PUTRESCINE TOPICAL FORMULATIONS

Abstract

The present invention describes complex topical aqueous compositions for the effective delivery of active ingredients such as putrescine and Vitamin C into the skin. These compositions may be used in a variety of cosmetic and therapeutic applications including for reducing or preventing skin's signs of aging, for promoting wound healing, for reducing or preventing the formation of hypertrophic scar tissue, for reducing or preventing skin irritation and/or inflammation.

Claims

1. An aqueous topical composition comprising (i) a primary polyamine; (ii) at least one of Vitamin C, Vitamin E (alpha tocopherol), a jojoba ester or a peptide; and (iii) (a) at least one viscosity increasing agent/anticaking agent, (b) at least one a binder/stabilizer; (c) at least one skin conditioning agent; (d) at least one humectant, binder, emulsion stabilizer, surfactant and viscosity increasing agent; (e) at least one rheology modifier; or (f) any combination of at least two of any one of (a) to (e).

2. The topical composition of claim 1, wherein said (i) primary polyamine is a primary aliphatic lower-alkyl (C1-5) monoamine; a primary aliphatic alkylamine; or a primary aliphatic lower-alkyl (C1-5) polyamine; (ii) comprises Vitamin C, wherein the Vitamin C consists of L-ascorbic acid, 3-O-ethyl ascorbic acid (ETVC), ascorbyl palmitate or any combination of at least two thereof, wherein the concentration of Vitamin C′s is between about 0.05% w/w and about 20% w/w; and/or comprises Vitamin E, wherein the concentration of Vitamin E is between about 0.1% w/w and about 1% w/w; or about 0.3% w/w; and/or comprises at least one peptide; and/or comprises a jojoba ester, wherein the concentration of jojoba ester is between about 0.1% w/w and about 1.5% w/w; or about 1%; and/or (iii) comprises at least one viscosity increasing agent/anticaking agent, wherein the concentration of the at least one viscosity increasing agent/anticaking agent is between about 0.6% w/w and about 3% w/w; and/or comprises at least one binder/stabilizer, wherein the concentration of the at least one binder/stabilizer is between about 0.1% w/w and about 0.9% w/w; and/or comprises at least one skin conditioning agent, wherein the concentration of the at least one skin conditioning agent is between about 2% w/w and about 36% w/w; and/or comprises at least one at least one humectant, binder, emulsion stabilizer, surfactant and viscosity increasing agent, wherein the concentration of the at least one at least one humectant, binder, emulsion stabilizer, surfactant and viscosity increasing agent is between about 1% w/w and about 5% w/w; and/or comprises at least one at least one rheology modifier, wherein the concentration of the at least one rheology modifier is between about 1% w/w and 3% w/w.

3. The topical composition of claim 2, wherein said primary aliphatic lower-alkyl (C1-5) monoamine is aminoacetonitrile, said primary aliphatic alkylamine is spermine or spermidine and said primary aliphatic lower-alkyl (C1-5) polyamine is putrescine or dansylcadaverine, and preferably putrescine.

4. (canceled)

5. The topical composition of claim 3, comprising between about 0.1% w/w and about 2% w/w of putrescine; or about 0.4% w/w of putrescine; or about 0.8% w/w of putrescine.

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17. The topical composition of claim 2, wherein the at least one peptide is (i) tripeptide 1, (ii) tripeptide 5, (iii) tripeptide 10 citrulline, (iv) tetrapeptide 2, (v) acetylarginyltryptophyl diphenylglycine or any combination of at least two of (i) to (v).

18. (canceled)

19. The topical composition of claim 2, comprising at least one viscosity increasing agent/anticaking agent, wherein the at least one viscosity increasing agent/anticaking agent is magnesium aluminum silicate.

20. (canceled)

21. The topical composition of claim 2, comprising at least one binder/stabilizer, wherein the at least one binder/stabilizer is xanthan gum.

22. (canceled)

23. The topical composition of claim 2, comprising at least one skin conditioning agent, wherein the at least one skin conditioning agent is squalane.

24. (canceled)

25. The topical composition of claim 2, comprising at least one humectant, binder, emulsion stabilizer, surfactant and viscosity increasing agent, wherein the at least one at least one humectant, binder, emulsion stabilizer, surfactant and viscosity increasing agent is a blend of glyceryl stearate and PEG-100 stearate in a ratio of between about 4:6 and about 6:4 of glyceryl stearate: PEG-100 stearate.

26. (canceled)

27. The topical composition of claim 2, comprising at least one at least one rheology modifier, wherein the at least one rheology modifier is a blend of acrylates/acrylamide copolymer, mineral oil and polysorbate-85.

28. The topical composition of claim 1, further comprising (a) at least one stabilizer which improves wet and dry compatibility and water resistance, wherein the concentration of the at least one stabilizer is between about 1% w/w and about 5% w/w; (b) hexamidine diisethionate as an antifoaming, skin conditioning, emollient and preservative agent; and/or (c) at least one antioxidant.

29. The topical composition of claim 28, wherein the at least one stabilizer which improves wet and dry compatibility and water resistance is also a skin conditioning agent, emollient; moisturizer and solvent.

30. The topical composition of claim 29, wherein the at least one stabilizer which improves wet and dry compatibility and water resistance is a blend of cyclopentasiloxane and dimethiconol.

31. (canceled)

32. The topical composition of claim28, comprising about 0.1% w/w hexamidine diisethionate.

33. (canceled)

34. The topical composition of claim 28, wherein the at least one antioxidant comprises a fruit extract, hydroquinone, a retinoid, resveratrol, tocopherol, tocopheryl acetate, retinol, retinyl palmitate, hydroquinone, proanthocyanidins, butylated hydroxytoluene, butylated hydroxyanisole, astaxanthin, alpha lipoic acid, tocotrienols, coenzyme Q10, a-hydroxy acid, kojic acid, kinetin, wine extract, vitamin K, a plant extract, resorcinol, lactic acid, salicylic acid or any combination of at least two thereof.

35. The topical composition of claim 1, wherein the pH of the composition is between about 6.5 and about 7.5.

36. The topical composition of claim 1, comprising at least 5 active ingredients; or at least 10 active ingredients; or at least 12 active ingredients.

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39. The topical composition of claim 1, comprising between about 55% and 65% w/w of water.

40. A method of using the topical composition defined in claim 1, for (a) treating or preventing skin inflammation, skin irritation, and/or skin's signs of aging; (b) increasing skin thickness; (c) promoting wound healing; or (d) preventing or reducing the formation of hypertrophic scar tissue.

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46. A process of preparing the composition defined in claim 1, comprising: (A) (a) in a main tank: (ai) combining water and the at least one viscosity increasing agent/anticaking agent; (aii) adding to the resulting mixture of (ai) the at least one binder/stabilizer; (aiii) heating the resulting mixture of (aii) to about 65-70° C. and mixing until obtaining an homogenous mixture; (b) in a separate tank, mixing (bi) the at least one humectant, binder, emulsion stabilizer, surfactant and viscosity increasing agent; (bii) squalane; and (biii) vitamin C, jojoba ester and/or vitamin E; and heating to 65-70° C. and mixing until obtaining an homogenous mixture; (c) adding the resulting mixture of (b) to (a) and mixing until homogenization; (d) cooling the resulting mixture of (c) to about 50° C.; (e) adding to (d) the rheology modifying agent and mixing until homogenization; (f) cooling the resulting mixture of (e) to about 40° C.; (g) in a separate tank, dissolving the primary polyamine (e.g., putrescine) in water (about 1-15% w/w, preferably about 5-15% w/w of water); and (h) adding the resulting mixture of (g) to the resulting mixture of (f); (B) (a) in a main tank: (ai) combining water and the at least one viscosity increasing agent/anticaking agent; (aii) adding to the resulting mixture of (ai) the at least one binder/stabilizer; (aiii) heating the resulting mixture of (aii) to about 65-70° C. and mixing until obtaining an homogenous mixture; (b) in a separate tank, mixing (bi) the at least one humectant, binder, emulsion stabilizer, surfactant and viscosity increasing agent; and (bii) squalane; heating to 65-70° C.; and mixing until obtaining an homogenous mixture; (c) adding the resulting mixture of (b) to the resulting mixture of (a) and mixing until homogenization; (d) cooling the resulting mixture of (c) to about 50° C.; (e) adding the rheology modifying agent to the resulting mixture of (d) and mixing until homogenization; (f) cooling the resulting mixture of (e) to about 40° C.; (g) in a separate tank, dissolving putrescine in water (about 1-15% w/w, preferably about 5-15% w/w of water) and optionally adding a peptide; (h) adding the resulting mixture of (g) to the resulting mixture of (f) and mixing until homogenization; and (i) adding Vitamin C to the resulting mixture of (h) under mixing; or (C) (a) in a main tank: (ai) combining water and the at least one viscosity increasing agent/anticaking agent; (aii) adding to the resulting mixture of (ai) the at least one binder/stabilizer; (aiii) heating the resulting mixture of (aii) to about 65-70° C. and mixing until obtaining a homogenous mixture; (b) in a separate tank, mixing (bi) the at least one humectant, binder, emulsion stabilizer, surfactant and viscosity increasing agent; and (bii) squalane; heating to 65-70° C.; and mixing until obtaining an homogenous mixture; (c) adding the resulting mixture of (b) to the resulting mixture of (a) and mixing until homogenization; (d) cooling the resulting mixture of (c) to about 50° C.; (e) in a separate tank, combining water with hexamidine diisethionate (about 1% w/w to about 3% w/w water), heating to about 75-80° C. and mixing until dissolved and clear; (f) adding to the resulting mixture of (d) at least one further stabilizer (e.g., cyclopentasiloxane and dimethiconol) and the rheology modifier; (g) in a separate container combining water (about 1% w/w to 5% w/w), Vitamin C, the primary polyamine (e.g., putrescine); heating to about 40° C. and mixing until homogenization; (h) adding the resulting mixture of (g) to the resulting mixture of (f) under mixing at 40° C.; and combining the resulting mixture of (e) and the resulting mixture of (h) under mixing.

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Description

EXAMPLE 1

[0173] Complex eye cream comprising multiple active ingredients including putrescine and Vitamin C

TABLE-US-00002 TABLE 2 Exemplary 0.4% putrescine and Vitamin C (0.05%) eye cream Ingredients Ingredients (Trade Name and Amount (INCI Name) Function(s) Manufacturer) CAS# Grade (% W/W) Part A 1 Water Diluent/carrier Purified Water N/A USP 58.80  2 Magnesium Aluminum Viscosity increasing agent; Absorbent; Veegum Ultra; RT 12199-37-0, MFR 0.90 Silicate Anticaking agent; Opacifying agent; Slip Vanderbilt 13463-67-7, modifier 14808-60-7 3 Xanthan Gum Binder; Emulsion Stabilizer (gel forming); Jungbunzlauer 11138-66-2 MFR 0.20 Skin conditioning agent; Surfactant - Xanthan Gum; Emulsifying agent; Viscosity increasing Pachem Distribution agent 4 Phenoxyethanol (69-72%), Broad spectrum preservative (inhibits the Lincocide P-MEPB; 122-99-6, MFR 0.60 Methylparaben (15-17%), growth of gram (+) and gram (−) bacteria, Lincoln fine 99-76-3, Ethylparaben (3.5-4.5%), yeasts and molds) Ingredients 94-26-8, Propylparaben 94-13-3, (1.7-2.3%), Butylparaben 120-47-8 (5.5-6.5%) (about 29% parabens in total) 5 Triethanolamine Surfactant and pH adjusting chemical Triethanolamine; 102-71-6 MFR 0.25 (buffer); Emulsifying agent Canada Colors and Chemicals 6 TetraSodium EDTA Chelating agent Versene 220; Canada 8013-51-2 MFR 0.10 Colors and Chemicals Part B 7 Behenyl Alcohol Binder; Emollient, Emulsifier and Lanette 22; Pachem 661-19-8 MFR 1.50 Viscosity increasing agent (thickener). Distribution (BASF) 8 Cetyl Palmitate Skin-conditioning agent - Emollient; Trivent CP; Alzo 540-10-3 MFR 1.50 Occlusive International 9 Glyceryl Stearate Humectants, solvents, binders, surfactant, Lipomulse 165; Tempo 123-94-4, MFR 4.00 (40-60%), emulsion stabilizers, and viscosity Canada 9004-99-3 PEG-100 Stearate increasing agents (40-60%) 10 Stearic Acid Surfactant; Emulsifying agent; refatting Stearic Acid; Univar 57-11-4 MFR 0.50 11 Tocopheryl Acetate Active ingredient, Antioxidant; Skin- Vitamin E; Pachem 7695-91-2 MFR 0.30 conditioning agent Distribution (BASF) 12 Butylated Hydroxy Preservative; antioxidant BHT; Andicor Specialty 128-37-0 MFR 0.10 Toluene Chemicals (Evonik) 13 Butyrospermum Parkii Active ingredient: Skin-conditioning Cetiol SB-45/Fancol 68920-03-6 MFR 2.00 (Shea) Butter Extract Shea Butter; Pachem (Cognis)/Unipex Solution (Elementis) 14 Dimethicone Lubricant and skin conditioning agent; DC 200/350/Elements 9006-65-9 or MFR 2.00 occlusive; skin protectant; emollient PDMS 350; Canada 63148-62-9 Colors and Chemicals (Momentive) 15 Argania Spinosa Active ingredient: Skin conditioning Argan Oil; Centerchem 223747-87-3 MFR 1.00 Kernel Oil agent - Emollient; Occlusive (DSM) 16 Squalane Active ingredient: Lubricant on the skin Keteol V; Pachem 111-01-3 MFR 5.00 surface. Skin conditioning agent with Distribution refatting properties - occlusive; emollient; refatting 17 Ascorbyl Palmitate Active ingredient: Antioxidant, and wound Ascorbyl Palmitate; 137-66-6 MFR 0.05 (Vit C) healing agent. Increases collagen Spectrum Chemicals production and reduce the inflammation. (VWR International)/ Green Wave Ingredients 18 Caprylic/Capric Caprylic/Capric Triglyceride: Fragrance 50% Ultrafine TiO.sub.2 in 65381-09-1, MFR 0.50 Triglyceride, Ingredient, Skin conditioning agent- Caprylic/Capric 13463-67-7, Titanium Dioxide, Occlusive Triglyceride 2943-75-1, Triethoxycaprylylsilane, Titanium dioxide: Colorant; Opacifying Dispersion (R3214, 68308-61-2 Castor Oil Phosphate agent; Sunscreen agent; Ultraviolet Light Sensient- Product Absorber discontinued and replaced Triethoxycaprylylsilane: Binder by Sensient Covascreen ™ Castor Oil Phosphate: Anticaking agent, UVR CCT product code: emulsion stabilizer 251351). 19 Jojoba Esters Active ingredient: Skin conditioning and Floraesters ™ 30; 61789-91-1 MFR 1.00 Derived from jojoba oil anti-aging: Improves skin barrier function Vivachem (Floratech) (Simmondsia chinensis) (occlusive); Increase skin's hydration; Blend of 99.95% Jojoba reduces skin dryness, roughness and Esters and 0.05% flakiness. Also reduces peri-ocular fine-line tocopherol wrinkles and increases skin firmness 20 Phenoxyethanol (69-72%), Broad spectrum preservative (inhibits the Lincocide ™ P-MEPB; 122-99-6, MFR 0.30 Methylparaben (15-17%), growth of gram (+) and gram (−) bacteria, Lincoln fine Ingredients 99-76-3, Ethylparaben (3.5-4.5%), yeasts and molds) 94-26-8, Propylparaben (1.7-2.3%), 94-13-3, Butylparaben (5.5-6.5%) 120-47-8 (about 29% parabens in total) Part C 21 Acrylates/Acrylamide Emulsifier; rheology modifier; Novemer ™ EC-1; N/A, MFR 1.50 Copolymer (about 26-28%), 27% solids, liquid, pre-neutralized polymer LV Lomas (Lubrizol) 8042-47-5, Mineral Oil (about 22-24%), dispersed in oil. It is a multifunctional 9005-70-3 and Polysorbate 85 (1-3%), polymer used in emulsions containing water (up to 100% i.e., active ingredients with electrolytes and 45-51%) suspended inorganic pigments. 22 Cyclopentasiloxane, Skin conditioning agent - Emollient; Abil ™ OSW-5; 541-02-6, MFR 1.50 Dimethiconol Moisturizer; Solvent. Improves wet and dry Andicor Specialty 31692-79-2 compatibility. Exhibits improved skin feel Chemicals (Evonik) and water resistance. Provides smooth but not greasy feel. Possesses non- fatty and non-sticky properties Part D 23 Water Diluent/carrier Purified Water N/A USP 5.00 24 1,4-Diaminobutane Active ingredient: Skin regeneration. 1,4-Diaminobutane 333-93-7 MFR 0.40 Dihydrochloride (putrescine) Promotes skin repair including wound Dihydrochloride; healing. Prevents and/or treats scars and Alfa Chemistry skin's signs or aging promotes healing of burns, thicken skin 25 Pseudoalteromonas Ferment Active ingredient: An anti-wrinkle active that Trylagen ™ 820959-16-8, MFR 5.00 Extract (about 12.5%), combines peptides and proteins which functional 94350-06-8, Hydrolyzed Wheat Protein increases collagen production; improves ingredient PCB; 68607-88-5, (about 2.86%), Hydrolyzed collagen organization and inhibits collagen Lipotec 960531-53-7, Soy Protein (about 1.86%), degradation. 72957-37-0, Tripeptide-10 Citrulline 8002-43-5, (about 0.04%), Tripeptide-1 11138-66-2, (about 0.01%), Lecithin 9003-01-4, (about 0.4%), Xanthan Gum 102-71-6, (0.45%), Carbomer (0.028%), 122-99-6, Triethanolamine, 107-88-0, Phenoxyethanol (about 0.45%), 1117-86-8, Butylene Glycol (about 0.6%), N/A Caprylyl Glycol (about 0.58%), Water (up to 100%) 26 Palmitoyl Tripeptide-5, Active ingredient: Synthetic tripeptide that Syn ™-Coll; 623172-56-6, MFR 2.00 Glycerin, Water helps slow down the skin aging process. Centerchem 56-81-5, N/A Simultaneously boosts collagen production and protects against collagen degradation. Part E 27 Palmitoyl Tripeptide-5, Active ingredient: Reduces the appearance SYN ®-EYE; 623172-56-5, MFR 1.00 Panthenol, Sodium of lines and wrinkles; Reduces the Centerchem 81-13-0, Hyaluronate, Dunaliella appearance of dark circles; Improves the 9067-32-7, Salina Extract, skin's texture and smooths the delicate skin 92128-82-0, Phenoxyethanol, Citric eye area; Moisturizes, and protects the 122-99-6, Acid, Sodium Benzoate, skin. 77-92-9, Ethylhexylglycerin, Excipients: 532-32-1, Potassium Sorbate, Ethylhexylglycerin: week preservative, 70445-33-9, Pantolactone, Water deodorant and skin conditioning agent 24634-61-5, Pantolactone: Skin conditioning agent- 599-04-2 Humectant Phenoxyethanol, sodium benzoate and potassium sorbate: preservatives Carbomer: Emulsion Stabilizer; Viscosity increasing agent 28 Leontopodium Alpinum Active ingredient: Reduces sagginess and Majestem ™; 391900-47-3, MFR 3.00 Callus Culture Extract, improves skin Croda Canada 56-81-5, Glycerin, Xanthan Gum (FR 3 031 454 - 11138-66-2 WO2016/113659) 100%

[0174] The above formulation was prepared by adding, in a suitable main stainless-steel tank equipped with a lightening type propeller mixer, all ingredients as indicated in Table 3 until the composition became clear and all ingredients have dissolved. Part A ingredients were combined in the main tank at 65-70° C. under constant mixing. Part B was prepared in a separate tank at the same temperature, under mixing. Part B was added to Part A and cooled at 50° C. Part C, was next added to Part A-B and cooled to 40° C. under mixing and homogenizing. Part D (putrescine/water) was prepared in a separate tank, mixed and added to Part A-B-C. Then, remaining ingredients of part D were added under mixing, followed by Part E (one ingredient at a time). The final mixture was cooled to 30° C. Platiné grey bottle (15 ml AS15 S/PP) with metalized cap and airless pump were used to store the finish product to reduce product contact with ambient light. The pH of the final composition was about 7.29 (may range from 6.8 to 7.5).

TABLE-US-00003 TABLE 3 Process for preparing the eye cream formulation of Table 2 Step Manufacturing Process 1 Sprinkle item 2 (Magnesium Aluminum Silicate) into item 1 (water) while vortexing. Mix for about 20 minutes. 2 Mix item 3 (Xanthan Gum) with item 4 (Triethanolamine) and add to main batch with mixing. Mix for an additional about 20 minutes. 3 Add remaining ingredients in Part A and heat to about 65-70 degrees C. 4 In a secondary manufacturing tank equipped with a mixer, add the ingredients as listed under Part B and Heat to about 65-70 degrees C. Mix until obtaining a homogenous mixture. 5 Add Part B to Part A under homogenization. 6 Homogenize for about 20 minutes at high speed until smooth and uniform. 7 Cool product to about 50 degrees C. while maintaining homogenization. 8 Add Part C one item at a time while mixing and homogenizing to main batch. 9 Homogenize for about 3-5 minutes at high speed until smooth and uniform. 10 Cool batch at about 40 degrees C. with mixing and homogenizing. 11 In a separate container, dissolve item 24 (1,4-Diaminobutane Dihydrochloride) into item 23 (water) (Part D) and add to main batch. Then add remaining ingredients listed under Part D while mixing. 12 Follow with Part E. Add one item at a time, in the order listed. Keep mixing. 13 Switch to sweep mixing and cool product. 14 Cool and side sweep mix until about 30 degrees C.

EXAMPLE 2

[0175] Complex neck cream comprising multiple active ingredients including putrescine and Vitamin C

TABLE-US-00004 TABLE 4 Exemplary 0.4% putrescine neck cream Ingredients Ingredients (Trade Name and Amount Amount (INCI Name) Function(s) Manufacturer) CAS# Grade % W/W % W/W Part A  1 Water Diluent/carrier Purified Water N/A USP 56.95  54.90   2 Magnesium Viscosity increasing agent; Absorbent; Veegum ™ Ultra; RT 12199-37-0, MFR 1.00 1.00 Aluminum Anticaking agent; Opacifying agent; Slip Vanderbilt(Cambrian) 13463-67-7, Silicate modifier 14808-60-7  3 Xanthan Gum Binder; Emulsion Stabilizer (gel forming); Jungbunzlauer Xanthan 11138-66-2 MFR 0.20 0.20 Skin conditioning agent; Surfactant - Gum; LV Lomas Emulsifying agent; Viscosity increasing agent  4 Triethanolamine Surfactant and pH adjusting chemical Triethanolamine; Canada 102-71-6 MFR 0.30 0.30 (buffer); Emulsifying agent Colors and Chemicals  5 TetraSodium EDTA Chelating agent Versene ™ 220; Canada 8013-51-2 MFR 0.20 0.20 Colors and Chemicals Part B  6 Behenyl Alcohol Binder; emollient, emulsifier and viscosity Lanette ™ 22; Pachem 661-19-8 MFR 1.50 1.50 Increasing (thickener). Distribution (BASF)  7 Cetyl Palmitate Skin conditioning agent - Emollient; Trivent ™ CP; Alzo 540-10-3 MFR 1.50 1.50 (Lipid composed Occlusive; International of cetyl alcohol and palmitic acid)  8 Glyceryl Stearate Humectants, solvents, binders, emulsion Lipomulse ™ 165; Tempo 123-94-4, MFR 4.00 4.00 (40-60%), PEG- stabilizers, and viscosity increasing agents Canada 9004-99-3 100 Stearate (40-60%)  9 Stearic Acid Surfactant - emulsifying agent; refatting Stearic Acid; Univar 57-11-4 MFR 0.50 0.50 (naturally occurring fatty acid) 10 Butylated Preservative; antioxidant; BHT; Andicor Specialty 128-37-0 MFR 0.10 0.10 Hydroxy Toluene Chemicals (Evonik) 11 Butyrospermum Active ingredient: Skin conditioning Cetiol ™ SB-45/Fancol Shea 68920-03-6 MFR 2.00 2.00 Parkii (Shea) Butter; Pachem (Cognis)/ Butter Extract Unipex Solution (Elementis) 12 Dimethicone Lubricant and skin conditioning agent; DC 200/350/Element 14 9006-65-9 MFR 2.00 2.00 occlusive; skin protectant; emollient. PDMS 350; Canada Colors or 63148- and Chemicals (Momentive) 62-9 13 Argania Spinosa Active ingredient: Skin conditioning agent - Argan Oil; Centerchem 223747-87- MFR 1.00 1.00 Kernel Oil emollient; occlusive; (DSM) 3 14 Squalane Active ingredient: Lubricant on the skin Keteol ™ V; Pachem 111-01-3 MFR 4.00 4.00 (vegetable source; surface. Skin conditioning agent with Distribution squalene refatting properties - occlusive; emollient. hydrogenation from olive oil.) 15 Caprylic/Capric Caprylic/Capric Triglyceride: Fragrance 50% Ultrafine TiO.sub.2 in 65381-09-1, MFR 1.50 1.50 Triglyceride, Ingredient, Skin conditioning agent- Caprylic/Capric Triglyceride 13463-67-7, Titanium Dioxide, Occlusive Dispersion (R3214, Sensient, 2943-75-1, Triethoxy- Titanium dioxide: Colorant; Opacifying discontinued and replaced by 68308-61-2 caprylylsilane, agent; Sunscreen agent; Ultraviolet Light Sensient Covascreen ™); Castor Oil Absorber Phosphate Triethoxycaprylylsilane: binder Castor Oil Phosphate: anticaking agent, emulsion stabilizer 16 Di-C12-15 Alkyl Active ingredient Skin conditioning agent - Marrix ™ SF; Alzo 142104-11- MFR 1.00 1.00 Fumarate Emollient; solvent International 8 (U.S. Pat. No. 5,840,285) Part C 17 Cyclopentasiloxane, Skin conditioning agent - emollient; Abil ™ OSW-5; 541-02-6, MFR 1.00 1.00 Dimethiconol moisturizer; solvent. Improves wet and dry Andicor Specialty 31692-79-2 compatibility. Exhibits improved skin feel Chemicals (Evonik) and water resistance. Provides smooth but not greasy after feel. Possesses non-fatty and non-sticky properties 18 Acrylates/ Emulsifier; rheology modifier Novemer ™ N/A, 8042- MFR 1.30 1.30 Acrylamide 27% solids, liquid, pre-neutralized polymer EC-1; LV Lomas 47-5, 9005- Copolymer dispersed in oil. It is a multifunctional (Lubrizol) 70-3 (about 26-28%), polymer used in emulsions containing Mineral Oil (about active ingredients with electrolytes and 22-24%), and suspended inorganic pigments. Enhances Polysorbate 85 skin feel, providing soft after feel (1-3%), water (up to 100% i.e., 45-51%)  19a Diazolidinyl Urea Broad-spectrum preservative system Liquid Germall ™ Plus 78491-02-8, MFR 0.5 — (39.6%) against Gram-positive and Gram-negative preservative; Ashland 55406-53-6, Iodopropynyl bacteria, yeast, and mold. (Tempo) 57-55-6 Butylcarbamate (0.4%), Propylene Glycol (60%)  19b Phenoxyethanol Euxyl ™ PE 9010 122-99-6, MFR — 1.00 (85-95%), 70445-33-9 Ethylhexylglycerin (7-13%)  19c 1,2-Hexanediol Symdiol ™ 68 6920-22-5, MFR — 0.60 (25-50), Caprylyl 1117-86-8 Glycol (25-50%) Part D 20 Water Diluent/carrier Purified Water N/A USP 5.00 5.00 21 1,4-Diaminobutane Active ingredient: Skin regeneration. 1,4 Diaminobutane 333-93-7 USP 0.40 0.40 Dihydrochloride Promotes skin repair including wound Dihydrochloride/ healing. Prevents and/or treats scars and Putrescine; skin's signs or aging Alfa Chemistry 22 Allyl Methacrylates Active ingredient: Multi-functional delivery Poly-pore 182212-41- MFR 0.05 0.05 Crosspolymer, system which provides sustained release 120RE; Amcol 5, 9005-64- Polysorbate 20, and reduce the irritation of retinol. Anti- Health and 5, 68-26-8, Retinol (20.5% ± aging and skin rejuvenation. Beauty Solutions 128-37-0 2.0%), Butylated Hydroxy Toluene 23 Pseudoalteromonas Active ingredient: An anti-wrinkle active Trylagen ™ 820959-16- MFR 3.00 3.00 Ferment that combines peptides and proteins which functional 8, 94350- Extract (12.5%), increases collagen production; improves ingredient PCB; 06-8, Hydrolyzed Wheat collagen organization and inhibits collagen Lipotec 68607-88-5, Protein (2.86%), degradation. 960531-53- Hydrolyzed Soy 7, 72957- Protein (1.86%), 37-0, 8002- Tripeptide-10 43-5, Citrulline (0.04%), 11138-66-2, Tripeptide-1 9003-01-4, (0.01%), Lecithin, 102-71-6, Xanthan Gum, 122-99-6, Carbomer, 107-88-0, Triethanolamine, 1117-86-8, Phenoxyethanol N/A (0.71%), Butylene Glycol, Caprylyl Glycol, Water 24 Acetyl Active ingredient: Skin conditioning agent. Uplevity ™ 7732-18-5, MFR 1.50 1.50 Tetrapeptide-2 Tetrapeptide which fights sagginess by peptide solution; 1117-86-8 (Aspartic enhancing key elements to the assembly Lipotec acid, Lysine, of elastin and several collagens and Tyrosine and overexpressing genes involved in cellular Valine adhesion. It induces the expression of residues), proteins Fibulin 5 and Lysyl Oxidase-Like Caprylyl Glycol, 1, contributing to the organisation of elastic Water fibre and upregulates key genes to cellular cohesion through focal adhesions (talin, zyxin, integrins). Moreover, it induces the synthesis of elastin and collagen I. Part E 25 Glycerin, Water, Active ingredient: A glaucine in a water- Bodyfit ™; 56-81-5, MFR 4.00 4.00 Coco-Glucoside, soluble excipient that enhances skin Croda Canada 7732-18-5, Caprylyl Glycol, firmness. (WO 2004/024695) 141464-42- Alcohol (Ethyl 8, 1117-86- alcohol), Glaucine 8, 64-17-5, 475-81-0 26 Leontopodium Active ingredient: Reduces sagginess and Majestem ™; 391900-47- MFR 2.00 2.00 Alpinum Callus improves skin Croda Canada 3, 56-81-5, Culture Extract, (FR 3 031 454 - 11138-66-2 Glycerin, Xanthan WO 2016/113659) Gum 27 Glycerin (used Active ingredient: Peptide solution which Relistase ™ 56-81-5, MFR 3.00 3.00 as a solvent, increases resilience and tightness. solution; 1334583- up to 100%), Lipotec 93-5 Acetylarginyl- tryptophyl Diphenylglycine (0.009-0.011%) 28 3-O-Ethyl Active ingredient: Antioxidant, and wound Et-VC ™ 86404-04-8 MFR 0.50 0.50 Ascorbic Acid healing agent. Increases collagen (Vit C) production and reduce the inflammation 29 Acrylates/ Emulsifier; rheology modifier Novemer ™ EC-1; N/A, 8042- MFR — 0.95 Acrylamide 27% solids, liquid, pre-neutralized polymer LV Lomas 47-5, 9005- Copolymer dispersed in oil. It is a multifunctional (Lubrizol) 70-3 (about 26-28%), polymer used in emulsions containing Mineral Oil (about active ingredients with electrolytes and 22-24%), and suspended inorganic pigments. Enhances Polysorbate 85 skin feel, providing soft after feel (1-3%), water (up to 100% i.e., 45-51%) see also # 18 above 100%

[0176] The above formulations are prepared by adding, in a suitable main stainless-steel tank equipped with a lightening type propeller mixer, all ingredients as indicated in Table until the composition becomes clear and all ingredients have dissolved. The propeller mixer was set to medium to high speed (held at room temperature, i.e., about 21 degrees Celsius). 40mL acrylic double-wall bottles with airless pump were used to store the finish product to reduce product contact with ambient light. The pH of the final compositions was about 6.9 (i.e. 6.93).

TABLE-US-00005 TABLE 5 Process for preparing the neck cream formulation of Table 4 Step Manufacturing Process 1 Sprinkle item 2 into item 1 while vortexing. Mix for about 20 minutes. 2 Sprinkle item 3 into 1 and 2 with mixing. Mix for about an additional 20 minutes or until hydration and no fish eyes are present. 3 Add remaining ingredients in Part A and heat to about 65-70 degrees C. 4 In a separate container, add ingredients in the order listed under Part B and heat Part B to about 70 degrees C. 5 Add Part B to Part A under homogenization. 6 Homogenize for about 20 minutes at high speed till smooth and uniform. 7 Cool product to about 50 degrees C. 8 Add Part C one item at a time with mixing to main batch. 9 Homogenize for about 3-5 minutes at high speed until smooth and uniform. 10 Dissolve item 21 into item 20, then disperse and wet item 22 into items 20 & 21 (Part D) and add to main batch at about 40 degrees C. with mixing. 11 Then add remaining ingredients listed under Part D while mixing. 12 Add ingredients listed under Part E. Add one item at a time in the order listed with mixing. 13 Switch to sweep mixing and cool product. 14 Cool and side sweep mix until about 30 degrees C.

EXAMPLE 3

[0177] Complex body cream compositions comprising putrescine and Vitamin C

TABLE-US-00006 TABLE 6 Exemplary body cream formulations Formu- lation Ingredients (A) Formu- Formu- Ingredients (Trade Name and Amount lation lation item (INCI Name) Function(s) Manufacturer) CAS# Grade % W/W (B) (C) Part A 1 Water Diluent/carrier Purified Water N/A USP 62.81  65.40  63.80  USP; 2 Magnesium Viscosity increasing agent; Veegum ™ Ultra 12199-37-0, MFR 1.00 1.00 1.00 Aluminum Absorbent; Anticaking agent; 13463-67-7, Silicate Opacifying agent; Slip 14808-60-7 modifier 3 Xanthan Gum Binder; Emulsion Stabilizer Jungbunzlauer 11138-66-2 MFR 0.20 0.20 0.20 (gel forming); Skin Xanthan Gum conditioning agent; Surfactant-Emulsifying agent; Viscosity increasing agent 4 Triethanolamine Surfactant and pH adjusting Triethanolamine 102-71-6 MFR 0.30 0.30 0.30 chemical (buffer); Emulsifying agent 5 TetraSodium EDTA Chelating agent Versene ™ 220 8013-51-2 MFR 0.20 0.20 0.20 Part B 6 Behenyl Alcohol Binder; emollient, emulsifier Lanette ™ 22 661-19-8 MFR 1.50 1.50 1.50 and viscosity Increasing (thickener). 7 Cetyl Palmitate Skin conditioning agent - Trivent ™ CP 540-10-3 MFR 1.50 1.50 1.50 Emollient; Occlusive; 8 Glyceryl Stearate, Humectants, solvents, Lipomulse ™ 165 123-94-4, MFR 4.00 4.00 4.00 PEG-100 Stearate binders, emulsion stabilizers, 9004-99-3 and viscosity increasing agents 9 Stearic Acid Surfactant - emulsifying Stearic Acid 57-11-4 MFR 0.50 0.50 0.50 agent; refatting 10 Butylated Preservative; antioxidant; BHT 128-37-0 MFR 0.10 0.10 0.10 Hydroxytoluene 11 Butyrospermum Active ingredient: Skin Cetiol ™ SB-45/ 68920-03-6 MFR 2.00 2.00 2.00 Parkii conditioning Fancol Shea (Shea) Butter Butter Extract 12 Dimethicone Lubricant and skin DC 200/350/ 9006-65-9 or MFR 1.00 1.00 1.00 conditioning agent; occlusive; Element14 PDMS 63148-62-9 skin protectant; emollient. 350 13 Argania Spinosa Active ingredient: Skin Argan Oil 223747-87-3 MFR 1.00 1.00 1.00 Kernel Oil conditioning agent - emollient; occlusive; 14 Squalane Active ingredient: Lubricant Keteol ™ V 111-01-3 MFR 4.00 4.00 4.00 on the skin surface. Skin conditioning agent with refatting properties - occlusive; emollient. 15 Caprylic/Capric Caprylic/Capric Triglyceride: 50% Ultrafine 65381-09-1, MFR 1.50 1.50 1.50 Triglyceride, Fragrance Ingredient, Skin TiO2 in 13463-67-7, Titanium conditioning agent - Caprylic/Capric 2943-75-1, Dioxide, Occlusive Triglyceride 68308-61-2 Triethoxy- Titanium dioxide: Colorant; Dispersion caprylylsilane, Opacifying agent; Sunscreen (R3214, Sensient - Castor Oil agent; Ultraviolet Light Product Phosphate Absorber discontinued and Triethoxycaprylylsilane: replaced by binder Sensient Castor Oil Phosphate: Covascreen ™ anticaking agent, emulsion UVR CCT product stabilizer code: 251351). 16 Di-C12-15 Alkyl Active ingredient Skin Marrix ™ SF 142104-11-8 MFR 1.00 1.00 1.00 Fumarate conditioning agent - (U.S. Pat. No. Emollient; solvent 5,840,285) Part C1 17 Water Diluent/carrier Purified Water N/A USP 2.50 — — USP 18 Hexamidine Antifoaming; skin Elastab ™ HP 100/ 659-40-5 MFR 0.09 — — Diisethionate conditioning; emollient; Minox ™ HD preservative Part D1/Part C2 19 Cyclopentasiloxane, Skin conditioning agent - Abil ™ OSW-5 541-02-6, MFR 1.00 1.00 1.00 Dimethiconol emollient; moisturizer; 31692-79-2 stabilizer and solvent. Improves wet and dry compatibility. Exhibits improved skin feel and water resistance. Provides smooth but not greasy after feel. Possesses non- fatty and non-sticky properties 20 Acrylates/Acrylamide Emulsifier; rheology modifier Novemer ™ EC-1 N/A, MFR 1.00 1.00 1.00 Copolymer (about 26- 27% solids, liquid, pre- 8042-47-5, 28%), Mineral Oil (about neutralized polymer 9005-70-3 22-24%), and Polysorbate dispersed in oil. It is a 85 (1-3%), water (up to multifunctional polymer used 100% i.e., 45-51%) (see in emulsions containing also item 34 below) active ingredients with electrolytes and suspended inorganic pigments. Enhances skin feel, providing soft after feel 21 Diazolidinyl Urea, Broad-spectrum preservative Liquid Germall ™ 78491-02-8, MFR 0.50 0.50 — lodopropynyl system against Gram- Plus preservative 55406-53-6, Butylcarbamate, positive and Gram-negative 57-55-6 Propylene Glycol bacteria, yeast, and mold. Part C3 (formulation (C) only) 22 Phenoxyethanol Preservative Eukyl ™ PE 9010 122-99-6, MFR — — 1.00 (85-95%), 70445-33-9 Ethylhexylglycerin (7-13%) 23 1,2-Hexanediol Preservative Symdiol ™ 68 6920-22-5, MFR — — 0.60 (25-50), 1117-86-8 Caprylyl Glycol (25-50%) Part E/Part D2 24 Water Diluent/Carrier Purified Water N/A USP 2.50 2.50 2.50 USP 25 Allyl Methacrylates Active ingredient: Multi- Poly-pore 120RE 182212-41-5, MFR 0.05 0.05 0.05 Crosspolymer, functional delivery system 9005-64-5, Polysorbate 20, which provides sustained 68-26-8, Retinol, release and reduce the 128-37-0 Butylated irritation of retinol. Hydroxytoluene Anti-aging and skin rejuvenation. 26 Pseudoalteromonas Active ingredient: An anti- Trylagen ™ 820959-16-8, MFR 1.50 1.50 1.50 Ferment Extract (12.5%), wrinkle active that combines functional 94350-06-8, Hydrolyzed Wheat Protein peptides and proteins which ingredient PCB 68607-88-5, (2.86%), Hydrolyzed Soy increases collagen 960531-53-7, Protein (1.86%), production; improves 72957-37-0, Tripeptide-10 Citrulline collagen organization and 8002-43-5, (0.04%), Tripeptide-1 inhibits collagen 11138-66-2, (0.01%), Lecithin, Xanthan degradation. 9003-01-4, Gum, Carbomer, 102-71-6, Triethanolamine, 122-99-6, Phenoxyethanol (0.71%), 107-88-0, Butylene Glycol, Caprylyl 1117-86-8, Glycol, Water N/A 27 Water (up to 100%), Active ingredient Skin Collagen-Hyal ™ N/A, MFR 2.50 2.50 2.50 Soluble Collagen (0.8- conditioning agent, 9067-32-7 1%), Sodium Hyaluronate humectant, skin hydration. (0.09-011%) In the presence of water Hyaluronic acid resume a spherical coiled shape binding and immobilizing water and conferring a superior smoothness to the skin. Native soluble collagen molecules are long linear coils and form a thin hydrated film on the skin surface. The complexation of these two actives by means of a special proceeding provides a powerful hydration factor. 28 Hydroxyresveratrol (1.0- Active ingredient: inhibitor NIO-Oxy 4721-07-7, MFR 1.00 1.00 1.00 3.0%), Polyglyceryl-10 of tyrosinase (enzyme which 79665-93-3, Oleate (20.0-25.0%), catalyzes the rate limiting 51033-38-6, Polyglyceryl-6 Laurate step in melanin synthesis. 26266-57-9, (12.0-16.0%), Sorbitan Skin lightener. 2197-63-9, Palmitate (6.0-8.0%), N/A Dicetyl Phosphate (6.0- 8.0%), Water (45.0- 50.0%) 29 Water, Hydrolyzed Milk Active ingredient. Skin Kelimilk ™ 92797-39-2 MFR 2.00 2.00 2.00 Protein (casein and free conditioning and film-forming (Liquid) amino acids, average properties, and moisturising molecular weight of 2500 and protecting effects. Daltons and about 20% of free amino acids) 30 Leontopodium Alpinum Active ingredient: Reduces Majestem ™ 391900-47-3, MFR 1.00 1.00 1.00 Callus Culture Extract, sagginess and improves skin (FR 3 031 454 - 56-81-5, Glycerin, Xanthan Gum WO 2016/113659) 11138-66-2 31 3-O-Ethyl Ascorbic Acid Active ingredient: Et-VC ™ 86404-04-8 MFR 0.50 0.50 0.50 Antioxidant, and wound healing agent. Increases collagen production and reduce the inflammation 32 1,4-Diaminobutane Active ingredient: Skin 1,4- 333-93-7 USP 0.40 0.40 0.40 Dihydrochloride regeneration. Promotes skin Diaminobutane repair including wound Dihydrochloride; healing. Prevents and/or Alfa Chemistry treats scars and skin's signs or aging 33 Hydrolyzed Sodium Active ingredient. MiniHA ™ (HA- 9067-32-7 MFR 0.30 0.30 0.30 Hyaluronate (<10 kDa) Moisturizing, repairing cells Oligo degraded by damaged by UV, scavenging hyaluronidase) free radical and anti-aging. 34 Mica, Titanium Dioxide pearlescent and iridescent Flamenco Satina 12001-26-2, MFR 0.50 0.50 0.50 pigment 120T 134-67-7 35 Fragrance N.A. Petal Blush Sozio N/A MFR 0.05 0.05 0.05 SZ1821OP Part E2 36 Acrylates/Acrylamide See item # 20 above Novemer ™ EC-1 MFR — — 0.5 Copolymer (about 26- 28%), Mineral Oil (about 22-24%), and Polysorbate 85 (1-3%), water (up to 100% i.e., 45-51%) pH: 6.62 6.62 6.62 100    100    100   

[0178] The above formulations were prepared by adding, in a suitable stainless-steel tank equipped with a lightening type propeller mixer, all ingredients as indicated in Table 6 until the composition became clear and all ingredients have dissolved. The propeller mixer was set to medium to high speed (held at room temperature, i.e., about 21 degrees Celsius). AS200J/PP 200 mL Moldey grey PMS 8C, metallic coating PMS877C, protective coating, silkscreen PMS426, hot stamp shiny silver airless pump bottle containers were used to store the finish product to reduce product contact with ambient light. A nitrogen blanket and yellow light was used for Part E until the end of the manufacturing process. The pH of the final compositions was between about 6.5 to 7.5.

[0179] The main differences between formulations (A), (B) and (C) described in Table 6 reside in the type of preservative system used. In Formula (A) of Table 6 a combination of hexamidine diisethionate (Part C, item 18) and broad spectrum preservative system (Diazolidinyl Urea, lodopropynyl Butylcarbamate, Propylene Glycol (Germall Plus, Item 21 in Table 6)) is used. Formula (B) is identical to Formula (A), except that hexamidine diisethionate (Part C, item 18) is not present (removed because discontinued). Formula (C) uses a further alternative preservative system comprising a first preservative agent comprised of Phenoxyethanol (85-95%) and Ethylhexylglycerin (7-13%) and a second preservative agent comprising 1,2-hexanediol and caprylyl glycol. All formulations ((A), (B) and (C)) comprise butylated hydroxytoluene as a further preservative agent which is also an antioxidant.

TABLE-US-00007 TABLE 7 Process for preparing the body cream Formulation (A) of Table 6 Step# Manufacturing Process N.B. Manufactured using a Nitrogen blanket and yellow light from Step 11 (Part E/D2 until the end) 1 Sprinkle item 2 into item 1 while vortexing. Mix for about 20 minutes. 2 Sprinkle item 3 into 1 and 2 while mixing. Mix for about an additional 20 minutes or until hydration and no fish eyes are present. 3 Add remaining ingredients in Part A and heat to about 65-70 degrees C. 4 In a separate container, add ingredients in the order listed under Part B and heat Part B to about 70 degrees C. 5 Add Part B to Part A with homogenization. 6 Homogenize for about 20 minutes at high speed till smooth and uniform. 7 Cool product to about 50 degrees C. 8 Heat ingredients listed under part C1 together to about 75-80 degrees C. and until all dissolved and clear and compensate for water loss, if necessary. Set aside to use later in the procedure. 9 Add Part D1 one item at a time with mixing to main batch (Parts A and B). 10 Homogenize for 3-5 minutes at high speed until smooth and uniform. 11 Prepare Part E 12 Wet and dissolve item 23 into item 22 (Part E), then add the remaining ingredients one by one to Part E while mixing in between additions until homogenous. Then, add to main batch at 40 degrees C. with mixing. 13 Now add Part C1 to Part A/B/D1/E with mixing. 13 Switch to sweep mixing and cool product. 14 Cool and side sweep mix until about 30 degrees C.

TABLE-US-00008 TABLE 8 Process for preparing the body cream Formulation (B) of Table 6: Step# Manufacturing Process N.B. Manufacture using a Nitrogen blanket and yellow light from Step 11 (Part E until the end) 1 Sprinkle item 2 into item 1 while vortexing. Mix for about 20 minutes. 2 Sprinkle item 3 into 1 and 2 with mixing. Mix for about an additional 20 minutes or until hydration and no fish eyes are present. 3 Add remaining ingredients in Part A and heat to about 65-70 degrees C. 4 In a separate container, add ingredients in the order listed under Part B and heat Part B to about 70 degrees C. 5 Add Part B to Part A with homogenization. 6 Homogenize for about 20 minutes at high speed till smooth and uniform. 7 Cool product to about 50 degrees C. 8 Heat ingredients listed under part C together to 75-80 degrees C. and until all dissolved and clear and compensate for water loss, if necessary. Set aside to use later in the procedure. 9 Add Part C2 one item at a time with mixing to main batch (Parts A and B). 10 Homogenize for about 3-5 minutes at high speed until smooth and uniform. 11 Prepare Part E/Part D2 12 Wet and dissolve item 21 into item 20 (Part D2) then add to main batch at about 40 degrees C. with mixing. Then add the remaining ingredients one by one listed under Part D2 while mixing in between additions until homogenous. 13 Now add Part C to Part A/B/D/E with mixing. 14 Switch to sweep mixing and cool product. 15 Cool and side sweep mix until about 30 degrees C.

TABLE-US-00009 TABLE 9 Process for preparing body cream Formulation (C) of Table 6: Step# Manufacturing Procedure N.B. Manufacture using a Nitrogen blanket and yellow light from Step 11 (Part E until the end) 1 Sprinkle item 2 into item 1 while vortexing. Mix for about 20 minutes. 2 Sprinkle item 3 into 1 and 2 while mixing. Mix for about an additional 20 minutes or until hydration and no fish eyes are present. 3 Add remaining ingredients in Part A and heat to about 65-70 degrees C. 4 In a separate container, add ingredients in the order listed under Part B and heat Part B to about 70 degrees C. 5 Add Part B to Part A with homogenization. 6 Homogenize for about 20 minutes at high speed till smooth and uniform. 7 Cool product to about 50 degrees C. 8 Add ingredients listed under Part C2: one by one mixing in between addition followed by about 10-15 minutes of homogenization and circulation. Formulation will thicken. 9 Add Part C3 one item at a time while mixing to main batch (Part A/B/C2). 10 Homogenize for about 3-5 minutes at high speed until smooth and uniform. Then cool main batch to about 40 degrees C. 11 Prepare Part D2 (during cooling). 12 Wet and dissolve item 22 into item 21 (Part D2), then add the remaining ingredients one by one to Part D2 while mixing in between additions until homogenous. Then add to main batch at about 40 degrees C. with mixing. 13 Now add Part E2 to Part A/B/C2/C3/D2 with mixing. Then homogenize about 10-15 with circulation to achieve desired. 14 Switch to sweep mixing and cool product. 15 Cool and side sweep mix until about 30 degrees C.

EXAMPLE 4

Stability Of Compositions of the Present Invention

[0180] Preliminary stability tests of compositions of the present invention comprising putrescine (0.4%) together with Retinol, and optionally Vitamin C (e.g. 0.05%, 0.5%, 1%, or more of 3-0-3thyl Ascorbic acid and/or ascorbyl palmitate) show that the compositions are stable. Indeed, no significant change in color, odor, pH and texture (including absence of multiple phases, and precipitate) were observed. Further stability tests were conducted at 25° C. in an atmosphere of +/−2% to 75% relative humidity as detailed in Table 10 below.

TABLE-US-00010 TABLE 10 Stability program designed for putrescine and Vitamin C formulations 25° C. .sup.+/−2 to 75% relative humidity Observed Time Points (in months): characteristic 0 3 6 9 12 18 24 30 36 42 48 Organoleptic C C C C C C C C C C C pH: USP <791>: .sup.(1) C C C C C C C C C C C Viscosity: USP C C C C C C C C C C C <912>: .sup.(2) Putrescine C C C C C C C C C C C level: HPLC Method.sup.(3) Microbiology; C C C C C C C C C C C USP<61>.sup.(4) and USP<62>.sup.(5) C = Results conform to specifications. .sup.(1) The pH value similar to the initial one overtime ±10%. .sup.(2) The Viscosity similar to the initial one over time ±10%. .sup.(3)The Putrescine ±10% of the initial concentration of the formula .sup.(4)USP<61> = Total Aerobic Count <100 cfu/g and yeasts and moulds <100 cfu/g .sup.(5)USP<62> = S. aureus, P. aeruginosa, E. coli, Salmonella sp all absent.

[0181] 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:

[0182] 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 SS.

[0183] 2. Use of topical ascorbic acid and its effects on photo damaged skin topography. Arch Otolaryngol Head Neck Surg 125:1091-98, 1999.

[0184] 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).

[0185] 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.

[0186] 5. Zhang M. et al., Spermine inhibits proinflammatory cytokine synthesis in human mononuclear cells: a counterregulatory mechanism that restrains the immune response. J. Exp. Med. 185, 1759-68 (1997);

[0187] 6. Soda K. et al., Spermine, a natural polyamine, suppresses LFA-1 expression on human lymphocyte. J. Immunol. 175, 237-45 (2005); and

[0188] 7. Soda K. et al., Polyamines' anti-aging effects. Food style 21, 10(10), 43-54 (2006);

[0189] 8. Sheokand, Sunita, Anita Kumari, and Veena Sawhney. “Effect of Nitric Oxide and Putrescine on Antioxidative Responses under NaCl Stress in Chickpea Plants.” Physiology and molecular biology of plants: an international journal of functional plant biology 14.4 (2008): 355-362. PMC. Web. 14 Jun. 2017.

[0190] 9. Dolynchuk K N et al., Effect of Putrescine on tissue transglutaminase activity in wounds: Decreased breaking strength and increased matrix Fucoprotein solubility, Plast Reconstr. Surg. 1994; 93: page 567-573.