IE20070395U1 - A process for the preparation of a stable anhydrous anthelmintic formulation - Google Patents
A process for the preparation of a stable anhydrous anthelmintic formulationInfo
- Publication number
- IE20070395U1 IE20070395U1 IE2007/0395A IE20070395A IE20070395U1 IE 20070395 U1 IE20070395 U1 IE 20070395U1 IE 2007/0395 A IE2007/0395 A IE 2007/0395A IE 20070395 A IE20070395 A IE 20070395A IE 20070395 U1 IE20070395 U1 IE 20070395U1
- Authority
- IE
- Ireland
- Prior art keywords
- approximately
- formulation
- ivermectin
- mixing
- manufacturing vessel
- Prior art date
Links
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- 238000009472 formulation Methods 0.000 title claims abstract description 59
- 238000000034 method Methods 0.000 title claims abstract description 41
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- 238000002360 preparation method Methods 0.000 title claims description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 55
- AZSNMRSAGSSBNP-XPNPUAGNSA-N 22,23-dihydroavermectin B1a Chemical compound C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 AZSNMRSAGSSBNP-XPNPUAGNSA-N 0.000 claims abstract description 53
- 229960002418 Ivermectin Drugs 0.000 claims abstract description 53
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- VNLRTFSQCPNNIM-UHFFFAOYSA-N octadecyl octanoate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)CCCCCCC VNLRTFSQCPNNIM-UHFFFAOYSA-N 0.000 claims description 3
- AXISYYRBXTVTFY-UHFFFAOYSA-N Isopropyl myristate Chemical compound CCCCCCCCCCCCCC(=O)OC(C)C AXISYYRBXTVTFY-UHFFFAOYSA-N 0.000 claims description 2
- 229940074928 isopropyl myristate Drugs 0.000 claims description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 claims 1
- 239000004540 pour-on Substances 0.000 abstract description 27
- 239000000243 solution Substances 0.000 description 32
- 239000004480 active ingredient Substances 0.000 description 18
- 230000035492 administration Effects 0.000 description 13
- 239000002904 solvent Substances 0.000 description 12
- 241000283690 Bos taurus Species 0.000 description 11
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 229960004418 Trolamine Drugs 0.000 description 8
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- 239000005660 Abamectin Substances 0.000 description 6
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- 241000243985 Onchocerca volvulus Species 0.000 description 3
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- 238000007792 addition Methods 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 238000011031 large scale production Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 230000035533 AUC Effects 0.000 description 2
- DWMMZQMXUWUJME-UHFFFAOYSA-N Hexadecyl Octanoate Chemical compound CCCCCCCCCCCCCCCCOC(=O)CCCCCCC DWMMZQMXUWUJME-UHFFFAOYSA-N 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 229940105132 Myristate Drugs 0.000 description 2
- 241000048284 Potato virus P Species 0.000 description 2
- 230000037034 TERMINAL HALF LIFE Effects 0.000 description 2
- 229940100613 Topical Solution Drugs 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 244000078703 ectoparasites Species 0.000 description 2
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- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 241000238876 Acari Species 0.000 description 1
- 206010003055 Application site reaction Diseases 0.000 description 1
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- 241000283073 Equus caballus Species 0.000 description 1
- 229940102223 Injectable Solution Drugs 0.000 description 1
- SPBDXSGPUHCETR-CVSKBELMSA-N Ivermectine Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-CVSKBELMSA-N 0.000 description 1
- 210000004731 Jugular Veins Anatomy 0.000 description 1
- 208000009874 Lice Infestations Diseases 0.000 description 1
- JMPFSEBWVLAJKM-UHFFFAOYSA-N N-{5-chloro-4-[(4-chlorophenyl)(cyano)methyl]-2-methylphenyl}-2-hydroxy-3,5-diiodobenzamide Chemical compound ClC=1C=C(NC(=O)C=2C(=C(I)C=C(I)C=2)O)C(C)=CC=1C(C#N)C1=CC=C(Cl)C=C1 JMPFSEBWVLAJKM-UHFFFAOYSA-N 0.000 description 1
- 241000244206 Nematoda Species 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 208000003177 Ocular Onchocerciasis Diseases 0.000 description 1
- 229940100688 Oral Solution Drugs 0.000 description 1
- 101700046291 PACK Proteins 0.000 description 1
- 241000517307 Pediculus humanus Species 0.000 description 1
- 241001674048 Phthiraptera Species 0.000 description 1
- 231100000614 Poison Toxicity 0.000 description 1
- 241001468227 Streptomyces avermitilis Species 0.000 description 1
- 241000244177 Strongyloides stercoralis Species 0.000 description 1
- UBCKGWBNUIFUST-YHYXMXQVSA-N Tetrachlorvinphos Chemical compound COP(=O)(OC)O\C(=C/Cl)C1=CC(Cl)=C(Cl)C=C1Cl UBCKGWBNUIFUST-YHYXMXQVSA-N 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008364 bulk solution Substances 0.000 description 1
- 231100000153 central nervous system (CNS) toxicity Toxicity 0.000 description 1
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- 239000006071 cream Substances 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 244000079386 endoparasites Species 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 244000144980 herd Species 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000000749 insecticidal Effects 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 230000002452 interceptive Effects 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
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- 230000001264 neutralization Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 244000045947 parasites Species 0.000 description 1
- 239000003090 pesticide formulation Substances 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
- A61K9/0017—Non-human animal skin, e.g. pour-on, spot-on
Abstract
ABSTRACT The present invention is directed to an industrial scale process for preparing a stable anhydrous anthelmintic liquid formulation containing ivermectin. The process comprises the steps of purging the manufacturing vessel with nitrogen gas, altering the pressure of the manufacturing vessel. rinsing the manufacturing vessel with isopropyl alcohol, adding isopropyl alcohol, Ivermectin and a fatty acid ester emollient, mixing, testing the solution, adding a buffering agent mixing, testing the solution, making up the total volume of the solution to 100 percent V/V with isopropyl alcohol and mixing and packaging the formulation. The formulation of the present invention is used for topical administration as a pour-on formulation.
Description
A PROCESS FOR THE PREPARATION OF A STABLE ANHYDROUS
ANTHELMINTIC FORMULATION
Field of the Invention
The present invention is directed to an industrial scale process for preparing a stable
anhydrous anthelmintic formulation containing ivermectin. The formulation of the
present invention is used for topical administration as a pour-on liquid formulation.
Background to the Invention
Ivermectin is an antiparasitic agent, an anthelmintic, with a broad spectrum of activity
against nematode worms and ectoparasites in animals, and has been in use for
nearly a decade. It is effective against most common intestinal worms, most mites,
and some lice. While normally used to treat animals, it is also prescribed to humans
to treat infections of Strongyloides stercoralis and onchocerciasis (river blindness).
Ivermectin is chemically related to the insecticide avermectin. Both ivermectin and
avermectin are derived from the bacterium Streptomyces avermitilis. Ivermectin has
the following general formula:
Ivermectin is a mixture of two components (5-o-demethyl-22,23-dihydroavermectin
A1,.) (25—(1-methylethyl)-5—O-demethyl—25-de(1-methylpropyl)—22,23-dihydro-
avermection A13). It is a white to yellowish-white crystalline powder.
Ivermectin acts by interfering with the target animal's central nervous system (CNS).
However. at recommended doses, ivermectin does not readily penetrate the CNS of
mammals. As such, ivermectin/avermectin formulations generally have low toxicity to
humans. This means that although highly poisonous to insects, mammals, in
particular humans, should not generally be adversely affected by normal use of
avermectin pesticide formulations.
Ivermectin may be delivered in many different ways to treat various different
conditions. For example, Ivermectin may be delivered by the oral route to treat
conditions in humans such as Onchocerciasis. Ivermectin tablets are generally used
to achieve this aim as it is easy to control the dosage level in such unit dose forms.
Alternatively, Ivermectin may be delivered as an oral solution to animals via a dosing
gun or as an injectable solution. A solution for oral ingestion will need to overcome
the palatability problems associated with lvermectin. Thus, it becomes apparent that
each delivery method chosen for lvermectin will need to overcome different problems.
lvermectin solutions which are used as injectable solutions usually contain several
ingredients such as alcohol, water and emulsifiers. There are many crucial aspects
to this type of formulation as the resultant emulsion formulation depends on the fine
balance between all ingredients. Furthermore, if such solutions are further diluted in
water by the end user, the emulsion can be negatively affected and lvermectin
delivery with be detrimentally effected.
The present invention is concerned with a stable anhydrous topical formulation of
lvermectin. which is generally delivered to animals on mass using a pour-on system.
This provides for the systemic delivery of lvermectin to the bloodstream of the animal.
However, there are several issues to be considered when making such a formulation
on a large-scale.
Topical formulations of lvermectin are known and include aqueous water based
solutions, such as the synergistic combination fonnulation disclosed in
US2006/0100165. However, such water based solutions are generally unsuitable for
use as a pour-on as dilution with water impacts on the delivery of the correct dosage
level of lvermectin to the animal. The present invention is not concerned with such
water containing formulations.
Other topical formulations are provided in the form of gels, ointments and creams for
example. They can be used as shampoos for treating head lice and, as such, the
need for the formulation to adhere to an area is crucial. Such formulations need
specific ingredients to provide the formulation with the necessary properties. e.g.
viscosity, for delivery of the correct dosage of lvermectin to the animal. The present
invention is not concerned with such formulations.
GB 2,403,905 is directed to a pour on formulation comprising a salicylinlide together
with avermectin in an alcohol solvent chosen from ethanol and isopropyl alcohol.
Ideally, other constituents are present included PVP, PEG, emollients. This patent
does not disclose the process for making the formulation. Furthermore, the polymeric
moiety (PEG or PVP) is an essential feature of the invention which allows a higher
quantity of the salicylinlide to be dissolved in the formulation. Thus, this patent is
directed to the problem of administering two active ingredients in the same
formulation.
W0 01/630380 is directed to a combination formulation comprising lvermectin and
closantel. This patent is directed to a different problem, that of providing an
appropriate solvent solution comprising two solvents. suitable for making such a
combination formulation. As such, the process steps outlined are specific to this
problem associated with combinations of active ingredients.
The present invention is directed to a stable anhydrous topical formulation of
lvermectin for use as a pour on solution for animals.
There are additional problems to be overcome when formulating such a pour on
lvermectin anhydrous solution on a large scale. These are outlined below.
Pure avermectin formulations are highly toxic to both insects and mammals.
Furthermore, some dog breeds, for example the collie, exhibit signs of ivermectin
related central nervous system toxicity at ivermectin doses generally exceeding 150
to 200 ug/kg. That is why commonly prescribed veterinary formulations of ivermectin
used for heartworm prophylaxis limit dosages to the range of 6 to 12 ug/kg and are
generally considered safe. Hence, it is crucial to ensure that the delivery system for
lvermectin to an animal provides the correct level of dosage of the active ingredient at
all times even when the lvennectin is delivered in aqueous solution as opposed to a
unit dose form (e.g. a tablet) where the dosage of the active ingredient can be
controlled.
Another problem associated with the large-scale manufacture of ivermectin
formulations is that ivermectin is water insoluble. The preparation of formulations
where the active ingredients are water insoluble provide problems when
manufacturing on an industrial scale. The formulations must be readily and efficiently
prepared and effective in use in that the lvermectin must be present homogenously in
the solution at the desired dosage level. Any slight differences in formulation may
change the plasma kinetics and efficacy of the resultant formulation.
A further problem is that there is a need for a process for preparing a stable
lvermectin formulation. Stability is needed in order to allow for the formulation to be
. 070395 -5*
prepared well in advance of their intended use. Again, the active ingredient must be
homogenously distributed throughout the solution at all times during manufacture,
packaging and storage prior to use. Long term stability of the solution, over a period
of months and years, must be addressed in any such manufacturing process.
Furthermore, it is necessary to prepare a formulation ready for topical use which
provides the active ingredient in a readily bioavailable form for systemic delivery. This
allows for easier administration to the animals, particularly in the case of a large herd
of large animals.
Thus. there is a need to develop an industrial large-scale process for the preparation
of ivermectin topical or pour-on formulations which deals with these problems.
Statement of the Invention
According to a first aspect of the invention, there is provided a process for the
preparation of a topical anhydrous anthelmintic formulation with a pH of from 5 to 7
containing an effective amount of lvermectin, wherein the process is carried out in a
manufacturing vessel having a capacity of at least 3000 litres, the manufacturing
vessel having additive vessels for adding the powder and liquid ingredients and a
magnetic stirrer, the process comprises the steps of:
a) Purging the manufacturing vessel with nitrogen gas;
b) Increasing the pressure in the manufacturing vessel from approximately
0.2bar to approximately 3.75 bar;
c) Reducing the pressure in the manufacturing vessel from approximately 3.75
bar to approximately 0.2 bar in 3 cycles;
d) Rinsing the manufacturing vessel with isopropyl alcohol;
e) Adding isopropyl alcohol in the range of 60 to 80% vlv to the manufacturing
vessel;
f) Adding ivermectin in the range of 0.1% to 5% w/v and mixing with agitation
for approximately 5 to 20 minutes at a low speed of approximately 100 to
150 rpm;
g) Adding a fatty acid ester emollient mixture comprising cetearyi
Ethyihexanoate and isopropyl Myristate in the range of 15% to 25% vlv and
mixing for approximately 1 to 20 minutes at a low speed of approximately
100 to 150 rpm;
h) Removing a sample of the solution obtained from step (g) for visual
assessment of ivermectin dissolution and mixing at a low speed of
approximately 100 to 150 rpm until the ivermectin has completely dissolved;
i) Adding the buffering agent triethanolamine in the range of 0.01% to 1% vlv
and mixing for approximately 2 to 15 minutes;
j) Removing a sample of the solution obtained from step (i) for visual
assessment of ivermectin dissolution and mixing at a low speed of
approximately 100 to 150 rpm until dispersion is complete;
k) Making up the total volume of the solution to 100% v/v with isopropyl
alcohol and mixing for a further approximately 5 to 15 minutes at a low
speed of approximately 100 to 150 rpm;
l) Obtaining a sample of the solution obtained from step (k) from the top,
middle and bottom of the vessel, sending the samples to be assessed for
quality control and awaiting approval from quality control; and
m) Mixing the solution for a further 5 to 20 minutes directly prior to packaging
the formulation obtained from step (k) into containers.
The process of the present invention provides an anhydrous topical formulation with
the ability of the active ingredient, ivermectin, to transfer into the bloodstream and
produce an efficacious homogenous dose of the active ingredient when administered
to an animal as a pour on formulation. Previously, homogenous distribution and
delivery of the correct dosage level of ivermectin has been hampered due to the fact
that lvennectin is insoluble. lvermectin can have severe adverse effects at incorrect
dosage levels.
In addition, the process and excipients used provide a formulation which has long
term stability. This is important when manufacturing on an industrial scale.
Furthermore, the formulation of the present invention only contains the active
ingredient, an alcohol solvent, a fatty acid ester emollient and a buffering agent. This
is in direct contrast to many other formulations which are complicated and contain
many ingredients which if not added at the correct level and in the correct manner
can adversely affect the ability of the formulation to deliver the active ingredient
correctly. On the contrary, the present invention limits the number of ingredients used
in the formulation and provides a straightforward and easy to apply process for use
on an industrial scale. This is one of the major advantages of the present invention.
Detailed Description of the Invention
In the specification the term “by weight” refers to the weight of the final composition
and “by volume” refers to the volume of the final composition. The term “effective
amount" refers to the amount of the active ingredient needed to destroy parasites.
The industrial large-scale manufacture of any drug presents the pharmaceutical
manufacturer with many issues to consider.
In the large-scale manufacture of a formulation, it is essential that the entire batch
being manufactured meets the various criteria set by regulatory legislation and there
must be little or no product variation within a batch.
Product variation is usually attributed to segregation of the ingredients, in particular
the active ingredient, within a batch. This is an unpredictable or random event. If
product variation is found within a batch, this could result in the batch not meeting the
required standards and the subsequent wastage of an entire batch. This is expensive
and time-consuming and something a pharmaceutical manufacturer will avoid. This
is also a particular problem when delivering lvermectin in a solution. Any process
must ensure the resultant solution has a homogenous dispersion of ivermectin. If
not, delivering the correct dosage of active ingredient is not possible.
The present invention is directed to solving these manufacturing problems and the
other problems outlined above when making an ivermectin formulation on a large-
scale.
In general terms, the process and formulation produced according to the invention
provides a robust, simple process for producing a formulation of good quality with
good short and long term stability results. Furthermore, the process provides for a
product with a homogenous distribution/dispersion of ivermectin in solution.
Specifically, the process of the invention provides process for the manufacture of a
formulation which has good uniformity when manufactured on a large-scale and is a
homogenous liquid where the components are uniformly distributed throughout the
mixture and is shelf stable.
The manufacturing vessel used in the present invention should be attachable to a
powder charging vessel/hopper and a liquid charging vessel. The manufacturing vessel
should ideally have a capacity of up to 4000 litres. The powder charging vessel should
have a capacity ideally of at least 20 litres and the liquid charging vessel should have a
capacity of ideally approximately 5 litres. The manufacturing vessel must be capable of
achieving containment of a micronised powder.
The manufacturing vessel may be made from conventional stainless steel or other
materials may be used.
In order to ensure that there is no residual water and the resultant formulation is
anhydrous, the following specific steps must be carried out in this order.
The manufacturing vessel requires a nitrogen supply to aid in the prevention of an
explosion by purging the equipment with nitrogen gas. Nitrogen gas is an inert gas
which shields a product from atmospheric oxygen and moisture. Nitrogen blanketing
during the manufacturing, holding and filling periods is essential and nitrogen
pressurization to remove oxygen before rinsing the manufacturing vessel with isopropyl
alcohol is required. The nitrogen gas forces air out of the manufacturing vessel and
provides a protective environment during start-up and shut-down
Furthermore, the manufacturing vessel must be provided with two pressure supplies.
The maximum vessel pressure is 3.75 bar. Ideally, one pressure supply is set at
approximately 2.0 bar gauge for inerting and one low pressure supply is set at
approximately 0.2 bar gauge for purging. Pressure must be controlled at an accuracy of
+/-10%. This step provides an advantage in terms of safety of the process.
The manufacturing vessel also contains a magnetic drive mixer which must achieve the
required mixing in the vessel range of 300 litres to 4000 litres. The advantage of using a
magnetic mixture is that no mechanical sealing is required either internally or externally
on the manufacturing vessel.
During the manufacturing process, it is a requirement that samples are taken to
ascertain the effectiveness of the vessel mixer. These monitoring steps are crucial to
the batch manufacturing process of the present invention and must be carried out at
each step of the process.
The resultant formulation made by the process of the present invention is an
lvermectin solution which is suitable for administration as a pour-on to deliver the
active ingredient for systemic effects.
An essential step in the manufacture of such an anhydrous formulation is the initial
step of purging the manufacturing vessel with the solvent, isopropyl alcohol. This
ensures that there is no water present in the manufacturing process. This is essential
as the formulation is an anhydrous or non-aqueous formulation.
Furthermore, the process of the present invention provides for a safe, easy to
administer application form which makes possible a more exact topical therapy for
systemic administrations than could previously be achieved. Clinical studies have
shown that sufficient levels of ivermectin are achieved after administration of the
topical anhydrous solution of the invention to the target animal.
Furthermore, as this is a pour on solution it is important to ensure the viscosity of the
solution is appropriate for this type of administration and that the viscosity of the
solution is within the range needed to allow for systemic delivery of the active
ingredient. Again, the choice of excipients ensures the correct viscosity is maintained
within the solution. Ideally, the viscosity of the product of the invention is from
approximately 40 to 80 centiposie (cP) and/or from approximately 5 to 25E Torque.
The components of the topical formulation are discussed in detail below.
ideally, isoproroyl alcohol Ph Eur. or propan-2—o| conforms to the monograph of the
European Pharmacopoeia 01/2005:0970. It is used as primarily as a solvent.
Preferably, lsopropyl (IPA) is added at a level of from 65 to 75% vlv.
Ideally, lvermectin Ph Eur. conforms to the monograph of the European
Pharmacopoeia O1/2005:1336 and as defined above is a mixture of two components
(5-odemethyl-22,23-dihydroavermectin A1,) and (25-(1-methylethyl)O-demethyl-
-de(1-methylpropyl)-22,23~dihydroavermection A1,). it is a white to ye|lowish—white
crystalline powder.
Preferably, lvermectin is added at a level of approximately 0.5% v/w. The weight is
determined by the dosage level needed in the resultant topical solution.
As this formulation is a pour-on formulation, an emollient is required to give the
formulation the necessary properties for topical administration such as good wetting
and stiffening/spreading properties. The emollient used in the present invention is a
mixture of fatty acids, preferably cetearyl ethylhexanoate and lsopropyl Myristate.
Cetearyl ethylhexanoate comprises stearyl octanoate and cetyl octanoate. Other fatty
acid esters may be contemplated.
Preferably, the emollient is used at a level of approximately 20 vlv.
The following is the typical fatty acid profile of crodamol cap” (super refined) which
may be used as an emollient according to the invention: lsopropyl myristate: 9.0%,
Cetyl Octanoate 68.5%, Stearyl Octanoate 21.6% and others 0.9%. Crodamol Cap”
can also act as a viscosity modifier and a solubilizer.
A buffering agent is used which may be any conventional buffering agent used in this
field. Ideally, Triethanolamine Ph Eur. 01/2005:1577 is used which is a buffer
conforms to the monograph of the European Pharmacopoeia. Triethanolamine or
trolamine is 2,2’,2”-nitrotriethanol. Other conventional buffers will be understood to
be within the scope of the present invention. The use of the buffering agent is an
essential step of the invention which provides a desired pH for lvermectin delivery.
Furthermore, it advantageously aids the permeation properties of the topical
formulation.
Preferably, triethanolamine is used at a level of 0.05% v/v to achieve a pH of
approximately 5 to 7. As this is a topical solution for use with animals, a pH of this
range is essential i.e. neutral pH.
It will be understood that other emollients, buffers and solvents generally used in the
pharmaceutical field may be used in the process of this invention.
The formulation of the invention may be applied in the veterinary field, for combating
endoparasites and ectoparasites affecting animals such as bovines and equines.
The invention will now be described by reference to the following non-limiting
examples and figures.
Figure 1 shows a process outline for preparing a 180 litre ivermectin formulation;
Figure 2 shows a process outline for preparing a 1,500 litre ivermectin formulation;
Figure 3 shows another process according to the invention.
As shown in Figures 1, 2 and 3, the general method involved the steps of sequentially
adding the ivermectin, emollient, buffering agent e.g. triethanolamine to at least part
of the solvent isopropyl alcohol.
The steps of purging the manufacturing vessel with nitrogen and pressurizing the
vessel from approximately 1 bar to approximately 0.2 bar are not shown. These
steps occur prior to the addition of the alcohol solvent to the manufacturing vessel.
After each ingredient is added, the mixture is mixed in a stainless steel manufacturing
vessel at a slow speed until the ivermectin in the formulation is completely dissolved
and dispersed in the solution.
The final step involves adding the remaining isopropyl alcohol and carrying out a final
mixing step.
The formulation is then subject to quality control analysis and samples from defined
areas of the formulation are obtained and tested to ensure they comply with the in-
process bulk testing specifications. \fisual inspection and HPLC analysis may be
carried out to assess whether the formulation complies with the in-process bulk
testing specification outlined in the examples.
By adding the excipients in this manner, the preparation time is minimised as there is
substantially no entrainment of air in the mixture. Thus, settlement time between
additives is not required. The production process is optimised as the production time
is minimised.
After a batch is complete, the manufacturing vessel and various additive vessels and
lines may be easily disconnected and cleaned in-situ.
Once the formulation has passed the quality control tests, it is then passed to the
packaging station, where it is filled through a liquid filler into containers. The closures
are screwed on and the appropriate labels with batch numbers etc are added. The
containers are then placed in outer cartons and then sealed.
Figure 3 shows a variation on the process of the invention. with the steps of purging
the manufacturing vessel with nitrogen and pressurizing the vessel from
approximately 1 bar to approximately 0.2 bar which occur prior to the addition of the
alcohol solvent to the manufacturing vessel. The remaining steps are as defined in
relation to Figures 1 and 2.
Example 1: Ivermectin Fgrmulation
The following table shows a typical ivermectin solution prepared according to the
present invention which is suitable for topical administration:
Ingredient Quantity and/or Function . Reference to
Percentage standard
°/ w/v Active Ph Eur
. 0 - .
Ivermectin ingredient
Excigients:
C'°dam°' Capm 20.00% vlv Emollient Product spec.
T"°“‘a"°'a’"‘"° 0.05% v/v Buffer Ph. Eur.
'5°P'°PY' a'°°“°' q.s. 100.0% vlv Solvent Ph. Eur.
Examgle 2: Manufacturing Process
Eguigment Reguired:
All the equipment used in carrying out the process is well known equipment and does
not need further description.
A conventional stainless steel vessel such as a pressure vessel PET 3 group 4, with
an internal finish below 0.4RA may be used. The stainless steel vessel is provided
with a magnetic stirrer and various inlets and outlets for the addition of active
ingredient power and liquid excipients. The vessel is also connected to a nitrogen
gas source for nitrogen purging and pressurization.
Method 1a: Ma_nufacture of 18OL Batch size
The following steps were carried out:
. Fill approx. 130L of lsopropyl alcohol into the manufacturing vessel;
2. Add Ivermectin and mix for approximately 5 min;
S-"’.U‘.‘>.°’
Add Crodamol Cap” and mix for approximately 5 min;
Add Triethanolamine and mix for approximately 3 min;
Bring to 18OL mark with Isopropyl alcohol and mix for approximately 5 min;
The bulk solution is sampled from the top. middle and bottom of the tank and
sent to quality control (QC) for analysis.
The times used in the above method are by means of example only and variations +/-
minutes are also contemplated.
Method 2a: Manufacture of 1500L Batch Size
The following steps were carried out:
.‘-"P$°.'°.-‘
Fill approx. 850Kg of Isopropyl alcohol into the manufacturing vessel;
Add Ivermectin and mix for approximately 5 min. at low speed;
Add Crodamol Cap“ and mix for approximately 15 min. at low speed;
Mix for a further approximately 15 min. at low speed;
Remove 100ml sample for visual assessment of ivermectin dissolution. If
ivermectin is not completely dissolved mix for a further 15min. at low speed;
. Add Triethanolamine and mix for approximately 10 min. at low speed;
. Remove 100ml sample for visual assessment of dispersion. If dispersion is not
complete mix for approximately a further 10 min. at low speed;
Bring to 1500L with Isopropyl alcohol and mix for approximately 20 min. at low
speed;
Prior to filling samples of the bulk product are taken form the top, middle and
bottom of the tank and sent for Q0 analysis. Tests and specifications are as per
the following table:
The times used in the above method are by means of example only and variations +/-
minutes are also contemplated.
In-Process Bulk Testing Specifications:
Test Specification
Appearance A clear colourless solution with a characteristic
odour
lvermectin Assay 0.5% w/v (5% limit) Range: 0.475 - 0.525% wlv
(% wlv)
Related Substances Known impurities RRT 1.3 to 1.5: <3%
All other known impurities: <2%
Any unknown impurity: <1%
Total impurities: <6%
Identification HPLC: The chromatography of the assay exhibits
major peaks due to lvermectin, the retention time
of which corresponds to that exhibited in the
chromatogram of the standard preparation.
Method 1b/2b : Packaging Procedure
The following steps were carried out:
. The formulation is cleared by QC and packaging materials are issued;
2. The containers are filled via the liquid filler
3. A container number check is made to establish the batch yield and to reconcile
the theoretical versus the actual yield;
4. The appropriate number of labels is requisitioned from the quality control
department and recorded on the packaging documentation along with the
manufacturing date, batch numbers, label numbers, reconciliation and signature
of the individual responsible;
. The closures are screwed onto the containers and the labels applied;
6. The containers are placed in outer cartons and the cartons sealed;
7. The cartons are palletised and placed in the finished product quarantine area for
final inspection.
°70395
Examgle 2: Stabilig Results for lvermectin Fonnulation
Stability data of the two batches of the product manufactured according to Example
1a after 3 years is presented in the following tables (Part I (0-10 months)) and Part
II (12 -36 months)):
PRODUCT STRENGTH PACK BATCH SIZE STORAGE CONDITIONS
lverrnectin 0.5“/owlv 1L Flat Bottomed 180L Temp: 25‘C/60%RH
Pour-On fvermectfn Flexi Pack
Part I
Specification Initial 4 mths 7 mths Qmths 10mths
Appearance A clear colourless Conforms Confonns Conforms Conforms Conforms
solution with a
characteristic odour.
Condition of Packaging intact Conforms Conforms Conforms Conforms Conforms
Packaging
identification Conforms Conforms Conforms Conforms Conforms Conforms
Assay Active 0.5%w/v 1: 5% 0.508% 0.484% 0.495% 0.502% NP
!.‘L9L'."..°_°ti_" i.e. 0.475%w/v —
.525%w/v
Part II
Specification 12 mths 18 mths 21mths 30 mths 36 mths
Appearance Aclear Conforms Conforms Conforms Conforms Conforms
colourless
soiution with a
characteristic
odour.
Condition of Packaging intact Conforms Conforms Conforms Conforms Conforms
Packaging
Identification Conforms Conforms Conforms Conforms Conforms Conforms
AssayActive 0.5%w/v15% 0.490% 0.516% 0.485% 0.484% 0.484
____|vermectin i.e. 0.475%w/v —
.525%w/v
ND:Not Detected
NP:Not Performed
At several intervals during this time the formulation was analyzed and compared to
the in-process bulk testing specifications outlined below.
Results are shown in the table below.
PRODUCT STRENGTH PACK BATCH SIZE STORAGE
CONDITIONS
lvermectin 0.5%wIv 1L Flat Bottomed 180L Temp:
Pour-On lvermectin Flexi Pack 40‘CI75%RH
Test Specification Initial 3mths 6mths 10 mths 12 mths 18mths
Appearance A clear
colourless
solution with a Conforms Conforms Confonns Conforms Conforms Conforms
characteristic
odour.
Condition of Packaging intact
Packaging
Conforms Conforms Confonns Conforms Conforms Conforms
identification
Conforms Conforms Conforms Confonns Conforms Conforms Conforms
Assay Active
lvermectin 0.5%w/v:t5% 0.503% 0.488% 0.495% NP 0.435% 0.507%
i.e. 0.4‘/5%w/v —
0.525%wlv
ND: Not Detected
NP : Not Performed
it can be seen in the above tables that the lvermectin pour-on produced in
accordance with the present invention was stable over two separate trials for a
period of 36 and 18 months respectively. Furthermore, the lvermectin was active at
all times during this test period.
Thus, the process defined in Example 1 provides a stable, homogenous, anhydrous
lvermectin solution which is shelf stable over at least a 3 year period.
The viscosity of the product made in accordance with Example 1 was measured
using a Brookfield viscometer (settings Spindle 1 and speed 5100) and the
following results were obtained:
Viscosity: 63.1 Cp
Torque: 15.71 E
Finally, clinical studies on target species have also shown that after administration
the product is absorbed at a level to provide excellent efficacy of the active
ingredient, Ivermectin.
Example 3 - Bio-gguivalence studies
The pharmacokinetics of the product manufactured according to Example 1 and
lvomec® Classic Pour-On for cattle, were compared in the target species, cattle.
The products were shown to be bioequivalent within 90% confidence limits and
within the 80 - 125% established in the Guideline EMEA/CVMP/016/O0 (Guide/ines
for the conduct of the bioequivalence study for veterinary medicinal products). On
this basis, lvermectin Pour-On is considered to be essentially similar or bio-
equivalent to lvomec® Classic Pour-On for cattle.
The present invention provides a new method suitable for industrial use for a new
lvermectin pour on formulation with only four essential and well-defined
components.
The study conducted was a two-way, single dose, crossover blood bio-equivalence
trial to determine the comparative plasma lvermectin concentrations in cattle
following treatment with the product manufactured according to Example 1
(lvermectin Pour-On) and the reference product (lvomec® Classic Pour-On for
Cattle).
This bioequivalence study was performed in accordance with the principles of GCP
and GLP at a GLP approved facility. The test and reference products are indicated
for cattle of all ages.
In this study, twenty-four male, 8 monthold Friesian cattle, weighing between 296
kg and 390 kg were allocated into two groups by restricted randomisation based on
pre-study bodyweight to ensure homogenous groups. Following an acclimatisation
period of 7 days, each animal was administered topically either the test or
reference product (determined by group allocation) at a dose rate of 500 ug
ivermectin per kg bodyweight.
The crossover design is summarised below:
Group l Group ll
Phase I Reference Test
(Days 0-42) lvomec® Classic Pour-On lvermectin Pour-On
Phase II Test Reference
(Days 72~114) lvermectin Pour-On |vomec®CIassic Pour-On
Serial blood samples were collected from the jugular vein of each animal before
and after product administration at the following times:
Days (Phase I/Phase ll)
Day -1/71 0/72 1/73 2/74 3/75 4/76 5/77 6/78
Times of Basal 6. 24, 48, 72, 96, 120, 126, 144
extraction 12 36 54, 78, 102, 132
(hours post 60 84 108
dose)
Days (Phase l/Phase II)
Day 7/79 9/81 14/86 21/93 28/100 35/107 42/114
Times of 168 216 336 504 672 840 1008
extraction
(hours post
dose)
Each phase of the study lasted 42 days from the first day of treatment with a
“wash-out” period of 72 days between the administration of the products in Phases
I and II. The “wash-out” period was determined based on at least 10 times the
terminal half-life of the active. The terminal half-life of ivermectin following
administration as a pour-on to cattle at the recommended dose rate was
determined as approximately 5.3 :t 1.8 days i.e. a maximum of 7.1 days or 170.4
hrs. (V. Gayrard et al 1999). After 72 days each animal was again administered
either the test or reference product in an identical manner, with the product—to-
group treatment being reversed. Serial blood samples were again collected for
analysis of plasma ivermectin concentration as described in the tables above.
All animals were clinically examined prior to and during the trial and were observed
daily for any signs of ill-health or intolerance to the product, including application
site reactions. No evidence of intolerance to either test or reference products was
noted.
Serial blood samples were centrifuged and the plasma frozen for transport to the
analytical laboratory immediately after collection. Analysis of the blood samples for
ivermectin concentration was performed using a fully validated H.P.L.C. method.
The pharmacokinetic profile of ivermectin in cattle following administration of either
test or reference products is characterised by a sharp rise in plasma ivermectin
concentration, followed by a slow depletion phase.
The bioequivalence of the test and reference products was determined by
calculating the confidence limits of the difference of the two means. The confidence
intervals for the quotient of the means from log-transformed data are the following:
Variable Lower Limit (%) Upper Limit (%)
Cm. 85.20% 1 16.65%
AUC 96.55% 112.88%
The study concluded that the ivermectin product manufactured according to
Example 1 is bioequivalent to the reference item lvomec® Classic Pour-On for
Cattle since the confidence interval for AUC and Cm, of the difference between the
test and reference items is within the interval 80-125% established in the Guideline
EMEA/CVMPl016l00 (Guidelines for the conduct of the bioequivalence study for
veterinary medicinal products).
In the specification, the terms “comprise, comprises. comprised and comprising"
and any variation thereof and the terms “include, includes, included and including"
and any variation thereof are considered to be totally interchangeable and they
should all be afforded the widest interpretation.
The invention is not limited to the embodiments described above but may be varied
within the scope of the claims.
Claims (1)
1. A process for the preparation of a stable topical anhydrous liquid anthelmintic formulation with a pH of from 5 to 7 containing an effective amount of ivermectin, wherein the process is carried out in a manufacturing vessel having a capacity of at least 3000 litres, the manufacturing vessel having additive vessels for adding the powder and liquid ingredients and a magnetic stirrer, the process comprises the steps of: a) Purging the manufacturing vessel with nitrogen gas; b) Increasing the pressure in the manufacturing vessel from approximately 0.2bar to approximately 3.75 bar; c) Reducing the pressure in the manufacturing vessel in 3 cycles from approximately 3.75 bar to approximately 0.2 bar; d) Rinsing the manufacturing vessel with isopropyl alcohol; e) Adding isopropyl alcohol in the range of 60 to 80% v/v to the manufacturing vessel; f) Adding lvermectin in the range of 0.1% to 5% w/v and mixing with agitation for approximately 5 to 20 minutes at a low speed of approximately 100 to 150 rpm; g) Adding a fatty acid ester emollient comprising cetearyl ethylhexanoate and isopropyl Myristate in the range of 15% to 25% v/v and mixing for approximately 1 to 20 minutes at a low speed of approximately 100 to 150 rpm; h) Removing a sample of the solution obtained from step (g) for visual assessment of ivermectin dissolution and mixing at a low speed of approximately 100 to 150 rpm until the iverrnectin has completely dissolved; i) Adding a buffering agent in the range of 0.01% to 1% v/v and mixing for approximately 2 to 15 minutes; i) Removing a sample of the solution obtained from step (i) for visual assessment of ivermectin dissolution and mixing at a low speed of approximately 100 to 150 rpm until dispersion is complete; k) Making up the total volume of the solution to 100% v/v with isopropyl alcohol and mixing for a further approximately 5 to 15 minutes at a low speed of approximately 100 to 150 rpm; l) Obtaining a sample of the solution obtained from step (k) from the top, middle and bottom of the vessel, sending the samples to be assessed for quality control and awaiting approval from quality control; and m) Mixing the solution for a further 5 to 20 minutes directly prior to packaging the formulation obtained from step (k) into containers. . The process according to claim 1 wherein cetearyl ethylhexanoate is a mixture of stearyl octanoate and oetyi octanoate. . The process according to claim 1 or claim 2 wherein the buffering agent is triethanolamine. . The process according to any of the preceding claims wherein the stable topical anhydrous liquid formulation has a viscosity from approximately 40 to 80 cPs. . The process according to any of the preceding claim wherein the sample obtained from steps (h), (j) and (I) are subjected to HPLC analysis. 070395
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IEIRELAND05/12/2006S2006/0882 |
Publications (2)
Publication Number | Publication Date |
---|---|
IES84905Y1 IES84905Y1 (en) | 2008-06-11 |
IE20070395U1 true IE20070395U1 (en) | 2008-06-11 |
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