CA2102072C - Combination preparation containing flupirtin and morphine for the treatment of pain and the prevention of morphine dependence - Google Patents
Combination preparation containing flupirtin and morphine for the treatment of pain and the prevention of morphine dependence Download PDFInfo
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- CA2102072C CA2102072C CA002102072A CA2102072A CA2102072C CA 2102072 C CA2102072 C CA 2102072C CA 002102072 A CA002102072 A CA 002102072A CA 2102072 A CA2102072 A CA 2102072A CA 2102072 C CA2102072 C CA 2102072C
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- Prior art keywords
- morphine
- flupirtin
- dependence
- pharmaceutically acceptable
- acceptable salt
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- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 title claims abstract description 79
- 229960005181 morphine Drugs 0.000 title claims abstract description 39
- JUUFBMODXQKSTD-UHFFFAOYSA-N N-[2-amino-6-[(4-fluorophenyl)methylamino]-3-pyridinyl]carbamic acid ethyl ester Chemical compound N1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 JUUFBMODXQKSTD-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title description 2
- 208000008013 morphine dependence Diseases 0.000 title 1
- 230000002265 prevention Effects 0.000 title 1
- 230000000202 analgesic effect Effects 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims description 11
- 238000011161 development Methods 0.000 claims description 6
- 239000012458 free base Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000013543 active substance Substances 0.000 abstract description 2
- 241001465754 Metazoa Species 0.000 description 9
- 206010012335 Dependence Diseases 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000000730 antalgic agent Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229940035676 analgesics Drugs 0.000 description 4
- 230000003502 anti-nociceptive effect Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- 230000000384 rearing effect Effects 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 240000001090 Papaver somniferum Species 0.000 description 2
- 235000008753 Papaver somniferum Nutrition 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 229960002069 diamorphine Drugs 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000003340 mental effect Effects 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- IVVNZDGDKPTYHK-JTQLQIEISA-N 1-cyano-2-[(2s)-3,3-dimethylbutan-2-yl]-3-pyridin-4-ylguanidine Chemical compound CC(C)(C)[C@H](C)N=C(NC#N)NC1=CC=NC=C1 IVVNZDGDKPTYHK-JTQLQIEISA-N 0.000 description 1
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000006887 Ullmann reaction Methods 0.000 description 1
- 241000282485 Vulpes vulpes Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 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 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000095 emetic effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002743 euphoric effect Effects 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000000380 hallucinogen Substances 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 240000004308 marijuana Species 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000011707 mineral Chemical class 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 229960002310 pinacidil Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000003033 spasmogenic effect Effects 0.000 description 1
- 230000001148 spastic effect Effects 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
Abstract
The combination of flupirtin and morphine has the property of having a strong analgesic action and of not causing any morphine-like dependence and tolerance. New medicaments containing this active substance combination are described.
Description
~., ~~o~o~~
Morphine, which is derived from opium, the dried milky exudate of unripe poppy capsules (Papaver somniferum;, has been used in the form of its hydrochloride as an agent against severe pain since its isolation by Sertiirner (1806).
When this analgesic is used frequently and over a long period of time, for example in tumor patients, there is a risk of addiction and the development of tolerance (morphinism).
The side effects observed during correct use, such as euphoric effect, emetic effect, spastic constipation and increase in smooth musculature tone, also reduce the therapeutic applicability of morphine. There has therefore been no lack of attempts to synthesize strongly acting, but side effect-free analgesics. Although the partially synthetic product diamorphine (heroin) is 10 times more effective than morphine, it leads to addiction much more easily. The action of pethidine is about 5 times weaker effective than morphine and is also less spasmogenic.
Pentazocine and buprenorphine fall within narcotics legislation on account of their addiction potential.
Tramadol is only about 1/10 - 1/5 as effective as morphine, but instead is not yet known to present an addiction potential.
~~o~~~z There thus remains a great need for a reliable analgesic medication that is also highly effective in severe pain with few side effects which, for social reasons, should present no addiction potential.
The solution of a combination of active substances has been adopted to reduce the use of analgesics, or to enhance the not always adequate analgesic effect. These attempts have aimed at making the side effects of morphine less pronounced and enhancing the analgesic effect by combining selected analgesics with morphine.
Since morphine has no anti-inflammatory effect, this deficit in the effect of morphine can be balanced out by combining morphine with anti-inflammatory or anti-pyretic analgesics. Thus, for example, Vergoni et al. (Life Sci., 50(16), page 135-138 (1992)) describe the potentiating effects of~pinacidil on the analgesic effect of morphine.
ZO A combination of rectally administered indomethacin with intravenously administered morphine is described by Segstro and Morley-Forster in Can. J. Anaesth. ~$(5), 578-581 (1991).
Animal experiments which describe the potentiation of analgesic effects of morphine and clonidine in rats were 2102Q'~~
reported by Wilcox, Carlsson, Jochim and Jurna in Brain Res.
~(1), 84-93 (1987).
All experiments are aimed at enhancing the analgesic effects in the sense of a synergistic effect in order to reduce the dose of analgesic or anti-inflammatory agent and morphine.
Flupirtin (INN) is an analgesic with muscle-relaxing components of action. (B. Nickel, V. Jakovlev, I. Szelenyi, Arzneim.-Forsch. ~Q(II)8, 909-911 (1990) Genaan published patent 36 01 195).
It has no dependence potential (B. Nickel, H.O. Barbe, I. Szelenyi, Arzneim.-Forsch. ~(II)8, 905-908 (1990)). The antinociceptive effect of flupirtin cannot be antagonized by naloxon. Flupirtin also shows no affinity with opiate receptors. (B. Nickel, A. Herz, V. Jakovlev, U. Tibes, Arzneim.- Forsch. ~(II), 1402 (1985)).
It has now been found that flupirtin, given alone, does not lead to the development of tolerance. It was also surprisingly found that there were no signs of tolerance when the combination of flupirtin and morphine was given. This is unexpected since the structure of flupirtin differs greatly from the known morphine antagonists naloxon or methadone.
Morphine, which is derived from opium, the dried milky exudate of unripe poppy capsules (Papaver somniferum;, has been used in the form of its hydrochloride as an agent against severe pain since its isolation by Sertiirner (1806).
When this analgesic is used frequently and over a long period of time, for example in tumor patients, there is a risk of addiction and the development of tolerance (morphinism).
The side effects observed during correct use, such as euphoric effect, emetic effect, spastic constipation and increase in smooth musculature tone, also reduce the therapeutic applicability of morphine. There has therefore been no lack of attempts to synthesize strongly acting, but side effect-free analgesics. Although the partially synthetic product diamorphine (heroin) is 10 times more effective than morphine, it leads to addiction much more easily. The action of pethidine is about 5 times weaker effective than morphine and is also less spasmogenic.
Pentazocine and buprenorphine fall within narcotics legislation on account of their addiction potential.
Tramadol is only about 1/10 - 1/5 as effective as morphine, but instead is not yet known to present an addiction potential.
~~o~~~z There thus remains a great need for a reliable analgesic medication that is also highly effective in severe pain with few side effects which, for social reasons, should present no addiction potential.
The solution of a combination of active substances has been adopted to reduce the use of analgesics, or to enhance the not always adequate analgesic effect. These attempts have aimed at making the side effects of morphine less pronounced and enhancing the analgesic effect by combining selected analgesics with morphine.
Since morphine has no anti-inflammatory effect, this deficit in the effect of morphine can be balanced out by combining morphine with anti-inflammatory or anti-pyretic analgesics. Thus, for example, Vergoni et al. (Life Sci., 50(16), page 135-138 (1992)) describe the potentiating effects of~pinacidil on the analgesic effect of morphine.
ZO A combination of rectally administered indomethacin with intravenously administered morphine is described by Segstro and Morley-Forster in Can. J. Anaesth. ~$(5), 578-581 (1991).
Animal experiments which describe the potentiation of analgesic effects of morphine and clonidine in rats were 2102Q'~~
reported by Wilcox, Carlsson, Jochim and Jurna in Brain Res.
~(1), 84-93 (1987).
All experiments are aimed at enhancing the analgesic effects in the sense of a synergistic effect in order to reduce the dose of analgesic or anti-inflammatory agent and morphine.
Flupirtin (INN) is an analgesic with muscle-relaxing components of action. (B. Nickel, V. Jakovlev, I. Szelenyi, Arzneim.-Forsch. ~Q(II)8, 909-911 (1990) Genaan published patent 36 01 195).
It has no dependence potential (B. Nickel, H.O. Barbe, I. Szelenyi, Arzneim.-Forsch. ~(II)8, 905-908 (1990)). The antinociceptive effect of flupirtin cannot be antagonized by naloxon. Flupirtin also shows no affinity with opiate receptors. (B. Nickel, A. Herz, V. Jakovlev, U. Tibes, Arzneim.- Forsch. ~(II), 1402 (1985)).
It has now been found that flupirtin, given alone, does not lead to the development of tolerance. It was also surprisingly found that there were no signs of tolerance when the combination of flupirtin and morphine was given. This is unexpected since the structure of flupirtin differs greatly from the known morphine antagonists naloxon or methadone.
The invention provides improved medicaments with an analgesic action that display a greatly reduced addiction potential or even no addiction potential at all.
More specifically, the present invention provides a pharmaceutical composition formulated to deliver to a patient flupirtin or a pharmaceutically acceptable salt thereof in an amount, calculated as a free base, of 5 mg/kg, and a pharmaceutically acceptable salt of morphine in an amount, calculated as a free base, of 2.5 mg/kg to 10 mg/kg, wherein the analgesic effectiveness of the morphine is preserved, and wherein potential for development of dependence on and tolerance to the morphine in the patient is reduced.
The invention will be further described by reference to the accompanying drawings, in which:
Figure 1 describes the development of tolerance over 45 days of combination compared to the individual substances.
Figure 2 shows the antinociceptive effect of the combination compared to the individual substances.
Figure 3 shows the results of a trial on mental dependence.
Figure 4 shows on the basis of the rearing of rats the stimulatory effect of morphine alone and the non-stimulatory effect of the combination of the invention.
Figure 5 shows a similar version as Figure 4: here the path is measured as an indication of the stimulation of the animals.
Figure 6 shows the influence of the individual substances on muscle relaxation compared to the combination 2~.02U'~2 of the invention.
The weights set out in the claims and in the specification always relate to the free bases:
Administration of flupirtin over several weeks did not lead to tolerance in animal experiments. (Figure 1). The analgesic effect was maintained over the entire duration of the experiment (45 days).
The examination was conducted in the electro-pain test in the rat (after Blake et al. Arz. Med. exp. ~, 146 (1963)).
An additive, antinociceptive effect was observed after the single administration of flupirtin in combination with morphine.(Ffgure 2). The sole administration of flupirtin leads to an antinociceptive effect of 45%, the administration of the combination yields an effect of 100%.
In examining physical dependence the already often described symptom of dependence due to morphine, decrease in animal weight after withdrawal, was significantly relieved by flupirtin in combination with morphine (Figure 3). Flupirtin cancels or weakens the physical dependence potential of morphine.
More specifically, the present invention provides a pharmaceutical composition formulated to deliver to a patient flupirtin or a pharmaceutically acceptable salt thereof in an amount, calculated as a free base, of 5 mg/kg, and a pharmaceutically acceptable salt of morphine in an amount, calculated as a free base, of 2.5 mg/kg to 10 mg/kg, wherein the analgesic effectiveness of the morphine is preserved, and wherein potential for development of dependence on and tolerance to the morphine in the patient is reduced.
The invention will be further described by reference to the accompanying drawings, in which:
Figure 1 describes the development of tolerance over 45 days of combination compared to the individual substances.
Figure 2 shows the antinociceptive effect of the combination compared to the individual substances.
Figure 3 shows the results of a trial on mental dependence.
Figure 4 shows on the basis of the rearing of rats the stimulatory effect of morphine alone and the non-stimulatory effect of the combination of the invention.
Figure 5 shows a similar version as Figure 4: here the path is measured as an indication of the stimulation of the animals.
Figure 6 shows the influence of the individual substances on muscle relaxation compared to the combination 2~.02U'~2 of the invention.
The weights set out in the claims and in the specification always relate to the free bases:
Administration of flupirtin over several weeks did not lead to tolerance in animal experiments. (Figure 1). The analgesic effect was maintained over the entire duration of the experiment (45 days).
The examination was conducted in the electro-pain test in the rat (after Blake et al. Arz. Med. exp. ~, 146 (1963)).
An additive, antinociceptive effect was observed after the single administration of flupirtin in combination with morphine.(Ffgure 2). The sole administration of flupirtin leads to an antinociceptive effect of 45%, the administration of the combination yields an effect of 100%.
In examining physical dependence the already often described symptom of dependence due to morphine, decrease in animal weight after withdrawal, was significantly relieved by flupirtin in combination with morphine (Figure 3). Flupirtin cancels or weakens the physical dependence potential of morphine.
-- , 21020'2 It may also be assumed that flupirtin cancels or markedly diminishes the dependence and withdrawal symptoms provoked by other combinations such as those of the barbiturate, alcohol, amphetamine, cocaine, cannabis or hallucinogen type.
The test for the possible presence of mental dependence was conducted according to the method of Hosoya, Pharnaacol.
Meth. Tox, ~, 515 (1979).
The behavior of animals on the day of withdrawal was recorded during the same long-term investigation. It was also found in this model that the behavior of the animals was markedly influenced by flupirtin in the combination after withdrawal of morphine (stimulation, rearing) (Figure 4,5).
The marked stimulation or rearing behavior of the animals after morphine is reduced in the combination with flupirtin and rather resembles that of untreated control animals.
Flupirtin also relieved the rigidity provoked in~animals by morphine. (Figure 6).
In one tablet the medicament contains for example 10 mg to 7,000 mg flupirtin in the form of a pharmaceutically acceptable salt and 5 mg to 500 mg morphine in the form of a pharmaceutically acceptable salt and preferably 50 mg - 500 mg flupirtin and 10 mg - 250 mg morphine.
The test for the possible presence of mental dependence was conducted according to the method of Hosoya, Pharnaacol.
Meth. Tox, ~, 515 (1979).
The behavior of animals on the day of withdrawal was recorded during the same long-term investigation. It was also found in this model that the behavior of the animals was markedly influenced by flupirtin in the combination after withdrawal of morphine (stimulation, rearing) (Figure 4,5).
The marked stimulation or rearing behavior of the animals after morphine is reduced in the combination with flupirtin and rather resembles that of untreated control animals.
Flupirtin also relieved the rigidity provoked in~animals by morphine. (Figure 6).
In one tablet the medicament contains for example 10 mg to 7,000 mg flupirtin in the form of a pharmaceutically acceptable salt and 5 mg to 500 mg morphine in the form of a pharmaceutically acceptable salt and preferably 50 mg - 500 mg flupirtin and 10 mg - 250 mg morphine.
21020'~~
Salt formers that may be considered in the case of flupirtin axe for example hydrochloric acid, gluconic acid, malonic acid and malefic acid; in the case of morphine, mineral acids such as hydrochloric acid and sulphuric acid may be considered.
The medicament of the invention may be present in the form of tablets, capsules, pellets, granulates, ampoules for intravenous and intramuscular injection, in the form of infusion solutions and suppositories. The preparation of the medicaments is effected in known manner, known and conventional pharmaceutical auxiliary substances as well as other conventional carriers and dilutants being used.
Carriers and auxiliary substances of this kind that may be used are for example substances recommended or listed in the following literature references as auxiliary substances for pharmaceutical, cosmetic and adjacent fields: Ullmanns Encyklopadie der technischen Chemie, Volume 4 (1953), page 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 et seq. H.v.Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie and angrenzende Gebiete: Pharm. Ind. Issue 2, 1961, page 72 et seq.; Dr. H.P. Fiedler, Lexikon der Hilfsstoffe fitr Pharmazie, Kosmetik and angrenzende Gebiete, 2nd edition, Editio Cantor, Aulendorf in Wurttemberg 1981 and Phanaazeutische Technologie (publishers: Fuchs, Sucker, Speiser, Georg Thieme Verlag, 2nd edition (1991).
_ 7 _
Salt formers that may be considered in the case of flupirtin axe for example hydrochloric acid, gluconic acid, malonic acid and malefic acid; in the case of morphine, mineral acids such as hydrochloric acid and sulphuric acid may be considered.
The medicament of the invention may be present in the form of tablets, capsules, pellets, granulates, ampoules for intravenous and intramuscular injection, in the form of infusion solutions and suppositories. The preparation of the medicaments is effected in known manner, known and conventional pharmaceutical auxiliary substances as well as other conventional carriers and dilutants being used.
Carriers and auxiliary substances of this kind that may be used are for example substances recommended or listed in the following literature references as auxiliary substances for pharmaceutical, cosmetic and adjacent fields: Ullmanns Encyklopadie der technischen Chemie, Volume 4 (1953), page 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 et seq. H.v.Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie and angrenzende Gebiete: Pharm. Ind. Issue 2, 1961, page 72 et seq.; Dr. H.P. Fiedler, Lexikon der Hilfsstoffe fitr Pharmazie, Kosmetik and angrenzende Gebiete, 2nd edition, Editio Cantor, Aulendorf in Wurttemberg 1981 and Phanaazeutische Technologie (publishers: Fuchs, Sucker, Speiser, Georg Thieme Verlag, 2nd edition (1991).
_ 7 _
Claims (2)
1. A pharmaceutical composition formulated to deliver to a patient flupirtin or a pharmaceutically acceptable salt thereof in an amount, calculated as a free base, of 5 mg/kg, and a pharmaceutically acceptable salt of morphine in an amount, calculated as a free base, of 2.5 mg/kg to 10 mg/kg, wherein the analgesic effectiveness of the morphine is preserved, and wherein potential in the patient for development of dependence on, and tolerance to, the morphine is reduced.
2. Use of flupirtin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt of morphine, in the manufacture of a medicament formulated to deliver to a patient the flupirtin, or the pharmaceutically acceptable salt thereof, in an amount, calculated as a free base, of 5 mg/kg, and the pharmaceutically acceptable salt of morphine in an amount, calculated as a free base, of 2.5 mg/kg to 10 mg/kg, wherein the analgesic effectiveness of the morphine is preserved, and wherein potential in the patient for development of dependence on, and tolerance to, the morphine is reduced.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4236752A DE4236752A1 (en) | 1992-10-30 | 1992-10-30 | Combination preparation of flupirtine and morphine for the treatment of pain and for avoiding morphine addiction |
| DEP4236752.2 | 1992-10-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2102072A1 CA2102072A1 (en) | 1994-05-01 |
| CA2102072C true CA2102072C (en) | 2005-01-04 |
Family
ID=6471783
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002102072A Expired - Lifetime CA2102072C (en) | 1992-10-30 | 1993-10-29 | Combination preparation containing flupirtin and morphine for the treatment of pain and the prevention of morphine dependence |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5521178A (en) |
| EP (1) | EP0595311B1 (en) |
| JP (1) | JP3665354B2 (en) |
| AT (1) | ATE147979T1 (en) |
| BR (1) | BR9304431A (en) |
| CA (1) | CA2102072C (en) |
| DE (2) | DE4236752A1 (en) |
| DK (1) | DK0595311T3 (en) |
| ES (1) | ES2099344T3 (en) |
| GR (1) | GR3022995T3 (en) |
| HU (1) | HU219907B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8268821B2 (en) | 2003-12-16 | 2012-09-18 | Relevare Aust. Pty Ltd | Methods and compositions |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ260408A (en) * | 1993-05-10 | 1996-05-28 | Euro Celtique Sa | Controlled release preparation comprising tramadol |
| US5891471A (en) | 1993-11-23 | 1999-04-06 | Euro-Celtique, S.A. | Pharmaceutical multiparticulates |
| KR100354702B1 (en) | 1993-11-23 | 2002-12-28 | 유로-셀티크 소시에떼 아노뉨 | Manufacturing method and sustained release composition of pharmaceutical composition |
| US5843480A (en) | 1994-03-14 | 1998-12-01 | Euro-Celtique, S.A. | Controlled release diamorphine formulation |
| GB9422154D0 (en) | 1994-11-03 | 1994-12-21 | Euro Celtique Sa | Pharmaceutical compositions and method of producing the same |
| US5965161A (en) | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
| DE19918325A1 (en) | 1999-04-22 | 2000-10-26 | Euro Celtique Sa | Extruded drug dosage form, e.g. granulate for tableting, comprising an active agent in a polysaccharide-containing matrix, giving a release profile which is controllable by extrusion conditions and/or the inclusion of additives |
| WO2001008682A2 (en) * | 1999-08-03 | 2001-02-08 | Awd.Pharma Gmbh & Co. Kg | Use of flupirtine for alleviating pain caused by degenerative joint diseases in dogs and cats |
| AU2004298288B2 (en) * | 2003-12-16 | 2011-06-30 | Relevare Aust. Pty Ltd | Methods and compositions |
| US7553858B2 (en) * | 2003-12-17 | 2009-06-30 | Meda Pharma Gmbh & Co. Kg | Combination of flupirtine and tramadol |
| US20060052370A1 (en) * | 2004-08-24 | 2006-03-09 | Meyerson Laurence R | Methods and compositions for treating nociceptive pain |
| US7619007B2 (en) | 2004-11-23 | 2009-11-17 | Adamas Pharmaceuticals, Inc. | Method and composition for administering an NMDA receptor antagonist to a subject |
| EP1688141A1 (en) | 2005-01-31 | 2006-08-09 | elbion AG | The use of flupirtine for the treatment of overactive bladder and associated diseases, and for the treatment of irritable bowel syndrome |
| DK1874282T3 (en) * | 2005-04-06 | 2010-10-25 | Adamas Pharmaceuticals Inc | Methods and Preparations for the Treatment of CNS Disorders |
| US20070042054A1 (en) * | 2005-04-20 | 2007-02-22 | Council Of Scientific And Industrial Research | Functional aphrodisiac rolled herbal bidis and cigarettes |
| ES2430063T3 (en) * | 2006-11-28 | 2013-11-18 | Purac Biochem Bv | Stable lactide particles |
| US20080279930A1 (en) * | 2007-05-07 | 2008-11-13 | Bernd Terhaag | Controlled-Release Flupirtine Compositions, Compacts, Kits and Methods of Making and Use Thereof |
| WO2010085848A1 (en) * | 2009-01-30 | 2010-08-05 | Relevare Aust. Pty Ltd | Drug abuse deterrent, methods and compositions |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI855016A (en) * | 1985-06-28 | 1986-12-29 | Degussa | SYNERGISTIC COMBINATION AV FLUPIRTIN OCH 4-ACETAMIDO-PHENOL. |
-
1992
- 1992-10-30 DE DE4236752A patent/DE4236752A1/en not_active Withdrawn
-
1993
- 1993-10-27 US US08/141,678 patent/US5521178A/en not_active Expired - Lifetime
- 1993-10-28 DE DE59305236T patent/DE59305236D1/en not_active Expired - Lifetime
- 1993-10-28 EP EP93117472A patent/EP0595311B1/en not_active Expired - Lifetime
- 1993-10-28 ES ES93117472T patent/ES2099344T3/en not_active Expired - Lifetime
- 1993-10-28 DK DK93117472.6T patent/DK0595311T3/en active
- 1993-10-28 AT AT93117472T patent/ATE147979T1/en active
- 1993-10-29 JP JP27173093A patent/JP3665354B2/en not_active Expired - Lifetime
- 1993-10-29 HU HU9303089A patent/HU219907B/en unknown
- 1993-10-29 CA CA002102072A patent/CA2102072C/en not_active Expired - Lifetime
- 1993-10-29 BR BR9304431A patent/BR9304431A/en not_active Application Discontinuation
-
1997
- 1997-04-01 GR GR970400669T patent/GR3022995T3/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8268821B2 (en) | 2003-12-16 | 2012-09-18 | Relevare Aust. Pty Ltd | Methods and compositions |
| US8334263B2 (en) | 2003-12-16 | 2012-12-18 | Raymond Nadeson | Analgesic methods and compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| BR9304431A (en) | 1994-06-07 |
| GR3022995T3 (en) | 1997-07-30 |
| DE59305236D1 (en) | 1997-03-06 |
| HU219907B (en) | 2001-09-28 |
| HU9303089D0 (en) | 1994-01-28 |
| JP3665354B2 (en) | 2005-06-29 |
| CA2102072A1 (en) | 1994-05-01 |
| DE4236752A1 (en) | 1994-05-05 |
| DK0595311T3 (en) | 1997-05-26 |
| ATE147979T1 (en) | 1997-02-15 |
| HUT66085A (en) | 1994-09-28 |
| ES2099344T3 (en) | 1997-05-16 |
| JPH06211663A (en) | 1994-08-02 |
| US5521178A (en) | 1996-05-28 |
| EP0595311B1 (en) | 1997-01-22 |
| EP0595311A1 (en) | 1994-05-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20131029 |