`
`United States Patent
`
`Will
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,664,231 B2
`Mar. 4, 2014
`
`US00866423lB2
`
`(54)
`
`(75)
`
`(:()N(fEN'|'RA'["El) NI]-i1TI]()'|'REXA'["|C
`SOLUTIONS
`.
`lnventor:
`lleiner Will. Hamburg (DIE)
`
`(73) Assignee: Medae Gesellsehaft fuer Klinisehe
`Spezialpl-acparal-ate mbH, Wede]
`..
`-
`-
`--
`E3ul:I_]ei:t tu any disclaimer. the term (11 this
`patent is extended or adjusted under 35
`U.S.C. 15-‘-l[l.')] by 632 days.
`
`-
`( * ) Notice:
`
`(2l] Appl. NIL:
`
`l2I‘374.,528
`
`.. .
`(22) P( 1
`
`_
`1
`_..
`I lkd‘
`
`Jul‘ 20" 2007
`
`(86) PCT N0-3
`1
`Q‘ 37]
`(CK ).-
`.x -
`(2
`(4) Date: Mar. 4.. 2009
`
`PCTl'EP200-#006491
`
`(37)
`
`p("1' pub_ Nu: w()2{||}g{|}|}9475
`
`l-’("l' Pub. Date: Jan. 24., 2ll'll'8
`
`D t
`t-
`P bf
`P '
`a 3
`"or u [ca '0“
`US 2(ll()i'Tl'l)l6326 Al
`Jan. 2|. 20] 0
`
`Foreign Applican-on Priority Data
`‘
`
`Jlll. 2l. 2006
`
`....................... ..
`
`l0 2006 033 837
`
`65
`
`(
`
`]
`
`(30)
`
`(51)
`
`(58)
`
`(200601 )
`(2006'0| )
`
`
`
`514:'262.l
`
`Int. Cl.
`Agflv 43/93
`/161K 3!/519
`(52) U.S. CI.
`USP(.'
`Field of Classification Search
`None
`See application file for Complete Search history
`
`(55)
`
`References Cited
`
`U.S. l-’A'lil ENT l)(J{.‘UMl7.N'l'S
`
`5.542.934 A "‘
`
`8.-‘"1996 Silver .......................... .. 504.-"191
`
`Ol'[ll*'.R PlJHl.l('fA'l'[()NS
`
`I-loekslra el al. (J Rheiimalul. vol. 3 I. pp. 645-548: 2004).“
`Wright et al. (International Journal of Pharmaceutics. vol. 45. Issue 3.
`abstract; I938)"
`Galinsky et al. [“Basic Phaririacnkinetics and Phannacody‘na.mics.”
`in: Remington: The Science and Practice of Pharmacy tBaltimore.
`Lippincotl \Villi:I.ms&' Wilkins. 2006). p. ] l’.-'l].‘°'
`Ja.nsen M M P M et al.. “Metliolrexale Outside the Clinic, lnlrzLmLIs—
`eular and Subcutaneous Administration to Patients with Rheumatoid
`
`l592—|596. vol.
`Arthritis" Phalmacetitiseh Weekhlail ([999) pp.
`l34{46). as recited in the lnl’l Search Report. filed Jul. 20. 200?.
`Rote Liste Service. GMBII. Rote Liste 1999!.-‘CV. L-'ditio Cantor
`V l
`..
`l
`Ll.(
`I‘
`[999 XPOD 4910
`,Ab.‘ " N . 36042.
`.‘
`reiriliéfi irfilnffi Szmih Relimn mil Jul‘ 3;,‘ 200:,i‘mLI
`U
`as
`Kurnik. D. et al.. "Bioavailability of Oral vs. Subcutaneous Low-
`Dose Methulrexale in Patients with Crohn’s Disease” Alimentary
`Pl'lfl.l'll'I§lC0l0g}" & Therapeutics
`).
`\’Ul.
`lloekstra. M. et al.. “Bioavailability oh Iligher Dose Methotrexate
`('3
`'0 lSbc.
`.‘l".‘.'
`"P"
`"h
`Ar:lh:T:S,,(.;:
`
`Vol‘ 31(4)
`Zaekheim. H. el al., “Subc.LIla.neu1isAdministration i'i['l\-"[eI.l1utrexa.te”
`J()iu'nzLl ufthe American Academy ulT)eri11a1ology (1992) pp. I008.
`"01- 26((‘)~
`_
`_
`_
`F.iiropea.n Sealcli Report dated May 4. 201 l issued In corresponding
`F.P PalenlApplic.ali0n1'o. lfl l94l45.S.
`Pharmachemie BV. Physician Package Insert. Abitrexate (1-"eh. 22.
`Ztltlfi).
`Melhotrexate I00 ingfml Injection Package Insert, Hospira UK I.lcl.
`(Jun. '3‘. 1994).
`Wright, M. P. el 31.. “Stability oflvlethotrexate Injection in Prefilled.
`Plastic Disposable Syringes” lnlemaliunal Journal ol‘Pl1annace-ulics
`(1988) pp. 23'i"—2-’-I4, vol. 45.
`0’l')ell. J .R.. “Mell10tre.‘cateUseinRheun1a1oiI:l Arthritis” Rheumatic
`Disease Clinics ol‘Norll1 America Nov. I997) pp. '?T‘)—'r’9fi, vol. 23.
`No. 4.
`Brooks. P. J. et .11.. “Pl1an'naeokinet'ics of Methotrcxate Administered
`bylntramtiseiilar and StlheulanemisInjections in Patients with Rheu-
`matoid Arthritis“ Arthritis and Rheumatism (Jan. [990] pp. 91-94.
`V0l-33.N0v 1-
`Silveniian. B. el al.. “l_e[lunomide or l\«"lel.l1oIr(-.'xa.le For Juvenile
`§i1CF1’IfltT6£;t;)::'dp.‘\.ll’é|ll§t¥llf;fiEl1:(:;c\:fi]3ngland Journal of Medicine (ADI.
`Bailis. F. M. el a.l.. “l"ha.ri11a.cokinetics oi" Siibciitaneous Metholrex—
`atc"_]0ul-nal of(_‘[in_ical0nco[ogy(Dcc_ I988) pp’ 18824886. VOL 6_
`No. I2.
`
`I5, 20] I received in curre-
`F.iiropea.n Opposition Brief dated &p.
`Lp ll-‘ztttent :’f\phpli§ation No. 2 $4: 35:12.0
`T D_ _
`I
`y
`e
`pposi Ion
`ivision
`'ng is
`ans a iono
`e ecision ISSUL
`on Nov. 19. 20 [2 in F.iirope;u1 Patent No. F.P—B—2 046 332.
`
`* cited by examiner
`S L d
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`I
`P _
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`_
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`l.ll.1 gren
`!'HlIa'f'_]’
`.\'ammer — . e re};
`As.s'isram ;"..\'miiiirer Michael Schniitt
`(74) Arrormfl.-', Agent‘. or I-inn
`Scully, Scott, Murphy &
`Presser. RC.
`
`ABS'l'RAC'I'
`(57)
`Concentrated niethotrexate solutions are described which are
`suitable for the use of an active substance in the prudtietinn u['
`a parenterally administered medicament for the treatment u['
`inflammatory autoimmune diseases. The methotrexate is
`added to a pliarmaceutically acceptable solvent at a concen-
`tration ofmore than 30 1ng.«’i11l. The invention also relates to a
`ready-made syringe and a earpule containing such a pham1a-
`ceutieal solution formulation, as well as a pen injeetur com-
`prising such a carpule andfor a ready—1nade syringe.
`
`22 Claims, ND Drawings
`
`Page 1 of 6
`Page 1 of 6
`
`ANTARES Exhibit 1001
`
`ANTARES Exhibit 1001
`
`
`
`US 8,664,231 B2
`
`1
`C()N('.'l*IN'l'RATl'Il) MIC'l'Il()TRICXATE
`SOLUTIONS
`
`The present invention relates to concentrated methotrexate
`solutions. In partictrlar, the present invention relates to the use
`of methotrexate iii the production of a parenterally adminis-
`tered medicament for the treatment of inflainniatory autoim-
`111une diseases. wherein the methotrexate is present in a phar-
`macetrtically acceptable solvent at a concentration of lnore
`tha11 25 mgfml. The invention also relates to a ready-made
`syringe a11d a carpule containing sucl1 a pharmaceutical sultr-
`tion formulation, as well as a pen injector comprising such a
`carpule andfor a ready—1nade syringe.
`The pharmaceutical active substance N-{4-[(2.4-diamir1o-
`6-pteridir1ylmethyl)methylamino] -benaoyl } -I ..-glutamic acid
`(INN: methotrexate, in short: MTX) has been known since the
`early 1950s. Methotrexate is a folic acid antagonist. As an
`antimetabolite of nucleic acid synthesis. it causes an intrac-
`ellular inhibitation of debydrofolate reductase (irreversible
`bond) with a consecutive inhibition of purine synthesis.
`inhibits LTB, synthesis in neutrophils, inhibits IL-1 synthe-
`sis. suppresses cell—n1ediated immunity and inhibits endothe-
`lial cell proliferation.
`Due to its effectiveness as a cytostatic agent, methotrexate
`has long been used predominantly in the field ofoncology. In
`particular, it was used to treat breast cancer, but also for the
`treatment ofleukemia in children. To this day, methotrexate is
`still highly significant for l.he latter indication. The effective-
`ness of methotrexate in the treat.ment of psoriasis was discov-
`ered early on. Since psoriasis can accompany rheumatoid
`arthritis, this therapy option was first observed in the late
`1950s in individual cases as well.
`
`Rhetmiatoid arthritis is usually therapeutically treated with
`fast-acting pain-relieving and short-term anti-inflammatory
`substances. In this connection. no11—steroidal antirheumatics
`(NSAR. e.g. the active substance diclofenac) and corticoids
`can be mentioned. However, these substances do not influ-
`ence t.he actual cotrrse of the disease. In most patients, NSAR
`and corticoids are only used until the pai11 and inllamnlation
`subside considerably. Then the dosage is often reduced or the
`drug is tapered completely.
`Only disease-modifying anti-rheumatic drugs {DMAR[)s)
`have a disease-modifying effect in rheumatoid arthritis. In
`addition to methotrexate, examples of these substances.
`which are also referred to as basic therapeutics. include aza-
`thioprine, sulfasalazine and anti—n1alaria substances. Basic
`therapeutics directly intervene i11 the course ofthe disease and
`can decelerate the progression of the disease, wh.ich is why
`they should be administered as early as possible. Since rheu-
`matoid arthritis is a chronic disease. the basic therapeutics
`usually have to be taken for long periods of time; ifthe drugs
`are effective and well tolerated. the treatment is ofte11 contir1-
`
`ued throughout the patients lifetitnc [continuous long-tenn
`therapy) whereby the dosage of the active substance can be
`adapted to the course of the disease.
`Contrary to chemotherapy in the treatment of tumors,
`methotrexate as a basic therapeutic in the treat1nent' of rheu-
`matoid arthritis is dosed significantly lower. sometimes up to
`1000 times lower. which is why the antirheumatic therapy is
`also referred to as “low-dosage methotrexate therapy". In
`Germany, a dosage range of 5.0 to 30.0 n1g per week is
`common Rn" antirheumatic therapy, in other liuropean coun-
`tries, dosages of up to 40.0 mg per week are administered. It
`is extremely important that methotrexate only be adminis-
`tered once a week.
`In principle, methotrexate can be administered orally and
`parenterally. l lowever, after a long time of oral therapy based
`
`S
`
`10
`
`15
`
`30
`
`40
`
`50
`
`60
`
`2
`
`on tablets, parenteral formulations are now being used since it
`has been found that methotrexate is resorbed more reliably
`from tablets and thus no sufficient accuracy can be guaranteed
`in dosagedependent
`therapy. Cytostatics
`suitable for
`parenteral administration are usually prepared by dissolving
`the active substance i11 a sttilable solvent, using a specific
`amount of active substance for each individual patient. How-
`ever. handiing cytostatics and preparing cytostatics—contain—
`ing medicaments is not without challenges and subject to
`strict legal restrictions. For example. cytostatics cannot be
`prepared outside ofa suitable venting system provided espe-
`cially for this purpose. Since rheumatologists and general
`practitioners usually do 11ot have such systems at their dis-
`posal. they are not authoriried to prepare methotrexate them-
`selves. whereby even drawing up a syringe from a brittle ( for
`example an injection bottle containing the active substance
`solution) is considered a preparation.
`For this reason. ready—made syringes were developed in
`order to eliminate this step of drawing up a syringe. lior the
`first time. the applicant in the present invention was able to
`have such ready—made syringes for subcutaneous application
`approved throughout Europe. These ready—1nade syringes
`allow the use by the physician. the medical stalf, or. in case of
`self-application, by the patient himself without a pharmacist
`having a suitable vent system at his disposal as a go-between.
`Ready—made syringes for parenteral administration con-
`taining methotrexate solutions wherein the active substance is
`present at a concentration of up to 25 mgfml in a pharmaceu-
`tically acceptable solvent (trade names: I.a1itarel-Li§?- of the
`company Wyeth. Metex® of the applicant) are known front
`the prior art for the treatment ofrheumatoid ar'thritis_. wherein
`the injection solution Lantarel'IE;‘ with the concentration 25
`mgfml (trade name: I.ztr1tarel'-i1;l- 1‘ S 25 mg) is not approved for
`subcutaneous application. Over the years, mcthotrexate has
`become the gold standard in the treatment of rheumatoid
`arthritis.
`
`As has already been described above, a successful basic
`therapy with methotrexate requires that the rheumatic patient
`be administered a suitable dose of methotrexate once a week
`over a very long period of time. sometimes throughout his
`entire lifetime. Due to its more advantageous bioavailability,
`parenteral application is superior to oral application l"'urther-
`more, children in particular exhibit a certain aversion to tak-
`ing tablets. Ilowever, it has been found that a subcutaneous
`administration in particular has its difliculties. When treated
`with the preparations known from the prior art, patients
`showed a disapproving attitude. This was due to the problem
`of having to inject the required relatively large amount of
`active substance solution {e.g. up to 3 ml in the case of a
`certain dosage) u11der the skin every week, which was espe-
`cially diflicult to convey to children, including the weekly
`doctor’s visit.
`There is therefore a need for pharmaceutical formulations
`of methotrexate which can be administered to the patient.
`including children. as easily and pain—free as possible. while
`providing good bioavailability, over a long period of time at
`regular intervals. ir1 particular weekly, which therefore leads
`to a high degree of patient compliance. As an added advan-
`tage. the patient should be able to self—ad1ninister the phar-
`maceutical formulation.
`Tl1e object underlying the present invention is therefore to
`provide a pharmaceutical formulation for the treatment‘ of
`inflammatory autoimmune diseases, in particular rheumatoid
`arthritis, which overcomes the disadvantages of the prior art
`preparations described above.
`Tl1e object underlying the present invention is achieved by
`the subject matter of the patent claims.
`
`Page 2 of 6
`Page 2 of 6
`
`
`
`US 8,664,231 B2
`
`3
`III a first embodiment, the inventio11 relates to tl1e use of
`methotrexate in the production ofa parenterally administered
`medicament for the treatment of inflarmnatory autoimmune
`disea ses. wherein the methotrexate is present in a pha rma ceu—
`tically acceptable solvent at a concentration of n1ore than 25
`mgfml.
`In another embodiment. the invention relates to a ready-
`111ade syringe containing such a pharmaceutical solution for-
`mulation of lnetholrexate in a phannaceutically acceptable
`solvent at a concentration of n1ore than 25 mgfml.
`liurthermore. in a11otl1er embodiment, the invention relates
`to a carpule containing a phamiaceutical solution fonnulation
`ofmethotrexate in a pharmaceutically acceptable solvent at a
`concentration of more than 25 mgfml. as well as a pen injector
`comprising such a carpule.
`According to the present invention, medicaments or phar-
`maceutical solution formulations are provided which com-
`prise methotrexate at a concentration of more than 25 mgfml
`in a pharmaeeutically acceptable solvent.
`In a preferred
`e111bodi1nent. the methotrexate is present in the medicament
`at a concentration ofmore than 25 mgfml to about 150 mgfml.
`Furthermore, concentration ranges of 30 mgfml
`to 100
`lng.I"ml, and in particular 40 nlgfml to 80 mgfml and further-
`more 50 mgfml to 75 nlghnl. are preferred In an especially
`preferred embodiment. the methotrexate is present in the
`medicament at a concentration ofabout 50 mgfml in a phar-
`maceutically acceptable solvent.
`All solvents which are pharrnaceutically acceptable and
`are not incompatible with t.l1e active substance or other pos-
`sible components of the medicament or the phannaceutical
`solution formulation can be used as the phannaceutically
`acceptable solvent. According to the present invention. espe-
`cially suitable solvents include water, in particular water for
`injection purposes, water comprising isotonization additives
`and sodium chloride solution. in particular isotonic sodium
`chloride solution. Water for injection purposes is especially
`preferred. Examples of isotonization additives
`include
`soluble salts (sodium ch.loride. potassium chloride). sugars
`(glucose, lactose), stlgar alcohols (mannitol, sorbitol) as well
`as combinations of these additives.
`In addition to isotonization additives, the medicament
`according to the present invention can comprise additives
`common in the field ofphamiaceutical solution fonnulations.
`ln particular. the medicament according to the present inven-
`tion can comprise additives with the following functionality:
`Eu—a’isohydration (acetate, phosphate, citrate buffers), anti-
`oxidants (ascorbic acid, sulfur compounds common i11 the
`technical field), solubility promoters (complexing agents.
`solubilizers, co—solvents: e.g. cyclodextrine. polyvidone,
`polysorbate.
`lecithin. glycocholate).
`increasing viscosity.
`adjusting pH (acids, bases, or acidic or basic salts). In an
`especially preferred embodiment, the p11 value of the 111edi-
`cament according to the present invention is between 7.5 and
`9.
`
`The medicaments according to the present invention are
`directed to the treatment of inflammatory autoimmune dis-
`eases. The term “inflammatory autoimn11n1e disease” encom-
`passes all inflammatory autoimmune diseases which can rea-
`sonably be
`treated with methotrexate. Examples of
`inflammatory autoimmune diseases which can be treated with
`the medicament according to the present invention include,
`but are not‘ limited to, rhetunatoid arthritis, juvenile arthriti-
`des. vasculitides. collagenoses, Crohn’s disease. colitis ulce-
`rosa. bronchial asthma, Alzheimer's disease. multiple sclero-
`sis. Bechterew’s disease, joint arthroses or psoriasis. as well
`as psoriasis ar1l1ritis a11d in particular plaque-type psoriasis
`vulgaris. The medicaments of tlie present invention are espe-
`
`10
`
`15
`
`30
`
`40
`
`50
`
`60
`
`4
`
`cially preferred for the treatment of rheumatoid arthritis,
`includingjuvenile arthritides. such as specifically the oligoar—
`thritic and polyarthritic forms ofjuvenile arthritis.
`The medicaments ofthe present invention are administered
`parenterally. In particular, the medicaments are administered
`by intravenous,
`intramuscular or subcutaneous injection.
`According to a preferred embodiment of the present inven-
`tion, the medicament is present in such a form which is
`suitable for subcutaneous administration. lt is furthermore
`
`preferred that the medicament be present in a form which
`allows subcutaneous self-administration by tile patient (self-
`application). Such a treatment ofsubcutaneous self—adminis—
`tration has for example proven successful in the administra-
`tion of insulin by the diabetic himself and leads to a l1.ig]1
`degree of treatment acceptance on the part of the patient
`(patient compliance). In the case of rheumatism, self—appli—
`cation also has the advantage that the weekly doctor’s visit is
`no lo11ger necessary.
`In a preferred embodiment of the present invention, the
`medicament according to the present invention is contained in
`an injection device for a single application, in particular a
`ready—n1ade syringe. According to the present invention. an
`injection device for a single application is a device which i11
`addition to a vessel containing the phannaceutical solution
`formulation according to the present invention comprises an
`injection needle (hypodermic needle) through which the
`medicament can be administered to the patient. Furthermore.
`such an injection device comprises a mechanical part (e.g. a
`stamp or a flexible bubble), by means of which the medica-
`ment can be pushed from the container through the injection
`needle. Such an injection device for a single application is
`furthermore characterized in that it contains a specific single
`dose of the active substance and thus that during application
`the vessel containing the pharmaceutical solution formula-
`tion according to the present invention has to be emptied
`completely in order to administer the prescribed dosage. Due
`to this fact, it is usually unnecessary in this embodiment to
`add a preservative to the pharmaceutical solution formulation
`of methotrexate.
`An injection device for a single application according to
`the present invention preferably contains a dose ofthe active
`substance methotrexate of 5 111g to 40 mg. It is especially
`preferred that an injection device for a single application
`according to the present invention contain a dose of 5.0. 7.5,
`10.0. 12.5. 15.0. 17.5. 20.0. 22.5. 25.0. 27.5. 30.0. 32.5. 35.0.
`37.5 or 40.0 mg. The volume of the liquid necessary to pro-
`vide the desired dose. which has to be contained in the injec-
`tion device for a single application, depends on the concen-
`tration of the active substance solution and is obvious to the
`
`person skilled in the art. Thus. in order to provide a dose of
`active substance of 30.0 mg at a methotrexate concentration
`in the pharmaceutically acceptable solve11t' of for example 50
`Ingfml. an injection device for a single application would
`have to contain a liquid volume of 0.6 ml.
`An especially preferred example ofan injection device for
`a single application according to the present invention is a
`ready-made syringe. Ready-made syringes are well-known in
`the pharmaceutical field. i11 particular also in the treatment of
`rheumatoid
`arthritis with methotrexate. Ready—made
`syringes containing methotrexate solutions with concentra-
`tions of 7.5 mgflnl, 10.0 mgflnl and 25 mgfml are already
`being distributed on the German market (trade names: Lan-
`tarel<E‘= of the company Wyeth, Metex® of the applicant.
`whereby the commercial product Lantarel® FS 25 mg is not
`approved for subcutaneous application). Although the provi-
`sion of methotrexate solutions in ready-made syringes, some
`for self-application. have had a positive impact on patient
`
`Page 3 of 6
`Page 3 of 6
`
`
`
`US 8,664,231 B2
`
`5
`
`compliance, the prior art preparations that are approved for
`subcutaneous application have the disadvantage tl1at_. depend-
`ing on the amount of active substance to be administered in
`each week, relatively large amounts of liquid have to be
`injected under the patient’s skill. In tl1e case of a common
`weekly dosage of active substance of 30 mg, this means that
`based on the currently highest concentration of active sub-
`stance solution for subcutaneous application of the prior art.
`namely l0 mg.I"ml {in the com_n1ercial product Metex® l0
`mgfml of the applicant]. a voltnne o'f 3 ml has to be injected
`under the skin. This large amount of liquid is often hard to
`convey to the patient, ir1 particular children, whicl1 leads to a
`reduced patient compliance.
`The tnedicaments provided by l.l1e present invention on the
`otherhand contain highly concentrated solutions ofthe active
`substance methotrexate which results in a reduction of the
`
`amount of liquid to be administered with a certain weekly
`active substance dosage. For example. in the case of a11 espe-
`cially preferred concentration of 50 mgJ'ml according to the
`present invention, it would be suliicient to administer a liquid
`volume ofonly 0.6 ml subcutaneously in order to keep with a
`weekly active substance dosage of30 n1g. It can be expected
`that this has a positive impact on patient compliance.
`Thus,
`in a preferred embodiment, the present invention
`provides a ready-made syringe containing a phannaceutical
`solution formulation of methotrexate at a concentration of
`
`more than 25 tngfml in a pharmaceutically acceptable sol-
`vent. Ready-made syringes are well known in the phanna-
`ceutical field a11d are not restricted iii any way in the present
`invention. Ready—n1ade syringes according to the present
`i.nvention for example also encompass disposable injection
`systems such as the Uniject\'l?;‘
`injection system.
`In one
`embodiment, the 'ady -made syringe can already be provided
`with a suitable hypodermic needle for intravenous, it1tratnus-
`cular or subcutaneous injection: in an alternative e1nbodi—
`ment. the ready—1nade syringe is at first provided with a rubber
`tip or the like which prior to application is replaced with a
`separately packaged sterile hypodermic needle by the physi-
`cian, the medical sta IT, or. in case of self-application. by tlle
`patient himself.
`Preferably,
`the ready—made syringe according to the
`present invention is designed such that it is suitable for the
`subcutaneous application of the active substance solution.
`which can be achieved by provid.ing a hypodermic needle
`suitable for subcutaneous injection. In a preferred e1nbodi—
`ment. the ready—made syringe is constructed such that even
`rheumatic patients with limited fme motor skills who may 11ot
`necessarily be able to self-inject a medicament with conve -
`tional ready—made syringes. can carry out a self'—administra—
`tion. In particular. the stamp and back stop are constructed
`and sized such that handling is facilitated for the rheumatic
`patient. Ready-made syringes with that type of design are
`known in the prior an.
`in another preferred embodiment oftl1e present invention.
`the medicament according to the present invention is con-
`tained in a storage container. A storage container according to
`the present‘ invention can be any container commonly used in
`the technical field in which the medicament or the phanna-
`ceutical solution formulation according to the present inve11—
`tion can be filled and stored professionally. i.e. in particular in
`a sterile 111a1mer. lixamples of storage containers include, bttt
`are not li111ited to. an injection bottle. a via]. a bag. a glass
`ampoule. or a carpule. According to an embodiment of the
`present invention, ir1 order to administer the medicament to
`the patient. the desired amount of phannaceutical solution
`fornmlation lirst has to be draw11 up from the storage con-
`tainer (for example an injection bottle) by means of an injec-
`
`10
`
`15
`
`30
`
`40
`
`50
`
`60
`
`6
`tio11 device (for example a conventional disposable syringe),
`while according to an alternative embodiment of the present
`invention the pharmaceutical solution formulation can be
`administered directly from the storage container (forexample
`a carpule) by means o fan injection device [for example a pen
`injector).
`In a preferred embodiment of the invention the storage
`container comprises, in addition to the active substance meth-
`otrexate dissolved in the pharmaceutical ly acceptable sol-
`vent. at least one preservative. The preservative suitable for
`use i11 the present invention is not partictllarly restricted and a
`person skilled in the art will have no difficulties selecting a
`suitable preservative frotn the preservatives commonly used
`for pharmaceutical purposes. Preferred preservatives include
`cresols. benzyl alcohols. and phenyl ethyl alcohols. The 1nain
`purpose of the preservative is to preserve the phannaceutical
`solution fonnulat ion remaining in the storage container
`according to the present invention (for example an injection
`bottle or a carpule) alter a portion ofthe medicament has been
`removed (for example by means ofa conventional disposable
`syringe or a pen injector).
`The total dosage amount of the active substance methotr-
`exate in a storage container according to the present invention
`is not particularly restricted and in addition to the used con-
`centration of methotrexate in the phannaceutically accept-
`able solvent is largely determined by the dimensions of the
`storage container and thus the amount of liquid the storage
`container can accommodate. Preferably, the storage container
`of the present invention contains a total dosage amount of 5 to
`5.000 mg methotrexate.
`A preferred example ofa storage container containing the
`medicament according to the present invention is a carpule.
`Carpules. also referred to as syringe cartridges. are well
`known in the art. To the person skilled in the an, a carpule is
`a preferably cylindrical sterile drug receptacle preferably
`tnade from glass ora preferably transparent inert plastic
`Topas<El'?). On one side of carpule cylinder there is usually a
`movable end plug. and on the other side a pierceable mem-
`brane made from rubber or a comparable elastic sealing mate-
`rial. For the application of the medicament, the pham1aceu-
`tical preparation in the carpule is pressed ottt of the carpttle
`through a hypodermic needle which pierces the rubber mem-
`brane described above by exerting pressure on the movable
`end plug with eg. an external stamp or piston.
`In another embodiment, the present invention therefore
`provides a carpule containing a pharmaceutical solution for-
`mulation ofmethotrexate at a concentration of 111ore than 25
`
`mgfml in a pharmaceutically acceptable solvent. In a pre-
`ferred embodiment, the carpule according to the present
`invention contains a total dosage amount of 5 to 500 mg.
`especially preferred 7.5 to 300 mg, of methotrexate.
`The tned_icament is preferably administered from the car-
`pule by means of an injection device. In an especially pre-
`ferred embodiment of the present invention. the carpule is
`therefore suitable for the application of the medicament via
`an injection device. Such injection devices are well known in
`the an. l-’rel‘erably.. one such injection device is a so-called pen
`injector. into which the carpttle can be inserted. Pen injectors
`usually look like large fo1mtai11 pens and are in particular
`commonly used by diabetics for comfortably injecting the
`insulin dose they require. Afier the inserted carpule has been
`emptied. a new carpule can easily be inserted in the pen
`irtiector (comparable to the replacement o'fa11 ink cartridge i11
`the fountain pen mentioned above as a comparison).
`
`Page 4 of 6
`Page 4 of 6
`
`
`
`US 8,664,231 B2
`
`7
`
`i11 another embodiment, the present invention pro-
`Thus,
`vides a pen injector comprising the above—described carpule
`of the present invention containing the medicament of the
`present invention.
`A pen injector according to the present invention is pref-
`erably designed such that it is suitable tor the subcutaneous
`application of the active substance which can ir1 particular be
`achieved by the provision ofa hypodermic needle suitable for
`subcutaneous injection. Furthermore, a pen injector accord-
`ing to tile present invention and the carpule contained therein
`are preferably designed such that multiple applications of
`single dosages can be carried out. For this purpose, a pen
`injector according to the present invention preferably com-
`prises a structural device (e.g. a control dial) by means of
`which a certain dosage o ft.he methotrexate to be administered
`can be adjusted (i.c. specifically the selection of a certain
`application volume ir1 combination with a known active sub-
`stance concentration of methotrexate in the pharmaceutical
`solution formulation) by the physician, the medical staff. or,
`in case ofself-application, by the patient himself. Thus, with
`this embodiment. the present invention also offers the possi-
`bility of selecting, if desired, intennediate dosages for which
`no other storage containers or injection devices, in particular
`no other injection bottles or ready-made syringes, are coin-
`mercially available. Pen injectors with that type of strticture
`are well known in the art. especially from the field of insulin
`injectors.
`According to a preferred embodiment of the invention. a
`pen injector according to the present invention is designed
`such that the single dosages per application can be adjusted
`from 5 to 40 mg methotrexate. In particular. a pen injector
`according to the present invention can be adjusted such that
`per application a single dosage of 5.0, 7.5. 10.0. 12.5. 15.0.
`17.5, 20.0. 22.5, 25.0, 27.5, 30.0, 32.5, 35.0, 37.5 or 40.0 mg
`can be administered.
`The invention is described in more detail in the following
`examples which are not intended to restrict the invention in
`any way:
`
`EXAMPLES
`
`lixample l
`
`The methotrexate solution described below (concentra-
`tion: 50 mgfml) was prepared from the following compo-
`nents.
`
`Mefliotrexate:
`Sodilun chloride:
`Sorlilnn hydroxide:
`Water for injection purposes:
`
`1.501."! g
`120 g
`301'] 1,;
`28.264 g
`
`Total:
`
`3u.6s4 p, = 3f1liIcrs
`
`For preparing the solution (lixample 1). about 60% of the
`required water for injection purposes (20-25" C.) was pro-
`vided in the solution vessel. The agitator was switched on and
`the amount of sodium chloride listed above was added and
`
`dissolved completely. The vessel and the solution were
`flooded with nitrogen. which essentially displaced the
`residual dissolved oxygen. The amount ofmethotrexate listed
`above was suspended in the solution while the agitator was
`running. The pH value of the solution was adjusted to a value
`between 8.5 and 8.9 using 1% sodium hydroxide solution
`(prepared from Na()I I and water for injection purposes). The
`temperature of the solution is between 20 and 30° (7. A clear
`
`Page 5 of 6
`Page 5 of 6
`
`8
`solution is obtained whose pll is stable between 8.5 and 8.9.
`The final volume was obtained by adding the remaining
`amount of water for injection purposes.
`By means ofsterile filtration through a 0.22 nm sterile filter
`the solution was tilled into the provided sterile glass recep-
`tacles ofglass type 1 (carpules or ready-made syringes) using
`protective gas (nitrogen) under clean-room conditions (class
`A).
`
`Iixamplc 2
`
`The methotrexate solution described below [concentra-
`tion: 50 mgtml) was prepared from the following coinpo—
`nents.
`
`Melllotrexate rlisutlinm:
`Sodium chloride:
`Water for injection [!IlII'|'1It.'tGUS2
`Total:
`
`1.645 g
`120 g
`arl 3tJ.684 g
`30.684 g = 30 liters
`
`I-‘or preparing the solution ffixaniple 2). about 60% of the
`required water for injection purposes [20-25" (7.) was pro-
`vided in the solution vessel. The agitator was switched on and
`the amount of sodium chloride listed above was added a11d
`
`dissolved completely. The vessel and the solution were
`flooded with nitrogen, which essentially displaced the
`residual dissolved oxygen. The amount o fmethotrexate listed
`above was dissolved in t.he solution while the agitator was
`running. The temperature of the solution is between 20 and
`30° C. The solution is clear and the pH value is stable between
`8.5 and 8.9. The final volume was obtained by adding the
`remaining amount of water for injection purposes.
`By means ofsterile filtration t.l1ro1Igh a 0.22 ],lJT] sterile filter
`the solution was filled into the provided steri