EP3063132A1 - Chlorhydrate de lorcasérine amorphe stabilisé - Google Patents

Chlorhydrate de lorcasérine amorphe stabilisé

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Publication number
EP3063132A1
EP3063132A1 EP14793150.5A EP14793150A EP3063132A1 EP 3063132 A1 EP3063132 A1 EP 3063132A1 EP 14793150 A EP14793150 A EP 14793150A EP 3063132 A1 EP3063132 A1 EP 3063132A1
Authority
EP
European Patent Office
Prior art keywords
lorcaserin hydrochloride
amorphous
hydrochloride
solvent
lorcaserin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14793150.5A
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German (de)
English (en)
Inventor
Gaj STAVBER
Jerome Cluzeau
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lek Pharmaceuticals dd
Original Assignee
Lek Pharmaceuticals dd
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Filing date
Publication date
Application filed by Lek Pharmaceuticals dd filed Critical Lek Pharmaceuticals dd
Priority to EP14793150.5A priority Critical patent/EP3063132A1/fr
Publication of EP3063132A1 publication Critical patent/EP3063132A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the present invention is directed to stabilized amorphous lorcaserin hydrochloride, a pharmaceutical composition comprising the same, as well as a process for obtaining the same.
  • Obesity is a life-threatening disorder associated with an increased risk of mortality arising from concomitant diseases such as type II diabetes, hypertension, stroke, cancer and gallbladder disease.
  • WO 03/086306 Al relates to 5HT 2C receptor modulators and discloses selective 5HT 2C agonists for reducing appetite and food consumption, thereby causing body weight loss.
  • Lorcaserin ((R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[d]azepine) has been identified to be useful for the treatment of obesity.
  • 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 2011/153206 Al discloses a crystalline form of lorcaserin hydrochloride (Form IV), described to be a new anhydrous form, and its conversion to Form III, the lorcaserin hemihydrate, upon exposure to moisture.
  • a pharmaceutical composition has to be stable in an environment having enhanced relative humidity in order to be suitable for tropical countries.
  • Forms I, II and IV (WO 2011/153206 Al) are hygroscopic and, thus, are problematic for the purpose of producing a pharmaceutical composition suitable for use in tropical countries. This is because a pharmaceutical composition comprising these solid crystalline forms of lorcaserin hydrochloride can be expected to absorb water when being exposed to an environment having a higher relative humidity.
  • Form III of lorcaserin hydrochloride has a 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 2011/153206 Al).
  • medicaments comprising Form III may not be stable at particular environmental conditions, such as elevated temperature.
  • WO 2011/153206 Al also refers to processes for the preparation of selective 5HT 2C 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. It is also described 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 described 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.
  • the pharmaceutical compositions comprising the 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 being exposed to an environment having an extreme relative humidity (high or low) and/or an elevated temperature.
  • the known solid forms of lorcaserin hydrochloride need to be improved with respect to the physicochemical as well as the pharmaceutical characteristics of pharmaceutical compositions containing lorcaserin.
  • 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 hydrochloride showing the characteristic XRPD peaks of either Form III and/or Form II (according to WO 2011/153206 Al) has been obtained .
  • the various different attempts failing to prepare amorphous lorcaserin hydrochloride suggest that pure amorphous lorcaserin hydrochloride is not stable in the amorphous state and readily crystallizes.
  • the present invention therefore aims at a stable amorphous dosage form of lorcaserin hydrochloride avoiding the drawbacks of the known crystalline forms. It is thus the object of the present invention to develop new solid forms of lorcaserin hydrochloride used as an API in order to improve the performance profile of a pharmaceutical composition comprising said API.
  • the present invention provides the following items.
  • Amorphous lorcaserin hydrochloride ((R)-8-chloro-l-methyl-2, 3,4,5- tetrahydro-lH-benzo[d]azepine hydrochloride) of formula 1
  • Amorphous lorcaserin hydrochloride according to item 1 wherein the at least one pharmaceutically acceptable inorganic adsorbent is selected from MgO and Si0 2 .
  • Amorphous lorcaserin hydrochloride according to any of item 1 to 3, wherein the at least one pharmaceutically acceptable inorganic adsorbent is Si0 2 selected from silica gel and fumed silica.
  • Amorphous lorcaserin hydrochloride according to any of items 1 to 7, wherein the loading of amorphous lorcaserin hydrochloride on the adsorbent is 12% or more.
  • Amorphous lorcaserin hydrochloride according to any of items 1 to 7, wherein the loading of amorphous lorcaserin hydrochloride on the adsorbent is 20% or more.
  • Amorphous lorcaserin hydrochloride according to any of items 1 to 7, wherein the loading of amorphous lorcaserin hydrochloride on the adsorbent is 30% or more.
  • Amorphous lorcaserin hydrochloride according to any of items 1 to 7, wherein the loading of amorphous lorcaserin hydrochloride on the adsorbent is 40% or more.
  • Amorphous lorcaserin hydrochloride according to any of items 1 to 11, wherein the loading of amorphous lorcaserin hydrochloride on the adsorbent is 65% or less.
  • step (ii) adding at least one pharmaceutically acceptable inorganic adsorbent to the solution obtained in step (i);
  • the at least one pharmaceutically acceptable inorganic adsorbent may alternatively be dispersed in the protic solvent, aprotic polar solvent, or mixture thereof, before dissolving the lorcaserin or lorcaserin hydrochloride.
  • step (i) is a CI to C4 alcohol, preferably methanol, ethanol or 2-propanol .
  • step (i) is a halogenated CI to C4 hydrocarbon, preferably dichloromethane, or acetonitrile.
  • step (i) is carried out at a temperature of 10 to 60 °C, preferably at 18 to 30 °C, more preferably 20 to 25 °C (r.t.), and further wherein when the solvent in the step (i) is 2-propanol or acetonitrile, a preferred temperature is 40 to 60 °C. 20.
  • the at least one pharmaceutically acceptable inorganic adsorbent is selected from MgO and Si0 2 .
  • Syloid ® and Aerosil ® are selected from Syloid ® 72 FP, Syloid ® 244 FP, Aerosil ® 200, Aerosil ® 300 and Aerosil ® 380.
  • a pharmaceutical composition comprising stabilized amorphous lorcaserin hydrochloride ((R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-benzo[d]azepine hydrochloride) according to any of items 1 to 14.
  • composition according to item 28 which further comprises at least one pharmaceutically acceptable ingredient.
  • composition according to item 28 or 29 for use as a medicament.
  • composition according to any of items 28 to 32, which is in the form of tablets, capsules, pills or lozenges.
  • composition according to any of items 28 to 33, which comprises 5 to 100 mg, preferably 7 to 20 mg, amorphous lorcaserin hydrochloride per dosage form.
  • composition according to any of items 28 to 34, which is a modified release dosage form.
  • lorcaserin hydrochloride ((fl)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-benzo[d]azepine hydrochloride) of formula 1
  • amorphous lorcaserin hydrochloride is intended to mean a non-crystalline form of lorcaserin hydrochloride as determined by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) analysis or by using a scanning electron microscope (SEM). Especially the absence of peaks on the X-ray powder diffractogram of the stabilized amorphous lorcaserin hydrochloride of the present invention, in particularly the absence of characteristic XRPD peaks for Form III of lorcaserin hydrochloride, suggests that the lorcaserin hydrochloride is amorphous.
  • Characteristic X-ray powder diffraction pattern of Form I comprises peaks at 2-theta angles of 11.5 ⁇ 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 term "inorganic adsorbent” is intended to mean a solid supporter represented by any inorganic substance onto which amorphous lorcaserin hydrochloride can be adsorbed and which is pharmaceutically acceptable.
  • the adsorption of amorphous lorcaserin hydrochloride onto the inorganic adsorbent serves to stabilize the lorcaserin hydrochloride in its amorphous form.
  • the lorcaserin hydrochloride is not simply deposited on the adsorbent, but stabilized by non-covalent forces as can be confirmed by methods known in the art, such as scanning electron microscopy (SEM) visualization or infrared (IR) shift.
  • SEM scanning electron microscopy
  • IR infrared
  • the inorganic adsorbent should preferably have a certain surface area and/or porosity, such that the lorcaserin hydrochloride can be adsorbed on the outer and/or inner surface of the adsorbent.
  • the surface area of the inorganic adsorbent usually has a BET-surface area of at least 1 m 2 /g, preferably of at least 50 m 2 /g, more preferably of at least 100 m 2 /g, still more preferably of at least 150 m 2 /g, and most preferably of at least 200 m 2 /g.
  • the upper limit of the surface area is not essentially limited, but may usually be 10000 m 2 /g or less, preferably 5000 m 2 /g or less, still more preferably 1000 m 2 /g or less, most preferably 750 m 2 /g or less.
  • a suitable surface area may preferably range 100 to 5000 m 2 /g, more preferably 150 to 1000 m 2 /g, still more preferably of from 200 to 750 m 2 /g.
  • the determination of the BET-surface area of the carrier can be carried out according to the method as described in the article: J. Am. Chem. Soc. 60, 309 (1938).
  • the inorganic adsorbent with the defined BET-surfaces has preferably a certain degree of porosity (open porosity determined according to DIN EN 623-2) of at least 10 %, 20 %, 30 %, 40 %, or 60 %.
  • the porosity ranges from 10 to 70 %, preferably from 20 to 70 %, more preferably from 30 to 70 % and still more preferably from 40 to 70%.
  • the size of the inorganic adsorbent, preferably in the particulate form is not specifically limited and may suitable be in the micro or nano scale.
  • a particulate inorganic adsorbent may be present as single particles or agglomerate thereof, preferably having an average particle size (via Malvern) of 20 pm or less, more preferably 15 pm or less and preferably of at least 5 nm, preferably of at least 10 nm.
  • Non-limiting preferred examples of the inorganic adsorbents include Si0 2 and MgO.
  • the inorganic adsorbent is silicon dioxide selected from silica gel and fumed silica, i.e. synthetic and amorphous silicas.
  • Such silicas may more preferably be selected from Aerosil, for example Aerosil 200, Aerosil 300, and Aerosil 380 (Evonik Industries), and Syloid, for example Syloid ALl, Syloid 72 FP and Syloid 244 FP (W. R. Grace & Co. -Conn.).
  • an especially preferred MgO is represented by NanoActive ® MgO featuring a high porosity and large BET surface area.
  • Loadings can also be measured by spectrometric assay methods.
  • the lower limit of the loading of the inorganic adsorbent with lorcaserin hydrochloride is not specifically limited, it is generally desirable to achieve a loading as high as possible in order to minimize the influence of inorganic adsorbent with respect to the content/volume in the final dosage form.
  • the loading of lorcaserin hydrochloride is at least 12 %, more preferably at least 20 %, still more preferably at least 30 %, and most preferred at least 40 %.
  • the upper limit of the loading of lorcaserin hydrochloride is not specifically limited and it is generally desirable to achieve a loading as high as possible, it is also desirable that essentially all of lorcaserin hydrochloride is present in amorphous from adsorbed to the inorganic adsorbent. If the loading percentage becomes too high, it may in the individual case be difficult to realize a condition of lorcaserin hydrochloride being entirely adsorbed to the inorganic adsorbent in amorphous state. Therefore, it is generally preferred that the upper limit of the loading is 65 % or less, more preferably 60 % or less, still more preferably 55 % or less.
  • the above described stabilized amorphous lorcaserin hydrochloride of the present invention may be obtained by a method comprising the steps (i) to (iv) : (i) dissolving lorcaserin hydrochloride in a protic solvent, an aprotic polar solvent, or a mixture thereof, or dissolving lorcaserin in said protic solvent, aprotic polar solvent, or mixture thereof upon in situ generation of lorcaserin hydrochloride;
  • step (ii) adding at least one pharmaceutically acceptable inorganic adsorbent to the solution obtained in step (i);
  • the at least one pharmaceutically acceptable inorganic adsorbent is alternatively initially dispersed in the protic solvent, aprotic polar solvent, or mixture thereof, before dissolving the lorcaserin or lorcaserin hydrochloride in the resulting dispersion, it is preferred that the at least one pharmaceutically acceptable inorganic adsorbent is dispersed in step (ii) after dissolving lorcaserin or lorcaserin hydrochloride in step (i).
  • the protic solvent, aprotic polar solvent or mixture thereof is not specifically limited as long as it is a solvent or mixture of solvents that is able to dissolve the lorcaserin hydrochloride while not dissolving the inorganic adsorbent.
  • aprotic solvent is intended to mean any solvent which cannot readily donate hydrogen atoms as protons (H + ), i.e. are not acidic.
  • Non-limiting examples of aprotic solvents include CH 2 CI 2 .
  • the term “protic solvent” is intended to mean any solvent which contains one or more labile hydrogen atoms that are capable of hydrogen bonding and which can be readily donated as protons (H + ).
  • protic solvents include alcohols.
  • the protic solvent used in step (i) is suitably a CI to C4 alcohol, most preferably methanol, ethanol or 2-propanol.
  • the aprotic polar solvent used in step (i) is preferably a halogenated CI to C4 hydrocarbon, such as dichloromethane, 1,2- dichloroethane, or acetonitrile, more preferably dichloromethane.
  • an alcoholic medium preferably methanol, ethanol or 2-propanol.
  • the conditions for the step (i) are not essentially limited and the step (i) may proceed at any suitable temperature. It is preferred that the temperature is below the boiling point of the solvent or solvent mixture. Under environmental and economical aspects, it is preferred to apply a temperature in the range of 10 to 60°C, preferably 18 to 30°C, most preferably at room temperature (r.t. ; 20 to 25°C), if 2-propanol or acetonitrile are used as solvents the preferred temperatures are higher, e.g., 40-60°C) .
  • the lorcaserin is dissolved as a free base, the free base is preferably converted to the hydrochloride salt by adding a solution providing hydrogen chloride.
  • the inorganic adsorbent added in the step (ii) may be the same as described above.
  • the inorganic adsorbent is selected from the above described fumed silica or silica gels selected from the Aerosil® or Syloid ® series or porous MgO having a large surface area, preferably NanoActive ® MgO.
  • the step (iii) is not specifically limited and the mixing may be accomplished by conventional mixing devices, such as a stirrer, an ultrasonic bath etc.
  • the mixing time is not specifically limited and may suitable be adjusted taking into consideration the solvent, the concentration of lorcaserin hydrochloride and the kind and amount of the inorganic adsorbent.
  • the mixing time is preferably adjusted to ensure a uniform distribution of the lorcaserin hydrochloride on the inorganic adsorbent.
  • the mixing proceeds within a few minutes.
  • the upper limit for the mixing time is not specifically limited. However, additional mixing time is not required in case the additional time does not contribute to improved uniformity any more.
  • a mixing time of 1 hour is sufficient to attain satisfactory results, while a mixing time is preferably not more than 45 minutes.
  • the mixing time is in a range between 5 to 45 minutes, more preferably 10 to 40 minutes.
  • the solvent can be removed in the step (iv) using any known method .
  • the solvent is removed by filtration or evaporation or by a combination of evaporation and filtration.
  • the excessive amount thereof will remain in the filtrate after removing the solvent by filtration.
  • Such lorcaserin hydrochloride contained in the filtrate may preferably be recovered for subsequent loading of inorganic adsorbents.
  • the solvent is removed in the step (iv) by evaporation.
  • the evaporation method enables to attain a higher loading of the inorganic adsorbent by lorcaserin hydrochloride.
  • the "evaporation period" corresponds to the time that is required to evaporate at least 80%, further preferred at least 90%, and further preferred at least 95% of the solvent.
  • a too fast evaporation of the solvent may lead to the formation of e.g . coprecipitates of lorcaserin hydrochloride, which would not be adsorbed on the carrier and which would be in the form of amorphous or crystalline particles.
  • Slowly removing the solvent has the benefit that uneconomic, complex and laborious process steps are not necessary, which would otherwise be necessary to achieve a fast removal. Additionally, the slow removal of the solvent leads to the formation of a stable adsorbate having improved properties with respect to stability and solubility of lorcaserin hydrochloride.
  • the amorphous lorcaserin hydrochloride stabilized by the at least one inorganic adsorbent is preferably manufactured in a solid dry state. If solvent remains in the adsorbate after the filtration and/or evaporation in step (iv), the residual solvent is preferably removed to pharmaceutically acceptable levels by a drying step carried out by any conventional drying means. If carrying out a drying step, the step is preferably carried out under mild conditions, more preferably under reduced pressure. Preferably, the evaporation in the step (iv) is carried out in a manner leading to a solid dry product without the need for an additional drying step.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the above described stabilized lorcaserin hydrochloride.
  • the present invention also relates to the use of the pharmaceutical composition as a medicament and especially to the use for the treatment of obesity.
  • pharmaceutical composition is intended to mean any mixture or solution containing amorphous lorcaserin hydrochloride stabilized by an inorganic adsorbent suitable for administration to a mammal, preferably a human, in order to prevent, treat or control a particular disease or condition affecting the mammal .
  • the stabilized amorphous lorcaserin hydrochloride 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 addresses known side effects of lorcaserin hydrochloride, such as a tendency to cause sedation in susceptible subjects.
  • modified release is generally used as defined by the US Pharmacopeia (USP).
  • modified release dosage forms comprising the stabilized amorphous lorcaserin hydrochloride 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 Encyclopedia of Pharmaceutical technology.
  • a preferred formulation of the pharmaceutical composition may be an oral dosage form and particularly preferred are solid formulations such as capsules, tablets, pills and lozenges.
  • the stabilized amorphous lorcaserin hydrochloride according to the present invention may be directly used as powders (micronized particles) or granules, or it may be combined together with one or more 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 formulations and may be for example binders such as natural or synthetic polymers, excipients, disintegrants, lubricants, surfactants and/or co-surfactants, sweetening and other flavouring agents, coating materials, preservatives, dyes, thickeners, fillers, adjuvants, antimicrobial agents and carriers for the various formulation types.
  • binders such as natural or synthetic polymers, excipients, disintegrants, lubricants, surfactants and/or co-surfactants, sweetening and other flavouring agents, coating materials, preservatives, dyes, thickeners, fillers, adjuvants, antimicrobial agents and carriers for the various formulation types.
  • binders such as natural or synthetic polymers, excipients, disintegrants, lubricants, surfactants and/or co-surfactants, sweetening and other flavouring agents,
  • 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.
  • polyglycolic acid polylactic acid
  • poly-d,l- lactide/glycolide examples 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, polyvinylimidazole, polyvinylpyrrolidone, and natural polymers like chitosan, carragenan or hyaluronic acid.
  • 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, poly
  • 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, l-acylamino-ethane-2-sulfonic acids, such as l-octanoylaminoethane-2-sulfonic acid, 1-decanoyl-aminoethane- 2-sulfonic acid, l-dodecanoylaminoethane-2-sulfonic acid, 1-tetra- decanoylaminoethane-2-sulfonic acid, l-hexadecanoylaminoethane-2-sulfonic acid, and l-octadecan
  • coating materials are gelatin, wax, shellac or biological degradable polymers.
  • preservatives examples include 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.
  • fillers include confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc.
  • 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 typically contain a solid composition within a capsule, which may be made of gelatin or other conventional encapsulating materials.
  • Tablets and powders may be coated, e.g . 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 stabilized amorphous lorcaserin hydrochloride according to the invention in order to achieve a more controlled release of the API in contact with the body fluids in the gastro intestinal tract, and to provide a substantial constant and effective level of the API in the gastric juice.
  • the stabilized amorphous lorcaserin hydrochloride of the present invention may be embedded 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 further relates to a solid oral dosage form, such as a tablet, which may be prepared by wet granulation comprising the steps of:
  • step (c) spraying the binder solution of step (b) on the mixture obtained in step (a),
  • 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-l-butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-l-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate and tetrahydrofuran.
  • water acetic acid, acetone, anisole, 1-butanol, 2-butanol, but
  • Formulations of the present invention typically comprise 5 to 100 mg, preferably 7 to 20 mg, more preferably about 10 mg of lorcaserin.
  • X-Ray powder d iff ractog rams 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, a 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 X-ray diffractometers under standard conditions.
  • DSC thermograms were obtained using a Mettler Toledo DSC822e differential scanning calorimeter. The sample (1-10 mg) was placed in an unsealed aluminium pan with a hole and heated at 10°C/min in the temperature range from 30 °C to 250 °C.
  • the samples is mounted on stubs with double faced adhesive tape and sputter coated with a 3 nm gold layer in a high vacuum sputter coater (Leica EM SCD 500).
  • Surface topography is analyzed with a scanning electron microscope (JSM FE SEM 7001, Jeol, Tokyo, Japan) using secondary electron imaging (SEI) detector and different magnifications (100 - 20 OOOx).
  • JSM FE SEM 7001, Jeol, Tokyo, Japan secondary electron imaging
  • SEI secondary electron imaging
  • An acceleration voltage of 2 kV and a working distance of 5 mm is used .
  • Example 1 Adsorption of (fl)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[c/]azepin-3-ium chloride on silica (Aerosil ® 200) as solid supporter
  • Example 8 Adsorption of (fl)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[d]azepin-3-ium chloride on magnesium oxide as solid supporter
  • Example 9 Adsorption of (fl)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[c/]azepin-3-ium chloride on silica (Syloid ® 72 FP) as solid supporter
  • Example 10 Adsorption of (fl)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[c/]azepin-3-ium chloride on silica (Syloid ® 244 FP) as solid supporter
  • Example 11 Adsorption of (fl)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[c/]azepin-3-ium chloride on silica (Syloid ® 72 FP) as solid supporter
  • Example 12 Adsorption of (fl)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[c/]azepin-3-ium chloride on silica (Syloid ® 72 FP) as solid supporter
  • Example 13 Adsorption of (fl)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[c/]azepin-3-ium chloride on silica (Syloid ® 244 FP) as solid supporter
  • Example 14 Adsorption of (fl)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[c/]azepin-3-ium chloride on silica (Syloid ® 72 FP) as solid supporter
  • silica silica
  • Syloid ® 72 FP (1 g) was added in portions and the suspension was stirred at r.t. for 30 minutes. Solvent was then slowly evaporated under reduced pressure and dried under vacuum to obtain dry adsorbate (1.29 g). Material was characterized with DSC and XRD where only amorphous material was detected within detection limits.
  • Example 15 Adsorption of (fl)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[c/]azepin-3-ium chloride on silica (Syloid ® 72 FP) as solid supporter
  • Example 16 Direct one-pot preparation of adsorbate of (fl)-8-chloro-l-methyl- 2,3,4,5-tetrahydro-lH-benzo[c/]azepin-3-ium chloride on silica (Syloid ® 72 FP) solid supporter in alcoholic media
  • liquid (fl)-8-chloro-l- methyl-2,3,4,5-tetrahydro-lH-benzo[c/]azepine free base (293 mg) which was dissolved in ethanol or methanol (15 ml_).
  • solution of hydrochloric acid in ethanol on methanol (1.44 ml of 1.25 M HCI) was slowly added and solution was stirred for 20 minutes.
  • Syloid ® 72 FP (1.05 g) was added in two portions and the suspension was stirred at r.t. for 30 minutes. Solvent was then slowly evaporated under reduced pressure and dried under vacuum to obtain dry adsorbate (1.32 g).
  • Example 17 Direct one-pot preparation of adsorbate of (fl)-8-chloro-l-methyl- 2,3,4,5-tetrahydro-lH-benzo[c/]azepin-3-ium chloride on silica (Syloid ® 72 FP) solid supporter in chlorinated solvents
  • 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).

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Abstract

La présente invention concerne le chlorhydrate de lorcasérine amorphe stabilisé ((R)-8-chloro-1-méthyl-2,3,4,5-tétrahydro-1H-benzo[d]-azépine-chlorhydrate), une composition pharmaceutique le comprenant ainsi qu'un procédé de préparation de ceux-ci.
EP14793150.5A 2013-11-05 2014-11-04 Chlorhydrate de lorcasérine amorphe stabilisé Withdrawn EP3063132A1 (fr)

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EP20130191659 EP2868656A1 (fr) 2013-11-05 2013-11-05 Hydrochlorure de lorcasérine amorphe stabilisé
EP14793150.5A EP3063132A1 (fr) 2013-11-05 2014-11-04 Chlorhydrate de lorcasérine amorphe stabilisé
PCT/EP2014/073706 WO2015067604A1 (fr) 2013-11-05 2014-11-04 Chlorhydrate de lorcasérine amorphe stabilisé

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KR101281919B1 (ko) 2004-12-21 2013-07-03 아레나 파마슈티칼스, 인크. (ｒ)-8-클로로-1-메틸-2,3,4,5-테트라히드로-1ｈ-3-벤즈아제핀 히드로클로라이드의 결정질 형태
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