AU698431B2 - Anthelmintic composition containing rafoxanide and fenbendazole - Google Patents
Anthelmintic composition containing rafoxanide and fenbendazole Download PDFInfo
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- AU698431B2 AU698431B2 AU12160/95A AU1216095A AU698431B2 AU 698431 B2 AU698431 B2 AU 698431B2 AU 12160/95 A AU12160/95 A AU 12160/95A AU 1216095 A AU1216095 A AU 1216095A AU 698431 B2 AU698431 B2 AU 698431B2
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- 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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/609—Amides, e.g. salicylamide
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- 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
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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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
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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
- A61K9/10—Dispersions; Emulsions
Description
WO95/16447 PCTIE93/00059 anthelmintic composition containing rafoxanide and fenbendazole This invention relates to compositions useful in the treatment and prevention of helminth infestation in non-human animals, more especially in animals of the bovine, caprine and ovine species. More particularly, the invention relates to compositions useful in the treatment of helminth infestations including fasciolides, flukes, in particular liver flukes and nematodes in bovines and ovines.
Rafoxanide (N-[3-chloro-4-(4-chlorophenoxy)-phenyl]-2benzamide) is a known fasciolicide. Fenbendazole ([5(phenylthio)-I H-benzimidazol-2-yl]carbamic acid methyl ester) is a benzimidazole derivative which is known to be useful in the treatment of helminthiasis, more especially, as a nematocidal agent. Each of rafoxanide and fenbendazole is poorly soluble in many pharmaceutically acceptable solvents.
EP-A 0 202 568 describes and claims compositions containing rafoxanide and optionally various anthelmintic benzimidazoles, including fenbendazole, in association with a solvent selected from dimethyl isosorbide and glycofurol. Such compositions are indicated to overcome the problems of the art. It is stated that administration of rafoxanide with or without an anthelmintic benzimidazole derivative in a convenient dosage form, by rumen injector or oral applicator, is hindered by the extremely low solubility of each component in nearly all pharmaceutically acceptable solvents or the high viscosity of any resulting solution or suspension.
Helminth infestation is a major problem in ruminant animals, especially those on pasture. The animals must be rounded up for dosing. In the case of sheep, the animals may have to be rounded up over a wide area.
o Rafoxanide and fenbendazole are both known to be tken up by the tissues, but additionally to persist in the bloodstream of ruminants and thus the amounts of rafoxanide and fenbendazole must be carefully 1 1 r 1 1 ~~Yh -r -I 2 selected so as to avoid the occurrence of toxic sequelae, especially in the case of animals which are slaughtered for human consumption. Fenbendazole and its metabolites persist in blood for approximately .5 days and in tissues for approximately 14 days. However, in the case of rafoxanide, there are conflicting reports in the literature on the persistence ofrafoxanide in blood ranging from of a few days to 28 days and in some cases for as long as 56 days. Rafoxanide binds strongly to protein in the blood and although levels persist in blood for some time, in may cases, corresponding tissue levels are not detectable.
c0 There is a need for an effective anthelmintic agent which can be administered 10 as a single dose and which can achieve levels of active agent sufficient to treat helminth f.st4 infestation, while avoiding toxic sequelae.
S" It is known that fenbendazole is metabolised in the body to fenbendazole sulphoxide and thence to fenbendazole sulphnne. The sulphoxide is the chemical entity C"S responsible for the majority of the nematocidal activity. The sulphone is non-active anthelmintically, but is formed by conversion from the sulphoxide.
c tt The present invention is based on the surprising finding that rafoxanide and fenbendazole can be administered to a subject to obtain a synergistic effect that increases the potency of the fenbendazole. The finding provides the significant advantage that the therapeutic efficacy of the fenbendaxole in the treatment or inhibition of a helminth infestation in a subject can be enhanced without increasing the dosage of the fenbendazole.
In one aspect of the invention there is provided an anthelmintic composition for oral administration, comprising an amount of rafoxanide in admixture with an amount of fenbendazole effective to achieve an elevated plasma level of an active 1 1 1 0 1 1 'y 1 1 1 1 1 1 1 1 1 1 1 W .t t t sulphur oxide metabolite of fenbendazole following administration relative to fenbendazole when administered alone.
Preferably, the active metabolite of fenbendazole is fenbendazole suiphoxide, which, as indicated above, is the chemical entity mainly responsible for the nematocidal activity of fenbendazole.
Further, preferably the rafoxanide is present in an amount of 1.5 to 15% w/v and the fenbendazole is present in an amount of 1.0 to 10% w/v.
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C CC CC C 44 4 4 *4 t**CCC C C CC Cf Ct C C C 31 August 1999 1 3 Suitable amounts for the respective active ingredients are as follows: Rafoxanide w/v Fenbendazole w/v 10.5 12.0 13.5 15.0 10.0
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Further, preferably, the rafoxanide is administered at a dose rate in the range 7.5-15.0 mg/kg body weight and the fenbendazole is administered at a dose rate in the range 5.0-10.0 mg/kg body weight.
Suitable dose rates (mg/kg body weight) for the respective active ingredients are as follows: Rafoxanide mg/kg Fenbendazole mg/kg 7.50 11.25 12.00 15.00 10.0 In a particularly preferred embodiment, each of the active ingredients is micronised.
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WO 95/16447 PCT/IE93/00059 4 The rafoxanide preferably has a particle size range wherein at least 99% by weight has an average particle size less than 20tm, at least by weight has an average particle size less than 10pm and at least by weight has an average particle size less than The fenbendazole preferably has a particle size range wherein at least 98% by weight has an average particle size less than 20.m, at least by weight has a particle size less than 15p[m and at least 50% by weight has a particle size less than The composition according to the invention is preferably in the form of a suspension.
Preferably, the suspension includes as a suspending agent a gum and/or a pharmaceutically-acceptable, polymeric material with the requisite properties.
A suitable gum is xanthan gum.
A suitable polymeric material is polyvinylpyrrolidone also known as Povidone.
The suspension may also include one ormore auxiliary agents selected from a buffering agent, a dispersing agent, a wetting agent, an anti-foaming agent, a preserving agent and a colouring agent secundem artem.
The pH of the suspension is suitably in the range 4.5-5.5.
Suitable buffering agents include citric acid monohydrate and disodium hydrogen phosphate or sodium citrate.
Suitable dispersing agents include colloidal silicon dioxide such as that sold under the Trade Mark Aerosil 200 and/or a non-ionic surfactant such as a polyoxyethylene derivative of a sorbitan ester marketed as Polysorbate r^ 1 A suitable wetting agent is propylene glycol.
A suitable antifoaming agent is simethicone.
Suitable preserving agents include hydroxybenzoate preservatives such as that sold under the Trade Marks Nipasept sodium, Nipasol and Nipagin M.
Suitable colouring agents are any colouring agent suitable for oral administration.
The invention also provides a method of treating or inhibiting helminth S" infestation in a subject involving administering to the subject fenbendazole and 5"1 10 rafoxanide in amounts that achieve an elevated plasma level of an active sulphur oxide metabolite of fenbendazole following administration, relative to fenbendazole S.when administered alone. Generally, the subject will be ruminant animal.
The composition and method according to the invention are especially suitable S' for the treatment of helminth infestation, including fluke infection in cattle and sheep.
1 The invention will be further illustrated in the following Examples.
31 August 1998 t.-l"f Fr- WO 95/16447 PCT/IE93/00059 Example 1 A suspension containing rafoxanide and fenbendazole was prepared having the following composition: Ingredient Amount w/v) Rafoxanide B.P. (Vet.) Fenbendazole Citric acid monohydrate B.P.
Disodium hydrogen phosphate B.P.
Aerosil 200 Povidone B.P.
Xanthan gum N.F.
Propylene glycol B.P.
Polysorbate 20 B.P.
Simethicone emulsion (PD30) USP XXI Nipasept sodium (BP components) Chlorophyll WSI E 140 Water 3.8 0.55 0.3 0.2 0.14 0.15 to 100 ml in the following manner.
For a 1,800 litre batch, a stainless steel tank is filled to circa the 1,400 litre mark with deionised water. The Nipasept sodium, citric acid monohydrate, disodium hydrogen phosphate and chlorophyll are added followed by thorough mixing with a Silv(SilveEX (Silverson EX is a Trade Mark) fine shear head. The mixer is switched off and the Aerosil 200 is added and the mixture is allowed to settle for circa 30-60 minutes. The xanthan gum and povidone are blended and gradually added to the main tank.
The Polysorbate 20 and propylene glycol are weighed into a separate 500 litre tank. The rafoxanide and the fenbendazole are added 4. S WO 95/16447 PCT/IE93/00059 7 to the latter tank and mixed together with -50-100 litres of deionised water by means of a Silverson EX coarse shear head. To the latter mixture is added the simethicone emulsion and the mixture is mixed well to ensure that all of the rafoxanide and fenbendazole is thoroughly wetted. The total minimum mixing time is approximately 30 minutes.
When the Aerosil has dispersed in the main tank, the mixer is switched on and the rafoxanide-fenbendazole mixture is added to the main tank with continuous mixing during the transfer process. The final mixture is allowed to settle for at least about 1 hour or, indeed, overnight and then is made up to the 1,800 litre mark with deionised water.
Each of the active ingredients is micronised to achieve an 1 average particle size range as hereinbefore specified. The pH of the j suspension prepared can be 5 0.5. The fenbendazole was obtained *rwe 15 from Cipla Ltd., Bombay, India.
V :Example 2 An experiment was carried out to investigate the pharmacokinetics of rafoxanide and fenbendazole when given singly and in combination to lambs.
20 Twelve lambs aged approximately seven months which had been reared in a large shed on expanded metal floors and which were helminth free were divided randomly into three groups of four. On day 0 of the experiment the lambs were weighed carefully. and each group treated separately with the following treatments.
Group I Fenbendazole 3% at a dose rate of 7.5 mg/kg.
Group 2 Rafoxanide 4.5% at a dose rate of 11.25 mg/kg.
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WO 95/16447 PCT/IE93/00059 Group 3 A mixture of fenbendazole 3% and rafoxanide at dose rates of 7.5 mg/kg and 11.25 mg/kg, respectively.
The mixture for Group 3 corresponded to the suspension prepared in Example 1. Suspensions of active ingredient were also administered to Group 1 and Group 2 which, in each case, corresponded to a suspension as prepared in Example 1 but without rafoxanide and fenbendazole, respectively.
Sampling. Blood samples were taken from the lambs before dosing at day 0, and afterwards at day 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 7, i4, 21 and 28. The samples were centrifuged, plasma removed and stored at -20 0 C until analysis. Samples taken from Groups 1 and 3 were analysed for fenbendazole and its metabolites up to day 5. All samples from Groups 2 an' 3 for rafoxanide concentrations were analysed.
Determination of fenbendazole and metabolites. The method used for extraction of the compounds from plasma was that of Barker, S.A.
et al. ((1986); Anal. Biochem., 155, 112-118). Thus, the plasma was made alkaline by addition of ammonium hydroxide and applied to a Chem-Elut (Chem-Elut is a Trade Mark) column. Fenbendazole was eluted from the column by addition of methylene chloride and the eluates evaporated to dryness in an atmosphere of nitrogen. The eluates were then dissolved in mobile phase and chromatographed using reverse phase HPLC and UV detection under conditions described by Bull, M.S. and Shume G.R.E. ((1987); J. Pharmaceutical and Biochem.
Analy. 5, 501-508).
Determination of plasma rafoxanide. The method used was that of Blanchflower, et al. ((1990); J. Liq. Chromatog. 13 1595- 1609) which basically consists of separation of rafoxanide from the plasma proteins to which it binds by extraction with acetone ether and acetonitrile, and subsequent injection on to an HPLC system with UV detection set at 282 nm. The method is specific and sensitive with a lower limit of detection of 0.1 pg/ml.
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WO 95/16447 PCT/IE93/00059 Staistical analysis. The mean plasma concentration of rafoxanide and fenbendazole and its metabolites was calculated for each group and sampling occasion. Differences between mean concentrations at each date were compared by t test. Areas Under Curve (AUC) were calculated by the trapezoidal method of Gibaldi, M and Perrier, D.
((1982); "Pharmacokinetics" published by Mancel Dekker, New York) from time 0 until the time of non-detectable concentration or the last observation, whichever occurred first.
Results.
Plasma rafoxanide concentrations.
The results are summarized in Tables 1 (Group 2 (rafoxanide only)) and 2 (Group 3 (rafoxanide ana fenbendazole)) and in Fig. 1.
Plasma concentrations are expressed in pg/ml.
TABLE 1 Time (days) Lamb No.
6 7 8 0 0.5 1 1.5 2 2.5 3 4 5 7 14 21 29 38.1 20.1 25.2 30.3 51.1 30.1 41.2 43.6 62.8 17.6 51.4 47.4 59.9 34.6 49.0 45.5 55.7 53.0 47.7 50.5 55.1 57.2 47.5 49.3 45.3 68.1 48.3 52.8 54.7 33.6 41.3 44.2 54.1 19.6 39.9 34.7 30.4 5.4 26.0 21.9 21.9 4.4 16.2 13.6 10.7 4.6 9.6 Mean 0 28.4 41.5 44.8 47.3 53.1 52.3 53.6 43.5 37.1 20.9 14.0 7.7 SD* 0 6.6 7.5 16.7 9.0 2.9 3.9 8.7 7.6 12.3 9.5 6.3 SD Standard deviation t *i
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WO 95/16447 PCT/IE93100059 TABLE 2 Time (days) Lamb 0 0.5 1 1.5 2 2.5 3 4 5 7 14 21 29 No.
9 11 12 24.7 13.8 23.2 29.4 39.7 38.5 34.0 44.0 63.4 62.0 41.0 61.4 62.3 54.2 37.1 47.8 61.7 55.1 37.1 48.2 53.3 51.4 40,8 57.3 50.2 46.2 30.8 63.2 51.1 46.8 28.1 54.6 50.4 36.0 20.1 47.1 25.2 18.7 9.5 30.7 13.9 8.2 4.4 20.3 Mean 0 22.8 39.1 56.9 50.4 55.5 50.7 47.6 45.2 38.4 21.0 11.7 3.9 SD* 0 5.7 3.6 9.2 9.2 11.6 6.1 11,6 10.2 11.8 7.9 SD Standard deviation Areas Under Curve Group 2 (rafoxanide only) Group 3 (rafoxanide and fenbendazole) 707.15 226.1 683.62 238.4 t 0.143; no significant difference There were no significant differe ices between plasma rafoxanide concentration (pg/ml) at each sampling date point, and between the AUC for each group.
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AR2 WO 95/16447 PCTIE93/00059 Plasma fenbendazole-concentrations.
A. Fenbendazole parent compound.
The results are summarized in 'Tables 3 (Group I (fenbendazole only)) and 4 (Group 3 (fcnbendazole and rafoxanide mixture)) and in Fig. 2.
TABiLE 3 Time (hours) 0 12 24 36 48 60 72 96 Lamb No.
2 3 4 .185 .192 .110 .105, .197 .209 .098 P097 .19 .186 .129 .078 .053 .120 .082 .046 .064 .073 .051 .062 .043 .055 .029 .009 .021 .023 0 0 Mean
SD*
.148 .041 .146 ,046 .075 .029 .063 .008 .034 .017 .011 .011 SID Standard deviation
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WO 95/16447 WO 9516447PCT/1E93/00059 TABLE 4 Time (hours) Lamb No.
9 11 12 Mean
SD*
0 12 24 36 48 .16 .1.6 .137 .23 .171 .035 .14 .128 107 .157 .133 .018 .194 .103 .144 .189 ,157 .036 .114 1 .066 .117 .099 .02 .072 .073 .043 .107 .074 .02 .046 .049 0 .054 .037 .02 .025 0 0 0 .006 3 .01 SD Standard deviation Mean AUC Group I 6.837 2.09 Mean AUC Group 3 7.332 1.54 t 0.38; no significant differences As can be seen from the above tables and Fig. 2 there were no significant differences between concentrations of fenbendazole parent compound and AUC in either the group given fenbendazole only and that given the mixture of fenbendazole and rafoxanide.
4 S IN~~EWRNATIONAL SEARCH REPORTtW*1AiaFnN Inwm A AnMicafion No WO 95/16447 PCT/1E93/00059 13 B. Fenbendazole sulphoxide.
The results are summarized in Tables 5 (Group 1 (fenbendazole only)) and 6 (Group 3 (fenbendazole and rafoxanidle midxture)) and Fig.
3.
Time (hours) Lamnb 0 12 24 36 48 60 72 96 No. 1 0 .169 .3 .31 .125 .191 .127 .049 2 0 .155 .24 .286 .224 .174 .112 .044 3 0 .089 .166 .264 .2 .137 .092 .023 4 0 .17 .192 .193 .127 .085 .034 .013 Mean 0 .15 .23 .26 .169 .15 .09 .03 SD* 0 .033 .05 .04 .04 .04 .04 .014 Standard deviation TABLE 6 Time (hours) LamW 0 12 24 36 48 60 72 96 9 0 .147 .269 .377 .305 .23 .172 .071 0 .182 .263 .322 .31 1248 .12 .061 o11 0 .22 .27 .314 .218 .133 .073 .02 12 0 .285 .352 .466 .339 .311 .178 .067 Mean 0 .21 .29 .37 .293 .23 .15 .0 SD* 0 .05 .04 .06 .05 .06 .04 .02 .2 L~.
o Rafoxanide and fenbendazole are both known to be taken up by 30 the tissues, but additionally to persist in the bloodstream of ruminants and thus the amounts of rafoxanide and fenbendazole must be carefully 4* V WO 95/16447 PCT/IE93/00059 SD Standard deviation Mean AUC Group 1 12.453 2.43 Mean AUC Group 3 18.77 3.3 t 3.0389 (DF6) p <0.05 As can be seen from Tables 5 and 6 there were differences between the plasma fenbendazole sulphoxide concentrations in each group, with that of the group given the anthelmintic mixture the greatest. Although there was a strong trend throughout, only at 36 and 48 hrs post dosing were the differences statistically significant (p <0.05 and <0.01 respectively).
Taken as a whole the differences in AUC (which can be seen in Fig. 3) were significant (p indicating that the presence of rafoxanide had altered the rate of metabolism of fenbendazole and its sulphoxide metabolite, although the resultant alteration would be of anthelmintic benefit since the sulphoxide is the chemical responsible for the majority of the nematocidal activity.
C. Fenbendazole sulphone. The results are summarized in Tables 7 (Group 1 (fenbendazole only)) and 8 (Group 3 (fenbendazole and rafoxanide mixture)) and in Fig. 4.
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oral administration, comprising an amount of rafoxanide in admixture with an amount of fenbendazole effective to achieve an elevated plasma level of an active WO 95/16447 PCT/IE93100059 TABLE 7 Time (hours) Lamb 0 No.
12 24 36 48 60 72 96 1 0 .021 .064 .095 .059 .109 .103 .078 2 0 .021 .059 .086 .106 .106 .106 .067 3 0 .009 .032 .074 .091 .097 .104 .067 4 0 .033 .065 .078 .087 .080 .059 .053 Mean 0 .021 .055 .083 .086 .098 .093 .066 SD* 0 .088 .01 .008 .01 .01 .01 .008 SD Standard deviation TABLE 8 Time (hours) Lamb 0 No.
12 24 36 48 60 72 9 0 .026 .072 .12 .166 .152 .153 .133 0 .031 .06 .116 .161 .174 .186 .145 11 0 .031 .08 .113 .122 .103 .089 .059 12 0 .04 .105 .158 .192 .215 .186 .162 Mean 0 .032 .079 .127 .16 .161 .154 .125 SD* 0 .005 .016 .018 .025 .04 .03 .039 :l r SD Standard deviation Mean AUC Group 1 6.45.9 .577 Mean AUC Group 3 10.779 2.17 t 3.767 (DF6) p <0.01
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.11e 31 August 1998 WO 95/16447 PCT/IE93/00059 16 As indicated above, the sulphone is non active anthelmintically but is formed by conversion from the sulphoxide. Since the sulphoxide concentrations differed between Groups 1 and 3, the sulphone concentrations were also significantly different at all sampling dates after 0 and 12 hours. The resultant AUC were significantly different (p <0.0 Conclusions.
It can be observed from these results that administration of the mixture of rafoxanide and fenbendazole did not alter the pharmacokinetics of rafoxanide from that when rafoxanide is given by itself. The pharmacokinetics of fenbendazole and its metabolites did differ from that of fenbendazole administered by itself in that the plasma concentrations of fenbendazole sulphoxide and sulphone were increased when the mixture was administered. Thus, it can be concluded that administering rafoxanide and fenbendazole in combination in accordance with the invention will potentiate the anthelmintic efficacy of the fenbendazole without significantly Sincreasing any toxic sequelae.
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Claims (19)
1. An anthelmintic composition for oral administration, comprising rafoxanide in admixture with fenbendazole wherein the rafoxanide and fenbendazole are present in amounts effective to potentiate the anthelmintic efficacy of the fenbendazole by achieving an elevated plasma level of an active sulphur oxide metabolite of fenbendazole following administration, relative to fenbendazole when administered alone.
2. A composition according to Claim 1, wherein the active metabolite of I 10 fenbendazole is fenbendazole sulphoxide.
3. A composition according to Claim 1 or 2, wherein the rafoxanide is Spresent in an amount of 1.5 to 15% w/v and the fenbendazole is present in an amount of 1.0 to 10% w/v. ,1 4. A composition according to any preceding claim, wherein each of the V"o .15 active ingredients is micronised. i 5. A composition according to Claim 4, wherein the rafoxanide has a i t 4 0 particle size range wherein at least 99% by weight has an average particle size less than 20im, at least 90% by weight has an average particle size less than 10pm and at least 55% by weight has an average particle size less than
6. A composition according to Claim 4 or 5, wherein the fenbendazole has a particle size range wherein at least 98% by weight has an average particle size less than 20pm, at least 90% by weight has a particle size less than 15pm and at least 50% by weight has a particle size less than 3IAugust 1998 I as that sold under the Trade Mark Aerosil 200 and/or a non-ionic surfactant such as a polyoxyethylene derivative of a sorbitan ester marketed as Polysorbate I' p -r ~ra Se :t CD ~C ci C E C c C C C CP CO 'C: C CC C CC C C Cb 18
7. A composition according to any preceding claim, which is in the form of a suspension.
8. A composition according to Claim 7, which includes as a suspending agent a gum and/or a pharmaceutically-acceptable, polymeric material.
9. A composition according to Claim 8, wherein the gum is xanthan gum. A composition according to Claim 8 or 9, wherein the polymeric material is polyvinylpyrrolidone.
11. A composition according to any preceding claim, which includes one 10 or more auxiliary agents selected from a buffering agent, a dispersing agent, a wetting agent, an anti-foaming agent, a preserving agent and a colouring agent.
12. A method of treating or inhibiting helminth infestation in a subject involving administering to the subject fenbendazole and rafoxanide in amounts that achieve an elevated plasma level of an active sulphur oxide metabolite of 15 fenbendazole following administration, relative to fenbendazole when administered alone.
13. A method according to claim 12 wherein the rafoxanide is administered to the subject at a dosage in a range of from 7.5 to 15.0 mg/kg body weight and the fenbendazole is administered at a dosage in a range of from 5.0 to I/ 10.0 mg/kg body weight. I'
14. A method according to claim/12 or 13 wherein the fenbendazole and rafoxanide are administered simultaneously. o 31Au1998 (1 31 August 1998 :1 I 1 t I 1 )31I August 1998 L7-7 ~i i i.~n~ ira I Clr S t C, 19 A method according to claim 12 or 13 wherein the rafoxanide and fenbendazole are administered admixed together.
16. A method according to any one of claims 12 to 15 wherein the subject is a ruminant animal.
17. A method according to any one of claims 12 to 15 wherein the subject is bovine, caprine or ovine.
18. An anthelmintic composition as defined in any one of claims 1 to 11 when used to treat or inhibit a helminth infestation in a subject by oral administration of the composition tothe subject so as to acheive an elevated plasma level of an active sulphur oxide metabolite of fenbendazole following administration, relative to fenbendazole when administered alone.
19. An anthelmintic composition according to claim 18 when used to treat 15 or inhibit a helminth infestation in a ruminant animal.
20. The use of rafoxanide and fenbendazole in the preparation of a medicament for the treatment or inhibition of helminth infestation in a subject, said medicament when administered to the subject in an effective amount being able to achieve an elevated plasma level of an active sulphur oxide metabolite of fenbendazole, relative to fenbendazole when administered alone.
21. The use according to claim 20 wherein the medicament is for oral administration to the subject and the subject is a ruminant animal.
22. An anthelmintic composition comprising rafoxanide and fenbendazole in amounts effective to potentiate the anthelmintic efficacy of the fenbendazole by August, 1998 l tj 1 1 1 1 1 y 1 1 i 1 1 1 1 1 1 1 1 6; *5 5+ ii S S C 0 LT" Ro
41. The Polysorbate 20 and propylene glycol are weighed into a separate 500 litre tank. The rafoxanide and the fenbendazole are added FI I achieving an elevated plasma level of an active sulphur oxide metabolite of fenbendazole following administration to a subject, relative to fenbendazole when administered alone, and substantially as hereinbefore described with reference to Example 1. 23. A method of treatinng inhibiting helminth infestation in a subject involving administering to the subject fenbendazole and rafoxainde in amounts that achieve an elevated plasma level of an active sulphur oxide metabolite of fenbendazole following administration, relative to fenbendaxole when administered alone, and substantially as hereinbefore described with reference to Example 2. Dated this 28th day of August 1998 MICHAEL HILLARY BURKE By His Patent Attorneys CARTER SMITH BEADLE C' C C0(C D C C C C( 44I Co C 14 C Ci 41 -Cf; I: 44* August31, 1998
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IE1993/000059 WO1995016447A1 (en) | 1993-12-13 | 1993-12-13 | Anthelmintic composition containing rafoxanide and fenbendazole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU1216095A AU1216095A (en) | 1995-07-03 |
| AU698431B2 true AU698431B2 (en) | 1998-10-29 |
Family
ID=11042485
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU12160/95A Ceased AU698431B2 (en) | 1993-12-13 | 1993-12-13 | Anthelmintic composition containing rafoxanide and fenbendazole |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0734258A1 (en) |
| AU (1) | AU698431B2 (en) |
| WO (1) | WO1995016447A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5861142A (en) * | 1996-03-25 | 1999-01-19 | Schick; Mary Pichler | Method for promoting hair, nail, and skin keratinization |
| EP1129713A1 (en) | 2000-02-29 | 2001-09-05 | New Pharma Research Sweden AB | Veterinary compositions for the treatment of parasitic diseases |
| GB2386066A (en) * | 2002-02-28 | 2003-09-10 | Norbrook Lab Ltd | Long-acting parasiticidal composition with improved bioavailability comprising a salicylanilide, a further anti-parasitic compound & a polymeric species |
| KR101403135B1 (en) * | 2006-06-14 | 2014-06-19 | 인터벳 인터내셔널 비.브이. | A suspension comprising benzimidazole carbamate and a polysorbate |
| TW200815001A (en) * | 2006-06-14 | 2008-04-01 | Intervet Int Bv | Benzimidazole carbamate composition |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0202568A1 (en) * | 1985-05-13 | 1986-11-26 | Syntex (U.S.A.) Inc. | Anthelmintic compositions |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2336931A1 (en) * | 1975-12-30 | 1977-07-29 | Dick Pierre | Anthelmintic compsns. contg. benzimidazole deriv(s). - and other anthelmintic(s), with extended activity against digestive tract parasites |
| CA1103164A (en) * | 1976-08-13 | 1981-06-16 | Dewi Ap Tudur Rowlands | Anthelmintic composition |
-
1993
- 1993-12-13 EP EP94900983A patent/EP0734258A1/en not_active Withdrawn
- 1993-12-13 AU AU12160/95A patent/AU698431B2/en not_active Ceased
- 1993-12-13 WO PCT/IE1993/000059 patent/WO1995016447A1/en not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0202568A1 (en) * | 1985-05-13 | 1986-11-26 | Syntex (U.S.A.) Inc. | Anthelmintic compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0734258A1 (en) | 1996-10-02 |
| WO1995016447A1 (en) | 1995-06-22 |
| AU1216095A (en) | 1995-07-03 |
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| Date | Code | Title | Description |
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| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |