US20100311738A1 - Pharmaceutical Composition For The Parenteral Administration Of Ultrashort-Effective Beta-Adrenoreceptor Antagonists - Google Patents

Pharmaceutical Composition For The Parenteral Administration Of Ultrashort-Effective Beta-Adrenoreceptor Antagonists Download PDF

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US20100311738A1
US20100311738A1 US12/809,927 US80992708A US2010311738A1 US 20100311738 A1 US20100311738 A1 US 20100311738A1 US 80992708 A US80992708 A US 80992708A US 2010311738 A1 US2010311738 A1 US 2010311738A1
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cyclodextrin
esmolol
salt
solution containing
landiolol
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Rudolf Stefan Widmann
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AOP Orphan Pharmaceuticals AG
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    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to a pharmaceutical composition for parenteral administration of an ultrashort-effective ⁇ -adrenoreceptor antagonist in the form of a solution.
  • ultrashort-effect ⁇ -adrenoreceptor antagonists such as esmolol hydrochloride, landiolol hydrochloride (two cardioselective ⁇ 1 blockers) and flestolol hydrochloride are used in the form of parenteral formulations, particularly in anaesthesia and in emergency and intensive care medicine.
  • the active substance concentration of, for example esmolol, used for administration is so high that these solutions are often hypertonic.
  • alcohol in concentrations of around 25% is added in many cases. Because of these technical formulation problems, the use of esmolol in intensive care medicine is associated with additional risks.
  • WO 85/04580 describes solutions of esmolol in a proportion by weight of 0.1% to 30% which also include a buffer and ethanol in a proportion of 5 to 60%.
  • EP 0 403 578 B1 claims an injectable, aqueous composition for treating heart conditions, which has an effective quantity of esmolol (hydrochloride) in a proportion of 1 mg to 250 mg esmolol/ml solution and 0.01 to 0.04 M buffer, and has a pH value in the range 4.5 to 5.5.
  • esmolol hydrochloride
  • European patent application EP 1 417 962 describes pharmaceutical compositions consisting of 30 ml to 70 ml dilution with an proportion of 1500 mg to 3500 mg esmolol or a pharmaceutically tolerable salt thereof.
  • the aim of the present invention is to provide a composition for parenteral administration of ultrashort-effective ⁇ -adrenoreceptor antagonist, more particularly for injection or infusion, which on the one hand exhibits a high degree of storage stability and on the other hand an osmolarity which is suitable for administration.
  • the composition should exhibit vaso-protective properties, which is important especially at high active substance concentrations (e.g. in the case of esmolol).
  • a cyclodextrin and/or a functional cyclodextrin derivative to increase the stability of an ultrashort-effective ⁇ -adrenoreceptor antagonist and/or a pharmaceutically acceptable salt thereof in a suitable storage-stable aqueous solution for parenteral administration fulfils the aim of the invention in an excellent manner.
  • the solution can also contain other auxiliary substances, in particular buffers, preservation agents, organic solvents that can be mixed with water, salts, sugar alcohols and/or sugar.
  • auxiliary substances in particular buffers, preservation agents, organic solvents that can be mixed with water, salts, sugar alcohols and/or sugar.
  • a further aspect of the present invention relates to a pharmaceutical composition for parenteral administration of an ultrashort-effective ⁇ -adrenoreceptor antagonist in the form of a storage-stable solution, essentially consisting of
  • ultrashort-effective ⁇ -adrenoreceptor antagonist solutions consisting solely of the ultrashort-effective ⁇ -adrenoceptor antagonist, cyclodextrin and water, are sufficiently storage-stable, even without the presence of other auxiliary substances (such as buffer or osmolarity-adjusting agents known from the prior art) and, in terms of osmolar properties are suitable for administration.
  • auxiliary substances such as buffer or osmolarity-adjusting agents known from the prior art
  • osmolar properties are suitable for administration. This applies particularly in the pH range from 3 to 7.5, preferably from 5 to 7.
  • the term “storage-stable” denotes an aqueous solution, which in contrast to a solution produced through the dissolution of freeze-dried products, can be stored for a longer period of time without any significant breakdown of the contained active substance taking place.
  • Understood as “storage-stable” in particular are aqueous solutions in which after one month less than 5% of the active substance has degraded.
  • the pH value of the solution is preferably 3 to 7.5, particularly preferably 5 to 7.
  • the concentration of the cyclodextrin or cyclodextrin derivative in the solution is preferably 0.1% to 20% (w/v), preferably 0.25% to 7% (w/v), particularly preferably 0.5% to 4%.
  • the cyclodextrin or the functional cyclodextrin derivative is preferably selected from the group comprising ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, functional derivatives and mixtures thereof.
  • “Functional cyclodextrin derivatives” is taken to mean all pharmaceutically acceptable derivatives of cyclodextrins in which the essential structure and size of the cyclodextrin molecules are retained.
  • functional cyclodextrin derivatives in particular are esters with pharmaceutically acceptable acids and ethers, especially low-alkyl ethers.
  • Particularly preferred cyclodextrin derivatives are (2-hydroxypropyl)- ⁇ -cyclodextrin and (sulfobutylether)-7 ⁇ cyclodextrin.
  • the ultrashort-effective ⁇ -adrenoreceptor antagonist used in the composition in accordance with the invention is preferably an active substance selected from the group comprising esmolol, landiolol and flestolol.
  • the concentration of the ultrashort-effective ⁇ -adrenoreceptor antagonist or the salt therefore in the solution can be 0.1% to 30% depending on the ⁇ -adrenoreceptor antagonist used.
  • Preferred concentrations in the case of esmolol or esmolol salts are 1 to 20%.
  • Preferred concentrations in the case of landiolol or laniolol salts are 1 to 20%.
  • Preferred concentrations in the case of flestolol or flestolol salts are 0.1 to 10%.
  • the solution preferably has an osmolarity of 270 mosmol/l to 310 mosmol/l, particularly preferably 280 mosmol/l to 300 mosmol/l. This corresponds to an isotonic solution.
  • composition in accordance with the invention is preferably present in the form of a sales unit selected from the group comprising
  • a 10 ml solution containing 100 mg esmolol as a “ready-to-use” product can be used directly for injection.
  • Conventional compositions with high proportions of esmolol (more particularly 10 ml/2500 mg esmolol) must be diluted before administration.
  • solutions in accordance with the invention can also be used with higher concentrations of esmolol as “ready-to-use” products.
  • composition according to the invention is preferably available in the form of a sales unit selected from the group comprising
  • the landiolol is already present in solution in a stable form.
  • comparatively higher concentrations of the ultrashort-effective ⁇ -adrenoreceptor antagonists than in the formulations to date can be used.
  • composition according to the invention can be produced in a known manner through mixing and subsequent dissolution of the constituents.
  • composition according to the invention can be used in particular to produce a medicinal product to reduce ventricular frequency in patients with atrial fibrillation, atrial flutter and sinus tachycardia, in atrioventricular and AV node tachycardia, tachycardic supra- and ventricular arrhythmias, in tachycardia and/or hypertension, before, during and after operations as well as in other emergency situations, for the prophylaxis and treatment of perioperative ischaemia, to treat unstable angina pectoris and acute myocardial infarction.
  • FIG. 1 shows the accelerated breakdown of a 5% esmolol reference solution and compositions according to the invention at 75° C.
  • FIG. 2 shows the influence of freeze-drying on the accelerated breakdown of esmolol-cyclodextrin complexes in water at 75° C.
  • FIG. 3 shows the influence of the concentration of ⁇ -cyclodextrin on the stability of esmolol at 75° C.
  • FIG. 4 shows the influence of hydroxypropyl- ⁇ -cyclodextrin on the stability of esmolol at 75° C.
  • FIG. 5 shows the influence of ⁇ -cyclodextrin in increasing concentrations on the stability of landiolol in aqueous solution at 70° C.
  • FIG. 6 shows the influence of 2-hydroxypropyl- ⁇ -cyclodextrin in increasing concentrations on the stability of landiolol in aqueous solution at 70° C.
  • FIG. 7 shows the influence of ⁇ -cyclodextrin in increasing concentrations on the stability of landiolol in aqueous solution at 70° C.
  • FIG. 8 shows the influence of the pH value on the stability of landiolol in aqueous solution at 70° C.
  • FIG. 9 shows the influence of cyclodextrins (2%, w/v) in which landiolol was stored by means of concentrated suspensions on the stability of aqueous landiolol solutions of 0.25% (w/v) at 70° C.
  • Esmolol and ⁇ -cyclodextrin are dissolved in final concentrations of 5% (w/v) (esmolol) and 14% (w/v) ⁇ -cyclodextrin) in water for injection purposes and stirred for 24 hours at room temperature.
  • Esmolol and optionally additionally ⁇ -cyclodextrin are dissolved in a final concentration of 5% (w/v) (esmolol) or 14%, 7%, 4%, 2%, 1% and 0% (w/v) ( ⁇ -cyclodextrin) in water for injection purposes and stirred for 24 hours at room temperature.
  • Esmolol and optionally additionally hydroxypropol- ⁇ -cyclodextrin are dissolved in a final concentration of 5% (w/v) (esmolol) or 7% and 0% (w/v) (hydroxypropyl- ⁇ -cyclodextrin) in water for injection purposes and stirred for 24 hours at room temperature.
  • a parenteral solution was produced in accordance with the recipe set out in table 1.
  • the flow rate was 1 ml/minute, the injection volume 20 ⁇ l.
  • Esmolol hydrochloride was detected at 274 nm.
  • the retention time of esmolol hydrochloride was on average 3.9 minutes, that of the principal degradation product (“contaminant A” in table 3 below) was 1.7 minutes.
  • To determine degradation the ratio of the principal degradation product to remaining esmolol hydrochloride was calculate and indicated in percent (“degraded esmolol (%)”).
  • FIG. 1 shows the accelerated degradation at 75° C. of the 5% esmolol reference solution and esmolol cycoldextrin complexes in water [( ⁇ ) 5% esmolol comparison solution with 0% cyclodextrin—example 3b; (X) 5% esmolol+ ⁇ -cyclodextrin—example 2b]; ( ⁇ ) 5% esmolol+(2-hydroxypropyl)- ⁇ -cyclodextrin—example 1); ( ⁇ ) 5% esmolol+ ⁇ -cyclodextrin—example 2a].
  • the values are mean values of 3 tests ⁇ SD.
  • FIG. 2 shows the influence of freeze drying on the accelerated degradation of esmolol-cyclodextrin complexes in water at 75° C.
  • the values are mean values of 3 tests ⁇ SD.
  • FIG. 3 shows the influence of the concentration of ⁇ -cyclodextrin on the stability of an aqueous 5% esmolol solution at 75° C.
  • the values are mean values of 3 tests ⁇ SD.
  • FIG. 4 shows the influence of hydroxypopyl- ⁇ -cyclodextrin on the stability of an aqueous 5% esmolol solution at 75° C. [( ⁇ ) 5% esmolol comparison solution with 0% hydroxypropyl- ⁇ -cyclodextrin—example 3c; ( ⁇ ) 5% esmolol+7% hydroxypropyl- ⁇ -cyclodextrin—in accordance with example 3c].
  • the values are mean values of 3 tests ⁇ SD.
  • the osmolarity/reduction in freezing point vis-à-vis water was determined with a Knauer semi-micro-osmometer. In order to be able to determine the osmolarity with this osmometer the samples are cooled to freezing in the osmometer.
  • the 5% solution with ⁇ -cyclodextrin in accordance with example 3a has an osmolarity of 290 mosmol/l. This corresponds to an isotonic solution as the range of isotonia extends from 281 to 297 mosmol/l. Solutions of >310 mosmol/l would be described as hypertonic and solutions of ⁇ 270 mosmol/l classified as hypotonic.
  • Landiolol was dissolved in purified water at a concentration of 0.25% (m/v). Subsequently ⁇ -cyclodextrin (Cyclolab, Budapest), 2-hydroxypropyl- ⁇ -cyclodextrin (CTD, Inc., Florida) and ⁇ -cyclodextrin (ISP, Germany) was added in final concentrations of 0%, 0.5%, 1%, 2% and 7% (w/v). The solutions were heated to 70° C. and the stability of landiolol determined in accordance with the HPLC method described in example 5. Landiolol was detected at 220 nm. The retention time of landiolol hydrochloride was on average 10.5 minutes, that of the principal degradation product 1.4 minutes.
  • FIG. 5-7 The results of this study are shown in FIG. 5-7 .
  • the shown values are mean values of 3 tests ⁇ SD.
  • FIG. 5 shows the influence of 0% ( ⁇ ), 0.5% (X), 1% ( ⁇ ), 2% ( ⁇ ), 4% ( ⁇ ) and 7% ( ⁇ ) ⁇ -cyclodextrin on the stability of landiolol at 70° C.
  • FIG. 6 shows the influence of 0% ( ⁇ ), 0.5% (X), 1% ( ⁇ ), 2% ( ⁇ ), 4% ( ⁇ ) and 7% ( ⁇ ) hydroxypropyl- ⁇ -cyclodextrin on the stability of landiolol at 70° C.
  • FIG. 7 shows the influence of 0% ( ⁇ ), 0.5% ( ⁇ ), 1% (X), 2% ( ⁇ ), 4% ( ⁇ ) and 7% ( ⁇ ) ⁇ -cyclodextrin on the stability of landiolol at 70° C.
  • Landiolol was dissolved in purified water at a concentration of 0.25 (w/v). The pH value was then adjusted to 3; 4; 5; 5.5; 6; 6.5; 7 and 8. The solutions were heated to 70° C. and the stability of landiolol determined with the HPLC method described in examples 5 and 8. The results of these studies are shown in FIG. 8 . These show the degradation of landiolol at pH 3.0 ( ⁇ ), pH 4.0 (X), pH 5.0 ( ⁇ ), pH 5.5 ( ⁇ ), ph 6.0 ( ⁇ ), pH 6.5 ( ⁇ ), pH 7.0 ( ⁇ ) and pH 8.0 ( ⁇ ). The shown values are mean values of 3 tests ⁇ SD.
  • Landiolol and ⁇ -cyclodextrin (Cyclolab, Budapest), 2-hydroxypropyl- ⁇ -cyclodextrin (CTD Inc., Florida) or ⁇ -cyclodextrin (ISP, Germany) were suspended in purified water in a concentration of 10% landiolol (w/v) and 80% cyclodextrin (w/v) and stirred for two hours at room temperature. After 5 minutes of ultrasound treatment the suspensions were diluted in stages so that the final concentration of landiolol was 0.25% (w/v). These solutions were incubated at 70° C. and the taken sample were analysed by means of the HPLC method described in examples 5 and 8. The results of this study are set out in FIG. 9 .

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US16/164,926 Active US10660964B2 (en) 2007-12-21 2018-10-19 Pharmaceutical composition for the parenteral administration of ultrashort-effective beta-adrenoreceptor antagonists
US16/860,336 Active US11517624B2 (en) 2007-12-21 2020-04-28 Pharmaceutical composition for the parenteral administration of ultrashort-effective β-adrenoreceptor antagonists
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Cited By (1)

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US20160074411A1 (en) * 2013-04-26 2016-03-17 Aop Orphan Pharmaceuticals Ag Use of landiolol hydrochloride in the long-term treatment of tachyarrhythmias

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EP2846776B1 (en) 2012-05-10 2020-04-15 AOP Orphan Pharmaceuticals AG Parenteral esmolol formulation

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US20030216349A1 (en) * 2002-04-18 2003-11-20 Luiz Belardinelli Method for treating arrhythmias
US20040053894A1 (en) * 2002-09-18 2004-03-18 Bone Care International, Inc. Formulation for lipophilic agents
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