Case 1:14-cv-01498-JBS-KMW Document 28-13 Filed 07/11/14 Page 1 of 11 PageID: 293
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`Exhibit 9
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`Case 1:14-cv-01498-JBS-KMW Document 28-13 Filed 07/11/14 Page 2 of 11 PageID: 294
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`7/212014
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`Patent EP2046332B1- Concentrated methotrexate solutions- Google Patents
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`ep 2046332
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`Application
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`Grant I [ English
`
`French
`
`German
`
`Concentrated methotrexate solutions
`EP 2046332 81
`
`ABSTRACT
`
`W02008009476A2
`
`The invention relates to concentrated methotrexate solutions containing an active
`substance for the production of a parenterally administered medicament for the
`treatment of inflammatory autoimmune diseases The methotrexate is added to a
`pharmaceutically compatible solvent, in a concentration of more than 25mg/ml
`The invention also relates to a ready-made syringe, a carpule containing such a
`pharmaceutical solution formulation, and a pen injector comprising such a carpule
`and/or a ready-made syringe.
`
`DESCRIPTION
`
`German
`
`(0001] The present invention relates to concentrated solutions of methotrexate.
`In particular the present invention relates to the use of methotrexate in
`the preparation of a medicament to be administered subcutaneously for
`the treatment of inflammatory autoimmune diseases, wherein the
`methotrexate is present in a concentration of about 50 mg I ml in a
`pharmaceutically acceptable solvent
`[0002] The active pharmaceutical ingredient N-{4- [(2,4-diamino-6-
`pteridinylmethyl) methyl] benzoyi}-L-glutamic acid (generic name:
`methotrexate, briefly: MD<) has been known since the early 50s.
`Methotrexate is a folic acid antagonist. It causes as the antimetabolite
`Nukleuisauresynthese intracellular inhibition of dehydrofolate reductase
`(irreversible binding) with subsequent inhibition of purine synthesis,
`inhibits LTB 4 synthesis in neutrophils, inhibits IL-1 synthesis,
`suppressed cell-mediated immunity. and inhibits endothelial cell
`proliferation.
`(0003] Methotrexate has been used for a long time due to its preference as a
`cytostatic effect in oncology. Here it was used in particular for breast
`cancer, but also for the treatment of children with leukemia . For the
`latter indication methotrexate is still crucial. Early on was also the
`efficacy of methotrexate in psoriasis noticed As the psoriasis may be
`associated with rheumatoid arthritis also own, and this was as a
`treatment option late 50s first observed in isolated cases.
`[0004] Rheumatoid arthritis is usually first treated therapeutically with fast pain
`relieling and anti-inflammatory substances in the short term. For this
`purpose, non-steroidal anti-inflammatory drugs (NSAIDs, such as
`diclofenac) and corticosteroids may be mentioned. However, this does
`not affect the actual course of the disease. In most patients, NSAIDs
`and corticosteroids are only so long used to the inflammation and pain
`subside significantly. Then the dose is often reduced or the drug
`completely phased out.
`[0005] A disease-modifying effect in rheumatoid arthritis. Only the disease
`modifiying anti rheumatic drugs (DMARD's) As examples of this, also
`known as "DMARDs" agents with methotrexate may also azathioprine,
`sulfasalazine, and antimalarial drugs are called. DMARDs directly
`intervene in the disease process and can slow the disease process, so
`that a possible early application is desirable. Since rheumatoid arthritis
`is a chronic disease that DMARDs are usually taking over sufficiently
`
`View PDF
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`
`Publication number
`Publication type
`Application number
`Publication date
`Filing date
`Priority date
`
`EP2046332 81
`Grant
`EP20070786239
`Dec 15, 2010
`Jul 20, 2007
`Jul 21, 2006
`
`Also published as
`
`CA2659662A 1, 9 More ,
`
`Inventors
`
`Applicant
`
`Heiner Will
`
`medac Gesellschaft fur klimsche
`Spezialpraparate mbH
`
`Ex port Citation
`
`BiBTeX, EndNote, ReiMan
`
`Classifications (15), Legal Events (40)
`
`External Links: Espacenet, EP Register
`
`CLAIMS
`
`1. Use of methotrexate for the production of a medicament to be administered
`subcutaneously for the treatment of inflammatory autoimmune diseases,
`wherein the methotrexate is present in a pharmaceutically acceptable
`solvent at a concentration of about 50 mg/ml.
`
`2. Use according to claim 1, wherein the pharmaceutically
`acceptable solvent is selected from water, water for injection
`purposes, water comprising isotonization additives and sodium
`chloride solution, in particular isotonic sodium chloride solution.
`
`3. Use according to any of the preceding claims, wherein the
`inflammatory autoimmune disease is selected from rheumatoid
`arthritis, ju-.enile arthritides, vasculitides, collagenoses. Grahn's
`disease. colitis ulcerosa, bronchial asthma. Alzheimer's disease,
`multiple sclerosis, Bechterew's disease, joint arthroses, or
`psonas1s
`
`4. Use according to claim 3. wherein the inflammatory autoimmune
`disease is rheumatoid arthritis. in particular ju~.enile rheumatoid
`arthritis.
`
`5. Use according to any of the preceding claims, wherein the
`medicament IS present in a form suitable for patient self(cid:173)
`administration
`
`6. Use according to any of the preceding claims. wherein the
`medicament is contained in an injection delice for a single
`application
`
`7. Use according to claim 6, wherein the injection deloice is a ready(cid:173)
`made syringe
`
`8. Use according to any of claims 1 to 5, wherein the medicament is
`contained in a storage container
`
`9. Use according to claim 8, wherein the medicament furthermore
`
`comprises a preservati~.e .
`
`10. Use according to any of claims 8 or 9. wherein the storage
`container is an 1n1ection bottle, a vial. a bag, a glass ampoule, or
`
`https:/f.Mwl.g oog le.cornlpatents/EP2046332B1 ?cl= en&dq =ep+ 2046332&hl =en&sa= X&ei= BB60U9PpKui msQTf34CABQ&\€d= OC C EQ6AEwAA
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`long periods of time, with good efficacy and tolerability of the therapy is
`often continued for life (long-term continuous therapy), the drug dose
`
`can be adapted to the disease process
`
`[0006]
`
`In contrast to chemotherapy in cancer patients is methotrexate. As a
`
`basic therapeutic for the treatment of rheumatoid arthritis is many times,
`
`sometimes up to 1 000-fold dose low, so we also speak at the
`
`antirheumatic therapy of the "low-dose methotrexate therapy" The
`
`antirheumatic therapy in Germany, a dose range of 5 0 to 30 0 mg per
`
`week is common in other European countries is dosed up to 40.0 mg
`
`per week . It is very important that methotrexate is only given once a
`week ,
`
`[0007] The application of methotrexate can in principle be as orally and
`parenterally However, the first orally via tablets for a long time was
`
`therapy was replaced by parenteral formulations , since it has been
`
`established that methotrexate is absorbed from tablets unreliable and
`
`therefore no sufficient accuracy is ensured with the dose-dependent
`therapy. Suitable for parenteral administration are usually cytotoxic
`
`drugs prepared by dissolving the active ingredient in a suitable solvent,
`
`for each individual patient by using a specific amount of active
`ingredient The handling of cytotoxic drugs and the formulation
`
`containing cytostatic drugs is not without problems and the legislature
`
`provided with strict conditions . For example, cytotoxic drugs may carry
`
`out a suitable and specially created for this extraction system is not
`
`prepared. As rheumatologists and primary care physicians have usually
`
`do not have such facilities, it is not permitted to methotrexate making
`
`facilities, where already the rearing of a syringe from a bottle (for
`
`example, a piercing surface, which contains the active ingredient
`
`solution) is seen as preparation.
`[0008] For this reason, pre-filled syringes are designed to eliminate the step of
`
`winding. First corresponding pre-filled syringes for subcutaneous
`administration for the present applicant has been appro-.ed throughout
`
`Europe. With these pre-filled syringes, the application by the physician,
`
`medical personnel or, in the self-application, it is possible by the patient
`
`himself without the need of an intermediate pharmacist needs, which
`
`has a suitable discharge system
`
`a carpule.
`
`11. Use according to claim 1 o. wheretn the storage container is a
`
`carpule and wherein said carpule is suitable for administering the
`
`medicament by means of an mjection device, in particular a pen
`
`injector
`
`12. Use according to cla1m 11. wherein the carpule and the pen
`injector are provided such that multiple applications of single
`
`dosages can be administered
`
`13. Use according to claim 7, wherein the ready-made syringe
`
`contains a dosage of 5 to 40 mg, in particular 50. 7 5. 10 o. 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, of methotrexate.
`
`14. Use according to any of claims 7 or 13. wherein the ready-made
`syringe is constructed such that it allows patient self(cid:173)
`
`administration by a patient with limited fine motor skills.
`
`15. Methotrexate for use in the treatment of inflammatory autoimmune
`diseases, wherein the methotrexate is to be administered subcutaneously
`and the methotrexate is present in a pharmaceutically acceptable sol-.ent
`
`at a concentration of about 50 mg/ml.
`
`16. Methotrexate for use according to claim 15, wherein the
`pharmaceutically acceptable solvent is selected from water, water
`
`for injection purposes, water comprising isotonization additives
`
`and sodium c hloride solut1on, in particular isotonic sodium
`chloride solution
`
`17. Methotrexate for use according to any of claims 15 or 16, wherein
`
`the innammatory autoimmune disease is selected from
`
`meumatoid arthritis, juvenile arthritides. vasculitides,
`collagenoses, Crohn's disease. colitis ulcerosa, bronchial
`
`asthma Alzheimer's disease, multiple sclerosis , Bechterew's
`
`disease, joint arthroses, or psoriasis.
`
`[0009] Known from the prior art in relation to the treatment of rheumatoid
`arthritis syringes for parenteral administration are solutions containing
`
`18. Methotrexate for use according to claim 17. wherein the
`
`innammatory autoimmune disease is rheumatoid arthritis, in
`
`methotrexate, in which the acti-.e ingredient in a concentration of up to
`
`particular Ju..enile rheumatoid arthntis
`
`25mg/ml in a pharmaceutically acceptable solvent is present (trade
`
`names: Lantarel ®from Wyeth, Metex ®of the applicant), the injection
`solution Lantarel ® concentration of 25 mg I ml (trade name: Lantarel ®
`FS is 25mg) not approved for subcutaneous administration ,
`Methotrexate has become the "gold standard" developed in the
`
`treatment of rheumatoid arthritis
`[001 0] The subcutaneous administration of methotrexate for the treatment of
`rheumatoid arthritis, but also with maximum concentrations of 25 mg I
`ml, is further described in Jansen et al, Pharmaceulisch Weekblad,
`
`19. Methotrexate for use according to any of claims 15 to 18, wherein
`
`the methotrexate is present in a forrn suitable for patient self(cid:173)
`
`administration
`
`20. Methotrexate for use according to any of claims 15 to 19, wherein
`the methotrexate is contained in an injection device for a single
`
`application
`
`21. Methotrexate for use according to claim 20 wherem the injection
`
`Year 1999, Volume 134, No, 46, pp. 1592- 1596 Kurnik et . al,
`
`device is a ready-made syringe
`
`Alimentary Pharmacology & Therapeutics, born 2003, Volume 18, No
`1, pp. 57-. 63 Zackheim et al, Journal of the American Academy of
`
`Dermatology, Year 1992 26, No, 6, page 1008
`
`[0011] As already described, it is necessary for successful treatment with
`
`methotrexate basis that the rheumatoid arthritis patients over a long
`
`period, sometimes a life - long, the appropriate dose weekly
`
`methotrexate is administered. For parenteral administration, the
`
`described speaks against the oral administration route fa1.0rable
`
`22. Methotrexate for use according to any of claims 15 to 19. wherein
`
`the methotrexate IS contamed 1n a storage contamer.
`
`23. Methotrexate for use according to cla•m 22. where1n the
`
`methotrexate-containing solvent fi.Jrthermore comprises a
`
`pres ervative.
`
`24. Methotrexate for use according to any of claims 22 or 23, wherein
`
`bioavailability Furthermore, children in particular have a certain a-.ersion
`
`the storage c onta1ner 1s an inJeCtion bottle, a vial, a bag. a glass
`
`to taking pills Howe-.er it has been found that precisely the
`
`ampoule, or a carpule
`
`subcutaneous administration is associated with difficulties. In therapies
`
`with those known in the prior art preparations turned out to a negative
`
`attitude on the part of patients . This is due to the problem. in the weekly
`
`25. Methotrexate for use according to claim 24 wherein the storage
`
`container is a carpule and wherein said carpule is suitable for
`
`adm1n1stering the methotrexate by means of an injection deVlce.
`
`https:/fv.Mw.g oog le.com/patents/EP2046332B1 ?cl= en&dq = ep+ 2046332&hl=en&sa= X&ei= BB60U9PpKuimsQTf34CABQ&\€d=OC C EQ6AEwAA
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`2110
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`Patent EP2046332B1- Concentrated methotre)(<lte solutions- Google Patents
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`1n particular a pen injector
`
`26. Methotrexate for use according to claim 25. wherem the carpule
`and the pen injector are pro\ided such that multiple applications
`of single dosages can be administered
`
`27. Methotrexate for use according to claim 21 , wherein the ready(cid:173)
`made syringe contains a dosage of 5 to 40 mg, in particular 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. of methotrexate
`
`28. Methotrexate for use according to any of claims 21 or 27. wherein
`the ready-made syringe is constructed such that it allows patient
`self-administration by a patient with limited fine motor skills
`
`time interval required relati~.ely large quantities can lead to drug solution
`(eg with appropriate drug dose up to 3 ml) under the skin, which is
`particularly inbegriffren children, the weekly \is it to the doctor is not
`easy to con~.ey .
`[0012] There is therefore a need for pharmaceutical formulations of
`methotrexate, which may allow the patient, including children, as simple
`and painless with good bioavailability o~.er a long period are administered
`regularly, especially a week, and thus a high "patient compliance"
`leads. Advantageously, the patient can self administer the
`pharmaceutical formulation.
`[0013] The present in~.ention is thus based on the object to pro\ide a
`pharmaceutical preparation for the treatment of inflammatory
`autoimmune diseases, especially rheumatoid arthritis, pro\ide, which
`o~.ercomes the abo~.e-descri bed drawbacks of the known in the prior art
`preparations .
`[0014] The problem underlying the present in~.ention is achie~.ed by the object of the appended claims .
`[001 5]
`In a first embodiment, the in~.ention pro\ides the use of methotrexate to be administered subcutaneously for
`preparing a medicament for the treatment of inflammatory autoimmune diseases, wherein the methotrexate is
`present in a concentration of about 50mg/ml in a pharmaceutically acceptable sol~.ent, ready ,
`In a further embodiment, the im.ention Methotrexate for use in the treatment of inflammatory autoimmune diseases
`is prepared, wherein the methotrexate is to be administered subcutaneously in a concentration of about 50mg/ml is
`in a pharmaceutically acceptable sol~.ent.
`[0017] According to the present in~.ent ion , drugs or pharmaceutical Losunssformulierungen are pro\ided which include
`methotrexate at a concentration of about 50mg/ml in a pharmaceutically acceptable sol~.ent.
`[0018] As the pharmaceutically acceptable sol~.ents according to the in~.ention can be considered in all sol~.ents , which are
`pharmaceutically acceptable and not with the acti~.e ingredient and any other ingredients of the drug or the
`pharmaceutical solution formulation are incompatible. According to the in~.ention are particularly suitable
`pharmaceutically acceptable sol~.ent is water, in particular water, for injections, as well as water comprising
`isotonization additil.es and sodium chloride solution, in particular isotonic sodium chloride solution Most preferably,
`water for injections. As exemplary isotonization, soluble salts (sodium chloride, potassium chloride), sugars
`(glucose. lactose), sugar alcohols (mannitol, sorbitol), and combinations of these excipients may be used in the
`
`[0016]
`
`in~.ention .
`[0019] Addition, the in~.enti~.e drug can lsotonierungszusatzen also in the art of pharmaceutical solution formulations
`contain con~.entional additi~.es . In particular, the in~.enti~.e medicament may contain con~.enti onal excipients with the
`following functionality: Eu I lsohydrisierung (acetate, phosphate, citrate buffer}, antioxidants (ascorbic acid, usual in
`the art of sulfur compounds) Uisungs~.ermittlung (complexing agents , solubilizers, coso l ~.ents eg cyclodextrins ,
`poly\idone, polysorbates, lecithin, glycocholate), increase in viscosity , pH adjusters (acids, bases , or acidic or
`basic salts). In a particularly preferred embcdiment, the pH of the in~.enti~.e medicament is between 7.5 and 9
`[0020] The no~.el drugs are directed to the treatment of inflammatory autoimmune diseases . The term "inflammatory
`autoimmune disease" encompasses all inflammatory autoimmune diseases, which can be treated with
`methotrexate useful. As examples of inflammatory autoimmune diseases , which can be treated with the in~.enti~.e
`drug can rheumatoid arthritis, ju~.enile arthritides, vasculitides, collagenoses, Crohn's disease, ulcerati~.e colitis,
`asthma, Alzheimer's disease, multiple sclerosis , ankylosing spondylitis, joint arthroses, or psoriasis, and psoriasis
`arthritis and psoriasis vulgaris in particular called plaque-type. Particularly preferably the in~.ention are suitable drugs
`for the treatment of rheumatoid arthritis, including ju~.enile arthritis, especially as the oligoarthritische and
`polyarthritische form of ju~.enile arthritis_
`[0021] The administration of the drug subcutaneously . In particular, the application of medications by injection
`subcutaneously. Furthermore, it is preferred that the medicament is in a form that makes it possible that the
`subcutaneous administration of the drug by the patient itself is made (self-administration). Such treatment of
`subcutaneous self-administration has pro~.ed, for example, the administration of insulin through the affected
`diabetics itself and leads to a high treatment acceptability by the patient ("patient compliance") In the case of
`rheumatism in self-application can also be dispensed to the usually weekly successful doctor's visit
`In a preferred Ausfuhrungsrorm the present in~.ention, the in~.enti~.e medicament is in an injection device for a single
`application , in particular a pre-filled syringe containing Under an injection device for a single application according
`to the in~.ention , a de\ice is to be understood that. Alongside a container which contains the pharmaceutical
`solution formulation according to the in~.ention, an injection needle (cannula). wherein by this the medicament can
`be administered to the patient Further comprising an injection device such a mechanical arrangement (such as a
`punch or a flexible bladder) with the aid of the drug can be forced through the needle from the container. Such an
`injection device for a single application is further characterized in that it contains a desired single dosage of the drug
`and thus the application, the container, which contains the pharmaceutical solution formulation according to the
`in~.ention, is to be emptied completely, in order to gi~.e the intended dosage. Because of this fact, according to the
`
`[0022]
`
`https://Wvl.w.g oog le.com/patents/EP2046332B1 ?cl = en&dq =ep+ 2046332&hl=en&sa= X&ei= BB60U9PpKuimsQTf34CABQ&\ed= OCC EQ6AEwAA
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`[0023]
`
`abo~.e embodiment, as a rule is not necessary to blend a preservati~.e to the pharmaceutical solution Formulation of
`methotrexate
`In a no~.el injection dellice for a single application is preferably a dose of the drug methotrexate 5mg to 40mg,
`included. Particularly preferably comprises an injection dellice for a single application of the in~.ention, 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 An obligation to prollide a
`particular desired dosage required I.Oiume of liquid contained in the injection dellice For a single application needs to
`be depends on the chosen concentration of the drug solution and opens up to the person skilled in a simple way.
`Thus to prol.ide a dose of acti~.e substance of 30 o mg in an in~.enti~.e concentration of methotrexate in the
`pharmaceutically acceptable sol~.ent of 50mglml should an injection dellice for a single application contain a liquid
`1.0lume of 0 6 mi.
`[0024] A particularly preferred embodiment of an in~.entive injection del.ice for a single application is a prefilled syringe.
`Syringes are on the pharmaceutical techniques well known, especially in the field of treatment of rheumatoid
`arthritis with methotrexate On the German market already pre-filled syringes are distributed containing
`methotrexate solutions with concentrations of7.5 mg I ml, 10.0 mg I ml and 25mglml (trade name: Lantarel ®from
`Wyeth, Metex ®of the applicant. with the commercial product Lantarel ®) FS 25 mg is not appro~.ed for
`subcutaneous administration) Application approl.ed preparations of the prior art ha~.e the disadvantage that,
`depending on the week to be administered amount of drug, relati~.ely large quantities of ftuid under . although the
`prollision of methotrexate solutions in prefilled syringe, sometimes for Seibstapplikation, patient compliance
`positi~.ely influenced the Subcutaneous ha~.e the patient's skin must be brought. At a dose of 30mg drug usual
`weekly means that the currently most concentrated drug solution of prior art for the subcutaneous administration,
`namely 1 Omglml (commercially product Met ex ® 1 Omglml of the applicant), a 1.0lume of 3 ml to be injected under
`the skin must. This high amount of liquid is the patients, especially children, sometimes difficult to explain what
`leads to reduced patient compliance.
`[0025] According to the in~.ention prollided drugs contain the acti~.e ingredient on the other hand, highly concentrated
`solutions methotrexate, and reduce the amount of liquid to be administered at a gi~.en dose of active ingredient
`weekly. For example, it would therefore be at the concentration of the present in~.ention to obser~.e a weekly
`50mglml acti~.e dose of 30 mg is sufficient to administer a liquid 1.0lume of only 0 6 ml subcutaneously. It can be
`expected that this will ha~.e a positi~.e impact on patient compliance,
`[0026] Syringes are on the pharmaceutical arts are well known and are not according to the in~.ention particularly limited.
`ln~.ention include pre-filled syringes, for example, disposable injection systems such as the Uniject ® injection
`system In one embodiment, the syringe can already be pro\1ded with a suitable needle for subcutaneous injection,
`in an alternati~.e embodiment, the syringe is initially prol.ided with a rubber cap or the like, which, prior to the
`application by the physician, the medical staff or in subcutaneous self-administration is replaced by the patient
`himself by a separately packaged sterile cannula.
`[0027] Preferably the in~.enti~.e syringe is designed so that it is suitable for subcutaneous administration of the drug
`solution, which can be accomplished in particular by pro>iding for a suitable hypodermic needle. In a more preferred
`embodiment, the syringe is designed in such a way that e~.en patients with rheumatoid arthritis who ha~.e limited
`manual fine motor skills and therefore not exclusi~.ely be able to inject himself a drug with con~.entional design
`syringes, can perform a self-application. These preferably ha~.e particular stamp and back stopping constructed and
`sized so that the rheumatic patient handling is facilitated Such enriched syringes are named in the art
`In a further preferred embodiment of the present imention. the in~.enti~.e medicament is contained in a storage
`~.essel. Under a storage ~.essel according to the in~.ention any con~.entional in the art, the container is to be
`understood, in which I wherein the medicament or the pharmaceutical solution formulation of the in~.ention properly,
`ie, in particular sterile, can be sensed and stored. As examples of supply ~.essel in the sense of the in~.ention, a llial,
`a Ilia I one bag, a glass ampoule, or a carpule may be cited. According to an embodiment of the in~.ention must for
`application of the medicament to the patient, first, the desired amount of pharmaceutical solution formulation by
`means of an injection del.ice (for example, a con~.entional disposable syringe) from the reseMir (such as a llial) are
`remo~.ed. whereas in an alternate embodiment of the in~.ention the pharmaceutical solution formulation means of an
`injection de>ice (such as a pen injector) directly from the supply ~.essel (for example, a carpule) can be applied.
`In a preferred embodiment of the in~.ention the storage ~.essel includes the drug methotrexate, which is dissol~.ed in
`the pharmaceutically acceptable sol~.ent, at least not a preservati~.e. The preservati~.e used in this in~.ention is not
`particularly restricted, and a skilled artisan will readily be able, from the known preservati~.es for pharmaceutical
`purposes, a select suitable. Preferred preservati~.es are cresols, benzyl alcohols, Phenylethylalkohole called. The
`preservati~.e is used in particular to the case of partial removal of the drug (for example, by a con~.entional disposable
`syringe or a pen-type injector), in a storage ~.essel according to the im.ention (for example, a llial or a carpule)
`preser~.e remaining pharmaceutical solution formulation.
`[0030] The total dosage amount of the drug methotrexate in a storage ~.esse I according to the in~.ention is not particularly
`limited and in particular by the dimensions of the Voratsgetar>es and thus frorn the fluid 1.0lume is determined, which
`can hold the reseMir. Preferably, an in~.enti~.e storage ~.esse I a total dosage amount of frorn 5 to 5000 mg
`methotrexate.
`(0031] A preferred example of a storage ~.essel, in which the in~.enti~.e medicament is contained, a carpule may be cited.
`
`[0028]
`
`[0029]
`
`https:/fwv..w.g oog le.com/patents/EP2046332B1 ?cl= en&dq =ep+ 2046332&hl=en&sa= X&ei= BB60U9PpKuimsQTf34CABQ&\€d= OCC EQ6AEwAA
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`Cartridges, also called cartridges, are well known in the art. Under a carpule understood by one skilled in the art,
`preferably cylindrical, sterile medicament container, which is preferably made of glass or preferably transparent,
`inert plastic: is made (eg Tapas ®). On one side of the carpule cylinder is usually located a mo.able end plug on
`the opposite side a pierceable membrane made of rubber or a similar elastic sealing material The application is
`located in the pharmaceutical preparation of the carpule as pressed by the action of an external plunger or piston to
`the mo.able end plug through a cannula, which pierces the rubber membrane described from the carpule
`[0032] Preferably, the administration of the medication from the carpule is performed by means of an injection device. In a
`particularly preferred embodiment of the in..ention therefore the carpule for administering the medicament by means
`of an injection device is suitable. Such injection devices are well known in the art. As such an injection device is
`preferably a so-called pen-type injector ("Pen") is mentioned in which the carpule can be used. Pen injectors look
`generally like larger pens (in English "pen") and are particularly common diabetics who can to help easily
`administer the required dose of insulin. After emptying the used carpule can be in the pen-injector used to easily
`create a new carpule (comparable to replace an ink cartridge in the previously mentioned for comparison pen) .
`[0033] A pen injector erfindungssemar..er is equipped so that it is suitable for subcutaneous administration of the drug
`solution, which can be accomplished in particular by providing for a suitable hypodermic needle. Further comprising
`a pen-type injector according to the in..ention and comprised therein carpule is preferably designed such that a
`place multiple applications of single dosages can. This is an in..enti..e pen injector preferably with a constructi;e
`device provided (eg, a control wheel), with the aid of the setting of a certain dosage (ie specifically selecting a
`particular application 1o0lume at a known drug concentration of methotrexate in the pharmaceutical solution
`formulation) of the to be administered methotrexate the doctor, the medical personnel or, in the self-application, can
`be made by the patient himself. Thus, the in..ention, this embodiment provides the possibility, if necessary, also to
`select the intermediate doses, for which no other storage ..essels or injection devices, in particular, no vials or pre(cid:173)
`filled syringes are a.ailable commercially . Constructed such pen injectors are in the art, particularly from the insulin
`area well known.
`[0034] According to a particularly preferred embodiment of the in..ention, a pen-type injector according to the in..ention is
`designed such that the individual dosages for each application can be set to each of 5 to 40 mg methotrexate In
`particular, a pen-type injector according to the in..ention can be adjusted such that each application each having a
`single 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 may be
`administered
`[0035] The following examples illustrate the in..ention,
`Examples
`Example 1:
`[0036] The following illustrated methotrexate solution (concentration: 50 mg I ml) was prepared based on the following
`formulation amounts,
`
`Methotrexate:
`
`1 500g
`
`Sodium chloride:
`
`120g
`
`Sodium hydroxide: 300g
`
`Water for Injection: 28 764g
`
`O..erall:
`
`30 6B4g = 30 liters
`
`[0037] To prepare the solution (Example 1) approximately 60% of the required water for injections were (20-25 • C)
`presented in the mixing ..essel. The agitator at the specified amount of sodium chloride was added and completely
`dissol..ed. The container and the solution was purged with nitrogen so that the residual oxygen has been largely
`displaced. The indicated amount of methotrexate was suspended in the solution with the agitator further. The pH of
`the solution was adjusted using 1% sodium hydroxide solution (made from NaOH and water for injection) to a .alue
`between 8,5 to B 9. The temperature of the solution is in this case between 20 and 30 • C. The result is a clear
`solution, the pH .alue of 8 5 to 8.9 is stable. By addition of the residual amount of water for injection was added up
`to the final 110lume
`[0038] By sterile filtration through a 0.22 micron sterile filter the solution using inert gas (nitrogen) was in the designated
`sterile glass container filled the glass type 1 (cartridges or prefilled syringes) under clean room conditions (class A).
`Example 2:
`[0039] The following illustrated methotrexate solution (concentration: 50 mg I ml) was prepared based on the following
`formulation amounts
`
`Methotrexatdinatrium: 1 645g
`
`Sodium chloride:
`
`120g
`
`Water for Injection:
`
`ad 30.684g
`
`O..erall:
`
`30.684g = 30 liters
`
`[0040] To prepare the solution (Example 2) about 60% of the required water for injections were (20-25 " C) presented in the
`mixing ..essel. The agitator at the specified amount of sodium chloride was added and completely dissol..ed. The
`container and the solution was purged with nitrogen so that the residual oxygen has been largely displaced. The
`
`https:/fw.N.N.g oog le.com/patents/EP2046332B1 ?cl=en&dq = ep+ 2046332&hl =en&sa= X&ei= BB60U 9PpKuimsQTf34CABQ&\€d= OCC EQ6AEwAA
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`5/10
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`Case 1:14-cv-01498-JBS-KMW Document 28-13 Filed 07/11/14 Page 7 of 11 PageID: 299
`
`7/2/2014
`
`Patent EP2046332B1 - Concentra