CA1280695C - Nalbuphine-local anesthetic analgesic composition and method of producing analgesia - Google Patents

Abstract

TITLE
NALBUPHINE-LOCAL ANESTHETIC ANALGESIC
COMPOSITION AND METHOD OF PRODUCING ANALGESIA
Abstract of the Disclosure An analgesic composition, particularly in an injectable or opthalmic dosage form, is provided which provides a fast onset of action and an extended dura-tion of action with smaller amounts of the active ingredients. The composition contains nalbuphine or pharmaceutically suitable salt thereof and at least one local anesthetic such as bupivacaine, mepivacaine, and tetracaine.
A method of producing analgesia in a mammal is also provided by administering to a mammal intra-venously, intraocularly or epidurally nalbuphine or a pharmaceutically suitable salt thereof and at least one local anesthetic.

Description

~ ~8~

~ BP-6299 NALBUPHINE-LOCAL ANES~HE~IC AN~L OE SIC
C0MPOSITION AND ~æTHOD-OF PRODUC~G ANALGESIA
BackgrQ~n9_D~ _he Invent~
Field of the Invention:
~ is invention relate~ to analgesic co~position6 and ~ethod~ of producing analge6ia in mammal~ and ~ore particularly to nalbup~ine-local ane~thetic analge6ic compo~ition~ or produ~ing analqe6ia in ma~mal6.
Prior Are:
U.S. ~atent 3,393,197 issued to Pachter and Mato~ian on July 16, 1g68 di~clo~e~ N-sub~tituted-14-hydro~y~ihydronor~orphines, i~clu~ing t~e N-~y~lobutyl-methyl derivatlve~. commonly called nalbuphine:

~ ;
HO O OH
Pachter aud Matos~ian and other6, ~uch ~8 ~. W.
~lliott, ~st al., J. Med. (Basel), ~, 7~-89 (1970):
H. Blumberg, t al.. P~armacolo~is~, 10. 109, rall 196B: P. aoberts, pru~s o~ t~e Future, Z, 613-5 (1977), ~isclose t~e use of nalbuphine ~8 an analge6ic for the ~ontrol of moderate to severe pain.
Analge~ic ~ixtures of ~albup~ine with other analqe~lcs have been ~Qscribed ~n nu~erou6 publi~a-tions. For exa~ple. U.fi. Patent ~237,140, i~ue~ to J. a. Du~zins~i on Dec. 2, 19~0, describe6 an ~nalge~i~
~ixture of nal~up~ine an~ acetoa~inophen. U.8. Patent ~,282,215, ls~uea to J. ~. Du~zin6ki ana ~ hmidt on Aug. 4, 1981, d~scribe6 an analgesic n~xture of nalbuphine and aspirin. U.S. Patent ~,366O15g~ isEued ~ ~ .

1~80695i to Michael R. ~agruder on Dec. 23. lg82. ~e~cribe~ an analgesic ~ompo~ition of nalbuphine and a narcotic anal~e~ic. U.S. Patent ~.404,21Q. is~ued t~ ~illiam ~.
Schmiat on Sept. 13. l9B3. ae~cribes an analge~c nixture of nalbuphine and ibuprofen. U.~. Pate~t 4,407,805, i6~ued to ~illiam ~. ~chmiat on Oct. 4, 1983, de~cribe~ an analge6ic ~ixture of nalbuphine ~nd zomepilac. U.S. Patent ~,qO2,962, is~ued to William K.
Schmidt on Sept. 6, 1983, ~e6cribe6 ~n analqe6ic mi~-ture of nalbuphine and ~.5-bi~(4-~etho~yphenyl)-2-(tri~luoromethyl6ulfonyl)-lH-imiaazole. U.~. Patent ~,407,804, ls6ued to William ~. ~c~midt on Oct. 4, 1983, describes an analge6ic ~i~ture of nalbuphine and indomet~acin. U.S. Patent 4,~0q,200, i~sued to William X. 8chmiat on Sept. 13. l9B3, de6cribes an analge6ic ~i~ture of nalbup~ine ~na tlfla~izole. U.5.
Paeent 4,404,209, isguea to Will~a~ c~at on Sept. 13, 1983. de6c~ibes an analgesic ~i~ture of nalbuph~ne and 6ulindac. U.S. Patent ~,404,211.
is~ued to ~illiam K. Schmidt on Sept. 13. 1983, describe~ an analge6ic ~i~ture of nalbuphine and flurbiprofen.
Bupivacaine, Depivacaine and tetracaine ~re theee of l~any well-known local anesthetic~, ~o called because tl~ey bloc~ norve conduct~on when applied locally ~o nerve tis~ue. Local ~nesthetics are described in Goodman and Giloan, The Pharmacoloaical ~a~is of TheraDeutic~. 5th ~d. Sec. III. Chap. 20, p. 379-403, (1975) MacMillan Publis~ing Co., Inc., N.Y.

06~j95 Summarv of t~e Invention Accor~ing to the pre6ent invention there i~
provided ~n analge6ic compo6ition which co~pri6e6 per analge6ic do6e of the comp~ition a~out Sa) 0.1-10 ~g of nalbuphine or a phar~aceutically ~uitable 6alt thereof nnd (b) about 0.1-20 mg of at lea~t one local ane~thetic or a pharmaceutically suitable Ealt t~ereof.
There i8 al60 provi~ea a ~ethod of producing anal~e~ia in a ~ammal compri6iug ad~ini~tering to a ~ammal intravenously, iutraocularly, or epidurally an analge~ic ~ose ~ontaininq ~a) about 0.1-10 ~g of nal-buphine or a pharmaceutically fiuitable ~alt thereof and (b) about 0.1-20 ~g of at lea~t one local ane6thetic.
DETAIL~D DESCRIPTION_OF THE INVENTION
Nalbuphine, which has the che~ical name ~ 17-(cyclobutylmethyl)-4,5a-epo~ymorphinan-3,6a, l~-triol, an~ ~t6 preparation are aescrib2d in U.s. Patent 3,393,197. It and t~e local analge6ic6 u6eful in the ~nalgesic compo6ition6 of the present invention, i.e., bupivacai~e, ~epivacaine, ana tetracaine, all are ~ell-known to have analgetic propertie~ in ~an aud other mammals.
~en the term nalbup~ine or the name of one of the above narcotic analgesic~ is usea herein, it i~ to be under~tood that any of the pharmaceutic~lly 6uit-able 6alt6 thereof are include~ by the ee~. Such ~alte include the hy~rochloriae6, ~yarobromide6, hydro-iodide6, sulfate6, bifiulfate~, nitr~tes, cit~ates, tartrates, bitartrate~, phogphate6, malate6, maleate6, fu~Arates, ~uccinate6, acetate6 a~d pamoa~e6.
Any local ane6t~etic or a ~alt thereof can be u~ed ic t~e compo6itions of the pre6ent invention.
Sueh local ane6thetic6 are ~e6cri~e~ in Good~an ana Gilman, ~u~ra, ~u~ include ~t lea6t one of cocaine, ~LX80695 procaine, bupivacaine, chloroprocaine, cyclo~ethyl-caine, ~ibucaine, ~imethi~oquin, dyclonine, hexylcaine~
lidoeaine. ~epivacaine, phenacaine, piperocaine, pramoxine, pr~locaine, proparacaine, and tetracaine.
Prefer~ed local ane~eheti~6 are bupi~acaine, ~epiva-caine, and tetracaine.
Combining nalbuphine ~it~ a local ~nesehetic in a compo~ition ~aintain~ analge6ia in a mammal for a long period of ti~e (up to about 72 houc6) for pain from ~uch ~ource6 a6 the first staqe of laboc, ter~inal cancer, ~ost-operative, ana dy~menorrhea.
on6et of action i6 ast, i.e., about ~5 ~inute6. A
long ~uration of action hb~ an advantage ln t~at smaller amounts of the acti~e lngreaieneg may ~e u6ed to provide analge6ia for period of 6-~ hour~.
The compo~ition~ of the pre6ent in~entio~ are ~ade by ~i~in~ (a) about 0.1-10 ~g, preferably about 0.5-2 og, of nalbuphine with (b) about 0.1-20 mq, preferably about 0.1~12 ~g, of ~t leaEt one local anesthetic. Do6age for~6 ~re formulated by ni~i~q a suitable phar~aceutieal ca~rier for an in3ectable do6aye form o~ an opthalmic dosage forD. ~u~table phar~aceutical carriers ~re descr~bed in ~emington~ B
Pharmaceutical Sciences, E. ~. Martin, ~ standard reference te~t in this fiQld~
In general, ~ater, a suitable oil, ~aline, aqueous dextrose Iglucofie)O and relatea ~ugar 801U-tion~ and ~lycols ~uch ~8 propylene glycol or poly-ethylene glycols ~re suitable carcier6 for parenteral 801ution8. Solution for parenteral administration contain prefe~ably a water ~oluble ~alt of the acti~e ing~e~ient, suita~le ~tabilizing agents, and if ~ece~-~ary, buffer sub6tance~. Antioxidizing agents ~uch a6 ~odium bisulfite, ~odium sulfite, or a6corbic aeid eit~e~ alone or eombined are ~uitable 6tabilizing ~ 69 ~

agent~. A180 u~ea are citric acid and çodium ED~A.
In addition, parenteral 601utions can contain preser-~ative6, 6uch a6 ~enzalkoniu~ ehloride, aethyl or prGpyl-par~en, ana chlorobutanol. rOr epidural S administration, it ~6 preferred that pre~er~ative6 ~houla be removed.
Ophthalmic do6age ~or~s are geneIally for~ulated a6 ointment6 or ~olutions. A6 an oph~hal~ic ointment, the active ingreaient6 are adaea to an appLopriate ointment base ~uch a~ a hydro~arbon ba6e e~emplified by W~ite Petrolatu~. Ophthal~ic 601utions are typi-cally isotonic 801utioa6 that ~ay be buffered to ~tabilize the drug ~n solution. 5uch ~olution~
usually contain an anti~icrobial agent to prevent the growth of, or to de6troy, nicroorgani~s ~ccidentally introduced when the con~ainer i~ opened ~or u~e.
U~eful p~ar~aceutical do6age for~6 for ad~ini-E~ration of the co~pound~ of this inveneion can be illu6t~atea a~ follo~6:

30~95 Injectable Parenteral compositions suitable for administration by injection can be prepared with the following ingredients:

Nalbuphine HCl 20 mg/mL
Lidocaine HCl 10 mg/mL
Citric Acid, USP Anhydrous 4.21 mg/mL
Sodium Citrate, USP Dihydrate 3.13 mg/mL
Sodium Metabisulfite 1.0 mg/mL
Methyl Paraben 1.8 mg/mL
Propyl Paraben 0.20 mg/mL
Hydrochloric Acid, Reagent Adjust pH
WFI, USP q.s. 1.0 mL

Nalbuphine HCl 4 mg/mL
Bupivacaine HCl 12 mg/mL
Citric Acid, USP Anhydrous 4.21 mg/mL
Sodium Citrate, USP Dihydrate 3.13 mg/mL
Sodium Metabisulfite 1.0 mg/mL
Methyl Paraben 1.8 mg/mL
Propyl Paraben 0.20 mg/mL
Hydrochloric Acid, Reagent Adjust pH
WFI, USP q.s. 1.0 mL

Opthalmic Ointment An ointment suitable for administration the the eye can be prepared with the following in~redients:

Nalbuphine HCl 5 Gm Lidocaine HCl 12.5 Gm Polyethylene Glycol 300 50.0 Gm Polyethylene Glycol 1500 q.s. 250.0 Gm Opthalmic Solution Solutions suitable for administration to the eye can be prepared with the following ingredients:

Tetracaine HCl 0.5% w/v Nalbuphine HCl 1.0% w/v Na EDTA 0.01% w/v Sodium Metabisulfite 0.1% w/v Benzalkonium Chloride 0.01% w/v Hydroxypropyl Methylcellulose 0.5~ w/v Hydrochloric Acid Adjust pH
WFI, USP q.s 1.0 mL

Bupivacaine HCl 0.5% w/v Nalbuphine HCl 1.0% w/v Na EDTA 0.1% w/v Sodium Metabisulfite 0.1% w/v Benzalkonium Chloride 0.01% w/v Hydroxypropyl Methylcellulose 1.5% w/v Hydrochloric Acid Adjust pH

WFI, USP q.s 1.0 mL

~ ~8069~

The invention can be further understood and its unexpectedly improved analgesic activity may be appreciated more precisely by the following tests conducted to bring about post-operative pain relief.
The patients were allowed to experience moderate to severe pain as the anesthetic wore off. When the patient could no longer tolerate the pain, the injectable composition was administered and the pain was then monitored as the pain was altered by the administered drug until it stabilized. A pain score of 10 on a 0 to 10 dolorimeter scale is used. Almost all of the time a pain score of 0 is reached, meaning complete relief of pain at rest.
CONTROL TESTS
An injectable composition containing 2 mg of nalbuphine HCl as the sole analgesic agent in 10 mL
solution of normal saline solution (0.02% by weight) injected epidurally at the level of the lumbar area in a mammal produced pain relief from post-operative pain for 2 to 4 hours. If the dosage is doubled the pain relief is maintained for about 4 to 8 hours.
The change in pain characteristics occur in 15 to 20 minutes with complete relief in 30 minutes. The routine use of local anesthetic exclusively is ~enerally known to produce analgesic effect which typically last within the ranqe of about ] to 6 hours.
COMBINED DR~G TESTS
The injection of a composition combination containing 4 mg nalbuphine HCl and 10 mL of 0.125% by weight of bupivacaine, in the epidural space produced pain relief in about 3 to 5 minutes with complete relief of (noceceptive) pain for a duration of as long as 72 hours. About 5 to 10 mL of this combined analgesic composition injected into the space between the dorsal arch and spine of vertebral bone and the 9 ~80695 the vertebral bone and the adjacent sucro spinalis muscle likewise produced the smae quality and duration of pain relief within 3 to 5 minutes from the time of injection. The injection of 5 mL of this same solution or even with a lower nalbuphine concentrate (to as low as l mg) intravenously produced pain relief that extended to about 72 hours within a 3-minute waiting time. Intramuscular injection, however, at the usual intramuscular sites produced pain relief in about 30 minutes while the duration lasted for 12 to 48 hours.
A similar combination of nalbuphine-pontocaine composition, when injected at all routes produced identical analgesic effects with a nalbuphine-lidocaine combination.

Claims (11)

1. An analgesic composition which comprises per analgesic dose of the composition about (a) 0.1-10 mg of nalbuphine or a pharmaceutically suitable salt thereof and (b) about 0.1-20 mg of at least one local anesthetic or a pharmaceutically suitable salt thereof.

2. The composition of Claim 1 in an injectable dosage form.

3. The composition of Claim 1 in an ophthalmic dosage form.

4. The composition of Claim 1 wherein the local anesthetic is at least one selected from the group consisting of cocaine, procaine, bupivacaine, chloroprocaine, cyclomethylcaine, dibucaine, dimeth-isoquin, dyclonine, hexylcaine, lidocaine, mepiva-caine, phenacaine, piperocaine, pramoxine, prilocaine, proparacaine, and tetracaine.

5. The composition of Claim 1 wherein the local anesthetic is at least one of bupivacaine, mepivacaine, and tetracaine.

6. The composition of Claim wherein each analgesic dose is in an injectable dosage form and contains (a) about 0.5-2 mg of nalbuphine or a pharmaceutically suitable salt thereof and (b) about 0.1-12 mg of at least one local anesthetic or a pharmaceutically suitable salt thereof.

7. The composition of Claim 1 wherein each analgesic dose is in an ophthalmic dosage form and contains (a) about 0.5-2 mg of nalbuphine or a pharmaceutically suitable salt thereof and (b) about 0.1-12 mg of at least one local anesthetic or a pharmaceutically suitable salt thereof.

8. The composition of Claim 6 wherein the local anesthetic is at least one selected from the group consisting of cocaine, procaine, bupivacaine, chloroprocaine, cyclomethylcaine, dibucaine, dimethisoquin, dyclonine, hexylcaine, lidocaine, mepivacaine, phenacaine, piperocaine, pramoxine, prilocaine, proparacaine, and tetracaine.

9. The composition of Claim 8 wherein the local anesthetic is at least one of bupivacaine, mepivacaine, and tetracaine.

10. The composition of Claim 7 wherein the lcoal anesthetic is at least one selected from the group consisting of cocaine, procaine, bupivacaine, chloroprocaine, cyclomethylcaine, dibucaine, dimethisoquin, dyclonine, hexylcaine, lidocaine, mepivacaine, phenacaine, piperocaine, pramoxine, prilocaine, proparacaine, and tetracaine.

11. The composition of Claim 10 wherein the local anesthetic is at least one of bupivacaine, mepivacaine, and tetracaine.