+

WO2009088959A1 - Délivrance améliorée d'agents antifongiques - Google Patents

Délivrance améliorée d'agents antifongiques Download PDF

Info

Publication number
WO2009088959A1
WO2009088959A1 PCT/US2009/000003 US2009000003W WO2009088959A1 WO 2009088959 A1 WO2009088959 A1 WO 2009088959A1 US 2009000003 W US2009000003 W US 2009000003W WO 2009088959 A1 WO2009088959 A1 WO 2009088959A1
Authority
WO
WIPO (PCT)
Prior art keywords
peg
drug
lipid
composition
dag
Prior art date
Application number
PCT/US2009/000003
Other languages
English (en)
Inventor
Brian Charles Keller
Nian WU
Original Assignee
Brian Charles Keller
Wu Nian
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
Priority claimed from US12/006,820 external-priority patent/US20090176795A1/en
Application filed by Brian Charles Keller, Wu Nian filed Critical Brian Charles Keller
Priority to JP2010541549A priority Critical patent/JP2011508780A/ja
Priority to EP09701160A priority patent/EP2240161A1/fr
Publication of WO2009088959A1 publication Critical patent/WO2009088959A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • This invention relates to drug delivery, particularly to delivery of tetrahydrofuran antifungal agents by microencapsulation and liposomal formulation.
  • Tetrahydrofuran antibiotics are widely used as antifungal agents. They include the drug ketoconazole and are described in United States patent 5,039,676. Newer tetrahydrofurans have been developed that are more effective and less toxic than ketoconazole. They are described in United States patent 5,661,151. The newer tetrahydrofurans include posaconazole and itraconazole.
  • Tetrahydroftiran antibiotics formulated with certain diacylglycerol- polytethyleneglycol (DAG-PEG) lipids have increased water solubility and bioavailabilty.
  • DAG-PEG diacylglycerol- polytethyleneglycol
  • PEG-12 GDO, PEG-12 GDLO, PEG-12 GDP and PEG-12 GDM are particularly suitable for forming liposomes that incorporate tetrahydrofurans in the bi layer.
  • Figure 1 shows comparison between blood concentrations of various posaconazole formulations administered intravenously.
  • Figure 2 shows a comparison between blood concentrations of a commercial posaconazole product and a DAG-PEG formulation of posaconazole administered orally.
  • Figure 3 shows a comparison between a DAG-PEG lipid formulation of itraconazole and an aqueous solution of itraconazole containing 5% of dimethyl sulfoxide and 10% of Cremophor after IV administration.
  • Figure 4 shows a comparison between oral administrations of DAG-PEG lipid formulation of itraconazole and an aqueous solution of itraconazole containing 5% of dimethyl sulfoxide and 10% of Cremophor.
  • DAG-PEG Diacylglycerol-polyethyleneglycol
  • acyl and polyethylene glycol chains may be attached to the backbone by a variety of chemical linkages, including but not limited to, ester and ether bonds. Linkers may be provided between the backbone and the chains. The chains may be attached at any position of the backbone.
  • United States Patent 6,610,322 which is hereby incorporated by reference, teaches the spontaneous formation of liposomes when certain lipids are added to aqueous solutions. Table 1 shows lipids described in that patent.
  • GDL refers to glycerol dilaurate having a 23 subunit PEG chain.
  • GDO refers to glycerol dioleates.
  • GDM refers to glycerol dimyristates, GDP refers to glycerol dipalmitates and GDS refers to glycerol distearates.
  • Table 1 includes two lipids that were not described in particular in United States Patent 6,610,322.
  • PEG-12 GDLO refers to glycerol dilinoleate having a 12 subunit PEG chain.
  • PEG-12 GDP refers to glycerol dipalmitate having a 12 subunit PEG chain.
  • PEG-12 GDP is semisolid at 25 degrees C, indicating that most of the molecules are in the disordered liquid crystalline phase and not in the ordered gel phase. Also, PEG-12 GDP readily mixes with water and forms lipsomes at 25 degrees C Therefore, for the purposes of this patent PEG-12 GDP is considered to have a melting temperature below about 25 degrees C.
  • Lipid packing parameters determine whether a lipid or combination of lipids are capable of forming liposomes. Because liposomes include one or more curved lipid bilayers, spacial configurations of individual lipid molecules must be such to allow the lipids to pack together correctly in order for liposomes to form. If the hydrophilic head groups are too large in relation to the volume of the lipophilic tails, the radius of curvature will be too small to encapsulate an aqueous space and micelles will form. If the hydrophilic head groups are too small in relation to the volume of the lipophilic tails, the radius of curvature will be too large to allow the bilayer to close back upon itself and form a sphere.
  • Liposome forming DAG-PEG lipids are preferred for drug delivery because they form particles of uniform size. When used for delivery of lipophilic drugs, as in the
  • - 7 - present invention they provide a maximum of uniform lipophilic environment for the drug to partition into. Because the liposomes from a stable suspension in aqueous environments, they allow for increased bioavailability and improved pharmacokinetics of such drugs.
  • DAG-PEG lipids with favorable packing parameters spontaneously form liposomes in aqueous environments above the melting temperature of the lipids. For example, with a melting point of 31.2 degrees C, PEG-23 GDP does not spontaneously form liposomes at room temperature. However, at temperatures above 31.2 degrees PEG-23 GDP will spontaneously form liposomes. Once liposomes are formed at higher temperatures, the liposomes will be stable even if the liposome suspension is cooled to below 31.2. With a melting temperature of about 40 degrees C and favorable packing parameters, PEG-12 GDS behaves similarly. DAG-PEG lipids with packing parameters outside the favorable range will not spontaneously form liposomes no matter the temperature.
  • DAG-PEG lipids are typically not pure.
  • a batch of PEG-23 GDP will contain other DAG-PEG species having slightly different acyl chains and slightly different PEG chains.
  • the properties of the batch will closely approximate a theoretically pure batch, because species with longer acyl chains will offset those with shorter acyl chains. Also species with longer PEG chains will offset those with shorter PEG chains.
  • Tetrahydrofuran antibiotics are lipophilic and have low solubility in aqueous solutions. Newer tetrahydrofuran antibiotics such as posaconazole are more lipophilic than earlier ones like ketoconazole.
  • Combinations of lipids may be used in the present invention. As described in United States Patent 6,610,322, combinations of lipids will have predictable physical properties such as melting temperature and packing parameters.
  • the tetrahydrofuran liposomes of the present invention are useful in several ways. They may be formulated into solutions for topical application. More importantly, they may be used internally to prevent and treat serious fungal infections. For internal use, they may be administered either orally or intravenously. Capsules and solutions are two possible formulations for oral administration. When intended for IV use, there are also several possible formulations.
  • the liposomes may be manufactured and distributed as a liposome suspension. They may be manufactured as a powder containing the drug, lipid,
  • - 9 - and a sugar such as sucrose may be manufactured as dehydrated liposomes.
  • the powder may be stored until needed. Then upon addition of water the powder will either form or reconstitute liposomes.
  • the liposomal formulations of the present invention are advantageous because they offer increased bioavailability and potentially reduced toxicity for tetrahydrofuran delivery. Laboratory studies have shown increased bioavailability over non-liposome preparations for both oral and IV administration. Additionally, the liposomes of the present invention have been shown to be superior to liposome formulations using DOPC
  • formulations described here have been described as liposome suspensions, but the formulations may include other types of microparticles.
  • the formulations described in the examples were observed using electromicroscopy. Small aggregates ( ⁇ 10 nm) and various sizes of multilamellar vesicles (100 to 500 nm) were observed, which showed that the solubilization of drugs was achieved by the lipid encapsulation.
  • the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a tetrahydrofuran drug, and a DAG-PEG lipid having a melting temperature below about
  • a combination of DAG-PEG lipids may be used.
  • the drug may be selected from the group consisting of posaconazole, itraconazole and equaconazole.
  • the DAG-PEG lipid may be selected from the group consisting of PEG-12 GDO, PEG-12 GDLO, PEG-12 GDM and
  • the drug to lipid ratio is preferably greater than about 1 to 20, and more preferably greater than about 1 to 5.
  • the composition may comprise a sugar and be in a dehydrated form for later addition with an aqueous solution.
  • the composition may be a liposome suspension.
  • the composition may comprise a combination of DAG-PEGs.
  • the drug concentration is preferably between about 1 to 50 mg/ml.
  • the composition may include solid excipients and be in the form of a capsule for oral administration.
  • the invention is method of making a pharmaceutical formulation comprising selecting a tetrahydrofuran drug; selecting a diacyl PEG lipid having a melting temperature below about 25 degrees C and having packing parameters favorable for the formation of liposomes; and combining the drug with the lipid in an aqueous solution.
  • the drug may be selected from the group consisting of posaconazole, itraconazole and equaconazole.
  • the lipid may be selected from the group consisting of PEG- 12 GDO, PEG- 12 GDLO, PEG- 12 GDM and PEG- 12 GDP.
  • the final drug concentration is preferably between about 1 to 50 mg/ml.
  • the final drug to lipid ratio is preferably greater than about 1 to 20, and more preferably greater than about 1 to 5.
  • the invention is method of treating or preventing a fungal infection comprising selecting a tetrahydrofuran drug; selecting a diacyl PEG lipid having a melting temperature below about 25 degrees C and having packing parameters favorable for the formation of liposomes; combining the drug with the lipid in an aqueous solution; and administering the solution.
  • the drug may be selected from the group consisting of posaconazole, itraconazole and equaconazole.
  • the lipid may be selected from the group consisting of PEG-12 GDO, PEG-12 GDLO, PEG-12 GDM and PEG-12 GDP.
  • the final drug concentration is preferably between about 1 to 50 mg/ml. The final
  • - 11 - drug to lipid ration is preferably greater than about 1 to 20, and more preferably greater than about 1 to 5.
  • the administration may be oral, topical or intravenous.
  • the gelation effect described in paragraphs 17 and 18 above can be exploited as a separate invention. Sometimes gelation of a tetrahydrofuran/lipid composition is desired, such as in preparation of a topical cream. In such cases, PEG- 12 GDS, PEG-23 GDS, and PEG 23 GDP may be used separately or in combination to prepare topical tetrahydrofuran creams.
  • the separate invention is a pharmaceutical cream comprising a tetrahydrofuran drug, and a DAG-PEG lipid having a melting temperature above about 25 degrees C and having packing parameters favorable for the formation of liposomes.
  • the drug may be selected from the group consisting of ketoconazole, posaconazole, itraconazole and equaconazole.
  • the DAG-PEG lipid may be selected from the group consisting of PEG- 12 GDS, PEG-23 GDS and PEG-23 GDP.
  • Solutions may be applied topically, also. If topical application of a solution is desired, lipids that do not exhibit the gelation effect are selected.
  • the invention includes a new tetrahydrofuran drug that is referred to herein as equaconazole. Equacoazole has the following structure(s).
  • Itraconazole was combined in an aqueous solution with DAG-PEG lipids. A variety of drug-to-lipid ratios were tested, as well as a variety of formation temperatures. After mixing, formulations were allowed to stand at room temperature. The results are shown in Table 2.
  • Posaconazole was combined in an aqueous solution with DAG-PEG lipids. A variety of drug-to-lipid ratios were tested, as well as a variety of formation temperatures. After mixing, formulations were allowed to stand at room temperature. The results are shown in Table 3.
  • Equaconazole was combined in an aqueous solution with DAG-PEG lipids. A variety of drug-to-lipid ratios were tested, as well as a variety of formation temperatures. After mixing, formulations were allowed to stand at room temperature. The results are shown in Table 4.
  • Ketoconazole was combined in an aqueous solution with DAG-PEG lipids. A variety of drug-to-lipid ratios were tested, as well as a variety of formation temperatures. After mixing, formulations were allowed to stand at room temperature. The results are shown in Table 5.
  • 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 6.
  • the drug may be itraconazole, posaconazole or equaconazole.
  • the lipid may be PEG- 12 GDO, or PEG- 12 GDM, PEG 12 GDLO or PEG- 12 GDP 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.
  • HCl is used to adjust pH if necessary
  • the IV solution was prepared as in Example 5, except that the targeted pH range was between 3.5 and 7.0.
  • a sample formulation is described in Table 7.
  • the drug may be itraconazole, posaconazole or equaconazole.
  • the lipid may be PEG- 12 GDO, PEG- 12 GDM, PEG- 12 GDLO or PEG- 12 GDP 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 3.5 to 7.0.
  • HCl is used to adjust pH if necessary.
  • Example 7 Antifungal Powder for IV administration
  • PEG lipids were weighed into a beaker supplied with a mixer. The agitation speed was set to 300 ⁇ 100 RPM. Foaming was avoided. Drug was added, keeping a constant mixing rate. The mixture was then homogenized at 850 - 900 RPM until the drug substance was visually dispersed in the lipids. Premixed buffer solution was then added at about 300 RPM, and the mixture was homogenized again at about 850 rpm. Finally, the mixture was spray dried using a suitable spray dryer, e.g. Niro Spray Dryer. A sample formulation is described in Table 8.
  • the drug may be Itraconazole or Posaconazole or Equaconazole.
  • the lipid may be PEG- 12 GDO, PEG- 12 GDM, PEG- 12 GDLO or PEG- 12 GDP 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.
  • Phosphoric acid is used to adjust pH if necessary. Water may be added during mixing and then removed by subsequent steps.
  • Example 8 Antifungal Capsules for oral administration
  • Capsules were prepared by first weighing out the required amount of lipids into a beaker, with agitation supplied by a mixer. The agitation speed was set to 300 ⁇ 100 RPM. Foaming was avoided. The drug was drug added with constant mixing. When agglomerates were no longer observed, the mixture was homogenized at about 850 - 900 RPM until the drug substance was visually dispersed in the lipids. Purified water was added and homogenization repeated. The mixture was pray dried using a suitable spray dryer, e.g., Niro Spray Dryer. The mixture was dried further using a vacuum oven at 65°C ⁇ 10°C until the moisture level was below 1.0%. The mixture was blended for 5 to ten minutes. Excipents were passed through a No. 30 mesh screen and added. Blending
  • the drug may be itraconazole, posaconazole or equaconazole.
  • the lipid may be PEG- 12 GDO, PEG- 12 GDM, PEG- 12 GDLO or PEG- 12 GDP or any mixture thereof. Water may be added during mixing and then removed by subsequent steps.
  • Example 9 Bioavailability of Posaconazole/Itraconazole formulations
  • PK Pharmacokinetics
  • heparinized mouse plasma samples obtained typically at 0 hr, 0.08 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 8 hr, 16 hr, 24 hr, 31 hr and 48 hr after the bolus IV injection or oral feeding for Posaconazole and at 0 hr, 0.08 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 8 hr, 16 hr and 24 hr for Itraconazole, respectively.
  • Samples were analyzed using a HPLC-MS method. To determine the level of each drug, the drug was first
  • PK data was analyzed using the WinNonlin program (ver. 5.2, Pharsight) compartmental models of analysis.
  • Figure 1 shows comparison between blood concentrations of various posaconazole formulations administered intravenously. Both a DOPC formulation (1) of posaconazole and (2) a posaconale solution containing 5% dimethyl sulfoxide and 10%
  • Cremophor were cleared more rapidly than a DAG-PEG (PEG-12 GDO) lipid formulation (3) of posaconazole.
  • the dosing strength was 10 mg/kg.
  • Figure 2 shows a comparison between blood concentrations of a commercial posaconazole product (1) and a DAG-PEG (PEG-12 GDO) formulation (2) of posaconazole administered orally.
  • the dosing strength was 50/mg/kg.
  • the bioavailability of the DAG-PEG formulation was 45% versus 28% for the commercially available product.
  • Figure 3 shows a comparison between (a) a DAG-PEG (PEG-12 GDO) lipid formulation of itraconazole and (b) an aqueous solution of itraconazole containing 5% dimethyl sulfoxide and 10% Cremophor after IV administration.
  • the dosing strength was
  • AUC Area under the curve
  • Figure 4 shows a comparison between oral administrations of (a) DAG-PEG
  • Example 10 Antifungal Topical Cream
  • 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.
  • Cholesterol and glycerin were added with mixing. Ethanol and ethyoxydiglycol were added with mixing. Finally Carbopol ETD 2020, purified water and triethylamine were added with mixing. Mixing continued until fully a homogenous cream was achieved.
  • the formulation is described in Table 10.
  • the drug may be ketoconazole, itraconazole, posaconazole or equaconazole.
  • the lipid may be PEG-12 GDS, PEG-23 GDS, PEG-23 GDP or any combination thereof.
  • Phosphoric acid is used to adjust pH if necessary. The targeted pH range was between 3.5 and 7.0.
  • Example 11 Antifungal Topical Solution
  • the topical solution was prepared as in Example 5, except that active was first dissolved in ethanol and the targeted pH range was between 3.5 and 7.0.
  • a sample formulation is described in Table 11.
  • the drug may be ketoconazole, itraconazole, posaconazole or Eequaconazole.
  • the lipid may be PEG-12 GDO, PEG-12 GDM or PEG-12 GDLO or PEG-12 GDP or any combination thereof.
  • Sodium hydroxide is used to prepare a 10% w/w solution in
  • Phosphoric acid is used to adjust pH if necessary.
  • the targeted pH is in a range of 3.5 to 7.0.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Dispersion Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des antibiotiques de tétrahydrofuranne formulés avec certains lipides de diacylglycérol-polyéthylèneglycol (DAG-PEG) qui ont une hydrosolubilité et une biodisponibilité accrues. PEG-12 GDO, PEG-12 GDLO, PEG-12 GDM et PEG-12 GDP sont particulièrement adaptés pour former des liposomes qui incorporent des tétrahydrofurannes dans la bicouche.
PCT/US2009/000003 2008-01-04 2009-01-02 Délivrance améliorée d'agents antifongiques WO2009088959A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2010541549A JP2011508780A (ja) 2008-01-04 2009-01-02 抗真菌薬の増強された送達
EP09701160A EP2240161A1 (fr) 2008-01-04 2009-01-02 Délivrance améliorée d'agents antifongiques

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US12/006,820 2008-01-04
US12/006,820 US20090176795A1 (en) 2008-01-04 2008-01-04 Enhanced delivery of antifungal agents
US12801108P 2008-05-16 2008-05-16
US61/128,011 2008-05-16

Publications (1)

Publication Number Publication Date
WO2009088959A1 true WO2009088959A1 (fr) 2009-07-16

Family

ID=40853389

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/000003 WO2009088959A1 (fr) 2008-01-04 2009-01-02 Délivrance améliorée d'agents antifongiques

Country Status (3)

Country Link
EP (1) EP2240161A1 (fr)
JP (1) JP2011508780A (fr)
WO (1) WO2009088959A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015061890A (ja) * 2011-01-05 2015-04-02 リブオン ラボラトリーズ リポソームの製造方法、該方法によって製造されるリポソーム組成物、及び該リポソーム組成物の使用方法
WO2017025292A1 (fr) * 2015-08-08 2017-02-16 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Formulation gastro-résistante contenant du posaconazole

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6297737B1 (ja) * 2017-09-25 2018-03-20 ジェイ−ネットワーク，インコーポレイテッド 正に帯電した荷電ニオソームの調製方法及び荷電ニオソーム

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6610322B1 (en) * 2000-12-20 2003-08-26 Brian Charles Keller Self forming, thermodynamically stable liposomes and their applications
US20070042031A1 (en) * 2005-07-27 2007-02-22 Protiva Biotherapeutics, Inc. Systems and methods for manufacturing liposomes
US20070053971A1 (en) * 1998-12-30 2007-03-08 Oligos Etc., Inc Antimicrobial and Antiviral Compounds and Methods for their Use
US20070207173A1 (en) * 2006-02-01 2007-09-06 Sd Pharmaceuticals, Inc. Vitamin E succinate stabilized pharmaceutical compositions, methods for the preparation and the use thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07503953A (ja) * 1992-02-12 1995-04-27 ジヤンセン・シラグ・ソチエタ・ペル・アチオニ リポソームイトラコナゾール組成物
EP4218730B1 (fr) * 2004-05-03 2023-11-01 Ipsen Biopharm Ltd. Liposomes utiles pour l'administration de médicaments

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070053971A1 (en) * 1998-12-30 2007-03-08 Oligos Etc., Inc Antimicrobial and Antiviral Compounds and Methods for their Use
US6610322B1 (en) * 2000-12-20 2003-08-26 Brian Charles Keller Self forming, thermodynamically stable liposomes and their applications
US20070042031A1 (en) * 2005-07-27 2007-02-22 Protiva Biotherapeutics, Inc. Systems and methods for manufacturing liposomes
US20070207173A1 (en) * 2006-02-01 2007-09-06 Sd Pharmaceuticals, Inc. Vitamin E succinate stabilized pharmaceutical compositions, methods for the preparation and the use thereof

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015061890A (ja) * 2011-01-05 2015-04-02 リブオン ラボラトリーズ リポソームの製造方法、該方法によって製造されるリポソーム組成物、及び該リポソーム組成物の使用方法
US10016389B2 (en) 2011-01-05 2018-07-10 Livon Laboratories Method of making liposomes, liposome compositions made by the methods, and methods of using the same
WO2017025292A1 (fr) * 2015-08-08 2017-02-16 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Formulation gastro-résistante contenant du posaconazole
EP3590505A1 (fr) * 2015-08-08 2020-01-08 Alfred E. Tiefenbacher (GmbH & Co. KG) Formulation gastro-résistante contenant du posaconazole
US11058682B2 (en) 2015-08-08 2021-07-13 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Gastro-resistant formulation containing posaconazole
US11590127B2 (en) 2015-08-08 2023-02-28 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Gastro-resistant formulation containing posaconazole

Also Published As

Publication number Publication date
EP2240161A1 (fr) 2010-10-20
JP2011508780A (ja) 2011-03-17

Similar Documents

Publication Publication Date Title
US7115565B2 (en) Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability
RU2260428C2 (ru) Фармацевтическая композиция, содержащая производное бензамида и обладающая повышенной растворимостью и поглощаемостью при оральном применении
US7923026B2 (en) Embedded micellar nanoparticles
AU2007312233B2 (en) Micellar nanoparticles of chemical substances
KR101688038B1 (ko) 벤다무스틴의 경구 투약 형태
EA006402B1 (ru) Комбинация лекарства и целлюлозного полимера, повышающего концентрацию; способ введения лекарства и водный раствор (варианты)
WO2009066146A2 (fr) Solutions stables d'actifs solubles de façon restreinte
US20080286373A1 (en) Ziprasidone formulations
US20200206139A1 (en) Compositions for the improved delivery of drugs
CN101848705A (zh) 氯吡格雷组合物的制备方法
US20070116770A1 (en) Tazobactam/piperacillin lyophilizate
TW200301108A (en) Pharmaceutical compositions based on azetidine derivatives
NZ539046A (en) Chemotherapeutic self-emulsifying microemulsion compositions of paclitaxel with improved oral bioavailability
WO2010085347A1 (fr) Conjugués peg-lipide pour augmenter la solubilité de composés médicamenteux
RU2557919C1 (ru) Сыпучий прессуемый порошок рапамицина и фармацевтическая композиция на его основе
EP2240161A1 (fr) Délivrance améliorée d'agents antifongiques
US20110105387A1 (en) Method of treatment with rapamycin
US20090291132A1 (en) Enhanced delivery of antifungal agents
CN112168781B (zh) 他克莫司的自微乳组合物及其制备方法
EP3691612A1 (fr) Compositions orales de taxane de grande puissance et procédés
US20090176795A1 (en) Enhanced delivery of antifungal agents
CN111012734A (zh) 一种载药网状原位相变凝胶缓释系统及其制备方法
US20100143461A1 (en) Palonosetron formulation
US20100221326A1 (en) Pharmaceutical compositions for oral use for treating patients affected by obesity
WO2020236083A1 (fr) Formules orales, leurs procédés de fabrication et leurs utilisations

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: 09701160

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2010541549

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2009701160

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载