DK169122B1

DK169122B1 - Antacid preparation

Info

Publication number: DK169122B1
Application number: DK22993A
Authority: DK
Inventors: J Rgen Foldager; Helle Toftkjaer; Rnaes Kim Kj
Original assignee: Ferrosan Int As
Priority date: 1987-04-08
Filing date: 1993-03-01
Publication date: 1994-08-22
Also published as: DK22993A; DK22993D0

Description

i DK 169122 B1and DK 169122 B1

Den foreliggende opfindelse angår et antacidpræparat.The present invention relates to an antacid composition.

Øvre abdominal dyspepsi er symptomatisk for en række sygdomme såsom ulcera, galdelidelser, pancreatitis og gastroøsofageal reflux. De symptomer (halsbrand, regurgitation og epigastrisk smerte), der ofte 5 er forbundet med sådanne lidelser, kan imidlertid også forekomme, uden at de tilsyneladende kan tilskrives nogen specifikke kliniske tilstande, der observeres ved røntgen eller endoskopiske analyser.Upper abdominal dyspepsia is symptomatic of a variety of diseases such as ulcers, bile disorders, pancreatitis and gastroesophageal reflux. However, the symptoms (heartburn, regurgitation and epigastric pain) often associated with such disorders may also occur without apparently being attributable to any specific clinical conditions observed by X-ray or endoscopic analyzes.

Symptomerne er således meget almindelige, i hvert fald en gang imellem, selv hos ellers sunde personer. Det formodes, at ca. 50-60% af 10 den voksne befolkning i USA lider af en eller anden form for akut øvre gastrointestinal lidelse. Kort- eller langtidsanvendelse af antacida er derfor vidt udbredt.The symptoms are thus very common, at least once in a while, even in otherwise healthy people. It is assumed that approx. 50-60% of the 10 adult population in the United States suffers from some form of acute upper gastrointestinal disorder. Short- or long-term use of antacids is therefore widespread.

Den antacide virkning af de fleste antacidpræparater, som for tiden er i brug, ligger i deres evne til at neutralisere mavesyrer, hvilket 15 medfører en forøget pH-værdi i maveindholdet. Sådanne konventionelle antacidas syreneutraliserende virkning vides at være kortvarig in vivo, hvilket skyldes to hovedårsager: den normale mavetømningshastighed, som får præparatet til at blive overført til tarmene, før dets syreneutraliserende og bufrende evner er opbrugt, og "syre-20 rebound" eller forøget syreudskillelse, som induceres af forøget afgivelse af gastrin fra de såkaldte G-celler i antrum, som er pH-følsomme, idet den forøgede produktion af gastrin sker ved en pH i maveindholdet på ca. 4-5 eller derover. Af disse grunde har maveind-holdets surhedsgrad sædvanligvis nået sit normale niveau 1-2 timer 25 efter indtagelse af antacidumet, således at et doseringsskema, der omfatter indtagelse af gentagne antacidumdoser, kan være påkrævet, især til langtidsbehandling af gastriske lidelser såsom ulcera, men ikke til kortvarig lindring af dyspepsi.The antacid effect of most antacids currently in use lies in their ability to neutralize stomach acids, leading to an increased pH in the stomach contents. The acid neutralizing effect of such conventional antacids is known to be short-lived in vivo, due to two main causes: the normal rate of gastric emptying which causes the preparation to be transferred to the intestines before its acid neutralizing and buffering abilities are exhausted, and "acid rebound" or increased acid secretion. , which is induced by increased release of gastrin from the so-called G-cells in the antrum, which are pH-sensitive, the increased production of gastrin taking place at a pH in the stomach content of approx. 4-5 or more. For these reasons, the acidity of the stomach contents has usually reached its normal level 1-2 hours 25 after ingestion of the antacid, so that a dosing schedule comprising repeated antacid dose may be required, especially for long-term treatment of gastric disorders such as ulcers, but not for short-term relief of dyspepsia.

De for tiden anvendte antacida indeholder sædvanligvis ét eller flere 30 alkalimetal- eller jordalkalimetalsalte, aluminiumsalte eller - mindre sædvanligt - vismutsalte som syreneutraliserende midler. De mest almindeligt anvendte mineralsalte er natriumhydrogencarbonat, calci-umcarbonat, aluminiumsalte eller magnesiumsalte.The antacids currently in use usually contain one or more alkali metal or alkaline earth metal salts, aluminum salts or - less commonly - bismuth salts as antacids. The most commonly used mineral salts are sodium bicarbonate, calcium carbonate, aluminum salts or magnesium salts.

DK 169122 B1 2DK 169122 B1 2

Natriumhydrogencarbonat er kendt som et kraftigt, effektivt og hurtigtvirkende antacidum, som imidlertid kun har en kortvarig virkning.Sodium bicarbonate is known as a powerful, effective and fast-acting antacid, which, however, has only a short-term effect.

Det er et systemisk antacidum, som ikke anbefales til langvarig anvendelse eller i store doser, da systemisk absorption af natrium-5 ionen i store mængder kan forårsage alkalose, som er karakteriseret ved forhøjede niveauer af carbondioxid og en forøget pH i plasmaet. Symptomer på alkalose omfatter hovedpine, sindsforstyrrelse og ano-rexi.It is a systemic antacid that is not recommended for long-term use or in large doses, as systemic absorption of sodium ions in large amounts can cause alkalosis, which is characterized by elevated levels of carbon dioxide and an increased pH in the plasma. Symptoms of alkalosis include headache, mental disorder and anorexia.

Calciumcarbonat, der er et ikke-systemisk gastrisk antacidum, vides 10 at forårsage hurtig, langvarig og effektiv neutralisering af mave-syre, men anbefales ikke som antacidum, primært på grund af dets "syre-rebound"-virkning. Undersøgelser har vist, at oral administration af en isotonisk calciumchloridopløsning medfører forøget mave-syreudskillelse, både hos sunde personer og især hos ulcuspatienter 15 (50-75%). I en anden undersøgelse har frit calcium i maven vist sig at frigive gastrin, som igen inducerer dannelse af mavesyre som beskrevet ovenfor. Bortset fra syre-rebound kan det bevirke hypercal-cæmi og forstoppelse.Calcium carbonate, which is a non-systemic gastric antacid, is known to cause rapid, long-lasting and effective neutralization of stomach acid, but is not recommended as an antacid, primarily due to its "acid-rebound" effect. Studies have shown that oral administration of an isotonic calcium chloride solution results in increased gastric acid secretion, both in healthy individuals and especially in ulcer patients 15 (50-75%). In another study, free calcium in the stomach has been shown to release gastrin, which in turn induces the formation of stomach acid as described above. Aside from acid rebound, it can cause hypercalcemia and constipation.

De mest almindeligt anvendte aluminiumsalte er hydroxidet, carbonatet 20 eller phosphatet, først og fremmest hydroxidet. Dets syreneutraliserende evne er mindre end andre konventionelle antacidas, og det kan bevirke forstoppelse. Aluminiumsalte kombineres derfor ofte med mag-nesiumsalte såsom oxidet, hydroxidet, carbonatet og trisilikatet, som har en større syreneutraliserende evne end aluminiumsaltene, men 25 som også kan medføre diarré. I kombinationspræparater afbalanceres de to komponenter for at opveje hinandens virkning på de gastrointesti-nale funktioner. En kombination af aluminium- og magnesiumhydroxidgeler er til stede i mange kommercielt tilgængelige antacida. For nylig er aluminium blevet mistænkt for at bidrage til udvikling af 30 præsenil demens (Alzheimers sygdom), hvorfor dets anvendelse som antacidum måske bør frarådes.The most commonly used aluminum salts are the hydroxide, carbonate 20 or phosphate, primarily the hydroxide. Its antacid ability is less than other conventional antacids and it can cause constipation. Aluminum salts are therefore often combined with magnesium salts such as the oxide, hydroxide, carbonate and trisilicate, which have a greater acid neutralizing ability than the aluminum salts, but which can also cause diarrhea. In combination preparations, the two components are balanced to offset each other's effect on the gastrointestinal functions. A combination of aluminum and magnesium hydroxide gels is present in many commercially available antacids. Recently, aluminum has been suspected of contributing to the development of 30 presenile dementia (Alzheimer's disease), so its use as an antacid may be discouraged.

Anvendelse af de forskellige alkalisalte som nævnt ovenfor er således forbundet med flere ulemper i form af en række bivirkninger af større eller mindre alvor. Disse bivirkninger har større betydning i tilfæl-35 de af langtidsbehandling, der omfatter en høj antacidumdosering. I de DK 169122 B1 3 senere år er der forsøgt andre indgangsvinkler til gastrointestinale sygdomme, og de har primært drejet sig om at reducere syreudskillelse. Midler, der er ansvarlige for en reduktion af syreudskillelsen i maven, omfatter anticholinergika og ^-receptorantagonister. Sådanne 5 midler har imidlertid den alvorlige ulempe, at de har alvorlige bivirkninger i større doser, og de kan kun fås på recept (hvilket er en ulempe, eftersom antacida ofte anvendes til korttidslindring af dyspeptiske symptomer, således at pålidelige og sikre antacidpræpara-ter fortrinsvis bør være tilgængelige i håndkøb).Thus, the use of the various alkali salts as mentioned above is associated with several disadvantages in the form of a number of side effects of greater or lesser severity. These side effects are more significant in the case of long-term treatment that includes a high antacid dose. In the DK 169122 B1 3 recent years, other approaches to gastrointestinal diseases have been tried, and they have primarily been about reducing acid secretion. Agents responsible for a reduction in gastric acid secretion include anticholinergics and β-receptor antagonists. However, such agents have the serious disadvantage that they have serious side effects in larger doses and they can only be obtained on prescription (which is a disadvantage since antacids are often used for short-term relief of dyspeptic symptoms, so that reliable and safe antacid preparations are preferably should be available over the counter).

10 Det er almindeligt anerkendt, at et antacidums effektivitet bør bedømmes efter følgende parametre: graden af syreneutraliserende evne, latensperioden, før den syreneutraliserende virkning sætter ind, dvs. før pH er steget til 3, den højeste pH, der måles, samt varigheden af den periode, i løbet af hvilken pH er i området 3-5 (det er ønske- 15 ligt, at denne periode er så lang som mulig). Selv om de fleste af de ovennævnte antacida udviser en høj score, når de testes ifølge disse parametre in vitro, er deres ydeevne in vivo mindre overbevisende på grund af de ovenfor beskrevne syre-rebound- og mave tømningsvirkninger.It is generally accepted that the effectiveness of an antacid should be assessed according to the following parameters: the degree of antacid ability, the latency period before the antacid effect sets in, ie. before the pH has risen to 3, the highest pH being measured, as well as the duration of the period during which the pH is in the range 3-5 (it is desirable that this period be as long as possible). Although most of the above antacids exhibit a high score when tested according to these parameters in vitro, their in vivo performance is less convincing due to the acid-rebound and gastric emptying effects described above.

20 Der er derfor behov for et sikkert og pålideligt antacidpræparat, som har de ovenfor nævnte ønskelige egenskaber med hensyn til en høj syreneutraliserende evne og langvarig virkning, uden at de udviser den syre - rebound-virkning, som er almindelig for flere af de kendte antacida, og hvilket præparat kun har få bivirkninger, om overhovedet 25 nogen.There is therefore a need for a safe and reliable antacid composition which has the above-mentioned desirable properties with respect to a high acid neutralizing ability and long-lasting effect, without exhibiting the acid-rebound effect which is common to several of the known antacids. , and which drug has few side effects, if any 25 at all.

Den foreliggende opfindelse angår således et antacidpræparat indeholdende pektin og ét eller flere syreneutraliserende midler, hvilket præparat indeholder a) et pektin eller et salt deraf, 30 b) et eller flere syreneutraliserende midler, som er i stand til at blive fanget i den gelstruktur, der dannes af det lavmethoxy-lerede pektin ved en sur pH, idet mindst ét af midlerne får DK 169122 B1 4 gelen til at skumme ved kontakt med en syre og er et carbonat, hydrogencarbonat eller subcarbonat eller en blanding deraf, og c) en substans, som er i stand til at virke som buffer, og som er i stand til at blive fanget i den gelstruktur, som dannes af 5 pektiner ved sur pH.Thus, the present invention relates to an antacid composition containing pectin and one or more acid neutralizing agents, which composition contains a) a pectin or a salt thereof, b) one or more acid neutralizing agents capable of being trapped in the gel structure is formed from the low methoxylated pectin at an acidic pH, at least one of the agents causing the gel to foam on contact with an acid and is a carbonate, bicarbonate or subcarbonate or a mixture thereof, and c) a substance, which is capable of acting as a buffer and which is capable of being trapped in the gel structure formed by 5 pectins at acidic pH.

Præparatet er især formuleret på en sådan måde, at pektinet eller saltet deraf opløses før indtagelse af præparatet, hvilket forbedrer de raftdannende egenskaber i et gastrisk miljø.In particular, the composition is formulated in such a way that the pectin or its salt is dissolved before ingestion of the composition, which improves the rafting properties in a gastric environment.

I nærværende sammenhæng betyder udtrykket "raftdannende egenskaber", 10 at præparatet ifølge opfindelsen i det gastriske miljø danner en højviskos sammenhængende gel, som flyder oven på maveindholdet på grund af en lavere bulkdensitet end mavesaften. Præparatet ifølge opfindelsen virker således som en barriere mellem øsofagus og mavesaften, hvorved det sure maveindhold forhindres i at strømme tilbage i 15 øsofagus. Endnu en fordel ved den raftdannende virkning er, at mavesaftens surhedsgrad ikke bliver reduceret til så kritisk et niveau efter indtagelse af præparatet, at dette resulterer i en pH-værdi i antrum, som ville medføre afgivelse af gastrin fra de pH-følsomme G-celler, hvilket igen ville inducere forøget syreudskillelse. En 20 yderligere fordel ved præparatet ifølge opfindelsen er, at det eller de syreneutraliserende midler b) er indeholdt i pektins gelstruktur og derfor ikke udtømmes fra maven med den samme hurtige hastighed, der ses med konventionelle antacidpræparater, hvor det syreneutraliserende middel udtømmes fra maven med en sådan hastighed, at den 25 syreneutraliserende virkning ikke er opbrugt. Bortset fra dette bidrager den buffer, der er inkorporeret i præparatet ifølge opfindelsen, til, at den syreneutraliserende virkning forlænges.In the present context, the term "raft-forming properties" means that the composition according to the invention in the gastric environment forms a highly viscous cohesive gel which floats on top of the stomach contents due to a lower bulk density than the gastric juice. The composition according to the invention thus acts as a barrier between the esophagus and the gastric juice, whereby the acidic stomach contents are prevented from flowing back into the esophagus. Another advantage of the rafting effect is that the acidity of the gastric juice is not reduced to such a critical level after ingestion of the preparation that this results in a pH value in the antrum which would result in the release of gastrin from the pH-sensitive G cells , which in turn would induce increased acid secretion. A further advantage of the composition according to the invention is that the acid-neutralizing agent or agents b) are contained in the gel structure of the pectin and therefore are not discharged from the stomach at the same rapid rate seen with conventional antacid compositions, where the acid-neutralizing agent is discharged from the stomach with a such a rate that the acid neutralizing effect is not exhausted. Apart from this, the buffer incorporated in the composition according to the invention contributes to prolonging the acid neutralizing effect.

Antacidpræparater, som indeholder et geldannende middel og et syreneutraliserende middel, er kendte (jfr. N. Washington et al., Int. J.Antacid preparations which contain a gelling agent and an acid neutralizing agent are known (cf. N. Washington et al., Int. J.

30 Pharm. 27, 1985, s. 279-286 og N. Washington et al., Int. J. Pharm.Pharm. 27, 1985, pp. 279-286 and N. Washington et al., Int. J. Pharm.

28, 1986, s. 139-143). Det geldannende middel i disse kendte præparater er alginsyre, og de indeholder endvidere natriumhydrogencarbonat og sædvanligvis mindst ét yderligere syreneutraliserende middel. Ved indtagelse danner natriumalginatet en skummende alginatgel, der DK 169122 Bl 5 indeholder det eller de andre syreneutraliserende midler. Denne gel flyder oven på maveindholdet og forhindrer tilbagestrømning af mavesaft til øsofagus. Imidlertid har man formodet, at præparater af denne type indeholder for små mængder syreneutraliserende midler til 5 effektivt at bufre mavesyre, og i modsætning til præparatet ifølge den foreliggende opfindelse indeholder de ikke en buffer fanget i den gelstruktur, der dannes ved kontakt med den sure mavesaft. I et in vitro eksperiment viste præparatet ifølge den foreliggende opfindelse sig at være bedre end et kommercielt tilgængeligt alginsyreholdigt 10 antacidum, hvad angår syreneutraliserende evne (jfr. eksempel 5). Der er også en antydning af, at disse kendte antacida har utilstrækkelig raftdannelse (Knight et al., J. Nucl. Med. 27, No. 6, 1986, s. 1011-1012).28, 1986, pp. 139-143). The gelling agent in these known compositions is alginic acid and they further contain sodium bicarbonate and usually at least one additional antacid. When ingested, the sodium alginate forms a foaming alginate gel which contains the other acid-neutralizing agent (s). This gel floats on top of the stomach contents and prevents the backflow of gastric juice to the esophagus. However, compositions of this type have been believed to contain too small amounts of antacids to effectively buffer gastric acid, and unlike the composition of the present invention, they do not contain a buffer trapped in the gel structure formed upon contact with the acidic gastric juice. . In an in vitro experiment, the composition of the present invention was found to be superior to a commercially available alginic acid-containing antacid in terms of acid neutralizing ability (cf. Example 5). There is also a suggestion that these known antacids have insufficient rafting (Knight et al., J. Nucl. Med. 27, No. 6, 1986, pp. 1011-1012).

Stanciu et al. har i Rev. Med. Chir. Soc. Med. Nat. Jasi, 1985, 15 89(2)-233-236 beskrevet behandling af gastroøsofageal reflux med to konventionelle suspensionspræparater. Den ene suspension indeholder natriumhydrogencarbonat, aluminiumhydroxid, magnesiumoxid samt natri-umalginat, hvor sidstnævnte virker stabiliserende på suspensionen, medens den anden suspension indeholder de samme bestanddele, blot er 20 natriumalginat erstattet af pektin. Ingen af præparaterne indeholder imidlertid en bufferkomponent. I modsætning hertil udmærker præparatet ifølge opfindelsen sig ved foruden at indeholde lavmethoxyleret pektin, der overraskende fører til raft-dannelse, og som hjælper med til at forhindre gastroøsofageal reflux, også at indeholde en buf-25 fersubstans, der forbedrer præparatets egenskaber, idet en buffersubstans, som vist i eksempel 12 og 13, giver et præparat med et mere stabilt skum (større skummængde) end et præparat uden buffer, ligesom latensperioden til opnåelse af den maksimale pH er kortere og varigheden længere, når der er en buffer til stede i præparatet.Stanciu et al. has in Rev. With. Chir. Soc. With. Night. Jasi, 1985, 15 89 (2) -233-236 described treatment of gastroesophageal reflux with two conventional suspension preparations. One suspension contains sodium bicarbonate, aluminum hydroxide, magnesium oxide and sodium alginate, the latter having a stabilizing effect on the suspension, while the other suspension contains the same ingredients, only sodium alginate is replaced by pectin. However, none of the compositions contain a buffer component. In contrast, the composition according to the invention is distinguished by, in addition to containing low methoxylated pectin, which surprisingly leads to raft formation, and which helps to prevent gastroesophageal reflux, also to contain a buffer substance which improves the properties of the composition, a buffer substance , as shown in Examples 12 and 13, gives a composition with a more stable foam (larger amount of foam) than a composition without buffer, just as the latency period to obtain the maximum pH is shorter and the duration longer when a buffer is present in the composition .

30 Ud over at danne en gel ved en sur pH bør komponent a) fortrinsvis også være en substans, der efter opløsning danner et viskost slim, fx når det opløses i munden som følge af tygning, idet slimen overtrækker slimhinderne i øsofagus og maven, hvorved disse beskyttes mod mavesyrernes inflammatoriske virkninger. Den slim, der dannes af 35 komponent a), bør fortrinsvis have en lav viskositet, da mere viskose stoffer har tendens til at klæbe temmelig fast til tænderne og frem- DK 169122 B1 6 bringe en tørhed i munden, hvilket giver præparatet en ubehagelig fornemmelse i munden. Til de foreliggende formål er det fordelagtigt at anvende geldannende komponenter a), der er valgt blandt naturlige eller syntetiske polysaccharider. Egnede polysaccharider, der kan 5 anvendes i præparatet ifølge opfindelsen, vælges blandt pektiner.In addition to forming a gel at an acidic pH, component a) should preferably also be a substance which, after dissolution, forms a viscous mucus, for example when it dissolves in the mouth as a result of chewing, the mucus coating the mucous membranes of the esophagus and stomach, whereby these are protected against the inflammatory effects of stomach acids. The mucus formed by component a) should preferably have a low viscosity, as more viscous substances tend to stick rather to the teeth and produce a dryness in the mouth, which gives the preparation an unpleasant sensation. in the mouth. For the present purposes, it is advantageous to use gelling components a) selected from natural or synthetic polysaccharides. Suitable polysaccharides which can be used in the composition according to the invention are selected from pectins.

Pektin har ud over den ovennævnte gunstige geldannende og slimhinde-overtrækkende egenskab også galdesyre- og lipidbindende egenskaber.Pectin has, in addition to the above-mentioned beneficial gelling and mucosal coating properties, also bile acid and lipid binding properties.

Da galdesyrer formodes at have indflydelse på forekomsten af gastro-øsofageale lidelser (gastritis) og ulcera, antages det, at pektin-10 holdige præparater udgør et særligt nyttigt aspekt. Særlig anvendelige pektiner til det foreliggende formål er lavmethoxylerede pektiner og amiderede pektiner. Ved lavmethoxyleret pektin skal forstås pektin med en methoxyleringsgrad på under 15¾. Pektiner med en met-hoxyleringsgrad på under 10%, fortrinsvis på højst 5%, er særlig 15 foretrukne. Salte af sådanne lavmethoxylerede pektiner kan også anvendes såsom alkalimetalsalte, fx natrium- eller kaliumsalte.Since bile acids are thought to influence the occurrence of gastro-oesophageal disorders (gastritis) and ulcers, it is believed that pectin-containing preparations constitute a particularly useful aspect. Particularly useful pectins for the present purpose are low methoxylated pectins and amidated pectins. By low methoxylated pectin is meant pectin with a methoxylation degree of less than 15¾. Pectins with a degree of methoxylation of less than 10%, preferably of at most 5%, are particularly preferred. Salts of such low methoxylated pectins can also be used such as alkali metal salts, eg sodium or potassium salts.

Buffersubstansen c), som er fanget i den gelstruktur, der dannes af komponent a) ved en sur pH, ændrer gelens karakteristika på grund af, at det er dispergeret i gelstrukturen, fx ved agglomerering i gelen i 20 et surt miljø, dvs. på gelens overflade. Det foretrækkes at anvende en buffersubstans c), som foruden de ovenfor anførte egenskaber også er i stand til at bibringe en større stivhed til den gel, der dannes af komponent a) ved en sur pH, således at den desintegrerer langsommere under mavebetingelser. Anvendelse af et pektin som geldannen-25 de komponent a) vil bevirke, at polysaccharidkæderne omslutter kol-loide partikler af buffersubstansen c) og forhindrer agglomerering eller koagulering deraf undtagen på geloverfladen. Uden at ville begrænse sig til nogen bestemt teori antages det, at den fastere gelstruktur fremkommer ved, at de kolloide partikler af buffersubs-30 tansen c) indesluttes af polysaccharidkæderne. Polysaccharidmoleky-lerne presses derved mere tæt sammen på grund af tilstedeværelsen af de kolloide partikler, som optager plads, der ellers ville blive optaget af polysaccharidkæderne (det fænomen, der kaldes "ekskluderede volumener").The buffer substance c), which is trapped in the gel structure formed by component a) at an acidic pH, changes the characteristics of the gel due to it being dispersed in the gel structure, e.g. by agglomeration in the gel in an acidic environment, i.e. on the surface of the gel. It is preferred to use a buffer substance c) which, in addition to the above properties, is also capable of imparting a greater stiffness to the gel formed by component a) at an acidic pH so that it disintegrates more slowly under stomach conditions. The use of a pectin as the gelling component a) will cause the polysaccharide chains to enclose colloidal particles of the buffer substance c) and prevent agglomeration or coagulation thereof except on the gel surface. Without wishing to be limited to any particular theory, it is believed that the firmer gel structure is obtained by entrapping the colloidal particles of the buffer substance c) by the polysaccharide chains. The polysaccharide molecules are thereby compressed more closely due to the presence of the colloidal particles, which occupy space that would otherwise be occupied by the polysaccharide chains (the phenomenon known as "excluded volumes").

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Stoffer, der har vist sig at have udmærkede gelforbedrende egenskaber samt bufferegenskaber, er primært proteiriholdige stoffer. Udtrykket "proteinholdige stoffer" skal betegne stoffer, som omfatter eller består af proteiner, peptider eller aminosyrer. Eksempler på egnede 5 stoffer er casein eller et caseinat såsom natrium-, kalium- eller ammoniumcaseinat, mælkepulver, gelatine, et vegetabilsk protein såsom sojaproteinisolat eller en aminosyre (såsom glycin) eller et salt deraf.Substances that have been shown to have excellent gel-enhancing properties as well as buffering properties are primarily proteinaceous substances. The term "proteinaceous substances" shall mean substances which comprise or consist of proteins, peptides or amino acids. Examples of suitable substances are casein or a caseinate such as sodium, potassium or ammonium caseinate, milk powder, gelatin, a vegetable protein such as soy protein isolate or an amino acid (such as glycine) or a salt thereof.

De for tiden mest foretrukne buffersubstanser c) er casein, caseina-10 ter og mælkepulver (som naturligvis indeholder det ene eller begge af disse), da mælkeproteiner vides at have en høj bufferkapacitet, hvilket medfører en længere varighed af det syreneutraliserende middels antacidvirkning. Endvidere danner mælkeproteiner kolloide partikler i gelstrukturen af komponent a) under mavebetingelser, 15 hvorved gelen brydes op som anført ovenfor. Mælkepulver er tidligere i sig selv blevet anvendt som antacidum, men dets gunstige virkning i et præparat ifølge den foreliggende opfindelse, der også omfatter et geldannende middel og et syreneutraliserende middel, er ikke tidligere erkendt. Når casein benyttes som buffersubstans c), er det sædvan-20 ligvis en casein, der er syrefældet med fx saltsyre eller mælkesyre, eller osteløbecasein.The currently most preferred buffer substances c) are casein, caseinates and milk powder (which of course contain one or both of these), as milk proteins are known to have a high buffer capacity, which results in a longer duration of the antacid action of the antacid. Furthermore, milk proteins form colloidal particles in the gel structure of component a) under gastric conditions, whereby the gel is broken up as indicated above. Milk powder has previously been used in itself as an antacid, but its beneficial effect in a composition of the present invention, which also comprises a gelling agent and an acid neutralizing agent, has not been previously recognized. When casein is used as buffer substance c), it is usually a casein which has been acid precipitated with, for example, hydrochloric acid or lactic acid, or cheese rennet casein.

Hvis gelen er tilstrækkelig stiv i sig selv, er det sædvanligvis ikke nødvendigt at forbedre dens egenskaber yderligere. I sådanne tilfælde kan en buffer primært vælges på grund af dens bufferkapacitet. En 25 klasse af fordelagtige buffere, som kan anvendes, når der ikke specifikt kræves gelforbedrende egenskaber, er phosphaterne, da deres bufferkapacitet sædvanligvis er høj ved ca. pH 5. Eksempler på anvendelige phosphater er natrium- , calcium- , magnesium- , ammonium- , aluminium- eller kaliumphosphat.If the gel is sufficiently rigid in itself, it is usually not necessary to further improve its properties. In such cases, a buffer can be selected primarily because of its buffer capacity. A class of advantageous buffers which can be used when no gel-improving properties are specifically required are the phosphates, as their buffer capacity is usually high at approx. pH 5. Examples of useful phosphates are sodium, calcium, magnesium, ammonium, aluminum or potassium phosphate.

30 Mindst ét af de syreneutraliserende midler, som inkorporeres som komponent b) i præparatet ifølge opfindelsen, er som anført et carbo-nat, hydrogencarbonat eller subcarbonat, som ved reaktion med syre bevirker skumning af den gel, der dannes af komponent a), på grund af dannelse af gasbobler ved reaktionen, hvilke gasbobler fanges i ge-35 len.At least one of the acid neutralizing agents which is incorporated as component b) in the composition according to the invention is, as stated, a carbonate, bicarbonate or subcarbonate which, upon reaction with acid, causes foaming of the gel formed by component a) on due to the formation of gas bubbles in the reaction, which gas bubbles are trapped in the gel.

DK 169122 B1 8DK 169122 B1 8

Midler, som er i stand til at få geler til at skumme, når de bringes i kontakt med syrer, og som er carbonater, hydrogencarbonater eller subcarbonater, kan vælges blandt nogle af de syreneutraliserende midler, der anvendes i konventionelle antacidpræparater, fx farma-5 ceutisk acceptable alkalimetal-, jordalkalimetal-, aluminium- , ammonium- eller vismutsalte. Alkalimetallet eller jordalkalimetallet kan vælges blandt natrium, kalium, magnesium og calcium.Agents which are capable of foaming gels when contacted with acids and which are carbonates, bicarbonates or subcarbonates may be selected from some of the antacids used in conventional antacid compositions, e.g. pharma-5 pharmaceutically acceptable alkali metal, alkaline earth metal, aluminum, ammonium or bismuth salts. The alkali metal or alkaline earth metal can be selected from sodium, potassium, magnesium and calcium.

En fordelagtig kombination af syreneutraliserende midler til inkorporering i præparatet ifølge opfindelsen har vist sig at være kalium-10 hydrogencarbonat og magnesiumsubcarbonat, da kaliumhydrogencarbonatet danner carbondioxid umiddelbart efter kontakt med mavesyre, hvorved gelen skummer, mens magnesiumsubcarbonatet reagerer langsommere, således at den del af det, som ikke anvendes øjeblikkeligt ved indtagelse af præparatet, fanges i den skummede gel og afgives langsomt 15 derfra under dannelse af carbondioxid, hvilket også bidrager til gelens kontinuerlige flydning.An advantageous combination of acid neutralizing agents for incorporation into the composition of the invention has been found to be potassium bicarbonate and magnesium subcarbonate, as the potassium bicarbonate forms carbon dioxide immediately upon contact with gastric acid, whereby the gel foams while the magnesium subcarbonate reacts more slowly so that which is not used immediately upon ingestion of the composition, is trapped in the foamed gel and slowly released therefrom to form carbon dioxide, which also contributes to the continuous flow of the gel.

De ovenfor anførte syreneutraliserende midler kan kombineres med ét eller flere andre syreneutraliserende midler, fx oxider eller hydroxider af et alkalimetal eller jordalkalimetal såsom natrium, 20 kalium, magnesium og calcium, eller af aluminium. Disse bidrager ikke til gelens skumning, men bliver fanget i gelstrukturen og afgives langsomt, således at de ikke udtømmes fra maven, før deres syreneutraliserende evne er opbrugt, hvilket er en ulempe ved konventionelle antacida som beskrevet ovenfor.The above-mentioned acid neutralizing agents may be combined with one or more other acid neutralizing agents, for example oxides or hydroxides of an alkali metal or alkaline earth metal such as sodium, potassium, magnesium and calcium, or of aluminum. These do not contribute to the foaming of the gel, but become trapped in the gel structure and are released slowly so that they are not depleted from the stomach until their acid neutralizing ability is exhausted, which is a disadvantage of conventional antacids as described above.

25 Antacidpræparatet ifølge opfindelsen kan formuleres som en flydende suspension af bestanddelene i en væske, som fungerer som opløsningsmiddel for komponent a), ikke bevirker gelering af komponent a) og ikke reagerer med det syreneutraliserende middel eller for den sags skyld med nogen af de andre bestanddele. En typisk formulering af et 30 flydende præparat ifølge opfindelsen er beskrevet i eksempel 4 nedenfor. Det foretrækkes imidlertid at formulere præparatet som en tyggetablet sammen med konventionelle tabletteringshjælpestoffer og dilu-enter. En sådan tablet skal tygges grundigt, før den synkes, for at opnå opløsning af komponent a) før indtagelse, da det ellers ikke DK 169122 B1 9 vil blive fordelt korrekt i maveindholdet til dannelse af den ønskede gel. I en alternativ udførelsesform kan præparatet formuleres som en brusetablet sammen med konventionelle hjælpestoffer. Tabletten er beregnet til at henfalde i en væske før indtagelse.The antacid composition of the invention may be formulated as a liquid suspension of the components of a liquid which acts as a solvent for component a), does not cause gelation of component a) and does not react with the acid neutralizing agent or for that matter with any of the other components. . A typical formulation of a liquid composition according to the invention is described in Example 4 below. However, it is preferred to formulate the composition as a chewable tablet together with conventional tableting excipients and diluents. Such a tablet must be thoroughly chewed before swallowing to obtain dissolution of component a) before ingestion, as otherwise it will not be properly distributed in the stomach contents to form the desired gel. In an alternative embodiment, the composition may be formulated as an effervescent tablet together with conventional excipients. The tablet is intended to dissolve in a liquid before ingestion.

5 Mængden af hver komponent i præparatet ifølge opfindelsen kan varieres inden for vide grænser. Komponent a) kan således være til stede i en mængde på op til 50 vægtprocent pr. enhedsdosis af præparatet, og komponent c), kan være til stede i en mængde på op til 50 vægtprocent. For at opnå en gunstig balance mellem egenskaberne bør kompo-10 nent a) og komponent c), fortrinsvis være til stede i i det væsentlige lige store mængder. Det syreneutraliserende middel b) kan være til stede i en mængde på 1-30 vægtprocent pr. enhedsdosis af præparatet, og det er fortrinsvis til stede i en mængde på mindst 5 milliæ-kvivalenter base pr. enhedsdosis af præparatet for at tilvejebringe 15 en passende syreneutralisering.The amount of each component in the composition according to the invention can be varied within wide limits. Component a) may thus be present in an amount of up to 50% by weight per unit dose of the composition, and component c), may be present in an amount of up to 50% by weight. In order to achieve a favorable balance between the properties, component a) and component c) should preferably be present in substantially equal amounts. The acid neutralizing agent b) may be present in an amount of 1-30% by weight per unit dose of the composition, and it is preferably present in an amount of at least 5 milliequivalents of base per unit dose of the composition to provide appropriate acid neutralization.

Præparatet ifølge den foreliggende opfindelse kan anvendes til alle de medicinske formål, der involverer administration af antacida, fx til behandling eller lindring af øvre gastrointestinale dyspeptiske lidelser, ved hvilken der til en patient, der har behov for en sådan 20 behandling, administreres en terapeutisk virksom mængde af præparatet ifølge opfindelsen. Disse lidelser omfatter gastroøsofageal reflux, gastritis, gastriske eller duodenale ulcera, pyrosis og øsofagitis.The composition of the present invention can be used for all the medical purposes involving the administration of antacids, for example for the treatment or alleviation of upper gastrointestinal dyspeptic disorders, in which a therapeutic agent is administered to a patient in need of such treatment. amount of the composition according to the invention. These disorders include gastroesophageal reflux, gastritis, gastric or duodenal ulcers, pyrosis and esophagitis.

Opfindelsen belyses nærmere i nedenstående eksempler.The invention is further illustrated in the following examples.

EKSEMPEL 1EXAMPLE 1

Der blev fremstillet en tyggetablet ifølge opfindelsen ud fra følgen de bestanddele: DK 169122 B1 10A chewable tablet according to the invention was prepared from the following ingredients: DK 169122 B1 10

Bestanddel Mængde i vægtprocent 5 -Ingredient Quantity in weight percent 5 -

Pektin* 21,2Pectin * 21.2

Sur casein 30,8On casein 30.8

Kaliumhydrogencarbonat 14,2Potassium bicarbonate 14.2

Magnesiumsubcarbonat Ph. Nord. 63 15,7 10 Sorbitol 8,5 Mælkepulver 8,5Magnesium Subcarbonate Ph. Nerd. 63 15.7 10 Sorbitol 8.5 Milk powder 8.5

Pebermynteolie 0,1Peppermint oil 0.1

Asp ar tam 0,1Asp is 0.1

Magnesiumstearat 0,5 15 Destillerede mono- og diglycerider 0,5 100,0 * Lavmethoxyleret pektin med en methoxyleringsgrad på op til 20 5%.Magnesium stearate 0.5 15 Distilled mono- and diglycerides 0.5 100.0 * Low methoxylated pectin with a degree of methoxylation of up to 20 5%.

ved at blande bestanddelene og komprimere blandingen til tabletter på i og for sig kendt måde. Hver tablet indeholdt 5 milliækvivalenter base og vejede ca. 1275 mg.by mixing the ingredients and compressing the mixture into tablets in a manner known per se. Each tablet contained 5 milliequivalents of base and weighed approx. 1275 mg.

Der blev fremstillet en tyggetablet ifølge opfindelsen ud fra følgen de bestanddele: EKSEMPEL 2 DK 169122 B1 11A chewable tablet according to the invention was prepared from the following ingredients: EXAMPLE 2 DK 169122 B1 11

Bestanddel Mængde i vægtprocent 5 -Ingredient Quantity in weight percent 5 -

Pektin* 15,0Pectin * 15.0

Casein 31,0Casein 31.0

Kaliumhydrogencarbonat 14,2Potassium bicarbonate 14.2

Magnesiumsubcarbonat Ph. Nord. 63 11,6 10 Sorbitol 27,0Magnesium Subcarbonate Ph. Nerd. 63 11.6 10 Sorbitol 27.0

Destillerede mono- og diglycerider 0,3Distilled mono- and diglycerides 0.3

Magnesiums tearat 0,5Magnesium tears 0.5

Siliciumdioxid 0,2Silica 0.2

Aromastoffer 0,1 15 Sødemiddel 0,1 100,0 * Lavmethoxyleret pektin med en methoxyleringsgrad på op til 20 5%.Flavorings 0.1 15 Sweetener 0.1 100.0 * Low methoxylated pectin with a degree of methoxylation of up to 20 5%.

EKSEMPEL 3EXAMPLE 3

Der blev fremstillet en tyggetablet ifølge opfindelsen ud fra følgen de bestanddele: DK 169122 B1 12A chewable tablet according to the invention was prepared from the following ingredients: DK 169122 B1 12

Bestanddel Mængde i vægtprocent 5 -Ingredient Quantity in weight percent 5 -

Pektin* 15,0Pectin * 15.0

Casein 15,0Casein 15.0

Kaliumhydrogencarbonat 7,2Potassium bicarbonate 7.2

Magnesiumsubcarbonat Ph. Nord. 63 18,6 10 Glycin 17,4Magnesium Subcarbonate Ph. Nerd. 63 18.6 10 Glycine 17.4

Sorbitol 10,0Sorbitol 10.0

Lactose 10,5 Mælkepulver 5,0Lactose 10.5 Milk powder 5.0

Mono-, di- og triglycerider 0,5 15 Magnesiumstearat 0,5 S iliciumdioxid 0,2 Sødemiddel 0,1Mono-, di- and triglycerides 0.5 15 Magnesium stearate 0.5 S silica 0.2 Sweetener 0.1

Aromastoffer 0,1 20 100,0 * Lavmethoxyleret pektin med en methoxyleringsgrad på op til 5%.Flavorings 0,1 20 100,0 * Low methoxylated pectin with a degree of methoxylation of up to 5%.

ved at blande bestanddelene og komprimere blandingen til tabletter på 25 i og for sig kendt måde. Hver tablet vejede ca. 1275 mg.by mixing the ingredients and compressing the mixture into tablets in a manner known per se. Each tablet weighed approx. 1275 mg.

EKSEMPEL 4EXAMPLE 4

Der blev fremstillet et flydende præparat ifølge opfindelsen ud fra følgende bestanddele: DK 169122 B1 13A liquid preparation according to the invention was prepared from the following ingredients: DK 169122 B1 13

Bestanddel Mængde 5 _Ingredient Quantity 5 _

Pektin* 380 mgPectin * 380 mg

Casein 380 mgCasein 380 mg

Magnesiumsubcarbonat Ph. Nord. 63 474 mgMagnesium Subcarbonate Ph. Nerd. 63 474 mg

Kaliumhydrogencarbonat 184 mg 10 Aromastoffer q.s.Potassium bicarbonate 184 mg 10 Flavorings q.s.

Sødemiddel q.s.Sweetener q.s.

Vand 25 g * Lavmethoxyleret pektin med en methoxyleringsgrad på op til 15 5%.Water 25 g * Low methoxylated pectin with a degree of methoxylation of up to 15 5%.

ved at blande bestanddelene på i og for sig kendt måde. Denne blanding kan fyldes i en egnet beholder før anvendelse.by mixing the ingredients in a manner known per se. This mixture can be filled into a suitable container before use.

EKSEMPEL 5 (Sammenligning)EXAMPLE 5 (Comparison)

Præparater ifølge opfindelsen (ifølge eksempel 1) blev testet in 20 vitro i simuleret mavesaft ved følgende metode: 100 ml af en blanding af simuleret mavesaft (USP XX) og destilleret vand (4:6), pH ca. 1,3, blev anbragt på en magnetomrører (FRAMO M22/1), der arbejdede ved 500 omdr./minut. Når pH havde stabiliseret sig (ca. 1,25), tilsattes den antacidumprøve, der skulle testes.Preparations of the invention (according to Example 1) were tested in vitro in simulated gastric juice by the following method: 100 ml of a mixture of simulated gastric juice (USP XX) and distilled water (4: 6), pH approx. 1.3, was placed on a magnetic stirrer (FRAMO M22 / 1) operating at 500 rpm. Once the pH had stabilized (about 1.25), the antacid sample to be tested was added.

25 Ét minut efter tilsætning af prøven blev der foretaget kontinuerlig tilsætning af simuleret mavesaft, pH 1,2, (med en hastighed på ca. 2 ml/minut, svarende til ca. 10 mmol/time) ved hjælp af en ISMATEC mini-S 840-pumpe forsynet med et ENE 09-rør. pH blev bestemt med et PHM 84 pH-måleapparat (Radiometer, Danmark) forbundet til en BBC, 30 SE-120-recorder.One minute after addition of the sample, continuous simulation of simulated gastric juice, pH 1.2, (at a rate of about 2 ml / minute, corresponding to about 10 mmol / hour) was performed using an ISMATEC mini-S 840 pump equipped with an ENE 09 pipe. The pH was determined with a PHM 84 pH meter (Radiometer, Denmark) connected to a BBC, 30 SE-120 recorder.

DK 169122 Bl 14DK 169122 Bl 14

Præparatet ifølge opfindelsen blev testet for følgende parametre: Varigheden af latensperioden, før der opnås en pH på > 3 (denne pH blev sat til den pH, ved hvilken antacidvirkningen forekommer), den højeste pH, der blev optegnet, variationer i pH-området på 3-5 samt 5 varigheden af tidsperioden, før reaktionsblandingen når en pH på 2, ved hvilken pH eksperimentet standses. Præparatet ifølge opfindelsen blev sammenlignet med to konventionelle antacida med hensyn til disse parametre: 1) kaliumhydrogencarbonat og magnesiumsubcarbonat og 2) Gaviscon® (en kombination af alginsyre, natriumhydrogencarbonat og 10 aluminiumhydroxid produceret af Ferring, Sverige). Resultaterne fremgår af tabel 1.The composition of the invention was tested for the following parameters: the duration of the latency period before a pH of> 3 is obtained (this pH was set to the pH at which the antacid effect occurs), the highest pH recorded, variations in the pH range of 3-5 as well as the duration of the time period before the reaction mixture reaches a pH of 2, at which the pH experiment is stopped. The composition of the invention was compared to two conventional antacids with respect to these parameters: 1) potassium bicarbonate and magnesium subcarbonate and 2) Gaviscon® (a combination of alginic acid, sodium bicarbonate and aluminum hydroxide produced by Ferring, Sweden). The results are shown in Table 1.

TABEL 1TABLE 1

Latensperiode Maksimal Varighed Varighed af pH > 3 pH af pH = periode, før 15 (sekunder) 3-5 pH = 2 nås (minutter) (minutter)Latency period Maximum Duration Duration of pH> 3 pH of pH = period before 15 (seconds) 3-5 pH = 2 reached (minutes) (minutes)

Blanding af 340 mg kaliumhydrogen-20 carbonat og 277 mg magnesiumsubcarbonat 70 3,74 6,5 21Mixture of 340 mg of potassium hydrogen-carbonate and 277 mg of magnesium subcarbonate 70 3.74 6.5 21

Præparat ifølge opfindelsen 24 4,88 30,5 55Composition according to the invention 24 4.88 30.5 55

Gaviscon®, 3000 mg - 1,56 -1) 25 - 1) Da pH ikke nåede 3, kunne varigheden af antacidvirkningen ikke måles.Gaviscon®, 3000 mg - 1.56 -1) 25 - 1) When the pH did not reach 3, the duration of the antacid effect could not be measured.

Det fremgår af tabellen, at den højeste pH (4,88) blev nået for præparatet ifølge den foreliggende opfindelse. Bufferevnen var også 30 mest udtalt for præparatet ifølge opfindelsen, idet pH-værdier på over 2 blev nået i løbet af 55 minutter. På basis af disse resultater konkluderes det, at i sammenligning med henholdsvis en blanding af alkalisalte og Gaviscon® viste produktet ifølge opfindelsen sig at DK 169122 B1 15 udvise den højeste syreneutraliserende bufferevne, når den blev bestemt ved denne in vitro metode.It can be seen from the table that the highest pH (4.88) was reached for the composition of the present invention. The buffering ability was also most pronounced for the composition according to the invention, with pH values of over 2 being reached within 55 minutes. Based on these results, it is concluded that in comparison with a mixture of alkali salts and Gaviscon®, respectively, the product according to the invention was found to exhibit the highest acid neutralizing buffer ability when determined by this in vitro method.

EKSEMPEL 6EXAMPLE 6

Præparater ifølge opfindelsen blev endvidere testet for virkningen af 5 at inkorporere varierende mængder af de aktive komponenter a), b) og c) med hensyn til den maksimale pH, der blev opnået, og varigheden af den syreneutraliserende virkning. Den metode, der blev anvendt til at teste disse parametre/variabler, svarede til den i eksempel 5 beskrevne, nemlig in vitro metoden under anvendelse af simuleret mave-10 saft.Compositions of the invention were further tested for the effect of incorporating varying amounts of the active components a), b) and c) with respect to the maximum pH obtained and the duration of the acid neutralizing effect. The method used to test these parameters / variables was similar to that described in Example 5, namely the in vitro method using simulated gastric juice.

Caseinvirkningen på den maksimale pH og på varigheden af den syreneutraliserende virkning fremgår af tabel 2 nedenfor. 184 mg KHCO3 + 480 mg MgCOg (subcarbonat) blev anvendt som base, svarende til 10 milliækvivalenter (mækv.) base.The casein effect on the maximum pH and on the duration of the antacid effect is shown in Table 2 below. 184 mg KHCO 3 + 480 mg MgCO 3 (subcarbonate) was used as the base, corresponding to 10 milliequivalents (meq) of base.

15 TABEL 2 10 mækv. 10 mækv. 10 mækv.15 TABLE 2 10 meq. 10 meq. 10 meq.

base + 397 mg + 794 mg (uden casein) casein casein 20 Maksimal pH 5,8 5,2 5,05base + 397 mg + 794 mg (without casein) casein casein 20 Maximum pH 5.8 5.2 5.05

Virkningsvarighed til pH 2,5 54 min. 56 min. 60 min.Duration of action to pH 2.5 54 min. 56 min. 60 min.

Pektinvirkningen på den maksimale pH og på varigheden af antacidvirk-25 ningen fremgår af tabel 3 nedenfor.The pectin effect on the maximum pH and on the duration of the antacid effect is shown in Table 3 below.

TABEL 3 DK 169122 B1 16 Mængde base 5 mækv. 92 mg KHCO3 intet pektin tilsat + 546 mg pektin 240 mg MgCOj 5 (subcarbonat)TABLE 3 DK 169122 B1 16 Quantity of base 5 meq. 92 mg KHCO3 no pectin added + 546 mg pectin 240 mg MgCO 3 (subcarbonate)

Maksimal pH 4 2,0Maximum pH 4 2.0

Virkningsvarighed til pH 2,5 16 min.Duration of action to pH 2.5 16 min.

10 -10 -

Af tabel 2 og 3 fremgår det, at inkorporering af en større mængde pektin i præparatet i modsætning til inkorporering af en' større mængde casein fører til en lavere maksimal pH samt en kortere virkningsvarighed af den syreneutraliserende virkning.Tables 2 and 3 show that the incorporation of a larger amount of pectin into the composition, as opposed to the incorporation of a larger amount of casein, leads to a lower maximum pH as well as a shorter duration of action of the acid neutralizing effect.

15 Virkningen af forholdet mellem casein og pektin på den maksimale pH, varigheden af antacidvirkningen og skumning fremgår af tabel 4 nedenfor. Den samme mængde base, 10 mækv. (343 mg KHCO3 + 283 mg Mg<X>3 (subcarbonat)), blev anvendt i hvert eksperiment.The effect of the ratio of casein to pectin on the maximum pH, the duration of the antacid effect and foaming is shown in Table 4 below. The same amount of base, 10 meq. (343 mg KHCO3 + 283 mg Mg <X> 3 (subcarbonate)), were used in each experiment.

TABEL 4 20 Eksperiment nr. 8 1 9 10TABLE 4 20 Experiment No. 8 1 9 10

Pektin* 238 mg 378 mg 630 mg 382 mgPectin * 238 mg 378 mg 630 mg 382 mg

Casein 1000 mg 800 mg 900 mg 382 mgCasein 1000 mg 800 mg 900 mg 382 mg

Maksimal pH 4,5 4,9 3,5 5,7 25 Skumning 20 ml 45 ml 55 ml 35 mlMaximum pH 4.5 4.9 3.5 5.7 25 Foaming 20 ml 45 ml 55 ml 35 ml

Virkningsvarighed til pH 2,5 37,5 min. 36,5 min. 24 min. 70 min.Duration of action to pH 2.5 37.5 min. 36.5 min. 24 min. 70 min.

* Lavmethoxyleret pektin med en methoxyleringsgrad på op til 5%.* Low methoxylated pectin with a degree of methoxylation of up to 5%.

30 Det fremgår af tabel 2-4, at den mængde casein, der inkorporeres i præparatet, påvirker varigheden af den syreneutraliserende virkning, udtrykt som tidsperioden, før der opnås en pH på 2,5, således at en større inkorporeret mængde casein fører til en længere varighed af virkningen, mens en større mængde inkorporeret pektin i modsætning DK 169122 B1 17 hertil fører til en lavere maksimal pH og en kortere varighed af den syreneutraliserende virkning. Mængden af pektin påvirker imidlertid også den opnåede grad af skumning, således at der ved formulering af præparatet ifølge opfindelsen skal opnås en balance mellem den mængde 5 casein og den mængde pektin, der inkorporeres i præparatet.It appears from Tables 2-4 that the amount of casein incorporated into the composition affects the duration of the acid neutralizing effect, expressed as the time period before a pH of 2.5 is obtained, so that a larger amount of casein incorporated leads to a longer duration of the effect, while a larger amount of incorporated pectin, in contrast, leads to a lower maximum pH and a shorter duration of the acid-neutralizing effect. However, the amount of pectin also affects the degree of foaming obtained, so that when formulating the composition according to the invention a balance must be achieved between the amount of casein and the amount of pectin incorporated in the composition.

EKSEMPEL 7 (Sammenligning)EXAMPLE 7 (Comparison)

Der blev fremstillet en tyggetablet ud fra følgende bestanddele: Mængde i vægt% 10 Casein 15,0A chewable tablet was prepared from the following ingredients: Amount by weight 10% Casein 15.0

Alginsyre *) 15,0Alginic acid *) 15.0

Kaliumhydrogencarbonat 7,2Potassium bicarbonate 7.2

Magnesiumsubcarbonat 18,6Magnesium subcarbonate 18.6

Glycin 6,35 15 Vallepulver 15 Δ 5,0Glycine 6.35 15 Whey powder 15 Δ 5.0

Xylitol 30,0Xylitol 30.0

Mono-, di-, triglycerider 0,5Mono-, di-, triglycerides 0.5

Magnesiumstearat 0,5Magnesium stearate 0.5

Siliciumdioxid 0,2 20 Saccharin 0,15Silica 0.2 Saccharin 0.15

Citronsyre 1,0Citric acid 1.0

Aroma 0,5 100,0 25 *) Leveret af Grindsted Products, Danmark (VLVA Sample I; kata- lognr. 2001814) Δ Leveret af De Melkindustrie Veghel, Holland (BV 15) ved at blande bestanddelene og komprimere blandingen til tabletter på i og for sig kendt måde. Hver tablet vejede ca. 1275 mg.Aroma 0,5 100,0 25 *) Supplied by Grindsted Products, Denmark (VLVA Sample I; catalog no. 2001814) Δ Supplied by De Melkindustrie Veghel, Holland (BV 15) by mixing the ingredients and compressing the mixture into tablets of i and per se known manner. Each tablet weighed approx. 1275 mg.

DK 169122 B1 18DK 169122 B1 18

Dette præparat blev testet som beskrevet i eksempel 5 og 6 og sammenlignet med præparatet ifølge eksempel 3. Resultaterne fremgår af tabel 5 nedenfor.This preparation was tested as described in Examples 5 and 6 and compared with the preparation of Example 3. The results are shown in Table 5 below.

TABEL 5 5 Alginsyre PektinTABLE 5 5 Alginic acid Pectin

Maksimal pH 5,2 5,7Maximum pH 5.2 5.7

Varighed af periode, før pH = 2,0 nås (minutter) 84 106 10 Skumning 1 tablet 6 ml 25 ml 30 min. 2 tabletter 12 ml 32 mlDuration of period before pH = 2.0 is reached (minutes) 84 106 10 Foaming 1 tablet 6 ml 25 ml 30 min. 2 tablets 12 ml 32 ml

Det fremgår af tabel 5, at alginsyre giver mindre skumning af gelen end pektin.Table 5 shows that alginic acid produces less foaming of the gel than pectin.

DK 169122 B1 EKSEMPEL 8 19DK 169122 B1 EXAMPLE 8 19

Der blev fremstillet tyggetabletter ifølge opfindelsen ud fra følgende bestanddele:Chewable tablets according to the invention were prepared from the following ingredients:

Protein Calcium- Intet casein Sur 5 caseinat caseinProtein Calcium- No casein Sur 5 caseinate casein

Pektin* 14,8 14,8 14,8 14,8Pectin * 14.8 14.8 14.8 14.8

Calciumcaseinat - 30,8Calcium caseinate - 30.8

Syre - - - 30,8 10 Sojaprotein 30,8Acid - - - 30.8 10 Soy protein 30.8

Kaliumhydro- gencarbonat 7,2 7,2 7,2 7,2Potassium bicarbonate 7.2 7.2 7.2 7.2

Magnesiumsub- carbonat 18,6 18,6 18,6 18,6 15 Tabletteringshjælpe- stoffer, aromastoffer og sødemidler 28,6 28,6 28,6 28,6 1 tablet 1200 mg 1200 mg 830 mg 1200 mg 20 _Magnesium subcarbonate 18.6 18.6 18.6 18.6 15 Tablet excipients, flavorings and sweeteners 28.6 28.6 28.6 28.6 1 tablet 1200 mg 1200 mg 830 mg 1200 mg 20 _

Skumning 24 ml 10 ml 20 ml 24 ml * Lavmethoxyleret pektin med en methoxyleringsgrad på op til 5% ved at blande bestanddelene og komprimere blandingen til tabletter på 25 i og for sig kendt måde.Foaming 24 ml 10 ml 20 ml 24 ml * Low methoxylated pectin with a degree of methoxylation of up to 5% by mixing the ingredients and compressing the mixture into tablets in a manner known per se.

Præparaterne blev testet i det væsentlige som beskrevet i eksempel 5 og 6 for den opnåede grad af skumning. Resultaterne er vist ovenfor.The compositions were tested essentially as described in Examples 5 and 6 for the degree of foaming obtained. The results are shown above.

Det fremgår af tabellen, at sojaprotein er sammenlignelig med sur casein med hensyn til skumning.The table shows that soy protein is comparable to acidic casein in terms of foaming.

DK 169122 B1 EKSEMPEL 9 20DK 169122 B1 EXAMPLE 9 20

Klinisk afprøvning af præparatet ifølge opfindelsenClinical trial of the composition according to the invention

Præparatet ifølge eksempel 1 blev testet for dets terapeutiske virkning, eventuelle bivirkninger samt acceptering i sammenligning med 5 konventionelle antacida (Balancid® [består af aluminiumhydroxid og magnesiumcarbonat], Novaluzid® [består af aluminiumhydroxid, magnesiumhydroxid og magnesiumcarbonat], Link® [består af aluminiumhydroxid og magnesiumcarbonat] og Titralac [består af calciumcarbo-nat]).The preparation according to Example 1 was tested for its therapeutic effect, possible side effects as well as acceptance in comparison with 5 conventional antacids (Balancid® [consists of aluminum hydroxide and magnesium carbonate], Novaluzid® [consists of aluminum hydroxide, magnesium hydroxide and magnesium carbonate], Link® [consists of aluminum hydroxide and magnesium carbonate] and Titralac [consists of calcium carbonate]).

10 Undersøgelsen blev foretaget på ambulatoriet ved den gastroenterolo-giske medicinske afdeling, Ullevål Hospital, Oslo, Norge, fra februar til maj 1986. Undersøgelsen omfattede 20 patienter (12 mænd og 8 kvinder med en alder på mellem 23 og 64 år), som havde symptomer på øvre abdominal dyspepsi, og hvis informerede samtykke var opnået.The study was conducted at the outpatient department of the gastroenterological medical department, Ullevål Hospital, Oslo, Norway, from February to May 1986. The study included 20 patients (12 men and 8 women aged between 23 and 64 years) who had symptoms of upper abdominal dyspepsia and if informed consent was obtained.

15 Gennemsnitsalderen var 40 år. 15 af patienterne anvendte Balancid® på det tidspunkt, de blev inkluderet i undersøgelsen. Patienter blev udelukket fra undersøgelsen, hvis de led af et gastroskopisk verificeret peptisk ulcus, erosive præpyloriske ændringer, alvorlig gastritis eller andre organiske gastrointestinale sygdomme, som kunne for-20 klare tilstedeværelsen af symptomer, eller hvis de brugte medikamenter, som vides at påvirke mave-tarmkanalen. Alle de patienter, der var omfattet af undersøgelsen, blev således diagnosticeret til at lide af non-ulcus-dyspepsi (NUD) .15 The average age was 40 years. 15 of the patients used Balancid® at the time they were included in the study. Patients were excluded from the study if they suffered from a gastroscopically verified peptic ulcer, erosive prepyloric changes, severe gastritis or other organic gastrointestinal diseases that could explain the presence of symptoms, or if they used drugs that are known to affect the stomach. intestinal tract. Thus, all the patients included in the study were diagnosed with non-ulcer dyspepsia (NUD).

Patienterne besøgte klinikken to gange, ved begyndelsen af testbe-25 handlingen og efter to ugers behandling. Tre af patienterne dukkede ikke op til den anden konsultation, hvilket gav terapeutiske resultater fra 17 patienter. Under testperioden udfyldte patienterne hver dag en doseringsformular og optegnede de bivirkninger og uønskede reaktioner, der blev oplevet. Under perioden på to uger blev præpara-30 tet ifølge eksempel 1 taget efter behov; der blev imidlertid ikke taget mere end to tabletter ad gangen. 13 af patienterne tog præparatet ifølge den foreliggende opfindelse under hele perioden med en gennemsnitlig indtagelse af 52 tabletter (i området 19-100). Fire af patienterne holdt op med at tage præparatet ifølge opfindelsen før tiden; DK 169122 B1 21 patient nr. 3 efter 7 dage, fordi han var nødt til at tage Balancid® som før og derfor ikke så nogen grund til at fortsætte behandlingen med præparatet ifølge opfindelsen; patient nr. 5 efter 8 dage, fordi han var symptomfri; nr. 11, fordi indtagelse af to doser på den før-5 ste dag førte til kvalme og opkastning; og nr. 18 efter 9 dage på grund af hospitalsindlæggelse med kraftig opkastning og dehydrering (diagnosticeret som alvorlig gastritis - skyldtes ikke indtagelse af præparatet ifølge opfindelsen).Patients visited the clinic twice, at the beginning of the test treatment and after two weeks of treatment. Three of the patients did not show up for the second consultation, yielding therapeutic results from 17 patients. During the test period, patients filled out a dosing form each day and recorded the side effects and adverse reactions experienced. During the two-week period, the preparation of Example 1 was taken as needed; however, no more than two tablets were taken at a time. Thirteen of the patients took the composition of the present invention during the entire period with an average intake of 52 tablets (in the range 19-100). Four of the patients stopped taking the preparation according to the invention prematurely; DK 169122 B1 21 patient no. 3 after 7 days because he had to take Balancid® as before and therefore saw no reason to continue treatment with the preparation according to the invention; patient No. 5 after 8 days because he was asymptomatic; No. 11 because ingestion of two doses on the first-5 days led to nausea and vomiting; and No. 18 after 9 days due to hospitalization with severe vomiting and dehydration (diagnosed as severe gastritis - was not due to ingestion of the preparation according to the invention).

En afsluttende samlet vurdering af præparatet ifølge opfindelsen blev 10 opnået fra 17 patienter; 11 af patienterne var tilfredse med testbehandlingen, 3 anså den for at være lige så god som tidligere behandling, mens 3 var utilfredse (to af patienterne på grund af en utilstrækkelig virkning og én på grund af kvalme/opkastning). Virkningen af præparatet ifølge opfindelsen er vist i tabel 6 med hensyn til 15 forskellige symptomer, der blev noteret ifølge alvorlighed og varighed.A final overall assessment of the composition of the invention was obtained from 17 patients; 11 of the patients were satisfied with the test treatment, 3 considered it to be as good as previous treatment, while 3 were dissatisfied (two of the patients due to an insufficient effect and one due to nausea / vomiting). The effect of the composition according to the invention is shown in Table 6 with respect to 15 different symptoms, which were noted according to severity and duration.

Resultaterne blev analyseret statistisk under anvendelse af Students T-test, p=0,05. Variabler med formodet kontinuert fordeling blev analyseret under anvendelse af ikke-parametriske tests. For variabler 20 med ikke-kontinuert fordeling blev der anvendt kategoridataanalyse.The results were statistically analyzed using Student's T test, p = 0.05. Variables with putative continuous distribution were analyzed using non-parametric tests. For variables 20 with non-continuous distribution, category data analysis was used.

TABEL 6TABLE 6

Symptomer Forbedret Uændret ForværretSymptoms Improved Unchanged Deteriorated

Regurgitation 10 6 0 p<0,01 25 Halsbrand 763 p=0,14Regurgitation 10 6 0 p <0.01 25 Heartburn 763 p = 0.14

Epigastrisk smerte 13 2 1 p<0,01Epigastric pain 13 2 1 p <0.01

Abdominal smerte 5 10 1 p=0,llAbdominal pain 5 10 1 p = 0, ll

Kvalme 10 6 0 p<0,01Nausea 10 6 0 p <0.01

Opkastning 4 12 0 p=0,13 30 -Vomiting 4 12 0 p = 0.13 30 -

Resultaterne viser, at regurgitation, epigastrisk smerte og kvalme blev signifikant reduceret (p<0,01) under testperioden på to uger, mens halsbrand, abdominal smerte og opkastning blev forbedret, men DK 169122 B1 22 ikke var statistisk signifikante. Latensperioder og virkningsvarigheden fremgår af tabel 7 og 8.The results show that regurgitation, epigastric pain and nausea were significantly reduced (p <0.01) during the two-week test period, while heartburn, abdominal pain and vomiting were improved, but DK 169122 B1 22 were not statistically significant. Latency periods and duration of action are shown in Tables 7 and 8.

TABEL 7TABLE 7

Latensperiode (minutter) 5 Tidligere Præparat ifølge Forskel behandling opfindelsenLatency Period (minutes) 5 Previous Preparation According to the Difference Treatment Invention

Antal patienter 12 13 10Number of patients 12 13 10

Middel 21,6 18,8 -5,9 10 Median 17,5 15 -3,5Mean 21.6 18.8 -5.9 10 Median 17.5 15 -3.5

Område 0,5-60 1-60 (-40)-50 p=0,24 TABEL 8Range 0.5-60 1-60 (-40) -50 p = 0.24 TABLE 8

Virkningsvarighed (timer) 15 Tidligere Præparat ifølge Forskel behandling opfindelsenDuration of action (hours) Previous Preparation according to the Difference treatment invention

Antal patienter 11 13 9Number of patients 11 13 9

Middel 5,3 7,1 0,8 20 Median 3,5 5 2,5Mean 5.3 7.1 0.8 20 Median 3.5 5 2.5

Område 1-24 1-24 (-23)-17 p=0,10Range 1-24 1-24 (-23) -17 p = 0.10

Det fremgår af tabellerne, at værdierne varierede i betydelig grad, men varighedsprofilen havde en tendens til at blive større med præ-25 paratet ifølge opfindelsen end med de konventionelle antacida, der blev benyttet som kontrol.It appears from the tables that the values varied considerably, but the duration profile tended to be greater with the preparation according to the invention than with the conventional antacids used as a control.

Det fremgår af disse resultater, at præparatets virkning er bedre end tidligere antacidbehandling.These results show that the effect of the drug is better than previous antacid treatment.

DK 169122 B1 EKSEMPEL 10 23DK 169122 B1 EXAMPLE 10 23

Præparatet ifølge eksempel 3 blev radioaktivt mærket med indium-113m, og præparatets fordeling og opholdstid i maven blev derpå målt i 5 seks sunde personer under anvendelse af ganuna-scintigrafiteknikken, og formuleringens virkning på maveudtømningen af et testmåltid blev målt.The preparation according to Example 3 was radiolabeled with indium-113m, and the distribution and residence time of the preparation in the stomach were then measured in 5 six healthy persons using the ganuna scintigraphy technique, and the effect of the formulation on the gastric emptying of a test meal was measured.

Fire sunde mænd og 2 sunde kvinder, alder 18-25 år, deltog i forsøget. Udelukkelseskriterier omfattede vægt uden for området ± 10% 10 af gruppens middelvægt, forbrug af medikamenter, som kunne påvirke resultatet af undersøgelsen, en sygdomshistorie med gastrointestinale lidelser, stort tobaks- eller alkoholforbrug eller deltagelse i en lignende undersøgelse inden for de foregående 12 måneder. Kvinder, som ikke havde haft menstruation inden for de foregående 28 dage, 15 blev også udelukket. Der blev opnået skriftligt, informeret samtykke fra personerne, før de gik i gang med forsøget.Four healthy men and 2 healthy women, ages 18-25, participated in the trial. Exclusion criteria included out-of-range weight ± 10% 10 of the group's mean weight, drug use that could affect the outcome of the study, a history of gastrointestinal disorders, heavy tobacco or alcohol consumption, or participation in a similar study within the previous 12 months. Women who had not menstruated within the previous 28 days, 15 were also excluded. Written, informed consent was obtained from the persons before embarking on the experiment.

Personerne lodes faste natten over, og om morgenen fik de en radioaktivt mærket morgenmad bestående af røræg med følgende sammensætning: 2 æg (60 g) radioaktivt mærket med 1 MBq technetium-99m-svovlkolloid 20 tilsat ægget før kogning, 30 ml mælk, 25 g smør, 2 skiver toastbrød, 200 ml usødet appelsinjuice.The subjects were fasted overnight and in the morning were given a radiolabelled breakfast consisting of scrambled eggs with the following composition: 2 eggs (60 g) radiolabeled with 1 MBq technetium-99m sulfur colloid 20 added to the egg before boiling, 30 ml milk, 25 g butter, 2 slices of toast, 200 ml of unsweetened orange juice.

25 Samlet kalorieværdi 1693 kJ.25 Total caloric value 1693 kJ.

Røræggene blev mærket ved tilsætning af technetium-99m-svovlkolloidet til bestanddelene før kogning.The scrambled eggs were labeled by adding the technetium-99m-sulfur colloid to the ingredients before boiling.

30 minutter senere fik personerne to tabletter svarende til eksempel 3. Tabletterne var blevet radioaktivt mærket med 3 MBq indium-113m.Thirty minutes later, the subjects received two tablets similar to Example 3. The tablets had been radiolabeled with 3 MBq of indium-113m.

DK 169122 B1 24DK 169122 B1 24

Tabletterne var blevet mærket ved tilsætning af 3 MBq indium-113m i 1 ml 0,04 M saltsyre til 2 knuste tabletter indeholdende præparatet ifølge eksempel 3, og det hele blev omrørt, indtil der var dannet en ensartet pasta. Denne blev tilsat 125 ml simuleret mavesaft (USP-5 formulering) ved 37°C. Blandingen blev omrørt til dannelse af en suspension i syren. 2 ml prøver af blandingen blev fjernet med intervaller og centrifugeret ved 2500 omdr./minut. Pelleten blev vasket ved resuspendering i destilleret vand og ved recentrifugering. Prøver af pektinet, vaskevandet og supernatanten blev talt for at bedømme 10 tenacitet af det radioaktive stof til pektinet.The tablets had been labeled by adding 3 MBq of indium-113m in 1 ml of 0.04 M hydrochloric acid to 2 crushed tablets containing the preparation of Example 3, and the whole was stirred until a uniform paste was formed. This was added to 125 ml of simulated gastric juice (USP-5 formulation) at 37 ° C. The mixture was stirred to form a suspension in the acid. 2 ml samples of the mixture were removed at intervals and centrifuged at 2500 rpm. The pellet was washed by resuspension in distilled water and by recentrifugation. Samples of the pectin, wash water and supernatant were counted to assess the tenacity of the radioactive substance for the pectin.

Der blev udført et "cross-over"-forsøg med én uges interval. Anatomiske referencemarkører blev fremstillet ved at tørre små mængder technetium-99m på 0,5 x 0,5 cm^ filtrerpapirstykker og dække dem med vandtæt tape. Markørerne blev sat på personernes hud fortil og bag-15 til, modsat maven, for at fungere som referencepunkt for indstilling af billeder.A "cross-over" trial was performed at one week intervals. Anatomical reference markers were prepared by wiping small amounts of technetium-99m on 0.5 x 0.5 cm 2 pieces of filter paper and covering them with waterproof tape. The markers were placed on the person's skin front and back 15 to, opposite the abdomen, to serve as a reference point for setting images.

Billeder fortil og bagtil af 30 sekunders varighed blev taget med 15 minutters intervaller, indtil maven var tom (ca. 5 timer). Technetium- og indiumbilledeme blev taget samtidigt, men lagret separat i 20 computeren til senere analyse.Front and back images of 30 seconds duration were taken at 15 minute intervals until the abdomen was empty (approximately 5 hours). The technetium and indium images were taken simultaneously, but stored separately in the computer for later analysis.

Hvert billede blev analyseret ved at skabe tre områder af interesse, ét rundt om hele maven, det andet rundt om den øverste halvdel af maven og det tredje for at bedømme baggrundsaktivitet. Tællingerne fra områderne af interesse blev korrigeret for baggrund og henfald.Each image was analyzed by creating three areas of interest, one around the entire abdomen, the other around the upper half of the abdomen, and the third to assess background activity. The counts from the areas of interest were corrected for background and decay.

25 Tællingerne for technetium blev også korrigeret for overlapning af indiumenergien ind i technetiumkanalen. Den geometriske middelværdi af aktiviteten i områderne af interesse i billederne fortil og bagtil blev udregnet for at korrigere for dæmpning.The technetium counts were also corrected for overlap of the indium energy into the technetium channel. The geometric mean of the activity in the areas of interest in the front and rear images was calculated to correct for attenuation.

Mere end 86% af indium- 113m viste sig at være forbundet med pektin-30 fasen efter to timers inkubation med simuleret mavesaft ved 37°C in vitro. Dette fastslog mærkets egnethed til, at man kunne følge denne formulerings opførsel ved gamma-scintigrafi.More than 86% of the indium-113m was found to be associated with the pectin-30 phase after two hours of incubation with simulated gastric juice at 37 ° C in vitro. This established the suitability of the mark for following the behavior of this formulation by gamma scintigraphy.

DK 169122 Bl 25DK 169122 Bl 25

Præparatet ifølge opfindelsen udtømtes signifikant senere end test-måltidet, og over 50% af dosen forblev i fundus i 3 timer. Den tid, det tog for halvdelen af formuleringen og maden at forlade maven (T50) for hver person, er vist i tabel 9, og gennemsnitlige T5Ø-5 værdier ± sd er henholdsvis 4,13 ± 0,69 timer og 2,17 + 0,15 timer. Præparatet ifølge opfindelsen viste sig ikke at have nogen signifikant virkning på mavetømningen af testmåltidet med T5Q-værdier på 2,17 ± 0,15 timer og 1,7 ± 0,32 timer for henholdsvis medikament og placebo.The composition of the invention was emptied significantly later than the test meal and over 50% of the dose remained in the fundus for 3 hours. The time it took for half of the formulation and the food to leave the stomach (T50) for each person is shown in Table 9, and mean T5Ø-5 values ± sd are 4.13 ± 0.69 hours and 2.17 +, respectively. 0.15 hours. The composition of the invention was found to have no significant effect on the gastric emptying of the test meal with T5Q values of 2.17 ± 0.15 hours and 1.7 ± 0.32 hours for drug and placebo, respectively.

10 TABEL 910 TABLE 9

Tid (timer) for at tømme maven halvtTime (hours) to empty the stomach halfway

Person Præparat Føde + præparat Føde + placebo 1 4,4 2,2 1,4 15 2 4,1 2,1 1,4 3 4,36 2,3 1,6 4 4,6 2,25 2,3 5 4,25 2,25 2,0 6 2,8 1,9 1,7 20 Middel ± s.d. 4,13 ± 0,69 2,17 ± 0,15 1,7 ± 0,32 EKSEMPEL 11 DK 169122 B1 26Person Preparation Food + preparation Food + placebo 1 4.4 2.2 1.4 15 2 4.1 2.1 1.4 3 4.36 2.3 1.6 4 4.6 2.25 2.3 5 4.25 2.25 2.0 6 2.8 1.9 1.7 20 Mean ± sd 4.13 ± 0.69 2.17 ± 0.15 1.7 ± 0.32 EXAMPLE 11 DK 169122 B1 26

Der blev fremstillet en brusetablet ifølge opfindelsen ud fra følgende bestanddele:An effervescent tablet according to the invention was prepared from the following ingredients:

Citronsyre 800 mg 5 Kaliumhydrogencarbonat 500 mgCitric acid 800 mg 5 Potassium bicarbonate 500 mg

Natriumhydrogencarbonat 500 mgSodium bicarbonate 500 mg

Magnesiumsubcarbonat 480 mgMagnesium subcarbonate 480 mg

Pektin* 380 mgPectin * 380 mg

Casein 380 mg 10 Tabletteringshj ælpestoffer, aromastof, farvestof og sødemiddel 960 mg 4000 mg 15 * Lavmethoxyleret pektin med en methoxyleringsgrad på op til 5% Mængden af skumning efter 30 minutter var 35 ml, når præparatet blev testet som beskrevet i eksempel 5 og 6.Casein 380 mg 10 Tablets, flavoring, coloring and sweetening agents 960 mg 4000 mg 15 * Low methoxylated pectin with a degree of methoxylation of up to 5% The amount of foaming after 30 minutes was 35 ml when the preparation was tested as described in examples 5 and 6.

EKSEMPEL 12EXAMPLE 12

Præparat ifølge opfindelsen, hvor der blev anvendt pektin med en 20 methoxyleringsgrad på 21%, blev testet for virkningen af at inkorporere forskellige buffersubstanser som aminosyrerne tryptofan og methionin.A composition according to the invention, in which pectin with a degree of methoxylation of 21% was used, was tested for the effect of incorporating various buffer substances such as the amino acids tryptophan and methionine.

DK 169122 B1 27DK 169122 B1 27

Bestanddel Mængder i vægtprocentIngredient Quantities in weight percent

Pektin 16,1 11,3 11,3Pectin 16.1 11.3 11.3

Sorbitol 54,5 38,5 38,5 5 Magnesiumsubcarbonat 19,8 14,0 14,0Sorbitol 54.5 38.5 38.5 5 Magnesium subcarbonate 19.8 14.0 14.0

Kaliumhydrogen- carbonat 7,6 5,4 5,4Potassium bicarbonate 7.6 5.4 5.4

Siliciumdioxid 0,5 0,4 0,4Silica 0.5 0.4 0.4

Calciumstearat 1,5 1,0 1,0 10 Tryptofan - 29,4Calcium Stearate 1.5 1.0 1.0 10 Tryptophan - 29.4

Methionin - - 29,4 100,0 100,0 100,0 15 Skumvo lumen ml 33 38 43Methionine - - 29.4 100.0 100.0 100.0 15 Foam lumen ml 33 38 43

Det fremgår, at tilsætning af buffer giver øget skumvolumen.It appears that the addition of buffer gives increased foam volume.

EKSEMPEL 13EXAMPLE 13

Præparat ifølge opfindelsen, hvor der blev anvendt pektin med en 20 methoxyleringsgrad på 21%, blev testet for virkningen af at inkorporere forskellige buffersubstanser som sojaproteinisolat og aminosyren methionin. Proteinisolatet var en hydrolyseret kvalitet af hensyn til opløseligheden.Compositions of the invention using pectin with a degree of methoxylation of 21% were tested for the effect of incorporating various buffer substances such as soy protein isolate and the amino acid methionine. The protein isolate was a hydrolyzed grade for solubility.

DK 169122 B1 28DK 169122 B1 28

Bestanddel Mængder i vægtprocentIngredient Quantities in weight percent

Pektin 16,1 11,3 11,3Pectin 16.1 11.3 11.3

Kaliumhydrogen- carbonat 7,6 5,4 5,4Potassium bicarbonate 7.6 5.4 5.4

Siliciumdioxid 0,5 0,4 0,4Silica 0.5 0.4 0.4

Calciumstearat 1,5 1,0 1,0 10 Sojaproteinisolat - 29,4Calcium Stearate 1.5 1.0 1.0 10 Soy Protein Isolate - 29.4

Methionin - - 29,4 100,0 100,0 100,0 15 Maksimal pH 7,7 5,2 5,7Methionine - - 29.4 100.0 100.0 100.0 Maximum pH 7.7 5.2 5.7

Latensperiode min.Latency period min.

til maksimal pH 80 25 10to maximum pH 80 25 10

Varighed min. 288 215 175 20 Det ses, at der ved tilsætning af buffer opnås et lavere maksimalt pH, hvilket ligger betydeligt nærmere det optimale område pH 3-5, samtidig med, at latensperioden bliver væsentligt forkortet.Duration min. 288 215 175 20 It is seen that by adding buffer a lower maximum pH is obtained, which is significantly closer to the optimal range pH 3-5, at the same time as the latency period is significantly shortened.

DK 169122 B1 29DK 169122 B1 29

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abstract.abstract.

Claims

An antacid composition containing pectin and antacids, characterized in that it contains a) a pectin or a salt thereof, b) one or more antacids capable of being trapped in the gel structure formed by the low methoxy clay pectin at an acidic pH, at least one of the agents causing the gel to foam upon contact with an acid and is a carbonate, bicarbonate or subcarbonate or a mixture thereof, and c) a substance capable of acting as a buffer, and which is capable of being trapped in the gel structure formed by the pectin at acidic pH.

Composition according to Claim 1, characterized in that the pectin is an amidated pectin.

Composition according to Claim 1 or 2, characterized in that the acid-neutralizing agent listed under b) is a pharmaceutically acceptable alkali metal or alkaline earth metal salt, preferably sodium, potassium, magnesium or calcium salt, an aluminum salt, an ammonium salt , preferably ammonium -20 carbonate and ammonium hydrocarbonate salt or a bismuth salt, preferably bismuth carbonate salt.

Composition according to Claim 3, characterized in that the antacid indicated under b) is a carbonate, bicarbonate or subcarbonate or a combination thereof with an oxide or hydroxide of an alkali metal or alkaline earth metal such as sodium, potassium, magnesium or calcium, or of aluminum. DK 169122 B1 31

Composition according to Claim 1, characterized in that at least one of the acid-neutralizing agents which causes the gel to foam on contact with an acid is chosen from alkali metal bicarbonates and carbonates.

The composition according to claim 1, characterized in that the substance listed under c) in claim 1 is further capable of giving the gel formed by the low methoxylated pectin at an acidic pH a greater stiffness.

Composition according to Claim 67, characterized in that the substance is a proteinaceous substance, preferably casein or a caseinate such as sodium, potassium or ammonium caseinate, milk powder, gelatin, a vegetable protein such as a soy protein isolate or an amino acid (such as glycine) or a salt thereof.

Composition according to Claim 1, characterized in that the substance listed under c) in claim 1 is a phosphate, preferably sodium, calcium, magnesium, ammonium, aluminum and potassium phosphate.

Composition according to Claim 1, 20, characterized in that it is in the form of a chewable tablet or is formulated as a liquid.

Composition according to Claim 1, characterized in that component a) is present in an amount of 1-50% by weight per unit dose of the preparation.

Composition according to Claim 1, characterized in that component c) is present in an amount of up to 50% by weight per unit dose of the preparation.

Composition according to Claim 1, characterized in that component a) and component c) are present in substantially equal amounts. DK 169122 B1 32

Composition according to Claim 1, characterized in that the acid neutralizing agent b) is present in an amount of 1-30% by weight per liter. unit dose of the preparation.

Composition according to Claim 1, characterized in that the acid neutralizing agent b) is present in an amount of at least 5 milliequivalents of base per unit dose of the preparation.

Composition according to Claim 1, 10, characterized in that the acid neutralizing agent b) is magnesium subcarbonate in combination with potassium bicarbonate.