CA1336326C - Microbeads of diltiazem, a process for their manufacture and a sustained-release pharmaceutical composition containing them - Google Patents
Microbeads of diltiazem, a process for their manufacture and a sustained-release pharmaceutical composition containing themInfo
- Publication number
- CA1336326C CA1336326C CA000596597A CA596597A CA1336326C CA 1336326 C CA1336326 C CA 1336326C CA 000596597 A CA000596597 A CA 000596597A CA 596597 A CA596597 A CA 596597A CA 1336326 C CA1336326 C CA 1336326C
- Authority
- CA
- Canada
- Prior art keywords
- microbeads
- diltiazem
- membrane
- microbeads according
- core
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Fee Related
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
Abstract
The microbeads are composed of a core containing the active ingredient and a microporous membrane, insoluble in aqueous medium, consisting of a film-forming polymer, a plasticizer and a filling material. The membrane has a thickness such that diltiazem is released in vitro at an approximately constant rate for at least 6 hours after a latent period of less than one hour. The active ingredient can be intimately mixed with the core or included in a polyvinyl pyrrolidone layer coating an inert grain. The sustained-release microbeads are formed by application to the core of a dispersion of the constituents of the membrane in a solvent and evaporation of the solvent. The pharmaceutical compositions consist of capsules containing the microbeads. They are administered orally one or twice per day, depending on the dose, for the treatment of angina or hypertension.
Description
The present invention relates to a sustained-release form of diltiazem, a calcium antagonist used in the treatment of angina and hypertension for several years.
It is known that the half-life of this active ingredient is short, of the order of four hours, and the drug is presently administered in the form of tablets three or four times per day, which is all the more exacting for the patient because his treatment must be 10 continued for prolonged periods. Furthermore, in the case of the administration of this pharmaceutical form, the plasma concentration varies widely between the two doses so that the therapeutic efficacy is not continuous and there exists an increased risk of side effects at peak 15 concentrations.
Consequently, it is desirable to have a pharmaceutical form which gives rise to sustained-release of an approximately constant concentration of this active ingredient so that it is possible to administer the drug 20 only once or twice a day.
Different means are known for the obtention of sustained-release pharmaceutical forms which can be administered orally either in the form of tablets or in the form of microgranules, such as those described in 25 EP-A-0 076 428, EP-A-0 061 217 and EP-A-0 216 743.
Such means must be adapted to each drug since the rate and duration of release of the active ingredient as well as its plasma concentration depend on its physico-chemical properties, including its solubility and 30 stability in the gastro-intestinal tract, and on its pharmacokinetic parameters.
Such a form is particularly difficult to prepare for compounds of short half-life, less than 4-5 hours, such as diltiazem, since the duration of its release in 35 vivo from the pharmaceutical form does not exceed the residence time of the drug in the gastro-intestinal tract, .~
--i.e., maximally 8 to 10 hours, and then only if release commences immediately on arrival in the stomach.
Furthermore, during this period release is required to be more or less constant although the pH of 5 the surrounding medium changes from 1.5 in the stomach to 6.9 in the jejunum.
One of the objects of the present invention is a sustained-release pharmaceutical composition of diltiazem which, depending on the type of treatment, 10 requires only one or two daily administrations by the oral route. It consists of a capsule of gelatin, starch or other polymer which can be rapidly degraded in the gastric environment, containing a large number of microbeads composed of a core containing the active ingredient 15 surrounded by a microporous membrane, this membrane being composed of a non-water-soluble film-forming polymer, a plasticizer and a filling material; the thickness of the membrane of the microbeads as well as the amount of active ingredient in the core and its size are chosen such that 20 diltiazem is liberated from the microbeads in vitro in artificial dissolution media in which the pH varies from 1.5 to 7, at a substantially constant rate for at least 6 hours, after a latent period of less than one hour.
The core may be constituted of small spheres, 25 produced by extrusion/sphere-formation from a plastic mass based on a polyol such as mannitol or a polymer such as polyglycol, and a water-soluble salt of diltiazem, but a core is preferred which consists of a inert grain composed of excipients, this inert grain being coated with the 30 active ingredient.
The inert grain may be constituted by a sugar, with a hydrocolloid, such as gum arabic, gelatin or starch or a biocompatible polymer such as the micro-crystalline celluloses, alkylcelluloses, carboxymethylcelluloses as 35 well as mixtures of them or other excipients well known to the specialist skilled in the art. A mineral filling material such as talc may be added if required. The inert grain can be prepared in a standard manner in a turbine, or by extrusion/sphere-formation from polymers or by granulation of a molten mass passing through a vibrating 5 nozzle before cooling.
The active ingredient is then bound to the inert grain in one or several successive layers in a turbine or ~ in a fluidized bed either by the spraying of a solution or suspension of the diltiazem salt and a polymeric binder lo with evaporation of the solvent, or by the spraying of an alcoholic solution of the binder onto the substrate followed by spraying of the diltiazem salt as a powder onto the viscous layer just deposited; the second solution is preferred since the cores thus obtained form 15 less aggregates and are more regular.
Preferably, an appreciable quantity of active ingredient should not be left in the microbeads when, in vivo, they leave the duodenal resorption zone, which corresponds in vitro to the release of at least 60% of the 20 active ingredient from the core within 8 hours, and the concentration of active ingredient in the core is calculated as a function of this.
Usually, for technical reasons, it is preferable that the concentration of active ingredient in the core is 25 30 to 50% by weight, but in particular in the case of the higher dosage pharmaceutical compositions according to the invention, there may be up to 85~ of active ingredient in the core.
It is desirable to have microbeads of a diameter 30 varying between 0.4 and 1.4 mm, so that the number of microbeads introduced into a capsule of acceptable dimensions which can be swallowed by the patient without difficulty, is more than loO and preferably lies between 200 and 600; thus the dose of the active ingredient and 35 the kinetics of its release will be of an acceptable reproducibility from one capsule to another in spite of 1 33-63`26 the unavoidable heterogeneity of the microbeads due to the manufacturing techniques. Under these conditions the cores will preferably have diameters varying between 0.4 mm and 1.3 mm. In the case in which the active ingredient 5 is bound by a binder to the inert grain from 5 to 20% by weight of binder is used in relation to the weight of the diltiazem salt. Binders which can be used are water-soluble binders well known to the technique, and which are compatible with the diltiazem salt, such as methylcellu-10 loses, water-soluble polyacrylates and polyvinylpyrroli-dones. A polyvinylpyrrolidone of molecular mass of approximately 50,000, marketed by GAF (FGR) under the trade name Plasdone, is preferably used.
As diltiazem salt, the standard salt, namely the 15 hydrochloride is usually used but other more or less water-soluble salts may be used, either salts of mineral acids such as the sulfate, or salts of organic acids such as fumarate, oxalate, succinate and similar compounds;
the amount of active ingredient in the core and the 20 thickness of the membrane will be defined as a function of the solubility of the salt in aqueous medium.
A fundamental feature of the invention resides in the choice of the properties of the microporous membrane which surrounds the core.
In fact, it has been observed that, in order to obtain a sustained-release pharmaceutical form, having acceptable in vivo kinetics, it is necessary that the in vitro diffusion kinetics of the diltiazem salt from the microbeads in standard artificial dissolution media in 30 which the pH varies from 1.5 to 7 is approximately constant for at least 6 hours and preferably up to 8 hours, and the time necessary to obtain a constant rate of diffusion, i.e. the latent period, is less than one hour.
Under these conditions, capsules containing 120 35 mg of active ingredient included in microbeads of the invention, administered twice a day to human subjects _.~
i~
gives rise, at equilibrium, to a plasma concentration which is always higher than 80 ng/ml, with a peak close to 130 ng/ml which is reached within 6 hours, whereas a standard pharmaceutical composition administered twice a 5 day at the same doses rapidly gives rise to a peak concentration of up to 180 ng/ml with a rapid decrease to 50 ng/ml after 6 hours.
of the non-water-soluble biocompatible polymers which are stable in vivo and capable of constituting the 10 microporous membrane, mention may be made of the polyacrylates and polymethacrylates of the Eudragit type, the alkylcelluloses including the methylcelluloses of the Tylose type (Hoechst) and the ethylcelluloses such as those marketed by Hercules and the lacquers of natural 15 origin such as the shellac gums. The properties of the last-mentioned are poorly reproducible from one batch to another and ethylcellulose, the viscosity of which, when measured according to the method of the US National ~ormulary, lies between lo and 50 mPa.s. is preferred 20 since it is of reproducible quality and chemically inert.
The polymers must be combined with a plas-ticizing agent so that the membrane is not brittle, and with a finely divided filling material which may amount to between 35 and 75~ by weight of the membrane.
Of the plasticizing agents which may be used, in particular phthalic esters, polyethylenglycols, castor oil and glycerol, castor oil is preferred.
The amount of plasticizing agent introduced depends on the type used. It usually represents from lo 30 to 30% by weight of the film-forming agent.
The presence of a filling material in sufficient amount is fundamental; it reduces the swelling time of the membrane in vivo, hence the latent period, without simultaneously increasing excessively the rate of 35 diffusion of the active ingredient; a low diffusion rate, necessary for a sustained release form, can be obtained by increasing the thickness of a membrane of conventional composition, but the latent period is simultaneously increased.
It is known that in the case of diltiazem, it is 5 of fundamental importance to have a short latent period, in order to avoid bioavailability losses and release of the active ingredient during too short a period before the microbeads leave the gastro-intestinal tract.
Nonetheless, in order to reduce this latent period, it is 10 not possible to reduce the thickness of the membrane excessively as this would make it difficult to reproduce its diffusion properties during manufacture; the heterogeneity which would result in the case of the beads thus obtained in the same batch or in successive batches 15 would make it practically impossible to manufacture pharmaceutical compositions, the rate of release of the active ingredient from which is defined and reproducible.
of the finely divided filling materials which can be used, and which are insoluble in the solvent in 20 which the membrane is applied, mention may be made of talc, silica, metal silicates such as A1 and Mg silicates, kaolin, powdered lactose and sucrose, metal oxides such as titanium oxides, or their mixtures. Neutral filling materials such as talc are preferred.
In a preferred embodiment of the invention, the membrane is constituted of 25 to 40% by weight of ethylcellulose, from 5 to 10% by weight of castor oil and from 50 to 70% by weight of talc.
The microporous membrane can be applied by 30 spraying an alcoholic or aqueous-alcoholic dispersion of the film-forming polymer, plasticizing agent and filling material into a turbine or into an air-operated fluidized bed.
In the case of an ethylcellulose-based membrane, 35 its thickness will vary between 15 micrometers and 60 micrometers.
.
- 1 33b326 The amount of the composition to be deposited in order to form a membrane of suitable thickness is determined by preliminary tests during which the rate of diffusion of diltiazem in vitro is measured under the 5 standard conditions of the United States Pharmacopea (USP
Z1. Chap. 711, page 1243; apparatus N 1) using artificial dissolution media of different pHs varying from 1.5 to 7 and being, for example, 1.5, 4.5 and 7, starting from microbeads containing the selected core and membranes of lo different thicknesses deposited in successive layers. The thickness of the membrane is then chosen so that an approximately constant rate of diffusion is established within less than one hour and from the measured value of the diffusion rate from the microbeads with this membrane 15 thickness are deduced what must be the dimensional characteristics of the core in order to insure the in vitro release per hour of about 10~ of the amount of active ingredient present.
It has in fact been observed that this in vitro 20 rate of release gives plasma concentrations in vivo which are satisfactory for the intended thereapeutic use.
The microbeads of the invention are stable; the kinetics of in vitro dissolution do not change during storage as has frequently been observed with this type of 25 pharmaceutical form.
The pharmaceutical compositions according to the invention can be made available in the form of capsules of conventional composition and size containing from loo to 600, and preferably from 200 to 350, microbeads of the 30 invention such that a unit dose contains from 90 mg to 350 mf of diltiazem. The required number of microbeads are introduced into each capsule; the same microbeads can be used irrespective of the unit dose to be made up but, for extreme doses, it is preferable in particular to select 35 the composition and size of the microbeads such that the number of microbeads per capsule lies between 300 and 350.
~3 These microbeads can be introduced into other pharmaceutical forms : cachets, divisible or indivisible tablets, suppositories and liquid or gelled suspensions.
In what follows, particular embodiments of the 5 invention are described as examples of the microbeads, the process for their preparation and novel sustained-release pharmaceutical compositions of the invention. The curves of dissolution in artificial media of various pH prepared as described in the U.s.P. have been plotted with an lo apparatus into which the quantity of microbeads corresponding to the dose of active ingredient have been introduced per liter of medium. The diltiazem hydrochloride released as a function of time is measured by spectrophotometry.
EXAMPLE:
In order to prepare about lo kg of granular substrate, about 2 kg of "seed" obtained by sieving crystallized sucrose through a 0.500 mm mesh sieve and 20 freed of dust by sieving through a 0,200 mm mesh sieve are introduced into a turbine.
An aqueous-alcoholic solution containing sucrose (6 parts) and polyvidone K30 (one part) in a water-ethyl alcohol mixture (50/50 -V/V), i.e. about 5 liters for 2.5 25 kg of sucrose/polyvidone mixture, are sprayed several times.
Between each spraying, dusting is done with a mixture of talc (one part), maize starch (one part) and sucrose (2 parts) until microspheres of about 0.5 to 30 0.6 mm diameter are obtained. After drying in an incubator at 40C, the fraction with diameters included between 0.600 mm and 0.300 mm is isolated; it will subsequently be used as the granular substrate.
About 1.5 kg of granular substrate are then 35 introduced into a turbine and its weight is approximately doubled by spraying with a 10% (wt/v) alcoholic solution X
of polyvidone and dusting between each spraying with diltiazem hydrochloride previously passed through a 0.5 mm mesh sieve until about 2.5 kg of cores are obtained.
Drying is performed in an incubator at 40C.
The content of active ingredient is of the order of 40% by weight. The small cores are removed by means of a 0.6 mm mesh sieve and the cores are reintroduced into a turbine equipped with a spraying device. An alcoholic solution containing about 12% by weight of a mixture of 10 ethyl cellulose (5 parts) and castor oil (one part) is spraying onto the cores which are dusted with talc between sprayings; the ethylcellulose has a viscosity of from 18 to 24 mPa.s.
When the mass of the beads has increased by 10%
15 a first sample A is taken, then the deposition of the membrane is continued to give a sample B taken after a weight increase of 30%, and a sample C taken after a weight increase of 55%; these three batches are dried in an incubator at 40OC. The kinetics of dissolution for 20 each of them are determined in vitro at pH 1.5, and hence the release per hour at constant rate (the percentage of active ingredient released by the microbeads in one hour) and the latent period can be deduced.
The results obtained are shown in the table 25 below:
Test sample : : Rate of corresponding to 120 mg : Latent period : release of active ingredient : : per hour Sample A : o :25 %
Sample B : 2 hours :13,75%
Sample C : 4 hours : 9 %
X
In this case, it is observed that the microbeads B and C did not comply with the characteristics of the invention tlatent period too long) and that the membrane was required to be thicker than that of the microbeads A
5 (too rapid dissolution) and consequently the operating conditions have been modified in order to give rise to the microbeads according to the invention.
Microbeads have thus been prepared to give a dose of 120 mg of active ingredient in a capsule N 1 with lo 250 microbeads per capsule; these microbeads contain 48%
by weight of active ingredient, the inert grain represents 31% by weight of the microbead whereas the membrane represents 17.5% by weight of the microbead.
Starting from a representing 11% of the final 15 weight of the microbead, microbeads have also been prepared to give a dose of 300 mg of active ingredient in a capsule N 0, which contained 75~ by weight of active ingredient; the membrane represents 11% by weight of the microbead.
In vitro, these microbeads show practically no latent period, the rate of release is constant and the amount of diltiazem released at the end of 4 hours is about 40% of the total quantity whereas it is about 60% at the end of 6 hours.
These properties are not altered after at least lB months storage at ambient temperature and after 3 months storage at 40C or at 55C.
It is known that the half-life of this active ingredient is short, of the order of four hours, and the drug is presently administered in the form of tablets three or four times per day, which is all the more exacting for the patient because his treatment must be 10 continued for prolonged periods. Furthermore, in the case of the administration of this pharmaceutical form, the plasma concentration varies widely between the two doses so that the therapeutic efficacy is not continuous and there exists an increased risk of side effects at peak 15 concentrations.
Consequently, it is desirable to have a pharmaceutical form which gives rise to sustained-release of an approximately constant concentration of this active ingredient so that it is possible to administer the drug 20 only once or twice a day.
Different means are known for the obtention of sustained-release pharmaceutical forms which can be administered orally either in the form of tablets or in the form of microgranules, such as those described in 25 EP-A-0 076 428, EP-A-0 061 217 and EP-A-0 216 743.
Such means must be adapted to each drug since the rate and duration of release of the active ingredient as well as its plasma concentration depend on its physico-chemical properties, including its solubility and 30 stability in the gastro-intestinal tract, and on its pharmacokinetic parameters.
Such a form is particularly difficult to prepare for compounds of short half-life, less than 4-5 hours, such as diltiazem, since the duration of its release in 35 vivo from the pharmaceutical form does not exceed the residence time of the drug in the gastro-intestinal tract, .~
--i.e., maximally 8 to 10 hours, and then only if release commences immediately on arrival in the stomach.
Furthermore, during this period release is required to be more or less constant although the pH of 5 the surrounding medium changes from 1.5 in the stomach to 6.9 in the jejunum.
One of the objects of the present invention is a sustained-release pharmaceutical composition of diltiazem which, depending on the type of treatment, 10 requires only one or two daily administrations by the oral route. It consists of a capsule of gelatin, starch or other polymer which can be rapidly degraded in the gastric environment, containing a large number of microbeads composed of a core containing the active ingredient 15 surrounded by a microporous membrane, this membrane being composed of a non-water-soluble film-forming polymer, a plasticizer and a filling material; the thickness of the membrane of the microbeads as well as the amount of active ingredient in the core and its size are chosen such that 20 diltiazem is liberated from the microbeads in vitro in artificial dissolution media in which the pH varies from 1.5 to 7, at a substantially constant rate for at least 6 hours, after a latent period of less than one hour.
The core may be constituted of small spheres, 25 produced by extrusion/sphere-formation from a plastic mass based on a polyol such as mannitol or a polymer such as polyglycol, and a water-soluble salt of diltiazem, but a core is preferred which consists of a inert grain composed of excipients, this inert grain being coated with the 30 active ingredient.
The inert grain may be constituted by a sugar, with a hydrocolloid, such as gum arabic, gelatin or starch or a biocompatible polymer such as the micro-crystalline celluloses, alkylcelluloses, carboxymethylcelluloses as 35 well as mixtures of them or other excipients well known to the specialist skilled in the art. A mineral filling material such as talc may be added if required. The inert grain can be prepared in a standard manner in a turbine, or by extrusion/sphere-formation from polymers or by granulation of a molten mass passing through a vibrating 5 nozzle before cooling.
The active ingredient is then bound to the inert grain in one or several successive layers in a turbine or ~ in a fluidized bed either by the spraying of a solution or suspension of the diltiazem salt and a polymeric binder lo with evaporation of the solvent, or by the spraying of an alcoholic solution of the binder onto the substrate followed by spraying of the diltiazem salt as a powder onto the viscous layer just deposited; the second solution is preferred since the cores thus obtained form 15 less aggregates and are more regular.
Preferably, an appreciable quantity of active ingredient should not be left in the microbeads when, in vivo, they leave the duodenal resorption zone, which corresponds in vitro to the release of at least 60% of the 20 active ingredient from the core within 8 hours, and the concentration of active ingredient in the core is calculated as a function of this.
Usually, for technical reasons, it is preferable that the concentration of active ingredient in the core is 25 30 to 50% by weight, but in particular in the case of the higher dosage pharmaceutical compositions according to the invention, there may be up to 85~ of active ingredient in the core.
It is desirable to have microbeads of a diameter 30 varying between 0.4 and 1.4 mm, so that the number of microbeads introduced into a capsule of acceptable dimensions which can be swallowed by the patient without difficulty, is more than loO and preferably lies between 200 and 600; thus the dose of the active ingredient and 35 the kinetics of its release will be of an acceptable reproducibility from one capsule to another in spite of 1 33-63`26 the unavoidable heterogeneity of the microbeads due to the manufacturing techniques. Under these conditions the cores will preferably have diameters varying between 0.4 mm and 1.3 mm. In the case in which the active ingredient 5 is bound by a binder to the inert grain from 5 to 20% by weight of binder is used in relation to the weight of the diltiazem salt. Binders which can be used are water-soluble binders well known to the technique, and which are compatible with the diltiazem salt, such as methylcellu-10 loses, water-soluble polyacrylates and polyvinylpyrroli-dones. A polyvinylpyrrolidone of molecular mass of approximately 50,000, marketed by GAF (FGR) under the trade name Plasdone, is preferably used.
As diltiazem salt, the standard salt, namely the 15 hydrochloride is usually used but other more or less water-soluble salts may be used, either salts of mineral acids such as the sulfate, or salts of organic acids such as fumarate, oxalate, succinate and similar compounds;
the amount of active ingredient in the core and the 20 thickness of the membrane will be defined as a function of the solubility of the salt in aqueous medium.
A fundamental feature of the invention resides in the choice of the properties of the microporous membrane which surrounds the core.
In fact, it has been observed that, in order to obtain a sustained-release pharmaceutical form, having acceptable in vivo kinetics, it is necessary that the in vitro diffusion kinetics of the diltiazem salt from the microbeads in standard artificial dissolution media in 30 which the pH varies from 1.5 to 7 is approximately constant for at least 6 hours and preferably up to 8 hours, and the time necessary to obtain a constant rate of diffusion, i.e. the latent period, is less than one hour.
Under these conditions, capsules containing 120 35 mg of active ingredient included in microbeads of the invention, administered twice a day to human subjects _.~
i~
gives rise, at equilibrium, to a plasma concentration which is always higher than 80 ng/ml, with a peak close to 130 ng/ml which is reached within 6 hours, whereas a standard pharmaceutical composition administered twice a 5 day at the same doses rapidly gives rise to a peak concentration of up to 180 ng/ml with a rapid decrease to 50 ng/ml after 6 hours.
of the non-water-soluble biocompatible polymers which are stable in vivo and capable of constituting the 10 microporous membrane, mention may be made of the polyacrylates and polymethacrylates of the Eudragit type, the alkylcelluloses including the methylcelluloses of the Tylose type (Hoechst) and the ethylcelluloses such as those marketed by Hercules and the lacquers of natural 15 origin such as the shellac gums. The properties of the last-mentioned are poorly reproducible from one batch to another and ethylcellulose, the viscosity of which, when measured according to the method of the US National ~ormulary, lies between lo and 50 mPa.s. is preferred 20 since it is of reproducible quality and chemically inert.
The polymers must be combined with a plas-ticizing agent so that the membrane is not brittle, and with a finely divided filling material which may amount to between 35 and 75~ by weight of the membrane.
Of the plasticizing agents which may be used, in particular phthalic esters, polyethylenglycols, castor oil and glycerol, castor oil is preferred.
The amount of plasticizing agent introduced depends on the type used. It usually represents from lo 30 to 30% by weight of the film-forming agent.
The presence of a filling material in sufficient amount is fundamental; it reduces the swelling time of the membrane in vivo, hence the latent period, without simultaneously increasing excessively the rate of 35 diffusion of the active ingredient; a low diffusion rate, necessary for a sustained release form, can be obtained by increasing the thickness of a membrane of conventional composition, but the latent period is simultaneously increased.
It is known that in the case of diltiazem, it is 5 of fundamental importance to have a short latent period, in order to avoid bioavailability losses and release of the active ingredient during too short a period before the microbeads leave the gastro-intestinal tract.
Nonetheless, in order to reduce this latent period, it is 10 not possible to reduce the thickness of the membrane excessively as this would make it difficult to reproduce its diffusion properties during manufacture; the heterogeneity which would result in the case of the beads thus obtained in the same batch or in successive batches 15 would make it practically impossible to manufacture pharmaceutical compositions, the rate of release of the active ingredient from which is defined and reproducible.
of the finely divided filling materials which can be used, and which are insoluble in the solvent in 20 which the membrane is applied, mention may be made of talc, silica, metal silicates such as A1 and Mg silicates, kaolin, powdered lactose and sucrose, metal oxides such as titanium oxides, or their mixtures. Neutral filling materials such as talc are preferred.
In a preferred embodiment of the invention, the membrane is constituted of 25 to 40% by weight of ethylcellulose, from 5 to 10% by weight of castor oil and from 50 to 70% by weight of talc.
The microporous membrane can be applied by 30 spraying an alcoholic or aqueous-alcoholic dispersion of the film-forming polymer, plasticizing agent and filling material into a turbine or into an air-operated fluidized bed.
In the case of an ethylcellulose-based membrane, 35 its thickness will vary between 15 micrometers and 60 micrometers.
.
- 1 33b326 The amount of the composition to be deposited in order to form a membrane of suitable thickness is determined by preliminary tests during which the rate of diffusion of diltiazem in vitro is measured under the 5 standard conditions of the United States Pharmacopea (USP
Z1. Chap. 711, page 1243; apparatus N 1) using artificial dissolution media of different pHs varying from 1.5 to 7 and being, for example, 1.5, 4.5 and 7, starting from microbeads containing the selected core and membranes of lo different thicknesses deposited in successive layers. The thickness of the membrane is then chosen so that an approximately constant rate of diffusion is established within less than one hour and from the measured value of the diffusion rate from the microbeads with this membrane 15 thickness are deduced what must be the dimensional characteristics of the core in order to insure the in vitro release per hour of about 10~ of the amount of active ingredient present.
It has in fact been observed that this in vitro 20 rate of release gives plasma concentrations in vivo which are satisfactory for the intended thereapeutic use.
The microbeads of the invention are stable; the kinetics of in vitro dissolution do not change during storage as has frequently been observed with this type of 25 pharmaceutical form.
The pharmaceutical compositions according to the invention can be made available in the form of capsules of conventional composition and size containing from loo to 600, and preferably from 200 to 350, microbeads of the 30 invention such that a unit dose contains from 90 mg to 350 mf of diltiazem. The required number of microbeads are introduced into each capsule; the same microbeads can be used irrespective of the unit dose to be made up but, for extreme doses, it is preferable in particular to select 35 the composition and size of the microbeads such that the number of microbeads per capsule lies between 300 and 350.
~3 These microbeads can be introduced into other pharmaceutical forms : cachets, divisible or indivisible tablets, suppositories and liquid or gelled suspensions.
In what follows, particular embodiments of the 5 invention are described as examples of the microbeads, the process for their preparation and novel sustained-release pharmaceutical compositions of the invention. The curves of dissolution in artificial media of various pH prepared as described in the U.s.P. have been plotted with an lo apparatus into which the quantity of microbeads corresponding to the dose of active ingredient have been introduced per liter of medium. The diltiazem hydrochloride released as a function of time is measured by spectrophotometry.
EXAMPLE:
In order to prepare about lo kg of granular substrate, about 2 kg of "seed" obtained by sieving crystallized sucrose through a 0.500 mm mesh sieve and 20 freed of dust by sieving through a 0,200 mm mesh sieve are introduced into a turbine.
An aqueous-alcoholic solution containing sucrose (6 parts) and polyvidone K30 (one part) in a water-ethyl alcohol mixture (50/50 -V/V), i.e. about 5 liters for 2.5 25 kg of sucrose/polyvidone mixture, are sprayed several times.
Between each spraying, dusting is done with a mixture of talc (one part), maize starch (one part) and sucrose (2 parts) until microspheres of about 0.5 to 30 0.6 mm diameter are obtained. After drying in an incubator at 40C, the fraction with diameters included between 0.600 mm and 0.300 mm is isolated; it will subsequently be used as the granular substrate.
About 1.5 kg of granular substrate are then 35 introduced into a turbine and its weight is approximately doubled by spraying with a 10% (wt/v) alcoholic solution X
of polyvidone and dusting between each spraying with diltiazem hydrochloride previously passed through a 0.5 mm mesh sieve until about 2.5 kg of cores are obtained.
Drying is performed in an incubator at 40C.
The content of active ingredient is of the order of 40% by weight. The small cores are removed by means of a 0.6 mm mesh sieve and the cores are reintroduced into a turbine equipped with a spraying device. An alcoholic solution containing about 12% by weight of a mixture of 10 ethyl cellulose (5 parts) and castor oil (one part) is spraying onto the cores which are dusted with talc between sprayings; the ethylcellulose has a viscosity of from 18 to 24 mPa.s.
When the mass of the beads has increased by 10%
15 a first sample A is taken, then the deposition of the membrane is continued to give a sample B taken after a weight increase of 30%, and a sample C taken after a weight increase of 55%; these three batches are dried in an incubator at 40OC. The kinetics of dissolution for 20 each of them are determined in vitro at pH 1.5, and hence the release per hour at constant rate (the percentage of active ingredient released by the microbeads in one hour) and the latent period can be deduced.
The results obtained are shown in the table 25 below:
Test sample : : Rate of corresponding to 120 mg : Latent period : release of active ingredient : : per hour Sample A : o :25 %
Sample B : 2 hours :13,75%
Sample C : 4 hours : 9 %
X
In this case, it is observed that the microbeads B and C did not comply with the characteristics of the invention tlatent period too long) and that the membrane was required to be thicker than that of the microbeads A
5 (too rapid dissolution) and consequently the operating conditions have been modified in order to give rise to the microbeads according to the invention.
Microbeads have thus been prepared to give a dose of 120 mg of active ingredient in a capsule N 1 with lo 250 microbeads per capsule; these microbeads contain 48%
by weight of active ingredient, the inert grain represents 31% by weight of the microbead whereas the membrane represents 17.5% by weight of the microbead.
Starting from a representing 11% of the final 15 weight of the microbead, microbeads have also been prepared to give a dose of 300 mg of active ingredient in a capsule N 0, which contained 75~ by weight of active ingredient; the membrane represents 11% by weight of the microbead.
In vitro, these microbeads show practically no latent period, the rate of release is constant and the amount of diltiazem released at the end of 4 hours is about 40% of the total quantity whereas it is about 60% at the end of 6 hours.
These properties are not altered after at least lB months storage at ambient temperature and after 3 months storage at 40C or at 55C.
Claims (16)
1. Diltiazem microbeads which consist of a core containing diltiazem, surrounded by a microporous membrane consisting of a film-forming polymer insoluble in aqueous medium, a plasticizing agent and a filling material representing 35 to 75% by weight of the membrane and which release diltiazem in vitro at a pH of between 1.5 and 7 in an approximatively constant manner for at least 6 hours, after a latent period of less than one hour.
2. Microbeads according to claim 1, in which diltiazem is under the form of a water soluble salt.
3. Microbeads according to claim 2, in which diltiazem is under the form of hydrochloride.
4. Microbeads according to claim 1, which have a diameter between 0.4 and 1.4 mm.
5. Microbeads according to claim 1, wherein the core consists of an inert grain substrate coated with a layer of active ingredient combined with a binder.
6. Microbeads according to claim 5 , wherein the binder is polyvinyl pyrrolidone.
7. Microbeads according to claim 1, wherein the film-forming polymer is ethylcellulose.
8. Microbeads according to claim 7, wherein the ethylcellulose has a viscosity between 10 and 50 mPa.s.
9. Microbeads according to any one of claims 1 to 8, wherein the plasticizing agent is castor oil.
10. Microbeads according to any one of claims 1 to 8, wherein the filling material is selected from talc, kaolin, silica, a metal silicate or a metal oxide.
11. Microbeads according to claim 1, wherein the membrane consists of 25 to 40% by weight of ethylcellulose, from 5 to 10% by weight of castor oil and from 50 to 70% by weight of talc.
12. Microbeads according to claim 11, which have a diameter from 0.4 to 1.4 mm and the thickness of the membrane is from 15 micrometers to 60 micrometers.
13. A process for the preparation of the microbeads according to any one of claims 1 to 8, 11 and 12 wherein the membrane is applied to the core by the spraying of a dispersion of its components in a solvent.
14. A sustained-release pharmaceutical composi-tion of diltiazem, consisting of capsules containing microbeads according to claim 1.
15. A pharmaceutical composition according to claim 14, wherein the capsule contains from 100 to 600 microeads.
16. A pharmaceutical composition according to claim 14 or 15, wherein the capsule contains from 90 to 350 mg of diltiazem.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8805629A FR2630647B1 (en) | 1988-04-27 | 1988-04-27 | DILTIAZEM MICROBALLS, PROCESS FOR PRODUCING THE SAME, AND SUSTAINED-RELEASE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR8805629 | 1988-04-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1336326C true CA1336326C (en) | 1995-07-18 |
Family
ID=9365751
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000596597A Expired - Fee Related CA1336326C (en) | 1988-04-27 | 1989-04-13 | Microbeads of diltiazem, a process for their manufacture and a sustained-release pharmaceutical composition containing them |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0340105B1 (en) |
| JP (1) | JPH01313431A (en) |
| AT (1) | ATE72974T1 (en) |
| AU (1) | AU614056B2 (en) |
| CA (1) | CA1336326C (en) |
| DE (1) | DE68900903D1 (en) |
| ES (1) | ES2032125T3 (en) |
| FR (1) | FR2630647B1 (en) |
| GR (1) | GR3003988T3 (en) |
| MX (1) | MX9203020A (en) |
| NZ (1) | NZ228846A (en) |
| ZA (1) | ZA892871B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5288505A (en) * | 1991-06-26 | 1994-02-22 | Galephar P.R., Inc., Ltd. | Extended release form of diltiazem |
| GB2258613B (en) * | 1991-08-12 | 1996-01-10 | Euro Celtique Sa | Pharmaceutical diltiazem formulation |
| KR100221695B1 (en) * | 1991-08-12 | 1999-09-15 | 그린 마틴, 브라이언 쥐 테슬리 | Pharmaceutical spheroid formulation |
| JPH08143450A (en) * | 1994-11-14 | 1996-06-04 | Taiyo Yakuhin Kogyo Kk | Sustained release preparation |
| FR2742660B1 (en) * | 1995-12-22 | 1998-04-03 | Ethypharm Lab Prod Ethiques | NOVEL FORMS OF EXTENDED RELEASE MICROGRANULES CONTAINING DILTIAZEM AS ACTIVE INGREDIENT |
| ES2530450T3 (en) * | 2008-10-02 | 2015-03-03 | Eyesense Ag | Implantable sensor element |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57120518A (en) * | 1981-01-19 | 1982-07-27 | Tanabe Seiyaku Co Ltd | Preparation of microcapsule |
| JPS58116414A (en) * | 1981-12-23 | 1983-07-11 | Yamanouchi Pharmaceut Co Ltd | Composition for pharmaceutical of prolonged release containing nicardipine and preparation thereof |
| JPS5916821A (en) * | 1982-07-16 | 1984-01-28 | Tanabe Seiyaku Co Ltd | Preparation of nonflocculating microcapsule |
| IE56999B1 (en) * | 1983-12-22 | 1992-03-11 | Elan Corp Plc | Pharmaceutical formulation |
| LU85943A1 (en) * | 1985-06-12 | 1987-01-13 | Galephar | PHARMACEUTICAL TABLETS FOR THE EASY ADMINISTRATION OF PELLETS, THEIR PREPARATION AND THEIR USE |
| JPS6232166A (en) * | 1985-08-06 | 1987-02-12 | Mitsui Toatsu Chem Inc | Adhesive for fabrication of foams |
| LU86077A1 (en) * | 1985-09-18 | 1987-04-02 | Pharlyse Sa | NEW GALENIC FORMS OF VERAPAMIL, THEIR MANUFACTURE AND THE MEDICINAL PRODUCTS CONTAINING THESE NEW GALENIC FORMS |
-
1988
- 1988-04-27 FR FR8805629A patent/FR2630647B1/en not_active Expired - Fee Related
-
1989
- 1989-04-13 CA CA000596597A patent/CA1336326C/en not_active Expired - Fee Related
- 1989-04-19 ZA ZA892871A patent/ZA892871B/en unknown
- 1989-04-21 NZ NZ228846A patent/NZ228846A/en unknown
- 1989-04-24 AU AU33363/89A patent/AU614056B2/en not_active Ceased
- 1989-04-25 EP EP89401180A patent/EP0340105B1/en not_active Expired - Lifetime
- 1989-04-25 DE DE8989401180T patent/DE68900903D1/en not_active Expired - Fee Related
- 1989-04-25 AT AT89401180T patent/ATE72974T1/en active
- 1989-04-25 ES ES198989401180T patent/ES2032125T3/en not_active Expired - Lifetime
- 1989-04-26 JP JP1107115A patent/JPH01313431A/en active Pending
-
1992
- 1992-03-05 GR GR920400339T patent/GR3003988T3/el unknown
- 1992-06-19 MX MX9203020A patent/MX9203020A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GR3003988T3 (en) | 1993-03-16 |
| AU614056B2 (en) | 1991-08-15 |
| MX9203020A (en) | 1992-07-01 |
| EP0340105B1 (en) | 1992-03-04 |
| ZA892871B (en) | 1990-12-28 |
| FR2630647B1 (en) | 1991-08-16 |
| NZ228846A (en) | 1991-06-25 |
| ATE72974T1 (en) | 1992-03-15 |
| FR2630647A1 (en) | 1989-11-03 |
| ES2032125T3 (en) | 1993-01-01 |
| AU3336389A (en) | 1989-11-02 |
| DE68900903D1 (en) | 1992-04-09 |
| EP0340105A1 (en) | 1989-11-02 |
| JPH01313431A (en) | 1989-12-18 |
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