CA2037410C - Therapeutic compositions with controlled release of medicaments supported on crosslinked polymers and coated with polymer films, and their preparation process - Google Patents
Therapeutic compositions with controlled release of medicaments supported on crosslinked polymers and coated with polymer films, and their preparation process Download PDFInfo
- Publication number
- CA2037410C CA2037410C CA002037410A CA2037410A CA2037410C CA 2037410 C CA2037410 C CA 2037410C CA 002037410 A CA002037410 A CA 002037410A CA 2037410 A CA2037410 A CA 2037410A CA 2037410 C CA2037410 C CA 2037410C
- Authority
- CA
- Canada
- Prior art keywords
- polymer
- medicament
- cross
- linked
- particles
- 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 - Lifetime
Links
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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- A61P9/12—Antihypertensives
Abstract
The described therapeutic compositions with controlled release of medicaments comprise a medicament loaded onto particles of a crosslinked non-ionic polymer insoluble but swellable in water, using either swelling with solutions of the medicament or high-energy co-grinding methods. The medicament-loaded particles are coated with a polymers film able to control medicament release, to obtain a prolonged release of the medicament (even exceeding 24 hours) while maintaining high bioavailability.
Description
THERAPEUTIC COMPOSITIONS WITH CONTROLLED RELEASE OF MEDICAMENTS
SUPPORTED ON CROSSLINKED POLYMERS AND COATED WITH POLYMER FILMS, AND
THEIR PREPARATION PROCESS
This invention relates to therapeutic compositions with controlled release of medicaments in which particles of non-ionic polymer which is insoluble but swellable in water are loaded with the medicament and coated with a polymer film, and to their preparation process.
State of the art Orally administered medicaments are often poorly absorbed, with consequent very low hematic levels. This problem is accentuated when ' prolonged release over twelve or even twentyfour hours is required. In this respect, with known pharmaceutical controlled release forms, poorly soluble medicaments normally give rise to hematic levels which in many cases are not even therapeutically valid.
Patent AU-A-8,770,043 describes dispersions or solutions of dihydropyridine derivatives (water-insoluble) .in semisolid or liquid non--ionic surfactants: These dispersions result in improved bioavailability. The controlled release is obtained by inserting the dispersions into gelling matrices based on hydrophilic polymers such as 2~ hydroxypropylmethylcellulose.
Patent GB-A-2,159,714 describes steroid medicaments with a water solubility of less than one part in 5000 by weight, which are sprayed onto inert cores in the form of suspensions in solutions of water-soluble polymer binders. Successive polymer films of controlled release type are then applied to these cores loaded with the medicament. The improvement in absorption is obtained by micronizing the medicament particles and introducing surface-active wetting agents into the suspension to be sprayed.
Patents DE-A-2,643,004, DE-A-3,320,583 and EP-A-78,430 describe the loading of poorly soluble medicaments onto crosslinked polyvinylpyrrolidone by a method comprising swelling in solvent.
Patent GB-A-2,153,676 describes the loading of the medicament onto crosslinked polyvinylpyrrolidone by a process involving heating the medicament and crosslinked polymer mixture. Patent GB-A-2,153,67$
attains the same result by a process involving co-grinding the mixture of medicament and crosslinked polymer in a high-energy mill.
The present applicant (see Italian patent applications IT 22336 A/88 and IT 22770 A/88) has proposed a further two methods for activating poorly soluble medicaments on crosslinked hydrophilic polymers which are insoluble but swellable in water.
All the described patents enable systems comprising medicaments 25 supported on hydrophilic crosslinked polymers to be obtained having a very high solubility or dissolution rate but a very short medicament release time.
Patent SA-A-870,738 (corresponding to EP-A-232,155) describes a system in which the crosslinked polyvinylpyrrolidone is loaded with a solution of the medicament and linear polyvinylpyrrolidone, the loaded product then being mixed with a gelling polymer. The mixture can be granulated or pressed after adding any other excipients.
Patent BE-A-729,827 describes systems consisting of particles or granules of ion exchange resins of size between 0.1 and 1 mm loaded with ionic medicaments and coated with impermeable polymers by coating in a pan.
Patents US-A~4,221,778 and EP-A-171,528 describe particles of ion exchange resin loaded with ionic medicaments which are pretreated with substances such as polyethyleneglycols or glycerin before coating with polymer films in a fluidized bed.
Patent EP-A-294,103 describes a method in which the ion exchange resins are coated by dispersing the polymer particles (between 5 and 1000 nm) in solutions of the coating polymer, followed by phase separation or spray drying.
Finally, patent US-A-4,795,644 describes ion exchange resin particles on which a polymer film containing water-soluble substances such as alkaline metal salts or sugars able to form pores is deposited.
It is apparent that in the aforegoing systems the achievement of controlled release is based on the synergic effect between the action of the polymer membrane deposited on the polymer microparticles and the ionic interaction between the resin and the medicament.
Summary of the Invention In contrast to that reported in the aforesaid state of the art, it has been unexpectedly found that the release of medicaments loaded onto particles of non-ionic polymer which is insoluble but swellable in water can be prolonged even for many hours if said medicament-loaded particles are coated with linear polymer delay films.
The present invention therefore provides systems for the controlled release of medicaments supported on cross-linked polymers and coated with polymer films, their preparation process and the pharmaceutical compositions which contain them.
In one aspect, the invention provides a process for preparing therapeutic compositions with controlled release of medicaments, comprising the following steps: (1 ) loading particles of at least one hydrophilic water-insoluble, but water-swelling, cross-linked polymer with a medicament, by swelling the cross-linked polymer with solutions of the medicament followed by drying, or by high-energy co-grinding; (2) optionally size-enlarging the medicament-loaded particles by wet or day granulation to form granules; (3) coating the medicament-loaded particles obtained from step 1 or the granules obtained from step 2 by suspending them in an air stream, spraying with a solution of a coating polymer,and then drying. In another aspect, the invention provides controlled release compositions obtainable by such process.
3a In another aspect, the invention provides therapeutic compositions with controlled release of medicaments, consisting of particles of a cross-linked, non-ionic polymer insoluble but swellable in water, which particles are loaded with the medicament by swelling and coated with a polymer film.
Detailed Description of the Invention The process for preparing the systems of the present invention consists essentially of the following steps:
1) loading the particles of water-insoluble but water-swellable polymer with the required medicament either by swelling with solutions of the medicament followed by drying, or by high-energy co-grinding;
2) suspending such loaded polymer particles, of between 1 and 200 um, in a current of air in a fluidized bed apparatus, spraying them with a solution of the coating polymer, and then drying them in the same apparatus or by another method;
SUPPORTED ON CROSSLINKED POLYMERS AND COATED WITH POLYMER FILMS, AND
THEIR PREPARATION PROCESS
This invention relates to therapeutic compositions with controlled release of medicaments in which particles of non-ionic polymer which is insoluble but swellable in water are loaded with the medicament and coated with a polymer film, and to their preparation process.
State of the art Orally administered medicaments are often poorly absorbed, with consequent very low hematic levels. This problem is accentuated when ' prolonged release over twelve or even twentyfour hours is required. In this respect, with known pharmaceutical controlled release forms, poorly soluble medicaments normally give rise to hematic levels which in many cases are not even therapeutically valid.
Patent AU-A-8,770,043 describes dispersions or solutions of dihydropyridine derivatives (water-insoluble) .in semisolid or liquid non--ionic surfactants: These dispersions result in improved bioavailability. The controlled release is obtained by inserting the dispersions into gelling matrices based on hydrophilic polymers such as 2~ hydroxypropylmethylcellulose.
Patent GB-A-2,159,714 describes steroid medicaments with a water solubility of less than one part in 5000 by weight, which are sprayed onto inert cores in the form of suspensions in solutions of water-soluble polymer binders. Successive polymer films of controlled release type are then applied to these cores loaded with the medicament. The improvement in absorption is obtained by micronizing the medicament particles and introducing surface-active wetting agents into the suspension to be sprayed.
Patents DE-A-2,643,004, DE-A-3,320,583 and EP-A-78,430 describe the loading of poorly soluble medicaments onto crosslinked polyvinylpyrrolidone by a method comprising swelling in solvent.
Patent GB-A-2,153,676 describes the loading of the medicament onto crosslinked polyvinylpyrrolidone by a process involving heating the medicament and crosslinked polymer mixture. Patent GB-A-2,153,67$
attains the same result by a process involving co-grinding the mixture of medicament and crosslinked polymer in a high-energy mill.
The present applicant (see Italian patent applications IT 22336 A/88 and IT 22770 A/88) has proposed a further two methods for activating poorly soluble medicaments on crosslinked hydrophilic polymers which are insoluble but swellable in water.
All the described patents enable systems comprising medicaments 25 supported on hydrophilic crosslinked polymers to be obtained having a very high solubility or dissolution rate but a very short medicament release time.
Patent SA-A-870,738 (corresponding to EP-A-232,155) describes a system in which the crosslinked polyvinylpyrrolidone is loaded with a solution of the medicament and linear polyvinylpyrrolidone, the loaded product then being mixed with a gelling polymer. The mixture can be granulated or pressed after adding any other excipients.
Patent BE-A-729,827 describes systems consisting of particles or granules of ion exchange resins of size between 0.1 and 1 mm loaded with ionic medicaments and coated with impermeable polymers by coating in a pan.
Patents US-A~4,221,778 and EP-A-171,528 describe particles of ion exchange resin loaded with ionic medicaments which are pretreated with substances such as polyethyleneglycols or glycerin before coating with polymer films in a fluidized bed.
Patent EP-A-294,103 describes a method in which the ion exchange resins are coated by dispersing the polymer particles (between 5 and 1000 nm) in solutions of the coating polymer, followed by phase separation or spray drying.
Finally, patent US-A-4,795,644 describes ion exchange resin particles on which a polymer film containing water-soluble substances such as alkaline metal salts or sugars able to form pores is deposited.
It is apparent that in the aforegoing systems the achievement of controlled release is based on the synergic effect between the action of the polymer membrane deposited on the polymer microparticles and the ionic interaction between the resin and the medicament.
Summary of the Invention In contrast to that reported in the aforesaid state of the art, it has been unexpectedly found that the release of medicaments loaded onto particles of non-ionic polymer which is insoluble but swellable in water can be prolonged even for many hours if said medicament-loaded particles are coated with linear polymer delay films.
The present invention therefore provides systems for the controlled release of medicaments supported on cross-linked polymers and coated with polymer films, their preparation process and the pharmaceutical compositions which contain them.
In one aspect, the invention provides a process for preparing therapeutic compositions with controlled release of medicaments, comprising the following steps: (1 ) loading particles of at least one hydrophilic water-insoluble, but water-swelling, cross-linked polymer with a medicament, by swelling the cross-linked polymer with solutions of the medicament followed by drying, or by high-energy co-grinding; (2) optionally size-enlarging the medicament-loaded particles by wet or day granulation to form granules; (3) coating the medicament-loaded particles obtained from step 1 or the granules obtained from step 2 by suspending them in an air stream, spraying with a solution of a coating polymer,and then drying. In another aspect, the invention provides controlled release compositions obtainable by such process.
3a In another aspect, the invention provides therapeutic compositions with controlled release of medicaments, consisting of particles of a cross-linked, non-ionic polymer insoluble but swellable in water, which particles are loaded with the medicament by swelling and coated with a polymer film.
Detailed Description of the Invention The process for preparing the systems of the present invention consists essentially of the following steps:
1) loading the particles of water-insoluble but water-swellable polymer with the required medicament either by swelling with solutions of the medicament followed by drying, or by high-energy co-grinding;
2) suspending such loaded polymer particles, of between 1 and 200 um, in a current of air in a fluidized bed apparatus, spraying them with a solution of the coating polymer, and then drying them in the same apparatus or by another method;
3) size-enlarging the medicament-loaded polymer particles by wet or dry granulation to a homogeneous size of between 100 and 1000 um and then coating them as described under point 2.
The size of the coated polymer particles is between the limits of 10-1500 um and preferably 100-1000 um.
The medicament release system obtained in this manner has a medicament release time which can be adjusted at will from a few hours to 24-48 hours. The medicament loaded onto the polymer particles is in a thermodynamically active state, ie amorphous or as extremely small crystals (nanocrystals).
The process according to the invention is implemented in two stages as follows:
1st Stage The medicament is loaded onto the particles of crosslinked polymer insoluble but swellable in water (or onto a mixture of two or more such polymers) by any known method, such as:
la) dissolving the medicament in a suitable solvent and spraying a certain volume of. the solution onto a given quantity of polymer with the weight ratio of solution to polymer chosen on the basis of the polymer swelling capacity and the medicament concentration in the solution. The spraying can be carried out in any apparatus used for the purpose, such as a continuously stirred reactor, a rotary evaporator under continuous rotation, a mortar by light mixing with a pestle, or a fluidized bed with the polymer kept suspended in an air stream.
The product obtained is then dried in the above apparatus or in other suitable apparatus.
1b) the medicament is dissolved in a suitable solvent and a quantity of a crosslinked polymer insoluble but swellable in water (or a mixture of two or more such polymers) is suspended in an excess of the solution IO obtained. The suspension is kept stirring until the polymer particles have swollen. The suspension is then filtered or separated by other suitable means, and the product recovered and dried.
lc) the medicament in powder form and the crosslinked polymer insoluble but sweilable in water (or a mixture of two or more such polymers), also in powder form, are homogeneously mixed together and then co-ground in a suitable apparatus such as a ball mill, a high-energy vibration mill, sn air jet mill etc.
ld) the medicament in powder form and the crosslinked polymer insoluble but swellable in water (or two or more such polymers), also in powder form, are homogeneously mixed together and then co-ground in a suitable apparatus in which the grinding chamber is saturated with solvent vapour or is subjected to a stream of solvent vapour, the solvent being chosen from those able to swell the polymer. The co-grinding is carried .out for example in a ball mill, a high-energy vibration mill or a hammer mill, in which the grinding chamber is connected via a valve and pipe to a solvent reservoir.
le) the medicament in powder form and the crosslinked polymer insoluble but swellable in water, also in powder form, are mixed together homogeneously and then co-heated to the medicament melting point in an apparatus such as an oven, rotary evaporator, reaction vessel, oil bath etc, until the medicament has melted and has been absorbed by the polymer.
The weight ratio of the medicament to said polymer or polymer mixture is in all-cases between 0,1 and 1000 parts by weight of medicament per 100 parts by weight of polymer, and preferably between 10 and 100 parts by weight of medicament per 100 parts by weight of polymer.
2nd Stage When the polymer has been loaded with the active principle, the powder is directly coated with polymer film. Alternatively the polymer film coating can be applied not directly to the medicament-loaded polymer powder bu;, to granules (or pellets) obtained by a size enlargement process carried out on either the starting powder alone or on a mixture of said powder with suitable~excipients.
Non-limiting exa~ples of such size enlargement pmcesses are:
- dry granulation, based on pressing the loaded polymer powder or its mixture with suitable excipients, followed by crumbling and screening to the desired size;
- wet granulation, based on wetting the loaded polymer powder or its mixture with suitable excipients with an aqueous or solvent solution of binders such as sugars, linear polymers etc. in an arm, sigma or other mixer, then wet-screening the paste, drying the resultant aggregates in a forced-air static dryer or in suspension in a fluidized air bed. then crumbling and screening to the desired size;
- rapid wet granulation, based on a process of wetting, kneading and sizing the aggregates in apparatus with high speed homogenization Lj !
systems, then drying and screening;
- wet granulation as heretofore described, followed by extrusion and spherodization to improve the morphology of the granules to be coated, then drying and screening.
When the medicament-loaded polymer powder or its granulate has been obtained, it is coated by suspending a weighed quantity of the powder or granulate in a hot air stream within the drum of a fluidized bed apparatus equipped with a Wurster insert and a binary nozzle. The air flow is such as to maintain a continuous change of suspended powder in am the region in which the solution or suspension of coating polymer is sprayed. The polymer dispersion (or solution) is fed with a peristaltic pump. The quantity of filming agent sprayed per unit time and the total quantity, the atomization pressure, the nozzle size, the temperature and the air volume used in executing a cycle depend on the quantity, the dimensions of the product to be coated and the extent of the controlled release to be obtained.
On termination of spraying, the product ~s dried directly in the Fluidized bed or in a forced-air oven. If necessary, an anti-adhesion agent can be added to the product to ensure separation of xhe film coated particles.
Examples of water-insaluble but water-swellable crosslinked polymers which can be used are:
- crosslinked polyvinylpyrrolidone (abbreviated to crospovidone), as described in National Formulary, Supplement 3, page 36$;
~5 - crosslinked sodium carboxymethylcellulose, as described in National Formulary, Supplement 3, page 367;
- crosslinked ~-cyclodextrin polymer, as described in patent WO
83/00809 and by Fenyvest et al. in Pharmazie 39. X73. 1984;
- crosslinked dextran, etc.
Of particular interest is the use of crosslinked ~-cyclodextrin polymer, which up to now has been used only as a disintegrator for solid pharmaceutical compositions and not as a support for medicaments, and the use of crospovidone.
It should however be noted that according to the present invention any polymer having the following characteristics can be used:
- a hydrophilic polymer lattice which results in considerable swellability in water - . water-insolubility by virtue of the nature of the polymer lattice.
Non-limiting examples of linear polymers which can be deposited as coating films on the particles of crosslinked polymer previously loaded with the medicament are:
Z5 - cellulose and derivatives soluble or insoluble in aqueous solutions, such as: ethylcellulose, . methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose acetate, cellulose acetobutyrate, cellulose acetotrimellitate, cellulose acetophthalate etc.
2p acrylic and methacrylic polymers and their copolymers soluble or insoluble in aqueous solutions such as: methacrylic acid-methylmethacrylate copolymer, ethylacrylate-methylmethacrylate copolymer, ethylacrylate°methylmethacrylate and trimethylammonium ethylmethacrylate chloride copolymer etc.
25 ° linear polyvinylpyrrolidone of differing molecular weight, vinylpyrrolidone-vinyl acetate copolymer etc.
- polyanhydrides such as vinylether-malefic anhydride copolymer - polyvinylalcohol.
It should however be noted that according to the present invention any polymer having the following characteristics can be used:
- insolubility at all pH values s - solubility only at determined pH values (eg. 4.5, 5.5, 6.0, ;.o) - solubility at all pH values.
The aforesaid polymers can be used either alone or in mixture, with the addition of suitable plasticizers such as glycerin, polyethyleneglycols, citric acid esters, glycerin esters, phthalic acid esters etc.; of anti-adhesion substances such as talc, silica, magnesium stearate etc.; or of porogenic substances such as microcrystalline lactose, calcium carbonate, calcium phosphate, saccharose, sodium chloride, potassium chloride etc.
There are no particular limitations to the medicaments which can be used according to the present invention, and in fact either water-soluble medicament or medicaments poorly soluble in water can be used. -Non-limiting examples of medicaments poorly soluble in water which can be used according to the present invention are: griseofulvin, indomethacin, diacerein, megestrol acetate, estradiol, progesterone, medroxyprogesterone acetate, nifedipine, nicergoline, paracetamol, clonidine, etoposide, lorazepam, temazepam, digoxin, glibenclamide ketoprofen, indobufen, ibuprofen, diclofenac, naproxene. acemethacine etc.
In the case of water-soluble medicaments, the main advantage of the 2~ present invention is that their incorporation into the spherical particles of the water-insoluble crosslinked palymer Facilitates the subsequent coating with polymer film. In this respect, in many cases the original morphology of said medicaments is very irregular (needles, very thin flakes etc.) and makes homogeneous and continuous coating of the particles over their entire surface difficult, with consequent poor control of the medicament release. In the particular case of insoluble 5 medicaments in the form of weak acid salts of strong bases one advantage of the present invention is that their incorporation into the insoluble crosslinked polymer provides them with greater protection against the surrounding pH-variable environment in the different segments of the intestinal tract, this variable pH being able to 10 influence the degree of ionization of the medicament and consequently its permeation characteristics. In order to control this ionization, the insoluble crosslinked polymer can also be loaded with agents able to suitably change the pH within the crosslinked polymer itself.
Non-limiting examples of water-soluble medicaments which can be used according to the present invention are: diltiazem hydrochloride, nicardipine hydrochloride, sodium chloride, captopril, enalapril, theophylline, ranitidine, verapamil hydrochloride, naproxene sodium salt, diclofenac sodium salt, propranolol, atenolol, sodium monofluorophosphate.
600 g of CROSPOVIDONE (Kollidon*CL, BASF) were loaded with 120 g of griseofulvin dissolved in 1.2 litres of methylenechloride in a chamber of a sigma mixer under continuous mixing. The thus swollen powder was dried in the same chamber at ambient temperature, at a residual pressure of 450-500 mbar; drying was completed in an oven under vacuum for 1 hour at 30~C.
'700 g of the powdered polymer loaded with griseofulvin in the aforesaid *Trade-mark manner were mixed with 35 g of talc F.U. and 3.5 g of Aerosil 200 and were suspended in a 6" Wurster column of a GPCG1 fluidised bed plant and coated with '700 g of colloidal suspension of acrylic polymer EUDRAGIT'~ RS 30D (ROEHM PHARMA) with added talc F.U., triethylcitrate plasticizer and Tween* 80 surfactant under the following operating conditions: atomization pressure 1-1.5 bar, feed rate of coating suspension 8-10 g/min, inlet air temperature 50~C, product temperature 22-25'C.
On termination of spraying, drying was carried out at the same inlet air temperature. The thus coated powder had the following percentage composition:
Griseofulvin 12.91 PVP CL 64.28 EUDRAGIT RS 8.11 TALC F.U. 12.68 CITROFLEX 2 1.63 TWEEN 80 0.01 Si02 p,3g 100.00 120 g of griseofulvin dissolved in 1.2 litres of methylene chloride were loaded onto 600 g of crospovidone (kollidon CL, BASF) kept under continuous mixing in a suitably sized sigma mixer. The thus swollen powder was dried in the same apparatus under vacuum (450-500 mbar of residual pressure) at ambient temperature. Drying was complete in an oven under vacuum for 1 hour at 30~C.
'700 g of the powdered polymer loaded with griseofulvin in the aforesaid *Trade-mark manner were mixed with 35 g of talc F.U. and 3.5 g of Aerosil 200 and were suspended in a 6" Wurster column of a GPCG1 fluidised bed plant (GLATT, West Germany) and coated with 1050 g of colloidal suspension of acrylic polymer Eudragit RS 30D (ROEHM PHARMA) with added talc F.U. -(anti-adhesion agent), triethylcitrate (plasticizer) and Tween 80 under the following operating conditions: atomization pressure 1-1.5 bar, feed rate of coating suspension 8-10 g/min, air volume during process 2-3 m3/min, inlet air temperature 50'C, product temperature 22-25'C.
On termination of spraying, drying was carried out at the same inlet air temperature and volume. The thus coated powder had the following percentage composition:
Griseofulvin 11.77 PVP CL 58.67 EUDRAGIT RS 11.33 TALC F.U. 15.60 CITROFLEX 2 2.26 TWEEN 80 0.02 Si02 ~ . 0.35 100.00 250 g of diacerein were activated by high-energy grinding with 250 g of povidone (Kollidon CL-M, BASF). 500 g of a mixture of excipients (30%
lactose, 40% microcrystalline cellulose and 30% corn starch) were added to the 500 g of co-ground product and the resultant mixture was wet-granulated using a 5% solution of hydroxypropylcellulose in water as binder. The mixture was wet-screened and dried in a fluidized bed (GPCG1 Glatt, West Germany) under the following operating conditions:
inlet air temperature 55~C, inlet air volume 1-1.5 m3/min. The product ~~~~.fl was then dry-screened in an oscillating granulator. 2 g of granulate prepared as described were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 160 g of colloidal suspension of acrylic polymer Eudragit NE 30D (ROEHM PHARMA) with added talc F.U. (anti-adhesion agent), under the following operating conditions: atomization pressure 1-1.5 bar, feed rate of coating suspension 2-3 g/min, inlet air temperature 30-40~C, product temperature 25-30'C, air volume during process 1.5-2 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume. The thus coated granulate had the following percentage composition:
Diacerein 21.45 PVP CL 21.45 EUDRAGIT NE 8.80 LACTOSE 12.83 MICROCRYSTALLINE CELLULOSE 17.14 HYDROXYPROPYLCELLULOSE 2.20 CORN STARCH 12.83 TALC F.U. ~~
100.00 500 g of granulate obtained as described in Example 3 (particle size distribution 300°800 um) were suspended in a 6" Wurster column of a GPCG1 fluidised bed plant ~(Glatt, West Germany) and coated with 560 g of colloidal suspension of acrylic polymer Eudragit RS 30D (ROEHhi PHARMA) with added talc F.U. (anti-adhesion agent), triethylcitrate (plasticizer) and Tween 80 under the following operating conditions:
i4 atomization pressure 1.5 bar, feed rate of coating suspension 10-12 g/min, air volume during process 2-3 m3/min, inlet air temperature 50- ' 60°C, product temperature 30-35°C. On termination of spraying, drying was carried out at the same inlet air temperature and volume. The thus coated granulate had the following percentage composition:
Diacerein 19.68 PVP CL 19.68 EUDRAGIT RS 12.09 LACTOSE 11.78 MICROCRYSTALLINE CELLULOSE 15.72 HYDROXYPROPYLCELLULOSE 2.01 .
CORN STARCH 11.78 TALC F.U. 4.83 TRIETHYLCITRATE 2.41 TWEEN 80 0.02 100.00 200 g of granulate prepared as described in Example 3 were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 125 g of colloidal suspension of Eudragit RS
30D and Eudragit RL 30D acrylic polymer with added talc F.U. (anti-adhesion agent), triethylcitrate (plasticizer) and Tween 80 under the following operating conditions: atomization pressure 1-1.5 bar, feed rate of coating suspension 2.5-5 g/min, inlet air temperature 55-60°C, product temperature 30-32°C, air volume during process 1-1.5 m3/min.
On termination of spraying, drying was carried out at the same inlet air temperature and volume. The thus coated granulate had the following percentage composition:
Diacerein 21.78 PVP CL 21.78 EUDRAGIT RS 3.35 LACTOSE 13.04 CELLULOSE 17.41 HYDROXYPROPYLCELLULOSE 2.23 CORN STARCH 13.04 TALC F.U. 2.67 TRIETHYLCITRATE 1.34 TWEEN 80~ . 0.01 100.00 200 g of granulate prepared as described in Example 3 were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 1000 g of a 10$ solution of Eudragit L100 acrylic polymer in a mixture composed of 6 parts of ethanol and 4 parts of deionized water with added talc F.U. (anti-adhesion agent) and n dibutylphthalate (plasticizes) under the followfng operating z0 conditions: atomization pressure 1 bar, feed rate of coating suspension 2-b g/min, inlet air temperature 40-45°C, product temperature 30-35~C, air volume during process 1.5-2 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume.
The thus coated granulate had the following percentage composition:
Diacerein 14.78 PVP CL 14.78 EUDRAGIT L 30~30 LACTOSE 8.84 zs CELLULOSE 11.82 HYDROXYPROPYLCELLULOSE 1.52 CORN STARCH 8.84 TALC F . U . 3 . 0~1 N-DIBUTYLPHTHALATE 6.08 100.00 45 g of nifedipine dissolved in 450 ec of methylene chloride were loaded onto 225 g of povidone (Kollidon CL-M, BASF) kept under constant stirring in a sigma mixer. After homogenization of the pasty mass the swelling solvent was extracted by a vacuum pump at a residual pressure of 450-500 mbar. After evaporation and recovery of the methylene chloride the loaded product was collected and drying completed in a vacuum oven (1 hour at 30~C).
The 270 g of prepared product were returned to the mixing chamber of the sigma mixer and exposed to methylene chloride vapour for 24 hours.
This operation was followed by drying in an oven, screening and homogenization by mixing the product. Colloidal silica (Aerosil 200, Degussa) was added to the final loaded product, which was then divided into flat tablets of l5 mm diameter weighing 500 mg and having a hardness of 7-10 Kp. These tablets were then reduced to granules with an oscillating granulator (or knife mill) . The 425-1200 um granulate fraction was removed by screening.
200 g of the granulate prepared as aforedescribed were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 1330 g of a solution of Eudragit S100 acrylic polymer (ROEHM PHARMA)in ethanol/H20 (80/20) with added talc F.U. (anti adhesion agent) and n-dibutylphthalate (plasticizer) under the following operating conditions: atomization pressure 1-1.5 bar, feed rate of coating suspension 3.5-5 g/min, inlet air temperature 3$-40'c, product temperature 30-32'C, air volume during process 1.5-2.5 m3/min.
On termination of spraying, drying was carried out at the same inlet air temperature and volume. The thus coated granulate had the following percentage composition:
Nifedipine 10 PvP cL 50 COLLOIDAL SILICA 0.61 to EUDRAGIT S 30.3 N-DIBUTYLPHT'HALATE 3.03 TALC F.U. 6.06 100.00 200 g of granulate prepared as described in Example 7 were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 833 g of colloidal suspension of Eudragit L30D
acrylic polymer (ROEHM PHARMA) with added talc F.U. (anti-adhesion agent), n-dibutylphthalate (plastieizer) and Tween $0 under the following operating conditions: atomization pressure 1-1.5 bar, Feed rate of coating suspension 3-5 g/mi.n, ' inlet air temperature 48-52'C, product temperature 30-34'C, air volume during process 1.5-2.5 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume. The thus coated granulate had the following percentage composition:
Nifedipine 10 i8 EUDRAGIT L30D 30.3 COLLOIDAL SILICA 0.61 N-DIBUTYLPHTFiALATE 3 . 0 TALC F.U. 6.06 TWEEN 80 _ 003 100.00 200 g of granulate prepared as described in Example ~ were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 525 g of solution of Povidone (Kollidon 25, BASF) in ethanol with added talc F.U. (anti-adhesion agent) and glycerin (plasticizes) under the following operating conditions:
spraying pressure 1 bar, feed rate of coating suspension 4.5-6 g/min, inlet air temperature 30-34'C, product temperature 28-30'C, air volume during process 1.5-2 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume. 215 g of this coated granulate were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 285 g of colloidal suspension of ethylcellulose (Aquacoat ECD-30 FMC) with added talc F.U. (anti-adhesion agent), n-triethylcitrate (plasticizes) under the following operating conditions: atomization pressure 1-1.5 bar, feed rate of coating suspension 3.5-5.5 g/min, inlet air temperature 50-55'C, product temperature 30-35~C, air volume during process 1.5-2 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume. Percentage composition of final coated product:
Nifedipine 12.35 PVP CL 61.8 *Trade-mark Colloidal silica 0.~5 P1/P K25 5.14 Glycerin 0.4$
ETHYLCELLULOSE 14.98 TRIETHYLCITRATE 4.5 100:00 215 g of granulate coated as described in the first part of Example 9 were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 285 g of colloidal suspension of ethylcellulose (Aquacoat ECD-30 FMC) with added hydroxypropyl methylcellulose (Methocel E5, Dow Chemical) and triethylcitrate {plasticizer) under the following operating conditions: atomization pressure 1-1.5 bar, feed rate of coating suspension 4-8 g/min, inlet air temperature 50-55°C, product temperature 32-35°C, air volume during process 1.5-2 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume. The coated product was then discharged and lx of powdered talc F.U. added, after which it was placed in an oven at a temperature of 60°C for 2 hours. The thus coated granulate had the following percentage composition:
Nifedipine 12.35 PVP CL 61.5 Colloidal silica 0.75 PvP x25 5.14 GLYCERIN 0.~1 HYDROXYPROPYLMETHYLCELLULOSE 3.'7 ETHYLCELLULOSE 11.1 *Trade-mark TRIETHYLCITRATE 4.5 100.00 45 g of ketoprofen dissolved in 450 cc of methylene chloride were loaded onto 225 g of crosslinked ø-cyclodextrin (Ciclolab - Chinoin, Budapest) kept under constant stirring in a sigma mixer. After homogenization of the pasty mass the swelling solvent was extracted by a vacuum pump at a residual pressure of 450-500 mbar. After evaporation and recovery of the methylene chloride the loaded product was collected and drying completed in a vacuum oven (1 hour at 30'C).
The 2'j0 g of prepared product were then screened and homogenized by mixing. Colloidal silica (Aerosil 200, Degussa) and magnesium stearate were added to the final loaded product, which was then divided into flat tablets of 15 mm diameter weighing 500 mg. These tablets were then reduced to granules with a knife mill (or oscillating granulator).
The 425-1000 pm granulate fraction ss removed by screening.
200 g of the granulate prepared as described above were suspended in a 4'° Wurster column of a GPCGl fluidised bed plant (Glatt, West Germany) and coated with 525 g of solution of Povidone (Kollidon 25, BASF) in ethanol with added talc F.U. (anti-adhesion agent) and glycerin (plasticizes) under the following operating conditions: spraying pressure 1 bar, feed rate of coating suspension 4.5-6 g/min, inlet air temperature 30-34'C, product temperature 28-30'C, air volume during process 1.5-2.5 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume.
215 g of this coated granulate were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 285 g of colloidal suspension of ethylcellulose (Aquacoat ECD-30 FMC) with added triethylcitrate (plasticizes) under the following operating conditions: spraying pressure 1-1.5 bar, feed rate of coating suspension 3.5-5.5 g/min, inlet air temperature 50-55'C, product temperature 30-35'C, air volume during process 1.5-2 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume. Percentage composition of final coated product:
Ketoprofen 12.35 Crosslinked ~-cyclodextrin 61.8 Colloidal silica 0.37 Magnesium stearate 0.37 PvP x25 5.15 Glycerin 0.48 Ethylcellulose 14.98 100.00 293 g of diltiazem hydrochloride are activated by high-energy co-grinding with 147g of PVP Cl using a ball mill.
The duration of the grinding cycle is 2 hours at the maximum speed of the mill.
424 g of 2:1 co-ground diltiazem/PVP CL are granulated in a fluidized be.d (Glatt GPCG1 W.G.) using a binding polymer granulating dispersion.
208 g of the obtained granulate are formulated as follows:
z5 Granulated diltiazem 208 g Magnesium stearate 4.5 g Micronized talc 1 g Avicel PH 102 38 a 251.5 g and the mixture is pressed using an automatic rotary press. The tablets obtained are granulated in a VIANI oscillating granulator through a screen of 1.3 mm mesh.
' 225 g of granulate prepared as described are suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, W.G.) and coated to the extent of l0~ with 301.6 g of an alcoholic solution of Eudragit RS PM
acrylic polymer (Rdhm Pharma) using the following formulation for the coating:
Eudragit RS PM 22.5 g Micronized talc 4.48 g Citroflex 2 4.48 g 96x ethanol 270.16 g 1S This first coating is' applied to the extent of lOx by weight of the granulate, under the following operating conditions:
atomization pressure 1 bar feed rate of casting suspension 5.6 g/min air inlet temperature 30~C
product temperature 25'C
230 g of the granulate previously coated with lOx of Eudragit RS PM are suspended in the previously used 4" Wurster column and coated with 182 g of a Eudragit NE 30D polymer suspension.
' Film coating composition:
Eudragit NE 30D 76.64 g (23 dry) Micronized talc 7 g Water 98.37 g The total coating is therefore 20x. On completion of the coating procedure, rapid drying is effected under the same air conditions. The thus coated granulate had the following percentage composition:
Diltiazem HC1 3g, g5 PVP CL 19.49 Eudragit NE 30D 14.68 Eudragit RS PM ~,g0 Magnesium stearate 1.39 Micronized talc 4,55 Avicel PH 102 11.'7 Citroflex 2 1.54 TOTAL 100.00 For purposes of comparison the following compositions were prepared by simply loading the medicament onto the swellable hydrophilic polymer but without coating with the polymer film.
332 g of sodium monofluorophosphate dissolved in 2000 g of demineralized water were loaded on 1660 g of crospovidone (Kollidon CL, BASF), previously mixed with 166 g of povidone (Kollidon 25, BASF), in a sigma mixer under continuous mixing. The homogenized mixture was dried in a fluidized bed (Glatt GPCG 1) for 2 hours at a temperature of 60-~O~C and with an air velocity of 4-5 m/sec.
After sieving, the granular product having particle size 200-500 ~m was suspended in a 4" Wurster column of a GPCG 1 fluidized bed plant (Glatt, West Germany) and coated with 140 g of a lOx povidone solution in ethanol 95~ with added talc and glycerol under the following conditions: atomization pressure 1-1.5 bar; nozzle size 1 mm; Feed rate *Trade-mark of coating suspension 4-6 g/min; inlet air temperature 40-45~C; product temperature 25-30'C; flow of air 1.5-2 m3/min.
On termination of spraying, drying was carried out at the same inlet air temperature. The thus coated granular product had the following percentage composition:
Sodium monofluorophosphate 14.40 Kollidon CL 72 Kollidon 25 12.09 Talc 1.08 Glycerol 0 ~ 43 100.00 210 g of the granulate previously coated as described in example 13 are suspended in a 4" Wurster column of a GPCG 1 fluidized bed plant (Glatt, West Germany) and coated with 1000 g of a 6% Ethylcellulose (NF
22, Hercules) in methylene chloride/ethanol 80/20 with added micronized talc and dibutyl sebacate under the following conditions: atomization pressure 1 bar; nozzle size 1.2 mm; feed rate 5-8 g/min; inlet air temperature 40-42'C; product temperature 28-30~C; flow of air 1.5-2 m3/min.
On termination of spraying, drying was carried out at the same inlet air temperature. The thus coated granular product had the following percentage composition:
Sodium monofluorophosphate 10.02 Kollidon CL 50.12 Kollidon 25 8.42 Glycerin 0.30 Talc 5.66 Ethylcellulose 19.60 Dibutyl sebacate 5.88 100.00 EXAMPLE A
600 g of crospovidone (Kollidon CL, BASF) were loaded with 120 g of griseofulvin dissolved in 1.2 litres of methylene chloride in a chamber of a sigma mixer under continuous mixing. The thus swollen powder is dried in the same chamber at ambient temperature under a residual pressure of 450-500 mbar. Drying is completed in a vacuum oven for 1 hour at 30°C.
composition:
Griseofulvin 16.6 PVP CL _834 2G 100.0 EXAMPLE B
250 g of diacerein were activated by high-energy grinding with 250 g of crospovidone (Kollidon CL-M, BASF). 500 g of a mixture of excipients (30% lactose, 40% microcrystalline cellulose, 30% corn starch) were then added to the 500 g of co-ground product and the resultant mixture wet-granulated using a 5% hydroxypropyl cellulose solution in water as binder. The mixture was wet-screened and dried in a fluidized bed (GPCG1 Glatt, West Germany) under the following operating conditions: air inlet temperature SS°C, air inlet volume 1-l.Sm3/min. The product was then dry-screened in an oscillating granulator.
composition:
Diacerein 24.4 PVP CL 24.4 Cellulose 19.5 Corn starch 14.6 Lactose 14.6 Hydroxypropyl cellulose 2.5 100.00 EXAMPLE C
45g of nifedipine dissolved in 450 cc of inethylene chloride were loaded onto 225g of crospovidone (Kollidon CL-M, BASF) kept under constant stirring in a sigma mixer. After homogenization of the pasty mass the swelling solvent was extracted by a vacuum pump at a residual pressure of 450-500 mbar. After evaporation and recovery of the methylene chloride the loaded product was collected and drying completed in a vacuum oven (1 hour at 30°C).
The 270 g of prepared product were returned to the mixing chamber of the sigma mixer and exposed to methylene chloride vapour for 24 hours. This operation was followed by drying in an oven, screening and homogenization by mixing the product. Colloidal silica (Aerosil 200, Degussa) was added to the final loaded product, which was then divided into flat tablets of 1 Smm diameter weighing 500 mg and having a hardness of 7-10 Kp.
These tablets were then reduced to granules with an oscillating granulator (or knife mill). The 425-1200 pm granulate fraction was removed by screening.
26a composition:
Nifedipine 16.6 PVP CL 82.9 Colloidal silica 0.5 100.0 EXAMPLE D
293 g of diltiazem hydrochloride are activated by high-energy co-grinding with 147g of PVP CL using a ball mill. The duration of the grinding cycle is 2 hours at the maximum speed of the mill.
composition:
Diltiazem HCI 66.6 PVP CL 33.4 100.0 Determination of dissolution rate The dissolution data for the productions prepared by the process of this invention (Examples 1 to 14) are given in Tables 1-6. For comparison, each table also shows the dissolution rate data for the products prepared by simple loading onto the swellable hydrophilic polymer without subsequent coating with a polymer film (Examples A, B, C
and D).
The method used for all the studied medicaments, with exception of medicament of example 14, was the U.S.P. XXI No. 2 method using the SOTAX apparatus at 37°C and a Beckman Du 65 spectrophotometer.
For the products containing griseofulvin 900 nil of pH 7.5 buffer were used with stirring at 150 r.p.m. The spectrophotometric reading of the suitably diluted samples was performed at a = 294 nm.
For the products containing diacerein 900 ml of pH 5.5 buffer were used ~~~'~_~~.~
with stirring at 100 r.p.m. The spectrophotometric reading of the suitably diluted samples was performed at a = 255 nm.
For the products containing nifedipine 900 ml of pH 7.5, pH 4.6 and pH
The size of the coated polymer particles is between the limits of 10-1500 um and preferably 100-1000 um.
The medicament release system obtained in this manner has a medicament release time which can be adjusted at will from a few hours to 24-48 hours. The medicament loaded onto the polymer particles is in a thermodynamically active state, ie amorphous or as extremely small crystals (nanocrystals).
The process according to the invention is implemented in two stages as follows:
1st Stage The medicament is loaded onto the particles of crosslinked polymer insoluble but swellable in water (or onto a mixture of two or more such polymers) by any known method, such as:
la) dissolving the medicament in a suitable solvent and spraying a certain volume of. the solution onto a given quantity of polymer with the weight ratio of solution to polymer chosen on the basis of the polymer swelling capacity and the medicament concentration in the solution. The spraying can be carried out in any apparatus used for the purpose, such as a continuously stirred reactor, a rotary evaporator under continuous rotation, a mortar by light mixing with a pestle, or a fluidized bed with the polymer kept suspended in an air stream.
The product obtained is then dried in the above apparatus or in other suitable apparatus.
1b) the medicament is dissolved in a suitable solvent and a quantity of a crosslinked polymer insoluble but swellable in water (or a mixture of two or more such polymers) is suspended in an excess of the solution IO obtained. The suspension is kept stirring until the polymer particles have swollen. The suspension is then filtered or separated by other suitable means, and the product recovered and dried.
lc) the medicament in powder form and the crosslinked polymer insoluble but sweilable in water (or a mixture of two or more such polymers), also in powder form, are homogeneously mixed together and then co-ground in a suitable apparatus such as a ball mill, a high-energy vibration mill, sn air jet mill etc.
ld) the medicament in powder form and the crosslinked polymer insoluble but swellable in water (or two or more such polymers), also in powder form, are homogeneously mixed together and then co-ground in a suitable apparatus in which the grinding chamber is saturated with solvent vapour or is subjected to a stream of solvent vapour, the solvent being chosen from those able to swell the polymer. The co-grinding is carried .out for example in a ball mill, a high-energy vibration mill or a hammer mill, in which the grinding chamber is connected via a valve and pipe to a solvent reservoir.
le) the medicament in powder form and the crosslinked polymer insoluble but swellable in water, also in powder form, are mixed together homogeneously and then co-heated to the medicament melting point in an apparatus such as an oven, rotary evaporator, reaction vessel, oil bath etc, until the medicament has melted and has been absorbed by the polymer.
The weight ratio of the medicament to said polymer or polymer mixture is in all-cases between 0,1 and 1000 parts by weight of medicament per 100 parts by weight of polymer, and preferably between 10 and 100 parts by weight of medicament per 100 parts by weight of polymer.
2nd Stage When the polymer has been loaded with the active principle, the powder is directly coated with polymer film. Alternatively the polymer film coating can be applied not directly to the medicament-loaded polymer powder bu;, to granules (or pellets) obtained by a size enlargement process carried out on either the starting powder alone or on a mixture of said powder with suitable~excipients.
Non-limiting exa~ples of such size enlargement pmcesses are:
- dry granulation, based on pressing the loaded polymer powder or its mixture with suitable excipients, followed by crumbling and screening to the desired size;
- wet granulation, based on wetting the loaded polymer powder or its mixture with suitable excipients with an aqueous or solvent solution of binders such as sugars, linear polymers etc. in an arm, sigma or other mixer, then wet-screening the paste, drying the resultant aggregates in a forced-air static dryer or in suspension in a fluidized air bed. then crumbling and screening to the desired size;
- rapid wet granulation, based on a process of wetting, kneading and sizing the aggregates in apparatus with high speed homogenization Lj !
systems, then drying and screening;
- wet granulation as heretofore described, followed by extrusion and spherodization to improve the morphology of the granules to be coated, then drying and screening.
When the medicament-loaded polymer powder or its granulate has been obtained, it is coated by suspending a weighed quantity of the powder or granulate in a hot air stream within the drum of a fluidized bed apparatus equipped with a Wurster insert and a binary nozzle. The air flow is such as to maintain a continuous change of suspended powder in am the region in which the solution or suspension of coating polymer is sprayed. The polymer dispersion (or solution) is fed with a peristaltic pump. The quantity of filming agent sprayed per unit time and the total quantity, the atomization pressure, the nozzle size, the temperature and the air volume used in executing a cycle depend on the quantity, the dimensions of the product to be coated and the extent of the controlled release to be obtained.
On termination of spraying, the product ~s dried directly in the Fluidized bed or in a forced-air oven. If necessary, an anti-adhesion agent can be added to the product to ensure separation of xhe film coated particles.
Examples of water-insaluble but water-swellable crosslinked polymers which can be used are:
- crosslinked polyvinylpyrrolidone (abbreviated to crospovidone), as described in National Formulary, Supplement 3, page 36$;
~5 - crosslinked sodium carboxymethylcellulose, as described in National Formulary, Supplement 3, page 367;
- crosslinked ~-cyclodextrin polymer, as described in patent WO
83/00809 and by Fenyvest et al. in Pharmazie 39. X73. 1984;
- crosslinked dextran, etc.
Of particular interest is the use of crosslinked ~-cyclodextrin polymer, which up to now has been used only as a disintegrator for solid pharmaceutical compositions and not as a support for medicaments, and the use of crospovidone.
It should however be noted that according to the present invention any polymer having the following characteristics can be used:
- a hydrophilic polymer lattice which results in considerable swellability in water - . water-insolubility by virtue of the nature of the polymer lattice.
Non-limiting examples of linear polymers which can be deposited as coating films on the particles of crosslinked polymer previously loaded with the medicament are:
Z5 - cellulose and derivatives soluble or insoluble in aqueous solutions, such as: ethylcellulose, . methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose acetate, cellulose acetobutyrate, cellulose acetotrimellitate, cellulose acetophthalate etc.
2p acrylic and methacrylic polymers and their copolymers soluble or insoluble in aqueous solutions such as: methacrylic acid-methylmethacrylate copolymer, ethylacrylate-methylmethacrylate copolymer, ethylacrylate°methylmethacrylate and trimethylammonium ethylmethacrylate chloride copolymer etc.
25 ° linear polyvinylpyrrolidone of differing molecular weight, vinylpyrrolidone-vinyl acetate copolymer etc.
- polyanhydrides such as vinylether-malefic anhydride copolymer - polyvinylalcohol.
It should however be noted that according to the present invention any polymer having the following characteristics can be used:
- insolubility at all pH values s - solubility only at determined pH values (eg. 4.5, 5.5, 6.0, ;.o) - solubility at all pH values.
The aforesaid polymers can be used either alone or in mixture, with the addition of suitable plasticizers such as glycerin, polyethyleneglycols, citric acid esters, glycerin esters, phthalic acid esters etc.; of anti-adhesion substances such as talc, silica, magnesium stearate etc.; or of porogenic substances such as microcrystalline lactose, calcium carbonate, calcium phosphate, saccharose, sodium chloride, potassium chloride etc.
There are no particular limitations to the medicaments which can be used according to the present invention, and in fact either water-soluble medicament or medicaments poorly soluble in water can be used. -Non-limiting examples of medicaments poorly soluble in water which can be used according to the present invention are: griseofulvin, indomethacin, diacerein, megestrol acetate, estradiol, progesterone, medroxyprogesterone acetate, nifedipine, nicergoline, paracetamol, clonidine, etoposide, lorazepam, temazepam, digoxin, glibenclamide ketoprofen, indobufen, ibuprofen, diclofenac, naproxene. acemethacine etc.
In the case of water-soluble medicaments, the main advantage of the 2~ present invention is that their incorporation into the spherical particles of the water-insoluble crosslinked palymer Facilitates the subsequent coating with polymer film. In this respect, in many cases the original morphology of said medicaments is very irregular (needles, very thin flakes etc.) and makes homogeneous and continuous coating of the particles over their entire surface difficult, with consequent poor control of the medicament release. In the particular case of insoluble 5 medicaments in the form of weak acid salts of strong bases one advantage of the present invention is that their incorporation into the insoluble crosslinked polymer provides them with greater protection against the surrounding pH-variable environment in the different segments of the intestinal tract, this variable pH being able to 10 influence the degree of ionization of the medicament and consequently its permeation characteristics. In order to control this ionization, the insoluble crosslinked polymer can also be loaded with agents able to suitably change the pH within the crosslinked polymer itself.
Non-limiting examples of water-soluble medicaments which can be used according to the present invention are: diltiazem hydrochloride, nicardipine hydrochloride, sodium chloride, captopril, enalapril, theophylline, ranitidine, verapamil hydrochloride, naproxene sodium salt, diclofenac sodium salt, propranolol, atenolol, sodium monofluorophosphate.
600 g of CROSPOVIDONE (Kollidon*CL, BASF) were loaded with 120 g of griseofulvin dissolved in 1.2 litres of methylenechloride in a chamber of a sigma mixer under continuous mixing. The thus swollen powder was dried in the same chamber at ambient temperature, at a residual pressure of 450-500 mbar; drying was completed in an oven under vacuum for 1 hour at 30~C.
'700 g of the powdered polymer loaded with griseofulvin in the aforesaid *Trade-mark manner were mixed with 35 g of talc F.U. and 3.5 g of Aerosil 200 and were suspended in a 6" Wurster column of a GPCG1 fluidised bed plant and coated with '700 g of colloidal suspension of acrylic polymer EUDRAGIT'~ RS 30D (ROEHM PHARMA) with added talc F.U., triethylcitrate plasticizer and Tween* 80 surfactant under the following operating conditions: atomization pressure 1-1.5 bar, feed rate of coating suspension 8-10 g/min, inlet air temperature 50~C, product temperature 22-25'C.
On termination of spraying, drying was carried out at the same inlet air temperature. The thus coated powder had the following percentage composition:
Griseofulvin 12.91 PVP CL 64.28 EUDRAGIT RS 8.11 TALC F.U. 12.68 CITROFLEX 2 1.63 TWEEN 80 0.01 Si02 p,3g 100.00 120 g of griseofulvin dissolved in 1.2 litres of methylene chloride were loaded onto 600 g of crospovidone (kollidon CL, BASF) kept under continuous mixing in a suitably sized sigma mixer. The thus swollen powder was dried in the same apparatus under vacuum (450-500 mbar of residual pressure) at ambient temperature. Drying was complete in an oven under vacuum for 1 hour at 30~C.
'700 g of the powdered polymer loaded with griseofulvin in the aforesaid *Trade-mark manner were mixed with 35 g of talc F.U. and 3.5 g of Aerosil 200 and were suspended in a 6" Wurster column of a GPCG1 fluidised bed plant (GLATT, West Germany) and coated with 1050 g of colloidal suspension of acrylic polymer Eudragit RS 30D (ROEHM PHARMA) with added talc F.U. -(anti-adhesion agent), triethylcitrate (plasticizer) and Tween 80 under the following operating conditions: atomization pressure 1-1.5 bar, feed rate of coating suspension 8-10 g/min, air volume during process 2-3 m3/min, inlet air temperature 50'C, product temperature 22-25'C.
On termination of spraying, drying was carried out at the same inlet air temperature and volume. The thus coated powder had the following percentage composition:
Griseofulvin 11.77 PVP CL 58.67 EUDRAGIT RS 11.33 TALC F.U. 15.60 CITROFLEX 2 2.26 TWEEN 80 0.02 Si02 ~ . 0.35 100.00 250 g of diacerein were activated by high-energy grinding with 250 g of povidone (Kollidon CL-M, BASF). 500 g of a mixture of excipients (30%
lactose, 40% microcrystalline cellulose and 30% corn starch) were added to the 500 g of co-ground product and the resultant mixture was wet-granulated using a 5% solution of hydroxypropylcellulose in water as binder. The mixture was wet-screened and dried in a fluidized bed (GPCG1 Glatt, West Germany) under the following operating conditions:
inlet air temperature 55~C, inlet air volume 1-1.5 m3/min. The product ~~~~.fl was then dry-screened in an oscillating granulator. 2 g of granulate prepared as described were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 160 g of colloidal suspension of acrylic polymer Eudragit NE 30D (ROEHM PHARMA) with added talc F.U. (anti-adhesion agent), under the following operating conditions: atomization pressure 1-1.5 bar, feed rate of coating suspension 2-3 g/min, inlet air temperature 30-40~C, product temperature 25-30'C, air volume during process 1.5-2 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume. The thus coated granulate had the following percentage composition:
Diacerein 21.45 PVP CL 21.45 EUDRAGIT NE 8.80 LACTOSE 12.83 MICROCRYSTALLINE CELLULOSE 17.14 HYDROXYPROPYLCELLULOSE 2.20 CORN STARCH 12.83 TALC F.U. ~~
100.00 500 g of granulate obtained as described in Example 3 (particle size distribution 300°800 um) were suspended in a 6" Wurster column of a GPCG1 fluidised bed plant ~(Glatt, West Germany) and coated with 560 g of colloidal suspension of acrylic polymer Eudragit RS 30D (ROEHhi PHARMA) with added talc F.U. (anti-adhesion agent), triethylcitrate (plasticizer) and Tween 80 under the following operating conditions:
i4 atomization pressure 1.5 bar, feed rate of coating suspension 10-12 g/min, air volume during process 2-3 m3/min, inlet air temperature 50- ' 60°C, product temperature 30-35°C. On termination of spraying, drying was carried out at the same inlet air temperature and volume. The thus coated granulate had the following percentage composition:
Diacerein 19.68 PVP CL 19.68 EUDRAGIT RS 12.09 LACTOSE 11.78 MICROCRYSTALLINE CELLULOSE 15.72 HYDROXYPROPYLCELLULOSE 2.01 .
CORN STARCH 11.78 TALC F.U. 4.83 TRIETHYLCITRATE 2.41 TWEEN 80 0.02 100.00 200 g of granulate prepared as described in Example 3 were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 125 g of colloidal suspension of Eudragit RS
30D and Eudragit RL 30D acrylic polymer with added talc F.U. (anti-adhesion agent), triethylcitrate (plasticizer) and Tween 80 under the following operating conditions: atomization pressure 1-1.5 bar, feed rate of coating suspension 2.5-5 g/min, inlet air temperature 55-60°C, product temperature 30-32°C, air volume during process 1-1.5 m3/min.
On termination of spraying, drying was carried out at the same inlet air temperature and volume. The thus coated granulate had the following percentage composition:
Diacerein 21.78 PVP CL 21.78 EUDRAGIT RS 3.35 LACTOSE 13.04 CELLULOSE 17.41 HYDROXYPROPYLCELLULOSE 2.23 CORN STARCH 13.04 TALC F.U. 2.67 TRIETHYLCITRATE 1.34 TWEEN 80~ . 0.01 100.00 200 g of granulate prepared as described in Example 3 were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 1000 g of a 10$ solution of Eudragit L100 acrylic polymer in a mixture composed of 6 parts of ethanol and 4 parts of deionized water with added talc F.U. (anti-adhesion agent) and n dibutylphthalate (plasticizes) under the followfng operating z0 conditions: atomization pressure 1 bar, feed rate of coating suspension 2-b g/min, inlet air temperature 40-45°C, product temperature 30-35~C, air volume during process 1.5-2 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume.
The thus coated granulate had the following percentage composition:
Diacerein 14.78 PVP CL 14.78 EUDRAGIT L 30~30 LACTOSE 8.84 zs CELLULOSE 11.82 HYDROXYPROPYLCELLULOSE 1.52 CORN STARCH 8.84 TALC F . U . 3 . 0~1 N-DIBUTYLPHTHALATE 6.08 100.00 45 g of nifedipine dissolved in 450 ec of methylene chloride were loaded onto 225 g of povidone (Kollidon CL-M, BASF) kept under constant stirring in a sigma mixer. After homogenization of the pasty mass the swelling solvent was extracted by a vacuum pump at a residual pressure of 450-500 mbar. After evaporation and recovery of the methylene chloride the loaded product was collected and drying completed in a vacuum oven (1 hour at 30~C).
The 270 g of prepared product were returned to the mixing chamber of the sigma mixer and exposed to methylene chloride vapour for 24 hours.
This operation was followed by drying in an oven, screening and homogenization by mixing the product. Colloidal silica (Aerosil 200, Degussa) was added to the final loaded product, which was then divided into flat tablets of l5 mm diameter weighing 500 mg and having a hardness of 7-10 Kp. These tablets were then reduced to granules with an oscillating granulator (or knife mill) . The 425-1200 um granulate fraction was removed by screening.
200 g of the granulate prepared as aforedescribed were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 1330 g of a solution of Eudragit S100 acrylic polymer (ROEHM PHARMA)in ethanol/H20 (80/20) with added talc F.U. (anti adhesion agent) and n-dibutylphthalate (plasticizer) under the following operating conditions: atomization pressure 1-1.5 bar, feed rate of coating suspension 3.5-5 g/min, inlet air temperature 3$-40'c, product temperature 30-32'C, air volume during process 1.5-2.5 m3/min.
On termination of spraying, drying was carried out at the same inlet air temperature and volume. The thus coated granulate had the following percentage composition:
Nifedipine 10 PvP cL 50 COLLOIDAL SILICA 0.61 to EUDRAGIT S 30.3 N-DIBUTYLPHT'HALATE 3.03 TALC F.U. 6.06 100.00 200 g of granulate prepared as described in Example 7 were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 833 g of colloidal suspension of Eudragit L30D
acrylic polymer (ROEHM PHARMA) with added talc F.U. (anti-adhesion agent), n-dibutylphthalate (plastieizer) and Tween $0 under the following operating conditions: atomization pressure 1-1.5 bar, Feed rate of coating suspension 3-5 g/mi.n, ' inlet air temperature 48-52'C, product temperature 30-34'C, air volume during process 1.5-2.5 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume. The thus coated granulate had the following percentage composition:
Nifedipine 10 i8 EUDRAGIT L30D 30.3 COLLOIDAL SILICA 0.61 N-DIBUTYLPHTFiALATE 3 . 0 TALC F.U. 6.06 TWEEN 80 _ 003 100.00 200 g of granulate prepared as described in Example ~ were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 525 g of solution of Povidone (Kollidon 25, BASF) in ethanol with added talc F.U. (anti-adhesion agent) and glycerin (plasticizes) under the following operating conditions:
spraying pressure 1 bar, feed rate of coating suspension 4.5-6 g/min, inlet air temperature 30-34'C, product temperature 28-30'C, air volume during process 1.5-2 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume. 215 g of this coated granulate were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 285 g of colloidal suspension of ethylcellulose (Aquacoat ECD-30 FMC) with added talc F.U. (anti-adhesion agent), n-triethylcitrate (plasticizes) under the following operating conditions: atomization pressure 1-1.5 bar, feed rate of coating suspension 3.5-5.5 g/min, inlet air temperature 50-55'C, product temperature 30-35~C, air volume during process 1.5-2 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume. Percentage composition of final coated product:
Nifedipine 12.35 PVP CL 61.8 *Trade-mark Colloidal silica 0.~5 P1/P K25 5.14 Glycerin 0.4$
ETHYLCELLULOSE 14.98 TRIETHYLCITRATE 4.5 100:00 215 g of granulate coated as described in the first part of Example 9 were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 285 g of colloidal suspension of ethylcellulose (Aquacoat ECD-30 FMC) with added hydroxypropyl methylcellulose (Methocel E5, Dow Chemical) and triethylcitrate {plasticizer) under the following operating conditions: atomization pressure 1-1.5 bar, feed rate of coating suspension 4-8 g/min, inlet air temperature 50-55°C, product temperature 32-35°C, air volume during process 1.5-2 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume. The coated product was then discharged and lx of powdered talc F.U. added, after which it was placed in an oven at a temperature of 60°C for 2 hours. The thus coated granulate had the following percentage composition:
Nifedipine 12.35 PVP CL 61.5 Colloidal silica 0.75 PvP x25 5.14 GLYCERIN 0.~1 HYDROXYPROPYLMETHYLCELLULOSE 3.'7 ETHYLCELLULOSE 11.1 *Trade-mark TRIETHYLCITRATE 4.5 100.00 45 g of ketoprofen dissolved in 450 cc of methylene chloride were loaded onto 225 g of crosslinked ø-cyclodextrin (Ciclolab - Chinoin, Budapest) kept under constant stirring in a sigma mixer. After homogenization of the pasty mass the swelling solvent was extracted by a vacuum pump at a residual pressure of 450-500 mbar. After evaporation and recovery of the methylene chloride the loaded product was collected and drying completed in a vacuum oven (1 hour at 30'C).
The 2'j0 g of prepared product were then screened and homogenized by mixing. Colloidal silica (Aerosil 200, Degussa) and magnesium stearate were added to the final loaded product, which was then divided into flat tablets of 15 mm diameter weighing 500 mg. These tablets were then reduced to granules with a knife mill (or oscillating granulator).
The 425-1000 pm granulate fraction ss removed by screening.
200 g of the granulate prepared as described above were suspended in a 4'° Wurster column of a GPCGl fluidised bed plant (Glatt, West Germany) and coated with 525 g of solution of Povidone (Kollidon 25, BASF) in ethanol with added talc F.U. (anti-adhesion agent) and glycerin (plasticizes) under the following operating conditions: spraying pressure 1 bar, feed rate of coating suspension 4.5-6 g/min, inlet air temperature 30-34'C, product temperature 28-30'C, air volume during process 1.5-2.5 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume.
215 g of this coated granulate were suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, West Germany) and coated with 285 g of colloidal suspension of ethylcellulose (Aquacoat ECD-30 FMC) with added triethylcitrate (plasticizes) under the following operating conditions: spraying pressure 1-1.5 bar, feed rate of coating suspension 3.5-5.5 g/min, inlet air temperature 50-55'C, product temperature 30-35'C, air volume during process 1.5-2 m3/min. On termination of spraying, drying was carried out at the same inlet air temperature and volume. Percentage composition of final coated product:
Ketoprofen 12.35 Crosslinked ~-cyclodextrin 61.8 Colloidal silica 0.37 Magnesium stearate 0.37 PvP x25 5.15 Glycerin 0.48 Ethylcellulose 14.98 100.00 293 g of diltiazem hydrochloride are activated by high-energy co-grinding with 147g of PVP Cl using a ball mill.
The duration of the grinding cycle is 2 hours at the maximum speed of the mill.
424 g of 2:1 co-ground diltiazem/PVP CL are granulated in a fluidized be.d (Glatt GPCG1 W.G.) using a binding polymer granulating dispersion.
208 g of the obtained granulate are formulated as follows:
z5 Granulated diltiazem 208 g Magnesium stearate 4.5 g Micronized talc 1 g Avicel PH 102 38 a 251.5 g and the mixture is pressed using an automatic rotary press. The tablets obtained are granulated in a VIANI oscillating granulator through a screen of 1.3 mm mesh.
' 225 g of granulate prepared as described are suspended in a 4" Wurster column of a GPCG1 fluidised bed plant (Glatt, W.G.) and coated to the extent of l0~ with 301.6 g of an alcoholic solution of Eudragit RS PM
acrylic polymer (Rdhm Pharma) using the following formulation for the coating:
Eudragit RS PM 22.5 g Micronized talc 4.48 g Citroflex 2 4.48 g 96x ethanol 270.16 g 1S This first coating is' applied to the extent of lOx by weight of the granulate, under the following operating conditions:
atomization pressure 1 bar feed rate of casting suspension 5.6 g/min air inlet temperature 30~C
product temperature 25'C
230 g of the granulate previously coated with lOx of Eudragit RS PM are suspended in the previously used 4" Wurster column and coated with 182 g of a Eudragit NE 30D polymer suspension.
' Film coating composition:
Eudragit NE 30D 76.64 g (23 dry) Micronized talc 7 g Water 98.37 g The total coating is therefore 20x. On completion of the coating procedure, rapid drying is effected under the same air conditions. The thus coated granulate had the following percentage composition:
Diltiazem HC1 3g, g5 PVP CL 19.49 Eudragit NE 30D 14.68 Eudragit RS PM ~,g0 Magnesium stearate 1.39 Micronized talc 4,55 Avicel PH 102 11.'7 Citroflex 2 1.54 TOTAL 100.00 For purposes of comparison the following compositions were prepared by simply loading the medicament onto the swellable hydrophilic polymer but without coating with the polymer film.
332 g of sodium monofluorophosphate dissolved in 2000 g of demineralized water were loaded on 1660 g of crospovidone (Kollidon CL, BASF), previously mixed with 166 g of povidone (Kollidon 25, BASF), in a sigma mixer under continuous mixing. The homogenized mixture was dried in a fluidized bed (Glatt GPCG 1) for 2 hours at a temperature of 60-~O~C and with an air velocity of 4-5 m/sec.
After sieving, the granular product having particle size 200-500 ~m was suspended in a 4" Wurster column of a GPCG 1 fluidized bed plant (Glatt, West Germany) and coated with 140 g of a lOx povidone solution in ethanol 95~ with added talc and glycerol under the following conditions: atomization pressure 1-1.5 bar; nozzle size 1 mm; Feed rate *Trade-mark of coating suspension 4-6 g/min; inlet air temperature 40-45~C; product temperature 25-30'C; flow of air 1.5-2 m3/min.
On termination of spraying, drying was carried out at the same inlet air temperature. The thus coated granular product had the following percentage composition:
Sodium monofluorophosphate 14.40 Kollidon CL 72 Kollidon 25 12.09 Talc 1.08 Glycerol 0 ~ 43 100.00 210 g of the granulate previously coated as described in example 13 are suspended in a 4" Wurster column of a GPCG 1 fluidized bed plant (Glatt, West Germany) and coated with 1000 g of a 6% Ethylcellulose (NF
22, Hercules) in methylene chloride/ethanol 80/20 with added micronized talc and dibutyl sebacate under the following conditions: atomization pressure 1 bar; nozzle size 1.2 mm; feed rate 5-8 g/min; inlet air temperature 40-42'C; product temperature 28-30~C; flow of air 1.5-2 m3/min.
On termination of spraying, drying was carried out at the same inlet air temperature. The thus coated granular product had the following percentage composition:
Sodium monofluorophosphate 10.02 Kollidon CL 50.12 Kollidon 25 8.42 Glycerin 0.30 Talc 5.66 Ethylcellulose 19.60 Dibutyl sebacate 5.88 100.00 EXAMPLE A
600 g of crospovidone (Kollidon CL, BASF) were loaded with 120 g of griseofulvin dissolved in 1.2 litres of methylene chloride in a chamber of a sigma mixer under continuous mixing. The thus swollen powder is dried in the same chamber at ambient temperature under a residual pressure of 450-500 mbar. Drying is completed in a vacuum oven for 1 hour at 30°C.
composition:
Griseofulvin 16.6 PVP CL _834 2G 100.0 EXAMPLE B
250 g of diacerein were activated by high-energy grinding with 250 g of crospovidone (Kollidon CL-M, BASF). 500 g of a mixture of excipients (30% lactose, 40% microcrystalline cellulose, 30% corn starch) were then added to the 500 g of co-ground product and the resultant mixture wet-granulated using a 5% hydroxypropyl cellulose solution in water as binder. The mixture was wet-screened and dried in a fluidized bed (GPCG1 Glatt, West Germany) under the following operating conditions: air inlet temperature SS°C, air inlet volume 1-l.Sm3/min. The product was then dry-screened in an oscillating granulator.
composition:
Diacerein 24.4 PVP CL 24.4 Cellulose 19.5 Corn starch 14.6 Lactose 14.6 Hydroxypropyl cellulose 2.5 100.00 EXAMPLE C
45g of nifedipine dissolved in 450 cc of inethylene chloride were loaded onto 225g of crospovidone (Kollidon CL-M, BASF) kept under constant stirring in a sigma mixer. After homogenization of the pasty mass the swelling solvent was extracted by a vacuum pump at a residual pressure of 450-500 mbar. After evaporation and recovery of the methylene chloride the loaded product was collected and drying completed in a vacuum oven (1 hour at 30°C).
The 270 g of prepared product were returned to the mixing chamber of the sigma mixer and exposed to methylene chloride vapour for 24 hours. This operation was followed by drying in an oven, screening and homogenization by mixing the product. Colloidal silica (Aerosil 200, Degussa) was added to the final loaded product, which was then divided into flat tablets of 1 Smm diameter weighing 500 mg and having a hardness of 7-10 Kp.
These tablets were then reduced to granules with an oscillating granulator (or knife mill). The 425-1200 pm granulate fraction was removed by screening.
26a composition:
Nifedipine 16.6 PVP CL 82.9 Colloidal silica 0.5 100.0 EXAMPLE D
293 g of diltiazem hydrochloride are activated by high-energy co-grinding with 147g of PVP CL using a ball mill. The duration of the grinding cycle is 2 hours at the maximum speed of the mill.
composition:
Diltiazem HCI 66.6 PVP CL 33.4 100.0 Determination of dissolution rate The dissolution data for the productions prepared by the process of this invention (Examples 1 to 14) are given in Tables 1-6. For comparison, each table also shows the dissolution rate data for the products prepared by simple loading onto the swellable hydrophilic polymer without subsequent coating with a polymer film (Examples A, B, C
and D).
The method used for all the studied medicaments, with exception of medicament of example 14, was the U.S.P. XXI No. 2 method using the SOTAX apparatus at 37°C and a Beckman Du 65 spectrophotometer.
For the products containing griseofulvin 900 nil of pH 7.5 buffer were used with stirring at 150 r.p.m. The spectrophotometric reading of the suitably diluted samples was performed at a = 294 nm.
For the products containing diacerein 900 ml of pH 5.5 buffer were used ~~~'~_~~.~
with stirring at 100 r.p.m. The spectrophotometric reading of the suitably diluted samples was performed at a = 255 nm.
For the products containing nifedipine 900 ml of pH 7.5, pH 4.6 and pH
5.5 buffer with and without Tween 80 as surfactant were used with stirring at 150 r.p.m. The spectrophotometric reading of the suitably diluted samples was performed at a = 235 nm.
For the products containing diltiazem 900 ml of pH 7.5, pH 5.5 and pH
1.2 buffer were used with stirring at 100 r.p.m. The spectrophotometric reading of the suitably diluted samples was performed at a = 233 nm.
The dissolution rate of the product containing sodium monofluorophosphate (example 14) was determined by the method U.S.P.
XXII No. 2 using the SOTAX apparatus at 37'C.
500 ml of deionized ultrapurified water with stirring at 100 r.p.m.
were used.
The reading of the samples was performed by potentiometric route after enzimatic digestion for obtaining the transformation in fluoride ion and after correction of ionic force.
As can be seen from the data of Tables 1-6, for all the medicaments and all the coating polymers used, in every case there was a clearly more delayed and controlled dissolution rate for the products prepared by the process of this invention than for the analogous products prepared exclusively by loading onto the swellable hydrophilic polymer.
Table 4 also shows the release at different pH values for nifedipine from particles of crosslinked polyvinylpyrrolidone coated with acrylic polymer of pH~dependent solubility. It is evidently possible with the product of the present invention to obtain release rates which differ greatly with pH.
Dissolution rate of products containing griseofulvin loaded onto crospovidone and coated with acrylic polymer:
TIME % GRISEOFULVIN RELEASED
Comparison Invention Invention preparation preparation preparation (EXAMPLE A) (EXAMPLE 1) (EXAMPLE 2) min 4'7.6% 16.2% 22.2%
1a 30 min 65.7% 26.3% 30.3%
6o min 83.8% 38.9% 41.5%
120 min 55.9% 54.2%
180 min 69.3% 68.5%
240 min ~6.b% 74.0%
15 360 min 80.2%
480 min 88.2% 81,2%
600 min 96.0% 85.6%
89.9%
720 min Dissolution of productscontaining loaded onto rate diacerein crospovidone and coated with acrylic polymer:
TIME % DIACEREIRi RELEASED
Comparison Invention InventionInventionInvention preparationpreparationpreparationpreparationpreparation (EXAMPLE (EXAMPLE (EXAMPLE(EXAMPLE (EXAMPLE
B) 3) 4) 5) 6) min 83.4% 5.4% 33% ~.9% 3.5%
30 min 94.6% 7.2% 4.2% 18.3% 5.3%
10 60 min 100.7% 12.9% 4.9% 31.4% 12.9%
120 min 22.6% 7.9% 47.8% 32.4%
180 min 29.1% 10:8% 60.6% 51.0%
240 min 36.2% 12.7% 64.4% 66.6%
360 min 44:1% 15.9% 71.5% 81.3%
is 420 min 45.5% 17.0% 75.2% 90.4%
480 min 48.5% 19.8x 79: z% 93.0%
540 min 49.4% 21.z% 82.4% .
600 min 51.3% 83.6%
X20 min 5 8:2%
C~ 'I ~ ~ '~
Dissolution rate of products containing nifedipine loaded onto crospovidone and coated with acrylic polymersand cellulose derivati ves:
5 TIME % NIFEDIPINE
RELEASED
Comparison Invention Invention Invention preparation preparationpreparation preparation (EXAMPLEC) (EXAMPLE (EXAMPLE 9) (EXAMPLE 10) 8) pH 7.5 pH 4:6 pH pH 7.5 + 1% 80 PH 7.5 +
'7.5 tween 10 1% tween 80 15 min 64.8% 80.0% 12.1% 34.4%
.
30 min 87.5% 30.0% 98.9% 13.0% 49.4%
60 min 104.8% 33.0% 13.2% 54.3%
120 min 36.1% 15.5% 58.6%
15 180 min 105.0% 16.4% 61.2%
300 min 41.2%
71.0%
360 min 22'. 4%
420 min 42:6% 75.1%
Influence of pH on dissolution rate of products containing nifedipine loaded onto crospovidone and coated v~ith acrylic polymer of pH-dependent solubility TIME ~ NIFEDIPINE RELEASED
Comparison preparation Invention preparation (EXRMPLE C) (EXAMPLE 'j) pH '7.5 pH 5.5 pH 7.5 15 min 64 ~ 8,~ 1'7 . 2x 62 . 3x to 30 min 8~.5x 29.0 64.696 ~60 min 104.8x 38.2 90.5 120 min 38.6 108.0 ~~~r~~a 3~
Dissolution rate of productscontaining diltiazem hydrochloride loaded onto crospovidone with polymers:
and coated TIME % DILTIAZEM HC1 RELEASED
Comparison Invention preparation preparation (EXAMPLE D) (EXANfPLE 12) 1 min 86.9%
2 min 96.0% -3 min 96.8%
min 2.5%
60 min 3.2%
120 min 10.5%
240 min 25.x%
1,5 360 min 41.4%
480 min 61.0%
600 min 85:4%
Dissolution rate of product containing sodium nonofluorophosphate (hIFP) loaded onto crospovidone and coated with ethylcellulose TIME % MFP RELEASED (EXAMPLE 14) 60 min 57.83%
120 min 74.77%
240 min 83.06%
480 min 94.29°°
12 h 99.7
For the products containing diltiazem 900 ml of pH 7.5, pH 5.5 and pH
1.2 buffer were used with stirring at 100 r.p.m. The spectrophotometric reading of the suitably diluted samples was performed at a = 233 nm.
The dissolution rate of the product containing sodium monofluorophosphate (example 14) was determined by the method U.S.P.
XXII No. 2 using the SOTAX apparatus at 37'C.
500 ml of deionized ultrapurified water with stirring at 100 r.p.m.
were used.
The reading of the samples was performed by potentiometric route after enzimatic digestion for obtaining the transformation in fluoride ion and after correction of ionic force.
As can be seen from the data of Tables 1-6, for all the medicaments and all the coating polymers used, in every case there was a clearly more delayed and controlled dissolution rate for the products prepared by the process of this invention than for the analogous products prepared exclusively by loading onto the swellable hydrophilic polymer.
Table 4 also shows the release at different pH values for nifedipine from particles of crosslinked polyvinylpyrrolidone coated with acrylic polymer of pH~dependent solubility. It is evidently possible with the product of the present invention to obtain release rates which differ greatly with pH.
Dissolution rate of products containing griseofulvin loaded onto crospovidone and coated with acrylic polymer:
TIME % GRISEOFULVIN RELEASED
Comparison Invention Invention preparation preparation preparation (EXAMPLE A) (EXAMPLE 1) (EXAMPLE 2) min 4'7.6% 16.2% 22.2%
1a 30 min 65.7% 26.3% 30.3%
6o min 83.8% 38.9% 41.5%
120 min 55.9% 54.2%
180 min 69.3% 68.5%
240 min ~6.b% 74.0%
15 360 min 80.2%
480 min 88.2% 81,2%
600 min 96.0% 85.6%
89.9%
720 min Dissolution of productscontaining loaded onto rate diacerein crospovidone and coated with acrylic polymer:
TIME % DIACEREIRi RELEASED
Comparison Invention InventionInventionInvention preparationpreparationpreparationpreparationpreparation (EXAMPLE (EXAMPLE (EXAMPLE(EXAMPLE (EXAMPLE
B) 3) 4) 5) 6) min 83.4% 5.4% 33% ~.9% 3.5%
30 min 94.6% 7.2% 4.2% 18.3% 5.3%
10 60 min 100.7% 12.9% 4.9% 31.4% 12.9%
120 min 22.6% 7.9% 47.8% 32.4%
180 min 29.1% 10:8% 60.6% 51.0%
240 min 36.2% 12.7% 64.4% 66.6%
360 min 44:1% 15.9% 71.5% 81.3%
is 420 min 45.5% 17.0% 75.2% 90.4%
480 min 48.5% 19.8x 79: z% 93.0%
540 min 49.4% 21.z% 82.4% .
600 min 51.3% 83.6%
X20 min 5 8:2%
C~ 'I ~ ~ '~
Dissolution rate of products containing nifedipine loaded onto crospovidone and coated with acrylic polymersand cellulose derivati ves:
5 TIME % NIFEDIPINE
RELEASED
Comparison Invention Invention Invention preparation preparationpreparation preparation (EXAMPLEC) (EXAMPLE (EXAMPLE 9) (EXAMPLE 10) 8) pH 7.5 pH 4:6 pH pH 7.5 + 1% 80 PH 7.5 +
'7.5 tween 10 1% tween 80 15 min 64.8% 80.0% 12.1% 34.4%
.
30 min 87.5% 30.0% 98.9% 13.0% 49.4%
60 min 104.8% 33.0% 13.2% 54.3%
120 min 36.1% 15.5% 58.6%
15 180 min 105.0% 16.4% 61.2%
300 min 41.2%
71.0%
360 min 22'. 4%
420 min 42:6% 75.1%
Influence of pH on dissolution rate of products containing nifedipine loaded onto crospovidone and coated v~ith acrylic polymer of pH-dependent solubility TIME ~ NIFEDIPINE RELEASED
Comparison preparation Invention preparation (EXRMPLE C) (EXAMPLE 'j) pH '7.5 pH 5.5 pH 7.5 15 min 64 ~ 8,~ 1'7 . 2x 62 . 3x to 30 min 8~.5x 29.0 64.696 ~60 min 104.8x 38.2 90.5 120 min 38.6 108.0 ~~~r~~a 3~
Dissolution rate of productscontaining diltiazem hydrochloride loaded onto crospovidone with polymers:
and coated TIME % DILTIAZEM HC1 RELEASED
Comparison Invention preparation preparation (EXAMPLE D) (EXANfPLE 12) 1 min 86.9%
2 min 96.0% -3 min 96.8%
min 2.5%
60 min 3.2%
120 min 10.5%
240 min 25.x%
1,5 360 min 41.4%
480 min 61.0%
600 min 85:4%
Dissolution rate of product containing sodium nonofluorophosphate (hIFP) loaded onto crospovidone and coated with ethylcellulose TIME % MFP RELEASED (EXAMPLE 14) 60 min 57.83%
120 min 74.77%
240 min 83.06%
480 min 94.29°°
12 h 99.7
Claims (23)
1. A process for preparing therapeutic compositions with controlled release of medicaments, the process comprising the following steps:
1) loading particles of at least one hydrophilic water-insoluble, but water-swelling, cross-linked polymer with a medicament, by swelling the cross-linked polymer with solutions of the medicament followed by drying, or by high-energy co-grinding;
1) loading particles of at least one hydrophilic water-insoluble, but water-swelling, cross-linked polymer with a medicament, by swelling the cross-linked polymer with solutions of the medicament followed by drying, or by high-energy co-grinding;
2) optionally size-enlarging the medicament-loaded particles by wet or dry granulation to form granules;
3) coating the medicament-loaded particles obtained from step 1 or the granules obtained from step 2 by suspending them in an air stream, spraying with a solution of a coating polymer, and then drying.
2. The process as claimed in claim 1, wherein step 1 is effected by any of the following methods:
1a) dissolving the medicament in a solvent, spraying a volume of the solution so obtained onto a given amount of the cross-linked polymer, and drying the product obtained;
1b) dissolving the medicament in a solvent and suspending the cross-linked polymer in an excess of the solution obtained, stirring the suspension until the polymer particles have swollen, recovering the product, and drying;
1c) homogeneously mixing the medicament and the cross-linked polymer, both in powder form, and co-grinding them in a high-energy apparatus;
1d) homogeneously mixing the medicament and the cross-linked polymer, both in powder form, and co-grinding them in a high-energy apparatus in which the grinding chamber is saturated with solvent vapor or subjected to a stream of vapor, the solvent being chosen from those able to swell the cross-linked polymer;
1e) homogeneously mixing the medicament and the cross-linked polymer, both in powder form, and co-heating to the medicament melting-point until the medicament has been absorbed by the polymer.
3. The process as claimed in claim 1 or 2, wherein step 3 is effected in a fluidized bed apparatus.
2. The process as claimed in claim 1, wherein step 1 is effected by any of the following methods:
1a) dissolving the medicament in a solvent, spraying a volume of the solution so obtained onto a given amount of the cross-linked polymer, and drying the product obtained;
1b) dissolving the medicament in a solvent and suspending the cross-linked polymer in an excess of the solution obtained, stirring the suspension until the polymer particles have swollen, recovering the product, and drying;
1c) homogeneously mixing the medicament and the cross-linked polymer, both in powder form, and co-grinding them in a high-energy apparatus;
1d) homogeneously mixing the medicament and the cross-linked polymer, both in powder form, and co-grinding them in a high-energy apparatus in which the grinding chamber is saturated with solvent vapor or subjected to a stream of vapor, the solvent being chosen from those able to swell the cross-linked polymer;
1e) homogeneously mixing the medicament and the cross-linked polymer, both in powder form, and co-heating to the medicament melting-point until the medicament has been absorbed by the polymer.
3. The process as claimed in claim 1 or 2, wherein step 3 is effected in a fluidized bed apparatus.
4. The process as claimed in claim 1, 2, or 3, wherein the weight ratio of the medicament to the cross-linked polymer is between 0.1 and 1000 parts by weight of medicament per 100 parts of polymer.
5. The process as claimed in claim 4, wherein the weight ratio of the medicament to the cross-linked polymer is between 10 and 100 parts by weight of medicament per 100 parts of polymer.
6. The process as claimed in any one of claims 1 to 5, wherein the cross-linked polymer is a mixture of cross-linked polymers.
7. The process as claimed in any one of claims 1 to 5, wherein the cross-linked polymer is crospovidone.
8. The process as claimed in any one of claims 1 to 5, wherein the cross-linked polymer is cross-linked .beta.-cyclodextrin.
9. The process as claimed in any one of claims 1 to 8, wherein the coating polymer consists of one or more linear polymers.
10. The process as claimed in any one of claims 1 to 9, wherein the medicament is selected from the group consisting of diltiazem hydrochloride, nicardipine hydrochloride, sodium chloride, captopril, enalapril, theophylline, ranitidine, verapamil hydrochloride, naproxene sodium salt, diclofenac sodium salt, propranolol, atenolol, and sodium monofluorophosphate.
11. The process as claimed in any one of claims 1 to 10, wherein the medicament is a poorly water-soluble one.
12. The process as claimed in any one of claims 1 to 10, wherein the medicament is a water-soluble one.
13. The process as claimed in any one of claims 1 to 12, wherein the loaded polymer particles obtained from step 1 have a size of between 1 and 200 µm.
14. The process as claimed in any one of claims 1 to 13, wherein the loaded polymer granules obtained from step 2 have a size of between 100 and 1000 Vim.
15. The process as claimed in any one of claims 1 to 14, wherein the coated polymer particles have a size of between 10 and 1500 Vim.
16. Controlled release compositions, obtainable by the process claimed in any one of claims 1 to 15.
17. Therapeutic compositions with controlled release of medicaments, consisting of particles of a hydrophilic, cross-linked, non-ionic polymer, insoluble but swellable in water, which particles are loaded with the medicament by swelling the particles with solutions of the medicament and which particles are coated with a polymer film.
18. Compositions as claimed in claim 17, wherein the cross-linked non-ionic polymer is a mixture of polymers.
19. Compositions as claimed in claim 17, wherein the cross-linked non-ionic polymer is crosslinked .beta.-cyclodextrin polymer.
20. Compositions as claimed in claim 17, wherein the cross-linked non-ionic polymer is crospovidone.
21. Compositions as claimed in claim 17, wherein the polymer coating film consists of one or more linear polymers.
22. Compositions as claimed in any one of claims 17 to 21, wherein the cross-linked non-ionic polymer particles have a size of between 1 and 200 µm.
23. Compositions as claimed in any one of claims 17 to 21, wherein the non-ionic polymer particles have a size of between 100 and 1000 µm.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT19571A/90 | 1990-03-06 | ||
| IT19571A IT1241417B (en) | 1990-03-06 | 1990-03-06 | THERAPEUTIC COMPOSITIONS WITH CONTROLLED RELEASE OF DRUGS SUPPORTED ON CROSS-LINKED POLYMERS AND COATED WITH POLYMER FILM, AND THEIR PREPARATION PROCESS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2037410A1 CA2037410A1 (en) | 1991-09-07 |
| CA2037410C true CA2037410C (en) | 2001-09-04 |
Family
ID=11159155
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002037410A Expired - Lifetime CA2037410C (en) | 1990-03-06 | 1991-03-01 | Therapeutic compositions with controlled release of medicaments supported on crosslinked polymers and coated with polymer films, and their preparation process |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US5275824A (en) |
| EP (1) | EP0446753B1 (en) |
| JP (1) | JP3240387B2 (en) |
| KR (1) | KR0175935B1 (en) |
| AT (1) | ATE114242T1 (en) |
| CA (1) | CA2037410C (en) |
| DE (1) | DE69105222T2 (en) |
| ES (1) | ES2067068T3 (en) |
| HU (1) | HUT59588A (en) |
| IT (1) | IT1241417B (en) |
| PL (1) | PL289322A1 (en) |
| RU (1) | RU2067859C1 (en) |
| YU (1) | YU34491A (en) |
Families Citing this family (84)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2572673B2 (en) * | 1990-07-25 | 1997-01-16 | エスエス製薬株式会社 | Sustained-release tablets |
| US5288505A (en) * | 1991-06-26 | 1994-02-22 | Galephar P.R., Inc., Ltd. | Extended release form of diltiazem |
| US6764697B1 (en) | 1991-06-27 | 2004-07-20 | Alza Corporation | System for delaying drug delivery up to seven hours |
| KR100221695B1 (en) * | 1991-08-12 | 1999-09-15 | 그린 마틴, 브라이언 쥐 테슬리 | Pharmaceutical spheroid formulation |
| GB2258613B (en) * | 1991-08-12 | 1996-01-10 | Euro Celtique Sa | Pharmaceutical diltiazem formulation |
| IT1252867B (en) * | 1991-12-31 | 1995-06-28 | Gentili Ist Spa | PHARMACEUTICAL COMPOSITIONS CONTAINING HIGH-BIOAVAILABILITY PROGESTERONE |
| US5262173A (en) * | 1992-03-02 | 1993-11-16 | American Cyanamid Company | Pulsatile once-a-day delivery systems for minocycline |
| DE4236090C1 (en) * | 1992-10-26 | 1994-01-05 | Asta Medica Arzneimittel | Pharmaceutical preparation for fluoride ion supply |
| RU2143896C1 (en) * | 1993-03-05 | 2000-01-10 | Хексаль Аг | Crystalline complex of cyclodextrin with ranitidin hydrochloride, method of preparation thereof, and pharmaceutical compositions containing thereof |
| GB9318880D0 (en) * | 1993-09-11 | 1993-10-27 | Smithkline Beecham Plc | Pharmaceutical composition |
| US5484607A (en) * | 1993-10-13 | 1996-01-16 | Horacek; H. Joseph | Extended release clonidine formulation |
| FR2711804B1 (en) * | 1993-10-22 | 1996-01-19 | Pf Medicament | Process for controlling the dissolution of dosage forms with modified release using a solid reagent and dose sachet containing such a reagent. |
| AT403988B (en) * | 1994-05-18 | 1998-07-27 | Lannacher Heilmittel | SOLID ORAL RETARDED PREPARATION |
| AU692565B2 (en) * | 1994-06-16 | 1998-06-11 | Pharmacia & Upjohn S.P.A. | Bioadhesive starches and process for their preparation |
| US5576311A (en) * | 1994-11-30 | 1996-11-19 | Pharmos Corporation | Cyclodextrins as suspending agents for pharmaceutical suspensions |
| AU4844796A (en) * | 1995-03-02 | 1996-09-18 | Takeda Chemical Industries Ltd. | A prolonged release composition, use and production thereof |
| JP3471977B2 (en) * | 1995-06-02 | 2003-12-02 | 信越化学工業株式会社 | Enteric preparations coated with solvent-free enteric coatings using liquid plasticizers |
| EP0761209A3 (en) * | 1995-09-01 | 1998-02-04 | J.B. Chemicals & Pharmaceuticals Ltd. | Controlled release formulations of ranitidine |
| US5773031A (en) * | 1996-02-27 | 1998-06-30 | L. Perrigo Company | Acetaminophen sustained-release formulation |
| HUP9600758A2 (en) * | 1996-03-27 | 1998-03-02 | Cyclolab Ciklodextrin Kutato F | Diclofenac composition of diminished gastrointestinal irritation and enhanced biological resorption |
| IT1282381B1 (en) * | 1996-04-29 | 1998-03-20 | Trans Bussan S A | NEW FORMULATIONS OF DIACEREIN, OBTAINED BY INCLUSION OF THE ACTIVE INGREDIENT IN HYDROGEL POLYSACCHARIDES |
| FR2757397B1 (en) * | 1996-12-23 | 1999-03-05 | Mazal Pharma | PHARMACEUTICAL COMPOSITION BASED ON RHEIN OR DIACERHEIN WITH IMPROVED BIOAVAILABILITY |
| US5891474A (en) | 1997-01-29 | 1999-04-06 | Poli Industria Chimica, S.P.A. | Time-specific controlled release dosage formulations and method of preparing same |
| US5788987A (en) * | 1997-01-29 | 1998-08-04 | Poli Industria Chimica Spa | Methods for treating early morning pathologies |
| WO1998044952A1 (en) | 1997-04-04 | 1998-10-15 | Monsanto Company | pH-SELECTIVE DELIVERY SYSTEM USING CROSS-LINKED POLYMERIC RESINS AS VEHICLES |
| AU6590598A (en) * | 1997-04-04 | 1998-10-30 | Monsanto Company | Hydrolysable delivery system using cross-linked polymeric resins as vehicles |
| US6890524B1 (en) | 1997-04-04 | 2005-05-10 | Monsanto Company | Hydrolyzable delivery system using cross-linked polymeric resins as vehicles |
| FR2766709B1 (en) * | 1997-07-31 | 2000-04-07 | Dominique Cingotti | METHOD FOR THE PREPARATION OF AN EXTRACT OF ACTIVE PRINCIPLES IN THE FORM OF MICROGRANULES BASED ON FULLY SOLUBLE DIETARY FIBERS INTENDED FOR DIFFERENT GALENIC FORMS |
| IT1298574B1 (en) * | 1998-02-06 | 2000-01-12 | Vectorpharma Int | PHARMACEUTICAL COMPOSITIONS IN THE FORM OF POLYMER-BASED MICROPARTICLES OBTAINED BY EXTRUSION AND SPHERONIZATION |
| UA65607C2 (en) | 1998-03-04 | 2004-04-15 | Орто-Макнейл Фармацевтикал, Інк. | Pharmaceutical composition (variants) and process for its preparation |
| US6048736A (en) * | 1998-04-29 | 2000-04-11 | Kosak; Kenneth M. | Cyclodextrin polymers for carrying and releasing drugs |
| US6509323B1 (en) | 1998-07-01 | 2003-01-21 | California Institute Of Technology | Linear cyclodextrin copolymers |
| US7091192B1 (en) | 1998-07-01 | 2006-08-15 | California Institute Of Technology | Linear cyclodextrin copolymers |
| FR2785539B1 (en) * | 1998-11-06 | 2004-04-09 | Prographarm Laboratoires | PARTICLES COATED WITH GRANULATED CRYSTALLINE IBUPROFENE |
| FR2792528A1 (en) * | 1999-04-22 | 2000-10-27 | Ethypharm Lab Prod Ethiques | Prolonged release ketoprofen microgranules giving a more even liberation with a lower initial peak of concentration in the plasma |
| WO2000071098A1 (en) * | 1999-05-24 | 2000-11-30 | Purepac Pharmaceutical Co. | A pharmaceutical composition containing an active agent that is maintained in solid amorphous form and method of making the same |
| US6555139B2 (en) | 1999-06-28 | 2003-04-29 | Wockhardt Europe Limited | Preparation of micron-size pharmaceutical particles by microfluidization |
| US6245913B1 (en) | 1999-06-30 | 2001-06-12 | Wockhardt Europe Limited | Synthetic procedure for 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-IH-benzimidazole hydrochloride and its conversion to omeprazole |
| KR20020062323A (en) | 1999-12-06 | 2002-07-25 | 펜웨스트 파머슈티칼즈 컴파니 | Pharmaceutical superdisintegrant |
| US20060153914A1 (en) * | 1999-12-10 | 2006-07-13 | Biovail Laboratories International S.R.L. | Chronotherapeutic diltiazem formulations and the administration thereof |
| US7108866B1 (en) | 1999-12-10 | 2006-09-19 | Biovall Laboratories International Srl | Chronotherapeutic diltiazem formulations and the administration thereof |
| JP2004529902A (en) * | 2001-03-13 | 2004-09-30 | ペンウェスト ファーマシューティカルズ カンパニー | Chronotherapeutic dosage forms containing glucocorticosteroids |
| KR20010069756A (en) * | 2001-05-08 | 2001-07-25 | 유형선 | Method for controlled release of acemetacin in the intestinal tract and more particularly in the colon |
| EP1269994A3 (en) * | 2001-06-22 | 2003-02-12 | Pfizer Products Inc. | Pharmaceutical compositions comprising drug and concentration-enhancing polymers |
| DK1414414T3 (en) * | 2001-06-29 | 2008-03-03 | Eurand Pharmaceuticals Ltd | Process for Thermodynamic Activation of Water-Insoluble Drugs With which Cross-linked Polymers Are Charged |
| DE60205491T2 (en) * | 2001-06-29 | 2006-06-01 | Eurand Pharmaceuticals Ltd. | METHOD FOR THE MEDICINAL ACTIVATION BY MEANS OF A SWORDING MILL |
| US7060498B1 (en) | 2001-11-28 | 2006-06-13 | Genta Salus Llc | Polycationic water soluble copolymer and method for transferring polyanionic macromolecules across biological barriers |
| JP3966459B2 (en) | 2002-05-23 | 2007-08-29 | 株式会社日立製作所 | Storage device management method, system, and program |
| CA2497792C (en) | 2002-09-06 | 2014-08-05 | Insert Therapeutics, Inc. | Cyclodextrin-based polymers for therapeutics delivery |
| DE10247037A1 (en) | 2002-10-09 | 2004-04-22 | Abbott Gmbh & Co. Kg | Solid, rapid release dosage form, especially for sparingly soluble drugs, obtained by forming and cooling softened, shapable mixture of crosslinked non-thermoplastic carrier, adjuvant and active agent |
| US20040132771A1 (en) * | 2002-12-20 | 2004-07-08 | Pfizer Inc | Compositions of choleseteryl ester transfer protein inhibitors and HMG-CoA reductase inhibitors |
| JP2006521300A (en) * | 2003-03-31 | 2006-09-21 | プリヴァ−ラケマ，エー．エス． | Pharmaceutical composition containing platinum complex as active substance and method for producing the same |
| US20050118267A1 (en) * | 2003-09-19 | 2005-06-02 | Penwest Pharmaceuticals Co. | Chronotherapeutic dosage forms |
| CN1882316A (en) * | 2003-09-19 | 2006-12-20 | 宾韦斯特医药公司 | Delayed release dosage forms |
| US7387793B2 (en) | 2003-11-14 | 2008-06-17 | Eurand, Inc. | Modified release dosage forms of skeletal muscle relaxants |
| CA2572928A1 (en) * | 2004-07-22 | 2006-02-26 | Amorepacific Corporation | Sustained-release preparations containing topiramate and the producing method thereof |
| US20070036859A1 (en) * | 2005-08-11 | 2007-02-15 | Perry Ronald L | Sustained release antihistamine and decongestant composition |
| WO2007096902A2 (en) * | 2006-02-23 | 2007-08-30 | Lupin Limited | Solid oral dosage forms of griseofulvin |
| JP5823093B2 (en) | 2006-03-28 | 2015-11-25 | ジャヴェリン ファーマシューティカルズ インコーポレイテッド | Low dose diclofenac and β-cyclodextrin formulation |
| US20080102128A1 (en) * | 2006-07-28 | 2008-05-01 | Flamel Technologies, Inc. | Modified-release microparticles based on amphiphilic copolymer and on active principles(s) and pharmaceutical formulations comprising them |
| KR20090051240A (en) * | 2006-09-01 | 2009-05-21 | 유에스브이 리미티드 | Process for the preparation of sevelamer hydrochloride and formulation thereof |
| US7964182B2 (en) * | 2006-09-01 | 2011-06-21 | USV, Ltd | Pharmaceutical compositions comprising phosphate-binding polymer |
| US20080176958A1 (en) | 2007-01-24 | 2008-07-24 | Insert Therapeutics, Inc. | Cyclodextrin-based polymers for therapeutics delivery |
| US20100172991A1 (en) * | 2007-06-08 | 2010-07-08 | Henry Joseph Horacek | Extended Release Formulation and Methods of Treating Adrenergic Dysregulation |
| AU2008261957A1 (en) * | 2007-06-08 | 2008-12-18 | Addrenex Pharmaceuticals, Inc. | Extended release formulation and method of treating adrenergic dysregulation |
| KR20100032863A (en) * | 2007-06-25 | 2010-03-26 | 엔싸이시브 파마슈티칼즈 인코퍼레이티드 | Formulations of n-(2-acetyl-4,6-dimethylphenyl)-3-{[(3,4 dimethyl-5-isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide |
| US20090024570A1 (en) * | 2007-07-20 | 2009-01-22 | Oracle Internatonal Corporation | User defined query rewrite mechanism |
| EP2471515A3 (en) | 2007-09-14 | 2012-12-26 | Wockhardt Limited | Rhein or diacerein compositions |
| CA2926563A1 (en) | 2007-09-27 | 2009-04-02 | Wockhardt Research Centre | Pharmaceutical compositions of rhein or diacerein |
| US20100285114A1 (en) * | 2007-09-27 | 2010-11-11 | Rahul Dabre | Pharmaceutical compositions of rhein or diacerein |
| AU2013200968B2 (en) * | 2007-09-27 | 2013-11-21 | Wockhardt Limited | Pharmaceutical compositions of rhein or diacerein |
| US8946277B2 (en) * | 2008-04-18 | 2015-02-03 | Warsaw Orthopedic, Inc. | Clonidine formulations in a biodegradable polymer carrier |
| TWI473610B (en) * | 2008-10-28 | 2015-02-21 | Twi Biotechnology Inc | Pharmaceutical compositions containing diacerein |
| WO2010086881A2 (en) * | 2009-01-22 | 2010-08-05 | Usv Limited | Pharmaceutical compositions comprising phosphate-binding polymer |
| JP6220126B2 (en) * | 2009-11-23 | 2017-10-25 | セルリアン・ファーマ・インコーポレイテッド | Polymers based on cyclodextrins for therapeutic delivery |
| IE20100799A1 (en) * | 2010-12-22 | 2012-08-01 | Eurand Pharmaceuticals Ltd | Pharmaceutical composites of poorly water soluble drugs and polymers |
| RU2648353C2 (en) * | 2011-06-01 | 2018-03-23 | Нитто Денко Корпорейшн | Particulate composition and process for obtaining it |
| US9452107B2 (en) | 2012-04-16 | 2016-09-27 | New Jersey Institute Of Technology | Systems and methods for superdisintegrant-based composite particles for dispersion and dissolution of agents |
| US20140094432A1 (en) | 2012-10-02 | 2014-04-03 | Cerulean Pharma Inc. | Methods and systems for polymer precipitation and generation of particles |
| US8999393B1 (en) | 2013-01-09 | 2015-04-07 | Edgemont Pharmaceuticals Llc | Sustained release formulations of lorazepam |
| CA3018328A1 (en) | 2014-10-31 | 2016-04-30 | Purdue Pharma | Methods and compositions particularly for treatment of attention deficit disorder |
| CA3012698A1 (en) * | 2016-02-05 | 2017-08-10 | Entrega Inc. | Oral dosage form with drying agent for delivery of active agent |
| ES2938609T3 (en) * | 2017-09-20 | 2023-04-13 | Tillotts Pharma Ag | Preparation of Solid Dosage Forms Comprising Antibodies by Solution/Suspension Layering |
| US10722473B2 (en) | 2018-11-19 | 2020-07-28 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1218102A (en) | 1968-03-15 | 1971-01-06 | Philips Nv | Improvements in medicaments comprising drug/ion-exchange resin compounds |
| DE2643004A1 (en) | 1975-09-25 | 1977-06-16 | Mitchell Beazley Encyclopedias | Data reception and indexing equipment - has units containing graphic details illustrations and index with reproductions |
| US4221778A (en) | 1979-01-08 | 1980-09-09 | Pennwalt Corporation | Prolonged release pharmaceutical preparations |
| HU189534B (en) | 1981-09-09 | 1986-07-28 | Chinoin Rt.,Hu | Process for producing new tablets containing cyclodextrin polymer as desintegrator |
| DE3270785D1 (en) | 1981-10-29 | 1986-05-28 | Bayer Ag | Process for preparing solid fast-releasing drug formulations of dihydropyridines |
| EP0147780A3 (en) | 1984-01-03 | 1987-03-11 | Merck & Co. Inc. | Drug delivery device |
| GB8403359D0 (en) | 1984-02-08 | 1984-03-14 | Erba Farmitalia | Pharmaceutical compositions |
| CA1236023A (en) | 1984-07-18 | 1988-05-03 | Yegnaswami Raghunathan | Controlled release pharmaceutical preparations |
| IE63321B1 (en) | 1986-02-03 | 1995-04-05 | Elan Corp Plc | Drug delivery system |
| ES2022454B3 (en) * | 1986-06-17 | 1991-12-01 | Recordati Ind Chimica E Farm S P A | THERAPEUTIC SYSTEM FOR THE CONTROLLED RELEASE OF DRUGS. |
| JPH0819004B2 (en) | 1986-12-26 | 1996-02-28 | 日清製粉株式会社 | Sustained-release pharmaceutical preparation |
| GB8705083D0 (en) * | 1987-03-04 | 1987-04-08 | Euro Celtique Sa | Spheroids |
| US4894239A (en) | 1987-06-02 | 1990-01-16 | Takeda Chemical Industries, Ltd. | Sustained-release preparation and production thereof |
| US4795644A (en) | 1987-08-03 | 1989-01-03 | Merck & Co., Inc. | Device for pH independent release of drugs through the Donnan-like influence of charged insoluble resins |
| IE63242B1 (en) * | 1988-06-24 | 1995-04-05 | Abbott Lab | Pharmaceutical granules and tablets made therefrom |
-
1990
- 1990-03-06 IT IT19571A patent/IT1241417B/en active IP Right Grant
- 1990-12-03 US US07/620,651 patent/US5275824A/en not_active Expired - Lifetime
-
1991
- 1991-02-27 YU YU34491A patent/YU34491A/en unknown
- 1991-03-01 CA CA002037410A patent/CA2037410C/en not_active Expired - Lifetime
- 1991-03-04 DE DE69105222T patent/DE69105222T2/en not_active Expired - Lifetime
- 1991-03-04 EP EP91103224A patent/EP0446753B1/en not_active Expired - Lifetime
- 1991-03-04 KR KR1019910003465A patent/KR0175935B1/en not_active IP Right Cessation
- 1991-03-04 AT AT91103224T patent/ATE114242T1/en not_active IP Right Cessation
- 1991-03-04 ES ES91103224T patent/ES2067068T3/en not_active Expired - Lifetime
- 1991-03-05 HU HU91707A patent/HUT59588A/en unknown
- 1991-03-06 PL PL28932291A patent/PL289322A1/en unknown
- 1991-03-06 RU SU4894969/14A patent/RU2067859C1/en not_active IP Right Cessation
- 1991-03-06 JP JP06373291A patent/JP3240387B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| PL289322A1 (en) | 1992-05-04 |
| IT9019571A0 (en) | 1990-03-06 |
| IT9019571A1 (en) | 1991-09-06 |
| YU34491A (en) | 1994-06-10 |
| DE69105222D1 (en) | 1995-01-05 |
| US5275824A (en) | 1994-01-04 |
| JP3240387B2 (en) | 2001-12-17 |
| IT1241417B (en) | 1994-01-14 |
| HUT59588A (en) | 1992-06-29 |
| DE69105222T2 (en) | 1995-04-06 |
| RU2067859C1 (en) | 1996-10-20 |
| KR910016320A (en) | 1991-11-05 |
| ES2067068T3 (en) | 1995-03-16 |
| ATE114242T1 (en) | 1994-12-15 |
| KR0175935B1 (en) | 1999-03-20 |
| HU910707D0 (en) | 1991-09-30 |
| JPH0769927A (en) | 1995-03-14 |
| CA2037410A1 (en) | 1991-09-07 |
| EP0446753B1 (en) | 1994-11-23 |
| EP0446753A1 (en) | 1991-09-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2037410C (en) | Therapeutic compositions with controlled release of medicaments supported on crosslinked polymers and coated with polymer films, and their preparation process | |
| JP4749639B2 (en) | Process for producing coated granules with masked taste and immediate release of active ingredients | |
| EP0237506B1 (en) | Pharmaceutical composition | |
| CA2281420C (en) | Preparation of pharmaceutically-active granules | |
| JP4652693B2 (en) | Sustained release coated particles and tablets containing them | |
| CZ2002672A3 (en) | Medicinal formulations for oral administration with retarded effect | |
| AU750617B2 (en) | Multiple unit controlled food effect-independent release pharmaceutical preparations and method for preparing the same | |
| JPH0733330B2 (en) | Stable solid preparation having elastic coating and method for producing the same | |
| EP0625353B1 (en) | Slow-release pharmaceutical composition containing a bile acid as an active ingredient | |
| US20030099710A1 (en) | Granule modulating hydrogel system | |
| CA2823622C (en) | Solid molecular dispersion of fesoterodine | |
| JPH10152440A (en) | Sustained release medicinal composition for oral administration containing nifedipine as active substance | |
| AU622254B2 (en) | Controlled-release, low dose aspirin | |
| JPWO2002034268A1 (en) | Sustained-release preparation containing 5-acetyl-4,6-dimethyl-2- [2- [4- (2-methoxyphenyl) piperazinyl] ethylamino] pyrimidine trihydrochloride as an active ingredient | |
| CN1232386A (en) | Colonic delivery of weak acid drugs | |
| US20040228918A1 (en) | Granule modulating hydrogel system | |
| US20100239681A1 (en) | Controlled Release Particulates Containing Water-Insoluble Drug | |
| EP1703900A1 (en) | Controlled release ketoprofen formulation | |
| JPH1160477A (en) | Preparation for sustained release of diclofenac sodium | |
| JPWO2003032998A1 (en) | Sustained release fine particles and method for producing the same | |
| JPH01172320A (en) | Spherical granular agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |