Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2009—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • 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 invention relates to an antacid and/or adstringent and absorbent pharmaceutical preparation containing at least one aluminium compound, as well as a process for the production of such preparations.
• aluminium-based e.g. aluminium hydroxide, magnesium-aluminium-hydrate, magaldrate etc.
• oral suspension oral suspension
• Another ob- ject of the invention relates to the provision of a pharma ⁇ ceutical preparation with sustained release of the antacid and/or adstringent and absorbent compounds.
• the principle of the invention is a phosphate delivery system controlled by the swelling mechanism of the hydro- colloid.
• Fig.1 the top left rectangle symbolizes the magaldrate example.
• Excess acid (AC) in the gastric fluid is neutralized (N) by the OH ⁇ -flux.
• the resulting Al3 + - flux is bound by the phosphate P and the swelled (arrow B) hydrocolloid HY to the phosphate/hydro- colloid/aluminium system (PHAS) .
• the phosphate/ hydrocolloid system (P+HY) controls the dissolution and binding of the aluminium as shown in
• Fig.2 (left of the dotted line: stomach ST; right of the dotted line: intestines IN) partly through an oscil ⁇ lating reaction mechanism influenced by the change of the intragastric pH-value, partly by binding the aluminium to the hydrocolloid, advantageously to a crosslinked polymer.
• Fig.3 shows the principle of the aluminium capture based partly on the significant difference in the solubility of aluminium hydroxide and aluminium phosphate; partly, it is also based on the function of the hydrocolloid-phosphate system, which binds the aluminium and is activated by the swelling of the hydrocolloid.
• the described aluminium capturing system does not decrease the acid neutralization ca ⁇ pacity of the aluminium compound at the acidic pH of the stomach (ST) but inhibits the absorption of alu- minium from the stomach (ST) and the duodenum (inte ⁇ stines (IN) , see Fig.2) of higher pH.
• Table I Change of the aluminium amount excreted by the urine of 5 patients over 24 hours after administration of 750 mg magaldrate compared to the control value of the pre ⁇ vious day: ⁇ g Al/24 h eliminated by urine Subject magaldrate magaldrate with the phosphate-hydrocolloid system ace. example 3
• Difference si ⁇ nificant not si ⁇ nificant s ⁇ (S.E.M.) is the standard deviation of the mean value; the t-value is the Student-t at 5% significance level.
• the aluminium compound may be selected from a wide range of inorganic and organic salts or complex compounds, such as aluminium hydroxide, aluminium glycinate (dihydroxyaluminium aminoacetate hydrate, USP XXII p. 445) , aluminiumsodium trisilicate, aluminium hydroxycarbonate (dihydroxyaluminium sodium carbonate, USP XXII p.447) , basic aluminium carbonate gel (USP XXII p.50) , aluminium phosphate (USP XXII p.53) , aluminium magnesium silicate (B.P.), natural or synthetic aluminium- and magnesium-containing compounds, preferably aluminiummagnesium hydroxycarbonate (hydrotalcite) and aluminiummagnesium hydroxysulphate (magaldrate) .
• inorganic and organic salts or complex compounds such as aluminium hydroxide, aluminium glycinate (dihydroxyaluminium aminoacetate hydrate, USP X
• the water-swellable compounds may be selected from the group comprising cellulose glycolic acid, starch glycolic acid, polyacrylic acid, copolymers of acrylic acid-methacrylic acid, alginic acid (polymannuronic acid, USNF XVII) , poly- vinylpyrrolidone, calcium alginate (BPC) , sodium alginate (USNF XVII) , Carbopol (R) 934P (carbomer, USNF XVII) , carb- oxymethylcellulose calcium (USNF XVII) , carboxymethylcellu- lose sodium (carmellose, USP XXII) , carrageenan (USNF XVII) , croscarmellose sodium (USNF XVII,Ac-Di-Sol (R) ) , cross-linked polyvinylpyrrolidone (USNF XVII, Polyplasdone XL (R) ) , hydroxypropylmethylcellulose (US
• the phosphate compound may be selected from the group com ⁇ prising mono-, di- and tribasic calcium phosphate; mono-, di- and tribasic magnesium phosphate; mono- and dibasic sodium phosphate; mono- and dibasic potassium phosphate; mono- and dicalcium glycerophosphate.
• Auxiliary materials may be disintegrants such as starch, microcellulose, cross-linked polyvinylpyrrolidone etc.; tableting aids, such as lubricants, e.g. talc, magnesium stearate etc.; sweeteners such as saccharose, glucose, sac ⁇ charin-sodium, sodium cyclamate, aspartame etc.; flavouring agents such as lemon, orange and cassis aroma; fillers such as lactose.
• disintegrants such as starch, microcellulose, cross-linked polyvinylpyrrolidone etc.
• tableting aids such as lubricants, e.g. talc, magnesium stearate etc.
• sweeteners such as saccharose, glucose, sac ⁇ charin-sodium, sodium cyclamate, aspartame etc.
• flavouring agents such as lemon, orange and cassis aroma
• fillers such as lactose.
• 500g hydrotalcite and 70g tribasic calcium phosphate powder are homogenized.
• 90g of cross-linked polyvinylpyrrolidone are swelled with 60-75 ml water (required for wet granulation) during 2 hours and then mixed with the powder mixture and kneaded.
• the wet mass is granulated by passing it through a sieve with openings of 1.4 mm.
• the granules are dried to a moisture content of 2.5% and then regranulated through a sieve with openings of 0.8 mm.
• Example 2 The same procedure is followed as in Example 1 with the following compounds (for 1000 tablets of 0.75 g average weight each) :
• Inner phase aluminium hydroxycarbonate 600 g tribasic magnesium phosphate 34 g carboxymethylcellulose sodium of low substitution grade 10 g cross-linked carboxymethyl ⁇ cellulose sodium (Ac-Di-Sol (R) ) 10 g water 80-100 ml outer phase: potato starch (disintegrant) 50 g talc 24 g magnesium stearate 12 g
• Example 2 The same procedure is followed as in Example 1 with the following compounds (for 1000 tablets of 1.3 g average weight each) :
• Example 2 The same procedure is followed as in Example 1 with the following compounds (for 1000 tablets for 1.5 g average weight each) : Inner phase: aluminium hydroxide 375 g tribasic calcium phosphate 100 g Nymcel ZSB 1 ⁇ (R) 200 g water 80-100 ml outer phase: microcrystalline cellulose Avicel PH 102 ⁇ R > 825 g
• Example 4 The same procedure is followed as in Example 4 with the following compounds (for 1000 tablets of 1.5 g average weight each) , with the exception that double-layered tablets are formed.
• the antacid active ingredient is pressed as the first layer, onto which the second layer containing the other components and the microcrystalline cellulose is pressed:
• First layer aluminium hydroxide 375 g microcrystalline cellulose
• Example 4 The same procedure is followed as in Example 4 - with the exception that three-layered tablets are formed - with the following compounds (for 1000 tablets of 1.5 g average weight each) :
• First layer Aluminium hydroxide 375 g microcrystalline cellulose
• Example 4 The same procedure is followed as in Example 4 - with the exception that the particles of the phosphate, compound are coated by spraying on them (and afterwards drying) an isopropanolic solution of Eudragit L100-55 - with the following compounds (for 1000 tablets of 1.5 g average weight each) : Inner phase (aluminium) : aluminium hydroxide 375 g inner phase (phosphate) : tribasic calcium phosphate 100 g coating:
• Nymcel ZSB 10 ⁇ R 200 g water 80-100 ml outer phase: microcrystalline cellulose
• Example 9 The same procedure is followed and composition used as in Example 7 with the exception that the tribasic calcium phosphate is coated with a solution of 4.5 g celluloseacetatephtalate in 30 ml of acetone.
• Example 9 The same procedure is followed and composition used as in Example 7 with the exception that the tribasic calcium phosphate is coated with a solution of 4.5 g celluloseacetatephtalate in 30 ml of acetone.
• 1000 ml of an antacid suspension are prepared, having the following composition: magaldrate 200 g cross-linked carboxymethylcellulose sodium (Ac-Di-Sol (R) ) 50 g tribasic calcium phosphate 75 g tribasic magnesium phosphate 75 g hydroxy-propylmethylcellulose 4000 12 g methylparaben 10 g alcohol 10 g water, deionized to 1000 ml
• Example 10 Example 9 is repeated except that the composition differs as follows: aluminium hydroxide 100 g alginic acid 140 g monobasic sodium phosphate 140 g hydroxy-propylmethylcellulose 4000 12 g propylparaben 2.5 g methylparaben 2.5 g alcohol 10 g water, deionized to 1000 ml The alginic acid is first swelled in the acidic hydroxy- propylmethylcellulose solution containing monobasic sodium phosphate to produce the limited swelling form of the hydrocolloid.
• aluminium hydroxide 100 g alginic acid 140 g monobasic sodium phosphate 140 g hydroxy-propylmethylcellulose 4000 12 g propylparaben 2.5 g methylparaben 2.5 g alcohol 10 g water, deionized to 1000 ml
• the alginic acid is first swelled in the acidic hydroxy- propylmethylcellulose solution containing monobasic sodium phosphate to produce the limited swelling form of the hydrocolloid
• aluminium hydroxide 250 g monobasic sodium phosphate 100 g alginic acid 100 g are mixed and granulated in the dry state or by adding water and drying; then, 0.5 g Aerosil R972 (R) lubricant is mixed with the dry granules. A 0.40-0.45 g portion of the mixture is filled into a hard gelatine capsule.
• Example 12 A tablet preparation with antacid and adstringent effect is formulated with the following composition for 1000 tablets: aluminium hydroxide 500 g aluminium glycinate 500 g cellulose glycolic acid 250 g Carbopol 934p (R) 25 g tribasic magnesium phosphate 100 g magnesium stearate 23 g
• the process is completed in the usual way: the cellulose glycolic acid is swelled in the Carbopol 934p (R *> solution. This liquid is used for the wet granulation of the powder mixture.
• the tablet preparation is formed as described in Example 1.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Public Health (AREA)
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• General Health & Medical Sciences (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Inorganic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1994
  • 1994-03-16 WO PCT/EP1994/000829 patent/WO1994021268A1/en not_active Application Discontinuation
  • 1994-03-16 AU AU64269/94A patent/AU6426994A/en not_active Abandoned
  • 1994-03-16 PL PL94310821A patent/PL310821A1/xx unknown
  • 1994-03-16 CA CA002158437A patent/CA2158437A1/en not_active Abandoned
  • 1994-03-16 EP EP94911900A patent/EP0689445A1/en not_active Withdrawn
  • 1994-03-16 JP JP6520643A patent/JPH08507775A/ja active Pending
• 1995
  • 1995-09-15 FI FI954348A patent/FI954348A/fi not_active Application Discontinuation

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