WO1997018801A1

WO1997018801A1 - Pharmaceutical formulation

Info

Publication number: WO1997018801A1
Application number: PCT/GB1996/002824
Authority: WO
Inventors: Ronald Brown Miller; Stewart Thomas Leslie; Sandra Therese Antoinette Malkowska; Derek Allan Prater
Original assignee: Euro-Celtique S.A.
Priority date: 1995-11-17
Filing date: 1996-11-15
Publication date: 1997-05-29
Also published as: AU7582696A; GB9523566D0

Abstract

A pharmaceutical formulation containing tramadol or a pharmaceutically acceptable salt thereof in combination with a substance having an anti-nauseant activity.

Description

PHARMACEUTICAL FORMULATION

This invention relates to pharmaceutical formulations and in particular pharmaceutical formulations containing tramadol or a pharmaceutically acceptable salt thereof and a substance having anti-nauseant activity and especially such formulations in which the tramadol or pharmaceutically acceptable salt thereof is in controlled release form.

Tramadol is an opioid analgesic which is used in the treatment of moderate to severe pain. It has been known since about 1965 and marketed in various countries as drops, injections, and powder filled capsules for a number of years. Controlled release (BD) tablet formulations have recently been introduced in Germany and the UK.

The widespread use of tramadol has enabled considerable data to be assembled concerning its side effects and it is noteworthy that although tramadol is not a narcotic, the rate of reporting nausea as an adverse reaction is about 30% in certain studies, which is similar to the rate found for morphine and other strong narcotic analgesics.

There is currently no generally accepted explanation of why tramadol causes nausea and it has not been shown whether this arises from a central effect or through a localised effect in the gastro-intestinai tract or by some other mechanism.

In the publication by Kainz et al. Z- Geburtshilfe- Perinatal 1992 Mar-April, Vol: 196 (2), P: 78-82 it is reported that no reduction in the incidence and severity of emetic side effects was observed when trifkφromazine was co-administered with intra¬ muscular tramadol, compared with intra-muscular tramadol alone.

There has been no suggestion or teaching in the literature that the co-administration of an anti-nauseant with tramadol or a pharmaceutically acceptable salt thereof in other dosage forms, especially oral dosage forms, could lead to any reduction in the severity and/or incidence of adverse emetic effects arising from the use of tramadol or its salts

In accordance with the present invention we provide a pharmaceutical formulation containing tramadol or a pharmaceutically acceptable salt thereof in combination with a substance having an anti-nauseant or anti-emetic activity.

The tramadol or salt thereof may be in a normal or controlled release form and the anti-nauseant substance may likewise, but independently, be in a normal or controlled release form. Preferably the tramadol or salt is in a controlled release form.

The present formulation may be presented as an oral dosage form suitable for delivery of the drug for absoφtion from the gastro-intestinai tract, or in a form suitable for buccaJ. sublingual, pharyngeal. oesophageal or nasal transmucosal delivery of the drugs. The oral dosage form may, for example be in the form of a suspension, controlled release suspension, powder granules, spheroids or multiparticulates and may be in a unit dosage form e.g. a sachet, tablet or a capsule or any other suitable oral dosage form. A dosage form for buccal, sublingual, pharyngeal and oesophageal transmucosal delivery may, for example include a composition in which the drug is dispersed in a soluble matrix and having a holder to permit insertion and removal from the mouth.

Dosage forms in accordance with the present invention also include effervescent preparations and pacdiatric preparations.

A unit dosage form in accordance with the present invention preferably contains between 50mg and 800me tramadol or salt thereof preferably in controlled release form. Dosage forms suitable for once a day dosing will usually contain e.g. 150, 200, 300 or 400mg tramadol or salt thereof and will preferably be presented as tablets. Twice a day preparations will generally contain 75, 100, 150 or 200 mg tramadol or salt thereof. Normal release tablets, enteric coated tablets or capsules will suitably contain 50mg tramadol or salt thereof.

Suitable anti-nauseants for use in the present formulations include compounds from the classes of dopamine antagonisns, phenothiazines, 5HT₃ antagonists and antihistamines. Examples of suitable dopamine antagonists are metoclopramide and domperidone, examples of the phenothiazines are prochlorperazine and promethazine. examples of suitable antihistamines arc dimenhydrinate, cinnarizine and cyclizine and examples of a 5HT₃ antagonist are ondansetron, granisetron and tropisetron.

The anti-nauseant substance may be presented in the formulation as a normal or modified release component or in a controlled release form. One preferred embodiment of the invention includes both the tramadol or salt thereof and the anti- nauseant components in controlled release form possibly having the same or approximately the same in vivo and/or in vitro release rates.

Another embodiment of the invention includes the tramadol or salt thereof or a part thereof in a controlled release form and the anti-nauseant compound or a part thereof in a normal release form: such a preparation may e.g. be in the form of a bi-layer tablet with the two components in the different layers, or a tablet or capsule containing a tablet and/or pellets in which the tablet or pellet core contains tramadol or salt in a controlled release matrix or a matrix having a controlled release coating, and the anti-nauseant component may be present in an outer coating from which it is rapidly released.

Preferred dosage strengths for the anti-nauseant component include those which are used for these substances for anti-emetic treatments as mono preparations or preferably dosages which are lower than such levels but which are still capable of reducing the incidence and/or severity of nausea experienced in patients treated with tramadol or salt thereof. The following table shows the normal daily dosages (NDD) for certain preferred anti-nauseant substances which can be given either as a single or divided dose, for example in a twice a day (BD) dose in controlled release form or as several e.g. 3 or 4 doses of a normal release (NR) preparation, as shown in the table below:-

in general, we have found that it is possible to use dosage strengths of the anti- nauseant compound which are 10% to 75% e.g. 25% to 50% of those normally recommended for their use as single dose preparations.

It is especially preferred to use anti-nauseant compounds which have a relatively short half life of, say, less than 6 hours, preferably 3 to 6 hours.

Suitably a unit dosage form in accordance with the invention may for instance comprise powders, granules, spheroids or multipart! culates; it may be in the form of a normal or controlled release tablet or capsule, an enteric coated tablet or capsule or enteric coated powder, granules, spheroids or multiparticulates or tablets formed by compression of the aforesaid powders, granules, spheroids or multiparticulates.

The two active ingredients may be incoφorated in a single unit dosage form in any convenient manner. For instance they may both be present as a mixture in a single matrix which may be presented as e.g. a tablet or granules or pellets. The matrix may be a normal or controlled release matrix or e.g. a normal release matrix having a controlled release coating or membrane. Alternatively the active ingredients may be present as separate components as in e.g. a bi- or multilayered tablet or in the case of beads or pellets one of the active ingredients may be present in a spheroid core and the other ingredient in a coat on the core. The latter system would be particularly suitable in the cases where an anti-nauseant is used in low dosages and may thus be conveniently incoφorated in a film coating without undue increase in the bulk of the film e.g. trifluoroperazine and prochloφerazine. Alternatively the dosage form in accordance with the invention may comprise a mixture of beads, pellets or multiparticulates containing separately an individual active ingredient.

Various controlled release systems and multi-component dosage forms are known which may be used for formulations in accordance with the present invention. European Patent Application Publication No. 220805 describes a multiphase tablet incoφorating a narcotic analgesic in one phase and a non-steroidal anti -inflammatory in another phase. The phases may be e.g. both normal release phases or one phase may be a normal release phase and the other controlled release. The present invention may utilise a multiphase system as described in this patent publication. European /18801

Patent Application Publication No. 271193 describes controlled release beads in the form of spheroid cores containing an active ingredient (in that case hydromoφhone hydrochloride) with a non water-soluble spheronising agent, e.g. microcrystalline cellulose, in a normal release core, the cores being coated with a controlled release film coating of e.g. wax, shellac or zεiru water insoluble cellulose or a polymethacrylate. Such a formulation may also be used with tramadol or salt thereof and an anti-nauseant to provide a controlled release preparation in accordance with the present invention.

Another suitable formulation is in the form of a plurality of beads comprising a core containing or being coated with one of the active ingredients preferably in a controlled release form and an outer coating layer comprising the other active ingredient e.g. for immediate release. Formulations such as this and methods for their preparation are described e.g. in European Patent Application Publication No. 527638.

Yet another suitable formulation is a ion-exchange resin/drug complex which constitutes a controlled release form of the drug. Such formulations are generally known for other drugs e.g. moφhine, and methods for their preparation are disclosed e.g. in European Patent Application Publication No. 0368682 and may be used to prepare formulations in accordance with the invention by e.g. preparing separately ion exchange complexes with respectively tramadol or salt thereof and anti-nauseant substance and granulating these together, or separately with a sugar or sugar alcohol. If granulated separately the resulting products may then be combined by simple blending.

Yet another suitable formulation comprises tramadol or salt and an anti-nauseant dispersed together or separately in a matrix or matrixes comprising a theπnosoftening binder which is preferably a fusible material which melts of softens below 150°C: preferably such a thermosoftening binder is a hydrophilic water soluble substance such as a polyethylene glycol (PEG) of molecular weight 1000 to 20000. preferably 1000 to 6000.

Also, the preparation may additionally contain die usual excipients e.g. diluents, sweeteners and flavourings.

Preferred processes for the production of such preparations are described in European Patent Application Publication Nos. 636370 and 654263. Such a process may for example comprise mechanically working in a mixer, graimlator e.g. a high shear mixer, such as a ColJett GraJ 10 or equivalent mixer, a mixture of the tramadol or salt thereof and the anti-nauseant in particulate form, and a particulate binder which melts or softens at a temperature of from 35°C to 150°C and optionally an organic, water soluble release enhancing material, at a speed and energy input which allows the binder to melt or soften whereby it forms agglomerates or granules. The vaπous components may be incoφorated with die mixture at various stages. The agglomerates or granules may be further processed, after cooling, to provide unit dosage forms. In a preferred embodiment the agglomerates or granules are broken down to give particles e.g. by passing through a suitably sized screen of a Jackson Crockart or equivalent milling machine or by extruding to form rods which may be cut into tablets or by moulding into tablets, or extrusion through a multiplicity of small diameter holes e.g. 0.5-1.0mm and cutting of the extrudates with a blade to form pieces e.g. 0.5-1. mm. The further processing may comprise filling into capsules or sachets or compressing the particles or extruded pieces to form tablets in known manner.

Effervescent and paediatric formulations may be prepared by any suitable conventional method described in the literature.

EXAMPLE 1

Normal release capsules are manufactured containing the following ingredients: -

Ingredients mg/capsule

Tramado 1 hy drochlori de 50.0

Domperidonc 10.0

Microcrystalline cellulose 50.0

Magnesium stearate 1.0

Colloidal anhydrous sillica 0.3

The ingredients are blended in a suitable mixer or blender and the resulting mixture is filled into hard gelatin capsules so that the amount of ingredient per capsule is as noted above.

E AMPLE 2

Controlled release tablets were manufactured containing the following ingredients:-

Ingredients mg/capsule

Tramadol hydrochloride 200.0

Domperidone 40.0

Hydrogenated vegetable oil 250.0

Talc 15.0

Magnesium stearate 5.0

The ingredients are mechanically worked in a high shear mixer equipped with heating facility (heated jacket and/or microwave heater). The temperature is increased to about 60°C whilst mixing until granulation occurs. Then the mixture is cooled and if necessary classified by passing through a suitable screen/mill. The resulting granules are compressed into tablets.

Claims

1. A pharmaceutical formulation containing tramadol or a pharmaceutically

acceptable salt thereof in combination with a substance having an anti- nauseant activity.

2. A formulation according to claim 1 , wherein the tramadol or salt thereof is in a normal or controlled release form and the anti-nauseant substance is independently in normal or controlled release form.

3. A formulation according to claim 1 or 2, wherein the tramadol or salt is in a controlled release form,

4. A formulation in accordance with any of the preceding claims, in which the anti-nauseant is chosen from the classes of dopamine antagonists, phenothiazines. 5HT-, antagonists and antihistamines.

5. A formulation according to claim 4, wherein the dopamine antagonists are metoclopramide and domperidone, the phenothiazines are prochlorperazine and promethazine. the antihistamines are dimenhydrinate, cinnarizine and cyclizine and the 5HT₃ antaoonists are ondansetron, granisetron and tropisetron.

6. A formulation according to claims 4 or 5, in which the anti-nauseant is a 5HT₃ antagonist.

7. A formulation according to any one of the preceding claims wherein the anti- nauseant substance is present in the formulation as a normal release component or in controlled release form, preferably in controlled release form.

8. A formulation according to any one of the preceding claims, in the form of powder, granules, spheroids or multiparticulates, which may optionally be enteric coated.

9. A pharmaceutical unit dosage form comprising a formulation according to any one of claims 1 to 8.

10. A unit dosage form according to claim 9 comprising powder, granules, spheroids or multiparticulates as defined in claim 8 or in the form of a normal release tablet or capsule, an enteric coated tablet or capsule or tablets formed by compression of an aforesaid powder, granules, spheroids or multiparticulates.

12. A dosage form according to claim 8. 9 or 10, containing between 50mg and 800mg tramadol or salt thereof preferably in controlled release form.

13. A dosage form according to claim 10, suitable for once a day dosing containing 150, 200, 300 or 400mg tramadol or salt thereof.

14. A dosage form according to claim 10, suitable for twice a day dosing containing 75, 100, 150 or 200 mg tramadol or salt thereof.

15. A dosage form according to claim 10. which is a normal release preparation preferably in the form of a normal release tablet, enteric coated tablet or capsule, containing 50mg tramadol or salt thereof.

16. A dosage form according to any one of claims 9 to 14, wherein both the tramadol or salt thereof and the anti-nauseant components are in controlled release form.

17. A dosage form according to any one of claims 9 to 16, containing an active ingredient as set forth in claim 5 at the dosage strengths in the following table:-

18. A dosage form according to any one of the claims 9 to 17, wherein the anti- emetic is present at 10% to 75% of normal recommended daily dose.