US2808361A - Solubilizer for preparing an aqueous soluble menadione - Google Patents

Description

United States Patent Ofiice 2,808,361" Patented Oct. 1, 1957 SOLUBILIZER FOR PREPARING AN AQUEOUS SOLUBLE MENADIONE Russell R. Bavouset, Pasadena, Calif.

No Drawing. Application March 9, 1955, Serial No. 493,309

Claims. (Cl. 167-81) necessity for adminismuscular absorption. used in isotonic dextrose solutions for slow intravenous administration. Further, if rendered water-soluble, it is subject to oral administration without requiring concurrent administration of bile salts to make the vitamin K activity available.

I have discovered that menadione can be solubilized and stabilized by incorporating it in an aqueous solutron of nicotinamide, and that it then becomes useful for the above indicated purposes. Such solubiliziug avoids the requirement for fat-solubilization by reason of bile flow, and bile-flow obstmction does not therefore I become a deterent to the stituent.

The usual dose of menadione is one or two milligrams daily. I have discovered that one (1) milligram of menadione may be solubilized and stabilized with one hundred (100) milligrams of nicotinamide, and that two (2) milligrams of menadione are readily solubilized with one hundred fifty (150) milligrams of nicotinamide. The nicotinamide is desirably used as a 33% aqueous solution (weight basis), that is 50 grams in 100 milliliters of water, but concentrations between about grams to 100 grams of nicotinamide in 100 milliliters of water may be used, or about 15% to solutions. Since menadione is decomposed by sunlight, it is important to protect it from light at all times. This is accomplished, for example, by agitation or stirring of the menadione into the aqueous nicotinamide solution in a bottle or other vessel, such as a small neck flask, capable of sufliciently retarding or excluding light passage. This condition may be attained by using brown glass vessels. Also air should be excluded as much as possible as by working in a carbon dioxide atmosphere, whereby to avoid oxidation. Avoidance of oxidation and maintaining the characteristic light yellow color of the solution is thus easily accomplished. Production of the solution is efiected at ordinary room temperatures around 70 R, or between about F. and 110 F., or a little higher, but temperatures above about 180 F., or especially at the boiling point of water, should be avoided to avoid discoloration and oxidation. Stabilization and oxidation control may be assisted by employing use of the vitamin K conbe readily accepted by the patient withvitamin C, as presently to be described. After producing the solution, such concentrations as required will be obtained by dilution, packaging of such as ampuling being then eifected.

Since nicotinamide is itself a desirable vitamin, being one of the B complex and the pellagra-prevention factor, and since the daily dose is in the order of the above mentioned to milligrams, it is a most desirable agent to be employed with the K vitamin constituent in accordance with this invention. Other vitamins may be added as may be desirable for different purposes, such as riboflavin, thiamine, and other water-soluble members of the B complex.

The overall permissible and practical range of proportions of nicotinamide which may be used in solubilizing menadione is from a minimum of about 100 milligrams per milligram of menadione up tothat higher amount required for the maximum therapeutic effect desired from the nicotinamide.

Since menadione, which is a synthetic naphthoquinone derivative, is water-insoluble, although soluble in alcohol, benzene, vegetable oils and the like, but possesses the desirable properties of vitamin K, and since nicotinamide which is water-soluble is both a valuable vitamin and a solubilizer for menadione, it is apparent that I have presented a valuable improvement in the present aqueous solution of menadione employing nicotinamide.

The aqueous solution of this invention, being acceptable for parenteral injection, has many advantages over oil solutions of menadione, inasmuch as many patients are allergic to oil injections, the oil solution is slowly absorbed, the present water solution is rapidly absorbed and therefore quickly available for utilization in the human body, and in addition this aqueous solution can be used for intravenous injections in emergencies whereas the oil solutions can never be used intravenously.

Also, by means of this improvement, it is possible to employ in aqueous solution the solubilized vitamin K in combination with other water-soluble vitamins than nicotinamide, such as other members of the B complex, and employ such a solution of multiple vitamins for parenteral and intravenous injections in preoperative treatment to guard against hemorrhage and fortify against periods of stress.

Another advantage of my discovery is its value for oral use when the flow of bile has been obstructed. Ordinarily some of the fat-soluble vitamins, including vitamin K and menadione, are not absorbed in the absence of bile flow unless bile salts are administered. Here the water-soluble vitamin K requires no bile or bile salts. This is very important because menadione is extraordinarily effective against hemorrhagic diaphesis of obstructive jaundice. It provides the vitamin K required for the liver to synthesize prothrombin, which is essential in the blood stream, but would be deficient in the event of bile obstruction if only oil-soluble vitamin K were supplied. When vitamin K as such is mentioned, it is in general intended to signify K1 and K2.

With respect to the employment of other vitamins, another phase of this invention is the use of vitamin C, because, in addition to its normal vitamin function, it serves to stabilize the menadione solution against discoloration and other oxidation evidences such as precipitation, which may render the menadione-nicotinamide solution unsuitable for parenteral injection. Such condition may be due to hydrolysis with subsequent oxidation of the liberated hydroquinone. This hydrolysis is prevented by the strong antioxidant properties of vitamin C, either as ascorbic acid or as the sodium salt thereof where a neutral solution is required, and which is to be considered as the equivalent when vitamin C or ascorbic acid is mentioned.

The vitamin C may be incorporated in the solution above described in any appropriate manner, a desirable means being the addition of a 10% solution to the menaiPR? lllt qn but i m be a de as a Weaker or trease solution 9 ind fo m i In general, 100 milligrams of ascorbic acid will be used for each 100 milligrams of nicotinamide and one milligram of menadione, but the proportion may be varied between about 50 and 200 milligrams of ascorbic acid (or sodium ascorbate). In fact, if only the antioxidant property is required, as little as about milligrams of vitamin C may be used for each milligram of menadione {to stabilise the same, whereas about 100 milligrams of nicotinamide is used to solubilize one milligram of menadione. In the case of both nicotinamide and vitamin C, the amounts may be increased up to 200 milligrams or more for each milligram of menadione, if desired for requires! h ra u i effects.

I Specific usable formulas, depending upon elfects desired, include the following:

Example 1 Each milliliter of water solution contains:

Milligrams Menadione 0.1 Nicotinamide t 10.0 Ascorbic acid 10.0 Example 11 Each milliliter of water solution contains:

Milligrams Menadione 0.5 Nicotinamide a 50.0 Ascorbic acid 50.0 Example 111 Each milliliter of water solution contains:

Milligrams Menadione 2.0 Nicotinamide 200.0 Ascorbic acid 100.0

The overall range of nicotinamide and vitamin C with respect to menadione is represented by the following table which also is representative of an average desirable menadione concentration in one milliliter of water as a dose:

Milligrams Menadione Nicotinamide 100 to 200 Ascorbic acid 5 to 200 While it is generally important, sometimes the ascorbic acid (or sodium ascorbate) may be entirely omitted from the above examples, as when storage periods and other conditions are such that objectionable discoloration, oxidation or precipitation does not occur to render the solution unusable for parenteral injection. Fresh preparation by the physician from the dry ingredients near the time of administration represents one such situation.

I claim:

1. A water solution of nicotinamide having dissolved therein a greater quantity of menadione than can be dissolved in an equal quantity of water alone.

2. A Water solution of nicotinamide having dissolved therein at least about 0.5 mg. of menadione per ml. of solution.

3. An aqueous therapeutic solution having dissolved therein from about 0.5 mg. to about 2 mg. of menadione and from about mg. to about 200 mg. of nicotinamide per ml. of solution.

4. An aqueous therapeutic solution as defined in claim 3 wherein said solution also contains about 5 to 200 mg. of ascorbic acid per ml. of solution.

5. An aqueous therapeutic solution having dissolved therein about 1 mg. of menadione, about mg. of nicotinamide, and about 100 mg. of ascorbic acid per ml. of solution.

References Cited in the file of this patent Modern Drugs, October 1950, p. 466.

Claims (1)

1. 3. AN AQUEOUS THERAPEUTIC SOLUTION HAVING DISSOLVED THEREIN FROM ABOUT 0.5 MG. TO ABOUT 2 MG. OF MENADIONE AND FROM ABOUT 50 MG. TO ABOUT 200 MG. OF NICOTINAMIDE PER ML. OF SOLUTION.