|||||||||||||||||||||||||||||||||l|l|||||||||||||l|||||||||||||||||||||||||
`
`US00848063l B2
`
`(12) United States Patent
`Wotton et al.
`
`(10) Patent No.:
`
`(45; Date of Patent:
`
`US 8,480,631 B2
`*Jul. 9, 2013
`
`(54) HAZARDOUS A(}E.\"l‘ I.\'JlC(.‘TION SYSTE.VI
`
`(55)
`
`RtJl'I3I'I3|J€9S Cited
`
`(75)
`
`Inventors: Paul Wotton. Stamtord, CT (U S): Peter
`L. S-adowsky. Woodbury, MN (US);
`John “’f]|iam “aye-§_ (‘[1agka__
`
`(73) Assignee: Antares Pharma. Im:.. l-Liwiltg. NJ (US)
`
`U -3- P/\Tl"3N'l“ DOC-‘UMl‘3N'l‘S
`4_553_69o A
`12.4955 Joyce
`5.279.543 A
`l.-1994 Glikrt-.‘lLl et ill.
`(Continued)
`_
`_‘
`j
`‘
`1
`__ .
`__
`EORl;lCrN PAI ENI DOCUMl:N"IS
`
`( * ) Notice:
`
`Subject to any disclaimer, the term ofthjs
`patent is extended or adjusted under 35
`U .S.C. l54[b) by 0 days.
`
`W0
`W0
`
`9831369
`9832451
`
`'I-' I998
`7- I998
`
`((.'o11tir1ued}
`()‘l‘[-I].£R PUl3I.,I(‘A'l‘l()NS
`
`This patent is subject to a terminal dis-
`clainter.
`
`(21) Appl.N0.:
`
`l3.r'607.659
`
`(22)
`
`l."ill:(_l:
`
`Sep. 7, 2012
`
`(65)
`
`Prim Publicathn Data
`US 2013!(}030367 A]
`Jan. 3 ] , 2013
`
`Related U-S. Application Data
`(63) Continuation ofapplication No. 1?-257.555. filed as
`application No. PCTlUS20l0l0280]l
`o11 Mar. 19.
`2010-
`(60) Pnwisimw] application N0’ m j] 61] 14‘ med on Mm,’
`20 2009,
`
`(51)
`
`Int. (:1.
`AMM 5,90
`A6“; 5,315
`(52) US. CL
`USPC
`
`(;;_006_01)
`(200601)
`
`fimnsl: 604,228: fimjzlg: 604,187.
`604K232
`
`(58) Field of Classification Search
`USPC
`604:'134—l36. 181. 18?. 218. 228.
`604K232
`
`(‘lien et al.. BM(.‘ Medicine 20} l. 9:4. htlp:.-"Fwww.biomedcentra].
`coin-"I74l-T015-'9.-"4. Blood lipid profiles and peripheral blood
`mononuclearcell cholesterol metabolism gene expression in patients
`with and without Inethtltrexale treatment.
`,
`(Conttuued)
`
`Primary" E.\‘cmu'ner — Bhisma Mehta
`A.s'.v:'.s-tcmr E.\‘atm'r:er -— Lauren M Peng
`(74) .'f!!0t‘J‘t'£’_t-‘. Agent. or firm -
`- Morgan. Iewis & Bockius
`LLP
`
`A ltazardous agent injection system including from about
`0.02 ml to about 4.0 111] ofmetliotrexate at a concentration of
`
`ll'0l11 about 7.5 mgfml to about 150 mgfml: a needle-assisted
`jet injector including a container conttgured to contain the
`methotnexate: :1 injection outlet member associated with the
`container: an injection-assisting needle coupled to the injec-
`lion outlet member; a firing mechaltism associated with the
`container; an energy source associated with the firing 111ecl1a—
`nis111; a11d a trigger mechanism associated with the firing
`mechanism. wherein the needle-assisted jet injector is con-
`tlgured to eject the methotrcxate trom the injection outlet
`member such that the CM‘. Tnm and bioavailability ofthe
`Iteedle-assistedjet injected Ittetltotrcxate falls between about
`man-'.~ I umx
`80% and about 125% of the C
`'
`‘
`and bioavailability ol‘
`ntetllotrcxate delivered by a hand-powered syringe.
`
`See application file for complete scarclt l1i story.
`
`13 Claims. 12 Drawing Sheets
`
`
`
`
`titan.-.1.
`
`_.—.a..\_
` “.2‘L“«R\
`
`
`
`
`MEDAC Exhibit 2012
`MEDAC Exhibit 2012
`Koios v. Medac
`Koios v. Medac
`IPR2016-01370
`IPR2016-01370
`Page 00001
`Page 00001
`
`

`

`US 8,480,631 B2
`Page 2
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`Al
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`cular and subcutaneous adjninistration to patients with rheumatoid
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`"‘ cited by examiner
`
`(cid:51)(cid:68)(cid:74)(cid:72)(cid:3)(cid:19)(cid:19)(cid:19)(cid:19)(cid:21)
`Page 00002
`
`

`

`US. Patent
`
`Jul. 9, 2013
`
`Sheetl of 12
`
`US 8,480,631 B2
`
`14
`
`(cid:51)(cid:68)(cid:74)(cid:72)(cid:3)(cid:19)(cid:19)(cid:19)(cid:19)(cid:22)
`Page 00003
`
`

`

`US. Patent
`
`Jul. 9, 2013
`
`Sheet 2 of 12
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`US 8,480,631 B2
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`US. Patent
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`Jul. 9, 2013
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`Us 8,480,631 B2
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`

`

`US. Patent
`
`Jul. 9, 2013
`
`Sheet 5 of 12
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`US 8,480,631 B2
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`

`US. Patent
`
`Jul. 9, 2013
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`
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`
`

`

`US. Patent
`
`Jul. 9, 2013
`
`Sheet 7 of 12
`
`US 8,480,631 B2
`
`PRESSURE
`
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`130
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`TIME
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`
`

`

`US. Patent
`
`Jul. 9, 2013
`
`Sheet 8 of 12
`
`US 8,480,631 B2
`
`Pharmacokinetic Profiles of Methotrexate in Gottingen Minipig
`Plasma Following Subcutaneous Injection of Methotrexate with
`Autoinjector or Syringe
`
`
`
`Concentration(rig/mL)
`
`1 0000.00
`
`1000.00
`
`100.00
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`Page 00010
`
`

`

`US. Patent
`
`Jul. 9, 2013
`
`Sheet 9 of 12
`
`US 8,480,631 B2
`
`Mean Pharmacokinetic Profiles of Methotrexate in Gottingen
`Minipig Plasma Following Subcutaneous injection of
`Methotrexate with Autoinjeotor or Syringe
`
`1000.00 1-,
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`Page 00011
`
`

`

`US. Patent
`
`Jul. 9, 2013
`
`Sheet 10 of 12
`
`US 8,480,631 B2
`
`Mean Pharmacokinetio Profiles of Methotrexate in Gottingen
`Minipig Plasma Following Subcutaneous Injection of
`Methotrexate with Autoinjector or Syringe
`
`10000.00 Autoinjector
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`Page 00012
`
`

`

`US. Patent
`
`Jul. 9, 2013
`
`Sheet 11 M12
`
`US 8,480,631 B2
`
`Comparison of Methotrexate Exposure(Cmax and AUC(0—t)] in
`Gottingen Minipig Plasma Following Subcutaneous Injection of
`Methotrexate with Autoinjector or Syringe
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`
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`Page 00013
`
`

`

`US. Patent
`
`Jul. 9, 2013
`
`Sheet 12 of 12
`
`US 8,480,631 B2
`
`Disclosed Autoinjector
`----- Known Autoinjector
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`39 N /201133
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`on
`
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`US 3,480,631 B2
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`1
`HAZARDOUS AGENT INJECTION SYSTEM
`
`CROSS REFERENCE TO RELATED
`APPLICATION
`
`This application is a continuation o f U .S. patent applica-
`tion Ser. No. l3!257,555, filed 6 Mar. 2012. which in turn is a
`U.S. National Stage Entry of the International Patent Appli-
`cation No. PCTt'US20l 01280} 1. filed 19 Mar. 2010. which in
`turn claims benefit of priority from 1J.S. Provisional Patent
`Application No. 6lfl62.l 14. filed 20 Mar. 2009. all ofwhich
`are incorporated by reference herein by in their entirety.
`
`FIELD
`
`The disclosure relates to injection of hazardous agents.
`
`BACKGROUND
`
`Since the late l98()’s hazardous agents. such as cytotoxic
`agents have been useful in managing and treating a nutnber of
`diseases such as rheumatoid arthritis (and other autoimmune
`diseases), juvenile rheumatoid arthritis. psoriatic arthritis,
`systemic lupus erytltematosus. steroid-resistant polymyositis
`or dennatomyositis, Wegener‘s granulomatosis. polyarteritis
`nodosa. and some forms ofvasculitis. I-lazardous agents tend
`to exhibit side effects. however. that are harmful or toxic to the
`subject. Many of these side eflects occur when hazardous
`agents are administered orally. but the oral form is generally
`the preferred method of delivery ofthese agents due to its ease
`of use.
`
`In addition to increased toxicity. variable and reduced bio-
`availability has been observed for some hazardous agents.
`such as methotrexate. that are orally administered. These
`limitations are particularly demonstrated when the oral dos-
`ing is escalated beyond 15 mg per week. It has been suggested
`that with parenteral administration. such as by injection. more
`predictable, reproducible and complete bioavailability along
`with bettertherapeutic results could be achieved. particularly
`at higher dosages.
`Only about 7% ofthe prescriptions for methotrexate writ-
`ten by rheumatologists are for an injectable fomtulation. Rea-
`sons for prescribing methotrexate injections are usually to
`improve bioavailability or to alleviate side effects. Physicians
`have expressed interest in increasing the number of prescrip-
`tions for cytotoxic agent injections. and particularly injec-
`tions for home use and administration by a patient. This is
`generally not considered feasible because it is not possible to
`ensure that patients can reliably and repeatably draw an aceti-
`rate dose from vials and correctly administer the product by
`subcutaneous (SC) injection. especially with agents used to
`treat patients suffering front certain debilitating diseases.
`Additionally. the toxicity of harardous agents increases the
`risk that non-users of the injections will come into contact
`with the cytotoxic agents in a home setting. lnsullicient data
`exists on the effect of low dose. chronic exposure to hazard-
`ous agents that are, or may be, candidates for home use or
`self-injection. 111 the absence of such 'Lnformation. practice
`guidelines direct one to assume a high degree risk for inject-
`able hazardous agents such as methouexate. with the recom-
`mendation of formal directives and risk assessments. includ-
`ing formal trainiug and mitigation strategies, to minimize risk
`(see Oliver. S.. and Livermore. P.. Adiirirristering subcutane-
`ous me!.u'2o!re.t'atef0r inflanrriratarj‘ arthritis.‘ RCN grridarice
`for mrrses. 2004: Royal College ofNursing, Wyeth, Publica-
`tion Code 002 269). Specific directives include: preparation
`of syringes in dedicated pltarmacies with aseptic preparation
`
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`areas; administration performed i11 specific locations and only
`by adequately trained personnel; spillage kits located proxi-
`mal to use areas: accounting for all who may be at risk in the
`event of an accident; and audits to assess compliance and
`execution of risk mitigation strategies. Because of the need
`for such directives. and thus the large number of precautions
`that must be learned and followed in order to safely inject a
`hazardous agent. it is presently thought that it is not practical
`for hazardous agents. and particularly methotrexate. to be
`self-injected by a patient outside of a clinical setting or widt-
`out the assistance of a health care provider.
`
`SUMMARY
`
`Thus. injector devices that allow for the safe self-adminis-
`tration ofhamrdous agents are useful. In some embodiments,
`hazardous agents can include. without
`limitation.
`toxic
`agents, cytotoxic agents, highly potent agents, agents that
`have profound physiological effects at low doses. analgesics.
`irnmunornodulating agents. IL-1 receptor antagonists. II.-2
`alpha receptor antagonists. anti—rejection compounds, hor-
`monal agents. prostaglandins.
`sedatives. anticholinergic
`agents, Pat-kinsons disease drugs, expensive agents, neuro-
`leptic agents. tissue necrosis factor ('l'Nl“) blockers. and other
`dangerous agents. Such injector devices would eliminate the
`risk of inadvertent contact of such agents to the subject and
`would also protect to non-users from exposure or Contact with
`the hazardous agent(s). Examples of cytotoxic agents
`include. without limitation. 6—rnercaptopurine. 6—thioinosinic
`acid, azathioprine, chloranibucil, cyclophosphamide, cyto-
`phosphane. cytarabine. lluorouracil. melphalan. methotrex-
`ate. uramustine. anti-cytoltine biologicals. cell
`receptor
`antagonists, cell receptor analogues, and derivatives thereof.
`lixatitples o fhighly potent agents include. without limitation.
`steroids such as dexamethasone, progesterone, somatostatin,
`and analogues thereof: biologically active peptides such as
`teriparatide: and anticholinergics such as scopolamine.
`Examples of agents that have profound physiological effects
`at low doses include. without limitation. antihypertensives
`andfor blood pressure down regulators. Examples ofanalge-
`sics include. without litnitation. fentanyl. fentanyl citrate.
`morphine, meperidine, and other opioids. Examples of
`imntunornodulating agents include. without limitation. adali—
`mumab (anti-tissue necrosis factor monoclonal antibody or
`anti-'f'l\ll7). Examples of IL-1 receptor antagonists include.
`without limitation. anakinra. Examples ofIL-2 alpha receptor
`antagonists include, without
`limitation, daclizumab and
`basilixiniab. Examples ofanti-rejection compounds include.
`without limitation, azathioprine. cyclosporine. and tacroli-
`mus. Examples of hormonal agents include, without limita-
`tion. testosterone, estrogen. growth honnone, insulin. thyroid
`homtone, follicle stimulating hormone ('1'-‘SI-I), epinephrine!
`adrenaline, progesterone. parathyroid hormone_. gonadotro-
`phi n releasing hormone (GHRHJ.
`leutinizing hormone
`releasing hormone (l.HRli). other hormones such as those
`where contact with the hormone by members of the opposite
`sex can lead to side effects, and derivatives thereof. Examples
`of prostaglandius include. without limitation. gamma—lino-
`lenic acid, docosahexanoic acid. arachjdonic acid and eicosa-
`pentaenoic acid. Exainples of sedatives include, without limi-
`tation. barbiturates such as amobarbital. pentobarbital.
`secobarbital. and plienobarbitol: benaodiazepines such as
`clonazepam.
`diazepam.
`estazolam,
`flunitrazepam.
`lorazeparn, midazolam, nitrazepam. oxazepam, triazolam.
`temazepazn, chlordiazepoxide. and alprazolam: herbal seda-
`tives such as asltwagandlta, duboisia hopwoodii. prosantltera
`striatillora. kava (piper metltysticum), mandrake, valerian.
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`US 3,480,631 B2
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`{a,k.a.
`sedatives
`non-benzodiazepine
`and marijuana:
`“Z-drugs") such as eszopielone. zaleplon. zolpideni. zopi-
`clone: antihistamines such as diphenhydramine, dime11hydri-
`nate, doxylarnine, and promethazine; and other sedatives
`such as chloral hydrate. Examples ofanticltolinergic agents
`include, without limitation, dicyclomine. atropine, ipratro-
`pium bromide. oxitropiuin bromide.
`and tiotropiunt.
`Examples of Parkinson’s disease drugs include. without iimi-
`tation. levodopa. dopamine, carbidopa. bettserazidc. co-cer-
`aldopa. co-beneldc-pa. tolcapone. entacapone. bnomocriptine.
`pergolide. pratnipexole. ropinirole. piribedil. cabergoline,
`apomorphine. and lisuride. Examples of expensive agents
`it1cludc_. without
`limitation. human growth hormone and
`erythropoietin. Examples of neuroleptic agents includes,
`without limitation. antipsychotics: butyrophenones such as
`haloperidol and droperidol: phenothiazines such as ch.lorpro-
`mazine. fluphenazine. pcrphenazine. prochlorpcrazine. t.l1ior-
`idazine,
`trifiuoperazine, mesoridazine, periciazinc, pro-
`mazine. triflupromazitie.
`levomepromazine. promethazine.
`and pirnozide: thioxanthenes such as chlorprotltixerte. clo-
`penthixol.
`flupenthixol,
`thiothixene. and zuclopenthixol;
`atypical antipsychotics such as clozapine. olanzapine. risperi-
`done, qttetiapinc, ziprasidone, amisulpride, ascnapine, pali-
`peridone.
`iloperidone, zotepine. and sertindole: and third
`generation antipsychotics such as aripiprazole and bifo-
`prunox. I-Examples ofTNF blockers includes. without limita-
`tion. etanercept.
`In some en1b-odiments, the hazardous agent can be selected
`from botulinum toxin. injectable gold. 6—n1ercaptopurine_.
`6-thioinosinic acid, azatliioprine. chlorambucil, cyclophos-
`phamidc. cytophosphane, cytarabine.
`Iluorouracil. mel-
`phalan. tnethotrexate. uramustine. anti-cytokine biologicals.
`cell receptor antagonists, cell receptor analogues, dexametha-
`sone. progesterone. somatostatiu. analogues of dexatnetha-
`sone. analogues of progesterone, analogues of sonzatostatin,
`teriparatide. soopolamine. antihypertensives. blood pressure
`down regulators. fentanyl. fentanyl citrate. inorpltine. rnep-
`eridine. other opioids. adalimumab (anti-tissue necrosis fac-
`tor monoclonal antibody or anti-TNF ). anakinra. daclizumab.
`basiliximab. azathioprine, cyclosporine,
`tacrolimus.
`test-
`osterone. estrogen. growth hormone.
`insulin. thyroid hor-
`mone.
`follicle stimulating hormone (FSH), epinephrine!
`adrenaline. gatmna—linolenic acid. docosahexanoic acid,
`aracllidonic acid. eicosapentaenoic acid. amobarbital. pento-
`barbital. secobarbital, phenobarbitol, clonazepam, diazepam,
`estazolam.
`flunitrazepam.
`lorazepain.
`midazolam.
`nitrazepam. oxazepam. triazolam. temazepam. cl1lordiazep-
`oxide. al [.'!!'87.it.1l€ll]], ashwagandha, duboisia hopwoodii, pro-
`santhera striatifiora, kava {piper methysticum). mandrake,
`valerian, marijuana, eszopiclone. zaleplon, zolpidem, zopi—
`clone.
`diphenhydramine.
`dimenhydrinate.
`doxylamine.
`promethazine, chloral hydrate. dicyclomine, atropine. iprat-
`ropium bromide, oxitropium bromide. tiotropium, levodopa,
`dopamine. earbidopa. benserazide. co-ceraldopa. co-benel-
`dopa.
`tolcapone, entacapone, bromocriptine. pergolide.
`pramipexole.
`ropinirole. piribedil. cabergoline. apomor—
`phine. lisuride, human growth hormone, erythropoietin, halo-
`peridol. droperidol, chlorpromazine. fluphenazine. perphena—
`zine.
`proclilorperazitte,
`thioridazine.
`trifluoperazine.
`mesoridazine,
`periciazine.
`promazine.
`triflupromazine.
`levomepromazine. prometllazine. pimozide. chlorprotl1ix-
`enc, clopenthixol. llupenthixol. thiothixene, zuclopenthixol.
`clozapine. oianzapine, risperidone. quetiapine. ziprasidone.
`amisulpride. asenapine. paliperidone. iloperidone, zotepine,
`sertindole, aripiprazole. bifeprttnox. etanercept. derivatives
`of any of the foregoing, and combinations of any of the
`foregoing.
`
`The hazardous agent can include a pharmaceutically
`acceptable salt, solvate. hydrate. oxide or N-oxide thereof. In
`some embodiments. the hazardous agent is a hazardous agent
`or a pharmaceutically acceptable salt. solvate, hydrate. oxide
`or N-oxide thereof. In some embodiments the 11a;/ardous
`agent is :1 compound of forrrulla (I):
`
`ll]
`
`I-[3N
`
`N
`
`NH;
`
`ll}
`
`N
`
`I
`‘Y
`X-N
`
`IK9”
`
`it./N
`
`o
`,,.lJ\
`
`"‘
`
`OR;
`
`it
`
`0
`
`0
`
`on;
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`35
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`50
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`60
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`or a pharmaceutically acceptable salt. solvate, hydrate, oxide
`or N—oxide thereof. In some embodiments. the hazardous
`agent is methotrexate.
`In one aspect. the present disclosure relates to powered
`injectors for the safe selfinjection ofone or more hazardous
`agents in less than about 5 seconds. In various aspects. the
`powered injectors may be utilized by patients to seif-inject
`hazardous agents.
`In certain embodiments,
`the powered
`injectors are needle assisted. In certain embodiments. the
`powered injectors are needle-free. In certain embodiments.
`the powered injectors may utilize pressure sufficient
`to
`deliver a therapeutically effective amount of one or more
`hazardous agents completely and quickly. in less than about 5
`seconds. In certain embodiments. the powered injectors may
`comprise a pre—filled syringe for containing the one or more
`hazardous agents.
`In certain embodiments,
`the powered
`injectors may comprise a syringe sleeve to contain the pre-
`fllled syringe and to minimize syringe movement from injec-
`tion force to decrease syringe shock. In certain embodiments.
`the powered injectors may comprise a needle exposure con-
`trol element. In certain embodiments. the powered injectors
`may comprise a safe means to prevent hazards after injection
`that may arise from the hazardous agents directly andfor from
`body fluids contacted with hazardous agents.
`in certain
`embodiments, the powered injectors may comprise a safe
`means to prevent hazards after injection that may arise from
`residual hazardous agents present in injector components that
`Contact the hazardous agents.
`In another aspect. the present disclosure relates to methods
`for safely injecting one or more hazardous agents into a
`subject. ln certain embodiments. the methods utilize a pow-
`ered injection system having a pre-filled syringe containing at
`least one hazardous agent that allows the subject to safely
`sell’-adnlinister the agent in less than about 5 seconds. In
`certain embodiments. the methods include using a spring-
`powered injection device comprising a needle with means to
`control needle exposure during the injection such that the
`exposure is sulficient to deliver one or more hazardous agents
`to the appropriate tissue site.
`I11 certain embodiments. the
`injector may have a spring sulliciently powerful to dc] ivcr one
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`US 3,480,631 B2
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`or more hazardous agems in less than about 2 seconds. In
`certain embodiments, the injector may have a syringe sleeve
`that minimizes syringe movement as a result of the injection
`spring action. In certain embodiments. the injector may have
`means for controlling needle exposure that locks following
`injection to prevent needle re-exposure. [11 certain cn1bodi-
`ments. the injector may have a liquid tight cap that covers the
`means for controlling needle exposure.
`that allows for
`removal ofthe cap when preparing injector for injection. and
`that locks to the injector when re-attached following injection
`to provide a sealed container.
`In several aspects. the present disclosure relates to an injec-
`tion system. In various aspects. the injection system com-
`prises a powered injector configured to inject one or more
`medicanrents in less than about 5 seconds. and one or more
`medicaments. In various aspects. the powered injector corn-
`prises a container configured to contain a medicament. a
`delivery member associated with the container for injecting
`the medicament. a firing mechanism configured to expel the
`medicament from the fluid chamber through the delivery
`member for injecting the medicament. an energy source asso-
`ciated with the firing mechanism to power the firing mecha-
`nism for causing the injection. and a trigger mcclianisrn asso-
`ciated with the firing mechanism to activate the firing
`mechanism. In some embodiments. the powered injector can
`be an autoinjector configured to inject one or more medica-
`ments in less than about 5 seconds. In some embodiments. the
`powered injector can be a jet injector. In some embodiments.
`the jet injector can be needle—assisted. In some embodiments.
`thejet injector can be needle-free.
`In another aspect, the present disclosure relates to an injec-
`tion system. which cart includea powered injector configured
`to inject one or more hazardous agents in less than about 5
`seconds. and one or more hazardous agents. One embodiment
`ofa powered injector has a container configured to contain a
`hazardous agent. a delivery member associated with the con-
`tainer for injecting the hazardous agent. a firing mechanism
`configured to expel the hazardous agent from the container
`through the delivery member for injecting the medicament.
`an energy source associated with the firing mechanistn to
`power the firing mechanism for causing the injection. and a
`trigger mechanism associated with the firing mechanism to
`activate the firing mechanism. The powered injector can be a
`single-shot injector. and can be pre-filled with the hazardous
`agent. or alternatively can be ftllable or take cartridges that
`can be loaded into the injector for firing. Other embodirnents
`can have adjustable dosages.
`In another embodiment. the present disclosure relates to an
`injection system which can include a jet injector and a com-
`pound of formula (1). One embodiment of a jet injector has a
`container configured to contain a hazardous agent comprising
`a compound of fomiula (I). a injection outlet member asso-
`ciated with the container and defining an injection outlet
`configured for injecting the hazardous agent. a firing Inecha-
`nism configured to expel the hazardous agent from the fluid
`chamber through the injection outlet for injecting the hazard-
`ous agent, an energy source associated with the firing mecha-
`nism to power the firing mechanisrnjet injecting the hazard-
`ous agent from the injection outlet. and a trigger niechanism
`associated with the firing mechanism to activate the firing
`mechanism. Thejet injector can be a single-shot injector. and
`can be pre-filled with the hazardous agent. or alternatively can
`be fillable or take cartridges that can be loaded into the injec-
`tor for firing. Other embodiments have adjustable dosages. In
`sortie embodiments. the hazardous agent is methotrexate or a
`pharmaeeutically acceptable salt. solvate. hydrate. oxide or
`N-oxide thereof.
`
`ll]
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`I11 another embodiment the present disclosure relates to an
`injection system for the treatment of inflammatory diseases.
`In one embodiment. the injection system includes ajet injec-
`tor and a therapeutically efiective amount of a medicament.
`wherein the therapeutically ellizctivc amount of medicament
`is suilicient to treat an inflartunatory disease. I11 one en1bodi-
`merit. thejet injector has a container configured to contain the
`medicament: an injection outlet member associated with the
`container for injecting the medicament: a firing mechanism
`configured to expel the medicament ii'on1 the fluid chamber
`through the outlet member for injecting the medicament: an
`energy source associated with the firing mechani sm to power
`the firing mechanism jet injecting the medicament from the
`injection outlet: and a trigger mechanism associated with the
`firing niecharrism to activate the firing mechauiism. In some
`embodiments. the medicament is a hazardous agent. In some
`embodiments. the medicament is rnethotrcxate or a pl1an11a-
`ceutically acceptable salt. solvate. hydrate. oxide or N-oxide
`thereof.
`In another embodiment the present disclosure relates to
`kits. In one embodiment. the kits can comprise a jet injector
`configured to inject a therapeutically effective amount ofone
`or more hazardous agents less than about 5 seconds. a thera-
`peutically effective amount of a hazardous agent. and instmc-
`lions for using the jet injector and the hazardous agent. In
`some embodiments. the jet injector comprises a container
`configured to contain the hazardous agent. an injection outlet
`member associated with the container for injecting the haz-
`ardous agent. a firing mechanism configured to expel the
`hazardous agent from the fiuid chamber through the outlet
`member for injecting the hazardous agent. an energy source
`associated with the firing mechanism to power the firing
`ntcchanism jet injecting the hazardous agent from the injec-
`tion outlet. and a triggpr mechanism associated with the firing
`mechanism to activate the firing mechanism. In one embodi-
`ment. the kits comprise a jet injector. a therapeutically effec-
`tive amount of methotrexate contained in the jet injector. and
`instructions for using the jet injector to inject the methotrex-
`ate into a subject.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`These and other objects. features and advantages of the