PUTRESCINE TOPICAL BARRIER FORMULATION

Abstract

The present invention describes stable topical barrier compositions comprising primary polyamines and uses thereof for protecting the skin from external stressors, for improving skin's moisture and fort stimulating healing of the skin. These compositions may be used in a variety of cosmetic and therapeutic applications including for promoting wound healing, for reducing or preventing the formation of hypertrophic scar tissue, for reducing or preventing skin irritation and inflammation, for increasing skin's moisture and/or for reducing or preventing skin's signs of aging.

Claims

1. A topical water free barrier composition comprising: (i) a polyamine; (ii) a phospholipid to encapsulate the primary polyamine; (iii) petroleum jelly; and (iv) mineral oil.

2. The barrier composition of claim 1, wherein the polyamine is a primary aliphatic lower-alkyl (C1-5) monoamine, preferably aminoacetonitrile; a primary aliphatic alkylamine, preferably spermine or spermidine; or a primary aliphatic lower-alkyl (C1-5) polyamine, preferably putrescine or dansylcadaverine.

3. The barrier composition of claim 1, wherein the polyamine is aminoacetonitrile; spermine or spermidine; or putrescine or dansylcadaverine, preferably putrescine.

4. The barrier composition of claim 3, wherein the putrescine is in a concentration of between about 0.1% w/w to about 1% w/w; about 0.4% w/w; or about 0.8% w/w.

5. The barrier composition of claim 1, wherein the petroleum jelly is in a concentration of between about 25% w/w and 65% w/w; or about 45% w/w.

6. The barrier composition of claim 1, wherein the mineral oil is in a concentration of between about 30% w/w and about 45% w/w; or of about 35% w/w.

7. The barrier composition of claim 1, wherein the phospholipid is a quaternary ammonium salt.

8. The barrier composition of claim 7, wherein the quaternary ammonium salt is cocamidopropyl PG-dimonium chloride phosphate.

9. The barrier composition of claim 8, wherein the cocamidopropyl PG-dimonium chloride phosphate is in a concentration of between about 3% w/w and about 6% w/w; or about 4% w/w.

10. The barrier composition of claim 1, further comprising (i) paraffin; (ii) lanolin oil; (iii) a lipophilic Vitamin C derivative; (iv) one or more humectants; and/or (v) bisabolol.

11. The barrier composition of claim 10, wherein the paraffin is in a concentration of between about 3% w/w and 15% w/w; or about 8.5% w/w.

12. The barrier composition of claim 10, wherein the lanolin oil is in a concentration of between about 3% w/w and 6% w/w; or about 5% w/w.

13. The barrier composition of claim 10, wherein the lipophilic Vitamin C derivative is in a concentration of between about 0.1% w/w and 10% w/w.

14. The barrier composition of claim 10, wherein the lipophilic Vitamin C derivative comprises 3-O-Ethyl Ascorbic Acid (3-O-EAA).

15. The barrier composition of claim 14, wherein the 3-O-EAA is in a concentration of about 0.5% w/w.

16. The barrier composition of claim 10, wherein the one or more humectants is(are) in a concentration of between about 0.5% w/w and 3% w/w.

17. The barrier composition of claim 10, wherein the one or more humectants comprise(s) glycerin, vitamin B5 or a combination thereof.

18. The barrier composition of claim 17, wherein the one or more humectants comprise(s) about 1% w/w of the glycerin and about 1% w/w of the Vitamin B5.

19. The barrier composition of claim 10, wherein the bisabolol is in a concentration of between about 0.1% w/w and 1% w/w; or about 0.5% w/w.

20. A method of using the barrier composition defined in claim 1, for (i) treating or preventing skin inflammation, skin's signs of aging and/or skin irritation; (ii) promoting wound healing; or (iii) preventing or reducing the formation of hypertrophic scar tissue.

Description

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0080] Not all cosmetic products are alike. Important factors affecting cosmetic and therapeutic results include the stability of the active ingredient(s) in the compositions, their solubility in the desired carrier and their ability to penetrate the skin and reach its targeted layer(s). Applicants have developed new non-aqueous (substantially water free) topical barrier compositions in which the active ingredients (e.g., putrescine and derivatives thereof) are stable and soluble in an ointment-like base, thereby protecting the skin from external irritants and contaminants and enabling the active ingredients to reach the cells and provide the desired effect.

[0081] A key ingredient of the composition of the present invention is a polyamine such as 1,4-Diaminobutane Dihydrochloride (also called Putrescine Dihydrochloride, or 1,4-DAB). The 1,4-DAB molecule has unique cellular properties. It promotes healing and repair at the cellular level, preserves skin elasticity and enhances skin smoothness. 1,4-DAB may lengthen the lifespan of a skin cell and thicken cellular matrix to rejuvenate skin, and therefore may reduce downtime for patients after skin treatment such as laser or peeling, or after cosmetic surgery intervention (ex. Eyelift, breast augmentation).

[0082] 1,4-DAB, is a highly reactive basic amine salt. It reacts easily with acidic compounds and is thus not very stable. Due to their polar nature, salts such as 1,4-DAB do not usually dissolve in ointment because they need water, which ointment base lacks. Even when they do, they generally become unstable.

[0083] Applicants have found that by encapsulating the primary polyamine (e.g., 1,4-DAB) in a phospholipid such as PG-Dimonium Chloride Phosphate, a stable ointment could be prepared. The encapsulation allows to dissolve the polyamine in an ointment base to provide a homogenous, stable composition.

[0084] Encapsulation in phospholipids such as PG-Dimonium Chloride Phosphate stabilizes the primary polyamine and prevents it from reacting with other ingredients in the ointment, thereby avoiding discoloration of the composition and preserving therapeutic and cosmetic activity. Encapsulation further facilitates delivery of the primary polyamine into the skin.

[0085] Applicants have further found that stability of the ointment composition comprising a primary polyamine and

[0086] Vitamin C could be further improved by using certain forms of Vitamin C derivatives over others. Indeed, L-Ascorbic Acid was difficult to combine with a primary polyamine, even when encapsulated. Moreover, even when liposoluble forms of vitamin C were used, it was found that the stability of the composition could be significantly improved by using 3-O-Ethyl Ascorbic Acid (3-O-EAA) instead of other forms of liposoluble vitamin C derivatives such as ascorbyl palmitate. Compositions comprising a combination of a primary polyamine (e.g., 1,4-DAB) and 3-O-EAA in an ointment base were found to be most stable.

[0087] Topical barrier compositions of the present invention were found to allow proper dissolution of active ingredients (e.g., polyamines) and to be stable thereby enabling the effective penetration and delivery of active ingredients into the skin.

[0088] In a first aspect, the present invention provides a topical barrier composition comprising (i) at least one primary polyamine (e.g., putrescine) in an ointment-like base comprising (ii) petroleum jelly; and (iii) mineral oil. The primary polyamine is encapsulated in phospholipids (e.g., cocamidopropyl PG-dimomium chloride phosphate). In embodiments, the active ingredient further comprises lanolin, glycerin, bisabolol, panthenol and/or a liposoluble Vitamin C derivative.

[0089] The primary polyamines used in accordance with the present invention are preferably amine group terminated linear structures such as unbranched aliphatic compounds (e.g., lower C1-C10, preferably, C1-05 alkyls). Such compounds include, but are not limited to naturally occurring putrescine (1,4-diaminobutane (Cas #333-93-7), H.sub.2N(CH.sub.2).sub.4NH.sub.2), cadaverine (Cas#462-94-2, 1,5-pentanediamine, H.sub.2N(CH.sub.2).sub.5NH.sub.2), spermidine (Cas#124-20-9, 1,4-butanediamine, N1-(3-aminopropyl, H.sub.2N(CH.sub.2).sub.3NH(CH.sub.2).sub.4NH.sub.2), spermine (Cas #71-44-3, 1,4-Butanediamine, N,N′-bis(3-aminopropyl), H.sub.2N(CH.sub.2).sub.3NH(CH.sub.2).sub.4NH(CH.sub.2).sub.3NH.sub.2) and their functional derivatives. The polyamines preferably have (CH.sub.2).sub.n groups linking the nitrogen atoms where n is 2 to 10, preferably 2 to 6, more preferably 2 to 5 and particularly ones comprising 2 to 6 nitrogen atoms, particularly 2, 3 or 4 nitrogen atoms. These polyamines are available from natural sources, e.g., mammalian semen or fermentation products (for example from soy or anchovies), or may be manufactured by conventional techniques, e.g., solid state polypeptide production followed by amidation and reduction. Polyamines useful in accordance with the present invention are described for example in WO2006/048671, U.S. Pat. No. 5,885,982 and CA 2,706,630. The polyamine(s) used in accordance with the invention may conveniently be in salt form with a physiologically tolerable counterion, (e.g., inorganic/mineral acid, an organic acid such as an alpha-hydroxyacid or a fatty acid). Such salts may be prepared by reaction of the polyamine and the acid, e.g., in solution in approximately equimolar amounts.

[0090] Under certain aspects, the total polyamine content in the compositions of the present invention is between about 0.0005 and about 5% w/w (e.g., between about 0.001% w/w and about 1% w/w, between about 0.005% w/w and about 1% w/w, between about 0.1% w/w and about 1% w/w.). Preferably, in compositions for use in stimulating wound healing (e.g., reducing the appearance of scar tissue, including hypertrophic scar tissue), the concentration of putrescine is preferably between about 0.1% w/w and about 1% w/w, more preferably between about 0.4% w/w and about 0.8% w/w.

[0091] Advantageously, the barrier compositions of the present invention comprise phospholipids (e.g., a quaternary ammonium salt) which encapsulates and helps to stabilize and solubilize the primary polymamine. Non-limiting examples of solubilizers for primary polyamines which may be used in the barrier composition of the present invention include cocamidopropyl PG-dimonium chloride phosphate. In embodiments, for a concentration of putrescine of about 0.8% w/w, compositions of the present invention comprise between about 1% and about 6%, preferably between about 3% w/w and about 6% w/w of phospholipids (e.g., quaternary ammonium salt acting as a solubilizer/stabilizer). In embodiments, the phospholipid (solubilizer/stabilizer) is cocamidopropyl PG-dimonium chloride phosphate. In particular embodiments, the barrier compositions of the present invention comprise about 4% of cocamidopropyl PG-dimonium chloride phosphate.

[0092] In the barrier compositions of the present invention, active ingredients are solubilized in a non-aqueous (water-insoluble) “barrier” base which comprises petroleum jelly, and/or mineral oil. In addition to its film-forming properties, which avoid contact with exterior irritants and contaminants, the base also contributes to healing and moisturization the skin. For example, a verified medicinal use of petroleum jelly is to protect and prevent moisture loss of the skin of patients in the initial post-operative period following laser skin resurfacing (Khan, Jemshed A. (2008). “CO2 Laser Resurfacing Immediate Postoperative Care Prior to Complete Epithelialization”. In Hartstein, Morris E.; Holds, John B.; Massry, Guy G. Pearls and Pitfalls in Cosmetic Oculoplastic Surgery. p. 417. doi:10.1007/978-0-387-69007-0_136. ISBN 978-0-387-25389-3 and Jeong, Jeung-Tae; Kye, Young-Chul (2001). “Resurfacing of Pitted Facial Acne Scars with a Long-Pulsed Er:YAG Laser”. Dermatologic Surgery. 27 (2): 107-10. doi:10.1046/j.1524-4725.2001.00201.x. PMID 11207680). It is also largely used to moisturize skin and combat cracking of the skin (e.g., chapped skin). Mineral oil is also one of the safest, most non-sensitizing moisturization ingredients found. Both ingredients are among the most effective and inert moisturization ingredients available.

[0093] In embodiments, the barrier compositions of the present invention comprise between about 25% w/w and about 65% w/w of petroleum jelly (25%, 26%, 27%, 28%, 29%, 30%, 31%, 31%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, or 65%). In embodiments, the barrier compositions comprise between about 40% w/w and 50% w/w of petroleum jelly. In particular embodiments, the barrier compositions comprise about 45% w/w of petroleum jelly.

[0094] In embodiments, the barrier compositions of the present invention comprise between about 25% w/w and about 45% w/w of mineral oil. In embodiments, the barrier composition comprises between about 30% w/w and 50% w/w of mineral oil. In embodiments, the barrier composition comprises about 35% w/w of mineral oil. In particular embodiments, the barrier composition comprises about 34% w/w of mineral oil.

[0095] In addition to petroleum jelly and mineral oil, the barrier composition of the present invention may also comprise a wax (e.g., paraffin such as ceresin wax). The wax is used as a thickener and stabilizer. In embodiments, the barrier compositions of the present invention comprise between about 3% w/w and about 15% w/w of wax. In embodiments, the barrier composition comprises between about 7% w/w and about 10% w/w of wax. In particular embodiments, the barrier composition of the present invention comprises about 8.5% w/w of wax. In embodiments, the wax is paraffin. In embodiments, the paraffin is cerasin. In embodiments, the barrier composition of the present invention comprises about 8.6% of paraffin.

[0096] In embodiments, the barrier compositions of the present invention further advantageously comprise Lanolin. Lanolin's beneficial effects on the human skin and hair have been known and valued by humans for thousands of years. This natural emollient is absorbed by the skin, and is said to help restore its correct moisture balance and softness without impairing natural skin functions. To prevent the intercellular water from evaporation, lanolin lipids form a semi-occlusive film on the skin and create a protective barrier. Accordingly, in embodiments, the barrier composition of the present invention comprise between about 2% w/w and about 10% w/w of lanolin, preferably between 3% w/w and 6% w/w. In particular embodiments, barrier compositions of the present invention comprise between 4% w/w and 5% w/w of lanolin.

[0097] In embodiments, the barrier composition of the present invention preferably further comprises one or more humectants (moisturization ingredients). Preferably, the one or more humectants comprise glycerin and/or Vitamin B5 (panthenol). Humectants such as glycerin and panthenol have the ability to draw water from the environment and the dermis (the lower layers of the skin) into the outer (surface) layer of the skin. They also help to keep the skin barrier intact. Thus, in embodiments, the barrier compositions of the present invention comprise between 0.25% and 15% w/w of an humectant. In embodiments, between zero and 5% w/w, preferably between and 3% w/w of humectants (e.g., glycerin and/or panthenol). In particular embodiments, the barrier compositions of the present invention comprise about 1% w/w of glycerin and about 1% w/w of panthenol.

[0098] Compositions of the present invention may also advantageously include bisabolol. Bisabolol is a scent ingredient naturally occurring in camomile. It is known to have anti-irritant, anti-inflammatory and anti-microbial properties. Bisabolol was also demonstrated to enhance the percutaneous absorption of certain molecules (J Am Oil Chem. Soc. (2010) 87; 1-7). In embodiments, barrier compositions of the present invention comprise between about 0.01 and 2% w/w of bisabolol. In particular embodiments, about 0.5% w/w of bisabolol.

[0099] In certain aspects, compositions of the present invention additionally comprise a liposoluble Vitamin C derivative. As used herein, the expression “liposoluble Vitamin C derivative” refers to an Ascorbic Acid derivative which is liposoluble (e.g., soluble in the non-aqueous barrier composition of the present invention which comprises petroleum jelly and mineral oil). Non-limiting examples of suitable liposoluble Vitamin C derivatives include: Ascorbyl palmitate (AA-PAL), Ascorbyl-6-caprylate, ascorbyl-6-laurate and Ascorbyl tetra-isopalmitate (VC-IP), 3-O-Ethyl Ascorbic Acid (3-O-EAA). In an embodiment, such liposoluble Vitamin C derivative is Ascorbyl palmitate and/or Tetra-isopalmitoyl Ascorbic acid (IPAA). In particular embodiments, compositions of the present invention comprise more than zero and up to about 10% w/w of a liposoluble Vitamin C derivative. In embodiments, about 10% w/w, about 5% w/w, about 2% w/w, about 1% w/w or about 0.5% w/w of a liposoluble Vitamin C derivative. Preferably, compositions of the present invention comprise at least about 0.5% w/w of a liposoluble Vitamin C derivative. In embodiments, the compositions comprise about 0.5% w/w of Ascorbyl palmitate.

[0100] Compositions of the present invention may additionally comprise one or more further active ingredients (e.g., useful for reducing or preventing skin aging, skin irritation and inflammation, for improving skin texture, skin tone and/or skin healing). As used herein, the term “active ingredient” refers to various types of optional additional active ingredients that may be used in compositions of the present invention. Actives are defined as skin benefit agents other than emollients and ingredients that merely improve the physical characteristics of the composition. Although not limited to this category, common examples include talcs and silicas, zinc salts, and sunscreens.

[0101] Non-limiting examples of active ingredients that may be added in compositions of the present invention include: retinol, resveratrol, polyphenol, Pseudoalteromonas ferment extract, hydrolyzed wheat protein, hydrolyzed soy protein, glycine soja (soybean) protein, citrulline, tripeptide-1 (glycine, -histidine-lysine), tripeptide-5, palmitoyl tripeptide-5, tripeptide-8, tripeptide-10, glycine, Butyrospermum parkii (shea) butter, argania spinosa kernel oil, jojoba esters, glucose, hydrolyzed rice protein, superoxide dismutase, Rosmarinus officinalis (rosemary) leaf extract, cetearyl olivate, sorbitan olivate, Ruscus aculeatus root extract, Centella asiatica extract, hydrolyzed yeast protein, hydrolyzed casein, Calendula officinalis flower extract, acetyl hexapeptide-3, allantoin, Citrus grandis (grapefruit) extract, hydrolyzed glycosaminoglycans, hyaluronic acid, acetylated hyaluronic acid, sodium hyaluronate, Persea gratissima (avocado) oil, tropolone, lysine HCll, Porphyridium cruentum extract, dimethiconol, caprylic/capric triglyceride, Cytokinol™, phytonadione (Vitamin K), Vitamin E (tocopherols (e.g., γ-tocopherol) and tocotrienols), escin, panthenol, Argireline, Kinetine, CE ferulic Acid, skin growth factors, Petrolatum/Canolin, dimethyl sulphoxide, coconut oil, keratolytic agents, unsaturated fatty acids (e.g., omega-3, omega-6 and omega-9 unsaturated fatty acids, especially omega-3 acids, for example EPA, DHA and ALA) and derivatives (particularly esters) thereof, HMG-CoA reductase inhibitors, natural triterpenes, Coenzyme Q10 (ubiquinone), Vitamin B3, hydroquinone (tocopheryl acetate), Aloe, Mallotus japonicus extract, hydroxyacids (e.g., alpha hydroxy acids such as glycolic acid), beta-(l,3) glucans, extract of unpolished rice, urea, pine seed oil, marine collagens, plant cell extracts, ceramides, cholesterol, glutathione, carnitine, caffeine, Rosa mosqueta oil, cystein derivatives, acid and alpha-amino acids, and salts of any of these.

[0102] In embodiments, compositions of the present invention comprise one or more further antioxidants. As used herein, the term “antioxidant” refers to compounds, natural or synthetic, capable of neutralizing reactive oxygen species (ROS). Commonly used antioxidants in compositions (dermatological compositions) include, for example, Ascorbic Acid (Vitamin C), tocopherol (Vitamin E), isoflavones, polyphenols, and retinoids, (including retinoic acid (0.25% to 0.1%), tretinoin, retinal, retinol (0.1% to 5%), Adapalene, tazorotene and retinyl esters. Reviewed in Sheri L. Rolewski. Dermatology Nursing. 2003; 15(5), Jannetti Publications, Inc.), alpha lipoic acid, beta-glucan, coenzyme Q10, grape seed extract, amino acids, green tea, soybean sterols, ergothioneine (EGT, a thiourea derivative of histidine), Resorcinol, Carcinine and mixtures thereof. In embodiments, compositions of the present invention comprise Vitamin C and at least one further antioxidant. In embodiments, compositions of the present invention further comprise (in addition to putrescine and/or Vitamin C) one or more of the following active ingredients: an antioxidant (e.g., a retinoid such as retinol), grapefruit extract, Vitamin E and/or hydroquinone. Generally, the concentration of retinoids (such as retinol) that may be used in accordance with the present invention is between about 0.01% and 5%.

[0103] Generally the total amount of active ingredients in compositions of the present invention may be up to 40% w/w of the composition. In embodiments, the total amount of active ingredients in compositions of the present invention is between about 0.1% w/w and about 35% w/w. In embodiments, the total amount of active ingredients is between about 0.1% and about 30% w/w. In embodiments, the total amount of active ingredients is up to 25% w/w of the composition. In embodiments, the total amount of active ingredients is up to 20% w/w of the composition.

[0104] The barrier compositions according to the invention may be in any form suitable for topical application, e.g., creams, ointments, balm, emulsions etc. and may if desired include a carrier substrate, e.g., a woven or nonwoven web. The compositions may contain conventional topical composition components, such as for example, solvents, oils (e.g., plant oils), aromas, sunscreens, colorants, viscosity modifiers, binders, diluents, emollients, thickeners, preservatives, stabilizers, humidifiers, skin penetration enhancers, vesicle wall formers, etc. Preferably, barrier compositions of the present invention are topical ointments.

[0105] Sunscreens include those materials commonly employed to block ultra-violet radiation. Illustrative compounds are the derivatives of para-aminobenzoic acid (PABA), cinnamate and salicylate. For example, avobenzophenone (Parsol 1789®), octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone (also known as oxybenzone) can be used. 2-ethylhexyl-3-(4-methoxyphenyl)-2-propenoate, 2-phenyl-benzimidazole-5 sulphonic acid, and 2-hydroxy-4-methoxy benzophenone are commercially available under the trade-marks, Parsol MCX™, Parsol HS™ and Benzophenone-3™, respectively. The exact amount of sunscreen employed in the compositions can vary depending upon the degree of protection desired from the sun's ultra-violet radiation. Additives that reflect or scatter the sun rays may also be employed. These additives include oxides like zinc oxide and titanium dioxide.

[0106] Non-limiting examples of conventional topical composition components that may be included in barrier compositions of the present invention include lecithin, xanthan gum, carbomer, triethanolamine, phenoxyethanol, butylene glycol, caprylyl glycol, glyceryl stearate, PEG-100 stearate, PEG-75 stearate, PEG 40, dimethicone, glycerin, behenyl alcohol, cetyl palmitate, cyclopentasiloxane, dimethiconol, acrylates/acrylamide copolymer, magnesium aluminum silicate, methylparaben, ethylparaben, propylparaben, butylparaben, stearic acid, caprylic/capric triglyceride, titanium dioxide, triethoxycaprylylsilane, castor oil phosphate, tocopheryl acetate, tetrasodium edta, butylated hydroxy toluene, allyl methacrylates crosspolymer, polysorbate 20, carrageenan (chondrus crispus), ethylhexylglycerin, cetyl alcohol, ceteth-20, steareth-20, pentylene glycol, sodium benzoate, sodium dextran sulfate, potassium sorbate, ammonium glycyrrhizate, ethoxydiglycol, propylene glycol, betaine, saccharide isomerate, trimethylolpropane, tricaprylate/tricaprate, cetyl alcohol, dmdm hydantoin, isobutylparaben, 1,2-hexanediol, 1,2-octanediol, hydrogenated palm glycerides, glyceryl polyacrylate, mineral oil, allyl methacrylate crosspolymer, polysorbate-85, glyceryl dilaurate, C13-14 isoparaffin, laureth-7, C12-13 pareth-23, hexamidine diisethionate, or benzoyl peroxide.

[0107] Many compositions may be protected against the growth of potentially harmful microorganisms. However, microorganisms generally don't grow or grow poorly in barrier compositions which comprise of no or only very small amounts of water. Nevertheless, anti-microbial compounds may be included in the compositions of the present invention. Suitable preservatives include alkyl esters of p-hydroxybenzoic acid (parabens), hydantoin derivatives, hexamidine diisethionate, propionate salts, parabens and a variety of quaternary ammonium compounds as well as chelating agents such as EDTA and well known antimicrobial non-parabens of all kinds.

Uses

[0108] Compositions of the present invention are intended to be used as is, or through the making of a composition or a medication, to prevent or to treat any skin condition that involves skin irritation or skin inflammation and to stimulate healing of wounded skin. The skin condition includes but is not limited to dermatitis, skin allergy, psoriasis, acne, eczema, rosacea, radiations exposure including U.V. or sun exposure, laser exposure, skin aging (e.g., reduction of wrinkles), dry skin, cracked or chapped skin, skin surgery and wound healing. Barrier compositions comprising putrescine are particularly useful for promoting wound healing and preventing and/or treating scars including hypertrophic scar tissue.

General Manufacturing Procedures

[0109] Compositions of the invention may be produced by standard cosmetic or pharmaceutical composition production techniques.

[0110] However, the process described in Examples 1 and 3 below, has been found particularly useful in preparing compositions of the present invention.

[0111] Other objects, advantages and features of the present invention will become more apparent upon reading the following non-restrictive description of specific embodiments thereof, given by way of example only.

Definitions

[0112] In order to provide clear and consistent understanding of the terms in the instant application, the following definitions are provided.

[0113] The articles “a,” “an” and “the” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

[0114] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, un-recited elements or method steps and are used interchangeably with, the phrases “including but not limited to” and “comprising but not limited to”.

[0115] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 18-20, the numbers 18, 19 and 20 are explicitly contemplated, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. The terms “such as” are used herein to mean, and is used interchangeably with, the phrase “such as but not limited to”.

[0116] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. For example, any nomenclature used in connection with, and techniques of biochemistry, microbiology, chemistry and cosmetics described herein are those that are well known and commonly used in the art. The meaning and scope of the terms should be clear; in the event however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0117] Practice of the methods, as well as preparation and use of the products and compositions disclosed herein employ, unless otherwise indicated, conventional techniques in chemistry and related fields as are within the skill of the art. These techniques are fully explained in the literature. See, for example The Handbook of

[0118] Pharmaceutical Excipients, American Pharmaceutical Association, Washington (Editors Raymond C Rowe, Paul J. Sheskey and Siân C. Owen, 2006).

[0119] The term “substantially water-free” means very small amounts of water that are usually introduced into the composition along with the components and manufacturing process, such as less than 3%, preferably less than 2%, more preferably less than 1% by weight based on the weight of the total composition. For example, propyleneglycol may contain small amount of water (e.g., 0.2% water), and thus a small amount of water will usually be introduced into the composition along with certain ingredients such as propyleneglycol. Water may also be introduced into the composition by precipitation during the cooling phase of manufacturing. Preferably, the amount of water should be maintained below 2% and preferably less than 1%. Most preferably, no water is intentionally added to the composition.

[0120] An important excipient in the formulation is petrolatum, also commonly referred to as petroleum jelly. Petroleum jelly is usually obtained as the semisolid residue from petroleum after the lighter and more volatile components have been boiled off. The Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington (Editors Ainley Wade and Paul J Weller) Second Edition 1994, defines petroleum jelly as a purified mixture of semisolid saturated hydrocarbons having the general formula C(n)H(2n+2) obtained from petroleum. The hydrocarbons comprise mainly branched and unbranched chains, although some cyclic alkanes and aromatic molecules with paraffin side chains may also be present. The term petroleum also includes other mixtures of petroleum based semisolid hydrocarbons that are commonly referred to in the art or commercially sold as “petroleum” or “petroleum jelly” that are suitable for application to skin. A common petroleum is sold under the trademark Vaseline. In the examples disclosed herein, a white petrolatum from Calumet has been utilized. If petrolatum from other manufacturers is used in the inventive formulation, the amounts disclosed herein may have to be slightly altered in order to achieve the desired properties of the formulation, which is well within the skill of one of ordinary skill in the art. Examples of other commercially available petrolatum include, but are not limited to, those from Ultra Chemical, Carolina Medical Products, Witco (Germany), and Amco Chemical.

[0121] The present invention is illustrated in further details by the following non-limiting examples.

EXAMPLE 1

Barrier Composition Comprising 0.4% Putrescine

[0122] The following barrier composition was prepared as described below.

TABLE-US-00001 TABLE 1 Barrier composition Formula A1 comprising 0.4% Putrescine. Amount Ingredients CAS# Grade (% W/W) 1 Petroleum Jelly 8009-03-8 USP 47.00 (perfecta Petrolatum) 2 Mineral oil (white) 8042-47-5 USP 35.30 3 Paraffin (ceresin wax 8001-75-0 MFR  9.00 130/135) 4 Lanolin oil 70321-63-0/ MFR  4.80 8038-43-5 5 Bisabolol 23089-26-1 USP  0.50 6 Putrescine (1,4- 110-60-1 or MFR  0.40 diaminobutane) 333-93-7 7 Cocamidopropyl PG- 83682-78-4 MFR  1.00 Dimonium Chloride Phosphate 8 Glycerin 56-81-5 USP  1.00 9 Panthenol (DL) 16485-10-2 MFR  1.00 100%  

[0123] The above composition was prepared by adding and mixing the ingredients as follows in a stainless steel tank equipped with a lightening-type propeller mixer.

TABLE-US-00002 TABLE 2 Manufacturing procedure of Formula A1. Step# Manufacturing Procedure 1 In a double jacketed stainless steel tank equipped with a lightening type propeller add ingredients identified as 1 to 5 (PART A). Start heating to allow melting of items 1 and 3 2 Heat ingredients in Part A to 80-85° C. while mixing gently until liquid and all of item 3 has melted and a homogeneous mixture is obtained. It is important that all of the paraffin (item 3) is melted. A clear, golden solution is obtained. 3 Gently cool to about 50-55° C., scraping the sides and bottom before adding PART B 4 In second double jacketed stainless steel tank add ingredients identified as 6-9 (PART B). 5 Mix items of Part B together until all of Cocamidopropyl PG-Dimonium Chloride Phosphate (item 8) has dissolved. Do not heat. 6 Add Part B to Part A while mixing and mix batch until homogeneous. 7 Slowly cool while mixing batch (preferably using sweep mixing) until room temperature. The formula will start thickening between 40-50° C. and solidify around 35° C.

EXAMPLE 2

Barrier Composition Comprising 0.8% Putrescine

[0124] The following barrier composition was prepared as described below.

TABLE-US-00003 TABLE 3 Barrier composition Formula A2 comprising 0.8% Putrescine. Amount Ingredients CAS# Grade (% W/W) 1 Petroleum Jelly 8009-03-8 USP 45.50 (perfecta Petrolatum) 2 Mineral oil (white) 8042-47-5 USP 34.00 3 Paraffin (ceresin wax 8001-75-0 MFR  8.62 130/135) 4 Lanolin oil 70321-63-0/ MFR  4.60 8038-43-5 5 Bisabolol 23089-26-1 USP  0.48 6 Putrescine (1,4- 110-60-1 or MFR  0.80 diaminobutane) 333-93-7 7 Cocamidopropyl PG- 83682-78-4 MFR  4.00 Dimonium Chloride Phosphate 8 Glycerin 56-81-5 USP  1.00 9 Panthenol (DL) 16485-10-2 MFR  1.00 100%  

[0125] The above composition was prepared by adding and mixing the ingredients as described in Example 1 in a stainless steel tank equipped with a lightening-type propeller mixer.

EXAMPLE 3

Barrier Composition Comprising 0.8% Putrescine and 0.5% 3-O-Ethyl Ascorbic Acid

[0126] The following barrier composition was prepared as described below.

TABLE-US-00004 TABLE 4 Barrier composition Formula B comprising 0.8% Putrescine and 0.5% 3-O-ethyl Ascorbic Acid. Amount Ingredients CAS# Grade (% W/W)  1 Petroleum Jelly 8009-03-8 USP 45.00 (Perfecta Petrolatum)  2 White Mineral oil 8042-47-5 USP 34.00  3 Paraffin (ceresin wax 8001-75-0 MFR  8.60 130/135)  4 Lanolin oil 70321-63-0/ MFR  4.60 8038-43-5  5 Bisabolol 23089-26-1 USP  0.50  6 Cocamidopropyl PG- 83682-78-4 MFR  4.00 Dimonium Chloride Phosphate  7 Putrescine (1,4- 110-60-1 or MFR  0.80 diaminobutane 333-93-7  8 Glycerin 56-81-5 USP  1.00  9 Panthenol (DL) 16485-10-2 MFR  1.00 10 3-O-Ethyl Ascorbic 86404-04-8 MFR  0.50 Acid (3-O-EAA, ET- VC ™) 100%  

[0127] The above composition was prepared by adding and mixing the ingredients as follows:

TABLE-US-00005 TABLE 5 Manufacturing procedure of Formula B. Step# Manufacturing Procedure 1 In a double jacketed stainless steel tank equipped with a lightening type propeller add ingredients identified as 1 to 5 (PART A). 2 Heat ingredients to 80-85° C. while mixing gently until liquid and all of item 3 has melted and a homogeneous mixture is obtained. 3 In second double jacketed stainless steel tank add ingredients identified as 6-10 in the order listed (PART B). 4 Mix items of Part B one item at a time, mix until items 6, 7, 8, 9 & 10 have dissolved well and a white frothy lather is obtained. 5 At 50-55 degrees Celsius, add Part B to Part A while mixing and mix batch until homogeneous. 6 Slowly cool while mixing batch to desired consistency.

EXAMPLE 4

Barrier Composition Comprising 0.4% Putrescine and 0.5% 3-O-Ethyl Ascorbic Acid

[0128] The following barrier composition was prepared as described below.

TABLE-US-00006 TABLE 6 Barrier composition Formula C comprising 0.4% Putrescine and 0.5% 3-O-ethyl Ascorbic Acid. Amount Ingredients CAS# Grade (% W/W)  1 Petroleum Jelly 8009-03-8 USP 46.20 (Perfecta Petrolatum)  2 White Mineral oil 8042-47-5 USP 34.90  3 Paraffin (ceresin wax 8001-75-0 MFR 8.8.00  130/135)  4 Lanolin oil 70321-63-0/ MFR  4.70 8038-43-5  5 Bisabolol 23089-26-1 USP  0.50  6 Cocamidopropyl PG- 83682-78-4 MFR  2.00 Dimonium Chloride Phosphate  7 Putrescine (1,4- 110-60-1 or MFR  0.40 diaminobutane 333-93-7  8 Glycerin 56-81-5 USP  1.00  9 Panthenol (DL) 16485-10-2 MFR  1.00 10 3-O-Ethyl Ascorbic 86404-04-8 MFR 0.5 Acid (3-O-EAA, ET- VC ™) 100%  

[0129] The above composition was prepared as described in Example 3.

EXAMPLE 5

Barrier Composition Comprising 0.8% Putrescine and 0.5% Ascorbyl Palmitate

[0130] The following barrier composition was prepared as described below.

TABLE-US-00007 TABLE 7 Barrier composition Formula D comprising 0.8% Putrescine and 0.5% Ascorbyl Palmitate. Amount Ingredients CAS# Grade (%W/W)  1 Petroleum Jelly 8009-03-8 USP 45.00  2 Mineral oil (white) 8042-47-5 USP 34.00  3 Paraffin (ceresin wax) 8001-75-0 MFR  8.62  4 Lanolin oil 70321-63-0/ MFR  4.60 8038-43-5  5 Bisabolol 23089-26-1 USP  0.48  6 Putrescine (1,4- 110-60-1 or MFR  0.80 diaminobutane) 333-93-7  7 Glycerin 56-81-5 USP  1.00  8 Cocamidopropyl PG- 83682-78-4 MFR  4.00 Dimonium Chloride Phosphate (Cola Lipid C)  9 Panthenol 16485-10-2 MFR  1.00 10 Ascorbyl palmitate 137-66-6 MFR 0.5 100%  

[0131] Another composition lacking Ascorbyl palmitate was also prepared. In such case, the absence of Ascorbyl palmitate was compensated by Petroleum Jelly.

[0132] The above composition was prepared by adding and mixing the ingredients as follows in a stainless steel tank equipped with a lightening-type propeller mixer.

TABLE-US-00008 TABLE 8 Manufacturing procedure of Formula D. Step Manufacturing Procedure 1 Add ingredients of items 1-5 in a first stainless steel tank (Part A) 2 Heat ingredients to 80-85° C. while mixing gently until liquid and all of item 3 has melted and a homogenous mixture is obtained. 3 In a second double jacketed stainless steel tank add ingredients listed under items 6-10 (Part B). 4 Mix items 6-10 together until putrescine and panthenol have dissolved. 5 At 50-55° C., add Part B to Part A with mixing and mix batch until homogeneous. 6 Slowly cool while mixing batch until room temperature.

EXAMPLE 6

Effect of the Barrier Composition Comprising 0.8% Putrescine

[0133] A clinical study was performed on 10 subjects having undergone laser treatment for mole removal. Subjects applied a thin layer of the composition of Example 2 twice a day (morning and night) on the treated area for 12 weeks. Application of the composition decreased healing time as compared to untreated subjects having undergone the same type of laser treatment.

EXAMPLE 7

Stability of Compositions of the Present Invention

[0134] Preliminary stability tests of compositions of the present invention comprising putrescine (from 0.4% or 0.8%) and optionally 0.5% Vitamin C (Ascorbyl palmitate or 3-O-Ethyl Ascorbic Acid) show that the compositions are stable. Indeed, no significant change in color, odor and texture (including absence of multiple phases, and precipitate) were observed after about 12 months. Further stability tests are underway and are conducted as follows.

TABLE-US-00009 TABLE 9 Stability program design for putrescine barrier formulations. Stability Program Design 25° C. /~2 to 75% RH Time Points (months) 0 3 6 9 12 18 24 30 36 42 48 1) Organoleptic C C C* C C* C C* C C* C C* 2) Viscosity: USP <912>: .sup.(1) 3) Assay Vitamin C: HPLC Method.sup.(2) 4) Assays Putrescine: HPLC Method.sup.(3) C = Anticipated results must be conform to all testing specifications C* = only time point 0, 6, 12, 24, 36 & 48 will be tested for viscosity since not enough samples .sup.(1) The Viscosity must be similar to the initial one over time ± 10% (Just on the slow release formula: Barrier composition Formula A2 comprising 0.8% Putrescine.) .sup.(2)The Vitamin C must be ± 10% of the initial concentration of the formula, if present .sup.(3)The Putrescine must be ± 10% of the initial concentration of the formula Quantity of unit needed: Viscosity: 300 mL min: 15 tubes of 30 mL Essays: 1 g: 1 tube of 30 mL Total: 16 tubes

Preliminary stability results

[0135] Compositions comprising Ascorbyl Palmitate, were much less stable than compositions comprising 3-O-ethyl Ascorbic Acid, when combined with putrescine. Indeed, formula comprising Ascorbyl Palmitate changed color (turned to brown) much more rapidly than compositions comprising 3-O-ethyl Ascorbic Acid in combination with putrescine in the ointment base.

[0136] Results obtained thus far from ongoing stability assays for formula A1, A2, B and C are provided in Tables 10-13 below.

TABLE-US-00010 TABLE 10 Formula A1 (Example 1). Finished Product Testing Specification RD-12-00 RD-12-00 RD-12-00 RD-12-00 Method or Initial 3 6 9 Test Specification Reference Testing Mth Mth Mth Appearance Beige to pale Organoleptic Pale Beige to Yellow Pale yellow yellow pale gel yellow yellow gel gel 1,4-Diaminobutane Target: 0.4% QIN-10-205 0.4 0.3 0.4 0.4 Dihydrochloride (%) concentration

TABLE-US-00011 TABLE 11 Formula A2 (Example 2). Finished Product Testing Specification SK-38-00 SK-38-00 SK-38-00 Method or Initial 3 6 Test Specification Reference Testing Mth Mth Appearance Beige to pale Organoleptic Pale yellow gel Beige gel Pale yellow yellow*gel) gel (*Product becomes pale yellow with time) Viscosity variation USP <912> 212 400 NT 243 600 cP 1,4-Diaminobutane Target: 0.8% QIN-10-205 0.7 0.9 0.7 Dihydrochloride (%) concentration

TABLE-US-00012 TABLE 12 Formula B (Example 3). Finished Product Testing Specification RD-13-00 RD-13-00 RD-13-00 RD-13-00 Method or Initial 3 6 9 Test Specification Reference Testing Mth Mth Mth Appearance Beige to pale Organoleptic Pale Beige to Yellow Pale yellow yellow pale yellow gel yellow gel gel gel 1,4-Diaminobutane Target: 0.8% QIN-10-205 0.9 0.7 0.8 0.7 Dihydrochloride (%) concentration 3-O Ethyl Ascorbic Target: 0.5% QIN-10-145 0.5 0.4 0.3 0.1 Acid (%) concentration

TABLE-US-00013 TABLE 13 Formula C (Example 4). Finished Product Testing Specification RD-13-00 RD-13-00 RD-13-00 RD-13-00 Method or Initial 3 6 9 Test Specification Reference Testing Mth Mth Mth Appearance Beige to pale Organoleptic Pale Beige to Yellow Pale yellow yellow pale yellow gel yellow gel gel gel 1,4-Diaminobutane Target: 0.4% QIN-10-205 0.5 0.3 0.4 0.4 Dihydrochloride (%) concentration 3-O Ethyl Ascorbic Target: 0.5% QIN-10-145 0.4 0.4 0.1 0.2 Acid (%) concentration

[0137] The scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.

REFERENCES

[0138] 1. Tajima S, Pinnell S R, Ascorbic acid preferentially enhances type I and III collagen transcription in human skin fibroblasts. J. Derm Science. 11:250-53, 1996. 2Traikovich S S. [0139] 2. Use of topical ascorbic acid and its effects on photo damaged skin topography. Arch Otolaryngol Head Neck Surg 125:1091-98, 1999. [0140] 3. Murray J, Darr D, Reich J. Pinnell S. Topical vitamin C treatment reduces ultraviolet B radiation-included erythema in human skin. J. Invest Dermatol 1991:96:587 (abstract). [0141] 4. C. W. Lynde. Moisturizers: What they are and how they work. Skin Therapy Letter, 2001; http://www.skintherapyletter.com/2001/6.13/2.html