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`20 N. Wacker Drive -Suite 1408 -Chicago, IL 60606 -312-977-9772 Fax-866-61 5-8606
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`Certification
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`VERIFIED TRANSLATION OF DOCWt,fENT & DECLARATION
`Tlte undersigned, oftlie below address, hereby certifies and declares tlzat he/she knows well both tl,e
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`of tile document and Fre11cJ, languages, and that the a/Jaclted is mt accurate translation
`English
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`listed below:
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`• Anna/es Francaises
`
`Anesthesie
`du Diprivan
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`Reanimation-Interactions physicochimiques et mode de conservation
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`I hereby declare tlzat all stateme11ts ill lite tn111slatioll made herein of my own kllowledge are true and
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`that all statements made i1t the tra11s/atio11 011 information and belief are believed IQ he true. Further,
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`and the tliat willful false stat.eme/lts these statements i11 tlze trans/atiott were malle with lite knowledge
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`like so made are punishable byfine, imprisomne11t, or both, under Section 1001 of Title 18 oftlie
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`United States Code.
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`Signed tliis 6th day of Febrllluy, 2015
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`Signatm�
`Name: Lisa Lapl,m e
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`Address: Newtow11, CT 06470
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`Subscribed and sworn to before me, a Notary Public in and for the County of Cook, State of Illinois, on
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`February 6, 2015.
`
`Marigr ace Clark,
`Notary
`
`CfflCW. .SfAL
`�a.ARK
`NOTMY ,ueuc ·� STATE� lll.ftOIS
`MY CCWSSION
`EXPIRES:10/29/18
`
`Bass and Spangenberg
`v.
`Fresenius Kabi USA, LLC
`
`U.S. Patent No. 8,476,010
`Exhibit 1007
`
`Exh. 1007
`
`

`
`©Masson, Paris.
`Ann FrAnesth Rea11im 13:453-456 1994
`
`WORKSHOP: DIPRIVAN®
`
`Physio-Chemical Interactions and Storage of Diprivan®
`
`Physio-Chemical Interactions and Storage ofDiprivan®
`
`R. FARJNOTTI
`Department of Pharmacology and Toxicology, Bichat-Cfaude-Bernard Hospital, 46, me Henri-Huchard, 75878 Paris Cede.x 18
`
`ABSTRACT I RECOMMENDATIONS
`
`There is very little literature available that addresses the physio-chemical interactions and stability of Diprivan®.
`On the basis of current experience, this agent is safe for use in polypropylene or polypropylene/polyethylene
`syringes, diluted I to 5 in 5% glucose if necessa1y. The potential hazards are as follows:
`
`I) Propofol may undergo oxidation when not stored in nitrogen, or when in contact with oxidizing agents
`(active ingredients or excipients of other preparations).
`2) The emulsion may be destabilized by contact with mineral or organic cations (calcium, magnesium, dibasic
`amino acids, etc.) or acids (citric acid, etc.);
`3) Losses ofpropofol may occur by adsorption-diffusion (surface adherence combined with penetration of
`plastic material) during storage in PVC bags or during administration by means of PVC infusion sets.
`Most of these hazards still have to be evaluated under controlled situations.
`
`Key word~: MFJJ!!.AT!()NS: storage, physio-chemical interactions; PR()P()F()f.
`
`Diprivan® is an injectable emulsion of propofol at l%
`weight/volume. Propofol or diisopropyl 2.6-phenol has
`low solubility in water at physiological pH. On the other
`hand, its octanol-water partition coefficient is high ( 15 with
`pH = 7.4). TI1is property has directed its galenic form of
`application to incorporation into a water/oil emulsion
`(W/0) in
`the oil phase:
`lntralipid® at 10% (Kabi
`Pharmacia). TI1e definition of the physio-chemical
`interactions and the way Diprivan® is stored must
`therefore be considered whilst taking into account the
`methods of administration, and the dmg combinations and
`their effect on the stability of propofol and on the stability
`of the excipient.
`
`CHEMICAL STABILITY OF PROPOFOL
`
`the identification of two degradation products:
`a dimer or tetraisopropyl 3.3',5.5' - dihydroxy
`4.4' biphenyl
`a quinone or diisopropyl 2.6- quinone
`
`These two compounds are formed in the presence of
`oxygen, which has made packaging and storage for
`Diprivan® (in nitrogen) necessary.
`Propofol's redox potential is lower than +0.60 V [6],
`likelihood of interactions with
`which suggests
`the
`oxidizing molecules. This property excludes the use of
`preservatives in the Diprivan® fonnula, whose sterility
`can be maintained only through the integrity of the final
`container.
`
`PHYSIO-CHEMICAL
`INTRALIPID®
`
`STABILITY OF
`
`10%
`
`Propofol is a phenol. As such, it is an electron donor, Intralipid® is an oil-in-water emulsion of soybean oil, egg
`lecithin,
`which, when exposed to an acceptor, may oxidize. This
`reducing nature of propofol has been demonstrated by
`
`Exh. 1007
`
`

`
`454
`
`glycerol and water for injection. The stability of the emulsion
`is achieved mainly tJu·ough the negative charges carried by
`the lecithin around dispersed lipid droplets. These charges
`maintain
`repelling
`forces between
`the droplets and
`counteract flocculation, creaming and coalescence. [3).
`The addition of various components, i.n an aqueous solution
`in
`the continuous phase of the emulsion, represents a
`potential destabilization factor by neutralizing the charges.
`This neutralization leads to an increase in the size of the
`lipid droplets. In this way, U1e cations, and in particular the
`trivalent and divalent cations such as caJcium at 7mmol
`L 1
`, lead to the creaming of the 20% Intra lipid® in 24 hours.
`This same phenomenon is observed in the presence of acid
`compounds. Glucose solutions contain traces of acids
`formed during heat sterilization. These traces neutralize the
`(negative) phosphate functions of the lecithin and can
`destabilize the emulsion. Consequently,
`the maximum
`accepted dilution of Oiprivan® in glucose solution at 5% is
`to 5
`I
`(one
`part Diprivan®
`to
`four
`parts
`
`of5% glucose solution).
`All sn1dies on the stability and storage of the pre-mix of
`Dipravan and another dmg must take into account the criteria
`for the stability of the emulsion. One must check, in
`particular, U1at there is no creaming due to a coalescence of
`the lipid globules; the average size of the globules (0.2 11m)
`and the size distribution; the number of globules larger than
`2 11111 (nonnal < 5000/mL of emulsion); and the pH of the
`aqueous phase, whose reduction reveals the production of
`free fatty acids through hydrolysis of ilie soybean oil and U1e
`egg phosphatides.
`
`STABILITY OF DIPRIVAN®
`
`Storage in diverse conditions (ampoules, vials) at an
`ambient temperature (25°C) for three years did not show
`any changes in the characteristics of the dmg. It is simply
`specified that it should not be frozen as this will obviously
`destroy the emulsion.
`
`Studies of Compatibility with U1e Container
`
`R. FARINOTTI
`
`Glass Vial
`
`In Type I glass vial packaging, we note good stability of
`Diprivan® and a lack of adsorption of propofol on ilie
`brornobutyl stopper. There is no interaction between the
`stopper and the lipid emulsion.
`
`Sy1inges.: Administration in a Bolus or Using a Syringe
`Pump
`
`The studies [4] were condu.cted with 20 mL and 50 mL
`syringes
`made
`from
`polypropylene
`or
`polypropylene/polyethylene
`for
`the purpose of
`understanding the stability of Diprivan® and its effect
`on ilie syringe.
`A static model (20 mL and 50 mL syringe over 24 hrs.)
`and a dynamic model (50 mL syringe, four hrs. of rest -1
`then 20 Ius. of administration at 2 mL * hr.
`) were
`implemented. The usual physio-chemical measures show
`that iliere are no changes in the emulsion's characteristics.
`We note a loss ofpropofol (< 5%), with no appearance of
`degradation products, which suggests an adsorption with
`or without associated diffusion in plastic materials.
`Propofol does not alter the mechanical properties of the
`syringe (which must not be refilled repeatedly).
`
`Bacterial Filters
`
`8JORAKER (2] has studied changes in ilie distribution of
`lipid vesicles induced through filtration of Diprivan® on
`0.22 ~m bacterial filters. Filtration on 19-mm diameter
`MSf cameo riS filters does not change ilie emulsion's
`characteristics, whereas vesicles larger U1an 0.72 ~m are
`partially retained on the 28-mm diameter Baxter®
`2C5662 filter. Filtration on a bacterial fi lter cannot be
`reconunended in a clinical setting, due to ilie weak
`surfaces of available filters (which limit the flow) and to
`possible changes in the emulsion's properties due to the
`type of filter used [2].
`
`BASIS: Equipment Required for Adtninistration
`DAILY
`A
`ON
`DIPRIVAN®
`COMPATffifLITIES AND INCOMPATIBILITIES
`
`Studies published on the topic are virtually non- existent.
`The only data available come from the manufacntring
`laborntory. The compatibility of Diprivan® with
`its
`container (the S)'linge necessary for adnlinistration), with
`solid solutes and with other active ingredients must be
`explored one by one.
`
`The study by BA1LEY and colleagues [I], which was
`conducted using dilutions at I to 5 of Diprivan® in the
`5% glucose solution, found that:
`The passage ofDiprivan® through a 5 ~m filter
`in
`does not cause any modifications
`the drug's
`composition, which authorizes this practice for retaining
`particles emanating from the packaging;
`Propofol coats (adsorption) and eventually
`penetrates (diffusion) polyvinyl chloride tubing: a static(cid:173)
`mode study (a 2-m line for 2 hrs.) reveals a 31 to 35%
`loss
`
`Exh. 1007
`
`

`
`DIPRNAN®
`
`455
`
`of propofol after 2 hrs. (with no appearance of degradation
`products).
`This model likely encourages the diffusion of propofol,
`given that the dynamic model (flow = 1.75 mL · min ·1
`corresponding to a dose of 0.05 mg · kg ·1 · min ·1 for a
`patient weighing 70 kg) does not show any quantifiable
`losses after one hour. A loss of 8% is observed after two
`hours.
`These results are easily explained by the hydrophobic
`characteristics of propofol and PVC [polyvinyl chloride].
`They suggest that the adsorption-diffusion phenomenon
`depends on the speed of administration. In the absence of
`studies on interactions between containers and their
`contents, these results suggest that the greatest caution
`should be exercised with regard to PVC bags.
`The trials perfonned by Zeneca Phanna laboratories show
`that the premix of Diprivan® and 5% glucose solution
`at a ratio of I : 4v/v in a PVC bag must be limited to a
`total volume of 500 rnL and kept for a maximum of six
`hours.
`
`Compatibility ofDiprivan® with Injectable Solutions
`
`Extemporaneous Mixture
`Diprivan® can be administered in a Y-tube
`without risk of mptming the emulsion with 5% glucose
`solution, 0.9% sodium. chloride, mixtures (5% glucose -
`0.45% sodium chloride or 5% glucose - 0.2% sodium
`chloride) or Ringer's lactate.
`
`Compatibility with Other A.ctive Ingredients [5]
`A 20-mL dose of propofol was mixed with I mL of
`lidocaine (1% xylocainc), mixed and stored for two hours
`in a syringe (Gillette Sabre polyethylene/polypropylene)
`at room temperature and ambient light. We did not
`observe any changes
`in physicochemical stability.
`However, the emulsion is unstable under continuous
`agitation. Thus, the mixture can be created to reduce pain
`upon inj ection. Nevertheless, it must be used immediately.
`
`Motphine-Like Substances, Curare-Like Substances and
`Atropine-Like Substances
`There are no published studies regarding the stability of
`Diptivan® with these dmgs.
`Analysis of the structure of active ingredients and the
`composition of galenical forms used suggests that there is
`a risk of destabilization of the emulsion in the presence of
`quatemary ammonias (curares) and citric acid (sufentanil
`excipient). This risk is perhaps negligible due to the weak
`concentrations used. Trials conducted by Zeneca Pharma
`laboratories show that it is possible:
`To mix Diprivan® and alfentanil in ratios of 20
`p.l and 50 p.l. The emulsions obtained must be
`administered within a maximum of six hours. The
`mixhtres created in ratios of less than 20 : I must be
`administered immediately.
`To simultaneously administer, by means of a Y(cid:173)
`connector, Diprivan® and pancuronium or
`suxamethonium hydrochloride, vecuronium, atropine,
`fentanyl and alfentanil.
`However, alracurium and mivacurium must not be
`extemporaneously mixed with or added to Dip1·ivan®.
`
`BrBLIOGRAPHY
`
`ll1e references are preceded:
`by a • when they are of particular interest,
`by • • in case of major interest.
`
`PremLt: Use in Administration
`The compatibility of Diprivan® with different injectable
`solutions, in variable proportions, was studied over a
`period of24 hours.
`The evolution of parameters, i.e. chemical (propofol
`content, pH) and physical (appearance, absence of an oily
`surface, average size of globules, number of globules larger
`than 2 Jlm) shows that Diprivan® can be mixed with a 5%
`glucose solution (neutral glass containers).
`The maximum acceptable dilution is I to 5 (I : 4 v/v). It
`must be used within six hours after its preparation, a factor
`Propofol
`that must be taken into account when it is to be used in
`PVC.
`sedation.
`2.
`Prernixing Diprivan® with 0.9% sodium chloride is •
`unstable and must not be done.
`There is no published study that refers to the stability of
`Diprivan® premixed in Ringer's lactate. The sodium and
`calcium ion content of this solution does not lead to a
`theoretical risk of destabilization of the emulsion within
`six hours. However, an experimental study is necessary,
`and premixing Diprivan® with Ringer's lactate is not
`recommended.
`
`I.
`•
`
`BAILEY LC, TANG KT, RoGOZISKI BA. Effect
`of syringe filter and IV administration set on delivery
`of propofol emulsion. Am J Hosp Pharm, 48: 2627-
`2630, 199 1.
`is adsorbed imo PVC; it may diffuse intensely in
`
`8JORAKER DG. Lipid emulsion changes induced
`by 0.22 ~tm filtration of propofol. Anesthesiology,
`79: A 1099, 1993.
`TI1e nature of 1he filter interferes with the emulsion's specific
`distribution.
`3.
`CHAUMElLJC, BROSSARD D. Stabili1y oflipid
`• •
`emulsions used in parenteral nutrition. Nlllr C/in
`Merabol, 7: 54-64, 1993.
`Lipid emulsions are unstable in the presence of cations and
`acids.
`
`Exh. 1007
`
`

`
`456
`
`DIPRIVAN®
`
`Diprivan® compatibility with plastic syringes.
`4.
`Internal document, Zeneca Phan na_
`• •
`There is no incompatibility of Diprivan® v.~th syringes
`made from polypropylene or polyethylene/polypropylene.
`5.
`Diprivan® injection compatibility with
`• •
`lignocaine injection. Internal document, Zeneca
`Phanna.
`Extemporaneous mixture is possible.
`
`6.
`
`UEBEL RA, WruM CA, HAWTR£ v AO, CoETZ££
`J. Electrochemical determination of 2.6-
`diisopropylpheno[ after high performance liquid
`chromatography of extracts from serum.
`J Chromatogr Biomed Appl, 526 : 293-295,
`1990.
`Propofol 's oxidation potential is less than + 0.6 volts.
`
`ABSTRACT I RECOMM.ENDATlONS
`
`There is very little literature available that addresses the physio-chemical interactions and stability of Diprivan®.
`On the basis of current experience, this agent is safe for use in polypropylene or polypropylene/polyethylene
`syringes, diluted I to 5 in 5% glucose if necessary. ll1e potential hazards are as follows:
`
`l) Propofol may undergo oxidation when not stored in nitrogen, or when in contact with oxidizing agents
`(active ingredients or excipients of other preparations).
`2) The emulsion may be destabilized by contact with mineral or organic cations (calcium, magnesium, dibasic
`amino acids, etc.) or acids (citric acid, etc.);
`3) Losses of propofolmay occur by adsorption-diffusion (surface adherence combined with penetration of
`plastic material) during storage in PVC bags or during administration by means of PVC infusion sets.
`Most of these hazards still have to be evaluated under controlled situations.
`
`Exh. 1007