[go: up one dir, main page]

WO2025034562A1 - Proliposomes et compositions, leurs procédés de fabrication et leurs procédés d'utilisation - Google Patents

Proliposomes et compositions, leurs procédés de fabrication et leurs procédés d'utilisation Download PDF

Info

Publication number
WO2025034562A1
WO2025034562A1 PCT/US2024/040749 US2024040749W WO2025034562A1 WO 2025034562 A1 WO2025034562 A1 WO 2025034562A1 US 2024040749 W US2024040749 W US 2024040749W WO 2025034562 A1 WO2025034562 A1 WO 2025034562A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
proliposomes
formulation
thin layer
sodium
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/US2024/040749
Other languages
English (en)
Inventor
Mohammed MANIRUZZAMAN
Bhupendra RAJ GIRI
Santosh BASHYAL
Ishaan Duggal
Muhammad ABDUR RAHIM
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.)
University of Texas System
University of Texas at Austin
Original Assignee
University of Texas System
University of Texas at Austin
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 University of Texas System, University of Texas at Austin filed Critical University of Texas System
Publication of WO2025034562A1 publication Critical patent/WO2025034562A1/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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K9/0043—Nose
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • 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
    • A61K9/0085—Brain, e.g. brain implants; Spinal cord
    • 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
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1277—Preparation processes; Proliposomes
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats

Definitions

  • Non-small cell lung cancer represents the most common form of lung cancer associated with relatively high mortality rates of around 18.0% (Rodak, O. et al ., 2021, Cancers (Basel), 13, 4705).
  • the subpar efficacy on account of the tumor heterogenicity, chemoresistance, altered protein expression associated with traditionally used chemotherapeutic drugs has resulted in major efforts being directed towards repurposing drugs.
  • Sorafenib a multi -kinase inhibitor originally approved for the treatment of hepatocellular carcinoma, advanced renal carcinoma and thyroid carcinoma (Shukla, S. K., 2020, Ther. Deliv., 11, 213).
  • the present invention relates to, in part, a composition comprising proliposomes, wherein the proliposomes comprise: a phospholipid; a stabilizer; a surfactant; a carrier; and an active pharmaceutical ingredient; and wherein the proliposomes have a diameter of less than or about 200 nm.
  • the phospholipid is selected from the group consisting of Phospolipon 90 G, Phosphatidylcholine (PC), Phosphatidylethanolamine (PE), Phosphatidylserine (PS), Phosphatidylinositol (PI), Phosphatidic acid (PA), Sphingomyelin (SM), Cardiolipin (CL), Lysophosphatidylcholine (LPC), Lysophosphatidylethanolamine (LPE), Phosphatidylglycerophosphate (PGP), Phosphatidylinositol phosphate (PIP), Phosphatidylthreonine (PT), Phosphatidylsulfate (PSA), Phosphatidylglyceroside (PGS), Plasmalogens (e.g., plasmenylcholine, plasmenylethanolamine), and any combination thereof.
  • PC Phosphati
  • the stabilizer is selected from the group consisting of cholesterol, ergosterol, P-Sitosterol, Stigmasterol, Campesterol, Fucosterol, 7- Dehydrocholesterol, Brassicasterol, Lanosterol, Cholestanol, Desmosterol, Coprostanol, Squalene, Squalane, Tocopherols (e.g., a-tocopherol, y-tocopherol), Tocotrienols (e.g., a- tocotrienol, y-tocotrienol), Dihydrocholesterol, 24-Methylenecholesterol, 24- Norchol esterol, 24,25-Dihydroxycholesterol, 25-Hydroxycholesterol, and any combination thereof.
  • Tocopherols e.g., a-tocopherol, y-tocopherol
  • Tocotrienols e.g., a- tocotrienol, y-tocotrienol
  • the surfactant is selected from the group consisting of Kolliphor P188 (Poloxamer P188), Kolliphor P407 (Poloxamer 407), Kolliphor P338 (Poloxamer 338), Kolliphor P124 (Poloxamer 124), Kolliphor P237 (Poloxamer 237), Polysorbate 80 (Tween 80), Polysorbate 20 (Tween 20), Sodium cholate, Sodium deoxycholate, Sodium taurocholate, Tween 80 (polysorbate 80), Tween 20 (polysorbate 20), Span 80 (sorbitan monooleate), Span 60 (sorbitan monostearate), Cetyltrimethylammonium bromide (CTAB), Sodium dodecyl sulfate (SDS), Polyethylene glycol (PEG), Sodium oleate, Lipid-based PEGylated surfactants (e.g., PEGylated phospholipids), Fatty acid-based surfactants (
  • the carrier is hydrophilic.
  • the carrier is selected from the group consisting of hydroxypropyl-P-cyclodextrin, Mannitol, Lactose, Sorbitol, Dextrose, Maltose, Sucrose, Fructose, Trehalose, Polyethylene glycol (PEG), Poloxamer (e.g., Poloxamer 188, Poloxamer 407), Hydroxypropyl-P- cyclodextrin, Microcrystalline cellulose, Calcium carbonate, Calcium phosphate, Lipid- based solid carriers (e g., solid lipid nanoparticles, lipid powders), Polymeric carriers (e.g., poly(lactic-co-glycolic acid), polyvinyl alcohol), and/or any combination thereof.
  • PEG Polyethylene glycol
  • Poloxamer e.g., Poloxamer 188, Poloxamer 407
  • Hydroxypropyl-P- cyclodextrin Microcrystalline cellulose, Calcium carbonate,
  • the active pharmaceutical ingredient is selected from the group consisting of a chemotherapeutic, a hormone, a corticosteroid, a vasodilator, analgesics, antibiotics, antidepressants, antipsychotics, anticoagulants, antihypertensives, anti-inflammatories, antihistamines, biologies, bronchodilators, diuretics, antidiabetic drugs, anticonvulsants, immunosuppressants, antiemetics, antivirals, antifungals, sedatives, stimulants, antineoplastics, antiretrovirals, antimalarials, anticholinergics, antispasmodics, antihyperlipidemics, proton pump inhibitors, antacids, laxatives, anticoagulant reversal agents, bone resorption inhibitors, antiplatelet drugs, antianxiety medications, antithyroid drugs, antihistamine-decongestant combinations, antitussives, anthelminthic
  • the composition further comprises a solvent.
  • the solvent comprises water, saline, a buffer solution, or any combination thereof.
  • the composition is a powder. In one embodiment, the composition has a particle size range from 50 nm to 200 nm.
  • the present invention also relates to, in part, a method of making a composition comprising proliposomes, comprising the steps of: providing a solution comprising: a phospholipid; a stabilizer; a surfactant; a carrier; an active pharmaceutical ingredient; and an optional solvent; applying pressure to the solution; and drying the solution to generate the composition.
  • the optional solvent is selected from the group consisting of ethanol, acetone, methanol, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), ethyl acetate, diethyl ether, chloroform, hexane, toluene, xylene, N,N- dimethylformamide (DMF), dichloromethane, acetonitrile, ethylene glycol, isopropyl alcohol, butanol, carbon disulfide, dimethyl carbonate, and propylene carbonate.
  • DMSO dimethyl sulfoxide
  • THF tetrahydrofuran
  • ethyl acetate diethyl ether
  • chloroform hexane
  • toluene toluene
  • xylene N,N- dimethylformamide
  • dichloromethane acetonitrile
  • ethylene glycol isopropyl alcohol, butanol
  • the step of applying pressure to the solution is performed using a method selected from the group consisting of bioprinting, extrusion 3D printing, inkjet printing, electrohydrodynamic jetting, microfluidic printing, and any combination thereof.
  • the step of drying the solution is performed using lyophilization.
  • the method further comprises the step of processing the composition to provide a final dosage form.
  • the final dosage form is selected from a tablet, a capsule, or suspension.
  • the step of processing the composition comprises the steps of: spreading a thin layer of the composition over a build platform; sintering the thin layer of the composition; spreading a new thin layer of the composition over the previous layer; sintering the thin layer of the composition; and repeating the previous two steps until a tablet is formed.
  • the present invention also relates to, in part, a method of making a final dosage form comprising a proliposomal composition, comprising the steps of: providing a proliposomal composition; spreading a thin layer of the proliposomal composition over a build platform; sintering the thin layer of the proliposomal composition; spreading a new thin layer of the proliposomal composition over the previous layer; sintering the thin layer of the proliposomal composition; and repeating the previous two steps until a final dosage form is formed.
  • the final dosage form is selected from a tablet, a capsule, or a pill.
  • the proliposomal composition is produced using a method comprising the steps of: preparing a liposomal composition using thin film hydration; and lyophilizing the liposomal composition to produce a proliposomal composition.
  • the proliposomal composition is produced using a method comprising the steps of: providing a solution comprising: a phospholipid; a stabilizer; a surfactant; a carrier; an active pharmaceutical ingredient; and an optional solvent; applying pressure to the solution; and drying the solution to generate the composition.
  • the step of applying pressure to the solution is performed using a method selected from the group consisting of bioprinting, extrusion 3D printing, inkjet printing, electrohydrodynamic jetting, microfluidic printing, and any combination thereof.
  • the present invention also relates to, in part, a method of treating a disease or disorder in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising the composition disclosed herein, or a pharmaceutical composition comprising the composition generated by the method disclosed herein.
  • the composition is formulated as an oral sterile formulation, an oral non-sterile formulation, an inhalation formulation, a parenteral formulation, a sublingual formulation, a topical formulation, a transdermal formulation, a nasal formulation, a ocular formulation, a otic formulation, a rectal formulation, a vaginal formulation, or any combination thereof.
  • the composition is formulated into a unit dosage form, the unit dosage form comprising a solution, a cream, a dry powder inhaler, a capsule, a pill, a gel, a lozenge, a chewable tablet, or an effervescent tablet.
  • the composition is formulated into a bulk dosage form, the bulk dosage form comprising a dry powder.
  • the composition is a modified release formulation, the modified release formulation comprising extended release, delayed release, targeted release, orally disintegrating tablet, targeted release, pulsatile release, and/or stimuli responsive release.
  • Fig. 1 provides a schematic illustration of proliposome composition elements.
  • Fig. 2 provides a schematic illustration of liposome composition elements.
  • Fig. 3 provides a schematic illustration of an example method for the production of proliposomes.
  • Fig. 4 provides a schematic illustration of an example method for the generation of liposomes, from herein described proliposomes.
  • Fig. 5 provides a schematic illustration of example methods for administering disclosed compositions to a subject.
  • Fig. 6 provides a flowchart illustrating a representative sintering process for the generation of 3D-printed tablets.
  • Fig. 7 provides a representative sintering process for the generation of 3D- printed tablets.
  • Fig. 8 provides a differential scanning calorimetry (DCS) curve of Docetaxel and Docetaxel-loaded proliposomes.
  • DCS differential scanning calorimetry
  • Fig. 9 provides a differential scanning calorimetry (DCS) curve of Levonorgestrel and Levonorgestrel-loaded proliposomes.
  • DCS differential scanning calorimetry
  • Fig. 10 provides a differential scanning calorimetry (DCS) curve of Sorafenib and Sorafenib-loaded proliposomes.
  • DCS differential scanning calorimetry
  • Fig. 11 provides a differential scanning calorimetry (DCS) curve of Ketoconazole and Ketoconazole-loaded proliposomes.
  • DCS differential scanning calorimetry
  • Fig. 12 provides thermogravimetric analysis of docetaxel, levonorgestrel, sorafenib, ketoconazole, dexamethasone and proliposomes loaded with them respectively.
  • Fig. 13 provides X-ray diffractometry (XRD) spectra of docetaxel, levonorgestrel, ketoconazole and dexamethasone proliposomes loaded with them respectively.
  • Fig. 14 provides X-ray diffractometry (XRD) spectra of sorafenib proliposomes loaded with them respectively.
  • Fig. 15 comprising Fig. 15A and Fig. 15B, provides Fourier-transform infrared spectroscopy (FTIR) analysis of drugs and proliposomes loaded with them.
  • Fig. 15A provides FTIR spectroscopy analysis of docetaxel, levonorgestrel, sorafenib and proliposomes loaded with them respectively.
  • Fig. 15B provides Fourier-transform infrared spectroscopy (FTIR) analysis of ketoconazole and dexamethasone neat drugs and proliposomes.
  • FTIR Fourier-transform infrared spectroscopy
  • Fig. 16 comprising Fig. 16A through Fig. 16C, provides scanning electron microscopy (SEM) images and data relating to Docetaxel.
  • Fig. 16A depicts an SEM image of Docetaxel.
  • Fig. 16B depicts an SEM image of Docetaxel -loaded proliposomes.
  • Fig. 16C depicts particle size and PDI of two samples of Docetaxel -loaded proliposomes.
  • Fig. 17, comprising Fig. 17A through Fig. 17C, provides scanning electron microscopy (SEM) images and data relating to Levonorgestrel.
  • Fig. 17A depicts an SEM image of Levonorgestrel.
  • Fig. 17B depicts an SEM image of Levonorgestrel -loaded proliposomes.
  • Fig. 17C depicts particle size and PDI of two samples of Levonorgestrel - loaded proliposomes.
  • Fig. 18, comprising Fig. 18A through Fig. 18C, provides scanning electron microscopy (SEM) images relating to Sorafenib.
  • Fig. 18A depicts an SEM image of Sorafenib.
  • Fig. 18B depicts an SEM image of Sorafenib-loaded proliposomes.
  • Fig. 18C depicts particle size and PDI for Sorafenib -loaded proliposomes before and after extrusion.
  • Fig. 19 provides in vitro release profile of Docetaxel and Docetaxel- loaded proliposomes.
  • Fig. 20 provides in vitro release profile of Levonorgestrel and Levonorgestrel-loaded proliposomes.
  • Fig. 21 provides in vitro release profile of Sorafenib and Sorafenib -loaded proliposomes.
  • Fig. 22 provides cell viability of human mesenchymal stem cells (hMSCs) exposed to varying concentrations of blank proliposomes.
  • Fig. 23 provides representative images of proliposome-loaded SLS 3D- printed tablets comprising indomethacin.
  • Fig. 24 provides a representative illustration demonstrating a redispersible powder formulation.
  • Fig. 25 provides a representative illustration demonstrating continuous manufacturing of proliposomes on large scale.
  • Fig. 26 provides representative results from factorial design study used to optimize the manufacturing process.
  • Fig. 27 provides representative images of proliposome-loaded 3D-printed tablets comprising indomethacin.
  • Fig. 28 provides transmission electron microscopy (TEM) images of comparative studies for the release of liposomes as nano-vesicles for free proliposome powder and proliposome-loaded 3D printed SLS tablet.
  • TEM transmission electron microscopy
  • Fig. 29 provides in vitro release profde of indomethacin in proliposome, pure drug, physical mixture, and proliposome-loaded 3D SLS printed tablets compared to free proliposome powder.
  • Fig. 30 provides X-Ray Diffraction (XRD) data for both proliposome and proliposome-loaded 3D printed tablets.
  • the present invention relates in part to the unexpected storage stability, shelf-life of the proliposomal compositions described herein.
  • the proliposomal compositions demonstrate unexpectedly enhanced dissolution of active compounds in the proliposomes.
  • compositions comprising proliposomes described herein show remarkable improvement in the storage stability and shelf-life of corresponding liposomes and also highlight the enhanced dissolution of the active moiety due to the presence of hydrophilic carriers.
  • Described herein include are liposomes, proliposomes and methods for generation of liposomes and proliposomes.
  • the liposomes and proliposomes include a layer of phospholipid encapsulating an active pharmaceutical ingredient, and can be useful for the treatment of different disease states.
  • the disclosed liposomes and proliposomes have very small cross-sectional dimensions with a very uniform size distribution or dispersity (poly dispersity index) and considerably smaller and more uniform than other liposomes and proliposomes currently available through conventional techniques.
  • the small cross-sectional dimensions of the liposomes and proliposomes can be achieved by use of an extrusion-based process in which a dispersion of a phospholipid, a carrier, and an active pharmaceutical ingredient, optionally in combination with a stabilizer and/or a surfactant, are extruded under pressure to form very small droplets that are collected and subjected to a lyophilization (freeze-drying) process to generate proliposomes with small cross-sectional dimensions and a narrow size distribution or dispersity (poly dispersity index).
  • a lyophilization freeze-drying
  • the extrusion-based processes used herein can reliably generate smaller and more uniform droplets allowing generation of smaller and more uniform proliposomes.
  • the extrusion-based processes used herein can allow for incorporation of virtually any active pharmaceutical ingredient, including biologies, which may be unstable under elevated temperature conditions, or cells, which may be or undergo damage or destruction by use of other atomization processes.
  • the proliposomes can be converted to liposomes by dispersing the proliposomes in water or another suitable solvent or solution (e.g., saline, buffer solution, etc.), to allow for preparation of administrable formulations, though in some cases the proliposomes themselves can be administered directly to a subject without conversion to liposomes.
  • the liposomes and proliposomes described herein have a markedly improved character for delivering the active pharmaceutical ingredient to a subject as compared to known liposomes and proliposomes.
  • the purpose of this invention is to provide a composition comprising proliposomes, which exhibit enhanced treatment (i.e. anti-cancer) efficacy,
  • This invention further provides the incorporation of proliposomes into powder-based 3D printing for advanced tablet manufacturing and drug delivery. It is a powder bed-based additive manufacturing technology that uses laser as a source of thermal energy to selectively sinter or fuse powder material to produce 3D structures in a layer-by-layer fashion (Giri, B. R. et al., 2022, AAPS PharmSciTech., 24, 4; Giri. B. R. et al., 2021, J. Pharm. Investig., 51, 1). Proliposomes' ability to self-assemble into liposomes upon contact with water distinguishes them as a potential medicinal delivery mechanism.
  • proliposomes of the present invention have various advantages, including enhanced drug stability and bioavailability, controlled drug release from the liposome matrix, targeted drug delivery, encapsulation of both the small and large molecules, and increases stability making them an attractive alternative for drug delivery applications (Shah, S. et al., 2020, Advanced Drug Delivery Reviews, 154, 102). Furthermore, proliposomes are versatile carriers that can encapsulate various pharmaceuticals, including hydrophobic and hydrophilic compounds, peptides, and nucleic acids, broadening their therapeutic applications.
  • proliposomes powder as a feed material into powder-based 3D printing technology such as selective laser sintering (SLS) for manufacturing 3D printed dosage formulations provides unique advantages and opportunities of both approaches. It opens a new avenue for pharmaceutical manufacturing and drug delivery in a variety of ways. For example, it enables the accurate and personalized dosing, point-of-care manufacturing, stability, and delivery of small and large molecules (biologies), improves solubility and bioavailability of poorly-water soluble APIs, allows the development of multi-drug combination products with tunable release profdes. Overall, the inclusion of proliposomes into powder-based 3D printed tablets offers a paradigm shift in drug manufacturing and delivery, providing accuracy, personalization, and efficiency that can greatly enhance patient outcomes and the pharmaceutical production landscape.
  • SLS selective laser sintering
  • proliposomes formulation of a poorly-water soluble and light sensitive active pharmaceutical ingredients can be used as a feed material in powder-based 3D printing technology to develop oral dosage forms.
  • the 3D printed oral tablet is subjected to release media, it starts forming liposomes and releases the drug from the lipid bilayer matrix.
  • the present invention increases drug solubility since the drug is being release as a liposome within nanometer range ( ⁇ 200 nm size) and was found stable during sintering, even though the indomethacin drug is known to be light sensitive (photoliable). Further excipients can be used to increase the bulk quantity of the proliposome powder or improve the flow property of the powder.
  • the technology utilizes minimal to low organic solvent for proliposome manufacturing and the ability to control specific process parameters allows for the control of liposome particle size and size distribution, use SLS printing to manufacture consolidated structures containing small or biologic molecules.
  • the current technologies present a unique approach of utilizing proliposome (loaded with API) as a feed material for powder-based 3D printing of oral dosage forms.
  • Proliposome and 3D printing technologies differ greatly from traditional approaches like tableting in the production and administration of pharmaceuticals. When paired with 3D printing, it allows for the fabrication of complicated tablet geometries and personalized drug release patterns that are difficult to create using traditional procedures.
  • the current technologies present unique approach of utilizing proliposome (loaded with active pharmaceutical ingredients) as a feed material for powder-based 3D printing of oral dosage forms and improves drug biopharmaceutical performance like solubility, bioavailability and stability.
  • the present invention offers creative ways to improve drug stability, solubility and bioavailability, controlled drug delivery and tailored treatment, putting it apart from conventional drug manufacturing and delivery methods.
  • proliposomes into the formulation of 3D printed oral tablets provides a novel and highly promising strategy to drug delivery.
  • the present invention exhibits that a proliposomes formulation of a poorly-water soluble and light sensitive pharmaceutical can be used as a feed material in powder-based 3D printing technology to develop oral dosage forms.
  • the 3D printed oral tablet is subjected to release media, it starts forming liposomes and releases the drug from the lipid bilayer matrix.
  • the aforementioned invention increases drug solubility since the drug is being release as a liposome within nanometer range ( ⁇ 200 nm size) and improves drug stability. Tablets are one of the most patient-friendly dose forms, and the use of the 3D printing technology presented herein to make them has several distinct advantages such as, precise dosing, customization according to patients need, complex dosage form development with multiple drugs, and point-of-care manufacturing.
  • This present invention is uniquely tailored for use in continuous manufacturing of fdms and other dosage forms containing biologic formulations or chemically unstable small molecules, and in personalized oral dosage forms with small and large active pharmaceutical ingredients and molecules. Definitions
  • a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.
  • a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.
  • a disease or disorder is “alleviated” if the severity of a sign or symptom of the disease or disorder, the frequency with which such a sign or symptom is experienced by a patient, or both, is reduced.
  • an “effective amount” or “therapeutically effective amount” of a compound is that amount of compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered.
  • An “effective amount” of a delivery vehicle is that amount sufficient to effectively bind or deliver a compound.
  • a subject is preferably a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats, etc.) and a primate (e.g., monkey and human), most preferably a human.
  • a non-primate e.g., cows, pigs, horses, cats, dogs, rats, etc.
  • a primate e.g., monkey and human
  • parenteral administration of a composition includes, e.g., subcutaneous (s.c ), intravenous (i.v.), intramuscular (i.m.), or intrastemal injection, or infusion techniques.
  • s.c subcutaneous
  • i.v. intravenous
  • i.m. intramuscular
  • intrastemal injection or infusion techniques.
  • peptide polypeptide
  • protein protein
  • a protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein’s or peptide’s sequence.
  • Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds.
  • polypeptides include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others.
  • the polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof.
  • a “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.
  • treating a disease or disorder means reducing the frequency with which a symptom of the disease or disorder is experienced by a patient.
  • Disease and disorder are used interchangeably herein.
  • terapéuticaally effective amount refers to an amount that is sufficient or effective to prevent or treat (delay or prevent the onset of, prevent the progression of, inhibit, decrease or reverse) a disease or condition, including alleviating symptoms of such diseases.
  • the term “attached to” refers to attaching two chemical groups through a chemical bond, for example a covalent bond or a non-covalent bond.
  • an element means one element or more than one element.
  • ranges throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
  • Proliposomes an alternative form of liposomes enabling rapid conversion on gentle hydration represents a unique design with increased shelf-life.
  • These powder-based formulations also allow for expanding the usage landscape of traditional liposomes to areas of inhalation, solid oral dosage forms, etc. (Omer, H. K. et al., 2018, AAPS PharmSciTech., 19, 2434; Arregui, J. R. et al., 2018, AAPS PharmSciTech., 19, 1802).
  • Their spatial arrangement with hydrophilic surface (coat) and lipophilic core allows provides opportunity for avoiding/delaying opsonization.
  • the structural disruption, drug leakage from vehicles, or phase transition associated with few of the manufacturing techniques used for proliposome fabrication highlights the need to seek better and more efficient fabrication techniques.
  • Proliposomes are an alternate form of liposomes, which may be converted into liposomes by hydration of the lipids. Proliposomes may be preferred over liposomes due to an increased shelf-life and ability to be converted into liposomes by adding buffer or water to the developed proliposomes, followed by agitation of the solution. They represent an elegant way to deposit drugs and phospholipids onto the microporous structure of water-soluble carrier without hampering the free-flowing surface characteristics of the carriers. This opens them up for use in different routes of administration including inhalation and solid dosage forms. Traditionally, techniques including spray drying, film deposition on carrier method, fluidized bed method and supercritical anti-solvent method are commonly used for the fabrication of proliposomes (Singh, N.
  • liposomes may comprise phospholipids and may be used for various biomedical applications, but use is restricted due to a typically short shelf-life and strict storage conditions.
  • Anticancer drugs in the form of liposomes or proliposomes may exhibit enhanced anticancer efficacy of the chemotherapeutic agents, such as established through active and passive targeting mechanisms.
  • Passive targeting for example, may be accomplished by avoiding/delaying opsonization, which in turn may be achieved through a cancer-simulated environment, a petite size of less than 200 nm, and/or steric stabilization through a hydrophilic surface (coat) and lipophilic core.
  • Proliposomes are associated with a hydrophilic surface, based on hydrophilic carrier, and lipophilic core, based on phospholipids, and so are useful for improved anticancer efficacy.
  • prior proliposomes produced by known methods are unable to fulfill the criteria of enhanced permeation and retention effect (EPR) and anticancer efficacy, such as due to the large size resulting from a dense coating with hydrophilic carrier.
  • EPR enhanced permeation and retention effect
  • anticancer efficacy such as due to the large size resulting from a dense coating with hydrophilic carrier.
  • conversion of large-sized proliposomes into a smaller size to make them suitable drug delivery carriers for anticancer treatment can be achieved through passive targeting various high-energy stress-based size reduction techniques like probe sonication.
  • proliposomes can be developed by thin film hydration techniques, which may be associated with the risk of instability regarding thermolabile excipients.
  • the present invention relates to, in part, liposomes, proliposomes and liposomal and proliposomal compositions comprising liposomes and/or proliposomes.
  • the liposomes and/or proliposomes comprise a layer of phospholipid, wherein the layer of phospholipid encapsulates an active pharmaceutical ingredient.
  • the liposomes and/or proliposomes have very small cross-sectional dimensions with a very uniform size distribution or dispersity (poly dispersity index, PDI).
  • proliposomes can be converted to liposomes by dispersing the proliposomes in a solvent.
  • the liposomes and proliposomes described herein have a markedly improved character for delivering the active pharmaceutical ingredient to a subject as compared to known liposomes and proliposomes.
  • Fig. 1 provides a schematic overview of an example proliposome 125 having a composition as described herein.
  • Proliposome 125 may have an outer shell of a phospholipid layer 130, composed of phospholipid 100.
  • the outer shell comprising phospholipid layer 130 may be in the form of continuous layer encapsulating an active pharmaceutical ingredient 120 as well as excipients, such as stabilizer 105, surfactant 110, and carrier 115.
  • Fig. 2 provides a schematic overview of an example liposome 235 having a composition as described herein.
  • liposome 235 is dispersed in solvent 230 and may have a lipid bilayer 240, composed of phospholipid 200.
  • the lipid bilayer 240 may be in the form of a continuous layer encapsulating an active pharmaceutical ingredient 220 as well as excipients, such as stabilizer 205, surfactant 210, and carrier 215.
  • Exemplary solvents include, but are not limited to, water, buffer solution, saline, organic solvent, and/or any combination thereof.
  • Exemplary organic solvents include, but are not limited to, methanol, ethanol, butanol, isopropanol, acetic acid, acetone, dichloromethane, Transcutol®(Diethylene glycol monoethyl ether), n-hexane, DMSO, acetonitrile, ethyl acetate and chloroform.
  • the present invention provides, in part, a composition comprising proliposomes, wherein the proliposomes comprise: a phospholipid; a stabilizer; a surfactant; a hydrophilic carrier; and an active pharmaceutical ingredient.
  • Exemplary phospholipids include, but are not limited to, Phospolipon 90 G, Phosphatidylcholine (PC), Phosphatidylethanolamine (PE), Phosphatidylserine (PS), Phosphatidylinositol (PI), Phosphatidic acid (PA), Sphingomyelin (SM), Cardiolipin (CL), Lysophosphatidylcholine (LPC), Lysophosphatidylethanolamine (LPE), Phosphatidylglycerophosphate (PGP), Phosphatidylinositol phosphate (PIP), Phosphatidylthreonine (PT), Phosphatidyl sulfate (PSA), Phosphatidylglyceroside (PGS), Plasmalogens (e g., plasmenylcholine, plasmenylethanolamine), and any combination thereof.
  • PC Phos
  • the phospholipid further comprises cholesterol.
  • the phosphatidylcholine is selected from the group consisting of l,2-didecanoyl-sn-glycero-3 -phosphocholine (DDPC), 1,2-dierucoyl-sn- glycero-3-phosphocholine (DEPC), l,2-dilinoleoyl-sn-glycero-3 -phosphocholine (DLOPC), l,2-dilauroyl-sn-glycero-3 -phosphocholine (DLPC), 1,2-dimyristoyl-sn- glycero-3-phosphocholine (DMPC), l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3 -phosphocholine (DPPC), l,2-distearoyl-sn-glycero-3- phosphocholine (DDPC), 1,2-dierucoy
  • the phospholipid is a lysophosphatidylcholine.
  • the lysophosphatidylcholine phosphatidylglycerol is selected from the group consisting of l-myristoyl-sn-glycero-3-phosphocholine, 1- palmitoyl-sn-glycero-3 -phosphocholine, and l-stearoyl-sn-glycero-3 -phosphocholine.
  • the phospholipid is a phosphatidic acid sodium salt.
  • the phosphatidic acid sodium salt is selected from the group consisting of l,2-dierucoyl-sn-glycero-3 -phosphate sodium salt (DEPA-NA), 1,2- dilauroyl-sn-glycero-3-phosphate sodium salt (DLPA-NA), l,2-dimyristoyl-sn-glycero-3- phosphate sodium salt (DMPA-NA), l,2-dioleoyl-sn-glycero-3 -phosphate sodium salt (DOPA-NA), l,2-dipalmitoyl-sn-glycero-3-phosphate sodium salt (DPPA-NA), 1,2- distearoyl-sn-glycero-3-phosphate sodium salt (DSPA-NA), and mixtures thereof.
  • DEPA-NA 1,2- dilauroyl-sn-glycero-3-phosphate sodium salt
  • DLPA-NA 1,2-
  • the phospholipid is a phosphatidylglycerol.
  • the phosphatidylglycerol is selected from the group consisting of 1,2-dierucoyl phosphatidylglycerol (DEPG), 1,2-dilauroyl phosphatidylglycerol (DLPG), 1,2-dimyristoyl phosphatidylglycerol (DMPG), 1,2-dioleoyl phosphatidyl glycerol (DOPG), 1,2-dipalmitoyl phosphatidylglycerol (DPPG), 1,2- distearoyl phosphatidylglycerol (DSPG), l-palmitoyl-2- oleoyl phosphatidylglycerol (POPG), egg phosphatidylglycerol (EPG), salts of any of the foregoing (e.g., sodium, ammonium, or sodium/ammonium), and mixtures
  • EPG egg phosphati
  • the phospholipid is a phosphatidylserine.
  • the phosphatidylserine is selected from the group consisting of l,2-dilauroyl-sn-glycero-3 -phosphoserine sodium salt (DLPS-NA), 1,2-dimyristoyl-sn- glycero-3 -phosphoserine sodium salt (DMPS-NA), l,2-dioleoyl-sn-glycero-3- phosphoserine sodium salt (DOPS-NA), l,2-dipalmitoyl-sn-glycero-3-phosphoserine sodium salt (DPPS-NA), l,2-distearoyl-sn-glycero-3-phosphoserine sodium salt (DSPS- NA) and mixtures thereof.
  • DLPS-NA l,2-dilauroyl-sn-glycero-3 -phosphoserine sodium salt
  • DMPS-NA 1,2-dimyristoyl-s
  • the phospholipid is a phosphatidylethanolamine.
  • the phosphatidylethanolamine is selected from the group consisting of l,2-dierucoyl-sn-glycero-3-phosphoethanolamine (DEPE), 1,2-dilauroyl-sn- glycero-3-phosphoethanolamine (DLPE), l,2-dimyristoyl-sn-glycero-3- phosphoethanolamine (DMPE), l,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), l,2-dipalmitoyl-sn-glycero-3 -phosphoethanolamine (DPPE), 1,2-distearoyl-sn- glycero-3-phosphoethanolamine (DSPE), and l-palmitoyl-2-oleoyl-sn-glycero-3- phosphoethanolamine (POPE) and mixtures thereof.
  • DEPE 1,2-dilauroyl-sn- glycer
  • the phospholipid comprises a stabilizer.
  • stabilizers include, but are not limited to, cholesterol, ergosterol, P-Sitosterol, Stigmasterol, Campesterol, Fucosterol, 7-Dehydrocholesterol, Brassicasterol, Lanosterol, Cholestanol, Desmosterol, Coprostanol, Squalene, Squalane, Tocopherols (e.g., a- tocopherol, y-tocopherol), Tocotrienols (e.g., a-tocotrienol, y-tocotrienol), Dihydrocholesterol, 24-Methylenecholesterol, 24-Norcholesterol, 24,25- Dihydroxycholesterol, 25-Hydroxycholesterol, and any combination thereof.
  • the composition comprises a surfactant.
  • surfactants include, but are not limited to, Kolliphor P188 (Pol oxamer Pl 88), Kolliphor P407 (Poloxamer 407), Kolliphor P338 (Poloxamer 338), Kolliphor P124 (Poloxamer 124), Kolliphor P237 (Poloxamer 237), Polysorbate 80 (Tween 80), Polysorbate 20 (Tween 20), Sodium cholate, Sodium deoxycholate, Sodium taurocholate, Tween 80 (polysorbate 80), Tween 20 (polysorbate 20), Span 80 (sorbitan monooleate), Span 60 (sorbitan monostearate), Cetyltrimethylammonium bromide (CTAB), Sodium dodecyl sulfate (SDS), Polyethylene glycol (PEG), Sodium oleate, Lipid-based PEGylated surfactants (e.g., PEGyl
  • the composition comprises a carrier.
  • exemplary carriers include, but are not limited to, hydroxypropyl-P-cyclodextrin, Mannitol, Lactose, Sorbitol, Dextrose, Maltose, Sucrose, Fructose, Trehalose, Polyethylene glycol (PEG), Pol oxamer (e.g., Poloxamer 188, Poloxamer 407), Hydroxypropyl-P-cyclodextrin, Microcrystalline cellulose, Calcium carbonate, Calcium phosphate, Glucose (monohydrate), Lipid-based solid carriers (e.g., solid lipid nanoparticles, lipid powders), Polymeric carriers (e.g., poly(lactic-co-glycolic acid), polyvinyl alcohol), and any combination thereof.
  • the carrier is hydrophilic.
  • the composition comprises hydroxypropyl-P-cyclodextrin.
  • the composition comprises an active pharmaceutical ingredient.
  • active pharmaceuticals include, but are not limited to, chemotherapeutic, a hormone, a corticosteroid, a vasodilator, analgesics, antibiotics, antidepressants, antipsychotics, anticoagulants, antihypertensives, anti-inflammatories, antihistamines, biologies, bronchodilators, diuretics, antidiabetic drugs, anticonvulsants, immunosuppressants, antiemetics, antivirals, antifungals, sedatives, stimulants, antineoplastics, antiretrovirals, antimalarials, anticholinergics, antispasmodics, antihyperlipidemics, proton pump inhibitors, antacids, laxatives, anticoagulant reversal agents, bone resorption inhibitors, antiplatelet drugs, antianxiety medications, antithyroid drugs, antihistamine-decongestant combinations, antitussives
  • compositions may be docetaxel, levonorgestrel, sorafenib, sorafenib, dexamethasone, ketoconazole, and/or any combination thereof.
  • the composition comprises an active pharmaceutical ingredient selected from the group consisting of docetaxel, levonorgestrel, sorafenib, indomethacin, dexamethasone, ketoconazole, and combinations thereof.
  • the composition further comprises an additional bioactive agent.
  • the additional bioactive agent is a chemotherapeutic agent.
  • chemotherapeutic agents include, but are not limited to, cytotoxic agents (e.g., 5-fluorouracil, cisplatin, carboplatin, methotrexate, daunorubicin, doxorubicin, vincristine, vinblastine, oxorubicin, carmustine (BCNU), lomustine (CCNU), cytarabine USP, cyclophosphamide, estramucine phosphate sodium, altretamine, hydroxyurea, ifosfamide, procarbazine, mitomycin, busulfan, cyclophosphamide, mitoxantrone, carboplatin, cisplatin, interferon alfa-2a recombinant, paclitaxel, teniposide, and streptozoci), cytotoxic alkylating agents (e.g., busulfan, chlorambucil, cyclophosphamide, melphalan, or eth
  • the chemotherapeutic agent is an antiproliferative agent.
  • Antiproliferative agents are compounds that decrease the proliferation of cells.
  • Antiproliferative agents include alkylating agents, antimetabolites, enzymes, biological response modifiers, miscellaneous agents, hormones and antagonists, androgen inhibitors (e.g., flutamide and leuprolide acetate), antiestrogens (e.g., tamoxifen citrate and analogs thereof, toremifene, droloxifene and roloxifene), Additional examples of specific antiproliferative agents include, but are not limited to levamisole, gallium nitrate, granisetron, sargramostim strontium-89 chloride, filgrastim, pilocarpine, dexrazoxane, and ondansetron.
  • the chemotherapeutic agent is a cytotoxic/antineoplastic agent or an anti-angiogenic agent.
  • Cytotoxic/anti -neoplastic agents are defined as agents which attack and kill cancer cells.
  • Some cytotoxic/antineoplastic agents are alkylating agents, which alkylate the genetic material in tumor cells, e.g., cis-platin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacabazine.
  • cytotoxic/anti-neoplastic agents are antimetabolites for tumor cells, e.g., cytosine arabinoside, fluorouracil, methotrexate, mercaptopuirine, azathioprime, and procarbazine.
  • Other cytotoxic/anti-neoplastic agents are antibiotics, e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin.
  • doxorubicin e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin.
  • mitotic inhibitors (vinca alkaloids).
  • cytotoxic/anti-neoplastic agents include taxol and its derivatives, L-asparaginase, antitumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.
  • Anti -angiogenic agents are well known to those of skill in the art. Suitable anti -angiogenic agents for use in the methods and compositions of the present disclosure include anti-VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers and antisense oligonucleotides. Other known inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 (including alpha and beta) interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinase- 1 and -2. (TIMP-1 and -2). Small molecules, including topoisomerases such as razoxane, a topoisomerase II inhibitor with anti-angiogenic activity, can also be used.
  • the chemotherapeutic agent is selected from the group consisting of acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; bortezomib; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin
  • anti-cancer drugs include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-
  • the active pharmaceutical ingredient is a hormone of natural or synthetic origin, and include but are not limited to, insulin, triamcinolone, testosterone, levonorgestrel, estradiol, phytoestrogen, estrone, dexamethasone, ethynodiol, prednisone, desogestrel, cyproterone, norethindrone, megestrol, hydrocortisone, danazol, cortisone acetate, aviane, nandrolone, fluoxymesterone, fludrocortisone, fluoxymesterone dexamethasone levora fludrocortisone low-ogestrel methylprednisolone, necon, levonorgestrel, estropipate, levoxyl, methimazole, propylthiouracil desmopressin, prednisolone orgestrel norethindrone triamcinolone trivora zovia gesto
  • the active pharmaceutical ingredient is a corticosteroid.
  • corticosteroids include, but are not limited to, prednisolone, hydrocorticosterone, prednisone, methylprednisolone, dexamethasone, betamethasone, triamcinolone Triamcinolone, beclometasone, fludrocortisone acetate, fluticasone (including fluticasone propionate (FP)), budesonide, ciclesonide), mometasone and flunisolide.
  • the ratio of phospholipid to stabilizer is about 1 : 1. In one embodiment, the ratio of phospholipid to surfactant is about 2: 1. In certain embodiments, the proliposomal composition is a powder. In one embodiment, the particle size of the composition is less than about 200 nm. In one embodiment, the particle size of the composition ranges from 50 nm to 200 nm. In one embodiment, the particle size of the composition ranges from 60 nm to 200 nm. In one embodiment, the particle size of the composition ranges from 70 nm to 200 nm. In one embodiment, the particle size of the composition ranges from 80 nm to 200 nm. In one embodiment, the particle size of the composition ranges from 90 nm to 200 nm.
  • the particle size of the composition ranges from 100 nm to 200 nm. In one embodiment, the particle size of the composition ranges from 50 nm to 150 nm. In one embodiment, the particle size of the composition ranges from 60 nm to 150 nm. In one embodiment, the particle size of the composition ranges from 70 nm to 150 nm. In one embodiment, the particle size of the composition ranges from 80 nm to 150 nm. In one embodiment, the particle size of the composition ranges from 90 nm to 150 nm. In one embodiment, the particle size of the composition ranges from 100 nm to 150 nm. In one embodiment, the particle size of the composition ranges from 50 nm to 140 nm.
  • the particle size of the composition ranges from 50 nm to 130 nm. In one embodiment, the particle size of the composition ranges from 50 nm to 120 nm. In one embodiment, the particle size of the composition ranges from 50 nm to 110 nm. In one embodiment, the particle size of the composition ranges from 50 nm to 100 nm. In one embodiment, the particle size of the composition ranges from 60 nm to 100 nm. In one embodiment, the particle size of the composition ranges from 60 nm to 90 nm. In one embodiment, the particle size of the composition ranges from 60 nm to 80 nm. In one embodiment, the particle size of the composition ranges from 70 nm to 90 nm.
  • the particle size of the composition ranges from 80 nm to 90 nm. In one embodiment, the particle size of the composition is about 50 nm. In one embodiment, the particle size of the composition is about 60 nm. In one embodiment, the particle size of the composition is about 70 nm. In one embodiment, the particle size of the composition is about 80 nm. In one embodiment, the particle size of the composition is about 90 nm. In one embodiment, the particle size of the composition is about 100 nm. In one embodiment, the particle size of the composition is about 110 nm. In one embodiment, the particle size of the composition is about 120 nm. In one embodiment, the particle size of the composition is about 130 nm.
  • the particle size of the composition is about 140 nm. In one embodiment, the particle size of the composition is about 150 nm. In one embodiment, the particle size of the composition is about 160 nm. In one embodiment, the particle size of the composition is about 170 nm. In one embodiment, the particle size of the composition is about 180 nm. In one embodiment, the particle size of the composition is about 190 nm. In one embodiment, the particle size of the composition is about 200 nm.
  • the composition has a poly dispersity index of 0.01 Mw/Mn to 0.5 Mw/Mn. In one embodiment, the composition has a poly dispersity index of 0.01 Mw/Mn to 0.4 Mw/Mn. In one embodiment, the composition has a polydispersity index of 0.01 Mw/Mn to 0.3 Mw/Mn. In one embodiment, the composition has a poly dispersity index of 0.1 Mw/Mn to 0.5 Mw/Mn. Tn one embodiment, the composition has a poly dispersity index of 0.1 Mw/Mn to 0.4 Mw/Mn. In one embodiment, the composition has a poly dispersity index of 0.1 Mw/Mn to 0.3 Mw/Mn.
  • the composition has a poly dispersity index of 0.1 Mw/Mn to 0.2 Mw/Mn. In one embodiment, the composition has a polydispersity index of 0.2 Mw/Mn to 0.3 Mw/Mn. In one embodiment, the composition has a poly dispersity index of about 0.1 Mw/Mn. In one embodiment, the composition has a poly dispersity index of about 0.2 Mw/Mn. In one embodiment, the composition has a poly dispersity index of about 0.3 Mw/Mn.
  • compositions described herein may comprise salts with acids or bases, and such salts are included in the present invention.
  • salts embraces addition salts of free acids or free basis that are useful within the methods of the invention. Salts may possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis or purification of compounds useful within the methods of the invention.
  • Suitable salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include perchlorate, hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, dibenzoyltartaric, dibenzyltartaric, benzoyltartaric, benzyltartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesul
  • the present invention further provides a method of making or generating the proliposomes described herein.
  • a method for the generation of proliposomes is depicted.
  • the method may include a step of preparing a solution 335 by optionally adding to a solvent 330 one or more of a phospholipid 300, a stabilizer 305, a surfactant 310, a carrier 315, and an active pharmaceutical ingredient 320.
  • the solution can then be transferred to any suitable extrusion-based printing method 340.
  • the extrusion-based printing method 340 may be, but is not limited to, extrusion bioprinting, extrusion 3D printing, inkjet printing, electrohydrodynamic jetting, microfluidic printing, or any combination thereof.
  • the solution can be caused to atomize generating a plurality of droplets 345.
  • the pressure may be about 50 kPa, about 51 kPa, about 52 kPa, about 53 kPa, about 54 kPa, about 55 kPa, about 56 kPa, about 57 kPa, about 58 kPa, about 59 kPa, about 60 kPa, from 50 kPa to 600, from 50 kPa to 500 kPa, from 50 kPa to 400 kPa, from 50 kPa to 300 kPa, from 50 kPa to 200 kPa, from 50 kPa to 100 kPa, from 50 kPa to 60 kPa, from 60 kPa to 70 kPa, from 70 kPa to 80 kPa, from 80 kPa to 90 kPa, from 90 kPa to 100 kPa, from 50 kPa to 60
  • the temperature of solution 230 during printing may be from -30 °C to 80 °C, from -20 °C to -15 °C, from -15 °C to -10 °C, from -10 °C to -5 °C, from -5 °C to 0 °C, from 0 °C to 5 °C, from 5 °C to 10 °C, from 10 °C to 15 °C, from 15 °C to 20 °C, from 20 °C to 25 °C, from 25 °C to 30 °C, from 30 °C to 35 °C, from 35 °C to 40 °C, from 40 °C to 45 °C, from 45 °C to 50 °C, from 50 °C to 55 °C, from 55 °C to 60 °C, from 60 °C to 65 °C, from 65 °C to 70 °C, from 70 °C to 75 °C, and/or from 75 °C to 80
  • the temperature is about -30. In one embodiment, the temperature is about -29 °C. In one embodiment, the temperature is about -28 °C. In one embodiment, the temperature is about -27 °C. In one embodiment, the temperature is about -26 °C. In one embodiment, the temperature is about -25 °C. In one embodiment, the temperature is about -24 °C. In one embodiment, the temperature is about -23 °C. In one embodiment, the temperature is about -22 °C. In one embodiment, the temperature is about -21 °C. In one embodiment, the temperature is about -20 °C.
  • the plurality of droplets may be generated upon, or collected within, any suitable surface 350.
  • the plurality of droplets may then be subjected to drying conditions to generate proliposome 325.
  • the drying conditions comprise lyophilization.
  • lyophilization is performed at a pressure of 90 mTorr to 110 mTorr. In one embodiment, the lyophilization pressure is about 90.1 mTorr. In one embodiment, the lyophilization pressure is about 90.2 mTorr. In one embodiment, the lyophilization pressure is about 90.3 mTorr. In one embodiment, the lyophilization pressure is about 90.4 mTorr. In one embodiment, the lyophilization pressure is about 90.5 mTorr. In one embodiment, the lyophilization pressure is about 90.6 mTorr. In one embodiment, the lyophilization pressure is about 90.7 mTorr. In one embodiment, the lyophilization pressure is about 90.8 mTorr.
  • the lyophilization pressure is about 90.9 mTorr. In one embodiment, the lyophilization pressure is about 91.0 mTorr. In one embodiment, the lyophilization pressure is about 92 mTorr. In one embodiment, the lyophilization pressure is about 93 mTorr. In one embodiment, the lyophilization pressure is about 94 mTorr. In one embodiment, the lyophilization pressure is about 95 mTorr. In one embodiment, the lyophilization pressure is about 100 mTorr. In one embodiment, the lyophilization pressure is about 105 mTorr. In one embodiment, the lyophilization pressure is about 110 mTorr.
  • the lyophilization temperature may be about -20 °C, about -19 °C, about -18 °C, about -17 °C, about -16 °C, about -15 °C, about -14 °C, about -13 °C, about -12 °C, about -11 °C, about -10 °C, about 0 °C, about 10 °C, about 20 °C, about 30 °C, about 40 °C, about 50 °C, about 60 °C, about 70 °C, and/or about 80 °C.
  • An example duration for lyophilization may be about 180 minutes to about 24 hours.
  • the duration may be about 160 minutes, about 161 minutes, about 162 minutes, about 163 minutes, about 164 minutes, about 165 minutes, about 170 minutes, about 175 minutes, about 180 minutes, about 190 minutes, about 4 hours, about 6 hours, about 10 hours, about 16 hours, and/or about 24 hours.
  • Proliposomes 325 generated by the method depicted in Fig. 3 exhibit enhanced stability.
  • the proliposomes exhibit enhanced stability when stored at temperatures less than or at about 4 °C.
  • the proliposomes are stored at a temperature of about 2 °C.
  • the proliposomes are stored at a temperature of about 2.1 °C.
  • the proliposomes are stored at a temperature of about 2.2 °C. In one embodiment, the proliposomes are stored at a temperature of about 2.3 °C. In one embodiment, the proliposomes are stored at a temperature of about 2.4 °C. In one embodiment, the proliposomes are stored at a temperature of about 2.5 °C. In one embodiment, the proliposomes are stored at a temperature of about 2.6 °C. In one embodiment, the proliposomes are stored at a temperature of about 2.7 °C. In one embodiment, the proliposomes are stored at a temperature of about 2.8 °C. In one embodiment, the proliposomes are stored at a temperature of about 2.9 °C.
  • the proliposomes are stored at a temperature of about 3 °C. In one embodiment, the proliposomes are stored at a temperature of 3 °C to 4 °C. In one embodiment, the proliposomes are stored at a temperature of 4 °C to 5 °C. In one embodiment, the proliposomes are stored at a temperature of 5 °C to 6 °C. In one embodiment, the proliposomes are stored at a temperature of 6 °C to 7 °C. In one embodiment, the proliposomes are stored at a temperature of 7 °C to 8 °C. In one embodiment, the proliposomes are stored at a temperature greater than 8 °C.
  • the proliposomes 325 are shelf stable for at least 30 days. In some examples, the proliposomes are stored for longer than 30 days. In some embodiments, the proliposomes maintain the form of the proliposomes 325 or inclusion of the active pharmaceutical ingredient 320 or the ability to be rapidly constituted or reconstituted into a liposomal form.
  • Fig. 4 depicts a schematic overview of a method for generating liposomes 435.
  • Solution 440 is generated by providing proliposomes 425 including a pharmaceutical ingredient, which may be the same as or different from proliposomes 125 or proliposomes 325, to a solvent 430.
  • Fig. 4 depicts the proliposomes 425 being added to a container holding the solvent 430, in some examples, the solvent 430 may be added to the proliposomes 425 or a container holding the proliposomes 425.
  • Example solvents include, but are not limited to water, an aqueous mixture, and/or one or more of ethanol, acetone, methanol, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), ethyl acetate, diethyl ether, chloroform, hexane, toluene, xylene, N,N-dimethylformamide (DMF), dichloromethane, acetonitrile, ethylene glycol, isopropyl alcohol, butanol, carbon disulfide, dimethyl carbonate, and/or propylene carbonate.
  • Liposomes 435 may be rapidly generated upon proliposomes 425 and solvent 430 coming into contact, such that the phospholipid component of proliposomes 425 may restructure to form a phospholipid bilayer.
  • the liposomes 435 may have a shelf life of about 30 days in solution 440, such as when stored in ambient or reduced temperature conditions, for example 25 °C or less and 1 atmosphere. In one embodiment, liposomes 435 are stored in ambient or reduced temperature conditions.
  • the temperature is from 20 °C to 30 °C. In one embodiment, the temperature is from 21 °C to 30 °C. In one embodiment, the temperature is from 22 °C to 30 °C. In one embodiment, the temperature is from 23 °C to 30 °C. In one embodiment, the temperature is from 24 °C to 30 °C. In one embodiment, the temperature is from 25 °C to 30 °C. In one embodiment, the temperature is from 26 °C to 30 °C.
  • the temperature is from 27 °C to 30 °C. In one embodiment, the temperature is from 28 °C to 30 °C. In one embodiment, the temperature is from 29 °C to 30 °C. In one embodiment, the temperature is from 20 °C to 21 °C. In one embodiment, the temperature is from 20 °C to 22 °C. In one embodiment, the temperature is from 20 °C to 23 °C. In one embodiment, the temperature is from 20 °C to 24 °C. In one embodiment, the temperature is from 20 °C to 25 °C.
  • the temperature is about 20 °C. In one embodiment, the temperature is about 21 °C. In one embodiment, the temperature is about 22 °C. In one embodiment, the temperature is about 23 °C. In one embodiment, the temperature is about 24 °C. In one embodiment, the temperature is about 25 °C. In one embodiment, the temperature is about 20 °C to about 25 °C, and/or about 25 °C to about 30 °C.
  • the liposomes are stored at ambient pressure. In one embodiment, the liposomes are stored at a pressure of 0.8 atm to 1.2 atm. In one embodiment, the liposomes are stored at a pressure of about 0.8 atm. In one embodiment, the liposomes are stored at a pressure of about 0.9 atm. In one embodiment, the liposomes are stored at a pressure of about 1.0 atm. In one embodiment, the liposomes are stored at a pressure of about 1.1 atm. In one embodiment, the liposomes are stored at a pressure of about 1.2 atm.
  • compositions such as proliposomes 125, liposomes 235, proliposomes 325, proliposomes 425, or liposomes 435, may be administered to a patient or subject, such as a patient or subject in need thereof.
  • the patient or subject has a disease, disorder, or medical condition. As depicted in Fig.
  • the compositions may be administered as a formulation such as an oral formulation 500, an inhalation formulation 507, a parenteral formulation 505, a sublingual formulation 510, a topical formulation 506, a transdermal formulation 504, a nasal formulation 501, a ocular formulation 502, a otic formulation 503, a rectal formulation 508, a vaginal formulation 509, and/or any combination thereof.
  • any of the formulations may be sterile formulations or non-sterile formulations.
  • the disease or disorder is cancer, such as, but not limited to, Acute Lymphoblastic; Acute Myeloid Leukemia; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; Appendix Cancer; Basal Cell Carcinoma; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bone Cancer; Osteosarcoma and Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Childhood; Central Nervous System Embryonal Tumors; Cerebellar Astrocytoma; Cerebral Astrocytotna/Malignant Glioma; Craniopharyngioma; Ependymoblasto
  • parenteral administration of a composition of the invention includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue.
  • Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like.
  • parenteral administration is contemplated to include, but is not limited to, intravenous, subcutaneous, intraperitoneal, intramuscular, intrasternal injection, bolus injections, and kidney dialytic infusion techniques.
  • parenteral administration includes depositing a composition of the present invention into an artery of a subject.
  • compositions comprising proliposomal compositions of the present invention.
  • the pharmaceutical compositions may be suitable for a variety of modes of administration described herein, including for example systemic or localized administration.
  • the pharmaceutical compositions can be in the form of eye drops, injectable solutions, or in a form suitable for inhalation (either through the mouth or the nose) or oral administration.
  • the pharmaceutical compositions described herein can be packaged in single unit dosages or in multidosage forms.
  • the pharmaceutical compositions comprise a pharmaceutically acceptable carrier suitable for administration to human. In some embodiments, the pharmaceutical compositions comprise a pharmaceutically acceptable carrier suitable for intraocular injection. In some embodiments, the pharmaceutical compositions comprise a pharmaceutically acceptable carrier suitable for topical application. In some embodiments, the pharmaceutical compositions comprise a pharmaceutically acceptable carrier suitable for intravenous injection. In some embodiments, the pharmaceutical compositions comprise and a pharmaceutically acceptable carrier suitable for injection into the arteries.
  • the pharmaceutical compositions are generally formulated as sterile, substantially isotonic, and in full compliance with all Good Manufacturing Practice (GMP) regulations of the U.S. Food and Drug Administration.
  • the composition is free of pathogen.
  • the pharmaceutical composition can be in the form of liquid solutions, for example in physiologically compatible buffers such as Hank's solution or Ringer's solution.
  • the pharmaceutical composition can be in a solid form and redissolved or suspended immediately prior to use. Lyophilized compositions are also included.
  • the pharmaceutical compositions can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate).
  • binding agents e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato star
  • Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., ationd oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid).
  • the preparations can also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
  • compositions comprising proliposomal compositions and a pharmaceutically acceptable carrier suitable for administration to the eye.
  • pharmaceutical carriers can be sterile liquids, such as water and oil, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, and the like.
  • Saline solutions and aqueous dextrose, polyethylene glycol (PEG) and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, sodium state, glycerol monostearate, glycerol, propylene, water, and the like.
  • the pharmaceutical composition can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • the proliposomal compositions and other components of the composition may be encased in polymers or fibrin glues to provide controlled release of the molecule.
  • These compositions can take the form of solutions, suspensions, emulsions, ointment, gel, or other solid or semisolid compositions, and the like.
  • the pharmaceutical compositions typically have a pH in the range of 4.5 to 8.0.
  • the compositions must also be formulated to have osmotic values that are compatible with the aqueous humor of the eye and ophthalmic tissues. Such osmotic values will generally be in the range of from about 200 to about 400 milli osmoles per kilogram of water (“mOsm/kg”), but will preferably be about 300 mOsm/kg.
  • the pharmaceutical composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for injection intravenously, intraperitoneally, or intravitreally.
  • compositions for injection are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • compositions may further comprise additional ingredients, for example preservatives, buffers, tonicity agents, antioxidants and stabilizers, nonionic wetting or clarifying agents, viscosity-increasing agents, and the like.
  • additional ingredients for example preservatives, buffers, tonicity agents, antioxidants and stabilizers, nonionic wetting or clarifying agents, viscosity-increasing agents, and the like.
  • Suitable preservatives for use in a solution include polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, benzethonium chloride, and the like.
  • such preservatives are employed at a level of from 0.001% to 1.0% by weight.
  • Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, sodium biphosphate and the like, in amounts sufficient to maintain the pH at between about pH 6 and pH 8, and preferably, between about pH 7 and pH 7.5.
  • Suitable tonicity agents are dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, and the like, such that the sodium chloride equivalent of the ophthalmic solution is in the range 0.9 plus or minus 0.2%.
  • Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea and the like.
  • Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol.
  • Suitable viscosity-increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxmethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose and the like.
  • viscosity enhancing agents to provide topical compositions with viscosities greater than the viscosity of simple aqueous solutions may be desirable.
  • viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose or other agents know to those skilled in the art. Such agents are typically employed at a level of from 0.01% to 2% by weight.
  • a pharmaceutical composition for delivery of a nucleotide encapsulated in a proliposomal composition can be in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle or compound is imbedded.
  • the pharmaceutical composition can comprise one or more cells which produce the gene delivery system.
  • a gene delivery system for a gene therapeutic can be introduced into a subject by any of a number of methods.
  • a pharmaceutical composition of the gene delivery system can be introduced systemically, e.g., by intravenous injection, and specific transduction of the protein in the target cells occurs predominantly from specificity of transfection provided by the gene delivery vehicle, cell-type or tissue-type expression due to the transcriptional regulatory sequences controlling expression of the receptor gene, or a combination thereof.
  • initial delivery of the recombinant gene is more limited with introduction into the animal being quite localized.
  • the gene delivery vehicle can be introduced by catheter, See U.S. Pat. No. 5,328,470, or by stereotactic injection, Chen et al. (1994), Proc.
  • the pharmaceutical compositions comprise one or more excipients (also called adjuvants).
  • excipients refers to pharmaceutically acceptable carriers that are relatively inert substances used to facilitate administration or delivery of an active pharmaceutical ingredient into a subject or used to facilitate the processing of an active pharmaceutical ingredient into drug formulations that can be used pharmaceutically for delivery to the site of action in a subject.
  • excipients include polymer-carriers, stabilizing agents, surfactants, surface modifiers, solubility enhancers, buffers, encapsulating agents, antioxidants, preservatives, nonionic wetting or clarifying agents, viscosity-increasing agents, and absorption-enhancing agents.
  • the pharmaceutical composition is substantially, essentially, or entirely free of any other excipient.
  • excipients for use with the present disclosure include, lactose, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, polyvinyl pyrrolidone, dried starch, sodium alginate, powdered agar, calcium carmelose, a mixture of starch and lactose, sucrose, butter, hydrogenated oil, a mixture of a quaternary ammonium base and sodium lauryl sulfate, glycerine and starch, lactose, bentonite, colloidal silicic acid, talc, stearates, and polyethylene glycol, sorbitan esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, poloxamers
  • excipients and adjuvants may be used in the pharmaceutical composition to enhance the efficacy and efficiency of the active pharmaceutical ingredient in the pharmaceutical composition.
  • Additional non-limiting examples of compounds that can be included are binders, carriers, cryoprotectants, lyoprotectants, surfactants, fillers, stabilizers, polymers, protease inhibitors, antioxidants, bioavailability enhancers, and absorption enhancers.
  • the excipients may be chosen to modify the intended function of the active ingredient by improving flow, or bioavailability, or to control or delay the release of the API.
  • sucrose trehalose
  • Span 80 Span 20
  • Tween 80 Brij 35
  • Brij 98 Pluronic
  • sucroester 7 sucroester 11
  • sucroester 15 sodium lauryl sulfate (SLS, sodium dodecyl sulfate.
  • DDS dioctyl sodium sulphosuccinate
  • DSS dioctyl sodium sulphosuccinate
  • DOSS dioctyl docusate sodium
  • oleic acid laureth-9, laureth-8, lauric acid
  • vitamin E TPGS Cremophor® EL, Cremophor® RH
  • Gelucire® 50/13, Gelucire® 53/10, Gelucire® 44/14 Labrafil®
  • Solutol® HS dipalmitoyl phosphatidyl choline, glycolic acid and salts, deoxycholic acid and salts, sodium fusidate, cyclodextrins, polyethyleneglycols.
  • Labrasol® pol vinyl alcohols, polyvinyl pyrrolidones, and tyloxapol.
  • the stabilizing carrier may also contain various functional excipients, such as: hydrophilic polymer, antioxidant, super-disintegrant, surfactant including amphiphilic molecules, wetting agent, stabilizing agent, retardant, similar functional excipient, or a combination thereof, and plasticizers including citrate esters, polyethylene glycols, PG, triacetin, diethyl phthalate, castor oil, and others known to those of ordinary skill in the art.
  • Extruded material may also include an acidifying agent, adsorbent, alkalizing agent, buffering agent, colorant, flavorant, sweetening agent, diluent, opaquing agent, complexing agent, fragrance, preservative or a combination thereof.
  • compositions of the active pharmaceutical ingredient that enhance bioavailability may comprise a mixture of the active pharmaceutical ingredient and one or more pharmaceutically acceptable adjuvants that enhance the bioavailability of the active pharmaceutical ingredient.
  • adjuvants include but are not limited to enzyme inhibitors.
  • enzyme inhibitors include but are not limited to inhibitors that inhibit cytochrome P-450 enzyme and inhibitors that inhibit monoamine oxidase enzyme.
  • Bioavailability can be indicated by the Cmax or the AUC of the active pharmaceutical ingredient as determined during in vivo testing, where Cmaxis the highest reached blood level concentration of the active pharmaceutical ingredient over time of monitoring and AUC is the area under the plasma-time curve.
  • Enhanced bioavailability can be represented as the ratio of Cmax or the AUC of the active pharmaceutical ingredient in a pharmaceutical composition of the present disclosure compared to Cmax or the AUC of the reference standard the active pharmaceutical ingredient under the same conditions.
  • This Cmax or AUC ratio reflecting enhanced bioavailability can be about 5: 1, 6: 1, 7:1, 8: 1, 9: 1, 10: 1, 12: 1, 15: 1, 20: 1, 25: 1, 30: 1, 35:1, 40: 1, 45: 1, 50: 1, 55: 1, 60:1, 65:1, 70: 1, 75: 1, 80: 1, 85: 1, 90: 1, 95: 1, 98:1, 99:1, 100: 1 or higher.
  • the amount of the excipient in the pharmaceutical composition is from about 0.5% to about 20% w/w, from about 1% to about 10% w/w, from about 2% to about 8% w/w, or from about 3% to about 7% w/w.
  • the amount of the excipient in the pharmaceutical composition comprises from about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 9%, to about 10% w/w, or any range derivable therein, of the total pharmaceutical composition.
  • the amount of the excipient in the pharmaceutical composition is at 4% to 6% w/w of the total weight of the pharmaceutical composition.
  • the pharmaceutical composition may further comprise one or more inorganic or organic material that have a high surface area where the active pharmaceutical ingredient may be absorbed onto the material.
  • these components of the pharmaceutical compositions may be referred to as an absorbent. Without wishing to be bound by any theory, it is believed that the active pharmaceutical ingredient is retained on the surface of the absorbent. Then once absorbed onto the absorbent the active pharmaceutical ingredient may then cool or recrystallize to form an agglomerate with the surrounding particles to form a granule.
  • the absorbent may be either an inorganic or an organic compound.
  • the organic absorbent is an organic polymer such as cellulose or another pharmaceutically acceptable polymer. In other embodiments, the organic absorbent is a lipid.
  • the absorbent may be an inorganic absorbent such as silica or silicate composition.
  • the absorbent may comprise either a high porosity and a high surface area.
  • the porosity of the absorbent may be from about 1% to about 80%, from about 2% to about 60%, from about 5% to about 50%, or from about 10% to about 45%.
  • the porosity of the absorbent may be from about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, to about 80%, or any range derivable therein.
  • the absorbent may further comprise a high specific surface area as measured by the Brunauer, Emmett, and Teller (BET) specific surface area.
  • the specific surface area of the absorbent may be greater than 50 m 2 /g, greater than 100 m 2 /g, greater than 150 m 2 /g, greater than 200 m 2 /g, or greater than 250 m 2 /g, or greater than 300 m 2 /g.
  • the absorbent may have a specific surface area from about 50 m 2 /g to about 5,000 m 2 /g, from about 100 m 2 /g to about 2,000 m 2 /g, or from about 200 m 2 /g to about 500 m 2 /g.
  • the absorbent may comprise a specific surface area from about 50 m 2 /g, 75 m 2 /g, 100 m 2 /g, 150 m 2 /g, 175 m 2 /g, 200 m 2 /g, 225 m 2 /g, 250 m 2 /g, 275 m 2 /g, 300 m 2 /g, 400 m 2 /g, 500 m 2 /g, 600 m 2 /g, 700 m 2 /g, 750 m 2 /g, 800 m 2 /g, 900 m 2 /g, 1,000 m 2 /g, 2,000 m 2 /g, 5,000 m 2 /g, to about 10,000 m 2 /g, or any range derivable therein.
  • either the first absorbent or the second absorbent is silica.
  • Silica has a chemical formula of SiCh and may show multiple different polymorphic forms. These polymorphic forms include a-quartz, 0-quartz, a-tridymite, - tridymite, a-cristobalite, -cristobalite, keatite, moganite, coesite, stishovite, seifertite, melanophlogite, fibrous W-silica, or 2D silica.
  • the silica comprises one or more pores that pass through the silica. The pores within the silica may have a diameter of less than 100 nm.
  • the diameter of the pores in the silica may be less than 50 nm.
  • the diameter of the pores may be mesoporous such that the silica is mesoporous silica with diameters from 2 nm to about 50 nm.
  • the silica may be microporous silica with a diameter of less than 2 nm.
  • the diameter of the pores in the silica may be from about 0.1 nm, 0.5 nm, 1 nm, 2 nm, 3 nm, 4 nm, 5 nm, 10 nm, 15 nm, 20 nm, 25 nm, 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, to about 100 nm, or any range derivable therein.
  • the pharmaceutical composition may comprise a first absorbent or a second absorbent, wherein the absorbent is a silicate.
  • the silicate may comprise a formula of silicon and oxygen comprising a general formula of [SiC x 4 ‘ 2x ]n, wherein x is greater than or equal to 0 but less than 2.
  • These silicates may be either a salt or an ester of an alkyl group.
  • the salt may comprise a counterion of either a transition metal, a metalloid, an alkali earth metal, or an alkali metal.
  • the counterion may be either sodium, potassium, magnesium, calcium, and aluminum.
  • the silicate may further comprise one or more or more aluminum ions wherein the aluminum is a tetravalent ion that replaces one or more of the silicon. These materials are also known as aluminosilicate. Silicates may be either orthosilicate, metasilicate, pyrosilicate, or a polymeric silicate such as chains, rings, double chains, or sheets. The silicate may be formulated in manners that comprise one or more pores. The pores within the silicate may have a diameter of less than 100 nm. In some embodiments, the diameter of the pores in the silicate may be less than 50 nm.
  • the diameter of the pores may be mesoporous such that the silicate is a mesoporous silicate with diameters from 2 nm to about 50 nm.
  • the silicate may be microporous silicate with a diameter of less than 2 nm.
  • the diameter of the pores in the silicate may be from about 0.1 nm, 0.5 nm, 1 nm, 2 nm, 3 nm, 4 nm, 5 nm, 10 nm, 15 nm, 20 nm, 25 nm, 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, to about 100 nm, or any range derivable therein.
  • the pharmaceutical composition described herein have a concentration of each of the absorbents ranging from about 1% to about 49% w/w.
  • the amount of each absorbent is from about 1% to about 49% w/w, from about 2% to about 47.5% w/w, 2.5% to about 45% w/w, or 10% to about 40% w/w.
  • the amount of each absorbent may be from about 1%, 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 32.5%, 35%, 37.5%, 40%, 42.5%, 45%, 47.5%, to about 49%, or any range derivable therein.
  • Each of the absorbents may be present in the same amounts. Alternatively, the amount of each absorbent is present in a different amount.
  • the pharmaceutical composition is substantially, essentially, or entirely free of any other absorbents.
  • Embodiments describing pharmaceutical compositions herein are equally applicable to embodiments describing liposomal and/or proliposomal compositions, and vice versa.
  • the present invention further provides a method of processing the compositions described herein to provide a final dosage form.
  • exemplary final dosage forms include, but are not limited to, a tablet, a capsule, and a pill.
  • the present invention provides a method of making or generating tablets comprising the proliposomal composition described herein. In one embodiment, the present invention provides a method of making or generating tablets comprising the liposomal composition described herein. In one embodiment, the present invention provides a method of making or generating tablets comprising the pharmaceutical composition described herein.
  • the present invention provides a method of making or generating tablets comprising a liposome, a liposomal composition, or a proliposomal composition prepared using any method previously known in the art.
  • Exemplary methods of preparing a liposome, a liposomal composition, or a proliposomal composition include, but are not limited to, thin film hydration (Bangham method), ether/ethanol injection, reverse phase evaporation, detergent depletion, heating method, microfluidic channel method, membrane extrusion, and homogenization and sonication.
  • the method of preparing a liposome, a liposomal composition, or a proliposomal composition further comprises the step of drying or lyophilization of prepared liposomes.
  • the method of preparing a liposome, a liposomal composition, or a proliposomal composition is a method presented herein, e.g. as shown in Fig. 3.
  • the method may include a step of preparing a solution 335 by optionally adding to a solvent 330 one or more of a phospholipid 300, a stabilizer 305, a surfactant 310, a carrier 315, and an active pharmaceutical ingredient 320.
  • the solution can then be transferred to any suitable extrusion-based printing method 340.
  • the extrusion-based printing method 340 may be, but is not limited to, extrusion bioprinting, extrusion 3D printing, inkjet printing, electrohydrodynamic jetting, microfluidic printing, or any combination thereof.
  • the proliposomal composition may also be used in an additive manufacturing platform.
  • additive manufacturing platforms include 3D printing, selective laser sintering (SLS), selective laser melting (SLM), stereolithography (SLA), material jetting, semi-solid extrusion, direct powder extrusion, or fused deposition modeling (FDM).
  • SLS selective laser sintering
  • SLM selective laser melting
  • SLA stereolithography
  • FDM fused deposition modeling
  • the pharmaceutical compositions described herein may be used these processes and exhibit a flowability as measured by the angle of repose of less than 25.
  • the pharmaceutical composition may have a flowability of less than 25, less than 26, less than 27, less than 28, less than 29, less than 30, less than 32.5, less than 35, or less than 40.
  • the proliposomal composition is processed to provide a unit dose.
  • the unit dose is formulated for oral delivery such as a tablet, capsule, or suspension.
  • unit dose refers to a formulation of the pharmaceutical composition such that the formulation is prepared in a manner sufficient to provide a single therapeutically effective dose of the active pharmaceutical ingredient to a patient in a single administration.
  • unit dose formulations that may be used include but are not limited to a single tablet, capsule, or other oral formulations, or a single vial with a syringeable liquid or other injectable formulations.
  • the resulting product can then undergo further downstream processing to create an intermediate product, such as granules, that can then be further formulated into a unit dose such as one prepared for oral delivery as tablets, capsules, three-dimensionally printed selective laser sintered (3DPSLS) or suspensions; pulmonary and nasal delivery; topical delivery as emulsions, ointments or creams; transdermal delivery; and parenteral delivery as suspensions, microemulsions or depot.
  • the final pharmaceutical composition that is produced is no longer a powder and is further produced as a homogenous final product. This final product has the capability of being processed into granules and being compressed or 3DPSLS into a final pharmaceutical unit dose form.
  • the pharmaceutical compositions are processed through laser sintering wherein a laser is aimed at a specific point on the pharmaceutical composition such that material is bound together to create a solid form.
  • the laser is passed over the powder’s surface in a sufficient amount of time and at a specific or certain location to produce the final desired dosage form.
  • the method relates to the use of the laser-based upon the power of the laser such as the peak laser power rather than the laser duration.
  • the method often will make use of a pulsed laser.
  • Exemplary lasers used in these methods often include a low-power laser such as ultraviolet (UV) or infrared (IR) or high-power laser such as a carbon dioxide (CO2) laser.
  • the process builds up the dosage form by moving the print platform up and down in Z-axis or sideways in the X-Y axis and using cross-sections of the material through multiple scanning passes over the material.
  • the chamber of the 3D printer device may also be preheated to a temperature just below or between the glass transition temperature and the melting point of the pharmaceutical composition such as the melting point of the composition as a whole or the active agent, the absorbent, or the surfactant.
  • the method may be used with or without the need for a secondary feeder of material into the chamber of the device.
  • the tablets may be generated using a sintering process comprising the steps of providing a proliposomal composition, spreading a thin layer of the composition over a build platform, sintering the thin layer of the composition, spreading a new thin layer of the composition over the previous layer, sintering the second thin layer of the composition, and repeating the previous two steps multiple times to print the final dosage form.
  • the final dosage form is a tablet or a capsule.
  • the thickness of the thin layer of the composition is 50 pm to 500 pm. In one embodiment, the thickness of the thin layer of the composition is 100 pm to 500 pm. In one embodiment, the thickness of the thin layer of the composition is 100 pm to 450 pm. In one embodiment, the thickness of the thin layer of the composition is 100 pm to 400 pm. In one embodiment, the thickness of the thin layer of the composition is 100 pm to 350 pm. In one embodiment, the thickness of the thin layer of the composition is 100 pm to 300 pm. In one embodiment, the thickness of the thin layer of the composition is 100 pm to 250 pm. In one embodiment, the thickness of the thin layer of the composition is 100 pm to 200 pm. In one embodiment, the thickness of the thin layer of the composition is 100 pm to 150 pm.
  • the thickness of the thin layer of the composition is 150 pm to 200 pm. In one embodiment, the thickness of the thin layer of the composition is 50 pm to 100 pm. In one embodiment, the thickness of the thin layer of the composition is 50 pm to 150 pm. In one embodiment, the thickness of the thin layer of the composition is 50 pm to 200 pm.
  • the thickness of the thin layer of the composition is about 50 pm. In one embodiment, the thickness of the thin layer of the composition is about 60 pm. In one embodiment, the thickness of the thin layer of the composition is about 70 pm. In one embodiment, the thickness of the thin layer of the composition is about 80 pm. In one embodiment, the thickness of the thin layer of the composition is about 90 pm. In one embodiment, the thickness of the thin layer of the composition is about 100 pm. In one embodiment, the thickness of the thin layer of the composition is about 110 pm. In one embodiment, the thickness of the thin layer of the composition is about 120 pm. In one embodiment, the thickness of the thin layer of the composition is about 100 pm. In one embodiment, the thickness of the thin layer of the composition is about 110 pm.
  • the thickness of the thin layer of the composition is about 120 pm. In one embodiment, the thickness of the thin layer of the composition is about 130 pm. In one embodiment, the thickness of the thin layer of the composition is about 140 pm. In one embodiment, the thickness of the thin layer of the composition is about 150 pm. In one embodiment, the thickness of the thin layer of the composition is about 160 pm. In one embodiment, the thickness of the thin layer of the composition is about 170 pm. In one embodiment, the thickness of the thin layer of the composition is about 180 pm. In one embodiment, the thickness of the thin layer of the composition is about 190 pm. In one embodiment, the thickness of the thin layer of the composition is about 200 pm.
  • the temperature of the build platform (also referred to as the print bed) is from 25 °C to 250 °C. In one embodiment, the temperature of the build platform is from 25 °C to 200 °C. In one embodiment, the temperature of the build platform is from 25 °C to 150 °C. In one embodiment, the temperature of the build platform is from 25 °C to 100 °C. In one embodiment, the temperature of the build platform is from 25 °C to 75 °C. In one embodiment, the temperature of the build platform is from 25 °C to 50 °C. In one embodiment, the temperature of the build platform is below the degradation of the drug or active pharmaceutical ingredient. In one embodiment, the temperature of the build platform is about 30 °C.
  • the temperature of the build platform is about 40 °C. In one embodiment, the temperature of the build platform is about 50 °C. In one embodiment, the temperature of the build platform is about 60 °C. In one embodiment, the temperature of the build platform is about 70 °C. In one embodiment, the temperature of the build platform is about 80 °C. In one embodiment, the temperature of the build platform is about 90 °C. In one embodiment, the temperature of the build platform is about 100 °C. In one embodiment, the temperature of the build platform is about 110 °C. In one embodiment, the temperature of the build platform is about 120 °C. In one embodiment, the temperature of the build platform is about 130 °C. In one embodiment, the temperature of the build platform is about 140 °C.
  • the temperature of the build platform is about 1 0 °C. In one embodiment, the temperature of the build platform is about 160 °C. In one embodiment, the temperature of the build platform is about 170 °C. In one embodiment, the temperature of the build platform is about 180 °C. In one embodiment, the temperature of the build platform is about 190 °C. In one embodiment, the temperature of the build platform is about 200 °C. In one embodiment, the temperature of the build platform is about 210 °C. In one embodiment, the temperature of the build platform is about 220 °C. In one embodiment, the temperature of the build platform is about 230 °C. In one embodiment, the temperature of the build platform is about 240 °C. In one embodiment, the temperature of the build platform is about 250 °C.
  • the hatching spacing is between 10 pm and 100 pm. In one embodiment, the hatching spacing is between 20 pm and 90 pm. In one embodiment, the hatching spacing is between 30 pm and 80 pm. In one embodiment, the hatching spacing is between 40 pm and 70 pm. In one embodiment, the hatching spacing is about 10 pm. In one embodiment, the hatching spacing is about 20 pm. In one embodiment, the hatching spacing is about 30 pm. In one embodiment, the hatching spacing is about 40 pm. In one embodiment, the hatching spacing is about 50 pm. In one embodiment, the hatching spacing is about 60 pm. In one embodiment, the hatching spacing is about 70 pm. In one embodiment, the hatching spacing is about 50 pm. In one embodiment, the hatching spacing is about 80 pm.
  • the hatching spacing is about 90 pm. Tn one embodiment, the hatching spacing is about 50 pm. In one embodiment, the hatching spacing is about 100 pm.
  • hatching spacing is defined as the space between energy beam travel tracks or the spacing between the centers of two adjacent beams.
  • the hatching offset is between 100 pm and 150 pm. In one embodiment, the hatching offset is about 100 pm. In one embodiment, the hatching offset is about 110 pm. In one embodiment, the hatching offset is about 120 pm. In one embodiment, the hatching offset is about 130 pm. In one embodiment, the hatching offset is about 140 pm. In one embodiment, the hatching offset is about 150 pm.
  • the number of perimeters is set to 1. In one embodiment, the perimeter offset is set to 200 pm.
  • the laser speed is between 10 mm/s to 100 mm/s. In one embodiment, the laser speed is between 10 mm/s and 100 mm/s. In one embodiment, the laser speed is between 20 mm/s and 90 mm/s. In one embodiment, the laser speed is between 30 mm/s and 80 mm/s. In one embodiment, the laser speed is between 40 mm/s and 70 mm/s. In one embodiment, the laser speed is about 10 mm/s. In one embodiment, the laser speed is about 20 mm/s. In one embodiment, the laser speed is about 30 mm/s. In one embodiment, the laser speed is about 40 mm/s. In one embodiment, the laser speed is about 50 mm/s.
  • the laser speed is about 60 mm/s. In one embodiment, the laser speed is about 70 mm/s. In one embodiment, the laser speed is about 50 mm/s. In one embodiment, the laser speed is about 80 mm/s. In one embodiment, the laser speed is about 90 mm/s. In one embodiment, the laser speed is about 50 mm/s. In one embodiment, the laser speed is about 100 mm/s.
  • compositions described herein can be administered to an individual via any route, including, but not limited to, oral, rectal (e.g., via suppository, vaginal (e.g, via pessary), intravenous (e.g., by infusion pumps), intraperitoneal, intraocular, intraarterial, intrapulmonary, oral, intravesicular, intramuscular, intra-tracheal, subcutaneous, intrathecal, transdermal, transpleural, topical, inhalational (e.g., as mists of sprays dry powders, or aerosols), mucosal (such as via nasal mucosa), gastrointestinal, intraarticular, intracisternal, intraventricular, intracranial, intraurethral, intrahepatic, and intratumoral.
  • oral rectal
  • vaginal e.g, via pessary
  • intravenous e.g., by infusion pumps
  • intraperitoneal intraocular, intraarterial, intrapulmonary, oral, intravesicular, intra
  • compositions are administered systemically (for example by intravenous injection). In some embodiments, the compositions are administered locally (for example by intraarterial or intraocular injection). In some embodiments, the compositions are administered by ex vivo incubation or perfusion.
  • the final dosage form as discussed elsewhere herein is crushed to form a powder.
  • the powder is administered via inhalation.
  • the powder is suspended in a solvent and subsequently administered.
  • Exemplary solvents are water or buffer solution.
  • a method for selfadministration of a dry powder preparation into a patient's lungs using a dry powder inhalation system comprising the following steps: provide a dry powder inhaler comprising a mouthpiece in a closed position; provide a cartridge containing a pre-dose of a dry powder preparation comprising a composition described herein in a retention configuration; opening the dry powder inhaler to install the cartridge; closing the inhaler to move the cartridge to the dispensing position; covering the mouthpiece with the subject’s mouth; and having the subject take a single deep breath to deliver a dry powder preparation.
  • the dry powder preparation comprises a proliposomal composition described herein.
  • the dry powder preparation comprises an active pharmaceutical ingredient.
  • the optimal effective amount of the compositions can be determined empirically and will depend on the type and severity of the disease, route of administration, disease progression and health, mass and body area of the individual. Such determinations are within the skill of one in the art.
  • the effective amount can also be determined based on in vitro complement activation assays. Examples of dosages of drug delivery particles which can be used for methods described herein include, but are not limited to, an effective amount within the dosage range of any of about 0.01 mg/kg to about 300 mg/kg, or within about 0.1 mg/kg to about 40 mg/kg, or with about 1 mg/kg to about 20 mg/kg, or within about 1 mg/kg to about 10 mg/kg.
  • the amount of biologically active agent administered to an individual is about 10 mg to about 500 mg per dose, including for example any of about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 500 mg, about 500 mg to about 1 mg, about 1 mg to about 10 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, or about 400 mg to about 500 mg per dose.
  • compositions comprising proliposomal compositions may be administered in a single daily dose, or the total daily dose may be administered in divided dosages of two, three, or four times daily.
  • the compositions can also be administered less frequently than daily, for example, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, once every two weeks, once every three weeks, once a month, once every two months, once every three months, or once every six months.
  • compositions may also be administered in a sustained release formulation, such as in an implant which gradually releases the composition for use over a period of time, and which allows for the composition to be administered less frequently, such as once a month, once every 2-6 months, once every year, or even a single administration.
  • the drug delivery particles may be administered by injection or surgical implantation in various locations.
  • Dosage amounts and frequency will vary according to the particular formulation, the dosage form, and individual patient characteristics. Generally speaking, determining the dosage amount and frequency for a particular formulation, dosage form, and individual patient characteristic can be accomplished using conventional dosing studies, coupled with appropriate diagnostics.
  • provided pharmaceutical formulations are administered to a subject in combination with one or more other therapeutic agents or modalities, for example, useful in the treatment of one or more diseases, disorders, or conditions treated by the relevant provided pharmaceutical formulation, so the subject is simultaneously exposed to both.
  • the particular combination of therapies (substances and/or procedures) to employ in a combination regimen will take into account compatibility of the desired substances and/or procedures and the desired therapeutic effect to be achieved.
  • provided compositions can be administered concurrently with, prior to, or subsequent to, one or more other therapeutic agents (e.g., desired known antimycobacterial therapeutics).
  • the therapies employed may achieve a desired effect for the same disorder (for example, a therapeutic compound useful for mycobacterial infections administered concurrently with a composition of the present invention), or they may achieve different effects (for example, a composition of the present invention may be administered concurrently with a therapeutic agent that is useful for alleviating adverse side effects, for instance, fever, pain, nausea, etc.).
  • a composition of the present invention is administered with a second therapeutic agent.
  • the terms "in combination with” and “in conjunction with” mean that the drug delivery particles of the present invention can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics such as an analgesic, antibacterial, antiviral, anticancer, or biologic agent including but not limited to a sub-therapeutic dose of such an agent.
  • each substance will be administered at a dose and/or on a time schedule determined for that agent.
  • the method comprises administering a composition comprising a combination of an antibacterial agent and the drug delivery particles described herein.
  • the method comprises administering one or more compositions.
  • the method comprises administering a first composition comprising an antibacterial agent and a second composition comprising the proliposomal compositions described herein.
  • the different compositions may be administered to the subject in any order and in any suitable interval.
  • the one or more compositions are administered simultaneously or near simultaneously.
  • the method comprises a staggered administration of the one or more compositions, where a first composition is administered and a second composition administered at some later time point. Any suitable interval of administration which produces the desired therapeutic effect may be used.
  • the method has an additive effect, wherein the overall effect of the administering a combination of therapeutic agents or procedures is approximately equal to the sum of the effects of administering each therapeutic agent or procedure alone. In other embodiments, the method has a synergistic effect, wherein the overall effect of administering a combination of therapeutic agents or procedures is greater than the sum of the effects of administering each therapeutic agent or procedure alone.
  • unit dosage forms of drug delivery particle compositions each dosage containing from about 0.01 mg to about 50 mg, including for example any of about 0.1 mg to about 50 mg, about 1 mg to about 50 mg, about 5 mg to about 40 mg, about 10 mg to about 20 mg, or about 15 mg of the biologically active agent.
  • the unit dosage forms of drug delivery particles comprise about any of 0.01 mg-0.1 mg, 0.1 mg-0.2 mg, 0.2 mg-0.25 mg, 0.25 mg-0.3 mg, 0.3 mg- 0.35 mg, 0.35 mg-0.4 mg, 0.4 mg-0.5 mg, 0.5 mg-1.0 mg, 10 mg-20 mg, 20 mg-50 mg, 50 mg-80 mg, 80 mg- 100 mg, 100 mg- 150 mg, 150 mg-200 mg, 200 mg-250 mg, 250 mg-300 mg, 300 mg-400 mg, or 400 mg-500 mg biologically active agent.
  • unit dosage form refers to a physically discrete unit suitable as unitary dosages for an individual, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.
  • suitable pharmaceutical carrier diluent, or excipient.
  • unit dosage forms can be stored in suitable packaging in single or multiple unit dosages and may also be further sterilized and sealed.
  • kits comprising compositions (or unit dosages forms and/or articles of manufacture) described herein and may further comprise instruction(s) on methods of using the composition, such as uses described herein.
  • the kits described herein may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, fdters, needles, syringes, and package inserts with instructions for performing any methods described herein.
  • a dry powder inhalation kit comprising the dry powder inhaler described above and at least a drug cartridge comprising a dry powder of a composition described herein for treating a disorder or disease, for example, respiratory disease, cancer, diabetes, and obesity.
  • the kit may contain instructions for use.
  • the dry powders are proliposome-containing powders.
  • the dry powders comprise at least one active pharmaceutical ingredient.
  • Bioavailability in the present case is understood to mean the load with either the active ingredient (for example, insulin) or diketopiperazine (in the embodiments related to diketopiperazine powders) obtained as a result of delivery to the patient’s large blood circulation and usually estimated according to the AUC graph of the concentration versus time .
  • the characteristics of the system can be determined by normalizing said measurements with respect to dosage.
  • the dosage used to standardize the load may be based on the incorporated or emitted dose and may be expressed in a uniform mass of powder. Alternatively, the load can be normalized with respect to the cartridge with a specific buried mass.
  • Each load method can be further adjusted to take into account the specific content of diketopiperazine or the active ingredient of a particular preparation, that is, the load can be normalized with respect to the amount of active agent or the amount of diketopiperazine in a fixed or emitted dose.
  • the observed load may be influenced by variables relevant to the patient, for example, fluid volume, therefore, in various embodiments, the bioavailability of the system will be expressed in a range or in limits.
  • Proliposomes were prepared according to the following process. Table 1 shows example conditions for the extmsion-based printing of proliposomes.
  • Phospholipon 90 and cholesterol in a 50:50 percentage molar ratio (60.65:7.73 mg) was provided to ethanol and allowed to dissolve.
  • Kolliphor P188 34.19 mg
  • hydroxypropyl cyclodextrin 250 mg
  • Proliposomes generated by the above-described method had a particle size less than or about 150 nm and a poly dispersity index of 0.01 Mw/Mn to about 0.5 Mw/Mn.
  • Table 2 shows the characterization of additional proliposomes generated by the disclosed method versus a conventional method known in the art.
  • the proliposomes produced have a mono model structure, as seen by the reduction in both particle size and poly dispersity index making the particles suitable for a wide range of challenging therapeutic applications, for example inhalation, nasal, nose-to-brain, oral, or the like.
  • the active pharmaceutical ingredient loaded proliposomes were subjected to thermal characterization using differential scanning calorimetry.
  • Fig. 8, Fig. 9, and Fig. 10 show a plot of temperature versus heat flow for the active pharmaceutical ingredient loaded proliposomes compared to the free active pharmaceutical ingredient.
  • the active pharmaceutical ingredient loaded proliposomes show a decrease in crystallinity, more amorphous character, and also enhanced thermal stability as compared to the free active pharmaceutical ingredient.
  • Thermal stability was also examined by thermogravimetric analysis of the active pharmaceutical ingredient loaded proliposomes as shown in Fig. 11. The encapsulation of the active pharmaceutical ingredient resulted in increased thermal stability as compared to its free state.
  • Proliposomes prepared according to the above procedure were subjected to imaging using scanning electron microscopy (SEM). As shown in Fig. 12, the proliposomes were observed to have a coarse, non-porous and irregular shape. This was attributed to the presence of a higher amount of the carrier, cyclodextrin.
  • Fig. 13 shows the Fourier-transform infrared (FTIR) spectrums of proliposomes loaded with the active pharmaceutical ingredients Sorafenib, Levonorgestrel and Docetaxel and their respective free form.
  • FTIR Fourier-transform infrared
  • the morphology of the proliposomes generated by the disclosed method was examined using scanning electron microscopy (SEM).
  • SEM scanning electron microscopy
  • the crystallinity of the active pharmaceutical ingredient shown in Fig. 14A, Fig. 15 A, and Fig. 16A, is reduced when encapsulated in the proliposome composition as shown in Fig. 14B, Fig. 15B, and Fig. 16B respectively.
  • the proliposomes were observed to have a coarse, non- porous and irregular shape. This was attributed to the presence of a higher amount of the carrier, cyclodextrin.
  • SEM shows a much larger size compared to zeta size results due to the fact that the SEM figure is based on the powder formulation provided. As powder may contain multiple proliposomes and entrapped liposome entities, the total size may increase.
  • Docetaxel Fig. 17, Levonorgestrel Fig. 18, and Sorafenib Fig. 19 increased as a result of being incorporated within the excipient matrix of the disclosed proliposomes.
  • the release of docetaxel, levonorgestrel, and sorafenib was achieved in a sustainable manner, e.g., the drug was gradually released from the proliposomes, leading to an increase in the concentration of the drug in the dissolution medium as time progressed. This implies a continuous or cumulative release of these drugs form the proliposomes over time.
  • Sorafenib was purchased from Hangzhou Longshine Biotech Co., Ltd. (Hangzhou, Zhejiang province, China). AquaSolveTM HPMC-AS MG was provided by AshlandTM (Wilmington, Delaware, United States). Eudragit LI 00-55 was purchased from Evonik nutrition & care GmbH (Kirschenalle, Darmstadt, Germany). PAA and HPLC grade methanol and acetone of were provided by Sigma-Aldrich Inc (St. Louis, Missouri, USA). HPLC grade acetonitrile was purchased from Fischer Scientific (Pittsburg, Pennsylvania, USA).
  • SMART involves the extrusion of the dissolved ink components through a syringe fitted with 27 G nozzle at a pressure of 600 Kpa. The printing speed was set to 10 mm/sec and the bed temperature was raised to 40 °C.
  • PDI photon correlation spectrometer
  • the thermal properties of the neat drug, excipients and final Proliposomes formulation were investigated using Mettler-Toledo TGA/DSC1 analyzer (Mettler- Toledo, Schwerzenbach, Switzerland). In ceramic crucibles, the samples were placed and ramped from 35 to 500 °C at 10 °C /min rate. Ultra-purified nitrogen/air was used to purge the furnace at a flow rate of 50 mL/min. The STAR software was used to operate the instrument and collect the data. The DSC analysis was carried out using DSC Q20 (TA® instruments, New Castle, DE, USA).
  • Samples of about 5-10 mg were placed in T- zero aluminum DSC pans and sealed with standard aluminum lids (DSC consumables incorporated, Austin, MN, USA) using a calibrated balance. The samples were ramped from 25 to 250°C at a 10 °C/min rate and ultra-purified nitrogen was purged at a 50 mL/min flow rate for all samples. The data were collected by TA advantage software (Q series, Version 2007 build 13029.20308). The results from both TGA and DSC were presented as a plot of using GraphPad Prism® version 5.00 for Windows (San Diego, California, USA).
  • the prepared samples were placed into the magnetic sample cell in the sample holder and scanned from a 20 angle of 5 to 45 degrees, with a scan speed of 2°/min and a scan step of 0.02°.
  • the voltage and current applied were 40 kV and 15 mA, respectively.
  • GraphPad Prism® version 5.00 for Windows (San Diego, California, USA) was used to plot the data as a plot of 20 (degree) versus intensity.
  • the morphology of the produced powder was determined by scanning electron microscopy.
  • the powdered SMART product was deposited on a carbon tape and coated with gold using an ESM sputter coater.
  • FEI Quanta 650 ESEM scanning electron microscopy (SEM) was then used to visualize the microscopic structure of the samples at various magnifications.
  • the operational acceleration voltage was 10 kV at a working distance (WD) of 9.2 mm.
  • Fourier Transform Infrared (FTIR) spectroscopic analysis of neat drug, excipients and final Proliposomes formulation was carried out using a modular NicoletTM iSTM 50 FTIR system (ThermoFisher Scientific, Waltham, Massachusetts, USA).
  • In-vitro release profiles of drugs from optimized proliposomes were obtained using a dialysis method. Amount of proliposomes with drug equivalent to 2mg were added to a dialysis cassette with a molecular weight cut off size of 2000 Da (Thermo-Scientific, Waltham, MA, USA); previously hydrated in water for 10 min.
  • the dialysis cassette was immersed in 100 m of release media composed of phosphate buffer saline (pH 7.4) along with 0.1% tween 80 (to maintain sink condition and aid in solubilization of released drug) at 37°C under continuous stirring at 100 rpm. At predetermined time intervals, 1 mb of release media was withdrawn and replenished with same amount of fresh release media. The concentration of released SF in withdrawn samples were analyzed using HPLC.
  • sorafenib concentration was performed by HPLC (Thermo Fisher Vanquish HPLC system, Thermo Fisher, Waltham, MA, USA).
  • HPLC Thermo Fisher Vanquish HPLC system, Thermo Fisher, Waltham, MA, USA.
  • a stainless-steel C-18 column 250 * 2.1 mm, 2 pm particle size) (Avantor ACE® EXCEL 3 C-18-AR column, VWR International, Radnor, PA, USA) was used for the analysis.
  • the mobile phase was composed of DW containing 2% (w/v) triethylamine (pH 5.4 adjusted with phosphoric acid) and an acetonitrile mixture (30:70 v/v %) and was delivered i Socratically.
  • sorafenib retention time was 3.2 min when the flow rate was maintained at 1 .0 mL/min and column oven temperature was kept at 25 °C.
  • the injection volume was 20 p L and the flow rate was maintained at 1.0 mL/min.
  • the column effluent was detected at 265 nm and the concentration of sorafenib was calculated based on a linear calibration curve of standard sorafenib solute.
  • Solid-state characterization and thermal analysis X-ray diffractometer (XRD) measurements were performed using a New D8-Advance XRD instrument (Bruker-AXS, Germany) equipped with a copper anode generating a Cu Ka radiation of 1.54178 A when struck by a 100-mA current at 40 kV. Patterns were collected using a step width of 0.02°/s over a range from 5 to 50° on a 20 scale at room temperature.
  • DSC Differential scanning calorimeter
  • Sorafenib proliposomes were incubated at different storage conditions (4 °C, 25 °C, and 37 °C) for the storage stability test. At the predetermined time points, samples were collected, diluted 100- fold with distilled water, and gently stirred (300 rpm) for 30 min. Unencapsulated drugs were removed via filtration through a 0.45 p m PTFE membrane filter, and the drug contents in the solutions were analyzed using HPLC.
  • Another example includes the use of Prussian blue-loaded alginate microparticle platforms for chemo-dynamic (chemo-photothermal) therapy and antibacterial activity. Additionally, the synthesis of core-shell microparticles has garnered great interest in the biomedical field for drug delivery (Heshmati, A. N. et al., 2022, Bioengineering, 9).
  • the proliposomes are the alternate form of liposomes which are readily converted into liposomes by the hydration of lipids.
  • the proliposomes are preferred over liposomes due to an increased shelf-life and may quickly be converted into liposomes whenever required by adding buffer or water to the developed proliposomes followed by gentle shaking or stirring (Rodak, O. et al., 2021, Cancers (Basel), 13, 4705).
  • the liposomes are generally of natural origin and composed of phospholipids and may be used for various biomedical applications, but low shelf-life and strict storage conditions make them arguable.
  • the enhanced anticancer efficacy of chemotherapeutic agents may primarily be established through active and passive targeting mechanisms.
  • the passive targeting may primarily be accomplished by avoiding/delaying opsonization, which in turn may be achieved through a cancer-simulated environment, a petite size of less than 200 nm, and steric stabilization through a hydrophilic surface (coat) and lipophilic core (Shepard, K.
  • proliposomes are associated with a hydrophilic surface based on hydrophilic carrier and lipophilic core based on phospholipids and so could be considered for improved anticancer efficacy. But still, the aforementioned feature associated with proliposomes is unable to fulfill the criteria of enhanced permeation and retention effect (EPR) and anticancer efficacy, due to the large size based on dense coating with hydrophilic carrier (Patel, K. et al., 2021, Particulate Science and Technology, 39, 990).
  • EPR enhanced permeation and retention effect
  • probe sonication For the conversion of large-sized proliposomes into a smaller size to make them suitable drug delivery carriers for anticancer efficacy through passive targeting various high-energy stress-based size reduction techniques like probe sonication (Wan, J. et al., 2020, J. Mater. Chem. B, 8, 7755; Zhong, T. et al., 2021, Drug. Delivery, 28, 2108; Omer, H. K. et al., 2018, AAPS PharmSciTech., 19, 2434) are used.
  • the probe sonication process is not preferred for anticancer agents loaded liposomes as it may cause the degradation of vesicles by structural disruption, drug leakage from vesicles, or phase transition (Arregui, J. R.
  • SMART Sprayed Multi-adsorbed Droplet Reposing Technology
  • AM additive manufacturing
  • Docetaxel, levonorgestrel, and sorafenib are selected as three models of anticancer therapeutics based on their wide applications in treating various cancers, including breast, lung, prostate, thyroid, stomach, head/neck, and endometrial cancers, as well as advanced renal cell and hepatocellular carcinoma.
  • the developed proliposomes by SMART resulted in the achievement of liposomes of less than 100 nm (nanosomes) without using any process regarding high energy or shear stress. Therefore, the SMART-based proliposomes-derived liposomes could be used for improved targeting through EPR and in turn for enhanced anti cancer efficacy.
  • proliposomes are developed by thin film hydration technique, which may be associated with the risk of instability regarding thermolabile excipients.
  • the present invention collectively suggests that SMART-based proliposomes that could be used for enhanced anticancer efficacy against different types of malignancies.
  • Example 3 ProLiDS: Platform Technology for Single Step 3D Printing Extrusion Enabled Proliposomes
  • the present invention is drawn to, in part, the design, development, and evaluation of proliposomes through Sprayed Multi Adsorbed-Droplet Reposing Technology (SMART).
  • SMART Sprayed Multi Adsorbed-Droplet Reposing Technology
  • the proliposomes are developed by extrusion of dispersion as a mixture of an insoluble hydrophilic carrier, and a solution of drug, surfactant, and lipid in ethanol followed by lyophilization, which resulted in the achievement of free-flowing proliposomes powder. It is important to identify the critical process parameters that influence the proliposomes performance and to optimize the formulation factors to achieve the desired proliposomes properties.
  • DoE design of experiment
  • the present Example delves into the optimization of the proliposomes through a design of experiment (DoE) and machine learning based approach. In doing so, the effect of important processing and formulation factors on the proliposomes performance are studied.
  • DoE design of experiment
  • the technology is used for wide ranging drugs with different physiochemical and pharmacological activities. Specifically, three different drugs namely ketoconazole, dexamethasone, and levonorgestrol are studied.
  • hMSCs Human bone marrow-derived mesenchymal stem cells
  • EDTA trypsin- trypsin-ethylenediaminetetraacetic acid
  • DLS Dynamic light scattering
  • the morphology of the produced powder was determined by scanning electron microscopy.
  • the powdered SMART product was deposited on a carbon tape and coated with gold using an ESM sputter coater.
  • FEI Quanta 650 ESEM scanning electron microscopy (SEM) was then used to visualize the microscopic structure of the samples at various magnifications.
  • the operational acceleration voltage was 10 kV at a working distance (WD) of 9.2 mm.
  • ATR-FTIR attenuated total reflectance Fourier-transform infrared spectroscopy
  • Infinity Gold FTIR Spectrometer Thermo Mattson
  • the thermal properties of the neat drug, excipients and final Proliposomes formulation were investigated using Mettler-Toledo TGA/DSC1 analyzer (Mettler- Toledo, Schwerzenbach, Switzerland). In ceramic crucibles, the samples were placed and ramped from 35 to 500 °C at 10 °C /min rate. Ultra-purified nitrogen/air was used to purge the furnace at a flow rate of 50 mL/min. The STAR software was used to operate the instrument and collect the data. The DSC analysis was carried out using DSC Q20 (TA® instruments, New Castle, DE, USA).
  • Samples of about 5-10 mg were placed in T- zero aluminum DSC pans and sealed with standard aluminum lids (DSC consumables incorporated, Austin, MN, USA) using a calibrated balance. The samples were ramped from 25 to 250°C at a 10 °C/min rate and ultra-purified nitrogen was purged at a 50 mL/min flow rate for all samples. The data were collected by TA advantage software (Q series, Version 2007 build 13029.20308). The results from both TGA and DSC were presented as a plot of using GraphPad Prism® version 5.00 for Windows (San Diego, California, USA).
  • the prepared samples were placed into the magnetic sample cell in the sample holder and scanned from a 29 angle of 5 to 45 degrees, with a scan speed of 2°/min and a scan step of 0.02°.
  • the voltage and current applied were 40 kV and 15 mA, respectively.
  • GraphPad Prism® version 5.00 for Windows (San Diego, California, USA) was used to plot the data as a plot of 20 (degree) versus intensity.
  • the cell viability of the proliposomes in the hMSCs cells was determined in a 96-well plate using the Cell Proliferation Assay kit (Sigma-Aldrich, Saint Louis, MO, USA) containing 3-(4, 5dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) according to the manufacturer’s instructions. Briefly, the cells were seeded at a density of 2 * 10 4 cells per well in a 96-well plate and incubated for 24 h at 37 °C.
  • the cells were washed twice with DPBS buffer (pH 7.4) and then treated with 100 pL of proliposomes, at different concentrations of lipid concentration ranging from 0.1 to 25 mg/mL, for 24 h at 37 ° C. Subsequently, 10% MTT solution was added to each well and incubated for 2 h at 37 °C. Finally, the absorbance was read at 570 nm using a multi-well plate reader (Bio Tek, Winooski, VT, USA). The cell viability (%) was calculated as follows: 100 ... where OD is the optical density.
  • the proliposomes can be readily utilized in continuous manufacturing (Fig. 25, Fig. 26).
  • Table 6 Formulation composition used to generate proliposomes.
  • Table 7. Feed stock composition used to develop proliposomes-loaded SLS 3D printed tablets.
  • Table 8. Dynamic light scattering (DLS) data of Lipo-Indo (free proliposome powder comprising indomethacin) and Tab-Lipo-Indo (proliposome-loaded 3D printed tablet).
  • DLS Dynamic light scattering

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Otolaryngology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Psychology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des compositions de proliposomes comprenant des ingrédients pharmaceutiques actifs et des procédés de fabrication et d'utilisation des compositions, notamment pour traiter une maladie ou un trouble chez un patient en ayant besoin.
PCT/US2024/040749 2023-08-04 2024-08-02 Proliposomes et compositions, leurs procédés de fabrication et leurs procédés d'utilisation Pending WO2025034562A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363517705P 2023-08-04 2023-08-04
US63/517,705 2023-08-04

Publications (1)

Publication Number Publication Date
WO2025034562A1 true WO2025034562A1 (fr) 2025-02-13

Family

ID=94535052

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/040749 Pending WO2025034562A1 (fr) 2023-08-04 2024-08-02 Proliposomes et compositions, leurs procédés de fabrication et leurs procédés d'utilisation

Country Status (1)

Country Link
WO (1) WO2025034562A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009120933A2 (fr) * 2008-03-28 2009-10-01 Particle Sciences, Inc. Solutions pharmaceutiques et procédé pour solubiliser des agents thérapeutiques
CN100551445C (zh) * 2006-01-06 2009-10-21 中国药科大学 一种含有难溶性药物的自组装前体脂质体及其制备方法
US20200121766A1 (en) * 2017-03-03 2020-04-23 Nordmark Arzneimittel Gmbh & Co. Kg Pharmaceutical composition comprising pancreatin and a lipase-containing coating

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100551445C (zh) * 2006-01-06 2009-10-21 中国药科大学 一种含有难溶性药物的自组装前体脂质体及其制备方法
WO2009120933A2 (fr) * 2008-03-28 2009-10-01 Particle Sciences, Inc. Solutions pharmaceutiques et procédé pour solubiliser des agents thérapeutiques
US20200121766A1 (en) * 2017-03-03 2020-04-23 Nordmark Arzneimittel Gmbh & Co. Kg Pharmaceutical composition comprising pancreatin and a lipase-containing coating

Similar Documents

Publication Publication Date Title
CA2903234C (fr) Compositions d'oxaliplatine liposomal pour la cancerotherapie
TWI377062B (en) Pharmaceutical compositions and dosage forms of thalidomide
US10383823B2 (en) Liposomal cisplatin compositions for cancer therapy
US11191774B2 (en) Drug formulations for cancer treatment
CN108712904B (zh) 2-(4-氯苯基)-n-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)-2,2-二氟乙酰胺的固体形式以及其药物组合物和用途
US20230310325A1 (en) High Surface-Area Lyophilized Compositions Comprising Arsenic For Oral Administration In Patients
TW201726696A (zh) 抗增生化合物,及其醫藥組合物及用途
US20220185795A1 (en) Compound form having enhanced bioavailability and formulations thereof
WO2017120437A1 (fr) Formulations de 2-(4-chlorophényl)-n-((2-(2,6-dioxopipéridin-3-yl)-1-oxoisoindolin-5-yl)méthyl)-2,2-difluoroacétamide
EP4054578A1 (fr) Polythérapie avec le 2-(4-chlorophényl)-n-((2-(2,6-dioxopipéridin-3-yl)-1-oxoisoindolin-5-yl)méthyl)-2,2-difluoroacétamide
US11191745B2 (en) Silica nanoparticle with an insoluble drug
WO2025034562A1 (fr) Proliposomes et compositions, leurs procédés de fabrication et leurs procédés d'utilisation
US20190099374A1 (en) Stable formulations for lyophilizing therapeutic particles
US20230330025A1 (en) Particle Modifiers for Multi-Drug Loaded Nanoparticles
HK40065292B (en) Compound form having enhanced bioavailability and formulations thereof
HK40073108A (en) High surface-area lyophilized compositions comprising arsenic for oral administration in patients
EA046804B1 (ru) Форма соединения, обладающая повышенной биодоступностью, и ее составы
HK1230524A (en) Compounds and methods for treating aberrant adrenocartical cell disorders

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24852619

Country of ref document: EP

Kind code of ref document: A1