CA1200501A - Nalbuphine - narcotic analgesic composition and method of producing analgesia - Google Patents
Nalbuphine - narcotic analgesic composition and method of producing analgesiaInfo
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- CA1200501A CA1200501A CA000410864A CA410864A CA1200501A CA 1200501 A CA1200501 A CA 1200501A CA 000410864 A CA000410864 A CA 000410864A CA 410864 A CA410864 A CA 410864A CA 1200501 A CA1200501 A CA 1200501A
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- nalbuphine
- analgesic
- suitable salt
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- 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
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- 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
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Abstract
Title NALBUPHINE - NARCOTIC
ANALGESIC COMPOSITION AND METHOD
OF PRODUCING ANALGESIA
Abstract of the Disclosure A narcotic analgesic composition particularly in oral dosage form is provided which provides excellent analgesia in a mammal while reducing or eliminating the respiratory depression and euphoria usually associated with narcotic analgesics. The composition comprises an analgesic effective amount of a narcotic analgesic or salt thereof and an analgesic effective amount of nalbuphine or a salt thereof.
A method of producing analgesia in a mammal is also provided, this method comprises administering to a mammal parenterally or orally an analgesic effective amount of a narcotic analgesic or salt thereof and an analgesic effective amount of nalbuphine or a salt there-of. Administration of the narcotic analgesic and nalbu-phine can be either sequentially or simultaneously.
ANALGESIC COMPOSITION AND METHOD
OF PRODUCING ANALGESIA
Abstract of the Disclosure A narcotic analgesic composition particularly in oral dosage form is provided which provides excellent analgesia in a mammal while reducing or eliminating the respiratory depression and euphoria usually associated with narcotic analgesics. The composition comprises an analgesic effective amount of a narcotic analgesic or salt thereof and an analgesic effective amount of nalbuphine or a salt thereof.
A method of producing analgesia in a mammal is also provided, this method comprises administering to a mammal parenterally or orally an analgesic effective amount of a narcotic analgesic or salt thereof and an analgesic effective amount of nalbuphine or a salt there-of. Administration of the narcotic analgesic and nalbu-phine can be either sequentially or simultaneously.
Description
Background o~ the Invention Field of the Invention This invention relates to analgesic compositions and methods of producing analgesia in mammals and more 5 particularly to nalbuphine-narcotic analgesic oral com-positions for producing analgesia in mammals.
Prior Art U.S. Paten~ 3,393,1g7 issued to Pach~er and Matos-sian on July 16, 1968 discloses N-substituted-14-10 hydroxydihydronormorphines, including the N-cyclobutyl-methyl dexivatives, con~nonly called nalbuphine:
CH
--N
r~ OH
HO O OH
20 P~chter and Matossian and others, such as H. W. Elliott, et al., J. Med. ~Basel), 1, 74-89 (1970); H. Blumberg, et al., Pharmacologist, 10, 189, Fall 1968; P. Roberts, Drugs o~ the Future, 2, 613-5 (1977), disclose the use of nalbuphine as an analgesic l'or the control of moderate
Prior Art U.S. Paten~ 3,393,1g7 issued to Pach~er and Matos-sian on July 16, 1968 discloses N-substituted-14-10 hydroxydihydronormorphines, including the N-cyclobutyl-methyl dexivatives, con~nonly called nalbuphine:
CH
--N
r~ OH
HO O OH
20 P~chter and Matossian and others, such as H. W. Elliott, et al., J. Med. ~Basel), 1, 74-89 (1970); H. Blumberg, et al., Pharmacologist, 10, 189, Fall 1968; P. Roberts, Drugs o~ the Future, 2, 613-5 (1977), disclose the use of nalbuphine as an analgesic l'or the control of moderate
2; to severe pain.
U.S. Patent 4,237,140, issued to J. R. Dudzinski on December 2, 1980, describes an analgesic mixture of nalbuphine and acetoaminophen. U.S. Patent 4,282,215, issued to J. R. ~udzinski and W. K. Schmidt on August 4, 30 l9Bl, describes an analgesic mixture of nalbuphine and aspirin.
Morphine, oxymorphone, oxycodone and hydromorphone are well known strong narcotic analgesics which can, unfortunately, be addicti~7e and/or euphoric a~d subjected 35 to abuse by parenteral administration. Furthermore, ,~
~2~)~5(~
o these narcotics tend to produce respiratory depression in patients, especially when given as part of anesthesia.
One attempt to m; nimj ze abuse of these and other strong analgesic agents is described in U.S. Patent 3,773,955, issued to Pachter and Gordon on November 20, 1973 (also U.K. Patent 1,353,815) wherein A combination of a parenterally efective but orally inef~ective dose of naloxone and an analgetic agent gives an orally effective, but parenterally inactive analgesic composition. While 10 naloxone will overcome the narcotic analgesic upon parenteral administration to reduce respiratory depres-sion, euphoria and other side effects, it also eliminates analgesia. Such a composition upon oral administxation provides analgesia, but the naloxone is inactive orally 15 such that there is no reduction in side effects.
B. J. Kripke et al., J. of the International Anesthesia Research Society, Vol. 55, No. 6, pages 800-805 Nov.-Dec. 1976, describe naloxone antagonism after narcotic-supplemented anesthesia.
Summary of the Invention According to the present invention, there is provided an analgesic composition which comprises an analgesic effective amount of a narcotic analgesic selected from the group consisting of morphine, 2S oxymorphone, oxycodone, hydromorphone and a pharma-ceutically suitable salt of one o the above, and an analgesic effective amount of nalbuphine or a phar-maceutically suitable salt thereof.
There is also provided a method of producing 30 analgesia in a mammal comprising administering to a m~mm~l an analgesic efective amount of a narco~ic analge~ic selected from the group consisting of morphine, oxymorphone, oxycodone, hydromorphone and a pharmaceu-tically suitable salt o~ one of the above, and an anal-35 gesic effectiYe amount of nalbuphine or a pharmaceuticallysuitable salt thereof.
~ Q~
Brief Description of the Drawing The drawing is a graph showing the interaction of nalbuphine hydrochloride and morphine sulfate on the phenyl-~-benzoquinone induced writhing in mice.
Detailed Description of the Invention Nalbuphine, which has the chemical name (-)-17-(cyclobutylmethyl)-4,5~-epoxymorphinan-3,6a, 14-triol, and its preparation are described in U.S. Patent 3,393,197.
It and the narcotic analgesics useful in the analgesic compositions of the present invention, i.e., morphine, oxymorphone, oxycodone and hydromorphone, all are well-known to have analgetic properties in man and other mA m~n~ 1 S .
When the term nalbuphine or the name of one of the above narcotic analgesics is used herein, it is to be understood that any of the pharmaceutically suitable salts thereof are included by the term. Such salts include the hydrochlorides, hydrobromides, hydroiodides, sulfates, bisulfates, nitrates, citrate~ ta~trates, bitartrates, phosphates, malates, maleates, fumarates, succinates, acetates and pamoates.
The eompositions of the presert i~vention are made into a dosage form to be taken orally or ~ ~l~e~dlly (preferably orally) by mixing an effective analgesic ~nt of 2; nalbuphine with an effective analgesic amount of mor-phine, oxymorphone, oxycodone or hydromorphone. The amount of ~lhlrhin~ in each dosage form whether to be administered orally or parenterally will be about 1-100 mq, preferably about 5-60 mg while the amount of narcotic analgesic will be as follows:
(a) about 1-100 mg, preferably about 5-60 mg, of morphinei (b) about 0.1-~Q mg, preferably about 0.5-10 mg, of oxymorphone;
(c) about~.5-50 mg, preferably about 2.5 30 mg, of oxycodone; or (d) about 0.1-20 mg, preferably about ~.5-10 mg, of hydromorphone.
The compositions of the present in~ention can be formulated into any of the known pharmaceutical forms suitable fGr oral administration. The term "oral dosage form" includes solid compositions for oral admin-istration in unit dosage form, eg. tablets, capsules granules, powders and cachets or in liquid dosage form e~. eli~irs, sy~uPs and susPensIons. Bulk Powders of fixed composition ~or subdivision into solutions, emulsions or suspensions of the composition are also included in the definition.
The oral co~positions of tne present invention can also optionally contain other ingredients, eg. acetylsali~lic acid acetaminopben, phenacetin, caffeine, antihistamines, homatropine, methylbromide, phenyltoloxamine citrate, barbiturates, or mix~ures ~hereof. The com~ositions can also contain o~her CII narcotics such as fentanyl, codeine, meperidine, methadone, etc.
Combining nalbuphine with morphine, oxymorphone, oxycodone, or hydromorphone in a composition m~intains 2~ the excellent analgesia of the ~arcotic while reducing or eliminating the respiratory depression and euphoria usually associated with narcotics. This is surprising since nalbuphine is known to have narcotic antagonistic properties as well as analgesic properties. Thus, a~
advantage o~ the composition is excellent analgesia with reduced side e~fects. A further advantage is its greatly reduced susceptibility to abuse by a narcotic addict who tries to feed his habit by the parenteral route (ma;nl;ning). Nalbuphine is at least as long acting as, ~or example, morphine. Thus, as long as the nalbuphine is in a m~mmAl'5 system, it will override the respiratory depression and euphoric proper ies of the narcotic without ~im;ni shing analgesia. In otber woras, an addict's attempt at mainlining will produce 35 withdrawal for a long time. These aforesaid advantages also provide a safety factor in that large doses of the p~werf~l narcotic analgesics can be gi~en safely for ~2~
analgesia in combination with nalbuphine and not cause significant respirator~ depression later since the nal-buphine will always be present to protect the respira-tory centers. This is particularly advantageous in the administration of anesthesia.
The present invention also provides a me~hod of producing analgesia in a mammal by administering morphine, oxymorphone, oxycodone or h~dromorphone in combination with nalbuphine in analgesie effective amounts. This administration can be simultaneous as will be the case when the pneferred oral analgesic composition of the present in~ention is administered to the mammal. How~ver, administration can also be sequential, i.e., adminis-tration of the narcotic analgesic followed later by nalbuphine, or vice versa, as well as parenteral.
Parenteral, se~uential administration will be a parti-cularly useful method in anesthesia where the narcotic analgesic can be given i.v. in the usual manner followed by nalbuphine yiv~n i.~. to re~erse respiratory depres-sion if the need arises. Of course, ~he optimum dose for parenteral ~dm;n;stration will change somewhat from the oral dose; however, these will be well known to those skilled in the pharmaceutical art.
Dosage Forms 2; The active ingredients can be administere~ orally in solid do~age forms, eg. ca~$u~es, t~le~s, ~nd powders, or in li~uid dosage forms, eg. elixirs, syrups and suspensions; they ean also be administered parenterally, in sterile liquid dosage forms.
Gelatin capsules can contain the active ingredients and powdered carriers, eg. lactose,-sucrose, man~i-tol, ~tarch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents-can be used to make compressed tablets. Both tablets and 35 capsules can be manufactured as s~stained release products ~os~
to provide for continuous release of medication over a period o~ hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and pxotect the tablet from the atmosphere, or enteric S coated for selective disintegration in the gastroin-testinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, watex, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols eg. pr~ylene ~ly~ol or ~:lyethylene glycols are suitable carriers or parenteral solutions.
Solution for parenteral administration contain pre-15 ferably a water soluble salt of the actiYe ingredient, suitable stabilizins agerts, and if necessary, buffer substances. Antioxidizing agents such as sodium bi-sulfite, sodium sulfite, or ascorbic acid either alone ~ ~ or combined are suitable stabilizing agents. Also used 20 are citric acid and sodium EDTA. In addition, paren-teral solutions can contain preservatives, eg. ben-zalkonium chloride, methyl or propyl-paraben, and chlorobutanol.
Suitable phar~aceutical carriers are described in 25 Remington's Pharmaceutical Sciences, E. W. Martin, a stan~ard reference text in this ~ield.
~ seful pharmaceutical dosage-forms for administra-tion of the compounds of ~his invention can be illustrated as follows:
t~AP~;ULES
A large number of unit cPpsules can be prepared by filling standard two-piece hard gelatin capsules each wi~h 1~ mg nalbuphine or a pharmaceutically suitable salt and 10 mg morphine or a pharmaceutically suitable 35 salt. Other inactive components of the formulation consist of 150.5 mg lactose, 90 mg microcrystalline cellulose (as diluents), 1.5 mg colloidal silicon dioxide (slidant), 30 mg corn starch (disintegrant) and 3 mg magne~ium stearate (lubricant).
CAPSULES
A mixture of active ingredients in soybean oil can ~e prepared and injected by means of a positi~e displacement pump into gelatin to form soft gelatin capsules con~in;~s 15 mg nalbuphine and 10 mg ~orphine 10 as active ingredients. The capsules can be washed in petroleum ether and dried.
TABLETS
A large number of tablets can be prepared by con-ventional pr~ceduxes so that dosage unit is 15 mg nal-15 buphine or a pharmaceutically suitable salt and 10 mgmorphine or a pharmaceutically suitable saltO Other components being 150 mg lactose and 90.5 mg microcry-stalline cellulose (diluents), 30 mg starch (disinte-gran ) and 3~5 mg stearic acid, 1.5 mg magnesium 20 stearate (lubricant~. Appropriate coatings may be applied to increase pala~ability or delay absorption.
INJECTABLES:
1. A parenteral composition suitable for admin-istration by injection can be prepared by dissolviny i-100 mg of nalbuphine or a pharmaceutically suitable salt and 1-100 of morphine or a pharmaceutically suit-able salt form in an a~ueous solution. Cosolvents eg.propylene glycol may be added along with a preser-vative e.g., parabens, buffer e.g. citrate, stabi-30 lizing agents e.g. ~x~um met~h;~lfite and EDI~ um chloride or other agen~s may be used to adjust isotonicity. The r~ting solution can be term;nal~y sterilized or sterilized by fi.~ tration.
SUSPENSION:
1. An aqueous suspension is prepared for oral administration such that each 5 milliliters contains 1 to 100 mg of finely dlvided nalbuphine or a pharma-ceutically suitable salt and 1-100 mg morphine or a pharmaceutically suitable salt suspended with a suit-able agent, eg. sodium carboxymethyl cellulose.
Protective colloide e. g. nethylcellulose, surfac-tants e.gO Tween*80, preservatives e.g. sodium benzoate, viscosity enhancing agents e.g. sorbital, fla~oring agents e.g. vanillin, stabilizers e.g. EDTA along with 10 a buffer e.g. pho~pha~e and s~ er may be required to prepare a suitable formulation.
~APSULES
~ large number of unit capsules can be prepared by filling standard wo-piece hard gelatin capsules et~h 15 with 15 mg nalbuphine or a p~r~ceutically sultable s~lt and 10 mg ofox~ ,t~l.,.P or a pharmaceutically suitable salt. Other inactive components of the formulation consist of 150.5 mg lactose, 90 mg microcrystalline cellulose (as diluents), 1.5 mg coll~idal silicon 20 dioxide (glidant), 30 mg corn starch (disintegrant) and 3 mg magnesium stearate (lubricant).
CAPSULES
A mixture o acti~e ingredients in soybean oil can be prepared and injected by means of a positive 25 displacement pump into gelatin to form so~t gelatin caps~les cont~in;ng 15 mg nalbuphine and 10 mg G~y~ ]~v"e as actiYe ingredients. The capsules can be washed in petroleum ether and dried.
TABLETS
A large number of t~blets can be prepared by con-ventional procedures so that dosage unit is 15 mg nal-buphine or a pharmaceutically suitable salt and 10 mg oxy-morphon~ or a E~h~ceutically suitable salt. Other comp~nents being 150 m~ lactose and 90.5 mg microcry-35 stalline cellulose ~diluents), 30 m~ starch (disinte-*denotes trade mark ~zoaso~
grant) and 3.5 mg stearic acid, 1.5 mg magnesium stearate (lubrican~). Appropriate coatings m~y be applied to increase palatability or delay absorption.
INJECTABLES:
2. A paxenteral composition suitable for admin-istration by injection can be prepared by dissolving 1-100 mg of nalbuphine or a pharmaceutically suitable salt and 0.1-20 mg of ox~l,u~ ol,e or a pharmaceutically suit~
able salt form in an a~ueous solution. Cosol~ents lD eg~propyl~ne glycol may ~e added along with a pr ser-vati~e e.g.! parabens, buffer e.g. citrate, sta~i-lizing agents e.g. sodium metabisulfite and EDTA.
Sodium chloride or other agents may be used to adjust isotonicity. The resulting solution can be terminally sterili7ed or sterilized by filtration.
SUSPENSI ON:
2. An a~ueous suspension is prepared for oral administration such that each 5 milliliters contains `` 1 to 100 mg of ~inely dlvided nalbuphine or a pharma-ceutically suitable salt and ~ 2D mg oxymorphone or a pharmaceutically suitable salt suspended with a suit-able agent such as sodium carboxymethyl cellulose.
Protective colloide e.g. methylcellulose, surfac-tants e.g. Tween 80r preser~atives e.g. sodium benzoate, 25 viscosity enhancing age~ts e,g. sorbital, fl~oring agents e.g. vanillin, stabili2ers e.g. EDTA along wi~h a buf~er e.g. phosphate and sweet~ may be required to prepare a suitable formulation.
C~P~ULES
~ large number of ~nit capsules can be prepaxed by filling standard two-piece hard gelatin capsules each wi~h 1~ mg nalbuphine or a pharmaceutically suitable salt and 5 mg oxyco~one or a pharmaceutically suitable salt. Other inactive components of the formulation `~ ~2q~
o 10 consist of 155~5 mg lactose, 90 mg microcrystalline cellulose (as diluents), 1.5 mg colloidal silicon dioxide (glidant), 30 mg corn starch (disin~egrant~
and 3 mg magnesiu~, SteArate (lubricant).
CAPSULES
A mixture of active ingredients in soybean oil can be preparea and injected by means of a positive displacement pump into gelatin to form so~t gelatin capsules ContA; n; ng 15 mg nalbuphine and 5 mg oxycodone as acti~e ingredients. The capsules can be washed in petroleum ether and dried.
TABLETS
A large number of tablets can be prepared by con-ventional procedures so that do~age unit is 15 mg nal~
buphine or a pharmaceuti~ally suitable salt a~d 5 mg o~y~ne or a rh~r~ceutically suitable salt. Other components being 155 mg lactose and 90.5 mg microcry-stalline cellulose (diluents), 30 mg starch (disinte-grant) and 3.5 mg stearic acid, 1.5 mg magnesium stearate (lubricant). Appropriate coatings may be applied to increase palatability or delay absorption.
INJ~CTABLES:
U.S. Patent 4,237,140, issued to J. R. Dudzinski on December 2, 1980, describes an analgesic mixture of nalbuphine and acetoaminophen. U.S. Patent 4,282,215, issued to J. R. ~udzinski and W. K. Schmidt on August 4, 30 l9Bl, describes an analgesic mixture of nalbuphine and aspirin.
Morphine, oxymorphone, oxycodone and hydromorphone are well known strong narcotic analgesics which can, unfortunately, be addicti~7e and/or euphoric a~d subjected 35 to abuse by parenteral administration. Furthermore, ,~
~2~)~5(~
o these narcotics tend to produce respiratory depression in patients, especially when given as part of anesthesia.
One attempt to m; nimj ze abuse of these and other strong analgesic agents is described in U.S. Patent 3,773,955, issued to Pachter and Gordon on November 20, 1973 (also U.K. Patent 1,353,815) wherein A combination of a parenterally efective but orally inef~ective dose of naloxone and an analgetic agent gives an orally effective, but parenterally inactive analgesic composition. While 10 naloxone will overcome the narcotic analgesic upon parenteral administration to reduce respiratory depres-sion, euphoria and other side effects, it also eliminates analgesia. Such a composition upon oral administxation provides analgesia, but the naloxone is inactive orally 15 such that there is no reduction in side effects.
B. J. Kripke et al., J. of the International Anesthesia Research Society, Vol. 55, No. 6, pages 800-805 Nov.-Dec. 1976, describe naloxone antagonism after narcotic-supplemented anesthesia.
Summary of the Invention According to the present invention, there is provided an analgesic composition which comprises an analgesic effective amount of a narcotic analgesic selected from the group consisting of morphine, 2S oxymorphone, oxycodone, hydromorphone and a pharma-ceutically suitable salt of one o the above, and an analgesic effective amount of nalbuphine or a phar-maceutically suitable salt thereof.
There is also provided a method of producing 30 analgesia in a mammal comprising administering to a m~mm~l an analgesic efective amount of a narco~ic analge~ic selected from the group consisting of morphine, oxymorphone, oxycodone, hydromorphone and a pharmaceu-tically suitable salt o~ one of the above, and an anal-35 gesic effectiYe amount of nalbuphine or a pharmaceuticallysuitable salt thereof.
~ Q~
Brief Description of the Drawing The drawing is a graph showing the interaction of nalbuphine hydrochloride and morphine sulfate on the phenyl-~-benzoquinone induced writhing in mice.
Detailed Description of the Invention Nalbuphine, which has the chemical name (-)-17-(cyclobutylmethyl)-4,5~-epoxymorphinan-3,6a, 14-triol, and its preparation are described in U.S. Patent 3,393,197.
It and the narcotic analgesics useful in the analgesic compositions of the present invention, i.e., morphine, oxymorphone, oxycodone and hydromorphone, all are well-known to have analgetic properties in man and other mA m~n~ 1 S .
When the term nalbuphine or the name of one of the above narcotic analgesics is used herein, it is to be understood that any of the pharmaceutically suitable salts thereof are included by the term. Such salts include the hydrochlorides, hydrobromides, hydroiodides, sulfates, bisulfates, nitrates, citrate~ ta~trates, bitartrates, phosphates, malates, maleates, fumarates, succinates, acetates and pamoates.
The eompositions of the presert i~vention are made into a dosage form to be taken orally or ~ ~l~e~dlly (preferably orally) by mixing an effective analgesic ~nt of 2; nalbuphine with an effective analgesic amount of mor-phine, oxymorphone, oxycodone or hydromorphone. The amount of ~lhlrhin~ in each dosage form whether to be administered orally or parenterally will be about 1-100 mq, preferably about 5-60 mg while the amount of narcotic analgesic will be as follows:
(a) about 1-100 mg, preferably about 5-60 mg, of morphinei (b) about 0.1-~Q mg, preferably about 0.5-10 mg, of oxymorphone;
(c) about~.5-50 mg, preferably about 2.5 30 mg, of oxycodone; or (d) about 0.1-20 mg, preferably about ~.5-10 mg, of hydromorphone.
The compositions of the present in~ention can be formulated into any of the known pharmaceutical forms suitable fGr oral administration. The term "oral dosage form" includes solid compositions for oral admin-istration in unit dosage form, eg. tablets, capsules granules, powders and cachets or in liquid dosage form e~. eli~irs, sy~uPs and susPensIons. Bulk Powders of fixed composition ~or subdivision into solutions, emulsions or suspensions of the composition are also included in the definition.
The oral co~positions of tne present invention can also optionally contain other ingredients, eg. acetylsali~lic acid acetaminopben, phenacetin, caffeine, antihistamines, homatropine, methylbromide, phenyltoloxamine citrate, barbiturates, or mix~ures ~hereof. The com~ositions can also contain o~her CII narcotics such as fentanyl, codeine, meperidine, methadone, etc.
Combining nalbuphine with morphine, oxymorphone, oxycodone, or hydromorphone in a composition m~intains 2~ the excellent analgesia of the ~arcotic while reducing or eliminating the respiratory depression and euphoria usually associated with narcotics. This is surprising since nalbuphine is known to have narcotic antagonistic properties as well as analgesic properties. Thus, a~
advantage o~ the composition is excellent analgesia with reduced side e~fects. A further advantage is its greatly reduced susceptibility to abuse by a narcotic addict who tries to feed his habit by the parenteral route (ma;nl;ning). Nalbuphine is at least as long acting as, ~or example, morphine. Thus, as long as the nalbuphine is in a m~mmAl'5 system, it will override the respiratory depression and euphoric proper ies of the narcotic without ~im;ni shing analgesia. In otber woras, an addict's attempt at mainlining will produce 35 withdrawal for a long time. These aforesaid advantages also provide a safety factor in that large doses of the p~werf~l narcotic analgesics can be gi~en safely for ~2~
analgesia in combination with nalbuphine and not cause significant respirator~ depression later since the nal-buphine will always be present to protect the respira-tory centers. This is particularly advantageous in the administration of anesthesia.
The present invention also provides a me~hod of producing analgesia in a mammal by administering morphine, oxymorphone, oxycodone or h~dromorphone in combination with nalbuphine in analgesie effective amounts. This administration can be simultaneous as will be the case when the pneferred oral analgesic composition of the present in~ention is administered to the mammal. How~ver, administration can also be sequential, i.e., adminis-tration of the narcotic analgesic followed later by nalbuphine, or vice versa, as well as parenteral.
Parenteral, se~uential administration will be a parti-cularly useful method in anesthesia where the narcotic analgesic can be given i.v. in the usual manner followed by nalbuphine yiv~n i.~. to re~erse respiratory depres-sion if the need arises. Of course, ~he optimum dose for parenteral ~dm;n;stration will change somewhat from the oral dose; however, these will be well known to those skilled in the pharmaceutical art.
Dosage Forms 2; The active ingredients can be administere~ orally in solid do~age forms, eg. ca~$u~es, t~le~s, ~nd powders, or in li~uid dosage forms, eg. elixirs, syrups and suspensions; they ean also be administered parenterally, in sterile liquid dosage forms.
Gelatin capsules can contain the active ingredients and powdered carriers, eg. lactose,-sucrose, man~i-tol, ~tarch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents-can be used to make compressed tablets. Both tablets and 35 capsules can be manufactured as s~stained release products ~os~
to provide for continuous release of medication over a period o~ hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and pxotect the tablet from the atmosphere, or enteric S coated for selective disintegration in the gastroin-testinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, watex, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols eg. pr~ylene ~ly~ol or ~:lyethylene glycols are suitable carriers or parenteral solutions.
Solution for parenteral administration contain pre-15 ferably a water soluble salt of the actiYe ingredient, suitable stabilizins agerts, and if necessary, buffer substances. Antioxidizing agents such as sodium bi-sulfite, sodium sulfite, or ascorbic acid either alone ~ ~ or combined are suitable stabilizing agents. Also used 20 are citric acid and sodium EDTA. In addition, paren-teral solutions can contain preservatives, eg. ben-zalkonium chloride, methyl or propyl-paraben, and chlorobutanol.
Suitable phar~aceutical carriers are described in 25 Remington's Pharmaceutical Sciences, E. W. Martin, a stan~ard reference text in this ~ield.
~ seful pharmaceutical dosage-forms for administra-tion of the compounds of ~his invention can be illustrated as follows:
t~AP~;ULES
A large number of unit cPpsules can be prepared by filling standard two-piece hard gelatin capsules each wi~h 1~ mg nalbuphine or a pharmaceutically suitable salt and 10 mg morphine or a pharmaceutically suitable 35 salt. Other inactive components of the formulation consist of 150.5 mg lactose, 90 mg microcrystalline cellulose (as diluents), 1.5 mg colloidal silicon dioxide (slidant), 30 mg corn starch (disintegrant) and 3 mg magne~ium stearate (lubricant).
CAPSULES
A mixture of active ingredients in soybean oil can ~e prepared and injected by means of a positi~e displacement pump into gelatin to form soft gelatin capsules con~in;~s 15 mg nalbuphine and 10 mg ~orphine 10 as active ingredients. The capsules can be washed in petroleum ether and dried.
TABLETS
A large number of tablets can be prepared by con-ventional pr~ceduxes so that dosage unit is 15 mg nal-15 buphine or a pharmaceutically suitable salt and 10 mgmorphine or a pharmaceutically suitable saltO Other components being 150 mg lactose and 90.5 mg microcry-stalline cellulose (diluents), 30 mg starch (disinte-gran ) and 3~5 mg stearic acid, 1.5 mg magnesium 20 stearate (lubricant~. Appropriate coatings may be applied to increase pala~ability or delay absorption.
INJECTABLES:
1. A parenteral composition suitable for admin-istration by injection can be prepared by dissolviny i-100 mg of nalbuphine or a pharmaceutically suitable salt and 1-100 of morphine or a pharmaceutically suit-able salt form in an a~ueous solution. Cosolvents eg.propylene glycol may be added along with a preser-vative e.g., parabens, buffer e.g. citrate, stabi-30 lizing agents e.g. ~x~um met~h;~lfite and EDI~ um chloride or other agen~s may be used to adjust isotonicity. The r~ting solution can be term;nal~y sterilized or sterilized by fi.~ tration.
SUSPENSION:
1. An aqueous suspension is prepared for oral administration such that each 5 milliliters contains 1 to 100 mg of finely dlvided nalbuphine or a pharma-ceutically suitable salt and 1-100 mg morphine or a pharmaceutically suitable salt suspended with a suit-able agent, eg. sodium carboxymethyl cellulose.
Protective colloide e. g. nethylcellulose, surfac-tants e.gO Tween*80, preservatives e.g. sodium benzoate, viscosity enhancing agents e.g. sorbital, fla~oring agents e.g. vanillin, stabilizers e.g. EDTA along with 10 a buffer e.g. pho~pha~e and s~ er may be required to prepare a suitable formulation.
~APSULES
~ large number of unit capsules can be prepared by filling standard wo-piece hard gelatin capsules et~h 15 with 15 mg nalbuphine or a p~r~ceutically sultable s~lt and 10 mg ofox~ ,t~l.,.P or a pharmaceutically suitable salt. Other inactive components of the formulation consist of 150.5 mg lactose, 90 mg microcrystalline cellulose (as diluents), 1.5 mg coll~idal silicon 20 dioxide (glidant), 30 mg corn starch (disintegrant) and 3 mg magnesium stearate (lubricant).
CAPSULES
A mixture o acti~e ingredients in soybean oil can be prepared and injected by means of a positive 25 displacement pump into gelatin to form so~t gelatin caps~les cont~in;ng 15 mg nalbuphine and 10 mg G~y~ ]~v"e as actiYe ingredients. The capsules can be washed in petroleum ether and dried.
TABLETS
A large number of t~blets can be prepared by con-ventional procedures so that dosage unit is 15 mg nal-buphine or a pharmaceutically suitable salt and 10 mg oxy-morphon~ or a E~h~ceutically suitable salt. Other comp~nents being 150 m~ lactose and 90.5 mg microcry-35 stalline cellulose ~diluents), 30 m~ starch (disinte-*denotes trade mark ~zoaso~
grant) and 3.5 mg stearic acid, 1.5 mg magnesium stearate (lubrican~). Appropriate coatings m~y be applied to increase palatability or delay absorption.
INJECTABLES:
2. A paxenteral composition suitable for admin-istration by injection can be prepared by dissolving 1-100 mg of nalbuphine or a pharmaceutically suitable salt and 0.1-20 mg of ox~l,u~ ol,e or a pharmaceutically suit~
able salt form in an a~ueous solution. Cosol~ents lD eg~propyl~ne glycol may ~e added along with a pr ser-vati~e e.g.! parabens, buffer e.g. citrate, sta~i-lizing agents e.g. sodium metabisulfite and EDTA.
Sodium chloride or other agents may be used to adjust isotonicity. The resulting solution can be terminally sterili7ed or sterilized by filtration.
SUSPENSI ON:
2. An a~ueous suspension is prepared for oral administration such that each 5 milliliters contains `` 1 to 100 mg of ~inely dlvided nalbuphine or a pharma-ceutically suitable salt and ~ 2D mg oxymorphone or a pharmaceutically suitable salt suspended with a suit-able agent such as sodium carboxymethyl cellulose.
Protective colloide e.g. methylcellulose, surfac-tants e.g. Tween 80r preser~atives e.g. sodium benzoate, 25 viscosity enhancing age~ts e,g. sorbital, fl~oring agents e.g. vanillin, stabili2ers e.g. EDTA along wi~h a buf~er e.g. phosphate and sweet~ may be required to prepare a suitable formulation.
C~P~ULES
~ large number of ~nit capsules can be prepaxed by filling standard two-piece hard gelatin capsules each wi~h 1~ mg nalbuphine or a pharmaceutically suitable salt and 5 mg oxyco~one or a pharmaceutically suitable salt. Other inactive components of the formulation `~ ~2q~
o 10 consist of 155~5 mg lactose, 90 mg microcrystalline cellulose (as diluents), 1.5 mg colloidal silicon dioxide (glidant), 30 mg corn starch (disin~egrant~
and 3 mg magnesiu~, SteArate (lubricant).
CAPSULES
A mixture of active ingredients in soybean oil can be preparea and injected by means of a positive displacement pump into gelatin to form so~t gelatin capsules ContA; n; ng 15 mg nalbuphine and 5 mg oxycodone as acti~e ingredients. The capsules can be washed in petroleum ether and dried.
TABLETS
A large number of tablets can be prepared by con-ventional procedures so that do~age unit is 15 mg nal~
buphine or a pharmaceuti~ally suitable salt a~d 5 mg o~y~ne or a rh~r~ceutically suitable salt. Other components being 155 mg lactose and 90.5 mg microcry-stalline cellulose (diluents), 30 mg starch (disinte-grant) and 3.5 mg stearic acid, 1.5 mg magnesium stearate (lubricant). Appropriate coatings may be applied to increase palatability or delay absorption.
INJ~CTABLES:
3. A parenteral compos~tio~ suitable ~or admin-istration by injection can be prepared by dissolving ~5 i-100 mg of ~albuphine or a pharmaceutically suitable salt and 0.5-50 mg oxycodone or a pharmaceutically suit~
able salt form in an aqueous solution. Cosolvents eg. propylene glycol may be added along with a preser-YatiYe e.g., parabens, buffer e.g. citrate, stabi-3~ lizing agents e.g. so~ium metabisulfite and EDTA.
Sodium chloride or other agents may be used to adjust isotonicity~ The resulting solution can be terminally sterilized or sterilized by filtration.
SUSPENSION:
3. An aqueous suspension is prepared for oral ~;~0~5~
o 11 administration such that each 5 milliliterq contains 1 to 100 mg of finely dlvided nalbuphine or a pharma-ceutically suitable salt and 0;5-~0 mg oxycodone or a pharmaceutically suitable salt suspended with a suit-able agent, eg. sodium carboxymethyl cellulose.
Protective colloide e.g. methylcellulose, surfac-tants e.g. Tween 80, preservati~es e.g. sodium benzoate, ~iscosity enhancing agents e.g. sorbital, flavoring agents e.g. vanillin, stabili~ers e.g. EDTA along with a buffer e.g. phosphate and ~ may be required to prepare a suitable formulation.
~AP~ S
A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each 15 with 15 mg nalbuphine or a pharmaceutically suitable salt and 4 my hy~ ~"e or a pharmaceutically suitable salt. O~her inactive components of the ~ormulation consist of i56.5 mg lactose, 90 mg microcrystalline cellulose (as diluents~, 1.5 mg colloidal silicon 20 dioxide (glid~nt), 30 mg corn starch (disintegrant) and 3 mg magnesium stearate (lubricant).
~psuT-~s A mixture of acti~e ingredients in soybean oil can be prepared and injected by means of a positive 25 displacement pump into gelatin to form so~t gelatin capsul~s cont~j~; ng 15 my nalbuphine and 4 mg h~ ~,e 3S acti~e ingredients. The capsules can be washed in petroleum ether and dried.
TABLETS
A large ~umber of tablets can be prepared by c~n-ventional procedures so that dosage unit is 15 mg nal-buphine or a pharmaceutically sui~able sal~ and 4 mg h~dx~
morphone or a pharmaceutically suitable salt~ Other components being 156 mg lactose and 90.5 mg microcry-35 stalline cellulose (diluents), 30 mg st~rch tdisinte-grant) and 3.5 mg stearic acid, l.S mg magnesium ~2~(~5~1~
s~earate (lubricant). Appropriate coatings may be applied to increase palatability or delay absorption.
INJECTABLES:
able salt form in an aqueous solution. Cosolvents eg. propylene glycol may be added along with a preser-YatiYe e.g., parabens, buffer e.g. citrate, stabi-3~ lizing agents e.g. so~ium metabisulfite and EDTA.
Sodium chloride or other agents may be used to adjust isotonicity~ The resulting solution can be terminally sterilized or sterilized by filtration.
SUSPENSION:
3. An aqueous suspension is prepared for oral ~;~0~5~
o 11 administration such that each 5 milliliterq contains 1 to 100 mg of finely dlvided nalbuphine or a pharma-ceutically suitable salt and 0;5-~0 mg oxycodone or a pharmaceutically suitable salt suspended with a suit-able agent, eg. sodium carboxymethyl cellulose.
Protective colloide e.g. methylcellulose, surfac-tants e.g. Tween 80, preservati~es e.g. sodium benzoate, ~iscosity enhancing agents e.g. sorbital, flavoring agents e.g. vanillin, stabili~ers e.g. EDTA along with a buffer e.g. phosphate and ~ may be required to prepare a suitable formulation.
~AP~ S
A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each 15 with 15 mg nalbuphine or a pharmaceutically suitable salt and 4 my hy~ ~"e or a pharmaceutically suitable salt. O~her inactive components of the ~ormulation consist of i56.5 mg lactose, 90 mg microcrystalline cellulose (as diluents~, 1.5 mg colloidal silicon 20 dioxide (glid~nt), 30 mg corn starch (disintegrant) and 3 mg magnesium stearate (lubricant).
~psuT-~s A mixture of acti~e ingredients in soybean oil can be prepared and injected by means of a positive 25 displacement pump into gelatin to form so~t gelatin capsul~s cont~j~; ng 15 my nalbuphine and 4 mg h~ ~,e 3S acti~e ingredients. The capsules can be washed in petroleum ether and dried.
TABLETS
A large ~umber of tablets can be prepared by c~n-ventional procedures so that dosage unit is 15 mg nal-buphine or a pharmaceutically sui~able sal~ and 4 mg h~dx~
morphone or a pharmaceutically suitable salt~ Other components being 156 mg lactose and 90.5 mg microcry-35 stalline cellulose (diluents), 30 mg st~rch tdisinte-grant) and 3.5 mg stearic acid, l.S mg magnesium ~2~(~5~1~
s~earate (lubricant). Appropriate coatings may be applied to increase palatability or delay absorption.
INJECTABLES:
4. A parenteral composition suitable ~or admin-istration by injection can be prepared by dissolYing 1-100 mg of nalbuphine or a pharmaceutically suitable salt and 0.1-20 mg oi hydromorphone or a pharmaceuticall~ suit-able salt form in an aqueous solution. Cosolvent~
eg.propylene glycol may be added along with a preser-vative e.g., parabens, bu~fer e.g, citr~te, ~tabi-lizing agents e.g. me~abis~lfite and EDTA. Sodlum chloride or other agents may be used to adjust isoto-nicity. Th~ resulting solution can be terminally sterilized for sterilized by filtration.
SUSPENSION:
4. An aqueous suspension is prepared for oral ~dministration such that each 5 milliliters contains 1 to 100 mg of finely divided nalbuphine or a pharma-ceutically suitable salt and 0.1 20 mg hydromorphone or a 20 pharmaceutically suitable salt suspen~ed with a suit-able agent, eg. sodium carboxymethyl cellulose.
Protr~tive colloide e.g. methylcellulose, surfac-tants e.g. Tween 80, preser~ati~es e.g. s~dium benzoate, viscosity enhancing agents e.g. sorbital, flavoring 2~ agents e.y. vanillin, stabilizers e.g. EDTA along with a buffer e.g. phosphate and s~ ~ may be required to prepare a suitable formulation.
Utilit~
Example 1 Test Methods The unexpectedly additive analgetic activity obtained in the method of the invention is evidenced by tests conducted on miceO ~ale CFl mice obtained from Charles River Breeding Laboratories, fasted fox 16-22 35 hours and weighing 18-~2 g at the time of test~ng are used thr~ughout. ~11 mice are dosed subcutaneously (s.c.~ with ~albuphine hydrochloride and/or morphine sulfate dissolved completely in saline and pre-mixed at the dose ratios stated. P. dosing volume of 10 ml/kg is used. All doses are coded and the test is perfoxmed under a code not known to the observer.
ANALGESIC ACTIVITY IN THE MOUSE
ANTIPHENYLQUINONE WRITHING TEST
A standard procedure for detecting and comparing the analgesic activity o~ different classes of analgesic drugs for which there is a good correlation with human 10 efficacy is the prevention of phenyl-p-benzoquinone induced writhing in mice (H. Blumberg et al.,; Proc.
Soc. Exp. Biol. Med. 118, 763-766, 1965?.
Mice, injected s.c. with variou~ doses of nalbuphine hydrochloride, morphine sulfate, combined doses of 15 nalbuphine hydrochloride and morphine sulfate, or vehicle, are inject~d intraperitoneally with a challenge dose of phenyl-~-benzoquinone. The phenyl-~-benzoquinone is prepared as a 0.1 mg/ml solution in 5% by volume of ethanol in water; the writhing dose is 1.25 mg/kg 20 injected at the rate of 0.25 ml/20 g. For scoring pur-poses a "writhe" is indicated by whole body stretching of contractions of the bdomen; mice are obserYed 10 minutes for the presence or absence of writhing beginning
eg.propylene glycol may be added along with a preser-vative e.g., parabens, bu~fer e.g, citr~te, ~tabi-lizing agents e.g. me~abis~lfite and EDTA. Sodlum chloride or other agents may be used to adjust isoto-nicity. Th~ resulting solution can be terminally sterilized for sterilized by filtration.
SUSPENSION:
4. An aqueous suspension is prepared for oral ~dministration such that each 5 milliliters contains 1 to 100 mg of finely divided nalbuphine or a pharma-ceutically suitable salt and 0.1 20 mg hydromorphone or a 20 pharmaceutically suitable salt suspen~ed with a suit-able agent, eg. sodium carboxymethyl cellulose.
Protr~tive colloide e.g. methylcellulose, surfac-tants e.g. Tween 80, preser~ati~es e.g. s~dium benzoate, viscosity enhancing agents e.g. sorbital, flavoring 2~ agents e.y. vanillin, stabilizers e.g. EDTA along with a buffer e.g. phosphate and s~ ~ may be required to prepare a suitable formulation.
Utilit~
Example 1 Test Methods The unexpectedly additive analgetic activity obtained in the method of the invention is evidenced by tests conducted on miceO ~ale CFl mice obtained from Charles River Breeding Laboratories, fasted fox 16-22 35 hours and weighing 18-~2 g at the time of test~ng are used thr~ughout. ~11 mice are dosed subcutaneously (s.c.~ with ~albuphine hydrochloride and/or morphine sulfate dissolved completely in saline and pre-mixed at the dose ratios stated. P. dosing volume of 10 ml/kg is used. All doses are coded and the test is perfoxmed under a code not known to the observer.
ANALGESIC ACTIVITY IN THE MOUSE
ANTIPHENYLQUINONE WRITHING TEST
A standard procedure for detecting and comparing the analgesic activity o~ different classes of analgesic drugs for which there is a good correlation with human 10 efficacy is the prevention of phenyl-p-benzoquinone induced writhing in mice (H. Blumberg et al.,; Proc.
Soc. Exp. Biol. Med. 118, 763-766, 1965?.
Mice, injected s.c. with variou~ doses of nalbuphine hydrochloride, morphine sulfate, combined doses of 15 nalbuphine hydrochloride and morphine sulfate, or vehicle, are inject~d intraperitoneally with a challenge dose of phenyl-~-benzoquinone. The phenyl-~-benzoquinone is prepared as a 0.1 mg/ml solution in 5% by volume of ethanol in water; the writhing dose is 1.25 mg/kg 20 injected at the rate of 0.25 ml/20 g. For scoring pur-poses a "writhe" is indicated by whole body stretching of contractions of the bdomen; mice are obserYed 10 minutes for the presence or absence of writhing beginning
5 minutes after receiving the phenyl-~-benzoquinone dose.
25 Each mouse is used only once, then discaxded.
All ED50 values are determi~ed numerically by the moving average method of Thompson (W.F. Thompson:
Bacteriological Rev. 11, 115-145, 1947) and 95~ confi-dence limits are calculated according to the method of 30 1itchfield and Wilcoxon (J. T. Litchfield, Jr. and F.
Wilcoxon: J. Phaxm. Exp. ~her. 96, 99-113, 1949). Ps used herein ED50 means the dosage at which 50% of the mice in a test group exhibit an analgesic response.
In order to study the interaction between nalbu-phine and morphine, precise dosage ratios of nalbuphine ï4 hydrochloride and morphine sulfate are selected. Fivecoded doses of each selected combination are studied for analgesic effectiveness at 10 minutes (the predicted peak efect time) using an experimental design which pexmits complete randomization of the separate dosage forms tested. Altogether 35 separate dosage forms are used and each form is represented in each exp~rimental session. The experiments are continued by running experimental sessions with an equal number of mice 10 being tested for each dosage group until the total number, N, of mice tested per group is 30.
The interaction of nalbuphine hydrochloride and morphine sulfate on phenyl-~-benzoquinone induced writh-ing in mice is demonstrated by the data in Table I and 15 in the Loewe isobologram (S. Loewe: Pharm. Rev. 9:
237-242, 1957) in the drawing. In the drawing, the diagonal li~e joining the ED50 ~alues of the two drugs qiven s~dtely rPrres~n~ the Ul~o~cal line for simple additivity of druq effects. The dashed lines on each side of the diagonal 20 line give the 95% confidence limits for this line of additivity. ED50's falling under the curve (between the line and the origin) would indicate potentiation (enhancement) of ef~ects while those outside of the curve would suggest antagonism between the two drugs.
25 The 5 diagonal lines radiating ~rom the origin represent the dose ratios of nalbuphine hydrochloride and mor~
phine sulfate used in mice receiving the combined drug dosages. The horizontal and vertical bars through each ED50 point are the 95~ confidence limits. The 30 drawing shows that in ~he method of the invention, com-positions having a weight ra~io of nalbuphine hydro-chloride to morphine sulfate from 1:0.137 to 1:3.43 give unexpectedly addi~ive analgesic activi~y since the 95~ confidence limits of the ED50 values for those 35 ratios overlap the line o~ additivity.
o O 1:~
TABI,E I
SU3CUTAN~OUS NAL3UPHINE/MORPHINE COMBINATIONS
IN THE MOUSE ANTIPHENYLQUINONE WRITHING TEST
(N = 30 Mice/Dose) DRUG ED50 AT 10 MIN.
CO~INATIONS DRUG DOSE (mq/kg) (95% Conf. Limits) Nalbuphine HCl: Nalbuphine Morphine % MICE Nalbuphine Morphine Morphine S04 HCl S04 8LOC~ED HCl SO~
Control (SalinP) O 0 10% _ _ s 0.543 0 37% 2.17 mg/kg O1 1:0 1.09 0 27~(1.55-(Nalbuphine 2.17 0 5043.03) HCl only) 4.34 0 67~
8.68 0 774 0.452 0.062 43% 1.01 mgikg 0.139 mg/kg 0.904 0.124 37% (0.694- (0.096-1:0.137 1.81 0.248 73~ 1.47) 0.202) 3.62 0.497 773 lS 7.23 0.993 733 0.362 0.124 20~ 0.902 mg/kg 0.310 mg/kg 0.723 0.2~8 40~ (0.657- (0.226-1:0.343 1.45 0.497 67% 1.24) 0.425) 2.89 0.993 93 5.79 1.99 93~
0.271 0.186 203 0.562 mg/kg 0.386 mg/kg 2~ 0.543 0.373 47~ (0.410- (0.281-u1 0.687 1.09 0.745 90% 0.771) 0.530) 2.17 1.~9 83 4.34 2,98 97~
0.181 0.248 274 0.460 mg/kg 0.632 mg/kg 0.362 0.497 50~ (0.344- (0.473-1:1.37 0.723 0.993 50~ 0.614~ 0.844) 1.45 1.99 93~
2.89 3.97 100%
0.0904 0.310 204 0.193 mg/kg 0.662 mg/kg 0.181 0.620 374 ~0.142- (0.485-1:3.43 0.362 1.24 9340.263) 0.903) 0.723 2.48 100%~
1.45 4.97 100%
0.373 0 17% - 0.832 mg/kg 30 0:1 0-745 0 37% (0~671-(Morphine S04 1.49 0 83% 1.03) only) 2.98 0 100~
os~
Example 2 The effect on anesthetic requirements and PaCO2 of combined doses o nalbuphine hydrochloride and morphine sulfate was evaluated in 18 Sprague-Dawley rats (200-350 gms). Anesthetic requirements for cyclopropane anesthe-tic of each rat was determined using a tail-clamp tech nique (Munson et al., l'he Effect of Acute Hypothyroidism and Hyperthyoidism on Cyclopropane Requirements (MAC) in Rats, Anesthesiology 1968; 29:1094-1098). After induc-10 tion of anesthesia with cyclopropane, the femoral arteryand vein were exposed and catheterized with PE50 tubing.
Ane~Ul~c requlrement as measured by ~;n;~A~ alveolar col~c~lk~Lion (M~C) was de~Prm;n~ and thereafter nalbuphine hydr~-chloride was administered intravenously. Upon comple-15 tion of control measurements, a bolus dose of0.04 m~ka of nalbuphine hydrochloride was ollowed with a constant in~usion of 0.1 m~/kg/min. After 45 minutes of continuous infusion, MAC was redetermined and arterial blood sampling repeated. The rat then received either 20 2, 4 or 8 mg/kg subcutaneously of morphine sulfate and after 30 minutes MAC and arterial blood gas (ABG) values ~PaO~, PaCO7, p~, HC03) redetermined.
The effect of morphine sulfate alone on anesthetic requirement and respiration was evaluated in a separate 25 group of five Sprague Dawley rats. After baseline measure-ments of anesthetic requirement (MAC) and ABG values, 2 mg/kg of morphine sulfate was given subcutaneously and ater 30 minutes, repeat measurements of anesthetic requirements and blood gases were carried out. For com-30 parative purposes, the anesthetic requirements from aprevious, similar study are included.
~0oso~
Statistical evaluation was carried out using analy-sis of variance comparing the groups of animals at differ-ent infusion rates of nalbuphine hydrochloride, and for the animals receiving the combined morphine sulfate-nalbuphine hydrochloride doses. The results are shownin Table II.
TABLE ~
Anesthetic and Respiratory Effect of Nalbuphine, Morphine and Nalbuphine plus Morphine MAC Reduction % PaC02 - mmHg (Mean ~ SEM) (Mean - SEM) Nalbuphine HCl 0.1 mg/kg/min. 21.62-0.69 48.31+1.07 Morphine SO
sc injectio~
2 mg/kg 22l0.55 53+1.05 2 mg/kg* 21.80~1.48 4 mg/kg* 32.63-0.98 8 mg/kg* 54.87+1.94 Nalbuphine HCL
0.1 mg/kg/min.
and Morphine SO4 sc iniection 2 mg/kg 22.60~1.29 49.67-~1.52 4 mg~kg 22.60+1~40 50.01~2.59 8 mg/kg 28.75+0.98 52.80+1.91 *From a pre~ious study.
~20~
As can be seen from Table II,the 22% reduction in anesthetic requirement by morphine alone in a dose of 2 mg/kg is comparable to that previously reported (Hoffman and DiFazio, Arch. Int. Pharmacodyn. Ther., 1970;
186: 261~268). Morphine at this dose produced a mean PaCO2 in the animals studied significantly higher than that seen with the comparable MAC reduction dose of nalbu-phine. The administration of morphine in a dose of 2 and 4 mg/kg during continuous nalbuphine infusion giving 10 peak nalbuphine anesthetic effect resulted in no further reduction in anesthetic requirement. A morphine dose of 8 mg/kg gave a further 5~ reduction in anesthetic require-ment. The PaCO2 did not increase significantly after the addition of morphine to nalbuphine except at 8 mg/kc.
Example 3 Nalbuphine hydrochloride was used as a supplement to oxymorphone or hydromorphone used in the anesthesia of human patients undergoing various types of surgery.
The nalbuphine was ~;niqtered paren~erally as each patient 20 was coming out of the anesthesia. The emergence was smooth, rapid and analgesia was maintained for 8-12 hGurs.
me respiratory effect of ~he n~lhllrh;net~as est~hl;~h~ ~y measure-ment of arterial PaCO2 using a blood gas analyzer~ell kn~n in respiratory therapy. Normal PaC02 is in the range of 3~42 2~ mmHg. All arterial samples were ob~ained on an inspired oxygen concentration of 100%. No patient was hypoxic, nor was there any significant shunt present. Respiratory acidosis present before the administration of nalbuphine was completely reversed, pH values being 7.35iO~6 after 0.1 mg/kg of nalbuphine.
The results are shown in Table III.
5Q~l TABLE II I PaCO~ PaC02 BEFORE AETER
WEIGHT N~RCOTIC TOq~L N~LBU- 0.1 TYPE OF ~U~kKY A~æ (KG) USED DCSE PHINE
5 ~ nu~ 55 85 Oxymorphone 15 mg.64 46 L. FemDral-Popli-62 74 H~Lvl,ul~lone 1~ mg. 69 47 teal graft F~rlor~tor~ Lapor- 45 48 Ox~ll~L~lu~le 6 mg. 63 42 abomy Turb 72 68 OxymDrphone 7.5 mg. 66 45 10~h~nm;r~l Hyster- 48 78 Hy~,u,~bJlle 10.5 mg. 70 41 ectomy Cholestectomy 52 89 Hydr~mDrphone 14 ~g. 61 43 Aortic Tube graft 57 83 OxymDrphone 8.0 mg. 67 44 Laryngeck~y ~7 96 H~ one 16 mg.68 43 Bilroth I 34 59 OX~ rL1~ 7.5 m~. 59 46 ~hor~co~ 59 77 Ox~,uL~ e 13.5 mg. 62 40 Bcwel Resection66 71 Hydlw~ e 9.0 mg. 57 45 ~h~m;n~l Hyster-48 70 Q~rphone 7.5 mg. 67 46 ectomy Choles~ 52 75 Hydromorphone 8.0 ms. 66 43 20~Yrl~r~toxy Lapor- 44 63 O~ ~nP9.0 mg. 58 47 atcmy ~u*~ Fusion 38 73 ~ rphone 12 mg.69 44 As can be seen from Table III,respixatory depression 2;resulting from the narcotic was xeversed in all cases after the administration of nalbuphine.
25 Each mouse is used only once, then discaxded.
All ED50 values are determi~ed numerically by the moving average method of Thompson (W.F. Thompson:
Bacteriological Rev. 11, 115-145, 1947) and 95~ confi-dence limits are calculated according to the method of 30 1itchfield and Wilcoxon (J. T. Litchfield, Jr. and F.
Wilcoxon: J. Phaxm. Exp. ~her. 96, 99-113, 1949). Ps used herein ED50 means the dosage at which 50% of the mice in a test group exhibit an analgesic response.
In order to study the interaction between nalbu-phine and morphine, precise dosage ratios of nalbuphine ï4 hydrochloride and morphine sulfate are selected. Fivecoded doses of each selected combination are studied for analgesic effectiveness at 10 minutes (the predicted peak efect time) using an experimental design which pexmits complete randomization of the separate dosage forms tested. Altogether 35 separate dosage forms are used and each form is represented in each exp~rimental session. The experiments are continued by running experimental sessions with an equal number of mice 10 being tested for each dosage group until the total number, N, of mice tested per group is 30.
The interaction of nalbuphine hydrochloride and morphine sulfate on phenyl-~-benzoquinone induced writh-ing in mice is demonstrated by the data in Table I and 15 in the Loewe isobologram (S. Loewe: Pharm. Rev. 9:
237-242, 1957) in the drawing. In the drawing, the diagonal li~e joining the ED50 ~alues of the two drugs qiven s~dtely rPrres~n~ the Ul~o~cal line for simple additivity of druq effects. The dashed lines on each side of the diagonal 20 line give the 95% confidence limits for this line of additivity. ED50's falling under the curve (between the line and the origin) would indicate potentiation (enhancement) of ef~ects while those outside of the curve would suggest antagonism between the two drugs.
25 The 5 diagonal lines radiating ~rom the origin represent the dose ratios of nalbuphine hydrochloride and mor~
phine sulfate used in mice receiving the combined drug dosages. The horizontal and vertical bars through each ED50 point are the 95~ confidence limits. The 30 drawing shows that in ~he method of the invention, com-positions having a weight ra~io of nalbuphine hydro-chloride to morphine sulfate from 1:0.137 to 1:3.43 give unexpectedly addi~ive analgesic activi~y since the 95~ confidence limits of the ED50 values for those 35 ratios overlap the line o~ additivity.
o O 1:~
TABI,E I
SU3CUTAN~OUS NAL3UPHINE/MORPHINE COMBINATIONS
IN THE MOUSE ANTIPHENYLQUINONE WRITHING TEST
(N = 30 Mice/Dose) DRUG ED50 AT 10 MIN.
CO~INATIONS DRUG DOSE (mq/kg) (95% Conf. Limits) Nalbuphine HCl: Nalbuphine Morphine % MICE Nalbuphine Morphine Morphine S04 HCl S04 8LOC~ED HCl SO~
Control (SalinP) O 0 10% _ _ s 0.543 0 37% 2.17 mg/kg O1 1:0 1.09 0 27~(1.55-(Nalbuphine 2.17 0 5043.03) HCl only) 4.34 0 67~
8.68 0 774 0.452 0.062 43% 1.01 mgikg 0.139 mg/kg 0.904 0.124 37% (0.694- (0.096-1:0.137 1.81 0.248 73~ 1.47) 0.202) 3.62 0.497 773 lS 7.23 0.993 733 0.362 0.124 20~ 0.902 mg/kg 0.310 mg/kg 0.723 0.2~8 40~ (0.657- (0.226-1:0.343 1.45 0.497 67% 1.24) 0.425) 2.89 0.993 93 5.79 1.99 93~
0.271 0.186 203 0.562 mg/kg 0.386 mg/kg 2~ 0.543 0.373 47~ (0.410- (0.281-u1 0.687 1.09 0.745 90% 0.771) 0.530) 2.17 1.~9 83 4.34 2,98 97~
0.181 0.248 274 0.460 mg/kg 0.632 mg/kg 0.362 0.497 50~ (0.344- (0.473-1:1.37 0.723 0.993 50~ 0.614~ 0.844) 1.45 1.99 93~
2.89 3.97 100%
0.0904 0.310 204 0.193 mg/kg 0.662 mg/kg 0.181 0.620 374 ~0.142- (0.485-1:3.43 0.362 1.24 9340.263) 0.903) 0.723 2.48 100%~
1.45 4.97 100%
0.373 0 17% - 0.832 mg/kg 30 0:1 0-745 0 37% (0~671-(Morphine S04 1.49 0 83% 1.03) only) 2.98 0 100~
os~
Example 2 The effect on anesthetic requirements and PaCO2 of combined doses o nalbuphine hydrochloride and morphine sulfate was evaluated in 18 Sprague-Dawley rats (200-350 gms). Anesthetic requirements for cyclopropane anesthe-tic of each rat was determined using a tail-clamp tech nique (Munson et al., l'he Effect of Acute Hypothyroidism and Hyperthyoidism on Cyclopropane Requirements (MAC) in Rats, Anesthesiology 1968; 29:1094-1098). After induc-10 tion of anesthesia with cyclopropane, the femoral arteryand vein were exposed and catheterized with PE50 tubing.
Ane~Ul~c requlrement as measured by ~;n;~A~ alveolar col~c~lk~Lion (M~C) was de~Prm;n~ and thereafter nalbuphine hydr~-chloride was administered intravenously. Upon comple-15 tion of control measurements, a bolus dose of0.04 m~ka of nalbuphine hydrochloride was ollowed with a constant in~usion of 0.1 m~/kg/min. After 45 minutes of continuous infusion, MAC was redetermined and arterial blood sampling repeated. The rat then received either 20 2, 4 or 8 mg/kg subcutaneously of morphine sulfate and after 30 minutes MAC and arterial blood gas (ABG) values ~PaO~, PaCO7, p~, HC03) redetermined.
The effect of morphine sulfate alone on anesthetic requirement and respiration was evaluated in a separate 25 group of five Sprague Dawley rats. After baseline measure-ments of anesthetic requirement (MAC) and ABG values, 2 mg/kg of morphine sulfate was given subcutaneously and ater 30 minutes, repeat measurements of anesthetic requirements and blood gases were carried out. For com-30 parative purposes, the anesthetic requirements from aprevious, similar study are included.
~0oso~
Statistical evaluation was carried out using analy-sis of variance comparing the groups of animals at differ-ent infusion rates of nalbuphine hydrochloride, and for the animals receiving the combined morphine sulfate-nalbuphine hydrochloride doses. The results are shownin Table II.
TABLE ~
Anesthetic and Respiratory Effect of Nalbuphine, Morphine and Nalbuphine plus Morphine MAC Reduction % PaC02 - mmHg (Mean ~ SEM) (Mean - SEM) Nalbuphine HCl 0.1 mg/kg/min. 21.62-0.69 48.31+1.07 Morphine SO
sc injectio~
2 mg/kg 22l0.55 53+1.05 2 mg/kg* 21.80~1.48 4 mg/kg* 32.63-0.98 8 mg/kg* 54.87+1.94 Nalbuphine HCL
0.1 mg/kg/min.
and Morphine SO4 sc iniection 2 mg/kg 22.60~1.29 49.67-~1.52 4 mg~kg 22.60+1~40 50.01~2.59 8 mg/kg 28.75+0.98 52.80+1.91 *From a pre~ious study.
~20~
As can be seen from Table II,the 22% reduction in anesthetic requirement by morphine alone in a dose of 2 mg/kg is comparable to that previously reported (Hoffman and DiFazio, Arch. Int. Pharmacodyn. Ther., 1970;
186: 261~268). Morphine at this dose produced a mean PaCO2 in the animals studied significantly higher than that seen with the comparable MAC reduction dose of nalbu-phine. The administration of morphine in a dose of 2 and 4 mg/kg during continuous nalbuphine infusion giving 10 peak nalbuphine anesthetic effect resulted in no further reduction in anesthetic requirement. A morphine dose of 8 mg/kg gave a further 5~ reduction in anesthetic require-ment. The PaCO2 did not increase significantly after the addition of morphine to nalbuphine except at 8 mg/kc.
Example 3 Nalbuphine hydrochloride was used as a supplement to oxymorphone or hydromorphone used in the anesthesia of human patients undergoing various types of surgery.
The nalbuphine was ~;niqtered paren~erally as each patient 20 was coming out of the anesthesia. The emergence was smooth, rapid and analgesia was maintained for 8-12 hGurs.
me respiratory effect of ~he n~lhllrh;net~as est~hl;~h~ ~y measure-ment of arterial PaCO2 using a blood gas analyzer~ell kn~n in respiratory therapy. Normal PaC02 is in the range of 3~42 2~ mmHg. All arterial samples were ob~ained on an inspired oxygen concentration of 100%. No patient was hypoxic, nor was there any significant shunt present. Respiratory acidosis present before the administration of nalbuphine was completely reversed, pH values being 7.35iO~6 after 0.1 mg/kg of nalbuphine.
The results are shown in Table III.
5Q~l TABLE II I PaCO~ PaC02 BEFORE AETER
WEIGHT N~RCOTIC TOq~L N~LBU- 0.1 TYPE OF ~U~kKY A~æ (KG) USED DCSE PHINE
5 ~ nu~ 55 85 Oxymorphone 15 mg.64 46 L. FemDral-Popli-62 74 H~Lvl,ul~lone 1~ mg. 69 47 teal graft F~rlor~tor~ Lapor- 45 48 Ox~ll~L~lu~le 6 mg. 63 42 abomy Turb 72 68 OxymDrphone 7.5 mg. 66 45 10~h~nm;r~l Hyster- 48 78 Hy~,u,~bJlle 10.5 mg. 70 41 ectomy Cholestectomy 52 89 Hydr~mDrphone 14 ~g. 61 43 Aortic Tube graft 57 83 OxymDrphone 8.0 mg. 67 44 Laryngeck~y ~7 96 H~ one 16 mg.68 43 Bilroth I 34 59 OX~ rL1~ 7.5 m~. 59 46 ~hor~co~ 59 77 Ox~,uL~ e 13.5 mg. 62 40 Bcwel Resection66 71 Hydlw~ e 9.0 mg. 57 45 ~h~m;n~l Hyster-48 70 Q~rphone 7.5 mg. 67 46 ectomy Choles~ 52 75 Hydromorphone 8.0 ms. 66 43 20~Yrl~r~toxy Lapor- 44 63 O~ ~nP9.0 mg. 58 47 atcmy ~u*~ Fusion 38 73 ~ rphone 12 mg.69 44 As can be seen from Table III,respixatory depression 2;resulting from the narcotic was xeversed in all cases after the administration of nalbuphine.
Claims (7)
1. An analgesic composition which comprises an analgesic effective amount of a narcotic analgesic selected from the group consisting of morphine, oxymorphone, oxycodone, hydromorphone and a phar-maceutically suitable salt of one of the above, and an analgesic effective amount of nalbuphine or a pharmaceutically suitable salt thereof.
2. A composition of Claim 1 in oral dosage form containing about 1-100 mg of nalbuphine or a pharmaceu-tically suitable salt thereof per analgesic dose of the composition.
3. A composition of Claim 2 wherein each analgesic dose of the composition contains:
(a) about 1-100 mg of morphine or a pharmaceutically suitable salt thereof;
(b) about 0.1-20 mg of oxymorphone or a pharmaceu-tically suitable salt thereof;
(c) about 0,5-50 mg of oxycodone or a pharmaceuti-cally suitable salt thereof; or (d) about 0.1-20 mg of hydromorphone or a pharma-ceutically suitable salt thereof.
(a) about 1-100 mg of morphine or a pharmaceutically suitable salt thereof;
(b) about 0.1-20 mg of oxymorphone or a pharmaceu-tically suitable salt thereof;
(c) about 0,5-50 mg of oxycodone or a pharmaceuti-cally suitable salt thereof; or (d) about 0.1-20 mg of hydromorphone or a pharma-ceutically suitable salt thereof.
4. A composition of Claim 1 wherein each analge-sic dose is in oral dosage form and contains about 5-60 mg of nalbuphine or a pharmaceutically suitable salt thereof and about 5-60 mg of morphine or a pharmaceutically suit-able salt thereof.
5. A composition of Claim 1 wherein each analgesic dose is in oral dosage form and contains about 5-60 mg of nalbuphine or a pharmaceutically suitable salt thereof and about 0.5-10 mg of oxymorphone or a pharmaceutically suitable salt thereof.
6. A composition of Claim 1 wherein each analgesic dose is in oral dosage form and contains about 5-60 mg of nalbuphine or a pharmaceutically suitable salt thereof and about 2.5-30 mg of oxycodone or a pharmaceutically suitable salt thereof.
7. A composition of Claim 1 wherein each analgesic dose is in oral dosage form and contains about 5-60 mg of nalbuphine or a pharmaceutically suitable salt thereof and about 0.5-10 mg of hydromor-phone or a pharmaceutically suitable salt thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US300,394 | 1981-09-08 | ||
| US06/300,394 US4366159A (en) | 1981-09-08 | 1981-09-08 | Nalbuphine-narcotic analgesic composition and method of producing analgesia |
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| US (1) | US4366159A (en) |
| EP (1) | EP0074105A1 (en) |
| JP (1) | JPS5855422A (en) |
| AR (1) | AR228984A1 (en) |
| AU (1) | AU549070B2 (en) |
| CA (1) | CA1200501A (en) |
| FI (1) | FI823112L (en) |
| GR (1) | GR76702B (en) |
| HU (1) | HU190699B (en) |
| IL (1) | IL66743A (en) |
| NZ (1) | NZ201841A (en) |
| PH (1) | PH18772A (en) |
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| US4477457A (en) * | 1982-10-28 | 1984-10-16 | E. I. Du Pont De Nemours And Company | Method for inducing anorexia using nalmetrene |
| US4478840A (en) * | 1983-10-11 | 1984-10-23 | E. I. Du Pont De Nemours And Company | Appetite suppressing compositions and methods |
| US4885173A (en) * | 1985-05-01 | 1989-12-05 | University Of Utah | Methods and compositions for noninvasive dose-to-effect administration of drugs with cardiovascular or renal vascular activities |
| US4769372A (en) * | 1986-06-18 | 1988-09-06 | The Rockefeller University | Method of treating patients suffering from chronic pain or chronic cough |
| GB8820327D0 (en) * | 1988-08-26 | 1988-09-28 | May & Baker Ltd | New compositions of matter |
| US5236714A (en) * | 1988-11-01 | 1993-08-17 | Alza Corporation | Abusable substance dosage form having reduced abuse potential |
| US5478577A (en) * | 1993-11-23 | 1995-12-26 | Euroceltique, S.A. | Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level |
| EP1442745A1 (en) * | 1993-10-07 | 2004-08-04 | Euro-Celtique | Orally administrable opioid formulations having extended duration of effect |
| US5965161A (en) * | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
| US6348216B1 (en) * | 1996-06-10 | 2002-02-19 | Knoll Pharmaceutical Company | Ibuprofen and narcotic analgesic compositions |
| US6361794B1 (en) | 1996-06-12 | 2002-03-26 | Basf Corporation | Method of making ibuprofen and narcotic analgesic composition |
| US8329216B2 (en) | 2001-07-06 | 2012-12-11 | Endo Pharmaceuticals Inc. | Oxymorphone controlled release formulations |
| ATE376832T1 (en) | 2001-07-06 | 2007-11-15 | Penwest Pharmaceuticals Co | DELAYED RELEASE FORMULATIONS OF OXYMORPHONE |
| EP1406630A1 (en) * | 2001-07-06 | 2004-04-14 | Endo Pharmaceuticals Inc. | Parenteral administration of 6-hydroxy-oxymorphone for use as an analgesic |
| US20140271788A1 (en) | 2013-03-15 | 2014-09-18 | Monosol Rx, Llc | Sublingual and buccal film compositions |
| PT1436012T (en) * | 2001-10-18 | 2018-03-27 | Nektar Therapeutics | Polymer conjugates of opioid antagonists |
| PT1551372T (en) | 2002-09-20 | 2018-07-23 | Alpharma Pharmaceuticals Llc | Sequestering subunit and related compositions and metohds |
| WO2004045551A2 (en) * | 2002-11-15 | 2004-06-03 | Branded Products For The Future | Pharmaceutical composition |
| WO2004054511A2 (en) * | 2002-12-13 | 2004-07-01 | The Regents Of The University Of California | Analgesic combination comprising nalbuphine |
| US20060182692A1 (en) * | 2003-12-16 | 2006-08-17 | Fishburn C S | Chemically modified small molecules |
| WO2005058367A2 (en) * | 2003-12-16 | 2005-06-30 | Nektar Therapeutics Al, Corporation | Pegylated small molecules |
| EP2526932B1 (en) | 2006-06-19 | 2017-06-07 | Alpharma Pharmaceuticals LLC | Pharmaceutical composition |
| US20080318994A1 (en) | 2007-06-21 | 2008-12-25 | Endo Pharmaceuticals, Inc. | Method of Treating Pain Utilizing Controlled Release Oxymorphone Pharmaceutical Compositions and Instruction on Dosing for Renal Impairment |
| US20080318993A1 (en) * | 2007-06-21 | 2008-12-25 | Endo Pharmaceuticals, Inc. | Method of Treating Pain Utilizing Controlled Release Oxymorphone Pharmaceutical Compositions and Instruction on Dosing for Hepatic Impairment |
| US8623418B2 (en) | 2007-12-17 | 2014-01-07 | Alpharma Pharmaceuticals Llc | Pharmaceutical composition |
| FR2963889B1 (en) * | 2010-08-20 | 2013-04-12 | Debregeas Et Associes Pharma | NALBUPHINE-BASED FORMULATIONS AND USES THEREOF |
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| GB769517A (en) * | 1953-10-20 | 1957-03-06 | Merck & Co Inc | Analgesic compositions |
| US3493657A (en) * | 1961-03-14 | 1970-02-03 | Mozes Juda Lewenstein | Therapeutic compositions of n-allyl-14-hydroxy - dihydronormorphinane and morphine |
| IL26896A (en) * | 1966-01-19 | 1970-11-30 | Endo Lab | 14-hydroxynormorphines and 14-hydroxynormorphinones |
| US3773955A (en) * | 1970-08-03 | 1973-11-20 | Bristol Myers Co | Analgetic compositions |
| US3879555A (en) * | 1970-11-16 | 1975-04-22 | Bristol Myers Co | Method of treating drug addicts |
| GB1390772A (en) * | 1971-05-07 | 1975-04-16 | Endo Lab | Oral narcotic composition |
| US3966940A (en) * | 1973-11-09 | 1976-06-29 | Bristol-Myers Company | Analgetic compositions |
| US4237140A (en) * | 1979-05-18 | 1980-12-02 | E. I. Du Pont De Nemours And Company | Analgesic mixture of nalbuphine and acetaminophen |
| US4282215A (en) * | 1980-06-17 | 1981-08-04 | E. I. Du Pont De Nemours And Company | Analgesic mixture of nalbuphine and acetylsalicylic acid, derivative or salt thereof |
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- 1981-09-08 US US06/300,394 patent/US4366159A/en not_active Expired - Fee Related
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1982
- 1982-09-01 AR AR290507A patent/AR228984A1/en active
- 1982-09-04 EP EP82108178A patent/EP0074105A1/en not_active Withdrawn
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- 1982-09-06 ZA ZA826500A patent/ZA826500B/en unknown
- 1982-09-06 AU AU88042/82A patent/AU549070B2/en not_active Ceased
- 1982-09-07 JP JP57154739A patent/JPS5855422A/en active Pending
- 1982-09-07 NZ NZ201841A patent/NZ201841A/en unknown
- 1982-09-07 IL IL66743A patent/IL66743A/en unknown
- 1982-09-07 PT PT75521A patent/PT75521A/en unknown
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- 1982-09-07 CA CA000410864A patent/CA1200501A/en not_active Expired
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| PT75521A (en) | 1982-10-01 |
| GR76702B (en) | 1984-08-29 |
| AU8804282A (en) | 1983-03-17 |
| FI823112L (en) | 1983-03-09 |
| PH18772A (en) | 1985-09-25 |
| US4366159A (en) | 1982-12-28 |
| EP0074105A1 (en) | 1983-03-16 |
| FI823112A0 (en) | 1982-09-08 |
| HU190699B (en) | 1986-10-28 |
| AR228984A1 (en) | 1983-05-13 |
| IL66743A (en) | 1986-07-31 |
| AU549070B2 (en) | 1986-01-09 |
| IL66743A0 (en) | 1982-12-31 |
| NZ201841A (en) | 1984-12-14 |
| ZA826500B (en) | 1984-04-25 |
| JPS5855422A (en) | 1983-04-01 |
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