WO1993000889A1 - METHOD FOR THE PREPARATION OF PROLONGED-RELEASE ORAL PHARMACEUTICAL FORMS CONTAINING ACTIVE SUBSTANCES HAVING A SOLUBILITY DEPENDENT UPON THE pH VALUE - Google Patents

METHOD FOR THE PREPARATION OF PROLONGED-RELEASE ORAL PHARMACEUTICAL FORMS CONTAINING ACTIVE SUBSTANCES HAVING A SOLUBILITY DEPENDENT UPON THE pH VALUE Download PDF

Info

Publication number
WO1993000889A1
WO1993000889A1 PCT/EP1992/001503 EP9201503W WO9300889A1 WO 1993000889 A1 WO1993000889 A1 WO 1993000889A1 EP 9201503 W EP9201503 W EP 9201503W WO 9300889 A1 WO9300889 A1 WO 9300889A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
active principle
polymeric material
pharmaceutical formulations
hydrophilic
formulations according
Prior art date
Application number
PCT/EP1992/001503
Other languages
French (fr)
Inventor
Ubaldo Conte
Paolo Giunchedi
Original Assignee
L.C. Pharchem Ltd.
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

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • A61K9/1694Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Abstract

A method is described which permits the release of a pharmaceutical product having weakly basic characteristics so as to be very soluble in an acid pH and virtually insoluble in a basic pH, at a constant rate, independently of the pH conditions in which the pharmaceutical product and the pharmaceutical form obtained from the latter are found. The method consists in the preparation of pellets composed of an active principle, a swellable polymeric material and a gastroresistant polymeric material. By carrying these pellets in a natural or synthetic polymeric material which is gellable and hydrophilic, or in a lipophilic polymeric or non-polymeric material, it is possible to obtain modified-release pharmaceutical forms which are capable of releasing the active principle at the same rate both in an acidic environment and in a basic environment.

Description

METHOD FOR THE PREPARATION OF PROLONGED-RELEASE ORAL PHARMACEUTICAL FORMS CONTAINING ACTIVE SUBSTANCES HAVING A SOLUBILITY DEPENDENT UPON THE PH VALUE

The present invention relates to oral pharma¬ ceutical formulations containing active principles having weak basic characteristics.

In particular, the formulations forming the subject of the invention permit the release of the active principle in a manner independent of the variations of the pH of the gastrointestinal tract.

The prolonged administration, by the oral route, of basic pharmaceutical products which may exhibit very significant variations of solubility depending on the variations of pH which are specific to the gastrointestinal tract, is a problem which has been recognised for some time.

This dependence of the rate of solubilisation upon the pH value of the medium proves to be one of the most difficult problems to resolve when it is necessary to design or to produce prolonged-release pharmaceutical forms.

In this specific case, in fact, basic or weakly basic pharmaceutical products are characterised by a high rate of solubilisation in a gastric (acidic) environment and by a dramatic reduction in the solubility in an intestinal (alkaline) environment.

In order to overcome these disadvantages, a multiplicity of proposals have been put forward: a - the formation of floating systems in an acidic environment capable of ensuring the persistence of the preparation in the gastric environment where the active principle is soluble as described in US No. 4,126,672 (21/11/1978); b - the incorporation in the pharmaceutical form of ancillary substances (excipients and technological coadjuvants) capable of slowing down gastric evacuation and thus able to cause the pharmaceutical form for a greater period of time to persist in the zone of high solubility of the active principle. Systems of this type are described in Drug Dev. Ind. Phar . 10, 527, 1984 and in Int. J. Pharm. 12, 315, 1982; c - the formation of systems adherent in an acidic environment (gastric bioadherent systems) with the objective, in this case also, of increasing the persistence of the pharmaceutical form in an environment having an acidic pH, as described, for example, in J. Pharm. Sci. 74, 399, 1985 and in Int. J. Pharm. 19, 107, 1984; d - the carrying in the pharmaceutical form of buffering substances which are capable of maintaining around the pharmaceutical form, once in contact with the fluids of the gastrointestinal tract, an acidic microenvironment such as to facilitate and in any event not to slow down the dissolving of the active principle; systems of this type are described in EP A 0,032,562 Al and in Int. J. Pharm. 50, 223, (1989).

However, all these systems exhibit numerous limitations and encounter significant difficulties either on account of the complexity in the standardisation of the preparation or since, in vivo, the system under consideration does not behave as foreseen by the in vitro tests. In fact, the physiological factors (housekeeper wave) may profoundly modify the performance levels of the pharmaceutical form or of the system under consideration, especially in respect of the differing conditions of the patient (whether or not under fasting conditions).

The invention proposes modified-release pharma- ceutical forms which are capable of releasing a basic active principle in a manner independent of the values of the pH within the range which is encountered in the gastrointestinal tract.

It has now been found that the incorporation of the basic active principle in modified-release pellets composed of a complex polymer matrix formed of a water- insoluble and swelling phase and of a gastroresistant, but enterosoluble phase, permits a slowing down of the high dissolution rate of the active principle in the gastric environment, and a very significant increase in the dissolution rate in the intestinal environment.

The modified-release pellets may be mixed with a polymer material, obtaining matrices from which the basic active principle (whose dissolution rate at the various pH values has been "standardised"), is released in a prolonged manner, without the releasing rate being substantially affected by the change of pH.

Thus, an object of the invention is provided by pharmaceutical formulations which permit the release, in a manner which is prolonged and independent of the pH of the entire gastrointestinal tract, of an active principle having a weakly basic character. A further object of the invention is a process for the preparation of said pharmaceutical formulations.

Examples of active principles which may conveniently be formulated according to the present invention comprise dipyridamole, ketanserin and cinnarizine.

The phase which is insoluble in water and swellable therein is a polymer selected from among the so called dispersants and "superdispersants", preferably from among crosslinked sodium carboxymethylcellulose, crosslinked polyvinyl- pyrrolidone, carboxymethy1 starch, potassium methacrylate-divinylbenzene copolymer, polyvinyl alcohols, derivatives of dextran, glucans, starches, modified starches, derivatives of cellulose; crosslinked sodium carboxymethylcellulose is particularly preferred. Such materials are characterised in that, being formulated also in the form of mixtures in tablets, they exhibit very hydrophilic properties and encounter a rapid interaction with water and/or aqueous solutions which cause a swelling with development of a pressure which can be measured using the apparatus described in Eur. Pat. 89104430.7.

The gastroresistant phase is a polymer selected from cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate trimellitate, zein, acrylic and methacrylic polymers and copolymers and their derivatives; cellulose acetate trimellitate and cellulose acetate phthalate are particularly preferred. The pellets are subsequently carried in a gellable hydrophilic matrix or in a lipophilic matrix, which is capable of controlling the release of the active principle for a prolonged period of time. The gellable hydrophilic matrix may be composed of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, xanthans, natural or synthetic rubbers, carboxyvinyl polymers, scleroglucans, mannans, galactomannans, chitin and chitosans, preferably hydroxypropylmethylcellulose.

The lipophilic matrix may be composed of mono-, bi- and trisubstituted natural and synthetic glycerides, or high molecular weight fatty acids.

The compositions of the invention may be obtained by various processes, as will be. described in the examples which will be given hereinbelow.

A first process is that of solubilisation in an organic solvent or in a mixture of organic solvents, preferably of low polarity, of the active principle and the enterosoluble polymeric material.

The polymeric material which swells rapidly and is insoluble in water and which, normally, also proves to be insoluble or poorly soluble in the organic solution is added to the solution obtained; thus, a suspension is obtained, which is stirred for 10 30 minutes.

The solvent is then evaporated under reduced pressure by means of a rotary evaporator (loading) or some other suitable apparatus at a temperature below 100βC and related to the type of solvent and to the physicochemical properties of the active principle and to the operational conditions under which the process of evaporation-concentration takes place.

A pasty residue is obtained, from which the residual traces of solvent are eliminated via suitable processes (heating in a heater with air circulation or under vacuum, evaporation in a rotary dryer under vacuum etc.) to obtain a solid product which may be a granulate or a vitreous or pasty mass which may be subjected to a grinding and/or crushing process in accordance with the known conventional technological processes.

This gives a granular product which is composed of the following three components: a - Active principle b - Polymeric material which is insoluble in water and which rapidly swells in contact with an aqueous medium (superdispersant) c - Enterosoluble and gastroresistant polymeric material.

The ratios in which the various components may be present in the mixture are not critical and may vary for all three components within very wide ranges, between 5 and 90%. A preferred ratio between the constituents a), b) and c) and the polymeric material constituting the matrix is equal to approximately 1:2:1:1, respectively.

The pharmaceutical form may also contain other known excipients.

The loading of the active principle and of the gastroresistant and enterosoluble polymeric material may also be effected via various processes such as that of fluidisation or of spray drying. In the case of fluidisation, the polymeric material which is insoluble and which rapidly swells in water is placed in the containing vessel of a fluidised-bed apparatus (of the Glatt, Aeromatic etc. type) and, following the application of the air flow, is brought to the fluidised condition at a temperature which may vary from ambient temperature to approximately 60-70°C, the organic solution of the active principle and of the enterosoluble polymer is sprayed onto the moving material. The active principle and the enterosoluble polymer may be dissolved in various solvents and may be loaded separately onto the hydrophilic material. The selection of the solvent or of the mixture of solvents to be utilised will be determined by the solubility characteristics of the active principle and of the polymeric material employed and by the safety requirements relating to the management of the plant and by the physicochemical and organoleptic properties of the finished product; said properties must comply with the standards which, with precise definitions and limits, are set out by the Health Authorities in the case where an active principle is intended for formulation into a pharmaceutical form for human or veterinary use. The process of spraying the solution of the mixture of enterosoluble polymeric material and active principle is carried out at a controlled temperature depending on the characteristics both of the solvent and of the active principle. For the loading, it is possible to use other techniques such as moistening and granulation, topogranulation, spherogranulation. rotogranulation and extrusion.

Proceeding as indicated above, the result is a loading of the active principle and of the enterosoluble polymer on the surface of the individual particles of the superdispersant polymeric material which is used as carrier.

The loaded product exists in the form of a flowing granular material which may be subjected to further known processes, for the preparation of suitable administration forms.

In the formulation of modified-release pharmaceutical forms, it is also possible to use other technological coadjuvants which are capable of imparting suitable technological properties to the mixture for the formation of the pharmaceutical forms.

By the above methods, it is possible to obtain pharmaceutical forms which are capable of releasing "in vitro" the active principle at a rate which is no longer determined by the pH value, as will be described in greater detail in the examples given hereinbelow.

By utilising the granular material thus obtained, it is also possible to obtain pulsed-release (or sustained-release) pharmaceutical forms by preparing, for example, two-layer tablets in which the first layer is obtained by using a conventional granulate, from which the active principle will be released rapidly and completely within the stomach, while the second layer containing the modified granulate, prepared in accordance with the invention, on its own or in combination with gellable polymers, will release the active principle at a later stage, irrespective of the pH value in which the pharmaceutical form is found.

Using the granulates thus described (conventional granulate and modified-release granulate) , it is furthermore possible to produce different tablets which are introduced, in the same or a different number, depending upon the therapeutic requirements, into a hard gelatin capsule.

To control the rate of dissolving "in vitro", it is possible to use the processes and the apparatuses which are usually employed for these types of controls, such as, for example, the apparatus described in USP, edition XXII.

In order to give a more precise statement of the features of the invention, certain embodiments will now be described.

Even though the examples which follow refer to the pharmaceutical use alone and to the preparation of pharmaceutical forms such as tablets, the invention may also be used for the preparation of other types of pharmaceutical forms (such as, for example: capsules containing powders and granular products obtained in accordance with the process indicated) or in other sectors of technology, in which it is desired to obtain the release of an active substance at a constant rate under differing pH conditions of the environment.

EXAMPLE 1

A preliminary study was carried out for the purpose of assessing the dissolution rate of the basic pharmaceutical product dipyridamole in an acid medium (simulated gastric fluid USP XXII, without enzyme component) at pH 1.2, and in an alkaline medium (simulated intestinal fluid USP XXII, without enzyme component), at pH 7.5.

The apparatus used for the test is that described in USP XXII (2-paddle apparatus), using 1000 ml of fluid, at 37 °C and stirring at 100 rpm.

The pharmaceutical product was determined by spectrophotometry (Spectracomp, Advanced Product,

Mi, I), using a wavelength of 283 nm for the determinations in gastric fluid, and of 294 nm for those in intestinal fluid.

The results of the dissolving tests are set out in the following tables.

Figure imgf000012_0001
EXAMPLE 2

Modified-release pellets based on dipyridamole: Composition:

Dipyridamole (Recordati, MI, I) 50 g Cellulose acetate trimellitate

(Eastman® C-A-T, Eastman Chem. Prod. Inc., Kingsport, TN, USA) 100 g

Crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®, FMC Corp. Philadelphia, PA, USA) 50 g

Preparation:

100 grams of cellulose acetate trimellitate are dissolved in 1000 ml of a 3:1 acetone-ethanol 95° mixture, and to the solution is added a solution of 50 g of dipyridamole in 200 ml of 95° ethanol, giving a complete solution of yellow colour.

50 g of crosslinked sodium carboxymethy1 cellulose are then added, giving a suspension which is evaporated under vacuum, using a Rotavapor (Buchi R 110, Flawil, CH) , at approximately 40-45βC, to obtain a residue, which is fluid but very viscous, of yellow colour, which is poured onto an extensive surface, so as to obtain a relatively thin layer.

The material is left in a heater with air circulation (60βC) for 24 hours and then in a dryer, so as to obtain a solid residue, which is ground using a plate mill, giving a powder product which is screened (ASTM series screens, Endecotts, London, UK), separating the following two particle-size fractions: 63-250 p , and 250-500 pm.

The dissolving test was carried out on the modified-release pellets of both the particle-size fractions, using the apparatus according to USP XXII no. 2 (paddle; see Example 1).

The test was carried out on a sample of powders equal to 100 mg of active principle in 1000 ml of simulated gastric fluid (pH 1.2) and 1000 ml of simulated intestinal fluid (pH 7.5), using the conditions and the apparatus which have been described in Example 1. The results obtained are set out in the following tables, as compared with those for the active principle alone.

Particle-size fraction 63-250 Jim (pH 1.2)

Figure imgf000014_0001
Particle-size fraction 250-500 μm (pH 1.2)

Figure imgf000015_0001
Particle-size fraction 250-500 μm (pH 7.5)

Figure imgf000016_0001
Starting from the modified-release pellets, particle-size fraction 63-250 μm prepared in accordance with Example 2, tablets were obtained with modified release of 100 mg of dipyridamole, each having the following composition: Dipyridamole (Recordati, MI, I, batch no. 88512/348) 100 mg

Cellulose acetate trimellitate (Eastman^ C-A-T, Eastman Chem. Prod. Inc. Kingsport, TN, USA) 200 mg Crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®, FMC Corp., Philadelphia, PA; USA) 100 mg

Hydroxypropylmethylcellulose (Methocel® K4M, Colorcon, Orpington, UK) 100 mg Magnesium stearate (Carlo Erba, MI, I) 5 mg Colloidal silica (Syloiα* 244, Grace, GmbH Worms, D) 2 mg

The granular material of Example 2 is intimately mixed with the hydroxypropylmethylcellulose in a Turbula mixer (type T2A, W.A. Bachofen, Basel, CH) for 15 minutes, and is then added to and mixed (for 5 minutes) with magnesium stearate and colloidal silica, to give a homogeneous mixture which is readily flowable.

Convex tablets, 12 mm in diameter, were prepared on a Korsch EKO reciprocating tableting machine (Berlin, D) , and were then subjected to the dissolution test in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.5), using the apparatus and under the conditions described in Example 1.

The results obtained are set out in the following table.

pellets,

Figure imgf000017_0001
red in Example 2, tablets were obtained with prolonged release of 100 mg of dipyridamole, each having the following composition:

Dipyridamole (Recordati MI, I, batch no. 88512/348) 100 mg

Cellulose acetate trimellitate (Eastman® C-A-T, Eastman Chem. Prod. Inc., Kingsport, TN, USA) 200 mg

Crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®, FMC Corp., Philadelphia, PA,

USA) 100 mg

Hydroxypropylmethylcellulose (Methocel^ K4M, Colorcon, Orpington, UK) 107 mg

Mannitol (Carlo Erba, MI, I) 27 mg Magnesium stearate (Carlo Erba, MI, I) 5 mg

Colloidal silica (Syloiόr^ 244, Grace, GmbH, Worms, D) 2 mg

The granular material of Example 2 is intimately mixed with the hydroxypropylmethylcellulose in a Turbula mixer (type T2A, W.A. Bachofen, Basel, CH) for

15 minutes, and is then added to and mixed (for

5 minutes) with magnesium stearate and colloidal silica, giving a homogeneous mixture which is readily flowable. Convex tablets, 12 mm in diameter, were prepared on a Korsch EKO reciprocating tableting machine

(Berlin, D), and were then subjected to the dissolution test in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.5), using the apparatus and under the conditions described in Example 1.

The results obtained are set out in the following pellets,

Figure imgf000019_0001
red in

Example 2, tablets were obtained with prolonged release of 100 mg of dipyridamole, each having the following composition:

Dipyridamole (Recordati MI, I, batch no. 88512/348) 100 mg

Cellulose acetate trimellitate

(Eastman^ C-A-T, Eastman Chem. Prod. Inc.,

Kingsport, TN, USA) 200 mg

Crosslinked sodium carboxymethylcellulose

(Ac-Di-Sol®, FMC Corp. , Philadelphia , PA,

USA) 100 mg

Hydroxypropylmethylcellulose (Methocel® K4M,

Colorcon, Orpington, UK) 80 mg

Mannitol (Carlo Erba, MI, I) 53 mg

Magnesium stearate (Carlo Erba, MI, I) 5 mg Colloidal silica (Syloid® 244, Grace,

GmbH, Worms, D) 2 mg

The granular material set out in Example 2 is intimately mixed with the hydroxypropylmethylcellulose in a Turbula mixer (type T2A, W.A. Bachofen, Basel, CH) for 15 minutes, and is then added to and mixed (for 5 minutes) with magnesium stearate and colloidal silica, giving a homogeneous mixture which is readily flowable.

Convex tablets, 12 mm in diameter, were prepared on a Korsch EKO reciprocating tableting machine (Berlin, D) , and were then subjected to the dissolution test in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.5), using the apparatus and under the conditions described in Example 1.

The results obtained are set out in the following table.

Figure imgf000020_0001
EXAMPLE 6

Modified-release pellets Composition: Dipyridamole (Recordati, MI, I 50 g Cellulose acetate phthalate (Eastman* C-A-P TM Eastman Chem. Prod., Inc.,

Kingsport, TN, USA) 100 g

Crosslinked sodium carboxymethylcellulose

(6)

(Ac-Di-Sol**, FMC Corp., Philadelphia, PA, USA) 50 g

Preparation:

100 grams of cellulose acetate phthalate are dissolved in 1000 ml of 2:1 acetone-ethanol 95° mixture, and to the solution is added a solution of 50 g of dipyridamole in 200 ml of 95° ethanol, giving a complete solution of yellow colour.

50 g of crosslinked sodium carboxymethylcellulose are then added, giving a suspension which is evaporated under vacuum, using a Rotavapor (Buchi R 110, Flawil, CH) , at approximately 40-45°C, so as to obtain a residue, which is fluid but very viscous, of yellow colour, which is poured onto an extensive surface, so as to obtain a relatively thin layer.

The material is left in a heater with air circulation (60βC) for 24 hours, and then in a dryer, so as to obtain a solid residue, which is ground using a plate mill, giving a powder product which is screened (ASTM series screen, Endecotts, London, UK), separating the following two particle-size fractions: 63-250 μm and 250-500 μm.

The dissolution test was carried out on the modified-release pellets of both the particle-size fractions, using the apparatus according to USP XXII no. 2 (paddle).

The test was carried out on a sample of powders corresponding to 100 mg of active principle in 1000 ml of simulated gastric fluid (pH 1.2) and 1000 ml of si¬ mulated intestinal fluid (pH 7.5), under the conditions and using the apparatus described in Example 1.

The results obtained are set out in the following tables, compared with those for the active principle

Figure imgf000022_0001
Particle-size fraction 250-500 μm (pH 1.2)

Figure imgf000023_0001
Particle-size fraction 250-500 μm (pH 7.5)

Figure imgf000024_0002
Starting from the modified-release pellets, particle-size fraction 63-250 μm, prepared in Example 6, tablets were obtained with modified release of 100 mg of dipyridamole, each having the following composition: Dipyridamole (Recordati MI, I, batch no. 88512/348) 100 mg

Cellulose acetate phthalate

Figure imgf000024_0001
C-A-PTM, Eastman Chem. Prod. Inc.,

Kingsport, TN, USA) 200 mg Crosslinked sodium carboxymethylcellulose

(Ac-Di-Sol®, FMC Corp., Philadelphia, PA,

USA) 100 mg

Hydroxypropylmethylcellulose (Methocel® K4M,

Colorcon, Orpington, UK) 100 mg Magnesium stearate (Carlo Erba, MI, I) 5 mg

Colloidal silica (Syloid® 244, Grace, GmbH, Worms, D) 2 mg

The granular material of Example 6 is intimately mixed with the hydroxypropylmethylcellulose in a Turbula mixer (type T2A, W.A. Bachofen, Basel, CH) for 15 minutes and is then added to and mixed (for 5 minutes) with magnesium stearate and colloidal silica, giving a homogeneous mixture which is readily flowable.

Convex tablets, 12 mm in diameter, were prepared on a Korsch EKO reciprocating tableting machine (Berlin, D) , and were then subjected to the dissolving test in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.5), using the apparatus and under the conditions described in Example 1.

The results obtained are set out in the following table.

Figure imgf000025_0001

Starting from the modified-release pellets, particle-size fraction 63-250 μm, prepared in Example 6, tablets were obtained with prolonged release of 100 mg of dipyridamole, each having the following composition:

Dipyridamole (Recordati MI, I, batch no. 88512/348) 100 mg

Cellulose acetate phthalate __. _=..a..-,.* ® C-A-PTM, Eastman Chem. Prod. Inc.,

Kingsport, TN, USA) 200 mg

Crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®, FMC Corp., Philadelphia, PA,

USA) 100 mg

Hydroxypropylmethylcellulose (Methocel"^ K4M,

Colorcon, Orpington, UK) 107 mg

Mannitol (Carlo Erba, MI, I) 27 mg Magnesium stearate (Carlo Erba, MI, I) 5 mg

Colloidal silica (Syloiα*^ 244, Grace, GmbH, Worms, D) 2 mg

The granular material of Example 6 is intimately mixed with the hydroxypropylmethylcellulose in a Turbula mixer (type T2A, W.A. Bachofen, Basel, CH) for 15 minutes and is then added to and mixed (for 5 minutes) with the magnesium stearate and the colloidal silica, giving a homogeneous mixture which is readily flowable. Convex tablets, 12 mm in diameter, were prepared on a Korsch EKO reciprocating tableting machine (Berlin, D) , and were then subjected to the dissolution test in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.5), using the apparatus and under the conditions described in Example 1.

The results obtained are set out in the following

Figure imgf000027_0002

Starting from the modified-release pellets, particle-size fraction 63-250 μm, prepared in Example 6, tablets were obtained with prolonged release of 100 mg of dipyridamole, each having the following composition:

Dipyridamole (Recordati MI, I, batch no. 88512/348) 100 mg

Cellulose acetate phthalate C-A-PTM

Figure imgf000027_0001
, Eastman Chem. Prod. Inc.,

Kingsport, TN, USA) 200 mg

Crosslinked sodium carboxymethylcellulose

(Ac-Di-Sol®, FMC Corp., Philadelphia, PA,

USA) 100 mg

Hydroxypropylmethylcellulose (Methocel® K4M,

Colorcon, Orpington, UK) 80 mg

Mannitol (Carlo Erba, MI, I) 53 mg

Magnesium stearate (Carlo Erba, MI, I) 5 mg Colloidal silica (Syloid®244, Grace,

GmbH, Worms, D) 2 mg

The granular material of Example 6 is intimately mixed with the hydroxypropylmethylcellulose in a Turbula mixer (type T2A, W.A. Bachofen, Basel, CH) for 15 minutes, and is then added to and mixed (for 5 minutes) with magnesium stearate and colloidal silica, giving a homogeneous mixture which is readily flowable.

Convex tablets, 12 mm in diameter, were prepared on a Korsch EKO reciprocating tableting machine (Berlin, D), and were then subjected to the dissolving test in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.5), using the apparatus and under the conditions described in Example 1.

The results obtained are set out in the following table.

Figure imgf000028_0001

Claims

1. Oral pharmaceutical formulations containing active principles having weak basic characteristics, comprising pellets composed of active principle, a swellable polymeric material and a gastroresistant polymeric material, which are carried in a gellable hydrophilic matrix or in a lipophilic matrix.
2. Pharmaceutical formulations according to Claim 1, in which the active principle is selected from dipyridamole, cinnarizine and ketanserin.
3. Pharmaceutical formulations according to Claim 1 or 2, in which the swellable polymeric material is selected from crosslinked sodium carboxy- methylcellulose, crosslinked polyvinyl-pyrrolidone, carboxymethyl starch, potassium methacrylate-divinyl- benzene copolymer, polyvinyl alcohols, derivatives of dextran, glucans, starches, modified starches and cellulose derivatives.
4. Pharmaceutical formulations according to any one of the preceding claims, in which the gastroresistant polymeric material is selected from cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate trimellitate, zein, acrylic and methacrylic polymers and copolymers and their derivatives.
5. Pharmaceutical formulations according to any one of the preceding claims, in which the pellets are carried in a gellable hydrophilic matrix.
6. Pharmaceutical formulations according to Claim 5, in which the gellable hydrophilic matrix is composed of hydroxypropylcellulose, hydroxypropylmeth lcellulose, methylcellulose, xanthans, natural or synthetic rubbers, carboxyvinyl polymers, scleroglucans, mannans, galactomannans, chitin and chitosans.
7. Pharmaceutical formulations according to any one of Claims 1-5, in which the pellets are carried in a lipophilic matrix.
8. Pharmaceutical formulations according to Claim 7, in which the lipophilic matrix is composed of mono-, bi- and trisubstituted natural and synthetic glycerides, or high molecular weight fatty acids.
9. Pharmaceutical formulations according to the preceding claims, in which the active principle is dipyridamole, the gastroresistant polymer is cellulose acetate trimellitate or cellulose acetate phthalate, the swelling polymer is crosslinked sodium carboxy¬ methylcellulose and the gelling hydrophilic matrix is composed of hydroxypropylmethylcellulose.
10. Pharmaceutical formulations according to Claim 9, in which the ratio by weight between active principle/gastroresistant polymer/swelling polymer/ gelling hydrophilic polymer is approximately 1:2:1:1, respectively.
11. Process for the preparation of the formulations of Claims 1 - 10, which comprises the addition of the hydrophilic polymeric material to a solution of the active principle and of the gastroresistant material in an organic solvent, the subsequent drying of the suspension, grinding and/or granulation and formulation of the pellets thus obtained in a hydrophilic or lipophilic matrix.
12. Process according to Claim 11, characterised in that the solution is added to the hydrophilic polymeric material maintained in suspension in an air jet, and the resulting moist product is dried in the same fluid bed.
13. Process according to Claim 11 or 12, characterised in that the active principle and the gastroresistant material are separately dissolved in different solvents and are then loaded onto the hydrophilic material separately or at the same time.
14. Process according to Claim 13, characterised in that the loading operation is carried out using moistening and granulation, topogranulation, sphero- granulation, rotogranulation or extrusion techniques.
PCT/EP1992/001503 1991-07-08 1992-07-03 METHOD FOR THE PREPARATION OF PROLONGED-RELEASE ORAL PHARMACEUTICAL FORMS CONTAINING ACTIVE SUBSTANCES HAVING A SOLUBILITY DEPENDENT UPON THE pH VALUE WO1993000889A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
ITMI91A001880 1991-07-08
IT1250654B IT1250654B (en) 1991-07-08 1991-07-08 Method for the preparation of oral pharmaceutical forms containing active substances in sustained release solubility 'dependent on the pH value.
CN 92111078 CN1082888A (en) 1991-07-08 1992-08-24 Method for the preparation of prolonged-release oral pharmaceutical forms containing active substances baving a solubility dependent upon the PH value

Publications (1)

Publication Number Publication Date
WO1993000889A1 true true WO1993000889A1 (en) 1993-01-21

Family

ID=36790863

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/001503 WO1993000889A1 (en) 1991-07-08 1992-07-03 METHOD FOR THE PREPARATION OF PROLONGED-RELEASE ORAL PHARMACEUTICAL FORMS CONTAINING ACTIVE SUBSTANCES HAVING A SOLUBILITY DEPENDENT UPON THE pH VALUE

Country Status (2)

Country Link
CN (1) CN1082888A (en)
WO (1) WO1993000889A1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0669129A2 (en) * 1994-02-28 1995-08-30 Bayer Ag Expandable release controlled medicaments
EP1027886A2 (en) * 1999-02-10 2000-08-16 Pfizer Products Inc. Pharmaceutical solid dispersions
EP1027885A2 (en) * 1999-02-09 2000-08-16 Pfizer Products Inc. Basic drug compositions with enhanced bioavailability
EP1027887A2 (en) * 1999-02-10 2000-08-16 Pfizer Products Inc. Matrix controlled release device
EP1469834A1 (en) * 2002-02-01 2004-10-27 Pacific Corporation Multi-stage oral drug controlled-release system
EP1591107A1 (en) * 2004-04-28 2005-11-02 Pfizer GmbH Arzneimittelwerk Gödecke Process for the selective increase of a release rate of an active material from a pharmaceutical composition
WO2007050294A2 (en) * 2005-10-24 2007-05-03 Eastman Chemical Company Liquid dosage forms having enteric properties of delayed and then sustained release
US8293273B2 (en) 1999-06-14 2012-10-23 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US8895064B2 (en) 1999-06-14 2014-11-25 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2348157T3 (en) 2006-12-15 2010-11-30 Campina Nederland Holding B.V. Modified-release excipient and usage.

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1005329A (en) * 1963-07-15 1965-09-22 Boehringer Sohn Ingelheim Process for the preparation of sustained release pharmaceutical tablets
EP0142877A2 (en) * 1983-10-24 1985-05-29 "PHARLYSE", Société Anonyme Pharmaceutical tablets with prolonged action, their preparation and their use
EP0168044A2 (en) * 1984-07-12 1986-01-15 Fujisawa Pharmaceutical Co., Ltd. Sustained release tablet
JPS6248618A (en) * 1985-08-27 1987-03-03 Zeria Shinyaku Kogyo Kk Slow-releasing drug preparation and production thereof
EP0271193A2 (en) * 1986-10-31 1988-06-15 Euroceltique S.A. Controlled release hydromorphone composition
EP0280571A2 (en) * 1987-02-27 1988-08-31 Eli Lilly And Company Sustained release matrix formulations
EP0250374B1 (en) * 1986-06-17 1991-05-02 RECORDATI INDUSTRIA CHIMICA E FARMACEUTICA S.p.a. Therapeutic system for controlled release of drugs

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1005329A (en) * 1963-07-15 1965-09-22 Boehringer Sohn Ingelheim Process for the preparation of sustained release pharmaceutical tablets
EP0142877A2 (en) * 1983-10-24 1985-05-29 "PHARLYSE", Société Anonyme Pharmaceutical tablets with prolonged action, their preparation and their use
EP0168044A2 (en) * 1984-07-12 1986-01-15 Fujisawa Pharmaceutical Co., Ltd. Sustained release tablet
JPS6248618A (en) * 1985-08-27 1987-03-03 Zeria Shinyaku Kogyo Kk Slow-releasing drug preparation and production thereof
EP0250374B1 (en) * 1986-06-17 1991-05-02 RECORDATI INDUSTRIA CHIMICA E FARMACEUTICA S.p.a. Therapeutic system for controlled release of drugs
EP0271193A2 (en) * 1986-10-31 1988-06-15 Euroceltique S.A. Controlled release hydromorphone composition
EP0280571A2 (en) * 1987-02-27 1988-08-31 Eli Lilly And Company Sustained release matrix formulations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPIL Section Ch, Week 8714, Derwent Publications Ltd., London, GB; Class A12, AN 87-099083 & JP,A,62 048 618 (ZERIA SHINYAKU KOGY) 3 March 1987 *

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0669129A2 (en) * 1994-02-28 1995-08-30 Bayer Ag Expandable release controlled medicaments
EP0669129A3 (en) * 1994-02-28 1995-11-22 Bayer Ag Expandable release controlled medicaments.
US5651985A (en) * 1994-02-28 1997-07-29 Bayer Aktiengesellschaft Expandable pharmaceutical forms
US6306439B1 (en) 1994-02-28 2001-10-23 Bayer Aktiengesellschaft Expandable pharmaceutical forms
US6548555B1 (en) 1999-02-09 2003-04-15 Pfizer Inc Basic drug compositions with enhanced bioavailability
EP1027885A2 (en) * 1999-02-09 2000-08-16 Pfizer Products Inc. Basic drug compositions with enhanced bioavailability
EP1027885A3 (en) * 1999-02-09 2001-03-14 Pfizer Products Inc. Basic drug compositions with enhanced bioavailability
EP1027887A3 (en) * 1999-02-10 2001-02-28 Pfizer Products Inc. Matrix controlled release device
EP1027886A3 (en) * 1999-02-10 2001-03-14 Pfizer Products Inc. Pharmaceutical solid dispersions
EP1027887A2 (en) * 1999-02-10 2000-08-16 Pfizer Products Inc. Matrix controlled release device
EP1027886A2 (en) * 1999-02-10 2000-08-16 Pfizer Products Inc. Pharmaceutical solid dispersions
US8828442B2 (en) 1999-02-10 2014-09-09 Bend Research, Inc. Pharmaceutical solid dispersions
US8481081B2 (en) * 1999-02-10 2013-07-09 Bend Research, Inc. Pharmaceutical solid dispersions
JP4694298B2 (en) * 1999-02-10 2011-06-08 ベンド・リサーチ・インコーポレーテッドBend Research,Incorporated Matrix controlled release devices
JP2005320354A (en) * 1999-02-10 2005-11-17 Pfizer Prod Inc Matrix control release device
US9192581B2 (en) 1999-06-14 2015-11-24 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US9592203B2 (en) 1999-06-14 2017-03-14 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US9532954B2 (en) 1999-06-14 2017-01-03 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical compositions
US9737489B2 (en) 1999-06-14 2017-08-22 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US8293273B2 (en) 1999-06-14 2012-10-23 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US10052286B2 (en) 1999-06-14 2018-08-21 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US8784888B2 (en) 1999-06-14 2014-07-22 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US10064878B2 (en) 1999-06-14 2018-09-04 Cosmo Technologies Ltd. Controlled release and taste masking oral pharmaceutical compositions
US8895064B2 (en) 1999-06-14 2014-11-25 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US9132093B2 (en) 1999-06-14 2015-09-15 Cosmo Technologies Limited Controlled release and taste making oral pharmaceutical composition
US10105374B2 (en) 1999-06-14 2018-10-23 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical compositions
US9320716B2 (en) 1999-06-14 2016-04-26 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical compositions
EP1469834A4 (en) * 2002-02-01 2006-07-05 Pacific Corp Multi-stage oral drug controlled-release system
EP1469834A1 (en) * 2002-02-01 2004-10-27 Pacific Corporation Multi-stage oral drug controlled-release system
WO2005105048A1 (en) * 2004-04-28 2005-11-10 Pfizer Inc. Process for the selective increase of a release rate of an active material from a pharmaceutical composition
EP1591107A1 (en) * 2004-04-28 2005-11-02 Pfizer GmbH Arzneimittelwerk Gödecke Process for the selective increase of a release rate of an active material from a pharmaceutical composition
WO2007050294A3 (en) * 2005-10-24 2007-07-12 Eastman Chem Co Liquid dosage forms having enteric properties of delayed and then sustained release
WO2007050294A2 (en) * 2005-10-24 2007-05-03 Eastman Chemical Company Liquid dosage forms having enteric properties of delayed and then sustained release

Also Published As

Publication number Publication date Type
CN1082888A (en) 1994-03-02 application

Similar Documents

Publication Publication Date Title
Hari et al. Chitosan/calcium alginate microcapsules for intestinal delivery of nitrofurantoin
US4404183A (en) Sustained release pharmaceutical composition of solid medical material
US6024982A (en) Immediate release tablet cores of insoluble drugs having sustained-release coating
US4971805A (en) Slow-releasing granules and long acting mixed granules comprising the same
US6589552B2 (en) Fenofibrate pharmaceutical composition having high bioavailability and method for preparing it
US6387404B2 (en) Immediate release tablet cores of insoluble drugs having sustained-release coating
US5968554A (en) Sustained release pharmaceutical preparation
US4716041A (en) Diffusion coated multiple-units dosage form
US5026559A (en) Sustained-release pharmaceutical preparation
US5958458A (en) Pharmaceutical multiple unit particulate formulation in the form of coated cores
US6805881B1 (en) Multiple unit controlled food effect-independent release pharmaceutical preparations and method for preparing the same
US5478573A (en) Delayed, sustained-release propranolol pharmaceutical preparation
US4713248A (en) Diffusion coated multiple-units dosage form
US20050008701A1 (en) Formulation and process for drug loaded cores
US4948581A (en) Long acting diclofenac sodium preparation
EP0327295A2 (en) Tetracycline dosage form
US5908638A (en) Pharmaceutical compositions of conjugated estrogens and methods for their use
US6027748A (en) Pharmaceutical tablet, completely coated, for controlled release of active principles that present problems of bio-availability linked to gastro-intestinal absorption
EP0548448A1 (en) Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US4970081A (en) Controlled-release, low-dose aspirin formulation and method of treating vascular occlusive disease therewith
US4661162A (en) Enteric-soluble preparations
US20060045865A1 (en) Controlled regional oral delivery
US6068854A (en) Sol-controlled thermocolloid matrix based on gelatin for oral sustained-release form
US5830503A (en) Enteric coated diltiazem once-a-day formulation
US5277916A (en) Tetracycline dosage form

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR CA CS FI HU JP KP KR LK MG MN MW NO PL RO RU SD US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE BF BJ CF CG CI CM GA GN ML MR SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
NENP Non-entry into the national phase in:

Ref country code: CA

122 Ep: pct application non-entry in european phase