Process for preparing a dermatological composition comprising oleosomes

Abstract

A method is described for producing an oil-in-water emulsion including oil globules, the mean diameter of which is less than 500 nm and each of which is provided with a lamellar liquid crystal coating, and which are dispersed in an aqueous phase. Each oil globule is individually coated with a unilamellar or oligolamellar layer obtained from at least one lipophilic surfactant, at least one hydrophilic surfactant, and at least one separate anionic surfactant, characterized in that the number of steps in the method is no greater than 5, in that the temperatures used during the different steps are no higher than 75 C., and in that the method requires neither the use of a high-pressure homogenizer nor any pre-emulsification step.

Claims

1. A process of manufacturing an oil-in-water emulsion, the process comprising: (a) mixing, at a temperature of between 65 C. and 75 C., at least one lipophilic surfactant, at least one hydrophilic surfactant, and at least one anionic surfactant to obtain a homogeneous fatty phase mixture (A), wherein the fatty phase mixture (A) comprises 45% to 50% by weight relative to the total weight of the fatty phase mixture (A) of the lipophilic surfactant, 30% to 35% by weight relative to the total weight of the fatty phase mixture (A) of the hydrophilic surfactant, and 20% to 25% by weight relative to the total weight of the fatty phase mixture (A) of the anionic surfactant, (b) heating a homogeneous aqueous phase mixture (B) to a temperature of between 65 C. and 75 C., (c) stirring the homogenous aqueous phase mixture (B) of (b) into the fatty phase mixture (A) of (a) to obtain a homogeneous emulsion, wherein the stirring is performed with a homogenizer at a speed between 10,000 rpm and 13,000 rpm or a turbomixer at a speed between 700 rpm and 3000 rpm between 25 minutes to 1 hour, and (d) cooling the homogeneous emulsion of (c) by introducing water into the mixture and stirring at a speed of between 1000 rpm and 3000 rpm until the temperature of the emulsion is between 25 C. and 50 C. to provide the oil-in-water emulsion, wherein: the oil-in-water emulsion comprises oil globules dispersed in the aqueous phase mixture (B) and each of the globules have a lamellar liquid crystal coating that is a monolamellar layer or an oligolamellar layer obtained from the lipophilic surfactant, the hydrophilic surfactant, and the anionic surfactant, the homogeneous aqueous phase mixture (B) comprises water and optionally a humectant, a basic agent, preserving agent, chelating agent, antioxidant, calmatives, anti-irritants, or combinations of two or more thereof, and every step of the process is performed at a temperature of less than or equal to 75 C., without a high pressure homogenizer, and without a pre-emulsification step, wherein the pre-emulsification consists of homogenizing the homogeneous fatty phase mixture (A) and the homogeneous aqueous phase mixture (B) in which both are heated to a temperature of 80 C. to 95 C.

2. The process as claimed in claim 1, wherein at least one lipophilic surfactant has an HLB of between 2 and 5.

3. The process as claimed in claim 2, wherein the lipophilic surfactant with an HLB of between 2 and 5 is selected from the group consisting of sucrose distearate, sucrose tristearate, diglyceryl distearate, tetraglyceryl tristearate, decaglyceryl decastearate, diglyceryl monostearate, sorbitan monostearate, sorbitan tristearate, 15 diethylene glycol monostearate, a glyceryl ester of palmitic acid, stearic acid, polyoxyethylene monostearate comprising 2 oxyethylene units, polyoxyethylene stearyl ether comprising 2 oxyethylene units, glyceryl monobehenate, glyceryl dibehenate and pentaerythrityl tetrastearate.

4. The process as claimed in claim 1, wherein at least one hydrophilic surfactant has an HLB of between 8 and 12.

5. The process as claimed in claim 4, wherein the hydrophilic surfactant with an HLB of between 8 and 12 is selected from the group consisting of polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene monostearate, hexaglyceryl monostearate, polyoxyethylene (10) monostearate, polyoxyethylene stearyl ether, polyoxyethylene distearate, and polyoxyethylene methylglucose distearate.

6. The process as claimed in claim 1, wherein the distinct anionic surfactant is a fatty acid or a fatty acid ester, the fatty acid comprising at least one saturated fatty chain having more than 12 carbon atoms, neutralized anionic lipids, amphoteric lipids, and alkylsulfonic derivatives.

7. The process as claimed in claim 6, wherein the fatty acid comprising at least one saturated fatty chain has between 16 and 22 carbon atoms.

8. The process as claimed in claim 1, wherein the distinct anionic surfactant is selected from the group consisting of stearic acid, palmitic acid, arachidic acid, behenic acid, and sodium stearoyl glutamate.

9. The process as claimed in claim 1, wherein the oil-in-water emulsion further comprises at least one active agent selected from the group consisting of a retinoid, glycyrrhetinic acid, and zinc gluconate.

10. The process as claimed in claim 9, wherein the active agent is 3-tert-butyl-4-(2-hydroxyethoxy)-4-pyrrolidin-1-yl-[1,1,3,1]-terphenyl-4-carboxylic acid.

11. The process as claimed in claim 9, wherein the oil-in-water emulsion comprises a retinoid in an amount of from 0.00001% to 0.05% by weight relative to the total weight of the oil-in-water emulsion.

12. The process as claimed in claim 1, wherein the mixing step a) is conducted with vigorous stirring by a turbomixer.

13. The process as claimed in claim 12, wherein the turbomixer of step a) is operated at a speed of from 700 rpm to 1500 rpm.

14. The process as claimed in claim 13, wherein the turbomixer of step a) is operated at a coaxial speed of from 20 rpm to 40 rpm.

15. The process as claimed in claim 1, wherein the mixing step c) is conducted with vigorous stirring by a turbomixer.

16. The process as claimed in claim 15, wherein the turbomixer of step c) is operated at a coaxial speed of between 20 rpm and 40 rpm.

17. The process as claimed in claim 1, wherein the mixing in step c) is conducted with vigorous stirring by a rotor-stator stirrer.

18. The process as claimed in claim 1, wherein the cooling in step d) is performed by introducing water into the mixture obtained in step c) until the temperature of the emulsion is less than or equal to 40 C.

19. The process as claimed in claim 1, wherein a gelling agent is introduced into the cooled mixture obtained in step d) to obtain a cream.

20. The process as claimed in claim 1, wherein the process limits destabilization or degradation of the emulsion.

21. The process as claimed in claim 1 wherein at least one heat-sensitive excipient and/or active principle is introduced into the fatty phase mixture (A) during step a), into the aqueous phase mixture (B) during step b), into the emulsion after step c) and before step d), or after cooling step d).

22. The process as claimed in claim 1, wherein the homogeneous aqueous phase mixture (B) comprises between 25% and 90% by weight water.

23. The process as claimed in claim 1, wherein the globules have a mean diameter of less than 800 nm.

Description

EXAMPLE 1

Manufacturing Process at the Laboratory Scale (100 g-2 kg)

(1) The composition that follows is prepared according to the protocol indicated below.

(2) Its macroscopic and microscopic appearance at TO are studied, and the pH is measured.

(3) The viscosity is also measured using a Brookfield viscometer.

(4) The physical and chemical stability are evaluated at 1, 2 and 3 months, at room temperature (RT) and at 40 C.

(5) The size of the oleosomes was checked just after manufacture by DLS (dynamic light scattering) using a Nano ZS Zetasizer particle size analyzer (Malvern Instruments), after diluting the samples in distilled water.

(6) The results obtained are given after each composition.

(7) TABLE-US-00001 EXAMPLE 1 - Composition Trade name INCI name % 3-tert-Butyl-4-(2-hydroxyethoxy)-4-pyrrolidin-1-yl- 0.01 [1,1; 3,1]-terphenyl-4-carboxylic acid (active agent hereinbelow) A BRIJ S10-SO STEARETH-10 1.25 A SPEZIOL L2SM GS PHARMA STEARIC-/PALMITIC ACID 0.85 A BRIJ S2-SO STEARETH-2 1.80 A SPEZIOL C18 PHARMA STEARYL ALCOHOL 0.25 A MIGLYOL 812 N CAPRYLIC/CAPRIC TRIGLYCERIDES 15.50 A PHENOXETOL PHENOXYETHANOL 1.00 A DL-ALPHA-TOCOPHEROL ALPHA TOCOPHEROL 0.20 A ST-CYCLOMETHICONE 5-NF CYCLOPENTASILOXANE 4.00 B PURIFIED WATER AQUA (WATER) 21.80 B TRIETHANOLAMINE TRIETHANOLAMINE 0.20 B TITRIPLEX III DISODIUM EDETATE 0.10 B GLYCEROL GLYCEROL 5.00 B NIPAGIN M METHYL PARABEN 0.20 C PURIFIED WATER AQUA (WATER) 43.84 D SIMULGEL 600 PHA ACRYLAMIDE/SODIUM ACRYLOYLDIMETHYL 4.00 TAURATE COPOLYMER & ISOHEXADECANE & POLYSORBATE 80 CHARACTERIZATION At T0 MACROSCOPIC APPEARANCE Thick, white, glossy cream MICROSCOPIC APPEARANCE Fine, homogeneous emulsion carpet pH 7.53 VISCOSITY 830000 cp 92.8% MEAN DIAMETER 377 nm Monitoring of stabilities 1 MONTH 2 MONTHS 3 MONTHS Physical stability pH RT/40 C. 7.45/7.37 7.38/7.29 7.42/7.27 Viscosity RT 827000 cP 831000 cP 826500 cP 91.4% 89.8% 83.2% 40 C. 826000 cP 821000 cP 823000 cP 88.9% 78.6% 77.2% Chemical stability Assay (% relative RT 101.4% 100.5% 100.0% active agent/T0) 40 C. 101.2% 97.1% 99.1%
Equipment Used:

(8) Formulation beakers of suitable size

(9) Rotor-stator stirrer: Polytron

(10) Stirrer equipped with a deflocculating paddle: VMI-Rayneri Turbotest

(11) Preparation of the Two Phases

(12) Weigh out all the elements of the fatty phase (A) in a formulation beaker and heat them at 70 C., with magnetic stirring, until a homogeneous mixture is obtained.

(13) Weigh out all the elements of the aqueous phase (B) in an additional beaker and heat them at 70 C., with magnetic stirring, until a clear mixture is obtained.

(14) Emulsification

(15) Pour the aqueous phase (B) rapidly into the fatty phase (A) with vigorous stirring: Rotor-stator: 10000-13000 rpm.

(16) Keep stirring for 30-40 minutes, until a fine fluid emulsion is obtained.

(17) Cooling

(18) Stop the Polytron stirring and place the beaker containing the emulsion in a cold-water bath to promote rapid cooling.

(19) Next, stir the emulsion slowly (deflocculating paddle-200 rpm).

(20) Gradually add the cooling water (phase C).

(21) Keep stirring slowly until the temperature of the emulsion is below 25 C.

(22) Gelation

(23) Gradually add the gelling agent (phase D) to the emulsion with moderate to vigorous stirring:

(24) Rayneri blender with a deflocculating paddle: 500-800 rpm.

(25) Keep stirring until a glossy smooth cream is obtained

EXAMPLE 2

Manufacturing Process at the Pilot Scale (10 kg)

(26) The composition that follows is prepared according to the protocol indicated below. The macroscopic and microscopic appearance at T0 are studied.

(27) The results obtained are given after each composition.

(28) TABLE-US-00002 EXAMPLE 2 - Composition Phase Trade name INCI name (w/w %) A1 BRIJ S10-SO STEARETH-10 1.25 A1 KOLLIWAX S STEARIC-/PALMITIC 0.85 ACID A1 BRIJ S2-SO STEARETH-2 1.80 A1 KOLLIWAX SA STEARYL ALCOHOL 0.25 A1 MIGLYOL 812 N CAPRYLIC/CAPRIC 11.50 TRIGLYCERIDES A1 ST- CYCLO- 4.00 CYCLOMETHICONE PENTASILOXANE 5-NF A2 PHENOXETOL PHENOXYETHANOL 1.00 A2 MIGLYOL 812 N CAPRYLIC/CAPRIC 4.00 TRIGLYCERIDES A2 DL-ALPHA- ALPHA TOCOPHEROL 0.20 TOCOPHEROL B1 PURIFIED WATER AQUA (WATER) 21.41 B1 GLYCEROL GLYCEROL 5.00 B1 BENZALKONIUM BENZALKONIUM 0.08 CHLORIDE CHLORIDE B1 TRIETHANOLAMINE TRIETHANOLAMINE 0.20 B2 PURIFIED WATER AQUA (WATER) 41.06 B3 BENZYL ALCOHOL BENZYL ALCOHOL 0.40 B3 PURIFIED WATER AQUA (WATER) 3.00 C SIMULGEL 600 PHA ACRYLAMIDE/SODIUM 4.00 ACRYLOYLDIMETHYL TAURATE COPOLYMER & ISOHEXADECANE & POLYSORBATE 80 CHARACTERIZA- MACROSCOPIC Thick, white, TION At T0 APPEARENCE glossy cream MICROSCOPIC Fine, APPEARENCE homogeneous emulsion carpet MEAN DIAMETER 440 nm
Equipment Used:

(29) Aqueous phase: OLSA melting vat

(30) Fatty phase: OLSA tank (preparation tank)

(31) Preparation of the Fatty Phase (Phases A1+A2)

(32) Place the various elements of the fatty phase A1 in an Olsa tank with stirring. Stir using a turbomixer at 1500 rpm.

(33) Switch off the turbomixer and heat the mixture to 70 C. with coaxial stirring (30 rpm).

(34) Add the rest of the fatty phase (A2) with coaxial stirring until a clear mixture is obtained.

(35) Preparation of the Aqueous Phase (Phase B1)

(36) Place the various elements of the aqueous phase (phase B1) in an Olsa melting vat.

(37) Heat the mixture at 70 C. with stirring (150 rpm) while covering the melting vat to limit the evaporation, until all the excipients are fully dissolved and the mixture becomes clear.

(38) Emulsification

(39) While stirring with a turbomixer, transfer the aqueous phase very slowly by suction from the bottom of the tank (Olsa melting vat) into the fatty phase (Olsa tank) using a pipe:

(40) Coaxial speed: 45 rpm

(41) Turbomixer speed: 3000 rpm

(42) Maintain the stirrings and the temperature (70 C.) until emulsification of the two phases is complete and a glossy, opaque, white liquid is obtained, which has, under an optical microscope, a very fine emulsion carpet.

(43) Cooling

(44) Introduce into the Olsa tank with stirring, by suction from the bottom of the tank, the cooling water (phase B2):

(45) Coaxial speed: 45 rpm

(46) Turbomixer speed: 3000 rpm

(47) Cool the mixture to 40 C. with stirring:

(48) Coaxial speed: 45 rpm

(49) Turbomixer speed: 3000 rpm

(50) When the mixture is at 40 C., add phase B3 with continued stirring.

(51) Gelation

(52) Introduce the gelling agent (phase C) into the preceding mixture at 40 C., with stirring:

(53) Coaxial speed: 45 rpm

(54) Turbomixer speed: 2000 rpm

(55) Cool to 25 C. with stirring, and keep stirring until a smooth, glossy white cream is obtained.

EXAMPLE 3

Manufacturing Process at the Industrial Scale (4000 kg)

(56) The composition that follows is prepared according to the protocol indicated below.

(57) TABLE-US-00003 EXAMPLE 3 - Composition Ingredients Con- Phase Trade name (INCI name) tent % A NEO HELIOPAN OS/BP ETHYLHEXYL 29.05 NEO HELIOPAN 303 SALICYLATE OCTOCRYLENE PARSOL 1789 BUTYLMETHOXY- DIBENZOYLMETHANE SILICONS FLUID 200 DIMETHICONE 350 cST TWEEN 61V POLYSORBATE 61 AMISOFT HS 11 SODIUM STEARYL GLUCAMATE RYOTO SUGAR ESTER SUCROSE S370 TRISTEARATE DUB DIS DIISOPROPYLE SEBACATE ELDEW SL 205 ISOPROPYL LAURYL SARCOSINATE ENOXOLONE/ GLYCYRRHETINIC PLANTACTIV ACID GLA 18 B CERAMIDE 5 HYDROXYPALMITOYL 42.8 PURIFIED WATER SPHINGANINE AQUA (WATER) RONACARE ALLANTOIN ALLANTOIN TITRIPLEX III DISODIUM EDETATE PHENOXETOL PHENOXYETHANOL HYDROLITE-5 PENTYLENE GLYCOL DERMOSOFT OCTIOL CAPRYLYL GLYCOL D-PANTHENOL USP PANTHENOL GLYCEROL 4810 GLYCEROL C DL ALPHA TOCOPHERYL 19.95 TOCOPHEROL ACETATE ACETATE PURIFIED WATER AQUA (WATER) POTASSIUM SORBATE ZINC GLUCONATE RHODICARE XT XANTHAN GUM CARBOPOL 980 CARBOMER D TRIETHANOLAMINE TRIETHANOLAMINE 2.2 CARE DC 1503 FLUID DIMETHICONE (AND) DIMETHICONOL E DRY FLO PLUS ALUMINUM STARCH 6 OCTENYLSUCCINATE SILICA BEAD SB 150 SILICA MICROPEARL M100 POLYMETHYL METHACRYLATE
Equipment Used:

(58) #4000 L skid with melting vat (preparation tank)

(59) 2 100 L containers, made of stainless steel

(60) 1 200 L container, made of stainless steel

(61) 2 20 kg containers, made of stainless steel

(62) Preparation of the Fatty Phase (Phase A)

(63) Place the various elements of the fatty phase A in the main tank with stirring.

(64) Heat the mixture to 70 C. with stirring:

(65) Coaxial speed: 20-40 rpm

(66) Scrapers: 20 rpm

(67) Turbomixer speed: 700-1500 rpm

(68) Preparation of the Aqueous Phase (Phase B)

(69) Place the various elements of the aqueous phase in a melting vat.

(70) Heat the mixture to 70 C. with stirring:

(71) Scrapers: 10-20 rpm

(72) Turbomixer speed: 1000-1500 rpm

(73) Keep stirring and heating until all the excipients are fully dissolved and the mixture becomes clear.

(74) Emulsification

(75) While stirring with a turbomixer, transfer the aqueous phase by suction from the bottom of the tank (melting vat) into the fatty phase (main preparation tank) using a pipe:

(76) Coaxial speed: 60-100 rpm

(77) Scrapers: 25 rpm

(78) Turbomixer speed: 1000-1800 rpm

(79) Keep stirring until emulsification of the two phases is complete and a glossy, opaque, white liquid is obtained, which has, under an optical microscope, a very fine emulsion carpet.

(80) Cooling

(81) Cool the mixture in the main tank to 50 C. with stirring:

(82) Coaxial speed: 50-100 rpm

(83) Turbomixer speed: 1000-1800 rpm

(84) Weigh out in a suitable container the elements of phase C, and stir until the excipients are homogeneously dispersed in the water:

(85) Scrapers: 20-30 rpm

(86) Turbomixer speed: 2000-3000 rpm

(87) Introduce the cooling phase C into the preparation tank with stirring, by suction from the bottom of the tank:

(88) Coaxial speed: 40 rpm

(89) Scrapers: 20 rpm

(90) Turbonnixer speed: 1000-1800 rpm

(91) Gelation

(92) When the preparation is at 40 C., introduce phase D into the preceding mixture with stirring:

(93) Scrapers: 0-20 rpm

(94) Turbomixer speed: 1000-1800 rpm

(95) Add the elements of phase E.

(96) Keep stirring until a glossy, smooth, white cream is obtained

(97) In Example 3, the content of phase A is 29.05% by weight, the content of phase B is 42.8% by weight, the content of phase C is 19.95% by weight, the content of phase D is 2.2% and the content of phase E is 6% by weight.