MICRONEEDLE ARRAY COMPRISING A HEAT-PRODUCING ELEMENT

Abstract

The invention relates to a microneedle array having a heat-generating element and its use for the intradermal application of active ingredients, particularly active pharmaceutical ingredients (API) and drugs, wherein this microneedle array is suitable for skin penetration on humans or animals and the microneedles consist of a water-soluble formulation, which contains at least one active ingredient.

Claims

1.-13. (canceled)

14. A microneedle array for use in intradermal application comprising a plurality of microneedles on a carrier and the microneedle array has at least one heat-generating element, wherein the microneedles contain a substantially water-soluble formulation and at least one water-soluble polymer which contain at least one active ingredient.

15. The microneedle array for use in intradermal application according to claim 14, wherein the water-soluble formulation containing at least one active ingredient is present in the tip of the microneedles and/or is part of a coating.

16. The microneedle array for use in intradermal application according to claim 14, wherein the heat-generating element is a heat store.

17. The microneedle array for use in intradermal application according to claim 16, wherein the heat is generated after recrystallization from a supersaturated solution i.) by chemical oxidation reaction, or ii.) by physicochemical processes.

18. The microneedle array for use in intradermal application according to claim 16, wherein the heat is generated after recrystallization from a supersaturated solution i.) by chemical oxidation reaction of atmospheric oxygen with pyrophoric iron on activated carbon in the presence of water or ii.) by physicochemical processes, by the release of crystallization heat.

19. The microneedle array for use in intradermal application according to claim 14, wherein the microneedle array contains an electrically conductive, textile fabric in which electrically conductive fibers are in contact with one another and heat can be generated by supplying an external or internal power source.

20. The microneedle array for use in intradermal application according to claim 14, wherein the microneedle array contains an ultrasound transmitter together with an electrically conductive piezo film, and heat can be generated by supplying an external or internal power source.

21. The microneedle array for use in intradermal application according to claim 14, wherein the heat of a heat-generating element is 42-50 degrees Celsius.

22. The microneedle array for use in intradermal application according to claim 14, wherein the penetrated microneedles are at least partially dissolved and resorb in situ under the influence of heat.

23. The microneedle array for use in intradermal application according to claim 14, wherein the water-soluble polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohols, cellulose, dextrans, alpha-hydroxy acids, polylactides, polyglycolides, polylactide-co-glycolides, and copolymers thereof.

24. The microneedle array for use in intradermal application according to claim 14, wherein the water-soluble polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohols, cellulose, dextrans, lactic acid and/or glycolic acid, polylactides, polyglycolides, polylactide-co-glycolides, and copolymers thereof is selected with polyethylene glycols, polyanhydrides, poly(ortho)esters, polyurethanes, polybutyric acids, polyvaleric acids, and polylactide-co-caprolactones.

25. The microneedle array for use in intradermal application according to claim 14, wherein the density of the microneedles on a carrier is 5-5,000 pieces/cm.sup.2.

26. The microneedle array for use in intradermal application according to claim 14, wherein the at least one active ingredient is selected from the group of hypnotics, sedatives, antiepileptics, wake amines, psychoneurotropics, neuromuscular blockers, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antitussives, expectorants, analgesics, thyroid hormones, sex hormones, glucocorticoid hormones, antidiabetics, antitumor agents, antibiotics, chemotherapeutic agents, narcotics, anti-Parkinson agents, anti-Alzheimer's agents, triptans and vaccine serums.

27. The microneedle array for use in intradermal application according to claim 14, wherein the heat store is designed as the top cover (backing layer) of a microneedle array.

28. The microneedle array for use according to claim 14, wherein the microneedle array has fixing means.

29. The microneedle array for use according to claim 14, wherein the microneedle array has fixing means selected from the group consisting of adhesive strips, plasters, tape, elastic band, rubber and belts.

Description

EXAMPLE 1

[0041] 1. Production of Microneedle Systems

[0042] Sumatriptan succinate, polyvinylpyrrolidone (PVP), polysorbate 80 and glycerin were dissolved in water according to Table 1 in different proportions.

[0043] The various solutions were poured into needle-negative matrices made of silicone, the surface of which was vapor-coated with a thin layer of platinum. The negative matrices were dried with the various solutions overnight at room temperature. The dried microneedle systems were then carefully pressed out of the matrices and stored in special PE containers that were moisture-proof until further use.

[0044] Prior to use in the in vitro permeation studies, random samples of the samples produced were examined analytically for their target active ingredient content, optically for their completeness and uniformity with regard to the microneedles and mechanically for their sufficient strength. In addition, an efficiency test was carried out with regard to sufficient perforation by measuring the transepidermal water loss (TEWL) before and after treatment. For sufficient perforation, the microneedle systems used should show at least one difference (before and after perforation) in the TEWL value of 40 g/m.sup.2×h.

TABLE-US-00001 TABLE 1 Composition of the various microneedle systems (in weight %) Sumatriptan Formulation Water succinate PVP Polysorbate 80 Glycerin F1 58 10 30 1 1 F2 63 5 30 1 1 F3 73 5 20 1 1

[0045] 2. Preparation of the Skin for the In Vitro Permeation Studies

[0046] The back part of Gottinger Minipighaut (Ellegaard Göttingen Minipigs Agricultural Service, Dalmose, Denmark) was used as the skin. The skin, which is delivered as a so-called full skin without subcutaneous fatty tissue in a frozen state, must first be thawed at room temperature and carefully shaved with plenty of water without using any shaving foam to remove the bristles. The skin is then dermatomized or cut to a layer thickness of 800 μm with the aid of an Acculan 3TI battery-powered electric dermatome (Aesculap AG, Tuttlingen, Germany). Circular punched pieces having a diameter of 25 mm are then knocked out of the pieces of skin treated in this way with the help of a corresponding punching tool, for example, a handle punch and are stored shrink-wrapped in PE bags until further use at −20 degrees Celsius (maximum storage period under these conditions up to 12 months).

[0047] 3. Performing the In Vitro Permeation Studies

[0048] The permeation studies were performed in static and vertical Franz cells (Glastechnik Gräfenroda, Germany) with a diffusion area of 1.595 cm.sup.2 and an acceptor volume of 10 ml. The acceptor medium used was phosphate buffer having a pH value of 7.4 according to DAB 10, tempered to 32° C. during the entire permeation time and constantly stirred for uniform mixing of the permeated active ingredient. The acceptor medium was completely replaced by fresh one at the scheduled sampling times. Before the pre-prepared skin punches are clamped in the Franz cells and filled with acceptor, the microneedle systems must first be pressed into the top layer of skin using a manufactured pressure adapter, in the sense of a nail gun with an impulse strength of 150 N/cm.sup.2.

[0049] Before filling with the acceptor and inserting the Franz cells into the water bath controlled to a temperature of 32° C., the temperature-controlled cell heads are put on or they are prepared with an active heat pack mixture, see also the figures including explanations.

[0050] 4. Analytical Determination of Sumatriptan Succinate in the Acceptor Samples

[0051] The analytical determination was carried out by means of HPLC on a C18-Inertsil separation column (250×4.6 mm, 5 μm particle size; VDS Optilab, Berlin) by means of UV detection at 282 nm and at 30 degrees Celsius. A mixture consisting of acetonitrile, methanol and 0.02167 m sodium dihydrogen phosphate solution 10:20:85 (v %/v %/v %) and a pH of 3.2 was used as the eluent. The flow rate was 1.0 ml/min and 20 μl were injected.

[0052] The present examples can be performed analogously for other active ingredients.

[0053] FIG. 5 shows, for example, the analogous performance with the active ingredient caffeine. The composition of the microneedle system is given in Table 2.

TABLE-US-00002 TABLE 2 Composition of the microneedle system (in weight %) with the active ingredient caffeine Formulation Water Caffeine PVP Na alginate Glycerin F4 77 1 20 1 1

[0054] 5. Analytical Determination of Caffeine in the Acceptor Samples

[0055] The analytical determination was carried out by means of HPLC on a C12-Synergi-Max-RP separation column (150×4.6 mm, 4 μm particle size; Phenomenex, Aschaffenburg) by means of UV detection at 273 nm and at 25 degrees Celsius. A mixture consisting of methanol and HPLC water 40:60 (v %/v %) was used as an eluent. The flow rate was 1.0 ml/min and 20 μl were injected.

FIGURES

[0056] FIG. 1: FIG. 1 shows the use of a heat store.

[0057] FIG. 2: Comparison of example 1 according to the invention with external heat generation in comparison to the reference system without additional heat generation in a period up to 6 hours. Both experiments were performed in a FRANZ cell. The heat was generated by means of a heatable (thermostated water) cell head specially designed for the FRANZ cell used (=heat store, so-called heat pack). The lag time of the inventive example is 20 minutes, while that of the reference is 40 minutes, that is, is larger by a factor of 2, which is then also associated with a later onset of action. The amount or rate of release of API, here sumatriptan succinate, of the inventive example is here approximately a factor of 5 greater than that of the reference.

[0058] FIG. 3: Comparison of a further example according to the invention with external heat generation in comparison to the corresponding reference system without additional heat generation within a period of 60 minutes. Both experiments were carried out in a FRANZ cell. The heat was generated by means of a heatable (thermostated water) cell head specially designed for the FRANZ cell used (=heat store, so-called heat pack). The lag time of the inventive example is 0.5 minutes, while that of the reference is 1.0 minutes, that is, is larger by a factor of 2, which is then also associated with a later onset of action. The amount or rate of release of API, here sumatriptan succinate, of the inventive example is here approximately a factor of 4 greater than that of the reference.

[0059] FIG. 4: Comparison of a further example according to the invention with external heat generation in comparison to the corresponding reference system without additional heat generation within a period up to 6 hours. Both experiments were carried out in a FRANZ cell. The heat was generated by means of a commercial heat pack (Thermopad from Thermopad GmbH from Freudenstadt, Germany). The heat pack used had a heat-generating mixture of pyrophoric iron, activated carbon and sodium chloride in a ratio of 16:3:3 percent by weight each and was started catalytically by small amounts of water, in the present case 50 μl (part of the content, 1700 mg, of the commercial heat pack was transferred to the head of the Franz cell used, wherein this head, in a special embodiment made of polypropylene, was provided with lateral opening holes for sufficient oxygen access). The lag time of the inventive example is 0.1 minutes, while that of the reference is 0.4 minutes, that is, is larger by a factor of 4, which is then also associated with a later onset of action. The amount or rate of release of API, here sumatriptan succinate, of the inventive example is approximately a factor of 8 greater than that of the reference.

[0060] FIG. 5: Comparison of a further example according to the invention with external heat generation in comparison to the corresponding reference system without additional heat generation within a period of 8 hours. Both experiments were carried out in a FRANZ cell. The heat was generated by means of a heatable (thermostated water) cell head specially designed for the FRANZ cell used (=heat store, so-called heat pack). The lag time of the inventive example is 40 minutes, while that of the reference is 100 minutes, that is, is larger by a factor of 2.5, which is then also associated with a later onset of action. The amount or rate of release of API, here caffeine, of the inventive example is here approximately a factor of 2 greater than that of the reference.

[0061] FIG. 6: Graphic representation of the FRANZ cell used in “heat pack” mode.