AU777330B2 - Analgesic with controlled active substance release - Google Patents

Analgesic with controlled active substance release Download PDF

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AU777330B2
AU777330B2 AU10107/00A AU1010700A AU777330B2 AU 777330 B2 AU777330 B2 AU 777330B2 AU 10107/00 A AU10107/00 A AU 10107/00A AU 1010700 A AU1010700 A AU 1010700A AU 777330 B2 AU777330 B2 AU 777330B2
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preparation according
release
microtablets
analgesic
preparation
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Johannes Dr Bartholomaus
Jurgen Dr Betzing
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Gruenenthal GmbH
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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
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  • Neurology (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

S&F Ref: 487637
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT
ORIGINAL
.6 Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Grunenthal GmbH Zieglerstrasse 6 D-52078 Aachen Germany Dr Johannes Bartholomaus Dr Jurgen Betzing Spruson Ferguson St Martins Tower 31 Market Street Sydney NSW 2000 Analgesic with Controlled Active Substance Release The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c Patent Application, GrOnenthal GmbH, D-52078 Aachen Internal ref.: G 2710 Analgesic with controlled active substance release The present invention relates to a pharmaceutical formulation from which the analgesic active substance is released in a controlled manner.
Many formulations of analgesic painkillers which provide controlled release of the active substance are known from the prior art.
EP-A-0647448 inter alia has thus already described an S 15 analgesically active preparation with delayed active substance release which consists of a plurality of substrates containing opioid in controlled release form having a diameter of 0.1 to 3 mm as a single daily dose.
Substrates suitable for this purpose may assume the form of 20 spheroids, microbeads, pell.ets or granules. The production of this type of substrate entails relatively elaborate formulation methods, such as for example layer accretion agglomeration processes for pellets or the extrusion/ spheronisation process for spheroids.
There is furthermore a requirement in many therapeutic applications to provide individual doses of a pharmaceutical containing an analgesic, as is possible with orally administered, liquid dosage forms in the form of drops and to be able to make use of conventional, uncomplicated formulation methods, such as tabletting, during the production thereof.
The object of the present invention was accordingly to provide an orally administered preparation w.ith controlled release of at least one analgesic, which preparation permits individual, precise dosing, comparable to the administration of drops, for example from storaae containers or makes it possible to subdivide a certain quantity of active substance into a readily and accurately controllable number of substrates, and which may be produced using standard, straightforward formulation methods.
According to an embodiment of the invention, there is provided an orally s administered preparation with controlled release of at least one opioid as an analgesic from a microtablet with a diameter of 1 to 3 mm.
These microtablets preferably have diameters of 1.5 to 3mm.
The microtablets according to the invention preferably contain at least one opioid as the analgesic active substance. Hydromorphone, oxycodone, morphine, levorphanol, methadone, dihydrocodeine, codeine, fentanyl, dihydromorphine, pethidine, piritramide, buprenorphine, tilidine, tramadol, the particular salts thereof or mixtures thereof are preferably used as the opioid.
Tramadol, tramadol hydrochloride, morphine, morphine hydrochloride and/or morphine sulfate are very particularly preferably used as the analgesic.
Apart from the stated opioid analgesics, the preparation according to the invention may contain non-opioid analgesics which optionally exhibit a synergistic action with the opioid analgesics. These non-opioid analgesics include ibuprofen, ketoprofen, flurbiprofen, paracetamol, naproxen, propyphenazone, acematacin, acetylsalicylic acid, metamizol and/or the salts thereof.
20 The microtablets used according to the invention are distinguished by controlled release of the analgesic.
[R:\LIBZZ]487637spci doc gym Controlled release of the analgesic is taken to mean both non-delayed and delayed release. The opioid active substance is preferably released in a delayed manner.
Release may be achieved by immobilising the active substance in a controlled release matrix. Incorporation into a matrix material ensures that controlled, delayed release of the active substance is achieved over the desired period of time. It is preferably endeavoured to adjust the release of the active substance in such a manner that it is sufficient to take the preparation twice, preferably only once, per 24 hours.
Suitable matrix materials are pharmaceutically compatible hydrophilic materials which are known to the person skilled in the art. Polymers, such as for example cellulose ethers, S* cellulose esters or acrylic resins are preferably used as hydrophilic matrix materials. Ethylcellulose, hydroxypropy].methylcellu lose, hydroxypropylcellu lose, hydroxymethylcellulose, poly(metlh)acry ic acid and/or the derivatives thereof, such as the salts, amides or esters, are very particularly preferred as matrix materials.
The matrix material may, however, also consist of 25 hydrophobic materials, such as for example hydrophobic polymers, waxes, fats, oils, long-chain fatty acids, fatty alcohols or corresponding esters or mixtures thereof. Monoor diglycerides of and/or fatty alcohols and/or waxes are preferably used as hydrophobic materials.
It is also possible to use a mixture of the stated hydrophilic and hydrophobic materials as a controlled release matrix material.
The microtablets according to the invention may furthermore contain pharmaceutically conventional auxiliaries as additional constituents, such as extenders, for example lactose, microcrystalline cellulose or calcium hydrogen phosphate, as well as slip additives, lubricants and flow control agents, such as for example highly disperse silicon dioxide, talcum, magnesium stearate and/or stearic acid.
A particularly preferred pharmaceutically compatible matrix material comprises at least one cellulose ether and/or cellulose ester, a 2 wt.% aqueous solution of which has a viscosity at 20 0 C of 3000 to 150000 mPas, preferably of 10000 to 150000 mPas, optionally in combination with an extender which is not swellable in an aqueous medium, such as for example calcium hydrogen phosphate, or with an insoluble extender swellable in an aqueous medium, such as for example microcrystalliLne cellulose, or an extender soluble in aqueous media, such as for example lactose.
15 The content of analgesic, preferably of opioid analgesic, is adjusted as a function of the desired duration of release and quantity of analgesic to be released. The active substance content is preferably between 10 and particularly preferably between 25 and 70 wt.', 20 relative to the complete mixture. On the basis of the action of opioid and non-opioid analgesics, the person skilled in the art is aware of the mixing ratios in which these should be used in order to achieve the desired release of active substances.
In the case of the preparations according to the invention, which comprise microtablets, controlled release of the active substance may also be achieved by coating the individual tablets with at least one coating which permits controlled, generally delayed, release of the active substance in an aqueous medium. Suitable controlled release coatings comprise water-insoluble waxes or polymers, such as for example acrylic resins, preferably poly(meth)acrylates or water-insoluble celluloses, preferably ethylcellulose. These materials are known from the prior art, for example Bauer, Lehmann, Osterwald, Rothgang "Uberzogene Arzneiformen", Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998, pages 69 et seq., and are hereby included by way of reference.
In addition to the water-insoluble polymers, it is optionally possible to adjust the active substance release rate by preferably also using quantities of up to 30 wt.
of non-controlled release, preferably water-soluble polymers, such as for example polyvinylpyrrolidone or water-soluble celluloses, preferably hydroxypropylmethylcellulose or hydroxypropylcellulose, and/or known plasticisers.
In addition to the controlled release coating, the microtablets according to the invention may additionally be provided with further coatings. It is thus possible to apply a coating containing the active substance, from which 15 coating the active substance is released in a noncontrolled manner after oral administration. Such multilayer microtablets may after administration very rapidly provide an initial dose of the analgesi.c for alleviating the pain, wherein the level of the analgesic may be maintained by the subsequent delayed release of the active substance.
Apart from the controlled release coating, the microtablets may furthermore also additionally have a coating which 25 dissolves in a pH-dependent manner. It is thus possible, for example, to ensure that a certain number of the microtablets of a preparation pass undissolved through the gastric tract and are not released until they reach the intestinal tract.
Another preferred embodiment of the preparations according to the invention consists in the microtablets', which are provided with a controlled release and optionally further coatings, already containing the active substance i.n a matrix which ensures controlled, delayed release of the active substance, or in the matrix controlled release microtablets' having no controlled release coating, but at least one of the stated coatings which ensure an initial dose and/or pH-dependent release.
The microtablets are produced using known methods, as are described, for example, in EP-A-0166315. The corresponding disclosure is hereby included by way of reference.
The microtablets are preferably produced by screening all the tablet constituents, preferably through a 0.6 mm screen, and then homogeneously mixing them. The mixture may be converted into granules, wherein the screening step is then preferably performed after granulation. Where granulation is performed, slip additives and/or lubricants are preferably incorporated before compression. The homogeneous mixture is compression moulded in a tablett.Ing press, preferably a rotary tabletting press, to form 15 tablets having a diameter of 1 to 3 nun, preferably of so. to 3 mm. This method is preferably also performed when producing microtablets with matrix controlled release, wherein melt granulation is a preferred production process for hydrophobic matrix materials fusible at 100 0 C. Methods suitable for this purpose are known to the person skilled in the art.
In the event that the preparations according to the invention contain microtablets with coatings, these may be 25 applied using conventional methods, such as for example by sugar coating, spraying witl solutions, dispersions or suspensions, by melt processing or by powder application processes.
The orally administered preparations according to the invention consisting of microtablets moreover have the major advantage that the desired dose of analgesic may be subdivided into a straightforwardly countable number of units. In this manner, it is possible to fornmil-ae t-he orally administered preparation in accordance with individual patient requirements by, for example, taking the desired number of microtablets from a supply of microtablets using a metering unit, preferably a dispenser, in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved.
The present invention accordingly also provides individually meterable, orally administered preparations, the number of microtablets of which is determined in accordance with the individually desired duration of release and quantity of analgesic for release.
The present invention also provides the orally administered preparations according to the invention in capsules which contain a defined number of the microtablets with controlled release of the analgesic in accordance with the individual duration of release and quantity of analgesic S15 for release which are to be achieved. The number of microtablets in a capsule is preferably selected such that the dose is sufficient for administration once or twice daily. It is advantageous in this dosage form too for the dose of the analgesic to be subdivided between a 20 straightforwardly countable number of microtablets, but the patient is relieved of the task of counting by the dose being determined in a capsule.
The orally administered preparations according to the 25 invention may furthermore assume the form of a so-called macrotablet, i.e. a tablet of conventional dimensions, into which a defined number of microtablets in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved are compression moulded with conventional tablet auxiliaries and additives to form a tablet. In this case, too, it is advantageous if the number of microtablets constituting the macrotablet is selected such that the duration of release and quantity of analgesic for release is suff-icipnt for administration once or twice daily.
The present invention accordingly also provides orally administered preparations with controlled release of at least one analgesic comprising microtablets, wherein a 8 certain number of microtablets in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved are compression moulded with conventional auxiliaries and additives to form a tablet.
Soo.
*g *oooo Examples The release profile of the preparations produced in the Examples was determined as follows: The preparations were placed in 600 ml of artificial gastric juices (pH 1.2) in a rotating basket apparatus (according to the European Pharmacopoeia) at a temperature of the release medium of 37°C and a rotational speed of the rotating basket of 100 min After 120 minutes, the pH value of the release medium was raised to pH 7.2 by addition of phosphate buffer solution. This pH- value was maintained until the end of the testing. The quantity of actLive substance released at a particular point in time is 15 determined spectrophotometrically.
Example 1: Composition: per tablet per capsule containing tablets *2 0 Components of Tramadol HC1 10.0 mg 100 mg the micro- Microcrystalline 4.0 mg 40 mg tablets cellulose Povidon® K30 0.8 mg 8 mg Magnesium stearate 0.2 mg 2 mg Total 15 mg 150 mg The tramadol salt and microcrystalline cellulose were granulated with an aqueous solution of Povidon® K30, dried, screened, mixed with magnesium stearate, compression moulded to form tablets having a diameter of 3 mm and a height of approx. 2 mm and packaged in capsules each containing 10 tablets.
The release profile was as follows: after 15 minutes 80% active substance release.
Example 2:
S
S
S
S
Composition: per tablet per capsule containing tablets Components of Tramadol HCI 10.0 mg 100 mcq the micro- Microcrystalline 4.0 mg 40 mg tablets cellulose Povidon@ K30 0.8 mg 8 mg Magnesium stearate 0.2 mg 2 mg Coating Ethylcellulose 0.8 mg 8 mg components (Aquacoat®) Dibutyl sebacate 0.2 mg 2 mg Total 16 mg 160 mg The tramadol salt and microcrystalline cellulose were granulated with an aqueous solution of Povidoti® K30 (polyvinylpyrrolidone), dried, screened, mixed with magnesium stearate, compression moulded to form tablets having a diameter of 3 mm and coated with an aqueous ethylcellulose/ dibutyl sebacate dispersion in a 4:1 quantity ratio in a fluidised bed apparatus by spraying on the dispersion with continuous drying. 10 microtablets were packaged in each capsule.
11 The average release profile was: Time after Active substance release in of original active substance concentration minutes 1% 240 minutes 18% 480 minutes 29% Example 3: Microtablets of a diameter of 2 mm and height of approx.
2 mmu of the following composition were produced and coated in a similar manner to Example 2. 20 microtablets were packaged in each capsule.
per tablet per capsule containing tablets Components of Tranadol IfC.1 5.0 ing 100 ing the micro- Microcrystalline 2.0 mrg 40 mg tablets cellulose Povidon® K30 0.4 Img 8 mg Magnesium stearate 0.1 mg 2 img Coating Ethylcellulose 0.4 Ing 8 Img components (Aquacoat®) Dibutyl sebacate 0.1 mg 2 mg Total mIg 160 mg Example 4: Matrix controlled release microtablets were produced by screening tramadol HC1 (5 ing/Lablet) and glyceryl behenate (Compritol 880 atoO) (5 ing/tablet) through a 0.6 nun mesh screen. The homogenised mixture was then compression moulded with 2 mm punches to form corresponding microtablets. These exhibited the following release profile: Time after Active substance release in A of original active subs tance concentratLion minutes 120 minutes 240 minutes 480 minutes 8 V00.* 00..

Claims (17)

1. An orally administered preparation with controlled release of at least one opioid as an analgesic from a microtablet with a diameter of 1 to 3 mm.
2. The preparation according to claim 1, wherein the microtablet has a diameter of 1.5 to 3 mm.
3. The preparation according to claim 1 or 2, wherein hydromorphone, oxycodone, morphine, levophanol, methadone, dihydrocodeine, fentanyl, codeine, dihydromorphine, pethidine, piritramide, buprenorphine, tilidine, tramadol, the particular salts thereof or mixtures thereof are used as the at least one opioid. o0 4. The preparation according to claim 3, wherein tramadol, tramadol hydrochloride, morphine, morphine hydrochloride and/or morphine sulfate are used as the at least one opioid. The preparation according to any one of claims 1 to 4, wherein the microtablets contain the analgesic uniformly distributed in a controlled release matrix.
6. The preparation according to claim 5, wherein the matrix comprises at least one polymer, a wax, a fat, an oil, a fatty acid, a fatty alcohol or a corresponding ester.
7. The preparation according to claim 6, wherein cellulose ethers, cellulose esters and/or acrylic resins are used as the polymers.
8. The preparation according to any one of claims 5 to 7, wherein ethylcellulose, 20 hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, mono- and/or diglycerides of C 12 -C 30 fatty acids and/or C 12 -C 30 fatty alcohols are used as the matrix material.
9. The preparation according to any one of claims 1 to 4, wherein the microtablets are provided with at least one coating.
10. The preparation according to claim 9, wherein the coating provides controlled release.
11. The preparation according to claim 9 or 10, wherein the coating is based on a water-insoluble polymer or wax.
12. The preparation according to claim 11, wherein an acrylic resin or cellulose derivative is used as the nnlvmer
13. The preparation according to claim 12, wherein the cellulose derivative is alkylcellulose.
14. The preparation according to claim 12 or 13, wherein ethylcellulose and/or a poly(meth)acrylate is used as the coating material. [R.\LIBZZ)487637specidoc gym 14 The preparation according to any one of claims 1 to 14, wherein the microtablets are in a capsule.
16. The preparation according to claim 15, wherein the capsules each contain a defined number of microtablets in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved.
17. The preparation according to claim 16, wherein the number of microtablets in the capsule is sufficient for administration once or twice daily.
18. The preparation according to any one of claims 1 to 14, wherein the microtablets are taken from a supply of microtablets using a metering unit in a countable 0o number in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved.
19. The preparation according to claim 18, wherein the metering unit is a dispenser The preparation according to any one of claims 1 to 14, wherein a certain number of microtablets in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved are compression moulded with conventional auxiliaries and additives to form a tablet.
21. The preparation according to any one of claims 1 to 4, wherein more than 75% of the analgesic is released within 30 minutes. 20 22. An orally administered preparation with controlled release of at least one analgesic, said preparation being substantially as hereinbefore described with reference to any one of the examples. Dated 16 March, 2004 Grunenthal GmbH 0 Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 0 [R:\LBZZ]487637speci doc:gym
AU10107/00A 1999-01-18 2000-01-05 Analgesic with controlled active substance release Ceased AU777330B2 (en)

Applications Claiming Priority (2)

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DE19901683 1999-01-18
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RU2244541C2 (en) 2005-01-20
SK652000A3 (en) 2000-08-14
HUP0000137A2 (en) 2001-02-28
IL134075A0 (en) 2001-04-30
AR021934A1 (en) 2002-09-04
JP2000212069A (en) 2000-08-02
PE20001453A1 (en) 2000-12-23
EP1020183A3 (en) 2000-09-20
HUP0000137A3 (en) 2001-03-28
CA2295469A1 (en) 2000-07-18
KR20000071245A (en) 2000-11-25
CO4910117A1 (en) 2000-04-24
NZ502260A (en) 2002-02-01
CN1270028A (en) 2000-10-18
HU0000137D0 (en) 2000-03-28
EP1020183A2 (en) 2000-07-19
AU1010700A (en) 2000-07-20

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