Dressing system

Abstract

The present invention provides a system comprising: (i) a layer containing a nitrite; and (ii) a hydrogel that contains hydrogen ions. The invention also provides the use of a system of the invention for the treatment of a condition associated with tissue ischaemia or a wound and the use of a system of the invention in combination with an anaesthetic for the treatment or prevention of pain.

Claims

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

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

3. The system according to claim 2, wherein the mesh is formed of a polymer.

4. The system according to claim 3, wherein the polymer is polypropylene.

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

6. The system according to any claim 5, wherein the nitrite is sodium nitrite.

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

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

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

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

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

12. The system according to claim 11, wherein the hydrogel is a co-polymer of polysulfonate and acrylic acid.

13. A method of treating a condition associated with tissue ischaemia or a wound in a subject comprising administering to the subject a hydrogel that contains hydrogen ions simultaneously, separately or sequentially with a layer containing a nitrite.

14. A method for the treatment of a condition associated with tissue ischaemia or a wound, comprising administering the system according to claim 1 to a subject in need thereof.

15. The method according to claim 14, 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.

16. A kit comprising a layer containing a nitrite and a hydrogel that contains hydrogen ions as a combined preparation.

17. The system according to claim 1 in combination with an aqueous-soluble drug.

18. A system comprising: (i) a layer containing a nitrite; and (ii) a hydrogel that contains hydrogen ions in combination with an anaesthetic.

19. The system according to claim 18, wherein the anaesthetic is selected from the group consisting of lignocaine (lidocaine), amethocaine (tetracaine), xylocaine, bupivacaine, prilocaine, ropivacaine, benzocaine, mepivocaine, cocaine or a mixture thereof.

20. A method of treatment or prevention of pain comprising administering a system comprising: (i) a layer containing a nitrite; and (ii) a hydrogel that contains hydrogen ions and an anaesthetic to a subject in need thereof.

21. The method according to claim 14, wherein the wound is an ulcer.

22. The method according to claim 21, wherein the ulcer is a leg ulcer, pressure ulcer or diabetic ulcer.

23. The method according to claim 14, wherein the wound is a skin donor site, a surgical wound, a burn, a laceration or an abrasion.

24. The method according to claim 14, wherein the condition associated with tissue ischaemia is Raynaud's syndrome or tissue ischaemia caused by septic shock.

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

(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 short-term changes in pH after application of the NOx gel dressing.

(5) FIG. 4 shows changes in pH over 72 hrs after application of the NOx gel dressing.

(6) FIG. 5 shows peak blood flow in the wound bed of diabetic foot ulcers as % of baseline in patients treated with a dressing system of the invention.

(7) FIG. 6 shows the reduction in size of 4 diabetic ulcers over time as % of original wound area.

(8) FIG. 7 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.

(9) FIG. 8 shows the amount of nitric oxide released from 0.1M and 1.02M sodium nitrite solutions over time.

EXAMPLE 1

Production of Dressing System of the Invention

(10) Primary Layer: Wound Contact Mesh (containing 1M Sodium Nitrite)

(11) 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.

(12) Description of Manufacturing Process

(13) 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.

(14) Secondary Layer: Hydrogel Top Layer

(15) 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.

(16) Description of Manufacturing Process

(17) 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.

(18) 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.

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

(20) The components of the hydrogel component are:

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

(22) Monomer, Acrylic Acid (BASF)

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

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

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

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

(27) Inspire 2304, polyurethane film (Exopack)

(28) 70 micron, low density polyethylene, siliconised (Adcoat)

(29) NeoCarta, peelable laminate (Safta)

(30) The components of the nitrite layer are:

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

(32) NeoCarta, peelable laminate (Safta)

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

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

EXAMPLE 2

Treatment of Diabetic Foot Ulcer

(35) A patient with diabetic foot ulceration was treated with a dressing according to the present invention. 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

Acidifying Effect of Wound Dressing

(38) Although normal skin is acidic, a wound is an alkaline environment. The chemical reaction occurring in the wound dressings of the invention depend on acid reacting with nitrite. Tests were therefore carried out to ensure that the dressing would be effective in a typical alkaline wound environment.

(39) Firstly, studies were performed to test the dressing in a static skin wound model. In this experiment, the NO.sub.x dressing was applied to a cellulose pad soaked in Hanks solution (pH 7.1-7.5) that reflects changes in pH. Within five minutes the pH of the solution in the filter paper had dropped to 5.65 (3-sigma, 5.41-5.89). Within 15 minutes the pH of the filter pad had dropped to 5.08 (3-sigma, 4.62-5.54). The pH of the controls remained between 7-8 (7.27-7.85 from 7.04-7.62) during the time frame of the experiment. The Hanks solution contains phenol red, which at pH <6.8 is yellow, 6.8 to 8.2 is red and >8.2 is purple. Two samples with gel placed over them turned yellow within five minutes; the control was still red.

(40) The experiment with the cellulosic pads is a static experiment. In an in-vivo scenario the wound will constantly exude fluid of an alkaline pH. Therefore the dressing must be able to continually modify the environment when alkaline fluid is infused. To evaluate this the NOx Gel Dressing was placed on a Dynamic Wound Model (DWM, WRAP model (Surgical Materials Testing Laboratory, UK)). The DWM simulates a wound by constantly infusing Hanks' Solution into a wound bed (two cellulosic filter papers) over an allotted period of time. The dressing has 5 kg of weight placed onto it to simulate compression bandaging. The pH was monitored over the first 6 hours (FIG. 3)

(41) The dressing was left on the wound model for 72 hours and the pH of the wound bed measured at various time-points (FIG. 4). The rate of infusion was 0.7 ml/hr, meaning a total of 50 ml of alkaline solution was delivered to the dressing.

(42) These findings were important because they show that dressing provides an acidifying effect, despite the alkaline environment of a wound.

EXAMPLE 4

Increase of Blood Flow within Diabetic Foot Ulcer Wound Bed

(43) 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.

(44) 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.

(45) 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. 5.

EXAMPLE 5

Stimulation of Healing in Diabetic Foot Ulcers

(46) The 2 layer, reductant free, nitric oxide generating dressing stimulated healing in diabetic foot ulcers in a clinical study.

(47) In an ongoing randomised, controlled clinical study examining healing in ulcers greater than 25 mm.sup.2 in area with mild or moderate ischaemia, 4 patients early in the recruitment have already shown a significant response measured by reduction in area. The patients' ulcers were measured at baseline using a SilhouetteStar camera and software, which accurately measures perimeter and area of the ulcer. Patients are treated using a primary layer and a secondary hydrogel top layer, as described in Example 1. The dressing system was changed at least every 48 hours. Patients were re-examined weekly for the first month and every 2 weeks thereafter. Images and measurements were taken at each re-examination using the SilhouetteStar camera.

(48) The initial results are:

(49) Ulcer 1, on a 58 year old patient had been present for 6 weeks prior to treatment. At baseline the ulcer was 0.9 cm.sup.2. The ulcer completely healed within 5 weeks of commencing treatment with the nitric oxide dressing.

(50) Ulcer 2, on a 58 year old patient had been present for 22 weeks prior to treatment. At baseline the ulcer was 4.3 cm.sup.2. The ulcer was still healing and measured 0.3 cm.sup.2 (7% of the original area) after 12 weeks of application of nitric oxide dressing.

(51) Ulcer 3, on a 45 year old patient had been present for 12 weeks prior to treatment. At baseline the ulcer was 0.3 cm.sup.2. The ulcer completely healed within 4 weeks of commencing application of the nitric oxide dressing.

(52) Ulcer 4, on a 75 year old patient had been present for over 12 months prior to treatment. At baseline the ulcer was 0.3 cm.sup.2. The ulcer completely healed within 9 weeks of commencing application of the nitric oxide dressing.

(53) FIG. 6 shows the healing of the wounds over time.

EXAMPLE 6

Nitric Oxide Production from Dressing System of the Invention

(54) 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).

(55) Primary Layer: Wound Contact Mesh (containing 0.1M Sodium Nitrite)

(56) 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.

(57) Description of Manufacturing Process

(58) 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.

(59) Secondary Layer: Hydrogel Top Layer

(60) 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. 7. As can be seen from FIG. 7, 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.

(61) The data in FIG. 7 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 7

Nitric Oxide Production from Dressing System of the Invention

(62) 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).

(63) Primary Layer: Wound Contact Mesh (containing 0.1M Sodium Nitrite)

(64) 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.

(65) Description of Manufacturing Process

(66) 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.

(67) Secondary Layer: Hydrogel Top Layer

(68) 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. 8.

(69) The data in FIG. 8 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 8

Use of Dressing System of the Invention as Pre-Treatment for Anaesthetic

(70) Control

(71) Firstly, as a control, 0.2 g of a 2% (w/v) lidocaine hydrochloride anaesthetic spray (Boots UK) was dispensed onto a circa 3 cm6 cm area of the the skin on the underside of the left forearm of a healthy male volunteer and left 5 minutes. After 5 minutes the skin was pinched by another party using their thumb and forefinger. The healthy male volunteer was then asked to rate the level of pain experienced. The volunteer reported that the pain level was moderate to high, rated 5-6 on a visual analogue scale of 0-10 where 0 is no pain and 10 is worst possible pain.

(72) Experiment

(73) A 3 cm6 cm mesh comprising 8 mg 1.0M NaNO.sub.2 solution per cm.sup.2 of mesh was placed on intact skin on the underside of the right forearm of the same healthy male volunteer as in the the previous example. A 6 cm10 cm Sheet of hydrogel from Example 1 was placed over the nitrite solution containing mesh and left in place for 5 minutes. The sheet hydrogel and mesh were removed. The area of skin covered by the mesh had turned red due to vasodilation. 0.2 g of a 2% (w/v) lidocaine hydrochloride anaesthetic spray (Boots UK) was dispensed onto the vasodilated area of the the skin previously covered by the mesh and left 5 minutes. After 5 minutes the skin was pinched by another party using the thumb and forefinger. The male volunteer was then asked to rate the level of pain experienced. The experiment was then repeated on a different area of the forearm. In both cases the volunteer noted a significant reduction in pain, rated 2 on a visual analogue scale, when compared to the treatment of the left forearm using only the lidocaine hydrochloride anaesthetic spray as the treatment. The reduction in pain experienced by the volunteer indicates that the nitric oxide producing dressing used as a pre treatment increases the effectiveness of a topically applied anaesthetic.