WO2002005647A1 - Sels et bases de 17-(cyclopropylmethyl)-4,5 alpha-epoxy-6-methylenemorphinan-3,14 diol permettant d'optimiser l'homeostasie de la dopamine pendant l'administration d'analgesiques opioides - Google Patents

Sels et bases de 17-(cyclopropylmethyl)-4,5 alpha-epoxy-6-methylenemorphinan-3,14 diol permettant d'optimiser l'homeostasie de la dopamine pendant l'administration d'analgesiques opioides Download PDF

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WO2002005647A1
WO2002005647A1 PCT/US2001/022007 US0122007W WO0205647A1 WO 2002005647 A1 WO2002005647 A1 WO 2002005647A1 US 0122007 W US0122007 W US 0122007W WO 0205647 A1 WO0205647 A1 WO 0205647A1
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opioid
nalmefene
analgesic
composition
opioid analgesic
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PCT/US2001/022007
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English (en)
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David Lew Simon
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Euro-Celtique, S.A.
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Priority to MXPA02003670A priority Critical patent/MXPA02003670A/es
Priority to CA002386794A priority patent/CA2386794A1/fr
Priority to EP01957138A priority patent/EP1272035A1/fr
Priority to AU78909/01A priority patent/AU782523B2/en
Publication of WO2002005647A1 publication Critical patent/WO2002005647A1/fr

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof

Definitions

  • the present invention relates to a method for optimizing dopamine levels in or out of the central nervous system during administration of exogenous opioid agonist drugs.
  • the result of maintaining an optimal homeostasis of dopamine levels at specific sites in human organs enhances the "positive" effects of opioid agonist analgesics, namely euphoria, analgesia, and improved motor and behavioral functioning, such that a lesser amount of opioid agonist analgesic is necessary to produce a given effect of analgesia or euphoria, which in turn, reduces the risk for becoming chemically dependent upon opioid agonist analgesics.
  • “Positive” effects of opioid agonist analgesics are effects which are desirable and which are the intended effects associated with the administration of exogenous opioid agonists. Such positive effects include analgesia or pain relief, euphoria or feeling good, and calming so as to reduce heart rate, blood pressure or breathing rate.
  • “Negative” effects of opioid agonist analgesics are effects that are undesirable and which are not the intended effects associated with administration of exogenous opioid agonists. Such negative effects include dysphoria, abnormal motor function, constipation, difficulty urinating and becoming chemically dependent upon the opioid agonist analgesics.
  • nalmefene The 17-(cyclopropylmethyl)-4,5 alpha-epoxy-6-methylenemorphinan-3,14 diol molecule, also known as nalmefene, is generally classified as a kappa-receptor preferring, pure opioid antagonist.
  • low doses of nalmefene are combined in structural preparations with an opioid agonist analgesic drug so as to increase the analgesic effect of, and to decrease the risk of chemical dependence to, said opioid agonist analgesic drug at therapeutic doses of opioid agonist.
  • the present invention will also tend to block positive effects of the opioid agonist, so as to dissuade the human from self-administering more opioid agonist than intended by a health professional. This is of very great importance because illicit abuse of opioid agonist analgesics by self-administration is a great societal problem which often leads to chemical dependency, addiction, ill health effects, crime, a burden on the criminal justice system, disruption of family well-being and many other bad outcomes.
  • Opioid agonist analgesic drugs are generally administered to reduce or relieve pain. Examples of such drugs are morphine, meperidine, fentanyl, opium and hydrocodone. There are many other opioid agonist analgesic drugs to which the present invention applies.
  • opioid agonist analgesic drug administered over a prolonged period of time, as common for treating many pain syndromes, generally results in the development of physiological tolerance to said opioid agonist analgesic drug, whereby an increasing amount of said opioid agonist analgesic drug is required over time to produce an equivalent analgesic effect.
  • This may lead to chemical dependence upon the opioid agonist analgesic, whereby abrupt withdrawal of opioid agonist drug will produce physical signs and psychological symptoms that, in general, are opposite to those positive effects which the opioid agonist originally produced.
  • Such withdrawal signs include excitation of the sympathetic nervous system such as release of norepinephrine from the locus coeruleus in the brain, increased heart rate and blood pressure, increased respiratory rate, altered gastrointestinal function leading to nausea, vomiting and/or diarrhea, piloerection ("goose bumps"), pain, and psychological or psychosomatic symptoms such as experiencing "hot and cold flashes," difficulty sleeping and chills.
  • Abdominal cramps, aches and pains - especially cramping in the legs, and involuntary movement - especially kicking of the legs, and feeling weak are other complaints associated with withdrawal of opioid agonists from a human chemically dependent upon them.
  • opioid agonist analgesic drugs In general, this myriad of signs and symptoms is what is known colloquially as being "dope sick.” It is this dope sickness that often is the incentive for humans chemically dependent upon opioid agonists to seek out and self-administer opioid agonist analgesic drugs without proper supervision by a medical professional.
  • opioid agonist analgesics to which humans are often addicted include heroin, methadone and their derivatives. Humans have the potential to become addicted to many other opioid agonist analgesic drugs.
  • Patent 5,783,583 in great detail the unique characteristics common only to the opioid antagonist nalmefene which set nalmefene apart from other opioid antagonists such as, for example, naloxone and naltrexone.
  • Patent 5,783,583 ('583) further describes how the unique opioid receptor subtype binding profile of nalmefene enables nalmefene alone, as compared to naloxone and naltrexone, to allow preferred antagonism of opioids at the kappa-opioid receptors versus the mu-opioid receptors, which in turn, results in an optimal homeostatic balance of dopamine.
  • Szekely (CRC Press, Inc. p. 160 (1994)) shows a schematic representation of two opposing opioid systems located in the mesolimbic system of the human central nervous system. These systems modulate A10 dopaminergic neurons projecting in the nucleus accumbens. Stimulation of mu-opioid receptors (the mu subtype of opioid receptor) in the ventral tegmental area (VTA), the site of origin of the A10 neurons, increase dopamine release in the nucleus accumbens (NA). Selective blockade of this mu-receptor results in significant decrease in dopamine release in the nucleus accumbens.
  • kappa-receptors the kappa subtype of opioid receptor
  • stimulation of kappa-receptors results in a decrease in the amount of dopamine released.
  • Selective blockade of kappa- receptors significantly increases dopamine release.
  • Spanagel et al. demonstrate that tonically active and functionally opposing mu and kappa opioid systems regulate mesolimbic dopamine release in the nucleus accumbens. They report that the injection of mu-opioid agonists such as DAGO into the NTA stimulate mu-opioid receptors and increase the release of dopamine from the NTA into the ⁇ A. As would be expected, administration of a mu- opioid receptor antagonist into the NTA decreases dopamine release.
  • kappa-opioid receptors agonists such as U-6953 infused into the ⁇ A inhibit dopamine release there, whereas kappa-opioid receptor antagonists such as nor-B ⁇ I increase dopamine release.
  • An "agonist” is a "like” chemical with similar action to a given drug.
  • An “antagonist” is a chemical, often with a similar chemical structure to a given drug, which exerts a dissimilar action to the given drug, in general preventing the "like" action of that given drug.
  • opioid receptors in general, an agonist binds to the receptor and activates it in such a way as to begin a cascade of chemical or pharmacological events so as to result in the end effect related to a particular opioid receptor subtype.
  • an antagonist will bind to the receptor but not activate it.
  • An antagonist exerts its actions by blocking the receptors from agonists, by physically occupying the space on the receptor where an agonist would otherwise bind.
  • the opposing mu and kappa-opioid systems acting together provide a homeostasis of dopamine levels within the central nervous system. Changes in these opioid systems, such as by activation or blockade of the specific receptors, would therefore be expected to modulate opioid-induced effects that are mediated by mesolimbic pathways. Mu and kappa receptors are found elsewhere in the human body. For example, they have been located in the spinal cord (See Fujimoto, Bakshi and Behrmann, below) and in other non-central nervous system organs such as the kidney and intestine (See Ohnishi and Kreek, below). Accordingly, the model presented provides a neurochemical framework for understanding the adaptive changes resulting from long term use of opioids, as well as the clinical response elicited by exogenously administered opioid agonists and antagonists having different binding profiles.
  • nalmefene relative to other opioid antagonists such as naloxone and naltrexone, is significantly more kappa-receptor preferring.
  • Kreeks et al. (Life Sciences 56: 1887 (1995)) conclude that nalmefene has more kappa binding activity than either naloxone or naltrexone.
  • nalmefene is more potent than either naloxone or naltrexone as a kappa-receptor antagonist, and therefore would block kappa a-onists (e.g., the naturally occurring dynorphin) to a greater extent than the other antagonists.
  • Fujimoto et al. demonstrate differences between mu and kappa receptor effects in the spinal cord. Specifically, these authors report that the administration of dynorphin, a potent kappa agonist, results in decreased analgesia. The dynorphin causes antianalgesic effects at the level of the spinal cord. Fujimoto shows that when a kappa-opioid receptor antagonist such as Cholera Toxin is given, the antianalgesic effect of dynorphin is inhibited.
  • a kappa-opioid receptor antagonist such as Cholera Toxin
  • 5,580,876) teach a method for "selectively enhancing the analgesic potency of a bimodally-acting opioid agonist" which comprises administering an opioid agonist such as morphine with "an excitatory opioid receptor antagonist such as naltrexone or nalmefene effective to enhance the analgesic potency of the bimodally-acting opioid agonist.”
  • an opioid agonist such as morphine
  • an excitatory opioid receptor antagonist such as naltrexone or nalmefene effective to enhance the analgesic potency of the bimodally-acting opioid agonist.
  • Crain teaches that nalmefene, naltrexone, naloxone, etorphine and dehydroetorphine are analogous compounds suitable for his invention, though, '583 shows clearly that naltrexone and naloxone are not analogous to nalmefene.
  • Suitable excitatory opioid receptor antagonists of the invention include nalmefene, naltrexone, naloxone, etorphine and dihydroetorphine, as well as similarly acting opioid alkaloids and opioid peptides.” (See column 4, lines 60-67.) Even when narrowing the scope of the invention of 5,580,876 ('876), the authors state that the "Preferred excitatory receptor antagonists are nalmefene and naltrexone because of their longer duration of action as compared to naloxone," but make no mention of the significant and distinct differences in characteristics between nalmefene and naltrexone as relating to differences in binding profiles for opioid receptor subtypes which are clearly and unequivocally shown in 5,783,583 ('583).
  • nalmefene as the antagonist "effective to enhance the analgesic potency of the bimodally-acting opioid agonist," the claims are not consistent with the detailed description of the invention which repeatedly teach, by way of the many examples described, that diprenorphinem, naloxone and naltrexone are analogous (example 2), and that nalmefene and naltrexone are analogous (example 8) - which is further supported by the authors' statement, "co-treatment with nalmefene is as effective as naltrexone in attenuating morphine dependence liability.” (See column 14, lines 51-53.) No definitive statement is made that nalmefene is superior to naltrexone for the purposes of the '876 invention.
  • '876 patent makes no mention of the positive and negative effects of opioid agonists taught in the present invention. For instance, no mention is made in '876 regarding euphoria versus dysphoria, or behavioral effects such as emotion, perception, drug reinforcement and place preference. Further, '876 does not address effects upon intestinal function or urination. Perhaps most convincingly, however, is that '876 makes no reference to the opposing mu and kappa opioid receptors in maintaining a homeostatic balance of dopamine in the mesolimbic region of the brain, in the spinal cord, or at other peripheral sites such as the intestine or kidney.
  • nalmefene stated is too vague as relating to the amount of bimodally-acting opioid agonist. This is because each particular opioid agonist has its characteristic potency. For instance, fentanyl is many more times as potent as morphine. Therefore, the effective dose range of nalmefene consistent with '876 would have to be significantly different for fentanyl as compared to morphine. However, '876 makes no such distinction.
  • nalmefene is the same for each of the very diverse group of opioid agonist drugs: "morphine, codeine, fentanyl analogous, pentazocine, methadone, buprenorphine, enkephalins, dynorphins and similarly acting opioid alkaloids and opioid peptides.”
  • the affinity with which each opioid agonist binds a particular opioid receptor subtype is of critical importance to the present invention.
  • '583 teaches that, for example, beta-endorphin binds mu receptors with a significantly greater affinity than the exogenously administered opioid morphine.
  • opioid agonist e.g. morphine
  • endogenous opioid agonist e.g. beta-endorphin, dynorphin
  • opioid antagonist in question e.g. nalmefene
  • opioid agonists may have different affinities for a particular opioid receptor, especially when all administered with the same mass unit doses, it is impossible that opioid agonist as diverse as those claimed in '876 can have equal effects when subject to equal amount of nalmefene.
  • the claims of '876 are excessively vague and should not preclude the claims of the present invention.
  • buprenorphine a relatively weak-activating mu-agonist and a kappa-preferring antagonist, and the mixed opioid agonist-antagonist pentazocine
  • '876 analogous compounds to "morphine, codeine, fentanyl analogous . . . methadone, enkephalins, dynorphins and similarly acting opioid alkaloids and opioid peptides" as relating to nalmefene, is further proof that Crain et al. do not have an appreciation for the utility of nalmefene's unique binding characteristics, and gives further evidence that the present invention is patentable over '876. See column 4, lines 34-38 of '876.)
  • nalmefene in '876 are too small to have a significant effect in dissuading a human from self-administering too much opioid agonist analgesic as in the present invention. Therefore, the present invention is not inherent in '876. Comparing '876 to the present invention, only the present invention appreciably dissuades a human from illicitly abusing opioid agonist analgesics. In fact, it is possible that '876 may have just the opposite effect.
  • nalmefene and naloxone are not analogous compounds. Therefore, the present invention would not be obvious to one skilled in the art simply because naloxone has previously been combined with opioid agonists. In fact, because of naloxone's opioid receptor subtype binding profile, it could not exert the positive opioid effects as nalmefene at similar doses, as taught in the present invention.
  • the present invention is directed to methods for magnifying the positive effects of opioid agonist analgesic drugs by effectively antagonizing kappa-opioid receptors to a much greater extent than mu-opioid receptors at recommended therapeutic doses, such that less opioid agonist will need to be administered for a given positive effect, thus decreasing the tendency for physiological tolerance to the drug, and hence decreasing the risk of chemical dependency or addiction, while also resulting in appreciable antagonism of mu-opioid receptors when the opioid agonist analgesic is administered at above the recommended therapeutic dose so as to dissuade a human being from self-administering excessive amounts of opioid agonist analgesic.
  • the methods consist of administering to a living human being or animal a prescribed dose of nalmefene in combination with a prescribed dose of opioid agonist analgesic, the amount of nalmefene being effective to significantly antagonize kappa receptors while at the same time having minimal antagonistic effect on mu receptors, thus enhancing the positive effects of opioid agonists, such that the agonist actions by mu opioid agonists will far outweigh any antagonism by nalmefene at said mu-opioid receptors at recommended therapeutic doses.
  • the present invention also provides a structural composition comprising a therapeutic dose of opioid agonist analgesic in combination with an amount of nalmefene effective to enhance the positive effects of the opioid agonist analgesic, while at the same time exerting minimal antagonistic effects at mu-opioid receptors, when the opioid agonist analgesic is administered in recommended therapeutic doses, such that the agonist actions of the opioid agonist analgesic will far outweigh any antagonism by nalmefene at said mu-opioid receptors.
  • nalmefene and opioid agonist analgesic are administered, enough nalmefene shall be administered as to begin to antagonize or block mu-opioid receptors from the exogenously administered opioid agonist analgesic in addition to kappa-opioid receptors, such that the human being will be dissuaded from self administering such excessive amounts of said structural composition.
  • this present invention is directed to a method for optimizing the homeostatic control of dopamine release in the central nervous system (CNS) which will tend to enhance the analgesic effect of a selected opioid agonist analgesic at intended therapeutic doses of said opioid agonist analgesic, and which at doses higher than the intended therapeutic dose of opioid agonist analgesic will tend to exert undesirable effects so as to dissuade a human from self-administering greater than the intended therapeutic dose of said opioid agonist analgesic.
  • CNS central nervous system
  • the method comprises administering to a human or animal an opioid agonist analgesic and an amount of nalmefene or other similar kappa-preferring opioid antagonist in definite proportions, such that relatively lesser amounts of the proportioned nalmefene and opioid agonist analgesic will tend to optimize CNS dopamine levels thus enhancing analgesic and other desirable effects of the opioid agonist analgesic, and relatively greater amounts of the proportioned nalmefene and opioid agonist analgesic will tend to produce an adverse balance of CNS dopamine thus limiting positive or desirable effects of the opioid agonist analgesic, and therefore dissuade a human or animal from self-administering greater than the intended therapeutic dose of opioid agonist analgesic.
  • each, nalmefene and opioid agonist analgesic will depend upon the potency of the particular opioid agonist analgesic, and pharmacokinetic profiles of the drugs, including volumes of distribution, elimination constants, blood half-lives, elimination half-lives, solubilities, binding to physiological proteins and so forth. In light of the present invention, one skilled in the art can compensate for these parameters. In general however, on a mass unit basis, the ratio of opioid agonist analgesic to nalmefene shall range from approximately 1.2:1 to 990:1.
  • both nalmefene and opioid agonist analgesic in amounts that when recommended therapeutic amounts of the composition are administered, nalmefene shall work in concert with the opioid agonist analgesic to produce the desirable effects of the opioid agonist analgesic drug, but which at higher amounts of composition will elicit undesirable effects;
  • composition for administration containing both nalmefene and an opioid agonist analgesic, such that release of the two drugs results in concentrations of nalmefene, relative to the opioid agonist analgesic, that will produce the intended effects as stated in the aforementioned object and advantage "g;" and
  • the present invention comprises the administration of nalmefene with an opioid agonist analgesic, in sufficient doses of nalmefene to, i) enhance the analgesic effect of the opioid agonist analgesic at recommended therapeutic doses of opioid agonist analgesic effective to produce positive effects such as relief of pain and euphoria, but which are not in excess of a recommended therapeutic dose of analgesic, and if) produce undesirable effects at larger doses of opioid agonist analgesic which are in excess of the recommended therapeutic dose.
  • One embodiment of the present invention is a method whereby nalmefene and opioid agonist analgesic are administered by titration to a human being, using pain relief and euphoria as endpoints for desirable effects, and using dysphoria and the experiencing of pain as endpoints for undesirable effects.
  • Titration of drugs may be of any acceptable method, such as, for example, by intravenous administration.
  • a more practical, and the preferred embodiment of the invention is a composition comprising an opioid agonist analgesic medication and nalmefene, in amounts of each drug, such that when the composition is administered to yield a prescribed amount of administered opioid agonist analgesic, an amount of nalmefene is administered such that, i) at therapeutic doses of opioid agonist analgesic, an amount of nalmefene is administered which effectively blocks kappa-opioid receptors but which has minimal activity at mu-opioid receptors, and ii) at doses in excess of recommended therapeutic doses of opioid agonist analgesic, an amount of nalmefene is administered which appreciably blocks by competition mu-opioid receptors in relation to the exogenously administered opioid agonist analgesic.
  • nalmefene The optimal amount of nalmefene to accomplish the objectives of the present invention will depend, in part, upon which opioid agonist analgesic is co-administered with nalmefene, as different opioid agonist analgesics have different potencies and different affinities for binding various opioid receptors at a given mass unit dose of opioid agonist, such as milligrams, micrograms or nanograms.
  • the preferred embodiment of the invention matches an opioid agonist analgesic to nalmefene which has a similar pharmacokinetic properties, such as elimination half-live, as nalmefene, so that the concentrations of each drug remain in proper proportion relative to one another over time, and so one drug does not accumulate over time to a greater extent than the other drug, to an effect detrimental to the scope of the present invention.
  • a time release formulation of either drug can be incorporated into the composition such that the pharmacokinetics of the two drugs become more compatible.
  • a recommended therapeutic dose of morphine e.g. 0.15 mg/kg morphine, preferably in the form of morphine sulfate, is co-administered parenterally with 0.00025 to 0.0015 milligrams per kilogram (mg/kg) nalmefene, preferably in the form of nalmefene hydrochloride, more preferably 0.0007 mg/kg nalmefene.
  • nalmefene preferably in the form of nalmefene hydrochloride
  • nalmefene hydrochloride e.g. 0.15 mg/kg morphine, preferably in the form of morphine sulfate
  • nalmefene This small amount of nalmefene, consistent with the present invention, will block, at least partially, kappa-opioid receptors.
  • the present invention teaches that these doses of nalmefene and morphine will result in optimal levels of dopamine in the brain or spinal cord, thus enhancing the positive effects of morphine.
  • morphine sulfate and nalmefene hydrochloride are co-existent in a common medium compatible for parenteral administration in the ratio, of 0.15 mg active morphine to 0.0007 mg active nalmefene.
  • the total amounts of the two co-administered active drugs would be contained within an injectable volume of approximately 1 to 2 milliliters (cc) for a 70 kg adult human. Assuming that 10.5 mg active morphine and 49 ug active nalmefene are contained within a 1.5 cc liquid vial, if a human self-administered twice the recommended therapeutic dose, i.e.
  • the human would receive 21 mg morphine and 98 ug nalmefene, or approximately 0.1 mg nalmefene.
  • This amount of nalmefene would serve a protective effect to greatly decrease the likelihood that said human would succumb to a morphine overdose, such as lifethreatening respiratory depression.
  • respiratory depression is regulated by kappa-opioid receptors in a part of the brain not necessarily correlating with homeostasis of dopamine in the nucleus accumbens, the ventral tegmental area or the spinal cord.
  • This amount of morphine and nalmefene administered together gives a ratio of morphine to nalmefene of approximately 214 to 1 on a unit mass basis.
  • nalmefene tends to significantly compete with the exogenously administered morphine, such that the mu-opioid blocking effect of nalmefene would tend to compete significantly with the mu-opioid activating effect of morphine, resulting in some negation of the desirable effects of the opioid agonist analgesic, resulting in a relative lack of pain relief.
  • Fentanyl is approximately 100 times as potent as morphine on a unit mass basis, e.g. per milligram or per microgram. In addition, depending on the amount administered, fentanyl may tend to be shorter acting as compared to morphine. Therefore, when fentanyl (in its citrate form or as another congener) and nalmefene are co-existent in a common medium compatible for parenteral administration, a ratio of 0.0015 mg active fentanyl to 0.0007 mg active nalmefene would have a similar compatibility profile as in example 1 immediately upon administration, i.e., before significant redistribution and elimination.
  • fentanyl is so relatively short-acting as compared to nalmefene
  • repeated administrations of a composition with this ratio of fentanyl to nalmefene may result in accumulation of nalmefene relative to fentanyl, such that fentanyl may become ineffective at mu-opioid receptors at a concentration of fentanyl that is not intended for this to occur. Therefore, a lower dose in the range of nalmefene consistent with this invention could be employed.
  • Fentanyl 0.0015 mg/kg and nalmefene 0.00025 mg/kg administered together gives a ratio of fentanyl to nalmefene of 15 to 2.5 on a unit mass basis.
  • 0.105 mg fentanyl 105 ug fentanyl
  • 0.0175 mg nalmefene 17.5 ug nalmefene
  • 105 ug fentanyl is a therapeutic dose to treat pain for a young adult human.
  • nalmefene 17.5 ug nalmefene would tend to have appreciable blocking effects at kappa- opioid receptors, because nalmefene is a kappa-preferring opioid antagonist.
  • this amount of nalmefene would not tend to compete effectively with endogenously produced beta-endorphin, and would also tend to be relatively inconsequential in competing with this amount of exogenously administered fentanyl at mu-1 receptors.
  • the overall expected effect would be an enhancement of the positive effects of fentanyl.
  • a human tried to self-administer by way of example only, the stated therapeutic dose of the combined fentanyl/nalmefene preparation every one hour, yielding doses of fentanyl (alone, i.e. with no nalmefene) that cumulatively could produce life-threatening respiratory depression in a 70 kg adult human not tolerant to opioid agonist analgesics, or doses that might be self-administered by a tolerant or non-tolerant human to attain euphoria on a frequent basis, the following would occur.
  • Nalmefene by virtue of its significantly longer plasma half-live, longer elimination half life, and greater affinity for staying bound to opioid receptors as compared to fentanyl, would accumulate and increase its concentration relative to fentanyl such that eventually concentrations of nalmefene would be present at mu- opioid receptors to significantly compete with the exogenously administered fentanyl, such that the mu-opioid blocking effect of nalmefene would tend to compete significantly with the mu-opioid activating effect of the exogenously administered opioid agonist analgesic, fentanyl.
  • This in addition to preventing a mortal respiratory depression, would dissuade a human from self-administering this amount of the fentanyl preparation so frequently.
  • the shorting acting drug e.g. fentanyl
  • the shorting acting drug can be prepared by encasing the drug particles as a microcapsule or covering it with a material, such as cellulose, lactic acid polymers or the like, so that its release into systemic circulation following release from a combination matrix will be delayed to more match the pharmacokinetic profile of the longer-acting drug, e.g. nalmefene.
  • a material such as cellulose, lactic acid polymers or the like
  • transdermal delivery system or a patch to be worn on the skin of a human, which contains both fentanyl and nalmefene in proportions consistent with the present invention.
  • a transdermal preparation for fentanyl the Duragesic ® patch.
  • a significant problem exists with this product in that drug addicts are know to boil the patch in a solvent solution and then distill the solution to obtain a fentanyl preparation which can be readily abused by injecting it intravenously into a human.
  • One preferred embodiment of the present invention involving a skin patch would be to formulate a patch with two drug delivery rates. Fentanyl could be delivered faster by being contained in an adhesive matrix that might be delivered by diffusion along a concentration gradient.
  • the nalmefene could be delivered more slowly by using a partially permeable membrane that limits the transfer of nalmefene across the membrane.
  • the fentanyl and nalmefene are contained within two different compartments within the patch - fentanyl in the adhesive matrix, and nalmefene in a reservoir which is separated from the fentanyl by a partially permeable membrane.
  • the partially permeable membrane may be temperature sensitive so that it degrades at a certain specified temperature, or made to degrade upon exposure to certain solvents.
  • Methadone is a relatively long-acting, orally administered opioid agonist analgesic, which is quite often used as a substitute for heroin in the treatment of humans addicted to heroin.
  • One significant problem with methadone, however, is its high potential for illicit abuse. So high is this potential, that in the United States, methadone is typically distributed only in specified methadone dispensaries specially licensed by state agencies and the federal Drug Enforcement Agency.
  • An embodiment of the present invention solves a long-sought need to formulate methadone in such a way as to i) optimize its action such that less drug is needed - this will slow down the process by which a human may become tolerant to methadone's effects, and if) yield a form of drug that when misused will result in unpleasant side effects.
  • Nalmefene is known to undergo extensive first-pass metabolism in the liver. Because of this, orally administered nalmefene is roughly bioequivalent to 1/20 to 1/25 of intravenously admimstered nalmefene. Stated differently, 50 mg of nalmefene orally administered into the gastrointestinal track of a human will be approximately equivalent to 2 mg of nalmefene administered intravenously.
  • nalmefene 1 mg of nalmefene orally administered into the gastrointestinal tract is bioequivalent to approximately 40 ug, or 0.040 mg, of intravenously administered nalmefene.
  • the ratio of methadone to nalmefene on a mass unit basis is 100 to 1 in this methadone/nalmefene preparation.
  • the nalmefene Upon the intended oral administration of this combination of methadone and nalmefene, the nalmefene will tend to block kappa-receptors, optimizing the homeostatic balance of dopamine in the central nervous system, without having an appreciable effect on competition with endogenous endorphins at mu-opioid receptors, and having little, if any, substantial effect in competing with methadone at mu-1 receptors.
  • the intended effect of methadone will be realized when administered per os.
  • a human self-administers this same preparation by intravenous route then enough nalmefene will be present at mu-1 receptors to substantially compete with the exogenously administered opioid agonist analgesic, methadone.
  • the human will not experience the expected "drug rush," and may experience other undesirable effects as well, and therefore will be dissuaded from taking such action in the future, such as injecting intravenously a drug preparation intended for oral use.
  • Sufentanyl is a derivative of fentanyl that on a mass unit basis is 5 to 10 times as potent as fentanyl, or approximately 500 times as potent as morphine.
  • a ratio of approximately 0.00030 mg active sufentanyl to 0.00025 mg active nalmefene may be administered. This, on a mass unit basis, yields a ratio of sufentanyl to nalmefene of approximately 1.2 to 1.
  • a typical therapeutic parenteral dose of sufentanyl to produce analgesia for a chronic pain syndrome in a young adult 70 kg human is approximately 21 ug. Therefore, approximately 18 ug nalmefene would be co-administered in a common composition with 21 ug sufentanyl. This amount of nalmefene would tend to optimize CNS dopamine as previously described. If 20 times the recommended therapeutic dose of sufentanyl were intravenously self-administered by a human, as for instance in an intentional suicide attempt, 420 ug of sufentanyl would be administered along with approximately 360 ug nalmefene. This amount of nalmefene would tend to substantially compete with that amount of exogenously administered opioid agonist analgesic sufentanyl at mu-2 opioid receptors and at kappa receptor to prevent mortal respiratory depression due to drug overdose.
  • a recommended therapeutic dose of meperidine e.g. approximately 90 mg parenteral meperidine, is co-administered parenterally with 0.00025 to 0.0015 milligrams per kilogram (mg/kg) nalmefene, preferably in the form of nalmefene hydrochloride, more preferably 0.0013 mg/kg nalmefene.
  • nalmefene hydrochloride parenterally For a young adult 70 kg human, for example, approximately 90 mg meperidine is admimstered parenterally, along with 0.091 mg, or 91 micrograms (ug), nalmefene hydrochloride parenterally. This small amount of nalmefene, consistent with the present invention, will block, at least partially, kappa-opioid receptors. This same dose of nalmefene, consistent with the present invention, produces minimal effect at mu-1 opioid receptors in relation to the 90 mg dose of meperidine, and even less of a competitive effect relating to the endogenous beta-endorphin.
  • nalmefene and meperidine will result in levels of dopamine in the brain or spinal cord that will not appreciably result in undesirable effects.
  • dose of nalmefene relative to the dose of meperidine may actually tend to avoid an unpleasant side effect of an opioid agonist analgesic administered alone, that is constipation.
  • meperidine will exhibit a typical analgesic effect, but perhaps with less of a tendency to cause constipation.
  • the ratio of meperidine to nalmefene is approximately 990 to 1.
  • this fifth example nevertheless is perfectly suitable for dissuading a human from self- administering excessive doses of opioid agonist analgesic, as well as preventing mortal respiratory depression.
  • Tramadol also known as the brand name Ultram®, is a unique pharmaceutical agent acting with some agonist properties at mu opioid receptors, but which is also believed to act through other central nervous system (CNS) systems such as influencing action at serotonin and norepinephrine receptors.
  • CNS central nervous system
  • the serotonin neurotransmitter system has long been implicated in regulating depression and anxiety, and has more recently been implicated in influencing the psychiatric malady known as Obsessive Compulsive Disorder (OCD).
  • OCD Obsessive Compulsive Disorder
  • the drug paroxetine HCL also know by the brand name Paxil®, is used to treat depression, panic disorder, Social Anxiety Disorder (SAD), as well as OCD.
  • SAD Social Anxiety Disorder
  • the noradrenergic system (where norepinephrine is the primary neurotransmitter) has also been implicated in depression and substance abuse.
  • tramadol may have a role in treating OCD. Their research appears to indicate that tramadol is especially efficacious in treating OCD as compared to placebo, and possibly other drugs used to treat OCD.
  • nalmefene By combining nalmefene with tramadol in a single pharmaceutical formulation consistent with the present invention, a drug preparation is prepared which has great promise for treating Obsessive Compulsive Disorder but which lacks the tolerance-producing and respiratory depression-producing effects of tramadol alone. Because OCD is a great psychiatric malady affecting 1 in 50 Americans, and because first lines of medical treatment yield improvement rates of only 20%, this example of the invention fills a much needed void in the treatment of OCD. Drugs typically used for treating OCD prior to the present invention include serotonin uptake inhibiting drugs and clomipramine, each having an associated adverse effect profile different from tramadol or tramadol in combination with nalmefene.
  • Buprenorphine is a partial opioid agonist. It has unique binding characteristics compared to other opioid agonist analgesics, in that buprenorphine binds mu-1 opioid receptors with a very high affinity, however, although wholly bound to these mu receptors, buprenorphine exerts a very weak mu-1 activating effect relative to other opioid agonist analgesics. In fact, buprenorphine' s affinity for mu-1 receptors is so great, that many times the recommended therapeutic doses of naltrexone or nalmefene only partially reverse or antagonize the binding of therapeutic doses of buprenorphine at mu-1 receptors.
  • a useful method for treating opioid addiction is to substitute buprenorphine for the abused illicit opioid.
  • This is well known in the art.
  • a human addicted to heroin will be administered buprenorphine instead.
  • Buprenorphine because it binds mu-1 receptors with such a great affinity, will tend to displace heroin from the mu-1 receptors.
  • the buprenorphine once bound to these mu-receptors, will tend to activate the receptors to a much lesser degree than would bound heroin or its metabolites. Thus, less dopamine will be released due to a lesser stimulation via mu-1 receptors, as compared to heroin.
  • naloxone has been added to the preparation containing buprenorphine.
  • Other investigators have contemplated the use of naltrexone for these purposes.
  • buprenorphine/naloxone or buprenorphine/naltrexone preparations will tend to produce undesirable effects, such as dysphoria due to a suboptimal homeostatic balance of CNS dopamine, much more so than would a preparation consisting of buprenorphine and nalmefene.
  • the ratio of buprenorphine to nalmefene will depend on the intended route of administration, i.e., whether the preparation common to both nalmefene and buprenorphine is administered enterally or parenterally. If administered parenterally, bioavailability will even differ with different parenteral routes of administration. For instance, bioavailability of buprenorphine, like many drugs, differs with different routes of administration. For example, sublingual buprenorphine in one study was shown to have a bioequivalence of approximately 51% as compared to direct intravenous administration, and buccal administration (through the mucosa lining the oral cavity near the inside of the cheek) was shown to be approximately 28%.
  • a convenient route of administration may be in tablet or liquid form for oral self-administration.
  • a nasal spray having a ratio of buprenorphine to nalmefene consistent with the present invention could also be easily self- administered by humans, while at the same time dissuading the human from self- administering excessive and abusive amounts of the preparation.
  • 0.3 mg i.v. buprenorphine is said to be "equianalgesic" to 10 mg i.v. morphine.
  • the affinities for mu-receptors and the pharmacokinetics of the two drugs differ. Therefore, the relative analgesic ability of 0.3 mg i.v.buprenorphine as related to 10 mg i.v. morphine may change over time after the two drugs are administered.
  • nalmefene has a special relationship with the binding of buprenorphine, as opposed to pure opioid agonist analgesics which have no antagonist properties, because both nalmefene and buprenorphine act as kappa-receptor antagonists.
  • Nalmefene is also a mu-antagonist in addition to being a "kappa-preferring" antagonist.
  • Buprenorphine in addition to being a kappa-antagonist, unlike nalmefene, is a "partial" mu- agonist.
  • buprenorphine binds mu-receptors with a very high affinity so as to displace other competing opioid agonist analgesics at mu-receptors.
  • buprenorphine only mildly activates these receptors.
  • a patient given an opioid agonist analgesic with a lesser affinity but a greater activating effect on mu-receptors relative to buprenorphine many opioid agonist analgesics fit this profile
  • buprenorphine when buprenorphine is administered it will cause less dopamine to be released as a result of mu-receptor activity.
  • buprenorphine is a good drug to use as a substitute for heroin for humans addicted to heroin.
  • buprenorphine is used as a substitute for heroin in maintenance therapy as a treatment for heroin addiction, it is generally administered in doses ranging from 0.3 mg to as high as 12 mg intravenously, but more typically between 0.3 mg and 1.2 mg.
  • buprenorphine is administered sublingually for such maintenance therapy, it is generally administered in doses that range from 4 to 12 mg, though higher* amounts may be administered.
  • Buprenorphine has also been administered by intramuscular injection and intranasal routes.
  • the present invention recognizes that because buprenorphine increases CNS dopamine by virtue of both being an agonist at mu-receptors and as antagonist at kappa- receptors, it may indeed have at least as high or higher potential for drug abuse than other maintenance drugs such as methadone and LAAM. In other words, a human may be more likely to self-administer buprenorphine than methadone. This has not been appreciated in the art prior to the present author's recognition of this phenomenon.
  • 0.3 mg of buprenorphine may be combined with 17.5 micrograms (ug) nalmefene. If 40 times a recommended therapeutic dose of 0.3 mg buprenorphine is administered parenterally (12 mg buprenorphine, which realistically may be self-injected in an attempt by a human to "get high") in a preparation with a ratio of buprenorphine to nalmefene of 17.1:1 on a mass unit basis, then 700 ug, or 0.7 mg, of nalmefene will be administered.
  • buprenorphine is similarly administered in a ratio to nalmefene of 6:1 on a mass unit basis (0.3 mg buprenorphine to 50 ug nalmefene), then when 12 mg buprenorphine is self- administered, 2 mg of nalmefene will necessarily be co-administered.
  • This high resultant amount of nalmefene will compete with buprenorphine at mu-receptors such that there will at least be a partial antagonistic effect of nalmefene on buprenorphine at mu-receptors.
  • This partial antagonism of buprenorphine at mu-receptors will tend to dissuade a human from self- administering even larger amounts of buprenorphine, as compared to a situation where nalmefene is not at all present in the administered preparation.
  • the precise ratio of buprenorphine to nalmefene will depend upon the intended dose of buprenorphine. In light of the present invention, this precise ratio can be readily determined by one skilled in the art.
  • nalmefene and opioid agonist analgesics for use in the present invention may be in the form of free bases or pharmacologically acceptable salts thereof.
  • suitable acids for salt formation include but are not limited to hydrochloric acid, glucuronic acid, citric acid and so forth.
  • the opioid agonist analgesic and nalmefene may be administered to a human or animal by any of known methods such as, but not limited to, intramuscular, intravenous, intranasal, oral, sublingual or transdermal methods.
  • Extended release formulations may be embodied in the present invention.
  • porous microspheres including nalmefene or an opioid agonist analgesic may be prepared from polymers or copolymers of gelatin, agar, starch, collagen, polyglycolic acid, polylactic acid, poly (epsilon-caprolactone-CO-lactic acid), and so forth, and mixed together.
  • any of known permeation enhancers suitably compatible with patch ingredients may be used.
  • a partially permeable barrier may separate the nalmefene and opioid agonist analgesic to control the release of the longer acting component to better match the physiological actions of nalmefene with those of the opioid agonist analgesic.
  • the opioid agonist analgesic When the opioid agonist analgesic is significantly shorter-acting in duration than nalmefene, it may be prepared in a sustained release form by any of known methods, which in light of the present invention, would be apparent to one skilled in the art. Likewise, if nalmefene has a shorter in vivo life span than the opioid agonist analgesic, as in the case of LAAM (levo-alpha-acetylmethadol), the nalmefene may be prepared in such a sustained release form.
  • One such sustained release form which may be applicable in this instance, is the sustained release preparation used for dextromethorphan and marketed in the United States as Delsym®.
  • Example 8 Other kappa-preferring opioid receptor antagonists may be used consistent with the present invention.
  • Example 8 Other kappa-preferring opioid receptor antagonists may be used consistent with the present invention.
  • analgesics consisting of an opioid agonist analgesic and a non-opioid analgesic such as acetaminophen, aspirin, ibuprofen or other non-steroidal anti- inflammatory drug ("NSAID").
  • NSAID non-steroidal anti- inflammatory drug
  • the combination of oxycodone and acetaminophen commonly known by the brand name Percocet®, is very often prescribed for a wide variety of pain syndromes, including pain secondary to surgery or trauma, and malignancies.
  • the drug formulation commonly known by the brand name Percodan® is composed of oxycodone and aspirin, and the opioid agonist analgesic hydrocodone in its bitartrate form is combined with the non-opioid analgesic acetaminophen.
  • combination drugs consisting of an opioid agonist analgesic and another drug(s) or medication(s) are among the most widely abused opioid agonists abused. If these combination drugs contain acetaminophen, as in the case with Percocet®, a large amount of Percocet® tablets may be orally ingested, so much so as to cause a toxic load of acetaminophen to be delivered. Acetaminophen is widely known to be toxic to the liver of humans when administered in excessive dosages, or when abused by self-administration either intentionally or unintentionally.
  • Hydrocodone as hydrocodone bitartrate, for example
  • opioid agonist analgesics are commonly mixed with other non-opioid analgesic drugs in formulating combination medications.
  • the high rate of first pass metabolism in the liver of nalmefene is taken into consideration. Approximately 95% of nalmefene is metabolized via first pass metabolism. Therefore, a relatively larger amount of nalmefene must be ingested orally as compared to when nalmefene is administered parenterally in order to obtain bioequivalent concentrations of nalmefene circulating in the blood at a given moment in time.
  • nalmefene will tend to accumulate over time relative to hydrocodone and acetaminophen such that as more time progressively transpires the nalmefene serum concentration relative to hydrocodone serum concentration will increase as the tablets are ingested over that time. Eventually, this will cause an appreciably different effect of the opioid agonist analgesic. This effect could include prevention of mortal respiratory depression, or lack of satisfaction due to opioid ingestion.
  • opioid agonist analgesics include the following opioids and their derived salts and bases: morphine, propoxyphene, fentanyl, methadone, levomethadyl (LAAM) and codeine.
  • LAAM levomethadyl
  • NMDA-receptor antagonists are thought to inhibit the mechanism by which tolerance to opioid-like effects occurs, and may also potentiate the effects of opioid agonist analgesics thereby enhancing their apparent potency.
  • MorphiDex® Endo Pharmaceuticals, Inc., Chadds Ford, PA. This product is a formulation of dextromethorphan, a NMDA-receptor antagonist, and morphine.
  • NMDA-receptor antagonist dextromethorphan a proposed product comprising Percocet® "enhanced" by the NMDA-receptor antagonist dextromethorphan is contemplated.
  • both of these described formulations attempt to decrease the liability for opioid addiction by decreasing the amount of opioid administered to obtain a given analgesic effect, neither one protects against mortal respiratory depression.
  • NMDA-receptor antagonists may in some way potentiate the opioid-like effects of opioid agonist analgesics, it remains to be demonstrated whether the combination of morphine and dextromethorphan may render a human even more susceptible to opioid drug overdose.
  • the present invention is extended to include a NMDA-receptor antagonist, as for example dextromethorphan, in the drug formulation along with nalmefene and an opioid agonist analgesic.
  • a NMDA-receptor antagonist as for example dextromethorphan
  • an opioid agonist analgesic analgesic

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Abstract

L'invention concerne l'utilisation d'un agent de blocage opioïde kappa permettant d'optimiser l'homéostasie de la dopamine pendant l'administration d'analgésiques opioïdes, de prévenir une dépression respiratoire mortelle entraînée par une surdose de médicaments et de dissuader des êtres humains ou des animaux de s'auto-administrer des quantités excessives d'analgésique opioïde.
PCT/US2001/022007 2000-07-13 2001-07-12 Sels et bases de 17-(cyclopropylmethyl)-4,5 alpha-epoxy-6-methylenemorphinan-3,14 diol permettant d'optimiser l'homeostasie de la dopamine pendant l'administration d'analgesiques opioides WO2002005647A1 (fr)

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MXPA02003670A MXPA02003670A (es) 2000-07-13 2001-07-12 Sales y bases de 17-(ciclopropilmetil)-4,5 alfa-epoxi-6-metilenomorfinan-3,14 diol para optimizar la homeostasis de dopamina durante la administracion de analgesicos.
CA002386794A CA2386794A1 (fr) 2000-07-13 2001-07-12 Sels et bases de 17-(cyclopropylmethyl)-4,5 alpha-epoxy-6-methylenemorphinan-3,14 diol permettant d'optimiser l'homeostasie de la dopamine pendant l'administration d'analgesiques opioides
EP01957138A EP1272035A1 (fr) 2000-07-13 2001-07-12 Sels et bases de 17-(cyclopropylmethyl)-4,5 alpha-epoxy-6-methylenemorphinan-3,14 diol permettant d'optimiser l'homeostasie de la dopamine pendant l'administration d'analgesiques opioides
AU78909/01A AU782523B2 (en) 2000-07-13 2001-07-12 Salts and bases of 17-(cyclopropylmethyl)-4,5 alpha-epoxy-6-methylenemorphinan-3,14 diol for optimizing dopamine homeostasis during administration of opioid analgesics

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EP1531792A2 (fr) * 2002-05-13 2005-05-25 Endo Pharmaceuticals Inc. Forme posologique opioide empechant une utilisation abusive
WO2007061828A2 (fr) * 2005-11-21 2007-05-31 Schering-Plough Ltd. Compositions pharmaceutiques
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US8329216B2 (en) 2001-07-06 2012-12-11 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
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US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9522119B2 (en) 2014-07-15 2016-12-20 Isa Odidi Compositions and methods for reducing overdose
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US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
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US10898479B2 (en) 2013-05-30 2021-01-26 Euro-Celtique S.A. Dihydroetorphine for the provision of pain relief and anaesthesia
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form

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US5783583A (en) * 1996-04-12 1998-07-21 Simon; David Lew 17-(cyclopropylmethyl)-4,5alpha-epoxy-6-methylenemorphinan-3,14-diol, hydrochloride salt for the purpose of rapid narcotic detoxification

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8309122B2 (en) 2001-07-06 2012-11-13 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US8329216B2 (en) 2001-07-06 2012-12-11 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
EP1515674A1 (fr) * 2002-05-13 2005-03-23 Endo Pharmaceuticals Inc. Forme pharmaceutique solide opioide a l'epreuve des abus d'opioides
EP1515674A4 (fr) * 2002-05-13 2008-04-09 Endo Pharmaceuticals Inc Forme pharmaceutique solide opioide a l'epreuve des abus d'opioides
EP1531792A2 (fr) * 2002-05-13 2005-05-25 Endo Pharmaceuticals Inc. Forme posologique opioide empechant une utilisation abusive
EP1531792A4 (fr) * 2002-05-13 2006-10-04 Endo Pharmaceuticals Inc Forme posologique opioide empechant une utilisation abusive
US8226979B2 (en) 2003-09-26 2012-07-24 Alza Corporation Drug coating providing high drug loading and methods for providing the same
US8246986B2 (en) 2003-09-26 2012-08-21 Alza Corporation Drug coating providing high drug loading
US8541026B2 (en) 2004-09-24 2013-09-24 Abbvie Inc. Sustained release formulations of opioid and nonopioid analgesics
WO2007061828A3 (fr) * 2005-11-21 2007-07-19 Schering Plough Ltd Compositions pharmaceutiques
WO2007061828A2 (fr) * 2005-11-21 2007-05-31 Schering-Plough Ltd. Compositions pharmaceutiques
WO2007061739A3 (fr) * 2005-11-21 2007-07-12 Schering Plough Ltd Compositions pharmaceutiques
WO2007061739A2 (fr) * 2005-11-21 2007-05-31 Schering-Plough Ltd. Compositions pharmaceutiques
US9481681B2 (en) 2008-12-08 2016-11-01 Euro-Celtique S.A. Dihydroetorphines and their preparation
US9206190B2 (en) 2008-12-08 2015-12-08 Euro-Celtique S.A. Dihydroetorphines and their preparation
US10745406B2 (en) 2008-12-08 2020-08-18 Euro-Celtique S.A. Dihydroetorphines and their preparation
WO2012089738A1 (fr) * 2010-12-28 2012-07-05 Euro-Celtique S.A. Combinaison d'un agoniste des opioïdes et d'un antagoniste des opioïdes dans le traitement de la maladie de parkinson
AU2011351447B2 (en) * 2010-12-28 2016-02-25 Mundipharma Pty Limited A combination of an opioid agonist and an opioid antagonist in the treatment of Parkinson's disease
EA025747B1 (ru) * 2010-12-28 2017-01-30 Эро-Селтик С.А. Комбинация агониста опиоидных рецепторов и антагониста опиоидных рецепторов для лечения болезни паркинсона
US10898479B2 (en) 2013-05-30 2021-01-26 Euro-Celtique S.A. Dihydroetorphine for the provision of pain relief and anaesthesia
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10639281B2 (en) 2013-08-12 2020-05-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10792254B2 (en) 2013-12-17 2020-10-06 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9700516B2 (en) 2014-07-15 2017-07-11 Isa Odidi Compositions and methods for reducing overdose
US9801939B2 (en) 2014-07-15 2017-10-31 Isa Odidi Compositions and methods for reducing overdose
US10293046B2 (en) 2014-07-15 2019-05-21 Intellipharmaceutics Corp. Compositions and methods for reducing overdose
US10653776B2 (en) 2014-07-15 2020-05-19 Intellipharmaceutics Corp. Compositions and methods for reducing overdose
US9700515B2 (en) 2014-07-15 2017-07-11 Isa Odidi Compositions and methods for reducing overdose
US9522119B2 (en) 2014-07-15 2016-12-20 Isa Odidi Compositions and methods for reducing overdose
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form

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