A solid pharmaceutical composition of a TLR7 agonist

Abstract

This application belongs to the field of medicinal chemistry, specifically relating to a solid pharmaceutical composition of a TLR7 agonist (2-butoxy-7-(4-(pyrrolidone-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine), its preparation method, and its pharmaceutical uses. The solid pharmaceutical composition described in this application exhibits excellent stability and dissolution properties, making it suitable for clinical use.

Description

[Technical Field] This application claims priority and benefit to Chinese Patent Application No. 201910326899.9, filed with the China National Intellectual Property Administration on April 23, 2019, the contents of which are incorporated herein by reference in their entirety. This application belongs to the field of medicinal chemistry. Specifically, this application relates to a solid pharmaceutical composition of a TLR7 agonist (2-butoxy-7-(4-(pyrrolidine-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine), its preparation method and its pharmaceutical use. [Previous Technology] TLR receptors are expressed on a variety of immune cells. They recognize highly conserved structural motifs: pathogen-associated microbial patterns (PAMPs) expressed by microbial pathogens or damage-associated molecular patterns (DAMPs) released by necrotic cells. Stimulation of TLR receptors via the corresponding PAMP or DAMP triggers a signaling cascade that leads to the initiation of transcription factors such as AP-1, NF-κB, and interferon regulators (stimulation-response functions). This results in a variety of cellular responses, including the production of interferon, pro-inflammatory cytokines, and effector cytokines, thereby generating an immune response. To date, 13 types of TLR receptors have been identified in mammals. TLR receptors 1, 2, 4, 5, and 6 are primarily expressed on the cell surface, while TLR receptors 3, 7, 8, and 9 are expressed in endosomes. Different TLR receptors can recognize different pathogen-derived ligands. TLR receptor 7 (TLR7) is primarily expressed by plasmacytoid dendritic cells (pDCs) and induces the secretion of interferon-α (IFN-α) through ligand recognition. TLR7 and TLR8 receptors are highly homologous; therefore, TLR7 ligands are often also TLR8 ligands. TLR8 stimulation primarily induces the production of cytokines such as tumor necrosis factor-α (TNF-α) and chemokines. Interferon-α is one of the main drugs for treating chronic hepatitis B or hepatitis C, while TNF-α is a pro-inflammatory cytokine, and excessive secretion of TNF-α can lead to serious side effects. WO 2016 / 023511 discloses some compounds used as TLR7 agonists. There remains a need in the art to develop pharmaceutical compositions of suitable TLR7 agonist compounds. [Summary of the Invention] In one aspect, this application relates to a solid pharmaceutical composition comprising a compound of formula I, a diluent, a binder, a disintegrant, and a lubricant, [Figure]. In one embodiment, the diluent is selected from microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin, or mixtures thereof; preferably microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or mixtures thereof; more preferably microcrystalline cellulose, pregelatinized starch, or mixtures thereof. In one embodiment, the adhesive is selected from hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, partially hydrolyzed starch, pregelatinized starch, glucose, polyethylene glycol, polyvinyl alcohol, or mixtures thereof; preferably hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose (L-HPC), polyvinylpyrrolidone, or mixtures thereof; more preferably hydroxypropyl methylcellulose. In one embodiment, the disintegrant is selected from sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropyl methyl cellulose or croscarmellose, sodium dodecyl sulfate or magnesium dodecyl sulfate or mixtures thereof; preferably sodium carboxymethyl starch, croscarmellose sodium or mixtures thereof; more preferably sodium carboxymethyl starch. In one embodiment, the lubricant is selected from magnesium stearate, colloidal silica (also known as colloidal silicon dioxide), talc, polyethylene glycol 4000, polyethylene glycol 6000, stearic acid, sodium stearate fumarate, sodium lauryl sulfate, or mixtures thereof; preferably magnesium stearate, colloidal silica, sodium lauryl sulfate, or mixtures thereof; more preferably magnesium stearate, colloidal silica, or mixtures thereof. In another aspect, this application also relates to a method for preparing the solid pharmaceutical composition of this application, which includes direct compression. In another aspect, this application also relates to the use of the solid pharmaceutical composition of this application in the preparation of medicaments for treating or preventing TLR7-related diseases. In one embodiment, the TLR7-related disease is selected from viral infections. In a preferred embodiment, the viral infection is selected from hepatitis B or hepatitis C.

Implementation Method

Claims

1. A solid pharmaceutical composition comprising a compound of formula I, a diluent, a binder, a disintegrant, and a lubricant, wherein the diluent is selected from microcrystalline cellulose, pregelatinized starch, or mixtures thereof; the disintegrant is sodium carboxymethyl starch; the binder is hydroxypropyl methylcellulose; the lubricant is selected from magnesium stearate, colloidal silicon dioxide, or mixtures thereof; the solid pharmaceutical composition is prepared by direct compression; and the amount of the compound of formula I is selected from 0.06% to 2.4% wt, the amount of the diluent is selected from 91% to 94% wt, the amount of the disintegrant is selected from 3.8% to 4.2% wt, the amount of the binder is selected from 0.8% to 1.2% wt, and the amount of the lubricant is selected from 0.8% to 1.2% wt.

2. The solid pharmaceutical composition as claimed in claim 1, characterized in that the solid pharmaceutical composition is a unit dose pharmaceutical composition, and the mass of the compound of formula I in each unit dose composition is 0.05 mg to 2 mg.

3. The solid pharmaceutical composition as claimed in claim 1, characterized in that the diluent comprises microcrystalline cellulose in an amount selected from 70 to 73% wt; or the diluent comprises pregelatinized starch in an amount selected from 20 to 22% wt.

4. The solid pharmaceutical composition as claimed in claim 3, characterized in that the diluent is 70-73% wt of microcrystalline cellulose and 20-22% wt of pregelatinized starch.

5. The solid pharmaceutical composition as claimed in claim 1, characterized in that the lubricant comprises colloidal silicon dioxide in an amount selected from 0.45 to 0.55 wt; or the lubricant comprises magnesium stearate in an amount selected from 0.45 to 0.55 wt.

6. The solid pharmaceutical composition as claimed in claim 5, characterized in that the lubricant is selected from 0.45 to 0.55 wt% colloidal silicon dioxide and 0.45 to 0.55 wt% magnesium stearate.

7. The solid pharmaceutical composition according to any one of claims 1-6, characterized in that the solid pharmaceutical composition comprises: Compounds of formula I, ranging from 0.06% to 2.35% wt; 91%~94%wt of microcrystalline cellulose, pregelatinized starch, or mixtures thereof; 3.8~4.2%wt of sodium carboxymethyl starch; 0.8%~1.2%wt of hydroxypropyl methylcellulose; 0.8%~1.2%wt of magnesium stearate, colloidal silicon dioxide, or mixtures thereof.

8. A method for preparing a solid pharmaceutical composition of a compound of formula I as claimed in any one of claims 1-7, the method comprising: 1) mixing the compound of formula I with a portion or all of a diluent and at least one of optionally present binders, disintegrants and lubricants; 2) mixing the mixture obtained in step 1) with the remaining diluent and at least one of the remaining binders, disintegrants and lubricants; optionally, 3) mixing the mixture obtained in step 2) with all remaining adjuvants; 4) compressing the mixture obtained in step 2) or step 3) into tablets.

9. A method for preparing a solid pharmaceutical composition of a compound of formula I as claimed in any one of claims 1-7, the method comprising the steps of: 1) mixing the compound of formula I, a diluent, a disintegrant, a binder, and a lubricant; and 2) tableting.

10. The method as claimed in claim 8 or 9, characterized in that the mixture comprising the compound of formula I and the diluent is not subjected to a grinding operation.

11. The method as claimed in claim 8, characterized in that the mixture obtained in step 2) or step 3) has at least one of the following: loose density ≤0.50 g / mL; tapped density ≤0.65 g / mL; Hausner ratio 1.31-1.40; ≥50% of the particles are <75 μm.

12. The method of claim 11, characterized in that the mixture has at least one of the following: a loose density of 0.30-0.50 g / mL; a tapped density of 0.50-0.65 g / mL; a Hausner ratio of 1.31-1.40; and 50-80% of the particles being <75 μm.

13. Use of a solid pharmaceutical composition of a compound of formula I as described in any one of claims 1-7 in the preparation of a medicament for treating TLR7-related diseases.

14. The use as described in claim 13, wherein the TLR7-related disease is selected from viral infection diseases.

15. The use as described in claim 14, characterized in that the viral infection is selected from hepatitis B or hepatitis C.