WO2021058990A1 - Midazolam en poches souples - Google Patents

Midazolam en poches souples Download PDF

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Publication number
WO2021058990A1
WO2021058990A1 PCT/IB2019/001026 IB2019001026W WO2021058990A1 WO 2021058990 A1 WO2021058990 A1 WO 2021058990A1 IB 2019001026 W IB2019001026 W IB 2019001026W WO 2021058990 A1 WO2021058990 A1 WO 2021058990A1
Authority
WO
WIPO (PCT)
Prior art keywords
midazolam
solution
preservative
free aqueous
terminally sterilized
Prior art date
Application number
PCT/IB2019/001026
Other languages
English (en)
Inventor
Sergio Dusci
Original Assignee
InfoRLife SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by InfoRLife SA filed Critical InfoRLife SA
Priority to PCT/IB2019/001026 priority Critical patent/WO2021058990A1/fr
Publication of WO2021058990A1 publication Critical patent/WO2021058990A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • This invention relates to ready -to-use midazolam intravenous solutions in flexible plastic bags.
  • Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant.
  • Midazolam is administered either intramuscularly (IM) or intravenously (IV).
  • Midazolam is provided in glass vials or ampules at concentrations lmg/ml and 5mg/ml having volumes of 1 ml, 2 ml, and 5ml.
  • IM intramuscularly
  • IV intravenously
  • Midazolam is provided in glass vials or ampules at concentrations lmg/ml and 5mg/ml having volumes of 1 ml, 2 ml, and 5ml.
  • IV administration it is necessary to introduce the midazolam into an IV bag containing a suitable IV solution.
  • the bag can be stored overnight at room temperature, other IV solutions such midazolam in lactate Ringer’s solution have a useful life of only 4 hours. Further, if the entire vial is not used, the vial must be disposed
  • Midazolam is used intramuscularly or intravenously for preoperative sedation/anxiolysis/amnesia; intravenously as an agent for sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants
  • Midazolam is also used intravenously for induction of general anesthesia, before administration of other anesthetic agents. With the use of narcotic premedication, induction of anesthesia can be attained within a relatively narrow dose range and in a short period of time.
  • Intravenous midazolam can also be used as a component of intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia).
  • Midazolam is also used for continuous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting.
  • midazolam IV bags There currently are no ready-to-use midazolam IV bags available. Accordingly there is a need for a midazolam IV bag which has a long shelf-life at room temperature. Preferably the shelf-life at room temperature will equal or exceed 24 months at room temperature.
  • the present invention is directed to ready-to-use midazolam IV solutions in flexible plastic bags.
  • Ready-to-use bags eliminate the need for the hospital pharmacy to predict the number of IV bags it will need each have them ready when needed. If the pharmacy overestimates the need, the bags must be disposed of because their short shelf-life. Making up too few can leave the hospital short of the needed medication. Neither is an optimum situation.
  • the midazolam IV solution in the ready -use-bags allows for the midazolam to be stored near where it will be used simplifying its use and keeping it available where it may be needed on short notice.
  • Drawing Figures 1 to 4 show the properties of a lmg/ml product after terminal sterilization and during the six month accelerated stability testing.
  • Drawing figure 1 shows the amount of degradation products as function of time over the six month stability period at 40°C.
  • Drawing figure 2 reports the amount of midazolam present in the product as a function of time over the stability test.
  • Drawing figure 3 reports the change in pH over the course of the stability testing.
  • Drawing figure 4 shows the variation of osmolarity over the course of the stability test.
  • Vials of midazolam are commonly available at concentrations of lmg/ml and 5 mg/ml in volumes of from 2ml to about 15 ml, most commonly in the United States in 2ml and 5 ml vials for the lmg/ml concentration and 1ml and 2ml vials for the 5mg/ml concentration.
  • IV administration the contents of the vial must be transferred to an IV bag containing a suitable IV fluid.
  • Suitable IV fluids include saline, 5% dextrose, Ringer’s lactate solution, and other IV solutions compatible with midazolam.
  • the formulations of the current invention will contain from about 0.25mg/ml up to about 1.5 mg/ml, more preferable about 0.5 mg/ml up to about 1.25 mg/ml. Most preferably the formulation will contain from about 0.5 mg/ml to about 1.0 ml/mg. The most preferred concentration is about 1.0 mg/ml or about
  • the formulation includes in addition to the midazolam, a tonicity adjusting agent in an amount sufficient to make the solution isotonic.
  • a solution is considered to be isotonic if it has an osmolality of between about 260 and 320 mosm/kg.
  • Suitable isotonic adjusting agents include sodium chloride, potassium chloride and calcium chloride or mixture a thereof. Sodium chloride is the preferred tonicity agent.
  • the amount of the tonicity agent used is sufficient to render the solution isotonic. If sodium chloride is the tonicity adjusting agent and the midazolam concentration is about 1.0 mg/ml, the amount of sodium chloride to be included in the formulation is about 9 mg per mg/ml of the midazolam solution. For a 50 ml solution at a midazolam concentration of 1 mg/ml, the amount of sodium chloride is about 450mg and for a 100ml solution at a midazolam concentration of 1 mg/ml, the amount of sodium chloride is about 900 mg. The amount of the tonicity agent may be adjusted to achieve the desired mosm/kg.
  • the solubility of midazolam is less than 0.1 mg/mL at neutral pH and it increases considerably in acidic media.
  • a solubility study has been performed to evaluate the use of midazolam base in the proposed formulation. Since the solubility of midazolam is pH-dependent, the purpose of this study was to evaluate the pH value at which midazolam becomes soluble in aqueous solution. Midazolam at a concentration of 2 mg/mL is soluble in a solution of 0.9% NaCl when the pH reaches a value of about 3.2 pH. The solubility increases at lower pHs.
  • the desired pH of the formulation is about from about 2.5 to about 3.5, preferably 2.8 to 3.2 and more preferably about pH 3.
  • Sufficient acid is added to the solution to achieve the desired pH.
  • Any pharmaceutically acid may be used.
  • the acid is a pharmaceutically acceptable mineral acid, most preferably hydrochloric acid.
  • a pharmaceutically acceptable base may be used to raise the pH if needed.
  • the preferred bases are pharmaceutically acceptable inorganic bases such as sodium hydroxide and potassium hydroxide. Sodium hydroxide is the preferred base.
  • Sufficient water is present to provide the desired midazolam concentration in the final formulation.
  • the formulation does not contain any preservatives.
  • the formulation consists essentially of the midazolam, water, acid, base, if needed, and tonicity agent. In a preferred embodiment, the formulation consists of midazolam, water, acid, base, if needed, and tonicity agent.
  • the flexible plastic container must be one which is compatible with midazolam. It must also be able to undergo heat sterilization in moist steam.
  • Suitable flexible plastic containers are those made of copolymerized ethylene and vinyl acetate.
  • the bag is laminated with the inner most layer comprising copolymerized ethylene and vinyl acetate. More preferably the bag comprises from 3 to 7 layers. These materials are commercially available under the tradename Nexcel® by Sealed Air.
  • the volume of the bag is dependent on the volume of premixed formula.
  • the volume of premixed formula can be from 10 ml to 1000 ml, preferable 50ml and 100ml based on current midazolam dosing. Larger or smaller volumes can be used depending on dosing requirements.
  • CR3 elastomer copolyester ether bags may also be used for formulations to be sterilized in moist steam provided but are not preferred.
  • a flexible plastic container with modified ports and closure system suitable for storing midazolam formulations of the present invention which is subjected to typically product sterilization by steam sterilization (e.g., autoclaving, 121°C for about 20 minutes) [is this correct?] without altering the thermal properties of the film layers, ports and closure system as well as maintaining the integrity container.
  • the primary polymeric materials which may be used include: polysulfone, polycarbonate, polypropylene, polyethylene (LDPE or HDPE), ethylene/propylene copolymers, polyolefins, acrylic-imide copolymers, polyester (e.g.
  • the ports and the closure system preferably uses commerciality available polymers, elastomers etc.
  • the administrative and additive ports can be made off external coextruded layer consists of synthetic thermoplastic rubber (Raumedic SRT320) ranging from about 20 to 30 % based on an elastomer modified polypropylene. While the internal coextruded layer (PE770) of not more that 50% in composition consists of ethylene vinyl acetate without any further additives (EVA).
  • the tubing ports can be made of two-layer materials, which can withstand both terminal sterilization and co-solvent matrix. Furthermore, the twist-off compositions can be made of polyproplene Granuflex® 4489 between 70-80% and Granuflex ®4371 15-20%.
  • the port tube may be a bilayer tube comprising an outer layer of polypropylene and an inner layer of EVA and the twist off made of LDPE and PP.
  • EVA polyethylene glycol
  • LDPE low density polyethylene
  • PP polypropylene
  • other polymers stable, low leachables, and without physical deformation during heat sterilization may alsobe used for the ports and closure assemblies.
  • bags such as Excel® (Braun Company) comprising a three-layered ethylene-polypropylene bag having polyester elastomer outer layer, Visiv® (Hospira), Nexcel® (Sealed Air), Intervia® (Baxter) preferably with a non-DEHP fluid path, Technoflex polyolefin bags, etc., for pharmaceutical formulation or medical liquids are assembled of different plastic materials of different properties, thermal resistance and functionalities. They are typically designed and tested mostly for aqueous formulations admixtures, premixed or ready -to-use pharmaceutical products.
  • the combination of the water and drug composition subjected to further heat sterilization can adversely affect plastic materials, sealing integrity and the solutions contained therein unless they are maintained at certain conditions.
  • the plastic container should be checked after sterilization for integrity before using it for the formulation.
  • the formulation after sterilization should be analyzed for the presence of substances leached from the container as a result of the sterilization cycle.
  • a flexible plastic container with modified ports and closure system suitable for storing the formulations of the present invention which is subjected to typically product sterilization by steam sterilization (e.g., autoclaving, 121°C for about 15 to 20 minutes) without altering the thermal properties of the film layers, ports and closure system as well as maintaining the integrity container.
  • the primary polymeric materials which may be used include: polysulfone, polycarbonate, polypropylene, polyethylene (LDPE or HDPE), ethylene/propylene copolymers, polyolefins, acrylic-imide copolymers, polyester (e.g. PET, PEN and the like), Teflon, Nylon, acetal (Delrin), polymethylpentene, PVDC, ethylvinylacetate, AN-copolymer etc.
  • Sterilization is accomplished by heat sterilization.
  • Heat sterilization is normally performed using steam, preferably wet steam, or superheated water.
  • the time period for the sterilization must be long enough to meet the sterility requirements required of an injectable product. When steam is used the period may be from about 5 to 30 minutes at temperatures of about 110°C to 130°C, or from about 10 to 30 minutes at temperatures of about 110°C to 130°C, preferably at 120°C to 125°C for 15 to 30 minutes. In another embodiment, the sterilization can be at 120°C for 15 to 20 minutes.
  • the tank is filled with about 90% of the target weight of WFI and the solution is cooled to a temperature between 85-70°C. Before the initial weight is reached, starts the recirculation for cooling the solution ( ⁇ 85°C).
  • the raw materials are added into the tri-blender in the following order: Hydrochloric Acid 37% (to dissolve the API), Midazolam, Sodium chloride. Add Water for Inj ection to the final weight.
  • the quantity of material to be used for batch will be the following: Adjust the pH to 2.9 - 3.1 by the addition of Hydrochloric acid 37% diluted in WFI to a concentration of about 1 N.
  • the minimum solution recirculation time is 5 minutes at the tri blender flow rate of > 3.0 1/sec.
  • the rinsing is activated; the solution recirculating in the filling line passing through the filters, the filling nozzles and returns to the dissolution tank.
  • the solution is cooling to a temperature of ⁇ 60°C.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)

Abstract

L'invention concerne une solution aqueuse de midazolam sans conservateur ayant subi une stérilisation terminale comprenant de 0,25 à 1,5 mg/ml de midazolam, un agent d'ajustement de tonicité pour fournir une osmolalité comprise entre 260 et 320 mosm/kg, ainsi qu'un acide et éventuellement une base en quantité suffisante pour fournir un pH d'environ 2,5 à 3,5, l'eau restante étant destinée à l'injection conditionnée dans un récipient en plastique souple.
PCT/IB2019/001026 2019-09-25 2019-09-25 Midazolam en poches souples WO2021058990A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IB2019/001026 WO2021058990A1 (fr) 2019-09-25 2019-09-25 Midazolam en poches souples

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2019/001026 WO2021058990A1 (fr) 2019-09-25 2019-09-25 Midazolam en poches souples

Publications (1)

Publication Number Publication Date
WO2021058990A1 true WO2021058990A1 (fr) 2021-04-01

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2019/001026 WO2021058990A1 (fr) 2019-09-25 2019-09-25 Midazolam en poches souples

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WO (1) WO2021058990A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017013677A1 (fr) * 2015-07-18 2017-01-26 Neon Laboratories Limited Solution injectable liquide stable de midazolam et de pentazocine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017013677A1 (fr) * 2015-07-18 2017-01-26 Neon Laboratories Limited Solution injectable liquide stable de midazolam et de pentazocine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "MIDAZOLAM INJECTION: Midazolam 1 mg/mL and 5 mg/mL Injection", 2 February 2018 (2018-02-02), pages 1 - 14, XP055598691, Retrieved from the Internet <URL:https://medsafe.govt.nz/profs/Datasheet/m/MidazolaminjPfizer.pdf> [retrieved on 20190624] *
SCHNEIDER J J ET AL: "A STUDY OF THE OSMOLALITY AND PH OF SUBCUTANEOUS DRUG INFUSION SOLUTIONS", VDI NACHRICHTEN, VDI VERLAG GMBH, DUSSELDORF, DE, vol. 27, no. 1, 1 January 1997 (1997-01-01), pages 29 - 31, XP008057817, ISSN: 0042-1758 *

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