IE85325B1 - A process for the preparation of a stable anhydrous anthelmintic formulation - Google Patents
A process for the preparation of a stable anhydrous anthelmintic formulation Download PDFInfo
- Publication number
- IE85325B1 IE85325B1 IE2007/0393A IE20070393A IE85325B1 IE 85325 B1 IE85325 B1 IE 85325B1 IE 2007/0393 A IE2007/0393 A IE 2007/0393A IE 20070393 A IE20070393 A IE 20070393A IE 85325 B1 IE85325 B1 IE 85325B1
- Authority
- IE
- Ireland
- Prior art keywords
- approximately
- low speed
- mix
- formulation
- ivermectin
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 116
- 238000009472 formulation Methods 0.000 title claims abstract description 62
- 238000000034 method Methods 0.000 title claims abstract description 41
- 230000000507 anthelmentic Effects 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 title claims description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 57
- 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000002156 mixing Methods 0.000 claims abstract description 19
- 239000003974 emollient agent Substances 0.000 claims abstract description 12
- 239000007788 liquid Substances 0.000 claims abstract description 12
- 238000004806 packaging method and process Methods 0.000 claims abstract description 12
- 230000000699 topical Effects 0.000 claims abstract description 11
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 10
- 239000000194 fatty acid Substances 0.000 claims abstract description 10
- 238000010926 purge Methods 0.000 claims abstract description 10
- 239000006172 buffering agent Substances 0.000 claims abstract description 9
- 229910001873 dinitrogen Inorganic materials 0.000 claims abstract description 7
- -1 fatty acid ester Chemical class 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical group OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 12
- 239000004615 ingredient Substances 0.000 claims description 11
- 238000003908 quality control method Methods 0.000 claims description 11
- 238000004458 analytical method Methods 0.000 claims description 8
- 239000006185 dispersion Substances 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 230000000007 visual effect Effects 0.000 claims description 7
- 238000011049 filling Methods 0.000 claims description 6
- 229940093528 Cetearyl Ethylhexanoate Drugs 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 4
- DWMMZQMXUWUJME-UHFFFAOYSA-N Hexadecyl Octanoate Chemical compound CCCCCCCCCCCCCCCCOC(=O)CCCCCCC DWMMZQMXUWUJME-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 3
- 230000000996 additive Effects 0.000 claims description 3
- 150000004665 fatty acids Chemical class 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 3
- 229940074928 isopropyl myristate Drugs 0.000 claims description 3
- VNLRTFSQCPNNIM-UHFFFAOYSA-N octadecyl octanoate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)CCCCCCC VNLRTFSQCPNNIM-UHFFFAOYSA-N 0.000 claims description 3
- 238000005070 sampling Methods 0.000 claims description 3
- 239000008364 bulk solution Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000004540 pour-on Substances 0.000 abstract description 27
- 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
- 241001465754 Metazoa Species 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 229960004418 Trolamine Drugs 0.000 description 9
- 239000012049 topical pharmaceutical composition Substances 0.000 description 7
- 239000005660 Abamectin Substances 0.000 description 6
- 210000004369 Blood Anatomy 0.000 description 5
- 210000002381 Plasma Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 230000035489 relative bioavailability Effects 0.000 description 5
- 238000004166 bioassay Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 229910001220 stainless steel Inorganic materials 0.000 description 4
- 239000010935 stainless steel Substances 0.000 description 4
- 210000003169 Central Nervous System Anatomy 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241000243985 Onchocerca volvulus Species 0.000 description 3
- 208000002042 Onchocerciasis Diseases 0.000 description 3
- 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
- 241000238631 Hexapoda Species 0.000 description 2
- 241000048284 Potato virus P Species 0.000 description 2
- 230000037034 TERMINAL HALF LIFE Effects 0.000 description 2
- 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 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
- 230000000694 effects Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 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
- 229950004178 Closantel Drugs 0.000 description 1
- 241000283073 Equus caballus Species 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
- 125000000998 L-alanino group Chemical group [H]N([*])[C@](C([H])([H])[H])([H])C(=O)O[H] 0.000 description 1
- 208000009874 Lice Infestations Diseases 0.000 description 1
- 229940105132 Myristate Drugs 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
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 231100000153 central nervous system (CNS) toxicity Toxicity 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 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
- 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
- 238000007689 inspection Methods 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
- 239000000463 material Substances 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-M myristate Chemical compound CCCCCCCCCCCCCC([O-])=O TUNFSRHWOTWDNC-UHFFFAOYSA-M 0.000 description 1
- 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
- 230000000275 pharmacokinetic Effects 0.000 description 1
- 230000036231 pharmacokinetics Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylaxis Effects 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 229940029612 triethanolamine Drugs 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
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
- A01N2300/00—Combinations or mixtures of active ingredients covered by classes A01N27/00 - A01N65/48 with other active or formulation relevant ingredients, e.g. specific carrier materials or surfactants, covered by classes A01N25/00 - A01N65/48
-
- 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
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
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% 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 lvermectin 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). lvermectin is chemically related to the insecticide avermectin. Both lvermectin and avermectin are derived from the bacterium Streptomyces avermitilis. lvermectin has the following general formula: Ivermectin is a mixture of two components (5-o—demethyl-22,23-dlhydroavermectin A13) and (25-(1-methylethyl)O-demethylde(1-methylpropyl)-22,23-dihydro- avermection A1a)- 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 iniectable solution. A solution for oral inoestinn will need tn nunrrnmn 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 formulation 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 ooncerned 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.
WO 01/60380 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 lvermectin 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 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 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 .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% v/v 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 cetearyl Ethylhexanoate and lsopropyl 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 ivermectin has completely dissolved; i) Adding the buffering agent triethanolamine 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 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 lvermectin 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 straightfonrvard 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. ldeally, 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 +/-‘lO%. 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 ivermectin 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 propanol conforms to the monograph of the European Pharmacopoeia 01/2005:0970. It is used as primarily as a solvent.
Preferably, isopropyl (IPA) is added at a level of from 65 to 75% v/v.
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-o-demethyl-22,23-dihydroavermectin Am) and (25-(1-methylethyl)0-demethyl— —de(1-methylpropyl)-22,23-dihydroavermection Ala). It is a white to yel|owish—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 isopropyl 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 v/v.
The following is the typical fatty acid profile of crodamol cap” (super refined) which may be used as an emollient according to the invention: isopropyl 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. O1/2005:1577 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 lvermectin formulation; Figure 2 shows a process outline for preparing a 1,500 litre lvermectin 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 lvermectin, 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 lvermectin 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. Visual 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 Formulation 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 . 0 . .
Mb-‘°’E"—°-95 0 5°/ w/v Active Ph Eur ivermectin ingredient Excigients: C’°d3'"°' Cap” 20.00% v/v Emollient Product spec.
Triethanolamine 0.05% v/v Buffer Ph. Eur. '5°P'°PY' a'°°“°' q.s. 100.0% v/v Solvent Ph. Eur.
Example 2: Manufacturing Process Eguipment 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: Manufacture of 180L Batch size The following steps were carried out: . Fill approx. 130L of lsopropyl alcohol into the manufacturing vessel; 2. Add ivermectin and mix for anoroximatelv 5 min: Add Crodamol Cap” and mix for approximately 5 min; Add Triethanolamine and mix for approximately 3 min; Bring to 180L mark with lsopropyl alcohol and mix for approximately 5 min; f3’.U":‘>.°° 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 +/- to minutes are also contemplated.
Method 2a: Manufacture of 15OOL Batch Size The following steps were carried out: Fill approx. 850Kg of lsopropyl alcohol into the manufacturing vessel; Add lvermectin 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; .°7:'>.°~’!°." Remove 100ml sample for visual assessment of ivermectin dissolution. If lvermectin 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 15OOL with lsopropyl 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 QC 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 +/- to minutes are also contemplated. in-Process Bulk Testinq Specifications: Test Specification Appearance A clear colourless solution with a characteristic odour lvermectin Assay (% w/v) .5% w/v (5% limit) Range: 0.475 — 0.525% w/v 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 lb/2b : Packaaind Procedure The following steps were carried out: . The formulation is cleared by QC and packaging materials are issued; . The containers are filled via the liquid filler . A container number check is made to establish the batch yield and to reconcile the theoretical versus the actual yield; . 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; . The containers are placed in outer cartons and the cartons sealed; . The cartons are palletised and placed in the finished product quarantine area for final inspection.
Example 2: Stabiliy Results for lvermectin Formulation Stability data of the two batches of the product manufactured according to Example a 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 lvermectin O.5%w/v 1L Flat Bottomed 180L Temp: 25'C/60%RH Pour-On lvermectin Flexi Pack P_ar1£ Specification Initial 4 mths 7 mths 9mths lomths Appearance A clear colourless Conforms Conforms 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 O.5%w/v 1 5% 0.508% 0.484% 0.495% 0.502% NP Mrmegtjn i.e. O.475%w/v — .525%w/v Part II Specification 12 mths 18 mths 21 mths 30 mths 36 mths Appearance Aclear Conforms Conforms Conforms Conforms Conforms colourless solution 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/v:t5% 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 Ivermectin 0.5%w/v 1L Flat Bottomed 180L Temp: Pour-On Ivermectin Flexi Pack 40°CI75%RH Test Specification initial 3mths 6mths 10 mths 12 mths 18mths Appearance A clear colourless Soiution witha Conforms Conforms Conforms Conforms Conforms Conforms characteristic odour.
Condition of Packaging intact Packaging Confonns Conforms Conforms Conforms Conforms Conforms Identification Conforms Conforms Conforms Conforms Conforms Conforms Conforms Assay Active Ivermectin O.5%w/vi5% 0.508% 0.488% 0.495% NP 0.485% 0.507% i.e. 0.475%w/v — 0.525%w/v ND: Not Detected NP 2 Not Performed It can be seen in the above tables that the Ivermectin 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 ivermectin was active at all times during this test period.
Thus, the process defined in Example 1 provides a stable, homogenous, anhydrous ivermectin 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, lvermectin.
Example 3 - Bio-eguivalence 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/016/00 (Guidelines 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 month-old 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 pg ivermectin per kg bodyweight.
The crossover design is summarised below: Group I Group II Phase I Reference Test (Days 0-42) lvomec® Classic Pour-On ivermectin Pour-On Phase ll Test Reference (Days 72-114) lvermectin Pour-On lvomec®Classic 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 ll) 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 l 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: r.>—<> ,.__.,...L,, _,.,..j_.....__.__....__._ ....___.............._ Variable Lower Limit (%) Upper Limit (%) Crnax 85.20% 116.65% 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/CVMP/016/O0 (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: Purging the manufacturing vessel with nitrogen gas; increasing the pressure in the manufacturing vessel from approximately 0.2bar to approximately 3.75 bar; Reducing the pressure in the manufacturing vessel in 3 cycles from approximately 3.75 bar to approximately 0.2 bar; Rinsing the manufacturing vessel with isopropyl alcohol; Adding isopropyl alcohol in the range of 60 to 80% v/v to the manufacturing vessel; 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; 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; 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; Adding a buffering agent in the range of 0.01% to 1% v/v and mixing for approximately 2 to 15 minutes; 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 m) Mixing the solution for a further 5 to 20 minutes directly prior to packaging b alcohol and mixing for a further approximately 5 to 15 minutes at a low speed of approximately 100 to 150 rpm; 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 the formulation obtained from step (k) into containers. . The process according to claim 1 wherein cetearyl ethylhexanoate is a mixture of stearyl octanoate and cetyl 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 (l) are subjected to HPLC analysis. Figure 1 Add 130 litres of isopropyl alcohol. l Add Ivermectin & mix for 5 mins. l Add fatty acid mixture & mix for 5 mins. l Add Triethanolamine & mix for3mins. l Bring to 180L mark with isopropyl alcohol & mix for 5 mins. l Send samples to QC for analvsis. ‘I1 2/3 Add approximately 850Kg of isopropyl alcohol. l Add lvermectin & mix for 5 mins. at low speed. l Add fatty acid ester mixture & mix for 15 mins. at low speed. l Mix for a further 15 mins. at low speed. l Add Triethanolamine & mix for 10 mins at low speed. l Bring to 1500L mark with isopropyl alcohol & mix for 20 mins. at low speed. l Send samples to QC for analysis. 7 Mix for 10 mins. at low speed immediately prior to filling 3 N 3/3 Purge with Nitrogen, 3 cycles to 1 bar (Volume 15M3) and then switch over to 0.2bar 7 Rinse Vessel, transfer lines and filling equipment with 100|tr of IPA. 7 Fill approx 850Kg of IPA pumped from externally located containers + Add 7.5kg lvennectin Powder. Mix at low speed (135 Rpm) for 5 minutes 7 Add 300kg fatty acid ester mixture from 2x200ltr container. Mix for set time at low speed(135Rpm) for 15 mins 7 Mix for a further 15 minutes at low speed (135 Rpm) — Add triethanoiamine 7 Remove 100ml Sample for visual assessment of dispersion. if dispersion not completed mix for a further 10 minutes at low speed (135 Rpm) Bring to 1500ltr with lsopropyl alcohol and mix for 20minutes at low speed (135 Rpm) Sampling & Analysis The bulk solution is sampled from the top and bottom of the tank and sent to QC for analysis, than Await approval to fill. Immediately prior to filling the solution is mixed for 10 minutes at low speed (140 Rpm) Fill from manufacturing tank using a filling device
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE2007/0393A IE85325B1 (en) | 2007-05-31 | A process for the preparation of a stable anhydrous anthelmintic formulation |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IEIRELAND05/12/2006S2006/0882 | |||
IE20060882 | 2006-12-05 | ||
IE2007/0393A IE85325B1 (en) | 2007-05-31 | A process for the preparation of a stable anhydrous anthelmintic formulation |
Publications (2)
Publication Number | Publication Date |
---|---|
IE20070393A1 IE20070393A1 (en) | 2008-12-10 |
IE85325B1 true IE85325B1 (en) | 2009-09-16 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9820959B2 (en) | Therapeutic compositions | |
AU762926B2 (en) | Methods and compositions for delivery of taxanes | |
CZ20013058A3 (en) | Pharmaceutical preparation for oral administration | |
CN104203235A (en) | Formulations of bendamustine | |
JP2016153438A (en) | Oral administration form of bendamustine | |
CA3023259A1 (en) | Compositions and methods for treatment of inflammation or infection of the eye | |
US20100016248A1 (en) | Tablet formulation | |
GB2444572A (en) | Process for the preparation of a stable anhydrous ivermectin formulation | |
CN109260158A (en) | A kind of Dimetridazole pre-mixing agent of highly-water-soluble high stability | |
NZ552816A (en) | Formulation for transdermal administration of antihyperthyroid drug comprising a penetration enhancer selected from oleic acid, d-limonene, pyrrolidones, a C2-C8 alcohol, glycol ethers, triacetin and combinations thereof | |
IE85325B1 (en) | A process for the preparation of a stable anhydrous anthelmintic formulation | |
IES84905Y1 (en) | A process for the preparation of a stable anhydrous anthelmintic formulation | |
US10335381B2 (en) | Stabilized formulation of triamcinolone acetonide | |
IE20070395U1 (en) | A process for the preparation of a stable anhydrous anthelmintic formulation | |
WO2013062425A1 (en) | Ionophore antibiotic veterinary composition and method of manufacture | |
AU2014201152B2 (en) | Tablet Formulation | |
US11324695B2 (en) | Transdermal solvent system and methods of use | |
Seshadri et al. | Formulation and evaluation of dapsone topical gel, 7.5% w/w | |
Sreelatha et al. | DESIGN AND INVITRO CHARACTERIZATION OF VORICONAZOLE GEL FOR TRANSDERMAL DRUG DELIVERY SYSTEM | |
AU2008201564A1 (en) | Levamisole, avermectins or similar in pyrrolidone solvent | |
CN114917221A (en) | Veterinary albendazole sulfoxide composition as well as preparation method and application thereof |