CN110958880A - Solid dispersion preparation - Google Patents

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 the treatment of hepatitis C virus infection.

Background

Hepatitis C Virus (HCV) infection is difficult to treat because the virus rapidly mutates and escapes the innate immune response. The HCV genome, which comprises a single polyprotein of about 3000 amino acids, contains the nucleocapsid proteins, the envelope proteins (E1 and E2) and several non-structural proteins (p7, NS2, NS3, NS4A, NS5A and NS 5B). Among these proteins, the NS3 protein has serine protease activity and is considered essential for viral replication and infection. The HCV NS3 protease can promote proteolysis at the connection points of NS3/NS4A, NS4A/NS4B, NS4B/NS5A and NS5A/NS5B, and can affect the production of four viral proteins in the viral replication process. Thus, the HCV NS3 protease is an attractive target for the treatment of HCV infection.

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

It is therefore desirable to develop new formulations containing these macrocyclic compounds which do not have the disadvantages described above.

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 is 4:1 to 1:4, and the pharmaceutically acceptable polymer is poloxamer, polyvinylpyrrolidone or hydroxypropyl cellulose.

The pharmaceutical compound has the general formula (I) shown below:

wherein R1 is H, C_1-6Alkyl radical, C_3-10Cycloalkyl radical, C_3-10Heterocycloalkyl, aryl or heteroaryl, wherein C_1-6Alkyl radical, C_3-10Cycloalkyl radical, C_3-10The heterocycloalkyl, aryl or heteroaryl groups may each be optionally mono-, di-or tri-substituted with: halogen, nitro, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, aryl or heteroaryl; r2 is H, halogen or C_1-6An alkyl group; r3 is H, halogen, nitro, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10Heterocycloalkyl, aryl or heteroaryl, or R3 may be fused with phenyl to form a bicyclic ring in which amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, aryl and heteroaryl groups may each be optionally mono-, di-or tri-substituted with halo; and R4 is H, halogen, nitro, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10Heterocycloalkyl, aryl or heteroaryl, wherein amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10The heterocycloalkyl, aryl or heteroaryl groups may each be optionally mono-, di-or tri-substituted with: halogen, nitro, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, aryl or heteroaryl.

A subgroup of the compounds described above is characterized in that R1 is C_1-6Alkyl or C_3-10A cycloalkyl group; r2 is H or C_1-6An alkyl group; r3 is H, halogen, amino, C_1-6Alkyl or C_1-6Alkoxy, wherein amino, C_1-6Alkyl and C_1-6Alkoxy may each be optionally mono-, di-or tri-substituted with halo; r4 is H, halogen, C_1-6Alkyl or C_1-6An alkoxy group.

The term "alkyl" in the present specification denotes a saturated straight or branched chain hydrocarbyl moiety, such as-CH₃or-CH (CH)₃)₂. The term "alkoxy" denotes-O- (C)_1-6Alkyl) radicals, e.g. -OCH₃or-OCH (CH)₃)₂. The term "alkenyl" denotes a straight or branched chain hydrocarbyl moiety containing at least one double bond, e.g., -CH ═ CH-CH₃. The term "alkynyl" denotes a straight or branched chain hydrocarbyl moiety containing at least one triple bond, e.g. -C.ident.C-CH₃. The term "cycloalkyl" denotes a saturated cyclic hydrocarbyl moiety, such as cyclohexyl. The term "heterocycloalkyl" denotes a saturated cyclic moiety having at least one ring heteroatom (e.g., N, O or S), such as 4-tetrahydropyranyl. The term "aryl" denotes a hydrocarbyl moiety having one or more aromatic rings. Examples of aryl groups include: phenyl (Ph), phenylene, naphthyl, naphthylene, pyrenyl, anthracenyl and phenanthrenyl. The term "heteroaryl" denotes 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, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolinyl, isoquinolinyl, and indolyl. The term "amino" denotes-NH₂，-NH-(C_1-6Alkyl) or-N- (C)_1-6Alkyl radical)₂A group of (A), e.g. -NHCH₃and-NHCH (CH)₃)₂. The term "halogen" denotes fluorine, chlorine, bromine or iodine.

Unless otherwise stated, the alkyl and alkenyl groups described in the specificationAlkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups include substituted and unsubstituted moieties. Possible substituents on cycloalkyl, heterocycloalkyl, aryl and heteroaryl include, but are not limited to: c_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10Heterocycloalkyl radical, C_1-10Alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C_1-20Alkylamino radical, C_1-20Dialkylamino, arylamino, diarylamino, C_1-10Alkyl sulfonamide, aryl sulfonamide, C_1-10Alkylimino, arylimino, C_1-10Alkylsulfonamido, arylsulfonylimino, hydroxy, halogen, thio, C_1-10Alkylthio, arylthio, C_1-10Alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidino, ureido, cyano, nitro, nitroso, azido, acyl, thioacyl, acyloxy, carboxyl and carboxylate groups. On the other hand, the substituent on the alkyl group, the alkenyl group or the alkynyl group includes all the substituents described above, but C_1-10Except for alkyl groups. Cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may also be fused to one another.

The above compounds include the compounds themselves, and if applicable, salts, prodrugs, polymorphs, stereoisomers and solvates thereof. For example, a salt may be formed from an anion and a positively charged group (e.g., amino) on a compound 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 can also be formed from cations and 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. Compounds also include those salts containing quaternary nitrogen atoms. For simplicity of calculation, reference to the weight of a compound in this specification refers to the weight of the free base form of the compound, unless otherwise indicated. 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 the complexes of the active compound with pharmaceutically acceptable solvents. Examples of pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.

Examples of 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.

An exemplary spray-dried solid dispersion contains the following compounds:

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

In the pharmaceutical formulation, 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, 100mg) 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 process for 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 present invention is a method 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 a therapeutically effective amount of a spray-dried solid dispersion or a pharmaceutical formulation containing a spray-dried solid dispersion to a human subject in need thereof.

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

Brief description of the drawings

FIG. 1 is a graph showing the plasma concentration-time curve of tablets and capsules of the present invention administered to beagle dogs.

Detailed description first disclosed in detail is the formation of a spray-dried solid dispersion of 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 Compounds of formula (I)

As shown in scheme 1, the halogen-substituted heteroaryl compound (i) is first coupled with N- (tert-butoxycarbonyl) -L-proline (ii) and then methylated to form intermediate (iii). Intermediate (iii) is then deprotected to remove the N-butoxycarbonyl group to form the free amino compound (iv), which is subsequently coupled with carboxylic acid (v) to give intermediate (vi). (vii) subjecting the intermediate (vi) to hydrolysis reaction to form an acid (vii), and coupling the acid with an amine compound (viii) to produce a pyrrolidine compound (ix) comprising two terminal alkenyl groups. Pyrrolidine compound (ix) undergoes an olefin metathesis reaction in the presence of Grubbs' catalyst to form the desired macrocyclic compound of formula (I).

The above synthesis may also include the addition or removal of suitable protecting groups before or after the steps shown in scheme 1, in order to finally synthesize the desired various compounds. In addition, various synthetic steps may be performed in an additional order or sequence to prepare certain compounds. Synthetic chemical transformations and protecting group methods (protection and deprotection) which 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 references: larock, Comprehensive Organic Transformations, VCH publishers (1989); greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, second edition, John Wigner and Sasung Press (John Wileyand Sons) (1991); fieser and m.fieser, Fieser and Fieser's Reagents for organic synthesis, john wilf and samsun press (1994); and encyclopedia of reagents for Organic Synthesis, John Power and Sasung Press (1995) and later versions thereof, by Paquette.

The compounds referred to in this specification contain non-aromatic double bonds and asymmetric centers. They may thus be in the form of racemates and racemic mixtures, individual enantiomers, individual diastereomers, diastereomeric mixtures, tautomers and cis-or trans-isomers. All of these isomeric forms are contemplated.

To practice the present invention, solid dispersions may be prepared comprising a compound of formula (I) and a pharmaceutically acceptable polymer. The compounds of formula (I) generally have low water solubility and their absorption in vivo is limited by the rate of dissolution. Solid dispersions containing the compounds of formula (I) can 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 denotes a dispersion of a pharmaceutically active ingredient, e.g. a compound of formula (I), in a solid inert polymer matrix. Solid dispersions 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. Solid dispersions comprise a co-precipitate of a pharmaceutically active ingredient and one or more water-soluble polymers, wherein the pharmaceutically active ingredient is uniformly dispersed within a matrix formed by 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 a single molecule in the polymer matrix. Typically, solid dispersions can be prepared by spray drying or hot melt extrusion. The solid dispersion of the present invention is prepared by a spray drying method.

The process for preparing the solid dispersion of the present invention comprises the steps of: (i) mixing a compound of formula (I) and a polymer in an organic solvent to provide a feed solution, (ii) spray drying the feed solution by spraying it through a nozzle into a chamber 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 an agitated dryer. Gases, humidified gases, vacuum may be applied to the second drying step and this application may be used to more rapidly remove residual solvent remaining in the spray-dried particles.

Any organic solvent that can readily dissolve or distribute the compound (I) and the polymer 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 for the spray drying method may be a homopolymer of N-vinylpyrrolidone, a copolymer of N-vinylpyrrolidone and vinyl acetate, a copolymer of N-vinylpyrrolidone and vinyl propionate, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyalkyl cellulose (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyalkyl alkylcellulose and hydroxypropyl methylcellulose), cellulose phthalate, cellulose succinate, cellulose acetate phthalate, hydroxypropyl methylcellulose succinate, hydroxypropyl methylcellulose acetate succinate, polyethylene oxide, polypropylene oxide, a copolymer of ethylene oxide and propylene oxide, a methacrylic acid/ethyl acrylate copolymer, a copolymer of N-vinylpyrrolidone, N-alkylcellulose, N-hydroxypropylmethylcellulose acetate succinate, polyethylene oxide, polypropylene oxide, a copolymer of ethylene oxide and propylene oxide, a copolymer of methacrylic acid/, Methacrylic acid/methyl methacrylate copolymer, butyl methacrylate/2-dimethylaminoethyl methacrylate copolymer, polyethylene oxide, polyethylene glycol, polyhydroxyalkyl acrylate, polyhydroxyalkyl methyl acrylate, a copolymer of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, carrageenan, galactomannan, or xanthan gum.

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), hydroxypropylcellulose (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 PVPK 30.

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 compound: polymer or drug: a polymer. The weight ratio may be from about 3:1 to about 1:3, from about 2:1 to about 1:2, from about 1.5:1 to about 1:1.5, from about 2:1 to about 1:1, from about 1:1 to about 1:2, from about 1.5:1 to about 1:1, from 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, 1:1.2, 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 spray-dried solid dispersion described above can be orally administered to a subject (e.g., a human) in need thereof to exert a therapeutic effect, e.g., to treat HCV infection.

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

The term "pharmaceutically acceptable ingredients" in this specification means inert additives used in the preparation of solid formulations (e.g. powders, granules, capsules, pellets and tablets) which increase the volume of the desired formulation containing the spray-dried solid dispersion described above. 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, bulking agents, binders, disintegrants, surfactants, lubricants, glidants, sweeteners, taste masking agents, coloring agents, and flavoring agents.

Suitable diluents, fillers and compatibilizers include, but are not limited to, microcrystalline cellulose, di-or tri-basic 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 components.

Suitable disintegrants include, but are not limited to, croscarmellose sodium (CC-Na), microcrystalline cellulose (e.g., MCC101 and MCC 102), crospovidone, cellulose, kaolin, crosslinked carboxymethylcellulose (e.g., AcDiSol), crosslinked polyvinylpyrrolidone (e.g., KollidonCL), and combinations thereof. The amount of disintegrant in the pharmaceutical formulation is from about 10% to about 40% (e.g., from about 20% to about 35% and from about 28% to about 32%) by 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%) by weight of the total 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 at 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 via oral administration in a single dose or in multiple doses. Administration can 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, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and ethylcellulose), 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 use in humans and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with the appropriate pharmaceutical ingredient. The compounds of formula (I) are generally administered in a pharmaceutically effective amount. The pharmaceutical dosage form typically contains 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 250mg) of the 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). It will be understood, however, that the amount of the compound actually administered will generally be determined by a physician, in the 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, the pharmaceutical formulation, or unit dosage form, contains about 100mg of a compound of formula (I) 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 values of the variable that are within experimental error of the indicated value or within 10 percent of the indicated value.

The term "effective amount" means the amount of the active compound of the present invention required to confer a therapeutic effect on 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, together with one or more pharmaceutically acceptable excipients or additives well known in the art for oral administration. The pharmaceutical preparations can be prepared in the form of conventional formulations, for example in the form of powders, granules, tablets, soft or hard capsules or coatings. For example, the solid dispersion in the form of powder or granules can be placed into a capsule, or it can be compressed into a tablet.

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

As previously described, the preparation method comprises the steps of mixing the compound and the 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 may be prepared from the compound of formula (I) in a variety of forms, for example, crystalline forms, amorphous forms, pharmaceutically acceptable salts, solvates and free bases thereof.

The spray-dried solid dispersion produced 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 present 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., a human) in need thereof a pharmaceutical formulation containing 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., BIT225), or other antiviral and immunomodulatory agents (e.g., CD81 inhibitors and cyclophilin inhibitors).

Examples of HCV NS5A inhibitors include: daclatasvir (BMS-790025), Lidipasvir (GS-5885), Obetavir (ABT-267), GSK2336805, PPI-461, PPI-668, ACH-2928, ACH-3102, GS-5816, BMS824393, Samaltasvir, Elmbavir (MK-8742) and Imitavir (DAG-181).

Examples of HCV NS5B inhibitors include: sofosbuvir (PSI-7977), Tegabuvir, non-ribavirin (PF-00868554), BMS-791325, VX-135, lomibivir (VX-222), VX-759, ANA598, Dasabovir (ABT-333) ABT-072, Deletabuvir (BI-207127), IDX375, Meisitabine (RG7128), RG7432, Sitacbuvir (RG7790) PSI-7851, PSI-352938, PSI-661, TMC 649128, IDX184, INX-08189, JTK-853, VCH-916, BILB1941, BISB-6620, GS-9669, and Mengsitabine.

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

Without further elaboration, it is believed that 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. All publications cited in this specification are herein incorporated in their entirety by reference.

Example 1: synthesis of Compounds of formula (I)

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

The Mass Spectrometry (MS) and NMR data for compounds 1-14 are shown below.

Compound 1: MS M/z 906.3 (M)⁺+1)；¹H NMR(CDCl₃)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 (I)2：MS:m/z 895.2(M⁺+1)；¹H NMR(CDCl₃)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)；¹H NMR(CDCl₃)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)；¹H NMR(CDCl₃)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)；¹H 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)；¹H NMR(CDCl₃)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)；¹H NMR(CDCl₃)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)；¹H NMR(CDCl₃)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)；¹H NMR(CDCl₃)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)；¹H NMR(CDCl₃)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)；¹H NMR(CDCl₃)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)；¹H NMR(CDCl₃)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, Reviews on Advanced Drug Delivery Reviews (Advanced Drug Delivery Reviews), 2016,100, 27-50.

Poloxamer 188, acrylic L100(Eudragit L100), acrylic 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 different polymers were mixed in different ratios and dissolved in absolute ethanol as a feed solution. The solvent is removed from the feed solution during the spray drying process. The obtained spray-dried sample was then dried in a vacuum oven to remove residual solvent remaining in the spray-dried sample. After powder mixing and dry granulation, the solid dispersion is made into tablet form or capsule form.

The solid dispersion was then tested for solubility. Each solid dispersion tested was weighed and added to a 1.5mL vial followed by 1.0mL of ph6.8 USP buffer. The vial was 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 the various conditions was determined by HPLC. The residual solid was collected and the form of the solid was determined by XRPD detection. The results are shown in table 1 below:

TABLE 1

LOQ (limit of quantitation) 621.6ng/mL

These results show that solid dispersions prepared with poloxamer 188, PVP VA64, PVPK30 and HPC-L unexpectedly exhibit high solubility compared to the originally poorly water soluble compound.

Example 3: effect of Compound-Polymer ratio on the solubility of various solid dispersions

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

TABLE 2

The equilibrium solubility results for 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 4 below shows the formulation of two different solid dispersions, each having a weight ratio of compound to polymer of 1:1 or 1: 1.5. the solid dispersions of these two ratios also unexpectedly exert similar and excellent dissolution properties after testing.

TABLE 4

Example 4: preparation of tablet and capsule preparations

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 accordance with methods 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 exhibited 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 in five male beagle dogs following oral administration of the tablet and capsule formulations at 100 mg/animal per dog. There was at least a 7 day washout period between the two phases. Dogs were given a 100 mg/animal dose of compound 4 in the first phase in the form of an oral tablet (formulation shown in table 5). Dogs were given a 100 mg/animal dose of compound 4 in an oral capsule (formulation shown in table 6) during the second phase. Blood samples were collected pre-dose (0) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose. The blood concentration of compound 4 was determined by LC MS/MS method. The blood concentration versus time is shown in figure 1.

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

Other embodiments

All features disclosed in the description may be combined in any combination. 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 one example only of a generic series of equivalent or similar features.

From the above description, one skilled in the art can easily ascertain the essential characteristics of the present 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 (29)

1. A spray-dried solid dispersion comprising:

(a) a compound of formula (I) or a pharmaceutically acceptable salt thereof as shown below,

wherein the content of the first and second substances,

r1 is H, C_1-6Alkyl radical, C_3-10Cycloalkyl radical, C_3-10Heterocycloalkyl, aryl or heteroaryl, wherein C_1-6Alkyl radical, C_3-10Cycloalkyl radical, C_3-10Heterocycloalkyl, aryl or heteroaryl are each optionally mono-, di-or tri-substituted with: halogen, nitro, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, aryl or heteroaryl;

r2 is H, halogen or C_1-6An alkyl group;

r3 is H, halogen, nitro, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10Heterocycloalkyl, aryl or heteroaryl, or R3 fused to a phenyl to form a bicyclic ring wherein amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, aryl and heteroaryl are each optionally mono-, di-or tri-substituted with halo; and

r4 is H, halogen, nitro, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10Heterocycloalkyl, aryl or heteroaryl, wherein amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10A cycloalkyl group, a,C_3-10Heterocycloalkyl, aryl or heteroaryl are each optionally mono-, di-or tri-substituted with: halogen, nitro, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, aryl or heteroaryl; and;

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

wherein the weight ratio of the drug compound to the pharmaceutically acceptable polymer is 4:1 to 1:4, and the pharmaceutically acceptable polymer is poloxamer, polyvinylpyrrolidone or hydroxypropyl cellulose.

2. The spray-dried solid dispersion of claim 1, wherein R1 is C_1-6Alkyl or C_3-10Cycloalkyl, and R2 is H or C_1-6An alkyl group.

3. The spray-dried solid dispersion of claim 1, wherein R1 is C_1-6Alkyl or C_3-10A cycloalkyl group; r2 is H or C_1-6An alkyl group; r3 is H, halogen, amino, C_1-6Alkyl radical, C_1-6Alkoxy, wherein amino, C_1-6Alkyl radical, C_1-6Alkoxy is each optionally mono-, di-or tri-substituted with halo; r4 is H, halogen, C_1-6Alkyl or C_1-6An alkoxy group.

4. The spray-dried solid dispersion of claim 1, wherein the compound is one of the following:

5. the spray-dried solid dispersion of claim 4, wherein the compound is

6. The spray-dried solid dispersion of claim 1, wherein the pharmaceutically acceptable polymer is poloxamer 188, PVP K30, PVP VA64, HPC-L, or HPC-SSL.

7. The spray-dried solid dispersion of claim 6, wherein the pharmaceutically acceptable polymer is PVP K30, HPC-L, or HPC-SSL.

8. The spray-dried solid dispersion of claim 7, wherein the pharmaceutically acceptable polymer is HPC-SSL.

9. The spray-dried solid dispersion of claim 1, wherein the weight ratio of the pharmaceutical compound to the pharmaceutically acceptable polymer is from 2:1 to 1: 2.

10. the spray-dried solid dispersion of claim 9, wherein the weight ratio of the pharmaceutical compound to the pharmaceutically acceptable polymer is from 1:1.

11. the spray-dried solid dispersion of claim 9, wherein the weight ratio of the pharmaceutical compound to the pharmaceutically acceptable polymer is from 1: 1.5.

12. the spray dried solid dispersion of claim 1, wherein the pharmaceutical compound is substantially amorphous.

13. 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.

14. The pharmaceutical formulation of claim 13, wherein the spray dried solid dispersion is 30 to 80% by weight.

15. The pharmaceutical formulation of claim 14, wherein the weight percent of the spray dried solid dispersion is 60 to 70%.

16. The pharmaceutical formulation of claim 15, wherein the pharmaceutical compound is

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

17. the pharmaceutical formulation of claim 13, wherein the formulation is manufactured in unit dosage form and contains 50 to 400mg of the pharmaceutical compound.

18. The pharmaceutical formulation of claim 17, wherein the formulation contains 50 to 250mg of the pharmaceutical compound.

19. The pharmaceutical formulation of claim 18, wherein the formulation contains 50mg of the pharmaceutical compound.

20. The pharmaceutical formulation of claim 18, wherein the formulation contains 100mg of the pharmaceutical compound.

21. The pharmaceutical formulation of claim 13, 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.

22. The pharmaceutical formulation of claim 13, wherein the pharmaceutical formulation is in the form of a tablet.

23. The pharmaceutical formulation of claim 13, wherein the pharmaceutical formulation is in the form of a capsule.

24. The pharmaceutical formulation of claim 13, wherein the pharmaceutical formulation comprises a film coating.

25. A method of preparing the spray-dried solid dispersion of claim 1, comprising: mixing the pharmaceutical 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.

26. The method of claim 25, wherein the solvent is absolute ethanol.

27. A method of treating a Hepatitis C Virus (HCV) infection in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of the spray-dried solid dispersion of claim 1.

28. The method of claim 27, 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.

29. The method of claim 28, wherein each of said one or more HCV NS5A inhibitors is daclatasvir, ridapavir, obitavir, GSK2336805, PPI-461, PPI-668, ACH-2928, ACH-3102, GS-5816, BMS824393, samatavir, elmba vir, or imietavir; each of the one or more HCV NS5B inhibitors is sofosbuvir, tegravir, felbuvir, BMS-791325, VX-135, lomibuvir, VX-759, ANA598, dasabuvir, ABT-072, Dretabwe, IDX375, mescitabine, RG7432, stambuvir, PSI-7851, PSI-352938, PSI-661, TMC 649128, IDX184, INX-08189, JTK-853, VCH-916, BILB1941, GS-6620, GS-9669, or montetabine; 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.

Images