HK1182944A - Ibuprofen for treating actinic keratosis - Google Patents

Description

The present invention relates to compounds for the treatment of actinic keratosis.

Actinic keratosis is a chronic damage to the cornea caused by long-term intense exposure to sunlight or UV radiation.

Actinic keratosis occurs mainly in people in their second half of life, with areas that have been exposed to sunlight unprotected being particularly commonly affected, such as the face, back of the hands, forehead, nose or ear.

Typical treatments include surgical removal or treatment with, for example, imiquimod, 5-fluorouracil, hyaluronic acid with diclofenac or photodynamic therapy with 5-aminolevulinic acid.

Surgical procedures, especially in the facial area or in larger diseases, may be cosmetically undesirable, so topical treatment, particularly in the facial area, is preferably with gels and creams, with the most tolerated treatment currently being a combination of diclofenac/hyaluronic acid.

The present invention was intended to provide further treatment options for actinic keratosis.

The problem is solved by the use of ibuprofen in the prevention and treatment of actinic keratosis.

Ibuprofen has been used for many years to treat osteoarthritis, sports injuries and rheumatic diseases, and is known for its topical use.

For general systemic effect, plasma levels in the range of 10 μg/ ml or higher are necessary. Topical use only achieves plasma levels of about 2 μg/ ml. Topical use therefore does not cause systemic effects and side effects are also extremely low.

The preferred use of ibuprofen according to the invention is therefore in a topical preparation.

The preparations are ointments, creams and gels, which are particularly suitable.

Concentrations of ibuprofen in a topical preparation of 1 to 20% by weight have been shown to be particularly suitable, with concentrations of 5 to 10% by weight being particularly preferred. Preferably the concentration should be greater than 5 or at least 6 or 7%, preferably 10 or less than 10% by weight, for example up to 9% by weight or up to 8%, the range of 5 to 10% by weight or 6-8% is particularly preferred for gel preparations.

In one embodiment, the preparation also contains penetration enhancers, which facilitate penetration into the skin.

Preparations which are particularly suitable as penetration enhancers include dimethyl isorbit, poloxamers, laurocapram, pyrolidone, dimethyl sulfoxide, oleic acid, ethylene glycols and derivatives thereof and mixtures thereof.

In one embodiment of the invention, ibuprofen is the only active substance in the preparation. Of course, depending on the form of application, ibuprofen requires auxiliary substances to produce an injectable medicinal product. However, this embodiment does not contain any other active substances.

In particular, one embodiment does not contain hyaluronic acid, which could be an excipient or active substance.

In another embodiment, diclofenac is added to ibuprofen, and the preferred diclofenac concentration is also in the range of 1 to 20% by weight, with concentrations of 3 to 10% by weight being preferred.

A preferred gel formulation (microemulsion gel) contains: The use of the drug in the treatment of acute and chronic pain is recommended for patients with severe acute and chronic pain.

Another preferred gel contains: The use of the product should be limited to the following: 5 to 10 g ibuprofen, 30 to 60 g ethanol 96%g, 5 to 20 g dimethyl isosorbide, 1 to 4 g hydroxypropyl cellulose, 0.75 to 4 g potassium hydroxide, water per 100 g.

The invention is further explained by the following examples.

Examples

In a preliminary study, the treatment of actinic keratosis with ibuprofen was compared with treatment with diclofenac. e study was conducted according to the relevant criteria and was approved by the Ethics Committee of the Slovak Dermatological Society.

The study included 24 patients with five or more lesions in the head, face, arms or hands.

12 patients were treated with ibuprofen 5% gel and the others with diclofenac 3% gel, administered twice daily.

At enrolment, the severity of the lesions was assessed on the basis of a baseline BSI score of 0 to 3, and only patients with BSI scores of 1 and 2 were enrolled.

The BSI score (baseline severity index score 1 to 3)

0 = no actinic keratosis (AKS) visible1 = clearly visible lesion2 = many small, moderately thick lesions or few large, scaly lesions visible3 = many thick, hypertrophic lesions that are clearly visible and tangible with a clear boundary.

The main efficacy endpoints were the total number of lesions in the treatment area and the IGII (Investigator Global Improvement Index) score between -2 and +4. Other Tabelle 1: Mittlere Anzahl der Läsionen zum Start der Studie

Stirn	4,6	7,1
Gesicht	5,7	7
Kopfhaut	6,3	15,8
Hände	18,5	18,1

Tabelle 2: Mittlere Anzahl der Läsionen nach 90tägiger Behandlung

Stirn	4	5,3
Gesicht	4,8	5,5
Kopfhaut	6	11,5
Hände	16,9	17,1

After 90 days of treatment, the mean number of lesions in the ibuprofen group decreased from 35.1 to 31.7 and in the diclofenac group from 48 to 39.4.

The number of employees in the company is also increasing.

- 2	signifikante Verschlechterung
- 1	leichte Verschlechterung
0	unverändert
1	leichte Verbesserung
2	Verbesserung
3	signifikante Verbesserung
4	komplette Heilung

The IGII was measured between each of the two visits and ranged from -2 (severe worsening) to +4 (cure) and changed over the course of 90 days of treatment as follows: Other Tabelle 3: Investigator Global Improvement Index zum Start der Studie (V0) und nach 90tägiger Behandlung (V3)

Stirn	0	1,33	0	1,55
Gesicht	0	1,38	0	1,7
Kopfhaut	0	1	0	1,75
Hand	0	1	0	1

Results

The differences in the reduction of lesions compared to ibuprofen and diclofenac are mainly due to the number of lesions at the start of the study. No adverse reactions were observed during the study. The therapy was well tolerated.

In another study, six patients were treated with ibuprofen 10% gel and another six patients with 3% diclofenac gel, and the study design was similar to the first study.

The total number of lesions in the ibuprofen group changed from 18 at baseline to 3.7 at the end of the 90-day treatment period, while the average number of lesions in the diclofenac group changed from 36.8 at baseline to 19.2 at the end of treatment. Other Tabelle 4: Mittlere Anzahl der Läsionen zum Start der Studie

Stirn	3,3	7,5
Gesicht	5,2	12,3
Kopfhaut	Keine Bewertung, da nur 1 Patient Läsionen zeigte.
Hände	9,5	17

Tabelle 5: Mittlere Anzahl der Läsionen nach 90tägiger Behandlung

Stirn	0,3	4,2
Gesicht	0,7	6,2
Kopfhaut	Keine Bewertung, da nur 1 Patient Läsionen zeigte.
Hände	2,7	8,8

The mean IGII at the end of treatment was 3.7 in the ibuprofen group (meaning that the lesions had almost completely healed) and 2.29 in the diclofenac group, which corresponds to a moderate cure rate. Other Tabelle 6: Investigator Global Improvement Index zum Start der Studie (V0) und nach 90tägiger Behandlung (V3)

	V0	V3	V0	V3
Stirn	0	3,8	0	2,3
Gesicht	0	3,7	0	2,17
Kopfhaut	Keine Bewertung, da nur 1 Patient Läsionen zeigte.
Hand	0	3,6	0	2,4

Results

Even considering the small number of patients in study 2, the treatment success in the ibuprofen 10% group shows that the formulation is highly effective in the treatment of mild and moderate keratosis lesions. The therapeutic outcomes of diclofenac treatment are also good, although due to the high initial lesions, no overall distribution was seen. It should also be noted that three patients in the ibuprofen group were completely free of the optically visible lesions at the end of 90 days of treatment.

Claims (13)

1. Ibuprofen for use in the prevention and treatment of actinic keratosis.
2. Ibuprofen for use as claimed 1, characterised by its presence in a topical formulation.
3. Ibuprofen for use as claimed 2, characterised by being in the form of an ointment, cream or gel.
4. Ibuprofen for use in accordance with claim 2 or claim 3, characterised by the concentration of ibuprofen between 1 and 20% by weight.
5. Ibuprofen for use in claim 4 characterised by a concentration of 5 to 10% by weight.
6. Ibuprofen for use in claim 5 is characterised by a concentration of 6 to 8% by weight.
7. Ibuprofen for use in accordance with claims 2 to 6 characterised by the presence of penetration enhancers selected from the group consisting of dimethyl isosorbide, poloxamers, laurocapram, pyrolidone, dimethyl sulfoxide, oleic acid, ethylene glycols and derivatives thereof and mixtures thereof.
8. Ibuprofen for use in accordance with claims 1 to 7, where ibuprofen is the only active substance.
9. Ibuprofen for use in accordance with claims 1 to 7, characterised by the addition of diclofenac.
10. Ibuprofen for use in accordance with claims 2 to 9 characterised by the absence of hyaluronic acid.
11. Pharmaceutical preparation containing 6 to 8% by weight of ibuprofen and 2 to 15% by weight of penetration enhancers.
12. Pharmaceutical preparation according to claim 11, characterised by the penetration enhancer being dimethyl isosorbide.
13. Pharmaceutical preparation according to claim 11 or 12 in the form of a gel.