WO2017114597A1

WO2017114597A1 - Pharmaceutical dosage forms comprising ((cis)-n-(4-(dimethylamino)-1,4- diphenylcyclohexyl)-n-methylcinnamamide

Info

Publication number: WO2017114597A1
Application number: PCT/EP2016/025182
Authority: WO
Inventors: Thomas Zöller; Stefanie Straub; Marc Schiller
Original assignee: Grünenthal GmbH
Priority date: 2015-12-28
Filing date: 2016-12-21
Publication date: 2017-07-06

Abstract

The present invention relates to pharmaceutical dosage forms comprising the hemi-L-tartrate salt of the compound according to formula (I) in particulate form, wherein the particles have a d₅₀ of more than 20 μm and less than 180 μm.

Description

Pharmaceutical dosage forms comprising ((cis)-N-(4-(dimethylamino)-1 ,4- diphenylcyclohexyl)-N-methylcinnamamide

FIELD OF THE INVENTION

The present invention relates to pharmaceutical dosage forms comprising the hemi-L-tartrate salt of the compound according to formula (I)

in particulate form, wherein the particles have a d₅₀ of more than 20 μηη and less than 180 m.

BACKGROUND OF THE INVENTION

One particular drug that is of great interest for use in treating pain is (cis)-N-(4- (dimethylamino)-1 ,4-diphenylcyclohexyl)-N-methylcinnamamide having the chemical structure according to formula (I) and which is known from WO 2009/1 18168 A1. The hemi- L-tartrate salt of (cis)-N-(4-(dimethylamino)-1 ,4-diphenylcyclohexyl)-N-methylcinnamamide is known from WO 2015/007388.

Both compounds display a high affinity against the μ-opioid-receptor and the NOP receptor, formerly also known as ORL1 -receptor, resulting in significantly increased safety margins compared to pure μ-opioids.

Although the hemi-L-tartrate salt shows improved solubility in various media compared to the (cis)-N-(4-(dimethylamino)-1 ,4-diphenylcyclohexyl)-N-methylcinnamamide in the form of the free base, it still has poor water solubility and therefore formulations are needed that provide a good bioavailability.

Therefore, it is an object of the present invention to provide a pharmaceutical dosage form comprising the hemi-L-tartrate salt of (cis)-N-(4-(dimethylamino)-1 ,4-diphenylcyclohexyl)-N- methylcinnamamide that provides good bioavailability of (cis)-N-(4-(dimethylamino)-1 ,4- diphenylcyclohexyl)-N-methylcinnamamide. In another aspect, the pharmaceutical dosage form preferably shows immediate release.

This object has been achieved by the present invention. It has been surprisingly found that pharmaceutical dosage forms containing hemi-L-tartrate salt of (cis)-N-(4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide in particulate form, wherein the particles have a d₅₀ of more than 20 μηη and less than 180 μηη, provide a good bioavailability of the hemi-L- tartrate salt. Furthermore, it has been surprisingly found that the production of the pharmaceutical dosage forms according to the present invention is good to handle in that, in particular, the dosage form or parts thereof do not stick or adhere to the production tools especially during the compression step.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows dissolution profiles in acetate buffer at pH 4.5 with 0.02% Brij. Figure 2 shows dissolution profiles in FaSSIF at pH 6.5. Figure 3 shows dissolution profiles in FeSSIF at pH 5.0. DETAILED DESCRIPTION

A first aspect of the invention relates to a pharmaceutical dosage form comprising the hemi- L-tartrate salt of the compound according to formula (I)

in particulate form,

wherein the particles have a d₅₀ of more than 20 μηη and less than 180 μηη.

(Cis)-N-(4-(dimethylamino)-1 ,4-diphenylcyclohexyl)-N-methylcinnamamide is one of two possible stereoisomers of N-(4-(dimethylamino)-1 ,4-diphenylcyclohexyl)-N-methyl- cinnamamide. Preferably, the diastereomeric excess of (cis)-N-(4-(dimethylamino)-1 ,4- diphenylcyclohexyl)-N-methylcinnamamide within the hemi-L-tartrate salt is according to the invention at least 90%de, more preferably at least 95%de, still more preferably at least 96%de, yet more preferably at least 97%de, even more preferably at least 98%de, most preferably at least 99%de, and in particular at least 99.5%de.

According to the present invention, the enantiomeric excess of the L-tartaric acid within the hemi-L-tartrate salt of (cis)-N-(4-(dimethylamino)-1 ,4-diphenylcyclohexyl)-N-methyl- cinnamamide is preferably at least 90%ee, more preferably at least 95%ee, still more preferably at least 96%ee, yet more preferably at least 97%ee, even more preferably at least 98%ee, most preferably at least 99%ee, and in particular at least 99.5%ee.

Further according to the present invention, the hemi-L-tartrate salt of (cis)-N-(4- (dimethylamino)-1 ,4-diphenylcyclohexyl)-N-methylcinnamamide can be regarded as an acid addition salt, whereas of the L-tartaric acid and the base (cis)-N-(4-(dimethylamino)-1 ,4- diphenylcyclohexyl)-N-methylcinnamamide. The stoichiometric ratio of (cis)-N-(4- (dimethylamino)-1 ,4-diphenylcyclohexyl)-N-methylcinnamamide : L-tartaric acid is about 1 : 0.5 (hemi salt).

The hemi-L-tartrate salt of (cis)-N-(4-(dimethylamino)-1 ,4-diphenylcyclohexyl)-N-methyl- cinnamamide is in the following also referred to as the "hemi-L-tartrate salt of the compound according to formula (I)" or the "hemi-L-tartrate salt".

According to the present invention, the term "hemi-L-tartrate salt" also encompasses any co- crystals or other complexes and types of complexes, respectively, such as "co-amorphic forms", particularly also possible solvates of the hemi-L-tartrate salt of (cis)-N-(4- (dimethylamino)-1 ,4-diphenylcyclohexyl)-N-methylcinnamamide.

However, in a preferred embodiment, the hemi-L-tartrate salt is present in at least partially crystalline form. More preferably, the hemi-L-tartrate salt is present in crystalline form.

According to the present invention, the pharmaceutical dosage form comprises the hemi-L- tartrate salt of the compound according to formula (I) in particulate form, wherein the particles have a d₅₀ of more than 20 μηη and less than 180 μηη.

For the purpose of specification, "d₅₀" refers to the median, volumetric diameter of the particles. The skilled artisan knows how to determine the size of particles. In particular, the d₅₀ can be determined with a Beckman Coulter PSD Type LS13320 equipped with a diode laser (λ = 750 nm).

In a preferred embodiment, the pharmaceutical dosage form comprises the hemi-L-tartrate salt of the compound according to formula (I) in particulate form, wherein the particles have a d₅₀ of more than 25 μηη, more preferably more than 30 μηη, still more preferably more than 35 μηη, even more preferably more than 40 μηη, yet more preferably more than 45 μηη, most preferably more than 50 μηη, in particular more than 55 μηη and, in each case, less than 180 μπι.

In another preferred embodiment, the pharmaceutical dosage form comprises the hemi-L- tartrate salt of the compound according to formula (I) in particulate form, wherein the particles have a d₅₀ of more than 20 μηη and less than 170 μηη, more preferably less than 150 μηη, still more preferably less than 130 μηη, even more preferably less than 1 10 μηη, yet more preferably less than 90 μηη, most preferably less than 80 μηη, and in particular less than 70 μπι.

In another preferred embodiment, the pharmaceutical dosage form comprises the hemi-L- tartrate salt of the compound according to formula (I) in particulate form, wherein the particles have a d₅o of from 21 μηη to 179 μηη. More preferably, the particles have a d₅o of from 25 μηη to 170 μηη, still more preferably 35 μηη to 150 μηη or 50 μηη to 160 μηη, yet more preferably 40 μηη to 130 μηη or 80 μηη to 150 μηη, even more preferably 45 μηη to 1 10 μηη or 100 μηη to 140 μηη, most preferably 50 μηη to 90 μηη or 1 10 μηη to 130 μηη, and in particular 50 μηη to 70 μηη.

In a preferred embodiment, the pharmaceutical dosage form comprises the hemi-L-tartrate salt of the compound according to formula (I) in particulate form, wherein the particles preferably have a d₅₀ of 60±35 nm, more preferably 60±30 nm, still more preferably 60±25 nm, even more preferably 60±20 nm, yet more preferably 60±15 nm, most preferably 60±10 nm, and in particular 60±5 nm.

In another preferred embodiment, the pharmaceutical dosage form comprises the hemi-L- tartrate salt of the compound according to formula (I) in particulate form, wherein the particles preferably have a d₅₀ of 90±65 nm, more preferably 90±55 nm, still more preferably 90±45 nm, even more preferably 90±35 nm, yet more preferably 90±25 nm, most preferably 90±15 nm, and in particular 90±10 nm. In still another preferred embodiment, the pharmaceutical dosage form comprises the hemi- L-tartrate salt of the compound according to formula (I) in particulate form, wherein the particles preferably have a d₅₀ of 120±59 nm, more preferably 120±50 nm, still more preferably 120±40 nm, even more preferably 120±30 nm, yet more preferably 120±20 nm, most preferably 120±10 nm, and in particular 120±5 nm.

In a preferred embodiment, the pharmaceutical dosage form according to the present invention contains the hemi-L-tartrate salt of the compound according to formula (I) in an amount of from 2 to 50 wt.-% relative to the total weight of the pharmaceutical dosage form.

In another preferred embodiment, the pharmaceutical dosage form according to the present invention comprises the hemi-L-tartrate salt in an amount of from 1 wt.-% to 80 wt.-%, more preferably 2 wt.-% to 60 wt.-%, still more preferably 5 wt.-% to 50 wt.-%, yet more preferably 8 wt.-% to 40 wt.-%, most preferably 12 wt.-% to 30 wt.-%, and in particular 15 wt.-% to 25 wt.-%, relative to the total weight of the pharmaceutical dosage form.

Preferably, the pharmaceutical dosage form according to the present invention comprises the hemi-L-tartrate salt in an amount of from 20±19 wt.-%, more preferably 20±15 wt.-%, still more preferably 20±12 wt.-%, even more preferably 20±10 wt.-%, yet more preferably 20±8 wt.-%, most preferably 20±5 wt.-%, and in particular 20±2 wt.-%, relative to the total weight of the pharmaceutical dosage form.

In another preferred embodiment, the pharmaceutical dosage form according to the present invention comprises the hemi-L-tartrate salt in an amount of from 50±30 wt.-%, more preferably 50±25 wt.-%, still more preferably 50±20 wt.-%, even more preferably 50±15 wt.- %, yet more preferably 50±10 wt.-%, most preferably 50±5 wt.-%, and in particular 50±2 wt- %, relative to the total weight of the pharmaceutical dosage form.

In still another preferred embodiment, the pharmaceutical dosage form according to the present invention comprises the hemi-L-tartrate salt in an amount of from 70±10 wt.-%, more preferably 70±8 wt.-%, still more preferably 70±6 wt.-%, most preferably 70±4 wt.-%, and in particular 70±2 wt.-%, relative to the total weight of the pharmaceutical dosage form.

Preferably, the pharmaceutical dosage form according to the present invention comprises at least 5 wt.-%, more preferably at least 7 wt.-%, still more preferably at least 10 wt.-%, even more preferably at least 12 wt.-%, yet more preferably at least 15 wt.-%, most preferably at least 17 wt.-%, and in particular at least 19 wt.-% of the hemi-L-tartrate salt, relative to the total weight of the pharmaceutical dosage form.

Preferably, the pharmaceutical dosage form according to the present invention does not contain any additional pharmacologically active ingredient apart from the hemi-L-tartrate salt of the compound according to formula (I).

In a particularly preferred embodiment, the pharmaceutical dosage form according to the present invention is for oral administration.

The pharmaceutical dosage form according to the present invention is preferably solid.

Further, the pharmaceutical dosage form according to the present invention preferably contains pharmaceutical excipients.

Preferably, the pharmaceutical dosage form comprises a filler or a binder. As many fillers can be regarded as binders and vice versa, for the purpose of specification "filler/binder" refers to any excipient that is suitable as filler, binder or both. Thus, the pharmaceutical dosage form preferably comprises a filler/binder.

Preferred fillers (=filler/binders) are selected from the group consisting of silicon dioxide (e.g. Aerosil^®, RxCipients^®GL), microcrystalline cellulose (e.g. Avicel^®, Elcema^®, Emocel^®, ExCel^®, Vitacell^®); cellulose ether (e.g. Natrosol^®, Klucel^®, Methocel^®, Blanose^®, Pharmacoat^®, Viscontran^®); mannitol; dextrines; dextrose; calciumhydrogen phosphate (e.g. Emcompress^®); maltodextrine (e.g. Emdex^®); lactose (e.g. Fast-Flow Lactose^®; Ludipress® Pharmaceutical dosage formtose^®, Zeparox^®); mixtures of lactose and microcrystalline cellulose, in particular a co-spray-dried mixture of 75% alpha-lactose monohydrate and 25% microcrystalline cellulose (e.g. Microcelac^®); polyvinylpyrrolidone (PVP) (e.g. Kollidone^®, Polyplasdone^®, Polydone^®); saccharose (e.g. Nu-Tab^®, Sugar Tab^®); magnesium salts (e.g. MgC0₃, MgO, MgSi0₃); starches and pretreated starches (e.g. Prejel^®, Primotab^® ET, Starch^® 1500). Preferred binders are selected from the group consisting of alginates; chitosanes; and any of the fillers mentioned above (= fillers/binders).

In a preferred embodiment, the pharmaceutical dosage form according to the present invention contains at least one filler selected from the group consisting of silicon dioxide, microcrystalline cellulose; cellulose ether; mannitol; dextrines; dextrose; calciumhydrogen phosphate; maltodextrine; lactose; a mixture of alpha-lactose monohydrate and microcrystalline cellulose; polyvinylpyrrolidone; saccharose; magnesium salts; starch and pretreated starch.

Preferably, the pharmaceutical dosage form according to the present invention comprises one or more filler/binder, more preferably a co-spray-dried mixture of 75% alpha-lactose monohydrate and 25% microcrystalline cellulose.

Some fillers/binders may also serve other purposes. It is known, for example, that silicon dioxide exhibits excellent function as a glidant. Thus, preferably, the pharmaceutical dosage form comprises a glidant such as silicon dioxide, more preferably precipitated silica.

In a preferred embodiment, the content of the filler/binder or mixture of fillers/binders in the pharmaceutical dosage form is within the range of 75±23 wt.-%, more preferably 75±20 wt.- %, still more preferably 75±16 wt.-%, yet more preferably 75±12 wt.-%, most preferably 75±8 wt.-%, and in particular 75±5 wt.-%, based on the total weight of the pharmaceutical dosage form.

Preferably, the pharmaceutical dosage form comprises one or more diluents or lubricants (herein forth lubricants), preferably selected from the group consisting of calcium stearate; magnesium stearate; sodium stearate; stearic acid; sodium lauryl sulfate (sodium dodecyl sulfate); magnesium lauryl sulfate; glycerol monobehenate (e.g. Compritol^®); Myvatex^®; Precirol^®; Precirol^® ATO 5; sodium stearylfumarate (e.g. Pruv^®); and talcum. Magnesium stearate and sodium lauryl sulfate are particularly preferred. Preferably, the content of the lubricant or the mixture of lubricants in the pharmaceutical dosage form is at most 10.0 wt.- %, more preferably at most 7.5 wt.-%, still more preferably at most 5.0 wt.-%, yet more preferably at most 2.0 wt.-%, and most preferably at most 1.5 wt.-%, based on the total weight of the pharmaceutical dosage form.

In particularly preferred embodiment, the outer matrix material comprises a combination of filler/binder and lubricant.

Preferably, the pharmaceutical dosage form comprises a disintegrant, preferably selected from the group consisting of crosslinked polyvinylpyrrolidone (PVP) (e.g. Kollidon^® CL), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium) and modified starch sodium starch glycolate. Crosslinked polyvinylpyrrolidone (PVP) is particularly preferred. Preferably, the content of the disintegrant in the pharmaceutical dosage form is within the range of 2.5±2.0 wt.-%, more preferably 2.5±1 .5 wt.-%, still more preferably 2.5±1.0 wt.-%, most preferably 2.5±0.5 wt.-%, and in particular 2.5±0.2 wt.-%, based on the total weight of the pharmaceutical dosage form.

In a preferred embodiment, the pharmaceutical dosage form according to the present invention contains a disintegrant selected from the group consisting of crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose and modified starch sodium starch glycolate.

In another preferred embodiment, the pharmaceutical dosage form according to the present invention contains

a disintegrant, which content is within the range of 2.5±2.0 wt.-%, relative to the total weight of the pharmaceutical dosage form; and/or

a filler, which content is within the range of 75±23 wt.-% relative to the total weight of the pharmaceutical dosage form.

The pharmaceutical dosage form according to the present invention may additionally contain other excipients that are conventional in the art, e.g. granulating aids, colorants, flavor additives and wet-regulating agents. The skilled person will readily be able to determine appropriate further excipients as well as the quantities of each of these excipients. Specific examples of pharmaceutically acceptable carriers and excipients are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986). Further, the skilled person knows that the selection of pharmaceutical excipients and the amounts of the same to be used depends, for example, on how the pharmacologically active ingredient, i.e. the hemi-L-tartrate salt, is to be administered, e.g. orally.

In a preferred embodiment, the pharmaceutical dosage form according to the present invention consists of the hemi-L-tartrate salt, one or more fillers/binders, of one or more disintegrants, one or more lubricants, and one or more surfactants but does not contain any other constituents.

Particularly preferred pharmaceutical excipients are magnesium stearate; sodium dodecylsulfate; alpha-lactose monohydrate; microcrystalline cellulose; mixtures of alpha- lactose monohydrate and microcrystalline cellulose, in particular a co-spray-dried mixture of 75% alpha-lactose monohydrate and 25% microcrystalline cellulose; precipitated silica and crosslinked polyvinylpyrrolidone (PVP). In a preferred embodiment, the pharmaceutical dosage form according to the present invention contains at least one pharmaceutical excipient selected from the group consisting of magnesium stearate; sodium dodecylsulfate; alpha-lactose monohydrate; microcrystalline cellulose; precipitated silica and crosslinked polyvinylpyrrolidone.

Pharmaceutical dosage forms which are suitable for oral administration include but are not limited to tablets, effervescent tablets, chewing tablets and dragees. Oral pharmaceutical dosage forms may also be in the form of multiparticulates such as granules, pellets, spheres, crystals and the like, optionally compressed into a tablet.

Solid pharmaceutical dosage forms, such as tablets or pills can also be coated with conventional film coating compositions. Suitable coating materials are commercially available and may contain excipients such as stabilizers. Further, the coating can principally be resistant to gastric juices and dissolve as a function of the pH value of the release environment. Corresponding materials and methods for the delayed release of pharmacologically active ingredients and for the application of coatings which are resistant to gastric juices are known to the person skilled in the art, for example from "Coated Pharmaceutical dosage forms - Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials" by Kurt H. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1 st edition, 1998, Medpharm Scientific Publishers.

In a preferred embodiment, the pharmaceutical dosage form according to the present invention is coated. In another preferred embodiment, the pharmaceutical dosage form according to the present invention is not coated.

In an especially preferred embodiment, the pharmaceutical dosage form according to the present invention is a tablet, more preferably a compressed tablet.

The production of the dosage forms according to the present invention preferably comprise the following steps (i) mixing the particulate hemi-L-tartrate salt with one or more pharmaceutical excipients, (ii) compressing the mixture obtained in step (i) into tablets and (iii) optionally coating the tablets obtained in step (ii).

Preferably, the mixture of the particulate hemi-L-tartrate salt and one or more pharmaceutical excipients does not segregate during storage. Further, the mixture of the particulate hemi-L- tartrate salt and one or more pharmaceutical excipients does not segregate during the tableting process.

In a preferred embodiment, the pharmaceutical dosage form according to the present invention is for administration six times daily, five times daily, four times daily, thrice daily, twice daily, once daily, or less frequently.

The pharmaceutical dosage form according to the present invention may provide under in vitro conditions immediate release or controlled release of the hemi-L-tartrate salt of the compound according to formula (I). In vitro release is preferably determined in accordance with Ph. Eur., paddle method without sinker, 50 rpm, 500 or 1000 mL artificial gastric juice, fasted state simulated intestinal fluid (FaSSIF) pH 6.5 or fed state simulated intestinal fluid (FeSSIF) pH 5.0.

The person skilled in the art knows how to prepare FaSSIF and FeSSIF. Preferably, FaSSIF and FeSSIF are prepared using the commercially available Phares SIF™ Powder.

Preferably, FaSSIF is prepared by first making FaSSIF phosphate buffer. The FaSSIF phosphate buffer is preferably prepared by dissolving NaOH (pellets, 2.10 g), NaH₂P0₄-H₂0 (19.77 g) and NaCI (30.93 g) in approximately 4.9 L of purified water. Then, the pH of this buffer solution is adjusted to exactly 6.5 using either 1 N NaOH or 1 N HCI and made up to volume thereby obtaining the FaSSIF phosphate buffer.

To prepare the FaSSIF, preferably approximately 500 mL of the FaSSIF phosphate buffer are used to dissolve 2.24 g of Phares SIF™ Powder. The dispersion is stirred and when a clear solution is obtained, the volume is increased to 1 L with FaSSIF phosphate buffer thereby obtaining the FaSSIF.

Preferably, FeSSIF is prepared by first making FeSSIF acetate buffer. The FeSSIF acetate buffer is preferably prepared by dissolving NaOH (pellets, 20.20 g), glacial acetic acid (43.25 g) and NaCI (59.37 g) in approximately 4.9 L of purified water. Then, the pH of this buffer solution is adjusted to exactly 5 using either 1 N NaOH or 1 N HCI and made up to volume thereby obtaining the FeSSIF acetate buffer.

To prepare the FeSSIF, preferably approximately 500 mL of the FeSSIF acetate buffer are used to dissolve 1 1.2 g of Phares SIF™ Powder. The dispersion is stirred and when a clear solution is obtained, the volume is increased to 1 L with FeSSIF acetate buffer thereby obtaining the FeSSIF. In a preferred embodiment, the pharmaceutical dosage form according to the present invention provides immediate release of the hemi-L-tartrate salt of the compound according to formula (I) contained therein.

In another preferred embodiment, the hemi-L-tartrate salt of the compound according to formula (I) is at least partially present in controlled-release form. The term controlled release as used herein refers to any type of release other than immediate release such as delayed release, sustained release, slow release, extended release and the like. These terms are well known to any person skilled in the art as are the means, devices, methods and processes for obtaining such type of release.

Preferably, under physiological conditions the pharmaceutical dosage form according to the present invention has released after 5 minutes 5 to 75%, after 10 minutes 15 to 95%, after 15 minutes 20 to 100% and after 30 minutes 40 to 100% of the hemi-L-tartrate salt. Further preferred release profiles Ri to R₃ are summarized in the table here below [all data in wt.-% of released hemi-L-tartrate salt]:

In a preferred embodiment, in FeSSIF at pH 5.0 after 5 min at least 30 wt.-%, more preferably at least 35 wt.-% and most preferably at least 40 wt.-% of the hemi-L-tartrate salt of the compound according to formula (I) have been released. In another preferred embodiment, in FeSSIF at pH 5.0 after 15 min at least 55 wt.-%, more preferably at least 60 wt.-%, most preferably at least 65 wt.-%, and in particular at least 70 wt.-% of the hemi-L- tartrate salt of the compound according to formula (I) have been released.

In still another preferred embodiment, in FaSSIF at pH 6.5 after 15 min at least 30 wt.-%, more preferably at least 33 wt.-% of the hemi-L-tartrate salt of the compound according to formula (I) have been released. In yet another preferred embodiment, in FaSSIF at pH 6.5 after 60 min at least 75 wt.-%, more preferably at least 78 wt.-%, of the hemi-L-tartrate salt of the compound according to formula (I) have been released. In another preferred embodiment, under physiological conditions the pharmaceutical dosage form according to the present invention has released after 30 minutes 0.1 to 75%, after 240 minutes 0.5 to 95%, after 480 minutes 1.0 to 100% and after 720 minutes 2.5 to 100% of the hemi-L-tartrate salt. Further preferred release profiles R₄ to R₆ are summarized in the table here below [all data in wt.-% of released hemi-L-tartrate salt]:

In a preferred embodiment, in FeSSIF at pH 5.0 after 30 min at most 50 wt.-%, more preferably at most 40 wt.-% and most preferably at most 30 wt.-% of the hemi-L-tartrate salt of the compound according to formula (I) have been released. In another preferred embodiment, in FeSSIF at pH 5.0 after 60 min at most 60 wt.-%, more preferably at most 50 wt.-% and most preferably at most 40 wt.-% of the hemi-L-tartrate salt of the compound according to formula (I) have been released.

In still another preferred embodiment, in FaSSIF at pH 6.5 after 30 min at most 50 wt.-%, more preferably at most 40 wt.-% and most preferably at most 30 wt.-% of the hemi-L-tartrate salt of the compound according to formula (I) have been released. In yet another preferred embodiment, in FaSSIF at pH 6.5 after 60 min at most 60 wt.-%, more preferably at most 50 wt.-% and most preferably at most 40 wt.-% of the hemi-L-tartrate salt of the compound according to formula (I) have been released.

Preferably, the release profile, the hemi-L-tartrate salt and the optionally present pharmaceutical excipients of the pharmaceutical dosage form according to the invention are stable upon storage, preferably upon storage at elevated temperature, e.g. 40°C, for 3 months in sealed containers.

In connection with the release profile, the term "stable" preferably means that when comparing the initial release profile with the release profile after storage, at any given time point the release profiles deviate from one another by not more than 50%, more preferably not more than 30%, most preferably not more than 20% and in particular not more than 15%. In a preferred embodiment, the pharmaceutical dosage form according to the present invention has a breaking strength of at least 30 N, more preferably at least 35 N, still more preferably at least 40 N, even more preferably at least 45 N, yet more preferably at least 50 N, most preferably at least 55 N, and in particular at least 60 N or at least 65 N or at least 70 N.

In another preferred embodiment, the pharmaceutical dosage form according to the present invention has a breaking strength in the range of from 30 N to 220 N, more preferably 35 N to 200 N, still more preferably 40 N to 170 N, even more preferably 45 N to 150 N, yet more preferably 50 N to 130 N, most preferably 55 N to 1 10 N, and in particular 60 N to 100 N.

In still another preferred embodiment, the pharmaceutical dosage form according to the present invention has a breaking strength of at most 220 N, more preferably at most 200 N, still more preferably at most 180 N, most preferably at most 150 N, and in particular at most 100 N.

The "breaking strength" (resistance to crushing) of a pharmaceutical dosage form is known to the skilled person. In this regard it can be referred to, e.g., W.A. Ritschel, Die Tablette, 2. Auflage, Editio Cantor Verlag Aulendorf, 2002; H Liebermann et al., Pharmaceutical dosage forms: Pharmaceutical dosage forms, Vol. 2, Informa Healthcare; 2 edition, 1990; and Encyclopedia of Pharmaceutical Technology, Informa Healthcare; 1 edition. For the purpose of specification, the breaking strength is preferably defined as the amount of force that is necessary in order to fracture a pharmaceutical dosage form (= breaking force). Methods for measuring the breaking strength are known to the skilled artisan. Suitable devices are commercially available.

In another embodiment of the present invention

• the pharmaceutical dosage form comprises the hemi-L-tartrate salt of the compound according to formula (I) in particulate form, wherein the particles have a d₅₀ of from 40 μηη to 130 μηη; and/or

• the pharmaceutical dosage form is for oral administration; and/or

• the pharmaceutical dosage form is a solid and/or compressed drug form; and/or

• the pharmaceutical dosage form provides immediate release of the hemi-L-tartrate salt contained therein; and/or

• the pharmaceutical dosage form contains the hemi-L-tartrate salt in a quantity of 5 wt.-% to 50 wt.-%, based on the total weight of the pharmaceutical dosage form; and/or • the pharmaceutical dosage form is a tablet.

In another aspect, the present invention relates to the use of the pharmaceutical dosage form according to the present invention in the treatment of pain.

In a preferred embodiment, the pharmaceutical dosage form according to the present invention is for use in the treatment of pain, wherein the pain is preferably acute, visceral, neuropathic or chronic pain.

For the purpose of specification, "acute pain" preferably refers to pain that lasts up to about 4 weeks and "chronic pain" preferably refers to pain that lasts for more than about 12 weeks.

In a particularly preferred embodiment, the present invention relates to the use of the pharmaceutical dosage form according to the present invention in the treatment of pain, wherein the pain is selected from the group consisting of acute, visceral, neuropathic or chronic pain.

Furthermore, the present invention relates to a method for treating pain in a patient, preferably in a mammal, which comprises administering a pharmaceutical dosage form according to the present invention to a patient.

EXAMPLES

(Cis)-N-(4-(dimethylamino)-1 ,4-diphenylcyclohexyl)-N-methylcinnam (hereafter referred to as "API free base") was synthesized according to the procedure disclosed in WO 2009/1 18168 (see Example 24).

MicroceLac 100 co-spray-dried mixture of 75% alpha-lactose monohydrate and

25% microcrystalline cellulose

RxCIPIENTS GL 100 precipitated silica

Kollidon CL crosslinked polyvinylpyrrolidone (PVP)

Brij 35 polyoxyethylene lauryl ether

Preparation of API salt particles

For the preparation of the hemi-L-tartrate salt of (cis)-N-(4-(dimethylamino)-1 ,4- diphenylcyclohexyl)-N-methylcinnamamide (hereafter referred to as "API salt"), API free base (2.30 kg), L(+) tartaric acid (0.79 kg) and 2-propanol (69 L) were charged into a 100 L-vessel equipped with a stirrer. The mixture was heated to 30°C and stirred at 200 rpm for 20 h. Then, the temperature was decreased to 20°C and the mixture was stirred for further 75 min at 200 rpm. Afterwards, the precipitated API salt was separated by filtration and dried in a drying cabinet at 45°C and <100 mbar for 22 h.

The API salt was sieved with sieves having the following US standard mesh sizes: 400 (37 μηη opening), 170 (88 μηη opening), 100 (149 μηη opening), 60 (250 μηη opening).

The particle size distribution of the sieved API salt and the volumetric diameter d₅₀ were determined with a Beckman Coulter PSD Type LS13320 equipped with a diode laser (λ = 750 nm).

Example 1 : Preparation of pharmaceutical dosage forms

For manufacturing the pharmaceutical dosage form, mixtures of the API salt particles and excipients were produced by weighing the ingredients (batch size 1 to 1 .5 kg), sieving (Mesh size 1.0 mm), blending in a Bohle LM 40 MC 20, followed by direct compression into tablets (rotary press Fette 102i without dusting system; punch format: 7 mm round, HPG-P (25 mg dose strength); rotational speed: 20,000 - 30,000 tablets/h). Tablets were prepared having the composition shown in Table 1 below.

Table 1 :

The amount of the API salt (20 wt.-%) was calculated based on the actual content of API salt in the respective API salt batch. The thus resulting variations in the amount of API salt required were compensated for by adapting the amount of MicroceLac 100 accordingly. Therefore, all tablets prepared contained 20 wt.-% of API salt but if e.g. the true content of API salt in the API salt batch was 95 wt.-% then the amount of weighed in API salt was adjusted to 23.53 wt.-% and the amount of MicroceLac 100 to 72.27 wt.-%.

Tablets were prepared having the composition according to Table 1 . The characteristics of these tablets are summarized in Table 2 below.

Table 2:

In Table 2 "-" means that the respective measurement was not carried out.

Breaking strength was determined with a Sotax HT 100 Multicheck system.

Disintegration in water was measured in a disintegration tester without disk according to Ph. Eur. Monograph 2.9.1 (2013, 7^th Edition Supplemen 7.8). The disintegration time given in Table 2 is the time after which the tablet had lost its shape and disintegrated into an amorphous mass.

Friability was measured after 100 rotations according to Ph. Eur. Monograph 2.9.7. The percentage value indicated in Table 2 is the relative weigh amount the tablet lost during this test.

Example 2: Content uniformity

Content uniformity of the pharmaceutical dosage forms of Example 1 was determined according to Ph. Eur. 2.9.40. The acceptance values determined are summarized in Table 3 below.

Sampling of tablets was carried out at the beginning, middle and end of the tableting (see also Table 2 for tableting speed).

Table 3:

In Table 3 "-" means that the respective measurement was not carried out.

As can be seen from above data, all the tablets had good acceptance values (<15) and accordingly good content uniformity.

Example 3: Dissolution profiles

Dissolution profiled of the pharmaceutical dosage forms of Example 1 were determined and are depicted in Figures 1 to 3.

The release profile of pharmaceutical dosage forms containing API salt particles (d₅₀ = 20 μηη, 60 μηη, 120 μηη and 180 μηη), respectively, was determined under in vitro conditions using the paddle method according to Ph. Eur. at 50 rpm in 1000 ml. of acetate buffer with 0.02% Brij (pH 4.5, without sinker, n = 3). The results are summarized in Figure 1.

For dissolution profils under in vitro conditions, FaSSIF and FeSSIF were prepared.

FaSSIF was prepared by first making FaSSIF phosphate buffer. The FaSSIF phosphate buffer was prepared by dissolving NaOH (pellets, 2.10 g), NaH₂P0₄-H₂0 (19.77 g) and NaCI (30.93 g) in approximately 4.9 L of purified water. Then, the pH of this buffer solution was adjusted to exactly 6.5 using either 1 N NaOH or 1 N HCI and made up to volume thereby obtaining the FaSSIF phosphate buffer. To prepare the FaSSIF, approximately 500 mL of the FaSSIF phosphate buffer were used to dissolve 2.24 g of Phares SIF™ Powder. The dispersion was stirred and when a clear solution was obtained, the volume was increased to 1 L with FaSSIF phosphate buffer thereby obtaining the FaSSIF.

FeSSIF was prepared by first making FeSSIF acetate buffer. The FeSSIF acetate buffer was prepared by dissolving NaOH (pellets, 20.20 g), glacial acetic acid (43.25 g) and NaCI (59.37 g) in approximately 4.9 L of purified water. Then, the pH of this buffer solution was adjusted to exactly 5 using either 1 N NaOH or 1 N HCI and made up to volume thereby obtaining the FeSSIF acetate buffer.

To prepare the FeSSIF, approximately 500 mL of the FeSSIF acetate buffer were used to dissolve 1 1.2 g of Phares SIF™ Powder. The dispersion was stirred and when a clear solution was obtained, the volume was increased to 1 L with FeSSIF acetate buffer thereby obtaining the FeSSIF.

The release profile of pharmaceutical dosage forms containing API salt particles (d₅₀ = 20 μηη, 60 μηη and 180 μηη) was determined under in vitro conditions using the paddle method according to Ph. Eur. at 50 rpm in 500 mL of fasted state simulated intestinal fluid (FaSSIF) (pH 6.5, without sinker, n = 3). The results are summarized in Figure 2.

The release profile of pharmaceutical dosage forms containing API salt particles (d₅₀ = 20 μηη, 60 μηη and 180 μηη) was determined under in vitro conditions using the paddle method according to Ph. Eur. at 50 rpm in 1000 mL of fed state simulated intestinal fluid (FeSSIF) (pH 5.0, without sinker, n = 3). The results are summarized in Figure 3.

Claims

1. A pharmaceutical dosage form comprising the hemi-L-tartrate salt of the compound according to formula (I)

in particulate form,

2. The pharmaceutical dosage form according to claim 1 which is for oral administration.

3. The pharmaceutical dosage form according to claim 1 or 2 which has a breaking strength of at least 30 N.

4. The pharmaceutical dosage form according to any of the preceding claims, wherein in fed state simulated intestinal fluid (FeSSIF) at pH 5.0 after 5 min at least 30 wt.-% of the hemi-L-tartrate salt of the compound according to formula (I) have been released.

5. The pharmaceutical dosage form according to any of the preceding claims, wherein in fed state simulated intestinal fluid (FeSSIF) at pH 5.0 after 15 min at least 55 wt.-% of the hemi-L-tartrate salt of the compound according to formula (I) have been released.

6. The pharmaceutical dosage form according to any of the preceding claims, wherein in fasted state simulated intestinal fluid (FaSSIF) at pH 6.5 after 15 min at least 30 wt.-% of the hemi-L-tartrate salt of the compound according to formula (I) have been released.

7. The pharmaceutical dosage form according to any of the preceding claims, wherein in fasted state simulated intestinal fluid (FaSSIF) at pH 6.5 after 60 min at least 75 wt.-% of the hemi-L-tartrate salt of the compound according to formula (I) have been released. The pharmaceutical dosage form according to any of the preceding claims, which provides immediate release of the hemi-L-tartrate salt of the compound according to formula (I) contained therein. 9. The pharmaceutical dosage form according to any of the preceding claims, which contains the hemi-L-tartrate salt of the compound according to formula (I) in an amount of from 2 to 50 wt.-% relative to the total weight of the pharmaceutical dosage form.

The pharmaceutical dosage form according to any of the preceding claims, which contains a disintegrant selected from the group consisting of crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose and modified starch sodium starch glycolate.

The pharmaceutical dosage form according to any of the preceding claims, which contains at least one filler selected from the group consisting of silicon dioxide, microcrystalline cellulose; cellulose ether; mannitol; dextrines; dextrose; calciumhydrogen phosphate; maltodextrine; lactose; a mixture of alpha-lactose monohydrate and microcrystalline cellulose; polyvinylpyrrolidone; saccharose; magnesium salts; starch and pretreated starch.

The pharmaceutical dosage form according to claim 10 or 1 1 , which contains a disintegrant, which content is within the range of 2.5±2.0 wt.-%, relative to the total weight of the pharmaceutical dosage form; and/or

13. The pharmaceutical dosage form according to any of the preceding claims, which contains at least one pharmaceutical excipient selected from the group consisting of magnesium stearate; sodium dodecylsulfate; alpha-lactose monohydrate; microcrystalline cellulose; precipitated silica and crosslinked polyvinylpyrrolidone.

14. Use of the pharmaceutical dosage form according to any of the preceding claims in the treatment of pain. 15. The use according to claim 14, wherein the pain is selected from the group consisting of acute, visceral, neuropathic or chronic pain.