Method of microencapsulation

• US 20060051425A1
• Filed: 08/22/2005
• Published: 03/09/2006
• Est. Priority Date: 11/17/1999
• Status: Active Grant

• Current Assignee: Tagra Biotechnologies Ltd. (EFAL Chemical Industries, Ltd.)
• Original Assignee: Tagra Biotechnologies Ltd. (EFAL Chemical Industries, Ltd.)
• Inventors: Kvitnitsky, Emma, Oleinik, Irena, Privalov, Olga, Polisher, Igor, Shapiro, Yury
• Granted Patent: US 7,838,037 B2
• Time in Patent Office: Days
• US Class Current: 424/490
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B01J 13/06 by phase separation
• CPC Class Codes: B01J 13/22 Coating
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]
• CPC Class Codes: Y10T 428/2985 Solid-walled microcapsule from synthetic polymer
• CPC Class Codes: Y10T 428/2987 Addition polymer from unsaturated monomers only
• CPC Class Codes: Y10T 428/2989 Microcapsule with solid core [includes liposome]
• CPC Class Codes: Y10T 428/2993 Silicic or refractory material containing [e.g., tungsten oxide, glass, cement, etc.]
• CPC Class Codes: Y10T 428/2998 including synthetic resin or polymer

Abstract

The present invention provides methods for microencapsulation of active ingredients for topical application, whereby single-layer and multi-layer, preferably double-layer, microcapsules, are obtained. The microcapsules protect the active ingredients, maintain their original activity throught processing, formulation and storage, and enable controlled release of the active ingredient only upon application onto the skin.

Claims

1. A method for the production of microcapsules for topical application, wherein the microcapsules consist of a core made of an encapsulated active ingredient and one or more shells of the same or different wall-forming polymer, said method comprising the steps of:

(a) dissolving or dispersing the active ingredient, optionally together with an antioxidant, a plasticizer or both, in an organic solvent of a kind that is partially miscible with water and is capable of dissolving or dispersing said substance, together with a wall-forming polymer selected from the group consisting of a polyacrylate, a polymethacrylate, low molecular weight poly(methyl methacrylate)-co-(methacrylic acid) (1;

0.16), poly(ethyl acrylate)-co-(methyl methacrylate)-co-(trimethylammmonium-ethyl methacrylate chloride) (1;

2;

0.1), poly(butyl methacrylate)-co-(2-dimethylaminoethyl methacrylate)-co-(methyl methacrylate) (1;

2;

1), poly(styrene)-co-(maleic anhydride), copolymer of octylacrylamide, cellulose ethers, cellulose esters and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), to form an organic solution or dispersion;

(b) preparing an aqueous continuous phase saturated with said organic solvent and comprising an emulsifier;

(c) while agitating, pouring the organic solution or dispersion obtained in (a) into the aqueous continuous phase obtained in (b), to form an emulsion;

(d) adding an excess amount of water to the emulsion obtained in (c) to initiate extraction of the organic solvent from the emulsion, and optionally incubating for further extraction of the solvent and formation of solid microcapsules(hereinafter “

the core microcapsules”

);

(e) either (i) isolating the core microcapsules, washing with water and drying, or (ii) immersing the core microcapsules into an aqueous solution of alcohol, separating the core microcapsules and drying, thus obtaining single-layer microcapsules; and

(f) if desired, treating the surface of the core single-layer microcapsules obtained in (e) with a material that modifies the morphology of the core surface, increases the specific surface area and facilitates the adhesion of an additional polymeric shell,

and repeating steps (a) to (e) to form double-layer microcapsules, or repeating steps (a) to (f) to add two or more additional layers around the core microcapsule, thereby obtaining multi-layer microcapsules.

2. The method according to claim 1, for the production of single-layer microcapsules wherein the active ingredient is a plant oil selected from the group consisting of Evening Primrose Oil, Borage Oil, Hippophae Oil and Tea Tree Oil.

3. The method according to claim 1, for the production of single-layer microcapsules wherein the active ingredient is a macrolide antibiotic.

4. The method according to claim 1, for the production of single-layer microcapsules wherein a plasticizer is added in step (a) and the single-layer microcapsules have an outer polymer-plasticizer shell.

5. The method according to claim 4, wherein the active ingredient is a vitamin, a plant oil or a fragrance.

6. Single-layer microcapsules for oral hygiene having an outer polymer-plasticizer shell obtained by the method of claim 1, wherein the wall-forming polymer is ethylcellulose and the active ingredient is a vitamin or a plant oil.

7. Single-layer microcapsules for oral hygiene according to claim 6, wherein the active ingredient is Retinol Palmitate, Tocopherol, Hippophae Oil or Tea Tree Oil.

8. A method according to claim 1 for the production of multi-layer microcapsules for topical application, wherein the microcapsules consist of an inner core microcapsule which contains an active ingredient located within a wall-forming polymer shell and one or more outer shells of the same or different wall-forming polymer coating the inner core microcapsule, said method comprising the steps of:

(a) dissolving or dispersing the active ingredient, optionally together with an antioxidant, a plasticizer or both, in an organic solvent of a kind that is partially miscible with water and is capable of dissolving or dispersing said substance, together with a wall-forming polymer selected from the group consisting of a polyacrylate, a polymethacrylate, low molecular weight poly(methyl methacrylate)-co-(methacrylic acid) (1;

0.16), poly(ethyl acrylate)-co-(methyl methacrylate)-co-(trimethylammmonium-ethyl methacrylate chloride) (1;

2;

0.1), poly(butyl methacrylate)-co-(2-dimethylaminoethyl methacrylate)-co-(methyl methacrylate) (1;

2;

1), poly(styrene)-co-(maleic anhydride), copolymer of octylacrylamide, cellulose ethers, cellulose esters and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), to form an organic solution or dispersion;

(b) preparing an aqueous continuous phase saturated with said organic solvent and comprising an emulsifier;

(c) while agitating, pouring the organic solution or dispersion obtained in (a) into the aqueous continuous phase obtained in (b), to form an emulsion;

(d) adding an excess amount of water to the emulsion obtained in (c) to initiate extraction of the organic solvent from the emulsion, and optionally incubating for further extraction of the solvent and formation of solid microcapsules (hereinafter “

the inner core microcapsules”

);

(e) either (i) isolating the inner core microcapsules, washing with water and drying, or (ii) immersing the core microcapsules into an aqueous solution of alcohol, separating the core microcapsules and drying;

(f) treating the surface of the dried inner core microcapsules obtained in (e) with a material that modifies the morphology of the surface, increases its specific surface area and facilitates the adhesion of an additional polymeric shell, thus obtaining microcapsules powdered with said material (hereinafter “

powdered modified inner cores”

);

(g) dissolving or dispersing a wall-forming polymer with a plasticizer or a mineral in an organic solvent of a kind that is partially miscible with water, to form a polymer-plasticizer solution or polymer-mineral dispersion;

(h) preparing an aqueous continuous phase saturated with said organic solvent and comprising an emulsifier;

(i) while agitating, pouring the polymer-plasticizer solution or polymer-mineral dispersion obtained in step (g) into the aqueous continuous phase obtained in step (h), to form a polymer-plasticizer emulsion or a polymer-mineral suspo-emulsion;

(j) while agitating, immersing the powdered modified inner cores obtained in step (f) into the polymer-plasticizer emulsion or polymer-mineral suspo-emulsion obtained in step (i), forming a multi-component emulsion or a new suspo-emulsion, in which a formation of “

embryo”

shells around said core microcapsules is initiated;

(k) while stirring, either (i) adding an excess amount of water to the multi-component emulsion or the new suspo-emulsion obtained in step (j), or (ii) pouring the multi-component emulsion or the new suspo-emulsion obtained in step (j) into water, and incubating the system for extraction of the organic solvent from said multi-component emulsion or suspo-emulsion, and conversion of the “

embryo”

shell into a solid polymer wall and formation of double-layer microcapsules;

(l) separating the obtained double-layer microcapsules from water and drying the wet capsules, thereby isolating double-layer microcapsules as a free flowing powder; and

(m) if desired, repeating steps (f) to (l) to form one or more additional layers around the double-layer microcapsules, thereby obtaining multi-layer microcapsules.

9. The method according to claim 8, wherein said active ingredient is at least one agent having biological activity, an odor agent or a color agent.

10. The method according to claim 9, wherein said agent having biological activity is selected from the group consisting of vitamins, natural extracts, individual compounds isolated from natural sources, essential oils, and pharmaceutical agents for topical application.

11. The method according to claim 10, wherein said vitamin is vitamin A, B, C, D, E, F, K, P, or mixtures thereof.

12. The method according to claim 11, wherein said vitamin A is Retinol or Retinol Palmitate, said vitamin E is α

-tocopherol, said vitamin F is a mixture of linoleic and linolenic acids, and said vitamin P is Rutin.

13. The method according to claim 10, wherein said natural extract is Licorice extract, Grape Seed extract, Evening Primrose Oil, Borage Oil, or Hippophae Oil.

14. The method according to claim 10, wherein said individual compound isolated from a natural source is a coumarin, a chalcone or a flavonoid selected from the group consisting of flavans, flavanols, flavonols, flavones, flavanones, isoflavones, anthocyanidins, and proanthocyanidins.

15. The method according to claim 10, wherein said flavonoid is Rutin.

16. The method according to claim 10, wherein said essential oil is Basil Essential Oil, Eucalyptus Essential Oil, Geranium Essential Oil, Grapefruit Essential Oil, Lemon Essential Oil, Peppermint Essential Oil, Tea Tree Oil, or mixtures thereof.

17. The method according to claim 10, wherein said pharmaceutical agent for topical application is an antibiotic.

18. The method according to claim 17, wherein said antibiotic is a macrolide antibiotic selected from the group consisting of Erythromycin, Azithromycin or Clarithromycin.

19. The method according to claim 9, wherein said odor agent is selected from the group consisting of fragrances, perfumes, essential oils, and volatile natural and synthetic compounds.

20. The method according to claim 19, wherein said volatile compound is Menthol.

21. The method according to claim 9, wherein said color agent is selected from the group consisting of organic and inorganic pigments, colorants and color agents from natural source.

22. The method according to claim 21, wherein said color agent is at least one agent selected from the group consisting of Carmine, iron oxides, titanium dioxide, chrome oxide/hydroxide, D&

C Red 21 Aluminum Lake, D&

C Red 7 Calcium Lake, D&

C Green 6 Liposoluble, and Aluminium Blue #1, and mixtures thereof.

23. The method according to claim 8, wherein the wall-forming polymer shell is a polymer-plasticizer or polymer-mineral shell.

24. The method according to claim 23, wherein the inner and outer polymer shells are both polymer-plasticizer shells and the polymer of the inner core microcapsule and of the outer shells are identical.

25. The method according to claim 23, wherein the inner and outer polymer shells are both polymer-plasticizer shells and the polymer of the inner core microcapsule and of the outer shells are different.

26. The method according to claim 23, wherein the inner and outer polymer shells are both polymer-mineral shells and the polymer of the inner core microcapsule and of the outer shells are identical.

27. The method according to claim 23, wherein the inner and outer polymer shells are both polymer-mineral shells and the polymer of the inner core microcapsule and of the outer shells are identical.

28. The method according to claim 23, wherein the inner polymer shell is a polymer-plasticizer shell and the outer polymer shell is a polymer-mineral shell or the inner polymer shell is a polymer-mineral shell and the outer polymer shell is a polymer-plasticizer shell and the polymers of both shells are identical.

29. The method according to claim 23, wherein the inner polymer shell is a polymer-plasticizer shell and the outer polymer shell is a polymer-mineral shell or the inner polymer shell is a polymer-mineral shell and the outer polymer shell is a polymer-plasticizer shell and the polymers of the inner and of the outer shells are different.

30. The method according to claim 8, wherein said wall-forming polymer is ethyl cellulose, poly(methyl methacrylate)-co-(methacrylic acid) (1:

0.16), poly(ethyl acrylate)-co-(methyl methacrylate)-co-(trimethylammonium-ethyl methacrylate chloride) (1;

2;

0.1), or a mixture thereof.

31. The method according to claim 8, wherein said organic solvent partially miscible with water is an organic solvent approved for topical applications.

32. The method according to claim 31, wherein said organic solvent is ethyl acetate, ethanol, ethyl formate, or a mixture thereof.

33. The method according to claim 8, wherein said plasticizer that forms the polymer-plasticizer solution in step (g) is selected from the group consisting of tricaprylin, trilaurin, tripalmitin, triacetin, triethyl citrate, acetyltriethyl citrate, isopropyl myristate, paraffin oil, and mixtures thereof.

34. The method according to claim 8, wherein said mineral that forms the polymer-mineral dispersion in step (g) is selected from the group consisting of titanium dioxide, boron nitride, magnesium silicate, potassium, sodium, magnesium hydroalumosilicate, and mixtures thereof.

35. The method according to claim 8, wherein said material in step (f) that changes the morphology of the core surface and increases the specific surface area is dioxosilicon or magnesium silicate.

36. The method according to claim 8, wherein the core microcapsule contains more than one active ingredient or said active ingredient is in mixture with an anti-oxidant.

37. The method according to claim 1, wherein the multi-layer microcapsules are double-layer or triple-layer microcapsules.

38. Multi-layer microcapsules for topical application, consisting of an inner core microcapsule which contains an active ingredient located within a wall-forming polymer, and one or more outer shells of the same or different wall-forming polymer coating the inner core microcapsule, wherein said multi-layer microcapsules are obtained according to the method of claim 1.

39. Multi-layer microcapsules for topical application, consisting of an inner core microcapsule which contains an active ingredient located within a wall-forming polymer, and one or more outer shells of the same or different wall-forming polymer coating the inner core microcapsule, wherein said multi-layer microcapsules are obtained according to the method of claim 8.

40. Multi-layer microcapsules according to claim 39, wherein the outer diameter of the inner core microcapsule is in the range of 1-100 μ

m and the outer diameter of the multi-layer microcapsule is in the range of 10-200 μ

m.

41. Multi-layer microcapsules according to claim 40, wherein said outer diameter of the multi-layer microcapsule is in the range of 30-50 μ

m.

42. Double-layer microcapsules for topical application, consisting of an inner core microcapsule which contains an active ingredient located within a wall-forming polymer, and one outer shell of the same or different wall-forming polymer coating the inner core microcapsule, wherein said double-layer microcapsules are obtained according to the method of claim 8.

43. Double-layer microcapsules according to claim 42, wherein said active ingredient is at least one agent having biological activity, an odor agent or a color agent.

44. Double-layer microcapsules according to claim 43, wherein said agent having biological activity is selected from the group consisting of vitamins, natural extracts, individual compounds isolated from natural sources, essential oils, and pharmaceutical agents for topical application.

45. Double-layer microcapsules according to claim 44, wherein said vitamin is vitamin A, B, C, D, E, F, K, P, or mixtures thereof.

46. Double-layer microcapsules according to claim 45, wherein said vitamin A is Retinol or Retinol Palmitate, said vitamin E is α

-tocopherol, said vitamin F is a mixture of linoleic and linolenic acids, and said vitamin P is Rutin.

47. Double-layer microcapsules according to claim 44, wherein said natural extract is Licorice extract, Grape Seed extract, Evening Primrose Oil, Borage Oil, or Hippophae Oil.

48. Double-layer microcapsules according to claim 44, wherein said individual compound isolated from a natural source is a coumarin, a chalcone or a flavonoid selected from the group consisting of flavans, flavanols, flavonols, flavones, flavanones, isoflavones, anthocyanidins, and proanthocyanidins.

49. Double-layer microcapsules according to claim 48, wherein said flavonoid is Rutin.

50. Double-layer microcapsules according to claim 44, wherein said essential oil is Basil Essential Oil, Eucalyptus Essential Oil, Geranium Essential Oil, Grapefruit Essential Oil, Lemon Essential Oil, Peppermint Essential Oil, Tea Tree Oil, or mixtures thereof.

51. Double-layer microcapsules according to claim 44, wherein said pharmaceutical agent for topical application is an antibiotic.

52. Double-layer microcapsules according to claim 51, wherein said antibiotic is a macrolide antibiotic selected from the group consisting of Erythromycin, Azithromycin or Clarithromycin.

53. Double-layer microcapsules according to claim 44, wherein said odor agent is selected from the group consisting of fragrances, perfumes, essential oils, and volatile natural and synthetic compounds.

54. Double-layer microcapsules according to claim 53, wherein said volatile compound is Menthol.

55. Double-layer microcapsules according to claim 43, wherein said color agent is selected from the group consisting of organic and inorganic pigments, colorants and color agents from natural source.

56. Double-layer microcapsules according to claim 55, wherein said color agent is at least one agent selected from the group consisting of Carmine, iron oxides, titanium dioxide, chrome oxide/hydroxide, D&

C Red 21 Aluminum Lake, D&

C Red 7 Calcium Lake, D&

C Green 6 Liposoluble, and Aluminium Blue #1, and mixtures thereof.

57. Double-layer microcapsules according to claim 42, wherein the wall-forming polymer shell is a polymer-plasticizer or polymer-mineral shell.

58. Double-layer microcapsules according to claim 57, wherein the inner and outer polymer shells are both polymer-plasticizer shells and the polymer of the inner core microcapsule and of the outer shells are identical.

59. Double-layer microcapsules according to claim 57, wherein the inner and outer polymer shells are both polymer-plasticizer shells and the polymer of the inner core microcapsule and of the outer shells are different.

60. Double-layer microcapsules according to claim 57, wherein the inner and outer polymer shells are both polymer-mineral shells and the polymer of the inner core microcapsule and of the outer shells are identical.

61. Double-layer microcapsules according to claim 57, wherein the inner and outer polymer shells are both polymer-mineral shells and the polymer of the inner core microcapsule and of the outer shells are different.

62. Double-layer microcapsules according to claim 57, wherein the inner polymer shell is a polymer-plasticizer shell and the outer polymer shell is a polymer-mineral shell or the inner polymer shell is a polymer-mineral shell and the outer polymer shell is a polymer-plasticizer shell and the polymers of both shells are identical.

63. Double-layer microcapsules according to claim 57, wherein the inner polymer shell is a polymer-plasticizer shell and the outer polymer shell is a polymer-mineral shell or the inner polymer shell is a polymer-mineral shell and the outer polymer shell is a polymer-plasticizer shell and the polymers of the inner and of the outer shells are different.

64. Double-layer microcapsules according to claim 42, wherein said wall-forming polymer is ethyl cellulose, poly(methyl methacrylate)-co-(methacrylic acid) (1:

0.16), poly(ethyl acrylate)-co-(methyl methacrylate)-co-(trimethylammonium-ethyl methacrylate chloride) (1;

2;

0.1), or a mixture thereof.

65. Double-layer microcapsules according to claim 57, wherein said plasticizer that forms the polymer-plasticizer shell is selected from the group consisting of tricaprylin, trilaurin, tripalmitin, triacetin, triethyl citrate, acetyltriethyl citrate, isopropyl myristate, paraffin oil, and a mixture thereof.

66. Double-layer microcapsules according to claim 57, wherein said mineral that forms the polymer-mineral shell is selected from the group consisting of titanium dioxide, boron nitride, magnesium silicate, potassium, sodium, magnesium hydroalumosilicate, mica (and) magnesium myristate, titanium dioxide (and) magnesium myristate, and mixtures thereof.

67. Double-layer microcapsules according to claim 42, wherein the core microcapsule contains more than one active ingredient or said active ingredient is in mixture with an anti-oxidant.

68. Double-layer microcapsules according to claim 58, wherein the active ingredient is Retinol, Retinol Palmitate, Licorice Extract, or Tea Tree Oil and the wall-forming polymer of the inner and outer polymer-plasticizer shells is poly(methyl methacrylate)-co-(methacrylic acid) (1:

0.16), or the active ingredient is Rutin and the wall-forming polymer of the inner and outer polymer-plasticizer shells is a mixture of poly(methyl methacrylate)-co-(methacrylic acid) (1;

0.16) and poly(ethyl acrylate)-co-(methyl methacrylate)-co-(trimethylammonium-ethyl methacrylate chloride) (1;

2;

0.1).

69. Double-layer microcapsules according to claim 62, wherein the active ingredient is Grape Seed Extract or Iron oxide pigments, and the wall-forming polymer of the inner polymer-mineral shell and of the outer polymer-plasticizer shell is poly(ethyl acrylate)-co-(methyl methacrylate)-co-(trimethyl-ammonium-ethyl methacrylate chloride) (1:

2;

0.1).

70. Double-layer microcapsules according to claim 62, wherein the active ingredient is Menthol and the wall-forming polymer of the inner polymer-plasticizer shell and of the outer polymer-mineral shell is poly(methyl methacrylate)-co-(methacrylic acid) (1:

0.16).

71. Double-layer microcapsules according to claim 62, wherein the active ingredient is Chrome oxide/hydroxide pigment or D&

C Red Calcium Lake and the wall-forming polymer of the inner polymer-plasticizer shell and of the outer polymer-mineral shell is poly(ethyl acrylate)-co-(methyl methacrylate)-co-(trimethyl-ammonium-ethyl methacrylate chloride) (1;

2;

0.1).

72. Double-layer microcapsules according to claim 63, wherein the active ingredient is Retinol, Carmine pigment, D&

C Red 21 Aluminum Lake or D&

C Green 6 Liposoluble, and the wall-forming polymer of the inner polymer-plasticizer shell is poly(methyl methacrylate)-co-(methacrylic acid) (1;

0.16) and of the outer polymer-mineral shell is poly(ethyl acrylate)-co-(methyl methacrylate)-co-(trimethyl-ammonium-ethyl methacrylate chloride) (1;

2;

0.1).

73. Triple-layer microcapsules according to claim 39, wherein the active ingredient is Aluminum Blue #1, the wall-forming polymer of the inner polymer-plasticizer shell is a mixture of poly(methyl methacrylate)-co-(methacrylic acid) (1:

0.16) and poly(ethyl acrylate)-co-(methyl methacrylate)-co-(trimethyl-ammonium-ethyl methacrylate chloride) (1;

2;

0.1), and of the two outer polymer-mineral shells is poly(ethyl acrylate)-co-(methyl methacrylate)-co-(trimethyl-ammonium-ethyl methacrylate chloride) (1;

2;

0.1).

74. Composition for topical application comprising single-layer microcapsules obtained by the method according to claim 1, wherein the active ingredient is a macrolide antibiotic selected from the group consisting of Erythromycin, Clarithromycin and Azithromycin.

75. Composition for oral hygiene comprising single-layer microcapsules according to claim 6.

76. Composition for topical application comprising multi-layer microcapsules according to claim 39.

77. Composition for topical application comprising double-layer microcapsules according to claim 42.

78. Composition comprising double-layer microcapsules according to claim 77 for skin care, skin supplement, hair care, sun care, and baby care oral hygiene, and oral care.

79. Composition comprising double-layer microcapsules according to claim 77 for oral hygiene and oral care.

80. Composition comprising double-layer microcapsules according to claim 77 for topical application, wherein the active ingredient is a pharmaceutical.