Transdermal therapeutic system

Abstract

A therapeutic system for supplying active substances to the skin consists of a backing layer remote from the skin, with at least one active substance depot. The depot may consist of a fluid active substance or a fluid composition comprising an active substance delivery control matrix. There is also included an adhesive fixing device for fixing the therapeutic system on the skin. The therapeutic system is characterized in that the active substance depots (14) consist of at least one adjuvant having a supporting and distributing function by being provided with a planar textile material completely surrounded by matrix (12).

Description

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 is a section through an inventive therapeutic system, which is fixed to the skin 18 by a fixing device 16, e.g. a porous pressure sensitive adhesive layer or the like. On fixing device 16 is located reservoir matrix 12 which, at the time of production, is preferably free from active substance (active substance saturation taking place during storage). In the reservoir matrix 12 is embedded a depot 14, which is represented here as a solid active substance which dissolves in the reservoir matrix material 12 and is supplied to the skin 18 by fixing device 16. The therapeutic system is sealed to the outside by a backing layer 10 which is impermeable for the active substance and preferably also moisture and simultaneously has a support function for the system.

FIG. 2 shows another variant of the inventive system, in which an active substance depot 14 is located on a reservoir matrix layer 12 and is covered by a backing layer 10. The fixing device is not shown in this drawing and can e.g. be a pressure sensitive adhesive border or edge or the like, which applies the skin contact surface of the therapeutic system closely to skin 18. This embodiment of the invention is advantageous in that its production is very simple. It is merely necessary to apply clearly defined quantities of active substance, in the form of a solid or a viscous liquid to the prefabricated matrix layer 12 and to seal or terminate the same by a backing layer 10.

The process for producing the system according to FIG. 2 is less expensive than for that according to FIG. 1. However, it can only be used if it is not absolutely necessary that active substance 14 is enclosed on all sides by matrix 12, e.g. due to the volatility of active substance 14 or due to a necessarily large contact surface between active substance 14 and reservoir matrix 12. It is e.g. advantageous for substances which very readily dissolve in active substance 14 reservoir and without difficulty diffuse in it, so that there is no need for a large contact surface between active substance 14 and active substance reservoir matrix 12.

FIG. 3 shows another preferred embodiment, in which an inventive therapeutic system is fixed to the skin 18 by means of adhesive particles or portions 16 embedded on the skin 18 side in the active substance reservoir matrix material. The active substance reservoir layer 12 here comprises an upper layer X and a lower layer Y, between which is introduced the active substance, which is e.g. here in liquid form. The provision of two reservoir matrix layers X, Y is advantageous if a system is being produced in such a way that firstly the lower active substance reservoir layer Y is provided, optionally with an already coated on covering film or the like and then in accordance with a predetermined pattern the active substance/material is applied, the next active substance reservoir layer X is superimposed, and finally in conventional manner the backing layer 10 or optionally various adhesive layers 16 are applied to complete the system. It may also be appropriate to firstly place the two active substance reservoir layers X, Y on top of one another, then inject a predetermined quantity of active substance between the two reservoir layers X, Y and in this way keep evaporation of the active substance 14 to a minimum.

FIG. 4 shows an embodiment of an inventive transdermal system with several active substance depots 14 arranged in one plane and placed between a pressure sensitive adhesive layer 16 and a reservoir matrix 12, layer 16 simultaneously fixing the backing layer 10 to the transdermal system. The transdermal system is sealed by a detachable protective layer 19.

FIG. 5 shows another embodiment of an inventive transdermal system, in which a backing layer 10 is coated on one side with an adhesive layer 16 and on it is located active substance 14, optionally with adjuvants, such as material for facilitating processing of active substance 14 (e.g. tabletting aids) or carriers, like fabrics and the like. To the flat active substance depot 14 is applied a reservoir matrix 12 which is in turn covered by a detachable protective film.

FIG. 6 shows the precursor of an inventive transdermal system, such as is obtained during a preferred production process. A web-like protective coating material 19, such as e.g. waxed paper or the like is covered by a reservoir matrix layer Y, which is here constructed in pressure sensitive adhesive manner and on same are located in accordance with a predetermined pattern of active substance depot bodies 14. Matrix layer Y is covered by a second matrix layer X, which can e.g. comprise a material differing from that of layer Y. The second matrix layer X is sealed by a backing film 10. Along the arrows are located the parting or separating lines, along which the intermediate product is cut or punched during the production of the inventive transdermal systems and then prepared in the usual way.

Typical thicknesses for inventive transdermal systems are in the case of a total thickness of approximately 123 to 5550 μm, preferably 285 to 1550 μm; thickness of the backing layer 8 to 150 μm and preferably 15 to 100 μm; thickness of the reservoir 100 to 5000 μm, preferably 200 to 1330 μm; thickness of the protective layer 15 to 400 μm, preferably 70 to 150 μm.

For special application it is also possible to market the "semifinished product" as such, so as to enable users to carry out the separation of the systems, so that the semifinished product acts in the manner of a "storage pack".

Preferred examples of the invention are described below.

EXAMPLE 1

PRODUCTION OF A NICOTINE PLASTER

Nicotine plasters, such as are used to stop people from smoking, are, according to the invention, produced as follows.

A pressure sensitive adhesive material comprising 2.0825 kg of a 40% solution of a self-crosslinking acrylate copolymer, e.g. of 2-ethyl-hexyl acrylate, vinyl acetate, acrylic acid and titanium chelate ester, or DUROTAC 280-2416 of the firm National Starch/Chemical B.V. in a mixture of ethyl acetate, ethanol, hexane and methanol, 147 g of an acrylic resin of dimethylaminoethylmethacrylate and neutral methacrylate (EUDRAGIT E 100 of the firm RÖHM PHARMA), and 20 g of a mixed acidic triglyceride of fractionated C₈-C₁₀ coconut fatty acids (Miglyol 812 of the firm Dynamit Nobel) are applied to a protective layer vapor-deposited with aluminum on one side and abhesively finished on both sides and the solvent is evaporated at 50°C to 80°C C. An approximately 300 g/m² layer is obtained. From the thus produced pressure sensitive adhesive layer are punched round discs with a diameter of 65 mm. The projecting edges are worked and central to the same is applied in each case one circular disc of a non-woven fabric e.g. fibrous mixture of viscose staple cotton fiber 50:50 with a substance weight of 80 g/m² and with a diameter of 40 mm. An example of such a product is PARATEX II/80, a product of LOHMANN GMBH & CO KG. PARATEX is a registered trademark of Lohmann GmbH & Co. KG. To this is applied nicotine as the active substance in solution (140 g nicotine in 100 g of an acrylic resin of dimethylaminoethylmethacrylate and neutral methacrylates (EUDRAGIT E 100 of the Firm RÖHM PHARMA) in 102 mg doses/disc. The thus produced patches are immediately laminated with a nicotine impermeable backing layer(a 15 μm thick polyester film on one side of which aluminum is vapor deposited) and sealed in four-edge sealing bags of a suitable packing material. The depot side of the backing layer may be layered with a layer of approximately 300 g/m² of the pressure sensitive adhesive layer, referred to above. The four-edge sealing bags may consist of a compound of paper (surface weight 50 g/m²), aluminum 9 μm and Barex (trademark of the firm Vistron Corp., Cleveland, Ohio, USA, for thermoplastic acrylonitrile-copolymers with negligible gas permeability and great resistance to solvents) with 26 g/m². Thus, those nitrile rubber modified acrylonitrile-methylacrylate copolymers serve as nicotine barrier layer, the aluminium as a nicotine degradation agent barrier, and the paper as a protective layer.

In the case of this example the non-woven fabric serves as the supporting fabric and to assist the uniform distribution of the nicotine as an inert adjuvant as defined hereinbefore.

The chemical composition of Barex has been known to the public, as is evident from the publication of M.TH. Schuler in "Kunststoffe-Plastics" 9/1974, pages 13-20. Particular reference is made to the title, page 13, left-hand column, lines 1 to 3 which both refer generally to "Barex-Harze", page 14/14-16, page 17, right-hand column, section "Untersuchungen an Barex zur Zulassung durch die FDA", lines 5-7 and page 18, column 2, paragraph 2 referring to the approval of the US FDA and stating that Barex (without specific reference to Barex 210) is obtained by graft polymerisation (Pfropf-Polymerisation) of 73-77 parts of acrylonitrile and 23-27 parts of methyl acrylate in the presence of 8-10 parts butadiene-acrylonitrile copolymer of 70% of butadiene, the parts and percents always being by weight. Moreover, the fact that Barex is a thermoplastic copolymer which has negligible gas permeability and good resistance to solvents is, for example, evident from page 13, left-hand column, paragraph 1. Line 1 specifically recites thermoplastic, while the sentence starting in line 5 reads in translation as follows:

"As already the term "barring plastic" means, this novel material has very good barring properties against various gases such as oxygen, carbon dioxide (carbonic acid), nitrogen and also many chemical agents such as acids, alkalis and solvents".

The next sentence refers to the copolymerization of acrylonitrile with selected monomers. Lines 7 to 13 of paragraph 2 of left-hand column of page 13 read in translation:

"Its (i.e. of Barex 210) permeability for oxygen and carbon dioxide is about ten times smaller than that of other conventional bulk plastics. This modern plastic is particularly suitable for applications in which glass-like clarity, prevention of loss of flavor and gas-impermeability are required."

As used herein, the term "sealing bag" refers to a package or other container which is generally flexible and is sealed on at least one side. The sealing bags of this invention can comprise, for example, two sheets or lamina which have been joined along all edges; a single sheet or lamina which has been folded and sealed along all edges or along all non-folded edges; a pouch or pocket which is sealed along one or more edges; and the like.

The term "nicotine barrier" as used herein, implies that the barrier material is inert to nicotine and does not permit nicotine to migrate through the material over a nicotine barrier material is a metal film such as aluminum, which may be provided on one side with a protective layer, e.g. of paper.

The term "nicotine degradation agent barrier" refers to a barrier layer which is substantially impermeable to nicotine degradation agents, such as oxygen and water in liquid or vapor form, and light. The invention may also be defined as a nicotine containment sealing bag comprising:

a) a nitrile rubber modified acrylonitrile-methyl acrylate copolymer nicotine barrier having a volume enclosed therein;

b) a nicotine degradation agent barrier serving to prevent entry of nicotine degradation agents into said volume; and

c) nicotine base within said volume.

Due to the fact that, according to the invention, an active substance solution can be rapidly applied to a matrix layer and is then covered by an active substance impermeable covering layer, it is possible for the first time to obtain in a satisfactory manner well dosed nicotine plasters.

NICOTINE RELEASE TEST (IN VITRO)

A nicotine plaster produced according to Example 1 after removing the protective layer is immersed in 80 ml of isotonic common salt solution at 37°C C. and the released nicotine quantity is determined liquid chromatographically after predetermined intervals. The release medium volume was chosen in such a way that "sink" conditions are obtained over the entire test period. The following results were obtained:

Nicotine released in vitro per plaster:

after 2 hours: 23.90 mg/plaster

after 4 hours: 32.34 mg/plaster

after 8 hours: 41.50 mg/plaster

after 24 hours: 56.54 mg/plaster

EXAMPLE 2

PRODUCTION OF A NICOTINE PLASTER

Another nicotine plaster according to the invention may be inventively produced as follows:

A pressure sensitive adhesive material (adhesive 1) comprising 1.9758 kg of a 40% solution of a self-crosslinking acrylate copolymer (DUROTAC 280- 2416 of the firm Delft National & Chemical B.V.) in a mixture of ethyl acetate, ethanol, heptane and methanol, 189.7 g of an acrylic resin of dimethylaminoethylmethacrylate and neutral methacrylate (EUDRAGIT E 100 of the firm RÖHM PHARMA), and 20 g of a mixed acidic triglyceride or fractionated C₈-C₁₀ coconut fatty acids (Miglyol 812 of the firm Dynamit Nobel) are applied to a protective layer vapor-deposited with aluminum on one side and abhesively finished on both sides and the solvent is evaporated at 50°C to 80°C C. An approximately 440 g/m² layer is obtained. From the thus produced pressure sensitive adhesive layer are punched round discs with a diameter of 51 mm. The projecting edges are worked and central to the same is applied in each case one circular disc of a non-woven fabric (fibrous mixture of viscose staple fibre/cotton 70:30 with a substance weight of 40 g/m²--PARATEX III/40 of LOHMANN GMBH & CO KG) and with a diameter of 42 mm. To this is applied nicotine as the active substance in solution (140 g nicotine in 100 g of an acrylic resin of dimethylaminoethylmethacrylate and neutral methacrylates--EUDRAGIT E 100 of the Firm RÖHM PHARMA) in 46 mg doses/disc. The thus produced patches are immediately laminated with a nicotine-impermeable backing layer (a 15 μm thick polyester film, on one side of which aluminum is vapor-deposited having an approximately 110 g/m² coating of adhesive 1), and sealed in four edge sealing bags of conventional suitable composite packing material.

In this case the non-woven fabric serves as the supporting fabric and to assist the uniform distribution of the nicotine as an inert adjuvant as defined hereinbefore.

Due to the fact that, according to the invention, an active substance solution can be rapidly applied to a matrix layer and is then covered by an active substance impermeable covering layer, it is possible for the first time to obtain in a satisfactory manner well dosed nicotine plasters.

NICOTINE RELEASE TEST (IN VITRO)

A nicotine plaster produced according to Example 2 after removing the protective layer is immersed in 80 ml of isotonic common salt solution at 37°C C. and the released nicotine quantity is determined liquid chromatographically after predetermined intervals. The release medium volume was chosen in such a way that "sink" conditions are obtained over the entire test period. The following results were obtained:

after 2 hours: 5.1 mg/plaster

after 4 hours: 7.2 mg/plaster

after 8 hours: 10.1 mg/plaster

after 24 hours: 16.5 mg/plaster

It is to be understood that the invention is not limited to nicotine plasters and the production thereof with the claimed build-up but that other substances as preferred substances are mentioned in the specification may be administered by this new therapeutic system.

Claims

1. A sealing bag containing a nicotine patch comprising:

a) a butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer layer, and

b) a composite layer comprising paper and, aluminum,

c) wherein the layers form a bag which is sealed on four edges, and

d) wherein a nicotine patch is contained within said bag.

2. A sealing bag according to claim 1, wherein the copolymer layer comprises a copolymer formed from about 73-77 parts by weight of acrylonitrile copolymerized with 23-27 parts by weight of methyl acrylate in the presence of 8-10 parts by weight of butadiene acrylonitrile copolymer containing about 70% by weight of polymer units derived from butadiene.

3. The sealing bag of claim 1 further comprising a protective layer forming the external surface of said sealing bag.

4. The sealing bag of claim 2 further comprising a protective layer forming the external surface of said sealing bag.

5. The sealing bag of claim 1 wherein said composite is disposed on the external surface of said copolymer layer.

6. The sealing bag of claim 2, wherein said composite is disposed on the external surface of said copolymer layer.

7. A sealing bag containing a nicotine patch comprising a four edged sealing bag made of a composite comprising paper, aluminum and a butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer, and wherein the nicotine patch is contained within said bag.

8. A sealing bag consisting of:

a) a thermoplastic butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer layer, and

b) a composite layer consisting of paper and aluminum,

c) wherein the layers from a bag which is sealed on four edges, and

d) wherein a nicotine patch is contained within said bag.

9. A sealing bag containing a nicotine patch comprising a four edged sealing bag made of a composite consisting of paper, aluminum and a thermoplastic butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer, and wherein the nicotine patch is contained within said bag.

10. A sealing bag according to claim 8, wherein the copolymer layer comprises a copolymer formed from about 73-77 parts by weight of acrylonitrile copolymerized with 23-27 parts by weight of methyl acrylate in the presence of 8-10 parts by weight of butadiene acrylonitrile copolymer containing about 70% by weight of polymer units derived from butadiene.

11. The sealing bag of claim 8, wherein said composite is disposed on the external surface of said copolymer layer.

12. The sealing bag of claim 10, wherein said composite is disposed on the external surface of said copolymer layer.

13. The sealing bag of claim 8 further comprising a protective layer forming the external surface of said sealing bag.

14. The sealing bag of claim 10 further comprising a protective layer forming the external surface of said sealing bag.

15. A sealing bag according to claim 7, wherein the copolymer layer comprises a copolymer formed from about 73-77 parts of acrylonitrile copolymerized with 23-27 parts by weight of methyl acrylate in the presence of 8-10 parts by weight of butadiene acrylonitrile copolymer containing about 70% by weight of polymer units derived from butadiene.

16. The sealing bag of claim 7, wherein said composite is disposed on the external surface of said copolymer.

17. The sealing bag of claim 15, wherein said composite is disposed on the external surface of said copolymer layer.

18. The sealing bag of claim 7 further comprising a protective layer forming the external surface of said sealing bag.

19. The sealing bag of claim 15 further comprising a protective layer forming the external surface of said sealing bag.

20. A sealing bag according to claim 9, wherein the copolymer layer comprises a copolymer formed from about 73-77 parts by weight of acrylonitrile copolymerized with 23-27 parts by weight of methyl acrylate in the presence of 8-10 parts by weight of butadiene acrylonitrile copolymer containing about 70% by weight of polymer units derived from butadiene.

21. The sealing bag of claim 9, wherein said composite is disposed on the external surface of said copolymer layer.

22. The sealing bag of claim 20, wherein said composite is disposed on the external surface of said copolymer layer.

23. The sealing bag of claim 9 further comprising a protective layer forming the external surface of said sealing bag.

24. The sealing bag of claim 20 further comprising a protective layer forming the external surface of said sealing bag.

25. A sealing bag containing a nicotine patch comprising a combination of

a) a butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer layer, and

b) a layer comprising aluminum,

wherein the layers form a bag which is sealed on all edges and the nicotine patch is contained within said bag.

26. A sealing bag containing a nicotine patch comprising a bag sealed on all edges made of a composite comprising an aluminum layer and a butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer layer, wherein the nicotine patch is contained within said bag.

27. A sealing bag consisting of a combination of

a) a thermoplastic butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer layer, and

b) an aluminum layer,

wherein said layers form a bag which is sealed on all edges and a nicotine patch is contained within said bag.

28. A sealing bag containing a nicotine patch comprising a bag sealed on all edges comprising a composite consisting essentially of an aluminum layer and a thermoplastic butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer layer, wherein the nicotine patch is contained within said bag.

29. A sealing bag as claimed in claim 25, which is sealed on four edges.

30. A sealing bag as claimed in claim 26, which is a four edged sealing bag.

31. A sealing bag as claimed in claim 27, which is sealed of four edges.

32. A sealing bag as claimed in claim 28, which is a four edged sealing bag.

33. A sealing bag as claimed in claim 25, which further comprises a paper layer.

34. A sealing bag as claimed in claim 26, wherein the composite further comprises a paper layer.

35. A sealing bag as claimed in claim 27, wherein layer (b) further comprises a paper layer.

36. A sealing bag containing a nicotine patch comprising a bag sealed on all edges comprising a composite consisting essentially of a paper layer, an aluminum layer and a thermoplastic butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer layer, wherein the nicotine patch is contained within said bag.

37. A bag for a patch with an active substance comprising a sealing bag made of a composite comprising an aluminum layer and a butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer layer wherein the patch with the active substance is contained within said bag.

38. The bag according to claim 37, where the active substance is nicotine.

39. The bag according to claim 37, wherein the sealing bag is sealed on four edges.

40. The bag according to claim 37, wherein the composite further comprises a paper layer.

41. A bag for a patch with an active substance comprising a sealing bag made of a composite comprising a degradation agent barrier layer for said active substance and a butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer layer wherein said layers are in contact with each other and the active substance is contained in the patch within said bag.

42. The bag according to claim 41, wherein the sealing bag is sealed on four edges.

43. The bag according to claim 41, wherein the composite further comprises a protective layer.

44. The bag according to claim 43, wherein the protective layer is paper and the active substance is nicotine.

45. A sealing bag containing a nicotine patch comprising a bag sealed on all edges made of a composite comprising an aluminum layer and a butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer layer, wherein said layers are in contact with each other and the nicotine patch is contained within said bag.

46. A sealing bag consisting of a combination of

a) a thermoplastic butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer layer, and

b) an aluminum layer,

wherein the layers are in contact with each other and form a bag which is sealed on all edges and a nicotine patch is contained within said bag.

47. A sealing bag containing a nicotine patch comprising a bag sealed on all edges comprising a composite consisting essentially of an aluminum layer and a thermoplastic butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer layer, wherein said layers are in contact with each other and the nicotine patch is contained within said bag.

48. A sealing bag as claimed in claim 45, which is a four edged sealing bag.

49. A sealing bag as claimed in claim 46, which is sealed on four edges.

50. A sealing bag as claimed in claim 47, which is a four edged sealing bag.

51. A sealing bag as claimed in claim 45, wherein the composite further comprises a paper layer.

52. A sealing bag as claimed in claim 46, wherein layer (b) further comprises a paper layer.

53. A sealing bag containing a nicotine patch comprising a bag sealed on all edges comprising a composite consisting essentially of a paper layer, an aluminum layer and a thermoplastic butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer layer, wherein said layers are in contact with each other and the nicotine patch is contained within said bag.

54. A bag for a nicotine patch comprising a sealing bag made of a composite comprising an aluminum layer and a butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer layer wherein said layers are in contact with each other and the nicotine patch is contained within said bag.

55. The bag according to claim 54, wherein the sealing bag is sealed on four edges.

56. The bag according to claim 54, wherein the composite further comprises a paper layer.

57. A bag for a nicotine patch comprising a sealing bag made of a composite comprising a degradation agent barrier layer for said nicotine patch and a butadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymer layer wherein said layers are in contact with each other and a nicotine patch is contained within said bag.

58. The bag according to claim 57, wherein the sealing bag is sealed on four edges.

59. The bag according to claim 57, wherein the composite further comprises a protective layer.

60. The bag according to claim 57, wherein the protective layer is paper.

61. A sealing bag for an active substance that can be applied in a transdermal manner comprising an acrylonitrile methyl acrylate copolymer containing medicament barrier layer and an aluminum-containing medicament-degradation agent barrier.

62. The sealing bag of claim 61, further including a paper protective layer.

63. The sealing bag of claim 61, wherein the transdermal substance is nicotine.

64. The sealing bag of claim 62, wherein the transdermal substance is nicotine.

65. The sealing bag of claim 61, wherein the active substance that can be applied in a transdermal manner is sealed within same sealing bag.

66. The sealing bag of claim 62, wherein the active substance that can be applied in a transdermal manner is sealed within same sealing bag.

67. The sealing bag of claim 65, wherein the active substance is nicotine that can be applied in a transdermal manner and is sealed within same sealing bag.

68. The sealing bag of claim 66, wherein the active substance is nicotine that can be applied in a transdermal manner and is sealed within same sealing bag.