WO1996004888A1 - Compositions d'antagonistes h2 s'administrant par voie orale - Google Patents

Compositions d'antagonistes h2 s'administrant par voie orale Download PDF

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Publication number
WO1996004888A1
WO1996004888A1 PCT/US1995/008142 US9508142W WO9604888A1 WO 1996004888 A1 WO1996004888 A1 WO 1996004888A1 US 9508142 W US9508142 W US 9508142W WO 9604888 A1 WO9604888 A1 WO 9604888A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
calcium carbonate
antagonist
weight
present
Prior art date
Application number
PCT/US1995/008142
Other languages
English (en)
Inventor
Henry C. Caldwell
Ashok J. Desai
Original Assignee
Applied Analytical Industries, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Applied Analytical Industries, Inc. filed Critical Applied Analytical Industries, Inc.
Priority to AU29126/95A priority Critical patent/AU2912695A/en
Publication of WO1996004888A1 publication Critical patent/WO1996004888A1/fr

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals

Definitions

  • This invention relates to pharmaceutically elegant compositions of therapeutic compounds having H 2 -antagonist activity especially adapted for convenient oral administration.
  • U.S. Patent No. 4,719,228 discloses the use of selected synthetic silicas to form free flowing powder products of a number of therapeutic classes of drugs including antiulcer drugs. No reference to H 2 -antagonists is made here.
  • ranitidine as the active H 2 -antagonist agent has been reported.
  • This pharmaceutical form which contains sodium acid pyrophosphate, an acid salt, demonstrated substantial reduced bioavailability of the active ingredient (54%) , K.M. Koch et al., Pharm.Res ..10 . 1027 (1993) .
  • U.S. Patent No. 5,219,563 reports adsorbates of ranitidine on synthetic ion exchange resin.
  • compositions containing one or more H 2 -antagonist drugs do not exhibit a bitter taste in the mouth and distribute the active ingredient substantially in the gastrointestinal tract.
  • the composition contains, as essential ingredients, an H 2 -antagonist - magnesium aluminum silicate complex and calcium carbonate.
  • the dosage unit form is any which would normally expose the bitter H 2 -antagonist to the taste of the patient but is preferably a chewable tablet. For larger doses, it may be a sachet, lozenge or packaged flavored granules .
  • H 2 -compounds are preferably administered orally.
  • the oral product forms of these compounds are capsules or coated tablets. Certain segments of the patient population prefer more easily ingested product forms . This is most evident in the over-the-counter market.
  • One of the most useful of such product forms is the chewable or frangible tablet, lozenge or troche. Examples of the preparation of chewable products are found in U.S. Patent No. 4,711,774 which is cited in the Background section above.
  • H 2 -antagonists form tasteless adsorbates with magnesium aluminum silicate readily and substantially completely.
  • the addition of a selected quantity of calcium carbonate dramatically improves the release of active ingredient from the silicate adsorbate, but does not cause overt side effects such as substantial release of carbon dioxide by effervescence. This is so especially when the formulations are prepared with acid addition salts of the biologically active ingredients or with added solid acid formulation aids such as the fruit acids, for example citric acid, within the granules in the formulation process.
  • the complex between the active biological ingredient and the magnesium aluminum silicate is usually formed in situ, that is, during the formulation of the dosage unit composition.
  • composition of this invention is in its preferred form a chewable tablet comprised essentially of a therapeutically effective but non- toxic dosage unit quantity of an H 2 -antagonist complex formed with a magnesium aluminum silicate, which complex is usually prepared during formulation, and a quantity of calcium carbonate.
  • the magnesium aluminum silicate which is the support component of this combination is preferably the commercial product known as "Veegum” supplied by R.T. Vanderbilt Company, Inc. Analysis of the commercial product is carried out as oxide contents. No control of the particle size of the commercial grade of product has been found necessary. Comprehensive descriptions of the product are in the Zentner-Denick patents noted above.
  • the exact quantity of the silicate support is not critical to the invention as long as enough is present to completely adsorb the drug component in situ. An excess is most convenient and preferred with ranges of from 10 - 30% by weight of the dosage unit.
  • Magnesium aluminum silicates have been used in the literature to delay the release of other active ingredients in time release products when used in excess. This is in contrast to the present invention which affords good quick release of drug.
  • the H 2 -antagonist in either the base or its acid addition salt form as appropriate, is preferably selected from those approved for use in either the prescription or over-the-counter pharmaceutical markets.
  • the dosage units will contain either a full therapeutic dose or a partial dose for a subject in need of relief so that from 1-5 units may be administered per day to obtain satisfactory treatment of symptoms.
  • the non-prescription products usually contain a lower doses, often about half the quantity.
  • active H 2 -antagonists and suggested doses are cimetidine (300 mg) , " nizatidine (150 mg) , roxatidine (acetate) , famotidine (20 mg) , ranitidine (150 mg) , tiotidine, lamtidine, mifentidine, zaltidine, KV-1257 or loxtidine (Handbook Exp. Pharmacol.97 573- 748 (1991) , "Histamine and Histamine Antagonists”) .
  • the daily dose range of active ingredient is a nontoxic but H 2 -antagonist effective quantity and may be chosen from 40 to 1600 mg.
  • the dosage units may range from 10 - 800 mg of active ingredient depending on the known individual activity and market of the H 2 -antagonist drug.
  • the units are administered from 1-5 times daily orally to a patient in need of H 2 -antagonist treatment.
  • the H 2 -antagonist may be present either as the base if appropriate or as a salt thereof with a nontoxic, pharmaceutically acceptable acid.
  • the dose and the form which is commercially available is conveniently used.
  • the H 2 -antagonist- silicate adsorbate is formed substantially completely during formulation despite which base or salt form of the active H 2 -antagonist is selected.
  • the calcium carbonate is selected from the range of 75-500 mg per dosage unit.
  • the calcium carbonate supplemented product is preferably used in non-toxic quantities in up to 5 units per day.
  • a general range of calcium carbonate content of the oral product is from about 1-35% by weight of the chewable tablet products. For example, for a 1500 mg. tablet as much as 500 mg. of calcium carbonate may be present. Overt evolution of carbon dioxide has not been observed when the compositions contact water.
  • One skilled in the art will recognize that the size of chewable tablets may be larger than that of normal compressed tablets.
  • composition of this invention in addition to the essential ingredients described above.
  • these are bulking agents, flavoring agents, granulating agents, buffering agents, coloring agents, preservatives, confectioneries and the like.
  • Especially useful optional ingredients are the solid fruit acids such as citric, malic or tartaric acids in up to 3% by weight for good stability and palatability of the chewable tablet as well as xylitol or mannitol as a sweetening-bulking agent in up to 70% by weight.
  • Citric acid as well as xylitol are particularly advantageous since each contributes unexpectedly well to the palatability of the chewable tablets.
  • quantity of calcium carbonate and acid should be selected to insure good release, but not to cause overt carbon dioxide evolution. The absence of the acid component gives acceptable products as well.
  • the chewable tablets of this invention are prepared by mixing the H 2 -antagonist compound with magnesium aluminum silicate in a weight ratio chosen from the range of 1 to 1 down to 1 to 10 with an optional sweetening agent in a agent in a mixer, adding water to form the complex and granulate .
  • the dried and milled granules are mixed with the calcium carbonate, bulking-sweetening agents and tabletting aids then compressed into tablets .
  • the chewable pharmaceutical products are taken by the subject in need of H 2 -antagonist treatment orally from 1 to 5 times daily as required to satisfy the acceptable daily dosage regimen of active ingredients. It should be particularly noted that the antacid component of the chewable tablet may also contribute to lowering the acid content of the gastrointestinal tract.
  • the dosage units should be prepared and used with this in mind.
  • the method of analysis used and detailed hereafter is the ultraviolet dissolution method as reported in the USP XXII (p.3074) . Usually times for pulling samples were 15, 30, 45, 60 minutes. The ultraviolet wave lengths vary, of course, with the active ingredient. Cimetidine is at 218 nm. Nizatidine and ranitidine are at 314 nm. Famotidine is at 265 nm.
  • Example 3 The percentage of cimetidine dissolved in water using the U. S . P . method II at 50 RPM to 60 minutes from granules with added citric acid ( 3%) , calcium carbonate ( 75 mg) and without calcium carbonate . Time Without CaCO, With CaCO-
  • Nizatidine with and without calcium carbonate compared at 0 time and l month stability (40°; 75%RH) , citric acid (1.5%) added to all samples.
  • Time Without CaCO Stability With CaCO, Stability
  • Nizatidine granules compared in water with tablet with 1.5% citric acid and tablet with 1.5% of citric acid and 37.5 mg of calcium carbonate.
  • Example 1 The process of Example 1 is used with 25% by weight of magnesium aluminum silicate, 5% of nizatidine, 0.25% of sodium saccharin and 1.2% of citric acid. The granules, before tabletting, were compared with the tabletted product and with the chewable tablet with 5% of calcium carbonate.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Medicinal Preparation (AREA)

Abstract

Des tablettes mâchables, constituées d'antagonistes H2 ne laissant pas de goût dans la bouche, mais permettant une bonne libération des ingrédients actifs, sont préparées à l'aide de carbonate de calcium et d'un silicate d'aluminium de magnésium d'appoint. Des ingrédients non essentiels, tels que le xylitol et des acides de fruits, sont également utilisés pour préparer la formulation.
PCT/US1995/008142 1994-08-12 1995-06-28 Compositions d'antagonistes h2 s'administrant par voie orale WO1996004888A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU29126/95A AU2912695A (en) 1994-08-12 1995-06-28 Oral compositions of h2-antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US28871194A 1994-08-12 1994-08-12
US288,711 1994-08-12

Publications (1)

Publication Number Publication Date
WO1996004888A1 true WO1996004888A1 (fr) 1996-02-22

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/008142 WO1996004888A1 (fr) 1994-08-12 1995-06-28 Compositions d'antagonistes h2 s'administrant par voie orale

Country Status (2)

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AU (1) AU2912695A (fr)
WO (1) WO1996004888A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996023494A1 (fr) * 1995-02-02 1996-08-08 Applied Analytical Industries, Inc. Compositions orales d'antagonistes de h¿2?
EP1020193A1 (fr) * 1997-09-30 2000-07-19 Daiichi Pharmaceutical Co., Ltd. Preparation orale

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992000102A1 (fr) * 1990-06-22 1992-01-09 Beecham Group Plc Nouveau traitement
US5229137A (en) * 1992-05-06 1993-07-20 Brigham And Women's Hospital, Inc. Methods and pharmaceutical compositions for treating episodic heartburn
WO1993024124A1 (fr) * 1992-05-26 1993-12-09 Smithkline Beecham Plc Compositions a base d'inhibiteurs de recepteur h2 a l'histamine et de complexes echangeurs cationiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992000102A1 (fr) * 1990-06-22 1992-01-09 Beecham Group Plc Nouveau traitement
US5229137A (en) * 1992-05-06 1993-07-20 Brigham And Women's Hospital, Inc. Methods and pharmaceutical compositions for treating episodic heartburn
WO1993024124A1 (fr) * 1992-05-26 1993-12-09 Smithkline Beecham Plc Compositions a base d'inhibiteurs de recepteur h2 a l'histamine et de complexes echangeurs cationiques

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996023494A1 (fr) * 1995-02-02 1996-08-08 Applied Analytical Industries, Inc. Compositions orales d'antagonistes de h¿2?
EP1020193A1 (fr) * 1997-09-30 2000-07-19 Daiichi Pharmaceutical Co., Ltd. Preparation orale
EP1020193A4 (fr) * 1997-09-30 2006-05-24 Daiichi Seiyaku Co Preparation orale

Also Published As

Publication number Publication date
AU2912695A (en) 1996-03-07

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