Classifications

• • 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
  • A61K33/42—Phosphorus; Compounds thereof
• • 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
• • 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
  • A61K33/08—Oxides; Hydroxides
• • 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

Definitions

• This invention relates to improved antacid compositions. More particularly, this invention relates to high-density antacid powders capable of being compounded into standard dosage forms, such as tablets and capsules, having increased amounts of active antacid per dose.
• Antacid compositions are designed for relieving hyperacidity and associated conditions caused by excess acid in the stomach. Such an antacid composition, inter alia, should neutralize an adequate amount of gastric hydrochloric acid and maintain its action during the period of gastric digestion; adequate and repeated doses should be palatable to the hyperacid patient; it should not have side effects such as gastric irritation; and it should maintain its antacid properties upon ageing so that the proper amount of active agent is ingested on extended use. Antacid compositions have been prepared in a variety of forms such as solutions, suspensions, emulsions, powders, capsules and tablets.
• the composition in each case includes an active antacid substance such as aluminum hydroxide-magnesium carbonate co-dried gel, dihydroxyaluminum sodium carbonate, magnesium trisilicate, aluminum hydroxide, aluminum basic carbonates, magnesium hydroxide and the like.
• active antacid substance such as aluminum hydroxide-magnesium carbonate co-dried gel, dihydroxyaluminum sodium carbonate, magnesium trisilicate, aluminum hydroxide, aluminum basic carbonates, magnesium hydroxide and the like.
• the beneficial response of conditions and diseases treated with antacid compositions is in direct proportion to the amount of antacid ingested and its duration of action with the stomach.
• the tablet or capsule form of antacid composition is more convenient than antacid liquid compositions to the patient. These may be carried in a small package and may be taken as needed without any need for extra equipment, such as a spoon, for the measuring of dosages.
• the convenience of these solid forms of the antacid makes them a popular kind of anta
• the solid antacid products of the prior art contain relatively small amounts of active antacid inqredients per tablet or capsule. And since the size of the capsules or tablets may not be increased substantially without rendering them too large for human consumption, it is necessary to repeat doses and increase frequency of ingestion to achieve the desirable therapeutic results. However, a higher density antacid powder would allow a smaller capsule or tablet size.
• high-density antacid powders are more flowable and directly compressible than lower density powders. Because of this property, the powders can be more easily processed into capsules and tablets, and they can be processed using a direct compression method. This is a less expensive method than the wet granulation method, typically used to process lower density powders.
• the highrdensity antacid powders of the present invention are produced by: preparing aqueous solutions of aluminum and magnesium compounds; precipitating the magnesium and aluminum compounds simultaneously in a reactor with an alkali metal hydroxide or ammonium hydroxide at a pH not exceeding 8.5; optionally adjusting the pH to 9-10 with a basic solution in the post-precipitation stage; optionally adding an alkali or ammonium salt in the post-precipitation stage; and making the precipitate into a powder.
• antacid compounds are known in the prior art and are used for various purposes, among others, as therapeutic agents for treating stomach hyperacidity.
• These and other types of antacid compounds can be produced in the form of powders which in turn can be formed into tablets and capusles of proper dosage.
• the antacid powders so produced normally have an apparent density in the range of about 0.1 to 0.4 g/cc.
• antacid powders having an apparent density greater than 0.5 g/cc may be produced.
• the use of such high density powders advantageously provides for the delivery of higher levels of active antacids in standard size tablets or capsules.
• the powders so produced normally have a composition in the range of:
• any water-soluble aluminum compounds may be used, such as an aluminum halide, alkali metal aluminate, aluminum nitrate, aluminum sulfate and the like.
• any water-soluble magnesium compound can be used, such as a magnesium halide, magnesium nitrate, magnesium sulfate and the like.
• the anionic species represented by A include OH-, Cl-, HCO 3 -, CO 3 --, HSO 4 -, SO4--, HPO 4 -,
• aqueous solutions of the reactants are mixed to precipitate the desired antacid complex, and the precipitate is formed into a powder as follows:
• Aqeuous solutions of an aluminum compound, a magnesium compound and sodium hydroxide are simultaneously metered into a reactor at a rate to maintain the pH below 8.5 to precipitate the magnesium- aluminum antacid.
• the aluminum and magnesium compound solutions can be mixed before metering into the reactor.
• the maintenance of the pH below 8.5 is critical in the precipitation process in order, to obtain the high-density antacid powder.
• the reactants are added at a rate to maintain the pH between 7.5 and 8.5. This pH range was found optimal for obtaining antacid powders having a density in the range of 0.5 to 1.1 g/cc. Above the pH of 8.5 powder densities decrease, while below 7.5 the washing time of the precipitate becomes excessive.
• a post-precipitation step to prevent the loss of soluble magnesium may be included in the process.
• This post-precipitation step is carried out with the addition of a base, normally a sodium, potassium, or ammonium hydroxide solution, to raise the pH to 9-10, without any detriment to the powder density.
• a solution of a salt such as Na 2 CO 3 , NaHCO 3 , Na 2 SO 4 , NaHSO 4 , NaH 2 PO 4 , Na 2 HPO 4 , Na 3 PO 4 and the like can be added with mixing to the magnesium-aluminum precipitate to substitute the anion carried by the precipitate with an anion from the added salt.
• the starting magnesium or aluminum compounds are chlorides, bromides or fluorides
• the chloride, bromide or fluoride ions will be substituted with anions such as carbonate, sulfate or phosphate.
• the precipitate obtained, with or without the inclusion of the post-precipitation steps, is washed and formed into a cake having a thick gel-like consistency.
• the cake is then repulped and dried at a temperature not exceeding about 150°C. Drying is accomplished using methods and equipment used in the art of processing materials into a powder, such as oven drying, freeze drying or spray drying.
• Another important aspect to the process of the present invention is the use of an alkali metal hydroxide or ammonium hydroxide as the base in the constant-pH precipitation process, instead of sodium carbonate or sodium bicarbonate, although small amounts of carbonates or bicarbonates can be tolerated. It has been found that precipitation with an alkali metal hydroxide or ammonium hydroxide produces the desired high-density antacid powders, while precipitation with alkali carbonates or bicarbonates results in the production of antacid powders having densities less than 0.5g/cc. This and other aspects of the present invention will be further illustrated by the examples that follow.
• Part D had an addition of 0.5 liter of 16° Baume Na 2 CO 3 solution with an end pH of 9.5. The slurries in each part were then washed, repulped and spray dried at an outlet temperature of 125°C. to a powder. The results obtained are shown in Table I.
• the pH stat* test here and hereinbelow is a measure of antacid rate of reactivity and total neutralization capacity.
• ACC** means acid-consuming capacity as determined by the pH-stat titration.
• ACCD*** is the ACC multiplied by the apparent density.
• the pH-stat titration is performed as follows. A weight of sample containing exactly 500 mg total oxide (Al 2 O 3 + MgO) is suspended in 300 ml of deionized water. The suspension is maintained at 37°C ⁇ 1° and stirred at 300 rpm. The sample is titrated with 1.0N HCl at such a rate as to maintain a constant pH of 3.0, while recording on a strip chart the volume of acid used versus time. The titration is continued until no more acid is consumed. The times, in minutes, when 50% (T 50 ) and 90% (T 90 ) of the total antacid are consumed by the acid are determined. The ACC is calculated by dividing the total number of millimeters (times10) of 1.0N HCl by the weight of the sample in grams.
• the apparent density is determined by transferring 15-20 grams of sample to a 250-ml, flat bottomed, graduated cylinder. The cylinder is given 60 taps (1 sec. lift, 1 sec. drop; 1 inch drop), and the volume in cubic centimeters is read. The apparent density (g/cc) is equal to the weight of the sample (g) divided by the measured volume of the sample (cc). In the following examples, the same procedures are followed to determine apparent density and pH-stat reactivity and total neutralization capacity.
• EXAMPLE 2 The precipitation process of Example 1 was repeated except that instead of sodium hydroxide a sodium carbonate solution was used as the base in the precipitation, and the precipitation slurry so obtained was divided into parts E and F. Part E of the precipitation slurry had no post-addition treatment, while part F had a post addition of NaOH solution to raise the pH to 9.0. The results are shown in Table II.
• Example 1 The precipitation process of Example 1 is repeated except that the rates were adjusted to hold a constant pH of 8.9.
• the precipitation slurry was divided into parts K, L, M, and N. Part K had. no post-precipitation addition; parts L, M, and N had additions of 0.25, 0.35, and 0.50 liter respectively of 16° Baume Na 2 CO 3 solution.
• the final pH's were 9.5, 10.2 and 10.5, respectively.
• Table IV The results obtained are shown in Table IV.
• EXAMPLE 5 The precipitation process of Example 1 was repeated.
• the precipitation slurry was divided into parts O, P, Q, and R.
• Part O had no post-precipitation addition
• parts P and Q had additions respectively of 300 ml and 600 ml of a 14.5% Na 2 SO 4 solution
• part R had an addition of 0.5 liter of 16° Baume Na 2 CO 3 solution.
• Table V The results are shown in Table V.
• the precipitation slurry so obtained was divided into parts S, T, U, and V.
• Part S had no post-precipitation addition
• parts T, U, and V had additions of 0.25, 0.35, and 0.50 liter respectively of 16° Baume Na 2 CO 3 solution.
• Table VI The powder results are shown in Table VI.
• This example shows the incorporation of calcium into high-density aluminum magnesium antacid powders.
• the high-density powders of the present invention prepared as above described may be compressed into tablets or filled into capsules of desired form using standard tableting and capsuling procedures, including wet granulation and direct compression.

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• Health & Medical Sciences (AREA)
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• General Health & Medical Sciences (AREA)
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• Chemical Kinetics & Catalysis (AREA)
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• General Chemical & Material Sciences (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)

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Cited By (2)

Citations (8)

• 1985
  • 1985-06-03 WO PCT/US1985/001038 patent/WO1985005552A1/en not_active Ceased
  • 1985-06-03 FI FI860480A patent/FI860480A0/fi not_active Application Discontinuation
  • 1985-06-03 DE DE8585902917T patent/DE3579568D1/de not_active Expired - Lifetime
  • 1985-06-03 AU AU44388/85A patent/AU578106B2/en not_active Ceased
  • 1985-06-03 CA CA000483061A patent/CA1243953A/en not_active Expired
  • 1985-06-03 EP EP85902917A patent/EP0183802B1/en not_active Expired - Lifetime
  • 1985-06-03 JP JP60502550A patent/JPS61502333A/ja active Granted
  • 1985-06-04 NZ NZ212283A patent/NZ212283A/xx unknown
  • 1985-06-04 ES ES544469A patent/ES8606201A1/es not_active Expired
  • 1985-06-04 IL IL75399A patent/IL75399A0/xx not_active IP Right Cessation
  • 1985-06-04 ZA ZA854218A patent/ZA854218B/xx unknown
  • 1985-06-04 IE IE137985A patent/IE58134B1/en not_active IP Right Cessation
• 1986
  • 1986-02-03 DK DK50986A patent/DK50986D0/da not_active Application Discontinuation
  • 1986-02-03 NO NO860375A patent/NO860375L/no unknown
  • 1986-02-04 KR KR1019860700063A patent/KR860700088A/ko not_active Ceased

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