US5149320.Pdf

||||||||||||||||| US005 14932OA United States Patent (19) 11) Patent Number: 5,149,320 Dhaliwal et al. 45 Date of Patent: Sep. 22, 1992 (54) COMPOSITE ANESTHETIC ARTICLE AND 3,477,431 l/1969 - Walecka ................................ 604/89 METHOD OF USE 3,978,212 8/1976 Barna ....... 424/56 4,234,083 1/1980 Cohen ...... ... 604/90 (76) Inventors: Avtar S. Dhaliwal; Shabir Z. Masih, 4.599,082 7/1986 Grinnard ...... ... 604/90 both of Suite 43, 408 State of 4,630,727 12/1986 Feriani et al. ....................... 604/416 Franklin Rd., Johnson City, Tenn. 4,663,166 5/1987 Veech ................................. 424/146 37604 Primary Examiner-C. Fred Rosenbaum 21 Appl. No.: 640,096 Assistant Examiner-Sharon Finkel 22) Filed: Jan. 11, 1991 57 ABSTRACT An aqueous composition for reducing pain at the site of Related U.S. Application Data injection of local parenteral anesthetic material, for (60) Division of Ser. No. 319.343, Mar. 6, 1989, which is a improving the onset thereof, and for increasing its dura continuation-in-part of Ser. No. 179,877, Apr. 11, 1988, tion, and a means for preparing and dispensing the same, abandoned. the composition containing a local parenteral anesthetic (51) Int. Cl. ............................................ A6M 31/00 which in normal doses gives an acid pH of from about (52) U.S. Cl. ...................................................... 604/49 2.5 to about 6.9, wherein the anesthetic comprises from (58) Field of Search ...... ... 604/49, 50, 415, 89-92, about 0.5 to about 2.0% by weight of the composition, 604/82, 56, 201, 415; 424/663, 686, 43 the composition further containing sufficient NaHCO3 to maintain the pH thereof between about 7.0 and about (56) References Cited 7.6, and further containing from about 0.0004 moles of U.S. PATENT DOCUMENTS dissolved CO2 per ml of composition up to the satura 2,533,165 12/1950 Hagedorn ........................... 604/45 tion level of dissolved CO2 at a CO2 head pressure of up 2.559,23 7/195. Seemar ...... ... 604/45 to about 2.5 atmospheres. 2,764,157 9/1956 Oliva et al. ... 604/45 2,766.755 10/1956 Greene ................................ 604/45 6 Claims, 8 Drawing Sheets 100 90 80 70 60 50 40 30 20 10 0 2 4 6 8 10 12 4. 5 8 20 22 24, 26 28 30 32 34 36 TIME Minutes U.S. Patent Sep. 22, 1992 Sheet 1 of 8 5,149,320 Fig. 3 U.S. Patent Sep. 22, 1992 Sheet 2 of 8 5,149,320 ssSse S sS e Sse s C O o O O C O o Co s Od N. Vd q er n vm A H sa, a H d - dip Old J O 9 - O - U.S. Patent Sep. 22, 1992 Sheet 3 of 8 5,149,320 U.S. Patent Sep. 22, 1992 Sheet 4 of 8 5,149,320 3. 9 8 3 S. S. SR SIZE OF ACTION POTENTIAL (%) U.S. Patent Sep. 22, 1992 Sheet 6 of 8 5,149,320 e N f e L C o O A. C L du us q r r N N vm C o E (a ?c 2: A C H 2 UD U O p a U.S. Patent Sep. 22, 1992 Sheet 8 of 8 5,149,320 S s on O N Vad q r CN rv El H E is - 2 d 5, 149,320 1. 2 The data from TABLE I lead to two important con COMPOSTE ANESTHETIC ARTICLE AND clusions: METHOD OF USE (1) the parenteral solutions containing epinephrine HCl are acidic with pH of 2.74-3.1. This acidic pH is This application is a division of Ser. No. 319,343 filed 5 responsible for local tissue irritation invoking "Bee Mar. 6, 1989 which is a continuation-in-part of pending Sting-like Pain" at the site of infiltration as well as occa Ser. No. 179,877 filed Apr. 11, 1988 now abandoned. sional chemical phlebitis; and This invention concerns the modification of materials (2) the amount of uncharged lipophilic portion of the normally employed as parenteral anesthetics in acidic local anesthetic, which is essential for passive transport solution, and particularly concerns a composite article O into the neuronal axoplasm through the nerve mem and its method of use which provides in a very conve brane, in most instances, is between 0.0007%-2.44% of nient manner a buffering system for addition to these the dose. Therefore, the rate and extent of diffusion of acidic materials for reducing certain adverse physiolog the uncharged local anesthetic free base is considerably ical effects thereof such as burning or stinging generally small. This, perhaps, is responsible for the delay of resulting from injections thereof. The invention also 15 about 2-7 minutes in the onset of analgesia and a waiting concerns a unique pH buffered, neutral or slightly basic period of about 4-12 minutes before surgical procedure aqueous composition containing a normally acidic par can be started, enteral anesthetic, but wherein a pH adjustment from The advantages therefore of buffered neutral or acid to neutral or basic is made completely within a slightly basic aqueous solutions of such anesthetics are composite article in a hermetically sealed manner sub 20 substantial, however, heretofore even though there has stantially immediately prior to injection of the composi been need for a convenient and sterile means for buffer tO. ing the anesthetic solutions to the correct pH and main The acid pH ranging, for example, between 3.5 to 6.5, taining such for an appropriate period, such has not of intradermal or subcutaneous anesthetic solutions and been obvious to those conversant in the art and there of most intravenous anesthetic solutions has been impli 25 fore is not available, and little if any real use of this cated as a factor responsible for local irritation at the technology has been made. In this regard it is noted that site of injection, which leads to pain or discomfort dur the physical and chemical stability of the free base form ing the period of infiltration. The local irritation, red of such local anesthetic materials cannot be maintained ness, tenderness, pain and discomfort near the site of for more than a few hours after adjustment of pH with, injection and along the course of any proximate vein. 30 e.g., either sodium hydroxide or sodium bicarbonate, appears to be related to the nature of the substances in and therefore the commercial injections of Lidocaine, the parenteral solution and the speed of infiltration. The Mepivacaine, and Bupivacaine cannot be buffered, e.g., pH of many commonly used parenteral products such as at pH 7.4 without sacrificing the normal two or more 0.5-1.0% lidocaine HCl by itself, lidocaine HCl with years of shelf life of these materials. 1:100,000 Epinephrine, and dextrose infusion, being low 35 Principal objects therefore of the present invention (pH 3.5 to 6.5), are known to cause chemical irritation are: to provide a means and its method of use for making of tissues leading to chemical phlebitis. buffer systems such as aqueous bicarbonate solutions As background information, the free esters or amides readily available to the medical community in a conve of local anesthetics such as Lidocaine, Mepivacaine and nient and easy to use unit for the pH adjustment of Bupivacaine are basic substances due to the presence of 40 acidic parenteral anesthetic materials; to provide a the amino group. Since free base of such anesthetics are means whereby a normally acidic parenteral anesthetic only slightly soluble in water and easily form stable and material can be converted to a stable neutral or slightly water soluble salts with mineral and organic acids, the basic material practically instantly before its use and in commercial injections of Lidocaine, Mepivacaine and an extremely simple manner; and to provide novel, Bupivacaine contain their hydrochloride salts. In the 45. basic buffered parenteral anesthetic compositions hav parenteral aqueous solutions, these local anesthetics ing markedly improved analgesic onset and duration. ionize to give solutions of pH of about 4.0-6.0. In order These and other objects hereinafter appearing have to decrease the rate and extent of absorption of the local been attained in accordance with the present invention anesthetics into systemic circulation, some of the paren which is defined in one of its principal embodiments as teral solutions contain small amounts of epinephrine. SO an aqueous composition containing local parenteral This further reduces the pH of the parenteral solution to anesthetic material, which in normal doses gives an acid about 2.7-3.9. pH of from about 2.5 to about 6.9, wherein said anes Table I hereof lists the pH of various commercial thetic comprises from about 0.5 to about 2.0% by local anesthetics, along with the percent of unionized weight of the system, said composition further contain Lidocaine, Mepivacaine and Bupivacaine in the vials as 55 ing sufficient NaHCO3 to maintain the pH of said sys calculated according to equation: ten between about 7.0 and about 7.6, and also contain ing from about 0.0004 moles of dissolved CO2 per ml of pKa-pH = Log C/C. composition to a saturated amount of dissolved CO2. In another embodiment, the invention is defined as a Where: composite article useful in the buffering of normally pKa is the negative logarithm of the dissociation acidic parenteral anesthetic material for reducing the constant for the local anesthetic; adverse physiological effects thereof, said article com pH is the negative logarithm of the hydrogen ion prising a vial containing a dilute aqueous system of an concentration; acid buffer such as an alkali metal bicarbonate, and a Ci is the moles of local anesthetic in the ionized or 65 closure cap on said vial hermetically sealing said system charged form; and therein, said cap having a portion which is readily pene C is the moles of local anesthetic in the uncharged or trable by tubular needle means for withdrawing said unionized form.

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