EP0999833A1 - Emulsion de taxol - Google Patents

Emulsion de taxol

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Publication number
EP0999833A1
EP0999833A1 EP98935215A EP98935215A EP0999833A1 EP 0999833 A1 EP0999833 A1 EP 0999833A1 EP 98935215 A EP98935215 A EP 98935215A EP 98935215 A EP98935215 A EP 98935215A EP 0999833 A1 EP0999833 A1 EP 0999833A1
Authority
EP
European Patent Office
Prior art keywords
composition according
emulsion composition
emulsion
emulsifier
tocopherol
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Withdrawn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
EP98935215A
Other languages
German (de)
English (en)
Inventor
Stanley Stewart Davis
Jihong Han
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.)
Kyowa Kirin Services Ltd
Original Assignee
West Pharmaceutical Services Drug Delivery and Clinical Research Center Ltd
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 West Pharmaceutical Services Drug Delivery and Clinical Research Center Ltd filed Critical West Pharmaceutical Services Drug Delivery and Clinical Research Center Ltd
Publication of EP0999833A1 publication Critical patent/EP0999833A1/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Withdrawn legal-status Critical Current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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K9/10—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

Definitions

  • the present invention relates to an emulsion and particularly to an emulsion comprising a drug, such as a taxane or derivative thereof. More particularly, the present invention relates to an emulsion comprising paclitaxel.
  • Taxanes are a class of natural products that includes the anticancer compound paclitaxel (Taxol). This compound is very poorly soluble in water and, as a result, it has been extremely difficult to develop mjectable formulations for clinical use. Various emulsion, liposome, nanoparticle and solubilized systems are described in the prior art - see, for example, the review by Jonkman-de Vries et al. Drug Dev. Ind. Pharm. 22 475 (1996)).
  • the marketed product Taxol sold by Bristol-Myers Squibb Pharmaceuticals, is a solubilized system containing paclitaxel, polyoxyethylated castor oil (Cremophor EL) and dehydrated alcohol. This formulation has the disadvantage that it must be diluted using aseptic techniques prior to infusion. Furthermore, the component Cremophor EL is known to give rise to hypersensitivity reactions.
  • Lipid emulsion formulations containing paclitaxel have also been described by Lundberg in J. Pharm. Pharmacol. 1997 49 16.
  • the oil phase used was triolein which was present at low concentration in the emulsion.
  • the emulsifiers were non-ionic block copolymers such as the poloxamers and poloxamines either as single components or in admixture with phospholipid emulsifiers such as egg lecithin.
  • the drug loading in the formulation was low.
  • Lundberg commented that most of the paclitaxel was situated in the surface layer of the emulsion droplet.
  • Examples of emulsion formulations containing Vitamin E and a drug have been described in WO-97/03651. These emulsion formulations comprised a lipid vehicle, such as vegetable oil, a drug contained in the lipid vehicle and Vitamin E to enhance the solubility of the drug in the lipid vehicle.
  • Vitamin E tocopherol
  • derivatives thereof such as tocopherol acetates, and tocotrienols which contain high loadings of taxanes such as paclitaxel
  • co-emulsifiers such as bile salts and fatty acids, the latter at alkaline pH, can impart good stability to Vitamin E and tocotrienol emulsions.
  • an emulsion composition having a lipid phase comprising a compound selected from tocopherol, tocotrienol and derivatives thereof, a phospholipid emulsifier and an ionic emulsifier.
  • an emulsion composition having a lipid phase comprising a compound selected from tocopherol, tocotrienol and derivatives thereof, a phospholipid emulsifier, an ionic emulsifier and a drug compound, such as a taxane or a taxane derivative.
  • tocopherol (Vitamin E) and tocotrienol we include the ⁇ -, ⁇ -, ⁇ - and ⁇ -forms thereof that differ by the number and position of methyl groups on the chromanol ring as well as the various isomers of these compounds.
  • derivatives of tocopherol and tocotrienol we are referring to the pharmaceutically acceptable derivatives of these compounds such as the esters of tocopherol, e.g. the linoleate, nicotinate, acetate or acid succinate ester.
  • Vitamin E and related compounds are not unequivocal in current practice and can vary when used by different compendia and organisations. This problem has been well addressed by Sheppard et al. in Vitamin E in Health and Disease, Editors Packer, L. and Fuchs, J. Dekker, New York 1993 p.9.
  • Vitamm E The United States Pharmacopoeia described Vitamm E as a form of ⁇ - tocopherol. This includes d- or d, 1 - ⁇ -tocopherol, d- or d, 1- ⁇ -tocopherol acetate and d- or d, 1 - ⁇ -tocopherol succinate.
  • Vitamin E is also used as a generic description for all tocopherol and tocotrienol derivatives that exhibit Vitamin E activity.
  • tocopherols is synonymous with Vitamin E, but also for methyl tocols.
  • tocopherol, tocotrienol and derivatives thereof we include all compounds that exhibit the general physiological activity of Vitamin E.
  • a mixture of two or more compounds selected from tocopherol, tocotrienol and the derivatives thereof may be used.
  • a preferred compound for use in the emulsions of the present invention is ⁇ -tocopherol as described in the United States Pharmacopoeia, Volume 23, 1995 which is also known as all-rac- ⁇ -tocopherol.
  • This material can be obtained from Roche Products Ltd., Heanor, UK.
  • the content of the tocopherol or tocotrienol or derivative in the emulsion can be from 5 to 30% w/v based on the total emulsion, i.e. from 5 to 30 g of tocopherol, tocotrienol or derivative per 100 mis of emulsion.
  • drug and drug compound we include all compounds which may be administered to a mammal and which are pharmaceutically, pharmacologically, therapeutically, diagnostically, cosmetically or prophylactically active or which are a prodrug for such a compound.
  • the drug is not a vitamin or dietary mineral such as zinc or iron.
  • the drug should have reasonable solubility in the tocopherol/tocotrienol lipid phase.
  • the drug has a solubility of at least 1 mg/ml, e.g. 1 to lOmg/ml, in the tocopherol, tocotrienol or derivative.
  • drugs that are poorly soluble in chlorinated organic solvents such as chloroform tend to be poorly soluble in Vitamin E.
  • drugs that have good solubility in chloroform have acceptable solubility in Vitamin E.
  • Suitable drugs preferably have a solubility in chloroform of 6mg/ml or more, preferably lOmg/ml or more.
  • the ratio of the solubility in chloroform (mg/ml) divided by the solubility in methanol (mg/ml) is preferably greater than 10, more preferably greater than 100.
  • saturated solutions of the drug in these solvents are prepared.
  • An appropriate means of preparing a saturated solution is to suspend approximately 60mg of drug in 3ml of the solvent and stir for 24 hours at room temperature. If all of the drug dissolves during this time, further 10 mg aliquots should be added until a suspension is again formed. After 24 hours, the suspension is centrifuged or filtered to separate drug in solution from undissolved particulate drug.
  • the drug solutions are assayed for drug content by an appropriate means, e.g. high performance liquid chromatography, and the saturated solubility calculated.
  • the suitability of a drug may also be determined by measuring its solubility parameter.
  • solubility parameter The ability of solvents to mix well together or for solvents to dissolve in solvents can be estimated using the procedure of solubility parameters. This method, based upon concepts of cohesion density, was developed originally by Hildebrand and refined by others for a wide range of materials. The concepts of solubility parameters is well reviewed by Barton in CRC Handbook of Solubility Parameters and Other Cohesion Parameters, 2nd Ed. CRC Press, 1991. Those skilled in the art often use this concept to estimate whether a particular drug (solute) will dissolve in a given solvent and the extent of such solubility. In order to do this the solubility parameter of the solute and solvent are required. While solubility parameter values are available for many solvents used in pharmaceutical formulations, solubility parameter values for drugs are not normally available. However, methods have been established wherein solubility parameter values can be calculated. The procedure described by Fedors is well known in this regard (Polym. Eng. Sci. 14 147, 1974).
  • solubility parameter for Vitamin E is estimated to be 9.7, similar to the value for chloroform (9.2). Methanol has a solubility parameter of 14.7. Those drugs that have solubility parameter values close to that of Vitamin E would be expected to show acceptable solubility in Vitamin E.
  • drugs that have a solubility parameter value between 8 and 13 and more especially between 9 and 12.
  • solubility parameter value between 8 and 13 and more especially between 9 and 12.
  • Drugs that are suitable for the emulsion formulation are antifungal agents such as itraconazole, anticancer agents such as taxol, hexamethylmelamine, penclomedine and lipophilic porphyrin derivatives, steroids such as pregnanolone, anaesthetic agents such as propofol (diisopropyl phenol), retinoid compounds, cardiovascular agents such as S-emapomil, agents such as prostaglandins, lipophilic peptides such as cyclosporin, and protein kinase C inhibitors such as dihydrosphingasine.
  • antifungal agents such as itraconazole
  • anticancer agents such as taxol, hexamethylmelamine, penclomedine and lipophilic porphyrin derivatives
  • steroids such as pregnanolone
  • anaesthetic agents such as propofol (diisopropyl phenol), retinoid compounds
  • cardiovascular agents such as S-emapomil
  • Especially preferred drugs for the emulsion compositions of the invention are taxanes and taxane derivatives including diterpenoid molecules that have antitumour activities by acting on microtubule assemblies in cells (microtubule stabilizing activity). These molecules include taxatere derivatives such as baccatin. Full details of such derivatives have been given by Parness et al. Biochem. Biophys. Res. Commun. 105 1082 (1982), Burkhart et al. Cancer 54 5779 (1994), guitarist et al., Fortschr. Chem. Org. Naturst. 61 1-206 (1993). Paclitaxel is especially preferred.
  • tocopherol and tocotrienols as carriers for the anti-tumour agent paclitaxel is expected to have the additional advantage in that tocopherols and especially tocotrienols have been shown to have anti- tumour activity (Kato et al. Abura Kajaku, 1985 24 375, Komiyama et al. Chem. Pharm. Bull. 1989 37 1369).
  • Oil in water emulsions of the present invention can contain up to 5 mg/ml, e.g. from 0.1 to 5 mg/ml and preferably from 1 to 5 mg/ml, of a taxane compound and still retain the desired stability.
  • desired stability we mean an emulsion in which the mean droplet diameter does not change by more than 20% over a storage period of 40 days and also that the taxane compound, which tends to dissolve in the lipid or oil phase provided by the Vitamin E or its derivative, does not precipitate as small crystals which would be hazardous on injection to a patient.
  • the phospholipid emulsifier which forms an essential component in the presently claimed emulsions can be any pharmaceutically acceptable material derived from soybeans or eggs, e.g. soy or egg lecithins.
  • Egg lecithins such as the material provided by Lipoid (Germany) known as Lipoid E80, are preferred, although other phospholipid materials could be used including phospholipid-polyethylene glycol (PEG) conjugates (PEGylated phospholipids) that have been described for use in liposome systems, e.g. by Litzinger et al, Biochem Biophys Acta, 1190 (1994) 99- 107.
  • PEG phospholipid-polyethylene glycol
  • Modified phospholipids of this type may be able to provide the emulsion with good- in vitro stability and may also minimise the interactions of the particles with elements of the reticuloendothelial system (in particular the Kupffer cells in the liver) as well as minimising the particle flocculation on injection and the capture of particles in the lung by mechanical filtration.
  • a suitable phospholipid-PEG conjugate is PEG- phosphatidyl ethanolamine.
  • the PEG chains in such an emulsifier will preferably have a molecular weight in the range of from about 2000 to about 5000, e.g. from about 2000 to about 4000.
  • a PEG chain having a molecular weight of about 2000 or about 5000 is especially preferred.
  • phospholipid emulsifiers such as a mixture of a PEGylated phospholipid and an unPEGylated phospholipid.
  • a preferred ratio of PEGylated to unPEGylated phospholipid is 1: 10 on a weight basis.
  • the phospholipid can be used at a concentration of 1 to 10% w/v but preferably from 2-4% w/v based on the total emulsion. In other words, the phospholipid can be present in an amount of from 1 to 10 g, preferably in an amount of from 2 to 4 g per 100 mis of emulsion.
  • Suitable ionic emulsifiers for use in the emulsions of the present invention include the fatty acids and salts thereof and bile acid and salts thereof.
  • Suitable fatty acids are those having greater than 8 carbon atoms in their structure with oleic acid being a preferred material.
  • the preferred ionic emulsifiers are the bile salts and the preferred bile salt is a salt of deoxycholic acid.
  • Suitable salts are the pharmaceutically acceptable salts such as the alkali metal, e.g. Na and K, salts.
  • the ionic co-emulsifier can be added at a concentration of 0.1 to 5% w/v on the total emulsion, but a preferred concentration range is 0.5 to 2 % w/v on the total emulsion.
  • the ionic -emulsifier can be present in an amount of from 0.1 to 5 g, preferably in an amount of from 0.5 to 2 g per 100 mis of emulsion.
  • the amount of the two emulsifier components may be increased with increase in the lipid or oil content of the emulsion.
  • the emulsifiers could be used at twice the concentration used for an emulsion containing 10 % w/v of the tocopherol, tocotrienol or derivative.
  • the pH of the final emulsion is preferably adjusted to a value equal to or greater than 8.5, e.g. in the range of from 8.5 to 9.5 in order to provide for improved stability.
  • the emulsions can be prepared by methods familiar to those skilled in the art including high pressure homogenisation and ultrasonics. We prefer to use a Microfluidizer system (Microfluidics Corporation, USA). Aseptic processing techniques can be used during the formation of the emulsion or, alternatively, the emulsion can be prepared and then terminally sterilized by heating in an autoclave. A rotating autoclave is preferred to m ⁇ imize instability in the emulsion system.
  • the emulsions of the -present invention are suitable for parenteral, nasal and oral administration, but are particularly useful for parenteral administration.
  • Paclitaxel (Taxol) was obtained from Bristol Myers Squibb. Vitamin E was obtained from Sigma. The phospholipid emulsifier, Lipoid E 80, was obtained from Lipoid, Germany. Sodium deoxycholate was obtained from Sigma.
  • An emulsion composition comprising 10% w/v of Vitamin E (i.e. lOg of Vitamin E per lOOmls of the final emulsion), 2% w/v of E80 (i.e. 2g of E80 per lOOmls of the final emulsion), 1 % w/v of sodium deoxycholate (i.e. lg of sodium deoxycholate per lOOmls of the final emulsion) and 2 or 4 mg/ml of paclitaxel was prepared as follows.
  • the paclitaxel, Vitamin E and E80 were dissolved in methanol. The solvent was removed using a stream of nitrogen. The mixture was then vacuum desiccated at room temperature for 2-3 hours. The resulting oily paste was then emulsified in water containing the sodium deoxycholate by sonication using a Dawe soniprobe. The pulse cycle was fixed at 50% . The output levels varied from 30-70% (normally the output level was gradually increased during the sonication). The emulsions were examined for the growth of paclitaxel crystals under a light microscope at different storage times over 30 days. Details are provided in Table 1.
  • Emulsions were prepared as in Example 1 containing 10% w/v and 20% w/v Vitamin E, 2 % w/v E80 and 0.5 % w/v sodium deoxycholate and 0.5 % w/v deoxycholic acid.
  • the drug content was varied from 2 to 8 mg/ml.
  • the particle size of the emulsion was measured by Photon Correlation Spectroscopy using a Malvern Instruments' PCS. The particle size was monitored over a period of 30 days at room temperature. The results on particle size of the emulsion and crystal growth are given in Table 2.
  • Table 2 Table 2
  • oleic acid was chosen as an ionic fatty acid emulsifier to be used in combination with the phospholipid material egg lecithin.
  • the oleic acid was converted to its sodium salt by the addition of sodium hydroxide so that in the final emulsion itself the ionic emulsifier was sodium oleate.
  • the Vitamin E and Lipoid E80 were dissolved in methanol and the solvent was then removed under a nitrogen stream. After the methanol had been removed the residue was vacuum desiccated at room temperature and the resulting oily paste was then emulsified in water containing the sodium oleate by microfluidisation to provide an emulsion with a fine particle size.
  • the emulsions had the following compositions.
  • Formulation 1 Vitamin E 10 g (20%)
  • Formulation 2 Vitamin E 10 g (20%)
  • Each emulsion was divided into two samples and one sample of each emulsion was left unchanged while the other had its pH adjusted using hydrochloric acid.
  • the stability of all the emulsions was then monitored by visual examination and, in particular, by looking for creaming of the oil particles to form a distinct layer at the top of the emulsion and the separation of free oil (a broken emulsion). If the emulsion was stable at the end of 43 days the particle size thereof was measured by Photon Correlation Spectroscopy using a Malvern Instruments' PCS. The results are given in Table 3 for Formulation 1 and in Table 4 for Formulation 2. It was found that stable emulsions could be produced using egg lecithin and sodium oleate as emulsifiers when the pH was greater than 8.5. Below this pH, the emulsions demonstrated poorer stability.
  • the oleic acid can be added as sodium oleate if required, once again the pH should be adjusted to 8.5 or greater, e.g. about 9.0 to provide good emulsion stability.
  • Example 4 Preparation of Emulsions Using PEGylated Phospholipids
  • Three emulsions were prepared using a modified phospholipid emulsifier comprising the conjugate of a polyethylene glycol moiety having a molecular weight of about 5000 and phosphatidyl ethanolamine (PEG5000-PE; Avanti Polar Lipids, USA).
  • a modified phospholipid emulsifier comprising the conjugate of a polyethylene glycol moiety having a molecular weight of about 5000 and phosphatidyl ethanolamine (PEG5000-PE; Avanti Polar Lipids, USA).
  • Emulsions containing Vitamin E, PEG5000-PE, Lipoid E80 and sodium deoxycholate or sodium oleate were prepared as follows.
  • Vitamin E, PEG5000-PE and Lipoid E80 were dissolved in methanol and the solvent was then removed under a nitrogen stream. After the methanol had been removed the residue was vacuum desiccated at room temperamre and the resulting oily paste was then emulsified in water containing the sodium deoxycholate or sodium oleate by sonication using a Dawe soniprobe. The pulse cycle was fixed at 50% . The output levels varied from 30-70% (normally the output level was gradually increased during the sonication). A typical increase scale was as follows:
  • the aqueous emulsions had the following compositions.
  • Formulation 3 Vitamin E 20 % w/v
  • Formulation 4 Vitamin E 5 % w/v
  • the particle size of the emulsions was measured by Photon Correlation Spectroscopy using a Malvern Instruments PCS. The results on the particle size and polydispersity after preparation are given in Table 5.
  • aqueous emulsions (Formulation 5 and Formulation 6) containing Vitamin E, PEG5000-PE, Lipoid E80 and sodium deoxycholate or sodium oleate (derived from the reaction of oleic acid with sodium hydroxide) were prepared using exactly the same technique as described in Example 4 except that microfluidization (15 cycles through the microfluidizer) was used instead of sonication to prepare the emulsion.
  • the aqueous emulsions had the following compositions.
  • Formulation 5 Vitamin E 10 % w/v
  • Formulation 6 Vitamin E 10 % w/v
  • the particle size for the emulsions stored at 4°C was measured by Photon Correlation Spectroscopy using a Malvern Instruments PCS. The results on the particle size and polydispersity at 0 days and 20 days are given in Table 6.
  • Example 5 Aggregation of the emulsions prepared in Example 5 in plasma was examined.
  • the emulsions were mixed with plasma (emulsio plasma weight ratio 1:2.5) and the mixmre was examined under a light microscope.
  • Example 5 The emulsions described in Example 5 were also prepared containing a loading of 2.5 mg/ml of paclitaxel. The same method as described in Example 5 was used with the paclitaxel being dissolved in the methanol along with the Vitamin E, PEG5000-PE and Lipoid E80. The emulsions prepared were of good stability.

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

Abstract

Composition émulsionnable comprenant une phase lipidique contenant un composé sélectionné dans tocophérol, tocotriénol et leurs dérivés, un émulsifiant phospholipidique et un émulsifiant ionique. Cette émulsion peut servir de support à un composé médicamenteux, tel qu'un taxane ou un dérivé de taxane.
EP98935215A 1997-07-26 1998-07-24 Emulsion de taxol Withdrawn EP0999833A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9715759.8A GB9715759D0 (en) 1997-07-26 1997-07-26 New emulsion formulations
GB9715759 1997-07-26
PCT/GB1998/002220 WO1999004787A1 (fr) 1997-07-26 1998-07-24 Emulsion de taxol

Publications (1)

Publication Number Publication Date
EP0999833A1 true EP0999833A1 (fr) 2000-05-17

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EP98935215A Withdrawn EP0999833A1 (fr) 1997-07-26 1998-07-24 Emulsion de taxol

Country Status (5)

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EP (1) EP0999833A1 (fr)
AU (1) AU8456198A (fr)
GB (1) GB9715759D0 (fr)
WO (1) WO1999004787A1 (fr)
ZA (1) ZA986645B (fr)

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US7030155B2 (en) 1998-06-05 2006-04-18 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
DE19843968A1 (de) * 1998-09-24 2000-04-13 Hans Dietl Taxane enthaltende pharmazeutische Zubereitung zur intravenösen Applikation und Verfahren zu ihrer Herstellung
CA2366884A1 (fr) * 1999-04-02 2000-10-12 Washington State University Research Foundation Administration amelioree de composes de vitamine e au niveau tissulaire et infracellulaire
CA2373994A1 (fr) * 1999-05-24 2000-11-30 Sonus Pharmaceuticals, Inc. Excipient en emulsion pour medicaments faiblement solubles
US6479540B1 (en) 1999-09-27 2002-11-12 Sonus Pharmaceuticals, Inc. Compositions of tocol-soluble therapeutics
AU2001293177A1 (en) * 2000-09-27 2002-04-08 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6919370B2 (en) * 2000-11-28 2005-07-19 Transform Pharmaceuticals, Inc. Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof
US6858227B1 (en) 2001-11-21 2005-02-22 Sonus Pharmaceuticals, Inc. Vitamin E conjugates
EP1340497A1 (fr) * 2002-03-01 2003-09-03 Novagali Sas Systèmes d'apport de médicament auto-émulsifiant pour médicaments à faible solubilité
WO2003074027A2 (fr) * 2002-03-01 2003-09-12 Novagali Pharma Sa Systemes d'apport de medicaments auto-emulsifiants pour medicaments faiblement solubles
KR20060110872A (ko) * 2003-10-29 2006-10-25 소너스파머슈티칼즈인코포레이티드 토코페롤 변성 치료제 약물 화합물
US7659310B2 (en) 2004-04-27 2010-02-09 Formatech, Inc. Methods of enhancing solubility of agents
EP1748759B1 (fr) * 2004-04-27 2013-03-27 Javeri, Indu Procedes permettant d'accroitre la solubilite d'agents
US7345093B2 (en) 2004-04-27 2008-03-18 Formatech, Inc. Methods of enhancing solubility of compounds
US8557861B2 (en) 2004-09-28 2013-10-15 Mast Therapeutics, Inc. Low oil emulsion compositions for delivering taxoids and other insoluble drugs
TWI376239B (en) 2006-02-01 2012-11-11 Andrew Xian Chen Vitamin e succinate stabilized pharmaceutical compositions, methods for the preparation and the use thereof
WO2010018596A2 (fr) 2008-07-23 2010-02-18 Bharat Serums And Vaccines Ltd. Nanoémulsion huile dans l'eau injectable stable de docétaxel
EP2480208A1 (fr) 2009-09-23 2012-08-01 Indu Javeri Méthodes de préparation de liposomes
US10143652B2 (en) 2009-09-23 2018-12-04 Curirx Inc. Methods for the preparation of liposomes

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AU8456198A (en) 1999-02-16
GB9715759D0 (en) 1997-10-01
ZA986645B (en) 2000-01-24
WO1999004787A1 (fr) 1999-02-04

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