Page 1 of 6
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`Frontier Therapeutics Exhibit 1001
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`US 8,664,231 B2
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`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
`
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`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.
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`US 8,664,231 B2
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`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-
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`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
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`US 8,664,231 B2
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`5
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`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-
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`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).
`
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`US 8,664,231 B2
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`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
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`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 sterile glass recep-
`tacles ofglass type 1 (carpules or ready-made syringes) using
`protective gas (nitrogen) under cleai1—room conditions (class
`A).
`
`The invention claimed is:
`
`1 .A method for the treatment of inflammatory autoinunune
`diseases in a patient ill need thereof, comprising subcutane-
`ously administering to said patient a medicament comprising
`methotrexate in a pharmaceutically acceptable solvent at a
`concentration of 111ore than 30 mgfml.
`2. The method according to claim I. wherein the n1ethotr-
`exate is present at a concentration of more than 30 mgfml to
`100 mgtml.
`3. The method according to claim 2, wherein the inethotr—
`exate is present at a conce11tratio11 of about 50 mgfml.
`4. The method according to claim 1, wherein the phanua-
`ceutically acceptable solvent is selected from water. water for
`injection purposes. water comprising isotonization additives
`and sodium chloride solution.
`5. The method according to claim 1, wherein the infla1n-
`rnatory autoimmune disease is selected from rheumatoid
`arthritis.
`juvenile arthritides, vasculitides, collagenoses.
`Crolufs disease. colitis ulcerosa. bronchial asthma. Alzhe-
`imer’s disease. multiple sclerosis, l3echterew’s disease, joint
`arthroses, or psoriasis.
`6. The method according to claim 5, wherein the inflam-
`matory autoimmune disease is rheumatoid arthritis.
`7. The method according to claim 1. wherein the medica-
`lnent is present in a form suitable for patient self-ad.lninistra-
`tio11.
`
`15
`
`30
`
`40
`
`50
`
`60
`
`

`
`9
`8. The method according to claim 1, wherein the medica-
`ment is contained iii an injection device for a single applica-
`tion.
`
`10
`16. The method according to claim 15. wherein the single
`dosages per application can be adjusted to 5 to 40 mg each of
`methotrexate.
`
`US 8,664,231 B2
`
`17. The method according to claim 4, wherein the sodium
`chloride solution is isotonic sodium chloride solution.
`
`10
`
`18. The method according to claim 6, wherein rheumatoid
`arthritis isjuvenile rheumatoid arthritis.
`19. The method according to claim 9. wherein the injection
`device contains a dosage selected from 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 or40.0
`mg of methotrexate.
`20. The method according to claim 14. wherein the injec-
`tion device is a pen injector.
`21. The method according to claim 16, wherein the single
`dosages ofniethotrexate per application is adjusted to be 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.
`22. The method according to claim 1. wherein the meth-
`olrexate is present at a concentration of from 40 mglml to 80
`En mgfml.
`
`15
`
`9. The method according to claim 8. wherein the injection
`device contains a dosage 015 to 40 mg of methotrexate.
`10. The method according to claim 8 or 9, wherein the
`injection device is a ready-made syringe.
`11. The method according to clai111 1, wherein the medica-
`ment is contained in a storage container.
`12. The method according to claim 11. wherein the storage
`container contains a total dosage amount of 5 to 5,000 mg.
`13. The method according to claim 11. wherein the storage
`container is an injection bottle. a vial, a bag, a glass ampoule.
`or a carpule.
`14. The method according to claim 13, wherein ll1e storage
`container is a cztrpule a11d wherein said carpule is suitable for
`administering the medicalnent by means ol‘ an injection
`device.
`
`15. The method according to claim 14, wherein the carpule
`and the pen injector are provided such that multiple applica-
`tions of single dosages can be administered.
`
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