AU650002B2 - Use of local anaesthetic agents in the manufacture of pharmaceutical preparations for iontophoresis - Google Patents

Description

WO 91/11182 PC/SE91/00053 1 Use of local anaesthetic agents in the manufacture of iontophoretic preparations Field of the invention The present invention is related to the use of pharmaceutically acceptable salts of ropivacaine in the manufacture of iontophoretic preparations.

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 30 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. 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 the form of its pharmaceutically acceptable salts, for instance, ropivacaine hydrochloride, is especially useful for iontophoresis. In contrast to the prior art, the indicated local anaesthetic agent 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 local anaesthetics gives an insufficient storage stability. Thus, 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 indicated local anaesthetic used in accordance with the invention may be incorporated into a jelly composition or may be used in the form of a solution. These local anaesthetic compositions may contain between 0.25 and 10 by weight of the local anaesthetic compound, preferably 0.5-2 by weight. Thus, as part of the present invention, there is provided a method for the preparation of an iontophoretic composition suitable for inducing local anaesthesia by iontophoresis, which compriseF formulating a jellified pharmaceutically acceptable carrier with a pharmaceutically acceptable salt of ropivacaine in an amount of between 0.5 and 10 by weight of the composition.

WO 91/11182 PCT/SE91/00053 Iontophoretic preparations Example 1 Jelly 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 2000 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 t

S

Solution 5 mg/ml, 10 mg/ml, 20 mg/ml Examples Ropivacaine hydrochloride monohydrate Sodium hydroxide 2M to pH 5.0-6.0 Purified water 0.53 kg 1.06 kg 2.12 kg qs ad 100 kg 100 kg 100 ka WO 91/11182 PCT/S E911/00053 4 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 intradermal 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, bupivacainr 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 WO 91/11182 PCr~/SE91/00053 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 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 WO 91/11182 PCr/S E91 /00053 6 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 mg, 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 ephinephrinf(, which diminishes the storage stability of the local anaesthetic compositions.

Claims (14)

1. A method for the preparation of an iontophoretic composition suitable for inducing local anaesthesia by iontophoresis, which comprises formulating a jellified pharmaceutically acceptable carrier with a pharmaceutically acceptable salt of ropivacaine in an amount of between and 10 by weight of the composition.

2. A method according to claim 1 wherein the amount of the pharmaceutically acceptable salt of ropivacaine is between 0.5 and 2 by weight of the composition.

3. A method according to claim 1 or 2 wherein the pharmaceutically acceptable salt of ropivacaine is ropivacaine hydrochloride.

4. A method of inducing local anaesthesia in mammals (including man) by iontophoresis, characterized in that an iontophoretic amount of a local anaesthetic composition comprising as active ingredient a pharmaceutically acceptable salt of ropivacaine is used for the purpose.

A method according to claim 4 wherein the pharmaceutically acceptable salt of ropivacaine is between 0.25 and 10 by weight of the composition.

6. A method according to claim 4 or 5 wherein the pharmaceutically acceptable salt of ropivacaine is between and 2 by weight of the composition.

7. A method according to any one of claims 4 to 6 wherein the active ingredient is ropivacaine hydrochloride.

8. A method according to claim 4 wherein the pharmaceutical composition is prepared by the method of any one of claims 1 to 3.

9. Use of a pharmaceutically acceptable salt of ropivacaine in inducing local anaesthesia by iontophoresis, utilizing for the purpose a jellified pharmaceutically acceptable iontophoretic composition containing between and 10 by weight of said salt.

Use according to claim 9, wherein ropivacaine is in the form of its hydrochloride.

11. A method according to claim 1 substantially as described herein.

12. A method aczording to claim 4 substantially as described herein.

13. Use according to claim 9 substantially as described herein. DATED this 12th day of January, 1994 AKTIEBOLAGET ASTRA By its Patent Attorneys, E. F. WELLINGTON CO., By: (B S. Wellin ton) S. Wellington) I: A/RR/2438/13 INTERNATIONAL SEARCH REPORT International Application No PCT/SE 91/00053 I. CLASSIFICATION OF SUBJECT MATTER (If several classification symbols apply, Indicate all) 6 According to International Patent Classification (IPC) or to both National Classification and IPC A 61 K 31/445, C 07 D 211/60 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbols A 61 K; C 07 D Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included in Fields Searched 6 SE,DK,FI,NO classes as above III. DOCUMENTS CONSIDERED TO BE RELEVANT 9 Category Citation of Document, 11 with Indication, where appropriate, of the relevant passages12 Relevant to Claim No. 13 X WO, 8500599 (A/S APOTHEKERNES LABORATORIUM FOR 4 SPECIALPRAEPARATER)

14 February 1985, see the whole document A 1-2 A Journal of dental research, vol. 60, no. 8, 1-2 August 1981, Louis P. Gangarosa, Sr.: "Newer local Anesthetics and techniques for administration", pages 1471-1480 Special categories of cited documents:'0 T' later document published after fhe International filing date A document deinnthe enera stae of the art which Is not or prlortty date and not n conflict With the applcation but A' ons dered to ie th paur reeva e doart cderstand the principle or theory underly ng the aflier document but published on or after the International document or particular relevance, the clairmd invention Ing date document of particular relevance, the clai m'-d invention cannot be considered novel or cannot be considered to document which may throw doubts on priority clam(s) or involve an inventive step which is cited to establish the publ callon dae of another citation or other special reason (as specified) aY' document of particular relevance, the claimed Invention ci n or ir peia reason as peci )cannot be considered to involve an inventive etep when the "O d men ferring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- men referring to an oral disclosure, use, exhibition or nmenf, such combination being obvious to a person skilled other means the art. document published prior to the International filing date but document member of the same patent family later than the priority date claimed IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this International Search Report 18th April 1991 1991 -04 2 2 International Searching Authority Signature of Authorized Officer SWEDISH PATENT OFFICE Gdran Karlsson torm PCT/ISAI210 (secona sheet) (January 1985) International Application No. PCT/SE 91/00053 FURTHER INFORMATION CONTINUFD FROM THE SECOND SHEET V.[X OBSERVATIONS WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHABLE This International search report has notbe~en established In respect of certain claims under Article 17(2) for the following reasons: iQclaim nUmrbe ,_I.because 4b reiatp subject matter not rer, ad to be switrched by this Authority, namely; A method for treatment of the human or animal body by theTri'v, see rule 39. 247 Claim numbers., because they rf.iate to orti3 0i the International appicotton Inst do not compiy with the prescribed require-. menta to such an extent thai no meaningful international search can be carried out. a~rrmcally 3 Claim nurnber...... bocusa tay are 69pendent claims and are not datlea in eoeotisnce wflh the second "n ffurd sentences Of PCT Rtule 6.4(a). VIE3 OFIXERV,-TIONU WHERE UNITY OF INVVNTIQN 1S LACKING2 This Internatic-nal Searching Au~thority found multiple Invention& In this International application a5 follows, IM Acl all required additional search foes were timeiy pafd by the applican~t. this fnternational search report covers all searchable claims of the International application, 2QE As only some of the required additional search fees *ero timely paid by the applicant, this International search report covers only those claims of the International application (or which fees were paid, specifically clairnz; 3EJ Ho required addttional search lees were timely paid by the applicant, Consequently, this Internalonal aaerch report 13 restricted to the Invention fatrt mvintioned Ir. the ctlms; It Is covered oy claim nuniora: 4F7 As all searchable claims could be searched without efft justifying an moditiona tooe. Inc tirnationa; Searching Authority did not Invite payment of any additional fee. It'rmcrt on Protest []The additional search fees were accompanied by applicantas protest, rlNo protest accompanied the payment of addhtiontal search te, Form PCTIISAM2O (supplemental sheet (January 12851 ANNEX TO THE INTERNATIONAL SEARCH REPORT, ON INTERNATIONAL PATENT APPLICATION NO.PCT/SE 91/00053 This annex lists the patent family members relating to the patent documents cited In the above-mentioned Iiternational search report, The members are as contained In the Swedish Patent Office EDP file on 91-0323 The Swedish Patent Office Is In no way liable for these particulars which are merety given for the purpose of intormation. Pa tent document Pubication Patent family Publication cited In search report date member(s) date WO-AI- 8500599 85-02-14 AU-B- 560367 87-04-02 AU-D- 1779683 85-03-04 EP-A-B- 0151110 85-08-14 JP-T- 60)502054 85-11-2S