NZ608177B2 - Long acting compositions - Google Patents
Long acting compositions Download PDFInfo
- Publication number
- NZ608177B2 NZ608177B2 NZ608177A NZ60817713A NZ608177B2 NZ 608177 B2 NZ608177 B2 NZ 608177B2 NZ 608177 A NZ608177 A NZ 608177A NZ 60817713 A NZ60817713 A NZ 60817713A NZ 608177 B2 NZ608177 B2 NZ 608177B2
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- New Zealand
- Prior art keywords
- composition
- oil
- cyclic amide
- present
- amide solvent
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 162
- YZBLFMPOMVTDJY-LSGXYNIPSA-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-LSGXYNIPSA-N 0.000 claims abstract description 67
- 239000002904 solvent Substances 0.000 claims abstract description 43
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 33
- 150000003950 cyclic amides Chemical class 0.000 claims abstract description 31
- 239000004359 castor oil Substances 0.000 claims abstract description 30
- 235000019438 castor oil Nutrition 0.000 claims abstract description 30
- 229960004816 Moxidectin Drugs 0.000 claims abstract description 27
- 239000005660 Abamectin Substances 0.000 claims abstract description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000008365 aqueous carrier Substances 0.000 claims abstract description 10
- 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 claims abstract description 8
- 229960003997 doramectin Drugs 0.000 claims abstract description 8
- 208000006551 Parasitic Disease Diseases 0.000 claims abstract description 7
- AZSNMRSAGSSBNP-XPNPUAGNSA-N 22,23-dihydroavermectin B1a Chemical compound 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 AZSNMRSAGSSBNP-XPNPUAGNSA-N 0.000 claims abstract description 5
- 229960002418 Ivermectin Drugs 0.000 claims abstract description 5
- 229950008167 Abamectin Drugs 0.000 claims abstract description 4
- 229960002245 Selamectin Drugs 0.000 claims abstract description 4
- 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 4
- AFJYYKSVHJGXSN-XHKIUTQPSA-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-XHKIUTQPSA-N 0.000 claims abstract description 4
- 229940000188 Cydectin Drugs 0.000 claims description 40
- -1 lactone compound Chemical class 0.000 claims description 18
- 239000003963 antioxidant agent Substances 0.000 claims description 15
- 230000003078 antioxidant Effects 0.000 claims description 13
- 239000003921 oil Substances 0.000 claims description 10
- 235000019198 oils Nutrition 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 229940095259 Butylated Hydroxytoluene Drugs 0.000 claims description 7
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims description 7
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical group CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 7
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 7
- 235000010469 Glycine max Nutrition 0.000 claims description 6
- 240000007842 Glycine max Species 0.000 claims description 6
- 239000007972 injectable composition Substances 0.000 claims description 6
- 235000012343 cottonseed oil Nutrition 0.000 claims description 5
- HNJBEVLQSNELDL-UHFFFAOYSA-N 2-Pyrrolidone Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000002385 cottonseed oil Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 239000008159 sesame oil Substances 0.000 claims description 3
- 235000011803 sesame oil Nutrition 0.000 claims description 3
- 150000003626 triacylglycerols Chemical class 0.000 claims description 3
- 235000019482 Palm oil Nutrition 0.000 claims description 2
- 235000019483 Peanut oil Nutrition 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- 235000019486 Sunflower oil Nutrition 0.000 claims description 2
- 239000000828 canola oil Substances 0.000 claims description 2
- 235000019519 canola oil Nutrition 0.000 claims description 2
- 239000003240 coconut oil Substances 0.000 claims description 2
- 235000019864 coconut oil Nutrition 0.000 claims description 2
- 235000005687 corn oil Nutrition 0.000 claims description 2
- 239000002285 corn oil Substances 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 239000004006 olive oil Substances 0.000 claims description 2
- 235000008390 olive oil Nutrition 0.000 claims description 2
- 239000002540 palm oil Substances 0.000 claims description 2
- 239000000312 peanut oil Substances 0.000 claims description 2
- 235000005713 safflower oil Nutrition 0.000 claims description 2
- 239000003813 safflower oil Substances 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 239000002600 sunflower oil Substances 0.000 claims description 2
- BVDRUCCQKHGCRX-UHFFFAOYSA-N 2,3-dihydroxypropyl formate Chemical compound OCC(O)COC=O BVDRUCCQKHGCRX-UHFFFAOYSA-N 0.000 claims 1
- 230000000975 bioactive Effects 0.000 abstract description 29
- 230000000507 anthelmentic Effects 0.000 abstract description 17
- 150000002596 lactones Chemical class 0.000 abstract description 8
- 239000003124 biologic agent Substances 0.000 abstract 2
- 238000009472 formulation Methods 0.000 description 27
- 238000002347 injection Methods 0.000 description 21
- 239000007924 injection Substances 0.000 description 21
- 230000000694 effects Effects 0.000 description 16
- 238000003197 gene knockdown Methods 0.000 description 15
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 10
- 239000000969 carrier Substances 0.000 description 9
- 235000013601 eggs Nutrition 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 244000045947 parasites Species 0.000 description 7
- 238000003307 slaughter Methods 0.000 description 7
- 238000003860 storage Methods 0.000 description 7
- 230000002459 sustained Effects 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 241000283898 Ovis Species 0.000 description 5
- 239000000921 anthelmintic agent Substances 0.000 description 5
- 229960002903 benzyl benzoate Drugs 0.000 description 5
- 210000001519 tissues Anatomy 0.000 description 5
- 229940036592 ANTHELMINTICS Drugs 0.000 description 4
- LVGKNOAMLMIIKO-QXMHVHEDSA-N Ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 4
- 229940093471 ethyl oleate Drugs 0.000 description 4
- 230000036512 infertility Effects 0.000 description 4
- 230000001418 larval Effects 0.000 description 4
- 231100000803 sterility Toxicity 0.000 description 4
- 241000893172 Chabertia Species 0.000 description 3
- 241001126268 Cooperia Species 0.000 description 3
- 241000243974 Haemonchus contortus Species 0.000 description 3
- 241000243797 Trichostrongylus Species 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 230000001965 increased Effects 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 210000003165 Abomasum Anatomy 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 241000202814 Cochliomyia hominivorax Species 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 241000510960 Oesophagostomum Species 0.000 description 2
- 241000243795 Ostertagia Species 0.000 description 2
- 210000000614 Ribs Anatomy 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N Triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 229960002622 Triacetin Drugs 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000001058 adult Effects 0.000 description 2
- 230000000111 anti-oxidant Effects 0.000 description 2
- 230000002051 biphasic Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 244000079386 endoparasites Species 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- 150000003278 haem Chemical class 0.000 description 2
- 230000000749 insecticidal Effects 0.000 description 2
- 239000002917 insecticide Substances 0.000 description 2
- 230000000968 intestinal Effects 0.000 description 2
- 210000002429 large intestine Anatomy 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 230000000590 parasiticidal Effects 0.000 description 2
- 239000002297 parasiticide Substances 0.000 description 2
- 230000002085 persistent Effects 0.000 description 2
- 230000000275 pharmacokinetic Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000001603 reducing Effects 0.000 description 2
- 231100000486 side effect Toxicity 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- HBOQXIRUPVQLKX-BBWANDEASA-N 1,2,3-trilinoleoylglycerol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/C\C=C/CCCCC)COC(=O)CCCCCCC\C=C/C\C=C/CCCCC HBOQXIRUPVQLKX-BBWANDEASA-N 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N Axona Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- WPNHOHPRXXCPRA-TVXIRPTOSA-N Eprinomectin Chemical compound O1[C@@H](C)[C@@H](NC(C)=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 WPNHOHPRXXCPRA-TVXIRPTOSA-N 0.000 description 1
- 239000004348 Glyceryl diacetate Substances 0.000 description 1
- 241000243976 Haemonchus Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levotetramisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- 210000004185 Liver Anatomy 0.000 description 1
- 241000244206 Nematoda Species 0.000 description 1
- 241001137882 Nematodirus Species 0.000 description 1
- 210000000664 Rectum Anatomy 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 241000244174 Strongyloides Species 0.000 description 1
- 210000004003 Subcutaneous Fat Anatomy 0.000 description 1
- 241000191771 Teladorsagia circumcincta Species 0.000 description 1
- 241000122945 Trichostrongylus axei Species 0.000 description 1
- 241000243796 Trichostrongylus colubriformis Species 0.000 description 1
- 241001489151 Trichuris Species 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000002924 anti-infective Effects 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 150000005676 cyclic carbonates Chemical class 0.000 description 1
- 230000003111 delayed Effects 0.000 description 1
- 230000003292 diminished Effects 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 244000078703 ectoparasites Species 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 229960002346 eprinomectin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229940074076 glycerol formal Drugs 0.000 description 1
- 235000019443 glyceryl diacetate Nutrition 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000002209 hydrophobic Effects 0.000 description 1
- 239000012051 hydrophobic carrier Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drugs Drugs 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 238000005020 pharmaceutical industry Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000001340 slower Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 239000004544 spot-on Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000002522 swelling Effects 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-M thioglycolate(1-) Chemical compound [O-]C(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-M 0.000 description 1
- 231100000730 tolerability Toxicity 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly Effects 0.000 description 1
Abstract
Disclosed is a long-acting composition for the treatment of an animal in need thereof wherein the composition includes a therapeutically effective amount of a bioactive agent, characterised in that the composition includes a non-aqueous carrier and a solvent system comprising castor oil and at least one cyclic amide (preferably N-Methylpyrrolidone(NMP)). Also disclosed is the method for treating a parasitic infection in an animal using the composition where the biological agent is an anthelmintic especially selected from the group consisting of that macrocyclic lactones avermectin, moxidectin, milbemycin, ivermectin, abamectin, doramectin, epinomectin and selamectin. one cyclic amide (preferably N-Methylpyrrolidone(NMP)). Also disclosed is the method for treating a parasitic infection in an animal using the composition where the biological agent is an anthelmintic especially selected from the group consisting of that macrocyclic lactones avermectin, moxidectin, milbemycin, ivermectin, abamectin, doramectin, epinomectin and selamectin.
Description
LONG ACTING COMPOSITIONS
TECHNICAL FIELD
The present invention relates to a long acting composition including a bioactive,
and particularly, but not limited to, compositions for the treatment or prevention of
parasitic infections in or on an animal.
BACKGROUND ART
In the medical and veterinary fields, there is need and long felt want to provide
improved long acting compositions. A significant advantage of utilising long acting
compositions is the ability to administer the composition on a less frequent basis.
This equates to less stress, time and hardship to the patient or animal, as well as
the caregiver. Less consumables and storage of the composition is also required,
also giving significant advantages.
Whilst there are many known bio-active agents already in use, it can often be
difficult to provide these in compositions with good pharmacokinetic properties,
including in this case, long acting delivery profiles.
Problems often persist with poor stability or solubility of the actives, uncontrolled or
unwanted release profiles, poor knockdown affects or unwanted side effects
following administration.
For example, in the field of veterinary medicine, anthelmintics are used to control
or treat internal and external parasites. There is a wide variety of different
anthelmintics and derivatives to utilise when treating such parasites. However,
many anthelmintics, such as macrocyclic lactones, are poorly soluble in
conventional solvents. They are particularly difficult to administer in an injectable
format, which is typically used for long acting protection against ecto- and endo-
parasites.
Macrocyclic lactone compounds such as avermectins, ivermectin, doramectin,
mibemycin and moxidectin can easily break down in water-based compositions.
To try to counter this issue, formulation chemists have included such actives
together with excipients such as glycol solvents, glycerol formal and / or
surfactants.
However, an additional significant problem encountered with many anthelmintic
compositions, many of which attempt to provide a long acting persistence, is that
the macrocyclic lactone is released too rapidly in the animal. This leads to a
shorter duration of protection from the active, disadvantageously requiring re-
administration on a more regular basis.
It can also be very dangerous to animals to be exposed to high levels of the
bioactive agent (e.g. a macrocyclic lactone), especially younger animals such as
calves under the age of 10 weeks. A further problem is therefore trying to avoid an
uncontrolled release profile of the active to avoid toxic results.
Furthermore, it is often be beneficial to provide a controlled “burst” of an active
agent to provide an initial “knockdown effect” to help rid the body of parasites. This
controlled burst can then be followed with a long acting slow release of the
anthelmintic to help ensure the parasites are completely removed, or provide long
term protection.
A controlled profile release such as this can be difficult to achieve, especially in a
single long acting composition. This is especially true for precarious actives such
as anthelmintics. Even if such a release is achieved, it often comes at the expense
of complicated combination of excipients, increased labour in manufacture,
equipment or other resources in preparing the composition.
Injectable compositions can be especially troublesome to formulate as long acting
compositions. For instance, many of the excipients used such as polymers,
glycols, alcohol based solvents and so forth can lead to unwanted characteristics
such as high viscosity in the composition which can make it difficult to administer
through a needle. Similarly, some of the excipients used in long acting injectables
can lead to an increased site reaction on injection. Also, some compositions can
have poor storage characteristics. Furthermore, despite attempting to provide a
long acting release of active and therefore persistency of protection, many fall
short of this goal.
WO 97/11709 (Harvey) discloses an anthelmintic lactone composition including a
vegetable oil and a co-solvent chosen from an alcohol having four or more carbon
atoms, such as benzyl alcohol.
US 6,552,002 (Steber) discloses sustained-release compositions including a
macrocyclic lactone compound at a high concentration (between 5-30% w/w),
together with a surfactant (described as sorbitan esters), a solvent and co-solvent.
Steber discusses that by increasing the active concentration above what is
normally used, a sustained release of the active is possible. However, higher
loading of actives can be dangerous due to toxicity problems as previously
discussed.
Furthermore, the higher concentration of active needed to provide the sustained
release profile in Steber requires a complicated combination of excipients. Despite
these requirements, it is likely the high loading of active could inherently lead to
stress on the composition, leading to a diminished shelf life. Other downfalls
include likely higher costs in preparation and/or a greater site reaction on delivery.
US 6,174,540 (Williams) discloses long acting injectable formulations including a
therapeutic agent (e.g. insecticides, parasiticides, NSAIDs, etc) together with
hydrogenated castor oil, a hydrophobic carrier (triacetin, benzyl benzoate, or ethyl
oleate), and one of acylated monoglycerides, propyl dicaprylates/dicaprate, or
caprylic/capric acid triglycerides). Williams found that the combination of
excipients identified, as expected, had the ability to provide a long acting release
profile to a range of bioactives.
NZ 332224 (Grosse-Bley) also discloses injectable formulations including
avermectins and mibemycins which include castor oil together with an additional
co-solvent selected from fatty acid esters of mono- or polyhydric alcohols, aliphatic
or aromatic alcohols, or cyclic carbonates.
(Soll) discloses long acting injectable formulations for treating
ectoparasites and endoparasites, wherein the formulation includes the bioactive
agent, a subcutaneously volatile solvent, a biologically acceptable polymer,
together with additional optional excipients. The use of polymers especially was
discussed as allowing the release profile to extend up to 42 days.
EP 393890 (Wicks) discloses the use of a combination of ethyl oleate (a fatty acid
ester) and sesame oil as a solvent for avermectin compounds. These formulations
were found to be well tolerated when administered as an injection. However they
lack storage stability, with a precipitate forming after a few days when stored at
4°C.
WO 2010116267 (Costa) discloses high-dose injectable formulations of doramectin
at 3.5% in a carrier of cottonseed oil and benzyl benzoate. A comparative example
is a formulation from NZ 332224 (Grosse-Bley), containing 3% doramectin in a
carrier of 40% v/v castor oil and 60% v/v ethyl oleate. Costa provides a comparison
of the efficacy in treating screwworm (the larvae of the myiasis-causing fly
Cochliomyia hominivorax), between the disclosed cottonseed oil/benzyl benzoate
composition and the comparative castor oil composition in Grosse-Bley. The
results showed that the release of active from the castor oil formulation is either
delayed or relatively slow, so that an efficacious systemic concentration is reached
noticeably later than the cottonseed/benzyl benzoate formulation. It was suggested
that the high affinity of castor oil for avermectins such as doramectin, unfavourably
slows the release of the drug from the carrier.
A currently available commercial product Cydectin Long Acting Injection for Sheep
is marketed as a long-acting formulation containing moxidectin. This product is
indicated to prevent reinfection with Haemonchus contortus for 91 days, Ostergia
circumcincta for 112 days and Trichostrongylus colubriformis for 42 days following
a single dose. Preliminary studies performed by the current inventors assessed
larvae counts from hatched eggs from faecal samples. This study found that
Cydectin Long Acting provided a reduced egg count for up to about 100 days.
(http://cydectin.co.nz/discover-cydectin/cydectin-long-action-injection-for-
sheep.aspx)
Furthermore, Cydectin can lead to site reaction (e.g. swelling and inflammation) at
the injection site in animals following administration.
There is a long felt need to provide stable, long acting formulations that can
provide protection against parasites for longer duration than currently available
compositions like Cydectin .
Even more so, there is a need to provide a formulation that provides a treatment
that allows a fast yet controlled “bleed” to provide a good initial knockdown effect to
quickly control the condition in the animal, yet then still provide a longer acting
protection to the animal.
Despite the attempts in the industry to formulate long acting compositions, the
problems outlined above continue to persist.
It is an object of the present invention to address the foregoing problems or at least
to provide the public with a useful choice.
All references, including any patents or patent applications cited in this
specification are hereby incorporated by reference. No admission is made that any
reference constitutes prior art. The discussion of the references states what their
authors assert, and the applicants reserve the right to challenge the accuracy and
pertinency of the cited documents. It will be clearly understood that, although a
number of prior art publications are referred to herein, this reference does not
constitute an admission that any of these documents form part of the common
general knowledge in the art, in New Zealand or in any other country.
Throughout this specification, the word “comprise”, or variations thereof such as
“comprises” or “comprising”, will be understood to imply the inclusion of a stated
element, integer or step, or group of elements integers or steps, but not the
exclusion of any other element, integer or step, or group of elements, integers or
steps.
Further aspects and advantages of the present invention will become apparent
from the ensuing description which is given by way of example only.
DISCLOSURE OF INVENTION
According to one aspect of the present invention there is provided a long acting
composition for the treatment of an animal in need thereof wherein the composition
includes a bioactive agent, characterised in that the composition includes a non-
aqueous carrier and a solvent system comprising castor oil and at least one cyclic
amide.
Throughout this specification the term “long acting” should be taken as meaning
being effective after an initial dosage and maintaining its effects over an extended
period of time.
Preferably, the term long acting nature of the composition provides an acceptable
and persistent efficacy for more than 40 days after an initial dosage.
Advantages of the present invention
The inventors surprisingly found that a composition of the present invention gave
both rapid-knockdown and excellent long acting characteristics of the composition
when delivered to an animal.
Without wishing to be bound by theory, the inventors believe the advantageous
properties of both rapid knockdown, and good long-term persistency of the present
invention may be provided the combination of castor oil with the at least one cyclic
amide solvent.
The inventors believe that the cyclic amide solvent allows an initial release of
bioactive agent in the short term, leaving behind the castor oil to provide a longer
release of the bioactive agent over an extended period of time. In other words, the
castor oil and cyclic amide solvent are thought to provide a biphasic release of the
active agent from the injection site over time, which act synergistically together to
provide a substantiated release profile of the active agent.
This biphasic release is expected to be seen when used with substantially any
active agent, despite the present invention most preferably using an anthelmintic
such as moxidectin.
The inventors foresee the composition may also be used to provide a controlled
short term “burst” of bioactive release after delivery to provide an initial knockdown
effect, followed by a longer term delivery of the bioactive agent. This may be very
useful to treat more acute conditions where the bioactive agent is needed at higher
levels in the short term to quickly stabilise or treat the animal, but at lower levels
over the longer term (e.g. once the condition’s severity has lessened). Without this
advantageous release profile, a caregiver may otherwise need to deliver two
treatments administered simultaneously or consecutively to achieve the same
result.
In summary, some advantages of the present invention may include:
- allowance of one dosage opposed to repeated dosages to avoids extra
handling stress to the animal;
- a sustained release profile of the bioactive, over both the short term period
and long term period after delivery;
- avoidance of toxicity problems which can otherwise be caused by
uncontrolled release of the active;
- improved persistency and knockdown effect compared to commercially
available long acting compositions such as Cydectin (see below)
- avoidance of high loading of active agent to achieve longer persistency as
taught in Steber et al.) and thereby reducing potential side effect, or
instability of the composition etc;
- long term storage stability
- efficiency in the manufacturing process
- little to no site reaction on delivery. Lower dose trials showed no site
reaction. Higher dose trials (discussed below) showed minimal site reaction
similar to Cydectin . This was unexpected as the inventive composition
appears to provide a slower release from the injection site, therefore a
higher site reaction than Cydectin was expected.
Comparison to Cydectin:
When an exemplary composition of the present invention was compared to
Cydectin (a long acting moxidectin injection) preliminary results showed
significantly higher residues in subcutaneous fat after 90 days compared to the
withhold period of Cydectin . This strongly supports the greater persistency
provided by the present composition. The studies were set up to ensure that the
same active ingredient (moxidection) and concentration were used in the test
composition as present in Cydectin .
These studies suggest moxidectin may be being absorbed into the fat tissues more
effectively than seen with Cydectin . It is possible that the rate of uptake of
moxidectin into the fat tissue has a maximum limit irrespective of the concentration
in the blood. Therefore, a potentially slower release from the injection site offered
by the present invention may actually allow greater amounts of the active to be
absorbed into the fat.
Once in the fat tissue, it is thought moxidectin is then slowly released into other
tissues.
In Cydectin , it is possible that the active agent that is released quicker is being
cleared from the bloodstream and/or injection site by other means such as the
liver, thereby preventing efficient transfer to the fat tissue.
It is also possible that a higher dosage of active agent may help to achieve the
illustrated persistency, which might assisted by the slow release from the injection
site. However, given that Cydectin included this same dosage of 2% w/w as the
tested formulation, it is thought a high level of moxidectin cannot be the sole
reason for the improved results as seen.
Preferred embodiments
Preferably, the composition is configured for parenteral injection.
A significant advantage of the present composition is that the excipients used allow
a good consistency for easy injection. Similar compositions currently available,
such as Cydectin can be quite viscous, which can be difficult for injection, and
potentially painful or harmful to the animal. For example, Cydectin requires a
special injector to be used due to its viscosity requirements. In preliminary studies,
the trial products of the present invention appeared easier to administer than
Cydectin .
However, the ability of the composition to provide a beneficial long acting release
profile may easily be adapted for other routes of administration, using known
excipients commonly used in the industry. Such modes of delivery may include
topical (such as composition adapted for a spot-on or spray-on), oral (such as
composition adapted for tablets or drenches), or internal (such as a composition
adapted as a bolus).
Preferably, the bioactive agent is an anthelmintic compound.
The anthelmintic may be present in the composition at a concentration between
0.005 to 30% w/v.
Preferably, the anthelmintic is present in the composition at a concentration
between 0.005 to 5% w/v.
A significant advantage of the present invention is that a desired release profile
may be achieved using normal and safe amounts of anthelmintic agent. This is
unlike US 6,552,002 (Steber) which discusses the need to increase the active
concentration to 5-30% in order to achieve a suitable release profile, potentially
putting the animal at risk of toxic doses of active agent.
Clearly, if an alternative bioactive agent is used, the amount of bioactive agent may
be adjusted accordingly to suit clinical and pharmacokinetic requirements.
However, the inventors acknowledge that the bioactive agent may alternatively be
any bioactive, such as an insecticide, parasiticide, growth enhancer, anti-infective
or NSAID without departing from the scope of the invention. It would be
reasonably expected that the inventive combination of an oil together with a cyclic
amide solvent may be used with any bioactive agent which requires a long acting
release profile as outlined above. This is supported by the disclosure in US
6,174,540 (Williams) which identified that the combination of excipients could be
utilised with a range of bio-actives yet still provide the desired outcome.
The inventors particularly consider the present invention would work well with
substantially any macrocyclic lactone compounds such as avermectins and
milbemycins.
Preferably, the anthelmintic is selected from the group consisting of avermectin,
moxidectin, milbemycin, ivermectin, abamectin, doramectin, eprinomectin and
selamectin.
Preferably, the anthelmintic is moxidectin.
Moxidectin is the most preferred active agent as it has a known persistency at
therapeutic levels for an extended period of time, as exemplified by Cydectin .
Moxidection also has a high level of efficacy, a broad spectrum of activity and is
relatively safe to use.
Regardless, it should be appreciated that the present invention extends to use of
other types of actives and compositions including same without departing from the
scope thereof.
Castor oil was found to be useful as part of a solvent system for the active agent,
and particularly beneficial in providing a sustained release of the active agent.
The castor oil may be present in the composition at a concentration between 1-
70% w/v.
Preferably, the castor oil is present in the composition at between 1- 20% w/v.
More preferably, the castor oil is present in the composition at between 1-15% w/v.
The inventors found that a concentration of approximately 7% w/v castor worked
particularly effectively. This amount of castor oil tended to result in the active being
released synergistically at an optimal rate from the injection site.
The composition includes a non-aqueous carrier.
Preferably the non-aqueous carrier is chosen to provide appropriate physical
properties to the composition, such as suitable viscosity and tolerability when
administered.
Preferably the non-aqueous carrier is a hydrophobic vehicle such as an oil.
Preferably the oil is of a vegetable, animal or synthetic origin.
More preferably, the carrier is selected from the group consisting of canola oil, corn
oil, cottonseed oil, olive oil, peanut oil, sesame oil, soybean oil, safflower oil,
coconut oil, sunflower oil, palm oil, monoglycerides, diglycerides and triglycerides,
medium chain succinic acid triglyceride, caprylic/capric triglyceride,
caprylic/capric/linoleic triglyceride, caprylic/capric/succinic triglyceride.
Most preferably, the carrier is soyabean oil.
Preferably the active is insoluble or relatively insoluble in the non-aqueous carrier
without the presence of the solvent system.
The inventors found that the combination of castor oil from the solvent system and
soyabean oil as the carrier provided particularly useful sustained release
characteristics. This is thought to be due to the soyabean oil as being a relatively
inert carrier that acts as a vehicle for administering the active solubilised by the
solvent system.
The cyclic amide solvent may be present in the composition at a concentration
between 1-50% w/v.
Preferably, the cyclic amide solvent is present in the composition at a concentration
of approximately 15% w/v.
The inventors identified that the use of the cyclic amide solvent in a long acting
composition allows an initial “bleed” of the bioactive before the long acting release
of the composition is governed by the remaining oil. A significant disadvantage
identified in the prior art with using castor oil as a solvent, particularly with
avermectins and milbemycins, is that if the affinity between the active and castor oil
is too high, the release of the active can be too slow. This may delay the effect of
the active, prevent the active from being entirely effective, and/or increase the
likelihood of resistance developing. The use of a cyclic amide in combination with
castor oil as the solvent system, surprisingly overcomes this problem.
Without wishing to be bound by theory, the inventors believe that the cyclic amide
solvent may be able to form a complex with the active, which rapidly releases some
of the active from the administered composition into the animal. The remainder of
the active is then able to more slowly release from the composition, enabling the
long-acting effect.
Additionally, the combination of the cyclic amide solvent and castor oil solvent may
help to lower the requirement of the castor oil compared to the prior art. This may
advantageously provide a greater ability to control the release rate/long acting
effect.
Furthermore, the inventors identified that manipulation of the concentration of the
cyclic amide solvent may allow careful control of the rate of this initial “bleed”. This
may provide the ability to carefully alter the initial release profile of the composition,
depending on the condition to be treated or the severity of the condition in the
animal. This may be an advantage as long-acting formulations can be notoriously
difficult to control, often with uncontrolled initial release of the active.
Preferably, the cyclic amide solvent is a pyrrolidone.
More preferably, the pyrrolidone is selected from the group consisting of 1-methyl-
2-pyrrolidinone (NMP), 2-pyrrolidone and combinations thereof.
Most preferably, the cyclic amide solvent is NMP. An advantage of NMP is that it is
commonly used in the pharmaceutical industry, it is well accepted and is relatively
inexpensive.
A particularly preferred composition includes moxidectin as the bioactive agent,
together with a combination of castor oil and NMP.
The composition may include an antioxidant. Substantially any antioxidant may be
used. However, the inventors consider particularly useful antioxidants may be
butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) or a combination
of both.
In the literature, antioxidants have been used to stabilise a macrocyclic lactone
compound in a composition. However, if a macrocyclic lactone compound is
combined together with another active, the antioxidant is often not sufficient to
stabilise the composition. The composition of the present invention may allow
multiple actives to be combined together (such as a macrocyclic lactone and
levamisole), yet also allow the antioxidant to be present to perform its normal
antioxidant function and/or help stabilise the formulation.
Typically, the antioxidant may be present in the formulation between 0.005 to 10%
w/v.
Preferably, the antioxidant is BHT and is present in the composition at a
concentration of approximately 0.05% w/v.
Other carriers or excipients may include any of the following: acetins (mono, di and
triacetin), ethyl oleate and benzyl benzoate.
Method of treatment
A method of treating an animal in need thereof with a composition as discussed
above, including the step of delivering the composition to the animal to provide
long acting protection against or treatment for a condition or disease.
In a preferred embodiment, the method is for the protection or treatment of internal
or external parasitic infection. For example, the method may be for the protection
or treatment of heartworm or intestinal worms. In this embodiment, the bioactive
agent used in the composition includes at least one anthelmintic such as
moxidectin.
The composition may be configured to provide long acting delivery of the bioactive
agent for at least 50 days or more. Initial studies (see best mode section) have
indicated the long acting formulation may be effective for 133 or more following an
initial administration. This is a significant advantage of currently available
formulations such as Cydectin .
A use, in the manufacture of a composition as substantially described above
wherein at least one bioactive agent in the composition is an anthelmintic, for a
long acting prevention or treatment against a parasitic infection.
Preferably, the use is for long acting prevention or treatment against heartworm or
intestinal worms.
Method of preparation
A method of preparing a long acting composition including a bioactive agent
characterized by the step of adding at least one oil and at least one cyclic amide
solvent to the bioactive agent.
Preferably, the method involves the steps:
a) adding the cyclic amide solvent to a manufacturing container;
b) adding the bioactive agent to the cyclic amide solvent;
c) adding the castor oil to the mixture; and
d) adding a non-aqueous carrier up to volume.
Preferably, the cyclic amide solvent is heated to approximately 40-50°C before step
b).
Preferably, the bioactive is dissolved in the cyclic amide solvent before step c.
Preferably, an antioxidant is added before step b). The inventors found this was an
important step to improve the overall effectiveness/stability of the composition.
This was found to be particularly the case if the cyclic amide solvent is to be
heated as preferred.
BRIEF DESCRIPTION OF DRAWINGS
Further aspects of the present invention will become apparent from the ensuing
description which is given by way of example only and with reference to the
accompanying drawings in which:
Figure 1 Pilot non-slaughter study on Haemonchus contortus larvae counts
from hatched eggs to persistency and knockdown effect
(comparison between Formulation 1 and Cydectin LA injectable);
Figure 2 Pilot non-slaughter study on Trichostrongylus larvae counts from
hatched eggs to persistency and knockdown effect (comparison
between Formulation 1 and Cydectin LA injectable);
Figure 3 Pilot non-slaughter study on Cooperia larvae counts from hatched
eggs to persistency and knockdown effect (comparison between
Formulation 1 and Cydectin LA injectable);
Figure 4 Pilot non-slaughter study on Oesophagostomum/Chabertia larvae
counts from hatched eggs to persistency and knockdown effect
(comparison between Formulation 1 and Cydectin LA injectable);
Figure 5 Pilot non-slaughter study on Ostertagia larvae counts from hatched
eggs to persistency and knockdown effect (comparison between
Formulation 1 and Cydectin LA injectable).
BEST MODES FOR CARRYING OUT THE INVENTION
Example 1: Formulation 1
Moxidectin Injection LA
SI No Ingredients %w/v Function
1 Moxidectin** 2.1 Active ingredient
2 BHT (Butylated hydroxytoluene) 0.05 Antioxidant
3 NMP (Pharmasolve) 15 Solvent
4 Castor oil 7 Solvent
Soyabean oil qs Carrier
**5% overages added to account for any minor losses in stability or losses during
manufacturing.
Tests for Formulation 1 Specifications
Description A clear yellow, slightly viscous solution
Relative Density 0.920 – 0.980 @ 20°C
1.96 – 2.20% w/v (At Manufacture)
Active: Moxidectin
1.80 – 2.30% w/v (To Expiry)
By Membrane Filtration Method (BP method)
No growth in fluid thioglycollate medium after 14
Sterility days (minimum) incubation at 30-35°C.
No growth in soyabean casein digest medium after
14 days (minimum) incubation at 20-25°C.
Example 2: Stability studies
Batch Number: T1782, Batch Size: 3.5L
Storage Conditions: 25°C/60%RH
Packaging: 100mL flexipack Gamma+Fluorinated
Initial 3 Months 6 Months 9 Months 18 Months
Description Complies Complies Complies Complies Complies
Relative
0.944 0.942 0.943 0.941 0.943
Density
Active:
2.10 2.11 2.10 2.10 2.05
Moxidectin
Sterility Complies Complies Complies Complies Complies
Batch Number: T1782 Batch Size: 3.5L
Storage Conditions: 30°C/65%RH
Packaging: 100mL flexipack Gamma+Fluorinated
Initial 3 Months 6 Months 9 Months 18 Months
Description Complies Complies Complies Complies Complies
Relative
0.944 0.942 0.939 0.941 0.942
Density
Active:
2.10 2.11 2.11 2.09 2.02
Moxidectin
Sterility Complies Complies Complies Complies Complies
Batch Number: T1782, Batch Size: 3.5L
Storage Conditions: 40°C/75%RH
Packaging: 100mL flexipack Gamma+Fluorinated
Initial 3 Months 6 Months 9 Months
Description Complies Complies Complies Complies
Relative
0.944 0.942 0.940 0.940
Density
Active:
2.10 2.08 2.05 2.03
Moxidectin
Sterility Complies Complies Complies -
Example 3: Pilot non-slaughter study on larvae counts from hatched eggs from
faecal samples to assess persistency and knockdown effect (results shown in
Figures 1-5 wherein Formulation 1 is labeled as Moxidectin LA).
The treatments were administered using a syringe (able to measure in 0.2mL
increments) and the dose to be administered to each animal was based on its
liveweight, which was determined on the day of treatment (Day 0). The dose rate
for the test formulation and the reference product (Cydectin Long Acting Injection
for Sheep) was 1mL/20kg (1mg/kg). This dose was administered by subcutaneous
injection into the side of the neck just below the ear.
Faecal samples were collected after treatment at approximately weekly intervals for
19 weeks. These samples were collected directly from the rectum and weighed a
minimum of 2g. Faecal egg counts were carried out on each sample and
quantitative larval cultures were carried out on pooled samples from each
treatment group at each sampling time.
The pilot study illustrated the improved persistent efficacy of Formulation 1 in all
the examples tested when compared to Cydectin long acting (LA) injection for
sheep, also containing 2% w/v moxidectin.
The general trend showed that Cydectin began to lose persistency by 100 days or
less, as larvae counts began to rise. In some cases this rise was gradual (Figure
1), yet in other cases the rise was dramatic (see Figures 4 and 5 for example).
However, in all cases Formulation 1 showed reduced larvae counts beyond the 100
day mark. This illustrates the improved persistency of the present invention
compared to the commercially available Cydectin .
Additionally, it is clear Formulation 1 showed overall better efficacy throughout the
trial period compared to Cydectin . In each of Figures 1-5, Formulation 1
remained close to the base line, whereas the Cydectin often showed deviations
from the base line as shown in Figures 2, 3, 4 and 5).
Example 4:
Pilot slaughter efficacy study to evaluate the knock-down efficacy of formulation 1,
as per example 1, against a natural mixed infection of roundworms in sheep when
administered at the recommended minimum dose rate, with a comparison with
Cydectin LA injectable. The study involved the determination of total worm counts
when the animals were slaughtered 13 days after the administration of the
treatments, along with faecal sample larval culture data at 7 and 13 days after
treatment.
Efficacy based on faecal sample larval culture data 7 and 13 days after treatment
is shown in the Table 1 below. Efficacy based on total adult worm count from
abomasum, small intestine and large intestine assays 13 days after treatment is
shown in Table 2 below.
These initial results showed no significant difference between the efficacy of
Formulation 1 and the Cydectin LA reference. This illustrates that Formulation 1
maintains an appropriate knockdown effect compared to the commercially
available Cydectin product.
Table 1: The number and level of control (%) of each parasite species 7 and 13
days after treatment with Moxidectin LA Injection or Cydectin Long Acting
Injection based on faecal sample larval culture data and compared to the
untreated controls
Days after treatment
7 13
Parasite Species
Product administered Product administered
Moxidectin LA
Cydectin LA Untreated Moxi LA Injection Cydectin Untreated
Injection
100% 100% 100% 100%
Haemonchus 10800 5200
(0) (0) (0) (0)
95.8% 95.8% 99.6% 98.4%
Ostertagia 6480 3380
(275) (271) (14) (53)
82.1% 63.1% 95.1% 96.8%
Trichostrongylus 864 1300
(155) (319) (64) (41)
100% 100% 100% 100%
Cooperia 2160 2340
(0) (0) (0) (0)
100% 100% 100% 100%
Oesoph/Chabertia 1296 780
(0) (0) (0) (0)
(Number in brackets indicates the actual number of larvae found)
1 th
Table 2: Efficacy (%) of the test and reference products against 5 stage
(adult) worms 13 days after treatment, based on total worm counts in
comparison to the untreated controls
Product Abomasum Small intestine Large intestine
Haem Ost T. axei Nem Trich Coop Strong Oes Chab Trichu
Moxi LA >99.9 >99.9 >99.9 99.9 90.6 99.9 87.8 >99.9 >99.9 >99.9
Cydectin
>99.9 >99.9 >99.9 99.9 95.7 >99.9 96.6 >99.9 >99.9 >99.9
based on % reduction of geometric means in comparison to the untreated control
animals
Haem = Haemonchus contortus , Ost = Ostertagia circumcincta, Nem=
Nematodirus sp., Trich = Trichostrongylus sp. Coop = Cooperia spp. Strong =
Strongyloides, Oes = Oesophagostomum sp. Chab = Chabertia and Trichu =
Trichuris sp
Aspects of the present invention have been described by way of example only and
it should be appreciated that modifications and additions may be made thereto
without departing from the scope thereof as defined in the appended claims.
James & Wells 132886/76 RD
WHAT I/WE
Claims (7)
- CLAIM 1. A composition for the treatment of an animal in need thereof wherein the composition includes a therapeutically effective amount of at least one macrocyclic lactone compound characterised in that the composition includes a non-aqueous carrier and a solvent system including castor oil and at least one cyclic amide solvent.
- 2. The composition as claimed in claim 1 wherein the cyclic amide solvent is a pyrrolidone.
- 3. The composition as claimed in either claim 1 or claim 2 wherein the cyclic amide solvent in the composition is N-Methylpyrrolidone (NMP).
- 4. The composition as claimed in any of the above claims wherein the cyclic amide solvent is present in the composition in an amount of between 1- 50% w/v.
- 5. The composition as claimed in any one of the above claims wherein the castor oil is present in the composition in an amount between 1-20% w/v.
- 6. The composition as claimed in any one of the above claims wherein the composition is an injectable composition.
- 7. The composition as claimed in any one of the above claims wherein the macrocyclic lactone compound is selected from the group consisting of avermectin, moxidectin, milbemycin, ivermectin, abamectin, doramectin, epinomectin and selamectin. 9. The composition as claimed in any one of claims 7 to 8 wherein the macrocyclic lactone compound is moxidectin. 10. The composition as claimed in any one of the above claims wherein the macrocyclic lactone compound is present in the composition between 0.005 to 15% w/v. 11. The composition as claimed in any one of the above claims wherein the macrocyclic lactone compound is present in the composition between 0.005 to 5% w/v. 12. The composition as claimed in any of the above claims wherein the non- aqueous carrier includes an oil selected from the group consisting of canola oil, corn oil, cottonseed oil, olive oil, peanut oil, sesame oil, soyabean oil, safflower oil, coconut oil, sunflower oil, palm oil, monoglyceride, diglyceride and triglyceride medium chain succinic acid triglyceride. 13. The composition as claimed in any of the above claims wherein the cyclic amide solvent is present in the composition at approximately 15% w/v. 14. The composition as claimed in any of the above claims wherein the castor oil is present in the composition at approximately 7% w/v. 15. The composition as claimed in any of the above claims wherein the composition includes an antioxidant. 16. The composition as claimed in claim 15 wherein the antioxidant is butylated hydroxytoluene (BHT). 17. The composition as claimed in either claim 15 or claim 16 wherein the antioxidant is present in the composition between 0.001 to 10% w/v. 18. The composition as claimed in any one of claims 15 to 17 wherein the antioxidant is present in the composition at approximately 0.05 % w/v. 19. A method of treating a non-human animal in need thereof with a composition as claimed in any one of claims 1 to 18, including the step of delivering the composition to the animal to provide a long acting protection against or treatment for a given condition or disease. 20. The method as claimed in claim 19 wherein the condition is a parasitic infection in or on a non-human animal. 21. A use of the composition as claimed in any one of claims 1 to 18 for the manufacture of a medicament for the long acting treatment or prevention against a parasitic infection in or on a non-human animal. 22. A method of preparing a composition including a macrocyclic lactone compound characterised by the step of adding castor oil and at least one cyclic amide solvent to the macrocyclic lactone compound. 22. The method as claimed in claim 21 including the steps of: a) adding the cyclic amide solvent to a manufacturing container; b) adding the macrocyclic lactone compound to the cyclic amide solvent; c) adding castor oil to the agent/cyclic amide mixture; and d) adding a non-aqueous carrier up to volume. 23. A composition as herein described with reference to the accompanying figures and examples in the Best Mode Section, but excluding the composition referred to in the figures and examples as Cydectin. 24. A method of treating a non-human animal in need thereof with the composition as claimed in claim 23 with reference to the accompanying figures and examples in the specification. 25. A method of manufacturing a composition as herein described with reference to the accompanying figures and examples in the Best Mode Section, but excluding the composition referred to in the figures and examples as Cydectin.
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