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`
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`I IIIII IIIIIIII 111111111111111111
`
`US008476010B2
`
`02)United States Patent
`
`
`
`Desai et al.
`
`No.: US 8,476,010 B2
`
`(10) Patent
`Jul. 2, 2013
`(45)Date of Patent:
`
`(54) PROPOFOL FORMULATIONS WITH
`
`
`NON-REACTfVE CONTAl�ER CLOSURES
`
`EP
`WO
`WO
`Palisades, CA (75) Inventors: Neil P. Desai, Pacific
`
`
`
`WO
`(US); Andrew Yang, Rosemead,
`CA
`WO
`
`
`(US); Sherry Xiaopei Ci, San Marino,
`WO
`WO
`CA (US)
`
`(73) Assignt:e: APP Pharmaceuticals LLC,
`
`
`
`Schaumburg, IL (US)
`
`(21)Appl. No.: 10/616,709
`
`(22) Filed: Jul.10, 2003
`
`Prior Publication Data
`
`(65)
`
`US 2005/0009731 Al Jan. 13, 2005
`
`Sautou-Miranda et al., f11iemmio11al .Journal of Pharmacewics,
`
`FOREJGN PATENT DOCUMENTS
`0 390 244 Al 10/1990
`WO 94/18954 9/1994
`W099/00IIJ 1/1999
`WOO l/64187 A2 9/200 I
`WO 02/45709 + 6/2002
`
`WO 2004/052401 A2 6/2004
`WO 02/45709 Al 6/2006
`OTHER PUBLICATIONS
`
`
`Sautou-Miranda et al., International Jou.rnal of Pharmaceutics,
`1996,
`
`130, pp. 251-255 ...
`Sautou-MiJanda et al., International Jomnal or Pharmaceutics, I 996,
`
`
`
`
`( *) Notice: Subject to a ny disclaimer, the term of this
`
`
`
`130,pp. 251-255 ...
`
`
`
`patent is extended or adjusted under 35
`
`
`
`
`Sautou-Mirandaet al., lnremational Journal of Pharmaceutics, 1996,
`
`U.S.C. 154(b) by 510 days.
`
`130, pp. 251-255 ...
`
`Rauer et al., Pharmazeutisrl1e 256-257 ( 1986).
`
`Tec/111nlngie,:
`Farinotti,
`13:
`
`
`A1111ales Fmncai,·es d 'A11esllii:sie et de Re<1nimaliu11.,
`453-456 (1994).
`Jones,
`
`
`
`587 (Oct. 2000). Anaesthesia and !11te11si1•e Care, 28(5):
`
`
`
`
`Naguib el al., A11e.tthe.ti<liogy <lj Absrracrs Srienrific Papers Annual
`J (Oct. 13, 2003).
`Meeting,:
`
`
`
`
`
`130(2): 251-255 (1996).
`278(1 ): 91-98
`
`
`Trapani el al., fntematio1wl.Jo11mal of Pharmace111ics,
`
`(J1ui. 18, 2004).
`(51)Int. Cl.
`
`
`West Furoree Barrier Film,: .1-2 (Dec. 3. 2003) [http:f/web.archivc.
`A61K 38/00 (2006.01)
`orglwebf20031203023630thttp:/lwww.wcstpharma.com/product
`s/
`(52)U.S. CI.
`flurotec.a.sp].
`
`
`
`
`USPC ................ 435/6; 435/6.11; 514/5.9; 514/9.3;
`Website, "Melagatran-Compound Summruy (CID 183797)", Nov.
`
`
`
`
`
`514/13.6; 514/15.2
`
`
`
`15, 2010. Publisher: hrtp:1/pubchem.ncbi.nlm.nih.gov/summaryl
`
`s1u111rnuy.cgi?cid• l 83797.
`(58)Field of Classification Search
`
`Website, "Propofol-Substance Sum111a1y (SID 9726)", 1 ov. l5.
`
`
`
`
`None
`
`
`
`2010. Publisher: http:/ipubcbem.ocbi .nhn.nih.gov/summaiy/sum­
`
`See application fille for complete search history.
`mary.cgi?sid=9726.
`International Scarclii.ng Authority, "International Search Report and
`
`
`
`
`
`
`
`
`Written Opinion for PCTflJS04/020923", Aug. l 8, 2005, Publisher:
`
`
`
`European Patent Office, Published iu: EP.
`A.rduino. el al.. "Microbial Grov.1h and Endotoxin Production in the
`
`
`
`
`
`
`
`
`
`Intravenous Anesthetic Propofol", "Infection Control and l lospital
`
`
`Epidemiology", Sep. 1991. pp. 535-539, vol. 12, No. 9.
`
`
`
`
`Ilaker, et al., "Sulfite Supported Lipid Peroxidation in Propofol
`
`
`
`Emulsions", "Anesthesiology". Nov. 2002, pp. 1162-[167. vol. 97,
`'fo. 5.
`Benz, et al.. ''Electrical Capacity of Black Lipid Films and of Lipid
`
`
`
`
`
`
`Bilayers Made from Monolayers", "Iliochin:uca ct I3iophysicaActa",
`
`1975, pp. 323-334, vol. 394.
`(Continued)
`
`
`
`(56)
`
`
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`1 JI 1977 Glen ct al.
`
`4,056,635 A
`6/1984 Glen et al.
`
`4,452,817 A
`
`4.798.876 A
`1/1989 Gould et al.
`811995 Desai et al.
`
`5,439,686 A
`
`3/ 1996 Grinscaff et al.
`
`5.498,421 A
`
`10/1996 Soon-Shiong et al.
`5,560,933 A
`
`5,637,625 A
`6! 1997 Haynes
`
`5,665,382 A
`
`9/ 1997 Grinstaff et al.
`2/1998 Jones et al.
`
`5.714,520 A
`311998 Jones et al.
`5,731,355 A
`311998 Jones et al.
`
`5.731,356 A
`
`5,908,869 I\
`611999 Jones et al.
`6/ 1999 Desai er al. ................... 424/489
`
`
`5,916,596 A •
`
`Primary Examiner- Jon P Weber
`
`10/l999 Komer
`
`5.962.536 A
`Examiner - Roy Teller Assistanl
`212000 George
`6,028,108 A
`
`
`
`(74)Allome;\ Agent, or Firm - Blanchard & Associates
`
`
`514/731 8/2000 Pejaveret al. ...........
`
`6,100,302 A •
`
`6,140,373 A
`10/2000 May et al.
`
`I J/2000 Mirejovsky et al.
`6.147,122 A
`(57)
`l J/2000 Carpenter
`6.150,423 A
`ABSTRACT
`A sterile phamiaceutical composition for parenteral admin­
`
`
`
`
`1/200 l George et al.
`
`6, 177,477 Bl
`
`
`
`
`istration of propofol, said composition comprising propofol,
`
`121200 l De Tommaso
`6.326,406
`Bl
`
`6.362,234 BI
`3/2002 HendJer
`
`
`optionaJly albumin, and less. than a bout 100/o by weight sol­
`
`6.399,087 Bl+
`
`6/2002 Zhang ct al. . ........ 424/405
`
`
`vent for propofol, wherein said composition is, stored in a
`10/2002 Mirejovs
`6,469,069
`ky et al.
`Bl
`
`
`
`
`container having a closure wherein said closure is i11ert to
`ct al. . . ..... 424/400
`
`6/2003 Lundgren
`
`6.576,245 B 1 +
`propofol.
`
`l/2002 Mishra et al.
`2002/0006442
`
`2007/0161601 Al
`7/2007 Desai et al.
`6/2008 Desai er al.
`
`200$/0132582 A I
`
`Al
`
`
`70 Claims, No Drawings
`Bass and Spangenberg
` v.
`Fresenius Kabi USA, LLC
`U.S. Patent No. 8,476,010
`Exhibit 1001
`
`Exh. 1001
`
`

`
`US 8,476,010 B2
`Page 2
`
`OfHER PUBLICATIONS
`
`De Sommer, et at., "Abstract- A comparative sn•dy on the effects of
`propolol in emulsion and lntralipid on fat metabolism", ''Acta
`Anaesthesia! Belg", 1990, pp. 133-138, vol. 41, No. 2.
`Eddleston, et al., "The effect on senun lipid concentrations of a
`prolonged infusion of propofol- hypcrtrig1yccridacmia associated
`with pro", ''Intensive Care Med", 1991, pp. 424-4126, vol. 17.
`Gonardis, et a!., ''Effect of prolonged sedation with propofol on
`serum triglyceride and cholest:rerol concentrations", ''Br. J. Anaesth.
`", 1989, pp. 393-396, vol. 62.
`Langevin, Paul B ., "Propofol Containing Sulfite-Potential for
`Injury". ''Che~t'', Ocl. 1999, pp. J 140-1141, vol. J 16, No.4.
`
`l.indhC>lm, M., "Abstract-Critically ill patients and f.-tt emulsions",
`"Mincrv;LAn~tcsiol", Ocl. 1992, pp. 875-879, vol. 58, 1o. 10.
`Mayhew, e.t al., "Characterization of liposomes prepared usin g a
`microemulsifier", "13iochimica et BiopbysicaAcla", 1984, pp. 169-
`174, vol. 775.
`Mi:rejovsky, et al., "Phannaceutical and antimicrobial differences
`between propofol emulsion products", "Am J Health-Syst Pharm",
`Jun. I 5, 2000, pp. 1174-1 177, vQl. 57.
`So sis, et a l., "Growth of Staphylococcus aureus in Fotu Intravenous
`Anesthetics", "Anesth Analg", 1993, pp. 766-768, vol. 77.
`
`* cited by examiner
`
`Exh. 1001
`
`

`
`US 8,476,010 B2
`
`1
`PROPOFOL FORMULATIO~S WITH
`NON-REACTIVE CONTAIJ~ER CLOSURES
`
`FIELD OF THE INVENTION
`
`111e invention generaHy pertains to phanuaceutical fonnu(cid:173)
`lations ofpropofol, an intravenous anesthetic with enhanced
`microbial inhibition. More particularly, the invention pertains
`to propofol formulations that are stored in containers having
`non-reactive, or inert closures.
`
`BACKGROUND OF THE INVENTION
`
`5
`
`2
`isrered over extended time periods.ln addition, compositions
`devoid of fats and triglycerides, with 3% w/v propofol
`(Haynes, U.S. Pat. No. 5,637,625) are said to be useful for
`sedation over extended periods oftime.
`TI1ere are two major problems associated with the formu(cid:173)
`lations described in the above patents: (1) the risk of micro(cid:173)
`bial contamination due to the high nutrient content and lack of
`antimicrobial preservatives. sn.dies by Arduino, et al., 1991;
`Sosis & Braverman, 1993; and PDR, 1995, have shown that a
`10 propofol emulsion formulated without preservatives will
`grow bacteria and present a risk of bacterial contamination;
`(2) Hyperlipidemia in patients undergoing long-term ICU
`sedation due to a large ammmt of fat content. Smdies have
`shown that triglyceride overload can become a significant
`15 problem when a 1% propoJol/10% soybean oil emulsion is
`used as the sole sedative for a long period ofiCU sedation by
`Gottardis, et al., 1989; DeSoreruer, et al., 1990'; Lindholm,
`1992; and F.ddieston, et al, 1991.
`To solve the problem of bacterial contamination of propo-
`20 fol emulsion, the following patented formulations of propofol
`have been developed:
`
`Propofol (2,6-Diisopropylphenol) is a well-known and
`wide ly used intravenous nncsthctic ngcnt. For example, in
`intensive care units (ICU) where the durafion of treatment
`may be lengthy, propofol has the advamage of a rapid onset
`nftcr infusion or bolus injection plus a very short recovery
`period of several minutes, instead of hours.
`Propofol is a hydrophobic, water-insoluble oil. To over(cid:173)
`come the solubility problem, it must be incorporated with
`solubilizing agents, surfactants, solvents, or an oil in water
`emulsion. There are a nwnber of known propofol formula(cid:173)
`tions, such as disclosed in U.S. Pat. Nos. 4,056,635, 4,452,
`R17 and 4,79R,R41) all of which are issued to G len and James. 25
`Propofol composition s have been the subject of seveml
`patellts. Typically, propofol compositions comprise 1-2% by
`weight propofol, 1-3% or 10-30% of a water inuuiscible
`solvent such as soybean oil, 1.2% of egg lecithin as a surfac(cid:173)
`tant, and 2.25% glycerin as a tonicity agent_ Variation in pH 30
`and/or addition of other components allows for various
`advantages and uses. For example, Hendler (U.S. Pat. No.
`6,362,234) uses propofo·l esters (100 mg-3 gm) in combina(cid:173)
`tion with anti-migraines to make aqueous, solid and other
`non-aqueous compositions for intemal and trausdermal 35
`delivery, for the treatment of migraines. De To=aso (U.S.
`Pat. No. 6,326,406) discloses a composition or pH 4.5-6.5
`com]prising 10 mg/ml propofol, 25-150 mg/ml bile salt, a
`lecithin, and preparatiol\ with substantially no oxygen. Mix(cid:173)
`ing propofol with bile acid produces a clear formulation and 40
`allows for t'<lsy dett:ction of foreign particles. For veterinary
`applications, benzyl alcohol and phospbolipjd free composi(cid:173)
`tion comprising from 1-30% by weight propofol, wherein the
`aqueous solution is steri le filtered has been used to anesthe(cid:173)
`tize animals (Carpenter, U .S. Pat. No. 6,150,423). Higher 45
`percentages of propofol allow for administration of smaller
`quantities.
`To prevem microbiaE growth, various components and
`methods of prepararion have been discussed. For example,
`Mirejovsky, et aJ., disclose compositions of pH 4 .5-6.4 with
`less ~han 1% sulfites and 1-2% by weight propofol (U.S. Pat.
`Nos. 6,469,069and 6,147, 122); George, eta!., disclose 0.15-
`0.25% tromethamine with 1-2% by weight propofol and pH
`8.5-10 (U.S. Pat. No. 6,177,477); 0.005% EDTA with 1-2%
`by weight propofol and pH 6-8.5 has been used by Jones, et
`al., (U.S. Pat. Nos. 5,714,520, 5,731 ,355, and 5,731 ,356);
`George (U.S. Pat. No. 6,028,108), discloses compositions
`with 0.005-0.1% pentetat that are 1-2% by weighr propofol
`and pH 6.5-9.5. Likewise,loweringpHranges(pH 5-7), using
`egg lecithin (0.2-1%) and soybean oil (1 -3%), without pre(cid:173)
`servatives and 0.1-6% pr,opofol by weight (Zl1ang, et al., U .S.
`Pat. No. 6,399,087), and lowering concentrations of soybean
`oil (1 -3%) to produce stable emulsions and reducing nutrients
`with 1% propofol by weight (Pejaver, et al., U.S. Pat. No.
`G,l 00,302), are said to provide protection against microbial 65
`contamination. Reducing lipid concentrations also reduces
`the chances of fat overload and is ideal for use when admiu-
`
`Patent No.
`
`Inventor
`
`5,637,625
`5,714,520
`6,028,t08
`6,100,302
`PCT 99/39696
`PCT 00/24376
`
`Dunca.n H. Haynes
`Christop!Jer B. J., et al.
`MaryM. G.
`Satish K. P., eta!.
`Mirejovsl-y D., et al.
`Mary T., et at.
`
`Js,sued
`
`10 Jun. 1997
`3 Feb. 1998
`22 Feb. 2000
`8 Aug. 2000
`12Aug. 1999
`4May2000
`
`The formu lations described in U.S. Pat. No. 5,714,520 is
`sold as DlPRlYAN® and comprises a sterile, pyrogen-free
`emulsion containing 1% ('V/v) propofol in 10% (w/v) soy(cid:173)
`bean oil. 1be formulation also confains 1.2% (w/v) egg leci-
`thin as a surfactant, 2.25% (w/v) glycerol to make the 1brmu(cid:173)
`latioo isotonic, sodium hydroxide to adj ust the pH, and EDTA
`0.0055% (w/v) as a preservative. This formulation prevents
`no more than a 10-fold increase against gram negative (such
`as Pseudomonas aeruginosa and Escherichia coli) and gram
`positive (Staphylococcus aureus) bacteria, as well as yeast
`(such as Candida albicans) over a twenty-four hour period.
`However, EDT.A., which is a metal ion chelator, removes
`cations like calcium maguesitm1 and zinc. This can be poten(cid:173)
`tially dangerous to some patients with low calcimm or other
`low cation levels, and especially critical for ICU patients .
`In U.S. Pat. No. 6,028,108 the propofol fomrulation con(cid:173)
`tains pentetate 0.0005% (w/v) as a preservative to prevent
`so microbia l contamination. Pentetate is a metal ion chelator
`similar to EDTA and therefore represents the same potential
`danger.
`The formulation described in W.O. Patent No. 99/39696, is
`generic propofol containing 0.25 mglmL sodium met-
`55 a bisulfite as a preservative to prevent microbial growth. At 24
`hours there is no more than a one log increase. Recently, P.
`Langevill, 1999, has expressed concem that generic propofol
`containiug 0.25 mg/mL sodium metabisulfite, jnfu sed at a
`rate of 50 uglkglmin, will result in sulfite administration
`60 approaching the toxic level (i.e., near the LDSO for rats) in
`about 25 hours.
`Particularly, the addition of sulphites to this dmg is worri(cid:173)
`some for the potential effects to the pediatric population and
`for sulphur allergy to the general population. In a June 2000
`letter, the manufacturer of metabisulphite-contaiuing propo(cid:173)
`fol emulsion (Gensia Sicor) stated that discoloration and a
`reductiou in pH occur when the product is exposed to air and
`
`Exh. 1001
`
`

`
`s
`
`3
`that both phenomena are caused by the oxidation of sodium
`metahisulphite Mirejovsl<y D. Ghosh M. Reply. (Pharmaceu(cid:173)
`tical and antimicrobial differences between propofol emul(cid:173)
`sion products) (Am J Health-Syst Pharm. 2000: 57: I I 76-7).
`Results show that the yellowing of the commercial metabisul-
`phite -containing propofol emulsion is an oxidized form of
`propofo l dimerquininewl1ich is lipid soluble. (U.S. Pat. No .
`6.39'9,087). Recent data also support pro-oxidanr activity by
`the sulfite anion resulting in propofol dimcrization and lipid
`peroxidation (Baker era]., Anesthesiology, 96, A472, 2002). 10
`The formulation described in PCT W.O. Parent No .
`00/2-4376 is a formulation having an antimicrobial agent,
`which is a member selected from the group consisting of
`benzyl alcohol and sodium ethylenediamine tetraacetate,
`bcnzcthonium chloride; and benzyl alcohol and sodium ben- 15
`zoate. The formulation contains EDTA, which was men(cid:173)
`tioned as related to the side effect above. Benzyl alcohol is
`linked to adverse reactions reported by Evens and Lopcz(cid:173)
`Herce, et al. The fom1ulation may be unsafe upon adminis(cid:173)
`tration, particularly to those patients who need an extended 20
`period of ICU sedation.
`1l1e fommlation described in U.S. Pat. No. 5,637,625 is of
`phospholipid-coated microdroplets of propofol, containing
`6.8% propofol with no soybean oil. However, it is believed
`that this formulation may increase injection site pain to an 25
`unacceptable level during administration.
`The formulation descr ibed in U.S. Pat. No. 6,100,302 is an
`emulsion of propofol that contains 1-3% of soybean oil to
`prevent against accidental microbial comamination during
`long-term IV infusions due to an increased availability of 30
`propofo l.
`Egg lecithin is mainly used in pharmaceutical products as
`a dispersing, emulsifying, and stabilizing agent. The lecithin
`is also used as component of emeral and paranteral nutrition
`formulations, Anhur H. Kibbe, 2000.
`It has been also found that in this invention a propofol
`·lormulation containing a reduced amount of egg lecithin
`resul ts in a significant increase in tbe ability to be antimicro(cid:173)
`bial. The soybean oil is also source of nutritio n to support the
`microbial growth.
`TI1us, it has been found that the presc:rvative-fnx, opti(cid:173)
`mized propofol fonnulation of this invention addresses tbe
`prior art· problems to the point where the problems are elimi(cid:173)
`nated or at the least are s ubstantially reduced .
`It has now been discovered that the propofol in propofol 45
`formulations with reduced oil content is degraded when
`stored in a container with a closure that is not inert to propo(cid:173)
`fol. T he problem of pmpofol degradation encountered was
`quite unexpected as c losures sealed with a rubber stopper or
`the like are known. For example, U.S. Pat. No . 6,576,245 so
`poin1s out that primary packages such as vials, bottles, car(cid:173)
`tridges, prefilled syringes and the like are typically sealed by
`a rubber stopper or plunger. U .S. Pat. No. 6,576,245 fi.1rther
`expresses a preference for a rubber material containing bro(cid:173)
`moblltyl instead of chlorobutyl to improve the stability of low 55
`molecular weight thrombin in.hibitors in solution. Heretofore,
`however, the art has not understood that the propofol in pro(cid:173)
`polo! formulations is susceptible to degradation due ro expo(cid:173)
`sm·e to the closure for the container. The fail ure of the art to
`recognize the effect of the container closme on propofol 60
`degradation, it is believed, is due to the fact that the commer(cid:173)
`cially available propofol fonnulation DJPRTVAN® com(cid:173)
`prises 10% (w/v) soybea n oil. Applicants have found that at
`the relatively high volume of soybean oil used in prior art
`formulations, the soybean oil apparently protects propofol 65
`from degradation. Howe ver, at oil contents (and/or propofol
`solvent contents) lower tban about 10% (w/v), degradation of
`
`Accordingly, the present invention in one of its embodi(cid:173)
`ments provides a sterile formulation of propofol for
`parenteral administration containing a reduced amount of egg
`lecithin and soybean oil triglycerides. T11e formulation is
`preferably comprised of an oil in water emulsion with a mean
`panicle size of from about WO to about 300 nanometers in
`diameter, in which the propofol is dissolved in a water-im(cid:173)
`miscible solvent such as soybean oil, and stabilized by a
`surfactant such as egg lecithin. The composition preferably
`has a pH in the range of from about pH 5 to about pH 8. 'I11e
`low amount of lecithin and soybean oil i.n the fommlarion
`offers a number of advantages. ]n other embodiments of the
`invention, the composition includes protein, such as albumin.
`The presence of protein such as albumin in the propofol
`formulation is also advantageous. The advantage s of the for(cid:173)
`mulation s in accordance with the embodimt:nts of the invc:n(cid:173)
`tion include:
`( I) eliminating preservatives, such as ED'IA that can result
`in zinc loss due to chelation,
`(2) providing fomm larions with excellent exhibition of
`antimicrobial activity compared to fonuu lations with higher
`amount of lecithin and oil solvent emulsion containing pre(cid:173)
`serv<ttives aud
`(3) a reduced risk of hyperlipidemia in patients.
`Further, the presence of protein, such as albumin in the
`propofol fomwlation reduces the propofol-induccd pain on
`injection . l'ain reduction is due to binding of free propolol
`with albumin and consequent reduction of the free propofol
`injected. It has also been found that the protein, and in par(cid:173)
`ticular, a lbumin, assists in forming the stabilizing layer at the
`interface of the so-called oil phase and aqueous p hase of the
`35 emulsion. Further, the use o f protein provides for composi(cid:173)
`tions which do not include a water-i=iscible solvent for
`propofol or a surfactant or both. Thus, in one embodiment of
`the invention, there is provided a sterile pharmaceutical com(cid:173)
`position for parenteral admi11istration of propofo l, in which
`40 the composition comprises propofol, an aqueous phase and
`protein, such as albumin.
`The propofol formulations of the present invention have no
`more than a 10-fold incre..ase in the growth of each of
`Pseudomonas aeruginosa, Escherichia coli, Staphylococcus
`au reus and Candida albicans for at least 24 hours after adven(cid:173)
`titious, extrinsic contamination.
`In a further embodiment of the present invention, the pro(cid:173)
`pofo l composition is stored in a container that is inert or
`non-reactive and that has an inert or non-reactive closure,
`such that the container and closure do not cause significant
`degradation or loss in potency of the propofol formulation.
`Thus. by way of illustration, the degradation or loss of
`potency o f propofol should be such that the propofol compo(cid:173)
`sition meets regulatory safety and efficacy standards. As a
`result, impurity levels, levels of degradation products, and
`potency loss are with.iJJ accepted regulatory limjts. The clo(cid:173)
`sure can itself be inert or non-reactive, or the closure can be
`coated w ith a suitable coating material to make it non-reactive
`or inert.
`TI1ese and other objects and advantages of the present
`invention will become apparent from the subsequent detailed
`description of the preferred embodiment and the appended
`claims.
`
`US 8,476,010 B2
`
`4
`propofol has been found to occur if the container closure is
`not inert or non-reactive to propofol.
`
`DISCLOSURE OF THE INVENTION
`
`DED\ILED DESCR1PT10N OF THE INVENTION
`
`TI1e invention in one of its embodiments is a sterile phar(cid:173)
`maceutical composition for parenteral administration com-
`
`Exh. 1001
`
`

`
`US 8,476,010 B2
`
`5
`prised of an oil-in-water emulsion, in which propofol is dis(cid:173)
`solved in a water-immiscihle solvent, preferahly soyhean oil,
`and stabilized by a surfactant, preferably egg lecithin. The
`composition further comprises a reduced amount of egg leci(cid:173)
`thin and soybean oil to i.nhibit microbial contamination dur(cid:173)
`ing l V infusions over a period of time. In other embodiments
`of tl1e invention, water immiscible solvents can also be used.
`The composition preferably comprises protein, such as albu(cid:173)
`min which binds free propofol to reduce the pain on injection.
`ln another embodiment, the invention comprises composi(cid:173)
`tions of propofol having no oil. ln this embodiment, the
`composition also preferably comprises protein, such as albu(cid:173)
`lllln.
`An oil-in-water emulsion is meant to be a distinct, two(cid:173)
`phase system that is in equilibrium and in effect, as a whole,
`is kinetically stable and thermodynamically unstable. Thus,
`as used herein, the aqueous phase refers generally to the phase
`which includes water or water of injection with or without
`other water soluble or water miscible compo111ents, and the oil
`phase refers to the phase that includes propofol. The propofol 20
`may be present neat, or with a solvent oil or other propofol
`miscible component.
`Prevention of a significant growth of microorganisms is
`meant to be growth of microorganisms, which is preferably
`no more than a one log increase following extrinsic contami- 25
`nation generally fotmd in treatment sellings such as JCU's
`and the like. For purposes of this definition, the contarnination
`is commonly about 50-200 colony forming units/ml at a tem(cid:173)
`perature in the range of20-25° C.
`TI1e composition of the present invenrion typically com- 30
`prises from 0.1 'Yo to H)O/o by weight of propo1ol, and, more
`prefembly from I to 5% propofol. Preferably, the composi(cid:173)
`tion comprises I %, 2% or 5% propofol. All references herein
`to weight percent are meant to be weight percent by volume of
`the composition.
`Thewarermiscible sonvent or the water-immiscible solvent
`is present in an amount that is pre1erably from 0 to 10%, by
`weight of the composition, and more preferably from I to 6%
`by weight of the composition for the fonnulation containing
`0.5-5% propo1ol. Also preferred are compositions that con- 40
`tain no water-immi~cible solvent~ ~o that the propofol i~
`present neat.
`'I11e oil-in-water emulsion can be prepared by using neat
`propofol or by dissolving propofol in a sol vent, and preparing
`an aqueous phase containingwaterofinjection and optionally 45
`a surfactant, protein and other water-soluble ingredients, and
`then mixing the oil with the aqueous phase. ll1e cmde emul(cid:173)
`sion is homogenized under high pressure to provide an emul(cid:173)
`sion.
`A wide range of water-illlllliscible solvents can be used in so
`the composition of the present invention. Typically, the water(cid:173)
`immiscible solvent is a vegetable oil, for example, soybean,
`safflower, cottonseed, corn, coconut, sunflower, arachis, cas-
`tor sesame, orange, limonene or olive oil. Preferably, the
`vegetable oil is soybean oil. Alternatively, the water-immis- 55
`cible solvent is an estero fa medium or long-chain fatty acid,
`for example a mono-, di-, or triglyceride, or is a chemically
`modified or manufactured palmitate, glycera l ester or poly(cid:173)
`oxyl , hydrogenated castor oil. In a further alternative, the
`water-immiscible solvent may be a marine oil, for example 60
`cod liver or other fish-derived oil. Suitable solvents also
`iJ1clude fractionated oils, for example, fractionated coconut
`oil, or modified soybean oil. Furthennore, the composition of
`the present invention may comprise a mixn1re of two or more
`of the above water-inuniscible solvents. Water-miscible sol(cid:173)
`vents may also be utilized. Thus, for example, suitable sol(cid:173)
`vents include chloroform, methylene chloride, ethyl acetate,
`
`6
`ethanol, tetrahydrofuraJl, dioxane, acetonitrile, acetone, dim(cid:173)
`ethyl sulfoxide, dimethyl formamide, me1hylpyrmlidinone,
`and the like. Additional sotv.cnts contemplated for usc in the
`practice of the present invention include C I-C20 alcohols,
`s C2-C20 esters, C3-C20 ketones, polyethylene g lycols, ali(cid:173)
`phatic hydrocarbons, aromatic hydrocarbons, l1alogenated
`hydrocarbons and combinations thereof. Certain solvents that
`are volatile or non-volatile may be utilized bur may be desir(cid:173)
`ably rcmov<.'<l in the fmal parenteral preparation to acceptable
`to levels for parenteral administration. ln addition mixtures of
`a11y two or more of the above solvents are also acceptable.
`The composition of the present invention can comprise a
`pharmaceutically acceptable surfactant to provide a stable
`emulsion. The amount of the surfactant present in the com-
`15 position will vary depending on the amount of so·lvcnt for the
`propotol. For example, the surJactant is suitably present in an
`amount that is no more than l % by weight ofthecomposirioo
`for a formulation that contains 1 to 6% ofwatcr-illlluiscible
`solvent, more preferably the amount of surJactant is 0 .2 to
`1.0% by weight of the composition, and even more preferably
`the amount of surfactant is 0.3-0.66% by weight ofthe com-
`position. For a formulation that contains 6 to 10% of water(cid:173)
`immiscible solvent, a suitable amoLllll ofsurfactruo.t is no more
`than5% by weight of the composition, and preferably is 0.5 to
`?.% by weight of the composition, and more preferably is
`0.8-1.2% by weight of the composition. Acceptable range of
`surfactant concentmtion is 0.1-5%, more prefembly, 0.2-3%
`and most preferably 0.3-0.&%. Suitable surfactants include
`synthetic non-ionic surfactant such as ethoxylated ethers and
`esters such as Tween 80 and Tocopherol polyethylene glycol
`stearate (Vitamin H-TPGS), and polypropylene-polyethylene
`block co-polymers, and phosphatides or lecithins, for
`example naturally occurring phosphatides such as egg and
`soya phosphatides, or egg and soya lecithins and modified or
`35 a1tificially manipulated pbosphatides (for example those pre(cid:173)
`pared by physical fractionation and/or chromatography), or
`mixture thereof. Preferred surtactants are egg and soya phos(cid:173)
`phat ides. Most preferred is egg lecithin.
`It is well recognized that a surfactant can stabilize an enml(cid:173)
`sion by forming a stabilizing layer at the surface of the oil
`phase or droplet phase of lhe emulsion. The presence of
`protein such as albnntin in the composition of the present
`invention has been found to stabilize the emulsion, with and
`without surfactant present in the composition. For propofol
`composi tioos of embodiments of the invention which contain
`protein, such as albumin as well as surfactant, it has been
`found that the emulsions are stabilized by the presence of
`albumin as well as the surfactant in the stabilizing layer at the
`surface oft be oil pbase or droplet phase of the emulsion. For
`propofol compositions of embodiments of the invention
`which contain protein such as albtunin, but no surfactant, it
`has also been found that albumin is present on the droplets of
`the oil phase of the emulsion and is included in th.e stabilizing
`layer. The total albumin measured in the droplet phase of the
`emulsion was at least 0.5-l 0% of the total albumin in the
`formulation. Thus tbe stabilizing layer in sucb invention for-
`mulations comprises both tl.1e surfactant (e.g., lecithin) as
`well as the protein (albumin). The mean size of the droplets
`typically is in the range from about 20 nanometers to about
`I 000 nanometers, desirably from about 50 nanometers to
`about 500 nanometers, and 1uore desirably from about I 00 to
`about 300 nanometers.
`Protei ns contemplated for use as stabilizing agents or for
`purposes of binding free propofol to reduce pain in accor-
`65 dance with the present invention include albwnins, globulins,
`immunoglobulins, lipoproteins, caseins, insulins, hemoglo(cid:173)
`bins, lysozymes, alpha.-2-macroglobulin, tlbronectins, vit-
`
`Exh. 1001
`
`

`
`US 8,476,010 B2
`
`7
`ronectins, fibrinogens, I ipases, and the like. Proteins, pep(cid:173)
`tides, enzymes, antihodies and cornhinations thereof, are
`contemplated for usc in t he present invention. Preferred con(cid:173)
`centrations of proteins are 0.01-5%, more preferably, O.l -3%
`and most preferably 0.2-1%. The preferred protein is albu(cid:173)
`min, most preferably hu.man albumin or recombinant human
`albumin.
`TI1e composition of the present invention is suitably for(cid:173)
`mulated to have a pH range of 4.5 to 9.0, preferably pH 5.0 to
`pH 7.5. A pl-1 ra nge of 6-8 is also suitable. The pH can be
`adjusted as required by means of a suitable pH modifier, that
`is, a component that can be used to adjust pH to the desired
`range and yet is suitable for parenteral administration. "Ibe pH
`of the composition can be aqjusted by the addition to the
`formulation of the pH modifier. lt will also be understood that
`the water of i1uection can include the pH modifier so the
`resul ting composition has the desired pH range. Thus, by way
`of example, the pH modifier can be added to the water of
`injection to achieve the desi red pH, and tl1e pH-modified
`water of injection can then be used to make the formulation.
`The pH adjustment is a matter of processing choice. Suitable
`pH modifiers include a lkali metal salts, such as sodium
`hydroxide, and acids, including mineral acid!s such as hydro(cid:173)
`chloric acid and organic acids.
`'Tl1e composition of the present invention may be made
`isotonic with blood by incorporation of a suitable tonicity
`modifier, for example glycerin.
`TI1e composition of the present invention comprises a phar(cid:173)
`maceutically acceptable carrier. The carrier is preferably a
`pyrogen-free water or water for injection U.S.P.
`'ll1e present invention's composition is a sterile aqueous
`formulation and is prepared by standard manufaclllring tech(cid:173)
`niques using, for exampl.e, aseptic manufacture, sterile filtra(cid:173)
`tion or terminal sterilization by autoclaving.
`TI1e compositions of the present invention are useful as
`anesthetics, which include sedation, induction and mainte(cid:173)
`nance of general anesthesia. Accordingly, in another aspect,
`the present invention provides a method of producing anes(cid:173)
`thesia (including sedation, induction and maintenaoce of gen(cid:173)
`eral anesthesia) in a warm-blooded animal, including
`hullHUlS.
`Producing anesthesia comprises administering parenter(cid:173)
`a lly a sterile, aqueous p bam1aceutical composition which
`comprise!> an oil-in-water emulsion in which neat propoJbl or
`propofol in a water-mise ible or a water-imrojscible solvent is
`emulsified with water and a surfactant.
`Typically, dosage levels of propofol for producing general
`anesthe!Sia are from, about 2.0-2.5 mgfkg for ao adult. Dosage
`for maintenance of anesthesia is generally about 4-12 mgfkgf
`hr. Sedative effects may be achieved with, for example, a
`dosage of 0.3-4.5 mgfkglhr. Dosage levels of propofol for
`producing general anesthesia, induction and maintenance,
`aod for produci