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WO2018229789A1 - An inorganic base antacid compound with improved and novel properties - Google Patents

An inorganic base antacid compound with improved and novel properties 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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French (fr)
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/en

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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

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Abstract

An inorganic base antacid compound with improved and novel properties The present invention relates to an inorganic base antacid compound. More particularly, the present invention relates to an inorganic base antacid compound, having chemical formula CaxMgy.Alz(CO3)a.(OH)b.mH2O, wherein 1<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 relates to a process for the preparation of an inorganic base antacid compound.

Description

FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
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. 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).
In general, 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). Of the above, the 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. In case of non systemic antacids, e.g., aluminium hydroxide gel, due to its amphoteric nature, the acid -base neutralization reaction maintains a reversible equilibrium leading to slow and sustained action:
Al (OH)3 + 3 H20 < > [Al (H20)3 (OH)3] eqn. (1)
[Al (H20)3 (OH)3]+ H30+→ [Al (H20)4 (OH)2]+ +H20 eqn. (2)
base
[Al (H20)4 (OH)2]+ + H30+→ [Al (H20)5 (OH)]+2 +H20.... eqn. (3)
[Al (H20)5(OH)2]+2 + H30+→ [Al (H20)6]+3 +H20 eqn. (4)
acid
In presence of the gastric hydrochloric acid, the above gel forms a soluble astring
Al (OH)3 + 3 HCl→ AICI3 +3H20 eqn. (5) 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.
In case of calcium carbonate, it is a rapid acting non-systemic antacid that neutralizes the gastric acid to form calcium chloride that gets converted to an insoluble salt in the intestine which tends to be constipating. Also, frequent administration of calcium based antacid in high dose, causes an increased level of calcium content in blood, hence an enhanced pH of blood and the condition is known as hypercalcemia. Further, another non systemic antacid, milk of magnesia (magnesium hydroxide), neutralizes the gastric acid to form a soluble salt, magnesium chloride that has a laxative action, causing dose related osmotic diarrhea. A small amount of magnesium and aluminium are absorbed systemically and have the potential to accumulate in patients with renal insufficiency that leads to toxicity and often renal failure.
In general, 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. Unfortunately, both of these market available compounds are far from being satisfactory, as the 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. On the contrary, 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:
1. The action of an antacid itself or of its degradation products should be restricted to the gastrointestinal tract and should not become systemic.
2. It should not have an effect on the intestinal peristalsis, i.e., should not induce constipation/diarrhea.
3. A relatively small amount of antacid should be sufficient to neutralize a substantial amount of gastric juice in a short time.
4. In addition to being prompt, the antacid effect should last for a reasonable amount of time.
5. 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.
6. The carbon dioxide production during the neutralization reaction should be minimal, so that enlargement of the gastric wall and flatulence can be avoided.
Reference may be made to Holtmeier W et al., in 'On-demand treatment of acute heartburn with the antacid hydrotalcite compared with famotidine and placebo: randomized double-blind cross-over study', J Clin Gastroenterol, 2007 41(6): 564-70, wherein it has been inferred that antacid hydrotalcite provides symptomatic relief significantly faster and within the first 3 h post dosing, more effective than H2 receptor antagonist famotidine, marked by a significantly better heartburn relief score and enhanced efficacy was observed 30 min and 3 h after the intake of hydrotalcite in comparison with famotidine.
Reference may also be made to Konturek JW et al., in 'The efficacy of hydrotalcite compared with OTC famotidine in the on-demand treatment of gastroesophageal reflux disease: a non-inferiority trial', Med Sci Monit. 2007 13(l):CR44-9, 2006 wherein the onset of action of the antacid hydrotalcite compared with the OTC H2-receptor antagonist famotidine in patients suffering from heartburn has been compared and the results indicate that hydrotalcite relieves the symptoms of gastroesophageal reflux disease faster than OTC famotidine and is equally effective for up to 2 h. It is a safe and effective self-medication for on-demand treatment of heartburn.
Reference may again be made to Lin MS et al., in 'Evaluation of buffering capacity and acid neutralizing-pH time profile of antacids', wherein a comparison has been made of seven number of antacids (both systemic and non systemic) with hydrotalcite in terms of acid neutralizing capacity and buffering pH profile test as per United States Pharmacopeia (USP XXIII). The results show that hydrotalcite has the highest acid neutralizing capacity (28.26 +/- 0.3 mEq), while sodium bicarbonate had the lowest (7.40 +/- 0.12 mEq). In the buffering pH profile test, aluminium-magnesium hydroxide suspensions and hydrotalcite tablets maintained a steady optimum pH (3-5) for around 1.5 h. One tablet of calcium carbonate, sodium bicarbonate or magnesium oxide could not raise the gastric pH to above 3, but two tablets increased the pH excessively (5.3 to 8.6). The higher dose (two tablets) of aluminium hydroxide hexitol complex could not raise the pH to the optimal level. These findings demonstrate that there is disparity in the antacid effectiveness estimated by the neutralizing capacity test and the buffering pH profile test and suggest that the efficacy of an antacid cannot be accurately predicted from its acid-neutralizing capacity. The dose of antacids greatly influences the neutralizing pH profiles.
Reference may be made to Simmons TC et al., in 'The effect of sodium bicarbonate versus aluminium-magnesium hydroxide on postprandial gastric acid in duodenal ulcer patients', Clin Gastroenterol. 1986, 8(2): 146-9, wherein a comparative observation on the buffering action of sodium bicarbonate based antacid has been examined compared to magnesium aluminium hydroxide gel on postprandial gastric acid on ten number patients with duodenal ulcer. It has been shown that sodium bicarbonate fails to reconstitute the protein buffer of the meal effectively and being water soluble, it leaves the stomach rapidly with the liquid phase of the meal, hence has a shorter duration of buffering action. On the contrary, the water insoluble aluminium, magnesium antacid has a longer duration of buffering because it leaves the stomach more slowly, largely with the solid portion of the meal.
Yet another reference be made to Xiao YL et al., in 'The efficacy, safety and cost- effectiveness of hydrotalcite versus esomeprazole in on-demand therapy of NERD: A multicenter, randomized, open-label study in China', J Dig Dis. 2013, 14(9):463-8, wherein investigation was made to see whether hydrotalcite was comparable to esomeprazole, a proton pump inhibitor, in on-demand therapy for non-erosive reflux disease (NERD). In this, 398 patients were recruited in the initial therapy group, among whom 253 were included in on-demand therapy, with 127 patients in the hydrotalcite group and the remaining 126 in the esomeprazole group. Cost-effectiveness calculated as the ratio of the cost of hydrotalcite to that of esomeprazole (per person/day) was 35.3% in the on-demand therapy. Similar number of patients achieved symptom relief in both groups. Hence, it was concluded that hydrotalcite is a good option of on-demand therapy for NERD patients due to its cost- effectiveness and speed of action. Reference may also be made to Linares CF et al., in ' Study of as-synthesized and calcined hydrocalumites as possible antacid agents', Bull. Mater. Sci., 2014, 37: 941 -44, wherein as synthesized hydrocalumite [Ca2Al(OH)6N03] .nH20 and calcined [Ca2Al(OH)6N03].nH20 at 700 and 900°C, exhibited similar behaviour of all the three (as prepared hydrocalumite and two number of calcined hydrocalumites) as above. Despite the high neutralization capacity shown for all the three compounds as above, they could not be considered as good candidate antacids as there is a high shooting up of the pH value initially, that led to a substantial amount of 'acid rebound effect'.
Reference may also be made to Parashar P et al., in 'Rapid synthesis of hydrotalcite with high antacid activity', Mater. Lett., 2012, 74: 93-95, wherein, hydrotalcite comprising different anions has been synthesized by various routes e.g., reflux method, hydrothermal method, direct mixing method, grinding method using Mg and Al in the molar ratio of 3: 1. It was observed that when four different anions i.e., CI , S04 , C03 , and N03 were employed in the structure, different synthesis routes showed different acid neutralizing
2
capacity. Despite the high acid neutralizing capacity (283 ml) of C03 containing hydrotalcite using grinding method, the buffering action of the said compound has not been stated which is one of the most important parameters associated with the effect of an ideal antacid compound.
Reference may further be made to Canadian patent No. 1181690, Miyata S, wherein a new type of gastric antacid that exhibits a rapid and long lasting buffering action of controlling the pH of gastric juice to an ideal pH range without any likelihood of causing undesirable side effects e.g., osteomalacia, phosphoric deficient syndrome including hypophosphoremia, hypophosphaturia, hypercalcinurea, anepithymia etc. Herein, a pharmaceutical compound comprising a phosphate ion containing hydrotalcite having formula Mgx Al2(OH)2x+6-nizi- n2z2 (Ai nl~ ) zl (A2 n2~ ) z2 .mH20, where Ainl" represents at least one anion having a valence of ni selected from the group consisting H2P04 — and HP042-" and P04 3" , A2 n2~ represents at least one anion having a valence n2 other than Ai nl~ and x, zi, z2 and m are positive numbers given as, 2<x<40, 0<x<2, 0< z2 <2, 0<m<40, 0< zi+ z2<2 and a pharmaceutically acceptable diluents/carrier and a method for controlling the pH of the gastric juice, using the abovesaid phosphate ion containing hydrotalcite, although, the complete mechanism of the phosphate ion containing hydrotalcite, used as supplement in phosphorous deficiencies, e.g., hypophosphoremia, hypophosphaturia, hypercalciuria, anepithymia etc. is not clear. Also, the disorder called osteomalacia is a result of inadequate levels of available phosphate, calcium and vitamin D, which could not be taken care of by the phosphorous supplement alone through the hydrotalcite based antacid.
Reference may also be made to UK patent application No. 2008 942 A, Haefeli R, wherein an antacid compound comprising microcrystalline calcium carbonate, alongwith microcrystalline magnesium carbonate hydroxide, dispersed in a matrix of amorphous aluminium hydroxide, has aluminium (AI2O3) in the range of 25 to 30% by weight, calcium (CaO) in the range of 1.0 to 1.8% by weight, while magnesium (MgO) is in the range of 13 to 19% by weight. The physical mixture comprising magnesium carbonate hydroxide and calcium carbonate microcrystals, homogeneously dispersed in aluminium hydroxide gel, does not exhibit very high buffering capacity (pH 3.45-3.60 at 2h). Also, the mixture as above exhibit very high pH initially, leading to the possibility of systemic alkalosis.
Reference could be made to patent No. US 2880136, Gore DN, wherein the coprecipitates including aluminium hydroxide in a form having an extended buffering effect together with at least one of the compounds, calcium carbonate and magnesium carbonate which has been taken from naturally occurring sources, e.g., the magnesian limestone and dolomite, comprising 42-50 parts by weight of calcium carbonate, 13-30 parts by weight of magnesium carbonate and 17-26 part by weight of aluminium hydroxide, finally, resulting in formation of a coprecipitate having 47 parts by weight of calcium carbonate, 30 parts by weight of magnesium carbonate and 23 parts by weight of aluminium hydroxide. This forms an anhydrous product, known as 'stomach powder', comprising aluminium hydroxide gel that can be produced in finely divided form and the drying operation was conducted in the range of 50-60°C, without any significant loss of antacid activity of the aluminium hydroxide component as above, although, the coprecipitated aluminium hydroxide, dried at 50-60°C, comprising calcium and magnesium carbonate from natural sources does not reveal the most necessary parameter for an antacid, i.e., the buffering action period.
Reference may be made to US patent No. 3539306, Kumura T et al., wherein a process for the preparation of hydrotalcite comprising an aluminium salt with a magnesium salt mixed in an aqueous medium in presence of carbonate ion at a pH of at least 8 in a ratio in terms of Al203:MgO of substantially 1:6 and thereafter recovering the resultant product. In this patent, a process by which hydrotalcite can be synthesized with industrial ease has been described that exhibits antacid property, having chemical formula, Al203.6MgO.C02.12H20 or Mg6Al2 (OH)i6C03.4H20, although it does not reveal any parameter (buffering action/acid neutralizing capacity) related to antacid activity.
In continuation to the above US patent, reference may also be made to US patent No. 3650704, Kumura T et al., wherein a process for synthesis of a novel synthetic hydrotalcite has been proposed that is free of impurities and has an excellent acid consuming property that has a desired combination of instant effect and substantially good buffering capacity. In addition to this, excellent stability on storage, good hardness and compressibility after shaping have been obtained for the said compound, expressed by the chemical formula: Al203.MgO.C02.12H20. The process of synthesis involves mixing an aluminium component with a magnesium component in an aqueous medium in the presence of carbonate ion at a pH of at least 8. 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. In this work, a step comprising 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. In this work, a claim has been made of attaining pH 4.0 at 15 s and maintaining the same for a period of 143 min (buffering action). Importantly, the pH mentioned is at the lower limit of the minimum criteria (pH 4-6) for a compound to have characteristics like an antacid. Also, the short period of the buffering action (143 min) indicates the need of multiple doses of the compound to achieve an effective therapeutic action.
Reference may be made to US patent No. 4576819, Miyata S and Nosu T, wherein an aluminium hydroxide gel of the formula [CaO, MgO, M20]x.Al203.(C02)y.mH20 wherein M represents an alkali metal, M20 may be zero, CaO and MgO are not zero at the same time, and x, y and m are positive numbers represented by the following expressions 0<x<l, 0.2<y≥l, 2>m<10. 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 C02/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. Further a modified aluminium hydroxide gel having compound (K20,Na20)p.Ai203.(C02)q.rH20 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.
Reference may also be made to US patent No. 4482542, Schneider M and Knecht A, wherein, a process for the preparation of an antacid material based upon magnesium aluminium hydroxide, wherein magnesium hydroxide and/or magnesium oxide is reacted in an atomic ratio of magnesium to aluminium of 1: 1 to 3: 1 with an aqueous solution of aluminium sulphate until the pH of the reaction mixture is from 4.0 to 8.0. No data w.r.t the acid neutralizing capacity (ANC) of the above has been presented. Also, it states about a particular suspension of the magnesium aluminium hydroxide based antacid, although no data related to the same has been provided.
Understanding the factors that alter the stability of pharmaceuticals and identifying ways to guarantee their stability is critical. Chemical and physical degradation of drug substances may change their pharmacological effects, resulting in altered therapeutic efficacy as well as toxicological consequences. Because pharmaceuticals are used therapeutically based on their efficacy and safety, they should be stable and maintain their quality until the time of usage or until their expiration date, under the various conditions that pharmaceuticals encounter, during production, storage in warehouses, transportation, and storage in hospital and community pharmacies, as well as in the home. Also, the acid neutralizing capacity of antacids is an important indicator of the efficacy/potency of such products and there is a recommended ANC value (>5 mEq) as per USP for an antacid compound/active pharmaceutical ingredient (API). Hence, it is mandatory to mention the same alongwith other necessary parameters for an antacid API.
Drawbacks of the above prior arts:
1. The hydrotalcite compounds having composition Mg6Al2 (OH)i6C03.4H20, prepared by simple laboratory technique using aqueous medium, a step involving reaction temperature in the range of 0-150°C, depending on the type of the bivalent and trivalent metal ions have been mentioned which might lead to loss of water of hydration and hence affecting its efficacy as antacid.
2. In some cases of hydrotalcite based antacid, no mention has been made of the buffering action and in most cases, acid neutralizing capacity (ANC) has not been mentioned.
3. In case of calcined hydrocalumites (700 and 900 °C), initial shooting up of pH value, (-8.0-9.0) at a substantially low dose of -50 mg that might exhibit acid rebound effect, substantially. The as prepared hydrocalumite, on the other hand exhibits a direct proportionality of the pH escalation (upto a range of 6-7) with regard to the dosage (mg) applied, upto an extent of 250-300 mg of the same, beyond which a saturation level is attained. Importantly, no mention has been made about the buffering action and acid neutralizing capacity, in both the above cases.
4. Most of the active ingredients comprising magnesium, calcium and aluminium ions are physical/mechanical mixtures that exhibit the characteristics of the individual components, rather than its integral property as antacid.
More specifically, the existing hydrotalcite and hydrocalumite based compounds that exhibit antacid properties are very limited in number. In this regard, as per officials, for any inorganic compound to exhibit an antacid action, the time dependent variation of pH is as following:
Figure imgf000010_0001
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 CaxMgy.Alz(C03)a.(OH)b.mH20, 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.
SUMMARY OF THE INVENTION
Accordingly 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 ΜΩ·αη), 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 to 2.2 parts of magnesium ion in the compound, 1.3 to 1.6 parts is calcium followed by the rest as magnesium ion, retaining the final molar ratio between magnesium and aluminium as above, insertion of the bivalent calcium ion at the site of magnesium ion as above, modifies 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 (Ca2+: Mg2+: Al3+) as (X:Y:Z), wherein 2<X<6, 0.1<Y<3 and 0.05<Z<2. The above process describes the synthesis of the inorganic base antacid compound also known as the active pharmaceutical ingredient (API) as final product.
In an embodiment of the present invention, the antacid compound of the present invention is useful for the treatment of hyperchlorhydria.
In another embodiment of the present invention, the magnesium ion is taken as involving a soluble salt of magnesium.
In yet another embodiment of the present invention, the aluminium ion used comprises a soluble salt of aluminium.
In still another embodiment of the present invention, the calcium ion used is comprises a soluble salt of calcium.
In an embodiment of the present invention, 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.
In another embodiment of the present invention the hydroxy! ion used is selected from the group consisting of sodium or ammonium hydroxide.
In yet another embodiment of the present invention the carbonate ion used is selected from the group consisting of sodium carbonate and sodium hydroxide pellets, taken in 2:1 ratio by weight.
In still another embodiment of the present invention, a process of synthesizing an inorganic base antacid compound also known as the active pharmaceutical ingredient (API) as final product, wherein the said process comprising the steps of:
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;
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) addition of solution B to the solution A slowly, at room temperature (25-28°C) with constant stirring speed ( @ 1000- 1400 rpm) to obtain the inorganic base antacid as a white gelati nou s preci pi ate ; d) separation of the above precipitate by vacuum filtration technique and washing the precipitate formed as above using ultrapure water, followed by drying the precipitate in air oven at a temperature range 8G-100°C, for 22-25 h.
in an embodiment of the present invention, the API is a white, free flowing, odourless, tasteless powder having particle size in the range of 2-10μηι.
In another embodiment of the present invention, the percentage yield of the active ingredient is in the range of 95-98%, when synthesized following the optimum process parameters as above.
In yet another embodiment of the present invention, the percent purity of the active ingredient is 99-102%.
In still another embodiment of the present invention, 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.
In an embodiment of the present invention, the API is insoluble in water, organic solvents and dilute alkali medium and it is freely soluble in dilute mineral acids.
In another embodiment of the present invention, the effective dose (single dose) of the API is in the range 170-180mg/60 kg human body weight.
In yet another embodiment of the present invention, 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.
In still another embodiment of the present invention, the API exhibits rapid onset of action.
In an embodiment of the present invention, 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.
In another embodiment of the present invention, the API has cytoprotective action, as prepared.
DETAILED DESCRIPTION OF THE INVENTION
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 (2-10μηι) 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 .
In one aspect of the present invention, the present invention provides an inorganic base antacid compound, having chemical formula CaxMgy.Alz(C03)a.(OH)b.mH20, 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.
In one embodiment of the present invention, the antacid compound is insoluble in water, organic solvents and dilute alkali medium; and is freely soluble in dilute mineral acids.
In one embodiment of the present invention, 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.
In one embodiment of the present invention, 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.
In one embodiment of the present invention, 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.
In another aspect of the present invention, 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 (Ca2+: Mg2+: Al3+) 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°€ with constant stirring speed of 1000-1400 rpm to obtain the inorganic base antacid compound as a white gelatinous precipitate; d) separating the above precipitate by vacuum filtration technique and washing the precipitate formed as above using ultrapure water, followed by drying in an air oven at a temperature in the range of 80-100°C for a period of 22-25 hours to obtain a white, free flowing, odourless, tasteless powder having particle size in the range of 2-1 Ομπι with purity of active ingredient 99-102%.
In one embodiment of the present invention, 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
In another aspect of the present invention, the antacid compound is useful for the treatment of hyperchlorhydria.
It is critical to note that 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 (Ca2+: Mg2+: Al3+) as (X:Y:Z), wherein 2<X<6, 0.1<Y<3 and 0.05<Z<2. Another important observation of the present invention is, 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 assay of the inorganic base antacid comprising the bivalent and trivalent metal ions both, ca be undertaken considering the component me al oxides as following, as per officials (BP, 2010):
For A1203
Dissolve 0.3 gm of sample in 2 ml of 7M hydrochloric acid, add 250 ml of water and 50 ml of O.OSM sodium edetaie volumetric solution (Vs), and neutralize with IM sodium hydroxide using methyl red solution as indicator. Heat the solution on a water bath for 30 min and allow to cool. Add 3 gm of hexamine and titrate the excess of disodium edetate with 0.05 M lead nitrate VS using xylenol orange solution as indicator, Each ml of 0.05 M disodium edetate VS is equivalent to 2.549 mg of AI2.O3.
For MgO
Dissolve 0.125 gm of sample in the minimum volume of 7M hydrochloric acid, add 30 ml of water, 1 gm of ammonium chloride, 10 ml of triethanol amine, 150 ml of water and 5 ml of ammonia buffer pH 10.9 and titrate immediately with 0.05M disodium edetate VS using moderant black 11 solution as indicator. Each ml of 0.05 M disodium edetate VS is equivalent to 2.015 mg of MgO. For CaO
Accurately transfer about 50 mg of sample to a 400 ml of beaker and add 200 ml of water, 5 ml of sodium hydroxide solution, and 250 mg of hydroxy! napthol blue. Stir using magnetic stirrer, and titrate immediately with 0.05 M edetate disodium VS until the solution is distinctly blue. Each ml of 0.05 edetate disodium is equivalent to 2.8 mg CaO.
Insertion of calcium as a divalent metal ion at the site of magnesium by partial replacement of the same in the octahedral hole in a specific molar ratio leads to enhancement of positive charge density and formation of strongly alkaline hydroxides when reacted with sodium hydroxide, for synthesis of the antacid compound by coprecipitation process. Down the group (group II A) of alkaline earth metals, the heavier elements exhibit more vigorous reaction compared to the lighter elements w.r.t formation of alkali hydroxides. Hence, presence of both the alkaline earth metals, magnesium and calcium ions (with higher alkalinity) at the octahedral site of the structure, renders high alkalinity in the compound which is balanced by the presence of the amphoteric aluminium ion at the tetrahedral hole that aids to attain a substantially long buffering action (due to the slow dissolution of both calcium and aluminium salts in gastric acid in presence of replaceable carbonate and hydroxyl ions in the structure) alongwith the high value of acid neutralizing capacity, to inhibit any possibility of 'rebound acidity'. 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. Taking this into account and aiming a rapid onset of action, 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.
The inventive steps of the present invention are:
(i) 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. (ii) The titration of solution A as above with solution B as mentioned in summary of invention (SOI) above, was carried out at a constant stirring speed of 1000-1400 rpm.
It has been found that on a small laboratory scale, the purity of the inorganic base antacid is 95-98%. On scaling up to industrial scale, the purity may drop to 93-96%.
The following examples are given by way of illustration of the working of the invention in actual practice and should not be construed to limit the scope of the present invention in any way.
Examples
Example 1
Calcium nitrate tetrahydrate, Ca (N03)2.4H20, magnesium nitrate hexahydrate, Mg (N03)2.6H20 and aluminium nitrate nonahydrate, Al (N03)3.9H20 weighed in a molar ratio of X:Y:Z, taken as 1<X<5, 0.2<Y<4 and 0.1<Z<3 respectively, dissolved in ultrapure water (Millipore, specific resistivity 18.2ΜΩ), taken in a 250 ml volumetric flask, volume made up. This is termed as 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. Next, 100 ml of solution B comprising sodium carbonate decahydrate (Na2 CO3. IOH2O) 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 μιη. The percentage yield calculated was 85%.
Example 2
Calcium nitrate tetrahydrate, Ca (N03)2.4H20, magnesium nitrate hexahydrate, Mg
(N03)2.6H20 and aluminium nitrate nonahydrate, Al (N03)3.9H20 weighed in a molar ratio of X:Y:Z, taken as 2<X<4, 0.25<Y<3.5 and 0.2<Z<4 respectively, dissolved in ultrapure water (Millipore, specific resistivity 18.2ΜΩ), taken in a 250 ml volumetric flask, volume made up. This is termed as 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. Next, 100 ml of solution B comprising sodium carbonate decahydrate (Na2 CO3. IOH2O) 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 @ 1000 rpm, using a magnetic stirrer, until the pH was raised to 11.0, to obtain a white gelatinous precipitate. The precipitate thus obtained was separated, washed using ultrapure water as above and dried in air oven at 90°C. The particles here bear a platelet morphology with an average particle size of 2-3 μιη. The percentage yield calculated was 90%.
Example 3
Calcium nitrate tetrahydrate, Ca (N03)2.4H20, magnesium nitrate hexahydrate, Mg (N03)2.6H20 and aluminium nitrate nonahydrate, Al (N03)3.9H20 weighed in a molar ratio of X:Y:Z, taken as 2<X<6, 0.1<Y<3 and 0.05<Z<2 respectively, dissolved in ultrapure water (Millipore, specific resistivity 18.2ΜΩ), taken in a 250 ml volumetric flask, volume made up. This is termed as 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. Next, 100 ml of solution B comprising sodium carbonate decahydrate (Na2 CO3. IOH2O) 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 μιη. The percentage yield calculated was 98%.
A chemical analysis of the synthesized inorganic base antacid was performed and the following chemical formula was derived:
Cax gy.Alz(C03)a.(OH) .me20, wherein l<x<6 is, 0.2<y<3, 0.15<z<2.5, 0.05<a<l, 5<b<12 and 0.5<m<5.
The purity of hydrotalcite is very important in determining its functionality in acid acceptor/stabilizing applications. For instance hydrotalcite is added to polyvinyl chloride (PVC) to function as an acid acceptor and thus enhance thermal stability. 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
b. ) Exhibits high acid neutralizing capacity with prolonged buffering action at low dose c. ) Rapid onset of action
c.) Significant cytoprotective action of the active moiety with negligible toxicity

Claims

Claims:
1. An inorganic base antacid compound, having chemical formula CaxMgy.Alz(C03)a.(OH)b.mH20, 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
2. The antacid compound as claimed in claim 1 is insoluble in water, organic solvents and dilute alkali medium; and is freely soluble in dilute mineral acids.
3. The antacid compound as claimed in claim 1, wherein the 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.
4. The antacid compound as claimed in claim 1, wherein the compound is cytoprotective in nature and is having buffering action for a time period in the range of 4-6.5 hours, retaining gastric pH in the range of 4-6.1 at a dose of 170-180 mg/60 kg human body weight..
5. The antacid compound as claimed in claim 1, wherein the 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.
6. A process for the preparation of an inorganic base antacid compound as claimed in claim
1, 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 (Ca2+: Mg2+: Al3+) 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°€ with constant stirring speed of 1000- 1400 rpm to obtain the inorganic base antacid compound as a white gelatinous precip tate;
d) separating the above precipitate by vacuum filtration technique and washing the precipitate formed as above using ultrapure water, followed by drying in an air oven at a temperature in the range of 80-100°C for a period of 22-25 hours to obtain a white, free flowing, odourless, tasteless powder having particle size in the range of 2-10μπι with purity of active ingredient 99-
102%.
7. The process as claimed in claim 1, wherein 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.
8. The antacid compound as claimed in claim 1, wherein the compound is useful for the treatment of hyperchlorhydria.
PCT/IN2018/050364 2017-06-12 2018-06-06 An inorganic base antacid compound with improved and novel properties WO2018229789A1 (en)

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