WO2020236950A1 - Formulations de microsphères thérapeutiques contenant des polymères chargés - Google Patents

Formulations de microsphères thérapeutiques contenant des polymères chargés Download PDF

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Publication number
WO2020236950A1
WO2020236950A1 PCT/US2020/033834 US2020033834W WO2020236950A1 WO 2020236950 A1 WO2020236950 A1 WO 2020236950A1 US 2020033834 W US2020033834 W US 2020033834W WO 2020236950 A1 WO2020236950 A1 WO 2020236950A1
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Prior art keywords
microspheres
therapeutic compound
polymer
jak3
solvent
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PCT/US2020/033834
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English (en)
Inventor
Olivier Laurent
Joel F. MARTIN
Alice Lee
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Dauntless 1, Inc.
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Publication of WO2020236950A1 publication Critical patent/WO2020236950A1/fr

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    • 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
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin

Definitions

  • microspheres e.g, single emulsion microspheres
  • a therapeutic compound or pharmaceutically acceptable salt thereof a poly(lactic-co-glycolic acid) (PLGA) polymer comprising at least one hydrophilic terminus
  • PLGA poly(lactic-co-glycolic acid)
  • Drug formulations such as microspheres are important for modulating the pharmacokinetic properties of the drug, such as release of the active compound.
  • a variety of microspheres and methods of microsphere preparation have been described. See, e.g., U.S. Pat. Nos. 5,639,480 and 8,916,196.
  • Double emulsion, water/oil/water microspheres have often been used for a variety of hydrophilic drug compounds. These are typically formed by emulsifying an aqueous solution of the hydrophilic drug with a solution of a polymer in organic solvent by high shear mixing (e.g, 20,000 rpm), generating an unstable water/oil emulsion. This unstable emulsion is then usually further emulsified in water, leading to a water/oil/water double emulsion that is then hardened by solvent exchange, and lyophilized into dry microspheres.
  • SANDOSTATIN® LAR depot octreotide acetate
  • This drug is formulated in a double emulsion microsphere for a long release, thereby decreasing the frequency of administration.
  • SANDOSTATIN® LAR is notoriously difficult to administer by injection; it frequently blocks flow through the needle (e.g, low
  • SANDOSTATIN® LAR is also characterized by low loading of the octreotide in the microspheres, necessitating a larger volume for injection that also causes significant pain during injection and can potentially lead to formation of painful nodules at the injection site. This further precludes subcutaneous injection in favor of more painful intramuscular injection. Finally, double emulsion microspheres are difficult to
  • microsphere formulations suitable for different active pharmaceutical ingredients (APIs) and characterized by improved pharmacokinetic properties, increased loading, a more uniform size distribution of particles, and easier, well-controlled manufacturing.
  • APIs active pharmaceutical ingredients
  • the methods comprise combining a first solvent and a therapeutic compound or pharmaceutically acceptable salt thereof to form a first mixture; combining a second solvent and a polymer to form a second mixture; combining the first and second mixtures to produce a self-forming biphasic solution; dispersing the self-forming biphasic solution into an aqueous continuous phase to form a plurality of droplets; and hardening the plurality of droplets to form a plurality of single emulsion microspheres.
  • the first solvent comprises an organic acid.
  • the therapeutic compound or salt thereof is present in the first mixture at a concentration that is 80% or greater than its limit of solubility in the first solvent.
  • the polymer comprises poly(lactic-co-glycolic acid) (PLGA) comprising at least one hydrophilic terminus.
  • the polymer has a molecular weight of at least 20 kD.
  • the second solvent is an organic solvent.
  • the limit of solubility of the therapeutic compound or pharmaceutically acceptable salt thereof in the second solvent is 10% or less than the limit of solubility of the therapeutic compound or pharmaceutically acceptable salt thereof in the first solvent.
  • the aqueous continuous phase is saturated with the therapeutic compound or pharmaceutically acceptable salt thereof.
  • At least 90% of the microspheres of the plurality produced are between 16 and 28 pm in diameter. In some embodiments, at least 60% of the microspheres of the plurality are between 20 and 26pm in diameter. In some embodiments, the therapeutic compound or salt is greater than 10% by total weight of the microspheres.
  • the polymer has a molecular weight of less than or equal to 54 kD. In some embodiments, the polymer has a molecular weight between 24 kD and 38 kD. In some embodiments, the polymer has a molecular weight between 38 kD and 54 kD. In some embodiments, the polymer has a ratio of lactide:glycolide of 50:50.
  • the first solvent comprises formic acid.
  • the methods further comprise adjusting the pH of the aqueous continuous phase into which the self-forming, biphasic solution is dispersed in step (d).
  • the pH of the aqueous continuous phase is less than 7, less than 6, less than 5, or about 4.5.
  • the first mixture comprises the therapeutic compound or pharmaceutically acceptable salt thereof at a concentration of at least
  • the self-forming, biphasic solution comprises the therapeutic compound or pharmaceutically acceptable salt thereof at a concentration of at least 30mg/mL.
  • the therapeutic compound comprises a tyrosine kinase inhibitor.
  • the therapeutic compound comprises a JAK inhibitor.
  • the JAK inhibitor is selected from the group consisting of ruxolitinib, tofacitinib, oclacitinib, baricitinib, filgotinib, gandotinib, lestaurtinib, momelotinib, pacritinib, PF-04965842, upadacitinib, peficitinib, fedratinib, cucurbitacin I, decemotinib, INCBO 18424, AC430, BMS-0911543, GSK2586184, VX-509, R348, AZD1480, CHZ868, PF-956980, AG490, WP-1034, JAK3 inhibitor IV, atiprimod, FM-381, SAR20347, AZD4205, ARN
  • the methods further comprise washing the plurality of microspheres in a second aqueous continuous phase, e.g ., after dispersing the self-forming biphasic solution and prior to hardening the plurality of droplets.
  • the methods further comprise washing the plurality of microspheres, (e.g, in water), e.g, after hardening the plurality of droplets.
  • the methods further comprise lyophilizing the plurality of microspheres.
  • the methods further comprise freeze drying the plurality of microspheres.
  • a plurality of single emulsion microspheres comprising: a therapeutic compound or pharmaceutically acceptable salt thereof; and a polymer, wherein the polymer comprises poly(lactic-co-glycolic acid) (PLGA) comprising at least one hydrophilic terminus.
  • PLGA poly(lactic-co-glycolic acid)
  • the polymer has a molecular weight of at least 20 kD.
  • At least 90% of the microspheres of the plurality are between 16 and 28 pm in diameter. In some embodiments, at least 60% of the microspheres of the plurality are between 20 and 26pm in diameter.
  • the therapeutic compound or salt is greater than 5% by total weight of the microspheres. In some embodiments, the therapeutic compound or salt is greater than 10% by total weight of the microspheres.
  • the polymer has a molecular weight of less than 54 kD.
  • the polymer has a molecular weight between 24 kD and 38 kD. In some embodiments, the polymer has a molecular weight between 38 kD and 54 kD. In some embodiments, the polymer has a ratio of lactide:glycolide of 50:50.
  • the therapeutic compound comprises a tyrosine kinase inhibitor.
  • the therapeutic compound comprises a JAK inhibitor.
  • the JAK inhibitor is selected from the group consisting of ruxolitinib, tofacitinib, oclacitinib, baricitinib, filgotinib, gandotinib, lestaurtinib, momelotinib, pacritinib, PF-04965842, upadacitinib, peficitinib, fedratinib, cucurbitacin I, decemotinib, INCBO 18424, AC430, BMS-0911543, GSK2586184, VX-509, R348, AZD1480, CHZ868, PF-956980, AG490, WP-1034, JAK3 inhibitor IV, atiprimod, FM-381, SAR20347, AZD4205, ARN
  • composition comprising a plurality of microspheres according to any one of the above embodiments.
  • FIG. 1 compares the size distributions of SANDOSTATIN® LAR microspheres (dotted line) with the size distribution of a octreotide/PLGA microspheres (dashed line) and tofacitinib/PLGA microspheres formulated as described in Table A (see preparation 15.2).
  • FIG. 2 shows a preparation of tofacitinib/PLGA microspheres imaged using light microscopy.
  • FIG. 3 shows the surface of tofacitinib/PLGA microspheres imaged using scanning electron microscopy (SEM).
  • microspheres e.g ., single emulsion microspheres
  • a therapeutic compound or pharmaceutically acceptable salt thereof e.g., a pharmaceutically acceptable salt thereof
  • a poly(lactic-co-glycolic acid) (PLGA) polymer comprising at least one hydrophilic terminus
  • the present disclosure is based, at least in part, on the finding that making microspheres with PLGA polymer having a hydrophilic, charged, and/or acidic terminus allowed for increased loading of compound (e.g ., tofacitinib) in the microspheres.
  • compound e.g ., tofacitinib
  • microspheres were also characterized by a more uniform size distribution that other microspheres, e.g., SANDOSTATIN® LAR depot double emulsion microspheres.
  • Certain aspects of the present disclosure relate to methods of preparing a microsphere of the present disclosure, e.g, a single emulsion microsphere comprising a therapeutic compound or pharmaceutically acceptable salt thereof and a PLGA polymer comprising at least one hydrophilic terminus.
  • the methods of preparing a microsphere of the present disclosure comprise: combining a first solvent (e.g, comprising an organic acid) and a therapeutic compound or pharmaceutically acceptable salt thereof to form a first mixture; combining a second solvent (e.g, an organic solvent) and a polymer (e.g, PLGA comprising at least one hydrophilic terminus and having a molecular weight of at least 20 kD) to form a second mixture; combining the first and second mixtures to produce a self forming biphasic solution; dispersing the self-forming biphasic solution into an aqueous continuous phase to form a plurality of droplets; and hardening the plurality of droplets to form a plurality of single emulsion microspheres.
  • a first solvent e.g, comprising an organic acid
  • a therapeutic compound or pharmaceutically acceptable salt thereof e.g., an organic solvent
  • a polymer e.g, PLGA comprising at least one hydrophilic terminus and having a mo
  • the first solvent (e.g, mixed with the therapeutic compound) comprises an organic acid.
  • the first solvent (e.g, mixed with the therapeutic compound) is selected from the group consisting of formic acid, dimethylsulfoxide (DMSO), dimethylacetamide (DMA), and dimethylformamide (DMF).
  • the first solvent (e.g, mixed with the therapeutic compound) comprises formic acid.
  • the first solvent (e.g, mixed with the therapeutic compound) comprises DMSO.
  • the second solvent e.g, mixed with the polymer
  • the second solvent is selected from the group consisting of dichloromethane (DCM), DMA, and DMF.
  • the therapeutic compound or salt thereof is present in the first mixture at a concentration that is 80% or greater than its limit of solubility in the first solvent.
  • the therapeutic compound or salt thereof is present in the first mixture at a concentration that is 80% or greater, 85% or greater, or 90% or greater than its limit of solubility in the first solvent.
  • the first mixture comprises the therapeutic compound or pharmaceutically acceptable salt thereof at a concentration of at least 300mg/mL.
  • the first mixture comprises the therapeutic compound or pharmaceutically acceptable salt thereof at a concentration of at least 300mg/mL, at least 325mg/mL, at least 350mg/mL, at least 375mg/mL, or at least 400mg/mL.
  • the limit of solubility of the therapeutic compound or pharmaceutically acceptable salt thereof in the second solvent is substantially less than the limit of solubility of the therapeutic compound or pharmaceutically acceptable salt thereof in the first solvent.
  • the limit of solubility of the therapeutic compound or pharmaceutically acceptable salt thereof in the second solvent is 10% or less than the limit of solubility of the therapeutic compound or pharmaceutically acceptable salt thereof in the first solvent.
  • the limit of solubility of the therapeutic compound or pharmaceutically acceptable salt thereof in the second solvent is 20% or less, 15% or less, 12% or less, 10% or less, 8% or less, or 5% or less than the limit of solubility of the therapeutic compound or pharmaceutically acceptable salt thereof in the first solvent.
  • the methods of the present disclosure comprise combining the first and second mixtures to produce a self-forming biphasic solution.
  • the self-forming bisphasic solution may arise, e.g ., due to differences in the solubility of the therapeutic compound in the first and second solvents.
  • the present disclosure demonstrates that this self- forming bisphasic solution formed during microsphere production correlates with greater loading of the API into the resultant microspheres.
  • the self-forming, biphasic solution comprises the therapeutic compound or pharmaceutically acceptable salt thereof at a concentration of at least 30mg/mL, e.g. , about 33mg/mL.
  • the self-forming, biphasic solution comprises an organic acid (e.g, formic acid) and an organic solvent (e.g, DCM).
  • the self-forming, biphasic solution comprises the organic acid (e.g, formic acid) and the organic solvent (e.g ., DCM) at a ratio of 2:8 or 1 :9 (organic acid:organic solvent).
  • the methods of the present disclosure comprise dispersing a self-forming biphasic solution of the present disclosure into an aqueous continuous phase to form a plurality of droplets.
  • the aqueous continuous phase is saturated with the therapeutic compound or pharmaceutically acceptable salt thereof.
  • the present disclosure demonstrates that saturating the aqueous continuous phase during microsphere production correlates with greater loading of the API into the resultant microspheres.
  • the aqueous continuous phase further comprises an alcohol, e.g., poly(vinyl alcohol) or PVA.
  • the aqueous continuous phase further comprises a buffer, e.g, an acetate buffer.
  • the aqueous continuous phase further comprises acetate.
  • the aqueous continuous phase further comprises DCM.
  • the aqueous continuous phase is saturated with DCM.
  • the pH of the aqueous continuous phase is less than 7. In some embodiments, the pH of the aqueous continuous phase is less than 6, or less than 5.
  • the pH of the aqueous continuous phase is about 4.5.
  • the methods of the present disclosure further include adjusting the pH of the aqueous continuous phase into which the self-forming, biphasic solution is dispersed (e.g, so as to achieve a pH of less than 7, less than 6, less than 5, or about 4.5).
  • the methods of the present disclosure further include (e.g, after dispersing the self-forming biphasic solution and prior to hardening) washing the plurality of microspheres in a second aqueous continuous phase.
  • the methods of the present disclosure comprise hardening a plurality of droplets of the present disclosure to form a plurality of single emulsion microspheres.
  • hardening the droplet(s) to form single emulsion microsphere(s) of the present disclosure comprises exacervation.
  • the methods of the present disclosure further include (e.g, after initial hardening the droplet to form a microsphere, and/or prior to optional lyophilization or freeze drying) washing the microsphere, e.g, in water.
  • the methods further include (e.g, after hardening the droplet to form a microsphere) lyophilizing or freeze drying the microsphere(s).
  • microspheres e.g. , single emulsion microspheres comprising a therapeutic compound or pharmaceutically acceptable salt thereof and a PLGA polymer comprising at least one hydrophilic terminus.
  • the PLGA polymer has a molecular weight of at least 20 kD.
  • microsphere denotes the encapsulation of the therapeutic
  • a polymer of the present disclosure refers to a PLGA polymer, e.g, a random or block copolymer made of two types of monomers: glycolyic acid and lactic acid.
  • the PLGA polymer comprises at least one hydrophilic or acidic terminus.
  • the PLGA polymer comprises more than one hydrophilic or acidic terminus.
  • the PLGA polymer comprises at least one carboxylic acid terminus.
  • a PLGA polymer of the present disclosure has a ratio of lactide:glycolide of 50:50.
  • Exemplary PLGA polymers comprising a hydrophilic or acidic terminus include, without limitation,
  • RESOMER® RG 502H, 503H, and 504H (Evonik Industries).
  • a PLGA polymer of the present disclosure has a molecular weight of at least 20 kD.
  • a molecular weight refers to the average molecular weight of a polymer species.
  • a molecular weight refers to the minimum or maximum molecular weight of a polymer species.
  • RESOMER® RG 502H (Evonik Industries) has a molecular weight of 7kD-17kD
  • RESOMER® RG 503H (Evonik Industries) has a molecular weight of 24kD-38kD.
  • a PLGA polymer of the present disclosure has a molecular weight of less than 54 kD.
  • a PLGA polymer of the present disclosure has a molecular weight of at least 20 kD but less than 54 kD. In some embodiments, a PLGA polymer of the present disclosure has a molecular weight between 24 kD and 38 kD. In some embodiments, a PLGA polymer of the present disclosure has a molecular weight between 38 kD and 54 kD (e.g, RESOMER® RG 504H; Evonik Industries).
  • a therapeutic compound or salt of the present disclosure comprises a small molecule drug or compound.
  • a therapeutic compound or salt of the present disclosure comprises a tyrosine kinase inhibitor.
  • the therapeutic compound or salt comprises a Janus kinase (JAK) inhibitor.
  • JAK inhibitor broadly encompasses molecules that inhibit the function of one or more JAK family kinases, such as JAK1, JAK2, JAK3, and TYK2.
  • a JAK inhibitor inhibits one or more activities of JAK 1; JAK2; JAK3; JAK1 and JAK2; JAK1 and JAK3; JAK3 and JAK2; TYK2 and JAK1; TYK2 and JAK2; TYK2 and JAK3; JAK1, JAK2, and JAK3; or JAK1, JAK2, TYK2, and JAK3.
  • JAK inhibitors include, without limitation, ruxolitinib (also known as JAKAFI®, JAKAVI®, and INCBO 18424, including the phosphate and sulfate salts and S enantiomer), tofacitinib (also known as tasocitinib, CP- 690550, XELJANZ® and JAKVINUS®, including (3R,4S), (3S,4R), and (3S,4S) enantiomers and the citrate salt), oclacitinib (also known as APOQUEL®, including the maleate salt), baricitinib (also known as LY3009104, INCB-28050, and OLUMIANT®, including the phosphate salt), filgotinib (also known as G- 146034 and GLPG-0634), gandotinib (also known as LY-2784544), lestaurtinib (also known as CEP-701), mom
  • JAK3 inhibitor IV also known as ZM-39923, including the hydrochloride salt), atiprimod (including the dihydrochloride salt), FM-381, SAR20347, AZD4205, ARN4079, NIBR- 3049, PRN371, PF-06651600 (including the malonate salt), JAK3i, JAK3 inhibitor 31, PF- 06700841 (including the tosylate salt), NCI 153, EP009, Gingerenone A, JANEX-1 (also known as WHI-P131), cercosporamide, JAK3-IN-2, PF-956980, Tyk2-IN-30, Tyk2-IN-2, JAK3-IN1, WHI-P97, TG-101209, AZ960, NVP-BSK805 (including the dihydrochloride salt), NSC 42834 (also known
  • JAK inhibitors see, e.g., U.S. Pat. Nos. 9,198,911; 9,763,866; 9,737,469; 9,730,877; 9,895,301; 9,249,149; 9,518,027;
  • a microsphere of the present disclosure comprises more than one therapeutic compound or pharmaceutically acceptable salt thereof.
  • a microsphere of the present disclosure comprises a therapeutic compound or pharmaceutically acceptable salt thereof at a loading level of greater than 5% by total weight of the microsphere. In some embodiments, a microsphere of the present disclosure comprises a therapeutic compound or pharmaceutically acceptable salt thereof at a loading level of greater than 10% by total weight of the microsphere. In some embodiments, a microsphere of the present disclosure comprises a therapeutic compound or pharmaceutically acceptable salt thereof at a loading level of greater than 5%, 6%, 7%, 8%, 9%, 10%, or 11% by total weight of the microsphere. In some embodiments, a microsphere of the present disclosure comprises a therapeutic compound or
  • the present disclosure provides a plurality of microspheres (e.g, as described supra) characterized by a uniform size distribution.
  • a plurality of microspheres of the present disclosure is provided in which at least 90% of the microspheres of the plurality are between 16 and 28 pm in diameter.
  • a plurality of microspheres of the present disclosure is provided in which at least 90% of the microspheres of the plurality are within 6pm of a mean diameter.
  • a plurality of microspheres of the present disclosure is provided in which 90%-95% of the microspheres of the plurality are between 16 and 28 pm in diameter.
  • a plurality of microspheres of the present disclosure is provided in which at least 60% of the microspheres of the plurality are between 20 and 26pm in diameter. In some embodiments, a plurality of microspheres of the present disclosure is provided in which at least 60% of the microspheres of the plurality are within 3 pm of a mean diameter. In some embodiments, a plurality of microspheres of the present disclosure is provided in which 60%-70% of the microspheres of the plurality are between 20 and 26pm in diameter. In some embodiments, a plurality of microspheres of the present disclosure is provided in which at least 20% of the microspheres of the plurality are between 22 and 26pm in diameter. In some embodiments, a plurality of microspheres of the present disclosure is provided in which at least 20% of the
  • microspheres of the plurality are within 2pm of a mean diameter. In some embodiments, a plurality of microspheres of the present disclosure is provided in which 20%-30% of the microspheres of the plurality are between 22 and 26pm in diameter. In some embodiments, a plurality of microspheres of the present disclosure is provided in which at least 90% of the microspheres of the plurality are between 16 and 28 pm in diameter, at least 60% of the microspheres of the plurality are between 20 and 26pm in diameter, and/or at least 20% of the microspheres of the plurality are between 22 and 26pm in diameter.
  • a plurality of microspheres of the present disclosure is provided in which 90%-95% of the microspheres of the plurality are between 16 and 28 pm in diameter, 60%- 70% of the microspheres of the plurality are between 20 and 26pm in diameter, and/or 20%-30% of the microspheres of the plurality are between 22 and 26pm in diameter.
  • microspheres produced by any of the methods of the present disclosure, e.g ., as described in section I.
  • Certain aspects of the present disclosure relate to methods of treating a condition by administering to an individual (e.g, in need thereof) a therapeutically effective amount of a microsphere (see sections I and II) or pharmaceutical composition (see section IV) of the present disclosure.
  • the condition is associated with JAK activity or dysregulated JAK function, or is a condition for which a JAK inhibitor is a suitable therapeutic.
  • the condition is rheumatoid arthritis, psoriatic arthritis, or colitis (e.g, ulcerative colitis).
  • the condition is alopecia.
  • methods of treating alopecia by administering a microsphere of the present disclosure comprising a JAK inhibitor, or a pharmaceutical composition containing a microsphere of the present disclosure comprising a JAK inhibitor.
  • the administration is dermal or subdermal injection.
  • the JAK inhibitor inhibits JAK1, JAK2, and JAK3 (and optionally TYK2). In some embodiments, the JAK inhibitor inhibits JAK1. In some embodiments, the JAK inhibitor inhibits JAK3. In some embodiments, the JAK inhibitor inhibits JAK1 and JAK3. [0053] In some embodiments, the microsphere or composition is administered by injection, e.g ., subcutaneous or intramuscular injection. In some embodiments, the microsphere or composition allows for use of a smaller needle size and/or less frequent administration, e.g. , as compared to a reference microsphere (e.g, a double emulsion microsphere) comprising the same active pharmaceutical ingredient.
  • a reference microsphere e.g, a double emulsion microsphere
  • an“individual” is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual is a human.
  • compositions comprising a microsphere of the present disclosure (e.g, as described in section II above, or prepared by a method described in section I above).
  • the pharmaceutical compositions may find use, e.g, in any of the methods described in section III above.
  • composition or “pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
  • a pharmaceutical composition of the present disclosure comprises a microsphere of the present disclosure and a pharmaceutically acceptable carrier.
  • A“pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
  • pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, diluent, or preservative.
  • excipients are relatively inert substances that facilitate administration of a pharmacologically effective substance and can be supplied as liquid solutions or suspensions, as emulsions, or as solid forms suitable for dissolution or suspension in liquid prior to use.
  • the excipient is external to the microsphere.
  • an excipient can give form or consistency, or act as a diluent.
  • Suitable excipients include but are not limited to stabilizing agents, wetting and emulsifying agents, salts for varying osmolarity, encapsulating agents, pH buffering substances, and buffers.
  • excipients include any pharmaceutical agent suitable for injection which may be administered without undue toxicity.
  • compositions include, but are not limited to, sorbitol, any of the various TWEEN compounds, and liquids such as water, saline, glycerol and ethanol.
  • Pharmaceutically acceptable salts can be included therein, for example, mineral acid salts such as
  • the excipient is selected from acetate, citrate, lactate, polyols (e.g ., mannitol or glycerol), carboxy-methyl cellulose and hydroxy-prolyl cellulose, and glycine.
  • Formulations described herein may be utilized in depot form, e.g. injectable microspheres or implants.
  • pharmaceutically acceptable excipients may include pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers can be sterile liquids, such as water and oil, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, and the like. Saline solutions and aqueous dextrose, polyethylene glycol (PEG) and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Additional ingredients may also be used, for example preservatives, buffers, tonicity agents, antioxidants and stabilizers, nonionic wetting or clarifying agents, viscosity-increasing agents (e.g., carboxymethylcellulose or a poloxamer), and the like.
  • the kits described herein can be packaged in single unit dosages or in multidosage forms.
  • kits or articles further comprise a package insert with instructions for using the microspheres or pharmaceutical compositions related thereto, e.g, in any of the methods described in section III above.
  • Example 1 Preparation of single emulsion microspheres using charged polymers
  • Tofacitinib citrate:PLGA microspheres were generated according to the formulations shown in Table A. Concentrations refer to the mixture prior to extrusion.
  • microspheres were generated as follows. Tofacitinib citrate was dissolved in the solvent indicated in Table A (DMSO, DMA, DMF, or formic acid), and PLGA (502, 502H, 503H, or 504H) was dissolved in the solvent indicated in Table A (DCM, DMA, or DMF). For octreotide microspheres, octreotide was dissolved in ethanol, and PLGA was dissolved in methylene chloride.
  • samples were mounted to an aluminum stub using a carbon tab followed by gold sputter coating and SEM imaging.
  • samples were mixed with Loctite epoxy and allowed to cure overnight. The samples were then frozen using liquid nitrogen and cracked using a mortar and pestle. Cracked portions were then mounted to an aluminum stub using carbon tape and colloidal graphite and sputter coated with gold. Size distribution
  • Size distribution of microsphere populations was quantitated using automated image analysis.
  • Cell Profiler (cellprofiler.org) software was used to find and measure microsphere diameter based on light microscopy images.
  • the identifyPrimaryObjects module was used and calibrated with a micrometric scale. Starting with light microscopic images of microspheres, images were analyzed to automatically detect microsphere shape, fill in microsphere shapes, and measure microsphere dimensions.
  • tofacitinib citrate ethanol, methanol, acetone, acetonitrile, tetrahydrofuran (THF), triethylamine, methyl tert-butyl ether (MTBE), dichloromethane (DCM), acetic acid, formic acid, ethyl acetate, dimethylsulfoxide (DMSO), dimethylacetamide (DMA), dimethylformamide (DMF), water, methyl acetate, PEG 300, ethyl formate, benzyl alcohol, isopropyl acetate, anisole, butyl acetate, chloroform, pyridine, ethyl ether, ethyl butyrate, 1- methyl-2-pyrrolidone, hexane, n-heptane, and sulfolane.
  • solvents formic acid, ethyl acetate, dimethylsulfoxide (DMSO), dimethylacetamide (DMA),
  • Microspheres with up to 11.5% loading of tofacitinib were generated.
  • Table B summarizes the conditions that led to maximum loading levels observed in microspheres with tofacitinib citrate or octreotide.
  • tofacitinib-containing microspheres produced as described above were characterized by a more uniform size distribution (FIG. 1). 90-95% of tofacitinib microspheres had a diameter from 16-28 pm, with 60-70% of the microspheres having a diameter from 20-26 pm, and 20-30% of the microspheres having a diameter from 22-26 pm.
  • Tofacitinib-containing microspheres were also examined by light microscopy and scanning electron microscopy (SEM). A relatively homogeneous distribution of spherical microspheres was observed using light microscopy (FIG. 2). SEM revealed that these microspheres had an extremely smooth and uniform surface (FIG. 3). [0077]

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Abstract

La présente invention concerne des procédés de préparation de microsphères (par exemple des microsphères à émulsion unique) comprenant un composé thérapeutique ou un sel pharmaceutiquement acceptable de celui-ci et un polymère poly(acide lactique-co-glycolique) (PLGA) comprenant au moins une extrémité terminale hydrophile, ainsi que des microsphères et des compositions pharmaceutiques associées à celles-ci.
PCT/US2020/033834 2019-05-21 2020-05-20 Formulations de microsphères thérapeutiques contenant des polymères chargés WO2020236950A1 (fr)

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