WO2018222172A1 - Formulation de dispersion de solide - Google Patents

Formulation de dispersion de solide Download PDF

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Publication number
WO2018222172A1
WO2018222172A1 PCT/US2017/035000 US2017035000W WO2018222172A1 WO 2018222172 A1 WO2018222172 A1 WO 2018222172A1 US 2017035000 W US2017035000 W US 2017035000W WO 2018222172 A1 WO2018222172 A1 WO 2018222172A1
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WIPO (PCT)
Prior art keywords
spray
solid dispersion
dried solid
compound
alkyl
Prior art date
Application number
PCT/US2017/035000
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English (en)
Inventor
Ming-Chu Hsu
Chu-Chung Lin
Chi-Hsin Richard King
Original Assignee
Taigen Biotechnology Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taigen Biotechnology Co., Ltd. filed Critical Taigen Biotechnology Co., Ltd.
Priority to PCT/US2017/035000 priority Critical patent/WO2018222172A1/fr
Priority to CN201780091536.0A priority patent/CN110958880B/zh
Publication of WO2018222172A1 publication Critical patent/WO2018222172A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention relates to a spray-dried solid dispersion containing a macrocylic compound and methods of preparing and using the solid dispersion for treating hepatitis C virus infection.
  • HCV Hepatitis C virus
  • the HCV genome containing a single polyprotein of about 3000 amino acids, includes a nucleocapsid protein, envelope proteins (El and E2), and several non- structural proteins (p7, NS2, NS3, NS4A, NS5A, and NS5B).
  • El and E2 envelope proteins
  • p7, NS2, NS3, NS4A, NS5A, and NS5B non- structural proteins
  • the NS3 protein possesses serine protease activity and is considered essential for viral replication and infectivity.
  • HCV NS3 protease which facilitates proteolysis at the NS3/NS4A, NS4A/NS4B, NS4B/NS5A, NS5A/NS5B junctions, is responsible for generating four viral proteins during viral replication. Consequently, the HCV NS3 protease is an attractive target in treating HCV infection.
  • Certain macrocyclic compounds have demonstrated a potential for inhibiting NS3/4A proteases activity, decreasing HCV RNA levels, and inhibiting HCV protease mutants that are resistant to various HCV inhibitors. See Liu et al., US Patent 8,389,560. On the other hand, these compounds exhibit poor pharmacological properties, e.g., low solubility and low bioavailability, thereby restricting their use as effective therapeutics for treating HCV infection.
  • An aspect of the present invention is a spray-dried solid dispersion that unexpectedly exhibits 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, in which the pharmaceutical compound or its salt is dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer.
  • the weight ratio of the pharmaceutical compound to the pharmaceutically acceptable polymer is from 4: 1 to 1:4, and the pharmaceutically acceptable polymer is poloxamer, polyvinylpyrrolidone, or hydroxypropylcellulose.
  • the pharmaceutical compound has formula (I) as shown below:
  • Rl is H, Ci_6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, aryl, or heteroaryl, each of Ci_6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, aryl, and heteroaryl being optionally mono-, di-, or tri-substituted with halo, nitro, cyano, amino, Ci_6 alkyl, Ci_6 alkoxyl, C 2 -6 alkenyl, C 2 -6 alkynyl, aryl, or heteroaryl;
  • R2 is H, halo, or Ci_6 alkyl;
  • R3 is H, halo, nitro, cyano, amino, Ci_6 alkyl, Ci_6 alkoxyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, aryl, or heteroaryl,
  • R4 is H, halo, nitro, cyano, amino, Ci_6 alkyl, Ci_6 alkoxyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, aryl, or heteroaryl, each of amino, Ci_6 alkyl, Ci_6 alkoxyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, aryl, and heteroaryl being optionally mono-, di-, or tri-substituted with halo, nitro, cyano, amino, Ci_6 alkyl, Ci_6 alkoxyl, C2-6 alkenyl, C2-6 alkynyl, aryl, or heteroaryl.
  • Rl is Ci_6 alkyl or C3-10 cycloalkyl
  • R2 is H or Ci_6 alkyl
  • R3 is H, halo, amino, Ci_6 alkyl, or Ci_6 alkoxyl, each of the amino, Ci_6 alkyl, and Ci_6 alkoxyl being optionally mono-, di-, or tri-substituted with halo
  • R4 is H, halo, Ci_6 alkyl, or Ci_6 alkoxyl.
  • alkyl herein refers to a saturated, linear, or branched hydrocarbon moiety, e.g., -CH 3 or -CH(CH 3 ) 2 .
  • alkoxy refers to an -Q(Cu 6 alkyl) radical, e.g., -OCH 3 and -OCH(CH 3 ) 2 .
  • alkenyl refers to a linear or branched hydrocarbon moiety that contains at least one double bond, e.g.,
  • alkynyl refers to a linear or branched hydrocarbon moiety that contains at least one triple bond, e.g., -OC-CH 3 .
  • cycloalkyl refers to a saturated, cyclic hydrocarbon moiety, e.g., cyclohexyl.
  • heterocycloalkyl refers to a saturated, cyclic moiety having at least one ring heteroatom (e.g., N, O, and S), e.g., 4-tetrahydropyranyl.
  • aryl refers to a hydrocarbon moiety having one or more aromatic rings. Examples of aryl include phenyl (Ph), phenylene, naphthyl, naphthylene, pvrenyl, anthryl, and phenanthryl.
  • heteroaryl refers to a moiety having one or more aromatic rings that contain at least one heteroatom (e.g., N, O, and S).
  • heteroaryl include furyl, furylene, fiuorenyl, pvrrolyl, thienyl, oxazolyl, imidazolyl, ihiazolyl, pyridy], pyrimidinyl , quinazolinyl, quinolyl, isoquinolyl, and indoiyl.
  • amino refers to a radical of -NH 2 , -NH(Ct-6 alkyl), or ⁇ N(Ci-6 alkyl)?., e.g., -NHCH3 and -NHCH(CH 3 j2
  • halo refers to fluoro, chloro, bromo, or iodo.
  • Alkyl, alkenyl, aikynyl, cycioalkyl, heterocycloalkyl, aryl, and heteroaryl mentioned herein include both substituted and unsubstituted moieties, unless specified otherwise.
  • cycioalkyl, heterocycloalkyl, aryl, and heteroaryl include, but are not limited to, d-Cio alkyl, C 2 -Cio alkenyl, C 2 -do aikynyl, C3-C10 cycioalkyl, C3-C10 heterocycloalkyl, Ci-do alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, Ci-C 2 o alkylamino, d-do dia kylamino, arylamino, diarylamino, Ci -Cio alkylsulfonamino, arylsulfonamino, Ci-Cio alkylimino, arylimino, d -Cio alkylsulforiirttino, arylsulfonimino, hydroxy!, halo, tliio
  • alkyl alkenyl, or aikynyl
  • substituents on alkyl, alkenyl, or aikynyl include all of the above-recited substituents except d-do alkyl.
  • Cycioalkyl, heterocycloalkyl, aryl, and heteroaryl can also be fused with each other.
  • a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a compound having one of the above formulas.
  • Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate,
  • a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a compound having one of the above formulas.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
  • the compounds also include those salts containing quaternary nitrogen atoms.
  • the weight of a compound mentioned herein refers to that of the free base form of that compound.
  • prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing active compounds.
  • a solvate refers to a complex formed between an active compound and a pharmaceutically acceptable solvent.
  • pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.
  • Examples of a pharmaceutical compound to be contained in a spray-dried solid dispersion of this invention include, but are not limited to, the compounds shown below:
  • Compound 13 Compound 14
  • the pharmaceutical compound contained in a spray-dried solid dispersion can be substantially amorphous.
  • An exem lary spray-dried solid dispersion contains the following compound:
  • Another aspect of this invention is a pharmaceutical formulation containing a spray-dried solid dispersion described above and optionally one or more
  • the pharmaceutical acceptable ingredients are diluents, disintegrants, binders, lubricants, glidants, surfactants, or a combination thereof.
  • the spray-dried solid dispersion can be present at 30% to 80% w/w (e.g., 60% to 70% w/w).
  • the formulation is produced in unit dosage form and contains one of the above-described pharmaceutical compounds in an amount of 50 to 400 mg (e.g., 50 to 250 nig, 50 mg, and 100 mg).
  • An exemplary pharmaceutical formulation contains a spray-dried solid
  • a further aspect of this invention is a method of making the spray-dried solid dispersion described above.
  • the method includes the steps of mixing the compound and the
  • Also within the scope of this invention is a method of using a spray-dried solid dispersion or a pharmaceutical formulation containing the spray-dried solid dispersion for treating HCV infection in a human in need thereof.
  • the method includes administering to the human a therapeutically effective amount of the spray-dried solid dispersion or a pharmaceutical formulation containing the same.
  • Figure 1 is a schematic depiction of the plasma concentration versus time curves from dosing in beagle dogs a tablet and a capsule formulation of this invention.
  • a spray-dried solid dispersion for forming a pharmaceutical formulation.
  • the spray-dried solid dispersion contains a
  • Variables Rl - R4 are defined as described in the SUMMARY section.
  • the compounds of formula (I) can be synthesized from commercially available starting materials by following the synthetic route shown in Scheme 1 below.
  • halo-substituted heteroaryl compound (i) is first coupled with N-(t-butoxycarbonyl)-L-proline (ii), followed by methylation, to form intermediate (iii).
  • Intermediate (iii) is then deprotected to remove the
  • the synthesis described above can also include additional steps, either before or after the steps shown in Scheme 1, to add or remove suitable protecting groups in order to ultimately allow synthesis of various compounds.
  • various synthetic steps may be performed in an alternate sequence or order to give certain compounds.
  • Synthetic chemistry transformations and protecting group methodologies useful in synthesizing applicable compounds of formula (I) are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2 nd Ed., John Wiley and Sons (1991); L. Fieser and M.
  • the compounds mentioned herein contain a non- aromatic double bond and asymmetric centers. Thus, they can occur as racemates and racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, tautomers, and cis- or trans-isomeric forms. All such isomeric forms are contemplated.
  • a solid dispersion that contains a compound of formula (I) and a pharmaceutically acceptable polymer.
  • Compounds of formula (I) generally have low aqueous solubility, and their absorption in vivo is dissolution-rate limited.
  • a solid dispersion containing a compound of formula (I) can increase the compound solubility/dissolution, thereby improving the
  • solid dispersion herein refers to the dispersion of a
  • a solid dispersion can be prepared by methods well known in the art, e.g., spray-drying or hot-melt extrusion.
  • the matrix can be either crystalline or amorphous.
  • a solid dispersion contains a co-precipitate of a pharmaceutically active ingredient and one or more water-soluble polymers, in which the pharmaceutically active ingredient is dispersed uniformly within a polymer matrix formed from the polymers.
  • the pharmaceutically active ingredient can be present in an amorphous state, a crystalline dispersed form, or a combination thereof. It can also be finely dispersed or dissolved as single molecules in the polymer matrix.
  • the solid dispersion is typically prepared by a spray-drying method or a hot-melt extrusion method.
  • the solid dispersion of this invention is prepared by the spray-drying method.
  • the method for preparing the solid dispersion of this invention includes steps of (i) mixing a compound of formula (I) and a polymer in an organic solvent to provide a feeder solution and (ii) spray-drying the feeder solution through a nozzle as a fine spray into a chamber where the solvent is evaporated quickly to generate particles containing the compound and polymer.
  • the resulting spray-dried particle can undergo a secondary drying step to remove residual solvents.
  • the secondary drying step can take place in a static dryer or an agitated dryer. Gas, humidified gas, vacuum can be applied to the secondary drying step and such application is useful in more rapidly removing residual solvents that remain in the spray-dried particle.
  • organic solvent that can easily dissolve or disperse the compound of formula (I) and the polymer described above can be used.
  • the organic solvent include lower carbon-number alcohols, e.g., methanol, ethanol, propanol, and isopropanol; ketones, e.g., methylethyl ketone and butanone; and a combination thereof.
  • the polymer used in the spray-dried method can be a homopolymer of N-vinyl pyrrolidone, a copolymer of N-vinyl pyrrolidone, a copolymer of N-vinyl pyrrolidone and vinyl acetate, a copolymer of N-vinyl pyrrolidone and vinyl propionate, polyvinylpyrrolidone, methylcellulose, ethylcellulose, a hydroxyalkylcellulose (e.g., hydroxyethylcellulose, hydroxypropylcellulose, hydroxyalkylalkylcellulose, and hydroxypropylmethylcellulose), cellulose phthalate, cellulose succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,
  • hydroxypropylmethylcellulose succinate hydroxypropylmethylcellulose acetate succinate
  • polyethylene oxide polypropylene oxide, copolymer of ethylene oxide and propylene oxide
  • methacrylic acid/ethyl acrylate copolymer methacrylic acid/methyl methacrylate copolymer, butyl methacrylate/2-dimethylaminoethyl methacrylate copolymer
  • polyethylene oxide polyethylene glycol
  • copolymer of vinyl acetate and crotonic acid partially hydrolyzed polyvinyl acetate, carrageenan, galactomannan, or xanthan gum.
  • the polymer used in forming the solid dispersion is a hydrophilic polymer.
  • a hydrophilic polymer include polyvinylpyrrolidone (e.g., PVP VA64 and PVP K30), hydroxypropylcellulose (e.g., HPC-L and HPC-SSL), and poloxamer (e.g., poloxamer 188).
  • the polymer is one of poloxamer 188, PVP VA64, PVP K30, HPC-L, and HPC-SSL.
  • the polymer is one of poloxamer 188, PVP K30, HPC-L, and HPC-SSL
  • the polymer is HPC-SSL or PVP K30.
  • the polymer is HPC-SSL.
  • the weight ratio of the compound of formula (I) to the polymer contained in a solid dispersion is typically from about 4:1 to about 1:4, which is expressed as compound:polymer or drug:polymer. It can 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, or about 1: 1 to about 1:1.5.
  • the weight ratio of compound to polymer is about 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 spray-dried solid dispersion described above can be administered orally to a subject (e.g., a human) in need thereof to exert a therapeutic effect, e.g., treating HCV infection.
  • a subject e.g., a human
  • a therapeutic effect e.g., treating HCV infection.
  • a pharmaceutical formulation that contains a spray-dried solid dispersion and optionally one or more pharmaceutically acceptable ingredients.
  • pharmaceutically acceptable ingredient refers to an inert additive used to prepare a solid formulation, e.g., a powder, a granule, a capsule, a pellet, and a tablet, to increase the bulk of the desired formulation containing the spray-dried solid dispersion described above.
  • the pharmaceutically acceptable ingredients can be added during or after the preparation of spray-dried form of the solid dispersion.
  • the pharmaceutically acceptable ingredients include diluents, fillers, bulking agents, binders, disintegrants, surfactants, lubricants, glidants, sweeteners, taste masking agents, colorants, and flavors.
  • Suitable diluents, fillers, and bulking agents include, but are not limited to, microcrystalline cellulose, di- or tri-basic calcium phosphate, crystalline cellulose, powdered cellulose, calcium carbonate, calcium sulphate, magnesium silicate, magnesium trisilicate, magnesium aluminium metasilicate, kaolin, starch, 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, crosslinked carboxy methyl cellulose (e.g., AcDiSol), crosslinked polyvinyl pyrrolidone (e.g., Kollidon CL), and a combination thereof.
  • the amount of disintegrants in the pharmaceutical formulation ranges from about 10% to about 40% (e.g., about 20% to about 35% and about 28% to about 32%) by total weight of the formulation.
  • Suitable surfactants include, but are not limited to, an anionic, cationic, non-ionic, or amphoteric surfactant.
  • An exemplary anionic surfactant is sodium lauryl sulfate (SLS).
  • SLS sodium lauryl sulfate
  • the amount of a surfactant present in the pharmaceutical formulation ranges from about 0.1% to about 2.5%, or about 0.5% to about 2% by total weight of the formulation.
  • Suitable lubricants and glidants include, but are not limited to, a stearic acid and its derivatives (e.g., sodium stearate, magnesium stearate and calcium stearate), sodium stearyi fumarate, and talc or colloidal silicon dioxide (CSD).
  • the amount of lubricants or glidants present in the pharmaceutical composition ranges from about 0.1% to about 5% (e.g., about 0.5% to about 4% and about 1% to about 3%) by total weight of the formulation.
  • the active pharmaceutical ingredient can be present in the pharmaceutical formulation in a therapeutically effective amount.
  • the pharmaceutical formulation contains a spray -dried solid dispersion present at about 30% to about 80% w/w(e.g., about 40% to about 70% w/w, about 50% to about 70% w/w, and about 60% to about 70% w/w).
  • An exemplary pharmaceutical formulation contains about 63% w/w of a spray-dried solid dispersion.
  • pharmaceutical formulation contains about 68% of a spray-dried solid dispersion.
  • the pharmaceutical formulation of the invention can be administered in either single or multiple doses via oral administration. Administration can be via solution, suspension, emulsion, capsule, tablet, or the like. In one embodiment, the formulation is in the form of a tablet. In a further embodiment, the formulation is in the form of a capsule.
  • the pharmaceutical formulation of the present invention can further be film-coated.
  • the film-coating contains film-forming polymers and one or more coating additives.
  • Suitable film-forming polymers include a cellulose derivative (e.g., methyl cellulose, hydroxymethyl cellulose, hydroxyethyi cellulose, hydroxypropyl cellulose, hydroxymethylethyl cellulose, hydroxypropylrnethyl cellulose, sodium carboxymethyl cellulose, and ethyl cellulose), a vinyl polymer, an acrylic poiymre, and a combination thereof.
  • the pharmaceutical formulation is formulated in a unit dosage or pharmaceutical dosage form.
  • unit dosage form or
  • pharmaceutical dosage form refers to a physically discrete unit suitable as a unitary dosage for human and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical ingredient.
  • the compounds of formula (I) are generally administered in a pharmaceutically effective amount.
  • the pharmaceutical dosage form typically contains a compound of formula (I) in an amount of about 50 to about 400 mg, (e.g., about 75 to about 375 mg, about 100 to about 350 mg, about 150 to about 325 mg, about 200 to about 300 mg, about 225 to about 270 mg, about 225 to about 250 mg, and about 50 to about 250 mg).
  • the pharmaceutical dosage form contains a compound of formula (I) in an amount of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, or about 315 mg. It will be understood, however, that the amount of the compound actually administered usually will 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.
  • the pharmaceutical formulation or alternatively, the unit dosage form contains about 100 mg of a compound formula (I) formulated in a spray-dried solid dispersion having a compound:polymer ratio of 1 : 1.5 and the spray-dried solid dispersion is present in an amount of about 68.5% w/w.
  • the term “about” refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value or within 10 percent of the indicated value.
  • the term “effective amount” refers to the amount of an active compound of this invention that is required to confer a therapeutic effect on the treated subject.
  • substantially amorphous refers to a composition in which 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 compound present in amorphous.
  • the present invention provides a pharmaceutical formulation comprising the spray-dried solid dispersion which contains a
  • the pharmaceutical formulation can be prepared into conventional dosage forms, such as powders, granules, tablets, soft or hard capsules, or coated forms.
  • the solid dispersion in the form of powder or granules can be put into the capsules, or it can be pressed into tablets.
  • the preparation method includes steps of mixing the compound and the pharmaceutically acceptable polymer in a solvent to provide a feeder solution and spray-drying the feeder solution to afford a spray-dried solid dispersion.
  • the solid dispersion can be prepared from a variety of forms of a compound formula (I), e.g., crystalline forms, amorphous form, pharmaceutical acceptable salts thereof, solvates, and free base.
  • a compound formula (I) e.g., crystalline forms, amorphous form, pharmaceutical acceptable salts thereof, solvates, and free base.
  • the spray-dried solid dispersion thus prepared contains the compound of formula (I) that is substantially in an amorphous state and dispersed within a polymer matrix formed by a pharmaceutically acceptable polymer.
  • Advantages of the spray-dried solid dispersion of this invention include better dissolution performance, acceptable disintegration time and drug release profiles for formulation, improved dissolution /solubility for rnanufacturability, and improved bioavailability.
  • a method 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 thus prepared.
  • the solid dispersion, pharmaceutical formulation, or unit dosage form is administered, either alone or in combination with one or more therapeutic agents for treating HCV infection.
  • therapeutic agents can be HCV NS5A inhibitors, HCV NS5B inhibitors, HCV NS4B inhibitors, HCV p7 inhibitors (e.g., BIT225), or other antiviral agents and immunomodulatory agents (e.g., CD81 inhibitors and cyclophilin inhibitors).
  • HCV NS5A inhibitors examples include Daclatasvir (BMS-790025), Ledipasvir (GS-5885), Ombitasvir (ABT-267), GSK2336805, PPI-461, PPI-668, ACH-2928, ACH-3102, GS-5816, BMS824393, Samatavir, Elbasvir (MK-8742), and Yimitasvir (DAG-181).
  • HCV NS5B inhibitors examples include Sofosbuvir (PSI-7977), Tegobuvir, Filibuvir (PF-00868554), BMS-791325, VX-135, Lomibuvir (VX-222), VX-759, ANA598, Dasabuvir (ABT-333), ABT-072, Deleobuvir (BI-207127), IDX375, Mericitabine (RG7128), RG7432, Setrobuvir (RG7790) PSI-7851, PSI-352938, PSI-661 ,TMC 649128, IDX184, INX-08189, JTK-853, VCH-916, BILB 1941, GS-6620, GS-9669, and Mencitabine.
  • PSI-7977 Sofosbuvir
  • Tegobuvir Filibuvir
  • Filibuvir PF-00868554
  • BMS-791325 VX-135, Lomibuvir (VX-222), VX-759,
  • HCV NS4B inhibitors examples include Clemizole and GS-9132.
  • the solid dispersions of the present invention were prepared by a spray-dried method well known in the art. For example, see Singh et al., Advanced Drug Delivery Reviews, 2016, 100, 27-50.
  • HPC-L Three polymers, i.e., HPC-L, PVP K30, and HPC-SSL, were used to examine the equilibrium solubility of solid dispersions when the weight ratio of Compound 4 to polymer was adjusted to 1 :2.
  • Components of HPC-L solid dispersion, PVP K30 solid dispersion, HPC-SSL solid dispersion are summarized in Table 2 below.
  • the tablet and capsule formulations were prepared by following protocols well known in the field. For example, see US Patent 9,345,712.
  • the tablet form contained the components shown in Table 5 below.
  • the capsule form contained the components shown in Table 6 and Table 7 also below. Acceptable disintegration time and drug release profile were achieved using these two formulations. TABLE 5
  • the in vivo pharmacokinetic study was conducted in five male beagle dogs after oral administration of tablet and capsule formulations each at 100 mg/animal to the dogs. There was at least a 7-day washout period between each of two phases. Dogs in phase 1 were administered Compound 4 orally in the tablet form (formula shown in Table 5) at a nominal dosage of 100 mg/animal. Dogs in phase 2 were administered Compound 4 orally in the capsule form (formula shown in Table 6) at a nominal dosage of 100 mg/animal. Blood samples were collected at pre-dose (0) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours post administration. Plasma concentrations of Compound 4 were determined by the LC-MS/MS method. A graph of plasma concentration vs. time is shown in Figure 1.

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  • Bioinformatics & Cheminformatics (AREA)
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Abstract

L'invention concerne une dispersion de solide séchée par pulvérisation contenant un composé pharmaceutique de formule (I) présentée ci-dessous et un polymère pharmaceutiquement acceptable, dans lequel le composé pharmaceutique est dispersé dans une matrice polymère formée à partir du polymère pharmaceutiquement acceptable. L'invention concerne en outre des méthodes de préparation d'une telle dispersion de solide et l'utilisation de celle-ci pour traiter une infection par le virus de l'hépatite C et une formulation pharmaceutique la contenant.
PCT/US2017/035000 2017-05-30 2017-05-30 Formulation de dispersion de solide WO2018222172A1 (fr)

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CN201780091536.0A CN110958880B (zh) 2017-05-30 2017-05-30 固体分散制剂

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Cited By (2)

* Cited by examiner, † Cited by third party
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