CA2066751A1 - Controlled-release pharmaceutical composition for the oral use containing non steroidal anti-inflammatory drugs - Google Patents
Controlled-release pharmaceutical composition for the oral use containing non steroidal anti-inflammatory drugsInfo
- Publication number
- CA2066751A1 CA2066751A1 CA002066751A CA2066751A CA2066751A1 CA 2066751 A1 CA2066751 A1 CA 2066751A1 CA 002066751 A CA002066751 A CA 002066751A CA 2066751 A CA2066751 A CA 2066751A CA 2066751 A1 CA2066751 A1 CA 2066751A1
- Authority
- CA
- Canada
- Prior art keywords
- release
- pharmaceutical composition
- units
- controlled
- sub
- 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.)
- Abandoned
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
- 238000013270 controlled release Methods 0.000 title claims abstract description 13
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 title claims abstract description 5
- 239000004480 active ingredient Substances 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 7
- 239000000463 material Substances 0.000 claims abstract description 7
- 239000007903 gelatin capsule Substances 0.000 claims abstract description 4
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 7
- 229960000991 ketoprofen Drugs 0.000 claims description 7
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 description 7
- 239000002775 capsule Substances 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000008119 colloidal silica Substances 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 108010001267 Protein Subunits Proteins 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 235000019759 Maize starch Nutrition 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 229920003091 Methocel™ Polymers 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000008240 homogeneous mixture Substances 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000004898 kneading Methods 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 description 1
- UJVBZCCNLAAMOV-UHFFFAOYSA-N 2h-1,2-benzothiazine Chemical compound C1=CC=C2C=CNSC2=C1 UJVBZCCNLAAMOV-UHFFFAOYSA-N 0.000 description 1
- SYCHUQUJURZQMO-UHFFFAOYSA-N 4-hydroxy-2-methyl-1,1-dioxo-n-(1,3-thiazol-2-yl)-1$l^{6},2-benzothiazine-3-carboxamide Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=CS1 SYCHUQUJURZQMO-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 229960004892 acemetacin Drugs 0.000 description 1
- FSQKKOOTNAMONP-UHFFFAOYSA-N acemetacin Chemical compound CC1=C(CC(=O)OCC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 FSQKKOOTNAMONP-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229960005142 alclofenac Drugs 0.000 description 1
- ARHWPKZXBHOEEE-UHFFFAOYSA-N alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000002060 circadian Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 1
- 229960000616 diflunisal Drugs 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229950002252 isoxicam Drugs 0.000 description 1
- YYUAYBYLJSNDCX-UHFFFAOYSA-N isoxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC=1C=C(C)ON=1 YYUAYBYLJSNDCX-UHFFFAOYSA-N 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229950005175 sudoxicam Drugs 0.000 description 1
- 229960004492 suprofen Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
-
- 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
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A pharmaceutical composition for the controlled release of non steroidal anti-inflammatory drugs, which gives effective plasmatic levels of drug during 12-24 hours. Said controlled-release composition includes: a) 3 or 4 dosage units (cores) containing 1/3 or 1/4 respectively of the drug total dose, said single dosage units consisting in tablets which can disgregate and/or in tablets which cannot disgregate, including the active ingredient as well as hydrophilic polymeric materials which can gradually release the active ingredients; and b) hard gelatin capsules containing 3 or 4 release units.
Description
'~ WO92100130 2 0 ~ 6 7 5 ~ PCT/EPgl/01246 A CONTROLLED-RELEASE PHARMACEHTICAL COMPOSITION FOR THE
OR~L ~S~ CONTAINING NON STEROIDAL ANTI-INFLAMMATORY
DR~GS
The present invention relates to pharmaceutical compositions for the controlled release of non steroidal anti-inflammatory drugs.
The use of antirheumatic medicaments generally in-volves long-term treatments with 3-4 daily administrations, thus implying a poor compliance of the posology by the patient, besides a remarkable variability in the drug hematic levels.
This problem can be overcome by controlled- or su-stained-release pharmaceutical formulations which allow to reduce the number of daily administrations, there-fore obtaining a more strict compliance of the posology by the patient.
This kind OL formulations can be classified in :
- single-unit dosage forms - multiple-unit dosage forms.
Single-unit dosage forms are generally easier and safer to be pre?ared, but sometimes they can suffer from the drawbacks of lacking release of the active in-qredient, or a "burst effect" due to a too fast releaseo, the active ingredient. Multiple-dosage forms (generally chronoids or pel-lets~ provide an improvement in bioavailability of the active ingredient and lower incidence of side-effects (such as gastrolesivity).
The present invention relates to a pharmaceutical composition for the controlled-release of non steroidal W092/00730 2 0 ~ PCT/EP91/0124G ~
.
anti-inflammatory drugs which assures safety and repro-ducibility of the preparation, a precise control of drug plasmatic levels after the administration, a com-plete bioavailability and an extremely reduced incidence of side-effects.
Said pharmaceutical composition is characterized in that the drug total dosage can be divided into 2,3 or ~ sub-units, consisting each of a small size tablet, which sub-units can be placed in a hard gelatin cap-sule.
Sub-units can either be identical as far as the release characteristics are concerned, or they can be different from each other, depending on the desired du-ration of the therapeutical effect.
Particularly, since symptomatology of the rheuma-tic disease can show exacerbations also depending on circadian rhyth~s, it sometimes is preferable to make use of dosage forms which can give rise to an initial high plasmatic concentration, foilowed by a slower re-lease of the drug, thereby lastins for a long time (for example overnight~.
In any case, the dosage form of the invention has the following advantages :
- Easiness of preparation : the preparation of the single dosage sub-units (small size tablets or coated tablets) involves no difficulties, since it is based on a well-established preparation techni~ue.
- Easiness of distribution : distribution of the 2, 3 or 4 dosage units in hard gelatin capsules can be carried out usins well-established and reliable processes.
W092/00730 2 0 6 ~ 15 1 PCT/EP91/01246 - Control of the release : the formulation and composition of the single units determines the release characteristics.
- Plasmatic levels and bioavailability : the con-trolled-release form administered to healthy volunteers gave rise to active plasmatic levels during a 12 24 hour period, with a complete bioavailability.
Variability of the plasmatic level values turned out to be extremely reduced.
; 10 - Side-effects: no healthy volunteer participating to the tests showed side-effects.
Said advantages are obtained, according to the in-vention, by means of a tuning of the release characte-ristics of the sub-units, according to methods known to ; 15 those skilled in the art.
For example, l or 2 sub-units can give rise to a quick release of the active ingredient, whereas the re ; maining l, 2 or 3 sub-units can consist of hydrophilic matrices (based on hydrophilic polymeric materials and/or hydrogels) which can release gradually the active ingredient. Examples of said hydrophilic matrices include cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose or polyvinyl alcohols of different molecular weights.
Said alcohols or polymeric substances are present in the sub-units at percentages ranging from 5 to 80%, depending on the desired release characteristics.
Of course, the capsule can also contain 2, 3 or 4 identical sub units (of either the quick-release type or the sustained-release one) depending on the desired . .
wo 92,00,30 2 ~ ~ 6 ~ ~ ~ PCT/EP91/01~4~ ~
therapeutical effect.
Examples of non steroidal anti-inflammatory drugs which can advantageously be used as active ingredients in the compositions of the invention include arylacetic acids such as diclofenac, alclofenac, acemethacin, in-domethacin; arylpropionic acids, such as ketoprofen, ibuprofen, naproxen, flurbiprofen, suprofen; salicylic derivatives, such as diflunisal; benzothiazine deriva-tives such as piroxicam, isoxicam, sudoxicam and the like.
Ketoprofen is particularly preferred, in form of 4 50 mg sub-units, one of which being immediately relea-sed, whereas the other ones are gradually released during time, thus assuring effective plasmatic levels for 12-24 hours.
A preparation as well as the "ln vitro" release characteristics and the plasmatic levels obtained after administration to healthy volunteers are reported by way of examples.
Controlled-release pharmaceutical formulation con-taining 200 mg ketopro~en, consisting in a capsule in-cluding 4 dosage units, each containing 50 mg ketopro-fen and being designed for a controlled-release of the active ingredient. Dosage units were prepared as fol-lows :
a) Preparation of sub-units (single units) The following material were used to prepare 1.000.00 cores :
kPtoprofen 50.00 kg hydroxypropylmethyl cellulose ': ' : ' ~ W092/00730 2 0 ~ ~ 7 ~ ~ PCT/EP91/01246 (Methocel K9M)R-(Colorcon) 37.50 kg mannitol 20.00 kg polyvinylpyrrolidone 7.500 kg colloidal silica 0.25 kg magnesium stearate 0.5 kg The active ingredient is mixed with hydroxypropyl-methyl cellulose and mannitol in a suitable mixing-kneading apparatus. The homogeneous mixture is wet with a 5% polyvinylpyrrolidone alcoholic solution, then kneaded, the resulting homogeneous humid mass is forced through a 400 micron screen and dried in an air-circulation oven. The dried granulate is added with magnesium stearate and colloidal silica, then it is compressed into tablets, according to the conventional technique, with 7 mm d. convex punches to obtain 3.0-3.2 mm height- tablets. Said tablets have hardness = 7 (Monsanto scale) and do not disgregate.
b) Film co~ting A pharmaceutical composition (for example, a single tablet) with improved organoleptic characteri-stics and with uniform diffusion into the dissolu~ion medium after the capsule disintegration, giving no aggregation, can be obtained by means of a typical film coating operation, for example, using an aqueous 25 suspension having the following composition:
Hydroxypropyl methyl cellulose g 4.01 (Methocel 606; Shinetzu, Tokyo) Talc g 0.30 Titanium dioxide g 0.20 Polyethylene glycol 6000 g 0.40 c) P~ckaging ~. :
wo 92/00730 2 ~ ~ ~ 7 5 1 PCT/EP9l/0124G ~
OR~L ~S~ CONTAINING NON STEROIDAL ANTI-INFLAMMATORY
DR~GS
The present invention relates to pharmaceutical compositions for the controlled release of non steroidal anti-inflammatory drugs.
The use of antirheumatic medicaments generally in-volves long-term treatments with 3-4 daily administrations, thus implying a poor compliance of the posology by the patient, besides a remarkable variability in the drug hematic levels.
This problem can be overcome by controlled- or su-stained-release pharmaceutical formulations which allow to reduce the number of daily administrations, there-fore obtaining a more strict compliance of the posology by the patient.
This kind OL formulations can be classified in :
- single-unit dosage forms - multiple-unit dosage forms.
Single-unit dosage forms are generally easier and safer to be pre?ared, but sometimes they can suffer from the drawbacks of lacking release of the active in-qredient, or a "burst effect" due to a too fast releaseo, the active ingredient. Multiple-dosage forms (generally chronoids or pel-lets~ provide an improvement in bioavailability of the active ingredient and lower incidence of side-effects (such as gastrolesivity).
The present invention relates to a pharmaceutical composition for the controlled-release of non steroidal W092/00730 2 0 ~ PCT/EP91/0124G ~
.
anti-inflammatory drugs which assures safety and repro-ducibility of the preparation, a precise control of drug plasmatic levels after the administration, a com-plete bioavailability and an extremely reduced incidence of side-effects.
Said pharmaceutical composition is characterized in that the drug total dosage can be divided into 2,3 or ~ sub-units, consisting each of a small size tablet, which sub-units can be placed in a hard gelatin cap-sule.
Sub-units can either be identical as far as the release characteristics are concerned, or they can be different from each other, depending on the desired du-ration of the therapeutical effect.
Particularly, since symptomatology of the rheuma-tic disease can show exacerbations also depending on circadian rhyth~s, it sometimes is preferable to make use of dosage forms which can give rise to an initial high plasmatic concentration, foilowed by a slower re-lease of the drug, thereby lastins for a long time (for example overnight~.
In any case, the dosage form of the invention has the following advantages :
- Easiness of preparation : the preparation of the single dosage sub-units (small size tablets or coated tablets) involves no difficulties, since it is based on a well-established preparation techni~ue.
- Easiness of distribution : distribution of the 2, 3 or 4 dosage units in hard gelatin capsules can be carried out usins well-established and reliable processes.
W092/00730 2 0 6 ~ 15 1 PCT/EP91/01246 - Control of the release : the formulation and composition of the single units determines the release characteristics.
- Plasmatic levels and bioavailability : the con-trolled-release form administered to healthy volunteers gave rise to active plasmatic levels during a 12 24 hour period, with a complete bioavailability.
Variability of the plasmatic level values turned out to be extremely reduced.
; 10 - Side-effects: no healthy volunteer participating to the tests showed side-effects.
Said advantages are obtained, according to the in-vention, by means of a tuning of the release characte-ristics of the sub-units, according to methods known to ; 15 those skilled in the art.
For example, l or 2 sub-units can give rise to a quick release of the active ingredient, whereas the re ; maining l, 2 or 3 sub-units can consist of hydrophilic matrices (based on hydrophilic polymeric materials and/or hydrogels) which can release gradually the active ingredient. Examples of said hydrophilic matrices include cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose or polyvinyl alcohols of different molecular weights.
Said alcohols or polymeric substances are present in the sub-units at percentages ranging from 5 to 80%, depending on the desired release characteristics.
Of course, the capsule can also contain 2, 3 or 4 identical sub units (of either the quick-release type or the sustained-release one) depending on the desired . .
wo 92,00,30 2 ~ ~ 6 ~ ~ ~ PCT/EP91/01~4~ ~
therapeutical effect.
Examples of non steroidal anti-inflammatory drugs which can advantageously be used as active ingredients in the compositions of the invention include arylacetic acids such as diclofenac, alclofenac, acemethacin, in-domethacin; arylpropionic acids, such as ketoprofen, ibuprofen, naproxen, flurbiprofen, suprofen; salicylic derivatives, such as diflunisal; benzothiazine deriva-tives such as piroxicam, isoxicam, sudoxicam and the like.
Ketoprofen is particularly preferred, in form of 4 50 mg sub-units, one of which being immediately relea-sed, whereas the other ones are gradually released during time, thus assuring effective plasmatic levels for 12-24 hours.
A preparation as well as the "ln vitro" release characteristics and the plasmatic levels obtained after administration to healthy volunteers are reported by way of examples.
Controlled-release pharmaceutical formulation con-taining 200 mg ketopro~en, consisting in a capsule in-cluding 4 dosage units, each containing 50 mg ketopro-fen and being designed for a controlled-release of the active ingredient. Dosage units were prepared as fol-lows :
a) Preparation of sub-units (single units) The following material were used to prepare 1.000.00 cores :
kPtoprofen 50.00 kg hydroxypropylmethyl cellulose ': ' : ' ~ W092/00730 2 0 ~ ~ 7 ~ ~ PCT/EP91/01246 (Methocel K9M)R-(Colorcon) 37.50 kg mannitol 20.00 kg polyvinylpyrrolidone 7.500 kg colloidal silica 0.25 kg magnesium stearate 0.5 kg The active ingredient is mixed with hydroxypropyl-methyl cellulose and mannitol in a suitable mixing-kneading apparatus. The homogeneous mixture is wet with a 5% polyvinylpyrrolidone alcoholic solution, then kneaded, the resulting homogeneous humid mass is forced through a 400 micron screen and dried in an air-circulation oven. The dried granulate is added with magnesium stearate and colloidal silica, then it is compressed into tablets, according to the conventional technique, with 7 mm d. convex punches to obtain 3.0-3.2 mm height- tablets. Said tablets have hardness = 7 (Monsanto scale) and do not disgregate.
b) Film co~ting A pharmaceutical composition (for example, a single tablet) with improved organoleptic characteri-stics and with uniform diffusion into the dissolu~ion medium after the capsule disintegration, giving no aggregation, can be obtained by means of a typical film coating operation, for example, using an aqueous 25 suspension having the following composition:
Hydroxypropyl methyl cellulose g 4.01 (Methocel 606; Shinetzu, Tokyo) Talc g 0.30 Titanium dioxide g 0.20 Polyethylene glycol 6000 g 0.40 c) P~ckaging ~. :
wo 92/00730 2 ~ ~ ~ 7 5 1 PCT/EP9l/0124G ~
4 Sub-units prepared as described in a~ are placed into a transparent capsule Capsugel CONI-SNAP SUPRO A
type 0.
"In vitro" release characteristics They were evaluated using the apparatus according to XXII (paddle) operating at 100 rpm, in 1000 ml of simulated intestinal ~luid at pH 7.5 (according to XXII) at 37C. The "ln vitro" release kinetic had the following profile :
¦ Time % Released amount (hours) 1 14.6 1 2 26.1 1 4 46.0 6 63.0 8 78.0 90.6 1 12 100.8 "In vitro" release characteristics The controlled-release formulation was administered to a healthy volunteer, recording the plasmatic concentration of the active ingredient at fixed time intervals. The results were as follows :
,, ' ,, ' :
. :
, . . ~. . - , ' ~ W092/00730 PCT/EP91/01246 .
_ . , Time Plasmatic concentration ¦ (hours) (mcg/ml) 4.5 1 24 0.01 Controlled-release pharmaceutical formulation con-taining 200 mg ketoprofen, consisting in a capsule in-cluding 4 dosage units, each containing 50 mg k6topro-fen and being designed ~or a controlled-release of the active ingredient. Dosage units were prepared as fol-lows :
a) Preparation of sub units (single units) The following materials were used to prepare 1.000.000 cores :
ketoprofen 50.00 kg maize starch 40.00 kg methyl cellulose 0.65 kg polyvinylpyrrolidone 10.00 kg 2S colloidal silica 0.25 kg magnesium stearate 0.5 kg The active ingredient is mixed with maize starch in a suitable mixing-kneading apparatus. The homogene-ous mixture is ~et with a 2% methyl cellulose alcoholic solution, then kneaded, the resulting homogenous humid mass being forced through a 400 micron screen and dried '' ' , in air-circulation oven; The dried granulate is added with cross-linked polyvinylpyrrolidone, Mg stearate and colloidal silica and it is compressed, according to the known technique, with 7 mm d. convex punches, to obtain 3.0-3.2 mm height tablets. The tablets have hardness =
3 (Monsanto scale) and do not disgregate.
Packaginq:
One core prepared as described above and 3 cores prepared as reported in Example l are placed into a transparent capsule Capsugel CONI-SNAP SUPRO A type.
"In vitro" release characteristics:
They were evaluated using the apparatus according to XXII (paddle) operating at l00 rpm, in l000 ml of simulated intestinal fluid at pH 7.5 taccording to U.S.P. XXI) at 37C.
..... ~
I Time % Released amount (hours) ____ _.
I l 36.4 1 2 44.5 i 4 59.0 i 6 72.8 jl 8 85.2 1 l0 95.2 i --- 12 10l.g : . : . .
' .
'.
type 0.
"In vitro" release characteristics They were evaluated using the apparatus according to XXII (paddle) operating at 100 rpm, in 1000 ml of simulated intestinal ~luid at pH 7.5 (according to XXII) at 37C. The "ln vitro" release kinetic had the following profile :
¦ Time % Released amount (hours) 1 14.6 1 2 26.1 1 4 46.0 6 63.0 8 78.0 90.6 1 12 100.8 "In vitro" release characteristics The controlled-release formulation was administered to a healthy volunteer, recording the plasmatic concentration of the active ingredient at fixed time intervals. The results were as follows :
,, ' ,, ' :
. :
, . . ~. . - , ' ~ W092/00730 PCT/EP91/01246 .
_ . , Time Plasmatic concentration ¦ (hours) (mcg/ml) 4.5 1 24 0.01 Controlled-release pharmaceutical formulation con-taining 200 mg ketoprofen, consisting in a capsule in-cluding 4 dosage units, each containing 50 mg k6topro-fen and being designed ~or a controlled-release of the active ingredient. Dosage units were prepared as fol-lows :
a) Preparation of sub units (single units) The following materials were used to prepare 1.000.000 cores :
ketoprofen 50.00 kg maize starch 40.00 kg methyl cellulose 0.65 kg polyvinylpyrrolidone 10.00 kg 2S colloidal silica 0.25 kg magnesium stearate 0.5 kg The active ingredient is mixed with maize starch in a suitable mixing-kneading apparatus. The homogene-ous mixture is ~et with a 2% methyl cellulose alcoholic solution, then kneaded, the resulting homogenous humid mass being forced through a 400 micron screen and dried '' ' , in air-circulation oven; The dried granulate is added with cross-linked polyvinylpyrrolidone, Mg stearate and colloidal silica and it is compressed, according to the known technique, with 7 mm d. convex punches, to obtain 3.0-3.2 mm height tablets. The tablets have hardness =
3 (Monsanto scale) and do not disgregate.
Packaginq:
One core prepared as described above and 3 cores prepared as reported in Example l are placed into a transparent capsule Capsugel CONI-SNAP SUPRO A type.
"In vitro" release characteristics:
They were evaluated using the apparatus according to XXII (paddle) operating at l00 rpm, in l000 ml of simulated intestinal fluid at pH 7.5 taccording to U.S.P. XXI) at 37C.
..... ~
I Time % Released amount (hours) ____ _.
I l 36.4 1 2 44.5 i 4 59.0 i 6 72.8 jl 8 85.2 1 l0 95.2 i --- 12 10l.g : . : . .
' .
'.
Claims (6)
1. A pharmaceutical composition for the controlled release of non steroidal anti-inflammatory drugs, including:
a) dosage units containing 1/3 or 1/4 of the drug total dose, which consist in tablets whose release cha-racteristics can be the same of different from each other;
b) hard gelatin capsules containing 3 or 4 of said dosage units.
a) dosage units containing 1/3 or 1/4 of the drug total dose, which consist in tablets whose release cha-racteristics can be the same of different from each other;
b) hard gelatin capsules containing 3 or 4 of said dosage units.
2. A pharmaceutical composition according to claim l, in which tablets constituting the dosage sub-units con-tain hydrophilic polymeric materials which can cause a delay in the release of the active ingredient.
3. A pharmaceutical composition according to claim 2, in which hydrophilic polymeric materials are selected from cellulose derivatives or polyvinyl alcohols having different molecular weights.
4. A pharmaceutical composition according to claim 2 or 3, characterized in that the polymeric materials are present in each sub-unit at a percentage from 5 to 80%.
5. A pharmaceutical composition according to any one of the preceding claims, containing ketoprofen as the active ingredient.
6. A pharmaceutical composition according to claim 5, in which the ketoprofen total dose is 200 mg, divided in four 50 mg sub-units with differentiate release of the active ingredient.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT20943A/90 | 1990-07-13 | ||
| IT02094390A IT1243341B (en) | 1990-07-13 | 1990-07-13 | PHARMACEUTICAL COMPOSITION FOR ORAL USE WITH MODIFIED RELEASE OF NON STEROID ANTI-INFLAMMATORS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2066751A1 true CA2066751A1 (en) | 1992-01-14 |
Family
ID=11174413
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002066751A Abandoned CA2066751A1 (en) | 1990-07-13 | 1991-07-04 | Controlled-release pharmaceutical composition for the oral use containing non steroidal anti-inflammatory drugs |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0491911A1 (en) |
| AU (1) | AU8186291A (en) |
| CA (1) | CA2066751A1 (en) |
| ES (1) | ES2043567T1 (en) |
| GR (1) | GR930300020T1 (en) |
| IT (1) | IT1243341B (en) |
| WO (1) | WO1992000730A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993017673A1 (en) * | 1992-03-03 | 1993-09-16 | Top Gold Pty., Limited | Sustained release analgesics |
| US5922722A (en) * | 1996-11-12 | 1999-07-13 | Merck & Co., Inc. | Alpha 1a adrenergic receptor antagonists |
| DE19718012C1 (en) * | 1997-04-29 | 1998-10-08 | Jenapharm Gmbh | Process for the production of orally applicable solid pharmaceutical forms with controlled release of active substances |
| DE19901683B4 (en) * | 1999-01-18 | 2005-07-21 | Grünenthal GmbH | Controlled-release analgesic |
| EP2070520A1 (en) | 2007-12-11 | 2009-06-17 | LEK Pharmaceuticals D.D. | Pharmaceutical composition comprising at least one active agent and a binder, which swells in an acidic media |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2021147A1 (en) * | 1970-04-30 | 1971-11-11 | Christian Brunnengraeber Chem | Medicinal capsule contg separate units |
| US4773907A (en) * | 1982-12-20 | 1988-09-27 | Alza Corporation | Primary delivery system comprising secondary dosage form |
| GB2176999B (en) * | 1985-06-22 | 1989-07-12 | Stanley Stewart Davis | Sustained release medicament |
| IT1230576B (en) * | 1988-10-20 | 1991-10-28 | Angeli Inst Spa | ORAL PHARMACEUTICAL FORMULATIONS WITH SELECTIVE LIBERATION IN THE COLON |
-
1990
- 1990-07-13 IT IT02094390A patent/IT1243341B/en active IP Right Grant
-
1991
- 1991-07-04 WO PCT/EP1991/001246 patent/WO1992000730A1/en not_active Application Discontinuation
- 1991-07-04 AU AU81862/91A patent/AU8186291A/en not_active Abandoned
- 1991-07-04 ES ES91912626T patent/ES2043567T1/en active Pending
- 1991-07-04 CA CA002066751A patent/CA2066751A1/en not_active Abandoned
- 1991-07-04 EP EP19910912626 patent/EP0491911A1/en not_active Withdrawn
-
1993
- 1993-04-28 GR GR930300020T patent/GR930300020T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU8186291A (en) | 1992-02-04 |
| WO1992000730A1 (en) | 1992-01-23 |
| IT9020943A0 (en) | 1990-07-13 |
| IT1243341B (en) | 1994-06-10 |
| EP0491911A1 (en) | 1992-07-01 |
| GR930300020T1 (en) | 1993-04-28 |
| ES2043567T1 (en) | 1994-01-01 |
| IT9020943A1 (en) | 1992-01-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |