WO1986006632A1

WO1986006632A1 - Long-acting antacid compositions

Info

Publication number: WO1986006632A1
Application number: PCT/US1986/001018
Authority: WO
Inventors: Max A. Tesler; John D. Flanagan
Original assignee: Pharmacontrol Corp.
Priority date: 1985-05-10
Filing date: 1986-05-09
Publication date: 1986-11-20
Also published as: EP0222881A4; DK10387D0; DK10387A; EP0222881A1

Abstract

Compositions for the prolonged reduction of gastric acidity. These compositions comprise one or more antacid compounds, a source of prostaglandin precursors and dietary fiber.

Description

LONG-ACTING ANTACID COMPOSITIONS

FIELD OF THE INVENTION

This invention relates to compositions that- can reduce gastric acidity for relatively long periods of time after administration. More particularly, the invention relates to novel combinations of acid-neutralizing compounds, dietary fiber and prostaglandin biosynthetic precursors. These compositions are in a highly palatable form and are useful _γ for the treatment or prevention of gastric hyperacidity and the discomfort and disease conditions that it can produce.

BACKGROUND ON THE INVENTION

Antacid drugs are an important palliative in the treatment of duodenal and gastric ulcer. In their most basic form, antacids consist of a simple acid-neutralizing composition such as calcium carbonate, sodium bicarbonate or aluminum-magnesium hydroxide. These simple antacids are deficient, however, in that the period of time during which they can reduce gastric acidity is relatively short, typically well under an hour from the time of administration. Moreover, some of the simple acid-neutralizing compounds such as calcium carbonate when administered alone cause a delayed gastric hypersecretion called acid rebound [Fordtran, New Eng. J. Med. 279:900 (1968)]

in an effort to improve the duration of action of the simple antacid compounds, Mitra [U.S. Patent 4,163,777]

incorporated a mixture of a magnesium and an aluminum antacid salt into matrix comprising a gel-forming swelling agent such as sodium carboxymethyl cellulose and a water insoluble lipid material. The result was an antacid lozenge that dissolved slowly in the mouth. Similarly, Schor e_t al. [U.S. Patent

4,369,172] used hydroxypropylmethyl cellulose or a mixture of that polymer and ethylcellulose and/or sodium carboxymethyl cellulose as a base to prolong the release of various active medicaments in lozenges, tablets, suppositories and other solid dosage forms. 10

Attempts have also been made to inhibit gastric emptying, thereby retaining antacid compositions within the stomach for a longer period of time. Kaplan e_t al. [U.S. Patent 3,555,151] combined magnesium oxide and an "aluminum

*^*-^* hydroxide-magnesium carbonate coprecipitate dried gel with locust bean gum to produce a composition that adhered to the walls of the stomach. Sheth et al. [D.S. Patent 4,140,755] used a hydrocolloid selected from a group of derivatized celluloses that produced a sustained release tablet 0 formulation in combination with a medicament. The formulation when taken orally became buoyant in gastric juice, thereby resisting passage through the pylorus. Watanabe et al. [U.S. Patent 4,127,622] prepared hollow particulates containing ethyl cellulose, a lower chlorinated

25 hydrocarbon and a lower chlorofluorinated hydrocarbon. Barium εulfate incorporated into these hollow particulates was retained longer in the stomach than was barium sulfate administered alone.

30 it has also been found that certain dietary fiber can delay gastric emptying. For example, Ray et al. [Am. J.

35 Clin. Nutr. 1*376 (1983)] have reported that a mixture of guar gum and wheat bran fed to noninsulin-dependent diabetic patients caused a statistically significant delay in the gastric emptying of both solid and liquid materials.

More recently, efforts to produce improved antacid compositions have focused on the prostaglandins and their precursors. These compounds can produce a variety of beneficial effects, as described in a short review by Sinar [Current Concepts in Gastroenterology, July/August, p.33 (1983)].

For example, erythro 15, 16-dioxyprostanoic acids and esters [Weiss, U.S. Patent 4,113,967], 11 α-homo-prostanoic acid derivatives [Floyd, Jr. et al_,., U.S. Patent 3,985,798], 16,16-ethylene derivatives of prostaglandin E, and its homologues [Walker, U.S. Patent 4,039,654], and arachidonic acid [Konture et al., J. Physiol. 286;15 (1979); Conolly et al., Gut 1 :429 (1977)] have been shown to inhibit gastric acid secretion. Arachidonic acid has been shown by Tarnawski et al. [J. Lab. Clin, Med. 3J52,:340 (1983)] to protect the gastric mucosa against alcohol injury, and Vantrappen et al. [Gastroenterology 8 :857 (1982)] have shown that 15[R]-15- methyl prostagladin facillitates the healing of gastric ulcers. Prostaglandins have also been shown to inhibit gastric emptying and to increase the production of a thick mucoid secretion which delays or reduces acid-induced damage to the gastric mucosa [Sinar, supra].

SUMMARY OF THE INVENTION

The present invention provides novel compositions for the prolonged reduction: of gastric acidity. This reduction

_ in gastric acidity is useful for the treatment or prevention o of a number of disorders caused by such acidity such as heartburn, epigastric buring pain, sour stomach, -indigestion, esophagitis, peptic ulcers and gastritis-duodenitis.

The prolonged gastric acid-reducing effects of the invention are achieved by novel combinations of one or more antacid compounds, a source of prostaglandin precursors and_t dietary fiber. These components act in concert to counter gastric acidity: the antacid compound (or compounds) acts to neutralize the acidity, while the prostaglandin precursors and dietary fiber serve to delay gastric emptying, thereby prolonging the antacid action.

Many other components can be added to the compositions of the invention to alleviate or reduce distress due to symptoms that often accompany gastric hyperacidity. For example, an antiflatulent may be added to alleviate or reduce symptoms of gas. Similarly, a laxative ingredient may be added to correct for constipation that might be caused by the antacid. Where pain and discomfort such as headache and acid indigestion accompany gastric hyperacidity, an analgesic ingredient may also be added to the compositions of the invention.

To improve palatability, a wide range of coloring and flavoring agents may be added to the compositions of the invention. Moreover, mouth feel may be optimized by manipulation of the granularity of the ingredients of the compositions, particularly the dietary fiber component.

Preferably, the compositons of the invention are incorporated into a solid wafer or cookie form. These dosage forms are

_ stable to storage and can be made pleasing to the taste, o unlike the chalky, bland or unpleasant tasting antacid preparations that have heretofore been available-.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel compositions containing one or more antacid compounds, a source of prostaglandin biosynthetic precursors and dietary fiber. Acting together, these components of the invention when administered orally produce a prolonged reduction in gastric acidity.

The invention further relates to compositions having other active components that can alleviate or reduce sources of discomfort that may accompany gastric hyperacidity or antacid treatment such as gas, constipation or generalized or 0 local pain. The invention still further relates to compositions having coloring and/or flavoring agents that enhance palatability.

PRIMARY ACTIVE INGREDIENTS 5

The antacid ingredients of the invention may be any nontoxic antacid compounds commonly used to neutralize gastric fluids. Such compounds include but are not limited to aluminum carbonate; aluminum hydroxide; dihydroxyaluminum 0 aminoacetate; aluminum phosphate; dihydroxyaluminum sodium carbonate; sodium bicarbonate; bismuth aluminate, carbonate, subcarbonate, subgallate or subnitrate; calcium carbonate or phosphate; citric acid or its salts; magnesium aluminosilicates, carbonate, glycinate, hydroxide, oxide or trisilicate; mono-, di-' or tribasic calcium phosphate; potassium bicarbonate; sodium potassium tartrate; magnesium o hydroxyaluminates and aluminum oxyhydroxide or combinations thereof. In the preferred embodiment of the invention, aluminum hydroxide and/or calcium carbonate are employed.

The quantity of antacid used per dosage unit may range from about 25 to about 95 milliequivalents ( Eq) of acid neutralizing capacity per dosage unit, with a preferred range of from about 60 to about 90 Eq. On a weight basis, the amount of calcium carbonate used per dosage unit may range from about 0.5 to about 4.0 grams, but preferably is in the range of from about 0.5 to about 2.0 grams. When aluminum hydroxide is the antacid a range of from about 0.6 to about

4.0 grams, but preferably from about 0.6 to about 2.0 grams may be used per dosage unit.

The acid neutralizing capacity of a sample can be determined by grinding the sample to a fine powder, mixing 10 grams of the power with 70 ml of deionized water, pipetting 25 mi of 1.0 N HCl into the solution and mixing for 15 minutes, and titrating the mixture with 1.0 N NaOH to pH 3.5.

Knowing the volume of the NaOH solution used, the mEq of acid neutralizing capacity per gram of the sample can be calculated as follows:

(25 mi)(normality of HCl)-(m* of NaDH)(noπr_ality of NaOH mEq/g = sample weight .in grams.

The overall acid neutralizing capacity of a dosage unit is of course the product of the above value and the total weight of the dosage unit in grams. A convenient dosage unit weights from about 26 to 31 grams, although of course other dosage sizes could be used instead.

The prostaglandin precursor source for the invention may be any material containing the polyunsaturated fatty acids that can be metabolized to the prostaglandins. The principal fatty acids are arachidonic acid, which is metabolized to prostaglandins E., P_2β- and G₂, and eicosatrienoic acid, which is converted in the body to prostaglandin G1. Of these fatty acids, arachidonic acid is more important.

Pure or partially purified arachidonic acid, either chemically synthesized or from natural sources, could be used. More economical and thus preferable sources are commercial lecithin, soybean oil or safflower oil. Safflower oil contains a mixture of fatty acids with varying chain lengths esterified to glycerol, as does soybean oil. In soybean oil there may also be up to 1% of free fatty acids not esterified to glycerol. Lecithin, which most often is produced commercially as a by-product in the manufacture of soybean oil is another good source of arachidonic acid. There, the prostaglandin precursor is present as part of a mixture of the diglycerids of stearic, palmitic, oleic and longer chain fatty acids linked to the choline ester of phosphoric acid. Commercial grade soybean lecithin contains about 5.5% C₂₀ to C₂₂ fatty acids, in which fraction arachidonic acid is found, and is a preferred source.

Presumably, with all of these sources the esterified arachidonic acid is hydrόlyzed in vivo to render it available for prostaglandin synthesis. The quantity of lecithin per dosage unit may range from about 0.5 to about 3.0 grams, with from about 0.8 to about 1.3 grams preferred for a 26 to 31 gram dosage unit.

Soybean oil may be used as a source of prostaglandin precursors in a range from about 0.5 to about 3.0 grams, with from about 0.8 to about 1.3 grams preferred for a 26 to 31 gram dosage unit. Where safflower oil is used as the source of prostaglandin precursors, it may be present in an amount of from about 0.5 to about 3.0 grams, and preferably from about 0.8 to about 1.3 grams for a 26 to 31 gram dosage unit.

The fiber component of the invention is preferably of plant origin, although synthetic polymers having similar physicochemical properties could be used instead.

Potentially useful dietary fibers include hemicelluloses, pectins and lignin. Convenient sources of fiber are wheat and corn bran, with corn bran being preferred. The quantity of corn bran for a 26 to 31 gram dosage unit may range from about 6.0 to about 9.0 grams, with about 7.5 grams preferred.

For improved mouth feel the bran may comprise a mixture of two or more grind sizes, as may be seen in the example below.

In preferred embodiment of the invention, two 26 to 31 gram dosage units are given containing together 170 mEq buffering capacity of a suitable antacid as described above,

15g bran, 2g soybean lecithin (arachidonic acid source) and

2g safflower oil (linoleic acid source). SECONDARY ACTIVE INGREDIENTS

Because many kinds f discomfort frequently accompany gastric hyperacidity, it may desirable to incorporate other

_ active agents into the compositions of the present invention 5 to alleviate these conditions. For example, an antiflatulent such as simethicone could be incorporated to combat gas that is often associated with heartburn, sour stomach or acid indigestion. Headache pain and the general discomfort from acid indigestion etc. may be relieved or reduced by the incorporation into the compositions of the invention of any pharmaceutically acceptable analgesic compound that would not cause further irritation of the gastric lining. Because antacid compounds may in some cases cause constipation, the incorporation of a safe and effective laxative compound into 5 the compositions may also prove beneficial.

INGREDIENTS TO ENHANCE PALATABILITY

A wide range of coloring, flavoring, sweetening and other ingredients may be incorporated into the compositions of the invention to produce a dosage form that is appealing to the eye and taste. For example, sweetening agents such as sucrose, fructose, lactose, aspartame (L-asartyl-L- phenylalanine methyl ester), annitol, sorbitol or xylitol may be added. A wide range of nontoxic food coloring agents may be added, as may flavoring agents such as oil of orange or lemon, lemon-lime, raspberry, cola, vanilla, mint, cinnamon, ginger, liquid butter or butterscotch flavoring or combinations thereof. The dosage form of the compositions of the invention may be powdered or granular, taken either dry or as a suspension in an appropriate carrier liquid such as water or milk.

Preferably, however, the compositions are incorporated into a convenient bakery product which will provide stability during storage and optimal appearance and palatability. Cupcake or biscuit dosage forms may be used, but a cookie dosage form is preferred since it provides enhanced stability of the active components of the invention^* uring storage. Where the dosage form is a bakery product, the ingredients characteristic of such products such as molasses, flour, baking powder or soda, animal or vegetable, shortening etc. will also be added to the compositions of the invention.

EXAMPLE: LONG-ACTING ANTACID FORMULATIONS

Formulations for a cookie dosage form of the present invention may be seen in Table 1.

TABLE 1

Typical Long-_toting Antacid Cookie Formulationsa

Quantity/Cookie (grams)

In Batch No.

Ingredient 1 2 3 4 5 6 7 8 9 10

Aluminum Hydroxide 1.02 1.02 1.02 1.02 1.02 1.02 _ 1.43 3.17

Magnesium Hydroxide - - - - - - - - - 1.58

Calcium Carbonate - - - - - - 1.43 2.70 - -

Regular Corn Bran - 3.78 5.29 5.67 4.91 4.54 4.54 4.54 4.54 4.54 Fine Corn Bran 7.56 3.78 2.27 1.89 2.65 3.02 3.02 3.02 3.02 3.02

Liquid Lecithin 0.25 0.25 0.25 0.25 0.25 0.30 0.30 0.30 0.30 0.30

Vegetable Shortening 4.84 4.84 4.84 4.84 4.84 4.84 4.84 4.84 4.84 5.80

Granulated Sugar 5.14 5.14 .5.14 5.14 5.14 5.14 5.14 5.14 5.14 4.67

Salt 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13

Cinnamon 0.28 0.28 0.056 0.056 0.056 0.056 0.056 0.056 0.056 0.056

HPCS^C 3.02 3.02 3.02 3.02 3.02 3.02 3.02 3.02 3.02 2.02

Ginger 0.028 0.028 0.056 - - - - - - -

Oil of Lemon 0.006 0.006 0.010 0.010 0.010 0.010 0.010 0.010 0.010 0.010

Molasses - 0.85 - - - - - - -

Water 7.59 2.0 2.0 2.10 2.10 2.10 2.10 2.10 1.90 5.80

Arrπonium Bicarbonate 0.065 0.065 0.065 0.065 0.065 0.065 0.065 0.065 0.065 0.098

Flour 6.52 6.52 6.52 6.52 6.52 6.52 6.10 4.74 6.10 2.78

Baking Soda 0.132 0.132 0.132 0.132 0.132 0.132 0.132 0.132 0.132 0.010

Liquid Vanilla - - 0.10 0.15 0.15 0.15 0.15 0.15 0.15 ^' 0.15

Butter Flavoring - - 0.020 0.15 0.15 0.15 0.15 0.15 0.15 0.15

Butterscotch Flavoring 0.10 0.10 0.10 0.10 0.10 0.10 0.10

^a The formulations are expressed as the quantities of ingredients in an amount of dough sufficient to make a single cookie.

^*•** The brans used were regular and find grind, both from the A.E. Staley Mfg. Co., Decatur Illinois. ^c HPCS = High fructose corn syrup, which was a product of A.D.M., Cedar Rapids, Iowa.

The ingredients in the formulations of Table 1 were generally combined in quantities sufficient to make 100 cookies in the following way:

1. The antacid, granular sugar, salt and vegetable shortening were weighed, combined and mixed throughly for 3 minutes in a 12-quart Hobart single blade mixer at the low speed setting. (At 1-minute intervals the mixing was stopped, the sides of the product bowl were scraped down, and mixing was resumed.) Then any flavoring agents used were added and mixed at speed one for 2 minutes.

2. The ammonium bicarbonate was dissolved in the water in a separate container and then added to the above mixed ingredients over a period of one minute while mixing at speed one.

3. The brans, flour and freshly sieved baking soda were added in succession to the top of the mixture and then mixed at speed one until the granulation was uniform.

The blended dough mixture was then formed into cookies in a (make and model) rotary machine and the cookies were baked at 400^*F for 10 to 11 minutes.

Many modifications and variations of this invention may be made without departing from its spirit and scope, as will become apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only, and the invention is limited only by the terms of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A long-acting antacid composition, comprising one or more antacids, a' source^' of prostaglandin precursors and a dietary fiber.

2. The long-acting antacid composition of claim 1 wherein the antacid is selected from the group consisting of aluminum hydroxide and calcium carbonate.

3. The long-acting antacid composition of claim 2 wherein the antacid is aluminum hydroxide at a concentration of from about 0.3 to about 4.0 grams for a 26 to 31 gram dosage unit.

4. The long-acting antacid composition of claim 2 wherein the antacid is aluminum hydroxide at a concentration of from about 0.6 to about 2.0 grams for a 26 to 31 gram dosage unit.

5. The long-acting antacid compostion of claim 2 wherein the antacid is calcium carbonate at a concentration of from about 0.3 to about 4.0 grams for a 26 to 31 gram dosage unit.

6. The long-acting antacid composition of claim 2 wherein the antacid is calcium carbonate at a concentration of from about 0.5 to about 2.0 grams for a 26 to 31 gram dosage unit.

7. The long-acting antacid composition of claim 1 wherein the dietary fiber is wheat bran.

8. The long-acting antacid composition of claim 1 wherein the dietary fiber is corn bran.

9. The long-acting antacid composition of claim 1 wherein the dietary fiber is present in an amount of from about 5 to about 10 grams for a 26 to 31 gram dosage unit.

10. The long-acting antacid composition of claim 1 wherein the dietary fiber is present in an amount of from about 6.0 to about 9.0 grams for a 26 to 31 gram dosage unit.

11. The long-acting antacid composition of claim 1 wherein the source of prostaglandin precursors is lecithin.

12. The long-acting antacid composition of claim 11 wherein the lecithin is present in an amount of from about

0.8 to about 1.3 grams for a 26 to 31 gram dosage unit.

13. The long-acting antacid composition of claim 1 wherein the source of prostaglandin precursors is safflower

14. The long-acting antacid composition of claim 13 wherein the safflower oil is present in an amount of from about 0.8 to about 1.3 grams for a 26 to 31 gram dosage unit.

15. The long-acting antacid composition of claim 1 wherein the source of prostaglandin precursors is soybean oil.

16. The long-acting antacid composition of claim 15 wherein the soybean oil is present in an amount of from about 0.8 to about 1.3 grams for a 26 to 31 gram dosage unit

17. A long-acting antacid composition, comprising in a 26 to 31 gram dosage unit about 85 mEq buffering capacity of an antacid, 7.5 grams of bran, 1 gram of soybean lecithin and 1 gram of safflower oil.

18. The long-acting antacid composition of claim 17 wherein the antacid is aluminum hydroxide.

19. The long-acting antacid composition of claim 17 wherein the antacid is calcium carbonate .