US2388261A - Riboflavin solution - Google Patents

Description

Patented Nov. 6, 1945 RIBOFLAVIN SOLUTION Douglas V. Frost, Waukegan, Ill., assignor to Abbott Laboratories, a corporation of Illinois No Drawing. Application October 27, 1941,

Serial No. 416,757

4 Claims.

The present invention relates to improved therapeutic agents and more particularly to stabilized and solubilized riboflavin complexes.

Riboflavin deficiency is very widespread and in certain parts of the United States it is considered to be the most widespread single vitamin deficiency, particularly among children. Clinical symptoms of riboflavin deficiency include keratitis, cheilosis, mydriasis, photophobia, lassitude and anorexia.

Riboflavin is only very slightly soluble in water and for this reason has not been found satisfactory for administration by hypodermic injection. The natural solubility of riboflavin in pure water, for example, is only about 0.012 per cent. Hypodermic administration or a good therapeutic dose in this form necessitates an injection of a very large volume of liquid. The dministration of mg. of riboflavin. for example, requires an injection of about 80 cc. of solution.

The need for a form of riboflavin satisfactory for hypodermic administration has long been recognized by the medical art. Prior attempts, however, to solve the problem, have been unsuccessful. Some prior suggestions have been found unsatisfactory because the proposed riboflavin com position precipitated or deteriorated on standing, while other suggestions have been found unsatisfactory because efiorts to improve solubility had deleteriously affected the desired therapeutic properties of the riboflavin. As far as is known, up to the time or the discovery upon which the present invention is based, no satisfactory form of riboflavin was available for hypodermic administration.

One of the principal objects of the present invention is to provide a solubilized riboflavin composition adaptable for hypodermic administration.

Another object of the present invention is to provide a stabilized riboflavin composition substantially free from deterioration.

A further object of the present invention is to provide an improved stabilized and solubilized riboflavin composition characterized by high therapeutic value.

Other objects will be apparent as the description proceeds in detail hereinafter.

I have discovered that boron compounds such as the acids and salts may be combined with riboflavin to form the desired complexes. Examples of boron compounds include: boric acid, boric anhydride, boron oxides, peroxides, etc, and salts including the alkali metal borates, sodium perborates, etc. The following examples will serve to illustrate the present invention.

Example I About .03-0.1 percent pure crystalline riboflavin is suspended in water and about 0.1-2.0 per cent pure crystalline boric acid added. The percentages used are dependent on the concentrations desiredthe optimum amounts being ascertainable by preliminary experiment.- The riboflavinboric acid mixture is then heated at about 100 C. until the riboflavin goes into solution and the desired stable boron complex is formed. An example of a heating period is 4 hours at 80-90 C.the optimum times and temperature varying with the concentrations of riboflavin and boric acid employed.

If considerable boric acid is used the pH may be adjusted to pH 3 to 7 by addition of an alkalinizer such as trior di-sodium phosphate. Ordinarily for hypodermic administration a pH range of 4-6.6 is preferred.

The riboflavin may be solubilized in the presence of other therapeutic agents, such as vitamin C or in B-complex factor solutions with thiamin, nicotinic acid, nicotinamide, pyridoxine, calcium pantothenate, choline, inositol, p-amino benzoic acid or any combination of the same, or in combination with amino acids.

Example II About 1 part of riboflavin and 25 parts of borax are ground together and dissolved in 1000 parts of water. When solution is complete about 7.1 parts of concentrated hydrochloric acid are added to produce a pH of about 6.3-6.6. The resulting solution is next heated for about 2 hours at -90" C. and then cooled to room temperature.

If solutions are desired comprising riboflavin and other compounds such as the various vitamins, amino-acids, or other physiologically valuable materials, such compounds may be added after the formation of the riboflavin-boron complex.

In the compositions of the present invention, as will be noted by the above examples, the pH is adjusted to 3-7, and preferably 4-6.6. If an acid boron compound is used the pH may be raised by addition of an alkalinizer such as in Example I, while if an alkaline boron compound is used the pH may be lowered by addition of an acidic agent such as in Example II. The reason for maintaining the compositions within the specified pH range is stability. I have discovered, for example. t at riboflavin solutions lack the desired stability it maintained at pH values above 7. Ordinarily an acid pH is preferred (e. g. 6.6-4) although stability does not decrease appreciably until the pH is alkaline, i. e. above pH '1 the neutral point.

The boron complexes oi the present invention are soluble in water, e. g. at least 10 mg. oil riboflavin per 10 cc. solution, and form stable isotonic solutions adaptable for hypodermic administration. Tests have shown the solutions to retain their therapeutic potency and to be tree from deterioration and precipitate formation under varying conditions, e. g. at to 40 C. for several months. Although particularly adaptable for hypodermic use the riboflavin complexes are also satisfactory for oral administration.

The efiect of the boron compounds in solubilizing riboflavin is not clearly understood at present. Investigations, however, indicate that a relatively loose complex is formed and tests have shown the same to be chemically and physiologically stable when maintained within the specified pH range.

While various boron compounds, such as the oxides, may be substituted for the acid 0! Example I or other salts for the sodium tetraborate of Example 11, it will be understood that the boron compounds employed should be substantiall nontoxic. It will also be understood that the present invention is not limited to the above illustrative examples. All modifications oi the presout invention are intended to be covered by the following claims.

I claim:

1. The method oi preparing a stable aqueous therapeutic solution containing not less than 0.03% of riboflavin and suitable for hypodermic administration, which comprises: P p ring a water solution containing from 0.1% to 2.0% of boric acid in solution, and from 0.03% to 0.10% of riboflavin; adjusting the pH 01' the solution to from 3.0 to 6.6; heating the solution until the CERTIFICATE OF Patent No. 2,588,261.

riboflavin dissolves; and thereafter continuing the heating at temperatures above about C. for a period of time of about two to four hours, to secure a liquid product from which material will not crystallize out even after standing for months or years.

2. The method 01 preparing a stable aqueous therapeutic solution containing not less than 0.03% o! riboflavin and suitable for hypodermic administration, which comprises: preparing a water solution having a pH not exceeding 7.0 and containing from 0.1% to 2.0% boric acid and from 0.03% to 0.10% o! riboflavin; heating the solution until the riboflavin dissolves; and thereafter continuing the heating at temperatures above about 80 C. until samples of the product show no precipitation on prolonged standing.

3. A stable aqueous therapeutic solution containing from 0.1% to 2.0% of boric acid and more than 0.03% of riboflavin, said solution having a pH i'rom 4.0 to 6.6; the riboflavin and boric acid being in that state of combination resulting from prolonged heating for about two hours above 80 C.; said solution remaining stable indefinitely at room temperatures, without the precipitation of the therapeutic in crystalline form, and without deleterious decomposition of the therapeutic.

4. The method of preparing a stable aqueous therapeutic solution containing not less than 0.33% of riboflavin and suitable for hypodermic administration which comprises: preparing a water solution having a pH not exceeding 7 and containing the negative radical of boric acid up to an amount corresponding to from 0.1% to 2.0% of boric acid, together with from 0.03% to 0.1% of riboflavin; heating the solution until the riboflavin dissolves; and thereafter continuing the heating at temperatures above about 00 C. until samples of the product show no precipitation on prolonged standing.

DOUGLAS V. FROST.

CORRECTION.

November 6, 1914.5.

Douoms v. FROST.

It is hereby cc of the above numbered patent requiring cor for "0.55%"

Letters Patent should be read with this correc conform to the record of the case in the Patent Signed and sealed this 26th day of February, A. D.

0nd column, line 50, claim i (Seal) rtified that error appears in the printed s pecification rection as follows: Page 2, sec-- read --0.05%--; and that the said tion therein that the same may Office.

Leslie Frazer First Assistant Commissioner of Patents.

stability it maintained at pH values above 7. Ordinarily an acid pH is preferred (e. g. 6.6-4) although stability does not decrease appreciably until the pH is alkaline, i. e. above pH '1 the neutral point.

The boron complexes oi the present invention are soluble in water, e. g. at least 10 mg. oil riboflavin per 10 cc. solution, and form stable isotonic solutions adaptable for hypodermic administration. Tests have shown the solutions to retain their therapeutic potency and to be tree from deterioration and precipitate formation under varying conditions, e. g. at to 40 C. for several months. Although particularly adaptable for hypodermic use the riboflavin complexes are also satisfactory for oral administration.

The efiect of the boron compounds in solubilizing riboflavin is not clearly understood at present. Investigations, however, indicate that a relatively loose complex is formed and tests have shown the same to be chemically and physiologically stable when maintained within the specified pH range.

While various boron compounds, such as the oxides, may be substituted for the acid 0! Example I or other salts for the sodium tetraborate of Example 11, it will be understood that the boron compounds employed should be substantiall nontoxic. It will also be understood that the present invention is not limited to the above illustrative examples. All modifications oi the presout invention are intended to be covered by the following claims.

I claim:

1. The method oi preparing a stable aqueous therapeutic solution containing not less than 0.03% of riboflavin and suitable for hypodermic administration, which comprises: P p ring a water solution containing from 0.1% to 2.0% of boric acid in solution, and from 0.03% to 0.10% of riboflavin; adjusting the pH 01' the solution to from 3.0 to 6.6; heating the solution until the CERTIFICATE OF Patent No. 2,588,261.

riboflavin dissolves; and thereafter continuing the heating at temperatures above about C. for a period of time of about two to four hours, to secure a liquid product from which material will not crystallize out even after standing for months or years.

2. The method 01 preparing a stable aqueous therapeutic solution containing not less than 0.03% o! riboflavin and suitable for hypodermic administration, which comprises: preparing a water solution having a pH not exceeding 7.0 and containing from 0.1% to 2.0% boric acid and from 0.03% to 0.10% o! riboflavin; heating the solution until the riboflavin dissolves; and thereafter continuing the heating at temperatures above about 80 C. until samples of the product show no precipitation on prolonged standing.

3. A stable aqueous therapeutic solution containing from 0.1% to 2.0% of boric acid and more than 0.03% of riboflavin, said solution having a pH i'rom 4.0 to 6.6; the riboflavin and boric acid being in that state of combination resulting from prolonged heating for about two hours above 80 C.; said solution remaining stable indefinitely at room temperatures, without the precipitation of the therapeutic in crystalline form, and without deleterious decomposition of the therapeutic.

4. The method of preparing a stable aqueous therapeutic solution containing not less than 0.33% of riboflavin and suitable for hypodermic administration which comprises: preparing a water solution having a pH not exceeding 7 and containing the negative radical of boric acid up to an amount corresponding to from 0.1% to 2.0% of boric acid, together with from 0.03% to 0.1% of riboflavin; heating the solution until the riboflavin dissolves; and thereafter continuing the heating at temperatures above about 00 C. until samples of the product show no precipitation on prolonged standing.

DOUGLAS V. FROST.

CORRECTION.

November 6, 1914.5.

Douoms v. FROST.

It is hereby cc of the above numbered patent requiring cor for "0.55%"

Letters Patent should be read with this correc conform to the record of the case in the Patent Signed and sealed this 26th day of February, A. D.

0nd column, line 50, claim i (Seal) rtified that error appears in the printed s pecification rection as follows: Page 2, sec-- read --0.05%--; and that the said tion therein that the same may Office.

Leslie Frazer First Assistant Commissioner of Patents.