COMPOSITION FOR TREATMENT OF CHRONIC WOUNDS

Abstract

The invention concerns novel pharmaceutical compositions comprising 2, 4, 4-trichloro-2-hydroxydiphenylether (triclosan) and a thickener for use in the treatment of chronic wounds, in particular, in treatment of diabetic chronic wounds, such as foot ulcers.

Claims

1. A pharmaceutical composition comprising: 2,4,4-trichloro-2-hydroxydiphenylether (triclosan); and at least one thickener at 0.5%-8% by weight of the composition, wherein the composition has a viscosity between 70000-150000 centipoise (cPs) at between 20-40 C.

2. The composition according to claim 1, formulated for topical administration.

3. The composition according to claim 1, wherein the composition is in the form of an emulsion, cream, ointment, lotion or balm.

4. The composition according to claim 1, wherein the thickener is selected from one or more of carbopol, polyacrylic acids, guar gum, carbomer, cetyl palmitate and/or other gelling agent.

5. The composition according to claim 1, wherein the 2,4,4-trichloro-2-hydroxydiphenylether is present at 0.1%-4.0% by weight of the composition, more preferably at 0.1%-2.0% by weight of the composition.

6. The composition according to claim 1, wherein the composition further comprises a therapeutically effective amount of an anti-inflammatory agent and/or an effective amount of an analgesic.

7. The composition according to claim 1, wherein the composition comprises at least one hydrophilic component; and at least one hydrophobic component; wherein either the hydrophobic component or the hydrophilic component forms the greatest portion of the composition by weight.

8. A method of treating a chronic wound in a subject, comprising administering to the subject an effective amount of a composition according to claim 1.

9. The method according to claim 8, wherein the chronic wound is a non-healing wound.

10. The method according to claim 8, wherein the chronic wound or ulcer is caused at least in part by one or more of the following: peripheral neuropathy, ischaemia from peripheral arterial disease, microvascular disease, biomechanical abnormalities and superimposed minor trauma.

11. The method according to claim 8, wherein the method is combined with use of one or further treatments selected from a debridement treatment, a systemic antibiotic treatment and/or a post-dressing treatment.

12. The method according to claim 8 wherein the method further comprises packing the wound with the composition, dressing or covering the wound and repeating the treatment at least once.

13. A method of manufacturing the pharmaceutical composition of claim 1, wherein the method comprises the steps of: i) preparing an oil phase comprising at least the triclosan and optionally one or more components selected from: castor oil, stearic acid, glycerol stearate, cetyl palmitate, silicon fluid, jojoba oil, liquid paraffin or a combination thereof; ii) preparing an aqueous phase comprising at least the thickener and optionally one or more components selected from monopropylene glycol, triethanolamine, water and aloe vera; iii) mixing the oil phase and the aqueous phase together; and iv) optionally adding further water to adjust the final viscosity of the composition.

14. The method according to claim 9, wherein the chronic wound is a leg ulcer, diabetic foot ulcer or pressure ulcer.

15. The method according to claim 14, wherein the composition is administered as a topical formulation filling the wound and optionally wherein the wound is covered with a dressing.

16. The method according to claim 8, wherein the method further comprises packing the wound with the composition, dressing or covering the wound and repeating the treatment on a regular basis.

Description

FIGURES

[0061] FIG. 1 (a) is a picture of a diabetic foot ulcer in patient 1. The first ulcer is on the dorsal interphalangeal joint on the second toe, size of 5p, 1 cm sq;

[0062] FIG. 1(b) is a further picture of patient 1 and the second diabetic foot ulcer is on the apex 1.sup.st toe, before debridement;

[0063] FIG. 2 (a) is a further picture, after debridement;

[0064] FIG. 2 (b) is a further picture after 3-4 weeks;

[0065] FIG. 3 (a) is a further picture after 4-6 weeks;

[0066] FIG. 3 (b) is a further picture at 6 weeks;

[0067] FIG. 4 (a) is a further picture at 8-9 weeks;

[0068] FIG. 4 (b) is a further picture just before it was fully healed;

[0069] FIG. 5 (a) (b) is a further picture of the healed apex of 1.sup.st toe;

[0070] FIG. 6a is a picture of a diabetic foot ulcer of patient 2, the picture shows the ulcer before (left) and after (right) debridement and cleaning;

[0071] FIG. 6b is a further picture of the diabetic foot ulcer of patient 2, taken in 4/5-week intervals from date of first treatment; and

[0072] FIG. 7 is a further picture of patient 2, when the ulcer is fully healed.

EXAMPLES

[0073] The formulations shown below were prepared as follows:

[0074] 1. The castor oil, stearic acid, glycerol stearate, cetyl palmitate, silicon fluid, jojoba oil and liquid paraffin were melted together.

[0075] 2. Mixed together well and heated to 60 C.

[0076] 3. In a separate vessel the monopropylene glycol, triethanolamine, 50% of water and carbomer pH 5.5 was mixed together using a Silverson High Shear Mixer 20000 rpm fine mesh head.

[0077] 4. The mixture was heated to 65 C.

[0078] 5. The active component (triclosan) was added to the mixture from step (1) immediately before stage (6) and mixed.

[0079] 6. The oil phase mixture from step (1) was added to the water phase from step (3) and mixed well under high shear conditions using a Silverson High Shear Mixer.

[0080] 7. When fully mixed aloe vera solution was added & stirred in.

[0081] 8. The remaining cold water was added and stirred in. Final pH 5.5

[0082] 9. The mixture was left overnight to stand and cool, then re-mixed the total batch.

[0083] The mixture was poured/filled while still warm at about 40 C.

[0084] Component wt % range in composition examples:

TABLE-US-00002 Ingredient Range (wt %) Castor oil 0.5-3.0 Stearic acid 0.5-8.0 Glycerol mono stearate (GMS SE) 0.1-3.0 Cetyl palmitate 0.1-2.0 Silicone fluid 200/100 CS dimethicone 0.1-10 Additional Preservative 0.0-0.5 Jojoba oil 0.1-0.5 Liquid paraffin 0.1-0.5 Triclosan 0.3-10 Water 35-95 Carbopol 5% 0.5-8.0 Aloe vera 0.1-2.0 Monopropylene glycol (MPG) 2.0-15 Triethanolamine 0.1-2.0

[0085] By varying thickener ratio of 0.5% to up to 8% of the composition weight, as per the examples below, the viscosity of the resulting product was between 70,000-150,000 cPs. The paste was typically thickened using Carbopol Triethanolamine, however one could use polyacrylic acids, Guar gum or Xanthan Gum as the thickener or other standard cosmetic or pharmaceutical thickeners suitable for topical use.

[0086] A number of different examples compositions were then produced with the following wt %:

Example 1

[0087]

TABLE-US-00003 Materials Wt % Phase Castor oil 2.00 A Stearic acid 6.00 GMS SE 2.00 Cetyl Palmitate 1.00 Silicone fluid 1.00 Additional Preservative 0.20 Jojoba oil 0.10 Liquid paraffin 0.10 MPG 10.00 B Triethanolamine 1.55 Hot water @ 65 C. 39.65 Carbopol 5.00 Triclosan 0.50 C Aloe vera 0.50 D Fragrance 0.15 Cold water 30.25 E

[0088] The ingredients of phase A were melted together at a temperature of 60 C. The ingredients of phase B were mixed together using a Silverson High Shear Mixer. Phase C was added to phase A and stirred until dissolved. Phase B was then added to phase A. Phase D was then added and mixed using a Silverson High Shear Mixer. Phase E was also added while mixing.

Example 2

[0089]

TABLE-US-00004 Materials Wt % Phase Castor oil 2.0 A Stearic acid 1.5 GMS SE 0.5 Cetyl Palmitate 0.5 Silicone fluid 1.0 Additional Preservative 0.2 Jojoba oil 0.1 Liquid paraffin 0.1 Triclosan 1.0 B Hot water @ 60 C. 80.4 C Carbopol (5%) 2.0 Aloe vera 10.1 0.5 MPG 10.0 Triethanolamine 0.2 D

[0090] The ingredients of phase A were melted together at a temperature of 70 C. until the phase was clear. The ingredients of phase C were mixed together using a Silverson High Shear Mixer. Phase B was added to phase A and stirred until dissolved. Phase C was then added to phase A. Phase D was then added and mixed using a Silverson High Shear Mixer.

Example 3

[0091]

TABLE-US-00005 Materials wt % Phase Castor oil 2.0 A Stearic acid 1.5 GMS SE 0.5 Cetyl Palmitate 0.5 Silicone fluid 1.0 Additional Preservative 0.2 Jojoba oil 0.1 Liquid paraffin 0.1 Triclosan 2.0 B MPG 10.0 C Hot water @ 60 C. 79.4 Carbopol 2.0 Aloe vera 0.5 Triethanolamine 0.2 D

[0092] The ingredients of phase A were melted together at temperature 65 C. until clear. The ingredients of phase C were mixed together using a Silverson High Shear Mixer. Phase B was added to phase A and stirred until dissolved. Phase C was then added to phase A. Phase D was then added and mixed using a Silverson High Shear Mixer.

Example 4

[0093]

TABLE-US-00006 Materials Wt % Phase Castor oil 2.0 A Stearic acid 1.5 GMS SE 0.5 Cetyl Palmitate 0.5 Silicone fluid 1.0 Additional Preservative 0.2 Jojoba oil 0.1 Liquid paraffin 0.1 Triclosan 2.0 B MPG 10.0 C Hot water @ 60 C. 78.6 Carbopol 5% 2.0 Aloe vera 10:1 0.5 Triethanolamine 1.0 D

[0094] The ingredients of phase A (oil) were melted together at a temperature 65-80 C. until clear. The ingredients of phase C (aq) were mixed together using a Silverson High Shear Mixer. Phase B was added to phase A (oil) and stirred until dissolved. Phase C (aq) was then added to phase A (oil). Phase D was then added and mixed using a Silverson High Shear Mixer.

Example 5

[0095]

TABLE-US-00007 Materials Wt % Phase Castor Oil 2 A Stearic Acid 1.5 G.M.S SE 0.5 Cetyl Palmitate 0.5 Silicone Fluid 200 100CS 1 Jojoba Oil 0.1 Liquid Paraffin Heavy 0.1 Nipastat (optional preservative) 0-0.2 Triclosan 2 B Water Hot (60 C.) 32 C Carbopol 980 5% Sol 2 Mono Propylene Glycol 10 Triethanolamine 1 Aloe Vera 10:1 0.5 Water Cold 46.6 D

[0096] Example 5 was prepared as outlined in example 4.

Clinical Use Examples

[0097] A triclosan cream formulation, according to an embodiment of the invention (Example 5), was applied to a number of patients, with differently presented conditions and symptoms. as described below:

[0098] Patient Profile 1:

[0099] 40 year female diabetic. Neuro ischaemic. Heart rate: pulse mono and biphasic depending on the weather. Indication of reduced arterial blood flow due to a blockage or low elasticity. Ex-smoker. Stage 3 Non healing dorsal diabetic foot ulcer.

[0100] The patient had 2 ulcers: [0101] 1) one on the dorsal IPJ on the 2nd toe, size of 5 pence, 1 cm sq and [0102] 2) one on apex of 1st toe, size of 5p, 1 cm sq.

[0103] No osteomyelitis was apparent in the patient.

[0104] Previous Treatment:

[0105] Prescribed Flucloxacilin antibiotic for 6 months intermittently and ongoing, this treatment was discontinued two weeks into the treatment with the triclosan cream. After 6 treatment courses the patient could not clear the infection in the wound.

[0106] Also treated patient with silver and iodine products and separately honey but no healing occurred.

[0107] Toe became sausage-like. With her co-morbidities and weight, a toe amputation would not be advised as she may not survive surgery.

[0108] Treatment with Triclosan Cream:

[0109] The patient was treated twice a week. The ulcer was filled with the cream to the brim, so the cream was level with skin surface. The cream was not washed off between treatments, but the ulcer had a hard debridement to base of ulcer before each treatment. Triclosan cream was applied for 8 weeks. The cream was packed into the wound and a non-adhesive foam dressing was applied. The patient then wore rocker bottom soles to reduce the weight and pressure. Treatment for this toe ulcer started on Mar. 11, 2017 and healed on 20/1/18. No other medication was used.

[0110] Results:

[0111] Both ulcers healed fully. FIGS. 1 to 5 demonstrate further triclosan cream of the invention is effective at treating diabetic foot ulcers.

[0112] Patient Profile 2:

[0113] The male patient had 1 ulcer on sole of foot, approximately the size of 50 pence.

[0114] No osteomyelitis was apparent in the patient.

[0115] Previous Treatment:

[0116] After treatment course of Flucloxacilin antibiotics the patient could not clear the infection in the wound. Also treated patient with silver and iodine products and separately honey but no healing occurred. Chemotherapy treatment. Debridement performed on ulcer and cleaning.

[0117] Treatment with Triclosan Cream:

[0118] While the patient was receiving chemotherapy, the triclosan cream was applied for 8 weeks. The triclosan cream was applied every alternate day, with a sharp debridement and cleansed with sterile saline solution prior to application of the cream. In the last two weeks of treatment the cream was applied daily. The cream was packed into the ulcer so as to be level with the skin surface and a non-adhesive dressing was applied. The patient then wore rocker bottom soles to reduce the weight and pressure.

[0119] Results:

[0120] Ulcer fully healed.

[0121] FIGS. 6 and 7 demonstrate triclosan cream of the invention is effective at treating diabetic foot ulcers.

[0122] Patient Profile 3:

[0123] Female, 65 years old, with Reynaud's Disease. The patient had very poor circulation with a monophasic pulse in feet. The patient was suffering with severe chilblains that had started to break down and ulcerate forming a chronic wound.

[0124] Previous Treatment:

[0125] No other treatment was helping to heal the ulcerations.

[0126] Treatment with Triclosan Cream:

[0127] The cream was applied into the wound and dressed with a Biatane dressing and then re-packed and re-dressed once a week. After one month the skin had healed and a further 2 weeks for the chilblain to resolve.

[0128] Patient Profile 4:

[0129] Female, 92 years old, ischaemic limbs, wound trauma to the top of her foot. The wound was filling with fluid and not healing.

[0130] Previous Treatment:

[0131] Wound care nurses had used standard of care (dressing) to treat her for over 2 months with no improvement.

[0132] Treatment with Triclosan Cream:

[0133] The cream was applied (packed into the wound) and dressed with a Biatane dressing and then re-packed and re-dressed once a week. The wound healed in 3 weeks.

[0134] Patient Profile 5:

[0135] Female, 50 years old, kidney removed 5 years prior. Verrucae on the bottom of the foot. Patient tried to treat herself with bazooka (verruca treatment) gel and nitrous oxide gas. She then went to doctors with cellulitis and a non-healing hole in her foot.

[0136] Previous Treatment:

[0137] Iodflex was used for a week, but the patient became very poorly with infection and was on verge of needing IV antibiotics.

[0138] Treatment with Triclosan Cream:

[0139] The cream was packed into the hole, dressed with a Biatane dressing and then re-packed and re-dressed once a week. The patient to felt better within a couple of days and the wound healed after 3-4 weeks of treatment advantageously removing the need for IV antibiotics.