GB2403408A - Process for preparing anthelmintic suspension formulation - Google Patents
Process for preparing anthelmintic suspension formulation Download PDFInfo
- Publication number
- GB2403408A GB2403408A GB0315617A GB0315617A GB2403408A GB 2403408 A GB2403408 A GB 2403408A GB 0315617 A GB0315617 A GB 0315617A GB 0315617 A GB0315617 A GB 0315617A GB 2403408 A GB2403408 A GB 2403408A
- Authority
- GB
- United Kingdom
- Prior art keywords
- suspension
- triclabendazole
- suspension formulation
- preparing
- formulation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000725 suspension Substances 0.000 title claims abstract description 95
- 239000000203 mixture Substances 0.000 title claims abstract description 83
- 238000009472 formulation Methods 0.000 title claims abstract description 58
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 23
- 230000000507 anthelmentic effect Effects 0.000 title abstract description 8
- NQPDXQQQCQDHHW-UHFFFAOYSA-N 6-chloro-5-(2,3-dichlorophenoxy)-2-(methylthio)-1H-benzimidazole Chemical compound ClC=1C=C2NC(SC)=NC2=CC=1OC1=CC=CC(Cl)=C1Cl NQPDXQQQCQDHHW-UHFFFAOYSA-N 0.000 claims abstract description 94
- 229960000323 triclabendazole Drugs 0.000 claims abstract description 94
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000003755 preservative agent Substances 0.000 claims abstract description 10
- 230000002335 preservative effect Effects 0.000 claims abstract description 10
- 239000000375 suspending agent Substances 0.000 claims abstract description 8
- 239000002518 antifoaming agent Substances 0.000 claims abstract description 7
- 239000004094 surface-active agent Substances 0.000 claims abstract description 7
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims abstract description 4
- 239000000600 sorbitol Substances 0.000 claims abstract description 4
- 241001465754 Metazoa Species 0.000 claims description 39
- -1 Guinoline Yellow Chemical compound 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000008213 purified water Substances 0.000 claims description 20
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 17
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 16
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 9
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 9
- 229960003415 propylparaben Drugs 0.000 claims description 9
- 239000000839 emulsion Substances 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 8
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- SGHZXLIDFTYFHQ-UHFFFAOYSA-L Brilliant Blue Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 SGHZXLIDFTYFHQ-UHFFFAOYSA-L 0.000 claims description 7
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 7
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 claims description 7
- 239000011777 magnesium Substances 0.000 claims description 7
- 229910052749 magnesium Inorganic materials 0.000 claims description 7
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- 235000014113 dietary fatty acids Nutrition 0.000 claims description 6
- 239000000194 fatty acid Substances 0.000 claims description 6
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- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 4
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims description 4
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- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 4
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 4
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 4
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- 239000004411 aluminium Substances 0.000 claims description 4
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- 229960002798 cetrimide Drugs 0.000 claims description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 4
- 229930002875 chlorophyll Natural products 0.000 claims description 4
- 235000019804 chlorophyll Nutrition 0.000 claims description 4
- 239000001752 chlorophylls and chlorophyllins Substances 0.000 claims description 4
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 4
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 claims description 4
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- 239000004179 indigotine Substances 0.000 claims description 4
- 235000012752 quinoline yellow Nutrition 0.000 claims description 4
- 239000004172 quinoline yellow Substances 0.000 claims description 4
- 235000010199 sorbic acid Nutrition 0.000 claims description 4
- 239000004334 sorbic acid Substances 0.000 claims description 4
- 229940075582 sorbic acid Drugs 0.000 claims description 4
- 235000012756 tartrazine Nutrition 0.000 claims description 4
- 239000004149 tartrazine Substances 0.000 claims description 4
- 229960000943 tartrazine Drugs 0.000 claims description 4
- UJMBCXLDXJUMFB-GLCFPVLVSA-K tartrazine Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-GLCFPVLVSA-K 0.000 claims description 4
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- 235000012677 beetroot red Nutrition 0.000 claims description 3
- 239000001654 beetroot red Substances 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
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- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 3
- 229940105329 carboxymethylcellulose Drugs 0.000 claims description 3
- OIQPTROHQCGFEF-UHFFFAOYSA-L chembl1371409 Chemical compound [Na+].[Na+].OC1=CC=C2C=C(S([O-])(=O)=O)C=CC2=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 OIQPTROHQCGFEF-UHFFFAOYSA-L 0.000 claims description 3
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 3
- 229940068965 polysorbates Drugs 0.000 claims description 3
- NDDLLTAIKYHPOD-ISLYRVAYSA-N (2e)-6-chloro-2-(6-chloro-4-methyl-3-oxo-1-benzothiophen-2-ylidene)-4-methyl-1-benzothiophen-3-one Chemical compound S/1C2=CC(Cl)=CC(C)=C2C(=O)C\1=C1/SC(C=C(Cl)C=C2C)=C2C1=O NDDLLTAIKYHPOD-ISLYRVAYSA-N 0.000 claims description 2
- JCIIKRHCWVHVFF-UHFFFAOYSA-N 1,2,4-thiadiazol-5-amine;hydrochloride Chemical compound Cl.NC1=NC=NS1 JCIIKRHCWVHVFF-UHFFFAOYSA-N 0.000 claims description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 claims description 2
- JMEVHYCNAPFOAB-UHFFFAOYSA-N 2-(3-hydroxy-5-sulfo-1H-indol-2-yl)-3-oxoindole-5-sulfonic acid Chemical compound Oc1c([nH]c2ccc(cc12)S(O)(=O)=O)C1=Nc2ccc(cc2C1=O)S(O)(=O)=O JMEVHYCNAPFOAB-UHFFFAOYSA-N 0.000 claims description 2
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 claims description 2
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 claims description 2
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 claims description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- CEZCCHQBSQPRMU-LLIZZRELSA-L Allura red AC Chemical compound [Na+].[Na+].COC1=CC(S([O-])(=O)=O)=C(C)C=C1\N=N\C1=C(O)C=CC2=CC(S([O-])(=O)=O)=CC=C12 CEZCCHQBSQPRMU-LLIZZRELSA-L 0.000 claims description 2
- 241000416162 Astragalus gummifer Species 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- LVDKZNITIUWNER-UHFFFAOYSA-N Bronopol Chemical compound OCC(Br)(CO)[N+]([O-])=O LVDKZNITIUWNER-UHFFFAOYSA-N 0.000 claims description 2
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- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 1
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- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
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- IMPKVMRTXBRHRB-UHFFFAOYSA-N cyclohexane-1,2,3,4,5-pentol Chemical compound OC1CC(O)C(O)C(O)C1O IMPKVMRTXBRHRB-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
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Classifications
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- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A process for preparing a stable anthelmintic suspension formulation, comprising an effective amount of triclabendazole. The stability of the triclabendazole in the suspension is retained after preparation. The invention also relates to the suspension formulation prepared by that process. The invention further relates to the use of the suspension formulation. The suspension should also comprise sorbitol; a suspending agent; a surface active agent; a preservative; and an anti-foaming agent and should be circulated through a colloidal mill.
Description
24034 08 1 - "Process for Drenarina a stable anthelmintic suspension
formulation"
Introduction
The present invention relates to a process for preparing a stable anthelmintic suspension formulation comprising an effective amount of triclabendazole and further relates to the suspension formulation prepared by that process.
In the specification the term "suspension" refers to a mixture of fine, non settling particles of any solid, within a liquid, the particles being in the dispersed phase, while the suspending medium is in the continuous phase. In the specification the term "solution', refers to a single homogenous liquid, solid or gas phase that is a mixture in which the components are uniformly distributed throughout the mixture. In the specification the term "effective amount" refers to the amount of triclabendazole necessary to destroy parasites. In the specification, the term "win" refers to the We Of the final suspension formulation.
Triclabendazole is an anthelmintic compound and is part of the benzimidazole group, which comprises compounds which are effective against parasites including liver fluke 2 0 and tapeworm. Triclabendazole is also known as 5-Chloro-6- (2,3- dichlorophenoxy) 2-methylthio-l H-benzimidazole.
Triclabendazole is particularly effective as an anthelmintic, however, previously it has been difficult to make up suspensions comprising triclabendazole due to the highly 2 5 insoluble nature of this compound. One of the problems associated with suspensions comprising triclabendazole is that the triclabendazole settles out of the suspension causing differences in concentration throughout the suspension.
POT Publication No. WO 00/61068 discloses a anthelmintic formulation wherein 3 0 triclabendazole is dissolved in at least one solvent such as benzyl alcohol and glycerol formal. Therefore, the formulation is a solution rather than a suspension. During preparation of this solution the components are heated. The disadvantage of heating the formulation is that the efficacy of triclabendazole is reduced. Furthermore, this solution is inappropriate for oral use in that the solvents are not particularly sortable l 2 - for ingestion by animals.
In addition, triclabendazole is more effective when administered as a suspension rather than as a solution as the particles of anthelmintic compound are freer to act on the parasites compared to particles which have been dissolved. Thus in a solution a higher concentration of triclabendazole is required in order to have an efficacy comparable to that of a suspension.
PCT Publication No. Wo 021080883 discloses a method and composition for solubilising a biologically active compound with low water solubility such as triclabendazole. The composition must be prepared in situ just prior to use, however and cannot be stored, and is therefore disadvantageous in that it cannot be prepared in advance There is therefore a need for a stable suspension formulation comprising triciabendazole which is suitable for oral use. There is a further need for a process of preparing such a stable suspension formulation. Stability is necessary in order to allow for the suspensions to be prepared well in advance of their intended use.
2 0 Statements of Invention
According to the invention there is provided a process for preparing a suspension forrmulation comprising an effective amount of triclabendazole; comprising 2 5 adding purified water to a vessel, adding sorbitol to purified water in the range 15-25% w/v of the final Suspension formulation and agitating to form a suspension, 3 0 adding a suspending agent to the suspension in the range 0.3-1.0% why, adding a surface acting agent to the suspension in the range 0.05-0.15% why, adding a preservative to the suspension in the range 0.01-0.3% who, adding an anti-foaming agent to the suspension in the range 0.04-0.06% w/v, adding triclabendazole to the suspension, adding purified water to make up to the desired volume, circulating the suspension through a colloidal mill, adding purified water to make up to the desired volume of liquid, and agitating the liquid Preferably, triclabendazole is added in the range 3-13% w/v.
Further, preferably triclabendazole is added in the range 5-10% who.
The components are mixed together in a cold mix, this is advantageous in that high temperatures can cause triclabendazole to loose its efficacy on storage. It is therefore recommended that preparations containing triclabendazole to not exceed 30 C. Triclabendazole formulations are stable if stored below 25OC. The rate of degradation of triclabendazole will double as the temperature rises by 10 C.
The suspension having of the order of 5% w/v, triclabendazole composition is more suitable for treating sheep.
The suspension having of the order of 10% who triclabendazole composition is more suitable for treating cattle.
An advantage of a suspension formulation rather than a solution, is that it is possible to use lower percentages of triclabendazole while still retaining the required efficacy.
The advantage of using lower percentages of triclabendazole are lower toxicity and better metabolism of the active pharmaceutical ingredient.
I J - 4 -
In one embodiment of the invention a dye solution is added to the suspension. The dye solution may be selected from the group comprising brilliant blue, carmoisine supra, curcum in, Lactoflavin, Tartrazine, Guinoline Yellow, Sunset Yellow FI F. Cochineal Carminic Acid, Carmoisine, Ponceau 4R, Patent Blue, Indigo Carmine, Chlorophylls, Copper Complexes or Chlorophylls and Chlorophylline, Acid Brilliant I Green BS, Caramel, Brilliant Black ON, Black PN, Carbo Medicinalis Vegetabilis, Carotenoids, Xanthophylls, Beetroot red, Betanin, Anthocyanins, Calcium Carbonate, Titanium Dioxide, Iron Oxide and Hydroxides, Brilliant Blue FCF, Indigotine, Alphazurine FG, Indanthrene blue, Fast Green FCF, Alizarin Cyanine, Green F. Quinizarine Green SS, Pyranine concentrated, Orange II, Dibromoflurescein, Dilodofluorescein, Erythrosine yellowish Na, Erythrosine, Ponceau SX, Lithol rubin B. Lithol rubin B Ca, Toney red, Tetrabromoflurescein, Eosine, l etrachlorotetrabromofluorescein, Phloxine B. Helindone pink CN, Brilliant lake red R. Acid fushsine, Lake Bordeaux B. Flaming Red, Alba Red, Allura red AC, Alizurol purple S S. Tartrazine, Sunset yellow FCF, Fluorescein, Naphthol I yellow S. Uranine, Quinoline yellow WS, Quinoline yellow SS.
The advantage of the dye solution is to allow easy identification of treated animals. I In a further embodiment of the invention, the suspending agent is selected from the group comprising magnesium, aluminium, silicate (veegum K), microcrystalline cellulose and carboxy methyl cellulose sodium (avicel), Medium Chain Glycerides, Alginic Acid, Sodium Alginate, Bentonite, Carbomer, Carboxy Methyl Cellulose, 2 5 Carboxy Methyl Cellulose Calcium, Powdered Cellulose, Microcrystalline Cellulose, Hydroxy Propyl Cellulose, Hydroxy Ethyl Cellulose, Colloidal Silicon Dioxide, Dextrin, :3elatin, Guar Gum, Xanthan Gum, Kaolin, Magnesium Aluminium Siclicate, Maititol, Maltitol Solution, Methyl Cellulose, Polyoxyethylene Fatty Acid Esters (Polynorbates), Povidone, Propoylene (31ycol Alginate, Sorbitan Esters, 3 0 Tragacanth.
The advantage of the suspending agent is to maintain triclabendazole in suspension and prevent it from settling out of the formulation.
J
In a still further embodiment of the invention, the surface acting agent is selected from the group comprising polysorbate, docusate Sodium, Sodium Lauryl Sulphate, Cetrimide, Polyoxyethylene Fatty Acid Esters (Polysorbates), Sorbitan Esters (Sorbitan Fatty Acid Esters).
The advantage of the surfactant is to reduce the interracial tension between the purified water and the suspended solids.
Preferably, the preservative is selected from the group comprising methyl paraben, propyl paraben, Phenolic Acid, Sorbic Acid, Editic Acid (EDTA), Benzoic Acid, Benzyl Alcohol, Benzethinium Chloride, Bronopol, Butyl Paraben, Cetrimide, Chlorhexidine, Chlorobutanol, Chlorocresol, Cresol, Ethyl Paraben, Glycerol, Imeburea, Methyl Paraben, Phenol, Phenoxy Ethanol, Phenylethyl Alcohol, Phenyl Mercuric Acetate, Phenyl Mercuric Borate, Phenyl Mercuric Nitrate, Potassium Sorbate, Propylene Glycol, Propyl Paraben, Sodium Benzoate, Sodium Propionate, Sorbic Acid, Thimerosol.
The advantage of the preservative is to increase the shelf life of the suspension formulation and to maintain the stability of the formulation.
Further, preferably the anti-foaming agent is selected from the group comprising simethicone emulsion, Simethicone Emulsion, Poloxamer- 188, Polacricin Potassium, Long Chain Alcohol, Silicrone Derivative. The advantage of the anti foaming agent is to inhibit the formation of bubbles in the suspension during its agitation by reducing the surface tension between the suspended solids and the purified water.
The invention further provides a suspension formulation as prepared by the process.
3 0 The invention still further provides the use of the suspension formulation for treating parasitic infestation in animals.
Preferably the suspension formulation is administered orally. The advantage of oral administration of the composition as compared to administration as a pour-on is that
J 6 -
oral administration is the most effective method of administration. Administration as a pour-on has only recently been employed to deliver drugs to the body for systemic effects. This topical route is limited in its ability to allow effective drug absorption for systemic drug action. Furthermore as it is possible to administer this suspension formulation orally it is possible to use lower percentages of triclabendazole than if administered as a pour on. Generally speaking, pour on formulations require higher percentages of a drug, than oral or parenteral formulations.
Detailed Description the Invention
The invention Will be more clearly understood from the following description with reference to the accompanying drawings wherein; Figs 1 and 2 are a process outline for preparing a 1,800 litre batch of triclabendazole 1 5 formulation.
Fig. 3 illustrates the concentration of triclabendazole-sulfone in sheep plasma (5% who triclabendazole).
2 0 Fig. 4 illustrates the concentration of triclabendazole-suHoxide in sheep plasma (5% w/v triclabendazole) Fig. 5 illustrates the concentration of triclabendazole-suHone in cattle plasma (10% w/v triclabendazole).
Fig. 6 illustrates the concentration of triclabendazole-suHoxide in cattle plasma (10% w/v triclabendazole).
All of the equipment used in carrying out the process is well known equipment and 3 0 accordingly does not require any further description. However, one item of equipment not normally used is a colloidal mill, the function of which is to make very fine dispersions of the liquids and solids by breaking down particles in an emulsion or paste. This can also be achieved by using a triple roller mill which is a series of roller mills in which the material is fed past spring-loaded rollers that apply force against the 7 - sides of a revolving bowl.
Referring to Fig. 1 in step 1, 1,200 litres of purified water are added to a mixing vessel. A liquid carrier such as 70% non-crystallising sorbitol solution is added to the purified water in the range 15-25% who of the final formulation in the manufacturing vessel and mixed for 10 minutes in step 2. In step 3, a dye such as brilliant blue solution previously prepared by dissolving a few brilliant blue drops in 8-10 litres purified water and mixing for 10 minutes, is added to the manufacturing vessel and further mixed for 10 minutes.
A suspending agent such as magnesium aluminium silicate is added to the manufacturing vessel slowly in the range 0.3-0.5% w/v and the mixture is agitated for minutes in step 4. In step 5 a suspending agent such as microcrystalline cellulose and carboxy methyl cellulose is added to the manufacturing vessel in the range 0.8 1.0% w/v and the mixture is agitated for 10 minutes. A surface acting agent such,as polysorbate is added to the manufacturing vessel in the range 0.05-0.15% wh and the mixture is agitated for 10 minutes in step 6.
In step 7, a preservative such as methyl paraben in the range 0.1-0.3% who is added 2 0 to the manufacturing vessel and the mixture is agitated for 10 minutes. A preservative such as propyl paraben is added to the manufacturing vessel in the range 0;()1-0.03% w/v and the mixture is agitated for 10 minutes in step 8. In step 9, an anti-foaming agent such as simethicone emulsion is added to the manufacturing vessel in the range 0.04-0.06% wh and the mixture is agitated for 5 minutes.
Referring now to Fig. 2 in step 10, the active pharmaceutical ingredient triclabendazole is added to the manufacturing vessel slowly in the amount 5-10% who and the mixture is agitated for 100 minutes. The volume of mixture in the water is then made up to the 1,800 litre mark using purified water in step 11, and the mixture is agitated for a further 30 minutes. In step 12, the mixture is circulated through a colloidal mill for 60 minutes. The mixture is then allowed to settle in step 13 and in step 14, the mixture is brought up to the 1,800 litre mark using purified water and mixed for a further 45 minutes. In step 15, the mixture is sampled from the top, middle and bottom of the tank and sent to quality control for analysis. As the
I - 8
suspension settles after mixing H may dip below the 1,800 litre mark. On the basis of the results of the analysis more purified water may be added to bring H back to the 1,800 litre mark and the mixture is further agitated for 30 minutes in step 16. In step 17, the mixture is further sampled from the top, middle and bottom of the tank and sent to quality control for analysis of the physical, microbiological, chemical and chromatographic parameters. During processing, the maximum temperature reached by the formulation is 25 C.
Examnle 1: Comparisons 5% Triclabendazole suspension formulation with 5% Triclabendazole solution (FASINE)( _ Novartis} The 5% triclabendazole suspension formulation was prepared according to the above process in the quantities as outlined in Table 1.
Table 1: Triclabendazole 5% w/v suspension formulation Component % who of Formulation Triclabendazole 5 70% non-crystallising sorbHol solution 20 _ _. _.
Magnesium aluminium silicate 0.4 Microcrystalline cellulose and carboxy methyl 0,9 cellulose sodium
_
Polysorbate 0.05
_
Methyl paraben 0.2 Propyl paraben 0.02
__
Simethicone Emulsion 0.05 Brilliant-Rlue 0.00175
_
Purified water 73.38 _.
The objective of this study was to investigate the pharmacokinetic behaviour of Triclabendazole in blood samples following a single oral administration of the test and reference formulations, Triclabendazole 5% ('treatment A") and Fasinex _ 5% 2 0 ("treatment B") to sheep. The pharmacokinetic parameters of the preparations were compared and a statistical evaluation performed. - 9 -
Study Design The study was a two-way, non-blinded, crossover study with 10 animals per treatment group.
Group A Group B Phase I Test Reference Phase II Reference Test The animals were subjected to a 2 week acclimatization period. At the start of this acclimatization period (day - 14), each animal was individually identified by an ear tag or skin tattoo. Each animal was clinically examined by the Study Investigator for signs which may have excluded the animals from the trial. Only healthy animals were included in the trial. Animals which received medication within the previous 14 days were excluded from the study. The weight of the animals included in the clinical trial was determined on Day- 7 and animals then were randomly allocated to the treatment groups.
Day 0 was the day of administration of the products to animals in Phase I. 10 animals were given Triclabendazole 5% and the remaining 10 animals were given Fasinex TM5%. All products were administered orally. This was followed by a 20 day wash out period. On day 20 animals were re-weighed in order to calculate the dose for phase 11 of the study.
Phase II of the study was commenced (Day 21), with the groups being crossed over and administered the formulation not received in phase 1. Both products were administered at a dose rate of 10 mg/kg triclabendazole.
Blood Sampling Immediately prior to oral administration of the test or reference product (hour 0), blood was collected from all test animals. Additional blood samples were collected from all test animals at the following post treatment times: 12, 18, 24, 30, 36, 48, 60, 72, 96, 134 and 168 hours. The sampling at 134 hours originally was scheduled for 132 hours after administration.
Following the 7 day post-treatment blood sampling period, the animals were held for an additional 13 days before being crossed-over to the other product. Following collection of the zero-hour blood in phase 11, the animals in each group were administered the second product and blood sampling performed at the intervals outlined for phase I above.
Analytical Method The concentrations of Triclabendazole were determined in the plasma samples by a validated HPLC-UV method. The analytical method was carried out by the HPLC department of AAI Deutschland. The lower limit of quantification was 0.1 ng/ml for Triclabendazole.
As illustrated in Figs. 3 and 4 the concentrations of triclabendazole, both in the suHone and sulfoxide forms decreased at the same rate as the triclabendazole solution. Triclabendazole reacts with sulphur in the animals body to form either triclabendazole sulfoxide or triclabendazole suHone. This would indicate that the 2 0 triclabendazole does not settle out of the suspension but is absorbed equally as well as though it was in a solution.
ExamDl0 2: Comoarlson of 10% Triclabendazole suspension formulation with 10% Triclabendazole solution ([ASINEX _. Novartis) The 10% triclabendazole suspension formulation was prepared according to the above process in the quantities as outlined in table 2.
- 11 - Table 2: Triclabendazole 10% w/v suspension formulation _. . Component % w/v of Formulation _. _. . ._ Triclabendazole 10:
_ _
70% non-cyrstallising sorbKol solution 20 _ _ _. _.
Magnesium aluminium silicate 0.4 I Microcrystalline cellulose and carboxy methyl 0.9 cellulose sodium
___
Polysorbate 0.1
_ _ _
Methyl paraben 0.2
_
Propyl paraben 0.02 : Simethicone Emulsion 0.05 1 _. _ Brilliant Blue 0. 002 Purified water 68.33 The objective of-this study was to investigate the pharmacokinetic behaviour of: triclabendazole in blood samples following a simple oral administration of the test and ' reference formulations, Triclabendazole 10% ("treatment A") and Fasinex _ 10% i ("treatment B") to cattle. The pharmacokinetic parameters of the preparations were compared and a statistical evaluation performed.
Study Design The study was a two-way, non-blinded, crossover study with 10 animals per treatment group.
Group A Group B Phase I Test Reference Phase II Reference Test The animals were subjected to a 2 week acclimatization period. At the start of this acclimatization period (day -14), each animal was individually identified by an ear tag 2 0 or skin tattoo. Each animal was clinically examined by the Study Investigator for signs which may have excluded the animals from the trial. Only healthy animals were - 12 - included in the trial. Animals which had received medication within the previous 14 days were excluded from the study. The weight of the animals included in the clinical trial was determined on Day - 7 and animals then were randomly allocated to the treatment groups.
Day 0 was the day of administration of the products to animals in Phase I. 10 animals were given Triclabendazole 10% and the remaining 10 animals were given Fasinex rM 10%. All products were administered orally. This was followed by a 20 day wash out period. On day 20 animals were re- weighed in order to calculate the dose for phase 11 of the study.
Phase II of the study was commenced (Day 21), with the groups being crossed over and administered the formulation not received in phase 1.
Both products were administered at a dose rate of 12 mg/kg triclabendazole.
Blood Sampling Immediately prior to oral administration of the test or reference product (hour 0), blood was collected from all test animals. Additional blood samples were collected from all 2 0 test animals at the following post treatment times: 12, 18, 24, 30, 36, 48, 60, 72, 96, 132 and 168 hours.
Following the 8 day post-treatment blood sampling period, the animals were held for an additional 13 days before being crossed-over to the other product. Following collection of the zero-hour blood in phase 11, the animals in each group were administered the second product and blood sampling performed at the intervals outlined for phase I above.
Analytical Method The concentrations of Triclabendazole were determined in the plasma samples by a validated HPLC-UV method. The analytical method was carried out by the HPLC department of Ml Deutschland. The lower limit of quantification was 0.1 pg/ml for Triclabendazole.
- 13 - As illustrated in Figs. 5 and 6 the concentrations of triclabendazole, both in the suHone and sulfoxide forms decreased at the same rate as the triclabendazole solution. This would indicate that the triclabendazole does not settle out of the suspension but is absorbed equally as well as though it was in a solution.
ExamDIe! 3: Homoqeneitv Results for 5% Triclabendazole SusDension The 5% triclabendazole suspension formulation was prepared as before, in the quantities as outlined in Table 1.
Samples from the Top-left (TL), Top-right (TR), Middle-left (ML), Middleright (MR), Bottom-lt (BL) and Bottom-right (BR) of the vessel were taken, and assayed for the active ingredient to confirm homogeneity of the suspension.
Based on the active results, the suspension was topped up with 59 litres of purified water and mixed for a further 30 minutes. A further 6 samples were taken as above and analysed for the active ingredient.
The results are shown in tables 3 and 4.
Table 3: 5% Triclabendazole Suspension Assay, Homogeneity Results, (Before Top Up)
_
Sample % w/v Triclabendazole _. _.
Top lefK (1TL) 5.116 Top right (2TR) - 5.107 Middle lea (3ML) 5.272* Middle right (4MR) 5.135 l Bottom lefK (5BL) _ 5.113 l Bottom right (6BR) 5.263*
* Out of specification
2 5 SDecific:ation 5% w/v (5% limit). Range: 4.75 - 5.25% w/v - 14 Table 4: 5% Triclabendazole Suspension Assay, Homogeneity Results, (After Top Up) Sample % w/v Triclabendazole Top left (1TL) 5.040 Top right (2TR) 4. 949 |
_
Middle left (3ML) 5.062
_
Middle right (4MR) 4.994 l Bottom left (5BL) 5.035
__
Bottom right (6BR) 5.052
-
SPecific;3tion: 5% w/v (5% limit). Range:4.75 - 5.25% wh ExrnDle 4: Homoneneity Results for 10% Triclabendazole Suspension The 10 y, Triclabendazole suspension formulation was prepared as before, in the quantities as outlined in Table 2.
Samples from the Top-left (TL), Top-right (TR), Middle-left (ML), Middleright (MR), Bottom-le,ft (BL) and Bottom-right (BR) of the vessel were taken, and assayed for the active ingredient to confirm homogeneity of the suspension.
Based on the active results, the suspension was topped up with 151 iitres of purified water and mixed for a further 30 minutes. A further 6 samples were taken as above and analysed for the active ingredient.
The results are shown in tables 5 and 6.
Table 5: 10% Triclabendazole Suspension Assay, Homogeneity Results, (Before Top Up) _._ _ Sample % w/v Triclabendazole Top left (1TL) 10.875* _ _. _ Top right (2TR) 10.937* __.
Middle left (3ML) 10.875* Middle right (4MR) 10.979* Bottom left (5BL) 10. 865* Bottom right (6BR) 10.995*
* Out of specification
Specification: 10% w/v (5% limit). Range: 9.50- 10.50% who Table 6: 10% Triclabendazole Suspension Assay, Homogeneity Results, (After Top Up) _. _ _ _.
Sample % w/v Triclabendazole l Top left (1TL) --10.188 _..
Top right (2TR) 10.056 Middle left (3ML) 10.078 Middle right (4MR) 10.075 - --
_
Bottom left (5BL) 9.929 Bottom right (6BR) 10.104 l Specification: 10% why (5% limit). Range: 9.50- 10.50% w/v The results show that the suspensions of triclabendazole at both 5% and 10% concentrations are homogenous, thereby indicating that the Triclabendazole has not settled out of suspension.
- 16 - Example 5: Stabilitv Results for 10% Triclabendazole suspension A 10% triclabendazole suspension formulation was prepared as before, in the quantities as outlined in Table 2.
The following analysis were carried out on the suspension and the results are tabulated in Table 7.
ANALYSIS
CHARACTERISTICS TESTS SPECIFICATIONS METHOD
Physical Description Pink coloured uniform Visual
Suspension Resuspendability Resuspends easily Visual Microbioloal Preservative efficacy Conform to PhEur, tested PhEur at 0 & 26 months Mlcroblal purity Conform to PhEur, tested PhEur at 0 & 36 months Chemical pH 5.5 - 7.5 Viscosity* 20 - 160 cp 2 0 ChromatrJurarJhic Identificatlon Triclabendazole Retention time of the major HPLC peak of the preparation corresponds to that of the standard preparation, in the 2 5 HPLC assay.
Methyl Paraben The chromatography of the HPLC Propyl Paraben assay exhibits major peaks due to Methyl and Propyi Parabens the retention 3 0 times of which correspond to those exhibited in the chromatogram of the standard.
Assays Triclabendazole 10% wh, (5%). HPLC i.e.9.5-10.5% Wh - 17 - Methyi Paraben 0.2% wh, (+10%) HPLC i.e. 0.18 - 0.22% Wh Propyl Paraben 0. 02% wh, (+10%), HPLC i.e. 0.018 - 0.22% wh Packaulng Condition of No evidence of leakage Visual Container Table 7: Stability Results, batch of 10% Triclabendazole Suspension
Test Specification inKiai 3 9 12 1 B 24 36
mths mths mths mths mths I mths mths 12/98 03/99 06/99 09/99 12/99 06/00 12/00 12/01
Description Pink coloured,1 _
uniform suspension l _ - 5.5 - 7.5 6.82 6.90 6.62 6.14 6.26 6.50 6.55 6.42 PresenvaLve Content: Methyl 0.18 - 0.22 h 0.20 1 0.19 0.19 0.18 0.18 0.18 0.18 0.18 Paraban wh Propyl Paraban 0.018 - 0.020 0.018 0.018 0.018 0.018 0.016 0.018 0.022% wh Impurities _ _ _.
Total impurities NMT 2.0% 0.73 0.64 O.B2 0.62 0.93 1.271 1.247 1.25 NT 0. 197 0: 0.20 0.32 0.37 0 30 0.33 il NT 0.11 0.11 0.12 0.11 0.11 0.15 0.20 i - NMT 1.5% NT 0.53 0.49 0.50 0.50 0.79 0.78 0.72
IV _ NT ND ND ND ND ND ND ND
Triclabendazole 9.50 - 9.94 9.90 9.98 9.92 9.90 9.85 9.72 9.63 Assay 10. 50% wh Preservative Ph. Eur. _ -; Efficacy Viscosity. 20 - 160 cps 157 145 95 95 90 57 49 42 Condition of No evidence NR NR NR NR 1,1 Container of leakage _ Resuspendability Resuspends NR NR NR NR easily _ _ - 18 NT=Not Tested ND-Not Detected ≤Complies NR=Not Recorded. The inspection of the containers was officially recorded from the 12 month time point onwards.
* Temporary specification, based on pilot batches
Impuritles: I - Total unknown impurities 11 - 5-chloro-6 (2, 3 dlchloro phenoxy) 2-methyl sulphonyl benzimidazole lit - Mix of 5-chloro-6-phenoxy-2-methyl thio 1 N-methyl benzimidazole and 5-chloro-6-phenoxy-2-methyl thio-3N-methyl benzimidazole IV- 5-chloro- 6 (2, 3 dichlorophenozy)-2-methyl benzimidazole sulphoxide Table 7 illustrates the stability of a 10% Triclabendazole suspension over a 3 year period. Each of the parameters measured, were within the specification allowed confirming that this suspension can be prepared well in advance of use.
2 0 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 to the widest possible interpretation.
The invention is not limited to the embodiments described above but may be varied within the scope of the claims. i
Claims (15)
- - 19 - Claims 1. A process for preparing a suspension formulationcomprising an effective amount of triclabendazole; comprising adding purified water to a vessel, adding sorbitol to purified water in the range 15-25% wh of the final suspension formulation and agitating to form a suspension, adding a suspending agent to the suspension in the range 0.3-1.0% wlv, adding a surface acting agent to the suspension in the range 0.05 0.15% wh, adding a preservative to the suspension in the range 0.01-0.3% we, adding an anti-foaming agent to the suspension in the range 0.04
- 2 0 0.06% we, adding triclabendazole to the suspension, adding purified water to make up to the desired volume, circulating the suspension through a colloidal mill, adding purified water to make up to the desired volume of liquid; and 3 0 agitating the liquid 2. A process for preparing a suspension formulation as claimed in claim 1, wherein triclabendazole is added in the range 3-13% we.
- 3. A process for preparing a suspension formulation as claimed in claim 2 wherein triclabendazole is added in the range 5-10% w/v.
- 4. A process for preparing a suspension formulation as claimed in any preceding claim, further comprising adding a dye solution to the suspension.
- 5. A process for preparing a suspension formulation as claimed in claim 4, Wherein the dye solution is selected from the group comprising brilliant blue, carmoisine supra, Curcumin, Lactoflavin, Tartrazine, Guinoline Yellow, Sunset Yellow FIF, Cochineal Carminic Acid, Carmoisine, Ponceau 4R, Patent Blue, Indigo Carmine, Chlorophylls, Copper Complexes or Chlorophylls and Chlorophylline, Acid Brilliant Green BS, Caramel, Brilliant Black BN, Black PN, Carbo Medicinalis Vegetabilis, Carotenoids, Xanthophyl Is, Beetroot red, Betan in, Anthocyan ins, Calcium Carbonate, Titanium Dioxide, Iron Oxide and Hydroxides, Brilliant Blue FCF, Indigotine, Alphazurine FG, Indanthrene blue, Fast Green FCF, Alizarin Cyanine, I Green F. Quinizarine Green SS, Pyranine concentrated, Orange II, Dibromoflurescein, Dilodofluorescein, Erythrosine yellowish Na, Erythrosine, Ponceau SX, Lithoi rubin B. Lithol rubin B Ca, Toney red, 2 0 Tetrabromoflurescein, Eosine, Tetrachlorotetrabromofluorescein, Phloxine B. Helindone pink CN, Brilliant lake red R. Acid fushsine, Lake Bordeaux B. I Flaming Red, Alba Red, Allura red AC, Alizurol purple SS, Tartrazine, Sunset yellow FCF, Fluorescein, Naphthol yellow S. Uranine, Quinoline yellow WS, Quinoline yellow SS.
- 6. A process for preparing a suspension formulation as claimed in any preceding claim wherein the suspending agent is selected from the group comprising magnesium, aluminium, silicate (veegum K), microcrystalline cellulose and carboxy methyl cellulose sodium (avicel), Medium Chain Glycerides, Alginic Acid, Sodium Alginate, Bentonite, Carbomer, Carboxy Methyl Cellulose, Carboxy Methyl Cellulose Calcium, Powdered Cellulose, Microcrystalline Gellulose, Hydroxy Propyl Cellulose, Hydroxy Ethyl Cellulose, Colloidal Silicon Dioxide, Dextrin, Gelatin, Guar Gum, Xanthan Gum, Kaolin, Magnesium Aluminium Siclicate, Maltitol, Maltitol Solution, Methyl Cellulose, t t - 21 - Polyoxyethylene Fatty Acid Esters (Polysorbates), Povidone, Propoylene Glycol Alginate, Sorbitan Esters, Tragacanth.
- 7. A process for preparing a suspension formulation as claimed in any preceding claim wherein the surface acting agent is selected from the group comprising polysorbate, docusate Sodium, Sodium Lauryl Sulphate, Cetrimide, Polyoxyethylene Fatty Acid Esters (Polysorbates), Sorbitan Esters (Sorbitan Fatty Acid Esters).
- 8. A process for preparing a suspension formulation as claimed in any preceding claim wherein the preservative is selected from the group comprising methyl paraben, propyl paraben, Phenolic Acid, Sorbic Acid, Editic Acid (EDTA), Benzoic Acid, Benzyl Alcohol, Benzethinium Chloride, Bronopol, Butyl Paraben, Cetrimide, Chlorhexidine, Chlorobutanol, Chlorocresol, Cresol, Ethyl Paraben, Glycerol, Imeburea, Methyl Paraben, Phenol, Phenoxy Ethanol, Phenylethyl Alcohol, Phenyl Mercuric Acetate, Phenyl Mercuric Borate, Phenyl Mercuric Nitrate, Potassium Sorbate, Propylene Glycol, Propyl Paraben, Sodium Benzoate, Sodium Propionate, Sorbic Acid, Thimerosol.
- 9. A process for preparing a suspension formulation as claimed in any preceding claim wherein the anti-foaming agent is selected from the group comprising simethicone emulsion, Simethicone Emulsion, Poloxamer- 188, Polacricin Potassium, Long Chain Alcohol, Silicrone Derivative.
- 10. A suspension formulation as prepared by the process of any one of claims to9.
- Use of a suspension formulation as claimed in claim 10 for treating parasKic 3 0 infestation in animals.
- 12. Use as claimed in claim 11 wherein the suspension formulation is administered orally.- 22 -
- 13. A process for preparing a suspension formulation substantially as described herein with reference to the examples and drawings.
- 14. A suspension formulation substantially as described herein with reference to the examples and drawings.
- 15. Use of a suspension formulation substantially as described herein with reference to the examples and drawings.
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GB0315617A GB2403408B (en) | 2003-07-03 | 2003-07-03 | Process for preparing a stable anthelmintic suspension formulation |
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GB0315617A GB2403408B (en) | 2003-07-03 | 2003-07-03 | Process for preparing a stable anthelmintic suspension formulation |
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GB0315617D0 GB0315617D0 (en) | 2003-08-13 |
GB2403408A true GB2403408A (en) | 2005-01-05 |
GB2403408B GB2403408B (en) | 2007-09-19 |
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GB0315617A Expired - Fee Related GB2403408B (en) | 2003-07-03 | 2003-07-03 | Process for preparing a stable anthelmintic suspension formulation |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2013041810A1 (en) * | 2011-09-22 | 2013-03-28 | Arcadophta | Stable, low-toxicity, sterilizable composition for ophthalmic dying |
WO2015028522A1 (en) * | 2013-09-02 | 2015-03-05 | Jacobs University Bremen Ggmbh | Compositions comprising bacteriostatic agents and brilliant blue g |
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CN113318079B (en) * | 2021-05-13 | 2024-01-09 | 江西博莱大药厂有限公司 | Method for improving dissolution rate of triclabendazole particles and dissolution rate detection method thereof |
CN115960474B (en) * | 2022-12-23 | 2023-10-31 | 湖南金桥新材料科技有限公司 | Preparation method of high-solid-content liquid brilliant blue |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000061068A2 (en) * | 1999-04-14 | 2000-10-19 | Ashmont Holdings Limited | Anthelmintic compositions |
US20020137781A1 (en) * | 1999-03-26 | 2002-09-26 | Olivier Froelich | Preparation and use of enantiomer-pure 2,4-disubstituted oxazolines |
-
2003
- 2003-07-03 GB GB0315617A patent/GB2403408B/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020137781A1 (en) * | 1999-03-26 | 2002-09-26 | Olivier Froelich | Preparation and use of enantiomer-pure 2,4-disubstituted oxazolines |
WO2000061068A2 (en) * | 1999-04-14 | 2000-10-19 | Ashmont Holdings Limited | Anthelmintic compositions |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013041810A1 (en) * | 2011-09-22 | 2013-03-28 | Arcadophta | Stable, low-toxicity, sterilizable composition for ophthalmic dying |
FR2980363A1 (en) * | 2011-09-22 | 2013-03-29 | Arcadophta | COMPOSITION WITH REDUCED TOXICITY OF AT LEAST ONE STABLE AND STERILIZABLE COLORANT |
WO2015028522A1 (en) * | 2013-09-02 | 2015-03-05 | Jacobs University Bremen Ggmbh | Compositions comprising bacteriostatic agents and brilliant blue g |
Also Published As
Publication number | Publication date |
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GB0315617D0 (en) | 2003-08-13 |
GB2403408B (en) | 2007-09-19 |
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