WO2022023211A1

WO2022023211A1 - Formulation containing dexketoprofen and tramadol and method for making the same

Info

Publication number: WO2022023211A1
Application number: PCT/EP2021/070694
Authority: WO
Inventors: Katja SKRLEC; Klemen KORASA; Katja PODGORSEK; Elena Smirnova; Radivoje RASKOVIC; Grega Hudovornik
Original assignee: Krka, D.D., Novo Mesto
Priority date: 2020-07-31
Filing date: 2021-07-23
Publication date: 2022-02-03
Also published as: EP4188337A1

Abstract

The present invention provides pharmaceutical compositions comprising dexketoprofen and tramadol, which are stable and easy to manufacture. The pharmaceutical compositions of the present invention are characterized by dexketoprofen being provided in an intragranular phase and tramadol being provided in an extragranular phase or vice versa. In addition, the present invention provides a simple method for manufacturing such pharmaceutical compositions. The key aspect of the manufacturing method according to the present invention is the preparation of a granulate containing dexketoprofen or, in another embodiment, tramadol by means of dry granulation, prior to admixing of tramadol, or in the other embodiment dexketoprofen, and optional further excipients. Medical uses of the pharmaceutical compositions of the present invention are also provided.

Description

Formulation containing Dexketoprofen and Tramadol and Method for making the Same

1 Technical Field

The present invention relates to a pharmaceutical composition comprising a combination of dexketoprofen and tramadol in a solid oral dosage form. The invention further relates to a process for the preparation of the composition of the invention comprising the combination of dexketoprofen and tramadol.

2 Background of the Invention

Pharmaceutical compositions comprising dexketoprofen and tramadol are known in the art. WO 2008/092219 states that dexketoprofen and tramadol are not compatible and thus teaches separation of the two actives e.g. by providing them as separate unit dosage forms or by providing a multilayer tablet with the two actives being placed in separate layers with at least one intermediate barrier layer. Such products have the disadvantage that they are inconvenient in manufacture and/or use. No commercial product has been developed on this basis. By contrast, the solid oral dosage form Skudexa^® is commercially available. This product is described in example 4 of EP 2956 129 A. The tablet core comprises microcrystalline cellulose, pregelatinised maize starch, croscarmellose sodium, sodium stearyl fumarate and silica colloidal, anhydrous. The tablet is further coated by film coating comprisingpolyvinyl alcohol, titanium dioxide, macrogol/PEG 3350, and talc. However, said commercial product still leaves room for improvement regarding ease of manufacture and performance characteristics of the resulting product.

It is therefore an object of the present invention to provide solid oral dosage forms comprising dexketoprofen and tramadol, which exhibit equal or superior performance characteristics compared to the Skudexa^® product. In particular, it is an object of the present invention to provide solid oral dosage forms comprising dexketoprofen and tramadol, which provide an excellent balance of performance characteristics including disintegration and dissolution properties as well as stability and which can be manufactured in a simple and convenient manner. A further object is to provide a method for manufacturing such solid oral dosage forms, which is simple and convenient and is optimized in respect to energy consumption and has so minimal environmental footprint. In particular, it is an object of the present invention to provide a method for manufacturing such solid oral dosage forms, which method involves the processing of mixtures exhibiting good flowability and compressibility.

3 Summary of the Invention

The above objectives are accomplished by the solid oral dosage forms and manufacturing methods specified in the appended claims. Preferred embodiments of the present invention are characterized by the appended dependent claims. Also provided is a packaged pharmaceutical product with the solid oral dosage form of the invention, which is characterized by an advantageously high stability. The invention furthermore provides solid oral dosage forms for use in the treatment of pain and related conditions. In particular, the subject matter of the present invention is characterized by the following numbered items:

1. Solid oral dosage form comprising dexketoprofen trometamol, tramadol hydrochloride and optional excipients, wherein the solid oral dosage form includes an intragranular phase and an extragranular phase, wherein either

(a) dexketoprofen trometamol is present in the intragranular phase and tramadol hydrochloride is present in the extragranular phase, or

(b) dexketoprofen trometamol is present in the extragranular phase and tramadol hydrochloride is present in the intragranular phase; and wherein any binder belonging to the group consisting of maize starch, pregelatinised maize starch, hypromellose and mixture thereof, is absent from the optional excipients.

2. Solid oral dosage form according to item 1, which is a tablet and preferably a film- coated tablet.

S. Solid oral dosage form according to item 1 or 2, wherein the average particle size of the components forming the extragranular phase is between 100 and S00 pm.

4. Solid oral dosage form according to anyone of item 1 to 3, wherein the intragranular phase contains a diluent selected from microcrystalline cellulose, silicified microcrystalline cellulose, and mixtures thereof or wherein the extragranular phase contains a diluent selected from microcrystalline cellulose, silicified microcrystalline cellulose, and mixtures thereof, or wherein both intragranular and extragranular phase contain a diluent selected from microcrystalline cellulose, silicified microcrystalline cellulose, and mixtures thereof, or wherein no lactose is contained in the solid oral dosage form.

5. Solid oral dosage form according to anyone of item 1 to 4, wherein the intragranular phase contains a disintegrant selected from croscarmellose sodium, carmellose sodium, carmellose calcium, carmellose, crospovidone, and mixtures thereof or wherein the extragranular phase contains a disintegrant selected from croscarmellose sodium, carmellose sodium, carmellose calcium, carmellose, crospovidone, and mixtures thereof, or wherein both intragranular and extragranular phase contain a disintegrant selected from croscarmellose sodium, carmellose sodium, carmellose calcium, carmellose, crospovidone, and mixtures thereof.

6. Solid oral dosage form according to anyone of item 1 to 5, wherein the intragranular phase contains a lubricant selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, talc, macrogols, and mixtures thereof or wherein the extragranular phase contains a lubricant selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, talc, macrogols, and mixtures thereof, or wherein both intragranular and extragranular phase contain a lubricant selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, talc, macrogols, and mixtures thereof. Solid oral dosage form according to anyone of item 1 to 6, wherein the intragranular phase contains a glidant selected from talc, silica derivates, anhydrous colloidal silica, hydrated colloidal silica, and mixtures thereof or wherein the extragranular phase contains a glidant selected from talc, silica derivates, anhydrous colloidal silica, hydrated colloidal silica, and mixtures thereof, or wherein both intragranular and extragranular phase contain a glidant selected from talc, silica derivates, anhydrous colloidal silica, hydrated colloidal silica, and mixtures thereof. Solid oral dosage form according to anyone of item 1 to 7, wherein tramadol having an average particle size between 10 and 300 pm, preferably between 60 and 150 pm is used. Method for manufacturing the solid oral dosage form of anyone of item 1 to 8, which comprises the steps of

(a) mixing dexketoprofen trometamol and one or more excipients;

(b) granulating the resulting mixture by dry granulation;

(c) mixing the resulting granulate with tramadol hydrochloride and optionally one or more excipients; and

(d) converting the resulting mixture into the solid oral dosage form. Method for manufacturing the solid oral dosage form of anyone of item 1 to 8, which comprises the steps of

(a) mixing tramadol hydrochloride and one or more excipients;

(b) granulating the resulting mixture by dry granulation;

(c) mixing the resulting granulate with dexketoprofen trometamol and optionally one or more excipients; and

(d) converting the resulting mixture into the solid oral dosage form. The method of item 9 or 10, wherein the mixture of step (a) and/or the mixture of step (c) is sieved before it is further processed. The method of item 9, 10 or 11, wherein step (d) includes compression of the mixture to obtain a tablet, optionally followed by film coating. Packaged pharmaceutical product, wherein the solid oral dosage form of anyone of item 1 to 8 is packaged in a primary packaging comprising a PVDC material. The packaged pharmaceutical product of item 13, wherein the PVDC material comprises PVDC in an amount of 120 g/m² or more such as 180 g/m², wherein the PVDC-containing material is preferably PVC/PVDC/PVC primary packaging with 120 g/m² PVDC content or PVC/PE/PVDC/PE/PVC primary packaging with 180 g/m² PVDC content. 15. Solid oral dosage form according to anyone of item 1 to 8 or packaged pharmaceutical product according to anyone of claims 13 or 14 for use in the treatment of pain.

4 Detailed Description of the Invention

4.1 Description of Figures

Figure 1 shows the initial value of the dissolution profiles of tramadol hydrochloride comprised in the film-coated tablets of Example 3 and of the Reference Example in Ph. Eur buffer pH 6.8 with baskets, at 100 rpm of stirring speed and 900 ml of buffer volume.

Figure 2 shows the initial value of the dissolution profiles of dexketoprofen comprised in the film-coated tablets of Example 3 and of the Reference Example in Ph. Eur buffer pH 6.8 with baskets, at 100 rpm of stirring speed and 900 ml of buffer volume.

4.2 Definitions

In the context of the present invention, the term "intragranular phase" is meant to characterize the phase of the pharmaceutical composition of the present invention, which is obtained by granulation, more specifically by dry granulation.

In the context of the present invention, the term "extragranular phase" is meant to characterize the phase of the pharmaceutical composition of the present invention, which is formed by the components that are admixed to the granulated components, i.e. the components that are added after granulation.

The present invention relates to pharmaceutical compositions containing dexketoprofen trometamol and tramadol hydrochloride as the active ingredients. Unless the context dictates otherwise, all references to dexketoprofen should be understood as references to dexketoprofen trometamol and all references to tramadol should be understood as references to tramadol hydrochloride.

In the pharmaceutical composition of the present invention, the "intragranular phase" and "extragranular phase" can be distinguished from each other by means of the following methods of analysis: Fourier transform infrared (FT-IR) microspectroscopy, Energy-dispersive X-ray spectroscopy (EDS) and Scanning electron microscopy (SEM).

Unless specified otherwise or unless the context dictates otherwise, relative amount indications are given as mass %. The basis for mass % indications regarding the extragranular phase components is the total of the pharmaceutical composition (excluding coating, if present) being 100 mass %.

If relative amount indications by means of ranges include values that cannot be combined with values or ranges disclosed for other components without exceeding 100 mass %, the present disclosure is to be understood as an additional proviso having the effect that only those values and sub-ranges are meant to be disclosed, which can be combined with the relative amounts of the other components such that the relative amounts add up to 100 mass% (or less to allow for optional further components).

The term "average particle size" as used herein refers to volume mean diameter of particles. The diameter and volume mean diameter can be determined by laser light scattering using e.g. a Malvern Mastersizer Aparatus. Particle sizes are determined by measuring the angular distribution of laser light scattered by a homogeneous suspension of particles. The particles to be subjected to the particle size measurement are first suspended in appropriate non polar dispersant and then subjected to a size determination in a Malvern Mastersizer instrument.

Unless specified otherwise and/or unless the context dictates otherwise, excipients are to be classified according to information provided in Handbook of Pharmaceutical Excipients (The Royal Pharmaceutical Society, 2020). In case a substance falls into the categories of two or more excipient types, the substance may exercise one, two or more of these functions in the composition of the present invention. The composition is in accordance with amount indications of the present invention as long as there is at least one (mental) way of splitting the total amount of the substance into separate fractions for the applicable excipient types such that each of these fractions complies with the amount specifications for the respective excipient type.

In some embodiments of the present invention, the expression "excipient of the same chemical structure" is meant to require identity in terms of the structural formula. In case of polymeric substances, it means identity in terms of the structural formula of the repeating units. Hence, two polymeric excipients may be seen as "excipient of the same chemical structure" if they are characterized by the same chemical structure of the repeating units. By contrast, differences in physical parameters such as particle size or average molecular weight are not relevant for the assessment whether excipients have the same chemical structure in the sense of these embodiments of the present invention.

Indications of tablet hardness are based on a determination of tablet hardness by means of Pharmacopoeia (Ph.Eur 10.0, 2.9.8).

Indications of tablet disintegration time are based on a determination of tablet disintegration time by means of Pharmacopoeia (Ph.Eur 10.0, 2.9.1).

Indications of tablet dissolution times are based on a determination of tablet dissolution times by means of Pharmacopoeia (Ph.Eur 10.0, 2.9.3).

Indications of compression mixture properties are based on a determination of compression mixture flowability by means of Pharmacopoeia (Ph.Eur 10.0, 2.9.36 Powder flow; Ph.Eur 10.0, 2.9.34 Measurement of bulk density and tapped density).

Indication of uniformity of dosage units are based on determination of content uniformity with calculation of acceptance value (AV) by means of Pharmacopoeia (Ph.Eur 10.0, 2.9.40)

In the context of the present invention, the term "comprising" is used to characterize a group of elements such that further unmentioned elements may additionally be present. However, in one specific aspect, the term comprising is intended to characterize a group of elements, which does not include further unmentioned elements. In other words, disclosures with the term "comprising" are to be understood in one aspect as disclosures using the term "consisting of'.

Unless specified otherwise or unless the context dictates otherwise, the use of the article "a", "an", etc. is meant to refer to the specified item both in singular and plural form.

Indications of values are to be understood in one aspect as indications of the specified value ± 10% permitted variation, in another aspect as the indicated value with a permitted variation as determined by conventional rounding rules, and in yet another aspect as the precise specified value without permitted variation.

4.3 Overview

The present invention relates to a pharmaceutical composition comprising a combination of dexketoprofen and tramadol, both as salts. The pharmaceutical composition of the present invention is provided as a solid oral dosage form. This may include coated or uncoated tablets, capsules filled with uncompressed powder/granules, capsules filled with compressed minitablets, microtablets or pellets, sachet comprising loose powder/granules. The preferred solid oral dosage form of the present invention is a film-coated tablet.

The composition is characterized by the absence of certain binders.

The solid oral dosage form of present invention is characterized by distribution of one active ingredient in the intragranular phase and the other active ingredient in the extragranular phase. Hence, in one main embodiment of the invention, dexketoprofen is distributed intragranularly and tramadol is distributed extragranularly. In the other main embodiment of the invention, dexketoprofen is distributed extragranularly and tramadol is distributed intragranularly. There are no particular restrictions or requirements regarding further excipients and their distribution within the intragranular phase and the extragranular phase.

The present invention is further characterized by a manufacturing of the solid oral dosage form of the invention using granulation methods without using solvents, such as dry granulation methods such as roller compaction or slugging.

The invention further relates to a process for the preparation of the composition of the invention comprising the combination of dexketoprofen and tramadol. In one main embodiment of the invention, the desired distribution of dexketoprofen in the intragranular phase and tramadol in the extragranular phase is achieved by preparing a first mixture comprising dexketoprofen, granulating it by dry granulation, followed by mixing with the components of the extragranular phase. In the other main embodiment of the invention, the desired distribution of tramadol in the intragranular phase and dexketoprofen in the extragranular phase is achieved by preparing a first mixture comprising tramadol, granulating it by dry granulation, followed by mixing with the components of the extragranular phase. The solid oral dosage form of the present invention exhibits excellent performance characteristics, including the desired dissolution properties as well as superior stability. Moreover, advantageous handling performance can be accomplished during manufacture: the materials to be processed exhibit advantageous flowability and compressibility. The manufacturing process of the present invention is furthermore characterized by its simplicity.

4.4 Dexketoprofen

Dexketoprofen is the active S-(+) enantiomer of ketoprofen. It belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs) and acts by reversible inhibition of cyclooxygenase to block or reduce prostaglandin formation. It has the following chemical structure:

Dexketoprofen is mainly used for the treatment of mild-to-moderate pain. Dexketoprofen is commercially available in the form of the tromethamine salt (2-amino-2-hydroxymethyl-l,3- propanediol, TRIS or trometamol salt). The tromethamine salt of Dexketoprofen is available on the markets in form of 12.5 mg and 25 mg film-coated immediate release oral tablets in which the dose is calculated on the weight of free dexketoprofen form, i.e. acid form. The present invention is, however, limited to the use of the specific tromethamine salt form of dexketoprofen.

There is also no limitation regarding the use of possible alternative polymorphs, hydrates or solvates of dexketoprofen and its salts.

In another embodiment, the pharmaceutical composition of the present invention can comprise dexketoprofen tromethamine having an average particle size between 2.5 and 110 pm, optionally between 20 and 60 pm. The average particle size is determined by laser method using a Malvern Mastersizer.

The solid oral dosage form of the invention may contain from 8 to 75 mg, preferably from 10 to 55 mg, more preferably 12.5 mg or 25 mg dexketoprofen (expressed as the free acid amounts; the 12.5 mg and 25 mg amounts being equivalent to 18.4 and 36.9 mg dexketoprofen tromethamine) per unit dosage form.

In one embodiment, dexketoprofen is present only in the intragranular phase (when tramadol is in the extragranular phase). In another embodiment, dexketoprofen is present only in the extragranular phase (when tramadol is in the intragranular phase).

4.5 Tramadol Tramadol is an opioid that is used as an analgesic to treat moderate to severe pain. It is a 1:1 mixture of the (1R,2R) and (lS,2S)-stereoisomers and it is characterized by the following chemical structure:

Tramadol is commercially available in the form of its hydrochloride salt. In the present invention, tramadol is used in the form of the hydrochloric acid salt. There is also no particular restriction regarding the possible use of polymorphs, hydrates or solvates of tramadol.

In another embodiment, the pharmaceutical composition of the present invention can comprise tramadol hydrochloride having an average particle size between 10 and 300 pm, optionally between 60 and 150 pm. The average particle size is determined by laser method using a Malvern Mastersizer.

The above-mentioned commercial product Skudexa^® comprises a combination of 75 mg of tramadol hydrochloride (together with 25 mg of dexketoprofen). The solid oral dosage form of the present invention may contain from 17.6 to 105.4 mg, preferably from 26.3 to 87.8 mg, more preferably 32.9 mg or 65.9 mg tramadol (expressed as the free base; the values 32.9 mg and 65.9 mg tramadol being equivalent to 37.5 mg and 75 mg tramadol hydrochloride, respectively) per unit dosage form.

4.6 Excipients

The pharmaceutical composition according to the present invention may, in addition to the active ingredients, comprise one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients used for the preparation of the pharmaceutical composition of the present invention preferably include two or more excipients with different functions. Excipients used for the preparation of pharmaceutical composition of the present invention are typically of pharmaceutical grade, i.e. their quality is appropriate for human use and intended for the preparation of solid pharmaceutical compositions. The pharmaceutical compositions of the present invention can comprise at least one excipient selected from the groups of diluents, disintegrants, lubricants, glidants and antitacking agents.

According to the present invention, the pharmaceutical compositions are characterized by the absence of any binder belonging to the group consisting of maize starch, pregelatinised maize starch, hypromellose and mixture thereof as disclosed in EP2956129. The pharmaceutical composition of the present invention can comprise one or more diluents. Suitable diluents are selected from carbohydrates or its derivatives such as lactose, e.g. lactose monohydrate, anhydrous lactose, spray dried and/or granulated lactose, sucrose, fructose, dextrates, saccharose, raffinose, trehalose, fructose or mixtures thereof, dextrin, sugar alcohols (sometimes referred to as polyols) such as xylitol, mannitol, maltitol, isomalt, and sorbitol, cellulosic materials such as powdered cellulose, microcrystalline cellulose, and silicified microcrystalline cellulose, magnesium aluminometasilicate such as Neusilin, calcium salts of phosphoric acid such as calcium hydrogen phosphate anhydrous or hydrate, calcium, sodium or potassium carbonate or hydrogencarbonate and calcium lactate or mixtures thereof. In another preferred embodiment of the present invention, the pharmaceutical composition comprises diluents selected from microcrystalline cellulose, silicified microcrystalline cellulose and sugar alcohols (polyols) or mixtures thereof. More preferably, the pharmaceutical formulation of the present invention comprises at least one diluent selected from microcrystalline cellulose, silicified microcrystalline cellulose or mixtures thereof. In some embodiments, no lactose is used. The absence of lactose from the pharmaceutical composition of the present invention is of course fully consistent with the preferred use of one of microcrystalline cellulose, silicified microcrystalline cellulose and sugar alcohols (polyols) or mixtures thereof and it is also consistent with the more preferred use of microcrystalline cellulose, silicified microcrystalline cellulose or mixtures thereof.

The diluent is preferably contained in the solid oral dosage form in a relative amount of from 40% to 75% w/w of the total amount, preferably from 50% to 65% by the total weight of the composition.

It is also preferred that the pharmaceutical composition of the present invention comprises one or more disintegrants. Suitable disintegrants may be selected from crospovidone, sodium starch glycolate, sodium and/or calcium salts of carboxymethyl cellulose, cross- linked carboxymethylcell ulose (e.g. croscarmellose sodium and/or croscarmellose calcium), polacrilin potassium, low substituted hyd roxy p ro py I ce 11 u I ose, sodium and/or calcium alginate, docusate sodium, methylcellulose, agar, guargum, chitosan, alginic acid or mixtures thereof. Preferably, disintegrants are selected from croscarmellose sodium and carmellose calcium, and mixtures thereof.

The disintegrant is preferably present in the solid oral dosage form of the invention in amounts from 1% to 15% of the total composition weight, preferably from 3% to 10% of the total weight of the composition.

The pharmaceutical composition of the present invention can comprise one or more lubricants. Suitable lubricants may be selected from the group of metal salts of fatty acids with 12 to 20 carbon atoms such as magnesium, calcium, aluminium or zinc stearate, magnesium palmitate and magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, meads wax or spermaceti, boric acid, sodium stearyl fumarate, macrogols or mixtures thereof. Preferably, lubricants are selected from magnesium and/or calcium stearate, talc, sodium stearyl fumarate and mixtures thereof; most preferably magnesium stearate is used. The lubricant is preferably present in the solid oral dosage form of the invention in amounts from 0.1 % to 5 % by the total composition weight, preferably from 0.5 % to 3 % by the total weight of the composition.

The glidant can be selected from various useful glidants or antisticking agents including talc, silica derivates, anhydrous colloidal silica, hydrated colloidal silica, or mixtures thereof. The preferred glidant is anhydrous colloidal silica.

The glidant is preferably present in the solid oral dosage form of the invention in amounts from 0.1 % to 2 % by the total composition weight, preferably from 0.5 % to 1.5 % by the total weight of the composition.

If not indicated otherwise, all percentages ("%") given herein are wt. % (w/w), based on the total weight of the tablet core without film coating layer. Preferably, the pharmaceutical composition of the present invention comprises dexketoprofen in an amount of 5-30%, more preferably 7.5-25%, most preferably 10-20% and tramadol in an amount of 5-40%, more preferably 10-35%, most preferably 15-30%. More preferably, the pharmaceutical composition of the present invention comprises dexketoprofen trometamol in an amount of 5-30%, more preferably 7.5-25%, most preferably 10-20% and tramadol hydrochloride in an amount of 5-40%, more preferably 10-35%, most preferably 15-30%.

According to a more preferred embodiment, the pharmaceutical composition of the present invention comprises: dexketoprofen: 5-30%, more preferably 7.5-25%, most preferably 10-20%; tramadol: 5-40%, more preferably 10-35%, most preferably 15-30%; diluent: 20-80%, more preferably 40-75%, most preferably 50-65%; disintegrant: 1 -20%, more preferably 1 -15%, most preferably 3 -10%; lubricant: 0 -10%, more preferably 0.1 -5%, most preferably 0.5 -3%; glidant: 0-10%, more preferably 0-6%, most preferably 0.1-4%.

According to an even more preferred embodiment, the pharmaceutical composition of the present invention comprises: dexketoprofen tromethamol: 5-30%, more preferably 7.5-25%, most preferably 10- 20%; tramadol hydrochloride: 5-40%, more preferably 10-35%, most preferably 15-30%; diluent: 20-80%, more preferably 40-75%, most preferably 50-65%; disintegrant: 1 -20%, more preferably 1 -15%, most preferably 3 -10%; lubricant: 0 -10%, more preferably 0.1 -5%, most preferably 0.5 -3%; glidant: 0-10%, more preferably 0.1-2%, most preferably 0.5-1.5%.

When an excipient of the same chemical structure, such as diluent e.g. microcrystalline cellulose, is present both in the intragranular phase and in the extragranular phase, the pharmaceutical composition according to the present invention may optionally comprise the ratios of each excipient of the same chemical structure, defined as w/w ratio of excipient in intragranular phase to excipient in extragranular phase, in the range of from 95:5 to 40:60, preferably from 90:10 to 50:50, more preferably from 80:20 to 50:50, even more preferably from about 70:30 to about 60:40. According to another embodiment of the invention, the ratio of each excipient of the same chemical structure, defined as w/w ratio of excipient in intragranular phase to excipient in extragranular phase, may optionally be in the range of from 70:30 to 20:80, preferably from 65:35 to 25:75, more preferably from 60:40 to 30:70. Herein the pharmaceutical composition of the present invention comprises different excipients which are divided between granulate (i.e. intragranular phase) and as additive to the granulate (i.e. as extragranular additive), the ratios are defined for each excipient of the same chemical structure individually.

A preferred composition according to the present invention comprises microcrystalline cellulose, croscarmellose sodium, silica and magnesium stearate. More preferred is a composition, wherein at least one of the listed excipients is divided between intragranular phase and extragranular phase. More preferred is a composition, wherein at least one of the listed excipients is divided between intragranular phase and extragranular phase, and wherein at least one of the listed excipients having a larger average particle size is incorporated extragranularly. Even more preferred is a composition which comprises microcrystalline cellulose and croscarmellose sodium, wherein both of the listed excipients are divided between intragranular phase and extragranular phase. Hence, it is particularly preferred that the composition according to the invention comprises granules (i.e. an intragranular phase) and an extragranular phase.

Preferably, the dexketoprofen trometamol is comprised in the intragranular phase and the tramadol hydrochloride in the extragranular phase. Moreover, it is preferred that the average particle size of microcrystalline cellulose of the extragranular phase is higher than the average particle size of these excipients of the intragranular phase. More preferably, the average particle size of microcrystalline cellulose of the extragranular phase is equal to or more than 100 pm.

4.7 Film Coating

The solid dosage forms described above can be optionally coated with an aqueous soluble film coating, typically having an average thickness of at least 1 pm, measured by scanning electron microscopy (SEM) of crossection of coated solid dosage form. The optional film coating comprises one or more aqueous soluble polymers. The film coating can optionally be functional having reduced permeability for water and/or moisture. Suitable methods for applying film coatings to tablet cores are generally known in the art, such as coating of tablet cores in perforated coating drums like Manesty, Ace I a cota, GS or Glatt coating drums.

Polymers that can be used for film coating can be selected from cellulose ethers such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose; polyvinyl alcohol, povidone, sodium carboxymethyl cellulose, waxy materials, acrylic polymers cuch as Eudragit^® L or E types , block polymer of polyvinyl alcohol and polyethylene glycol. Film coating can optionally comprise other excipients from the functional groups of lubricants, antitacking agents, pigments, colourant and/or plasticizers.

Film coatings characterized by low permeability for gases such as water vapor and/or oxygen may be based on polymers such as polyvinyl alcohol (e.g. Opadry AMB), low viscosity hypromellose types, sodium carboxymethyl cellulose, aminoalkyl methycrylate copolymers (e.g. Eudragit E PO or Eudragit E 12,5). Commonly used plasticizers (which can be used for coating the pharmaceutical compositions of the present invention) can be categorized into three groups: polyols (glycerol, propylene glycol, macrogols having average molecular weight in the range from 200 to 10,000, preferably B00 to 8,000), organic esters (phthalate esters, dibutyl sebacate, citrate esters, triacetin), oils/glycerides (castor oil, acetylated monoglycerides, fractionated coconut oil). Commonly used lubricants and/or antitacking agents (which can be used for coating the pharmaceutical compositions of the present invention) can be selected from the group of metal salts of fatty acids with 12 to 20 carbon atoms such as magnesium stearate, calcium stearate, aluminium stearate or zinc stearate, magnesium palmitate and magnesium oleate, fatty acids with 12 to 20 carbon atoms such as stearic acid, palmitic acid and oleic acid, hydrogenated vegetable oil, hydrogenated castor oil, talc, meads wax or spermaceti, boric acid, sodium stearyl fumarate, and mixtures thereof.

Colourants/opacifiers (which can be used for coating the pharmaceutical compositions of the present invention) are classified into several groups: organic dyes and their lakes, inorganic colours, natural colours. Pigments can be selected from metal oxides such as iron or titanium oxides.

Combination of different materials from each group can be combined, in particular in defined ratios. Film coating suspensions can be used as ready-to-make preparations which are available on the market. Film coating dispersion can be prepared by using different solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), preferably water.

A composition of film-coating suspension (calculated on dry material) is particularly preferred which comprises:

1-98.8% by weight of polymer, preferably 1-95% of polymer,

1-50% by weight of plasticizer, preferably 1-40% of plasticizer,

0.1-20% by weight of lubricant, preferably 1-10% of lubricant,

0.1-20% by weight of colourant/opacifier and/or pigment, preferably 0.1-10% of colourant/opacifier and or/pigment. All weight% indications are based on the total of the film coating being 100 weight%.

The composition of the film-coating layer of the pharmaceutical composition of the present invention preferably comprises at least one excipient selected from excipients with the function as defined of polymer and plasticizer. In another embodiment of the present invention, the composition of the coating layer of the present invention preferably comprises at least one excipient selected from excipients with the function as defined polymer, plasticizer, lubricant, antitacking agent and colourant/opacifier.

4.8 Manufacturing

The composition of the present invention can be prepared by any known technological procedures which are absent of solvents, e.g., dry granulation. In another embodiment of the present invention, the composition is prepared in a manner known per se, for example by means of conventional mixing, granulating, or coating processes. In the preparation of the pharmaceutical composition of the present invention, the active ingredients will usually be mixed with at least one excipient or a mixture of excipients, or diluted by an excipient or mixture of excipients, or enclosed within an excipient or a mixture of excipients.

Based on the knowledge of the properties and stability of dexketoprofen, it is a moisture sensitive drug. Therefore, processes for the preparation of the pharmaceutical formulation of the present invention comprise steps, which exclude solvents and especially water from all technological steps of incorporation of dexketoprofen into tablet cores. This means that the processes are preferably selected from dry granulation.

The "dry granulation" method is a method of formulation wherein the raw material powder is subjected to a compression molding into a pellet or sheet, using granules produced by crushing.

Dry granulation can be performed by processes known in the art as slugging and/or roller compaction, the latter being preferred. Dexketoprofen or tramadol, optionally sieved to eliminate agglomerates, are usually mixed and dry-granulated with at least one excipient or a mixture of excipients into slugs/compacted material by using roller compactor or compression machine. The obtained slugs/compacted material is crushed and optionally sieved to obtain a uniform distribution of the granules of a dry granulate.

In the preparation of granulate, by dry granulation, active ingredients and excipients, preferably selected from diluents, disintegrants, glidants and lubricants can be incorporated partially intragranularly and partially extragranularly, alone or in combination with at least one excipient or a mixture of excipients. In another embodiment of the present invention, at least one excipient or a mixture of excipients can be used partially intragranularly and partially extragranularly.

The mixing of dexketoprofen or tramadol, and at least one excipient or a mixture of excipients may be effected in conventional devices used for mixing of powder, e.g. motionless (passive) mixers, fluidized bed, diffusion, biconic diffusion, biconic, tubular, cubic, planetary, Y-, V-shaped or high-shear mixers. In another embodiment of the present invention, the same equipment may be used in the preparation of compression mixture with the prior step of a granulate preparation by a granulation as described by the terms "dry granulation".

In the processes according to the invention, the compression, in particular to tablet ortablet cores, can be effected using an automatic rotary compressing machine from different manufacturers of equipment for use in pharmaceutical industry.

Conventional equipment can be used for applying a film coating, such as a Wurster coating system or conventional coating pans for use in pharmaceutical industry.

In another embodiment of the present invention, the dry granulation process comprises:

- granulating optionally sieved dexketoprofen trometamol and at least one excipient or a mixture of excipients using processes known in the art such as slugging and/or roller compaction;

- addition of tramadol hydrochloride and at least one excipient or a mixture of excipients to the granulate and mixing to give a compression mixture;

IB - compressing the compression mixture to obtain the desired solid dosage form;

- optionally, applying a film coating to the solid dosage form.

- granulating optionally milled and sieved tramadol hydrochloride, at least one sieved excipient or a mixture of excipients using process known in the art such as slugging and/or roller compaction;

- addition of dexketoprofen trometamol and excipient or a mixture of excipients to the granulate to give a compression mixture;

- compressing the compression mixture to obtain the desired solid dosage form;

- optionally, applying a film coating to the solid dosage form.

When an excipient of the same chemical structure, e.g. microcrystalline cellulose, is divided between granulate (i.e. intragranular phase) and as an additive to the granulate (i.e. as extragranular additive), the use of different particle size and/or particle morphology of the excipient is preferred for each phase. For incorporation into the granulate smaller average particle size of the excipient is preferred in comparison to the extragranular phase.

The particle size of an excipient is evaluated by sieve analysis already by its manufacturer. For the microcrystalline cellulose, the term «smaller particle size« means average particle size less than 100 pm, and the term «larger average particle size« means average particle size equal or more than 100 pm. The average particle size is determined according to the publicly available data of the manufacturers of excipients.

When an excipient of the same chemical structure, such as diluent e.g. microcrystalline cellulose, is divided between granulate (i.e. intragranular phase) and as an additive to the granulate (i.e. as extragranular additive), the pharmaceutical composition according to the present invention may optionally comprise the ratios of each excipient of the same chemical structure, defined as w/w ratio of excipient in intragranular phase to excipient in extragranular phase, in the range of from 95:5 to 40:60, preferably from 90:10 to 50:50, more preferably from 80:20 to 50:50, even more preferably from about 70:30 to about 60:40. According to another embodiment of the invention, the ratio of each excipient of the same chemical structure, defined as w/w ratio of excipient in intragranular phase to excipient in extragranular phase, may optionally be in the range of from 70:30 to 20:80, preferably from 65:35 to 25:75, more preferably from 60:40 to 30:70. Herein the pharmaceutical composition of the present invention comprises different excipients which are divided between granulate (i.e. intragranular phase) and as additive to the granulate (i.e. as extragranular additive), the ratios are defined for each excipient of the same chemical structure individually.

It has been observed that use of a microcrystalline cellulose with larger particle size in extragranular phase significantly increases flowability of the compression mixture. It is therefore preferred to use excipients and/or active ingredient for the extragranular phase with larger average particle size. For instance, microcrystalline cellulose and/or active ingredient with larger average particle size may be used for the extragranular phase. The terms «smaller average particle size« and «larger average particle size« of specific excipients are as described hereinabove.

A preferred composition according to the present invention comprises microcrystalline cellulose, croscarmellose sodium, silica and magnesium stearate.

More preferred is a composition, wherein at least one of the listed excipients is divided between intragranular phase and extragranular phase.

More preferred is a composition, wherein at least one of the listed excipients is divided between intragranular phase and extragranular phase, and wherein at least one of the listed excipients having a larger average particle size is incorporated extragranularly.

Even more preferred is a composition which comprises microcrystalline cellulose and croscarmellose sodium, wherein both of the listed excipients are divided between intragranular phase and extragranular phase.

Hence, it is particularly preferred that the composition according to the invention comprises granules (i.e. an intragranular phase) and an extragranular phase.

The dexketoprofen trometamol is preferably comprised in the intragranular phase and the tramadol hydrochloride in the extragranular phase.

Moreover, it is preferred that the average particle size of microcrystalline cellulose of the extragranular phase is higher than the average particle size of these excipients of the intragranular phase. More preferably, the average particle size of microcrystalline cellulose of the extragranular phase is equal to or more than 100 pm.

4,9 Uses

4.9.1 Medical Indications

The solid oral dosage form of the present invention is suitable for the treatment of pain. In particular, it is suitable for the treatment of acute, chronic and postoperative pain of moderate to severe intensity originating from any cause and/or disease comprising especially those selected from the group of headache, toothache, inflammations, cancer, orthopaedic pain and migraine. The fixed combination of both compounds is intended to allow optimised pain control with fewer side effects than observed for both compounds alone.

4.9.2 Administration

The solid oral dosage form of the present invention is to be administered orally. It may be administered by means of 1, 2, 3 or 4 unit dosage forms per day. The total daily dosage of dexketoprofen should be in the range of from more than 0 to 100 mg, preferably 25 to 75 mg. The total daily dosage of tramadol should be in the range of from more than 0 to 250 mg, preferably 75 to 225 mg.

4.9.3 Combination with optional further Agents

The solid oral dosage form of the present invention does not require combination with further agents to accomplish the desired therapeutic, i.e. analgesic effect. However, combination with further active agents may nevertheless be helpful or even advantageous. For instance, it may be advantageous to combine therapy with the solid oral dosage of the present invention with administration of an agent that may reduce the side effects of the opioid tramadol, such as an agent against opioid induced constipation. Such agents may include but are not limited to lactulose or naloxone.

4.10 Packaged Pharmaceutical Product

Another aspect of the present invention provides a packaged pharmaceutical product, which comprises the solid oral dosage form of the present invention within a primary packaging. Typical primary packagings are blisters or larger containers with a screw cap. According to this embodiment of the present invention, the packaged pharmaceutical product uses a primary packaging with a packaging material containing polyvinylidene chloride (PVDC).

According to a particularly preferred embodiment, the primary packaging is a blister, wherein one or both of the foils forming the blister is made from the PVDC-containing material. For instance, the packaged pharmaceutical product according to the present invention may be a blister, wherein the upper foil with cavities is made from a PVDC- containing material, which is laminated to a lower foil made from aluminium material, and wherein the solid oral dosage form of the invention is contained in the cavities.

Preferably, the PVDC-containing material is PVC/PVDC/PVC primary packaging or PVC/PE/PVDC/PE/PVC primary packaging, more preferably the amount of PVDC is 120 g/m² in PVC/PVDC/PVC primary packaging or 180 g/m² in PVC/PE/PVDC/PE/PVC primary packaging.

The following examples illustrate the invention and are not intended to restrict the scope of the invention in any way.

4.11 Examples

Reference Example

The reference product, Skudexa^® tablets, was used as commercially available. The qualitative and quantitative composition of commercially available Skudexa^® tablets is as disclosed in Example 4 of EP2956129.

Comparative Example Dexketoprofen trometamol and tramadol hydrochloride were sieved together with the intragranular part of microcrystalline cellulose, croscarmellose sodium, silica, colloidal anhydrous and magnesium stearate through 1.0 mm mesh size to prepare blend for roller compaction. Table 1 below specifies the amounts of active substances and excipients that were used.

Compaction was performed applying standard procedures in roller compaction technology, employing Hosokawa C250 equipment. Afterwards, the compacts were sieved through 1.0 mm mesh size and mixed with the extragranular part of microcrystalline cellulose, croscarmellose sodium, silica, colloidal anhydrous and magnesium stearate in the amounts specified in table 1. The components were mixed in the container mixer to obtain the compression mixture.

The compression mixture was compressed on a standard rotary tablet press to tablet cores with the following properties:

Oblong with dimensions of 13x8 mm

• Tablet mass: 350 mg ± 2%

• Resistance to crushing: 77 - 99 N

• Disintegration time: < 5 min.

The resulting tablet cores were subsequently coated with an aqueous film coating system based on polyvinyl alcohol, which was prepared according to the manufacturer's recommendation (Colorcon). The film-coating was performed in a standard film-coater.

Example 1 and 2

Tramadol hydrochloride was sieved together with the intragranular part of microcrystalline cellulose, croscarmellose sodium, silica, colloidal anhydrous and magnesium stearate through 1.0 mm mesh size to prepare a blend for roller compaction. The compaction was performed applying standard procedures in a roller compaction technology. Afterwards, the compacts were sieved and mixed with dexketoprofen trometamol and the extragranular part of microcrystalline cellulose, croscarmellose sodium, silica, colloidal anhydrous and magnesium stearate. The components were mixed in the container mixer to obtain the compression mixture.

The compression mixture was compressed on a standard rotary tablet press to obtain tablet cores. Compression force from 8 to 20 kN was applied during the process and tablet cores with hardness between 70 and 150 N were obtained.

The resulting tablet cores were subsequently coated with an aqueous film coating system based on polyvinyl alcohol, which is prepared according to the manufacturer's recommendation (Colorcon). The film-coating was performed in a standard film-coater.

Example 3

Dexketoprofen trometamol was sieved together with the intragranular part of microcrystalline cellulose, croscarmellose sodium, silica, colloidal anhydrous and magnesium stearate through 1.0 mm mesh size to prepare a blend for roller compaction. Table 1 below specifies the amounts of active substances and excipients that were used.

The compaction was performed applying standard procedures in roller compaction technology. Afterwards, the compacts were sieved and mixed with tramadol hydrochloride and the extragranular part of microcrystalline cellulose, croscarmellose sodium, silica, colloidal anhydrous and magnesium stearate in amounts as specified in table 1 below. The components were mixed in the container mixer to obtain the compression mixture.

The compression mixture of Example 3 was compressed on a standard rotary tablet press to tablet cores with the same properties as specified above for the Comparative Example.

The resulting tablet cores were subsequently coated with an aqueous film coating system based on polyvinyl alcohol (Opadry II), which is prepared according to the manufacturer's recommendation (Colorcon). The film-coating is performed in a standard film-coater.

Examples 4 to 14

Dexketoprofen trometamol was sieved together with the intragranular excipients through 1.0 mm mesh size to prepare a blend for roller compaction. Amounts were employed as specified in table 1 below.

The compaction was performed applying standard procedures in roller compaction technology. Afterwards, the compacts were sieved and mixed with tramadol hydrochloride and the extragranular excipients. The components were mixed in the container mixer to obtain the compression mixture. The compression mixture was compressed on a standard rotary tablet press to obtain a tablet core. A compression force from 8 to 20 kN was applied during the process and tablet cores with hardness between 70 and 150 N were obtained.

Table 1: Tablet compositions

*Not part of the final product

Table 1 (continued): Tablet compositions

Table 1 (continued): Tablet compositions

Table 1 (continued): Tablet compositions

Physical properties of tablets

The properties of the film-coated tablets were as follows:

• Film-coated tablet mass: 360 mg ±5%

• Resistance to crushing: > 90 N

• Disintegration time: < 6 min.

Handling properties

By moving tramadol hydrochloride to the extragranular phase (Example 3), the flow properties of the compression mixture were significantly improved (lower Hausner ratio, measurable bulk angle and time) with respect to the comparative example.

Table 2: Physical characteristics and sieve analysis of compression mixtures of Comparative example and Example 3.

The improvement in the flowabillity of the compression mixture is also reflected in the lower fluctuation of the uniformity of the content in the film-coated tablets.

Table 3: Content uniformity of film-coated tablets of Comparative example and Example 3

Content uniformity was determined according to Ph.Eur. 2.9.40, Uniformity of dosage units.

Dissolution

The dissolution profiles of the film-coated tablets are shown in figure 1 and 2. Figure 1 presents the dissolution profile of tramadol hydrochloride at initial value and Figure 2 presents the dissolution profile of dexketoprofen at initial value.

Stability

Table 4 shows the results of the stability tests of the film-coated tablets according to Reference Example (Skudexa), Comparative Example and Example 3 at 40 °C/75 % RH at 3 and 6 months, packed in PVC/PVDC/PVC forming film and sealing paper/aluminium foil. Stability was assessed by determining the relative amounts of dexketoprofen tromethamine amide as a degradation product.

Table 4: Stability tests of reference and examples

Both before (initial, t=0) and after exposureto accelerated storage conditions (3 or 6 months at 40°C and 75% RH), the amount of the amide impurity of dexketoprofen - dexketoprofen tromethamine amide present in the compositions was measured by HPLC (XBridge column with C18 stationary phase, mobile phase: mixture of water/acetonitrile/potassium hydrogencarbonate, UV detection at 270 nm). The data in the above table 4 indicates that the formulations of the present invention show significantly better chemical stability than the film-coated tablets of the reference example (Skudexa) under stress conditions at 40 °C / 75% RH for 6 months.

Packaging Example

The impact of different packaging materials on the stability of the product was evaluated in this example.

Table 5 shows the results of stability tests of the film-coated tablets according to the Reference Example (Skudexa) and Example 3, at 40 °C/75 % RH at 3 and 6 months, packed in PVC/PVDC/PVC forming film and sealing paper/aluminium foil (120 g/m² of PVDC) and a special type of blisters with a higher amount of PVDC (180 g/m²) - PVC/PE/PVDC/PE/PVC forming film and sealing paper/aluminium foil. Stability was assessed by determining the relative amounts of the degradation product dexketoprofen tromethamine amide.

Table 5: Stability tests in different primary packaging

Both before (initial, t=0) and after exposure to accelerated storage conditions (3 or 6 months at 40°C and 75% RH), the amount of the amide impurity of dexketoprofen - dexketoprofen tromethamine amide present in the compositions was measured by HPLC (XBridge column with C18 stationary phase, mobile phase: mixture of water/acetonitrile/potassium hydrogencarbonate, UV detection at 270 nm).

The data in table 5 above reveals that the stability of the solid oral dosage forms of the present invention can be further improved by using a primary packaging with a higher amount of PVDC (180 g/m²). Even after exposure to stress conditions of 40 °C and 75 % RH for 3 or 6 months, the tablet retains appropriate physical properties, as only a small drop in hardness comparable to the initial measurements are detected (Table 6).

Table 6: Hardness of film-coated tablets after accelerated conditions in different primary packaging.

Claims

2. Solid oral dosage form according to claim 1, which is a tablet and preferably a film- coated tablet.

S. Solid oral dosage form according to claim 1 or 2, wherein the average particle size of the components forming the extragranular phase is between 100 and S00 pm.

4. Solid oral dosage form according to anyone of claims 1 to 3, wherein the intragranular phase contains a diluent selected from microcrystalline cellulose, silicified microcrystalline cellulose, and mixtures thereof or wherein the extragranular phase contains a diluent selected from microcrystalline cellulose, silicified microcrystalline cellulose, and mixtures thereof, or wherein both intragranular and extragranular phase contain a diluent selected from microcrystalline cellulose, silicified microcrystalline cellulose, and mixtures thereof, or wherein no lactose is contained in the solid oral dosage form.

5. Solid oral dosage form according to anyone of claims 1 to 4, wherein the intragranular phase contains a disintegrant selected from croscarmellose sodium, carmellose sodium, carmellose calcium, carmellose, crospovidone, and mixtures thereof or wherein the extragranular phase contains a disintegrant selected from croscarmellose sodium, carmellose sodium, carmellose calcium, carmellose, crospovidone, and mixtures thereof, or wherein both intragranular and extragranular phase contain a disintegrant selected from croscarmellose sodium, carmellose sodium, carmellose calcium, carmellose, crospovidone, and mixtures thereof.

6. Solid oral dosage form according to anyone of claims 1 to 5, wherein the intragranular phase contains a lubricant selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, talc, macrogols, and mixtures thereof or wherein the extragranular phase contains a lubricant selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, talc, macrogols, and mixtures thereof, or wherein both intragranular and extragranular phase contain a lubricant selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, talc, macrogols, and mixtures thereof.

7. Solid oral dosage form according to anyone of claims 1 to 6, wherein the intragranular phase contains a glidant selected from talc, silica derivates, anhydrous colloidal silica, hydrated colloidal silica, and mixtures thereof or wherein the extragranular phase contains a glidant selected from talc, silica derivates, anhydrous colloidal silica, hydrated colloidal silica, and mixtures thereof, or wherein both intragranular and extragranular phase contain a glidant selected from talc, silica derivates, anhydrous colloidal silica, hydrated colloidal silica, and mixtures thereof.

8. Solid oral dosage form according to anyone of claims 1 to 7, wherein tramadol having an average particle size between 10 and 300 pm, preferably between 60 and 150 pm is used.

9. Method for manufacturing the solid oral dosage form of anyone of claims 1 to 8, which comprises the steps of

(a) mixing dexketoprofen trometamol and one or more excipients;

(b) granulating the resulting mixture by dry granulation;

(d) converting the resulting mixture into the solid oral dosage form.

10. Method for manufacturing the solid oral dosage form of anyone of claims 1 to 8, which comprises the steps of

(a) mixing tramadol hydrochloride and one or more excipients;

(b) granulating the resulting mixture by dry granulation;

(d) converting the resulting mixture into the solid oral dosage form.

11. The method of claim 9 or 10, wherein the mixture of step (a) and/or the mixture of step (c) is sieved before it is further processed.

12. The method of claim 9, 10 or 11, wherein step (d) includes compression of the mixture to obtain a tablet, optionally followed by film coating.

13. Packaged pharmaceutical product, wherein the solid oral dosage form of anyone of claims 1 to 8 is packaged in a primary packaging comprising a PVDC material.

14. The packaged pharmaceutical product of claim 13, wherein the PVDC material comprises PVDC in an amount of 120 g/m² or more such as 180 g/m², wherein the PVDC-containing material is preferably PVC/PVDC/PVC primary packaging with 120 g/m² PVDC content or PVC/PE/PVDC/PE/PVC primary packaging with 180 g/m² PVDC content.

15. Solid oral dosage form according to anyone of claims 1 to 8 or packaged pharmaceutical product according to anyone of claims 13 or 14 for use in the treatment of pain.