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WO2018144845A1 - Microparticules de métalloporphyrines pour le traitement de l'anémie et de maladies tropicales - Google Patents

Microparticules de métalloporphyrines pour le traitement de l'anémie et de maladies tropicales Download PDF

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Publication number
WO2018144845A1
WO2018144845A1 PCT/US2018/016622 US2018016622W WO2018144845A1 WO 2018144845 A1 WO2018144845 A1 WO 2018144845A1 US 2018016622 W US2018016622 W US 2018016622W WO 2018144845 A1 WO2018144845 A1 WO 2018144845A1
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WIPO (PCT)
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subject
composition
organ
administering
microparticle
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PCT/US2018/016622
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English (en)
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Mohammed Inayathullah Nazir Ahmed
Jayakumar Rajadas
David K. Stevenson
Ronald James Wong
Cecilia ESPADAS
David Lechuga
Lakhmir Chawla
James Rolke
George Tidmarsh
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The Board Of Trustees Of The Leland Stanford Junior University
La Jolla Pharmaceutical Company
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Application filed by The Board Of Trustees Of The Leland Stanford Junior University, La Jolla Pharmaceutical Company filed Critical The Board Of Trustees Of The Leland Stanford Junior University
Publication of WO2018144845A1 publication Critical patent/WO2018144845A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/795—Porphyrin- or corrin-ring-containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/60—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation occurring through the 4-amino group of 2,4-diamino-butanoic acid

Definitions

  • Iron is an essential element required for growth and survival of almost every organism. In mammals, the iron balance is primarily regulated at the level of duodenal absorption of dietary iron. Following absorption, ferric iron is loaded into apo- transferrin in the circulation and transported to the tissues, including erythroid precursors, where it is taken up by transferrin receptor-mediated endocytosis. Reticuloendothelial macrophages play a major role in the recycling of iron from the degradation of hemoglobin of senescent erythrocytes, while hepatocytes contain most of the iron stores of the organism in ferritin polymers.
  • iron transporters DMT1 also called Nramp2 or DCT1
  • ferroportin also called IREG1 or MTP1
  • copper oxidases coupled to ferroportin, namely ceruloplasmin and haephastin.
  • HH hereditary hemochromatosis
  • iron plays the most critical role in relation to the host's interactions with the pathogen ⁇ e.g., virus, bacterium, or protozoan).
  • pathogen e.g., virus, bacterium, or protozoan
  • iron is a highly abundant element, it is highly insoluble at physiological pH and in the oxidative conditions of life, and therefore, it is difficult to acquire.
  • iron has very useful redox characteristics that have resulted in its incorporation in a very wide range of enzyme and oxygen transport systems; these same redox characteristics also make free iron potentially very harmful because of the generation of free radicals.
  • the present disclosure relates to a method for reducing the serum iron concentration in a subject to treat a condition, comprising administering to the subject a composition comprising a microparticle comprising or consisting essentially of a metal porphyrin complex and a pharmaceutically acceptable stabilizer, wherein the concentration of the metal porphyrin complex is from about 5% by weight of the microparticle.
  • the metal porphyrin complex (also referred to herein as an active agent) is a metal mesoporphyrin complex or a metal protoporphyrin complex.
  • the metal is a neutral or ionic atom of an element selected from iron, tungsten, cobalt, magnesium, palladium, platinum, chromium, tin, and zinc, preferably iron.
  • the metal is a neutral or ionic atom of iron.
  • the active agent may be heme, hemin, or iron protoporphyrin (FePP).
  • the stabilizer comprises or consists essentially of a lipid, a cationic lipid, alginate, chitosan, lecithin, a poloxamer, sodium trimetaphosphate, a cationic lipid, a protein, an oil, polyvinylpyrrolidone, or a combination thereof.
  • the condition is selected from anemia, thalassemia, hemochromatosis, and sickle cell disease.
  • the condition is selected from a viral infection, a bacterial infection, a fungal infection, a protist infection, iron overload ⁇ e.g., resulting from a blood transfusion, physical trauma, tissue injury, a cardiovascular surgery, cardiopulmonary bypass, acute coronary syndrome, or sepsis), and iron-induced injury.
  • the complex is formulated for oral delivery.
  • These formulations provide microparticles of a metal porphyrin complex, for example, a metal mesoporphyrin complex or a metal protoporphyrin complex, wherein the metal porphyrin complex is coated with a pharmaceutically acceptable excipient.
  • a method of reducing, preventing, or reversing organ damage or enhancing organ preservation comprising administering to the subject or to an organ a composition comprising a microparticle comprising or consisting essentially of a metal porphyrin complex and a pharmaceutically acceptable stabilizer, wherein the concentration of the metal porphyrin complex is from about 5% by weight of the microparticle.
  • the method facilitates an organ transplant procedure or enhances the success of an organ transplant procedure, and comprises contacting the organ ex vivo with a preservation solution comprising microparticles of a metal porphyrin complex.
  • the method prolongs organ viability ex vivo, and comprises contacting the organ ex vivo with a preservation solution comprising microparticles of a metal porphyrin complex.
  • Figure 1 depicts a schematic of the luciferase-catalyzed transformation of luciferin to oxyluciferin and light.
  • the transgenic mouse has the full-length HO-1 promoter, which drives expression of the reporter gene, luciferase.
  • Figure 2 shows the structure of iron protoporphyrin (FePP).
  • Figure 3 depicts a timeline for the study of transgenic mice described in Example 2.
  • Figure 4 depicts data showing the heme degradation.
  • MHA Heme-Lipid and methemalbumin
  • Figure 5 depicts total HO activity after MHA treatment compared to the Heme- Lipid. All values were significantly higher than control levels.
  • Figure 6 depicts HO-1 promoter activity. Using BLI, the effect of each preparation on liver and spleen HO-1 transcriptional activity or imRNA levels was investigated. Significant and similar increases over baseline levels in both tissues for both preparation 24 h after administration were observed.
  • Figure 7 depicts plasma AST levels. Plasma ALT levels were measured to determine whether the heme-lipid was toxic. No increases in ALT levels following administration of either of the heme preparations were found, compared to controls.
  • Figure 8 depicts the percentage of parasitaemia as tracked in mice via tail- bleed and counting from thin smears; parasitaemia increased at equivalent rates in wt and Erfe KO mice but declined more rapidly in mice lacking Erfe ( *** indicates p ⁇ 0.001 ).
  • Porphyrin are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their a carbon atoms via methine bridges.
  • the parent porphyrin is porphin (or porphine), and substituted porphines are called porphyrins.
  • Porphyrin macrocycles are highly conjugated systems and typically have very intense absorption bands in the visible region.
  • a porphyrin without a metal ion in its cavity is a free base.
  • Metal porphyrin complexes (also referred to herein as a metalloporphyrin or an active agent) comprise an organic porphyrin structure complexed with a metal, e.g., a neutral or ionic atom of an element selected from iron, tungsten, cobalt, magnesium, palladium, platinum, chromium, zinc, etc. Included in complexes of interest are metals complexed with protoporphyrin or mesoporphyrin.
  • the active agent may be hemin.
  • the metal is a neutral or ionic atom of iron.
  • the metal porphyrin complex is a heme, for example, heme A, heme B, heme C, or heme O, preferably heme B.
  • Protoporphyrin is a tetrapyrrole containing 4 methyl, 2 propionic acid, and 2 vinyl side chains that is a metabolic precursor for hemes, cytochrome c and chlorophyll.
  • Protoporphyrin IX is produced by oxidation of the methylene bridge of protoporphyrinogen by the enzyme protoporphyrinogen oxidase, and is identified as lUPAC 3-[18-(2-carboxyethyl)-8,13-bis(ethenyl)-3,7,12,17- tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid.
  • Mesoporphyrin compounds include any one of the isomeric porphyrins C 34 H 38 N 4 O 4 produced from protoporphyrin by reducing the vinyl groups to ethyl groups. Included is mesoporphyrin IX, lUPAC designation 3-[18-(2-carboxyethyl)- 8,13-diethyl-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid, and N- methyl mesoporphyrin, lUPAC designation 3-[18-(2-carboxyethyl)-7, 12-diethyl- 3,8,13,17,22-pentamethyl-23H-porphyrin-2-yl]propanoic acid.
  • the metal porphyrin complex is iron protoporphyrin (also referred to as hematin and FePP).
  • treating and “treatment” and the like are used herein to generally mean obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of a partial or complete cure of a condition, symptom or adverse effect attributed to the condition.
  • treatment covers particularly the application of a composition comprising a metal porphyrin complex active agent in microparticle form, including oral administration.
  • prevention of hyperbilirubinemia includes, for example, reducing the likelihood that a subject receiving the composition will experience hyperbilirubinemia relative to a subject that does not receive the composition, and/or delaying the onset of hyperbilirubinemia, on average, in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
  • prophylaxis is used herein to refer to a measure or measures taken for the prevention or partial prevention of a disease or condition.
  • agents of the invention may be used alone or conjointly administered with another type of therapeutic agent.
  • the phrase "conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body ⁇ e.g., the two agents are simultaneously effective in the subject, which may include synergistic effects of the two agents).
  • the different therapeutic agents can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially.
  • the different therapeutic agents can be administered within about one hour, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, or about a week of one another.
  • a subject who receives such treatment can benefit from a combined effect of different therapeutic agents.
  • subject includes mammals, e.g., cats, dogs, horses, pigs, cows, sheep, rodents, rabbits, squirrels, bears, and primates such as chimpanzees, gorillas, and humans.
  • pharmaceutically acceptable refers to a compound or combination of compounds that will not impair the physiology of the recipient human or animal to the extent that the viability of the recipient is compromised.
  • the administered compound or combination of compounds will elicit, at most, a temporary detrimental effect on the health of the recipient human or animal.
  • carrier refers to any pharmaceutically acceptable excipient, diluent, or other dispersant of agents that will allow a therapeutic composition to be administered by the desired route, e.g., by oral administration.
  • the formulations described herein comprise stabilized microparticles of a metalloporphyrin where, relative to the uncoated metalloporphyrin, the microparticles have increased stability in acidic conditions, and/or enhanced solubility at neutral pH.
  • the microparticles are at least 10% more stable to acidic conditions, at least 20% more stable, at least 30% more stable, at least 40% more stable, at least 50% more stable, at least 75% more stable, and may be at least 2-fold more stable, at least 5-fold, at least 10-fold or more. Stability can be experimentally determined by observing precipitation and degradation in experimental conditions in vitro.
  • the stabilizer may protect the active agent from instability at low pH, e.g., the acidic conditions present in the stomach. In other embodiments, the stabilizer may also increase the solubility of the active agent in neutral pH, e.g., to increase absorption in the neutral conditions present in the intestine.
  • Stabilized microparticle formulations of the disclosure also confer enhanced absorption at neutral pH, e.g., at a pH greater than 5.5 but less than 8.5, including a pH of greater than about 6.0, greater than about 6.5, greater than about 7.0, and less than about 8.5, less than about 8.0.
  • the microparticles are at least 10% more soluble in neutral pH, at least 20% more soluble, at least 30% more soluble, at least 40% more soluble, at least 50% more soluble, or at least 75% more soluble, and may be at least 2-fold more soluble, at least 5 fold, at least 10-fold or more. Solubility can be experimentally determined by conventional methods.
  • the microparticle can comprise or consist essentially of an active agent and a stabilizer.
  • the concentration of the active agent in the microparticle is up to about 5%, up to about 10%, up to about 15%, up to about 20%, up to about 25%, up to about 30%, up to about 35%, up to about 40%, up to about 45%, up to about 50% of the total weight, and the like, and may be from about 5% to about 50%, from about 10% to about 40%, from about 15% to about 35%, from about 20% to about 30% by weight, preferably about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 1 1 %, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% by weight.
  • the balance of the microparticle weight is typically provided by stabilizer, i.e., up to about 95%, up to about 90%, up to about 85%, up to about 80%, up to about 75%, up to about 70%, up to about 65%, up to about 60%, up to about 55%, up to about 50%, up to about 45%, up to about 40% of the total weight.
  • stabilizer i.e., up to about 95%, up to about 90%, up to about 85%, up to about 80%, up to about 75%, up to about 70%, up to about 65%, up to about 60%, up to about 55%, up to about 50%, up to about 45%, up to about 40% of the total weight.
  • the concentration of stabilizer in the microparticle is preferably about 95%, about 94%, about 93%, about 92%, about 91 %, about 90%, about 89%, about 88%, about 87%, about 86%, about 85%, about 84%, about 83%, about 82%, about 81 %, about 80%, about 79%, about 78%, about 77%, about 76%, about 75%, about 74%, about 73%, about 72%, about 71 %, or about 70% by weight.
  • the stabilizer confers increased stability at acidic conditions, and allows for increased solubility at neutral pH conditions.
  • the microparticles comprise a metal porphyrin complex, for example, a metal mesoporphyrin complex or a metal protoporphyrin complex, wherein the metal porphyrin complex is coated with a pharmaceutically acceptable excipient.
  • a metal porphyrin complex for example, a metal mesoporphyrin complex or a metal protoporphyrin complex, wherein the metal porphyrin complex is coated with a pharmaceutically acceptable excipient.
  • the microparticles may have a controlled size, as appropriate for optimization of drug delivery.
  • the particle will have a diameter of up to about 10 nm, up to about 50 nm, up to about 100 nm, up to about 250 nm, up to about 500 nm, up to about 1 ⁇ , up to about 2.5 ⁇ , up to about 5 ⁇ , and not more than about 10 ⁇ in diameter.
  • the microparticle size is from about 100 nm to about 5 ⁇ in diameter, for example from about 100 to about 500 nm, from about 500 nm to about 1 ⁇ , and the like.
  • a plurality of microparticles optionally has a defined average size range, which may be substantially homogeneous, where the variability may not be more than 100%, 50%, or 10% of the diameter. Diameters of microparticles may be measured, for example, using scanning electron microscopy (SEM).
  • Microparticles can be formed by various methods, including, in some embodiments, the methods exemplified herein. Methods of interest may include, without limitation, controlled cation-induced micro-emulsion; and spray drying. Polymeric microparticle fabrication methods can involve polyelectrolyte complex formation, double emulsion/solvent evaporation techniques, emulsion polymerization techniques, and the like. Spray drying is a process that uses jets of dissolved or suspended drug in an aqueous or other fluid phase that is forced through high pressure nozzles to produce a fine mist. Often, a bulking agent will be added to the fluid as well. The aqueous or other liquid contents of the mist evaporate, leaving behind a fine powder.
  • a modification of spray drying uses two wedge-shaped nozzles through which compressed air passes and liquid solutions pass at high velocity.
  • the wedge-shaped nozzle acts as a fluid acceleration zone where the four streams collide at high velocity, producing a shock wave that generates fine droplets.
  • the droplets then descend into a column while being dried into a solid powder by heated air before being collected.
  • Stabilizers of interest include, without limitation, alginate, chitosan, lecithin, which are naturally occurring mixtures of diglycerides of stearic, palmitic, and oleic acids, linked to the choline ester of phosphoric acid; sodium trimetaphosphate; poloxamers, i.e., nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), including various sizes, e.g., Poloxamer 188, poloxamer 407, etc.; cationic lipids, particularly phospholipids; oils, such as coconut oil, etc.
  • Chitosan is a linear polysaccharide composed of randomly distributed ⁇ -(1 ,4) D-glucosamine and N-acetyl-D-glucosamine.
  • Other stabilizers of interest include, for example a protein, such as albumin (for example bovine serum albumin, human serum albumin, etc.), and polyvinylpyrrolidone (PVP) (a water-soluble branched polymer of N-vinylpyrrolidone).
  • PVP polyvinylpyrrolidone
  • cationic lipids is intended to encompass molecules that are positively charged at physiological pH, and more particularly, constitutively positively charged molecules, comprising, for example, a quaternary ammonium salt moiety.
  • Cationic lipids used in the methods of the disclosure typically consist of a hydrophilic polar head group and lipophilic aliphatic chains. See, for example, Farhood et al. (1992) Biochim. Biophvs. Acta 1111 :239-246; Vigneron et al. (1996) Proc. Natl. Acad. Sci. (USA) 93:9682-9686.
  • Cationic lipids of interest include, for example, imidazolinium derivatives (WO 95/14380), guanidine derivatives (WO 95/14381 ), phosphatidyl choline derivatives (WO 95/35301 ), and piperazine derivatives (WO 95/14651 ).
  • Examples of cationic lipids that may be used in the present disclosure include 1 ,2-distearoyl-sn- glycero-3-phosphocholine (DSPC); 1 ,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC); DOTIM (also called BODAI) (Solodin et al., (1995) Biochem.
  • the metalloporphyrin is stabilized in a microparticle formulation with a cationic lipid or lipids.
  • Lipids of interest include any of those listed above, e.g., including cholesterol, DSPC, DPPC, DOTIM, DDAB, DOTMA, DMRIE, EDMPC, DCChol, DOGS, MBOP, etc., which may be used singly or as a cocktail of different lipids, e.g., two lipids at a 10:1 , 5:1 , 2:1 , 1 :1 , 1 :2, 1 :5, 1 :10, etc. ratio.
  • the cocktail includes three lipids at a 10:1 :1 , 3:1 :1 , 5:2:2, 4:3:2, 3:4:2, 2:2:1 , 1 :1 :1 , 1 :1 :10, etc. ratio.
  • the lipids can comprise up to about 90% of the microparticle, up to about 85% of the microparticle, up to about 80% of the microparticle, up to about 75% of the microparticle, up to about 70% of the microparticle, up to about 65% of the microparticle, or up to about 50% of the microparticle by weight, where the balance can be the active agent, or can be combined with, for example, EUDRAGIT® L 30 D-55, which is an aqueous dispersion of anionic polymers with methacrylic acid as a functional group, at a concentration of from about 35% to about 75% of the formulation weight. In some embodiments, however, the microparticles are free of EUDRAGIT®. In certain embodiments, the microparticles comprise about 10% to about 25% Metal porphyrin complex by weight, and the balance is a mixture of DSPC and DPPC in the ratios described above.
  • the microparticles comprise or consist essentially of DSPC, DPPC, and metalloporphyrin. In one embodiment, the microparticles comprise or consist essentially of DSPC (ranging in the amount of 10% to 90% w/w), DPPC (ranging in the amount of 10% to 90% w/w), and FePP (ranging in the amount of 10% to 20% w/w).
  • the microparticles comprise or consist essentially of DSPC (ranging in the amount of 10% to 90% w/w, e.g., 0%, 20%, 25%, 30%, 40%, 45%, 50%, 60%, 65%, and 90% w/w), DPPC (ranging in the amount of 10% to 90% w/w, e.g., 0%, 20%, 25%, 30%, 40%, 45%, 50%, 65%, and 90% w/w), and zinc protoporphyrin (ZnPP) (ranging in the amount of 10% to 20% w/w).
  • the microparticles comprise or consist essentially of DSPC, DPPC, cholesterol, and metalloporphyrin.
  • the microparticles comprise or consist essentially of DSPC (ranging in the amount of 10% to 90% w/w), DPPC (ranging in the amount of 10% to 90% w/w), cholesterol (ranging in the amount of 10% to 20% w/w), and FePP (ranging in the amount of 10% to 20% w/w).
  • the microparticles comprise or consist essentially of DSPC (ranging in the amount of 10% to 90% w/w), DPPC (ranging in the amount of 10% to 90% w/w), cholesterol (ranging in the amount of 10% to 20% w/w), and ZnPP (ranging in the amount of 10% to 20% w/w).
  • the microparticles comprise or consist essentially of DPPC, EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol), and metalloporphyrin.
  • the microparticles comprise or consist essentially of DPPC, EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol), and FePP.
  • the microparticles comprise or consist essentially of DPPC (5%), EUDRAGIT® L100- 55 (75%), and FePP (20%) (w/w).
  • the microparticles comprise or consist essentially of DPPC (42%), EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol) (38%), and FePP (20%) (w/w).
  • the microparticles comprise or consist essentially of DPPC, EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol), and ZnPP.
  • the microparticles comprise or consist essentially of DPPC (5%), EUDRAGIT® L100-55 (75%), and ZnPP (20%) (w/w).
  • the microparticles comprise or consist essentially of DPPC (42%), EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol) (38%), and ZnPP (20%) (w/w).
  • a powder blend comprises or consists essentially of D- glucose (ranging in the amount of 10% to 90% w/w) and microparticles comprising DPPC, EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol), and metalloporphyrin (ranging in the amount of 10% to 90% w/w).
  • a powder blend comprises or consists essentially of D-glucose (ranging in the amount of 10% to 90% w/w) and microparticles comprising DPPC, EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol), and FePP (ranging in the amount of 10% to 90% w/w).
  • a powder blend comprises or consists essentially of D-glucose (ranging in the amount of 10% to 90% w/w) and microparticles comprising DPPC, EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol), and AnPP (ranging in the amount of 10% to 90% w/w).
  • a powder blend comprises or consists essentially of D-glucose (90%) and microparticles (10%) comprising DPPC, EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx.
  • a powder blend comprises or consists essentially of D-glucose (90%) and microparticles (10%) comprising DPPC (5%), EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol) (75%), and metalloporphyrin (20%) (w/w).
  • a powder blend comprises or consists essentially of D-glucose (90%) and microparticles (10%) comprising DPPC (42%), EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol) (38%), and metalloporphyrin (20%) (w/w).
  • the metal porphyrin complex is stabilized in a microparticle formulation with a mixture comprising or consisting essentially of lecithin, a poloxamer, a neutral oil carrier, e.g., coconut oil, and one or more of alginate, sodium trimetaphosphate and chitosan.
  • the microparticles comprise about 5% to about 25% metalloporphyrin, about 10% to about 20% metalloporphyrin by weight.
  • the lecithin is present at a concentration of from about 10% to not more than about 40%, from about 20% to not more than about 30% by weight of the microparticle.
  • the poloxamer is present at a concentration of from about 10% to not more than about 40%, from about 15% to not more than about 25% by weight of the microparticle.
  • the balance of the formulation comprises, consists essentially, or consists of the neutral oil carrier and the stabilizer.
  • the stabilizer is alginate, which is present at about 3% to about 6%, at about 4% to about 5%, and may be about 4.5% by weight of the microparticle.
  • the microparticles comprise or consist essentially of coconut oil, lecithin, metalloporphyrin, poloxamer-188, sodium alginate, and calcium chloride.
  • the microparticles comprise Coconut oil (35%), Lecithin (20%), FePP (20%), Poloxamer-188 (20%), Sodium Alginate (4.5%), and Calcium chloride (0.5%).
  • the microparticles comprise Coconut oil (35%), Lecithin (20%), ZnPP (20%), Poloxamer-188 (20%), Sodium Alginate (4.5%), and Calcium chloride (0.5%).
  • the stabilizer is chitosan, which is present at about 3% to about 6%, at about 4% to about 5%, and may be about 4.5% to 5% by weight of the microparticle.
  • the microparticles comprise or consist essentially of coconut oil, lecithin, metalloporphyrin, poloxamer-188, and chitosan.
  • the microparticles comprise Coconut oil (40%), Lecithin (30%), FePP (5%), Poloxamer-188 (20%), and Chitosan (MW-15000) (5%).
  • the microparticles comprise or consist essentially of Coconut oil (40%), Lecithin (30%), ZnPP (5%), Poloxamer-188 (20%), and Chitosan (MW-15000) (5%).
  • the stabilizer is sodium trimetaphosphate, which is present at about 3% to about 6%, at about 4% to about 5%, and may be about 4.5% to 5% by weight of the microparticle.
  • the microparticles comprise or consist essentially of coconut oil, lecithin, metalloporphyrin, poloxamer-188, and Sodium trimetaphosphate (STMP).
  • the microparticles comprise Coconut oil (35%), Lecithin (20%), FePP (20%), Poloxamer-188 (20%) and STMP (5%).
  • the microparticles comprise Coconut oil (35%), Lecithin (20%), ZnPP (20%), Poloxamer-188 (20%) and STMP (5%).
  • the microparticles are formed by spray drying.
  • the microparticles are formed by evaporation, e.g., by a Buchi evaporator.
  • compositions are formulated for oral delivery.
  • the microparticles of the disclosure are provided, e.g., in a unit dose, such as a dry powder for reconstitution immediately prior to administration.
  • Pharmaceutical compositions can include, depending on the formulation desired, pharmaceutically-acceptable, non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration.
  • the diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, buffered water, physiological saline, PBS, Ringer's solution, dextrose solution, and Hank's solution.
  • compositions or formulation can include other carriers, or non-toxic, nontherapeutic, non-immunogenic stabilizers, excipients and the like.
  • compositions can also include additional substances to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, wetting agents and detergents.
  • an oral delivery formulation is provided as a thin film, for example where a dried powder formulation of microparticles is dispersed in a solvent containing a film forming polymer, which can be cast in a thin film and packaged, for example as a unit dose.
  • a composition for a thin film comprises or consists essentially of a metalloporphyrin, DPPC, DSPC, an organic solvent, and a film-forming polymer.
  • the composition for a thin film comprises or consists essentially of FePP, DPPC, DSPC, an organic solvent, and a film-forming polymer.
  • the composition for a thin film comprises or consists essentially of ZnPP, DPPC, DSPC, an organic solvent, and a film-forming polymer.
  • the composition for a thin film comprises or consists essentially of a metalloporphyrin, DPPC, EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol), an organic solvent, and a film-forming polymer.
  • the composition for a thin film comprises or consists essentially of a FePP, DPPC, EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol), an organic solvent, and a film-forming polymer.
  • the composition for a thin film comprises or consists essentially of a ZnPP, DPPC, EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol), an organic solvent, and a film-forming polymer.
  • oral formulations include, without limitation, tablets, lozenges, capsules, sprinkles, sachets, stick-packs, etc. as known in the art and adapted for the microparticles of the disclosure.
  • a composition for a tablet comprises or consists essentially of a metalloporphyrin, DPPC, DSPC, and citrate buffer ⁇ e.g., 0.25% (w/v), pH 4.7).
  • a composition for a tablet comprises a metalloporphyrin, DPPC, DSPC, citrate buffer ⁇ e.g., 0.25% (w/v), pH 4.7), and mannitol.
  • the composition for a tablet comprises or consists essentially of FePP, DPPC, DSPC, citrate buffer ⁇ e.g., 0.25% (w/v), pH 4.7), and mannitol.
  • the composition for a tablet comprises or consists essentially of ZnPP, DPPC, DSPC, citrate buffer ⁇ e.g., 0.25% (w/v), pH 4.7), and mannitol.
  • the composition for a tablet comprises or consists essentially of a metalloporphyrin, DPPC, EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol), and citrate buffer ⁇ e.g., 0.25% (w/v), pH 4.7).
  • the composition for a tablet comprises or consists essentially of a metalloporphyrin, DPPC, EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol), citrate buffer ⁇ e.g., 0.25% (w/v), pH 4.7), and mannitol.
  • the composition for a tablet comprises a FePP, DPPC, EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx.
  • the composition for a tablet comprises or consists essentially of a ZnPP, DPPC, EUDRAGIT® L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol), citrate buffer ⁇ e.g., 0.25% (w/v), pH 4.7), and mannitol.
  • the total dose per day is preferably administered at least once per day, but may be divided into two or more doses per day. Some patients may benefit from a period of "loading" the patient with a higher dose or more frequent administration over a period of days or weeks, followed by a reduced or maintenance dose.
  • Specific information regarding formulations which can be used in connection with aerosolized delivery devices are described within Remington's Pharmaceutical Sciences, A. R. Gennaro editor (latest edition) Mack Publishing Company. For a brief review of methods for drug delivery, see, Langer, Science 249:1 527-1 533 (1 990).
  • the pharmaceutical compositions can be administered for prophylactic and/or therapeutic treatments.
  • Toxicity and therapeutic efficacy of the active ingredient can be determined according to standard pharmaceutical procedures in cell cultures and/or experimental animals, including, for example, determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 5 o/ED 5 o.
  • Compounds that exhibit large therapeutic indices are preferred.
  • the data obtained from cell culture and/or animal studies can be used in formulating a range of dosages for humans.
  • the dosage of the active ingredient typically lies within a range of circulating concentrations that include the ED 50 with low toxicity.
  • the dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.
  • compositions intended for in vivo use are usually sterile. To the extent that a given compound must be synthesized prior to use, the resulting product is typically substantially free of any potentially toxic agents, particularly any endotoxins, which may be present during the synthesis or purification process.
  • compositions for parental administration are also sterile, substantially isotonic and made under GMP conditions.
  • compositions of the disclosure may be administered using any medically appropriate procedure.
  • the composition is administered topically, enterally, or parenterally.
  • the composition may be administered subcutaneously, intravenously, intramuscularly, intranasally, by inhalation, orally, sublingually, by buccal administration, topically, transdermal ⁇ , or transmucosally.
  • the composition may be administered by injection.
  • the composition is administered by subcutaneous injection, orally, intranasally, by inhalation, or intravenously.
  • the composition is administered orally.
  • compositions can be administered to the subject in a series of more than one administration.
  • dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Some of the drugs are more potent than others. Preferred dosages for a given agent are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.
  • formulations are provided for use in the methods of the disclosure.
  • Such formulations may comprise a stabilized microparticle comprising a metalloporphyrin, etc., which can be provided in a packaging suitable for clinical use, including packaging as a lyophilized, sterile powder; packaging of a stable suspension of, for example, microparticles, in carrier; separate packaging of microparticles and carrier suitable for mixing prior to use; and the like.
  • the packaging may be a single unit dose, providing an effective dose of active agent in microparticle form in the manufacture of a medicament, e.g., for reducing the serum iron concentration in a subject suffering from hemochromatosis, ⁇ -thalassemia, sickle cell disease, refractory anemia, or hemolytic anemia, etc.
  • the present disclosure relates to the use of a metal porphyrin complex in therapeutic methods for the treatment of various conditions in which decreasing serum iron concentration may be beneficial.
  • the disclosure relates to a method for reducing the serum iron concentration in a subject to treat a condition, comprising administering to the subject a composition comprising a metal porphyrin complex.
  • Methods described herein include the administration, preferably oral administration, of a pharmaceutical composition comprising metalloporphyrin- containing microparticles described herein in a dose effective to reduce the serum iron concentration in a subject.
  • Oral administration allows targeted delivery by taking advantage of "first pass effect" resulting in localization to liver and spleen.
  • the metalloporphyrin can also be systemic after oral delivery.
  • the effective dose may vary depending on the age of the individual, the condition being treated, and the like.
  • a microparticle composition comprising a metalloporphyrin may administered at an initial dosage of about 0.1 mg to about 100 mg of active agent/kg BW (IM).
  • treatment with the metalloporphyrin is a one-time single dose treatment, in other embodiments, dosing is repeated daily, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 8 days, every 9 days, every 10 days, every 1 1 days, every 12 days, every 13 days, every 2 weeks, every 3 weeks, monthly, etc., as needed.
  • a condition in which decreasing serum iron concentration may be beneficial is selected from hemochromatosis, thalassemia, sickle cell disease, refractory anemia, hemolytic anemia, a viral infection, a bacterial infection, a fungal infection, a protist infection, iron overload ⁇ e.g., resulting from a blood transfusion, physical trauma, tissue injury, a cardiovascular surgery, cardiopulmonary bypass, acute coronary syndrome, or sepsis), iron induced injury, and organ transplant.
  • the condition may be anemia, thalassemia, hemochromatosis, and sickle cell disease.
  • the condition may be hemochromatosis and the hemochromatosis may be hereditary hemochromatosis.
  • the condition may be hemochromatosis and the hemochromatosis may be associated with hepatocarcinoma, cardiomyopathy, or diabetes.
  • the condition may be anemia.
  • Anemia may be, for example, anemia associated with myelodysplastic syndrome (MDS), aplastic anemia, a congenital anemia, a hemoglobinopathy, hemolytic anemia, refractory anemia, iron-refractory iron deficiency anemia (IRIDA), and sideroblastic anemia.
  • MDS myelodysplastic syndrome
  • the condition may be hemoglobinopathy, sideroblastic anemia, or a congenital anemia.
  • the condition may be thalassemia.
  • Thalassemia may be, for example, a-thalassemia, thalassemia intermedia, ⁇ -thalassemia, hemoglobin ⁇ - ⁇ -thalassemia (Hb E/3-thalassaemia) and hemoglobin E thalassemia.
  • the subject may be experiencing or about to experience physical trauma ⁇ e.g., physical trauma (including surgical intervention) resulting in blood loss or need for or administration of a blood transfusion).
  • the subject may have a tissue injury ⁇ e.g., a crush injury or a burn injury).
  • Treatment of such patients with metalloporphyrin-containing microparticles can protect such subjects from iron- induced injury resulting from the injury or transfusion.
  • the subject may have acute kidney injury.
  • a condition e.g., iron overload resulting from cardiovascular surgery such as a cardiopulmonary bypass, acute coronary syndrome, or sepsis
  • a composition comprising metalloporphyrin-containing microparticles to the subject according to any of the methods discussed herein.
  • the condition may be hepatocarcinoma, cardiomyopathy, or diabetes.
  • the condition may be a viral, bacterial, fungal, or protist infection.
  • the condition is a bacterial infection
  • the bacterium is Escherichia coli, Mycobacterium (such as M. africanum, M. avium, M. tuberculosis, M. bovis, M. canetti, M. kansasii, M. leprae, M. lepromatosis, or M. microti), Neisseria cinerea, Neisseria gonorrhoeae, Staphylococcus epidermidis, Staphylococcus aureus, or Streptococcus agalactiae.
  • the condition is a fungal infection, and the fungus is Candida albicans.
  • the condition is a protist infection, and the protist is Trypanosoma ⁇ Trypanosoma brucei, such as T. brucei gambiense or T. brucei rhodesiense, and T. cruzi,), Plasmodium (such as P. falciparum, P. vivax, P. ovale, or P. malariae), or Leishmania.
  • the condition may be a viral, bacterial, fungal, or protist infection, and the viral, bacterial, fungal, or protist infection may be resistant to one or more agents for treating the viral, bacterial, fungal, or protist infection.
  • the condition may be a bacterial infection and the bacterial infection may be tuberculosis.
  • the condition may be Chagas disease (caused by T. cruzi,), malaria (caused by P. falciparum, P. vivax, P. ovale, or P. malariae), African sleeping sickness (caused by T. brucei gambiense or T. brucei rhodesiense), or leishmaniasis.
  • the condition is a viral infection, and the virus is hepatitis B, hepatitis C, or dengue virus.
  • the method may comprise the conjoint administration of 4-aminosalicylic acid, aldesulfone, amikacin, amithiozone, bedaquiline, capreomycin, clofazimine, cycloserine, dapsone, delamanid, ethambutol, a fluoroquinolone, isoniazid, kanamycin, modified vaccinia Ankara 85A (MVA85A), morinamide, ofloxacin, pyrazinamide, recombinant Bacillus Calmette-Guerin 30 (rBCG30), rifampicin, rifater, streptomycin, terizidone, and/or thioacetazone to the subject.
  • 4-aminosalicylic acid aldesulfone, amikacin, amithiozone, bedaquiline, capreomycin, clofazimine, cycloserine, dapsone, delamanid, ethambutol,
  • the method may comprise the conjoint administration of balofloxacin, cinoxacin, ciprofloxacin, clinafloxacin, danofloxacin, delafloxacin, difloxacin, enoxacin, enrofloxacin, fleroxacin, Fourth-generation, gatifloxacin, gemifloxacin, grepafloxacin, ibafloxacin, JNJ-Q2, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, nadifloxacin, nalidixic acid, nemonoxacin, norfloxacin, ofloxacin, orbifloxacin, oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic acid, prulifloxacin, rosoxacin, rufloxacin, sarafloxacin, sitafloxacin
  • the condition may be tuberculosis and/or a Mycobacterium infection.
  • the condition may be tuberculosis and the tuberculosis may be a drug-resistant tuberculosis.
  • the condition may be tuberculosis and the tuberculosis may be multi-drug-resistant tuberculosis (MDR-TB), extensively drug- resistant tuberculosis (XDR-TB), or totally drug-resistant tuberculosis (TDR-TB).
  • MDR-TB multi-drug-resistant tuberculosis
  • XDR-TB extensively drug- resistant tuberculosis
  • TDR-TB totally drug-resistant tuberculosis
  • the condition may be tuberculosis, and the tuberculosis may not be drug-resistant, multi- drug-resistant, extensively drug-resistant, or totally drug-resistant.
  • the condition may be tuberculosis and/or a Mycobacterium infection and the condition may be resistant to isoniazid, ethambutol, rifampicin, pyrazinamide, ofloxacin, one or more fluoroquinolones, amikacin, kanamycin, and/or capreomycin.
  • the method may comprise the conjoint administration of fluconazole, ketoconazole, miconazole, and/or itraconazole to the subject.
  • the condition may be Chagas disease and/or Trypanosoma cruzi infection, and the condition may be resistant to one or more of fluconazole, ketoconazole, miconazole, and/or itraconazole.
  • the method may comprise the conjoint administration of fluconazole, benznidazole, and/or amphotericin B to the subject.
  • the condition may be African sleeping sickness and the method may comprise conjointly administering an arsenical and/or diamidine to the subject.
  • the condition may be African sleeping sickness and/or Trypanosoma bruce infection, and the condition may be resistant to arsenicals and/or diamidines.
  • the condition may be leishmaniasis and the method may comprise conjointly administering a pentavalent antimonial to the subject.
  • the condition may be leishmaniasis and the condition may be resistant to pentavalent antimonials.
  • the method may comprise conjointly administering amphotericin, amphotericin B, pentavalent antimonials, miltefosine, paromomycin, and/or fluconazole to the subject.
  • the condition may be malaria.
  • the condition may be malaria and the malaria may be resistant to one or more agents for treating malaria.
  • the condition may be malaria, and the method may comprise conjoint administration of chloroquine, quinine, sulfadoxine-pyrimethamine, halofantrine, atovaquone, and/or mefloquine to the subject.
  • the condition may be malaria, and the malaria may be resistant to one or more of chloroquine, quinine, sulfadoxine-pyrimethamine, halofantrine, atovaquone, and/or mefloquine.
  • the condition may be a multidrug-resistant falciparum malaria infection.
  • the method may comprise the conjoint administration of one or more of proguanil, chlorproguanil, pyronaridine, lumefantrinel, mefloquine, dapsone, atovaquone, and/or artesunate to the subject.
  • the method may comprise the conjoint administration of artemisinin or an artemisinin derivative to the subject.
  • the method may comprise the conjoint administration of artesunate, artemisinin, dihydro- artemisinin, artelinate, arteether, and/or artemether to the subject.
  • provided herein are methods of treating and/or preventing iron overload in a subject who has acquired iron overload.
  • methods for treating and/or preventing a condition ⁇ e.g., iron overload resulting from cardiovascular surgery such as a cardiopulmonary bypass, acute coronary syndrome or sepsis
  • a condition ⁇ e.g., iron overload resulting from cardiovascular surgery such as a cardiopulmonary bypass, acute coronary syndrome or sepsis
  • the condition is comorbid with iron overload ⁇ e.g., acquired iron overload or non-acquired iron overload).
  • the subject is undergoing a cardiovascular surgery such as cardiopulmonary bypass.
  • the subject has previously undergone cardiovascular surgery such as a cardiopulmonary bypass.
  • the subject has undergone a blood transfusion or cardiovascular surgery such as a cardiopulmonary bypass ⁇ e.g., within the past day, 2 days, 3 days, 4 days, 5 days, 6 days, week, 2 weeks, 3 weeks, 4 weeks, month, 2 months, 3 months, 4 months, 5 months, 6 months).
  • the subject has undergone at least 1 , at least 2, at least 3, at least 4 or at least 5 blood transfusions within the past week.
  • the subject has undergone at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 blood transfusions within the past month.
  • the subject has undergone at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 1 1 , at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19 or at least 20 blood transfusions within the past six months. In some embodiments, the subject has undergone at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 1 1 , at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19 or at least 20 blood transfusions within the past year.
  • the subject is a subject who is undergoing a blood transfusion.
  • the subject is administered a composition described herein before undergoing a blood transfusion ⁇ e.g., no more than 1 day before, no more than 2 days before, no more than 3 days before, no more than 4 days before, no more than 5 days before, no more than 6 days before, or no more than a week before).
  • a composition described herein before undergoing a blood transfusion e.g., no more than 1 day before, no more than 2 days before, no more than 3 days before, no more than 4 days before, no more than 5 days before, no more than 6 days before, or no more than a week before.
  • the composition is administered at least 1 hour before, at least 2 hours before, at least 3 hours before, at least 4 hours before, at least 5 hours before, at least 6 hours before, at least 7 hours before, at least 8 hours before, at least 9 hours before, at least 10 hours before, at least 1 1 hours before, at least 12 hours before, at least 13 hours before, at least 14 hours before, at least 15 hours before, at least 16 hours before, at least 17 hours before, at least 18 hours before, at least 19 hours before, at least 20 hours before, at least 21 hours before, at least 22 hours before, at least 23 hours before, or at least 1 day before.
  • the subject has a disease or disorder that results in frequent blood transfusions.
  • the subject has anemia ⁇ e.g., aplastic anemia, hemolytic anemia, or sideroblastic anemia).
  • the subject has thalassemia ⁇ e.g., hemoglobin E-beta thalassemia or hemoglobin E thalassemia).
  • the subject has sickle cell disease.
  • the subject has myelodysplastic syndrome.
  • the subject has undergone, is undergoing, or is about to undergo physical trauma.
  • the subject may have a tissue injury ⁇ e.g., crush injury or a burn injury). Because kidneys are especially prone to damage resulting from iron overload, in some embodiments, the subject that has undergone, is undergoing, or is about to undergo physical trauma also has a chronic or acute kidney injury.
  • pharmacological agents are known to be effective in organ preservation solutions. Injuries to organs generally increase as a function of the length of time an organ is maintained ex vivo. For example, in the case of a lung, typically it may be preserved ex vivo for only about 6 to about 8 hours before it becomes unusable for transplantation. A heart typically may be preserved ex vivo for only about 4 to about 8 hours before it becomes unusable for transplantation.
  • compositions to prevent organ or tissue damage to an organ e.g., an organ for transplant
  • an organ, or organ donor may be perfused post-mortem with compositions provided herein to prevent damage to the organ.
  • methods for reducing, preventing or reversing organ damage or enhancing organ preservation and/or survival comprising administering a composition disclosed herein.
  • the composition is administered to the organ and/or organ donor less than 24 hours prior to removal of the organ, such as less than 12, eight, six, four or two hours prior to removal of the organ.
  • the composition is administered to the organ and/or organ donor immediately prior to removal of the organ (e.g., less than one hour prior to removal of the organ, such as less than 30, 15, or 10 minutes prior to removal of the organ).
  • the organ donor patient is a human.
  • provided herein are methods of facilitating an organ transplant procedure and/or enhancing the success of an organ transplant procedure, comprising administering a composition disclosed herein (i.e., a composition comprising metalloporphyrin-containing microparticles) to the organ or organ donor prior to transplantation.
  • a composition disclosed herein i.e., a composition comprising metalloporphyrin-containing microparticles
  • methods and compositions for prolonging organ viability ex vivo comprising administering a compound disclosed herein (i.e., a composition comprising metalloporphyrin- containing microparticles).
  • the organ is contacted with a composition disclosed herein while the organ is still in a body, during the removal of the organ from a body, after the organ is removed from a body, while the organ is being transplanted into a recipient, immediately after the organ is transplanted into a recipient, or any combination thereof.
  • the organ in contact with, and preferably partially or wholly submersed in, an organ preservation solution, wherein the organ preservation solution comprises a composition disclosed herein.
  • the organ preservation solution further comprises potassium, sodium, magnesium, calcium, phosphate, sulphate, glucose, citrate, mannitol, histidine, tryptophan, alpha- ketoglutaric acid, lactobionate, raffinose, adenosine, allopurinol, glutathione, glutamate, insulin, dexamethasone, hydroxyethyl starch, bactrim, trehalose, gluconate, or combinations thereof.
  • the organ preservation solution comprises sodium, potassium, magnesium, or combinations thereof. In certain embodiments, the organ preservation solution is free or substantially free of cells, coagulation factors, DNA, and/or plasma proteins. In certain embodiments, the organ preservation solution is sterile.
  • metalloporphyrin is administered in a dosage of from about 0.5 to about 6 mg/kg metalloporphyrin active agent/kg (IM). In some embodiments, metalloporphyrin is administered in a dosage of from about 0.5 mg/kg to about 4 mg/kg, from about 0.5 mg/kg to about 2 mg/kg, from about 0.75 mg/kg to about 1 .5 mg/kg, from about 1 .5 mg/kg to about 4.5 mg/kg or from about 3.0 mg/kg to about 4.5 mg/kg, including about 1 .5 mg/kg, about 3.0 mg/kg and about 4.5 mg/kg.
  • IM metalloporphyrin active agent/kg
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. For example, treatment may be initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum effect under the circumstance is reached.
  • the serum iron concentration of the subject is at least about 50 pg/dL prior to administering the composition, such as at least about 55 Mg/dL, at least about 60 MQ/dL, at least about 65 MQ/dL, at least about 70 MQ/dL, at least about 75 MQ/dL, at least about 80 MQ/dL, at least about 85 MQ/dL, at least about 90 MQ/dL, at least about 95 MQ/dL, at least about 100 MQ/dL, at least about 1 10 MQ/dL, at least about 120 Mg/dL, at least about 130 Mg/dL, at least about 140 MQ/dL, at least about 150 MQ/dL, at least about 160 MQ/dL, at least about 170 MQ/dL, at least about 175 MQ/dL, at least about 176 MQ/dL, at least about 177 MQ/dL, at least about 180 Mg/dL, at least about a
  • the serum iron concentration of the subject is about 50 Mg/dL to about 500 MQ/dL prior to administering the composition, such as about 55 Mg/dL to about 500 MQ/dL, about 60 MQ/dL to about 500 MQ/dL, about 65 MQ/dL to about 500 MQ/dL, about 70 MQ/dL to about 500 MQ/dL, about 75 MQ/dL to about 500 MQ/dL, about 80 MQ/dL to about 500 MQ/dL, about 85 MQ/dL to about 500 MQ/dL, about 90 Mg/dL to about 500 MQ/dL, about 95 MQ/dL to about 500 MQ/dL, about 100 MQ/dL to about 500 MQ/dL, about 1 10 Mg/dL to about 500 MQ/dL, about 120 Mg/dL to about 500 Mg/dL, about 130 MQ/dL to about 500 MQ/dL, about 140 MQ/
  • administering the composition to a subject decreases the serum iron concentration of the subject.
  • administering the composition may decrease the serum iron concentration of a subject by at least about 5 MQ/dL, at least about 10 MQ/dL, at least about 5 MQ/dL, at least about 20 MQ/dL, at least about 30 MQ/dL, at least about 40 MQ/dL, at least about 50 MQ/dL, at least about 60 MQ/dL, at least about 70 MQ/dL, at least about 80 MQ/dL, at least about 90 Mg/dL, or at least about 100 Mg/dL.
  • administering the composition decreases the serum iron concentration of the subject for at least 24 hours.
  • administering the composition may decrease the serum iron concentration of the subject by at least about 5 Mg/dL for a period of time of at least 24 hours.
  • Administering the composition may decrease the serum iron concentration of the subject by at least about 5 Mg/dL for at least 4 hours, at least 6 hours, or at least 12 hours.
  • Administering the composition may decrease the serum iron concentration of the subject by at least about 5 Mg/dL for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or at least 8 days.
  • administering the composition decreases the serum iron concentration of the subject by at least about 5%, such as at least about 10%, at least about 15%, at least about 20%, at least about 25%, or even at least about 30%.
  • Administering the composition may decrease the serum iron concentration of the subject by at least about 5% for at least 4 hours, at least 6 hours, or at least 12 hours.
  • Administering the composition may decrease the serum iron concentration of the subject by at least about 5% for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or at least 8 days.
  • the subject has a serum hepcidin concentration of less than about 1000 ng/mL prior to administering the composition, such as less than about 900 ng/mL, less than about 800 ng/mL, less than about 700 ng/mL, less than about 600 ng/mL, less than about 500 ng/mL, less than about 400 ng/mL, less than about 300 ng/mL, less than about 200 ng/mL, less than about 100 ng/mL, less than about 90 ng/mL, less than about 80 ng/mL, less than about 70 ng/mL, less than about 60 ng/mL, less than about 50 ng/mL, less than about 40 ng/mL, less than about 30 ng/mL, less than about 20 ng/mL, or less than about 10 ng/mL.
  • a serum hepcidin concentration of less than about 1000 ng/mL prior to administering the composition, such as less than about 900 ng/mL,
  • the subject may have a serum hepcidin concentration of about 1 ng/mL to about 1000 ng/mL prior to administering the composition, such as about 1 ng/mL to about 900 ng/mL, about 1 ng/mL to about 800 ng/mL, about 1 ng/mL to about 700 ng/mL, about 1 ng/mL to about 600 ng/mL, about 1 ng/mL to about 500 ng/mL, about 1 ng/mL to about 400 ng/mL, about 1 ng/mL to about 300 ng/mL, about 1 ng/mL to about 200 ng/mL, about 1 ng/mL to about 100 ng/mL, about 1 ng/mL to about 90 ng/mL, about 1 ng/mL to about 80 ng/mL, about 1 ng/mL to about 70 ng/mL, about 1 ng/mL to about 60 ng/m
  • the subject has a serum ferritin concentration greater than about 10 ng/mL prior to administering the composition, such as greater than about 20 ng/mL, greater than about 30 ng/mL, greater than about 40 ng/mL, greater than about 50 ng/mL, greater than about 60 ng/mL, greater than about 70 ng/mL, greater than about 80 ng/mL, greater than about 90 ng/mL, greater than about 100 ng/mL, greater than about 200 ng/mL, greater than about 300 ng/mL, greater than about 400 ng/mL, greater than about 500 ng/mL, greater than about 600 ng/mL, greater than about 700 ng/mL, greater than about 800 ng/mL, greater than about 900 ng/mL, greater than about 1000 ng/mL, greater than about 2000 ng/mL, greater than about 3000 ng/mL, greater than about 4000 ng/mL, greater than about 5000
  • the subject has a serum ferritin concentration of about 10 ng/mL to about 100 g/mL prior to administering the composition, such as about 20 ng/mL to about 100 pg/mL, about 30 ng/mL to about 100 pg/mL, about 40 ng/mL to about 100 Mg/mL, about 50 ng/mL to about 100 pg/mL, about 60 ng/mL to about 100 Mg/mL, about 70 ng/mL to about 100 Mg/mL, about 80 ng/mL to about 100 Mg/mL, about 90 ng/mL to about 100 MQ mL, about 100 ng/mL to about 100 MQ mL, about 200 ng/mL to about 100 MQ/mL, about 300 ng/mL to about 100 MQ/mL, about 400 ng/mL to about 100 MQ/mL, about 500 ng/mL to about 100 MQ/mL,
  • the subject has a serum ferritin concentration of about 10 ng/mL to about 20 MQ/mL prior to administering the composition, such as about 20 ng/mL to about 20 MQ/mL, about 30 ng/mL to about 20 MQ/mL, about 40 ng/mL to about 20 MQ/mL, about 50 ng/mL to about 20 MQ/mL, about 60 ng/mL to about 20 MQ/mL, about 70 ng/mL to about 20 MQ/mL, about 80 ng/mL to about 20 Mg/mL, about 90 ng/mL to about 20 MQ/mL, about 100 ng/mL to about 20 MQ/mL, about 200 ng/mL to about 20 MQ mL, about 300 ng/mL to about 20 MQ mL, about 400 ng/mL to about 20 MQ/mL, about 500 ng/mL to about 20 MQ/mL, about 600 ng
  • the subject has a serum ferritin concentration of less than about 10 g /mL prior to administering the composition, such as less than about 1000 ng/mL, less than about 900 ng/mL, less than about 800 ng/mL, less than about 700 ng/mL, less than about 600 ng/mL, less than about 500 ng/mL, less than about 400 ng/mL, less than about 300 ng/mL, less than about 200 ng/mL, less than about 100 ng/mL, less than about 90 ng/mL, less than about 80 ng/mL, less than about 70 ng/mL, less than about 60 ng/mL, less than about 50 ng/mL, less than about 40 ng/mL, less than about 30 ng/mL, less than about 20 ng/mL, or less than about 10 ng/mL.
  • a serum ferritin concentration of less than about 10 g /mL prior to administering the composition, such as less than about
  • the subject has a serum ferritin concentration of about 1 ng/mL to about 1000 ng/mL prior to administering the composition, such as about 1 ng/mL to about 900 ng/mL, about 1 ng/mL to about 800 ng/mL, about 1 ng/mL to about 700 ng/mL, about 1 ng/mL to about 600 ng/mL, about 1 ng/mL to about 500 ng/mL, about 1 ng/mL to about 400 ng/mL, about 1 ng/mL to about 300 ng/mL, about 1 ng/mL to about 200 ng/mL, about 1 ng/mL to about 100 ng/mL, about 1 ng/mL to about 90 ng/mL, about 1 ng/mL to about 80 ng/mL, about 1 ng/mL to about 70 ng/mL, about 1 ng/mL to about 60 ng/mL, about 1
  • administering the composition decreases the serum ferritin concentration of the subject.
  • administering the composition may decrease the serum ferritin concentration of the subject by at least about 10 ng/mL, at least about 20 ng/mL, at least about 30 ng/mL, at least about 40 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL, at least about 70 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, or at least about 100 ng/mL.
  • the subject has a total body iron content of about 40 to about 50 mg/kg prior to administering the composition.
  • the subject may have a total body iron content greater than about 50 mg/kg prior to administering the composition, such as greater than about 55 mg/kg, greater than about 60 mg/kg, greater than about 65 mg/kg, or greater than about 70 mg/kg.
  • the subject has a transferrin saturation percentage greater than about 10% prior to administering the composition, such as greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, or even greater than about 90%.
  • the subject has a transferrin saturation percentage of about 10% to about 99% prior to administering the composition, such as about 15% to about 99%, about 20% to about 99%, about 25% to about 99%, about 30% to about 99%, about 35% to about 99%, about 40% to about 99%, about 45% to about 99%, about 50% to about 99%, about 55% to about 99%, about 60% to about 99%, about 65% to about 99%, about 70% to about 99%, about 75% to about 99%, about 80% to about 99%, or about 85% to about 99%.
  • the subject has a transferrin saturation percentage of about 10% to about 95% prior to administering the composition, such as about 15% to about 95%, about 20% to about 95%, about 25% to about 95%, about 30% to about 95%, about 35% to about 95%, about 40% to about 95%, about 45% to about 95%, about 50% to about 95%, about 55% to about 95%, about 60% to about 95%, about 65% to about 95%, about 70% to about 95%, about 75% to about 95%, about 80% to about 95%, or about 85% to about 95%.
  • administering the composition decreases the transferrin saturation percentage of the subject.
  • administering the composition to a subject may decrease the transferrin saturation percentage of the subject by at least about 1 % transferrin saturation, such as at least about 2% transferrin saturation, at least about 3% transferrin saturation, at least about 4% transferrin saturation, at least about 5% transferrin saturation, at least about 6% transferrin saturation, at least about 7% transferrin saturation, at least about 8% transferrin saturation, at least about 9% transferrin saturation, at least about 10% transferrin saturation, at least about 1 1 % transferrin saturation, at least about 12% transferrin saturation, at least about 13% transferrin saturation, at least about 14% transferrin saturation, at least about 15% transferrin saturation, at least about 16% transferrin saturation, at least about 17% transferrin saturation, at least about 18% transferrin saturation, at least about 19% transferrin saturation, at least about 20% transferrin saturation, at least about 25% transfer
  • Bilirubin is formed in the heme catabolic pathway, where heme is degraded by the enzyme, heme oxygenase or HO, to produce equimolar amounts of carbon monoxide, iron, and biliverdin, which is rapidly reduced to bilirubin.
  • heme bound to albumin or methemalbumin (MHA) was used as a source of heme in acute hemolytic rats, monkeys, and mice.
  • An albumin-free heme preparation was tested for oral bioavailability and subsequent in vivo potency and safety.
  • Heme-Lipid This lipid-based formulation contains 10% heme and biodegradable phospholipids (45% DPPC and 45% DSPC), both of which are endogenous phospholipids as well as FDA-approved excipients, and the main constituents of artificial lung surfactant already approved for use in premature newborns. Powder was dissolved in PBS prior to use.
  • Methemalbumin Hemin (chloro[3,7,12,17-tetramethyl-8,13- divinylporphyrin-2,18-dipropanoato(2-)]iron(lll)) (Sigma-Aldrich, St Louis, MO) was first dissolved in 60 ⁇ of 0.4 M Na 2 PO 4 . bovine serum albumin (BSA), and 8 imL of dH 2 O was then added under constant stirring. 0.1 M HCI was then slowly added until pH was 7.40.
  • BSA bovine serum albumin
  • HO-1 -luc Transgenic Mouse This mouse contains a transgene that consists of the full-length HO-1 promoter driving expression of the reporter gene, luciferase ( Figure 1 ). This model lets us monitor, noninvasively, any changes in HO-1 transcription through proportional changes in luciferase transcription and activity. When luciferin is administered to the transgenic mice, it is rapidly converted to oxy- luciferin by luciferase resulting in the production of light. The timeline for this study is shown in Figure 3.
  • HO-1 Transcription (BLI): For these measurements, adult mice were imaged using the IVIS. Bioluminescence was then quantitated at the ventral (for liver) and left lateral (for spleen) regions as total number of photons emitted per second or flux. HO- 1 promoter activity was then expressed as fold change from baseline levels.
  • VeCO Heme Degradation
  • Plasma AST Levels Blood was collected at sacrifice by intracardiac puncture. Plasma was then separated by centrifugation and sent to the Diagnostics Laboratory (Dept. of Comparative Medicine, Stanford, CA) for measurements of plasma AST levels.
  • HO Activity Total HO enzyme activity in 20 ⁇ of liver or spleen sonicates was measured by GC. Data were expressed as pmol CO produced/h/mg fresh weight and fold change from control levels were calculated.
  • HO-1 Promoter Activity When we compared the effect of each preparation on liver and spleen HO-1 transcriptional activity or imRNA levels using BLI, we observed significant and similar increases over baseline levels in both tissues for both preparation 24 h after administration ( Figure 6).
  • Plasma AST Levels To see if there was any toxicity related to the Heme- Lipid, we measured plasma ALT levels. We found no increases following administration of either of the heme preparations compared to controls ( Figure 7).
  • heme-lipid showed similar potency by significantly: increasing in vivo bilirubin production rates; upregulating HO-1 imRNA in liver and spleen; and inducing HO activity in the liver and spleen. Neither MHA nor Heme-Lipid increased ALT levels.
  • Microparticles are formed by spray drying which ensures a straightforward path for scale-up under a GMP environment which will be required for the GMP manufacturing of a final dosage form.
  • metalloporphyrin 20% w/w
  • the feeding solution container and spray dryer compartments are protected from light during the process.
  • the dry powder is stored frozen protected from light.
  • EUDRAGIT® L100-55 poly(methacrylic acid-co-ethyl acrylate) 1 :1 , approx. 320,000 g/mol); 38% w/w
  • the desired dose of metalloporphyrin may be contained in a small amount of spray-dried powder or less depending on the final metalloporphyrin content and depending on the target subject.
  • Spray-dried powders are usually small in size and tend to be more cohesive than granular powders.
  • a bulking agent can be used to blend the spray-dried powder to facilitate filling into a vial to be then resuspended with an appropriate diluent prior to administration to the test subject. This can be achieved as described below.
  • Metalloporphyrin -DPPC- EUDRAGIT® spray-dried powder is mixed with D- glucose as bulking agent to obtain a uniform mixture containing the target amount of spray dried powder, calculated based on the amount of metalloporphyrin content and the required dose, with an appropriate amount of D-glucose (ranging in the amount of 10% to 90% w/w) the powder blend can then be filled in a glass or plastic vial or syringe manually or using a filling machine.
  • a suspension Prior to administration, a suspension is then formed by adding the appropriate amount of diluent containing 0.25% (w/v) citrate buffer, pH 4.7, to the target amount of powder containing the required dose.
  • the pH of the diluent is selected to minimize dissolution of the polymer microparticles, but not too low to cause chemical degradation of the metalloporphyrin.
  • the suspension is agitated and ready for administration.
  • the metalloporphyrin spray-dried powder formulation can be dispersed in a solution of an organic solvent containing a film-forming polymer.
  • the polymer solution containing the suspended spray-dried powder is then cast into a thin film, which is then cut in appropriate size sections, each of the sections containing one dose.
  • the thin film is expected to instantaneously dissolve in the mouth without the need of any extra liquid.
  • the metalloporphyrin spray-dried powder formulation can be suspended in diluent containing 0.25% (w/v) citrate buffer, pH 4.7 to which mannitol can be added in an appropriate amount.
  • the suspension is then transferred into tablet-size molds, which then are frozen in a stream of liquid nitrogen.
  • the frozen suspension is then lyophilized and the mold containing the tablets obtained can be sealed with a protective cover.
  • the lyophilized tablets are expected to instantaneously dissolve in the mouth without the need of any extra liquid.
  • Formulation contents (w/w): Coconut oil (40%), Lecithin (30%), metalloporphyrin (5%), Poloxamer-188 (20%) and Chitosan (MW-15000) (5%)
  • Formulation contents (w/w): Coconut oil (35%), Lecithin (20%), metalloporphyrin (20%), Poloxamer-188 (20%) and Sodium Alginate (4.5%) Calcium chloride (0.5%)
  • Formulation contents (w/w): DSPC (45%), DPPC (45%), metalloporphyrin (10%).
  • metalloporphyrin (10 mg) is dissolved with sonication in 10 mL of 1 M ammonium hydroxide solution.
  • DPPC 45 mg
  • DSPC 45 mg
  • dissolved in 45 mL of ethanol is added and mixed well.
  • the solution mixture is spray dried using Buchi-290 mini spray dryer.
  • the set parameters are inlet temperature 55 °C, outlet temperature 50 °C, aspirator at 75%, solution feed pump at 8% and nitrogen flow at 30 mm.
  • the feeding solution container and spray dryer compartments are protected from light during the process.
  • the dry powder is stored frozen protected from light.
  • Iron microparticle formulations for treating anemia Iron microparticle formulations for treating anemia
  • Patients suffering from anemia are administered an iron protoporphyrin microparticle formulation of the invention.
  • patients administered the iron protoporphyrin microparticle formulation of the invention experience a reduction in undesirable gastrointestinal side effects, such as upset stomach, diarrhea, constipation, and epigastric abdominal discomfort. This is particularly important in anemic patients who also suffer from irritable bowel syndrome (IBS).
  • IBS irritable bowel syndrome
  • Iron microparticle formulations for treating a model of malaria Iron microparticle formulations for treating a model of malaria
  • An iron protoporphyrin microparticle formulation of the invention in combination with increasing concentrations of artemisinin (ART) is added to P. falciparum (Pf) cultures with standard red blood cells and with immature reticulocytes using Fibach culture medium. Red blood cells express the heme exporter protein FLVCR1 , which may be counteracted by addition of an iron protoporphyrin microparticle to increase the effectiveness of ART.
  • ART artemisinin
  • Iron microparticle formulations for treating malaria and anemia in vivo Iron microparticle formulations for treating malaria and anemia in vivo
  • Plasmodium infection causes anaemia, which leads to Epo-induced upregulation of the hormone Erythroferrone (Erfe).
  • Erfe Erythroferrone
  • 6 week-old female Erfe -/- or +/+ mice were infected with 10e5 PccAS iv for 1 1 days (4-5 days post peak parasitaemia in this experiment).
  • Erfe knockout mice infected with P. chabaudi have higher hepcidin and lower parasitaemia than wild-type controls ( Figure 8).
  • Subjects suffering from Plasmodium infection and anemia are administered an iron protoporphyrin microparticle formulation of the invention in combination with increasing concentrations of artemisinin (ART).
  • ART artemisinin
  • the P. chabaudi model is used to evaluate the effect of a combination of an iron protoporphyrin microparticle formulation and ART on the development and clearance of parasitaemia, the drop and recovery of Hb, and the concentration of gametocytes.
  • This study uses both wild-type and in an inducible-hepcidin deficient animals (Armitage et al., J. Innate Immunity, 2016, 8(5): 517-528).
  • ART-resistant chabaudi strains are generated following established protocols (Pollitt et al., PLoS Pathogens, 2014, 10(4): e1004019). The combination of an iron protoporphyrin microparticle formulation and ART is evaluated in these strains, and again track parasitaemia, Hb and gametocytes.

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Abstract

L'invention concerne des procédés d'utilisation pour réduire la concentration de fer sérique dans le traitement de divers états pathologiques à l'aide d'une composition comprenant des microparticules contenant un complexe de porphyrine métallique et un stabilisant pharmaceutiquement acceptable.
PCT/US2018/016622 2017-02-03 2018-02-02 Microparticules de métalloporphyrines pour le traitement de l'anémie et de maladies tropicales WO2018144845A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111603472A (zh) * 2020-06-09 2020-09-01 上海市闵行区中心医院 一种锡-中卟啉与青蒿素联合应用在制备抗肿瘤药物中的用途
WO2021188787A1 (fr) * 2020-03-19 2021-09-23 Renibus Therapeutics, Inc. Procédé de traitement d'une infection à coronavirus
EP4056038A1 (fr) * 2021-03-10 2022-09-14 Basf Se Microparticules contenant des substances actives

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5162313A (en) * 1989-03-16 1992-11-10 The Rockefeller University Control of heme and iron concentrations in body tissues
US5756492A (en) * 1996-09-09 1998-05-26 Sangstat Medical Corporation Graft survival prolongation with porphyrins
US6147070A (en) * 1998-06-05 2000-11-14 Facchini; Francesco Methods and compositions for controlling iron stores to treat and cure disease states
US8334320B2 (en) * 2004-08-04 2012-12-18 University Of Utah Research Foundation Methods for chelation therapy
US20150224202A1 (en) * 2014-02-03 2015-08-13 The Board Of Trustees Of The Leland Stanford Junior University Formulations and uses for microparticle delivery of zinc protoporphyrins
US20160184244A1 (en) * 2012-08-30 2016-06-30 The Board Of Trustees Of The Leland Stanford Junior University Iron Chelators and Use Thereof for Reducing Transplant Failure During Rejection Episodes
US20170035778A1 (en) * 2015-08-05 2017-02-09 The Board Of Trustees Of The Leland Stanford Junior University Formulations and uses for microparticle delivery of metalloporphyrins

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5162313A (en) * 1989-03-16 1992-11-10 The Rockefeller University Control of heme and iron concentrations in body tissues
US5756492A (en) * 1996-09-09 1998-05-26 Sangstat Medical Corporation Graft survival prolongation with porphyrins
US6147070A (en) * 1998-06-05 2000-11-14 Facchini; Francesco Methods and compositions for controlling iron stores to treat and cure disease states
US8334320B2 (en) * 2004-08-04 2012-12-18 University Of Utah Research Foundation Methods for chelation therapy
US20160184244A1 (en) * 2012-08-30 2016-06-30 The Board Of Trustees Of The Leland Stanford Junior University Iron Chelators and Use Thereof for Reducing Transplant Failure During Rejection Episodes
US20150224202A1 (en) * 2014-02-03 2015-08-13 The Board Of Trustees Of The Leland Stanford Junior University Formulations and uses for microparticle delivery of zinc protoporphyrins
US20170035778A1 (en) * 2015-08-05 2017-02-09 The Board Of Trustees Of The Leland Stanford Junior University Formulations and uses for microparticle delivery of metalloporphyrins

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021188787A1 (fr) * 2020-03-19 2021-09-23 Renibus Therapeutics, Inc. Procédé de traitement d'une infection à coronavirus
US20210338708A1 (en) * 2020-03-19 2021-11-04 Renibus Therapeutics, Inc. Method for treatment of coronavirus infection
CN111603472A (zh) * 2020-06-09 2020-09-01 上海市闵行区中心医院 一种锡-中卟啉与青蒿素联合应用在制备抗肿瘤药物中的用途
EP4056038A1 (fr) * 2021-03-10 2022-09-14 Basf Se Microparticules contenant des substances actives
WO2022189208A1 (fr) * 2021-03-10 2022-09-15 Basf Se Nouvelles microparticules contenant des substances actives

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