Para-aminosalicylic acid containing compositions

Patented Apr. 27, 1954

2,676,902

UNITED STATES PATENT OFFICE

2,676,902

PARA-AMINOSALICYLIC ACID CONTAINING COMPOSITIONS

William P. Boger, Upper Darby, and Charles S. Miller, Prospect Park, Pa., assignors to, Merck & Co., Inc., a corporation of New jersey

No Drawiafe. Application February 24,1951, (Cl. 167—55) ......2......

which PAS is given in the treatment of tuberculosis.

The compositions _;of this invention provide, a means for overcoihing the difficulties hitherto _e experienced with the. use of PAS because they make it possible to obtain elevated and prolonged plasma, concentrations of the drug thus probably providing an actual increase in the therapeutic efficacy of PAS. Another advantage of the com10 positions of this invention is that they provide a means for obtaining therapeutically effective plasma concentrations of PAS with greatly reduced dosage. Another important and practical value of this invention is the attainment of these 15 advantages by the use of a non-toxic compound which is effective when giveh in small oral doses.

The compositions of the invention are composite products including para-aminosalicylic acid and the adjuvant, para- (di-n-propyl-sul2o famyl)-benzoic acid, hereinafter referred to by the non-proprietary chemical name, probenecid.

Probenecid is prepared by the method described in Charles S. Miller’s copending U. S. patent application Serial No. 162,811, now Patent 25 No. 2,608,502, issued August 26, 1953, of Which the instant application is in part a continuation The. compound is a crystalline, white powder., slightly soluble in; water. It is absorbed rapidly from the .gastrointestinal tract; and after a single 30 oral dose, can be demonstrated iri the. plasma of dogs for periods as long as about 36 hours and for about 24 hours in man. In the blood stream, the adjuvant is bound by adsorption to the plasma proteins to,the extent of almost 75 per35 cent, and is excreted in the urine largely in a conjugated form, probably tfe' a glucuronide. Extensive toxicologic and pharmacologic studies established the fact that probenecid has a high therapeutic index. It. produces no toxic mani40 festations when administered orally, or parenterally in humans or other animals' in amounts large enough to inhibit the rapid excretion of PAS. In mice, the oral L. D.,so.is 1,1'56 mg; per kg. of body weight, and'when’ihjected subcutaneously the L. D.so. is , 1,665 mg. per kg. of. body weight. Dogs have been dosed with as much as 200 mg. per kg. of body weight per day for . as long as six weeks without, significant toxicity, and human subjects have received 3; grams per day for 12 weeks, and 2 grams per day for 8 months without evidence of system toxicity.

The pharmacologic, action of probenecid is believed to reside in its ability to inhibit’ an enzymatic system which in activates PAS hy conjugating it with glycine in whffih form it is

Claims.

This invention relates' to new compositions which are valuable in the administration of paraaminosalicylic, acid in the therapy of tuberculosis.

A major difficulty in the. clinical application of para-aminosalicylic acid', hereinafter referred to as PAS, is that doses in excess of 8 to 12 grams per day induce nausea and gastrointestinal symptoms manifested by anorexia, vomiting and diarrhea in a majority of patients. These symptoms make it nearly impossible to administer daily doses of 20 to 24 grams that have been recommended in the treatment of this disease. As PAS is usually administered orally, the physical characteristics of the form in which the drug is given have some bearing on the patient’s tolerance, the hydrochloride being more irritating than the free para-aminosalicylic acid, and the latter⁴ being more irritating than its' sodium salt. Thus, the attainment of higher plasma concentrations of PAS by the use of larger quantities of the free acid is impractical because of the gastrointestinal symptoms caused by large doses of the drug, and, although the sodium salt of PAS is tolerated better, the drug in this form is more rapidly excreted; That PAS produces these symptoms' because of local’ gastrointestinal irritation is substantiated by studies in which massive does of PAS have been administered intravenously for periods of up to six weeks without the development of gastrointestinal symptom’s even’ though plasma concentrations reached 40 mg. per 100 ml.

Although it has not been definitely established that.· there is a direct correlation between the clinical Course of tuberculosis treated With PAS and the plasma concentrations of PAS, it seemed reasonable to strive for plasma concentrations of PAS in excess of the in vitro sensitivity of the tubercle bacillus which ranges from as low as 0.015 mg. of PAS per 100 ml. of plasma to 1.53 mg. per 100 ml. for the more resistant strains of organism tested. Thus, it is recommended that concentrations rahging from 2 to 7 mg. of drug per 100 ml', of plasma, attainable when 10 to 14 gr. of PAS are administered daily, be maintained for satisfactory chemotherapy of this disease.

The problem of maintaining adequate plasma concentrations of PAS' was not easily solved since, as pointed out abbve, the administration of larger daily doses of the drug cannot be re- 50 sorted to'because of the untoward patient reaction when a dose larger than 8 to 12 gm . per day is; adihinistdre'd,; and; since the intravenous administration-of the sodium salt όί PAS is impractical· for the extended periods of time 'over 5S

2,676,902 rapidly excreted by way of the renal tubules. It has been found that PAS in unconjugated form is less readily excreted than in the conjugated form. Consequently, by preventing the conjugation of the drug, probenecid retards both the 5 inactivation and elimination of PAS, and provides an increased and effective plasma concentration over a prolonged period of time. In this relation, probenecid may be thought to function as an anticatabolite. 10

Probenecid, administered together with or separately from PAS in a daily dose of about 1 to 4 grams, and advantageously in a daily dose of about 2 grams, increases the plasma concentrations of PAS from two- to four-fold. A single, 15 oral dose of from 1 to 4 gm. of probenecid generally produces about a two-fold increase in the PAS plasma concentration, while the same quantity distributed over a twenty-four hour period, for example doses of 0.5 gr. every 6 hours, 20 produces about a four-fold increase. Furthermore, these small quantities of probenecid maintain increased plasma concentrations of PAS, after a single dose, for as long as eight hours. Probenecid plasma concentrations as low as 2 to 6 25 mg. per ICO ml. produce measurable effects on the plasma concentration of PAS. Concentrations of this magnitude can be maintained by the administration of 1 gm. of adjuvant at 12 hour intervals. While it has been demonstrated that 1 gm. 30 of probenecid every 12 hours maintains a pharmacologic effect in man, the effect may hot be optimal over this entire period in all patients, and the quantity of adjuvant administered must be adjusted accordingly. Probenecid thus offers the 35 possibility of attaining therapeutic plasma concentrations of PAS even after the smaller doses of PAS that may be necessitated by reason of gastric intolerance of the patient to whom PAS is being administered. This increase in PAS plasma ⁴⁰concentrations is observed whether the PAS is administered in the form of the free acid, its hydrochloride, or its sodium salt. However, it is preferred to administer the sodium salt of PAS because it is generally less irritating and more ₄₅rapidly absorbed from the gastrointestinal tract than either the free acid or the hydrochloride.

Examples illustrating the compositions of this invention are given below. It is to be understood, however, that the examples merely illustrate and ₅₀do not limit the invention.

Example 1.—Compressed tablets

Five thousand grams of para-aminosalicylic acid and 1,670 grams of probenecid were mixed ⁰together and then passed through a fine screen. The screened material was remixed and then granulated with about 150 cc. of a mixture composed of 2 parts com starch paste (prepared by θθ mixing 1 part of dry corn starch with 7 parts of water) and 1 part of a 20% gelatin solution. The moist granules were passed through a coarse screen, then spread thinly on trays and dried at 120° F. for about 18 hours. The dried material θ₅was reduced to a No. 14 granule. 644 grams of dry, sifted corn starch were intimately mixed with the granules, and finally a screened mixture of 150 grams of talc and 15 grams of magnesium stearate was added to the granulation and the ₇₀composition was then compressed into tablets using one-half inch die standard curvature punches, yielding 10,000 tablets of 0.75 gram each, and each containing 0.5 gram of PAS and 0.167 gram of adjuvant. 75

Example 2. —Compressed tablets containing sodium PAS

5,000 grams of sodium para-aminosalicylate and 1,670 grams of probenecid were mixed together and then passed through a fine screen. The screened material was remixed and then granulated with about 400 cc. of corn starch paste prepared by mixing 1 part of dry corn starch with 7 parts of water. The moist granules _v were passed through a coarse screen, spread thinly on trays, and then dried in an oven at about 130° F. for about 24 hours. The dried material was reduced to a No. 14 granule. 630 grams of dried, sifted corn starch were intimately mixed with the granules, and finally a screened mixture of 135 grams of talc and 15 grams of magnesium stearate was added to the granulation and the composition was then compressed into tablets using one-half inch die standard curvature punches, yielding 10,000 tablets of 0.75 gram each, and each containing 0.5 gram sodium PAS and 0.167 gram of adjuvant.

Example 3. —Compressed tablets containing PAS hydrochloride

5,000 grams of para-aminosalicylic acid hydrochloride and 1,670 grams of probenecid were mixed together and then passed through a fine screen. The screened material was remixed and then granulated with about 150 cc. of a mixture composed of 2 parts corn starch paste (prepared by mixing 1 part of dry corn starch with 7 parts of water) and 1 part of a 20% gelatin solution. The moist granules were passed through a coarse screen, then spread thinly on trays and dried at 120° F. for about 18 hours. The dried material was reduced to a No. 14 granule. 644 grams of dry, sifted corn starch were intimately mixed with the granules, and finally a screened mixture of 150 grams of talc and 15 grams of magnesium stearate was added to the granulation and the composition was then compressed into tablets using one-half inch die standard curvature punches, yielding 10,000 tablets of 0.75 gram each, and each containing 0.5 gram of PAS hydrochloride and 0.167 gram of adjuvant.

Example 4. —Effervescent tablets

10,000 grams of para-aminosalicylic acid, 3,330 grams of probenecid, 9,790 grams of sodium bicarbonate and 80 grams of saccharin soluble were mixed together and then passed through a fine screen. The screened material was remixed and wetted with sufficient acetone to permit its ready granulation in the usual way. The moist granules were passed through a coarse screen, then spread thinly on trays and dried in an oven with circulating air at about 120° F. The dried material was reduced to a No. 12 granule, 4 fluid ounces of oil of peppermint were intimately admixed, and the composition was then compressed '< into tablets using 1 inch die flat face, beveled edge punches, yielding 10,000 tablets of 2.32 grams each, and each containing 1 gram of PAS and _y

0.333 gram of adjuvant.

Example 5. —Soluble elastic capsules

5,000 grams of para-aminosalicylic acid and 1,670 grams of probenecid were mixed together and then passed through a fine screen. The screened material was remixed and the mixture homogeneously dispersed in 3,330 grams of corn oil. The resulting composition was encapsulated in known manner in soft, elastic, sheet gelatin, hermetically sealed capsules, yielding 10,000 cap2,67 sules, each holding 1 gram net of the composition and each containing 0.5 gram of PAS and 0.167 gram of adjuvant.

Example 6,—Soluble elastic capsules containing sodium PAS

000 grams of sodium para-aminosalicylate and 1,670 grams of probenecid were mixed together and then passed through a fine screen. 3,330 grams of com oil were added gradually to the screened material and stirring continued until a homogeneous dispersion was obtained. The resulting composition was encapsulated in known manner in soft, elastic, sheet gelatin, hermetically sealed capsules, yielding 10,000 capsules, each containing 1 gram, net of the composition and each containing 0.5 gram of sodium PAS and 0.167 gram of adjuvant.

Example 7.—Dry filled capsules

000 grams of para-aminosalicylic acid, 1,670 grams of probenecid, and 30 grams of dried corn starch were intimately and uniformly mixed, and the mixture filled into capsules, yielding 10,000 capsules each containing 0.67 gram of mixture containing 0.5 gram of FAS and 0.167 gram of adjuvant.

Example 8,—Dry, filled capsules containing sodium PAS

5,000 grams of sodium para-aminosalicylate, 1,670 grams of probenecid, and 30 grams of dry corn starch were intimately and uniformly mixed, and the mixture filled into capsules, yielding 10,000 capsules, each containing 0.67 grams net of the composition and each containing 0.5 gram of sodium PAS and 0.167 gram of adjuvant.

In the above examples where no particular specifications for individual ingredients are given, it is understood that there is used such quality of the various ingredients as is suitable for incorporation in pharmaceutical preparations.

Although each of the preceding examples contains probenecid as the adjuvant, any non-toxic, soluble salt of probenecid can be substituted for

The compositions of the invention can also include an antacid material, such as aluminum hydroxide, magnesium trisilicate, trisodium citrate,

6,002 calcium carbonate, magnesium oxide, or other antacid substance suitable for administration for the purpose of neutralizing gastric acidity. The amount of antacid material is limited only to 5 that which is desirable to use in connection with

PAS or which can be physically incorporated in a tablet or capsule of suitable size for oral administration. .

As to binders and lubricants used in making 10 the tablets, such materials as lactose, corn starch, gum karaya, talc, calcium stearate, gelatin, ethyl cellulose, mineral oil, propylene glycol, glycerin, and the like, may be included in proportions commonly used in preparing tablets of this nature.

If the compositions are produced in the form of suspensions or solutions in an oleaginous material, there are available various substances which may be used for this purpose. Com oil or other suitable oil can be used with advantage.