EP0857070A2 - Compositions de phospholipides stabilisees - Google Patents

Compositions de phospholipides stabilisees

Info

Publication number
EP0857070A2
EP0857070A2 EP96931893A EP96931893A EP0857070A2 EP 0857070 A2 EP0857070 A2 EP 0857070A2 EP 96931893 A EP96931893 A EP 96931893A EP 96931893 A EP96931893 A EP 96931893A EP 0857070 A2 EP0857070 A2 EP 0857070A2
Authority
EP
European Patent Office
Prior art keywords
composition
contrast
nmt
phosphoiipids
agent
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.)
Withdrawn
Application number
EP96931893A
Other languages
German (de)
English (en)
Inventor
Kari Nycomed Imaging a/s DYVIK
Harald Nycomed Imaging a/s DUGSTAD
Roald Nycomed Imaging a/s SKURTVEIT
Jo Nycomed Imaging a/s KLAVENESS
Jonny Nycomed Imaging a/s OSTENSEN
Kiyoto Daiichi Pharmaceutical Co. Ltd. Yachi
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.)
Daiichi Pharmaceutical Co Ltd
GE Healthcare AS
Original Assignee
Daiichi Pharmaceutical Co Ltd
Nycomed Imaging AS
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 Daiichi Pharmaceutical Co Ltd, Nycomed Imaging AS filed Critical Daiichi Pharmaceutical Co Ltd
Publication of EP0857070A2 publication Critical patent/EP0857070A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A61K49/0461—Dispersions, colloids, emulsions or suspensions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes

Definitions

  • This invention relates to stabilised aqueous phospholipid compositions.
  • Phospholipid compositions are used in a variety of diagnostic, therapeutic and cosmetic applications.
  • lipid compositions in particular liposomes, are used to incorporate diagnostic and therapeutic agents, as vehicles for transfer of genetic material, as immunological adjuvants, in preparation of vaccines and in cancer detection.
  • diagnostic and therapeutic agents as vehicles for transfer of genetic material, as immunological adjuvants, in preparation of vaccines and in cancer detection.
  • the stability of the phospholipid is important for the protection of any entrapped substance from degradation reactions and also for optimum performance of the phospholipid itself.
  • Contrast agents are employed to effect imaging enhancement in a variety of diagnostic techniques, the most important of these being X-ray imaging, magnetic resonance imaging (RI) , ultrasound imaging and nuclear medicine imaging. There is a continuing need for contrast agents which combine good storage stability and stability in vivo. Another area of particular interest is the development of stable phospholipid compositions for use in techniques involving autoclavation.
  • trometamol and related buffer compounds have a specific effect on the hydrolysis of phosphoiipids. Many of these studies show general acid/base catalysis by the trometamol buffer with increased hydrolysis of the phosphoiipids with increasing concentration of buffer species (see for example Journal of Pharmaceutical Sciences .82 . : 362-366 ( 1993 ) ) .
  • the trometamol buffer appeared to provide resistance to hydrolysis and the reference indicates that the reduced oxidation/ hydrolysis observed is due to the fact that trometamol acts as an efficient scavenger of hydroxyl free radicals.
  • a similar conclusion is reached in J.Pharm. Pharmacol. 45.: 490-495 (1993) , where a protective effect of buffers such as trometamol against lipid peroxidation is reported.
  • WO-95/26205 there are described diagnostic compositions containing multilamellar liposomes containing at least one imaging agent and being suspended in an aqueous medium containing said imaging agent, wherein the liposomes comprise a neutral phospholipid and a charged phospholipid, the average particle diameter of the liposomes is 50-3000 nm and the concentration of imaging agent in any aqueous phase filling the interior of the liposomes is substantially the same as that in the aqueous medium in which the liposomes are suspended.
  • substantially saturated phospholipid compounds can be stabilised by buffers, the buffers providing a reduced degree of aqueous hydrolysis of the phosphoiipids.
  • the present invention provides an aqueous lipid composition, preferably a liposomal composition and preferably a composition in physiologically tolerable form, comprising one or more substantially saturated phosphoiipids in combination with a buffer system comprising ammonia or a water soluble amine having a pH at 15°C of less than or equal to 9.5, with the proviso that where said phosphoiipids comprise a combination of charged and neutral phosphoiipids and said composition is a liposomal composition containing a nonionic multiply hydroxylated X-ray contrast agent then said agent is not present within the liposomes and within the surrounding aqueous medium at substantially the same concentration.
  • a buffer system comprising ammonia or a water soluble amine having a pH at 15°C of less than or equal to 9.5
  • a method for stabilising a substantially saturated phospholipid composition comprises including in a substantially saturated phospholipid composition a buffer system comprising ammonia or a water soluble amine having a pH at 15°C of less than or equal to 9.5, other than by adding a said buffer system to a liposomal composition containing a nonionic multiply hydroxylated X-ray contrast agent having said agent present within the liposomes and within the surrounding aqueous medium at substantially the same concentration.
  • the buffer may be added before or after liposome generation.
  • the invention also provides a method of contrast enhanced imaging in which a contrast medium is administered to a subject (eg. a human or non-human animal, preferably a mammal) and an image of the subject is generated, characterised in that as said contrast medium is used a composition according to the invention containing a contrast effective material.
  • a contrast medium may be administered after activation of the contrast effective material, eg. by hyperpolarization.
  • the invention provides a method of treatment in which a therapeutic or prophylactic agent is administered to a subject (eg. a human or non-human animal, preferably a mammal) , characterised in that there is administered a composition according to the invention containing a said therapeutic or prophylactic agent.
  • a subject eg. a human or non-human animal, preferably a mammal
  • the invention provides a method of cosmetic treatment in which a cosmetic agent is administered to a subject (eg. a human or non-human animal, preferably a mammal) characterised in that there is administered a composition according to the invention containing a said cosmetic agent.
  • a cosmetic agent eg. a human or non-human animal, preferably a mammal characterised in that there is administered a composition according to the invention containing a said cosmetic agent.
  • the compositions administered should contain an effective amount of the active agent (the contrast effective material, the therapeutic or prophylactic agent or the cosmetic agent) , namely an amount sufficient to achieve contrast enhancement or to achieve the desired therapeutic, prophylactic or cosmetic effect.
  • the phosphoiipids used in the compositions and methods of the invention may be charged or neutral (ie. carry no net charge) .
  • the use of neutral phosphoiipids however is particularly preferred as their protection against hydrolysis by the buffer system is particularly pronounced.
  • the phosphoiipids in the compositions of the invention are entirely or substantially entirely neutral phosphoiipids.
  • the buffer systems for use in the methods or compositions of the present invention preferably have a pH of 6.0 to 9.5 at room temperature (15°C) , more preferably 6.5 to 8.0, particularly preferably 6.8 to 7.8.
  • compositions of the present invention show a reduced degree of hydrolysis of the phospholipid(s) when compared with formulations not including the specified buffer system.
  • Preferred compositions according to the present invention show a greater than 5% reduction in the extent of hydrolysis over a given time (eg. a normal shelf life, for example 30 days or more) than occurs with formulations not including the buffer; more preferred compositions show a greater than 10% and most preferably greater than 25% reduction.
  • the stabilisation achieved is of especial advantage during storage, during processing and during exposure of the phospholipid compositions to temperature, including during autoclaving.
  • the phospholipid compositions are stable at temperatures in the range from 4 to 30°C; in a more preferred embodiment the compositions are stable for temperatures in the range from 4 to 50°C; in another more preferred embodiment the compositions are stable for temperatures in the range of 4 to 125°C (which includes autoclaving) .
  • the phospholipid compositions are preferably stable under storage for a period of up to 2 years, more preferably up to 3 years, particularly preferably up to 5 years. "Stable” in this context means that at least 75%, preferably at least 80%, more preferably at least 90%, of undegraded phospholipid is present in the composition after the specified storage period.
  • one particular advantage of the stabilization method of the invention is that the resulting phospholipid compositions have the ability to withstand a wide temperature range for a short period. It is preferred, therefore, that for stabilising phospholipid compositions to be autoclaved the buffer system is added prior to autoclaving.
  • Buffers which may be employed in the methods or compositions of the present invention are preferably those of formula (I)
  • water soluble amines which may be employed as buffers include amino alcohols and amino sugars .
  • More preferred amines include trometamol (tris (hydroxymethyl)methylamine, also denoted TRIS) , N,N-bis (2-hydroxyethyl) -tris (hydroxymethyl) methylamine (denoted BIS-TRIS) , 2-amino-2-methylpropane-l, 3-diol (denoted AMPD) , TES, 2- [4- (2-hydroxyethyl) -1- piperazinyl] ethanesulphonic acid (denoted HEPES) , diethanolamine, meglumine, triethanolamine and ammonia.
  • TRIS tris (hydroxymethyl)methylamine
  • BIS-TRIS N,N-bis (2-hydroxyethyl) -tris (hydroxymethyl) methylamine
  • AMPD 2-amino-2-methylpropane-l
  • TES 2- [4- (2-hydroxyethyl) -1- pipe
  • Especially preferred amines for use according to the invention are TRIS, BIS-TRIS, TES and meglumine in view of their advantageous physiological acceptability and/or advantageous pH values at room temperature.
  • the phosphoiipids for inclusion in the compositions of the present invention are, as indicated above, comprised of substantially saturated phosphoiipids.
  • substantially saturated means that the fatty acid residues of the phosphoiipids are fully saturated (i.e. contain no C-C double bonds) or that the extent of their unsaturation is very low, e.g. as shown by an iodine value of no more than 10, preferably no more than 5.
  • a small proportion of unsaturated phosphoiipids giving an analogous overall extent of unsaturation may also be present in the compositions of the present invention.
  • the phosphoiipids may be charged or neutral and may be of natural, synthetic or semi-synthetic origin (including chemically modified substantially saturated phosphoiipids) . As mentioned above the use of neutral phosphoiipids is preferred.
  • the number of carbon atoms in the fatty acid residues is usually at least 14, preferably at least 16.
  • the number of carbon atoms in the fatty acid residue is also preferably 26 or less, eg. 25 or less, preferably 24 or less.
  • Neutral phosphoiipids useful in the present invention include, for example, neutral glycerophospholipids, for example a fully hydrogenated naturally occurring (e.g. soybean- or egg yolk-derived) or synthetic phosphatidylcholine, particularly semisynthetic dipalmitoyl phosphatidylcholine (DPPC) or distearoyl phosphatidylcholine (DSPC) , phosphatidylethanolamine (PE) or phosphatidylethanolamine-polyethyleneglycol (PE- PEG) . More than one neutral phospholipid may be used.
  • DPPC dipalmitoyl phosphatidylcholine
  • DSPC distearoyl phosphatidylcholine
  • PE phosphatidylethanolamine
  • PE- PEG phosphatidylethanolamine-polyethyleneglycol
  • More than one neutral phospholipid may be used.
  • Charged phosphoiipids useful in the present invention include, for example, positively or negatively charged glycerophospholipids.
  • Negatively charged phosphoiipids include, for example, phosphatidylserine, for example a fully hydrogenated naturally occurring (e.g. soybean- or egg yolk-derived) or semi-synthetic phosphatidylserine, particularly semi-synthetic dipalmitoyl phosphatidylserine (DPPS) or distearoyl phosphatidylserine (DSPS) - phosphatidylglycerol (PG) , for example fully hydrogenated naturally occurring (e.g.
  • DPPS semi-synthetic dipalmitoyl phosphatidylserine
  • DSPS distearoyl phosphatidylserine
  • PG phosphatidylglycerol
  • soybean- or egg yolk-derived soybean- or egg yolk-derived
  • semi-synthetic phosphatidylglycerol particularly semi-synthetic or synthetic dipalmitoyl phosphatidylglycerol (DPPG) ; or distearoyl phosphatidylglycerol (DSPG) ; phosphatidylinositol, for example a fully hydrogenated naturally occurring (e.g.
  • soybean- or egg yolk-derived or semi-synthetic phosphatidylinositol, particularly semi-synthetic or synthetic dipalmitoyl phosphatidylinositol (DPPI) or distearoyl phosphatidylinositol (DSPI) ; phosphatidic acid, for example a fully hydrogenated naturally occurring (e.g. soybean- or egg yolk-derived) or semi-synthetic phosphatidic acid, particularly semi-synthetic or synthetic dipalmitoyl phosphatidic acid (DPPA) or distearoyl phosphatidic acid (DSPA) .
  • DPPI dipalmitoyl phosphatidylinositol
  • DSPA distearoyl phosphatidic acid
  • Positively charged phosphoiipids include, for example, an ester of phosphatidic acid with an aminoalcohol, such as an ester of dipalmitoyl phosphatidic acid or distearoyl phosphatidic acid with hydroxyethylenediamine. Although such charged phosphoiipids are commonly used alone, more than one charged phospholipid may be used.
  • the concentration of the buffer for use in the method of the present invention or in the compositions of the present invention is preferably in the range 2 mM to 200 mM, more preferably 2 mM to 100 mM and particularly preferably 2 mM to 20 mM.
  • the molar ratio of buffer:lipid in the compositions of the present invention is preferably in the range 1:60 to 2000:1 (eg. 1:60 to 100:1) , more preferably 1:60 to 1:0.02, particularly preferably 1:60 to 1:0.1.
  • Another preferred range of molar ratio of buffer:lipid for some diagnostic and other medical applications is 1:50 to 1:0.1, more preferably 1:20 to 1:0.5, particularly preferably 1:5 to 1:1.
  • the concentration of phosphoiipids in the compositions of the present invention for imaging and medical applications is preferably in the range 0.01 mM to 120 mM, eg. 1 mM to 120 mM.
  • the phospholipid compositions of the present invention may be in any of the formulation types generally encountered, for example liposomes, emulsions, micelles, microemulsions, lipid particles, lipid solutions and microbubbles. They can be produced by conventional procedures for each particular formulation type.
  • the method and the phospholipid compositions of the present invention are suitable for use in a variety of applications and in particular those where increased stability is of especial importance.
  • the stabilised compositions can be used in a variety of diagnostic, therapeutic and cosmetic applications and particular mention can be made of phospholipid compositions for use with contrast media (X-ray, MRI , US and scintigraphy) , and for use in cancer therapy, chemotherapy, therapy for fungal infections and treatment of psoriasis.
  • the liposomal compositions of the invention will include a contrast-effective material, eg. in the inner cavity of the liposomes, attached to the inner or outer wall of the liposome membrane or contained within the membrane, or in the liquid medium in which the liposomes are dispersed.
  • contrast effective it is meant that the material is capable of enhancing contrast in the imaging modality of interest.
  • conventional imaging modalities eg. X-ray, MR, ultrasound, magnetotomography, electrical impedance tomography, scintigraphy, SPECT, PET, etc.
  • the nature of appropriate contrast effective materials is well known, for example gases (eg.
  • the contrast effective material is gaseous (at ambient or body temperature) , eg.
  • the contrast effective material is water soluble (eg. a soluble triiodophenyl compound or a paramagnetic metal chelate) it is preferably in solution in the liposome core and especially preferably also in solution in the suspension medium.
  • Therapeutic or cosmetic agents may be similarly dispersed within the liposomal core, in or on the liposome membrane and/or in the suspension medium. Conventional therapeutic or cosmetic agents capable of liposomal delivery may be used.
  • the concentration of total lipid is generally 5 mg/ml to 100 mg/ml (eg. 20 to 100 mg/ml, conveniently at least 40 or 50 mg/ml) , preferably 10 mg/ml to 90 mg/ml, and more preferably 10 mg/ml to 80 mg/ml, in order to enhance encapsulation of contrast agent in the lipid.
  • a preferred range for the concentration of total lipid is generally 0.01 mg/ml to 20 mg/ml, preferably 0.01 mg/ml to 10 mg/ml (eg. 0.5 mg/ml to 10 mg/ml) .
  • agents are encapsulated in the phospholipid (particularly in liposomes) this is preferably in the form of an isotonic solution or suspension (relative to physiological osmotic pressure in the body) .
  • an isotonic solution or suspension the agent is generally dissolved or suspended in a medium at a concentration which provides an isotonic solution.
  • other conventional tonicity adjusters e.g non-toxic water soluble substances
  • Such substances include: salts such as sodium chloride,- sugars such as mannitol, glucose, sucrose, mannose, galactose, sorbitol or the like; and polyhydric alcohols such as propylene glycol, glycerine and the like. If sorbitol is employed this is preferably at a concentration of 1 to 500 g/1, more preferably 0.1 to 20 g/lOOml. If glycerine is employed this is preferably at a concentration of 0.05 to 10 g/l00 ml. If the phospholipid compositions are liposomal compositions, the amount of salts used is preferably as small as possible to facilitate stability of the liposomes during storage and autoclaving.
  • Isotonic solutions provided by means of the substances mentioned above are also preferably included in those phospholipid compositions according to the present invention which do not incorporate diagnostic, therapeutic or cosmetic agents.
  • the present phospholipid compositions may also contain various optional components in addition to the above ⁇ mentioned components.
  • vitamin E ⁇ - tocopherol
  • vitamin E acetate ester as an antioxidant may be added in an amount of 0.01 to 2 molar %, preferably 0.1 to 1 molar % relative to total amount of lipids.
  • Diagnostic, therapeutic and cosmetic agents referred to above may be incorporated into the phospholipid compositions of the present invention by techniques well known in the art.
  • the prior art describes the inhibition of phospholipid hydrolysis to be by an indirect mechanism involving inhibition of a phospholipase; such a mechanism clearly does not apply in the present invention since the compositions concerned do not contain phospholipase.
  • the reduced oxidation/hydrolysis observed in the prior art using unsaturated phosphoiipids cannot be important in the method of the present invention involving saturated phosphoiipids (not withstanding that traces of unsaturated phosphoiipids can be present) .
  • the method of the present invention appears to demonstrate a different inhibition mechanism involving general inhibition of the acid/base catalysed hydrolysis of phospholipid esters.
  • composition 1 ml containing:
  • the composition was prepared by mixing the lipids with a mixture of chloroform, methanol and water (volume ratio 80:20:0.05) .
  • the mixture was heated on a water bath (at 50°C) to dissolve the lipids and the solvents were then removed by heating the solution in a rotary evaporator
  • the dispersion was then split into two parts and a buffer of trometamol/HCl having a pH of 7.4 was added to one of the two parts.
  • the resulting composition was then filled into vials and autoclaved. Samples were stored at each of 30°, 40° and 50°C for one month. The content of free fatty acids was measured before autoclaving, after autoclaving and after storage.
  • FFA free fatty acids
  • composition 1 ml containing:
  • compositions according to the present invention are prepared as in Example 1 as follows:
  • Example 1 As a further Example demonstrating the method of the present invention the following composition (as disclosed in WO-95/26205) was also tested as in Example 1.
  • composition 1 ml containing:
  • composition was prepared as in Example 1 but additionally adding an isotonic solution of iodixanol and sorbitol prior to the formation of the liposome.
  • Examples 8 to 13 below disclose the preparation of stabilized liposome suspensions suitable for use as contrast media in ultrasound (Examples 8 to 10) and magnetic resonance imaging (Examples 11 to 13) investigations. Ratios and percentages are by volume unless otherwise stated, except lipid ratios which are by weight . If 19 F labelled fluorocarbons are used in Examples 8 to 10 these compositions could be used as MR contrast media.
  • Hydrogenated egg phosphatidylcholine (HEPC) and dipalmitoylphosphate (10:1) are dissolved m chloroform- methanol (2:1) , and the solvent is then removed in a rotary evaporator.
  • the lipids are then dispersed m purified water, and the dispersion is introduced m a gas tight glass reactor equipped with a high speed emulsifier.
  • the gas m the reactor is air with 10% C 5 F 12 .
  • HEPES 5 mM is added.
  • Distearoylphosphatidylcholme DSPC
  • dipalmitoylphosphatidic acid DPPA
  • polyethyleneglycol PEG 4000
  • the lipids are then dispersed in purified water, and the dispersion is introduced in a gas tight glass reactor equipped with a high speed emulsifier.
  • the gas in the reactor is C 3 F 8 .
  • trometamol 8mM is added.
  • Dipalmitoylphosphatidylcholme (DPPC) , dipalmitoylphosphatidic acid (DPPA) and dipalmitoylphosphatidylethanolamine (DPPE) (8:1:1) are dissolved in chloroform-methanol-water (10:20:0.5), and the solvent is then removed in a rotary evaporator.
  • the lipids are then dispersed in purified water, and the dispersion is introduced in a gas tight glass reactor equipped with a high speed emulsifier.
  • the gas in the reactor is C 4 H 10 .
  • TES 10 mM is added.
  • Hydrogenated egg phosphatidylcholine (HEPC) and methoxy(PEG) -distearoylphosphatidylethanolamine (MPEG- DSPE) (9:1) are dry blended and dispersed in gadodiamide-caldiamide 0.5 M solution. Liposomes are then prepared by homogenisation and extrusion. HEPES 8 mM is added and the product is sterilised by autoclaving.
  • HEPC Hydrogenated egg phosphatidylcholine
  • MPEG- DSPE methoxy(PEG) -distearoylphosphatidylethanolamine
  • Hydrogenated egg phosphatidylcholine (HEPC) and dipalmitoylphosphatidylglycerol (DPPG) (9:1) are dry blended and dispersed in dimegluminegadopentetate- meglumine diethylenetriaminepentetate-meglumine 0.5 M solution. Liposomes are then prepared by homogenisation and extrusion. TRIS 50 mM is added and the product is sterilised by autoclaving.
  • Hydrogenated egg phosphatidylcholine (HEPC) is dispersed in gadodiamide 0.5 M solution. Liposomes are then prepared by homogenisation and extrusion. TES 50 mM is added and the product is sterilised by autoclaving.
  • HEPC Hydrogenated egg phosphatidylcholine
  • compositions were prepared, as in Example 1, using TRIS, HEPES or TES buffers.
  • TES is 1- [tris (hydroxymethyl)methyl] -2-aminoethane sulphonic acid.
  • compositions were prepared for comparison.
  • the buffer was TRIS, HEPES or TES
  • a second no buffer was used with pH being adjusted with NaOH/HCl
  • a third phosphate buffer or phosphate/citrate buffer was used.
  • the compositions were prepared as in Example 1.
  • Degradation of the phospholipid, measured as free fatty acids (mg/mL) after autoclaving and after 3 months storage at 40°C was as follows: Buffer After autoclaving 3 months, 40°C
  • samples with TRIS and TRIS- like buffers show less degradation of the phospholipid as seen by the reduced level of free fatty acids compared with other buffers (phosphate buffer and phosphate/citrate buffer) and solutions without buffer (pH adjusted by NaOH/HCl) .
  • the reduction in pH observed after autoclaving and storage was less pronounced in the samples with TRIS, HEPES and TES (a reduction of less than 0.30 pH units) compared with the other samples (a reduction of 0.30-1.00 pH units) .
  • Example 16 Composition:
  • the buffer was TRIS, HEPES or TES
  • a second no buffer was used with pH being adjusted with NaOH/HCl
  • a third phosphate buffer or phosphate/citrate buffer was used.
  • the compositions were prepared as in Example 1.
  • Degradation of the phospholipid, measured as free fatty acids (mg/mL) after autoclaving and after 1 month's storage at 40°C and 50°C was as follows: Buffer After autoclaving 1 month 40°C 1 month 50°C

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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Colloid Chemistry (AREA)

Abstract

On a amélioré la stabilité de compositions de phospholipides par l'addition d'un système de tampon comprenant de l'ammoniaque ou une amine hydrosoluble d'un pH, à 15 °C, inférieur ou égal à 9,5.
EP96931893A 1995-09-27 1996-09-25 Compositions de phospholipides stabilisees Withdrawn EP0857070A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9519654 1995-09-27
GBGB9519654.9A GB9519654D0 (en) 1995-09-27 1995-09-27 Stabilised phospholipid compositions
PCT/GB1996/002364 WO1997011683A2 (fr) 1995-09-27 1996-09-25 Compositions de phospholipides stabilisees

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EP0857070A2 true EP0857070A2 (fr) 1998-08-12

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EP96931893A Withdrawn EP0857070A2 (fr) 1995-09-27 1996-09-25 Compositions de phospholipides stabilisees

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EP (1) EP0857070A2 (fr)
JP (1) JP2000515487A (fr)
CN (1) CN1202830A (fr)
CA (1) CA2233135A1 (fr)
GB (1) GB9519654D0 (fr)
NO (1) NO981340L (fr)
WO (1) WO1997011683A2 (fr)

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JP4752987B2 (ja) * 2000-10-12 2011-08-17 ライオン株式会社 外用剤組成物
WO2007129311A2 (fr) * 2006-05-04 2007-11-15 Pan Sci Tech S.A. Nanoparticules avec agents de contraste pour systeme de delivrance diagnostique pour radiographie et tomodensitometrie
KR101565624B1 (ko) * 2007-12-20 2015-11-03 노파르티스 아게 콘택트 렌즈의 제조 방법
JP5299449B2 (ja) * 2011-02-23 2013-09-25 ライオン株式会社 外用剤組成物
CN104561156B (zh) * 2013-10-28 2020-07-07 丰益(上海)生物技术研发中心有限公司 制备饱和型磷脂的方法
GB201821049D0 (en) * 2018-12-21 2019-02-06 Ge Healthcare As Ultrasound contrast agent and methods for use therof

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IE60901B1 (en) * 1986-08-21 1994-08-24 Vestar Inc Improved treatment of systemic fungal infections with phospholipid particles encapsulating polyene antifungal antibiotics
US4962022A (en) * 1986-09-22 1990-10-09 Becton Dickinson And Company Storage and use of liposomes
ZA902710B (en) * 1989-05-22 1991-12-24 Univ Georgia Res Found Enzyme luminescence assay
CN1148812A (zh) * 1994-03-28 1997-04-30 尼科梅德成像有限公司 “脂质体”

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CA2233135A1 (fr) 1997-04-03
NO981340D0 (no) 1998-03-24
GB9519654D0 (en) 1995-11-29
NO981340L (no) 1998-03-24
JP2000515487A (ja) 2000-11-21
WO1997011683A3 (fr) 1997-06-26
WO1997011683A2 (fr) 1997-04-03
CN1202830A (zh) 1998-12-23

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