US 2977281 A
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United States Pat fif '0 BUFFERED PARA-AMINOSALICYLIC ACID ORAL COMPOSITIONS Milton Feier, New York, and Myron Pantzer, Brooklyn, N.Y., assignors to The Panray Corp., Englewood, NJ., a corporation of New York No Drawing. Filed Mar. 10, 1954, Ser. No. 415,417 4 Claims. (Cl. 167-65) This invention is that of pharmaceutical preparations containing para-aminosalicylic' acid (briefly designated PAS) accompanied with certain agents that enable the administration of PAS in the treatment of tuberculosis, with practical elimination of the undesirable eflects normally experienced by patients taking PAS or its available salts.
More specifically the preparations of the invention contain the PAS together with certain proportions of calcium carbonate and dihydroxy aluminum aminoacetate. These.
enable the administration of an effective dosage of the PAS whereby the PAS is buffered on dissolving in the alimentary tract, and at the same time in a size of, tablet that can be comfortably taken by the patient.
PAS continues to be a very valuable drug in the treatment of tuberculosis. Tubercular patients require ten to twelve grams of it daily for periods from six months to a year, and generally take six half gram tablets four times a day. Its administration and at such a regimen frequently causes gastro-intestinal symptoms. Because of advantages in solubility, sodium para-aminosalicylate became a very popular salt form for providing this medication. Twenty-eight to thirty-four tablets of the sodium salt provide the daily requirement of active PAS.
The sodium salt likewise causes frequent severe gastrointestinal irritations. These abdominal distresses include nausea, vomiting, diarrhea, colicky abdominal pain, and other upsets. Such irritating effects are highly variable within each batch of sodium para-aminosalicylate and also differ between batches. Many patients cannot tolerate this drug in adequate doses or in the prolonged regimen required.
Many patients then do not take the required number of tablets of PAS or its sodium salt and often toss them away if not watched. Some patients cannot tolerate any form of PAS. In many cases, these disturbances necessitated discontinuing for a few'days administration of sodium para-aminosalicylate (briefly called sodium-PAS) and then resuming it. Enteric coating the sodium-PAS tablets, in an attempt to avoid these undesirable effects, does not result in satisfactorily doing so.
In many instances, these gastro-intestinal disturbances are ameliorated by administering aluminum hydroxide gel as an antacid. However, that introduces a different disadvantage for the aluminum hydroxide apparently inhibits not alone the absorption of the sodium-PAS or the PAS but possibly also its retention in the blood stream. This is indicated by the following results obtained in a study: sodium-PAS showed a blood level of four milligrams percent after two hours, and of between eighttenths and one milligram percent after four hours. However, with the additional administration of aluminum hydroxide gel, it showed a blood level of one milligram percent after two hours and no trace at all at four hours.
Calcium para-aminosalicylate (briefly called calcium- PAS) is more palatable than sodium-PAS and appears to provoke less gastro-intestinal side effects than it. However, some patients find it more irritating and with them "ice and others it is not well tolerated. Moreover, the therapy with calcium-PAS is considerably more costly. This is so because calcium-PAS for tablet making purposes costs about one and three-quarters times what PAS for tablet making use costs.
It might be attempted to replacecalcium-PAS by PAS together with the'necessary equivalent amount of calcium carbonate to seek to obtain the same improved results at lower cost. However, the quantity of the latter required is sogreat that the resulting tablet is of a size that would be very diflicult to swallow even as a single tablet 'let alone at least six at a time and four times daily.
The compositions of this invention not only overcome this diflicult-to-swallow tablet size disadvantage, but also lack for at least the vast majority of patients the various gastro-intestinal disturbances provoked by PAS alone and its salts. Moreover, the compositions of the invention require no enteric coating.
This is accomplished by using calcium carbonate with PAS and reducing the quantity of the former considerably below the molecular or stoichiometric equivalent amount required by the quantity of PAS used, and replacing some of the omitted calcium carbonate by dihydroxy aluminum arninoacetate (briefly termed DAA) likewise in a quantity significantly below its PAS molecular equivalent, so that the calcium carbonate and the DAA jointly are below the total stoichiometric equivalent amount required by the PAS present.
Thus, broadly considered, the compositions of the invention comprise PAS as the tuberculostatic constituent accompanied by from about one to about two parts of DAA and from about four to about three parts of calcium carbonate for about twenty parts of PAS. Considered otherwise, each tablet containing one-half gram of PAS.
contains also from about twenty-five to about fifty milligrams of "DAA and also from about one hundred to seventy five milligrams of calcium carbonate. words, within the just indicated ranges, the higher the content of DAA the lower that of the calcium carbonate, and vice versa.
In still another way, the compositions of the invention contain PAS accompanied by from about three-quarters to about four-fifths of its stoichiometric equivalent of DAA and calcium carbonate jointly and with the DAA in.
the proportions of from about one-quarter to about twothirds of the calcium carbonate.
The PAS with the DAA and calcium carbonate in the foregoing proportions to one another can be worked up with suitable compatible diluents and binders and made up into tablets containing, for example, one-half gram of PAS each. These tablets require no enteric coating and even no sugar coating. While tablets are the most advantageous dosage form, these compositions of the invention can also be put up in capsules or as pharmaceutical powders. In the capsule and powder dosage forms, it i may be possible to forego admixing any diluent ingredients.
Conveniently suitable tablets are prepared by using the three essential ingredients in such proportions to provide per tablet one-half gram of PAS, seventy-five milligrams of calcium carbonate and fifty milligrams of DAA. Known, suitable and compatible diluents and binders can be included, and the tablets prepared in the usual manner. The resulting tablets, containing the indicated respective r amounts of the three essential ingredients, provide about a thirty percent reduction in the number of tablets. the patient needs to take daily. This is so because twenty four of these tablets daily provide the para-aminosalicylic acid equivalent of the thirty-four tablets of sodium-PAS required to be taken daily.
0n oral administration in any of their applicable dosage forms, the compositions of the invention are efiective In other processes; and are. unusually well% tolerated. They: are.
notably better toleratedthan a composition of PAS, magnesiumcarbonate and aluminum glycinate also developed in the project that yielded the compositions of this invention. The compositions claimed herein do not provoke the gastro-intestinal. disturbances experienced with the earlier preparations containing PAS or its salts, to overcome which the patients took sodium bicarbonate.
There areindications that the compositions of this invention tend to provide a somewhat lower rate of elimination of the drug fromtheblood stream than occurs-from the same amount of PASalone or as sodium-PAS or calcium-PAS, therebyproviding a longer sustained blood level ofYPAS..
In the compositions of. the. invention, containing the three essential ingredients, calcium carbonate, DAA, and PAS, the latter is thus buffered without introducing the sodium ion. Thus, these compositions can be used by patients required to follow a restricted-sodium intake.
While the invention has been explained in detail in relation to various specific embodiments of it, it is understood that many modifications and substitutions can be made in it within the scope of the appended claims which are intended also to cover equivalents of these specific embodiments.
What is claimed is:
1. A pharmaceutical preparation for oral administration and effective in the treatment of tuberculosis, which comprises from about one to about two parts of dihydroxy aluminum amino acetate and from about four to about three parts of calcium carbonate to about twenty parts of para-aminosalicylic acid, which preparation is generally free of the gastric disturbances ordinarily provoked by para-aminosalicylic acid and its water-soluble salts when taken alone.
2. A pharmaceutical preparation for oral administration and effective in the treatment of tuberculosis, which comprises para-aminosalicylic acid (PAS) together with calcium. carbonate and dihydroxy aluminum aminoacetate with the latter in the proportions of from about onequarter to about two-thirds of the calcium carbonate, and the calcium carbonate and dihydroxy aluminum aminoacetate constituting together from about seventy-five to about eighty percent of their total stoichiometric equivalent of the PAS, which preparation is generally free of the gastric disturbances ordinarily provoked" by paraaminosalicylic acid and its water-soluble salts when taken alone.
3 A pharmaceutical preparationvin solid'dosage units for oral administration and effective in the treatment of tuberculosis, which comprises per dosage unite about onehalf gram of para-aminosalicylic acid, about seventy'five milligrams of calcium carbonateand about fifty milligrams of dihydroxy aluminum aminoacetate, which preparation is generally free of the gastric disturbances ordinarily provoked by para-aminosalicylic.acid and its water-soluble salts when taken alone.
4. A pharmaceutical preparation in tablet form and efiective in the treatment of tuberculosis, which comprises per tablet about one-half gram of para-aminosalicylic acid, about seventy-five milligrams of calcium carbonate and about fifty milligrams of dihydroxy aluminum aminoacetate, which preparation is generally free of the gastric disturbances ordinarily provoked by para-aminosalicylic acid and its water-soluble salts when taken alone.
References Cited in the file of this patent UNITED STATES PATENTS Abramson Oct. 28, 1947 Smith June 21, 1955 OTHER REFERENCES