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KR-102964750-B1 - Solid pharmaceutical composition containing a TLR7 agonist

KR102964750B1KR 102964750 B1KR102964750 B1KR 102964750B1KR-102964750-B1

Abstract

A solid pharmaceutical composition comprising the TLR7 agonist 2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl) -5H -pyrrolo[3,2- d ]pyrimidine-4-amine, a method for preparing the same, and a medical application thereof. The solid pharmaceutical composition has excellent stability and solubility characteristics.

Inventors

  • 징, 지앙훼이
  • 쟈오, 씨안동
  • 순, 펭
  • 동, 리훼이
  • 쑤, 이
  • 리, 씬루
  • 루, 씨펭
  • 왕, 샹
  • 장, 하이샨
  • 리, 민
  • 첸, 지린

Assignees

  • 치아타이 티안큉 파마수티컬 그룹 주식회사

Dates

Publication Date
20260513
Application Date
20200423
Priority Date
20190423

Claims (20)

  1. A solid pharmaceutical composition for the treatment or prevention of TLR7-related diseases, comprising a compound of Formula I , a diluent, a binder, a disintegrant, and a lubricant, Here The diluent is selected from the group consisting of microcrystalline cellulose, pregelatinized starch, and mixtures thereof; The disintegrant is sodium carboxymethyl starch; The binder is hydroxypropyl methylcellulose; The lubricant is selected from the group consisting of magnesium stearate, colloidal silicon dioxide, and mixtures thereof; Herein, the disease associated with the TLR7 is selected from hepatitis B and hepatitis C, and the solid pharmaceutical composition is manufactured by a direct compression method.
  2. In paragraph 1, The solid pharmaceutical composition is a unit dose pharmaceutical composition, and the mass of the compound of Formula I in the composition per unit dose is 0.01 mg to 10 mg; or A solid pharmaceutical composition in which the amount of the compound of Formula I is selected from 0.01% to 10% by weight.
  3. In paragraph 1, A solid pharmaceutical composition in which the amount of diluent is selected from 50 weight% or more.
  4. In paragraph 3, The diluent comprises microcrystalline cellulose, and the amount of microcrystalline cellulose is selected from 30% to 90% by weight; or The diluent comprises pregelatinized starch, and the amount of pregelatinized starch is selected from 5% to 35% by weight; or A solid pharmaceutical composition in which the diluent is microcrystalline cellulose and pregelatinized starch.
  5. In paragraph 4, A solid pharmaceutical composition in which the diluent is 30%-90% by weight of microcrystalline cellulose and 5%-35% by weight of pregelatinized starch, and the amount of diluent is 50% by weight or more.
  6. In paragraph 1, A solid pharmaceutical composition in which the amount of disintegrant is selected from 1.0% to 7.0% by weight.
  7. In paragraph 1, A solid pharmaceutical composition in which the amount of binder is selected from 0.1% to 5% by weight.
  8. In paragraph 1, The amount of lubricant is selected from 0.1% to 5 weight%; or The lubricant comprises colloidal silicon dioxide, and the amount of colloidal silicon dioxide is selected from 0.05% to 3.0% by weight; or The lubricant comprises magnesium stearate, and the amount of magnesium stearate is selected from 0.05% to 3.0% by weight; or A solid pharmaceutical composition in which the lubricant is selected from the group consisting of colloidal silicon dioxide and magnesium stearate.
  9. In paragraph 8, A solid pharmaceutical composition in which the lubricant is selected from the group consisting of 0.05%-3.0% by weight of colloidal silicon dioxide and 0.05%-3.0% by weight of magnesium stearate, and the amount of lubricant is selected from 0.1%-5% by weight.
  10. In any one of paragraphs 1 through 9, A solid pharmaceutical composition is, 0.02%-8.0 wt% of a compound of Formula I ; 50 weight percent or more of microcrystalline cellulose, pregelatinized starch, or a mixture thereof; 1.0%-7.0 wt% sodium carboxymethyl starch; 0.1%-5 wt% of hydroxypropyl methylcellulose; and A solid pharmaceutical composition comprising 0.1% to 5% by weight of magnesium stearate, colloidal silicon dioxide, or a mixture thereof.
  11. In any one of paragraphs 1 through 9, A solid pharmaceutical composition having at least one of the following characteristics: The bulk density is 0.50 g/mL or less; The tap density is 0.65 g/mL or less; The Hausner ratio is 1.31–1.40; It is a particle with an amount of more than 50%.
  12. In Paragraph 11, A solid pharmaceutical composition having at least one of the following characteristics: The bulk density is 0.30 g/mL–0.50 g/mL; The tap density is 0.50 g/mL-0.65 g/mL; Particles with an amount of 50%-80% have a size of less than 75 μm.
  13. A method for preparing a solid pharmaceutical composition of a compound of Formula I according to any one of claims 1 to 9, comprising a direct compression method.
  14. A method for preparing a solid pharmaceutical composition of a compound of Formula I according to any one of claims 1 to 9, 1) A step of mixing the compound of Formula I with part or all of the diluent and, optionally, at least one of a binder, a disintegrant, and a lubricant; 2) A step of mixing the mixture of results obtained in step 1) with the remainder of the diluent and at least one of the remainder of the binder, disintegrant, and lubricant; Optionally, 3) a step of mixing the mixture of the result obtained in step 2) with the remainder of the excipient; and 4) A step of purifying the mixture of results obtained in Step 2) or Step 3) A method including
  15. In Paragraph 13, A method comprising the following steps: 1) preparing a mixture of the compound of Formula I , a diluent, a disintegrant, a binder, and a lubricant; and 2) a purification step.
  16. In paragraph 15, A method in which a mixture containing the compound of Formula I and a diluent is not milled.
  17. delete
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Description

Solid pharmaceutical composition containing a TLR7 agonist Cross-reference regarding related applications This application claims the benefit and priority of Chinese Patent No. 201910326899.9 filed with the National Intellectual Property Administration of China on April 23, 2019, the full contents of which are incorporated herein by reference. Technology field The present application belongs to the field of pharmaceutical chemistry, specifically to a solid pharmaceutical composition comprising a TLR7 agonist (2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl) -5H -pyrrolo[3,2- d ]pyrimidine-4-amine), a method for preparing the same, and a medical use thereof. Toll-like receptors are expressed in various immune cells. Toll-like receptors recognize highly conserved structural motifs: pathogen-associated molecular patterns (PAMPs) expressed by microbial pathogens or damage-associated molecular patterns (DAMPs) released by necrotic cells. Toll-like receptors are stimulated by corresponding PAMPs or DAMPs to induce signaling cascades, leading to the activation of transcription factors such as AP-1, NF-κB, and interferon regulators (impulse response functions). Consequently, various cellular responses are induced, including the production of interferons, pro-inflammatory cytokines, and effector cytokines, thereby promoting the immune response. To date, 13 Toll-like receptors have been identified in mammals. Toll-like receptors 1, 2, 4, 5, and 6 are primarily expressed on cell surfaces, while toll-like receptors 3, 7, 8, and 9 are expressed in endosomes. Different toll-like receptors can recognize ligands derived from different pathogens. Toll-like receptor 7 (TLR7) is primarily expressed in plasmacytic dendritic cells (pDCs) and induces the secretion of interferon alpha (IFN-α) through ligand recognition. Toll-like receptor 7 (TLR7) and toll-like receptor 8 (TLR8) are highly homologous; therefore, TLR7 ligands are, in many cases, additional TLR8 ligands. TLR8 is stimulated to induce the production of cytokines, such as tumor necrosis factor alpha (TNF-α) and chemokines. While interferon alpha is one of the primary drugs used to treat chronic hepatitis B or C, TNF-α is a pro-inflammatory cytokine, and its excessive secretion can cause severe side effects. WO2016/023511 discloses specific compounds used as TLR7 agonists. There remains a need in the art to develop suitable pharmaceutical compositions containing TLR7 agonist compounds. In one aspect, the present application relates to a solid pharmaceutical composition comprising a compound of Formula I , a diluent, a binder, a disintegrant, and a lubricant: . In one embodiment, the diluent is selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin, and mixtures thereof; preferably, microcrystalline cellulose, mannitol, lactose, pregelatinized starch, and mixtures thereof; more preferably, microcrystalline cellulose, pregelatinized starch, and mixtures thereof. In one embodiment, the binder is selected from the group consisting of hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, partially hydrolyzed starch, pregelatinized starch, glucose, polyethylene glycol, polyvinyl alcohol, and mixtures thereof; preferably, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), polyvinylpyrrolidone, and mixtures thereof; more preferably, hydroxypropyl methylcellulose. In one embodiment, the disintegrant is selected from the group consisting of sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose, low-substituted hydroxypropyl methylcellulose or crospovidone, sodium dodecyl sulfate or magnesium dodecyl sulfate, and mixtures thereof; preferably, sodium carboxymethyl starch, sodium croscarmellose, and mixtures thereof; more preferably, sodium carboxymethyl starch. In one embodiment, the lubricant is selected from the group consisting of magnesium stearate, colloidal silicon dioxide (colloidal silica), talc, polyethylene glycol 4000, polyethylene glycol 6000, stearic acid, sodium stearyl fumarate, sodium dodecyl sulfate, and mixtures thereof; preferably, magnesium stearate, colloidal silicon dioxide, sodium dodecyl sulfate, and mixtures thereof; more preferably, magnesium stearate, colloidal silicon dioxide, and mixtures thereof. In another aspect, the present application further relates to a method for preparing a solid pharmaceutical composition disclosed herein, the method comprising a direct compression method. In another aspect, the present application further relates to the use of the