MALATONIN IN COMBINATION WITH ANALGESICS

Abstract: The present invention is a method and composition for potentiating bio-affecting properties of an analgesic agent by administering to mammals (1) at least one analgesic agent and (2) melatonin, wherein said analgesic agent is selected from the group consisting of aspirin, indomethacin, salicylate, dexamethasone, paracetamol, benzydamine hydrochloride, acetaminophen, dipyrone, lapidin, santonin, ibuprofen, indomethacin, oxicam, etodolac, buprenorphine, diclofenac, fentanyl, morphine, nalbuphine, pethidine, and dingetegna.

Description: MALATONIN IN COMBINATION WITH ANALGESICS BACKGROUND OF THE INVENTION This invention relates to the art of administering bio-affecting agents, and, in particular, to potentiating the effect of an analgesic agent. Analgesics are generally used in medicine to relieve pain. Unfortunately, almost all potent analgesics evoke adverse reactions. Some of the adverse reactions are gastrointestinal disturbances, nausea, constipation, and vomiting. Other severely adverse reactions are respiratory depression, impairment of consciousness, mental confusion, incoordination or paralysis, or other derangements of the nervous system. To qualify as a desirable analgesic, a compound must selectively reduce or abolish pain without causing any serious adverse reactions. It is, however, difficult to identify a single chemical compound that satisfies these requirements because (1) a potent analgesic generally have serious adverse reactions, and (2) a compound with little or no side effects generally has less analgesic effect. One solution to this problem is to combine two or more drugs in such proportions as to produce maximum analgesic effect with little or no side effects. When one or both of the components of a combination are known to possess pain relieving properties, and these properties are increased by many folds, the net effect of the combination is commonly referred to as "potentiation." It would be very beneficial to the medical community to be able to potentiate analgesics. In particular, enhancement of the bio-affecting properties of analgesics would increase the range of application and usefulness. U.S. Patent No. 5,403,851 to D'Orlando et al. discloses that melatonin may possess analgesic properties, and thus, it may be useful as an alternative to non-steroidal anti- inflammatory, anti-pyric drugs, such as aspirin, acetaminophen, and ibuprofen. It is known that melatonin, 5-methoxy-N-acetyltryptamine, is a hormone produced primarily by the pineal gland. Melatonin is important for the regulation of a variety of neural and endocrine functions, especially those that exhibit circadian and circannual rhyrhrnicity. The synthesis and secretion of melatonin show a circadian rhythm that changes with the seasons and with age. The result of circadian rhythm is due to both endogenous mechanisms and physical environment. Most notably, the exposure of light inhibits melatonin synthesis and secretion. Thus, melatonin levels are high at night and low during the day. Melatonin has been utilized to treat many human disorders. Some disorders are known to be linked to chronobiologic abnormalities, such as jet lag, delayed sleep syndrome, shift-work, and seasonal affective disorder. Some disorders are known to central nervous system and psychiatric disorders, such as sleep disorders, epilepsy and other convulsive disorders, anxiety, psychiatric disease neurodegenerative disease, and fever. Other disorders are endocrine associated, such as contraception and infertility, precocious puberty, premenstrual syndrome, hyperprolactinemia, and growth hormone deficiency. Melatonin has also been administered to treat cancer and other proliferative diseases, immune system disorders and conditions associated with senescence, ophthalmo logical diseases, and animal breeding, such as regulation of fertility, puberty, and pelage color. In addition, it has been suggested that melatonin and melatonin-like compounds possess analgesic properties. For example, U.S. Patent Nos. 4,665,086 to Short et al. and 5,430,029 to Biella et al. disclose that the sleep/wake disorders experienced by blind people and those experienced rapid crossing of time zones (such as jet lags and changes in work shifts) can be treated with melatonin or melatonin derivatives. U.S. Patent No. 5,093,352 issued to Dubocovich discloses the use of melatonin or melatonin derivatives to treat psychiatric conditions such as depression, mania, and schizophrenia. U.S. Patent Nos. 4,855,305 to Cohen, 5,196,435 to Clemens et al., and 5,272,141 to Fraschini et al. disclose that melatonin and melatonin derivatives have contraceptive and oncostatic properties. U.S. Patent No. to 4,746,674 to Pierpaoli et al. discloses the use of melatonin to improve the cosmetic or physical appearance of skin and /or scalp. However, nothing known in the art to date indicates treatment which provides enhanced or potentiated analgesic properties, and it is an object of the present invention to potentiate bio-affecting properties of analgesics. SUMMARY OF THE INVENTION The present invention is a method and a composition for potentiating bio-affecting properties of an analgesic agent which includes administering to mammals (1) at least one analgesic agent and (2) melatonin in an amount sufficient to potentiate the bio-affecting properties of the analgesic agent. The method and composition of the present invention contemplate that the analgesic include systemic administration of an analgesic agent and melatonin, e.g., intravenously, orally, transdermally, or any other manner by which it is introduced into the biological system of the mammals. The analgesic agent and melatonin can be administered simultaneously or sequentially, and either one can be aclministered first. The analgesic agent and melatonin can be aclministered with or without pharmaceutical carriers. Preferably, the analgesic agent and melatonin are administered simultaneously. More preferably, the analgesic agent and the melatonin are administered simultaneously in a dosage unit form of a capsule or a tablet. Some of the examples of the analgesic agents include, but are not limited to, aspirin, indomethacin, salicylate, dexamethasone, paracetamol, benzydamine hydrochloride, acetaminophen, dipyrone, lapidin, santonin, ibuprofen, indomethacin, oxicam, etodolac, buprenorphine, diclofenac, fentanyl, morphine, nalbuphine, pethidine, and dingetegna. "Melatonin" is used to mean melatonin, melatonin analogs, melatonin derivatives, and pharmaceutically acceptable salts thereof. The pharmaceutical carriers of the present invention can be liquid carriers or solid carriers. Some examples of the liquid carriers are water, glycols, oils, and alcohols. Some examples of the carrier are starches, sugars, kaolin, calcium stearate, magnesium stearate, methyl cellulose, ethyl cellulose, dibasic calcium phosphate, calcium silicate, tragacanth, gelatin, hydrous, lactose, sorbitol, mannitol, and talc. The efficacy of the combination of an analgesic agent and a melatonin is unexpectedly much greater than that which would result from simply the additive effect of the components. In addition, the use of the combination of an analgesic agent and a melatonin provides the maximum analgesic effects and little or no side effects. For a better understanding of the present invention together with other and further objects, reference is made to the following description and its scope will be pointed out in the appended claims. DETAILED DESCRIPTION OF THE INVENTION The present invention is a method and composition for potentiating bio-affecting properties of analgesic agents. The present invention relates to a method for potentiating analgesics which includes administering to mammals (1) at least one analgesic agent and (2) an effective amount of melatonin in an amount sufficient to potentiate the bio-affecting properties of melatonin. The method of the present invention contemplates that the analgesic agent and melatonin can be administered systemically, e.g., intravenously, orally, transdermally, or any other manner by which it is introduced onto the biological system of the mammals. The analgesic agent and melatonin can be administered simultaneously or sequentially and either one may be administered first. The analgesic agent and melatonin can be administered with or without carriers. Preferably, the analgesic agent and melatonin are administered simultaneously. More preferably, the analgesic agent and melatonin are administered simultaneously in a dosage unit form of a capsule or a tablet. The dosage ranges of the analgesic agent are generally from about 2.5 mg to 7.5 mg, preferably from about 2.5 mg to 7.1 mg, and more preferably from about 2.8 mg to 4.25 mg. The dosage ranges of melatonin are generally from about 0.17mg to about 2.5 mg, preferably from about 0.58 mg to about 2.2 mg, and more preferably from about 0.35 mg to about 0.85 mg. Some of the examples of the analgesic agents are aspirin, indomethacin, salicylate, dexamethasone, paracetamol, benzydamine hydrochloride, acetaminophen, dipyrone, lapidin, santonin, ibuprofen, indomethacin, oxicam, etodolac, buprenorphine, diclofenac, fentanyl, morphine, nalbuphine, pethidine, and dingetegna. "Melatonin" is used herein to mean melatonin, melatonin analogs, melatonin derivatives, and pharmaceutically acceptable salts thereof. The pharmaceutical carriers of the present invention can be liquid carriers or solid carriers. Some examples of the liquid carriers are water, glycols, oils, and alcohols. Some examples of the carrier are starches, sugars, kaolin, calcium stearate, magnesium stearate, methyl cellulose, ethyl cellulose, dibasic calcium phosphate, calcium silicate, tragacanth, gelatin, hydrous, lactose, sorbitol, mannitol, and talc. The present invention also includes a composition for potentiating bio-affecting properties of an analgesic agent which includes an analgesic agent and a melatonin in an amount sufficient to potentiate the bio-affecting properties of the analgesic agent. The composition of the present invention contemplates that the analgesic agent and melatonin can be administered systemically, e.g., intravenously, orally, transdermally, or any other manner by which it is introduced onto the biological system of the mammals. The analgesic agent and melatonin can be administered simultaneously or sequentially and either one may be administered first. The analgesic agent and melatonin can be administered with or without carriers. Preferably, the analgesic agent and melatonin are administered simultaneously. More preferably, the analgesic agent and melatonin are administered simultaneously in a dosage unit form of a capsule or a tablet. * The dosage ranges of the analgesic agent are generally from about 2.5 mg to 7.5 mg, preferably from about 2.5 mg to 7.1 mg, and more preferably from about 2.8 mg to 4.25 mg. The dosage ranges of melatonin are generally from about 0.17 mg to about 2.5 mg, preferably from about 0.58 mg to about 2.2 mg, and more preferably from about 0.35 mg to about 0.85 mg. The efficacy of the combination of an analgesic agent and melatonin is unexpectedly much greater than that which would result from simply the additive effect of the components. In addition, the use of the combination of an analgesic agent and melatonin provides the maximum analgesic effects and little or no side effects. PROPHETIC EXAMPLES Prophetic examples have been set forth as a guide to the practitioner, and are not meant in any way to limit the scope of the present invention. EXAMPLE 1 In the present example, 1,000 hard gelatin capsules, each containing 85 milligrams of melatonin as a primary active ingredient and 280 milligrams of acetaminophen as another active ingredient are prepared from the following formulation: 85 grams of melatonin, 280 grams of acetaminophen, 250 grams of starch, 750 grams of lactose, 250 grams of talc, and 10 grams of calcium stearate. A uniform mixture of the ingredients is prepared by blending, and used to fill two- piece hard gelatin capsules. It is believed that the capsules would be suitable for use as providing satisfactory analgesic effect upon administration to subjects suffering from pain. EXAMPLE 2 1,000 compressed tablets, each containing 35 milligrams of melatonin as a primary active ingredient and 425 milligrams of acetaminophen as another active ingredient are prepared from the following formulation: 35 grams of melatonin, 425 grams of acetaminophen, 750 grams of starch, 5,000 grams of dibasic calcium phosphate hydrous, and 2.5 grams of calcium stearate. The finely powdered ingredients are mixed well and granulated with 10 percent starch paste. The granulation is dried and compressed into tablets. It is believed that the tablets would be suitable for use as providing satisfactory analgesic effect upon administration to subjects suffering from pain. EXAMPLE 3 In the present example, 1,000 hard gelatin capsules, each containing 85 milligrams of melatonin as a primary active ingredient and 280 milligrams of aspirin as another active ingredient are prepared from the following formulation: 85 grams of melatonin, 280 grams of aspirin, 250 grams of starch, 750 grams of lactose, 250 grams of talc, and 10 grams of calcium stearate. A uniform mixture of the ingredients is prepared by blending, and used to fill two- piece hard gelatin capsules. It is believed that the capsules would be suitable for use as providing satisfactory analgesic effect upon administration to subjects suffering from pain. EXAMPLE 4 1,000 compressed tablets, each containing 35 milligrams of melatonin as a primary active ingredient and 425 milligrams of aspirin as another active ingredient are prepared from the following formulation: 35 grams of melatonin, 425 grams of aspirin, 750 grams of starch, 5,000 grams of dibasic calcium phosphate hydrous, and 2.5 grams of calcium stearate. The finely powdered ingredients are mixed well and granulated with 10 percent starch paste. The granulation is dried and compressed into tablets. It is believed that the tablets would be suitable for use as providing satisfactory analgesic effect upon administration to subjects suffering from pain. EXAMPLE 5 In the present example, 1,000 hard gelatin capsules, each containing 85 milligrams of melatonin as a primary active ingredient and 280 milligrams of ibuprofen as another active ingredient are prepared from the following formulation: 85 grams of melatonin, 280 grams of ibuprofen, 250 grams of starch, 750 grams of lactose, 250 grams of talc, and 10 grams of calcium stearate. A uniform mixture of the ingredients is prepared by blending, and used to fill two- piece hard gelatin capsules. It is believed that the capsules would be suitable for use as providing satisfactory analgesic effect upon administration to subjects suffering from pain. EXAMPLE 6 1,000 compressed tablets, each containing 35 milligrams of melatonin as a primary active ingredient and 425 milligrams of ibruprofen as another active ingredient are prepared from the following formulation: 35 grams of melatonin, 425 grams of ibruprofen, 750 grams of starch, 5,000 grams of dibasic calcium phosphate hydrous, and 2.5 grams of calcium stearate. The finely powdered ingredients are mixed well and granulated with 10 percent starch paste. The granulation is dried and compressed into tablets. It is believed that the tablets would be suitable for use as providing satisfactory analgesic effect upon administration to subjects suffering from pain. EXAMPLE 7 In the present example, 1,000 hard gelatin capsules, each containing 85 milligrams of melatonin as a primary active ingredient and 280 milligrams of fentanyl as another active ingredient are prepared from the following formulation: 85 grams of melatonin, 280 grams of fentanyl, 250 grams of starch, 750 grams of lactose, 250 grams of talc, and 10 grams of calcium stearate. A uniform mixture of the ingredients is prepared by blending, and used to fill two- piece hard gelatin capsules. It is believed that the capsules would be suitable for use as providing satisfactory analgesic effect upon administration to subjects suffering from pain. EXAMPLE S 1,000 compressed tablets, each containing 35 milligrams of melatonin as a primary active ingredient and 425 milligrams of fentanyl as another active ingredient are prepared from the following formulation: 35 grams of melatonin, 425 grams of fentanyl, 750 grams of starch, 5,000 grams of dibasic calcium phosphate hydrous, and 2.5 grams of calcium stearate. The finely powdered ingredients are mixed well and granulated with 10 percent starch paste. The granulation is dried and compressed into tablets. It is believed that the tablets would be suitable for use as providing satisfactory analgesic effect upon administration to subjects suffering from pain. Thus, while there had been described what are presently to believe to be the preferred embodiments of the present invention, those skilled in the art will appreciate that other and further modifications and changes can be made without departing from the true spirit of the invention. It is intended to include all such further modifications and changes which come within the true scope of the inventions as set forth in the appended claims.

Claims: WHAT IS CLAIMED IS: 1. A method for potentiating bio-affecting properties of an analgesic agent comprising administering to a mammal (1) at least one analgesic agent and (2) melatonin in an amount sufficient to potentiate the bio-affecting properties of said analgesic agents. 2. The method of Claim 1, wherein said analgesic agent is selected from the group consisting of aspirin, indomethacin, salicylate, dexamethasone, paracetamol, benzydamine hydrochloride, acetaminophen, dipyrone, lapidin, santonin, ibuprofen, indomethacin, oxicam, etodolac, buprenorphine, diclofenac, fentanyl, morphine, nalbuphine, pethidine, and dingetegna. 3. The method of Claim 1, wherein said melatonin is selected from the group consisting of melatonin analogs, melatonin derivatives, and pharmaceutically acceptable salts thereof. 4. The method of Claim 1, wherein said at least one analgesic agent and said melatonin are administered systemically. 5. The method of Claim 1 , wherein said melatonin is administered in conjunction with said at least one analgesic agent. 6. The method of Claim 1 , wherein said melatonin is adrnimstered separately with said at least one analgesic agent. 7. The method of Claim 1 , wherein said at least one analgesic agent and said melatonin are in a dosage unit form. 8. The method of Claim 7, wherein said dosage unit form is a tablet. 9. The method of Claim 7, wherein said dosage unit form is a capsule. 10. A composition for potentiating bio-affecting properties of an analgesic agent comprising (1) at least one analgesic agent and (2) a melatonin in an amount sufficient to potentiate said bio-affecting properties of said analgesic agent. 11. The composition of Claim 10, wherein said analgesic agent is selected from the group consisting of aspirin, indomethacin, salicylate, dexamethasone, paracetamol, benzydamine hydrochloride, acetaminophen, dipyrone, lapidin, santonin, ibuprofen, indomethacin, oxicam, etodolac, buprenorphine, diclofenac, fentanyl, morphine, nalbuphine, pethidine, and dingetegna. 12. The composition of Claim 10, wherein said melatonin is selected from the group consisting of melatonin analogs, melalatonin derivatives, and pharmaceutically acceptable salts thereof. 13. The composition of Claim 10, wherein said at least one analgesic agent and said melatonin are administered systemically. 14. The composition of Claim 10, wherein said melatonin is administered in conjunction with said at least one analgesic agent. 15. The composition of Claim 10, wherein said melatonin is administered separately with said at least one analgesic agent. 16. The composition of Claim 10, wherein said at least one analgesic agent and said melatonin are in a dosage unit form. 17. The composition of Claim 16, wherein said dosage unit form is a tablet. 18. The composition of Claim 16, wherein said dosage unit form is a capsule.

Inventors: FUISZ RICHARD C, FUISZ, RICHARD, C.
Applicants: FUISZ TECHNOLOGIES LTD, FUISZ TECHNOLOGIES LTD.
Application year: 1997
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P25, A61P29