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EP0901376A1 - Malatonin in combination with analgesics - Google Patents

Malatonin in combination with analgesics

Info

Publication number
EP0901376A1
EP0901376A1 EP97922687A EP97922687A EP0901376A1 EP 0901376 A1 EP0901376 A1 EP 0901376A1 EP 97922687 A EP97922687 A EP 97922687A EP 97922687 A EP97922687 A EP 97922687A EP 0901376 A1 EP0901376 A1 EP 0901376A1
Authority
EP
European Patent Office
Prior art keywords
melatonin
analgesic agent
composition
analgesic
grams
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97922687A
Other languages
German (de)
French (fr)
Inventor
Richard C. Fuisz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biovail Technologies Ltd
Original Assignee
Fuisz Technologies Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fuisz Technologies Ltd filed Critical Fuisz Technologies Ltd
Publication of EP0901376A1 publication Critical patent/EP0901376A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • 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.
  • 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.
  • melatonin 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.
  • melatonin and melatonin-like compounds possess analgesic properties.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the use of the combination of an analgesic agent and a melatonin provides the maximum analgesic effects and little or no side effects.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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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.
EP97922687A 1996-05-20 1997-05-06 Malatonin in combination with analgesics Withdrawn EP0901376A1 (en)

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US65047496A 1996-05-20 1996-05-20
US650474 1996-05-20
PCT/US1997/007626 WO1997044045A1 (en) 1996-05-20 1997-05-06 Malatonin in combination with analgesics

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CA2231557A1 (en) * 1995-10-03 1997-04-10 Interneuron Pharmaceuticals, Inc. Compositions of melatonin and analgetic agents and methods of use thereof
FR2809618A1 (en) * 2000-05-31 2001-12-07 Didier Henri Michel Louis Cugy Optimizing delivery of drugs to improve effectiveness and/or reduce toxicity, by synchronizing condition of patient using chronoactive agent such as adenosine or melatonin
US20180264013A1 (en) * 2010-07-08 2018-09-20 Wellesley Pharmaceuticals, Llc Composition and methods for treating sleep disorders
PL3069733T3 (en) * 2013-11-13 2023-02-13 National Defense Education And Research Foundation New acetaminophen compound composition without side effect to liver
JP6858729B2 (en) * 2018-05-25 2021-04-14 ▲財▼▲団▼法人国防教育研究基金会Ｎａｔｉｏｎａｌ Ｄｅｆｅｎｓｅ Ｅｄｕｃａｔｉｏｎ Ａｎｄ Ｒｅｓｅａｒｃｈ Ｆｏｕｎｄａｔｉｏｎ New acetaminophen complex composition with no side effects on the liver
CN111265517A (en) * 2018-12-05 2020-06-12 中国科学院昆明动物研究所 Application of melatonin and morphine combination in preparation of analgesic

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US4945103A (en) * 1989-01-17 1990-07-31 Michael Cohen Method of treating pre-menstrual syndrome
CA2231557A1 (en) * 1995-10-03 1997-04-10 Interneuron Pharmaceuticals, Inc. Compositions of melatonin and analgetic agents and methods of use thereof

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CA2255838A1 (en) 1997-11-27
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