WO1992000730A1 - A controlled-release pharmaceutical composition for the oral use containing non steroidal anti-inflammatory drugs - Google Patents

A controlled-release pharmaceutical composition for the oral use containing non steroidal anti-inflammatory drugs Download PDF

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Publication number
WO1992000730A1
WO1992000730A1 PCT/EP1991/001246 EP9101246W WO9200730A1 WO 1992000730 A1 WO1992000730 A1 WO 1992000730A1 EP 9101246 W EP9101246 W EP 9101246W WO 9200730 A1 WO9200730 A1 WO 9200730A1
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WO
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Application
Patent type
Prior art keywords
release
pharmaceutical composition
units
controlled
composition according
Prior art date
Application number
PCT/EP1991/001246
Other languages
French (fr)
Inventor
Ubaldo Conte
Original Assignee
Farcon Ag
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

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET 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 TOILET 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

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

A CONTROLLED-RELEASE PHARMACEUTICAL COMPOSITION FOR THE ORAL USE CONTAINING NON STEROIDAL ANTI-INFLAMMATORY DRUGS

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 of formulations can be classified in : - single-unit dosage forms

- multiple-unit dosage forms.

Single-unit dosage forms are generally easier and safer to be prepared, but sometimes they can suffer from the drawbacks of lacking release of the active in- gredient, or a "burst effect" due to a too fast release of 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 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 4 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 rhythms, it sometimes is preferable to make use of dosage forms which can give rise to an initial high plasmatic concentration, followed by a slower re- lease of the drug, thereby lasting 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 technique.

- Easiness of distribution : distribution of the 2, 3 or 4 dosage units in hard gelatin capsules can be carried out using well-established and reliable processes. - 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. - Side-effects: no healthy volunteer participating to the tests showed side-effects.

Said advantages are obtained, according to *.he in¬ vention, by means of a tuning of the release characte¬ ristics of the sub-units, according to methods known to those skilled in the art.

For example, 1 or 2 sub-units can give rise to a quick release of the active ingredient, whereas the re¬ maining 1, 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 carboxy ethyl 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 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- do ethacin; 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 "_in vitro" release characteristics and the plasmatic levels obtained after administration to healthy volunteers are reported by way of examples. EXAMPLE 1

Controlled-release pharmaceutical formulation con¬ taining 200 mg ketoprofen, 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 : ketoprofen 50.00 kg hydroxypropylmethyl cellulose (Methocel K4M)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 coating

A pharmaceutical composition (for example, a single tablet) with improved organoleptic characteri¬ stics and with uniform diffusion into the dissolution medium after the capsule disintegration, giving no aggregation, can be obtained by means of a typical film coating operation, for example, using an aqueous 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) Packaging 4 Sub-units prepared as described in a) are placed into a transparent capsule Capsugel CONI-SNAP SϋPRO 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 fluid at pH 7.5 (according to XXII) at 37CC. The "in_ vitro" release kinetic had the following profile :

Figure imgf000008_0001
Figure imgf000008_0002

"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 :

Figure imgf000009_0001

EXAMPLE 2

Controlled-release pharmaceutical formulation con¬ taining 200 mg ketoprofen, 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 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 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 wet 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.

Packaging:

One core prepared as described above and 3 cores prepared as reported in Example 1 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 100 rpm, in 1000 ml of simulated intestinal fluid at pH 7.5 (according to U.S.P. XXI) at 37°C.

Figure imgf000010_0001

Claims

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 1, 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.
PCT/EP1991/001246 1990-07-13 1991-07-04 A controlled-release pharmaceutical composition for the oral use containing non steroidal anti-inflammatory drugs WO1992000730A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
IT20943A/90 1990-07-13
IT2094390 1990-07-13

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE1991912626 DE491911T1 (en) 1990-07-13 1991-07-04 Non-steroidal drug-entzuendungshemmenden enthaldende pharmaceutical preparation for oral administration with delayed release.

Publications (1)

Publication Number Publication Date
WO1992000730A1 true true WO1992000730A1 (en) 1992-01-23

Family

ID=11174413

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1991/001246 WO1992000730A1 (en) 1990-07-13 1991-07-04 A controlled-release pharmaceutical composition for the oral use containing non steroidal anti-inflammatory drugs

Country Status (4)

Country Link
EP (1) EP0491911A1 (en)
CA (1) CA2066751A1 (en)
ES (1) ES2043567T1 (en)
WO (1) WO1992000730A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998048782A1 (en) * 1997-04-29 1998-11-05 Jenapharm Gmbh & Co. Kg Method for producing orally administered, solid pharmaceutical products with controlled release of the active substance
US5922722A (en) * 1996-11-12 1999-07-13 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
EP1020183A2 (en) * 1999-01-18 2000-07-19 Grünenthal GmbH Analgesic composition with controlled release
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

Citations (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
GB2176999A (en) * 1985-06-22 1987-01-14 Stanley Stewart Davis Multiparticulate sustained release medicament
US4773907A (en) * 1982-12-20 1988-09-27 Alza Corporation Primary delivery system comprising secondary dosage form
EP0366621A1 (en) * 1988-10-20 1990-05-02 BOEHRINGER INGELHEIM ITALIA S.p.A. Orally pharmaceutical preparations with colon selective delivery

Patent Citations (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
GB2176999A (en) * 1985-06-22 1987-01-14 Stanley Stewart Davis Multiparticulate sustained release medicament
EP0366621A1 (en) * 1988-10-20 1990-05-02 BOEHRINGER INGELHEIM ITALIA S.p.A. Orally pharmaceutical preparations with colon selective delivery

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BOLL. CHIM. FARM. vol. 126, no. 11, November 1987, MILANO IT pages 441 - 448; R. BIANCHINI ET AL: 'Modified Release Beads Coated with Cellulose Derivatives by Pan Technique ' see page 441, column 2, paragraph 2 3 see page 443 - page 444 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5922722A (en) * 1996-11-12 1999-07-13 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
WO1998048782A1 (en) * 1997-04-29 1998-11-05 Jenapharm Gmbh & Co. Kg Method for producing orally administered, solid pharmaceutical products with controlled release of the active substance
EP1020183A2 (en) * 1999-01-18 2000-07-19 Grünenthal GmbH Analgesic composition with controlled release
EP1020183A3 (en) * 1999-01-18 2000-09-20 Grünenthal GmbH Analgesic composition with controlled release
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
WO2009074517A1 (en) 2007-12-11 2009-06-18 Lek Pharmaceuticals D.D. Pharmaceutical composition comprising at least one active agent and a binder, which swells in an acidic media
US8753681B2 (en) 2007-12-11 2014-06-17 Lek Pharmaceuticals D.D. Pharmaceutical composition comprising at least one active agent and a binder, which swells in an acidic media

Also Published As

Publication number Publication date Type
ES2043567T1 (en) 1994-01-01 application
CA2066751A1 (en) 1992-01-14 application
EP0491911A1 (en) 1992-07-01 application

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