WO2023052652A1 - Forme cristalline d'acoramidis chlorhydrate - Google Patents

Forme cristalline d'acoramidis chlorhydrate Download PDF

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Publication number
WO2023052652A1
WO2023052652A1 PCT/EP2022/077587 EP2022077587W WO2023052652A1 WO 2023052652 A1 WO2023052652 A1 WO 2023052652A1 EP 2022077587 W EP2022077587 W EP 2022077587W WO 2023052652 A1 WO2023052652 A1 WO 2023052652A1
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WO
WIPO (PCT)
Prior art keywords
acoramidis
crystalline form
hydrochloride
pharmaceutical composition
present
Prior art date
Application number
PCT/EP2022/077587
Other languages
English (en)
Inventor
Verena Adamer
Arthur Pichler
Renate MARGREITER
Original Assignee
Sandoz Ag
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sandoz Ag filed Critical Sandoz Ag
Publication of WO2023052652A1 publication Critical patent/WO2023052652A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a crystalline form of acoramidis hydrochloride and a process for its preparation. Furthermore, the invention relates to a pharmaceutical composition comprising the crystalline form of acoramidis hydrochloride of the present invention and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment of TTR amyloidosis (ATTR).
  • Acoramidis formerly AGIO, is a potent and selective transthyretin (TTR) stabilizer being developed to treat TTR amyloidosis (ATTR).
  • TTR TTR amyloidosis
  • ATTR is a progressive, fatal disease in which deposition of amyloid derived from either mutant or wild type TTR causes severe organ damage and dysfunction.
  • Acoramidis 3-(3-(3,5-dimethyl-U7-pyrazol-4-yl)propoxy)-4- fluorobenzoic acid.
  • Acoramidis can be represented by the following chemical structure according to Formula (A)
  • Acoramidis and its preparation are disclosed in WO 2014/100227 Al.
  • WO 2018/151815 Al describes various crystalline forms of acoramidis and pharmaceutically acceptable protic acid addition salts thereof.
  • various crystalline forms of acoramidis hydrochloride are disclosed including several anhydrous forms designated Type A, Type B and Type E, a hydrate form designated Type I and two solvated forms designated Form H (methanol solvate) and Form J (dimethylacetamide solvate), which were the result of an extended solid form screening program.
  • Different solid-state forms of an active pharmaceutical ingredient often possess different properties. Differences in physicochemical properties of solid-state forms can play a crucial role for the improvement of pharmaceutical compositions, for example, pharmaceutical formulations with improved dissolution profile and bioavailability or with improved stability or shelf-life can become accessible due to an improved solid-state form of an active pharmaceutical ingredient. Also processing or handling of the active pharmaceutical ingredient during the formulation process may be improved. New solid-state forms of an active pharmaceutical ingredient can thus have desirable processing properties. They can be easier to handle, better suited for storage, and/or allow for better purification, compared to previously known solid forms.
  • the present invention provides a crystalline form of acoramidis hydrochloride, which is hereinafter also designated as “Form 1”.
  • Acoramidis hydrochloride Form 1 of the present invention posesses one or more advantageous properties selected from the group consisting of chemical stability, physical stability, melting point, hygroscopicity, solubility, dissolution, morphology, crystallinity, flowability, bulk density, compactibility and wettability.
  • the term “measured at a temperature in the range of from 20 to 30°C” refers to a measurement under standard conditions.
  • standard conditions mean a temperature in the range of from 20 to 30°C, i.e. at room temperature.
  • Standard conditions can mean a temperature of about 22°C.
  • standard conditions can additionally mean a measurement under 20-60% RH, preferably 30-50% RH, more preferably 40% RH.
  • room temperature refers to a temperature in the range of from 20 to 30°C.
  • reflection with regard to powder X-ray diffraction as used herein, means peaks in an X-ray diffractogram, which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order.
  • a solid material is classified as crystalline material, whereas amorphous material is defined as solid material, which lacks long-range order and only displays short-range order, thus resulting in broad scattering.
  • long-range order e.g.
  • the term “essentially the same” with reference to powder X-ray diffraction means that variabilities in reflection positions and relative intensities of the reflections are to be taken into account.
  • a typical precision of the 2-Theta values is in the range of ⁇ 0.2° 2-Theta, preferably in the range of ⁇ 0.1° 2-Theta.
  • a reflection that usually appears at 6.9° 2-Theta for example can appear between 6.7° and 7.1° 2-Theta, preferably between 6.8° and 7.0° 2- Theta on most X-ray diffractometers under standard conditions.
  • relative reflection intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, particle size, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.
  • Crystalline Form 1 of acoramidis hydrochloride of the present invention may be referred to herein as being characterized by graphical data "as shown in" a figure.
  • Such data include, for example, powder X-ray diffraction.
  • factors such as variations in instrument type, response and variations in sample directionality, sample concentration and sample purity may lead to small variations for such data when presented in graphical form, for example variations relating to the exact reflection positions and intensities.
  • a comparison of the graphical data in the figures herein with the graphical data generated for another or an unknown solid form and the confirmation that two sets of graphical data relate to the same crystal form is well with in the knowledge of a person skilled in the art.
  • solid-state form refers to any crystalline and/or amorphous phase of a compound.
  • a “predetermined amount” as used herein with regard to acoramidis hydrochloride Form 1 refers to the initial amount of acoramidis hydrochloride Form 1 used for the preparation of a pharmaceutical composition having a desired dosage strength of acoramidis.
  • acoramidis hydrochloride Form 1 encompasses an amount of acoramidis hydrochloride Form 1 which causes the desired therapeutic and/or prophylactic effect.
  • the term “about” means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1% and most typically within 0.1% of the indicated value or range. Sometimes, such a range can lie within the experimental error, typical of standard methods used for the measurement and/or determination of a given value or range.
  • pharmaceutically acceptable excipient refers to substances, which do not show a significant pharmacological activity at the given dose and that are added to a pharmaceutical composition in addition to the active pharmaceutical ingredient. Excipients may take the function of vehicle, diluent, release agent, disintegrating agent, dissolution modifying agent, absorption enhancer, stabilizer or a manufacturing aid among others. Excipients may include fillers (diluents), binders, disintegrants, lubricants and glidants.
  • fillers dilute the active pharmaceutical ingredient prior to delivery. Diluents and fillers can also serve as stabilizers.
  • binder refers to substances which bind the active pharmaceutical ingredient and pharmaceutically acceptable excipient together to maintain cohesive and discrete portions.
  • disintegrant or “disintegrating agent” as used herein refers to substances which, upon addition to a solid pharmaceutical composition, facilitate its break-up or disintegration after administration and permits the release of the active pharmaceutical ingredient as efficiently as possible to allow for its rapid dissolution.
  • lubricant refers to substances which are added to a powder blend to prevent the compacted powder mass from sticking to the equipment during tableting or encapsulation process. They aid the ejection of the tablet from the dies and can improve powder flow.
  • glidant refers to substances which are used for tablet and capsule formulations in order to improve flow properties during tablet compression and to produce an anti-caking effect.
  • Figure 1 illustrates a representative PXRD of acoramidis hydrochloride Form 1 according to the present invention.
  • the x-axis shows the scattering angle in °2-Theta
  • the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.
  • the present invention provides a crystalline form of acoramidis hydrochloride, herein also designated as “Form 1”.
  • crystalline form (Form 1) of acoramidis hydrochloride of the present invention may be represented by the chemical structure according to Formula (B) Formula (B).
  • the crystalline Form 1 of acoramidis hydrochloride of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to powder X-ray diffraction, FTIR spectroscopy, DSC, TGA and GMS.
  • Acoramidis hydrochloride Form 1 of the present invention may be characterized by one of the aforementioned analytical methods or by combining two or more of them.
  • Form 1 of acoramidis hydrochloride of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.
  • the invention relates to a crystalline form (Form 1) of acoramidis hydrochloride characterized by having a PXRD comprising reflections at 2-Theta angles of: (6.9 ⁇ 0.2)°, (13.6 ⁇ 0.2)° and (19.5 ⁇ 0.2)°; or
  • the present invention relates to a crystalline form (Form 1) of acoramidis hydrochloride characterized by having a PXRD comprising reflections at 2-Theta angles of:
  • the present invention relates to a crystalline form of acoramidis hydrochloride (Form 1) characterized by having a PXRD essentially the same as shown in Figure 1 of the present invention, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the PXRD of acoramidis hydrochloride Form 1 of the present invention can be readily distinguished from the PXRDs of the acoramidis hydrochloride forms disclosed in WO 2018/151815 Al.
  • the present invention relates to the use of the crystalline form of acoramidis hydrochloride (Form 1) of the present invention, or the composition comprising the crystalline form of acoramidis hydrochloride (Form 1) of the present invention as defined in any one of the above described aspects and their corresponding embodiments for the preparation of a pharmaceutical composition comprising acoramidis.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form of acoramidis hydrochloride (Form 1) of the present invention as defined in any one of the above described aspects and their corresponding embodiments, preferably in a predetermined and/or effective amount, and at least one pharmaceutically acceptable excipient.
  • the predetermined and/ or effective amount of the crystalline form of acoramidis hydrochloride (Form 1) of the present invention as defined in any one of the above described embodiments is in the range of from about 10 to 500 mg.
  • the predetermined and/ or effective amount is selected from the group consisting of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg,
  • the predetermined and/ or effective amount is selected from the group consisting of 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg and 500 mg. Most preferably the predetermined and/ or effective amount is selected from the group consisting of 50 mg, 100 mg, 200 mg and 400 mg.
  • the at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention is preferably selected from the group consisting of one or more fillers, disintegrants, binders, lubricants, and any combinations thereof.
  • the at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention is selected from the group consisting of microcrystalline cellulose, croscarmellose sodium, colloidal silicone dioxide, magnesium stearate and any combinations thereof.
  • the pharmaceutical composition of the present invention as defined in any one of the above described embodiments is an oral solid dosage form, more preferably a tablet or a capsule.
  • the pharmaceutical composition of the present invention as described above is a tablet, preferably a film-coated tablet.
  • compositions of the present invention as defined in any one of the above described embodiments may be produced by standard manufacturing processes, which are well- known to the skilled person e.g. selected from the group consisting of micronization, blending, milling, granulation (wet or dry granulation), capsule filling, tabletting, film-coating and any combinations thereof.
  • Processes for preparing tablets comprising acoramidis hydrochloride are for example disclosed in WO 2020/037189 Al, the disclosure of which is incorporated herein by reference in its entirety.
  • the present invention relates to the crystalline form of acoramidis hydrochloride (Form 1) or the pharmaceutical composition comprising the crystalline form of acoramidis hydrochloride (Form 1) as defined in any one of the above described aspects and their corresponding embodiments for use as a medicament.
  • the present invention relates to the crystalline form of acoramidis hydrochloride (Form 1) or the pharmaceutical composition comprising the crystalline form of acoramidis hydrochloride (Form 1) as defined in any one of the above described aspects and their corresponding embodiments for use in the treatment of transthyretin amyloidosis (ATTR).
  • TRR transthyretin amyloidosis
  • the present invention relates to a method of treating a transthyretin amyloidosis (ATTR), the method comprising administering an effective amount of the crystalline form of acoramidis hydrochloride (Form 1) or the pharmaceutical composition comprising the crystalline form of acoramidis hydrochloride (Form 1) as defined in any one of the above described aspects and their corresponding embodiments to a patient in need of such a treatment.
  • TRR transthyretin amyloidosis
  • the transthyretin amyloidosis is selected from TTR amyloid cardiomyopathy (ATTR-CM) or TTR amyloid peripheral polyneuropathy (ATTR-PN).
  • Acoramidis (about 50 mg, e.g. prepared according to the teaching of WO 2014/100227 Al) was suspended in a solvent according to Table 1 (0.5 mL) at room temperature. To the suspension ethanol (3 drops) and trimethyl silyl chloride (26 pL) were added and the obtained mixture was stirred at room temperature for 1 hour. The solid was collected by filtration and investigated by PXRD, which confirmed the receipt of acoramidis hydrochloride Form 1.
  • Powder X-ray diffraction was performed with a PANalytical X’Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphai,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector.
  • Diffractograms were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-theta with 40s 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 ⁇ 0.2° 2-Theta, preferably of ⁇ 0.1° 2-Theta.
  • a representative diffractogram of acoramidis hydrochloride Form 1 of the present invention is displayed in Figure 1 hereinafter.
  • the corresponding reflection list of crystalline form 1 of acoramidis hydrochloride of the present invention is provided in Table 2 below.
  • Table 2 Reflection positions of crystalline Form 1 of acoramidis hydrochloride in the range of from 2 to 30° 2-Theta; a typical precision of the 2-Theta values is in the range of ⁇ 0.2° 2-Theta, preferably of ⁇ 0.1° 2-Theta.

Abstract

La présente invention concerne une forme cristalline d'acoramidis chlorhydrate et son procédé de préparation. En outre, l'invention concerne une composition pharmaceutique comprenant la forme cristalline d'acoramidis chlorhydrate de la présente invention et au moins un excipient pharmaceutiquement acceptable. La composition pharmaceutique de la présente invention peut être utilisée en tant que médicament, en particulier pour le traitement de l'amyloïdose TTR (ATTR).
PCT/EP2022/077587 2021-10-01 2022-10-04 Forme cristalline d'acoramidis chlorhydrate WO2023052652A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP21200394.1 2021-10-01
EP21200394 2021-10-01

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WO2023052652A1 true WO2023052652A1 (fr) 2023-04-06

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014100227A1 (fr) 2012-12-21 2014-06-26 The Board Of Trustees Of The Leland Stanford Junior University Stabilisants de transthyrétine et leur utilisation pour inhiber l'amylose de la transthyrétine et les interactions protéine-protéine
WO2018151815A1 (fr) 2017-02-17 2018-08-23 Eidos Therapeutics, Inc. Procédés de préparation d'ag-10, de ses intermédiaires et de sels correspondants
WO2019183463A1 (fr) * 2018-03-23 2019-09-26 Eidos Therapeutics, Inc. Méthodes de traitement de l'amylose ttr à l'aide d'ag10
WO2020037189A1 (fr) 2018-08-17 2020-02-20 Eidos Therapeutics, Inc. Formules d'ag10

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014100227A1 (fr) 2012-12-21 2014-06-26 The Board Of Trustees Of The Leland Stanford Junior University Stabilisants de transthyrétine et leur utilisation pour inhiber l'amylose de la transthyrétine et les interactions protéine-protéine
WO2018151815A1 (fr) 2017-02-17 2018-08-23 Eidos Therapeutics, Inc. Procédés de préparation d'ag-10, de ses intermédiaires et de sels correspondants
WO2019183463A1 (fr) * 2018-03-23 2019-09-26 Eidos Therapeutics, Inc. Méthodes de traitement de l'amylose ttr à l'aide d'ag10
WO2020037189A1 (fr) 2018-08-17 2020-02-20 Eidos Therapeutics, Inc. Formules d'ag10

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FOX JONATHAN C. ET AL: "First-in-Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers", CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT, vol. 9, no. 1, 1 January 2020 (2020-01-01), GB, pages 115 - 129, XP055897658, ISSN: 2160-763X, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003869/pdf/CPDD-9-115.pdf> DOI: 10.1002/cpdd.700 *
JONATHAN C.FOX ET AL.: "First in-Human-Study of AGIO, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase I Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study", HEALTHY ADULT VOLUNTEERS, CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT, 2019, pages 1 - 15
VITALIJ K. PECHARSKYPETER Y. ZAVALIJ: "Fundamentals of Powder Diffraction and Structural Characterization of Materials", 2003, KLUWER ACADEMIC PUBLISHERS, pages: 3

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