WO2014135545A1 - Solid dispersion comprising amorphous lorcaserin hydrochloride - Google Patents

Solid dispersion comprising amorphous lorcaserin hydrochloride Download PDF

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Publication number
WO2014135545A1
WO2014135545A1 PCT/EP2014/054184 EP2014054184W WO2014135545A1 WO 2014135545 A1 WO2014135545 A1 WO 2014135545A1 EP 2014054184 W EP2014054184 W EP 2014054184W WO 2014135545 A1 WO2014135545 A1 WO 2014135545A1
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WO
WIPO (PCT)
Prior art keywords
solid dispersion
lorcaserin hydrochloride
hydrochloride
amorphous
lorcaserin
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PCT/EP2014/054184
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French (fr)
Inventor
Nolwenn Martin
Arthur Pichler
Franz Richter
Franz Xaver Schwarz
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Sandoz Ag
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Publication of WO2014135545A1 publication Critical patent/WO2014135545A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines

Definitions

  • Solid dispersion comprising amorphous lorcaserin hydrochloride
  • the present invention is directed to a solid dispersion comprising amorphous lorcaserin hydrochloride, a pharmaceutical composition comprising the solid dispersion as well as a process for obtaining the same.
  • Obesity is a life-threatening disorder in which there is an increased risk of morbity and mortality arising from concomitant diseases such as type II diabetes,
  • Lorcaserin (R)-8-chloro-1 - methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepin) is useful for treating obesity.
  • WO 03/086306 A1 focuses on 5HT 2 c receptor modulators and discloses selective 5HT 2 c agonists which reduce appetite and food consumption and, as a result, cause body weight loss to occur.
  • Lorcaserin racemate ((R)-8-chloro-1 -methyl-2, 3,4,5- tetrahydro-1 H-benzo[d]azepin) is disclosed in said reference.
  • WO 2006/069363 A2 refers to crystalline forms of lorcaserin, namely three crystalline forms of lorcaserin hydrochloride, individually designated as Form I, Form II and Form III.
  • Forms I and II are anhydrous, hygroscopic forms, both of which readily convert to Form III, a hemihydrate, upon exposure to moisture.
  • WO 201 1/153206 A1 discloses a further crystalline form of lorcaserin hydrochloride, namely Form IV, described to be a new anhydrous form, and its conversion to Form III, a lorcaserin hemihydrate, upon exposure to moisture.
  • a pharmaceutical composition must be stable in an environment having enhanced relative humidity in order to be suitable for tropical countries.
  • Forms I, II and IV (WO 201 1/153206 A1 ) are hygroscopic and, thus, are problematic for the purpose of producing a pharmaceutical composition suitable for use in tropical countries, since a pharmaceutical composition comprising these solid forms of lorcaserin hydrochloride can be expected to absorb water when exposed to an environment having a higher relative humidity.
  • Form III of lorcaserin hydrochloride has the drawback that it can convert (at least partially) to another form, such as Form II, under particular environmental conditions, for example when exposed to elevated temperature (see WO 201 1/153206 A1 ).
  • medicaments comprising Form III may not be stable at particular environmental conditions, such as elevated temperature.
  • WO 201 1/153206 A1 also refers to processes for the preparation of selective 5HT 2 c agonists.
  • Example 5 of said reference is directed to the thermodynamic relationships between lorcaserin hydrochloride salt hemihydrate Form III and the anhydrous polymorphs of lorcaserin hydrochloride salt.
  • WO 201 1/153206 A1 describes that at a critical water activity a w a given anhydrous form and lorcaserin hydrochloride salt hemihydrate will have equal solubility and can coexist in equilibrium. Below the critical a w , the anhydrous form is described to be more thermodynamically stable, thus less soluble. Above the critical water activity lorcaserin hydrochloride salt hemihydrate Form III is described to be more thermodynamically stable, thus less soluble.
  • the water activity dependent equilibrium of lorcaserin hydrochloride hemihydrate Form III and the anhydrous polymorphs of lorcaserin hydrochloride salt can be a drawback for manufacturing a pharmaceutical composition based on lorcaserin hydrochloride Form III, as the pharmaceutical compositions comprising the desired Form III might not be obtained reliably or might not be stable upon storage with regard to the polymorphic form of the comprised lorcaserin hydrochloride.
  • the known crystalline forms of lorcaserin hydrochloride including Form III can be prone to polymorphic conversion when exposed to an environment having a higher relative humidity and/or an elevated temperature.
  • an active pharmaceutical ingredient can offer an opportunity to improve the performance profile of a pharmaceutical composition comprising said API.
  • the known solid forms of lorcaserin hydrochloride still leave room for improvement of the physicochemical as well as the pharmaceutical characteristics of lorcaserin containing pharmaceutical compositions.
  • Processability of the API during manufacture of the pharmaceutical composition and characteristics of the finished dosage form such as storage stability under difficult environmental conditions, such as high relative humidity and/or high temperature, can still be improved or optimized.
  • the presence of the high energy form of the API in a pharmaceutical composition usually improves the dissolution rate. However, these systems are not often physically stable.
  • WO 03/086306 A1 WO2005/019179 A2, WO 2006/069363 A2 and WO 201 1/153206 A1 refers to amorphous lorcaserin hydrochloride.
  • an object of the present invention is to provide a pharmaceutical composition comprising lorcaserin hydrochloride in a solid form, wherein the physicochemical stability of the solid form is improved, the dissolution characteristics of the solid form are improved and wherein lorcaserin hydrochloride is rendered more suitable for use in a storable pharmaceutical composition.
  • a solid dispersion comprising amorphous lorcaserin hydrochloride ((R)-8-chloro-1 -methyl- 2,3,4,5-tetrahydro-1 H-benzo[d]azepin hydrochloride) of formula 1
  • the present invention also provides a pharmaceutical composition comprising the solid dispersion as described above.
  • the present invention further describes processes for the preparation of the solid dispersion and the pharmaceutical composition described above.
  • the following abbreviations have the indicated meaning, unless explicitly stated otherwise:
  • XRPD specifications x-axis represents peak positions [°2 Theta] (Cu-K Q radiation) and y-axis shows relative intensities (counts).
  • Figure 1 XRPD of lorcaserin hydrochloride after fast solvent evaporation in rotary evaporator
  • Figure 2 XRPD of amorphous lorcaserin hydrochloride in form of a solid dispersion with HPMC (1 :3, prepared from lorcaserin hydrochloride), at ambient conditions
  • Figure 3 XRPD of amorphous lorcaserin hydrochloride in form of a solid dispersion with HPMC (1 :3) after storage at 40 °C and 63% r.h. for 2 months
  • amorphous lorcaserin hydrochloride apparently converts very quickly to one of the crystalline forms.
  • lorcaserin hydrochloride was prepared from lorcaserin free base and a solution of hydrogen chloride according to the literature (Comparative Example 1 ). Fast solvent evaporation in a rotary evaporator yielded lorcaserin hydrochloride as a crystalline powder. A representative diffractogram is displayed in Figure 1 .
  • amorphous lorcaserin hydrochloride such as a) dissolving crystalline lorcaserin hydrochloride in water and ethanol, fast freezing the homogeneous solution in a liquid nitrogen bath and lyophilizing (Comparative Example 2), b) putting crystalline lorcaserin hydrochloride (Form II) on a glass plate, heating over a Kofler bench until melting, followed by fast cooling over a metal plate at 0 °C and c) by grinding experiments where crystalline lorcaserin hydrochloride, Form II or Form III, was manually grinded in a mortar, always lorcaserin
  • the present invention relates to a solid dispersion comprising amorphous lorcaserin hydrochloride ((R)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepin hydrochloride) of formula 1
  • solid dispersion defines a system in a solid state (as opposed to a liquid or gaseous state) wherein one component is dispersed more or less evenly
  • amorphous lorcaserin hydrochloride within the water soluble polymer e.g. in the context of the present invention amorphous lorcaserin hydrochloride within the water soluble polymer.
  • Preferred solid dispersions are "solid solutions", where the dispersion of the components is such that the system is chemically and physically uniform or homogeneous throughout or even consists of one phase as defined by measurement of thermodynamic properties of the system, e.g. the amorphous lorcaserin
  • hydrochloride and the water soluble polymer form a system that is chemically and physically uniform or homogeneous throughout or even consists of one phase as defined by measurement of thermodynamic properties of the system.
  • Characteristic X-ray powder diffraction pattern of Form I comprises peaks at 2-theta angles of 1 1 .5 ⁇ 0.2°, 14.5 ⁇ 0.2°, 16.0 ⁇ 0.2°, 23.0 ⁇ 0.2° and 23.3 ⁇ 0.2°.
  • Characteristic X-ray powder diffraction pattern of Form II comprises peaks at 2-theta angles of 6.5 ⁇ 0.2°, 12.9 ⁇ 0.2°, 17.1 ⁇ 0.2°, 17.5 ⁇ 0.2° and 18.5 ⁇ 0.2°.
  • Characteristic X-ray powder diffraction pattern of Form III comprises peaks at 2-theta angles of 13.7 ⁇ 0.2°, 14.9 ⁇ 0.2°, 15.4 ⁇ 0.2°, 16.7 ⁇ 0.2° and 19.2 ⁇ 0.2°.
  • Characteristic X-ray powder diffraction pattern of Form IV comprises peaks at 2-theta angles of 8.9 ⁇ 0.2°, 10.7 ⁇ 0.2°, 15.3 ⁇ 0.2°, 17.8 ⁇ 0.2° and 18.3 ⁇ 0.2°.
  • the present invention circumvents the drawback of the known crystalline
  • hydrochloride salts of 3-benzazepine, 5-HT 2 c agonist compound of formula 1 i.e. Forms I, II, III and IV, by providing a solid dispersion comprising amorphous lorcaserin hydrochloride and a water soluble polymer as matrix material.
  • the solid dispersion of the present invention is obtainable as a solid dispersion that is stable and pure with regard to the physical form of amorphous lorcaserin hydrochloride therein, and that is obtainable in an easy and reliable manner, e.g. even in large scale.
  • the lorcaserin hydrochloride in the context of the solid dispersion of the present invention is stable in the amorphous state upon storage, as judged by the absence of characteristic XRPD peaks after storage.
  • "Stable in the amorphous stage upon storage" within the meaning of the present invention means that the solid dispersion of the present invention after storage at a relative humidity of 45% at 23°C for 14 days, preferably even after storage for 50 days, shows no signs of the presence of crystalline lorcaserin hydrochloride form III as judged by the absence of peaks at 2- theta angles of 13.7 ⁇ 0.2°, 14.9 ⁇ 0.2°, 15.4 ⁇ 0.2°, 16.7 ⁇ 0.2° and 19.2 ⁇ 0.2°, and in particular shows no signs of the presence of any one of the four known forms of crystalline lorcaserin hydrochloride, as judged by the absence of peaks at 2-theta angles of 1 1 .5 ⁇ 0.2°, 14.5 ⁇ 0.2°, 16.0 ⁇
  • Solid in the amorphous state upon storage under stress conditions in the context of the present invention means that the solid dispersion of the present invention when stored at a relative humidity of 70 % at 40°C for 14 days, preferably after storage for 50 days, shows no signs of the presence of crystalline lorcaserin hydrochloride form III as judged by the absence of peaks at 2-theta angles of 13.7 ⁇ 0.2°, 14.9 ⁇ 0.2°, 15.4 ⁇ 0.2°, 16.7 ⁇ 0.2° and 19.2 ⁇ 0.2°, and in particular shows no signs of the presence of any one of the four known forms of crystalline lorcaserin hydrochloride, as judged by the absence of peaks at 2-theta angles of 1 1 .5 ⁇ 0.2°, 14.5 ⁇ 0.2°, 16.0 ⁇ 0.2°, 23.0 ⁇ 0.2° and 23.3 ⁇ 0.2° (form I), 6.5 ⁇ 0.2°, 12.9 ⁇ 0.2°, 17.1 ⁇ 0.2°, 17.5
  • the solid dispersion of the present invention is a solid dispersion wherein the amorphous lorcaserin hydrochloride is stable in the amorphous stage upon storage. More preferably the solid dispersion of the present invention is a solid dispersion wherein the amorphous lorcaserin hydrochloride is stable in the amorphous stage upon storage under stress conditions.
  • the solid dispersion of the present invention is a chemically stable solid dispersion.
  • chemically stable it is meant that amorphous lorcaserin hydrochloride present in the solid dispersion of the present invention shows very little degradation upon storage under stress conditions, i.e. when stored at a relative humidity of 70 % at 40°C for 14 days, preferably after storage for 50 days.
  • the solid dispersion of the present invention is essentially non-hygroscopic. Consequently, controlled and expensive storage conditions, special and expensive packaging or addition of a stabilizing agent during preparation or for storage is not necessary (even though a stabilizing agent may be comprised in the pharmaceutical compositions of the present invention).
  • the solid dispersion of the present invention is thus suitable for the preparation of a pharmaceutical composition, in particular a solid pharmaceutical composition such as a solid oral dosage form, like a tablet.
  • the solid dispersion of the present invention is also easier to handle under typical pharmaceutical processing conditions, such as wet granulation, than crystalline lorcaserin hydrochloride Forms I, II, III and IV.
  • the solid dispersion of the present invention enables standard pharmaceutical processing conditions to be used, such as work in an atmosphere having a relative humidity of about 0 to 90 %.
  • solid dispersion of the present invention and a pharmaceutical composition comprising the same need not to be packaged into special
  • Inexpensive containers or blisters can be used for packaging.
  • the weight ratio of lorcaserin hydrochloride and the one or more water-soluble polymers is of from 1 : 10 to 2:1 , preferably from 1 : 10 to 1 :2,
  • the one or more water-soluble polymers have a solubility in water (23 °C, pH 7.0 or more) of at least 10 g/l and even more preferred of at least 33 g/l.
  • the one or more watersoluble polymers are homopolymers and/or copolymers.
  • Polymers that contain only a single type of repeat unit are known as homopolymers, while polymers containing a mixture of repeat units are known as copolymers.
  • the one or more water-soluble polymers are selected from the group consisting of chemically modified cellulose, cellulose ether,
  • polyvinylpyrrolidone polyethylene glycol, polyethylene glycol based copolymer, polyacrylic acids and salts thereof, polyvinylalcohol, polyacrylamides copolymer, methacrylic acid copolymer, methacrylate copolymer, pectines, chitin and chitosan derivatives, polyphosphates, polyoxazoline, polysaccharides or mixtures thereof.
  • the water soluble polymer is a chemically modified cellulose and/or cellulose ether, and in particular is selected from the group consisting of alkylcellulose, e.g. methylcellulose, ethylcellulose, propylcellulose;
  • hydroxalkylcellulose e.g. hydroxymethylcellulose, hydroxyethylcellulose,
  • hydroxypropylcellulose hydroxyalkylalkylcellulose, e.g. hydroxyethylmethylcellulose (HEMC), hydroxypropylmethylcellulose (HPMC); carboxyalkylcellulose, e.g carboxymethylcellulose (CMC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxyethylcarboxymethylcellulose (HECMC), sodium carboxymethylcellulose, cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose acetate (HPMCA), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS) or mixtures thereof.
  • CMC carboxymethylcellulose
  • CHEC carboxymethylhydroxyethylcellulose
  • HECMCMC hydroxyethylcarboxymethylcellulose
  • CAP hydroxypropylmethylcellulose acetate
  • HPMCA hydroxypropylmethylcellulose phthalate
  • HPMCP hydroxypropylmethylcellulose acetate succinate
  • HPMCAS hydroxy
  • the chemically modified cellulose and/or cellulose ether is selected from the group consisting of alkylcellulose, e.g. methylcellulose,
  • ethylcellulose propylcellulose
  • hydroxalkylcellulose e.g. hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose
  • hydroxyalkylalkylcellulose e.g.
  • HEMC hydroxyethylmethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • carboxyalkylcellulose e.g carboxymethylcellulose (CMC)
  • CMVEC carboxymethylhydroxyethylcellulose
  • HECMC hydroxyethylcarboxymethylcellulose
  • sodium carboxymethylcellulose or mixtures thereof.
  • a particularly preferred chemically modified cellulose is hydroxypropylmethylcellulose.
  • the present invention relates to a solid dispersion comprising amorphous lorcaserin hydrochloride and a chemically modified cellulose and/or cellulose ether, wherein the chemically modified cellulose and/or cellulose ether is selected from the group consisting of alkylcellulose, e.g. methylcellulose,
  • ethylcellulose propylcellulose
  • hydroxalkylcellulose e.g. hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose
  • hydroxyalkylalkylcellulose e.g.
  • HEMC hydroxyethylmethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • carboxyalkylcellulose e.g carboxymethylcellulose (CMC)
  • CMVEC carboxymethylhydroxyethylcellulose
  • HECMC hydroxyethylcarboxymethylcellulose
  • sodium carboxymethylcellulose or mixtures thereof
  • ChMC/CE it is preferred that the weight ratio of lorcaserin hydrochloride and the one or more water soluble polymers is of from 1 :10 to 2:1 , even more preferred from 1 :7 to 1 :1 , and most preferred from 1 :5 to 1 :2.
  • amorphous lorcaserin hydrochloride is the only solid form of lorcaserin hydrochloride present in the solid dispersion, as determined by the absence of characteristic XRPD peaks for Form III of lorcaserin hydrochloride.
  • lorcaserin hydrochloride is chemically stable upon storage under stress conditions.
  • the modified cellulose and/or cellulose ether has a degree of substitution of 0.3 to 2.8, more preferably of 0.6 to 2.5, even more preferred 1 .0 to 2.3 and most preferred 1 .3 to 2.0.
  • the degree of substitution (DS) of a given form of cellulose or cellulose ether is defined as the average number of substituted hydroxyl groups per glucose.
  • the average molecular weight of the modified cellulose and/or cellulose ether is from 7000 Da to 225000 Da, preferably from 7000 Da to 100000 Da, more preferably of from 7000 Da to 30000 Da.
  • the solid dispersion of the present invention can be used for the preparation of a pharmaceutical composition for the treatment of obesity.
  • a further aspect of the present invention is a pharmaceutical composition comprising amorphous lorcaserin hydrochloride as the only form of lorcaserin hydrochloride present in said pharmaceutical composition.
  • the present invention relates to a pharmaceutical composition comprising the solid dispersion of the present invention, in particular comprising the solid dispersion of embodiment ChMC/CE.
  • lorcaserin hydrochloride is only present as amorphous lorcaserin hydrochloride.
  • the solid dispersion according to the present invention allows for the easier preparation of modified release dosage forms containing lorcaserin hydrochloride.
  • a modified release dosage form the lorcaserin hydrochloride can be released gradually over a relatively long period so that the drug is maintained in the blood stream for a long time and at a more uniform concentration as compared to an immediate release dosage form.
  • a modified release dosage form comprising locaserin hydrochloride is desirable because it would address known side effects of lorcaserin hydrochloride, such as a tendency to cause sedation in susceptible subjects.
  • modified release is used as defined by the US Pharmacopeia (USP).
  • modified release dosage forms comprising the solid dispersion of the present invention are those whose drug release characteristics accomplish therapeutic or convenience objectives not offered by immediate release forms.
  • immediate release (IR) forms release at least 70 percent of the drug within 1 hour or less.
  • modified release can comprise delayed release, prolonged release, sustained release, extended release and/or controlled release. Delayed release usually indicates that the drug (i.e., lorcaserin hydrochloride) is not being released immediately after administration but at a later time, preferably less than 10 percent are released within two hours after administration.
  • Prolonged release usually indicates that the drug (i.e., lorcaserin hydrochloride) is provided for absorption over a longer period of time than IR forms, preferably for about 2 to 24 hours, in particular for 3 to 12 hours.
  • Sustained release usually indicates an initial release of drug (i.e., lorcaserin hydrochloride), sufficient to provide a therapeutic dose soon after administration, preferably within two hours after administration, and then a gradual release after an extended period of time, preferably for about 3 to 18 hours, in particular for 4 to 8 hours.
  • Extended release usually indicates a slow drug (i.e., lorcaserin hydrochloride) release, so that plasma concentrations are maintained at a therapeutic level for a time period of between 6 and 36 hours, preferably between 8 and 24 hours.
  • Controlled release dosage forms usually release the drug (i.e., lorcaserin hydrochloride) at a constant rate and provide plasma concentrations that remain essentially invariant with time.
  • the preparation of the various modified release dosage forms starting from the solid dispersion of the present invention is well within the capabilities of the person skilled in the art, as exemplified by standard pharmaceutical textbooks such as the Encyclopdia of Pharmaceutical technology.
  • Oral fornnulations of the pharmaceutical composition may be an oral dosage form and particularly preferred are solid formulations such as capsules, tablets, pills and lozenges.
  • the solid dispersion according to the invention may be directly used as powders (micronized particles) or granules, or they may be combined together with other pharmaceutically acceptable ingredients in admixing the components and optionally finely divide them, and then filling capsules, composed for example from hard or soft gelatin, compressing tablets, pills or lozenges.
  • capsules composed for example from hard or soft gelatin, compressing tablets, pills or lozenges.
  • coatings may be applied after compression to form pills.
  • the pharmaceutical composition is a solid oral dosage form, in particular an extended release solid oral dosage form.
  • Pharmaceutically acceptable ingredients are well known for the various types of formulation and may be for example binders such as natural or synthetic polymers, excipients, disintegrants, lubricants, surfactants, sweetening and other flavouring agents, coating materials, preservatives, dyes, thickeners, adjuvants, antimicrobial agents and carriers for the various formulation types.
  • binders comprise gum tragacanth, acacia, starch, gelatin, and biological de-gradable polymers such as homo- or co-polyesters of dicarboxylic acids, alkylene glycols, polyalkylene glycols and/or aliphatic hydroxyl carboxylic acids; homo- or co-polyamides of dicarboxylic acids, alkylene diamines, and/or aliphatic amino carboxylic acids; corresponding polyester-polyamide-co-polymers, polyanhydrides, polyortho-esters, polyphosphazene and polycarbonates.
  • the biological degradable polymers may be linear, branched or crosslinked. Specific examples are polyglycolic acid, polylactic acid, and poly-d,l-lactide/glycolide. Other examples for polymers are water-soluble polymers such as polyoxaalkylenes
  • polyoxaethylene, polyoxapropylene and mixed polymers thereof poly-acrylamides and hydroxylalkylated polyacrylamides, polymaleic acid and esters or -amides thereof, polyacrylic acid and esters or -amides thereof, polyvinylalcohol and esters or -ethers thereof, polyvinyl imidazole, polyvinylpyrrolidone, and natural polymers like chitosan, carragenan or hyaluronic acid.
  • Suitable disintegrants which can be used for the pharmaceutical compositions of the present invention comprise e.g. starch, ion exchange resins, e.g. Amberlite, cross- linked polyvinylpyrrolidone, modified cellulose gum, e.g croscarmellose sodium, sodium starch glycolate, sodium carboxymethylcellulose, sodium dodecyl sulphate, modified corn starch, microcrystalline cellulose, magnesium aluminium silicate, alginic acid, alginate and powdered cellulose.
  • ion exchange resins e.g. Amberlite, cross- linked polyvinylpyrrolidone
  • modified cellulose gum e.g croscarmellose sodium
  • sodium starch glycolate sodium carboxymethylcellulose
  • sodium dodecyl sulphate modified corn starch
  • microcrystalline cellulose magnesium aluminium silicate
  • alginic acid alginate and powdered cellulose.
  • Suitable lubricants which can also be used for the pharmaceutical compositions of the present invention comprise e.g. magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulphate and magnesium lauryl sulphate.
  • Surfactants may be anionic, amphoteric or neutral.
  • Examples for surfactants are lecithin, phospholipids, octyl sulfate, decyl sulfate, dodecyl sulfate, tetradecyl sulfate, hexadecyl sulfate and octadecyl sulfate, 1 -acylamino-ethane-2-sulfonic acids, such as 1 -octanoylaminoethane-2-sulfonic acid, 1 -decanoyl-aminoethane-2-sulfonic acid, 1 -dodecanoylaminoethane-2-sulfonic acid, 1 -tetra-decanoylaminoethane-2-sulfonic acid, 1 -hexadecanoylaminoethane-2-sulfonic acid, and 1 -oct
  • coating materials are gelatin, wax, shellac or biological degradable polymers.
  • preservatives are methyl-, propyl, -or butylparabens, propylene paraben, sorbic acid, chlorobutanol, phenol, thimerosal, potassium sorbate, glycerin, propylene glycol, cysteine and/or methionine.
  • thickeners are synthetic polymers, fatty acids and fatty acid salts and esters and fatty alcohols.
  • the formulation according to the invention may also contain isotonic agents, such as sugars, buffers or sodium chloride.
  • Suitable dosage forms include solid dosage forms, like tablets, powders, capsules, suppositories, sachets, troches and lozenges.
  • Capsules will typically contain the solid composition within a capsule which may be made of gelatin or other conventional encapsulating material.
  • Tablets and powders may be coated.
  • Tablets and powders may be coated with an enteric coating.
  • the enteric coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethylcellulose phthalate, polyvinylalcohol phthalate, carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents.
  • a coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric coating.
  • Modified release formulations may also be prepared from the solid dispersion according to the invention in order to achieve a more controlled release of the active agent in contact with the body fluids in the gastro intestinal tract, and to provide a substantial constant and effective level of the active agent in the gastric juice.
  • the solid dispersion of the present invention may be embedded for this purpose in a polymer matrix of a biological degradable polymer, a water soluble polymer or a mixture of both, and optionally suitable surfactants. Embedding can mean in this context the incorporation of micro-particles in a matrix of polymers.
  • Modified release formulations can also be obtained through encapsulation of dispersed micro-particles or emulsified micro-droplets via known dispersion or emulsion coating technologies.
  • the present invention also relates to a container comprising a pharmaceutical composition of the present invention, in particular a pharmaceutical composition comprising the solid dispersion of the present invention, in particular embodiment ChMC/CE.
  • the container is prepared from a material having a permeability for water vapor as measured according to DIN 53 122 at a foil thickness of 50 ⁇ of from 1 g * m "2 * d-1 to 5000 g * m "2 * d "1 , more preferably of from 5 g * m "2 * d "1 to 2000 g * m “2 * d “1 .
  • Preferred examples of such an inexpensive packaging material with relatively high permeability for water vapor are polyvinylchloride, polystyrole, polyamide, polyethylenevinylacetate, cellophane and celluloseacetate.
  • the use of these materials for blistering the pharmaceutical compositions comprising the solid dispersion becomes possible due to the low hygroscopicity of the solid dispersion of the present invention. This represents a further advantage of the solid dispersion of the invention.
  • the present invention also relates to the use of solid dispersion of the present invention, and in particular embodiment ChMC/CE, for the production of a
  • the present invention also relates to a pharmaceutical composition prepared for a tropical country having areas with an Af or Am climate according to the Koppen-Geiger climate classification.
  • a further aspect of the present invention is directed to a process for the preparation of the solid dispersion of the present invention comprising the steps of:
  • step c) optionally concentrating the obtained composition of step a) or b).
  • step a) adding a water-soluble polymer and a suitable solvent B to the composition of step a), b) or c)
  • solvent A of step a) and/or b) is selected from the group consisting of water, halogenated hydrocarbon, C1 -C4 alcohol, C3-C6 ketone, organic ether, organic ester or mixtures thereof.
  • solvent B of step d) is selected from the group consisting water, halogenated hydrocarbon, C1 -C4 alcohol, C3-C6 ketone, organic ether, organic ester or mixtures thereof.
  • a solid oral dosage form such as a tablet, of the present invention may be prepared by wet granulation comprising the steps of:
  • step b) spraying the binder solution of step b) on the mixture obtained in step a), d) drying the obtained granulate and sieving the same,
  • Suitable solvents in step b) of the herein disclosed wet granulation process are e.g. water, acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert- butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1 - propanol, pentane, 1 -pentanol, 1 -propanol, 2-propanol, propyl acetate and
  • Formulations of the present invention typically comprise about 5 to about 100 mg, preferably about 10 mg of lorcaserin.
  • X-Ray powder diffractograms were obtained with an X'Pert PRO diffractometer (PANalytical, Almelo, The Netherlands) equipped with a theta/theta coupled goniometer in transmission geometry, programmable XYZ stage with well plate holder, Cu-K a i ,2 radiation source (wavelength 0.15419 nm) and a solid state PIX'cel detector.
  • the diffractograms were recorded at a tube voltage of 45 kV, tube current of 40 mA applying a stepsize of 0.013° 2-theta with 40 s per step (255 channels) in the angular range of 2° to 40° 2-theta at ambient conditions.
  • a typical precision of the 2-theta values is in the range of about ⁇ 0.2° 2-theta.
  • a diffraction peak that appears at 5.0° 2-theta can appear between 4.8 and 5.2° 2-theta on most X-ray diffractometers under standard conditions.
  • lorcaserin free base (1 .92 g, 9.81 mmol)
  • 25 mL of dichloromethane 25 mL
  • solution of hydrogen chloride 15.00 mmol
  • the mixture was stirred at room temperature for 5 min and the solvents were evaporated in rotary evaporator.
  • the solid residue was dissolved in 25 mL of dichloromethane and treated with a solution of hydrogen chloride (15.00 mmol).
  • Crystalline lorcaserin hydrochloride (or in-situ prepared lorcaserin hydrochloride from lorcaserin free base) and water soluble polymer were mixed together and dissolved in water or in water and ethanol. If necessary, the mixture was stirred at about 40 °C and sonicated for a few minutes to obtain a clear and homogeneous solution. The mixture was fast frozen and directly lyophilized at -40 °C and 0.2-0.4 mbar to yield the solid dispersion.
  • Example 1 Preparation of a solid dispersion of lorcaserin hydrochloride with HPMC Type E5 (1 :3, starting from crystalline lorcaserin hydrochloride)
  • Lorcaserin free base (50.0 mg, 0.255 mmol) was diluted in 2 mL of ethanol. After addition of 2 mL of distilled water, hydrochloric acid (10% aqueous solution, 9.3 mg, 0.225 mmol) was added and the mixture was stirred at RT for 5 min. HPMC (177.9 mg) was added to the solution, followed by successive addition of 5 mL of ethanol and 24 mL of distilled water. The mixture was stirred at about 40 °C and sonicated until a clear and homogeneous solution was obtained.
  • Amorphous solid dispersion of lorcaserin hydrochloride with HPMC (1 :3) was stored at room temperature and 45% r.h., 63% r.h. and 76% r.h.. After one month under these storage conditions, the presence of crystalline material was not detectable as determined by XRPD and a microscopic search for birefringent material.
  • Amorphous solid dispersion of lorcaserin hydrochloride with HPMC E5 (1 :3) was also stored under stressed conditions, i.e. at 40 °C and about 70% r.h. After two months under these storage conditions the sample was analyzed by X-ray powder diffraction. A representative diffractogrann is displayed in Figure 3. The stored samples remained amorphous as judged by the absence of XRPD peaks, in particular those peaks typical for lorcaserin hydrochloride Form III. Presence of crystalline material was not detectable.

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Abstract

The present invention is directed to an amorphous solid dispersion comphsing lorcaserin hydrochloride ((R)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepin hydrochloride) of formula (1), and one or more pharmaceutically acceptable water soluble polymers, a pharmaceutical composition comprising the amorphous solid dispersion as well as a process for obtaining the same.

Description

Solid dispersion comprising amorphous lorcaserin hydrochloride
The present invention is directed to a solid dispersion comprising amorphous lorcaserin hydrochloride, a pharmaceutical composition comprising the solid dispersion as well as a process for obtaining the same.
Obesity is a life-threatening disorder in which there is an increased risk of morbity and mortality arising from concomitant diseases such as type II diabetes,
hypertension, stroke, cancer and gallbladder disease. Lorcaserin ((R)-8-chloro-1 - methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepin) is useful for treating obesity.
WO 03/086306 A1 focuses on 5HT2c receptor modulators and discloses selective 5HT2c agonists which reduce appetite and food consumption and, as a result, cause body weight loss to occur. Lorcaserin racemate ((R)-8-chloro-1 -methyl-2, 3,4,5- tetrahydro-1 H-benzo[d]azepin) is disclosed in said reference.
Preparation and characterization of, amongst others salts, lorcaserin ((R)-8-chloro-1 - methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepin) hydrochloride is described in
WO2005/019179 A2.
WO 2006/069363 A2 refers to crystalline forms of lorcaserin, namely three crystalline forms of lorcaserin hydrochloride, individually designated as Form I, Form II and Form III. Forms I and II are anhydrous, hygroscopic forms, both of which readily convert to Form III, a hemihydrate, upon exposure to moisture.
WO 201 1/153206 A1 discloses a further crystalline form of lorcaserin hydrochloride, namely Form IV, described to be a new anhydrous form, and its conversion to Form III, a lorcaserin hemihydrate, upon exposure to moisture.
A pharmaceutical composition must be stable in an environment having enhanced relative humidity in order to be suitable for tropical countries. Forms I, II and IV (WO 201 1/153206 A1 ) are hygroscopic and, thus, are problematic for the purpose of producing a pharmaceutical composition suitable for use in tropical countries, since a pharmaceutical composition comprising these solid forms of lorcaserin hydrochloride can be expected to absorb water when exposed to an environment having a higher relative humidity. However, also Form III of lorcaserin hydrochloride has the drawback that it can convert (at least partially) to another form, such as Form II, under particular environmental conditions, for example when exposed to elevated temperature (see WO 201 1/153206 A1 ). Thus, medicaments comprising Form III may not be stable at particular environmental conditions, such as elevated temperature.
WO 201 1/153206 A1 also refers to processes for the preparation of selective 5HT2c agonists. Example 5 of said reference is directed to the thermodynamic relationships between lorcaserin hydrochloride salt hemihydrate Form III and the anhydrous polymorphs of lorcaserin hydrochloride salt. WO 201 1/153206 A1 describes that at a critical water activity aw a given anhydrous form and lorcaserin hydrochloride salt hemihydrate will have equal solubility and can coexist in equilibrium. Below the critical aw, the anhydrous form is described to be more thermodynamically stable, thus less soluble. Above the critical water activity lorcaserin hydrochloride salt hemihydrate Form III is described to be more thermodynamically stable, thus less soluble.
The water activity dependent equilibrium of lorcaserin hydrochloride hemihydrate Form III and the anhydrous polymorphs of lorcaserin hydrochloride salt can be a drawback for manufacturing a pharmaceutical composition based on lorcaserin hydrochloride Form III, as the pharmaceutical compositions comprising the desired Form III might not be obtained reliably or might not be stable upon storage with regard to the polymorphic form of the comprised lorcaserin hydrochloride. For example, the known crystalline forms of lorcaserin hydrochloride including Form III can be prone to polymorphic conversion when exposed to an environment having a higher relative humidity and/or an elevated temperature.
The discovery of further solid forms of an active pharmaceutical ingredient (API) can offer an opportunity to improve the performance profile of a pharmaceutical composition comprising said API. As explained above, the known solid forms of lorcaserin hydrochloride still leave room for improvement of the physicochemical as well as the pharmaceutical characteristics of lorcaserin containing pharmaceutical compositions. Processability of the API during manufacture of the pharmaceutical composition and characteristics of the finished dosage form, such as storage stability under difficult environmental conditions, such as high relative humidity and/or high temperature, can still be improved or optimized. The presence of the high energy form of the API in a pharmaceutical composition (amorphous form) usually improves the dissolution rate. However, these systems are not often physically stable. The API can crystallize over time, causing the loss of the desired properties associated with the amorphous state and reduced shelf-life. Neither one of WO 03/086306 A1 , WO2005/019179 A2, WO 2006/069363 A2 and WO 201 1/153206 A1 refers to amorphous lorcaserin hydrochloride.
Also, the inventors of the present invention failed to manufacture pure amorphous lorcaserin hydrochloride (see below). Thus, an object of the present invention is to provide a pharmaceutical composition comprising lorcaserin hydrochloride in a solid form, wherein the physicochemical stability of the solid form is improved, the dissolution characteristics of the solid form are improved and wherein lorcaserin hydrochloride is rendered more suitable for use in a storable pharmaceutical composition.
Summary of the invention
The technical problem underlying the present invention is solved by a solid dispersion comprising amorphous lorcaserin hydrochloride ((R)-8-chloro-1 -methyl- 2,3,4,5-tetrahydro-1 H-benzo[d]azepin hydrochloride) of formula 1
Figure imgf000005_0001
formula 1
and one or more pharmaceutically acceptable water-soluble polymers.
The present invention also provides a pharmaceutical composition comprising the solid dispersion as described above.
The present invention further describes processes for the preparation of the solid dispersion and the pharmaceutical composition described above. In the context of the present invention the following abbreviations have the indicated meaning, unless explicitly stated otherwise:
XRPD: X-ray powder diffraction/diffractogram
RT: room temperature
r.h.: relative humidity
Brief description of the figures
XRPD specifications: x-axis represents peak positions [°2 Theta] (Cu-KQ radiation) and y-axis shows relative intensities (counts).
Figure 1 : XRPD of lorcaserin hydrochloride after fast solvent evaporation in rotary evaporator
Figure 2: XRPD of amorphous lorcaserin hydrochloride in form of a solid dispersion with HPMC (1 :3, prepared from lorcaserin hydrochloride), at ambient conditions Figure 3: XRPD of amorphous lorcaserin hydrochloride in form of a solid dispersion with HPMC (1 :3) after storage at 40 °C and 63% r.h. for 2 months
Detailed description of the invention
The present inventors have discovered that it was not possible to obtain pure amorphous lorcaserin hydrochloride by standard methods. Without wishing to be bound to any theory, amorphous lorcaserin hydrochloride apparently converts very quickly to one of the crystalline forms.
For example, lorcaserin hydrochloride was prepared from lorcaserin free base and a solution of hydrogen chloride according to the literature (Comparative Example 1 ). Fast solvent evaporation in a rotary evaporator yielded lorcaserin hydrochloride as a crystalline powder. A representative diffractogram is displayed in Figure 1 .
Also in a further attempts to prepare amorphous lorcaserin hydrochloride, such as a) dissolving crystalline lorcaserin hydrochloride in water and ethanol, fast freezing the homogeneous solution in a liquid nitrogen bath and lyophilizing (Comparative Example 2), b) putting crystalline lorcaserin hydrochloride (Form II) on a glass plate, heating over a Kofler bench until melting, followed by fast cooling over a metal plate at 0 °C and c) by grinding experiments where crystalline lorcaserin hydrochloride, Form II or Form III, was manually grinded in a mortar, always lorcaserin
hydrochloride showing the characteristic XRPD peaks of either Form III and/or Form II (according to WO 201 1/153206 A1 ) was obtained, essentially amorphous lorcaserin hydrochloride was not obtained. The various different failed attempts to prepare amorphous lorcaserin hydrochloride and the obtained crystalline products suggested that pure amorphous lorcaserin hydrochloride is not stable in the amorphous state and readily crystallizes.
The present invention relates to a solid dispersion comprising amorphous lorcaserin hydrochloride ((R)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepin hydrochloride) of formula 1
Figure imgf000006_0001
formula 1
and one or more pharmaceutically acceptable watersoluble polymers. The term "solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous state) wherein one component is dispersed more or less evenly
throughout the other component or components, e.g. in the context of the present invention amorphous lorcaserin hydrochloride within the water soluble polymer.
Preferred solid dispersions are "solid solutions", where the dispersion of the components is such that the system is chemically and physically uniform or homogeneous throughout or even consists of one phase as defined by measurement of thermodynamic properties of the system, e.g. the amorphous lorcaserin
hydrochloride and the water soluble polymer form a system that is chemically and physically uniform or homogeneous throughout or even consists of one phase as defined by measurement of thermodynamic properties of the system.
The absence of peaks on the X-ray powder diffractogrann of the solid dispersion of the invention, in particularly the absence of characteristic XRPD peaks for Form III of lorcaserin hydrochloride, suggests that in the solid dispersion of the present invention lorcaserin hydrochloride is substantially amorphous. Characteristic X-ray powder diffraction pattern of Form I comprises peaks at 2-theta angles of 1 1 .5 ± 0.2°, 14.5 ± 0.2°, 16.0 ± 0.2°, 23.0 ± 0.2° and 23.3 ± 0.2°. Characteristic X-ray powder diffraction pattern of Form II comprises peaks at 2-theta angles of 6.5 ± 0.2°, 12.9 ± 0.2°, 17.1 ± 0.2°, 17.5 ± 0.2° and 18.5 ± 0.2°. Characteristic X-ray powder diffraction pattern of Form III comprises peaks at 2-theta angles of 13.7 ± 0.2°, 14.9 ± 0.2°, 15.4 ± 0.2°, 16.7 ± 0.2° and 19.2 ± 0.2°. Characteristic X-ray powder diffraction pattern of Form IV comprises peaks at 2-theta angles of 8.9 ± 0.2°, 10.7 ± 0.2°, 15.3 ± 0.2°, 17.8 ± 0.2° and 18.3 ± 0.2°.
The present invention circumvents the drawback of the known crystalline
hydrochloride salts of 3-benzazepine, 5-HT2c agonist compound of formula 1 , i.e. Forms I, II, III and IV, by providing a solid dispersion comprising amorphous lorcaserin hydrochloride and a water soluble polymer as matrix material. The solid dispersion of the present invention is obtainable as a solid dispersion that is stable and pure with regard to the physical form of amorphous lorcaserin hydrochloride therein, and that is obtainable in an easy and reliable manner, e.g. even in large scale.
The lorcaserin hydrochloride in the context of the solid dispersion of the present invention is stable in the amorphous state upon storage, as judged by the absence of characteristic XRPD peaks after storage. "Stable in the amorphous stage upon storage" within the meaning of the present invention means that the solid dispersion of the present invention after storage at a relative humidity of 45% at 23°C for 14 days, preferably even after storage for 50 days, shows no signs of the presence of crystalline lorcaserin hydrochloride form III as judged by the absence of peaks at 2- theta angles of 13.7 ± 0.2°, 14.9 ± 0.2°, 15.4 ± 0.2°, 16.7 ± 0.2° and 19.2 ± 0.2°, and in particular shows no signs of the presence of any one of the four known forms of crystalline lorcaserin hydrochloride, as judged by the absence of peaks at 2-theta angles of 1 1 .5 ± 0.2°, 14.5 ± 0.2°, 16.0 ± 0.2°, 23.0 ± 0.2° and 23.3 ± 0.2° (form I), 6.5 ± 0.2°, 12.9 ± 0.2°, 17.1 ± 0.2°, 17.5 ± 0.2° and 18.5 ± 0.2° (form II), 13.7 ± 0.2°, 14.9 ± 0.2°, 15.4 ± 0.2°, 16.7 ± 0.2° and 19.2 ± 0.2° (form III) and 8.9 ± 0.2°, 10.7 ± 0.2°, 15.3 ± 0.2°, 17.8 ± 0.2° and 18.3 ± 0.2° (form IV) in an X-ray powder diffractogram (XRPD).
"Stable in the amorphous state upon storage under stress conditions" in the context of the present invention means that the solid dispersion of the present invention when stored at a relative humidity of 70 % at 40°C for 14 days, preferably after storage for 50 days, shows no signs of the presence of crystalline lorcaserin hydrochloride form III as judged by the absence of peaks at 2-theta angles of 13.7 ± 0.2°, 14.9 ± 0.2°, 15.4 ± 0.2°, 16.7 ± 0.2° and 19.2 ± 0.2°, and in particular shows no signs of the presence of any one of the four known forms of crystalline lorcaserin hydrochloride, as judged by the absence of peaks at 2-theta angles of 1 1 .5 ± 0.2°, 14.5 ± 0.2°, 16.0 ± 0.2°, 23.0 ± 0.2° and 23.3 ± 0.2° (form I), 6.5 ± 0.2°, 12.9 ± 0.2°, 17.1 ± 0.2°, 17.5 ± 0.2° and 18.5 ± 0.2° (form II), 13.7 ± 0.2°, 14.9 ± 0.2°, 15.4 ± 0.2°, 16.7 ± 0.2° and 19.2 ± 0.2° (form III) and 8.9 ± 0.2°, 10.7 ± 0.2°, 15.3 ± 0.2°, 17.8 ± 0.2° and 18.3 ± 0.2° (form IV) in an X-ray powder diffractogram (XRPD). Thus, in a preferred embodiment, the solid dispersion of the present invention is a solid dispersion wherein the amorphous lorcaserin hydrochloride is stable in the amorphous stage upon storage. More preferably the solid dispersion of the present invention is a solid dispersion wherein the amorphous lorcaserin hydrochloride is stable in the amorphous stage upon storage under stress conditions.
In a further preferred embodiment, the solid dispersion of the present invention is a chemically stable solid dispersion. By "chemically stable" it is meant that amorphous lorcaserin hydrochloride present in the solid dispersion of the present invention shows very little degradation upon storage under stress conditions, i.e. when stored at a relative humidity of 70 % at 40°C for 14 days, preferably after storage for 50 days. Very little degradation means that an HPLC analysis of lorcaserin shows no impurity of more than 0.1 area% under the following analysis conditions: sample concentration of I mg/mL in isopropanol or ethanol, CHIRALPAK AD-H (250 x 4,6 mm) column, flow of solvent A and solvent B (90:10) of 1 .0 mL/min with hexane as solvent A and hexane/ethanol/butylamine ( 90:10:0.02) as solvent B, column temperature of 10 °C and wavelength of 226 nm . In addition the solid dispersion of the present invention does essentially not suffer from weight fluctuations due to loss or gain of water molecules and is stable over a broad range of relative humidities and temperatures. The solid dispersion of the present invention is essentially non-hygroscopic. Consequently, controlled and expensive storage conditions, special and expensive packaging or addition of a stabilizing agent during preparation or for storage is not necessary (even though a stabilizing agent may be comprised in the pharmaceutical compositions of the present invention). The solid dispersion of the present invention is thus suitable for the preparation of a pharmaceutical composition, in particular a solid pharmaceutical composition such as a solid oral dosage form, like a tablet.
The solid dispersion of the present invention is also easier to handle under typical pharmaceutical processing conditions, such as wet granulation, than crystalline lorcaserin hydrochloride Forms I, II, III and IV. In particular, the solid dispersion of the present invention enables standard pharmaceutical processing conditions to be used, such as work in an atmosphere having a relative humidity of about 0 to 90 %.
Furthermore, the solid dispersion of the present invention and a pharmaceutical composition comprising the same, need not to be packaged into special
containments for proper product quality during storage. Inexpensive containers or blisters can be used for packaging.
In a preferred embodiment the solid dispersion of the present invention is
characterized in that the weight ratio of lorcaserin hydrochloride and the one or more water-soluble polymers is of from 1 : 10 to 2:1 , preferably from 1 : 10 to 1 :2,
alternatively from 1 :7 to 1 :1 , and most preferably from 1 :5 to 1 :2.
In a further preferred embodiment, the one or more water-soluble polymers have a solubility in water (23 °C, pH 7.0 or more) of at least 10 g/l and even more preferred of at least 33 g/l.
Preferably, the one or more watersoluble polymers are homopolymers and/or copolymers. Polymers that contain only a single type of repeat unit are known as homopolymers, while polymers containing a mixture of repeat units are known as copolymers.
In a preferred embodiment, the one or more water-soluble polymers are selected from the group consisting of chemically modified cellulose, cellulose ether,
polyvinylpyrrolidone, polyethylene glycol, polyethylene glycol based copolymer, polyacrylic acids and salts thereof, polyvinylalcohol, polyacrylamides copolymer, methacrylic acid copolymer, methacrylate copolymer, pectines, chitin and chitosan derivatives, polyphosphates, polyoxazoline, polysaccharides or mixtures thereof.
Even more preferably, the water soluble polymer is a chemically modified cellulose and/or cellulose ether, and in particular is selected from the group consisting of alkylcellulose, e.g. methylcellulose, ethylcellulose, propylcellulose;
hydroxalkylcellulose, e.g. hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose; hydroxyalkylalkylcellulose, e.g. hydroxyethylmethylcellulose (HEMC), hydroxypropylmethylcellulose (HPMC); carboxyalkylcellulose, e.g carboxymethylcellulose (CMC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxyethylcarboxymethylcellulose (HECMC), sodium carboxymethylcellulose, cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose acetate (HPMCA), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS) or mixtures thereof.
Even more preferably, the chemically modified cellulose and/or cellulose ether is selected from the group consisting of alkylcellulose, e.g. methylcellulose,
ethylcellulose, propylcellulose; hydroxalkylcellulose, e.g. hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; hydroxyalkylalkylcellulose, e.g.
hydroxyethylmethylcellulose (HEMC), hydroxypropylmethylcellulose (HPMC);
carboxyalkylcellulose, e.g carboxymethylcellulose (CMC),
carboxymethylhydroxyethylcellulose (CMHEC), hydroxyethylcarboxymethylcellulose (HECMC), sodium carboxymethylcellulose, or mixtures thereof. A particularly preferred chemically modified cellulose is hydroxypropylmethylcellulose.
Even more preferably, the present invention relates to a solid dispersion comprising amorphous lorcaserin hydrochloride and a chemically modified cellulose and/or cellulose ether, wherein the chemically modified cellulose and/or cellulose ether is selected from the group consisting of alkylcellulose, e.g. methylcellulose,
ethylcellulose, propylcellulose; hydroxalkylcellulose, e.g. hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; hydroxyalkylalkylcellulose, e.g.
hydroxyethylmethylcellulose (HEMC), hydroxypropylmethylcellulose (HPMC);
carboxyalkylcellulose, e.g carboxymethylcellulose (CMC),
carboxymethylhydroxyethylcellulose (CMHEC), hydroxyethylcarboxymethylcellulose (HECMC), sodium carboxymethylcellulose, or mixtures thereof,
and wherein the amorphous lorcaserin hydrochloride is stable in the amorphous stage upon storage, in particular upon storage under stress conditions. This embodiment is referred to as embodiment ChMC/CE. For this embodiment ChMC/CE it is preferred that the weight ratio of lorcaserin hydrochloride and the one or more water soluble polymers is of from 1 :10 to 2:1 , even more preferred from 1 :7 to 1 :1 , and most preferred from 1 :5 to 1 :2. For this embodiment ChMC/CE it is further preferred that amorphous lorcaserin hydrochloride is the only solid form of lorcaserin hydrochloride present in the solid dispersion, as determined by the absence of characteristic XRPD peaks for Form III of lorcaserin hydrochloride. For this embodiment ChMC/CE it is further preferred that lorcaserin hydrochloride is chemically stable upon storage under stress conditions.
In a preferred embodiment of embodiment ChMC/CE, the modified cellulose and/or cellulose ether has a degree of substitution of 0.3 to 2.8, more preferably of 0.6 to 2.5, even more preferred 1 .0 to 2.3 and most preferred 1 .3 to 2.0. The degree of substitution (DS) of a given form of cellulose or cellulose ether is defined as the average number of substituted hydroxyl groups per glucose.
In a preferred embodiment of embodiment ChMC/CE the average molecular weight of the modified cellulose and/or cellulose ether is from 7000 Da to 225000 Da, preferably from 7000 Da to 100000 Da, more preferably of from 7000 Da to 30000 Da.
The solid dispersion of the present invention can be used for the preparation of a pharmaceutical composition for the treatment of obesity.
Thus, a further aspect of the present invention is a pharmaceutical composition comprising amorphous lorcaserin hydrochloride as the only form of lorcaserin hydrochloride present in said pharmaceutical composition. In particular the present invention relates to a pharmaceutical composition comprising the solid dispersion of the present invention, in particular comprising the solid dispersion of embodiment ChMC/CE.
Preferably, in the pharmaceutical composition lorcaserin hydrochloride is only present as amorphous lorcaserin hydrochloride.
Among other advantages, the solid dispersion according to the present invention, and in particular embodiment ChMC/CE, allows for the easier preparation of modified release dosage forms containing lorcaserin hydrochloride. In a modified release dosage form the lorcaserin hydrochloride can be released gradually over a relatively long period so that the drug is maintained in the blood stream for a long time and at a more uniform concentration as compared to an immediate release dosage form. A modified release dosage form comprising locaserin hydrochloride is desirable because it would address known side effects of lorcaserin hydrochloride, such as a tendency to cause sedation in susceptible subjects.
Within the present application generally the term "modified release" is used as defined by the US Pharmacopeia (USP). Preferably, modified release dosage forms comprising the solid dispersion of the present invention are those whose drug release characteristics accomplish therapeutic or convenience objectives not offered by immediate release forms. Generally, immediate release (IR) forms release at least 70 percent of the drug within 1 hour or less. The term "modified release" can comprise delayed release, prolonged release, sustained release, extended release and/or controlled release. Delayed release usually indicates that the drug (i.e., lorcaserin hydrochloride) is not being released immediately after administration but at a later time, preferably less than 10 percent are released within two hours after administration. Prolonged release usually indicates that the drug (i.e., lorcaserin hydrochloride) is provided for absorption over a longer period of time than IR forms, preferably for about 2 to 24 hours, in particular for 3 to 12 hours. Sustained release usually indicates an initial release of drug (i.e., lorcaserin hydrochloride), sufficient to provide a therapeutic dose soon after administration, preferably within two hours after administration, and then a gradual release after an extended period of time, preferably for about 3 to 18 hours, in particular for 4 to 8 hours. Extended release usually indicates a slow drug (i.e., lorcaserin hydrochloride) release, so that plasma concentrations are maintained at a therapeutic level for a time period of between 6 and 36 hours, preferably between 8 and 24 hours. Controlled release dosage forms usually release the drug (i.e., lorcaserin hydrochloride) at a constant rate and provide plasma concentrations that remain essentially invariant with time. The preparation of the various modified release dosage forms starting from the solid dispersion of the present invention is well within the capabilities of the person skilled in the art, as exemplified by standard pharmaceutical textbooks such as the Encyclopdia of Pharmaceutical technology. Oral fornnulations of the pharmaceutical composition may be an oral dosage form and particularly preferred are solid formulations such as capsules, tablets, pills and lozenges. The solid dispersion according to the invention may be directly used as powders (micronized particles) or granules, or they may be combined together with other pharmaceutically acceptable ingredients in admixing the components and optionally finely divide them, and then filling capsules, composed for example from hard or soft gelatin, compressing tablets, pills or lozenges. Optionally, coatings may be applied after compression to form pills.
In a preferred embodiment, the pharmaceutical composition is a solid oral dosage form, in particular an extended release solid oral dosage form. Pharmaceutically acceptable ingredients are well known for the various types of formulation and may be for example binders such as natural or synthetic polymers, excipients, disintegrants, lubricants, surfactants, sweetening and other flavouring agents, coating materials, preservatives, dyes, thickeners, adjuvants, antimicrobial agents and carriers for the various formulation types.
Examples for binders comprise gum tragacanth, acacia, starch, gelatin, and biological de-gradable polymers such as homo- or co-polyesters of dicarboxylic acids, alkylene glycols, polyalkylene glycols and/or aliphatic hydroxyl carboxylic acids; homo- or co-polyamides of dicarboxylic acids, alkylene diamines, and/or aliphatic amino carboxylic acids; corresponding polyester-polyamide-co-polymers, polyanhydrides, polyortho-esters, polyphosphazene and polycarbonates. The biological degradable polymers may be linear, branched or crosslinked. Specific examples are polyglycolic acid, polylactic acid, and poly-d,l-lactide/glycolide. Other examples for polymers are water-soluble polymers such as polyoxaalkylenes
(polyoxaethylene, polyoxapropylene and mixed polymers thereof), poly-acrylamides and hydroxylalkylated polyacrylamides, polymaleic acid and esters or -amides thereof, polyacrylic acid and esters or -amides thereof, polyvinylalcohol and esters or -ethers thereof, polyvinyl imidazole, polyvinylpyrrolidone, and natural polymers like chitosan, carragenan or hyaluronic acid.
Suitable disintegrants which can be used for the pharmaceutical compositions of the present invention comprise e.g. starch, ion exchange resins, e.g. Amberlite, cross- linked polyvinylpyrrolidone, modified cellulose gum, e.g croscarmellose sodium, sodium starch glycolate, sodium carboxymethylcellulose, sodium dodecyl sulphate, modified corn starch, microcrystalline cellulose, magnesium aluminium silicate, alginic acid, alginate and powdered cellulose.
Suitable lubricants which can also be used for the pharmaceutical compositions of the present invention comprise e.g. magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulphate and magnesium lauryl sulphate.
Surfactants may be anionic, amphoteric or neutral. Examples for surfactants are lecithin, phospholipids, octyl sulfate, decyl sulfate, dodecyl sulfate, tetradecyl sulfate, hexadecyl sulfate and octadecyl sulfate, 1 -acylamino-ethane-2-sulfonic acids, such as 1 -octanoylaminoethane-2-sulfonic acid, 1 -decanoyl-aminoethane-2-sulfonic acid, 1 -dodecanoylaminoethane-2-sulfonic acid, 1 -tetra-decanoylaminoethane-2-sulfonic acid, 1 -hexadecanoylaminoethane-2-sulfonic acid, and 1 -octadecanoylaminoethane- 2-sulfonic acid, and taurocholic acid and taurodeoxycholic acid, bile acids and their salts, such as cholic acid, deoxycholic acid and sodium glycocholates, sodium caprate or sodium laurate, sodium oleate, sodium lauryl sulphate, sodium cetyl sulphate, sulfated castor oil and sodium dioctyl sulfosuccinate, co- camidopropylbetaine and laurylbetaine, fatty alcohols, cholesterols, glycerol mono- or distearate, glycerol mono- or -dioleate and glycerol mono- or -dipalmitate, and polyoxyethylene stearate. Examples for coating materials are gelatin, wax, shellac or biological degradable polymers. Examples for preservatives are methyl-, propyl, -or butylparabens, propylene paraben, sorbic acid, chlorobutanol, phenol, thimerosal, potassium sorbate, glycerin, propylene glycol, cysteine and/or methionine. Examples for thickeners are synthetic polymers, fatty acids and fatty acid salts and esters and fatty alcohols.
The formulation according to the invention may also contain isotonic agents, such as sugars, buffers or sodium chloride.
Suitable dosage forms include solid dosage forms, like tablets, powders, capsules, suppositories, sachets, troches and lozenges.
Capsules will typically contain the solid composition within a capsule which may be made of gelatin or other conventional encapsulating material. Tablets and powders may be coated. Tablets and powders may be coated with an enteric coating. The enteric coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethylcellulose phthalate, polyvinylalcohol phthalate, carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric coating. Modified release formulations may also be prepared from the solid dispersion according to the invention in order to achieve a more controlled release of the active agent in contact with the body fluids in the gastro intestinal tract, and to provide a substantial constant and effective level of the active agent in the gastric juice. The solid dispersion of the present invention may be embedded for this purpose in a polymer matrix of a biological degradable polymer, a water soluble polymer or a mixture of both, and optionally suitable surfactants. Embedding can mean in this context the incorporation of micro-particles in a matrix of polymers. Modified release formulations can also be obtained through encapsulation of dispersed micro-particles or emulsified micro-droplets via known dispersion or emulsion coating technologies.
The present invention also relates to a container comprising a pharmaceutical composition of the present invention, in particular a pharmaceutical composition comprising the solid dispersion of the present invention, in particular embodiment ChMC/CE.
Preferably the container is prepared from a material having a permeability for water vapor as measured according to DIN 53 122 at a foil thickness of 50 μιτι of from 1 g * m"2 * d-1 to 5000 g * m"2 * d"1, more preferably of from 5 g * m"2 * d"1 to 2000 g * m"2 * d"1 . Preferred examples of such an inexpensive packaging material with relatively high permeability for water vapor are polyvinylchloride, polystyrole, polyamide, polyethylenevinylacetate, cellophane and celluloseacetate. The use of these materials for blistering the pharmaceutical compositions comprising the solid dispersion becomes possible due to the low hygroscopicity of the solid dispersion of the present invention. This represents a further advantage of the solid dispersion of the invention. The present invention also relates to the use of solid dispersion of the present invention, and in particular embodiment ChMC/CE, for the production of a
pharmaceutical composition intended for sale in a tropical country having areas with an Af or Am climate according to the Koppen-Geiger climate classification. The present invention also relates to a pharmaceutical composition prepared for a tropical country having areas with an Af or Am climate according to the Koppen-Geiger climate classification.
A further aspect of the present invention is directed to a process for the preparation of the solid dispersion of the present invention comprising the steps of:
a) providing a solution of lorcaserin of formula 2 in a suitable solvent A
Figure imgf000018_0001
formula 2 and adding a solution providing hydrogen chloride or
b) providing a solution of lorcaserin hydrochloride of formula 1
Figure imgf000018_0002
formula 1 in a suitable solvent A.
c) optionally concentrating the obtained composition of step a) or b).
d) adding a water-soluble polymer and a suitable solvent B to the composition of step a), b) or c)
e) lyophilization or spray-drying of the composition of step d) or concentrating the obtained composition of step d) followed by extrusion / melt extrusion. Preferably, solvent A of step a) and/or b) is selected from the group consisting of water, halogenated hydrocarbon, C1 -C4 alcohol, C3-C6 ketone, organic ether, organic ester or mixtures thereof.
In a further preferred embodiment, solvent B of step d) is selected from the group consisting water, halogenated hydrocarbon, C1 -C4 alcohol, C3-C6 ketone, organic ether, organic ester or mixtures thereof.
In a further embodiment a solid oral dosage form, such as a tablet, of the present invention may be prepared by wet granulation comprising the steps of:
a) dry blending the amorphous solid dispersion of the present invention and a part of the diluent, b) preparing a binder solution by dissolving a binder and a wetting agent in a suitable solvent,
c) spraying the binder solution of step b) on the mixture obtained in step a), d) drying the obtained granulate and sieving the same,
e) mixing the obtained granulate with the remaining part of diluent and a disintegrant,
f) adding an optional glidant and/or an optional lubricant to the mixture, g) compressing the obtained mixture into a tablet and
h) film-coating the obtained tablet.
Suitable solvents in step b) of the herein disclosed wet granulation process are e.g. water, acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert- butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1 - propanol, pentane, 1 -pentanol, 1 -propanol, 2-propanol, propyl acetate and
tetrahydrofuran.
Formulations of the present invention typically comprise about 5 to about 100 mg, preferably about 10 mg of lorcaserin.
Other objects, features, advantages and aspects of the present invention will become apparent to those of skill from the following description. It should be understood, however, that the description and the following specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the description and the other parts of the present disclosure.
The present invention is illustrated in the following examples, which should not be construed as limiting. Examples:
X-Ray powder diffractograms (XRPD) were obtained with an X'Pert PRO diffractometer (PANalytical, Almelo, The Netherlands) equipped with a theta/theta coupled goniometer in transmission geometry, programmable XYZ stage with well plate holder, Cu-Kai ,2 radiation source (wavelength 0.15419 nm) and a solid state PIX'cel detector. The diffractograms were recorded at a tube voltage of 45 kV, tube current of 40 mA applying a stepsize of 0.013° 2-theta with 40 s per step (255 channels) in the angular range of 2° to 40° 2-theta at ambient conditions. A typical precision of the 2-theta values is in the range of about ± 0.2° 2-theta. Thus a diffraction peak that appears at 5.0° 2-theta can appear between 4.8 and 5.2° 2-theta on most X-ray diffractometers under standard conditions.
Comparative Example 1 : Preparation of lorcaserin hydrochloride by fast solvent evaporation
To a 100 mL-round bottom flask were added lorcaserin free base (1 .92 g, 9.81 mmol), 25 mL of dichloromethane and solution of hydrogen chloride (15.00 mmol). The mixture was stirred at room temperature for 5 min and the solvents were evaporated in rotary evaporator. The solid residue was dissolved in 25 mL of dichloromethane and treated with a solution of hydrogen chloride (15.00 mmol). The mixture was stirred at room temperature for 5 min and the solvents were fast evaporated in rotary evaporator (700 to 20 mbar, 40 °C), yielding crystalline lorcaserin hydrochloride (Forms II and III) as a light salmon powder (2.22 g, 9.56 mmol, 97% yield, Figure 1 ). 1 H NMR (500 MHz, CDCI3): δ 10.22 (br s, 1 H), 9.94 (br s, 1 H), 7.20 (d, 1 H, J = 2.0 Hz), 7.18 (dd, 1 H, J = 8.0 Hz, 2.0 Hz), 7.09 (d, 1 H, J = 8.0 Hz), 3.63-3.57 (m, 2H), 3.51 -3.44 (m, 2H), 3.07-2.89 (m, 3H), 1 .50 (d, 3H, J = 7.2 Hz).
Comparative Example 2: Lyophilization of crystalline lorcaserin hydrochloride
100 g of Crystalline lorcaserin hydrochloride, prepared according to Example 1 , was dissolved in 6.0 mL of distilled water and 0.7 mL of ethanol . The homogeneous solution was fast frozen in a bath of liquid nitrogen followed by lyophilization at -40 °C and 0.2-0.4 mbar over 20 hours, yielding crystalline lorcaserin hydrochloride General procedure for the preparation of the solid dispersions:
Crystalline lorcaserin hydrochloride (or in-situ prepared lorcaserin hydrochloride from lorcaserin free base) and water soluble polymer were mixed together and dissolved in water or in water and ethanol. If necessary, the mixture was stirred at about 40 °C and sonicated for a few minutes to obtain a clear and homogeneous solution. The mixture was fast frozen and directly lyophilized at -40 °C and 0.2-0.4 mbar to yield the solid dispersion.
Example 1 : Preparation of a solid dispersion of lorcaserin hydrochloride with HPMC Type E5 (1 :3, starting from crystalline lorcaserin hydrochloride)
To crystalline lorcaserin hydrochloride (60 mg, prepared according to Comparative example 1 ) and hydropropylnnethylcellulose (HPMC, 180 mg) were successively added 1 mL of ethanol and 17 mL of distilled water. The mixture was stirred at about 40 °C and sonicated until a clear and homogeneous solution was obtained. The mixture was fast frozen in a liquid nitrogen bath followed by lyophilization at -40 °C and 0.2-0.4 mbar, yielding lorcaserin hydrochloride in a form of a colorless, substantially non-crystalline solid dispersion. A representative diffractogram is displayed in Figure 2. Example 2: Preparation of a solid dispersion of lorcaserin hydrochloride with HPMC E5 (1 :3, starting from lorcaserin free base)
Lorcaserin free base (50.0 mg, 0.255 mmol) was diluted in 2 mL of ethanol. After addition of 2 mL of distilled water, hydrochloric acid (10% aqueous solution, 9.3 mg, 0.225 mmol) was added and the mixture was stirred at RT for 5 min. HPMC (177.9 mg) was added to the solution, followed by successive addition of 5 mL of ethanol and 24 mL of distilled water. The mixture was stirred at about 40 °C and sonicated until a clear and homogeneous solution was obtained. The mixture was fast frozen in a liquid nitrogen bath, followed by lyophilization at -40 °C and 0.2-0.4 mbar, yielding lorcaserin hydrochloride in a form of a colorless solid dispersion. The XRPD was essentially identical to Figure 2, indicating that a substantially non-crystalline material was obtained. Moisture stability:
Moisture stability of the amorphous solid dispersion of lorcaserin hydrochloride with HPMC E5 (1 :3):
Amorphous solid dispersion of lorcaserin hydrochloride with HPMC (1 :3) was stored at room temperature and 45% r.h., 63% r.h. and 76% r.h.. After one month under these storage conditions, the presence of crystalline material was not detectable as determined by XRPD and a microscopic search for birefringent material.
Amorphous solid dispersion of lorcaserin hydrochloride with HPMC E5 (1 :3) was also stored under stressed conditions, i.e. at 40 °C and about 70% r.h. After two months under these storage conditions the sample was analyzed by X-ray powder diffraction. A representative diffractogrann is displayed in Figure 3. The stored samples remained amorphous as judged by the absence of XRPD peaks, in particular those peaks typical for lorcaserin hydrochloride Form III. Presence of crystalline material was not detectable.
One may conclude that contrary to crystalline lorcaserin hydrochloride known in the art the solid dispersion of the present invention is not prone to solid form conversion when exposed to an environment having a high relative humidity.

Claims

Claims
1 . A solid dispersion comprising amorphous lorcaserin hydrochloride ((R)-8-chloro- 1 -methyl-2,3,4,5-tetrahydro-1 /-/-benzo[d]azepin hydrochloride) of formula 1
Figure imgf000023_0001
formula 1
and one or more pharmaceutically acceptable water soluble polymers.
The solid dispersion according to claim 1 , wherein the weight ratio of lorcaserin hydrochloride and the one or more water-soluble polymers is of from 1 : 10 to 1 :2.
The solid dispersion according to claim 1 or 2, wherein the one or more water soluble polymers have a solubility in water (23 °C) of at least 10 g/l.
The solid dispersion according to at least one of claims 1 to 3, wherein the one or more water soluble polymers are homopolymers and/or copolymers.
The solid dispersion according to at least one of claims 1 to 4, wherein the one or more water soluble polymers are selected from the group consisting of chemically modified cellulose, cellulose ether, polyvinylpyrrolidone,
polyethylene glycol, polyethylene glycol based copolymer, polyacrylic acids and salts thereof, polyvinylalcohol, polyacrylamides copolymer, methacrylic acid copolymer, methacrylate copolymer, pectines, chitin and chitosan derivatives, polyphosphates, polyoxazoline, polysaccharides or mixtures thereof.
The solid dispersion according to claim 5, wherein the chemically modified cellulose and/or cellulose ether is selected from the group consisting of alkylcellulose, e.g. methylcellulose, ethylcellulose, propylcellulose;
hydroxalkylcellulose, e.g. hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose; hydroxyalkylalkylcellulose, e.g.
hydroxyethylmethylcellulose (HEMC), hydroxypropylmethylcellulose (HPMC); carboxyalkylcellulose, e.g carboxymethylcellulose (CMC), carboxymethylhydroxyethylcellulose (CMHEC),
hydroxyethylcarboxymethylcellulose (HECMC), sodium
carboxymethylcellulose, cellulose acetate phthalate (CAP),
hydroxypropylmethylcellulose acetate (HPMCA), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate
(HPMCAS) or mixtures thereof.
7. The solid dispersion according to claim 5 or 6, wherein the modified cellulose and/or cellulose ether has a degree of substitution of 0.3 to 2.8
8. The solid dispersion according to at least one of claims 5 to 7, wherein the
chemically modified cellulose and/or cellulose ether is selected from the group consisting of alkylcellulose, methylcellulose, ethylcellulose, propylcellulose; hydroxalkylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; hydroxypropylmethylcellulose (HPMC), hydroxyl alkyl alkyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose or mixtures thereof.
9. The solid dispersion according to at least one of claims 1 to 8, wherein the
amorphous lorcaserin hydrochloride is stable in the amorphous stage upon storage, preferably upon storage under stress conditions.
10. A pharmaceutical composition comprising amorphous lorcaserin hydrochloride. 1 1 . A pharmaceutical composition comprising the solid dispersion according to at least one of the claims 1 to 9, in particular wherein lorcaserin hydrochloride is only present in the pharmaceutical composition as amorphous lorcaserin hydrochloride.
12. The solid dispersion according to at least one of the claims 1 to 9 and/or
pharmaceutical composition according to claim 10 or 1 1 for use in the treatment of obesity.
13. Process for the preparation of the solid dispersion of amorphous lorcaserin hydrochloride with one or more water soluble polymer(s) according to at least one of the claims 1 to 9 comprising the steps of: a) providing a solution of lorcaserin of formula 2 in a suitable solvent A
Figure imgf000025_0001
and adding a solution providing hydrogen chloride or
b) providing a solution of lorcaserin hydrochloride of formula 1
Figure imgf000025_0002
in a suitable solvent A.
c) optionally concentrating the obtained composition of step a) or b).
d) adding a water-soluble polymer and a suitable solvent B to the composition of step a), b) or c)
e) lyophilization or spray-drying of the composition of step d) or concentrating the obtained composition of step d) followed by extrusion / melt extrusion.
14. The process according to claim 13, characterized in that solvent A of step a) and or b) is selected from the group consisting of water, halogenated hydrocarbon, C1 -C4 alcohol, C3-C6 ketone, organic ether, organic ester or mixtures thereof. 15. The process according to claim 13 or 14, characterized in that solvent B of step d) is selected from the group consisting water, halogenated hydrocarbon, C1 - C4 alcohol, C3-C6 ketone, organic ether, organic ester or mixtures thereof.
PCT/EP2014/054184 2013-03-05 2014-03-04 Solid dispersion comprising amorphous lorcaserin hydrochloride WO2014135545A1 (en)

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CN104829532A (en) * 2015-05-15 2015-08-12 浙江理工大学 Method for preparing lorcaserin hydrochloride single crystal
EP2924024A3 (en) * 2014-03-21 2016-01-20 Medichem, S.A. Solid forms of lorcaserin hydrochloride
CN106074558A (en) * 2016-06-12 2016-11-09 佛山市腾瑞医药科技有限公司 A kind of hydrochloric acid lorcaserin preparation and application thereof
CN106880648A (en) * 2015-12-16 2017-06-23 深圳翰宇药业股份有限公司 A kind of pharmaceutical composition and preparation method thereof
EP3210975A1 (en) 2016-02-24 2017-08-30 Enantia, S.L. Cocrystals of lorcaserin
CN107802603A (en) * 2017-12-14 2018-03-16 乐普制药科技有限公司 One kind receives general ether alcohol dispersion and preparation method thereof
WO2021041824A1 (en) 2019-08-28 2021-03-04 Lubrizol Advanced Materials, Inc. Drug-polymer amorphous solid dispersions using linear poly (acrylic acid) polymers

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US20080255093A1 (en) * 1999-06-14 2008-10-16 Tam Peter Y Compositions and methods for treating obesity and related disorders
WO2009051747A1 (en) * 2007-10-15 2009-04-23 Concert Pharmaceuticals, Inc. Deuterated lorcaserin
WO2012030951A1 (en) * 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Fast-dissolve dosage forms of 5-ht2c agonists

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2924024A3 (en) * 2014-03-21 2016-01-20 Medichem, S.A. Solid forms of lorcaserin hydrochloride
CN104829532A (en) * 2015-05-15 2015-08-12 浙江理工大学 Method for preparing lorcaserin hydrochloride single crystal
CN106880648A (en) * 2015-12-16 2017-06-23 深圳翰宇药业股份有限公司 A kind of pharmaceutical composition and preparation method thereof
EP3210975A1 (en) 2016-02-24 2017-08-30 Enantia, S.L. Cocrystals of lorcaserin
WO2017144598A1 (en) 2016-02-24 2017-08-31 Enantia, S.L. Cocrystals of lorcaserin
CN106074558A (en) * 2016-06-12 2016-11-09 佛山市腾瑞医药科技有限公司 A kind of hydrochloric acid lorcaserin preparation and application thereof
CN107802603A (en) * 2017-12-14 2018-03-16 乐普制药科技有限公司 One kind receives general ether alcohol dispersion and preparation method thereof
WO2021041824A1 (en) 2019-08-28 2021-03-04 Lubrizol Advanced Materials, Inc. Drug-polymer amorphous solid dispersions using linear poly (acrylic acid) polymers

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