Orug Delivery Systems I 103
`
`1n Phamlac;:eutical Care
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`ctaapter 8 I Shaifali Bhalla
`Parenteral Drug Delivery
`
`CHAPTER OUTLINE
`Overview of Parenteral Delivery
`common Routes of Parenteral Delivery
`lntr81'enous lnjeclion
`Intramuscular lnjectlOll
`Subcutaneous llljection
`lnl/adermal Injection
`Specialized Routes
`Advantaees and Disadvantages of Parenteral Delivery
`General Characteristics of Parenteral Delivery Systems
`Pharmaceutical Ingredients and Additives
`Vehicles
`Co-solvents
`Other Additives
`General Categories of lnjectables
`Injection
`For Injection
`Injectable Emulsion
`lnjoctable Suspension
`For Injectable Suspension
`Special Intravenous Delivery Systems
`liposomes for ln1ection
`UpkMssoci ated AmphOtericin
`Polymeric Systems for Parenteral Delivery
`Poi)1ller Nanoparticles
`Spec1a1 ized Devices
`Implantable Pumps
`Electronic Pumos
`Preloaded Syringes
`
`OBJECTIVES
`1. Describe the different routes of parenteral delivery an<! the
`factors influencing the absorption of drugs from different
`injection sites.
`2. Define parenteral drug delivery and describe its advantages
`over other routes of drug administration.
`3. Describe the -cllaracterlstics of parenteral dosage formulations.
`4. Explain the purpose of components of parenteral formula(cid:173)
`tions: vehiefe, co-solvent, btlffer. tomclty agent. preserva(cid:173)
`tive, protectant, surfactant, and antioxidant.
`5. Differentiate among dosage formulations available for
`parenteral administration an<! explain how drug is released
`fron1 various injectable preparations.
`6. Examine the application of drug-targetirc systems in paren(cid:173)
`teral dfUg delivery.
`7. Descnbe the use of specialized parenteral delr;ery devices.
`
`Overview of Parenteral Delivery
`Pttmirem/ delivery has been defined by the Cencer for
`Drug Eva luation and Research of 1he U.S. Food and
`Drug Adminisuacion (FDA) as the adminisuacion of a
`drug by injection, infusion, or implan rarion. 1 Parniuml
`deliwry means introducing drugs imo rhc body outside
`of the cntcral roure; that is, oucside of the gastrointesti(cid:173)
`nal 1racr.1 This delivery route can also be u.~ed ro
`adminiuer drugs directly to specific body organs and
`cissues to produce a desired therapeutic effect at a target
`site while minimjzing systemic side effects.
`Common rouces of parenteral adm inistration are
`described in rhe following seccions. Table I lists the
`routes of parenteral administrarion.
`
`Common Routes of Parenteral Delivery
`Intravenous Injection
`D rugs adminiscered by the inuavcnous (IV) route pro(cid:173)
`vide rhe fustest onser of action because rhey are injected
`directly into the systemic circulation, and there is no lag
`time or absorption phase for che drug. Drugs adminis(cid:173)
`tered by the IV roure exhibit I 00% bioavailability.
`The three most common mechods by which drugs
`are delivered IV are IV bolus, continuous IV infusion,
`and patiem-comrolled analgesia.
`
`• JV bolus is IV adm inistration of a dose of a drug
`all at once, typically in a few minutes, within or
`into a vein or veins.
`• IV drip or IV infusion is IV adminisuarion of a
`drug within or into a vein over a sustained
`period. For a drug with a narrow therapeutic
`range, IV infusion can control the amount of
`drug administered over a fixed time period by
`comrolling the infusion rare. Loading doses arc
`administered at the stare of IV infusions for drugs
`that have long biological half-lives. Tbis quickly
`achieves effective berum concentrations of che
`drug. Steady-siate serum c.onccntr.itions can be
`maintained by giving the drug as a continuous IV
`infusion at a corm~nt rate over longer pe~·iods. ~
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`104 I Cnopter 8
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`Parenteral Drug Delivery
`
`Epidural
`
`Table 1.
`Routes of Parenteral Administration*
`Definition/characteristics of administration
`Name
`Administration on or over the dura mater
`Administration w11hio a joint
`Adm;nistration within an artery or artc1ies
`
`Intra.articular
`
`lntra·arterial
`
`lntracardiac
`
`lntracavitary
`
`lmradcrmal
`
`lntralymphatic
`
`lntramusoolar
`
`lntraosseous
`
`Admlnlstratron w'lh1n the heart
`Administration within a oalhologic cavity. such as
`occurs In the lung 1n tuberculosis
`Admlnlslration within the dermis
`Injection is gr.er rnto the dermal layer of the sk.n.
`Administration within a lymph channel or node
`Administration "'1th1n a musc.e
`Injection is given Into the muscle fibers of the
`upper ann or gluteal area.
`
`Administration directly Wlllllll Ille marrow of a oone
`The needle is injected right througri tile bone and
`mto tne soft ma<row interior
`
`lntraperitoneal Administration within the peritoneal cavity
`Adminrsvation v.;t111n tile vertebra. eo<umn.
`Refers to both epidural and mtrathecal routes.
`
`lntraso nal
`
`lntralhecal
`
`Intravenous
`
`lniraceretxo
`ventrlcular
`
`Administration within the cerebrospinal Puid at
`any 'evel of :he cerebrospinaJ axis. ioelud ng injec(cid:173)
`bon into the cerebral ventricles. ln.iect on is mto
`subarachnoid spaces.
`
`Admm•stration within Of Into a vein or ve-;ns(cid:173)
`lnjectlon is given directly Into me vein.
`Admmistrat1011 w1Ulin a ventrlcie o' the brain
`
`lrtravrtreal
`
`Admi~lstration wlth.n the Vll/00\Js body of the eye
`
`Su'bcutaneous Administration beneath the skin; also known as
`hypodermic injection
`Injection •S g;.en below the epidennis and dermis
`layer of the skin.
`
`The preferred route for analgesics is a continuous
`IV infusion, because it produces less llucruation
`in scrum concentrations of the drug than do
`intermi1tent intramuscular (IM) injections.
`• Patient-controlkd analgesia i$ designed to deliver
`IV bolus doses in addirion co a slow, conti nuous
`IV infusion.4 Tl1is method allows palients to ~)f.
`administer analgesics as needed for breakthrough
`pain. The drugs m05L commonly delivered by
`
`this route are narcotic analgesics such as fenta·
`nyl,' methadone,'' and morphinc. 1
`Drug.~ that arc commonly administered by the IV rouce
`are analgesics, general anet.theric.~, antiviral agenrs, antibi(cid:173)
`otics, immunosuppressi,,e agems, antifungal agenis, anti(cid:173)
`bacterial agents, antihypertensivc agents, vasodilators,
`antiarrhythmic drugs, and chemotherapeu1ic agenlS.
`The TV rouce i; nor without adverse e£Tccrs. IV injec-
`1ions are admi11istc1·ed direcdy into the venous circula(cid:173)
`tion, :md hence highly vascular and perfused organs, such
`as the hc;Jrt, lungs, liver, and kidney, rapidly acquire the
`dnig. In some cases, however, a sudden increase in :.erum
`drug concentration may lead to toxiciry. This can be pre·
`vcnced by giving a slow IV bolus injection. Other drugs
`with poor aqueous solubiliry may precipitate from solu(cid:173)
`tion and produce an embolism. Proper selection of the
`diluenc and slow IV adminisua1ion allows for proper
`mixing of the drug in the circulalion. Finally, some vehi(cid:173)
`cles may cause adverse effects in pediatric patient;. Fo1·
`example, phenobatbital sodium is dissolved in propylene
`glycol, which may cause hyperosmolaliry in in F.rnts.1 In
`addition, because the akohol and aldehyde debydrogen(cid:173)
`ase pathway char mcrabolizes propylene glycol is not well
`developed in infants and children younger than 4 years,
`repeated use oflV injections conh1i11ing propylene glycol
`can lead co toxicity.
`Lipid-soluble drugs like diazepam can easily cross the
`blood-brain barrier and are effective when given by the
`IV romc. However, lipid-insoluble drugs are ineffective
`when given by the IV route if the desited target site of
`action is in the brain. Thus, lipid insoluble drug~ often
`need to be admini;tered by specialized routes of delivery
`that bypass rhe blood-brain barrier. These specialized
`romes include intraspinal and intracercbroventricular
`injeciion, which wi ll be discussed later in chis chapter.
`
`Intramuscular Injection
`Drugs that may he irritating co the subcu1aneous (SC)
`tissues are administered via IM injec11on. The IM
`injection sire is usually 1he deltoid muse.le of the upper
`arm or the vastu~ lateral is muscle in the an terolateral
`aspect of rhe middle or upper thigh. A needle long
`enough to reach deep into the muscle mus1 be used
`and should be inserted at an angle of 80 to 90 degrees·
`Because of the rime required for the drug ro b~-come
`available from the muscle to the systemic circulation,
`IM inject ions have a longer time to onset of effect and
`
`
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`Drug Delivery Syatem• I 105
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`in Pharmaceutical Care
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`·on of acrion 1han JV injections. The rate
`d
`longer urau
`• n and ex.tcnc of avAilabiliry of drugs depend
`J
`0 f;1bsorpuo
`.
`. harmaccucical fuccor; such as formulation char-
`. . p. :md the physi ol~>gy 0
`b
`f 1 . ·
`· a IM
`·
`on
`top
`t lC lflJCCCIOn Site.
`Jcr~risu~ ·
`. .
`.
`.
`s nrc safer th;rn IV 1niccnons; however, rncor
`·
`. .
`tllJCCrt011· •
`.
`.
`rcet IM ad mi nistration rcch111ci uc.o; can result in blood
`dois, scarri ng of rbe ski n, ab~ccsscs, and nerve darnagc
`le3ding 10 paralytic condirions.
`DifTe.renr fonnulacion ~ nd delivery strategies are
`used for the administration of water-insoluble drugs.
`Water-insoluble drugs arc solubilized in solvencs
`such as propylene glycol and mineral oil for injec(cid:173)
`tion . T hese nonaqucous vehi cles stay at the site of
`injection and release che d rug slowly, which rcsulcs in
`prolonged serum drug concenirations and a longer
`duration of action. Sparingly soluble ioni:iable drugs
`prepared as solutions for injection must be buffered
`co physiologic pH.8 Precipitaiion of rhe drug may
`occur as a rcsulc of this change in pH. Absorption
`may be prolo nged as the drug re<lissolves in tissue
`10
`fluids. 9
`•
`Another faccor affecting drug absorption is che blood
`Aow w the injecrion site. IM injections given into the
`deltoid muscle in che arm arc absorbed fa51er than glu(cid:173)
`real injections. This difference is likely due ro rhc
`increased blood Row in chc deltoid muscle and lower
`blood Row in the gluteus maximus muscle, which hai. a
`high contetlt of adipose tissue. Slower races of absorp(cid:173)
`tion after gluteal injections were seen in a higher per·
`ccnrnge of women
`t han men.•·''·" Moreover,
`the
`injection volume is lim ited depending on the sire of
`admin istration. Large muscles like the gluteal muscle
`can efTc:ctively absorb 4 to 5 mL of injected solution,
`whereas smaller muscles like rhe deltoid muscle in the
`arm can absorb up ro 2 co 3 mL. 11
`IM injections are available in immediate-release for(cid:173)
`mulations as well as depot formulations for sustained
`release. Examples of t hese formulations are described in
`the following seccions.
`Immediate-Release Intramuscular Injection
`Water-soluble drugs are di'iS<>lvcd in aqueous vehicles
`and prepared as solutions for injection. On IM injec-
`1ion, chcy disiribuce into rhe circulation and release che
`drug rapid~y. The usual onset of action is 30 minu1es,
`and the duration of action depends on che drug's half(cid:173)
`lifc. One example is thyrotropin alfa for injecti on
`(Thyrogc:n®), a sterile, lyophili~d product char forms
`
`a solution afcer rcconscitution and is injecced IM for
`immediate release. 11 "
`Depot Formulations for Intramuscular Injection
`Depot injecrions release the drug slowly and maintain
`scrum drug concemr.uions for a longer duration. Depoe
`injections are long-acting dosage forrnulacions irtdica1c:d
`for maintenance creacment rather chan initiation o f ther(cid:173)
`apy. Depoe formulation~ are available as oil-based injec(cid:173)
`tions (eg. fluphenaiine cnamhate and escradiol cypionate),
`aq ueous suspension> (eg. penicillin G pCOClinc and peni(cid:173)
`cillin G benzarhinc, methylprcdnisolone acetate [Dcpo(cid:173)
`Medrol®], and medroxyprogesterone acecacc/c:smtdiol
`9pionatc [Lunelle®)), and microsphercs (eg, lcuprolide
`ace.ate [Lupron Depoe®}).
`An example of a long-acting depot formulacion con(cid:173)
`r::tining the drug in the form of salt is lluphcnazinc
`cnamhace (Prolixin Enanthate® injection). 14 h is indi(cid:173)
`cated for the maincenance treatment of nonagitated
`patients with chronic schirophrenia. Fluphcna1ine
`enanrhace is water insoluble and is therefore dissolved
`in oil. On IM adm iniscration, it forms a depnt of the
`d rng dissolved in oil.1\·11' T he d rug is released ;lowly
`From 1hc depo1 and enters rhc blood circulation. Dosing
`intervals vary from 2 co 6 weeks and arc: decermined by
`the response of che paticm to therapy.
`An example of an aqueous suspension acting as a
`depot is penicillin G ben1.achine/penicillin G procaine
`~uspension (Bicillin® C-R). The injection contains
`water-insoluble drug~ suspended in an aqueous vehicle.
`It is a stabilized, long-acti ng aqueous suspension <:nn(cid:173)
`taining sodiu m cirrare buffer and the suspending agents
`lecithin and carboxymei:hylcdlulose (CMC). 1 he ac1ive
`i ngredients are hydrolyred in the blood co penicillin.
`1be slow absorption from the IM injeccion ~i1c and
`~ubsequem hydrolysi~ leads to prolonged ;erum levels
`of penicillin, which allow~ dosi ng every 2 ro 3 days
`when repeated dost:.~ are nceded. 17
`Encapsulati ng d rugs in polymer matrices and biode(cid:173)
`gradable microspheres provides a way to mainrai tt ther(cid:173)
`apeucic levels of the drugs for a longer rime. An example
`of a polymer-based microsphere system used i n depot
`formulations is leuprolide aectare for depor su5pcnsion
`(Lupron Depoe®). Lupron Depor® microsphercs are
`indicated for JM injection and are avai lable in a prc(cid:173)
`fi lled dual-chamber syringe. T he drug charnbcr co n(cid:173)
`tains leuprolide acetate, incorporated in a biodegradable
`polymer of polylaccic acid and D-mannirol.18 T he dilu-
`
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`Amneal Pharmaceuticals LLC – Exhibit 1046 – Page 105
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`10s I CMptcr 8
`
`Parenteral Drug Dell•ery
`
`col chamber coor:iins sodium C MC, warer for injec(cid:173)
`tion, D-manniml, polysorbarc, and glad.ii acetic acid to
`maintain pH. The microsphercs form a depot ar the sire
`of injection, and die drng is released slowly ar a con(cid:173)
`srant rate as a resnh of chc hydrolysis of the polymer.
`Depending on i:hc prcscribeJ dose, L11pro n Dcpor®
`can be injected once every I to 4 monchs. 19 Other
`ei<_llmpb of mic:rosphere fonnula1ions Jre di~d in
`detail in the sccrion Polymctic l.liodegradablc Systems
`for Parenteral Adminiscration.
`
`Subcuraneous lajcction
`SC injection> are given inro the SC or fatty layer of tis(cid:173)
`sue below chc epidermis and dermis. These injections
`are also referred to as hyp11tkr111ic mjeuion.r because the
`drug is administer<-d beneath die skin.'> SC injcc1ions
`are usually small-volume injcccions and arc ad minis(cid:173)
`tered at an angle of 45 degrees m the skin. They can
`generally be sdf-adrninis1ered and are easy ro adminis.
`rer wi rh minim um discomfon. P:irienr cduc:nion
`regarding proper SC injcccion techniques is imponanc
`co minimize infection and ocher local adverse effects.
`Drugs are ahso1·hcr.l ar a slower race after SC injcccio11s
`than afrcr IM injcclioos bccmi<: cbcre is less blood flow co
`the fouy 1i.ssuc below the skin d1an co rhe muscle. The rate
`of ahsorp1ion aho depends on die penetration wcflicicnc
`and the amount of drug a1 cbc ~ile. 2 Absorption takes place
`dirough 1he c:tpillary wall in chc connccrivt.: tissue. Pcncrrn(cid:173)
`cion of drug.~ inco 1hc connective tissue depends on die
`conccntrncion g111cJic111 of drugs across die c:1pillary wall
`and conJocccivc tissue, die area of chc membrane exposed
`co 1he solurion, and the distance of diffusion. Medic:ttions
`cha1 arc injected by rhis rourc include vaccines, heparin.~.
`insulins, g1·owrh hormone, and epinephrine.
`
`ln tradcrmal In jcction
`lnrradermal (JD) injections arc administcrud within the
`dermis layer of the skin, 1 the upper layer of rhe skin jus1
`below die epidermis. lD injections :ore very-small-volume
`injection~ (O. I mL) and :uc ui<:<I ro cldivcr drugs to pro(cid:173)
`duce local elfoas. Examples or uses of JD delivery arc
`injections for skin rcsring. antigen delivery ro evaluate for
`allergic n.>actions, and adminisirariou of vaccines (cg,
`iuAuem~ vacciue).• JD adminisrmtion or vaccine$ ha.•
`been shown In enhance immune response more dfcc-
`1ively than SC administration.' 0 Thus, 1hc ID mute may
`target lymph nodes more efficiently than the SC rouie.
`
`Specialized Routes
`lntrasynovlaf
`lntrasynovial injection is administration of a drug
`directly imo 1he synovial cavity of a joinr.1 This form of
`parenreral delivery is used for die treatment of inOam(cid:173)
`mation in patients wich rhcumacoid arthritis and col(cid:173)
`lagen vascular diseases. Drugs administered by rhis
`route include merhylprcdnisolone acetate and triamcin(cid:173)
`olone aceconide, which are available as injccrable SIJS(cid:173)
`pcnsions. The duration of action
`is significantly
`increased when a drug is injccced
`inrrasynovially.
`Rcpeaccd injections, if given, arc generally administered
`no more frequently than every 3 monrhs.
`Intra-Articular
`lntra-arcicular injection is administration of a drug
`within a joint. lnrra-arricular administration of local
`ancsdietics and adjuvanrs is an alternate method for post(cid:173)
`operative analgesia. Paricms who have undergone liga(cid:173)
`ment reconstruction and cxpericn~ moderate to severe
`post0pcrativc pain can benefit from intra-articular injec(cid:173)
`tion of ropivacaine and morphine via a catheter in the
`knee joinr. This approad1 decreases die need for supple(cid:173)
`mental lV morphinc.21 for the first few hours after inrra(cid:173)
`synovial or intra-articular injecrion, local di5COmfon in
`die joi111 may occur, bu1 chis is rapidly followed by effec(cid:173)
`tive relief of pain and improvement oflocal function.
`
`lntraspinal
`lntrnspinal delivery is adrninisuacion or drugs directly imo
`the vertebral column.' lt includes <:pidut:"J.i and intrarhecal
`injection. With epidural injection, drug is ddivered to 1hc
`ouisidc of die dura and nor into rhc ccrcbrospinal fluid.
`Thus the clinical cffecrs arc tnorc localired to the spinal
`cord. Drugs can be delivered by a single bolus injection or
`as a oominuous infusion (Figure l).'2 Advanced primary or
`mecasracic cancer pain, thoracic and lumbar pain, nerve
`root injuries, and ncuroparhic pain are rrcared with inm(cid:173)
`rhccal injections and infusions of opioid.s, local ;u1csrhecics,
`donidine, bacloren, and ocher drugs used for the treatmenr
`of chronic pain, cane.er pain, and intractable spasriciiy.23
`Morphine sulfate ex1endcd-rdeasc liposorne in~-ction
`(DcpoDw®) is a special liposoma.1 dosage fonnularion
`injected into the epidural space.M.25 DcpuDur® injection
`is a sterile, preservative-free m~pension of multivesicular
`liposomcs containing morphine sulfucc pn:scnt as a sus(cid:173)
`pension in 0.9% sodium chloride solution. O n epidurol
`injccrion, the mulrivcsicular liposomes release morphine
`
`
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1046 – Page 106
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`Dural&Bc
`
`flllu,.1 Anatomy of the spinal cord indicating the epidu(cid:173)
`ral spac~ and the subarachoold space. (Reprinted with
`pormlssion from Moore and Dalley.")
`
`systemically and into the inuachecal ~pace rhrough the
`meninges at a slow rate ovc1 a prolonged period.'6 When
`given as a single d~ 30 minutes prcoperarivcly, Depo(cid:173)
`Dur® has produced persisrcm analgesia for 48 hours post(cid:173)
`operatively. The distribution, metabolism, and elimination
`pattern of lipo.'t-Omal morphine sulfate is similar to that
`after delivery of othec parenteral morphine formularions.
`DcpoDur® is designed for single-do.~ administration and
`does nor accumulate significantly in patients with
`impaired renal or hepatic funct:ion. Other examples of
`liposomal formulations arc de;cribcd in detail in the sec(cid:173)
`cion on special IV delivery systems.
`lntrathecal and lntracerebroventricular
`injection is the administration of drugs
`lntrathecal
`within the ccrcbrospinal fluid at any level of rbc cere(cid:173)
`brospinal axis, including injection into chc cerebral ven(cid:173)
`tciclcs.1 When lipid insoluble drugs arc needed 10 treat
`some neurologic disorders, ir is necessary to bypass the
`blood-brain barrier and deliver drugs directly inco the
`brain. This can be achieved by imrathecal administra(cid:173)
`tion, in which drugs are injected into the cerebrospinal
`Auid surrou nding the spinal cord, or by d irect injection
`of drugs into the brain by intracercbroventricular injec(cid:173)
`tion. which is an invasive 2pproach. 11 lntr.uhecal injec·
`tions can be given as a single dose or as c.ontinuous
`infusion via an indwelling catheter. Drugs that require
`long-term i mrathecal infusion can be delivered by imra(cid:173)
`thccal catheters connected to an SC implanted infusion
`device. The intrarhecal route is commonly used to
`deliver small lipophilic molecules for pain management.
`Opioid analgesics such as morphine, hydromorphone,
`
`Drug Delivery Systems I 1 07
`
`In Pharmaceutical Care
`
`and fcntanyl arc dfecrivc when delivered by the intrathc(cid:173)
`cal route. 23.z•
`lmraccrcbrovencricular administration is commonly
`used for chemotherapy u·eatmcnc of gliornas or for
`delivering ncurotrophic factors to many areas of the
`u:mral nervous system.'°
`
`Intra-Arterial
`The imra-arterial route is used to reduce drug exposure
`to the sysremic circulation and IO increase drug con(cid:173)
`centrations in the areas supplied by the artery inco
`which the drug is injected. The intra-arterial rouce is
`used to deliver chemothcrapeu ric drugs such as cis(cid:173)
`platin ro treat head and neck cancer and co inJecc vaso(cid:173)
`pressin ro control gamoimesrinal bleeding. New and
`$afc angiographic techniques enable the placement of
`microcatheters into small ancri~ under direct vision
`using Auoroscopy. 3' I lowever, intra-arrerial injections
`have been associated with embolism, occlusion of
`arreries, and drug toxicity.
`
`Advantages and Disadvantages of
`Parenteral Delivery
`The main advancages of parenteral delivery are rhe
`following:
`
`l. It can be used in patients who arc unable or refuse to
`rake medications by mouth.
`2. Rapid and complete absorption of drugs from the
`sysremic circulation takes place if tbe drug is ad min(cid:173)
`istered IV as a solution.
`3. First-pass hepatic metabolism is avoided, which leads
`to improv~-d bioavailabilicy for drugs chat undergo sig(cid:173)
`nificanr first-pass mccabolism after oral administrarion.
`4. Smaller doses can be used with IV administrarion
`tha11 wirh om! administration.
`5. The parenteral route avoids drug degradation in the
`gascroimestinal tracr. A large number of proteins are
`adm inistered parenterally.
`G. IV administration of drugs has been shown to provide
`a more pralictable pharmacokinetic and pharmacody(cid:173)
`namic profile for drugs than oral adminisrration.
`7. The route of parenteral delivery can be tailored co
`che needs and condition of the patient. Direct injec(cid:173)
`tion of rhc drug by the IV rourc is beneficial in emer(cid:173)
`gency situations when the need for therapeutic
`accion is immediate. For a slower onset and a longer
`durarion of action, drugs can be administered IM.
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1046 – Page 107
`
`

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`108 l Chapter 8
`
`parenteral Drug Delivery
`
`Although pa1·cnren1l del ivery is preferred for many
`drugs. administering drugs by rhis route has some d is(cid:173)
`advantages:
`
`I. Asepric prcou1rions musr be followed co avoid co n(cid:173)
`raminarion and minimi~ rhe risk of infoction when
`rhe drug is being administered.
`2. Most often, parentcrnll y cld ivcred drugs are admi11 is(cid:173)
`cercd by trained health care professionals in clinics
`and hospitals. T his is more inconveniem and costly
`than sclf-: adrninisrration ofdru~s.
`3. For sdf:administracion of all parenteral dosage formu(cid:173)
`lations, pacients mu.sc be adequately trained, which
`can be t ime consuming an<l resource imensive.
`4. Manufacturing is also more cosdy than the nrnnufac(cid:173)
`cure of convenrio MI tablets and capsules.
`5. Once drugs are injected JV, they cannor be removed
`easily from the bloodsncam. This can he a prohlcm if
`an incorrect dose or drug is ad1ninisrercd, because
`;1dverse effects can .-csulc. Dialysis or hemofi ltration
`can be used to remove excess drng, hut chesc arc
`complicated procedures and can cause discomfort to
`the paricm.
`6. Injections ma)' be ;iccompani ed by pain .ind infec(cid:173)
`tion ac the sire of in jeccion.
`
`agent~, smbili'l.ers, and toniciry agents must be sterilized
`separately and then combinL'<i in the formulation.
`3. They must be isoton ic. ' Jonicity-adjusring agents
`d.:crcase th.: hcmolysis of blood cells and reduce pain
`:md irritation ac rhe injection sire. Large-volu me
`injectable preparations must be isown ic wi rh blood
`(ie, must have the same osmolality as blood or orher
`body fluids). Large-volume p;Hcnternls are given ro
`prevent d ectrolyte imbai<ince.·12
`
`Pharmaceutical Ingredients
`and Additives
`Pare1iteral dosage formulations are composed of the follow·
`ing pharmaceutical ingredients and additives:
`
`l. Veh icles
`2. Co-solvcnrs
`3. O th.:r add itives: buffers, tonid(y-adjusting agents,
`amimicrobial prcserv;nives, pmtcctants, surfaccancs,
`antioxidams
`
`Vehicles
`Vd1 ides for injections must be scerilc ;ts well <lS particle
`;ind pyrogen free. Exampl.;s of vehicles and essencial
`vchidc charncreristics for w:1cer- and oil-based injtc(cid:173)
`rions are shown in Table 2.
`
`General Characteristics of
`Parenteral Delivery Systems
`Certain requi rements muse be satisfied for dosage formu(cid:173)
`lations and delivery sys tems to be approved for injection.
`
`l . They rnust be free o f pyrogens. Because of microbi;1 I
`contam ination, pryogcns or fever-producing sul>(cid:173)
`srances may be found in parenteral fornrnlations.
`The-;c suhsranccs can lead m complications after the
`fo rmulat ion is injecced; therefore, all paremcrnl for(cid:173)
`mulations must be pyrogen free.
`2. T hey muse be sterile. All paremeral fonnularions must
`be free of all microbbl organisms. Stcrili1~11ion is rhc
`process by which all livi1tg and pachogenie organ isms
`are destroyed and removed from the formulation. The
`most common tech niques u~J to swrili?.c injecrion
`formulations and parc1nernl implams arc steam and
`dry hear. If the drug is hen labile, gas sterilizarion by
`ethylene oxide, film1tion using filters wirh various pore
`sizes for differcnc formulations, and ioni<ing radiation
`techniques may be use<l. The individual componcncs
`of dispersions or suspensions such as drugs, suspending
`
`Co-Solvencs
`Co-solvents <He used to solubilize drugs that must be
`injected as solurious. Drugs with poor warcr solubil iLy
`ma)• be formu lared with co-solv·en ts such as ethanol,
`p1·opylcnc glycol, :md polyethylene glycol (PEG) 300.
`Co-solvcm solutions are confined ro IV and JM use.
`for IV adminis1rario11 , the injection must be adminis(cid:173)
`tered slowly ro prcvcnc precipirntion of the drug and ro
`avoid cardiovascular toxiciry from the co-solvcn c. If
`drng prcci pitacion occurs during IM injection, che dos(cid:173)
`age form ulation tends w ace lik.e a depot injection,
`which resulcs in delayed absorption1 of rhe drug. Precip·
`itation may also result in incompkte ahsorpcion of 1-be
`drug from rhe precipitate, which leads co lower chera·
`peuric levels of rhe drug and pain ar th1: iujcctio.n sire.
`A good example of co-solvent use is phenymin injec(cid:173)
`tion. Phcnyroin (sodium injection) is a dear, colorless solu(cid:173)
`rion containi ng propylene glycol, ethanol, and water for.
`injc.u:ion. Phe11yroio is insoluble in water; 1hcrefure, pro(cid:173)
`pylene glycol and ethanol arc used a.~ co-solvents ro dis·
`solve phcnytoin and produce a clea.r solution for JV
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1046 – Page 108
`
`

`

`Drug Delivery Syatems
`in Pharmaoeuttcal care
`
`J 1D9
`
`Teble 2.
`.
`.
`Vehicles for lnJcct1ons
`Characteristics
`Examples
`- - -
`Vofllcl:•:____,~~-;:::::;;:-:::;::----------- ~~ - - -- - -- - --
`A<1UeOUS inJectlons
`Sterile l'ater _ror_in_jeel_io_n _____ o;_·s_til_led_ a_nd_ s_te_11_11ze<1 ____ _______ - - - - - -- --
`Sterile saline tor injection
`Used as a final-step solvent for steri!o solids or ror dilution or sterile solutions
`
`
`- Bact- -eros-.- tlll....,.lc_w_-a-1et-:fo-,-lll-:-ect- ion ___ Di_.st_l_led-and- -st-e-1•-ized __ _
`
`Sterile water for ioiganon
`
`Contains p<eservatNe
`Used for multiple-dose containers
`linited use •n large volume parentetal infusions
`Contraindicated ror use in neonates
`Contra ndlcated ror epidural and intrathecal injec11ons
`Pun'.ed, pyrogen free. and s1eole
`Does not have to meet particulate standards ror large-volume parcnte<al 1nrus1ons
`Typically available in a volume of 1 l or more in a sctcw-cap contalne<
`
`Oil based mJec'liOnSOOs for injeclion
`Sesame. corn. peanu1, mineral,
`soybean. and cottonseed oils
`
`Pure, sterole. low rrcc ratty acid conient
`Used ror Intramuscular depot Injections
`Allergic reactioos can occur
`Vehicle composition must be hs1ed on label
`
`inj<'Ctiou. SotliLu11 hydrnxide or hydmchloric :1cid is used
`as buffering agencs cu .1djust 1.hc pH of the injection co 12.
`Ptt'tipimcion or crysralliJ.:1tion of pJ..,nyioin m:iy occur if
`d1c pl [ is altered o.r if the co-solvencs or vehicles ;Lre modi-
`6ed. lnc drug is admini.o;iere<I slowly as an N bolus injec(cid:173)
`tion, ar a race no fuMe1 than 50 mg/min in adulrs m
`prevent cardiovascula1 adverse effects. The alkalini ty of 1.he
`injection can resulr in irrication, pain, and inflammation ar
`the injection site. 1 lcncc, each injection of phcnyroin
`should be followed by a 0.9% sodium chloride JV infusion
`through rhc same cathc:tc:r u1 11<.-cdlc to a>"Oid irritacion at
`the site of injccrion:11 Alternatively, phcnyroin c<tn be
`administerec.I as an IV infusion over 15 ro 30 minutes. To
`avoid precipiration, phcnycoin ~hould be diluted wich
`0.9o/o sodium chloride or lactated Ringer injection. Use of
`an inline filter is recommended with such infusions. Phen
`ytoin injection should nor be administered IM because of
`its erraric absorption and tissue rcaccions at the JM injec(cid:173)
`tion site. Fruphenyto111 is a prodmg of phenytoin that is
`freely sol uble iH warer and hence does no1 produu: the dis·
`comfort and erratic absorption associared with phcnycoin.
`
`Orher Additives
`BuHers
`Major concerns during parenrentl administration of drug.~
`arc maximiz.ation of rhe solubility and srabiliry of drugs
`and improvcmenr of paLient comfort during the injection
`
`process. Weak acids and weak bases are U\cd as bu/Ters m
`mainrain an optimal plI of rhc injecrion, which can
`enhance rhe solubility and srabiliry of some dru~. Drug
`solubility and absorprion also depend on che fo1mulat.ion
`pH. 1ncrcfore, buffers play an important role in the
`absorption of drugs from injection sites. Examples of
`commonly used buffers are citric acid/monosodium cit(cid:173)
`rate, acetic acid/sodium acetate, phosphoric acid/ monoso(cid:173)
`diu m phosphate, benzoic acid/sodium benzoatc, and
`uis(hydJ'Oxymcthyl)aminornechane (TRIS buffer). 13uffers
`such >.s ciuat<" •ncl TRIS undergo minimal change. in pH
`during freezing cycles in lyoph.ili:r.ation. Therefore, the
`addition of low concentrations of these buffers is mosl
`suitable for lyophiliud formulacions.}4
`One example of the use of buffers is i11 ondansetron
`hydrochloride (Zofran®) injection. :Wftan® is avail(cid:173)
`able as a clear, colorless, sterile solurion for injt.-crion.
`The ac1.ive ingredient, ondansctron, is buffered using
`citric acid monohydr:nc and sodium citrate dchydrare
`to minimize patient. discomfon at che iojecrion sire
`while maintaining drug solubility. Zofr.in® is indicated
`for IM or IV injection and should nor be mixed wirh
`any olher injections, because precipitation may occur as
`a resulr of changes in pH. 1~
`Tonlclty-Adjusting Agents
`lsoconiciry is n<"edcd to reduce pain and irricarion and
`co pr~cnt hcmolysis of blood cells ar the sire of injcc-
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1046 – Page 109
`
`

`

`u o I Chapler 8
`
`Parent eral Dru& Delivery
`
`tion. Injection routes 1ha1 require isotonicity arc incra(cid:173)
`arricular, ID, and 'entral nervous system routes such as
`intrachccal, epidural, and in tracercbrov