United States Patent [191
`Lewis et al.
`
`[11] Patent Number:
`[45] Date of Patent:
`
`8 4,582,835
`‘Apr. '15, 1986
`
`[54] ANALGESIC COMPOSITIONS
`[75] Inventors: John w. Lewis, North Ferriby; John
`G. Lloyd-Jones, Cottingham, both of
`England
`
`[73] Assignee:
`
`Reckitt & Colman Products Limited,
`London, England
`[21] Appl. No.: 678,478
`[22] Filed:
`Dec. 5, 1984
`[30]
`Foreign Application Priority Data
`Dec. 6, 1983 [GB] United Kingdom ............... .. 8332556
`
`[51] Int. v01.4 ............................................ .. A61V 31/44
`[52] US. Cl. .................................... .. 514/282; 424/10;
`514/812
`[58] Field of Search ................ .. 424/ 10, 260; 514/282,
`514/812
`
`[56]
`
`References Cited
`PUBLICATIONS
`Chem. Abst. 94-150268y (1984).
`ChemicalAbstracts 90, 145726j.
`
`Manara et al., Dev. Neurosci, (Amsterdam) 1978, 4
`(Charact. Funct. Opioids) 225-6.
`’
`'
`Dettmar et al., Biochem. Soc. Trans. 1978, 6(5), 1004-6
`(=Chem. Abs. 90, 197597n (1979).
`>
`Ramabadran et al., Endog. Exog. Opiate Agonists An
`tagonists, Proc. Int. Narc. Res. Club. Conf. 1979 (Pub
`1980) 471-4 (-Chem. Abs. 94, 15027u (1981)).
`Rance et al., Endog. Exog. Opiate Angonists Antago
`nists, Proc. Int. Narc. Res. Club. Conf. 1979 (Pub 1980)
`387-90 (-Chem. Abs., 94, 150268y (1981)).
`Primary Examiner-Stanley J. Friedman
`Attorney, Agent, or Firm-Bacon & Thomas
`[57]
`ABSTRACT
`A method of treating pain which comprises the adminis
`tration to a patient of a parenterally or sublingually
`effective dose of buprenorphine together with an
`amount of naloxone sufficient to prevent substitution in
`an opiate dependent subject. Preferably when the ad
`ministration is parenteral the weights of naloxone and
`buprenorphine are within the ratio of 1:3 to 1:1 and
`when administered sublingually the weights are within
`the ratio of 1:2 to 2:1.
`
`4 Claims, 2 Drawing Figures
`
`Page 1
`
`

`

`> U. S. Patent I
`
`I Apr. 15,1986
`
`4,582,835
`
`1110- p
`
`tbuprenorphine 0-U3mg/kg
`
`E
`
`_ saline
`
`E aojnixu-nz
`50-
`:niXU-Uh
`g’:
`‘5% w_ nixU-OB
`ea 20
`
`pretreatment timetmin)
`FIG].
`
`10th saline
`
`morphine 3mgli<g
`
`‘T’
`
`pretreatment tim-e(min)
`
`FIGZ. ,
`
`"
`
`percentage maximum '
`
`
`
`
`_ possible effect
`
`
`
`Page 2
`
`

`

`1
`
`ANALGESIC COMPOSITIONS
`
`15
`
`This invention relates to analgesic compositions and
`more particularly to compositions containing buprenor- ‘
`phine.
`Buprenorphine (International Non-proprietary Name
`for
`N-cyclopropylmethyl-7a-[l-(S)-hydroxy-1,2,2
`trimethylpropyl16, l4-endoethano-6,7, 8, l4-tetrahy
`dronororipavine) has been shown in clinical ‘trials to be
`a potent antagonist analgesic lacking the psychotomi
`v metic effects found with other antagonist analgesics.
`Buprenorphine effectively relieves moderate to severe
`pain in doses of 0.1 mg or more administered either
`parenterally or sublingually. The optimum therapeutic
`range for single doses is 0.3 mg—0.6 mg by injection and
`0.1 mg—0.4 mg for sublingual tablets.
`In animal tests and in man buprenorphine has been
`shown to have both agonist (morphine-like) and antago
`nist properties. However from direct dependence stud
`ies in animals and in man it has been concluded that
`‘buprenorphine does not produce signi?cant physical
`dependence and the potential to produce psychological
`dependence is low as indicated by animal self adminis
`tration studies and by the measurement of euphorigenic
`effects in human post addicts.
`In man the agonist and narcotic antagonist character
`istics of buprenorphine have been demonstrated in opi
`ate addicts. In a study in Hong Kong oral buprenor
`phine in the dose range 6-16 mg precipitated abstinence
`in opiate addicts presenting for detoxi?cation. On the
`other hand in a study involving subjects stabilised on a
`relatively low daily dose of oral methadone, sublingual
`buprenorphine could be substituted for methadone with
`only a low level of discomfort. In this situation bupren
`orphine was behaving as an opiate-agonist of low intrin- ,
`sic activity.
`This limited ability of buprenorphine to substitute for
`the opiates and its low-level opiate-like euphorigenic
`effects makes buprenorphine acceptable to some opiate
`misusers particularly when their favoured opiates are
`unavailable, and this has led to some illicit use of the
`drug. As will be discussed below the compositions of
`the present invention provide a means of enhancing the
`45
`abstinence-precipitating properties of buprenorphine,
`and thus the aversive characteristics, without compro
`mising its analgesic effect.
`Preparations have been developed which protect the
`oral preparations of certain opioids from parenteral
`abuse by the incorporation of naloxone. These prepara
`tions are based on the low oral bio-availability (~ 1%)
`of the narcotic antagonist naloxone (naloxone, chemi
`cally known as l-N-allyl-l4-hydroxynordihydro-mor
`phinone) when compared to that of methadone (~ 50%)
`and pentazocine (~30%). Thus a signi?cant quantity of
`naloxone can be introduced into oral preparations of
`these central analgesics without compromising their
`analgesic effect. If the opioid-naloxone preparations are
`dissolved in water and injected the naloxone is active
`and shows its narcotic antagonist activity. It thus blocks
`the euphorigenic activity of the opioid and eliminates
`the development of psychological dependence. The
`inhibition of opiate effects by naloxone also prevents the
`development of physical dependence.’ U.S. Pat. No.
`3,773,955 to Pachter and Gordon describes the oral
`combination of naloxone with a number of opiates par
`ticularly methadone.
`
`4,582,835
`2
`There are also examples in which naloxone has been
`incorporated into oral preparations of opioids to pre
`vent primary oral abuse. The combination of tilidine
`and naloxone affords such an example. Tilidine acting
`through a metabolite is more potent when given by the
`oral route than the parenteral route. Consequently no
`advantage can be gained by the addict in self adminis
`tration of tilidine by injection and as such the observed
`abuse of tilidine has been by oral administration. A
`product containing naloxone was introduced to protect
`tilidine against this abuse.
`U.S. Pat. No. 4,457,933 (issued July 3, 1984) to
`Pachter and Gordon describes the protection with nal
`oxone of oral dosage forms of various opioids against
`both oral and parenteral abuse. In this patent mention is
`made of the incorporation of l-3 mg of naloxone in an
`oral unit dose of buprenorphine (2 mg).
`To our knowledge there is no reference in the scien
`title or patent literature to the incorporation of nalox
`one (for purposes of abuse prevention) into formulations
`' of opioids for parenteral or sublingual administration.
`It will be appreciated from the foregoing discussion
`' that when naloxone is combined with an opioid for
`parenteral administration, the effects of the opioid in
`cluding its analgesic effect would be expected to be ~
`reduced. The literature on the pharmacology of bupren
`orphine would lead one to conclude that this would be
`true of buprenorphine. The interaction between bupren
`orphine and a specific opiate antagonist, diprenorphine
`when co-administered parenterally has been reported
`(Cowan et al., Br. J. Pharmacol, 60, 537 (1977)) to
`result in a reduction in the analgesic potency of bupren- ‘
`orphine by a factor of 300. It would therefore not have
`been expected that any combination of buprenorphine
`with naloxone for parenteral administration could be
`I found which would contain sufficient naloxone to be
`effective in limiting misuse, and would leave the analge
`sic effect of buprenorphine intact.
`Surprisingly, in animal experiments we have now
`found that there is a limited range of ratios of buprenor
`phine with naloxone for which, by injection, the analge
`sic performance is equal to that of buprenorphine alone
`whilst the abstinence-precipitating effects in opiate
`-dependent subjects are equivalent to that of naloxone
`alone. When the opiates such as morphine, methadone,
`and oxycodone are mixed with naloxone the agonist
`antagonist interaction reduces the analgesic perfor
`mance of the agonist and in complementary fashion
`reduces the antagonist performance of the naloxone.
`There is no teaching in the prior art regarding the
`protection of preparations of opioids intended for sub
`lingual administration by the incorporation of naloxone.
`We have found that the bioavailability of naloxone by
`the sublingual route is very much better (20%) than by
`the oral route (1%) and thus the concept which was
`developed by others for the protection of oral opioid
`preparations against parenteral abuse would not be ex
`pected to apply to sublinqual and buccal preparations.
`However, the sublingual bioavailability of buprenor
`phine (50%) is superior to that of naloxone and since we ‘
`have shown that in a limited range of dosage ratios by .
`parenteral administration naloxone, with full bioavaila
`bility, could be combined with buprenorphine without
`affecting its analgesic performance, we were able‘ to
`extend our ?ndings to an equivalent limited range of ‘
`dosage ratios for sublingual and buccal administration
`which would achieve similar results and afford protec- '
`tion against parenteral misuse.
`
`55
`
`60
`
`65
`
`Page 3
`
`

`

`4,582,835
`3
`According to this invention there is provided a
`method of treating pain which comprises the adminis
`tration to a patient of a parenterally or sublingually
`effective dose of buprenorphine together with an
`amount of naloxone suf?cient to prevent substitution in
`an opiate dependent subject.
`This invention also provides an analgesic composi
`tion in parenteral or sublingual dosage form comprising
`an active dose of buprenorphine and an amount of nal
`oxone suf?cient to prove aversive to a narcotic addict
`by parenteral administration but insuf?cient to compro
`mise the analgesic action of the buprenorphine.
`It is to be understood that the use of the terms bupren
`orphine and naloxone comprehend not only the bases
`but also their pharmaceutically acceptable salts. Partic
`ular preferred salts are the hydrochlorides.
`It will be appreciated that the required ratio of nalox
`one to buprenorphine is dependent upon the proposed
`route of administration. Preferably the parenteral dos
`age form contains naloxone and buprenorphine within
`the weight ratio of 1:3 to 1:1 and the sublingual form
`within the ratio 1:2 to 2:1.
`The ratios were determined in our laboratories ac
`cording to the following methods.
`25
`In the rat tail pressure test (Green, Young, Br. J.
`Pharmac. Chemother., 6, 572 (1957)) the maximum
`antinociceptive effect (ED9Q) with buprenorphine was
`achieved at a dose of 0.03 mg/kg, by subcutaneously
`administration (s.c.). The equivalent antinociceptive
`dose of morphine was 3.0 mg/kg. These doses were
`selected for evaluation of the in?uence of co-adminis
`tration of naloxone on the antinociceptive effect of both
`buprenorphine and morphine. Inclusion of naloxone at
`the dose of 0.02 mg/kg with the buprenorphine dose
`produced no signi?cant antagonism (FIG. 1). Increas
`ing the naloxone content to 0.04 and 0.08 mg/kg pro
`duced signi?cant antagonism (Dunnett’s test) of the
`antinociceptive effect of buprenorphine at 15 minutes
`and at these ratios the trend was maintained over 60
`minutes.
`Naloxone at all three dose levels produced signi?cant
`falls in the antinociceptive effect of morphine (FIG. 2).
`These results show that buprenorphine is signi?cantly
`less sensitive than morphine to the antagonist effects of
`45
`naloxone. In particular a dose of 0.02 mg/kg of nalox
`one has no effect on the EDgQ dose of buprenorphine
`but it reduces by greater than 30% the antinociceptive
`action of the equivalent dose of morphine.
`The ability to precipitate abstinence in morphine
`dependent rats has been evaluated using the method of
`Teiger D. G., J. Pharmac. exp. Ther. 190, 408 (1974).
`Table l presents the mean behavioural scores precipi
`tated by intraveneous administration of the challenge
`drug after 48 hour infusions of 100 mg/kg/ 24 h of mor
`phine.
`
`Challenge
`Drug
`Naloxone
`
`TABLE l-continued
`Dose
`Mean behavioural
`mg/ kg
`score
`0.2
`
`P
`
`Buprenorphine (0.03 ing/kg or 0.3 mg/kg) produced
`only very mild signs of withdrawal, as indicated by low
`mean behaviour scores. Naloxone (0.02 mg/kg and 0.2
`mg/kg) produced rapid and intense abstinence effects
`which were maintained when combined with buprenor
`phine in a 2:3 ratio.
`This ratio of naloxone to buprenorphine has been
`evaluated in analgesic studies in patients. The ef?cacy
`and safety of buprenorphine (0.3 mg per patient) in
`combination with naloxone (0.2 mg) was compared
`with buprenorphine (0.3 mg) alone following intramus
`cular or intravenous administration to 162 patients with
`moderate to severe post operative pain. Patients were
`assessed for pain intensity, pain relief and vital signs
`(pulse rate and systolic and diastolic blood pressure) at
`regular intervals for a six hour period after administra
`tion. The duration of analgesia was measured by record
`ing the time to analgesic remedication and all unwanted
`effects occurring during the assessment period were
`recorded. Both treatments provided good analgesia
`which lasted for approximately l0-l2 hours. Statistical
`analysis of the ef?cacy data showed no signi?cant dif
`ference between the two treatments for pain intensity,
`pain relief or duration of analgesia. Analysis of the un
`wanted effects and vital signs data also showed no sig
`ni?cant differences between the two treatments. These
`results show that the buprenorphine/naloxone combi
`nation provides safe and effective analgesia and there is
`no signi?cant differences between the combination and
`buprenorphine along with regard to ef?cacy.
`It is preferable to formulate the compositions in uni
`tary dosage forms i.e. physically discrete units contain
`ing the appropriate amounts of buprenorphine and nal
`oxone together with pharmaceutically acceptable dilu~
`ents and/or carriers. Such unitary dosage forms for
`parenteral administration are suitably in the form of
`ampoules and for sublingual administration in the form
`of tablets.
`Compositions intended for parenteral administration
`comprise an isotonic solution of buprenorphine and
`naloxone in sterile water. Conveniently the solution is
`made isotonic by use of dextrose and sterilised by auto
`claving or by ?ltration through a membrane ?lter.
`Compositions in the form of sublingual tablets con
`tain soluble excipients such as lactose, mannitol, dex
`trose, sucrose or mixtures thereof. They will also con
`tain granulating and disintegrating agents such as
`starch, binding agents such as povidone or hydroxypro
`pyl-methyl cellulose and lubricating agents such as
`magnesium stearate.
`The compositions in unitary dosage form for paren
`teral administration comprises from about 0.3 to about
`0.6 mg buprenorphine together with an amount of nal
`oxone such that the ratio by weight of naloxone to
`buprenorphine is within the range of 1:3 to 1:1, plus a
`pharmaceutically acceptable carrier.
`The compositions in the form of a sublingual tablet
`comprise from about 0.1 to about 0.4 mg buprenorphine
`together with an amount of naloxone such that the ratio
`by weight of naloxone to buprenorphine is within the
`range of 1:2 to 2:1, plus at least one pharmaceutically
`acceptable carrier or diluent.
`
`20
`
`40
`
`50
`
`55
`
`Challenge
`Drug
`
`Saline
`Buprenorphine
`Buprenorphine
`Naloxone
`Naloxone
`Buprenorphine +
`
`Naloxonc
`Buprenorphine +
`
`TABLE 1
`Dose
`Mean behavioural
`mg/kg
`score
`
`0.03
`0.03
`0.3
`0.02
`0.2
`0.03
`
`0.02
`0.3
`
`}
`
`)
`
`6.7
`11.7
`14.2
`40.8
`63.3
`31.7
`
`54.2
`
`60
`
`65
`
`P
`
`—
`NS
`NS
`<0.01
`<0.01
`<0.05
`
`<0.01
`
`Page 4
`
`

`

`4,582,835
`5
`6
`The invention is illustrated by the following Exam
`dure and dried at 50° C. The resulting granules were
`ples:
`forced through a 750 um sieve and blended with mag
`nesium stearate (pre-sieved through a 500 um sieve).
`The‘tablet granules were compressed to yield tablets of
`5.56 mm diameter and weight 60 mg.
`
`5
`
`EXAMPLE 1
`A parenteral formulation having the following com
`position
`
`Buprenorphine HCl
`Naloxone HCl
`Anhydrous dextrose
`Hydrochloric acid to pH
`Water for injection to
`
`mg/ml
`0.324
`0.3
`50.0
`4.0
`1.0 ml
`
`EXAMPLE 5
`The formulation of Example 4 was varied by using
`0.4 mg/tablet of naloxone hydrochloride and 30.734
`mg/ tablet lactose.
`-
`
`EXAMPLE 6
`The formulation of Example 4 was varied by using
`0.1 mg/tablet of naloxone hydrochloride and 31.034
`mg/tablet lactose.
`-
`
`15
`
`was prepared by dissolving dextrose, buprenorphine
`hydrochloride and naloxone hydrochloride in that
`order with stirring, in about 95% batch volume of ‘
`Water for Injection. vThe acidity of the solution was
`adjusted to pH 4.0 by the addition of 0.1 M hydrochlo
`ric acid, and the solution was made up to volume with
`Water for Injection. The solution was ?ltered through a
`0.22 pm membrane ?lter and transferred to sterilised 1
`ml or 2 ml glass ampoules containing 1 ml or 2 ml of the
`solution containing 0.3 or 0.6 mg of buprenorphine base
`respectively. The ampoules were sealed and the prod
`uct sterilised by autoclaving.
`EXAMPLE 2
`The formulation of Example 1 was varied by using
`0.15 mg/ml of naloxone hydrochloride instead of 0.3
`mg/ml.
`
`20
`
`EXAMPLE 7
`The formulation of Example 4 was varied by using
`0.108 mg/tablet of buprenorphine hydrochloride, 0.1
`mg/ tablet naloxone hydrochlorite and 31.142 mg/ tablet
`lactose.
`We claim:
`1. A method of treating pain which comprises the
`‘administration to a patient of a parenterally effective
`25
`unit dosage of buprenorphine wherein the weight of
`buprenorphine is between about 0.3 to about 0.6 mg and
`simultaneously an amount of naloxone sufficient to pre
`vent substitution in an opiate dependent subject, the
`weights of naloxone and buprenorphine administered
`parenterally being within the ratio of 1:3 to 1:1.
`2. A method of treating pain which comprises the
`administration to a patient of a sublingually effective
`unit dosage of buprenorphine wherein the weight of
`buprenorphine is between about 0.1 to about 0.6 mg and
`simultaneously an amount of naloxone sufficient to pre
`vent substitution in an opiate dependent subject, the
`weights‘ of naloxone and buprenorphine administered
`sublingually being within the ratioof 1:2 to 2:1.
`3. An analgesic composition in parenteral unit dosage
`form comprising an active dose of buprenorphine of '
`‘ from about 0.3 to about 0.6 mg and an amount of nalox
`one sufficient to prove aversive to a narcotic addict by
`parenteral administration but insufficient to compro
`mise the analgesic action of the buprenorphine, the
`weights of naloxone and buprenorphine being within I
`the ratio of 1:3 to 1:1.
`4. An analgesic composition in sublingual unit dosage _
`form comprising an active dose of buprenorphine of
`from about 0.1 to about 0.6 mg and an amount of nalox
`one sufficient to prove aversive to a narcotic addict by
`parenteral administration but insufficient to compro
`mise the analgesic action of the buprenorphine, the
`weights of‘ naloxone and buprenorphine being within
`the ratio of 1:2 to 2:1.
`4'
`
`EXAMPLE 3
`The formulation of Example 1 was varied by using
`0.20 mg/ml of naloxone hydrochloride instead of 0.3
`mg/ml.
`
`EXAMPLE 4
`A sublingual tablet formulation having the following
`composition
`I
`
`Buprenorphine l-lCl
`Naloxone HCl
`Lactose
`Mannitol
`Maize starch
`Povidone
`Magnesium stearate
`
`mg/tablet
`0.216
`0.2
`30.934
`18.0
`9.0
`1.2
`0.45
`60.0
`
`45
`
`50
`
`was prepared by screening all the materials with the
`exception of the magnesium stearate through a 750 um
`seive and blending them together. The mixed powders
`were then subjected to an aqueous granulation proce
`
`* 1k
`
`* *
`
`65
`
`Page 5
`
`