WO2016093781A1

WO2016093781A1 - Concentrated parenteral methotraxate formulations

Info

Publication number: WO2016093781A1
Application number: PCT/TR2015/050136
Authority: WO
Inventors: Ender KOÇAK
Original assignee: Koçak Farma İlaç Ve Ki̇mya Sanayi̇ Anoni̇m Şi̇rketi̇
Priority date: 2014-12-09
Filing date: 2015-10-12
Publication date: 2016-06-16

Abstract

The present invention relates to a parenteral administration of methotraxate for the treatment of inflammatory autoimmune diseases, wherein methotraxate is formulated at a concentration of 40mg/mL in a pharmaceutically acceptable solvent.

Description

CONCENTRATED PARENTERAL METHOTRAXATE FORMULATIONS

This invention relates to a parenteral administration of concentrated methotraxate solutions. Especially, the present invention relates to a parenteral administration of methotraxate for the treatment of inflammatory autoimmune diseases, wherein methotraxate is formulated at a concentration of 40mg/ml in a pharmaceutically acceptable solvent. The invention is also related to ready-use syringe and a carpule containing above mentioned concentrated solution, as well as pen injector comprising such a carpule and/or a ready–use syringe.

Methotraxate belongs to antifolate agents. These agents work by inhibiting the action of key enzymes thymidylate synthase and dihydrofolate reductase. Antifolates have found clinical utility as antitumor and antineoplastic agents. Antifolates inhibit both purine and pyrimidine synthesis by blocking enzyme functions and cause cell death. They have a greater toxic effect on rapidly dividing cell like cancer cells. High doses of methotraxate up to 5000 mg are used in the cancer treatment.

Besides its use in cancer therapies, methotraxate is also used in low doses for the treatment of rheumatoid arthritis (RA). Methotraxate was reviewed in Pharmacol Rev 57:163–172, 2005. Although the first reported use of methotrexate in the treatment of rheumatoid arthritis was in the early 1950s, it did not come into common use in the treatment of rheumatoid arthritis until in the beginning of 1980s.

Methotrexate is generally administered to patients with rheumatoid arthritis as a single weekly dose given either intramuscularly or orally. In the treatment of rheumatoid arthritis, the usual dose of methotrexate is in the range of 10 to 25 mg/week. At the doses commonly used for the treatment of rheumatoid arthritis, the bioavailability of oral methotrexate varies considerably between individuals.

Methotrexate was an effective therapy for rheumatoid arthritis (RA). As experience with methotrexate in the therapy of rheumatoid arthritis increased, it quickly became apparent that this drug was more effective and better tolerated than the other agents available for the treatment of RA. A greater percentage of patients continued to take methotrexate for their rheumatoid arthritis longer than any other second-line agent.

In the patent application PCT/EP2012/670074 disclosed the use of methotraxate in the treatment of rheumatoid arthritis, which is a chronic inflammatory and destructive joint disease that affects approximately 1% of the population in the industrialized world. It affects approximately 3 times more women than men and onset is generally between 40-60 years of age. RA is characterized by hyperplasia and inflammation of the synovial membrane, inflammation within the synovial fluid, and progressive destruction of the surrounding bone and cartilage. It is a painful condition, can cause severe disability and ultimately affects a person’s ability to carry out everyday tasks. Effects of RA vary between individuals, but disease can progress very rapidly, causing swelling and damaging cartilage and bone around the joints. Any joint may be affected but its commonly the hands, feet and wrists. Internal organs such as the lungs, heart and eyes can also be affected.

The cause of RA remains unknown, although studies have elucidated some aspects of the inflammatory processes underlying the disease. RA is believed to be initiated and driven through a T-cell mediated, antigen-specific process. In brief, the presence of an unidentified antigen in a susceptible host is thought to initiate a T-cell response that leads to the production of T-cell cytokines with consequent recruitment of inflammatory cells, including neutrophils, macrophages and B-cells.

Methotraxate is an antimetabolite and antifolate, although its efficacy is believed to be due to the suppression of T cell activation and expression of adhesion molecule.

Methotraxate can be taken orally or parenterally as other cytostatic drugs. There are two reasons why one should take Methotrexate by injection; some patients have distressing side-effects with the tablets such as feeling sick or having diarrhea, and when the drug is taken orally, absorbing the full medication dose from the stomach is not possible due to the low bioavailability. Absorption of full medication dose is important for the cytostatic drugs.

Makwana et al. tells in Int. J. Investig. 2011, 1, 200 about advantages of ready to use syringes. Prefilled syringes provide greater patient safety by reducing the potential for inadvertent needle sticks and exposure to toxic products that can occur while drawing medication from vials. Prefilled syringes, with their pre-measured dosage, can reduce dosing errors and increase patient compliance. Prefilled syringes can virtually reduce the manufacturers’ need to overfill unlike vials those are overfill by as much 20-30% to account for potential waste. Prefilled syringes assure delivery of particulate free solution and accommodate volumes that typically range from 0.25 to 5.0 ml. They are therefore best suited to products administered by subcutaneous or intramuscular injection. The advantages of prefilled syringe cartridges are their convenience, affordability, accuracy, sterility, and safety.

Ready to use syringe for the parenteral administration of methotraxate solution is already known in world market (trade names: Lantare and Metex). The concentrations of these drugs are around 25 mg/ml and 10 mg/ml respectively. The solvent used for the concentrated methotraxate solution is usually water for injection which can also contain some isotonicity agent like sodium chloride and sodium hydroxide to adjust the pH.

In a recent patent (US8644231 B2) methotraxate is prepared as a concentrated solution 50 mg/ml for the treatment of inflammatory autoimmune diseases. The owner of this patent state that the prior art preparation that are approved for subcutaneous application have the disadvantage that, depending on the amount of active substances to be administrated in each week, relatively large amounts of liquid have to be injected under the patients skin. This large amount of liquid is hard to convey especially for the children. On the other hand 50mg/ml is too concentrated for the parenteral formulation of methotraxate, if it is thought that use of methotraxate is in the range of 10 to 25 mg/week.

There is still a need for the parenteral formulations of methotraxate which can be administrated to the patient especially to children for the treatment of inflammatory autoimmune diseases.

It is an object of the present invention to provide a parenteral formulation of methotraxate for the treatment of inflammatory autoimmune diseases, especially rheumatoid arthritis, which provides advantages than prior art.

It is an embodiment of the invention that the use of methotraxate in the formulation of parenterally administered drug for the treatment of inflammatory autoimmune disease, wherein, methotraxate is present in a pharmaceutically acceptable solvent in a concentration ranges from 30 mg/ml to 45 mg/ml, preferably 35 – 45 mg/ml, more preferably 40 mg/ml to 45 mg/ml and most preferably 40 mg/ml.

Another embodiment of the invention is that concentrated methotraxate solutions are administered preferably by subcutaneous administration.

It is another embodiment of the invention that methotraxate concentrated solutions defined above are stored in an injection device which can be a ready to use syringe, a carpule or a pen injector comprising such a carpule.

The pharmaceutically acceptable solvent in this invention is water for injection; wherein water for injection contains isotonicity agent like sodium chloride and a pH adjusting agent like sodium hydroxide.

The parenteral formulation containing concentrated methotraxate solutions according to present invention are used for the treatment of inflammatory autoimmune diseases including rheumatoid arthritis, juvenile, vasculitides, collagenoses, crohn’s disease, colitis ulcerose, bronchial asthma, Alzheimer’s disease, multiple sclerosis, Bechterew’s disease, joint arthroses, or psoriasis.

An injection device for a single application according to present invention contains a dose of drug substance methotraxate from 5mg to 45mg. In particular injection device for a single application 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, 40.0, 42.5 or 45.0 mg. The liquid volume of injectable 20mg dose for a single application containing methotraxate would be 0.5 ml according to 40mg/ml concentration present in this invention.

The methotraxate formulations according to the present invention can be prepared in a storage container. The storage container according to the present invention is a container, in which the concentrated methotraxate formulations of the invention can be filled and stored sterile. The inventive storage container comprising methotraxate solutions prepared according to the invention contains a total dosage amount of 5 to 5000 mg methotraxate.

In another embodiment of the present invention the storage container which contains the concentrated methotraxate formulations of the invention is preferably a carpule.

According to present invention an injection device can be a pen injector comprising a carpule containing the drug of the present invention.

Furthermore the storage container according to the invention is preferably a pen injector comprised in the carpule such that multiple application of single dosage can be carried out. According to present invention a pen injector for a single application contains a dose of drug substance methotraxate from 5mg to 45mg. In particular pen injector for a single application 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, 40.0, 42.5 or 45.0 mg.

Ready to use syringe according to present invention is constructed such a way that even a rheumatoid arthritis patient be able to self-inject the finished product.

The invention is described in more detail in the following examples.

Example 1

The concentrated methotraxate solution 40mg/ml was prepared from the following excipients.

Methotraxate	1200 g
Sodium chloride	96 g
Sodium hydroxide	240 g
Water for injection	28764 g
Total	30 L

In order to prepare the concentrated solution the half of the water for injection was added into the reactor at 24-28 ^oC while stirring. The amount of sodium chloride (96 g) was added and the mixture was stirred to give a clear solution. To remove dissolved oxygen nitrogen gas is passed through the solution. Methotraxate (1200 g) was added to the solution to give a suspension. The pH of the suspension was adjusted to 8.5 to 9.0 by adding dilute sodium hydroxide in water for injection. The mixture was stirred at this temperature for 15-20 minutes to afford a clear solution with a stable pH in the range of 8.5 to 9.0. The rest of water for injection was added to the reactor. The solution was filtered through 0.22µm filter and filled to ready-use syringe under inert atmosphere in sterile room (Class A).

Example 2

Methotraxate disodium	1316 g
Sodium chloride	120 g
Water for injection	30684 g
Total	32,9 L

In order to prepare the concentrated solution the half of the water for injection was added into the reactor at 24-28 ^oC while stirring. The amount of NaCl (96 g) was added and the mixture was stirred to give a clear solution. To remove dissolved oxygen nitrogen gas is passed through the solution. Methotraxate disodium (1316 g) was added to the solution. The mixture was stirred at this temperature for 15-20 minutes to afford a clear solution with a stable pH in the range of 8.5 to 9.0. The rest of water for injection was added to the reactor. The solution was filtered through 0.22µm filter and filled to ready-use syringe under inert atmosphere in sterile room (Class A).

Claims

A method for treating patients having inflammatory autoimmune diseases, characterized in that parenterally administering to the patients a drug comprising methotraxate in water for injection at a concentration of 30 – 45 mg/ml.
The method according to claim 1, wherein parenterally administering to the patients a drug comprising methotraxate in water for injection at a concentration of 35 – 45 mg/ml.
The method according to claim 2, wherein parenterally administering to the patients a drug comprising methotraxate in water for injection at a concentration of 40 – 45 mg/ml.
The method according to claim 3, wherein parenterally administering to the patients a drug comprising methotraxate in water for injection at a concentration of 40 mg/ml.
The method according to claims 1 - 4, wherein the concentrated methotraxate solutions are administered by subcutaneous administration
The method according to claim 5, wherein water for injection comprises isotonicity agents like sodium chloride and a pH adjusting agent like sodium hydroxide.
The method according to claim 5, wherein inflammatory autoimmune diseases include rheumatoid arthritis, juvenile, vasculitides, collagenoses, crohn’s disease, colitis ulcerose, bronchial asthma, Alzheimer’s disease, multiple sclerosis, Bechterew’s disease, joint arthroses, or psoriasis.
The method according to claim 6, wherein the inflammatory autoimmune disease is rheumatoid arthritis.
The method according to claim 5, characterized in that the drug is contained in an injection device for a single use
The method according to claim 9, characterized in that the injection device contains a dosage of from 5mg to 45mg of methotrexate.
The method according to claim 10, characterized in that the injection device is a ready to use syringe.
The method according to claim 11, characterized in that 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, 40.0, 42.5 or 45.0 mg of methotraxate
The method according to claim 5, characterized in that the drug is contained in a storage container.
The method according to claim 13, characterized in that the storage container contains a total dosage amount of 5 to 5000 mg.
The method according to claim 14, characterized in that the storage container is a carpule.
The method according to claim 15, characterized in that the carpule can be placed in a pen injector to provide multiple application of single dosage administration.
The method according to claim 16, characterized in that the pen injector 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, 40.0, 42.5 or 45.0 mg of methotraxate.