gut! I Shalfali Bhalla
`
`Parenteral Drug Delivery
`
`flfiflflt 0Un.lt£
`overview or Parenteral Delivery
`common Routes oi Parenteral Delivery
`tntnwenous Injection
`flrunusula Idectlon
`Sunwlanooti Woctlon
`Intndanmi Election
`Specialized norms
`Advantages and Dttnavantqee of Parenteral Delivery
`Gevtemcnaracterlstiesowuvnerelooiiverysysterns
`Pharmaceutical Incedients and Additives
`ventricles
`conowents
`Other Additives
`General Categories of Injectebtes
`Wuflon
`For Itioclion
`lniectnble Emulsion
`Inioctable Suspension
`For Iniectable Suspension
`Soeeid Intravenous Delivery Systems
`Uoooomes for hpctlon
`uoud-Associated Amohotencln
`Polymeric systems for Parenteral Delivory
`Polymer Nanooartlclot
`Soedalizod Devices
`Inplantable mros
`Electronic Puros
`Preloaded writs
`OBIECYIVES
`1. Descriaetrteditlerenttotnesofperentaraldellveryandthe
`tactonlnfluoruume dasorptionofdruafrommierett
`upctionsiles.
`2.DeIneparenteraldI'ugdelIveryanddesorDeitsatNantaes
`overotherroutesoidrug aaninistmtion.
`3. Doaorbothedaauulatetdpurenteroldosqetormloutxit.
`-ttxnldnthoptrmoaeofoontooneritsofpueruteraliarnula
`u’ons:vehiele.ot>solvent.btflet.tonidty¢rit.vreserv&
`uw.protectant.sunaeunt.nnd antioauomt.
`5. Orfbrantlatn among douse lonnuletbons available for
`pnrenteraladrnlnlstratlonondexplaln hovvdrug is released
`lromvanouslriedablo orenorations.
`6. Enrrnirtotltoaotl-cuionoftttgtataotijvysternsinpuerv
`Iariovuulelncry.
`7.0eIcriJelheus!olspedal|zcdparerIteIn|mliverydevi:es.
`
`ovorvlotvoflhnnuralbollvory
`Pamitmrl delivery has been defined by the Center for
`Drug Evaluation and Research of the Us. Food and
`Drug Administration (FDA) as the administration of a
`drug by injection. infusion, or implantation.‘ Pnrrntrml
`Jeliuqy means introducing drugs into the body outside
`of the entcral route; that is, outside of the gastrointesti-
`nal
`tract.‘ This delivery route can also be used to
`administer drugs directly to specific body organs and
`tissues to produce a desired therapeutic effect at a target
`site while minimiting systemic side effects.
`Common routes of parenteral administration are
`described in the following sections. Table 1
`lists the
`routes of parenteral administration.
`
`0ornnoullouueofPuuIhnIDollvory
`
`Intravenous Injection
`Drugs administered by the inuavenout (IV) route pro-
`vide the fastest onset of anion because they are injected
`directly into the systemic circulation, and there is no lag
`time or absorption phase for the drug. Drugs adminiv
`teted by the IV route exhibit 100% bioavailubility.
`The three moa common methods by which drugs
`are delivered IV an: IV holus. continuous IV infusion.
`
`and patient—control|ed analgesia.
`
`' IV 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 [V administration of a
`drug within or into a vein over a sustained
`period. For a dnrg with a narrow therapeutic
`range. IV infusion can control
`the amount of
`drug administered over a fixed time period by
`controlling the infusion rate. Loading dost: are
`administered at the start of IV infusions for drug;
`that have long biological half-lives. This quickly
`achieva effective serum concentrations of the
`
`drug. Steady-state serum concentrations can be
`maintained by giving the dmg as a continuous IV
`infusion at a constant rate over longer periods.‘
`
`Petition for Inter Panes Review of us 8,648,106
`Amneal Phannaceutils LLc — Exhibit 1046 — Page 103
`
`

`
`
`
`this route are narcotic analgesia such as fema-
`nyl.‘ methadone." and morphine.‘
`
`Drug that are commonly administered by the IV route
`general anesthetics. antiviral agents. antibi-
`are
`otia. irnmunosuppressive agents. antifirnpl agents. anti-
`bacterial agents. antihypertensive agents, vasodilarots.
`antiarthythrnic drug. and
`agents.
`The IV route is not without adverse effects. IV injec-
`tions are administered directly into the venous circula-
`tion. and hence hifirly vascular and perfused organs. such
`as the heart. lungs. liver. and ltidncy, rapidly acquire the
`drug. In some cases. however, a sudden incruse in serum
`drug concentration may lead to toxicity. This can be pre-
`vented by giving a slow IV bolus injection. Other drug
`with poor aqueous solubility may precipitate from solu-
`tion and produce an embolism. Proper selection of Elli?
`diluent and slow IV administration allows for proper
`mixing of the drug in the circulation. Finally. some vehi-
`cles may cause adverse effects in pediatric patients. For
`example. phenobarbital sodium is dissolved in propylene
`glycol. which may cause hyperotmolality in infants.’ In
`addition. because the aluultol and aldehyde dehydrogena-
`ase pathway that metabolites propylene glycol is not well
`developed in infants and children younger than 4 yan.
`repeated use of IV injections containing propylene glycol
`can land to toxicity.
`Lipid-soluble dnrgs like diaupam can easily cross the
`blood-brain barrier and are effective when given by the
`IV route. However. lipid-insoluble drug are ineffective
`when given by the IV route if the desired target site of
`action is in the brain. Thus. lipid-insoluble drugs often
`need to be administered by specialized routes olidelivery
`that bypass the blood-brain barrier. These specialized
`routes include intraspinal and intracerehrtwentriarlar
`injection. which will be discussed later in this chapter.
`
`Intramuscular Injection
`Drugs that may be irritating to the subcutaneous (SC)
`tissues are administered via IM injection. The [M
`injection site is usually the deltoid muscle of the upptf
`arm or the vastus lareralis muscle in the anterolatcfll
`
`aspect of the middle or upper thigh. A needle I008
`enough to reach deep into the muscle must bt "594
`and should be inserted at an angle of 80 to 90 ¢l¢3'°5‘
`Bcmuse of the time required for the drug to b¢C°“‘_°'
`available from the muscle to the systemic circuli!5°"{.
`lM injections have a longer time to onset of clltci
`
`Petition for Inter Parties Review of us 8,648,106
`Amneal Phamtaceutils LLc — Exhibit 1046 - Page 104
`
`chapter 8
`Parenteral nun Delivery
`
`=°-
`
`I
`
`Title 1.
`
`Routes of Parenteral Administration‘
`line
`Daliritiau/ebactarhaaalatmthtrdurt
`Endtni
`Mministmon on or over in on meter
`
`intm-articular
`Ifluneriai
`Intnctrtlac
`
`htracaviiary
`
`Imraoermai
`
`Attninistrattott within a pm
`Attninrstraion within an artery or arteries
`Mrninlltrlmn within the hurt
`
`Mninistration wiihlnanathoiogiccmtgsucitas
`occurs in the its; in tuberculosis
`Aaninltiraiiort within the dermis
`
`ljectiatogtnrtnlatreaamaihytrointeaim.
`Administration vritiun a lymph channel or none
`lrtraiymhatic
`intramuscular Mrniristraonrt within a muscle
`
`iranossoous
`
`irtlectron is gven Into the muscle fibers of the
`taper arm orguteal area
`Aanirtirtrntontlrectiyvntrratthevmrrouoianone
`
`Themodlosimocudrvttimugtitrebotteand
`
`Intratnecai
`
`intraoentoneai Administration within the peritoneal cavity
`htnuoinal
`Adrrinisrration within me mineral column
`Refers to both epidural and intratrraai rues.
`Administration within the oerobrospinal mid at
`my level oi the cerdrrnqind axis. iruadrvg irtiee
`tion irttotrioceteoraivertnties. mowontsmto
`subarudtnoid spaces.
`khtiiistrotliti within or no a veil cl nits
`
`htnrtenous
`
`Injection is given directly into the vein
`Arirvrtistntim wnhh a verancie of the brain
`
`nracarebro
`ventricular
`
`Attrtinistntion witrm the vitreous boo; at the eye
`imuneai
`Subcutaneous Arininistratim beneath the skin: also imam an
`hypodermic injection
`injet.1ion-aownbeloutrteootoernvisutdderntis
`layer 0! the slim.
`-rvurnccnterIor0rtgEvtIuatnonmaituoum'
`
`The preferred route for artalgaics is a continuous
`IV infusion. because it produces less llucnrarion
`in serum concentrations of the drug than do
`intermittent intramuscular (IM) injections.
`0 Patient-controlled analgesia is designed to deliver
`IV bolus dose: in addition to a slow. continuous
`
`IV infusion‘ '|his method allows patients to self-
`administer analgesics as needed for breakthrough
`pain. The drugs most commonly delivered by
`
`

`
`'
`
`_
`
`,
`
`,
`
`ofaction than IV injections. The rate
`* on ma extent ofavailability ofdrugs depend
`’
`I
`_
`I
`_
`dcgl factors such as formulation char-
`‘ ma .1-3 Physiology of the injection site.‘ lM
`g are safer than IV injections: however. incor-
`‘dminigu-ation techniques can result in blood
`‘gig of the skin. abscesses. and nerve damage
`conditions.
`V to
`t formulation and delivery strategies are
`.
`:
`,.
`' for (he administration of water-insoluble drugs.
`.
`r-insoluble drugs are solubilired in solvents
`g; propylene glycol and mineral oil for injec-
`ftion. These nonaqueous vehicles stay at the site of
`"injection and release the drug slowly. which results in
`prolonged serum drug concentrations and a longer
`duration of action. Sparingly soluble ionizable drugs
`prepared as solutions for injection must be buffered
`to physiologic pH." Precipitation of the drug may
`occur as a result of this change in pH. Absorption
`may be prolonged as the drug redissolves in tissue
`fluids.’-'°
`
`‘
`
`'
`
`Another factor affecting drug absorption is the blood
`How to the injection site. lM injections given into the
`deltoid muscle in the arm are absorbed faster than glu-
`teal
`injections. This difference is likely due to the
`incrased blood flow in the deltoid muscle and lower
`
`blood how in the gluteus tnaximus muscle. which has a
`hiyt content of adipose tissue. Slower rates of absorp-
`tion aftct gluteal injections were seen in a higher per-
`centage of women than mcn.""' Moreover.
`the
`injection volume is limited depending on the site of
`administration. Large muscles like the glutal muscle
`tan effectively absorb 4 to 5 ml. of injected solution.
`wheres snnller muscles like the deltoid musde in the
`
`arm can absorb up to 2 to 3 ml.."
`lM injections are available in immediate-release for-
`mulations as well as depot formulations For sustained
`release. Examples of these formulations are dacribed in
`the following sections.
`Inrruotlttto-Release lntrarntraeabr lrfiocflon
`Water-soluble drug are dissolved in aqueous vehicles
`and prepared as solutions for injection. On [M injec-
`tion. they distribute into the circulation and release the
`drug rapidly. The usual onset of action is 30 minutes.
`and the duration of action depends on the drug's half-
`life. One example is
`thyrotropin alfa for injection
`(Thyrogen®). a sterile. lyophilized product that forms
`
`Drug Delivery Iyuurtu
`ln Pharmaceutical Care
`
`105
`
`a solution after reconstitution and is injected IM for
`immediate release." "
`
`fl FOHIIUGUNI '0! lntraniusctlar wectlon
`Depot injections release the drug slowly and maintain
`serum drug concentrations for a longer duration. Depot
`injections are long-acting dosage formulations indicated
`for maintenance treatment rather than initiation of ther-
`
`apy. Depot formulations are available as oil-based injec-
`tions (cg lluphenaaine enanthate and estradiol cypionate).
`aqueous
`(cg. penicillin G proaine and perti-
`cillin G bertzathine. rnethylprednisolone acetate [Depo-
`Medrol®l. and medmxyprog.-stemnc acetate/estradiol
`cypionate ['Lunelle®]). and microsphetcs (cg. lettprolide
`acetate [Lupron l)epot®]).
`An example of a long-acting depot formulation con-
`taining the drug in the form of salt is lluphcnazinc
`enanthate (Ptolixin Enanthate® injection)."’ It is indi-
`tzted for the maintenance treatment of nonagitared
`patients with chronic schizophrenia. Fluphenarine
`enanthate is water insoluble and is therefore dissolved
`in oil. On lM administration. it fonns a depot of the
`drug dissolved in oil.'‘'"‘ The drug is released slowly
`from the depot and enters the blood circulation. Dosing
`intervals vary from 2 to 6 weelts and are determined by
`the response of the patient to therapy.
`An example of an aqueous suspension acting as a
`depot is penicillin G benzathinelpenicillin G proaine
`suspension (Bicillin® (‘.-R). The injection contains
`water-insoluble drugs suspended in an aqueous vehicle.
`It is a stabilized, long-acting aqueous suspension con-
`taining sodium citrate buffer and the suspending agents
`lecithin and tatrboxymethylcellulose (CMC). The active
`ingredients are hydtolyted in the blood to penicillin.
`The slow absorption from the IM injection site and
`subsequent hydrolysis leads to prolonged serum levels
`of penicillin, which allows dosing every 2 to 3 days
`when repeated doses are needed."
`Encapsulating drugs in polymer matrices and biode-
`gratlahle microsphcrt: provides a way to maintain ther-
`apeutic levels of the dmgs for a longer time. An example
`of a polymer-based microsphete system used in depot
`formulations is lettpmlide acetate for depot suspension
`(Lupron Depot®). Lupron Depot® microspheres are
`indicated for IM injection and are available in a pre-
`filled dual-chamber syringe. The drug chamber con-
`tains leuprolide acetate. incorporated in a biodegradable
`polymer of polylactic acid and D-mannitol." The dilu-
`
`t._______________
`
`Petition for Inter Parties Review of us 8,648,106
`Amneal Phamtaceutils LLc - Exhibit 1046 - Page 105
`
`

`
`100
`
`cnoatotfi
`nmmvumgoonnq
`
`Specialized Routes
`Intrasynovlal
`lntrasynovial
`injection is administration of at drug
`directly into the synovial cavity ofa joint.‘ This form of
`parenteral delivery is used for the treatment of inflam-
`mation in patients with rheumatoid arthritis and col-
`lagen vascular diseases. Drugs administered by this
`route include methylprcdnisolonc acetate and triamcin-
`olone acctonidc. which are available as injectable sus-
`pensions. The duration of action is
`significantly
`increased when a drug is
`injected intrasyuovially.
`Repeated injections, if given. are generally administered
`no more ftequendy than every 3 months
`Intro-Articular
`
`
`
`injection is administration of a drug
`Intra-articular
`lntra-articular administration of local
`within a joint.
`anesthetics and adiuvants is an alternate method for post-
`operative analgesia. Patients who have undergone liga-
`ment reconstruction and experience moderate to severe
`postoperative pain can benclit from intra-articular injec-
`tion of ropivacaine and morphine via a catheter in the
`knee joint. This approach decreases the need for supple-
`mental IV morphine." For the firs: few hours after intra-
`wnovial or intra-articular injection. loal discomfort in
`the joint may occur. but this is rapidly followed by effec-
`tive rclicfof pain and improvement of local function.
`Intrasplnal
`lntraspinal delivery is administration ofdrugs directly into
`the vertebral column.‘ It includes epidural and intrarheatl
`injection. Vfttlt epidural injection. drug is delivered to the
`outside of the dura and not into the ccrcbtospinal fluid.
`Thus the clinical effects are more localized to the spinal
`cord. Drugs an be delivered by a single bolus injection or
`as a continuous infusion (Figure 1)." Advanced primary or
`metastatic Cancer pain, thoracic and lumbar pain. IIGW
`root injuries. and neuropathic pain are treated with intnr
`thotxtl injections and infusions ofopioids. local anesthetics.
`clonidinc, baclofen. and other drugs used for the tnntmcnl’
`ofchronic pain, cancer pain, and intractable spasticity-"
`Morphine sulfate extended-reletme Iiposome injccl-5°“
`(DepoDur®) is a spatial
`dosage lbrtnul=llil°“
`injected am the epidural spacc."'” DepoDur® iniecdw
`is a sterile, preservative-free suspension of multivtslcul"
`liposorncs containing morphine sullitte present as I 5”’? .
`pension in 0.9% sodium chloride solution. 0!!
`injection, the multivcsicular liposomcs release
`
`cut cltamber contains sodium CMC. water for injec-
`tion. D-mttnnitol, polyaorbate. and glacial acetic acid to
`maintain pH. The mitmapherm form a depot at the site
`of injection. and the drug is reltstsed slowly at a con-
`stant rate as I! rcsull of the hydrolysis of the polymer.
`Depending on the prescribed dose. Lupron Dcpot®
`can be injected once every I
`to 4 months." Other
`exampla of micmephere formulations are discussed in
`detail in the section llolymeric Biodegradable Systems
`for Parenteral Administration.
`
`Subcutaneous Injection
`SC injections are given into the SC or fatty layer of tis-
`sue hdow the epidermis and dermis. These injections
`are also referred to as I.t_y/nodermit rnjmr'nnr because the
`drug is administered benath the sltin." SC injections
`are usually srnall-volume injections and are adminis-
`tered at an angle ol? 4'5 degrees to the skin. They can
`generally be self-administered and are easy to adminis-
`ter with minimum discomfort. Patient education
`
`regarding proper SC injection techniques is important
`to minimize infection and other local adverse ellccts.
`
`Drug: are ahsorhetl at it slower mt: after SC injections
`t:l1anafietlMinjectiombccausethereislcmbloodflowto
`the fatty tissue below the ttltin than to the muscle. The rate
`of ahnorption also depends on the penetration cocllicient
`and the amount ofdrug It the time.’ Absorption talts plane
`throng: the mpillary wall in the connective tissue. Penetra-
`tion of drug into lhe connective tksue depends on the
`concentration gradient of drugs actors the atpillnry wall
`and connective tissue, the area of the membrane exposed
`to the solution. and the distance ofdilhrsion. Mediattions
`
`that are injected by this route include vaccines. lteparins.
`insulins, growth hormone. and epinephrine.
`
`Intradermal Injection
`lntrademtal (ID) injections are administered within the
`dermis hyer of the skin.‘ the ripper layer of the skin just
`below the epidermis. ID injections are very-small-volume
`injections (0.! mL) and are used to deliver drug; to pro-
`duoe local efliacts.
`lixamplea of uses of [D delivery are
`injections for skin testing. antigen
`to evaluate for
`allerp'c reactions, and administration of vatriou (cg.
`inlluema vaccint:)." ID administration of vaccine: has
`been shown to enhance immune rmpomc more elToc-
`tively than SC adminisuation.” Thus. the ID route may
`target lytnph nodes more ell-iciently than the SC mute.
`
`Petition for Inter Partes Review of us 8,648,106
`Amneal Pharmaceuticals LLc - Exhibit 1046 - Page 106
`
`

`
`Drugnolvuyiyeeana
`lnmumaeoullealcare
`
`10'!
`
`and fentanyl are effective when delivered by the intrathe-
`cal route.“-’°
`
`lntracerebroventricular administration is commonly
`used for chemotherapy trmuncnr of gliomas or for
`delivering neurotrophic factors to many areas of the
`central nervous system.”
`Intro-Arterial
`
`The intra-arterial route is used to reduce drug exposure
`to the systemic circulation and to increase drug con-
`ccntrations in the areas supplied by the artery into
`which the drug is injected. The intra-arterial route is
`used to deliver chemotherapeutic drugs such as cis-
`platin to treat head and neck ancer and to inject vaso-
`pressin to control gastrointestinal bleeding. New and
`safe angiographic techniques enable the placement of
`microcatheters into small arteries under direct vision
`
`intra—arterial injections
`using fluoroscopy." However,
`have been assodated with embolism. occlusion of
`
`arteries. and drug toxicity.
`
`Atlvontqos and Dludvuntuos of
`Panntorol Delivery
`The main advantages of parenteral delivery are the
`following:
`
`I. it can be used in patients who are unable or refuse to
`talte medications by mouth.
`2. Rapid and complete absorption of drugs from the
`systemic cimilation taltcs place if the drug is admin-
`istered IV as a solution.
`
`ntetabolistn is avoided. which leads
`. Fun-pant
`to improved hioavailabiliry for drugs that undergo sig-
`nificant first-pas metabolism after oral administration.
`. Smaller doses can be used with IV administration
`than with oral administration.
`
`. The parenteral route avoids drug degradation in the
`gastrointestinal tract. A large number of proteins are
`administered parenterally.
`. lV administration of drugs has been shown to
`a more predictable pharmacoltinetic and pharmaoody~
`namic profile for drugs than oral administration.
`. The route of parenteral delivery can be tailored to
`the needs and condition of the patient. Direct injec-
`tion of the drug by the IV route is beneficial in emer-
`gency situations when the need for
`therapeutic
`action is immediate. For a slower onset and a longer
`duration of action. drugs can be administered IM.
`
`....
`
`.~
`
`' M
`gtqwotttreeoholcoroirtdteatlrgtrteepudtr
`the
`and
`uh-aehtola space. (Reprinted with
`from Moore and Datleyf’)
`
`_
`
`and into the inttathecal space through the
`at a slow rate over a prolonged period.“ When
`fivcn as a single dose 50 minutes preopetatively. Depo
`Dtu®hasprtxlucedpersistentanalgaiaR:r48ltoutspost—
`opetatively. The distribution. metabolism. and elimination
`patient of lipoaomal morphine sulfate is similar to that
`after delivery of other parenteral morphine formulations.
`DepoDur® is
`for single-dose administration and
`does not accumulate significantly in patients with
`impaired renal or hepatic function. Other examples of
`Iiposontal formulations are dacribcd in detail in the sec-
`tion on special IV delivery systems.
`Intnthocal and Intneorobronntrleuler
`
`the administration of drugs
`injection is
`lntrathecal
`within the cerebrospinal fluid at any level of the cere-
`brospinal axis. including injection into the cerebral ven-
`tricles} When lipid insoluble drug are needed to treat
`some neurologic disorders, it is necessary to bypass the
`blood-brain barrier and deliver druy directly into the
`brain. '11-iis can be achieved by intrathecal administra-
`tion. in which drugs are injected into the cerebrospinal
`fluid surrounding the spinal cord. or by direct injection
`of drugs into the brain by inrracercbroventricular injec-
`tion. which is an invasive approach.” lnttathecal injec-
`tions can be given as a single dose or as continuous
`infusion via an indwelling catheter. Drugs that require
`long-term intrathecal infusion can be delivered by intra—
`thecal catheters connected to an SC implanted infusion
`device. The intrathecal
`route is commonly used to
`deliver small Iipophilic molecules for pain management.
`Opioid analgesics such 3 morphine. hyclromorphone.
`
`Petition for Inter Partes Review of us 8,648,106
`Amneal Phamtaeeuticals LLc — Exhibit 1046 - Page 107
`
`

`
`108
`
`Cnanter 8
`Parenteral Drug Denvecy
`
`lot ntany
`Although patenterttl delivery is prclt't'I'etl
`drttgs. atltttittisterittg drugs hy this route has some dis-
`-.ttlv:utt;tges:
`
`l. Aseptic prt-cautions must he followed to avoid con-
`tamination antl tninimi/;e the rislt oli infection when
`the drug is hcing il(lllIinl.\|L'I‘Ctl.
`2. Most often, parettterztlly delivered drugs are adminis-
`tered hy ll".llllCLl health care professionals in clinics
`and hospitals. 'l'his is more inconvenient and costly
`than self—adtninistmtion ofdrttgs.
`5. For sell‘-atlntinistration oliztll p.trcnrer:tl dosage fortmt—
`lations, patients must he adequately trained, which
`can be time consuming and resottrte intensive.
`4. Mmtulacturing is also more costly than the m-.tnnl'ac—
`lure of‘ conventional tahlets and capsules.
`5. ()ucr drugs are iniectcd lV. they cannot he removed
`easily from the bloodstream. This can he .1 problem if
`an Incorrect dose or drug is atltninisteretl. because
`adverse effects can result. Dialysis or liemntiltration
`can be used to remove excess drug, hut
`these are
`cornplicatt-tl procetlnrcs and can cause discotnlort tn
`the patient.
`6. Injections may he ztccompanied by pain and infec-
`tion at the site oliniection,
`
`agents. st;thili'1.ct's. and ttmicity agents must be stcrilivetl
`separately and then combined in the lotmulzttinn.
`3. They must be isotonic.
`'l‘onicity-adjusting agents
`dcctt:
`‘e the ltetnolysis Ul.l)lU()tl cells and retlttu.‘ pain
`and irritation at
`the injection Silt‘.
`l,.arge-volutne
`injt-ctahlc pn.-partitions must he isotonic with blood
`(ie. must have the same osmolality as blood or other
`hotly lluids). Large-volume p;IfL'lllt:l':llS are given to
`prevent electrolyte itnh;t|:tnce."
`
`Pharmaceutical Ingredients
`and Additives
`
`l’arcnter.tl dosage formulations are 0on‘tp0st.‘.v.l of the follow-
`ing pliartttacetttie.tl ingtuliettts and atltlitives:
`l. Vehicles
`2. (Io-solvents
`
`tonicily-adjttstint; agents.
`5. Other atltlitives: hullcrs,
`2I|Illl1llLl‘0l)l;\l preservatives. protctunts, surfactants.
`:tntioxid:tnts
`
`Vehicles
`Vehicles for injections must he sterile as well as particle
`.lI|ll pyrogen free. Exatnplcs of vehicles and L'$St‘n[i;ll
`vehicle Cl1.1l‘:lL‘lL'riSllc.s for water- and oil-hasetl
`injec-
`tinns are shown in Table 2.
`
`General characteristics of
`Parenteral Delivery systems
`
`('/xrtain requirements must he satisfied for tlusage formu-
`lations and delivery systems to be approved for injection.
`
`I. They must be free of pyrogens. Because ol"microhi:tl
`contamination. pryogcns or
`fCVCl‘-|)l’0(lll(.'lllg sub-
`stances may he found in pat'enteI'al
`lortuttlatitms.
`These stthstanccs can lead to complications after the
`lortnulation is injected: therefore. :tll p;n'enter.tl for-
`mulations must he pyrogen free.
`2. They must he sterile. All pattntcml lhrmttlatit)ns must
`he live of all microbial org-.tnisms. Sterili'I.-ttion is the
`process by which all living and pathogenic organisms
`are destroyed and removed from the formulation. The
`most common tc(lIniqI.tt's used to sterilize injection
`lot‘tnulations and p'.trL1itet".tl
`implants are srtxam and
`dry heat. ll. the drug is heat labile. gas sterili'/.11 ion by
`ethylene oxide. filtration using filters with various potc
`siuzs for different! formulations. antl ionivjng l‘.l(.li;lli0l‘|
`teclmiqttes may he used. The individual C()lllpOIl(‘nl.\‘
`ofdispcrsinns or suspensions such as drugs. suspending
`
`Co—Solvents
`(io-solvents are used to solnhilive drugs that must he
`injected as solutions. Drugs with poor water solubility
`may be formulated with co-solvent: such as ethanol,
`propylene glycol. and polyethylene glycol (PEG) 300.
`Co-solvent solutions are confined to IV and IM use.
`For IV adtninistration. the injection must he :tdtninis-
`tercd slowly to prevent precipitation ol the drug and to
`avoid cartliovascttlar
`toxicity front
`the co-solvent.
`ll
`drug precipitation occurs during IM injection. the dos-
`age formulation tends to act
`like a depot
`injection.
`which results in delayed absorption of the drug. Precip-
`itation may also result in incomplete absorption of the
`drug front the precipitate. which leads to lower thera-
`peutic levels of the dmg and pain at the injection sin:
`A good example of oo-solvent use is phcnytoin injec-
`tion. Phcnytoin (sodium injection) is a dear. culorlcsa s0ll|'
`tion containing propylene glycol. ethanol. and watcl’ lb‘
`injcaion. Phcnytuin is insoluble in water; then-firm P“~"
`pylcne glycol and ethanol are used as co—solvcnts to di5‘
`solve phcnytoin and produce a clear solution for W
`
`
`
`Petition for Inter Panes Review of us 8,648 106
`Amneal Pharmaceuticals LLc - Exhibit 1046 — Page’108
`
`

`
`' -r Injections
`
`'
`
`- “mfg;
`
`Sififlle #0! l0
`sterile saline tor injection
`§iG"lJ§flK waterlor
`
`who and sterilized
`
`Used as a final-slap soivent for sterile solids or for dilution of sterile solutions
`Distiled ltd steniud
`cantons preservative
`Used for mumpboose containers
`Lhlteo use in taint.-mourn: parenteral flusions
`Corvtratttoieated lot use In neonates
`Cofllllllfliclted Ior epidural and intramecal injections
`Pmte<t.c;vogpnt:oe.anaatovte
`Doesoothavatomoetpartlculate staodardsforlarge-volurne parenterallniusions
`lypicalyavoilablonavoumeotitormorelnaauewcaooorualrter
`Puru,ttarte.towtmtattyaciacontant
`Usedlorintramusculardeootlttjectiarts
`Alteryeteoctionscanoeeut
`vahtclocompositlon rrustboltstadonloboi
`
`injection. Sodium hytlttnidt: or hydrochloric acid is used
`as bufleting spots to adjust the pH ofthe injection to 12.
`Ptedpitationoraystalliationofpltettymintttayoeutrif
`thepH isaltctedorii'rheeo-tolventxorvehiclauemodi-
`lied.'l‘hed.rugisadminiaeeredt|ow|yaun Whttltu injec-
`tion. at a rate no Faster
`than 50 mg/min in adults to
`prevent tatrdiovasculat adverse «mm. 'l1\e alkalinity of the
`injection an ruult in initation. pain, and inflammation at
`tlte injection site. Hence. each injection of phcnytoin
`should be followed by a 0.9% sodium chloride W infitsion
`through the same catheter at ntufle to avoid irritation at
`the site of injection." Alternatively. phcnytoin can be
`administered asan IV infusion over 15 to 30 minutes. To
`
`avoid precipitation. phenytoin should be diluted with
`0.9% sodium chloride or lactated Ringer injection. Use of
`an inline filter is recommended with such inlinions. Phen-
`
`ytoin injection should not be administered lM because of
`its erratic absorption and tisue reactions at the IM injec-
`tion site. Fotphenytoin is a prodrug of phenytoin that is
`freely soluble in water and hence dot: not produce the dis-
`comfort and erratic absorption mandated with phcnytoin.
`
`Other Additives
`Ellen
`
`process. V/ealt acids and wait beau are used as buffers to
`maintain an optimal pH of the injection. which can
`enhance the solubility and stability of some
`Drug
`solubility and absorption also depend on the formulation
`pH. Therefore, buffers play an important role in the
`absorption of drug from injection sites Exampla of
`commonly used buffers are citric acid/monosodium cit-
`rate. acetic aeidltodium acetate. phosphoric acid/monoso-
`dium phosphate. betmoic acidlsodium henaoate. and
`tris(hydmxymethyl)aminomethane (TRIS buffer). Buffers
`such an Ciuau.‘ anrl'l‘Rl.‘~i undergo minimal changes in pH
`during freezing eydes in lyophiliution. Therefore. the
`addition of low comxttuations of these bufl"ers is most
`
`suitable for lyophiliaed formulations.”
`One example of the use of buffers is in ondansetron
`hydrochloride (Zofran®) injection. Zoi'ran® is avail-
`able as a dear. colorless. sterile solution For injection.
`The active ingredient. ondantetron. it huflcred using
`citric acid monohydrate and sodium citrate dehydrate
`to minimize patient discomfort at
`the injection site
`while maintaining drug solubility. Zoft'an® is indicated
`for IM or [V injection and should not be mixed with
`any other injections, because precipitation may occur as
`a result ofchanges in pH."
`
`Major concerns during parenteral administration ofdrugs
`are
`of the solubility and stability of dmg
`and improvement of patient comfort during the injection
`
`TonIclty~AtflustIo¢Agonu
`lsotonicity is needed to reduce pain and irritation and
`to prevent hemolysis of blood cells at the site of injec-
`
`Petition for Inter Fortes Review of us 8,648,106
`Amneal Phamtaoeuticals LLC — Exhibit 1046 - Page 109
`
`

`
`bonding between the protectants and protein mole-
`cules. This mimics the hydrogen bonding between pro-
`tein molecules and water that is being replaced during
`the freeu—drying process. The drug and water mole-
`cules are immobilized in the viscous glassy matrix. This
`also results in stabilization of the formulation. because
`
`very high activation energies are required for any reac-
`tion to occur. Examples of commonly used prntectants
`are sugars lilte glucose, lactose. and treltalose “
`surfactants
`
`Surfactants are used for solubiliaration of lipid~soluble
`drugs. for preparation of oil-in-water emulsions. and as
`wetting agnts. Ettamplctr of surfactants are lecithin.
`various phospholipidt. polysorbate (Twcens®). and
`polyoxyethylerle ustor oils such as Cremophor® EL.
`lecithin it a mixture ofrriglycerides and phospholipids
`and is used as a surfactant in fat emulsions. Egg and
`soybean phospholipids are common sources of lecithin.
`'l'ween® series (l'woen® 20 and 80) and sorbitan
`mono-oleate are also used as surfactants for parenteral
`use. Cremophor® EL. or polyoxyethylated 35 castor
`oil, is a nonionic surfactant used to solubilizc cyclospor-
`ine. paclitaxel. and fat-soluble vitamins for injections. A
`major disadvantage of Cremophor® EL. however. is its
`potential to muse serious hypersensitivity reactions.
`Cyclosporine injection. (Sandimmune® Injection)
`is available as a 5-mL sterile ampule for administration
`as a slow [V infusion. Absorption of cyclosporine from
`the gastrointestinal tract after oral administration is
`variable and incomplete; hence it is formulated as an
`injection. Sandimmune® contains Cremophor® EL
`and alcohol and requires further dilution with 0.9%
`sodium chloride injection or DSW injection before
`use. Alcohol is used as a co-solvent with CrerrtoplI0f®
`EL.” Nitrogen replaces the air
`in the ampule (0
`improve the stability of cyclocporinc by prevemifllf
`oxidation. Cremophot® El. can cause an anaphylacllli '
`reaction; therefore. the patient must be observed "
`the first 30 minutes after the start ofthe IV infusi0l'|-
`
`
`
`"
`
`-
`
`ll maphylaxis occurs. the infusion should be
`'
`and the patient should be treated with oral
`ine. Cremophor® EL or polysorbate 80 can I150 " p
`phthalate stripping from devices made of pol!‘
`chloride. Polyvinyl Chloride is a plastic polymer
`to provide flexibility in various medial devices.
`one of its components. di(2-ethylltexyl)pltthttlnI
`leach out of medical device into solutions
`
`Petition for Inter Patties Review of us 8,648,106
`Amneal Phannaceutils LLc - Exhibit 1046 - Page 110
`
`1.10
`
`Cr&erB
`Pflfillfiflliflvfly
`
`tion. In