A SOLID COMPOSITION OF ELIGLUSTAT

Abstract

A SOLID COMPOSITION OF ELIGLUSTAT A solid pharmaceutical composition comprising a crystalline form of eliglustat free base and a pharmaceutically acceptable excipient, wherein the composition is free of binder.

Description

FIELD OF THE INVENTION The present invention relates to a solid composition of crystalline form R1 of eliglustat free base wherein the composition is free of binder and a process for the preparation of such solid compositions. BACKGROUND OF THE INVENTION Eliglustat is chemically known as N-[(1R,2R)2-(2,3-dihydro-1,4-benzodioxin-6yl)2- hydroxy -1-(1-pyrrolidinyl-methyl)ethyl]octanamide. Eliglustat hemitartrate (Genz112638), is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses. Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses. which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. Eliglustat hemitartrate is an improved inhibitor of glucocerebroside synthase. European Patent EP1409467B1 discloses the compound eliglustat and its preparation method. However, the 467 patent does not suggest any compositions of eliglustat free base or its pharmaceutically acceptable salts. Various publications provide different salts of eliglustat like European Patent 2504332 prepares the tartrate salt of eliglustat and exemplifies compositions with the hemitartrate salt in capsule form; PCT publication 2015059679 discloses the crystalline form R1 of eliglustat; European Patent 3283483 discloses the hydrochloride salt of eliglustat; PCT publication 2023083293 discloses the oxalate salt of eliglustat crystal form A, naphthalene, disulfonate, mucate and glutarate. However, none of the publications teach compositions of free base. Further, due to the hygroscopic nature of the salts the composition comprises binder for preparation of the granules for filling in capsules. It is therefore advantageous to provide compositions of eliglustat free base which would avoid an unnecessary step of preparation of the salt form of eliglustat and the cumbersome work of storing the salt form. SUMMARY OF THE INVENTION The present invention is defined in the appended claims. In accordance with a first aspect, there is provided a solid composition of crystalline form of eliglustat free base. The preferred crystalline form of eliglustat free base is form R1. The solid composition of crystalline form of eliglustat free base is free of binder. In accordance with a second aspect, there is provided a process for the preparation of a solid composition according to the first aspect. In embodiments, the solid composition is prepared by using wet granulation. Certain embodiments of the present invention may provide one or more of the following advantages: . desired stability of crystalline form of eliglustat free base compositions; . desired cost of crystalline form of eliglustat free base compositions; . desired ease of handling of crystalline form of eliglustat free base; . desired ease of preparation of crystalline form of eliglustat free base compositions The inventors surprisingly found that a solid composition according to the present invention may exhibit favourable physical attributes sufficient for manufacturing, alongside sufficient stability when compared to a current commercial product. Examples of the present invention were shown to display comparable dissolution and / or assay performance and / or stability when compared to solid compositions without binders. BRIEF DESCRIPTION OF THE DRAWINGS The invention will further be illustrated by reference to the following figures: Figure 1: XRD spectrum illustrating the stability of crystalline form R1 of eliglustat free base in solid composition of the present invention. DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the surprising finding that compositions of crystalline eliglustat with good stability can be obtained in the absence of a binder. Preferably, the crystalline form of eliglustat according to the present invention is crystalline form R1. When ranges are used herein, all combinations and sub-combinations of ranges and specific embodiments therein are intended to be included. As used herein, the term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary. As used herein, the term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") has an open meaning and therefore a pharmaceutical composition comprising described features may comprise additional components in addition to the described features. Abbreviations used herein have their conventional meaning within the chemical and biological arts, unless otherwise indicated. As used herein, the term dispersion generally refers to a system where a substance is dispersed within another substance. As used herein, the term solid dispersion generally refers to the solid-state dispersion of one or more active substances in an inert carrier excipient, for example, one or more poorly soluble drugs within a water-soluble polymer. As used herein, the term "excipient" refers to an inactive ingredient in a composition. As used herein, the term "diluent" or "filler" refers to an excipient that adds bulk to a composition. As used herein, the term "disintegrant" refers to an excipient that promotes disintegration of a tablet / capsule composition into smaller fragments in an aqueous environment. As used herein, the term "surfactant" refers to an excipient that decreases surface or interfacial tension to impart compositions with enhanced solubility and / or wettability. As used herein, the term "binder" refers to an excipient that improves cohesion, and plasticity of a composition. As used herein, the term "treatment" refers to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and / or a prophylactic benefit. The term patient refers to an animal, such as a mammal, for example a human. As used herein, the term "intragranular" refers to a component added before a granulation process. As used herein, the term "extragranular" refers to a component added after granulation and before a compression process. In certain embodiments, a solid composition of crystalline R1 form of eliglustat further comprises a filler / diluent, a disintegrant, a glidant, a lubricant and / or a surfactant,. In certain embodiments, the solid composition of crystalline R1 form of eliglustat comprises a surfactant selected from sodium lauryl sulfate, poly(ethylene oxide)- poly(propylene oxide)poly(ethylene oxide), poloxamer, polysorbate 20 and polysorbate 80, or a combination thereof. In some embodiments, the solid composition comprises surfactant in an amount of about 0.1 wt.% to about 5 wt.%, for example, of from about 0.1 wt.% to about 4 wt.%, of from about 0.5 wt.% to about 3 wt.%, or of from about 1 wt.% to about 2 wt.%. In some embodiments, for example, the solid composition according to the present invention comprises a surfactant in an amount of about 2 wt.%. In certain embodiments, the solid composition is free from intragranular lubricant. The term free from intragranular lubricant as used herein refers to compositions where lubricant has not been added to a composition to achieve a particular effect prior to granulation. For example, free from intragranular lubricant means that an intragranular lubricant is present in the composition in an amount of less than about 0.5 wt.%, or less than about 0.3 wt.%, or less than about 0.2 wt.%, or less than about 0.1 wt.%, or less than about 0.05 wt.%, or less than about 0.01 wt.%, or less than about 0.005 wt.% based on the total weight of the solid composition. In certain embodiments, the solid composition of crystalline R1 form of eliglustat free base comprises about 20 wt.% to about 45 wt.% of eliglustat free base; for example, from about 25 wt.% to about 45 wt.% of eliglustat free base. In certain embodiments, the solid composition of crystalline R1 form of eliglustat comprises from about 20 wt.% to about 45 wt.% of eliglustat free base based on the total weight of the solid composition. In certain embodiments, the solid composition of crystalline R1 form of eliglustat comprises a filler or diluent selected from silicified microcrystalline cellulose, microcrystalline cellulose, mannitol, starch, pregelatinized starch and lactose, or a combination thereof. In some embodiments, the lactose may be lactose anhydrous. In alternative embodiments, the lactose may be lactose monohydrate. In some embodiments, the solid composition comprises filler or diluent in an amount of about 45 wt.% to about 75 wt.%, for example, from about 45 wt.% to about 70 wt.%. In certain embodiments, the solid composition comprises filler or diluent in an amount of about 50 wt.% to about 70 wt.% based on the total weight of the solid composition. In certain embodiments, the solid composition of crystalline R1 form of eliglustat comprises a disintegrant selected from pregelatinized starch, croscarmellose sodium and crospovidone, or a combination thereof. In some embodiments, the solid composition comprises disintegrant in an amount of about 1 wt.% to about 10 wt.%, for example, from about 1 wt.% to about 9 wt.%, from about 2 wt.% to about 8 wt.%, from about 3 wt.% to about ? wt.%, or from about 4 wt.% to about 6 wt.%. In certain embodiments, the solid composition comprises disintegrant in an amount from about 5 wt.% to about 8 wt.% based on the total weight of the solid composition. In certain embodiments, the solid composition of crystalline R1 form of eliglustat comprises a glidant selected from colloidal silica, fumed silica, talc and magnesium carbonate, or a combination thereof. In some embodiments, the solid composition comprises glidant in an amount of about 0.1 wt.% to about 5 wt.%, for example, from about 0.5 wt.% to about 4.5 wt.%, from about 1 wt.% to about 4 wt.%, or from about 1 wt.% to about 3 wt.%. In some embodiments, for example, the solid composition according to the present invention comprises a glidant in an amount of about 2 wt.% based on the total weight of the solid composition. In certain embodiments, the solid composition of crystalline R1 form of eliglustat comprises a lubricant selected from magnesium stearate, sodium stearyl fumarate, glyceryl behenate (such as Compritol 888®) or a combination thereof. In some embodiments, the solid composition comprises lubricant in an amount of from about 0.1 wt.% to about 5 wt.%, for example, from about 0.5 wt.% to about 4.5 wt.%, from about 1 wt.% to about 4 wt.%, or from about 2 wt.% to about 4 wt.%. In some embodiments, for example, the solid composition according to the present invention comprises a lubricant in an amount of about 3 wt.% based on the total weight of the solid composition. Binders are substances that are added either dry or in liquid form during wet granulation to form granules or to promote cohesive compacts for directly compressed tablets. E.g., starch, pregelatinized starch, PEG, sorbitol, and HPMC, etc. Binders and disintegrants in general, have opposite uses in an oral solid formulation. Binder delays disintegration while disintegrant increase disintegration. In order to prevent a delayed disintegration time and as a result maybe an impact on dissolution rate versus innovator, the inventors eliminated the presence of a binder agent. In certain embodiments, the solid composition of crystalline R1 form of eliglustat is free from solid dispersions. Solid dispersions may be prepared by mixing eliglustat with a polymer and subjecting the mixture to spray drying or hot melt extrusion process. Hot-melt extrusion is a manufacturing process where polymeric materials are heated above their glass-transition temperature and mechanically mixed with active compounds in order to disperse the drug substance molecularly into the polymeric net. Spray -drying consists in two main steps: i) complete dissolution of the drug substance and a dilution material (e.g., a polymer) in a solvent or mixture of solvents and ii) fast spray -drying of the previous solution in order to collect the solid material. The polymer may be selected from HPMC, HPMCAS, PVP, HPC, methacrylic acid / methacrylate copolymers or any combinations thereof. In certain embodiments, the solid composition of crystalline R1 form of eliglustat is a free-flowing powder, granules, capsules, tablets, films, sublingual tablets or mouth dissolving tablets and pellets. Preferred embodiment of the solid composition of crystalline form of eliglustat free base of the present invention is capsules. In certain embodiments, the solid composition of crystalline R1 form of eliglustat free base comprises: (a) crystalline R1 form of eliglustat free base in an amount from about 20 wt.% to about 45 wt.%; (b) a surfactant in an amount from about 0.1 wt.% to about 5 wt.%; (c) a diluent or a filler in an amount from about 45 wt.% to about 70 wt.%; (d) a disintegrant in an amount from about 1 wt.% to about 10 by wt.%; (e) a glidant in an amount from about 0.1 wt.% to about 5 wt.%; (f) a lubricant in an amount from about 0.1 wt.% to about 10 wt.%; wherein each component is based on the total weight of the solid composition. In certain embodiments, the solid composition of crystalline R1 form of eliglustat free base comprises: (a) crystalline R1 form of eliglustat free base in an amount from about 20 wt.% to about 45 wt.%; (b) a filler or a diluent in an amount from about 45 wt.% to about 75 wt.%; (c) a disintegrant in an amount from about 4 wt.% to about 8 wt.%; (d) a glidant in an amount from about 0.1 wt.% to about 4 wt.%; (e) a lubricant in an amount from about 0.1 wt.% to about 4 wt.%; wherein each component is based on the total weight of the solid composition. In certain embodiments, the solid composition of crystalline R1 form of eliglustat free base comprises: (a) crystalline R1 form of eliglustat in an amount from about 20 wt.% to about 45 wt.%; (b) a filler or a diluent in an amount from about 45 wt.% to about 75 wt.%; (c) a glidant in an amount from about 0.1 wt.% to about 4 wt.%; (d) a lubricant in an amount from about 0.1 wt.% to about 10 wt.%; wherein each component is based on the total weight of the solid composition. In certain embodiments, the solid composition of crystalline R1 form of eliglustat free base comprises: (a) crystalline R1 form of eliglustat in an amount from about 20 wt.% to about 45 wt.%; (b) a filler or a diluent in an amount from about 45 wt.% to about 75 wt.%; (c) a lubricant in an amount from about 1 wt.% to about 10 wt.%; wherein each component is based on the total weight of the solid composition. In certain embodiments, the solid composition of crystalline R1 form of eliglustat free base comprises: (a) crystalline form R1 of eliglustat free base in an amount from about 20 wt.% to about 45 wt.%; (b) a diluent or a filler in an amount from about 45 wt.% to about 75 wt.%; (c) a lubricant in an amount from about 4 wt.% to about 12 wt.%; wherein each component is based on the total weight of the solid composition and the diluent or filler comprises lactose and microcrystalline cellulose in ratio of 8:1 to 12:1 by weight and the solid composition is capsules. In certain embodiments, the solid composition of crystalline R1 form of eliglustat is coated with a polymeric film coating material. Numerous suitable polymeric film coating materials are known in the art. In certain embodiments, the polymeric film coating material is selected from a film-coating polymer such as polyvinyl alcohol and / or polyethylene glycol. In some embodiments, the polymeric film-coating polymer is selected from hydroxypropylmethylcellulose or hydroxypropylcellulose. In certain embodiments, the solid composition of crystalline R1 form of eliglustat free base is an immediate release composition. As used herein, the term immediate release generally refers to a composition that is developed to dissolve without delaying or prolonging dissolution or absorption of the drug. In certain embodiments, the dissolution of eliglustat from a capsule formed from the solid composition of the present invention is at least about 75 % when the capsule is subjected to dissolution tests at pH range from 1.2 to 6.8 at 37° C i- 0.5°C using a USPII paddle apparatus with stirring speed of 50 rpm for 30 minutes. For example, the dissolution of eliglustat from a capsule formed from the solid composition of the present invention is at least about 80%, at least about 85%, or at least about 90% when the capsule is subjected to dissolution tests at a pH range from 1.2 to 6.8 at 37° C i- 0.5°C using a USPII paddle apparatus with stirring speed of 50 rpm for 30 minutes. Such dissolution is beneficial, as it shows the capsule has good bioavailability. A capsule formed from the solid composition of the present invention having a high percentage of dissolution may illustrate the rate at which the active ingredient would be released during treatment of a patient. In certain embodiments, the solid composition of crystalline R1 form of eliglustat free base is stable for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months at about 40 °C and about 75% relative humidity & at about 25 °C and about 60% relative humidity. The term stable is defined herein with regards to polymorphic stability and / or chemical stability. The chemical stability may be measured by suitable methods such as X-ray diffraction (XRD), dissolution and High-Performance Liquid Chromatography (HPLC). For example, the crystalline nature and active purity of the solid composition of crystalline eliglustat is retained at about 40 °C and about 75% relative humidity & at about 25 °C and about 60% relative humidity for at least about 3 months. For example, the crystalline nature and active purity of the solid composition of crystalline eliglustat is retained at about 40 °C and about 75% relative humidity & at about 25 °C and about 60% relative humidity for at least about 6 months. In certain embodiments, the capsules formed from the solid composition of the present invention comprise up to about 84 mg of eliglustat in a single dose. The capsule compositions of eliglustat are suitable for oral administration of eliglustat as a treatment for a patient. In certain embodiments the solid composition of crystalline R1 form of eliglustat may be prepared by wet granulation or dry granulation followed by filling in capsules. The preferred process is wet granulation using purified water. In certain embodiments, the solid composition may have one or more of the following effects: - increased simplicity of the composition; - increased stability of the composition; - maintenance of the stability of the composition; - reduced cost of the composition; - increased ease of preparing the composition. EXAMPLES Test methods and methodology XRD was performed according to the methodology of Chapter 2.9.33 of the European Pharmacopoeia, 11th Edition (2023), using a Bruker D2 Phaser Instrument, with a Cu Ku (A=1.54 À) source and a LynxEye detector. The d90 particle size ofthe crystalline R1 form of eliglustat is measured in a well-known manner by a laser light diffraction according to the method of Chapter 2.9.31 of the European Pharmacopoeia, 11th Edition (2023). AMalvern Mastersizer (3000), Hydro- 3000MV (accessory) and Analytical balance were used for dgo particle size determination. Particle size is determined by passing a laser beam through a dispersed sample and measuring the variation in angular scattered light intensity. The median particle size dgo is the value at which there are 90% by number of particles which have an equivalent spherical diameter less than that dgo value. Dissolution tests at a pH range from 1.2 to 6.8 at 37° C i- 0.5°C using a USPII paddle apparatus with stirring speed of 50 rpm and 900ml volume for 30 minutes. The following illustrates examples of the solid composition of crystalline form of eliglustat, and related aspects described herein. Thus, these examples should not be considered to restrict the present disclosure but are merely in place to teach how to carry out the present disclosure. Section I: Solid compositions of the present invention - Eliglustat free 84.40 84.40 84.40 84.40 ----- Glyceryl 2.70 18.9 behenate (compritol 888) ___ Capsule filling 270.00 270.00 270.0 270.00 ___-- Caps No.1 pearl white pearl green op. prin Section II: Dissolution study in 0.1N HCI with 50 rpm BATCH Example 4 DISS. MED HCL 0.1N HCL 0.1N APPARATUS PADDLES PADDLES INSTRUMENT DISTEK DISTEK 30 MIN 100.9 In the table above, RLD refers to pharmaceutical product Cerdelga® 84mg capsules, which has the qualitative composition shown in the table below. CERDELGA® 84mg Capsules Capsule contents Microcrystalline cellulose Lactose monohydrate Hypromellose Glycerol dibehenate Capsule shell Gelatin Potassium aluminium silicate (E555) Titanium dioxide (E171) Yellow iron oxide (E172) lndigotine (E132) Printing ink Shellac Black iron oxide (E172) Propylene glycol Ammonia solution, concentrated Section III: Stability studies The polymorphic stability of Example 4 was also investigated using XRD. The stability of Example 4 after 3 months and after 6 months of being stored in high-density polyethylene, with desiccant, and stored at 25 °C and 60 % relative humidity was investigated. A placebo sample was prepared with the same qualitative and quantitative (adjusted to 100% final ratio) composition as per Example 4, without the use of the eliglustat active ingredient. As shown in Figure 1, after both 3 months and 6 months Example 4 maintains its crystallinity and shows good polymorphic stability. Figure 4 also demonstrates the crystalline nature of the eliglustat active ingredient used.

Claims

1. A solid pharmaceutical composition that is a crystalline form of a free base of eliglustat includes and a pharmaceutically acceptable excipient, whereby the composition is free of binder.

2. The solid pharmaceutical composition as referred to in claim 1, where the crystalline form form R1 is.

3. The fixed pharmaceutical composition in accordance with one of the preceding claims, where the composition is prepared by wet granulation.

4. The fixed pharmaceutical composition in accordance with one of the preceding claims, where the pharmaceutically acceptable excipient is selected from a diluent or filler, disintegrant, lubricant, sliding agent, stabilizer and surfactant substance or a mixture thereof.

5. The fixed pharmaceutical composition in accordance with one of the preceding claims, where the composition is a fixed dosage form, chosen from powder, granules, capsules, tablets, films, sublingual tablets or orally disintegrating tablets and pellets.

6. The fixed pharmaceutical composition in accordance with one of the preceding claims, where the composition comprises: (a) crystalline form Rl of eliglustat free base in an amount of approximately 20 weight percent to about 45 weight percent; (b) a diluent or bulking agent in an amount of approximately 45 weight percent up to approximately 75 weight percent; (c) a lubricant in an amount of approximately 4 weight percent to approximately 12 weight percentage; where each component is based on the total weight of the solid composition.

7. The fixed pharmaceutical composition in accordance with one of the preceding claims, where the composition includes (a) crystalline form R1 of eliglustat free base in an amount of approximately 20 wt.% up to approximately 45 wt.%; (b) a diluent or a bulking agent in an amount of approximately 45 wt.% to approximately 75 wt.%; (c) a lubricant in an amount of approximately 4 wt.% to approximately 12 wt.%; where each component is based on the total weight of the solid composition and the diluent or filler lactose and microcrystalline cellulose comprises in a ratio of 8:1 to 12:1 by weight and the fixed composition of the capsules are.

8. The fixed pharmaceutical composition in accordance with one of the preceding claims, where the crystalline form R1 of eliglustat for at least 12 months at 40 °C and maintains 75% relative humidity.

9. The fixed pharmaceutical composition in accordance with one of the preceding claims, where the composition is an immediate-release composition.

10. A solid pharmaceutical composition comprising (a) crystalline form R1 of eliglustat free base in an amount of approximately 20 wt.% up to approximately 45 wt.%; (b) microcrystalline cellulose in an amount of approximately 4 wt.% to approximately 10 weight%; (c) lactose or lactose monohydrate in an amount of approximately 45 wt.% to approximately 65 wt.%; and (d) glyceryl behenate in an amount of approximately 5 wt.% to approximately 10 wt.%; where each component is based on the total weight of the solid composition.

11. The fixed pharmaceutical composition according to claim 10, where the composition is in capsule form.

12. The fixed pharmaceutical composition according to claim 10 or 11, where the crystalline form R1 of eliglustat for at least 12 months at 40 °C and 75% relative humidity is maintained.

13. The fixed pharmaceutical composition according to one of claims 10 to 12, where the composition is an immediate-release composition. 1 / 1 Ex. 4 - 6M, 25°C / 60% RH Ex. 4 – Zero time Ex. 4 - 3M, 25°C / 60% RH Placebo sample Eliglustat free base Figure 1 REPORT CONCERNING THE RESEARCH INTO THE STATE OF THE ART Patent application 2041315 or patent application 2041315 no prior art search was conducted. The result of the earlier search into the state of the art, conducted by the European Patent Office carried out for the European patent application EP 24300009, has in fact been declared also applicable. patent application 2041315. The earlier research result is attached in its original form. Application Number EUROPEAN SEARCH REPORT EP 24 30 0009 DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document with indication, where appropriate, Relevant CLASSIFICATION OF THE Category APPLICATION (IPC) of relevant passages to claim T Anonymous -: "LYCATAB l Pregelatinized INV. Starch", A61K9 / 00 , A61K9 / 14 1 January 2016 (2016-01-01), XP093246027, A61K9 / 16 Retrieved from the Internet: A61K9 / 20 URL: https: / / www.roquette.com / pharma-and-nu A61K31 / 4025 traceuticals-pregelatinized-starch * the whole document * ----- T Hebbink Gerald A. ET AL: "Chapter 5 - Application of lactose in the pharmaceutical industry" In: "Lactose", 1 January 2019 (2019-01-01), Elsevier ScienceDirect, XP093246036, ISBN: 978-0-12-811720-0 pages 175-229, DOI: 10.1016 / B978-0-12-811720-0.00005-2, Retrieved from the Internet: URL:https: / / www.sciencedirect.com / science / TECHNICAL FIELDS article / abs / pii / B9780128117200000052> SEARCHED (IPC) * abstract * ----- A61K Y,D EP 2 504 332 B1 (GENZYME CORP [US]) 1-13 4 June 2014 (2014-06-04) * paragraph [0017]; claims 1-5; example 5; tables * ----- Y,D WO 2015 / 059679 A1 (REDDYS LAB LTD DR [IN]) 1-13 30 April 2015 (2015-04-30) * claims; figure 1; example 6 * ----- Y EP 3 865 125 A1 (KASHIV BIOSCIENCES LLC 1-13 [US]) 18 August 2021 (2021-08-18) * paragraphs [0008], [0044]; claims 1,10; examples * ----- - / -- The present search report has been drawn up for all claims 1 Place of search Date of completion of the search Examiner Munich 4 February 2025 Härtinger, Stefan CATEGORY OF CITED DOCUMENTS T : theory or principle underlying the invention E : earlier patent document, but published on, or X : particularly relevant if taken alone after the filing date Y : particularly relevant if combined with another D : document cited in the application document of the same category L : document cited for other reasons A : technological background ...................................................................................................... O : non-written disclosure & : member of the same patent family, corresponding P : intermediate document document page 1 of 2 EPO FORM 1503 03.82 (P04C01) Application Number EUROPEAN SEARCH REPORT EP 24 30 0009 DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document with indication, where appropriate, Relevant CLASSIFICATION OF THE Category APPLICATION (IPC) of relevant passages to claim Y COTABARREN IVANA ET AL: "Binder-free 1,3,10 twin-screw melt granulation: An effective approach to manufacture high-dose API formulations", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER, AMSTERDAM, NL, vol. 606, 21 July 2021 (2021-07-21), XP086763211, ISSN: 0378-5173, DOI: 10.1016 / J.IJPHARM.2021.120886 [retrieved on 2021-07-21] * pages 3,19; figures; tables * ----- TECHNICAL FIELDS SEARCHED (IPC) The present search report has been drawn up for all claims 1 Place of search Date of completion of the search Examiner Munich 4 February 2025 Härtinger, Stefan CATEGORY OF CITED DOCUMENTS T : theory or principle underlying the invention E : earlier patent document, but published on, or X : particularly relevant if taken alone after the filing date Y : particularly relevant if combined with another D : document cited in the application document of the same category L : document cited for other reasons A : technological background ...................................................................................................... O : non-written disclosure & : member of the same patent family, corresponding P : intermediate document document page 2 of 2 EPO FORM 1503 03.82 (P04C01) EP24300009 04-02-2025 EP2504332 B1 04-06-2014 AR 079152A1 28-12-2011 AR 121611A2 22-06-2022 AR 121612A2 22-06-2022 AU 2010324810A1 07-06-2012 AU 2016202591A1 19-05-2016 AU 2017265180A1 14-12-2017 BR112012012947A2 01-03-2017 CA 2781676A1 03-06-2011 CA 3075788A1 03-06-2011 CA 3140959A1 03-06-2011 CL 2012001348A1 24-08-2012 CL 2016002589A1 19-05-2017 CN 102712629A 03-10-2012 CN 105753846A 13-07-2016 CN 105777707A 20-07-2016 CN 112521366A 19-03-2021 CN 112521367A 19-03-2021 CR 20120277A 05-09-2012 CY 1115880T1 25-01-2017 CY 1117996T1 17-05-2017 CY 1122698T1 12-03-2021 DK 2504332T3 25-08-2014 DK 2796457T3 29-08-2016 DK 3133070T3 11-11-2019 DO P2012000141A 30-09-2012 DO P2016000250A 15-02-2017 EA 201270646A1 30-01-2013 EA 201592195A1 29-04-2016 EA 201890254A2 31-10-2018 EC SP12011926A 31-07-2012 EC SP18063798A 28-02-2020 EP 2504332A1 03-10-2012 EP 2796457A1 29-10-2014 EP 3133070A1 22-02-2017 EP 3599237A1 29-01-2020 EP 3896069A1 20-10-2021 ES 2493940T3 12-09-2014 ES 2586947T3 19-10-2016 ES2754398T3 17-04-2020 ES 2875382T3 10-11-2021 GT 201200161A 27-01-2014 HK 1172031A1 12-04-2013 HK 1203485A1 30-10-2015 HR P20140780T1 07-11-2014 HR P20161038T1 21-10-2016 HR P20191647T1 13-12-2019 page1of3ANNEXTOTHEEUROPEANSEARCHREPORTONEUROPEANPATENTAPPLICATIONNO.Thisannexliststhepatentfamilymembersrelatingtothepatentdocumentscitedin theabove-mentionedEuropeansearchreport.ThemembersareascontainedintheEuropeanPatentOfficeEDPfileonTheEuropeanPatentOfficeisinnowayliablefortheseparticularswhicharemerelygivenforthepurposeofinformation.PatentdocumentcitedinsearchreportPublicationdatePatentfamilymember(s)PublicationdateFormoredetailsaboutthisannex:seeOfficialJournaloftheEuropeanPatentOffice,No.12 / 82

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