[go: up one dir, main page]

WO2025184398A1 - Formulations liposomales et leurs procédés d'utilisation et de préparation - Google Patents

Formulations liposomales et leurs procédés d'utilisation et de préparation

Info

Publication number
WO2025184398A1
WO2025184398A1 PCT/US2025/017681 US2025017681W WO2025184398A1 WO 2025184398 A1 WO2025184398 A1 WO 2025184398A1 US 2025017681 W US2025017681 W US 2025017681W WO 2025184398 A1 WO2025184398 A1 WO 2025184398A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
intraliposomal
cdg
compartment
extraliposomal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/017681
Other languages
English (en)
Inventor
Geoffrey Hird
Teppei SHIRAKURA
Drew Steven FOLK
Kevin Patrick HERLIHY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glycomine Inc
Original Assignee
Glycomine 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 Glycomine Inc filed Critical Glycomine Inc
Publication of WO2025184398A1 publication Critical patent/WO2025184398A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to compositions containing carbohydrates encapsulated in a liposome, methods of delivering the encapsulated carbohydrates, and methods of using such compositions for treating diseases and disorders, such as congenital disorders of glycosylation (CDG).
  • CDG congenital disorders of glycosylation
  • the present invention relates to methods for preparation of carbohydrates and liposomes for pharmaceutical uses.
  • Glycosylation the enzymatic attachment of carbohydrates (glycans) to proteins and lipids, is a co-translational and post-translational modification (PTM) that is more common than any other PTM as it applies to a majority of proteins synthesized in the rough endoplasmic reticulum (ER).
  • PTM co-translational and post-translational modification
  • ER rough endoplasmic reticulum
  • Glycosylation plays a critical role in a variety of biological processes of membrane and secreted proteins. In the ER, glycosylation defines the protein structure and folding and acts as a quality control mechanism that dictates the export of properly folded proteins to Golgi or targets misfolded ones for degradation.
  • Glycan moieties may also act as ligands for cell surface receptors to mediate cell attachment or stimulate signal transduction pathways.
  • CDG syndromes Congenital disorders of glycosylation, also known as CDG syndromes, are a group of rare genetic diseases where tissue proteins and/or lipids carry defective glycosylation and/or lack of glycosylation. These diseases are linked to numerous enzymatic deficiencies and often times cause severe, sometimes fatal, impairments of the nervous system, muscles, intestines, and several other organ systems.
  • Common clinical symptoms in children with CDG include hypotonia, developmental delay, failure to thrive, hepatic dysfunction, coagulopathy, hypothyroidism, esotropia, abnormal fat pattern and inverted nipples, hypoglycemia, seizure, cerebellar hypoplasia, and stroke-like episodes in a developmentally delayed child.
  • the presentation may include ataxia, cognitive impairment, the absence of puberty in females, small testes in males, retinitis pigmentosa, scoliosis, joint contractures, and peripheral neuropathy.
  • CDG may be classified into two groups: CDG type I and CDG type II.
  • CDG type I is characterized by defects in the initial steps of N-linked protein glycosylation, z.e., biosynthesis of dolichol pyrophosphate linked oligosaccharide (DLO), which occur in the ER, or transfer of the DLO to asparagine residues of nascent polypeptides.
  • CDG type II involves defects in further processing (synthetic or hydrolytic) of the protein-bound glycan.
  • DLO dolichol pyrophosphate linked oligosaccharide
  • CDG-Ia phosphomannomutase 2
  • PMM2 phosphomannomutase 2
  • CDG-Ib is one known CDG for which a treatment is available, namely oral D-mannose administration.
  • a treatment namely oral D-mannose administration.
  • such therapy may not be as effective in treating CDG-Ia patients and there are currently limited treatment options for other CDG type I subtypes and CDG type II diseases.
  • One of the reasons for the lack in established therapy for CDG-I disorders may be due to the plethora of heterogeneous clinical phenotypes presented that do not show a direct correlation to the PMM2 enzyme activity.
  • M1P mannose- 1 -phosphate
  • Man-l-P mannose- 1 -phosphate
  • M1P mannose- 1 -phosphate
  • it is important to supply downstream enzymes with the required substrate (z.e., M1P).
  • M1P mannose- 1 -phosphate
  • the delivery and maintenance of such a systemic supply of M1P is problematic, as extracellular enzymes within bodily fluids degrade M1P when delivered exogenously by oral or intravenous administration.
  • M6P mannose-6-phosphate
  • PMI phosphomannose isomerases
  • Another potential solution is to use a delivery vehicle (e.g., lipid particles) to encapsulate and deliver M1P.
  • a delivery vehicle e.g., lipid particles
  • the optimal delivery vehicle must overcome challenges of stability, phosphorylated carbohydrates loading rate and concentration, toxicity, and delivery efficiency.
  • compositions and methods for formulating and delivering phosphorylated carbohydrates such as M1P and M6P, for treating disorders, such as a congenital disorder of glycosylation (CDG), to subjects (including, for example, humans) in need of such treatment.
  • CDG congenital disorder of glycosylation
  • the disclosure provides stabilized buffered liposomal formulations comprising a mannose phosphate, including specifically mannose- 1 -phosphate (M1P).
  • M1P mannose- 1 -phosphate
  • the stabilized liposomal formulations are not prone to lipid degradation and are stable for significant periods of time. Additionally, the liposome particles do not form agglomerates upon storage, which would compromise their efficacy.
  • compositions that include liposomes having a lipid membrane enclosing an intraliposomal compartment, in which the liposomes encapsulate a mannose phosphate (e.g., M1P) in the intraliposomal compartment.
  • the compositions further include an intraliposomal buffer comprising a buffering agent, and optionally an acid or base.
  • the pH of the intraliposomal buffer is from about 6.0 to about 7.9.
  • the pH of the intraliposomal buffer is from about 6.2 to about 7.4.
  • the pH of the intraliposomal buffer is from about 6.4 to about 7.5.
  • the pH of the intraliposomal buffer is from about 6.5 to about 7.2. In some embodiments, the pH of the intraliposomal buffer is about 6.5. In some embodiments, the pH of the intraliposomal buffer is about 6.8. In some embodiments, the pH of the intraliposomal buffer is about 7.0. In some embodiments, the pH of the intraliposomal buffer is about 7.2. In some embodiments, the pH of the intraliposomal buffer is about 7.4.
  • the intraliposomal buffer comprises tri s(hydroxymethyl)aminom ethane (Tris). In some embodiments, the intraliposomal buffer comprises 4-(2 -Hydroxy ethyl)- 1 -piperazineethanesulfonic acid (HEPES). In some embodiments, the Tris or HEPES buffer maintain the pH of the intraliposomal compartment at from about 6.8 to about 7.6, or from about 7.0 to about 7.4.
  • the intraliposomal buffer comprises a histidine or a citrate buffer.
  • the histidine or citrate buffer maintains the pH of the intraliposomal compartment from about 6 to about 7.2, or at a pH of from about 6.2 to about 7.0, or from about 6.4 to about 6.8.
  • the concentration of the buffering agent in the intraliposomal compartment of the liposomes is at least 15 mM, at least 25 mM, at least 35 mM, at least 50 mM, or at least 60 mM. In other embodiments, the concentration of the buffering agent in the intraliposomal compartment of the liposomes is from about 15 mM to about 75 mM, from about 25 mM to about 75 mM, from about 30 mM to about 60 mM, from about 40 mM to about 60 mM, or from about 45 mM to about 55 mM.
  • the concentration of the buffering agent in the intraliposomal compartment of the liposomes is about 40 mM, or about 50 mM. In some embodiments, the concentration of the buffering agent in the intraliposomal compartment of the liposomes is higher than the concentration of the buffering agent in the extraliposomal compartment of the liposomes.
  • the pH of the intraliposomal buffer changes to a minimal extent or does not change upon storage of the liposomal composition for 2 years at 5 °C or 6 months at room temperature.
  • the pH of the intraliposomal buffer changes by less than 0.4 units (e.g., less than 0.3 units, less than 0.2 units, or less than 0.1 unit) upon storage of the liposomal composition for 2 years at 5°C or 6 months at room temperature. For instance, if the starting pH of the intraliposomal buffer is 7.2, the pH of the intraliposomal buffer will be no less than 6.8 and no more than 7.6 following storage of the liposomal composition for 2 years at 5°C or 6 months at room temperature.
  • the liposomal compositions further include an extraliposomal buffer comprising a buffering agent and a tonicity modifier.
  • the pH of the extraliposomal buffering agent is from about 6.5 to about 7.5.
  • the extraliposomal buffering agent is the same as the intraliposomal buffering agent.
  • the concentration of the buffering agent in the extraliposomal buffer is from about 10 mM to about 20 mM. In some embodiments, the concentration of the buffering agent in the extraliposomal buffer is from about 15 mM to about 20 mM.
  • the pH of the extraliposomal buffer changes to a minimal extent or does not change upon storage of the liposomal composition for 2 years at 5 °C or 6 months at room temperature.
  • the pH of the extraliposomal buffer changes by less than 0.4 units (e.g., less than 0.3 units, less than 0.2 units, or less than 0.1 unit) upon storage of the liposomal composition for 2 years at 5°C or 6 months at room temperature. For instance, if the starting pH of the extraliposomal buffer is 7.2, the pH of the extraliposomal buffer will be no less than 6.8 and no more than 7.6 following storage of the liposomal composition for 2 years at 5°C or 6 months at room temperature.
  • the compositions optionally further include a radical scavenging antioxidant, present in the lipid bilayer.
  • the radical scavenging antioxidant is butylated hydroyanisole (BHA), butylated hydroxytoluene (BHT), or tocopherol.
  • the tocopherol is alpha-tocopherol.
  • the radical scavenging antioxidant is BHT.
  • any combinations of the radical scavenging antioxidants described herein may be used. For example, in one variation, both BHT and tocopherol are present in the compositions.
  • trace amounts of one or more radical scavengers may be present.
  • such components may be present in commercially available lipids purchased, and get incorporated into the composition.
  • BHT is absent.
  • both alpha-tocopherol and BHT are absent.
  • the composition has no detectable amount of alpha-tocopherol and BHT.
  • the extraliposomal buffer comprises tri s(hydroxymethyl)aminom ethane (Tris). In some embodiments, the extraliposomal buffer comprises Tris and saline. In other embodiments, the extraliposomal buffer comprises Tris and sugars, such as sucrose.
  • the intraliposomal buffer and/or the extraliposomal buffer comprises a buffering agent that allows a mannose phosphate (e.g., M1P) to remain solubilized in the presence of ethanol.
  • the intraliposomal buffer and/or the extraliposomal buffer comprises a buffering agent that allows the mannose phosphate (e.g., M1P) to remain solubilized at between about 10 mM and about 20 mM in the presence of ethanol.
  • the intraliposomal buffer and/or the extraliposomal buffer comprises a buffering agent that allows the mannose phosphate (e.g., M1P) to remain solubilized at between about 15 mM and about 20 mM in the presence of ethanol.
  • the intraliposomal buffer and/or the extraliposomal buffer comprises a buffering agent that allows the mannose phosphate (e.g., M1P) to remain solubilized at between about 10 mM and about 15 mM in the presence of ethanol.
  • the buffering agent is Tris or HEPES.
  • the buffering agent is Tris.
  • the buffering agent is HEPES.
  • the lipid membrane comprises: (a) at least one phospholipid having an ethanolamine head group and at least one unsaturated fatty acid tail; (b) at least one phospholipid having a choline group and at least one unsaturated fatty acid tail; and (c) at least one phospholipid having an ethanolamine head group and at least one saturated fatty acid tail, conjugated to polyethylene glycol (PEG).
  • the lipid membrane comprises DOPE, DOPC and DSPE conjugated to PEG.
  • compositions comprising: liposomes having a lipid membrane enclosing an intraliposomal compartment, wherein the liposomes encapsulate in the intraliposomal compartment the mannose phosphate (e.g., M1P), and wherein the lipid membrane comprises DOPC, DOPE, and DSPE conjugated to PEG; intraliposomal buffer comprising a buffering agent that allows the mannose phosphate (e.g., MlP)to remain solubilized in the presence of ethanol; extraliposomal buffer comprising (1) a buffering agent that allows the mannose phosphate (e.g., MlP)to remain solubilized in the presence of ethanol, and (2) saline; and BHT.
  • intraliposomal buffer comprising a buffering agent that allows the mannose phosphate (e.g., MlP)to remain solubilized in the presence of ethanol
  • extraliposomal buffer comprising (1) a buffering agent that allows the mannose
  • compositions comprising: liposomes having a lipid membrane enclosing an intraliposomal compartment, wherein the liposomes encapsulate in the intraliposomal compartment the mannose phosphate (e.g., M1P), and wherein the lipid membrane comprises DOPC, DOPE, and DSPE conjugated to PEG; intraliposomal buffer comprising a buffering agent that allows the mannose phosphate (e.g., M1P) to remain solubilized in the presence of ethanol; and extraliposomal buffer comprising (1) a buffering agent that allows the mannose phosphate (e.g., M1P) to remain solubilized in the presence of ethanol, and (2) saline.
  • intraliposomal buffer comprising a buffering agent that allows the mannose phosphate (e.g., M1P) to remain solubilized in the presence of ethanol
  • extraliposomal buffer comprising (1) a buffering agent that allows the mannose phosphate (
  • the extraliposomal buffer has no ethanol, or substantially no ethanol, or no detectable amount of ethanol.
  • the extraliposomal buffer has no mannose phosphate (e.g., M1P) , or substantially no mannose phosphate (e.g., M1P), or no detectable amount of mannose phosphate (e.g., M1P). It should be understood that this buffer system in the composition helps to maintain pH, rather than solubility of mannose phosphate (e.g., M1P).
  • compositions comprising: liposomes having a lipid membrane enclosing an intraliposomal compartment, wherein the liposomes encapsulate in the intraliposomal compartment mannose phosphate (e.g., M1P), and wherein the lipid membrane comprises DOPC, DOPE, and DSPE conjugated to PEG; intraliposomal buffer comprising Tris; extraliposomal buffer comprising Tris and saline; and BHT.
  • M1P mannose phosphate
  • compositions comprising: liposomes having a lipid membrane enclosing an intraliposomal compartment, wherein the liposomes encapsulate in the intraliposomal compartment mannose phosphate (e.g., M1P), and wherein the lipid membrane comprises DOPC, DOPE, and DSPE conjugated to PEG; intraliposomal buffer comprising Tris; and extraliposomal buffer comprising Tris and saline.
  • the liposomal compositions of the disclosure show minimal or no degradation of the individual lipids comprising the liposome.
  • each of the individual lipids of the liposomal composition degrade less than 10%, less than 5%, less than 1%, less than 0.5%, less than 0.25%, or less than 0.1% when stored at 5°C or room temperature for up to 2 years.
  • the buffered liposomal compositions of the disclosure show high purity levels upon storage for 6 months or more.
  • the total impurity level observed in the liposomal compositions of the disclosure is less than 1%, less than 0.5%, less than 0.25%, or less than 0.1% following storage at 5°C or at room temperature for up to 2 years.
  • the liposomal compositions of the disclosure also display negligible leakage of the mannose phosphate (e.g., MlPjfrom the intraliposomal component, even following storage of the liposomal composition for up to 2 years.
  • the mannose phosphate e.g., MlPjfrom the intraliposomal component
  • less than 10% of the intraliposomal mannose phosphate e.g., MlP
  • the intraliposomal mannose phosphate e.g., MlP
  • MlP the intraliposomal mannose phosphate
  • a method of treating a congenital disorder of glycosylation in a subject in need thereof comprising administering to the subject the liposomal compositions described herein.
  • the congenital disorder of glycosylation is CDG-Ia, CDG-Ie, CDG-Ii, CDG-Ik, CDG-Io, CDG-Ip, or DPM2-CDG.
  • the compositions are administered intravenously, e.g., by intravenous infusion.
  • the mannose phosphate used in the methods herein is M1P.
  • FIG. 1 depicts degradation of individual lipids in a liposomal composition formulated without an intraliposomal buffer (Formulation 1-A) and six liposomal compositions formulated with an intraliposomal buffer (Formulas 1, 2, 3, 4, 5 and 6) at various temperatures over a period of one month.
  • FIG. 2 depicts total lipid degradation of a liposomal composition formulated without an intraliposomal buffer (Formulation 1-A) and six liposomal compositions formulated with an intraliposomal buffer (Formulations 1, 2, 3, 4, 5 and 6) at various temperatures , wherein the horizontal line indicates the upper specification limit (USL) of 4%, and no impurities were detected at 0 month.
  • FIG. 3 depicts pH changes over time of a liposomal composition formulated without an intraliposomal buffer (Formulation 1-A) and six liposomal compositions formulated with an intraliposomal buffer (Formulations 1, 2, 3, 4, 5 and 6) at various temperatures, wherein the horizontal “USL” and “LSL” lines indicate the upper and lower limits of pH based on target specifications of Formulation 1-A, while the horizontal “Target” line indicates the target pH of 7.
  • FIGS. 4A and 4B depict particulate count over 10 pm and 25 pm, respectively, for a liposomal composition formulated without an intraliposomal buffer (Formulation 1-A) and six liposomal compositions formulated with an intraliposomal buffer (Formulations 1, 2, 3, 4, 5 and 6) at various temperatures, wherein the horizontal “USL” line show the upper limit of number of particles per guidance of USP ⁇ 788> and expected vial fill volume.
  • FIGS. 5A, 5B and 5C depict Z average, PDI, and population over 200 nm, respectively, for a liposomal composition formulated without an intraliposomal buffer (Formulation 1-A) and six liposomal compositions formulated with an intraliposomal buffer (Formulations 1, 2, 3, 4, 5 and 6) at various temperatures.
  • FIG. 6 depicts leeching of mannose- 1 -phosphate (M1P) over time for a liposomal composition formulated without an intraliposomal buffer (Formulation 1-A) and six liposomal compositions formulated with an intraliposomal buffer (Formulations 1, 2, 3, 4, 5 and 6).
  • FIG. 7 shows the osmolality of samples for a liposomal composition formulated without an intraliposomal buffer (Formulation 1-A) and six liposomal compositions formulated with an intraliposomal buffer (Formulations 1, 2, 3, 4, 5 and 6).
  • compositions of a mannose phosphate such as mannose- 1- phosphate (M1P) encapsulated by liposomes.
  • M1P mannose- 1- phosphate
  • pharmaceutical compositions and kits containing these compositions are also provided here.
  • CDG congenital disorder of glycosylation
  • the liposomes may encapsulate a mannose phosphate.
  • the mannose phosphate is mannose- 1 -phospate (M1P).
  • references to “between” two values or parameters herein includes (and describes) embodiments that include those two values or parameters per se.
  • description referring to “between x and y” includes description of “x” and “y” per se.
  • “between x and y” can also be expressed as “about x to y” or “about x-y”.
  • compositions comprising: liposomes having a lipid membrane enclosing an intraliposomal compartment, wherein the liposomes encapsulate in the intraliposomal compartment mannose phosphate (e.g., M1P); intraliposomal buffer; extraliposomal buffer; and a radical scavenging antioxidant.
  • mannose phosphate e.g., M1P
  • compositions comprising: liposomes having a lipid membrane enclosing an intraliposomal compartment, wherein the liposomes encapsulate in the intraliposomal compartment mannose phosphate (e.g., M1P); intraliposomal buffer; and extraliposomal buffer.
  • M1P mannose phosphate
  • the liposomes have an interior surface in contact with the intraliposomal buffer and an external surface in contact with the extraliposomal buffer. In some embodiments the interior and exterior surfaces are both in contact with a buffer solution of neutral pH.
  • the lipid membrane comprises: (a) at least one phospholipid having an ethanolamine head group and at least one unsaturated fatty acid tail; (b) at least one phospholipid having a choline group and at least one unsaturated fatty acid tail; and (c) at least one phospholipid having an ethanolamine head group and at least one saturated fatty acid tail, conjugated to polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • the unsaturated fatty acid tail independently comprises at least one Cio-28 carbon chain.
  • the unsaturated fatty acid tail is an optionally substituted Cio-28 alkenyl or an optionally substituted Cio-28 alkynyl.
  • each of the fatty acid chains is an unsubstituted Cio-28 alkenyl.
  • the alkenyl is linear or branched.
  • each of the fatty acid chains has one or more double bonds.
  • each double bond has cis configuration. In some embodiments, each double bond has trans configuration.
  • each of the fatty acid chains is a Cio-28 alkenyl substituted by a substituent selected form the group consisting of acyl, hydroxyl, cycloalkyl, alkoxy, acyloxy, amino, aminoacyl, nitro, halo, thiol, thioalkyl, alkyl, alkenyl, alkynyl and heterocyclyl.
  • the phospholipid having an ethanolamine head group in (a) of the lipid membrane has oleoyl tail groups.
  • the phospholipid having an ethanolamine head group and at least one unsaturated fatty acid tail is l,2-dioleoyl-sn-glycero-3 -phosphoethanolamine (DOPE) or a salt thereof.
  • DOPE dioleoyl-sn-glycero-3 -phosphoethanolamine
  • the phospholipid having an ethanolamine head group and at least one unsaturated fatty acid tail is: or a salt thereof.
  • the unsaturated fatty acid tail independently comprises at least one Cio-28 carbon chain.
  • the unsaturated fatty acid tail is an unsubstituted Cio-28 alkenyl.
  • the alkenyl is linear or branched.
  • the unsaturated fatty acid tail has one or more double bonds.
  • each double bond has cis configuration.
  • each double bond has trans configuration.
  • the unsaturated fatty acid tail is a Cio-28 alkenyl substituted by a substituent selected form the group consisting of acyl, hydroxyl, cycloalkyl, alkoxy, acyloxy, amino, aminoacyl, nitro, halo, thiol, thioalkyl, alkyl, alkenyl, alkynyl and heterocyclyl.
  • the phospholipid having choline group in (b) of the lipid membrane has oleoyl tail groups.
  • the phospholipid having a choline group and at least one unsaturated fatty acid tail is l,2-dioleoyl-sn-glycero-3 -phosphocholine (DOPC), or a salt thereof.
  • DOPC l,2-dioleoyl-sn-glycero-3 -phosphocholine
  • the phospholipid having a choline group and at least one unsaturated fatty acid tail is: or a salt thereof.
  • the saturated fatty acid tail independently comprises at least one C4-28 carbon chain.
  • the saturated fatty acid tail is an optionally substituted alkyl.
  • the saturated fatty acid tail is an unsubstituted C4-28 alkyl.
  • the saturated fatty acid tail is a C4-28 alkyl substituted by a substituent selected form the group consisting of acyl, hydroxyl, cycloalkyl, alkoxy, acyloxy, amino, aminoacyl, nitro, halo, thiol, thioalkyl, alkyl, alkenyl, alkynyl and heterocyclyl.
  • the phospholipid having an ethanolamine head group in (c) of the lipid membrane has stearoyl tail groups.
  • the phospholipid having an ethanolamine head group and at least one saturated fatty acid tail is l,2-distearoyl-sn-glycero-3 -phosphoethanolamine (DSPE), or a salt thereof.
  • the phospholipid having an ethanolamine head group and at least one saturated fatty acid tail is: or a salt thereof.
  • the phospholipid conjugated to PEG is DSPE or a salt thereof.
  • PEGylated phospholipid is DSPE-PEG.
  • PEGylated phospholipid is DSPE-PEG2000.
  • the DSPE- PEG is further conjugated to a carbohydrate.
  • the DSPE-PEG is further conjugated to a monosaccharide.
  • the DSPE-PEG is further conjugated to a galactose moiety.
  • the DSPE-PEG-galactose has the following structure: or a salt thereof.
  • the lipid membrane comprises DOPC, DOPE and DSPE conjugated to PEG.
  • the lipid membrane comprises DOPC:DOPC:DSPE- PEG2000 at a molar ratio of from about 58 : 38 : 3 to 75 : 22 : 3; or from about 48.5 : 48.5 : 3 to about 80 : 17 : 3.
  • the lipid membrane comprises DOPC:DOPE:DSPE- PEG2000 at a molar ratio of about 58 : 39 : 3.
  • the lipid membrane comprises DOPC:DOPE:DSPE-PEG2ooo at a molar ratio of about 67 : 30 : 3.
  • PEG is present in the composition at a concentration that ranges from about 0.5 molar percent to about 20 molar percent. In some embodiments, PEG is present in the composition at a concentration of about 0.5 molar percent, about 1 molar percent, about 2 molar percent, about 3 molar percent, about 4 molar percent, about 5 molar percent, about 6 molar percent, about 7 molar percent, about 8 molar percent, about 9 molar percent, about 10 molar percent, about 11 molar percent, about 12 molar percent, about 13 molar percent, about 14 molar percent, about 15 molar percent, about 16 molar percent, about 17 molar percent, about 18 molar percent, about 19 molar percent, or about 20 molar percent.
  • PEG is present in the composition at a concentration of at least about 0.5 molar percent, at least about 1 molar percent, at least about 2 molar percent, at least about 3 molar percent, at least about 4 molar percent, at least about 5 molar percent, at least about 6 molar percent, at least about 7 molar percent, at least about 8 molar percent, at least about 9 molar percent, at least about 10 molar percent, at least about 11 molar percent, at least about 12 molar percent, at least about 13 molar percent, at least about 14 molar percent, at least about 15 molar percent, at least about 16 molar percent, at least about 17 molar percent, at least about 18 molar percent, at least about 19 molar percent, or at least about 20 molar percent; or between 0.5 molar percent and 50 molar percent, between 0.5 molar percent and 40 molar percent, between 0.5 molar percent and 30 molar percent, or between 0.5 molar percent
  • PEG is present in the composition at a molecular weight that ranges from about 200 Da to about 40,000 Da. In some embodiments, PEG is present in the composition at a molecular weight that ranges from about 200 Da to about 10,000 Da.
  • PEG is present in the composition at a molecular weight of about 200 Da, about 300 Da, about 400 Da, about 500 Da, about 600 Da, about 700 Da, about 800 Da, about 900 Da, about 1,000 Da, about 1,500 Da, about 2,000 Da, about 2,500 Da, about 3,000 Da, about 3,500 Da, about 4,000 Da, about 4,500 Da, about 5,000 Da, about 5,500 Da, about 6,000 Da, about 6,500 Da, about 7,000 Da, about 7,500 Da, about 8,000 Da, about 8,500 Da, about 9,000 Da, about 9,500 Da, or about 10,000 Da; or between about 200 Da and about 10,000 Da.
  • compositions that include liposomes having a lipid membrane enclosing an intraliposomal compartment, in which the liposomes encapsulate a mannose phosphate, such as M1P, in the intraliposomal compartment.
  • the compositions further include an intraliposomal buffer comprising a buffering gent, and optionally an acid or a base.
  • the pH of the intraliposomal buffer is from about 6.0 to about 7.9. In some embodiments, the pH of the intraliposomal buffer is from about 6.2 to about
  • the pH of the intraliposomal buffer is from about 6.4 to about
  • the pH of the intraliposomal buffer is from about 6.5 to about
  • the pH of the intraliposomal buffer is from about 6.8 to about
  • the pH of the intraliposomal buffer is about 6.5. In some embodiments, the pH of the intraliposomal buffer is about 6.8. In some embodiments, the pH of the intraliposomal buffer is about 7.0. In some embodiments, the pH of the intraliposomal buffer is about 7.2. In some embodiments, the pH of the intraliposomal buffer is about 7.3. In some embodiments, the pH of the intraliposomal buffer is about 7.4. In some embodiments, the pH of the intraliposomal buffer is about 7.5. [0064] In some embodiments, the intraliposomal buffer comprises tri s(hydroxymethyl)aminom ethane (Tris).
  • Tris tri s(hydroxymethyl)aminom ethane
  • the intraliposomal buffer comprises 4-(2 -Hydroxy ethyl)- 1 -piperazineethanesulfonic acid (HEPES).
  • the intraliposomal buffer comprises bicarbonate.
  • the Tris or HEPES buffer maintain the pH of the intraliposomal compartment at from about 6.8 to about 7.6, or from about 7.0 to about 7.4.
  • the pH of the intraliposomal buffer is about 7.0.
  • the pH of the intraliposomal buffer is about 7.2.
  • the pH of the intraliposomal buffer is about 7.3.
  • the pH of the intraliposomal buffer is about 7.4.
  • the pH of the intraliposomal buffer is about 7.5.
  • the intraliposomal buffer comprises a histidine or a citrate buffer.
  • the histidine or citrate buffer maintains the pH of the intraliposomal compartment from about 6 to about 7.2, or at a pH of from about 6.2 to about 7.0, or from about 6.4 to about 6.8.
  • the intraliposomal buffer comprises an acetate, ascorbate, benzoate, diethanolamine, phosphate, succinate, tartrate or tromethamine buffering agent.
  • the concentration of the buffering agent (e.g., Tris) in the intraliposomal compartment of the liposomes is at least 15 mM. In other embodiments, the concentration of the buffering agent (e.g., Tris) in the intraliposomal compartment of the liposomes is at least 35 mM. In other embodiments, the concentration of the buffering agent (e.g., Tris) in the intraliposomal compartment of the liposomes is at least 50 mM. In other embodiments, the concentration of the buffering agent (e.g., Tris) in the intraliposomal compartment of the liposomes is at least 50 mM.
  • the concentration of the buffering agent (e.g., Tris) in the intraliposomal compartment of the liposomes is at least 50 mM.
  • the concentration of the buffering agent (e.g., Tris) in the intraliposomal compartment of the liposomes is from about 15 mM to about 75 mM. In other embodiments, the concentration of the buffering agent (e.g., Tris) in the intraliposomal compartment of the liposomes is from about 30 mM to about 60 mM. In other embodiments, the concentration of the buffering agent (e.g., Tris) in the intraliposomal compartment of the liposomes is about 40 mM. In other embodiments, the concentration of the buffering agent (e.g., Tris) in the intraliposomal compartment of the liposomes is about 50 mM.
  • the concentration of the buffering agent (e.g., Tris) in the intraliposomal compartment of the liposomes is about 50 mM.
  • the pH of the intraliposomal buffer changes to a minimal extent or does not change upon storage of the liposomal composition for 6 months or 2 years at 5°C or at room temperature.
  • the pH of the intraliposomal buffer changes by less than 0.4 units (e.g., less than 0.3 units, less than 0.2 units, or less than 0.1 unit) upon storage of the liposomal composition for six month or for 2 years at 5°C or at room temperature. For instance, if the starting pH of the intraliposomal buffer is 7.2, the pH of the intraliposomal buffer will be no less than 6.8 and no more than 7.6 following storage of the liposomal composition for up to 2 years at 5°C or at room temperature.
  • the buffering agent comprises a buffer salt.
  • the extraliposomal buffer comprising a buffer salt and a tonicity modifier.
  • the pKa of the buffer salt is between 6.5 to 7.5.
  • the extraliposomal buffer is in a physiological pH range.
  • the buffer salt is tri s(hydroxymethyl)aminom ethane (Tris).
  • the extraliposomal buffer comprises bicarbonate, Tris, or HEPES, or any combination thereof.
  • the concentration of the buffering agent in the extraliposomal buffer is from about 10 mM to about 20 mM. In some embodiments, the concentration of the buffering agent in the extraliposomal buffer is from about 15 mM to about 20 mM.
  • the pH of the extraliposomal buffer changes to a minimal extent or does not change upon storage of the liposomal composition for 6 months or 2 years at 5°C or at room temperature. In some embodiments, the pH of the extraliposomal buffer changes by less than 0.4 units (e.g., less than 0.3 units, less than 0.2 units, or less than 0.1 unit) upon storage of the extraliposomal composition for six month or for 2 years at 5°C or at room temperature.
  • the pH of the extraliposomal buffer will be no less than 6.8 and no more than 7.6 following storage of the liposomal composition for up to 2 years at 5 °C or at room temperature.
  • the tonicity modifier comprises sugar or saline, or a combination thereof.
  • Suitable sugars that may be used for tonicity include, for example, sucrose and dextrose.
  • the tonicity modifier is an ionic tonicity modifier.
  • the tonicity modifier comprises saline.
  • the osmolality of the liposomal compositions is isotonic.
  • the osmolality of the liposomal compositions is from about 270 to about 320 mOsm/kg.
  • the osmolality of the liposomal compositions is from about 290 to about 320 mOsm/kg.
  • concentration of the tonicity modifier in the extraliposomal buffer is from about 5 mM to about 25 mM, from about 5 mM to about 15 mM, from about 10 mM to about 20 mM, from about 10 mM to about 15 mM, or from about 15 mM to about 20 mM.
  • the M1P and Tris, and optionally an acid are present in the composition at a ratio suitable to maintain a neutral pH.
  • the buffer capacity of the intraliposomal solution may be increased to maintain a neutral pH in the presence of mannose- 1 -phosphate (M1P).
  • M1P mannose- 1 -phosphate
  • the concentration of the intraliposomal buffer is increased to maintain the neutral pH.
  • the composition further comprises a radical scavenging antioxidant.
  • a radical scavenging antioxidant Any suitable radical scavenging antioxidants may be used in the liposomal compositions provided herein.
  • the radical scavenging antioxidant is butylated hydroyanisole (BHA), butylated hydroxytoluene (BHT), or alpha tocopherol.
  • the radical scavenging antioxidant is BHT.
  • the compositions comprises more than one radical scavenging agent. Any combinations of the radical scavenging antioxidants described herein may be used.
  • the compositions comprise BHT and alpha tocopherol. It should be understood that, in certain variations, certain of these radical scavenging antioxidants may be present in the liposomal compositions due to their presence in the lipids used (that are commercially available).
  • compositions described herein are optimized for treating diseases and disorders such as congenital disorders of glycosylation (CDG).
  • CDG congenital disorders of glycosylation
  • the composition has a drug-to-lipid (D/L) ratio of at least 0.01, at least 0.1, or at least 0.2.
  • the composition has a D/L ratio from about 0.1 to about 2, from about 0.1 to about 1, from about 0.1 to about 0.5, from about 0.1 to about 0.4, from about 0.1 to about 0.3, from about 0.1 to about 0.2, or from about 0.5 to about 1.5.
  • the D/L ratio is about 0.1, 0.2, or 0.3. It should be understood that the drug-to-lipid (D/L) ratio refers to the mass ratio of drug to total lipids in a given sample.
  • the total mannose phosphate (e.g., MlP)concentration in the sample is between 1 mg/ml and 50 mg/ml, between 1 mg/ml and 25 mg/ml, 1 mg/ml and 15 mg/ml, between 5 mg/ml and 25 mg/ml, between 5 mg/ml and 12 mg/ml, or between 6 mg/ml and 10 mg/ml.
  • the encapsulated D/L ratio refers to the mass ratio of drug encapsulated in the liposome to total lipids in a given sample. In some variations, the encapsulated D/L ratio does not exceed 0.15. In other variations, the encapsulated D/L ratio is between 0.001 and 0.15, between 0.01 and 0.15, between 0.1 to 0.15, between 0.1 and 0.14, between 0.1 and 0.13, between 0.1 and 0.12, or between 0.1 and 0.11. In other variations, the encapsulated D/L ratio is about 0.1 +/- 0.25%, about 0.1 +/- 0.20%, about 0.1 +/- 15%, or about 0.1 +/- 0.1%.
  • the total encapsulated mannose phosphate (e.g., MlP)concentration in the sample is between 1 mg/ml and 15 mg/ml, between 5 mg/ml and 12 mg/ml, or between 6 mg/ml and 10 mg/ml.
  • the composition has a mannose phosphate (e.g., MlP)concentration (based on the free acid) from about 1 mg/ml to about 10 mg/ml.
  • the mannose phosphate (e.g., M1P) concentration is from about 1 mg/ml to about 10 mg/ml, from about 1 mg/ml to about 9 mg/ml, from about 1 mg/ml to about 8 mg/ml, from about 1 mg/ml to about 7 mg/ml, from about 1 mg/ml to about 6 mg/ml, from about 1 mg/ml to about 5 mg/ml, or from about 1 mg/ml to about 4 mg/ml, from about 1 mg/ml to about 3 mg/ml, or from about 1 mg/ml to about 2 mg/ml.
  • the mannose phosphate (e.g., M1P) concentration is at least 1 mg/ml. In some variations, the mannose phosphate (e.g., M1P) concentration is about 1 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, or 10 mg/ml.
  • the composition has a mannose phosphate (e.g., MlP)concentration (based on the free acid) from about Img/mL to 250 mg/ml, between 1 mg/mL and 200 mg/ml, 1 mg/ml to about 100 mg/ml, from about 1 mg/ml to about 75 mg/ml, from about 1 mg/ml to about 50 mg/ml, from about 25 mg/ml to about 75 mg/ml, from about 30 mg/ml to about 55 mg/ml, or from about 30 mg/ml to about 50 mg/ml, or from about 40 mg/ml to about 55 mg/ml, or from about 50 mg/ml to about 55 mg/ml.
  • the mannose phosphate (e.g., MlP)concentration is the maximum concentration of mannose phosphate (e.g., MlP)in the liposome.
  • the composition minimizes both lipid degradation and liposomal agglomeration.
  • the lipid degradation of the composition is less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5% or less than 0.1%.
  • the liposomal compositions of the disclosure show minimal or no degradation of the individual lipids comprising the liposome.
  • the buffered liposomal compositions are far less prone to lipid degradation compared to compositions formulated in unbuffered solutions (e.g., unbuffered saline solutions).
  • each of the individual lipids of the liposomal composition degrade less than 10% when stored at 5°C or room temperature for up to 2 years.
  • each of the individual lipids of the liposomal composition degrade less than 1% when stored at 5°C or room temperature for up to 2 years.
  • each of the individual lipids of the liposomal composition degrade less than 0.5% when stored at 5°C for up to 2 years. In some embodiments, each of the individual lipids of the liposomal composition degrade less than 0.25% when stored for up to 2 years.
  • the composition has less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5% or less than 0.1% of total lipid impurities.
  • the buffered liposomal compositions of the disclosure show high purity levels upon storage for 6 months or more.
  • the total impurity level observed in the liposomal compositions of the disclosure is less than 1%, less than 0.5%, less than 0.25%, or less than 1% following storage at 5°C or at room temperature for up to 2 years.
  • the composition maintains a pH range between 6.5 and 7, 7 and 7.4 or between 7.35 and 7.45. In certain embodiments, the composition maintains a physiological pH range. [0088] In some embodiments, the composition has a Z-average between 80 nm and 130 nm, between 80 nm and 120 nm, between 80 nm and 110 nm, between 80 nm and 100 nm, between 90 nm and 130 nm, between 90 nm and 120 nm, between 90 nm and 110 nm, or between 90 nm and 100 nm.
  • the composition has a poly dispersity index of less than 0.2 or less than 0.1.
  • no free mannose phosphate e.g., MlP
  • MlP mannose phosphate
  • percentage (%) of encapsulated M1P is the percent of encapsulated mannose phosphate (e.g., M1P) divided by the total mannose phosphate in the finished drug product. It should be understood that the finished drug product refers to the liposomal composition.
  • the percentage of encapsulated mannose phosphate (e.g., M1P) is at least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, or between 90% and 99%, or between about 90% and 95%, or close to 100%.
  • percentage (%) encapsulation efficiency is the efficiency of mannose phosphate (e.g., M1P) encapsulation in the liposomes e.g., of the finished drug product) relative to the starting amount of mannose phosphate. In some variations, the %EE is between about 5% and 50%, between about 10% and 30%, or between about 10% and 25%.
  • compositions provided herein may have any one or more of the properties described above.
  • the composition provided herein has all of the following properties:
  • composition provided herein has all of the following properties:
  • Stability of the liposomal compositions provided herein may be measured over a time period over a range of temperatures, such as 5°C, 25°C and 40°C.
  • the time period is 1-3 months. In other variations, the time period is at least 6 months, at least 1 year, or at least 2 years.
  • the liposomal compositions of the disclosure also display negligible leakage of the M1P from the intraliposomal component, even following storage of the liposomal composition for up to 2 years. For instance, in some embodiments, less than 10%, less than 5%, less than 2%, less than 1%, less than 0.5%, less than 0.25%, or less than 0.1% of the intraliposomal mannose phosphate (e.g., M1P) is released from the intraliposomal component of the liposomal composition following storage for up to 2 years at 5°C or at room temperature.
  • M1P intraliposomal mannose phosphate
  • Liposomal compositions of the present disclosure can be incorporated into a variety of formulations for therapeutic use (e.g., by administration) or in the manufacture of a medicament (e.g., for delivering M1P to a subject in need thereof, including for treating or preventing a disease or disorder such as a congenital disorder of glycosylation (CDG) in a subject in need thereof) by combining the composition with appropriate carriers (including, for example, pharmaceutically acceptable carriers or diluents), and may be formulated, for example, into preparations in liquid form.
  • appropriate carriers including, for example, pharmaceutically acceptable carriers or diluents
  • compositions intended for in vivo use are 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 present disclosure may be used in accord with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time.
  • Dosages and desired concentration of pharmaceutical compositions of the present disclosure may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary artisan. Animal experiments provide reliable guidance for the determination of effective doses for human therapy. Interspecies scaling of effective doses can be performed following the principles described in Mordenti, J. and Chappell, W. “The Use of Interspecies Scaling in Toxicokinetics,” In Toxicokinetics and New Drug Development, Yacobi et al., Eds, Pergamon Press, New York 1989, pp.42-46.
  • normal dosage amounts may vary from 10 ng/kg up to 100 mg/kg of a subject’s body weight per day.
  • Administration of the liposomal compositions provided herein can be continuous or intermittent, depending, for example, on the recipient’s physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners.
  • different formulations will be effective for different treatments and different disorders, and that administration intended to treat a specific organ or tissue may necessitate delivery in a manner different from that to another organ or tissue.
  • dosages may be administered by one or more separate administrations, or by continuous infusion. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays.
  • the liposomal compositions provided herein may be chronically or intermittently administered to a subject (including, for example, a human) in need thereof.
  • chronic administration is administration of the medicament(s) in a continuous as opposed to acute mode, so as to maintain the initial therapeutic effect (activity) for an extended period of time.
  • intermittent administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature.
  • compositions are useful for delivering M1P to a subject in need thereof.
  • the subject is a mammal, such as a human, domestic animal, such as a feline or canine subject, farm animal (e.g., bovine, equine, caprine, ovine, and porcine subject), wild animal (whether in the wild or in a zoological garden), research animal, such as mouse, rat, rabbit, goat, sheep, pig, dog, and cat, and birds.
  • the subject is a human.
  • the subject may be at risk.
  • the subject is an at risk human.
  • a subject at risk of developing a particular disease, disorder, or condition, such as a congenital disorder of glycosylation may or may not have detectable disease or symptoms of disease, and may or may not have displayed detectable disease or symptoms of disease prior to the treatment methods described herein.
  • an individual “at risk” is an individual having risk factors, which are measurable parameters that correlate with development of a particular disease, disorder, or condition, as known in the art.
  • a subject having one or more of these risk factors has a higher probability of developing a particular disease, disorder, or condition such as a congenital disorder of glycosylation, than a subject without one or more of these risk factors.
  • congenital disorders of glycosylation is a group of genetic disorders that result in errors of metabolism in which glycosylation of a variety of tissue proteins and/or lipids is deficient or defective.
  • Congenital disorders of glycosylation may also be known as CDG syndromes.
  • CDG syndromes may often cause serious, occasionally fatal, malfunction of several different organ systems, such as the nervous system, brain, muscles, and intestines, in affected infants.
  • Manifestations of CDG syndromes may range from severe developmental delay and hypotonia beginning in infancy, to hypoglycemia and protein-losing enteropathy with normal development. Developmental delay can be a common initial indication for a CDG diagnosis.
  • CDG-Ia also known as PMM2-CDG
  • phosphomannomutase 2 which is the enzyme responsible for the conversion of mannose-6-phosphate into mannose- 1 -phosphate
  • CDG syndromes may be classified as type I (CDG-I) and type II (CDG-II). Such classification may depend on the nature and location of the biochemical defect in the metabolic pathway relative to the action of oligosaccharyltransferase. Methods for screening for CDG subtype may include the analysis of transferrin glycosylation status by, for example, isoelectric focusing or ESI-MS.
  • CDG type I include, for example, la (PMM2-CDG), lb (MPI- CDG), Ic (ALG6-CDG) , Id (ALG3-CDG), le (DPMI -CDG), If (MPDU1-CDG), Ig (ALG12-CDG), Ih (ALG8-CDG), li (ALG2-CDG), Ij (DPAGT1-CDG), Ik (ALG1-CDG), IL (ALG9-CDG), Im (DOLK-CDG), In (RFT1-CDG), Io (DPM3-CDG), Ip (ALG11-CDG), Iq (SRD5A3-CDG), Ir (DDOST-CDG), DPM2-CDG, TUSC3-CDG, MAGT1-CDG, DHDDS- CDG, and I/IIx.
  • CDG type II include, for example, Ila (MGAT2-CDG), lib (GCS1-CDG), lie (SLC335C1-CDG), lid (B4GALT1-CDG), lie (COG7-CDG), Ilf (SLC35A1-CDG), Ilg (COG1-CDG), Ilh (COG8-CDG), Hi (COG5-CDG), Ilj (COG4-CDG), IIL (COG6-CDG), ATP6V0A2-CDG, MAN1B1-CDG, and ST3GAL3-CDG.
  • CDG glycosylation
  • la PMM2-CDG
  • MPI- CDG Ic
  • AG6-CDG Id
  • AG3-CDG Id
  • le DPMI -CDG
  • compositions and methods described herein are suitable to treat CDG-Ia, CDG-Ib, CDG-Ie, CDG-Ig, CDG-Ii, CDG-Ik, CDG-Io, CDG-Ip, or DPM2-CDG.
  • treatment includes an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • a) inhibiting the disease or condition e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease
  • prevention includes any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop.
  • Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
  • an “effective amount” is at least an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
  • An effective amount can be provided in one or more administrations.
  • a “therapeutically effective amount” is at least the minimum concentration required to effect a measurable improvement of a particular disease, disorder, or condition, such as a congenital disorder of glycosylation.
  • a therapeutically effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the lipid compositions of the present disclosure to elicit a desired response in the subject.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the lipid compositions of the present disclosure are outweighed by the therapeutically beneficial effects.
  • provided herein is a method for delivering M1P to a subject in need thereof.
  • the methods provided herein comprise administering to the subject any of the liposomal compositions described herein.
  • a method for treating a congenital disorder of glycosylation (CDG) in a subject in need thereof comprises administering to the subject any of the compositions described herein.
  • the congenital disorder of glycosylation (CDG) is a CDG-Ia disorder.
  • the administration of the composition induces a 0.05-fold to at least a 3-fold increase in cellular production of higher-order lipid-linked oligosaccharides in the human, as compared to cellular production of higher-order lipid-linked oligosaccharides in the human in the absence of administering the composition to the subject.
  • the compositions are administered at a weekly or biweekly dose of M1P or a pharmaceutically salt thereof from about 10 mg/kg to about 40 mg/kg, from about 20 mg/kg to about 40 mg/kg, from about 30 mg/kg to about 30 mg/kg, from about 25 mg/kg to about 30 mg/kg.
  • the compositions are administered parenterally (e.g., intravenously).
  • the compositions may be administered by intravenous infusion.
  • the present disclosure also provides articles of manufacture and/or kits containing any of the liposomal compositions described herein.
  • Articles of manufacture and/or kits of the present disclosure may include one or more containers comprising a purified liposomal composition of the present disclosure.
  • Suitable containers may include, for example, bottles, vials, syringes, and IV solution bags.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the articles of manufacture and/or kits further include instructions for use in accordance with any of the methods of the present disclosure.
  • these instructions comprise a description of administration of any of the liposomal compositions described herein to deliver the mannose phosphate (e.g., M1P) to a subject in need thereof, to treat a congenital disorder of glycosylation (CDG) to a subject in need thereof, according to any of the methods of the present disclosure.
  • the instructions comprise a description of how to detect a congenital disorder of glycosylation (CDG), for example in a subject, in a tissue sample, or in a cell.
  • the article of manufacture and/or kit may further comprise a description of selecting a subject suitable for treatment based on identifying whether that subject has the disease and the stage of the disease.
  • the instructions generally include information as to dosage, dosing schedule, and route of administration for the intended treatment.
  • the containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • Instructions supplied in the articles of manufacture and/or kits of the present disclosure are typically written instructions on a label or package insert (e.g., a paper sheet included in the article of manufacture and/or kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.
  • the label or package insert indicates that the composition is used for delivering M1P and/or treating, e.g., a congenital disorder of glycosylation (CDG). Instructions may be provided for practicing any of the methods described herein.
  • CDG congenital disorder of glycosylation
  • the articles of manufacture and/or kits of the present disclosure may be in suitable packaging.
  • suitable packaging includes, for example, vials, pre-filled syringes, bottles, jars, and flexible packaging (e.g., sealed Mylar or plastic bags).
  • packages for use in combination with a specific device such as an inhaler, nasal administration device (e.g., an atomizer) or an infusion device such as a minipump.
  • An article of manufacture and/or kit may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • the container may also have a sterile access port (e.g., the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • At least one active agent in the composition is a carbohydrate such as M1P capable of treating a congenital disorder of glycosylation (CDG) and/or improving one or more symptoms thereof.
  • the container may further comprise a second pharmaceutically active agent.
  • Articles of manufacture and/or kits may optionally provide additional components such as buffers and interpretive information. Normally, the article of manufacture and/or kit comprises a container and a label or package insert(s) on or associated with the container.
  • a composition comprising liposomes having a lipid membrane enclosing an intraliposomal compartment, wherein the liposomes encapsulate in the intraliposomal compartment mannose- 1 -phosphate (M1P), and wherein the intraliposomal compartment comprises a buffering agent and optionally an acid or base, wherein the pH of the intraliposomal compartment is from about 6.0 to about 7.9.
  • M1P mannose- 1 -phosphate
  • composition of embodiment Al wherein the pH of the intraliposomal compartment is from about 6.2 to about 7.4.
  • composition of embodiment Al or A2, wherein the buffering agent in the intraliposomal compartment is tri s(hydroxymethyl)aminom ethane (Tris).
  • composition of any one of embodiments A1-A3, wherein the buffering agent in the intraliposomal compartment is 4-(2 -Hydroxy ethyl)- 1 -piperazineethanesulfonic acid (HEPES).
  • HEPES 4-(2 -Hydroxy ethyl)- 1 -piperazineethanesulfonic acid
  • composition of any one of embodiments A1-A3, wherein the intraliposomal buffer comprises an acetate, ascorbate, benzoate, diethanolamine, phosphate, succinate, tartrate or tromethamine buffering agent.
  • A8. The composition of embodiment A7, wherein the pH of the extraliposomal compartment is from about 6.2 to about 7.4.
  • composition of embodiment A7 or A8, wherein the buffering agent in the intraliposomal compartment is tri s(hydroxymethyl)aminom ethane (Tris).
  • composition of any one of embodiments A1-A9, wherein the lipid membrane comprises:
  • composition of embodiment A10 wherein at least one phospholipid having an ethanolamine head group and at least one unsaturated fatty acid tail is 1,2-dioleoyl-sn- glycero-3 -phosphoethanolamine (DOPE), or a salt thereof.
  • DOPE 1,2-dioleoyl-sn- glycero-3 -phosphoethanolamine
  • composition of embodiment A10 or Al l, wherein at least one phospholipid having a choline group and at least one unsaturated fatty acid tail is 1,2-dioleoyl-sn-glycero- 3 -phosphocholine (DOPC), or a salt thereof.
  • DOPC 1,2-dioleoyl-sn-glycero- 3 -phosphocholine
  • composition of any one of embodiments A10-A12, wherein at least one phospholipid having an ethanolamine head group and at least one saturated fatty acid tail is l,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), or a salt thereof.
  • DSPE l,2-distearoyl-sn-glycero-3-phosphoethanolamine
  • composition of any one of embodiments A10-A13, wherein the lipid membrane comprises DOPC, DOPE and DSPE conjugated to PEG.
  • composition of embodiment A14, wherein the lipid membrane comprises DOPC, DOPE and DSPE-PEG2000.
  • A17 The composition of any one of embodiments A1-A15, wherein the pH of the intraliposomal buffer does not change upon storage of the liposomal composition for up to 6 months at room temperature.
  • A25 The composition of any one of embodiments A1-A24, further comprising at least one radical scavenging antioxidant.
  • A26 The composition of embodiment A25, wherein at least one radical scavenging antioxidant is butylated hydroyanisole (BHA), butylated hydroxytoluene (BHT), or alpha tocopherol, or any combination thereof.
  • composition of embodiment A27 further comprises alpha tocopherol.
  • a method of treating a congenital disorder of glycosylation in a subject in need thereof comprising: administering to the subject a composition of any one of embodiments A1-A30.
  • A32 The method of embodiment A31, wherein the congenital disorder of glycosylation is CDG-Ia, CDG-Ib, CDG-Ie, CDG-Ig, CDG-Ii, CDG-Ik, CDG-Io, CDG-Ip, or DPM2-CDG.
  • A33 The method of embodiment A31 or A32, wherein the composition is administered intravenously.
  • a composition comprising liposomes having a lipid membrane enclosing an intraliposomal compartment, wherein the liposomes encapsulate in the intraliposomal compartment mannose- 1 -phosphate (M1P), and wherein the intraliposomal compartment comprises a buffering agent and optionally an acid or base, wherein the pH of the intraliposomal compartment is from about 6.0 to about 7.9.
  • M1P mannose- 1 -phosphate
  • composition of embodiment Bl, wherein the pH of the intraliposomal compartment is from about 6.2 to about 7.4.
  • composition of embodiment B 1 or B2, wherein the buffering agent in the intraliposomal compartment comprises tri s(hydroxymethyl)aminom ethane (Tris).
  • Tris tri s(hydroxymethyl)aminom ethane
  • B4 The composition of embodiment B 1 or B2, wherein the buffering agent in the intraliposomal compartment comprises 4-(2 -Hydroxy ethyl)- 1 -piperazineethanesulfonic acid (HEPES).
  • composition of embodiment B 1 or B2, wherein the buffering agent in the intraliposomal compartment comprises a histidine or citrate buffer.
  • composition of embodiment B 1 or B2, wherein the buffering agent in the intraliposomal compartment comprises an acetate, ascorbate, benzoate, diethanolamine, phosphate, succinate, tartrate, or tromethamine.
  • composition of embodiment B7, wherein the pH of the extraliposomal compartment is from about 6.2 to about 7.4.
  • Tris tri s(hydroxymethyl)aminom ethane
  • composition of any one of embodiments B 1 to B9, wherein the lipid membrane comprises:
  • PEG polyethylene glycol
  • B 11 The composition of embodiment BIO, wherein at least one phospholipid having an ethanolamine head group and at least one unsaturated fatty acid tail is 1,2-dioleoyl-sn- glycero-3 -phosphoethanolamine (DOPE), or a salt thereof.
  • DOPE 1,2-dioleoyl-sn- glycero-3 -phosphoethanolamine
  • composition of embodiment BIO or Bl 1, wherein at least one phospholipid having a choline group and at least one unsaturated fatty acid tail is 1,2-dioleoyl-sn-glycero- 3 -phosphocholine (DOPC), or a salt thereof.
  • DOPC 1,2-dioleoyl-sn-glycero- 3 -phosphocholine
  • composition of any one of embodiments BIO to Bl 2, wherein at least one phospholipid having an ethanolamine head group and at least one saturated fatty acid tail is l,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), or a salt thereof.
  • DSPE l,2-distearoyl-sn-glycero-3-phosphoethanolamine
  • composition of any one of embodiments BIO to B13, wherein the lipid membrane comprises DOPC, DOPE, and DSPE conjugated to PEG.
  • composition of embodiment Bl 4, wherein the lipid membrane comprises DOPC, DOPE, and DSPE-PEG2000.
  • Bl 7 The composition of any one of embodiments B 1 to Bl 5, wherein less than 10% of the intraliposomal M1P is released from the intraliposomal component of the liposomal composition following storage for up to 2 years at 5°C or at room temperature.
  • Bl 8. The composition of any one of embodiments B 1 to B17 wherein, over a period of time at temperatures between 5 °C and 40°C, the composition has a Z-average between 80 nm and 130 nm.
  • Bl 9 The composition of any one of embodiments B 1 to Bl 8, wherein, over a period of time at temperatures between 5°C and 40°C, the composition has a poly dispersity index of less than 0.2 or less than 0.1.
  • B20 The composition of any one of embodiments B 1 to Bl 9, wherein, over a period of time at temperatures between 5°C and 40°C, no free M1P is detected in the composition.
  • B21 The composition of any one of embodiments B 1 to B20, wherein, over a period of time at temperatures between 5 °C and 40°C, the composition has a mean osmolality within the range of 290 mOsm/kg to 320 mOsm/kg.
  • composition B22 The composition of any one of embodiments Bl to B21, wherein (a) the composition has an encapsulation efficiency between 5% and 50%; or (b) the percentage of encapsulated M1P is at least about 70%, or a combination of (i) and (ii).
  • a composition comprising liposomes having a lipid membrane enclosing an intraliposomal compartment, wherein the liposomes encapsulate in the intraliposomal compartment a mannose phosphate, and wherein the intraliposomal compartment comprises tri s(hydroxymethyl)aminom ethane (Tris), wherein the liposomes further comprise an extraliposomal component, wherein the extraliposomal component comprises Tris and saline, wherein the concentration of Tris in the intraliposomal compartment is higher than the concentration of Tris in the extraliposomal compartment.
  • Tris tri s(hydroxymethyl)aminom ethane
  • composition of embodiment B26, wherein the mannose phosphate is M1P.
  • composition of any one of embodiments B26 to B28, wherein the molar ratio of Tris in the intraliposomal compartment to extraliposomal compartment is between about 6: 1 and 2 : 1.
  • B30 The composition of any one of embodiments B26 to B29, wherein the saline present in the extraliposomal component is at least about 125 mM.
  • a method of treating a congenital disorder of glycosylation in a subject in need thereof comprising: administering to the subject a composition of any one of embodiments Bl to B30.
  • Saline Formulation 1-A is a liposomal M1P formulation prepared in 0.9% (w/v) NaCl. Based on stability studies, lipid degradation due to hydrolysis and/or oxidation was observed. To optimize the formulation to stabilize the lipids, a formulation development study was performed leading to the development of Formulation 1.
  • Tris Formulation l is a liposomal M1P formulation optimized for treatment of phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG).
  • PMM2-CDG phosphomannomutase 2-congenital disorder of glycosylation
  • the lipid excipients which make the liposomes are DOPC, DOPE, and DSPE- PEG2000. Table 1 summarizes the formulations were tested.
  • the liposomal formulations were tested under the following stability conditions: accelerated (25°C), long-term (5°C) and stress (40°C), at initial concentrations, 0.5 months, 1 month, and 3 months.
  • the upper threshold of total impurity was set to 4%.
  • Saline Formulation 1-A sample exceeded the set threshold at 25°C and 40°C.
  • Formulation 5 and Formulation 6 samples exceeded the set threshold at 40°C. The rest of the samples did not exceed the threshold.
  • FIGS. 5A-5C The horizontal lines in FIG. 5A indicates the upper and lower limit of z-average based on the target specifications of Formulation 1-A.
  • the lines in FIG. 5C represent population over 200 nm vs time.
  • IVR in-vitro release
  • the osmolality of samples is shown in FIG. 7.
  • the horizontal lines indicate the upper and lower limit of osmolality (“USL” and “LSL”) based on the target specifications (horizontal “Target” line) of Formulation 1-A.
  • Tris Formulation 1 displays improved long-term stability over Saline Formulation 1-A in terms of stabilization of pH, potential particle distribution/agglomeration and leakage of M1P out of the liposomes. Hence, Tris Formulation 1 was chosen as the drug product for further clinical development. The components of the drug product assessed in long-term stability assays are listed in Table 2.
  • the resultant formulations were subjected to long-term stability studies in which vials containing the compositions were stored inverted at various temperatures.
  • the pH, osmolality, particle size, and encapsulation % (M1P) were evaluated for each formulation. pH and Osmolality were evaluated based on known protocols, such as USP ⁇ 791> and USP ⁇ 975> respectively.
  • Encapsulation % (M1P) was evaluated by a liquid chromatography- charged aerosol detection (HPLC-CAD) method.
  • Particle size was determined by dynamic light scattering using an intensity weighted distribution calculation.
  • Saline Formulation 1-A was evaluated at 5°C at 1 month, 3 months, 6 months, 12 months, 18 months, and 24 months; at 25°C/60% RH (relative humidity) at 1 month, 3 months, and 6 months; and at 40°C/75% RH at 1 month.
  • the pH decreased from 7.4 at initial to 7.1 and 7.0 respectively at the final timepoints.
  • the % encapsulation decreased from >95% to 92% and 90% respectively.
  • Formulation Z showed that lipid impurities remained at ⁇ 0.1% after 6 months at 5°C, and showed an increase in lipid impurities from 0% at initial release to only 1.78% after 6 months at 25°C.
  • a comparable formulation containing BHT at 20 pg/mL showed an increase in lipid impurities from 0% at initial release to 1.99% after 6 months at 25°C.
  • the degree of lipid degradation was measured utilizing HPLC-CAD and is reported as % chromatographic area. The lipid method was demonstrated to meet the levels of accuracy and precision required of a development study.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dispersion Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

La divulgation concerne des thérapies de remplacement de glucides phosphorylées (CRT) qui comprennent des compositions de glucides phosphorylés, tels que le mannose-1-phosphate (M1P), et des phospholipides, ainsi que des procédés de préparation de telles compositions. De telles compositions sont appropriées pour une administration pharmaceutique de glucides phosphorylés, tels que M1P, pour traiter des maladies CDG de type I et de type II ainsi que d'autres troubles métaboliques.
PCT/US2025/017681 2024-02-29 2025-02-27 Formulations liposomales et leurs procédés d'utilisation et de préparation Pending WO2025184398A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463559841P 2024-02-29 2024-02-29
US63/559,841 2024-02-29

Publications (1)

Publication Number Publication Date
WO2025184398A1 true WO2025184398A1 (fr) 2025-09-04

Family

ID=96921996

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/017681 Pending WO2025184398A1 (fr) 2024-02-29 2025-02-27 Formulations liposomales et leurs procédés d'utilisation et de préparation

Country Status (1)

Country Link
WO (1) WO2025184398A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030124181A1 (en) * 2001-11-13 2003-07-03 Paul Tardi Lipid carrier compositions with enhanced blood stability
US20220184107A1 (en) * 2019-03-29 2022-06-16 Glycomine, Inc. Liposomal formulations, and methods of using and preparing thereof
WO2023225102A1 (fr) * 2022-05-18 2023-11-23 Glycomine, Inc. Procédés d'écoulement continu pour produire du mannose-1-phosphate, des polymorphes de mannose-1-phosphate, et compositions et utilisations associées

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030124181A1 (en) * 2001-11-13 2003-07-03 Paul Tardi Lipid carrier compositions with enhanced blood stability
US20220184107A1 (en) * 2019-03-29 2022-06-16 Glycomine, Inc. Liposomal formulations, and methods of using and preparing thereof
WO2023225102A1 (fr) * 2022-05-18 2023-11-23 Glycomine, Inc. Procédés d'écoulement continu pour produire du mannose-1-phosphate, des polymorphes de mannose-1-phosphate, et compositions et utilisations associées

Similar Documents

Publication Publication Date Title
US20230172868A1 (en) Lipid-based nanoparticles with enhanced stability
US20250186345A1 (en) Pharmaceutical preparation of carbohydrates for therapeutic use
US20240108585A1 (en) Compositions comprising lipid-based nanoparticles for treating diabetes mellitus
JP2023550203A (ja) 新生児における使用に好適な組成物
US20250170218A1 (en) Stable pharmaceutical composition of receptor agonist, and preparation method and application thereof
JP2024174107A (ja) インスリンプレミックスの配合物と製品、それを調製する方法、及びそれを使用する方法
WO2017147193A1 (fr) Traitement de troubles du cycle de l'urée chez les nouveau-nés et les nourrissons
WO2025184398A1 (fr) Formulations liposomales et leurs procédés d'utilisation et de préparation
AU2020252005B2 (en) Liposomal formulations, and methods of using and preparing thereof
EP3261648B1 (fr) Formulations d'insuline liquides et procédés s'y rapportant
JP2012107023A (ja) 治療用栄養組成物又は組合せ、及びそれらの使用方法
TW202543582A (zh) 脂質體調配物及其使用及製備方法
WO2025184395A1 (fr) Méthodes de traitement de troubles congénitaux de glycosylation (cdg) et d'ataxie chez les sujets souffrant de cdg
US20110097363A1 (en) Therapeutically Effective Preparations of Insulin

Legal Events

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

Ref document number: 25762633

Country of ref document: EP

Kind code of ref document: A1