WOUND DRESSING OR DERMAL PATCH

Abstract

The invention relates to a pharmaceutical composition and in particular a dermal patch or wound dressing comprising an acid-hydrolyzing oligomer and/or polymer and an acid-activated prodrug such that the active principle in the pharmaceutical composition or in the dermal patch or wound dressing is formed A from the prodrug under the effect of acid. The invention further relates to a corresponding method for releasing active principles from a pharmaceutical composition.

Claims

1-19. (canceled)

20. Skin or wound patch comprising (a) an oligomer and/or polymer that can produce an acidic environment by its hydrolysis, and (b) an acid-activatable prodrug, whereby the acid-activatable prodrug is activatable in the skin or wound patch by the acid produced by hydrolysis.

21. Skin or wound patch according to claim 20, characterised in that it contains an additional inductor or catalyst of oligomer or polymer hydrolysis.

22. Skin or wound patch according to claim 21, characterised in that the catalyst is an enzyme, whereby the enzyme is preferred to be an esterase or lipase.

23. Skin or wound patch according to claim 20, characterised in that the polymer is selected from the group containing polyester, polyanhydride, and polyorthoester, whereby a polyester is preferred.

24. Skin or wound patch according to claim 23, characterised in that the polymer is a polyester selected from the group containing poly(D,L-lactide), poly(D-lactide), poly(L-lactide), poly(D,L-glycolide) (PDLLA), poly(D-glycolide), poly(L-glycolide), poly(lactide-co-glycolide) (PLGA), polyhydroxybutyrate, poly(-caprolactone) (PCL), poly(-caprolactone-co-glycolide-co-DL-lactide), and poly(p-dioxanone) (PPDO), poly(butylene succinate), poly(ethylene succinate) (PES), poly(butylene succinate-co-adipate), poly(trimethylene carbonate), poly(propylene fumarate) (PPF), and other aliphatic polyesters as well as the copolymers there of including segmented block copolymers made of polyether and polyester segments.

25. Skin or wound patch according to claim 23, characterised in that the polymer is formed as a fibre or as an enveloping layer of a core fibre.

26. Skin or wound patch according to claim 25, characterised in that the fibre has a flat, oval, round, triangular, trilobate, Y-shaped, T-shaped, M-shaped, S-shaped, H-shaped, star-shaped or snowflake-like cross-section.

27. Skin or wound patch according to claim 25, characterised in that the fibre contains a knitted fabric, woven fabric or non-woven fabric as component.

28. Skin or wound patch according to claim 20, characterised in that the oligomer is a cyclic ester or a cyclic anhydride, whereby glycolide or lactide are preferred.

29. Skin or wound patch according to claim 20 for the release of nitrogen monoxide, characterised in that the acid-activatable prodrug is a pH-labile precursor, whereby a nitrite salt is preferred.

30. Skin or wound patch according to claim 20, characterised in that the acid-activatable prodrug is present as a micro- or nano-particle, which preferably is embedded in the polymer matrix.

31. Skin or wound patch according to claim 20, characterised in that it comprises a system, which degrades or neutralises multiply oxidised nitrogen oxides, oxygen radical anions or hydroxyl radicals, whereby the system preferably is selected from the group containing ascorbic acid, vitamin E and derivatives thereof, thiols, and radical scavengers.

32. Skin or wound patch according to claim 20, characterised in that it comprises the following: (a) a carrier layer: and (b) a layer containing i. the oligomer; ii. a polymer; iii. the acid-activatable prodrug; and (c) optionally, a backing layer.

33. Skin or wound patch according to claim 20 for use during the treatment of diseases by placing or sticking the patch onto the area to be exposed to it.

34. Skin or wound patch according to claim 33 for use during the treatment of diseases by placing or sticking the patch onto the area to be exposed to it, characterised in that the treatment is selected from the group containing: (a) treatment of diabetic feet and wounds; (b) treatment of neuropathic pain; (c) treatment of varicose veins; (d) treatment of local superficial or deep-seated ischaemia and thrombopathic diseases of tissues; (e) treatment of acute and chronic inflammations of the skin; (f) treatment of skin allergies; (g) treatment of parasitic skin infections; (h) treatment of atopic dermatitis in particular neurodermatitis, dermatomyositis, and pemphigus vulgaris; (i) treatment of wound defects, such as chronic diabetic-neuropathic ulcers, crural ulcer, decubital wounds; (j) treatment of secondary healing infected wounds; (k) treatment of primary healing wounds, such as ablative lacerations or ablative abrasions; (l) treatment of extensive body regions for therapy of systemic diseases, e.g. such as elevated blood pressure (hypertension) and related haemodynamic diseases; (m) treatment of patients having skin grafts; (n) treatment of diabetic pain in the lower extremities (foot or leg); and (o) treatment of poorly perfused flap grafts.

35. Skin or wound patch according to claim 34, characterised in that it is used for treatment of chronic lower limb wounds of diabetics.

36. Pharmaceutical composition for the release of a pharmaceutically active substance, comprising: (a) an oligomer or polymer that can produce acid by means of hydrolysis; and (b) an acid-activatable prodrug; (c) a radical scavenger system; whereby the acid-activatable prodrug is activatable by the acid produced by hydrolysis.

37. Pharmaceutical composition according to claim 36 for the release of nitrogen monoxide, characterised in that it contains a pH-labile NO precursor as prodrug.

38. Method for the release of an active substance from a pharmaceutical composition and, in particular, from a skin or wound patch, comprising the following steps: (a) providing a pharmaceutical composition and, in particular, a skin or wound patch comprising an oligomer and/or polymer that can produce an acid environment by means of hydrolysis, and an acid-activatable prodrug; (b) contacting the polymer and/or oligomer to an inductor or catalyst such that the inductor or catalyst effects at least partial hydrolysis of the oligomer and/or polymer and such that an acidic environment is thus produced; (c) conversion of the acid-activatable prodrug into an active substance by the acidic environment from step (b); (d) release of the active substance from the pharmaceutical composition and, in particular, from the skin or wound patch.

Description

FIGURES

[0168] The invention is illustrated in the following in more detail based on the figures without limiting the invention to the figures shown. In the figures:

[0169] FIG. 1: shows two embodiments of a fibre according to the invention: In (A) with a core fibre made of an acid-non-hydrolysing polymer (1) and a fibre jacket made of an acid-hydrolysing polymer (2) containing NO prodrug particles (3). In (B), a fibre made of an acid-hydrolysing polymer (2) containing NO prodrug particles (3) is shown.

[0170] FIG. 2: shows selected cross-sections of a fibre according to the invention. A schematic depiction shows the following in the order from top left to bottom right: Circular with an even diameter; polygonal with lumen; oval to round with overlapping scales, oval-flat with lumen pleating, star-shaped, bean-shaped, serrated bean-shaped, triangular with rounded corners, trilobate, lobular with notches, dumbbell-shaped, flattened, concertina-shaped, collapsed tube with hollow core, rounded square with four hollow spaces.

[0171] FIG. 3: shows the production of NO over a period of 100 min in a PLA membrane after the addition of water, sodium nitrite, and sodium-L-ascorbate. The plot shows the amount of NO produced in ppm over the time in seconds. For details, see Example 1.

[0172] FIG. 4: shows a wound patch according to the invention with a carrier (4) (e.g. as a film or fabric backing) onto which a knitted fabric or non-woven fabric (5) is applied that comprises fibres made of acid-hydrolysing polymers or oligomers and a final protective layer (6) that is permeable to NO and prevents the knitted fabric or non-woven fabric from sticking to the wound.

EXAMPLES

[0173] I. Generation of NO in a wound patch by means of an acid-hydrolysing polymer

1. Materials:

[0174] NO gas analysis device Eco physics CLD 822 (ECO PHYSICS AG, Duernten, Switzerland) for quantification of NO [0175] Sodium nitrite (90 mg) and sodium-L-ascorbate (90 mg) [0176] 2 ml distilled water [0177] 15 cm.sup.2 polylactide (PLA) membrane (membrane with micropores with a diameter of 2-50 m, composition: Polylactide tri-polymer as the main component, trimethylene carbonate and -caprolactone (lactocapromer) as ingredients.

2. Method

[0178] 90 mg sodium-L-ascorbate and 90 mg NaNO.sub.2 were distributed evenly on a PLA membrane with a size of 15 cm.sup.2.

[0179] After the addition of 2 ml distilled water, a nitrogen carrier gas (25 ml/min) was streamed over the membrane in a chamber to feed the outgassing NO to the quantification by CLD.

[0180] The NO concentration was quantified continuously for a period of 100 minutes using the CLD system.

3. Results

[0181] The NO quantification by means of CLD is shown in FIG. 3. A continuous increase in the NO concentration was observed, whereby relevant values of 4 ppm were attained after approximately 75 minutes. Due to the presence of the antioxidant, ascorbate, highly pure NO was obtained as the reaction product through suppression of the production of N0.sub.2.