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  • 专利说明
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  • 类似技术
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  • 优先权
    • 专利摘要:
    There is a focused disclosure of methotrexate solutions useful in the use of a drug for the preparation of a parenterally-administered medicament for the treatment of autoimmune inflammatory diseases. The methorexate is used in a concentration of greater than 25 mg / ml in a pharmaceutically acceptable solvent. The invention also relates to a pre-filled syringe and a carpule containing such a pharmaceutical solution formulation and a pen-type injector comprising such a carpule and / or a pre-filled syringe.
    公开号:AT14872U1
    申请号:TGM50122/2015U
    申请日:2007-07-20
    公开日:2016-08-15
    发明作者:
    申请人:Medac Ges Für Klinische Spezialpräparate Mbh；
    IPC主号:
    专利说明:

    description
    CONCENTRATED METHOTREXATE SOLUTIONS
    The present invention relates to concentrated methotrexate solutions. In particular, the present invention relates to the use of methotrexate for the manufacture of a parenterally-administered medicament for the treatment of autoimmune inflammatory diseases, wherein the methotrexate is present in a concentration of greater than 25 mg / ml in a pharmaceutically acceptable solvent. Furthermore, the present invention relates to a pre-filled syringe and a carpule containing such a pharmaceutical solution formulation, as well as a pen injector comprising such a carpule and / or a pre-filled syringe.
    The pharmaceutical active ingredient N- {4 - [(2,4-diamino-6-pteridinylmethyl) methylamino] benzoyl} -L-glutamic acid (free name: methotrexate, MTX short) has been known since the early 50s. Methotrexate is a folate antagonist. It acts as an antimetabolite of nucleic acid synthesis, intracellular inhibition of dehydrofolate reductase (irreversible binding) with consecutive inhibition of purine synthesis, inhibits LTB4 synthesis in neutrophils, inhibits IL-1 synthesis, suppresses cell-mediated immunity and inhibits endothelial cell proliferation.
    For a long time, methotrexate has been used preferentially in oncology because of its action as a cytostatic agent. It has been used in particular for breast cancer, but also in children for the treatment of leukemia. For the latter indication, methotrexate is still crucial today. Early on, the efficacy of methotrexate in psoriasis was also noted. Since psoriasis can also be associated with rheumatoid arthritis, this option was also observed as a treatment option for the first time in individual cases at the end of the fifties.
    Rheumatoid arthritis is usually treated therapeutically first with fast analgesic and short-term anti-inflammatory substances. Non-steroidal anti-inflammatory drugs (NSAIDs, such as the active ingredient diclofenac) and corticosteroids should be mentioned here. However, these do not affect the actual course of the disease. In most patients, NSAIDs and corticosteroids are used only until the inflammation and pain subsides significantly. Subsequently, their dose is often reduced or the preparation is completely swollen out.
    Disease Modifying Anti Rheumatic Drugs (DMARD's) only have a disease modifying effect in rheumatoid arthritis. Examples of these active substances, also referred to as "basic therapeutics", besides methotrexate, also include azathioprine, sulfasala-zine and antimalarial drugs. Basic therapies directly intervene in the disease and can slow down the disease process, which is why the earliest possible use should be sought. Since it is a chronic disease in rheumatoid arthritis, the basic therapies are usually over long periods to take, with good efficacy and tolerability, the therapy is often continued throughout life (continuous long-term therapy), the drug dose can be adapted to the disease process.
    In contrast to chemotherapy for tumor diseases methotrexate as a basic therapeutic for the treatment of rheumatoid arthritis by a multiple, occasionally up to 1000-fold, lower doses, which is why one also speaks in the anti-rheumatic therapy of the "low-dose methotrexate therapy" , In antirheumatic therapy, a dose range of 5.0 to 30.0 mg per week is usual in Germany, in other European countries up to 40.0 mg per week is dosed. Most importantly, methotrexate is given only once a week.
    The application of methotrexate can in principle be oral or parenteral. However, the oral therapy, which had been taken orally for a long time by means of tablets, was superseded by parenteral formulations, since it was found that methotrexate is unacceptably absorbed from tablets and thus no sufficient accuracy is ensured in the dose-dependent therapy. Cytostatic agents suitable for parenteral administration are normally prepared by dissolving the active ingredient in a suitable solvent by individually using a specific amount of drug for each patient. However, the handling of cytotoxic drugs and the preparation of cytostatic drug-containing drugs is not without problems and provided by the legislature with strict conditions. For example, cytostatics may not be prepared outside of a specially created and suitable extraction system. Since rheumatologists and GPs usually do not have appropriate facilities, they are not allowed to prepare methotrexate themselves, even taking a syringe from a bottle (such as a vial containing the drug solution) is considered a preparation.
    For this reason, pre-filled syringes have been developed to eliminate the winding up operation. For the first time, corresponding prefilled syringes for subcutaneous administration have been approved throughout Europe for the present applicant. With these pre-filled syringes, the application by a doctor, medical staff or, if self-application, by the patient itself possible without the need for an intervening pharmacist who has a suitable trigger system.
    For the therapy of rheumatoid arthritis known from the prior art ready-made syringes for parenteral administration containing methotrexate solutions in which the active ingredient is present in a concentration of up to 25mg / ml in a pharmaceutically acceptable solvent (trade name: Lantarel ® from Wyeth, Metex® the applicant), the injection solution Lantarel® the concentration 25 mg / ml (trade name: Lantarel® FS 25mg) is not approved for subcutaneous administration. Methotrexate has become the "gold standard" in the treatment of rheumatoid arthritis.
    As already described, it is necessary for successful basic therapy with methotrexate that the rheumatoid patient over a very long period, sometimes for a lifetime, weekly the appropriate dose of methotrexate is administered. For parenteral administration, the more advantageous bioavailability compared to the oral route of administration speaks. Furthermore, children in particular have a certain aversion to taking tablets. However, subcutaneous administration has been found to be difficult. In therapies with the known from the prior art preparations turned out a negative attitude on the part of the patient. This is based on the problem of getting the required relatively large amount of active ingredient solution (for example with a corresponding active ingredient dose of up to 3 ml) under the skin at weekly intervals, which is particularly difficult to convey to children, including the weekly visit to the doctor.
    There is thus a need for pharmaceutical formulations of methotrexate which can be administered to the patient, including children, as simply and painlessly as possible with good bioavailability over a long period of time, in particular weekly, and thus to a high patient compliance " leads. Advantageously, the patient should be able to administer the pharmaceutical formulation himself.
    The present invention is therefore an object of the invention to provide a pharmaceutical preparation for the treatment of inflammatory autoimmune diseases, in particular rheumatoid arthritis, which overcomes the disadvantages of the known from the prior art preparations described above.
    The object underlying the present invention is achieved by the subject of the appended claims.
    In a first aspect, the invention provides the use of methotrexate for the manufacture of a parenterally-administered medicament for the treatment of autoimmune inflammatory diseases wherein the methotrexate is present in a concentration of greater than 25 mg / ml in a pharmaceutically acceptable solvent.
    In another embodiment, the invention provides a pre-filled syringe containing a pharmaceutical solution formulation of methotrexate at a concentration greater than 25 mg / ml in a pharmaceutically acceptable solvent.
    Further, in another embodiment, the invention provides a carpule containing a pharmaceutical solution formulation of methotrexate at a concentration of greater than 25 mg / ml in a pharmaceutically acceptable solvent, and a pen injector comprising such a carpule.
    According to the present invention, medicaments or pharmaceutical solution formulations are provided which comprise methotrexate at a concentration greater than 25 mg / ml in a pharmaceutically acceptable solvent. In a preferred embodiment, the methotrexate is present in the medicament at a concentration greater than 25 mg / ml to about 150 mg / ml. Further preferred concentration ranges are from 30 mg / ml to 100 mg / ml, and in particular from 40 mg / ml to 80 mg / ml and further from 50 mg / ml to 75 mg / ml. In a particularly preferred embodiment, the methotrexate is present in the medicament at a concentration of about 50 mg / ml in a pharmaceutically acceptable solvent.
    According to the invention, all solvents which are pharmaceutically acceptable and are incompatible with the active ingredient and possibly other ingredients of the medicament or of the pharmaceutical solution formulation can be considered as the pharmaceutically acceptable solvent. According to the invention, particularly suitable pharmaceutically acceptable solvents are water, in particular water for injection purposes, and water comprising isotonizing additives and saline, in particular isotonic saline solution. Most preferred is water for injections. As exemplary isotonizing additives, soluble salts (sodium chloride, potassium chloride), sugars (glucose, lactose), sugar alcohols (mannitol, sorbitol) and combinations of these excipients may be used according to the invention.
    In addition to isotonizing additives, the medicament of the invention may further include conventional additives in the art of pharmaceutical solution formulations. In particular, the medicament according to the invention may comprise customary auxiliaries having the following functionality: Eu / isohydration (acetate, phosphate, citrate buffer), antioxidants (ascorbic acid, sulfur compounds customary in the art), solubilization (complexing agents, solubilizers, cosolvents: eg cyclodextrins, polyvidone, polysorbates , Lecithin, glycocholate), viscosity increase, pH adjustment (acids, bases, or acidic or basic salts). In a particularly preferred embodiment, the pH of the medicament according to the invention is between 7.5 and 9.
    The medicaments of the invention are directed to the treatment of inflammatory autoimmune diseases. The term "inflammatory autoimmune disease" includes all inflammatory autoimmune diseases that can be treated with methotrexate meaningful. Non-limiting examples of autoimmune inflammatory diseases that can be treated with the medicaments of the invention include rheumatoid arthritis, juvenile arthritis, vasculitis, collagenosis, Crohn's disease, ulcerative colitis, bronchial asthma, Alzheimer's disease, multiple sclerosis, ankylosing spondylitis, arthritis or psoriasis, as well as psoriatic arthritis and especially plaque-type psoriasis vulgaris. Particularly preferred are the medicaments of the invention for the treatment of rheumatoid arthritis, including juvenile arthritis, especially the oligoarthritische and polyarthritic form of juvenile arthritis.
    The administration of the medicaments according to the invention is parenteral. In particular, the medication is administered intravenously, intramuscularly or subcutaneously by injection. According to a preferred embodiment of the present invention, the medicament is in such a form that it is suitable for subcutaneous administration. Furthermore, it is preferred that the medicament be in a form that allows the subcutaneous administration of the medicament to be performed by the patient himself (self-application). Such a therapy of subcutaneous self-application has proven itself, for example, in the administration of insulin by the affected diabetic and leads to a high acceptance of therapy by the patient ("patient compliance"). In the case of rheumatism therapy, self-administration can also be dispensed with the usually weekly visit to the doctor.
    In a preferred embodiment of the present invention, the medicament according to the invention is contained in an injection device for single application, in particular a pre-filled syringe. An injection device for single application is to be understood according to the invention as a device which, in addition to a container which contains the pharmaceutical solution formulation according to the invention, comprises an injection needle (cannula), by means of which the medicament can be administered to the patient. Furthermore, such an injection device comprises a mechanical arrangement (for example a stamp or a flexible bladder) with the aid of which the medicament can be forced out of the container through the injection needle. Such an injection device for single application is further characterized in that it contains a desired single dose of the active ingredient and thus to completely empty the container containing the pharmaceutical solution formulation according to the invention during administration in order to administer the intended dosage. Due to this fact, according to the above embodiment, the admixture of a preservative to the pharmaceutical solution formulation of methotrexate can usually be dispensed with.
    In an injection device according to the invention for single application, a dose of the active substance methotrexate of 5 mg to 40 mg is preferably contained. More preferably, a single-use injection device according to the invention contains 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 40.0mg. The volume of liquid required to provide a respective desired dosage, which must be contained in the single-application injection device, depends on the particular concentration of the active substance solution selected and is readily apparent to one skilled in the art. Thus, to provide a drug dose of 30.0 mg at a concentration of methotrexate in the pharmaceutically acceptable solvent of, for example, 50 mg / ml, a single-use injection device would require a fluid volume of 0.6 ml.
    A particularly preferred example of an injection device according to the invention for single application is a pre-filled syringe. Pre-filled syringes are well known in the pharmaceutical art, especially in the field of rheumatoid arthritis therapy with methotrexate. Pre-filled syringes containing methotrexate solutions having concentrations of 7.5 mg / ml, 10.0 mg / ml and 25 mg / ml are already marketed on the German market (trade names: Lantarel® from Wyeth, Metex® by the applicant, the commercial product Lantarel® FS 25 mg is not approved for subcutaneous administration). Although the provision of methotrexate solutions in pre-filled syringes, sometimes for self-administration, positively influences patient compliance, prior art devices approved for subcutaneous administration have the disadvantage that, depending on the amount of drug to be administered weekly, relatively large amounts of fluid are among those Skin of the patient must be brought. With a usual weekly drug dose of 30 mg this means that in the currently highly concentrated drug solution of the prior art for subcutaneous administration, namely 10 mg / ml (in the commercial product Metex® 10 mg / ml of the Applicant), a volume of 3 ml must be injected under the skin , This high amount of fluid is sometimes difficult to communicate to the patient, especially children, resulting in reduced patient compliance.
    In contrast, the medicaments provided according to the invention contain highly concentrated solutions of the active substance methotrexate, which reduces the amount of liquid to be administered at a certain weekly dose of active substance. For example, it would therefore be sufficient, given a particularly preferred concentration of 50 mg / ml according to the invention for maintaining a weekly active ingredient dose of 30 mg, to administer a liquid volume of only 0.6 ml subcutaneously. It can be expected that this will have a positive impact on patient compliance.
    Thus, in a preferred embodiment, the present invention provides a prefilled syringe containing a pharmaceutical solution formulation of methotrexate at a concentration greater than 25 mg / ml in a pharmaceutically acceptable solvent. Pre-filled syringes are well known in the pharmaceutical art and are not particularly limited in the present invention. Pre-filled syringes according to the invention also include, for example, disposable injection systems, such as the Uniject® injection system. In one embodiment, the pre-filled syringe may already be provided with a suitable cannula for intravenous, intramuscular or subcutaneous injection, in an alternative embodiment the pre-filled syringe is first provided with a rubber cap or the like pre-applied by the physician, the medical staff or, in the case of subcutaneous self-administration, through which the patient himself is replaced by a separately sterile-packed cannula.
    Preferably, the prefilled syringe according to the invention is designed so that it is suitable for subcutaneous administration of the drug solution, which can be accomplished in particular by providing a suitable for Subkutaninjektion cannula. In a more preferred embodiment, the prefilled syringe is structurally designed so that even rheumatism patients who have limited manual fine motor skills and are therefore not able to inject themselves a drug with conventionally configured pre-filled syringes, can perform a self-application. For this purpose, in particular stamp and back stop are preferably constructed and dimensioned so that the handling of the rheumatism patient is facilitated. Such prefilled syringes are well known in the art.
    In a further preferred embodiment of the present invention, the medicament according to the invention is contained in a storage vessel. According to the invention, a storage vessel is to be understood as meaning any container customary in the field in which the medicament or pharmaceutical solution formulation of the invention is used properly, that is to say in accordance with the invention. especially sterile, can be bottled and stored. As non-limiting examples of storage containers in the context of the invention, a vial, a vial, a bag, a glass ampoule or a carpule can be mentioned. According to one embodiment of the invention, in order to apply the drug to the patient, the desired amount of pharmaceutical solution formulation must be withdrawn from the storage vessel (eg, a vial) by means of an injection device (eg, a conventional disposable syringe), while according to an alternative embodiment of the invention, the pharmaceutical solution formulation by means of an injection device (for example, a pen-injector) directly from the storage vessel (for example, a carpule) can be applied.
    In a preferred embodiment of the invention, the storage vessel comprises in addition to the active substance methotrexate, which is dissolved in the pharmaceutically acceptable solvent, at least one preservative. The preservative usable in the present invention is not particularly limited, and one skilled in the art will readily be able to select a suitable one from the known preservatives for pharmaceutical use. Cresols, benzyl alcohols, phenylethyl alcohols may be mentioned as preferred preservatives. In particular, the preservative serves to preserve the pharmaceutical solution formulation remaining upon partial withdrawal of the medicament (for example, by a conventional disposable syringe or pen injector) in a storage vessel (e.g., a vial or carpule) of the present invention.
    The total dosage amount of the drug methotrexate in a storage vessel according to the invention is not particularly limited and is determined in addition to the concentration of methotrexate used in the pharmaceutically acceptable solvent in particular by the dimensions of the storage vessel and thus the liquid volume, which can accommodate the storage vessel. A storage vessel according to the invention preferably contains a total dosage amount of 5 to 5000 mg methotrexate.
    As a preferred example of a storage vessel in which the medicament according to the invention is contained, a carpule may be mentioned. Cartridges, also called cylindrical ampoules, are well known in the art. Under a carpule, the expert understands a preferably cylindrical, sterile medicament container, which is preferably made of glass or transparent as possible, inert plastic (for example: Topas®). On one side of the carpule cylinder is usually a movable end plug, on the opposite side a pierceable membrane made of rubber or a similar elastic closure material. For application, the pharmaceutical preparation in the carpule is removed by the action of e.g. of an external punch or plunger on the movable end plug is forced out of the carpule by a cannula piercing the described rubber membrane.
    In a further embodiment, the present invention thus provides a carpule containing a pharmaceutical solution formulation of methotrexate at a concentration greater than 25 mg / ml in a pharmaceutically acceptable solvent. In a preferred embodiment, a carpule according to the invention contains a total dosage amount of 5 to 500 mg, more preferably 7.5 to 300 mg, methotrexate.
    Preferably, the administration of the drug from the carpule by means of an injection device is made. In a particularly preferred embodiment of the invention, therefore, the carpule is suitable for administration of the medicament by means of an injection device. Such injection devices are well known in the art. As such an injection device is preferably a so-called pen-injector ("pen") call, in which the carpule can be used. Pen injectors usually look like larger fountain pens (in English "pen") and are especially common to diabetics who can easily administer the necessary dose of insulin with their help. After emptying of the cartridge used can be in the pen injector in a simple way a new carpule are used (comparable to the replacement of an ink cartridge in the above-mentioned for comparison fountain pen).
    In a further embodiment, the present invention accordingly provides a pen injector comprising a carpule according to the invention described above, which contains the medicament according to the invention.
    Preferably, an inventive pen-injector is designed so that it is suitable for subcutaneous administration of the drug solution, which can be accomplished in particular by providing a suitable for Subkutaninjektion cannula. Furthermore, a pen-type injector according to the invention and the carpule included in it are preferably configured in such a way that a multiple application of single dosages can take place. For this purpose, a pen-injector according to the invention is preferably provided with a constructive device (eg a control wheel), by means of which the setting of a certain dosage (ie concretely the selection of a certain application volume with known drug concentration of methotrexate in the pharmaceutical solution formulation) of the methotrexate to be administered by the doctor, the medical staff or, if self-applied, by the patient himself. Thus, with this embodiment, the invention provides the possibility, if necessary, of also selecting intermediate dosages for which no other storage containers or injection devices, in particular no vials or prefilled syringes, are commercially available. Such constructed pen injectors are well known in the art, particularly in the insulin field.
    According to a particularly preferred embodiment of the invention, an inventive pen-injector is designed such that the individual dosages per application can be set to each of 5 to 40 mg methotrexate. In particular, a pen injector according to the invention can be set in such a way that in each case 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 40.0mg can be administered.
    The invention is further described by the following subjects: 1. Use of methotrexate for the preparation of a parenterally administered
    A medicament for the treatment of inflammatory autoimmune diseases, wherein the methotrexate is present in a concentration of greater than 25 mg / ml in a pharmaceutically acceptable solvent.
    2. Use according to item 1, wherein the methotrexate is present in a concentration of greater than 25 mg / ml to 150 mg / ml.
    3. Use according to item 2, wherein the methotrexate is present in a concentration of about 50 mg / ml.
    Use according to any one of the preceding subjects, wherein the pharmaceutically acceptable solvent is selected from water, water for injections, water comprising isotonizing additives and saline, in particular isotonic saline.
    5. Use according to any one of the preceding articles, wherein the inflammatory
    Autoimmune disease is selected from rheumatoid arthritis, juvenile arthritides, vasculitis, collagenosis, Crohn's disease, ulcerative colitis, bronchial asthma, Alzheimer's disease, multiple sclerosis, ankylosing spondylitis, arthritis or psoriasis.
    Use according to item 5, wherein the autoimmune inflammatory disease is rheumatoid arthritis, especially juvenile rheumatoid arthritis.
    Use according to any of the preceding subjects, wherein the medicament is in a form suitable for subcutaneous administration.
    Use according to claim 7, wherein the medicament is in a form suitable for administration by the patient himself.
    9. Use according to one of the preceding objects, wherein the medicament is contained in an injection device for single application.
    10. Use according to item 9 wherein the injection device is 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 methotrexate.
    11. Use according to item 9 or 10, wherein the injection device a
    Pre-filled syringe is.
    12. Use according to any one of items 1 to 8, wherein the medicament in a
    Reservoir is included.
    Use according to item 12, wherein the medicament further comprises a preservative.
    14. Use according to item 12 or 13, wherein the storage vessel contains a total dosage amount of 5 to 5000 mg.
    15. Use according to one of the items 12 to 14, wherein the storage vessel a
    Vial, pouch, glass ampoule or carpule.
    16. Use according to item 15, wherein the storage vessel is a carpule and this is suitable for administering the medicament by means of an injection device, in particular a pen-injector.
    17. Use according to item 16, wherein the carpule and the pen-injector are designed such that a multiple application of single dosages can be done.
    18. Use according to item 17, wherein the individual dosages per application to in each case from 5 to 40 mg, in particular in each case 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 methotrexate can be adjusted.
    19. Pre-filled syringe containing a pharmaceutical solution formulation of Methotr exat with a concentration greater than 25 mg / ml in a pharmaceutically acceptable solvent.
    20. Pre-filled syringe according to item 19, wherein the methotrexate is present in a concentration greater than 25 mg / ml to 150 mg / ml.
    21. Pre-filled syringe according to item 20, wherein the methotrexate is present in a concentration of about 50 mg / ml.
    22 pre-filled syringe according to one of the items 19 to 21, wherein 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 methotrexate.
    23. Pre-filled syringe according to any one of items 19 to 22, wherein the pharmaceutically acceptable solvent is selected from water, water for injections, water comprising isotonizing additives and saline, in particular isotonic saline.
    24. Pre-filled syringe according to any one of items 19 to 23 for subcutaneous administration.
    25. Pre-filled syringe according to item 24, wherein the prefilled syringe is structurally ausgestal tet, that a patient with limited fine motor skills self-application is made possible.
    26 carpule containing a pharmaceutical solution formulation of methotrexate with a concentration of greater than 25 mg / ml in a pharmaceutically acceptable solvent.
    27. Cartridge according to item 26, wherein the methotrexate is present in a concentration of greater than 25 mg / ml to 150 mg / ml.
    28. carpule according to item 27, wherein the methotrexate is present in a concentration of about 50 mg / ml.
    29. A carpule according to any one of items 26 to 28, wherein the pharmaceutical solu- tion formulation further contains a preservative.
    30. Cartridge according to one of the items 26 to 29, wherein this total dosage amount of 5 to 500 mg, in particular 7.5 to 300 mg, contains methotrexate.
    31. A carpule according to any one of items 26 to 30, wherein the pharmaceutically acceptable solvent is selected from water, water for injections, water comprising isotonizing additives and saline, in particular isotonic saline.
    32. Pen-type injector comprising a carpule according to any one of items 26 to 31.
    33. Pen-injector according to item 32 for subcutaneous administration.
    34. Pen-injector according to item 32 or 33, wherein the carpule and the pen-injector are designed such that a multiple application of single dosages can take place.
    35. pen injector according to item 34, wherein the individual dosages per application to each of 5 to 40 mg, in particular in each case 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 methotrexate can be adjusted.
    The following examples illustrate the invention without limiting it: EXAMPLES
    Example 1: The methotrexate solution (concentration: 50 mg / ml) illustrated below was prepared on the basis of the following formulation amounts.
    Methotrexate: 1.500g Sodium chloride: 120g Sodium Hydroxide: 300g Water for Injection: 28,764g Total: 30,684g = 30 liters To prepare the solution (Example 1) about 60% of the required water for injections (20-25 ° C) presented in the batch tank. With the stirrer switched on, the indicated amount of sodium chloride was added and completely dissolved. The container and the solution were flooded with nitrogen, whereby the residual oxygen was largely displaced. The indicated amount of methotrexate was suspended in the solution while still stirring. The pH of the solution was adjusted to between 8.5 to 8.9 using 1% sodium hydroxide solution (made from NaOH and water for injection). The temperature of the solution is between 20 and 30 ° C. The result is a clear solution whose pH is stable between 8.5 and 8.9. By adding the remaining amount of water for injections was made up to the final volume.
    By sterile filtration through a 0.22 micron sterile filter, the solution was filled using protective gas (nitrogen) in the intended glass type 1 sterile glass containers (carpules or pre-filled syringes) under clean room conditions (class A).
    Example 2: The methotrexate solution (concentration: 50 mg / ml) illustrated below was prepared on the basis of the following formulation amounts.
    Methotrexate disodium: 1.645 g Sodium chloride: 120 g Water for injections: 30.684 g Total: 30.684 g = 30 liters To prepare the solution (Example 2) about 60% of the required Water for injections (20-25 ° C) presented in the batch tank. With the stirrer switched on, the indicated amount of sodium chloride was added and completely dissolved. The container and the solution were flooded with nitrogen, whereby the residual oxygen was largely displaced. The indicated amount of methotrexate disodium salt was dissolved in the solution while still stirring. The temperature of the solution is between 20 and 30 ° C. The solution is clear and the pH is stable between 8.5 and 8.9. By adding the remaining amount of water for injections was made up to the final volume.
    By sterile filtration through a 0.22 m 2 sterile filter, the solution was filled using protective gas (nitrogen) in the provided sterile glass containers of glass type 1 (carpules or pre-filled syringes) under clean room conditions (Class A).
    权利要求:
    Claims (28)
    [1]
    claims
    A methotrexate solution for use in the treatment of autoimmune inflammatory diseases selected from rheumatoid arthritis, juvenile arthritides, vasculitis, collagenosis, Crohn's disease, ulcerative colitis, bronchial asthma, Alzheimer's disease, multiple sclerosis, ankylosing spondylitis, arthritic arthrosis or psoriasis in that the methotrexate solution is to be administered subcutaneously and the methotrexate is present in a single dose per application of 5 to 40 mg methotrexate and in a concentration of approximately 50 mg / ml in a pharmaceutically acceptable solvent.
    [2]
    2. Methotrexate solution for use according to claim 1, characterized in that the pharmaceutically acceptable solvent is selected from water, water for injections, water comprising isotonizing additives and saline, in particular isotonic saline.
    [3]
    A methotrexate solution for use according to claim 1 or 2, characterized in that the inflammatory autoimmune disease is rheumatoid arthritis.
    [4]
    A methotrexate solution for use according to claim 3, characterized in that the autoimmune inflammatory disease is juvenile rheumatoid arthritis.
    [5]
    5. Methotrexate solution for use according to one of claims 1 to 4, characterized in that the methotrexate solution is contained in an injection device for single application.
    [6]
    6. Methotrexate solution for use according to claim 5, characterized in that the injection device is a pre-filled syringe.
    [7]
    7. Methotrexate solution for use according to one of claims 1 to 4, characterized in that the methotrexate solution is contained in a storage vessel.
    [8]
    A methotrexate solution for use according to claim 7, characterized in that the methotrexate-containing solvent further comprises a preservative.
    [9]
    9. Methotrexate solution for use according to claim 7 or 8, characterized in that the storage vessel is a vial, a vial, a bag, a glass ampoule or a carpule.
    [10]
    10. Methotrexate solution for use according to claim 6, characterized in that the pre-filled syringe has an active ingredient content 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 methotrexate.
    [11]
    11. Methotrexate solution for use according to any one of claims 1 to 10, characterized in that the methotrexate solution is to be administered subcutaneously and the methotrexate is present in a concentration of about 50 mg / ml in a pharmaceutically acceptable solvent, the methotrexate Solution is contained in a single-application injection device and wherein the single-application injection device has an active ingredient content of 5.0, 7.5, 10.0, 12.5, 15.0, 17.5, 20.0 or 22.5 mg methotrexate contains.
    [12]
    12. A methotrexate solution for use according to any one of claims 1 to 11, characterized in that the methotrexate solution is to be administered subcutaneously and the methotrexate is present in a concentration of about 50 mg / ml in a pharmaceutically acceptable solvent, the pharmaceutically acceptable Solvent water for injection includes.
    [13]
    13. Methotrexate solution for use according to claim 12, characterized in that the water for injection contains as Isotonisierungszusatz sodium chloride.
    [14]
    14. Methotrexate solution for use according to any one of claims 1 to 13, characterized in that the methotrexate solution is to be administered subcutaneously and the methotrexate is present in a concentration of about 50 mg / ml in a pharmaceutically acceptable solvent, the pharmaceutically acceptable Solvent Water for injection, wherein the methotrexate solution is contained in a single-application injection device, and wherein the injection device is a pre-filled syringe.
    [15]
    A methotrexate solution for use according to claim 14, characterized in that the inflammatory autoimmune disease is rheumatoid arthritis.
    [16]
    16. Methotrexate solution for use according to claim 14, characterized in that the inflammatory autoimmune disease are juvenile arthritis.
    [17]
    The methotrexate solution for use according to claim 14, characterized in that the inflammatory autoimmune disease is psoriasis.
    [18]
    The methotrexate solution for use according to claim 14, characterized in that the inflammatory autoimmune disease is Crohn's disease.
    [19]
    A methotrexate solution for use according to claim 14, characterized in that the autoimmune inflammatory disease is the polyarthritic form of juvenile arthritis.
    [20]
    20. A methotrexate solution for use according to any one of claims 1 to 19, characterized in that the methotrexate solution is to be administered subcutaneously and the methotrexate is present in a concentration of about 50 mg / ml in a pharmaceutically acceptable solvent, the methotrexate Solution is contained in a single-application injection device which is a pre-filled syringe, the pre-filled syringe being provided with a cannula for subcutaneous injection, and wherein the pharmaceutically-acceptable solvent comprises water for injection containing as sodium isocyanate additive and sodium hydroxide.
    [21]
    21. Methotrexate solution for use according to any one of claims 1 to 20, characterized in that the methotrexate solution is to be administered subcutaneously and the methotrexate is present in a concentration of about 50 mg / ml in a pharmaceutically acceptable solvent, wherein the methotrexate Solution is contained in a single-application injection device which is a pre-filled syringe, the pre-filled syringe being provided with a cannula for subcutaneous injection, the pharmaceutically-acceptable solvent comprising water for injection containing as the isotonizing additive sodium chloride, and wherein the concentration is about 50 mg / ml Methotrexate is achieved by using Methotr-exate disodium.
    [22]
    22. Methotrexate solution for use according to any one of claims 1 to 21, characterized in that the methotrexate solution is to be administered subcutaneously and the methotrexate is present in a concentration of about 50 mg / ml in a pharmaceutically acceptable solvent, wherein the methotrexate Solution is contained in a single-application injection device which is a pre-filled syringe, the pre-filled syringe being provided with a cannula for subcutaneous injection, the pharmaceutically-acceptable solvent comprising water for injection containing as sodium isotonic acid sodium chloride and further sodium hydroxide, and the concentration of about 50 mg / ml methotrexate is achieved by using methotrate disodium.
    [23]
    A methotrexate solution for use according to any one of claims 20 to 22, characterized in that the inflammatory autoimmune disease is rheumatoid arthritis.
    [24]
    24. Methotrexate solution for use according to any one of claims 20 to 22, characterized in that the inflammatory autoimmune disease is juvenile arthritis.
    [25]
    25. Methotrexate solution for use according to any one of claims 20 to 22, characterized in that the inflammatory autoimmune disease is psoriasis.
    [26]
    26. Methotrexate solution for use according to any one of claims 20 to 22, characterized in that the inflammatory autoimmune disease is Crohn's disease.
    [27]
    A methotrexate solution for use according to any one of claims 20 to 22, characterized in that the autoimmune inflammatory disease is the polyarthritic form of juvenile arthritis.
    [28]
    28. Methotrexate solution for use according to one of claims 1 to 27, characterized in that the solution has a pH between 7.5 and 9. No drawings for this
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    同族专利:
    公开号 | 公开日
    DK2046332T3|2011-03-07|
    US20140179703A1|2014-06-26|
    RS51688B|2011-10-31|
    AU2007276387A2|2009-04-02|
    AT491455T|2011-01-15|
    US20190038629A1|2019-02-07|
    EP2046332B1|2010-12-15|
    EP2292235A3|2011-06-01|
    UA95488C2|2011-08-10|
    KR101260554B1|2013-05-06|
    JP5683810B2|2015-03-11|
    US8664231B2|2014-03-04|
    PL2046332T3|2011-05-31|
    HRP20110148T1|2011-03-31|
    MX2009000812A|2009-07-10|
    US10610531B2|2020-04-07|
    US20200246342A1|2020-08-06|
    AU2007276387B2|2010-09-30|
    CY1111159T1|2015-06-11|
    DE502007005972D1|2011-01-27|
    US20170246172A1|2017-08-31|
    WO2008009476A2|2008-01-24|
    EP2046332A2|2009-04-15|
    WO2008009476A3|2008-11-06|
    BRPI0715433A2|2013-07-23|
    JP2009544636A|2009-12-17|
    ES2355399T3|2011-03-25|
    CA2869671A1|2008-01-24|
    SI2046332T1|2011-02-28|
    EP2292235A2|2011-03-09|
    CA2659662A1|2008-01-24|
    PT2046332E|2011-02-04|
    KR20090079876A|2009-07-22|
    US20150164902A1|2015-06-18|
    DE202007019703U1|2015-10-28|
    ME01940B|2011-10-31|
    RU2009106053A|2010-08-27|
    DE102006033837A1|2008-01-31|
    US20100016326A1|2010-01-21|
    CA2659662C|2015-01-20|
    RU2403044C1|2010-11-10|
    US20140155405A1|2014-06-05|
    AU2007276387A1|2008-01-24|
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    法律状态:
    2017-09-15| MK07| Expiry|Effective date: 20170731 |
    优先权:
    申请号 | 申请日 | 专利标题
    DE102006033837A|DE102006033837A1|2006-07-21|2006-07-21|Concentrated methotrexate solutions|
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