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WO2025170943A1 - Méthodes et compositions pour administrer des agents thérapeutiques à des surfaces de tissu mou - Google Patents

Méthodes et compositions pour administrer des agents thérapeutiques à des surfaces de tissu mou

Info

Publication number
WO2025170943A1
WO2025170943A1 PCT/US2025/014512 US2025014512W WO2025170943A1 WO 2025170943 A1 WO2025170943 A1 WO 2025170943A1 US 2025014512 W US2025014512 W US 2025014512W WO 2025170943 A1 WO2025170943 A1 WO 2025170943A1
Authority
WO
WIPO (PCT)
Prior art keywords
insert
tissue
water
protein
drug delivery
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/US2025/014512
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English (en)
Other versions
WO2025170943A9 (fr
Inventor
Shikha P. Barman
Kevin Ward
Akshita BHARDWAJ
Sagan STANCZAK
Ivan Guerrero
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Integral Biosystems LLC
Original Assignee
Integral Biosystems LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Integral Biosystems LLC filed Critical Integral Biosystems LLC
Publication of WO2025170943A1 publication Critical patent/WO2025170943A1/fr
Publication of WO2025170943A9 publication Critical patent/WO2025170943A9/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B32—LAYERED PRODUCTS
    • B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B5/00—Layered products characterised by the non- homogeneity or physical structure, i.e. comprising a fibrous, filamentary, particulate or foam layer; Layered products characterised by having a layer differing constitutionally or physically in different parts
    • B32B5/02—Layered products characterised by the non- homogeneity or physical structure, i.e. comprising a fibrous, filamentary, particulate or foam layer; Layered products characterised by having a layer differing constitutionally or physically in different parts characterised by structural features of a fibrous or filamentary layer

Definitions

  • sustained release formats have issues of retention on the target site.
  • tissue surfaces e.g., skin, sublingual, intranasal, vaginal, and ocular
  • a sustained release "film-type” format is a preferred strategy.
  • tissue spaces like ocular mucosa a film dosage format is an insert.
  • cavity-type tissues such as intranasal, sublingual, rectal and buccal tissues
  • delivery of a medication that requires a sustained presence is challenging, due to the rapid turnover of fluid.
  • Another tissue type is the esophageal mucosa, which requires retention on-site for site-specific sustained administration of medication.
  • Vaginal, rectal, intranasal and urological mucosal tissues can benefit from sustained release from inserts, particularly where the force of gravity can extrude any viscous solutions, gels, and ointments.
  • a well-adherent insert that will adhere to the tissue (mucosal and non-mucosal) and resist extrusion by gravity can achieve site-specific targeted dosing, without waste of medication.
  • labile active pharmaceutical ingredients or mixtures of pharmaceutical ingredients are required to be encapsulated in their intact forms, within the polymeric delivery system, and should stay intact, or maintain a high degree of integrity during storage and during release from the drug delivery system matrix.
  • the components of the delivery system cannot react with the active ingredient, potentially compromising its biological potency.
  • This class of labile molecules normally fall into the category of biomolecules such as antibodies, proteins, peptides, aptamer and polynucleotides such as DNA.
  • Mucosa present in accessible and inaccessible spaces have the challenge of insert retention after placement. These include ocular, intranasal, rectal, vaginal and cervical, intra-uterine, intra-urological, esophageal, buccal, sublingual, pulmonary and bronchial mucosa.
  • Fig. 1 Exemplary Size and Shape of an Ophthalmic Insert
  • Fig. 2 Exemplary Applicator Tool Design
  • Fig. 3 Left-top: Scanning Electron Micrograph of the Dissolvable Insert, (b) Leftbottom: Scanning Electron Micrograph of Ocular Mucosa, (c) Hydrated Insert placed on the ocular surface
  • Fig. 7 Cross-linking between borate ions and the hydroxyl groups in the polymer chains of polyvinyl alcohol
  • Fig. 8 Crosslinking Kinetics and Dissolution of Collagen-Containing Hydrogel Formulation
  • Fig. 14 Insert Intercalated into Tissue after 1 Hour in both Eyes
  • Fig. 24 Mucosa- Adhered Annular Hydrogel- Sheath Hydrophobic Core Fiber Insert
  • Fig. 28 IgG-Containing Drug Product
  • Fig. 30 Sustained Release of IgG from Insert Drug Product with P(TMC)- Lactide
  • Fig. 32 Size Exclusion Chromatograms of Protein-Containing Inserts Sterilized by Electron Beam Exposure at 25 kGy (Left) and 15 kGy (Right)
  • Fig. 33 Dimensional Stability Comparison: PCL12 (Blend), PLGA, PDO and PCL80K
  • Fig. 34 tO (on left) and 114 days (on right) of the PCL12 Blended Composition showing the dimensional stability over time.
  • Fig. 36 (A) 6 mm insert to be placed on tissue; (B) square insert to be placed on tissue, (C, D) 8 mm inserts
  • Fig. 38 Scanning Electron Micrograph of a core-shell only, insert
  • Fig. 39 In-vitro release of protein (Core-sheath vs. Sandwich)
  • Fig. 41 Scanning Electron Micrographs of the Sandwich Insert in the Preannealed, Post- annealed and Optimized-annealed states.
  • Fig. 42 Scanning Electron Micrographs of the partially annealed sandwich insert (expanded, to show middle core-shell fibers
  • Fig. 43 Effect of Annealing and E-Beam Sterilization of the Microstructure of the Insert (AB-NANOM-X-07-65).
  • Fig. 44 Effect of Annealing on Release Rate of a Model protein (MW 85- 140K)
  • Fig. 45 Effect of E-beam Sterilization on In-Vitro Release of Incorporated Protein (MW ⁇ 25K)
  • the invention describes several different strategies to deliver therapeutic molecules (proteins, peptides, nucleic acids, or small molecules) through electrospun (a) “layered” (sandwich) inserts, while also providing means of modulating release of bioactive substance, protecting the integrity of encapsulated substance, increasing biocompatibility of said device with underlying tissue and retention of device at site of application, and (b) dissolvable inserts, with said insert dissolving on tissue surface in a thin transparent film after placement, forming an airoil-water interface on the tissue surface due to incorporated ingredients, with or without drug, for the purpose of alleviating a tissue surface disorder.
  • compositions of fiber-based inserts produced by the process of electrospinning and electro- spraying described herein have been focused on (a) encapsulation of concentrated molecules with various levels of water solubility and lability (stability), (b) varying compositions and methods to release said molecules in sustained manner, (c) minimization of irritation at the local tissue, and (d) maximization of retention at the local site of delivery.
  • the inserts described have a hydrophobic barrier to drug release, in the form of a hydrophobic outer "shell” layer encasing a hydrophilic "core” layer, which contains the drug.
  • a “sandwich” insert has been described, with the drug-contained fibers (core- shell, or monolithic) sandwiched by two polymeric layers (“Encasing Layers").
  • the sandwich devices have 3 layers.
  • the 2 outer layers (encasing layers) have a hydrophobic polymer composition that modulates release of the encapsulated substance, provides flexibility, is tissue pliant (wraps on the tissue), has dimensional strength and stability upon hydration with tissue fluids.
  • the two outer layers are electrospun and form fibers upon deposition, but "flow" upon drying to form a continuous, or almost-continuous film that covers/encases the inner layer.
  • the inner layer of the sandwich device consists of fibers (that remain as fibers, unlike the encasing layers which transform upon drying into the continuous encasing layers).
  • the inner layer can contain a homo-fiber (single channel), or a coreshell fiber (dual channel), depending upon the release profile desired.
  • the encasing "layer” polymers have properties that allow them to "flow” to form the encasing layer. "Flow” can be obtained if the glass transition temperature of the encasing polymer
  • the encasing layer may be selected from the group that is derived from poly (trimethylene carbonate)(PTMC).
  • the derivatives may be PTMC derivatized with polycaprolactone, poly(lactide), or poly(siloxane), to impart various properties to the final polymer.
  • PTMC of one molecular weight can be blended with PTMC of another molecular weight, to provide flow properties to form a continuous, or almost continuous sandwich layer.
  • the purpose of generating a layered drug delivery system is to generate a flexible tissue-device interface to eliminate/minimize irritation using an elastomeric polymer. If the modulus of tissue and the modulus of insert is matched, or if the modulus of the insert ⁇ modulus of tissue, insert will not delaminate and slide on the tissue causing irritation.
  • the properties of the encasing polymer layer enable tissue-conformance, which enhances retention on mucosal surfaces
  • the inner encased layer contains the drug that can be released in a sustained manner.
  • the drug may be contained within a core-shell fiber matrix.
  • the drug optionally, may also be contained within the encasing layer.
  • the inserts may be inserts (thin films), annular (“ring”), elliptical, curved or tubular in shape.
  • the tubes may be 1-10 mm is length, and 0.2-10 mm in diameter.
  • the said delivery device is biodegradable, and degrades by surface erosion.
  • All layers of the insert are fabricated by the process of electrospinning of fibers, which are deposited onto a collector. However, most polymers that are electrospun stay as fibers. To form the encasing layers, PTMC polymers, derivatives and blends of PTMC would need to be used. These types of layered drug delivery systems can be used to deliver water soluble compounds, water-insoluble compounds. These compounds can be small molecules, or macromolecular biologies such as antibodies, nucleic acids and inactivated viruses. [0034] Attributes of the Inner Layer of the Sandwich Device
  • the drug delivery system has the drug encapsulated in an inner "core” (comprised of water-soluble, protective components) and encased by hydrophobic polymers to create a "shell", to achieve slow release from the matrix.
  • core comprised of water-soluble, protective components
  • hydrophobic polymers to create a "shell”
  • the polymer "shell” matrix is protective to degradative elements and is a barrier to drug release.
  • the components of the core protect the drug from degradation (such as oxidation, proteolysis, deamidation).
  • the drug delivery system has the drug encapsulated in a "core” by hydrophobic "shell” polymers, to achieve slow release from the matrix while being protected from endogenous proteases, nucleases or oxidative species that are known to trigger degradation.
  • excipients can be included to protect the drug from oxidation, deamidation, aggregation.
  • Water-soluble bioactive molecules are extremely difficult to encapsulate in concentrations that enable long durations for drug release.
  • One way to effectively encapsulate water-soluble proteins in a hydrophobic polymeric matrix is to generate inserts of the core- shell design, with the protein as the hydrophilic core and the annular polymer encasing as the hydrophobic barrier to release.
  • the water-soluble drug like a protein needs to be dissolved in an aqueous medium and the hydrophobic polymer dissolved in an organic solvent. Methods are disclosed below that minimize the precipitation of protein at the aqueous-organic interface. Methods of creating an interface that is biocompatible to ingredients present in both phases are also disclosed.
  • Another way to encapsulate drugs effectively is by "sandwiching" drug-containing electrospun fibers within two continuous film layers effectively sandwiching the drug into a fully encapsulated drug delivery system.
  • the highly elastomeric outer layers act to "mold” itself onto the tissue surface minimizing or eliminating any biomaterial-tissue reactions.
  • the membrane sandwich layers are polymers that have flow properties once dried; polytrimethylene carbonate and derivatives thereof, have characteristics that enable the formation of membranes.
  • the sandwich insert construct allows drug molecules to be encapsulated in the "middle" layer, while the outer layers act as barrier to release.
  • the insert can be placed within a tissue space as an implant, whereupon the implant is surgically placed into the tissue space.
  • the insert containing drug can be placed surgically in the tissue space.
  • the insert can also be implanted into tissue that can have large amounts of liquid such as the urological space, as in the bladder.
  • the topical insert can be placed in sinusoidal cavities.
  • a sustained drug-eluting insert can be placed in other tissue surfaces, such as rectal tissue, vaginal tissue and esophageal tissue.
  • an insert that is bonded to the tissue can be removed by application of an isotonic salt/excipient composition.
  • Compositions of hydrating solutions are disclosed that will de-adhere the insert from mucosal tissue surfaces.
  • the insert form incorporates an inner hydrophilic core (that also contains the drug) and an outer hydrophobic flexible, elastomeric sheath, and co-spun with a biocompatible adhesive.
  • the inserts are removable with the application of a fluid, and applied with a fit-for-purpose designed applicator.
  • the drug delivery system does not have a bioadhesive, but is held-in-place by tissue geometry, and/or tissue folds. Additionally, methods and compositions are disclosed to encapsulate and sustain-release intact, highly water soluble, bioactive compounds such as proteins, peptides, nucleic acids and small molecules in electrospun nanofibrous inserts.
  • dissolvable implies slow, or fast dissolution of the insert in the tissue space that this is placed in. All components in the dissolvable insert dissolve by dissolution or emulsification of the components.
  • the inserts are dissolvable, tissue- conforming, highly hydrating and adherent to tissue. Dissolvable inserts can be used in all mucosal tissues.
  • the foci of the drug-delivery system were to: (a) generate a biocompatible, highly flexible electrospun surface, so the biomaterial-tissue interface generates minimal or no irritation, (b) generate insert formats that will achieve sustained release of proteins, nucleic acids and small molecules, (c) generate insert formats that encapsulates high concentrations of proteins without causing the generation of aggregated proteins, (d) generate insert compositions that can be sterilized by various sterilizing means, and yet not result in loss of integrity of the encapsulated protein.
  • the "sandwich” insert has three layers: (a) a lower hydrophobic, elastomeric layer, (b) a middle layer containing the therapeutic to be delivered and (c) upper hydrophobic, elastomeric layer.
  • Other variations of the "sandwich” insert would be a simpler middle layer with any polymer with any drug incorporated, be it hydrophilic (MW>100), or hydrophobic (MW>100), synthetic or biologic.
  • the middle layer could contain any drug class.
  • the properties of the polymers that comprise the insert may not be ionic, or charged, but elastomeric to create Van Der Waal type forces with the tissue surface that results in long term adherence.
  • the tissue types may be dermal, ocular, vaginal, intranasal, rectal, esophageal, urological, esophageal, sublingual, or buccal.
  • the shape of the device thus formed can be in the form of a round-shaped disc, an oval-shaped disc, a shape that is contoured specifically to fit in the cul-de-sac of the conjunctiva, a ring-shape that fits on the ocular surface.
  • the round-shape disc may be 2 mm to 10 mm in diameter, preferably 3 mm to 6 mm in diameter, most preferably 4 mm- 6 mm in diameter.
  • the device diameter can be 10-50 mm in diameter.
  • the device diameter is less than 10 mm in diameter.
  • the device may be inserted into the bladder with the assistance of a catheter.
  • the device for urological drug delivery may be tubular in structure.
  • the top and bottom layer would contain an elastomeric polymer such as poly(TMC), poly(TMC-polycaprolactone), poly(caprolactone), polydioxanone, ethylene-vinyl acetate and blends thereof to achieve the properties that would lead to a continuous film layer generated by electrospinning.
  • the top and bottom layer would contain a PEGylated compound to modulate release of drug from the middle layer (diffusion aid).
  • Inserts have Elastomeric Elongation >100%
  • the inserts have elastomeric elongation > 100%, to be conforming to tissue.
  • a stress-strain curve was generated to determine the strain at break.
  • Fig. 27 demonstrates a >100% elongation of the insert. The testing was performed using a Shimadzu Mechanical Tester.
  • the middle layer has a core-sheath structure, and optionally, a monolithic layer (not core- sheath).
  • the middle layer to encapsulate the hydrophilic compound so that: (a) high concentrations of the compound (protein, etc.) can be encapsulated in a stable manner, (b) excipients that stabilize the protein can stay encapsulated with the protein.
  • the water-soluble drug is incorporated within the core of an annular fiber structure of the electrospun insert, with the sheath containing the encapsulating hydrophobic polymer.
  • the capacity of the sheath to function as a contiguous layer defines the ability to slow down release of an encapsulated compound, although the top/bottom layers of the insert would primarily perform that function.
  • the microstructure of the insert may be such that labile water-soluble molecules are encapsulated within core-shell fibers of the insert, to enable protection from proteases, nucleases other enzymes and oxidative degradation.
  • the drug delivery system (insert) has the drug encapsulated in a core by hydrophobic "shell" polymers, to slow down release from the matrix while being protected from endogenous proteases, nucleases or oxidative species that are known to trigger degradation.
  • excipients can be included to protect the drug from oxidation, deamidation, etc.
  • the outer shell is hydrophobic and is the encapsulating polymer, ideally causing a continuous layer.
  • the drug molecules encapsulated in the "core” can be hydrophilic, hydrophobic, or amphiphilic. The drug molecules could also be hydrophobic as a free base or the free acid, but rendered water-soluble by conversion into a salt form.
  • the salt forms can be selected from salt form available in the list of pharmaceutical salt form, including but not limited to, acetate, hydrochloride, malate, iodide, bromide, chloride, malonate, tartrate, gluconate, glycolate, or any other salt form that may render a water-insoluble drug soluble in water.
  • the active molecules may be amphiphilic, i.e., soluble in both aqueous and non-aqueous media.
  • the active molecules may be selectively soluble as a function of pH, with a pH range of 4.2 to 7.4, and a preferred pH range of 5.5-6.5 and another preferred pH range 4.2-5.5.
  • the active drug molecule may be a biologic in nature, such as an antioxidant, peptide, a peptide-nucleic acid, plasmid DNA or linear DNA, a protein.
  • the drug may be biologically derived or synthetic, or a synthetic derivative from a biological molecule.
  • the preferred molecule is a protein, with a preferred molecular weight between 10-30 KD, a preferred molecular wright between 30kD and 100KD, a preferred molecular weight between 100KD and 150KD and a preferred molecular weight between 150-250KD.
  • the molecule may be a nucleic acid, such as an antisense oligonucleotide, or messenger RNA, or RNAi, or aptamer, or a peptidenucleic acid (PNA).
  • the molecule may be either small molecule or macromolecule, a water-soluble molecule, or a molecule rendered less water soluble by salt formation, or derivatization with another molecule.
  • the molecule may be anti-glaucoma, antiinflammatory, anti-microbial.
  • the molecule may be a muscarinic agent, or an agent that has a therapeutic effect.
  • the active may be complexed with another molecule to enable higher encapsulation.
  • the active drug contained in the "core” may be complexed into nanoforms such as calcium complexes of DNA, positively charged peptide complexes with negatively charged polymers such as hyaluronate, xanthan.
  • the drug-containing solution may contain dissolved excipients that lower the surface tension, to enable the process of electrospinning.
  • the surface tension of the aqueous liquid (which contains the water-soluble active ingredient) is in the range 25-55 mN/m, measured by a AttensionTM Theta Contact Angle Optical Tensiometer.
  • surface tension of the aqueous liquid is in the range 20-45 mN/m.
  • the surface tension of the aqueous drugcontaining core is in the range 30-40 mN/m, and most preferably, in the range 30-36 mN/m.
  • the conductivity of the aqueous core is in the range 2000-6000 pS/cm, with a preferable range between 2000-4000 pS/cm.
  • the viscosity of the aqueous core solution containing the drug is in the range 1-900 cP (25°C, shear rate 40 s-1)
  • viscosity of the encapsulating layer is in the range 1500-10,000 cP, with a preferable viscosity range as 1500-6000 cP, measured with an Anton Paar MCR92 Cone-Plate Rheometer using a spindle CP50-0.5/T.
  • the interfacial tension between the aqueous and the organic phase is less than 30 mN/m, preferably ⁇ 20 mN/m. Electrospinning of the core solution and encapsulating polymer solution is performed with a tri-axial set-up, with an organic vapor flowing at a low flow rate of 70 mL/min.
  • the organic vapor is a class III solvent and preferably methyl acetate, or acetone.
  • the distance from the emitter (needle tip) to the collector is in the range 15-21 cm, with a preferable range 16-19 cm.
  • the aqueous core-solution containing the dissolved water-soluble drug may contain excipients that are protective to the active ingredient. These excipients include but are not limited to histidine, glycine, methionine, sorbitol, sucrose, trehalose, sodium chloride, glycerin, hydroxypropyl beta cyclodextrin, cyclodextrins, polyethylene glycol 400, polyethylene glycol 8000-200,000, propylene glycol, polypropylene glycol 400-5,000, polyvinyl alcohol, polyvinyl pyrrolidone, PEG2K- DSPE, PEG5K-DSPE, PEG2K-DPPC, PEGylated phosphatidyl choline, phosphatidic acid, lecithin.
  • the aqueous solution may contain a protein as an excipient, such as collagen, or albumin.
  • Measures of success were: (a) visual assessment of the interfacial layer and assessment of lack, or presence of precipitation of protein, (b) assessment of protein integrity by assessment of % recovery from expected value, assessment of % HMW, in relation to percent Monomer by Size Exclusion Chromatography (SEC).
  • SEC Size Exclusion Chromatography
  • the aqueous "core” solutions all contained protein at 20 mg/g, reconstituted first at 50 mg/g with a phosphate buffer solution.
  • the interface between aqueous and the organic phase is addressed by the presence of PEG2K-DSPE in the aqueous phase and span 40 in the organic phase.
  • concentration of PEG-DSPE can be 0.05% to 1% in the aqueous phase, with a preferable concentration range of 0.1% to 0.4%.
  • the PEG-DSPE may be PEG2K- DSPE or PEG5K-DSPE.
  • the (shell) polymer may be biodegradable or durable.
  • the encapsulating polymer is dissolved in an organic solvent such as dichloromethane (DCM), methyl acetate, ethyl acetate, acetone, butanone, or tetrahydrofuran, mixtures and blends thereof, or a suitable organic solvent that dissolves the polymer and does not have a large diffusion coefficient into aqueous.
  • DCM dichloromethane
  • methyl acetate ethyl acetate
  • acetone butanone
  • tetrahydrofuran mixtures and blends thereof
  • the concentration of the polymer dissolved in the organic solvent is in the range 5-50%, depending upon the molecular weight of the polymer. The preferred range is 10-20%.
  • the shell polymer may also be dissolved with an acetic acid component to increase polarity of the solution, provided the drug is compatible with acetic acid.
  • an acetic acid component to increase polarity of the solution, provided the drug is compatible with acetic acid.
  • a small molecule drug may be compatible with acetic acid in the formulation, but a macromolecule such as protein or DNA will not be.
  • acetic acid may be a good
  • Chelating agents such as ethylenediaminetetraacetic acid (EDTA) and citric acid can bind and destabilize proteins or bind harmful metal ions and prevent oxidation. Protein concentration can also influence aggregation and in some cases chemical degradation, depending on the mechanism. Higher concentrations create more chances for unwanted self-association, and consequently high viscosities.
  • EDTA ethylenediaminetetraacetic acid
  • citric acid can bind and destabilize proteins or bind harmful metal ions and prevent oxidation. Protein concentration can also influence aggregation and in some cases chemical degradation, depending on the mechanism. Higher concentrations create more chances for unwanted self-association, and consequently high viscosities.
  • Chemical degradation pathways include not only oxidation, hydrolysis, and deamidation, but also isomerization, succinimidation, disulfide bond formation and breakage, non-disulfide crosslinking, and deglycosylation.
  • Deamidation of asparagine and glutamine residues is most common, and the rate, mechanism, and location of deamidation are all pH-dependent.
  • Oxidation is another important chemical degradation mechanism, particularly the oxidation of the thio groups in methionine and cysteine residues.
  • the formation of disulfide bond linkages or thiodisulfide exchanges can result in protein aggregation or polymerization.
  • Topical administration to the eye involves eye-drops, which rapidly clear from the surface and result in low bioavailability ( ⁇ 10%) due to drainage from naso-lacrimal channel, overflow due to induction of tearing and blinking.
  • a slow-dissolving insert can efficiently release polymer excipients and/or drug, without overwhelming the ocular space.
  • two different fibers are electrospun to form an insert construct.
  • components in one fiber can react with components in the other fiber to form an in-situ forming hydrogel film on the tissue surface, that dissolves/biodegrades slowly in the biological milieu.
  • the water-dissolvable inserts may act as a bandage (with no drug) to allow a wound to heal, or optionally contain a pharmaceutical drug with a therapeutic effect, or a biologic with biological pharmacology, or a polymer, or polymers that are co-electrospun to mutually crosslink with one another and the tissue.
  • the dissolution time can be varied (1 hour to 2 weeks) by varying the type of polymer included in the electrospun and its concentration, thereof.
  • the water-dissolvable inserts can be applied onto tissue surfaces.
  • the type of tissue is ocular, intranasal, vaginal, rectal and oral.
  • the water-dissolvable inserts may be applied on a wound, or abrasion as a bandage barrier, optionally containing an anti-microbial, pain reliever or a drug that is a wound healing compound.
  • a corneal bandage for wound healing of corneal abrasions. The benefit of this is due to the transparent nature of the film, there is no vision impairment due to the device.
  • an oral mucosa-adherent insert to cover canker sores, while lubricating the oral cavity.
  • An example is an oral insert containing ingredients to alleviate dry mouth.
  • Another example is an intravaginal insert to alleviate dryness of the vaginal mucosa.
  • Another example of utility for a dissolvable insert is one that is incorporated with clotting factors and that can be packed into a deep wound to stop bleeding.
  • Dissolution time of the insert can be an hour, or it can be 12-24 hours, or even 1 day to 14 days.
  • a water-soluble insert can efficiently deliver ingredients to the ocular surface, or any mucosal surface.
  • the ingredients may comprise a drug or polymeric excipients, being released to the ocular surface.
  • the ingredients are a mixture of oils and aqueous polymers, emulsified and electrospun to form an air-oilwater interface. Inserts are normally designed to be placed under the lower eyelid in the conjunctival fornix, but a fast-dissolving thin hydrogel may be placed on the sclera (white part of the eye) to enable better absorption of the ingredient.
  • the insert For treatment of ocular surface disorders, it is logical to place the insert on the corneal surface, as in Fig. 3.
  • the ocular insert may be placed in the conjunctival fornix (lower eyelid), for ease of placement and fast dissolution.
  • Variants of water-dissolvable, biodegradable insert were developed and formulated with ingredients that are biocompatible and soothing to the tissue surface.
  • the inserts are of the shape circular, or a shape that is curved to fit the contours of the underlying tissue.
  • the insert can be placed on the cornea to aid healing, or to aid in a surgical procedure.
  • the insert as a dry device is white and opaque, but after hydration can be transparent, or translucent.
  • the inserts can be sterilized by e beam sterilization at doses between 6-25 kGy, and gamma irradiation at doses between 6-25 kGy, cold.
  • composition of the insert may be varied to vary the dissolution time of the insert in aqueous fluid of the eye. This can be accomplished by incorporation of water-soluble polymers of different molecular weights. These can be selected from, e.g., polyethylene glycol, polyvinyl alcohol, hyaluronate, sodium alginate, xanthan, pectin, celluloses (carboxymethyl-, hydroxypropyl-, hydroxypropylmethyl-), guar gum, tamarind seed polysaccharide, l->-3 Beta Glucan, poly(arginine), and polylysine to treat ocular dryness and lack of lubrication and ocular itching due to allergens or dryness.
  • water-soluble polymers of different molecular weights. These can be selected from, e.g., polyethylene glycol, polyvinyl alcohol, hyaluronate, sodium alginate, xanthan, pectin, celluloses (carboxymethyl-,
  • inserts are dissolvable instantly, in less than an hour or prolonged, with dissolution time modulated by insert composition.
  • Other tissue dryness can be alleviated as well, such as oral dryness and vaginal discomfort and dryness.
  • the insert is comprised of one or more mucoadhesive polymers, and one or more biocompatible polymers.
  • Biocompatible electrospun insert is comprised of two different compositions of fibers, with components in one type of fiber optionally capable of reaction with components included in the other type of fiber, both co-spun simultaneously by electrospinning, to form a water-dissolvable nano structured insert.
  • the structure of the insert is nano structured, generated by the process of electrospinning, or electrospraying, or a combination of the two processes.
  • one type of fiber contains sodium hyaluronate of MW in the range 50,000-5000,000 Daltons, polysorbate 20 or polysorbate 80 and polyvinyl alcohol of MW in the range 20- 130,000 Daltons and optionally, sodium chloride in the range 0.1-3.5%, boric acid or its sodium salt thereof in the range 0.0001% to 5%, sodium alginate in the range 0.01%-20%, polyethylene glycol with MW in the range 100-100,000 Daltons and between 0.01-60%, dextran 70 in the range 0.01-50%, calcium chloride in the range 0.0001%-l%, polyvinyl pyrrolidone in the range 0.1-50%, albumin in the range 0.01- 10% and the second fiber contained in the insert is comprised of polyvinyl alcohol of MW in the range 20-130,000 Daltons, and, optionally, calcium chloride (0.0001-1%), sodium borate (0.0001-1%), dextran 70 (1-50%), polyethylene glycol (of MW between 100-100,000
  • the duration of dissolution can be varied by altering the concentrations of the cross -linkable moieties such as alginate crosslinking with calcium chloride, or another type of divalent salt such as magnesium chloride, or zinc chloride.
  • Another type cross -linkable moiety is boric acid crosslinking with polyvinyl alcohol or other multi-hydroxyl containing species such as glycerol, sorbitol, or mannitol.
  • polyethylene oxide multi-arm amine can be varied in concentration along with polyethylene oxide multi-arm succinimidyl ester to form a loose or tightly crosslinked hydrogel. It is not necessary that each type of fiber actually be crosslinked tightly; optionally, each type of fiber may contain polymers that slow dissolve and may not be crosslinked at all, should the dry device be required to dissolve quickly, within 2 hours of placement onto the tissue.
  • the viscosity of PVA based solutions is in the range 1000-5000 centipoise at 25°C
  • viscosity of PEG solutions is in the range 7000-15000 centipoise
  • surface tension is between 25-50 mN/cm
  • conductivity is between 1-30 mS/cm.
  • the insert is comprised of hyaluronate and polyvinyl alcohol in the first fiber and polyethylene glycol and alginate in the other fiber type.
  • Boric acid and calcium chloride can be used in the fiber compositions to crosslink the insert upon hydration.
  • the insert is administered as a dry device, which rapidly absorbs water from the surface of the eye, or the soft tissue on which it is placed.
  • the insert upon hydration, absorbs water from the surrounding tissue to form a tissue adherent hydrogel.
  • the insert device comprised of electrospun fibers may optionally, cross-react with components in the device and including water, transforms into a tissue-compliant hydrogel.
  • the insert may not have components that react with one another.
  • the two fibers may have the same components or different components.
  • the hydrogel dissolves over time, with dissolution time modulated by composition. Upon dissolution, the hydrogel releases its ingredients slowly over time. By slow release of high viscosity polymeric components, the ocular space is not overwhelmed as in eye-drops which induces higher volumes of tear fluid and tear flow.
  • the dry insert can contain tissue-lubricating excipients including but not limited to hyaluronate (0.05-15%, MW 80,000-3,000000 Daltons), xanthan (0.05- 15%), guar (0.05-15%), gelatin (0.05-15%), soluble collagen (0.1-17%), hydroxypropyl cellulose (HPC)(0.1-15%), hydroxypropyl methyl cellulose (0.05-5%) lecithin (0.001-1%), dextran (0.05-15%), carboxymethyl cellulose (0.05-15%), glycerin (0.05-25%), tamarind seed polysaccharide (TSP)(0.05-15%), polyvinyl alcohol (MW 20,000 Daltons to 130,000 Daltons), polyethylene glycol 100-100,000, polyethylene glycol 100, polyethylene glycol 8000, polyethylene glycol 20K, polyethylene glycol 35K, trehalose, mannitol, glycerol, propylene glycol, polypropylene glycol 400-4000, PEG40-stea
  • the dissolvable inserts can be utilized as an artificial lubricant, as a slow dissolving resource for lubrication in the eye, or as a surgical aid, or as a vehicle to release a molecule to relieve redness, or irritation, or an emollient.
  • the dissolvable insert can be utilized to release a protein, DNA, mRNA, a RNAi, a CRISPR construct, or a small molecule ⁇ 1000 Daltons.
  • a medication can be incorporated into the insert, whereupon the medication can be complexed prior to incorporation, or not complexed prior to incorporation.
  • the insert is produced by the process of electrospinning of each fiber type, by simultaneously spinning them (co-spinning) and collecting on a collector, thus producing a mixture of fibers.
  • Each fiber type may be identical in composition, slightly different with slight modifications, or completely different. Once hydrated, the insert transforms into a tissue-compliant hydrogel, with tensile strength and Young's modulus ⁇ modulus of soft tissue.
  • the range of Young's modulus is between 0.0001 MPa to 1 MPa .
  • the brain has a Young's modulus of 0.0001- 0.001 MPa
  • skin has a modulus of between 0.001-0.01 MPa
  • the spleen and pancreas have modulus values in the range of 0.0025-0.005 MPa
  • glands and muscles have modulus values of between 0.008-0.017 MPa.
  • the Young's Modulus of all dry inserts was less than 0.5 MPa.
  • the Young's Modulus of hydrated insert inserts were in similar ranges as soft tissue moduli, i.e., ⁇ 0.5 MPa (Fig. 5). This allows seamless integration of biomaterial with underlying tissue.
  • Aspect 2 The dry drug delivery system of Aspect 1, wherein the ethylene vinyl acetate has a degree of vinyl acetate substitution of 42%, the P(TMC) has an inherent viscosity of 0.3- 1.2 dL/g, the P(TMC)-co-PCL has an inherent viscosity of 1.2- 1.6 dL/g) and a copolymer ratio of 90:10, and the PCL has an inherent viscosity of 1-1.5 dL/g). wherein the mixture of electrospun fibers in the two outer layers are annealed to form a continuous layer.
  • Aspect 3 The dry drug delivery system of Aspect 1 or Aspect 2, wherein the mixture of electrospun fibers in the two outer layers are annealed to form a continuous layer.
  • Aspect 4 The dry drug delivery system of any one of Aspect 1 to 3, wherein a content of the one or more polymers in the two outer layers is 0-10% w/w P(TMC), 60-95% w/w P(TMC)-co-PCL, 5-20% w/w PCL, and 0-2.5% P(TMC)- PEG-P(TMC), based on the weight of the two outer layers.
  • Aspect 5 The dry drug delivery system of any one of Aspects Ito 4, wherein the system is biodegradable.
  • Aspect 9 The dry drug delivery system of Aspect 1, wherein the bioactive substance is hydrophobic and selected from an anti-microbial, a steroid, an NSAID, a decongestant, an antihistamine, an antioxidant, a vasoconstrictor, an antiallergic, a lubricant, an antifungal, an anti-inflammatory, and an anti-glaucoma agent.
  • the bioactive substance is hydrophobic and selected from an anti-microbial, a steroid, an NSAID, a decongestant, an antihistamine, an antioxidant, a vasoconstrictor, an antiallergic, a lubricant, an antifungal, an anti-inflammatory, and an anti-glaucoma agent.
  • Aspect 10 The dry drug delivery system of any one of Aspects 1 to 9, further comprising water-soluble adhesive fibers deposited onto the system, the water- soluble adhesive fibers selected from polyacrylic acid, PEG-multi-armed amine, polyethyleneimine, polyamidoamine, polylysine, polyarginine, chitosan gluconate, and derivatives and blends thereof.
  • Aspect 11 The dry drug delivery system of any one of Aspects 1 to 10, wherein the one or more excipients in the core of the core- shell fibers interact with the bioactive substance as a water substitute, complex with the bioactive substance, or form an interfacial layer between polymer-containing organic and water phases during fabrication of the system by electrospinning.
  • Aspect 12 The dry drug delivery system of Aspect 11, wherein the one or more excipients are selected from the group consisting of hydroxypropyl [3- cyclodextrin, gamma cyclodextrins, sulfobutyl P-cyclodextrins, PEG40-stearate, trehalose, sorbitol, sucrose, mannitol, poloxamer 407, poloxamer 188, polysorbate 80, polysorbate 20, dextran, polyvinyl alcohol, polyethylene oxides, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, human serum albumin, and soluble collagen, the one or more excipients being present in the dry drug delivery system in a concentration of 1-75% w/w.
  • Aspect 13 The dry drug delivery system of Aspect 1, wherein the system has been sterilized by cold e-beam radiation at a dose range between 6-25 kGy.
  • Aspect 14 The dry drug delivery system of Aspect 1, wherein the system is round, oval, ere scent- shaped, elliptical, annular, square, rectangular, or tubular.
  • Aspect 15 The dry drug delivery system of Aspect 1, wherein the hydrophobic elastomeric polymer forming the outer shell of the core- shell fibers is selected from the group consisting of ethylene vinyl acetate (EVA), polydioxanone, polysiloxane, P(TMC), and PCL, and the P(TMC)-co-PCL is present in the two outer layers at a concentration of 50-95% w/w based on the weight of the two outer layers.
  • EVA ethylene vinyl acetate
  • TMC polysiloxane
  • PCL PCL
  • a method for delivering a bioactive substance to a soft tissue of a subject comprising: obtaining a dry drug delivery system of Aspect 1, and applying the system to a surface of a soft tissue of a subject before or after adding a hydrating fluid to the soft tissue, the hydrating fluid comprising an isotonic solution that contains one or more of sodium chloride, a phosphate, a citrate, albumin, a magnesium salt, a calcium salt, borate, boric acid, a balanced salt solution, multi-branched PEG-amine, PVA, multi-branched polylysine, multi-branched polyarginine, guar gum, gellan, sodium alginate, xanthan gum, carboxymethyl cellulose, the hydrating fluid having a pH of 6-7.8 and an osmolality of 270-340 mOsm/kg.
  • a water-dissolvable dry device comprising a physical mixture of a first fiber and a second fiber different from the first fiber, the first fiber containing sodium hyaluronate, polyethylene glycol (PEG), and polysorbate 80 or polysorbate 20, and, optionally, castor oil, a buffer salt, an amino acid, calcium chloride, mannitol, sucrose, trehalose, sodium alginate, polyvinyl pyrrolidone, dextran 70, albumin, PEG-multi- arm amine, collagen type 1, glycerol, or PEG40-stearate, and the second fiber containing polyvinyl alcohol (PVA) and sodium alginate and, optionally, sodium borate, dextran 70, PEG, PEG-multi-arm-succinimidyl ester, polypropylene glycol, propylene glycol, collagen type I, a bioactive substance, sodium hyaluronate, xanthan gum, gu
  • Aspect 18 The water-dissolvable dry device of Aspect 17, wherein the PVA has a molecular weight of 88,000-130,000 Dal with degrees of hydrolysis between 88-100%, the sodium hyaluronate has a molecular weight between 50,000- 5,000,000 Dal and the sodium alginate has a molecular weight between 32,000- 400,000 Dal, the first fiber including 80-90% by weight PEG, 0.5-5% by weight sodium hyaluronate, 0.1-0.3% by weight sodium chloride, 0.001-2% by weight polysorbate 20 or polysorbate 80, and the second fiber including 80-95% by weight PVA.
  • Aspect 19 The water-dissolvable dry device of Aspect 17 or 18, further comprising a bioactive substance selected from a small molecule of molecular weight ⁇ 1000 Dal, a large molecule of molecular weight > 1000 Dal, a protein of molecular weight between 10,000 Dal and 250,000 Dal, an amino acid, a peptide of 2-100 amino acid residues, or a nucleic acid.
  • a bioactive substance selected from a small molecule of molecular weight ⁇ 1000 Dal, a large molecule of molecular weight > 1000 Dal, a protein of molecular weight between 10,000 Dal and 250,000 Dal, an amino acid, a peptide of 2-100 amino acid residues, or a nucleic acid.
  • Aspect 20 The water-dissolvable dry device of Aspect 19, wherein the bioactive substance is water-soluble, minimally water-soluble, or water-insoluble.
  • Aspect 21 The water-dissolvable dry device of Aspect 17, wherein, upon placement on a biological tissue, the device dissolves by simple solubilization in aqueous fluids or by biodegradation.
  • Aspect 22 The water-dissolvable dry device of any one of Aspects 17 to 21, wherein the device is round, oval, crescent- shaped, elliptical, annular, square, rectangular, or tubular.
  • Aspect 23 The water-dissolvable dry device of Aspect 17, wherein the device has been sterilized by cold e-beam radiation at a dose range between 6-25 kGy.
  • Aspect 24 The water-dissolvable dry device of Aspect 19, wherein the first fiber or the second fiber includes the bioactive substance, the bioactive substance being selected from an immunoglobulin, an antigen-binding domain, an anti-bacterial, an anti-viral, a steroid, an anti-glaucoma agent, an NSAID, an UV blocking agent, a healing agent, a decongestant, an antihistamine, an antioxidant, a vasoconstrictor, an anti-allergic, a lubricant, an analgesic, an antifungal, an anti-inflammatory, a protein, a peptide, a growth factor, an enzyme, a vitamin, a hormone, a polysaccharide, a peptide-nucleic acid, a nucleic acid, or a mixture thereof.
  • the bioactive substance being selected from an immunoglobulin, an antigen-binding domain, an anti-bacterial, an anti-viral, a steroid, an anti-glaucoma agent
  • Aspect 25 The water-dissolvable dry device of Aspect 21, wherein the biological tissue is the ocular mucosa, vaginal mucosa, rectal mucosa, nasal mucosa, or oral mucosa.
  • a hydrogel-forming insert was prepared by the process of electrospinning, by co-spinning two fibers simultaneously from two different solutions.
  • the insert was prepared using sodium hyaluronate EP2.0 (Freda Bloomage, Inc.), polysorbate 20/80, PVA88 (130,000 MW) (Sigma-Millipore), sodium chloride, and polyethylene glycol (20,000-35,000 MW) (Sigma-Millipore).
  • Solution 1 contained polyethylene glycol 35,000 MW (48%), boric acid (0.052%), calcium chloride (0.049%), polysorbate 80 or polysorbate 20 (0.21%), sodium chloride (0.41%) and endotoxin-free water.
  • Solution 1 had a pH of 5.5-6.0, conductivity of 1.154 mS/cm, surface tension 31.59 mN/m, viscosity 9264.4 cP.
  • Solution 2 contained PVA 88 (8.97%), sodium alginate LVP (0.5%), polysorbate 20 (0.20%), acetic acid (0.146%), sodium chloride (0.40%), sodium hyaluronate (0.5%) and endotoxin-free water.
  • Solution 2 had a pH of 3.9-4.2, conductivity of 5.23 (mS/cm), surface tension 35.12 mN/m and viscosity of 1918.8 cP.
  • the final dry insert had a composition (by weight) of 28% PEG35K, 0.03% boric acid, 0.03% calcium chloride, 1.51% polysorbate 20, 61.15% PVA88, 3.4% sodium alginate, 2.93% sodium chloride, and 3.7% sodium hyaluronate.
  • the insert formed a hydrogel in 1 minute and became entirely transparent in 30 minutes.
  • the insert was present as a thin hydrogel at 4 hours and dissolved over 4-6 hours.
  • the use of calcium chloride in Solution 1 caused light crosslinking of the sodium alginate in the insert and boric acid in Solution 1 caused the PVA in Solution 2 to crosslink.
  • the modulation of calcium chloride and boric acid in the insert composition can lower the crosslink density of the insert and the lower the dissolution time consequently.
  • a control insert formed with no calcium chloride and boric acid dissolved quickly in less than 3 hours.
  • Example 3 Dissolvable Collagen/polyvinyl alcohol Based In-Situ Forming Mucoadhesive Inserts (using a hydrating solution)
  • the insert was formulated with the addition of acetic acid to make the solution more compatible with the collagen component, which was supplied in a 0.01M HC1 solution, and to add more conductivity.
  • the solution was notably clearer and uniform.
  • the model drug was water-soluble with a molecular weight ⁇ 500 Da.
  • the insert device is formed by co-electrospinning of two solutions, one containing a drug at a concentration that is therapeutically relevant (1-35%), PEG35K (10-60%), calcium chloride (up to 0.5%), boric acid (0.01-5%) and the other containing 0.01-0.5% polysorbate 20, 0.40-0.50% sodium alginate and 7 - 25 % PVA1OO/PVA88.
  • Glycerol may be included as a surface wetting agent, and other buffer salts such as phosphates, or acetates, or histidine or citrate may be utilized.
  • the viscosity of the first solution was 23,184 cP, Conductivity: 56.8 pS/cm, pH 6.2 and surface tension 45 mN/m; the viscosity of the second solution was 2270 cP, conductivity 565 pS/cm, pH 4.3 and surface tension > 45 mN/m.
  • the dry insert composition was 15.8% PEG35KDa, 0.028% boric acid, 0.01% calcium chloride, 0.003% polysorbate 20, 10.3% PVA100, 31% PVA88, 1.78% sodium alginate, 0.42% polysorbate 20, glycerol 0.7% and 40% model compound.
  • the insert was formed by co- spinning a first solution containing 35-55% PEG35kDa (Merck lot# 57742792 924, cat# 8.18892.1000); 0.14% boric acid (Boric acid: Spectrum lot#: 2GE0219, cat# B0120, NF, EP, BP, JP Grade); 0.15% calcium chloride (Calcium Chloride (dihydrate): Millipore Sigma lot# A0300782 629, Cat#1.02382, ACS, EP grade), 0.1% polysorbate 20 (Tween 20; Croda, super refined.
  • PEG35kDa Merck lot# 57742792 924, cat# 8.18892.1000
  • boric acid Boric acid: Spectrum lot#: 2GE0219, cat# B0120, NF, EP, BP, JP Grade
  • 0.15% calcium chloride Calcium Chloride (dihydrate): Millipore Sigma lot# A0300782 629, Cat#1.02382, ACS, EP
  • SR40800 in water for injection (Q.S.), or distilled water, and a second solution containing PVA100 (6%), PVA88 (3.2%), Sodium alginate (0.46%), polysorbate 20 (0.01%), acetic acid (0.5%), drug (6%).
  • the viscosity of the first solution was 24,000 centipoise (CP), measured at 25°C and 40 shear rate (Anton Paar Rheometer MC92, Spindle: Part# 18163, diameter 25 mm, Angle: 1°); Conductivity: 279 pS/cm (Mettler Toledo model#), pH 4.63 and surface tension >50 mN/m, and the viscosity of the second solution was 24,000 cP, Conductivity: 225 pS/cm, pH 4.63 and surface tension >45 mN/m.
  • the dry insert composition was 19.9% PEG35KDa, 0.04% boric acid, 0.06% calcium chloride, 0.04% polysorbate 20, 28.2% PVA100, 15.2% PVA88, 2.13% sodium alginate, 0.05% polysorbate 20, 35% drug substance.
  • Example 10 Longer Lasting Formulation: Dissolvable In-Situ Crosslinkable PEG35K/PVA100/PVA88/Alginate Insert
  • Example 12 Longer Lasting Formulation: The Effect of Glycerol Added in the Formulation of a Dissolvable In-Situ Crosslinkable PEG35K/PVA100/PVA88/Alginate Insert
  • insert characteristics were maintained after 15 kGy ebeam irradiation.
  • the insert device was sterilized by gamma irradiation under dry ice at 9 kGy. Insert characteristics were maintained.
  • Ocular disorders may include blepharoconjunctivitis, chalazion, conjunctivitis, contact lens problem, corneal abrasion, corneal dystrophy, corneal edema, corneal erosion, corneal ulcer, dacryocystitis, ectropion, endophthalmitis, entropion, episcleritis, eye tumor, foreign body, fungal keratitis eye infection, glaucoma, Graves' ophthalmology, hypotony, keratitis, migraine, mucormycosis, neuroretinitis, ophthalmoplegia, optic nerve problem, orbital cellulitis, photokeratitis, scleritis, sinusitis, stye, surgery, ocular bum, trauma, uveitis, UV damage, glaucoma, corneal vascularization.
  • the dissolvable insert can also be utilized as a way to treat Sjogren's syndrome of mucosal tissues of other routes, such as the nose, rectum, mouth, and vagina.
  • the dissolvable insert may be used with or without drugs, including small molecule, proteins, peptides, hormones, adenovirus-based drugs, RNAi, CRISPR-CAS9.
  • the insert can be utilized to treat diseases of the brain, specifically for oncology applications.
  • Example 13 Preparation of Dissolvable Inserts with Water-soluble and Insoluble (Oil) Ingredients
  • Example 14 Preparation of a Mutually-Crosslinkable Dissolvable Dry Insert Containing a 39-Amino Acid Peptide
  • the dissolvable inserts described in this example are comprised of 2 different types of fibers, one fiber containing multifunctional PEG8arm-NHS and the other containing PEG8arm-NH2.
  • the insert is a dry device, which absorbs physiological water from the soft tissue surface. Crosslinking is triggered at pH>7, which mutually crosslinks the fibers and the tissue, generating a slow-dissolving insert.
  • the solutions were prepared as per the compositions in Table 30 below. In this example, two solutions, each of them containing a multifunctional polyethylene oxide (either PEG8-arm- Amine, or PEG8arm-NHS) were prepared.
  • the composition of the combined solution can be in the pH range 4- 5.5.
  • pH ⁇ 4 degradation of PEG10K-8arm-GAS (NHS) occurs with hydrolysis of the ester linkages.
  • pH > 5.5 premature reaction between the PEG components occurs, and consequently, the solution cannot be electrospun.
  • pH range 4-5.5 hydrolysable linkages in PEG10K-GAS are stable, rendering this an ideal pH range.
  • the hydration solution was 0.25% gellan/30 mM borate, pH 7.8.
  • the insert was hydrated right on fresh bovine conjunctiva. After a 30-minute crosslinking time, the insert was subjected to the peel test model, using the Mechanical tester.
  • the peel strength for hydrated YL-NanoM-pep-21 was 1.4-3 N, based on multiple measurements.
  • pH of the solution was lowered further to 4.5 and 5.
  • the adhesive strength of the hydrated insert was measured by the peel test and determined to be greater >3N.
  • Solutions 1 and 2 were simultaneously electro-spun to form the drug delivery system on the same substrate.
  • Peptide Integrity The peptide extracted from the insert was also analyzed for degradation products, characterized as % oxidization. The peptide maintained its integrity throughout the encapsulation process, (see Fig. 23). [0264] In-Vivo Evaluation of Dissolvable Hydrated Insert
  • Fig. 24 shows a hydrated insert adhered to rabbit ocular tissue.
  • the tested insert was identical in composition to YL-NanoM-pep-02-13 (see Table 41 below) except for the absence of any protein.
  • the optimized borate buffer, pH 7.8 was utilized for hydrating the inserts on tissue. The hydrated inserts were retained for 7-10 days (the study ended at 14 days).
  • Fig. 25 demonstrates release of exenatide, a highly water-soluble 39-amino acid peptide from the electrospun inserts of varied composition.
  • Insert YE-NanoM-pep-1-64 (having the same composition as YE- NanoM-pep-02-13 except with exenatide instead of BSA and IgG) demonstrated a much slower rate than control peptide diffusing from the dialysis tube, compared to peptide in an aqueous solution (buffer at pH 7.4).
  • the encapsulation of other peptides has been accomplished in the electrospun insert.
  • the insert was fabricated using an electrospinning process, and encapsulated in a blend of PEGA (RG504+poly(TMC-LL), 50:50).
  • the solvent was methyl acetate, and the polymer concentration was 20%.
  • the peptide was Thymosin Beta-4 a protein that in humans is encoded by the TMSB4X gene.
  • the human protein consists of 43 amino acids (SDKPDMAEIEKFDKSKLKKTETQEKNPLPSKETIEQEKQAGES (SEQ ID NO: 1) and has a molecular weight of 4921 g/mol. Post fabrication, the insert was dried in vacuum to remove residual solvents.
  • Encapsulation 20 mg of the drug-loaded insert product was dissolved in 1 mL of a dissolution solvent, to dissolve all contents. 1 mL of an aqueous solution was added to precipitate the polymers. ImL of the slurry was centrifuged and the supernatant was removed for HPLC analysis (RP C18 column) and analyzed for peptide content. Peptide encapsulation is expressed in pg peptide/mg product.
  • Peptide Integrity The drug product was dissolved in an organic solvent and analyzed for degradation products characterized as % oxidation.
  • Bovine IgG (Sigma Aldrich) a protein of MW -120,000 g/mole, was encapsulated in a dissolvable insert. Analysis of the IgG demonstrated that the protein had been encapsulated intact, and that the IgG was released intact over time.
  • inserts were produced having both IgG (MW 120,000 g/mole) and Bovine Serum Albumin (BSA; MW 62,000 g/mole).
  • the composition is shown in Table 41 below.
  • Example 15 Incorporation of Intact Proteins at High Concentrations into Inserts
  • protein solution is loaded as the "core” aqueous solution, and a polymeric polymer is loaded as the "sheath" organic solution, in a core-shell electrospinning set-up. After electrospinning, the protein is incorporated in the core channel, surrounded by a hydrophobic sheath later.
  • the compatibility of different solvents and polymers used to make the electrospun mesh insert prototypes with IgG protein was evaluated. In the experiments below, excipients that stabilize proteins at high concentrations were identified.
  • PEGs polyethylene glycols
  • PVA polyvinyl alcohol
  • PVP polyvinylpyrrolidone
  • PAA polyacrylic acid
  • borate buffer phosphate buffer
  • TritonX-100 TritonX-100
  • ethyl acetate DMSO
  • poly (LLA-TMC) polyacrylic acid
  • Hydrophobic polymers that are compatible with IgG and can be spun into nanofibrous inserts incorporating the protein are poly (trimethylene carbonate) (1-20%), poly(caprolactone) (1-20%), poly (lactic-co-glycolic acid) (1-25%), poly (sebacic anhydride) (1-20%), polyanhydrides (1-25%), poly-orthoesters (1-25%), polyester-amides (10-25%), poly(silicone)s (1-30%), polyurethanes, polyesterurethanes, polyanhydride-urethanes, ethylene vinyl acetate polymers with 20-50% vinyl acetate content and blends thereof.
  • Other proteins that are stable in the combinations above are nerve growth factor, fibroblast growth factor, epidermal growth factor, recombinant antibodies, therapeutic antibodies, antibody-like scaffold proteins, glycoengineered proteins and immunoglobulins.
  • therapeutic proteins antibody-based drugs, Fc fusion proteins, anticoagulants, blood factors, bone morphogenetic proteins, engineered protein scaffolds, enzymes, growth factors, hormones, interferons, interleukins, thrombin, fibrin, fibrinogen, clotting proteins and thrombolytics can be dissolved at high concentrations and stabilized by these combinations of excipients in the amounts stated.
  • the IgG-containing insert was composed of two types of electrospun fibers, with one type containing a core-sheath fiber containing the protein.
  • the core-sheath fiber (much like a co-axial cable), the "sheath" is hydrophobic and polymeric and acts as the encapsulating barrier to slow down diffusion of the water- soluble protein (contained in the core), so that sustained release of the protein can be achieved.
  • Fig. 29 graphically shows the release of intact protein expressed as % monomer and other species (expressed as HMW1, HMW2 and LMW).
  • a comparison of the standard at 1 mg/g and the released protein at each time point to 192 hours (8 days) shows that protein released at each timepoint is intact, and matches the standard.
  • the data demonstrate sustained release of a highly water- soluble protein (IgG) from an insert that is less than 250 microns in thickness.
  • the IVRT data from insert shown in Fig. 29 is a coaxially spun insert with (PCL and PCL-TMC (10:90) blended at a ratio of 50:50) as the sheath polymer dissolved in methyl acetate, with 0.1% span 40 as a and IgG in PEG40-stearate, 0.1% polysorbate 20 in 20 mM phosphate buffer, pH 7 at a concentration of 11% as the core solution.
  • the data demonstrate that it is feasible to incorporate high concentrations of protein in the thin insert, without a resultant high aggregated fraction (HMW1,2).
  • Figs. 29 and 30 demonstrates the sustained release of a protein from an insert. Both inserts were co-axially spun using an electrospinning apparatus.
  • the protein was contained in the core solution that also contained hydroxypropyl beta-cyclodextrin, which likely complexed with the protein providing protection from aggregation;
  • the sheath polymer was polycaprolactone (PCL12) blended 50:50 with poly (trimethylene carbonate-polylactide) (90:10) co-dissolved in methyl acetate at a concentration of 20%, 0.1% span40.
  • PCL12 polycaprolactone
  • poly (trimethylene carbonate-polylactide) 90:10
  • aqueous protein solutions emulsified in an organic polymeric solution resulted in immediate burst of protein from the insert.
  • Fig. 30 shows sustained release from a poly(trimethylene carbonate)- co-poly(lactide) fibers.
  • the inserts did not show dimensional stability, was highly stiff and thus not biocompatible on tissue.
  • the release profiles on multiple inserts were not reproducible, more given to process nuances than release profiles obtained with the sandwich insert, which contained poly(TMC)-co- poly(caprolactone)(90: 10).
  • Fig. 31 shows high recoveries of protein from multiple batches using co-axial electrospinning of aqueous protein solution as the core, and an organic polymeric solution as the sheath.
  • the data demonstrates the utility and reproducibility of protein-containing core-sheath insert products.
  • batches that did not contain PEG40-stearate, PEG2K-DSPE, 0.1% polysorbate 20, or sorbitol (0.1-11%), or 1-50% HPpCD had recoveries ⁇ 20% consistently.
  • the amphiphilic surfactants create a protective interface between the aqueous protein solution (core solution) and organic polymer solution (sheath), thus preventing denaturation events that lead to aggregation.
  • Fig. 31 shows the relative recovery of different batches as a percent. Batches 12-995 A, 12-995B and 12-665C all had the excipients above, but at concentrations ⁇ 0.2%. This resulted in % recoveries that were comparatively lower.
  • PCL/PTMC blend polycaprolactone 80K blended with 90:10 polytrimethylene carbonate: polycaprolactone
  • PDO polydioxanone
  • PCL80K maintained dimensional stability, with zero percent of dimensional change upon hydration.
  • the inserts upon hydration increased ⁇ 20% in weight, indicating that these are low-swelling insert devices. Additionally, these inserts when extended could be pulled (strain) could be extended to > 100% its original size prior to cohesive failure demonstrating its elastomeric character.
  • PLGA inserts could not be extended to higher elongation ( ⁇ 10%), resulting in rapid cohesive fracture. Additionally, the PLGA inserts upon hydration, became highly stiff with sharp edges.
  • the inserts demonstrate high % burst of protein. This implies the core-shell fibers with the protein contained in the core, do not adequately provide a barrier to provide a sustained release of the protein. While Fig. 30 (Sustained Release of IgG) did show sustain release, this result is difficult to achieve in a reproducible manner. Often, the % burst of protein is >70%, with 100% released within 1 day. To solve this issue, the sandwich inserts were designed and implemented, with the core-shell fibers (containing protein) encapsulated further by two outer layers.
  • Sheath solutions For the sandwich insert, there are two sheath solution which are used: Coaxial sheath and Film sheath.
  • the coaxial sheath is the polymer solution which encapsulates the core solution, also called the middle layer.
  • the film sheath is used in the top and the bottom layer. Both these solutions together make the sandwich mesh/insert.
  • Encapsulation procedure This process is used to analyze the encapsulated protein/drug inside the insert.
  • organic solvents are used to dissolve the polymer.
  • 50:50 Methyl Acetate: Dichloromethane is used to perform multiple washes to dissolve the polymer.
  • the protein pellet is dried to remove left over solvents. This step is followed by reconstituting the dry pellet using 50 mM phosphate buffer, 1.2% Sodium chloride, 0.1% Poloxamer.
  • the insert is analyzed by using a UPLC method.
  • Example 26 Sandwich (Layered) Insert with Incorporated Protein (MW>100K) and
  • Table 65 AB-NANOM-X-07-69 Composition
  • Table 66 Process Parameters, Insert Composition and Analysis
  • Example 27 Sandwich (Layered) Insert with Incorporated Protein (MW ⁇ 70K) and Diffusion Aid (containing PTMC homopolymer with an inherent viscosity of 0.65 dL/g)
  • Example 28 Sandwich (Layered) Insert with Incorporated Protein (MW ⁇ 70K) and Diffusion Aid (containing PCL-PTMC (10:90) and PCL-PTMC (90:10) in outer layers)
  • Fig. 40 demonstrates sustained release profiles from "sandwich” insert. Sustained release of the highly water-soluble proteins is not possible without the unique micro structure of the sandwich insert.
  • the polymers that are able to flow are comprised of polymers that are poly (trimethylene carbonate), poly (trimethylene carbonate) copolymerized with other polymers such as poly(caprolactone), or blended with other polymers to impart strength. The molecular weight of the polytrimethylene carbonate would influence the flow properties of the encasing insert.
  • the "middle layer” remain as electrospun fibers (Fig. 42). As demonstrated in Fig. 41, the encasing layers also begin as electrospun fibers, but transform into continuous layers (top and bottom) as the encasing layer.
  • the encasing layer polymer is necessary to slow down the diffusion of the incorporated bioactive agent.
  • the role of the diffusion aid poly(trimethylene carbonate)-polyethylene oxide- poly(trimethylene carbonate) is to generate water soluble phases for the incorporated protein to diffuse through.
  • the polymers in the encasing layers need to be able to "flow” to transform the top layer into the continuous layer.
  • These are polymers based on poly(trimethylene carbonate)-based polymers and blends and copolymers with pol(caprolactone) to add strength and durability.
  • This mesh has the film sheath composition as 18% w/v (90:10) PCL- PTMC: PCL with 0.116% PTMC-PEG-PTMC (diffusion aid).
  • This composition had a good release profile (30 min burst 20.1%, post E-beam (6 kGy) 30 min burst 23.4%).
  • Fig. 43 shows pre-annealing and post annealing SEM images.
  • the third image shows the effect of E-beam on the structure of the mesh. The number of holes reduced slightly visually, but has a significant effect on the release profile. This is a good example showing the effect of temperature and E-beam on the release profile and the flowability of polymer.
  • Fig. 44 demonstrates the rate of release of model proteins before and after annealing, with the % protein burst lowered from 60% (pre- annealing) to 35% (post- annealing). Scanning Electron Micrographs of the wafers post-annealing shows more a continuous outer layer.
  • Fig. 45 shows release of a protein from inserts before and after e- beam sterilization. The release profile before sterilization releases rapidly with greater than 60% released in 1 day, whereas post-sterilization demonstrates a more sustained release of protein. As shown in Fig.
  • both annealing and energy from sterilizing radiation has the effect of causing flow of the outer layers to form diffusional barriers to protein release.
  • Other sterilizing radiation such as X-Ray or gamma radiation would work similarly to e-beam (P-radiation).
  • the sterilizing radiation would be in the range 6-25 kGy, preferably cold.

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Abstract

Système d'administration de médicament sec comprenant une couche intermédiaire enfermée dans deux couches externes, la couche intermédiaire et les deux couches externes comprenant chacune un mélange de fibres électrofilées. Est également divulgué un dispositif sec hydrosoluble contenant un mélange physique d'une première fibre et d'une seconde fibre dans lequel la première fibre et la seconde fibre sont configurées pour réagir l'une avec l'autre et avec un tissu biologique lors de l'hydratation, et le dispositif se transforme en un hydrogel lors du contact avec le tissu biologique. L'invention concerne en outre une méthode d'administration d'une substance bioactive à un tissu mou à l'aide du système ou du dispositif.
PCT/US2025/014512 2024-02-08 2025-02-04 Méthodes et compositions pour administrer des agents thérapeutiques à des surfaces de tissu mou Pending WO2025170943A1 (fr)

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CN102776170A (zh) * 2012-07-19 2012-11-14 上海应用技术学院 一种核壳结构的纳米纤维固定化酶的制备方法
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US20210308323A1 (en) * 2015-04-17 2021-10-07 Rochal Industries, Llc Composition and kits for pseudoplastic microgel matrices
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US20140230373A1 (en) * 2006-07-13 2014-08-21 Abbott Cardiovascular Systems Inc. Reduced temperature sterilization of stents
US20220054255A1 (en) * 2011-08-16 2022-02-24 The University Of Kansas Biomaterial based on aligned fibers, arranged in a gradient interface, with mechanical reinforcement for tracheal regeneration and repair
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US20190207186A1 (en) * 2013-12-04 2019-07-04 Cornell University Ceramic-polymer hybrid nanostructures, methods for producing and applications thereof
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CN120837730A (zh) * 2025-09-25 2025-10-28 浙江崇山生物制品有限公司 一种经氧化透明质酸交联的胶原蛋白水凝胶及其制备方法和应用

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