MXPA99008920A - Antacid and papain combination - Google Patents

Abstract

A composition for relieving stomach distress is disclosed. The composition comprises a combination of one or more compositions that reduce gastric acidity and a composition extracted from papaya, preferably comprising one or more proteolytic enzymes. Also disclosed are methods of making and methods of using such compositions.

Description

COMBINATION OF PAPAIN AND AN ANTI-FLOOR Field of the invention This invention relates to a composition for treating the symptoms of excess gastric acid secretion, such as heartburn, heartburn, acid indigestion and the stirred stomach. The composition of this invention is a combination of: 1) one or more compositions that reduce gastric acidity and 2) papaya extract.

Background of the Invention It is well known that the excess production of stomach acid can cause symptoms of gastric discomfort, heartburn, dyspepsia and the like. For the vast majority of people, symptoms of gastric hyperacidity occur after certain foods have been consumed. Spicy food, marinated foods, pepper, tomatoes and citrus fruits are among the foods that frequently cause hyperacidity. There is a large number of compositions that provide relief for gastric hyperacidity. Such compositions include, but are not limited to, compositions that reduce the intragastric concentration of hydrogen by chemical neutralization; such as calcium carbonate (e.g., Tums ™), magnesium hydroxide (e.g., Mylanta ™), a combination of calcium carbonate and magnesium hydroxide (e.g., Rolaids ™) and similar compositions; H2 receptor antagonists such as ranitidine (eg, Zantac ™), cimetidine (eg, tagamet ™) and similar antagonists; proton-releasing inhibitors such as omeprazole, bismuth compounds, prostaglandins, sucralfate and dopamine antagonists such as cisapride. Each of said classes of compositions have different mechanisms of action and have been shown to be effective in reducing or eliminating the symptoms of gastric hyperacidity.

While the above compositions are effective, some are not long-lasting effects and others have delayed action mechanisms. More specifically, compositions such as Tums ™, Mylanta ™ and Rolaids ™ do not have long-lasting effects, whereas h-receptor antagonists, proton-releasing inhibitors and others do not have a rapid action (less than one minute). Therefore, a composition capable of overcoming this disadvantage is desirable.

The digestive action of papaya, a fruit of the Carica papaya Linn tree has been known for centuries. Studies have shown that fruit juice, also referred to as latex, contains proteolytic enzymes, which have been identified as papain, cymopapain and papaya proteinase III. Papain is the most characteristic of the three. Its approximate molecular weight is 21,000 and it contains 18 different amino acids in a sequence of 211 amino acids.

Although it is not exactly true that papaya compounds reduce gastric acidity, studies in rats have shown that immature papaya latex feeding significantly reduces acid secretion induced by methocholine. Papain feeding in crystals at a dose of 3.2 mg / kg reduces gastric acid secretion. The reduction of gastric acid secretion in the rats was observed at 2 hours after administration and in the terminal phase, at 48 hours. Cho, et al., Proc. Nati Sci. Counc. ROC (B), 8 (2), 177-181 (1984).

Combinations of pure digestive enzymes, such as proteases, in stable aqueous colloidal suspension with aluminum hydroxide are described in U.S. Pat. No. 3,329,564. Proteases or other digestive enzymes are added to the aluminum hydroxide antacid in small amounts to provide digestive benefits of enzymatic action to the antacid preparation. However, these compositions are inconvenient to use because they are suspensions.

It is therefore an object of the present invention to provide a composition that is capable of providing improved relief of the effects of excess gastric secretion. It is also desired to supply a composition in a convenient form for carrying or transporting.

SUMMARY OF THE INVENTION The present invention is directed to a composition comprising: 1) one or more compositions that reduce stomach acidity and 2) a composition extracted from papaya, preferably comprising one or more proteolytic enzymes, including but not limited to, papain, cymopapain and papaya proteinase III. This composition can be used to provide a better and convenient relief of gastric discomfort resulting from excess gastric acid secretion.

The present invention is further directed to a method of preparing a composition comprising: 1) one or more compositions that reduce stomach acid and 2) a composition extracted from papaya, preferably comprising one or more proteolytic enzymes, including but not limited to limited to, papain, cymopapain and papaya proteinase III.

The present invention is further directed to a method of using a composition comprising: 1) one or more compositions that reduce stomach acidity and 2) a composition extracted from papaya, preferably comprising one or more proteolytic enzymes, including but not limited to limited to, papain, cymopapain and papaya proteinase III.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a composition for alleviating stomach discomfort comprising: 1) one or more compositions that reduce gastric acidity and 2) a composition extracted from papaya, preferably comprising one or more proteolytic enzymes, including but not limited to , papain, cymopapain and papaya proteinase III. This composition can be used to provide better and convenient improved relief of gastric discomfort resulting from excess gastric acid secretion. This invention is further directed to a method of preparation and method of using such a composition to provide better relief of gastric discomfort.

The amounts of the ingredients that can be used in this composition are generally the ordinary doses required to obtain the desirable result. In one embodiment, the amount of the first component that reduces gastric acidity is present in an amount of about 10 mg / dose to about 1,500 mg / dose and the amount of the papaya extract is present in an amount of about 50 mg / dose. Dosage up to approximately 3000 mg / dose.

In accordance with this invention, compositions that reduce gastric acidity can be any of the following: compositions that reduce the intragastric concentration of the hydrogen ion by chemical neutralization, H2 receptor antagonists, proton release inhibitors, bismuth, prostaglandins, sucralfate and dopamine antagonists. These compositions are defined herein as "antacids". The composition of this invention may comprise one or more of these antacids.

In accordance with this invention the improved relief of gastric distress may be either a relief of prolonged duration of action and / or a more rapid action that occurs from the ingestion of the antacid component alone of this single inventive composition.

Non-limiting examples of compositions that reduce gastric acidity by chemical neutralization may be: active ingredients containing aluminum, active ingredients containing bicarbonate, active ingredients containing bismuth, active ingredients containing calcium, active ingredients containing citrate, glycine, active ingredients containing magnesium, dehydrated milk solids, active ingredients containing phosphate, active ingredients containing potassium, active ingredients containing sodium, active ingredients containing silicates and tartrate and other compositions recognized by the United States Food and Drug Administration (FDA) as useful for the relief of heartburn, heartburn or acid indigestion and the stomach upset. Said compositions are listed in 21 C.F.R. § 331, which is incorporated herein in its entirety as a reference.

In this invention, the preferred neutralizing chemical compositions are calcium carbonate and magnesium hydroxide. Calcium carbonate is the most preferred.

The receptor antagonists reduce gastric acid secretion by blocking the histamine receptors in the stomach walls. Histamine stimulates gastric secretion via H2 receptors. Non-limiting examples of H2O receptor antagonists are: ranitidine, cimetidine, famotidine, mifentidine, roxatidine and mizatidine. The amount of H2 receptor antagonists that can be used in this invention is from about 10 mg / dose to about 800 mg / dose. In this invention, ranitidine is the preferred h-receptor antagonist. The amount of ranitidine that can be used in this invention is from about 75 mg / dose to about 300 mg / dose.

Proton-releasing inhibitors block the release of the membrane from the parietal cells in the stomach that are responsible for the exchange of potassium from the gastric opening with hydrogen ions. Blocking this membrane release inhibits gastric acid secretion. A non-limiting example of a proton-releasing inhibitor is omeprazole.

Bismuth compounds act in various ways to reduce gastrointestinal discomfort. A non-limiting example of a bismuth compound is bismuth subcitrate, also known as tripotassium dicitrate bismuthate.

Prostaglandins are lipid hormones that are found in virtually all tissues. It is believed that an effect of prostaglandins in the stomach is the reduction of acid secretion. They can also improve the resistance of the mucosa to stomach irritation. Non-limiting examples of prostaglandins are PGEi, of which misoprostol is an analogue: PGE2, of which arabaprostil and enprostil are analogous; PG and the methylated analogs of the prostaglandins of the E series.

Sucralfate is a complex salt of polyaluminium hydroxide with a sulfated saccharide structure that has been clinically proven and declared effective in the treatment of gastric and duodenal ulcers. It is a weak buffer with a pH of about 4.5.

It is believed that dopamine antagonists relieve gastric distress by increasing gastrointestinal motility and decreasing transit time. Non-limiting examples of dopamine antagonists are metoclopramide, domperidone and cisapride.

The amount of the compositions mentioned above that reduce gastric acidity that are used in this invention may vary depending on the therapeutic dose recommended or allowed by the particular agent. In general, the amount of these compositions is the ordinary dose required to obtain the desired result. In one embodiment of this invention, the amount of compositions that reduce gastric acidity by chemical neutralization are present in an amount from about 250 mg to about 1450 mg / dose. The dosage form can be a tablet, a capsule, a powder, an elixir and the like. Such doses are known to the person skilled in the medical art. The preferred dosage forms are tablets.

In a preferred embodiment, magnesium hydroxide is present in an amount from about 50 to about 800 mg / dose; preferably in an amount from about 80 mg to about 600 mg / dose and more preferably from about 100 mg to approximately 400 mg / dose.

In another preferred embodiment, the calcium carbonate is present in an amount of from about 200 to about 1250 mg / dose, preferably from about 400 mg to about 1000 mg / dose and more preferably from about 500 mg to about 800 mg / dose.

Another preferred embodiment of this invention contains magnesium hydroxide and calcium carbonate in an amount of magnesium hydroxide from about 50 mg to about 400 mg / dose and calcium carbonate in an amount from about 200 mg to about 1250 mg / dose; preferably an amount of magnesium hydroxide from about 80 mg to about 300 mg / dose and calcium carbonate in an amount from about 400 mg to about 1000 mg / dose and more preferably an amount of magnesium hydroxide from about 100 mg to about 260 mg / dose and calcium carbonate in an amount from about 500 mg to about 800 mg / dose.

The present invention also includes a composition extracted from juice, pulp and other parts of the papaya. In this invention, the composition extracted from papaya is defined as papaya extract. One embodiment of this invention comprises one or more proteolytic enzymes of the papaya extract. Non-limiting examples of proteolytic enzymes are papain, cymopapain and papaya proteinase III. The preferred enzyme is papain. The papaya extract of this invention can be in various forms. Non-limiting examples of these forms are: dehydrated powdered papaya latex, frozen dehydrated papaya powder, papaya powder juice, papain in crystals and cymopapain in crystals. Preferred forms are the spraying of frozen dehydrated papaya and the spraying of papaya juice.

In one embodiment of this invention, the amount of papaya extract in each dose of the composition of this invention is from about 50 mg to about 3000 mg. The preferred amount is from about 100 mg to about 1000 mg. The most preferred amount is from about 200 mg to about 800 mg.

Another embodiment of this inventive composition contains one or more proteolytic enzymes found in the papaya extract, including but not limited to, papain, cymopapain and papaya protease III. These enzymes may be relatively pure (eg, pharmaceutical grade), but less pure enzyme preparations are also acceptable. The amount of one or more proteolytic enzymes per dose in this embodiment is from about 0.5 to about 600 mg; preferably from about 1.5 mg to about 300 mg and more preferably from about 2.5 mg to about 200 mg.

The composition of this invention may also contain other ingredients and excipients known to those skilled in the art. Non-limiting examples of these additional ingredients include excipients, binders, colorants, flavors, sugars, starches and the like. The composition of this invention can be used in many different physical forms well known in the pharmaceutical art to provide an initial dose of the inventive composition and / or an additional form of gradual release of the inventive composition. Without being limited to those mentioned herein, such physical forms include tablets, capsules, powders, elixirs and the like.

This invention extends to the methods of manufacturing the inventive composition. In general the composition of this invention is made by mixing one or more of the antacids of this invention with dehydrated papaya extract, as well as other dehydrated ingredients such as excipients, binders, starches, sugars and the like. Said ingredients are mixed and prepared as powders, tablets, capsules and the like according to the techniques known in the art. Another method of preparing the composition of this invention comprises mixing the dehydrated ingredients and then combining them with liquid extract of papaya and then further combining them with water, corn syrup and the like to prepare a liquid form of the invention. Using additional methods known to those skilled in the art, this liquid form of the invention can be prepared in the specific manner desired.

This invention extends to methods of using the inventive composition. In general, these methods employ the ingestion of the inventive composition in an amount and frequency sufficient to provide a better treatment of symptoms caused by excess gastric acid secretion.

Examples of the compositions according to this invention are provided to illustrate, but not limit, the claimed invention.

Example 1 Sugar, Sweets 6X (with starch) 35.54 grams Heavy Calcium Carbonate USP 18.54 grams Calcium carbonate 9.13 grams Magnesium hydroxide 5.53 grams Starch, pregelatinized, NF 0.77 grams Polyethylene glycol 800 (Pulverized) 0.70 grams Pulverized papaya juice 25.00 grams Flavor 0.60 grams Starch 1500 3.376 grams Silica, amorphous smoked 0.30 grams Magnesium stearate 0.50 grams The papaya juice powder was obtained from Island Organics, Inc., located at 500 Metuchen Rd., South Plainfield, New Jersey 07080.

The ingredients mentioned above were formed into 50 tablets following the procedure indicated below: The sugar, the calcium carbonates, the magnesium hydroxide, the pregelatinized starch and the polyethylene glycol were previously combined with water and mixed to form a uniform, dry and powdered composition. These ingredients were then mixed with the papaya juice spray, the flavor, the 1500 starch and the silica for twenty minutes using a half gallon P-K mixer. The magnesium stearate was added to this mixture and mixed for five minutes.

The blended composition was compressed into hard, pleasant-tasting tablets using conventional technology.

Example 2 Sugar, Sweets 6X (with starch) 21.32 grams Heavy Calcium Carbonate USP 11.12 grams Calcium carbonate 5.48 grams Magnesium hydroxide 3.32 grams Starch, pregelatinized, NF 0.46 grams Polyethylene glycol 800 (Pulverized) 0.42 grams Frozen pulp of dehydrated papaya 30.00 grams Flavor 0.45 grams Starch 1500 1.816 grams Silica, smoked amorphous 0.225 grams Magnesium stearate 0.375 grams The frozen spray of dehydrated papaya is available from Freeze Dry Product, USA located at 68 Leveioni Court, Suite 100, Navato, California. Thirty tablets were manufactured using the same method described in Example 1. The tablets tasted good, but the blended ingredients showed less than the ideal fluidity.

The amount of papaya extract contained in each dose (or tablet) may be within a range of from about 50 mg to 3000 mg with about 100 mg to about 1000 mg preferred. The particular form of the papaya extract used is not critical in the present invention, however, the purest form used is the least amount of extract needed for each dose.

Claims (22)

1. - A composition for the relief of upset stomach, comprising: 1) one or more compositions that reduce gastric acidity and 2) papaya extract.

2. The composition according to claim 1, wherein said compositions that reduce gastric acidity are selected from the group consisting of: compositions that reduce the intragastric concentration of the hydrogen ion by chemical neutralization, H2 receptor antagonists, inhibitors of the release of protons, bismuth compounds, prostaglandins, sucralfate and dopamine antagonists.

3. The composition according to claim 2, wherein said composition that reduces gastric acidity is a composition that reduces the intragastric concentration of the hydrogen ion by chemical neutralization.

4. The composition according to claim 3, wherein said composition that reduces the intragastric concentration of the hydrogen ion by chemical neutralization is selected from the group consisting of calcium carbonate, magnesium hydroxide and combinations thereof.

5. The composition according to claim 4, wherein said composition that reduces the intragastric concentration of the hydrogen ion by chemical neutralization is calcium carbonate and magnesium hydroxide.

6. The composition according to claim 5, wherein said magnesium hydroxide is present in an amount from about 50 mg / dose to about 400 mg / dose and said calcium carbonate is present in an amount from about 200 mg / dose to approximately 1250 mg / dose.

7. The composition according to claim 6, wherein said magnesium hydroxide is present in an amount from about 80 mg / dose to about 300 mg / dose and said calcium carbonate is present in an amount from about 400 mg / dose to approximately 1000 mg / dose.

8. The composition according to claim 7, wherein said magnesium hydroxide is present in an amount from about 100 mg / dose to about 260 mg / dose and said calcium carbonate is present in an amount from about 500 mg / dose to approximately 800 mg / dose.

9. The composition according to claim 2, wherein said composition that reduces gastric acidity in an H2 receptor antagonist and wherein said H2 receptor antagonist is present in an amount from about 10 mg / dose to about 800 mg / dose .

10. The composition according to claim 9, wherein said H2 receptor antagonist is ranitidine and wherein said ranitidine is present in an amount from about 75 mg / dose to about 300 mg / dose.

11. - The composition according to claim 1, wherein said papaya extract is present in an amount from about 50 mg to about 3000 mg / dose.

12. - The composition according to claim 1, wherein said papaya extract consists of one or more proteolytic enzymes.

13. The composition according to claim 12, wherein said proteolytic enzymes are selected from the group consisting of papain, cymopapain and papaya proteinase III.

14. - The composition according to claim 13, wherein said proteolytic enzyme is papain.

15. The composition according to claim 14, wherein said one or more proteolytic proteins are present in an amount from about 0.5 mg / dose to about 600 mg / dose.

16. The composition according to claim 15, wherein said one or more proteolytic enzymes are present in an amount from about 1.5 mg / dose to about 300 mg / dose.

17. The composition according to claim 16, wherein said one or more proteolytic enzymes are present in an amount from about 2.5 mg / dose to about 200 mg / dose.

18. The composition according to claim 1, wherein said one or more compositions that reduce gastric acidity are present in an amount from about 250 mg to about 1450 mg per tablet and said papaya extract is present in an amount from about 50. mg / dose to approximately 3000 mg / dose.

19. - A method for preparing a composition for relieving stomach upset comprising one or more compositions that reduce gastric acidity and a composition extracted from papaya comprising the steps of: 1) mixing one or more compositions that reduce gastric acidity that are in dried form, dehydrated papaya extract and other dry ingredients selected from the group consisting of excipients, binders, starches and sugars and 2) mixing the ingredients of stage 1 and 3) preparing the ingredients of stage 2 as a powder.

20. - The method of claim 19, further comprising the step of compressing said powder to form a tablet.

21. - A method for preparing a composition for relieving stomach upset comprising one or more compositions that reduce gastric acidity and a composition extracted from papaya comprising the steps of: 1) mixing one or more compositions that reduce gastric acidity that are in dry form with other dry ingredients selected from the group consisting of excipients, binders, starches and sugars; 2) in addition the combination of the ingredients of stage 1 with the liquid papaya extract and mix and 3) subsequently also combine the ingredients of stage two with water and corn syrup.

22. - A method of using a composition for relieving stomach upset which comprises: 1) one or more compositions that reduce gastric acidity and 2) a composition extracted from the papaya comprising the step of ingesting said composition in an amount and frequency enough to provide relief from that upset stomach.