EP1381374A1 - Veterinary compositions comprising avermectin-oxime derivatives and praziquantel - Google Patents
Veterinary compositions comprising avermectin-oxime derivatives and praziquantelInfo
- Publication number
- EP1381374A1 EP1381374A1 EP02716978A EP02716978A EP1381374A1 EP 1381374 A1 EP1381374 A1 EP 1381374A1 EP 02716978 A EP02716978 A EP 02716978A EP 02716978 A EP02716978 A EP 02716978A EP 1381374 A1 EP1381374 A1 EP 1381374A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- praziquantel
- selamectin
- monosaccharide
- formulation
- treatment
- 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- Withdrawn
Links
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 title claims abstract description 98
- 229960002957 praziquantel Drugs 0.000 title claims abstract description 93
- 239000000203 mixture Substances 0.000 title claims description 60
- 229960002245 selamectin Drugs 0.000 claims abstract description 69
- AFJYYKSVHJGXSN-KAJWKRCWSA-N selamectin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1C(/C)=C/C[C@@H](O[C@]2(O[C@@H]([C@@H](C)CC2)C2CCCCC2)C2)C[C@@H]2OC(=O)[C@@H]([C@]23O)C=C(C)C(=N\O)/[C@H]3OC\C2=C/C=C/[C@@H]1C AFJYYKSVHJGXSN-KAJWKRCWSA-N 0.000 claims abstract description 67
- 239000005660 Abamectin Substances 0.000 claims abstract description 30
- RRZXIRBKKLTSOM-XPNPUAGNSA-N avermectin B1a Chemical compound C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 RRZXIRBKKLTSOM-XPNPUAGNSA-N 0.000 claims abstract description 26
- -1 selamectin Chemical compound 0.000 claims abstract description 6
- 238000009472 formulation Methods 0.000 claims description 46
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 45
- 238000011282 treatment Methods 0.000 claims description 34
- QCAHUFWKIQLBNB-UHFFFAOYSA-N 3-(3-methoxypropoxy)propan-1-ol Chemical compound COCCCOCCCO QCAHUFWKIQLBNB-UHFFFAOYSA-N 0.000 claims description 30
- 241001465754 Metazoa Species 0.000 claims description 26
- 241000242722 Cestoda Species 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- 206010061217 Infestation Diseases 0.000 claims description 14
- 230000003071 parasitic effect Effects 0.000 claims description 11
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 claims description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 8
- 241000002163 Mesapamea fractilinea Species 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 5
- 230000000699 topical effect Effects 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims description 2
- 239000004544 spot-on Substances 0.000 claims description 2
- 238000002648 combination therapy Methods 0.000 abstract description 4
- 230000002141 anti-parasite Effects 0.000 abstract description 3
- 239000003096 antiparasitic agent Substances 0.000 abstract description 3
- 241000282326 Felis catus Species 0.000 description 40
- 239000000243 solution Substances 0.000 description 18
- 241000282472 Canis lupus familiaris Species 0.000 description 16
- 239000003826 tablet Substances 0.000 description 16
- 239000004480 active ingredient Substances 0.000 description 13
- 208000015181 infectious disease Diseases 0.000 description 8
- 208000026368 Cestode infections Diseases 0.000 description 6
- 239000003963 antioxidant agent Substances 0.000 description 6
- 230000003078 antioxidant effect Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 5
- 241000935794 Dipylidium Species 0.000 description 4
- 241000244156 Hydatigera taeniaeformis Species 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 244000045947 parasite Species 0.000 description 4
- 239000011877 solvent mixture Substances 0.000 description 4
- 239000007916 tablet composition Substances 0.000 description 4
- 241000935792 Dipylidium caninum Species 0.000 description 3
- 206010047700 Vomiting Diseases 0.000 description 3
- 231100000313 clinical toxicology Toxicity 0.000 description 3
- 230000035935 pregnancy Effects 0.000 description 3
- 241000244206 Nematoda Species 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 241000244155 Taenia Species 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 244000078703 ectoparasite Species 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- PBYJDHRFPFHVKZ-UHFFFAOYSA-N n,n-dibutyl-4-hexoxynaphthalene-1-carboximidamide;hydrochloride Chemical compound Cl.C1=CC=C2C(OCCCCCC)=CC=C(C(=N)N(CCCC)CCCC)C2=C1 PBYJDHRFPFHVKZ-UHFFFAOYSA-N 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 229940075304 praziquantel injectable solution Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229940102101 selamectin topical solution Drugs 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- WGYZMNBUZFHYRX-UHFFFAOYSA-N 1-(1-methoxypropan-2-yloxy)propan-2-ol Chemical compound COCC(C)OCC(C)O WGYZMNBUZFHYRX-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 description 1
- MRBKEAMVRSLQPH-UHFFFAOYSA-N 3-tert-butyl-4-hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1 MRBKEAMVRSLQPH-UHFFFAOYSA-N 0.000 description 1
- IBSREHMXUMOFBB-JFUDTMANSA-N 5u8924t11h Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O3)C=C[C@H](C)[C@@H](C(C)C)O4)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 IBSREHMXUMOFBB-JFUDTMANSA-N 0.000 description 1
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 description 1
- 241001626718 Anoplocephala Species 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 241001660203 Gasterophilus Species 0.000 description 1
- 241000244187 Parascaris Species 0.000 description 1
- 206010039424 Salivary hypersecretion Diseases 0.000 description 1
- 241001126263 Strongylidae Species 0.000 description 1
- 241001672170 Taenia pisiformis Species 0.000 description 1
- 229950008167 abamectin Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 230000002598 avermectinlike Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- QLFZZSKTJWDQOS-YDBLARSUSA-N doramectin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O3)C=C[C@H](C)[C@@H](C3CCCCC3)O4)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C QLFZZSKTJWDQOS-YDBLARSUSA-N 0.000 description 1
- 229960003997 doramectin Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 230000000408 embryogenic effect Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 230000008175 fetal development Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229960002418 ivermectin Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- FXWHFKOXMBTCMP-WMEDONTMSA-N milbemycin Natural products COC1C2OCC3=C/C=C/C(C)CC(=CCC4CC(CC5(O4)OC(C)C(C)C(OC(=O)C(C)CC(C)C)C5O)OC(=O)C(C=C1C)C23O)C FXWHFKOXMBTCMP-WMEDONTMSA-N 0.000 description 1
- ZLBGSRMUSVULIE-GSMJGMFJSA-N milbemycin A3 Chemical class O1[C@H](C)[C@@H](C)CC[C@@]11O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 ZLBGSRMUSVULIE-GSMJGMFJSA-N 0.000 description 1
- YZBLFMPOMVTDJY-CBYMMZEQSA-N moxidectin Chemical compound O1[C@H](C(\C)=C\C(C)C)[C@@H](C)C(=N/OC)\C[C@@]11O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 YZBLFMPOMVTDJY-CBYMMZEQSA-N 0.000 description 1
- 229960004816 moxidectin Drugs 0.000 description 1
- 229940023486 oral product Drugs 0.000 description 1
- 239000013588 oral product Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 208000026451 salivation Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 238000005303 weighing Methods 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/14—Ectoparasiticides, e.g. scabicides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the invention described herein relates to the provision of a combination therapy in the field of treatment (including prophylaxis) of parasitic infestations and consequences thereof, particularly in veterinary medicine.
- the invention relates to antiparasitic therapy using a combination of avermectin- like compounds, specifically 13-monosaccharide-5-oxime compounds, and praziquantel.
- EP 0 717 993 describes a synergistic combination of avermectins/milbemycins with praziquantel, in particular for the treatment of cestode and nematode infestations in horses.
- Particular species mentioned therein include Anoplocephala perfiolata, Strongylidae, Gasterophilus spp., and Parascari aquorum.
- Particular avermectins mentioned therein include ivermectin, abamectin, moxidectin and doramectin.
- Formulations of selamectin in di(C 2 -4 glycol) mono(C ⁇ -4 alkyl) ethers including dipropylene glycol monomethyl ether (DPGMME), and alcohols such as ethanol and isopropy alcohol (IPA) are disclosed in International Patent Application, publication no. WO00/30449, herein incorporated by reference.
- DPGMME dipropylene glycol monomethyl ether
- IPA isopropy alcohol
- Selamectin is the active ingredient of the product marketed under the trade names RevolutionTM, StrongholdTM, etc. by Pfizer Inc. and associated companies, particularly for the treatment (including prophylaxis) of endo- and ecto-parasite infestations in companion animals such as cats and dogs.
- Praziquantel is 2-(cyclohexylcarbonyl)-1 ,2,3,6,7-11b-hexahydro-4H- pyrazino[2,1-a]isoquinolin-4-one, also known as an active ingredient in EMBAY 8440TM, BiltricideTM, CesolTM, and DroncitTM. It is mentioned in the Merck Index, 11th edition, para.7714, and references therein, herein incorporated by reference.
- Desirable attributes in particular for a topical application for administration to companion animals such as cats and dogs, and especially in relation to a treatment for the control of flea, heartworm and tapeworm infestation, include: efficacy; persistence of efficacy; low volume; cosmetically acceptable; convenient; need for small number of applications for broad spectrum parasite control; compliant treatment; safe; suitable pharmacokinetic profile; suitable transdermal flux profile; rapid rate of onset; low dose of active ingredient(s); cutaneous tolerability; and stability on storage.
- Praziquantel has a widespread use in animals orally at higher doses than those which we have tested.
- Dr. J.A. Shmidl in Shawnee, Kansas treated two cats orally with doses of 25 and 50 mg/kg. There were no signs of clinical toxicity or evidence of gross lesions in the gastrointestinal tract.
- Dr. S.M. Kruckenberg reports on the oral treatment of seven cats (6 females and 1 male) with a 5 mg/kg dose during all critical periods of reproduction. Two groups of seven cats (6 females and 1 male) each were also treated subcutaneously and intramuscularly with a praziquantel injectable solution with a 5 mg/kg dose during all critical periods of reproduction. Dr. Kruckenberg further evaluated the oral use of praziquantel in one male and three female cats in a controlled study. Two groups of 4 cats (1 male and 3 females) each were also treated subcutaneously and intramuscularly with the praziquantel injectable solution. All treated cats received 3X the label rate. Four females and 1 male served as untreated controls.
- the treated males received 7 treatments at 2-week intervals throughout the breeding season. Each treated female received a treatment prior to breeding, during the embryogenic period of pregnancy, during late pregnancy and again during lactation.
- the study confirmed the lack of effects on fertility, conception, fetal development or pregnancy when praziquantel was administered at 3X dosage levels.
- Dr. Shmidl further treated two kittens (4 1/2 to 7 1/2 weeks old) twice at a 14- day interval.
- the dosage rate was 5X the label dose. Slight depression was observed in one kitten. No significant clinical toxicity signs or clinical pathology and histopathology changes were attributed to this dosage rate.
- the safety index for the use of praziquantel tablets in cats has been derived from controlled studies using the final tablet formulation (vomiting was the only effect with dual treatments of 100 mg/kg at a 14-day interval). Vomiting at high dosage rates is the typical reaction which prevents significant clinical toxicity signs from occurring.
- the safety factor is at least 5X the label rate when the product is administered at 14 day intervals to kittens 5 1/2 weeks of age and older.
- CUTTER Tape-Tabs (praziquantel) Tapeworm Tablets will remove the common tapeworms, Dipylidium caninum and Taenia taeniaeformis , from cats and kittens.
- CUTTER Tape-Tabs (praziquantel) Tapeworm Tablets for Cats and Kittens are sized for easy administration to either adult cats or kittens.
- the tablets may be given directly in the mouth or crumbled and mixed with the food.
- praziquantel tablets were 100% effective in the treatment of tapeworm infections of dogs and cats due to Taenia pisiformis , Taenia taeniaeformis and Dipylidium caninum. Additionally praziquantel effectively (100%) eliminated experimental T. taeniaeformis infections as young as seven (7) days from cats. Summary of Preclinical Effectiveness Data for Praziquantel Tablets in Cats
- praziquantel has a solubility above 60 mg/g (6% w/w) even in the presence of selamectin at up to 120 mg/g (12% w/w). Above 50% IPA however, this solubility may be increased to over 90 mg/g (9% w/w) in the supersaturated state.
- a series of IPA / DPGMME mixtures were prepared in duplicate as outlined in Table 1. To these were added a fixed amount of selamectin to provide a constant concentration of 120 mg per ml i.e. the maximum selamectin concentration found in StrongholdTM.
- Praziquantel was analysed using an gradient HPLC method modified from that developed for selamectin. This method was validated with respect to praziquantel linearity over the range 10 to 200 mg per ml of praziquantel (in the solubility test solutions) and in the presence of 120 mg per ml of selamectin. This same method was also used to check on the selamectin content in these same solutions.
- compositions containing selamectin and praziquantel are shown below, wherein the composition within the formulation is expressed % weight by volume:
- An aspect of the invention is the provision of a combination therapy using a formulation comprising a 13-monosaccharide 5-oxime avermectin such as selamectin at around 6-12% w/v, and praziquantel at around 3-9% w/v (preferably around 6% w/v), in a veterinarily acceptable carrier, diluent or adjuvant.
- a formulation comprising a 13-monosaccharide 5-oxime avermectin such as selamectin at around 6-12% w/v, and praziquantel at around 3-9% w/v (preferably around 6% w/v), in a veterinarily acceptable carrier, diluent or adjuvant.
- the (13-monosaccharide 5-oxime avermectin such as selamectin)- containing formulation comprises a di(C 2 - 4 glycol) mono(C 1 ⁇ alkyl) ether and an optional skin-acceptable solvent.
- the (13-monosaccharide 5-oxime avermectin such as selamectin)- containing formulation is suitable for topical, preferably spot-on, application.
- Another aspect of the invention is the provision of an antiparasitic combination therapy whereby a 13-monosaccharide 5-oxime avermectin such as selamectin is provided at around 6-12mg/kg (re. host animal) and praziquantel is provided at up to 18mg/kg (re. host animal).
- a 13-monosaccharide 5-oxime avermectin such as selamectin is provided at around 6-12mg/kg (re. host animal) and praziquantel is provided at up to 18mg/kg (re. host animal).
- the selamectin is present in the formulation at about 1 % to about 16% (w/v), more preferably about 4% to about 12% w/v, and most preferably about 6% to about 12% w/v.
- Specific preferred formulations contain selamectin at about 6% w/v and about 12% w/v.
- the praziquantel is present in the formulation at about 0.5 to about 10% w/v, more preferably about 3 to about 9% w/v , most preferably about 6% w/v.
- the di(C 2-4 glycol) mono(C ⁇ - alkyl) ether is diethylene glycol monomethyl ether (DEGMME) or dipropylene glycol monomethyl ether (DPGMME), more preferably DPGMME.
- DEGMME diethylene glycol monomethyl ether
- DPGMME dipropylene glycol monomethyl ether
- the skin-acceptable solvent is present and is ethanol or isopropanol, more preferably isopropanol.
- the formulation containing the avermectin 13-monosaccharide oxime has a w/v to v/v ratio of avermectin 13-monosaccharide oxime to the glycol monomethyl ether is in the range (0.5 to 2) to 1 , more preferably (0.7 to 1.4) to 1 , yet more preferably (0.9 to 1.1 ) to 1 , most preferably about 1 :1.
- a preferred formulation according to the invention also contains antioxidant, preferably selected from propylgallate, BHA (2-t-butyl-4-methoxyphenol), and BHT (2,6-di-f-butyl-4-methylphenol), more preferably BHT.
- antioxidant preferably selected from propylgallate, BHA (2-t-butyl-4-methoxyphenol), and BHT (2,6-di-f-butyl-4-methylphenol), more preferably BHT.
- a preferred formulation according to the invention consists of:
- DEGMME or DPGMME at 1 to 16% w/v, and at a w/v or v/v ratio of active compound to DEGMME/DPGMME of about 1 :1 ;
- a more preferred formulation consists of (a) selamectin at a level of 6% to 12% w/v;
- a pharmaceutical or veterinary composition which comprises a 13- monosaccharide 5-oxime avermectin such as selamectin and praziquantel and a pharmaceutical or veterinary carrier;
- kits useful in the treatment of a parasitic infestation of flea and/or heartworm and tapeworm in a mammal which comprises a 13- monosaccharide 5-oxime avermectin, such as selamectin, and praziquantel and a pharmaceutical or veterinary carrier, and instructions for the treatment of a parasitic infestation of flea and/or heartworm and tapeworm in a mammal.
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Abstract
An antiparasitic combination therapy using a combination of a 13-monosaccharide 5-oxime avermectin, such as selamectin, and praziquantel.
Description
VETERINARY COMPOSITIONS COMPRISING AVERMECTIN-OXIME DERIVATIVES AND PRAZIQUANTEL
The invention described herein relates to the provision of a combination therapy in the field of treatment (including prophylaxis) of parasitic infestations and consequences thereof, particularly in veterinary medicine. In particular the invention relates to antiparasitic therapy using a combination of avermectin- like compounds, specifically 13-monosaccharide-5-oxime compounds, and praziquantel.
EP 0 717 993 describes a synergistic combination of avermectins/milbemycins with praziquantel, in particular for the treatment of cestode and nematode infestations in horses. Particular species mentioned therein include Anoplocephala perfiolata, Strongylidae, Gasterophilus spp., and Parascari aquorum. Particular avermectins mentioned therein include ivermectin, abamectin, moxidectin and doramectin.
GB 2252730, EP 0 930 077, WO 98/06407 and WO 95/05181 also describe combinations of avermectins with praziquantel.
Selamectin, or 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 , is disclosed as Example 5 in International Patent Application, publication no. WO94/15944, herein incorporated by reference.
Formulations of selamectin in di(C2-4 glycol) mono(Cι-4 alkyl) ethers, including dipropylene glycol monomethyl ether (DPGMME), and alcohols such as ethanol and isopropy alcohol (IPA) are disclosed in International Patent Application, publication no. WO00/30449, herein incorporated by reference.
Selamectin is the active ingredient of the product marketed under the trade names Revolution™, Stronghold™, etc. by Pfizer Inc. and associated companies, particularly for the treatment (including prophylaxis) of endo- and ecto-parasite infestations in companion animals such as cats and dogs.
Praziquantel is 2-(cyclohexylcarbonyl)-1 ,2,3,6,7-11b-hexahydro-4H- pyrazino[2,1-a]isoquinolin-4-one, also known as an active ingredient in EMBAY 8440™, Biltricide™, Cesol™, and Droncit™. It is mentioned in the Merck Index, 11th edition, para.7714, and references therein, herein incorporated by reference.
Workers at Pfizer disclosed efficacy data for selamectin vs. gastrointestinal nematodes in cats and ascarids in dogs in Veterinary Parasitology 91 (2000) 321 ; 333.
We have now discovered that a combination of a 13-monosaccharide 5-oxime avermectin derivative, preferably selamectin, with praziquantel, gives good broad spectrum activity vs. endo- and ecto-parasites in companion animals such as dogs and especially cats.
Desirable attributes, in particular for a topical application for administration to companion animals such as cats and dogs, and especially in relation to a treatment for the control of flea, heartworm and tapeworm infestation, include: efficacy; persistence of efficacy; low volume; cosmetically acceptable; convenient; need for small number of applications for broad spectrum parasite control; compliant treatment; safe; suitable pharmacokinetic profile; suitable transdermal flux profile; rapid rate of onset; low dose of active ingredient(s); cutaneous tolerability; and stability on storage.
Efficacy
We have demonstrated excellent efficacy against tapeworms (Dipylidium and Taenia spp) for praziquantel dosed topically to cats at a dose of 1 mg/kg, in combination with selamectin at 8mg/kg in a DPGMME / IPA formulation. Reducing the dose of praziquantel to 0.5 mg/kg reduced efficacy levels against Dipylidium spp. Praziquantel and selamectin loading in the formulation were 1 % and 8% respectively, and animals were dosed with a single topical administration between the shoulder blades (0.1 ml / kg). Cats harbouring natural tapeworm infections were used, and randomised to
treatment based on pre-trial infections. Animals were killed 30 days after treatment, and post mortem tapeworm counts were conducted.
Summary of topical co-formulation efficacy : selamectin / praziquantel combinations in cats
Trial "A"
Treatment Dose Mean Dipylidium % Efficacy
(mg/kg) post mortem count (n=4 / gp)
Control 12.2
Selamectin 8 7.2 40%
Praziquant 1 3.25 74% el
Sela + 8 & 1 0.2 92%
Prazi
Trial "B"
Treatment Dose Mean Dipylidium % Efficacy Mean Taenia % Efficacy
(mg/kg) post mortem post mortem count (n=5 / gp) count (n=5 / gp)
Control 9 4.2
Selamectin 8 No infection N/A No infection N/A
Praziquant 1 1 89% 1.2 72% el
Praziquant 0.5 7.6 16% 0 100% el
Sela + 8 & 1 0 100% 0 100%
Prazi
Sela + 8 & 0.5 1.4 85% 0.6 86%
Prazi
The efficacy of praziquantel against tapeworm infections after oral dosing is summarised in the FOI for Cutter Tape Tabs, an oral tablet approved for use in dogs and cats in the USA. Abstracted information can be found below. In
summary, acceptable efficacy was established as 100% elimination of the tapeworm parasites in all animals dosed. Initial oral studies were done with a range of dosages, some as low as 0.5 mg/kg body weight. The results were not always reproducible, and the recommended dosage schedule for cats is a single tablet (23mg praziquantel) for animals weighing 5 - 11 pounds (2.3-5.0 kg) (ie approx 5 - 10mg/kg).
Our topical data indicate that 1 mg/kg praziquantel, in combination with selamectin, will control tapeworm infections.
Praziquantel has a widespread use in animals orally at higher doses than those which we have tested.
Cutter Tape Tabs FOI abstract
Preclinical Safety Evaluation:
The preclinical safety evaluations for this praziquantel tablet formulation were conducted in the United States by or under the direction of Mobay Corporation, Animal Health Division.
Dr. J.A. Shmidl in Shawnee, Kansas treated two cats orally with doses of 25 and 50 mg/kg. There were no signs of clinical toxicity or evidence of gross lesions in the gastrointestinal tract.
Three cats received two oral 100 mg/kg treatments at 14 day intervals in a study by Dr. Shmidl. Only nausea and vomiting occurred in two animals with no additional clinical signs observed. No significant clinical pathology or histopathology changes occurred.
Dr. S.M. Kruckenberg reports on the oral treatment of seven cats (6 females and 1 male) with a 5 mg/kg dose during all critical periods of reproduction.
Two groups of seven cats (6 females and 1 male) each were also treated subcutaneously and intramuscularly with a praziquantel injectable solution with a 5 mg/kg dose during all critical periods of reproduction. Dr. Kruckenberg further evaluated the oral use of praziquantel in one male and three female cats in a controlled study. Two groups of 4 cats (1 male and 3 females) each were also treated subcutaneously and intramuscularly with the praziquantel injectable solution. All treated cats received 3X the label rate. Four females and 1 male served as untreated controls.
The treated males received 7 treatments at 2-week intervals throughout the breeding season. Each treated female received a treatment prior to breeding, during the embryogenic period of pregnancy, during late pregnancy and again during lactation. The study confirmed the lack of effects on fertility, conception, fetal development or pregnancy when praziquantel was administered at 3X dosage levels.
Eight cats received three oral doses by Dr. Shmidl at 14-day intervals of either 5X or 10X the labeled rate. No significant clinical signs of toxicity were observed, nor did changes occur for hematology, clinical chemistry and histopathology.
Dr. Shmidl further treated two kittens (4 1/2 to 7 1/2 weeks old) twice at a 14- day interval. The dosage rate was 5X the label dose. Slight depression was observed in one kitten. No significant clinical toxicity signs or clinical pathology and histopathology changes were attributed to this dosage rate.
Clinical Field Trial Safety
The tablet formulation was further administered to 135 cats (eight weeks to 13 years of age and two to 191b) in clinical field trials. One instance of diarrhea and one of salivation (total = 2, 1.5%) were reported and were rated as nonsignificant.
Safety Summary
In summary, the safety index for the use of praziquantel tablets in cats has been derived from controlled studies using the final tablet formulation (vomiting was the only effect with dual treatments of 100 mg/kg at a 14-day interval). Vomiting at high dosage rates is the typical reaction which prevents significant clinical toxicity signs from occurring. The safety factor is at least 5X the label rate when the product is administered at 14 day intervals to kittens 5 1/2 weeks of age and older.
Efficacy of Oral Praziquantel in Cats (FOI Summary)
Indications for cats
The approved oral product CUTTER Tape-Tabs (praziquantel) Tapeworm Tablets will remove the common tapeworms, Dipylidium caninum and Taenia taeniaeformis , from cats and kittens.
Dosage Form(s), Route(s) of Administration and Recommended Dosage(s):
CUTTER Tape-Tabs (praziquantel) Tapeworm Tablets for Cats and Kittens are sized for easy administration to either adult cats or kittens. The tablets may be given directly in the mouth or crumbled and mixed with the food.
Dosage Schedule for Cats and Kittens* CUTTER Tape-Tabs Tapeworm Tablets Each tablet contains 23 mg of praziquantel
4 pounds and under 1/2 tablet 5 - 11 pounds 1 tablet
Over 11 pounds 1 1/2 tablets
* Not intended for use in kittens less than 6 weeks of age.
Effectiveness:
Studies were conducted to determine the dosage and formulation of praziquantel which produced the most reliable results when used for the removal of tapeworms from cats.
Acceptable efficacy was established as 100% elimination of the tapeworm parasites in all animals dosed. Initial oral studies were done with a range of dosages, some as low as 0.5 mg/kg body weight. The results were not always reproducible.
Twenty-five separate well-controlled critical anthelmintic studies (which involves the sacrificing of animals and examination to determine the number of parasites in the intestinal tract) were conducted with the final tablet formulation in dogs and cats. Investigators for these studies were Dr. M.L. Sharp, Vernon Texas; Dr. S.M. Kruckenberg, Manhattan, KS; Dr. A.C. Todd, Madison, Wl; and Drs. D.D. Cox and R.G. Arther, Mobay Corporation, Animal Health Division, Shawnee, KS.
A summary table of the investigators' results appears below. Two hundred and ninety-two animals were studied; 157 (100 dogs and 57 cats) were treated with praziquantel tablets orally or in food and 135 (80 dogs and 55 cats) served as untreated controls. Both natural and experimental infections were studied with some animals being infected with two species of tapeworms. All dogs and cats treated according to the recommended dosage schedule, and some treated at less than the recommended dosage schedule, were cleared of their tapeworm infections. At the same time, the untreated control animals, confirmed as positive before treatment, maintained their tapeworm infections, with the exception of four dogs and one cat that lost their infections spontaneously. In these studies, praziquantel tablets were 100% effective in the treatment of tapeworm infections of dogs and cats due to Taenia pisiformis , Taenia taeniaeformis and Dipylidium caninum. Additionally praziquantel effectively (100%) eliminated experimental T. taeniaeformis infections as young as seven (7) days from cats.
Summary of Preclinical Effectiveness Data for Praziquantel Tablets in Cats
% Efficacy Against Tapeworms Investigator/ Treated
Location Cats T. taeniaeformis D. caninum
M.L. Sharp Not Studied 100 Vernon, TX
S.M. Kruckenberg 24 100 100 Manhattan, KS
D.D Cox/
R.G. Arther 29* 100* 100
Mobay Corporation Animal Health Div. Shawnee, KS
TOTAL 57
* One animal underdosed was not cleared of its infection. ** Includes cats with experimentally induced immature (7-day old) infections.
Field investigations of praziquantel tablets were conducted by 12 investigators geographically distributed as follows:
1. Dr. Donald E. Berdan, Wenatchee, Washington
2. Dr. Harold Brauetigam, Frankenmuth, Michigan
3. Dr. W.F. Braunschweig, San Rafael, California
4. Dr. S.F. Cheesman, Pine Bluff, Arkansas
5. Dr. John Durling, Fort Scott, Kansas
6. Dr. J.S. Elder, Youngstown, Ohio
7. Dr. Douglas R. Funk, Wenatchee, Washington
8. Dr. M.A. Groh, Blue Springs, Missouri
9. Dr. Robert Isenhart, Wenatchee, Washington
10. Dr. Larry E. Martin III, Turlock, California
11. Dr. E.E. Schobert, Tampa, Florida
12. Dr. H. Travasos, Abbeville, Louisiana
The field trials were well-controlled using bunamidine hydrochloride as the positive control drug. Overall, 279 dogs and 173 cats were studied, including a wide range of ages, breeds, and weights of both sexes. Praziquantel Tablets were administered to 218 dogs and 135 cats while 61 dogs and 38 cats were dosed with bunamidine hydrochloride. Dosing was administered according to label directions. The animals were observed for the presence of tapeworms proglottids 10-14 days post-treatment; any proglottid found was identified. Investigators were asked to evaluate praziquantel for ease of administration, efficacy and safety on a scale of excellent, good, fair and poor. Investigators rated efficacy in dogs as excellent to good in 97% of the cases in dogs and cats. These trials confirmed preclinical efficacy results and demonstrated that praziquantel tablets, when used according to label directions, did have the effect it purports in its labeling.
FORMULATION
A range of solubility studies have shown that in any ratio of IPA/DPGMME, praziquantel has a solubility above 60 mg/g (6% w/w) even in the presence of selamectin at up to 120 mg/g (12% w/w). Above 50% IPA however, this solubility may be increased to over 90 mg/g (9% w/w) in the supersaturated state. These data indicate that a formulation of selamectin and praziquantel in
combination, with levels of up to 9% w/w praziquantel /12% w/w selamectin would be possible in IPA/DPGMME mixtures.
As part of a feasibility study into the development of a selamectin/praziquantel combination topical formulation, the solubility of praziquantel in the IPA / DPGMME type vehicle used for development of Selamectin Topical Solution (Stronghold ™/Revolution™), was determined. To achieve this a series of solutions of varying IPA / DPGMME ratio were prepared. To help minimise any solubility issues, which could arise due to the presence of selamectin in a formulation, a constant amount of selamectin was added to each solution. After achieving saturated solubility in these solutions and following filtration to remove excess undissolved praziquantel, the level of praziquantel (and selamectin) in solution was determined by HPLC.
Preparation of Solutions
A series of IPA / DPGMME mixtures were prepared in duplicate as outlined in Table 1. To these were added a fixed amount of selamectin to provide a constant concentration of 120 mg per ml i.e. the maximum selamectin concentration found in Stronghold™.
After preparation these solutions were placed at 30°C and rolled continuously for 48 hours. On inspection it was found that complete dissolution of the praziquantel had occurred and so further praziquantel was added until a saturated solution was obtained.
Table 1 :
SOLVENT MIXTURES FOR PRAZIQUANTEL SOLUBILITY STUDIES
nd so only a single solution (2A) was assayed.
Praziquantel Analysis
Praziquantel was analysed using an gradient HPLC method modified from that developed for selamectin. This method was validated with respect to praziquantel linearity over the range 10 to 200 mg per ml of praziquantel (in the solubility test solutions) and in the presence of 120 mg per ml of selamectin. This same method was also used to check on the selamectin content in these same solutions.
RESULTS
The solubility of praziquantel and selamectin in the IPA/DPGMME solutions was calculated as both mg per g and mg per ml. The mass of a 1 ml solution taken for analysis was also measured so that an approximate density could be calculated. This data is shown in Table 2 and the mean values are shown graphically in the Figure below.
TABLE 2:
SOLUBILITY RESULTS FOR PRAZIQUANTEL AND SELAMECTIN IN IPA/DPGMME
SOLUTIONS
Figure 1 :
0 10 20 3300 4400 5500 6600 7700 80 90 100 IPA Concentration (% V/V)
For both praziquantel and selamectin there is a relationship between % IPA in the solvent mixture and increasing solubility, although this is much less marked for selamectin. If the solubility data are taken solely on a mg/ml basis then this trend is still present but it is much less visible. The reasons for this are two fold. Firstly as the solvent mixture changes from IPA to DPGMME the density of the solution increases (given that the densities of IPA and DPGMME are 0.787 and 0.950 g/cm3 respectively) and secondly as the amount of praziquantel dissolved in solution increases, so does the total amount of solids and so this leads to an increase in density. Given that
solubility increases with increasing IPA, then these two effects work counter to each other. A better guide to solubility effects is therefore found by using the mass/mass data.
The data in table 2 and shown graphically in figure 1 , both indicate that praziquantel solubility is increased as the IPA concentration increases. The range of praziquantel solubilities found (based on mean values) are between 68 mg/g (67 mg/ml) in 100% DPGMME, increasing to 102 mg/g (86 mg/ml) for a 100% IPA solution. It should be noted that above 50% IPA the solubility of praziquantel changes relatively little increasing IPA level and is always above the 90 mg/g level. There is also a decrease in selamectin solubility as the IPA concentration reduces although this never goes below 100 mg/g. In fact this process is used in selamectin topical solution to create a selamectin saturated DPGMME solution as the IPA evaporates on the back of the treated animals and so drive the selamectin through the dermal layer.
Example formulations -:
Experimental data shows, that in a solvent mixture of IPA / DPGME, varying from 0 to 100 %v/v IPA, praziquantel can be solubilised at concentrations of up to 10%w/w in the presence of up to 12%w/w selamectin. Given the requirement to ensure that both selamectin and praziquantel remain solubilised after evaporation of the IPA, and to minimise the risk of selamectin and praziquantel precipitation from the formulation on storage, an Example formulation is:
Example 1
Ingredient Composition (% w/v) Function
Selamectin 6.0 (note a) Active ingredient
Praziquantel 6.0 (note b) Active ingredient
BHT 0.08 Antioxidant
DPGMME 5.6 Solubiliser
IPA to volume (note c) Solubiliser
Notes:
(a) Assumes 100% potency - the actual amount used is adjusted according to assay value
(b) Assumes 100% potency - the actual amount used is adjusted according to assay value
(c) The quantity of IPA is adjusted to correct for the amounts of selamectin and praziquantel used.
The formulation as detailed in Examples 1-5 can be prepared by the following method :-
1 ) Add the appropriate amount of IPA to mixing vessel.
2) Add the appropriate amount of DPGMME to mixing vessel.
3) Mix the two solvents together until homogeneous.
4) Add the BHT to the solution and mix until dissolved.
5) Add the appropriate amount selamectin to the solution.
6) Add the appropriate amount of praziquantel to the solution.
7) Mix until all the selamectin and praziquantel have dissolved.
Further Examples of formulations containing selamectin and praziquantel are shown below, wherein the composition within the formulation is expressed % weight by volume:
Example 2
Ingredient Composition (% w Function
Selamectin 8.0 (note a) Active ingredient
Praziquantel 0.5 (note b) Active ingredient
BHT 0.08 Antioxidant
DPGMME 5.6 Solubiliser
IPA to volume (note c) Solubiliser
Example 3
Ingredient Composition (% w/v) Function
Selamectin 8.0 (note a) Active ingredient
Praziquantel 1.0 (note b) Active ingredient
BHT 0.08 Antioxidant
DPGMME 5.6 Solubiliser
IPA to volume (note c) Solubiliser
Example 4
Ingredient Composition (% w/v) Function
Selamectin 12.0 (note a) Active ingredient
Praziquantel 9.0 (note b) Active ingredient
BHT 0.08 Antioxidant
DPGMME 5.6 Solubiliser
IPA to volume (note c) Solubiliser
Example 5
Ingredient Composition (% w/v) Function
Selamectin 6.0 (note a) Active ingredient
Praziquantel 3.0 (note b) Active ingredient
BHT 0.08 Antioxidant
DPGMME 5.6 Solubiliser
IPA to volume (note c) Solubiliser
Notes:
(a) Assumes 100% potency - the actual amount used is adjusted according to assay value
(b) Assumes 100% potency - the actual amount used is adjusted according to assay value
(c) The quantity of IPA is adjusted to correct for the amounts of selamectin and praziquantel used.
An aspect of the invention is the provision of a combination therapy using a formulation comprising a 13-monosaccharide 5-oxime avermectin such as selamectin at around 6-12% w/v, and praziquantel at around 3-9% w/v (preferably around 6% w/v), in a veterinarily acceptable carrier, diluent or adjuvant.
Preferably the (13-monosaccharide 5-oxime avermectin such as selamectin)- containing formulation comprises a di(C2-4 glycol) mono(C1^ alkyl) ether and an optional skin-acceptable solvent.
Preferably the (13-monosaccharide 5-oxime avermectin such as selamectin)- containing formulation is suitable for topical, preferably spot-on, application.
Another aspect of the invention is the provision of an antiparasitic combination therapy whereby a 13-monosaccharide 5-oxime avermectin such as selamectin is provided at around 6-12mg/kg (re. host animal) and praziquantel is provided at up to 18mg/kg (re. host animal). Preferably the selamectin is
present in the formulation at about 1 % to about 16% (w/v), more preferably about 4% to about 12% w/v, and most preferably about 6% to about 12% w/v. Specific preferred formulations contain selamectin at about 6% w/v and about 12% w/v.
Preferably the praziquantel is present in the formulation at about 0.5 to about 10% w/v, more preferably about 3 to about 9% w/v , most preferably about 6% w/v.
Preferably the di(C2-4 glycol) mono(Cι- alkyl) ether is diethylene glycol monomethyl ether (DEGMME) or dipropylene glycol monomethyl ether (DPGMME), more preferably DPGMME.
Preferably the skin-acceptable solvent is present and is ethanol or isopropanol, more preferably isopropanol.
Preferably the formulation containing the avermectin 13-monosaccharide oxime has a w/v to v/v ratio of avermectin 13-monosaccharide oxime to the glycol monomethyl ether is in the range (0.5 to 2) to 1 , more preferably (0.7 to 1.4) to 1 , yet more preferably (0.9 to 1.1 ) to 1 , most preferably about 1 :1.
A preferred formulation according to the invention also contains antioxidant, preferably selected from propylgallate, BHA (2-t-butyl-4-methoxyphenol), and BHT (2,6-di-f-butyl-4-methylphenol), more preferably BHT.
A preferred formulation according to the invention consists of:
(a) selamectin, at a level of 1% to 16% w/v;
(b) DEGMME or DPGMME at 1 to 16% w/v, and at a w/v or v/v ratio of active compound to DEGMME/DPGMME of about 1 :1 ;
(c) praziquantel at 0.5 to 10% w/v;
(d) isopropanol to volume (100%); and, optionally (e) BHT (at less than 0.1% w/v).
A more preferred formulation consists of
(a) selamectin at a level of 6% to 12% w/v;
(b) DEGMME or DPGMME 6 to 12% w/v , and at a w/v or v/v ratio of active compound to DEGMME/DPGMME of about 1 :1 ;
(c) praziquantel at 3-9 % w/v;
(d) isopropanol to volume (100%); and, optionally (e) BHT (at less than 0.1% w/v).
The most preferable formulations are those described in the Examples, especially Example 1.
Further aspects of the invention include:
(a) a method of treatment (including prophylaxis) of parasitic infestation of flea and/or heartworm and tapeworm in a mammal which comprises treatment with a 13-monosaccharide 5-oxime avermectin, such as selamectin, and praziquantel;
(b) a method of treatment as in (a) wherein the 13-monosaccharide 5-oxime avermectin such as selamectin and praziquantel are administered separately in different formulations;
(c) a method of treatment as in (a) wherein the 13-monosaccharide 5-oxime avermectin such as selamectin and praziquantel are administered in the same formulation;
(d) a method of treatment as in (a) or (b) wherein the 13-monosaccharide 5- oxime avermectin such as selamectin and praziquantel are administered via the same route;
(e) a method of treatment as in (a) or (b) wherein the 13-monosaccharide 5- oxime avermectin such as selamectin and praziquantel are administered via different routes;
(f) a pharmaceutical or veterinary composition which comprises a 13- monosaccharide 5-oxime avermectin such as selamectin and praziquantel and a pharmaceutical or veterinary carrier;
(g) the use of selamectin and praziquantel in the manufacture of a medicament for the treatment of a parasitic infestation, or condition mediated by a parasitic infestation, on or in a mammal, especially a companion animal such as a cat;
(g) a kit useful in the treatment of a parasitic infestation of flea and/or heartworm and tapeworm in a mammal, which comprises a 13- monosaccharide 5-oxime avermectin, such as selamectin, and praziquantel and a pharmaceutical or veterinary carrier, and instructions for the treatment of a parasitic infestation of flea and/or heartworm and tapeworm in a mammal.
Claims
1. A veterinary formulation comprising a 13-monosaccharide 5-oxime avermectin at around 1% to 16% w/v, and praziquantel at around 0.5-10% w/v, in a veterinarily acceptable carrier, diluent or adjuvant.
2. A formulation as defined in claim 1 wherein the13-monosaccharide 5-oxime avermectin is selamectin.
3. A formulation as defined in claim 1 or 2 wherein the praziquantel is present at around 6% w/v.
4. A formulation according to any one of claims 1 to 3 which comprises a di(C2-4 glycol) mono(Cι_4 alkyl) ether and an optional skin-acceptable solvent.
5. A formulation according to any one of claims 1 to 4 which is suitable for topical application.
6. A formulation according to claim 5 wherein the formulation is sutable for spot-on application.
7. A formulation according to any one of claims 1 to 6 wherein the 13- monosaccharide 5-oxime avermectin is provided at around 6-12mg/kg (re. host animal) and praziquantel is provided at up to 18mg/kg (re. host animal).
8. A formulation according to any one of claims 1 to 7 wherein the 13- monosaccharide 5-oxime avermectin is present at about 6% to about 12% w/v.
9. A formulation according to any one of claims 1 to 8 wherein the 13- monosaccharide 5-oxime avermectin is present at about 6% w/v or about 12% w/v.
10. A formulation according to any one of claims 1 to 9 wherein the praziquantel is present in the formulation at about 3% to about 9% w/v.
11. A formulation according to any one of claims 1 to 10 wherein the praziquantel is present in the formulation at about 6% w/v.
12. A formulation according to any one of claims 1 to 11 wherein a i(C2_4 glycol) alkyl) ether is present and is diethylene glycol monomethyl ether (DEGMME) or dipropylene glycol monomethyl ether (DPGMME).
13. A formulation according to any one of claims 1 to 12 wherein a skin- acceptable solvent is present and is ethanol or isopropanol.
14. A formulation according to claim 1 which consists of:
(a) selamectin, at a level of 1% to 16% w/v;
(b) DEGMME or DPGMME at 1 to 16% w/v, and at a w/v or v/v ratio of active compound to DEGMME/DPGMME of about 1 :1 ;
(c) praziquantel at 0.5 to 10% w/v;
(d) isopropanol to volume (100%); and, optionally (e) BHT (at less than 0.1% w/v).
15. A method of treatment (including prophylaxis) of parasitic infestation of flea and/or heartworm and tapeworm in a mammal which comprises treatment with a 13-monosaccharide 5-oxime avermectin, such as selamectin, and praziquantel.
16. A method as defined in claim 15 wherein the 13-monosaccharide 5-oxime avermectin such as selamectin and praziquantel are administered separately in different formulations.
17. A method of treatment as defined in claim 15 wherein the 13- monosaccharide 5-oxime avermectin such as selamectin and praziquantel are administered in the same formulation.
18. A method of treatment as defined in claim 15 or 16 wherein the 13- monosaccharide 5-oxime avermectin such as selamectin and praziquantel are administered via the same route.
19. A method of treatment as defined in claim 15 or 16 wherein the 13- monosaccharide 5-oxime avermectin such as selamectin and praziquantel are administered via different routes.
20. The use of a 13- monosaccharide 5-oxime avermectin such as selamectin and praziquantel in the manufacture of a medicament for the treatment of a parasitic infestation, or condition mediated by a parasitic infestation, on or in a mammal, especially a companion animal such as a cat.
21. A kit useful in the treatment of a parasitic infestation of flea and/or heartworm and tapeworm in a mammal, which comprises a 13- monosaccharide 5-oxime avermectin, such as selamectin, and praziquantel and a pharmaceutical or veterinary carrier, and instructions for the treatment of a parasitic infestation of flea and/or heartworm and tapeworm in a mammal.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0108485.4A GB0108485D0 (en) | 2001-04-04 | 2001-04-04 | Combination therapy |
GB0108485 | 2001-04-04 | ||
PCT/IB2002/001025 WO2002094288A1 (en) | 2001-04-04 | 2002-03-28 | Veterinary compositions comprising avermectin-oxime derivatives and praziquantel |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1381374A1 true EP1381374A1 (en) | 2004-01-21 |
Family
ID=9912257
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP02716978A Withdrawn EP1381374A1 (en) | 2001-04-04 | 2002-03-28 | Veterinary compositions comprising avermectin-oxime derivatives and praziquantel |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP1381374A1 (en) |
JP (1) | JP2004526804A (en) |
BR (1) | BR0208654A (en) |
CA (1) | CA2443068A1 (en) |
GB (1) | GB0108485D0 (en) |
MX (1) | MXPA03009023A (en) |
WO (1) | WO2002094288A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2528892C2 (en) * | 2008-10-07 | 2014-09-20 | Сева Санте Анималь Са | Veterinary anti-prolactin composition for ruminants |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MXPA05010659A (en) * | 2003-04-04 | 2005-12-12 | Merial Ltd | Topical anthelmintic veterinary formulations. |
DE10358525A1 (en) | 2003-12-13 | 2005-07-07 | Bayer Healthcare Ag | Endoparasiticides Means for topical application |
US8563554B2 (en) | 2009-03-17 | 2013-10-22 | Concert Pharmaceuticals, Inc. | Deuterated pyrazinoisoquinoline compounds |
GB0905365D0 (en) | 2009-03-27 | 2009-05-13 | Norbrook Lab Ltd | A topical parasiticide composition |
UA108641C2 (en) | 2010-04-02 | 2015-05-25 | PARASITICID COMPOSITION CONTAINING FOUR ACTIVE AGENTS AND METHOD OF APPLICATION | |
JP5723567B2 (en) * | 2010-08-06 | 2015-05-27 | 丸石製薬株式会社 | Determination of nitrogen-containing heterocyclic compounds |
DE112013000869T5 (en) | 2012-02-06 | 2014-10-16 | Merial Ltd. | Oral parasiticidal veterinary compositions comprising systemic agents, methods and uses thereof |
RU2765231C2 (en) | 2012-04-04 | 2022-01-26 | Интервет Интернэшнл Б.В. | Soft chewable pharmaceutical products |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9300883D0 (en) * | 1993-01-18 | 1993-03-10 | Pfizer Ltd | Antiparasitic agents |
BG61064B1 (en) * | 1993-08-12 | 1996-10-31 | Илия Илиев | Medicamentous form for the deparasitation of animals |
AUPM969994A0 (en) * | 1994-11-28 | 1994-12-22 | Virbac S.A. | Equine anthelmintic formulations |
CA2260143C (en) * | 1996-07-30 | 2004-07-13 | Ashmont Holdings Limited | Anthelmintic formulations |
GB9825402D0 (en) * | 1998-11-19 | 1999-01-13 | Pfizer Ltd | Antiparasitic formulations |
-
2001
- 2001-04-04 GB GBGB0108485.4A patent/GB0108485D0/en not_active Ceased
-
2002
- 2002-03-28 BR BR0208654-9A patent/BR0208654A/en not_active IP Right Cessation
- 2002-03-28 CA CA002443068A patent/CA2443068A1/en not_active Abandoned
- 2002-03-28 MX MXPA03009023A patent/MXPA03009023A/en unknown
- 2002-03-28 JP JP2002591005A patent/JP2004526804A/en not_active Withdrawn
- 2002-03-28 EP EP02716978A patent/EP1381374A1/en not_active Withdrawn
- 2002-03-28 WO PCT/IB2002/001025 patent/WO2002094288A1/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO02094288A1 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2528892C2 (en) * | 2008-10-07 | 2014-09-20 | Сева Санте Анималь Са | Veterinary anti-prolactin composition for ruminants |
Also Published As
Publication number | Publication date |
---|---|
JP2004526804A (en) | 2004-09-02 |
BR0208654A (en) | 2004-03-09 |
WO2002094288A1 (en) | 2002-11-28 |
CA2443068A1 (en) | 2002-11-28 |
MXPA03009023A (en) | 2004-02-12 |
GB0108485D0 (en) | 2001-05-23 |
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