II 1111111111111
`
`US005714520A
`[11] Patent Number:
`[451 Date of Patent:
`
`5,714,520
`Feb.3, 1998
`
`United States Patent [19]
`Jones et al.
`
`[54] PROPOFOL COMPOSTION CONTAINING
`EDETATE
`
`[75]
`
`Inventors: Christopher Buchan Jones. Prestbury;
`John H-enry Platt. Congleton. both of
`United Kingdom
`
`[73] Assignee: Zeneca Limited. London. United
`Kingdom
`
`[21] Appl. No.: 408,707
`
`[22] Filed:
`
`Mar. 22, 1995
`
`[30]
`
`Foreign AppliC1ltioo Priority Data
`
`Mar. 22, 1994 [GB) Ua..ited Kingdom ................... 9405593
`Int. CL 6
`.................. ................................... A61K 31/&5
`[51]
`[52] U.S. CI ............................................................... 514/731
`[58] F1eld of Search ............................................... 514n31
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENfS
`
`Re. 32,393
`3,334,545
`4,056,635
`4,452,817
`4,567,161
`4,798,846
`
`4/1987 Wretlind et al ......................... 514/219
`5/1968 Aidlo et al ............................... 167/81
`11/1977 Glen eta!. .............................. 424/346
`6/1984 Glen et al ............................... 4241346
`1/1986 Posa.oski ct al . .......................... 514123
`1/1989 Glen et al .
`.............................. 5141731
`
`FOREIGN PATENT DOCUMENI'S
`
`220152
`0372331
`0572190
`4281835
`930069
`1472793
`
`4/1987
`6/1990
`12/1993
`7/1992
`6/1993
`5/1977
`
`European Pat. Off ..
`Ewopea.n Pat. Off ..
`European Pat. Off ..
`Japan.
`South Africa .
`United Kingdom .
`
`OfHER PUBUCATIONS
`
`Russell et al .. Ethylenediaminetetra-acetic acid. Inhibition
`and Destruction of the Microbial Cell. 1971. pp. 209-224.
`Chew et al .. In Vitro Growth Inhibition of Mastitis Causing
`Bacteria by Phenolics and Metal Chelators. Journal of Dairy
`Science, 1985.68.pp.3037-3046.
`Morita et al.. The Effects of Copper and EIJfA on the
`Autoxidation of Phospholipid Emulsions. Agr. Bioi. Chem..
`1972. vol. 36. No.7. pp. 1163-1167.
`Hart et al. Chelating Agents as Preservative Potentiators.
`Cosmetic and Drug Preservation: Principles and Practice.
`Chapter 18. 1985, pp. 323-337.
`Postsurgical Infections Associated with an Extrinsically
`Contaminated Intravenous Anesthetic Agent -California.
`Dlinois. Maine. and Michigan. 1990. Morbidity and Mor(cid:173)
`tality Weekly Report (MMR). Jun. 29. 1990. pp. 426-427.
`433.
`Trissel, Handbook on Injectable Drugs. 1994. 8th Edition.
`pp. 63, 115. 125-127. 133. 269. 308. 314-316. 318-319.
`484-485.536-537.590-591.612-613.687-689.722-723.
`664-665.770-771.815.902-903.920-921.934-935. 1007.
`1104.
`Nakamura et al .. Direct Vasoconstrictor And Vasodilator
`Effects Of Propofolln Isolated Dog Arteries, British Journal
`of Anaesthesia. Feb. 1992. pp. 193-197.
`
`Patel et al .. Dosodium Salt Of EDTA As An Antimicrobial
`Agent. Indian Journal of Pharmacy. May. 1995, pp.
`147-148.
`Mouton et al .. Effect Of I.V. Anaethesia With Propofol On
`Drug Distribution And Metabolism In The Dog. B-ritish
`Journal of Aoaethesia. Jan. 1991. pp. 66-72.
`Chemical Abslract No. 113:84881. Morita et al .. Ophthalmic
`Solutions Containg Benzalkonium Chloride. P-hydroxyben(cid:173)
`zoate Esters and Chelating Agents. Sep. 3. 1990.
`Derwent Publication Absttact JP2096515. Apr .. 1990.
`Patent Abstracts of Japan No. JPA 02096515. Apr .• 1990.
`Russell. Effect of Magnesium Ions and Ethylenediamine
`Tetra-acetic Acid on the Activity of Vancomycin against
`Escherichia coli and Staphylococcus aureus. 1967. J. appl.
`Bact.. 30. 395-401.
`Bennett et al .. Postoperative Infections Traced to Contami(cid:173)
`nation of an Intravenous Anesthetic. Propofol. The New
`England Journal of Medicine. Jul.. 1995. pp. 147-154.
`Simmons. CDC Guidelines for the Prevention and Control
`of Nosocomial Infections; Guidelines for prevention of
`intravascular infection. American Journal of Infection Con(cid:173)
`trol. Oct.. 1983. pp. 183-193.
`Crocker et al.. Microbial Growth Comparisons of Five
`Conunercial Parenteral
`lipid Emulsions. Journal of
`Parenteral and Enteral Nutrition. 1984. pp. 391-395.
`D' Angio et al .. The Growth of Microorganisms in Total
`Parenteral Nutrition Admixtures. Journal of Parenteral and
`Enteral Nutrition. 1987. pp. 394-397.
`Melly et al. Microbial Growth in Lipid Emulsions Used in
`Parenteral Nutrition. Arch Surg. 1975. pp. 1479-1481.
`Gilbert et al.. Microbial Growth Patterns in a Total
`Parenteral Nutrition Formulation Containing Lipid Emul(cid:173)
`sion. Journal of Parenteral and Enteral Nutrition. 1986. pp.
`99.494-497.
`Thompson et al .. Infection Control of Parenteral Nutrition
`Solutions. Nutrition in Clinical Practice. Apr. 1991. pp.
`49-54.
`Grier et al .. So Much Writing. So Little Science: A Review
`of 37 Years of Literature on Edetate Sodium Chelation
`Therapy. The Annals of Pharmacotherapy, Dec .. 1993. pp.
`1504-1509.
`Haque and Russell. Effect of Ethylenediaminetelraacetic
`Acid and Related Chelating Agents on Whole Cells of
`Gram-Negative Bacteria. Antimicrobial Agents and Chemo(cid:173)
`therapy. May. 1974, pp. 447-452.
`
`(List continued on next page.)
`
`Primary Emminer-William R.A. Jarvis
`Anome~ Agent, or Film-Cushman Darby & Cushman
`Intellectual Property Group of Pillsbury Madison & Sutro.
`LLP
`
`[57]
`
`ABSTRACT
`
`Sterile pharmaceutical compositions for parenteral admin(cid:173)
`istration containing 2.6-diisopropy1phenol (propofol) are
`described for use as anesthetics. The compositions comprise
`an oil-in-water emulsion of propotol additionally containing
`a amount of edetate sufficient to prevent significant growth
`of microorganisms for at least 24 hours after adventitious.
`extrinsic contamination.
`
`39 Claims, No Drawings
`
`Dr. Reddy's Laboratories
`v.
`Fresenius Kabi USA, LLC
`U.S. Patent No. 8,476,010
`Exhibit 1014
`
`Exh. 1014
`
`

`
`5,714,520
`Page2
`
`OTHER PUBUCATIONS
`
`Haque and Russell. Effect of Chelating Agents on the
`Susceptiblity of Some Strains of Gram-Negative Bacteria to
`Some Antibacterial Agents. Antimicrobial Agents and Ch~
`motherapy. Aug. 1974. pp. 200-206.
`Russell. Modification of the Bacterial Cell Envelope and
`Enhancement of Antibiotic Susceptibility. Olapter of The
`Control of Antibiotic-Resistant Bacteria. Academic Press.
`1982. pp. 119-165.
`Hart. EDT A-Type Chelating Agents in Personal Care Prod(cid:173)
`ucts. Cosmetics & Toiletries. Apr. 1983. pp. 54-58.
`Hart. Chelating agents in cosm etic and toiletry products.
`Cosmetics & Toiletries. Dec. 1978. pp. 28-30.
`Hart. EUfA-Type Chelating Agents in Everyday Consumer
`Products: Some Medicinal and Personal Care Products.
`Journal of Chemical Education. Dec. 1984. pp. 1060-1061.
`Kabara. GRAS antimicrobial agents for cosmetic products.
`J. Soc. Cosmet Chern.. Jan./Feb. 1980. pp. 1-10.
`Kraniak ct al .. Effect of Ethylcnediamioctctraacetic Acid
`(EDTA) and Metal ions on Growth of Staphylococcus
`aureus 196E in Culture Media. Journal of Food Science.
`1988. pp. 910-913.
`Bhagat et aL Growth response of Pseudomonas stutzeri
`RS34 to ethylenediaminetetraacetic acid (EDTA) and its
`interaction with zinc. Indian Journal of Experimental Biol(cid:173)
`ogy. Jul. 1993. pp. 590-594.
`
`Houben et al .• C()ntrolling Growth of Streptococcus faecium
`in a Ham Model with Heat and Ethylenediamine Tetraacetic
`Acid. Tertiary butylhydroquinone or Nisin. Meat Science.
`1985. pp. 205-215.
`Trissel. Handbook of Injectable Drugs. 1994. pp. 381-383.
`Martindale's Pharmacopeia. 1993. p. 681.
`U.S. Data Sheet for Edetate Disodium. 1990.
`Professional Information Brochure. DIPRIVAN (propofol)
`Injection. Emulsion For IV Administration. Rev L Oct.
`1994.
`Parenteral Preparations. British Pharmacopoeia 1993. vol.
`n. PP· 746-747.
`The Pharmaceutical CODEX. Principles and Practice of
`Pharmaceutics. 1\velfth Edition. pp. 102-103. 1992.
`The United States Pharmacopeia. The National Formulary.
`1995. pp. 1650-1652: 1733-1735; 1681.
`Trissel. Handbook of Injectable Drugs. 1994. pp. 464-465.
`558-559. 593-9 and 662-663.
`Shooter et al .. Mineral Requirements for Growth of Staphy(cid:173)
`lococcus Pyrogenes. Effect of Magnesium and Calcium
`Ions. The British Journal of Experimental Pathology. 1955.
`pp. 341-350.
`Sack et al .. Factors Affecting The Production of Staphylo(cid:173)
`coagulase in a Chemically Defined Medium. The Ohio
`Journal of Science. Sep .• 1963. pp. 232-240.
`
`Exh. 1014
`
`

`
`5,714,520
`
`1
`PROPOFOL COMPOSTION CONTAINING
`EDETATE
`
`The present invention relates to 2.6-diisopropylphenol.
`known as propofol. and in particular to new pharmaceutical
`compositions containing propofol.
`Propofol is an injectable anaesthetic which has hypnotic
`properties and can be used to induce and maintain general
`anaesthesia and for sedation for example in Intensive Care
`Units. Propofol is a highly successful anaesthetic and is
`marketed under the trademark 'Diprivan' for use in treating
`humans and under the trademark 'Rapinovet' for veterinary
`use.
`Injectable anaesthetics., such as propofol, are adminis(cid:173)
`tered directly into the blood stream. This gives rise to a rapid
`onset of anaesthesia influenced almost entirely by the rate at
`which the anaesthetic agent crosses the blood-brain barrier.
`It is therefore necessary for the anaesthetic agent to have
`sufficient lipid solubility to be able to cross lh.is barrier and
`depress the relevant mechanisms of the brain. However 20
`highly lipid soluble molecules are generally poorly soluble
`in water and thus are difficult to formulate for intravenous
`injection. In some cases it may be possible to obtain a water
`soluble salt of the anaesthetic agent which releases a lipid
`soluble free base in vivo. This is not possible in many cases 2S
`and. despite considerable research. it did not prove to be
`feasible with propofol. Thus it was necessary to conduct
`very substantial research and development into the formu(cid:173)
`lation of propofol in order to obtain pharmaceutical com(cid:173)
`positions for administration to warm-blooded animals 30
`includin.g humans.
`The p resent applicants identified the anaesthetic proper(cid:173)
`ties of propofol and filed UK patent application no l3739n4
`which was granted as United Kingdom Patent 1472793.
`Corresponding patents have been granted in the USA (U.S. 3S
`Pat. Nos. 4,056.635. 4.452.817 and 4.798.846) and many
`other territories.
`1bis patent claims inter alia a sterile pharmaceutical
`composition which comprises propofol in association with a
`sterile pharmaceutically-acceptable diluent or carrier the 40
`composition being suitable either directly or after dilution
`with a liquid diluent for parenteral administration to a
`warm-blooded animal.
`In one aspect. UK 1472793 described the composition as
`preferably aqueous with propofol in sterile admixture with
`water aod a surfactant or other solubilising agent. Io another
`aspect the composition was described as aqueous with
`propofol in sterile admixture with water and an additional
`water-miscible, non-aqueous solvent. In a further aspect the
`composition was described as an oil-in-water emulsion in
`whlch propofol , either alone or dissolved in a water(cid:173)
`immiscible solvent. is emulsified with water by means of a
`surfactant. In yet a further aspect the composition was
`described as a sterile solid or semi-solid mixture of propofol
`with a s<>lid diluent. for example lactose. saccharin sodium
`or a cydodextran which composition is suitable for dilution
`with a sterile aqueous diluent.
`The patent describes many particular Examples of inject(cid:173)
`able compositions containing propofol including Examples
`with various surfactants. various solubilising agents. addi(cid:173)
`tional solvents. additional constituents (selected from
`stabilisers. preservatives and antioxidants). buffering agents
`and tonicity modifiers.
`The present applicants conducted a wide range of studies
`to determine which type of formulation would be most
`appropriate for development to provide a formulation for
`marketing. After considerable effort a formulation of pro.-
`
`2
`pofol and the surfactant Cremophor EL (Cremophoc is a
`trade mark for a polyoxyethylene castor oil derivative) in
`water was selected. Cremophor EL was used as the carrier
`to solubilise the existing intravenous anaesthetic
`s alphaxalone/alphadolone ('Althesin') and a modified form
`of Cremophor was used as the carrier to solubilise the
`intravenous anaesthetic propanidid ('Epontol').
`The present applicants conducted a detailed series of
`studies in animals and ultimately administered the fonnu-
`10 lation to over 1000 humans. However. after about five m six
`years. anaphylactoid reactions wa:e reported in a very small
`number of patients. Anaphylactoid reactions are allergic(cid:173)
`type reactions. It was not clear that Cremophor EL bad
`caused the anaphylactoid reactions in all instances but the
`15 present applicants concluded that an alternative formulation
`of propofol would have to be found and developed.
`A substantial amount of work on alternative formulations
`was performed and an oil-in-water emulsion was eventually
`selected for development. This was developed and in 1986
`was launched in a number of markets under the trade mark
`'Diprivan'. Since then this formulati on has been launched in
`many markets throughout the world and propofol is highly
`successful being regarded by anaesthetists as a drug of great
`merit having unique qualities. In summary propofol is a
`short-acting anaesthetic. suitable for both induction and
`maintenance of general anaesthesia. for sedation to Sllpple-
`ment regional analgesic techniques. for sedation of venti(cid:173)
`lated patients receiving intensive care and for conscious
`sedation for surgical and diagnostic procedures in Intensive
`Care Units. Propofol may be administered by single or
`repeated intraven<>us bolus injections or by continuous infu-
`sion. It is very rapidly removed from the blood stream and
`metabolised. Thus the depth of anaesthesia is easily con(cid:173)
`trolled and patient recove:cy on discontinuing the drug is
`usually rapid and the patient is often significantly more clear
`beaded as compared to after administration of other anaes-
`thetics. Side-effects such as nausea and vomiting occur
`significantly less frequently following administration of
`propofol than following other general anaesthetic techniques
`such as with inhalational anaesthetics.
`The present applicants have considered extending the
`range of propofol formulations in order to give the anaes(cid:173)
`thetist a wider armamentariwu from which to select an
`appropriate drug. For example applicants have developed. as
`45 an alternative. an oil-in-water emulsion formulation of pro(cid:173)
`pofol wherein the concentration of propofol is twice that of
`the presently marketed drug.
`In considering appropriate further formulations it is
`desirable to maintain the qualities that make 'Diprivan' of
`so such merit, such as those aforementioned and provide a
`formulation with acceptable chemical and physical stability
`and which is readily manipulable by the anaesthetist or
`Intensive Care Unit (ICU) specialist.
`An increasing proportion of the usage of 'Diprivao • is in
`ss the sedation of seriously ill patients particularly in Intensive
`Care Units and the like. In the sedation of such seriously ill
`patients administration of 'Diprivan' is typically by means
`of infusion. 1bis requires the use of a 'giving set', which
`involves the linkage of a reservoir (typically a vial or
`60 syringe) of propofol. via appropriate tubing. to a luer con(cid:173)
`nector and thence to a needle positioned in the patient's vein.
`Microbial contamination of parenteral fluids used in
`'giving sets' of this type has been recognised as one of many
`causes of nosocomial infection amongst ICU patients.
`6S Accordingly. for example in the USA. the general require(cid:173)
`ments of the Federal Food and Drug Administration (FDA)
`are that such 'giving sets' are changed frequently and in the
`
`Exh. 1014
`
`

`
`5,714,520
`
`3
`case of 'Ditxivan'. it is required that the 'giving sets' are
`changed at least every 6 or 12 hours dependent on the
`presentation being used.
`Intensive Care environments are busy and. as in other
`parts of the health services. there are pressures for cost(cid:173)
`containment. The changing of 'giving sets' at least every 6
`or 12 hours is relatively tim.e-conswning for the highly
`skilled ICU nurse. Intensive Care Specialist or anaesthetist.
`This would particularly be the case when a number of
`seriously ill patients in an ICU are being infused at the same
`time.
`Therefore. the applicants have sought to develop a new
`formulation of propofol which would enable 'giving sets' to
`be changed significantly less frequently (for example every
`24 hours). This would be much more convenient for the
`nurse. Intensive Care Specialist or anaesthetist; would lower
`the pressure on staff. would result in fewer manipulations of
`'giving sets' and may contribute to cost-saving in the ICU
`environment.
`We have conducted substantial research and have found
`that the addition of s.mall amounts of a selected agent to
`'Diprivan' will enable the formulation to be administered in
`'giving sets' that require changing significantly less fre(cid:173)
`quently than is presently the case; in other words the time for
`administration and time between changes of the giving sets
`has been significantly imp£oved. This increase in such times
`enables packs of increased size to be administered. increas(cid:173)
`ing convenience for the users. deaeasing wastage of 'Ditxi(cid:173)
`van ' and contributing to cost-containment.
`Furthermore. in the unlikely event of mishandling lead(cid:173)
`ing to accidental extrinsic contamination. the formulation
`will minimise the chance of miaobial growth.
`Our own UK Patent 1472793 discloses !hat formulations
`of propofol may optionally contain one or more additional
`constituents selected from stabilisers, preservatives and
`antioxidants. for example parabens derivatives. for example
`propyl p-hydroxybenzoate. butylated hydroxytoluene
`derivatives. ascorbic acid and sodium metabisulphite; metal
`ion sequestering agents. for example sodium edetate; and
`antifoaming agents. for example a silicone derivative. for
`example dimethicone or simethicooe.
`The:re is a difficulty in the addition of koown preserva(cid:173)
`tives to oil-in-water emulsions such as 'Diprivan'. As stated
`above, 'Diprivan' is an anaesthetic used fe6 induction and
`maintenance of general anaesthesia and for sedation. The
`volumes administered can be considerable. partirularly in
`the case of sedation. Accordingly. significant volumes of
`preservative may be administered to the patient receiving
`treatment. Thus very careful selection of additive must be
`made in order to satisfy drug Regulatory Authorities; par(cid:173)
`ticularly as the use of preservatives in single-dose. termi(cid:173)
`nally sterilised, parenteral injectables is not s uggested and/or
`is the subject of cautionary statements in various Guidelines.
`for example those of the US. UK and European Pbarma(cid:173)
`copcias.
`Furthermore there is a particular p-oblcm in the inclusion
`of additives in an oil-in-water emulsion for parenteral
`administration. It is believed that fer effectiveness. the
`antimicrobial properties of any preSCl'Vative have to be
`exerted in the aqueous phase. Thus, a preservative with
`lipophilic properties incCipCiated at typical usage levels
`would not be effective as, although there would be some
`partitioning between the phases, there would be insufficient
`material in the aqueous phase. Increasing the overall quan(cid:173)
`tity of such preservative would result in unacceptably high
`levels of preservative in the lipid layer leading to toxicity
`problems at least.
`
`lS
`
`10
`
`4
`O n the other hand. addition of a preservative with
`hydrophilic properties, eg an ionic material. also leads to
`problems. The addition of ionic material to an oil-in-water
`emulsion tends to destabilise the emulsion. With a higher
`s ionic load (that is· concentration of ionic material) the
`stabilising electrical charge (Zeta potential) on the oily
`droplets can change. Such electrical charge changes increase
`the probability of droplet collisions and increase the physical
`instability of the emulsion.
`We studied the possibility of adding one of a number of
`antimicrobial agents to the oil-in-water emulsion. Such an
`agent would have to have no significant detrimental effect on
`the physical and chemical stability of the emulsion.
`Furthermore. such an agent would have to provide the
`antimicrobial activity being sought.
`A number of potential agents were found to cause
`instability of the emulsion. Other potential agents failed to
`provide the level of antimicrobial activity being sought. In
`addition. we were seeking an agent that would provide these
`levels of activity at as low a concentration as possible in
`20 order to minimise the potential for physical instability and to
`minimise safety concerns.
`After significant effort including consideration of the
`known preservatives phenylmercuric acetate, phenylmercu(cid:173)
`ric nitrate. benzyl alcohol, chlorobutanol. chlorocresol and
`~ phenol and the study of the known preservatives sodium
`metabisulphite. sodium sulphite. sodium methyl hydroxy(cid:173)
`benzoate and sodium propyl hydroxybenzoate. we were
`unable to find a preservative that met our requirements. We
`then investigated the possible use of other agents which
`30 might have the action th.at we sought. We unexpectedly
`found that edetate. which is not regarded as a broad spec(cid:173)
`trum antimicrobial agent was the only agent that would meet
`our requirements. As referred to above. edetate as the
`sodium salt is mentioned in our UK Patent 1472793 as a
`3S possible metal io n sequestering agent. Sodium edetate is
`included in two of tbe many Cremophor-containing
`examples of that Patenl
`Accordingly the present invention provides a sterile
`pharmaceutical composition for parenteral administration
`40 which comprises an oil-in-water emulsion in which propofol
`dissolved in a water-immiSCible solvent. is emulsified with
`water and stabilised by means of a surfactant. and which
`further comprises an amount of edetate sufficient to prevent
`significant growth of microorganisms for at least 24 hours
`45 (in the event of :adventitious. extrinsic contamination).
`By an oil-in-water emulsion we mean a distinct two(cid:173)
`phase system that is in equilibrium and in effect. as a whole.
`is kinetically stable and thennodynamically unstable. 'This is
`in complete contrast to a micellar formulation, for example
`so with Cremophor EL. which is thttmodynamically stable ..
`By the term .. edet.ate" we mean ethylenediaminetetraace(cid:173)
`tic acid (EDTA) and derivatives thereof, for example the
`disodium derivative is kDown as disodium edetate. In gen(cid:173)
`eral suitable edelates of this invention are those salts having
`ss lower affinity for EDTA than calcium. Particular derivatives
`of use in the present invention include trisodium edetate.
`tetrasodium edet.ate and disodium calcium edet.ate. The
`nature of the edetate is not criticaL provided that it fuUils the
`function of preventing si&nificant growth of microorganisms
`60 for at least 24 hours in the event of adventitious extrinsic
`contamination (e.g. preferably no more than 10-fold increase
`following a low level of extrinsic contaminll.tion. sucb as
`10-103 colony fami.ng units. at temperatures in the range of
`20°-25° C.). As can be seen from the experimental section.
`6S sodium calcium edctate bas some advantages over other
`additives but disodium edetate is exceptional. Accordingly.
`most preferably the edetate is disodium edetate.
`
`Exh. 1014
`
`

`
`5,714,520
`
`5
`Typically the edetate will be present in the compositions
`of the present invention in a molar concentration (with
`respect to the EDTA free acid) in the range 3xlo-s to
`9xl0 ....... Preferably the edetate is present in the range 3xlo-s
`to 7.5xto-<~ for example in the range Sxlo-s to Sxl0--4 and
`more pa:eferably in the range l.Sxl0--4 to 3.0xl0-'~ most
`preferably about l.Sxl0--4.
`A composition of the present invention typically com(cid:173)
`prises from 0.1 to 5%. by weight. of propofol. Preferably the
`composition comprises from 1 to 2% by weight of propofol
`and. in particular. about 1% or about 2%.
`In another aspect of the invention propofol alone is
`emulsified with water by means of a surfactant. It is pre(cid:173)
`ferred that propofol is dissolved in a water-immiscible
`solvent prior to emulsification.
`The water-immiscible solvent is suitably present in an
`amount that is up to 30% by weight of the composition, more
`suitably 5-25%. preferably 10-20% and in particular about
`10%.
`A wiide range of water-immiscible solvents can be used
`in the compositions of the present invention. Typically the
`water-immiscible solvent is a vegetable oil. for example soy
`bean. sa:fflower. cottonseed. corn. sunflower. arachis. castor
`or olive oil. Preferably the vegetable oil is soy bean oil.
`Alternatively. the water-immiscible solvent is an ester of a
`medium or long-chain fatty acid for example a mono-. di-.
`or triglyceride; or is a chemically modified or manufactured
`material such as ethyl oleate. isopropyl myristate. isopropyl
`palmirate. a glycerol ester or polyoxyl hydrogenated castor
`oil. In a further alternative the water-immiscible solvent may
`be a marine oil. for example cod liver or another fish-derived
`oil. Suitable solvents also include fractionated oils for
`example fractionated coconut oil or modified soy bean oil.
`Furthermore. the compositions of the present invention may
`comprise a mixture of two or more of the above water(cid:173)
`immiscible solvents.
`Propofol. either alone or dissolved in a water-immiscible
`solvent. is emulsified by means of a surfactant Suitable
`surfactants include synthetic non-ionic sUtfactants. for
`example ethoxylated ethers and esters and polYP£opylene(cid:173)
`polyethylene block co-polymers. and phosphatides for
`example naturally occuring phosphatides such as egg and
`soya phosphatides and modified or artificially manipulated
`phosphatides (for example prepared by physical fraction(cid:173)
`ation and/or chromatography). or mixtures thereof. Pre(cid:173)
`ferred surfactanis are egg and soya phosphatides.
`The composition of the present invention is suitably
`formulated to be at physiologically neutral pH. typically in
`the range 6.0-8.5. if necessary by means of alkali such as
`sodium hydroxide.
`The composition of the present invention may be made
`isotonic with blood by the incorporation of a suitable
`tonicity modifier for example glycerol.
`The composition of the present inventions are typically
`sterile aqueous formulations and are prepared according to 55
`conventional manufacturing techniques using for example
`aseptic manufacture or terminal sterilisation by autoclaving.
`The comp<>sitions of the present invention are useful as
`anaesthetics which includes sedation and induction and
`maintenance of general anaesthesia. Accordingly in another 60
`aspect the present invention provides a method of producing
`anaesthesia (including sedation and induction and mainte(cid:173)
`nance of general anaesthesia) in a warm-blooded animal,
`including humans. which comprises administering parenter(cid:173)
`ally a sterile aqueous pharmaceutical composition which 65
`comprises an oil-in-water emulsion in which propofol. either
`alone or in a water-immiscible solvent. is emulsified with
`
`6
`water and stabilised by means of a surfactant and which
`further comprises an effective amount of edetate.
`Dosage levels of propofol for producing general
`anaesthesia. both induction (for example about 2.0-2.5
`5 mgfkg for an adult) and maintenance (for example about
`4-12 mglkglhr). and for producing a sedative effect (for
`example 0.3-4.5 mglkglhr). may be derived from the sub(cid:173)
`stantial literature on propofol. Furthermore the anaesthetist
`and/or physician would modify the dose to achieve the
`10 desired effect in any particular patient. in accordance with
`normal skill in the art.
`The advantages referred to above for including edetate in
`propofol compositions apply also to intravenous fat emul-
`15 sions which typically are administe-red. to patients in need
`thereof. over periods of a day or more. Intravenous fat
`emulsions (also known as parenteral nutrition emulsions) are
`administered. usually by infusion. to patients having require(cid:173)
`ments for additional calories and adequate nutrition. by oral
`20 or other means. is not desirable or is not possible. Intrave(cid:173)
`nous fat emulsions typically maintain a positive nitrogen
`balance and provide an a~uate source of energy (e.g. as
`fat). vitamins and trace elements. Such emulsions are used
`typically in intensive care environments but also in other
`25 hospital and domestic settings. Examples of such intrave(cid:173)
`nous fat emulsions include Intralipid (marketed by
`Pharmacia), Upofundin (Braun) and.Travamulsion (Baxter).
`lntralipid. Upofundin and TravamuJ.sion are all trademarks.
`Accordingly .i!n another aspect. the present invention
`30 provides an intravenous fat emulsion which comprises an
`amount of edetate sufficient to prevent significant growth of
`microorganisms for at least 24 hours. In particular the
`present iove!ltion pro-vi<ies a st~i!e, aqueous composition
`35 for parenteral administration which comprises an oil-in(cid:173)
`water emulsion in which a water-immiscible solvent is
`emulsified with water and stabilised by means of a surfactant
`and which further comprises an amount of edetate sufficient
`to prevent significant growth of microorganisms for at least
`40 24 hours.
`Furthermore. it has been proposed that various drugs
`may be administered in oil-in-water emulsions. for example
`see U.S. Pat. No. 4.168308. Accordingly in a further aspect.
`the present invention provides a sterile. aqueous composi-
`45 tion for parenteral administration which comprises an oil(cid:173)
`in-water emulsion containing a therapeutic or pharmaceuti(cid:173)
`cal agent. in which the agent. either alone or dissolved in a
`water-immiscible solvent. is emulsified with water and sta-
`bilised by means of a surfactant and which further comprises
`50 an amount of edetate sufficient to prevent significant growth
`of microorganisms for at least 24 hours.
`Suitable therapeutic or pharmaceutical agents are those
`capable of being administered parenterally in an oil-in-water
`emulsion. Typically such agents are lipophilic compounds
`and may for ex.ample be antifungal agents. anaesthetics.
`antibacterial agents. anti-cancer agents. anti-emetics. agents
`acting on the central nervous system such as diazepam.
`steroids. barbiturates and vitamin preparations. In particular
`the present invention relates to sucb oil-in-water emulsions
`which typically are administered. to patients in need thereof.
`over periods of a day or more.
`Comments herein relating to typical and preferred pro(cid:173)
`pofol compositions of this invention and the preparation
`thereof apply mutatis mutandis to intravenous fat emulsions
`and to oil-in-water emulsions containing a therapeutic or
`pharmaceutical agent
`
`Exh. 1014
`
`

`
`7
`EXPERlMENTAL
`
`5,714,520
`
`8
`
`Quantities:
`
`propoful
`soy bcao oil
`eag pbospbatidc
`glycerol
`disodi.UIII edetlle diby<hle
`(equivalent 10 disodium edotate
`sodium hydroxide
`Water fur Jnjectjoos
`
`1.0
`10.0
`1.2
`2.2S
`0.0055
`0.005)
`q.s.
`10 100
`
`s
`
`10
`
`----------------------------------------- IS
`
`Preparation:
`
`All processing stages are carried out under Nitrogen and
`weights refer to weight in the final volume.
`
`20
`
`A sterile aqueous oil-in-water emulsion for parenteral
`administration is prepared as follows:
`
`2S
`
`An oil-in-water emulsion containing 2% (by weight) of
`propofol may be prepared in a similar manner using the
`following quantities of ingredients:
`Quantities:
`
`1. AD aqueous phase is prepared from glycerol (2.25% by
`weight). disodium edeUte dihydrate (0.0055% by weight).
`sodium hydroxide (typically 60 mgL - I ) and Water for 30
`Injections. This mixture is stirred and taken to a temperature
`of awoximatcly 65° c.
`
`2. The aqueous phase is passed throuab a :filter to remove 35
`particulate matter and transferred to a m.ixiog vessel.
`
`'J> (we-i&ht)
`
`2.0
`popofol
`10.0
`S>Y bean oil
`egg pbolphttide
`1.2
`2.2S
`sJycerol
`o.ooss
`disodium edewe dihychle
`q.s.
`sodium hydroxide
`Water for Injectioos
`10 100
`--------------------------------------
`
`3. In parallel to the above. an oil phase is prepared from
`soy bean oil (10.0% by weight). propofol (1.0% by weight)
`and egg phosphatide (1.2% by weight) iD a vesse