WO2008147715A2 - Multi-dose concentrate esmolol with benzyl alcohol - Google Patents

Multi-dose concentrate esmolol with benzyl alcohol Download PDF

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Publication number
WO2008147715A2
WO2008147715A2 PCT/US2008/063755 US2008063755W WO2008147715A2 WO 2008147715 A2 WO2008147715 A2 WO 2008147715A2 US 2008063755 W US2008063755 W US 2008063755W WO 2008147715 A2 WO2008147715 A2 WO 2008147715A2
Authority
WO
WIPO (PCT)
Prior art keywords
composition
esmolol
benzyl alcohol
buffering agent
volume
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2008/063755
Other languages
English (en)
French (fr)
Other versions
WO2008147715A3 (en
Inventor
Deepak Tiwari
George Owoo
Rekha Nayak
Kenneth E. Burhop
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Baxter Healthcare SA
Baxter International Inc
Original Assignee
Baxter Healthcare SA
Baxter International Inc
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 Baxter Healthcare SA, Baxter International Inc filed Critical Baxter Healthcare SA
Priority to CA002686566A priority Critical patent/CA2686566A1/en
Priority to AU2008256949A priority patent/AU2008256949B2/en
Priority to CN2008800170791A priority patent/CN101677943B/zh
Priority to EP08755579A priority patent/EP2164464A2/en
Priority to BRPI0811850-7A2A priority patent/BRPI0811850A2/pt
Priority to MX2009012614A priority patent/MX2009012614A/es
Priority to JP2010509457A priority patent/JP2010528025A/ja
Publication of WO2008147715A2 publication Critical patent/WO2008147715A2/en
Publication of WO2008147715A3 publication Critical patent/WO2008147715A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention is directed to enhanced stability concentrate esmolol formulations. More specifically, the invention is directed to a concentrate esmolol formulation stabilized with benzyl alcohol.
  • the compositions of the present invention are also suitable as multiple-dose compositions. Additionally, the present invention is directed to ready-to-use, diluted compositions made by dilution of the concentrate esmolol compositions of the present invention.
  • Esmolol and its pharmaceutically acceptable salts, e.g., hydrochloride salt) and related compounds have ⁇ -adrenergic blocking activity, ⁇ -blockers are therapeutically effective agents for the treatment and prophylaxis of cardiac disorders when administered in the appropriate dosage.
  • Esmolol which is a short-acting ⁇ -blocker, is often times used in acute care settings to control the heart rate of a patient.
  • the short acting property of esmolol is due to its rapid hydrolysis of the labile aliphatic methyl ester group in the blood.
  • Ready-to-use isotonic, and concentrate formulations, of esmolol are disclosed in U.S. Patent Nos.
  • a current commercial esmolol concentrate formulation covered under U.S. Patent No. 5,017,609, comprises about 250 mg/ml of esmolol hydrochloride, 25% by volume ethanol, 25% by volume propylene glycol, 17 mg/ml sodium acetate trihydrate, and 0.715% by volume of glacial acetic acid. This composition is not intended for direct injection but for subsequent dilution with a suitable diluent.
  • the current commercial concentrate formulation employs excipients (ethanol and propylene glycol) to stabilize the hydrolytic reaction, but those excipients leads to the formation of other related ester degradants. Therefore, the current commercial esmolol concentrate formulation under long term storage conditions results in the formation of ethyl and propoyl esters of esmolol in addition to ASL- 8123. Furthermore the excipients (ethanol and propylene glycol) used to stabilize the current commercial esmolol concentrate formulation have been associated with potential injection site pain or irritation.
  • a concentrate esmolol formulation comprises about 25-1000 mg/ml of esmolol
  • compositions are pH adjusted to between about 3.5 and about 7.0.
  • Benzyl alcohol typically used as a preservative, has been surprisingly found to stabilize the concentrate esmolol compositions of the present invention.
  • a ready-to-use composition and a method of dosing such composition comprises the steps of providing a concentrate esmolol formulation of about 25-1000 mg/ml of esmolol (or a pharmaceutically acceptable salt thereof) and 1-25 % weight/volume benzyl alcohol, selecting a volume from the liquid for further dilution with a suitable diluent, followed by injection of the diluted product to the patient.
  • An advantage of the present invention is that, unlike prior art concentrate compositions of esmolol, the formulation does not form degredants of other related esters of esmolol.
  • Another advantage of the present invention is that it offers the flexibility of multiple-dose use of the formulation without microbial cross-contamination.
  • Another advantage of the present invention is that it reduces the potential of injection site pain/irritation contributed by propylene glycol and ethanol excipients.
  • Still another advantage of the present invention is that it provides sterile, concentrate esmolol compositions that contain less excipients and are simpler to make than prior art concentrates.
  • FIG. 1 is a chemical scheme depicting the transecterification of esmolol in the presence of ethanol and propylene glycol to yield respective esters.
  • compositions of the present invention comprise esmolol, or pharmaceutically acceptable salts thereof, e.g., hydrochloride, and benzyl alcohol.
  • esmolol refers to esmolol free base and pharmaceutically acceptable salts thereof.
  • concentration of esmolol in the concentrate ranges from about 25-1000 mg/ml, and preferably is about 250 mg/ml.
  • the main degradation pathway for esmolol is the hydrolysis of its aliphatic carboxy methyl ester moiety to yield ASL-8123. This degradation depends on the pH, buffer concentrations and concentration of esmolol.
  • the current commercial esmolol concentrate formulation is stabilized by the presence of ethanol and propylene glycol.
  • the historical stability data indicate that esmolol in the presence of these solvents undergoes transesterification reactions to yield ethyl and propylene glycol esters of esmolol. (See Figure 1.)
  • compositions of the present invention contain an amount of benzyl alcohol to stabilize the esmolol concentrate compositions.
  • benzyl alcohol is typically used as a preservative, it has surprisingly been found to stabilize concentrate esmolol compositions of the present invention.
  • the amount of benzyl alcohol present will depend on the concentration of esmolol present.
  • a typical range of benzyl alcohol in the compositions will be from about 1 to 25 % weight/volume (w/v).
  • benzyl alcohol will be present in a concentration of about 10 % w/v.
  • the concentrate of present invention can also include a pharmaceutically acceptable buffer to aid in maintaining the pH in a range of from about 3.5 to about 7.0.
  • the pH is maintained between about 4.5 and about 5.5, more preferably between 4.9 and 5.1.
  • Degradation of esmolol occurs most rapidly when the pH is outside the range of 4.0 to 6.0 and is most stable around a pH of about 5.0.
  • Suitable buffers are those buffers that provide sufficient buffering capacity at the desired pH range and are pharmaceutically acceptable for injection into a patient.
  • buffers useful in the present invention include, but are not limited to, acetate, glutamate, citrate, tartrate, benzoate, lactate, gluconate, phosphate and glycine and conjugate acids thereof.
  • concentration of the buffer can be from about 0.005 to about 2 M.
  • the buffering agent comprises a combination of sodium acetate and glacial acetic acid.
  • a preferred combination of buffers can include sodium acetate at from about 0.005 to about 0.3 M and glacial acetic acid at from about 0.05 to about 0.3 M.
  • Suitable containers for housing the esmolol concentrate are known in the art. They include vial, syringe and ampoule presentations. Containers may be fabricated of polymeric materials or from glass. Preferred polymeric containers are free of polyvinylchlorine (PVC). Preferably, the container has excellent barrier properties. A preferred container retains a moisture barrier such as glass containers or polymeric containers including barrier layers or secondary packaging. An aluminum overpouch is a preferred moisture barrier for use as secondary packaging for polymeric containers lacking a moisture barrier of their own. Preferred containers should be able to withstand terminal sterilization such as autoclaving.
  • compositions of the present invention are sterile.
  • the compositions are preferably prepared and then sterilized in their final containers by autoclaving.
  • the concentrate can be aseptically prepared or terminally sterilized via autoclaving separately and then placed in sterile containers using an aseptic procedure.
  • Typical autoclave cycles used in the pharmaceutical industry to achieve terminal sterilization of the final product are 121 0 C for 15 minutes.
  • the esmolol concentrate of the present invention can be autoclaved at a temperature ranging from 115 to 130 0 C for a period of time ranging from about 5 to 40 minutes with acceptable stability.
  • Autoclaving is preferably carried out in the temperature range of about 119 to 122 0 C for a period of time ranging from about 10 to 36 minutes.
  • the concentrate is housed in a clear glass or plastic syringe and terminally sterilized. These pre-filled syringes can be provided in various volumes to permit quick and easy preparation of either small volume or large volume parental dosage by dispensing the contents of the pre-filled syringes into standard or customized, pre-filled intravenous fluid bags.
  • the concentrate esmolol compositions of the present invention are packaged in sealed vials, preferably of type I treated glass.
  • the present invention is also directed to diluted, esmolol compositions made with the esmolol concentrates of the present invention.
  • a practitioner can make a diluted concentration of esmolol with the use of a preferred diluent for infusion into the patient.
  • Suitable diluents include diluents used by practitioners skilled in the art. Typical examples include but are not limited to, sodium chloride solutions, Ringers' or dextrose solutions. While the desired, diluted concentration of esmolol will vary depending on need, typical concentrations range from about 5 to about 25 mg/ml, and preferably 10 mg/ml of esmolol.
  • Suitable routes of administration for the diluted compositions of the present invention include intravenous, subcutaneous, intradermal, intramuscular, intraarticular, and intrathecal.
  • the diluted composition is preferably administered by intravenous infusion.
  • the equipment and glassware for compounding, filtering, and filling are properly washed and depyrogenated.
  • the filter assembly, filling tube assembly, and other parts and equipment are sterilized.
  • Eighty percent (80%) of the final volume of cool water for injection is collected in a compounding tank. Glacial acetic acid and sodium acetate are then added to the tank.
  • Esmolol hydrochloride is weighed and added to the tank.
  • Required quantity of the benzyl alcohol is weighed and added to the tank.
  • the solution is stirred until all excipients are dissolved.
  • the solution is then adjusted to pH 5.0 with sodium hydroxide or hydrochloric acid.
  • the solution is brought to final volume with water for injection and mixed.
  • the solution is filled in 10-mL type I treated flint ampoules and sealed.
  • the product is the sterilized at 122 0 C for 20 minutes.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/US2008/063755 2007-05-22 2008-05-15 Multi-dose concentrate esmolol with benzyl alcohol Ceased WO2008147715A2 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CA002686566A CA2686566A1 (en) 2007-05-22 2008-05-15 Multi-dose concentrate esmolol with benzyl alcohol
AU2008256949A AU2008256949B2 (en) 2007-05-22 2008-05-15 Multi-dose concentrate esmolol with benzyl alcohol
CN2008800170791A CN101677943B (zh) 2007-05-22 2008-05-15 使用苯甲醇的多剂量浓缩艾司洛尔
EP08755579A EP2164464A2 (en) 2007-05-22 2008-05-15 Multi-dose concentrate esmolol with benzyl alcohol
BRPI0811850-7A2A BRPI0811850A2 (pt) 2007-05-22 2008-05-15 Composição concentrada de esmolol, composição pronta para uso, e, método de dosagem de um paciente com uma composição de esmolol.
MX2009012614A MX2009012614A (es) 2007-05-22 2008-05-15 Esmolol concentrado de multiples dosis con alcohol bencilico.
JP2010509457A JP2010528025A (ja) 2007-05-22 2008-05-15 ベンジルアルコールとの多用量濃縮エスモロール

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11/752,103 US8722736B2 (en) 2007-05-22 2007-05-22 Multi-dose concentrate esmolol with benzyl alcohol
US11/752,103 2007-05-22

Publications (2)

Publication Number Publication Date
WO2008147715A2 true WO2008147715A2 (en) 2008-12-04
WO2008147715A3 WO2008147715A3 (en) 2009-05-22

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/063755 Ceased WO2008147715A2 (en) 2007-05-22 2008-05-15 Multi-dose concentrate esmolol with benzyl alcohol

Country Status (10)

Country Link
US (1) US8722736B2 (https=)
EP (1) EP2164464A2 (https=)
JP (1) JP2010528025A (https=)
KR (1) KR20100022992A (https=)
CN (1) CN101677943B (https=)
AU (1) AU2008256949B2 (https=)
BR (1) BRPI0811850A2 (https=)
CA (1) CA2686566A1 (https=)
MX (1) MX2009012614A (https=)
WO (1) WO2008147715A2 (https=)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011039780A2 (en) 2009-09-22 2011-04-07 Vlife Sciences Technologies Pvt. Ltd. Topical formulation for diabetic foot ulcers

Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
HRP20121045T1 (hr) 2007-12-21 2013-01-31 Aop Orphan Pharmaceuticals Ag Farmaceutska smjesa za parenteralnu primjenu antagonista beta-adrenoreceptora ultrakratkog djelovanja

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