WO1997048390A1 - Analgesics combining acetaminophen with meclizine - Google Patents
Analgesics combining acetaminophen with meclizine Download PDFInfo
- Publication number
- WO1997048390A1 WO1997048390A1 PCT/US1997/010922 US9710922W WO9748390A1 WO 1997048390 A1 WO1997048390 A1 WO 1997048390A1 US 9710922 W US9710922 W US 9710922W WO 9748390 A1 WO9748390 A1 WO 9748390A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acetaminophen
- meclizine
- weight
- composition
- pharmaceutically acceptable
- Prior art date
Links
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 title claims abstract description 76
- OCJYIGYOJCODJL-UHFFFAOYSA-N Meclizine Chemical compound CC1=CC=CC(CN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=C1 OCJYIGYOJCODJL-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 229960001474 meclozine Drugs 0.000 title claims abstract description 32
- 229960005489 paracetamol Drugs 0.000 title claims abstract description 23
- 239000000730 antalgic agent Substances 0.000 title description 7
- 229940035676 analgesics Drugs 0.000 title description 4
- 239000000203 mixture Substances 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 9
- 230000036592 analgesia Effects 0.000 claims abstract description 6
- 230000000202 analgesic effect Effects 0.000 claims description 22
- -1 fatty acid esters Chemical class 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000004094 surface-active agent Substances 0.000 claims description 8
- 239000002552 dosage form Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 230000001939 inductive effect Effects 0.000 claims description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 4
- 239000004166 Lanolin Substances 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 claims description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 4
- 235000019388 lanolin Nutrition 0.000 claims description 4
- 229940039717 lanolin Drugs 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 3
- 206010028813 Nausea Diseases 0.000 claims description 3
- 239000005642 Oleic acid Substances 0.000 claims description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 3
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 3
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 3
- 239000000194 fatty acid Substances 0.000 claims description 3
- 229930195729 fatty acid Natural products 0.000 claims description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 3
- 230000008693 nausea Effects 0.000 claims description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 3
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 2
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 claims description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 2
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 claims description 2
- 241000220479 Acacia Species 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- 125000000129 anionic group Chemical group 0.000 claims description 2
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 2
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 claims description 2
- 229960001950 benzethonium chloride Drugs 0.000 claims description 2
- 229960002903 benzyl benzoate Drugs 0.000 claims description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 2
- 229960001631 carbomer Drugs 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- 229940082500 cetostearyl alcohol Drugs 0.000 claims description 2
- 229960000541 cetyl alcohol Drugs 0.000 claims description 2
- 235000012000 cholesterol Nutrition 0.000 claims description 2
- 229940107161 cholesterol Drugs 0.000 claims description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 2
- 229940043237 diethanolamine Drugs 0.000 claims description 2
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 claims description 2
- 229960000878 docusate sodium Drugs 0.000 claims description 2
- 239000008387 emulsifying waxe Substances 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 2
- UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 229940099367 lanolin alcohols Drugs 0.000 claims description 2
- 239000000787 lecithin Substances 0.000 claims description 2
- 235000010445 lecithin Nutrition 0.000 claims description 2
- 229940067606 lecithin Drugs 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 229960002900 methylcellulose Drugs 0.000 claims description 2
- 239000002480 mineral oil Substances 0.000 claims description 2
- 235000010446 mineral oil Nutrition 0.000 claims description 2
- 229940042472 mineral oil Drugs 0.000 claims description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 2
- 229940045641 monobasic sodium phosphate Drugs 0.000 claims description 2
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 239000008388 non-ionic emulsifying wax Substances 0.000 claims description 2
- 229960000502 poloxamer Drugs 0.000 claims description 2
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 2
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 claims description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims 3
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 208000029618 autoimmune pulmonary alveolar proteinosis Diseases 0.000 description 28
- 239000004480 active ingredient Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 7
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- 150000001875 compounds Chemical class 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 230000003187 abdominal effect Effects 0.000 description 4
- 229960001138 acetylsalicylic acid Drugs 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940121367 non-opioid analgesics Drugs 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
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- 239000007788 liquid Substances 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 235000021355 Stearic acid Nutrition 0.000 description 2
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 2
- 229960004373 acetylcholine Drugs 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 2
- 229960001017 tolmetin Drugs 0.000 description 2
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-M 3-carboxy-2-(carboxymethyl)-2-hydroxypropanoate Chemical compound OC(=O)CC(O)(C(O)=O)CC([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-M 0.000 description 1
- 241001550224 Apha Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- HDSBZMRLPLPFLQ-UHFFFAOYSA-N Propylene glycol alginate Chemical compound OC1C(O)C(OC)OC(C(O)=O)C1OC1C(O)C(O)C(C)C(C(=O)OCC(C)O)O1 HDSBZMRLPLPFLQ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 210000003815 abdominal wall Anatomy 0.000 description 1
- ZEHGKSPCAMLJDC-UHFFFAOYSA-M acetylcholine bromide Chemical compound [Br-].CC(=O)OCC[N+](C)(C)C ZEHGKSPCAMLJDC-UHFFFAOYSA-M 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- IFKLAQQSCNILHL-QHAWAJNXSA-N butorphanol Chemical compound N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 IFKLAQQSCNILHL-QHAWAJNXSA-N 0.000 description 1
- 229960001113 butorphanol Drugs 0.000 description 1
- 229960002798 cetrimide Drugs 0.000 description 1
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- 229940097362 cyclodextrins Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
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- 229940052303 ethers for general anesthesia Drugs 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
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- 150000003840 hydrochlorides Chemical class 0.000 description 1
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
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- 230000008569 process Effects 0.000 description 1
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- 239000000375 suspending agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
- 229960003414 zomepirac Drugs 0.000 description 1
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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
Definitions
- the present invention relates to analgesic compositions. More particularly, the present invention relates to analgesic compositions containing acetaminophen and meclizine.
- Acetaminophen, N-(4-hydroxyphenyl)acetamide or herein referred to as APAP was first used in medicine by Van Mering in 1893, but only since 1949 has it gained in popularity as an effective alternative to aspirin for
- No 4,260,629 discloses that an orally administered composition of APAP and zomepirac, a non-opioid analgesic, in a particular weight ratio range produces a superadditive relief of pain in mammals Furthermore, U.S. Pat. No. 4,132,788 discloses that 5- aroyl-1-(lower)alkylpyrrole-2-acet ⁇ c acid derivatives, non-opioid analgesics, when combined with APAP or aspirin exhibit superadditive antiarth ⁇ tic activity. Also, U.S. Pat.
- No 5,336,691 discloses that the combination of tramadol, a centrally active analgesic analgesic, and APAP exhibits a synergistic analgesic effect when combined in certain ratios.
- G. B. Pat. No. 1 ,442,159 teaches that combinations of APAP and diphenhydramme hydrochlo ⁇ de in certain proportions are satisfactory in the treatment of migraine headache
- U. S. Pat. Nos. 4,401 ,665 and 4,505,862 disclose combinations of aspirin, APAP and diphenhydramme dihydrogencitrate for use as an analgesic.
- FIG. 1 is an isobologram showing the analgesic effect of combinations of APAP and meclizine hydrochlo ⁇ de with inhibition of acetylcholine induced writhing in mice.
- composition for use as an analgesic comprising:
- Meclizine is an anttnauseant now sold for this use in formulations under a variety of names. It has the chemical formula:
- meclizine is well known and a description of a suitable process for its preparation may be found in Morren, Belg. Pat. No. 502,889; Brit. Pat. No. 705,979 and U.S. Pat. No. 2,709,169.
- the pharmaceutically acceptable salts referred to above are generally salts with strong mineral acids.
- suitable such acids are hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, methanesulfonic or hydroxyethanesulfonic.
- the APAP is compounded with the meclizine in a suitable carrier in the proportions recommended above.
- a suitable carrier in the proportions recommended above.
- the ⁇ meclizine is present only to enhance the analgesic effect of the acetaminophen. In such case, the meclizine should be present in an amount insufficient to produce substantial relief from nausea.
- APAP and meclizine are only poorly soluble in water.
- it is desirable to employ methods designed to improve the availability of the actives such as, grinding the the actives to a small particle size or using a surface active agent to stabilize the suspension and/or act as a solubilizing agent.
- Suitable such agents include well known surfactants such as glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol, sorbitan esters, benzalkonium chloride, benzethonium chloride, cetrimide, docusate sodium and sodium lauryl sulfate.
- Suitable such agents may also include solubilizing agents/wetting agents such as polyoxyethylene castor oil derivatives, poloxamer, polyoxyethylene stearates, polyoxyethylene alkylene ethers, stearic acid, lecithin, glyceryl monostearate, cyclodextrins and benzyl benzoate.
- solubilizing agents/wetting agents such as polyoxyethylene castor oil derivatives, poloxamer, polyoxyethylene stearates, polyoxyethylene alkylene ethers, stearic acid, lecithin, glyceryl monostearate, cyclodextrins and benzyl benzoate.
- Suitable such agents may also be emulsifying agents such as acacia, anionic emulsifying wax, carbomer, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, hydrous lanolin, hydroxypropyl cellulose lanolin, lanolin alcohols, methyl cellulose, mineral oil, monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax, oleic acid, propylene glycol alginate and triethanolamine.
- emulsifying agents such as acacia, anionic emulsifying wax, carbomer, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, hydrous lanolin, hydroxypropyl cellulose lanolin, lanolin alcohols, methyl cellulose, mineral oil, monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax, oleic acid, propylene glycol alginate and triethanolamine.
- Persons skilled in the art can easily determine how much
- compositions of the present invention may be used to treat mild to moderately severe pain in warm-blooded animals such as humans by administration of an analgesically effective dose.
- the dosage range, based on the principle active ingredient would be from about 10 to 2000 mg, in particular about 25 to 1000 mg or about 100 or 500 mg, of active ingredient 1 to 4 times per day for an average (70 kg) human although it is apparent that activity of individual compounds of the invention will vary as will the pain being treated.
- Pharmaceutical compositions of the invention comprise the active ingredients as defined above, particularly in admixture with a pharmaceutically-acceptable carrier.
- the dose of meclizine should not exceed about 200 mg, up to four times per day, for an average (70 kg) human.
- a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenterai such as intra muscular.
- any of the usual pharmaceutical media may be employed.
- suitable carriers and additives include water, glycols, oils, alcohols, ftavo ⁇ ng agents, preservatives, coloring agents and the like;
- suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical earners are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
- the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
- injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
- the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
- the active ingredients instead of administering the active ingredients as a single composition, they may be administered simultaneously of sequentially as separate compositions. To obtain the advantages described herein, it is only important that the active ingredients be administered in combination, regardless of whether they are in the same tablet, capsule, powder, injection or elixir.
- the combination products of Table I were prepared with active ingredients which were administered in distilled water containing containing one drop of Tween ⁇ 80 surface active agent (containing 100% polysorbate 80, a monooleate of polyoxyethylenesorbitan with a fatty acid content of about 75% oleic acid and the balance linoleic, palmitic and stearic acids) per 10 ml of preparation.
- the concentration of the active ingredients in the distilled water was such to provide a dosing volume of about 10 ml/kg.
- the mouse acetylcholine-induced abdominal constiction assay as described by Collier et al. in Brit. J. Pharmacol. Chem. Ther., 32: 295-310, 1968, with minor modifications was used to assess analgesic potency of the combination products herein.
- the test drugs and appropriate vehicle were administered orally (p.o.) and 30 minutes later the animal received an intrapentoneal (i.p.) injection of 5.5 mg/kg acetylcholme bromide (Matheson, Colema ⁇ and Bell, East Rutherford, NJ).
- mice were then placed in groups of three into glass bell jars and observed for a ten minute observation period for the occurrence of an abdominal constriction response (defined as a wave of constnction and elongation passing caudally along the abdominal wall, accompanied by a twisting of the trunk and followed by extension of the hind limbs)
- an abdominal constriction response defined as a wave of constnction and elongation passing caudally along the abdominal wall, accompanied by a twisting of the trunk and followed by extension of the hind limbs
- ED50 that dose which would produce 50% analgesia
- An experimental design was used which permitted the complete randomization of the separate dosage forms tested.
- the ED50 values and their 95% fiducial limits were determined by a computer assisted probit analysis.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU35763/97A AU3576397A (en) | 1996-06-20 | 1997-06-20 | Analgesics combining acetaminophen with meclizine |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US66783496A | 1996-06-20 | 1996-06-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997048390A1 true WO1997048390A1 (en) | 1997-12-24 |
Family
ID=24679844
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/010922 WO1997048390A1 (en) | 1996-06-20 | 1997-06-20 | Analgesics combining acetaminophen with meclizine |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU3576397A (en) |
WO (1) | WO1997048390A1 (en) |
ZA (1) | ZA975444B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103543231A (en) * | 2012-07-11 | 2014-01-29 | 北大方正集团有限公司 | Separation analysis method of residual amount of chloroform in meclizine dihydrochloride |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1442159A (en) * | 1973-08-03 | 1976-07-07 | Restien H | Pharmaceutical compositions containing paracetamol |
US4017614A (en) * | 1969-12-05 | 1977-04-12 | Henry Wild | Compositions for the relief of migraine |
WO1991001132A1 (en) * | 1989-07-24 | 1991-02-07 | Fertin Laboratories Ltd. (Dansk Tyggegummi Fabrik A/S) | Chewing gum composition with accelerated, controlled release of active agents |
EP0426479A1 (en) * | 1989-11-02 | 1991-05-08 | McNEIL-PPC, INC. | Use of a composition for the manufacture of a medicament for curing the symptoms of overindulgence |
WO1993004675A1 (en) * | 1991-09-06 | 1993-03-18 | Mcneilab, Inc. | Composition comprising a tramadol material and acetaminophen and its use |
WO1995019759A1 (en) * | 1994-01-24 | 1995-07-27 | The Procter & Gamble Company | Process for solubilizing difficultly soluble pharmaceutical actives |
-
1997
- 1997-06-19 ZA ZA975444A patent/ZA975444B/en unknown
- 1997-06-20 AU AU35763/97A patent/AU3576397A/en not_active Abandoned
- 1997-06-20 WO PCT/US1997/010922 patent/WO1997048390A1/en active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4017614A (en) * | 1969-12-05 | 1977-04-12 | Henry Wild | Compositions for the relief of migraine |
GB1442159A (en) * | 1973-08-03 | 1976-07-07 | Restien H | Pharmaceutical compositions containing paracetamol |
WO1991001132A1 (en) * | 1989-07-24 | 1991-02-07 | Fertin Laboratories Ltd. (Dansk Tyggegummi Fabrik A/S) | Chewing gum composition with accelerated, controlled release of active agents |
EP0426479A1 (en) * | 1989-11-02 | 1991-05-08 | McNEIL-PPC, INC. | Use of a composition for the manufacture of a medicament for curing the symptoms of overindulgence |
WO1993004675A1 (en) * | 1991-09-06 | 1993-03-18 | Mcneilab, Inc. | Composition comprising a tramadol material and acetaminophen and its use |
WO1995019759A1 (en) * | 1994-01-24 | 1995-07-27 | The Procter & Gamble Company | Process for solubilizing difficultly soluble pharmaceutical actives |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103543231A (en) * | 2012-07-11 | 2014-01-29 | 北大方正集团有限公司 | Separation analysis method of residual amount of chloroform in meclizine dihydrochloride |
CN103543231B (en) * | 2012-07-11 | 2015-09-16 | 北大方正集团有限公司 | The method for separating and analyzing of chloroform residual quantity in a kind of meclozine hydrochloride |
Also Published As
Publication number | Publication date |
---|---|
ZA975444B (en) | 1998-12-21 |
AU3576397A (en) | 1998-01-07 |
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