NZ619027B2 - Transdermal parasiticidal formulations - Google Patents
Transdermal parasiticidal formulations Download PDFInfo
- Publication number
- NZ619027B2 NZ619027B2 NZ619027A NZ61902713A NZ619027B2 NZ 619027 B2 NZ619027 B2 NZ 619027B2 NZ 619027 A NZ619027 A NZ 619027A NZ 61902713 A NZ61902713 A NZ 61902713A NZ 619027 B2 NZ619027 B2 NZ 619027B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- formulation
- levamisole
- transdermal
- compound
- animal
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 219
- 230000000590 parasiticidal Effects 0.000 title claims abstract description 13
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levotetramisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 claims abstract description 60
- XMGQYMWWDOXHJM-JTQLQIEISA-N (+)-(4R)-Limonene Chemical compound CC(=C)[C@@H]1CCC(C)=CC1 XMGQYMWWDOXHJM-JTQLQIEISA-N 0.000 claims abstract description 52
- 229960001614 levamisole Drugs 0.000 claims abstract description 52
- AXISYYRBXTVTFY-UHFFFAOYSA-N Isopropyl myristate Chemical compound CCCCCCCCCCCCCC(=O)OC(C)C AXISYYRBXTVTFY-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229940074928 isopropyl myristate Drugs 0.000 claims abstract description 33
- 239000005660 Abamectin Substances 0.000 claims abstract description 18
- 229950008167 Abamectin Drugs 0.000 claims abstract description 18
- 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 18
- 150000002596 lactones Chemical class 0.000 claims abstract description 13
- 239000000921 anthelmintic agent Substances 0.000 claims abstract description 11
- -1 lactone compounds Chemical class 0.000 claims abstract description 11
- 229960004816 Moxidectin Drugs 0.000 claims abstract description 10
- 244000079386 endoparasites Species 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 6
- 229960002418 Ivermectin Drugs 0.000 claims abstract description 6
- 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 claims abstract description 5
- 229960002245 Selamectin Drugs 0.000 claims abstract description 5
- 229960002346 eprinomectin Drugs 0.000 claims abstract description 5
- 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 5
- 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 4
- 230000000699 topical Effects 0.000 claims abstract 3
- 238000009472 formulation Methods 0.000 claims description 152
- 239000003795 chemical substances by application Substances 0.000 claims description 64
- 150000001875 compounds Chemical class 0.000 claims description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 34
- MTHSVFCYNBDYFN-UHFFFAOYSA-N Diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 25
- 230000002335 preservative Effects 0.000 claims description 16
- 239000003755 preservative agent Substances 0.000 claims description 16
- 239000003085 diluting agent Substances 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 15
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- 235000019441 ethanol Nutrition 0.000 claims description 14
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 12
- 230000000149 penetrating Effects 0.000 claims description 11
- 239000004540 pour-on Substances 0.000 claims description 9
- WRMNZCZEMHIOCP-UHFFFAOYSA-N Phenethyl alcohol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims description 8
- 229920001577 copolymer Polymers 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002736 nonionic surfactant Substances 0.000 claims description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 7
- 230000000749 insecticidal Effects 0.000 claims description 6
- 239000002917 insecticide Substances 0.000 claims description 6
- 230000000507 anthelmentic Effects 0.000 claims description 5
- 229930007650 limonene Natural products 0.000 claims description 5
- 229940087305 limonene Drugs 0.000 claims description 5
- 235000001510 limonene Nutrition 0.000 claims description 5
- 230000035515 penetration Effects 0.000 claims description 5
- 229940067107 Phenylethyl Alcohol Drugs 0.000 claims description 4
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 4
- 150000002334 glycols Chemical class 0.000 claims description 4
- XXJWXESWEXIICW-UHFFFAOYSA-N 2-(2-Ethoxyethoxy)ethanol Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 3
- 229950000775 CYROMAZINE Drugs 0.000 claims description 3
- OSASVXMJTNOKOY-UHFFFAOYSA-N Chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 3
- 229960004926 Chlorobutanol Drugs 0.000 claims description 3
- 239000005891 Cyromazine Substances 0.000 claims description 3
- LVQDKIWDGQRHTE-UHFFFAOYSA-N Cyromazine Chemical compound NC1=NC(N)=NC(NC2CC2)=N1 LVQDKIWDGQRHTE-UHFFFAOYSA-N 0.000 claims description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N Diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 3
- 239000005893 Diflubenzuron Substances 0.000 claims description 3
- QQQYTWIFVNKMRW-UHFFFAOYSA-N Diflubenzuron Chemical compound FC1=CC=CC(F)=C1C(=O)NC(=O)NC1=CC=C(Cl)C=C1 QQQYTWIFVNKMRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000005942 Triflumuron Substances 0.000 claims description 3
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 claims description 3
- 229940019503 diflubenzuron Drugs 0.000 claims description 3
- 230000001984 ectoparasiticidal Effects 0.000 claims description 3
- 239000002728 pyrethroid Substances 0.000 claims description 3
- XAIPTRIXGHTTNT-UHFFFAOYSA-N triflumuron Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC(=O)NC(=O)C1=CC=CC=C1Cl XAIPTRIXGHTTNT-UHFFFAOYSA-N 0.000 claims description 3
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-Methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 claims description 2
- OAYXUHPQHDHDDZ-UHFFFAOYSA-N 2-(2-butoxyethoxy)ethanol Chemical compound CCCCOCCOCCO OAYXUHPQHDHDDZ-UHFFFAOYSA-N 0.000 claims description 2
- 229960004217 benzyl alcohol Drugs 0.000 claims description 2
- 229940028356 diethylene glycol monobutyl ether Drugs 0.000 claims description 2
- 229960004756 ethanol Drugs 0.000 claims description 2
- 206010061217 Infestation Diseases 0.000 claims 4
- 244000078703 ectoparasites Species 0.000 claims 4
- 206010014143 Ectoparasitic infestation Diseases 0.000 abstract 2
- 230000035492 administration Effects 0.000 description 39
- 210000003491 Skin Anatomy 0.000 description 21
- 235000013601 eggs Nutrition 0.000 description 18
- 241000283898 Ovis Species 0.000 description 16
- 210000002268 Wool Anatomy 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000003921 oil Substances 0.000 description 14
- 229940039717 Lanolin Drugs 0.000 description 13
- 239000004166 Lanolin Substances 0.000 description 13
- 210000002374 Sebum Anatomy 0.000 description 13
- 235000019388 lanolin Nutrition 0.000 description 13
- 239000001993 wax Substances 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 11
- 239000003925 fat Substances 0.000 description 11
- 238000009792 diffusion process Methods 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 210000002615 Epidermis Anatomy 0.000 description 6
- YZBLFMPOMVTDJY-RWJZGKSFSA-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-RWJZGKSFSA-N 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 4
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000004544 spot-on Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 3
- 241000283707 Capra Species 0.000 description 3
- 229920005682 EO-PO block copolymer Polymers 0.000 description 3
- 238000004140 cleaning Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000004519 grease Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000005871 repellent Substances 0.000 description 3
- 230000002940 repellent Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000037317 transdermal delivery Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- XMGQYMWWDOXHJM-UHFFFAOYSA-N (+-)-(RS)-limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 2
- 210000004207 Dermis Anatomy 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000003466 anti-cipated Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 230000004059 degradation Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- PZBXEEXMBBGCML-UHFFFAOYSA-N ethane-1,2-diol;prop-1-ene Chemical group CC=C.OCCO PZBXEEXMBBGCML-UHFFFAOYSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 125000005313 fatty acid group Chemical group 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000003906 humectant Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 244000045947 parasites Species 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000003019 stabilising Effects 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 229960002669 Albendazole Drugs 0.000 description 1
- 235000002198 Annona diversifolia Nutrition 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 241000282842 Lama glama Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000283903 Ovis aries Species 0.000 description 1
- 208000006551 Parasitic Disease Diseases 0.000 description 1
- 210000001732 Sebaceous Glands Anatomy 0.000 description 1
- 241001416177 Vicugna pacos Species 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- HXHWSAZORRCQMX-UHFFFAOYSA-N albendazole Chemical compound CCCSC1=CC=C2NC(NC(=O)OC)=NC2=C1 HXHWSAZORRCQMX-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000845 anti-microbial Effects 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000295 complement Effects 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 230000001586 eradicative Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable Effects 0.000 description 1
- 201000009608 hair disease Diseases 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 229940006093 opthalmologic coloring agents Diagnostic Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000036281 parasite infection Effects 0.000 description 1
- 230000037368 penetrate the skin Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 230000036620 skin dryness Effects 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Abstract
Provided are transdermal parasiticidal formulations comprising levamisole, an anthelmintic agent, dissolved in a solution that includes isopropyl myristate and D-limonene. The formulations provided may further comprise at least one macrocyclic lactone. Preferable macrocyclic lactone compounds include abamectin, moxidectin, eprinomectin, selamectin, ivermectin and milbemycins. Further provided are methods of treating endo-parasite or ecto-parasitic infestations in non-human animals through the topical administration of the formulations. lude abamectin, moxidectin, eprinomectin, selamectin, ivermectin and milbemycins. Further provided are methods of treating endo-parasite or ecto-parasitic infestations in non-human animals through the topical administration of the formulations.
Description
TRANSDERMAL PARASITICIDAL FORMULATIONS
TECHNICAL FIELD
Described herein are transdermal parasitical formulations. Methods of treatment and use of the
formulations are also described.
BACKGROUND ART
Transdermal vehicle formulations are known and used for delivery of a variety of active agents.
In veterinary applications, such formulations are often referred to as ‘pour on’ treatments. The
transdermal route of administration is favourable as it minimises the amount of work required to
deliver an agent or agents to an animal and avoids potential harm or danger in handling
distressed animals. A further advantage of transdermal administration is that the dose can easily
be metered, measured and delivered to the animal.
Despite the above advantages, transdermal methods of administration are rarely commercialised
for use with woolly animals such as sheep and goats. This is because such animals present a
major challenge for transdermal delivery as it is necessary to penetrate through not only the skin
or epidermis but also diffuse the active agent through wool, dirt that is usually present on the
wool, and then to also penetrate the sebum – mainly comprising lanolin in woolly animals.
Lanolin is a highly difficult waxy substance to penetrate as it is highly immiscible with water and
repels most agents and vehicle systems.
Art exists describing transdermal formulations for treatment of internal and external parasites in
animals where different active ingredients from anthelmintic range are used. However, with the
exception of cattle pour on’s, few other pour on formulations have been commercialised and
there remains a demand for a parasiticidal topically applied product, particularly for animals other
than cattle.
Attempts have been made to develop reliable transdermal formulations suitable for woolly animal
application, particularly for sheep and goats. These formulations typically have significant
limitations in application timing and method. One example of an art composition commercialised
in Australia is produced by Coopers, marketed under the brand Maverick™. This product is an
endo-parasite transdermal formulation. The product has a number of limitations hence the
uptake by the market has not been big with most farmers still preferring the difficulties of
drenching sheep as opposed to using the Maverick™ product. By way of example, the
Maverick™ product is recommended to be used only within 24 hours of shearing thereby
severely limiting the window of application time. Further, a special applicator gun is needed in
order to administer Maverick™. This greatly increases the cost and complexity to the farmer in
using the product. The Maverick™ product is also a specialised micellar formulation that may
require special manufacture and potentially expensive compounds to manufacture.
Further, as may be appreciated, it can be useful to combine two or more active agents in the one
formulation. This can further complicate the formulation process for pour on design (for woolly
and non-woolly animals) as different agents may have different characteristics such as varying
miscibility. Patents that describe potential solutions to formulating multiple agents together
include: NZ336139 that describes levamisole in an emulsion with ivermectin and albendazole
and NZ507445 that describes a composition containing an antibiotic and an anthelmintic
compound in the form of a suspension.
Production of emulsions or suspensions is not ideal since preparation of products containing
different phases, such as solid/liquid or oil/water phases can be associated with significant
manufacturing costs. For example, high shear dispensers and/or mills or homogenisers may be
needed to produce the end product. Further, emulsions and suspensions can settle during
storage and require the user to for example shake the product to re-suspend or, in worst cases,
the agents will not re-mix resulting in ineffective products. In some cases, separation issues can
result in short product storage time periods thereby limiting the usefulness of the product.
As should be appreciated from the above, there may be value in providing transdermal
formulations that are simple to manufacture; minimise the amount of excipients used; are able to
penetrate the skin barrier in an efficacious manner; deliver the agent or agents in a measurable
and easily applied manner; and be able to deal with challenging conditions when the skin also
has wool, dirt or sebum fats, oils or waxes present; or at least to provide the public with a choice.
Further aspects and advantages of the formulations, methods of treatment and use will become
apparent from the ensuing description that is given by way of example only.
SUMMARY
Described herein are transdermal parasiticidal formulations and methods of treatment and use,
wherein the formulation is not only able to deliver an agent or agents through the skin layer, but
is able to do so through wool, dirt and/or a sebum layer on the skin if such layers are present.
In a first aspect there is provided a transdermal parasiticidal formulation in the form of a solution
including a therapeutically effective amount of levamisole anthelmintic agent dissolved in a
solution including isopropyl myristate and D-limonene.
In a second aspect, there is provided a transdermal parasiticidal formulation in the form of a
solution including:
(a) a therapeutically effective amount of levamisole anthelmintic agent dissolved in a
solution including isopropyl myristate and D-limonene;
(b) at least one diethylene glycol ether (DGE) compound;
(c) a penetrating agent or agents selected from at least one non-ionic surfactant;
(d) at least one preservative; and
(e) at least one diluent.
In a third aspect there is provided a dual active anthelmintic formulation formulated for
transdermal administration including:
(a) a therapeutically effective amount of levamisole anthelmintic agent dissolved in a
solution including isopropyl myristate and D-limonene;
(b) a therapeutically effective amount of at least one macrocyclic lactone dissolved in at
least one diethylene glycol ether (DGE) compound;
(c) a penetrating agent or agents selected from at least one non-ionic surfactant;
(d) at least one preservative; and
(e) at least one diluent.
In a fourth aspect there is provided a method of treatment of a condition and/or disease in an
animal by administration of a composition substantially as described above.
In a fifth aspect there is provided the use of a formulation substantially as described above along
with at least one active agent in the manufacture of a composition formulated for transdermal
administration in the treatment of a condition and/or disease.
Advantages of the formulations, simplicity of manufacturing, methods of treatment, and uses
thereof should be apparent including the ability to penetrate the epidermis in an effective manner
even when the skin is covered by wool, dirt and sebum barriers such as oils, waxes and fats. A
yet further advantage is that the formulation described maintains a viscosity sufficiently low to
allow for accurate administration by pouring or spot application of the formulation to an animal.
DETAILED DESCRIPTION
As noted above, described herein are transdermal parasiticidal formulations and methods of
treatment and use, wherein the formulation is not only able to deliver an agent or agents through
the skin layer, but is able to do so through wool, dirt and/or a sebum layer on the skin if such
layers are present.
For the purposes of this specification, the term ‘about’ or ‘approximately’ and grammatical
variations thereof mean a quantity, level, degree, value, number, frequency, percentage,
dimension, size, amount, weight or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6,
5, 4, 3, 2, or 1% to a reference quantity, level, degree, value, number, frequency, percentage,
dimension, size, amount, weight or length.
For the purpose of this specification the term 'comprise' and grammatical variations thereof shall
have an inclusive meaning - i.e. that it will be taken to mean an inclusion of not only the listed
components it directly references, but also other non-specified components or elements.
The term ‘substantially’ or grammatical variations thereof refers to at least about 50%, for
example 75%, 85%, 95% or 98%.
The terms ‘oil’, ‘fat’, ‘grease’ or ‘wax’ or grammatical variations thereof collectively referred to as
‘sebum’ are produced by sebaceous glands and refer to compounds that are at least moderately
immiscible to completely immiscible in water and are characterised by having fatty acid groups.
The term ‘transdermal’ or grammatical variations thereof refers to the route of administration
where an agent or agents are transported via diffusion through the epidermis layer of the skin
and into the dermis layer to reach the microcirculation of the dermis.
The term ‘vehicle’ and grammatical variations refer to a therapeutically inactive formulation that
may be mixed with one or more active agents and used to convey the active agent or agents.
The term ‘therapeutically effective’ with reference to an amount or dosage of a composition as
described herein, refers to an amount of a composition and/or active compound which is
sufficient to effectively treat a disorder or condition requiring treatment.
The term ‘treat’ or grammatical variations thereof refers to control of a disorder or disease
including control or eradication of parasites on or within an animal.
In a first aspect there is provided a transdermal parasiticidal formulation in the form of a solution
including a therapeutically effective amount of levamisole anthelmintic agent dissolved in a
solution including isopropyl myristate and D-limonene.
The inventor has unexpectedly found that the above described combination of isopropyl myristate
and D-limonene as a solvent system stabilises levamisole in solution for long periods of time
without an appreciable change in levamisole activity and avoids any separation and/or
sedimentation. This may be useful as it enables manufacturing to be completed in multiple
steps, the first being a stabilisation step and subsequent storage of the ‘stock’ or ‘base’
levamisole solution in preparation for later smaller batch production of transdermal formulations
such as those noted further below. Alternatively, the formulation described may be used as is, or
with a diluent or other compounds.
Levamisole may be present, the highest concentration of levamisole being defined by the point at
which the levamisole shifts from being soluble to being insoluble in the formulation. For the
purposes of this specification, the term ‘insoluble’ in context of levamisole concentration refers to
the levamisole no longer fully dissolving into the solution and separating into a separate phase
and/or forming undissolved droplets. Levamisole may be present in sufficient quantities in an
amount of at least 0.1% w/v of the total solution. Levamisole may be present in sufficient
quantities to be diluted in further manufacturing and still provide about 0.1, or 0.2, or 0.3, or 0.4,
or 0.5, or 0.6, or 0.7, or 0.8, or 0.9, or 1.0, or 1.5, or 2.0, or 2.5, or 3.0, or 3.5, or 4.0, or 4.5, or
.0, or 5.5, or 6.0, or 6.5, or 7.0, or 7.5, or 8.0, or 8.5, or 9.0, or 9.5, 10% w/v of the total end
formulation. In one embodiment, the levamisole may be present in sufficient quantities to be
diluted in further manufacturing and still provide about 0.1 to 10% w/v of the total end formulation.
Isopropyl myristate was identified by the inventor as an excellent solvent with good solubilising
characteristics particularly for levamisole powder. D-Limonene was found to add a high degree
of stability to the formulation preventing any crystallisation occurring during storage plus no
degradation of the levamisole activity was noted once stabilised as described. Both compounds
also confer other properties once example being the penetrating activity of the isopropyl
myristate.
Isopropyl myristate and D-limonene may be present in total at a rate of 1, or 2, or 3, or 4, or 5, or
6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or
22, or 23, or 24, or 25, or 30, or 35, or 40, or 45, or 50, or 55% w/v of the total formulation. In
one embodiment, isopropyl myristate and D-limonene may be present in total at a rate of 1-55%
w/v of the total formulation. The molar ratio of isopropyl myristate to D-limonene may be from
about 10:1, or 11:1, 12:1, or 13:1, or 14:1, or 15:1. The molar ratio of isopropyl myristate to D-
limonene may be from about 10:1 to about 15:1. These ratios and concentrations in the
inventor’s experience maximises the solubility of the levamisole in the solvent solution and
confers the ideal stability.
The above formulation may further include a therapeutically effective amount of at least one
additional macrocyclic lactone compound as an active anthelmintic agent. In one embodiment
the macrocyclic lactone compound may be selected from: abamectin, moxidectin, eprinomectin,
selamectin, ivermectin, milbemycins, and combinations thereof. The formulation may include
0.1, or 0.2, or 0.3, or 0.4, or 0.5, or 0.6, or 0.7, or 0.8, or 0.9, or 1, or 1.5, or 2, or 2.5, or 3, or 3.5,
or 4, or 4.5, or 5, or 5.5, or 6, or 6.5, or 7, or 7.5, or 8, or 8.5, or 9, or 9.5, or 10% w/v macrocyclic
lactone(s) in the total formulation. The formulation may include 0.1 to 10% w/v macrocyclic
lactone(s) in the total formulation.
The above noted macrocyclic lactone may be dissolved in a further solvent. The solvent may be
selected from one or more diethylene glycol ether (DGE) compounds. The solvent may be a
DGE compound selected from: diethylene glycol monobutyl ether, diethylene glycol monoethyl
ether, diethylene glycol monomethyl ether and combinations thereof. The solvent(s) may be
present at a total concentration of about 30, or 35, or 40, or 45, or 50, or 55, or 60, or 65, or 70,
or 75, or 80% w/v total composition. The solvent may be present at a total concentration of 30-
70% w/v total composition. In one embodiment, diethylene glycol monoethyl ether may be used.
DGE’s are understood by the inventor to be useful as a solvent particularly when a macrocyclic
lactone present. DGE’s also only evaporate slowly meaning their solvent properties are
maintained for longer. DGE’s maintain the active agent, macrocyclic lactone, within the
formulation and prevent dissolution of the agent into any fats, oils or waxes that may be present
approximate the skin of an animal.
The formulation may include at least one penetrating agent or agents selected from at least one
non-ionic surfactant. It may be appreciated that isopropyl myristate itself may act as a
transdermal agent however it may be useful to add additional transdermal agents. In the
inventor’s experience, non-ionic surfactants are a useful choice as penetrating agent(s). The
transdermal penetration agent or agents may be selected from EO/PO block co-polymers,
alcohol ethoxylates, cocamide diethanolamine (DEA) and combinations thereof. The above
described transdermal agents increase the pore size of the skin and sebum allowing the
formulation and/or agent or agents to pass through the skin barrier. These agents may also be
particularly useful as they may aid dissolution of any sebum oils, waxes or fats present at the site
of administration thereby removing these barriers to diffusion. The transdermal agent or agents
may be present at a concentration of 0.1, or 0.2, or 0.3, or 0.4, or 0.5, or 0.6, or 0.7, or 0.8, or
0.9, or 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16,
or 17, or 18, or 19, or 20% w/v of total formulation. The transdermal agent or agents may be
present at a concentration of 0.1 to 20% w/v. The transdermal agent or agents may be present
at a concentration of 5 to 15% w/v. The transdermal agent or agents may be present at a
concentration of 5 to 12% w/v. The transdermal agents may also act as surfactants and/or
wetting agents in the above described formulation thereby minimising the number of excipients
required.
The formulation may further include at least one preservative. The preservative may be at least
one alcohol. Examples of alcohols that may be used as preservatives include benzyl alcohol,
chlorobutanol, phenylethyl alcohol, ethyl alcohol and combinations thereof. Where used, the
preservative may be present in an amount from 0.1, or 0.2, or 0.3, or 0.4, or 0.5, or 0.6, or 0.7, or
0.8, or 0.9, or 1.0, or 1.1, or 1.2, or 1.3, or 1.4, or 1.5, or 1.6, or 1.7, or 1.8, or 1.9, or 2.0, or 2.1,
or 2.2, or 2.3, or 2.4, or 2.5, or 2.6, or 2.7, or 2.8, or 2.9, or 3.0, or 3.1, or 3.2, or 3.3, or 3.4, or
3.5, or 3.6, or 3.7, or 3.8, or 3.9, or 4.0, or 4.1, or 4.2, or 4.3, or 4.4, or 4.5, or 4.6, or 4.7, or 4.8,
or 4.9, or 5.0 w/v of the total formulation. The preservative may be present at a concentration of
about 0.1 to 5.0% w/v of total formulation. The preservative may be present at a concentration of
about 0.5 to 5.0% w/v of total formulation. Besides the stabilising effects of alcohols, the inventor
has also found that alcohols may also enhance the transdermal properties of the formulation
when lanolin is present about the area of administration. Lanolin present in woolly animals is
highly repellent to transdermal formulations primarily due to the hydrophobicity or fatty acids
present in the lanolin. Alcohols may act to shift the equilibrium dramatically in the conversion of
fatty acid or hydroxyl groups on the lanolin molecule into esters with aryl groups. While this
reaction may occur anyway without alcohols present, the reaction speed is slow and hence does
not assist or only minimally assists with transdermal penetration. Addition of alcohols may
dramatically change the equilibrium in favour of esterification resulting in greatly enhanced
transdermal penetration as the esterified lanolin acts like a soap encouraging transfer through the
epidermis rather than the repellent effects of fatty acids. By way of further explanation, esters act
as surfactants and wetting agents hence the converted lanolin aids transdermal transfer.
The formulation may further include at least one diluent. The diluent may be selected from one
or more glycol compounds. Examples of glycols that may be used include: propylene glycol
compounds and/or ethylene glycol compounds. Such diluents may be useful due to their
humectant properties and may also have emollient properties as well. In addition, such carriers
may assist by preventing skin dryness at the site of administration. The humectant carrier may
be added to volume (q.v.) and does not require any specific concentration but for example, may
be present at a concentration of 5, or 10, or 15, or 20, or 25, or 30, or 35, or 40, or 45, or 50%
w/v of total composition. The diluent may be present at a concentration of 5 to 50% w/v. The
diluent may be present at a concentration of 10 to 20% w/v.
The above formulation may be administered to a woolly animal. The above formulation has
significant advantages over many art formulations when administered to woolly animals or
animals with a skin layer that includes sebum fats, oils or waxes, one example being sheep. The
inventor has found that on administration, the above formulation diffuses the active agent or
agents present in the formulation through the epidermis layer and at least partly, dissolves or
penetrates sebum barrier fats, oils, waxes or greases present at the administration site.
Excellent penetration occurs as measured in trials completed by the inventor. It is even possible
to visually observe the diffusion process taking place with the formulation appearing to dissolve
any fats, oils or waxes present. The inventor has also found and shown in experiments that the
formulation may be administered to the back of a woolly animal such as a sheep without needing
to prepare the site of administration in any way – the site need not be freshly shorn or cleaned.
The formulation is able to penetrate through any dirt or fat, oils or waxes present. The
formulation is also sufficient labile to diffuse down any woolly hairs presents and then into the
skin layer. As may be appreciated, diffusion in such environments is a major challenge as the
skin layer is difficult to reach from wool, dirt, and for sheep, a tough and repellent lanolin layer.
The above formulations in fact use lanolin to help with diffusion by converting lanolin at the
administration site chemically to an ester form that assists diffusion.
The final formulation viscosity may be less than or equal to 5000cps, or 4500cps, or 4000cps, or
3500cps, or 3000cps, or 2500cps, or 2000cps. The viscosity may be less than or equal to
2000cps. The inventor has found that the formulation described herein is easy to handle such as
when pouring the formulation or when delivering in spot form. A lower viscosity and low shear
rates means easier mixing for less energy input during manufacture and less force being required
to administer the formulation and more accurate measuring of required dose. Having to exert
large amounts of energy in order to mix the formulation or pour/spot on administration is not ideal
as, besides added labour or energy costs, mixing may not be as complete as desired. A lower
viscosity particularly at low energy inputs is preferable.
The formulation may include at least one further active compound. In one embodiment, the at
least one further active compound may be a compound with endo- parasiticidal and/or ecto-
parasiticidal activity. The active may be one or more insecticides. The insecticides may be
selected from one or more of the following compounds: triflumuron, diflubenzuron, cyromazine, or
at least one compound selected from the group of pyrethroid compounds. Where further actives
are added, they may be added directly to the base formulation or dissolved in a solvent prior to
dissolution in the base formulation above. In one embodiment, additional actives, if used, may
comprise less or equal to 20%, or 19%, or 18%, or 17%, or 16%, or 15%, or 14%, or 13%, or
12%, or 11%, or 10%, or 9%, or 8%, or 7%, or 6%, or 5%, or 4%, or 3%, or 2%, or 1% w/v/ of the
total formulation. The amount may be less than 20% w/v.
Other formulation aids, such as colouring agents, additional antimicrobials, buffering agents, pH
adjusters and antifoaming agents may also be added depending on the end application or
desired characteristics. These aids are preferably non-toxic and complementary to transdermal
administration.
In a second aspect, there is provided a transdermal parasiticidal formulation in the form of a
solution including:
(a) a therapeutically effective amount of levamisole anthelmintic agent dissolved in a
solution including isopropyl myristate and D-limonene;
(b) at least one solvent selected from one or more diethylene glycol ether (DGE)
compounds;
(c) a penetrating agent or agents selected from at least one non-ionic surfactant;
(d) at least one preservative; and
(e) at least one diluent.
In a third aspect there is provided a dual active anthelmintic formulation formulated for
transdermal administration including:
(a) a therapeutically effective amount of levamisole anthelmintic agent dissolved in a
solution including isopropyl myristate and D-limonene;
(b) a therapeutically effective amount of a macrocyclic lactone dissolved in at least one
diethylene glycol ether (DGE) compound;
(c) a penetrating agent or agents selected from at least one non-ionic surfactant;
(d) at least one preservative; and
(e) at least one diluent.
In a fourth aspect there is provided a method of treatment of a condition and/or disease in an
animal by administration of a composition substantially as described above.
In a fifth aspect there is provided the use of a formulation substantially as described above along
with at least one active agent in the manufacture of a composition formulated for transdermal
administration in the treatment of a condition and/or disease.
In the above aspects, the animal may be a non-human animal. The non-human animal may be a
woolly species of animal. Examples of animals particularly well suited to use of the described
formulation include sheep or lambs, goats, rabbits, alpaca and llama. The animal may also be a
non-woolly species, examples including cattle and deer.
In the above methods and uses, the transdermal formulation may be stored in a tube or plunger
for an extended period of time without risk of separation or other changes in the product that
might impact on stability.
Further, the formulations may be applied via readily available applicators such as drench guns or
other spray systems or simply directly from a syringe or tube. The ability to use existing forms of
applicator was unexpected – art formulations often require proprietary administrations devices to
be used. In the present case, the inventor found that the formulation efficacy does not depend
on application technique, unlike prior art compositions.
In the above aspects, the method of administration may be by applying the composition to the
back of an animal. Administration may be as a stripe or stripes (‘pour on’). Administration may
be as a spot or spots (‘spot on’). A ‘stripe’ refers to a strip along part or all of the length of the
back of an animal. A ‘spot’ refers to a localised area of application, generally approximately
circular in shape. As may be appreciated, one draw back of pour on formulations is that they are
generally applied as a stripe or two stripes typically running from the back of neck of animal
through to the rump. This requires a moderate volume of formulation and requires uninterrupted
application, which is complicated due to the animal moving during application or due to the
operator not being used for the full length. Spot on application by the present formulation
resolves the above issues related to pour on formulations since only one or more spots need be
applied and these need not be in any uniform location.
One advantage of the transdermal formulation described herein is that no special preparation of
the administration site is required since the formulation is able to diffuse through any dirt or fats,
oils or waxes that may be present on the skin. Further, it is not necessary to directly apply the
composition to the skin layer itself and instead the formulation may be applied to animal wool or
fur. The formulation is sufficiently labile and slow to evaporate to allow diffusion and movement
along any fibres such as wool or fur that may be present.
In summary, advantages of the formulations, methods of treatment, and uses thereof should be
apparent including the ability to penetrate the epidermis in an effective manner even when the
skin is covered by barriers such as wool, dirt and sebum oils, waxes, fats. A yet further
advantage is that the formulation described maintains a viscosity sufficiently low to allow for
accurate administration by pouring or spot application of the formulation to an animal.
As noted in the background section, existing products contain inherent problems or difficulties
limiting their use. The above described formulation may be used at any stage of wool growth and
hence does not have any limits on application time such as around shearing. No special
applicator is required for delivery. The above formulation is an organic solvent formulation so is
physiologically acceptable. Finally, the above formulation has the considerable advantage of
being able to be spot applied thereby reducing the risk of varying dosages and minimising the
volume of formulation needed.
The embodiments described above may also be said broadly to consist in the parts, elements
and features referred to or indicated in the specification of the application, individually or
collectively, and any or all combinations of any two or more said parts, elements or features, and
where specific integers are mentioned herein which have known equivalents in the art to which
the embodiments relates, such known equivalents are deemed to be incorporated herein as of
individually set forth,
Where specific integers are mentioned herein which have known equivalents in the art to which
this invention relates, such known equivalents are deemed to be incorporated herein as if
individually set forth.
WORKING EXAMPLES
The above described formulations, methods of treatment and uses thereof are now described by
reference to specific examples.
EXAMPLE 1
A levamisole formulation in the form of a solution is described below in Table 1:
Table 1 – Example Formulation
Compound Amount (w/v)
Levamisole 3%
Isopropyl myristate 90%
D-limonene 7%
EXAMPLE 2
The formulation of Example 1 may be made by measuring out and mixing together the
levamisole (typically in the form of a powder) into the liquid isopropyl myristate and D-limonene
and agitating the mixture for 30 seconds to an hour to ensure full dissolution occurs. The
resulting formulation may be used for further formulating or stored in this form with no risk of loss
in stability such as by levamisole degradation or crystallisation.
EXAMPLE 3
An example of a levamisole transdermal formulation is described below in Table 2:
Table 2 – Example Formulation
Compound Amount (w/v)
Diethylene glycol monobutyl 40-55%
ether (DGBE)
Diethylene glycol monoethyl 10-15%
ether (DEGEE)
Levamisole base solution in 10-25% equivalent to
isopropyl myristate/ D- 0.05 to 1% levamisole in
limonene the total solution
Benzyl alcohol 0.1-5%
Ethylene glycol-propylene 5-10%
glycol block co-polymer
Monopropylene glycol To volume q.v.
EXAMPLE 4
An alternative formulation is described below in Table 3 containing both levamisole and a
macrocyclic lactone:
Table 3 – Example Formulation
Compound Amount (w/v)
Diethylene glycol monobutyl 40-55%
ether (DGBE)
Macrocyclic lactone 0.1-5%
Levamisole base solution in 10-25% equivalent to
isopropyl myristate/ D- 0.05 to 1% levamisole in
limonene the total solution
Phenylethyl alcohol 0.1-5%
Ethylene glycol-propylene 5-10%
glycol block co-polymer
Monopropylene glycol To volume q.v.
EXAMPLE 5
An example transdermal formulation to deliver abamectin and levamisole is described below in
Table 4:
Table 4 – Example Formulation
Compound Amount (w/v)
Abamectin 0.4-1%
Diethylene glycol monobutyl 40-55%
ether (DGBE)
Levamisole base solution in 10-25% equivalent to 0.05 to
isopropyl myristate/ D-limonene 1% levamisole in the total
solution
Benzyl alcohol 0.5-2%
Ethylene glycol-propylene glycol 0.1-0.5%
block co-polymer
Monopropylene glycol To volume (anticipated
concentration approximately
– 40%)
EXAMPLE 6
An example transdermal formulation to deliver moxidectin and levamisole is described below in
Table 5:
Table 5 – Example Formulation
Compound Amount (w/v)
Moxidectin 0.2-1%
Diethylene glycol monobutyl 40-55%
ether (DGBE)
Levamisole base solution in 10-25% equivalent to 0.05 to
isopropyl myristate/ D-limonene 1% levamisole in the total
solution
Ethyl alcohol 0.5-2%
Ethylene glycol-propylene glycol 0.1-0.5%
block co-polymer
Monopropylene glycol To volume (anticipated
concentration approximately
– 40%)
EXAMPLE 7
An example transdermal formulation to deliver abamectin and levamisole is described below in
Table 6:
Table 6 – Example Formulation
Compound Amount (w/v)
Abamectin 0.4-1%
Diethylene glycol monobutyl 40-55%
ether (DGBE)
Levamisole base solution in 10-25% equivalent to 0.05 to
isopropyl myristate/ D-limonene 1% levamisole in the total
solution
Chlorobutanol 0.5-2%
Ethylene glycol-propylene glycol 0.1-0.5%
block co-polymer
Ethylene glycol 10%
Propylene glycol To volume of about 10 -30%
EXAMPLE 8
An example transdermal formulation to deliver abamectin and levamisole is described below in
Table 7:
Table 7 – Example Formulation
Compound Amount (w/v)
Abamectin 0.4-1%
Levamisole base solution in 50% equivalent to 0.05 to 1%
isopropyl myristate/ D-limonene levamisole in the total
solution
Ethyl alcohol 0.2%
EO / PO block copolymers 0.1-0.5%
Diethylene glycol monoethyl 40%
ether
Ethylene glycol-propylene glycol 0.1-0.5%
block co-polymer
Propylene glycol To volume of about 8.3-9.6%
EXAMPLE 9
An example transdermal formulation to deliver moxidectin and levamisole is described below in
Table 8:
Table 8 – Example Formulation
Compound Amount (w/v)
Moxidectin 0.2-0.6%
Levamisole base solution in 55% equivalent to 5 to 6%
isopropyl myristate/ D-limonene levamisole in the total
solution
Phenyl ethyl alcohol 0.1%
EO / PO block copolymers 0.3%
Diethylene glycol monobutyl 40%
ether
Propylene glycol 4%
EXAMPLE 10
An example transdermal formulation to deliver abamectin and levamisole is described below in
Table 9:
Table 9 – Example Formulation
Compound Amount (w/v)
Abamectin 0.6%
Levamisole base solution in 35% equivalent to 0.2-0.5%
isopropyl myristate/ D-limonene levamisole in the total
solution
Ethyl alcohol 0.2%
EO / PO block copolymers 0.5%
Diethylene glycol monoethyl 40%
ether
Propylene glycol To volume approximately
23.7%
EXAMPLE 11
A method of manufacturing the products described in Examples 4 to 10 may be via the following
steps:
(a) Prepare a solution of levamisole in isopropyl myristate and D-limonene;
(b) Add required amount of diethylene glycol ether and macrocyclic lactone e.g. abamectin
or moxidectin;
(c) Mixing until the macrocyclic lactone is dissolved;
(d) Add preservative and penetrating agent and bringing to volume by using glycols.
EXAMPLE 12
The efficacy of the formulation was tested using composition with double active ingredients
levamisole and abamectin as agents.
The formulation was administered via a plunger at the calculate dose to the backs of sheep as
two separate spots (‘spot on’ treatment) of approximately 20ml each at the back of the neck and
about the rump of the animal (n=25 sheep). No cleaning or special pre-treatment of the wool or
skin occurred prior to administration. The sheep had not been sheared prior to treatment and
represented a difficult challenge for transdermal delivery due to the long wool coating
(approximately 3 inches long), dirt and sebum oil/wax/grease layer on the animal skin, mainly
being lanolin.
Results are shown in Table 10 below of the faecal egg count (measured in eggs per gram)
before administration and 11 days post administration:
Table 10 – Efficacy Trial Results
Sheep Mob Faecal Egg Count Before Faecal Egg Count at Faecal Egg Count at
Number (n=25 Administration [eggs per Day 11 Post Day 15 Post
total) gram] Administration [eggs per Administration [eggs
gram] per gram]
Sample A 45 0 0
Sample B 90 0 0
Sample C 0 0 0
Sample D 660 0 0
EXAMPLE 13
The efficacy of the formulation was tested using a formulation with levamisole and abamectin as
agents.
The formulation was administered via a drench gun used for power drenching of sheep, at the
calculate dose to the backs of sheep as two separate spots of approximately 20ml each at the
back of the neck and about the rump of the animal (n=55 sheep). No cleaning or special pre-
treatment of the wool or skin occurred prior to administration. The sheep had not been sheared
prior to treatment and represented a difficult challenge for transdermal delivery due to the long
wool coating (more than 3 inches long), dirt and sebum oil/wax/grease layer on the animal skin,
mainly being lanolin.
Readings were taken on 11, 17 and 24 days of post treatment.
Results are shown in Table 8 below of the faecal egg count (measured in eggs per gram) before
administration and 11, 17, 24 days post administration:
Table 11 – Efficacy Trial Results monitored for 24 days post-application
Sheep Mob Faecal Egg Count Faecal Egg Count Faecal Egg Faecal Egg
Number Before at Day 11 Post Count at Day 17 Count at Day
(n=25 total) Administration [eggs Administration Post 24 Post
per gram] [eggs per gram] Administration Administration
[eggs per gram] [eggs per
gram]
Sample 300 0 0 0
As can be seen from the above, the results were positive with a complete removal of the
parasite infection thereby showing that excellent transdermal transfer had occurred.
Aspects of the formulations, methods of treatment and uses thereof 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 of the claims herein.
Claims (43)
1. A transdermal parasiticidal formulation in the form of a solution including a therapeutically effective amount of levamisole anthelmintic agent dissolved in a solution including isopropyl myristate and D-limonene.
2. The formulation as claimed in claim 1 wherein the highest concentration of levamisole is defined by the point at which the levamisole shifts from being soluble to being insoluble in the formulation.
3. The formulation as claimed in claim 1 or claim 2 wherein the isopropyl myristate and D- limonene is in total present at a rate of 1-55% w/v of the total formulation.
4. The formulation as claimed in any one of the above claims wherein the molar ratio of isopropyl myristate to D-limonene is from about 10:1 to about 15:1.
5. The formulation as claimed in any one of above claims wherein the formulation also includes at least one macrocyclic lactone compound.
6. The formulation as claimed in claim 5 wherein the macrocyclic lactone compound is selected from: abamectin, moxidectin, eprinomectin, selamectin, ivermectin, milbemycins, and combinations thereof.
7. The formulation as claimed in claim 5 or claim 6 wherein the formulation includes 0.1 to 10% w/v macrocyclic lactone compound(s) in the total formulation.
8. The formulation as claimed in any one of above claims wherein the formulation further includes at least one solvent selected from one or more diethylene glycol ether (DGE) compounds.
9. The formulation as claimed in claim 8 wherein the solvent compound or compounds may be selected from: diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether and combinations thereof.
10. The formulation as claimed in claim 8 or claim 9 wherein the solvent is present at a total concentration of 30-70% w/v total composition.
11. The formulation as claimed in any one of above claims wherein the formulation further includes at least one transdermal penetrating agent selected from at least one non-ionic surfactant.
12. The formulation as claimed in claim 11 wherein the transdermal penetration agent or agents are selected from: EO/PO block co-polymers, alcohol ethoxylates, cocamide diethanolamine, and combinations thereof.
13. The formulation as claimed in claim 11 or claim 12 wherein, the transdermal penetrating agent or agents may be present at a concentration of 0.1 to 20% w/v.
14. The formulation as claimed in any one of above claims wherein the formulation further includes at least one preservative.
15. The formulation as claimed in claim 14 wherein the preservative or preservatives include: benzyl alcohol, chlorobutanol, phenylethyl alcohol, ethyl alcohol, and combinations thereof.
16. The formulation as claimed in claim 14 or claim 15 wherein the preservative is present at a concentration of about 0.1 to 5.0% w/v of total formulation.
17. The formulation as claimed in any one of above claims wherein the formulation further includes at least one diluent.
18. The formulation as claimed in claim 17 wherein the diluent is selected from one or more glycol compounds.
19. The formulation as claimed in claim 18 wherein the diluent is be selected from: propylene glycol, ethylene glycol, and combinations thereof.
20. The formulation as claimed in claim 17 or claim 18 wherein the diluent is present at a concentration of 5 to 50% w/v.
21. The formulation as claimed in any one of the above claims wherein the final formulation viscosity is less than or equal to 5000cps.
22. The formulation as claimed in any one of the above claims wherein the formulation further includes at least one further active compound.
23. The formulation as claimed in claim 22 wherein the at least one further active compound is a compound with endo-parasiticidal, ecto-parasiticidal activity and/or an insecticide.
24. The formulation as claimed in claim 22 or claim 23 wherein the insecticide is selected from: triflumuron, diflubenzuron, cyromazine, or at least one compound selected from the group of pyrethroid compounds.
25. The formulation as claimed in any one of claims 22 to 24 wherein the at least one further active compound is included at a rate of equal to or less than 20% w/v of the total formulation.
26. A method of treatment of an endo-parasite or ecto-parasite infestation in a non-human animal by topical administration of a formulation as claimed in any one of the above claims.
27. The method as claimed in claim 26 wherein the composition is administered as a pour on stripe or stripes to a non-human animal.
28. The method as claimed in claim 26 wherein the composition is administered as a spot or spots to a non-human animal.
29. The method as claimed in any one of claims 26 to 28 wherein the non-human animal is a woolly animal.
30. Use of a formulation as claimed in any one of claims 1 to 25 in the manufacture of a composition formulated for transdermal administration in the treatment of an endo-parasite or ecto-parasite infestation in an animal.
31. The use as claimed in claim 30 wherein the composition is administered as a pour on stripe or stripes to an animal.
32. The use as claimed in claim 30 wherein the composition is administered as a spot or spots to an animal.
33. The use as claimed in any one of claims 30 to 32 wherein the animal is a woolly animal.
34. A dual active anthelmintic formulation formulated for transdermal administration including: a. a therapeutically effective amount of levamisole anthelmintic agent dissolved in a solution including isopropyl myristate and D-limonene; b. a therapeutically effective amount of a macrocyclic lactone dissolved in at least one diethylene glycol ether (DGE) compound; c. a penetrating agent or agents selected from at least one non-ionic surfactant; d. at least one preservative; and e. at least one diluent.
35. The formulation as claimed in claim 34 wherein the macrocyclic lactone compound is selected from: abamectin, moxidectin, eprinomectin, selamectin, ivermectin, milbemycins, and combinations thereof.
36. The formulation as claimed in claim 34 or claim 35 wherein the formulation includes 0.1 to 10% w/v macrocyclic lactone compound(s) in the total formulation.
37. The formulation as claimed in claim 34 wherein the formulation further includes at least one further active compound.
38. The formulation as claimed in claim 37 wherein the at least one further active compound is a compound with endo-parasiticidal, ecto-parasiticidal activity and/or an insecticide.
39. The formulation as claimed in claim 37 or claim 38 wherein the insecticide is selected from: triflumuron, diflubenzuron, cyromazine, or at least one compound selected from the group of pyrethroid compounds.
40. The formulation as claimed in any one of claims 37 to 39 wherein the at least one further active compound is included at a rate of equal to or less than 20% w/v of the total formulation.
41. A transdermal parasiticidal formulation including a therapeutically effective amount of levamisole anthelmintic agent dissolved in a solution including isopropyl myristate and D- limonene substantially as hereinbefore described with reference to Examples 1 to 10.
42. A method of treatment of an endo-parasite or ecto-parasite infestation in a non-human animal by administration of a composition comprising abamectin and levamisole dissolved in a solution including isopropyl myristate and D-limonene substantially as hereinbefore described with reference to Examples 12 and 13.
43. Use of a formulation substantially as hereinbefore described with reference to Examples 12 and 13 in the manufacture of a composition comprising abamectin and levamisole dissolved in a solution including isopropyl myristate and D-limonene formulated for transdermal administration in the treatment of an endo-parasite or ecto-parasite infestation in an animal.
Publications (1)
Publication Number | Publication Date |
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NZ619027B2 true NZ619027B2 (en) | 2015-03-03 |
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