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WO1996017594A1 - Agents sequestrants - Google Patents

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Publication number
WO1996017594A1
WO1996017594A1 PCT/GB1995/002908 GB9502908W WO9617594A1 WO 1996017594 A1 WO1996017594 A1 WO 1996017594A1 GB 9502908 W GB9502908 W GB 9502908W WO 9617594 A1 WO9617594 A1 WO 9617594A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrophilic
phase
hydrophobic
amphiphile
solvent
Prior art date
Application number
PCT/GB1995/002908
Other languages
English (en)
Inventor
Roger Randal Charles New
Christopher John Kirby
Original Assignee
Cortecs Limited
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 Cortecs Limited filed Critical Cortecs Limited
Priority to FI972411A priority Critical patent/FI972411A0/fi
Priority to AU41834/96A priority patent/AU4183496A/en
Priority to JP8517441A priority patent/JPH10510207A/ja
Priority to EP95940365A priority patent/EP0796086A1/fr
Publication of WO1996017594A1 publication Critical patent/WO1996017594A1/fr
Priority to NO972607A priority patent/NO972607L/no

Links

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
    • A61K9/10—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 the use of certain compounds aiding retention of hydrophilic molecules, solubilised in a hydrophobic phase in which they would not normally be soluble, in the hydrophobic phase when said hydrophobic phase is dispersed in a hydrophilic phase.
  • the present invention relates to the use of such agents for aiding retention of hydrophilic macromolecules in a hydrophobic phase in which they would not normally be soluble.
  • lipidic barriers eg skin, cell membranes
  • the ability to disperse proteins in lipidic vehicles would open up a new route to introduction of these macromolecules into biological systems, whereby the lipid medium containing the protein can integrate with the hydrophobic constituents of barriers, instead of being excluded by them.
  • Dispersion of hydrophilic substances in oil phase rather than aqueous media confers other benefits in terms of increasing their stability with respect to temperature- mediated denaturation, hydrolysis, light sensitivity etc.
  • Oils can be chosen which remain fluid over a wider temperature range than aqueous solutions, or that have a higher viscosity, resulting in greater protection against physical damage.
  • incorporation of hydrophobic substances in oil can limit mutually harmful interactions - eg oxidation - with other agents, both within the oil and in the aqueous phase.
  • formulations containing both macromolecules and oil there are examples of formulations containing both macromolecules and oil and one such example is disclosed in EP-A-0366277.
  • the formulation disclosed in this document is an emulsion having both a hydrophobic and a hydrophilic phase, wherein the hydrophobic phase contains chylomicra or chylomicron-forming lipids.
  • the macromoiecule is dissolved in the hydrophilic phase not in the hydrophobic phase.
  • EP-A-0521994 also relates to a composition suitable for the oral delivery of macromolecules which comprises a biologically active material in association with lecithin or a compound capable of acting as a precursor for lecithin in vivo.
  • All of the compositions exemplified are formulations which comprise a hydrophilic and a lipophilic phase.
  • the macromoiecule is initially dissolved in the hydrophilic phase rather than in the lipophilic phase.
  • UK patent application No. 9323588.5 discloses a process by which a hydrophilic species can be solubilised in a hydrophobic solvent in which it would not normally be soluble.
  • the process relies on the surprising discovery that if a hydrophilic species is mixed with an amphiphile under certain conditions, the resultant composition will be readily soluble in lipophilic solvents such as oils.
  • one potential problem with the product of such a process relates to its use in the production of an emulsion, by dispersion of the single phase hydrophobic preparation in a hydrophilic phase, for instance water.
  • a hydrophilic phase for instance water.
  • the solubilised hydrophilic species to "leak" into the hydrophilic phase thus reversing the solubilisation process.
  • the present invention provides the use of an agent to reduce the direct interaction between a hydrophilic species solubilised in a hydrophobic phase and a hydrophilic phase in which the hydrophobic phase is dispersed.
  • the term "agent” relates to any species which is capable of reducing direct interaction between a hydrophilic species solubilised in a hydrophobic phase in which it would not normally be soluble, when the hydrophobic phase is itself dispersed in a hydrophilic phase, for example to form an emulsion, and the hydrophilic phase.
  • the present invention provides a single phase hydrophobic preparation comprising a hydrophilic species solubilised in a hydrophobic solvent in which it would not normally be soluble and in addition an agent which reduces direct interaction between the hydrophobic species and a hydrophilic phase in which the hydrophobic preparation is dispersed.
  • hydrophilic species may be able to come into contact with individual molecules of the hydrophilic phase, it cannot come into contact with the bulk of the hydrophilic phase and hence this results in reduced “leakage” of the hydrophilic species into the hydrophilic phase.
  • hydrophilic species relates to any species which is generally soluble in aqueous solvents but insoluble in hydrophobic solvents.
  • the agent can be: (i) an acidic lipid, for example, cholesterol hemisuccinate (Chems) or phosphatidic acid; or
  • an emulsion stabiliser which cannot penetrate the hydrophobic phase e.g. a compound such as casein.
  • the invention also provides an agent for use in reducing direct interaction between a hydrophilic species, solubilised in a hydrophobic solvent in which it would not normally be soluble, and a hydrophilic phase in which the hydrophobic phase is dispersed, eg as an emulsion.
  • the agents described herein are used in a solubilisation process as described in UK patent application No. 9323588.5.
  • the invention provides a process for the preparation of a single phase hydrophobic preparation comprising a hydrophilic species, in a hydrophobic solvent, the process comprising:
  • the agent is added with the amphiphile in stage (i) and is preferably an emulsion stabiliser which cannot penetrate the hydrophobic phase, e.g. a compound such as cholesterol hemisuccinate (Chems) or phosphatidic acid (PA) .
  • an emulsion stabiliser which cannot penetrate the hydrophobic phase, e.g. a compound such as cholesterol hemisuccinate (Chems) or phosphatidic acid (PA) .
  • the term "chemical interaction” relates to an interaction such as a covalent or ionic bond or a hydrogen bond. It is not intended to include van der aals forces or other interactions of that order of magnitude.
  • the present invention provides a process for dispersing a single phase hydrophobic preparation, comprising a hydrophilic species in a hydrophobic solvent, in a hydrophilic phase, which comprises the step of adding to the hydrophilic phase an agent which reduces direct interaction between the hydrophilic species and the hydrophilic phase.
  • the agent is preferably an emulsion stabiliser which cannot penetrate the hydrophobic phase, e.g. a compound such as casein.
  • macromolecules can suitably be solubilised using the processes of the present invention.
  • the macromolecular compound will be hydrophilic or will at least have hydrophilic regions since there is usually little difficulty in solubilising a hydrophobic macromoiecule in oily solutions.
  • suitable macromolecules include proteins and glycoproteins, oligo and polynucleic acids, for example DNA and RNA, polysaccharides and supramolecular assemblies of any of these including, in some cases, whole cells, organelles or viruses (whole or parts thereof) .
  • Other macromolecules may be used are FITC-labelled dextran and RNA extract from Torulla yeast.
  • the process of the present invention is of use in solubilising smaller organic molecules.
  • small organic molecules include glucose, ascorbic acid, carboxyfluorescin and many pharmaceutical agents, for example anti-cancer agents, but, of course, the process could equally be applied to other small organic molecules, for example other vitamins or pharmaceutically or biologically active agents.
  • molecules such as calcium chloride and sodium phosphate can also be solubilised using the process of the invention.
  • the present invention would be particularly advantageous for pharmaceutically and biologically active agents since the use of non aqueous solutions may enable the route by which the molecule enters the body to be varied, for example to increase bioavailability.
  • an inorganic material such as a small inorganic molecule or a colloidal substance, for example a colloidal metal.
  • a colloidal metal such as colloidal gold, palladium, platinum or rhodium
  • amphiphiles which may be used in the present invention and zwitterionic amphiphiles such as phospholipids are among those which have been found to be especially suitable.
  • Phospholipids having a phosphatidyl choline head group have been used with particular success and examples of such phospholipids include phosphatidyl choline (PC) itself, lyso-phosphatidyl choline (lyso-PC) , sphingo yelin, derivatives of any of these, for example hexadecylphosphocholine or amphiphilic polymers containing phosphoryl choline and halogenated amphiphiles, e.g. fluorinated phospholipids.
  • PC phosphatidyl choline
  • lyso-PC lyso-phosphatidyl choline
  • sphingo yelin derivatives of any of these, for example hexadecylphosphocholine or amphiphilic poly
  • phosphatidyl choline PC
  • lecithin Suitable natural lecithins may be derived from any convenient source, for example egg and, in particular, soya. In most cases, it is preferable to select an amphiphile which is chemically similar to the chosen hydrophobic solvent and this is discussed in greater detail below.
  • hydrophobic solvent of choice will depend on the purpose for which the composition is intended, on the type of species to be solubilised and on the amphiphile.
  • Suitable solvents include non-polar oils such as mineral oil, squalane and squalene, long chain fatty acids with unsaturated fatty acids such as oleic and linoleic acids being preferred, alcohols, particularly medium chain alcohols such as octanol and branched long chain alcohols such as phytol, isoprenoids, e.g. nerol and geraniol, terpineol, monoglycerides such as glycerol monooleate
  • GMO GMO
  • esters e.g. ethyl acetate, amyl acetate and bornyl acetate, diglycerides and triglycerides, particularly medium chain triglycerides and mixtures thereof, halogenated analogues of any of the above including halogenated oils, e.g. long chain fluorocarbons or iodinated triglycerides, e.g. lipidiol.
  • halogenated oils e.g. long chain fluorocarbons or iodinated triglycerides, e.g. lipidiol.
  • amphiphile molecules into an array with their hydrophilic head groups facing the moieties of a hydrophilic species can be achieved in several ways and examples of particularly suitable methods are discussed in more detail below.
  • a hydrophilic species is mixed with a dispersion of an amphiphile in a hydrophilic solvent, such that the amphiphile molecules form an assembly in which the hydrophilic head groups face outwards towards the hydrophilic phase which contains the hydrophilic species.
  • the hydrophilic solvent is then removed to leave a dry composition in which the hydrophilic head groups of the amphiphile molecules are orientated towards the hydrophilic species.
  • the hydrophilic solvent is water although other polar solvents may be used.
  • the form taken by the amphiphile assembly may be micelles, unilamellar vesicles, preferably small unilamellar vesicles which are generally understood to have a diameter of about 25 nm, multilamellar vesicles or tubular structures, for example cochleate cylinders, hexagonal phase, cubic phase or myelin type structures.
  • the form adopted will depend upon the amphiphile which is used and, for example, amphiphiles such as phosphatidyl choline (PC) tend to form small unilamellar vesicles whereas lyso-phosphatidyl choline forms micelles.
  • the hydrophobic tails of the amphiphile molecules face inwards towards the centre of the structure while the hydrophilic head groups face outwards towards the solvent in which the hydrophilic species is dispersed.
  • the weight ratio of amphiphil :hydrophilic species will generally be in the region of from 1:1 to 100:1, preferably from 2:1 to 20:1 and most preferably about 8:1 for PC and 4:1 for lyso-PC.
  • ratios are preferred ratios only and, in particular, it should be pointed out that the upper limit is set by economic considerations which mean that it is preferable to use the minimum possible amount of amphiphile.
  • the lower limit is somewhat more critical and it is likely that ratios of 2:1 or below would only be applicable in cases where the hydrophilic species has a significant hydrophobic portion or is exceptionally large.
  • salts in the hydrophilic solution may be helpful to include salts in the hydrophilic solution, particularly if the hydrophilic species is a macromolecular compound such as a large protein.
  • organic salts are used rather than inorganic salts such as sodium chloride.
  • Ammonium acetate is especially suitable for this purpose since it has the additional advantage that it is easily removed by freeze drying.
  • a second method for the preparation of a composition containing an array of amphiphiles with their head groups pointing towards the moieties of the hydrophilic species is to co-solubilise the hydrophilic species and the amphiphile in a common solvent followed by removal of the solvent.
  • the product of the process of the invention is new and therefore, in a further aspect of the invention there is provided a single phase hydrophobic preparation comprising a hydrophilic species in a hydrophobic solvent obtainable by the process of the invention.
  • the preparation may include, for example, bile salts, vitamins or other small molecules which bind to or are otherwise associated with the macromolecules.
  • preparations of the present invention are effectively anhydrous and therefore more stable to hydrolysis.
  • proteins they are also stable to freeze-thawing and have greater stability at high temperatures, probably because water must be present in order for the protein to unfold and become denatured. This means that they may be expected to have a much longer shelf life than aqueous preparations of the hydrophilic species.
  • solutions of the present invention are extremely versatile and have many applications. They may either be used alone, but preferably they are combined with an aqueous phase to form an emulsion or similar two phase composition which forms yet a further aspect of the invention.
  • a two phase composition comprising a hydrophilic phase and a hydrophobic phase, the hydrophobic phase comprising a preparation of a hydrophilic species in a lipophilic solvent obtainable by a process as described herein.
  • the hydrophobic phase will be dispersed in the hydrophilic phase.
  • the two phase compositions may be emulsions which may either be transient or stable, depending on the purpose for which they are required.
  • the average size of the emulsion particles will depend on the exact nature of both the hydrophobic and the aqueous phases. However, it may be in the region of 2 ⁇ m
  • Dispersion of the hydrophobic preparation in the aqueous phase can be achieved by mixing, for example either by vigourous vortexing for a short time for example about 10 to 60 seconds, usually about 15 seconds, or by gentle mixing for several hours, for example using an orbital shaker.
  • the present invention provides a process for preparing a dispersion, eg an emulsion, of a hydrophobic phase in which is solubilised a hydrophilic species which comprises dispersing the hydrophobic phase in a hydrophilic phase to which has been added an agent which reduces the direct interaction between the hydrophilic species when so solubilised and the hydrophilic phase in which the hydrophobic phase is dispersed.
  • a 0.0015M borate buffer was prepared by dissolving 60mg of sodium tetraborate in 100 ml of distilled water, and adjusting the pH to 8.00.
  • 5 mg of BAPNA was weighed into a B9 glass screw-capped vial and dissolved in 3 ml of methanol.
  • 10 mg of trypsin was weighed into a 15 ml plastic centrifuge and 10 ml borate buffer added with vortexing. The suspension was mixed on a roller mixer, then undissolved material spun down, and the supernatant decanted.
  • Dilutions of aprotinin (50 ⁇ l/well) were dispensed along the rows of the microplate between 0 and 30 ⁇ g/ml concentration.
  • BAPNA solution from above was diluted 20-fold by adding 1 ml to 20 ml of buffer and 100 ⁇ l of BAPNA working solution was then introduced into each well and mixed thoroughly. The plate was incubated with shaking at 37°C for forty minutes and then read on a plate reader at 405 nm.
  • Aprotinin was solubilised in Miglyol 818 by lyophilising a mixture of 100 ⁇ l of soya phosphatidyl choline dispersion (100 mg/ml in distilled water) , sonicated as per the protocol in Example 4, and 25 ⁇ l of aprotinin solution (20 mg/ml in distilled water) , followed by addition of 100 ⁇ l of Miglyol 818.
  • the concentration of aprotinin was 5 mg/ml in oil .
  • a control solution was prepared as above, in which aprotinin was omitted.
  • Aqueous dispersions of these oils were prepared by 5 vortexing 10 ⁇ l of each oil with 1ml of borate buffer for ten seconds. The final concentration of aprotinin in these secondary dispersions was 0 and 50 ⁇ g/ml.
  • the dispersions were diluted two-fold and added to the wells of a microplate as described in the method above, where
  • Aprotinin was solubilised in Miglyol 818 as described in the example above, except that the phospholipid 5_ dispersion contained 10% by weight of phosphatidic acid in addition to phosphatidyl choline.
  • the dispersions were tested neat, and compared with control standards of 25 ⁇ g/ml and 12.5 ⁇ g/ml. Comparison with these standards indicates that no more than 25% of the aprotinin is 0 released into the aqueous phase.
  • Buffer 234 0.26 0 .273 0.283 0 .277
  • Aprotinin was solubilised in Miglyol 818 as described in the examples above, except that the phospholipid dispersion contained 10% by weight of cholesterol hemisuccinate (Chems) in addition to phosphatidyl choline.
  • the dispersions were tested neat, and compared
  • aqueous dispersion of soy phosphatidyl choline was prepared, containing lOOmg/g of suspension, flushed thoroughly with nitrogen, and sonicated at an amplitude of 8 microns peak to peak. Each aliquot was subjected to a total sonication time of 4 minutes, in pulses of 30 seconds interspersed by cooling for 30 seconds in an ice slurry bath. The resulting opalescent dispersion of small unilamellar vesicles (SUV) was then centrifuged for 15 minutes to remove particles of titanium.
  • soy phosphatidyl choline soy PC
  • Colloidal gold sol was prepared as follows. 15 ⁇ l of 25mM potassium carbonate, 15 ⁇ l of 1% tannic acid and 50mg of trisodium citrate were made up to a total weight of 22.5g with distilled water and 10ml was transferred to a 25ml stoppered glass conical flask (A) and heated to 60 C in a water bath. 25mg of gold chloride trihydrate was made up to 250mg with distilled water and 50 ⁇ l of the resulting solution was added to 40ml of distilled water in a 50ml stoppered glass conical flask (B) and heated to 60 C in the same water bath. The contents of flask A were mixed with those of flask B, and heating maintained for
  • Each of the resulting o/w emulsions was diluted with a further 9ml of PBS and then centrifuged for 40 minutes at 80000 g to break it down into its component fractions.
  • the surface layer of oil phase was carefully transferred to a vial for counting gamma radioactivity due to residual I 125 - labelled insulin.
  • the supernatent, containing any released I 125 -labelled insulin was transferred to a separate vessel, leaving behind any pellet that might have been formed.
  • the pellet, representative portions of supernatent and the residual oil fraction were all counted for radioactivity, making appropriate corrections for any contamination of the oil fraction with supernatant.
  • I- 125 -labelled insulin was prepared and incorporated into oil phases as described in Example 3 , but using the compositions listed below. Preparation no. Amphiphile System Oil phase
  • the pellet obtained is thought to be composed of oil containing a high proportion of phospholipid.
  • the preparation containing phosphatidic acid considerably less of the radiolabelled insulin is released into the aqueous supernatant than with the preparation containing just phosphatidyl choline alone.
  • 125 labelled insulin was prepared and incorporated into oil phases as described in Example 2, but using the composition listed below.
  • Preparation 1 One lOOmg aliquot of Preparation 1 was weighed into a 10ml centrifuge tube, and lml of 0.5% casein solution was added and vortexed thoroughly for 10 seconds. The contents of the tube were then diluted with 10ml of the 0.5% casein. The emulsion was then centrifuged and fractionated into its component phases as described in Example 2.
  • the resulting opaque emulsion was centrifuged at 500 g for 5 minutes and the upper, pink, oil-rich phase was decanted from the underlying clear aqueous phase and examined under the light microscope. All of the oil was now seen to be present as numerous, small, discrete droplets which showed no signs of coalescence. A proportion of the oil droplets appeared to be surrounded by an outer wall which was presumed to be due to interfacial complexation of the alginate by calcium ions released from the oil droplets. After standing for 12 days, there was still no signs of breakdown of the emulsion, either micro- or macroscopically.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biophysics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Colloid Chemistry (AREA)
  • Crystals, And After-Treatments Of Crystals (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Detergent Compositions (AREA)

Abstract

L'invention décrit l'utilisation d'un agent pour réduire l'interaction directe entre une phase hydrophobe et une phase hydrophile dans laquelle est dispersée la phase hydrophobe. L'invention décrit aussi des procédés pour obtenir des préparations hydrophobes monophasées contenant une espèce hydrophile, auxquelles est ajouté un tel agent.
PCT/GB1995/002908 1994-12-09 1995-12-08 Agents sequestrants WO1996017594A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
FI972411A FI972411A0 (fi) 1994-12-09 1995-12-08 Sekvestraatioaineet
AU41834/96A AU4183496A (en) 1994-12-09 1995-12-08 Sequestration agents
JP8517441A JPH10510207A (ja) 1994-12-09 1995-12-08 隔離剤
EP95940365A EP0796086A1 (fr) 1994-12-09 1995-12-08 Agents sequestrants
NO972607A NO972607L (no) 1994-12-09 1997-06-06 Sekvestreringsmidler

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9424901.8A GB9424901D0 (en) 1994-12-09 1994-12-09 Sequestration Agents
GB9424901.8 1994-12-09

Publications (1)

Publication Number Publication Date
WO1996017594A1 true WO1996017594A1 (fr) 1996-06-13

Family

ID=10765693

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1995/002908 WO1996017594A1 (fr) 1994-12-09 1995-12-08 Agents sequestrants

Country Status (11)

Country Link
EP (1) EP0796086A1 (fr)
JP (1) JPH10510207A (fr)
CN (1) CN1169114A (fr)
AU (1) AU4183496A (fr)
CA (1) CA2207274A1 (fr)
FI (1) FI972411A0 (fr)
GB (1) GB9424901D0 (fr)
IL (1) IL116311A0 (fr)
NO (1) NO972607L (fr)
WO (1) WO1996017594A1 (fr)
ZA (1) ZA9510459B (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997015331A1 (fr) * 1995-10-25 1997-05-01 Cortecs (Uk) Limited Procedes de preservation de micro-organismes
WO1998000169A1 (fr) * 1996-07-02 1998-01-08 Cortecs (Uk) Limited) Preparations hydrophobes contenant des monoglycerides de chaine moyenne
US6165773A (en) * 1995-10-25 2000-12-26 Provalis Uk Limited Methods of preserving viruses
US6368619B1 (en) 1993-11-16 2002-04-09 Provalis Uk Limited Hydrophobic preparations of hydrophilic species and process for their preparation
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US7030155B2 (en) 1998-06-05 2006-04-18 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2381520A1 (fr) * 1977-02-28 1978-09-22 Yamanouchi Pharma Co Ltd Compositions pour usage rectal
JPS574913A (en) * 1980-06-11 1982-01-11 Green Cross Corp:The Urokinase preparation for oral administration
FR2519864A1 (fr) * 1982-01-20 1983-07-22 Yamanouchi Pharma Co Ltd Composition huileuse a base de medicaments antitumoraux
WO1995013795A1 (fr) * 1993-11-16 1995-05-26 Cortecs Limited Preparations hydrophobes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2381520A1 (fr) * 1977-02-28 1978-09-22 Yamanouchi Pharma Co Ltd Compositions pour usage rectal
JPS574913A (en) * 1980-06-11 1982-01-11 Green Cross Corp:The Urokinase preparation for oral administration
FR2519864A1 (fr) * 1982-01-20 1983-07-22 Yamanouchi Pharma Co Ltd Composition huileuse a base de medicaments antitumoraux
WO1995013795A1 (fr) * 1993-11-16 1995-05-26 Cortecs Limited Preparations hydrophobes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
OKAHATA ET AL.: "a lipid-coated lipase as a new catalyst for triglyceride synthesis in organic solvent", J. CHEM. SOC. CHEM. COMMUN., 15 October 1988 (1988-10-15), pages 1392 - 1394 *
PATENT ABSTRACTS OF JAPAN vol. 006, no. 063 (C - 099) 22 April 1982 (1982-04-22) *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6368619B1 (en) 1993-11-16 2002-04-09 Provalis Uk Limited Hydrophobic preparations of hydrophilic species and process for their preparation
WO1997015331A1 (fr) * 1995-10-25 1997-05-01 Cortecs (Uk) Limited Procedes de preservation de micro-organismes
US6165773A (en) * 1995-10-25 2000-12-26 Provalis Uk Limited Methods of preserving viruses
WO1998000169A1 (fr) * 1996-07-02 1998-01-08 Cortecs (Uk) Limited) Preparations hydrophobes contenant des monoglycerides de chaine moyenne
US6258377B1 (en) 1996-07-02 2001-07-10 Provalis Uk Limited Hydrophobic preparations containing medium chain monoglycerides
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6660286B1 (en) 1997-01-07 2003-12-09 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6667048B1 (en) 1997-01-07 2003-12-23 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6982282B2 (en) 1997-01-07 2006-01-03 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US7030155B2 (en) 1998-06-05 2006-04-18 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs

Also Published As

Publication number Publication date
GB9424901D0 (en) 1995-02-08
ZA9510459B (en) 1997-06-09
AU4183496A (en) 1996-06-26
CN1169114A (zh) 1997-12-31
FI972411L (fi) 1997-06-06
NO972607D0 (no) 1997-06-06
IL116311A0 (en) 1996-03-31
EP0796086A1 (fr) 1997-09-24
MX9704272A (es) 1998-07-31
CA2207274A1 (fr) 1996-06-13
NO972607L (no) 1997-08-07
JPH10510207A (ja) 1998-10-06
FI972411A7 (fi) 1997-06-06
FI972411A0 (fi) 1997-06-06

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