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WO2025184656A1 - Nanosuspensions de linsitinib pour administration locale - Google Patents

Nanosuspensions de linsitinib pour administration locale

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Publication number
WO2025184656A1
WO2025184656A1 PCT/US2025/018174 US2025018174W WO2025184656A1 WO 2025184656 A1 WO2025184656 A1 WO 2025184656A1 US 2025018174 W US2025018174 W US 2025018174W WO 2025184656 A1 WO2025184656 A1 WO 2025184656A1
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WO
WIPO (PCT)
Prior art keywords
linsitinib
suspension
nano
lin
formulation
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/US2025/018174
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English (en)
Inventor
Laura ENSIGN-HODGES
Yub Raj NEUPANE
Fatemeh RAJAII
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Johns Hopkins University
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Johns Hopkins University
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Publication of WO2025184656A1 publication Critical patent/WO2025184656A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • 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

Definitions

  • This invention is generally in the field of pharmaceutical formulations for treatment of adipose tissue and for ophthalmologic conditions associated with IGF1-R related thyroid eye disease, and specifically to nano and microsuspension formulations of linsitinib.
  • Obesity is a complex metabolic disorder characterized by excessive accumulation of white adipose tissue, leading to a range of health complications.
  • Clinically, obesity is defined by a body mass index (BMI) of >30 kg/m 2 .
  • BMI body mass index
  • WHO World Health Organization
  • epidemiological data estimated that more than 1.9 billion adults worldwide were classified as overweight, with a significant portion meeting the criteria for obesity.
  • Obesity is a major risk factor for numerous chronic diseases, including hypertension, dyslipidemia, insulin resistance (IR), type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, and various forms of cancer. These conditions contribute to increased morbidity and mortality.
  • IGF insulin-like growth factor
  • the IGF system in conjunction with the growth hormone (GH) axis, regulates metabolism, body composition, aging, and cellular growth.
  • IGF-1 a key anabolic hormone primarily secreted by the liver, is synthesized and released in response to GH signaling.
  • GH growth hormone
  • the IGF system is further characterized by a reduction in IGF-binding protein- 1 (IGFBP-1), which is suppressed in response to elevated insulin levels. This disruption is predictive of future metabolic disease, as lower IGFBP-1 levels have been linked to an increased risk of developing T2DM.
  • visceral adiposity, hepatic steatosis, and chronic inflammation contribute to an altered IGF system profile in individuals with metabolic syndrome and T2DM, making it a potential target for therapeutic intervention.
  • TED Thyroid Eye Disease
  • IGF-1R IGF-1 receptor
  • TSHR-Abs thyroid-stimulating hormone receptor autoantibodies
  • teprotumumab a monoclonal antibody that inhibits IGF-1R signaling, has demonstrated clinical efficacy in reducing disease severity.
  • teprotumumab is limited by intravenous administration requiring multiple infusions over several months, potential adverse effects such as hyperglycemia and severe hearing impairment, and the risk of relapse after treatment discontinuation.
  • Small molecule inhibitors are being developed to target diseases and disorders driven by dysregulated IGF-1R signaling.
  • Sling Therapeutics has developed Linsitinib, an orally administered IGF-1R inhibitor, as a potential treatment for Thyroid Eye Disease (TED) and Graves’ disease.
  • Linsitinib By blocking IGF-1R signaling, Linsitinib disrupts the metabolic and inflammatory pathways that drive adipose tissue expansion and fibrotic changes in TED.
  • existing formulations of Linsitinib are limited by systemic toxicity, off-target effects, and adverse side effects that can impact long-term tolerability and patient compliance.
  • a sustained-release nano- or microparticulate linsitinib suspension has been developed to achieve efficacy comparable to existing formulations while minimizing systemic side effects.
  • the linsitinib formulations are suitable for treating diseases and conditions characterized by white fat accumulation and dysregulated insulin-like growth factor 1 (IGF-1) signaling.
  • IGF-1 insulin-like growth factor 1
  • the linsitinib formulations can be used to treat ocular diseases (e.g., the local treatment of thyroid eye disease (“TED”)) and metabolic disorders such as obesity and diabetes.
  • TED thyroid eye disease
  • the linsitinib formulations are typically formulated as suspensions, and can further include one or more excipients such as carboxymethyl cellulose (“CMC”), hydroxypropyl methylcellulose (“HPMC”), hydroxyethyl cellulose (“HEC”), polyvinyl alcohol (“PVA”), and hyaluronic acid (“HA”).
  • CMC carboxymethyl cellulose
  • HPMC hydroxypropyl methylcellulose
  • HEC hydroxyethyl cellulose
  • PVA polyvinyl alcohol
  • HA hyaluronic acid
  • the formulations of linsitinib nano- and microcrystals inhibit adipogenesis in orbital fibroblasts in vitro and provide progressive, sustained loss of abdominal white fat, as shown by the examples in mice.
  • These can be administered topically, as to the eye, in nano or microsuspensions in sterile saline, as a powder, as a depo, or as an injectable suspension for local tissue treatment.
  • FIGs. 1A-1C are graphs showing cell viability decreases in a dose-dependent manner over one day (FIG. 1 A), one (FIG. IB) week, and two weeks (FIG. 1C) after treatment with linsitinib, linsitinib crystals dissolved in DMSO, or linsitinib nanocrystals.
  • the intact nanocrystal formulations show markedly reduced cell toxicity compared to free linsitinib or nanocrystals dissolved in DMSO.
  • * indicates p ⁇ 0.05, ** indicates p ⁇ 0.01, *** indicates p ⁇ 0.001, **** indicates p ⁇ 0.0001 compared to vehicle by Bonferroni’s multiple comparison test; n l, performed in triplicate).
  • FIG 2 shows that 1 pM linsitinib or 1 pM linsitinib nanocrystals (Xtal) dissolved in DMSO cause complete loss of adipogenic differentiation of orbital fibroblasts at day 9.
  • (* indicates p ⁇ 0.05, ** indicates p ⁇ 0.01, and *** indicates p ⁇ 0.001 by Si'dak's multiple comparisons test; n l, performed in triplicate).
  • FIG 4A is a graph of the ratios of the weight of the abdominal fat pad relative to body weight.
  • FIG 4B is a graph of the weight of the liver relative to body weight. Data presented as mean + SEM (n - 4-5). *p ⁇ 0.05 vs Lin-PEG-400 (Oral) and Lin-PEG-400 (Peritoneal).
  • FIGs 9A-9C are bar graphs showing that nanocrystal formulation decreases linsitinib toxicity in orbital fibroblasts.
  • FIG 9A shows cell viability decreases in a dose-dependent manner 1 day after treatment with linsitinib (Lin), or 200 nm linsitnib nanocrystals (Lin-NCs).
  • FIG 9B shows cell viability decreases in a dose-dependent manner 1 week after treatment with linsitinib (Lin), or 200 nm linsitnib nanocrystals (Lin-NCs).
  • FIG 9C shows that cell viability decreases in a dose-dependent manner 2 weeks after treatment with linsitinib (Lin), or 200 nm linsitnib nanocrystals (Lin-NCs).
  • FIG 10 is a bar graph showing that linsitinib nanocrystals decrease adipogenesis of orbital fibroblasts.
  • N 2 cell lines tested in triplicate. * indicates p ⁇ 0.05 and **** indicates p ⁇ 0.0001 by Dunnett’s multiple comparisons test.
  • Nanosuspension of an active agent refers to a nanoparticulate form of the agent, typically a synthetic or natural compound having a molecular weight of less than 2000 Da, more typically less than 1500 or 1000 Da, having dimensions between about 1 nm and less than about 1 micron, inclusive, which is suspended in a pharmaceutically acceptable carrier effective for the route of administration.
  • Nanosuspensions typically are submicron colloidal dispersions of nanosized drug particles stabilized by surfactants.
  • an “aerosolized” formulation is one in which the agent to be delivered is in the form of a fine spray or colloidal suspension in the air.
  • This may be pure agent or agent in combination with excipient or carrier, which will typically be a liquid such as sterile water and saline if the drug is in the form of a nanosuspension.
  • sustained release refers to release of a substance over an extended period of time in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • small molecule generally refers to an organic molecule that is less than about 2000 g/mol in molecular weight, less than about 1500 g/mol, preferably less than about 1000 g/mol, or less than about 800 g/moll. Small molecules are non-polymeric and/or non- oligomeric.
  • Surfactant is a general name for substances that absorb to surfaces or interfaces to reduce surface or interfacial tension. These agents aid wetting and dispersion of hydrophobic active pharmaceutical ingredients, and they usually act by reducing the interfacial tension between solids and liquids in suspensions.
  • Excipient is used herein to include a pharmaceutically acceptable compound that is not a therapeutically or biologically active compound.
  • An excipient should generally be inert and non-toxic to the subject.
  • biocompatible and “biologically compatible” generally refer to materials that are, along with any metabolites or degradation products thereof, generally non-toxic to the recipient, and do not cause any significant adverse effects to the recipient.
  • biocompatible materials are materials which do not elicit a significant inflammatory, immune or toxic response when administered to an individual.
  • treating mean to ameliorate, reduce or otherwise stop a disease, disorder or condition from occurring or progressing in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition.
  • Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.
  • Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis.
  • an individual is successfully “treated” if one or more symptoms associated a disease or disorder of the eye is mitigated or eliminated.
  • an effective amount or “therapeutically effective amount” means a dosage sufficient to treat, inhibit, or alleviate one or more symptoms of a disease state being treated or to otherwise provide a desired pharmacologic and/or physiologic effect.
  • the precise dosage will vary according to a variety of factors such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or disorder, and the treatment being administered.
  • the effect of the effective amount can be relative to a control.
  • analog refers to a chemical compound with a structure similar to that of another “reference” compound, but differing from it in respect to a particular component, functional group, atom, etc.
  • derivative refers to a compound, which is formed from a parent compound by one or more chemical reaction(s).
  • the formulations include linsitinib or an analog or derivative thereof.
  • Linsitinib C26H23N5O
  • IGF-1R insulin-like growth factor type 1 receptor
  • Its chemical name is 3-[8-amino-l-(2-phenyl-7-quinolinyl)-3-imidazo[l,5- a]pyrazinyl]-l -methyl- 1 -cyclobutanol, classifying it as both a quinoline and a cyclobutane derivative.
  • Linsitinib exhibits a half-maximal inhibitory concentration (ICso) of 35 nmol/L for IGF-1R and also inhibits the homologous insulin receptor (IR) with an ICso of 75 nmol/L.
  • the insulin receptor plays a key role in mediating insulin signaling, regulating glucose metabolism, lipid storage, and systemic metabolic responses, particularly in adipose tissue.
  • Exemplary linsitinib salts that that can be used to prepare the linsitinib nano and microcrystal formulations are described, for example, in U.S. Patent No. 11,976,074 to Dadino.
  • Linsitinib has be studied for treatment of multiple types of cancer, with efficacy in clinical trials for treatment of metastatic prostate carcinoma, gastrointestinal stromal tumors and other cancers including non-small cell lung cancer, epithelial ovarian cancer, relapsed and refractory Ewing sarcoma, recurrent/metastatic head and neck squamous cell carcinoma, advanced or metastatic adrenocortical carcinoma, heptatocellular carcinoma and relapsed or refractory multiple myeloma.
  • the linsitinib is administered orally twice a day at a dose of 150 mg-
  • IGF-1R insulin growth factor type 1 receptor
  • Exemplary small molecule inhibitors of IGF-1R activity include, but are not limited to: BMS-754807 (IUPAC name: (2S)-l-[4-[(5-cyclopropyl-lH-pyrazol-3- yl)amino]pyrrolo[2,l-f][l,2,4]triazin-2-yl]-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2- carboxamide-, molecular formula: C23H24FN9O); NVP-ADW742 (IUPAC name: 5-(3- phenylmethoxyphenyl)-7-[3-(pyrrolidin-l-ylmethyl)cyclobutyl]pyrrolo[2,3-d]pyrimidin-4-amine; Molecular formula: C28H31N5O), GSK1838705A (IUPAC name: 2-[[2-[[l-[2-[[l-[2-[l-[
  • Graves’ disease is an autoimmune disorder caused by autoantibodies against the thyroid stimulating hormone receptor (TSHR) leading to overstimulation of the thyroid gland.
  • Thyroid eye disease TED
  • Therapeutic options to treat TED are very limited and novel treatments need to be developed. As reported in Front. Endocrinol., 25 June 2023 Sec. Cellular Endocrinology.
  • Linsitinib orally administered for four weeks with therapy initiating in either the early (“active”) or the late (“chronic”) phases of the disease showed that Linsitinib prevented autoimmune hyperthyroidism in the early state of the disease, by reducing morphological changes indicative for hyperthyroidism and blocking T-cell infiltration, visualized by CD3 staining.
  • linsitinib had its main effect in the orbit. Linsitinib reduced immune infiltration of T-cells (CD3 staining) and macrophages (F4/80 and TNFa staining) in the orbita in experimental GD, suggesting an additional, direct effect of linsitinib on the autoimmune response.
  • the linsitinib can be present in the formulation as a nanocrystal having a size distribution in a range from about 20 nm to about 1000 nm, or from about 40 nm to about 1000 nm, with a majority distributed in a range from about 100 nm to about 1000 nm or from about 50 nm to about 500 nm.
  • the linsitinib nanocrystals can have an average size of less than 500 nm, less than 400 nm, less than 300 nm, or less than 200 nm, such as ranging from about 50 nm to about 500 nm, from about 50 nm to about 400 nm, from about 50 nm to about 300 nm, from about 50 nm to about 200 nm, from about 100 nm to about 300 nm, from about 100 nm to about 200 nm, or from about 200 nm to about 300 nm.
  • the average size of the linsitinib nanocrystals can be determined using known methods, for example, by using nanoparticle tracking analysis (NTA) or imaging such as TEM.
  • NTA nanoparticle tracking analysis
  • TEM imaging such as TEM.
  • the specific size distribution of the linsitinib nanocrystals depends on the specific organic solvent used in preparation, the specific hydrophobic compound, the presence of dispersing agent(s), etc.
  • the linsitinib can be present in the formulation as a microparticle having a size distribution in a range from about 1 pm to about 25 pm, or from about 5 pm to about 20 pm.
  • the linsitinib can be formulated with one or more stabilizers to form microparticles having a size distribution in a range from about 6 pm to about 22 pm.
  • the linsitinib microparticles i.e., the linsitinib nanocrystals + the stabilizers
  • the linsitinib microparticles can have an average size of from about 1 pm to about 5 pm, from about 5 pm to about 10 pm, from about 10 pm to about 15 pm, from about 15 pm to about 20 pm, or from about 20 pm to about 25 pm.
  • the weight percentage of the linsitinib nanocrystals or microcrystals in the pharmaceutical formulation is in a range of from about 0.01% w/v to about 50% w/v, such as 0.01% w/v, 0.03% w/v, 0.05% w/v, 0.1% w/v, 0.3% w/v, 0.5% w/v, 1% w/v, 2% w/v, 3% w/v, 4% w/v, 5% w/v, 6% w/v, 7% w/v, 8% w/v, 9% w/v, 10% w/v, up to 50% m/v.
  • Surfactants and Other Excipients are examples of surfactants and Other Excipients.
  • the linsitinib formulations can include one or more surfactants and optionally one or more excipients.
  • pharmaceutically acceptable excipients include but are not limited to, preservatives, viscosity regulators, pH-adjusting agents, and stabilizers.
  • Non-ionic surfactants are the largest group of surfactants used in the formulation of pharmaceutical suspensions. These surfactants are nonelectrolytes: that is, their hydrophilic groups do not ionize at any pH value. There are several different types of nonionic surfactants available. Since many of the surfactants in this group are esters, they are usually susceptible to hydrolysis under conditions of high or very low pH.
  • non-ionic surfactant depends on a variety of factors, but chief among them is the Hydrophilic-lipophilic balance (HLB) value and their chemical compatibility with other components of the formulation.
  • HLB Hydrophilic-lipophilic balance
  • examples of substances under this group of surfactants are polyoxyethylene sorbitan fatty acid esters (Polysorbate, TWEEN®), polyoxyethylene 15 hydroxy stearate (MACROGOL 15 hydroxy stearate, SOLUTOL HS15®), polyoxyethylene castor oil derivatives (CREMOPHOR® EL, ELP, RH 40), polyoxyethylene stearates (MYRJ®), sorbitan fatty acid esters (SPAN®), polyoxyethylene alkyl ethers (BRU®), and polyoxyethylene nonylphenol ether (NONOXYNOL®).
  • Preferred surfactants are those approved by the Food and Drug Administration for pulmonary or respiratory use, such as polysorbate 80.
  • the surfactant is PLURONIC Fl 27, a triblock copolymer composed of a central hydrophobic chain of polypropylene oxide) (70 units) flanked by two hydrophilic chains of poly (ethylene oxide) (20 units each), also referred to as a nonionic polyoxyethylene-polyoxypropylene block co-polymer with the general formula HO(C2H4O)a(- C3H6O)b(C2H4O)a. It is available in different grades which vary from liquids to solids. It is used as an emulsifying agent, solubilizing agent, surfactant, and wetting agent for antibiotics. Poloxamer is also used in ointment and suppository bases and as a tablet binder or coater.
  • Exemplary stabilizers that can be present in the linsitinib formulation include, but are not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), methylcellulose (MC), hydroxyethylcellulose (HEC), cellulose and derivatives thereof, polycarbophil, polyoxyethylene glycol (PEG), hyaluronic acid (HA), amylase and derivatives thereof, amylopectins and derivatives thereof, dextran and derivatives thereof, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and acrylic polymers such as derivatives of polyacrylic or polymethacrylic acid including hydroxylmethyl methacrylate (HEMA), carbomer or a mixture thereof.
  • the stabilizers included in the linsitinib formulation are HPMC, HEC, CMC, PVA, and/or HA, or mixtures thereof.
  • pH-adjusting agents include, but are not limited to, acids, such as boric acid, citric acid, hydrochloric acid, and salts thereof; and alkali metal salts, such as disodium phosphate, monosodium phosphate, sodium borate, sodium citrate, sodium hydroxide, and potassium phosphates.
  • preservatives can be included in the linsitinib formulation.
  • exemplary preservatives include, but are not limited to, enzalkonium chloride, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, thiomersal, chlorobutanol, benzyl alcohol, phenoxyethanol, phenylethyl alcohol, sorbic acid, methyl and propyl parabens, chlorhexidine digluconate, EDTA, polyquad, purite, perborate-based preservatives, other mercuric compounds, zinc polyol complexes, or mixtures thereof.
  • Linsitinib nano- and microparticulate suspensions can be formulated as sterile injectable preparations, which can be provided in the form of aqueous or oleaginous solutions or suspensions.
  • Sterile injectable formulations may be prepared using non-toxic, parenterally- acceptable vehicles, including distilled water, de-ionized water, pure or ultrapure water, saline, Ringer's solution, isotonic sodium chloride solution, and acceptable solvents such as 1,3 -butane diol.
  • sterile fixed oils may also be employed as solvents or suspending media.
  • the carrier is a physiologically acceptable vehicle containing salts and/or buffers, such as phosphate -buffered saline (PBS), or any other vehicle suitable for administration to animals or humans.
  • Aqueous suspensions may further include suspending agents, such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone, or gum tragacanth, as well as wetting agents, such as lecithin.
  • suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone, or gum tragacanth
  • wetting agents such as lecithin.
  • Preservatives suitable for use in aqueous suspensions include ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoate.
  • the nano or microsuspensions can be formulated as a suspension, dried to produce a powder, which can be resuspended at the time of administration, or pressed to form a depo, tablet, or implant.
  • the nanosuspension can be formulated in a gel or ointment or suspended in a sterile aqueous solution which is preferably pH and osmotically balanced for administration, for example, as an eyedrop.
  • the osmolality of an isotonic or slightly hypotonic ophthalmic formulation such as eyedrops can be about 250-300 milliosmoles per kilogram (mOsm/kg).
  • a tonicity adjustor can be used to bring the osmolality of the formulation to a level at or near 250-350 mOsm/kg.
  • Suitable tonicity adjustors include, but are not limited to, ionic and nonionic osmotic adjusting agents such as sodium chloride, potassium chloride, dextran, cyclodextrins, mannitol, dextrose, glycerol, sorbitol, boric acid, borax and propylene glycol and combinations thereof.
  • Excipients such as some of the PLURONICs could be added to modify viscosity and/or provide stabilization.
  • the formulations are prepared using standard techniques such as crystallization and milling, as exemplified below. Nearly 90% of newly discovered drugs are poorly water-soluble, a factor that limits their biological application, and poses a challenge to their pharmaceutical development. Nanocrystals improve the aqueous solubility of drugs, therefore enhancing their bioavailability. Briefly, the surface area of drug particles increases by downsizing them to the nanometer range, facilitating their dissolution and then enhancing their solubility as well as ease of delivery by injection.
  • Linsitinib microparticles and nanoparticles can be prepared using both “top-down” and “bottom-up” approaches to achieve improved solubility, bioavailability, and stability for pharmaceutical applications, including topical formulations and parenteral formulations.
  • Top- down methods such as wet milling and high-pressure homogenization, rely on mechanically generated shear forces to break down larger drug particles into the nanoscale range.
  • the linsitinib microparticles and nanoparticles are produced using dry or wet milling techniques to achieve controlled particle size reduction for improved solubility, bioavailability, and formulation stability.
  • Dry milling methods such as jet milling, planetary ball milling, vibrational rod milling, and hammer or knife milling, can be used to grind linsitinib into microparticles with sizes in the micron range.
  • conventional dry milling methods struggle to achieve submicron particles ( ⁇ 1 pm) due to limitations in energy transfer and particle aggregation.
  • wet milling can be used, which utilizes a liquid dispersion medium and mechanical grinding forces to reduce Linsitinib to nanoparticle size.
  • Media mills such as planetary ball mills and bead mills, which use zirconium oxide (ZrCh) or other high-density beads, are frequently used for wet milling.
  • high-pressure homogenization can be applied, where a linsitinib suspension is forced through a small aperture under high pressure, generating intense shear forces that further reduce particle size.
  • linsitinib can dispersed in a liquid medium where it has low solubility, such as water, ethanol, polyethylene glycol (PEG), glycerin, t-butanol, or safflower oil.
  • a liquid medium where it has low solubility such as water, ethanol, polyethylene glycol (PEG), glycerin, t-butanol, or safflower oil.
  • Surface stabilizers such as Pluronic F-127, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), polyvinyl alcohol (PVA), or lecithin, can be added before or during milling to prevent aggregation and crystal growth. Alternatively, stabilizers may be introduced after the milling process to increase dispersion stability.
  • Other components, such as a diluent can be added to a composition containing the linsitinib and surface stabilizer during the size reduction process.
  • Nanoprecipitation involves the controlled nucleation and aggregation of drug molecules to form nanoparticles with narrow size distribution and increased solubility.
  • Nanomorph technology facilitates the conversion of crystalline linsitinib into amorphous nanoparticles on an industrial scale.
  • This process involves dissolving linsitinib in a suitable organic solvent and rapidly introducing it into a mixing chamber containing a nonsolvent, in which linsitinib has low solubility.
  • the rapid mixing causes supersaturation, nucleation, and subsequent precipitation of nanoparticles.
  • Another method, MicroJet Reactor technology uses high-velocity jet streams to mix organic solutions of linsitinib with nonsolvents in a gas-filled chamber.
  • This approach can include the use of polymers such as hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC), carbomer, polycarbophil, polyethylene glycol (PEG), and hyaluronic acid (HA) to stabilize the nanoparticles.
  • HPMC hydroxypropyl methylcellulose
  • CMC sodium carboxymethylcellulose
  • PEG polyethylene glycol
  • HA hyaluronic acid
  • Nanosuspensions can also be generated by the emulsion- solvent evaporation technique, that consists of drug dissolution in an organic solvent, emulsification into an aqueous phase, and rapid evaporation of the organic phase under low pressure.
  • the template emulsion method can be utilized to produce Linsitinib nanoparticles (Lin-NPs) with precise size control, improved solubility, and rapid dissolution properties.
  • This technique involves the formation of an oil-in-water (O/W) emulsion, where droplet size directly determines the final nanoparticle size.
  • O/W oil-in-water
  • a non-aqueous solution containing Linsitinib and a stabilizer is introduced into the pre-formed emulsion, allowing the drug to be loaded into the emulsion droplets.
  • the solvent and water are then removed, resulting in the formation of nanostructured particles with a controlled size distribution.
  • the final particle size of Linsitinib nanoparticles is largely dictated by the initial droplet size of the emulsion, meaning that improved emulsification conditions facilitate precise particle size control.
  • Surfactants and other additives can be incorporated into the formulations as described in the examples. In most cases drug is administered by injection or implant, but may be administered by topically by aerosol or nasal spray. Frequency of administration will vary from one or more times per day, per week, or month.
  • IGF insulin-like growth factor
  • GH growth hormone
  • IGFBP IGF-binding protein
  • Visceral adiposity and hepatic steatosis contribute to the IGF system phenotype in individuals with metabolic syndrome and type 2 diabetes mellitus, including changes in the normal inverse relationship between IGFBP-1 and insulin, with IGFBP-1 concentrations that are inappropriately normal or elevated.
  • the IGF system is implicated in the vascular and other complications of these disorders and is therefore a potential therapeutic target.
  • IGFs insulin-like growth factors
  • IGFBPs IGF-binding proteins
  • the IGF system is ubiquitous, with paracrine and endocrine metabolic roles.
  • the IGFs interact with insulin receptor (IR) A and B isoforms, the type 1 IGF receptor (IGF1R), and hybrid receptors (IRA-IGF1R and IRB-IGF1R) to mediate signals in a variety of tissues to coordinate protein, carbohydrate and fat metabolism.
  • IR insulin receptor
  • IGF1R type 1 IGF receptor
  • IRA-IGF1R and IRB-IGF1R hybrid receptors
  • Thyroid Eye Disease is a debilitating autoimmune disease that affects about 20,000 people in the U.S. per year and has a similar prevalence in Europe. Dysfunction in the IGF-1R signaling pathway leads to a prevalence of thyroid-stimulating hormone receptor autoantibodies (TSHR-Abs) that drive excess fibrous tissue growth behind the eyes. The inflammation can push the eyes forward or cause the eyes and eyelids to become red and swollen. As the disease progresses it can lead to pain, eye bulging, and double vision. TED predominantly affects women, and most frequently affects people with hyperthyroidism due to Graves' disease. Few treatments are effective. IGF1-R and its role in thyroid eye disease (TED) has been highlighted by the recent approval of teprotumumab, a systemically dosed antibody (8 infusions spaced 3 weeks apart) that blocks IGF-1R.
  • Linsitinib a small molecule inhibitor of insulin growth factor type 1 receptor (IGF-1R), which transmits insulin’s actions to metabolic responses in systemic tissues, including adipose tissue, is useful in treatment of Graves Disease.
  • IGF-1R insulin growth factor type 1 receptor
  • the formulation can be administered by injection, implantation or as a topical suspension.
  • Example 1 Preparation and characterization of linsitinib nanocrystals (Lin-NCs)
  • Linsitinib (10 mg/mL) was weighed and dissolved in 85% v/v methanol. The suspension was heated to 80°C until fully dissolved, then cooled to room temperature. Recrystallization of Linsitinib was performed from methanol under vacuum, followed by drying for 24 hours.
  • Orbital fibroblasts were seeded at 2,500 cells per well. After 24 hours, cells were treated with low-serum media with linsitinib, 200 nm linsitinib nanocrystals dissolved in DMSO, 200 nm linsitinib nanocrystals, or 500 nm linsitinib nanocrystals (0.1 pM to 500 pM dose curve for each condition). Cell viability was assayed at day 1, week 1 and week 2 using CELLTITERBLUE® Reagent.
  • Orbital fibroblasts (passages 4-8) were seeded at 25,000 cells/well. After a week, cells were treated with control media, adipogenic media, and adipogenic media plus linsitinib (1 pM) or 200 nm linsitinib crystals (1 pM in DMSO). At days zero and nine days, cells were fixed and stained with Oil Red O to identify adipocytes. Adipocytes/high power field (HPF) were counted by a masked observer.
  • HPF high power field
  • Linsitinib nanocrystals are provided in Table 1 above.
  • FIGs 1A-1C shows that cell viability decreases in a dose-dependent manner (FIG 1A) 1 day, (FIG IB) 1 week, and (FIG 1C) 2 weeks after treatment with linsitinib, linsitinib crystals dissolved in DMSO, or linsitinib nanocrystals.
  • the intact nanocrystal formulations show markedly reduced cell toxicity compared to free linsitinib or nanocrystals dissolved in DMSO.
  • Nanocrystals were formulated for testing in human-derived orbital fibroblasts in vitro (Table 1). Nanocrystals are likely to have faster dissolution time in culture, which is an important factor when considering dose matching and drug availability in the culture. However, linsitinib is highly insoluble, and when formulated as a nanocrystal, maintains particle stability in culture. Thus, formulation as a nanocrystal reduces the toxicity of linsitinib to orbital fibroblasts. When the nanocrystals are dissolved in DMSO, the observed dose-dependent toxicity was similar to that of free linsitinib dissolved in DMSO (FIGs 1A-1C). This supports the benefit of sustained release when both considering potential efficacy and reduction of toxicity or dose-related side effects.
  • Example 3 Preparation, characterization and Use of linsitinib microcrystals (Lin-MCs) as Local Treatment of Obesity
  • Linsitinib (10 mg/mL) was weighed out and dissolved in 85% v/v methanol. The suspension was heated at 80°C until fully dissolved, then cooled back to room temperature before being recrystallization of linsitinib from methanol under vacuum dried for 24 hrs. Crystal size was reduced using wet-bead milling at 40 os/second for 30 mins in the presence of 1.0 mm Zr beads using a TissueLyser (TissueLyser LT, Qiagen Inc, Germantown, MD).
  • CMC carboxymethylcellulose
  • HPMC hydroxypropyl methylcellulose
  • HEC hydroxyethyl cellulose
  • PVA polyvinyl alcohol
  • HA hyaluronic acid
  • mice Female CD1 mice, 10- 12 weeks old, were used to characterize the efficacy of Lin-MCs in reducing white fat. An incision was made in the abdomen to allow for injecting 30 pL of crystals or Lin- PEG-400 at 4 different sites (1 mg linsitinib) in the peritoneal muscle on Day 0. Another control group received 150 pL of Lin- PEG-400 (7.5 mg/mL) per oral daily at a dose previously described to reduce visceral body fat in adult mice (45 mg/kg) (Tajima el al. 2017). The skin was then closed up using sutures and surgical staples and dosed with Buprenex SR analgesic. Mice were weighed on every day through day 7.
  • the real-time PCR primer sequences are listed in Table 2. Table 2. Real-time PCR primer sequences
  • FIG 2 shows that 1 pM linsitinib or 1 M linsitinib nanocrystals (Xtal) dissolved in DMSO causes complete loss of adipogenic differentiation of orbital fibroblasts at day 9.
  • mice lost weight initially which was consistent across the three groups on Day 2.
  • the mice receiving oral linsitinib were visibly sick on day 3, and sacrificed for tissue collection.
  • the weight loss was consistent at day 3.
  • the mice dosed with free drug (Lin-PEG-400) showed recovery in the weight, which continued through day 7 (FIG 3).
  • Mice dosed with the Lin-MC injection showed continued weight loss that was significant on days 6 and 7 compared to the Lin-PEG-400 injection (FIG 3).
  • FIG 4 A is a graph of the ratios of (A) the weight of the abdominal fat pad relative to body weight and FIG 4B is a graph of the weight of the liver relative to body weight.
  • Example 4 Effect of linsitinib nanocrystals (Lin-NCs) on Reducing White Fat
  • Lin-NCs approximately 200 nm in diameter, were milled in the presence of 2% Fl 27 (PLURONIC F-127).
  • the characteristics of the Lin-NCs are provided in Table L.
  • Female CD1, 10-12 weeks old mice were used to characterize the efficacy of Lin-NCs in reducing white fat. An incision was made in the abdomen to allow for injecting 50 L of crystals or saline at 4 different sites (total 1 mg of linsitinib) in the peritoneal muscle on Day 0. The skin was then closed up using sutures and surgical staples and dosed with BUPRENEX SR analgesic. Mice were weighed on every 3 rd day through day 15 and allowed free access to unlimited standard rodent chow and water. Mice were sacrificed on day 15 to collect the abdominal fat pad and liver.
  • mice treated with Lin-NCs dispersed in 2% F127 exhibited a loss in body weight starting from day 1 compared to saline treated group. From day 6 onward, there was significant (p ⁇ 0.05) reduction in body weight in Lin-NCs treated group compared to saline treated controls. Similarly, Lin-NCs provided a significant ( ⁇ 0.05) reduction in the ratio of the weight of the abdominal fat pad relative to body weight at day 15, as well as a reduction in the apparent visual size of the abdominal fat pad (FIG 7). In contrast, no effects were observed on the ratio of the weight of the liver to body weight (linsitinib has known liver toxicity with systemic exposure) or the visual appearance of the liver, suggesting that the formulations are safe to use (FIG 8).
  • Example 5 Effect of linsitinib nanocrystals (Lin-NCs) on Orbital Fibroblasts and Adipogenesis
  • Cell viability assays were conducted to compare the effects of linsitinib in its free drug form to -200 nm linsitinib nanocrystals (Lin-NCs). Orbital fibroblasts were seeded at a density of 2,500 cells per well. After 24 hours, the cells were treated with low-serum media containing either linsitinib free drug dissolved in DMSO (Lin) or Lin-NCs at concentrations of 1 pM, 5 pM, 10 pM, and 20 pM. Cell viability was assessed using the CellTiter-Blue® Reagent at three time points: day 1, week 1, and week 2.
  • Lin-NCs To evaluate the ability of Lin-NCs to inhibit adipogenesis in orbital fibroblasts, cells (passages 4-8) were seeded at a density of 25,000 cells per well. After one week, cells were treated with either adipogenic media alone or adipogenic media supplemented with Lin (1 pM) or Lin-NCs at concentrations of 1 pM, 5 pM, 10 pM, and 20 pM. On day nine, cells were fixed and stained with Oil Red 0 to identify adipocytes.
  • FIGs 9A-9C cell viability decreases in a dose-dependent manner 1 day after treatment with Lin, or 200 nm linsitnib nanocrystals (Lin-NCs).
  • FIG 9C cell viability decreases in a dose- dependent manner 2 weeks after treatment with linsitinib (Lin), or 200 nm linsitnib nanocrystals (Lin-NCs).
  • the number of adipocytes per high-power field (HPF) was counted by a masked observer.
  • Treatment with Lin or Lin-NCs resulted in reduced adipogenesis (FIG 10).
  • 1 pM linsitinib (Lin) or various doses of linsitinib nanocrystals (Lin-NCs) decrease adipogenesis of orbital fibroblasts 9 days after treatment with adipogenic media.

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Abstract

L'invention concerne une suspension à libération prolongée de linsitinib sous forme de nanoparticules ou de microparticules, ou d'un produit similaire à celui-ci, capable d'offrir une efficacité similaire avec des effets secondaires systémiques réduits. Les formulations de nano- et microcristaux de linsitinib inhibent l'adipogenèse, comme démontré dans des fibroblastes orbitaux in vitro et dans la présentation d'une perte progressive et prolongée de graisse blanche abdominale chez des souris in vivo. Ceux-ci peuvent être administrés par voie topique, par exemple dans l'œil, dans des nano- ou microsuspensions dans une solution saline stérile, sous forme de poudre, ou sous forme d'un injectable pour un traitement local des tissus.
PCT/US2025/018174 2024-03-01 2025-03-03 Nanosuspensions de linsitinib pour administration locale Pending WO2025184656A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3017295A1 (fr) * 2014-02-07 2015-08-14 Guerbet Sa Composition destinee a vectoriser un agent anticancereux
FR3039767A1 (fr) * 2015-08-04 2017-02-10 Guerbet Sa Composition destinee a vectoriser un agent anticancereux
CN113143928A (zh) * 2021-04-02 2021-07-23 苏州普乐康医药科技有限公司 一种osi-906的应用
US11976074B1 (en) 2023-06-20 2024-05-07 Sling Therapeutics, Inc. Crystalline salts of Linsitinib

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3017295A1 (fr) * 2014-02-07 2015-08-14 Guerbet Sa Composition destinee a vectoriser un agent anticancereux
FR3039767A1 (fr) * 2015-08-04 2017-02-10 Guerbet Sa Composition destinee a vectoriser un agent anticancereux
CN113143928A (zh) * 2021-04-02 2021-07-23 苏州普乐康医药科技有限公司 一种osi-906的应用
US11976074B1 (en) 2023-06-20 2024-05-07 Sling Therapeutics, Inc. Crystalline salts of Linsitinib

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* Cited by examiner, † Cited by third party
Title
ARCARO, FRONTIERS IN PHARMACOLOGY, vol. 4, 2013
FAIRHURST ET AL., BIOORG. MED. CHEM. LETTERS, vol. 26, no. 8, 2016, pages 2057 - 2064
FRONT. ENDOCRINOL., 25 June 2023 (2023-06-25)
GULBINS ANNE ET AL: "OR26-03 Treatment With Linsitinib, An IGF-1 Receptor Inhibitor, Prevents Disease Development And Progression In An Experimental Model Of Thyroid Eye Disease", 1 January 2023 (2023-01-01), XP093286426, Retrieved from the Internet <URL:https://pmc.ncbi.nlm.nih.gov/articles/PMC10555290/pdf/bvad114.2052.pdf> DOI: 10.1210/jendso/bvad114 *
PHILIPPOU ET AL., MUTATION RESEARCH, vol. 772, 2017, pages 105 - 122
TAJIMA, KAZUKI ET AL.: "Metabolic recovery of lipodystrophy, liver steatosis, and pancreatic β cell proliferation after the withdrawal of OSI-906", SCIENTIFIC REPORTS, vol. 7, no. 1, 2017, pages 4119

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