(12,) United States Patent
`Wotton et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,480,631 B2
`*Jul. 9, 2013
`
`US00848063lB2
`
`(54)
`
`(75)
`
`HAZARDOUS AGENT INJECTION SYSTEM
`
`(5 6)
`
`InVe11tors: Paul VVotton, Stamford, CT (US); Peter
`L. Sadowsky, Woodbury, MN (US);
`John \Villiam Ilayes, Chaska, MN (US)
`
`(73)
`
`Assignee: Antares Pharma, Inc., Ewing, NJ (US)
`
`(*)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. l54(b) by 0 days.
`This patent is subject to a temiinal dis-
`claimer.
`
`(21)
`
`Appl. N0.: 13/607,659
`
`(22)
`
`Filed:
`
`(65)
`
`Sep. 7, 2012
`Prior Publication Data
`
`US 2013/0030367 A1
`
`Jan. 31, 2013
`
`(63)
`
`(50)
`
`(51)
`
`(52)
`
`(58)
`
`Related U.S. Application Data
`Continuation of application No. 13/257,555, filed as
`application No. PCT/US2010/028011 on Mar. 19,
`2010.
`
`Provisional application No. 61/1621 14, filed on Mar.
`20, 2009.
`
`I11t. Cl.
`A61M 5/00
`A61M 5/315
`U.S. Cl.
`USPC ......... .. 604/181; 604/228; 604/218; 604/187;
`604/232
`
`(2006.01)
`(2006.01)
`
`Field of Classification Search
`USPC ............... .. 604/l34—l36, I81, 187, 218, 228,
`604/232
`See application file for complete search history.
`
`References Cited
`U.S. PATENT DOCUMENTS
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`(Continued)
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`com/I741-7015/9/4, Blood lipid profiles and peripheral blood
`mononuclear cell cholesterol metabolism gene expression in patients
`with and without methotrexate treatment.
`
`(Continued)
`Primary Fxaminer — Bliisma Mehta
`Assistant Examiner — Lauren M Peng
`(74) Anorney. Agent, or Firm — Morgan. Lewis & Bockius
`LLP
`
`ABSTRACT
`(5 7)
`A hazardous agent injection system including from about
`0.02 ml to about 4.0 ml of methotrexate at a concentration of
`from about 7.5 mg/ml to about 150 mg/ml; a needle-assisted
`jet injector including a container configured to contain the
`methotrexate; a injection outlet member associated with tl1e
`container; an injection—assisting needle coupled to the inj ec-
`tion outlet member; a firing mechanism associated with the
`container; an energy source associated witli the firing mecha-
`nism; and a trigger mechanism associated with the firing
`mechanism, wherein the needle-assisted jet injector is con-
`figured to eject the methotrexate from the injection outlet
`member such that the CTWU, Tm“ and bioavailability of the
`needle-assisted jet injected methotrexate falls between about
`80% a11d about 125% ofthe Cm”, Tm, and bioavailability of
`metholrexale delivered by a hand—powered syringe.
`13 Claims, 12 Drawing Sheets
`
`
`
` nun.‘
`
`
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`,1|‘
`
`
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`
`
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`
`
`
`
`Medac Exhibit 2013
`
`Frontier Therapeutics v. Medac
`IPR2016-00649
`
`Page 00001
`
`Medac Exhibit 2013
`Frontier Therapeutics v. Medac
`IPR2016-00649
`Page 00001
`
`

`

`US 8,480,631 B2
`Page 2
`
`7,218,962
`7,292,885
`7,488,313
`7,488,314
`7,517,342
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`7,762,996
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`2005/0240145
`2007/0025890
`2007/0185432
`2009/0204062
`2009/0304812
`2010/0016326
`2010/0152702
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`2012/0095443
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`U.S. PATENT DOCUMENTS
`B2
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`B2
`7/2010
`B2
`1 1/201 1
`B2
`4/2012
`A1
`12/2004
`A1
`10/2005
`A1
`2/2007
`A1
`8/2007
`A1
`8/2009
`A1
`12/2009
`A1*
`1/2010
`A1
`6/2010
`A1
`6/2010
`A1
`4/201 1
`A1
`5/201 1
`A1
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`A1
`4/2012
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`7/2012
`A1
`8/2012
`
`Freyman
`Scott et al.
`Segal et al.
`Segal et al.
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`Joshi et al.
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`Julian et al.
`Uhland et a1
`Kraft ct al.
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`Fcrrari ct al.
`Drapeau et al.
`Sclz ct al.
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`FOREIGN PATENT DOCUMENTS
`9962525
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`WO 2006079064 A1 *
`WO 2007131025 A1 * 11/2007
`2008009476
`1/2008
`
`VVO
`WO
`VVO
`VVO
`VVO
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`OTHER PUBLICATIONS
`Reiss et al., Arthritis & Rheumatism, vol. 58, No. 12, Dec. 2008, pp.
`3675-3683, DOI 10.1002/art.24040. © 2008, American College of
`Rheumatology, Atheroprotective Effects of Methotrexate on Reverse
`Cholesterol Transport Proteins and Foam Cell Transformation in
`Human THP-1 Monocyte/Macrophages.
`Westlake et al., The effect of methotrexate on cardiovascular disease
`in patients with rheumatoid arthritis: a systematic literature review,
`Rheurnatology
`2010;
`49:295—307,
`doi:10.1093/rheumatology/
`kep366, Advance Access publication Nov. 17. 2009
`Hoekstra et al., Bioavailability of higher does methotrexate compar-
`mg oral and subcutaneous administration in patients with rheumatoid
`arthritis, The Journal of Rheurnatology, vol. 31, No. 4, J Rheumatol
`2004;3l;645-648, hllp://wwwfirheum.org/conlenl/3l/4/645.
`Zachheim et al., Subcutaneous administration of methotrexate, Jour-
`nal ofthe American Academy of Dermatology, vol. 26. No. 6, Jan. 1.
`1992, p. 1008.
`Kurnik et al., Bioavailability of oral vs. subcutaneous low-dose
`methotrexate in patients with Crohn’s disease, Aliment Pharmacol
`Ther 2003: 18: 57-63. doi 10.1046/j.0269-2813.2003.01614.x, Apr.
`22, 2003.
`Bonetti et al., An extended-release formulation of methotrexate for
`subcutaneous administration, Cancer Chemother Pharmacol (1994)
`33: 303-306.
`Jansen M M P M et al: “Methotrexate outside the clinic, intramus-
`cular and subcutaneous administration to patients with rhcurr1atoid
`arthritis” Pharrnaceutisch Weekblad 19991119 NL, vol. 134, No. 46.
`Nov. 19, 1999, pp. 1592-1596.
`
`* cited by examiner
`
`Page 00002
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`

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`U.S. PatentU.S. Patent
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`
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`Jul. 9, 2013Jul. 9, 2013
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`
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`Sheet 1 of 12Sheet 1 0f 12
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`
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`US 8,480,631 B2US 8,480,631 B2
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`12
`
`14
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`
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`Page 00003
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`Page 00003
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`U.S. Patent
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`Jul. 9, 2013
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`21f02t6ehS
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`US 8,480,631 B2
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`U.S. Patent
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`Jul. 9, 2013
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`21f03t6ehS
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`US 8,480,631 B2
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`U.S. Patent
`
`Jul. 9, 2013
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`US 8,480,631 B2
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`

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`U.S. Patent
`
`Jul. 9, 2013
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`21f05t6ehS
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`US 8,480,631 B2
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`Page 00007
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`U.S. Patent
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`Jul. 9, 2013
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`21f0/Dt6ehS
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`US 8,480,631 B2
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`U.S. PatentU.S. Patent
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`
`
`Jul. 9, 2013Jul. 9, 2013
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`
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`Sheet 7 of 12Sheet 7 0f 12
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`
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`US 8,480,631 B2US 8,480,631 B2
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`
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`
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`Page 00009
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`

`

`U.S. Patent
`
`Jul. 9, 2013
`
`Sheet 8 of 12
`
`US 8,480,631 B2
`
`
`
`Concentration(ng/mL)
`
`
`
`Concentration(ng/mL)
`
`Pharmacokinetic Profiles of Methotrexate in Gottingen Minipig
`Plasma Following Subcutaneous Injection of Methotrexate with
`Autoinjector or Syringe
`
`10000-00 Autoinjector
`
`"‘ 35196273
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`-A— 85195757
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`
`Time (h)
`
`F|G.12
`
`Page 00010
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`

`

`U.S. Patent
`
`Jul. 9, 2013
`
`Sheet 9 of 12
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`US 8,480,631 B2
`
`Mean Pharmacokinetic Profiles of Methotrexate in Gottingen
`Minipig Plasma Following Subcutaneous Injection of
`Methotrexate with Autoinjector or Syringe
`
`10000-00 Autoinjector
`
`-0- Males (Day 1)
`
`-0- Females (Day 8)
`
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`
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`
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`
`Page 00011
`
`

`

`U.S. 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 Autolnjector or Syringe
`
`10000-00 Autoinjector
`
`
`
`
`
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`
`
`
`
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`
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`
`Page 00012
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`

`

`U.S. Patent
`
`Jul. 9, 2013
`
`Sheet 11 of 12
`
`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
`
`EIJAutoinjector
`El Syringe
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`
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`
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`
`F|G.15
`
`Page 00013
`
`

`

`U.S. Patent
`
`Jul. 9, 2013
`
`Sheet 12 of 12
`
`US 8,480,631 B2
`
`89N/20|bs
`
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`
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`
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`
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`
`

`

`US 8,480,631 B2
`
`1
`HAZARDOUS AGENT INJECTION SYSTEM
`
`CROSS REFERENCE TO RELATED
`APPLICATION
`
`This application is a continuation of U.S. patent applica-
`tion Scr. No. 13/257,555, filcd 6 Mar. 2012, which in turn is a
`U.S. National Stagc Entry of the International Patent Appli-
`cation N o. PC'l'/U S2010/28011, filcd 19 Mar. 2010, which in
`turn claims bcncfit of priority from U.S. Provisional Patent
`Application No. 61/162,114, filed 20 Mar. 2009, all ofwhich
`are incorporated by reference herein by i11 their entirety.
`
`FIELD
`
`The disclosure relates to injection of hazardous agents.
`
`BACKGROUND
`
`Since the late 1980’s hazardous agents, such as cytotoxic
`agents have been useful in managing and treating a number of
`diseases such as rheumatoid arthritis (and other autoimmune
`diseases), juvenile rheumatoid arthritis, psoriatic arthritis,
`systemic lupus erythematosus, steroid—resistant polymyositis
`or dermatomyositis, Wege11er’s granulomatosis, polyarteritis
`nodosa, and some forms of vasculitis. Hazardous agents tend
`to exhibit side effects, however, that are harmful or toxic to the
`subject. Many of these side effects 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 incrcascd toxicity, variable and rcduccd bio-
`availability has been observed for some hazardous agents,
`such as mcthotrcxatc, that are orally administered. Thcsc
`lin1itatio11s arc particularly dcmonstratcd 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 better therapeutic results could be achieved, particularly
`at higher dosages.
`Only about 7% of the prescriptions for methotrexate writ-
`ten by rheumatologists are for an inj ectable formulation. 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 fea sible because it is not possible to
`ensure that patients can reliably and repeatably draw an accu-
`rate dose from vials and correctly administer the product by ,
`subcuta11eous (SC) injection, especially with agents used to
`treat patients suffering from certain debilitating diseases.
`Additionally, the toxicity of hazardous agents increases the
`risk that non-users of the injections will come into contact
`with the cytotoxic agents in a home setting. Insufficient 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. In the absence of such information, practice
`guidelines direct one to assume a high degree risk for inject-
`able hazardous agents such as methotrexate, with the recom-
`mendation of formal directives and risk assessments, includ-
`ing formal trai11ing and mitigation strategies, to minimize risk
`(see Oliver, S., and Livermore, P., Administering subcutane-
`ous methotrexatefor inflammatory arthritis: RCN guidance
`for nurses, 2004; Royal College of Nursing, Wyeth, Publica-
`tion Code 002 269). Specific directives include: preparation
`of syringes in dedicated pharmacies with aseptic preparation
`
`2
`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 n1ust 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 with-
`out the assistance of a health care provider.
`
`SUMMARY
`
`Thus, injector devices that allow for the safe self-adminis-
`tration ofhazardous 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,
`immunomodulating agents, IL-1 receptor antagonists, IL-2
`alpha receptor antagonists, anti-rejection compounds, hor-
`monal agents, prostaglandins,
`sedatives, anticholinergic
`agents, Parkinsons disease drugs, expensive agents, neuro-
`leptic agents, tissue necrosis factor (TNF) blockers, a11d 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—mercaptopuri11e, 6—thioino sinic
`acid, azathioprine, chlorambucil, cyclophosphamide, cyto-
`phosphane, cytarabine, fiuorouracil, melphalan, metl1otrex—
`atc, uramustinc, anti-cytokinc biologicals, ccll
`rcccptor
`antagonists, cell receptor analogues, and derivatives thereof.
`Examples ofhighly potent agcnts include, without limitation,
`stcroids such as dcxamcthasonc, progcstcronc, 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
`and/or blood pressure down regulators. Exarnp es of analge-
`sics include, without limitation, fenta11yl, fentanyl citrate,
`morphine, meperidine, and other opioids. Examples of
`immunomodulating agents include, without limitation, adali-
`mumab (anti-tissue necrosis factor monoclonal antibody or
`. anti-TNF‘). Examples of ll.-l receptor antagonists include,
`without limitation, anakinra. Examples ofIL-2 alpha receptor
`antagonists include, Without
`limitation, daclizumab and
`basiliximab. Examples of anti-rejection compounds include,
`without limitation, azatl1iopri11e, cyclosporine, and tacroli-
`mus. Examples of hormonal agents include, without limita-
`tion, testosterone, estrogen, growth hormone, insulin, thyroid
`hormone, follicle stimulating hormone (FSH), epinephrine/'
`adrenaline, progesterone, parathyroid hormone, gonadotro-
`phi11 releasing hormone (GHRH),
`leutinizing hormone
`releasing hormone (LHRH), other hormones such as those
`where contact with the hormone by members of the opposite
`sex ca11 lead to side effects, and derivatives thereof. Examples
`of prostaglandins include, without limitation, garnma-lino-
`lenic acid, docosahexanoic acid, arachidonic acid and eicosa-
`pentaenoic acid. Examples of sedatives include, wit iout limi-
`tation, barbiturates
`such as amobarbital, pentobarbital,
`secobarbital, and phenobarbitol; benzodiazepines such as
`clonazepam,
`diazepam,
`estazolam,
`fiuni razepam,
`lorazepam, midazolam, nitrazepam, oxazepam, triazolam,
`temazeparn, chlordiazepoxide, and alprazolam; herbal seda-
`tives such as ashwagandha, duboisia hopwoodii, prosanthera
`striatifiora, kava (piper methysticum), mandrake, Valerian,
`
`,
`
`Page 00015
`
`

`

`US 8,480,631 B2
`
`3
`(a.k.a.
`sedatives
`11on-benzodiazepine
`a11d marijuana;
`“Z-drugs”) such as eszopiclone, zaleplon, zolpidem, zopi-
`clone; antihistamines such as diphenhydramine, di1nenhydri-
`nate, doxyla111i11e, and promethazine; and otl1er sedatives
`such as chloral hydrate. Examples of anticholinergic agents
`include, witl1out lin1itation, dicyclon1ine, atropine, ipratro-
`pium bromide, oxitropium bromide,
`and tiotropiun1.
`Exan1ples ofParkinson’s disease drugs include, without limi-
`tation, levodopa, dopamine, carbidopa, benserazide, co-cer-
`aldopa, co-beneldopa, tolcapone, entacapone, bromocriptine,
`pergolide, pramipexole, ropinirole, piribedil, cabergoline,
`apomorphine, and lisuride. Examples of expensive agents
`include, without limitation, human growth hormone and
`erythropoietin. Examples of neuroleptic agents includes,
`without limitation, antipsychotics; butyrophenones such as
`haloperidol and droperidol, phenothiazines such as chlorpro-
`mazine, fluphenazine, perphenazine, prochlorperazine, thior-
`idazine,
`trifluoperazine, mesoridazine, periciazine, pro-
`mazine, triflupromazine,
`levomepromazine, promethazine,
`a11d pimozide, thioxanthenes such as chlorprothixene, clo-
`penthixol,
`flupenthixol,
`thiothixene, and zuclopenthixol;
`atypical a11tip sychotics such as clozapine, olanzapine, risperi-
`done, quetiapine, ziprasidone, amisulpride, asenapi11e, pali-
`peridone,
`iloperidone, zotepine, a11d sertindole, and third
`generation antipsychotics such as aripiprazole and bife—
`prunox. Examples of TNF blockers includes, without lin1ita—
`tion, etanercept.
`In some embodiments. the hazardous agent can be selected
`from botulinum toxin,
`injectable gold. 6—n1ercaptopurine,
`6—thioi11osinic acid, azathioprme, chlorambucil, cyclophos—
`phamide. cytophosphane. cytarabine.
`fluorouracil, mel-
`phalan, methotrexate, uramustine, anti-cytokine biologicals,
`cell receptor antagonists, cell receptor analogues, dexarnetha—
`sone, progesterone, somatostatin, analogues of dexarnetha-
`sone, analogues of progesterone, analogues of somatostatin,
`teriparatide, scopolamine, antihypertensives, blood pressure
`down regulators, fentanyl, fentanyl citrate, morphine, mep-
`eridine, other opioids, adalimumab (anti-tissue necrosis fac-
`tor monoclonal antibody or anti-TNF), anakinra, daclizumab,
`basiliximab, azathioprine, cyclosporine,
`tacrolirnus,
`test-
`osterone, estrogen, growth hormone,
`insulin, thyroid hor-
`mone,
`follicle stimulating hormone (FSII), epinephrine’
`adrenaline, gamma-linolenic acid, docosahexanoic acid,
`arachidonic acid, eicosapentaenoic acid, amobarbital, pento-
`barbital, secobarhital, phenobarbitol, clonazepam, diazepam,
`estazolam,
`fiunitrazepam,
`lorazepam,
`midazolam,
`nitrazepam, oxazepam, triazolam, temazepam, chlordia7ep-
`oxide, alprazolan1, asl1wagandl1a, duboisia hopwoodii, pro-
`santl1era striatiflora, kava (piper methysticum), 111a11drake,
`Valerian, marijuana, eszopiclone, zaleplon, zolpiden1, zopi-
`clone,
`diphenhydramine,
`dimenhydrinate,
`doxylamine,
`promethazine, chloral hydrate, dicyclomine, atropine, iprat-
`ropium bromide, oxitropium bromide, tiotropium, levodopa,
`dopamine, carbidopa, benserazide, co-ceraldopa, co-benel-
`dopa,
`tolcapone, entacapone, bromoeriptine, pergolide,
`pramipexole,
`ropinirole, piribedil, cabergoline, apomor-
`phine, lisuride, human growth hormone, erythropoietin, halo-
`peridol, droperidol, chlorpromazine, fluphenazine, perpl1ena-
`zine,
`prochlorperazine,
`thioridazine,
`trifluoperazine,
`mesoridazine,
`periciazine,
`promazine,
`triflupromazine,
`levomepromazine, promethazine, pimozide, chlorprothix-
`e11e, clopenthixol, flupenthixol, thiothixene, zuclopenthixol,
`clozapine, olanzapi11e, risperidone, quetiapine, ziprasidone,
`amisulpride, asenapine, paliperidone, iloperidone, zotepine,
`sertindole, aripiprazole, bifeprunox, etanercept, derivatives
`of any of the foregoing, and combinations of any of the
`foregoing.
`
`4
`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 hazardous
`agent is a compound of formula (I):
`
`OR3
`
`.
`
`.
`
`.
`
`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 self injection of one or more hazardous
`agents in less than about 5 seconds. I11 various aspects, the
`powered injectors may be utilized by patients to self-inject
`hazardous agents. In certain embodiments,
`the powered
`injectors are needle assisted.
`I11 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-
`filled 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 i11j ection
`that may arise fron1 the hazardous a gents directly and/or fron1
`body lluids 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. In 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
`self-administer 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
`expo sure is sufficient to deliver one or n1ore hazardous agents
`to the appropriate tissue site. In certain embodiments, the
`injector may have a spring sufficiently powerful to deliver one
`
`Page 00016
`
`

`

`US 8,480,631 B2
`
`5
`or more hazardous agents 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. I11 certain embodiments, the injector may have
`means for controlling needle exposure that locks following
`injection to prevent needle re-exposure. In certain embodi-
`r11ents, the injector may have a liquid tight cap that covers the
`means for controlling needle exposure,
`that allows for
`removal of the cap wl1er1 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
`medicarnents in less than about 5 seconds, and one or more
`medicarnents. In various aspects, the powered inj ector com-
`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 mechanism asso-
`ciated with the firing mechanism to activate the firing
`mechanism. In some embodiments, the powered injector can
`be an autoiru ector configured to inject one or more medica-
`ments in less than about 5 seconds. In some embodiments, the
`powered injector ca11 be a jet injector. In some embodiments,
`the jet injector can be 11eedle—assisted. In some embodiments,
`the jet injector can be needle—free.
`In another aspect, the present disclosure relates to an injec-
`tion system, which can include a powered injector configured
`to inject one or more hazardous agents in less than about 5
`seconds, and one or more hazardous agents. One embodiment
`of a powered injector has a co11tainer 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,
`a11 energy source associated with the firing mechanism 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 fillable or take cartridges that
`can be loaded into the injector for firing. Other embodiments
`can have adjustable dosages.
`In another embodiment, the present disclosure relates to ar1
`injection system wl1icl1 ca11 include a jet injector and a co111-
`pour1d of formula
`One embodiment of a jet injector l1as a
`container configured to contain a hazardous agent comprising
`a compound of formula (I), a injection outlet member asso-
`ciated with the container and defining an injection outlet
`configured for injecting the hazardous agent, a firing mecha-
`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 mechanism jet injecting the hazard-
`ous agent from the injection outlet, and a trigger mechanism
`associated with the firing mechanism to activate the firing
`mechanism. The jet 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 do sages. In
`some embodiments, the hazardous agent is methotrexate or a
`pharmaceutically acceptable salt, solvate, hydrate, oxide or
`N—oxide thereof.
`
`6
`In another embodiment the present disclosure relates to an
`injection system for the treatment of inflammatory diseases.
`In one embodiment, the injection system includes a jet injec-
`tor and a therapeutically effective amount of a medicament,
`wherein the therapeutically effective amount of medicament
`is suflicient to treat a11 inflammatory disease. In one embodi-
`ment, thejet inj ector 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 from the fluid chamber
`through the outlet member for i11j ecti11g the medicament; an
`energy source associated with the firing mechanism to power
`the firing mechanism jet injecting the medicament fror11 the
`injection outlet; and a trigger mechanism associated with the
`firing mechanism to activate the firing mechanism. In some
`embodiments, the medicament is a hazardous agent. In some
`embodiments, the medicament is methotrexate or a pharrna-
`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 ajet injector
`configured to ir1j ect a therapeutically effective amount of one
`or more hazardous agents less than about 5 seconds, a thera-
`peutically eflective amount ofa hazardous agent, and instruc-
`tions 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 fluid chamber through the outlet
`member for injecting the hazardous agent, an energy source
`associated with the firing mechanism to power the firing
`mechanism jet injecting the hazardous agent from the injec-
`tion outlet, ar1d a trigger 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 r11et.hotrexate 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
`. disclosure will be apparent from a consideration of the fol-
`lowing non-limiting detailed description considered in con-
`junction with the drawing figures, in which:
`3IG. 1 is a side view of ar1 injection device according to ar1
`embodiment of the present disclosure;
`3IG. 2 is a cross-sectional view of the injection device of
`FIG. 1 i11 a safety state taken along lir1e A-A;
`3IG. 3 is an enlarged view of a portion of the cross-section
`shown in FIG. 2;
`3IGS. 4A and 4B are perspective views ofa safety member
`used in connection with the injection device of FIG. 1;
`3IG. 5 is a11 additional cross-sectional view oftlie device of
`FIG. 1 iii the safety state;
`3IG. 6A is a cross-sectional view ofthe injection device of
`FIG. 1 iii a ready state;
`3IG. 6B is a cross-sectional view of the injection device of
`FIG. 1 at the start of an injection state;
`3IG. 6C is a cross-sectional view of the injection device of
`FIG. 1 at the end of an injection state;
`3IG. 6D is a cross-sectional view ofthe injection device of
`FIG. 1 iii a locked state;
`3IG. 7 is an exploded view of a portion of the trigger
`mechanism associated with the injection device of FIG. 1;
`
`Page 00017
`
`

`

`US 8,480,631 B2
`
`7
`FIG. 8 is a perspective View of a needle guard according to
`an embodiment of tl1e injector of FIG. 1;
`FIG. 9 is a cross-sectional View ofthe cap shown in FIG. 1;
`FIG. 10 is a graph showing the pressure within the liquid
`cl1amber of an embodiment of an injection device according .
`to the present disclosure, as a function of time;
`FIG. 11 is a cross-sectional view of a needle-free jet injec-
`tion nozzle;
`FIG. 12 shows the pharrnacokinetic profiles of methotrex-
`ate i11 Gottingen minipig plasma following subcutaneous
`injection of methotrexate with an embodiment of an autoin-
`jector of the present disclosure as compared to a known
`hypodermic syringe;
`FIG. 13 shows the mean pharmacokinetic profiles ofmeth-
`otrexate in Gottingen minipig plasma following subcutane-
`ous injection of methotrexate with an embodiment of an
`autoinj ector ofthe present disclosure as compared to a known
`hypodermic syringe;
`FIG. 14 shows further mean pharmacokinetic profiles of
`mcthotrcxatc in Gottingen minipig plasma following subcu-
`taneous injection of methotrexate with an embodiment of an
`autoinj cctor ofthe present disclosure as compared to a known
`hypodermic syringe;
`FIG. 15 shows a comparison of metl1otrexate exposure
`(Chm andAU