AU1010700A

AU1010700A - Analgesic with Controlled Active Substance Release

Info

Publication number: AU1010700A
Application number: AU10107/00A
Authority: AU
Inventors: Johannes Dr Bartholomaus; Jurgen Dr Betzing
Original assignee: Gruenenthal GmbH; Chemie Gruenenthal GmbH
Current assignee: Gruenenthal GmbH
Priority date: 1999-01-18
Filing date: 2000-01-05
Publication date: 2000-07-20
Anticipated expiration: 2020-01-05
Also published as: HU0000137D0; HUP0000137A2; JP2000212069A; DE19901683A1; AR021934A1; PE20001453A1; CN1270028A; DE19901683B4; PL337868A1; IL134075A0; KR20000071245A; EP1020183A2; RU2244541C2; ZA200000171B; NZ502260A; EP1020183A3; SK652000A3; HUP0000137A3; CO4910117A1; AU777330B2

Description

S&F Ref: 487637

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

C

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, Grtnenthal 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 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, pellets 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 with controlled release of at least one analgesic, which preparation permits individual, precise dosing, comparable to the administration of drops, for example from storage 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.

This object is achieved according to the invention by the provision of an orally administered preparation with controlled release of at least one analgesic from a microtablet with a diameter of 3 mmn.

These microtablets preferably have diameters of 1 to 3 mm, particularly preferably of 1.5 to 3 mm.

"i 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, dihydro- 20 morphine, pethidine, piritramide, buprenorphine, tilidine, tramadol, the particular salts thereof or mixtures thereof are preferably used as the opioid.

Tramadol, tramadol hydrochloride, morphine, morphine 25 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.

The microtablets used according to the invention are distinguished by controlled release of the analgesic.

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 irmobilising 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 15 hydrophilic materials which are known to the person skilled o*o in the art. Polymers, such as for example cellulose ethers, S" cellulose esters or acrylic resins are preferably used as hydrophilic matrix materials. Ethylcellulose, •hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic 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 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 4 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 microcrystalline 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 S• release and quantity of analgesic to be released. The active substance content is preferably between 10 and particularly preferably between 25 and 70 wt.%, 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.w 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 analgesic 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 in 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 tabletting press, preferably a rotary tabletting press, to form 15 tablets having a diameter of 1 to 3 mm, preferably of 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 with 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 formulate the 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 for release which are to be achieved. The number of microtablets in a capsule is preferably selected such that the dose is sufficient for admninistration once or twice daily. It is advantageous in this dosage form too for the dose of the analgesic to be subdivided between a 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 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 sufficient 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.

*e o *oo 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 0 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 active substance released at a particular point in time is 15 determined spectrophotometrically.

Example 1: Composition: .999 99999 per tablet per capsule containing tablets 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: Composition: per tablet per capsule containing tablets 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 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 Povidon® 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:

S..

9* 9 Microtablets of a diameter of 2 mm and height of approx.

2 mm 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 Tramadol ILCI 5.0 mg 100 mg the micro- Microcrystalline 2.0 mg 40 mg tablets cellulose Povidon® K30 0 4 mg 8 mg Magnesium stearate 0.1 mg 2 mg Coating Ethylcellulose 0.4 mg 8 mg components (Aquacoat®) Dibutyl sebacate 0.1 mg 2 mg Total 8.0 mg 160 mg Example 4: Matrix controlled release microtablets were produced by screening tramadol HCI (5 amg/tablet) and glyceryl behenate (Compritol 880 ato®) (5 mg/tablet) through a 0.6 imm mesh screen. The homogenised mixture was then compression moulded with 2 mm punches to form corresponding microtablets. These exhibited the following release profile: -r Time after Time fterActive substance release in %4 of minutes 120 minutes 240 minutes 480 minutes 000

Claims

1. Orally administered preparation with controlled release of at least one analgesic from microtablets with a diameter of 3 Imn.

2. Preparation according to claim 1, characterised in that the microtablets have a diameter of 1 to 3 nmn, preferably of 1.5 to 3 mm.

3. Preparation according to claim 1 or 2, characterised in that the analgesic is at least one opioid.

4. Preparation according to claim 3, characterised in 15 that hydromorphone, oxycodone, morphine, levorphanol, methadone, dihydrocodeine, fentanyl, codeine, dihydro- morphine, pethidine, piritramide, buprenorphine, tilidine, tramadol, the particular salts thereof or mixtures thereof are used as the opioid.

Preparation according to claim 4, characterised in that tramadol, tramadol hydrochloride, morphine, morphine hydrochloride and/or morphine sulfate are used as the opioid. see

6. Preparation according to one or more of claims 1 to characterised in that the microtablets contain the analgesic uniformly distributed in a controlled release matrix.

7. Preparation according to claim 6, characterised in that the matrix comprises at least one polymer, a wax, a fat, an oil, a fatty acid, a fatty alcohol or a corresponding ester.

8. Preparation according to claim 7, characterised .in that that cellulose ethers, cellulose esters and/or acrylic resins are used as the polymers. 14

9. Preparation according to one of claims 6 to 8, characterised in that ethylcellulose, hydroxpropyl- methylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, mono- and/or diglycerides of C 1 fatty acids and/or C-i-C3. fatty alcohols are used as the matrix material.

Preparation according to one of claims 1 to characterised in that the microtablets are provided with at least one coating.

11. Preparation according to claim 10, characterised in that the coating provides controlled release. *00o0o 15

12. Preparation according to claim 10 or 11, characterised .ao* in that the coating is based on a water-insoluble S* polymer or wax. 0

13. Preparation according to claim 12, characterised in that an acrylic resin or cellulose derivative, preferably alkylcellulose, is used as the polymer.

14. Preparation according to claim 13, characterised in that ethylcellulose and/or a poly(meth)acrylate is used as the coating material.

Preparation according to one or more of claims 1 to 14, characterised in that the microtablets are in a capsule.

16. Preparation according to claim 15, characterised in that 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. Preparation according to claim 16, characterised in that the number of microtablets in the capsule is sufficient for administration once or twice daily.

18. Preparation according to one of claims 1 to 14, characterised in that the microtablet(s) may be taken from a supply of microtablets using a metering unit, preferably a dispenser, in a countable number in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved.

19. Preparation according to one or more of claim I to 14, characterised in that 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.

Preparation according to one or more of claims 1 to 5, characterised in that more to than 75% of the analgesic is released within 30 minutes.

21. 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 21 December, 1999 15 Grunenthal GmbH *pos Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 0 o o [R:\LIBC1078045 doc.bav