Europaisches Patentamt
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`0'
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`European Patent Office
`Office européen des brevets
`
`63 Publication number:
`
`0 31 9 243
`A1
`
`®
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`EUROPEAN PATENT APPLICATION
`
`@ Application number: 883112905
`
`63 Int. 01.4: A61K 31/485
`
`@ Date of filing: 29.11.88
`
`@ Priority: 03.12.87 GB 8728294
`
`63 Applicant: RECKITT & COLMAN PRODUCTS
`LIMITED
`
`
`
`
`
`
`
`
`Date of publication of application:
`07.06.89 Bulletin 89/23
`
`Designated Contracting States:
`AT BE CH DE FR IT LI LU NL SE
`
`One Burlington Lane
`London W4 2RW(GB)
`
`® inventor: Lewis, John William
`20 Sldlngs Court Skillings Lane
`Brough North Humberside(GB)
`
`Representative: Hardisty, David Robert et al
`BOULT. WADE & TENNANT 27 Furnival Street
`London EC4A IPQ(GB)
`
`
`Pharmaceutical compositions.
`
`@ A pharmaceutical composition in sublingual unit dosage form for maintenance treatment of opiate addicts
`comprising from 2 to 8mg buprenorphine and an amount of naltrexone sufficient to substantially attenuate the
`euphorigenic effect of the buprenorphine when injected and to provide greater opiate blocking effect than that of
`naltrexone alone.
`
`EP0319243A1
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`Xerox Copy Centre
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`

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`EP 0319 243 A1
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`PHARMACEUTICAL COMPOSITIONS
`
`for the treatment of opiate dependence and more
`This invention relates to compositions useful
`particularly to compositions containing naltrexone and buprenorphine.
`Naltrexone (INN for 1-N-cyclopropyimethyI-14-hydroxynordihydromorphinone) is a pure opiate antago-
`nist which, when administered orally (50 mg/day) as a maintenance drug for opiate addicts. blocks the
`effects of self-administered opiates and this contributes to the extinction of drug craving. Unfortunately, only
`about 10 per cent of addicts inducted on to a naltrexone treatment regime remain in treatment since
`naltrexonehas no positive reinforcing effect to satisfy the needs of the addict.
`it also has the disadvantage
`that
`it precipitates abstinence in opiate abusers including those with only a low level of physical
`dependence. Thus an addict must be detoxified and be drug free for at least ten days before starting
`naltrexone treatment.
`
`Buprenorphine (INN for N-cyclopropylmethyl-7&-[1-(S)-hydroxy-1,2,2-trimethylpropyl]6,14-endoethano-
`6,7,8,14-tetrahydronororipavine) has been shown in man to be a potent antagonist analgesic lacking the
`psychotomimetic effects found with other antagonist analgesics. Buprenorphine effectively relieves mod-
`erate 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 (morphine) antagonist properties. However from direct dependence studies in animals
`and in man it has been concluded that buprenorphine does not produce significant physical dependence
`and the potential to produce psychological dependence is low as indicated by animal self administration
`studies and by the measurement of euphorigenic effects in human post addicts.
`ln man the agonist and
`narcotic antagonist characteristics of buprenorphine have been demonstrated in opiate addicts. Thus oral
`buprenorphine in the close range 6-16 mg has been shown to precipitate abstinence in highly dependent
`opiate addicts presenting for detoxification. 0n 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 buprenorphine was behaving as an opiate agonist of low
`intrinsic activity.
`Thus buprenorphine has many of the desired characteristics of a treatment for opiate dependence (a)
`the ability to substitute for opiates in moderately dependent individuals (b) provide limited,
`long-lasting
`reinforcing (euphorigenic) effects which are acceptable to addicts (c) produce very mild abstinence effects
`when the drug is withdrawn, and (d) provide very good safety. With respect to (c) and (d) buprenorphine is
`markedly superior to methadone which is the only opioid agonist presently used for maintenance therapy.
`For maintenance treatment there is the need for a product which can be safely administered on a "take
`home" basis. One of the potential problems of a sublingual buprenorphine product for the treatment of
`opiate addicts is its vulnerability to diversion if it is made available as a "take home" medication. Since the
`sublingual preparations to be absorbed have to be totally and relatively easily soluble, an addict
`in
`treatment could dissolve up the product and inject it. The useful sublingual dose range of buprenorphine for
`addict treatment (2 mg - 8 mg) is about ten times higher than the analgesic dose range and when injected
`is potentially equivalent to 60-240 mg morphine or 30-120 mg heroin; as such it will have a significant value
`to street addicts. It is therefore to be expected that if such a sublingual buprenorphine product were made
`available as “take home" medication a proportion of it would fall
`into the hands of street opiate users.
`Injection of
`the diverted buprenorphine would negate the primary purpose of a treatment for opiate
`dependence - to prevent intravenous drug use which is a major source of AlDS infection.
`Our US Patent No 4661492 describes and claims in particular 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 0.4 mg and simultaneously an amount of
`naltrexone sufficient to precipitate abstinence and thus prevent substitution in an opiate dependent subject,
`the weights of naltrexone and buprenorphine administered sublingually being within the ratio of 1:4 to 1:2.
`There is also disclosed and claimed an analgesic composition in sublingual unit dosage form comprising an
`active dose of buprenorphine of from about 0.1 to about 0.4 mg and an amount of naltrexone sufficient to
`prove aversive to a narcotic addict by parenteral administration but insufficient to compromise the analgesic
`action of the buprenorphine, the weight of naltrexone and buprenorphine being within the ratio of 1:4 to 1:2.
`The analgesic effect of these combination doses was equal to that of the equivalent dose of buprenorphine
`alone; however the ability of the combinations to precipitate abstinence in opiate-dependent subjects when
`injected was as great as that of the equivalent doses of naltrexone. Consequently an opiate dependent
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`EP 0 319 243 A1
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`abuser would be discouraged from injecting the combination.
`We have now found that there are doses of buprenorphine and naltrexone which when co-administered
`may be used in the treatment of opiate addicts.
`According to this invention there is provided a pharmaceutical composition in sublingual unit dosage
`form for maintenance treatment of opiate addicts comprising from 2 to 8 mg buprenorphine and an amount
`of naltrexone sufficient to substantially attenuate the euphorigenic effect of the buprenorphine when injected
`and to provide greater opiate blocking effect than that of naltrexone alone wherein the weights of naltrexone
`and buprenorphine are within the ratio of 1:4 to 1:1. The preferred weight of buprenorphine is 4 mg and that
`of naltrexone is in the range of 1 to 4 mg.
`In an aspect of the invention there is provided a pharmaceutical composition in sublingual unit dosage
`form for maintenance treatment of opiate addicts comprising from 2 to 8 mg buprenorphine and an amount
`of naltrexone sufficient to substantially attenuate the euphorigenic effect of the buprenorphine when injected
`and to provide greater opiate blocking effect than that of naltrexone alone wherein the amount of naltrexone
`is in the range of 2 to 8 mg. The preferred weight of buprenorphine is 4 mg and that of naltrexone is in the
`range of 2 to 4 mg.
`it is to be understood that the use of the terms buprenorphine and naltrexone comprehend not only the
`bases but also their pharmaceutically acceptable salts. Particular preferred salts are the hydrochlorides.
`The sublingual combinations of
`the present
`invention contain in unit doses greater amounts of
`naltrexone than the sublingual analgesic compositions of our earlier invention. This amount of naltrexone
`exerts a substantial opiate antagonist effect sublingually as well as when injected and in this respect the
`drug abuse treatment combinations differ
`from the analgesic combinations. The addiction treatment
`combinations will have substantially less reinforcing (euphorigenic) effect than buprenorphine alone particu-
`larly when injected and will not be attractive to any opiate abuser even those who are not physically
`dependent. They will also act sublingually in precipitating abstinence in dependent individuals. For this
`reason it is desirable that opiate addicts should first be stabilised on buprenorphine alone before transfer to
`the combination. This transfer can be made without a drug free period as is necessary in the present
`procedure for transferring addicts from opiates to oral naltrexone since there is no precipitated abstinence
`when buprenorphine-maintained subjects are treated with naltrexone.
`The preparations of the present invention are superior to equivalent preparations of buprenorphine alone
`for maintenance treatment of opiate dependence since they can be safely dispensed for "take home" use
`without fear of diversion. Furthermore we have shown that the abstinence effects following repeated
`administration of the combination are of an even lower level than those associated with buprenorphine
`alone.
`.
`
`The preparations of the present invention are superior to the present oraE naltrexone maintenance
`product
`(a) based on their limited level of agonist effect which makes them more acceptable to addicts and
`therefore gives improved rates of retention in treatment.
`(b) based on our finding that they have greater ability to block the acute effects of opiates. This is a
`most important factor determining the efficacy of a maintenance treatment for opiate dependence.
`
`In the rat tail pressure test (Green and Young, Br. J. Pharmac., 6, p572, 1957), dose-response curves
`for morphine were determined after four days' pretreatment with twice-daily subcutaneous doses of saline,
`naltrexone (1 mg/kg) and buprenorphine/naltrexone (1 mg/kg + 1mg/kg). On day five, two hours after the
`last dose of the pretreatment drug.
`the dose-response curve for morphine was determined. Naltrexone
`shifted the morphine dose-response curve substantially to the right indicating blockade of opiate receptors
`whereas a combination of naltrexone (1 mg/kg) and buprenorphine (1 mg/kg) not only shifted the curve
`further to the right but also reduced the peak effect produced by morphine.
`It is preferable to formulate the compositions in unit dosage forms ie physically discrete units containing
`the appropriate amounts of buprenorphine and naltrexone together with pharmaceutically acceptable
`diluents and/or carriers. Such compositions may be in the form of solid or liquid formulations.
`thereof plus
`Liquid preparations may be for example comprise buprenorphine or a non-toxic salt
`naltrexone or a non-toxic salt thereof dissolved in 20-30% v/v aqueous ethanol buffered to between pH 4.5
`to 5.5.
`
`Compositions in the form of sublingual tablets contain soluble excipients such as lactose, mannitol,
`dextrose. sucrose or mixtures thereof. They will preferably also contain granulating and disintegrating
`agents such as starch. binding agents such as povidone or hydroxypropyi-methyl cellulose and lubricating
`agents such as magnesium stearate.
`The invention is illustrated by the following Examples:-
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`EP 0 319 243 A1
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`EXAMPLE 1
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`10 ml of a sublingual solution containing 10 mg/ml buprenorphine and 10 mg/ml naltrexone in a pH5
`mixture of a 30% v/v aqueous ethanol: citric acid/disodium hydrogen phosphate buffer was prepared as
`follows:
`
`1. The buffer was prepared by mixing 3.8 ml 0.1 M citric acid and 3.2 ml 0.2 M disodium hydrogen
`phosphate.
`2. 3.0 ml 95% v/v ethanol was added to the buffer increasing the pH from 4.6 to 5.0.
`3. 108 mg buprenorphine hydrochloride was added with stirring until dissolved.
`4. 110.7 mg naltrexone hydrochloride was added with stirring until dissolved.
`5. Unit dose packs containing 0.2 ml were dispensed to give single doses of 2 mg buprenorphine and
`2 mg naltrexone.
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`1O
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`u
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`15
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`Unit dose packs containing 0.8 ml were dispensed to give single doses of 8 mg buprenorphine and 8
`mg naltrexone.
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`20
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`EXAMPLE 3
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`A sublingual tablet having the following composition:
`
`
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`2.16
`
`Bupernorphne HCI
`2.21
`Naltrexone HCI
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`
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`26.98
`Lactose
`Mannitol
`1 8.0
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`
`
`
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`mg/tablet
` Maize starch
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`Povidone
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`Magnesium stearate
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`
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`was prepared by screening all the materials with the exception of the magnesium stearate through a 750nm
`sieve and blending them together. The mixed powders were then subjected to an aqueous granulation
`process and dried at 50°C. The resulting granules were forced through a 750LLm sieve and blended with
`magnesium stearate (pre-sieved through a SOOum sieve). The tablet granules were compressed to yield
`tablets of 5.56 mm diameter and weight 60 mg.
`
`EXAMPLE E
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`45
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`5D
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`55
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`The formulation of Example 2 was varied as follows, the method of manufacture being as for Example
`
`mg/tablet
`Buprenorphine HCI
`Naltrexone HCI
`
`Lactose
`Mannitol
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`Maize starch
`Povidone
`
`
`Magnesium stearate
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`EP 0 319 243 A1
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`In this Example the tablet granules were compressed to yield tablets of 7 mm diameter and weight 120 mg.
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`EXAMPLE 5
`
`The formulation of Example 3 was varied as follows. the method of manufacture being as for Example
`
`Buprenorphine HCI
`Naltrexone HCI
`Lactose
`Mannitol
`Maize starch
`Povidone
`
`Magnesium stearate
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`2.
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`10
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`15
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`20
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`In this Example the tablet granules were compressed to yield tablets of 7 mm diameter and weight 120 mg.
`In the claims the weights and ratios refer to buprenorphine and naltrexone in base form.
`
`Claims
`
`25
`
`1. A pharmaceutical composition in sublingual unit dosage form for maintenance treatment of opiate
`addicts comprising from 2 to 8mg buprenorphine and an amount of naltrexone sufficient to substantially
`attenuate the euphorigenic effect of the buprenorphine when injected and to provide greater opiate blocking
`effect than that of naltrexone alone wherein the weights of naltrexone and buprenorphine are within the ratio
`of 1:4 to 1:1.
`
`2. A pharmaceutical composition in sublingual unit dosage form for maintenance treatment of opiate
`addicts comprising from 2 to 8mg buprenorphine and an amount of naltrexone sufficient to substantially
`attenuate the euphorigenic effect of the buprenorphine when injected and to provide greater opiate blocking
`effect than that of naltrexone alone wherein the amount of naltrexone is in the range of 2 to 8mg.
`3. A pharmaceutical composition according to Claim 1 wherein the weight of buprenorphine is 4mg and
`that of naltrexone is in the range of 1
`to 4mg.
`7
`4. A pharmaceutical composition according to Claim 1 or Claim 2 wherein the weight of buprenorphine
`is 4mg and that of naltrexone is in the range of 2 to 4mg.
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`a,
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`illfi;::ean Patent
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`EUROPEAN SEARCH REPORT
`
`Applimtion Number
`
`EP
`
`88 31 1290
`
`Category
`
`A
`
`
`
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`
`
`
`
`CLASSIFICATION OF THE
`Relevant
`CitationVof document with indication, where appropriate,
`APPLICATION (Int. 0-4)
`to claim
`of relevant passages
`
`
`EP-A-0 185 472
`(RECKITT & COLMAN
`
`
`
`A 61 K 31/485
`PRODUCTS LTD)
`* & us-A-4 661 492 (Cat.D) *
`
`
`
`SEARCHED (Int. Cl.4)
`
`
`-
`
`TECHNICAL FIELDS
`
`
`
`
`
`
`Place of search
`
`THE HAGUE
`
`Date of completion of the search
`
`Examiner
`
`09-03-1989
`
`BRINKMANN C.
`
`:5
`5‘
`§
`...
`2
`3‘
`xx.
`it:
`2
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`CATEGORY 0F CITED DOCUMENTS
`
`T : theory or principle underlying the invention
`E : earlier patent document, but published on, or
`
`
`after the filing date
`X : particularly relevant if taken alone
`D : document cited in the application
`Y: particularly relevant if combined with another
`L : document cited for other reasons
`document of the same utegory
`
`
`A: technological background
`......................................................................................................
`0 : non-written disclosure
`& : member of the same patent family, corresponding
`
`
`
`P : intermediate document
`document
`
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`