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 formula­tions: vehiefe, co-solvent, btlffer. tomclty agent. preserva­tive, 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 paren­teral dfUg delivery.

7. Descnbe the use of specialized parenteral delr;ery devices.

Orug Delivery Systems I 103 1n Phamlac;:eutical Care

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 implanrarion . 1 Parniuml deliwry means introducing drugs imo rhc body outside

of the cntcral roure; that is, oucside of the gastrointesti­nal 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 administration are

described in rhe following seccions. Table I lists the routes of parenteral administrarion.

Common Routes of Parenteral Delivery

Intravenous Injection Drugs adminiscered by the inuavcnous (IV) route pro­

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 adminis­tered 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 administration 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 Parenteral Drug Delivery

Table 1.

Routes of Parenteral Administration* Name Definition/characteristics of administration

Epidural Administration on or over the dura mater

Intra.articular Administration w11hio a joint

lntra·arterial Adm;nistration within an artery or artc1ies

lntracardiac Admlnlstratron w'lh1n the heart

lntracavitary Administration within a oalhologic cavity. such as occurs In the lung 1n tuberculosis

lmradcrmal Admlnlslration within the dermis

Injection is gr.er rnto the dermal layer of the sk.n.

lntralymphatic Administration within a lymph channel or node

lntramusoolar Administration "'1th1n a musc.e

Injection is given Into the muscle fibers of the upper ann or gluteal area.

lntraosseous 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

lntraso nal Adminrsvation v.;t111n tile vertebra. eo<umn. Refers to both epidural and mtrathecal routes.

lntralhecal Administration within the cerebrospinal Puid at any 'evel of :he cerebrospinaJ axis. ioelud ng injec­bon into the cerebral ventricles. ln.iect on is mto subarachnoid spaces.

Intravenous Admm•stration within Of Into a vein or ve-;ns­

lnjectlon is given directly Into me vein.

lniraceretxo Admmistrat1011 w1Ulin a ventrlcie o' the brain ventrlcular

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, continuous 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, antibi­otics, immunosuppressi,,e agems, antifungal agenis, anti­bacterial 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 circula­tion, :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 solu­tion 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 vehi­cles 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 debydrogen­ase 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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d ·on of acrion 1han JV injections. The rate

longer urau J • n and ex.tcnc of avAilabiliry of drugs depend 0 f;1bsorpuo .

b. harmaccucical fuccor; such as formulation char-

on top f 1 . · · · a IM . . p. :md the physi ol~>gy 0 t lC lflJCCCIOn Site. Jcr~risu~ · . . . . . . · s nrc safer th;rn IV 1niccnons; however, rncor tllJCCrt011· • . . rcet IM ad ministration 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 injec­tion . T hese nonaqucous vehicles stay at the site of injection and release che d rug slowly, which rcsulcs in prolonged serum drug concenirations and a longer

duration of act ion. 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 prolonged as the drug re<lissolves in tissue

fluids. 9•10

Another faccor affect ing drug absorption is che blood Aow w the injecrion site. IM injections given into the

deltoid muscle in che arm arc absorbed fa51er than glu­real 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

tion after gluteal injections were seen in a higher per· ccnrnge of women than men.•·''·" Moreover, the injection volume is limited 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

mulations as well as depot formulations for sustained release. Examples of these 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 half­lifc. One example is thyrotropin alfa for injecti on (Thyrogc:n®), a sterile, lyophili~d product char forms

Drug Delivery Syatem• I 105 in Pharmaceutical Care

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 init iation o f ther­apy. Depoe formulation~ are available as oil-based injec­

tions (eg. fluphenaiine cnamhate and escradiol cypionate), aq ueous suspension> (eg. penicillin G pCOClinc and peni­cillin G benzarhinc, methylprcdnisolone acetate [Dcpo­Medrol®], and medroxyprogesterone acecacc/c:smtdiol

9pionatc [Lunelle®)), and microsphercs (eg, lcuprolide

ace.ate [Lupron Depoe®}). An example of a long-acting depot formulacion con­

r::tining the drug in the form of salt is lluphcnazinc cnamhace (Prolixin Enanthate® injection). 14 h is indi­

cated for the maincenance treatment of nonagitated patients with chronic schirophrenia. Fluphcna1ine enanrhace is water insoluble and is therefore dissolved

in oil. On IM adminiscration, 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

taining sodiu m cirrare buffer and the suspending agents lecithin and carboxymei:hylcdlulose (CMC). 1 he ac1ive ingredients 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

gradable microspheres provides a way to mainrai tt ther­apeucic levels of the drugs for a longer rime. An example

of a polymer-based microsphere system used in depot

formulations is leuprolide aectare for depor su5pcnsion (Lupron Depoe®). Lupron Depor® microsphercs are

indicated for JM injection and are avai lable in a prc­fi lled dual-chamber syringe. T he drug charnbcr con­tains leuprolide acetate, incorporated in a biodegradable

polymer of polylaccic acid and D-mannirol. 18 T he dilu-

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10s I CMptcr 8 Parenteral Drug Dell•ery

col chamber coor:iins sodium C MC, warer for injec­tion, 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 con­srant rate as a resnh of chc hydrolysis of the polymer. Depending on i:hc prcscribeJ dose, L11pron 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 tis­sue 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 adminis­tered at an angle of 45 degrees m the skin. They can generally be sdf-adrninis1ered and are easy ro adminis. rer wi rh minimum 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. Pcncrrn­cion 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 pro­duce 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 lntrasynovia l 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 inOam­mation in patients wich rhcumacoid arthritis and col­lagen vascular diseases. Drugs administered by rhis route include merhylprcdnisolone acetate and triamcin­olone aceconide, which are available as injccrable SIJS­

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 post­operative analgesia. Paricms who have undergone liga­ment reconstruction and cxpericn~ moderate to severe post0pcrativc pain can benefit from intra-articular injec­tion of ropivacaine and morphine via a catheter in the knee joinr. This approad1 decreases die need for supple­mental lV morphinc.21 for the first few hours after inrra­synovial or intra-articular injecrion, local di5COmfon in die joi111 may occur, bu1 chis is rapidly followed by effec­tive 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 inm­rhccal 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 sus­pension in 0.9% sodium chloride solution. O n epidurol injccrion, the mulrivcsicular liposomes release morphine

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Dural&Bc

flllu,.1 Anatomy of the spinal cord indicating the epidu­ral 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, Depo­Dur® has produced persisrcm analgesia for 48 hours post­

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

cion on special IV delivery systems.

lntrathecal and lntracerebroventricular lntrathecal injection is the administration of drugs within the ccrcbrospinal fluid at any level of rbc cere­

brospinal axis, including injection into chc cerebral ven­tciclcs.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 administra­tion, 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

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 imra­thccal 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 107 In Pharmaceutical Care

and fcntanyl arc dfecrivc when delivered by the intrathc­cal 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 con­centrations in the areas supplied by the artery inco

which the drug is injected. The intra-arterial rouce is used to deliver chemothcrapeuric drugs such as cis­

platin ro treat head and neck cancer and co inJecc vaso­pressin 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 min­istered IV as a solution.

3. First-pass hepatic metabolism is avoided, which leads to improv~-d bioavailabilicy for drugs chat undergo sig­nificanr 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

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

tion of rhc drug by the IV rourc is beneficial in emer­gency situations when the need for therapeutic accion is immediate. For a slower onset and a longer

durarion of action, drugs can be administered IM.

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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

advantages:

I. Asepric prcou1rions musr be followed co avoid con­

raminarion and minimi~ rhe risk of infoction when rhe drug is being administered.

2. Most often, parentcrnll y cld ivcred drugs are admi11 is­

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

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

cure of convenrioMI 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 .-csu lc. 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 ;iccompanied by pain .ind infec­

tion ac the sire of in jeccion.

General Characteristics of Parenteral Delivery Systems Certain requi rements muse be satisfied for dosage formu­

lations and delivery sys tems to be approved for injection.

l . They rnust be free o f pyrogens. Because of microbi;1 I

contamination, pryogcns or fever-producing sul>­

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

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

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 isownic 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. Vehicles

2. Co-solvcnrs 3. O th.:r add itives: buffers, tonid(y-adjusting agents,

amimicrobial prcserv;nives, pmtcctants, surfaccancs,

antioxidams

Vehicles Vd1ides 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

rions are shown in Table 2.

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

tered slowly ro prcvcnc precipirntion of the drug and ro

avoid cardiovascular toxiciry from the co-solvcn c. If

drng prccipitacion occurs during IM injection, che dos­

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

tion. Phcnyroin (sodium injection) is a dear, colorless solu­

rion containing propylene glycol, ethanol, and water for. injc.u:ion. Phe11yroio is insoluble in water; 1hcrefure, pro­pylene glycol and ethanol arc used a.~ co-solvents ro dis·

solve phcnytoin and produce a clea.r solution for JV

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Teble 2. . . Vehicles for lnJcct1ons

Drug Delivery Syatems J 1D9 in Pharmaoeuttcal care

Examples Characteristics 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 __ _

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

Sterile water for ioiganon 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 Pure, sterole. low rrcc ratty acid conient Sesame. corn. peanu1, mineral, soybean. and cottonseed oils

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 injec­tion, 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 injec­tion site. Fruphenyto111 is a prodmg of phenytoin that is freely soluble 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 cit­rate, acetic acid/sodium acetate, phosphoric acid/ monoso­diu 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 avail­able as a clear, colorless, steri le 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-

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u o I Chapler 8 Parent eral Dru& Delivery

tion. Injection routes 1ha1 require isotonicity arc incra­arricular, ID, and 'entral nervous system routes such as

intrachccal, epidural, and in tracercbrovcmricular. As noted earlier, large-volume parenceral injecrions must

be isotonic with blood; char is, their osmolaliry must be

the same a; that of blood or orher body fluids. Largc­volume parcnrcral injections are single-unit doses of more 1han I 00 mL rhar generally contain water, dcx­tro;c, and sodium. Amino acids are ofren added. Due to

the large volume being administered t0 the patienc, pre­servatives should not be used, beciuse large amount>

may cause toxicity.'-'2 Examples of solutions char are isotonic arc 5% dextrose in water (DSW), glycerin, mannitol, and 0.9% sodium chloride.

Antimicrobial Preservatives Antimicrobial prcservacives are used in mulriple-dose vials to prevent microorganism growth. Mos1 preserva­

tives are bactericidal or fungiStaric. Preservacivcs are used to prolong the shdf life of formula1ions. Appropri­ate amoums of preservatives muse be selected for paren­

teral formulation$, because large amouuts can c:1use

toxicity and irrirarion after inje~t ion. Commonly used preservatives include bem:yl alcoliol, henzcrhonium

chloride, mcthylparahen, <:hlorobutanol, chlorocresol, propylparaben, and thimerosal. Epidural and inrrathe­cal injections should be preservative free to preven1 nerve damage.

Protectants Protein-based therapeutic agents are more su;cep1iblc to

degradation, which resulrs in loss of biological activit)'. shorter shelf life, and po~sibly increased side effects.

Hence, proteins are form11lated as freeze-dried powders to preserve: 1hc stabiliry of the drug. Proteccanrs are used to safeguard proteins during the fouI stages of lyophifo.ation (free:i.c: drying): freezing, drying, storage,

and rehydration.)(! These agents stabilize the strucrure of protein and peptide drugs through the freezing and

drying stages. During the freezing stage of lyophiliza­

tion, the protein solu1ion is filled into a glass vial and cooled in a lyophilizer. A~ the vial cools to a tempera­ture below the freezing point, pure ice crystallizes out of

1he solution and the liquid becomes more concenmned. During this freeze-concentration process, a glass transi­tion Lempcrawrc is reached, and the protecrnnts form a glassy matrix in the interstitial spaces between rhe crys­

Lals.J<> The stabilizing effect is amibmed ro hydrogen

bonding between the prorecrancs and pro1cin mole­cule>. This mimics the hydrogen bonding bcrwecn pro­tein roolc.-cules and water chat is being replact-d during

the freeze-drying process. The drug and water mole­cules arc immobili7.ed in the viscous glassy matrix. This

also results in stabilization of the formulation, because very high activ:ition energies are required for any reac­tion to occur. Examples of commonly used prorecrams

are sugars like glucose, lacrose, and trehalose.'."

Surfactants Surfactants are used for solubili7..a1ion of lipid-soluble

dmgs, for preparation of oil-in-water emulsions, and as wetting agents. Examples of surfactants are lecithin,

v:irious phospholipids, polysorbnte (Twcens®), and polyoxyethylenc casr.or oils such as Crernophor® EL. Lecithin is a mixtur~ of triglycerides and phospholipids and is used as a surfuctant in fut emulsions. Egg and

soybean phospholipids are common sources of lecid1in. '[ween® series (Tween® 20 and 80) and sorbitan

mono-oleatc are also used as mrfactants for parenteral use. Crcmophor® EL, or polyoxyerhylared 35 casror

oil, is a nonionic smfacrant used to solubilize cyclospor­

ine, pacliraxcl, and fat-soluble vitamins for injecrions. A major d isadvantage ofCremophor® EL, however, is its

poientiaJ co cause serious hypersensitivity reactions. Cyclo;porinc injection, (Sandimmune® lnjcctjon)

is avnibble as a 5-ml, sterile ampule for adminisrration as a slow fV infusion. Absorption of cyclosporine from

1he gastrointes1inal tract after oral administration is variable and incomplete; hence ir is formulated as an injection. Sandimmune® contains Crcmophor® El. and alrohol and requires further dilution with 0.9%

sodium chloride injection or DSW injection before use. Alcohol is used as a co-solvent wirh C remophor® EL.-17 Nitrogen replaces the air in the ampule to

improve rhc srability of cyclosporine by prevcnring ox.idarion. Cremophor® EL can cause an :i.naphylaciic

reaction; therefore, the pauer11 mu.sl be observed fur the firsr 30 minu rcs afrcr the ~tart of 1hc IV infusion.

If anaphylaxis occurs, the infosion should be st0ppcd,

and the patient should be creaced with oral cydo•p<>r­ine. Crcmophor@ EL or polysorba1c 80 can also cause phrhalate stripping from devices made of p0lyvinyl chloride. Polyvinyl chloride is a plastic polymer us~cf to provide Rexibili1y in Vllriou> medica l devices, and one of its compontms, d i(2-e1hyllicllyl)phthalate. c~n leach out of medical devices into solutions chat are

111

Petition for Inter Partes Review of US 8,242,158 Amneal Pharmaceuticals LLC – Exhibit 1046 – Page 110

. h he plastic.3738 This is a major concern, Cl Wit l

conta 1 1 -' ·re cn11 lu1ve adve rse cff.,cts on rhc tes-

L- se p 11 i:u .. '"''3~ ·, d lungs. I lcncc, rhe Jrug solurion should

hver, .in 1"

5'. d visually for particu late marrer and discol-

bt• lflspeere . . . . ifrhc infusion system contams polyvinyl chlo­

ora!I011

d di(Z-ethylhcxyl)phd1a1:11c tubing. rt e or

Ant/oxidants . . • · x'idant> are added co formulanons to prcvcnc "n110 . oxidacion rcaetions between the drug and free radi,Jls and rhus ro increase die sc."Lbiliry of rhc drug prc.~c:nt in ibc injecrion. lly being prcfcrenri:1lly ox idized ,

antioxidan ts prevent oxidative degradntion or the d rug. Common antiox idants used arc ascorbic acid, cy,tcine , sodi1u11 bisulfirc, sodium mernbisullirc,

10 copherols, and monorhioglyccrol. An alternative

w~y co prevent oxidation of a ti rug is ro remove the

11ir from the drug ampule or vial and ro replace it wi1h an inerc gas like nitrogen.

General Categories of lnjectables According to the United Staus Pharmaropoeia, injccca­

bles can be divided inco five major cacegorics:19

I. Injection

2. for injection 3. Injectable emulsion 4. Injectable suspension

S. For injectable suspension

T he categories of injcc1ables arc described in chc fol­lowing sections.

Injection Injections are liquid preparations char arc drug sub­

stances or solutions thereof. Injections can be aqueous solutions or solutions in oil.

Aqueous solucions are the most common and versa­

rile parenteral formulation and can be administered by all the parenteral rou1es. An immediate therapeutic

effect of the dn1g is seen after IV adminimarion of an aqueous solution. In contrast, a slower onset of action is

observed when a drug is adminis1ered by 1he SC route. An example of an aqueous solution injection is human insulin of rccombinanr DNA origin (Vclosulin® BR).

Vdosulin@ BR is a dear solution of insulin in phos­phate buffer meant for SC injection. The onset of

accion is rapid (30 minutes), and che peak efTec1 is

Drug Delivery Systems I U1 in Pharmaceutical C111e

observed be<ween I and 3 hours after administration . The duration of effect is 8 hours after injt<.tion.•0

D rugs chat are warer insoluble but lip id soluble may be formulated as ~olurions by dissolution in veg­etable oils. O il -based injections may cause far emboli,

and rhercfore should be injected IM but no1 JV. When such formulations arc administered into the muscle, rhc onset of action is generally slower because

of the rime requi red for drug di>solutio11 and absorp· tion from the muscle site. As a result, rhc duration of action is longer than with water-soluble drugs. An

example of an oil-ba;cd injec1 ion is esr radiol c.ypi­onate, (DEPO®-Esrradiol) for IM injection. Corron· seed oil is used as rhe vehicle co dissolve the drug.

Chlorobutanol anhydrous (a chloral derivative) is used as a preservative for DEPO®-Estradiol injec­tion. Before use, 1he vial should be warmed by rolling

chc vial between che two hands and should be shaken genrly to redissolve any parricles or crystals that may have formed if chc formulation was accidentally

scored at low remperacures.4' DEPO-F.stradiol® can be administered every 4 weeks.

For Injection "For injeetion" formulauons arc dry solids chat, on the addition of suitable vehicles, yield soluriono char con­form in al l respects lo injection requirements. Dmgs

chat are not stable in solution are first prepared as a solution, sterilized by fi ltration, and then frcC'te-dricd as powders. Formulating drugs as freeze-dried powders increases rheir stability and shelf >torage. These powders can then be reconstituted into solution immediately

before use with a suitable vehicle. An example of a dmg available as a "for injection" product is ccfuroximc

(Zinacef®) for injection. Cefuroximc is not stable in solution and is provided as a scc1·ile Cr)•Stal line powder

for injcccion. l11e solu tion is prc1>a1·ed by dissolving the powder in 8 mL of sccl'ilc w:ircr for injeclion, and it is

injected IV. If rhe comcnrs of 1hc vial arc dissolved in 3 ml of Sterile waccr for injeclion, cbe drug forms a sus· pension and it is injecced IM.42

Injeccable Emulsion Injectable emulsions arc liquid preparations of a drug substance dissolved OI' dispersed in a suitable emulsion medium. An emulsion is a dispcr>ion of rwo immiscible

liquids, che dispersed phase and the continnous phase.

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112 j Chapter 8 Parenteral Drug Delivery

The dispersed pha~e is finely ~ubdivided and uniformly

dimibuted as droplets throughout the medium or the cominuous phase.41 An emulsion is an e(Fcccivc delivery system for wlubili-zacion of waccr-insoluble drugs. Ir produces a dosage formularion with increased stability and sustained-release char.\eterisriQ. o.H

IV emulsions usually conrain lipid-soluble drugs dis­

solved in an oil-based vehicle for injection. On IV iniec­rion, emulsions must mix wich aqueous body Auids to access the target site. Emulsions release drug ac a slower

rate chan solucions buc more prompdy than IM depot injcctions0 When they are in direct contact with che bloodstream, rhc dispersed phase droplecs of emulsions

should be smaller rhan l µm. Maintai 11ing a small

dropler size is c~cntial ro provide a large surface area of interaction with the aqueous environment,4~ and co

mini mite rhe 1·isk of capillary embolism. Propofol is a sedative-hypnotic agent used 2s an IV

general anesthetic. Because of ics high lipid solubility, propofol is formulated as a fat emulsion, Diprivan® (propofol injectable emulsion, USP). Propofol was

previously ~olubil i ·1.ed in Crcmophor® EL; however, Crcrnophor® EL has the main disadvantage of caus­ing anaphylactic rcaccions. The currently available

dosage formulation contains 1 % propofol solubilizcd with glycerol, soybean oil, and lecithin. Diprivan® contains ethylenediamin~rerrnacetic acid as an antimi ­

crobial preservarivc: agent, whereas newer generic for­mulations of propofol contain bcuzyl alcohol or

sodium metabisulfice. The main advantage of chc fac emulsion is rapid distribution into peripheral rissues, wh ich results in an immediate onset and a shorter duration of acrion.'>

fat emulsions :1 re administered for total parenrcr:il nutririon. Formulations for t0tal JX!rcntcral nutrition con­tain water, i.ourccs of nucrient fur (corconsced, safflower,

and soybe-.u1 oil), surfuct:111r:s, roniciry agcnrs, and :mrioxi­danrs as required. "l11e main rourc for paremem.I nutrition is IV, 1hrough either cen1ral (subdavian, i11rcmal jugular,

external iliac, or cephalic) or periphcr:il veins. Pcoipher:il parcnrcnil nu11 i1ion is as~xKiaicd wiih phlebitis and infec­t ion; therefore, ir is recommend~-d for shorHerm chcmpy only in p.1ricnts with robust peripheral vein~. ;.43

Injecrablc Suspension Injectable suspensions :m: liq ~1id preparations of solids suspended in a sui1able liqnicl medium. A suspension is

a di~pcrsion sy~tem in which the undissolved solid drug is present in a sterile aqueous vehicle. The undis­

solved drug should be capable of aspiration into a syringe and should rcsuspend easily. Suspensions are generally prepared for drugs that arc unstable in solu

t ion. Drugs in a suspension arc generally more stable than drugs in a solmion or emulsion and can be adininisrcred by IM, SC, and incra-a1 ticular injection.

Drugs in aqueous suspensions arc more rap idly accing than are those in oil-based sw.pcnsions. Aqueous sus­

pensions can be used for immediate relc:1se and su1-

tai11cd release. Examples of aqueous suspensions arc

described in rhe following sections.

Aqueous Suspensions for Immediate Release Novolin® N Jnnolet® is a human insulin isophane

(neutral proramine H~gedum INPHJ insulin) suspen­sion conta ining I 00 uni rs of insulin per milliliter and is ind icated for SC adminimation ... The suspension is

cloudy and milky. The cloudy material is chc drug, insulin, which generally settles at the borcom of the vial

or reservoir of a prelilled pen injector. When che lauer is used, the comenls muse be uniformly mixed by rotating the pen gently. Each injwor contaim a small glass ball

to ensure proper mixing of die suspension panides. The lnnolcr® may comain some air in the syringe; thc1efore, the air must be forced our by an air shot

before rhc injection is administered co the patient. The Innolct® is designed as a dial-a-dose delivery system. The onser of action i> defayed, and duration of action is

longer than that of regular insulin solucion.

Aqueous Suspensions for Sustained Release If a drug is pool'iy solu l>le, 011 admir1istrntion as a depot injec1io11, it can form an insoluble depoc of drug para­

des .1nd release the drug slowly over a long time. Dcpo­Medrol® is an example or a steri le, aq ueous suspension of methylprcdnisolonc acet;Ue for sustained release." In

add ition to the drug, Depo-Mcdrol® contains 'rerile warer, benzyl akohol, PEG 3350, polysorb.uc 80, and sodium cliloride. PEG 3350 increase.~ the viscosiiy or

tbe injeccio11, and sod ium di loridc is :1 tonicicy-adjusc­ing agenr. t h is fomml:it.ion is given as an intra-anicular injccr[on co trt'.:11 os1eoarrhriris or as an JM, incrak~ sional, or inrr.isynovial injcuion ro trcaL inllammation.

Consistent and prolonged release of the d rug fro111 the parride.~ in suspension as a result of ilS i.low clissolurion

provides su;ta.incd therapeutic elfo<::t.

Petition for Inter Partes Review of US 8,242,158 Amneal Pharmaceuticals LLC – Exhibit 1046 – Page 112

I ·•pension av.iilable commercially as an IM

Ano! ier Siu • • • • •1, Depo-Provcra®, which provides a sus-SC IOJ<.'CllOO . •

0~ d le:~ of the conuacepuve mcdroxyprogescerone c:unc re · .r MPA · · I bl

(MPA). The active mgn.-u1em, , 1s mso u e acemrc . . . • 11d is forrnulaLt:J as an aqueous >Wp<:oston m in warer .. PEG ancl poly~orb~ue 80. Methylparabcn ancl propyl-araben arc added ns prcserva1ives, and sodium chloride

fs used ro adjust 1he 1011ici1y of rhc injection. Depo-Provera® is available as Ocpo subQ Provcra

I04"'' for SC iujcetion41 and Depo-Provern® Contra­

cepci11e lnjccrion (Oepo-Provera® Cl)49 for LM iojec­cion. Depo-subQ Provera I 04TM for SC injection is available in prcfillcd syringes, which should be shaken well before injection 10 disperse the drug. MPA is absorbed sysremically afrer SC injccrion, a11d steady­scate serum conccnrrations are reached afrcr multiple SC injections into the abdomen or the anterior chigh. Slow dissolution of MPA from the suspension is beneficial, because Depo-subQ Provera 104™ is administered once every 12 to 14 weeks.48 Depo-subQProvera 104™ cle.livers I 04 mg of medroxyprogestcrone per dose. Depo-Provcra® Cl IM is administered every 12 weeks into che ddroid or gluteal muscle. It is avai lable in vials and prefillcd syringes, which must be shaken wdl to ensure uniform suspension of the drug. The half-life of MPA is approximately 50 days, and steady-state serum concencration~ are reached in 3 weeks.19 Dcpo-Provera® CI delivers 150 mg medroxyprogcsterone per dose.

For Injectable Suspension "For injeccablc suspension" formulations are dry solids that, on the addition of a suirable vehicle, yield a disper­sion conforming in all respects to the requirements of an injectable susi--ension. Drugs char arc poorly soluble in water and arc unstable are provided as "for injectable suspension" fornulations. The drug is supplied as a dry powder wirh susrending agencs and is rcconsticutcd in che appropriate vehicle immediately before miection. Formulation as "For injectable suspension" ensures che stability of the drug.

Azaciridine for injectable suspension (VidazaTM),

which is available as a sterile lyophilize<l powder fur SC injection, is used ro rreat myelodysplastic syndromes such as refracrory anemia and chronic myclomonocyric leukemia. A·1acitidine is insoluble in organic solvents such as erhanol a11d propylene glycol and is slighrly solu­ble in erhanol/water (50/50) :ind 5'Vo 'lwc:cn® 80 in

Drug Oellverr Systems I 113 In PharmaceLtical Care

waccr. Hence, it is formulated as a sLeri lc, lyophilized pewder and forms a suspension on n:wnscirution in 4 mL sterile water for injection. The lyophilizcd powder is av,iilablc in a single-use, preservative-free vial and con­tains mannitol as a ton icity adjusting egent. Doses of

more than 4 mL should be divided and adrninisrercd ar cv.o different SC sites to prevent bruising and redness. The dl'Ug is rapidly absorbed aflcr SC injecrion, and i1s absolute bioavailabilicy is 90%. The recommended dos­age is 75 mg/ m 1 for 7 days every 4 weeks. lO

Abarclix for injectable suspension (Plenaxis TM) was in~icated for use in patiencs with advanced sympto­matic prostate cancer when luteinii.ing hormcne-rcleas­ing hormone agonisr therapy was contraindicated. PlenaxisTM contained abarelix as a sterile dry powder for reconscirution with 0.9% sodium chloride. Plena· xis rM was available as a single-use vial containing a complex of anhydrous free-base abarclix peptide ( 113 mg) with CMC (19.1-31 mg) as a ~uspending agcnr. The abarclix-CMC complex had a pH of 5 ± 1, and rhc dose of abardix after reconsrirurion was 100 mg. A depot suspension was formed after reconsrirurion. ft was injected JM, and rhe drug was released slowly from the depot. si After an initial induction period with doses given on days I, 15, and 29, abarelix injections were repeated every 4 weeks while treatment was continued. T.1c ulc of Plenaxis°'1 on the market has been discon­tinued for economic reasons.

Special Intravenous Delivery Systems In addition to the five major types of injectablcs, special IV delivery systems have been developed based on J>2tients' needs and drug characteristics.

Liposomes for Injection Lipo-~omcs arc closed spherical microscopic vesicles com­posed of a phospholipid bilayer chat has the abilicy ro encapsulate therapeutically active drugs. Liposomes ace as drug carriers co enable loading of various therapeutic moicLies such ::IS small drug molecules, nucleot.ides, pro­teins, and plasmids.s2 Incorporation of a drug into a lipid complex (liposomal cncap~ulation) subsranrially alfects the functional properties of the drug.si Different lipid-complex or liposomal products may wnrain the same active drug bur may vary in the lipid component. Uposomes are formulated by mixing specific propor­tions of amphiphilic substances such as cholesterol and

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114 [ CMpter 8 Parenteral Drug Delivery

phospholipids. These sub;ranccs then arrange rhc:m­s.:lves imo multiple conccrmic bilayer membranes when hydrated in aqueous solutions. The lipopbilic moicrics of rhe bilayers face each orhcr, creating an inner hydro­phobic environment in the membrane. Lipophilic or amphiphilic drugs can be associated with the nonpolar part.~ of lipid bilayers. The hydrophilic molecular hc:ad groups foce the outer water phase and the inner aqueous core of the vesicles.'.>< Liposomc:s undergo dcgrada1ion when given orally due to the acidic pH of rhe stomach and arc also broken down by intestinal enzymes and bile sales. ~ lcncc, rhe preferred route of delivery of liposome:. is TM or IV injection or IV infusion.51•55

Examples of liposomal delivery systems include drugs such as doxorubicin and amphocericin B.

Doxorubicin Hydrochloride Llposome Injection Doxorubicin hydrochloride lipoIDme injection (Doxil®} contains doxorubicin hydrochloride encapsulared in STI.AJTH® liposomes. STEAJ.:n I® liposomes of

Doxil® are formulared wirh surface-bound merhoxypoly­echylcnc glycol by a process referred co as pegylmion. T h is process protects the Ii posomcs from detection by rhe mononuclear phagocyticsystcm and increases blood circu­larion time.56 Precli nical srudics and clinical trials have i.hown chat che use of Doxil® produces higher concencra­rions in tumor sires rhan adminimation of free doxorubi­cin hydrochloridc.57 Llposomal doxorubicin possessing che same properties as Doxil® is available in the Uniccd King­dom(!.') Caclyx®.511.S9 TI1e avcrngc diameter of STEALTH® liposomes is I 00 nm. Precipiration of the drug occurs i11sidc lhe liposome without c:aw.ing degradation of the liposomc. Then:fore, leakage of the drug is minimized, and at le:ut 90% of the drug rcmai1u encapsulated during cir­cular ion."° These liposomcs are stable in blood, and the half-life of doxorubicin is 55 hours in humans. The small si?.e and long circulation half-life of liposomcs ensure rhac rhe liposomes can be delivered th rough rhe tumor vascula­mre. 111c volume of distribution is significantly decreased after encapsulation of doxorubicin in the liposome, whid1 reduce.~ the risk for nephro1oxici1y."'·;' Because of rhc: long half-life, Doxil® liposomes arc administered once every 4 weeks. The shdflife of these liposomcs is similar to that of ocher injectable formulations.

Lipid-Associated Amphotericin Amphotericin B is used to creat systemic an tifungal infections. Common problems associated with conven-

tional amphotericin B trcarmenr are break1h1ough infections, nephrorox.ic cffecrs because of high dosages, and infusion-related roxicity. A number of lipid-associ­aLcd and liposomal amphotcricin formulations have been developed with the aim of enhancing efficacy and reducing the severe tox icity associated with the drug. Lipid-associated formulations yield lower concentra­tions of amphorcricin in the kidneys and remain con­cencrared in the rcticuloendothelial tissues such as the liver and spleen; therefore, rhey dcmonstrare improved efficacy and lower roxicity.61

Amphotericin B Liposome for Injection Amphotericin B liposome for injection (AmBisome®} is a sterile, nonpyrogcnic lyoph il ized product for slow IV infusion using a comrolled-infusion dcvicc.62 Aml:li­some® consists of unilamd lu bilayer liposomcs with amphotericin B imcrcalated wichin rhc membrane. Because ofirs lipophilic nature, the amphorericin B molc­~uk lxcomes an integral part of the AmBisomc® lipo­some structure. Amllisoml'® penetrares rhe cell wall of cxLracellular and intracellu lar forms of susceptible fungi. T he liposomal formulatio11 forms a translucent suspen­sion after reconstitution with sterile water for injcccion and further dilution with D5W6l Mixing with other drugs or with saline may cause precipiration of the drug from the liposomcs. The reconstituted fonnula1ion is administered over 2 hours by IV infusion. Steady-stare concemrncions are ach ieved within 4 days of the start of dosing. Slow redistribution of the formulation from the tissues leads to a long terminal half-life of the drug, which increases the time chc drug spends in che body. The con­centrarion of amphotcricin in chc kidney !issue is lower wirh AmBisome® chan w1th conventional amphotcricin 13 U'CalmenL I fence, rhc incidence of infusion-related renal adverse events is lower with AmBisome.4> Excretion of amphocericin after AmBiwme® administration has not been investigated.

Lipid-Based Complex Amphocericin B lipid complex injection (Abdc"t®) is a sterile, pyrogcn-frec suspe11sion for IV infusion. Abel· cct@ consiscs of amphorcricin B complexed wirh rwo

pho>pholipids in a I: I drug-to-lipid molar mrio. To prepare the admixwrc for infwion. chc: vial is shnlu n gently ro ensure thac lhcrc is 110 sedimcmation of th~ suspended drug paniclc.~. A ~-µm Glrer needle is use

cl I. I 1· I . I . . cusion bag to e aver n c contents o t 1c via llltO an 1111 1

Petition for Inter Partes Review of US 8,242,158 Amneal Pharmaceuticals LLC – Exhibit 1046 – Page 114

. . 5W injection. The conrcncs of che infu-

c;0nrainmg D b thoroughly mixed before infusion. If bag muse e

ilon . . c exceeds 2 hours, the comencs of cbe he jnfus1on urn . .

1 b baken again co prevent any scd1mencat1on I.no must es . ....., ·c1es Unused drug should be discarded of drug paru · . ·

he SI• ngle-use fornulanon does not comam

1>rcause t • · A•e 0·c agenrs or prC>crvauves. Ar.says used co w1cr1 .... a

de rmine levels of free amphocericin can also be used cc easure blood levels of ampho1cricin afrer adminis-

io ro fo I " 6HSh tion of the Lipid c..vmplcx rmu anon · ; owever, :od level monit0ring of amphocericin is nor used

commonly in clinical pracrice.

Polymeric Systems for Parenteral Delivery Prolonged-release parcncer:J formulations control the release of drugs over a period of days to weeks. Various

drugs are being formulated a~ microspheres for IM or SC depot injection. Bo1h biodegradable and nonbiode­gradablc polymers arc available to provide susrained release. Mose nonbiodegracable polymer delivery sys­eems release the drug by diffusion. Diffusion-con­

uoUed delivery systems have che advan1age of providing a predetermined race of drug release and delivery bue are dependent on drug characreristics and

che permeability of the polymer. 66 These delivery sys­tems are feasible for drugs rhat have low molecular

weights and high solubili:y, a11d tha t d issolve and remai n in chc polymer matrix. Nonbiodegradable poly­mer systems must be surgically removed. Biodegrad­

able polymers arc natural or synthetic polymers char undergo degradation in vivo, thereby releasing the dis­solved or dispersed drug anJ producing biocompatible

or noncoxic products." Mose biodegradable polymers arc nonrmcic and arc casil)' diminated from rhe ~y<· tcmic circulation; therefore, 1hcy :ue preferred over nonbiodegradable pol)•mm. The release of drug from

biodegradable polymers depends on rwo processes. In the inj cial phase, the release is controlled by d iffusion

of the drug. In the second phase, the drug bound co the polymer matrix is rdeased by erosion of che

m:mix.67 The rate of hydration of the polymer matrix depends on uptake of water by the polymer.

Polymeric Biodegradable Systems for Parenteral Administration Synthetic biodegradable polymers include polyesters, polyanhydrides, polyamides, and polyord1ocsccrs. Polyes­ters include polylactic acid (Pl A), polyglycolic acid

Drue Delivery Systems I 1.15 in Pharmaceubcal Care

(PGA). and their copolymer, poly-lactic-co-glycolic (PLGA). PGA is more hydrophilic, alld its water up1ake

is relatively higher than chat oi Pl.A, which is more hydrophobic. Therefore, PLA releases the drug more slowly than che PGA matriJ<.66.68 The approach of encap­

sulating dl'Ugs in different polymer matrices and biode­gradable microsphcres provides a way to maintain therapeutic levels of drugs for a longer time. This

increases 1he durarion of acc:ion and reduces rhc need for mulriplc injection>, whid1 an: paiuful a11J irn .. u11vc:1Lic111.

Drugs available in biodegradable polymer-based SUS·

caint:d-relea.~e parenceral formulations include oc1rco· tide aecra1e (Sandosiaiin® I.AR Depot for !M injection), recombinant somatropin (Nucropin Depot®

for SC admi nistration), triprorelin (Dccapcpcyl® SR for IM injection), leuprolide acetate (Lupron Depoi® for IM injection), goscrelin acetate (Zoladex® for SC

iroplantation), and carmuscine (Gliadcl® \V.1fcr for intracranial implancacion). Dosage formulations con­taining PLGA and polyanhydride microsphcrcs arc

described in 1he following sections.

Poly-Lactide-co-GJycol idc Microspheres

Octrco1idc ace1are for injecrable suspension (San· doscacin® LAR Depot) is an example of a formulation containing PLGA microsphercs. It is a long-ac1ing

depot preparat ion formulared for lM injection.6' The

drug is encapsula1cd in the biodegradable polymer PLCA. Cleavage of che polymer ester linkage occurs

through tissue hydrolysis and results in slow release of 1he drug.70•71 This allows che maintenance of drug lev­

els over an extended period and injection of die depot preparation every 28 days.70 Mannicol is added to 1he

microsphcres 10 improve suspending properties in the injection. Sandostotin® LAR Depoe should be •dmin­isiercd JM inco che gluteal muscle; sires may need to

be alternated 10 avoid irrirarion due co repeated injec­tion. I njeciion inco the deltoid muscle should be

avoided because it causes discomfort and pain at the injection site. T hi s depot preparat ion should not be

injected IV or SC. Anoe her example of an injecrable suspension using hio­

degradable l'LGA microspheres is somatropin (of recorn­binan1 DNA origin) for sustained release (Nuuopin

Depo1®). Nutropin Depoe® is a "for injcciable" sus­pension prepared for SC injection. Ir consiStS of sterile, free-Howing micronizcd particles of recombinant human growth hormone embedded in biodegradable

Petition for Inter Partes Review of US 8,242,158 Amneal Pharmaceuticals LLC – Exhibit 1046 – Page 115

116 I Chapter 8 Parenteral Dr!Jl: Delivery

PLGA microsphcres. On injecrion, rccombinalll human growch hormone is released from the micro;pheres into the SC tiisues by diffusion. Further release of rhc drug occurs via polymer degradation and d iffusion. Distribution, metabolism, and elimination of recom­binant human growth hormone afccr release from rhc depot form ulation is similar to that after admmistra­rion of 1hc somacropin daily-use formularion. Nutropin Depor® is adminisrered once or cwice a month, and c:hc dose should be adjusted based on the chosen dos­ing frequency. Tbc lyophilized powder should be sus­pended only in che diluent provided wirh the formularion and administered using rhc needles sup­plied in the kir.72

Ocher dmgs available in formularions containing microsphcres for sustained-release injection are rrip­torclin (Decapeptyl® SR) and leuprolidc acetate (Lupron Depor®). Decapepryl® SR is a microsphcr~ dosage formulation of triptorclin encapsulated in PLGA mrcrospheres for sustained release. Chemically, triptorelin is a decapeptide and an analog of lureini't­ing hormone-releasing hormone. The suspension medium for the injection concains polysorbate and sodium CMC. The recommended therapy regimen for Dccapepryl® SR is one JM injection every 4 wecks. 1~

Lu pron Depot® is a depot suspension meanc for IM injcccion.74 Depending on the dose used, Lupron Dcpor® can be: injected every l or 3 months for treat­ment of endometriosis and once every l, 3, 4, or 6 monchs for crearmcnt of prostate cancer.'"''"

Polyanhydridc Microsphcre Polymer Implants lmplanc~ are parenceral dosage formulacions used as a reservoir for prolonged rdcase of various drugs. As in chc case of microsphercs, implants can be biodegradable or nonbiodcgradable. lmplancs generally can be adminis­tered SC or implanccd inrracranially via a surgical proce­dure, whereas microsphcres are generally administered by SC or JM injection.

Goscrelin :tcecate implant (Zoladex®) contains a potenr syndmic dccapepride analog of lureini?.ing hor­mone-releasing hormone and is prescribed for 1hc treJtment of prosrace and breasr cancer. Zoladoc® is available as a steri le biodegradable pcllct.7'"'' Jr is adminiscercd SC every 12 weeks uuo che anterior abdominal wall below the navel line. Ar the injecciou sice, the polymer becomes hydrolyz.ed and releases the drug for up ro 3 monrhs. Slow and continuou~ release

of rhc drug ensures drat cffeccive sccady-scate scrum concemrat ions are maintained.

Another implanr used for slow release of a drug ove1· rime is an implant of polifeprosan 20 wirh carmustine (Gli­add® Wafer). Gliadel@ Wafer is admini,tercd as an incra­c1·anial implant and requires surgical incervcnrion for placement. It is used to rrear brain rumors such as high­grade malignant glioma1 and recurrcnr glioblasroma multi­

formc as an adjunct ro surgery and radiation therapy. Glia­del® is chc only FDA-approved brain cancer treatment capable of providing localized delivery of chemotherapy direcrly co rhe sire of chc tumor.17 Gliadd® wafers arc com­posed of a biodt:g1adablc polyanhydride copolymer matrix system (prolr feprosan 20) and arc 1.45 cm in diameter and l mm thick. The copolymer, polifcprosan 20, oonsists of polylbi;(p-carboxyphenoxy)propanc:sebacic acid) in a 20:80 molar rario. The drug is clistribuced homogenously in the polymer matrix. The wafer shape allows slow rek.-asc of the drug over cime, and several wafers can be implanced inco rhe brain cavity after exci~ion of che wmor. More than 700A> of the copolymer degrades in 3 weeks. The monomer carboxyphcnoxypropanc is diminared through the kidney in animals. The ;econd monomer, seb:icic acid, is an endogenous fatty acid and is mecaholized by the liver and exhaled in the form of carbon dioxide. The pharmacoki­netic.1 of the copolymer in humans is nor known. In some CISCS, wafer remnants consisring of water and monomers formed aficr polymer degradation may remain in rhe brain c;aviry. ·11iesc can be removed if surgery is repeated ro implant new Gliadcl® wafers.18

Polymeric Nonbiodegradable Systems for Parenteral Administration Various nonbiodegradablc delivery systems have been developed for sustained release of drug> by parenteral administrar ion. Nonbiodegradablc: systems allow for longer release of drugs than do biodegradable systems. The control of the dmg relca>e rate is generally accom­pl ished by the membrane in nonbiodegradable sy~tems and i1 more effective than in biodegradable syscc:ms.

79

The main disadvantage of nonbiodegradablc system~ is the need for ~urgical insertion and removal.

Leuprolide acetate is available as ,1 ;terilc, nonblo· degradable, osmocically cl1 iven irnpl.1111 (Viadur®l designed for controlled-me delivery of the dru~· Unlike Zobdex®, which i ~ injected SC, Viadur® ~ surgically mserced SC for the crcJtmCnt of ndv:inct prostate cancer in men. Surgic.1 1 imercion muse be

Petition for Inter Partes Review of US 8,242,158 Amneal Pharmaceuticals LLC – Exhibit 1046 – Page 116

I '· t· e~ lth c~rc pl'ofcssionah wbo have been

rfcrmet ,,y 1 • I · I h pe . roper inseruon tee rniques am ave

(f'lincd in p h . be I . . J . k' ll · Local ancsr enc musr ac mmistc:rc

1ur1ng s i s. W . . 'on site before ioscnion 1'0 prevent pain.

1he UlJC'll • . . • al . . m alloy reservoir in ihc implant con1a10s a The man1u .

I le rai e·conrroll1 ng membrane, n pnlyci·hy-P"lyurct 13i . . ,.,

l ·fli sion moderato r, and an clasromcnc p1scon. (enc t I u . . The osinotic tablets prese lll .in the i?1pbm system ai:c

•bd of sodium chlomle, ~odi um CMC, povi-compo... . .. done, magnesium steara rc , and s1cnlc w:ner for 1niec-

cion. These tablets are nor rclc~ed with the drug formulation . Tn rhc inirial stages o f release, water and orher biological fl uids diffuse into rhc impl:int , and rhe drng is released by dilTusion. Viadur@ provides conrinuous 1·cleasc of the drug for up 10 I ye.tr. Tile impbnt is removed after 12 months and a new one is

inserted depcndi ns on tlw t reatmenr r<:gimen for l'hc pacicnr. After removal and rein~crtion, stcady-statc serum concenuatioi1s arc maim.Li ned."'

Another example of a nonbiodc:gradable implant is the ct0nO!(CMrd implant (lmpl:1 non®). lmplllno n® is a single flexible $ubdcrmal implant ;ystem with a conmtceprivc life of 3 years. The 40- mm-long :ind 2-mm-widc flexible rod in lmplanon® contains etby­

lcnc vinyl acetate imprcgnarcd wirh 611 mg of etonogesrrcl.111 The impbm relea~cs approximately 40 µg of etonogcstrcl every d.1y and prcvcnrs ovulation

in women. Wich su rgical inrcrvcnrion, the rod is implanted SC in rhe inner side of the upper arm under local anesthesia. The implan t re mains intact in

the body and must be removed by a surgical proce­dure under local anesthesia . The drug is released from the implanr via diffusion and absorbed into the

bloodstream. The main advantage of lmplanon® is rhe release of low daily doses of the drug, which con­

tributes to prolonged contracept ive acrion." The implanr docs not interfere with breast-feeding and

can be inscned during rhe lactation period ro provide safe and effective contraception. l mplanon® has been approved by the PDA; however, it is nor ycr

available on the marker.

Polymer Nanoparticles Nanoparrid..-, have been developed ro acr :<~ ca rrier~

fo r poorly wnrer-solub lc drugs and chcrcby increas.: bioavailabil iry. 111ey .tre 'olid colloid;il particles. g~n­

crally 200 11m in d iameter.M Nanoparricles serve as

Drug Delivery System• I 117 In Phamiaceuucal Caro

carriers for a variery of agent~. including antigens, drugs, enzymes, anJ vaccines. They arc also used ns vaccine adjuvams and delivery systems. Polymers like

polyalkylcyanoacrylate, and polyesters (PLGA) arc used in nanoparticlcs for parenteral delivery.•~

Because vehicle toxicicy is one of rhc major side

effects of taxane formulations, novel dosage formula­tions such as chose containing nanoparricles and lipo­somes &ee of Crcmophor® EL have been developed.

Incorporation of padirnxel inio liposomes eliminates hypersensitivity rcaccions associaced with chc vehicle Cremophor® EL and also decreases roxiciry from che intrinsic pharmacologic action of the drug. An exam­

ple of padiraxcl incorporated inro nanopartides is Abraxane® injection.

Abraxane® injection is a Cremophor®-free, albu­

min-bound nanoparticlc formulation oF paclicaxel for treatment of metastatic breast cancer. Ir is available as a "for injectable suspens ion" formularion and was

devdoped to eliminarc the toxicicy associated with Crcmophor® El.. Abraxane® is admi nistered by IV infusion.81' The albumin-bound nanoparticlcs internet

wirh gp60, a protein on the endothelial cell lining of blood vessels, which facilirares transport of the drug

from rhe bloods1rcam into mmor site~. This transport mechanism results i.n higher concenrrnrions of pacl i­taxel in the mmor sites. The infusion is given over a

shoner period of lime than the Taxol® injection for­mulation of paclitaxd, and no special IV equipmenc h needed. Because the formulation conta ins no solvents,

prcmedication ro prevent severe hypersensitivity reac­tions is not needed. Therefore, Abraxane® has a m uch

more favorable side effecr profile than paclitaxel for­mulations containing Cremophor® EL.87

Specialized Devices Various delivery systems have been developed to pro­

vide specific drug targeting, rate-controlled drug deliv­ery, and increased parienr compl iance and convenience. Some ex:unple. of specialized devices for improved

parenteral delivery of drugs arc implantable pumps and preloaded syringe:;.

Implantable Pumps lmplantabl~ drug delivery pu mps were firsr developed

wirh the aim of providing external comrol of delivery race or administering volumes of drug rha1 may be

Petition for Inter Partes Review of US 8,242,158 Amneal Pharmaceuticals LLC – Exhibit 1046 – Page 117

118 I cnapter 8 Parenteral Drug Delivery

beyond 1he capabilities of conventional sustaincd­

releasc dosage formulations. Implantable systems pro­vide coniiouous therapeutic serum drug levels. Major applications of such devices include delivery of insu­lin co patients with diabetes and of chemotherapeutic

agcms to cancer patients. Implantable pumps are also used for 1he treatment of A'7heimer disease and spas­ticity, and for long-term pain control. When patiencs

do not respond to oral or parenteral analgesics, implantable pumps are used to deliver a continuous Row of analge;ic drugs and provide enhanced relief

from pain. Implantable delivery systems consist of a mcdic;1tion chamber, a pump that is used ro infuse

the medication, and a catheter attached to the pump. The pump is implanted surgically into the lower abdomen, and the mcdicarion is released through a

tunneled catheter. The medication ch:1mber is rcfillccl by insening a needle into the septum of the chamber. Pumps can be refilled with medication by physicians

or registered nurses. The LWO main caregories of implanrable pumps ar'e bellows-activated mechanical pumps and programmable dcc.:uonic pur11ps." Elecr ronic

pumps arc more commonly used, hecause che race of drug delivery can be controlled cxcernally by the phy­sician. These devices are described in detail in che fol­lowing section.

Electronic Pumps Electron ic pumps are battery opcrarcd, and their main advantage is chat tbey allow external control of rbe

delivery race and amounr of drug being infused. The physician c:m also maintain a computer-generated report of the pltmp status, bolu1 doses of medication

used, and the amounr of drug remaining in chc: pu-np. Tite pumps can be programm~>d using cdemctric com­purer-generatecl radio waves. Electronic pumps arc less

sensitive to changes in body 1cmpemturc rhan arc mechanic.ii pumps.

Bartery life depends on the type of pump, program­

mable paramccers, and drug !low rate. When the bac­rery wears our alier a few years of u.o;e, a programmable electronic pump must be surgically removed and

replaced. lf problems arise with the mechanical compo­nents, a soft alarm can be heard from the pump; the physician should be consulted, and the pump may need 10 be rcplacccl.8, The maJOr disadvantage of clecrronic

pumps is the cosr of the programming un its required to

send rhe celcmerry signal co the pump.88

Preloaded Syringes Preloaded syringes have been developed for the selfodmin­istrarion ol' drugs by patients in the convenience of their homes or workplaces. These devices arc easy co use and eliminate chc need to prepare injt:Ctions for self-adminis­

tration, which leads to improved pacic:nr compliance. Sumauiprnn sucdnate is available as a prefillecl

auroinjector pen with d isposable cartridges (lmirrex

STATdose System®). The dnrg is delivered SC by pressing a button on the pen and docs not require the

use of needles or syringes. Tite 6-mg injection can he adminisrcred up to a maximum of rwice per 24-hour

period. A major advantage of the 4-mg injection STATdose System® is char three injections may be used within the same period.9<' This is beneficial for

patients who suffer from clusrcr headaches and need frequent doses of lmi1rex®. Oral sumacriptan is cffec­rive for most patients, but 1he lmitrex STATdose Sys­

tem® provides effective pain relief for patients who wake up with a migraine already in progress a11d for patienrs with nausea and vomiting.90

Exenacide injection (l3yctta®) is a prefilled pcn­injec1or device with a glass carrridge containing exenatide solution. The injection contains rnannirol ai. a

t0uicicy-acljusring agcnc and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solurion. Each prefilled pen is used to deliver

prcmeasurcd doses and contains solution for multiple iujecc ions. Byetca® is prescribed for twice-daily SC adminiscrarion for 30 days, and each prefilled pen pro­

vides a rota! of 60 doses of cxenaride for creacmenc in type 11 diaberc• mcllitus. Patient cducarion regarding injecrion technique, proper st0ragc, and ciming of

injection> if other drugs are being administered is criti­cal. Byetta® should be injected 60 minmes before morning and evening meals. If a close is mi~ecl, the

ncxc dose should be adminisrcred ar the scheduled rime. Byena® is not intended for JM or IV injection.9 '·"2

Other examples of drugs provided in preloaded devices arc insulin deremir (recombinanr DNA origin) injection

(U:vemit® FlexPen®),'>l human insulin isoplianc suspen­sion (Novolin® N lnnolct®}.4'• pramlimi<le accr:r.te (Sym­lin®)," and fondaparinux sodium (Arixtr:1®).9'-'"•

Petition for Inter Partes Review of US 8,242,158 Amneal Pharmaceuticals LLC – Exhibit 1046 – Page 118

r eaming Points

Learning Point 1 A pa• icnt has sch izoph rcnii and requires maintenance

I lk has been p rescribed oral drug X every 12 t icrapy. hours. Bcc:iuse of his recurrcm ~chiioph rcnic episodes,

che p.Hienr forgers ro rnkc. doses at the sch~dulcd rimes.

Therefore, paciern compliance and efTecnve treatment

aft' major issues. Drug Xis water insoluble. Whar is chc:

most appropria~c alccrnativc do~age formu'ation in this

situation? An oil-based depot foanulation of drug X by IM

injection with a duration of action of 4 to 6 weeks may be die most cffea ivc w:iy 10 mainrain rherapeucic d rug

fevds for,, prolonged pct'iod. On JM adm inistration, rhc

drug \\/ill form a depuc ac the site of injccrion. The drug

will be released ~lowly from che depot formed at the

injection sicc, which wi ll result in prolonged effective

scrum concentr.uions and n.'Cluce che need fur frequent

inj=ion<. T he decreased frequency of dosing and maiJ1-rcnance of chcrapeucic scnun concentrations should lead

to eifccrivc therapy and improved patient compliance.

Learning Point 2

A lip id-insoluble drug, drug I, is prescribed co a patient

for the treatment of Parkinson dise:ise. Jes major site of

action is in the central nervous system, and sustained

levels of this drug in the brain corrdace with improved

control of Parkinson disease symptoms. When drug I is

given via IV injection, however, the patient does not

respond ro 1hc drug. \Xfhy does the pati:nc continue co

experience symptoms in spite of drug thernpy?

When d rug I is given JV, ic discribuces inco che sys­

temic circulation, which leads co an immediate increase

in serum drug levels. Because of its lipid insolubility,

however, it does not cros~ the blood- brain barrier.

Drug Delivery System• I 119 in Phar~utic&I care

Therefore, a likely explanation is that rhe drug is nor

delivered 10 rhe brain, which is the major sire of drug

action in the trearmenc of Parkimon disc:L<e. Therefore,

drug1 n~'el!s co be administered by a specialized route of

delivery char bypasses che blood-brain barrier. Drug I could be admillistercd by inrrachccal or inrracere­

brovenrricular injcccio11s to ensure delivery of the drug

directly into chc brain anti surrounding fluid.

Learning Point 3

Microsphercs are designed for sustained ielease ranging

from hours co several days or months. Microsphcl't'S arc composed of synthetic biodegradable polymers like

PLA, PGA, and PLGA. Encapsulating a tlrug in differ­

ent polymer marrices provides an effeccivc way ro main­rain chcrapcutic levels of chc drug for a long~r time.

\Xfhat is the mecha11istu of release of rhe :lrug from spe­cial ized drug delivery systems such as microsphcrcs?

How can rhe rcle:ise of~ drug over time be modified by using microsphc:res as delivery systems?

The rate of release of drugs from microspheres

depend~ on rhc molecular weight and composition of

the polymers. PGA is more hydrophilic, and water

up1ake is rela1ively higher with PGA than with PLA. which is more hydrophobic. Hence, 2 PLA polymer

matrix relc~ses drug more slowly than a PGA matrix. By varying chc amount of PLA and PGA. r!ie rate of release

of the drug over rime can be controlled. For slower

release (up co 3-4 months), PIA can be uled co form

rhe polymer matrix of the micrnsphcres. In comparison,

a slightly faster race of release (l month) can be

achieved by using PGA in rhe polymer matrix. In the

latter case, the microsphcres contain the monomers

PLA and PGA in a ratto of75:25.

Petition for Inter Partes Review of US 8,242,158 Amneal Pharmaceuticals LLC – Exhibit 1046 – Page 119

120 I Cllapter 8 Porenteral Drug Delivery

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11. Ni.sl~:t AC. I ncr:unt...scul:tr gluteal lflJcctio11s in the 1m:rc.1si1l&ly ubcs< J'Ol'Ulation: ,...ll0$Jl0Clivt s1udy. BM}. 2006;3J2:637-63H.

12. Thy•"&"" for injc«ion ldr\lg infor111:uionJ. /\v;1ilablc at: hup:// www.rxlis1.tomh'gi/gc11cric2/1hyrocropiu.lmn. Accessed 1-d>ru­·•ry 2007.

13. Thyrogcn® (package inmil. Cambridge, MA: Genzyme \,orp; 2005.

14. Prolixin F.n1111d1•1<'® (p•ckugc in;cri). Princc1on, NJ: Bri<tol­M)'ers ~u1bb Co10pany; Aut;ust 2006

15 Modiirn faumh.m proc:lua monosr.ph. In: Cillis MC. ed. CPS Cump#mlium of p/J11nmtct11tit'+1/J and rp«i11/1in. 33rrl td. Ou.1w2, Ont>rio: C:uruli.1n l'h>rmadni; Asioci>liou; 1998: I Ol9.

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Petition for Inter Partes Review of US 8,242,158 Amneal Pharmaceuticals LLC – Exhibit 1046 – Page 122