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`Parenteral Grim Assdclation
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`Science and Technology
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`harmaceutica
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`Solubility Principles and Practices for Parenteral Drug
`Dosage Form Development
`Stephanie Sweetana and Michael J. Akers
`
`PDA J Pharm Sci and Tech 1996, 50 330-342
`
`AstraZeneca Exhibit 2052 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01910
`
`

`

`REVIEW ARTICLE
`
`Solubility Principles and Practices for Parenteral Drug Dosage
`Form Development
`
`STEPHANIE SWEETANA and MIGHAEL J. AKERS*
`
`Pharmaceutical Sciences, Lily Research Laboratories, Indianapolis, Indiana
`
`introduction
`
`A common problem experienced in the early develop-
`mentof drigs intended for parenteral, especially intrave-
`nous, administration is the solubilization of a slightly
`soluble or water insoluble active ingredient. Drug solubi-
`lization has been the subject of many scientific. articles
`and textbooks (referenced throughout this article}; yet
`despite this attention and avaliable Ierature, product
`development scientists still encounter significant difficul-
`ties in solving their solubility problems.
`‘Theories of solute solubilization. are mot easy to
`understand. Solubilization processes are amazingly com-
`plex and require a fair amount of expertise in physical
`chemistry to.
`interpret and apply current theoretical
`models, Much of the literature deals. with solubilization
`theory and does not offer much practical help to the
`inexperienced scientist wmder alot of pressure to find a
`solution to his/her solubility problem.
`This article intends to help the scientist in early drug
`formulation design for parenterally administered: drag
`products by reviewing pertinent literature on solubiliza-
`tion and reducing it to simple approaches one can-use-to
`solve solubility problems. The classical thearies of solu-
`bility, and how they relate to pharmaceutical systems of
`interest will be reviewed and practical applications
`discussed. Because of the common concerns regarding
`cosolvent
`toxicity and. acceptability by medical and
`regulatory bodies, we-also will treat this topic in-some
`detail,
`
`|. Pertinent Theory of Solubilization of Drugs
`
`Solubility theories deal with conversion of a substance
`from one state to another, and the equilibrium phenom-
`ena that are involved, “Through pioneering work of
`Henry, Raoult and vant: Hoff-in the late 1800's, the
`properties of various solutions have been. defined.
`in
`theoriés. These early theories form the basis by which
`more complex systems, such as those encountered in the
`biological sciences, are compared and understood,
`No single theory can adequately explain solubility
`behavior of uncharged molecules in avariety of solvent
`systems, Each theory is suited for select combinations of
`
`Recewed June 29, 1995. Accepted for publication March 21, 1996.
`* Author 10 whorcorrespondence should be addressed: Lily Corpo-
`rate Center, Indianapolis, IN 40285,
`
`solutes and solvents where certain intermolecular forces
`are assumed to. predominate, or-conversely, be absent.
`The-classical theories of solubility have been explamed
`most simply in terms of intermolecular interactions.
`ideal
`‘solution theary assumes solite-solute, salvent-
`solvent and solute-solvent interactions are completely
`uniform in “strengty and. nature. An cxample of-a
`solution behaving ideally is a non-polar solute ina
`non-polar solvent
`such. as-naphthalene in benzene.
`Regular solution theary evolved to account for the imbal-
`ance of intermolecular interactions that often occur
`between dissimilar systems of a solute and solvent: The
`focus of this theory are systems of low polarity such as
`steroids in hydrocarbon solvents. Edended regular solu-
`don theory incorporated additional parameters such as
`dispersion, polar and hydrogen-bonding interactions
`info regular solution theory. Various approaches have
`been used to represent these molecular interactions,
`leading to a variety of models io predict and-explain
`solubility. behavior of polar solutes in polar systems, cach
`with diferent approximations and assumptions (1-4).
`In most pharmaceutical systems, the routine applica-
`tion of these models to predict solubility and ‘simplify
`formulation development.is complex. Mast drags of
`interest are ionizable, contain polar polyfunctional
`groups; and are.capable of forming multiple hydrogen
`bonds. The majority of parenterally acceptable cosol-
`vents-—such as propylene glycol,-polyethylene glycol,
`ethanol and water—are capable of self association
`through hydrogen bond formation. Such interactions
`may alter solvent structure and, a a result, influence
`solubility: in. an unpredictable manner.(1). Exampics-of
`this phenomena are deviations from log-linear solubliza-
`tion of nonpolar solutes in a polar cosolvent system (5).
`For the models to adequately describe solubility behav-
`ior, proper weighting must be assigned to the relative
`importance of competing self-associations and strong
`intermolecular interactions, Currently this is being mod-
`eled by various conmiputer mtensive group-contmbution
`approaches, some of which allow for the mutual intérac-
`tions of various functional groups (1).
`In the biological sciences, many solutes of interest are
`capable of acting as acids or bases, In an ionizing media
`such as water, they may dissociate into ions which are
`usually highly water soluble. To what extent a molecule
`is ionized in an aqueous solution is largely dependent on
`its pKa and the pH of the media. The Henderson-
`
`330
`
`PDA Journal of Pharmaceutical Science & Technology
`
`AstraZeneca Exhibit 2052 p. 2
`
`

`

`Hasselbaich equation isa mathematical expression of
`this relationship (3). Ia formiilation development, cor
`sideration of the amount.ofain-ionized drug in solution
`is. helpful to. avoid unexpected precipitation of this form.
`As the pH of a drug solution is changed, the amount.of
`free acid or base may increase and eventually exceed the
`limited solubility of this form: It is possible to calculate
`the oH of precipitation and of maximum solubility, if the
`pKa of the molecule and the solubility of the un-ionized
`and ionized forms are known (3,.6). Generally, two pH
`units above or below the pHy. value establishes the
`desired pH for formulation. For drug molecules with
`multiple ionizable. groups.
`these equations..are more
`complicated to apply-and-sa experimentally generated
`solubility data are usually collected,
`‘Through owrown experience, we find that theory gives
`is some direction with respect
`to experimental ap-
`proaches, but we still need to rely on the empirical
`experimentation (6 screen for systems which offer the
`most promise in solubilizing water-insoluble drugs.
`
`ll. Formulation Desiqn
`
`the first approach used to imerease the
`Usually,
`solubllity of an insoluble drug inawatér is to forrmemore
`water soluble salis.. Berge and co-workers:(/) wrote what
`is now a -neéar classic review of salt form strategies
`acceptable ior pharmaceuticals. If salt lormation is ‘not
`possible, e.g.
`too unstable, ar does not render the
`molecule sufficiently water solubie, a series of formula-
`tion approaches maybe investigated. Table | summa-
`rizes these general strategies, Often a useful approach to
`increase the aqueous solubility of an ionizable drag is
`pH adjustment. The nest approach most frequentlytried
`is the use of water-miscible.cosolvents: Other ap-
`proaches to. be discussed briefly:include the use of
`surface active.agents and complexing agents. Develap-
`ment of emulsified and colloidal drug delivery systems
`for intravenous administration are becoming more widely
`and successfully applied. They may confer to the en-
`trapped or associated drug significantly different proper-
`
`
`
`TSBLE |
`Summary of Parenteral Formulation Approaches
`
`
`important Formula
`
`Approach
`Examples
`Considerations
`Useful Tests
`
`pH adjustment
`
`pH 2 to le
`
`Cosolvent
`
`Polyethylene glycol
`Propylene giycal
`Ethanol
`Dimethylacetamide
`
`Surface Active Agents
`
`Polysorbates
`Poloxamers
`Cremophor EL.
`Lecithin
`Bile salts
`
`Complexing Agents
`
`Gyelodextrans
`Water-soluble vitamitis
`
`Dispersed Systems
`
`Emulsions
`Liposomes
`Nanoparticles
`
`Drug stability
`pH
`ions. to buffer or adjust pH
`Drug precipitation upon infusion
`drug concentration
`use of buffer/buffer capacity
`infusion rate
`Formula irritation
`isotonicity
`infusion rate & duration
`drug vs vehicle
`drug precipitation
`
`Systemic toxicity
`total cosolvent administered
`Drug precipitation upon infusion
`drug concentration
`infusion rate
`Formula irritation
`isotonicity
`infusion rate & duration
`drug ve vehicle
`drug precipitation
`
`Hypersensitivity in animals
`Formula intitation
`isotoriicity
`infusion rate &duration
`drug vs vehicle
`
`Purity of excipients and drugs
`Formula irritation
`isotornicity
`pifusion rate & duration
`drugvs vehicle
`
`Sterility
`Particle size
`Pharmacokinetics
`Stability
`
`pH rate profile
`pH solubility profile
`Freezing point depression
`ia vitre precipitation model
`da vive phiebitis model
`Esviire cell lysis studies
`
`Mixture studies for maximum
`solubility
`fevitro precipitation model
`de vive phlebitis model
`in vitro celliysis studies
`
`fnvive phlebitis model
`Javitro-cell lysis studies
`
`Phase solubility diagrams
`In vive phlebitis model
`Br vitro cell lysis studies
`
`Particle size
`
`Vol. 50,No.5 / September-October 1996
`
`331
`
`AstraZeneca Exhibit 2052 p. 3
`
`

`

`ties from the free form. providing the opportunity to
`prolong drug presence ithe bloodstream or to aller
`disposition in the body." Heroic” methods. reported in
`the [Herafure for°-waridus Cancer drugs. will alsa’ be
`reviowed although these methods tse types and amounts
`of excipients that probably would not commonly. be
`considered approvable for intravenous administration,
`is
`The basis for reliable formulation development
`accurate determination of solubility. Traditional method-
`ology is the “equilibrium method” (8) where excess drug
`is added to the solvent system, and some means of
`agitation is employed under constant.
`temperature.
`Samples are withdrawn, filtered, and analyzed for drug
`coricentration over a period of time and equilibration: is
`demonstrated by uniformly of the data over the time
`interval. Por sparingly soluble drugs where equilibria are
`slow, accurate determinations of solubliny may be diffi-
`cult. Useful techniques im these mstances include using
`highly specific analytical methods.to detect parent com-
`pounds, minimizmg the amount of excess solid added,
`and assuring sufficient equilibration time (1). Solid’staté
`factors and batch-te-batch vatiation (different poly-
`morphs, hydration state, crystallinity, crystal homogene-
`ity, and impurities) may aflect reproducibility of drug
`solubility determinations.
`
`A. pi Adjusinient
`
`Current FDA approved marketed: parenteral: prod-
`ucisrange in pH from 2 to.11. A.comprehensive listing of
`these products. may be found in Table U1. For biocompat-
`ability reasons, formulation of injectables within.the pH
`ranges of 4 to 8 is most common. However, to achieve
`sufficient drug solubility, a pH outside this range may be
`necessary.
`‘The pH at.which a product is formulated is usually
`determined from the pH solubility and pH rate profiles
`of the drug (9). A recent example of their application to
`aid parenteral formulation development is CI-O88, a
`cholecystokinin-B receptor antagonist (10).
`Additional formulation variables to be considered are
`the necessity. of a buffer, bufler capacity, and. drug
`eoncentration. Thesé can influence supersaturated drug
`concentrations in the bloodstream, a condition that may
`lead to in vivo drug precipitation. The blood is very
`efficient at pH neutralization and normally maintams a
`narrow pH range of 7.38 to. 7.42. For example, a low
`meidence of phlebitis was observed in the rabbit ear vein
`model when:sclutions over the pHi -range-af 3.to L1.with
`buffer concentrations of approximately Os M, were
`administered in a single small volume (1 mL.) bolus dose
`(11). Simple screening tests consisting.ol a computa-
`tional model where drug solubility is plotted. as a
`function of dilution, and in viiro dilution experiments
`were shown to be eflective tools in evaluating the ability
`of the pH-solubilized drug to remain in solution dilution
`(12,13). Davio et al. (14) showed that in vive precipita-
`tion of the pH-solubilized drug ditekiren was dependent
`upon drag concentration and infusion rate. Low concen-
`tration drug solutions, which are rapidly diluted below
`
`322
`
`saturation solubility. and rapid infusions were preferred
`tominimize precipitation.
`The most commonly used buffercormponents in paren
`teral products and their pKa‘s are: citric acid (3.13, 4.76,
`6.40), acetic acid (4.76) and phosphoric acid (2.15, 7.20.
`12.33). Wher: buffers are-ermployed, the stability of the
`molecule twist alsa be considered, since i may be
`influenced by the jons-in solution (9) Exaniples.of buffer
`catalyzed solution degradation include famotidine, a
`histamine. H2.receptor imbibitor (15) and loracarbel, a
`awitterionic cephalosparin (16),
`
`B. Use of Cosalvents
`In recent years, surveys of FDA-approved parenteral
`products (17-19) showfive water-miscible cosoivents—
`glycerin, ethanol, propylene glycol, polyethylene glycol,
`and N,N,-dimethylacetamide—as components of sterile
`formulations (Table IT] and IV). Cosolvents are em-
`ployed in- approximately 10% of FDA approved paren-
`téral products. They are useful because they may often
`provide exponential increases in- solubility (20) and also
`allow exclusion of water for compounds susceptible to
`hydrolysis.
`Investigation of the solubilizing potential of various
`cosolvents may be approached empirically by determin-
`ing the compounds solubility in cosolyent compositions
`simular to marketed products (21-23), or by one of
`several systematic approaches, such as log-linear solubil-
`ity relationships or statistical experimental design.
`In the study of log-linear solubility relationships,
`Yalkowsky and Roseman (20) investigated a range-of
`solutes in binary cosolvent mixtures of ethanol, propyl-
`ene glycol, and glycerin im water and discussed the
`closeness of fit of apparent solubility to a loa-linear
`solubility equation. Briefly, this technique involves experi-
`mentally determining the solubility of a compound in
`increasing percentages of a cosolvent and generating.a
`sémi-logarithmic plot of the apparent-solubility of the
`drug as a function of the volume-fraction of the cosol-
`vent, Using the slope and the solubility of the compound
`in pure water, an equation may be wriften. to describe
`the solubility ina binary system.
`Assuming that the log-linear increases in solublity of
`individual cosolvents.are additive, equations may aiso be
`written for-lernary and quaternary mixed cosolvent
`systems (24). Mathematically, these relationships are
`described by the following equations:
`
`Binary cosolvent syster
`
`log C, = log C+ agh
`
`Ternary cosolvent sysiem
`
`log C, = log+ age + anf,
`
`Qualernary cosolvent spsiem
`
`log C, = log Cy + of, + Oufy + Of,
`
`where Cy is the drag solubility in water; o's are the
`slopes of the semi
`logarithmic plotsy C..is the drug
`solubility, fis the volume fraction of the cosolvent; and
`the subscripts 4, 6, x denote the coselvents A, B, and X
`
`PDA Journal of Pharmaceutical Science & Technology
`
`AstraZeneca Exhibit 2052 p. 4
`
`

`

`TABLE li
`Exampies of Marketed Parenteral Praducis with Solution pk Outside Range of 410 8 (18, 19)
`
`pH
`pH
`Generic
`Marketed
`
`(constituted)
`Adjustment
`Namie
`Trade Name
`Form
`Routes
`
`Solution
`Solution
`
`Powder
`Powder
`Concentrate
`Powder
`Solution
`Solution
`
`Poweder
`
`
`
`
`
`Solution
`Sohition
`
`Sohution
`
`Solution
`Solution
`Solution
`
`Solution
`Solution
`
`Solution
`Solution
`Powder
`Solution
`Solution
`Solution
`Solution
`Solution
`Solution
`Solution
`
`IB, IF
`TB, IF
`
`IB
`IM, IF
`TF
`TE, IF
`IF
`IF, TB
`
`IF
`
`IM, IP, 1B
`IM, 1B
`
`IM, 1B, IF
`
`IM, 1B
`IM
`TB, IF
`
`TF
`IM, IF
`
`IM, IF
`TF
`IF
`IM, IB
`IM, TRUIF
`IF
`iF
`1B, IF
`IM, 1B
`TB,IM
`
`Powder
`Powder
`
`TM, UB, IF
`iB
`
`Solution
`
`IB TF
`
`Powder
`Powder
`
`Powder
`
`Solution
`
`Powder
`Solution
`Solution
`
`IM, TF
`1B, TF
`
`IM, TBIP
`
`TR; EM
`
`TBy TE
`IB
`IF
`
`Solution
`Sohution
`Solution
`
`IETF
`1B
`IM, TROIF
`
`pu<4
`3.24
`325-365
`
`Lactic acid, NaOH
`Benzenesulfonic acid
`
`Amrnone Lactate
`Atracurium Besylate
`
`3
`ie
`3.33.9
`oad
`25-45
`SI
`
`LB-3.3
`
`33:8
`23S
`
`3.2-3.8
`
`23
`3-3.6
`3-4
`
`34.2
`27-35
`
`3
`32-4
`2-28
`38
`3-4
`3.34
`25-45
`34
`238
`3-4
`
`pli>s§
`a2
`1O0.5-DL.6
`
`8.069
`
`9.6-10.4
`9.6
`
`8-10
`
`8.5
`
`92-10
`116
`9-105
`
`Lactticacid, WC)
`Citric acid
`NaOH, HC)
`Cittie acid, Nacitraté
`
`Lactic acid
`Lactic acid, ethyl
`lactate
`Lactic acid
`
`NaOH/HC
`Lactic acid
`
`NaOH, citric acid
`Tartaric acid
`
`NaOHHC
`
`Na cltrate,citric acid.
`Hcl
`Citric. acid, Na citrate
`Acetic acid
`NaQH
`
`Tartaric acid, Na
`cltrate
`
`HCUNaOtH
`
`NaOH
`
`NazsHFOy, NaGH
`
`NaOH
`NaQH
`
`O28
`8-11
`89.3
`
`NaQH
`NaQh
`NaQH
`
`Chiordiazepoxide HC].
`Benzquinamide HCl]
`Ciprofloxacin
`Dacarbazine
`Dopamine HCl
`Dillazem HC!
`
`Doxyeyeline Hyctate
`
`Droseridol
`Ersonovine Maleate
`
`Fentanyl Citrate and
`Droperido!
`Glycopyrrolate
`Haloperide! Lactate
`Labetalol HCI
`
`Methyidopate HC!
`Metivlergonovine
`Maleate
`Midazolam HC!
`Murinone Lactate
`Minocyeline HC)
`-Nalbuphine HC]
`Naloxone HCl
`Ondansetron HCI
`Oxytocin
`Papaverine HC!
`Pyridoxine HE)
`Tolazoline HC]
`
`Acelavolamide Na
`Acyclovir Na
`
`Asninophylline
`
`Amobarbital Na
`Azaihioprine Na
`
`Anipicihn Na
`
`Betamethasone Na
`PO,
`Chiorothiazide Na
`Diazoxide
`Diethylstilbestrol
`Diphesphate
`Fluerouracti
`Folie aciel
`Lasix
`
`Inocor Ganoh Winthrop)
`Tracrium (Burroughs
`Wellcome)
`Librium (Roche)
`Emete-Con (Roerig)
`Cipro DV. (Miles)
`DTEC-Dome (Miles)
`Intropin (DuPont)
`Cardizem (Marion Merrell
`Dow)
`Vibramycin TV (Roerig,
`Elkins-Sinn)
`Inapsine Ganssen)
`Ergotrate Maleate (Lilly)
`
`Tonovar (Janssen)
`
`Robinul (Robins)
`Haldel (McNeil}
`Normodyne (Schering)
`Trandate (Glaxa)
`Aldomet Ester HC] (Merck)
`Methergine (Sandoz)
`
`VYersed (Roche)
`Primacor (Sanofi Winthrop}
`Minocin (Lederic}
`Nubain (DuPont)
`Narean (DuPont)
`Zotran (Cerenex)
`Pitocin.(Parke-Davis)
`Papaverine HCI {Lilly}
`Pyridoxine HCI (Steris)
`Priscollne HC] (Ciba)
`
`Diamox (Lederle)
`Zoviras (Burrougs
`Wellcomé}
`Aminophylline (Abbott,
`Elkins-Sinn, American
`Regent}
`Anmyial Na (Lilly)
`Imuran (Burroughs
`Wellcome)
`Polveillin-N (Apothecon)
`Totacillin-N (Beecham)
`Onuupen-N Wyeth)
`Celestone Phosphate
`(Schering)
`Sodium Diuril{Merck)
`Hyperstat (Schering)
`Sblphostrol (Miles)
`
`Fluorouracil (Roche)
`Folvite (Lederle)
`Furosemide
`(Hoechst-Roussel
`tf
`Powder
`Cytovene (Syntex)
`Ganciclovir Na
`lt
`Bl
`Leueovorin Ca
`Wellcovorin. (immunex,
`Powder
`IM, TB, TR
`Burroughs Wellcome)
`
`95-105
`Na carbonate
`Methohexital Na
`Brevital Na (Lilly)
`Powder
`1B, TF
`IM = intcamuscular, 1F = intravenous infusion, TB = intravenous directinjection.
`
`Vol. 80,No. 5 | September—October 1996
`
`339
`
`AstraZeneca Exhibit 2052 p. 5
`
`

`

`TABLE Hl
`Cosolvent Concentrations in Some Currently Marketed: Parenterals (16, 19)
`
`Coselvent in
`Marketed Vehicle
`
`Appx.
`Vehicle
`Marketed
`Generic
`Name
`Trade Name
`Form
`Routes
`Administration
`per Dose
`
`
`Ethane! 10c
`
`Crrmmrstine
`
`BICNU(Bristol Myers Drug
`Oncology)
`+.Dibvent
`
`iF
`
`Dilete bid
`
`ann!
`
`Propylene glycol 40%
`Ethyl alcohol: 10°.
`
`Diazepam
`
`Valnon (Roche)
`
`Solution
`
`IMJIB
`
`Direct Injection
`
`O54 ml
`
`Propylene Glycol 4002
`Alcohol 10%
`
`Digoxin
`
`Larioxin (Burroughs
`Wellcome)
`
` Dimenhydrinate
`(Steris)
`
`Solution
`
`iB
`
`Direct injection
`
`I-3ral
`
`Solution
`
`IM. IF
`
`Dilate 1:10
`
`Lomi
`
`Dimenhydrinaie
`
`Benzyl aleohol 5%
`Propylene givcal 50%
`
`Propylene glycol 250°
`Ethanol 25%
`
`Esmolel AC!
`
`Breviblec (DuPont)
`
`Concentrate TF
`
`Dilute 1:25
`
`l-liiml
`
`Hydralazine HC]=Apresoline HCL(Ciba). Solution IM, TB Direct injection (h3-1 mil
`
`
`Propylene glycol
`iS3a%
`
`
`
`
`
`Ethanol 10°
`
`Ketorolac
`‘Tromethamine
`
`Lorazepam
`
`Toradol (Syntex)
`
`Solution
`
`IMenly
`
`DirectinjectionIM lm
`
`Ativan (Wyeth-
`Ayerst}
`
`Solution
`
`IMTB
`
`IM Direct Injection.
`Delate ISDE
`
`doal
`
`PEG 400 1.18 mi/ml
`Berzyl aleahol 2%
`Propylene-glycol
`
`Povidone 20- meg
`Diueat 10m)
`Propylene elycol Gm
`Ethanol 052 mi
`
`Ethanol 30%
`Propylene glycol 30%.
`
`Propylene glycol 400%
`Alcohol 10%
`
`Alesho! 10%
`Propylene glycol 67.8%
`
`Propylene glycol 40%
`Aleanol 10%
`
`Phenobarbital Na
`
`Phenytonr Na
`
`‘Luminal Na (Sanofi
`Winthrop)
`Dileotin (Parke Davis)
`
`Polyethylene glveal 30%
`
`Secobarbital Na
`
`Secobarbital Na
`C(Wyeth-Ayerst)
`
`Propylene glycol 40%
`Ethane) 10
`
`Trimethoprin-Sul- Sentra {Burroughs
`famethoxazole
`Wellcome)
`Bactrim (Roche)
`
`Metphalan HCI
`
`Alkeran (Burroughs
`Wellcome)
`
`Drug
`+ Dilwent
`
`iF
`
`Dilate constinte
`2119
`
`imal
`
`Nitroglycerin
`
`Tridd (DuPont)
`
`Concentrate IF
`
`Dilute 1:100
`
`25-10 ml
`
`Peniobarbital Na
`
`“Nembutal (Abbott)
`
`Sotation
`
`IM: 1B
`
`Slow direct injection. 2 ml
`
`Solution
`
`TM TB
`
`Direet injection
`
`tml
`
`Solution
`
`IM.TB
`
`Direct imection
`
`3-3.)
`
`Solution
`
`IML TBTF Direct injection
`
`i-om
`
`Concentrate TF
`
`Dilute P25
`
`S<10 ml
`
`Agmsacrine
`
`N.N-Dimethylacet-
`amide LOO:
`
`Lami
`Dilute 1500
`IF
`Drug
`Amsidine.Coneén-
`
`trate (Parke-Davis)! + Dituent
`ive intramuscular TF = intravenous infusion, 1S = intravenous ditect injection.
`«Drug available outside the United States
`
`respectively. In its simplest form, determining the drug
`solubility in water and pure cosdlvents would. allow
`estimation of the amount.and type of cosolvent required
`to altaim-a desired solubility. In mostocases however,
`deviations from log-linear increases of solubility occur in
`aqueous Cosolvent mixtures.as indicated by curvature in
`the solubility plots. The deviations are attributed to
`solvent-solvent interactions (5,25).
`this
`For first approximations:.of solubility however,
`approach has been shown to be usetul (26-27). Chien
`(28) used this technique. and polarity indexes of coscl-
`vents to calculate the. polarity of a solution that pro-
`duced the greatest solubility of the drug metronidazole.
`
`Aqueous/casolvent ratios of corresponding polarity could
`then be calculated for other cosolvent systems to provide
`qualitative identification of solubility maximums. (9,
`30). Polarity indexes.of commom water miscible cosol-
`vents have been tabulated and discussed by Rubino and
`Yalkowsky. These indexes reflect the cohesive proper-
`hes of the solvent. (solubility parameter and interfacial
`tension}, hydrogen bonding ability (proton donor and
`acceptor density), and polarity (electric constant).
`Another. solubility determination. approach. particu-
`lariv belpful for complex mixtures isa statistical experi-
`mental design (31). Identifying the optimum combina-
`tion of coselvents for solubilization may reduce the net
`
`334
`
`PDA Journal ot Pharmaceutical Science & Technology
`
`AstraZeneca Exhibit 2052 p. 6
`
`

`

`TABLE TV
`Surlactant Concentrations in Sere Currently Marketed Parenterals (18, 19)
`
`
`Generic Name
`Trade Name
`Routes
`Administration
`
`Appx.
`Vehicle
`per Dose
`
`“Teniposide
`
`Vurnon (Bristal-Myers
`Squibb}
`
`TF
`
`Dilnte TO or 1000
`
`3-Oml
`
`Solabilizer in
`Marketed Vehicle
`
`NN-dimethylacetamide 60
`mg/ml
`Cremopbor ELS00
`ma/ml
`Dehydrated alcohol
`427%
`
`Polysorbate 8020 mg/ml Direct injection TM=1-25 milPhvtonadione Konakion (Roche) IM only
`
`Propylene giyeol 207
`ma/ml
`
`
`
`
`
`
`
`Cremophor EL 527
`me/ral
`Ethanol 49.7%
`
`Propylene givool 30%
`Polysorbate 801,69
`Polysorbate 20 0.028%
`
`Paclitaxel
`
`Taxol (Bristal:Myers
`Squibb}
`
`Moaltvitamins
`
`MOV.L-12 (Astra)
`
`iF
`
`IF
`
`Dilute 1:5 or 1:20
`
`20 ml
`
`Dhlefe b10Q0n.6500 Sal
`
`
`
`Polysorbate 804% Direct injection IM=2 mlChiordiazepoxide HC] Librium (Roche) IM only
`
`Propylene glycol 207.
`
`
`
`
`
`
`
`Cremophor EL.650
`mg/ml
`Alcohol. 32.9%
`
`Polyethylene glycol 300
`650 mg/ml
`Ethyl aleohol 305% viv
`Polysorbate 80.8%
`
`Polyoxyethylated fatty
`acid 7.0%
`
`PEG40 castor o10.115
`mlm
`
`Cyclosporine
`
`Sandimmune (Sandoz)
`
`IF
`
`Eroposide
`
`VePesid (Bristol-Myers
`Oncology)
`
`IP
`
`Dilute 1:20-1:100
`
`Dilute 12100
`
`Smal
`
`Simi
`
`Phytonadione
`
`AquaMEPAYTON
`(Merck)
`
`IM. TB
`
`Direct inject IM,
`preferred
`
`i-25ml
`
`Miconazole
`
`Monistativ.Ganssen}
`
`IP
`
`Dilute 1:10
`
`mi
`
`
`
`Polysorbate 80.12% Directinjection IM=1-2.Vitamin A, Aquasol A Parenteral IM
`
`(Astra)
`
`
`
`
`
`Polysorbate 80 0.008%
`Na desoxycholate 0.41%
`Polysorbate 20.0.40%
`
`Alteplase
`Amphotericin B
`Calcitriol
`
`Polysorbate 80.0.04%
`
`Cefazolin Na
`
`Polysorbate 60 0.004%
`
`FPolerastim
`
`Sodium dodecyl sulfate
`0.18 me/mil
`
`Aldesieukin
`
`Activase (Genentech)
`Fungizone (Apothecon}
`Caleijex (Abbott)
`
`TF
`IF
`IB
`
`Direct infusion
`Dilete 1:0
`Direct- injection
`
`20-106-mi
`2-20-ml
`035-1) ml
`
`Kheiol (Lilly)
`Ancef (SmithEline
`Beecham)
`
`Neupogen (Amgen)
`
`Proleulin (Cetus
`Oncology)
`
`IM.IF, TB Direct injection
`
`IB
`
`IF
`
`Direct injection
`
`(25-3 mil
`
`Dilute 1:42
`
`L2ml
`
`Fam
`Dilute 1:50
`IF
`Cordarone MTV (Sanofi,
`Amiodarone HC]
`Polysorbate 80 10%
`
`Winthrop|
`IM = intramuscular, IF = intraverious infusnin, 1B = mtravenous direct myéction.
`“ Drug available-outsule the United States.
`
`in the formula (6). They also
`amount of cosolvent
`facilitate the study of systems characterized by non-
`linear Increases in solubility, Optimization techniques in
`pharmaceutical
`formulation. have recently been ré-
`viewed (32). An example of their useé.is a suaplex search
`for solvent blends producing maximum drug solubility
`
`tions are not easily defined. A review of currently
`
`marketed parenteral products shows that percentages
`range from.10 t0.100% (TableLand TV}. Appropriate
`prodiict amounts are offen:a matter of considering a
`diverse set of factors such as; 1) administration condi-
`tions, 2) total dose, 3) target population and 4) duration
`af therapy. Toxicity and adverse clinical effects of
`chifittion. cosolvents. are summarized (33-34), Recent
`safety assessment reviews of propyleme glycol (35) poly-
`ethylene glycol (36) and glycerol (37) have been pub-
`
`QQ).*ccna levels of cosolvent in parenteral formula-
`
`Vol. 80,No.5 ) September-October 1996
`
`$35
`
`AstraZeneca Exhibit 2052 p. 7
`
`

`

`TABLE .V
`Some Currently Marketed Parenterals Utilizing Complexing
`Agents, Mixed Micelles, of Lipid Systems
`
`Solubilizer
`Generic
`
`Systent
`Name
`Trade Name
`
`Complexing Agents
`Hydrolwzed
`gelatin 0.7
`Ethylenediamine Aminophylline
`
`Corticotropin
`
`Athear (Xhone-
`Poulene Rorer)
`Aminophylline
`(Abbott, Elkins
`SinnAmerican
`Regent)
`Amphotericin BB Aleleet (The Lipe-
`some Co.)
`
`Amphotericin B Amphocil (lipo-
`some Tech-
`nology)
`
`DMPG and
`PMPC lipid
`complex
`Na cholesteryl
`sulfate, col-
`loidal disper-
`sion
`Mixed. Micelles
`Clycocholic acid- Diazepam
`lecithin
`Glycocholic'acid- Vitamin K
`lecithin
`Emulsions or Lipdsomes
`Lipid emulsion
`Diazepam
`
`Valium MM
`( Roche}
`Konakion/ 120
`(Roche)"
`
`Lipid emalsion
`Lipid emulsion
`
`Propofol
`Perflucrodeealin
`
`Dizac (Ohmeda)
`Diagemuls
`(Dumex)}*
`Diprivan (Zeneca)
`Fluosol-DA.CAlpha
`Therapeutics)
`AmBisome
`Amphotericin B
`Liposome
`
`(Vestary’
`TM. = intramuscular..TF = intravenous infesion; EB. intravenous
`direct.injection,
`* Drug available otitside the United States,
`
`-cosolvent vehicles in
`toxicity of several
`lished. Local
`animals issummarized in Table VL.
`
`C. Use ef Surface Active Agents
`
`Surlace active agents are usually incorporated into
`parenicrals to provide one of several desirable proper-
`ties; 1) increase-drug-solubility-through micellization, 2)
`to preventdrue ‘precipitation upon dilution (38), 3)
`improve the stability of adrugin solution by incorpora-
`tion of. the drug into.a micellar structure (39). and 4) in
`protein formulations, prevent aggregation due to liquid;
`air or liquid/solid interlacial mieractions.
`‘Table [V provides-cxamples of FDA-approved paren-
`teral products containing surface active agents. While
`many diflerent types of surfactants exst (4), only an
`extreme few have precedence for use in parenteral
`sroducts. Por example, for stabilization..of proteins
`against problems of aggregation, only polyoxyethylene
`sorbitan monodleate (polysorbate 80)
`is an FDA-
`approved surfactant (18). Other surfactants which have
`been usedin. parenteral products are poloxamer 188
`(polyoxyethylene-polyaxypropylene copalymer), polysor-
`bate 20.and 40 (polyoxyeihylene-polyoxypropylene (poly
`oxyethylene sorbitan monolatty acid esters}, Cremophor
`BEL*and Emulphor EL.719° (polyethowlated fatty acid
`esters and oils}. Which surfactant is most cllective as a
`solubiliger or stabilizer is often a matter of emprrical
`
`336
`
`investigation. (41). Detailed reviews of micelle struc-
`tures, characterization techniques, and pharmaceutical
`applications have been published.(42,.43):
`The toxicity of surfactants reported in- the literature
`priorto 1983 are summarized by Attwood.and Florence
`(43). Reviews on the pharmacology of polysorbate 80
`(44) and the incidence of clinical side effects of Cremo-
`
`phor EL® (42) have been published, Children and
`newborns may be particularly sensitive to these. agents
`and administration to this population is discisssed (46).
`
`D. Ose of Complexing Agents
`
`Complexation of water insoluble drugs usally in-
`volves the incorporation of the drug within the inner
`core of the complexing agent.so that the outer hydro-
`philic groups of the complexing agent interacts with
`water rendering the complex soluble.
`An example Of successiul application of this technol-
`ogy 1s Amphocil®, a lipid complex formed between
`amphotericin Band sodium cholesteryl sulfate, a natu-
`rally occurring cholesterol metabolite (47), In solution,
`the complex.
`is postulated to be a stable disc-like
`structure (hat remains intact inthe systemic circulation.
`Comparative studies in animals with micelle solubilized
`amphotericin B (Pungigone®) have showt a significant
`reduction in syitemic (Oxicity asa result of altered
`systemic distribution atid elimination characteristics (48),
`Naturally occurring cyclodextrins, particularly G-cyelo-
`dextrin, are able-to complex water insoluble drugs and
`render them soluble in water. However, 6-cyclodextrin
`have been associated with renal toxicity upon parenteral
`administration. The toxicity has been attributed the low
`aqueous solubility of 6-cyclodextrin and precipitation in
`the kidney. Newer cyclodextrins are chemically modified
`to improve water solubility and increase their usefulness
`(49). Brewster et al. (50) have described the preparation
`anc successful use of chemically modified. cyclodextrins
`such as Z-lvdroxypropyl-B-cyclodextrin in solubilizing
`and everstabilizing various proteins and peptides.
`An example where the crug was not
`incorporated
`within some kind of matrix, but combined with an
`additive fo obtain basically @ soluble salt complex
`involved ascorbic acid ($1). Similarly, tromethamine has
`been reported to solubilize zomepirac, an. anionic drug,
`by. micelle (association colloid) formation (52). The
`aqueous solubility of metronidazole was reported to be
`enhanced by the water soluble vitamins nicotinamide,
`ascorbic acid or pyridoxine HCI] (32). A cage-like struc-
`ture formed by the vitarnins around molecules of metro-
`nidazole was postulated,
`
`£.. Emulsion Systems
`
`if a molecule has sufficient lipid solubility, emulsions
`may be employed. Typical emulsions contain trighyceride-
`rich vegetable oils-and lecithin and may also contain
`nonionic surface active agents: as-ernulsifyine agents.
`Insoluble drugs may be incorporated into commercial
`fat enmilsions or
`through emulsification of the -cil-
`solubilized drug: The former is usually not. successful
`
`PDA Journal of Pharmaceutical Science & Technology
`
`AstraZeneca Exhibit 2052 p. 8
`
`

`

`because drugs influence the stability of these commer-
`cial ermuilsions (53).
`
`Emulsion formulas have shown advantages over high
`cosolvent levels by reducing local venous irritation (34).
`While emulsions hold potential as carriers for lipophilic
`drugs, great challenges exist inj; 1) efficient incorpora-
`tion of the driig ita the dispersed phase,2) validation of
`consistency In preparation and sterilization, and 3)
`dependable. biological evaluation .of
`the safety and
`efficacy of drugs delivered from erulsions. These topics
`are addressed in some detail in several review articles
`(35-38).
`More recent examples include a parenteral water-in-
`oil ermulsion of an LH-RH analog (59) and solubilization
`ofan anti-HIV thiocarbamate drug by extemporaneous
`emulsification (60). The patent literature contains 2
`large number of refererices-claiming safe and Stable
`emulsion. systems for parenteral injection. The commer-
`clal application for drug delivery has yet to be pro-
`nounced in the United States. Marketed products are
`mostly found in the European and Japanese market
`(Table V).
`Microemiulsion systems are.thermodynamically stable
`transparent. colloidal dispersions. The advantages they
`have over macroemulsions are their stabiliry and ease of
`manufacture. Droplet sizes are typically 10 times smaller
`than macroemulsions and are on the order of 10-100
`am. To achieve such a small size, usually high amounts
`of surfactant-are required (43). Microemulsion systems
`have. found utility in enhancing. penetration by the
`topical and recently oral route (61, 62). Requirements
`for-such high levels of surfactants haveaimposed limite:
`tions on their use by the parenteral route,
`
`F.. Mixed Micelles
`
`Mixed micelle systems are usually composed