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 drugs

Info

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
Application number
CA002066751A
Other languages
French (fr)
Inventor
Ubaldo Conte
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Drug Research Srl
Original Assignee
Individual
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2066751A1 publication Critical patent/CA2066751A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808Preparations 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 ~
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 : . : . .
' .
'.

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.
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.
CA002066751A 1990-07-13 1991-07-04 Controlled-release pharmaceutical composition for the oral use containing non steroidal anti-inflammatory drugs Abandoned CA2066751A1 (en)

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)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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

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