WO2010092415A1

WO2010092415A1 - Combination of hesperidin and antacids in the treatment of gastro-esophageal reflux disease (gerd)

Info

Publication number: WO2010092415A1
Application number: PCT/IB2009/000252
Authority: WO
Inventors: Carlo Ghisalberti
Original assignee: Carlo Ghisalberti
Priority date: 2009-02-13
Filing date: 2009-02-13
Publication date: 2010-08-19

Abstract

The present invention relates to a composition and method for the simultaneous alleviation of the symptoms form both acute and chronic in gastro-esophageal reflux disease (GERD) and related conditions. The composition of the present invention comprises hesperidin and at least an alkaline calcium, sodium, potassium, and aluminium salt, wherein the metal salts treat the acute phase of the aforementioned disorder and hesperidin is used to treat the chronic phase.

Description

COMBINATION OF HESPERIDIN AND ANTACIDS IN THE TREATMENT OF GASTRO-ESOPHAGEAL REFLUX DISEASE (GERD)

FIELD OF THE INVENTION

The present invention relates to methods and compositions for alleviating heartburn. Specifically, the present invention relates to methods and compositions for alleviating the symptoms of acute and chronic gastro-esophageal reflux disorder. BACKGROUND

Gastro-Esophageal Reflux Disease (GERD) is the most common ailment in the upper gastro-intestinal tract; its cardinal feature and symptom is commonly known as "heartburn". Current therapies in GERD aim at suppressing gastric acid secretion or enhancing gastrointestinal motility to limit the exposure of the esophagus to acidic gastric contents. Frequent exposure of the esophageal mucosa to acid can trigger pain (often perceived as heartburn) and lead to erosions in the esophagus.

Medicinal therapies in treating gastric acid conditions include proton pump inhibitors such as omeprazole, pantoprazole, lansoprazole, and rabeprazole; histamine H2-receptor antagonists such as ranitidine, famotidine and cimetidine; prostaglandin analogues; sulphated polysaccharides, antacids, and prokinetics.

As an alternative to pharmacological treatments, melatonin seems effective in healing GERD and esophageal ulcer (de Souza Pereira R, J Pineal Res. 2006; 41(3):195-200; ibid 2006; 40(4):355-6.; Werbach MR, Altern Ther Health Med. 2008;14(4):54-8).

Another non-prescription approach in GERD is limonene, as disclosed in U.S. Pat. No. 6,420,435; in U.S. Pat. No. 2008248136 for the combination of limonene and antacids; and in U.S. Pat. No. 2008292693 for the combination of limonene and Aloe v. The effects of Rikkunshi-to, a traditional Japanese medicine, on the delay of gastric emptying has been studied by Kido T et al. J Pharmacol Sci. 2005, 98(2):161-7. The results suggest that the ability of Rikkunshi-to to ameliorate delayed gastric emptying is mainly due to these two ingredients: hesperidin and L-arginine.

However, in our experience hesperidin has been never applied in GERD and related conditions. It means that the sole action of this phytochemical was in need of an improvement so to fit with the request of an effective care for the aforesaid disorder. SUMMARY

The foregoing needs and other needs and objectives that will become apparent for the following description are achieved in the present invention, for treating both acute and chronic GERD. The present invention provides both a method and composition comprising an effective amount of hesperidin and at least one antacid, such as for example potassium bicarbonate and magnesium hydroxide.

The method provides orally administering to a mammal an effective amount of the composition. DETAILED DESCRIPTION

In accordance with the present invention it has now surprisingly been found out that a combination of hesperidin and antacid is effective to treat GERD and related conditions.

Hesperidin is a flavanone glycoside (flavonoid) of formula C₂₈H₃₄Oi₅ commonly found in citrus fruits, whose aglycone form is called hesperetin. Hesperidin is believed to play a role in plant defense but also contributes to the blood vessels integrity when added to the human nutrition. Various studies reveal positive biological properties of hesperidin, e.g. cholesterol and blood pressure reduction, protective effects against sepsis, decrease of bone density loss, and anti-inflammatory effects.

Hesperidin useful for our purpose include a purified material of at least 50% purity, preferably at 90%, 95% or 99% purity, e.g. as supplied by Luna Chemicals Co. Ltd, Hangzhou, China.

In one embodiment, the present invention comprises an dosage from 1 to 10 mg/kg of hesperidin, i.e. an amount between from 50 mg to 1,000 mg of hesperidin per serving of the nutritional composition. In an additional embodiment, the composition comprises from about 150 mg to about 500 mg of hesperidin per serving.

The term "antacid(s)" (AA) as used herein, refers to any compound which neutralize hydrochloric acid. In the frame of the present invention AA may be usefully added to exert a fast action on the gastric secretion. Antacid agents are fully described in the following publications: G.B. 925,001, to Fielding et al., May 1,1963; and Remington: The Science and Practice of Pharmacy, Vol. II, 19^th Edition, 886-890 (1995). Antacids are already used to address the acute symptoms of several digestion-related disorders such as duodenal and gastric ulcers, stress gastritis, GERD, pancreatic insufficiency, biliary reflux, and constipation.

Antacids useful herein include aluminium carbonate (A1₂(CO₃)₃), aluminium hydroxide (Al(OH)₃), aluminium phosphate (Al(PO₄)), aluminium hydroxy-carbonate

(AlCO₃OH), dihydroxy aluminium sodium carbonate (NaAlCO₃(OH)₂), dihydroxy aluminium amino acetate (Al(OH)₂GIy), dihydroxy aluminium aminoacetic acid

(AI(OH)₂NH₂CH₂COOH), calcium carbonate (CaCO₃), calcium phosphate (Ca₃(PO₄)₂), magnesium aluminate (Mg(A10₄)₂), magnesium alumino silicates (MgAlSiO_x), magnesium carbonate (MgCO₃), magnesium glycinate (MG(GIy)₂), magnesium hydroxide (Mg(OH)₂), magnesium oxide (MgO), magnesium trisilicate (Mg₂Si₃O₈), sodium bicarbonate (NaHCO₃), sodium carbonate (Na₂CO₃), potassium bicarbonate

(KHCO₃), sodium carbonate (K₂CO₃), and hydrated form thereof, and mixtures thereof.

In one embodiment, the present invention comprises analogous amount of magnesium hydroxide and potassium bicarbonate, or equivalent antacids.

In another embodiment, the invention comprises between from 100 mg to 1,500 mg of Mg(OH)₂ per serving of the composition. In an additional embodiment, the composition comprises from about 100 mg to about 500 mg Of Mg(OH)₂ per serving.

In another embodiment, the invention comprises between from 100 mg to 2,000 mg of KHCO₃ per serving of the composition. In an additional embodiment, the composition comprises from about 150 mg to about 1,500 mg OfKHCO₃ per serving.

The composition according to the invention may further comprise physiologically acceptable excipient(s). As used herein, a composition or compound is "physiologically acceptable" if it is suitable for use with humans without undue adverse side effects. The physiologically acceptable excipient can be chosen from the classes of diluents (such as Na/Ca carbonates, Na/Ca phosphates, and lactose), disintegrants (such as cornstarch and alginic acid), granulating agents, lubricants (such as Mg stearate, stearic acid, and talc), binders (such as starch and gelatine), thickeners (such as paraffin, waxes, and petrolatum), flavouring agents, colouring agents, preservatives, fillers, sweeteners, antioxidants, coating materials, and combinations thereof. As used herein, the term "nutritional" refers to dietetic supplements and food products, usually from natural sources, having nutritional/pharmaceutical benefits.

The nutritional/pharmaceutical preparation can be prepared by conventional compounding techniques. Examples of suitable unit dosage forms are coated tablets, capsules, coated pills. Powders, powder packets, granules, wafers, and the like, as well as liquid preparations should not be applied as these would cause high viscosity in the mouth and esophagus, rather than in the stomach. The material preferably is protected from early exposure to moisture as in a capsule. Alternatively tablets can be used, coated by sugar, compression or film coating to facilitate easy and quick swallowing and dissolution in the stomach. As an example materials like hydroxypropyl methylcellulose or hydroxypropyl cellulose can be used for this purpose.

The effective doses of hesperidin in combination with an antacid that are applied in the unit dosage form may be ascertained by conventional methods. The specific dosage level required for a particular subject will depend on a number of factors, including severity of GERD and the administration of other medicaments such as antacids, inhibitors of proton pumps, histamine H2-receptor antagonists, and NSAIDs.

It is preferred that the unit dosage form is administered before a meal, in particular from 90-20 minutes before the meal, preferably from 60-30 minutes before the meal. The actual dose an individual needs can be adjusted as a response to the amount of food or the individual's sensitivity to particular foods, beverages or spices.

In another aspect, the present invention is directed to a method for reducing the heartburn and/or GERD comprising administering an effective amount of hesperidin and an antacid.

In a further aspect, the invention encompasses the use of a preparation as described above for the preparation of a medicament for treating GERD.

In a further aspect, the invention encompasses the use of a nutritional/pharmaceutical preparation as described above for the preparation of a medicament for treating GERD related disease such as non-ulcer dyspepsia (NUD), functional dyspepsia, or to reduce temporary acid reflux symptoms due to pregnancy. The invention is elucidated by way of the following, non-restrictive examples. EXAMPLES

Example 1 - Hard gel capsules Ingredient quantity

Hesperidin 90% 300 mg Magnesium hydroxide 50 mg Potassium bicarbonate 200 mg Calcium carbonate 450 mg Excipients q.b. Example 2 - Tablets Ingredient quantity

Hesperidin 95% 150 mg Magnesium hydroxide Potassium bicarbonate 500 mg Sodium alginate 250 mg Excipients q.b.

Example 3 - Sachets Ingredient quantity

Hesperidin 90% 450 mg Magnesium hydroxide 100 mg Potassium bicarbonate 250 mg Aluminum hydroxide gel 400 mg 1-Arginine HCl 15 mg Excipients, sweeteners and flavours q.b. Example 4 - Sachets Ingredient quantity

Hesperidin 90% 250 mg Magnesium hydroxide 250 mg Potassium bicarbonate 700 mg Sodium alginate 250 mg Excipients, sweeteners and flavours q.b. Case history 1

A female subject suffering from regurgitation due to pregnancy is treated according to the present invention by administering a composition of invention in the sachet of Ex. 3 correspondence with the disorder occurrence, with prompt resolution of the symptoms. Case history 2

A human subject suffering from recalcitrant GERD is treated according to the present invention by administering a composition of invention in the sachets of Ex. 4 in correspondence with the disorder occurrence, with prompt resolution of the symptoms.

Claims

1. The use of hesperidin in combination with an antacid in the treatment of gastroesophageal reflux disease (GERD) and related conditions.

2. Use of hesperidin in combination with an antacid according to claim 1 for the manufacture of a nutritional/pharmaceutical composition for the treatment of heartburn, regurgitation, non-ulcer dyspepsia (NUD), diabetic gastroparesis and functional dyspepsia.

3. A nutritional/pharmaceutical composition comprising hesperidin in combination with an antacid for use in the treatment of GERD and related conditions.

4. Composition according to claim 3 comprising from about 0.05 g to about 0.5 g of hesperidin.

5. Composition according to claim 3 comprising from about 0.1 g to about 1.5 g of at least one antacid.

6. Composition according to claim 5 wherein the antacid is selected from the group consisting of aluminium, sodium, potassium, and calcium basic salt.

7. Composition according to claim 5 wherein the antacid is a potassium, calcium or magnesium alkaline salt.

8. Composition of any of claims 3 to 7, wherein said composition is provided to a mammal in need thereof in an acceptable oral dosage.

9. Composition of claims 8, wherein the acceptable oral dosage form is selected from the group consisting of tablets, caplets, sachets, capsules and soft-gel capsules.

10. Composition of claims 8 and 9, wherein said composition comprises at least one nutritional/pharmaceutical carrier, diluent or other food ingredients.

1 1. Composition of claim 10, wherein said ingredient is 1-arginine HCl.

12. Composition of claim 10, wherein said ingredient is a alginic acid or salt thereof.

13. A method for treating GERD, regurgitation and dyspepsia in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of hesperidin in combination with an antacid.