HU210322B - Process for production of preparations containing ropivacaine for treatment of iontophoresis - Google Patents

Abstract

Use of a pharmaceutically acceptable salt of ropivacaine for the manufacture of a pharmaceutical preparation for iontophoresis.

Description

(57) EXTRAS

FIELD OF THE INVENTION The present invention relates to a process for the preparation of a medicament for the treatment of iontophoresis comprising pharmaceutically acceptable salts of ropivacaine by processing the pharmaceutically acceptable salt of ropivacaine together with standard pharmaceutically inert excipients into a stable gel or solution for iontophoretic treatment.

Scope of the description: 4 pages

HU 210 322 B

HU 210 322 Β

The present invention relates to a process for the preparation of a medicament for use in iontophoresis comprising pharmaceutically acceptable salts of ropivacaine (S-N- (2,6-dimethylphenyl) -1-propyl-2-piperidinecarboxamide).

Topical anesthetics are generally administered by application to a tissue surface or by injection into a tissue or vascular system, thereby inhibiting the generation and conduction of pulses in peripheral nerves. Topical anesthetics, which act by blocking the nerves, are generally used to relieve pain. Pain relief occurs during surgical interventions using local anesthesia or in various diseases where analgesia is needed. Generally, the desired effect is achieved by using a single topical anesthetic compound or by administering multiple formulations when analgesia is required over an extended period of time.

Recently, a new method of applying topical anesthetics has been developed. This procedure is iontophoresis, which involves the introduction of ionized substances into intact tissues, such as human skin, by means of an electric current. The device consists of a container and electrode containing the active substance in ionized form, one of which is located above the container and the other distal to the surface of the skin.

Iontophoresis is described, for example, in Gangarosa Louis P., 1981, Meth. And Find. Expt. Clin. Pharmacol. 3 (2): 29-34, and in Tyle P., Pharmaceutical Research, 3 (6). 1986).

Ropivacaine as a topical anesthetic is described in WO 85/00599.

Surprisingly, the present invention has found that the topical anesthetic, ropivacaine, in the form of its hydrochloride, is particularly useful for iontophoresis. Other local anesthetics such as lidocaine and bupivacaine have previously been used in combination with epinephrine. Epinephrine was needed to ensure that the previously applied topical anesthetics were absorbed through the skin (without penetrating the skin) without causing significant skin irritation. The above-mentioned topical anesthetic of the invention does not need to be combined with epinephrine as it is already vasoconstrictive. This is of great importance because the addition of epinephrine to hydrochloric solutions of local anesthetics results in inadequate storage stability.

The topical anesthetic compound of the invention is used in the form of pharmaceutically acceptable salts. A particularly preferred salt is ropivacaine hydrochloride.

The topical anesthetic is formulated as a gel or solution.

The local anesthetic composition will contain from about 0.25% to about 10% by weight, preferably from about 0.5% to about 2% by weight, of the local anesthetic compound.

The following examples illustrate pharmaceutical formulations.

Example 1:

Gel, 0.5%

Ropivacaine hydrochloride monohydrate 5.3 kg (Hydroxypropyl) methyl / cellulose 4000 cps 24.5 kg

Water for injection qs ad 10001

Ropivacaine hydrochloride monohydrate and (hydroxypropyl) methylcellulose are dissolved in water for injection. The volume is then made up to 1000 liters with water. The solution thus obtained is autoclaved.

Example 2:

Jelly, 2%

Ropivacaine hydrochloride monohydrate 8.5 kg (Hydroxypropyl) methyl / cellulose4000 cps 9.8 kg

Water for injection qs ad 4001

Ropivacaine hydrochloride monohydrate and (hydroxypropyl) methylcellulose are dissolved in water for injection. The volume was then made up to 400 liters with water. The solution thus obtained is autoclaved.

3-5. example:

Solutions: 5 mg / ml, 10 mg / ml, 20 mg / ml.

Examples

3_4_5

Ropivacaine hydrochloride monohydrate 0.53 kg 1.06 kg 2.12 kg Sodium hydroxide 2 M pH 5.0-6.0

Purified water qs ad 100 kg 100 kg 100 kg Ropivacaine is dissolved in water and adjusted to pH 5.0-6.0 with sodium hydroxide solution. The solution thus obtained is autoclaved.

The most preferred embodiment of the present invention now appears to be the pharmaceutical composition of Example 4.

Biological test

In an orientation study, it was determined by laser Doppler flowmeter that insertion of an intradermal needle significantly increased blood flow. Thus, intradermal injection can be considered as an appropriate test for the effect of an active substance on the blood flow of the skin, ie not only the increase but also the decrease of the flow, if the effect of introducing the needle itself is taken into account. evaluating the combined effect of needle insertion and injection drug delivery.

The following test was used to evaluate the changes in skin blood flow induced by intradermal injection of topical anesthetics used in the clinic. The agents tested are as follows

HU 210 322 Β were: lidocaine, bupivacaine and a new long-acting topical anesthetic, ropivacaine.

Materials and Methods

The studies were conducted in healthy young male volunteers. In the study group [n = 12, mean age 31.7 years (25-45 years)], the effects of needle insertion, saline injection, lidocaine, bupivacaine and injection of the new topical anesthetic ropivacaine on skin blood flow were studied. . Anem-treated skin was used as a control.

Six volunteers participated in the study. In accordance with the Randonr assay design, the following procedure was performed in the various assay areas.

In this test, measurements were taken in the untreated control area, after needle placement and after injection of topical anesthetics (0.1 ml through the needle) as follows: 1 mg lidocaine, 0.25 mg and 0.75 mg bupivacaine, 0.25 and 0.75 mg ropivacaine.

The solutions were coded to allow double blind testing of injections containing the various solutions. The pH of the saline solution was 6.0, the lidocaine 6.7 and all solutions containing bupivacaine and ropivacaine 5.5. All intradermal injections were given by the same person. Intradermal needle insertion and injection were given exactly 2 minutes after the initial blood flow levels were determined.

Measurements were initiated within 30 seconds of insertion of the needle and injection of fluid at a given site to investigate their effect on the circulation.

Registration began 20 minutes after the first injection of the first site. Two minutes later, the recording probe was moved to the next location, etc. In this way, each site was registered in the first two series after 20, 40 and 60 minutes. In the third series, 90 minutes after the needle insertion and injection were recorded. The untreated area served as a control.

When the intradermal test procedure described above was applied to bupivacaine and ropivacaine, injection of 0.75 mg bupivacaine significantly increased blood flow, similar to that observed after 1 mg lidocaine, but more persistently, administration of 0.25 mg bupivacaine resulted in a smaller increase. blood flow to the skin, similar to those seen after saline injection. This observation is consistent with previous studies that showed greater growth at higher concentrations of topical anesthetics than at lower concentrations. However, after the injection of ropivacaine, the blood flow was reduced compared to the effect of the saline solution, which was most pronounced with the 0.25 mg injection, which indicates the unique effect of this new topical anesthetic.

Based on this exceptional activity of ropivacaine, it can be concluded that this compound is particularly useful for iontophoresis. Due to its antihypertensive activity, the agent can be administered without the addition of epinephrine which adversely affects the storage stability of topical anesthetics.

Claims (2)

PATIENT INDIVIDUAL POINTS A method for the preparation of a topical anesthetic composition comprising a pharmaceutically acceptable salt of ropivacaine (SN- (2,6-dimethylphenyl) -1-propyl-2-piperidinecarboxamide) as active ingredient, characterized in that the pharmaceutically acceptable salt of ropivacaine is conventional, inert, with auxiliary substances, processed into a stable gel or solution for iontophoretic treatment. 2. A method according to claim 1, wherein the pharmaceutically acceptable salt of ropivacaine is a hydrochloride.