US2793157A - Anticonvulsant 3-ethyl-5-phenyl hydantoin unit dosages and method of using same - Google Patents

Description

United States Patent ANTICONVULSANT S-ETHYL-S-PHENYL HYDAN- UNIT DOSAGES AND METHOD OF USING Warren J. Close, Waukegan Township, Lake County, 111., assignor to Abbott Laboratories, North Chicago, 11]., a corporation of Illinois No Drawing. Application December 28, 1954,

Serial No. 478,189

5 Claims. (Cl. 167-65) This invention relates to a new article of manufacture and to methods of compounding and using the same. More particularly, the invention relates to the compound S-ethyI-S-phenyl hydantoin in dosage unit form suitable for use as an anticonvulsant.

A considerable number of chemicals have been used as anticonvulsants for control of the various types of epileptic seizures and to a certain extent have met with success in the control of the convulsions. Unfortunately, most of the compounds which have achieved success possess undesirable side reactions which either limit their use or add further to the distress of the unfortunate user. Many of the known compounds cause dizziness, lethargy and incoordination in the patient, as well as nervousness and visual disturbances. Another group results in in coordination, gastric distress and similar undesirable reactions. Toxic effects of a more serious nature are common and agranulocytosis and aplastic anemia are oftentimes observed. It is apparent, therefore, that the need for a safe and efficient anticonvulsant has not been fully met by compounds known in the prior art.

It has now been found that the compound 3-ethyl5- phenyl hydantoin is a highly efiective anticonvulsant agent. It is of relatively more importance in the control of epileptic seizures of the grand mal type, but it is also beneficial in the control of seizures of the other types. It has low toxicity and does not tend to produce physiological disturbances of the type mentioned above to any substantial degree, and it can be administered orally in dosage units of the size, type and kind to be described hereinafter.

The compound 3-ethyl-5-phenyl hydantoin is a white solid which is neutral in character and is only very slightly soluble in water. It nevertheless is readily absorbed by the body upon oral administration. The compound was first made and identified by Pinner in Berichte, 21, 2325 (1888).

Extensive laboratory tests have established 3-ethyl-5- phenyl hydantoin as an effective anticonvulsant of low toxicity. Clinical investigations have confirmed the laboratory results and the compound has been proven to be effective and reliable in the treatment of epilepsy.

The effective clinical dose of 3-ethy1-5-phenyl hydantoin for adults ranges from about 0.25 gram per day upwardly. It is known that amounts up to about 2.5 grams per day will control most situations and in a multiple dosage schedule, toxic symptoms are neglible at this dose. In children the dosage ranges correspondingly lower according to the age and weight of the child. Usually about half the adult dose will sufiiee in children and at least about 0.125 gram per day will ordinarily be given. The drug may be administered in the form of tablets, capsules, powders or in a flavored oral suspension. A preferred form of administration is 250 mg. scored tablets which will provide the minimum dose for "ice children when broken in half, and when taken in multiples will provide amounts up to the maximum dose.

The preferred dose forms may take the form of active material, namely 3-ethyl-5-phenyl hydantoin, administered with solid diluents and tableting adjuvants such as corn starch, acacia, lactose, talc, stearic acid, magnesiurn stearate, gums and the like. Any of the tableting materials used in pharmaceutical practice may be employed where there is no incompatibility with the active material. Alternatively, the active material with or without its adjuvant materials may be placed in a soft or hard gelatin capsule and administered in capsule form.

In still another dosage form the active material, which is substantially insoluble in water (less than 1% by weight), may be compounded with flavoring materials and suspending agents such as acacia or carboxymethylcellulose in the preparation of an aqueous suspension which is particularly suitable for chlidren and infirm persons who have difficulty swallowing a tablet or capsule.

In illustration of the tablet dosage form a large number of tablets each containing 250 mg. of active material were prepared by massing together 12.52 lbs. of S-ethyl- S-phenyl hydantoin, 4.5 lbs. of lactose, 1.8 lbs. of polyvinylpyrrolidone and 7.2 lbs. of water. The granulation is forced through a screen and dried and to the dried material is added 1.26 lbs. of sodium carboxymethylcellulose, 1.08 lbs. of talc and 0.36 lb. of stearic acid, as lubricants. The material thus prepared is compressed into approximately 40,000 tablets, each containing 250 mg. of active material. The tablets are scored so that they can easily be broken in half. If desired, the tablets may be coated with the usual tablet coating ingredients in order to make them more acceptable.

Others may practice the invention in any of the numerous ways which will be suggested by this disclosure to one skilled in the art. All such practice of the invention is considered to be a part hereof provided it falls within the scope of the appended claims.

I claim:

1. article of manufacture characterized by anticonvulsant activity comprising at least about 0.125 gram of 3-ethyl-5-phenyl hydantoin and a solid pharmaceutical carrier in dosage unit form.

2. An article of manufacture characterized by anticonvulsant activity comprising at least about 0.125 gram of 3-ethyl-5phenyl hydantoin and a non-toxic pharmaceutical binding agent placed together in a tablet.

3. A composition of matter characterized by antieonvulsant activity comprising between about 0.125 gram and 2.5 grams of 3-ethyl-5-phenyl hydantoin and a solid pharmaceutical carrier in dosage unit form.

4. The method of controlling epileptic seizures which comprises administering at least about 0.125 gram of 3-ethyl-5-phenyl hydantoin to a human host subject to said seizures.

5. The method of controlling epileptic seizures which comprises administering a tablet comprising between about 0.125 gram and 2.5 grams of 3-ethyl-5-phenyl hydantoin and a solid pharmaceutical carrier, to a human host subject to said seizures.

References Cited in the file of this patent Jenkins et al.: The Chem. of Organic Med. Prod., 2nd ed., 1943, New York, page 549.

Putnam et al.: Archives of Neurology and Psychiatry, March 1941, vol. 45, p. 505-516.

Toman et al.: Physiological Reviews, vol. 28, October 1948, pp. 409, 424, 425.

Pinner: Berichte 21, 2325 (1888).

Claims (1)

1. 5. THE METHOD OF CONTROLLING EPILEPTIC SEIZURES WHICH COMPRISES ADMINISTERING A TABLET COMPRISING BETWEEN ABOUT 0.125 GRAM AND 2.5 GRAMS OF 3-ETHYL-5-PHENYL HYDANTOIN AND A SOLID PHARMACEUTICAL CARRIER, TO A HUMAN HOST SUBJECT TO SAID SEIZURES.