METHOD FOR PROVIDING LONG-LASTING LOCAL ANESTHESIA AND COMPOUNDS AND COMPOSITIONS THEREFORE

Abstract: Method for providing ultra-long local anesthetic effects. The method comprises administering an N,N,N-triethyl-N-alkyl ammonium salt wherein the alkyl group contains from 8 to 16 carbon atoms. The local anesthetic effect producing quarternary ammonium salts and pharmaceutical preparations containing such quaternary salt are also described.

Description: METHOD FOR ERDVIDINΞ LCKG- δS ING LOCAL ANffπ-BESTA AND CCKPOONDS AND COMPOSITIONS THEREFORE Field of the Indention This invention relates to local anesthetics and particularly to ultra-long local anesthetics, to pharmaceutical preparations for providing local anesthesia, and to methods for treating acute and chronic pain using such local ultra-long acting anesthetics. Ra koround of the Tnypn-Kion Hundreds of local anesthetics have been synthesized and tested over the past century. Only a few, however, have proven to be clinically useful. Most of the drugs tested conformed to Lofgren's schene. This scheme consists of an intermediate chain separating a lipophilic end from a hydrcphobic end. The intermediate chain is typically 6 to 9 A in length and centains a carbonyl group. Ωiese cαπponents have appeared to be essential to a clinically useful local anesthetic. The few clinically useful local anesthetics have problems associated with them. Local anesthetics are still probably r sponsible for more deaths than any other class of drugs. This is most likely due to their widespread use and to their lew therapeutic to toxic ratio. In spite of many improvements in anesthesia and post-cperative care, pulmonary ccmplicaticns still occur in up to 50% of surgical patients and these complications are responsible for-20 to 25 percent of post-operative deaths. The incidence of pulmonary complications can be closely correlated with the anatomical site of surgery and its effect en the lung volumes and lung function. It has been shown that the incidence of pulmonary complication to be 35% after gastric or dαoάenal - surgery, 15% after herniorrhaphy, and 1% after peripheral surgery. The corresponding changes found in another study were 50.9 ± 2.9% reduction in forced vital capacity and a decrease of 18.6±11.6 ram Hg in PA02 after upper abdαπinal surgery. For lower • 'Mnm.naf surgery, the respective values were 24.4 - 18.1% and 9.5 ± 10mm Hg and for peripheral surgery 8.2 ± 13.7% and 5.7 ± 10 mm Hg. Formerly, the hypoxia was thought to be caused by increased shunting from iliary atelectasis since often nothing could be seen on X-ray. However, it was shown that it was rather a disturbance in the matching of ventilation and perfusicn in the lung. It has been found that patients with severe abdominal pain take spontaneous deep breaths, but these are much shallower than normal sighs. Morphine in the usual post-operative dosage suppresses the frequency of even these sub-normal sighs. With this reduction of lung volume and loss ofLsigh mechanism, it is obvious why so many develop atelectasis, collapse, pnemonia and other complications. The most effective means of dealing with this problem has been removal of the pain with block analgesia. Lung volumes and lung function improve and the need for narcotics is reduced or eliminated. This, in turn, leads to a redaction in -post-operataive pulmonary complications and length of hospital stay. These differences are quite significant. For example, in one study the forced vital capacity (FTC) was 43.7 ± 4.2% of the preoperative value in patients on narcotic analgesia foliating upper abdominal surgery. The comparable group who received a set of intercostal blopks had an FVC of 60.8 ±3.3%. The differences in blood gas changes were even more profound. The PaP2 drcgped 11.1 ± 3.1 m Bg in the narcotic group but only 3.3 - 4.2 πsα Hg in the block group. Of the 230 patients in this series, eleven had post-operative pulmonary complications. Nine of the eleven were receiving narcotics for analgesia. Thoracic epidural blocks give comparatively good results. Metabolic response may also inhibit recovery frcπi trauma and surgery. It consists of a marked catabolic response characterized by increased excretion of urinary nitrogen as a result of protein breakdown. Siis phenomenon is mediated by the central nervous and-endocrine systeπs. For the response to occur, an intact afferent neural pathway is necessary. Previous studies have shewn that afferent block by regional anesthesia will prevent the endocrine response to surgery, but the response occurs as the block subsides. This metabolic response may act to the patient's detriment. Blockade of the catabolic response seems to allow fast recovery with less morbidity. The reason block techniques are not used more frequently is that with currently available local anesthetics, blocks cannot be sustained for more than twelve hours. In order to cover the period of high pain level after surgery, four to six sets of blocks are necessary arid the quantity of skilled manpower for this kind of patient management is not routinely available. If an ultra-long local anesthetic were available, the blocks could conveniently be done at surgery. The resultant reduction in mortality, morbidity, and length of hospital stay would be extremely worthwhle. Some local anesthetics arpear to increase the absolute refractory period of the nerve with increasing frequency of transmission and this results in a frequency dependent or use-dependent inhibition. That is, a given άcse of the drug produces more inhibition of the action potential as the frequency of impulses increases. The same anesthetics that shew frequency dependent inhibition in vitro show clinically an increased sensory to motor dissociation of block, in agreement with the frequency coding of motor versus noxious sensory information. The clinical importance of anesthetics with sensory/motor dissociation is most apparent in obstetrical analgesia where appropriate doses of local anesthetics with frequ ncy dependent action (i.e., bupivicaine and lidocaine) provide freedom from pain while sparing enough motor function to allow participation in delivery. Sensory-motor discrimination will also be of great importance to the clinical efficacy of ultra-long acting local ■ anesthetics. Whether it be for the treatment of chronic pain or long term postoperative analgesia new local anesthetics will have to offer the same block of noxious stimuli without loss of motor function and inocuous stimuli characteristic of the narcotic drugs presently in use for this purpose. OM?I Thus, it can be seen that new and improved local anesthetics are highly desirable. Specifically, it would be desirable to have a local anesthetic that will give ultra-long (for instance, about three to 14 days) blockage of axonal conduction without causing any neural damage? that have a permanent charge to reduce or eliminate central nervous system toxiciry and facilitate renal excretion; and that act primarily against sensory fibers (as opposed to motor) . Summary of the Invention The present invention provides a method for pro icing a long-lasting local anesthetic effect. The method cαtprises administering to a maπmal an anesthetic producing amount of an N,N,l^triet^l-N-alkyl-a_ππonium salt wherein the aikyl group contains from 8 to about 16 carbon atoms. It is surprising that these triethylalkyi quarteraary arrmcπium salts produce a local .anesthetic effect because they do not meet the requirenents described by Lofgren which were thought necessary to produce such an effect. Indeed the local anesthetic compounds of the present invention have no carboπyl group, no aromatic group and the a inc group is a quartεmary aπmonium rather than the usual tertiary amine having a pKa in the physiologic range. The-quarternary ammonium salts useful in this invention provide a surprisingly long-lasting local anesthetic effect, i.e. up to 20 days or more. The duration of the local anesthetic effect varies with the length of the alltyl group. Straight chain aikyl groups are preferred for the quarternary salts used in the practice of this invention. The quarternary ammonium local anesthetics of this invention do not appear to act as neurolytic agents but appear ' to block axonal conduction by interfering in seme fashicn with the function of the axonal iπeπbrane. Ωiese ccπpounds have little- apparent neurotoxicity, and less systeπic toxicity than cσventicπal tertiarv amine local anesthetics. Rr P Dgs r-i- r-inn of Drawings Fig. 1 is a graph illustrating the duration of local anesthetic effect vs. aikyl carbon chain length for the quarternary ammonium compounds of this invention. Fig. 2 is a graph illustrating the concentration of N,N,S-triethyl-N-dodecyl ammonium bromide in the nerve and in excretions at various times after injections. Fig. 3 is a graph illustrating the concentration of N,N,N-triethyl-N-dodecyl ammonium bromine in the rat infra-orbital nerve at various times after injection. Detaile Description of the Invention In accord with the present invention long lasting local anesthetic ccπcounds are provided. The compounds are quarternary ammonium compounds having the following structure: ( CH3CH2 ) 3 +- R 2T CD wherein R is an aikyl group having from about 8 to about 16 carbon atoms, preferably 8 to 12 carbon atoms and X- is a suitable pharmacological aπicn. The aikyl group is preferably a normal aikyl group. Suitable aikyl groups include, for instance, octyl, ncnyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, and hexadecyl, as well as substituted such groups. The quaternary ammonium compounds used in this invention are readily prepared by standard chemical procedures. For example, triethylamine and the appropriate brcmoalkane are combined in a 1:1 molar ratio with excess acetone. The acetone is driven off at 60°C for about two hours and the desired quarternary salt crystallized by immersion in ice water. The resulting product is then washed with petroleum ether on filter paper to' remove unreacted starting materials. Purity is tested by thin layer chrcmotograpby. In use, the quarternary aasncniuaa compound can be administered by a variety of techniques such as, for example, by injection, by topical application, or by suppository, etc. The OMPI compound is conveniently formulated with a suitable pharmacological carrier dependent upon the desired administrated route. For instance, for injection, the carrier is conveniently physiological saline solution. For topical use, the compound is conveniently formulated into a cream or ointment, etc. The administered dose depends upon many criteria, including the site for the desired effect, the route of administration, the particular local anesthetic used, its toxicity and its half-life, the medical problen being treated, etc. When injecting a composition of the compound in normal saline onto the nerve, a dose of from 1 mg to 5 mg in 0.2 ml saline has been found effective for obtaining localized anesthetic ef ect. The invention will now be further illustrated by the following examples. Examples 1 - 7 Tetraetiylarπmonium bromide ( C2) was obtained from Alάrich Chemical Co. Compounds of formula I wherein R is a six carbon chain length aikyl group (Cs) , an eight carbon aikyl group (C8) , tan (Cio) , fourteen (C14 and sixteen (Ci£) carbon aikyl groups, respectively were prepared as the bromide salt by the synthesis described previously. Brαnoalkanes having varying carbon chain lengths and triethylamine are readily available and were purchased from cαππercial sources such as, for exaaaple, Eastman Organic Chemicals, Aldrich Chβπical Co., and Sigma Chenical Co. Male Sprague-Bawley rats were obtained having a 300-400 g body weight. After light ether anesthes±artfie rats were injected with 10 mg of sodium pentobarbital, I.P., and then given additional pentobarbital, if necessary, until the animal lost righting reflex and allowed injection of the test coπpoun s. 1.0 and 5.0 mg of each compound in 0.2 ml of normal saline was injected onto the trige inal nerve through a 30 gauge needle guided to the nerve by a metal jig positioned on the roof of the mouth by the incisors and molars. The contralateral trigeninal nerve was used as a control throughout the experiment. Anesthesia was tested by stimulating the lip/whisker area innervated by the maxillary nerve on experimental and control sides and observing whether the stimulus produced a reflex contraction of abdominal muscles (unanesthetizεd) or not (anesthetized) . Stimulation consisted of 1-lOV 6 msec square wave pulse trains (2 pulses/sec for 5 sec) produced by a Grass S48 stimulator triggering a stimulus isolation unit (DS-2, Digitimer Ltd.), and were delivered through bipolar electrodes (two 30 gauge needles 2 mm apart) . The muscle twitch response was quaπtitateά by recording the HG from muscle of the abdominal wall, and displaying it on a Tektronic 5111 oscilloscope after amplicaticn (Tektronic AM502 differential amplifier) . Comparison of the EMΞ response produced by stimulating the control and treated side allowed an accurate determination of the presence or absence of trigeminal nerve block. The time required for the onset of nerve blocking (anesthesia) and the total period for which nerve blocking was provided is tabulated below in Table 1 and the blocking duration versus chain length of R is plotted in Fig. 1. TAEI I * Example No. of Onset of Duration of No. R Animals Dose Block(ππ_n) a - Block (hrs) a 1 4. 5.0 mg 19 ± 2 1.2 1.6 2 4 C 2 2.5_mg 18 ± 6 6— 1 3 C 8 4 1.7 mg 10 ± 5 21 2 4- So 4- 2.0 mg 6 ± 3 SO 8 5 C 12 5 1.0 mg ■ 3 = 2 388 95 6 c 4 1.0 mg 11 ± 6 402 72 7 C 16 4 2.3 mg 24 ± 7 480 96 ' mean ± S.D. I Carbon 14 labeled C12 (Ethyl-l-l-^C, N,N,N-trietoy-N-dodecyl amnonium brαπide ) was used to determine the binding of C12 to the infraorbital nerve, and its mode of excretion, rats were injected with a blocking dose of C12 containing 0.5 μCi of 14c, and placed in an amimal metabolism unit. Feces and urine were collected daily. Feces were dissolved in Soluene 350 at 50°C and after decclorization with hydrogen peroxide and isopropyl alcohol, were counted in Dimilume 30 liquid scintillation cocktail (Packard Instruments); urine was added directly to cocktail. At the end of the binding experiments, rats were sacrificed and the infraorbital nerve dissected free, washed, divided into five 5 am sections, and.dissolved in Soluene prior to counting in Dimilume on a packard 2RIAS LSC. The infraorbital nerve was dissected from the treated animals 7 - 10 days after injection and fixed in Kamovsky's fixative (1% paraformaldehyde, 1% glutεraldehyde in 0.1 Nar-caccylate buffer pfi 7.4) overnight, post-fixed in osmium, dehydrated in alcohol, and embedded in Epon prior to sectioning. Fig. 2 shows the concentration of anesthetic in the nerve and excreted in the feces of the rats at various times after injection. Fig. 3 illustrates the concentration of anesthetic in the infraorbital nerve at various times after injection. All points in the firgures respresent the mean data f om three rats. Electron micrographs of 20 to 30 myelinated and u πyelinated axons from three Cχ2 treated and three control infraorbital nerves were evaluated from axonal swelling, nyelin ultrastructure and general integrity on a 1 - 5 scale. Ko obvious ultrastructural damage was observed on the treated nerves. The invention has been described in detail with reference to the preferred embodiments thereof. However, it will be appreciated that those skilled in the art, upon reading this disclosure, may make modifications and improvements within the spirit and scope of the invention. O PI

Claims: AMENDED CLAIMS (received by the International Bureau on 1 June 1982 (01.06.82)) 1. A method for providing a local anesthetic effect in a mammal, said method comprising administering to said marnπal a local anesthetic effect producing amount of an N,N,N-triethyl-N-alkyl ammonium salt wherein the aikyl group contains from about 8 to about 16 carbon atoms. 2. The method of claim 1 wherein said aikyl group contains from about 8 to about 12 carbon atoms. 3. The method of claim 1 wherein the aikyl group is a normal aikyl group. 4. The method of claim 1 wherein said ammonium salt is N,N,N-triethyl-R-dodecyl ammonium bromide. 5. The method of claim 1 wherein said ammonium salt is N,N,N-triethyl-l-H3Cfcyl ammonium bromide. 6. The method of claim 1 wherein said ammonium salt is N,N,SM_riethyl-N-decyl aπmαiium bromide. 7. The method of claim 1 wherein said anmcnium salt.is N,N,N-triethyl-K-hexadecyl artmonium bromide. 8. The method of claim 1 wherein- said ammonium salt is N,N,K-triethyl-K-tetradecyl ammonium bromide. 9. A pharmaceutical preparation comprising an anesthetic effect producing smoutnt of an N,N,N-triethyl-N-alkyl aimcnium salt in a pharmacological carrier, wherein said aikyl group contains from about 8 to about 16 carbon atoms. 10. The pharmaceutical preparation of claim 9 wherein said aikyl group contains from about 8 to about 12 carbon atoms. 11. The pharmaceutical preparation of claim 9 wherein said aikyl group is decyl. 12. The pharmaceutical preparation of claim 9 wherein said aikyl group is undecyl. 13. The pharmaceutical preparation of claim 9 wherein said • aikyl group is tridecyl. 14. The pharmaceutical preparation of claim 9 wherein said aikyl group is tetradecyl. 15. The pharmaceutical preparation of claim 9 wherein said aikyl group is peπtadecyl. 16. The pharmaceutical preparation of claim 9 wherein said aikyl group is hexadecyl. 17. A quaternary ammonium salt having the formula: (CΞ3CH2)-afr R X"" wherein R is an aikyl group containing 10, 11, 13, 14, 15 or 16 carbon atoms and X is an anicn. 18. The quaternary ammonium salt of claim 17 wherein X is a halide. 19. The quaternary amncnius salt of claim 17 wherein R is a normal aikyl group. 20. The quaternary ammonium slat of claim 17 wherein R is decyl. 21. The quaternary aπmcnium salt of claim 17 wherein R is undecyi. 22. The quaternary ammonium salt of claim 17 wherein R is tridecyl. 23. The quaternary ammonium salt of claim 17 wherein R is tetradecyl. 24. The quaternary aπsncnium salt of claim 17 wherein R is pentadecyl. 25. The quaternary artrocπiua salt of claim 17 wherein R is hexadecyl. O PI & EDITORIAL NOTE The applicant failed to renumber the amended claims in accordance * wϊth Section 205 of the Administrative Instructions. In the absence of any specific indication from the appUcaπt as to the correspon¬ dence between original and amended claims, these claims are published as filed and as amended.

Inventors: CURTIS BENSON M, SCURLOCK JAMES E
Applicants: VIRGINIA MASON RES CENTER
Application year: 1981
Main classification: C07C87
IPC codes: A61K31