WO2011139343A2 - Conjugués peg-lipide reliés à un acide aminé - Google Patents

Conjugués peg-lipide reliés à un acide aminé Download PDF

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WO2011139343A2
WO2011139343A2 PCT/US2011/000745 US2011000745W WO2011139343A2 WO 2011139343 A2 WO2011139343 A2 WO 2011139343A2 US 2011000745 W US2011000745 W US 2011000745W WO 2011139343 A2 WO2011139343 A2 WO 2011139343A2
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peg
acid
compound
lipid
drug
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PCT/US2011/000745
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WO2011139343A3 (fr
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Nian WU
Brian Charles Keller
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Wu Nian
Brian Charles Keller
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Priority claimed from US12/802,197 external-priority patent/US20110040113A1/en
Application filed by Wu Nian, Brian Charles Keller filed Critical Wu Nian
Publication of WO2011139343A2 publication Critical patent/WO2011139343A2/fr
Publication of WO2011139343A3 publication Critical patent/WO2011139343A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/49—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/10—General cosmetic use

Definitions

  • the present invention relates to polyethyleneglycol (PEG)-amino acid-lipid conjugates and to convenient synthetic methods and compositions for preparing such conjugates. More particularly, the present invention relates to new PEG-amino acid-lipid conjugates and their use for drug delivery, cosmetics and other purposes.
  • PEG polyethyleneglycol
  • PEG-lipid conjugates When used as a drug delivery vehicle, PEG-lipid conjugates have the capacity to improve the pharmacology profile and solubility of lipophilic drugs. They also provide other potential advantages such as minimizing side effects and toxicities associated with therapeutic treatments.
  • Simple PEG-lipid conjugates include PEG chains directly linked to lipids. Glycerol backbones are often employed to produce PEG-lipid conjugates for particular purposes.
  • diacyl glycerol PEGs (DAG-PEGs) are used for delivery of bioactive compounds via topical, oral and IV administration. DAG-PEGs may also be used for cleaning up oil spills, among other uses. DAG-PEGs may be used by themselves or in conjunction with other compounds to create microstructures such as liposomes, which have a variety of uses.
  • Distearyl phosphatidylethanolamine PEG may be used in preparation of liposomes for IV use.
  • the wide range of possible structure of PEG-lipid conjugates available provides the potential for a broad range of applications. However, there is a continuing need for additional PEG-lipid conjugates to address problems in many technology areas.
  • L-AA-PEG New lipid-amino acid-polyethylene glycol conjugates are described. Amino acids are used as a backbone to conjugate lipids and PEG chains. L-AA-PEGs may be selected to optimize formulations of pharmaceuticals and cosmetics, among other uses.
  • DAG-PEGs diacylglycerol- polyethyleneglycols
  • DAA-PEGs diacylamino acid- polyethyleneglycols
  • DSA-PEGs disteroidamino acid- polyethyleneglycols
  • DOS- 12 dioleoyl-rac-serinyl-dodecaethylene glycol
  • Embodiments of the present invention are described herein in the context of lipid- amino acid-PEG (L-AA-PEG) conjugates for liposomes and drug delivery, among other uses.
  • L-AA-PEG lipid- amino acid-PEG
  • Those of ordinary skill in the art will realize that the following detailed description of the present invention is illustrative only and is not intended to be in any way limiting. Other embodiments of the present invention will readily suggest themselves to such skilled persons having the benefit of this disclosure. Reference will now be made in detail to
  • the compounds of the invention comprise an amino acid backbone and three side groups.
  • Lipid-amino acid-PEG compounds of the present invention comprise two basic forms.
  • the first form has two lipid groups and one PEG chain. When the lipids are acyl chains, this form is somewhat similar to a DAG-PEG.
  • the first form is shown in Chemical Structure 1.
  • PEG is a polyethyleneglycol chain having between 6 and 45 subunits; Ri preferably has a molecular weight of less than about 215; R 2 and R 3 are lipids; and AA represents an amino acid backbone.
  • the second form comprises one lipid group and two PEG chains, as shown in Chemical Structure 2.
  • PEG represents polyethyleneglycol chains each having between 6 and 45 subunits; R] and R2 preferably each have a molecular weight of less than about 215; R 3 is a lipid; and AA represents an amino acid backbone.
  • amino acids must have at least three reactive groups.
  • Workable amino acids include arginine, aspartic acid, glutamic acid, asparagine, cysteine, histidine, lysine, glutamine, ornithine, tryptophan, tyrosine, serine, threonine, as well as certain synthetic amino acids.
  • aminio acids with exactly three reactive groups are preferable.
  • those without heterocyclic rings or reactive sulfur groups are preferable. Therefore, the most preferable amino acid backbones are aspartic acid, glutamic acid, asparagine, glutamine, ornithine, serine, lysine and threonine.
  • Such moieties preferably have a molecular weight of less than 215, and more preferably a molecular weight of less than 45.
  • Rj may be a functional group that facilitates linking therapeutic or targeting agents to the surface of lipid vesicle aggregates.
  • Amino acids amino alkyl esters, maleimide, diglycidyl ether, maleinimido propionate, methylcarbamate, tosylhydrazone salts, azide, propargyl-amine, propargyl alcohol, NHS esters (e.g., propargyl NHS ester, sulfo-NHS-LC-biotin, or NHS carbonate), hydrazide, succinimidyl ester, succinimidyl tartrate, succinimidyl succinate, and
  • Linked therapeutic and targeting agents may include Fab fragments, cell surface binding agents, and the like.
  • Rl may include functional cell-targeting ligands such as folate, transferrin and molecules such as monoclonal antibodies, ligands for cellular receptors or specific peptide sequences can be attached to the liposomal surface to provide specific binding sites.
  • Rl can include either negatively or positively charged head-groups such as decanolamine, octadecylolamine, octanolamine, butanolamine, dodecanolamine, hexanolamine, tetradecanolamine, hexadecanolamine, oleylamine, decanoltrimethylaminium, octadecyloltrimethylaminium, octanoltrimethylaminium, butanoltrimethylaminium, dodecanoltrimethylaminium, hexanoltrimethylaminium, tetradecanoltrimethylaminium, hexadecanoltrimethylaminium, oleyltrimethylaminium, for example.
  • head-groups such as decanolamine, octadecylolamine, octanolamine, butanolamine, dodecanolamine, hex
  • Presently preferred compounds of the invention have chemically inert terminal groups with a MW of less than 215, as initial applications are expected to be primarily in the formulation of active drug compounds.
  • the invention can be practiced using a wide variety of fatty acids (acyl chains).
  • Table 1 lists some saturated lipids for use in the invention.
  • Table 2 lists some unsaturated lipids for use in the invention.
  • Suitable lipids for synthesis of PEG-lipid conjugates include bile acids (steroid acids) as well as alkyl chains. Therefore, the present invention includes a variety of PEG- AA-lipid conjugates and the steroid acid-AA-PEG conjugates can be incorporated into liposomes as a targeting moiety for lipid-based drug delivery to specific cells or as self-emulsifying drug delivery systems (SEDDS).
  • Bile acids (steroid acids) constitute a large family of molecules, composed of a steroid structure with four rings, a five or eight carbon side-chain terminating in a carboxylic acid, and the presence and orientation of different numbers of hydroxyl groups.
  • the four rings are labeled from left to right A, B, C, and D, with the D-ring being smaller by one carbon than the other three.
  • An exemplary bile acid is shown in Chemical Structure 3. All bile acids have side chains. When subtending a carboxyl group that can be amide-linked with taurine or glycine, the nuclear hydroxyl groups can be esterified with glucuronide or sulfate which are essential for the formation of water soluble bile salts from bile alcohols.
  • Ri and R 2 may be hydroxyl or proton
  • lipid-PEG conjugates of the present invention may be used for many applications. Formulation and delivery of pharmaceutical and cosmetic agents have been described.
  • conjugates of the present invention may be used in other contexts where water soluble lipids are advantages, for example industrial and/or cleaning processes.
  • Embodiments of the present invention are described herein in the context of preparation of pharmaceutical compositions including purified PEG-lipid conjugates for increasing the solubility and enhancing the delivery of active agents, among other uses.
  • the approximate preferable compositions for formulated drug products are generally described herein, though different drugs typically have differing optimal formulations.
  • the preferable concentration of drug is 0.1% to 30%. More preferable is 0.5 to 10%. Most preferable is 0.5 to 5%.
  • the preferable weight ratio of conjugate to the drug (conjugate/drug) is 1 to 20. More preferable is 1 to 10. Most preferable is 1 to 5.
  • the preferable concentration of drug is 1% to 40%. More preferable is 2.5 to 30%. Most preferable is 5 to 30%.
  • the preferable ratio of conjugate to the drug (conjugate/drug) is 0.5 to 20. More preferable is 1 to 5. Most preferable is 1 to 3.
  • the preferable concentration of drug is 0.01 to 5%. More preferable is 0.05 to 2%. Most preferable is 0.1 to 2%.
  • the preferable ratio of conjugate to the drug (conjugate/drug) is 1 to 20. More preferable is 3 to 15. Most preferable is 5 to 10.
  • the preferable concentration of drug is 0.05 to 5%. More preferable is 0.1 to 5%. Most preferable is 0.1 to 2%.
  • the preferable ratio of conjugate to the drug (conjugate/drug) is 1 to 20. More preferable is 3 to 15. Most preferable is 5 to 10.
  • the preferable capsule content of drug is 10 mg to 250 mg. More preferable is 25 mg to 200 mg. Most preferable is 25 mg to 100 mg.
  • the preferable ratio of conjugate to the drug (conjugate/drug) is 1 to 10. More preferable is 1 to 5. Most preferable is 2 to 5.
  • the preferable concentration of drug is 0.05 to 5%. More preferable is 0.1 to 5%. Most preferable is 0.5 to 2%.
  • the preferable ratio of conjugate to the drug (conjugate/drug) is 1 to 50. More preferable is 3 to 20. Most preferable is 5 to 10.
  • the invention is a compound represented by the formula
  • PEG is a polyethyleneglycol chain having between 6 and 45 subunits, where R] has a molecular weight of less than about 215; where R 2 and R 3 are lipids; and where AA represents an amino acid backbone.
  • AA is preferably a single amino acid having three reactive groups.
  • AA may be selected from the group comprising aspartic acid, glutamic acid, asparagine, glutamine, ornithine, serine, lysine and threonine.
  • R2 and R3 may be alkyl (acyl) groups having between 6 and 22 carbons.
  • R 2 and R 3 may be each selected from the group consisting of oleate, myristate, linoleate and palmitate.
  • R2 and R3 may be bile acids.
  • R2 and R3 may preferably be selected from the group comprising cholic acid, desoxycholic acid, dehydrocholic acid, glycochenodeoxycholic acid.
  • R may have a molecular weight of less than about 45.
  • Ri may be either -OH or -OCH 3 .
  • the PEG chain may consist of between about 8 and 23 subunits.
  • the PEG chain may consist of between about 12 and 23 subunits.
  • the PEG chain may be monodisperse.
  • the PEG chain may be branched.
  • the invention is a compound represented by the formula
  • PEG represents polyethyleneglycol chains each having between 6 and 45 subunits; Rj and R2 each have a molecular weight of less than about 215; R 3 is a lipid; and AA represents an amino acid backbone.
  • AA may be a single amino acid having three reactive groups. AA may be selected from the group comprising aspartic acid, glutamic acid, asparagine, glutamine, ornithine, serine, lysine and threonine.
  • R3 may be an alkyl groups having between 6 and 22 carbons. R 3 may be selected from the group consisting of oleate, myristate, linoleate and palmitate.
  • R3 may be a bile acid.
  • R3 may be selected from the group comprising cholic acid, desoxycholic acid, dehydrocholic acid, and
  • Ri and R2 may each have a molecular weight of less than about 45.
  • Rj and R2 may each be either -OH or -OCH 3 .
  • the PEG chains may consist of between about 8 and 23 subunits.
  • the PEG chains may more preferably consist of between about 12 and 23 subunits.
  • the PEG chains may be monodisperse.
  • the PEG chain may be branched.
  • the invention comprises a method of solubilizing a water-insoluble agent, i.e., a drug compound that, because of low solubility in water, typically requires formulation with a pharmaceutically acceptable carrier for effective delivery to an intended site of action.
  • a water-insoluble agent i.e., a drug compound that, because of low solubility in water, typically requires formulation with a pharmaceutically acceptable carrier for effective delivery to an intended site of action.
  • the invention comprises selecting a relatively water insoluble drug, selecting a conjugate of the present invention, and combining the drug and the conjugate to form an effective drug delivery formulation.
  • Such delivery may be intravenous, oral, topical, subdermal, sublingual, or any other mode of drug delivery.
  • the invention also includes compositions for such delivery. Both the methods and the compositions related to delivery of water-insoluble agents employ the PEG-lipid conjugates of the present invention and the methods and materials described herein.
  • N, N'-dicyclohexylurea, N, N'-dicyclohexylcarbodiimide, DL 1,2 -rac-dioleoylglycerol, and other chemicals were obtained from Sigma- Aldrich (St. Louis, MO, USA). Bulk quantity of DL 1,2 -rac-dioleoylglycerol was supplied by WuXi LipoTech, Ltd (WuXi, China).
  • Example 1 Preparation of tert-Butyl Carbamates (Boc)-Protected Amino Groups A high yield and effective synthetic method under a catalyst-free and room temperature was reported previously [S. V. Chankeshwara, A. K. Chakraborti, Org. Lett., 8 (2006) 3259] and used with slightly modification. To a solution of starting compound containing amino group in MeOH, di-t-butyl dicarbonate was added as one to one molar ratio. The resulting mixture was stirred overnight at room temperature.
  • Effective reagents for the deprotection of tert-butyl carbamates or tert-butyl esters include phosphoric acid and tnfluoroacetic acid. The reactions give high yields and very convenient [B. Li, M. Hopkins, etc, J. Org. Chem., 71 (2006) 9045]. Equal volumes of Tnfluoroacetic acid was added to a solution of Boc-carbamate (1% of crude product) in CH 2 C1 2 . The resulting solution was stined at room temperature for overnight and the solvent was evaporated and the residue was re-dissolved into CH 2 C1 2 , then washed with saturated
  • Active oleoyl intermediate is prepared by dissolving 0.1 moles of oleic acid in
  • DL-dioleoylglycerol (0.0 5 mol) was dissolved in 25 mL of dry (molecular sieve) dioxane and warm up in a water batch until the solution was clear then cooled down to room temperatyure.
  • N-N'-disuccinimidyl carbonate (0.5 mol in 100 mL acetone) was added.
  • 0.5 mol of 4-(dimethylamino)pyridine was added dropwise under a constant stirring. The resulting mixture was stirred for 6 hours. When the reaction was complete, the solution was evaporated to afford a sticky colorless liquid (Chemical Structure 8) and was used in next step without further purification.
  • glycinylmonomethoxyldodecaethylene glycol (0.01 moles, 20 mL) and stirred for about 4 hours.
  • An assay is performed to verify the yield and then the solution is added to ether to precipitate the crude product, which is filtered and washed with 50 mL of a mixture of ether and ethyl acetate mixture (v/v, 3/1), and extracted with water (30 mL) three times.
  • the combined aqueous phase was further extracted with ethyl acetate (30mL) three times.
  • the combined ethyl acetate phases were dried over Na 2 S04 and yielded pale yellowish oil ( ⁇ 65%, Chemical Structure 9).
  • the purity (> 95%) was determined by 1H NMR and HPLC- MS.
  • the mobile phase consisted of a water and acetonitrile mixture (v/v, 20/80) with a flow rate of 1.0 mL/min.
  • the Rapamycin peak was monitored at 220 nm and quantitated using external standard sets of Rapamycin.
  • the drug loading capacity (%DLC) was then calculated from the following equation and the calculated results are summarized in Table 5.
  • C is the concentration measured and W is the sample concentration based on the weight of rapamycin added.
  • Example 10 Values of Hydrophilic-lipophilic Balance
  • Hydrophilic-lipophilic Balance is commonly used as a semi-quantitive tool for predicting the drug solubility with a PEG-lipid, which can be calculated by the following equation [Griffin WC, Journal of the Society of Cosmetic Chemists 5 (1954) 259]:
  • Mw h is the molecular mass of the hydrophilic portion of the Molecule
  • MWT is the molecular mass of the whole molecule with a giving arbitrary scale of 0 to 20. While a HLB value of 0 corresponds to a completely hydrophobic molecule, a value of 20 represents a hydrophilic molecule.
  • a preferable PEG-lipid conjugate should have a HLB value in the range of 8 to 14, most preferable 9 to 12.
  • Example 11 Solid Dose Compositions
  • a liquid PEG-lipid conjugate is added to a stainless steel vessel equipped with propeller type mixing blades.
  • the drug substance is added with constant mixing. Mixing continues until the drug is visually dispersed in the lipids at a temperature to 55° - 65 °C.
  • a PEG-lipid conjugate with a melting temperature above about 30 degrees C is melted with heating or dissolved in ethanol and added to the vessel with mixing. Mixing continues until fully a homogenous solution is achieved. If necessary, ethanol is removed by vacuum.
  • the solution is filled into capsule shells or predesigned packaging configurations (molds) when the solution is warm. Filled capsules or molds are placed under refrigeration (2-8 °C) until the cream-like mixture is solidified when cooled.
  • a sample formulation is described in Table 7.
  • the liquid conjugate may be selected from DAA-PEG or DS A-PEG including SG- bisPEG-12, SG-AA-bisPEG-12, GDOG-12 or DOS- 2 or GDOG-12.
  • the solid lipid conjugate may be GDO-23, GDO-27, GDM-23, GDM-27, or GDS-23.
  • the drug may be modafinil or nifedapine or esomeprazole or rapamycin or triazole or another active agent.
  • a liquid PEG lipid conjugate (having a melting point below about 15 degrees C) was added to a stainless steel vessel equipped with propeller type mixing blades. The drug substance was added with constant mixing. Mixing continued until the drug was visually dispersed in the lipids at a temperature to 55° - 65 °C.
  • TPGS-VE was dissolved in ethanol and added to the vessel with mixing. Mixing continued until fully a homogenous solution was achieved. Ethanol was be removed by vacuum. The solution was filled into capsule shells or predesigned packaging configuration (molds) when the solution was warm. The filled capsules or molds were placed under refrigeration (2-8 °C). The cream-like mixture was solidified when cooled.
  • a sample formulation is described in Table 8.
  • the liquid conjugate may be DAA-PEG or DAG-AA-PEG or DSG-PEG or DSA- PEG including SG-bisPEG-12, SG-AA-bisPEG-12, GDOG-12 or DOS- 12 or GDOG-12.
  • the drug may be modafinil or nifedapine or esomeprazole or rapamycin or another active agent.
  • Example 13 Oral Solution Compositions
  • PEG-lipid was added to a vessel equipped with a mixer propeller.
  • the drug substance was added with constant mixing. Mixing continued until the drug was visually dispersed in the lipids. Pre-dissolved excipients were slowly added to the vessel with adequate mixing. Mixing continued until fully a homogenous solution was achieved.
  • a sample formulation is described in Table 9.
  • the lipid may be DAA-PEG or DAG-AA-PEG or DSG-PEG or DSA-PEG including SG-bisPEG-12, SG-AA-bisPEG-12, GDOG-12 or DOS-12 or GDOG-12 or any combination thereof.
  • Sodium hydroxide is used to prepare a 10% w/w solution in purified water.
  • the targeted pH is in a range of 4.0 to 7.0.
  • NaOH is used to adjust pH if necessary.
  • the drug may be modafinil or nifedapine or esomeprazole or rapamycin or another active agent.
  • PEG-lipid was added to a vessel equipped with a mixer propeller.
  • the cyclosporine drug substance was added with constant mixing. Mixing continued until the drug was visually dispersed in the lipids. Pre-dissolved excipients and sterile purified water were slowly added to the vessel with adequate mixing. Mixing continued until fully a
  • the lipid may be DAA-PEG or DAG-AA-PEG or DSG-PEG or DSA-PEG including SG-bisPEG-12, SG-AA-bisPEG-12, GDOG-12 or DOS-12 or GDOG-12 or any combination thereof.
  • Sodium hydroxide is used to prepare a 10% w/w solution in purified water.
  • the targeted pH is in a range of 6.0 to 7.4.
  • NaOH is used to adjust pH if necessary.
  • Example 15 Injection Solution Compositions
  • the injectable solution was prepared as in Example 13, except that the targeted pH range was between 6.0 and 8.0.
  • a sample formulation is described in Table 11.
  • the lipid may be DAA-PEG or DAG-AA-PEG or DSG-PEG or DSA-PEG including SG-bisPEG-12, SG-AA-bisPEG-12, GDOG-12 or DOS-12 or GDOG-12 or any combination thereof.
  • Sodium hydroxide is used to prepare a 10% w/w solution in purified water.
  • the targeted pH is in a range of 6.5 to 7.4.
  • NaOH is used to adjust pH if necessary.
  • the drug may be modafinil or nifedapine or esomeprazole or rapamycin or another active agent.
  • PEG lipid was added to a stainless steel vessel equipped with propeller type mixing blades.
  • the drug substance was added with constant mixing. Mixing continued until the drug was visually dispersed in the lipids at a temperature to 60° - 65 °C.
  • Organic acid, Cholesterol and glycerin were added with mixing. Ethanol and ethyoxydiglycol were added with mixing. Finally Carbopol ETD 2020, purified water and triethyJamine were added with mixing. Mixing continued until fully a homogenous cream was achieved.
  • the formulation is described in Table 12.
  • the lipid may be DAA-PEG or DAG-AA-PEG or DSG-PEG or DSA-PEG including SG-bisPEG-12, SG-AA-bisPEG-12, GDOG-12 or DOS-12 or GDOG-12 or any combination thereof.
  • Organic acid may be lactic acid or pyruvic acid or glycolic acid.
  • Sodium hydroxide is used to adjust pH if necessary. The targeted pH range was between 3.5 and 7.0.
  • the drug may be itraconazole, posaconazole, voriconazole or equaconazole, Terbinafine , Amorolfine, Naftifine, Butenafine, Benzoic acid, Ciclopirox, Tolnaftate, Undecylenic acid, Flucytosine , Griseofulvin , Haloprogin, Sodium bicarbonate or Fluocinolone acetonide.
  • Example 17 Topical Solution Composition
  • the lipid may be DAA-PEG or DAG-AA-PEG or DSG-PEG or DSA-PEG including SG-bisPEG-12, SG-AA-bisPEG-12, GDOG-12 or DOS- 12 or GDOG-12 or any combination thereof.
  • Organic acid may be lactic acid or pyruvic acid or glycolic acid.
  • Sodium hydroxide is used to adjust pH if necessary. The targeted pH range was between 3.5 and 7.0.
  • the drug may be itraconazole, posaconazole, voriconazole or equaconazole, Terbinafine , Amorolfine, Naftifine, Butenafine, Benzoic acid, Ciclopirox, Tolnaftate, Undecylenic acid, Flucytosine , Griseofulvin , Haloprogin, Sodium bicarbonate or Fluocinolone acetonide.
  • PEG-lipid was added to a vessel equipped with a mixer propeller.
  • the azithromycin drug substance was added with constant mixing. Mixing continued until the drug was visually dispersed in the lipids. Pre-dissolved excipients and sterile purified water were slowly added to the vessel with adequate mixing. Mixing continued until fully a
  • the lipid may be DAA-PEG or DAG-AA-PEG or DSG-PEG or DSA-PEG including SG-bisPEG-12, SG-AA-bisPEG-12, GDOG-12 or DOS- 12 or GDOG-12 or any combination thereof.
  • Sodium hydroxide is used to prepare a 10% w/w solution in purified water.
  • the targeted pH is in a range of 7.0 to 7.8.
  • NaOH is used to adjust pH if necessary.
  • the active may be azithromycin or itraconazole or posaconazole or voriconazole or another active agent.
  • Preferable concentration of active is 0.5 to 3%, more preferable is 0.5 to 2%, most preferable is 1 to 2%.
  • the preferable ratio of PEG-lipid to the drug (PEG-Lipid/drug) is 1 to 20, more preferable is 3 to 15, most preferable is 5 to 10.

Abstract

L'invention concerne de nouveaux conjugués lipide-acide aminé-polyéthylène glycol (L-AA-PEG). Les acides aminés sont utilisés en tant que squelette pour conjuguer des lipides et des chaînes PEG. Les L-AA-PEG peuvent être choisis pour optimiser des formulations de produits pharmaceutiques et cosmétiques, entre autres utilisations.
PCT/US2011/000745 2010-04-28 2011-04-28 Conjugués peg-lipide reliés à un acide aminé WO2011139343A2 (fr)

Applications Claiming Priority (4)

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US34339610P 2010-04-28 2010-04-28
US61/343,396 2010-04-28
US12/802,197 US20110040113A1 (en) 2009-06-02 2010-06-01 Pure PEG-lipid conjugates
US12/802,197 2010-06-01

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WO2011139343A3 WO2011139343A3 (fr) 2012-04-05

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US20130183236A1 (en) * 2011-11-30 2013-07-18 Mallinckrodt Inc. Mmp-targeted therapeutic and/or diagnostic nanocarriers
US8871189B2 (en) * 2011-11-30 2014-10-28 Mallinckrodt Llc MMP-targeted therapeutic and/or diagnostic nanocarriers
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CN112110834A (zh) * 2019-06-19 2020-12-22 浙江智达药业有限公司 一种改性疏水辅料及其制备方法及其应用
CN112110834B (zh) * 2019-06-19 2022-10-21 浙江智达药业有限公司 一种改性疏水辅料及其制备方法及其应用

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