising administering to skin of the subject a topical pharmaceutical gel composition comprising modified-diallyl disulfide oxide, 5-methyl-1-phenyl-2(1H)-pyridone, and one or more pharmaceutically acceptable excipients; wherein the chronic skin damage is caused by vascular ulcers, decubitus ulcers, arterial ulcers, or venous ulcers.

2. The method of claim 1, wherein the composition comprises from 0.01 to 0.1% weight/weight of modified-diallyl disulfide oxide, from 5 to 10% weight/weight of 5-methyl-1-phenyl-2(1H)-pyridone, and from 89% to 95% weight/weight of one or more pharmaceutically acceptable excipients.

3. The method of claim 1, wherein the one or more pharmaceutically acceptable excipients are gel-forming agents, neutralizing agents, wetting agents, flavoring agents, stains, and aqueous solvent.

4. The method of claim 3, wherein the gel-forming agent is selected from the group consisting of Carbomer, Carbopol 940, Carbopol 940P, Neopol 40, glycerin polyacrylates, crosslinked alkyl acrylates, polyacrylamides, acrylic acid polymers, methylcellulose, polyethylene glycols of high molecular weight, and sodium carboxymethyl cellulose.

5. The method of claim 3, wherein the neutralizing agent is selected from the group consisting of amines, sodium hydroxide, potassium hydroxide, triethanolamine, aminomethylpropanol, and 2,2′,2″-nitrilotrietanol.

6. The method of claim 3, wherein the wetting agent is selected from the group consisting of polyols, glycerin, sorbitol, propylene glycol, polyethylene glycol, and 1,2-propanediol.

7. The method of claim 3, wherein the flavoring agent and the stain are selected from the group comprising natural essences, essential oils, extracts, balsams, compounds isolated from natural essences, compounds isolated from aromatic sapid chemical compound extracts, or compounds isolated from artificial sapid chemical compound extracts.

8. The method of claim 1, wherein the composition comprises an aqueous solvent selected from the group comprising water and mixtures of water-soluble alcohol and water.

9. The method of claim 3, wherein the gel-forming agent is present in an amount equivalent to 0.5 to 1.5% weight/weight of the composition.

10. The method of claim 3, wherein the wetting agent is present in an amount equivalent to 38 to 45% weight/weight of the composition.

11. The method of claim 3, wherein the neutralizing agent is present in an amount equivalent to 0.5 to 1.5% weight/weight of the composition.

12. The method of claim 3, wherein the flavoring agents and the dye stains are each present in an amount not greater than 0.01% weight/weight of the composition.

13. The method of claim 1, wherein the chronic skin damage is caused by vascular ulcers.

14. The method of claim 1, wherein the chronic skin damage is caused by decubitus ulcers.

15. The method of claim 1, wherein the chronic skin damage is caused by arterial ulcers.

16. The method of claim 1, wherein the chronic skin damage is caused by venous ulcers.

17. The method of claim 1, wherein the composition comprises: (i) 8% 5-methyl-1-phenyl-2(1H)-pyridone by weight; (ii) 0.016% modified-diallyl disulfide oxide by weight; (iii) 1% Carbomer 940 by weight; (iv) 40% propylene glycol by weight; (v) 1% triethanolamine by weight; and (vi) 49.984% water by weight.

18. The method of claim 1, wherein the composition comprises: (i) 8% 5-methyl-1-phenyl-2(1H)-pyridone by weight; (ii) 0.016% modified-diallyl disulfide oxide by weight; (iii) 1% Carbomer 940 by weight; (iv) 50% propylene glycol by weight; (v) 1% triethanolamine by weight; (vi) 13% macrogol-glycerol hydroxystearate by weight; and (vii) 26.984% water by weight.

19. The method of claim 1, wherein the composition comprises: (i) 6% 5-methyl-1-phenyl-2(1H)-pyridone by weight; (ii) 0.02% modified-diallyl disulfide oxide by weight; (iii) 1% acrylamide/copolymer of sodium acryloylmethyl fumarate, isohexadecane polysorbate by weight; (iv) 1% 2,2′,2″-nitrilotrietanol by weight; (v) 2.5% 1,2-propanediol by weight; and (vi) 89.479% water by weight.

20. The method of claim 1, wherein the composition comprises: (i) 8% 5-methyl-1-phenyl-2(1H)-pyridone by weight; (ii) 0.016% modified-diallyl disulfide oxide by weight; (iii) 1% Carbomer 940 by weight; (iv) 1% 2,2′,2″-nitrilotrietanol by weight; (v) 40% 1,2-propanediol by weight; and (vi) 49.974% water by weight.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1. 67 years old male treated with pirfenidone with an initial RUV of 48 cm and an RRUV of 91.7%

(2) FIG. 2. 53 years old male treated with pirfenidonc with an initial RUV of 18 cm and an RRUV of 88.3%

(3) FIG. 3. 47 years old male treated with pirfenidone with an initial RUV of 11.8 cm and an RRUV of 71.2%

(4) FIG. 4. 49 years old male treated with pirfenidone with an initial RUV of 6.4 cm and an RRUV of 93.8%

(5) FIG. 5. 63 years old male treated with pirfenidone with an initial RUV of 16 cm and an RRUV of 80.9%

(6) FIG. 6. 67 years old female treated with ketanserin with an initial RUV of 2.5 cm and an RRUV of 38.8%

(7) FIG. 7. 56 years old male treated with ketanserin with an initial RUV of 5.9 cm and an RRUV of 27% FIG. 8. 53 years old female treated with ketanserin with an initial RUV of 42 cm and an RRUV of 26.6%

(8) FIG. 9. 57 years old male treated with ketanserin with an initial RUV of 5 cm and an RRUV of 40%

DESCRIPTION OF THE INVENTION

(9) The present invention relates to topical pharmaceutical compositions comprising a combination of 5-methyl-1-phenyl-2(1H)-pyridone (Pirfenidone) and some topical antibiotic agent, which comprise 0.01 to 5% w/w of the antimicrobial agent, from 5% to 10% w/w of the composition of 5-methyl-1-phenyl-2(1H)-pyridone, and from 85 to 95% w/w of the composition of one or more suitable excipients for the preparation of the gel.

(10) Specifically, the invention relates to topical pharmaceutical compositions comprising a combination of Modified Diallyl Disulfide Oxide (M-DDO) and 5-methyl-1-phenyl-2(1H)-pyridone (Pirfenidone) topically applied, which comprise 0.01 to 0.1% weight/weight of the composition of M-DDO, 5% to 10% weight/weight of the composition of 5-methyl-1-phenyl-2(1H)-pyridone, and 89% to 95% weight/weight of the composition of one or more suitable excipients for the preparation of the gel.

(11) Formulation of Topical Gels

(12) The topical application of the combination of the aforementioned molecules is clearly reinforced by the formulation of the pharmaceutical compositions in gel form.

(13) They are called gels (from the Latin gelu—cold, or gelatus—frozen, immobile) to transparent colloids; semisolids, which can be suspensions of small inorganic particles, or large organic molecules interpenetrated by a liquid that do not usually have fatty oils, intended to be applied on the mucous membranes, have no penetration power, that is why it is used to exert topical action (from surface). The common characteristic of them is the presence of a type of continuous structure that gives them the properties of semisolids.

(14) The fact that an active substance is adsorbed, penetrates, permeates the skin or is absorbed, depends on its physical and chemical properties, such as its solubility in water, its lipid-water partition coefficient, its dissociation constant, its chemical structure and its molecular weight. In addition, it depends on the properties of the active principle once it is incorporated in a pharmaceutical form, for example, the pH, the nature of the vehicle, etc., as well as the type of barrier that will cross, which may present morphological and functional variations and others such as the presence of electric charges.

(15) In the absorption site, the active ingredient must cross a lipid rod, which can be a complex barrier such as skin or the intestinal epithelium. This passage can be carried out according to several mechanisms:

(16) TABLE-US-00001 Passive diffusion Facilitated diffusion Conective absorption Absorption by ion-couple Active transport Pinocytosis

(17) In the design of a gel, it is essential to select a formulation that presents organoleptic and rheological characteristics suitable for its topical administration, with appropriate extensibility and texture. It is also important to make sure that the preparation is aesthetically acceptable to the patient and easy to use.

(18) Several factors must be keep in mind: Choice of the active ingredients necessary to obtain the desired therapeutic action. Choice of the pharmaceutical form and suitable excipients. Evaluation of the compatibility of the active principles with the possible excipients. Consideration of the dermatological effects of the vehicle.

(19) Gels can by classified into: Organic or inorganic according to their nature. Aqueous (hydrogels) or organic (organogels), depending on whether the aqueous component is water or some organic solvent. Colloidal or coarse grain, depending on the size of the particles. Rigid, elastic or thixotropic gels, according to their mechanical properties.

(20) The advantages in the use of gels are, among others: they are well tolerated, easily washable and produce freshness. For the appropriate selection of the type of gel, it is considered that they must meet the following general characteristics: pH: neutral or weakly acid, the closest thing to the skin's pH, physical and chemical stability, as well as compatibility with the active ingredients that are incorporated, rheological properties must provide the preparation with adequate extensibility and adaptability to the surface and skin cavities. For this, it is recommended that they have plastic-thixotropic type flows, characterized by an increase in fluidity during application, followed by a recovery of the initial texture after the drug has been extended, which allows it to be localized and adhered to the treated area. The possibility of being eliminated from the treated area by simple washing. However, this recommendation should not, in any case, influence the general appearance of the medication, as, for example, with those pathologies that require the rejection of highly occlusive fatty vehicles and which, logically, are not washable. They should not stain, as far as possible, neither the skin nor the tissues. They must not present primary irritation or hypersensitization effects.

(21) The criteria for the selection and formulation of a vehicle should be established, based on the type of skin lesion on which it is to be used. The simple appearance or condition of the affected area may be indicative in this regard.

(22) Due to dermatological pathologies can be classified into three general types: acute, chronic and subacute processes or injuries, of intermediate symptomatology to the two previous ones; the vehicles, in turn, are classified in three groups depending on the type of injury for which they should preferably be used.

(23) Possibility of desiccation of wounds, on the one hand, and the characteristics of occlusion, on the other, are the two properties that, in a general way, are more representative of the vehicles used for the formulation of dermatological medicines used for the treatment of severe and chronic processes.

(24) Among the excipients for the preparation of the gels are gel-forming agents, neutralizing agents, wetting agents, or flavoring and coloring agents. These are derived from a variety of natural and artificial substances that give it its texture, viscosity, stability and microstructure.

(25) The gelling agent is selected from the group comprising: Carbomer, Carbopol 940, Carbopol 940P, Neopol 40, glycerin polyacrylates, crosslinked alkyl acrylates, polyacrylamides, acrylic acid polymers, methylcellulose, high molecular weight polyethylene glycol, sodium carboxymethyl cellulose. Those gel-forming agents can be obtained under their trade name, for example: Carbopol, Ultrez 21, Hispogel, Pemlente; Simugel 600, Sepigel 305 and Methocel A.

(26) The neutralizing agents are selected from the group consisting of amines, sodium hydroxide, potassium hydroxide, triethanolamine, aminomethylpropanol, 2,2′,2″-nitrilotrietanol.

(27) The wetting agent is selected from the group consisting of polyols, glycerin, sorbitol, propylene glycol, polyethylene glycol, 1,2-propanediol.

(28) The flavoring agent and the colorant are selected from the group comprising natural essences or essential oils; extracts, balsams, compounds isolated from natural essences or from aromatic or artificial sapid chemical compound extracts.

(29) An aqueous solvent is selected from the group comprising purified water and mixtures of watersoluble alcohol-water.

(30) Based on the foregoing, the composition of the present invention, for example, may comprise a gelling agent that is present in an amount equivalent to 0.5 to 1.5% w/w of the composition; a wetting agent that is present in an amount equivalent to 38 to 45% w/w of the composition; a neutralizing agent that is present in an amount equivalent to 0.5 to 1.5% w/w of the composition; a flavoring agent and the colorant which are present in an equivalent amount each not greater than 0.01% w/w of the composition and/or a solvent that is present in a quantity g.s (c.b.p.) 100 grams of the gel.

(31) Thus, it is possible to make a wide range of gel compositions such as those exemplified below:

Example 1. Topical Formulation in Gel

(32) It was prepared a gel composition containing:

(33) TABLE-US-00002 Component g Pirfenidone 8 M-DDO 0.016 Carbomer 940 1 Propylene glycol 40 Triethanolamine 1 Purified water q.s 100

Example 2

(34) It was prepared a second composition containing the following elements:

(35) TABLE-US-00003 Component Kg Pirfenidone 6 M-DDO 0.02 acrylamide/copolymer of sodium acryloylmethyl fumarate, 1 isohexadecane polysorbate 2,2′,2″-nitrilotrietanol 1 1,2-propanediol 2.5 Floral fragrance 0.001 Purified water q.s 100

Example 3

(36) A third composition was prepared containing the following elements:

(37) TABLE-US-00004 Component g Pirfenidone 8 M-DDO 0.016 Carbomer 940 1.00 Propylene glycol 50 Triethanolamine 1.00 Purified water q.s 100 Macrogolglycerol hydroxystearate 40 13

Example 4

(38) A fourth example of the compositions object of the present invention is presented, which demonstrates that the modalities thereof are limited only to the preservation of the characteristics of all the components in the gel:

(39) TABLE-US-00005 Component Kg Pirfenidone 8 M-DDO 0.016 Carbomer 940 1 2,2′,2″-nitrilotrietanol 1 1,2-propanediol 40 Pink stain 0.01 Purified water q.s 100

(40) Next, a process for preparing the topical formulation in gel form is described.

(41) 1. Mixture A

(42) 1.1. Place 45 L of purified water in the Reactor. 1.2. Gradually add the following material: Carbomer 940 (2 kg). 1.3. Start stirring constantly at 71-rpm±10% for 3 hours with 30 minutes; 5 minutes before finished the 3 hours and 30 minutes, turn on the homogenizer. 1.4. Homogenize for 5 minutes at a speed of 3900-rpm±10%.
Identify as Mixture “A”
2. Solution “A” 2.1.1. Place in the stockpot and heat at (45° C.-50° C.) the propylene glycol (100 kg) move the speed controller to position 30 and stir. 2.1.2. Gradually add PIRFENIDONE (5-METHYL-1-PHENYL-2-(1H)-PIRIDONE), 16.000 Kg and keeping heating at (45° C.-50° C.) until complete dissolution: Keep stirring with the controller speed at position 50 and heating for 30 minutes. 2.1.3. Gradually add MACROGOLGLICEROL HIDROXIESTEARATO 40 26.000 Kg maintaining the constant agitation and heating at (45-50° C.) until complete dissolution: Keep stirring with the speed controller in position 50 and heating for 30 minutes. 2.1.4. Gradually add maintaining the constant agitation and heating at (45-50° C.) until complete dissolution: MODIFIED-DIALLYL DISULFIDE OXIDE AT 2% 1.6 kg. Keep stirring with the controller speed at position 50 and heating for 30 minutes. Identify as SOLUTION “A” 2.2. SOLUTION “B” 2.2.1. Place in a 15-liter capacity stainless steel container: 7.4 L Purified Water and 85% triethanolamine 2 kg. 2.2.2. Stir until obtain a homogenous solution at a speed of 300-rpm±5%. Identify as SOLUTION “B” 2.3. FINAL MIXTURE 2.3.1. Add with constant agitation SOLUTION “A” to the Reactor with MIXTURE “A”. 2.3.2. Add with constant agitation SOLUTION “B”. 2.3.3. Shake constantly at a speed of 71-rpm±10%, for 90 minutes. 2.3.4. After the mixing time, turn on the homogenizer for 15 minutes at a speed of 3900-rpm±10% and maintain the stirring simultaneously for the same period.

Experimental Design

(43) Gene Behavior of Patients with Diabetic Foot Ulcer Treated for One Month with Pirfenidone+MDDO or Ketanserin.

(44) Clinical trials were conducted as of March 2013 in Hospitals of the Federal District, metropolitan area and Guadalajara, Jalisco following patients scrupulously.

(45) We studied 20 patients with diabetic foot ulcers. 10 were treated with 8% pirfenidone and 0.016% MDDO (Kitoscell Q™) and 10 treated with Ketanserina (Sufrexal™).

(46) Prior to the application of the composition, the damaged area is cleaned, either by washing with neutral soap and abundant water or any other cleaning method normally used. In case the patient has the wound covered with gauze, the gauze is impregnated with an antiseptic solution before removing it and thus prevent the granulation tissue from detaching. In case of necrotic tissue, it is necessary to debride the wound to remove it.

(47) Once the damaged area is cleaned and dried, the gel object of the present invention is applied on the wound or ulcer, starting from the outer edge toward the center. It can be used gauze or bandage to place it on the injury.

(48) The clinical/morphological analyzes shown in table 1 were performed by medical specialists who did not know which patients were treated with a certain medication at the first month of treatment (three times a day with 8% pirfenidone gel+0.016% MDDO after cleaning the affected region, and three times a day with ketanserin).

(49) TABLE-US-00006 TABLE 1 Percentage of reduction of the relative ulcer volume (RUV) in patients treated with pirfenidone + MDDO and ketanserin, during a month, measured with the Kundin rule in cm. 1.sup.st Initial month First Pa- Treat- RUV.sup.1 RUV Initial month tient Age ment cm.sup.3 cm.sup.3 RUV % RUV % RRUV.sup.2 % 1 67 PFD.sup.3 48.0 4.0 100 8.3 91.7 2 53 PFD 18.0 2.1 100 11.7 88.3 3 49 PFD 6.4 0.4 100 6.3 93.8 4 47 PFD 11.8 3.4 100 28.8 71.2 5 63 PFD 16.0 3.1 100 19.1 80.9 6 67 KTS.sup.4 2.5 1.5 100 61.2 38.8 7 56 KTS 5.9 4.3 100 73.0 27.0 8 53 KTS 42.0 30.8 100 73.4 26.6 9 57 KTS 5.0 3.0 100 60.0 40.0 .sup.1Relative ulcer volume. .sup.2Percentage of reduction of relative ulcer volume. .sup.38% Pirfenidone + 0.016% MDDO .sup.4Ketanserin
Results
Gene Behavior of Patients with Diabetic Foot Ulcer Treated for One Month with Pirfenidone+MDDO or Ketanserin.

(50) Twenty patients with diabetic foot ulcers were studied. Ten were treated with 8% pirfenidone+0.016% M-DDO (Kitoscell Q™) and 10 treated with Ketanserina (Sufrexal™).

(51) The clinical/morphological analyzes shown in Appendix 1 were performed by medical specialists who did not know which patients were treated with a certain drug at the first month of treatment (three times a day with 8% pirfenidone gel+0.016% MDDO after cleaning the affected region, and three times a day with ketanserin).

(52) The difference in the percentage of reduction of the relative ulcer volume of patients treated with Kitoscell Q is evident when compared to the size and dimensions of the ulcer in patients treated with ketanserin. In other words, the wound in the first heals at a higher speed. The photographs show images of representative patients.

(53) The increase of pro-inflammatory cytokines modifies the normal balance, thus inducing the production of TGF-β1. Due to these conditions, there is a delay in re-epithelialization and extracellular matrix production, as shown in FIG. 1.

(54) To demonstrate the induction of collagenic and non-collagenic proteins involved in the process of REGENERATION/REPAIR OF THE WOUND and of the proteins that are necessary in the subsequent process of re-epithelialization, we proceeded to take biopsies of ulcerous tissue from each of the patients to analyze the expression of target genes that code for the production of those proteins.

(55) Thus, 83% of patients treated with pirfenidone+MDDO showed a dramatic and significant increase in COL1α expression in the first month of treatment, while only 43% of patients treated with ketanserin showed a slight increase. It is noteworthy that the relative units of gene expression of each of the mentioned genes was 20 to 200 times higher in patients treated with pirfenidone+MDDO.

(56) Another fundamental protein in the process of extracellular matrix formation is TGFβ1.

(57) During the first month of treatment, 50% of patients treated with pirfenidone+MDDO showed an increase in TGFβ1 gene expression. The increase was found in the same patients who expressed high regulation of COL1α. However, in the protocol arm with Ketanserin patients showed an increase in only 29% of them.

(58) The 40% of patients treated with pirfenidone+MDDO showed a considerable increase in TGFβ3 expression in the first month of treatment. The increase was found in the same patients who expressed high regulation of COL1α and TGFβ1.

(59) TGFβ3 is a protein that plays a key role in the re-epithelization of tissues after having suffered considerable and extensive damage.

(60) Finally, 50% of patients treated with pirfenidone+MDDO showed an increase in the expression of KGF (Keratinocyte growth factor) that promotes cell migration, accelerates the regeneration of wounds in response to damage of the skin or its internal structures. KGF is a paracrine growth factor derived from mesenchymal cells that specifically stimulates the growth of epithelial cells.

(61) At last, all these results demonstrate the PIRFENIDONE MODULATOR ROLL IN THE REGENERATION/REPAIR OF WOUNDS. This effect is enhanced by the antiseptic effect of MDDO, by avoiding infection of the wound; it allows the therapeutic effect of PIRFENIDONE.

(62) Although the present invention has been described with respect to a limited number of embodiments, the specific characteristics of an embodiment should not be attributed to other embodiments of the invention. An individual embodiment is not representative of all aspects of the invention. In some embodiments, the compositions or methods may include numerous compounds or steps not mentioned herein. In other embodiments, the compositions or methods do not include, or are substantially free of, compounds or steps not indicated herein. Variations and modifications exist from the described embodiments.