WO1996040061A1 - Procede d'encapsulation de materiaux pharmaceutiques - Google Patents

Procede d'encapsulation de materiaux pharmaceutiques Download PDF

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Publication number
WO1996040061A1
WO1996040061A1 PCT/US1996/007892 US9607892W WO9640061A1 WO 1996040061 A1 WO1996040061 A1 WO 1996040061A1 US 9607892 W US9607892 W US 9607892W WO 9640061 A1 WO9640061 A1 WO 9640061A1
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WO
WIPO (PCT)
Prior art keywords
liposomes
aqueous
perhalocarbon
solvent
aqueous medium
Prior art date
Application number
PCT/US1996/007892
Other languages
English (en)
Inventor
Eric A. Forssen
Mitsuo Oka
Original Assignee
Nexstar Pharmaceuticals, Inc.
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 Nexstar Pharmaceuticals, Inc. filed Critical Nexstar Pharmaceuticals, Inc.
Priority to AU59389/96A priority Critical patent/AU5938996A/en
Publication of WO1996040061A1 publication Critical patent/WO1996040061A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes

Definitions

  • the present invention relates generally to the field of pharmaceuticals and more particularly to a method for encapsulating aqueous soluble materials with high entrapment efficiency, by using an immiscible perhalocarbon cosolvent during fabrication.
  • Liposomes are closed, nearly spherical, vesicles containing one or more concentric bilayer membranes which enclose an equal number of aqueous compartments.
  • Bilayer membrane vesicles can be formed from a variety of synthetic and/or naturally occurring substances, either alone or in mixtures.
  • a common physico-chemical property shared by molecules that form bilayer membranes is that they are amphiphilic. Amphiphilic molecules contain both a polar (hydrophilic) region or head group and a non-polar (lipophilic) region.
  • the hydrophilic portion comprises phosphato, glycerylphosphato, carboxy, sulfato, amino, hydroxy, choline and other polar groups.
  • non-polar groups are saturated or unsaturated hydrocarbons such as alkyl, acyl, alkenyl or other lipid groups, which form chains or tails extending from the head group.
  • the amphiphiles most often included in liposomes are the phospholipids, of which phosphatidylcholine is the most widely used.
  • the head group is zwitterionic and consists of a negatively charged phosphate and a positively charged choline.
  • the lipophilic portion typically comprises two fatty acid chains
  • hydrocarbon chains are typically long; fatty acid hydrocarbon chains of less than fourteen carbon atoms are found in only small amounts.
  • cholesterol is composed principally of pure, lipophilic hydrocarbon in the form of a rigid steroid ring and a small polar region consisting of a single hydroxy group.
  • synthetic compounds used in the manufacture of liposomes include dicetyl phosphate and N,N-dimethyl-N,N-didodecylamine.
  • Naturally occurring compounds include the phosphatidylcholines, phosphatidylserines, and sphingomyelins.
  • Other pharmaceutically acceptable adjuvants, including anti-oxidants such as alpha-tocopherol, are sometimes included to improve vesicle stability or to confer other desirable characteristics to the liposome.
  • each side of the membrane presents a hydrophilic surface while the interior of the membrane comprises a lipophilic medium.
  • MLVs multilamellar vesicles
  • Micelles are relatively small structures with diameters on the order of 5 nm and are composed of approximately 100 amphiphilic molecules. In water, micellar amphiphiles are arrayed with the lipophilic chains directed inward, forming a hydrocarbon core with the polar head groups located at the surface, in order to maintain aqueous solubility. Micelles, unlike liposomes, do not contain an aqueous core, and consequently, cannot encapsulate water-soluble materials.
  • amphiphiles within a micelle or liposome is driven by the internal "structure" of water.
  • Water molecules exert a strong attractive force between one another (hydrogen bonds) that must be disrupted or distorted in order for solute molecules to be dispersed.
  • Any attractive forces between amphiphilic hydrocarbons and water are quite weak relative to that between the water molecules themselves.
  • the organization of the micelle or liposome bilayer minimizes the surface areas of the hydrocarbon chains exposed to water and this, in turn, minimizes the disruption of the strong attractive force between the water molecules.
  • Attraction between the nonpolar hydrocarbon chains plays only a minor role in the organizational arrangement of the micelle.
  • amphiphiles with two hydrocarbon chains also attempt to minimize interactions between the lipophilic groups and water when dispersed in aqueous media, and curve back on themselves to form closed bilayer vesicles (liposomes).
  • the bilayer structure is preferred over that of the micelle since it has a larger radius of curvature and can thus accommodate the added bulk of the second hydrocarbon chain in each amphiphile.
  • the behavior of the lipids in the bilayer is strongly influenced by the length and homogeneity of the hydrocarbon chains. At sufficiently low temperatures, amphiphiles show little lateral motion in the plane of the membrane bilayer and behave like solid hydrocarbon crystals. As the temperature is increased, the bilayer can demonstrate abrupt changes in its properties at one or more transition temperatures. Above a transition temperature the bilayer behaves more like a fluid system, and the lipid molecules can display rapid translational motion within the bilayer. The bilayer can also show an increased permeability or leakiness. The temperature(s) at which the phase transition(s) occurs is (are) a function of the precise lipid composition of the vesicles.
  • Lipid bilayers that are composed primarily of unsaturated phospholipids (hydrocarbon chains with one or more double bonds), or include phospholipids with shorter hydrocarbon chains and/or limited amounts of single chain amphiphiles, have lower transition temperatures.
  • phosphatidylcholine vesicles causes the phase transition to occur over a wide temperature range that broadens as the proportion of cholesterol
  • Liposomes are well known in the art, and there are numerous liposome preparation techniques that may be employed to produce various types of liposomes. Liposomes are generally classified
  • UVs multilamellar vesicles
  • UVs unilamellar vesicles
  • UVs can be formed by detergent removal techniques.
  • Liposomes that have been referred to as large unilamellar vesicles (LUVs) can be prepared using the solvent infusion or reverse-phase evaporation (REV) methods.
  • lipids are dissolved in an organic solvent, to which is added an aqueous buffer; formation of liposomes proceeds via the formation of inverted micelles which collapse into a gel-state upon evaporation of the organic solvent.
  • liposomes are advantageous for encapsulating or incorporating a wide variety of therapeutic and diagnostic agents.
  • Drugs or other biologically active compounds may be entrapped in the liposomes interior aqueous space, in the case of aqueous soluble materials, or in the membrane bilayer, in the case of lipid-soluble materials.
  • Lipophilic agents may be incorporated directly into the lipid bilayer by inclusion in the lipid formulation.
  • this technique involves mixing the lipid-soluble agent with the liposomal lipid components in an organic solvent, evaporating the solvent to form a dried film and dispersing the dried mixture in an aqueous medium to form MLVs.
  • Aqueous soluble agents may be incorporated into liposomes by one of two methods: active loading or passive entrapment. Active loading of certain ionizable materials (i.e., charged at certain pH's) into preformed liposomes is possible where an ionic or pH gradient has been generated by entrapment of a counterion of opposite charge within the vesicle. This method is described in U.S. Patent No. 4,946,683 to Forssen, whose disclosure is incorporated herein by reference. If sufficiently lipid soluble, the ionizable agent will then pass through the membrane bilayer, neutralizing the counterion. With this method, encapsulation efficiencies approaching 100% may be obtained.
  • Unstable lipid domains may also form within membrane bilayers resulting from changes in the electrical charge and/or hydration states of the lipid head groups due to protonation-deprotonation of titratable moieties in the lipids.
  • Passive entrapment was historically the first method developed for encapsulating materials within liposomes and relies on the natural ability of amphiphilic molecules to form liquid-filled spheres when dispersed in aqueous media. The extent of encapsulation using passive techniques is limited simply by the aqueous volume that can be entrapped during the
  • liposome formation process As liposomes are formed, aqueous soluble molecules dissolved in the solution in which the phospholipids are dispersed will be incorporated into the aqueous interior and thus be
  • entrapment percentages are proportional to the aqueous lipid concentration, one strategy for maximizing entrapment efficiency has involved minimizing, for a given amount of lipid, the total volume of aqueous media used in the preparation. Thus, greater efficiencies can be achieved by using higher lipid concentrations.
  • the maximum aqueous concentration of lipids which is practical for making liposomes is limited to about 15 to 20% (150 to 200 mg/ml), due largely to processing difficulties associated with the high viscosity encountered at the increased lipid concentrations.
  • Perfluorocarbons have previously been used as solvents for the preparation of phospholipid emulsions. Such a preparation is described in Japanese Patent No. 51-26213, which discloses a method for preparing an aqueous emulsion containing water-soluble drugs, phospholipids, vegetable oils, and perhalocarbon. Lyophilization of the dispersion produced micro-
  • a vegetable oil triglyceride
  • aqueous suspensions prepared from phospholipids and triglycerides are emulsions rather than liposomal suspensions. Accordingly, it is a desideratum to provide a method for passively encapsulating aqueous soluble agents in liposomes at high entrapment efficiencies; the need for such a method is particularly acute with respect to higher molecular weight compounds which due to their size cannot be actively loaded.
  • the invention relates to the formation of liposomes using immiscible perhalocarbon solvents. This method results in encapsulation of aqueous soluble agents with entrapment efficiencies exceeding 50%, substantially greater than typical passive encapsulation values of 1 - 10%. High entrapment efficiencies may be obtained by preparing a liposome suspension consisting of phospholipids, aqueous media and one or more
  • the perhalocarbon solvent is not only immiscible with the aqueous phase, it is immiscible with the lipid components as well. Accordingly, a wide variety of lipids and other amphiphilic molecules may be used in the practice of the present invention. In addition, due to their inertness and low vaporization temperature, perhalocarbon solvents are
  • perhalocarbon solvents which have a high vapor pressure and are a liquid at room temperature may be used in the invention described here.
  • the perhalocarbon solvent is also pharmacologically acceptable and non-toxic in trace amounts.
  • perhalocarbons suitable for use in the present invention include perfluorocarbons, especially perfluorodecalin, perfluoromethyldecalin and perfluorotributylamine. Perfluorodecalin is particularly preferred.
  • a preferred embodiment of the present invention involves using a mixture of a neutral phospholipid and cholesterol in a 2:1 mole ratio.
  • neutral phospholipids suitable for use in the present invention include phospholipids having lipid tails from 14 to 22 carbons, such as egg phosphatidylcholine (egg-PC) and hydrogenated egg phosphatidylcholine (HEPC).
  • the lipids Preferably, the lipids contain carbon chain lengths between sixteen and eighteen carbons long.
  • Distearoylphosphatidylcholine (DSPC) is particularly preferred as a neutral phospholipid component of the liposomes.
  • the present invention does not include cholesterol esters, triglycerides, or other molecules which prevent liposome formation.
  • the liposomes may be formed according to a variety of techniques known to those skilled in the art and include sonication, homogenization and extrusion. It is also readily apparent to one skilled in the art that the particular liposome preparation method will depend on the intended use, the agent to be entrapped and the type of lipids used to form the bilayer membrane. Any aqueous soluble agent is suitable for encapsulation according to the method described herein. Multiple aqueous soluble agents may be encapsulated simultaneously; lipophilic compounds may also be incorporated subsequent to liposome formation using, for example, active loading techniques. Therapeutic and diagnostic agents are contemplated within the scope of the present invention.
  • One aspect of the present invention is the removal of the perhalocarbon solvent following liposome formation by lyophilization (freeze- drying) or evaporation.
  • the low vaporization temperature of perhalocarbons ensures that sensitive lipids are not oxidatively degraded and that maximum membrane stability is preserved.
  • the perhalocarbon solvent is removed by lyophilization and that a lyoprotectant agent such as a carbohydrate, particularly sucrose, is present during lyophilization.
  • the lyophilized cake may be stored for an extended period of time until ready for use, at which time rehydration with aqueous media will reconstitute the liposome suspension with entrapped agent.
  • aqueous components including solubilized drugs or agents, are "forced" into the aqueous volume of the liposomes during their formation.
  • the invention is not limited to this particular proposed mode of encapsulation, and other mechanisms may be applicable.
  • the method provides the ability to dilute the lipids and agent using a solvent which is immiscible both with these components and a small amount of water which is used to hydrate the lipids.
  • the immiscible cosolvent is removed from the liposome suspension following this processing step.
  • Perhalocarbons especially perfluorocarbons such as perfluorodecalin, are biologically inert, removable by evaporation or lyophilization and are immiscible with water, lipids, and most agents that are candidates for liposome entrapment. Because of the immiscibility of perhalocarbons, lipids are not dissolved in the solvent and liposome formation does not proceed via a micelle or inverted micelle intermediate.
  • a method for encapsulating aqueous soluble agents in liposomes with high efficiency is described. Specifically, a suspension of amphiphilic molecules (e.g., lipids), an aqueous medium (containing one or more agents to be entrapped), and one or more perhalocarbon solvents is prepared. The suspension is exposed to a shearing force (e.g., sonication or homogenization) in order to form small, uniformly sized liposomes. Following formation of the liposomes, additional agents may optionally be incorporated into the liposomes by active loading techniques.
  • a shearing force e.g., sonication or homogenization
  • Lyophilization of the suspension removes water and perhalocarbon solvent from the suspension and yields a dried cake which is stable upon long-term storage. Rehydration of the lyophilized cake with an aqueous medium reconstitutes the liposomes with the aqueous soluble agent still encapsulated. Rehydration may be accomplished using any pharmaceutically acceptable aqueous medium, including water-for-injection (WFI), buffer solutions, or solutions which contain a carbohydrate such as sucrose.
  • WFI water-for-injection
  • buffer solutions or solutions which contain a carbohydrate such as sucrose.
  • Unentrapped material may be separated by any of a variety of techniques known in the art, including chromatography, dialysis and ultrafiltration. The removal of unentrapped material may be performed either following initial liposome formation or following rehydration.
  • the rehydrated liposomes may be used for a variety of applications, including administration to a patient for therapeutic or diagnostic purposes.
  • the rehydrated liposome suspension may be filtered immediately prior to use in order to remove larger liposomes.
  • the present invention may be practiced with a wide variety of agents, but is particularly advantageous for aqueous soluble materials which are poorly entrapped using conventional passive entrapment techniques.
  • Aqueous soluble agents are substances which partition predominantly within the interior aqueous space of liposomes, rather than in the bilayer membrane.
  • the aqueous soluble agent to be entrapped is preferably a biologically active substance, i.e., one which is a naturally occurring substance in vivo or one which elicits a physiological response.
  • This method is particularly suitable for encapsulating nucleic acid (DNA and RNA) oligonucleotides in liposomes intended for use in gene therapy.
  • the inertness of the perhalocarbon solvent and the gentle processing steps of the present invention prevent damage to or modification of sensitive biomolecules.
  • a liposome encapsulated oligonucleotide (20-bp) sample was prepared as follows. A spray-dried powder of distearoylphosphatidylcholine (DSPC) and cholesterol (2:1 molar ratio; 200 mg total weight) were mixed with perfluorodecalin (0.80 ml) and 1.20 ml of an aqueous 9% sucrose solution (pH 6.7) containing the oligonucleotide (1.0 mg). The heterogeneous system was sonicated for approximately 15 min. using a Sonics and Materials Vibra Cell Sonicator at 65°C to produce a
  • liposomes was bimodal with median diameters of 0.288 ⁇ m (67% relative
  • the entrapment efficiency of the oligonucleotide was calculated to be 58%.
  • cholesterol 2:1 molar ratio; 200 mg total weight
  • carboxyfluorescein solution (1.20 ml total volume; 263 ⁇ g/ml concentration).
  • the heterogeneous system was sonicated for approximately 15 min using a Sonics and Materials Vibra Cell Sonicator at room temperature to produce a homogeneous dispersion of liposomes.
  • the size distribution was bimodal

Abstract

L'invention concerne un procédé d'encapsulation de matériaux pharmaceutiques. Elle concerne la mise en application de cosolvants immiscibles d'hydrocarbure halogéné dans le processus de fabrication et permet d'obtenir un niveau élevé de piégeage (efficacités d'encapsulation supérieure à 50 %) de matériaux solubles aqueux dans des liposomes.
PCT/US1996/007892 1995-06-07 1996-05-29 Procede d'encapsulation de materiaux pharmaceutiques WO1996040061A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU59389/96A AU5938996A (en) 1995-06-07 1996-05-29 Method for encapsulating pharmaceutical materials

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US48360695A 1995-06-07 1995-06-07
US08/483,606 1995-06-07

Publications (1)

Publication Number Publication Date
WO1996040061A1 true WO1996040061A1 (fr) 1996-12-19

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AU (1) AU5938996A (fr)
WO (1) WO1996040061A1 (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4430592A1 (de) * 1994-08-20 1996-02-22 Max Delbrueck Centrum Liposomale Zubereitung, ihre Herstellung und ihre Verwendung
US6613352B2 (en) 1999-04-13 2003-09-02 Universite De Montreal Low-rigidity liposomal formulation
EP2218442A1 (fr) 2005-11-09 2010-08-18 CombinatoRx, Inc. Procédés, compositions et kits pour le traitement des maladies ophthalmiques
WO2011075688A1 (fr) 2009-12-18 2011-06-23 Exodos Life Sciences Limited Partnership Méthodes et compositions de traitement et de prévention des céphalées trigémino-autonomiques, des migraines et des pathologies vasculaires
WO2011094450A1 (fr) 2010-01-27 2011-08-04 Anacor Pharmaceuticals, Inc Petites molecules contenant du bore
EP2564857A1 (fr) 2008-03-06 2013-03-06 Anacor Pharmaceuticals, Inc. Petites molécules contenant du bore en tant qu'agents anti-inflammatoires
WO2017024037A1 (fr) 2015-08-03 2017-02-09 President And Fellows Of Harvard College Bloqueurs de canal d'ions chargés et procédés d'utilisation
WO2018172504A1 (fr) 2017-03-23 2018-09-27 Lipid Systems Sp. Z.O.O. Encapsulation à haut rendement de composés hydrophiles dans des liposomes unilamellaires
US10729664B2 (en) 2009-07-10 2020-08-04 President And Fellows Of Harvard College Permanently charged sodium and calcium channel blockers as anti-inflammatory agents
WO2020185830A1 (fr) 2019-03-11 2020-09-17 Nocion Therapeutics, Inc. Bloqueurs de canaux ioniques chargés et procédés d'utilisation
US10780083B1 (en) 2019-03-11 2020-09-22 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10786485B1 (en) 2019-03-11 2020-09-29 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10842798B1 (en) 2019-11-06 2020-11-24 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10927096B2 (en) 2019-03-11 2021-02-23 Nocion Therapeutics, Inc. Ester substituted ion channel blockers and methods for use
US10934263B2 (en) 2019-03-11 2021-03-02 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10933055B1 (en) 2019-11-06 2021-03-02 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US11026882B2 (en) 2014-12-01 2021-06-08 Achelios Therapeutics, Inc. Methods and compositions for treating migraine and conditions associated with pain
US11332446B2 (en) 2020-03-11 2022-05-17 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US11597744B2 (en) 2017-06-30 2023-03-07 Sirius Therapeutics, Inc. Chiral phosphoramidite auxiliaries and methods of their use
US11981703B2 (en) 2017-08-17 2024-05-14 Sirius Therapeutics, Inc. Polynucleotide constructs

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0043327A1 (fr) * 1980-07-01 1982-01-06 L'oreal Procédé d'obtention de dispersions stables dans une phase aqueuse d'au moins une phase liquide non miscible à l'eau et dispersions correspondantes
EP0055576A1 (fr) * 1980-12-22 1982-07-07 THE PROCTER & GAMBLE COMPANY Procédé de préparation de structures contenant des membranes lipoides
WO1994000110A1 (fr) * 1992-06-26 1994-01-06 Lancaster Group Ag Composition galenique pour application topique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0043327A1 (fr) * 1980-07-01 1982-01-06 L'oreal Procédé d'obtention de dispersions stables dans une phase aqueuse d'au moins une phase liquide non miscible à l'eau et dispersions correspondantes
EP0055576A1 (fr) * 1980-12-22 1982-07-07 THE PROCTER & GAMBLE COMPANY Procédé de préparation de structures contenant des membranes lipoides
WO1994000110A1 (fr) * 1992-06-26 1994-01-06 Lancaster Group Ag Composition galenique pour application topique

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6399094B1 (en) 1994-08-20 2002-06-04 Martin Brandl Unilamellar liposomal preparations with high active substance content
DE4430592A1 (de) * 1994-08-20 1996-02-22 Max Delbrueck Centrum Liposomale Zubereitung, ihre Herstellung und ihre Verwendung
US6613352B2 (en) 1999-04-13 2003-09-02 Universite De Montreal Low-rigidity liposomal formulation
EP2218442A1 (fr) 2005-11-09 2010-08-18 CombinatoRx, Inc. Procédés, compositions et kits pour le traitement des maladies ophthalmiques
EP2564857A1 (fr) 2008-03-06 2013-03-06 Anacor Pharmaceuticals, Inc. Petites molécules contenant du bore en tant qu'agents anti-inflammatoires
EP3246034A1 (fr) 2008-03-06 2017-11-22 Anacor Pharmaceuticals, Inc. Petites molécules contenant du bore en tant qu'agents anti-inflammatoires
US10729664B2 (en) 2009-07-10 2020-08-04 President And Fellows Of Harvard College Permanently charged sodium and calcium channel blockers as anti-inflammatory agents
WO2011075688A1 (fr) 2009-12-18 2011-06-23 Exodos Life Sciences Limited Partnership Méthodes et compositions de traitement et de prévention des céphalées trigémino-autonomiques, des migraines et des pathologies vasculaires
WO2011094450A1 (fr) 2010-01-27 2011-08-04 Anacor Pharmaceuticals, Inc Petites molecules contenant du bore
US11026882B2 (en) 2014-12-01 2021-06-08 Achelios Therapeutics, Inc. Methods and compositions for treating migraine and conditions associated with pain
WO2017024037A1 (fr) 2015-08-03 2017-02-09 President And Fellows Of Harvard College Bloqueurs de canal d'ions chargés et procédés d'utilisation
US11021443B2 (en) 2015-08-03 2021-06-01 President And Fellows Of Harvard College Charged ion channel blockers and methods for use
WO2018172504A1 (fr) 2017-03-23 2018-09-27 Lipid Systems Sp. Z.O.O. Encapsulation à haut rendement de composés hydrophiles dans des liposomes unilamellaires
US11597744B2 (en) 2017-06-30 2023-03-07 Sirius Therapeutics, Inc. Chiral phosphoramidite auxiliaries and methods of their use
US11981703B2 (en) 2017-08-17 2024-05-14 Sirius Therapeutics, Inc. Polynucleotide constructs
US11377422B2 (en) 2019-03-11 2022-07-05 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10786485B1 (en) 2019-03-11 2020-09-29 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10934263B2 (en) 2019-03-11 2021-03-02 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10780083B1 (en) 2019-03-11 2020-09-22 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10968179B2 (en) 2019-03-11 2021-04-06 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US11643404B2 (en) 2019-03-11 2023-05-09 Nocion Therapeutics, Inc. Ester substituted ion channel blockers and methods for use
US10828287B2 (en) 2019-03-11 2020-11-10 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US11603355B2 (en) 2019-03-11 2023-03-14 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
WO2020185830A1 (fr) 2019-03-11 2020-09-17 Nocion Therapeutics, Inc. Bloqueurs de canaux ioniques chargés et procédés d'utilisation
US11512058B2 (en) 2019-03-11 2022-11-29 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10927096B2 (en) 2019-03-11 2021-02-23 Nocion Therapeutics, Inc. Ester substituted ion channel blockers and methods for use
US10842798B1 (en) 2019-11-06 2020-11-24 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US11696912B2 (en) 2019-11-06 2023-07-11 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10933055B1 (en) 2019-11-06 2021-03-02 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US11332446B2 (en) 2020-03-11 2022-05-17 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use

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