WO2010108494A1

WO2010108494A1 - Dayspepsia treatment with alginate

Info

Publication number: WO2010108494A1
Application number: PCT/DK2010/000036
Authority: WO
Inventors: Jens Steen Olsen; Finn Larsen
Original assignee: S-Biotek Holding Aps
Priority date: 2009-03-25
Filing date: 2010-03-25
Publication date: 2010-09-30

Abstract

The present invention relates to a pharmaceutical composition comprising alginate. The pharmaceutical composition is intended for the treatment of dyspepsia in a mammal, wherein the composition comprises an alkali metal alginate, the average molecular weight being 150,000 or below, for reaction with excess stomach acid thereby forming a protonated alginic acid and a salt comprising cross-linking polyvalent metal ions in an amount based on the weight of the alginate of less than 1 % by weight.

Description

DAYSPEPSIA TREATMENT WITH ALGINATE

Introduction

The present invention relates to a pharmaceutical composition for the treatment of dyspepsia in a mammal. In particular the invention relates to a pharmaceutical composition for the treatment dyspepsia caused by stomach acid.

Background art Dyspepsia, also known as indigestion, is a general term for the pain or discomfort a person can feel in the stomach and under the ribs, usually after eating or drinking e.g. alcoholic beverages or coffee, although similar symptoms can occur on an empty stomach.

Caused by stomach acid, indigestion can strike at any time and can amongst others also be due to excess of stomach acid. Indigestion may be a result of: eating too much or too quickly, gulping down fizzy drinks, eating rich or spicy food, drinking too much a\coho\_r irregular eating patterns, or stress.

Some people experiences indigestion a few times per year whilst others suffer every day with symptoms ranging from mild discomfort lasting a few minutes to longer lasting severe pain, sometimes accompanied by nausea and vomiting, which can go on for several hours.

The most common indigestion symptoms are: pain or discom- fort in the stomach and under the ribs, heartburn, feeling of being bloated or uncomfortably full after eating, rumbling or gurgling noises in the stomach, stomach cramps, a clenched or knotted feeling in the stomach, excessive burping or flatulence, trapped wind, and nausea or vomiting. The disorder is experienced by an increasing number of people in the developed world. At least one third of the population suffers from episodic dyspepsia. Dyspepsia is generally relieved by antacids. Antacids are normally over-the-counter products, which can be purchased at any pharmacy. Calcium carbonate is commonly used as the active ingredient in antacids. Some calcium-based antacids add other ingredients, such as magnesium or aluminium. Common over-the-counter antacids include: Turns, which is simply calcium carbonate; Rennie, which has magnesium added to ease the potential side effect of constipation with too much calcium; and Maalox, which has aluminium added to calcium carbonate and comes as liquid or tablet forms. Antacids are useful as self-medication in dyspeptic patients with mild or moderate heartburn.

The clinical efficacy of antacids is well documented (Hacki WH: Diskrepanz zwischen In-vivo und In-vitro Saurebindungs-kapazitaten von Magaldrat (Riopan), Gelusil und Maaloxan in Hacki WH, Conti F, Uehlinger M (eds): Magaldrat. Experimentelle und klinische Erfahrun- gen. Nϋmberg, Verlag Christian M. Silinsky, 1985, pp 57-61; Hϋrlimann S, Michel K, Inauen W, Halter F: Effect of Rennie Liquid versus Maalox Liquid on intragastric pH in a doubleblind, randomized, placebo- controlled, triple cross-over study in healthy volunteers. Am J Gastroenterol. 1996; 91: 1173-1180; Feldman M: Pros and cons of over-the- counter availability of histamine2-receptor antagonists. Arch Intern Med 1993; 153; 2415-2424; Netzer P, Brabetz-Hoefliger A, Bruendler R, Flogerzi B, Huesler J, Halter F: Comparison of the effect of the antacid Rennie versus low dose; and H2-receptor antagonists (ranitidine, famotidine) on intragastric acidity. Aliment Pharmacol Ther 1998; 12: 337- 342).

Antacids are fast-acting but also short-acting, so they are less useful for frequent or severe heartburn and do not work well as a pre- ventive measure. Acid blockers for heartburn and acid reflux are generally used for severe and chronic symptoms. These drugs work by blocking how much stomach acid is being produced. These acid blockers are not as fast-acting as antacids, but last longer and can be effective for several hours at a time. Over-the-counter acid blockers include Axid, Pepcid, Tagamet, and Zantac. These brands are also available in prescription strength if the more mild forms do not bring enough relief.

Acid blockers work by blocking a type of histamine produced by the stomach, which in turn blocks acid production. These histamine blockers are typically taken twice a day, 30 to 60 minutes before eating to be most effective. The acid blockers are best used as a preventive measure, rather than for sudden, fast relief of symptoms.

Drugs called proton pump inhibitors, or PPIs, shut down tiny proton pumps in the stomach that produce acid, lowering acid levels dramatically. They are often used when histamine blockers do not provide enough relief or when people have erosions in the oesophagus or other complications from GERD (Gastro Esophageal Reflux Disease). One proton pump inhibitor, Prilosec, is available over the counter in certain countries. Others, such as Aciphex, Nexium, Prevacid, Protonix, and stronger Prilosec may require a doctor's prescription depending on the regional requirements.

Reglan is another prescription drug that works to stop acid reflux by speeding up how quickly the stomach empties. Reglan strengthens the digestive contractions that move food through your oesophagus. Faster digestion means less heartburn.

Gaviscon, an over-the-counter heartburn treatment, works as both an antacid and a foam barrier where the oesophagus empties into the top of the stomach. When the tablet is swallowed or the liquid is ingested, the antacid neutralizes stomach acid and the foaming agent creates a physical barrier that helps prevent acid reflux.

Gaviscon is described in GB-A-1, 524, 740. The prior art document discloses pharmaceutical compositions for the suppression of gastric reflux comprising a low viscosity grade sodium alginate for which the viscosity of a 1% weight volume aqueous solution, when determined on a Brookfield viscometer model RVT using spindle No. 1 at 20 r.p.m. at 25 C is from 3 to 60 centipoise, from 0.16 to 2.60 parts by weight of sodium bicarbonate per part by weight of sodium alginate and from 0.10 to 1.04 parts by weight of calcium carbonate per part by weight of sodium alginate. The compositions may be administered orally in the form of a dry powder or aqueous suspension which may also contain a suspending agent and/or a preservative. The preparation reacts with gastric acid to form a raft on the contents of the stomach. A liquid formulation comprises an aqueous medium containing 2.5 to 8.0 % weight/volume of the low viscosity grade sodium alginate is disclosed. To suspend the calcium carbonate particles in the aqueous medium a suspending agent like acrylic polymer cross-linked with 1 % by weight allyl-sucrose is used.

US 4,140,760 discloses a pharmaceutical composition for the suppression of gastric reflux comprising a low viscosity grade sodium alginate with 0.16 to 2.60 parts by weight of sodium bicarbonate per part by weight of sodium alginate and 0.10 to 1.04 parts by weight of calcium carbonate per part by weight of sodium alginate. The composition is intended as a liquid preparation and forms a raft upon ingestion. An improved pourability is obtained GB 2298365 relating to a pharmaceutical liquid composition comprising potassium bicarbonate instead of sodium bicarbonate and at least 8% w/v sodium alginate. The composition obtains a viscosity which does not possess thickening problems even when stored at low temperatures. The viscosity of a 10% w/v alginate composition falls within the range 200 - 1500mPas. The prior art document describes the use of Protanal LFR 5/60 as the alginate of the composition. Salt of divalent metal ions, such as calcium carbonte, are generally included in the pharmaceutical composition in an amount of 8 to 32 g/100 g alganate in order to obtain a satisfying raft forma- tion.

US 6,395,307 also relates to a method for treating reflux oesophagitis as well as dyspepsia using alginates such as Protanal LFR 5/60. It further relates to the preparation of a pourable liquid sodium alginate composition. The composition preferably comprises alginates with a higher mannuronic acid residue to guluronic acid residue ratio and a sodium alginate content of 8 to 15% w/v. The composition further comprises an amount of bicarbonate. The inventors found that bicarbonate, e.g. sodium bicarbonate, is required in order to produce adequate carbon dioxide in the stomach to obtain a proper raft formation of the alginate.

GB-A-2324725 discloses a pharmaceutical composition suitable for forming a mucoadhesive lining in the gastrointestinal tract. It comprises an alginic acid or alginate salt with an M/G ratio of at least unity. The composition may be formulated as a liquid for treatment of reflux oesophagitis. In the examples 32 g calcium carbonate or 100 g of a 10% aluminium hydroxide gel is used per 100 g sodium alginate for the formation of the raft.

WO 01/87282 relates to the treatment of reflux oesophagitis using alginates to inhibit proteolytic enzymes. Especially the invention relates to inhibiting the proteolytic activity of pepsin and/or gastric juice. According to the invention, one or more sodium alginates with a preferred molecular weight of less than 40OkD are used. The one or more alginate may comprise Protonal LFR 5/60. The pharmaceutical composition may be in the form of a dry powder, which can be admixed with water. Furthermore, the concentration of the preparations in liquid form preferably contain in the amount of from 0.1 to 12% w/v of alginate. The viscosity of the solution for LFR 5/60 is measured to 6 mPas for a 1% solution. The composition further comprises a neutralising agent for neutralising gastric acid such as sodium hydroxide.

The composition preferably also comprises divalent or trivalent metal cations to strengthen the formation of a raft. The cations may be calcium or aluminium ions. According to the examples the composition contains in the amount of from 16 to 6Og of calcium carbonate per lOOg alginate.

Gaviscone and similar products exercise its effect by dissolving the solid calcium carbonate salt in the stomach under the influence of the acid gastric fluid. The increasing calcium concentration will stimulate the alginate gellation as calcium ions and the polysaccharides form a rigid matrix. Furthermore, the dissolving of calcium carbonate and sodium bicarbonate will liberate CO₂ gas which will be entrapped in the alginate matrix thereby forming foam.

The rigid matrix is formed when calcium ions are complexed with homogeneous blocks of guluronic acid in alginate to form an "egg box" structure. Control of the calcium concentration through out the gelling process is crucial for a uniform gel to evolve. If the initial concentration of calcium is too high the polysaccharide will precipitate rather than forming a gel. The conditions may be difficult to control in the stomach due to interpersonal differences and pre- or post-eaten food products. Calcium-induced gelation implies that a high amount of solid calcium carbonate must be present in the product before consumption.

Apart from the inconvenience of the consumption an inhomoge- neous product, Gaviscon and products derived thereof furthermore have the disadvantage that the consumer may not obtain the calcium salt in a proper dose for an optimal gelation to progress. More importantly, the sodium alginate salt will not be available react with the acid present in the stomach because it is occupied with calcium ions in the "egg box" structure. US 2007/0281015 describes an antacid pharmaceutical composition for the rapid and prolonged neutralization of gastric acidity with mucosa-protecting activity. The pharmaceutical is intended as a liquid preparation for oral ingestion. It includes at least 30% of sodium alginate, an antacid soluble agent, and an inhibitor of proton pump, such as omeprazol. The sodium alginate used in the composition has a molecular weight in the range between 20,000 and 200,000. The antacid soluble agent of choice is sodium bicarbonate, which neutralizes hyperacidity acting directly in the digestive tract, the alginate form a viscous suspension or gel after it has entered the stomach environment exerting protecting activity over gastric mucosa, and the inhibitor of a proton pump acts by selectively blocking the H⁺/K⁺-ATPase enzyme of stomach parietal cells.

It is the object of the present invention to provide a pharmaceutical composition which avoids some or all of the disadvantages of the prior art. Notably, the invention is aimed at providing a pharmaceutical composition, which has the ability to raise the pH of the stomach content and maintain the pH at a certain level for a prolonged period of time.

Disclosure of the invention

The present invention suggests a pharmaceutical composition for the treatment of dyspepsia caused by stomach acid in a mammal, wherein the composition comprises an alkali metal alginate, the average molecular weight being 150,000 or below, for reaction with excess stomach acid thereby forming alginic acid which is dispersed in the content of the stomach and a salt comprising cross-linking polyvalent metal ions in an amount based on the weight of the alginate of less than 1 % by weight. For the purposes of the present invention, dyspepsia includes any medical condition that is caused by gastric acid. In certain aspects of the invention dyspepsia includes gastro-oesophageal reflux disease, reflux oesophagitis, gastritis, dyspepsia, peptic ulceration and/or Barretts oesophagus. Alginate is soluble in water and is activated by acid causing the pharmaceutical composition to become a gel in the stomach due to the low pH value present here. During the gelling process the gastric acid (H⁺) is consumed, thus resulting in an increase of pH. The general reaction between the alkali metal carboxylic acid groups of the alkali metal alginate and stomach is illustrated by the reaction scheme below.

(Alginate backbone)-COO^"M⁺ + H⁺ -^ (Alginate backbone)-COOH + M⁺

For illustrative purposes only a single carboxylic group is shown on the alginate backbone. The skilled person is aware that a multitude of such groups are present on the backbone. In the present claims and description (Alginate backbone)-COO^'M⁺ is referred to as the alkali metal carboxylic acid group, while such groups when at least partly reacted with acid to form (Alginate backbone)-COOH is referred to as alginic acid.

The rise in pH relieves the symptoms of dyspepsia. According to the invention it has surprisingly been shown that alkali metal alginate possesses a relatively high buffering capacity, which is exerted over a prolonged time period, without the necessity of including an inhibitor of a proton pump, such as omeprazol, lansoprazol, etc. or an antacid like calcium or magnesium carbonates, sodium bicarbonate, aluminium hydroxide, aluminium phosphate etc. Thus in a certain embodiment of the invention, the symptoms of dyspeptia caused by excess stomach acid is relieved for 15 minutes or more, such a 25 minutes, preferably 30 minutes or more.

The absence of vast amounts of cross-linking polyvalent ions, such as calcium and aluminium, makes more groups available for reaction with the stomach acid, thereby enabling the alginate to act as an antacid. In many prior art disclosures, alginates have been prevented from acting as antacids due to the cross-linking with polyvalent ions. When the alginate has reacted with the stomach acid it generally becomes dispersed in the stomach content rather than forming a raft floating on the surface of the stomach content.

While it is not necessary to obtain a fast initial acid scavenging effect it may in some instances be desirable that the pharmaceutical composition comprises further compounds for the initial reaction with stomach acid. Such compounds are generally salts that produce a weak alka- line pH when dissolved in distilled water. Specific examples include Na- HCO₃, Na₂CO₃, KHCO₃, K₂CO₃, NaH₂PO₄, Na₂HPO₄, KH₂PO₄, K₂HPO₄, Mg(OH)₂, and any combinations thereof. In general, however, the alkali metal alginate accounts for more than 70% of the increase in the pH of the stomach content. In a certain embodiment the alkali metal alginate account for 80% or more, such as 90% or more , preferably 99% or more of the increase in pH of the stomach content. The dispersion of the sodium alginate in the stomach content results in a uniform action of the acid scavenging effect.

The relatively low molecular weight of the alkali metal alginate provides for the possibility of obtaining a relatively high concentration of the alginate in a liquid pharmaceutical composition. A high concentration makes it possible to ingest relatively large amounts of the acid absorbing alginate in a small amount of water. Furthermore, the relatively low viscosity ensures patient compatibility. In certain applications of the invention polyvalent ions like calcium and aluminium are not present in any substantial amount. Since the alginate forms a gel under the influence of gastric acid alone, the reverse action occurs easily in the body, i.e. when the alginate gel enters the intestine and the environment becomes closer to neutral pH, the gel destabilises and returns to the original viscosity. Thus, the pharmaceutical composition of the invention is easily cleared from the body. This is contrary to prior art compositions in which the gel is formed by the influence of the calcium ion. The prior art compositions remains, at least to a certain extent in a gelled stated when passed into the intestine.

Alginate is, according to the invention, used as an alkali metal salt, such as sodium, lithium or potassium alginate. Sodium alginate is commonly preferred due to ease of solubility and inclusion hereof on the approved list (E401). Hence, sodium alginate is approved as an additive to foods. It is widely used in foods where a thickening of the food in question is desired. Usually, this involves a gelled sodium alginate in contrast to this invention, wherein an inactivated, sodium alginate is used, which gels upon a lowering of the pH value to the acidity of the stomach. Sodium alginate can be obtained in pharmaceutical and food approved varieties. Sodium alginate originates in seaweed, especially brown seaweed from the Norwegian Sea. A particular preferred alginate has a viscosity below 300 cP (0.3 Pas) in a 5 % aqueous solution measured at 20⁰C on a Bohlin C-Vor rheometer (Malvern Instruments Ltd., UK). Since aqueous solutions of alginates cannot be expected to be Newtonian the viscosity experiments was performed at different shear rates between 0.1 and 90 s^"1 with 15 time registrations during 5 min. Suitably the alginate has a viscosity in a 5 % aqueous solution not exceeding 0.2 Pas, preferably 0.1 Pas.

A suitable sodium alginate is available under the name of Sa- tialgine SATIALGINE XPU - LVE500 from Cargill as a test compound. Another suitable sodium alginate is Protanal LFR 5/60 from FMC Bioply- mer AS. This alginate is processed from the plant Laminaria hyperborean and has a viscosity in a 1 % aqueous solution of 6 mPas, a molecular weight of around 40,000 D, an M/G of around 0.64. Initial tests have shown that SATIALGINE XPU - LVE500 and Protanal LFR 5/60 possesses similar capabilities to react with acid. Other alginates of interest are SATIALGINE XPU - LVG500 and Satialgine S20 from Cargill and Protanal LFlOL from FMC Biopolymer AS. Alginates are polyuronides made up of a sequence of two hex- uronic acids: β-D-mannuronic acid and α-L-guluronic acid. Usually, the two sugars are not distributed at random along the chain, but sometimes form blocks of up to twenty units. The proportion of these blocks depends on the species of seaweed and whether the stripe of the blade of the seaweed is used. Less important factors are the degree of maturity, age and where the material was harvested. The ratio of mannuronic to guluronic acid (M/G) in an alginate can vary from 0.4 to 1.6. When the gelling is induced by calcium ions the gelling properties increase with higher content of guluronic acid. The present invention is, however, not particular dependent on the M/G ratio since the gelling of the alginate in the absence of calcium is caused by hydration of the polymer. In a certain aspect an M/G ratio below 1.0 is useful, for example below 0.8, such as below 0.7. It is presently believed that the effect on dyspepsia is due to the depletion of acid in the stomach subsequently due to reaction with the alginate. The reaction of the gastric acid with alginate results in an increase of the pH value of above a critical value, which alleviates the discomfort of dyspepsia. The gelling of the alginate if ingested in a suffi- cient amount creates a satiety sensation for the patient resulting in less intake of food. The latter effect is especially importance when the dyspepsia is caused or influenced by obesity or eating habits.

The pharmaceutical composition according to the invention may be formulated in any suitable form, e.g. a solid form, liquid form or an effervescent form.

A pharmaceutical composition in solid form may contain conventional excipients in addition to the alkali metal alginate. Conventional excipients and methods for producing a solid form of the pharmaceutical composition may be found in the European Pharmacopoeia. The pharmaceutical composition of the invention may contain a minor amount of a salt comprising a cross-linking polyvalent metal ion to support the gelation, if desired, when contacted with the gastric juice. The cross-linking polyvalent metal ion may be ions of calcium and aluminium and the salt may as an example be selected among calcium carbonate, aluminium carbonate and aluminium hydroxide. The salt of comprising the cross-linking polyvalent metal ion is usually present in an amount of less than 1% weight, preferably less than 0.1 %weight, based on the weight of the alginate. The salt is generally insoluble in the pharmaceutical composition but is suitable highly dissolvable at a pH present in the stomach. In an aspect of the invention the salt provides less than 200 ppm polyvalent metal ions when the pH of the pharmaceutical composition is changed to about pH = 2. In a preferred aspect the amount of insoluble calcium salt in the pharmaceutical composition provides less than 50 ppm dissolved calcium ions when the pH is changed to about pH = 2.

In a preferred aspect, however, the liquid pharmaceutical composition of the invention does not contain an added salt comprising a cross-linking polyvalent metal ion, such as a calcium salt, insoluble in the formulation, said salt being capable of dissolving at a pH present in the stomach. Insignificant amounts of calcium salts may be present in the tap water used for preparation of the pharmaceutical composition. The insoluble calcium salts may be salts formed by the combination of the calcium cation with the carbonate anion or the phosphate anion. Specific examples of calcium salts regarded as insoluble in the present context include CaHPO₄ and CaCO₃. In a preferred embodiment at least 70% of the alkali metal carboxylic acid groups of the alkali metal alginate are available for reaction with the stomach acid, i.e. is not reacted with a cross-linking polyvalent metal ion. In a further preferred em- bodiment, 80% or more, such as 90% or more of the alkali metal carboxylic acid groups of the alkali metal alginate is reacted with the stomach acid

To obtain a sufficiently low viscosity of a liquid pharmaceutical composition the average molecular weight of the alginate is usually not above 150,000 Daltons, more preferred not above 100,000 Daltons, such as not above 60,000 Daltons. In general, the average molecular weight is above 10,000 Daltons, preferably above 25,000 Daltons. In a solid pharmaceutical composition an alginate in the above molecular weight range is also preferred due to the ability easy to dissolve and disperse in the stomach content.

Sodium alginate can be formulated in any aqueous solution to obtain a liquid pharmaceutical composition, including pure water. Depending on the quality of the alginate the taste may be of significance. In liquids such as soft drinks, squash or juice the sodium alginate can be masked to an extent where it essentially cannot be tasted or felt. The pharmaceutical composition of the invention may, besides water and alginate, comprise pharmaceutically acceptable components. In a certain embodiment of the invention, the pharmaceutical composition is in the form of a chewable soft gelatine capsule with a fill an aqueous solution containing the alginate and optionally commonly used pharmaceutically acceptable adjuvants. In a further embodiment of the invention, the pharmaceutically composition is formulated as a tablet or pill to be ingested directly or to be pre-dissolved in a minor amount of water prior to consumption.

The liquid pharmaceutical composition according to this invention can have any pH value not causing gelling of the alginate. Thus, it is considered essential that the metallic cation, i.e. the sodium ion, is not dissociated from the carboxylic acid group of mannuronic acid and guluronic acid of the alginate. The pH value, at which the alginate gels, is dependent upon the cation, origin and pre-treatment. The pH value is, in an aspect of the related invention, above 4, suitably 5 or above.

The concentration of sodium alginate in the pharmaceutical composition of the present invention is adjusted to meet the result de- sired. In a ready-to-use liquid preparation the alginate is usually present in a concentration above 50, such as above 9Og per kg. The maximum concentration is determined by the saturation point for the solubility of the alginate in the liquid. Usually, the concentration does not exceed 20Og per kg, such as 150 g per kg pharmaceutical composition. In an- other embodiment the alginate is present as a concentration intended for addition to food, including beverages, before consumption. The concentrate may be solid.

In an aspect of the invention, insoluble calcium salts are usually not present in the pharmaceutical composition in substantial amounts. In aspects of the invention in which insoluble calcium salts are present, though, the amount thereof is suitably less than 1 % weight based on the weight of the alginate. Preferably the amount of calcium salts is less than 0.1 % weight based on the weight of the alginate. Besides alginate, the liquid pharmaceutical composition of the present invention can furthermore contain a mono- or disaccharide, e.g. saccharose, glucose or invert sugar, as a mono- or disaccharide improves the solubility of alginate. The concentration of mono- or disaccharide is usually chosen depending on the concentration of alginate. According to an aspect of the invention the concentration of mono- or disaccharide is in the range of 0.1 to 60 g per kg of the pharmaceutical composition, suitably 10 to 40 g per kg of the pharmaceutical composition.

The alginates used in the present invention are characterised by a certain increase in the viscosity when the pH is decreased. In a certain aspect of the invention the viscosity of the pharmaceutical composition increased 20 times or more when the pH is lowered from around pH 7 to pH 2. In certain aspect, the increase of the viscosity is 50 times or more, such as 100 times or more. However, it is generally desired that the viscosity at low pH does not exceeds a certain threshold because it presently is believed that a too dense gel will cause an unpleasant feeling by the person ingesting the pharmaceutical composition. Thus, is may be desired ,to obtain an increase in viscosity of no more than 100 times when the pH is lowered from around pH 7 to pH 2, such an in- crease in viscosity of no more than 50 times.

Examples

Example 1 SATIALGINE XPU - LVE500 was obtained from Cargill as a powder.

The powder was dissolved in water in a concentration of 5 %(W/V). The viscosity was measured using a Bohlin C-Vor rheometer (Malvern Instruments Ltd., UK). Since aqueous solutions of alginates cannot be expected to be Newtonian the viscosity experiments was performed at dif- ferent shear rates between 0.1 and 90 s^"1 with 15 time registrations during 5 min. The viscosity was measured as 0.031 Pas.

Example 2 An aqueous composition of 6%(W/V) SATIALGINE XPU - LVE500 was compared with commercially available Rennie (mixture of calcium carbonate and magnesium carbonate) in a titration test.

The stock alginate solution was prepared by dissolving 6Og SATIALGINE XPU - LVE500 in 1.0 I 0.45 μm MiIIi-Q H₂O. 100ml of the stock solution was used in the test. The solution of the Rennie tablet was prepared by dissolving a 500mg Rennie tablet in 100ml 0.45 μm MiIIi-Q H₂O.

The alginate solution and the Rennie solution were titrated using

IM HCI. When 15 ml IM HCI was added to the alginate solution a pH of 3.0 was reached. The same pH was reached for the Rennie solution when 14 ml 1 M HCI was added. It is concluded that both solutions have a similar capability to take up acid.

Example 3 Acid neutralizing effect of SATIALGINE XPU - LVE500

Study aim: Comparison of one dose of 100ml aqueous 10 %(W/V) SATIALGINE XPU - LVE500 to placebo with respect to acid inhibition

Methods: Open, randomised, placebo-contolled, cross-over study in 6 healthy subjects: Comparison of one dose of SATIALGINE XPU - LVE500 to placebo.

Inclusion criteria: Healthy subjects aged 18 to 40 years, Helicobacter pylori negative based on a ¹³C-Urea-breath test.

Parameter: Intragastric acidity over 3 hours.

Primary endpoint: The primary endpoint of the study is the time lag be- fore an intragastric pH > 3.0 is reached for a minimum of 10 consecutive min after drug intake.

Secondary endpoints: Secondary endpoints will include (1) peak pH, (2) percentage of time with pH > 3.0, (3) the time lag before the peak pH is reached after the initial 10-min period at pH > 3.0, (4) median pH during the first 60 min after drug administration and (5) integration of time period with pH > 3.0 after drug administration. The safety will be evaluated by assessment of adverse events.

The aim of the present study is to compare a new preparation, SA- TIALGINE XPU - LVE500 with respect to its gastric acid inhibitory potency with a special interest in the time lag before intragastric acidity reaches a pH > 3.0. This acidity value threshold is considered for the ef- ficacy of gastric antisecretory drugs.

2. Material and Methods: The study was conducted as an open, randomised, placebo-controlled, cross-over study. The aim is to compare the activities of the antacid test Compound, SATIALGINE XPU - LVE500, at one dose to placebo with respect to various intragastric acidity parameters. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and the international principles of Good Clinical Practice.

Six healthy male, H. pylori-negative, subjects participated in this study. They all had clinically normal physical findings, no history of hepatic or significant gastrointestinal disease and take no regular medication. A full medical history will be taken and a physical examination will be performed.

Each subject underwent 2 different treatments after an overnight fast of at least 10 h. On 2 different days and in random order, each study participant received eitherone dose of test Compound, SATIALGINE XPU - LVE500, or no drug (control treatment). The treatments were separated by a wash-out phase of at least 4 days.

For the intragastric pH monitoring a glass electrode (Medical Instruments Corporation, Solothurn, Switzerland) was used which is attached to a Digitrapper Mark III GastrograpH (Medical Instruments Corporation). The electrode was calibrated in buffer solutions at pH 7.0 and 1.7 before and after each recording. The pH electrode was inserted transna- sally into the gastric body by a skilled person at the study site. The position of the pH electrode in the stomach was 8-10 cm below the ga- stro-oesophageal junction, which was recognised by an abrupt drop in pH from neutral (oesophageal pH 5-7) to acid (intragastric pH < 2). Sudden changes in recorded pH can be caused by differences in intensity of contact between electrode tip and the gastric mucosa (Fimmel CJ, Etienne A, Cilluffo T, et al: Longterm ambulatory gastric pH monitoring: validation of a new method and effect of H2-antagonists. Gastroenterology 1985; 88: 1842-1851). Variations in the intensity of contact can also be caused by gastric motility and changes in body position. In order to reduce the incidence of these artifacts, all subjects was asked to remain in an upright position.

Measurements of the intragastric pH was continued for a basal period of 60 min. During this period, the intragastric pH had to be < 3.0 for at least 50% of the recording time. If this was not the case, the entire pH measurement has to be repeated. After the basal period, one dose 1 of 10 %weight aqueous SATIALGINE XPU - LVE500, or placebo was given according to the randomisation scheme and the pH monitoring was continue for the following 2 h.

Due to the high variability of intragastric pH measurements, statistical analysis was done by non-parametric methods, which do not require assumptions on the distribution of data. Parameters were compared between the two treatment groups by two-sided Wilcoxon signed ranks test. The level of significance was P = 0.05. All statistical comparisons were done using SPSS for Windows software (version 17.0). Results

Intragastric pH was comparable between the treatment groups before drug administration (at baseline) :

Table 1 :

Median pH Basal

Alginate Placebo

Subject 1 1.40 1.10

Subject 2 2.00 1.70

Subject 3 1.70 2.30

Subject 4 1.50 0.90

Subject 5 NA NA

Subject 6 1.10 1.10

Mean 1.54 1.42

Median 1.50 1.10

STD 0.34 0.58

SEM 0.15 0.26

Wilcoxon Signed Ranks test P = 0.75

Therefore, treatment effects could be compared between the treatments. After alginate administration, there was a significant rise in intragastric pH. Increase in intragastric pH was statistically significant for the first 30 min as shown in Figure 1 and Figure 2. After 2-3 min the pH climbed above pH 3, indication an almost instant relief. When the first hour after administration was considered, this rise was statistically significant (p = 0.043): Table 2:

Median pH 60 - 90 min

Alginate Placebo

Subject 1 3.20 1.00

Subject 2 4.40 1.90

Subject 3 4.00 2.60

Subject 4 2.50 1.40

Subject 5 NA NA

Subject 6 1.40 1.00

Mean 3.10 1.58

Median 3.20 1.40

STD 1.20 0.68

SEM 0.54 0.30

Wilcoxon P= 0.043

Signed

Ranks test

The time of onset (defined as first time-point after administration, where intragastric pH raised above 3 for at least 1 min) was although strikingly different only borderline significantly different (P = 0.08). This was due to the use of the non-parametric test and the low number of evaluable subjects.

Table 3:

Time of Onset (min after

Application)

Alginate Placebo

Subject 1 0.67 60.00

Subject 2 9.80 2.47

Subject 3 6.67 60.00

Subject 4 0.60 60.00

Subject 5 NA NA

Subject 6 5.47 60.00

Mean 4.64 48.49

Median 5.47 60.00

STD 3.98 25.73

SEM 1.78 11.51

Wilcoxon Signed P= 0.08 Ranks test

NA = Not applicable due to no significant rise in intragastric pH within the first 30 min after drug administration.

The pH distribution curve in Figure 3 shows the percent time (60 min) after drug administration, where the intragastric pH was higher than the corresponding pH on the abscissa. This distribution was significantly different between the treatments.

The percentage of time after drug administration, where the pH was higher than the corresponding pH on the placebo was tested statistically for three pH values (pH 3, 4, and 5): Table 4:

Percent time above pH 3

Alginate Placebo

Subject 27.33 0.00

1

Subject 46.22 21.78

2

Subject 53.00 0.33

3

Subject 13.44 0.67

4

Subject NA NA

5

Subject 13.11 0.00

6

Mean 30.62 4.56

Median 27.33 0.33

STD 18.42 9.63

SEM 8.24 4.31

Wilco- P= 0.043 xon

Signed

Ranks test

On average, 30.62 % of the first hour after administration, pH was higher than 3 after alginate administration, whereas after placebo administration this was only the case in 5.56% of the time. This difference was statistically significant (P = 0.043). Table 5:

Percent time above pH 4

Alginate Placebo Subject 15.33 0.00

1

Subject 38.33 15.22

2

Subject 23.11 0.33

3

Subject 2.33 0.00

4

Subject NA NA

5

Subject 9.44 0.00

6

Mean 17.71 3.11

Median 15.33 0.00

STD 13.83 6.77

SEM 6.18 3.03

Wilcox- P= 0.043 on

Signed

Ranks test

On average, 17.71 % of the first hour after administration, pH was higher than 4 after alginate administration, whereas after placebo administration this was only the case in 3.11% of the time. This difference was statistically significant (P = 0.043). Table 6:

Percent time above pH 5

Alginate Placebo

Subject 1 5.56 0.00

Subject 2 28.67 10.22

Subject 3 2.00 0.33

Subject 4 0.44 0.00

Subject 5 NA NA

Subject 6 6.11 0.00

Mean 8.56 2.11

Median 5.56 0.00

STD 11.49 4.54

SEM 5.14 2.03

Wilcoxon P= 0.043

Signed

Ranks test

On average, 8.56% of the first hour after administration, pH was higher than 5 after alginate administration, whereas after placebo administra- tion this was only the case in 2.11% of the time. This difference was statistically significant (P = 0.043).

Conclusion: In this pilot study, in healthy males, it has been demonstrated that the sodium alginate SATIALGINE XPU-LVE 500 from Cargill has a marked effect on gastric acidity. A statistical significant effect on time of onset, increase in pH and duration of effect was observed when compared to placebo (water).

Claims

2.3P A T E N T C L A I M S

1. A pharmaceutical composition for the treatment of dyspepsia caused by stomach acid in a mammal, wherein the composition comprises an alkali metal alginate, the average molecular weight being 150,000 or below, for reaction with excess stomach acid thereby forming alginic acid and a salt comprising cross-linking polyvalent metal ions in an amount based on the weight of the alginate of less than 1 % by weight.

2. The pharmaceutical composition according to claim 1, wherein 70 % of the alkali metal carboxylϊc acid groups of the alkali metal alginate is reacted with the stomach acid.

3. The pharmaceutical composition according to claim 1 or claim 2, wherein the reaction between the alkali metal alginate and the stomach acid takes place during a time period of 15 min or more.

4. The pharmaceutical composition according to any of the claims 1 to 3, wherein the alkali metal alginate account for more than 70% of the increase in the pH of the stomach content.

5. The pharmaceutical composition according to any of the claims 1 to 4, wherein the average molecular weight is 100,000 or be- low, preferable 60,000 or below.

6. The pharmaceutical composition according to any of the claims 1 to 5, wherein the pharmaceutical composition is a liquid composition having a concentration of the alginate in the liquid composition of 7 % (W/V) or more.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the alginate has a viscosity in a 5 % aqueous solution not exceeding 0.3 Pas.

8. The pharmaceutical composition according to any of the claims 1 to 7, wherein the pharmaceutical composition is a liquid and the pH value is 4 or above.

9. The pharmaceutical composition according to any of the claims 1 to 8, wherein the salt comprising cross-linking polyvalent metal ions is present in an amount based on the weight of the alginate of less than 0.1 % weight based on the weight of the alginate.

10. The pharmaceutical composition according to any of the claims 1 to 9, wherein the amount of alginate in a liquid composition is selected in the range of 50 to 200 g per kg of the pharmaceutical composition, for example in the range of 90 to 150 g per kg of the pharma- ceutical composition.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein it is present in a concentrated state intended for use as an additive to articles of food, beverages included, before consumption.

12. Use of a pharmaceutical composition according to any of the claims 1 to 11, for the treatment of dyspepsia caused by excess stomach acid in a mammal.