ZA200203902B - Analgesix compositions containing buprenorphine. - Google Patents
Analgesix compositions containing buprenorphine. Download PDFInfo
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- ZA200203902B ZA200203902B ZA200203902A ZA200203902A ZA200203902B ZA 200203902 B ZA200203902 B ZA 200203902B ZA 200203902 A ZA200203902 A ZA 200203902A ZA 200203902 A ZA200203902 A ZA 200203902A ZA 200203902 B ZA200203902 B ZA 200203902B
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- South Africa
- Prior art keywords
- buprenorphine
- naloxone
- naltrexone
- nalmefene
- weight
- Prior art date
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- 229960001736 buprenorphine Drugs 0.000 title claims description 70
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 title claims description 70
- 239000000203 mixture Substances 0.000 title claims description 41
- 229960004127 naloxone Drugs 0.000 claims description 41
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 claims description 40
- 229960003086 naltrexone Drugs 0.000 claims description 40
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 claims description 33
- 229960005297 nalmefene Drugs 0.000 claims description 33
- 230000000202 analgesic effect Effects 0.000 claims description 15
- 239000002552 dosage form Substances 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
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- SFNLWIKOKQVFPB-KZCPYJDTSA-N bunavail Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C.C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 SFNLWIKOKQVFPB-KZCPYJDTSA-N 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 claims 13
- RGPDIGOSVORSAK-STHHAXOLSA-N naloxone hydrochloride Chemical compound Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C RGPDIGOSVORSAK-STHHAXOLSA-N 0.000 description 45
- 238000009472 formulation Methods 0.000 description 16
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000000829 suppository Substances 0.000 description 8
- 210000002683 foot Anatomy 0.000 description 7
- ZFSXKSSWYSZPGQ-UHFFFAOYSA-N (2-hydroxycyclopentyl)azanium;chloride Chemical group Cl.NC1CCCC1O ZFSXKSSWYSZPGQ-UHFFFAOYSA-N 0.000 description 6
- 229960000858 naltrexone hydrochloride Drugs 0.000 description 6
- GYWMRGWFQPSQLK-OPHZJPRHSA-N (4r,4as,7as,12bs)-3-(cyclopropylmethyl)-7-methylidene-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol;hydron;chloride Chemical group Cl.N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 GYWMRGWFQPSQLK-OPHZJPRHSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
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- 239000008121 dextrose Substances 0.000 description 3
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- 239000003401 opiate antagonist Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000006190 sub-lingual tablet Substances 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 229920005439 Perspex® Polymers 0.000 description 2
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 2
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 229940056146 buprenorphine / naloxone Drugs 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
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- 239000008215 water for injection Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
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- GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 101000637771 Homo sapiens Solute carrier family 35 member G1 Proteins 0.000 description 1
- 208000004454 Hyperalgesia Diseases 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- FRLKJAAPFJROFZ-UHFFFAOYSA-N N-nororipavine Natural products COC1=CC=C2C(NCC3)CC4=CC=C(O)C5=C4C23C1O5 FRLKJAAPFJROFZ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 229940089206 anhydrous dextrose Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
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- 239000003085 diluting agent Substances 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 230000002743 euphoric effect Effects 0.000 description 1
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- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- 102000053339 human SLC35G1 Human genes 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
N
PHARMACEUTICAL COMPOSITIONS
The present invention relates to analgesic compositions, containing buprenorphine and, in particular, to compositions which contain buprenorphine at a sub-clinical analgesic dose level in combination with naloxone, naltrexone or nalmefene.
Buprenorphine (International Non-proprietary Name for N-cyclopropylmethyl-7a-[1-(S)-hydroxy-1,2,2- trimethylpropyl]6,l4-endoethano-6,7,8,14-tetrahydro-~ nororipavine) has been shown in clinical trials to be a potent opiate partial agonist analgesic lacking the psychotomimetic effects found with other opiate 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 0.2 mg-0.8 mg for sublingual tablets.
In animal tests and in man buprenorphine has been ’ 20 shown to have both agonist (morphine-like) and antagonist properties. However from direct dependence studies in animals and in man it has been concluded that buprenorphine does not produce significant physical dependence, as indicated by animal self administration studies and by the measurement of euphorigenic effects in human post addicts. However, buprenorphine suffers from side effects typical of opiate agonists such as nausea and vomiting, constipation and respiratory depression in some patients, although there is a ceiling to its effects on respiratory depression as a direct consequence of its partial agonist properties.
Naloxone (International Non-proprietary Name for 1-N-allyl-14-hydroxynorhydromorphinone) is a narcotic antagonist which has been incorporated into oral and sublingual preparations of various opioids in order to protect the preparations from parenteral abuse, whilst maintaining the analgesic effect of the opioid.
GB-A-2150832 describes analgesic compositions in sublingual or parenteral dosage form comprising an active
SUBTITUTE SHEET (RULE 26)-
dose of buprenorphine and an amount of naloxone sufficient to prove aversive to a narcotic addict by parenteral administration but insufficient to compromise the analgesic action of the buprenorphine. Preferably the parenteral dosage 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.
Naltrexone (International Non-proprietary Name for 1-N-cyclopropylmethyl-14-hydroxynordihydro-morphinone) is a pure opiate antagonist 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.
Nalmefene (International Non-Proprietary Name for (5a) -17-(cyclopropylmethyl) -4,5-epoxy-6-methylene- morphinan-3,14~diol) is a structural analogue of naltrexone with opiate antagonist activity.
GB-A-2167633 describes an analgesic composition in parenteral or sublingual unit dosage form comprising an active dose of buprenorphine 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 wherein the dose of buprenorphine in the parenteral form is from about 0.3mg to about 0.6mg and in the sublingual form from about 0.lmg to about 0.4mg and the weights of buprenorphine to naltrexone for the parenteral form are within the ratio of 12:1 to 3:1 and for the sublingual form are within the ratio 4:1 to 1:1.
We have now surprisingly found that sub-clinical dosage levels of buprenorphine are potentiated and enhanced by low doses of naloxone or naltrexone or nalmefene. The interaction between the drugs is a synergistic interaction and more than the additive effects of the separate drug entities.
Accordingly, the present invention provides in its broadest aspect an analgesic composition in parenteral unit dosage form or in a unit dosage form suitable for delivery via the mucosa comprising an amount of
SUBTITUTE SHEET (RULE 26)
buprenorphine which is less than the clinical dose required to achieve pain relief and (i) an amount of naloxone such that the ratio by weight of buprenorphine to naloxone is in the range of from 12:5:1 to 27-5:1, or (ii) an amount of naltrexone or nalmefene such that the ratio by weight of buprenorphine to naltrexone or nalmefene is in the range of from 12-.5:1 to 22:5:1 whereby the analgesic action of the buprenorphine is potentiated by the low dose of naloxone, naltrexone or nalmefene.
In a first aspect the present invention provides an = analgesic composition in parenteral or sublingual unit + 15 dosage form or in a unit dosage form suitable for --delivery via the mucosa comprising from 15pug to 200pg of = g buprenorphine per unit dose and : (1) an amount of naloxone such that the ratio by - weight of buprenorphine to naloxone is in the ’ 20 range of from 12-5:1 to 27.5:1, or _ (ii) an amount of naltrexone or nalmefene such that the ratio by weight of buprenorphine to naltrexone or nalmefene is in the range of from 12u5:1 to 22us5:1. : ’
It is to be understood that the terms buprenorphine, naloxone, naltrexone and nalmefene as used herein are meant to cover not only the bases but their pharmaceutically acceptable salts. Particularly preferred salts are the hydrochlorides.
It is preferable to formulate the compositions in unit dosage forms i.e. physically discrete units containing the appropriate amounts of buprenorphine and naloxone, naltrexone or nalmefene, together with pharmaceutically acceptable diluents and/or carriers.
Such unit dosage forms for parenteral administration are suitably in the form cf ampoules and for delivery via the mucosa may, for example, be in the form of tablets for sublingual administration. -SUBTITUTE SHEET {RULE 26)
The term parenteral is intended to encompass administration of the compositions by any way other than through the alimentary tract.
The term mucosa is intended to encompass any mucous membrane and includes oral mucosa, rectal mucosa, vaginal mucosa and nasal mucosa.
Compositions intended for parenteral administration comprise an isotonic solution of buprenorphine and naloxone, naltrexone or nalmefene in sterile water.
Conveniently the solution is made isotonic by use of : dextrose and sterilised by autoclaving or by filtration through a membrane filter. The compositions may be administered intramuscularly, intradermally, intraperitonealy, intravenously, intraarterially, subcutaneously or by the epidural route. The compositions may also be administered transdermally.
Compositions in the form of sublingual tablets : contain soluble excipients such as lactose, mannitol, dextrose, sucrcse or mixtures thereof. They will also contain granulating and disintegrating agents such as ) starch, binding agents such as povidone or hydroxypropyl- methyl cellulose and lubricating agents such as magnesium stearate.
The compositions for parenteral administration, or for delivery via the mucosa, such as by sublingual administration, as detailed above, may be prepared by manufacturing techniques which are well known to those skilled in the art.
The compositions of the present invention in unit dosage form preferably contain the naloxone, naltrexone or nalmefene in an amount such that the ratio by weight of buprenorphine to naloxone, naltrexone or nalmefene is in the range of from 15:1 to 20:1.
The compositions of the present invention contain buprenorphine in an amount which is below that required in a unit dose to obtain pain relief. In the human being, dosages of about 40pg of buprenorphine per kilogram of body weight are required to obtain satisfactory pain relief in the absence of potentiation.
SUBTITUTE SHEET (RULE 26)
Thus for typical body weights of 50 to 80 kg, the dosage would be from 2000ug to 3200ug, i.e. from 2mg to 3.2mg of buprenorphine per day. This would conveniently be administered as 4 unit doses. The amounts of buprenorphine which are effective in the present invention are below the amounts which are effective in the absence of the potentiating effects of naloxone, naltrexone or nalmefene.
In a second aspect the present invention provides a method for the treatment of pain in a human or animal subject, which method comprises the administration to the human or animal by the parenteral or via the mucosa route of from 1-25ug to 10ug per kilogram of body weight of buprenorphine per day and (i) an amount of naloxone such that the ratio by weight of buprenorphine to naloxone . administered is in the range of from 12:-5:1 to 27-5:1, or (ii) an amount of naltrexone or nalmefene such that ’ 20 the ratio by weight of buprenorphine to naltrexone or nalmefene administered is in the range of from 12.5:1 to 22-5:1.
In a third aspect the present invention provides the use of naloxone, naltrexone or nalmefene in the manufacture of a medicament for the treatment of pain comprising a sub-clinical amount of buprenorphine, wherein the ratio by weight of buprenorphine to naloxone is in the range of from 12:5:1 to 27-5:1 or the ratio by weight of buprenorphine to naltrexone or nalmefene is in the range of from 12-5:1 to 22-5:1.
The ratios for the potentiation of the sub-clinical dosages of buprenorphine by low doses of the opiate antagonists were determined by the University Department of Anaesthesia, Addenbrookes Hospital, Cambridge according to the paw withdrawal method of Hargreaves,
K.M., Dubner, R., Brown, F., Flores, C. and Joris, J.: A
New and Sensitive Method for Measuring Thermal
Nociception in Cutaneous Hyperalgesia. Pain 32: 77-88, ~ _SUBTITUTE SHEET (RULE 26)
1988. This method enables the researcher to discern a peripherally mediated response to thermal stimulation caused by drugs in the unrestrained rat.
The results were obtained using a BASILE Plantar
Test Device (Ugo Basile, Comerio-Italy). It basically consists of a movable I.R. (infrared) Generator placed below a glass pane upon which the operator places the rat. A perspex enclosure defines the space within which the animal is unrestrained. It is divided into three compartments, which helps the operator to carry out rapid “screening” work: up to three rats can be tested with no appreciable delay in between.
The operator positions the I.R. Generator directly beneath the hind paw of the rat and activates both the
I.R. Source and a reaction time counter. When the rat feels pain and withdraws its paw, the I.R. Generator is automatically switched off and the timer stops, . determining the withdrawal latency.
The effects of buprenorphine at various dosages, naloxone at various dosages, naltrexone at various dosages and buprenorphine in combination with naloxone or naltrexone at various dosages were determined by testing adult rats in which peripheral mononeuropathy was produced by placing three loosely constrictive ligatures around the common sciatic nerve. The testing was carried out on the eighth day following the operative procedure.
In order to determine a baseline for comparison purposes, rats were subjected to the Hargreaves paw withdrawal test before the subcutaneous injection of the various drugs or drug combinations being tested. The rats were then injected subcutaneously with the particular drug or drug combination being tested and the percentage change in time for the rat to withdraw its paw from the thermal stimulation, in comparison with the baseline, was recorded as a percentage in paw withdrawal latency.
The invention is further described with reference to the following Examples.
SUBTITUTE SHEET (RULE 26)
METHODS }
Surgery
Lister Hooded rats (180-200g) were anaesthetised with halothane and the left sciatic nerve was loosely ligated with 3 chromic cat gut sutures to induce a neuropathy.
Rats were left to recover for one week after the : ‘procedure before commencing behavioural testing. 10 .
Drug Preparation
The drugs (buprenorphine, naloxone and naltrexone) were prepared freshly in water at a concentration of 1 mg/ml. The stocks were then diluted in saline to obtain the different concentrations used in the study.
Drugs were injected sub-cutaneously in the fold of . the neck.
Testing . 20 After 8 days, thermal nociceptive threshold, as : determined by hindpaw withdrawal latency, was measured using a plantar test Ugo Basile, Comero, Italy). Prior to testing, the rat was placed in the perspex box and allowed 5 minutes to habituate. The heat source was positioned under the plantar surface of one hind paw at random and activated. This initiated a timing circuit which measured the time interval between the application of the light beam and the withdrawal of the hind paw.
This value was assigned as the withdrawal latency.
Paw withdrawal latency was determined before injection and at different times after injection. Three measurements were taken per paw.
EXAMPLE 1
The effects of buprenorphine and buprenorphine/ naloxone at weight ratios of 20:1 and 15:1 were determined at various doses of buprenorphine expressed as ~ SUBTITUTE SHEET (RULE 26)
ng/kg of body weight of the drug administered subcutaneously to rats (n=3).
The results of these tests are given in Figure 1.
The potentiation of sub-clinical doses of buprenorphine by low dose naloxone can be clearly seen from the graph of Figure 1. Both of the buprenorphine/naloxone combinations showed marked increases in pain withdrawal latencies at both weight ratios where the buprenorphine dose was 1.25pg and 2.5pg, compared to buprenorphine alone which had no significant effect at these dosage levels.
EXAMPLE 2 : Buprenorphine was administered to rats (n=6) at a dosage level of 2.5ug/kg of body weight of the rats.
Buprenorphine was co-administered subcutaneously with ) either naloxone or naltrexone at various weight ratios ranging from 5:1 to 30:1. In order to provide appropriate baseline points naloxone and naltrexone alone were also administered subcutaneously to rats at the same dosage levels as those used in the combined treatments.
The results are given in Figure 2 from which the potentiation of the sub-clinical doses of buprenorphine by naloxone or naltrexone can be clearly seen.
EXAMPLE 3
To investigate the duration of action of several ratios (10:1, 15:1 and 20:1 buprenorphine:naloxone, with a fixed dose of buprenorphine) the effect on PWL was followed over a 26 hour period following subcutaneous injection. The results are given in Figure 3 from which it can be seen that the effect was already maximal after 40 minutes and then decreased sharply over 6 hours.
However at 26 hours a residual effect was still visible, although this was not statistically significant. The maximal effect of each ratio (40min) was compatible with the results shown in Figure 2. The effect observed with
SUBTITUTE SHEET (RULE 26)
the 10:1 ratio combination was not statistically significant.
EXAMPLE 4
A parenteral formulation having the following composition: mg/ml.
Buprenorphine HCl 0.1
Naloxone HCl 0.0067
Anhydrous dextrose 50.0
Hydrochloric acid to pH 4.0
Water for injection to 1.0 ml : 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. The acidity of the solution was adjusted to : | pH 4.0 by the addition of 0.1M hydrochloric acid, and the solution was made up to volume with Water for Injection. : The solution was filtered through a 0.22 Om membrane filter and transferred to sterilised 1 ml or 2 ml glass ampoules containing 1 ml or 2 ml of the solution. The ampoules were sealed and the product sterilised by autoclaving.
EXAMPLE 5
The formulation of Example 4 was varied by using 0.005 mg/ml of naloxone hydrochloride instead of 0.0067 mg/ml.
EXAMPLE 6
The formulation of Example 4 was modified with 0.0067 mg/ml of naltrexone hydrochloride substituted for the naloxone hydrochloride of Example 1. -SUBTITUTE SHEET (RULE 26) :
EXAMPLE 7
The formulation of Example 4 was modified with 0.005 mg/ml of naltrexone hydrochloride substituted for the naloxone hydrochloride of Example 1.
EXAMPLE 8
The formulation of Example 4 was modified with 0.0067 mg/ml of nalmefene hydrochloride substituted for the naloxone hydrochloride of Example 4. ) EXAMPLE 9
The formulation of Example 4 was modified with 0.005 mg/ml of nalmefene hydrochloride substituted for the naloxone hydrochloride of Example 4. :
EXAMPLE 10
A sublingual tablet having the following composition: mg/tablet
Buprenorphine HC1 0.1
Naloxone HCl 0.0067
Lactose 31.2433
Mannitol 18.0
Maize starch 9.0
Povidone 1.2
Magnesium stearate 0.45 60.0 was prepared by screening all the materials with the exception of the magnesium stearate through a 750 pum sieve and blending them together. The mixed powders were then subjected to. an aqueous granulation procedure and dried at 50°C. The resulting granules were forced through a 750 pm sieve and blended with magnesium stearate (pre-sieved through a 500 um sieve). The tablet
SUBTITUTE SHEET (RULE 26)
granules were compressed to yield tablets of 5.56 mm diameter and weight 60 mg.
EXAMPLE 11
The formulation of Example 10 was varied by using 0.005 mg/tablet of naloxone hydrochloride and adjusting the weight of lactose.
EXAMPLE 12
The formulation of Example 10 was modified with 0.0067 mg/tablet of naltrexone hydrochloride substituted for the naloxone hydrochloride of Example 10. : 15
The formulation of Example 10 was modified with 0.005 mg/tablet of naltrexone hydrochloride substituted ) 20 for the naloxone hydrochloride of Example 10.
EXAMPLE 14
The formulation of Example 10 was modified with 0.0067 mg/tablet of nalmefene hydrochloride substituted ‘for the naloxone hydrochloride of Example 10.
EXAMPLE 15
The formulation of Example 10 was modified with 0.005 mg/tablet of nalmefene hydrochloride substituted for the naloxone hydrochloride of Example 10. _ _ SUBTITUTE SHEET (RULE 26)
EXAMPLE 16
A suppository having the following composition: mg/suppository
Buprenorphine HCL 0.1
Naloxone HCL 0.0067
Gelatin 200
Glycerin 700
Deionised water 89.9 was prepared by mixing the ingredients together and melting them at between 60° and 70°C. The melted mass is poured into a disposable-mould of plastic material in which the suppositories are cast and remain enclosed until removed by the patient.
EXAMPLE 17 :
The formulation of Example 16 was varied by using 0.005mg/suppository of naloxone hydrochloride.
EXAMPLE 18
The formulation of Example 16 was modified with 0.0067 mg/suppository of naltrexone hydrochloride substituted for the naloxone hydrochloride of Example 16.
EXAMPLE 189
The formulation of Example 16 was modified with 0.005 mg/suppository of naltrexone hydrochloride sustituted for the naloxone hydrochloride of Example 16.
EXAMPLE 20
The formulation of Example 16 was modified with 0.0067 mg/suppository of nalmefene hychloride substituted for the naloxone hydrochloride of Example 16.
SUBTITUTE SHEET (RULE 26)
EXAMPLE 21
The formulation of Example 16 was modified with 0.005mg/suppository of nalmefene hydrochloride substituted for the naloxone hydrochloride of Example 16.
SUBTITUTE SHEET (RULE 26) .
Claims (11)
- » CLAIMS: . : 1. An analgesic composition in parenteral unit dosage form or in a unit dosage form suitable for delivery via the mucosa comprising an amount of- . buprenorphine which is less than the clinical dose : required to achieve pain relief and (i) an amount of naloxone such that the ratio by . weight of buprenorphine to naloxone is in the range of from 12:5:1 to 27:5:1, or (ii) an amount of naltrexone or nalmefene such that - - the ratio by weight of buprenorphine to - naltrexone or nalmefene is in the range of from - 12-5:1 to 22-5:1 . = 15 whereby the analgesic action of the buprenorphine is potentiated by the low dose of naloxone, naltrexone or . nalmefene.
- 2. An analgesic composition in parenteral or sublingual unit dosage form or in a unit dosage form suitable for delivery via the mucosa comprising from 15ug to 200pug of buprenorphine per unit dose and (i) an amount of naloxone such that the ratio by weight of buprenorphine to naloxone is in the range of from 12:5:1 to 27-5:1, or (ii) an amount of naltrexone or nalmefene such that the ratio by weight of buprenorphine to naltrexone or nalmefene is in the range of from 12=5:1 to 22=5:1. SUBTITUTE SHEET (RULE 26)
- 3. A composition as claimed in claim 1 or claim 2 wherein the unit dosage form contains an amount of naloxone such that the ratio by weight of buprenorphine to naloxone is in the range of from 15:1 to 20:1.
- 4. A composition as claimed in claim 1 or claim 2 wherein the dosage form contains an amount of naltrexone or nalmefene such that the ratio by weight of buprenorphine to naltrexone or nalmefene is in the range of from 15:1 to 20:1.
- 5. Use of buprenorphine and naloxone or naltrexone or nalmefene in the manufacture of a medicament for the treatment of pain in a human or animal subject by administration to the human or animal by the parenteral or via the mucosa route wherein from 1:25pg to 10pg per kilogram of body weight of buprenorphone is administered per day and (1) an amount of naloxone such that the ratio by weight of buprenorphine to naloxone administered is in the range from 12:5:1 to 27-5:1, or (ii) an amount of naltrexone or nalmefene such that the ratio by weight of buprenorphine to naltrexone or nalmefene administered is in the range of from 12:5:1 to 22-5:1.
- 6. Use as claimed in claim 5 wherein an amount of buprenorphine administered to the human or animal is from 1-25ug to 5ug per kilogram of body weight.
- 7. Use as claimed in claim 5 or claim 6 wherein the ratio by weight of buprenorphine to naloxone, AMENDED SHEET TT naltrexone or nalmefene administered to the human or animal is in the range of from 15:1 to 20:1.
- 8. Use of naloxone, naltrexone or nalmefene in the manufacture of a medicament for the treatment of pain comprising a sub—clinical amount of buprenorphine, wherein the ratio by weight of buprenorphine to naloxone is in the range of from 12-5:1 to 27:5:1 or the ratio by weight of buprenorphine to naltrexone or nalmefene is in the range of from 12:5:1 to 22-5:1.
- 9. Use as claimed in claim 8 wherein the ratio by weight of buprenorphine to naloxone, naltrexone or nalmefene is in the range 15:1 to 20:1.
- 10. An analgesic composition according to the invention, substantially as hereinbefore described or exemplified.
- 11. Use as claimed in any one of claims 5, 8 or 9, substantially as hereinbefore described or exemplified. AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9927359.1A GB9927359D0 (en) | 1999-11-19 | 1999-11-19 | Improvements in or relating to organic compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200203902B true ZA200203902B (en) | 2003-06-10 |
Family
ID=10864788
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200203902A ZA200203902B (en) | 1999-11-19 | 2002-05-16 | Analgesix compositions containing buprenorphine. |
Country Status (3)
| Country | Link |
|---|---|
| GB (1) | GB9927359D0 (en) |
| PE (1) | PE20010853A1 (en) |
| ZA (1) | ZA200203902B (en) |
-
1999
- 1999-11-19 GB GBGB9927359.1A patent/GB9927359D0/en not_active Ceased
-
2000
- 2000-11-16 PE PE2000001228A patent/PE20010853A1/en not_active Application Discontinuation
-
2002
- 2002-05-16 ZA ZA200203902A patent/ZA200203902B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB9927359D0 (en) | 2000-01-19 |
| PE20010853A1 (en) | 2001-08-31 |
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