WO1992004013A1 - Multiparticulate sustained release matrix system - Google Patents

Multiparticulate sustained release matrix system Download PDF

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Publication number
WO1992004013A1
WO1992004013A1 PCT/EP1991/001562 EP9101562W WO9204013A1 WO 1992004013 A1 WO1992004013 A1 WO 1992004013A1 EP 9101562 W EP9101562 W EP 9101562W WO 9204013 A1 WO9204013 A1 WO 9204013A1
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WO
WIPO (PCT)
Prior art keywords
xanthan gum
minitablets
dosage form
matrix
pharmaceutical dosage
Prior art date
Application number
PCT/EP1991/001562
Other languages
French (fr)
Inventor
Giovanni Bongiovanni
Massimo Maria Calanchi
Marco Giuseppe Raffaele Marconi
Original Assignee
Eurand International Spa
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Filing date
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Publication of WO1992004013A1 publication Critical patent/WO1992004013A1/en

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    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • 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

Definitions

  • the present invention relates to an oral dosage system of pharmacologically active substances consisting of different small tablets, each having a prolonged and controlled release, filled into hard gelatin capsules.
  • Hydrophilic matrix tablets consist fundamentally of a homogeneous mixture of the active medicament and one or more polymers which dissolve slowly in water.
  • US Patent No. 4,259,341 to Lowey US Patent No. 3,870,790 to Lowey et al and US Patent No. 4,226,849 to Schor and US Patent No 4,357,469 to Schor concern the preparation of tablets with a hydrophilic matrix of hydroxypropylmethylcellulose, alone cr mixed with other cellulose derivatives, which have undergone treatments, that is forced dehydration, humidification, hydrolysis aned oxidation.
  • hydroxypropylmethylcellulose to prepare controlled-release hydrophilic matrix and examines the influence of various parameters characteristic of hydroxypropylmethylcellulose, such as molecular weight, degree of substitution; granulometric distribution, hydration velocity, on the release of the active medicamen .
  • the EURO PCT Patent Application EP 261,213 C O 87/5212 discloses hydrophilic matrix tablets in which the matrix consists of Xanthan Gum alone or in a mixtrue (50% maximum) with hydrophilic cellulose polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose.
  • the following advantages are obtained: a more reproducible release; an improved gastro-intestinal tolerance; a more uniform concentration of the active medicament in the blood without "peaks" , which often cause negative side effects, and therefore a greater acceptability for the patient.
  • the methods of producing the small sustained-release spheres are very long and complex and therefore expensive.
  • the dimensions of the spherules are not equal, but since they are distributed in a large range the release of single spherules, after coating with the delaying membrane, will not be homogeneous either.
  • the second is due to the fact that the minitablets form gelatinous layer and stick together on contact with the gastro-intestinal juices.
  • the colvmer constituent of the minitablet matrix hydrates and forms a gelatinous layer.
  • the single units stick together giving rise to a single mass which proceeds along the gastro-intestinal tract like a single large tablet so cancelling out the desired advantages of the multiparticulate form.
  • the object of the present invention are small hydrophilic matrix tablets which are not only slow-releasing but also do not aggregate when hydratec.
  • these minitabs permit the administration of an economical controlled-release multiparticulate form and the units remain in single entities along the gastro-intestinal tract .
  • pharmaceutical dosage form comprising a hard gelatin capsule containing a multiplicity of minitablets providing prolonged and regular release of the active ingredient, said tablets comprising one or more active medicaments contained within a matrix which provides a sustained release effect, the matrix consisting essentially of xanthan gum or a mixture of xanthan gum and one or more natural or synthetic polymers, which hydrate and dissolve in water or gastric juices.
  • the present invention concerns the preparation of controlled-release minitablets obtained by compression of an active medicament, xanthan gum and possible other inert excipients commonly utilized for the production of tablets such as lubricants, fillers and flowing agents.
  • the xanthan gum is a natural polymer with a high molecular weight or more specifically a biopolysaccharide , fermentation product of the microorguni ⁇ iu Xa.ithou-onas C ⁇ mpe-ctris.
  • the structure, the molecular weight, and the dissolution properties of this polymer are constant and reproducible in strictly controlled working conditions.
  • Xanthan gum is used in numerous fields including the pharmaceutical, cosmetic and food industries. in these cases the thickening and stabilizing properties of emulsions or suspensions given by xanthan gum in solution are made use of .
  • the matrix can consist of xanthan gum only or as a mixture of xanthan gum always being 50% or higher with respect to the polymer.
  • the delaying matrix is mixed in suitable apparatus with the desired active medicament or even medicaments to be administered in a sustained-release formulation.
  • active medicaments we cite as an illustrative, but not restrictive, example adrenergicamines (ethylephrine , phenylephrine, phenylpropanolamine, d-pseudoephendrin) , antispasmodics (scopolamine, and other alkaloids of belladonna, papaverine and derivatives), antihistamines (broncopheniramine, chlorpheniramine , diphenylpiraline, dimenhydr(in)ate) , anorexics (norpsuedoephedrin, fentermine, diethylpropion, flenfuramine) , antiasthmatics (theophylline , salbutamol, terbutaline) , antianginous (isosorbide-5-mononitrate, isosorbide
  • inert excipients commonly used by experts in the art may be present in the formulation, in order to improve its characteristics .
  • lubricants for example in the preparation of minitablets, lubricants, inert excipients, etc. can be added to improve the flowability of the powder, the appearance, the precision of the dose.
  • the quantity of matrix used to delay the release of the active medicament can vary widely depending on whether the formulation consists only of active medicament and matrix or if there are other excipients present, in various quantities according to whether the active medicament is very or not very soluble and whether the dose is high or low.
  • the minitablets are produced using the usual tabletting machines as for example the Ronchi rotary type AM13 equipped with punches and matrices adapted in order to obtain minitablets with a diameter less than 4 mm and preferably between 2 - 2.5 mm.
  • the invention also includes a method for the preparation of a pharmaceutical dosage form which method comprises mixing an active medicament with xanthan gum or a mixture of xanthan gum and one or more natural or synthetic polymers, which hydrate and dissolve in water or gastro-intestinal juices, forming the mixture into minitablets, filling the minitablets into hard gelatin capsules so that each capsule contains a multiplicity of minitablets, the xanthan gum or xantham gum mixture providing a matrix from which in use the active medicament has a prolonged and regular release .
  • the mixture obtained from A) is compressed with a tablettin ⁇ machine, model Ronchi AM13 e ⁇ uipped with punchers (diameter 2 mm, bending radius 3 mm) giving minitablets with an average weight of 9.2 g and each containing 6 mg of ibuprofen.
  • Each capsule contains 200 mg of ibuprofen.
  • the minitablets were analysed with the rotating paddle method described in the current edition of the US Pharmacopoeia (USP) using 90C ml of artificial intestinal juice with pH 6.8 and a rotation speed of 50 rpm.
  • the granules are dried at about 40 C for 12-15 hours in a circulating air oven and selected between 300 and 700 ⁇ m.
  • the following materials are transferred in a double cone shaped laboratory mixer: granulated sodium diclofenac (300-700 ⁇ m) 800. Og xanthan gum 1140. Og silicon dioxide 20. Og magnesium stearate 40. Og mix for about 15 minutes.
  • the mixture obtained from A) is compressed with a tabletting machine , model Ronchi AM13 equipped with punchers (diameter 2mm, bending radius 3mm) giving minitablets with an average weight of 7.7 mg and each containing 2.9 mg of diclofenac.
  • type Snap Fit size 1,35 of the small tablets produced in B were introduced into each capsule with a suitable capsule filling machine •
  • Each capsule contains 100 mg of sodium diclofenac.
  • the minitablets were analysed with the rotating paddle mthod described in the current edition of the US Pharmacopoeia (USP) using 900 ml of artificial intestinal juice with pH 6.8 and a rotation speed of 50 rpm.
  • type Coni Snap Fit size 0 ,45 of the small tablets produced in B were introduced into each capsule with a suitable filling machine.
  • Each capsule contains 200 mg of theophylline.
  • the minitablets were analyzed with the rotating paddle method described in the current edition of the US Pharmacopoeia (USP) using 900 ml of artificial intestinal juice with pH 7.5 and a rotation speed of 50 rpm.
  • the minitablets were analyzed as described above using 900ml of artificial gastric juice with pH 1.2

Abstract

The present invention relates to an oral dosage system of pharmacologically active substances consisting of different small tablets, each having a prolonged and controlled release, filled into hard gelatin capsules. Specifically the small tablets have a hydrophilic matrix made of xanthan gum, alone or mixed with other hydrophilic polymers, by which the slow release of the drug along the gastro-intestinal tract is obtained.

Description

MULTIPARTICULATE SUSTAINED RELEASE MATRIX SYSTEM
The present invention relates to an oral dosage system of pharmacologically active substances consisting of different small tablets, each having a prolonged and controlled release, filled into hard gelatin capsules.
Hydrophilic matrix tablets consist fundamentally of a homogeneous mixture of the active medicament and one or more polymers which dissolve slowly in water.
For Example:
US Patent No. 4,259,341 to Lowey , US Patent No. 3,870,790 to Lowey et al and US Patent No. 4,226,849 to Schor and US Patent No 4,357,469 to Schor concern the preparation of tablets with a hydrophilic matrix of hydroxypropylmethylcellulose, alone cr mixed with other cellulose derivatives, which have undergone treatments, that is forced dehydration, humidification, hydrolysis aned oxidation.
US Patent No. 4,369,172 and No. 4,389,393 to Schor et al which concern the use of one or more types and well-defined quantities of hydroxypropylcel1ulose alone or mixed with methylcellulose and/or sodium carboxymethylcellulose.
US Patent No. 4,167,446 and No. 4,126,672 to Sheth et al which concern the use of hydroxypropylmethylcellulose for the preparation of tablets and especially hydrophilic matrix capsules in such a form that they float in the digestive juices of the stomach. The article entitled "A Review of Cellulose Ethers in Hydrophylic Matrices for Oral Controlled-release Dosage Forms" by D.A. Alderman, published in Int.J.Pharm.Tech and Prod.Mfr. , 5 (3) 1-9, 1984, describes extensively the use of hydroxypropylmethylcellulose to prepare controlled-release hydrophilic matrix and examines the influence of various parameters characteristic of hydroxypropylmethylcellulose, such as molecular weight, degree of substitution; granulometric distribution, hydration velocity, on the release of the active medicamen .
The EURO PCT Patent Application EP 261,213 C O 87/5212) (corresponding to Italian Patent application No. 19 675 A/86) discloses hydrophilic matrix tablets in which the matrix consists of Xanthan Gum alone or in a mixtrue (50% maximum) with hydrophilic cellulose polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose.
The advantage of these large matrix polymers is their low cost, but they have various disadvantages since they tend to adhere to the stomach and intestinal walls, causing irritation of the mucosa and irregular absorption of the active medicament.
These disadvantages are overcome by the multiparticulate form as spherules composed of active medicament coated with a polymeric membrane which delays the dissolution. These spherules of controlled-release medicament are filled into hard gelatin capsules which, when ingested, dissolve to release the tens and sometimes hundreds of spherules which disperse along the gastro-intestinal tract, thus avoiding a high local concentration of the active medicament.
With this multiparticulate form the following advantages are obtained: a more reproducible release; an improved gastro-intestinal tolerance; a more uniform concentration of the active medicament in the blood without "peaks" , which often cause negative side effects, and therefore a greater acceptability for the patient. However, the methods of producing the small sustained-release spheres are very long and complex and therefore expensive. In addition the dimensions of the spherules are not equal, but since they are distributed in a large range the release of single spherules, after coating with the delaying membrane, will not be homogeneous either.
These disadvantages can be overcome by preparing the tablets with a matrix of small dimensions (also called minitablets* to fill hard gelatin capsules, sc obtaining a multiparticulate form.
The production of small hydrophilic matrix tablets however is not very easy and presents two main problems. The first is due to the fact that the small dimensions, the permeability and the solubility of the polymers utilized for the hydrophilic matrix preparation do not permit to delay sufficiently the dissolution of the active medicament.
The second is due to the fact that the minitablets form gelatinous layer and stick together on contact with the gastro-intestinal juices. In fact when the gelatin capsule is ingested and dissolves, the colvmer constituent of the minitablet matrix hydrates and forms a gelatinous layer. The single units stick together giving rise to a single mass which proceeds along the gastro-intestinal tract like a single large tablet so cancelling out the desired advantages of the multiparticulate form.
G.B. Patent No 2,176,999 managed to get around the first of these problems by the addition of an ionic substance to the minitablet formulation, in addition to the hydroxylalkylcellulose ethers , with a large opposite to that of the active medicament, preferably an ionic exchange resin, with the function of delaying the release of the active medicament as specified in the text of the patent and as known (see for example European Patent Appln. 0294103 A of Muneo Nonomura et al) . *
The object of the present invention are small hydrophilic matrix tablets which are not only slow-releasing but also do not aggregate when hydratec.
In fact we have discovered, very surprisingly, that if natural xanthan gum is used as the hydrophilic matrix, minitablets with the above-mentioned characteristics are obtained.
Once put in the capsule, these minitabs permit the administration of an economical controlled-release multiparticulate form and the units remain in single entities along the gastro-intestinal tract .
According to the invention there is provided a - _- -
pharmaceutical dosage form comprising a hard gelatin capsule containing a multiplicity of minitablets providing prolonged and regular release of the active ingredient, said tablets comprising one or more active medicaments contained within a matrix which provides a sustained release effect, the matrix consisting essentially of xanthan gum or a mixture of xanthan gum and one or more natural or synthetic polymers, which hydrate and dissolve in water or gastric juices.
The present invention concerns the preparation of controlled-release minitablets obtained by compression of an active medicament, xanthan gum and possible other inert excipients commonly utilized for the production of tablets such as lubricants, fillers and flowing agents.
We have found, very surprisingly, that if xanthan gum is used as a hydrophilic matrix, the release of the active medicament is slowed down. Moreover when the polymer is hydrated giving rise to the formation of a superficial gelatinous layer the single units do not stick together therefore maintaining all the advantages of multiparticulate form.
The xanthan gum is a natural polymer with a high molecular weight or more specifically a biopolysaccharide , fermentation product of the microorguni≤iu Xa.ithou-onas Cάmpe-ctris. The structure, the molecular weight, and the dissolution properties of this polymer are constant and reproducible in strictly controlled working conditions.
Xanthan gum is used in numerous fields including the pharmaceutical, cosmetic and food industries. in these cases the thickening and stabilizing properties of emulsions or suspensions given by xanthan gum in solution are made use of .
With the present invention we found that it is possible to make use of xanthan gum's properties also in solid forms of medicament, using it for the preparation of the hydrophilic matrix in which xanthan gum has a retarding effect on the dissolution of the medicament.
The matrix can consist of xanthan gum only or as a mixture of xanthan gum always being 50% or higher with respect to the polymer.
The delaying matrix is mixed in suitable apparatus with the desired active medicament or even medicaments to be administered in a sustained-release formulation. Among the active medicaments we cite as an illustrative, but not restrictive, example adrenergicamines (ethylephrine , phenylephrine, phenylpropanolamine, d-pseudoephendrin) , antispasmodics (scopolamine, and other alkaloids of belladonna, papaverine and derivatives), antihistamines (broncopheniramine, chlorpheniramine , diphenylpiraline, dimenhydr(in)ate) , anorexics (norpsuedoephedrin, fentermine, diethylpropion, flenfuramine) , antiasthmatics (theophylline , salbutamol, terbutaline) , antianginous (isosorbide-5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, nitroglycerin, nifedipin, diltiazem) , anti-inflammatory and antipyretics (indomethacin, ibuprofen, ketoprofen, aspirin, paracetamol, phenacetin), antiphypertensives (nifedipin, idralazin, prazosin, verapamil), antidepressives (amitriptyline , lithium salts), antitussive (destromethorphan, noscapine, codeine), gastroenteric (cimetidine, ranitidine, metoclopramide) antiarrhythmic (procainamide , lidocaine, flecainide, propafenone ) , analgesics (morphine), vitamins (ascorbic acid) and their salts used in the pharmaceutical field.
Apart from polymers and medicaments, inert excipients commonly used by experts in the art may be present in the formulation, in order to improve its characteristics .
For example in the preparation of minitablets, lubricants, inert excipients, etc. can be added to improve the flowability of the powder, the appearance, the precision of the dose.
The quantity of matrix used to delay the release of the active medicament can vary widely depending on whether the formulation consists only of active medicament and matrix or if there are other excipients present, in various quantities according to whether the active medicament is very or not very soluble and whether the dose is high or low.
The minitablets are produced using the usual tabletting machines as for example the Ronchi rotary type AM13 equipped with punches and matrices adapted in order to obtain minitablets with a diameter less than 4 mm and preferably between 2 - 2.5 mm.
The invention also includes a method for the preparation of a pharmaceutical dosage form which method comprises mixing an active medicament with xanthan gum or a mixture of xanthan gum and one or more natural or synthetic polymers, which hydrate and dissolve in water or gastro-intestinal juices, forming the mixture into minitablets, filling the minitablets into hard gelatin capsules so that each capsule contains a multiplicity of minitablets, the xanthan gum or xantham gum mixture providing a matrix from which in use the active medicament has a prolonged and regular release .
The following examples which serve to better illustrate the invention must not be considered in any way as restrictive of the scope of the present invention and possible variations are obvious for experts in this field.
EXAMPLE 1
A) Preparation of the Mixture
Transfer the following raw materials, previously sieved through a 0.5 mm sieve, in a stainless steel laboratory cube mixer
ibuprofen 219.Og xanthan gum 45. Og cornstarch 12. Og glyceryl behenate 4.5g magnesium stearate 4.5g mix for about 15 minutes.
B) Preparation of the Minitablets
The mixture obtained from A) is compressed with a tablettinα machine, model Ronchi AM13 eσuipped with punchers (diameter 2 mm, bending radius 3 mm) giving minitablets with an average weight of 9.2 g and each containing 6 mg of ibuprofen.
C) Preparation of the Final Pharmaceutical Form
Utilizing hard gelatin capsules, type Coni Snap Supro-A, 34 of the smail tablets produced in B were introduced into" each capsule with a suitable capsule filling machine.
Each capsule contains 200 mg of ibuprofen.
D) Analysis
The minitablets were analysed with the rotating paddle method described in the current edition of the US Pharmacopoeia (USP) using 90C ml of artificial intestinal juice with pH 6.8 and a rotation speed of 50 rpm.
% Release
-after 1 hour : 27.0
-after 2 hours: 44.4
-after 3 hours: 59.7 -after 4 hours: 73.0
-after 5 hovrs: 85.1
-after 6 hours: 94.5
EXAMPLE 2
A) Preparation of the mixture Transfer 2550 g of sodium diclofenac into ' a laboratory blender and blend with 570 g of a solution of 15% hydroxypropylcellulose in 95% alcohol.
Granulate the paste obtained through a 1200 μm mesh screen and subsequently through 800 μm and 700 μm mesh screens .
The granules are dried at about 40 C for 12-15 hours in a circulating air oven and selected between 300 and 700 μm.
The following materials are transferred in a double cone shaped laboratory mixer: granulated sodium diclofenac (300-700 μm) 800. Og xanthan gum 1140. Og silicon dioxide 20. Og magnesium stearate 40. Og mix for about 15 minutes.
B) Preparation of the Minitablets
The mixture obtained from A) is compressed with a tabletting machine , model Ronchi AM13 equipped with punchers (diameter 2mm, bending radius 3mm) giving minitablets with an average weight of 7.7 mg and each containing 2.9 mg of diclofenac.
C) Preparation of the Final Pharmaceutical Form
Utilizing hard gelatin capsules, type Snap Fit size 1,35 of the small tablets produced in B were introduced into each capsule with a suitable capsule filling machine • Each capsule contains 100 mg of sodium diclofenac.
D) Analysis
The minitablets were analysed with the rotating paddle mthod described in the current edition of the US Pharmacopoeia (USP) using 900 ml of artificial intestinal juice with pH 6.8 and a rotation speed of 50 rpm.
% Release -
-after 1 hour: 30.2
-after 2 hours: 52.9
-after 3 hours: 65.1
-after 4 hours: 72.6
-after 6 hours: 99.0
EXAMPLE 3
A) Preparation of the Mixture
Transfer the following raw materials, previously sieved through a 0.5 mm sieve, in a stainless steel laboratory cube mixer
granulate theophylline (200-400 μm) 108.7g xar.than gum 41.5g hydroxypropylmethylcellu.lose 44.5g silicone dioxide 0.9g magnesium stearate 1.4g Mix for about 15 minutes
B) Preparation of the Minitablets The mixture obtained from A) is compressed with a compressing machine, model Ronchi AM13 equipped with punchers (diameter 2 mm,- bending radius 3 mm) giving minitabs with an average weight of 8.1 mg and each containing 4.4 mg of theophylline.
C) Preparation of the Final Pharmaceutical Form
Utilizing hard gelatin capsules, type Coni Snap Fit size 0 ,45 of the small tablets produced in B were introduced into each capsule with a suitable filling machine.
Each capsule contains 200 mg of theophylline.
D) Analysis
The minitablets were analyzed with the rotating paddle method described in the current edition of the US Pharmacopoeia (USP) using 900 ml of artificial intestinal juice with pH 7.5 and a rotation speed of 50 rpm.
% Release
-after 1 hour: 43.5
-after 2 hours: 68.9
-after 3 hours: 99.0
The minitablets were analyzed as described above using 900ml of artificial gastric juice with pH 1.2
% Release -after 1 hour: 53.9
-after 2 hours: 77.7
-after 4 hours: 100

Claims

1. A pharmaceutical dosage form comprising a hard gelatin capsule containing a multiplicity of minitablets providing prolonged and regular release of the active ingredient, said tablets comprising one or more active medicaments contained within a matrix which provides a sustained release effect, the matrix consisting essentially of xanthan gum or a mixture of xanthan gum and one or more natural or synthetic polymers, which hydrate and dissolve in water or gastric juices.
2. A pharmaceutical dosage form as claimed in Claim 1, wherein the matrix comprises at least 50% of xanthan gum.
3. A pharmaceutical dosage form as claimed in Claim 1 or Claim 2, wherein the matrix consists essentially of xanthan gum and one or both of hydroxypropylcellulose or hydroxypropylmethylcellulose .
4. A pharmaceutical dosage form as claimed in any one of the preceding Claims wherein the minitablets also contain conventional inert excipients.
5. A pharmaceutical dosage form as claimed in any one of the preceding claims wherein the active medicament is ibuprofen, theophylline or sodium diclofenac .
6. A pharmaceutcal dosage form as claimed in any one of the preceding Claims wherein the capsule contains from 30 - 50 minitablets.
7. A method for the preparation of a pharmaceutical dosage form which method comprises mixing an active medicament with xanthan gum or a mixture of xanthan gum and one or more natural or synthetic polymers, which hydrate and dissolve in water or gastro-intestinal juices, forming the mixture into minitablets, filling the minitablets into hard gelatin capsules so that each capsule contains a multiplicity of minitablets, the xanthan gum or xantham gum mixture providing a matrix from which in use the active medicament has a prolonged and regular release .
8. A method as claimed in Claim 7, wherein the dosage form is as claimed in any one of Claims 1 - 6.
9. A pharmaceutical dosage form as claimed in Claim 1, substantially as hereinbefore described in any one of Examples 1 - 3.
PCT/EP1991/001562 1990-08-30 1991-08-15 Multiparticulate sustained release matrix system WO1992004013A1 (en)

Applications Claiming Priority (2)

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IT21338A/90 1990-08-30
IT02133890A IT1250483B (en) 1990-08-30 1990-08-30 MULTIPLE DIE DELAY SYSTEM

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IE (1) IE912885A1 (en)
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PT (1) PT98791A (en)
WO (1) WO1992004013A1 (en)
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993018755A1 (en) * 1992-03-25 1993-09-30 Depomed Systems, Incorporated Alkyl-substituted cellulose-based sustained-release oral drug dosage forms
DE4310963A1 (en) * 1993-04-03 1994-10-06 Knoll Ag Extended-release tablet of beta-phenylpropiophenone derivatives
EP0804174A1 (en) * 1993-07-21 1997-11-05 The University of Kentucky Research Foundation A multicompartment hard capsule with control release properties
US5948437A (en) * 1996-05-23 1999-09-07 Zeneca Limited Pharmaceutical compositions using thiazepine
WO2003082804A1 (en) 2002-03-28 2003-10-09 Synthon B.V. Venlafaxine besylate
EP1424069A2 (en) * 1996-09-19 2004-06-02 Depomed, Inc. Gastric-retentive, oral drug dosage forms for the controlled-release of sparingly soluble drugs and insoluble matter
EP1581160A2 (en) * 2001-07-31 2005-10-05 Capricorn Pharma, Inc. Encapsulation products for controlled or extended release
NO20072938L (en) * 2004-11-19 2007-08-20 Smithkline Beecham Corp Pharmaceutical product and process for its preparation.
EP2359814A1 (en) * 2010-02-11 2011-08-24 Laboratorios Liconsa, S.A. Pharmaceutical mini-tablets for sustained release of flecainide acetate
US8333991B2 (en) 2001-10-25 2012-12-18 Depomed, Inc. Gastric retained gabapentin dosage form
US8394409B2 (en) 2004-07-01 2013-03-12 Intellipharmaceutics Corp. Controlled extended drug release technology
US8440232B2 (en) 2001-10-25 2013-05-14 Depomed, Inc. Methods of treatment using a gastric retained gabapentin dosage
US8592481B2 (en) 2005-12-29 2013-11-26 Depomed, Inc. Gastric retentive gabapentin dosage forms and methods for using same
US8603520B2 (en) 2003-06-26 2013-12-10 Intellipharmaceutics Corp. Oral multi-functional pharmaceutical capsule preparations of proton pump inhibitors
US9078827B2 (en) 2006-05-12 2015-07-14 Isa Odidi Pharmaceutical composition having reduced abuse potential
US9561188B2 (en) 2006-04-03 2017-02-07 Intellipharmaceutics Corporation Controlled release delivery device comprising an organosol coat
US10064828B1 (en) 2005-12-23 2018-09-04 Intellipharmaceutics Corp. Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems
US10624858B2 (en) 2004-08-23 2020-04-21 Intellipharmaceutics Corp Controlled release composition using transition coating, and method of preparing same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2176999A (en) * 1985-06-22 1987-01-14 Stanley Stewart Davis Multiparticulate sustained release medicament
EP0234670B1 (en) * 1986-01-18 1992-06-24 The Boots Company PLC Sustained-release pharmaceutical formulation containing xanthan gum

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2176999A (en) * 1985-06-22 1987-01-14 Stanley Stewart Davis Multiparticulate sustained release medicament
EP0234670B1 (en) * 1986-01-18 1992-06-24 The Boots Company PLC Sustained-release pharmaceutical formulation containing xanthan gum

Cited By (38)

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Publication number Priority date Publication date Assignee Title
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DE4310963A1 (en) * 1993-04-03 1994-10-06 Knoll Ag Extended-release tablet of beta-phenylpropiophenone derivatives
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US5948437A (en) * 1996-05-23 1999-09-07 Zeneca Limited Pharmaceutical compositions using thiazepine
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US8440232B2 (en) 2001-10-25 2013-05-14 Depomed, Inc. Methods of treatment using a gastric retained gabapentin dosage
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US8333991B2 (en) 2001-10-25 2012-12-18 Depomed, Inc. Gastric retained gabapentin dosage form
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WO2003082804A1 (en) 2002-03-28 2003-10-09 Synthon B.V. Venlafaxine besylate
US8802139B2 (en) 2003-06-26 2014-08-12 Intellipharmaceutics Corp. Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient
US8603520B2 (en) 2003-06-26 2013-12-10 Intellipharmaceutics Corp. Oral multi-functional pharmaceutical capsule preparations of proton pump inhibitors
US9636306B2 (en) 2003-06-26 2017-05-02 Intellipharmaceutics Corp. Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient
US8394409B2 (en) 2004-07-01 2013-03-12 Intellipharmaceutics Corp. Controlled extended drug release technology
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US10064828B1 (en) 2005-12-23 2018-09-04 Intellipharmaceutics Corp. Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems
US8592481B2 (en) 2005-12-29 2013-11-26 Depomed, Inc. Gastric retentive gabapentin dosage forms and methods for using same
US9561188B2 (en) 2006-04-03 2017-02-07 Intellipharmaceutics Corporation Controlled release delivery device comprising an organosol coat
US9078827B2 (en) 2006-05-12 2015-07-14 Isa Odidi Pharmaceutical composition having reduced abuse potential
US10960077B2 (en) 2006-05-12 2021-03-30 Intellipharmaceutics Corp. Abuse and alcohol resistant drug composition
WO2011098194A3 (en) * 2010-02-11 2012-01-26 Laboratorios Liconsa, S. A. Pharmaceutical mini-tablets for sustained release of flecainide acetate
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IE912885A1 (en) 1992-03-11
PT98791A (en) 1992-07-31
ZA916518B (en) 1992-05-27
NZ239567A (en) 1992-06-25
IT9021338A1 (en) 1992-02-29
IT1250483B (en) 1995-04-07
AU8395691A (en) 1992-03-30
IT9021338A0 (en) 1990-08-30

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