Use of local anaesthetic agents in the manufacture of pharmaceutical preparations for iontophoresis

Field of the invention

The present invention is related to the use of pharmaceutically acceptable salts of ropivacaine in the manufacture of pharmaceutical preparations for iontophoresis.

Background of the invention

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 effect has been obtained by the single application of a local anaesthetic

^• composition or when pain relief during a longer period of time is needed by several applications.

Recently a new way of applying local anaesthetics has been developed. This is called iontophoresis. Ionized substances are then introduced into intact tissue such as human skin by an electric current. The equipment consists of one reservoir containing the drug in ionic form and two electrodes, one above the reservoir and one at a distal skin location.

Prior art

Iontophoresis is described e.g. by Gangarosa Louis P. in

Meth and Find Expt. Clin. Pharmacol. 3(2), p. 89-34 (1981) and by Tyle P. in Pharmaceutical Research, Vol. 3, No. 6, 1986.

The local anaesthetic ropivacaine is described e.g. in WO 85/00599.

Outline of the invention

According to the present invention it has surprisingly been found that the local anaesthetic agent ropivacaine in form of its hydrochloride is especially useful for iontophoresis. Earlier other local anaesthetics such as lidocaine and bupivacaine have been used together with ephinephrine. Ephinephrine is necessary in order to make it possible for the earlier used local anaesthetics to penetrate the skin without significant irritation. The local anaesthetic agent defined above need not be combined with ephinephrine as it has a vasoconstrictive effect itself. This is very important as the addition of ephinephrine to hydrochloric solutions of the local anaesthetics gives an insufficient storage stability.

The local anaesthetic compound used according to the invention is in the form of its pharmaceutically acceptable salts. It is especially preferred to use ropivacaine hydrochloride.

The local anaesthetic is incorporated into a jelly or a solution.

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

Pharmaceutical preparations

Example 1

Jelly 0.5%

Ropivacaine hydrochloride monohydrate 5.3 kg

Hydroxypropyl methylcellulose 4000 cps 24.5 kg

Water for injection qs ad 1000 1

Ropivacaine hydrochloride monohydrate and hydroxypropyl methylcellulose are dissolved in water for injection. The volume is adjusted to 1000 1 with water. The resulting solution is autoclaved.

Example 2

Jelly 2%

Ropivacaine hydrochloride monohydrate 8.5 kg

Hydroxypropyl methylcellulose 4000 cps 9.8 kg Water for injection qs ad 400 1

Ropivacaine hydrochloride monohydrate and hydroxypropyl methylcellulose are dissolved in water for injection. The volume is adjusted to 400 J. with water. The resulting solution is autoclaved.

Examples 3 - 5

Solution 5 mg/ml, 10 mg/ml, 20 mg/ml Examples

3 4

Ropivacaine hydrochloride monohydrate 0.53 kg 1.06 kg 2.12 Sodium hydroxide 2M to pH 5.0-6.0 Purified water qs ad 100 kg 100 kg 100

Ropivacaine is dissolved in the water. Sodium hydroxide is added to pH 5.0-6.0. The resulting solution is autoclaved.

The best mode of carrying out the invention known at present is to use the preparation according to Example 4.

Biological test

In a pilot study it was observed that the insertion of an intrader al needle provoked a marked increase in blood flow as measured by laser Doppler flowmetry. Thus, an intradermal injection might be a suitable test method, elucidating drug effects on skin blood flow, i.e. not only showing an increase but also a decrease in flow, if the effect of the needle insertion, per se, is considered in the evaluation of the net circulatory effect of both needle insertion and the injected drug.

The following test was used to evaluate the skin blood flow changes provoked by the intradermal injection of clinically used local anaesthetic agents. Drugs tested were lidocaine, bupivacaine and a new long-acting local anaesthetic agent, ropivacaine.

Material and methods

The studies were carried out on healthy, young male volunteers. In the test group (n=12, mean age 31.7 years, range 25-45) the effects of needle insertion, ^" injection of saline, injection of lidocaine, of bupivacaine and of the new local anaesthetic agent, ropivacaine on skin blood flow were studied. An untreated area of skin served as a control.

Six volunteers took part in the test. According to a

randomized pattern the following procedure was carried out at the various test sites.

In this test measurements at an untreated control area, after needle insertion and after injection of local anaesthetic agents (0.1 ml through a needle) as follows; 1 mg lidocaine, 0.25 mg and 0.75 mg bupivacaine, 0.25 mg and 0.75 mg ropivacaine.

The solutions were coded enabling the studies to be double blind as regards the injection of different solutions. The pH of saline was 6.0, of lidocaine 6.7 and of all solutions of bupivacaine and ropivacaine 5.5. All intradermal injections were made by one and the same person. After the original blood flow levels had been determined, intradermal needle insertions or injections were made exactly 2 minutes apart.

Measurements after needle insertion or fluid injection were started at one site within 30 seconds to elucidate their circulatory effect.

Twenty minutes after the first injection at the first site the recording was started. After 2 minutes the recording probe was moved to the next site etc. In this way a recording was made at each site at 20, 40 and 60 minutes in the first two series. In the third series a recording 90 minutes after the needle insertion or injection was also done. An untreated area served as a control.

When the intradermal test procedure described above was applied to bupivacaine and ropivacaine the injection of 0.75 mg bupivacaine produced a marked increase in blood flow, similar to the increase seen after 1 mg lidocaine but longer lasting. The injection of 0.25 mg of bupivacaine showed a smaller increase in skin blood flow, similar to that after the injection of saline. This

finding is in line with earlier studies showing increase in flow more marked with higher concentrations of local anaesthetics compared to weaker concentrations. Injections of ropivacaine, however, caused a decrease in blood flow compared to saline, most marked when injecting 0.25 rag, indicating a unique effect of this new local anaesthetic drug.

Conclusion

From the unique effect of ropivacaine the conclusion can be drawn that said compound is especially useful for iontophoresis. Due to its decrease in the blood flow it can be used without the addition of ephinephrine, which diminishes the storage stability of the local anaesthetic compositions.