Note: Descriptions are shown in the official language in which they were submitted.
~ ~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.
