CN110958880B

CN110958880B - Solid dispersion preparation

Info

Publication number: CN110958880B
Application number: CN201780091536.0A
Authority: CN
Inventors: 许明珠; 林助强; 金其新
Original assignee: Dongguan East Sunshine Medicine Research And Development Co ltd
Current assignee: Dongguan East Sunshine Medicine Research And Development Co ltd
Priority date: 2017-05-30
Filing date: 2017-05-30
Publication date: 2023-08-08
Anticipated expiration: 2037-05-30
Also published as: WO2018222172A1; CN110958880A

Abstract

A spray-dried solid dispersion comprising a pharmaceutical compound of formula (I) as shown below and a pharmaceutically acceptable polymer, wherein the pharmaceutical compound is dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer. The invention further discloses a method for preparing the solid dispersion, a method for treating hepatitis C virus infection by using the solid dispersion and a pharmaceutical preparation containing the solid dispersion.

Description

Solid dispersion preparation

Technical Field

The present invention relates to spray-dried solid dispersions containing macrocyclic compounds and methods of making and using the solid dispersions for treating hepatitis C virus infections.

Background

Hepatitis C Virus (HCV) infection is difficult to treat because the virus can mutate rapidly and escape the natural immune response. The genome of HCV, which comprises a single polyprotein of about 3000 amino acids, comprises nucleocapsid proteins, envelope proteins (E1 and E2) and several nonstructural proteins (p 7, NS2, NS3, NS4A, NS a and NS 5B). Among these proteins, the NS3 protein has serine protease activity, which is thought to be essential for viral replication and infection. The HCV NS3 protease is capable of promoting proteolysis at the NS3/NS4A, NS4A/NS4B, NS B/NS5A, NS5A/NS5B junction, which can affect the production of four viral proteins during viral replication. Thus, HCV NS3 protease is an attractive target for the treatment of HCV infection.

Certain macrocyclic compounds have shown potential to inhibit NS3/4A protease activity, reduce HCV RNA levels, and inhibit HCV protease mutants that are resistant to various HCV inhibitors. See U.S. patent 8,389,560 to Liu et al. On the other hand, these macrocyclic compounds exhibit poor pharmacological properties, such as low solubility and low bioavailability, which limit their use as effective therapeutic agents for the treatment of HCV infection.

There is therefore a need to develop new formulations containing these macrocyclic compounds without having the above-mentioned disadvantages.

SUMMARY

One aspect of the present invention relates to spray-dried solid dispersions that unexpectedly exhibit high solubility and high bioavailability.

The spray-dried solid dispersion contains a pharmaceutically acceptable polymer and a pharmaceutical compound or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical compound or salt thereof is dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer.

In the spray-dried solid dispersion, the weight ratio of the pharmaceutical compound to the pharmaceutically acceptable polymer was 4:1 to 1:4, and the pharmaceutically acceptable polymer is poloxamer, polyvinylpyrrolidone or hydroxypropyl cellulose.

The pharmaceutical compounds have the general formula (I) as shown below:

wherein R1 is H, C _1-6 Alkyl, C _3-10 Cycloalkyl, C _3-10 Heterocycloalkyl, aryl or heteroaryl, wherein C _1-6 Alkyl, C _3-10 Cycloalkyl, C _3-10 The heterocycloalkyl, aryl or heteroaryl groups can each be optionally mono-, di-or tri-substituted with the following substituents: halogen, nitro, cyano, amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, aryl or heteroaryl; r2 is H, halogen or C _1-6 An alkyl group; r3 is H, halogen, nitro, cyano, amino or C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _3-10 Heterocycloalkyl, aryl or heteroaryl, or R3 may be fused with phenyl to form a bicyclic ring, wherein amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, aryl and heteroaryl groups may each be optionally mono-, di-or tri-substituted with halogen; and R4 is H, halogen, nitro, cyano, amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _3-10 Heterocycloalkyl, aryl or heteroaryl, wherein amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _3-10 The heterocycloalkyl, aryl or heteroaryl groups can each be optionally mono-, di-or tri-substituted with the following substituents: halogen, nitro, cyano, amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, aryl or heteroaryl.

A subgroup of the compounds mentioned above is characterized in that R1 is C _1-6 Alkyl or C _3-10 Cycloalkyl; r2 is H or C _1-6 An alkyl group; r3 is H, halogen, amino or C _1-6 Alkyl or C _1-6 Alkoxy, wherein amino, C _1-6 Alkyl and C _1-6 Alkoxy groups may each be optionally mono-, di-, or tri-substituted with halogen; r4 is H, halogen or C _1-6 Alkyl or C _1-6 An alkoxy group.

The term "alkyl" in this specification means a saturated straight or branched hydrocarbon moiety, e.g. -CH ₃ or-CH (CH) ₃ ) ₂ . The term "alkoxy" means-O- (C) _1-6 Alkyl) groups, e.g. -OCH ₃ or-OCH (CH) ₃ ) ₂ . The term "alkenyl" means a straight or branched hydrocarbon moiety containing at least one double bond, e.g., -ch=CH-CH ₃ . The term "alkynyl" denotes a straight or branched hydrocarbon moiety containing at least one triple bond, e.g. -C.ident.C-CH ₃ . The term "cycloalkyl" refers to a saturated cyclic hydrocarbyl moiety, such as cyclohexyl. The term "heterocycloalkyl" means a saturated cyclic moiety having at least one ring heteroatom (e.g., N, O or S), such as 4-tetrahydropyranyl. The term "aryl" means a hydrocarbyl moiety having one or more aromatic rings. Examples of aryl groups include: phenyl (Ph), phenylene, naphthyl, naphthylene, pyrenyl, anthryl, and phenanthryl. The term "heteroaryl" means a moiety comprising one or more aromatic rings having at least one heteroatom (e.g., N, O or S). Examples of heteroaryl groups include: furyl, furanylene, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolinyl, isoquinolinyl, and indolyl. The term "amino" means-NH ₂ ，-NH-(C _1-6 Alkyl) or-N- (C) _1-6 Alkyl group ₂ Groups of (2), e.g. -NHCH ₃ and-NHCH (CH) ₃ ) ₂ . The term "halogen" means fluorine, chlorine, bromine or iodine.

Unless otherwise indicated, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups described herein include both substituted and unsubstituted moieties. Possible substituents on cycloalkyl, heterocycloalkyl, aryl, and heteroaryl include, but are not limited to: c (C) _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-10 Cycloalkyl, C _3-10 Heterocycloalkyl, C _1-10 Alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C _1-20 Alkylamino, C _1-20 Dialkylamino, arylamino, diarylamino, C _1-10 Alkyl sulfonamide, aryl sulfonamide, C _1-10 Alkylimino, arylimino, C _1-10 Alkylsulfonyimino, arylsulfonyiamino, hydroxy, halogen, thio, C _1-10 Alkylthio, arylthio, C _1-10 Alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidino, ureido, cyano, nitro, nitrosylGroup, azido group, acyl group, thioacyl group, acyloxy group, carboxyl group and carboxylate group. On the other hand, substituents on alkyl, alkenyl or alkynyl groups include all of the substituents described above, but C _1-10 Except for alkyl groups. Cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may also be fused with each other.

The above compounds include the compounds themselves, and if applicable, salts, prodrugs, polymorphs, stereoisomers and solvates thereof. For example, salts may be formed from anions with positively charged groups (e.g., amino groups) on compounds of the above formula. Suitable anions include: chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methylsulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate, and maleate. Similarly, salts may also be formed from cations with negatively charged groups (e.g., carboxylate ions) on compounds of the above formula. Suitable cations include sodium, potassium, magnesium, calcium and ammonium ions, such as tetramethylammonium. The compounds also include those salts containing quaternary nitrogen atoms. For simplicity of calculation, unless otherwise indicated, the weight of a compound referred to in this specification refers to the weight of the free base form of the compound. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, when administered to a subject, are capable of providing the active compound. Solvates refer to complexes of an active compound with a pharmaceutically acceptable solvent. Examples of pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.

Examples of the compounds contained in the spray-dried solid dispersion of the present invention include, but are not limited to, the compounds shown below:

the compound contained in the spray-dried solid dispersion may be substantially amorphous.

Exemplary spray-dried solid dispersions contain the following compounds:

in another aspect, the invention relates to a pharmaceutical formulation comprising the above spray-dried solid dispersion and optionally one or more pharmaceutically acceptable ingredients. Pharmaceutically acceptable ingredients include diluents, disintegrants, binders, lubricants, glidants, surfactants, or combinations thereof.

In pharmaceutical formulations, the spray-dried solid dispersion is present at 30 to 80 weight percent (% w/w) (e.g., 60 to 70 weight percent). Typically, the formulations are manufactured in unit dosage form and contain from 50 to 400mg (e.g., 50 to 250mg, or 50mg, 100 mg) of one of the compounds described above.

An exemplary pharmaceutical formulation contains 60 to 70 weight percent of a spray-dried solid dispersion wherein the compound is

And the weight ratio of the compound to the pharmaceutically acceptable polymer is 2:1 to 1:2.

in another aspect, the present invention also relates to a method of preparing the above spray-dried solid dispersion. The method comprises the following steps: the compound and the pharmaceutically acceptable polymer are mixed in a solvent to provide a feed solution, and the feed solution is spray dried to provide a spray dried solid dispersion.

Also within the scope of the invention are methods of using the spray-dried solid dispersion or a pharmaceutical formulation containing the spray-dried solid dispersion for treating Hepatitis C Virus (HCV) infection in a human. The method comprises administering to a human subject in need thereof a therapeutically effective amount of a spray-dried solid dispersion or a pharmaceutical formulation comprising a spray-dried solid dispersion.

The present invention will be described in detail below. Other features, objects, and advantages of the invention will be apparent from the description and from the several detailed embodiments, and from the claims.

Brief description of the drawings

Figure 1 is a graphical representation of the blood concentration versus time profile of the tablets and capsules of the present invention administered in beagle dogs.

Detailed descriptionfirst disclosed in detail is a spray-dried solid dispersion for forming a pharmaceutical formulation.

As described above, the spray-dried solid dispersion contains a pharmaceutically acceptable polymer and a compound of formula (I) or a pharmaceutically acceptable salt thereof as shown below:

wherein R1-R4 are as defined in the summary section.

The compounds of formula (I) can be synthesized from commercially available starting materials by the synthetic route shown in scheme 1 below.

Scheme 1: synthesis of Compound of formula (I)

As shown in scheme 1, a halogen substituted heteroaryl compound (i) is first coupled with N- (t-butoxycarbonyl) -L-proline (ii) and then methylated to form intermediate (iii). The intermediate (iii) is then deprotected to remove the N-butoxycarbonyl group to form the free amino compound (iv), which is subsequently coupled with the carboxylic acid (v) to give the intermediate (vi). The intermediate (vi) is subjected to hydrolysis reaction to form an acid (vii), and the acid is coupled with an amine compound (viii) to produce a pyrrolidine compound (ix) containing two terminal alkenyl groups. Pyrrolidine compounds (ix) undergo olefin metathesis in the presence of Grubbs' catalyst to form the desired macrocyclic compounds of formula (I).

The above synthesis may further include a step of adding or removing a suitable protecting group before or after the step shown in scheme 1, so as to finally synthesize the desired various compounds. Furthermore, the various synthetic steps may be performed in additional order or sequence to prepare certain compounds. Synthetic chemical transformations and protecting group methods (protection and deprotection) that can be used to synthesize useful compounds of formula (I) are known in the art and include, for example, the methods described in the following documents: larock, comprehensive Organic Transformations, VCH Press (1989); greene and p.g.m.wuts, protective Groups in Organic Synthesis, second edition, john power and sa Sun Chuban (John Wiley and Sons) (1991); fieser and M.Fieser, fieser and Fieser's Reagents for Organic Synthesis, john's power and Sa Sun Chuban (1994); and Encyclopediaof Reagents for Organic Synthesis from the l.paquette works, john power and sa Sun Chuban (1995) and its successor.

The compounds mentioned in this specification contain non-aromatic double bonds and asymmetric centers. Thus, they may be racemates and racemic mixtures, individual enantiomers, individual diastereomers, diastereomeric mixtures, tautomers, or cis-or trans-isomeric forms. All such isomeric forms are contemplated.

To practice the present invention, solid dispersions comprising a compound of formula (I) and a pharmaceutically acceptable polymer may be prepared. The compounds of formula (I) generally have low water solubility and their absorption in vivo is limited by the dissolution rate. Solid dispersions containing the compounds of formula (I) may increase the solubility/dissolution of the compounds, thereby improving the bioavailability of the compounds of formula (I).

The term "solid dispersion" in the present specification means a dispersion of a pharmaceutically active ingredient, such as a compound of formula (I), in a solid inert polymer matrix. The solid dispersion may be prepared by methods well known in the art, such as spray drying or hot melt extrusion. The matrix may be crystalline or amorphous. The solid dispersion comprises a co-precipitate of the pharmaceutically active ingredient and one or more water-soluble polymers, wherein the pharmaceutically active ingredient is uniformly dispersed within a matrix formed of the polymers. The pharmaceutically active ingredient may be in amorphous form, crystalline dispersed form, or a combination thereof. It may also be finely dispersed or dissolved as individual molecules in a polymer matrix. Typically, the solid dispersion may be prepared by spray drying or hot melt extrusion. The solid dispersion of the present invention is prepared by a spray drying method.

The method for preparing the solid dispersion of the invention comprises the following steps: (i) Mixing a compound of formula (I) and a polymer in an organic solvent to provide a feed solution, (ii) spraying the feed solution into a chamber through a nozzle for spray drying to rapidly evaporate the solvent to produce particles comprising the compound and the polymer. After forming the solid dispersion, the obtained spray-dried particles may be subjected to a second drying step to remove residual solvent. The second drying step may be carried out in a static dryer or a stirred dryer. Gas, humidified gas, vacuum may be applied to the second drying step and such application may be used to more rapidly remove residual solvent remaining in the spray dried particles.

Any organic solvent that readily dissolves or distributes the compounds and polymers of formula (I) may be used. Examples of the organic solvent include lower alcohols such as methanol, ethanol, propanol, and isopropanol; ketones such as methyl ethyl ketone and butanone; and combinations thereof.

The polymer used in the spray drying process may be a homopolymer of N-vinylpyrrolidone, a copolymer of N-vinylpyrrolidone and vinyl acetate, a copolymer of N-vinylpyrrolidone and vinyl propionate, polyvinylpyrrolidone, methyl cellulose, ethylcellulose, hydroxyalkyl celluloses (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyalkyl alkyl cellulose and hydroxypropyl methyl cellulose), cellulose phthalate, cellulose succinate, cellulose acetate phthalate, hydroxypropyl methyl cellulose succinate, hydroxypropyl methyl cellulose acetate succinate, polyethylene oxide, polypropylene oxide, a copolymer of ethylene oxide and propylene oxide, a methacrylic acid/ethyl acrylate copolymer, a methacrylic acid/methyl methacrylate copolymer, a butyl methacrylate/2-dimethylaminoethyl methacrylate copolymer, polyethylene oxide, polyethylene glycol, polyhydroxyalkyl acrylate, polyhydroxyalkyl methyl acrylate, a copolymer of vinyl acetate and acid, partially hydrolyzed polyvinyl acetate, galactosaccharide, or carrageenan.

Typically, the polymer used to form the solid dispersion is a hydrophilic polymer. Examples of hydrophilic polymers include polyvinylpyrrolidone (e.g., PVP VA64 and PVP K30), hydroxypropyl cellulose (e.g., HPC-L and HPC-SSL), and poloxamers (e.g., poloxamer 188).

In one embodiment, the polymer is one of poloxamer 188, PVP V A64, PVPK30, HPC-L and HPC-SSL.

In one embodiment, the polymer is one of poloxamer 188, PVPK30, HPC-L and HPC-SSL.

In another embodiment, the polymer is HPC-SSL or PVPK30.

In another embodiment, the polymer is HPC-SSL.

The solid dispersion typically comprises a weight ratio of compound of formula (I) to polymer of from about 4:1 to about 1:4, expressed as compounds: polymers or drugs: a polymer. The weight ratio may be about 3:1 to about 1:3, about 2:1 to about 1:2, about 1.5:1 to about 1:1.5, about 2:1 to about 1:1, about 1:1 to about 1:2, about 1.5:1 to about 1:1, about 1:1 to about 1:1.5. For example, the weight ratio of compound to polymer is 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2.

The above spray-dried solid dispersion may be orally administered to a subject (e.g., a human) in need thereof to exert a therapeutic effect, such as treating HCV infection.

Also within the scope of the invention are pharmaceutical formulations comprising a spray-dried solid dispersion, optionally with one or more pharmaceutically acceptable ingredients.

The term "pharmaceutically acceptable ingredient" in this specification means inert additives used in the preparation of solid formulations (e.g., powders, granules, capsules, pellets, and tablets) that increase the volume of the desired formulation containing the above-described spray-dried solid dispersion. The pharmaceutically acceptable ingredients may be added during or after the spray drying process to prepare the solid dispersion. Examples of pharmaceutically acceptable ingredients include diluents, fillers, compatibilizers, binders, disintegrants, surfactants, lubricants, glidants, sweeteners, taste masking agents, colorants and flavoring agents.

Suitable diluents, fillers and compatibilizers include, but are not limited to, microcrystalline cellulose, di-or tri-base calcium phosphate, crystalline cellulose, powdered cellulose, calcium carbonate, calcium sulfate, magnesium silicate, magnesium trisilicate, magnesium aluminum metasilicate, kaolin, starch derivatives, magnesium carbonate, magnesium oxide, and co-processed insoluble ingredients.

Suitable disintegrants include, but are not limited to, croscarmellose sodium (CC-Na), microcrystalline cellulose (e.g., MCC 101 and MCC 102), crospovidone, cellulose, kaolin, cross-linked carboxymethylcellulose (e.g., acDiSol), cross-linked polyvinylpyrrolidone (e.g., kollidon CL), and combinations thereof. The content of disintegrant in the pharmaceutical formulation is about 10% to about 40% (e.g., about 20% to about 35% and about 28% to about 32%) of the total weight of the formulation.

Suitable surfactants include, but are not limited to, anionic, cationic, nonionic, or amphoteric surfactants. An exemplary anionic surfactant is Sodium Lauryl Sulfate (SLS). The surfactant is present in the pharmaceutical formulation in an amount of about 0.1% to about 2.5%, or about 0.5% to about 2%, by weight of the total formulation.

Suitable lubricants and glidants include, but are not limited to, stearic acid and its derivatives (e.g., sodium stearate, magnesium stearate, and calcium stearate), sodium stearyl fumarate, and talc or Colloidal Silicon Dioxide (CSD). The lubricant or glidant is present in the pharmaceutical formulation in an amount of about 0.1% to about 5% (e.g., about 0.5% to about 4% and about 1% to about 3%) of the total weight of the formulation.

The pharmaceutically active ingredient may be present in the pharmaceutical formulation in a therapeutically effective amount. Typically, the pharmaceutical formulation contains a spray-dried solid dispersion present in about 30 to about 80 weight percent (% w/w) (e.g., about 40 to about 70% w/w, about 50 to about 70% w/w, or about 60 to about 70% w/w). An exemplary pharmaceutical formulation contains about 63 weight percent of the spray-dried solid dispersion. Another exemplary pharmaceutical formulation contains about 68 weight percent of the spray-dried solid dispersion.

The pharmaceutical formulations of the present invention may be administered orally in single or multiple doses. Administration may be in the form of solutions, suspensions, emulsions, capsules, tablets, and the like. In one embodiment of the invention, the pharmaceutical formulation is in the form of a tablet. In another embodiment, the pharmaceutical formulation is in the form of a capsule.

The pharmaceutical formulation of the present invention may further comprise a film coating. The film coating comprises a film-forming polymer and one or more coating additives. Suitable film-forming polymers include cellulose derivatives (e.g., methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl ethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and ethyl cellulose), vinyl polymers, acrylic polymers, and combinations thereof.

In one embodiment, the pharmaceutical formulation is formulated as a unit dose or pharmaceutical dosage form. The term "unit dosage form" or "pharmaceutical dosage form" means a single dosage, physically discrete unit suitable for human and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in combination with the appropriate pharmaceutical ingredient. The compounds of formula (I) are generally administered in pharmaceutically effective amounts. Pharmaceutical dosage forms typically contain about 50 to 400mg (e.g., about 75 to 375mg, about 100 to 350mg, about 150 to 325mg, about 200 to 300mg, about 225 to 270mg, about 225 to 250mg, and about 50 to 250 mg) of a compound of formula (I). In some embodiments, the pharmaceutical dosage form contains about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, or about 315mg of the compound of formula (I). However, it will be appreciated that the amount of the compound actually administered will generally be determined by the physician, in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

In one embodiment, a pharmaceutical formulation, or unit dosage form, contains about 100mg of a compound of formula (I), which is prepared as a compound: the polymer ratio was 1:1.5, and the spray-dried solid dispersion is present in an amount of about 68.5 weight percent.

The term "about" means the indicated value of the variable and all variable values within experimental error of the indicated value or within 10 percent of the indicated value.

The term "effective amount" means the amount of active compound of the present invention required to impart a therapeutic effect to a subject.

The term "substantially amorphous" means that greater than about 70%, or greater than about 75%, or greater than about 80%, or greater than 85%, or greater than 90%, or greater than 95%, or greater than 99% of the compounds in the composition are amorphous.

In one embodiment, the present invention provides a pharmaceutical formulation comprising a spray-dried solid dispersion comprising a pharmaceutically active ingredient and a polymer, and one or more pharmaceutically acceptable excipients or additives well known in the art for oral administration. The pharmaceutical formulations may be prepared in conventional dosage forms, for example in the form of powders, granules, tablets, soft or hard capsules or coatings. For example, the solid dispersion in powder or granule form may be put into a capsule, or compressed into a tablet.

The above-described method of preparing a spray-dried solid dispersion also falls within the scope of the present invention.

As previously described, the method of preparation comprises the steps of mixing a compound and a pharmaceutically acceptable polymer in a solvent to serve as a feed solution, and spray drying the feed solution to provide a spray dried solid dispersion.

Solid dispersions can be prepared from various forms of the compound of formula (I), such as crystalline forms, amorphous forms, pharmaceutically acceptable salts, solvates and free bases thereof.

The prepared spray-dried solid dispersion comprises a compound of formula (I) substantially amorphous and dispersed within a polymer matrix formed from a pharmaceutically acceptable polymer.

Advantages of the spray-dried solid dispersions of the invention include better dissolution performance, acceptable formulation disintegration time and drug release profile, improved dissolution/solubility and improved bioavailability.

The invention further encompasses methods of treating HCV infection by administering to a subject (e.g., human) in need thereof a pharmaceutical formulation comprising the spray-dried solid dispersion so prepared.

In some embodiments, the solid dispersion, pharmaceutical formulation, or unit dosage form may be used alone or in combination with one or more therapeutic agents for treating HCV infection. These therapeutic agents may be HCV NS5A inhibitors, HCV NS5B inhibitors, HCV NS4B inhibitors, HCV p7 inhibitors (e.g., BIT 225), or other antiviral and immunomodulatory agents (e.g., CD81 inhibitors and cyclophilin inhibitors).

Examples of HCV NS5A inhibitors include: dakatavir (BMS-790025), rittavir (GS-5885), obetavir (ABT-267), GSK2336805, PPI-461, PPI-668, ACH-2928, ACH-3102, GS-5816, BMS824393, sha Ma tavir, emotion (MK-8742) and Yimigtavir (DAG-181).

Examples of HCV NS5B inhibitors include: sofosbuvir (PSI-7977), tetebuvir, non-Li Buwei (PF-00868554), BMS-791325, VX-135, lo Mi Buwei (VX-222), VX-759, ANA598, daxabuvir (ABT-333) ABT-072, debbuvir (BI-207127), IDX375, mexitabine (RG 7128), RG7432, stavbuvir (RG 7790) PSI-7851, PSI-352938, PSI-661, TMC 649128, IDX184, INX-08189, JTK-853, VCH-916, BILB 1941, GS-6620, GS-9669 and Meng Xi tabine.

Examples of HCV NS4B inhibitors include clemizole and GS-9132.

Without further elaboration, one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. The following specific examples are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Publications cited in this specification are incorporated by reference in their entirety into this specification.

Example 1: synthesis of Compound of formula (I)

14 compounds of formula (I), i.e., compounds 1-14, of the present invention can be prepared according to the synthetic route shown in scheme 1, described previously, and the protocol disclosed in U.S. Pat. No. 8,389,560 to Liu et al.

Mass Spectrum (MS) and nuclear magnetic resonance data for compounds 1-14 are shown below.

Compound 1: MS: M/z 906.3 (M) ⁺ +1)； ¹ H NMR(CDCl ₃ )δ10.18(s,1H),8.62(d,2H),8.25(d,1H),7.78(d,2H),7.70-7.61(m,2H),7.55-7.46(m,1H),7.01(1H),6.18(1H),5.71(q,1H),5.12(d,1H),5.02(dd,1H),4.77(dd,1H),4.64(d,1H),4.53-4.43(1H),4.31-4.18(m,2H),2.83-2.44(m,3H),2.28(q,1H),1.95-1.22(m,23H),0.83(s,3H)。

Compound 2: MS: M/z 895.2 (M) ⁺ +1)； ¹ H NMR(CDCl ₃ )δ10.45(s,1H),8.60(d,2H),8.22(d,1H),7.55(d,2H),7.67-7.60(m,2H),7.45(dd,1H),7.20(s,1H),6.12(s,1H),5.65(q,1H),5.13(d,1H),4.97(dd,1H),4.81-4.71(m,2H),4.14-4.10(m,2H),2.82-2.45(m,3H),2.27(q,1H),1.97-1.21(m,14H),1.08(s,9H),0.89-0.80(m,4H)。

Compound 3: MS: M/z 883.4 (M) ⁺ +1)； ¹ H NMR(CDCl ₃ )δ10.42(s,1H),8.43(d,2H),8.23(d,1H),7.61-7.39(m,4H),7.03(d,2H),6.18(s,1H),5.71(q,1H),5.30(d,1H),4.96(dd,1H),4.79-4.57(m,4H),4.41-4.22(m,1H),4.15-4.08(m,1H),2.96-2.67(m,3H),2.57-2.42(m,1H),2.25(q,1H),1.98-0.87(m,29H)。

Compound 4: MS: M/z 897.4 (M) ⁺ +1)； ¹ H NMR(CDCl ₃ )δ10.31(s,1H),8.42(d,2H),8.21(d,1H),7.57-7.25(m,4H),7.02(d,2H),6.14(s,1H),5.67-5.64(m,1H),5.40(d,1H),5.03-4.93(m,1H),4.79-4.54(m,4H),4.39-4.12(m,2H),2.77-2.72(m,2H),2.54(br,1H),2.26(q,1H),2.03-1.24(m,29H),0.80(s,3H)。

Compound 5: MS: M/z 915.2 (M) ⁺ +1)； ¹ H NMR(CDCl3)δ10.29(s,1H),8.38(d,2H),7.74(d,1H),7.57-7.24(m,3H),7.27(d,2H),6.14(s,1H),5.66(q,1H),5.32(d,1H),4.98(dd,1H),4.76(dd,1H),4.71-4.48(m,3H),4.39-4.08(m,2H),2.85-2.42(m,3H),2.31(q,1H),2.03-1.24(m,29H),0.80(s,3H)。

Compound 6: MS: M/z 901.2 (M) ⁺ +1)； ¹ H NMR(CDCl ₃ )δ10.42(s,1H),8.46(d,2H),7.82(d,1H),7.54(dd,1H),7.42(s,1H),7.32(m,1H),6.98(d,2H),6.14(s,1H),5.65(q,1H),5.33(d,1H),4.97(dd,1H),4.76(dd,1H),4.71-4.50(m,3H),4.41-4.08(m,2H),2.93-2.42(m,4H),2.31(q,1H),2.03-0.80(m,29H)。

Compound 7: MS: M/z 885.3 (M) ⁺ +1)； ¹ H NMR(CDCl ₃ )δ10.26(s,1H),8.42(d,2H),8.23(d,1H),7.58(m,2H),7.44(dd,1H),7.22(s,1H),7.01(d,2H),6.17(s,1H),5.67(q,1H),5.16(d,1H),4.98(dd,1H),4.75(dd,1H),4.62(m,2H),4.38-4.08(m,2H),2.80-2.42(m,3H),2.32(q,1H),1.96-1.20(m,21H),1.13(s,9H),0.81(m,3H)。

Compound 8: MS: M/z 923.2 (M) ⁺ +1)。

Compound 9: MS: M/z 882.5 (M) ⁺ +1)。

Compound 10: MS: M/z 881.4 (M) ⁺ +1)； ¹ H NMR(CDCl ₃ )δ10.47(s,1H),8.40(d,2H),8.23(d,1H),7.76(s,1H),7.62-7.41(m,5H),6.13(s,1H),5.65(q,1H),5.33(d,1H),5.03-4.87(m,2H),4.78(dd,1H),4.57(d,1H),4.38-4.04(m,2H),2.95-2.43(m,4H),2.21(q,1H),2.01-1.37(m,20H),1.33(s,9H),1.21-0.86(m,3H)。

Compound 11: MS: M/z 895.4 (M) ⁺ +1)； ¹ H NMR(CDCl ₃ )δ10.30(s,1H),8.40(d,2H),8.23(d,1H),7.59-7.43(m,5H),6.98(d,1H),6.16(s,1H),5.65(q,1H),5.41(d,1H),4.98(dd,1H),4.79(q,1H),4.62-4.52(m,1H),4.36-4.09(m,3H),2.75(brs,2H),2.59-2.56(m,1H),2.28(q,1H),1.91-1.18(m,31H),0.89-0.78(m,4H)。

Compound 12: MS: M/z 869.4 (M) ⁺ +1)； ¹ H NMR(CDCl ₃ )δ10.41(s,1H),8.42(d,2H),8.23(d,1H),7.62-7.43(m,5H),7.44(dd,1H),6.17(s,1H),5.64(q,1H),5.17(d,1H),4.97(dd,1H),4.77-4.63(m,2H),4.21-4.10(m,2H),2.94-2.55(m,4H),2.27(q,1H),1.89-1.15(m,23H),1.10(s,9H),0.98-0.87(m,1H)。

Compound 13: MS: M/z 925.4 (M) ⁺ +1)； ¹ H NMR(CDCl ₃ )δ10.28(s,1H),8.37(d,2H),8.03(d,1H),7.50(d,2H),7.48(s,1H),7.01-6.92(m,2H),6.13(s,1H),5.65(q,1H),5.39(d,1H),4.98(dd,1H),4.88(dd,1H),4.64(s,1H),4.53(d,1H),4.41-4.23(m,1H),4.19-4.11(m,1H),3.88(s,3H),2.78-2.42(m,3H),2.26(q,1H),2.04-1.18(m,31H),0.89-0.78(m,4H)。

Compound 14: MS: M/z 925.4 (M) ⁺ +1)； ¹ H NMR(CDCl ₃ )δ10.23(s,1H),8.35(d,2H),7.77(d,1H),7.48(d,2H),7.38-7.22(m,1H),7.04-6.81(m,2H),6.16(s,1H),5.68(q,1H),5.21(d,1H),4.99(dd,1H),4.78(dd,1H),4.57(d,1H),4.22-4.03(m,3H),4.00(s,3H),2.80-2.43(m,3H),2.31(q,1H),1.96-1.20(m,31H),0.95-0.78(m,4H)。

Example 2: preparation and evaluation of solid Dispersion

The solid dispersions of the present invention are prepared by spray drying methods well known in the art. See, for example, singh et al, advanced drug delivery reviews (Advanced Drug Delivery Reviews), 2016,100,27-50.

Different polymers of poloxamer 188, acrylic resin L100 (Eudragit L100), acrylic resin S100 (Eudragit S100), PVP VA64, HPC-L and PVP K30 were tested for their preferred properties in solid dispersions. The test compound (e.g., compound 4) and the different polymers were mixed in different proportions and dissolved in absolute ethanol as feed solutions. The solvent is removed from the feed solution during spray drying. The resulting spray-dried samples were then dried in a vacuum oven to remove residual solvent remaining in the spray-dried samples. After powder mixing and dry granulation, the solid dispersion is made into tablet form or capsule form.

The solubility of the above solid dispersion was then tested. Each solid dispersion tested was weighed and added to a 1.5mL vial, followed by 1.0mL of pH6.8 USP buffer. The vials were shaken at 25℃for 24 hours. After 24 hours of equilibration, each mixture was centrifuged at 10,000rpm for 10 minutes. The concentration of the test compound under each condition was determined by HPLC. The residual solids were collected and the form of the solids was determinable by XRPD detection. The results are shown in table 1 below:

TABLE 1

* LOQ (limit of quantitation) = 621.6ng/mL

These results demonstrate that solid dispersions prepared with poloxamer 188, PVP VA64, PVP K30 and HPC-L unexpectedly exhibit high solubility compared to compounds that were originally poorly water soluble.

Example 3: effect of compound-polymer ratio on solubility of various solid dispersions

When the weight ratio of compound-polymer was adjusted to 1:2, three polymers, such as HPC-L, PVP K30 and HPC-SSL, were used to test the equilibrium solubility of the solid dispersion. Table 2 below lists the components of HPC-L solid dispersion, PVP K30 solid dispersion, HPC-SSL solid dispersion.

TABLE 2

The equilibrium solubility results of the solid dispersions loaded with HPC-L, HPC-SSL and PVP K30 in Table 2 are shown in Table 3 below. The HPC-L solid dispersion, PVP K30 solid dispersion, and HPC-SSL solid dispersion all unexpectedly exhibited high equilibrium solubility in water or pH6.8 buffer.

TABLE 3 Table 3

Table 4 below shows the formulation of two different solid dispersions, wherein the weight ratio of compound to polymer in each solid dispersion is 1:1 or 1:1.5. after testing, these two proportions of solid dispersion also unexpectedly exhibited similar and superior dissolution properties.

TABLE 4 Table 4

Example 4: preparation of tablet and capsule preparation

The spray-dried solid dispersion described in example 3 above was used to prepare formulations in the form of tablets and capsules.

Tablet and capsule formulations may be prepared in a manner well known in the art. See, for example, U.S. patent 9,345,712.

The tablet form contained the components shown in table 5 below. The capsule form contained the components shown in tables 6 and 7 below. Both formulations exhibit satisfactory disintegration times and drug release profiles.

TABLE 5

TABLE 6

Watch seven

Example 5: pharmacokinetics of different formulations in dogs

A comparative study was performed on the plasma pharmacokinetics of the following two formulations containing compound 4.

Pharmacokinetic in vivo studies were performed after oral administration of tablet and capsule formulations per 100 mg/animal in five male beagle dogs. There is a purge period of at least 7 days between the two phases. Dogs in the first stage were administered compound 4 in the form of oral tablets (formulation shown in table 5) at a dose of 100 mg/animal. Dogs in the second phase were dosed with 100 mg/animal of compound 4 in the form of an oral capsule (formulation shown in table 6). Blood samples were collected at pre-dose (0) and post-dose hours 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72. The blood concentration of compound 4 was determined by LC MS/MS method. The relationship between the blood concentration and time is shown in FIG. 1.

The results indicate that solid dispersion tablet and capsule dosage forms unexpectedly exhibit high bioavailability.

Other embodiments

All of the features disclosed in the specification may be combined in any combination. The various features disclosed in the specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Accordingly, other embodiments are within the scope of the following claims.

Claims

1. A spray-dried solid dispersion comprising:

(a) A compound as shown below or a pharmaceutically acceptable salt thereof,

；

(b) A pharmaceutically acceptable polymer, the compound being dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer;

wherein the weight ratio of the compound to the pharmaceutically acceptable polymer is 2:1 to 1:2, and the pharmaceutically acceptable polymer is HPC-SSL or HPC-L.

2. The spray-dried solid dispersion of claim 1, wherein the pharmaceutically acceptable polymer is HPC-SSL.

3. The spray-dried solid dispersion according to claim 1, wherein the weight ratio of the compound to HPC-SSL is from 1:1 to 1:2.

4. the spray-dried solid dispersion of claim 1, wherein the weight ratio of the compound to HPC-L is 2:1.

5. the spray-dried solid dispersion of claim 1, wherein the weight ratio of the compound to the pharmaceutically acceptable polymer is 1:1.

6. the spray-dried solid dispersion of claim 1, wherein the weight ratio of the compound to the pharmaceutically acceptable polymer is 1:1.5.

7. the spray-dried solid dispersion of claim 1, wherein the compound is amorphous.

8. A pharmaceutical formulation comprising the spray-dried solid dispersion of claim 1, and optionally one or more pharmaceutically acceptable ingredients, wherein the pharmaceutically acceptable ingredients are selected from the group consisting of: one or more diluents, one or more disintegrants, one or more binders, one or more lubricants, one or more glidants, and one or more surfactants.

9. The pharmaceutical formulation of claim 8, wherein the spray-dried solid dispersion is 30 to 80% by weight.

10. The pharmaceutical formulation of claim 9, wherein the spray-dried solid dispersion is 60 to 70% by weight.

11. The pharmaceutical formulation of claim 8, wherein the formulation is manufactured in unit dosage form and contains 50 to 400mg of the compound.

12. The pharmaceutical formulation of claim 11, wherein the formulation contains 50 to 250mg of the compound.

13. The pharmaceutical formulation of claim 12, wherein the formulation contains 50mg of the compound.

14. The pharmaceutical formulation of claim 12, wherein the formulation contains 100mg of the compound.

15. The pharmaceutical formulation of claim 8, wherein the one or more pharmaceutically acceptable ingredients are selected from the group consisting of: microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate or colloidal silicon dioxide.

16. The pharmaceutical formulation of claim 8, wherein the pharmaceutical formulation is in the form of a tablet.

17. The pharmaceutical formulation of claim 8, wherein the pharmaceutical formulation is in the form of a capsule.

18. The pharmaceutical formulation of claim 8, wherein the pharmaceutical formulation comprises a film coating.

19. A method of preparing the spray-dried solid dispersion of claim 1, comprising: mixing the compound and pharmaceutically acceptable polymer in a solvent to provide a feed solution, and spray drying the feed solution to provide a spray dried solid dispersion.

20. The method of claim 19, wherein the solvent is absolute ethanol.

21. Use of the spray-dried solid dispersion of claim 1 in the manufacture of a medicament for treating Hepatitis C Virus (HCV) infection.

22. The use of claim 21, wherein the spray-dried solid dispersion is administered alone or in combination with one or more therapeutic agents selected from the group consisting of: one or more HCV NS5A inhibitors, one or more HCV NS5B inhibitors, one or more HCV NS4B inhibitors, one or more HCV p7 inhibitors, and one or more immunomodulators.

23. The use of claim 22, wherein each of said one or more HCV NS5A inhibitors is daclatasvir, lopamivir, obetavir, GSK2336805, PPI-461, PPI-668, ACH-2928, ACH-3102, GS-5816, BMS824393, sha Ma tavir, elban Wei Huoyi mitavir; each of the one or more HCV NS5B inhibitors is sofosbuvir Weite, febuvir Li Buwei, BMS-791325, VX-135, lox Mi Buwei, VX-759, ANA598, dasabuvir, ABT-072, debuvir, IDX375, mexitabine, RG7432, stavbuvir, PSI-7851, PSI-352938, PSI-661, TMC 649128, IDX184, INX-08189, JTK-853, VCH-916, BILB 1941, GS-6620, GS-9669, or Meng Xi tabine; each of the one or more HCV NS4B inhibitors is clemizole or GS-9132; and each of the one or more immunomodulators is a CD81 inhibitor or a cyclophilin inhibitor.