|Número de publicación||US3062715 A|
|Tipo de publicación||Concesión|
|Fecha de publicación||6 Nov 1962|
|Fecha de presentación||18 Nov 1953|
|Fecha de prioridad||18 Nov 1953|
|Número de publicación||US 3062715 A, US 3062715A, US-A-3062715, US3062715 A, US3062715A|
|Inventores||Henry W Reese|
|Cesionario original||George S Pfaus, Reuben A Posner, Jerome Stein|
|Exportar cita||BiBTeX, EndNote, RefMan|
|Citas de patentes (3), Citada por (74), Clasificaciones (13)|
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet|
3,062,715 VAGINAL TABLET Henry W. Reese, Briarclilf Manor, N.Y., assiguor of onefourth to George S. Pfaus, East Orange, NJ., onefourth to Reuben A. Posner, New York, N.Y., and one-fourth to Jerome Stein, Brooklyn, N.Y.
No Drawing. Filed Nov. 18, 1953, Ser. No. 392,980 2 Claims. (Cl. 167-58) My invention relates to a new and improved medicinal composition, a new and improved medicinal tablet or other carrier for medicinal agents, and a new and improved method of making the same. The invention includes the new and improved composition or carrier, irrespective of the method of making the same. The invention also includes a new and improved method of distributing a medicinal agent in a cavity of the body.
The improved tablet is especially useful as a vaginal tablet, in order to apply a medicinal agent, which may also be a spermicide.
According to my invention, I provide a tablet which is substantially wholly dissolved or disintegrated in about twice its weight of water in a maximum period of two minutes. The tablet is provided with ingredients which form a harmless gas when the tablet is contacted with water. One of these gas-forming ingredients is an hydroxy acid, which is exemplified by tartaric acid. The tablet-- is also provided with a sufiicient proportion of boric acid, so that some of the boric acid reacts with some of .the hydroxy acid to form water. Hence, if the body cavity has a scant supply ofmoisture, so that the gas-forming reaction i slow or cannot be completed, additional water is provided by the reaction between the hydroxy acid and the boric acid. Also, the reaction between the boric acid and the hydroxy acid results in an organic boron compound, which is readily soluble in water.
According to the improved method, when the'medicinal agent is inserted in the body cavity, there is a simultaneous supply of added water due to said reaction of the hydroxy acid and the boric acid, and a stable, dense and viscous foam is produced by the moisture, gas and a foaming agent, so that the medicinal agents are efiiciently spread over the mucosa of the body cavity.
Additional features and elements of my invention are later stated herein.
Without limitation thereto, several embodiments thereof are disclosed below. All proportions stated herein are by weight. The tablet, which is specifically disclosed,
is intended for use as a vaginal tablet. The ingredients and figures stated below are illustrative, and the invention is not limited thereto. However, the specific embodiment is highly preferred, if the tablet is to be used as a vaginal tablet.
According to one formula, the tablet is made substantially of the seven starting materials stated below, in the starting proportions stated below, plus certain active or medicinal agents and certain additives.
Ingredient: Proportion, percent No. l--Sodium bicarbonate 30 No. 2-Tartaric acid 26 No. 3'Boric acid 26 No. 4Starch 12 No. 5--Talcum -c 3 No. 6-Duponol C 1 No. 7Gum arabic 2 The sodium bicarbonate is of the grade specified in the US. Pharmacopoeia. This grade, when dried over sul- 3,o62,11s- 7 Patented Nov. 6, 1 962 NaHCO The tartaric acid is also of U.S.P. grade. It is d-tartaric acid, whose formula is HOOC(CHOH) C00H, with it molecular weight of 150.07. Its weight, like the weight of the other ingredients, may be calculated on a waterfree basis. When dried over sulfuric acid for 3 hours, it contains not less than 99.7% of 0 1-1 0 The boric acid is also of said grade. When dried over sulfuric acid for 5 hours, it contains not less than 99.5% of H 30 The starch is preferably an undried starch. It is preferably a native or an unchanged potato starch. When this starch is moistened with water in the tablet, it swells and disiutegrates the tablet. That is, it is well-known to modify native starches, and to dry native starches in heated tunnels. I prefer to use a native starch, which may or may not be dried in the process of its extraction from the starting material, and which has its cells in original undisrupted form. I prefer to use potato starch because its granules vary in size from 15 to microns, and these granules, when used in the tablet, swell when moistened with water, and quickly disintegrate the tablet.
The tale or talcum powder is used as a lubricant. It
may be replaced by other lubricants or omitted. The Dupona'l C is described at page 189 of Handbook of Material Trade Names," by Zimmerman and It is used as a wetting and dispersing agent to reduce surffice tension. It may be replaced by any other wetting or ispersing agent. Many such agents are well-known.
The gum arabic is an example of a binder and it may be replaced'by other binders. 1
The sodium bicarbonate and the tartaric acid exemplify a well-known class of ingredients which react in aqueous solution to produce etfervescence, and they may be replaced by other ingnredients in this class, which is wellknown in chemistry and pharmacy. However, the specific combination of sodium bicarbonate and tartaric acid is highly preferred.
The reaction is sodium bicarbonate and tartaric acid are 84 and 150. In the above equation, 168 parts by weight of sodium bicarbonate react with parts of tartaric acid. The st'oichiometric ratio is substantially 10 to 9. As later I disclosed, the tablet has 0.345 gram of sodium bicar-i bonate, and 0.299 gram of tartaric acid. The 0.299 gram of tartaric acid reactswith about 0.332 gram of sodium bicarbonate in the above equation, thus providing an excess of 0.013 gram of sodium bicarbonate, above the stoichiometric ratio. In the above equation, if 0.299 gram of tartaric acid reacts with 0.332 gram of sodium' bicarbonate, the weight of the reaction water is about 24% of the weight of the tartaric acid, or about 0.07 gram of water.
The reaction between about 0.332 gram of sodium bicarbonate and 0.299 gram of tartaric acid (total weight about 0.631 gram) results in substantially 0.38 gram of sodium tartrate; 0.18 gram of carbon dioxide; and 0.07 gram of water.
The tartaric acid can be replaced by a salt thereof, or by other hydroxy acids or salts thereof, such as citric acid, malic acid and salts thereof. Any gas-forming ingredients can be used, if the by-product of the gas-forming reaction is non-toxic and the gas is non-toxic. Of
course, it is old to provide an efiervescing vaginal tablet,
as disclosed in Fitzgerald US. Patent No. 1,878,766, and Karreth British Patent No. 368,423, accepted March 10, 1932.
Said gas-forming reaction requires the presence of water. The normal amount of moisture in the vagina is 2 cc., and there is often a scant supply of water therein. Hence a compressed tablet of this class will often not dissolve rapidly or completely in the vagina, and there will often be a Wholly inadequate supply of gas for producing the desired foam, which should be dense, and copious viscous and stable, so that the active medicinal agent or agents can penetrate the rugae and cover the mucous membrane with active foam.
I use the boric acid for several purposes other than medicinal effect.
One of the important uses of the boric acid is that it reacts with tartaric acid, citric acid and other hydroxy acids, when these reactants are moistened with water at body temperature, namely 98 F., or 36.67 C. This reaction is a quick and energetic esterification and produces water as a by-product. This water accelerates the gas-forming reaction and also supplies enough additional water to dissolve the water-soluble ingredients of the tablet,'so as to reliably and uniformly produce the desired dense, viscous and stable foam. One mole of tartaric acid thus reacts with one mole of boric acid to produce two moles of water. This reaction proceeds rapidly when the reactants are moistened with water at body temperature.
The organo-boron compound which is thus formed is readily soluble in water.
This reaction between tartaric acid and boric acid is evidenced when these dry acids are granulated with an aqueous granulating solution. If tartaric acid alone, or boric acid alone, is granulated, each will require a certain amount of water. If a mixture of these two dry acids is granulated with the sum of the respective amounts of water, the resultant mass will be a paste or sludge, due to the formation of additional water by the reaction between the moistened tartaric acid and the moistened boric acid. In the tablet only a part of the boric acid reacts with only a part of the tartaric acid. The remainder of the tartaric acid reacts with a part of the sodium bicarbonate in the gas-forming reaction. The remainder of the boric acid reacts with a part of the sodium bicarbonate. The pH of this solution is preferably 6.5. It may be in a range of 6.0 to 6.5.
Method of Manufacture The dry sodium bicarbonate is moistened with a 16% solution or dispersion of egg albumen in water. By thus attaching the egg albumen to the sodium bicarbonate to produce a granulated form of the sodium bicarbonate, a. superior result is secured. 44 cubic centimeters of this solution are used per pound of the dry sodium bicarbonate. This is in the ratio of 7.04 grams of dry weight of egg albumen per pound of dry sodium bicarbonate, or about grams of dry weight of egg albumen per kilogram of dry sodium bicarbonate. One function of the egg albumen is to provide a harmless and efficient foaming agent, which produces a copious dense and stable foam when the tablet is dissolved in the vaginal moisture. The egg albumen also has good adhesive Properties, so that the sodium bicarbonate can be granulated. It may be replaced by other foaming agents, such as gelatine, whey, soap, saponin, etc. Substantially the entire tablet is readily soluble in water, to make a true solution. The mixture of the sodium bicarbonate and the aqueous dispersion of the egg albumen is granulated by forcing said mixture through a No. 16 sieve, which has openings of 0.0390 inch or 0.991 millimeter.
The dry tartaric acid is separately moistened with a 2% aqueous solution of a binder, such as karaya gum or other binder, in the ratio of 24 cubic centimeters of said solution per pound of tartaric acid. This is about 0.48
gram dry weight ofsaid binder gum per pound of dry tartaric acid, or about one gram dry weight of said binder gum per kilogram of dry tartaric acid.
Instead of using a water-soluble gum or binder, which is exemplified by karaya gum, which can be replaced by other water-soluble binders, I prefer to use a solution of a material which coats the particles or granules of the tartaric acid, and which, when thus applied as a finished dry coating is substantially impervious to water vapor. Otherwise, if the tablet absorbs water vapor, an internal reaction will take place. In order to stabilize the tablet, I prefer to use a methyl cellulose coating binder, which, although moderately soluble in cold water, is resistant to water vapor in the form of a finished dry coating. This dry methyl cellulose coating binder is much more impervious to water vapor than the ordinary gum binders, so that a very desirable stabilizing effect isproduced.
The methyl cellulose coating binder which I prefer to use is known as Methocel. It is described at page 361 of said Handbook of Material Trade Names." It is water-soluble, colorless, and non-toxic. I prefer to use the well-known grade of this Methocel, whose 2% solution in water at 20 C. has a viscosity of 1,500 centipoises. Methocel is soluble in cold water, partly soluble in hot water, and insoluble in saturated salt solutions, and it is a good binding and thickening agent. The use of methyl cellulose is highly desirable in making a tablet which remains stable for at least six months. The improved tablets described herein are stable when properly packaged, for at least two years. It is used as a 2% aqueous solution in the granulating operation. This Methocel" solution is added to the tartaric acid in the ratio of substantially 1-4 grams of Methocel, calculated on its dry basis, per kilogram of the dry tartaric acid. The tartaric acid which has been moistened with the 2% aqueous solution of the gum binder, or with the 2% aqueous solution of the Methocel, is granulated by being forced through said No. 16 sieve.
The dry boric acid is moistened with the following solution.
This solution has 26 grams of hydroquinone in 1,560 cc. of solvent. Hence 300 cc. of this solution have substantially five grams of hydroquinone.
A. Water ....cubic centimeters-.. 1300 B. Oxyquinoline sulfate grams 26 C. Gum karaya do 26 D. Boric acid ....do 26 E. Hydroquinone ....do 26 F. Ethyl alcohol or denatured industrial alcohol,
whichmay contain 70% by volume of the alcohol, the remainder being water cc 260 'in water, but it is much more soluble in ethyl alcohol,
which is included in the solution for this purpose.
The boric acid is used in the solution to make it slightly acidic. Hydroquinone darkens in aqueous alkaline solution, and such darkening is undesirable. This is one of the reasons for providing a slight acidity in the final solution of the tablet in the aqueous body fluid.
The dry boric acid is moistened with this solution, in the ratio of cubic centimeters of said solution per pound of dry boric acid or in the ratio of about 300 cubic centimeters of said solution per kilogram of dry boric acid. The ratio is 1000 grams of boric acid per about 5 grams of hydroquinone, or about 0.005 gram of hydroquinone per gram of boric acid.
anemia thoroughly dried by heating in an oven for two hours at about 54 C. to 60 C. The tablets are made in an atmosphere of minimum relative humidity, whose maximum is 30 percent.
The purpose is to have a minimum of water or water vapor in the tablets, with resultant maximum stability.
The sodium bicarbonate, tartaric acid and boric acid are used in granular form in making the tablets. The starch, talc or talcum powder or other filler, Duponel C or an equivalent and the gum arabic or other binder are used in fine powder form to make the tablets. The ingredients are thoroughly mixed at C.- C. in an atmosphere of said low relative humidity and they are then compressed into tablets under such condition of low humidity, so that the tablets have a minimum amount of water or water vapor.
The weight of each tablet is about 1.15 grams. Each tablet is compressed to such hardness that it will dissolve easily.
Due to the granulation of the sodium bicarbonate, tartaric acid and boric acid, the dry weights of these ingredients in dry 1.15 gram tablet are as follows:
Weight in grams NaHCO .345 0,1 1.0 .299 H3BO3 .299
As above noted, if the reaction isonly between the sodium bicarbonate and the tartaric acid, the stoichiometric ratio is about 10 to 9, and the 0.299 gram of tartaric acid will react with about 0.332 gram of sodium bicarbonate, to produce 0.07 gram of reaction water. Hence, if the boric acid is omitted, and the tablet, with its remaining ingredients, is contacted with 2 cc. of water at 36.67 C., the reaction will produce only 0.07 gram of additional water. I
According to the 24th edition of The Dispensatory of the United States of America," the solubility of sodium bicarbonate, tartaric acid and boric acid at 25 C. are as Hence, if the above ingredients were separately dissolved in water at 25 C., the resepective required amounts of water would be,
0.345 gram of sodium bicarbonate 7.90 cc. of water.
0.299 gram of tartaric acid 0.2392 cc. of water.
0.299 gram of boric acid 5.382 cc. of water,
As above calculated, if the complete tablet is contacted with 2 cc. of external water, and if only 0.07 cc. of reaction water is formed by the reaction between the sodium bicarbonate and the tartaric acid, theresultant total volume of 2.07 cc. of water would dissolve only about 0.01 gram of boric acid.
As above noted, the boric acid is granulated or coated with the hydroquinone, in the ratio of substantially 0.005 gram of hydroquinone per gram of boric acid. Hence this tablet has a dose of substantially 0.001495 gram of hydroquinone, which is far below any toxic level.
The total weight of the sodium bicarbonate, tartaric acid and boric acid is 0.943 gram, which is about 82% of the total weight of the tablet. Hence the major part of the composition consists of sodium bicarbonate, the
hydroxy acid, and the boric acid.
Optionally, enough tartaric acid can be provided in the tablet to react with all of the sodium bicarbonate,
plus an additional amount of tartaric acid to react with some of the boric acid. Both reactions occur simultaneously when the tablet is contacted with water. The
above proportions have been 'found by actual test to produce a tablet which forms a true and substantially clear and complete solution in 2 cc. of water at body temperature, in a maximum period of two minutes.
In an actual test, 2 cc. of distilled water were put into seconds, up to a height of fifty millimeters.
At the end of one minute, the height of the foam was I, one hundred millimeters. When the glass tube was then inverted, the foam remained in position; showing its stability and strong adherence.
The pH of the solution was 6.5. The hydroquinone did not darken and the solution remained clear. The tablet is thus disintegrated and its medicinal agent or agents are released, when the tablet is contacted with substantially of its weight of external water at sub-.
stantially 36.67 C.
As above noted, two moles of water are produced per mole of boric acid, whose molecular weight is 61.84.
Hence the weight of the water which is produced by the reaction between the boric acid and the tartaricacid is about 60% of weight of the boric acid in this reaction.
The hydroxy acid and the boric acid are proportioned in the tablet, which is substantally wholly water-soluble,
so that while the tablet is dissolved in the water, only some of the hydroxy acid reacts with only some of the boric acid.
This invention covers the compositions per se and is not limited to a tablet or other one-piece carrier.
1. A dry vaginal tablet which is soluble in water; said tablet consisting substantially wholly of dry granulated" sodium bicarbonate which is coated with a foaming agent;
and dry granulated tartaric acid which is coated with methyl cellulose which is resistant to water vapor; and dry granulated ortho-boric acid which is intermixed with a medicinal agent in a non-toxic level of said medicinal agent; and a filler; and a wetting agent; said tablet having substantially equal ratios by dry weight of said dry granulated tartaric acid and of said dry granulated orthoboric acid, the total weight of said dry granulated tartaric acid and of said dry granulated ortho-boric acid being substantially 52% of the weight of said tablet;
the total dry-weight of said granulated sodium bicarbonate and said granulated tartaric acid and said granulated ortho-boric acid being substantially 84% of the weight of said tablet.
2. A tablet according to claim 1, in which the medicinal agent is a spermicide.
References Cited in the file of this patent UNITED STATES PATENTS 2,382,546 Curtis Aug. 14, 1945 FOREIGN PATENTS 117,165 Australia Jan. 30, 1942 11,601 Great Britain 1905 (Other references on following page) This water was kept at body temperature A dense, viscous and stable foam was produced in the test tube at the end of thirty 3,062,715 7 8 OTHER REFERENCES Lesser: Drug and Cosmetic Industry, June 1948, vol.
Greenblatt et aL: J. Med. Assn., 6a., December 1949, 62, PP- pp 549 552 Gutman: Modern Drug Encyclopedia and Therapeutic Voge: C. I. B. Chemistry and Physics of Contracep- Guide New Ymk, 1934- The American Journal tives, 1933, pp. 180, 181, 249, 250. 5 fi 1116-, P
Dickinson: Control of Conception, Williams and Wilkins Co., 2nd Ed., 1938, pp. 74-75.
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|Clasificación de EE.UU.||424/433, 514/311, 424/466, 424/465, 424/44, 424/DIG.140|
|Clasificación internacional||A61K33/22, A61K9/46|
|Clasificación cooperativa||Y10S424/14, A61K9/0007, A61K33/22|
|Clasificación europea||A61K33/22, A61K9/00L6|