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KR-20260066189-A - TABLET FORMULATION FOR CGRP-ACTIVE COMPOUNDS

KR20260066189AKR 20260066189 AKR20260066189 AKR 20260066189AKR-20260066189-A

Abstract

The present invention relates to a composition comprising, in a water-soluble polymer matrix, an extruder or solid solution of a compound of the following formula I (API) or a salt thereof, and further comprising a disintegration system that enables a tablet prepared therefrom to rapidly disintegrate in an environment where said API is to be released: <Chemical Formula I> In the above formula, "R a " is independently H or -F.

Inventors

  • 존슨, 메리 앤
  • 파텔, 파레쉬, 비.
  • 시, 한미
  • 쉬, 웨이
  • 알레인, 레오나르도 레센드
  • 아익호프, 더블유. 마크
  • 이케다, 크레이그, 비.
  • 브라운, 차드, 디.
  • 플래너건, 프란시스, 제이., 주니어
  • 노프싱어, 레베카
  • 마로타, 멜라니
  • 럽튼, 리사

Assignees

  • 머크 샤프 앤드 돔 엘엘씨

Dates

Publication Date
20260512
Application Date
20150130
Priority Date
20140205

Claims (10)

  1. (i) polymer matrix; (ii) Dispersant; (iii) Compound of the following chemical formula I or a salt thereof that is permitted by the law: <Chemical Formula I> (In the above formula, "R a " is independently -H or -F); and (iv) Disintegration system comprising powdered sodium chloride and sodium croscarmellose Includes, A tablet in which a dispersant and a compound of Formula I are dispersed within the polymer matrix, It has a hardness of 12 kP to 18 kP, and A tablet that achieves complete disintegration in less than 5 minutes in a standard tablet disintegration test according to USP 31-NF26 Chapt. 701 using aqueous HCl (pH 1.8) at 37°C.
  2. (a) (i) A polymer matrix which is a water-soluble polyvinylpyrrolidone/vinyl acetate copolymer; (ii) dispersant; and (iii) Compound of the following chemical formula I or a salt thereof that is permitted by the law: <Chemical Formula I> (In the above formula, "R a " is independently -H or -F) An extruder comprising; and (b) Disintegration system comprising powdered sodium chloride and sodium croscarmellose As a tablet containing, A tablet in which a dispersant and a compound of chemical formula I are dispersed within the polymer matrix.
  3. A tablet according to claim 1, wherein the polymer matrix is a polyvinylpyrrolidone/vinyl acetate (PVP-VA) copolymer.
  4. A tablet according to paragraph 2, wherein the disintegration system comprises powdered sodium chloride and sodium croscarmellose in a 1:1 weight ratio.
  5. In paragraph 2, It has a hardness of 12 kP to 18 kP, and A tablet that releases more than 90% of the compound of Formula I contained therein within 20 minutes when applied to a dissolution test in accordance with USP 30 NF25 Chapt. 711 in 900 ml of artificial gastric fluid (pH 1.8) at 37°C in a paddle-stirring device operated at 50 rpm and equipped with a USP 2 paddle.
  6. In paragraph 2, It has a tensile strength of 1.75 MPa, and A tablet that releases more than 90% of the compound of Formula I contained therein within 20 minutes when applied to a dissolution test in accordance with USP 30 NF25 Chapt. 711 in 900 ml of artificial gastric fluid (pH 1.8) at 37°C in a paddle-stirring device operated at 50 rpm and equipped with a USP 2 paddle.
  7. A tablet according to claim 1, wherein the dispersant is d-alpha-tocopheryl polyethylene glycol succinate (TPGS).
  8. A tablet according to paragraph 2, wherein the dispersant is d-alpha-tocopheryl polyethylene glycol succinate (TPGS).
  9. A tablet according to any one of claims 1 to 8, wherein the compound of formula I is a compound of formula Ia or a salt thereof: <Chemical Formula Ia> In the above equation, "R b " is -H or "R b " is -F.
  10. In any one of paragraphs 1 through 8, (a) Mannitol; (b) colloidal silica; (c) microcrystalline cellulose; and (d) Sodium stearyl fumarate A tablet additionally containing

Description

Tablet Formulation for CGRP-Active Compounds CGRP (calcitonin gene-related peptide) is a naturally occurring 37-amino acid peptide produced by tissue-specific alternative processing of calcitonin messenger RNA and widely distributed in the central and peripheral nervous systems. Calcitonin gene-related peptide (CGRP) is a potent vasodilator neurotransmitter considered to play an important role in the pathophysiology of migraines. Early human clinical validation of CGRP targets was provided by a report published by Boehringer Ingelheim in 2003 stating that an IV formulation containing olcegepant was effective in the acute treatment of migraines, and that the mechanism was confirmed by a study using telcagepant (a CGRP antagonist) in oral formulations. A newly developed CGRP antagonist compound is described in International Application Publication No. WO 2012/064910, which is based on the structure of the following chemical formula I : <Chemical Formula I> In the above formula, "R a " is various substituents, for example, when "R a " is hydrogen, it is (S)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidine-3-yl)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide, and for example, when three of "R a " are selected to be fluorine, (S)-N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidine-3-yl)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide. These compounds show potential as potent CGRP antagonists with excellent tolerability and low potential for side effects and metabolic complications. However, these compounds have low solubility and generally do not form salts suitable for the manufacture of stable pharmaceutical formulations. In early in vivo studies, it is common practice to administer poorly soluble "Class II" compounds formulated as liquid formulations, for example, as a co-mold or as lipid-based solutions using a co-mold such as PEG400 and other components as needed to promote solubility and enhance oral absorption. While useful for clinical studies, providing liquid formulations for oral delivery of drugs intended for use in therapies for acute or chronic conditions, or for the prophylactic treatment of chronic conditions, is generally not commercially attractive. Preferably, such drugs should be in a solid form for oral administration, for example, a squeeze tablet or capsule containing the API. However, generally, drugs with poor aqueous solubility are difficult to deliver to the gastrointestinal system without the presence of some solubility enhancer or penetration enhancer, or both, at the absorption site. Solid dispersions, and in particular solid solutions, have been used to enhance the oral absorption of water-insoluble active pharmaceutical ingredients (APIs) (see, e.g., the literature [Ford, Pharm Acta Helv, 1986, 61:69-88]). Solid dispersions and solid solutions are compositions in which the API is dispersed within or dissolved in a solid matrix, typically a polymer matrix. Solid solutions and solid dispersions (where the active pharmaceutical ingredient forms a homogeneous or nearly homogeneous glass in the excipient matrix) are of particular interest for the oral delivery of water-insoluble compounds. These materials are believed to improve the absorption of orally administered APIs by (i) improving the wetting properties of the API; (ii) inducing a transient supersaturation point of absorption for lower-energy (e.g., crystalline) phase APIs; or (iii) through the effects of both of these. Generally, solid solutions are believed to enable drug absorption by enhancing the degree and/or dissolution rate of the drug from the matrix. One example of a Class II drug that has been formulated as a solid solution is posaconazole, as described in International Patent Application No. WO2009/129300 published on October 22, 2009. This composition of posaconazole was prepared by forming an extruder of posaconazole from a hydroxypropylmethylcellulose acetate-succinate-derivative polymer (HPMC-AS), in succession, blending the solid dispersion with microcrystalline cellulose, additional HPMC-AS, hydroxypropylcellulose, and magnesium stearate. This mixture was made into a tablet to provide an orally bioavailable posaconazole formulation exhibiting a desirable pharmacokinetic and bioavailability. Another example of a polymer used to provide a solid solution of a polymer and an API is reported by Goertz et al. in U.S. Patent No. 4,801,460, which describes a solid dispersion comprising a poorly soluble drug (exemplified as theophylline) and a cross-linked polyvinylpyrrolidone/vinyl acetate copolymer (PVP copolymer). While the '460 patent reports drug release times of 8 hours or less in several studies, it does not discuss immediate-release drugs using the polymer matrix solid solution. In another example, International Application Publication No. WO98/029137