GB2055575A - Palatable anthelmintic tablets for companion animals - Google Patents

Abstract

Palatable anthelmintic compositions for animals, contain anthelmintically effective amounts of an N,N - dialkylpiperazine carboxamide, with or without a styrylpyridinium compound, in which the active ingredients are ionically bound to sulfonic cation exchange resins. The compositions also contain desiccated liver, brewers yeast, microcrystalline cellulose and stearic acid and may also contain sodium aluminium silicate or silicon dioxide.

Description

SPECIFICATION Diethylcarbamazine resinate and styrylpyridinium resinate-diethylcarbamazine resinate edible anthelmintic tablets for companion animals The present invention relates to palatable acidic resinate compositions which contain a styrylpyridinium compound and/or an N,Ndialkylpiperazine carboxamide and find utility as a papatable anthelmintic compositions for the treatment of helminthiasis in companion animals.

Styrylpyridinium compounds and methods for their preparation are disclosed in United States Patents 3,177,116 and 3,179,559, issued April 6, 1965 and April 20, 1965, respectively. Similarly, N,Ndialkylpiperazine carboxamides are disclosed in United States Patent 2,467,895, issued April 19,1949.

The above-identified compounds are known to be useful forcombatting helminthiasis in domestic animals. They are said to be effective when administered by the oral route. Administration of both the N,N-dialkylpiperazine carboxamides and the styrylpyridinium halides, in the form of capsules, tablets and in the feed, is contemplated by the patentees.

However, it has been found that the styrylpyridinium compounds are unpalatable when taken orally and the N,N-dialkylpiperazine carboxamides are only partially acceptable to companion animals when administered in a form in which the active compound is permitted to come in contact with the animals taste buds. Over the years, veterinarians have continually complained that the available tablets, pills or formulated compositions marketed for admixture of the styrylpyridinium halides with feeds is unsatisfactory and has resulted in the reluctance of the animals to ingest the medicated feed, tablets or pills. It would therefore be highly advantageous and most desirable if the above-named compounds could be rendered palatable without destroying their efficacy.Furthermore, it would be most advantageous if a palatable composition, containing a N,Ndialkylpiperazine carboxamide, alone or in combination with a styrylpyridinium compound such as a 1 methyl - 2 - (p - chlorostyryl) pyridinium salt, could be prepared in the form of a chewable tablet, pill, granulated productorthe like.

Heretofore, it has been stated that, "both olfaction and taste are involved in canine food preferences".

Thus, the use of split plate evaluations for preference are crucial in delineating olfactory medicated preferences. Actual consumption of an article is a function of combined odor and taste acceptability which is herein interpreted as palatability.

It is, therefore, an object of this invention to provide palatable, therepeutically effective compositions, containing a N,N-dialkylpiperazine carboxamide alone or in combination with a styrylpyridinium compound, useful for the treatment of helminthiasis in companion animals.

It is also an object of the present invention to provide methods for preparing diethylcarbamazine and/or styrylpyridin ium compositions which are palatable and stable when admixed with animal feed stuffs.

The present invention accomplishes these objectives by the provision of novel resinates of N,Ndialkylpiperazine carboxamide compounds having the formula:

where R is hydrogen or C1 -C6 alkyl and R1 is alkyl C1-C5; and of styrylpyridinium compounds having the formula:

wherein R2 is C,-C4 alkyl and R3 is hydrogen or halogen.

The above compounds are described in United States Patents 2,467,895 issued April 19, 1949 and 3,177,116 issued April 6, 1965; however, no mention is made by the patentees of resinate forms of said compounds or the improved palatability obtained with said forms.

The resinates of the above-identified compounds are prepared by reacting the free base or pharmacologically acceptable salt of the N,Ndialkylpiperazine carboxamide or the pharmacologically acceptable salt of the styrylpyridinium compound with an acidic cationic exchange resin under conditions whereby said compound becomes ionically bound to the acidic anion of the resin.

The diethylcarbamazine and/or the styrylpyridinium compound is bonded to the resin with sufficient ionic strength to withstand ionization in the mouths of animals. However, the efficacy of these anthelmintic agents is retained since the active compound is released from the resin in the stomach and/or intestinal tract of the animal after being swallowed.

The present invention also provides a palatable anthelmintic composition for warm-blooded animals, the composition comprising the novel resinated N,N-dialkylpiperazine carboxamide of this invention and/orthe novel resinated styrylpyridinium compound of this invention, together with an orally acceptable carrier or diluent. Preferably, the carrier includes one or more of the following ingredients: dessicated liver, Brewers yeast, microcrystalline cellulose, stearic acid, sodium aluminum silicate and silicon dioxide. However, it is within the skill of the expert in this art to select other compounding ingredients in the preparation ofsuit- able carriers for the active anthelmintic agents of this invention.

In the most preferred practice of the invention, the novel resinates are admixed with from 18% to 60% The chemical formulae appearing in the printed specification were submitted after the date of filing, the formulae originally submitted being incapable of being satisfactorily reproduced by weight of desiccated granular or powdered liver, but preferably granular liver; 0%to 40% by weight of Brewers yeast; 23.95% to 31% by weight of microc rystalline cellulose; 7% by weight of stearic acid; 0% to .05% by weight sodium aluminum silicate or silicon dioxide; 2% to 5% by weight of diethylcarbamazine resinate and from 0 to 7% by weight of a styrylpyridinium resinate; said resin employed in the preparation of said resinates having a particle size of less than 800,a and preferably an average particle size between about 45y and 300,xb. Said ion exchange resin being furthercharacteried as a strongly acidic high capacity sulfonic cation exchange resin preferably of the polystyrene divinylbenzene type having from 4to about 8% cross linkage.

Preferred compositions comprise about 3% by weight of diethylcarbamazine resinate, about 5% by weight of 1 - methyl -2 - (p - chlorostyryl)pyridinium resinate, about 55% by weight of dessicated liver, about 30% by weight of microcrystalline cellulose, and about 7% by weight of stearic acid. The said resinates being high capacity sulfonic cationic exchange resins of the polystyrene divinylbenzene type with an average particle size in the range of from 45,ato 300cm.

Another preferred composition comprises about 3% by weight of diethylcarbamazine resinate, 5% by weight of 1 - methyl - 2 - (p - chlorostyryl)pyridinium resinate, 18% to 37% by weight of desiccated liver, 37% to 18% Brewers yeast, 30% by weight of microcrystalline cellulose, and 7% by weight of stearic acid.

Still another preferred composition comprises 3% by weight of diethylcarbamazine, 40% by weight of Brewers Yeast, 20% by weight of granular liver, 30% by weight of microcrystalline cellulose, and 7% by weight of stearic acid.

Preparation ofthe diethylcarbamazine resinate and styrylpyridinium resinate can be achieved by admixing the diethylcarbamazine compound with deionized water or the styrylpyridinium compound with an alcohol-deionized water mixture and intimately contacting the resulting mixture with a high capacity, sulfonic acid cationic exchange resin having a 4% to 8% divinylbenzene cross-linkage and a screen size of about 16 to 50 mesh. The thus prepared resinate is then separated from the supernatant liquid and washed repeatedly with deionized water until the wash water has a pH of about 4.5.The resin is then dried and ground or milled to at least about 800,u and preferably to an average particle size between 45,a and 300y. The resinates, thus prepared, can be used separately to formulate edible tables or they may be admixed to prepare edible tablets containing both compounds.

In the preparation of the above-mentioned resinates, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol-1, or pentanol-2, may be employed.

Strongly acidic resins are preferred in the preparation of the resinates of this invention since they provide resinates in which the diethylcarbamazine and/or styrylpyridinium compounds are more strongly bonded to the ion exchange resin to substantially prevent the compounds ionizing in the mouth of the animal to which they are fed. Among the preferred strongly acidic resins are sulfonated polystyrenes prepared from styrene and divinylbenzene which functions as a cross-linking agent. These resins include AMBERLITE lR-120, and DOWEX 50 and 50W. Sulfonated phenolic resins, may also be used and may includeAMBERLITE IR-1; cellulose alkylsulfonic acid resins such as CELLEX SE resin and the like may also be utilized in the preparation of the resinates of this invention.

The reaction to form the resinates can be carried out over a wide temperature range so long as the solvent remains fluid and is not evaporated in excessive amounts. For example, the reactions may be conducted at a temperature between about 0 and 100"C and preferably at from about 20" to 50"C.

The diethylcarbamazine or styrylpyridinium so lution can be contacted with the resin in any convenient manner such as by mixing the solution with the finely divided resin or by passing the solution of the anthelmintic agent through a resin bed. The molar ratio of anthelmintic agentto resin employed is not critical and is usually within the range of 0.125:1 to 3:1, preferably 0.5:1 to 2:1. A ratio within the preferred range permits efficient loading of the resin within a reasonable period of time. The anthelmintic resinates obtained in accordance with this invention contain about 10%to 60% by weight of anthelmintic and preferably about 40% to 55% of said anthelmintic.The resinate compositions can be prepared by either a batch or a continuous process and if desired both the diethylcarbamazine and styrylpyridinium compound may be loaded on a single resin. However, it is essential that in this arrangement the styrylpyridinium be loaded first and then the loaded resin thoroughly washed before the diethylcarbamazine is loaded on the resin. In this practice the resin is loaded only to about 25% to 33% by weight with the styrylpyridinium, determined on the basis of the dry weight on the resin, and then with about 13% to 18% by weight with diethylcarbamazine, determined on the basis of the dry weight of the resin. The preferred loading ration of styrylpyridinium to diethylcarbamazine or sequentially loaded resins is about 1.7 to 1. However, ratios as low as 1.3 to 1 can be used.

The sequentially loaded resinate, containing both the N,N-dialkylpiperazine carboxamide and the styrylpyridinium compound, may be illustrated as follows:

where R, R1, R2 and R3 are as described above.

Other embodiments and advantages of this invention will become more apparent from the examples set forth below. These examples are provided for the purpose of demonstrating the invention and are not intended to limit the scope hereof.

EXAMPLE 1 Preparation of Diethylcarbamazine Resinates and Styrylpyridinium Resinates Diethylcarbamazine Resinate Diethylcarbamazine (1125 kg real, 5.653 kg mole) also named N,N-diethyl -4 - methyl - 1 piperazinecarboxamide, is charged to 2240 liters of deonized water and agitated to dissolve it. To this solution is then added a high capacity sulfonic cation exchange resin ofthe polystyrene divinylbenzene type (2380 kg) AMBERLITE IR-1209 manufactured by Rohm & Haas Co.. The reaction slurry is filtered, washed with deionized water (2240 liters), and dried at 80"-900C. The dried diethylcarbamazine resinate (2380 kg) which assays 45.0% diethylcarbamazine free base is then milled to -30 mesh particle size.

The above-mentioned cation exchange resin has a density of 0.85g/cc apparent, 1 .26g/cc true; water content 4448%; exchange capacity of 4.40 milliequivalents /g dry and a screen size of from 16 to 50 mesh.

Styrylpyridinium Resinate A 3960 gram quantity of a sulfonic acid divinylbenzene resin (H + form) calculated to contain 1500 grams or 7.620 equivalents capacity of dry resin is mixed with a solution containing 2074 grams of 1 methyl -2 - (p -chlorostyryl)pyridinium chloride, 3000 ml of methanol and 3900 ml of deionized water.

The mixture is diluted to 11,000 ml with deionized water and then allowed to settle and the supernatant liquid separated from the mixture by filtration. This washing treatment is repeated 10 times. The pH of the final wash is 4.50 and the pH of the deionized water is 4.85. The resonate is then dried at 75"C for 48 hours and weighs 2,739 grams. The resinate passes through a 20 mesh screen and assays 52.38% 1 methyl - 2 - (p - chlorostyryl) - pyridinium as the chloride and has a KF moisture content of 1.305%.

The resin used in the above preparation is marketed under the tradename Powdex by the Graver Water Conditioning Co., N.Y., N.Y. and is essentially 20-50 mesh material.

EXAMPLE 2 Preparation ofDiethylcarbamazine Resinate A mixture of 20-50 mesh washed Powdex resin (16679 wet resin, calculated to contain 698.0g dry resin or 3.546 equivalents capacity) and 500 ml of deionized water are mixed in a vessel. To this mixture is added 719.28 (706.6g, real; 3.546 moles) of diethylcarbamazine base. The mixture is stirred for4 hours and then filtered and washed repeatedly with deionized water. The resinate is collected and dried at 85"C for 24 hours. The dried resinate weighs 13899 and assays 50.59% and 50.30% diethylcarbamazine base.

EXAMPLE 3 Preparation of Diethylcarbamazine Resinate-Edible Tablets Diethylcarbamazine resinate (71.28kg 3.24% w/w) prepared in accordance with the procedure of Example 1 above is blended with 1.10 kg ofcolloidal silicon dioxide. Brewers yeast 873.62 kg (39.71% w/w) is passed through a 30 mesh screen and blended with the prepared diethylcarbamazine mixture. The resulting mixture is then admixed with 660.00 kg of microcrystalline cellulose. The mixture is passed through a 30 mesh screen, blended with 154.00 kg of stearic acid, 440.00 kg of dessiccated, granular, liver (20% w/w) and compacted into 2.20 g tablets using a commercial tableting machine.

EXAMPLE 4 Preparation of Diethylcarbamazine Resinate-Edible Tablets Diethylcarbamazine resinate (71.2 kg 3.24%w/w) prepared in accordance with example 3 is admixed with 0.44 kg of sodium aluminum silicate. Desiccated, powdered, liver 444.0 kg 20.0% w/w) is then passed through a 30 mesh screen and blended with the previously prepared resinate mixture and to this mixture is added 874.28 kg (34.94% w/w) of Brewers yeast, 660.00 kg of microcrystalline cellulose and 1540.00 kg of stearic acid. The thus prepared mixture is thoroughly blended and then formed into 2.20 g tablets using a commercial tableting machine.

EXAMPLE 5 Preparation of diethylcarbamazine resinate -- styryl- pyridinium resinate edible tablets Diethylcarbamazine resinate (71.28 kg 3.24% w/w) and 1 - methyl - 2 - (p - chlorostyryl) - pyridinium resinate (104.94 kg 4.77%w/w) prepared in accordance with Example 1 are blended with 1.1 kg of colloidal silicon dioxide. Desiccated-granular liver (440.0 kg 20.0% w/w) is screened through a 30 mesh screen and admixed with the resinate mixture. Brewers yeast (768.68 kg ) 34.94% w/w) is then passed through a 30 mesh screen and mixed with the previously prepared resinate mixture. Microcrystalline cellulose (660.00 kg) and 154.00 kg of stearic acid are blended with the above-noted mixture and the resulting formulation formed into 2.2 g tablets using a commercial tableting machine.

EXAMPLE 6 Palatability Evaluation of Styrylpyridinium Diethylcarbamazine edible tablets The following tests are conducted to determine comparative acceptabliity of various acceptability of various formulations of tablets containing 1 - methyl - 2 - (p - chlorostyryl) - pyridinium resinate and diethylcarbamazine resinate.

Twenty adult purebred English Pointers are used in these evaluations. The dogs are housed individu ally in outside pens. Each pen is 4 feet wide,10 10 feet long and is provided with an attached house. Pointers are used for this test because of their organoleptic sensitivity to differences between products.

Each dog is tested for intestinal parasites by a flotation method using sodium nitrate solution and Fecasol 9 kits. Dog 7 is found to have a slight infestation of Toxascarisleonina and Dog 12 a ruminant parasite. Both infestations are gone after 14 days.

Tests for Dirofilariasis are conducted using Knott's technique and all blood samples are free of mic rofilaria.

In the tests each dog is fed, adlibitum, commercial dry dog food in self-feeders, and fresh, clean, water is available at all times.

A double choice format is employed with each dog being offered two choices of tablet formulations simultaneously to determine acceptability prefer once.

The fes@ containers used are rectangular plywood sheets @@ by 31 cm, 2cm thick, with routed depres sons 3; sm in diameter and 1.1 cm deep.

Ear@ @g is offered two tablets each morning and afternoon for four days. Presentation is ak@@@@@ @ach time by turning the containers 180 before @@@@lacing it in the cage. Time acceptance is ncteo - tr each proffering. The container is left in the cage 5s) minutes if the tablets are not readily con susm. d.

All dogs are less than 4 years of age and weigh between 35 and 52 pounds. The sex, habitus and initial and final weights of each dog are recorded and reported below. Also reported are the findings obtained in this test along with formulation used.

Table I English Pointers used in this test

Initial Final Den Sex Habitus weight ibis weights.

1 F muscular 48 43 2 F light 35 43 3 F light 38 35.5 4 F muscular 49 46 5 F light 37 35.5 6 F fat 49 47.5 7 F light 39 39 8 F average 41.5 43 9 F muscular 46 42.5 10 F light 40.5 40 11 M average 45 42.5 12 F fat 49.5 50 13 M muscular 52 50 14 F light 37 36 15 M muscular 52.5 50.5 16 F average 40 39 17 M muscular 50 50.5 18 F light 37 38.5 19 F average 45 43 20 F light 38 38.5 First Preference Test Results for Styrylpyridinium-Diethylcarbamazine Resinate Tablets

Comparisons: . A B B C A D B E F G G H Dog# 1 2 3 7 2 8 1 8 2 5 5 3 7 2 3 6 6 3 4 5 6 4 5 5 4 6 3 5 5 7 3 7 3 10 0 5 4 3 7 4 2 8 7 3 7 3 4 6 2 8 6 4 5 3 6 5 5 5 5 1 9 3 7 4 6 6 7 3 8 2 5 5 6 4 6 4 5 5 7 4 6 4 6 9 1 5 5 6 4 5 5 8 5 5 7 3 8 2 7 3 6 4 4 6 9 4 6 5 5 10 0 6 4 5 5 6 4 10 5 5 5 5 6 4 5 5 5 5 6 4 11 4 6 7 3 8 2 4 6 4 6 5 5 12 3 7 4 6 7 3 6 4 5 5 7 3 13 6 4 4 6 5 5 5 5 6 4 5 5 14 2 8 4 6 7 3 5 5 7 3 4 6 15 6 4 5 5 7 3 8 2 2 7 7 2 16 5 5 6 4 5 5 5 5 5 5 5 5 17 5 5 6 4 4 6 8 2 6 0 2 3 18 4 6 5 5 6 3 5 5 6 4 7 3 19 6 4 4 6 10 0 8 2 4 6 7 3 20 4 6 6 4 9 1 6 4 6 4 3 7 Totals: 85 108 112 86 137 60 118 82 99 95 98 96 Selected First) Tablet Compositions % w/w A = 36.36% Desiccated liver 18.18% Brewers yeast 30.67% Microcrystalline cellulose 2.92% Diethylcarbamazine resinate 7.00% Stearic acid 4.87% 1 - methyl - 2-, (p - chlorostyryl) - pyridinium resinate Resinate particle size 300-800,a 4% Sulfonic acid-divinylbenzene cross linkage B = 54.55% Desiccated liver 30.66% Microcrystalline cellulose 4.87% 1 - methyl - 2 - (p - chlorostyryl) - pyridinium resinate 2.92% Diethyicarbamazine resinate 7.00% Stearic acid Resin particle size 300-800,u 4% Sulfonic acid-divinylbenzene cross linkage C = 36.36% Brewers yeast 18.18% Desiccated liver 30.67% Mycrocrystalline Cellulose 4.87% 1 - methyl - 2 - (p - chlorostyryl ) - pyridinium resinate 2.92% Diethylcarbamazine resinate 7.00 Stearic acid Resin particle size 300-800,a 4% Sulfonic acid-divinylbenzene cross linkage D = Filarabits -Commercial edible formulation of Diethylcarbamazine E = 36.36% Brewers yeast 18.18% Desiccated powdered liver 5.19% 1 - methyl - 2 - (p - chlorostyryl) - pyridinium resinate 3.01% Diethylcarbamazine resinate 30.26% Microcrystalline cellulose 7.00% Stearic acid Resin particle size 147-300,u, 4% Sulfonic acid-divinylbenzene cross linkage F = 35.8% Brewers yeast 18.0% Desiccated powdered liver 5.97% 1 - methyl -2 - (p -chlorostyryl) - pyridinium resinate 3.18% Diethylcarbamazine resinate 0.05% Colloidial Silicon Dioxide 30.00% Microcrystalline cellulose 7.00% Stearic acid Resin particle size 147-300,t, 4% Sulfonic acid-divinylbenzene cross linkage G = 36.77% Brewers yeast 18.0% Desiccated powdered, liver 5.28% 1 - methyl - 2 - (p - chlorostyryl) - pyridinium resinate 2.95% Diethylcarbamazine resinate 30.00% Microcrystalline cellulose 7.00% Stearic acid Resin particle size < 147,cL, 8% Sulfonic acid-divinylbenzene cross linkage H = 36.52% Brewers yeast 18.00% Desiccated powdered, liver 5.30% 1 - methyl - 2 - (p - chlorostyryl) - pyridinium resinate 3.18% Diethylcarbamazine resinate 30.00% Microcrystalline cellulose 7.00% Stearic acid Average resin particle size 45ju 4% Sulfonic acid-divinylbenzene cross linkage From the above data it can be seen that formulation B, which contains approximately 55% by weight of liver, is most aggressively accepted by dogs. For mulation A, containing approximately 18% by weight of Brewers yeast and 40% by weight of liver is the next most palatable formulation, and formulation C, containing about 18% by weight of liver and 40% by weight of Brewers yeast is the third most palatable formulation to the dogs. All these formulations were most palatable than the commercial Filarabit (diethylcarbamazine) formulation. Formulation F, G and H were all readily acceptable to the test dogs and were equivalent in palatability ratings. In all cases, most dogs ate both tablets as treats within 1 minute. The use of about 20% liver or more improves the rate of acceptance primarily by beneficial olfactory stimulation.

EXAMPLE 7 Palatability evaluation ofstyrylpyridinium - diethylcarbamazine edible tablets The test described in example 6 above is repeated using 20 to 60 pound mongrel dogs. Tablets A, B, C and D, described in example 6, are evaluated in this test along with three different formulations designated I, J and K.The latter formulations have the following compositions: I = 18.18% Desiccated liver powder 36.36% Brewers yeast 30.10% Monocrystalline cellulose 5.28% 1 - methyl - 2 - (p - chlorostyryl ) - pyridinium resinate 3.08% Diethylcarbamazine citrate (no resin) 7.00% Stearic acid J = 46.36% Brewers yeast 8.18% Desiccated liver powder 30.49% Monocrystalline cellulose 5.05% 1 - methyl - 2 - (p - chlorostyryl) - pyridinium resinate 2.92% Diethylcarbamazine resinate 7.00% Stearic acid K = 54.54% Brewers yeast 30.49% Monocrystalline cellulose 5.05% 1 - methyl - 2 - (p - chlorostyryl) - pyridinium resinate 2.92% Diethylca rbamazine resinate 7.00% Stearic acid As in example 6, the tablets are offered to each dog twice daily for five days. Preference for formula- tions is reported as % consumed first.

First Preference test Results Styrylpyridinium-Diethylcarbamazine formulations % consumed Formulation %liver %yeast first A 36.36 18.18 56.4 C 18.18 36.36 43.6 A 36.36 18.18 41.0 B 54.55 0 59.0 B 54.55 0 66.0 D (Filari - - 34.0 bits) C 18.18 36.36 67.0 I = Nonresin- 18.18 36.36 33.0 ated Diethyl carbamazine Styryl pyridinium resinate J 8.18 46.36 56 K 0 54.54 44 From the above data it can be seen that the formulation prepared with about 54.55% liver was the most preferred formulation, However, formulations A, B and C, were all acceptable and preferred over the commercial "Filaribits" diethylcarbamazine formulation.Thus it is apparent that styrylpyridinium resinate-diethylcarbamazine resinate formulations containing 20% to 60% by weight of liver and 0-40% by weight of yeast are more acceptable i.e. palatable to dogs than the presently offered commercial preparations. The formulation containing non-resinated, diethylcarbamazine was not well accepted nor were the formulations containing 0 to 9% by weight of liver.

EXAMPLE 8 Palatability Evaluation of"L' Styrylpyridinium Diethylcarbamazine edible tablets Twenty-five to 29 privately-owned pet dogs representing a variety of ages, bodyweights, breeds and both sexes were used in a series of 3 day acceptance studies. STYRID-CARICIDE Tablets to provide therepeutic ievels ofstyrylpyridinium and diethylcarbamazine for a 201b. dog were formulated with a variety of liver contents and resinated or non resinated active drug components.The formulation used (Athru K) were specified in Examples 6 and 7 as follows: Formulation % Liver % Yeast Drugs A 36.36 18.18 CARICIDE Resinate STYRID Resinate B 54.55 0 CARICIDE Resinate STYRID Resinate C 18.18 36.36 CARICIDE Resinate STYRID Resinate 18.18 36.36 CARICIDE Citrate STYRID Resinate J 8.18 46.36 CARICIDE Resinate STYRID Resinate K 0 54.54 CARICIDE Resinate STYRID Resinate One additional formulation to be designated formu lation "L" using about 20% liver, 40% yeast with * Styrylpyridinium = STYRID * Diethylcarbamazine = CARICIDE CARICIDE resinate as the only active drug was also evaulated as was Diroform & an edible formulation of diethylcarbamazine made by Vet-A-Mix, Inc., Shenandoah, Iowa.

Whole or parts of tablets were offered free-choice appropriate to the individual dogs body weight once daily for 3 consecutive days. A period of about 2 weeks separated each 3 day test. Acceptance of each formulation was calculated at the percentage of the total number of daily tablet presentations which were readily consumed by the dogs. If less than the entire daily dosage was accepted, then that day was considered a rejection of medication. Results are listed below: Formulation % Liver % Yeast %Acceptance K 0 54.54 61 J 8.18 46.36 80 C 18.18 36.36 96 A 36.36 18.18 96 B 54.55 0 96 18.18 36.36 76 L about 20 about 40 89 Diroform - - 79 All results were made using a resin of 300-800,u particle size with 4% divinylbenzene cross linkage.

An excellent acceptance was attained with liver present at a concentration of about 20% or greater. Relatively poor acceptance was observed at about 10% or less liver content. A relatively low acceptance rate was seen for the now resinated diethylcarbamazine formulation (I) which was nearly equivalent to that observed for Diroform a potentially competitive pro duct. When diethylcarbamazine resinate alone was incorporated into the 20% liver matrix it compared very favorably with the non-resinated diethylcar bamazine formulation.

EXAMPLE 9 Sequentially Loaded Styrylpyridin ium - Diethylcarbamazine Resin DOWEX 9 50W, sulfonated polystyrene - divinyl benzene cross-linked acidic resin, 3000g is placed in a 101. graduated cylinder. Styrylpyridinium chloride (510.5g) is then dissolved in 1200ml of deionized water and 300ml of methanol and added to the DOWEX 50W resin. The mixture is stirred for 2 hours and then permitted to settle and the acidic supernatant liquid decanted. The remaining styrylpyridinium resinate is washed 3 times with deionized water, then permitted to settle and the supernatant liquid separated from the resinate. Diethylcarbamazine base (306.39) is then added to the resinate and sufficient deionized water added to adjust the volume of the mixture to 111.The resulting mixture is stirred for 2 hours until the diethylcarbamazine is loaded on the resin along with the styrylpyridinium. The mixture is washed several times and until the final wash and resin mixture has a pH of 4.30. The supernatant liquid is separated from the styrylpyridiniumdiethylcarbamazine resinate which is then dried and ready for use in preparation of the edible tablets.

The above procedures are repeated using POWDEX Resin (IR 120) ground to 45,a (28209). The styrylpyridinium chloride (501.9) is the first drug to be loaded on the resin as described above. This is accomplished in a methanol water solution. The resin is washed three times with deionized water and the supernatant liquid decanted. Diethylcarbamazine (291.g) is then sequentially loaded onto the washed styrylpyridinium resinate and stirred for 17 hours.

The mixture is permitted to settle, the supernatant liquid decanted and the remaining resinate washed with deionized water until the pH of the wash water mixture is about 1.7.

EXAMPLE 10 Preparation of Styrylpyridinium - Diethylcarbamazine edible tablets using sequentially loaded resin Styrylpyridinium - diethylcarbamazine sequentially loaded resinate (355.49) is admixed with 8009 of desiccated powdered liver, 12009 of microcrystalline cellulose (AVICEL PH102); 1362.69 of Brewers yeast; 2.0g of silicon dioxide and 280.9 of stearic acid. The composition, thus prepared, contained 8.885% by weight of the resinated drug, 20% by weight of liver, 30% by weight of microcrystalline cellulose, 34.065% by weight of the yeast, 0.05% by weight of the silicon dioxide and 7.0% by weight of the stearic acid.

The composition is compressed into chewable 2.2g tablets having a Kilopond hardness rating of about 8.5 Kp. The palatability of the thus prepared tablets is excellent.

EXAMPLE 71 Diethylcarbamazine Edible Tablet Palatability Evaluations using privately owned dogs maintained under Home Environment Conditions In this study, heartwarm (Dirofilaria immitis) negative dogs representing a random variety of breeds, ages, body weights, and both sexes, are offered diethylcarbamazine edible tablets prepared as described in example 3 above. The medicated edible tablets were offered to each dog once a day for 30 consecutive days.

Each dog is rated according to the number of acceptance as a percentage of the total number of daily presentations using the following classifications criteria: Rating Acceptance Excellent Accepted 90% or more of the daily doses Good Accepted 89% to 75% of the daily doses Fair Accepted 74% to 51% of the daily doses Poor Accepted 50% or less of the daily doses Tablets are presented at the owner's convenience, usually prior to or during a meal. The acceptability panel was made up of 37 dogs representing a random variety of breeds, both sexes, a body weight range of 4.5 to 55.4 kg, and an age range of 6 months to 12.5 years as shown in table I.Acceptability results are shown in Table II, and are summarized below: Rating Number of Dogs % of Total Panel Excellent 30 81 Good 2 5 Fair 0 0 Poor 5 14 "Excellent" to "Good" acceptance was observed for 86% of the panel members and "Fair" to "Poor" acceptance for 14% of the panel. In general, acceptance or rejection of the tablets was not a function of the method of administration, i.e. as a treat vs.

mixed with food. If the tablets were consistently rejected, the test, while still reported, was terminated for that individual prior to completion ofthe full test period. Throughout the trial, only one dog, was "sick". This occurred on the twenty-first day of medication and lasted for one day only. This dog was continued on medication for an additional 12 days (total of 42 days of treatment), with no adverse effects noted. Two of the smaller dogs preferred the tablets broken into pieces, but when broken, accepted them well.

TABLE I Acceptability Panel Composition Body Weight Breed Males Females Age (Range) (Range in kgJ Borzoi 1 1 2.5-3.5yr. 31.5-55.5 Collie 1 13 months 27.5 Dachshund 1 3 3 - 10 years 6.0 - 8.0 German Shepherd 1 2.5 years 29.5 G.S.H. Pointer 1 6 months 18.0 Golden Retriever 2 1.5 - 6 years 29.5 - 32.0 Irish Setter 1 8 months 27.5 Labrador Retriever 1 2 11 months-5years 31.0-36.5 Miniature Poodle 1 12.5 years 8.0 Miniature Schnauzer 3 2 1 years 4.5-9.0 Shetland Sheepdog 1 1.5 years 7.0 Standard Poodle 1 3 years 26.0 Welch Corgi 2 3 5 - 11 years 7.5 - 13.5 West Highland 1 2 years 8.5 White Terrier Mixed 4 4 1.5-8 years 8.5-45.5 Totals 15 22 Range:6monthsto Range::4.5to 12.5 years 55.4 kg TABLE II Dog Acceptance In formation and Owners Comments

Dog %of Days Days Presentations How Breed Age Sex' Accepted Rejected Accepted Given Comments Irish Setter 8 my. M 30 0 100 Treat Loved it German Shepherd 2.5 yr. F 45 0 100 Treat Ate it Schnauzer 1 yr. F 31 0 100 Treat Ouick Acceptance Schnauzer 7 yr. M 0 100 Treat Quick Acceptance chnauzer lOyr. M 27 4 87 Treat Occasionally crumbled prior to ~~ to presentation Schnauzer 5 yr. M 24 7 77 Treat Occasionally crumbled tablet or combined with food TABLE II {Continued) Dog Acceptance Information and Owners Comments

Dog %of Days Days Presentations How Breed Age Sex' Accepted Rejected Accepted Given Comments Collie Mix 3 yr. M 31 0 100 Treat Readily accepted tablet, may betoo hard Mix 7 yr. M 33 0 100 Treat Enthusiastically Received Schnauzer 4 yr. F 31 0 100 Treat No adverse effects Corgi 5 yr. F 31 0 100 Treat Excellent Corgi 5 yr. M 31 0 100 Treat Good Corgi 7 yr. F 30 0 100 Treat Excellent Corgi 11 yr. F 31 0 100 Treat Excellent Corgi 6 yr. M 31 0 100 Treat Excellent Collie 13 mo. F 31 0 100 Treat Some day-to-day variation in acceptance-mostly excellent Mix 2 yr. F 8 20 28 Treat Usually didn't want it Terrier Mix 4 yr. M 9 22 29 Treat or with Accepted only by accident food Mix 6 yr. F 1 9 10 Treat or with None food Mix 1.5 yr. M 1 30 3 Treat or with Not like the taste or food consistency Borzoi 2.5 yr. F 30 0 100 Treat No adverse effects Mix 7.5yr. F 30 0 100 Treat No adverse effects Borzoi 3.5 yr. M 30 0 100 Treat No adverse effects Labrador 17 mo. M 30 0 100 Treat Excellent-swallowsthemquickly Labrador Syr. F 31 0 100 Treat Comes running forthem Pointer 6 mo. F 41 1 98 Treat or with Never refused - either food way presented Labrador 11 mo. F 42 0 100 Treat or with Never refused - either food way presented Shetland 1.5 yr. M 15 0 100 Treat None Sheepdog Dachshund 3 yr. M 31 0 100 Treat or with None food TABLE II (Continued) Dog Acceptance In formation and Owners Comments

Dog %of - Days Days Presentations How Breed Age Sex1 Accepted Rejected Accepted Given Comments Dachshund 7 yr. F 31 0 100 Treat or with None food Golden Retriever 1.5yr. F 31 0 100 Treat or with None food Golden Retriever 6yr. F 25 1 96 Treat Excellent W.H.W. Terrier 2 yr. M 29 2 94 Treat or with Good food Miniature Poodle 12.5yr F 30 1 97 Treat Well accepted Standard Poodle 3 yr. F 31 0 100 Treat Well accepted Mix 8 yr. F 0 3 0 Treat orwith None food Dachshund 4 yr. F 30 0 100 Treat None Edible Tablet Composition Ingredient % Composition 1. Diethylcarbamazine Resinate* 3.063 2. Silicon dioxide, colloidal 0.05 3. Brewer's Yeast 39.887 4. Cellulose, microcrystalline 30.0 5. Stearic Acid, powder USP 7.0 6. Liver, dessicated (granular) 20.0 Total: 100.0% Mean tablet weight: 2.232 g.

Assay: 2.75%w/w as DEC citrate

Claims (9)

1. A palatable anthelmintic resinate composition comprising from 2% to 5% by weight of a resinated N,N-dialkylpiperazine carboxamide compound having the formula:

where R is hydrogen or alkyl Ci-C6 and R1 is alkyl C-Cs; from 0 to 7% by weight of a resinated styryl- pyridinium compound having the formula:

where R2 is alkyl Ct-C4, R3 is hydrogen or halogen; 18%to 60% by weight of desiccated liver; Oto40% by weight of Brewers yeast; 23.95% to 31% by weight of microcrystalline cellulose, 7% by weight of stearic acid; and 0% to 0.05% by weight of sodium aluminum silicate or silicon dioxide.

2. The composition according to Claim 1 wherein the N,N-dialkylpiperazine carboxamide is diethylcarbamazine and is present in the composition in the amount of 3% by weight as the resinate, the styrylpyridinium compound is 1 - methyl -2 - (p - chlorostyryl)pyridinium resinate and is present in the composition in the amount of 5% by weight; the desiccated liver is 18% to 37% by weight of the composition, Brewers yeast is 37% to 18% by weight of the composition; microcrystalline cellulose is 30% by weight of said composition and stearic acid is 7% by weight of said composition.

3. The composition according to Claim 1, wherein said composition comprises about 3% by weight of diethylcarbamazine resin; 5% by weight of 1 methyl -2 - (p -chlorostyryl)pyridinium resin; 55% by weight of desiccated liver; 30% by weight of microcrystalline cellulose; and 7% by weight of stearic acid.

4. The composition according to any preceding claim, wherein the resin is a high capacity sulfonic cationic exchange resin of the polystyrenedivinylbenzene type having a particle size of less than 8wop.

5. The composition according to Claim 4, wherein the resin has an average particle size range between 45,u and 300tri.

6. The composition according to any preceding claim, wherein said composition is formed into a chewable tablet for administration to companion animals.

7. A palatable, chewable, anthelmintictablet comprising from 2% to 5% by weight of diethylcarbamazine resinate; from 18% to 60% by weight of desiccated liver; from Oto 40% by weight of Brewers yeast; 23.95 to 31% by weight of microcrystalline cellulose; 7% stearic acid and from 0 to 0.05% of sodium aluminum silicate or silicon dioxide.

8. A method for the preparation of a sequentially loaded, medicated cationic exchange resin having the formula:

wherein R is hydrogen or C1-C6 alkyl; R, is C1-Cs alkyl; R2 is C1-C4 alkyl; R3 is hydrogen or halogen and the resin is a high capacity, sulfonic acid, cationic exchange resin, comprising; reaction a styrylpyridinium compound having the formula:

where in R2 and R3 are as described and X is a pharmacologically acceptable anion, dissolved in an aqueous solution of deionized water and a lower alkyl C,-C4 alcohol, with a high capacity, sulfonic acid, cationic exchange resin until said resin is loaded to about 25% to 33% by weight with a stypyridinium compound of the structure:

where R2 and R3 are as described above; separating the aqueous alcoholic solution from the loaded resin and washing the loaded resin with deionized water until the pH of the wash water-resin mixture is 4.30 or below; separating said wash water from said resin and reacting the partially loaded styrylpyridinium-resin with an aqueous solution containing from 15% to 21% by weight of diethylcarbamazine, determined on the basis of dry resin, until said partially loaded resin is loaded with from 15% to 21 % by weight of diethylcarbamazine, thereafter separating the aqueous solution from the loaded resin, washing said resin with deionized water, separating said wash water from said resin and recovering the desired sequentially resin.

9. A method according to claim 8 wherein said resin has a loading capacity of about 5 milliequivalents per gram dry weight of resin and the styrylpyridinium to diethylcarbamazine loading ratio is about 1.67 to 1.