US3452138A

US3452138A - Urea-containing chewable antacid tablets

Info

Publication number: US3452138A
Application number: US392269A
Authority: US
Inventors: Edmund S Granatek; Alphonse P Granatek
Original assignee: Bristol Myers Co
Current assignee: Bristol Myers Co
Priority date: 1964-08-26
Filing date: 1964-08-26
Publication date: 1969-06-24
Anticipated expiration: 1986-06-24
Also published as: BR6572554D0; FR5146M; GB1106157A; BE668830A

Description

United States Patent 3,452,138 UREA-CDNTAINING CHEWABLE ANTACID TABLETS Edmund S. Granatek and Alphonse P. Granatek, Baldtablets is such that they are too gritty as a practical matter to be conveniently chewed to any finer particle size.

The antacid activity of a given tablet can therefore Winsville, N.Y., assignors to Bristol-M Company 5 be measured, when particle size is taken into account, New York, N.Y., a corporation of Delaware by the Pmcedure of Fuchs, g d m ti In- No Drawing Filed Aug 26, 19 4 Sen 392 259 dustry, 64, 692 (1949). As this method was used herein I t, C], A611; 27/06 a reaction vessel was charged with 25 ml. of 0.1 N US. Cl. 424-455 4 Claims hydrochloric acid and 125 ml. of deionized water. The This invention relates to particularly elegant and effec- 1O reactlon Vessel eqlllpped WItDh gm l' and pH tive antacid tablets and, more particularly, to a chewable electrodes and mamtalned at 37 C. :1 ma constant antacid tablet comprising a major proportion of Water temperature bath. Intact tablets were placed in a U.S.P. insoluble antacid agent, a major proportion of mannitol dlsintegration apparatus and introduced directly into this and a minor proportion of urea" reaction medium. The powdered tablets were first wet Aqueous suspensions of antacids such as aluminum f P F 10% Solutlon of a Wetfmg agent hydroxide, alone or in combination with other antacids five of Water and diluted with such as magnesium hydroxide, are effective medication an addltlogal 1111- Of Water- T 2? ml. of 0.l N for the control of gastric hyperacidity and gastric ulcers. y q l p 9 was then added mm diately and agita- In the practical management f these conditions however t1on initiated simultaneously. The surfactant was found the need exists for a dosage form which is more con- 20 necessary to assure wettlng 511166 the y phobic nature venient and readily available to the patient during his the Fonlponents In y of the tablets P v n ed ready routine, daily activities. Tablets have been used to meet dlspefslonthis need but for maximum usefulness such tablets must Wlth h Start of lmmerslon or agltatlon, the PH was be capable of being chewed and swallowed without water recorded lmmedlatflly and at e d f the first, thlrd, and if chewed, be free of objectionable characteristics fifth P tenth lllmutes- All thls P and after ach and must also provide sufiicient antacid activity. ten m readlng thereafter, 1 ml. Of 1.0 N hydro- It is commonly accepted that the human stomach conchlor 9 Was added- The Procedure as f llOWed until tains about ml. of 0.1 N hydrochloric acid after a the llsadlng Was below P 3 l the l X increment meal. During the next two hours this will be supplemented of acld was due to be added- Trlpllcate runs Were made, by the secretion of about 240 ml. of 0.1 N hydrochloric 30 and the results averaged acid. It is expected that patients secreting larger amounts A Fablet W t not consldered 9 p f isfactory of hydrochloric acid will be able to obtain relief by taking q actlvlty unless the p i t is test was held a suflicient number of doses of an antacid as measured wlthln the range of P for all least elghty by their own observed relief from discomfort. It is also r mlnutesrecognized that an individual with a gastric ulcer will Ten antacid tablets of the composition listed below in TABLE Ave. Comb. active ingredients per Average tablet Composition Labeled dosage and instructions tablet weight, grams Calcium carbonate, glycine 1 orh2 tablets as needed, chew, melt in mouth o s ll 600 651 \V O G. Dried aluminum hydroxide gel (stabilized With hexitol), 2 to 4 tablets as necessary, chewed or swallowed whole. 395 690 magneisum hydroxide. Aluminum hydroxide, magnesium hydroxide 2 to 4 tablets, chewed or swallowed 4 4 Aluminum hydroxide with magnesium hydroxide 1 or 2 tablets as required. May be chewed before swallowing 420 925 Dried aluminum hydroxide gel Swallow 1 or 2 tablets 324 2 Dried aluminum hydroxide gel, magnesium trisilicate, 1 or 2 tablets chewed, sucked or taken with water as .520 .987

magnesium hydroxide. necessary. Aluminum hydroxide-magnesium carbonate co-dried gel 1 or 2 tablets as required. Chewed or swallowed .375 1. 634

in a dextrose and milk soilds base. Aluminum hydroxide, magnesium hydroxide 1 1 0r 2 tablets, may be chewed or swall w d with at 420 923 Dried aluminum hydroxide gel 1 1 or two tablets 324 993 Magnesium trisilicate, dried aluminum hydroxide gel 1 to 4 tablets as necessary, c ewed, swallowed or allowed to 748 1. 340

disintegrate in the mouth.

1 Australian products.

obtain relief by adjusting the contents of his stomach to a pH of from 3 to 5. Any lesser pH will result in pain from the acid and any pH substantially greater than 5 will result in the highly undesirable phenomenon known as acid rebound as is observed, for example, when simple sodium bicarbonate is used as an antacid.

It is further recognized that any test of the antacid activity of the tablet must take into account the manner in which it disintegrates in the stomach and the size of the particles into which the tablet has been broken if it is chewed before it is swallowed. The USP. XVI tablet disintegration test has been used extensively to simulate the conditions which prevail in the human stomach. Examination of commercially available antacid tablets after they have been chewed and expectorated shows that the majority of particles are no finer than sufiicient to pass a IO-mesh screen; the nature of the material in these the table were obtained from the open market in the USA. or Australia and their duration of action in the effective range of pH 3.0-5.0 in minutes was measured.

To provide the proper analogy to conditions in the human body it was also necessary to take into account the particle size after disintegration of these tablets. This was done in two ways.

In the first method the tablet in the acid reaction cell was placed in a basket having a IO-mesh screen on the bottom which was raised and lowered as in the U.S.P. disintegration test. This simulated the conditions found when the tablet was swallowed without chewing.

In a second test the tablet was ground to pass a lO-mesh screen (simulating the size obtained when the tablet was chewed and then swallowed), placed in the acid of the reaction cell and mixed with a perforated disc which was raised and lowered as in the U.S.P. disintegration test.

It was found that, under these conditions simulating what actually occurs in the human body, such commercial tablets in general failed to provide anything approaching their theoretical buffering capacity. For example six of the ten whole tablets never raised the pH to the minimum satisfactory level of pH 3 and one of the ten whole tablets quickly raised the pH above the maximum acceptable level of pH 5 and kept it there for a considerable time.

When the tablets were ground to -mesh to duplicate the effect of chewing prior to swallowing, only one gave a duration of action greater than 65 minutes in the desired range of pH 3-5 and six of the tablets remained in the effective range for periods of less than 40 minutes with two of them not reaching that range at all and another going above pH 5 for all but 16 minutes. In addition, the three tablets which when 10-mesh remained in the effective range of pH for 65, 65 and 90 minutes respectively, were each evaluated as being much too grittty upon chewing. This would obviously militate against their continued use and chewing by the patient for the extended periods of time over which these tablets must be taken by patients with gastric ulcers. It was therefore apparent that the presently available antacid tablets as judged by the ten different products tested were far from being acceptable antacid agents.

Chewable tablets of other types of pharmaceutical agents, e.g. antibiotics, have been formulated using large amounts of mannitol in the tablet but this is not practical in the case of antacids such as aluminum hydroxide and the like because such tablets if of a reasonably small size are much too astringent and dry to chew without water, i.e. antacid agents of this type dry up the mouth to an unacceptable extent.

The use in ordinary antacid tablet formulation of agents such as aluminum hydroxide in finely divided form (e.g., greater than ZOO-mesh) is customary but fails to provide particles of such small size in the stomach when used. This undesirable effect may be due to the compression which must be applied to form the tablet or due to the other conventional manufacturing procedures used in preparing the tablets. Other common expedients do not serve to provide the proper particle size. Thus, use of wetting agents gives too bitter a taste. Admixture with simple water-soluble substances is not effective; thus, sodium chloride is too saline, sucrose is too sweet and lactose is not effective.

It was therefore the objective of the present invention to provide an antacid tablet, e.g., of the type containing aluminum hydroxide alone or in combination with similar antacids such as magnesium hydroxide, which would provide, as measured by the test described above, a duration of action in the effective range of pH 3-5 of at least 80 minutes and which would also have chewing properties of sufficient elegance to encourage and make possible longterm use, i.e., would give a feel in the mouth upon chewing which was not astringent, pasty, dry, chalky or slimy, which was neither too hard nor too soft when chewed and which was not gritty when chewed and which could be chewed and swallowed without water.

The objects of the present invention have been achieved by the provision, according to the present invention of a chewable antacid tablet comprising a major proportion of water-insoluble antacid agent, a major proportion of mannitol and a minor proportion of urea.

Preferred embodiments of the present invention are a chewable antacid tablet comprising by Weight 35 to 60% of water-insoluble antacid agent selected from the group consisting of aluminum hydroxide, magnesium hydroxide, magnesium oxide, magnesium carbonate and magnesium trisilicate and mixtures thereof, at least about 25% and preferably about 25 to 50% of mannitol and about 4 to 10% urea; a chewable antacid tablet comprising by weight about 35 to 60% of water-insoluble antacid agent, said agent being a mixture consisting of more than one-half 4 aluminum hydroxide and less than one-half magnesium hydroxide, about 25 to 50% of mannitol and about 4 to 10% urea; a chewable antacid tablet comprising by weight about 50% of water-insoluble antacid agent, about 35% by weight of mannitol and about 7% by weight of urea.

The water-insoluble antacids used in the tablet of the present invention include the hydroxides, carbonates, trisilicates and oxides of aluminum, magnesium and calcium and other known neutralizing agents such as are disclosed above and in textbooks of pharmacy and medicine and, for example, in U.S. Patents 1,964,696; 2,446,981; 2,588,- 090; 2,641,604; 2,686,800; 2,797,978; 2,802,773; 2,907,- 781; 3,047,602 and 3,099,524 and mixtures thereof.

The term antacid agent as used herein includes both such individual compounds and mixtures thereof.

The tablets of the present invention contain, when desired, sweetening agents, flavors, tableting lubricants, fillers and the like and may also contain additional therapeutic agents such as antispasrnodics (e.g., aminopentamide), antisecretory agents, tranquilizers (e.g., reserpine, meprobamate), antiflatulents (e.g., methylpolysiloxane), sedatives (e.g., phenobarbital), analgesics, local anesthetics or compatible combinations thereof.

Included within the present invention is the process of preparing a chewable antacid tablet which comprises first blending a major proportion of antacid agent and a major proportion of mannitol with a minor proportion of urea, next further reducing said mixture in particle size by mechanical means and 'finally forming said mixture into tablets.

The following example will serve to illustrate the present invention but the invention is not limited thereto and includes within its scope such variations in ingredients and proportions thereof as are well known to those skilled in this art.

EXAMPLE Formula Per tablet, gm. Aluminum hydroxide, U.S.P., dried gel, medium powder 0.300 Magnesium hydroxide, NP. 0.090 Mannitol, N.F., ZOO-mesh 0.300 Urea, N.F., 60-mesh 0.060 Sodium Sucaryl, ZOO-mesh 0.020 Sodium saccharin, U.S.P. 200-mesh 0.002 Corn starch, U.S.P. 0.0133 Flavors 0.013 Magnesium stearate, U.S.P. 0.0456

Tablet weight, anhydrous basis 1 0.8439

Finished tablet weight must be adjusted to include the Water remaining in the granulation after drying.

MANUFACTURING INSTRUCTIONS FOR 1,000 TABLETS (1) Prepare 266.0 grams of 5% (w./w.) starch paste by heating 13.30 grams of corn starch dispersed in 252.7 ml. of purified water, U.S.P., to boiling. Sufficient agitation should be used during this step to avoid scorching. Remove heat and maintain agitation until cooled to 25 C. Add sufiicient purified water, U.S.P., to bring the weight up to 266.0 grams and mix to obtain a homogeneous paste.

(2) Combine the aluminum hydroxide, magnesium hydroxide, mannitol, urea, sodium Sucaryl and sodium saccharin (e.g., in a pony pan) and blend at slow speed for 15 minutes.

(3) Pass the blend through a milling machine to break up any lumps (e.g. through a Fitz mill at high speed with impact forward using a M00 screen).

(4) Return the milled material to blender and continue mixing for one-half hour.

(5) With agitation in the blendor remaining at low speed, rapidly add all of the starch paste from step No. 1 and mix until a uniform dispersion is obtained. The mix appears dry at this point but usually contains enough moisture to form the granulation. If necessary, additional water may be added to facilitate the formation of the strands of granulation described in the next step.

(6) Pass the mix through a granulator (e.g., a Stokes oscillator, with funnel removed using a No. 6 mesh stainless steel screen) and collect directly on drying trays. If strands of granulation are not being formed, additional water must be added to the mix.

(7) Spread the granulation evenly on the trays and dry (e.g., in a Stokes oven) at 38 C. until the moisture content is 45-55%.

(8) Mill using a combination of screen, speed and blade adjustment which will produce the greatest yield of 30- to 60-mesh granules.

(9) Separate the granules retained on a 60-rnesh screen, add 5.48% magnesium stearate and hold.

(10) To the fines passing through a 60-mesh screen add 5.48% magnesium stearate and blend thoroughly.

(11) Slug at a weight of 0.470 gram using /2 inch, flat punches to a hardness of 5 to 7 kg. Reduce the slugs to 30- to 60-mesh granules and repeat the process until not more than nor less than 10% of fines passing through a 60-mesl1 screen remain.

(l2) Combine the lubricated granules from step No. 9 with the granules and fines from step No. 11. Add the flavors and blend thoroughly for 30 minutes.

(13) Tablet using /3 inch, flat, beveled edge punches to a hardness of 11 kg. or /2 inch square, concave punches to a hardness of 9 to 10 kg. (Strong-Cobb-Arner tester).

These tablets when chewed and expectorated were found to pass a 100-mesh screen. These tablets when ground to l00-mesh and tested as described above gave a duration of action in the effective pH range (3.05.0) of 81 minutes. The chewing properties of these tablets were evaluated as follows:

Flavor Very good. Mouth feel Cooling. Chewing characteritsics Very good. Chewing hardness Medium. Not gritty.

While in the foregoing specification various embodiments of this invention have been set forth and specific details thereof elaborated for the purpose of illustration, it will be apparent to those skilled in the art that this invention is susceptible to other embodiments and that many of these details can be varied widely without departing from the basic concept and spirit of the invention.

We claim:

1. A chewable antacid tablet comprising by weight about 35-60% of water-insoluble antacid agent selected from the group consisting of aluminum hydroxide, magnesium hydroxide, magnesium oxide, magnesium carbonate and magnesium trisilicate and mixtures thereof, about 25-50% of mannitol and about 410% urea.

2. A chewable antacid tablet comprising by weight about one-half water-insoluble antacid agent selected from the group consisting of aluminum hydroxide, magnesium hydroxide, magnesium oxide, magnesium carbonate and magnesium trisilicate and mixtures thereof, about onethird mannitol and about one-tenth urea.

3. A chewable antacid tablet comprising by weight about 35 to 60% of water-insoluble antacid agent, said agent being a mixture consisting of more than one-half aluminum hydroxide and less than one-half magnesium hydroxide, about 25 to of mannitol and about 4 to 10% urea.

4. A chewable antacid tablet comprising by weight about one-half water-insoluble antacid agent, said agent being a mixture consisting of more than one-half aluminum hydroxide and less than one-half magnesium hydroxide, about one-third mannitol and about one-tenth urea.

References Cited UNITED STATES PATENTS 6/1958 Goodfriend l6755 12/1965 Ainsworth 167-55 OTHER REFERENCES ALBERT T. MEYERS, Primary Examiner.

S. FRIEDMAN, Assistant Examiner.

US. Cl. X.R.

Claims

1. A CHEWABLE ANTACID TABLET COMPRISING BY WEIGHT ABOUT 35-60% OF WATER-INSOLUBLE ANTACID AGENT SELECTED FROM THE GROUP CONSISTING OF ALUMINUM HYDROXIDE, MAGNESIUM HYDROXIDE, MAGNESIUM OXIDE, MAGNESIUM CARBONATE AND MAGNESIUM TRISILICATE AND MIXTURES THEREOF, ABOUT 25-50% OF MANNITOL AND ABOUT 4-10% UREA.