WO2018229789A1 - Composé antiacide de base inorganique présentant des propriétés améliorées et nouvelles - Google Patents

Composé antiacide de base inorganique présentant des propriétés améliorées et nouvelles Download PDF

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Publication number
WO2018229789A1
WO2018229789A1 PCT/IN2018/050364 IN2018050364W WO2018229789A1 WO 2018229789 A1 WO2018229789 A1 WO 2018229789A1 IN 2018050364 W IN2018050364 W IN 2018050364W WO 2018229789 A1 WO2018229789 A1 WO 2018229789A1
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Prior art keywords
antacid
compound
solution
magnesium
aluminium
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PCT/IN2018/050364
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English (en)
Inventor
Jui Chakraborty
Sayantan RAY
Suman SAHA
Bishwanath SA
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Council Of Scientific & Industrial Research
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Publication of WO2018229789A1 publication Critical patent/WO2018229789A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to an inorganic base antacid compound with improved and novel properties. More particularly, the present invention relates to an inorganic base gastrointestinal tract agent for treatment of hyperacidity.
  • Gastric acid is a colourless, watery, acidic digestive fluid secreted from the parietal or oxyntic cells present in the stomach, continuously. It has a pH of 1-2, comprises mainly of hydrochloric acid (HCl) (around 0.5% or 5000 ppm), along with large quantities of potassium and sodium salts. HCl kills the bacteria that enters the stomach and converts the inactive enzyme pepsinogen into active enzyme pepsin that is responsible for digestion of proteins/other foods in the stomach.
  • HCl hydrochloric acid
  • Hyperacidity is generally a consequence of several external factors like eating habits, fad diets, stress, smoking and alcohol consumption, lack of physical activity, irregularity in eating pattern and certain medications like non steroidal anti-inflammatory drugs (NSAID's) also predisposes individuals to gastric acidity. Antacids are used to neutralize the excess of gastric acidity, a condition which is known as hyperchlorhydria (hyperacidity).
  • inorganic base antacids there are two classes of inorganic base antacids: a.) systemic (alkalotic agents, e.g., sodium bicarbonate injection and tablets) and b.) non-systemic (e.g., aluminium hydroxide gel IP, milk of magnesia, calcium carbonate IP, BP).
  • systemic antacids exhibit rapid action and are easily absorbed in the systemic circulation although are capable of raising the pH of the blood leading to severe systemic alkalosis.
  • non systemic antacids e.g., aluminium hydroxide gel
  • the acid -base neutralization reaction maintains a reversible equilibrium leading to slow and sustained action:
  • Aluminium containing antacids commonly binds to dietary phosphate within the gastrointestinal tract to form insoluble salt, i.e., aluminium phosphate that can lead to hypophosphatemia and constipation simultaneously.
  • antacids exhibit cytoprotective effect on gastric mucosal layer and are known to heal gastric and duodenal ulcerations, although the mechanism is still unknown. They relieve the pain of peptic ulcer and help to reduce spasms and cause symptomatic relief to pain. As the actual mechanism of relieving pain is not known, the evaluation of antacids is done quantitatively in terms of their acid neutralizing capacity (ANC) value.
  • the ANC value is defined as the number of milliequivalents of hydrochloric acid required to maintain 1.0 ml of an antacid suspension at pH 3 for a period of 2 h, in vitro. Antacids have been used for the past 2000 years and the initial compounds were based on calcium carbonate (coral/limestone).
  • the antacid market is a significant income stream for the pharmaceutical industry and the demand is expected to grow. The number of people suffering from heartburn increases with an increasing ageing population and more stressful lifestyle, eating habits, addiction to smoke, alcohol etc.
  • Inorganic based antacids as above are over the counter (OTC) products and most of the OTC products available commercially are either bicarbonate or hydroxide based salts.
  • OTC counter
  • bicarbonate salts provide instant relief due to rapid onset of action but are unable to provide long term buffering capacity and hence exhibit 'acid rebound effect' within a short period of time.
  • Another disadvantage of such type of compound is that, it might lead to severe alkalosis due to enhanced solubility of the alkali metal ions.
  • hydroxide based compounds are slow in action and hence, fail to provide instant relief analogous to bicarbonate salts.
  • the criteria of an 'ideal inorganic antacid' are:
  • a relatively small amount of antacid should be sufficient to neutralize a substantial amount of gastric juice in a short time.
  • the antacid effect should last for a reasonable amount of time.
  • the neutralization, by the antacid should give a pH in the range 3.5 to 4.5. It is known that at pH 5.00 and above, there is an increase in the bacterial growth due to fermentation and an increase in histamine stimulates an increased acid secretion, which also occurs at pH 7 and above that results in an increased 'acid rebound' effect.
  • the carbon dioxide production during the neutralization reaction should be minimal, so that enlargement of the gastric wall and flatulence can be avoided.
  • a pharmaceutical compound comprising a phosphate ion containing hydrotalcite having formula Mg x Al 2 (OH) 2x+6 - n izi- n2z2 (Ai nl ⁇ ) zl (A 2 n2 ⁇ ) z2 .mH 2 0, where Ai nl" represents at least one anion having a valence of ni selected from the group consisting H 2 P0 4 — and HP0 4 2- " and P0 4 3" , A 2 n2 ⁇ represents at least one anion having a valence n 2 other than Ai nl ⁇ and x, zi, z 2 and m are positive numbers given as, 2 ⁇ x ⁇ 40, 0 ⁇ x ⁇ 2, 0 ⁇ z 2 ⁇ 2, 0 ⁇ m ⁇ 40, 0 ⁇ zi+ z 2 ⁇ 2 and a pharmaceutically acceptable diluents/carrier and a method for controlling the pH of the gastric juice, using the abovesaid phosphate ion
  • hydrotalcite in this patent, a process by which hydrotalcite can be synthesized with industrial ease has been described that exhibits antacid property, having chemical formula, Al 2 0 3 .6MgO.C0 2 .12H 2 0 or Mg 6 Al 2 (OH)i 6 C0 3 .4H 2 0, although it does not reveal any parameter (buffering action/acid neutralizing capacity) related to antacid activity.
  • the aluminium component can be from the group consisting of aluminium hydroxide, basic aluminium carbonate, aluminium hydroxide-alkali carbonate complexes, aluminium amino acid salts, aluminium alcoholates, water-soluble aluminium salts, and water-soluble aluminates, and the said magnesium component being selected from the group consisting of magnesium oxide, magnesium hydroxide, magnesium carbonate and water-soluble magnesium salts.
  • reaction temperature in the range of 0-150°C has been mentioned, primarily depending on the type of the aluminium and magnesium components. In this condition, the loss of water of hydration from the hydrotalcite structure may occur, leading to lack of equilibrium and loss in antacid property of the same.
  • the aluminium hydroxide gel can be produced by reacting an aluminium compound soluble in water and/or lower alcohols with a carbonate ion yielding compound soluble in water and/or lower alcohols at a pH of 6 to 9.5 under such conditions that the C0 2 /A1 mole ratio of the resulting aluminium hydroxide gel is at least about 0.1, and ion exchanging the alkali metals of the resulting compound with magnesium and/or calcium, it provides an antacid compound comprising said aluminium hydroxide gel as an active ingredient.
  • modified aluminium hydroxide gel having compound (K 2 0,Na 2 0) p .Ai 2 0 3 .(C0 2 ) q .rH 2 0 has also been proposed that exhibits improved rate of reaction and aging resistance, although leads to renal trouble and hypertension at the same time which could be attributed to sodium and potassium ions under physiological condition. Additionally, the method of synthesis of the said compound and the insertion of the active ingredients (cations) has not been clearly stated. Also, most importantly, the parameters, e.g., acid neutralizing capacity and buffering action of the claimed compound with respect to the conventional aluminium hydroxide gel has not been mentioned/represented.
  • the existing hydrotalcite and hydrocalumite based compounds that exhibit antacid properties are very limited in number.
  • the time dependent variation of pH is as following:
  • the present invention addresses such problems existing in the prior-art documents in an effective way.
  • the present invention relates to an inorganic base antacid compound, having chemical formula Ca x Mg y .Al z (C03) a .(OH)b.mH 2 0, wherein l ⁇ x ⁇ 6, 0.2 ⁇ y ⁇ 3, 0.15 ⁇ z ⁇ 2.5, 0.05 ⁇ a ⁇ 2, 5 ⁇ b ⁇ 12 and 0.5 ⁇ m ⁇ 5. Further, the present invention also provides process for the preparation of said antacid compound. OBJECT OF THE INVENTION
  • the main object of the present invention is to provide an inorganic base antacid compound with improved and novel properties which obviates the drawbacks of the hitherto known prior art as detailed above.
  • Another object of the present invention is to provide a single step cost effective process, using easily available precursors, to obtain the antacid compound, as active pharmaceutical ingredient (API).
  • Still another object of the present invention is to provide a high acid neutralizing capacity of the API as above.
  • Yet another object of the present invention is to provide a prolonged buffering action by inclusion of calcium and aluminium ions in the chemical structure of the API.
  • Another object of the present invention is to provide a higher efficacy at a low dose (single dose).
  • Still another object of the present invention is to provide rapid onset of action of the inorganic base antacid compound.
  • the present invention provides an inorganic base antacid compound with improved and novel properties which comprises a modified hydrotalcite, prepared by a simple laboratory technique based on coprecipitation method, which involves reacting a mixture of a calcium source involving a soluble salt of calcium, a magnesium source involving a soluble salt of magnesium, and a soluble salt of aluminium, titrated using an alkali, e.g., sodium/ammonium hydroxide under room temperature conditions, at a constant rotation speed of 1000-1400 rpm, to attain the pH in the range 10-12, for completion of the precipitation, followed by separation of the precipitate by vacuum suction and washing using ultrapure water (specific resistivity: 18.2 ⁇ ), dried using air oven in the temperature range (80-100°C) for a period of 22-25h, the molar ratio of magnesium to aluminium is in the range of 1.8: 1 to about 2.2: 1, the bivalent magnesium ion has been partially substituted by bivalent calcium ion, so that out of 1.9
  • the antacid compound of the present invention is useful for the treatment of hyperchlorhydria.
  • the magnesium ion is taken as involving a soluble salt of magnesium.
  • the aluminium ion used comprises a soluble salt of aluminium.
  • the calcium ion used is comprises a soluble salt of calcium.
  • the molar ratio of the bivalent metal ions (calcium and magnesium): trivalent metal ion (aluminium) in the antacid compound is X:Y:Z (calcium:magnesium:aluminium) which is represented as 2 ⁇ X ⁇ 6, 0.1 ⁇ Y ⁇ 3 and 0.05 ⁇ Z ⁇ 2.
  • the hydroxy! ion used is selected from the group consisting of sodium or ammonium hydroxide.
  • the carbonate ion used is selected from the group consisting of sodium carbonate and sodium hydroxide pellets, taken in 2:1 ratio by weight.
  • solution A a) weighing the precursor salts of calcium, magnesium and aluminium as per the given molar ratio and preparing the mixed metal solution of the same in aqueous medium, termed as solution A;
  • solution B a solution of the same in aqueous medium which is termed as solution B;
  • the API is a white, free flowing, odourless, tasteless powder having particle size in the range of 2-10 ⁇ .
  • the percentage yield of the active ingredient is in the range of 95-98%, when synthesized following the optimum process parameters as above.
  • the percent purity of the active ingredient is 99-102%.
  • pH of the API at 5 min is 1.99- 2.08, 15 min is 2.83-3.12 and 25 min is 3.5-4.2, 60 min 4.5-4.6, 120 min 4.9-5.3, 240 min 5.5-5.75, 360 min 5.8-6.2, at a dose of 170-180 mg/60 kg b.w.
  • the API is insoluble in water, organic solvents and dilute alkali medium and it is freely soluble in dilute mineral acids.
  • the effective dose (single dose) of the API is in the range 170-180mg/60 kg human body weight.
  • the acid neutralizing capacity of the API is in the range of 9-10 mEq/170-180 mg and 18-20 mEq/500-520 mg, showing a dose dependent variation, e.g., 37-40 mEq/1000-1050 mg.
  • the API exhibits rapid onset of action.
  • the buffering action of the API is in the range 4-6.5 h, retaining the gastric pH at a dose of 170-180 mg, in the range 4-6.1.
  • the API has cytoprotective action, as prepared.
  • the present invention provides an inorganic base antacid compound comprising calcium containing synthetic crystalline hydrotalcite, which is a basic magnesium alumino carbonate hydrate.
  • the product thus synthesized is 99-102 % pure and has an optimum particle size (2-10 ⁇ ) for its characteristic properties with regard to buffering action and acid neutralizing capacity.
  • the product is synthesized by a single step cost effective method that has a source of calcium, a source of magnesium and a source of aluminium alongwith a source of hydroxide and carbonate ions thai are reacted in stoichiometric ratios at room temperature (25-28°C) at an optimum stirring speed (1000-1400 rpm), to precipitate the calcinated hydrotalcit .
  • the present invention provides an inorganic base antacid compound, having chemical formula Ca x Mg y .Al z (C0 3 ) a .(OH) b .mH 2 0, wherein l ⁇ x ⁇ 6, 0.2 ⁇ y ⁇ 3, 0.15 ⁇ z ⁇ 2.5, 0.05 ⁇ a ⁇ 2, 5 ⁇ b ⁇ 12 and 0.5 ⁇ m ⁇ 5.
  • the antacid compound is insoluble in water, organic solvents and dilute alkali medium; and is freely soluble in dilute mineral acids.
  • the antacid compound is having effective single dose in the range 170-180mg/60 kg human body weight and is having a pH of 1.99-2.08 at 5 minutes, 2.83-3.12 at 15 minutes, 3.5-4.2 at 25 minutes, 4.5-4.6 at 60 minutes, 4.9-5.3 at 120 minutes, 5.5-5.75 at 240 minutes, 5.8-6.2 at 360 minutes.
  • the antacid compound is cytoprotective in nature and is having buffering action for a time period in the range of 4-6.5 hours and retaining gastric pH in the range of 4-6.1 at a dose of 170-180 mg/60 kg human body weight.
  • the antacid compound is having rapid onset of action with acid neutralizing capacity in the range of 9-10 mEq/ 170-180 mg, 18-20 mEq/500-520 mg and 37-40 mEq/1000- 1050 mg.
  • the present invention provides a process for the preparation of said inorganic base antacid compound, wherein the process comprises the steps of: a) weighing precursor salts of calcium, magnesium and aluminium and preparing a mixed metal solution in aqueous medium, termed as solution A, wherein the mutual molar ratio among the two number of bivalent metal ions (calcium and magnesium) and one trivalent metal ion (aluminium), taken in the order as (Ca 2+ : Mg 2+ : Al 3+ ) as (X:Y:Z), wherein 2 ⁇ X ⁇ 6, 0.1 ⁇ Y ⁇ 3 and 0.05 ⁇ Z ⁇ 2; b) weighing the precursor salts of carbonate ion, e.g., sodium, carbonate, taken as 2 parts by weight, mixed with sodium/ammonium hydroxide, taken as 1 part by weight and preparing a solution of the same in aqueous medium which is termed as solution B; c) adding the solution B to the solution A slowly at 25-28
  • the precursor salt of carbonate ion is sodium carbonate and the precursor salt of alkali metal/base is selected from the group consisting of sodium hydroxide and ammonium hydroxide
  • the antacid compound is useful for the treatment of hyperchlorhydria.
  • the source of all the metal salts can be soluble (aq.) salts only, for all of bi alent and trivalent ions comprising calcium, magnesium and aluminium.
  • the ratio of the bivalent metal ion to the trivalent metal ion is 1.8 to 2.2:1, and the bivalent metal ion, magnesium, has been uniquely replaced partially by calcium ion, so that the overall molar ratio of calcium : magnesium : aluminium is taken in the order (Ca 2+ : Mg 2+ : Al 3+ ) as (X:Y:Z), wherein 2 ⁇ X ⁇ 6, 0.1 ⁇ Y ⁇ 3 and 0.05 ⁇ Z ⁇ 2.
  • the molar ratio of the bivalent alkaline earth metals of calcium and magnesium should be calculated appropriately to avoid precipitation of the excess calcium as calcium carbonate, making the product more difficult to wash.
  • the end product of neutralization of the present calcium aluminium based antacid compound with the gastric acid will be aluminium and calcium chloride which are the water soluble astringent salts and might cause unwarranted side effect, like constipation.
  • magnesium ion has been partially incorporated at the site of the calcium ion in the chemical structure of the active moiety for rendering a laxative action.
  • the novelty of the present invention lies in a.) prolonged buffering action of the active moiety (API) in the range 4-6.5 h, retaining the gastric pH at the dose of 170-180 mg, in the range 4-6.1, with high acid neutralizing capacity of 9-10 mEq/ 170-180 mg b.) higher efficacy at a dose (single dose) in the range 170-180 mg/60 kg of human body weight c.) rapid onset of action and d.) cytoprotective property of the as prepared API.
  • API active moiety
  • the inventive steps of the present invention are:
  • the mixed metal solution (solution A) comprises two numbers of bivalent metal ions, e.g., calcium and magnesium, apart from the trivalent metal ion, e.g., aluminium ion.
  • solution A comprises two numbers of bivalent metal ions, e.g., calcium and magnesium, apart from the trivalent metal ion, e.g., aluminium ion.
  • SOI summary of invention
  • the purity of the inorganic base antacid is 95-98%.
  • the purity may drop to 93-96%.
  • solution B comprising sodium carbonate decahydrate (Na 2 CO 3 . IOH 2 O) and sodium hydroxide (NaOH), taken in a molar ratio of 2: 1 was prepared in a beaker and transferred to burette slowly (50 ml).
  • Solution B was added to solution A in a dropwise manner with constant stirring @ 900 rpm, using a magnetic stirrer, until the pH was raised to 10.5, to obtain a white gelatinous precipitate.
  • the precipitate thus obtained was separated, washed using ultrapure water as above and dried in air oven at 80°C.
  • the particles here bear a platelet morphology with an average particle size of 4-5 ⁇ . The percentage yield calculated was 85%.
  • solution A or mixed metal solution and is transferred to a 500 ml three necked flask.
  • the initial pH of solution A is 3-4.
  • solution B comprising sodium carbonate decahydrate (Na 2 CO 3 .
  • solution B comprising sodium carbonate decahydrate (Na 2 CO 3 . IOH 2 O) and sodium hydroxide (NaOH), taken in a molar ratio of 2: 1 was prepared in a beaker and transferred to burette slowly (50 ml).
  • Solution B was added to solution A in a dropwise manner with constant stirring @ 1100 rpm, using a magnetic stirrer, until the pH was raised to 11.5, to obtain a white gelatinous precipitate.
  • the precipitate thus obtained was separated, washed using ultrapure water as above and dried in air oven at 100°C.
  • the particles here bear a platelet morphology with an average particle size of 4 ⁇ . The percentage yield calculated was 98%.
  • hydrotalcite is added to polyvinyl chloride (PVC) to function as an acid acceptor and thus enhance thermal stability.
  • PVC polyvinyl chloride
  • Hydrotalcite is known to react with HC1 generated as the PVC begins to degrade to form the insoluble chloride form of hydrotalcite.
  • a trace amount (2 to 5 percent) of magnesium hydroxide contaminant reacts to form the soluble magnesium chloride. Soluble chloride can cause yellowing of the PVC and aid in early degradation.
  • the main advantages of the present invention are: a. ) Ease of synthesis procedure by conventional technique, using low cost precursor materials

Abstract

La présente invention concerne un composé antiacide de base inorganique. Plus particulièrement, la présente invention concerne un composé antiacide de base inorganique, ayant la formule chimique CaxMgy.Alz(CO3)a. (OH)b.mH2O, dans laquelle 1<x<6, 0.2<y<3, 0.15<z<2.5, 0.05<a<2, 5<b<12 et 0.5<m<5. En outre, la présente invention concerne un procédé de préparation d'un composé antiacide de base inorganique.
PCT/IN2018/050364 2017-06-12 2018-06-06 Composé antiacide de base inorganique présentant des propriétés améliorées et nouvelles WO2018229789A1 (fr)

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Cited By (1)

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CN110624529A (zh) * 2019-09-26 2019-12-31 中国天辰工程有限公司 一种氢氧根插层钙镁铝水滑石固体碱催化剂制备及使用方法

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Publication number Priority date Publication date Assignee Title
CN110624529A (zh) * 2019-09-26 2019-12-31 中国天辰工程有限公司 一种氢氧根插层钙镁铝水滑石固体碱催化剂制备及使用方法

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