IE912885A1 - Multiparticulate sustained release matrix system - Google Patents

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. 10 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 or 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 hydroxypropyIce 1lulose alone or mixed with methylcellulose and/or sodium carboxymethylcellulose.

US Patent No. 4,167,448 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.

EUR-90015 - 2 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 medicament.

The EURO PCT Patent Application EP 261,213 (WO 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 20 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. 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 gelatin capsules which, when release the tens and sometimes hundreds of spherules which disperse along the gastro-intestinal tract, thus These disadvantages are filled into hard ingested, dissolve to EUR-90015 - 3 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, so 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 polymer EUR-90015 - 4 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 hydrated.

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 EUR-90015 - 5 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 molecular weight biopolysaccharide , a natural polymer with a high or more specifically a fermentation product of the microorganism Xanthomonas campestris. 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 EUR-90015 - 6 cases the thickening and stabilizing properties of emulsions or suspensions solution are made use of. given by xanthan gum 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. papaverine and (broncophenirami ne, 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, derivatives), antihistamines 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), EUR-90015 - 7 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 EUR-90015 - 8 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 tabletting machine, model Ronchi AM13 equipped with EUR-90015 - 9 punchers (diameter 2 mm, bending radius 3 mm) giving minitablets with an average weight of 9.2 mg 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 small 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 900 ml of artificial intestinal juice with pH 6.8 and a rotation speed of 50 rpm. 7O Release -after 1 hour : 27 -after 2 hours : 44 -after 3 hours : 59 -after 4 hours : 73 -after 5 hours : 85 -after 6 hours : 94 EXAMPLE 2 A) Preparation of the mixture EUR-90015 - 10 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 pm mesh 5 screen and subsequently through 800 pm and 700 pm 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 pm.

The following materials are transferred in cone shaped laboratory mixer: a double granulated sodium diclofenac (300-700 pm) 800 . Og xanthan gum 1140 . Og silicon dioxide 20.0g 15 magnesium stearate mix for about 15 minutes. 40 . Og 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· EUR-90015 - 11 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. 70 Release -after 1 hour : 30 -after 2 hours : 52 -after 3 hours : 65 -after 4 hours : 72 -after 6 hours : 99 EXAMPLE 3 A) Preparation of the Mixture Transfer the following through a 0.5 mm sieve cube mixer raw in materials , a stainless previously sieved steel laboratory granulate theophylline (200-400 pm) 108.7g xanthan gum 44.5g hydroxypropylmethylcellulose 44.5g silicone dioxide 0.9g magnesium stearate 1.4g Mix for about 15 minutes B) Preparation of the Minitablets EUR-90015 - 12 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 15 Pharmacopoeia (USP) using 900 ml of artificial intestinal juice with pH 7.5 and a rotation speed of 50 rpm . °ZO Re lease -after 1 hour : 43 . 5 20 -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 7„ Release -after 1 hour: 53.9 -after 2 hours: 77.7 -after 4 hours: 100 EUR-90015

Claims (9)

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 hydroxypropy lcel lulose 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 pharmaceutca.1 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 EUR-90015 - 14 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.