US2916417A - Article of manufacture - Google Patents

Description

United States Patent ARTICLE OF MANUFACTURE Bruce W. Horrom, Waukegan, Ill., assigmor to Abbott Laboratories, North Chicago, Ill., a corporation of Illinois No Drawing. Application December 24, 1956 Serial No. 630,086

8 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 dicyclopropyl ketoxime in a dosage unit form suitable for use as a muscle relaxant.

The compound dicyclopropyl ketoxime has the following structural formula 1l\lr01-1 M It is a white crystalline solid material that is sparingly soluble in water up to a level of 0.5%, and highly soluble in organic solvents such as benzene, ether, alcohol and the like. It has a boiling point of 141-146" C. (60 mm.) and when recrystallized from petroleum solvent, the solid material has a melting point of 76-77 C.

The method for preparing dicyclopropyl ketoxime has been described by H. Hart and O. E. Curtis, Jr., J.A.C.S., volume 78, page 112 (1956).

The muscle relaxant properties refer to relief of skeletal muscle tension and spasms by interrupting synaptic transmissions at various levels of the central nervous cord rather than interrupting peripheral nervous impulses at the myoneural junction of skeletal muscle, thus distinguishing their mode of action from curare-like drugs.

It is the object of this invention to provide convenient dosage unit forms of a compound having marked muscle relaxant properties, in particular dosage unit forms of the compound dicyclopropyl ketoxime.

Another object is to prepare said dosage forms in solid and liquid carriers suitably selected for either oral or injectable administration.

It has now been found that the compositions of this invention employing dicyclopropyl ketoxime are highly effective muscle relaxants of the internuncial neuron depressant type. They have low toxicity and can be administered orally in dosage units of the size, type and kind to be described hereinafter.

The effective clinical dose of dicyclopropyl ketoxime for adults ranges from about 100 mg. per day upwardly. In children the dosage ranges correspondingly lower according to the age and Weight of the child. The drug may be administered in the forms of tablets, capsules, powder or in a flavored suspension or solution. A preferred form of administration is in scored tablets each containing 10 mg. of drug, which will provide the minimum dose for children when broken in half, and when taken in multiples will provide amounts up to the maximum dose.

In one of the preferred compositions the active ingredient, dicyclopropyl ketoxime, may be incorporated into tablets by utilizing standard ingredients and steps in the preparation thereof. In particular, solid diluents and "ice tableting adjuvants such as corn starch, acacia, lactose, talc, stearic acid, magnesium stearate, gums and the like may be used. Any of the tableting materials used in the pharmaceutical art 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 another embodiment of the invention a solution dose form is made. Although solubility in water is low (0.5%), a sufficient concentration of dicyclopropyl ke toxime can be dissolved to provide a therapeutic dosage. A solution dosage form can contain from about 2 mg. per cc. (10 mg. per teaspoon) to about 5 mg. per cc. of the active ingredient. Should a liquid dosage form containing a greater concentration of the active material be desired, a suspension of dicyclopropyl ketoxime may be prepared by compounding the active ingredient in concentration above about 5 mg. per cc. of liquid with suspending agents such as acacia or carboxymethylcellulose along with the usual flavoring materials. Such a liquid preparation is particularly suitable for children and infirm persons who have difliculty swallowing a tablet or capsule.

The following examples illustrate preferred embodiments of the dosage forms, but it should be understood that they are not meant to restrict the dosage forms to ingredients and proportions named therein.

EXAMPLE I Dicyclopropyl ketoxime tablets Dicyclopropyl ketoxime (1.33 pounds) is mixed with 37.31 pounds of lactose and passed through a 30-mesh screen. A starch paste is prepared using 1.05 pounds of corn starch and 5.98 pounds of distilled water. The starch paste is massed with the prior mixture and passed through a 4-mesh screen and then dried at F. for 17 hours. The dried paste is granulated and passed through a 16 screen. Stearic acid (0.446 pound), corn starch (3.87 pounds) and talc (2.036 pounds) are passed through a 40-rnesh screen and blended well with the granulated dicyclopropyl ketoxime, lactose and corn starch.

The blended material is compressed into tablets each containing 10 mg. of active material.

EXAMPLE II Dicyclopropyl ketoxime in solution dose form A pharmaceutical solution of dicyclopropyl ketoxime is prepared by combining the following ingredients:

Dicyclopropyl ketoxime gms 2.0 Sucrose gms 200.0 Glucose gms" 250.0 Glycerin cc 50.0 Methyl-p-aminobenzoate -gms- 1.5 Propyl-p-aminobenzoate gms 0.15 F.D. & C. orange #1 gms 0.05 Imitation orange aroma cc 0.02 Oil orange cc 0.5 Water, Ilco, q.s. cc 1000.0

The foregoing solution provides a concentration of active ingredient at a level of 2 mg. per cc. or 10 mg. per teaspoon.

The esters of p-hydroxybenzoic acid prevent fermentation and mold formation.

3 EXAMPLE n1 Dicyclopropyl ketoxime in suspension dose form A pharmaceutical suspension of dicyclopropyl ketoxime is prepared by combining the following ingredicuts:

The foregoing suspension provides a concentration of active ingredient at a level of 10 mg. per cc. or 50 mg. per teaspoon.

While the foregoing preparations are designed for oral administration, appropriate solutions or suspensions containing dicyclopropyl ketoxime may be devised for injectable introduction into the body. The term injectable introduction is intended to include all the routes available to this form of dosage, namely intravenous, intramuscular and intraperitoneal. Such injectable compositions resemble the product of Example II except that the sugars, flavors, colors and glycerin are replaced with an equivalent amount of water.

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

I claim:

1. An article of manufacture characterized by skeletal muscle relaxant activity comprising at least about 10 mg. of dicyclopropyl ketoxime and a non-toxic pharmaceutical carrier.

All such practice of the in- 2. An article of manufacture characterized by skeletal muscle relaxant activity comprising at least about 10 mg. of dicyclopropyl ketoxime and a non-toxic solid pharmaceutical carrier in dosage unit form.

3. An article of manufacture characterized by skeletal muscle relaxant activity comprising an aqueous liquid pharmaceutical carrier containing at least about 2 mg. of dicyclopropyl ketoxime per cc. of liquid.

4. A composition characterized by skeletal muscle relaxant activity comprising an aqueous pharmaceutical suspension including a non-toxic suspending agent and at least about 5 mg. per cc. of dicyclopropyl ketoxime.

5. The method of causing muscle relaxation in persons subject to excessive skeletal muscle tension which comprises administering to the human host a non-toxic composition containing at least about 10 mg. of dicyclopropyl ketoxime.

6. The method of causing skeletal muscle relaxation in a living host afilicted with excessive muscle tension which comprises administering orally to the living host a non-toxic composition comprising at least about 10 mg. of dicyclopropyl ketoxime and a pharmaceutical carrier.

7. The method of causing skeletal muscle relaxation in a living host afilicted with excessive tension which comprises administering by injection a non-toxic pharmaceutical solution containing at least about 2 mg./cc. of dicyclopropyl ketoxime.

8. The method of causing skeletal muscle relaxation in a living host afilicted with excessive muscle tension which comprises administering orally to the living host a non-toxic, aqueous pharmaceutical suspension containing at least about 5 mg./cc. of dicyclopropyl ketoxime and a non-toxic suspending agent.

References Cited in the file of this patent Colman et al.: Ber. Deut. Chem, vol. 19 (II), 1896, pp. 3113-3114.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent Non 2,916,417 December 8, 1959 Bruce W, Horrom appears in the printed specification It is hereby certified that error correct-ion and that the said Letters of the above numbered patent requiring Patent should read as corrected below.

Column 4, line 24, for excessive tension" read excessive' muscle tension Signed and sealed this 24th day of May 1960,

(SEAL) Attest:

KARL AXLINE Attesting @mcer ROBERT C. WATSON Commissioner of Patents

Claims (1)

1. AN ARTICLE OF MANUFACTURE CHARACTERIZED BY SKELETAL MUSCLE RELAXANT ACTIVITY COMPRISING AT LEAST ABOUT 10 MG. OF DICYCLOPROPYL KETOXIME AND A NON-TOXIC PHARMACEUTICAL CARRIER.