Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Solid synthetic organic polymer
Reexamination Certificate
2002-08-29
2004-08-17
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Solid synthetic organic polymer
C514S617000, C514S622000, C514S423000
Reexamination Certificate
active
06777448
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns compositions comprising rafoxanide, the compositions being intended to be used in the veterinary field, and preferably for the treatment of parasitic diseases in farm and domestic animals, like the liver fluke or bot fly infestations.
BACKGROUND OF THE INVENTION
Rafoxanide is the generic name of 3′-chloro-4′-(4-chlorophenoxy)-3,5-di-iodosalicylanilide. Rafoxanide is sold, for example, by the company Pfizer Animal Health Inc., Zimbabwe, under the trade name Ranox®, or by the company Ventron, India.
It is known that rafoxanide is useful as an anthelmintic and fasciolicide agent and is active for the treatment of parasitic diseases affecting animals and caused by parasitic worms or nematodes infestations.
It is also known that rafoxanide is extremely water insoluble (see for example Nessel, GB patent 1 472 385), its solubility in water at 25° C. being approximately 0.005% weight/volume.
Attempts to improve the solubilisation of rafoxanide by adding surface-active agents in the composition have been made. The results have shown that in a 1% surface-active agent composition, the solubility of rafoxanide is 0.14%.
This has the drawback that, when given orally, the absorption of rafoxanide by the body is low. As a consequence, its plasma concentration in the body is also low, and the majority of the active substance is unabsorbed and excreted in the faeces. For example, the absorption may be as low as 10% in non-gastric species, and only up to 50% or less in ruminants where the rumen aids in the absorption process.
As far as the anthelmintic activity is directly related to the plasma concentration of rafoxanide, to achieve a sufficient plasma concentration, a high dose of rafoxanide must be given to the subject to be treated, which is clearly economically disadvantageous.
Another solution would be to deliver the drug via injection, but here again, rafoxanide has been shown to be irritating and it is therefore not desirable to inject it as such.
In addition, rafoxanide is known to persist in the bloodstream of animals and to bind strongly to protein in the blood. This can lead to toxicity, which is clearly undesirable in the case of animals which are slaughtered for human consumption.
Several studies have been conducted to improve the absorption of rafoxanide by the body or its solubility in a composition which would be acceptable for administration.
Nessel (GB Patent 1 472 385) describes an aqueous composition which contains rafoxanide, polyvinylpyrrolidone and a caustic agent like sodium hydroxide or the sodium salt of cholic acid, deoxycholic acid, stearic acid or isostearic acid. According to the author, the presence of polyvinylpyrrolidone and of the caustic agent in the composition enhances the solubility of the active agent to such an extent that an aqueous composition containing up to 7.5% of rafoxanide can be prepared.
However, polyvinylpyrrolidone is an expensive material and, as mentioned in Nessel, the molecular weight of the polyvinylpyrrolidone molecules varies widely within the range of about 10,000 to about 360,000. This causes a drawback in the use of polyvinylpyrrolidone since only biologically pure grades of polyvinylpyrrolidone exempts of pyrogens and other toxic materials and with a molecular weight of 3,000 to 50,000 should be used.
In a similar manner, Lo et al. (U.S. Pat. No. 4,128,632) describes an aqueous composition which contains a complex of rafoxanide and polyvinylpyrrolidone. The process for the preparation of the composition differs from the process of Nessel by the use of a specific solvent like acetone or glycerol formal, which can optionally be removed by evaporation. According to Lo et al., the advantage over Nessel is that the process is faster and less expensive since it does not require the expensive step of spray drying of the rafoxanide/polyvinylpyrrolidone complex formed in the solvent before its dissolution in water.
However, in addition to the drawbacks mentioned above for the compositions of Nessel and which are due to the use of polyvinylpyrrolidone, the compositions of Lo et al. may also contain traces of acetone, which is a toxic chemical compound not desired in veterinary or pharmaceutical compositions.
It should also be noted that the processes of Nessel or Lo et al. both contain a step of heating the composition at a temperature higher than +40° C. which, at an industrial level, is an expensive and inconvenient step.
In another reference, Burke (WO 95/16447) describes an anthelmintic composition for oral administration containing 4.5% rafoxanide and 3% of another insoluble nematocidal agent belonging to the benzimidazole derivatives, fenbendazole. The compositions are micronised compositions, i.e. in the form of a suspension of particles, and contain also several additional components such as xanthan gum, polyvinylpyrrolidone and a dispersing agent. The author reports that the composition shows an improved anthelmintic effect without undesirable toxic side effects. The improved effect is connected with an increased plasma concentration of fenbendazole, originated by the combined administration of both agents. However, no improvement of the absorption of rafoxanide is reported.
From the above examples, it can be concluded that there is still a need for a composition for the treatment of parasitic diseases in animals which is based on the active substance rafoxanide, which can be prepared in an easy way, which is sufficiently concentrated to permit satisfactory dosage forms and which, when administered parenterally, topically or orally, shows good absorption characteristics by the body.
Surprisingly, the inventor of the present invention has found that the efficacy of rafoxanide in the treatment of parasitic diseases in animals is improved when it is dissolved in a specific combination of solvents which is able to keep the active molecule in a micellar stable state in the composition even at high concentrations. Thus, the resulting composition is a non-aqueous micellar composition.
A stable composition in the meaning of the present invention is a composition wherein the compounds are present in a soluble form, i.e. there is for example no precipitate, the composition also remaining stable during storage.
The inventor of the present invention has also found that, if necessary, water can be added to the composition, to obtain an aqueous micellar composition.
The inventor of the present invention has also found that said compositions are particularly effective in the treatment of parasitic worms or nematodes infestations in animals, like for example the liver fluke in cattle, buffaloes, sheep and goats, the blood sucking nematodes infestations, and the larval stages of the nasal bot fly infestation in sheep and goats.
Thus, the main object of the present invention is to provide new anthelmintic and fasciolicide compositions.
Another object of the present invention is to provide these compositions as compositions which are stable upon storage.
Another object of the present invention is to provide these compositions as compositions which can be administered orally, topically or parenterally (e.g. by injection).
One of the advantages of the present invention is therefore that the composition can be prepared in an easy manner, i.e. by simply mixing the components together, and without the addition of expensive or toxic substances.
Another advantage of the present invention is that the compositions have good absorption characteristics when compared to the above mentioned known compositions of the prior art.
Further problems which can be solved by this invention with respect to known prior art compositions will become apparent to the reader of the following description.
SUMMARY OF THE INVENTION
The present invention provides a solution to the aforementioned problems.
The aforementioned object is achieved by a micellar composition having the features defined in claim
1
and comprising as an essential active ingredient rafoxanide and a combination of solvents which act as a s
Corless Peter F.
Edwards & Angell LLP
Fubara Blessing
New Pharma Research Sweden AB
Page Thurman K.
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