Transdermal delivery system

Abstract

The present invention provides a system comprising: (i) a layer containing a nitrite; and (ii) a hydrogel that contains hydrogen ions; wherein the layer containing a nitrite and/or the hydrogel comprises a pharmaceutically active agent. The invention also provides the use of a system of the invention in medicine, and in the treatment of pain.

Claims

1. A system comprising: (i) a layer containing a nitrite; and (ii) a hydrogel that contains hydrogen ions; wherein the layer containing a nitrite and/or the hydrogel comprises a pharmaceutically active agent; and wherein the system does not contain a thiol or a reductant.

2. The system according to claim 1, wherein the layer is a dissolvable film.

3. The system according to claim 2, wherein the dissolvable film is formed of a polyvinyl alcohol, polyvinylpyrrolidone, a cellulose-based polymer or cellulose.

4. The system according to claim 1, wherein the layer is a mesh.

5. The system according to claim 4, wherein the mesh is formed of a polymer.

6. The system according to claim 5, wherein the polymer is polypropylene.

7. The system according to claim 1, wherein the nitrite is an alkaline metal nitrite or an alkaline earth metal nitrite.

8. The system according to claim 7, wherein the nitrite is sodium nitrite.

9. The system according to claim 1, wherein the system comprises a plurality of layers containing a nitrite.

10. The system according to claim 1, wherein the nitrite is present as a nitrite solution.

11. The system according to claim 1, wherein the hydrogel is partially hydrated.

12. The system according to claim 1, wherein the hydrogel is cross-linked.

13. The system according to claim 1, wherein the hydrogel is a co-polymer.

14. The system according to claim 13, wherein the hydrogel is a co-polymer of polysulfonate and acrylic acid.

15. The system according to claim 1, wherein the pharmaceutically active agent is an anaesthetic selected from the group consisting of lignocaine (lidocaine), amethocaine (tetracaine), xylocaine, bupivacaine, prilocaine, ropivacaine, benzocaine, mepivocaine, cocaine or a mixture thereof.

16. A method of treating a disease or condition in a subject comprising administering to the subject a hydrogel that contains hydrogen ions simultaneously, separately or sequentially with a layer containing a nitrite, wherein the layer containing the nitrite and/or the hydrogel comprises a pharmaceutically active agent, and wherein the layer containing the nitrite and/or the hydrogel does not contain a thiol or a reductant.

17. A method for the treatment of a disease or condition, comprising administering the system according to claim 1 to a subject in need thereof.

18. The method according to claim 17, wherein the layer containing the nitrite is administered simultaneously with the hydrogel that contains hydrogen ions or is administered prior to administration of the hydrogel that contains hydrogen ions, wherein the layer containing the nitrite and/or the hydrogel comprises a pharmaceutically active agent.

19. The method according to claim 17, wherein the disease or condition is pain and the pharmaceutically active agent is an anaesthetic selected from the group consisting of lignocaine (lidocaine), amethocaine (tetracaine), xylocaine, bupivacaine, prilocaine, ropivacaine, benzocaine, mepivocaine, cocaine or a mixture thereof.

20. A kit comprising (i) a layer containing a nitrite, and (ii) a hydrogel that contains hydrogen ions as a combined preparation, wherein the layer containing a nitrite and/or the hydrogel comprises a pharmaceutically active agent, and wherein the layer containing the nitrite and/or the hydrogel does not contain a thiol or a reductant.

Description

(1) The present invention will now be described by way of illustration only with reference to the following Examples and Figures, in which:

(2) FIG. 1 is a schematic diagram of the system of the present invention. This Figure shows the first layer as a mesh, but it can alternatively be a dissolvable layer.

(3) FIG. 2 shows changes in blood flow in treated and untreated feet in a patient with diabetes and a foot ulcer on one foot.

(4) FIG. 3 shows peak blood flow in the wound bed of diabetic foot ulcers as % of baseline in patients treated with a dressing system comprising: (i) a layer containing a nitrite; and (ii) a hydrogel that contains hydrogen ions.

(5) FIG. 4 shows the amount of nitric oxide released from 0.1M sodium nitrite solutions over time when the amount (by weight) of sodium nitrite solution in contact with the hydrogel is varied.

(6) FIG. 5 shows the amount of nitric oxide released from 0.1M and 1.02M sodium nitrite solutions over time.

(7) FIG. 6 shows Verbal Rating Score (VRS). Values are categories; n=100; p<0.0001. (1) No pain, (2) minimal sensation, (3) mild pain, (4) moderate pain, (5) severe pain (including withdrawal of hand).

EXAMPLE 1

Production of Dressing System

(8) This Example describes the production of a dressing system comprising: (i) a layer containing a nitrite; and (ii) a hydrogel that contains hydrogen ions.

(9) Primary Layer: Wound Contact Mesh (Containing 1M Sodium Nitrite)

(10) The Mesh is a polypropylene mesh (RKW-Group), imbibed with 1M Sodium Nitrite solution, from Sodium Nitrite Extra Pure ph Eur, USP Merck and deionised water.

(11) Description of Manufacturing Process

(12) Sodium nitrite is weighed into a suitably sized vessel and then transferred carefully into a known volume of deionised water, which is then stirred until dissolution is complete to make a solution of appropriate concentration. In this embodiment the sodium nitrite solution is dispensed onto the mesh and then is placed into each petri dish for a minimum time to imbibe the mesh with the sodium nitrite solution. The finished products are sterilised by irradiation.

(13) Secondary Layer: Hydrogel Top Layer

(14) The hydrogel chosen for this study has high capability for absorption and facilitates a moist wound-healing environment. The hydrogel comprises a cross-linked anionic copolymer, circa 30% water and circa 30% glycerol. It has an integral polyurethane film that provides a bacterial barrier and aesthetically pleasing outer surface to the dressing. The gel has a surface pH circa 4.2-4.6 arising from the presence of some carboxylic acid groups. These groups provide the acidity for the conversion of Sodium Nitrite to Nitric Oxide. As the carboxylic acid groups are covalently bound to the hydrogel network they are not released into the wound.

(15) Description of Manufacturing Process

(16) The hydrogel is manufactured from the list of ingredients set out below. The process of manufacture is as according to patents EP1100555B1 and EP110556B1, which are incorporated by reference in their entirety herein.

(17) The ingredients are dispensed into a suitable mixing vessel (dispensing is controlled by weight) and stirred overnight. Once mixed, a portion of the liquid solution is dispensed onto a moving substrate (clear polyurethane film, Inspire 2304) at the required coat weight. Then a mesh made of polypropylene (RKW 20 g/m.sup.2) is laid onto the top of the liquid formulation, which is then exposed to UV light and cured. A second layer is coated on top of the first at the required coat weight and exposed to UV light, thus making a sandwich with the mesh in the middle.

(18) The hydrogel is cut to the required size and pouched, sealed and sterilised. The finished products are sterilised by gamma irradiation.

(19) The components of the hydrogel component are:

(20) Monomer, Sodium AMPS 2405A (58% solution in water) (Lubrizol)

(21) Monomer, Acrylic Acid (BASF)

(22) Glycerine BP, EP (H. Fosters)

(23) Darocur 1173, 2-hydroxy-2-methylpropiophenone (BASF)

(24) SR 344, poly (ethylene glycol) diacrylate (Sartomer)

(25) Mesh, Carded non-woven 20 gsm (RKW-Group)

(26) Inspire 2304, polyurethane film (Exopack)

(27) 70 micron, low density polyethylene, siliconised (Adcoat)

(28) NeoCarta, peelable laminate (Safta)

(29) The components of the nitrite layer are:

(30) Mesh, Carded non-woven 20 gsm (RKW-Group)

(31) NeoCarta, peelable laminate (Safta)

(32) Sodium Nitrite, extra pure, Ph Eur, USP (Merck)

(33) De-ionised water (First Water Ltd)

EXAMPLE 2

Treatment of Diabetic Foot Ulcer

(34) A patient with diabetic foot ulceration was treated with a dressing comprising: (i) a layer containing a nitrite; and (ii) a hydrogel that contains hydrogen ions.

(35) The patient was a 62 year old lady with long-standing diabetes and an ulcer on the dorsum of her left foot that had been present for a year. The ulcer had partially healed but was still present and the skin surrounding the ulcer was swollen and of poor quality.

(36) The NOx dressing was applied for 1 hour and measurements of blood flow made at time 0, 20 mins and 60 mins. For comparison, blood flow was also measured in the contralateral foot, at the same time points.

(37) In the contralateral foot, the blood flow remained unchanged during the test period. By comparison, the blood flow in the treated foot increased by over 500% within 20 mins, and remained almost 300% above baseline at 1 hour (FIG. 2). In addition, there was a very noticeable effect at 1 hour. The blood flow in the contralateral foot remained low and sluggish. However, the blood flow in the treated foot not only increased in volume but also acquired a pulsatile form. This is vasomotion and is also perfectly normal in healthy skin. It is a combination of the heartbeat, which also was clearly seen in the traces after treatment with the NOx dressing, and the effect of respiration.

EXAMPLE 3

Increase of Blood Flow Within Diabetic Foot Ulcer Wound Bed

(38) Blood flow within the diabetic foot ulcer wound bed, as measured using Laser Doppler Fluxmetry (LDF), increased significantly from baseline using a 2 part nitric oxide generating dressing in the absence of a reductant.

(39) 6 patients with diabetic foot ulcers, of at least 25 mm.sup.2 that had been present for more than 6 weeks, were consented to join the clinical study. In a controlled environment perfusion units, the accepted measure of blood flow, were monitored using a Moor VMS LDF2 within the wound centre and around the wound bed. Measurements were taken at baseline on the affected foot and at an equivalent site on the contralateral foot. The primary layer and secondary hydrogel top layer, as described in Example 1, were applied to the wound. After 30 minutes the dressing was removed and the blood flow measured in and around the wound bed and at the contralateral foot site. The dressing was reapplied for a further 30 minutes before being removed and again blood flow measurements were taken in and around the wound site and the contralateral foot site.

(40) The average increase in blood flow units was 74.8PU (p=0.012) however as the baseline blood flow in the study subjects ranged from 24.6 to 294.9 it is also pertinent to report that the average percentage increase in blood flow was 82.8% (p=0.016). The full range of increases can be seen in FIG. 3.

EXAMPLE 4

Nitric Oxide Production From Dressing System of the Invention

(41) The amount of Nitric Oxide produced by dressing systems comprising: (i) a layer containing a nitrite; and (ii) a hydrogel that contains hydrogen ions was determined by detecting the gas evolved from the dressing system by the chemiluminescence of its reaction with ozone. The NO concentration was determined with a NOx analyser (Thermo Scientific, UK).

(42) Primary Layer: Wound Contact Mesh (Containing 0.1M Sodium Nitrite)

(43) The Mesh is a polypropylene mesh (RKW-Group), imbibed with 0.1M Sodium Nitrite solution, from Sodium Nitrite Extra Pure ph Eur, USP Merck and deionised water.

(44) Description of Manufacturing Process

(45) Sodium nitrite is weighed into a suitably sized vessel and then transferred carefully into a known volume of deionised water, which is then stirred until dissolution is complete to make a solution of appropriate concentration (0.1M). In this embodiment the sodium nitrite solution is dispensed onto the mesh (25 cm.sup.2) and then placed into each petri dish for a minimum time to imbibe the mesh with the sodium nitrite solution. The finished products are sterilised by irradiation. The weight of nitrite solution entrapped within each mesh was circa 0.4 g in this example.

(46) Secondary Layer: Hydrogel Top Layer

(47) A sheet hydrogel from Example 1 (100 cm.sup.2) was placed onto either one mesh (15.6 mg nitrite solution per cm.sup.2 of mesh in contact with the hydrogel) or 5 meshes (79.2 mg nitrite solution per cm.sup.2 of mesh in contact with the hydrogel) overlaying a glass sinter leading to the NOx analyser. The evolution of nitric oxide was monitored over a ten minute time period. The data obtained are shown in FIG. 4. As can be seen from FIG. 4, the amount of nitric oxide produced was much greater and the duration of release much longer in the experiment where the 5 meshes were used.

(48) The data in FIG. 4 show that amount and duration of release is dependent on the amount (weight) of sodium nitrite solution constrained to the area of contact with the acidifying sheet hydrogel.

EXAMPLE 5

Nitric Oxide Production From Dressing System of the Invention

(49) The amount of Nitric Oxide produced by dressing systems of the invention was determined by detecting the gas evolved from the dressing system by the chemiluminescence of its reaction with ozone. The NO concentration was determined with a NOx analyser (Thermo Scientific; UK).

(50) Primary Layer: Wound Contact Mesh (Containing 0.1M Sodium Nitrite)

(51) The Mesh is a polypropylene mesh (RKW-Group), imbibed with 0.1M Sodium Nitrite solution, from Sodium Nitrite Extra Pure ph Eur, USP Merck and deionised water.

(52) Description of Manufacturing Process

(53) Sodium nitrite is weighed into a suitably sized vessel and then transferred carefully into a known volume of deionised water, which is then stirred until dissolution is complete to make a solution of appropriate concentration (0.1M or 1.02M). In this embodiment the sodium nitrite solution is dispensed onto the mesh (25 cm.sup.2) and then placed into each petri dish for a minimum time to imbibe the mesh with the sodium nitrite solution. The finished products are sterilised by irradiation. The weight of nitrite solution entrapped within each mesh was circa 0.4 g in this example.

(54) Secondary Layer: Hydrogel Top Layer

(55) A sheet hydrogel from Example 1 (100 cm.sup.2) was placed onto one mesh comprising 15.6 mg 0.1M nitrite solution per cm.sup.2 of mesh in contact with the hydrogel and or 15.6 mg 1.02M nitrite solution per cm.sup.2 of mesh in contact with the hydrogel overlaying a glass sinter leading to the NOx analyser. The evolution of nitric oxide was monitored over a ten minute time period. The data obtained are shown in FIG. 5.

(56) The data in FIG. 5 show that amount of release is dependent on the concentration of sodium nitrite solution constrained to the area of contact with the acidifying sheet hydrogel.

EXAMPLE 6

A Placebo-Controlled, Double-Blind Trial of a Combined Percutaneous Local Anaesthetic and Nitric Oxide-Generating System for Venepuncture

(57) This is an abridged version of the data presented in Example 8 of WO 02/17881 and describes a study using a nitric oxide-generating system that is not in accordance with the present invention.

(58) The study was a placebo-controlled, double-blind controlled trial. One hundred healthy, normotensive volunteers were recruited.

(59) A nitric oxide generating system was prepared by mixing two viscous solutions (A and B). Solution A was prepared in KY jelly (Johnson & Johnson Ltd) a sterile lubricant, to which Analar grade sodium nitrite was added to make a 10% (w/v) gel in a sterile plastic specimen pot. Solution B was prepared by adding Analar grade ascorbic acid (vitamin C) to KY jelly to make a 10% (w/v) gel in a separate sterile plastic pot.

(60) The NO-generation gel was termed the placebo treatment, and when further supplemented with lidocaine in aqueous cream to produce a final concentration of 5% local anaesthetic, was termed the active treatment.

(61) The active treatment was applied to the dorsal surface of a randomly selected hand and the placebo treatment was simultaneously applied to the contralateral hand. Following 10 min of application a vein on each hand within the treatment area was then cannulated using a 20 G butterfly needle.

(62) Severity of pain was assessed by a VRS pain classification system and a visual analogue scale (VAS).

(63) Results

(64) The VRS pain classification recorded significant differences in median scores (FIG. 6). The active treatment resulted in a greater reduction in pain response to cannulation than the placebo treatment (p<0.0001). The active formulation also produced a statistically significant reduction in mean VAS pain score of 40.3% (p<0.001).

(65) This Example demonstrates that a nitric oxide-generating system, although not in accordance with the present invention, can be used to deliver a pharmaceutically active agent, lidocaine.