Topical liposome compositions containing phenolic anti-inflammatory agents and their methods of preparation

Abstract

Liposomal topical compositions containing phenolic anti-inflammatory agents, and methods for making thereof, are presented. These compositions are generally used for helping to prevent solar radiation-induced skin damage and helping to prevent and/or treat inflammatory dry skin conditions caused by eczema and contact dermatitis.

Claims

1. A method for preparing an aqueous liposome concentrate composition to be dispersed into a cosmetically-acceptable base, said method comprising the steps of: a) mixing and dissolving into one or more cosmetically-acceptable alcohol solvents: one or more phenolic anti-inflammatory agents, one or more glycerophospholipids, and one or more skin-related lipids selected from the group consisting of cholesterol, cholesterol derivatives, ceramides, sphingomyelin, long chain fatty acids and mixtures thereof; step a) being performed at a temperature superior to the transition temperature of the glycerophospholipid and under nitrogen blanketing; and b) adding an aqueous medium to the solution made in a) with constant stirring until formation of the liposome concentrate composition as a homogeneous milky dispersion; step b) being performed at a similar temperature than in step a) and under nitrogen blanketing.

2. The method as claimed in claim 1 wherein the liposome concentrate composition comprises spherical vesicles having membranes in a bilayer arrangement of said one or more phenolic anti-inflammatory agents, said one or more glycerophospholipids and said one or more skin-related lipids.

3. The method as claimed in claim 1, wherein the one or more phenolic anti-inflammatory agents comprise green tea catechin, proanthocyanidin, resveratrol, curcumin, silibinin, silymarin, carnosic acid, genestein, nordihydroguaiaretic acid, apigenin, quercetin, caffeic acid, ferulic acid, ellagic acid, kaempferol or a mixture thereof.

4. The method as claimed in claim 1, wherein the phenolic anti-inflammatory agent is epigallocatechin gallate.

5. The method as claimed in claim 1, wherein the one or more glycerophospholipids are phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphatidylinositol or a mixture thereof.

6. The method as claimed in claim 1, wherein the one or more cosmetically acceptable alcohol solvents is ethyl alcohol.

7. The method as claimed in claim 2, wherein the spherical vesicles comprise multilamellar membranes.

8. A topical composition comprising an aqueous liposome concentrate composition as prepared by the method of claim 1, and dispersed under nitrogen blanketing in a cosmetically-acceptable aqueous base having an acidic pH and optionally comprising an antioxidant.

9. The topical composition as claimed in claim 8, wherein the liposome concentrate composition contains epigallocatechin gallate and further comprises a water soluble antioxidant selected from ascorbic acid and its derivatives.

10. The topical composition as claimed in claim 9, having a pH value between 4.2 and 4.6.

11. The topical composition of claim 8, wherein the liposomal composition is present at a concentration of 5% to 40% by weight of the topical composition.

12. The topical composition of claim 8, wherein the topically acceptable base is in a form of a suspension, a gel, a cream or a lotion.

13. The topical composition as claimed in claim 8, wherein the one or more phenolic anti-inflammatory agents comprise green tea catechin, proanthocyanidin, resveratrol, curcumin, silibinin, silymarin, carnosic acid, genestein, nordihydroguaiaretic acid, apigenin, quercetin, caffeic acid, ferulic acid, ellagic acid, kaempferol or a mixture thereof.

14. The topical composition as claimed in claim 8, wherein the phenolic anti-inflammatory agent is epigallocatechin gallate.

15. The topical composition as claimed in claim 8, wherein the one or more phenolic anti-inflammatory agents are present at a concentration of about 0.1% to about 5.0%.

16. The topical composition as claimed in claim 8, wherein the one or more glycerophospholipids are phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphatidylinositol or a mixture thereof.

17. The topical composition as claimed in claim 16, wherein the one or more glycerophospholipids are present at a concentration of about 1% to about 4%.

18. The topical composition as claimed in claim 8, wherein the one or more skin-related lipids are present at a concentration of about 0.001% to about 0.1%.

19. The topical composition as claimed in claim 8, wherein the cosmetically-acceptable alcohol solvent is ethyl alcohol.

20. The topical composition as claimed in claim 19, wherein the ethyl alcohol is present at a concentration of about 0.5% to about 3%.

21. A method for reducing inflammatory skin conditions comprising the step of administering an effective amount of the topical composition as claimed in claim 8 to a subject in need thereof.

22. The method as claimed in claim 21, wherein the inflammatory skin conditions are redness, itchiness or dryness of the skin due to atopic dermatitis, allergic dermatitis, contact dermatitis, or environmentally-induced skin damage.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) According to a preferred aspect of the invention, it is provided topical compositions containing lamellar bilayer vesicles comprised of glycerophospholipids, stratum corneum type lipids and one or more encapsulated phenolic anti-inflammatory agents.

(2) Preferably the bilayer vesicles are unilamellar, oligolamellar or multilamellar, more preferably multilamellar vesicles.

(3) Preferably the vesicles are comprised of glycerophospholipids from natural or synthetic sources. Preferably the natural glycerophospholipids are chosen from egg or soy lecithin, and more preferably from soy lecithin. Preferably the glycerophospholipids are chosen from one or more of phosphatidylcholine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, phosphatidic acid, phosphatidylethanolamine. More preferably the glycerophospholipid is chosen from phosphatidylcholine, and more preferably a phosphatidylcholine with side chains comprised of 10 to 18 carbon atoms and even more preferably with saturated side chains. Preferably the glycerophospholipids are present in the final topical composition at a concentration of about 1% to about 4%, and more preferably between 1.5 and 2.5%.

(4) Preferably the stratum corneum type lipids are present in the final topical composition at a concentration of about 0.001% to about 0.10%. Preferably, the stratum corneum lipids are chosen from cholesterol and its derivatives, ceramides, sphingomyelin, long chain fatty acids such as stearic, palmitic and myristic acid.

(5) Preferably the phenolic anti-inflammatory agent is present in the composition at a concentration of about 0.1% to about 5%, more preferably 0.5 to 2.5% (all weights given herein are by percentages unless otherwise specified). Preferably, the phenolic anti-inflammatory agent is chosen from natural or synthetic sources. More preferably the phenolic agent is selected from plant, fruit, and vegetable sources such as a green tea catechin, proanthocyanidins, resveratrol, curcumin, silibinin, silymarin, carnosic acid, genestein, nordihydroguaiaretic acid, apigenin, quercetin, caffeic acid, ferulic acid, kaempferol. Preferably, the anti-inflammatory agent is selected from green tea catechins, and even more preferably epigallocatechin gallate.

(6) The final compositions of the invention may further include from about 0.5 to 3% ethyl alcohol; from about 1% to about 10% of a humectant; from about 1% to about 5% of an emollient; from about 1% to about 5% of a viscosity promoting agent; from about 0.1% to about 2% of an alkalizing agent; from about 0.05 to about 0.25% of an antioxidant; from about 0.1% to about 2% of a preservative.

(7) Preferably, the humectant is selected from glycerol, propylene glycol and sorbitol.

(8) Preferably, the emollient is selected from a vegetable oil, mineral oil or a fatty acid ester, or mixtures thereof that are capable of providing a solubility support role for poorly water soluble and non-encapsulated polyphenols presenting with crystal deposition in the continuous aqueous phase.

(9) Preferably, the viscosity-promoting agent is selected from polyvinyl carboxy polymers, polyacrylamides, guar gum, xanthan gum, caesalpinia spinosa gum, alginates, carboxymethylcelluose (CMC), hydroxyethyl cellulose (HEC), gum arabic, locust bean gum, tragacanth, agar agar, or mixtures thereof. More preferably, the viscosity-promoting agent consists of polyacrylamides and caesalpinia spinosa gum.

(10) Preferably, the alkalizing agent is selected from citrates, phosphates, acetates, ascorbates, and triethanolamine. More preferably, it consists of triethanolamine.

(11) Preferably the pH is adjusted in the range of 4.0 to 4.8, more preferably in the range of 4.4 to 4.6.

(12) Preferably the antioxidant is selected from ascorbic acid, its esters or its sodium salt, or mixtures thereof.

(13) Preferably, the preservative is selected from methylparaben, propylparaben, butylparaben, phenoxyethanol, benzoic acid, diazolidinyl urea, sorbic acid or its salts, or mixtures thereof. More preferably, the preservative is a mixture of methylparaben, propylparaben and diazolidinyl urea.

(14) 1) Processes for Preparing Liposome Concentrate Compositions

(15) According to another aspect of the invention there is provided processes for preparing liposome concentrate compositions that are easily dispersed into conventional topical hydrophilic base compositions. Although any method and material similar to those described herein can be used in the practice for testing of the present invention, the preferred methods and materials are described.

(16) According to a preferred aspect of the invention the entire processing operation is conducted under nitrogen blanketing.

(17) The batch sizes for the liposome concentrate phase of the operation are preferably in the range of about 5 to 40% of the final topical composition, more preferably in the range of about 15 to about 25% percent.

(18) Alcohol, glycerophospholipid, other stratum corneum type lipids and one or more phenolic anti-inflammatory agents are stirred until dissolved in a suitable container. In a separate container purified water is added in small portions to the alcohol phase with continuous stirring. When transition temperatures (TC) of the glycerophospholipids exceed room temperatures, both alcohol and aqueous phases are preheated to temperatures several degrees above TC. The water phase is initially added slowly and immediately following a thickening and then thinning phase of the stirred dispersion, the water phase can be added at a more rapid rate. In the event of excessive precipitation problems occurring during the concentrate preparation, a suitable portion of the contributing bioactive agent(s) must be removed from the batch and incorporated in the base cream phase with special attention to its oil/water solubility characteristics and inclusion if necessary of appropriate oil-solubilizing ingredients. The end result for the liposome concentrate composition is a homogeneous milky emulsion which is stored under nitrogen blanketing in well-sealed containers until required.

(19) The base composition is easily prepared by anyone skilled in the art. The liposome concentrate is than added to the base composition with continuous stirring and storage under nitrogen until required for packaging.

EXAMPLES

(20) The following example is illustrative of the wide range of applicability of the present invention and is not intended to limit its scope. Modifications and variations can be made therein without departing from scope of the invention. Although any method and material similar or equivalent to those described herein can be used in the practice for testing of the present invention, the preferred methods and materials are described.

Example 1

(21) Gel-Cream:

(22) In this formulation containing 0.5% EGCG, it was necessary to reduce the bioactive to approximately 40% in the concentrate component because of excessive precipitation occurring when the total amount of EGCG was used in the preparation. Bioactive remainder possessing adequate water solubility properties is easily included in the base cream aqueous phase. Since the transition temperature of hydrogenated phosphatidylcholine is ˜55° C., both alcohol and aqueous phases in the concentrate portion need to be preheated to ˜58-62° C. prior to mixing.

(23) Part 1—15% Concentrate:

(24) TABLE-US-00001 Ingredients % in Conc. % in Cream *Phospholipon 90H ™ 11.000 2.200 **Teavigo ™ 0.950 0.190 Ceramide 2 0.015 0.003 Cholesterol 0.060 0.012 Alcohol 10.000 2.000 Purified Water 52.950 10.595 TOTAL 100.000 15.000 *Hydrogenated soy phosphatidylcholine (HPC), Lipoid LLC, Newark NJ; **Epigallocatechin gallate, DSM Nutrition;
Part 2—85% Cream Base:

(25) TABLE-US-00002 Ingredients % Purified Water 73.790 Ascorbic acid 0.200 Teavigo 0.310 Sorbitol 70% 4.000 Triethanolamine (50%) - QS to 0.260 adjust pH to 4.5 ± 0.1 Isopropyl Palmitate 2.500 Cyclomethicone 1.000 Germaben II 1.000 Sepigel 307 1.100 Solagum Tara 1.100 TOTAL 85.000
Part 3—Final Formulation Processing:

(26) Add Part 1 to Part 2 with continuous stirring under nitrogen blanketing. Final pH=4.50.

Example 2

(27) Antibiotic-Induced Skin Rashes:

(28) The formulation provided in EXAMPLE 1 was used to treat severe skin rashes developed on the legs and arms of an 82 year old woman who had been prescribed the antibiotic Cipro by her physician to treat a lung infection. The itching was severe enough to cause spot bleeding at some skin sites due to scratching but most importantly to her discomfort was lack of sleep at night. Cream application not only immediately relieved the itching but allowed her to sleep uninterrupted through the first and subsequent nights after applying the medication. Cipro administration was eventually stopped due to occurrence of another more serious adverse event but her affected skin areas had returned to normal.

Example 3

(29) Mild-to-Moderate Eczema:

(30) The formulation provided in EXAMPLE 1 was used in a short term study to treat a 48 year old woman who has had eczema year-round all her life and is currently employed in the international marketing department of a pharmaceutical company. She previously used OTC hydrocortisone creams to relieve itching on her hands and other skin areas during eczema flare-up episodes. Her experience with our formulation as recorded in a daily diary started with eczema flare-ups caused by onset of cold wintry weather and use of heavy clothing. The flare-ups included dry itchy cracked skin on hands as well as itching and redness in the neck area brought on through skin contact with a scarf or wool coat. Twice daily cream application, morning after showering and evening before retirement, was performed over a 4 day period. After Day 1 she recorded less itching and the cream to be instantly soothing and Day 2 starting to see the eczema diminish. After Day 3 she observed “remarkable improvement” with no evidence of itchiness and redness is gone. After Day 4 her hands had almost healed but skin still a little raw. However symptoms of eczema had disappeared and the neck area had completely healed. Her overall comment on the cream was that the formulation was soothing and moisturized the skin immediately.

Example 4

(31) Severe Eczema:

(32) The formulation provided in EXAMPLE 1 was used on nightly application only along with Betaderm (betamethasone valerate) by a 52 year old woman who has had a more severe form of eczema year-round all her life and is currently employed in the nursing profession. Her eczema consisted of redness, scaling and swelling appearing on crack on little finger along with lesions behind the right knee and inside the right elbow. Her overall comments of the cream after a four day application were that once the eczema episode is gone the cream seems to keep the eczema away. Her personal feeling of the cream is very good to keep the eczema away and a great moisturizer but does not appear to heal the lesions.

INCORPORATION BY REFERENCE

(33) The entire contents of all published patent applications and other references cited herein are hereby expressly incorporated herein in their entireties by reference.

EQUIVALENTS

(34) Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents were considered to be within the scope of this invention and are covered by the following claims. The contents of all references, issued patents, and published patent applications cited throughout this application are hereby incorporated by reference.