EP0988055A1 - Compositions contenant des particules souples, un surfactant non ionique et un modificateur non ionique de point de trouble - Google Patents

Compositions contenant des particules souples, un surfactant non ionique et un modificateur non ionique de point de trouble

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Publication number
EP0988055A1
EP0988055A1 EP98909643A EP98909643A EP0988055A1 EP 0988055 A1 EP0988055 A1 EP 0988055A1 EP 98909643 A EP98909643 A EP 98909643A EP 98909643 A EP98909643 A EP 98909643A EP 0988055 A1 EP0988055 A1 EP 0988055A1
Authority
EP
European Patent Office
Prior art keywords
composition
cloud point
weight
ionic
flexible particles
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Withdrawn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
EP98909643A
Other languages
German (de)
English (en)
Inventor
George C. Nycomed Inc. NA
Jack H. Nycomed Inc. STEVENS
Barbara O. Nycomed Inc. YUAN
Daryl M. Nycomed Inc. SIMMONS
Gregory L. Nycomed Inc. McINTIRE
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.)
GE Healthcare AS
Original Assignee
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 Nycomed Imaging AS filed Critical Nycomed Imaging AS
Publication of EP0988055A1 publication Critical patent/EP0988055A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—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
    • 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
    • A61K47/06—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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasonic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasonic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/225—Microparticles, microcapsules
    • 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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers

Definitions

  • This invention relates to aqueous pharmaceutical or diagnostic compositions containing flexible particles, eg. emulsion droplets or vesicles, and in particular to formulation improvements which facilitate the heat sterilization of such compositions .
  • compositions containing emulsion droplets or flexible vesicles have been proposed for both therapeutic and diagnostic use.
  • vesicles may be used to carry or contain diagnostically or therapeutically effective agents, eg. contrast agents for diagnostic imaging modalities such as X-ray, MR, ultrasound, scintigraphy, light imaging, SPECT, PET, magnetotomography and electrical impedance tomography .
  • water-insoluble, liquid agents eg. iodinated contrast media for X-ray imaging, or fluorocarbons for use as oxygen carriers in blood replacements, have been formulated as oil-in-water emulsions.
  • Dispersions for parenteral administration generally require the use of a surfactant as an emulsifier or stabilizer, routinely at low concentrations, eg. 2% by weight .
  • non-ionic surfactants as emulsifiers (the term "emulsifier” will be used hereinafter to cover such surfactants used as emulsifiers and/or stabilizers in particulate dispersions) .
  • the use of non-ionics is further desirable since they impart steric stability.
  • non-ionic surfactant is used as an emulsifier for such flexible particle dispersions
  • problems of thermal sterilization are exacerbated as at elevated temperatures such non-ionic surfactants undergo a well-known phase separation (referred to- as a cloud point) which may cause the compositions to flocculate or coalesce.
  • non-ionic surfactant containing dispersions of flexible particles can be stabilized for thermal sterilization by the inclusion in the dispersion medium of a non-ionic water-soluble cloud point modifier at a concentration such that the cloud point of the dispersion medium is above the temperature used for steam sterilization, ie. generally 121°C or above.
  • a non-ionic water-soluble cloud point modifier at a concentration such that the cloud point of the dispersion medium is above the temperature used for steam sterilization, ie. generally 121°C or above.
  • Such modifiers are also useful for steam sterilization of such dispersions at lower temperatures, eg. at 90°C.
  • a diagnostic or therapeutic composition comprising physiologically tolerable, diagnostically or therapeutically effective flexible particles and a physiologically tolerable non-ionic surfactant emulsifier in an aqueous dispersion medium, characterised in that said aqueous dispersion medium further contains a physiologically tolerable non-ionic water-soluble cloud point modifier at a concentration such that the cloud point of said medium is above a temperature usable for steam sterilization, preferably above the temperature required for sterilization, usually 121°C or above.
  • the invention provides a process for the preparation of a sterile aqueous dispersion, said process comprising steam heat sterilizing (eg. by autoclaving) a composition comprising physiologically tolerable, diagnostically or therapeutically effective flexible particles, and a physiologically tolerable non-ionic surfactant emulsifier in an aqueous dispersion medium, characterised in that said aqueous dispersion medium further contains a physiologically tolerable non-ionic water-soluble cloud point modifier at a concentration such that the cloud point of said medium is above the steam sterilization temperature, preferably above 121°C.
  • steam heat sterilizing eg. by autoclaving
  • a composition comprising physiologically tolerable, diagnostically or therapeutically effective flexible particles, and a physiologically tolerable non-ionic surfactant emulsifier in an aqueous dispersion medium, characterised in that said aqueous dispersion medium further contains a physiologically tolerable non-ionic water-soluble cloud point modifier at a concentration
  • the invention provides the use of heat sterilized compositions according to the invention in therapy or diagnosis, eg. in a diagnostic imaging procedure.
  • Non-ionic, water-soluble cloud point modifiers useful according to the invention include poly (ethylene glycols) (eg. PEG 300, PEG 400, PEG 1000, PEG 1450 and PEG 2000, preferably PEG 1450), propylene glycols, monoalcohols (such as methanol, ethanol and isopropanol) , polyols (such as sorbitol, mannitol and glycerol) and cyclodextrins .
  • the compositions according to the invention may contain a single non-ionic cloud point modifier or a mixture of two or more non-ionic cloud point modifiers .
  • the quantity of non-ionic cloud point modifier used will depend upon the nature and quantity of the other excipients present in the dispersion medium but will be a quantity sufficient to raise the cloud point above the temperature required for sterilization.
  • the necessary amount may readily be determined by the person of ordinary skill in pharmaceutical science. Generally the amount will be in the range 0.1 to 50% by weight (relative to the weight of the aqueous phase of the composition) , particularly 1 to 30%, more particularly 5 to 20%.
  • non-ionic surfactant emulsifiers used in the compositions of the invention may be for example alkylene oxide polymers or copolymers, eg. poloxamers such as the Pluronics (eg. Pluronic F68 and 108 which are block copolymers of ethylene oxide and propylene oxide) or poloxamines such as the Tetronics (eg.
  • Tetronic 908 Tetronic 908 and the Carbowaxes (which are polyethylene glycols (PEGs) ) , tyloxapol, polyvinylpyrrolidone, polyoxyethylene sorbitan fatty acid esters (Tweens) , polysorbates (Spans) , polyoxyl hydrogenated castor oil (Cremophore) , polyoxyl stearates, alkylpolyoxyethylenes, PEG-modified phospholipids, and P-79.
  • PEGs polyethylene glycols
  • Tweens polyoxyethylene sorbitan fatty acid esters
  • Spans polysorbates
  • Cremophore polyoxyl hydrogenated castor oil
  • PEG-modified phospholipids PEG-modified phospholipids
  • P-79 The preparation of P-79 is described in Example 2k of WO96/07437 which is herein incorporated by reference .
  • the non-ionic surfactant emulsifier is P-79, especially preferably a poloxamer and most preferably a polyoxyethylene sorbitan fatty acid ester or polysorbate.
  • compositions according to the invention contain at least one non- ionic surfactant together with at least one different water-soluble non-ionic material in concentrations sufficient that a stable dispersion (one which does not settle out in less than 24 hours, preferably one which does not settle out in less than 6 months) of the flexible particles is formed in a dispersion medium having a cloud point above a steam sterilization temperature, eg. above 121°C, preferably in the range 90°C to 140°C, especially 121°C to 135°C.
  • the total concentration of emulsifier and cloud point modifier will generally lie in the range 5 to 70% by weight, especially 8 to 30%, relative to the weight of the aqueous phase of the composition.
  • the dispersion medium is preferably substantially free from dissolved ionic species, eg. salts and other ionic excipients . This is important as the presence of such ionic species generally lowers the cloud point (the temperature at which phase separation of the non-ionic surfactant occurs) and may provoke aggregation of the suspended particles .
  • the ionic strength of the dispersion medium is 0.5M or below, preferably 0.15M or below.
  • the medium will preferably be made substantially isotonic by the inclusion of physiologically tolerable non-ionic osmolality adjusting agents, eg. sugars and polyols such as sucrose, glucose and mannitol, or by the cloud point modifier itself.
  • physiologically tolerable non-ionic osmolality adjusting agents eg. sugars and polyols such as sucrose, glucose and mannitol, or by the cloud point modifier itself.
  • the particles in the compositions of the invention may be any flexible particles which have a desired diagnostic or therapeutic effect. Examples include droplets of insoluble iodinated liquids (eg. the X-ray contrast agents described in US-A-5260049) , or fluorocarbons (eg.
  • fluorocarbons such as are used in blood substitutes, for example perfluorodecalin
  • vesicles containing or carrying a diagnostic or therapeutic agent eg. the vesicles disclosed in PCT/GB96/01362, W096/24381, US-A-5425366 , W096/25955, EP-A-458745, W092/22298, US-A-5573751 , WO95/26205, DE-A- 4219723, PCT/GB95/02378 etc
  • the particles are X-ray, MR, ultrasound or scintigraphic contrast agents, and especially preferably they are iodinated X-ray contrast agents.
  • the particles may be substantially neutrally charged (eg. to produce extended blood residence times) but may alternatively if desired carry a small net surface charge.
  • the cloud point modifier used according to the invention must be non-ionic and must be essentially free from ionic impurities (ie. no more than 1% wt, preferably no more than 0.5%, most preferably no more than 0.1% ionic impurity is generally permissable) in order to avoid modifying the surface charge of the particles.
  • the particles in the compositions of the invention may be of any size suitable for parenteral administration, eg. 5 to 8000 n , but since the option for sterile filtration is not available for larger particles it is particularly preferred that the particles have a mean size of 100 to 8000 nm, especially 250 to 6000 nm.
  • the particle concentration may be the conventional value for diagnostic or therapeutic efficacy for the particular particles chosen, eg. 0.05 to 50% by weight, preferably 0.5 to 20%, relative to the overall weight of the composition.
  • the compositions may contain the particles at higher concentrations than are required on administration, and may be diluted, eg. with water for injections, saline, Ringer's solution, or a sugar solution, just before administration.
  • the diluent fluid need not be, but preferably is, non-ionic and/or isotonic.
  • pyrogen- free water eg. water for-injections .
  • Certain insoluble plant oils eg. soya oil, do have cloud point modifying abilities . It is known that plant oils such as soya oil are contaminated with ionic phospholipids (such as lecithin) , which are known to impart heat stability and charge to flexible particles (see US-A-5298262) . However, as they represent mixtures of various different chemical species such plant oils are not desirable excipients for parenteral use.
  • compositions of the invention are preferably essentially free of such oils, eg. containing at maximum 0.5% by wt. plant oil.
  • Heat sterilization in the process of the invention may be carried out in a conventional fashion, eg. by autoclaving (steam or moist heat sterilization) .
  • Sterilization is preferably effected for at least 15 minutes, preferably 20 minutes or more, at a temperature of 121°C or slightly higher. In some cases, sterilization is performed at lower temperatures for longer times, eg. 110°C for 90 minutes.
  • the cloud point modifiers of the invention are useful in such conditions .
  • NC 65373 is the sec-octyl ether of 2 , 4, 6-triiodophenol . It is prepared as described in Example 1 of US-A- 5260049.
  • An emulsion of sesame oil was prepared by combining sesame oil, P-79, and water in a ratio of 10:2:88 (ie., 10% sesame oil, 2% P-79, and 88% water) .
  • P-79 described in Example 2k of PCT/GB95/02109 is a PEG- double ester of molecular weight about 10 kD and formula CH 3 (CH 2 ) 14 COO(CH 2 ) 15 COO( (CH 2 ) 2 0) n CH 3 .
  • the cloud point of P- 79 is 104°C in the absence of modifiers) .
  • the resulting suspension was then passed through a Microfluidics MHOS microfluidizer at 14,000 PSI at least 6 times.
  • the particle size of the emulsion was 196 nm.
  • this emulsion was autoclaved under standard conditions (ie. 121°C for 20 minutes), it took on the appearance of cottage cheese, being somewhat flocculated. Upon shaking, this appearance was broken and an emulsion of 229 nm was obtained (particle sizing by light scattering with a Horiba 901a particle sizer) .
  • sesame oil was selected to produce a model emulsion system.
  • parenteral use it would be replaced by a therapeutic or diagnostic agent oil or a combination of sesame oil and a therapeutic or diagnostic agent oil or other parenteral oils.
  • An emulsion was prepared as in Example 2 using 10% sesame oil, 15% NC 65373 (an iodinated contrast agent which is also an oil at room temperature) , 2% P-79, and 15% PEG 1450 (58% water) with a droplet size of 196 nm.
  • NC 65373 an iodinated contrast agent which is also an oil at room temperature
  • PEG 1450 15% PEG 1450 (58% water) with a droplet size of 196 nm.
  • the emulsion retained its appearance with a particle size of 216 nm without agitation of the sample.
  • the addition of the non-ionic cloud point modifier, PEG 1450 afforded an autoclavable emulsion.
  • Micelles are defined as thermodynamically stable aggregates of amphiphilic molecules in solution.
  • the amphiphilic molecules may be ionic (ie. cationic, anionic, or zwitterionic) depending on the charge associated with the hydrophilic moiety of the molecule or the "head group” .
  • Another large class of amphiphilic molecules is nonionic in character having either polyhydroxy or polyoxyethylene oxide polar moieties . These molecules aggregate into micelles and can solubilize otherwise water insoluble molecules such as therapeutic and diagnostic agents. Unlike the ionic micelles, these aggregates undergo a distinct phase separation at elevated temperatures known as the cloud point .
  • Table 1 illustrates the impact of nonionic cloud point modifiers (i.e. PEG 1450, and propylene glycol) on a 3% (wt/vol%) solution of nonionic surfactant, Tyloxapol, which is above the critical micelle concentration (cmc) . It is apparent from the data that the addition of nonionic cloud point modifiers avoids phase separation during heat sterilization and maintains the micelles in their conventional form.
  • Table 1 Impact of Propylene Glycol and PEG 1450 on the Cloud Point of a 3% Solution of Tyloxapol.
  • Table 2 illustrates the effect of the addition of nonionic cloud point modifiers upon the cloud point of a 2% (wt/vol%) solution of the nonionic, polymeric surfactant P-79.
  • Both nonionic cloud point modifiers are able to elevate the cloud point of a 2% solution of P-79 above that require for steam sterilization (e.g. 121°C) .
  • this level of P-79 is above the cmc and thus micelles are present in the solution.
  • contrast agents and some therapeutic drugs are in themselves nonionic amphiphilic molecules such that they will aggregate into micelles in aqueous solution and will exhibit the same cloud point behavior as more conventional nonionic surfactants . These types of nonionic micelles will also benefit from the addition of nonionic cloud point modifiers and accompanying heat sterilization.
  • Liposomes are hollow spheres of phospholipids arranged in a bilayer such that there are aqueous media both inside and outside the membrane/liposome . While several phospholipids are neutral inasmuch as they exhibit a net charge of zero, they are still zwitterionic molecules (eg. lecithin) . Thus, in general, liposomes are charged particles. However, the process of making these particles "invisible" to the defense systems of the body requires the use of polyethylene oxide (PEG) modified phospholipids to effectively mask the charge of the liposome and make them act like nonionic particles. Thus the use of nonionic cloud point modifiers may further benefit these "stealth" liposomes with respect to steam sterilization.
  • PEG polyethylene oxide
  • liposomes can be prepared at a concentration of 1.2% lecithin, 0.8% dimyristylphosphatidyl glycerol (DMPG) and 0.5% dipalmitoylphosphatidyl ethanolamine conjugated to PEG or methoxy PEG 5000 (molecular weight) .
  • DMPG dimyristylphosphatidyl glycerol
  • dipalmitoylphosphatidyl ethanolamine conjugated to PEG or methoxy PEG 5000 (molecular weight) a nonionic cloud point modifier
  • heat sterilization of these particles would not be expected to be successful due to unacceptable particle size growth and aggregation.
  • the liposomes should survive steam sterilization.
  • the nonionic cloud point modifier should be both inside and outside the phospholipid membrane. This is to maintain an equiosmolar concentration across the membrane. Without this, the osmotic pressure may be enough to cause the liposomes to shrink due to water transport to the outside of the membrane where the concentration of nonionic cloud point modifier is higher.
  • P-79 can be used to "stealth" these types of liposomes and that the cloud point of this nonionic surfactant can be elevated above the temperature required for steam sterilization.
  • Polymer microbubbles are prepared by generating an emulsion using 5 mL of 5 P-73 (a membrane forming polymer having the repeat unit
  • shelf temperature is raised to -20°C for primary drying under 300 m torr for 36 to 48 hours. Shelf temperature is then raised to -5°C for secondary drying for about 4 hours.
  • the lyophilised product is reconstituted by adding glucose solution to give a total concentration of 10 mg/mL (or 1%) for P-73 and P-7 combined and an isotonic aqueous phase. The product is then steam sterilized at 121°C for 20 minutes.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biophysics (AREA)
  • Acoustics & Sound (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Physics & Mathematics (AREA)
  • Radiology & Medical Imaging (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention se rapporte à une composition de diagnostic ou une composition thérapeutique contenant dans un milieu aqueux de dispersion, d'une part, des particules souples physiologiquement tolérables, efficaces du point de vue du diagnostic ou du point de vue thérapeutique, et d'autre part, un surfactant non ionique physiologiquement tolérable, utilisé comme émulsifiant. Ladite composition est caractérisée par le fait que ledit milieu aqueux de dispersion contient en outre un modificateur de point de trouble physiologiquement acceptable, non ionique et soluble dans l'eau, ledit modificateur se trouvant dans une concentration telle que le point de trouble dudit milieu est supérieure à une température utilisable pour la stérilisation à la vapeur.
EP98909643A 1997-03-14 1998-03-16 Compositions contenant des particules souples, un surfactant non ionique et un modificateur non ionique de point de trouble Withdrawn EP0988055A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9705340 1997-03-14
GBGB9705340.9A GB9705340D0 (en) 1997-03-14 1997-03-14 Compositions
PCT/GB1998/000778 WO1998041239A1 (fr) 1997-03-14 1998-03-16 Compositions contenant des particules souples, un surfactant non ionique et un modificateur non ionique de point de trouble

Publications (1)

Publication Number Publication Date
EP0988055A1 true EP0988055A1 (fr) 2000-03-29

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Application Number Title Priority Date Filing Date
EP98909643A Withdrawn EP0988055A1 (fr) 1997-03-14 1998-03-16 Compositions contenant des particules souples, un surfactant non ionique et un modificateur non ionique de point de trouble

Country Status (6)

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EP (1) EP0988055A1 (fr)
JP (1) JP2001515503A (fr)
AU (1) AU6412598A (fr)
GB (1) GB9705340D0 (fr)
NO (1) NO994335L (fr)
WO (1) WO1998041239A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7255877B2 (en) 1996-08-22 2007-08-14 Jagotec Ag Fenofibrate microparticles
US6979456B1 (en) 1998-04-01 2005-12-27 Jagotec Ag Anticancer compositions
GB9822158D0 (en) * 1998-10-09 1998-12-02 Nycomed Imaging As Compositions
CN103550155A (zh) * 2013-11-08 2014-02-05 江南大学 一种抑制卵磷脂/非离子表面活性剂混合胶束中溶血磷脂产生的方法
TWI820051B (zh) * 2017-11-01 2023-11-01 日商武田藥品工業股份有限公司 醫藥組合物、醫藥組合物之安定化方法、及評價醫藥組合物之保存安定性之方法

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Publication number Priority date Publication date Assignee Title
JPS6078916A (ja) * 1983-10-03 1985-05-04 Tanpei Seiyaku Kk 安定な内服用懸濁液
JPS6087222A (ja) * 1983-10-19 1985-05-16 Shionogi & Co Ltd イミダゾ−ル系抗真菌性外用乳化製剤
SE470477B (sv) * 1992-10-05 1994-05-24 Procell Bioteknik Ab Salva innehållande fibronektin för behandling av sår
US5346702A (en) * 1992-12-04 1994-09-13 Sterling Winthrop Inc. Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization
US5352459A (en) * 1992-12-16 1994-10-04 Sterling Winthrop Inc. Use of purified surface modifiers to prevent particle aggregation during sterilization
US5326552A (en) * 1992-12-17 1994-07-05 Sterling Winthrop Inc. Formulations for nanoparticulate x-ray blood pool contrast agents using high molecular weight nonionic surfactants

Non-Patent Citations (1)

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Title
See references of WO9841239A1 *

Also Published As

Publication number Publication date
AU6412598A (en) 1998-10-12
JP2001515503A (ja) 2001-09-18
WO1998041239A1 (fr) 1998-09-24
GB9705340D0 (en) 1997-04-30
NO994335L (no) 1999-11-05
NO994335D0 (no) 1999-09-07

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