WO2023096899A1 - Compositions pharmaceutiques à hydrogel - Google Patents

Compositions pharmaceutiques à hydrogel Download PDF

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Publication number
WO2023096899A1
WO2023096899A1 PCT/US2022/050717 US2022050717W WO2023096899A1 WO 2023096899 A1 WO2023096899 A1 WO 2023096899A1 US 2022050717 W US2022050717 W US 2022050717W WO 2023096899 A1 WO2023096899 A1 WO 2023096899A1
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pharmaceutical composition
derivative
hydrogel
tumor
methylcellulose
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PCT/US2022/050717
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English (en)
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Sena BISWAS
Michael J. Cooke
Molly S. Shoichet
Laura Smith
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Amacathera
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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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes

Definitions

  • This invention relates to combination pharmaceutical compositions.
  • Solid tumors are also notorious for cloaking themselves from the immune system; these immunologically “cold” tumors suppress inflammatory cues that would trigger immune attack and are often unresponsive to immunotherapies.
  • Single agent therapies are typically limited in efficacy for treating cancer, partially because multiple signalling pathways are aberrant in cancer. Additionally, systemically administered therapeutics can lead to major adverse effects. Hence, there remains needs to develop combinatorial therapeutic strategies for treating solid tumors with high efficiency and safety. There also remains needs to develop combination therapies formulations that provide a localized and sustained release of therapeutics.
  • the invention is based, in part, upon the development of new hydrogel pharmaceutical compositions and delivery vehicles useful for delivering combination therapies, e.g., for cancer.
  • the present disclosure provides pharmaceutical composition comprising: i) a hydrogel; ii) at least one small molecule therapeutic; and iii) at least one biologic therapeutic.
  • the hydrogel comprises one or more polymers each independently selected from the group consisting of agarose, alginate, carboxymethyl cellulose, carrageenan, collagen, chitosan, dextran, fibrin, gelatin, hyaluronan, hydroxypropyl methylcellulose, methylcellulose, polyacrylamide, polypeptides, polypropylene oxide, polyvinyl alcohol, poly(acrylates), polyethylene glycol), polyethylene oxide), poly(caprolactone), poly(lactide-co-glycolic acid), poly(N-isopropylacrylamide), poly(urethane), small intestinal submucosa, or derivatives, co-polymers, or mixtures thereof.
  • polymers each independently selected from the group consisting of agarose, alginate, carboxymethyl cellulose, carrageenan, collagen, chitosan, dextran, fibrin, gelatin, hyaluronan, hydroxypropyl methylcellulose, methylcellulose, polyacrylamide, polypeptides,
  • the hydrogel comprises hyaluronan or a derivative thereof and methylcellulose or a derivative thereof.
  • the pharmaceutical composition comprises about 0.1% to about 3% by weight hyaluronan or derivative thereof and about 0.1% to about 3% by weight of methylcellulose or derivative thereof.
  • the methylcellulose or derivative thereof has a viscosity of above 400 cP.
  • the hyaluronan or derivative thereof has a molecular weight between 100,000 Da and 7,000,000 Da and the methylcellulose or derivative thereof has a molecular weight between 2,000 Da and 1 ,000,000 Da.
  • the weight-to-weight ratio of the hyaluronan or derivative thereof and the methylcellulose or derivative thereof is between about 1 :1 to about 1 :20.
  • the pharmaceutical composition further comprising one or more microparticles or nanoparticles each comprising a biocompatible polymer, wherein the microparticles or nanoparticles each independently includes the small molecule therapeutic, the biologic therapeutic, or both or is empty.
  • the biocompatible polymer is selected from the group consisting of caprolactone (CL), chitosan, glycolide (GA), lactide (LA), polyamide, polyanhydride, polycaprolactone (PCL), polylactide-co-glycolide (PLGA), polylactic acid (PLA), polyethylene glycol (PEG), poly(alkyl cyanoacrylate) (PACA), poly(ester amide), poly(glycolic acid) (PGA), poly(ortho ester), poly(phosphoester) (PPE), hyaluronan, and gelatin.
  • the biocompatible polymer is PLGA.
  • the microparticles or nanoparticles are dispersed in the hydrogel.
  • the small molecule drug is a histone deacetylase (HDAC) inhibitor.
  • HDAC histone deacetylase
  • the HDAC inhibitor is selected from the group consisting of abexinostat, AES-350, AR-42, butyric acid, belinostat, CHR-3996, CKD-504, citarinostat, domatinostat, entinostat, fimepinostat, gavinostat, KA2507, mocetinostat, panobinostat, phenylbutyric acid, practinostat, QTX125, quisinostat, resminostat , RGFP966, ricolinostat, romidepsin, tacedinaline, tasquinimod, tefinostat, trichostatin A, tucidinostat, valproic acid, and vorinostat, or a derivative thereof.
  • the HDAC inhibitor is panobinostat or a derivative thereof.
  • the small molecule drug is encapsulated in the microparticle or nanoparticle.
  • the pharmaceutical composition comprises about 0.1% to about 40% by weight of the small molecule drug.
  • the biologic drug is a vascular endothelial growth factor (VEGF) antagonist.
  • the VEGF antagonist is selected from the group consisting of abicipar pegol, aflibercept, bevacizumab, brolucizumab, OPT-302, and ranibizumab. In some embodiments, the VEGF antagonist is bevacizumab.
  • the biologic drug is encapsulated in the microparticle or nanoparticle. In some embodiments, the biologic drug is not encapsulated in the microparticle or nanoparticle. In some embodiments, the biologic drug is electrostatically adsorbed to the microparticle or nanoparticle. In some embodiments, the pharmaceutical composition comprises about 0.1% to about 10% by weight of the biologic drug.
  • the pharmaceutical composition is suitable for administration to a patient by injection.
  • the composition pharmaceutical is capable of crossing the blood-brain barrier.
  • the present disclosure provides a delivery vehicle for delivering one or more therapeutic agents to the brain of a subject or for transporting across the bloodbrain barrier of a subject, comprising: i) a hydrogel; and ii) a plurality of a microparticle or nanoparticle comprising a biocompatible polymer.
  • the hydrogel comprises: a. hyaluronan or a derivative thereof; and b. methylcellulose or a derivative thereof.
  • the biocompatible polymer is PLGA.
  • the one or more therapeutic agents comprise a HDAC inhibitor, e.g., panobinostat or a derivative thereof.
  • the one or more therapeutics comprise a VEGF antagonist, e.g., bevacizumab or a derivative thereof.
  • the present disclosure provides a method of transporting one or more therapeutics across the blood-brain barrier of a subject, comprising administering to the subject a pharmaceutical composition disclosed herein.
  • the present disclosure provides a method of delivering one or more therapeutics to the brain of a subject, comprising administering to the subject a pharmaceutical composition disclosed herein.
  • the present disclosure provides a method of preventing, ameliorating, or treating tumor angiogenesis and/or tumor metastasis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein.
  • the present disclosure provides a method of preventing, ameliorating, or treating a solid tumor in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein.
  • the solid tumor is liver tumor, pancreatic tumor, lung tumor, breast tumor, prostate tumor, colorectal cancer, or central nervous system (CNS) tumor.
  • CNS central nervous system
  • the CNS tumor is selected from the group consisting of astrocytoma, glioblastoma, meningioma, oligodendroglioma, craniopharyngioma, ependymoma, germ cell tumor, pineal region tumor, medulloblastoma, primary CNS lymphoma, and primitive neuroectodermal tumor.
  • the CNS tumor is glioblastoma.
  • the pharmaceutical composition is administered by injection, e.g., intracavitary injection, intratumoral injection, or intralesional injection. In some embodiments, the pharmaceutical composition is administered intratumorally, subcutaneously, intradermally, or intramuscularly.
  • a hydrogel pharmaceutical composition comprising: a) a hydrogel comprising about 0.1% to about 3% methylcellulose or a derivative thereof, and about 0.1% to about 3% hyaluronan or a derivative thereof; b) at least one antibody; and c) at least one small molecule.
  • the pharmaceutical composition is suitable for administration to a patient by injection.
  • the pharmaceutical composition is administered via intracavitary administration, intratumoral administration, or intralesional administration.
  • the antibody is bevacizumab and the small molecule is panobinostat.
  • the therapeutic agents are biosimilars or derivatives of bevacizumab and panobinostat.
  • the antibody and/or small molecule is encapsulated or electrostatically adsorbed to particulate preparations of biocompatible polymers.
  • the biocompatible polymer is poly(lactic-co-glycolic acid) PLGA.
  • the methylcellulose or derivative thereof has viscosity above 400 cP.
  • the composition comprises between 0.1 and 10 percent by weight antibody relative to the combined weight of the methylcellulose or a derivative thereof and hyaluronan or derivative thereof.
  • the composition comprises between 0.1 and 40 percent by weight small molecule relative to the combined weight of the methylcellulose or a derivative thereof and hyaluronan or derivative thereof.
  • the pharmaceutical composition is a sustained release composition.
  • a method of treating or preventing tumour metastasis comprising administering a therapeutically effective amount of the hydrogel pharmaceutical composition described herein to a subject in need thereof.
  • the hydrogel pharmaceutical composition is administered by injection.
  • the present disclosure relates to hydrogel pharmaceutical compositions for delivering combination therapies to treat or ameliorate cancers.
  • use of pharmaceutical compositions disclosed herein result in localized delivery of the active pharmaceutical ingredients (APIs) to the site where they are needed.
  • use of pharmaceutical compositions disclosed herein result in reduced off-target side effects and improved efficacy.
  • the terms “about,” “approximately,” and “comparable to,” when used in reference to a value refer to a value that is similar to the referenced value in the context of that referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by "about,” “approximately,” and “comparable to” in that context.
  • the terms "about,” “approximately,” and “comparable to” may encompass a range of values that within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.
  • the terms “antagonist,” “antagonistic,” “neutralizing,” or “blocking,” when used in reference to a biologic therapeutic is intended to refer to a biologic therapeutic whose binding to its target results in inhibition of at least some of the biological activity of the target.
  • a “hydrogel” refers to a three-dimensional network of hydrophilic polymers, which can be natural or synthetic, that are able to swell in water or an aqueous environment without dissolution. Such hydrophilic polymers are crosslinked physically and chemically.
  • An “injectable hydrogel” or “injectable hydrogel polymer,” as used herein, refers to a solution that is capable of forming a hydrogel after being injected into a subject (e.g., a mammal).
  • the injectable hydrogel described herein may have a gelling temperature range of from about 10°C to about 70° C.
  • microparticles and “nanoparticles” refer to particles between 0.1 and 100 pm and between 1 to 100 nm in size, respectively.
  • microparticles include microspheres, which are typically solid spherical microparticles.
  • microparticles include microcapsules, which are spherical microparticles typically having a core of a different polymer, drug, or composition.
  • the phrases “therapeutically effective amount” and “effective amount” are used interchangeably and refer to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.
  • a effective amount may vary according to factors such as the type of disease (e.g., cancer), disease state, age, sex, and/or weight of the subject, and the ability of a therapeutic agent(s) (e.g., a small molecule therapeutic and/or a biologic therapeutic), or pharmaceutical composition thereof, to elicit a desired response in the subject.
  • An effective amount may also be an amount for which any toxic or detrimental effects of the therapeutic agent(s) or pharmaceutical composition thereof are outweighed by therapeutically beneficial effects.
  • beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition (e.g., of a primary cancer and/or of a secondary metastases); delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable.
  • beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition (e.g., of a primary cancer and/or of a secondary metastases); delay or slowing the progress of the disease, disorder, or condition; amelioration
  • “Ameliorating” a disease, disorder, or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.
  • compositions comprising: i) a hydrogel; ii) at least one small molecule therapeutic; and iii) at least one biologic therapeutic.
  • the pharmaceutical composition comprises about 0.1% to about 6% hydrogel.
  • the hydrogel comprises hyaluronan or a derivative and methylcellulose or a derivative.
  • the pharmaceutical composition comprises about 0.1% to about 3% by weight hyaluronan or derivative thereof.
  • the pharmaceutical composition comprises about 0.1% to about 3% by weight methylcellulose or derivative thereof.
  • the pharmaceutical composition comprises about 0.1% to about 40% by weight of the small molecule drug. In some embodiments, the pharmaceutical composition comprises about 0.1% to about 10% by weight of the small molecule drug. [0032] In some embodiments, the pharmaceutical composition further comprises one or more microparticles or nanoparticles each comprising a biocompatible polymer. In some embodiments, the pharmaceutical composition comprises about 1% to about 20% by weight of the biocompatible polymer. In some embodiments, the microparticles or nanoparticles each independently encapsulates the small molecule therapeutic, the biologic therapeutic, or both or is empty. In some embodiments, microparticles or nanoparticles comprise about 0.1% to about 30% by weight of the small molecule therapeutic and biologic therapeutic.
  • the pharmaceutical composition is administered adjacent to cancerous tissues at the time of tumor resection.
  • the pharmaceutical composition exhibits improved safety and effectiveness compared to a reference composition comprising the same small molecule therapeutic and biologic therapeutic.
  • the pharmaceutical composition targets multiple cancer pathways.
  • the pharmaceutical composition may be prepared by a method comprising steps including: physical blending of hyaluronan and methylcellulose in an aqueous solution; after hyaluronan and methylcellulose are dispersed in the solution and allowed to dissolve, an antibody and a small molecule, suitably in particle form, may be dispersed in the mixture; the pharmaceutical compositions may be sterilized by autoclave, gamma sterilization, filter sterilization or aseptically prepared.
  • the preparation method comprises encapsulating the small molecule therapeutic and/or biologic therapeutic in the microparticle or nanoparticle prior to dispersing it in the HAMC hydrogel.
  • the small molecule therapeutic and/or biologic therapeutic is encapsulated in a biodegradable polymer (e.g., poly(lactic-co- glycolic acid) (PLGA)).
  • PLGA poly(lactic-co- glycolic acid)
  • the hydrogel comprises an inverse thermal gelling polymer and an anionic gelling polymer.
  • an anionic gelling polymer of the present disclosure has a preferable molecular weight between about 100,000 and about 7,000,000 Da.
  • anionic gelling polymers include alginate, carboxymethylcellulose, hyaluronan (hyaluronic acid, HA), or derivatives, co-polymers, or mixtures thereof.
  • the anionic gelling polymer is hyaluronan.
  • Hyaluronan is a linear polysaccharide composed of repeating disaccharide units of N-acetyl-glycosamine and D-glucoronic acid.
  • Hyaluronan is a highly viscoelastic and shear-thinning fluid that has been used for drug delivery, tissue engineering applications as well as for soft tissue augmentation.
  • Hyaluronan is known to have wound-healing effects such as antiinflammation, as well as to minimize tissue adhesion and scar formation. It is degraded enzymatically by hyaluronidase, which can be produced by all cells. Its polymeric chains, of lengths 10-15 thousand disaccharides, form random coils with large spheroidal hydrated volumes of up to 400-500 nm in diameter. Because of the high solubility of hyaluronan in water, it must be chemically modified to form a gel. Reactions can occur at the carboxyl group, or the hydroxyl group of hyaluronan and also at the amino group once the N-acetyl group is removed.
  • Hyaluronan is injectable upon an application of force to a syringe because the shear-thinning properties of hyaluronan cause the polymer chains to straighten and align themselves permitting flow through the needle. Hyaluronan then returns to its gel structure upon exiting the needle as the polymeric chains once again become entangled amongst themselves.
  • hyaluronan is described as a shear-thinning polymer.
  • a disclosed anionic gelling polymer may be chemically modified to result in derivatives bearing different chemical and/or physical properties and functions. Such modification may be achieved using known methods in the art.
  • the anionic gelling polymer is chemically modified to introduce functional groups, such as carboxylic acid, primary amine, aldehyde, hydrazide, maleimide, thiol, furan, alkyne, azide, alkene, urethane, or primary alcohol.
  • chemical modifications of the anionic gelling polymer permit subsequent biological utility, for example, forming covalent linkage with a therapeutic agent.
  • the anionic gelling polymer is a hyaluronan derivative.
  • inverse thermal gelling polymers described herein are capable of gelling upon an increase in temperature.
  • inverse thermal gelling polymers are of a molecular weight between about 2000 and about 1 ,000,000 Da.
  • non-limiting examples of inverse thermal gelling polymers include methylcellulose (MC), a chitosan and a-glycerophosphate solution, collagen, tri-block copolymer of polyethylene glycol)-poly(lactic-co-glycolic acid)-poly(ethylene glycol), tri-block copolymer of polypropylene glycol)-poly(ethylene glycol)-poly (propylene glycol), poly(N- isopropyl acrylamide), agarose, copolymers of poly-N-isopropylacrylamide, polysaccharides and mixtures thereof.
  • the inverse thermal gelling polymer is methylcellulose.
  • Methylcellulose is a of derivative of cellulose, where the one or more hydroxyl groups on cellulose are substituted by methoxide, and gels upon increase in temperature.
  • the degree of substitution of hydroxyl groups with methoxide groups is between 1 .4-1 .9
  • methylcellulose has inverse thermogelling properties whereby it gels upon an increase of temperature. As the temperature increases, hydrogen bonds with the surrounding solvent break and hydrophobic junctions form to produce a gel.
  • Methylcellulose generally forms weak gels at 37°C when in water, but the gelation temperature can be decreased by an increase in salt concentration.
  • Methylcellulose has previously been considered as a scaffold for experimental traumatic brain injury where in vivo tests in rats indicated biocompatibility over a span of two weeks. Methylcellulose has also been used as a scaffold in the peripheral nervous system for nerve regeneration with promising results, without any adverse pathological reactions over 8 weeks. Although it is not found to degrade enzymatically, the weak gel structure does dissolve at 37°C and swells minimally.
  • a disclosed inverse thermal gelling polymer may be chemically modified to result in derivatives bearing different chemical and/or physical properties and functions. Such modification may be achieved using known methods in the art.
  • the inverse thermal gelling polymer is chemically modified to introduce functional groups, such as carboxylic acid, primary amine, aldehyde, hydrazide, maleimide, thiol, furan, alkyne, azide, alkene, urethane, or primary alcohol.
  • chemical modifications of the anionic gelling polymer permit subsequent biological utility, for example, forming covalent linkage with a therapeutic agent.
  • the inverse thermal gelling polymer is a methylcellulose derivative.
  • a hydrogel of the present disclosure comprises hyaluronan or a derivative thereof and methylcellulose or a derivative thereof.
  • the hyaluronan or derivative thereof and the methylcellulose or derivative thereof are blended to form a disclosed hydrogel.
  • the combination of an aqueous solution of methylcellulose and lyophilized hyaluronan results in dispersal of hyaluronan within the solution; the resulting polymer matrix is a fast-gelling polymer and is referred to as HAMC.
  • HAMC does not flow significantly at room temperature and is unique amongst physical gelling polymers in its ability to return to its initial viscosity more rapidly.
  • physical gelling polymers undergo a phase transition from a solution to a gel after injection, whereas HAMC is a gel both prior to and following injection.
  • the shear thinning properties of hyaluronan enable HAMC gel to be injectable, while the thermal gelling properties of methylcellulose aid in returning the HAMC to a gel following injection.
  • the properties of HAMC gel are highly sensitive to the amount of hyaluronan, and altering the concentration of hyaluronan may affect the injectability of the polymer matrix and the gelation rate. For example, higher molecular weights of hyaluronan are likely to dissolve more slowly and may have improved shear thinning properties.
  • a hydrogel of the present disclosure is a HAMC hydrogel.
  • concentrations of hyaluronan and methylcellulose are varied to adjust the properties (e.g., for enhanced injection suitability) of the HAMC gel.
  • a HAMC hydrogel of the present disclosure may be prepared by the steps involving preparing a sterile solution of methylcellulose in a buffered salt solution, which is cooled to 4° C prior to the addition of sterile; and lyophilizing hyaluronan which dissolves over time.
  • the aqueous solution of hyaluronan or a derivative thereof and methylcellulose or other cellulose derivative may be selected from the group comprising water, saline, artificial cerebrospinal fluid, and buffered solutions.
  • a hydrogel of the present disclosure comprises hyaluronan or a derivative from about 100 to about 7,000 kg/mol and methylcellulose or a derivative thereof from about 1 ,500 to about 3,000 kg/mol. In some embodiments, the hydrogel comprises hyaluronan or a derivative thereof from about 1 ,500 to about 3,000 kg/mol and methylcellulose or a derivative thereof from about 10 to about 400 kg/mol. When other combinations are used to form the hydrogel composite these amounts can be adjusted.
  • a hydrogel of the present disclosure comprises hyaluronan or a derivative and methylcellulose or a derivative at a ratio from about 1 :20 to about 1 :1 w/w, such as from about 1 :5 to about 2:3 w/w.
  • a hydrogel of the present disclosure comprises about 0.5% to about 5.0% by weight hyaluronan or a derivative thereof and about 1 .0% to about 10% by weight methylcellulose or a derivative thereof. In some embodiments, the hydrogel comprises from about 1 .0% to about 2.0% by weight hyaluronan or a derivative thereof and from about 3.0% to about 7.0% by weight methylcellulose or a derivative thereof may comprise.
  • Therapeutic agents may be any substances useful for the treatment of a disease, disorder, or condition.
  • the therapeutic agent is a small molecule therapeutic.
  • the therapeutic agent is a biologic therapeutic.
  • the biologic therapeutic comprises a protein or polypeptide.
  • the biologic therapeutic is selected from the group consisting of antibodies or antigen binding fragments thereof, nanobodies, affibodies, anticalins, and consensus sequences from Fibronectin type III domains.
  • the therapeutic agent inhibits histone deacetylase (HDAC) or vascular endothelial growth factor (VEGF).
  • HDAC histone deacetylase
  • VEGF vascular endothelial growth factor
  • the therapeutic agent at least partially inhibits one or more functions of HDAC or VEGF.
  • the therapeutic agent impairs signaling downstream of HDAC or VEGF, e.g., resulting in the suppression of tumors (e.g., brain tumors).
  • the therapeutic agent is directly dispersed in the hydrogel described herein. In some embodiments, the therapeutic agent is included (encapsulated) in a microparticle or nanoparticle described herein.
  • Histone deacetylases are a class of enzymes that remove acetyl groups from histone proteins on DNA, making the DNA less accessible to transcription factors. HDACs regulate the expression and activity of numerous proteins involved in both cancer initiation and cancer progression. HDAC inhibitors have been explored in various cancers and shown to have direct anti-cancer effects on tumor cells, including induction of apoptosis, cell cycle arrest, senescence, and autophagy, as well as increasing tumour immunogenicity through increased expression of putative tumour antigens. HDAC inhibitors have also been shown to provide anti-cancer effects through regulation of non-tumour cells present in the tumour microenvironment, including promotion of tumour cell killing by NK and cytotoxic T cells, and suppression of pro-angiogenic genes to inhibit angiogenesis.
  • Panobinostat is a potent HDAC inhibitor and approved for use in patients with multiple myeloma. It has not been successful in treating solid tumors, such as glioblastoma. Many other HDAC inhibitors are also being studied in various clinical trials, including abexinostat (PCI-24781 , CRA-024781), AES-350, AR-42, butyric acid, belinostat (PXD101 , PX105684), CHR-3996, CKD-504, citarinostat (ACY-241), domatinostat (4SC-202), entinostat (SNDX-275, MS-275), fimepinostat (CUDC-907), gavinostat (ITF2357), KA2507, mocetinostat (MGCD0103), panobinostat (LBH589), phenylbutyric acid, practinostat (SB939), QTX125, quisinostat (JNJ-26481585)
  • VEGF is a regulator of angiogenesis, vasculogenesis, and vascular permeability.
  • VEGFR VEGF/VEGF receptor
  • Aflibercept a VEGF trap, is a fusion protein between the Fc portion of human IgG 1 and the extracellular domains of VGEFR1 and VEGFR2.
  • OPT-302 is a VEGF-C/D trap.
  • Abicipar pegol is a DARPin (Designed Ankyrin Repeat Proteins) directed to bind all VEGF-A isoforms.
  • anti-VEGF antibodies include bevacizumab, brolucizumab, and ranibizumab.
  • Exemplary small molecule inhibitors of VEGF/VEGFR includes pazopanib, sunitinib, bevacizumab, sorafenib, regorafenib, cabozantinib, lenvatinib, ponatinib, cabozantinib, axitinib, tivozanib, and vandetanib.
  • microparticles or nanoparticles of the present disclosure comprises biocompatible polymers.
  • the microparticles or nanoparticles are formed by the biocompatible polymers.
  • the microparticles or nanoparticles include (encapsulate) one or more therapeutic agents.
  • biocompatible polymers suitable for forming the described microparticles or nanoparticles are biodegradable.
  • the degradable polymers include, for example, polyesters such as polylactide, polyglycolide, copolymers of lactide and glycolide, polyhydroxybutyrate, polycaprolactone, copolymers of lactic acid and lactone, copolymers of lactic acid and PEG, copolymers of a-hydroxy acids and a-amino acids (polydepsipeptides), polyanhydrides, polyorthoesters, polyphosphazenes, copolymers of hydroxybutyrate and hydroxyvalerate, polyethylene carbonate), copoly(ethylene carbonate), polyethylene terephthalate, lactide homopolymers poly(L-lactide), poly(D,L- lactide), and copolymers of lactide and glycolide such as 50:50 poly(DL lactide co- glycolide)(PLG), and poly(lactic-co-glycolic acid) (PLGA), or derivatives, copolymers or mixtures thereof
  • polyesters
  • the biocompatible polymers are water soluble polymers, such as polyethylene glycol (PEG), poly(oxyethylene oxide) (PEG), poly(oxyethylene)- poly(oxypropylene) (PEO-PPO) block copolymers such as tri-block PEO-PPO-PEO copolymers (Poloxamers, Pluronics) and tetra-functional block copolymers derived from the sequential addition of propylene oxide and ethylene oxide to ethylene diamine (Poloxamines, Tetronics), copolymers of PEG with poly(lactic acid), oligomers of poly(lactic acid), lactides, copolymers of PEG and amino acids, and conjugates of PEG with polysaccharides, proteins or collagen, or derivatives, copolymers or mixtures thereof.
  • PEG polyethylene glycol
  • PEG poly(oxyethylene oxide)
  • PEO-PPO poly(oxypropylene)
  • block copolymers such as tri-block PEO-PPO-PEO copolymers
  • biocompatible polymers suitable for forming the described microparticles or nanoparticles are non-degradable.
  • the non- degradable polymers include, for example, cellulose, starch, polystyrene, polyethylene, polypropylene, and alkylated poly(acrylates), or derivatives, copolymers or mixtures thereof.
  • the biocompatible polymer is PLGA.
  • the hydrophobic polymeric particles may have particle sizes selected from particle sizes of about 150 nm to about 40 pm, and more particularly, from about 220 nm to about 830 nm.
  • the particle sizes are selected to provide the desired release profile.
  • a suitable sustained release profile has been found to be provided by dispersing polymeric particles selected from particle sizes of from about 220 nm to about 37 pm.
  • microparticles e.g., microspheres
  • nanoparticles are known in the art, including, for example, single or double emulsion steps followed by solvent removal. Solvent removal may be accomplished by extraction, evaporation or spray drying among other methods.
  • the polymer is dissolved in an organic solvent that is at least partially soluble in the extraction solvent such as water.
  • the therapeutic agent either in soluble form or dispersed as fine particles, is then added to the polymer solution, and the mixture is dispersed into an aqueous phase that contains a surface-active agent such as poly (vinyl alcohol).
  • the resulting emulsion is added to a larger volume of water where the organic solvent is removed from the polymer/bioactive agent to form hardened microparticles.
  • the polymer is dissolved in a volatile organic solvent.
  • the therapeutic agent either in soluble form or dispersed as fine particles, is then added to the polymer solution, and the mixture is suspended in an aqueous phase that contains a surface-active agent such as poly (vinyl alcohol).
  • a surface-active agent such as poly (vinyl alcohol).
  • the resulting emulsion is stirred until most of the organic solvent evaporates, leaving solid microspheres.
  • the polymer is dissolved in a suitable solvent, such as methylene chloride (e. g., 0.04 g/mL).
  • a suitable solvent such as methylene chloride (e. g., 0.04 g/mL).
  • a known amount of bioactive molecule (drug) is then suspended (if insoluble) or co-dissolved (if soluble) in the polymer solution.
  • the solution or the dispersion is then spray-dried.
  • Microspheres ranging in diameter between one and ten microns can be obtained with a morphology, which depends on the selection of polymer.
  • microparticles or nanoparticles of the present disclosure are about 150 nm to about 40 pm in size. In some embodiments, microparticles or nanoparticles of the present disclosure are about 220 nm to about 37 pm in size. In some embodiments, microparticles or nanoparticles of the present disclosure are about 220 nm to about 830 nm in size. Delivery Vehicle
  • the present disclosure provides delivery vehicles comprising a hydrogel and a plurality of a microparticle or nanoparticle comprising a biocompatible polymer.
  • the delivery vehicle comprises a hydrogel described herein (e.g., comprising hyaluronan or a derivative thereof and methylcellulose or a derivative thereof) and a microparticle or nanoparticle described herein (e.g., a microparticle or nanoparticle formed by PLGA).
  • a hydrogel described herein e.g., comprising hyaluronan or a derivative thereof and methylcellulose or a derivative thereof
  • a microparticle or nanoparticle described herein e.g., a microparticle or nanoparticle formed by PLGA.
  • provided delivery vehicles are for delivering one or more therapeutic agents to the brain of a subject. In some embodiments, provided delivery vehicles are for transporting across the blood-brain barrier of a subject.
  • the delivery vehicle delivers the one or more therapeutic agents into a fluid-filled (or partially-filled) cavity.
  • a fluid-filled (or partially-filled) cavity include all cavities throughout the body, including but not limited to the intrathecal space and the intra-articular cavity.
  • the delivery vehicle is suitable to deliver via injection, transdermal administration, oral administration, intranasal administration, vaginal administration, or buccal administration. In some embodiments, the delivery vehicle is suitable to deliver the one or more therapeutic agents via injection. In some embodiments, the injection is administered subcutaneously, intrathecally, intratumorally, intramuscularly, intraarticularly, or intravenously. In some embodiments, the injection is through a fine needle which allows for a minimally invasive surgery.
  • the delivery vehicle is capable of locally delivering the one or more therapeutic agents. In some embodiments, the delivery vehicle is capable of fast gelling.
  • the delivery vehicle exhibits minimal swelling. In some embodiments, the delivery vehicle does not cause and causes minimal spinal cord compression.
  • the delivery vehicle exhibits minimal or no cell adhesion. In some embodiments, the delivery vehicle does not cause or causes minimal cellular invasion or scar formation.
  • the delivery vehicle causes minimal foreign-body reaction.
  • the delivery vehicle is degradable in the subject.
  • the delivery vehicle provides sustained release of the therapeutic agent(s).
  • components of the delivery vehicle may be modified to alter the degradation rate, thereby modulating the rate of release of the therapeutic agent(s) comprised in the delivery vehicle.
  • the modification may involve addition of salts to alter the pH.
  • the modification may be formulating a more stable gel for slower degradation, e.g., via crosslinking comprised polymers.
  • the modification may be increasing the hydrophobicity of hyaluronan, e.g., via modifying the carboxyl group of hyaluronan with acetic hydrazide using coupling agents.
  • the sustained release may be enhanced taking advantage of ionic interactions between the agent and the polymer.
  • the highly negatively charged anionic gelling polymer engages in ionic interactions with positively charged molecules.
  • the charge can be modified with the use of charged stabilizers.
  • Cationic particles or a mixture of cationic and anionic particles are used within the anionic gelling polymer to prevent the particles from dispersing away from the gel, as well as to promote increased gel strength through ionic crosslinks. Methods for incorporating cationic or cationic/anionic charge stabilizers into pharmaceutical compositions may be employed and are known to those of skill in the art.
  • the drug release is modified by tethering or covalently bonding the therapeutic agent(s) to the polymer comprised in the delivery vehicle.
  • the agent releases from the hydrogel composite upon breakage of the covalent bond or upon dissolution of the chain from the hydrogel composite network.
  • Methods of covalently bonding pharmaceutical agents to polymers may be employed and are known to those of skill in the art.
  • the present disclosure provides methods of transporting one or more therapeutics across the blood-brain barrier of a subject and delivering one or more therapeutics to the brain of a subject, comprising administering to the subject a pharmaceutical composition as disclosed herein. Also provided herein are methods of preventing, ameliorating, or treating tumor metastasis and central nervous system (CNS) tumor, comprising administering to a subject in need thereof a pharmaceutical composition as disclosed herein.
  • CNS central nervous system
  • a pharmaceutical composition (e.g., comprising one or more therapeutic agents) is administered to a subject.
  • the subject is a mammal, e.g., a human.
  • the subject has cancer or is at risk of developing cancer.
  • the subject may have been diagnosed with cancer, e.g., primary cancer or a metastatic cancer.
  • the subject may be receiving or have received cancer treatment, e.g., cancer surgery.
  • Provided pharmaceutical compositions may prevent or reduce further growth of the cancer and/or otherwise ameliorate the cancer (e.g., prevent or reduce metastases) or prevent cancer recurrence.
  • the subject does not have cancer but has been determined to be at risk of developing cancer (e.g., recurrent cancer) , e.g., because of the presence of one or more risk factors such as environmental exposure, presence of one or more genetic mutations or variants, family history, etc.
  • the subject has not been diagnosed with cancer.
  • the subject is in complete or partial cancer remission.
  • the cancer is any cancer that is mediated by HDAC and/or VEGF or HDAC- and/or VEGF-related signaling pathways.
  • the cancer is solid tumor.
  • the cancer is CNS tumor, e.g., astrocytoma, glioblastoma, meningioma, oligodendroglioma, craniopharyngioma, ependymoma, germ cell tumor, pineal region tumor, medulloblastoma, primary CNS lymphoma, and primitive neuroectodermal tumor.
  • the cancer is glioblastoma.
  • compositions thereof disclosed herein may be administered by any routes of administration, including systemic and local routes of administration.
  • Systemic administration routes include parenteral routes (e.g., injection, infusion, or implantation) and enteral routes (e.g., absorption of the drug through the gastrointestinal tract).
  • Local administration routes include topical administration, intraarticular administration, intranasal administration, intrathecal administration, inhalation, transdermal administration, and ocular drops.
  • the pharmaceutical compositions are administered by injection.
  • the injection is administered to the brain, subcutaneously, intrathecally, intratumorally, intramuscularly, intraarticularly, or intravenously.
  • the injection is administered by a syringe, via a catheter or other device.
  • the injection is administered by ejecting the material from a syringe without a needle, topically, or into an open wound in some embodiments.
  • the composition can operate as a depot injection, the composition forming a localized mass, which is gradually absorbed by surrounding tissue.
  • the composition is administered by a single injection and is gradually absorbed by the surrounding tissue over a period of time, e.g., 1 month.
  • Therapeutically effective amounts may be administered via a single dose or via multiple doses (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten doses).
  • any of a variety of suitable therapeutic regimens may be used, including administration at regular intervals (e.g., once every other day, once every three days, once every four days, once every five days, thrice weekly, twice weekly, once a week, once every two weeks, once every three weeks, etc.).
  • the dosage regimen (e.g., amounts of each therapeutic, relative timing of therapies, etc.) that is effective in methods of treatment may depend on the severity of the disease or condition and the weight and general state of the subject.
  • the therapeutically effective amount of a particular composition comprising a therapeutic agent applied to mammals can be determined by the ordinarily-skilled artisan with consideration of individual differences in age, weight, and the condition of the mammal.
  • Therapeutically effective and/or optimal amounts can also be determined empirically by those of skill in the art.
  • administration results in a therapeutic effect in the subject.
  • a single administered dose of a pharmaceutical composition as described herein provides a therapeutic effects for a period of greater than 24 hours, for example, greater than 1 week, greater than 1 month, or greater than 3 months.
  • administration results in a measurable improvement in the subject.
  • this improvement may include any or any combination of tumor growth inhibition, tumor growth reduction, tumor regression, inhibition or reduction of metastases, prevention of recurrence, improved survival, or improvement in any clinical sign indicative of cancer status or progression.
  • PLGA poly(lactic-co-glycolic acid)
  • nanoparticles encapsulating small molecules were formed by oil-in-water emulsion-solvent evaporation. Briefly, 120mg of PLGA, 0.05 wt% Pluronic F-127 and 60mg of Panobinostat were dissolved in 500 pL DMSO. 1 mL of chloroform was added and vortexed. The solution was then added to 10mL of hardening bath (2% PVA in water) and sonicated to create an emulsion.
  • PLGA nanoparticles encapsulating antibodies were formed by water/oil/water double emulsion-solvent evaporation. Briefly, 120 mg PLGA and 0.05 wt% Pluronic® NF-127 were dissolved in 900 pL dichloromethane (DCM) and vortexed with 100 pL 120 mg/mL human serum albumin (HSA) in artificial cerebrospinal fluid (aCSF) (149 mm NaCI, 3 mM KCI, 0.8 mm MgCI 2 , 1.4 mM CaCI 2 , 1.5 mM Na 2 HPO 4 , 0.2 mm NaH 2 PO 4 , pH 7.4) to achieve 10% w/w BSA/PLGA in the final formulation.
  • DCM dichloromethane
  • HSA human serum albumin
  • aCSF artificial cerebrospinal fluid
  • Antibodies to be encapsulated were dissolved in the solution, followed by 2 minutes sonication on ice. The resulting emulsion was then added to 3 mL 2.5% w/v PVA, vortexed, and sonicated for 2 minutes on ice, and was subsequently added to a hardening bath of PVA and stirred for a minimum of 4 h to allow the DCM to evaporate. The resulting nanoparticles were washed four times by ultracentrifugation, lyophilized, and stored at -20°C. The size of the nanoparticles was determined by dynamic light scattering. [0102] EXAMPLE 3 - Preparation of hyaluronan-methylcellulose (HAMC) hydrogel/PLGA nanoparticle composite
  • methyl cellulose (MC) and sodium hyaluronate were dissolved in aCSF using a dual asymmetric centrifugal mixer to a final concentration of 2.8% w/v hyaluronic acid (HA) and 6% w/v MC.
  • PLGA nanoparticles were dispersed in aCSF at 2x desired concentration by 5 min of bath sonication.
  • Composite HAMC hydrogel was formed by blending the PLGA nanoparticle dispersion and HAMC at a 1 :1 ratio using a dual asymmetric centrifugal mixer.

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Abstract

L'invention concerne une composition pharmaceutique à hydrogel (par exemple, un hydrogel de hyaluronane-méthyl cellulose) comprenant au moins un agent thérapeutique biologique (par exemple, un anticorps) et au moins un agent thérapeutique à petites molécules. L'agent thérapeutique biologique et/ou l'agent thérapeutique à petites molécules peut être dispersé dans un polymère biocompatible tel que le poly(acide lactique-co-glycolique) (PLGA).
PCT/US2022/050717 2021-11-24 2022-11-22 Compositions pharmaceutiques à hydrogel WO2023096899A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110033540A1 (en) * 2007-02-05 2011-02-10 George Daniloff Polymer formulations for delivery of bioactive agents
US20150290337A1 (en) * 2012-10-11 2015-10-15 Ascendis Pharma A/S Diagnosis, prevention and treatment of diseases of the joint
US20200031930A1 (en) * 2016-08-30 2020-01-30 Dana-Farber Cancer Institute, Inc. Drug delivery compositions and uses thereof
US20210100744A1 (en) * 2018-05-11 2021-04-08 North Carolina State University Bioresponsive hydrogel matrixes and methods of use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110033540A1 (en) * 2007-02-05 2011-02-10 George Daniloff Polymer formulations for delivery of bioactive agents
US20150290337A1 (en) * 2012-10-11 2015-10-15 Ascendis Pharma A/S Diagnosis, prevention and treatment of diseases of the joint
US20200031930A1 (en) * 2016-08-30 2020-01-30 Dana-Farber Cancer Institute, Inc. Drug delivery compositions and uses thereof
US20210100744A1 (en) * 2018-05-11 2021-04-08 North Carolina State University Bioresponsive hydrogel matrixes and methods of use

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