Note: Descriptions are shown in the official language in which they were submitted.
14383
104'~797
The instant invention relates to new and useful
pharmaceutical formulations containing rafoxanide, [3,5-diiodo
-3'-choro-4'-(p-chlorophenoxy)salicylanide], as the essen-
tial active ingredient and to the method of preparing such
formulations. More particularly, the instant invention re-
lates to a~ueous rafoxanide formulations suitable for injec-
tion as well as oral administration and to the preparationthereof by a process which employ~ a combination of a solid
solution comprising polyvinylpyrrolidone and rafoxanide and
an aqueous caustic solution whereby the water solubility of
rafoxanide is markedly enhanced and there is obtained a
stable aqueous rafoxanide solution suitable for injection
and oral administration. Such rafoxanide formulations are
ùseful in the treatment of liver flukQ in animals, preferably
domestic animals.
Rafoxanide is one of a family of salicylanilides,
characterized by having an aromatic ring on the anilide
moiety lin~ed thereto through one or more non-metallic ~toms,
which have been shown to be useful in the treatmeDt of p~ra-
sitic diseases in animals. This compound i9 described in
United States Patent 3,798,258, issued March 19, 1974, and
may be prepared readily by the methods fully described there-
in. Rafoxanide has been found to be particularly use ~ in
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1()4;~797
the treatment of liver fluke infestations in animals. Its
extreme insolubility in water, however, has lead to con-
tinuing difficulty in devising pharmaceutical formulations
which will provide upon administration significant blood
levels of the active agent. In particular, the water in-
solubility of rafoxanide has made it impossible heretofore
to prepare aqueous, non-irratating rafoxanide formulations
suitable for intravenous injection. Accordingly, it is an
object of the instant invention to prepare stable aqueous
rafcxanide formulations suitable for oral and parenteral
administration including intravenous, sub-cutaneous and
intramuscular injection.
It has long been known in the literature that
certain chemical species, including some drugs, are cap-
able of forming solid solutions with highly selective poly-
meric materials, including polyvinylpyrrolidone (see, for
example, United States Patent 3,673,163, issued June 27,
1972) and that such preparations often have increased water
solubility over the pure compound. It is also well-known
in the literature that various surface active agents, cat-
ionic, anionic and non-ionic, are capable of solubilizing
some chemical species through the formation of micelles
(see, for example, Solubilization by Surface Active Agents,
Elworthy, Florence and MCFarlane, Chapman and Hall Limited,
London, 1968) In most cases, however, the increase in water
solubility is limited and not sufficient for preparing
marketable dosage forms.
Attempts to apply the techniques of the prior art
to the water solubilization of rafoxanide proved to be
disappointing. The solubility of rafoxanide in water at
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~4Z797
25C is approximately 0.00005 gms. per ml. (0.005%); sub-
stantially water insoluble. The water solubility of a ra-
foxanide~polyvinylpyrrolidone solid solution under same
conditions was 0.000007 gms. per ml. (0.0007~); again sub-
stantially water insoluble and indeed less soluble than
the pure drug. In 1% aqueous soap solution, the solubility
of rafoxanide was measured at 0.0014 gms. per ml. (0.14~).
Although significantly more soluble in the soap solution;
the solubility of rafoxanide remained far too low to per-
mit formulation of satisfactory aqueous dosage forms.
The instant invention is based upon applicant's
discovery that, surprisingly, when a solid solution of
rafoxanide and polyvinylpyrrolidone is treated with an
aqueous solution of a caustic agent selected from the
group consisting of water soluble alkali metal hydroxides,
such as sodium, potassium and lithium hydroxides, the corres-
ponding alkali metal salt of a long chain fatty acid, and
the corresponding alkali metal salt of a bile acid, the
water solubility of rafoxanide is markedly enhanced readily
; 20 permitting the formulaltion of stable aqueous rafoxanide
solutions containing 7.5%, or higher, of rafoxanide. While
applicant does not understand precisely the reason for the
enhancement of rafoxanide water solubility achieved by the
formulations of the instant invention, it is apparent that
the combination of the rafoxanide/polyvinylpyrrolidone
solid solution and the aqueous caustic solution has achieved
a water solubility enhancing effect far in excess of that
produced by either component alone.
In its composition aspect, therefore, the instant
invention may be described as residing in the concept of a
stable aqueous rafoxanide formulation comprising a solid
solution of rafoxanide and polyvinylpyrrolidone dissolved in
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~ - 14383
l~Z797
an aqueous solution of a caustic agent selected from the
group consisting of a water soluble alkali metal hydroxide,
a water soluble alkali metal salt of a long chain fatty
acid and a water soluble alkali metal salt of a bile acid.
It is contemplated that dosage units of such formulations
containing a therapeutically effective amount of rafoxanide
will be administered both orally and by injection in the
treatment of liver fluke infestations in animals.
The solid solution employed as an essential com-
ponent of the formulations of this invention consist essen-
tially of a coprecipitate of polyvinylpyrrolidone and rafox-
; anide. The ratio of polyvinylpyrrolidone to rafoxanide in
such solid solution may range from 1:1 to 5:1 (parts poly-
vinylpyrrolidone to rafoxanide by weight). A ratio of poly-
pyrrolidone to rafoxanide of 3:1 is preferred. Any
commercially available pharmaceutical grade of polyvinyl-
pyrrolidone may be employed in the preparation of the solid
solution. Such polyvinylpyrrolidones will vary widely in
moleculax weight within the range of about 10,000 to about
360,000. The rafoxanide is either commercially available
or may be prepared readily by the techniques already fully
described in the art.
The solid solution may be prepared conveniently
by dissolving rafoxanide and the polyvinylpyrrolidone in a
2S suitable volatile inert solvent medium and evaporating the
~; solvent, preferrably under vacuum, thereby forming a solid
solution. The solvent employed in the preparation of the
solid solution is not critical. Any inert volatile solvent
or mixtures thereof may be employed. Representative inert
volatile solvents are, for example, methanol, ethanol, iso-
propanol, ethylacetate, ether, chloroform and methylene
chloride. Preferred solvents are ethyl acetate, methanol,
ethanol, isopropanol and mixtures thereof.
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14383
1(~4'~7~7
As noted above, the caustic agent employed in the
preparation of the rafoxanide formulations of this inven-
tion is a member selected from the group consisting of water
soluble alkali metal hydroxides, such as, for example sodium
potassium and lithium hydroxides, water soluble alkali metal
salts of long chain fatty acids (e.g., soaps) and water sol-
uble alkali metal salts of bile acids. Typical water soluble
alkali metal salts of long chain fatty acids include salts of
both saturated and unsaturated fatty acids having 12 to 22
carbon atoms, such as, for example, lauric acid, myristic
acid, palmitoleic acid, palmitic acid, stearic acid, iso-
stearic acid, oleic acid, linoleic acid, linolenic ac d,
arachidic acid and behenic acid. Representative water sol-
uble alkali metal salts of bile acids include salts cholic
lS acid, deoxycholic acid, chendeoxycholic acid, lithocholic
acid, hyodeoxycholoic acid, hyocholic acid and epimers of
hyocholic acid. The preferred caustic agents are sodium
hydroxide and the sodium salts of cholic acid, deoxycholic
acid, stearic acid and isostearic acid; sodium hydroxide and
the sodium salt of isostearic acid being particularly pre-
ferred.
The aqueous rafoxanide formulations of this inven-
tion may be prepared readily by adding to the solid solution,
prepared as described above, with agitation an aqueous sol-
ution of the desired caustic agent. Where the caustic agentis the alkali metal salt of a fatty acid or bile acid, the
preformed salt may be used per se or, alternatively, the
salt may be formed by adding the free acid to at least a
stoichiometric quantity of aqueous alkali metal hydroxide.
The resulting mixture is stirred and heated at about 40 to
about 70C until complete solution is obtained and the solu-
tion is then cooled with continued agitation to room tempera-
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104Z797
ture. Additional water is then added to bring the solution
to the desired volume and to adjust the concentration of
rafoxanide to the desired value. The solution then is
filtered to remove any trace of undissolved material.
Alternatively, the aqueous rafoxanide formula-
tions of this invention may be prepared by incorporating
the caustic agent directly in the solid solution. In this
case the rafoxanide, polyvinylpyrrolidone, and caustic
agent are dissolved in an suitable solvent and the solvent
is then evaporated to yield a ~olid solution containing the
three components. It is merely necessary then to add water
to the solid solution to achieve complete solution and to
adjust for desired volume and concentration of active; the
work-up being the same as described above.
In order to achieve maximum stability of rafox-
anide in the formulations of this invention, it has been
found that the pH of the solution should be kept in the
range of 7.5 to 9. Preferrably the pH range is 8 to 8.5.
The pH of the formulation may be adjusted by dilution and/
or by the addition of an appropriate aqueous phosphate
buffer solution.
The amount of rafoxanide contained in the formu-
lations of this invention is conveniently adjusted to fall
within the range of about 2 to about 11~ by weight of the
total formulation. Preferrably, rafoxanide will constitute
from about 2 to about 7.5% by weight of the total formulation.
Particularly preferred formulations of the instant invention,
therefore, are those wherein the weight ratio of polyvinyl-
pyrrolidone to rafoxanide in the solid solution is 3:1;
wherein the concentration of rafoxanide in the total formu-
lation is 2 to 7.5% by weight, and wherein the pH of the
~ 14383
1(~4Z797
formulation is adjusted to 8 to 8.5.
As noted above, the a~ueous rafoxanide formu-
lations of this invention are effective in the treatment
of animals afflicted with liver fluke. They may be ad-
ministered both orally and parenterally in dosage unitformulations either with or without the addition of con-
ventional non-toxic pharmaceutically acceptable adjuvants.
The term, "parenterally", as used herein includes intra-
venous, intramuscular and subcutaneous injection. The
specific dosage level for any particular animal may vary
greatly depending upon a variety of factors including the
mode of administration, the age, weight and general health
of the animal and the severity of the condition to be
treated. In general, however, effective action against
liver fluke is obtained at single dose levels of about 1
to about 300 mg/kg body weight. This dosage level may be
- divided in any desired manner for convenience of administra-
tion.
The rafoxanide employed in the formulations of
this invention may be prepared as follows:
3,5-diiodo-3'-chloro-4'-(p-chlorophenoxy)salicylanide
A mixture of 31 gm. of 4-amino-2,4'-dichloro-
biphenyl ether, 47.4 gm. of 3,5-diiodo salicylic acid and
4.3 ml. of phosphorous trichloride in 235 ml. of chloro-
benzene is refluxed for 3 hours. The hot solution is de-
; canted from some insoluble residue and the crude product
settles out of solution upon cooling to rOOm temperature.
Upon recrystallization from benzene, 27.5 gm. of 3,5-diiodo-
3'- chloro-4'-(p-chlorophenoxy)salicylanide, m.p. 168-
170C, is obtained.
The best mode contemplated by applicant for
carrying out the instant invention is set forth in the
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~ 14383
1()4'~797
following working examplesi it being understood that no
limitation is intended except as set forth in the appended
claims.
~ .
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~_ 143
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14383
~4Z797
Procedur_
With moderate agitation, rafoxanide and poly-
vinylpyrrolidone are dissolved into a sufficient amount of
solvent, an equal mixture of ethylacetate and ethanol, to
achieve complete solution. The solvent is evaporated by
heating under vacuum to obtain a solid solution. An
aqueous caustic solution is prepared by adding isostearic
acid to a pre-dissolved aqueous sodium hydroxide solution
and mixing thoroughly until solution is obtained. The solid
solution is agitated while adding thereto the caustic solution
and the resulting mixture is then heated at about 40-70C.
until solution is effected. The solution thus obtained is
cooled with continued agitation to approximately room temper-
ature. Distilled water is added to obtain the desired volume
and the resulting solution filtered.
Other bile or fatty acids or alkali metal salts ~;
thereof, such as, for example, cholic acid, deoxycholic acid,
stearic acid, chenodeoxycholic acid, lithocholic acid, hyo-
- cholic acid, hyodeoxycholic acid or epimers of hyocholic
acid can be substituted for isostearic acid and other bases,
such as, potassium hydroxide or lithium hydroxide can be sub-
stituted for sodium hydroxide.
- 10 --
1~)4Z797
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--- 14383
lV4Z79 ~)
Procedure:
With moderate agitation, rafoxanide and poly-
vinylpyrrolidone are dissolved into a sufficient amount of
solvent, an equal mixture of ethylacetate and isopropanol,
to achieve complete solution. The solvent is evaporated by
heating under vacuum thereby obtaining a solid solution. A
caustic solution is prepared by adding deoxycholic acid to a
pre-dissolved aqueous solution which contains sodium hydrox-
ide and sodium phosphate buffer and thoroughly mixing until
solution is obtained. While agitating the solid solution,
the caustic solution is added thereto and the resulting mix-
ture is then heated at about 40-70C. until solution is
effected. The solution thus obtained is cooled to approxi-
mately room temperature while agitating and then distilled
water added to obtain the desired volume and the resulting
solution is filtered.
Other bile acids-fatty acids or salts thereof, such
as cholic acid, deoxycholic acid, stearic acid, chenodeoxy-
cholic acid, lithocholic acid, hyocholic acid, hyodeoxy-
cholic acid or epimers of hyocholic acid, can be substitutedfor isostearic acid and other bases, such as potassium hy-
droxide or lithium hydroxide can be substituted for sodium
hydroxide.
- 12 -
- 143~
1~)42797
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~ 14383
1~42~797
Procedure:
With moderate agitation, rafoxanide and poly-
vinylpyrrolidone are dissolved into a sufficient amount of
solvent, an equal mixture of ethyl acetate and methyl
alcohol, to achieve complete solution and sodium hydroxide
is added. The mixture is stirred at ambient temperature
for approximately 15 minutes. The solvent is evaporated by
heating under vacuum to form a ~olid solution. Distilled
water is added with agitation and the mixture is heated at
about 40 to 70C. until solution is effected. The resulting
solution is then cooled to room temperature with continued
agitation. To this solution is added distilled water to
obtain the desired volume and the resulting solution is
filtered.
Other bases, such as potassium hydroxide or
lithium hydroxide can be substituted for sodium hydroxide.
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