US3017329A - Method of locating enteric constrictions with a plurality of pills containing an x-ray contrast agent - Google Patents

Description

United States Patent METHOD OF TIONS WITH This invention relates to X-ray-opaque pills having a controlled rate of disintegration in the stomach and intestines, thus being adapted to facilitate the location of obstructions and the estimation of their severity.

An enteric obstruction in man or domestic animals is a sudden, acute and highly dangerous condition which, unless quickly diagnosed and corrected, causes serious complications or death. Such obstructions may be partial or total and are diflicult to locate by X-ray, especially when only partial. The usual X-ray technique is to administer a slurry of barium sulfate or other X-ray-opaque material and follow its movement through the body by means of X-rays. Frequently, the stoppage is less than 100% complete, in which case the slurry leaks past the constriction and thus fails to show where the latter is.

According to the invention, barium sulfate or other X-ray-opaque material is mixed with methylcellulose which may optionally contain hydroxyalkyl groups, and then molded into a pill which when taken internally disintegr-ates at a controllable rate. The rate of disintegration depends primarily on the type and percentage of methylcellulose used and the density of the pill. Thus, a highly substituted, highly soluble, low viscosity methyl cellulose dissolves faster than a lower substituted, high viscosity methylcellulose. Similarly, a porous, low density pill, molded under low pressure, dissolves faster than a hard, dense pill molded under high pressure.

When desired, the time at which the disintegration of the pill begins can be delayed for up to several hours after it has been taken internally by coating the pill with a protective coating of hydroxypropyl methylcellulose or, better, a mixture of hydroxypropyl methylcellulose and ethylcellulose. Ethylcellulose being substantially insoluble in water, its presence in the coating greatly reduces the solubility of the latter and increases the time required for disintegration of the pill. Thus, by controlling the thickness of the coating and the percentage of ethylcellulose therein, if any, one can control over a wide range the initiation of and the rate of disintegration of the pill. We generally prefer to keep the ratio of ethylcellulose to hydroxypropyl methylcellulose in the range 1:3 to 3:1. Lower ratios give quite rapid dissolution while higher ones yield pills having unduly long dissolving times.

We have found it advantageous to plasticize the coatings mentioned above in order to soften them and facilitate their uniform dissolution. Any water-soluble non-toxic plasticizer may be used, a suitable one being 1,2,3-tris- (2-hy droxypropoxy) -prop ane.

When the pills of the invention are used to locate an obstruction in the alimentary canal, a variety of techniques may be used. Thus, a single large pill may be administered and its progress followed by use of X-rays. When it arrives at a blockage or a constriction too narrow to permit its passage, it stops and thus shows where the obstruction is. If the obstruction is a constriction, the pill is stopped until the process of dissolution has reduced its size to that which can pass the constriction. It then passes the constriction. If this process is followed by X- rays, not only the location but also the severity of the constriction is apparent.

A quicker measure of the size of the free passage at a constriction can be made by simultaneously administering several pills of different sizes. Upon arriving at the constriction the smaller ones will pass through while the larger ones Will be held back, thus providing an accurate measure of the size of the passageway.

The practice of the invention is illustrated by the following examples. The viscosities shown for the cellulose ethers were determined by the standard methods used in the cellulose chemistry field.

Example 1 A mixture of barium sulfate (35%) and Methocel, U.S.P., methylcellulose (65%) was molded in a spherical die to make spheres of 0.5 inch diameter. These were then coated by being dipped into a 10% solution in benzene-methanol (1:1) of 50 parts of ethylcellulose-medium, 50 cps.; 30 parts of hydroxypropyl methylcellulose (50 cps., 6% Z-hydroxypropoxy, 28% methoxy by weight); and 20 parts of tris(2-hydroxypropoxy)-propane.

The pills prepared as above required one hour to begin to disintegrate in an aqueous medium at room temperature. When administered to a dog they were easily fol lowed by X-ray observation and were sharply outlined and hence easily measured. Disintegration began after one hour, when the coating had been dissolved, and was substantially complete in another hour.

Example 2 A pill identical to that of Example 1 was prepared except that the ratio of ethylcellulose to hydroxypropyl methylcellulose was increased from 50:30 to 55:25; This coating required 2 hours instead of 1 hour to dissolve.

The coating on the pill is optional and is omitted when it is desired that the pill begin dissolving sooner or dissolve at a higher rate.

The methylcellulose used as a binder for the barium sulfate should contain about 27.5 to 32.0% of methoxyl groups (by weight), its viscosity or molecular weight being relatively unimportant. Also, it may optionally contain up to about 15% of hydroxyalkyl groups containing 2 to 3 carbon atoms each; that is, hydroxyethyl, or 2- or 3- hydroxypropyl groups. Such hydroxyalkyl groups improve the moldability and cohesion of the barium sulfate pill composition.

The ratio of cellulose ether to barium sulfate in the pill may be varied widely, it being only necessary to use sufficient ether to form a strong, coherent pill on the one hand and enough barium sulfate to insure the pill showing adequate X-ray contrast on the other. For general use, it is preferred that the barium sulfate constitute about 25 to 50% by weight of the pill-forming composition.

I claim:

A method for locating and gauging an enteric constriction comprising administering orally a plurality of enteric pills comprising barium sulfate and, as a binder therefor, a water-soluble cellulose ether wherein the etherifying radical is a member selected from the group consisting of methyl, hydroxyethyl and hydroxypropyl radicals and mixtures thereof, the combined content of hydroxyethyl and hydroxypropyl radicals not exceeding about 15%, by weight, of said ether, said pills being substantially spherical and of widely different diameters; tracking the pills by means of X-rays; locating the constriction by noting where the larger pills are stopped and gauging the size of the constricted passage by noting the size of the largest pills that pass through it.

References Cited in the file of this patent UNITED STATES PATENTS 2,196,768 Hiatt Apr. 9, 1940 (Other references on following page) 4 UNITED STATES PATENTS Remington: Practice of Pharmacy, 11th ed. (1956), 2,721,142 t 1 O L 18 1955 Mack Publ. 00., Easton, Pa., pp. 375-376. 2,785,075 52 i i 12, 1957 Feinblatt et al.: New Eng. J. Med., vol. 254, May 17, 2,798,837 Sayh-un July 9, 1957 1 2- 2,801,203 Lab et a1 July 30, 1957 5 Practlcal Phys1olog1ca1 Chemlstry, Ph1l1p B. Hawk,

1923, pp. 181 and 182.

OTHER REFERENCES J.A.P.A., Prac. Pharm. Ed., August 1956, p. 539.

Marks: Am. J. Surg., January 1951, pp. 6-9.