US3584126A - Anthelmintic method employing phosphonate derivative - Google Patents

Abstract

THIS DISCLOSURE DESCRIBES A METHOD TO OF TREATING WARMBLOODED MAMMALS INFECTED WITH ENDOPARASITIC HELMINTHS WITH A HIGH EFFECTIVE ANTHELMINTIC, DIMETHYL-2,2,2-TRICHLORO-1-N-BUTYRYLOXYETHYLPHOSPHATE, HAVING LOW MAMMALIAN TOXICITY. THE SUPERIORITY OF THE COMPOUND COMPARED TO KNOWN ORGANOPHOSPHONATE ANTHELMINTICS IS EFFECTIVELY DEMONSTRATED.

Description

United States Patent Office 3,584,126 Patented June 8, 1971 3,584,126 ANTHELMINTIC METHOD EMPLOYING PHOSPHONATE DERIVATIVE Jack Greenberg, Richmond, Va., assignor to A. H. Robins Company, Incorporated, Richmond, Va. No Drawing. Filed Apr. 18, 1968, Ser. No. 722,531 Int. Cl. A61k 27/00 US. Cl. 424-212 3 Claims ABSTRACT OF THE DISCLOSURE This disclosure describes a method of treating warmblooded mammals infected with endoparasitic helminths with a highly effective anthelmintic, dimethyl-2,2,2-trichloro-l-n-butyryloxyethylphosphate, having low mammalian toxicity. The superiority of this compound compared to known organophosphonate anthelmintics is effectively demonstrated.

largely eliminated from the tissues of rats in a few days, (ref. Technical Brochure, Prentiss Drug and Chemical Co., Inc.). For example, 50-1500 mg./kg./day by oral administration, are effective, depending on the host animal and the extent of infection. Canines administered a single therapeutic dose of butonate in the range of about 200- 800 mg./kg. did not display intolerable side effects; the anthelmintic effect was excellent.

Butonate has been shown to be highly effective in eliminating helminths common to canines, having an average endoparasite elimination in the order of 90-96% against the following: Ancylostoma canium, T oxocara canis, and Trichuris vulpis.

The following table indicates the high degree of anthelmintic effectiveness in dogs in a single does of about 200 mg./kg. of butonate. Butonate was administered orally in capsule form at the time of feeding. No fasting or purgatives were employed. The dogs were necropised at 72 hours and fecal counts were made.

INDIVID UAL TESTIN G This invention relates to a method of treating warmblooded mammals infected with endoparasitic helminths, and specifically to the use of dimethyl-2,2,2-trichloro-1- n-butyryloxyethylphosphonate, hereafter butonate, Casida et al. (US. Pat. 2,911,435). This compound, having low mammalian toxicity, has been discovered to possess highly effective anthelrnintic properties. Moreover, this invention relates to a method of treating mammals, infected with endoparasites, with butonate in a pharmaceutically acceptable sustained action dosage form.

In the treatment of mammals infected with endoparasites, several vital criteria must be achieved, including low toxicity in the host animal, toxicidal activity against the endoparasites therein and chemical stability in the digestive tract of the host animal. For example, other, organophosphates have been known to 'be parasiticidal, but have been ineffective by oral application due to their tendency to be readily hydrolyzed in the digestive tract of the host animal.

The compound of this invention, butonate, has satisfied all the above mentioned criteria. In acute toxicity studies in adult white rats of the Sprague-Dawley strain, the oral LD is about 1000-1600 mg./kg. Large oral doses are Ancylostoma Toxocara Trichuris Expd., Expd., Expd., Expd. Left percent Expd. Left percent Expd Left percent GROUP EVALUATION Average Nematode Harbor percent Animals range average expelled cleared .Ancylostorna 1-124 11 94.1 16/17 T0xoeara l-70 14 97. 2 10/13 T1'1chur1s 1-29 10 95.1 12/13 The required, effective dose of butonate can be incorporated in the animals feed in the form of tablets, capsules, pellets, or the like, along with inert, pharmaceutically acceptable carriers. For example, for encapsulation, the following carrier materials may be used: lactose, starch, mganesium stearate and the like. For tableting, the same may be used with or without such other materials as corn starch, corn starch (paste), dicalcium phosphate and calcium stearate.

A preferred method of preparing a suitable encapsulated dosage form is illustrated in the composition having the following content:

Mg./capsule (1) Butonate 100.00 (2) Dicalcium phosphate 100.00 (3) Lactose 98.00 (4) Corn starch 98.00 (5) Magnesium stearate 4.00

Procedure following content:

Mgs. per tablet (1) Butonate 100.00 (2) Magnesium trisilicate 100.00 (3) Corn starch 20.00 (4) Polyvinylpyrrolidine 10.00 (5) Guar gum 10.00 (6) Calcium stearate 2.50

Procedure Deposit #1 and #2 by gradually adding #1 dissolved in 100 ml. methylene chloride to #2 while mixing gently using a sigma mixer. When #1 and #2 are thoroughly mixed, pass the moist mass through an oscillating granulator using a #10 mesh screen. Allow the granules to air dry overnight. The granules are then blended with #3 and this mixture is granulated with a solution of #4 in 95% alcohol. The wet mass is passed through an oscillating granulator using a #14 screen. The Wet granules are dried in a fluid bed drier. The dried granules are blended with #5 and #6. The mixture is then tableted using a suitable tablet press.

The presently preferred method is to include the dosage in a capsule and administer orally.

Butonate can be incorporated into a suitable sustained action dosage form which prolongs its effectiveness in the digestive tract of the host animal. A preferred method of preparing a suitable sustained dosage form is illustrated in the composition having the following content:

Parts by wt.

(1) Stearyl alcohol 140 (2) Pyrogenic colloidal silica 60 (3) Butonate 100 33.3% Butonate by weight.

Procedure Stearyl alcohol is heated to about followed by addition of pyrogenic colloidal silica and butonate. The reagents are intimately mixed to disperse and then cooled. After the mixture congeals, the mass is broken up by passing through an oscillating granulator equipped with a #8 mesh screen. The resulting granules, being 33.3% by weight of the active ingredient butonate, are incorporated into capsules for convenient administration.

Thus, a prolonged-acting anthelmintic such as butonate can be used in the treatment of warm-blooded mammals infected with endoparasites with a high degree of success. The dose would be determined on the basis of the degree of existing infection as well as the type of mammal being treated. Having eliminated the existing endoparasites from the host animal, butonate can also be used as a prophylactic, the dose being less than treatment of an infected animal, for example, 1-50 mg./kg./day; the dose, however, would again depend on the size and species of the mammal being treated.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt to various usages and conditions. Consequently, such changes and modifications are properly, equitably, and intended to be, within the full range of equivalence of the following claims.

What is claimed is:

1. A method of treating dogs internally infected with ancylostoma, toxocara and trichuris nematode worms comprising the step of orally administering an effective amount of a composition comprising dimethy1-2,2,2-trichloro-1-n-butyryloxyethylphosphonate and pharmaceutically acceptable carrier therefor.

2. A method as defined in claim 1 wherein said phosphonate compound is administered in an amount ranging from -1500 mg./kg./day.

3. A method of treating dogs comprising orally administering an etfective amount of dimethyl-2,2,Z-trichloro- 1-n-butyryloxyethylphosphate as a prophylactic against ancylostoma, toxocara and trichuris nematode worms.

Knowles et al.-I. of Agriculture & Food Chemistryvol. 14l966, pp. 566-572.

DrumondChem. Abst., vol. 611964-p. 12571g.

SAM ROSEN, Primary Examiner