CA1304294C - Pharmaceutical preparations with extended release - Google Patents
Pharmaceutical preparations with extended releaseInfo
- Publication number
- CA1304294C CA1304294C CA000533985A CA533985A CA1304294C CA 1304294 C CA1304294 C CA 1304294C CA 000533985 A CA000533985 A CA 000533985A CA 533985 A CA533985 A CA 533985A CA 1304294 C CA1304294 C CA 1304294C
- Authority
- CA
- Canada
- Prior art keywords
- preparation according
- active compound
- solubilizer
- weight
- preparation
- 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
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
ABSTRACT
An extended release preparation of an active compound with very low solubility containing the active compound dissolved or dispersed in a semi-solid or liquid non-ionic solubilizer and whereby the amount by weight of the solubilizer is at least equal to the amount by weight of the active compound as well as a process for the preparation thereof.
An extended release preparation of an active compound with very low solubility containing the active compound dissolved or dispersed in a semi-solid or liquid non-ionic solubilizer and whereby the amount by weight of the solubilizer is at least equal to the amount by weight of the active compound as well as a process for the preparation thereof.
Description
~3~1~2~
N~W PHARMACEUTICAL PREPARATIONS WITH EXTENDE3 RELEASE
~ield of the Invention __ The present invention is related to pharmaceutical extended release preparations of active compounds with very low solubility, especially substituted dihydropyridines, and to methods of preparing such preparations.
The object of this invention is to obtain a solid preparation with high extent of bioavailability and extended release of an active compound which normally has ~ery low solubility.
Background of the Invention Pharmaceuticals with very poor water solubility present formulation problems due to their slow rate of dissolution.
Their efficacy can be severely limited and large interindividual variations of absorption can occur. Examples of drugs with very low solubility are some substituted dihydrcpyridine compounds such as nifedipine and felodipine. The mentioned dihydro-pyridines are commonly classified as calcium antagonists, which are widely used for the treatment of cardiovascular disorders such as ischaemic heart disease and arterial hypertension. One of the mentioned dihydropyridines, namely felodipine, has a solubility of only 0.5 mg/l in water. Other examples of drugs with very low solubility are griseofulvin, digoxin, oxazepam, phenytoin and cyclosporine.
Several ways to increase drug absorption have been described in the prior literature. One way is described in DE-A-3024858 published on January 22, 1981, where a sparingly ;~
~' ~3~
soluble substituted dihydropyridine, nicardipine, is used in its amorphous form in order to obtain increased absorption of the active compound ~rom the intestine. Another way is described in EP-A-47899 published on March 24, 1982, where very small crystals of a practically insoluble dihycLropyridine, nifedipine, have been used in order to increase the extent of the bioavailability. These methods and others are also described in "Techniques of solubilization of drugs", Ed S. H. Yalkowsky in Drugs and the pharmaceutical sciences t Vol. 12. Of particular relevance to the present invention is that surfactant solubilizing agents may be employed in order to increase the bioavailability of the drugs with very low solubility. It is sta~ed that the improvement of absorption properties can be ascribed to three processes: (1) increased wetting, (2~ increased permeability of membranes and ~31 solubilization. The cited publication describes several examples and serves as a good review of the state of the art concerning the solubilizing of drugs, especially in order to increase the bioavailability of drugs with very low solubility.
From DE-A~3~00106 published on July 11, 1985, controlled release preparations are known containing one or more natural, partially synthetic or synthetic polymers, one or more lipophilic and/or hydrophilic solvents or thickeners together with one or more pharmaceutically active compounds. In the examples it is described to use a solubilizer in an amount of weight to the active compound which is much less than 1:1.
In the medical treatment of various diseases, e.g. in ~3~2~
the cardiovascular, gastrointestinal and chemotherapeutic field, it is an advantage to have a constant concentration of the administered drug in the blood. Thus an extended release of the drug from the pharmaceutical preparation is wanted.
It is important that the extended release preparation delivers the amount of drugneeded ~ maintain an adequate and even effect during the entire therapeutic dosage interval. This usually means that the drug should be delivered at a constant rate to give an even concentration of administered drug in the blood. This is of specific importance for drugs having a small therapeutic index, that is a small difference between effective and toxic concentration. A delayed and constant release of the drug will also be of importance for locally irritating drugs having potential risk of causing gastrointestinal disturbances when present in large local concentrations or for drugs having a short elimination half-life. In the latter case a less frequent administration and thus better patient compliance tcf-Hayes R. s. et al. Clin.Pharm.Ther. (1977~, 22, p. 125-130~ may be obtained with extended release preparations compared with conventional dosage forms.
A drug in extended release form is generally given via the oral route. The preparations should preferably give an ; extended and reproducible release of drug and contribute to a reproducible absorption, have no toxic or irritating constituents and be suitable also for high dosage drugs. Conventionally, extended release is achieved by controlling dissolution and/or diffusion of medicament from the dosage form. Several materials ~3~2~
239~0-563 are employed for this purpose e.g. waxes, fatty materials, polymers, natural, synthetic and semisynthetic gums. Among the gums, hydroxypropyl methylcellulose (HPMC) constitutes an important class because of its pH-independent properties as well as its semisynthetic origin. A r~view of cellulose ethers in hydrophilic matrices for oral controlled release dosage forms is given by Alderman D. A. Int. J. Pharm. Tech. & Prod. Mfr. (1984), 5(3) 1-9. The chemical treatment of HPMC to generate a desired constitution and the use of these qualities are disclosed in U. S. 3,087,790, U. S. 4,226,849, U. S. 4,357,469 and U. S.
4,369,172. SE-A-8008646-5 published on June 10, 1981 describes a combination of HPMC and hydroxypropyl cellulose which is used to control the release rate of a pharmaceutically active compound.
When a hydrophilic matrix is used the soluble polymer forms a gelatinous layer around the tablet after the exposure of the tabletto gastro-intestinal fluids or saliva. The release of the drug is limited by the rate of water penetration into, and diffusion of drug through, the gel formed (Bamba et al. Int.
J. Pharm. (1979), 2, 307). Erosion of the gel structure is also an important release mechanism of a drug from the system.
; The polymers used have to hydrate rapidly in order to protect the tablet from fast dissolution (Alderman 1984).
The rate of absorption of a drug with very low solubility into the circulation from the intestinal tract is closely related to the rate of dissolution. Since a low dissolution rate ~enerally results in a low extent of bio-availability it is difficult to decrease the rate of absorption, A ~
~3~2~4L
3b i.e. increase the duration, without at the same time lowering the extent of bioavailability.
' 2~
4 ~3940-563 Description of the invention It is the object of the present inven-tion to provlde a pharmaceutical preparation of a drug with very low solubility ~hat shows prolonged and nearly conætant rate of drug absorption for a long period of time and concurrently ~aintains a high extent of bioavailability~ The object is reached b~ u in~ a solubilizer which is mixed with the drug with very low solubility. The solubilizers suitable according to the invention are deflned below. The active compound is pre~erably dissolved or dispersed in the solubilizer. the mixture of active compound (drug) and solubilizer can be diluted with water or intestinal juice without significant precipitation of the dlssolved drug. In the solution the drug is included in a mlcell-structure formed by the solubilizer. Wi~h o~her commonly used solubilizeræ or co-solvents dilution may cause precipltation o f the drug. The mixture o~ the drug and the solubilizer is incorporaked into a pharmaceutical ormulation, whlch give~ prolonged release.
Accordingly, in one aspect the present invention provides a solid pharmaceutical preparation with extended release of an active compound having a solubility less than 0.1 per cent by weight in water, characterized in that the active compound is diæsolved or dispersed in a se~1-solid or liquid non-ionlc solubillzer selected from the group consisting of esters and ethers of polyethyleneglycolæ and in that ~he a~ount by weight of the solubilizer is at leask equal to the amount by weight of the active compound.
.
~3~2~
4a 23940-563 In another aspect the invention provides a pxocess or preparing a solid pharmaceutical prep~ration with extended release of an active compound having a solubi ll~y less than 0.1 per cent by weight in w~ter, characterized in that the active compound is dissolved or dispersed in a semi~solld or liguid non-ionic solubllizer selected from the ~roup consisting of esters and ethers of polyethyleneglycols in at least equal amount by wei~ht to the active compound, whereafter the mixture is incorporated into a suitable release controllin~ systam and formed to a pharmaceutical dosage ~nit.
Vrugs suitable for the extended release preparation according to the invention are compounds characterized by their very low solubility, that is less than 0.1 per cent by welght in water. In addition they are solubllizable in a solu~ilizer or in a combination of a solubilizer and water. Examples of drugs suitable accordlng to the invention are some substituted dlhydropyridines, such as nifedipine and felodipine. Felodipine is 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ethyl methyl ester. Nifedipine is 1,4-dihydro-2,6-dimethyl-4-~2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethylester. Filodipine and nifedipine both are practically insoluble compounds and therefore they are very suitable to solubilize. Other examples of drug with very low solubility are grisieofulvin, digoxin, oxazepam, phenytoin and cyclosporine.
1~3 ~b 23940-563 The solubillzers suitable for the preparations accorclin~ to the invention are semi-solid or liquid non-ionic surface actlve agen~s, especially such containiny polyethyleneglycols as esters or ethers. They are preferably chosen from polyethoxylated fatt.y aclds, hydroxylated fatty acids and fatty alcohols. It is especially preferred to choo~e the ::) ~3~
sol~lbilizer from the group polyethoxylated castor oil, polyethoxylated hydrogenated castor oil, polyethoxylated fatty acid from castor oil or polyethoxylated fatty acid from hydrogenated castor oil. Commercially available solubilizers, which can be used are known under the trade names Cremophor, Myrj, Polyoxyl 40 stearate, Emerest 2675, Lipal 395 and HCO 50. A specially preferred solubilizer is Cremophor @~RH 40 (BASF).
The active compound mixed with the solubilizer is incorporated into different kinds of known controlled release systems, e.g. a hydrophilic gel systenl, beads coated with a rate controlling membrane, which can be a diffusion retarding coating or a disintegrating coating or tablets with an inert porous matrix. According to the inven~ion the solubilized drug is preferably combined with a hydrophilic gel system, namely a hydrophilic swelling matrix e.g. HPMC. This form of controlled release mechanism is a suitable way to control the release of the micelles of drug and solubilizer. The technical propert;es are good and also the performance in vivo is good. Among different hydrophilic materials tested, HP~C, hydroxypropyl methylcellulose, is the best gel-forming rnaterial. Other examples of suitable compounds effecting the release of the active compound from the hydrophilic gel system are guar gum, xanthan gum, carboxypolymethylene, different cellulosic materials e.g.
sodium carboxymethylcellulose and hydroxypropyl cellulose, lactose and aluminium silicate.
The preparation according to the invention contains 20-80% by weight, preferably 30-50% by weight oF the hydrophilic gel system.
The major part of the hydrophilic gel system has a viscosity below lDO cps. It is especially preferable ~o use HPM~ having a hydroxy-propoxyl content of 4-12% by weightg especially about 8.5% by ~eight and a viscosity lower than 100 cps, e.g. ~,15 and/or 50 cps. The viscosity ~ is measured by a standardized method described e.g. in United States ;~ Pharmacopeia XXI, 1985, p. 672.
The final preparation is e.g.in the form of a gel tablet~ By a careful choice of fillers and binders as well as ~el forming material the preparation can be manufactured into a commercially acceptable form, rl'd d ~
~3~42~
e.g. a tablet or a hard gelatin capsule comprising the gel forming granulate, that shows unexpectedly good absorption of the active compound as well as a prolonged duration of action. In the preparation according to the invention the proportions between the active compound S and the solubilizer varies in the range from 1:1 to 1:10, preferably in the range from 1:2 to 1:6.
Also other types of controlled release preparations may be used acsording to the invention e.g. tablets with an inert porous matrix;
capsules comprising granules with a diffusion retarding coating or a disintegrat;ng coating.
The tablets with an inert porous matrix are obtained by mixing the drug and the solubilizer with water insoluble polymers or waxes and with fillers and binders. Polyvinylacetate, polyvinylchloride, ethyl-cellulose, paraffin and cellulose acetate phthalate could be used as suitable diffusion-retarding polymers. The fillers and binders are solid, powdered carriers such as lactose, saccharose, sorbitol, ; mannitol, starch~ amylopectin, cellulose derivative9 gelatine or other suitable carrier. The mixture is moistened with a solvent, e.g. water or ethanol or a solution consisting of e.g. water and a polymer e.g.
polyvinylpyrrolidone. Also a lubricating agent e.g rnagnesium stearate7 calcium stearate, sodium stearyl fumarate and polyethyleneglycol wax may be added. The mixture is then formed to tablets.
The capsules comprising of granules with extended release character-istics are obtained by making a core material consisting of the drug and the solubilizer together with fillers. The surface of the core is then coated with diffusion-retarding water insoluble polymers or waxes. The granules are then filled into hard gelatine capsules. The core material could e.g. be prepared by mixing the drug and the solubili7er with carefully selected fillers such as lactose, sorbitol, starch, cellulose derivatives or other suitable fillers. The mixture is moistened with a solvent, e.g. water or ethanol or a solution consisting of e.g. water and a polymer e.g. polyvinylpyrrolidone. The mass is formed to granules e.g. by extrusion and spheronization. The surfaces of the cores formed are coated with a solution consisting of a solvent e.g. methylene "
~L3~2~3~
chloride and/or isopropyl alcohol and water insoluble polymers e.g.
ethylcellulose. The granules are filled in hard gelatine capsules.
Examples The following examples illustrate the invention:
Example 1 10 Felodipine 10 Cremophor RH 40 90 Calcium phosphate 250 Hydroxypropyl methylcellulose 2910 6 cps 250 Xanthan gum 25 Guar gum 25 Sodium stearyl fumarate 13 The composition according to Example 1 was formed to hydrophilic matrix tablets containing 10 mg o~ felodipine/tablet. The tablets were prepared in the following wayO
Felodipine was dissolved in Cremophor RH 40 and the solution obtained was carefully mixed with the carrier materials, HPMC, xanthan gum, guar gum and calcium phosphate~ The mixture was granulated with ethanol and dried. Sodium stearyl fumarate was added as a lubricant and tablets were prepared by compression in a tabletting machine.
Example 2 30 Felodipine 10 Cremophor RH 60 go Aluminium silicate 100 ~; Paraffin 80 Hydroxypropyl cellulose 7.4 35 Sodium stearyl fumarate 5.0 ;
., ~3~
The composition according to Example 2 was formed to controlled release tablets, inert porous matrix type, containing 10 mg of telodipine/
tablet. The tablets were prepared in the following way:
Felodipine was dissolved in Cremophor RH 60 and the solution obtained was mixed carefully with the carrier materials aluminium silicate and paraffin. The mixture was granulated with a solution of hydroxypropyl cellulose in ethanol and dried. Sodium stearyl fumarate was added as a lubricant and tablets were prepared by compression in a tabletting machine. A controlled release of felodipine was achieved according to the in vitro resultsg 50% released after 2 hours and 100~ released after 6 hours.
Example 3 Felodipine 20 Cremophor RH 40 100 Polyvinylpyrrolidone 66.5 Cellulose, microcrystalline 62 20 Maize starch 29.5 Lactose 157 Ethylcellulose 36 Hydroxypropyl methylcellulose 2910 6 cps 12 Gelatin capsules The composition according to Example 3 was formed to controlled release capsules containing 20 mg of felodipine/capsule. The capsules were prepared in the following way:
Felodipine was dissolved in Cremophor and the solution obtained was mixed carefully with the carrier, polyvinylpyrrolidone, cellulose, maize starch and lactose. The mixture was moistened with water and spheronized. The granules obtained were dried and sieved, the fraction 0.71-1.12 mm was used. The cores were coated with ethylcellulose dissolved in a mixture of methylene chloride and ethanol. The coated granules were filled into hard gelatine capsules.
~3~
Example 4 Felodipine 20 Myrj 51 120 Hydroxypropyl methylcellulose 2910 50 cps 200 Cellulose~ microcrystalline 20 Lactose 167 Sodium stearyl fulnarate 10.5 The composition according to Example 4 was formed to controlled release tablets containing 20 mg of felod;pine/tablet. The tablets were prepared in the same way as described in Example 1.
Example 5 9_ Nifedipine 20 Cremophor RH 40 50 Hydroxypropyl methylcellulose 2910 50 cps 70 Hydroxypropyl methylcellulose 2910 6 cps 160 20 Cellulose microcrystalline 6 Lactose 56 Aluminium silicate 94 Sodium stearyl fumarate 10 The composition according to Example 5 was formed to hydrophilic matrix tablets containing 20 mg of nifedipine/tablet. The tablets were prepared in the same way as described in Example 1.
: The best mode of carrying out the inventiQn is at present considered to be Example 5.
~3~2~
. , .
Reference Example A
The following example i11ustrates the reference tablet used in in vivo studies g Felodipine 25 Lactose 250 Methylcellulose 0.5 10 Polyvinylpyrrolidone 1.5 Magnesium stearate 3 The composition according to reference Example A was formed to fast-dissolving, conventional tablets containing 25 mg of felodipine/tablet.
The tablets were prepared in the following way:
Felodipine was m;cronized and mixed with lactose and methylcellulose.
The mixture was granulated with water and dried. Polyvinylpyrrolidone ~ and magnesium stearate were added and the mass was compressed to - 20 tablets.
Reference Example B
g Felodipine 66 25 Methylcellulose 13 Mannitol 870 Polyvinylpyrrolidone 30 Cellulose, microcrystalline 40 Ethylcellulose N 10 34 30 Polyethyleneglycol 6000 41.8 . ~
The composition according to Re~erence Example B was formed to controlled release capsules containing 10 mg felodipine/capsule. The capsules were prepared in the following way:
Felodipine was micronized and care~ully mixed with the carrier, mannitol, methylcellulose, polyvinylpyrrolidone and cellulose. The ~ . .
~31D~2~4 mixture was moistened ~ith water and spheronized. The granu1es obtained were dried and sieved, the fraction 0.71-1.12 mm was used. The cores were coated with ethylcellulose and polyethyleneglycol dissolved in a mixture of methylene chloride and isopropyl alcohol. The coated granules were filled into hard gelatine capsules.
Biopharmaceutical studies Felodipine 1~
In the attached Figure 1 the average plasma values (nmol/l~ for the compositions according to Example 1, 4 and Reference Example A have been illustrated. A single dose of 20 mg Felodipine in a controlled release preparation according to the present invention was administered ~o healthy male subjects. The plasma concentrations of felodipine were compared with the plasma concentrations after a single dose of a fast dissolving tablet containing 25 mg of felodipine. As can be seen the preparations according to the invention gave lower peaks in the plasma concentration whereas the fast-dissolving tablet gave an unwanted high peak.
The area under the plasma concentration curve (AUC) from time 0 to infinity was 25 Preparation Dose mg AUC/dose nmol ~ h 1. ~-mg 1 -Reference A 25 7.2 Example 1 20 8.8 Example 4 20 7.4 As can be seen from this table the bioavailability of felodipine was not decreased with the controlled release preparations.
In the attached Figure Z the average plasma values (nmol/l) for the compositions according to Example 3 and Reference Example B have been illustrated. A single dose of Z0 mg felodipine in a controlled release preparation according to the present invention was adm;nistered to 5 ~3~
. .
healthy male subjects. The plasma concentrations of felodipine were compared with the plasma concentrations after a single dose of a conventional controlled release preparation, that is without the solubilizer, containing 10 mg o~ felodipine. As can be seen the preparation according to the invention gave a low peak in the plasma concentration and a considerable extent of bioavailability. The Reference gave no detectable plasma concentration which clearly indicates the need of a solubilizer if a controlled release effect is wanted.
Nifedipine In the attached Figure 3 the average plasma values (nmol/l) for the composition according to Example 5 and a reference formulation containing nifedipine, Adalato~ 10 mg ~Bayer) (Reference C) have been illustrated. Adalat~Dis a fast release preparation on the market. A
single dose of 20 mg nifedipine in the controlled release preparation according the present invention was administered to 6 healthy male subjects. The plasma concentrations of nifedipine were compared w;th the plasma concentration after a single dose of the reference formulation containing ln mg nifedipine. As can be seen the preparation according to the invention gave a lower peak in the plasma concentration, whereas the reference preparation gave an unwanted high peak in spite of the fact " that the dose is the half. No substantial reduction in bioavailability can be seen when the Reference C was co~pared with Example 5.
The area under the plasma concentration curve from time 0 to infinity was:
30 Preparation Dose mg AUC/dose nmol- h 1~ ~- m Adala ~, Bayer 10 46.S
Example 5 20 36.0 ~;
Discussion The examples above and the attached figures 1~ 2 and 3 illustrate the advantages of the controlled release preparation according to the invention in comparison with a conventional preparation or a controlled release preparation without solubilizer, all containing the same active compound. By the solubilization of the active compound with very low solubility it is possible to obtain a tablet having a more constant plasma concentration profile and without any unwanted high peaks. Also an effect during an extended period of ti~e was obtained. Often there is a reduction in the extent of thè bioavailability, when drugs with very low solubility are formulated. This invention provides however a technique of making controlled release preparations of drugs with very low solubility with the above-mentioned advantages and without any substantial reduction in the extent of the bioavailability.
N~W PHARMACEUTICAL PREPARATIONS WITH EXTENDE3 RELEASE
~ield of the Invention __ The present invention is related to pharmaceutical extended release preparations of active compounds with very low solubility, especially substituted dihydropyridines, and to methods of preparing such preparations.
The object of this invention is to obtain a solid preparation with high extent of bioavailability and extended release of an active compound which normally has ~ery low solubility.
Background of the Invention Pharmaceuticals with very poor water solubility present formulation problems due to their slow rate of dissolution.
Their efficacy can be severely limited and large interindividual variations of absorption can occur. Examples of drugs with very low solubility are some substituted dihydrcpyridine compounds such as nifedipine and felodipine. The mentioned dihydro-pyridines are commonly classified as calcium antagonists, which are widely used for the treatment of cardiovascular disorders such as ischaemic heart disease and arterial hypertension. One of the mentioned dihydropyridines, namely felodipine, has a solubility of only 0.5 mg/l in water. Other examples of drugs with very low solubility are griseofulvin, digoxin, oxazepam, phenytoin and cyclosporine.
Several ways to increase drug absorption have been described in the prior literature. One way is described in DE-A-3024858 published on January 22, 1981, where a sparingly ;~
~' ~3~
soluble substituted dihydropyridine, nicardipine, is used in its amorphous form in order to obtain increased absorption of the active compound ~rom the intestine. Another way is described in EP-A-47899 published on March 24, 1982, where very small crystals of a practically insoluble dihycLropyridine, nifedipine, have been used in order to increase the extent of the bioavailability. These methods and others are also described in "Techniques of solubilization of drugs", Ed S. H. Yalkowsky in Drugs and the pharmaceutical sciences t Vol. 12. Of particular relevance to the present invention is that surfactant solubilizing agents may be employed in order to increase the bioavailability of the drugs with very low solubility. It is sta~ed that the improvement of absorption properties can be ascribed to three processes: (1) increased wetting, (2~ increased permeability of membranes and ~31 solubilization. The cited publication describes several examples and serves as a good review of the state of the art concerning the solubilizing of drugs, especially in order to increase the bioavailability of drugs with very low solubility.
From DE-A~3~00106 published on July 11, 1985, controlled release preparations are known containing one or more natural, partially synthetic or synthetic polymers, one or more lipophilic and/or hydrophilic solvents or thickeners together with one or more pharmaceutically active compounds. In the examples it is described to use a solubilizer in an amount of weight to the active compound which is much less than 1:1.
In the medical treatment of various diseases, e.g. in ~3~2~
the cardiovascular, gastrointestinal and chemotherapeutic field, it is an advantage to have a constant concentration of the administered drug in the blood. Thus an extended release of the drug from the pharmaceutical preparation is wanted.
It is important that the extended release preparation delivers the amount of drugneeded ~ maintain an adequate and even effect during the entire therapeutic dosage interval. This usually means that the drug should be delivered at a constant rate to give an even concentration of administered drug in the blood. This is of specific importance for drugs having a small therapeutic index, that is a small difference between effective and toxic concentration. A delayed and constant release of the drug will also be of importance for locally irritating drugs having potential risk of causing gastrointestinal disturbances when present in large local concentrations or for drugs having a short elimination half-life. In the latter case a less frequent administration and thus better patient compliance tcf-Hayes R. s. et al. Clin.Pharm.Ther. (1977~, 22, p. 125-130~ may be obtained with extended release preparations compared with conventional dosage forms.
A drug in extended release form is generally given via the oral route. The preparations should preferably give an ; extended and reproducible release of drug and contribute to a reproducible absorption, have no toxic or irritating constituents and be suitable also for high dosage drugs. Conventionally, extended release is achieved by controlling dissolution and/or diffusion of medicament from the dosage form. Several materials ~3~2~
239~0-563 are employed for this purpose e.g. waxes, fatty materials, polymers, natural, synthetic and semisynthetic gums. Among the gums, hydroxypropyl methylcellulose (HPMC) constitutes an important class because of its pH-independent properties as well as its semisynthetic origin. A r~view of cellulose ethers in hydrophilic matrices for oral controlled release dosage forms is given by Alderman D. A. Int. J. Pharm. Tech. & Prod. Mfr. (1984), 5(3) 1-9. The chemical treatment of HPMC to generate a desired constitution and the use of these qualities are disclosed in U. S. 3,087,790, U. S. 4,226,849, U. S. 4,357,469 and U. S.
4,369,172. SE-A-8008646-5 published on June 10, 1981 describes a combination of HPMC and hydroxypropyl cellulose which is used to control the release rate of a pharmaceutically active compound.
When a hydrophilic matrix is used the soluble polymer forms a gelatinous layer around the tablet after the exposure of the tabletto gastro-intestinal fluids or saliva. The release of the drug is limited by the rate of water penetration into, and diffusion of drug through, the gel formed (Bamba et al. Int.
J. Pharm. (1979), 2, 307). Erosion of the gel structure is also an important release mechanism of a drug from the system.
; The polymers used have to hydrate rapidly in order to protect the tablet from fast dissolution (Alderman 1984).
The rate of absorption of a drug with very low solubility into the circulation from the intestinal tract is closely related to the rate of dissolution. Since a low dissolution rate ~enerally results in a low extent of bio-availability it is difficult to decrease the rate of absorption, A ~
~3~2~4L
3b i.e. increase the duration, without at the same time lowering the extent of bioavailability.
' 2~
4 ~3940-563 Description of the invention It is the object of the present inven-tion to provlde a pharmaceutical preparation of a drug with very low solubility ~hat shows prolonged and nearly conætant rate of drug absorption for a long period of time and concurrently ~aintains a high extent of bioavailability~ The object is reached b~ u in~ a solubilizer which is mixed with the drug with very low solubility. The solubilizers suitable according to the invention are deflned below. The active compound is pre~erably dissolved or dispersed in the solubilizer. the mixture of active compound (drug) and solubilizer can be diluted with water or intestinal juice without significant precipitation of the dlssolved drug. In the solution the drug is included in a mlcell-structure formed by the solubilizer. Wi~h o~her commonly used solubilizeræ or co-solvents dilution may cause precipltation o f the drug. The mixture o~ the drug and the solubilizer is incorporaked into a pharmaceutical ormulation, whlch give~ prolonged release.
Accordingly, in one aspect the present invention provides a solid pharmaceutical preparation with extended release of an active compound having a solubility less than 0.1 per cent by weight in water, characterized in that the active compound is diæsolved or dispersed in a se~1-solid or liquid non-ionlc solubillzer selected from the group consisting of esters and ethers of polyethyleneglycolæ and in that ~he a~ount by weight of the solubilizer is at leask equal to the amount by weight of the active compound.
.
~3~2~
4a 23940-563 In another aspect the invention provides a pxocess or preparing a solid pharmaceutical prep~ration with extended release of an active compound having a solubi ll~y less than 0.1 per cent by weight in w~ter, characterized in that the active compound is dissolved or dispersed in a semi~solld or liguid non-ionic solubllizer selected from the ~roup consisting of esters and ethers of polyethyleneglycols in at least equal amount by wei~ht to the active compound, whereafter the mixture is incorporated into a suitable release controllin~ systam and formed to a pharmaceutical dosage ~nit.
Vrugs suitable for the extended release preparation according to the invention are compounds characterized by their very low solubility, that is less than 0.1 per cent by welght in water. In addition they are solubllizable in a solu~ilizer or in a combination of a solubilizer and water. Examples of drugs suitable accordlng to the invention are some substituted dlhydropyridines, such as nifedipine and felodipine. Felodipine is 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ethyl methyl ester. Nifedipine is 1,4-dihydro-2,6-dimethyl-4-~2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethylester. Filodipine and nifedipine both are practically insoluble compounds and therefore they are very suitable to solubilize. Other examples of drug with very low solubility are grisieofulvin, digoxin, oxazepam, phenytoin and cyclosporine.
1~3 ~b 23940-563 The solubillzers suitable for the preparations accorclin~ to the invention are semi-solid or liquid non-ionic surface actlve agen~s, especially such containiny polyethyleneglycols as esters or ethers. They are preferably chosen from polyethoxylated fatt.y aclds, hydroxylated fatty acids and fatty alcohols. It is especially preferred to choo~e the ::) ~3~
sol~lbilizer from the group polyethoxylated castor oil, polyethoxylated hydrogenated castor oil, polyethoxylated fatty acid from castor oil or polyethoxylated fatty acid from hydrogenated castor oil. Commercially available solubilizers, which can be used are known under the trade names Cremophor, Myrj, Polyoxyl 40 stearate, Emerest 2675, Lipal 395 and HCO 50. A specially preferred solubilizer is Cremophor @~RH 40 (BASF).
The active compound mixed with the solubilizer is incorporated into different kinds of known controlled release systems, e.g. a hydrophilic gel systenl, beads coated with a rate controlling membrane, which can be a diffusion retarding coating or a disintegrating coating or tablets with an inert porous matrix. According to the inven~ion the solubilized drug is preferably combined with a hydrophilic gel system, namely a hydrophilic swelling matrix e.g. HPMC. This form of controlled release mechanism is a suitable way to control the release of the micelles of drug and solubilizer. The technical propert;es are good and also the performance in vivo is good. Among different hydrophilic materials tested, HP~C, hydroxypropyl methylcellulose, is the best gel-forming rnaterial. Other examples of suitable compounds effecting the release of the active compound from the hydrophilic gel system are guar gum, xanthan gum, carboxypolymethylene, different cellulosic materials e.g.
sodium carboxymethylcellulose and hydroxypropyl cellulose, lactose and aluminium silicate.
The preparation according to the invention contains 20-80% by weight, preferably 30-50% by weight oF the hydrophilic gel system.
The major part of the hydrophilic gel system has a viscosity below lDO cps. It is especially preferable ~o use HPM~ having a hydroxy-propoxyl content of 4-12% by weightg especially about 8.5% by ~eight and a viscosity lower than 100 cps, e.g. ~,15 and/or 50 cps. The viscosity ~ is measured by a standardized method described e.g. in United States ;~ Pharmacopeia XXI, 1985, p. 672.
The final preparation is e.g.in the form of a gel tablet~ By a careful choice of fillers and binders as well as ~el forming material the preparation can be manufactured into a commercially acceptable form, rl'd d ~
~3~42~
e.g. a tablet or a hard gelatin capsule comprising the gel forming granulate, that shows unexpectedly good absorption of the active compound as well as a prolonged duration of action. In the preparation according to the invention the proportions between the active compound S and the solubilizer varies in the range from 1:1 to 1:10, preferably in the range from 1:2 to 1:6.
Also other types of controlled release preparations may be used acsording to the invention e.g. tablets with an inert porous matrix;
capsules comprising granules with a diffusion retarding coating or a disintegrat;ng coating.
The tablets with an inert porous matrix are obtained by mixing the drug and the solubilizer with water insoluble polymers or waxes and with fillers and binders. Polyvinylacetate, polyvinylchloride, ethyl-cellulose, paraffin and cellulose acetate phthalate could be used as suitable diffusion-retarding polymers. The fillers and binders are solid, powdered carriers such as lactose, saccharose, sorbitol, ; mannitol, starch~ amylopectin, cellulose derivative9 gelatine or other suitable carrier. The mixture is moistened with a solvent, e.g. water or ethanol or a solution consisting of e.g. water and a polymer e.g.
polyvinylpyrrolidone. Also a lubricating agent e.g rnagnesium stearate7 calcium stearate, sodium stearyl fumarate and polyethyleneglycol wax may be added. The mixture is then formed to tablets.
The capsules comprising of granules with extended release character-istics are obtained by making a core material consisting of the drug and the solubilizer together with fillers. The surface of the core is then coated with diffusion-retarding water insoluble polymers or waxes. The granules are then filled into hard gelatine capsules. The core material could e.g. be prepared by mixing the drug and the solubili7er with carefully selected fillers such as lactose, sorbitol, starch, cellulose derivatives or other suitable fillers. The mixture is moistened with a solvent, e.g. water or ethanol or a solution consisting of e.g. water and a polymer e.g. polyvinylpyrrolidone. The mass is formed to granules e.g. by extrusion and spheronization. The surfaces of the cores formed are coated with a solution consisting of a solvent e.g. methylene "
~L3~2~3~
chloride and/or isopropyl alcohol and water insoluble polymers e.g.
ethylcellulose. The granules are filled in hard gelatine capsules.
Examples The following examples illustrate the invention:
Example 1 10 Felodipine 10 Cremophor RH 40 90 Calcium phosphate 250 Hydroxypropyl methylcellulose 2910 6 cps 250 Xanthan gum 25 Guar gum 25 Sodium stearyl fumarate 13 The composition according to Example 1 was formed to hydrophilic matrix tablets containing 10 mg o~ felodipine/tablet. The tablets were prepared in the following wayO
Felodipine was dissolved in Cremophor RH 40 and the solution obtained was carefully mixed with the carrier materials, HPMC, xanthan gum, guar gum and calcium phosphate~ The mixture was granulated with ethanol and dried. Sodium stearyl fumarate was added as a lubricant and tablets were prepared by compression in a tabletting machine.
Example 2 30 Felodipine 10 Cremophor RH 60 go Aluminium silicate 100 ~; Paraffin 80 Hydroxypropyl cellulose 7.4 35 Sodium stearyl fumarate 5.0 ;
., ~3~
The composition according to Example 2 was formed to controlled release tablets, inert porous matrix type, containing 10 mg of telodipine/
tablet. The tablets were prepared in the following way:
Felodipine was dissolved in Cremophor RH 60 and the solution obtained was mixed carefully with the carrier materials aluminium silicate and paraffin. The mixture was granulated with a solution of hydroxypropyl cellulose in ethanol and dried. Sodium stearyl fumarate was added as a lubricant and tablets were prepared by compression in a tabletting machine. A controlled release of felodipine was achieved according to the in vitro resultsg 50% released after 2 hours and 100~ released after 6 hours.
Example 3 Felodipine 20 Cremophor RH 40 100 Polyvinylpyrrolidone 66.5 Cellulose, microcrystalline 62 20 Maize starch 29.5 Lactose 157 Ethylcellulose 36 Hydroxypropyl methylcellulose 2910 6 cps 12 Gelatin capsules The composition according to Example 3 was formed to controlled release capsules containing 20 mg of felodipine/capsule. The capsules were prepared in the following way:
Felodipine was dissolved in Cremophor and the solution obtained was mixed carefully with the carrier, polyvinylpyrrolidone, cellulose, maize starch and lactose. The mixture was moistened with water and spheronized. The granules obtained were dried and sieved, the fraction 0.71-1.12 mm was used. The cores were coated with ethylcellulose dissolved in a mixture of methylene chloride and ethanol. The coated granules were filled into hard gelatine capsules.
~3~
Example 4 Felodipine 20 Myrj 51 120 Hydroxypropyl methylcellulose 2910 50 cps 200 Cellulose~ microcrystalline 20 Lactose 167 Sodium stearyl fulnarate 10.5 The composition according to Example 4 was formed to controlled release tablets containing 20 mg of felod;pine/tablet. The tablets were prepared in the same way as described in Example 1.
Example 5 9_ Nifedipine 20 Cremophor RH 40 50 Hydroxypropyl methylcellulose 2910 50 cps 70 Hydroxypropyl methylcellulose 2910 6 cps 160 20 Cellulose microcrystalline 6 Lactose 56 Aluminium silicate 94 Sodium stearyl fumarate 10 The composition according to Example 5 was formed to hydrophilic matrix tablets containing 20 mg of nifedipine/tablet. The tablets were prepared in the same way as described in Example 1.
: The best mode of carrying out the inventiQn is at present considered to be Example 5.
~3~2~
. , .
Reference Example A
The following example i11ustrates the reference tablet used in in vivo studies g Felodipine 25 Lactose 250 Methylcellulose 0.5 10 Polyvinylpyrrolidone 1.5 Magnesium stearate 3 The composition according to reference Example A was formed to fast-dissolving, conventional tablets containing 25 mg of felodipine/tablet.
The tablets were prepared in the following way:
Felodipine was m;cronized and mixed with lactose and methylcellulose.
The mixture was granulated with water and dried. Polyvinylpyrrolidone ~ and magnesium stearate were added and the mass was compressed to - 20 tablets.
Reference Example B
g Felodipine 66 25 Methylcellulose 13 Mannitol 870 Polyvinylpyrrolidone 30 Cellulose, microcrystalline 40 Ethylcellulose N 10 34 30 Polyethyleneglycol 6000 41.8 . ~
The composition according to Re~erence Example B was formed to controlled release capsules containing 10 mg felodipine/capsule. The capsules were prepared in the following way:
Felodipine was micronized and care~ully mixed with the carrier, mannitol, methylcellulose, polyvinylpyrrolidone and cellulose. The ~ . .
~31D~2~4 mixture was moistened ~ith water and spheronized. The granu1es obtained were dried and sieved, the fraction 0.71-1.12 mm was used. The cores were coated with ethylcellulose and polyethyleneglycol dissolved in a mixture of methylene chloride and isopropyl alcohol. The coated granules were filled into hard gelatine capsules.
Biopharmaceutical studies Felodipine 1~
In the attached Figure 1 the average plasma values (nmol/l~ for the compositions according to Example 1, 4 and Reference Example A have been illustrated. A single dose of 20 mg Felodipine in a controlled release preparation according to the present invention was administered ~o healthy male subjects. The plasma concentrations of felodipine were compared with the plasma concentrations after a single dose of a fast dissolving tablet containing 25 mg of felodipine. As can be seen the preparations according to the invention gave lower peaks in the plasma concentration whereas the fast-dissolving tablet gave an unwanted high peak.
The area under the plasma concentration curve (AUC) from time 0 to infinity was 25 Preparation Dose mg AUC/dose nmol ~ h 1. ~-mg 1 -Reference A 25 7.2 Example 1 20 8.8 Example 4 20 7.4 As can be seen from this table the bioavailability of felodipine was not decreased with the controlled release preparations.
In the attached Figure Z the average plasma values (nmol/l) for the compositions according to Example 3 and Reference Example B have been illustrated. A single dose of Z0 mg felodipine in a controlled release preparation according to the present invention was adm;nistered to 5 ~3~
. .
healthy male subjects. The plasma concentrations of felodipine were compared with the plasma concentrations after a single dose of a conventional controlled release preparation, that is without the solubilizer, containing 10 mg o~ felodipine. As can be seen the preparation according to the invention gave a low peak in the plasma concentration and a considerable extent of bioavailability. The Reference gave no detectable plasma concentration which clearly indicates the need of a solubilizer if a controlled release effect is wanted.
Nifedipine In the attached Figure 3 the average plasma values (nmol/l) for the composition according to Example 5 and a reference formulation containing nifedipine, Adalato~ 10 mg ~Bayer) (Reference C) have been illustrated. Adalat~Dis a fast release preparation on the market. A
single dose of 20 mg nifedipine in the controlled release preparation according the present invention was administered to 6 healthy male subjects. The plasma concentrations of nifedipine were compared w;th the plasma concentration after a single dose of the reference formulation containing ln mg nifedipine. As can be seen the preparation according to the invention gave a lower peak in the plasma concentration, whereas the reference preparation gave an unwanted high peak in spite of the fact " that the dose is the half. No substantial reduction in bioavailability can be seen when the Reference C was co~pared with Example 5.
The area under the plasma concentration curve from time 0 to infinity was:
30 Preparation Dose mg AUC/dose nmol- h 1~ ~- m Adala ~, Bayer 10 46.S
Example 5 20 36.0 ~;
Discussion The examples above and the attached figures 1~ 2 and 3 illustrate the advantages of the controlled release preparation according to the invention in comparison with a conventional preparation or a controlled release preparation without solubilizer, all containing the same active compound. By the solubilization of the active compound with very low solubility it is possible to obtain a tablet having a more constant plasma concentration profile and without any unwanted high peaks. Also an effect during an extended period of ti~e was obtained. Often there is a reduction in the extent of thè bioavailability, when drugs with very low solubility are formulated. This invention provides however a technique of making controlled release preparations of drugs with very low solubility with the above-mentioned advantages and without any substantial reduction in the extent of the bioavailability.
Claims (18)
1. A solid pharmaceutical preparation with extended release of an active compound having a solubility less than 0.1 per cent by weight in water, characterized in that the active compound is dissolved or dispersed in a semi-solid or liquid non-ionic solubilizer selected from the group consisting of esters and ethers of polyethyleneglycols and in that the amount by weight of the solubilizer is at least equal to the amount by weight of the active compound.
2. A preparation according to claim 1 wherein the non-ionic solubilizer is selected from polyethoxylated fatty acids, hydroxylated fatty acids or fatty alcohols.
3. A preparation according to claim 1 wherein the non-ionic solubilizer is selected from polyethoxylated castor oil, polyethoxylated hydrogenated castor oil, a polyethoxylated fatty acid from castor oil or a polyethoxylated fatty acid from hydrogenated castor oil.
4. A preparation according to claim 3 wherein the non-ionic solubilizer is one or more esters of hydrogenated castor oil fatty acids with oxyethylated glycerine, Cremophor R RH 40 (BASF).
5. A preparation according to claim 3 wherein the non-ionic solubilizer is Cremophor R RH 40 (BASF).
6. A preparation according to claim 1 wherein the ratio of the active compound to the solubilizer is in the range from 1:1 to 1: 10.
7. A preparation according to claim 1 wherein the ratio of the active compound to the solubilizer is in the range from 1:2 to 1:6.
8. A preparation according to any one of claim 1 to 7 wherein the active compound has a solubility in water of 1:1000 or less by weight and is solubilizable in the non-ionic solubilizer or in a combination of water and the non-ionic solubilizer.
9. A preparation according to any one of claim 1 to 7 wherein the active compound comprises one or more substituted dihydropyridines.
10. A preparation according to claim 8 wherein the substituted dihydropyridine is nifedipine.
11. A preparation according to claim 8 wherein the substituted dihydropyridine is felodipine.
12. A preparation according to any one of claim 1 to 7, 10 and 11 wherein the release is controlled by an inert porous matrix, a diffusion retarding coating or a disintegrating coating.
13. A preparation according to any one of claim 1 to 7, 10 and 11 wherein the release is controlled by a hydrophilic gel system.
14. A preparation according to claim 13 wherein the hydrophilic gel-forming component constitutes between 20-80% by weight of the preparation.
15. A preparation according to claim 13 wherein the hydrophilic gel system comprises hydroxypropyl methylcellulose.
16. A preparation according to claim 15 wherein the hydroxypropyl methylcellulose has a hydroxypropyl content of 4 - 12% by weight.
17. A preparation according to claim 13 wherein the hydrophilic gel system contains carboxypolymethylene.
18. A process for preparing a solid pharmaceutical preparation with extended release of an active compound having a solubility less than 0.1 per cent by weight in water, characterized in that the active compound is dissolved or dispersed in a semi-solid or liquid non-ionic solubilizer selected from the group consisting of esters and ethers of polyethyleneglycols in at least equal amount by weight to the active compound, whereafter the mixture is incorporated into a suitable release controlling system and formed to a pharmaceutical dosage unit.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8601624-3 | 1986-04-11 | ||
| SE8601624A SE8601624D0 (en) | 1986-04-11 | 1986-04-11 | NEW PHARMACEUTICAL PREPARATIONS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1304294C true CA1304294C (en) | 1992-06-30 |
Family
ID=20364135
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000533985A Expired - Lifetime CA1304294C (en) | 1986-04-11 | 1987-04-07 | Pharmaceutical preparations with extended release |
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| EP (1) | EP0249587B1 (en) |
| JP (1) | JPH0778016B2 (en) |
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| AT (1) | ATE76288T1 (en) |
| AU (1) | AU602677B2 (en) |
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| IS (1) | IS1553B (en) |
| MY (1) | MY101553A (en) |
| NO (1) | NO174795B (en) |
| NZ (1) | NZ219633A (en) |
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| DE2714065A1 (en) * | 1977-03-30 | 1978-10-12 | Boehringer Mannheim Gmbh | INSTILLATION PREPARATION |
| JPS5495721A (en) * | 1978-01-11 | 1979-07-28 | Nippon Kayaku Co Ltd | Nifedipine preparation |
| CA1146866A (en) * | 1979-07-05 | 1983-05-24 | Yamanouchi Pharmaceutical Co. Ltd. | Process for the production of sustained release pharmaceutical composition of solid medical material |
| JPS58109412A (en) * | 1981-12-23 | 1983-06-29 | Toa Eiyou Kagaku Kogyo Kk | Nifedipine solid preparation |
| DE3318649A1 (en) * | 1983-05-21 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | TWO-PHASE FORMULATION |
| DE3400106A1 (en) * | 1984-01-04 | 1985-07-11 | Klaus-Dieter Dr. 3550 Marburg Bremecker | Pharmaceutical compositions with controlled release of medicinal substance |
| KR850700212A (en) * | 1984-03-21 | 1985-12-26 | 죠지 드모트 | Sustained Release Pharmaceutical Wexel |
| JPS618A (en) * | 1984-06-09 | 1986-01-06 | Sawai Seiyaku Kk | Nifedipin-containing drug preparation |
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| IT1187751B (en) * | 1985-10-15 | 1987-12-23 | Eurand Spa | PROCEDURE FOR THE PREPARATION OF SOLID FORMULATIONS OF NIFEDIPINE WITH HIGH BIO AVAILABILITY AND WITH PROLONGED EFFECT AND FORMULATIONS SO OBTAINED |
-
1986
- 1986-04-11 SE SE8601624A patent/SE8601624D0/en unknown
-
1987
- 1987-03-10 PH PH35003A patent/PH22494A/en unknown
- 1987-03-12 YU YU40787A patent/YU47258B/en unknown
- 1987-03-16 NZ NZ219633A patent/NZ219633A/en unknown
- 1987-03-16 AU AU70043/87A patent/AU602677B2/en not_active Expired
- 1987-03-16 ZA ZA871911A patent/ZA871911B/en unknown
- 1987-03-22 EG EG171/87A patent/EG18265A/en active
- 1987-03-23 NO NO871199A patent/NO174795B/en unknown
- 1987-03-25 DE DE8787850098T patent/DE3779183D1/en not_active Expired - Lifetime
- 1987-03-25 EP EP87850098A patent/EP0249587B1/en not_active Expired - Lifetime
- 1987-03-25 AT AT87850098T patent/ATE76288T1/en not_active IP Right Cessation
- 1987-03-25 ES ES198787850098T patent/ES2031929T3/en not_active Expired - Lifetime
- 1987-03-26 DK DK198701549A patent/DK173033B1/en not_active IP Right Cessation
- 1987-04-03 US US07/034,500 patent/US4803081A/en not_active Expired - Lifetime
- 1987-04-07 MY MYPI87000450A patent/MY101553A/en unknown
- 1987-04-07 CA CA000533985A patent/CA1304294C/en not_active Expired - Lifetime
- 1987-04-07 DZ DZ870056A patent/DZ1067A1/en active
- 1987-04-09 IE IE92587A patent/IE59419B1/en not_active IP Right Cessation
- 1987-04-09 PL PL1987265078A patent/PL265078A1/en unknown
- 1987-04-09 DD DD87301670A patent/DD263231A5/en unknown
- 1987-04-10 SU SU874202349A patent/SU1743332A3/en active
- 1987-04-10 HU HU871622A patent/HU204699B/en unknown
- 1987-04-10 CS CS872587A patent/CS270560B2/en not_active IP Right Cessation
- 1987-04-10 CN CN87102758A patent/CN1025150C/en not_active Expired - Lifetime
- 1987-04-10 JP JP62087250A patent/JPH0778016B2/en not_active Expired - Lifetime
- 1987-04-10 FI FI871585A patent/FI91826C/en not_active IP Right Cessation
- 1987-04-10 UA UA4202349A patent/UA12336A/en unknown
- 1987-04-10 PT PT84663A patent/PT84663B/en unknown
- 1987-04-10 KR KR870003416A patent/KR870009720A/en not_active Application Discontinuation
- 1987-04-10 IS IS3214A patent/IS1553B/en unknown
- 1987-07-06 KR KR1019870007169A patent/KR950002147B1/en not_active IP Right Cessation
-
1992
- 1992-07-29 GR GR920401616T patent/GR3005286T3/el unknown
-
1995
- 1995-01-11 SG SG4295A patent/SG4295G/en unknown
- 1995-03-02 HK HK26795A patent/HK26795A/en not_active IP Right Cessation
- 1995-12-01 CY CY182695A patent/CY1826A/en unknown
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