WO1997044045A1 - Melatonine combinee a des analgesiques - Google Patents

Melatonine combinee a des analgesiques Download PDF

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Publication number
WO1997044045A1
WO1997044045A1 PCT/US1997/007626 US9707626W WO9744045A1 WO 1997044045 A1 WO1997044045 A1 WO 1997044045A1 US 9707626 W US9707626 W US 9707626W WO 9744045 A1 WO9744045 A1 WO 9744045A1
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WO
WIPO (PCT)
Prior art keywords
melatonin
analgesic agent
composition
analgesic
grams
Prior art date
Application number
PCT/US1997/007626
Other languages
English (en)
Inventor
Richard C. Fuisz
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.
Priority to CA002255838A priority Critical patent/CA2255838A1/fr
Priority to EP97922687A priority patent/EP0901376A1/fr
Priority to JP9542420A priority patent/JP2000500159A/ja
Publication of WO1997044045A1 publication Critical patent/WO1997044045A1/fr

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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.
  • 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.
  • 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.
  • 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.
  • the use of the combination of an analgesic agent and melatonin provides the maximum analgesic effects and little or no side effects.
  • 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.
  • 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.
  • 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.
  • 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)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un procédé et une composition servant à potentialiser les propriétés à effets biologiques d'un agent analgésique en administrant à des mammifères (1) au moins un agent analgésique et (2) mélatonine. Ledit agent analgésique est sélectionné dans le groupe constitué par aspirine, indométhacine, salicylate, dexaméthasone, paracétamol, hydrochlorure de benzydamine, acétaminophène, dipyrone, lapidine, santonine, ibuprofène, indométhacine, oxicam, étodolac, buprénorphine, diclofénac, fentanyl, morphine, nalbuphine, péthidine et dingetegna.
PCT/US1997/007626 1996-05-20 1997-05-06 Melatonine combinee a des analgesiques WO1997044045A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002255838A CA2255838A1 (fr) 1996-05-20 1997-05-06 Melatonine combinee a des analgesiques
EP97922687A EP0901376A1 (fr) 1996-05-20 1997-05-06 Melatonine combinee a des analgesiques
JP9542420A JP2000500159A (ja) 1996-05-20 1997-05-06 メラトニンと組み合わせた鎮痛剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US65047496A 1996-05-20 1996-05-20
US08/650,474 1996-05-20

Publications (1)

Publication Number Publication Date
WO1997044045A1 true WO1997044045A1 (fr) 1997-11-27

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Application Number Title Priority Date Filing Date
PCT/US1997/007626 WO1997044045A1 (fr) 1996-05-20 1997-05-06 Melatonine combinee a des analgesiques

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EP (1) EP0901376A1 (fr)
JP (1) JP2000500159A (fr)
CA (1) CA2255838A1 (fr)
WO (1) WO1997044045A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0854713A1 (fr) * 1995-10-03 1998-07-29 Interneuron Pharmaceuticals Incorporated Compositions a base de melatonine et d'antalgiques et utilisations
FR2809618A1 (fr) * 2000-05-31 2001-12-07 Didier Henri Michel Louis Cugy Procede relatif a l'optimisation de la delivrance de substances pharmacologiques
US20180264013A1 (en) * 2010-07-08 2018-09-20 Wellesley Pharmaceuticals, Llc Composition and methods for treating sleep disorders
CN111265517A (zh) * 2018-12-05 2020-06-12 中国科学院昆明动物研究所 褪黑素和吗啡联合在制备镇痛药物中的应用

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102017550B1 (ko) * 2013-11-13 2019-09-03 내셔널 디펜스 에듀케이션 앤드 리서치 파운데이션 간에 대한 부작용이 없는 신규의 아세트아미노펜 화합물 조성물
JP6858729B2 (ja) * 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 肝臓に対する副作用がない、新しいアセトアミノフェン複合組成

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4945103A (en) * 1989-01-17 1990-07-31 Michael Cohen Method of treating pre-menstrual syndrome
WO1997012612A1 (fr) * 1995-10-03 1997-04-10 Interneuron Pharmaceuticals, Inc. Compositions a base de melatonine et d'antalgiques et utilisations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4945103A (en) * 1989-01-17 1990-07-31 Michael Cohen Method of treating pre-menstrual syndrome
WO1997012612A1 (fr) * 1995-10-03 1997-04-10 Interneuron Pharmaceuticals, Inc. Compositions a base de melatonine et d'antalgiques et utilisations

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE MEDLINE STN; XP002038886 *
DATTA ET AL.: "Attenuation of morphine analgesia by alpha-MSH, MIF-I, melatonin and naloxone in the rat", PEPTIDES, vol. 3, no. 3, 1982, pages 433 - 437, XP002038885 *
YING ET AL.: "effects of the pineal body and melatonin on sensitivity to pain in mice", ACTA PHARMACOLOGICA SINICA, vol. 11, no. 5, September 1990 (1990-09-01), pages 411 - 414 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0854713A1 (fr) * 1995-10-03 1998-07-29 Interneuron Pharmaceuticals Incorporated Compositions a base de melatonine et d'antalgiques et utilisations
EP0854713A4 (fr) * 1995-10-03 1999-01-07 Interneuron Pharma Compositions a base de melatonine et d'antalgiques et utilisations
FR2809618A1 (fr) * 2000-05-31 2001-12-07 Didier Henri Michel Louis Cugy Procede relatif a l'optimisation de la delivrance de substances pharmacologiques
US20180264013A1 (en) * 2010-07-08 2018-09-20 Wellesley Pharmaceuticals, Llc Composition and methods for treating sleep disorders
CN111265517A (zh) * 2018-12-05 2020-06-12 中国科学院昆明动物研究所 褪黑素和吗啡联合在制备镇痛药物中的应用

Also Published As

Publication number Publication date
EP0901376A1 (fr) 1999-03-17
CA2255838A1 (fr) 1997-11-27
JP2000500159A (ja) 2000-01-11

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