EP0080341A2
Expired / Lapsed
EP
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Pharmaceutical multiple-units formulation
Assignee: BENZON PHARMA TE HVIDOVRE DENEMARKEN AS
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Filing: 1982-11-19
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Granted: —
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Expires: 2002-11-19
Abstract
Abstract A pharmaceutical oral controlled release multiple-units formulation in which individual units comprise cross-sectionally substantially homogeneous cores containing particles of a sparingly soluble active substance, the cores being coated with a coating which is substantially resistant to gastric conditions, but which is erodable under the conditions prevailing in the small intestine, in particular an enteric coating which is substantially insoluble at a pH below 7 such as Eudragit 0 S (an anionic polymerisate of methacrylic acid and methacrylic acid methyl ester), is prepared by a process comprising comminuting an active substance together with a substance which is readily soluble in intestinal fluids such as an anionic detergent to obtain particles containing the active substance in intimate admixture with the readily soluble substance, combining the resulting particles into cross-sectionally substantially homogeneous cores together with components which accelerate the disintegration of the cores in intestinal fluids such as talc and sucrose, coating the individual cores with the coating, and combining a multiplicity of the coated cores into a capsule or tablet formulation. As the coating is erodable in an alkaline environment only, the active substance is not released until the units arrive at a section ofthe small intestine with an alkaline pH. Thus, a reduction and delay of the peak plasma concentration is obtained without affecting the extent of drug availability. A coating of the above-defined type may also be used when the active substance is a substance which exerts an irritating effect on the gastric mucosa and/or is unstable in an acidic environment.
Inventors
- 👤 Helle Bechgaard
- 👤 Peter Houmoeller
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-02 13:18
CPC Classifications
A; A61; A61K; A61K9/00; A61K9/48; A61K9/50; A61K9/5005; A61K9/5021; A61K9/5026; A61K9/14; A61K9/16; A61K9/1605; A61K9/1611; A61K9/1617; A61K9/1623
Claims Analysis
Total Claims: 48
Claim 1
Independent Claim
48 words
A pharmaceutical oral controlled release multiple-units formulation in which individual units comprise cross-sectionally substantially homogeneous cores containing particles of an active substance, the cores being coated with a coating which is substantially resistant to gastric conditions but which is erodable under the conditions prevailing in the small intestine.
Claim 2
Dependent Claim
48 words
A pharmaceutical oral controlled release multiple-units formulation in which individual units comprise cross-sectionally substantially homogeneous cores containing particles of an active substance, the cores being coated with a coating which is substantially resistant to gastric conditions but which is erodable under the conditions prevailing in the small intestine.
Claim 3
Dependent Claim
36 words
A formulation according to claim 1 which is a capsule or tablet formulation which disintegrates substantially immediately upon ingestion in the stomach into a multiplicity of individual units which are distributed freely throughout the gastrointestinal tract.
Claim 4
Dependent Claim
16 words
A formulation according to claim 1 or 2 in which the cores comprise substantially homogeneous mixtures.
Claim 5
Dependent Claim
37 words
A formulation according to any of the preceding claims in which the active substance is a substance which exerts an irritating effect on the gastric mucosa, and/or is unstable in an acidic environment, and/or is sparingly soluble.
Claim 6
Dependent Claim
37 words
A formulation according to claim 4 in which the active substance is a substance which requires more than 30 parts by volume of water to dissolve 1 part by weight of the active substance at ambient temperature.
Claim 7
Dependent Claim
39 words
A formulation according to claim 5 in which the sparingly soluble active substance is a substance which requires more than 1000 parts by volume of water to dissolve 1 part by weight of the active substance at ambient temperature.
Claim 8
Dependent Claim
52 words
A formulation according to any of the preceding claims in which the active substance is present in the cores in the form of particles of a size of about 1 - 10 lim, in particular about 2 - 5. µm, together with components accelerating the disintegration of the cores in intestinal fluids.
Claim 9
Dependent Claim
46 words
A formulation according to claim 7 in which the components accelerating the disintegration of the cores in intestinal fluids comprise insoluble bodies, such as plate-shaped bodies, e.g., talc, and/or compact-shaped bodies, such as aluminium silicate, zinc oxide, magnesium oxide, titanium dioxide, colloidal silica or magnesium trisilicate.
Claim 10
Dependent Claim
33 words
A formulation according to claim 7 or 8 in which the disintegration-accelerating components comprise particles of a substance which is readily soluble in intestinal fluids such as sucrose, glucose, mannitol, sorbitol or lactose.
Claim 11
Dependent Claim
17 words
A formulation according to claim 9 wherein the disintegration-accelerating components comprise a combination of talc and sucrose.
Claim 12
Dependent Claim
47 words
A formulation according to any of claims 7 - 10 in which the active substance is present in the form of 1 - 10 µm particles in which it is in intimate admixture with a substance which is readily dissolved in intestinal fluids to disperse the particles.
Claim 13
Dependent Claim
27 words
A formulation according to claim 11 wherein particles contain the dispersion-accelerating substance in an amount of at the most 10% by weight, calculated on the active substance.
Claim 14
Dependent Claim
32 words
A formulation according to claim 11 or 12 in which the substance which is readily dissolved in intestinal fluids to disperse the particles is a surface-active substance such as an anionic detergent.
Claim 15
Dependent Claim
57 words
A formulation according to claim 13 in which the surface-active substance is selected from the group consisting of sodium salts of fatty alcohol sulphates, sulphosuccinates, partial fatty acid esters of sorbitans such as sorbitanmonooleate, partial fatty acid esters of polyhydroxyethylene sorbitans such as polyethylene glycolsorbitan monooleate or polyhydroxyethylene fatty alcohol ether such as polyhydroxyethylene (23) lauryl ether.
Claim 16
Dependent Claim
14 words
A formulation according to claim 14 in which the surface-active substance is sodium laurylsulphate.
Claim 17
Dependent Claim
20 words
A pharmaceutical formulation according to any of claims 1 - 15 in which the erodable coating is an enteric coating.
Claim 18
Dependent Claim
119 words
A formulation according to claim 16 in which the enteric coating is selected from the group consisting of acrylic polymers and copolymers, e.g. a polymerisate of methacrylic acid and methacrylic acid methyl ester, shellac, cellulose acetate esters such as mixed partial esters of cellulose containing phthalate groups, acetyl groups and free acid groups (cellulose acetate phthalate), polyvinyl acetate esters such as polyvinyl acetate phthalate, hydroxypropylmethyl cellulose esters such as hydroxypropylmethylcellulose phthalate, or alkylene- glycolether esters of copolymers such as partial ethyleneglycol monomethylether ester of ethylacrylate-maleic anhydride copolymer, propyleneglycol monomethylether ester of ethylacrylate-maleic anhydride copolymer, dipropyleneglycol monomethylether ester of ethylacrylate-maleic anhydride copolymer or diethyleneglycol monomethylether ester of methylacrylate-maleic anhydride copolymer, N-butylacrylate-maleic anhydride copolymer, isobutylacrylate-maleic anhydride copolymer or ethylacrylate-maleic anhydride copolymer.
Claim 19
Dependent Claim
26 words
A formulation according to any of claims 1 - 16 wherein the coating is a coating which erodes selectively in the distal part of small intestine.
Claim 20
Dependent Claim
23 words
A formulation according to claim 18 wherein the erodable coating is an enteric coating which is substantially insoluble at a pH below 7.
Claim 21
Dependent Claim
15 words
A formulation according to claim 19 in which the enteric coating comprises an acrylic polymer.
Claim 22
Dependent Claim
26 words
A formulation according to claim 20 in which the enteric coating comprises an anionic polymerisate of methacrylic acid and methacrylic acid methyl ester or mixtures thereof.
Claim 23
Dependent Claim
14 words
A formulation according to claim 21 in which the enteric coating comprises Eudragit® S.
Claim 24
Dependent Claim
43 words
A formulation according to any of claims 7 - 22 in which the diameter of each coated core is about 0.4 - 1.2 mm, in particular about 0.5 - 1.0 mm, especially about 0.5 - 0.8 mm, such as 0.5 - 0.7 mm.
Claim 25
Dependent Claim
31 words
A formulation according to any of claims 16 - 23 wherein the amount of enteric coating is about 2 - 25% by weight, calculated on the total weight of the multiple-units.
Claim 26
Dependent Claim
42 words
A formulation according to claim 24 in which the cores each have a diameter of about 0.5 - 0.6 mm, and the amount of enteric coating applied is about 4 - 12% by weight, calculated on the total weight of the cores.
Claim 27
Dependent Claim
52 words
A formulation according to any of the preceding claims in which the active substance is selected from the group consisting of indomethacin, spironolactone, ibuprofen, furosemide, sulfadiazine, sulfamerazine, progesterone, reserpine, pyrvinium embonate, mofebutazone, hydrochlorothiazide, tetracycline, tolbutamide, acetaminophen, testosterone, valproic acid, estradiol, acetazolamide, erythromycin, iron salts, hydralazine, carbamazepine, quinidine, and cardiac glycosides, e.g., digoxin.
Claim 28
Dependent Claim
31 words
A formulation according to any of claims 1 - 26 in which the active substance is selected from the group consisting of methy(dopa, morphine, naproxene, prazosin, theophyllin, verapamil, amilorid, and disopyramide.
Claim 29
Dependent Claim
29 words
A formulation according to any of claims 1 - 26 in which the active substance is selected from the group consisting of acetylsalicylic acid, and other non-steroid antiinflammatory drugs.
Claim 30
Dependent Claim
31 words
A formulation according to any of claims 1 - 26 in which the active substance is selected from the group consisting of erythromycin, iron salts, cardiac glycosides, e.g., digoxin, and L-Dopa.
Claim 31
Dependent Claim
15 words
A formulation according to any of the preceding claims in the form of a capsule.
Claim 32
Dependent Claim
14 words
An individual unit showing the features stated in any of claims 1 - 29.
Claim 33
Independent Claim
89 words
A method .for preparing a pharmaceutical oral controlled release multiple-units formulation or units therefor, comprising comminuting an active substance together with a substance which is readily soluble in intestinal fluids to obtain particles containing the active substance intimately admixed with the said substance, combining the resulting particles into cross-sectionally substantially homogeneous cores together with components which accelerate the disintegration of the cores in intestinal fluids, coating the individual cores with an erodable coating, and, if desired, combining a multiplicity of the coated cores into a capsule or tablet formulation.
Claim 34
Independent Claim
89 words
A method .for preparing a pharmaceutical oral controlled release multiple-units formulation or units therefor, comprising comminuting an active substance together with a substance which is readily soluble in intestinal fluids to obtain particles containing the active substance intimately admixed with the said substance, combining the resulting particles into cross-sectionally substantially homogeneous cores together with components which accelerate the disintegration of the cores in intestinal fluids, coating the individual cores with an erodable coating, and, if desired, combining a multiplicity of the coated cores into a capsule or tablet formulation.
Claim 35
Dependent Claim
31 words
A pharmaceutical oral controlled release multiple-units formulation in which individual units comprising an active substance are coated with a coating which erodes selectively in the distal part of the small intestine.
Claim 36
Dependent Claim
31 words
A pharmaceutical oral controlled release multiple-units formulation in which individual units comprising an active substance are coated with a coating which erodes selectively in the distal part of the small intestine.
Claim 37
Dependent Claim
23 words
A formulation according to claim 33 in which the coating is an enteric coating which is substantially insoluble at a pH below 7.
Claim 38
Dependent Claim
38 words
A formulation according to claim 34 in which the enteric coating is a coating which will release at least 90% of the active substance within one hour at a pH of 7.5 under the experimental conditions defined herein.
Claim 39
Dependent Claim
27 words
A formulation according to any of claims 33 - 35 in which the units are cross-sectionally substantially homogeneous cores, or units of the non-pareil type, or crystals.
Claim 40
Dependent Claim
19 words
A formulation according to any of claims 33 - 36 in which the enteric coating comprises an acrylic polymer.
Claim 41
Dependent Claim
26 words
A formulation according to claim 37 in which the enteric coating comprises an anionic polymerisate of methacrylic acid and methacrylic acid methyl ester or mixtures thereof.
Claim 42
Dependent Claim
14 words
A formulation according to claim 21 in which the enteric coating comprises Eudragit@ S.
Claim 43
Dependent Claim
31 words
A formulation according to any of claims 33- 39 in which the amount of enteric coating is about 2 - 25% by weight, calculated on the total weight of the multiple-units.
Claim 44
Dependent Claim
53 words
A formulation according to any of claims 33 - 40 in which the active substance is selected from the group consisting of indomethacin, spironolactone, ibuprofen, furosemide, sulfadiazine, sulfamerazine, progesterone, reserpine, pyrvinium embonate, mofebutazone, hydrochlorothiazide, tetracycline, tolbutamide, acetaminophen, testosterone, valproic acid, estradiol, acetazolamide, erythromycin, iron salts, hydralazine, carbamazepine, quinidine, and cardiac glycosides, e.g., digoxin.
Claim 45
Dependent Claim
31 words
A formulation according to any of claims 33 - 40 in which the active substance is selected from the group consisting of methyldopa, morphine, naproxene, prazosin, theophyllin, verapamil, amilorid, and disopyramide.
Claim 46
Dependent Claim
29 words
A formulation according to any of claims 33 - 40 in which the active substance is selected from the group consisting of acetylsalicylic acid, and other non-steroid antiinflammatory drugs.
Claim 47
Dependent Claim
31 words
A formulation according to any of claims 33 - 40 in which the active substance is selected from the group consisting of erythromycin, iron salts, cardiac glycosides, e.g., digoxin, and L-Dopa.
Claim 48
Dependent Claim
13 words
A unit showing the features according to any of claims 33 - 44.
References Cited (Backward Citations)
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