FIELD OF THE INVENTION

The present invention relates to a sterile, ready-to-use infusion container comprising a stable aqueous solution of Midazolam or a pharmaceutically acceptable salt thereof, suitable for intravenous infusion. The invention also relates to a novel construction of an infusion bag having plurality of ports for delivering or receiving sterile fluid that is suitable for the said stable aqueous solution of Midazolam or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

Midazolam is a white to light yellow crystalline compound, insoluble in water. The hydrochloride salt of Midazolam is a water soluble benzodiazepine. Chemically, Midazolam hydrochloride is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo [1, 5-a] [1, 4] benzodiazepine hydrochloride. It is a short-acting benzodiazepine central nervous system (CNS) depressant and is generally administered alone or in combination with second medicament for e.g. morphine, atropine, scopolamine, mepiridine.

Midazolam is used via intravenous administration to treat or as a supportive medication such as preoperative anxiolysis, sedation or amnesia, prior to or during diagnostic, therapeutic or endoscopic procedures such as bronchoscopy, gastroscopy. Also it is used as an anaesthetic in cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants. It can be used for induction of general anaesthesia before administration of other anaesthetic agents. It can also be used as a component of intravenous supplementation of nitrous oxide and oxygen. It may further be used for sedation of intubated and mechanically ventilated patients as a component of anaesthesia or during treatment in a critical care setting. It is important to note that a mixture of Midazolam solution with other premeditations like morphine sulphate, mepiridine, atropine sulphate or scopolamine before administration is also prescribed.

Currently Midazolam is marketed at concentration of 5 mg/ml (2 ml and 10 ml ampoules) or 2 mg/ml (5 ml ampoules) which exceeds the dose required for most patients. For continuous infusion, high strength Midazolam formulations are diluted at a concentration of 0.5 mg/ml using 5% dextrose in water or 0.9% sodium chloride. It is also extremely important that no microbial contamination occur during this manipulation and the sterile nature of the product is preserved. Any deviation from recommended sterile techniques poses a risk to the safety of patient. Moreover, manual manipulations such as steps of reconstitution, dilution and incorporation into a sterile, aqueous vehicle suitable for intravenous infusion can result in the wrong dose being administered or even in the error of infusing different drugs in cases where the patient is prescribed combination or sequential therapy with multiple drugs. The National Reporting and Learning Service received 498 patient safety incidents between November 2004 and November 2008 where the dose prescribed or administered to the patient was inappropriate, and three incidents resulted in death. Till date, there is no single intravenous dosage form that provides a sterile, ready to use stable, liquid formulation of Midazolam that can be administered without any manipulation to a patient in need thereof, thereby avoiding a compromise with the sterility, an error in dosing accuracy and/or in medicament preparation etc. This necessitates the need of a sterile, ready to use infusion container comprising a stable, liquid formulation of Midazolam which can be administered to a patient in need thereof without deviation or manipulations and while preserving the sterility of the product, and also with a provision of mixing other medicaments for combination of sequential therapy, if needed.

There are also reports on Midazolam getting adsorbed onto the wall of the body of the plastic container in which it is stored, particularly polypropylene plastic containers. In 1993, Hagan et al. Am J Hosp Pharma. 1993; 50:2379-81, studied the stability of Midazolam hydrochloride 0.5 mg/ml, diluted with 5% dextrose solution and 0.9% sodium chloride in polyolefin bags. It was found that diluted preparations were stable over a period of 30 days when stored in dark at room temperature. Similarly, Karlage et al. 2011 Am J Health Syst Pharm. 2011; 68:1537, studied stability of Midazolam hydrochloride 1 mg/ml solution diluted with 5% dextrose in polyvinyl chloride and polyolefin bags. The study concluded that the diluted solution remained stable for about 27 days in both type of bags, regardless of storage conditions. McMullin et al., 1985 Am J Health Syst Pharm. 1995; 52:2018-2020, also studied stability of Midazolam 1 mg/ml in 0.9% sodium chloride, and filled in polyvinyl chloride bags under fluorescent light and reported about 10 days of stability stored at room temperature. However, there is no disclosure or suggestion in the art for a long term stability of Midazolam solution formulations in a sterile, ready-to use infusion container. Further, the present inventors while testing the stability of Midazolam hydrochloride solution in various types of infusion containers, also witnessed the problem of the adsorption of Midazolam on the wall of such containers. It was also found that the problem is concentration dependent i.e. more the solution in dilute form, more is the adsorption of Midazolam on the wall of the container, particularly when the container is a plastic infusion bag and it has been subjected to sterilization by autoclaving. This problem was found to be aggravating with increasing temperature.

In the present invention, the inventors have overcome multiple problems of prior art, such as providing a sterile, ready-to-use infusion container comprising a stable, aqueous solution of Midazolam hydrochloride, which can be administered to a patient without any manipulations and without compromising the sterility of the product. The inventors have also stabilized the formulation by designing an innovative infusion container which not only solves the problems associated with physico-chemical stability of Midazolam or a salt thereof, but also allows ease of administration of a second sterile fluid, if needed. The invention further provides a method of treating a disease or a condition or providing a supportive medication, by intravenously administering the sterile aqueous solution of Midazolam from the said infusion container, without any intermediate step(s) of dilution/reconstitution or any other type of manipulation(s) that may otherwise compromise the sterility of the solution in the infusion container or may cause an error in dosing to a patient in need thereof. The said infusion container in the preferred embodiments on the invention may have two ports. This unique feature of having two ports in the infusion bag allows simultaneous or sequential administration of a second sterile fluid, with or without a second medicament. Most importantly, the ready to use, stable liquid formulation of Midazolam hydrochloride in an infusion container according to the present invention can be terminally sterilized.

SUMMARY OF THE INVENTION

The present invention provides a sterile, ready-to-use, infusion container comprising a body filled with a stable, aqueous solution of Midazolam or a pharmaceutically acceptable salt thereof. The aqueous solution or formulation of Midazolam in an infusion container according to the present invention remains stable for a long time at different storage conditions, including after terminal sterilization by autoclaving at 121° C. for 15 minutes. Such terminally sterilized ready to use, stable aqueous formulation of Midazolam neither shows the presence of any sub-visible particles (Nylon particles) nor an adsorption of Midazolam on the inner walls of the body of infusion container, immediately after preparation as well as during long term storage, with or without terminal sterilization by autoclaving.

In one aspect, the present invention provides a sterile, ready-to-use infusion container comprising a stable, aqueous solution of Midazolam comprising:

a. Midazolam or a pharmaceutically acceptable salt thereof;

b. A tonicity adjusting agent;

c. A pH adjusting agent; and

d. water for injection.In a preferred embodiment, the said aqueous solution comprises 0.1 mg/ml to 2 mg/ml, and preferably 0.5 mg/ml to 1.0 mg/ml of Midazolam or a base equivalent concentration of a pharmaceutically acceptable salt thereof.In another preferred embodiment, the said aqueous solution has a pH of 3.0 to 4.5, more preferably 3.0 to 4.0, and most preferably 3.4±0.2.In another preferred embodiment, the tonicity adjusting agent in the said aqueous solution is Sodium chloride.In another preferred embodiment, the present invention provides a sterile, ready-to-use infusion container comprising:

a) a body filled with about 80 ml to about 500 ml of a stable, aqueous solution of Midazolam or a pharmaceutically acceptable salt thereof, and

b) one or more tubes fixed to the body of the container.In a more preferred embodiment, the container comprises at least two tubes fixed to the body of the container wherein one of the at least two tubes is fitted to an outlet port which is designed to attach to a sterile infusion set, and another tube is fitted to an inlet port which is designed to receive a sterile fluid which is with or without a medicament other than Midazolam.

In one embodiment, the infusion container is a rigid, semi-rigid or a flexible container. Preferably, the infusion container is a flexible infusion bag. More preferably, the wall of the body of the said flexible infusion bag comprises at least two layers wherein the innermost layer is made-up of a Cyclo-olefin polymer or a Cyclo-olefin co-polymer. In one of the most preferred embodiments, the wall of the body of the said flexible infusion bag comprises three layers wherein the outermost layer is made-up of Polypropylene (PP), middle layer is made-up of linear low-density Polyethylene (LDPE), and the innermost layer is made-up of a Cyclo-olefin polymer or a Cyclo-olefin co-polymer.

In another specific aspect, the present invention provides a method of treating a disease or a condition or providing a supportive medication, by intravenously administering to a patient in need thereof, the stable aqueous solution of Midazolam or a pharmaceutically acceptable salt thereof, from a sterile, ready-to-use infusion container.

In one more aspect, the invention provides use of a sterile, ready-to-use infusion container comprising a stable, aqueous solution of Midazolam or a pharmaceutically acceptable salt thereof for treating a disease or a condition or for providing a supportive medication, by intravenously administering to a patient in need thereof.

