WO1989011853A1

WO1989011853A1 - Use of local anaesthetic agents in the manufacture of preparations with wound healing effect

Info

Publication number: WO1989011853A1
Application number: PCT/SE1989/000298
Authority: WO
Inventors: Hans Christer Arvid Evers
Original assignee: Aktiebolaget Astra
Priority date: 1988-06-01
Filing date: 1989-05-26
Publication date: 1989-12-14
Also published as: AU3764689A; SE8802040D0

Abstract

Use of one or more local anaesthetic agents, especially lidocaine, for the manufacture of a pharmaceutical preparation with healing effect on wounds.

Description

Use of local anaesthetic agents in the manufacture of preparations with wound healing effect -____

Field of the Invention

The present invention is related to the use of one or more local anaesthetic agents, or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceutical preparations for wound healing, especially for the treatment of leg ulcers.

Background of the invention

Chronic ulcers on legs are a coπmon cause of considerable morbidity. They often cause a therapeutic problem. Many different methods and , drugs have been tried in attempts to initiate and complete the healing process. An often used method is the pinch grafts technique, sometimes used together with a semipermeable dressing. C.f. Gilmore W.A. and Wheeland R.6., J. Dermatol . Surg. Oncol. 8: 3, March 1982, p. 177-183.

The common use of local anaesthetic agents is to apply them onto a tissue surface or inject them into a tissue or a vascular bed in order to inhibit impulse generation and conduction in peripheral nerves. Local anaesthetics are generally used to reduce painful sensations, by blocking the nerves. Freedom from pain is obtained by use for local anaesthesia at surgical operations or when used to reduce pain at different kinds of illnesses. The local anaesthetic effect has also been used in connection with the treatment of ulcers, partly in order to reduce the pain and also in order to avoid the pain the patient feels when his ulcers, especially leg ulcers, are cleaned. The wanted effect has been obtained by the single applica- tion of a local anaesthetic composition or when pain relief during a longer period of time is needed by several applications.

The local anaesthetic compounds have also other biological effects in addition to the local anaesthetic, e.g. anti-inflammatory, anti- trombotic and protecting effect at irradiation. Prior art

Schnellen B., Med. Welt 1968: 3, p. 198-200 describes the use of Achtiaemyl, which 1s an albumin free extract from the blood of calves, in comparison with lidocaine for the treatment of leg ulcers. Both Achtiaemyl and lidocaine were injected around and under the ulcers. The best effect was obtained with Achtiaemyl. Lidocaine gave initially a healing effect but it did not last.

Roenigk Jr., H.H., describes in Modern Medicine of Asia, Vol. 16: 9, September 1980, p.31-36 and Primary Care, Vol.10:3, 1983, p.411-427 the use of viscous lidocaine when leg ulcers are cleaned. Lidocaine is in this case only used because of its local anaesthetic effect. The leg ulcer is according to Roenigk covered with a special bandage called an "Unna boot". It is the bandage that should give the healing effect.

Outline of the invention

According to the present invention it has now surprisingly been found that chronical ulcers of different kinds can be treated by the continuous application of a local anaesthetic composition, without the use of any pinch grafts technique or special bandage.

The local anaesthetic compound used according to the invention is lidocaine in the form of its base or a pharmaceutically acceptable salt thereof or a eutectic mixture of lidocaine and prilocaine, in form of their bases. It is especially preferred to use lidocaine hydrochloride.

The local anaesthetic is incorporated into a jelly, an emulsion, a cream, an ointment, a spray solution or a film forming formulation. It is very important that no preservative is present in the formulation.

It is also possible to incorporate the local anaesthetic compound into a pharmaceutical composition with sustained release of the active compound. Hereby an even concentration of the active compound during a long period of time is obtained without the need to change dressings. The cream described below is an example of a sustained release preparation.

A further way to applicate the local anaesthetic preparation is to use sterile dressings drenched with the local anaesthetic prepara¬ tion.

The local anaesthetic composition contains between 0.25-10 % by weight of the local anaesthetic compound, preferably 0.5-2 % by weight.

Pharmaceutical preparations

Example 1

Jelly 1 %

Lidocaine hydrochloride onohydrate 10.8 kg

Hydroxypropyl methylcellulose 4000 cps 24.5 kg Sodium hydroxide 2M to pH 6.3-6.7

Water for injection qs ad 10001

Lidocaine hydrochloride monohydrate and hydroxypropyl methyl- cellulose are dissolved in water for injection. The pH is adjusted to 6.3-6.7 with sodium hydroxide and the volume to 1000 1 with water.

Example 2

Jelly 2 %

Lidocaine hydrochloride monohydrate 8.65 kg

Hydroxypropyl methylcellulose 4000 cps 9.8 kg Sodium hydroxide 2M to pH 6.2-6.6

Water for injection qs ad 400 1 Lidocaine hydrochloride monohydrate and hydroxypropyl methyl- cellulose are dissolved in water for injection. The pH is adjusted to 6.2-6.6 with sodium hydroxide and the volume to 400 1 with water^, The resulting solution is autoclaved.

Example 3

Solution 40 mg/m

Lidocaine hydrochloride monohydrate 4.28 kg Sodium hydroxide 2M to pH 6.5-6.7 «*0.46 kg Purified water qs ad 95.56 kg

Lidocaine is dissolved in the water. Sodium hydroxide is added to pH 6.5-6.7. The resulting solution is autoclaved.

Example 4

Emulsion cream

Lidocaine 10 9

Miglyol^R 812 27.6 "

Arlatone^R 289 9.0 "

Carbopol^R 934 1.0 " Water ad 100 "

The emulsion is prepared by dissolving lidocaine in the oil

(Miglyol 812), whereafter it is melted together with the e ulsifier (Arl tone 289). A minor amount of water is then added to the hot mixture. The resulting mixture is cooled, whereafter the thickening agent (Carbopol ) mixed with the rest of the water is added as a gel. The resulting mixture is homogenized to such an extent that the substantial part of the oil droplets have a diameter of - _3μ. Miglyol 812 is a hardened coco-fat with mean chain length. Arlatone 289 is a polyoxyethylene fatty acid ester and Carbopol^R 934 is a vinyl polymer with active carboxyl groups. Example 5

Lidocaine 5 g

Miglyol^R 812 13.8 "

Arlatone^R 289 4.5 "

Carbopol^R 934 1.0 "

Water ad 100 "

An emulsion cream is prepared as described in example 3.

Example 6

Lidocaine 2.5 g

Miglyol^R 812 6.9 "

Arlatone^R 289 2.25 "

Carbopol^R 934 1.0 "

Water ad 100

An emulsion cream is prepared as described in example 3.

Example 7

Prilocaine, base 52 g

Lidocaine, base 48 g

The two local anaesthetically active compounds in crystalline form are weighed together and heated to 30°C, whereby the two compounds melt and form a homogenous oil. The mixture of crystals have a melting point of 22°C. The mixture is then applied onto a carrier ooff ppaappeerr iinn aann aammoouunntt ooff 11..55 mg/cm . At use the carrier in suitable size is applied on the ulcer.

The best mode of carrying out the invention known at present is to use the preparation according to Example 2. Biological examples

Example A

Patient A with two chronical arterial ulcers on the malleolus of each_.foot had been treated for a long period of time in a surgical clinic at a big hospital. The ulcers were extremely painful and the patient must be given strong analgetics. The prospects were bad and no kind of treatment seemed to be successful. As the blood flow through the ulcerous area was inadequate it was not possible to transplantate new skin covering the injured area.

At the treatment the two ulcerous areas were covered with dressings containing a lidocaine jelly. The dressings were changed policlinic- ally.once a day. After 2 days the pain of the ulcers disappeared and the treatment with analgetics could be discontinued. By con¬ tinuous treatment as described, where the dressings containing lido¬ caine were changed e^ery day patient A recovered and left the hospital after about 4 months of treatment.

Example B

An elderly Patient B with several chronical ulcers on both feet came to another big hospital. As Patient B had diabetes the con- elusion was that as the condition of the feet were very bad the feet would soon have to be amputated. As in the earlier described case, the new treatment was started by covering the ulcers with a lidocaine jelly.

After almost 4 years of treatment there are still some minor wounds, which, however, do not need intensive treatment. It has not been necessary to amputate Patient B's feet. The positive outcome is in completely contrast to what was expected, namely that the in¬ sufficient flow of flood should result in necrosis, whereafter the feet should have had to be amputated.

Claims

Cl aims

1. Use of one or more local anaesthetic agents or pharmaceutically acceptable salts thereof in the manufacture of a pharmaceutical preparation without preservatives with healing effect on wounds.

2. Use according to claim 1, wherein the preparation is,used for its healing effect on leg ulcers.

3. Use according to claim 1, wherein the local anaesthetic agent is lidocaine.

4. Use according to claim 1, wherein the local anaesthetic is an eutectic mixture of lidocaine and prilocaine.

5. Use according to claim 3, wherein lidocaine is in the form of its hydrochloride.

6. Use according to claim 4, wherein lidocaine and prilocaine are in the form of their bases.

7. Use according to claim 2, wherein lidocaine is present in an amount of 0.5-2 % by weight of the pharmaceutical preparation.

8. A method of obtaining healing effect on wounds comprising application to a patient in the need of healing an amount of a pharmaceutical preparation without preservatives containing one or more local anaesthetic agents or pharmaceutically accept¬ able salts thereof effective to obtain healing.