MXPA02003670A - Salts and bases of 17-(cyclopropylmethyl)-4,5 alpha-epoxy-6-methylenemorphinan-3,14 diol for optimizing dopamine homeostasis during administration of opioid analgesics. - Google Patents

Abstract

A kappa opioid blocking agent is used for optimizing dopamine homeostasis during administration of opioid analgesics, for preventing mortal respiratory depression due to drug overdose, and for dissuading a human or animal from self-administering excessive amounts the opioid analgesic.

Description

SALTS AND BASES OF 17- (CICLOPROPILME IL) -, 5 ALPHA-EPOXY-6-METHYLENOMORFINAN-3.14 DIOL TO OPTIMIZE THE HOMEOSTASIS OF DOPAMINE DURING THE ADMINISTRATION OF OPIOID ANALGESICS Technical Field of the Invention The present invention relates to a method for optimizing dopamine levels inside or outside the central nervous system during the administration of exogenous agonist opioid drugs. The result of maintaining an optimal homeostasis of dopamine levels in the specific sites of human organs intensifies the "positive" effects of opioid agonist analgesics, to say euphoria, analgesia and improved motor and behavioral functioning, in such a way , that a smaller amount of the opioid analgesic agonist is necessary to produce a certain effect of analgesia or euphoria, which in turn, reduces the risk of becoming chemically dependent on the analgesics of opioid agonists.The "positive" effects of opioid analgesics agonists are effects that are desirable and intended effects associated with the administration of opioid agonists REF 137847 exogenous These positive effects include analgesia or pain relief, euphoria or well-being and a calming effect to reduce heart rate, blood pressure or respiratory rate. Negative effects "of opioid agonist analgesics are undesirable effects and are not the intended effects associated with the administration of exogenous agonist opioids.These negative effects include dysphoria, abnormal motor function, constipation, difficulty in urination and becoming chemically dependent on opioid analgesics agonists The molecule of 17- (cyclopropylmethyl) -4,5-alpha-epoxy-6-methylene-morphinan-3, 14, diol also known as nalmefene, is generally classified as a receptor-kapa that prefers the pure opioid antagonist. In the present invention, low doses of nalmefene in structural preparations are combined with an opioid agonist analgesic drug to thereby increase the analgesic effect of, and to decrease the risk of, chemical dependence on the opioid analgesic drug agonist at therapeutic doses of the opioid agonist. In higher doses than the therapeutic ones for the opioid agonist, the present inv This also tends to block the positive effects of the opioid agonist, in order to dissuade humans from self-administering more opioid agonist that is intended by a health professional. This is very important because the illicit abuse of opioid analgesics agonists, due to self-administration, is a major problem in society that usually leads to chemical dependence, addiction, serious health effects, crime, a burden on the criminal justice system and family welfare disorders and several undesired outcomes due to this.

BACKGROUND OF THE INVENTION Opioid agonist analgesic drugs are generally administered to reduce or alleviate pain. Examples of these drugs are morphine, meperidine, fentanyl, opium and hydrocodone. There are several opioid agonist analgesic drugs to which the present invention applies. Unfortunately, the administration of an opioid agonist analgesic drug over a prolonged period of time, as is common for treating various pain syndromes, generally results in the development of a physiological tolerance to the opioid analgesic agonist drug, and therefore, requires, with the passage of time, an increasing amount of the analgesic drug opioid agonist to produce an analgesic equivalent effect. This can lead to a chemical dependence on the opioid agonist analgesic, and in this way, to an abrupt withdrawal of the opioid agonist drug that will produce physical signs and physiological symptoms that, in general, are opposite to the positive effects originally produced by the opioid. agonist These signs of withdrawal include excitation of the sympathetic nervous system such as norepinephrine release from the locus coeruleus in the brain, an increased heart rate and blood pressure, increased respiratory rate, altered gastrointestinal function leading to nausea, vomiting and / or diarrhea, piloerection ("goosebumps"), pain and psychological or psychosomatic symptoms such as experiencing "fleeting episodes of heat and cold," difficulty sleeping and chills. Abdominal cramps, pains - especially cramping in the legs and involuntary movements - especially the movement of involuntary kicking of the legs and feeling weak and other complaints associated with the withdrawal of opioid agonists from a human being chemically dependent on them. In general, this myriad of signs and symptoms is what is colloquially known as "withdrawal syndrome". It is this abstinence syndrome that it is usually the incentive for humans chemically dependent on opioid agonists to seek and self-administer opioid agonist analgesic drugs without proper supervision by a health professional. When there are other behavioral factors, such as the impossibility of functioning in society, criminal behavior to support the use of the opioid agonist drug and / or psychiatric or psychological deterioration that can be directly attributed to the use of the drug, it is said that the human has a addiction to the opioid analgesic agonist. Common opioid analgesic agonists to which humans usually become addicted include heroin, methadone and its derivatives. Humans have the potential to become addicted to many other opioid agonist drugs and analgesics. The need to develop ways to administer agonist opioid drugs without causing, or attenuating to the greatest extent possible, the negative effects of drugs at their therapeutically prescribed doses has been felt for some time. This is achieved by attacking the optimal balance of effects between dopamine and an increase in opioid receptors, such as mu-opioid and dopamine receptors and decreased opioid receptors, such as kappa-opioid receptors. The present invention fulfills this need in a unique and novel way that had not been appreciated by those skilled in the opioid analgesic art. The present author describes in U.S. Patent Application No. 5,783,583 in great detail the unique characteristics common only to the opioid antagonist nalmefene, which put nalmefene apart from the other opioid antagonists such as, for example, naloxone and naltrexone. U.S. Patent No. 5,783,583 (583) further describes how the unique agglutination profile of the subtype for the opioid receptor of nalmefene allows only nalmefene, compared to naloxone and naltrexone, to allow a preferred antagonism of the opioids for the kappa-opioid receptors against 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 opposite opioid systems located in the mesolimbic system of the human central nervous system. These systems modulate the A10 dopaminergic neurons that protrude into the nucleus accumbens. The stimulation of mu-opioid receptors (the mu subtype of the opioid receptor) in the ventral area of the tegmentum (VTA), the site of origin of the A10 neurons, increases the release of dopamine in the nucleus accumbens (NA). Selective blocking of this mu-receptor results in a significant decrease in the release of dopamine in the nucleus accumbens. In strict contrast, the stimulation of the kapa-receptors (the kappa subtype of the opioid receptor) either in the VTA or in the NA results in a decrease in the amount of dopamine released. Selective blocking of kapa receptors significantly increases dopamine release. Spanagel et al. (Proc. Natl. Acad. Sci., 89: 2046 (1992)) demonstrate that the mu and kappa tonically active and functionally opposed opioid systems regulate the mesolimbic release of dopamine in the nucleus accumbens. They indicate that the injection of mu-opioid agonists such as DAGO in the VTA stimulate the mu-opioid receptors and increase the release of dopamine from the VTA in the NA. As expected, administration of the mu-opioid receptor agonist in the VTA decreases the release of dopamine. The authors also indicate that kappa receptor agonists such as U-6953 implanted in NA inhibit the release of dopamine there, while kappa-opioid receptor antagonists such as nor-BNI increase the release of dopamine. An "agonist" is a "similar" chemical with an action similar to a given drug; an "antagonist" is a chemical, usually with a chemical structure similar to that of a given drug, which exerts an action other than that particular drug, and generally preventing the "similar" action of that particular drug. With opioid receptors, in general, an agonist agglutinates the receptor and activates it in such a way that a cascade of chemical or pharmacological events begins that results in a final effect related to an opioid receptor subtype. In contrast, an antagonist binds to the receptor but does not activate it. An antagonist exerts its actions by blocking the receptors of the agonists, by occupying in physical form the space in the receptor where the agonist had agglutinated. Opposed mu-and kappa-opioid systems work together to provide a homeostasis of dopamine levels within the central nervous system. Therefore, it would be expected that changes in these opioid systems, such as due to the activation or blocking of specific receptors, modulate the effects induced by opioids. that are mediated by the mesolimbic pathways. The mu and kappa receptors are found in other parts of the human body. For example, they have been located in the spinal cord (see Fujimoto, Bakshi, and Behrmann, below) and in other organs that are not of the central nervous system, such as the kidney and intestine (see Ohnishi and Kreek, below). Consequently, the presented model provides a neurochemical structure to understand the adaptive changes resulting from the long-term use of opioids, as well as the clinical response produced by exogenously administered agonist opioids and antagonists having different agglutination profiles. .

For example, modifications in opioid-induced behavior resulting from changes in these mu and kappa systems are reported by Pan et al. (Nature 389: 382 (1997)). These authors indicate that the effects of the opposition of mu and kappa receptors extend to the action of opioids on the emotion, perception and reinforcement of the drug. While morphine and other mu-opioid agonists increase dopamine release and produce euphoria and site preference, kappa agonist opioids reduce the mesolimbic release of dopamine and produce dysphoria and aversion.

Scientists have shown that nalmefene, related to other opioid antagonists such as naloxone and naltrexone, is significantly more preferable for the kappa receptor. In the manner of. example, Kreeks et al. (Life Sciences 56: 1887 (1995)), concludes that nalmefene has a higher binding activity for kappa than either for naloxone or naltrexone. Specifically, nalmefene is more potent than naloxone or naltrexone as a receptor-kapa antagonist, and thus blocks kappa agonists (eg, the naturally occurring dynorphin) to a greater degree than the other antagonists. Fujimoto et al. (Pharmcol. Biochem. And Behavior 46: 623 (1993)) demonstrate differences between the effects of the mu and kappa receptor on the spinal cord. Specifically, these authors indicate that administration of dynorphin, a potent kappa agonist, results in decreased analgesia. Dynorphin causes anti-analgesic effects at the level of the spinal cord. Fugimoto shows that when the kappa-opioid receptor antagonist such as cholera toxin is administered, the anti-analgesic effect of dynorphin is inhibited. Bakshi et al. (J. Neuroscience 19 (12): 3793 (1990)) show that kappa receptors are widely distributed in the spinal cord, and that dynorphin administration causes a motor malfunction. These authors also demonstrate that nalmefene is selective for these intraspinal kappa receptors, and limits dynorphin-induced motor dysfunction after damage to the spinal cord. Behrmann et al. (Experimental Neurology 119: 258 (1993)) indicate that a single dose of nalmefene has an increased activity at kappa receptors and that a single dose of nalmefene exerts a significant neuroprotective effect after acute damage to the spinal cord, in direct contrast to preferred mu opioid antagonist, naloxone, which shows no effect on neurological recovery after spinal cord damage. Ohnishi et al. (J. Pharm. Exp. Ther 270 (1) (March 19, 1994)) show the effects on urine production due to a pharmacology of the kappa-opioid receptor at both the pituitary and kidney levels. Crain et al. (U.S. Patent No. 5,580,876) show a method for "selectively enhancing the analgesic potency of an opioid agonist acting in two modes" comprising administering an opioid agonist such as morphine with an "opioid receptor excitatory antagonist such as naltrexone or nalmefene" , effective to intensify the analgesic potency of the opioid agonist acting in bimodal form. "However, Crain shows that nalmefene, naltrexone, naloxone, etorphine and dehydroetorphine are analogous compounds suitable for this invention, although, * 583 clearly shows that naltrexone and naloxone do not They are analogous to nalmefene, Crain et al., to such a degree that they say that "suitable excitatory antagonists for the opioid receptors of the invention include nalmefene, naltrexone, naloxone, etorphine and dihydroetorphine, as well as the opioid alkaloids and peptides. opioids that act in a similar way. "(See column 4, lines 60-67.) Even when narrowing the scope of the invention to 5,580,876 (876), the authors indicate that the" preferred excitatory antagonists of the receptor are nalmefene and naltrexone. due to its longer period of action compared to naloxone, "but they do not mention the different and significant differences in terms of characteristic s between nalmefene and naltrexone, as related to differences in agglutination profiles for opioid receptor subtypes that are clearly and unambiguously shown in 5,783,583 (x583). Although '876 claims only nalmefene as the "effective antagonist to enhance the analgesic potency of the opioid agonist that acts in a bimodal manner ", the claims are not consistent with the detailed description of the invention which repeatedly shows, in the manner of several described examples, that diprenorfinem, naloxone and naltrexone are analogues (example 2), and that nalmefene and naltrexone are analogous (example 8) - which is further supported by the author's statement, "simultaneous treatment with nalmefene is as effective as naltrexone in attenuating the likelihood of morphine dependence." (See column 14, lines 51- 53) No definitive statement is made that nalmefene is superior to naltrexone for the purposes of the invention 876. The '876 patent does not mention the positive and negative effects of the agonist opioids shown in the present invention. example, no mention is made in? 876, with respect to the euphoria against dysphoria, or of behavioral effects such as emotion, perception, drug reinforcement and pre In addition,? 876 does not mention effects on bowel function or urination. Perhaps the most convincing, however, is that? 876 does not refer to mu and kappa opioid receptors in opposition to maintaining a homeostatic balance of dopamine in the mesolimbic region of the brain, in the medulla spinal or other peripheral sites such as the intestine or kidney. In addition to the drawbacks previously mentioned in the '876 patent, the dosing of the nalmefene which is indicated is too imprecise in relation to the amount of the opioid agonist acting in bimodal form. This is because each opioid agonist, in particular, has its characteristic potency. For example, fentanyl is many times more potent than morphine. Therefore, the effective dosage range of nalmefene consistent with * 876 should be significantly different for fentanyl compared to morphine. However,? 876 does not make this distinction. In fact, '876 claims that the required dose of nalmefene is the same for each of the very diverse agonist opioid drug groups: "morphine, codeine, fentanyl analogue, pentazocine, methadone, buprenorphine, enkephalin, dynorphin, and opioid alkaloids. that act in a similar way and opioid peptides that act in a similar way ". The affinity with which each opioid agonist binds to a particular subtype of opioid receptor is of critical importance for the present invention. ? 583 shows that, for example, beta-endorphin agglutinates mu receptors with a significantly higher affinity than opioid morphine exogenously administered This is important for establishing dopamine homeostasis by mu and kappa opposing receptors because an exogenously administered opioid agonist (eg, morphine) will compete with both endogenous opioid agonists (eg, beta-endorphin), dynorphin) as well as the opioid antagonist in question (for example nalmefene). Because different opioid agonists may have different affinities for a particular opioid receptor, especially when all are administered with the same unit mass doses, it is impossible for opioid agonists as diverse as those claimed in '876 to have equal effects. when they undergo an equal amount of nalmefene. Therefore, the claims of? 876 are excessively vague and should not obviate the claims of the present invention. Speaking still more about the vagueness and unfinished nature of the invention claimed in '876, it is indicated in? 876 (column 6, row 47) that the amount of the opioid agonist to treat an opioid addict "is easily determined by someone skilled in the technique ", and no attempt is made to indicate a dose of antagonists which in fact causes this aspect of the invention to work? The invention? 583 emphatically rejects the ideas that all opioid antagonists are similar, and it is obvious with respect to the optimal antagonist and its respective doses, to treat an opioid addiction. Moreover, buprenorphine, an agonist that activates relatively weak mu and an antagonist that prefers kappa, and the mixed opioid agonist-antagonist, pentazocine, are listed in '876 as analogous compounds for "morphine, codeine, analogs of pentanyl ... etadone, encephaliins, dynorphins, alkaloids and opioid peptides that act similarly "as related to nalmefene, is still further evidence that Chain et al. they have no appreciation for the usefulness of the unique agglutination characteristics of nalmefene, and give further evidence that the present invention is patentable with respect to 876. (See column 4, lines 34-38 of 876) .85 It is one great importance, that the claimed doses of nalmefene at? 876 are too small to have a significant effect in deterring a human from self-administering too much opioid agonist analgesic as in the present invention. Therefore, the present invention is not inherent to '876. By comparing '876 with the present invention, only the present invention appreciably deters a human from abusing illicitly opioid analgesics agonists. In fact, it is possible that '876 may have just the opposite effect. Other researchers have looked at the preparations of opioid agonists in combination with naloxone. However, as' 583 clearly shows, nalmefene and naloxone are not analogous compounds. Therefore, the present invention would not have been obvious to someone skilled in the art simply because naloxone has previously been combined with opioid agonists. In fact, due to the agglutination profile of the opioid receptor subtype of naloxone, it can not exert positive opioid effects such as nalmefene at similar doses, as shown in the present invention.

Description of the Invention The present invention is directed to methods for amplifying the positive effects of opioid agonist analgesic drugs by effectively antagonizing kappa-opioid receptors to a greater extent than mu-opioid receptors at recommended therapeutic doses, such that need to administer a smaller amount of the opioid agonist to give a certain positive effect, and in this way decrease the tendency to a physiological tolerance to the drug, and therefore decrease the risk of a chemical dependency or addiction, while also resulting in an appreciable antagonism of the mu-opioid receptors when an opioid analgesic agonist is administered above the recommended therapeutic dose in order to deter a human of self-administering excessive amounts of the opioid agonist analgesic. The methods consist of administering to a living human or animal, a prescribed dose of nalmefene in combination with a prescribed dose of an opioid analgesic agonist, the amount of nalmefene being effective to significantly antagonize the kappa receptors while at the same time having a minimal antagonist effect on mu receptors, and thus be able to intensify the positive effects of opioid agonists in such a way, that the actions of mu-opioid agonists have much more weight than any antagonism of nalmefene in mu-opioid receptors in doses therapeutic treatments. The present invention also provides a structural composition comprising a therapeutic dose of an opioid agonist analgesic in combination with an amount of nalmefene effective to enhance the positive effects of the opioid agonist analgesic, while at at the same time exerts minimal antagonistic effects on mu-opioid receptors, when the opioid agonist analgesic is administered at recommended therapeutic doses, such that the agonist actions of the opioid agonist analgesic far exceed any antagonism of nalmefene at the mu-opioid receptors . If excessive amounts of the structural composition comprising nalmefene and the opioid analgesic agonist are administered, a sufficient amount of nalmefene must be administered to begin to antagonize or block the mu-opioid receptors of the exogenously administered opioid agonist analgesic in addition to the kappa-opioid receptors, such that a human being is dissuaded from self-administering these excessive amounts of the structural composition. Briefly, this present invention is directed to a method for optimizing the homeostatic control of dopamine release in the central nervous system (CNC) which tends to intensify the analgesic effect of the opioid analgesic agonist selected in the therapeutic doses intended for opioid analgesic agonist , and in which doses higher than the intended therapeutic dose of the opioid analgesic agonist will tend to exert undesirable effects in order to dissuade a human being from self-administering a greater amount to the intended therapeutic dose of the opioid analgesic agonist. The method comprises administering to a human or animal an opioid agonist analgesic and an amount of nalmefene or other similar opioid antagonist having a preference for kappa in defined proportions, such that relatively minor amounts of the nalmefene provided and the opioid analgesic agonist tend to optimize dopamine levels in the CNC and in this way intensify analgesia and other desirable effects of the opioid agonist analgesic, and the relatively greater amounts of nalmefene provided and the opioid analgesic agonist will tend to produce an adverse balance of dopamine in the CNC, and in this way, limit the positive or desirable effects of the opioid agonist analgesic, and thus discourage a human or animal from self-administering a greater quantity than the intended therapeutic dose of the opioid agonist analgesic. The specific proportions of nalmefene and the opioid agonist analgesic will depend on the potency of the opioid agonist analgesic in particular, and on the pharmacokinetic profiles of the drugs, including the volumes of distribution, elimination constants, half-life in the blood, half-life of elimination, solubilities, protein agglutination physiological and so on. In light of the present invention, one skilled in the art can compensate for these parameters. However, generally, on a unit mass basis, the proportion of opioid analgesic agonist to nalmefene should range from about 1.2: 1 to 990: 1. Accordingly, in addition to the objects and advantages of combining nalmefene in a common carrier medium with an opioid analgesic agonist to form a structural composition for administration in a human being described in the present invention, some objectives and advantages of the present invention are : a) Administer the opioid agonist analgesic drugs in a less effective amount to produce the desired effects of the analgesic opioid drug; and b) The aforementioned goal and "a" advantage saves expensive resources in the manufacture of opioid agonist drugs; and c) The aforementioned goal and the "a" advantage reduces the speed at which tolerance to the opioid agonist painkiller occurs, resulting in a reduced risk for the development of a chemical dependence and addiction; Y d) Put an effective "limit" on the amount of the opioid agonist medication that is likely to be self-admitted by a human being - in excessively high amounts of the composition containing both the nalmefene and the opioid agonist analgesic, the amount of nalmefene administered will begin to exert undesirable [negative] effects by antagonizing or blocking mu-opioid receptors relative to the exogenously administered opioid agonist analgesic in addition to antagonizing or blocking the kappa receptors; and e) The aforementioned objective and the "d" advantage greatly limits the abuse potential of opioid agonist analgesics, resulting in a reduced risk for the development of a chemical dependency and addiction; and f) That, with a single composition containing both the nalmefene and the opioid agonist analgesic, results in both the aforementioned objectives and their "a" and "d" advantages in amounts of a single administered composition that reasonably limits self-administration of very high doses of the opioid analgesic agonist (as might occur if the concentration of nalmefene in the single composition was lower in the present invention in terms of orders of magnitude); Y g) Produce an easy-to-administer composition, both nalmefene and the opioid agonist analgesic, in amounts that when the recommended therapeutic amounts of the composition are administered, nalmefene works in conjunction with the opioid analgesic agonist to produce the desired effects of the analgesic drug opioid agonist, but that in larger amounts of the composition produce undesirable effects; and h) Producing a composition to be administered, containing both the nalmefene and the opioid agonist analgesic, such that the release of both drugs results in concentrations of nalmefene, relative to the opioid analgesic agonist, which produces the intended effects as indicated. in the aforementioned objective and in the "g" advantage; and i) To greatly reduce the likelihood of fatal respiratory depression for a human or animal that is administered a too high dose of the opioid agonist analgesic, either by mistake or intention; and j) decrease the likelihood or severity of constipation in association with the administration of an opioid analgesic agonist.

BEST METHOD FOR CARRYING OUT THE INVENTION AND INDUSTRIAL APPLICATION The present invention comprises the administration of nalmefene with an opioid analgesic agonist, in sufficient doses of nalmefene to, (i) intensify the analgesic effect of the opioid analgesic agonist at recommended therapeutic doses of the opioid analgesic. effective agonists to produce positive effects such as pain relief and euphoria, but not exceeding a recommended therapeutic dose for the analgesic; and (ii) producing undesirable effects at higher doses of the opioid agonist analgesic that exceed the recommended therapeutic dose. One embodiment of the present invention is a method wherein the nalmefene and the opioid agonist analgesic are administered by titration in a human being, using the relief of pain and euphoria as a baseline for the desirable effects, and using dysphoria and pain as basal points of the undesirable effects. The titration of the drugs can be by any acceptable method, for example by intravenous administration. A more practical and preferred embodiment of the invention is a composition comprising an opioid analgesic drug agonist and nalmefene in amounts of each drug, that when the composition is administered to produce a prescribed amount of the opioid analgesic agonist administered, a quantity of nalmefene is administered such that (i) a therapeutic dose of the opioid analgesic agonist is administered, and an amount of nalmefene which effectively block the kappa-opioid receptors but have minimal activity in the mu-opioid receptors, and (ii) in excessive doses at the recommended therapeutic doses of the opioid agonist analgesic, a quantity of nalmefene is administered which blocks appreciably , by competition, to mu-opioid receptors in relation to the exogenously administered opioid agonist analgesic. The optimum amount of nalmefene to achieve the objectives of the present invention will depend, in part, on which opioid analgesic agonist is administered simultaneously with nalmefene, since the different opioid agonists have different potencies and different affinities of agglutination to the various receptors. opioids in a given dose of unit mass of the opioid agonist, such as milligrams, micrograms or nanograms. Ideally, the preferred embodiment of the invention equals the opioid analgesic agonist with nalmefene, the which has similar pharmacokinetic properties as nalmefene, as the elimination half-life, so that the concentrations of each drug remain in an appropriate proportion in relation to each other during a certain period of time, so that a drug does not accumulate in this way for a period of time to a greater degree than the other drug, to a deleterious effect for the scope of the present invention. Where the half-life of the opioid agonist is significantly different from that of nalmefene, a prolonged release formulation can be incorporated into the composition in such a way that the pharmacokinetics of both drugs become more compatible.

Example 1 A recommended therapeutic dose of morphine, for example 0.15 mg / kg of morphine, preferably in the form of morphine sulfate, is administered simultaneously and parenterally with 0.00025 to 0.0015 milligrams per kilogram (mg / kg) of nalmefene, preferably in the form of nalmefene hydrochloride, more preferably 0.0007 mg / kg nalmefene. For example, for a young 70 kg human adult, 10.5 mg of morphine sulfate is administered parenterally, along with 0.049 mg, or 49 micrograms (ug), of hydrochloride nalmefene parenterally. This small amount of nalmefene, consistent with the present invention, will block, at least partially, the kappa-opioid receptors. This same dose of nalmefene, consistent with the present invention, does not produce appreciable effects on mu-1 opioid receptors in relation to the 10.5 mg dose of morphine. Thus, taking into consideration the agglutination affinities of nalmefene for the different opioid receptors as described in '583, the present invention shows that these doses of nalmefene and morphine result in optimal levels of dopamine in the brain or spinal cord, and in this way the positive effects of morphine intensify. In a preferred embodiment of the present invention, morphine sulfate and nalmefene hydrochloride coexist in a compatible common medium for parenteral administration in the ratio of 0.15 mg of active morphine to 0.0007 mg / kg of active nalmefene. Ideally, if administered subcutaneously, the total amounts of the two active drugs administered simultaneously may be contained within an injectable volume of about 1 to 2 ml (cc) for a 70 kg adult human.

Assuming that 10.5 mg of active morphine and 49 ug of active nalmefene are contained in a bottle with 1.5 cc of liquid, if a human self-administered twice the recommended therapeutic dose, ie 3 cc, then the human would receive 21 mg of morphine and 98 ug of nalmefene, or approximately 0.1 mg of nalmefene. This amount of nalmefene would serve as a protective effect to greatly reduce the likelihood that the human would succumb to an overdose of morphine, such as from life-threatening respiratory depression. Some researchers believe that respiratory depression is regulated by kappa-opioid receptors in a part of the brain that is not necessarily correlated with dopamine homeostasis in the nucleus accumbens, the ventral tegmental area, or the spinal cord. This amount of morphine and nalmefene co-administered gives a ratio of morphine to nalmefene of about 214 to 1 on a unit mass basis. If a human were to self-administer 10 times the recommended therapeutic dose of morphine, or 105 mg of morphine, the invention incorporated in this example would result in approximately 0.5 mg of nalmefene administered. This dose of nalmefene tends to compete significantly with the morphine exogenously administered, such that the mu-opioid blocking effect of nalmefene tends to compete significantly with the mu-opioid activating effect of morphine, resulting in a certain degree of negation of the desirable effects of the opioid analgesic agonist, that would result in a relative lack of pain relief. In addition to being quite protective against an overdose of the drug that attempts against life, the human tends to be dissuaded from using 10 times the medium containing morphine and nalmefene in the proportion described in this example. Some researchers believe that respiratory depression is regulated by mu-2 opioid receptors. If a sufficiently high dose of the morphine / nalmefene preparation is administered, the concentration of nalmefene in the mu-1 receptors may be high enough to compete appreciably with the endogenously produced beta-endorphin, which would manifest negative effects such as dysphoria . This also tends to dissuade the human from administering a greater amount of preparation, or to repeat this series of events in the future.

Example 2 Fentanyl is approximately 100 times more potent than morphine on a unit mass basis, for example per milligram or per microgram, furthermore depending on the amount administered, fentanyl tends to have a shorter action compared to morphine. Therefore, when fentanyl (in its citrate form or as another congener) and nalmefene coexist in a compatible common medium for parenteral administration, a ratio of 0.0015 mg of active fentanyl to 0.0007 mg of active nalmefene would have a similar profile of compatibility as in example 1 immediately at the time of administration, ie before a redistribution and significant elimination. However, because fentanyl has a relatively short action compared to nalmefene, repeated administrations of a composition with this ratio of fentanyl to nalmefene may result in the accumulation of nalmefene in relation to fentanyl, such that fentanyl it may become ineffective in mu-opioid receptors at a concentration of fentanyl that is not intended for this to occur. Therefore, a lower dose is used in the nalmefene range consistent with this invention.

Fentanyl 0.0015 mg / kg and nalmefene 0.00025 mg / kg administered together give a ratio of fentanyl to nalmefene from 15 to 2.5 on a unit mass basis. A young human of 70 kg. Was administered simultaneously 0.105 g of fentanyl (105 ug fentanyl) with 0.0175 mg of nalmefene (17.5 ug nalmefene). 105 ug of fentanyl is a therapeutic dose to treat pain in a young adult human. 17.5 ug of nalmefene tend to block appreciably the effects on kappa-opioid receptors, because nalmefene is a preferred opioid antagonist for kappa. However, in mu-1 opioid receptors this amount of nalmefene tends to compete effectively with endogenous beta-endorphin, and also tends to be relatively inconsequential to compete with this amount of fentanyl exogenously administered at mu-1 receptors. . Therefore, the expected general effect would be an intensification of the positive effects of fentanyl. If a human tried to self-administer, by way of example only, the indicated therapeutic dose of the combined preparation of fentanyl / nalmefene every hour, which would produce doses of fentanyl (alone, ie without nalmefene) that could cumulatively produce a Respiratory depression that threatens life in a 70 kg human adult who is not tolerant to opioid analgesics agonists, or doses that could be self-administered by a tolerant or non-tolerant human to achieve euphoria on a frequent basis, the following could occur. Nalmefene, by virtue of its significantly longer plasma half-life, a longer elimination half-life, and a greater affinity for remaining bound to opioid receptors compared to fentanyl, would accumulate and increase its concentration in relation to fentanyl in such a way , that eventually nalmefene concentrations would be present in the mu-opioid receptors to compete significantly with the exogenously administered fentanyl, such that the mu-opioid blocking effect of nalmefene tends to compete significantly with the mu-opioid activating effect of the opioid analgesic exogenously administered agonist, fentanyl. This, in addition to preventing lethal respiratory depression, should deter a human being from self-administering that amount of fentanyl preparation on a frequent basis. Alternatively, when two drugs with these different pharmacokinetic profiles are combined into one preparation, such as fentanyl and nalmefene, the short acting drug, for example fentanyl, can be prepared by encapsulating the drug particles in the form of a microcapsule or coating them with a material, such as cellulose, lactic acid polymers or the like, for that its release into the systemic circulation after release from a combined matrix is delayed to even out the pharmacokinetic profile of the longer acting drug, for example nalmefene. In light of the present invention, one skilled in the art could easily prepare this preparation. Another alternative is to formulate a transdermal delivery system, or a patch for use on the skin of a human, that contains both fentanyl and nalmefene in proportions consistent with the present invention. There exists in the prior art a transdermal preparation for fentanyl, the Duragesic® patch. However, there is a significant problem with this product in that drug addicts boil the patch in a solvent solution and then distill the solution to obtain a fentanyl preparation that can easily be abused by injecting it intravenously into a human. A preferred embodiment of the present invention that Involving the transdermal patch would be to formulate a patch with two cups of drug administration. Fentanyl could be administered faster by being contained within an adhesive matrix that can be administered by diffusion through a concentration gradient. Nalmefene may be administered more slowly by using a partially permeable membrane that limits the transfer of nalmefene through the membrane. In this way, fentanyl and nalmefene are contained within two different compartments within the patch - fentanyl in the adhesive matrix, and nalmefene in a pool that is separated from fentanyl by a partially permeable membrane. One skilled in the art, in light of the present invention, can prepare other structures that achieve the same objective. The partially permeable membrane may be sensitive to temperature so that it degrades at a certain specified temperature, or be made to degrade upon exposure to certain solvents. Thus, if the skin patch containing fentanyl and nalmefene was washed or boiled in a solvent, nalmefene would be mixed with fentanyl, and in fact nalmefene would be released in amounts to compete significantly with the exogenously administered opioid agonist analgesic, fentanyl, in the mu-1 receptors. This tends to dissuade a human from repeating this act in the future. In this way, the illicit abuse of transdermal fentanyl could be easily prevented, while at the same time a fentanyl / nalmefene skin patch would be allowed to be effective enough to produce the desired effects and pain relief.

Example 3 Methadone is a relatively long-acting opioid analgesic agonist which is administered orally, which is commonly used as a substitute for heroin in the treatment of humans addicted to heroin. A significant problem with methadone, however, is its great potential for illicit abuse. So high is this potential, that in the United States of North America, methadone is normally distributed only in specified distributors of methadone especially authorized by government agencies and the Federal Agency Against Drug Trafficking. One embodiment of the present invention solves a long-sought need to formulate methadone in such a way that i) optimizes its action in a way that requires less amount of drug - this would decrease the process by which a human can become tolerant to the effects of methadone and ii) produce a form of the drug that, when used in the wrong way, results in unpleasant side effects. It is known that nalmefene undergoes extensive first-pass metabolism within the liver. Because of this, orally administered nalmefene is hardly bioequivalent at 1/20 to 1/25 of nalmefene administered intravenously. In other words, 50 mg of nalmefene administered orally in the gastrointestinal tract of a human will be approximately equivalent to 2 mg of nalmefene administered intravenously. It is known that some humans addicted to opioid agonist analgesics are prescribed an oral methadone liquid preparation, and if they are not properly supervised, they are injected intravenously in order to achieve a greater "crush" of the drug or sensation. going up". To greatly reduce the likelihood of this misuse, a therapeutic dose of methadone is prepared in an oral preparation, for example 100 mg, when combined with 1 mg of nalmefene (Nalmefene lmg orally administered in the gastrointestinal tract is bioequivalent to approximately 40 ug, or 0.040 mg, of intravenously administered nalmefene). The The proportion of methadone for nalmefene on a unit mass basis is 100 to 1 in the methadone / nalmefene preparation. With respect to the intended oral administration of this combination of methadone and nalmefene, nalmefene will tend to block the kapa receptors, which would optimize the homeostatic balance of dopamine in the central nervous system, without having an appreciable effect on the competition with endorphins. endogenous in the mu-opioid receptors, and would have very little if any substantial effect in competing with methadone in the mu-1 receptors. Therefore, the intended effect of methadone would be evident when administering per os, however, if a human self-administers this same preparation via the intravenous route, then a sufficient amount of nalmefene will be present in the mu-1 receptors to compete Substantially with the exogenously administered opioid agonist analgesic, methadone. As such, the human will not experience the expected "drug crush or rise sensation", and may experience other undesirable effects as well, and will therefore be dissuaded from taking such an action in the future, such as intravenously injecting a drug preparation intended for its oral use.

EXAMPLE 4 Sufentanil is a derivative of fentanyl which on a unit mass basis is 5 to 10 times as potent as fentanyl, or about 500 times more potent than morphine. When the salts or bases of sufentanil and nalmefene coexist simultaneously in a compatible common medium for parenteral administration consistent with the present invention, a ratio of about 0.00030 mg of active sufentanil to 0.00025 mg of active nalmefene can be administered. This, on a unit mass basis, produces a sufentanil proportion for nalmefene of about 1.2 to 1. A typically therapeutic parenteral dose of sufentanil to produce analgesia for a chronic pain syndrome in a 70 kg young adult human is approximately 21 ug. . Thusapproximately 18 ug of nalmefene would be administered simultaneously with 21 ug of sufentanil. This amount of nalmefene will tend to optimize the CNC dopamine as previously described. If they are administered intravenously by a human 20 times the therapeutic dose of sufentanil, as for example in an intentional suicide attempt, then 420 ug of sufentanil would be administered together with approximately 360 ug of nalmefene. This amount of nalmefene tends to compete substantially with the amount of the exogenously administered opioid agonist analgesic, sufentanil in the mu-2 opioid receptors and in the kappa receptor to prevent fatal respiratory depression due to an overdose of the drug.

Example 5 10 mg of parenteral morphine (subcutaneous) are hardly equivalent in analgesic effect to 90 mg of parenteral meperidine (subcutaneous). Therefore, eperidine has approximately ninth of the analgesic effect that the same amount of morphine on a unit mass basis. Therefore, a recommended therapeutic dose of meperidine, for example about 90 mg of parenteral meperidine, is administered simultaneously and parenterally with 0.00025 to 0.0015 milligrams per kilogram (mg / kg) of nalmefene, preferably in the form of nalmefene hydrochloride, more preferably 0.0013 mg / kg nalmefene. For a young 70 kg human adult, for example, approximately 90 mg of meperidine are administered parenterally together with 0.091 mg or 91 micrograms (ug) of Nalmefene hydrochloride in a parenteral form. This small amount of nalmefene, consistent with the present invention, partially blocks the kappa-opioid receptors. This same dose of nalmefene, consistent with the present invention, produces a minimal effect on mu-1 opioid receptors in relation to the 90 mg dose of meperidine and even a lower degree of competitive effect in relation to the endogenous beta-endorphin. Therefore, taking into consideration the agglutination affinities of nalmefene for the different opioid receptors as described in '583, the present invention shows that these therapeutic doses of nalmefene and meperidine would result in dopamine levels in the brain or spinal cord that they do not result appreciably with undesirable effects. In fact, it is theoretically possible that the dose of nalmefene in relation to the dose of meperidine may prevent an unpleasant side effect of an opioid analgesic agonist administered alone, ie constipation. In other words, meperidine exhibits a typical analgesic effect, but perhaps with a lower degree of tendency to cause constipation. However, if 10 times the amount of meperidine is administered, intentionally or by mistake, then almost 1 mg of nalmefene would be administered. A millmeth of nalmefene definitely prevents fatal respiratory depression under these conditions, and also contributes considerably to deter a human from self-administering an equal amount of the combined preparation of meperidine-nalmefene in the future. A unit mass basis, in this embodiment, the ratio of meperidine to nalmefene is about 990 to 1. Although not necessarily the most preferred embodiment of the present invention, this fifth example however is perfectly adequate to deter a human from self administering excessive doses of the opioid agonist analgesic, as well as preventing fatal respiratory depression.

Example 6 Tramadol, also known as the trademark Ultram, is a unique pharmaceutical agent that acts with some agonist properties in mu-opioid receptors, but which is also believed to act through other systems of the central nervous system (CNC) such how to influence the action of the serotonin and norepinephrine receptors. The serotonin neurotransmitter system has been involved for some time in the regulation of depression and anxiety, and more recently it has been implicated in the influence of a psychiatric illness known as obsessive-compulsive disorder (OCD). For example, the drug paroxetine HCL, also known by the brand name Paxil®, is used to treat depression, panic disorders, social anxiety disorder (SAD)., as well as OCD. The noradrenergic system (where norepinephrine is the main neurotransmitter) has also been implicated in depression and substance abuse. Recently, doctors working in the state of Florida have discovered that tramadol may have a role in the treatment of OCD. His research seems to indicate that tramadol is especially effective in treating OCD compared to a placebo, and possibly other drugs used to treat OCD. Serious and potential adverse experiences in the treatment of patients with OCD with tramadol, however, include tolerance at opioid receptors due to prolonged administration of tramadol (which acts as an agonist at mu receptors), as well as the potentially fatal reaction of respiratory depression. By combining nalmefene with tramadol in a single pharmaceul formulation consistent with the present invention, a drug preparation is prepared which has great promise for treating Obsessive Compulsive Disorder but which lacks the production of tolerance and the producing effects of the respiratory depression of the scavenger alone. Because OCD is a psychiatric condition that affects 1 in 50 Americans, and because the first lines of medical treatment produce improvement rates of only 20%, this example of the invention fills a much-needed vacuum for treatment of OCD. The drugs that are normally used to treat OCD before the present invention include serotonin and clomipramine uptake inhibitor drugs, each having a profile of associated adverse effects other than tramadol or tramadol in combination with nalmefene.

Example 7 Buprenorphine is a partial opioid agonist. It has unique agglutination characteristics in comparison to other opioid agonist analgesics, in which buprenorphine agglutinates mu-1 opioid receptors with a very high affinity; however, although it is totally bound to these mu receptors, buprenorphine exerts a mu-activating effect. -1 very weak in relation to other analgesics opioid agonists. In fact, the affinity of buprenorphine for mu-1 receptors is so high that many times the recommended therapeutic doses of naltrexone or nalmefene only partially reverse or partially antagonize the agglutination of the therapeutic doses of buprenorphine at mu-1 receptors. . A useful method to treat opioid addiction is to replace buprenorphine with the abused illicit opioid. This is well known in the art. For example, a human addicted to heroin will be given buprenorphine instead. Buprenorphine, because it agglutinates mu-1 receptors with such high affinity, tends to displace heroin from mu-1 receptors. Buprenorphine, once bound to these mu receptors, tends to activate the receptors to a much lesser degree than agglutinated heroin or its metabolites. Therefore, a lower amount of dopamine will be released due to less stimulation by mu-1 receptors, compared to heroin. It has also been demonstrated in the art that there is the abuse potential of buprenorphine, as other agonist opioid analgesics are also abused. In an effort to prevent humans from self-administering amounts Excessive and abusive buprenorphine, naloxone has been added to the buprenorphine-containing preparation. Other researchers have contemplated the use of naltrexone for these purposes,. However, at the recommended therapeutic doses of buprenorphine, these preparations of buprenorphine / naloxone or buprenorphine / naltrexone tend to produce undesirable effects, such as dysphoria due to a suboptimal homeostatic balance of the CNC dopamine, much more than a preparation would which consists of buprenorphine and nalmefene. This example emphasizes the drawback of the Crain '876 patent in discouraging a human from administering excessive amounts of the opioid agonist analgesic. Because the dose of nalmefene is as small as shown '876, and because buprenofine binds to mu-1 receptors with such a relatively high affinity, it is impossible for the quantities of nalmefene described in' 876 to compete with the therapeutic doses of buprenorphine in mu-1 receptors to be clinically effective. Therefore, it is impossible for doses of '876 of nalmefene to effectively dissuade a human from administering excessive and abusive amounts of a buprenorphine / nalmefene preparation.

In this example, the ratio of buprenorphine to nalmefene will depend on the intended route of administration, i.e., whether the common preparation for both nalmefene and buprenorphine is administered enterally or parenterally. If administered parenterally, the bioavailability will even be different with the different routes of parenteral administration. For example, the bioavailability of buprenorphine, as well as several drugs, differs with the different routes of administration. For example, sublingual buprenorphine in one study showed a bioequivalence of approximately 51% compared to direct intravenous administration, and buccal administration (through the lining of the mucosa in the oral cavity near the inside of the cheek) It showed to be approximately 20%. A convenient administration route may be in the form of a tablet or liquid for oral self-administration. Alternatively, a nasal sprinkler having a proportion of buprenorphine to nalmefene consistent with the present invention could also be self-administered easily by humans, while at the same time deterring a human from self-administering excessive and abusive amounts of the preparation.

Buprenorphine administered intravenously at a dose of 0.3 mg initially gives approximately similar levels of analgesia as if they were 10 mg of morphine intravenously administered in adult humans. Therefore, 0.3 mg i.v. of buprenorphine is said to be "equianalgesic" at 10 mg i.v. of morphine. However, the affinities for mu-receptors and the pharmacokinetics of the two drugs differ. Therefore, the analgesic ability of 0.3 mg i.v. of buprenorphine in relation to 10 mg i.v. of morphine can change over a period of time after the two drugs are administered. The unique agglutination profile of nalmefene has a special relationship with the agglutination of buprenorphine, as opposed to pure agonist opioid analgesics that do not have antagonistic properties, since both nalmefene and buprenorphine act as kapa receptor antagonists. Nalmefene is also a mu-antagonist in addition to being an antagonist that "prefers-kappa" buprenorphine, in addition to being an antagonist-kappa, unlike nalmefene, it is a "partial" mu-agonist. This means that buprenorphine agglutinates mu-receptors with a very high affinity in order to displace other analgesic opioid agonists that compete in mu-receptors. Without However, despite having such high affinity for mu-receptors, buprenorphine only partially activates these receptors. Therefore, if a patient is given an opioid analgesic agonist with a lower affinity but with a greater activating effect on mu-receptors in relation to buprenorphine (several opioid analgesics agonists meet this profile), when administering buprenorphine will cause less dopamine to be released as a result of mu-receptor activity. Because of these characteristics, some researchers in the art believe that buprenorphine is a good drug to be used as a substitute for heroin in humans addicted to heroin. When 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 in an intravenous form, but more typically in 0.3 mg and 1.2 mg. When buprenorphine is administered sublingually for this maintenance therapy, it is usually administered in doses ranging from 4 to 12 mg, although larger amounts may be administered. Buprenorphine has also been administered by intramuscular injection and intranasal routes.

The present invention recognizes that because buprenorphine increases CNC dopamine by virtue of being both an agonist at mu-receptors and an antagonist at kapa-receptors, it can in fact have at least as high or higher a potential for the abuse of 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 prior art in the recognition of the present author for this phenomenon. By way of example, Bedi et al, in Indian Journal of Physiology and Pharmacology 1998, Jan; 42 (1): 95-100, showed that in comparison to a placebo, pentazocine and morphine, post-detoxified addicts identified buprenorphine as heroin, and the effects of buprenorphine were parallel to morphine to a considerable degree that either pentazocine or placebo. Therefore, it is of great importance to discover a method to allow a human self to administer buprenorphine that is less likely to result in excessive self-administration and illicit abuse of buprenorphine. The nalmefene, due to all the reasons indicated here, uniquely solves this very important problem. It is essential for economic reasons and quality of life allow addicted individuals to be able to self-administer buprenorphine without the overwhelming supervision of professionals for the treatment of addictions. In an embodiment of the present invention, 0.3 mg of buprenorphine can be combined with 17.5 micrograms (ug) of nalmefene. If administered parenterally 40 times the recommended therapeutic dose of 0.3 mg of buprenorphine (12 mg of buprenorphine, which can realistically be injected in a human attempt to "be traveling or rise under the influence of a drug") in a preparation with a proportion of buprenorphine for nalmefene of 17.1: 1 on a unit mass basis, then 700 ug, or 0.7 mg, of nalmefene will be administered. In a more preferred embodiment of the present invention, if buprenorphine is administered similarly in a nalmefene ratio of 6: 1 on a unit mass basis (0.3 mg of buprenorphine for 50 ug of nalmefene), then when self-administered 12 mg of buprenorphine, 2 mg of nalmefene will be administered simultaneously and in necessary form. This high resultant quantity of nalmefene will compete with buprenorphine in the mu-receptors in such a way that there will be a minor partial antagonistic effect of nalmefene in buprenorphine on the receptor-mu. This partial antagonism of buprenorphine in the mu-receptors tends to discourage a human from self-administering even large amounts of buprenorphine, compared to a situation where nalmefene is not present in the administered preparation. The precise ratio of buprenorphine to nalmefene will depend on the intended dose of buprenorphine. In light of the present invention, this precise ratio can easily be determined by one skilled in the art. These seven examples mentioned in no way intend to limit the scope of the present invention, instead of this, by way of example only, they intend to comprehensively communicate the utility of the present invention by showing the modalities of how the invention can currently be used. It is to be understood that these mentioned modalities are merely illustrative of the various aspects of the present invention. It is further understood that modifications and other preparations can be devised without departing from the spirit and scope of the present invention. For example, opioid agonist analgesics and nalmefene for use in the present invention may be in the form of free bases or pharmacologically acceptable salts thereof. The examples of Suitable acids for the formation of salts, by way of example only, include but are not limited to hydrochloric acid, glucuronic acid, citric acid and so on. The opioid agonist analgesic and nalmefene can be administered to a human or animal by any of the known methods such as but not limited to intramuscular, intravenous, intranasal, oral, sublingual or transdermal methods. Prolonged-release formulations may be incorporated in the present invention. For example, porous microspheres including nalmefene or an opioid agonist analgesic can be prepared from polymers and copolymers of gelatin, agar, starch, collagen, polyglycolic acid, polylactic acid, poly (epsilon-caprolactone-CO-lactic acid), and so on, and mix together. For transdermal preparations, any of the known permeability enhancers that are adequately compatible with the patch ingredients can be used. A partially permeable barrier can separate the nalmefene from the 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.

When the opioid agonist analgesic acts significantly shorter in duration than nalmefene, it can be prepared in a sustained release form by any known method, which in the light of the present invention will be apparent to someone skilled in the art. technique. Likewise, if nalmefene has a shorter duration of life in vivo than the opioid agonist analgesic, as is the case of LAAM (levo-alpha-acetylmethadol), nalmefene can be prepared in this prolonged release form. One of these forms of prolonged release, which may be applicable in this example, is the prolonged-release preparation used for dextromethorphan and marketed in the United States.

United States as Delsym®. Other preferred kappa receptor opioid antagonists can be used consistent with the present invention.

Example 8 Among the prescriptions most commonly written in the United States of America, are the prescriptions for the combination of oral analgesics consisting of an opioid analgesic agonist and a non-opioid analgesic such as acetaminophen, aspirin, ibuprofen or other non-steroidal anti-inflammatory drugs ("NSAIDs"). By way of example only, the combination of oxycodone and acetaminophen, commonly known by the trade name Percocet®, is very commonly prescribed for a wide variety of pain syndromes, including pain secondary to surgery or trauma and ailments. Similarly, the formulation of the drug commonly known under the trade name Percodan® is composed of oxycodone and aspirin, and the opioid analgesic agonist idrocodone in its bitartrate form is combined with the non-opioid analgesic acetaminophen. Combined orally administered drugs consist of an opioid analgesic agonist and other drugs or medications are among the most widely abused opioid agonists. If these combination drugs contain acetaminophen, as is the case with Percocet®, a large number of Percocet® tablets can be taken orally, so as to cause a toxic load of acetaminophen to be administered. Acetaminophen is widely known to be toxic to the liver in humans when administered in excessive doses, or when it is abused for self-management whether intentional or unintentional. Normally, due to the accumulation of tolerance to the component of the opioid analgesic agonist of Percocet®, the patient will progressively ingest a greater and greater amount of Percocet® tablets during the time in an attempt to satisfy the effect of the opioid analgesic agonist in the receptors. -opioids. Because of the stealthy side effects of acetaminophen toxicity, a human commonly may not be aware of the damage caused to him or her by an excessive intake of acetaminophen in combination with the drug formulation, until a medical examination reveals a liver function. abnormal, or until suddenly a liver failure becomes apparent. Combining this problem is the fact that orally administered drugs are administered relatively directly to the liver, through a mechanism normally called "first pass metabolism". Therefore, there is presently a great need to formulate an orally administrable combination of drug therapy that allows the additive or synergistic effects of the combination of analgesics, such as opioids and acetaminophen, but which greatly prevents or limits the probability of developing a liver failure secondary to liver toxicity. In the case of Percodan® a large number of Percodan® tablets can be taken orally, so as to cause a toxic load of aspirin to be administered. Aspirin and other NSAIDs are widely known to cause gastrointestinal bleeding in humans when administered in excessive doses. Normally, due to the accumulation of tolerance of the opioid agonist analgesic component in Percodan®, the patient will progressively ingest a greater and greater amount of Percodan® tablets over a period of time in an attempt to satisfy the effect of the opioid analgesic agonist on the receptors. mu-opioids. Because of the early obvious signs of the adverse effects of aspirin or NSAIDs, a human may not normally be aware of the damage caused to him or her by a large intake of aspirin or NSAIDs in combination with the drug formulation, until an examination doctor reveals abnormal gastric function, or until acute gastric bleeding becomes suddenly apparent. Combined to this problem is that when aspirin or other NSAIDs are administered orally, or per os, they are administered directly through the esophagus in where its unfolding begins to occur in direct contact with the lining of the gastric mucosa in the stomach. This is precisely the site where a gastric bleeding is caused. Therefore, there is presently a need to formulate an orally administrable drug combination therapy that allows the additive or synergistic effects of combining analgesics, such as opioids and NSAIDs (of which aspirin is an example), but which can prevent or Limit to a large extent the likelihood of developing gastrointestinal bleeding. Hydrocodone (in the form of hydrocodone bitartrate, for example) and other opioid analgesic agonists are commonly mixed with other non-opioid analgesic drugs to formulate the combination drugs. In this eighth example of the invention, the high rate of metabolism of the first passage of nalmefene in the liver is taken into consideration. Approximately 95% of nalmefene is metabolized by the metabolism of the first pass. Therefore, a relatively high amount of nalmefene should be taken orally compared to when nalmefene is administered parenterally in order to obtain bioequivalent concentrations of nalmefene circulating in the blood over a period of time.

By way of example only, if a tablet of a combination drug that is formulated with 10 milligrams (mg) of hydrocodone and 0.5 mg of nalmefene (= 500 micrograms) is ingested orally, only approximately 20 micrograms (mcg) of nalmefene will be administered without being metabolized in the bloodstream. A formulation proportional to 10 mg of hydrocodone and 250 mcg of nalmefene (0.25 mg), perhaps mixed with acetaminophen 500 mg, would be expected to produce analgesia in a way that is not significantly different or not very appreciably different from a 10 mg formulation. hydrocodone and 500 mg of acetaminophen without nalmefene. However, if a human ingested 2 of these tablets formulated in this way every 4 hours, as occurs when human patients self-administer these drugs in doses greater than those prescribed or sought by a physician, then for a period of time of 12 hours or more, a human would ingest 8 tablets comprising 80 mg of hydrocodone and 1 mg of nalmefene. Because the plasma half-life of both hydrocodone and acetaminophen is about 3 hours, and the plasma half-life of nalmefene is about 3 times this duration, nalmefene would tend to accumulate over a period of time relative to hydrocodone and acetaminophen in such a way that while a longer period of time transpire progressively the serum concentration of nalmefene in relation to the serum concentration of hydrocodone will increase as the tablets are ingested during that period of time. Eventually, this will have an appreciably different effect from the opioid agonist analgesic. This effect may include the prevention of fatal respiratory depression, or the lack of satisfaction due to opioid ingestion. The exact nature of this interaction is easily altered by changing the relative amounts of nalmefene in the opioid analgesic agonist in the tablet, as well as by altering the pharmacokinetic profile of either drug by including a prolonged-release preparation of either the nalmefene or the opioid analgesic. agonist This has to be calculated during the normal course of the experimentation routine to derive this data. This experimentation is routinely employed to formulate the pharmaceutical preparations to the required standards. In this way the doses are usually written in terms of pharmacological effect. Although hydrocodone and oxycodone are mentioned by way of example herein, the scope of the invention encompasses any orally administered opioid agonist analgesic. These opioid analgesic agonists applicable include following opioids and their derived salts and bases: morphine, propoxyphene, fentanyl, methadone, levomethadyl (LAAM) and codeine.

Example 9 In an attempt to decrease the likelihood of addiction to analgesic opioid drugs, preparations of opioid analgesic agonists combined with an NMDA receptor antagonist, such as dextromethorphan, have been contemplated. It is thought that NMDA receptor antagonists inhibit the mechanism by which tolerance of opioid-like effects occurs, and may also potentiate the effects of opioid agonist analgesics and thus enhance their apparent potency. An example of this prior art is the proposed product with the MorphiDex® brand (Endo Pharmaceuticals, Inc., Chadds Ford, PA). This product is a formulation of dextromethorphan, an NMDA receptor antagonist, and morphine. In addition, a proposed product comprising Percocet® "enhanced" by an NMDA-receptor antagonist is contemplated. Although both formulations described try to decrease the likelihood of an addiction to opioids by decreasing the amount of opioid administered to obtain an effect Certain analgesic, none of these protects against a fatal respiratory depression. In fact, NMDA-receptor antagonists can potentiate in some way the opioid-like effects of opioid agonist analgesics, yet it remains to be proven whether the combination of morphine and dextromethorphan can make a human even more susceptible to an overdose. opioid drugs. Therefore, the present invention extends to include the NMDA-receptor antagonist, for example dextromethorphan, in a drug formulation together with nalmefene and an opioid analgesic agonist. Therefore, the nalmefene added to the "intensified" dextromethorphan, Percocet®, is included in the present invention. It is noted that with respect to this date, the best method known by the applicant to carry out said invention is the conventional one. for the manufacture of the objects to which it refers.

Claims (27)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property. 1. An opioid analgesic composition characterized in that it comprises: an opioid analgesic having an agonist pharmacological activity in both the mu and kappa opioid receptors in a dose sufficient to produce analgesia in the treated patient; a non-opioid analgesic; nalmefene in a dose sufficient to block the kappa opioid receptor agonist and its activity produced by the opioid analgesic.
2. 2. The opioid analgesic composition according to claim 1, characterized in that the dose of nalmefene is such that upon achieving a supratherapeutic dose of the opioid analgesic, the opioid-mu receptor agonist activity of the analgesic is substantially blocked. opioid
3. 3. The opioid analgesic composition according to claim 1, characterized in that the opioid analgesic is buprenorphine.
4. 4. - The opioid analgesic composition, according to claim 1, characterized in that the opioid analgesic is a combination of opioid analgesics.
5. 5. The composition of opioid analgesic, according to claim 1, characterized in that the opioid analgesic is oxycodone.
6. 6. The composition of opioid analgesic, according to claim 1, characterized in that the opioid analgesic is hydrocodone.
7. 7. The opioid analgesic composition according to claim 1, characterized in that the analgesic is selected from a group consisting of: morphine, propoxyphene, fentanyl, methadone, levomethadyl and codeine.
8. 8. The opioid analgesic composition according to claim 1, characterized in that the non-opioid analgesic is a non-steroidal anti-inflammatory drug.
9. 9. The composition of opioid analgesic, according to claim 8, characterized in that the non-opioid analgesic is aspirin.
10. 10. The composition of opioid analgesic, according to claim 1, characterized in that the non-opioid analgesic is acetaminophen.
11. 11. - The opioid analgesic composition, according to claim 3, characterized in that the weight ratio of buprenorphine to nalmefene is about 17 to 1.
12. 12. The opioid analgesic composition, according to claim 3, characterized in that the weight ratio of buprenorphine to nalmefene is about 6 to 1.
13. 13. The opioid analgesic composition, according to claim 1, characterized in that the composition comprises a transdermal preparation.
14. 14. The composition of opioid analgesic, according to claim 1, characterized in that the composition comprises an enteral dosage form.
15. 15. The composition of opioid analgesic, according to claim 1, characterized in that the composition comprises a parenteral dosage form.
16. 16. The composition of opioid analgesic, according to claim 1, characterized in that the composition comprises a rectal suppository.
17. 17. The opioid analgesic composition, according to claim 1, characterized in that the The composition comprises a dosage form that is administered by the ear.
18. 18. The opioid analgesic composition according to claim 1, characterized in that the composition comprises an intranasal dosage form.
19. 19. A composition to treat obsessive-compulsive disorders characterized because it comprises: tramadol; and nalmefene; wherein tramadol is in a pharmaceutically effective dose for the treatment of obsessive-compulsive disorders.
20. 20.- The composition according to the claim 19 characterized in that the amount of nalmefene in the composition is sufficient to substantially prevent the tramadol agonist activity at the mu opioid receptor in a therapeutic dose of tramadol.
21. 21. A method for treating obsessive-compulsive disorders characterized in that it comprises: administering a pharmaceutically effective dose of tramadol to reduce the obsessive compulsive state; administer nalmefene in an amount sufficient to reduce tolerance tolerated by tramadol in opioid receptors.
22. 22. An analgesic composition characterized in that it comprises: an NMDA-receptor antagonist; an opioid analgesic having a pharmacological agonist activity in both the mu and kappa opioid receptors in a dose sufficient to produce analgesia in the treated subject; and nalmefene.
23. 23. The analgesic composition according to claim 22, characterized in that the NMDA receptor antagonist is dextromethorphan.
24. 24. The analgesic composition according to claim 22, characterized in that the opioid analgesic is selected from a group consisting of: morphine, oxycodone, hydrocodone, propoxyphene, fentanyl, methadone, levomethadyl and codeine.
25. 25. An oral analgesic composition characterized in that it comprises between approximately 2.5 to approximately 20 mg of hydrocodone; and between about 0.1 to about 1 mg of nalmefene.
26. 26. An oral analgesic composition characterized in that it comprises: an opioid analgesic agonist for the mu-receptor; and nalmefene. wherein the administered amount of nalmefene is bioequivalent to 0.00025 to 0.0015 milligrams per kilogram (mg / kg) of parenteral nalmefene and the amount of the opioid analgesic agonist administered has an equivalent potency at the mu-1 receptors of 0.15 mg / kg of parenteral morphine .
27. 27. An opioid analgesic agonist characterized in that it comprises: an opioid analgesic; and nalmefene, wherein the amount of nalmefene administered is 1.2 to 990 fewer times on a unit mass basis than the amount of the opioid analgesic administered.