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
• • 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

Definitions

• hydrophilic molecules for instance proteins
• hydrophobic species for example a lipid phase
• Advantages such as increased stability can be conferred on hydrophilic molecules in a lipid environment.
• transport of such hydrophilic species across lipidic barriers, e.g. the skin, would be facilitated.
• hydrophobic carriers for protein delivery
• liposomes Early proposals for using hydrophobic carriers for protein delivery included the use of liposomes. Later systems were non-liposomal, but still relied on the provision of a hydrophilic phase which carried the protein or other hydrophilic molecule, this hydrophilic phase forming an emulsion with a hydrophobic phase. Examples of such systems are disclosed in EP-A-0366277 and EP-A-0521994.
• the present 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 hydrophilic species and the amphiphile are first dissolved in a hydrophilic solvent, eg an aqueous solvent, often water alone, and this solution is then brought into association with the hydrophobic solvent.
• a hydrophilic solvent eg an aqueous solvent, often water alone
• the hydrophilic solvent removal step is conveniently achieved by lyophilisation, such that i is carried out at temperatures which will ensure that the hydrophobic solvent is maintained in the solid state until all the water has been removed.
• the oil may become liquid during lyophilisation, as a result of local rises in temperature in parts of the solid block (usually at the surface and edges) where all the hydrophilic solvent has already been removed.
• the cooling effect deriving from sublimation of hydrophilic solvent no longer exists, and in those areas the oil will melt. This situation will lead to the production of a satisfactory end-product providing that the oil is allowed to drain away from the remainder of the solid block as soon as it appears (if not, thenaccumulating oil will form a layer which prevents further
• the temperature during lyophilisation can be maintained such that the oil remains solid even after the hydrophilic solvent has been driven off.
• the temperature of the preparation is elevated to produce the single phase preparation. This can often simply be achieved by bringing the lyophilised preparation up to room temperature which in turn will cause the hydrophobic phase to return to the liquid state.
• Other methods for removal of hydrophilic solvent may also be employed, eg spray drying.
• hydrophilic species relates to any species which is generally soluble in hydrophilic solvents, eg aqueous solvents, but insoluble in hydrophobic solvents.
• the range of hydrophilic species of use in the present invention is diverse, but hydrophilic macromolecules represent an example of a species which may be used.
• the method of the present invention provides a convenient and relatively fast way of producing single phase preparations as described.
• the speed of the process is a particular advantage when one is concerned with the stability of the oil, the hydrophilic species or both, particularly when the concentration of amphiphile is high.
• lower ratios of amphiphile to hydrophilic species can be achieved, e.g. as low as 7:1, even when using , for instance, triglycerides as the hydrophobic phase, which permit a higher loading capacity for the preparations.
• amphiphile is "presented" in the hydrophilic phase.
• the amphiphile can first be dissolved or dispersed in the oil. This is particularly appropriate when using amphiphiles which do not disperse well in water.
• a further advantage of the ' method of the present invention is that it allows the use of amphiphiles which do not lyophilise well, for instance ones which are liquid at temperatures at which lyophilisation is normally carried out.
• macromolecules are suitable for use in 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 macromolecule 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 or organelles. It may also be convenient to co-solubilise a complex of a small molecule such as a vitamin in association with a macromolecule, for example a polysaccharide such as a cyclodextrin.
• Small molecules such as vitamin B12 may also be chemically conjugated with macromolecules and may thus be included in the compositions.
• proteins which may be successfully solubilised by the method of the present invention include insulin, calcitonin, haemoglobin, cytochrome C, horseradish peroxidase, aprotinin, mushroom tyrosinase, erythropoietin, somatotropin, growth hormone, growth hormone releasing factor, galanin, urokinase, Factor IX, tissue plasminogen activator, superoxide dismutase, catalase, peroxidase, ferritin, interferon, Factor VIII, microbial toxins, peptide and protein antigens and fragments thereof (all of the above proteins can be from any suitable source) .
• 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, 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 vitamins or pharmaceutically or biologically active agents.
• compounds such as calcium chloride and sodium phosphate can also be solubilised using this process.
• 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) , sphingomyelin, derivatives of any of these, for example hexadecylphosphocholine or amphiphilic polymers containing phosphoryl choline.
• PC phosphatidyl choline
• lecithin are used interchangeably.
• 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.
• the 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 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, monoglycerides such as glycerol monooleate (GMO) , diglycerides and triglycerides, particularly medium chain triglycerides and mixtures thereof.
• GMO glycerol monooleate
• Optimum results are generally obtained when the hydrophobic solvent and the amphiphile are appropriately matched.
• a solvent such as oleic acid
• lyso-PC is a more suitable choice of amphiphile than PC
• the converse is true when the hydrophobic solvent is a triglyceride.
• the hydrophobic phase is one with hydrophobic properties and wherein the hydrophilic solvent removal step is carried out under conditions which maintain the hydrophobic phase in a solid state.
• the base ia volatile base such as triethylamine.
• Suitable hydrophobic solvents include medium and long chain fatty acids examples of which include oleic acid and linoleic acid. This method is particularly useful for solubilising calcitonin or insulin.
• compositions produced using the methods of the invention may be used is for the oral delivery to mammals, including man, of substances which would not, under normal circumstances, be soluble in lipophilic solvents.
• This may be of use for the delivery of dietary supplements such as vitamins or for the delivery of biologically active substances, particularly proteins or glycoproteins, including insulin and growth hormones .
• hydrophobic preparations of hydrophilic compounds can very easily be incorporated into a cosmetic formulation.
• macromolecules which may be used in this way include those with moisturising or enzymatic action of some sort.
• the invention can also be used for the incorporation of proteins such as collagen into dermatological creams and lotions.
• the present invention provides the use of a process of the invention in the preparation of a pharmaceutical, cosmetic, nutrient, foodstuff or food supplement composition.
• a process of the invention in the preparation of a pharmaceutical, cosmetic, nutrient, foodstuff or food supplement composition.
• the processes of the invention when used in the preparation of a pharmaceutical composition, it will be one for topical, oral or opthalmic use.
• the invention has numerous uses in the field of chemical and biological synthesis, for example, non- aqueous enzymatic synthesis.
• BIO glass-screw capped vials were prepared containing the following quantities of the two solutions described above. The contents were mixed well.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Dispersion Chemistry (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Biophysics (AREA)
• Molecular Biology (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicinal Preparation (AREA)
• Coloring Foods And Improving Nutritive Qualities (AREA)

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• 1996
  • 1996-03-19 GB GBGB9605709.6A patent/GB9605709D0/en active Pending
• 1997
  • 1997-03-18 BR BR9708089A patent/BR9708089A/pt not_active Application Discontinuation
  • 1997-03-18 AU AU19364/97A patent/AU1936497A/en not_active Abandoned
  • 1997-03-18 ZA ZA972353A patent/ZA972353B/xx unknown
  • 1997-03-18 JP JP9533251A patent/JP2000507935A/ja active Pending
  • 1997-03-18 EP EP97907228A patent/EP0891184A1/de not_active Ceased
  • 1997-03-18 CA CA002248351A patent/CA2248351A1/en not_active Abandoned
  • 1997-03-18 KR KR1019980707401A patent/KR20000064684A/ko not_active Application Discontinuation
  • 1997-03-18 CN CN97193180A patent/CN1213962A/zh active Pending
  • 1997-03-18 WO PCT/GB1997/000749 patent/WO1997034581A1/en not_active Application Discontinuation
• 1998
  • 1998-09-18 NO NO984351A patent/NO984351D0/no unknown

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