NZ748250B2 - Veterinary transdermal formulation - Google Patents
Veterinary transdermal formulation Download PDFInfo
- Publication number
- NZ748250B2 NZ748250B2 NZ748250A NZ74825014A NZ748250B2 NZ 748250 B2 NZ748250 B2 NZ 748250B2 NZ 748250 A NZ748250 A NZ 748250A NZ 74825014 A NZ74825014 A NZ 74825014A NZ 748250 B2 NZ748250 B2 NZ 748250B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- composition
- skin
- solvent
- terpene
- abamectin
- Prior art date
Links
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Abstract
The present invention relates to a non-aqueous composition that comprises a permeation enhancer such as a terpene, for delivering an active ingredient transdermally. The composition comprises at least on one active ingredient, a terpene, and a solvent, such as a non-hydroxyl containing solvent, non-heterocyclic ester solvent and/or a tripropylene glycol alkyl ether. The composition can be used to deliver a range of actives, such as anthelmintics. The present invention provides a platform composition and can be used to deliver a wide variety of active ingredients and combinations thereof transdermally to mammals. heterocyclic ester solvent and/or a tripropylene glycol alkyl ether. The composition can be used to deliver a range of actives, such as anthelmintics. The present invention provides a platform composition and can be used to deliver a wide variety of active ingredients and combinations thereof transdermally to mammals.
Description
VETERINARY TRANSDERMAL FORMULATION
INCORPORATION BY REFERENCE
All documents cited or referenced herein (“herein cited documents”), and all
documents cited or referenced in herein cited documents, together with any
manufacturer’s instructions, descriptions, product specifications, and product sheets for
any products mentioned herein or in any document incorporated by reference herein, are
hereby incorporated herein by reference, and may be employed in the practice of the
invention. More specifically, all referenced documents are incorporated by reference to
the same extent as if each individual document was specifically and individually indicated
to be incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to an anhydrous transdermal formulation that
contains a terpene, and more specifically a formulation suitable for transdermal delivery
of active therapeutic agents to mammals. The present invention also relates to methods
of manufacturing such compositions, and the use such compositions for treating animals.
BACKGROUND TO THE INVENTION
Skin forms an excellent barrier against drug permeation, due to the rigid
lamellar structure of the stratum corneum (SC) lipids. The SC limits the rate of drug
transfer through the skin. The rate of transfer is generally too slow for massive systemic
absorption, making transdermal application unsuitable for the delivery of large amounts
of drug in short periods of time. Transdermal application is more commonly used for the
sustained delivery of drugs over a prolonged period of time.
Transdermal formulations typically include permeation enhancers, which
improve the rate of transfer of the drug across the skin. Permeation enhancers may act
by disrupting the highly ordered structure of stratum corneum lipid, interacting with
intercellular protein, and/or improving partition of the drug into the stratum corneum. A
problem with transdermal formulations is that these permeation enhancers can cause
skin irritation and inflammation.
Small molecules of moderate lipophilicity permeate through skin most easily.
The partition co-efficient P in water and a hydrophobic organic solvent, such as octanol or
hexane, is a useful measure lipophilicity. Molecules having a low log P (i.e. hydrophilic
compounds) have low permeability because partitioning into the skin lipids is low.
Permeability at high log P is also low. This may be due to the accumulation of lipophilic
drugs in the stratum corneum due to low water solubility.
There is a need for new transdermal formulations that avoid one or more of
the aforementioned disadvantages. It is an object of the present invention to go some
way to meeting this need; and/or to at least provide the public with a useful choice.
Citation or identification of any document in this application is not an
admission that such document is available as prior art to the present invention.
SUMMARY OF THE INVENTION
In a first aspect the invention relates to an anhydrous transdermal
composition comprising
at least one active ingredient having a log P in hexane and water of less than
about 8 at pH 7.4,
at least 15% by weight terpene terpene hydrocarbon or terpene alcohol, and
a solvent system comprising
i) a non-hydroxyl containing solvent
ii) a non-heterocyclic ester solvent, or
iii) a tripropylene glycol alkyl ether;
wherein if the solvent is a non-hydroxyl containing solvent, the solvent
additionally comprises at least one of a non-heterocyclic ester solvent or a tripropylene
glycol alkyl ether solvent, and
wherein the composition is in the form of a solution.
In another aspect the invention relates to a method of manufacturing a
transdermal composition which may comprise
mixing a first composition which may comprise an active ingredient that is
substantially insoluble in water, and a terpene, with a fatty acid ester, or
mixing a first composition comprising a terpene, with a second composition which
may comprise an active ingredient that is substantially insoluble in water and a fatty acid
ester, or
mixing a first composition which may comprise a first active ingredient that is
substantially insoluble in water, and a terpene, with a second composition which may
comprise a second active ingredient that is substantially insoluble in water, and a fatty
acid ester,
thereby providing the transdermal composition.
In another aspect the present invention relates to a transdermal composition
manufactured by a method of the present invention.
In another aspect the present invention relates to use of a composition of the
present invention for treating an animal in need thereof.
In another aspect the present invention relates to a kit comprising a
composition of the invention and instructions for use.
Any one or more of the following embodiments may relate to any of the
above aspects.
In one embodiment the permeation enhancer may be present from at least
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,
27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,
50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60% by weight of the composition, and useful
ranges may be selected between any of these values.
In one embodiment the non-hydroxyl containing solvent may be a non-
heterocyclic ester solvent.
In one embodiment at least one of the active ingredients may be lipophilic.
In one embodiment the active ingredient or ingredients may have a logP
(partition coefficient in hexane and water) of less than about 10, 9, 8, 7, 6, 5, 4, 3 or 2.
In one embodiment the active ingredient or ingredients may have a logP (partition
coefficient in octanol and water) of less than about 10, 9, 8, 7, 6, 5, 4, 3 or 2.
In one embodiment the platform composition of the present invention may
deliver active ingredients with a molecular weight of less than about 1000, 900, 800,
700, 600, 500, 400, 300 or 200 gmol , and useful ranges may be selected between any
of these values.
In one embodiment an active ingredient may be selected from
? an anthelmintic,
? a non-steroidal anti-inflammatory,
? a steroidal anti-inflammatory,
? a steroid hormone,
? an anti-histamine
? an anti-emetic,
? a metabolic regulator,
? a productivity regulator,
? a hypothyroidism treatment,
? a behavioural treatment,
? an analgesic,
? a parasiticide,
? an insecticide,
? an anti-microbial,
? an anti-biotic,
? an anti-fungal,
? an anti-viral,
? a coccidostat,
? a skin treatment agent, or
? any combination of one or more of the above.
In one embodiment the non-heterocyclic ester may be present at 1, 2, 3, 4,
, 6, 7, 8, 9, 10, 11, 15, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29 or 30%, by weight of the composition, and useful ranges may be selected between
any of these values.
In one embodiment the non-heterocyclic ester solvent may be a fatty acid
ester.
In one embodiment the non-heterocyclic ester solvent is selected from a
triglyceride, a glycerol ester or a combination thereof.
In one embodiment the anhydrous veterinarily acceptable carrier may be
selected from a non-hydroxyl containing solvent, a non-heterocyclic ester solvent or a
combination thereof.
In one embodiment the non-hydroxyl containing solvent or the non-
heterocyclic ester solvent may be a fatty acid ester.
In one embodiment the non-hydroxyl containing solvent or the non-
heterocyclic ester solvent may be selected from a triglyceride, glycerol ester or
combination thereof.
In one embodiment, the composition comprises a tripropylene glycol alkyl
ether and a non-hydroxyl containing solvent, a non-heterocyclic ester solvent or a
combination thereof.
In one embodiment, the composition comprises a fatty acid ester and a
solvent selected from a triglyceride, glycerol ester or combination thereof.
In one embodiment, the composition comprises a fatty acid ester and a
glycol ether.
In one embodiment, the composition comprises a glycol ether and a solvent
selected from a triglyceride, glycerol ester or a combination thereof.
In one embodiment, the composition comprises a glycol ether, a fatty acid
ester and a solvent selected from a triglyceride, glycerol ester or a combination thereof.
In one embodiment, the composition comprises one or more surfactants.
In one embodiment the composition may comprise a surfactant having the
following structure:
Z O CR1R2CR3R4
where
z is an optionally substituted C14 to C22 linear alkenyl,
R , R , R and R are each independently selected from methyl or hydrogen, and
1 2 3 4
n is an integer from 1 to 10.
In one embodiment R , R , R or R may be selected from the group
1 2 3 4
consisting of methyl, ethyl and hydrogen.
In one embodiment R1, R2, R3 or R4 may be selected from the group
consisting of methyl and hydrogen.
In one embodiment at least one of R1, R2, R3 or R4 may be hydrogen.
In one embodiment at least two of R1, R2, R3 or R4 may be hydrogen.
In one embodiment at least three of R , R , R or R may be hydrogen.
1 2 3 4
In one embodiment R , R , R and R may be hydrogen.
1 2 3 4
In one embodiment n may be an integer from 1 to 5, and more preferably
from 1 to 3. In one embodiment n is 2.
In one embodiment Z may be mono, di or tri –unsaturated.
In one embodiment Z may be C to C linear alkenyl.
16 22
In one embodiment Z may be C to C linear alkenyl.
16 20
In one embodiment Z may be C18 linear alkenyl.
In one embodiment Z may be selected from oleyl, elaidy, vaccenyl, linoeyl,
linoelaidyl, ?-linolenyl.
In one embodiment Z may be oleyl.
In one embodiment Z may have four or more carbon-carbon double bonds.
In one embodiment the alkenyl may comprise from 1 to 3 carbon-carbon
double bonds.
In one embodiment the alkenyl may have 1 or 2 carbon-carbon double
bonds.
In one embodiment the alkenyl may have 1 carbon-carbon double bond.
In one embodiment at least one of the carbon-carbon double bonds of Z may
have a cis configuration.
In one embodiment all of the carbon-carbon double bonds of Z may have a
cis configuration.
In one embodiment at least one of the carbon-carbon bonds of Z may have a
trans configuration.
In one embodiment at least one of the carbon-carbon double bonds may
have a cis configuration and at least one of the carbon-carbon double bonds may have a
trans configuration.
In one embodiment the composition may comprise more than one surfactant.
For example, the composition may comprise two or more surfactants in which the
surfactants differ in the number, position or configuration of the carbon-carbon double
bonds present in Z.
In one embodiment the surfactant may have a polyoxyethylene (2) oleyl
ether such as Brij 93.
In one embodiment the surfactant may provide a hydrophilic-lipophilic
balance of about 4.0 to about 8.0, and more preferably about 4.0 to about 6.0.
In one embodiment the surfactant may provide a hydrophilic-lipophilic
balance of about 4.5.
In one embodiment the composition comprising the surfactant is stable at
4°C.
In one embodiment the composition comprising the surfactant is stable at
4°C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, or 168
hrs.
In one embodiment, the composition comprises at least two active
ingredients.
In one embodiment the composition may comprise at least two lipophilic
active ingredients.
In one embodiment one of the active ingredients may be an imidazothiazole.
In one embodiment the imidazothiazole may be selected from levamisole
base, pyrantel pamoate, butamisol or tetramisole.
In one embodiment, at least one of the active ingredients has a log P in
hexane and water at pH 7.4 of at least about 4, at least about 5, or at least about 6.
In one embodiment the active may be, or may comprise, a macrocyclic
lactone.
In one embodiment the macrocyclic lactone may be selected from
avermectin, ivermectin, abamectin, eprinomectin, moxidectin, selamectin, doramectim,
milbemycin, abamectin or cydectin.
In one embodiment, the macrocyclic lactone is selected from abamectin and
moxidectin.
In one embodiment the composition may comprise
optionally about 1 to about 60% w/w levamisole base,
optionally about 0.1 to about 20% w/w macrocyclic lactone,
optionally about 1 to about 40% w/w fatty acid ester,
optionally about 1 to about 60% w/w terpene, and
optionally about 1 to about 25% w/w non-aqueous solvent.
In one embodiment the terpene may be selected from limonene or
phellandrene. In one embodiment, the terpene is limonene.
In one embodiment the first composition may be heated to at least 20°C.
In one embodiment the composition may include a further penetration
enhancer in addition to a terpene. In such embodiments the further penetration enhancer
is present at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 15, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60%, by weight of the
composition, and useful ranges may be selected between any of these values.
In one embodiment the further penetration enhancer that is present with a
terpene penetration enhancer is a non-heterocyclic ester. In further embodiments the
further penetration enhancer is a fatty acid ester. Preferably the fatty acid ester that
may be present as a further penetration enhancer to the terpene is isopropyl myristate,
triacetin, propylene glycol octanoate decanoate (PGOD), polysorbate 20, or a mixture
thereof.
In one embodiment the composition is administered at 0.005, 0.006, 0.007,
0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25,
0.3, 0.35, 0.4, 0.45, 0.5, 1 mL/kg of live weight animal, and useful ranges may be
selected between any of these values.
In one embodiment the fatty acid ester may have a C8–C20 alkyl chain.
In one embodiment the fatty acid ester may have a C10–C16 alkyl chain.
In one embodiment the fatty acid ester may be isopropyl myristate.
In one embodiment the non-aqueous solvent may be selected from a glycol
ether, a triglyceride, a glycerol ester or a mixture thereof.
In one embodiment the composition may comprise an antioxidant. In one
embodiment, the antioxidant stabilises the composition. In one embodiment, the
antioxidant stabilises the active ingredient to chemical reaction, degradation, or
decomposition in the composition.
In one embodiment the composition delivers at least one of the active
ingredients transdermally at an average post-lag flux rate of at least 30, 40, 50, 60, 70,
80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240,
250, 260, 270, 280, 290 or 300 µg/cm /h, and useful ranges may be selected between
any of these values.
In one embodiment the composition delivers a macrocyclic lactone at an
average post-lag flux rate of at least 150, 200, 250, 300, 350, 400, 450, 500, 550, 600,
650, 700 µg/cm /h, and useful ranges may be selected between any of these values.
In one embodiment the composition delivers levamisole at an average post-
lag flux rate of at least 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850,
900, 950, 1,000, 1,050, 1,100, 1,150, 1,200 µg/cm /h, and useful ranges may be
selected between any of these values.
In one embodiment, the composition delivers abamectin at an average post
lag flux rate of at least 0.1, 0.2, 0.3, 0.4, 0.5 ,0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4,
1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.5, 4.0, 4.5,
or 5.0 µg/cm /h.
In one embodiment, the composition is a veterinary composition.
In one embodiment, the composition is a pour on or spot on formulation.
In one embodiment, the composition is fast acting with respect to at least
one active ingredient. In one embodiment, the composition is fast acting with respect to
at least one active ingredient relative to at least one other active ingredient in the
composition. In one embodiment, the fast acting active ingredient acts within at least 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 48, 72, 96, 120 hours and useful ranges may be
selected from within these values
In one embodiment, the action of at least one of the active ingredients is
delayed relative to at least one other active ingredient in the composition. In one
embodiment, the action is delayed by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
or 15 days, and useful ranges may be selected from within these values.
In one embodiment, the composition provides sustained or prolonged release
of at least one of the active ingredients.
In one embodiment, the pH of the composition is from about 3 to about 12,
about 3 to about 11, from about 4 to about 12, from about 4 to about 11, from about 5
to about 12, from about 5 to about 11, from about 5 to about 10, from about 5 to about
9, from about 5 to about 8, from about 6 to about 11, form about 6 to about 10, from
about 6 to about 9, from about 7 to about 11, from about 7 to about 10, from about 7 to
about 9, or from about 7 to about 8.
In one embodiment, the pH of the composition is at least about 3, 4, 5, 5.5,
6, 6.5, 7, 7.5, or 8.
In one embodiment, the log P of the at least one act ingredient at the pH of
the composition is within at least about 3, 3.5, 2, 2.5, 1, 1.5, or 0.5 of the log P of the
active ingredient at physiological pH (7.4).
In one embodiment the first composition may be formed from a mix of at
least one active ingredient that is substantially insoluble in water, a terpene and a non-
aqueous solvent.
In one embodiment the dissolved mixture may be formed from a mix of the
first composition and any one or more of
i) an antioxidant,
ii) a non-aqueous solvent,
iii) a fatty acid ester, or
iv) a mixture of any one or more of (i) to (iii).
In one embodiment the non-aqueous solvent may be a glycol ether.
In one embodiment the glycol ether may be a tripropylene glycol alkyl ether.
In one embodiment the tripropylene glycol alkyl ether may be present at
about 1, 2, 3, 4, 5, 6, 7, 8 ,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24,
, 26, 27, 28, 29, or 30% by weight of the platform composition, and useful ranges may
be selected between any of these values.
In one embodiment the tripropylene glycol alkyl ether may be selected from
tripropylene glycol methyl ether, tripropylene glycol mono-n-propyl ether or tripropylene
glycol mono-n-butyl ether.
In one embodiment the second composition may also include a lipophilic
organic antioxidant compound.
In one embodiment the lipophilic organic antioxidant compound is present at
about 0.01, 0.02, 0.04 0.06, 0.08, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55,
0.6, 0.65, 0.7, 0.75. 0.8, 0.85, 0.9, 0.95, 1.0, 1.5 or 2% by weight of the composition.
Preferably the lipophilic organic antioxidant compound is a phenol derivative
such as butylated hydroxytoluene, BHA, tocopherol, propyl gallate, or any combination
thereof.
In one embodiment the composition may comprise a reducing agent such as
ascorbyl palmitate.
In one embodiment the composition may comprise a synergist such as
sodium edentate or propyl gallate.
In one embodiment the heating may be performed for between 10 minutes
to 12 hrs or 10 min to 8 hrs. In one embodiment the dissolved mixture is heated for 10,
, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, 480, 540, 600,
660, or 720 minutes, and useful ranges may be selected between any of these values.
In one embodiment the dissolved mixture may be heated to 20, 25, 30, 32,
34, 36, 38, 40, 42, 44, 46, 48 or 50 ?C, and useful ranges may be selected between any
of these values.
In one embodiment the heated mixture may be cooled.
In one embodiment the cooled mixture may be packaged.
In one embodiment the composition may have good physical and chemical
stability, providing at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29 or 30 months shelf life, and useful ranges may be selected between any of these
values.
In one embodiment the composition may be effective to reduce parasitic
faecal egg count by at least 90, 95, 96, 97, 98 or 99%.
In another aspect the invention may be the use of any one or more of the
compositions described above.
In one embodiment, the kit comprises a second composition comprising at
least one active ingredient, wherein at least one of the active ingredients in the second
composition is incompatible with at least one of the active ingredients in the composition
of the invention.
In one embodiment, the instructions comprise mixing the composition of the
invention and the second composition, and immediately administering the mixture to an
animal in need thereof.
It is intended that reference to a range of numbers disclosed herein (for
example, 1 to 10) also incorporates reference to all rational numbers within that range
(for example, 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) and also any range of rational
numbers within that range (for example, 2 to 8, 1.5 to 5.5 and 3.1 to 4.7).
This invention 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 of said parts, elements or
features, and 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.
In this specification, where reference has been made to external sources of
information, including patent specifications and other documents, this is generally for the
purpose of providing a context for discussing the features of the present invention.
Unless stated otherwise, reference to such sources of information is not to be construed,
in any jurisdiction, as an admission that such sources of information are prior art or form
part of the common general knowledge in the art.
The term “alkenyl” employed alone or in combination with other terms
means, unless otherwise stated, a monovalent straight chain hydrocarbon group
including a carbon-carbon double bond.
Accordingly, it is an object of the invention to not encompass within the
invention any previously known product, process of making the product, or method of
using the product such that Applicants reserve the right and hereby disclose a disclaimer
of any previously known product, process, or method. It is further noted that the
invention does not intend to encompass within the scope of the invention any product,
process, or making of the product or method of using the product, which does not meet
the written description and enablement requirements of the USPTO (35 U.S.C. §112, first
paragraph) or the EPO (Article 83 of the EPC), such that Applicants reserve the right and
hereby disclose a disclaimer of any previously described product, process of making the
product, or method of using the product.
It is noted that in this disclosure and particularly in the claims and/or
paragraphs, terms such as “comprises”, “comprised”, “comprising” and the like can have
the meaning attributed to it in U.S. Patent law; e.g., they can mean “includes”,
“included”, “including”, and the like; and that terms such as “consisting essentially of”
and “consists essentially of” have the meaning ascribed to them in U.S. Patent law, e.g.,
they allow for elements not explicitly recited, but exclude elements that are found in the
prior art or that affect a basic or novel characteristic of the invention.
These and other embodiments are disclosed or are obvious from and
encompassed by, the following Detailed Description.
BRIEF DESCRIPTION OF THE DRAWINGS
The following detailed description, given by way of example, but not
intended to limit the invention solely to the specific embodiments described, may best be
understood in conjunction with the accompanying drawings.
Figure 1 depicts a representative schematic of the invention.
Figure 2 depicts a formulation absent surfactant that was examined for
moxidectin permeability with n = 5. The results show the permeability of moxidectin over
72 hours. The moxidectin had a flux rate of 475 ± 185.2 ng/cm /hr from linear section of
profile (R2 = 89.4%). Error bars are standard deviation.
Figure 3 depicts formulation absent stability agent that was examined for
levamisole permeability with n = 5. The results show the permeability of levamisole over
72 hours. Levamisole has a flux rate of 949.6 ± 80.8 µg/cm /hr from linear section of
profile (R2 = 99.4%). Error bars are standard deviation.
Figure 4 depicts testing of a commercial formulation. The Eclipse PO
formulation contains abamectin and levamisole. The results show the permeability of
abamectin in Eclipse over 72 hours with n =3. The abamectin had a flux rate of 33.9 ±
26.3 µg/cm /hr. Error bars are standard deviation.
Figure 5 depicts the permeability of levamisole in Eclipse over 72 hours with
n =3. The levamisole had a flux rate of 204.4 ± 17.1 µg/cm /hr. Error bars are standard
deviation.
Figure 6 depicts the transport of diphenhydramine across rabbit skin (flux
rate of 41.47 ± 10.18 µg/cm /hr).
Figure 7 depicts the transport of diphenhydramine across horse skin (flux
rate 25.3 ± 1.9 µg/cm /hr).
Figure 8 depicts the transport of diphenhydramine across bovine skin (flux
rate 95.1 ± 33.1 µg/cm /hr).
Figure 9 depicts the transport of cetirizine across rabbit skin (flux rate of 4.6
± 2.7 ± 10.18 µg/cm /hr).
Figure 10 depicts the transport of cetirizine across horse skin (flux rate
254.4 ± 1.5 µg/cm /hr).
Figure 11 depicts the transport of cetirizine across bovine skin (flux rate 77.9
± 14.5 µg/cm /hr).
Figure 12 depicts the transport of hydrocortisone across rabbit skin (flux rate
of 2.9 ± 0.9 µg/cm /hr).
Figure 13 depicts the transport of hydrocortisone across horse skin (flux rate
.3 ± 5.8 µg/cm /hr).
Figure 14 depicts the transport of hydrocortisone across bovine skin (flux
rate 61.3 ± 19.1 µg/cm /hr).
Figure 15 depicts the transport of metoclopramide across rabbit skin (flux
rate of 38.6 ± 9.2µg/cm /hr).
Figure 16 depicts the transport of metoclopramide across horse skin (flux
rate 67.0 ± 24.6 µg/cm /hr).
Figure 17 depicts the transport of metoclopramide across bovine skin (flux
rate 109.4 ± 11.8 µg/cm /hr).
Figure 18 depicts Permeability of abamectin across split bovine skin. Data
points are mean, n = 3 ± SD. Triangle = eclipse, Circle = Formulation of Table 11.
Square = formulation of Table 12.
Figure 19 depicts Permeability of levamisole across split bovine skin. Data
points are mean, n = 3 ± SD. Triangle = eclipse, Circle = Formulation of Table 11.
Square = formulation of Table 12.
Figure 20 depicts a FA typical IR spectrum for untreated bovine skin where A
= Amide II (weak), B = Amide I, C = CH2 symmetrical stretching, D = CH2 asymmetrical
stretching, and E = water content.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a non-aqueous composition that may
comprise a permeation enhancer such as a terpene, for delivering an active ingredient or
ingredients transdermally to mammals.
The composition may comprise at least on one active ingredient, a terpene,
and a solvent, such as a non-hydroxyl containing solvent, non-heterocyclic ester solvent
and/or a tripropylene glycol alkyl ether.
The composition may be used to deliver a range of actives, such as
anthelmintics. A non-limiting example of suitable anthelmintics includes levamisole base
and macrocyclic lactones. Compositions prepared in accordance with the present
invention for delivering animal remedies such as anthelmintics may also include the
present of an anhydrous veterinarily acceptable carrier.
The present invention provides a platform composition and may be used to
deliver a wide variety of active ingredients transdermally.
1. Active Ingredient
The platform composition of the present invention delivers a therapeutic
quantity of the active ingredient or ingredients. The active ingredient or ingredients,
once applied to the skin of the recipient animal, may be absorbed into the systemic
circulation.
A wide range of active ingredients may be delivered transdermally by the
platform composition of the present invention.
For example, the active ingredient or ingredients may be lipophilic in nature.
Preferably the active ingredient has a logP (partition coefficient in hexane and water at
pH 7.4) of less than about 10, 9, 8, 7, 6, 5, 4, 3 or 2 and useful ranges may be selected
between any of these values (for example, from about 2 to about 10, from 2 to about 8,
from 2 to about 6, from 2 to about 4, from 3 to about 10, from 3 to about 8, from 3 to
about 7, from 3 to about 6, from 4 to about 10, from 4 to about 8, from 4 to about 7,
from 4 to about 6). Preferably the active ingredient has a logP (partition coefficient in
octanol and water at pH 7.4) of less than about 10, 9, 8, 7, 6, 5, 4, 3 or 2 and useful
ranges may be selected between any of these values (for example, from about 2 to about
, from 2 to about 8, from 2 to about 6, from 2 to about 4, from 3 to about 10, from 3
to about 8, from 3 to about 7, from 3 to about 6, from 4 to about 10, from 4 to about 8,
from 4 to about 7, from 4 to about 6). Examples of possible lipophilic active ingredients
that can be delivered by the platform composition of the present invention include
anthelmintics, non-steroidal and steroidal anti-inflammatory agents, anti-emetics,
hypothyroidism treatment agents, behavioural treatment agent, or analgesics.
In one embodiment, at least one of the active ingredients has a log P in
hexane and water at physiological pH (pH 7.4) of at least about -1, at least about 0, at
least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at
least about 6, or at least about 7. In one embodiment, at least one of the active
ingredients has a log P in octanol and water at physiological pH (pH 7.4) of at least about
-1, at least about 0, at least about 1, at least about 2, at least about 3, at least about 4,
at least about 5, at least about 6, or at least about 7.
In one embodiment the platform composition of the present invention may
deliver multiple lipophilic active ingredients. For example, 2, 3, 4 or 5 actives delivered
transdermally in a single composition. Preferably the active ingredients account for 1, 5,
, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90% of the composition,
and useful ranges may be selected between any of these values (for example, from about
1 to about 90, about 1 to about 75, about 1 to about 60, about 5 to about 100, about 5
to about 80, about 5 to about 55, about 25 to about 90, about 25 to about 65, about 25
to about 50, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30
to about 55, about 50 to about 90, about 50 to about 75, about 65 to about 90, about 65
to about 75 or about 70 to about 90% of the composition).
In one embodiment the platform composition of the present invention may
deliver active ingredients with a molecular weight of less than about 1000, 900, 800,
700, 600, 500, 400, 300, 200 gmol and useful ranges may be selected between any of
these values (for example, from about 100 to about 1000, about 100 to about 900, about
100 to about 800, about 100 to about 600, about 100 to about 500, about 200 to about
1000, about 200 to about 900, about 200 to about 800, about 200 to about 700, about
200 to about 500, about 200 to about 400, about 300 to about 1000, about 300 to about
900, about 300 to about 700, about 300 to about 500, about 500 to about 1000, about
500 to about 800, about 500 to about 700, about 500 to about 600, about 700 to about
1000, about 700 to about 900, about 800 to about 1000).
In one embodiment, at least one of the active ingredients has a molecular
weight of at least about 300, at least about 400, at least about 500, or at least about 600
gmol .
As mentioned above, anthelmintic agents may be delivered transdermally by
the platform composition of the present invention. A candidate anthelmintic agent
includes imidazothiazoles. For example, the imidazothiazole may be selected from
levamisole, pyrantel pamoate, butamisol or tetramisole. Macrocyclic lactones are also
candidate agents for delivery transdermally. For example, the macrocyclic lactone may be
selected from avermectin, ivermectin, abamectin, eprinomectin, moxidectin, selamectin,
doramectim, milbemycin, abamectin or cydectin.
If an imidazothiazole, such as levamisole, is incorporated into the platform
composition for transdermal delivery, preferably the composition may contain 1, 5, 10,
, 20, 25, 30, 35, 40, 45, 50, 55 or 60% imidazothiazole, and useful ranges may be
selected between any of these values (for example, from about 1 to about 60, about 1 to
about 40, about 1 to about 30, about 5 to about 60, about 5 to about 45, about 5 to
about 35, about 5 to about 25, about 10 to about 60, about 10 to about 45, about 10 to
about 30, about 10 to about 20, about 15 to about 60, about 15 to about 40, about 15 to
about 30, about 15 to about 35, about 15 to about 30, about 15 to about 25, about 20 to
about 60, about 20 to about 40, about 20 to about 30, about 25 to about 60, about 25 to
about 45, about 25 to about 35, about 30 to about 60, about 30 to about 40, about 40 to
about 60% imidazothiazole).
If a macrocyclic lactone, such as moxidectin, is incorporated into the
platform composition for transdermal delivery, preferably the composition may contain
0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20%
macrocyclic lactone, and useful ranges may be selected between any of these values (for
example, from about 0.1 to about 20, about 0.1 to about 15, about 0.1 to about 12,
about 0.1 to about 10, about 0.1 to about 5, about 0.1 to about 4, about 0.5 to about 20,
about 0.5 to about 14, about 0.5 to about 10, about 0.5 to about 5, about 1 to about 20,
about 1 to about 16, about 1 to about 11, about 1 to about 6, about 3 to about 20, about
3 to about 13, about 3 to about 7, about 5 to about 20, about 5 to about 14, about 5 to
about 10, about 8 to about 20, about 8 to about 12, about 14 to about 20, about 16 to
about 20% macrocyclic lactone).
It should be appreciated that the exemplification of anthelmintics such as
levamisole and moxidectin is not intended to be limiting, and that other lipophilic active
ingredients could also be delivered within the composition.
Anthelmintics include benzimidazoles, imidazothiazoles,
tetrahydropyrimidines, macrocyclic lactones, salicylanilides, substituted phenols,
aromatic amides, isoquinolines, amino acetonitriles, spiroindoles, and the like.
Anthelmintic benzimidazoles include mebendazole, flubendazole,
fenbendazole, oxfendazole, oxibendazole, albendazole, albendazole sulfoxide,
thiabendazole, thiophanate, febantel, netobimin, and triclabendazole. Further examples
include mebendazole, and ricobendazole.
Benzimidazole based anthelmintics interfere with the worm's energy
metabolism on a cellular level. They bind to a specific building block called beta tubulin
and prevent its incorporation into certain cellular structures called microtubules, which
are essential for energy metabolism. Interfering with energy metabolism is a much more
basic mode of activity than that which occurs with other classes of anthelmintics. For this
reason, benzimidazoles are also able to kill worm eggs. Benzimidazoles have a wide
margin of safety and broad spectrum activity.
Imidazothiazoles and tetrahydropyrimidines and both nicotinic agonists.
Anthelmintic imidathiazoles include levamisole, tetramisole, and butamisole.
Tetrahydropyrimidine anthelmintics include, for example, morantel, oxantel, and
pyrantel.
The tetrahydropyrimidines mimic the activity of acetylcholine, a naturally
occurring neurotransmitter that initiates muscular contraction. The worm is unable to
feed and quickly starves. Tetrahydroyrimidines only affect adult populations of worms.
They do not have activity against the larval stages and are ineffective against cestodes
(tapeworms) and trematodes (liver flukes).
Imidazothiaoles have a similar mode of action causing spastic paralysis of
the worms. Levamisole has a broad spectrum of activity and is effective against many
larval stages of parasites.
Macrocyclic lactones include abamectins, for example abamectin,
doramectin, eprinomectin, ivermectin, and selamectin, and milbemycins, for example
milbemycin oxime and moxidectin.
The macrocyclic lactones (avermectins and milbemycins) are products or
chemical derivatives of soil microorganisms belonging to the genus Streptomyces. All of
the macrocyclic lactone anthelmintics have the same mode of action. They interfere with
GABA-mediated neurotransmission, causing paralysis and death of the parasite.
Macrocyclic lactones are the most potent killer of worms and are more persistent in their
effect. The duration of persistent activity varies according to the drug and formulation.
Macrocyclic lactones also have the unique quality of also killing several types
of external parasite such as lice, mites, and ticks. They have a wide margin of safety for
livestock and are effective against all stages of worms, including inactive forms.
Salicylanilides include brotianide, clioxanide, closantel, niclosamide,
oxyclozanide, rafoxanide, substituted phenols include bithionol, disophenol,
hexachlorophene, niclofolan, menichlopholan, nitroxynil, and aromatic amides include
diamfenetide (diamphenethide).
Insoquinoline anthelmintics include praziquantel and epsiprantel.
Praziquantel and epsiprantel have high efficacy against cestode parasites at relatively low
dose rates but no effect on nematodes. Praziquantel is rapidly and almost completely
absorbed from the GI tract.
Amino-acetonitrile derivatives include monepantel, which acts by paralyzing
worms by attacking a previously undiscovered receptor HCO-MPTL-1, present only in
nematodes.
Further examples of anthelmintics include piperazine and derivatives thereof
such as piperazine and diethylcarbamazine (DEC, a derivative of piperazine),
benzenesulfonamides such as clorsulon, amidines such as bunamidine, isothiocyantes
such as nitroscanate, and organophosphates such as dichlorvos, and spiroindoles such as
derquantel (2- deoxoparaherquamide).
The active ingredient may be a non-steroidal or steroidal anti-inflammatory.
Examples of non-steroidal anti-inflammatory drugs include, but are not limited to,
acemetacin, acetylsalicylic acid (aspirin), alminoprofen, benoxaprofen, bucloxic acid,
carprofen, celecoxib, clidanac, deracoxib, diclofenac, diflunisal, dipyrone, etodolac,
fenoprofen, fentiazac, firocoxib, flobufen, flufenamic acid, flufenisal, flunixin, fluprofen,
flurbiprofen, ibuprofen, indomethacin, indoprofen, isoxicam, ketoprofen, ketorolac,
meclofenamic acid, mefenamic acid, meloxicam, miroprofen, nabumetone, naproxen,
niflumic acid, oxaprozin, oxepinac, phenylbutazone, piroxicam, pirprofen, pramoprofen,
sudoxicam, sulindac, suprofen, tepoxalin, tiaprofenic acid, tiopinac, tolfenamic acid,
tolmetin, trioxaprofen, zidometacin, or zomepirac, pharmaceutically acceptable salts
thereof and mixtures thereof.
Most commercially available veterinary NSAIDs belong to two broad classes:
carboxylic acid and enolic acid derivatives. The main groups of enolic acids are the
pyrazolones (phenylbutazone, oxyphenbutazone, and ramifenazone) and the oxicams
(meloxicam, piroxicam, and tenoxicam). Carboxylic acid groups include the salicylates
(aspirin), propionic acids (ibuprofen, naproxen, carprofen, ketoprofen, and vedaprofen),
anthranilic acids (tolfenamic and meclofenamic acids), phenylacetic acids
(acetaminophen), aminonicotinic acids (flunixin), and indolines (indomethacin).
Anti-inflammatory steroids include steroids which have an anti-inflammatory
activity either locally or systemically. These are well-known within the art. Non-limiting
examples of steroids include the adrenocorticoid steroids, whether endogenous or
synthetic. These include, without limitation, hydrocortisone, betamethasone, cortisone,
dexamethasone, prednisolone, prednisone, methylprednisilone, triamcinolone,
flumethasone, and their pharmaceutically acceptable derivitives. In one embodiment, the
steroid is hydrocortisone or cortisone. These steroids may be used at levels known in the
art.
The composition may comprise a steroid hormone. Steroid hormones include
growth promoters and production enhancers. In one embodiment, the steroid hormone is
a natural steroid hormone, such as estradiol, progesterone, and testosterone, or a
synthetic steroid hormone, such as trenbolone acetate, estradiol benzoate, estradiol 17ß,
and melengestrol acetate, and zeranol.
Steroid hormones include natural and synthetic steroid hormones, steroid
hormone precursors, steroid hormone metabolites, and derivatives thereof that are
structurally derived from cholesterol. Steroid hormones can be synthesized from
cholesterol via pathways that involve cytochrome P450 (cP450) enzymes, which are
heme-containing proteins. Exemplary steroid hormones, include, but are not limited to,
androgens, estrogens, progestogens, mineralcorticoids, and glucocorticoids. Exemplary
androgens include, but are not limited to, testosterone, dehydroepiandrosterone,
dehydroepiandrosterone sulphate, dihydrotestosterone, androstenedione, androstenediol,
androstanedione, androstanediol, and any combination thereof. Exemplary estrogens
include, but are not limited to, estrone, estradiol, estriol, estetrol, equilin, equilenin, and
any combination thereof. Exemplary progestogens include, but are not limited to,
progesterone, 17-hydroxy- progesterone, pregnenolone, dihydroprogesterone,
allopregnanolone, 17-hydroxy- pregnenolone, 17-hydroxy-dihydroprogesterone, 17-
hydroxy-allopregnanolone, and any combination thereof. Exemplary mineralcorticoids
include, but are not limited to, aldosterone, 11- deoxycorticosterone, fludrocortisones, 1
1-deoxy-cortisol, pregnenedione, and any combination thereof. Exemplary
glucocorticoids, include, but are not limited to, cortisol (hydrocortisone), corticosterone,
18-hydroxy-corticosterone, cortisone, and any combination thereof.
The composition may comprise an anti-histamine. Non-limiting examples of
suitable antihistamines include clemastine, clemastine fumarate (2(R)-[2-[1-(4-
Chlorophenyl)phenyl-ethoxy]ethylmethylpyrrolidine), dexmedetomidine,
doxylamine, loratidine, desloratidine and promethazine, and diphenhydramine, or
pharmaceutically acceptable salts, solvates or esters thereof.
The composition may comprise an anti-emetic. Non-limiting examples of
suitable anti-emetic agents include phenothiazines (e.g., prochloperazine, promethazine,
thiethylperazine, perphenazine, chlorpromazine, metopimazine, acepromazine, etc.);
5HT-3 receptor antagonists such as ondansetron, granisetron, tropisetron, dolasetron,
hydrodolasetron, azasetron, ramosetron, lerisetron, indisetron and palonosetron; and
others such as dimenhydrinate, diphenhydramine (which can also act as an
antihistamine), cyclizine, meclizine, promethazine, hyroxyzine, metoclopramide,
domperidone, hyoscine, hyoscine hydrobromide, hyoscine hydrochloride, scopolamine,
clebopride, alizapride, itopride, bromopride, droperidol, haloperidol, benzquinamide,
cerium oxalate, diphenidol, dronabinol, nabilone, ginger, levosulpiride, butorphanol and
aprepitant.
The composition may comprise a metabolic regulator, such a hypothyroidism
treatment. Metabolic diseases may be inherited or acquired and are clinically important
because they affect energy production or damage critical tissues. Storage diseases and
inborn defects in metabolism may be either genetic or acquired. The diseases are
characterized by the accumulation or storage of specific lysosomal enzyme substrates or
byproducts within cells due to the partial or complete deficiency of those enzymes. The
development of the metabolic diseases is largely related to production or management
factors. However, the pathogenesis of the diseases is primarily related to alterations in
metabolism. In many cases the basis of disease is not a congenital or inherited metabolic
defect, but rather an increased demand for a specific nutrient that has become deficient.
In one embodiment the metabolic regulator is a growth promoter, probotic or prebiotic,
antibiotic or anti-infective supplement, electrolyte, mineral, vitamin, or other nutritional
additive.
The composition may comprise a productivity regulator, for example
polyethers such as monensin. In one embodiment, the productivity regulator is a
productivity enhancer.
The composition may comprise a hypothyroidism treatment. Suitable
hypothyroidism treatments include treatment with thyroid hormones and derivatives
thereof. Examples of thyroid hormones include thyroixines such as T2, T3 and T4. “T3”
refers to the art recognized thyroid hormone, triiodothyronine (also known as (2S)
amino[4-(4-hydroxyiodo-phenoxy)-3,5-diiodo-phenyl]propanoic acid). “T ” refers
to the art recognized thyroid hormone, thyroxine, or 3,5,3',5'-tetraiodothyronine (also
known as (2S)amino[4-(4-hydroxy-3,5-diiododophenoxy)-3,5-
diiodophenyl]propanoic acid). “T2” refers to the thyroid hormone iodothyronine or 3,5-
diiodothyronine.
The composition may comprise a behavioural treatment agent. Behavioral
treatments include, for example, serotonin reuptake inhibitors and tricyclic
antidepressants, pheromones, nutritional products, and calming agents. Examples of
serotonin reuptake inhibitors and tricyclic antidepressants include, clomipramine.
The composition may comprise an analgesic. Analgesics include the opioid
analgesics such as buprenorphine, butorphanol, dextromoramide, dezocine,
dextropropoxyphene, diamorphine, fentanyl, alfentanil, sufentanil, hydrocodone,
hydromorphone, ketobemidone, levomethadyl acetate, mepiridine, methadone,
morphine, nalbuphine, opium, oxycodone, papaveretum, pentazocine, pethidine,
phenoperidine, piritramide, dextropropoxyphene, remifentanil, tilidine, tramadol,
codeine, dihydrocodeine, meptazinol, dezocine, eptazocine and flupirtine. Analgesics also
include non-opioid analgesics, for example, non-steroidal anti-inflammatories, such as
those described herein.
The composition may comprise a parasiticide. Parasiticides include, for
example the macrocyclic lactones such as abamectin, ivermectin, eprinomectin,
doramectin, moxidectin, selamectin, milbemycin oxime. In one embodiment, the
antiparasitic agents include, but are not limited to, endoparasiticidal agents,
ectoparaciticidal agents, and endectoparaciticidal agents. Ectoparasiticides include, for
example, organochlorines, organophosphates, carbamates, amidines, pyrethrins and
synthetic pyrethroids, benzoylureas, juvenile hormone analogues, macrocyclic Lactones,
neonicotinoids, phenylpyrazoles, and spinosyns. Endectoparaciticides include, for
example, macrocyclic lactones, such as ivermectin. Endoparasiticides include, for
example, anhelmintics, such as those described herein. In one embodiment, the
antiparasitic agent is an avermectin, milbemycin, phenylpyrazole, nodulisporic acid,
clorsulon, closantel, quinacrine, chloroquine, vidarabine, nitenpyram, ivermectin,
milbemycine oxime, lufenuron, salimectin, moxidectin, or dorimectin. In a more
particular embodiment, the antiparasitic agent is nitenpyram, ivermectin, milbemycine
oxime, lufenuron, salimectin, moxidectin, dorimectin, or paraherquamide, or
pharmaceutically acceptable salts, solvates or esters thereof.
In one embodiment, the composition comprises an insecticide. Examples of
insecticides include, but are not limited to, pyrethrins, pyrethroids, and limonene.
Insecticides also include certain parasiticides.
In one embodiment, the composition comprises a skin treatment agent. Skin
treatment agents include skin conditioning agents, for example glycerine. Other skin
conditioning agents may be used. Categories of skin conditioning agents include, but are
not limited to emollients, humectants and plasticizers.
Humectants include, but are not limited to sorbitol, propylene glycol,
alkoxylated glucose, hexanetriol, ethanol, and the like. Emollients include, but are not
limited to, hydrocarbon oils and waxes; silicone oils; triglyceride esters, acetoglyceride
esters, ethoxylated glycerides; alkyl esters; alkenyl esters; fatty acids, fatty alcohols;
fatty alcohol ethers; ether-esters (fatty acid esters of ethoxylated fatty alcohols); lanolin
and its derivitives; polyhydric alcohols and polyether derivatives; polyhydric alcohol
esters; wax esters; beeswax derivatives; vegetable waxes; phospholipids; steroids; and
amides. These may all be used at art-established levels.
Other examples of skin treatment agents include anti-ageing agents and
wound care agents.
The composition may comprise an anti-microbial. Anti-microbials include
antibiotics, antifungals, antivirals, anhelmintics, and the like. Anti-microbials also
include
The composition may comprise an antibiotic, antifungal, or antiviral.
The anti-biotic may be an inhibitor of cell wall synthesis (e.g. penicllins,
cephalosporins, bacitracin and vancomycin), inhibitor of protein synthesis
(aminoglycosides, macrolides, lincosamides, streptogramins, chloramphenicol,
tetracyclines), inhibitor of membrane function (e.g. polymixin B and colistin), an inhibitor
of nucleic acid synthesis (e.g. quinolones, metronidazole, and rifampin), or an inhibitor of
other metabolic processes (e.g. anti-metabolites, sulfonamides, and trimethoprim). Non-
limiting examples of antibiotics include polyethers ionophores such as monensin and
salinomycin, beta-lactams such as penicillins, aminopenicillins (e.g., amoxicillin,
ampicillin, hetacillin, etc.), penicillinase resistant antibiotics (e.g., cloxacillin, dicloxacillin,
methicillin, nafcillin, oxacillin, etc.), extended spectrum antibiotics (e.g., axlocillin,
carbenicillin, mezlocillin, piperacillin, ticarcillin, etc.); cephalosporins (e.g., cefadroxil,
cefazolin, cephalixin, cephalothin, cephapirin, cephradine, cefaclor, cefacmandole,
cefmetazole, cefonicid, ceforanide, cefotetan, cefoxitin, cefprozil, cefuroxime, loracarbef,
cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftiofur, ceftizoxime,
ceftriaxone, moxalactam, etc.); monobactams such as aztreonam; carbapenems such as
imipenem and eropenem; quinolones (e.g., ciprofloxacin, enrofloxacin, difloxacin,
orbifloxacin, marbofloxacin, etc.); chloramphenicols (e.g., chloramphenicol,
thiamphenicol, florfenicol, etc.); tetracyclines (e.g., chlortetracycline, tetracycline,
oxytetracycline, doxycycline, minocycline, etc.); macrolides (e.g., erythromycin, tylosin,
tlimicosin, clarithromycin, azithromycin, etc.); lincosamides (e.g., lincomycin,
clindamycin, etc.); aminoglycosides (e.g., gentamicin, amikacin, kanamycin, apramycin,
tobramycin, neomycin, dihydrostreptomycin, paromomycin, etc.); sulfonamides (e.g.,
sulfadmethoxine, sfulfamethazine, sulfaquinoxaline, sulfamerazine, sulfathiazole,
sulfasalazine, sulfadiazine, sulfabromomethazine, suflaethoxypyridazine, etc.);
glycopeptides (e.g., vancomycin, teicoplanin, ramoplanin, and decaplanin; and other
antibiotics (e.g., rifampin, nitrofuran, virginiamycin, polymyxins, tobramycin, etc.).
Antifungals include polyenes, azoles, allylamines, morpholines,
antimetabolites, and combinations thereof. For example, fluconazole, itraconazole,
clotrimazole, ketoconazole, terbinafine, 5-fluorocytosine, and amphotericin B.
Non-limiting examples of antivirals include didanosine, lamivudine,
stavudine, zidovudine, indinavir, and ritonavir.
The composition may comprise a coccidostat. Coccidiostats are antiprotozoal
agents that acts on Coccidia parasites. Examples include, but are not limited to,
amprolium, arprinocid, artemether, clopidol, decoquinate, diclazuril, dinitolmide,
ethopabate, halofuginone, lasalocid, monensin, narasin, nicarbazin, oryzalin, robenidine,
roxarsone, salinomycin, spiramycin, sulfadiazine, and toltrazuril.
In one embodiment, the active ingredient is stable in the composition. For
example, the active ingredient(s) in the composition is typically stable to chemical
reaction with other components in the reaction mixture or to degradation or
decomposition by other means.
In one embodiment, the composition comprises levamisole base and the
recovery of levamisole base after 3 months at 75% relative humidity and 40°C is at least
about 95, 96, 97, 98, or 99%. In one embodiment, the recovery is at least about 95%.
In one embodiment, the composition comprises abamectin and the recovery
of abamectin after 3 months at 75% relative humidity and 40°C is at least about 95, 96,
97, 98, or 99%. In one embodiment, the recovery is at least about 95%. In one
embodiment, the composition comprises abamectin and at least one surfactant. In one
embodiment, at least one of the surfactants is a polyoxyethylene alkenyl ether as
described herein.
In one embodiment, the composition comprises moxidectin and the recovery
of moxidectin after 3 months at 75% relative humidity and 40°C is at least about 90, 91,
92, 93, 94, 95, 96, 97, 98, or 99%. In one embodiment, the recovery is at least about
90%.
In one embodiment, the at least one active ingredient is soluble in at least
one of the other liquid components of the composition.
In one embodiment, at least one of the active ingredients is substantially
insoluble in water.
2. Permeation enhancer
The platform composition of the present invention may comprise a
permeation enhancer, or combination of permeation enhancers. The permeation
enhancer, or combination of permeation enhancers, helps to maximise the transport of
the active ingredient(s) across the skin by improving partitioning of the active
ingredients, and minimises the residency time of the active ingredient(s) on the surface
of the skin, reducing the potential for irritation. In some embodiments, the penetration
enhancer acts as a sorption promoter or accelerant.
The permeation enhancer of the present invention may comprise at least a
terpene. Terpenes are a diverse class of organic compounds produced from a wide
variety of sources. The fundamental building block of terpenes is the isoprene unit, C5H8.
Larger structures are then formed from multiples of isoprene. Terpenes can be cyclic or
acyclic. Some examples of cyclic terpenes are given below.
menthol ?-phellandrene
limonene ß-phellandrene
The terpene may be a terpene hydrocarbon, terpene alcohol, terpene ketone,
or terpene oxide. In one embodiment, the terpene is a terpene hydrocarbon, terpene
ketone, or terpene oxide. In another embodiment, the terpene is a terpene hydrocarbon.
In one embodiment, the terpene is a mono-terpene. In another
embodiment, the terpene is mono-cyclic or bi-cyclic.
In one embodiment the terpene may be selected from limonene, menthol, ?-
phellandrene, ß-phellandrene or a combination thereof. In another embodiment, the
terpene is selected from limonene, ?-phellandrene, and ß-phellandrene. In yet another
embodiment, the terpene is limonene.
In one embodiment, the composition does not comprise a terpene alcohol.
In one embodiment, the composition does not comprise menthol.
In one embodiment, the terpene is the sole permeation enhancer in the
composition.
In one embodiment, the composition comprises a single terpene.
In one embodiment the terpene permeation enhancer may be present from
at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,
, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,
48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60% by weight of the composition, and
useful ranges may be selected between any of these values (for example, from about 2 to
about 60, 2 to about 50, 2 to about 40, 2 to about 30, 2 to about 20, 2 to about 10, 5 to
about 60, 5 to about 50, 5 to about 40, 5 to about 30, 5 to about 20, 5 to about 10, 10
to about 60, 10 to about 50, 10 to about 40, 10 to about 30, 10 to about 20, 15 to about
60, 15 to about 55, 15 to about 50, 15 to about 45,15 to about 40, about 15 to about 35,
about 15 to about 30, about 15 to about 25, about 17 to about 60, about 17 to about 50,
about 17 to about 40, about 17 to about 36, about 17 to about 29, about 17 to about 25,
about 18 to about 60, about 18 to about 50, about 18 to about 40, about 18 to about 38,
about 18 to about 32, about 18 to about 28, about 18 to about 26, about 18 to about 25,
about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 37,
about 20 to about 35, about 20 to about 31, about 20 to about 30, about 20 to about 26,
about 20 to about 25, about 22 to about 60, about 22 to about 50, about 22 to about 40,
about 22 to about 34, about 22 to about 30, about 22 to about 28, about 22 to about 25,
about 25 to about 60, about 25 to about 50, about 25 to about 40, about 25 to about 35,
about 25 to about 30, about 28 to about 60, about 28 to about 50, about 28 to about 40,
about 28 to about 36, about 32 to about 60, about 32 to about 50, about 32 to about 40,
about 32 to about 38, about 35 to about 60, about 35 to about 50, about 35 to about 40,
about 40 to about 60, about 40 to about 50, about 45 to about 60, about 45 to about 50,
about 50 to about 60% by weight of the composition).
In addition to a terpene penetration enhancer, the composition may include a
further penetration enhancer. The further penetration enhancer may work in combination
with the terpene penetration enhancer.
In one embodiment, the combination of penetration enhancers (i.e. terpene
and further penetration enhancer) may possess unique penetration enhancer properties,
such as a synergistic interaction to increase the passage of the active ingredient across
the skin or a reversible effect on skin lipids.
In one embodiment the further penetration enhancer may be present at 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 15, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29 or 30%, by weight of the composition, and useful ranges may be selected between
any of these values (for example, from about 1 to about 30, about 1 to about 25, about 1
to about 20, about 1 to about 15, about 1 to about 10, about 4 to about 30, about 4 to
about 26, about 4 to about 21, about 4 to about 16, about 4 to about 10, about 5 to
about 30, about 5 to about 25, about 5 to about 20, about 5 to about 15, about 5 to
about 14, about 5 to about 13, about 5 to about 12, about 5 to about 10, about 7 to
about 30, about 7 to about 27, about 7 to about 23, about 7 to about 15, about 7 to
about 14, about 7 to about 13, about 7 to about 12, about 7 to about 10, about 10 to
about 30, about 10 to about 21, about 10 to about 15, about 14 to about 30, about 14 to
about 24, about 14 to about 20, about 14 to about 18, about 20 to about 30 or about 24
to about 30% by weight of the composition).
In one embodiment the further penetration enhancer that may be present
with a terpene penetration enhancer may be a non-heterocyclic ester. In further
embodiments the further penetration enhancer may be a fatty acid ester. In one
embodiment the fatty acid ester may have a C –C alkyl chain. In one embodiment the
8 20
fatty acid ester may have a C –C alkyl chain. In one embodiment the fatty acid ester
16
may be isopropyl myristate.
An example of a fatty acid ester that may be present as a further penetration
enhancer to the terpene may be isopropyl myristate, triacetin, propylene glycol octanoate
decanoate (PGOD), polysorbate 20, or a mixture thereof.
3. Solvents
In one embodiment the platform composition may comprise an anhydrous
veterinarily acceptable carrier selected from a non-hydroxyl containing solvent, a non-
heterocyclic ester solvent or a combination thereof.
The platform composition of the present invention may comprise at least one
solvent. In one embodiment the solvent may be a non-heterocyclic ester.
In one embodiment the non-heterocyclic ester may be present at 1, 2, 3, 4,
, 6, 7, 8, 9, 10, 11, 15, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29 or 30%, by weight of the composition, and useful ranges may be selected between
any of these values (for example, from about 1 to about 30, about 1 to about 25, about 1
to about 20, about 1 to about 15, about 1 to about 10, about 4 to about 30, about 4 to
about 26, about 4 to about 21, about 4 to about 16, about 4 to about 10, about 5 to
about 30, about 5 to about 25, about 5 to about 20, about 5 to about 15, about 5 to
about 14, about 5 to about 13, about 5 to about 12, about 5 to about 10, about 7 to
about 30, about 7 to about 27, about 7 to about 23, about 7 to about 15, about 7 to
about 14, about 7 to about 13, about 7 to about 12, about 7 to about 10, about 10 to
about 30, about 10 to about 21, about 10 to about 15, about 14 to about 30, about 14 to
about 24, about 14 to about 20, about 14 to about 18, about 20 to about 30 or about 24
to about 30% by weight of the composition).
In one embodiment the non-heterocyclic ester may be a fatty acid ester. In
one embodiment the fatty acid ester may have a C –C alkyl chain. In one embodiment
8 20
the fatty acid ester may have a C –C alkyl chain. Preferably the fatty acid ester may be
16
selected from isopropyl myristate, triacetin, propylene glycol octanoate decanoate
(PGOD), polysorbate 20, or a mixture thereof.
In one embodiment the platform composition of the present invention may
include an additional solvent selected from a triglyceride, glycerol ester or combination
thereof. In one embodiment this additional solvent is present only when particular active
ingredients are to be delivered. For example, in one embodiment this additional solvent
(i.e. triglyceride, glycerol ester or combination thereof) may be present when an active
ingredients such as levamisole forms part of the composition. In one embodiment the
additional solvent is present at 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48,
50, 52, 54, 56, 58 or 50% by weight of the composition, and useful ranges may be
selected between any of these values (for example, from about 20 to about 60, about 20
to about 50, about 20 to about 48, about 20 to about 46, about 20 to about 42, about 20
to about 38, about 26 to about 60, about 26 to about 52, about 26 to about 56, about 26
to about 50, about 26 to about 46, about 26 to about 42, about 26 to about 40, about 30
to about 60, about 30 to about 56, about 30 to about 50, about 30 to about 48, about 30
to about 46, about 30 to about 44, about 30 to about 42, about 36 to about 60, about 36
to about 52, about 36 to about 48, about 36 to about 46, about 36 to about 44, about 36
to about 42, about 40 to about 60, about 40 to about 50, about 40 to about 44, about 42
to about 60, about 42 to about 50, about 42 to about 46, about 42 to about 44, about 50
to about 60% by weight of the composition).
In one embodiment the solvents used in the platform composition of the
present invention may be non-hydroxyl containing solvents.
In one embodiment the anhydrous veterinarily acceptable carrier may be a
non-aqueous solvent. Preferably the non-aqueous solvent may be selected from a glycol
ether, a triglyceride, a glycerol ester or a mixture thereof.
In one embodiment the platform composition may include a tripropylene
glycol alkyl ether. In one embodiment the tripropylene glycol alkyl ether may be present
at about 1, 2, 3, 4, 5, 6, 7, 8 ,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, or 30% by weight of the platform composition, and useful ranges
may be selected between any of these values (for example, from about 1 to about 30,
about 1 to about 25, about 1 to about 20, about 1 to about 18, about 1 to about 15,
about 1 to about 12, about 1 to about 9, about 1 to about 6, about 2 to about 30, about
2 to about 25, about 2 to about 20, about 2 to about 18, about 2 to about 15, about 2 to
about 13, about 2 to about 10, about 2 to about 8, about 2 to about 6, about 4 to about
, about 4 to about 25, about 4 to about 20, about 4 to about 18, about 4 to about 15,
about 4 to about 14, about 4 to about 11, about 4 to about 7, about 5 to about 30, about
to about 25, about 5 to about 20, about 5 to about 18, about 5 to about 15, about 5 to
about 10, about 5 to about 8, about 5 to about 6, about 6 to about 30, about 6 to about
, about 6 to about 20, about 6 to about 18, about 6 to about 15, about 6 to about 12,
about 6 to about 9, about 9 to about 30, about 9 to about 25, about 9 to about 20, about
9 to about 18, about 9 to about 15, about 9 to about 14, about 9 to about 10, about 12
to about 30, about 12 to about 25, about 12 to about 20, about 12 to about 18, about 12
to about 15, about 12 to about 14 or about 13 to about 30, about 13 to about 25, about
13 to about 20, about 13 to about 18, about 13 to about 15, about 15 to about 30, about
to about 25, about 15 to about 20, about 15 to about 18, about 18 to about 30, about
18 to about 25, about 18 to about 20, about 20 to about 30, about 20 to about 25, about
to about 30% by weight of the platform composition). Preferably the tripropylene
glycol alkyl ether is selected from tripropylene glycol methyl ether, tripropylene glycol
mono-n-propyl ether, tripropylene glycol mono-n-butyl ether, or tripropylene glycol
monomethyl ether (TPGME) or a combination of any two or more thereof.
In one embodiment the selection of the active ingredient may stipulate use
of a particular solvent. For example, applicants have found that in those embodiments
that contain levamisole base, use of a solvent such as glycerol formal, dimethyl
isosorbate (DMI), tetraglycol or a mixture thereof is preferred.
The platform composition of the present invention provides for a high active
loading in the composition. In one embodiment the platform composition will also
include a co-solvent. Applicants have found that a benefit from the use of the co-solvent
is the increased solvency powder of the composition allowing for a higher drug loading in
the platform composition.
4. Surfactant
In one embodiment the composition may comprise a surfactant. In such an
embodiment the surfactant assists maintaining the stability of the composition at low
temperatures, for example at fridge storage temperatures of around 4°C.
Any suitable surfactant may be used. The composition may comprise one or
more surfactants.
In one embodiment, at least one of the surfactant has the following
structure:
CR R CR R
Z O 1 2 3 4
where
z is an optionally substituted C to C linear alkenyl,
14 22
R1, R2, R3 and R4 are each independently selected from methyl or hydrogen, and
n is an integer from 1 to 10.
R1, R2, R3 or R4 may be selected from the group consisting of methyl, ethyl
and hydrogen, and more preferably from methyl and hydrogen. Alternately, at least 1, 2,
3 or all of R , R , R or R are hydrogen.
1 2 3 4
In one embodiment n may be an integer from 1 to 5, preferably from 1 to 3,
and more preferably is 2.
Z may be mono, di or tri –unsaturated. In one embodiment Z may have four
or more double bonds.
In one embodiment the alkenyl may comprise at least 1 to 3 carbon-carbon
double bonds.
Of the carbon-carbon double bonds in Z, at least one of them has a cis
configuration. In some embodiments one of the carbon-carbon double bonds may have a
trans configuration provided there remains at least one carbon-carbon double bond with
a cis configuration. In one embodiment all of the carbon-carbon double bonds have a cis
configuration.
In one embodiment Z may be an optionally substituted
? C to C linear alkenyl,
16 22
? C to C linear alkenyl, or
16 20
? C linear alkenyl.
In one embodiment Z is selected from oleyl, elaidy, vaccenyl, linoeyl,
linoelaidyl, ?-linolenyl. In one embodiment Z is oleyl.
The surfactant composition may comprise a mixture of compositions each
having a different cis trans configuration. For example, the surfactant may be a mixture
of a compound in which all of the carbon-carbon double bonds may have a cis
configuration with some compounds in which some of the carbon-carbon double bonds
may have a cis and some may have a trans configuration.
In one embodiment, the surfactant is a wetting agent. Examples of wetting
agents include ethoxylated fatty alcohols, such as a Brij.
In one embodiment, the surfactant is a polyoxyethylene alkyl ether or a
polyoxyethylene alkenyl ether.
In one embodiment the surfactant may be a polyoxyethylene (2) oleyl ether
such as Brij 93.
In one embodiment the surfactant may have a hydrophilic-lipophilic balance
(HLB) value of about 4.0 to about 8.0, and more preferably about 4.0 to about 6.0.
In one embodiment the surfactant may have a hydrophilic-lipophilic balance
of about 4.5.
In one embodiment, the composition may comprise two or more surfactants
that in combination provide a hydrophilic-lipophilic balance of about 4.0 to about 8.0, or
about 4.0 to about 6.0, or about 4.5. The desired hydrophilic-lipophilic balance may be
provided by combining surfactants having different hydrophilic-lipophilic balances, which
may or may not be within the desired hydrophilic-lipophilic balance range, in appropriate
proportions.
In some embodiments, the one or more surfactant stabilises the composition.
In one embodiment, the surfactant inhibits crystallisation or precipitation of one or more
components of the composition. In another embodiment, the surfactant inhibits phase
separation in the composition.
In one embodiment the composition comprising the surfactant is stable at
4°C.
In one embodiment the composition comprising the surfactant is stable at
4°C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, or 168
hrs. In one embodiment, the composition may comprise at least one surfactant and is
stable at 4 °C for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2
weeks, 1 month, 2 months, or 3 months.
In one embodiment the composition may comprise at least 0.2, 0.4, 0.6, 0.8,
1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10% surfactant by
weight of the composition, and useful ranges may be selected between any of these
values (for example, from about 0.2 to about 10, about 0.2 to about 8.5, about 0.2 to
about 7, about 0.2 to about 6, about 0.2 to about 5, about 0.2 to about 4, about 0.2 to
about 3.5, about 0.2 to about 3, about 0.2 to about 2.5, about 0.2 to about 2, about
0.2 to about 1, about 0.2 to about 0.8, about 0.4 to about 10, about 0.4 to about 8.5,
about 0.4 to about 7, about 0.4 to about 6, about 0.4 to about 5, about 0.4 to about 4,
about 0.4 to about 2, about 0.4 to about 1, about 0.6 to about 10, about 0.6 to about
8.5, about 0.6 to about 7, about 0.6 to about 6, about 0.6 to about 5, about 0.6 to about
4, about 0.6 to about 3.5, about 0.6 to about 2, about 0.6 to about 1.5, about 1 to
about 10, about 1 to about 8.5, about 1 to about 7, about 1 to about 6, about 1 to about
, about 1 to about 4, about 1 to about 3.5, about 1 to about 3, about 1 to about 2.5,
about 1 to about 1.5, about 1.5 to about 10, about 1.5 to about 8.5, about 1.5 to about
7, about 1.5 to about 6, about 1.5 to about 5, about 1.5 to about 4, about 1.5 to about
3.5, about 1.5 to about 2.5, about 1.5 to about 2, about 2 to about 10, about 2 to about
8.5, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4,
about 2 to about 3.5, about 2 to about 3, about 2 to about 2.5, about 2.5 to about 10,
about 2.5 to about 8.5, about 2.5 to about 7, about 2.5 to about 6, about 2.5 to about 5,
about 2.5 to about 4, about 2.5 to about 3.5, about 2.5 to about 3.5, about 3 to about
, about 3 to about 8.5, about 3 to about 7, about 3 to about 6, about 3 to about 5,
about 3 to about 4, about 3 to about 3.5 or about 3.5 to about 4, about 4 to about 10,
about 4 to about 8.5, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5
to about 10, about 5 to about 8.5, about 5 to about 7, about 5 to about 6, about 6 to
about 10, about 6 to about 8.5, about 6 to about 7, about 7 to about 10, about 7 to
about 8.5, about 8.5 to about 10% by weight of surfactant in the composition).
Surfactants suitable for use include ionic and non-ionic detergents,
dispersing agents, wetting agents, emulsifiers and the like.
Examples of surfactants include those selected from the group consisting of
anionic surfactants, nonionic surfactants, amphoteric surfactants, non-lathering
surfactants, emulsifiers and mixtures thereof.
Examples of anionic surfactants include those selected from the group
consisting of sarcosinates, sulfates, isethionates, taurates, phosphates, lactylates,
glutamates, and mixtures thereof. Anionic surfactants also include fatty acid soaps.
Non-limiting examples of nonionic surfactants include those selected from
the group consisting of alkyl glucosides, alkyl polyglucosides, polyhydroxy fatty acid
amides, alkoxylated fatty acid esters and fatty alcohols, sucrose esters, amine oxides,
and mixtures thereof.
Examples of amphoteric lathering surfactants include derivatives of aliphatic
secondary and tertiary amines.
Non-limiting examples of zwitterionic surfactants are those selected from the
group consisting of betaines, sultaines, hydroxysultaines, alkyliminoacetates,
iminodialkanoates, aminoalkanoates, and mixtures thereof.
Non-limiting examples of non-lathering surfactants include polyethylene
glycol 20 sorbitan monolaurate (Polysorbate 20), polyethylene glycol 5 soya sterol,
Steareth-20, Ceteareth-20, PPG-2 methyl glucose ether distearate, Ceteth-10,
Polysorbate 80, cetyl phosphate, potassium cetyl phosphate, diethanolamine cetyl
phosphate, Polysorbate 60, glyceryl stearate, PEG-100 stearate, polyoxyethylene 20
sorbitan trioleate (Polysorbate 85), sorbitan monolaurate, polyoxyethylene 4 lauryl ether
sodium stearate, polyglyceryW isostearate, hexyl laurate, steareth-20, ceteareth-20,
PPG-2 methyl glucose ether distearate, ceteth-10, diethanolamine cetyl phosphate,
glyceryl stearate, PEG-100 stearate, and mixtures thereof.
Surfactants also include silicone surfactants. Examples of silicone surfactants
include dimethicone based surfactants, surfactant silicone elastomers, and combinations
thereof.
. Kits
The kit of the present invention comprises a composition of the present
invention and instructions for use. The kit may comprise a second composition that
comprises at least one active ingredient that it incompatible with at least component of
the composition of the present invention.
Incompatibility between active ingredients or between active ingredients and
excipients, for example, is well known in the art and may prevent the formulation of such
components in a single, stable composition.
In one embodiment, the at least one active ingredient of the second
composition is incompatible with at least one active ingredient in the composition of the
present invention.
The instructions for use may include instructions to mix the composition of
the present invention and second composition and to immediately administer the mixture
to an animal in need thereof. The mixture is administered immediately to prevent or
minimise the incompatibility causing adverse effects on the stability of the active
ingredients or other components of the mixture.
In one embodiment, the mixture is administered within about 12, 11, 10, 9,
8, 7, 6, 5, 4, 3, 2, 1 hours after mixing. In another embodiment, the mixture is
administered within about 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5 minutes after
mixing.
The composition of the invention and the second composition are separated
from each other in the kit. The composition may be separated using, for example, a
container, divided bottle or divided foil package.
6. Method of Manufacture
In one embodiment there is a method of manufacturing a transdermal
composition which may comprise
1. mixing a first composition which may comprise an active ingredient that is
substantially insoluble in water, and a terpene, with a fatty acid ester, or
2. mixing a first composition which may comprise a terpene, with a second
composition which may comprise an active ingredient that is substantially
insoluble in water and a fatty acid ester, or
3. a first composition which may comprise a first active ingredient that is
substantially insoluble in water, and a terpene, with a second composition
which may comprise a second active ingredient that is substantially
insoluble in water, and a fatty acid ester,
thereby providing the transdermal composition.
In one embodiment the first composition may include a triglyceride or
glycerol ester. Preferably the first composition may contain triacetin (glycerin triacetate).
In one embodiment the second composition may include a tripropylene glycol
alkyl ether. Preferably the tripropylene glycol alkyl ether may be selected from
tripropylene glycol methyl ether, tripropylene glycol mono-n-propyl ether, tripropylene
glycol mono-n-butyl ether, or tripropylene glycol monomethyl ether (TPGME) or a
combination of any two or more thereof.
In one embodiment the second composition may include a non-heterocyclic
ester. In one embodiment the non-heterocyclic ester may be a fatty acid ester. In one
embodiment the fatty acid ester may have a C –C alkyl chain. In one embodiment the
8 20
fatty acid ester may have a C –C alkyl chain. Preferably the fatty acid ester may be
16
selected from isopropyl myristate.
One example is of an anthelmintic composition. In this example the active
ingredient of the first composition may be a lipophilic active such as levamisole base.
Preferably the first composition may comprise a combination of levamisole base, a
triglyceride or glycerol ester such as triacetin and a terpene penetration enhancer.
Preferably the terpene penetration enhancer may be selected from limonene, menthol ?-
phellandrene, ß-phellandrene or a combination thereof. The first composition ingredients
are mixed by stirring until a homogenous mixture if the ingredients is formed. The first
composition may be combined with at least a fatty acid ester. In one embodiment the
second composition may also include a further active ingredient. By way of example, the
active ingredient of the second composition may be different to the active ingredient of
the first composition. For example, the active ingredient of the second composition may
be a macrocyclic lactone.
In one embodiment the second composition may include a triglyceride or
glycerol ester. Preferably the second composition may contain triacetin (glycerin
triacetate). The triglyceride or glycerol ester may be present in the first composition, the
second composition or the first and the second compositions.
The second composition may therefore comprise a second active such as a
macrocyclic lactone, a triglyceride or glycerol ester such as triacetin and a tripropylene
glycol alkyl ether.
In one embodiment the second composition may also include a lipophilic
organic antioxidant compound. In one embodiment the lipophilic organic antioxidant
compound is present at about 0.01, 0.02, 0.04 0.06, 0.08, 0.1, 0.15, 0.2, 0.25, 0.3,
0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75. 0.8, 0.85, 0.9, 0.95, 1.0, 1.5 or 2% by
weight of the composition, and useful ranges may be selected between any of these
values (for example, from about 0.01 to about 2. 0.01 to about 1, about 0.01 to about
0.85, about 0.01 to about 0.35, about 0.010.2, about 0.01 to about 0.08, about 0.06 to
about 2, about 0.06 to about 1.5, about 0.06 to about 0.85, about 0.06 to about 0.45,
about 0.06 to about 0.25, about 0.08 to about 2, about 0.08 to about 1.5, about 0.08 to
about 0.85, about 0.08 to about 0.45, about 0.08 to about 0.25, about 0.1 to about 2,
about 0.1 to about 0.95, about 0.1 to about 0.5, about 0.1 to about 0.25, about 0.15 to
about 2, about 0.15 to about 0.95, about 0.15 to about 0.5, about 0.15 to about 0.25,
about 0.4 to about 2, about 0.4 to about 1, about 0.4 to about 0.9, about 0.4 to about
0.7, about 0.7 to about 2, about 0.7 to about 1, about 1 to about 2 or about 1.5 to about
2% by weight of the composition).
Preferably the lipophilic organic antioxidant compound may be a phenol
derivative such as butylated hydroxytoluene.
In one embodiment the lipophilic organic antioxidant compound may be
required to assist or enhance the stability of one or more of the active ingredients. For
example, in an anthelmintic platform compositions the lipophilic organic antioxidant
compound may enhance the stability of the levamisole base, the macrocyclic lactone or
the levamisole base and the macrocyclic lactone.
In one embodiment the lipophilic organic antioxidant compound may assist
or enhance the stability of the terpene penetration enhancer. For example, the lipophilic
organic antioxidant compound may assist or enhance the stability of the limonene
penetration enhancer.
In one embodiment the second composition may comprise an active
ingredient, a triglyceride or glycerol ester, a tripropylene glycol alkyl ether, and a non-
heterocyclic ester such as a fatty acid ester.
In one embodiment the second composition may comprise an active
ingredient, a triglyceride or glycerol ester, a tripropylene glycol alkyl ether, a non-
heterocyclic ester such as a fatty acid ester, and a lipophilic organic antioxidant
compound.
The first and second compositions may be combined together. As mentioned
above, in the instance where the second composition does not include an active
ingredient, the second composition may only comprise 1 or more solvents. For example,
the first composition may combine solely a fatty acid ester. When the second composition
comprises an active ingredient then the second composition may also include additional
solvents to the fatty acid ester, such as one or more of a triglyceride or glycerol ester or a
tripropylene glycol alkyl ether. The second composition may also comprise the lipophilic
organic antioxidant compound regardless of whether the second composition contains an
active ingredient or not. It should be appreciated that where the second composition does
not comprise an active ingredient, the presence of the lipophilic organic antioxidant
compound may act to assist or enhance the stability of the active ingredient in the first
composition. The lipophilic organic antioxidant compound may also act to stabilise the
terpene penetration enhancer.
In one embodiment, once combined the mixtures may be mixed until
dissolved.
Following dissolution, in one embodiment additional terpene penetration
enhancer may be added to the dissolved composition q.s.
Following the option addition of q.s. terpene penetration enhancer to the
dissolved mixture, in one embodiment the mixture may then be incubated above room
temperature. In one embodiment the incubation is carried out with stirring.
The dissolved mixture may be heated at any suitable temperature. The
temperature may depend on the active ingredient(s) present in the mixture. In one
embodiment the dissolved mixture may be heated to 20, 22, 24, 26, 28, 30, 32, 34, 36,
38, 40, 42, 44, 46, 48 or 50 ?C, and useful ranges may be selected between any of these
values (for example, from about 20 to about 50, about 20 to about 44, about 20 to
about 40, about 20 to about 30, about 20 to about 26, about 24 to about 50, about 24
to about 44, about 24 to about 40, about 24 to about 36, about 24 to about 30, about
to about 50, about 30 to about 46, about 30 to about 42, about 30 to about 40, about
34 to about 50, about 34 to about 48, about 34 to about 52, about 34 to about 48, about
34 to about 46, about 34 to about 44, about 34 to about 42, about 34 to about 40, about
36 to about 50, about 36 to about 46, about 36 to about 42, about 36 to about 30, about
38 to about 50, about 38 to about 44, about 38 to about 40, about , about 40 to about
50, about 40 to about 48, about 40 to about 46, about 40 to about 42 or about 44 to
about 50 ?C). Higher temperatures may be suitable, depending on the active
ingredient(s) present in the mixture.
In one embodiment the dissolved mixture may be heated for 10, 30, 60, 90,
120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, 480, 540, 600, 660, or 720
minutes, and useful ranges may be selected between any of these values (for example,
from about 10 to about 720, about 10 to about 660, about 10 to about 600, about 10 to
about 540, about 10 to about 480, about 10 to about 360, about 10 to about 240, about
to about 120, about 10 to about 60, about 60 to about 720, about 60 to about 660,
about 60 to about 600, about 60 to about 540, about 60 to about 480, about 60 to about
390, about 60 to about 330, about 60 to about 240, about 60 to about 180, about 60 to
about 120, about 120 to about 720, about 120 to about 660, about 120 to about 600,
about 120 to about 540, about 120 to about 480, about 120 to about 420, about 120 to
about 300, about 120 to about 270, about 120 to about 240, about 120 to about 180,
about 210 to about 720, about 210 to about 660, about 210 to about 600, about 210 to
about 540, about 210 to about 480, about 210 to about 390, about 210 to about 360,
about 210 to about 270, about 270 to about 720, about 270 to about 660, about 270 to
about 600, about 270 to about 540, about 270 to about 480, about 270 to about 420,
about 270 to about 360, about 270 to about 300, about 360 to about 720, about 360 to
about 660, about 360 to about 600, about 360 to about 540, about 360 to about 480,
about 360 to about 420, about 420 to about 720, about 420 to about 660, about 420 to
about 600, about 420 to about 540, about 420 to about 480 or about 450 to about 720,
about 450 to about 660, about 450 to about 600, about 450 to about 540, about 450 to
about 480, about 540 to about 720, about 540 to about 660, about 540 to about 600,
about 600 to about 720, about 600 to about 660, about 660 to about 720minutes).
The heated composition may be then cooled and packaged for use.
Once cooled, in one embodiment the composition may be assayed for the
active ingredient activity.
In one embodiment the composition may comprise
optionally about 1 to about 60% w/w levamisole base,
optionally about 0.1 to about 20% w/w macrocyclic lactone,
optionally about 1 to about 40% w/w fatty acid ester,
optionally about 1 to about 60% w/w terpene, and
optionally about 1 to about 25% w/w non-aqueous solvent.
In one embodiment the composition may have good physical and chemical
stability, providing at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29 or 30 months shelf life, and useful ranges may be selected between any of these
values (for example, from about 12 to about 30, about 12 to about 26, about 12 to
about 20, about 12 to about 17, about 13 to about 30, about 13 to about 25, about 13
to about 17, about 13 to about 15, about 16 to about 30, about 15 to about 30, about
to about 27, about 15 to about 22, about 15 to about 19, about 14 to about 30, about
14 to about 28, about 14 to about 22, about 14 to about 18, about 14 to about 17, about
17 to about 30, about 17 to about 28, about 17 to about 23, about 17 to about 20, about
18 to about 30, about 18 to about 27, about 18 to about 24, about 18 to about 22, about
to about 30, about 20 to about 28, about 20 to about 26, about 25 to about 30, about
to about 28, about or about 27 to about 30 months shelf life).
In one embodiment the platform composition may be a solution, suspension,
emulsion, microemulsion, or micelle composition.
In another embodiment, the composition may be a homogeneous or
heterogeneous mixture, a solution, suspension (e.g. of submicron to micron particles),
emulsion, microemulsion, micellar or encapsulated composition.
7. Use of the anhydrous transdermal platform composition
The platform composition is capable of delivering a range of drug candidates,
including anthelmintics, as single entities or in combination. The platform composition
delivers the actives to the systemic circulation by passive diffusion.
The composition is for treating an animal in need thereof. The suitability of
the composition for treating a particular disease or condition, for example, depends on
the active ingredients present in the composition.
The term “treatment”, and related terms, such as “treating” and “treat” as
used herein, relates generally to treatment, of either a human or a non-human animal, in
which some desired therapeutic effect is achieved. The therapeutic effect may, for
example, be the inhibition of progress of a disease or condition, including a reduction in
the rate of progress, a halt in the rate of progress, amelioration, and cure. Treatment as
a prophylactic measure is also included. Treatment also includes combination
treatments and therapies, in which two or more treatments or therapies are used, for
example, sequentially or simultaneously, in combination.
The present invention therefore provides use of a composition of the present
invention for treating an animal in need thereof.
The present invention also provides a method of treating an animal in need
thereof, comprising administering a therapeutically effective amount of a composition of
the present invention.
The present invention also provides use of a composition of the present
invention in the manufacture of a medicament for treating an animal in need thereof.
The animal to be treated may be human or non-human. Non-human animals
include, for example, production animals, such as, cattle, sheep, swine, deer, and goats;
companion animals, such as, dogs, cats, and horses; zoo animals, such as, zebras,
elephants, giraffes, and large cats; research animals, such as, mice, rats, rabbits, and
guinea pigs; fur-bearing animals, such as, mink; birds, such as, ostriches, emus, hens,
geese, turkeys, and ducks.
In one embodiment, the animal is a non-human animal. In one
embodiment, the animal is a non-human mammal. In one embodiment, the animal is a
production animal or companion animal.
In one embodiment, the composition is for treating a helminth infection or
infestation. The composition comprises at least one anthelmintic.
Helminths include, but are not limited to, cestodes (flatworms), nematodes
(roundworms), and trematodes (flukes), such as, Trichostrongyloidea, inlcuding
Haemonchus contortus; Trichostrongylus spp.; Dictyocaulus spp.; Ascaridoidea, including
Toxocara spp.; Strongylus spp.; Filarioidea, including Dirofilariaimmitis and Onchocerca
spp: Trematoda, including Fasciolahepatica and Schistosoma spp.; Taenia spp.; and
Moniezia spp.; Ostertagia spp.; Nematodirus spp.; Cooperia spp.; Bunostomum spp.;
Oesophagostomum spp.; Chabertia spp, Trichuris spp.; Trichonema spp.; Capillaria spp.;
Heterakis spp.; Toxocara spp.;, Oxyuris spp.; Ancylostoma spp.; Uncinaria spp.;
Toxascaris spp.; and Parascaris spp.
In one embodiment, the helminth is selected from Haemonchus spp.;
Ostertagia spp.; Trichostrongylus spp.; Nematodirus spp.; and Cooperia spp.
The transdermal composition is for topically administration. The composition
may be administered, for example, in the form of a sterile cream, gel, pour-on or spot-on
formulation, suspension, lotion, ointment, dusting powder, spray, drug- incorporated
dressing, skin patch, dip, spray, emulsion, jetting fluid, or shampoo.
In one embodiment, the composition is a pour-on or spot-on formulation.
Such formulations may be prepared by the method described herein. Pour-on, spot-on
or, spray formulations can be prepared to leave a residue of active agent on the surface
of the animal.
Kits of the invention are suitable for administering different dosage forms of
more than one anti-parasitic agent by separating the agents using, for example, a
container, divided bottle or divided foil package.
A person skilled in the art will be able to readily determine the appropriate
dosage of administration for treating an animal. The dosage will depend upon the active
ingredient(s) present in the composition and may also depend on the frequency of
administration, the sex, age, weight and general condition of the animal treated, the
nature and severity of the condition treated, any concomitant diseases to be treated, and
any other factors evident to those skilled in the art.
In one embodiment the platform composition may comprise doses at low
volume. In one embodiment the composition is administered at 0.005, 0.006, 0.007,
0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25,
0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, or 1 mL/kg of live
weight animal and useful ranges may be selected between any of these values (for
example, from about 0.005 to about 1, from 0.005 to about 0.8, from 0.005 to about 0.6,
from 0.005 to about 0.5, from 0.005 to about 0.3, from 0.005 to about 0.2, from 0.005
to about 0.1, from 0.005 to about 0.05, from 0.005 to about 0.01, from 0.008 to about 1,
from 0.008 to about 0.8, from 0.008 to about 0.6, from 0.008 to about 0.5, from 0.008
to about 0.4, from 0.008 to about 0.1, from 0.008 to about 0.09, from 0.008 to about
0.05, from 0.008 to about 0.01, from 0.01 to about 1, from 0.01 to about 0.8, from 0.01
to about 0.6, from 0.01 to about 0.5, from 0.01 to about 0.3, from 0.01 to about 0.1,
from 0.01 to about 0.09, from 0.01 to about 0.06, from 0.01 to about 0.05, from 0.01 to
about 0.04, from 0.03 to about 1, from 0.03 to about 0.8, from 0.03 to about 0.6, from
0.03 to about 0.5, from 0.03 to about 0.4, from 0.03 to about 0.2, from 0.03 to about
0.1, from 0.03 to about 0.09, from 0.03 to about 0.08, from 0.03 to about 0.06, from
0.03 to about 0.05, from 0.05 to about 1, from 0.05 to about 0.8, from 0.05 to about
0.6, from 0.05 to about 0.5, from 0.05 to about 0.4, from 0.05 to about 0.3, from 0.05 to
about 0.1, from 0.05 to about 0.09, from 0.05 to about 0.07, from 0.1 to about 1, from
0.1 to about 0.8, from 0.1 to about 0.6, from 0.1 to about 0.5, from 0.1 to about 0.4,
from 0.1 to about 0.3, from 0.3 to about 1, from 0.3 to about 0.8, from 0.3 to about 0.6,
from 0.3 to about 0.5, from 0.5 to about 1, from 0.5 to about 0.8, from 0.5 to about 0.6,
from 0.6 to about 1, from 0.6 to about 0.8, from 0.8 to about 1 mL/kg of live weight
animal). Regardless of this low volume, the platform composition delivers the active
ingredients within their therapeutic dose range to the target animal.
The volume of the dose may depend on the active ingredients present in the
composition and also on the animal to be treated. For example, the composition may be
administered at from about 0.025 mL/ kg to about 0.1 mL/kg for production animals,
such as cattle, or from about 0.01 mL/kg to about 0.1 mL/kg for companion animals,
such as cats and dogs.
The platform technology provides a number of advantages including
? good wetting/spreading properties,
? no, or very little, hair loss or skin damage,
? no, or very little, apparent residue/oil on skin, and/or
? no, or very little, apparent photosensitivity.
Spreadability can be measured directly by applying a known volume and
measuring wetted area. UV light can be used to visualize certain formulations. Residue
on skin can be measured by swabbing/extraction. Hair loss and photosensitivity may be
evaluated by field observation.
In one embodiment the composition delivers at least one of the active
ingredients transdermally at an average post-lag flux rate of at least 100, 110, 120, 130,
140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 or 300
µg/cm /h, and useful ranges may be selected between any of these values (for example,
from about 100 to about 300, about 100 to about 280, about 100 to about 250, about
100 to about 200, about 100 to about 180, about 120 to about 300, about 120 to about
260, about 120 to about 200, about 120 to about 150, about 160 to about 300, about
160 to about 270, about 160 to about 240, about 160 to about 200, about 190 to about
300, about 190 to about 280, about 190 to about 240, about 190 to about 200, about
210 to about 300, about 210 to about 280, about 210 to about 260, about 210 to about
230, about 240 to about 300, about 240 to about 280, about 240 to about 260, about
260 to about 300, about 260 to about 290, about 280 to about 300 µg/cm /h).
In one embodiment the composition delivers a macrocyclic lactone at an
average post-lag flux rate of at least 150, 200, 250, 300, 350, 400, 450, 500, 550, 600,
650, 700 µg/cm /h, and useful ranges may be selected between any of these values (for
example, from about 150 to about 700, about 150 to about 600, about 150 to about 500,
about 150 to about 400, about 150 to about 200, about 250 to about 700, about 250 to
about 600, about 250 to about 500, about 250 to about 400, about 300 to about 700,
about 300 to about 650, about 300 to about 450, about 300 to about 400, about 400 to
about 700, about 400 to about 650, about 400 to about 600, about 400 to about 500,
about 450 to about 700, about 450 to about 650, about 450 to about 500, about 500 to
about 700, about 500 to about 600, about 550 to about 700, about 550 to about 650
µg/cm /h).
In one embodiment the composition delivers levamisole at an average post-
lag flux rate of at least 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850,
900, 950, 1,000, 1,050, 1,100, 1,150, 1,200 µg/cm /h, and useful ranges may be
selected between any of these values (for example, from about 300 to about 1200, about
300 to about 1100, about 300 to about 850, about 300 to about 700, about 300 to about
550, about 400 to about 1200, about 400 to about 1050, about 400 to about 950, about
400 to about 650, about 500 to about 1200, about 500 to about 1100, about 500 to
about 1000, about 500 to about 950, about 500 to about 850, about 500 to about 700,
about 550 to about 1200, about 550 to about 1150, about 550 to about 1000, about 550
to about 700, about 550 to about 600, about 650 to about 1200, about 650 to about
1000, about 650 to about 800, about 650 to about 700, about 750 to about 1200, about
750 to about 1100, about 750 to about 1000, about 750 to about 900, about 750 to
about 800, about 800 to about 1200, about 800 to about 1000, about 800 to about 900
950 to about 1200, about 950 to about 1150, about 950 to about 1100, about 950 to
about 1000, about 1000 to about 1200, about 1000 to about 1150, about 1000 to about
1100, about 1100 to about 1200 µg/cm /h).
In one embodiment the composition delivers moxidectin at an average post-
lag flux rate of at least 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850,
900, 950, 1,000, 1,050, 1,100, 1,150, 1,200 ng/cm /h, and useful ranges may be
selected between any of these values (for example, from about 300 to about 1200, about
300 to about 1100, about 300 to about 850, about 300 to about 700, about 300 to about
550, about 400 to about 1200, about 400 to about 1050, about 400 to about 950, about
400 to about 650, about 500 to about 1200, about 500 to about 1100, about 500 to
about 1000, about 500 to about 950, about 500 to about 850, about 500 to about 700,
about 550 to about 1200, about 550 to about 1150, about 550 to about 1000, about 550
to about 700, about 550 to about 600, about 650 to about 1200, about 650 to about
1000, about 650 to about 800, about 650 to about 700, about 750 to about 1200, about
750 to about 1100, about 750 to about 1000, about 750 to about 900, about 750 to
about 800, about 800 to about 1200, about 800 to about 1000, about 800 to about 900
950 to about 1200, about 950 to about 1150, about 950 to about 1100, about 950 to
about 1000, about 1000 to about 1200, about 1000 to about 1150, about 1000 to about
1100, about 1100 to about 1200 ng/cm /h).
In one embodiment the platform composition may be effective to reduce
faecal egg count by at least 90, 95, 96, 97, 98 or 99%.
Although the present invention and its advantages have been described in
detail, it should be understood that various changes, substitutions and alterations can be
made herein without departing from the spirit and scope of the invention as defined in
the appended claims.
The present invention will be further illustrated in the following Examples
which are given for illustration purposes only and are not intended to limit the invention
in any way.
EXAMPLE 1 –STABILITY STUDIES
1. Solvent Stability
The purpose of these studies was to identify solvents and co-solvents to
optimise solubility of actives and the physical/chemical stability of product.
The solubility, and recovery after one month, of levamisole base and/or
abamectin were measured in a range of solvents, as shown in Table 1.
Table 1. Solubility data for solvents which were used individually to check the stability of
the two actives levamisole base and abamectin
Solvent Active Maximum % Recovery after
Solubility %w/w 1 month at 50°C
Tripropylene glycol Lev. Base 38 97.7
methylether (TPGME) Abamectin 8 78.7
Dimethyl Isosorbate Lev. Base 37 101.3
(DMI)
Isosorbide Abamectin At least 1 89.3
Triacetin Lev. Base 13 98.1
Abamectin 3 83.8
Isopropyl Mirystate Lev. Base 4 115.2
Abamectin At least 1 96.9
AGNIQUE AMD 810 Lev. Base At least 20 102.6
Abamectin At least 1 85
AGNIQUE AMD 10 Lev. Base At least 20 94.6
Abamectin At least 1 84
Teric 169 Lev. Base 19 101.8
Glycerol Formal Lev. Base More than 50 101.5
Solvent Active Maximum % Recovery after
Solubility %w/w 1 month at 50°C
Isopropyleneglycol Lev. Base 62 101.2
Estol 1526 Lev. Base 9 101.2
Tetraglycol Lev. Base 49 100.9
DMSO Lev. Base At least 20 98.9
Propylene Glycol Lev. Base 19 96.7
Ecoteric T80 Lev. Base At least 20 96.6
Dipropylenglycol Lev. Base 16 94.9
dimethylether
Cremophor Lev. Base At least 20 91.1
Tersperse 4894 Lev. Base At least 20 91
Soy Bean Oil with mixed Lev. Base At least 20 87.5
tocopherols
PGOD Propylene Glycol ML 2 92.9
Octanoate Decanoate
Crodamol ML At least 1 89.9
Polysorbate 20 Lev. Base At least 20 68.3
Abamectin At least 1 76.6
DMSO Lev. Base At least 20 98.9
Abamectin At least 1 76.5
Ecoteric T80 Lev. Base At least 20 96.6
Abamectin At least 1 71.6
Dipropylenglycol Lev. Base 16 94.9
dimethylether
Abamectin At least 1 70.6
Isopropyleneglycol Lev. Base 62 101.2
Abamectin 7 69.1
Tetraglycol Lev. Base 49 100.9
Abamectin 8 68.9
Glycerol Formal Lev. Base More than 50 101.5
Abamectin 19 59.1
Cremophor Lev. Base At least 20 91.1
Abamectin At least 1 58.7
Solvent Active Maximum % Recovery after
Solubility %w/w 1 month at 50°C
Span 80 Lev. Base At least 20 72.1
Abamectin At least 1 79.1
Soy Bean Oil with mixed Lev. Base At least 20 87.5
tocopherols
Mineral oil Lev. Base 0.51 117.6
PEG400 Abamectin At least 1 81.3
Span 80 Abamectin At least 1 79.1
2. Abamectin stability
The purpose of this study was to examine the stability of abamectin in
glycerol formal (GF) alone and solvent systems containing complexing (e.g. PVP),
acidifiers (e.g. malic acid) and chelating agents (e.g. EDTA) in combination with glycerol
formal.
Table 2. Stability data for Levamisol base and abamectin in solvent system containing
glycerol formal (GF).
No. Formulation % Abamectin recovery
After 1 week at 50°C
1 Lev + Aba + GF 89.1
2 Lev + Aba + GF + Malic (0.5%) 94.5
3 Lev + Aba + GF + oxalic (0.5%) 94.0
4 Lev + Aba + GF + citric (2.0%) 93.3
Lev + Aba + GF + PVP (5.0%) 93.4
6 Lev + Aba + GF + EDTA (0.1%) 91.2
7 Lev + Aba + GF + methionine (2.0%) 83.9
As shown in Table 2, the percentage recovery of abamectin after one week at
50°C was highest in those formulations that contained malic, oxalic, and citric acid, and
PVP. A formulation comprising levamisole, abamectin and glycerol formal did not
perform as well as the formulations containing malic, oxalic, and citric acid, and PVP.
Other solvent systems comprising tripropylene glycol methylether (TPGME),
isopropylenglycol and tetraglycol to replace glycerol formal were evaluated.
TPGME was found to be a good candidate.
3. Carrier stability
These studies looked at the stability of compositions of the invention which
may comprise the carriers dimethyl isosorbate (DMI), triacetin, agnique 810, and
isopropyl mirystate (IPM) if necessary as a penetration enhancer.
This study also looked at tripropylene glycol methylether (TPGME) or
tetraglycol or isopropyleneglycol.
This study also further analysed the effect of the following on stability.
? The addition of acidifiers. e.g. Malic acid
? The addition of complexing agents. e.g. PVP.
? Use of non polar solvents. e.g. limonene.
Table 3. Formulation stability (Stability data after two weeks stored at 50 ?C)
# Ingredients % Recovery after 2
weeks
GF DMI Triacetin PVP + malic EDTA PGOD Isopropyl Limonene Agnique Agnique Levamisole Abamectin
acid 5%- Myristate 810 10 base
0.5%
1 12% 60% QS 101 83
2 12% 60% v QS 99 81
3 12% 60% QS 102 94
4 12% 60% v QS 111 88
32% 35% QS 100 70
6 32% 35% v QS 94 68
7 12% 30% 30% QS 97 87
8 12% 30% 30% v QS 96 82
9 12% 30% 30% v 0.1% QS 101 82
22% 35% QS 10% 105 79
11 22% 35% v QS 10% 99 76
12 12% 10% QS 91 70
13 32% 10% QS 103 78
Table 4. Formulation stability (stability data after two months stored at 30 ?C, 40 ?C and 50 ?C)
Formulation Ingredients Active % Recovery after 2 months
Tetraglycol IPM TPGME Isopropylene Triacetin Limonene 30 ?C 40 ?C 50 ?C
glycerol
14 20% 42 QS Levamisole 97.3
Abamectin 96.7 94.5 64.8
10% 6% 42 QS Levamisole 99.7
Abamectin 95.8 87.4 68.4
16 12% 7% 42 QS Levamisole 97.5
Abamectin 94.6 89.1 68.5
17 19% 42 QS Levamisole 98.1
Abamectin 91.2 85.7 62.2
As shown in Table 3, DMI, triacetin and limonene demonstrated good
recovery of levamisole and abamectin when incorporated into the formulation.
As shown in Table 4 each of the formulations tested demonstrated good
recovery of levamisole and abamectin after two months at 30°C, reduced but still good
recovery of abamectin after two months at 40°C, and reduced abamectin recovery after
two months at 50°C.
4. Stability with formulations comprising surfactants
The purpose of this study was to examine the stability of the formula which
may comprise surface active agents such as surfactants.
The formulation of the platform composition is given in Table 5.
Table 5. Test composition
Ingredient Classification Quantity
Abamectin or Moxidectin Macrocyclic lactone 1
Levamisole (Base) Imidazothiazole derivative 20
Triacetin glycerin triacetate / glycerol triester 42
Isopropyl mirystate (IPM) FA ester 10
tripropylene glycol Glycol ether 6
monomethyl ether (TPGME)
Limonene cyclic terpene QS (21)
TOTAL 100
A screen of a various surfactants was conducted to improve the formulation
stability of the test composition containing 20% w/w Levamisole base in combination
with either 1 % w/w Abamectin or 1 % w/w Moxidectin. Three temperatures (RT, 4.5°C
and -20°C) were used to monitor for phase separation and/or drug crystal formation
every one or two days from 6 days. Each surfactant was added to the test composition as
a percentage of weight, therefore changing the concentrations of the original ingredients.
However, most of the tests used less than 4% of each surfactant. Only in the 5% and
% Brij 93 samples was the higher concentration of surfactant present likely to have an
effect on the test composition.
The formulations were studied at room temperature (24 ± 1°C) and fridge
temperature (4.2–4.5°C).
As shown in Table 6 each of the surfactants tested maintained the solubility
of the test composition at room temperature.
Brij 93 (polyoxyethylene (2) oleyl ether) was effective in maintaining the
stability of the test composition at fridge temperature (~4°C).
Table 6. List of selected and tested surfactants for stability of test composition
Agent HLB** RT Fridge
- - S US
Brij 93 4.5 ± 0.4 S S*
Brij 78 15.3 S US
Brij 72 4.9 S US
Brij 52 5.0 S US
Tocopherol 6.0 S US
Span 20 8.6 S US
Span 60 4.7 S US
Span 80 4.3 S US
Lauroglycol 5.0 S US
Pluronic P 123 7 – 9 S US
Tween 80 15 S US
Labrafil M 4.0 S US
PC-3 (lethicin) 8.5 ND -
US = unstable, phase separation, crystals
S = stable, no crystals
ND = not dissolvable
* = stable for at least 12 days
** = at RT
Table 2. Stability study using Brij 93 for the test composition
% RT Fridge Fridge Fridge Freezer Freezer
weight (2/3 days) (4 days) (6 days) (2 days) (4 days)
0.2 S US – 1 US – 1 US – 1 - -
0.5 S US – 1 US – 1 US – 1 - -
1.0 S US – 1 US – 1 US – 1 - -
1.5 S US US – 1 US – 1 - -
2.0 S S US – 1 US – 1 US – 1 -
3.0 S S US – 1 US – 1 US -
3.5 S S US – 2 US – 1 - US – 3
4.0 S S US – 2 US – 1 - US – 3
KEY Stability and type;
US = unstable, two phases, minimal crystal formation, reversible on
shaking
US – 1 = unstable, phase separation, irreversible crystal formation
US – 2 = unstable, no phase separation, irreversible crystal formation
US – 3 = unstable, phase separation, but no crystal formation
S = stable, no phase separation, no crystal formation
EXAMPLE 2 –EX VIVO STUDIES
. Permeability studies
This example describes the use of the platform composition to deliver a
range of different actives across the skin of a range of different animals (cow, horse,
rabbit).
The actives investigated in this example are
? levamisole base (anthelmintic),
? macrocyclic lactones (abamectin and moxidextin) (anthelmintics),
? hydrocortisone (steroidal anti-inflammatory),
? metoclopramide (antiemetic),
? cetirizine (antihistamine), and
? diphenhydramine (anti-histamine).
The characteristics for each of the actives tested are shown below in Table 7.
Table 7. Characteristics of the APIs tested
API Solubility Mol logP pKa pKa pKa MP
(Aq) Weight (acidic) (acidic) (basic) (? C)
Abamectin Insoluble 873 4.4 156
Levamisole (base) Insoluble 204 1.8 8 60
Moxidectin Insoluble 640 6.0 150
Diphenhydramine
Insoluble 292 3.5 8.9 168
Cetirizine 2HCl 10mg/mL 462 3.0 2.2 2.9 7.8 112.5
Freely
Metacloprimide HCl 300 2.6 9.3 147
soluble
Hydrocortisone
Soluble 263 1.6 12.6 -2.8 220
(base)
The formulation of the platform composition is given in Table 8.
Table 8. Formulation for abamectin/levamisole base formulation
Ingredient Classification Quantity
Abamectin anthelmintic active 1
Levamisole base anthelmintic active 20
Triacetin glycerin triacetate / glycerol triester 42
Isopropyl mirystate (IPM) FA ester 10
tripropylene glycol glycol ether 6
monomethyl ether (TPGME)
Limonene cyclic terpene QS (21)
TOTAL 100
Table 9. Formulation for moxidectin/levamisole base formulation
Ingredient Classification Quantity
Moxidectin anthelmintic active 1
Levamisole base anthelmintic active 20
BHT (Butylated hydroxytoluene) anti-oxidant 0.1
Ethanol (EtOH) solvent 1
Butyl cellosolv acetate (BCA) solvent 5
tripropylene glycol monomethyl glycol ether 6
ether (TPGME)
Isopropyl mirystate (IPM) FA ester 10
Triacetin glycerin triacetate / glycerol triester 50
Limonene cyclic terpene QS (~12)
TOTAL 100
Table 10. Formulation for non-anthelmintic actives
Ingredient Classification Quantity
API Active 1
Triacetin glycerin triacetate / glycerol triester 54.31
Isopropyl mirystate (IPM) FA ester 6.47
BHT (Butylated hydroxytoluene) Anti-oxidant 0.13
Brij 93 Surfactant 6.47
tripropylene glycol monomethyl Glycol ether 7.76
ether (TPGME)
Limonene cyclic terpene QS (~24)
TOTAL 100
A further formulation as follows was examined.
Table 11. Formulation for abamectin/levamisole combination
Ingredient Classification Quantity (%)
Abamectin Active 1
Levamisole base Active 20
TPGME Glycol ether 6
IPM FA ester 10
Triacetin glycerin triacetate / 42
glycerol triester
BHT Anti-oxidant 0.1
Limonene cyclic terpene q.s. (~23
A further formulation as follows was examined.
Table 12. Modified formulation for abamectin/levamisole combination
Ingredient Classification Quantity (%)
Abamectin Active 1
Levamisole base Active 20
TPGME Glycol ether 6
IPM FA ester 5
Triacetin glycerin triacetate / 42
glycerol triester
Brij 93 Surfactant 5
BHT Anti-oxidant 0.1
Limonene cyclic terpene q.s. (~23
.1 Methods
.1.1 Skin Sample Preparation
Full thickness rabbit or horse skin samples and half thickness bovine (~500
µm) skin samples were excised from different animals above the scapular and over the
withers regions. The bovine samples were obtained from 2–5 year old steers, horse
samples were obtained from the abattoir, and rabbit skin from euthanized animals after
research studies. Immediately after excision, the skin was wrapped in aluminium foil, put
into plastic bags, and stored at below 6ºC for delivery to the research laboratory. Hair of
the collected skin was cut using a hair clipper with surgical blade 50 (0.4 mm) and the
underlying excessive fat layer was also carefully removed from the hypodermis using a
scalpel (size 20) and discarded. The skin samples were then frozen at = -20°C for further
preparation and stored for no more than 16 weeks prior to use.
Before each experiment, partially thawed skin was sheared to remove the
entire hair layer and skin samples of 500 ± 30 µm thickness were cut using a
dermatome. The dermatome was fitted with duplex blades from Stericut, Reference S11-
103. Skin samples with epidermis/dermis were then finally cut into approximately 2 to
2.5 cm and placed on a Franz cell between the donor (containing 1 mL formulation) and
receptor compartments (12 mL).
The ex vivo permeation of each drug was determined by using Franz
diffusion cell; VTC 200 by Logan Instruments Corporation (New Jersey, USA), which takes
its name from Dr. Thomas Franz who first popularised this method. This method has
been used in many skin permeation studies, including topical and transdermal drug
delivery formulations, as well as opthalmics, cosmetics, skin care products and
pesticides. This system is approved by the FDA. See "Guidance for Industry Nonsterile
Semisolid Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing,
and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation", U.S.
Department of Health and Human Services, Food and Drug Administration, Center for
Drug Evaluation and Research (CDER), May 1997, SUPAC-SS, CMC 7.
Briefly described, the Franz Cell chamber is an in vitro skin permeation assay
that consists of two primary chambers separated by a membrane. Bovine skin was used
as the membrane. The sub-cutaneous layer was first removed by scalpel having a
thickness of 0.1 to 1 mm. The skin sample was placed in propylene glycol 40% v/v (q.s.
Milli Q water) and phosphate buffer to pH 7.4 at a temperature of 39°C ± 1°C and
equilibrated for 12 hours. The bovine epidermis hair was sheared to 0.4 cm and the
remaining hair sheared to just above the stratum corneum layer. The epidermis and
some dermis was removed (approximately 500 µm) and sections were cut to 2 cm by 2
cm for each Franz cell unit. The test composition was loaded into a loading volume of 1.0
mL and applied to the membrane via the top chamber. The bottom chamber contains
fluid from which samples are taken at regular intervals for analysis. This testing
determines the amount of active that has permeated the membrane at each time point.
The chamber is maintained at a constant temperature of 37° C.
The moxidectin, abamectin and levamisole tests on bovine skin was tested
using the Franz cell system FDC-6 (Logan Instruments, USA). The reminder of the APIs
were tested using a new Franz cell system DHC-6T (Logan Instruments, USA). Further
more, the new test included the use of dry heated cell as opposed to a water bath,
syringe sample collection and the use of Teflon (TFE) coated cells to prevent bubble
formation.
The samples were taken up to 58 hrs post-administration and drug
concentrations were measure by UHPLC.
The in vitro method (Franz Cell) differs to in vivo because it uses dead skin
with no functioning vascular system. Therefore, the drug needs to permeate through the
entire piece of skin before being collected in the receptor fluid for analysis. To compare
the actual flux rates of the drugs, the lag time before drug enters the receptor fluid was
ignored, and the rate of increasing concentration was calculated from when the active
was detected in the fluid. This removes some of the variability due to skin thickness.
The bovine skin was mounted on the receptor compartment with the SC side
facing upwards into the donor compartment (12 mL and 1 mL, respectively). Receptor
medium was composed of propylene glycol (PG) 39%, ethanol (1%), and buffer
phosphate 0.1M (19% NaH PO 0.1M and 81% Na HPO 0.1M, pH 7.4). Ethanol was
2 4 2 4
added to the receptor medium to maintain sink condition for the lipophilic drugs which
only partially mimics in vivo where blood flow provides constant elimination by transport
of the drug away from the site of delivery. The medium was proved to have no drug
degradation at 40°C for 12 days. Buffer was used due to the presence of basic the drug:
LEV (pK = 8). The available diffusion area of cell was 1.77 cm . The receptor
compartment was maintained at 39 ± 1°C and stirred by a magnetic bar at 600 rpm,
which also helps improve the problem of a static diffusion cell system (i.e. increased drug
dissolution). At periodic intervals, samples (400 µL) were withdrawn from the sampling
port and immediately replaced by an equal volume of fresh receptor medium which was
pre-warmed at 39 ± 1°. The samples were then analyzed by an HPLC method with UV
detection. All formulations were tested at least in triplicate.
.1.2 Moxidectin Skin Deposition Study
The amount of moxidectin accumulating in the bovine skin was determined
using whole skin thickness (approx. 4 cm) and split skin thickness (approx. 500 µM) after
72 hours. The skin tissue was physically broken down using a Gentle MACS dissociator
(Miltenyi Biotec GmbH, Germany) with 5 mL of methanol added into each sample. The
dissociator setting was RNA-02.01 with M-type tubes for 90 seconds. Centrifuged
samples had the supernatant collected and diluted 2 times with ACN before being
analysed by the HPLC method.
.2 Results
.2.1 Permeability Studies
The formulation of Table 9 was tested for its flux across bovine skin with n =
. The results are shown in Figure 2 that shows the permeability of moxidectin over 72
hours. The moxidectin had a flux rate of 475 ± 185.2 ng/cm /hr from linear section of
profile (R = 89.4%). Error bars are standard deviation.
The formulation of Table 9 was tested for its flux across bovine skin with n =
. The results are shown in Figure 3 that shows the permeability of levamisole over 72
hours. Levamisole has a flux rate of 949.6 ± 80.8 µg/cm /hr from linear section of profile
(R = 99.4%). Error bars are standard deviation.
A commercial formulation was also tested. The Eclipse PO formulation
contains abamectin and levamisole. The results are shown in Figure 4 that shows the
permeability of abamectin in Eclipse over 72 hours with n =3. The abamectin had a flux
rate of 33.9 ± 26.3 µg/cm /hr. Error bars are standard deviation. The results are shown
in Figure 5 that shows the permeability of levamisole in Eclipse over 72 hours with n =3.
The levamisole had a flux rate of 204.4 ± 17.1 µg/cm /hr. Error bars are standard
deviation.
The formulation containing diphenhydramine exhibited a flux rate of 41.47 ±
.18 µg/cm /hr in rabbit skin (see Figure 6), 25.3 ± 1.9 µg/cm /hr in horse skin (see
Figure 7), and 95.1 ± 33.1 µg/cm /hr in bovine skin (see Figure 8) as shown below in
Table 13.
Table 13. Diphenhydramine permeability through rabbit, horse and bovine skin.
Time Rabbit Horse Bovine
Mean SD Mean SD Mean SD
(µg/cm2) (µg/cm2) (µg/cm2)
0 0 0 0 0 0.0 0.0
2 0 0 0 0 132 114
4 0 0 0 0 278 52.1
6 0 0 0 0 388 77.5
8 0 0 0 0 621 100
9.25 16.0 9.25 16.0
378 242 375 97.2 1765 624
24 455 286 466 144 2290 816
26 542 267 482 136 2514 872
28 594 236 529 124
44 1025 196 1011 50.0 3157 1256
46 1168 330 1052 85.9
48 1320 340 1113 86.3 3218 1326
50 1414 376 1127 52.9
52 1529 429 1208 103 3272 1331
68 2425 749 1514 62.8 3318 1394
70 2539 782 1560 57.2 3229 1411
72 2547 787 1569 82.3 3408 1428
The formulation containing cetirizine exhibited a flux rate of 4.6 ± 2.7
µg/cm /hr in rabbit skin (see Figure 9), 4.4 ± 1.5 µg/cm /hr in horse skin (see Figure
), and 77.9 ± 14.5 µg/cm /hr in bovine skin (see Figure 11) as shown below in Table
Table 14. Cetirizine permeability through rabbit, horse and bovine skin.
Time Rabbit Horse Bovine
Mean SD Mean SD Mean SD
(µg/cm2) (µg/cm2) (µg/cm2)
0 0.00 0.00 0.0 0.0 0 0
2 0.00 0.00 0.0 0.0 67.5 55.9
4 0.00 0.00 0.0 0.0 86.0 69.7
6 9.13 15.82 0.0 0.0 26.7 11.5
8 6.18 10.70 0.0 0.0 452.1 29.9
22.6 7.60 13.9 0.0
30.6 4.64 43.1 3.4 1152 67.1
24 37.9 6.80 48.8 8.7 1201 101.4
26 40.0 4.48 50.3 11.8 1484 88.9
28 43.6 4.12 61.1 21.5
44 147 81.9 155 50.9 3726 799
46 161 87.8 176 65.6
48 162 82.3 183 76.6 3726 799
50 171 81.8 192 72.1
52 186 91.7 206 70.7 3879 829
68 280 148 261 83.2 4619 994
70 285 133 262 81.4 4799 1277
72 275 123 263 87.6 4723 1154
The formulation containing hydrocortisone exhibited a flux rate of 2.9 ± 0.9
µg/cm /hr in rabbit skin (see Figure 12), 10.3 ± 5.8 µg/cm /hr in horse skin (see Figure
13), and 61.3 ± 19.1 µg/cm /hr in bovine skin (see Figure 14) as shown below in Table
Table 15. Hydrocortisone permeability through rabbit, horse and bovine skin.
Time Rabbit Horse Bovine
Mean SD Mean SD Mean SD
(µg/cm2) (µg/cm2) (µg/cm2)
0 0 0 0 0 0 0
2 0 0 0 0 1.16 2.02
4 0 0 0 0 57.8 84.8
6 4.63 8.02 0 0
8 12.41 14.58 0 0 287 189
4.12 0.88 2.33 2.02
19.83 6.49 19.8 7.76 981 187
24 43.41 35.17 27.0 14.6 1227 296
26 65.56 47.41 29.3 17.5 1470 382
28 47.36 34.05 41.1 31.7
44 112 52.5 160 141 2645 760
46 113 56.2 179 155
48 116 55.2 200 162 2686 1029
50 131 62.1 245 208
52 2870 1050
68 157 49.1 423 300 3084 1279
70 158 46.0 438 300 3270 1349
72 166 51.4 448 294 3016 1101
The formulation containing metoclopramide exhibited a flux rate of 38.6 ±
9.2 µg/cm /hr in rabbit skin (see Figure 15), 67.0 ± 24.6 µg/cm /hr in horse skin (see
Figure 16), and 109.4 ± 11.8 µg/cm /hr in bovine skin (see Figure 17) as shown below in
Table 16.
Table 16. Metoclopramide permeability through rabbit, horse and bovine skin.
Time Rabbit Horse Bovine
Mean SD Mean SD Mean SD
(µg/cm2) (µg/cm2) (µg/cm2)
0 0 0 0 0 0 0
2 0 0 0 0 16.2 28.0
4 0 0 0 0 251 83.6
6 0 0 0 0 456 205
8 0 0 68.1 118 960 378
32.3 28.0 679 596
685 235 1372 181 2188 322
24 772 214 1533 404 2252 440
26 831 191 1477 296 2718 482
28 925 233 1640 370
44 1537 167 2604 722 4779 502
46 1612 231 2784 831
48 1567 257 2910 986 5169 653
50 1782 398 2930 1041
52 1968 346 3078 929 5394 340
68 2391 569 3350 948 5336 459
70 2387 469 3440 678 5613 405
72 2515 643 3454 1043 5346 711
A summary of the lag T, flux rate, APC and extent (72 hrs) for
diphenhydramine, cetirizine, hydrocortisone and metoclopramide is shown in Table 17
below.
Table 17. A summary of the lag T, flux rate, APC and extent (72 hrs) for
diphenhydramine, cetirizine, hydrocortisone and metoclopramide.
Active Skin lag T Flux APC Extent
type 72h
2 -8 2
(hrs) µg/cm /hr cm/s ×10 µg/cm
Diphenhydramine Rabbit 13.6 41.5 46.3 2547
(2.01) (10.2) (14.3) (787)
Horse 6.03 25.3 28.5 1569
(4.17) (1.91) (1.49) (82.3)
Bovine 0.72 95.1 61.9 3408
(0.27) (33.1) (25.9) (1428)
Cetirizine Rabbit 10.3 4.61 4.99 275
(4.55) (2.69) (2.24) (123)
Horse 8.83 4.41 4.78 263
(2.32) (1.53) (1.59) (87.6)
Bovine 2.61 77.9 85.8 4723
(1.42) (14.5) (21.0) (1154)
Hydrocortisone Rabbit 8.14 2.92 3.01 166
(5.08) (0.96) (0.93) (51.4)
Horse 21.6 10.3 8.14 448
(16.9) (5.83) (5.35) (294)
Bovine 2.44 61.2 54.8 3016
(1.27) (19.1) (20.0) (1101)
Metoclopramide Rabbit 4.84 38.6 45.7 2515
(4.18) (9.21) (11.7) (643)
Horse 3.11 67.0 62.7 3454
(3.10) (24.6) (18.9) (1043)
Bovine 1.07 109 97.1 5346
(0.50) (11.8) (12.9) (711)
The cumulative amount (Qt) of active permeated through the skin was
calculated using the following equation:
t ?1
Qt ?[VrCt ? VnCn]
t ?0
where Vr is the volume of the receptor chamber (12 mL), Ct is the drug
concentration in the receptor chamber at each time interval, Vn and Cn are the volume
and concentration for the cumulated number of samples withdrawn and A is the relative
diffusion surface area (1.77 cm ). The amount of active permeated over 24 hours was
plotted over time (hours). Regression analysis was carried out on linear regions of each
plot. The lag time, Lag , was then calculated using the steady state flux (Jss) by
measuring the linear portion of the cumulative penetration curve to the time axis where
drug release was equal to zero, such that the following formula can be deducted:
Lag ?
where, h is the skin membrane thickness (µm) and D is the diffusion coefficient
provided that the membrane thickness is available. On the permeation profile the Flux
-2 -1
(µg·cm ·h ) was represented by the y-axis and time (t) was plotted on the x-axis. The
apparent permeability coefficient (P ) was calculated using the following equation.
P ? ?d ? / dt ? ?C
app r o
where P is determined with the final units as cm·s , X is the amount of active
app r
in the receptor chamber, A is the surface area of skin exposed (cm ), and C is the initial
active concentration at specific time point (µg·mL ).
The formulations of Table 11 and Table 12 were also tested against Eclipse.
Both abamectin and levamisole were able to permeate across in vitro bovine
split skin over 72 hours. Figures 18 and 19 show the cumulative drug mass (µg/cm ) over
time (hrs) for abamectin and levamisole, respectively.
Table 18. Permeability parameters for abamectin
Papp
Lag T Extent 48 hrs Extent 72 hrs Flux
Abamectin (cm/s × 10-
(hrs) (µg/cm2) (µg/cm2) (µg/cm2/hr)
6.12 ± 105.45 ± 198.92 ±
Eclipse PO 2.77 ± 0.71 3.61 ± 1.32
0.58 33.71 72.39
Formulation of 6.91 ± 186.34 ± 186.34 ±
2.66 ± 0.38 3.34 ± 0.56
Table 11 1.46 30.95 30.95
Formulation of 21.15 ± 85.94 ± 10.66 166.96 ±
4.73 ± 1.76 3.03 ± 0.71
Table 12 9.56 * 38.79
* = 60 hrs
Table 19. Permeability parameters for levamisole.*
Extent 48 Flux
Lag T Extent 72 hrs Papp
LEV hrs (µg/cm2/hr
(hrs) (µg/cm2) (cm/s × 10-8)
(µg/cm2) )
0.31 ± 47659.57 ± 77606.34 ± 991.83 ± 1409.64 ±
Eclipse PO
0.23 2821.42 11011.15 35.46 200.01
Formulati
2.62 ± 49697.63 ± 83933.69 ± 982.76 ± 1524.57 ±
on of
1.24 6850.21 17451.81 112.13 316.99
Table 11
Formulati
2.54 ± 34080.96 ± 68480.85 ± 784.71 ± 1262.05 ±
on of
0.78 8486.37 15841.05 84.17 287.84
Table 12
* Data from split skin samples
Table 18 presents the permeability parameters for ABM from each
formulation. At steady-state, ABM was observed to have a P of 3.3 ± 0.6 cm/s × 10
from the Formulation of Table 11, while the Formulation of Table 12 had a P of 3.0 ±
0.7 cm/s × 10 . The mean lag time for the Formulation of Table 11 was significantly
shorter to that of the Formulation of Table 12, 6.9 hours compared to 21.2 hours,
respectively (p-value < 0.01). A shorter lag time is ideal, indicating that steady state is
reached more quickly. In this case, although the lag time for the Formulation of Table
12was much longer than the Formulation of Table 11 it was able to almost reach a similar
mean permeability extent after 72 hours, 166.9 and 186.3 µg/cm , respectively.
Furthermore, this delayed ABM permeability but similar extent of permeability across the
bovine skin, explains the improved flux observed from the Formulation of Table 12.
Interestingly, the Formulation of Table 12 had a higher flux (permeability rate) of 4.6 ±
1.8 µg/cm /hr, while Formulation of Table 11 had a flux of 2.7 ± 0.4 µg/cm /hr, although
these results were not significantly different (p-value > 0.05). For clarity, flux is the slope
of the amount permeated over time, hence the delayed ABM permeation from
Formulation of Table 12 compared to Formulation of Table 11, yet similar permeation
extent, meant the slope (flux) from Formulation of Table 12 was steeper compared to
that of Bola (original). Finally, the Formulation of Table 11 and Eclipse PO had generally
similar ABM permeability parameters, see Table 2. The one way ANOVA results are given
in Table 3.
For Levamisole, the Formulation of Table 11 had a lag time of 2.6 ± 1.2
hours and the Formulation of Table 12 had a similar lag time of 2.5 ± 0.8 hours (p-value
> 0.05). A summary of the permeability parameters describing the in vitro permeability
of LEV are given in Table 4. The one way ANOVA results are given in Table 5.
.2.2 Moxidectin Deposition Study
The proportion of the drug at the three compartments, donor, skin and
receptor at 72 hours is shown below.
Table 20. Table showing the proportion of the drug in the three compartments: donor,
skin and receptor at 72 hours.
Receptor Skin Donor
Whole skin 3% 32% 65%
500 µm skin 31% 18% 51%
6. Upper skin permeability
The purpose of this study is to test the permeability of the active ingredients
through the upper skin layer only. The upper skin provides the "real" barrier to the
transport of actives across the skin. In vivo, once an active penetrates the skin it is then
transported away by a network of blood vessels.
When testing whole skin in vitro, the whole skin provides a variable result
and probably gives an artificially low estimate of permeability for lipophilic compounds
that tend to be trapped in the subcutaneous fat when no blood vessels are present to
transport the actives away. More hydrophilic compounds progress faster into the receptor
fluid.
6.1 Method
A skin sample is prepared for the Franz cell technique, which has been
described above. The skin sample is prepared absent the subcutaneous fat.
The test composition is used to determine the flux rate of moxidectin and
levamisole.
6.2 Result
A result showing a higher flux rate that for whole skin moxidectin and/or
levamisole demonstrates that moxidectin and/or levamisole pass the upper skin barrier
easily and that the sub cutaneous layers limit their passage in vitro.
7. Effect of limonene on skin disruption
The purpose of these studies was to examine the effects of limonene on skin
disruption.
7.1 Method
The Franz chamber, as described above, was used to determine permeability.
The test composition was carried out with three different concentrations of
limonene: 6, 12 and 24% by weight.
7.1.1 Histology
Histology was carried out to look at the effect of the formulation on the
degree of stratum corneum disruption. The skin tissue was sectioned and stained and
the examined under a light microscope or electron microscope to visualize or
differentially identify microscopic structures through the use of histological stains.
7.1.2 FTIR
Fourier transform infrared spectroscopy (FTIR) was used to measure how
well the samples absorbed light at each wavelength.
Lipid disruption was monitored by IR spectrum. A change in water content
observed in IR spectrum was used as an indication of lipid disruption.
8. Results
8.1.1 Histology
Microscopic analysis of the membrane exposed to 6% limonene showed the
top layer begins to lift from the epidermis. Membrane exposed to 12% limonene
exhibited a broken layer of epidermis. Membrane exposed to 24% limonene exhibited a
highly disrupted and mashed layer of epidermis.
The results show that the top layer of the epidermis is damaged. However,
this damage is reversible as the top layer is refreshed almost constantly. The results also
showed that there was no damage to the dermis or the epidermis.
Histological analysis also showed that there was increased oil in the
epidermis, which suggests that the limonene may result in pushing cells apart to create
channels through which the active ingredients can more easily pass.
8.1.2 FTIR
A typical IR spectrum for untreated bovine skin is shown as Figure 18 where
A = Amide II (weak), B = Amide I, C = CH2 symmetrical stretching, D = CH2
asymmetrical stretching, and E = water content.
Shown below in Table 21 is a comparison of IR spectrum data for untreated
and treated skin.
Table 21. Comparison of IR spectrum data for untreated and
treated skin
Formulation E D C B A
(AUC) (cm-1) (cm-1) stretching stretching
(cm-1) (cm-1)
Untreated skin 302.5 ± 2920.2 ± 0.7 2850.9 ± 1634.7 ± 1547.0 ± 7.5
13.3 0.4 0.6
PE 6% PO 250.4 ± 2929.1 ± 3.7 2855.1 ± 1636.0 ± 1555.7 ± 0.7
8.2 2.0 0.5
PE 12% PO 244.1 ± 2929.2 ± 4.3 2855.4 ± 1643.0 ± 1555.7 ± 0.3
8.8 1.4 6.0
24 % PO 250.6 ± 2929.0 ± 2.0 2852.9 ± 1639.0 ± 1556.1 ± 0.2
9.2 7.2 6.1
The data suggests that the formulation does cause a significant disruption to
the structure of the SC probably by causing changes to the lipid layers. There does not
appear to be any apparent cellular damage of the SC. This (transient) disruption of the
lipid layer will potentially "open" a passage for the diffusion of drug. This is confirmed by
the FTIR studies below.
EXAMPLE 3 –CLINICAL STUDIES
Two clinical efficacy studies were carried out. The study design for each
study is summarised below.
? Study 1–Winter coat
o Control
o Test composition with no rain
o Test composition with rain 2 hours after application
? Study 2–Summer coat
o Control
o Test composition
o Comparator product (Eclipse–combination dual pour-on containing
abamectin and levamisole)
o Single-active comparator product
The purpose of study 1 was to evaluate the efficacy of the test composition
against gastrointestinal parasites in cattle with a winter coat, and to determine the effect
of rain, after application of the composition to the skin of the cattle, on the composition's
efficacy.
The purpose of study 2 was to evaluate the efficacy of the test composition
against gastrointestinal parasites in cattle with a summer coat, and to compare against
the comparator product Eclipse.
The test composition is shown below in Table 22.
Table 22. Composition for efficacy study
Ingredient Classification Quantity
Abamectin Macrocyclic lactone 1
Levamisole (Base) Imidazothiazole derivative 20
Triacetin glycerin triacetate / glycerol triester 42
Isopropyl mirystate (IPM) FA ester 10
tripropylene glycol Glycol ether 6
monomethyl ether
(TPGME)
Limonene cyclic terpene QS (21)
TOTAL 100
The test composition was observed to be a clear straw-coloured solution with
a citrus like smell, with good syringability. It was found to be free flowing, to readily wet
the hair coat and rapidly passed down the hair coat to the skin, without leaving any oily
residue.
9. Efficacy study – Winter coat
9.1 Treatment groups
The study comprised six infected beef and dairy calves per treatment group.
Treatment Groups consisted of Group 1 that remained as untreated controls,
Group 2 were animals treated with the test composition applied to a dry coat then
showered with 10 mL simulated rain 2 hours after treatment, then protected from any
rain for at least 24 hours and Group 3 were animals treated with the test composition
applied to a dry coat and then protected from any rain for at least 24 hours.
Table 23. Treatment groups
Group Treatment Animal
Number Number
1 Untreated Control 6
2 Test composition 6
mL Simulated Rain at 2 hours
3 Test composition 6
No rain for 24 hours
TOTAL 18
Each animal was treated at a rate of 1 ml/20 kg body weight, which equates
to 500 ?g macrocyclic lactone and 10 mg levamisole per kg.
9.2 Study design
This study was carried out as a randomised, stratified controlled study on
cattle, less than 12 months of age, with winter coats and a mean weight of 118.5 kg.
The test composition was administered as a single topical treatment to two
groups of dry cattle at standard label dose rates, based on individual body weight. Two
hours after treatment, one group was sprayed with 10 mL of simulated rain by overhead
nozzles, and then kept dry until 24 hours after treatment. The other pour-on group was
kept dry for 24 hours.
Efficacy of treatment was measured by faecal egg counts at 6 and 10 days
post treatment and at slaughter on Day 13. Efficacy was also measured 13 days after
treatment by abomasal, small intestinal and large intestinal worm counts, assessed by
genus and stage, relative to the parasite burden in the control group animals, with
speciation of appropriate worm genera. Lungworm burden in the control group was
investigated by counting lungworm in three animals to determine if a suitable lungworm
burden was present, and if further lungworm counts were justified.
Clinical behavioural observations and measurements and pour-on site
inspections post treatment were made. Two separate studies were performed. The first
study was carried out on beef and dairy calves with a winter coat. Testing was carried
out without and with rain 2 hours after application The second study was carried out on
beef and dairy calves with a summer coat. Testing was carried out comparing the test
composition to a comparator product and to single-active comparator product.
The animals were slaughtered at day 13/14 after treatment and faecal egg
count (FEC) and worm count measured.
The study protocol is shown below in Table 24.
Table 24. Study protocol
Activity Trial Day Dates performed/Details
Clean out drench 2 -46 Oxfendazole +Levamisole (Scanda) oral 10
ml/calf+ Metacam 2 ml Subcut Inj/calf
Clean out drench 3 -45 Ivermectin (Ivomec liquid) oral (22 ml/calf).
+ lice treatment Bendicarb (Niltime) pour on for lice (10 ml/calf).
Artificially oral -39, -36, - Orally dose calves with infective larvae via plastic
infection 29, -20, - syringe on D -39, -36, -29, -20 and D-12. See
12 detail larval dosing/artificial infection.
Faecal sampling -6, -2, 6, Day -6, Day -2, then post treatment at Days 6, 10,
, 13 13. FEC at all points, lungworm larvae at Day 10.
Quantative larval culture Day 13
Weighing -1 Weigh, Day -1
Treatment 0 Day 0. T=0 Controls (Group 1), Test composition
treated (Group 2 & 3)
Simulated rain 0 2 hours post treatment (Group 2 only). 10 mm in
approximately 30 min.
Skin observations -1, 0, 1, 4, Pre-allocation Day, 4 hours, 24 hours,
Clinical 0, 1, 12 Pre-treatment, 1 hours, 4 hours, 24 hours and 12
Observations days
Clinical 0, 1 Pre-treatment (0), 4 hours and 24 hours post
measurements treatment
Weather and -6 to 13 Activities log then Daily log Day-6 until Slaughter
general (Day 13) including weather from treatment day
observations
Slaughter 13 Recover lungs for lungworm, collect and ligate
abomasum, small intestine and large intestine for
worm count. Collect faeces for egg count/larval
culture. Collect hides and also fixed skin sections
(4 animals).
To supplement natural infection the number of larvae orally dosed was
increased as shown in Table 25.
Table 25. Total number of infective larvae dosed per calf by worm genera
Dose day Total Genera
Haemonchus Ostertagia Trichostrongylus Cooperia Oesph/Chab
Dose 1 (D -39) 1600 32 208 48 1232 80
Dose 2 (D -36) 2500 41 424 75 1844 116
Dose 3 (D -29) 4333 0 390 0 3943 0
Dose 4 (D -20) 2167 0 195 0 1972 0
Dose 5 (D -12) 3000 0 750 80 1530 660
Total (1-5) 13600 73 1967 183 10521 856
9.3 Statistics
The primary data in the study were the individual worm counts. The worm
count data was tabulated and statistically analysed including tests for normal distribution
(Bartlett’s test of equal variance) and tests for significance between the means of treated
and control groups compared using One Way Analysis of Variance (ANOVA). Efficacy of
treatment on worm count and egg counts (for each sampling) was calculated according to
the following equation using both arithmetic and geometric means:
GroupMean(untreated) ? GroupMean(treated)
% Reduction (Efficacy%)
? ?100
GroupMean(untreated)
Secondary data including the observations was tabulated including totals and
means to determine if there were any treatment effects.
9.4 Results
9.4.1 Faecal egg counts
The faecal egg counts showed that the untreated control animals (n=6) were
uniformly positive (150-500 epg) over the trial period. At allocation (Day –2) they had a
mean of 317 epg AM (296 epg GM) with the mean egg counts remaining at 300 epg AM
(284-293epg) GM at Days 6, 10 and 13. The mean of Groups 2 (n=6) and 3 (n=6), had
similar means at the time of allocation at 325 epg (AM) or 304epg (GM) for Group 2 and
308 epg (AM) or 291 (GM) for Group 3. After treatment both test composition treated
groups had uniformly negative egg counts at 6, 10 and 13 days after treatment. There
was no significant difference in group mean faecal egg counts at the time of allocation,
but the differences between control and treated groups at the post-treatment counts was
highly significant (>0.0001). There was no difference in FEC between Group 2 calves and
showered with simulated rain 2 hours post-treatment, or the Group 3 calves that were
treated and remained dry with no rain for over 24 hours, see Table 26.
Table 26. Mean faecal egg count (eggs per gram) and significance
FEC (Day-2) FEC (Day 6) FEC (Day 10) FEC (Day 13)
Group 1 - Untreated Controls
3 150 200 200 200
400 250 500 350
9 300 200 350 250
11 500 350 250 400
13 400 400 300 300
400 400 200 300
AM 316.7 300.0 300.0 300
GM 296.3 287.1 284.1 292.8
Group 2 – Test composition with simulated rain (10 mm) at 2 hours
AM 325.0 0 0 0
GM 303.9 0 0 0
% Reduction 100 100 100
P-value >0.0001 >0.0001 >0.0001
Group 3 - Test composition with no rain for 24 hours.
AM 308.3 0 0 0
GM 291.1 0 0 0
% Reduction 100 100 100
P-value >0.0001 >0.0001 >0.0001
AM= Arithmetic mean GM = Geometric mean
9.4.2 Larval cultures
Larval cultures (see Table 27) confirmed that at the time of slaughter a
mixed worm infection including large intestinal worms were present. Quantitative larval
culture analysis confirmed that no larvae could be detected in either test composition
treated group. This result indicates it is a highly effective anthelmintic and also that the
levamisole component of the test composition was effective as no surviving Cooperia
larvae (resistant) were detected.
Table 27. Larval cultures pre-treatment (-6) and 13 days after treatment (quantitative
culture)
Group Pre-Allocation Group 1 Group 2 Group 3
Trial Day -6 13 13 13
Haemonchus (%) 0 0 0 0
Ostertagia (%) 17 13 0 0
Trichostrongylus (%) 0 0 0 0
Cooperia (%) 83 72 0 0
Oesophagostomum/Chabertia 0 15 0 0
Total larvae NQ 2400 0 0
Gram of faeces cultured NA 50 g 50 g 50 g
Larvae per gram NQ 48 0 0
NQ =Not quantified, NA = Not applicable
9.4.3 Worm counts
Abomasum
Worm counts confirmed that the control animals were uniformly infected with
adult Ostertagia (1483 AM, 1335 GM) and smaller numbers of L4 stages (100AM, 49GM)
in the abomasum with only occasional Trichostrongylus axei and Haemonchus contortus
present. The test composition treatments gave complete (100%) reductions, with no
worms found. These reductions were highly significant for Ostertagia (adult and L4
stages), but there were insufficient T. axei or Haemonchus in the controls to allow
assessment and statistical analysis. The Ostertagia present were confirmed as Ostertagia
ostertagi (94.7%)and Ostertagia lyrata (5.3%), with a total of 57 male worms available
for speciation from the controls.
Table 28. Abomasal worm counts
Ostertagia spp. Trichostrongylus axei Haemonchus
contortus
th th th
Stage L4 E4 5 Stage L4/E4 5 Stage L4/E4
Group 1 - Untreated Controls
3 1000 0 0 0 0 50 0
2500 150 0 150 0 0 0
9 700 100 0 0 0 0 0
11 1150 50 0 0 0 0 0
13 2300 200 0 0 0 0 0
1200 100 0 100 0 0 0
AM 1483.3 100.0 0 41.7 0 8.3 0
GM 1335.3 49.1 0 4.0 0 0.9 0
Group 2 - Test composition with simulated rain (10 mm) at 2 hours
AM 0 0 0 0 0 0 0
GM 0 0 0 0 0 0 0
% Red 100 100 NA 100 NA 100 NA
P-value <0.0001 0.0003 NA 0.07297 NA 0.2313 NA
Group 3 - Test composition with no rain for 24 hours.
AM 0 0 0 0 0 0 0
GM 0 0 0 0 0 0 0
% Red 100 100 NA 100 NA 100 NA
P-value <0.0001 0.0003 NA 0.07297 NA 0.2313 NA
P-value for Groups 2 & 3 combined, to give greater power as the two groups
are indistinguishable with the same means and distribution of values. 2% aliquot over a
38µm sieve. AM = Arithmetic mean, GM = Geometric mean, NA = Not applicable, %
Red= % Reduction.
Small intestine
Small intestinal worm counts confirmed that the control animals were
uniformly infected with moderate Cooperia burdens, mainly adults (10,142 AM, 5912 GM)
and smaller numbers of L4 (258AM, 107GM) and E4 stages (50 AM, 16 GM) with only
occasional Trichostrongylus spp and Nematodirus spp present. The test composition
treatment gave complete (100%) reductions, with no worms found (Group 2 and Group
3). These reductions were highly significant for Cooperia (adult, L4, and E4 stages) but
there were insufficient Trichostrongylus or Nematodirus in the controls to allow
assessment and statistical analysis. The Cooperia present were confirmed as Cooperia
oncophora (99.6%) with very small numbers of Cooperia punctata (0.4%), with a total of
252 male worms available for identification from the controls. Only two male
Nematodirus were found in one animal (Tag #13) both identified as N. helvetianus, and
no male Trichostrongylus spp were found so species identification could not be
performed.
Table 29. Small intestine worm counts
Trichostrongylus
Cooperia spp Nematodirus spp
5th 5th 5th
L4 E4 L4/E4 L4/E4
Stage Stage Stage
Group 1 - Untreated Controls
3 13100 100 50 50 0 0 0
10200 400 50 50 0 0 0
9 200 0 0 0 0 0 0
11 7950 450 0 0 0 0 0
13 18700 250 50 0 0 150 0
10700 350 150 0 0 0 0
AM 10141.7 258.3 50.0 16.7 0 25.0 0
GM 5912.0 107.3 15.5 2.7 0 1.3 0
Group 2 - Test composition with simulated rain (10mm) at 2 hours
AM 0 0 0 0 0 0 0
GM 0 0 0 0 0 0 0
100 100 100 100 NA 100 NA
Reduction
P-value <0.0001 0.00029 0.00354 0.07266 NA 0.2313 NA
Group 3 - Test composition with no rain for 24 hours.
AM 0 0 0 0 0 0 0
GM 0 0 0 0 0 0 0
100 100 100 100 NA 100 NA
Reduction
P-value <0.0001 0.00029 0.00354 0.07266 NA 0.2313 NA
P-value for Groups 2 & 3 combined to give greater power, as the two groups
are indistinguishable with the same means and distribution of values. 2% aliquot over
38µm sieve. Animal #9 was recounted using another 2% aliquot to confirm count. Retest
(400 5th Stage Cooperia spp, only). AM = Arithmetic mean, GM = Geometric mean, NA
= Not applicable.
Large intestine
Large intestinal worm counts confirmed that the control animals were
uniformly infected with small numbers of Trichuris adults (15 AM, 13.6 GM) and greater
numbers of Oesophastomum adults (42AM, 39.5GM). The test composition treatment
gave complete (100%) reductions, with no worms found (Group 2, and Group 3). These
reductions were highly significant for both Trichuris and Oesophagostomum.
Differentiation for Trichuris is not performed routinely and is referred to as Trichuris
species. Oesophagostomum in cattle is assumed to be Oesophagostomum radiatum.
Table 30. Large intestinal worm counts
Oesophagostomum Trichuris
5th Stage 5th Stage
Group 1 - Untreated Controls
3 30 10
50 10
9 30 30
11 40 10
13 30 20
70 10
AM 41.7 15.0
GM 39.5 13.6
Group 2 - Test composition with simulated rain (10mm) at 2 hours
AM 0 0
GM 0 0
% Red 100 100
P-value <0.0001 <0.0001
Group 3 - Test composition with no rain for 24 hours
AM 0 0
GM 0 0
% Red 100 100
P-value <0.0001 <0.0001
P-value for Groups 2 & 3 combined to give greater power, as the two groups
are indistinguishable with the same means and distribution of values. 10% aliquot over
150 mesh sieve. AM = Arithmetic mean, GM = Geometric mean, NA = Not applicable, %
Red= % Reduction.
Lung worm
Lung worm counts of three controls animals and also pooled faeces of the
control animals cultured for Dictyocaulus demonstrated no evidence of lungworm
infection in the control animals so further processing of lungs for lungworm was
abandoned.
Table 31. Dictyocaulus spp. counts on three control animals
5th Stage Adult JuvenileL5 (<20mm) InhibitedL5 (<1.5mm)
3 0 0 0
0 0 0
11 0 0 0
AM 0 0 0
GM 0 0 0
9.4.4 Skin observations
Skin observations at the pour-on site were graded prior to pour-on
application, at 4 hours, 24 hours, 4 days and 12 days after treatment (just prior to
slaughter). Prior to pour-on application the treated calves had no lesions with back
scores of zero for hair loss, scurf, redness or inflammation, and there were no findings at
4 or 24 hours post treatment. At 3 days post-treatment some mild reaction was noted in
treated calves and the skin was assessed at both Day 4 and prior to slaughter. The
results are summaries in Table 32.
Table 32. Skin observations at pour-on site (number and score of treatment animals)
Time after Hairloss Scurf Inflammation
treatment 0 1 2 3 0 1 2 3 0 1 2 3
Group 1. Untreated control
-1 day 6 0 0 0 6 0 0 0 6 0 0 0
4 hours 6 0 0 0 6 0 0 0 6 0 0 0
24 hours 6 0 0 0 6 0 0 0 6 0 0 0
4 days 6 0 0 0 6 0 0 0 6 0 0 0
12 days 6 0 0 0 6 0 0 0 6 0 0 0
Group 2. Test composition with simulated rain at 2 hours
-1 day 6 0 0 0 6 0 0 0 6 0 0 0
4 hours 6 0 0 0 6 0 0 0 6 0 0 0
24 hours 6 0 0 0 6 0 0 0 6 0 0 0
4 days 6 0 0 0 2 4 0 0 0 2 4 0
12 days 6 0 0 0 5 1 0 0 5 1 0 0
Group 3. Test composition with no rain for 24 hours
-1 day 6 0 0 0 6 0 0 0 6 0 0 0
4 hours 6 0 0 0 6 0 0 0 6 0 0 0
24 hours 6 0 0 0 6 0 0 0 6 0 0 0
4 days 6 0 0 0 3 2 1 0 1 0 5 0
12 days 6 0 0 0 0 4 2 0 5 1 0 0
(0=no lesions, 1 =mild, 2- moderate, 3 = severe, 6 animals/group)
At Day 4 some mild-moderate exudate (mean score 1.67) was noted in
11/12 calves treated with the Test composition pour-on without noted skin reddening,
with some early developing scurf and some crusts (mean score 1.67) forming. The
exudate often had small white lines/fissures, which appeared to be early lifting of the
outer layer of the epidermis and formation of scurf/scale (exfoliation). This reaction was
not uniform. It was focused particularly in the first 10 cm near the withers and an area
some 20-30 cm from the withers (mid-back) suggesting some types of skin are more
reactive. The back midline of the calves was approximately 90-100cm long and other
quite large areas were unaffected despite the pour-on being applied evenly along the
entire length. At Day 12 after application the exudate had largely resolved (score 0.17)
with lifting epidermal flakes/scurf (score 1 to 1.33) growing out in the hair with the
underlying skin intact. These epidermal flakes varied from very small 1-2 mm up to
flakes 2x3 cm in the hair coat. There was no hair loss, and the changes were considered
mild and within the range observed for some other similar registered pour-ons and could
be easily missed without close observation. The underlying skin also appeared intact,
with no reddening and there was rapid measured resolution even at 12 days without any
treatment and no undue animal distress or changes in behaviour. It was considered that
these skin changes may be in part related to one of the active components rather than
simply the solvent system, as almost identical lesions with the same distribution pattern
were observed with another registered levamisole base pour on formulation - see Eclipse
pour on skin findings in Efficacy Study AR-CSR-0004.
Excluding the four hides sampled for histology the remaining hides were
recovered at slaughter on Day 13, identified to treatment group by punching 1, 2 or 3
holes in the hide in the area of the tail head and delivered to Warren Bell, Acting Plant
Manager, Graeme Lowe Corporation, Fellmonger/Tannery, Onehunga, Auckland. The
skins were processed to the wet blue stage of tanning and graded by the plant manager
for quality as 1st, 2nd or 3rd grade hides, with the results shown in Table 33. Light
discolouration (darkening) corresponding to the pour-on site as occurred with the test
composition treatments is often seen on “wet-blue” hides and was not graded as a fault.
Table 33. Hide grade assessment by treatment group
st nd rd
1 grade 2 grade 3 grade Total hides
Controls 5 0 0 5
Group 2 4 1 0 5
Group 3 2 plus 1 graded as 1-2 1 0 4
st nd
Key: 1 grade hide does not have any serious defect, 2 grade hide has
moderate sized or moderately severe defect(s), 3 grade hide has a severe defect(s). The
defects observed comprised a roughened surface.
As shown above eleven of the 14 hides were graded as 1st, with all Controls
assessed as 1st Grade (5 of 5) while 4 of the 5 test composition treated hides were 1st
Grade in Group 2 and 2 of 4 in Group 3. Those graded as 2nd Grade included 1of 5 in
st nd
Group 2 and 1 of 4 in Group 3. One hide in Group 3 was graded mid way as a 1 -2
grade.
Causes for the 2 grades included: Two small areas of roughened hide, 5x5
cm, one at withers and one in the lumbar region on one of the five Group 2 hides and two
similar areas of roughened hide in the withers and lumbar region on one of the four
st nd
Group 3 hides. A second Group 3 hide was classified as borderline grade 1 -2 due to a
single 4x5 cm area of slightly roughened hide. Two or three of 9 hides recording a 2
grade were regarded by the plant manager as a typical grading result for a line of hides.
Hides from the calves were recovered and processed 13 days post treatment,
22 days earlier than would occur with a withhold period of 35 days. The observation that
a majority of hides in the test composition treated groups were 1 Grade, the lesions
were Grade 2 and that the skin observations indicated a rapid resolution of the epidermal
flakes/scurf following application is expected to further reduce any affects of treatment
on the quality of tanned hides when harvested at the normal withhold time. No lesions,
epidermal flakes or scurf were reported when the test composition was administered in
older 300 kg animals in the Residue Study ARAB2679 at Armidale Australia, and detailed
observations from the Safety Study AR-CSR-0003 noted the following “There was mild
superficial non painful scurf formation along midline areas of the back, particularly the
withers in all treated animals 6 days after treatment, but without reddening, oedema or
ulceration or hair loss. There was a reduction and early resolution in this scurf reaction by
14 days after treatment and the scurf had virtually completely resolved in all animals by
Day 35 without treatment”.
9.5 Conclusions
The Test composition Pour-on (abamectin and levamisole base) when applied
along the midline of the back in beef calves with winter coats, at a dose rate of 1 ml per
kg, gave complete, and highly significant (p<0.0001) reductions in egg count and
worm count relative to untreated controls. Efficacy was not affected by 10 ml of
simulated rain applied 2 hours after application.
The reductions of roundworm numbers were significant (p<0.05) or highly
significant (p<0.01) for the parasites present in the various organs including: Ostertagia
spp (adult and L4 stage) in the abomasum, Cooperia spp (adult, L4 and E4 stage) in the
small intestine and Oesophagostomum radiatum and Trichuris spp in the large intestine.
Speciation of the worm types showed predominantly Ostertagia ostertagi
with small numbers of Ostertagia lyrata, and mainly Cooperia oncophora with small
numbers of Cooperia puntata.
The reductions in worm numbers were in excess of >98% AM or GM, and are
consistent with a highly effective anthelmintic as defined in both ACVM and VICH
guidelines.
The Test composition was well tolerated. Some initial reaction and
awareness to the application of the pour on including licking or kicking at the back was
seen in the first 10 minutes but this passed rapidly, and by 30 minutes all calves were
grazing normally. Mild scurf and some exfoliation of the superficial epidermis was seen at
Day 3-4 post treatment, more particularly at the withers or sometimes mid back, but this
was resolving and the underlying skin was intact at the time of slaughter (Day 13 post
treatment). The skin reaction was considered mild and within the range of skin reactions
observe with other similar pour ons. All behavioural observations and clinical
measurements showed no difference to untreated controls.
Two of nine Test composition treated hides were found with moderate
defects following slaughter at Day 13 and processing to the wet blue stage and one hide
had a lesser fault, an acceptable and typical industry result which is expected to improve
further when hides are harvested at or after the proposed withhold time of 35 days.
. Efficacy study – Summer coat
.1 Treatment groups
The study comprised six infected beef and dairy calves per treatment group
(group 2a contained two animals).
Treatment Groups consisted of Group 1 that remained as untreated controls,
Group 2 were animals treated with the test composition applied to a dry coat then
showered with 10 mL simulated rain 2 hours after treatment, then protected from any
rain for at least 24 hours and Group 3 were animals treated with the test composition
applied to a dry coat and then protected from any rain for at least 24 hours.
Table 34. Treatment groups
Group Treatment Animal
Number Number
1 Untreated Control 6
2 Test composition. 6
Applied midline, withers to tail head
2b Test composition. 2
Applied midline, mid-back to tail head
3 RP1 (Bomectin Gold pour-on) as per label 6
4 RP2 (Eclipse pour-on) as per label 6
TOTAL 26
Each animal was treated at a rate of 1 ml/20 kg body weight, which equates
to 500 ?g macrocyclic lactone and 10 mg levamisole per kg.
.2 Study design
The study protocol is shown below in Table 35.
Table 35. Study protocol
Activity Trial Dates performed/Details
Clean out drench 1 -68 Levamisole+Oxfendazole oral ( Scanda), 10 ml/calf
Artificial oral -64 Orally dose 27 calves with larvae (10 ml/calf)
infection 1
Artificial oral -56 Orally dose 27 calves with larvae (20 ml/calf)
infection 2
Treat skin with -54 Wash with Vetadine (iodine) to assist in control of
iodine (ringworm) ringworm.
Artificial oral -29 Orally dose 27 calves with larvae (10 ml/calf)
infection 3
Faecal sampling -5, 6,9, Day -5, then post treatment at Days 6, 9, 12, larval
12 culture at Day -5 and 12, and lungworm larvae at Day
6 in controls.
Weighing -4 Weigh for calculation of treatment dose.
Treatment 0 Day 0. T=0 Controls (Group 1), Test composition
pour-on (Groups 2 & 2b, Abamectin+Levamisole),
Group 3-Bomectin Gold pour-on (Abamectin), Group
4-Eclipse pour-on (Abamectin+Levamisole). Protect
all pour-on groups from rain for 24 hours.
Skin observations 0, 1, 6, Pre-treatment, 4 hr, 24hr, 6 and 11 days in all groups
Clinical 0, 1, 11 Pre-treatment, 1hr, 4hr, 24 hr and 11 days in all
Observations groups
Clinical 0 Pre-treatment (0), 4hrs in Groups 1 & 2, 2b
measurements
Weather and -6 to 12 Activities log then Daily log Day -6 until Slaughter
general (Day 12) including weather from treatment day
observations
Slaughter 12 Collect and ligate abomasum, small intestine and
large intestine for worm count. Collect faeces for egg
counts.
To ensure suitable infection of trial animals both natural and artificial
infection (oral dosing) were used.
An estimated total of 15,912 larvae of 5 genus were dosed per calf as per
Table 36. Details of larval dosing are summarised below.
? Dose 1. Twenty-seven trial calves individually orally dosed with 10 ml of
larval culture (Approximately 3110 larvae/calf).
? Dose 2. Twenty-seven trial calves individually orally dosed with 20 mL of
larval culture (Approximately 7302 larvae/calf).
? Dose 3. Twenty-seven trial calves individually orally dosed with 11 ml of
larval culture (Approximately 5500 larvae/calf.
Table 36. Total number of infective larvae dosed per calf by worm genera
Total Genus
Haemonchus Ostertagia Trichostrongylus Cooperia Oesph/Chab
Dose 1 3110 100 640 70 1830 470
Dose 2 7301 292 1314 0 5111 584
Dose 3 5500 0 4345 0 1155 0
Total dose 15911 392 6299 70 8096 1054
Calves were orally dosed using a plastic syringe with the liquid larval culture
administered over the back of the tongue.
Natural roundworm infection was acquired from calves grazing infective
pasture.
.3 Statistics
The primary data in the study were the individual worm counts. The worm
count data was tabulated and statistically analysed including tests for normal distribution
and tests for significance between the means of treated and control groups compared
using One Way Analysis of Variance (ANOVA). Efficacy of treatment on worm count and
egg counts (for each sampling day) was calculated according to the following equation
using both arithmetic and geometric means:
GroupMean(untreated) ? GroupMean(treated)
% Reduction (Efficacy %) ? ?100
GroupMean(untreated)
Secondary data including the observations was tabulated including totals and
means to determine if there were any treatment effects.
.4 Results
.4.1 Faecal egg counts
The faecal egg counts showed that the untreated control animals (n=6) were
uniformly positive with eggs counts varying from 150-500 epg over the trial period. The
pour-on treatment groups including Groups 2, 2b, 3 and 4 had similar mean egg counts
at Day –5 (the counts that were used for allocation to treatment). There was no
significant difference in group mean faecal egg counts at the time of allocation, but the
differences between control and all treated groups at all times post treatment was highly
significant (>0.01). All animals treated with the abamectin+levamisole pour-ons, (Test
composition and Eclipse in Groups 2, 2b and 4) gave complete control of egg output. In
contrast Group 3 animals treated with the single active abamectin pour-on (Bomectin
Gold pour-on) gave incomplete reductions in egg count, with a reduction relative to
controls of 97.3% at 6 days post treatment and 93.1% at Day 12 post treatment. This
finding was consistent with the larval culture and worm count findings for this group
discussed later (Section 15.3), and the selection criteria of farms with a history of ML
resistant Cooperia.
Table 37. Mean faecal egg count (eggs per gram) and significance
Ear tag FEC (Day-5) FEC (Day 6) FEC (Day 9) FEC (Day 12)
Group 1 - Untreated Controls
44 350 300 200 300
70 250 300 100 200
74 550 450 150 150
92 500 250 200 250
127 300 200 200 200
128 150 250 250 350
AM 350.0 291.7 183.3 241.7
GM 321.6 283.3 176.3 232.4
Group 2&2b – Test composition pour on, withers to base of tail
AM 393.8 0 0 0
GM 349.3 0 0 0
% Reduction (AM) 100 100 100
P-value 1.0 >0.001 >0.001 >0.001
Group 3. Abamectin pour on (Bomectin pour-on)
500 0 0 0
39 400 50 0 0
46 250 0 0 0
49 300 0 0 0
58 200 0 0 0
94 200 0 0 0
AM 308.3 8.3 0 16.7
GM 291.5 1.9 0 3.6
% Reduction (AM) 97.3 100 93.1
P-value 1.0 >0.001 >0.001 >0.001
Group 4 . Abamectin +Levamisole pour on (Eclipse pour-on)
AM 358.3 0 0 0
GM 333.5 0 0 0
% Reduction 100 100 100
P-value 1.0 >0.001 >0.001 >0.001
AM= Arithmetic mean GM = Geometric mean
.4.1 Larval cultures
Larval cultures 5 days before treatment confirmed that at the time of
treatment a mixed worm infection including large intestinal worms were present. Pooled
Quantitative larval culture analysis (40 g/group) conducted on faecal samples collected at
the time of slaughter confirmed that a mixed worm population was present with high
numbers of larvae detected (13,000 larvae/40 g). Low numbers of larvae (140 larvae/ 40
g) were also found in the cattle treated with Abamectin pour-on alone (Bomectin Gold).
The larvae recovered from this group were all Cooperia spp (100%). This is consistent
with an ML resistant Cooperia worm strain as also discussed under worm counts.
Abamectin is more potent on gastrointestinal parasites than ivermectin so the apparent
level of resistance in this study would be more pronounced with a product containing
ivermectin. In contrast, no larvae could be detected in a pooled 40 g sample from either
of the Abamectin+Levamisole pour-on groups, including the Test composition treatment
(Groups 2&2b) and Eclipse treatment (Group 4). The sensitivity of this test was increased
further by separately culturing 40 g of faeces from each of the two calves treated with
the Test composition on the lower back only (Group 2b). Again no larvae were recovered
from either animal in Group 2b (80 g total). This result is consistent with the Test
composition having very high efficacy with effective removal of adult worm stages, and
that the levamisole component of the Test composition (as with Eclipse pour-on) is
effective in removing ML resistant adult Cooperia stages which was confirmed in worm
count results discussed in Section 15.3.1.
Table 38. Larval cultures 12 days post treatment (quantitative culture)
Group Group 1 Group Group 3 Group 4
2&2b
Trial Day 12 12 12 12
Haemonchus (%) 2 0 0 0
Ostertagia (%) 9 0 0 0
Trichostrongylus (%) 0 0 0 0
Cooperia (%) 73 0 100 0
Oesophagostomum/Chabertia 16 0 0 0
Total larvae 13000 0 140 0
Gram of faeces cultured 40 g 40 g +80g 40 g 40 g
(2a+2b)
Larvae per gram 325 0 3.5 0
.4.2 Worm counts
Abomasum
Worm counts confirmed that the control animals were uniformly infected with
adult Ostertagia (3650 AM, 2815 GM) and smaller numbers of L4 stages (158AM,
137GM), adult Trichostrongylus axei (292 AM, 278 GM) and almost uniformly infected
(5/6) with adult Haemonchus contortus. The Test composition treatment gave complete
(100%) reductions, with no worms found. These reductions were highly significant for
Ostertagia (adult and L4 stages), T. axei adults and significant for Haemonchus
contortus. This was also true for those treated with the Test composition on the lower
back only (Group 2b), and also for those calves treated with Eclipse pour-on (Group 4).
What was notable however was that while the reduction in abomasal worm numbers was
still effective with Bomectin Gold pour-on, it did not completely remove Ostertagia with
an adult stage and L4 stage found in two separate animals, while nothing was detected in
any of those treated with an abamectin+levamisole pour-on. Typically ML’s are highly
effective against Ostertagia in cattle, and levamisole frequently less effective.
The Ostertagia spp from the controls was speciated using 50 male worms
and confirmed as Ostertagia ostertagi (98%) and Ostertagia lyrata (2.0%). The 2 male
worms found in the Group 3 were both identified as Ostertagia ostertagi. Abomasal
Trichostongylus spp and Haemonchus spp in cattle are considered monospecific in New
Zealand which has been confirmed in other studies, so were not typed.
Table 39. Abomasal worm counts
Trichostrongylus Haemonchus
Ostertagia spp.
axei contortus
th th
Stage L4 E4 5 Stage L4/E4 L4/E4
Stage
Group 1 - Untreated Controls
44 5900 250 0 250 0 150 0
70 8250 100 0 350 0 100 0
74 2200 250 0 350 0 100 0
92 1150 200 0 400 50 0 0
127 1300 100 0 150 0 200 0
128 3100 50 0 250 0 100 0
AM 3650.00 158.3 0 291.7 0 108.3 0
GM 2815.0 136.9 0 278.8 0 56.1 0
Group 2&2b – Test composition pour-on
AM 0 0 0 0 0 0 0
GM 0 0 0 0 0 0 0
% Red AM 100 100 NA 100 NA 100 NA
P-value <0.001 <0.001 NA <0.001 NA <0.05 NA
Group 3 – Abamectin pour on (Bomectin Gold pour-on)
0 0 0 0 0 0 0
39 0 0 0 0 0 0 0
46 100 0 0 0 0 0 0
49 0 0 0 0 0 0 0
58 0 0 0 0 0 0 0
94 0 50 0 0 0 0 0
AM 16.7 8.3 0 0 0 0 0
GM 2.2 1.9 0 0 0 0 0
% Red AM 95.4 94.8 NA 100 NA 100 NA
P-value <0.001 <0.001 NA <0.001 NA <0.05 NA
Group 4 – Abamectin+Levamisole pour-on ( Eclipse pour-on)
AM 0 0 0 0 0 0 0
GM 0 0 0 0 0 0 0
% Red 100 100 NA 100 NA 100 NA
P-value <0.001 <0.001 NA <0.001 NA <0.05 NA
P-value for Groups 2 & 2b combined, to give greater power as the two
groups are indistinguishable with the same means and distribution of values. 2% aliquot
over a 38 µm sieve. AM = Arithmetic mean, GM = Geometric mean, NA = Not applicable,
% Red= % reduction.
Small intestine
Small intestinal worm counts confirmed that the control animals were
uniformly infected with moderate-high Cooperia burdens, mainly adults (26092 AM,
21692GM) and moderate numbers of L4 (3408AM, 2596GM) and no E4 stages. There
were no Trichostrongylus detected in the small intestine but the controls were almost
uniformly (5/6) infected with L4 stages of Nematodirus spp (200 AM, 83GM) and slightly
less uniformly infected with small numbers of adult stages (75 AM, 11 GM). The Test
composition treatment (Group 2 and Group 2b) gave complete (100%) reductions of
these worms and worm stages, with no difference detected in those receiving the pour on
only on the lower back (Group 2b). These reductions were highly significant for Cooperia
(adult, L4 stages) and Nematodirus L4 and significant for Nematodirus adults.
Interestingly a small number of E4 Cooperia larvae were detected in 4/8 Test composition
treated animals (AM 112), but not seen in the controls, indicating very early re-infection
post treatment and possibly suggesting less persistent activity than the positive control
abamectin pour ons in this study. Eclipse pour-on treated animals in Group 4 gave similar
reductions but no E4 larvae were seen. Bomectin Gold pour-on containing abamectin
alone did not give full reductions against Cooperia stages, with only 89.4% control of
adult stages (AM) and 98.8% reductions of L4 stages. While the Cooperia reduction for
this treatment remained statistically highly significant, the product achieved only
moderate efficacy (80-89%), which was lower than its “effective” label claim. Experience
with abamectin versus ivermectin via topical treatment in cattle, suggest that if a less
potent ML such as ivermectin had been used the efficacy (inefficacy) would have been
even lower. Fifty male Cooperia present in the controls were speciated and confirmed to
consist of Cooperia oncophora (76%) and Cooperia punctata (24%), while 50 male
worms in the Bomectin Gold pour on group (Group 3) were entirely Cooperia oncophora
(100%). Only four male Nematodirus were found in two control animals and all four
worms were identified as N. helvetianus.
Table 40. Small intestine worm counts
Trichostrongylus
Cooperia spp Nematodirus spp
th th th
Stage L4 E4 5 Stage L4/E4 5 Stage L4
Group 1 - Untreated Controls
44 20650 1500 0 0 0 50 0
70 42100 7700 0 0 0 0 400
74 31700 3800 0 0 0 150 100
92 37250 4750 0 0 0 250 400
127 5150 750 0 0 0 0 100
128 19700 1950 0 0 0 0 200
AM 26091.7 3408.3 0 0 0 75 200
GM 21692.2 2595.7 0 0 0 11.2 83.1
Group 2&2b – Test composition pour-on
AM 0 0 0 0 0 0 0
GM 0 0 0 0 0 0 0
% Red AM 100 100 NA NA NA 100 100
P-value <0.001 <0.001 NA NA NA <0.05 <0.001
Group 3 – Abamectin pour-on (Bomectin Gold pour-on)
500 0 0 0 0 0 0
39 4450 0 0 0 0 0 0
46 5350 200 0 0 0 0 0
49 3500 0 0 0 0 0 0
58 0 0 0 0 0 0 0
94 2800 50 0 0 0 0 0
AM 2766.7 41.7 0 0 0 0 0
GM 699.4 4.7 0 0 0 0 0
% Red AM 89.4 98.8 NA NA NA 100 100
P-value <0.001 <0.001 NA NA NA <0.05 <0.001
Group 4 – Abamectin+Levamisole pour on ( Eclipse pour on)
AM 0 0 0 0 0 0 0
GM 0 0 0 0 0 0 0
% Reduction 100 100 NA NA NA 100 100
P-value <0.001 <0.001 NA NA NA <0.05 <0.001
P-value for Groups 2 & 2b combined to give greater power, as the two
groups are indistinguishable with the same means and distribution of values. 2% aliquot
over 38 µm sieve. AM = Arithmetic mean, GM = Geometric mean, NA = Not applicable.
Large intestine
Large intestinal worm counts confirmed that the control animals were
uniformly infected with small numbers of Oesophastomum adults (113.3 AM, 105 GM)
and variably infected with lower numbers of Trichuris adults (6.7AM, 4.9 GM). The Test
composition pour on treatment (Groups 2&2b) and both Bomectin Gold pour on (Group
3) and Eclipse pour on (Group 4) gave complete (100%) reductions in both worm genera.
These reductions were highly significant for the Oesophagostomum spp, but the reduction
in Trichuris were not significant because of low worm numbers and variable infection in
the controls. Differentiation for Trichuris is not performed routinely and is referred to as
Trichuris species. Oesophagostomum in cattle is assumed to be O. radiatum as it is
assumed to be monspecific in New Zealand.
Table 41. Large intestinal worm counts
Oesophagostomum Trichuris
th th
Stage 5 Stage
Group 1 - Untreated Controls
44 100 10
70 130 10
74 110 10
92 210 0
127 70 0
128 60 10
AM 113.3 6.67
GM 105.0 4.9
Group 2 & 2b – Test composition pour-on
AM 0 0
GM 0 0
% Red 100 100
P-value <0.001 0.2
Group 3 – Abamectin pour on (Bomectin Gold pour-on)
AM 0 0
GM 0 0
% Reduction 100 100
P-value <0.001 0.3
Group 4 – Abamectin+Levamisole pour on (Eclipse pour-on)
AM 0 0
GM 0 0
% Red 100 100
P-value <0.001 0.3
P-value for Groups 2 & 2b combined to give greater power, as the two
groups are indistinguishable with the same means and distribution of values. 10%
aliquot over 150 mesh sieve. AM = Arithmetic mean, GM = Geometric mean, NA = Not
applicable, % Red= % Reduction.
Lung worm
Lung worm larval culture from the pooled faecal sample (25-30 g) of the
control animals at Day 6 using a modified Baemann technique were negative for
lungworm larvae and so no lungs were collected at slaughter for lungworm examination.
.5 Conclusions
The test composition pour-on (abamectin + levamisole base) when applied
along the midline of the back in dairy calves with summer coats, at a dose rate of 1 ml
per 20 kg, gave complete and highly significant (p<0.001) reductions in egg count and
worm count relative to untreated controls. The efficacy and safety of the pour-on did not
appear affected by the product being applied only to the midline of the lower back (from
mid-back to the base of tail) compared to application along the entire midline of the
back, from the withers to the base of the tail
The reductions of roundworm numbers were significant (p<0.05) or highly
significant (p<0.001) for the parasites present in the various organs including: Ostertagia
spp (adult and L4 stage), Trichostrongylus axei (adult) and Haemonchus contortus
(adult) in the abomasum, Cooperia spp (adult, L4 stages) and Nematodirus spp (adult
and L4) in the small intestine and Oesophagostomum radiatum in the large intestine.
Speciation of the worm types showed predominantly Ostertagia ostertagi
with small numbers of Ostertagia lyrata, and Cooperia oncophora and Cooperia punctata.
The adult stages of Nematodirus were identified as N. helvetianus.
The reductions in worm numbers were in excess of >98% AM or GM, and are
consistent with a highly effective anthelmintic as defined in both ACVM and VICH
guidelines.
The reference product Eclipse Pour-on, which also delivers abamectin and
levamisole base at the same dose rate as the investigational product gave similar
complete reductions in worm count.
In contrast Bomectin Gold pour-on containing only abamectin was only
moderately effective on adult Cooperia oncophora (89.4% AM) and did not achieve
“effective” control as per its label claim. It appeared to give effective control of Cooperia
punctata. It did not achieve complete control of L4 stages (98.8% AM) which the
combinations achieved. It is considered that if a less potent ML such as ivermectin had
been used then the efficacy against this Cooperia strain would have been considerably
lower and the level of resistance demonstrated substantial. The findings however are
considered entirely consistent with an ML resistant strain of Cooperia oncophora and
supports the test composition’s claim of efficacy against ML resistant Cooperia strains. A
less common finding with Bomectin Gold in this study was the incomplete control of
Ostertagia ostertagi (95.4% adult, 94.8% L4, AM). Typically the efficacy of ML pour-ons
including ivermectin against Ostertagia spp is extremely high (>98%). As the most
pathogenic worm genera in cattle this finding is of concern, whether it is the effect of
ineffective skin absorption, or evidence of emerging resistance or tolerance by the
parasite. It does however demonstrate the benefit of combination anthelmintics in
delivering very high efficacy, which reduces the selection for potentially resistant worm
strains
The Test composition was well tolerated including at the pour-on site. Some
initial reaction and awareness to the application of the pour-on including licking at the
application site was seen in occasional animals but this passed rapidly, and by 10 to 15
minutes the test composition treated calves were grazing normally. Mild scurf and some
exfoliation of the superficial epidermis was seen at Day 6 post treatment, more
particularly at the withers or sometimes mid-back, but this was resolving and the
underlying skin was intact, at the time of slaughter (Day 12 post-treatment) without
treatment or negative effects on behaviour. The skin reaction was considered mild and
within the range of skin reactions observed for the reference product Eclipse pour-on. It
is speculated because of the similarly of the skin reactions in these pour-ons that this
reaction may be related to the levamisole base which both pour-ons contain. All
behavioural observations and clinical measurements relative to the controls showed no
differences that could be attributed to the Test composition treatment. Despite Bomectin
Gold pour-on being apparently a better tolerated, formulation based on skin observations
and measurement, this was not supported by observational data. There appeared to be
avoidance behaviour of bright sunlight by Bomectin Gold pour-on treated animals, which
possibly negatively impacted grazing behaviour for up to 11 days. This was not observed
for either the Test composition or the reference combination pour-on, or the untreated
controls.
11. Summary
The studies have demonstrated that the test composition is
? highly effective (>99%) against resident parasites in the abomasum, small
instestine and large intestine.
? effective on ML-resistant Cooperia,
The studies have also demonstrated that the test composition is not affected
? rain 2 hours after treatment,
? breed, or
? summer/winter coat.
The results also showed that the test composition did not perform
significantly different to the orally administered Eclipse product.
The following field observations were made on the studies. The test
composition
? has good wetting/spreading properties,
? does not cause hair loss or skin damage,
? leaves no apparent residue/oil on skin,
? causes mild, transient scurf,
? does not cause any apparent photosensitivity,
? has a similar withholding period to equivalent registered products, and
? results in mild hide defects (wet blue stage) 13 days after treatment (cf 35
day WHP).
The field observations also noted that the calves grazed normally 30 minutes
after treatment.
Where in the foregoing description reference has been made to elements or
integers having known equivalents, then such equivalents are included as if they were
individually set forth.
Although the invention has been described by way of example and with
reference to particular embodiments, it is to be understood that modifications and/or
improvements may be made without departing from the scope or spirit of the invention.
Having thus described in detail preferred embodiments of the present
invention, it is to be understood that the invention defined by the above paragraphs is
not to be limited to particular details set forth in the above description as many apparent
variations thereof are possible without departing from the spirit or scope of the present
invention.
Claims (25)
1. An anhydrous transdermal veterinary composition comprising ? at least one active ingredient having a log P in hexane and water of less than about 8 at pH 7.4, ? at least 15% by weight terpene hydrocarbon or terpene alcohol, and ? a solvent system comprising i) a non-hydroxyl containing solvent, ii) a non-heterocyclic ester solvent, or iii) a tripropylene glycol alkyl ether, wherein if the solvent is a non-hydroxyl containing solvent, the solvent additionally comprises at least one of a non-heterocyclic ester solvent or a tripropylene glycol alkyl ether solvent, and wherein the composition is in the form of a solution.
2. A composition of claim 1, wherein at least one of the active ingredients is lipophilic.
3. A composition of claim 1 or 2, wherein at least one of the active ingredients is an anthelmintic.
4. A composition of claim 3, wherein the anthelmintic is levamisole base.
5. A composition of claim 1 or 2 wherein at least one of the active ingredients is an insecticide.
6. A composition of any one of claims 1 to 5 wherein the non-hydroxyl containing solvent or the non-heterocyclic ester solvent is a fatty acid ester.
7. A composition of any one of claims 1 to 5 wherein the non-hydroxyl containing solvent or the non-heterocyclic ester solvent is a triglyceride, glycerol ester or combination thereof.
8. A composition of any one of claims 1 to 7, comprising a glycol ether.
9. A composition of claim 8 wherein the glycol ether is tripropylene glycol methyl ether, tripropylene glycol mono-n-propyl ether or tripropylene glycol mono-n-butyl ether.
10. A composition of any one of claims 1 to 9, wherein the composition comprises at least about 20% w/w terpene.
11. A composition of any one of claims 1 to 10, wherein the terpene is a terpene hydrocarbon.
12. A composition of any one of claims 1 to 11, wherein the terpene is selected from limonene, phellandrene, menthol or a combination thereof.
13. A composition of any one of claims 1 to 11, wherein the terpene is limonene.
14. A composition of any one of claims 1 to 13, comprising at least one surfactant.
15. A composition of any one of claims 14, wherein at least one of the sufactants has the following structure: Z O CR1R2CR3R4 where z is an optionally substituted C14 to C22 linear alkenyl, R1, R2, R3 and R4 are each independently selected from methyl or hydrogen, and n is an integer from 1 to 10.
16. A composition of claim 15 wherein at least two of R1, R2, R3 and R4 are hydrogen.
17. A composition of claim 15 or 16 wherein R1, R2, R3 and R4 are all hydrogen.
18. A composition of any one of claims 15 to 17 wherein n is an integer from 1 to 5.
19. A composition of any one of claims 15 to 18 wherein at least one of the carbon- carbon double bonds in Z has a cis configuration.
20. A composition of any one of claims 15 to 19 wherein Z is C16 to C22 linear alkenyl.
21. A composition of any one of claims 15 to 20 wherein the surfactant is a polyoxyethylene (2) oleyl ether.
22. A composition of any one of claims 14 to 21, wherein the at least one surfactant provides a hydrophilic-lipophilic balance of about 4.0 to about 6.0.
23. A composition of any one of claims 14 to 22 wherein the composition is stable at 4°C.
24. A composition of any one of claims 1 to 23, wherein at least one of the active ingredients has a log P in hexane and water at pH 7.4 of at least about 4, at least about 5, or at least about 6.
25. A composition of any one of claims 6 to 24 wherein the fatty acid ester has a C8– C20 alkyl chain. Stir (1 –4 hours)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US61/770,312 | 2013-02-27 | ||
US61/793,699 | 2013-03-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ748250B2 true NZ748250B2 (en) | 2021-02-02 |
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