Methods of treatment using an aminosterol composition

Abstract

This invention relates to stable aminosterol phosphate compositions. The aminosterol phosphate compositions permit administration without associated tissue damage and achieve a sustained release effect.

1 .- 15 . (canceled) 
     
     
         16 . A method of treating a subject in need having a condition susceptible to treatment with an aminosterol comprising administering a pharmaceutical composition comprising:
 (a) at least one pharmaceutical grade aminosterol; and   (b) at least one phosphate selected from the group consisting of an inorganic phosphate, an inorganic pyrophosphate, and an organic phosphate,   wherein the aminosterol is formulated as a weakly water soluble salt of the phosphate.   
     
     
         17 . The method of  claim 16 , wherein the subject in need has a condition selected from the group consisting of viral infections, antimicrobial infections, Gram-negative bacterial infections, Gram-positive bacterial infections, Mycobacteria infections, fungal infections, protozoan infections, disease states known to be associated with pathological neovascularization, cancer, vascular disorders of the eye, macular degeneration, retinopathy of prematurity, corneal neovascularization, diabetic retinopathy, weight loss where sodium-hydrogen exchanger (“NHE-3”) plays a critical role, treatment of fibrodysplasia ossificans progressiva, and disorders of neovascularization. 
     
     
         18 . The method of  claim 16 , wherein the effective daily dosing amount is about 0.1 to 20 mg/kg body weight. 
     
     
         19 . The method of  claim 16 , wherein the effective amount is administered in a regimen that achieves and maintains a tissue concentration of squalamine in body organs and tissues of between about 0.1-200 μg/gram (tissue wet weight). 
     
     
         20 . The method of  claim 16 , wherein:
 (a) the composition does not demonstrate an altered IC 50  or IC 90  (drug concentration required to inhibit viral growth by 50% or 90% respectively) over time;   (b) the composition demonstrates an IC 50  or IC 90  which does not increase by more than 0%, 0.5%, 1%. 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, or 30% over time;   (c) the composition demonstrates an IC 50  or IC 90  which does not increase by an amount described in (b) over a time period selected from the group consisting of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 1.5 months, 2 months, 2.5 months, 3 months, 3.5 months, 4 months, 4.5 months, 5 months, 5.5 months, 6 months, 6.5 months, 7 months, 7.5 months, 8 months, 8.5 months, 9 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, and 5 years; or   (d) any combination thereof.   
     
     
         21 . The method of  claim 16 , wherein condition to be treated is a viral infection caused by a virus selected from the group consisting of Yellow Fever, Cytomegalovirus, Eastern Equine Encephalitis virus, Hepatitis B virus, Hepatitis Delta virus, Dengue virus, and Human Immunodeficiency virus. 
     
     
         22 . The method of  claim 16 , wherein the condition to be treated is a viral infection caused by a virus selected from the group consisting of “African Swine Fever Viruses,” Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Astroviridae, Baculoviridae, Bimaviridae, Birnaviridae, Bunyaviridae, Caliciviridae, Caulimoviridae, Circoviridae, Coronaviridae, Cystoviridae, Dengue, EBV, HIV, Deltaviridae, Filviridae, Filoviridae, Flaviviridae, Hepadnaviridae (Hepatitis), Herpesviridae (such as, Cytomegalovirus, Herpes Simplex, Herpes Zoster), Iridoviridae, Mononegavirus (e.g., Paramyxoviridae, Morbillivirus, Rhabdoviridae), Myoviridae, Orthomyxoviridae (e.g., Influenza A, Influenza B, and parainfluenza), Papiloma virus, Papovaviridae, Paramyxoviridae, Prions, Parvoviridae, Phycodnaviridae, Picomaviridae (e.g. Rhinovirus, Poliovirus), Poxviridae (such as Smallpox or Vaccinia), Potyviridae, Reoviridae (e.g., Rotavirus), Retroviridae (HTLV-I, HTLV-II, Lentivirus), Rhabdoviridae, Tectiviridae, Togaviridae (e.g., Rubivirus), herpes, pox, papilloma, corona, influenza, hepatitis, sendai, sindbis, vaccinia viruses, west nile, hanta, viruses which cause the common cold, and any combination thereof. 
     
     
         23 . The method of  claim 16 , wherein the condition to be treated is selected from the group consisting of AIDS, viral meningitis, Dengue, EBV, hepatitis, a chronic disease suspected to be of viral origin, multiple sclerosis, Type I diabetes, Type II diabetes, atherosclerosis, cardiomyopathies, Kawaski disease, aplastic anemia, and any combination thereof. 
     
     
         24 . The method of  claim 16 , further comprising administering an additional active agent, wherein the additional active agent is administered via a method selected from the group consisting of
 (a) concomitantly;   (b) as an admixture;   (c) separately and simultaneously or concurrently; and   (d) separately and sequentially.   
     
     
         25 . The method of  claim 16 , wherein the mammal is human. 
     
     
         26 . The method of  claim 16 , wherein the phosphate is an inorganic polyphosphate, and the number of phosphates ranges from 3 (tripolyphosphate) to 400. 
     
     
         27 . The method of  claim 16 , wherein the phosphate is an organic phosphate which comprises glycerol 2 phosphate. 
     
     
         28 . The method of  claim 16 , wherein the aminosterol is selected from the group consisting of
 (a) squalamine or a pharmaceutically acceptable salt or derivative thereof;   (b) a squalamine isomer;   (c) Aminosterol 1436;   (d) an aminosterol comprising a sterol nucleus and a polyamine, attached at any position on the sterol, such that the molecule exhibits a net charge of at least +1, the charge being contributed by the polyamine;   (e) an aminosterol which is a derivative of squalamine modified through medical chemistry to improve biodistribution, ease of administration, metabolic stability, or any combination thereof;   (f) an aminosterol modified to include one or more of the following: (1) substitutions of the sulfate by a sulfonate, phosphate, carboxylate, or other anionic moiety chosen to circumvent metabolic removal of the sulfate moiety and oxidation of the cholesterol side chain; (2) replacement of a hydroxyl group by a non-metabolizable polar substituent, such as a fluorine atom, to prevent its metabolic oxidation or conjugation; and (3) substitution of various ring hydrogen atoms to prevent oxidative or reductive metabolism of the steroid ring system;   (g) an aminosterol that can inhibit the formation of actin stress fibers in endothelial cells stimulated by a ligand known to induce stress fiber formation, having the chemical structure of Formula I:   
       
         
           
           
               
               
           
         
       
       wherein,
 W is 24S —OSO 3  or 24R—OSO 3 ; 
 X is 3β-H 2 N—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH— or 3α-H 2 N—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH—; 
 Y is 20R—CH 3 ; and 
 Z is 7α or 7β —OH; or 
 (h) any combination thereof. 
 
     
     
         29 . The method of  claim 16 , wherein the composition is formulated:
 (a) for administration selected from the group consisting of oral,-pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, intravenous. subcutaneous, intramuscular, nebulization, inhalation, ocular, otic, local, buccal, nasal, and topical administration;   (b) into a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, lyophilized formulations, tablets, capsules;   (c) into a dosage form selected from the group consisting of controlled release formulations, fast melt formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or   (d) any combination of (a), (b), and (c).   
     
     
         30 . The method of  claim 16 , wherein the composition further comprises at least one additional active agent. 
     
     
         31 . The method of  claim 30 , wherein the additional active agent is selected from the group consisting of
 (a) an antiretroviral agent;   (b) nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs);   (c) non-nucleoside reverse transcriptase inhibitors (NNRTIs);   (d) nucleotide or nucleoside analogues   (e) protease inhibitors (PIs);   (f) drugs based on “antisense” molecules;   (g) ribozyme antivirals;   (h) assembly inhibitors;   (i) release phase inhibitors;   (j) drugs which stimulate the immune system, such as interferons and synthetic antibodies;   (k) fusion inhibitors/gp41 binders;   (l) fusion inhibitors/chemokine receptor antagonists;   (m) integrase inhibitors;   (n) hydroxyurea-like compounds;   (o) inhibitors of viral integrase;   (p) inhibitors of viral genome nuclear translocation;   (q) inhibitors of HIV entry;   (r) nucleocapsid zinc finger inhibitors;   (s) targets of HIV Tat and Rev;   (t) pharmacoenhancers;   (u) cytokines;   (v) lymphokines; and   (w) an anti-inflammatory agent;   (x) antibiotic;   (y) antifungal, antiyeast, and/or antimold agent;   (z) anticancer agent;   (aa) weight loss agent; and   (bb) any combination thereof.   
     
     
         32 . The method of  claim 16 , further comprising at least one adjuvant. 
     
     
         33 . The method of  claim 32 , wherein the adjuvant is selected from the group consisting cytokines, interleukins, IL2, 1L3, IL4, IL5, IL6, IL7, IL8 IL-9, IL10, IL-11, IL12, IL13, IL-14, IL15, IIL16, IL-17, IL-18, IL-19, IL-20, IL-21, anti-CD40, CD40L, IFN-gamma, TNF-alpha, IL-Ialpha, IL-lbeta, alum, Lipid A, including monophosphoryl lipid A, bacterial products, endotoxins, cholesterol, fatty acids, aliphatic amines, paraffinic and vegetable oils, threonyl derivative, and muramyl dipeptide, alum, alum plus deoxycholate (ImmunoAg), MTP-PE, QS21, BCG, MPL, nonviable preparations of Corynebacterium, parvum, Monophosphoryl lipid immunomodulator, AdjuVax 100a, QS-21, QS-18, CRL1005, Aluminum salts, MF-59, and Virosomal adjuvant technology. 
     
     
         34 . The method of  claim 16 , wherein the squalamine salt is in the form of a particulate suspension varying in particle size from between about 0.1 to about 100 microns. 
     
     
         35 . The method of  claim 16 , wherein the pharmaceutical composition is formulated as an oral tablet or capsule.