WO2008065142A1 - Stabilized solution of rocuronium comprising a sulfoalkyl-ether-beta-cyclodextrin derivative - Google Patents

Stabilized solution of rocuronium comprising a sulfoalkyl-ether-beta-cyclodextrin derivative Download PDF

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Publication number
WO2008065142A1
WO2008065142A1 PCT/EP2007/062958 EP2007062958W WO2008065142A1 WO 2008065142 A1 WO2008065142 A1 WO 2008065142A1 EP 2007062958 W EP2007062958 W EP 2007062958W WO 2008065142 A1 WO2008065142 A1 WO 2008065142A1
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cyclodextrin
rocuronium
pharmaceutical composition
solution
cyclodextrin derivative
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PCT/EP2007/062958
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French (fr)
Inventor
Herman Vromans
Hendrikus A.G. De Ronde
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N.V. Organon
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    • 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

  • the present invention relates to a pharmaceutical composition in the form of an aqueous solution for parenteral administration comprising rocuronium and a derivative of ⁇ -cyclodextrin.
  • Rocuronium is a neuromuscular blocking agent.
  • a neuromuscular blocking agent is routinely used during the administration of anaesthesia to facilitate endotracheal intubation and to allow surgical access to body cavities, in particular the abdomen and thorax, without hindrance from voluntary or reflex muscle movement.
  • Neuromuscular blocking agents are also used in the care of critically-ill patients undergoing intensive therapy, to facilitate compliance with mechanical ventilation when sedation and analgesia alone have proved inadequate.
  • Rocuronium 1-[(2 ⁇ , 3 ⁇ , 5 ⁇ , 16 ⁇ , 17 ⁇ )-17-(acetyloxy)-3-hydroxy-2-(4-morpholinyl)- androstan-16-yl]-1-(2-propenyl)pyrrolidinium (US 4,894,369, Akzo Nobel N.V.), is a steroidal neuromuscular blocking agent which is marketed as its bromide using the tradenames Esmeron® and Zemuron®.
  • the market product is a 10 mg/ml solution of rocuronium bromide in an aqueous acetate buffer of pH 4.0, which is to be stored at 2-8 0 C in order to attain a sufficient shelf-life.
  • an aqueous pharmaceutical composition of rocuronium which can be stored at ambient temperature and/or at higher pH while maintaining an adequate shelf-life.
  • This object is achieved by providing an aqueous solution comprising in addition to rocuronium a sulfoalkylether- ⁇ -cyclodextrin derivative or a pharmaceutically acceptable salt thereof.
  • ⁇ -Cyclodextrin is a cyclic oligosaccharide containing seven ⁇ -(1-4)-linked D- glucopyranose units.
  • sulfoalkylether- ⁇ -cyclodextrin derivative means ⁇ -cyclodextrin which has been derivatised at one or more of its 2-, 3- and 6-hydroxyl functions to introduce an anionic (C 2 -6alkylene)-SO 3 " substituent.
  • anionic (C 2 -6alkylene)-SO 3 " substituent Such derivatives are disclosed in US Patent 5,134,127 (University of Kansas).
  • a sulfoalkylether- ⁇ -cyclodextrin derivative may either be a single well defined derivative or may be a mixture of derivatives obtained by random derivatisation of the ⁇ -cyclodextrin hydroxyl functions with a certain molecular excess of an alkylating reagent, such as for example an (C 2-6 alkyl)sultone in the presence of a base, for instance by procedures described in US 6,153,746 (Pfizer Inc).
  • an alkylating reagent such as for example an (C 2-6 alkyl)sultone in the presence of a base, for instance by procedures described in US 6,153,746 (Pfizer Inc).
  • Such randomly derivatised sulfoalkylether- ⁇ -cyclodextrin derivatives are characterized by a degree of substitution, meaning the average number of derivatised hydroxyl groups per molecule.
  • the degree of substitution may range from about 1 to about 8 sulfoalkylether groups per ⁇ -cyclodextrin.
  • Preferred sulfoalkylether- ⁇ -cyclodextrin derivatives for use in the invention are the sulfobutylether- ⁇ -cyclodextrin derivatives.
  • the invention comprises a sulfobutylether- ⁇ - cyclodextrin having an average of about 7 sulfobutylether substituents per cyclodextrin molecule (annotated as: sulfobutylether 7- ⁇ -cyclodextrin).
  • Sulfobutylether 7- ⁇ -cyclodextrin has been commercialized by CyDex, Inc. as Captisol® and Advasep 7 ®, and with an average of about 4 substituents as Advasep 4 ®.
  • the pharmaceutical composition according to the invention preferably comprises rocuronium as the bromide salt in a concentration in the range of 0.2 to 2.5% m/v.
  • a preferred concentration of rocuronium bromide is 0.5 to 1.5% m/v.
  • the pharmaceutical composition of the invention preferably comprises from 1 to 40% m/v of the sulfoalkylether- ⁇ -cyclodextrin derivative, more preferably from 5 to 15% m/v of the sulfoalkylether- ⁇ -cyclodextrin derivative.
  • a preferred pharmaceutical composition of the invention for parenteral administration is an aqueous solution containing about 1 % m/v rocuronium bromide and about 10% m/v of sulfobutylether 7- ⁇ -cyclodextrin.
  • the pharmaceutical composition is preferably isotonic and may comprise a buffer.
  • the buffer is selected from the group consisting of a phosphate buffer, a phosphate/citrate buffer, a citrate buffer.
  • the buffer is a phosphate/citrate buffer.
  • the pH of the pharmaceutical composition according to the invention may be anywhere in the range of 3.5 to 7.5.
  • the pH is in the range of 5.5 to 7.5.
  • citrate/phosphate buffers with a pH of 5.0 and 6.0 (buffers prepared by applying a 1 OmM citrate and a 2OmM phosphate solution):
  • A1 rocuronium bromide (1 mg/ml) (comparative example; reference solution);
  • A2 rocuronium bromide (1 mg/ml) and 2-hydroxypropyl- ⁇ -cyclodextrin (10mg/ml)
  • the solutions were stored at 40 0 C for a period of 3 months in closed containers and subsequently analyzed by means of HPLC.
  • A4 rocuronium bromide (1 mg/ml) (comparative example; reference solution);
  • A5 rocuronium bromide (1 mg/ml) and 2-hydroxypropyl- ⁇ -cyclodextrin (approx. 8 mg/ml) (comparative example);
  • A6 rocuronium bromide (1 mg/ml) and sulfobutylether 7- ⁇ -cyclodextrin (Captisol®)
  • the solutions were stored at 22-24 ° C for a period of 44 hours and subsequently analyzed by means of HPLC.
  • citrate/phosphate buffer with a pH of 7.0 (buffer prepared by mixing a 0.1 M citrate and a 0.2 M phosphate solution):
  • A7 rocuronium bromide (1 mg/ml)(comparative example; buffer solution pH 7.0);
  • A8 rocuronium bromide(1 mg/ml) and ⁇ -cyclodextrin (10mg/ml)(comparative example);
  • A10 rocuronium bromide(1 mg/ml) and ⁇ -cyclodextrin (10mg/ml)(comparative example);
  • A1 1 rocuronium bromide(1 mg/ml) and sulfobutylether 4- ⁇ -cyclodextrin(Advasep 4 ®) (10mg/ml);
  • A12 rocuronium bromide(1 mg/ml) and sulfobutylether 7- ⁇ -cyclodextrin (Captisol®) (10mg/ml).
  • the solutions were treated by heat sterilization at 121 ° C for 1 hour in closed containers and subsequently analyzed by means of HPLC.

Abstract

The present invention relates to a pharmaceutical composition in the form of an aqueous solution for parenteral administration comprising rocuronium and a sulfoalkylether-ß-cyclodextrin derivative or a pharmaceutically acceptable salt thereof.

Description

STABILIZED SOLUTION OF ROCURONIUM COMPRISING A SULFOALKYL-ETHER-BETA-CYCLODEXTRIN DERIVATIVE
The present invention relates to a pharmaceutical composition in the form of an aqueous solution for parenteral administration comprising rocuronium and a derivative of β-cyclodextrin.
Rocuronium is a neuromuscular blocking agent. A neuromuscular blocking agent is routinely used during the administration of anaesthesia to facilitate endotracheal intubation and to allow surgical access to body cavities, in particular the abdomen and thorax, without hindrance from voluntary or reflex muscle movement. Neuromuscular blocking agents are also used in the care of critically-ill patients undergoing intensive therapy, to facilitate compliance with mechanical ventilation when sedation and analgesia alone have proved inadequate.
Rocuronium, 1-[(2β, 3α, 5α, 16β, 17β)-17-(acetyloxy)-3-hydroxy-2-(4-morpholinyl)- androstan-16-yl]-1-(2-propenyl)pyrrolidinium (US 4,894,369, Akzo Nobel N.V.), is a steroidal neuromuscular blocking agent which is marketed as its bromide using the tradenames Esmeron® and Zemuron®. The market product is a 10 mg/ml solution of rocuronium bromide in an aqueous acetate buffer of pH 4.0, which is to be stored at 2-8 0C in order to attain a sufficient shelf-life. There is a need for an aqueous pharmaceutical composition of rocuronium which can be stored at ambient temperature and/or at higher pH while maintaining an adequate shelf-life.
Cyclodextrins and their pharmaceutical applications have been reviewed by Stella and Rajewski (Pharmaceutical Research, 14, 556-567, 1997). The effects on solubility and stability of the addition of cyclodextrins or cyclodextrin derivatives to aqueous solutions of steroid hormones have been described in the art. In Journal of Pharmaceutical Sciences (1992), 81.(8), 756-61 , Albers, E. and Mϋller B. W. disclose a reduction in the rate of degradation of steroid esters by inclusion of 2-hydroxypropyl-β-cyclodextrin. Loftsson T. et al, International Journal of Pharmaceutics (1993), 98(1-3), 225-30, describe the stabilizing effects of 2-hydroxypropyl-β- cyclodextrin, reducing the degradation of medroxyprogesteron acetate and megestrol acetate in buffered solutions 2.5 to 4 times. In a review article on pharmaceutical applications of cyclodextrins by Loftsson and Brewster (J. Pharm. Sci. 85, 1017- 1025, 1996) it is emphasized that cyclodextrin interactions with labile drug molecules can either have stabilizing or destabilizing effects, depending on the particular combination of drug and cyclodextrin. It is the object of the present invention to provide a pharmaceutical composition comprising rocuronium in the form of an aqueous solution for parenteral administration which has a pH and/or a storage temperature range which allows easy manufacture and storage.
This object is achieved by providing an aqueous solution comprising in addition to rocuronium a sulfoalkylether-β-cyclodextrin derivative or a pharmaceutically acceptable salt thereof.
β-Cyclodextrin is a cyclic oligosaccharide containing seven α-(1-4)-linked D- glucopyranose units.
The term sulfoalkylether-β-cyclodextrin derivative means β-cyclodextrin which has been derivatised at one or more of its 2-, 3- and 6-hydroxyl functions to introduce an anionic (C2-6alkylene)-SO3 " substituent. Such derivatives are disclosed in US Patent 5,134,127 (University of Kansas). A sulfoalkylether-β-cyclodextrin derivative may either be a single well defined derivative or may be a mixture of derivatives obtained by random derivatisation of the β-cyclodextrin hydroxyl functions with a certain molecular excess of an alkylating reagent, such as for example an (C2-6alkyl)sultone in the presence of a base, for instance by procedures described in US 6,153,746 (Pfizer Inc).
Such randomly derivatised sulfoalkylether-β-cyclodextrin derivatives are characterized by a degree of substitution, meaning the average number of derivatised hydroxyl groups per molecule. The degree of substitution may range from about 1 to about 8 sulfoalkylether groups per β-cyclodextrin.
Preferred sulfoalkylether-β-cyclodextrin derivatives for use in the invention are the sulfobutylether-β-cyclodextrin derivatives.
In a further preferred embodiment the invention comprises a sulfobutylether-β- cyclodextrin having an average of about 7 sulfobutylether substituents per cyclodextrin molecule (annotated as: sulfobutylether 7-β-cyclodextrin). Sulfobutylether 7-β-cyclodextrin has been commercialized by CyDex, Inc. as Captisol® and Advasep 7 ®, and with an average of about 4 substituents as Advasep 4 ®.
The pharmaceutical composition according to the invention preferably comprises rocuronium as the bromide salt in a concentration in the range of 0.2 to 2.5% m/v. A preferred concentration of rocuronium bromide is 0.5 to 1.5% m/v. The pharmaceutical composition of the invention preferably comprises from 1 to 40% m/v of the sulfoalkylether-β-cyclodextrin derivative, more preferably from 5 to 15% m/v of the sulfoalkylether-β-cyclodextrin derivative.
A preferred pharmaceutical composition of the invention for parenteral administration is an aqueous solution containing about 1 % m/v rocuronium bromide and about 10% m/v of sulfobutylether 7-β-cyclodextrin.
The pharmaceutical composition is preferably isotonic and may comprise a buffer. The buffer is selected from the group consisting of a phosphate buffer, a phosphate/citrate buffer, a citrate buffer. Preferably the buffer is a phosphate/citrate buffer.
The pH of the pharmaceutical composition according to the invention may be anywhere in the range of 3.5 to 7.5. For convenience in terms of low incidence of pain induction on injection, it is preferable that the pH is in the range of 5.5 to 7.5.
The invention is illustrated in the following Examples:
Example 1
The following solutions were prepared in citrate/phosphate buffers with a pH of 5.0 and 6.0 (buffers prepared by applying a 1 OmM citrate and a 2OmM phosphate solution):
A1 : rocuronium bromide (1 mg/ml) (comparative example; reference solution); A2: rocuronium bromide (1 mg/ml) and 2-hydroxypropyl-β-cyclodextrin (10mg/ml)
(comparative example); A3: rocuronium bromide (1 mg/ml) and sulfobutylether 7-β-cyclodextrin (Captisol®)
(10mg/ml).
The solutions were stored at 40 0C for a period of 3 months in closed containers and subsequently analyzed by means of HPLC.
The contents of rocuronium bromide after storage expressed as percentage of the initial content are reflected in Table 1. Table 1 : Content of rocuronium bromide (%) after storage
Figure imgf000005_0001
The solution of rocuronium bromide comprising 2-hydroxypropyl-β-cyclodextrin (Table 1 : A2) shows that a slight to no reduction of the degradation of rocuronium as compared to the reference solution A1 at both pH 5 and 6.
The chemical stability of rocurinium bromide in a solution according to the invention comprising sulfobutylether 7-β-cyclodextrin is significantly improved during storage at 40° C, both a pH 5 and 6 (Table 1 : A3).
Example 2
The following solutions with pH 10 were prepared in a buffer system (25 mM phosphate buffer pH 7.1 brought to pH with a 10% ammonium hydroxide solution):
A4: rocuronium bromide (1 mg/ml) (comparative example; reference solution); A5: rocuronium bromide (1 mg/ml) and 2-hydroxypropyl-β-cyclodextrin (approx. 8 mg/ml) (comparative example); A6: rocuronium bromide (1 mg/ml) and sulfobutylether 7-β-cyclodextrin (Captisol®)
(approx. 8 mg/ml).
The solutions were stored at 22-24 °C for a period of 44 hours and subsequently analyzed by means of HPLC.
The percentage of rocuronium bromide recovered after storage expressed as percentage of the initial content are reflected in Figure 1.
The results show that for the solution buffered at pH 10 no significant improvement of the stability of rocuronium bromide was obtained by 2-hydroxypropyl-β-cyclodextrin (Figure 1 : A5), whereas at this high pH sulfobutyl ether 7-β-cyclodextrin (Captisol®) significantly improved the stability of rocuronium bromide (Figure 1 : A6). Example 3
The following solutions were prepared in citrate/phosphate buffer with a pH of 7.0 (buffer prepared by mixing a 0.1 M citrate and a 0.2 M phosphate solution):
A7: rocuronium bromide (1 mg/ml)(comparative example; buffer solution pH 7.0); A8: rocuronium bromide(1 mg/ml) and α-cyclodextrin (10mg/ml)(comparative example);
A9: rocuronium bromide(1 mg/ml) and β-cyclodextrin (10mg/ml))(comparative example);
A10: rocuronium bromide(1 mg/ml) and γ-cyclodextrin (10mg/ml)(comparative example);
A1 1 : rocuronium bromide(1 mg/ml) and sulfobutylether 4-β-cyclodextrin(Advasep 4 ®) (10mg/ml); A12: rocuronium bromide(1 mg/ml) and sulfobutylether 7-β-cyclodextrin (Captisol®) (10mg/ml).
The solutions were treated by heat sterilization at 121 °C for 1 hour in closed containers and subsequently analyzed by means of HPLC.
The contents of rocuronium bromide after storage expressed as percentage of the initial content are reflected in Table 2.
Table 2: Recovery of rocuronium bromide (%) after storage at pH 7.0.
Figure imgf000007_0001
The chemical stability of rocuronium bromide upon heat sterilization at 121 °C for 1 hour in a solution according to the invention (A11 and A12) is significantly improved (Table 2).

Claims

Claims
1. A pharmaceutical composition in the form of an aqueous solution for parenteral administration comprising rocuronium, characterized in that the solution further comprises a sulfoalkylether-β-cyclodextrin derivative or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition according to claim 1 , wherein the sulfoalkylether-β- cyclodextrin derivative is a sulfobutylether-β-cyclodextrin derivative.
3. A pharmaceutical composition according to claim 2, wherein the sulfobutylether-β- cyclodextrin derivative is sulfobutylether 7-β-cyclodextrin.
4. A pharmaceutical composition according to any one of claims 1-3, wherein the solution comprises a phosphate/citrate buffer.
5. A pharmaceutical composition according to any one of claims 1 to 4, wherein the pH of solution is in the range of 3.5 to 7.5.
6. A pharmaceutical composition according to any one of claims 1 to 5, wherein rocuronium is rocuronium bromide.
7. A pharmaceutical composition according to claim 6, wherein the concentration of rocuronium bromide is in the range of is 0.2 to 2.5% m/v.
8. A pharmaceutical composition according to any one of claims 1 to 7, wherein the concentration of the cyclodextrin is in the range of 1 to 40 % m/v.
9. A pharmaceutical composition according to any one of claims 1 to 7, wherein the concentration of the cyclodextrin is in the range of 5 to 15 % m/v.
PCT/EP2007/062958 2006-11-29 2007-11-28 Stabilized solution of rocuronium comprising a sulfoalkyl-ether-beta-cyclodextrin derivative WO2008065142A1 (en)

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Cited By (8)

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WO2013189800A1 (en) * 2012-06-22 2013-12-27 Farmhispania S.A. Cisatracurium and beta-cyclodextrin derivative compositions
EP2712611A1 (en) 2012-09-27 2014-04-02 B. Braun Melsungen AG Stabilized aqueous compositions of neuromuscular blocking agents
JP5684954B1 (en) * 2014-06-26 2015-03-18 丸石製薬株式会社 Rocuronium formulation with improved stability
EP3017817A4 (en) * 2013-07-01 2017-03-22 Maruishi Pharmaceutical Co., Ltd. Rocuronium preparation with improved vascular pain, method for producing same, and method for suppressing and relieving vascular pain using same
ES2658115A1 (en) * 2016-05-10 2018-03-08 Farmhispania S.A. Compositions of cisatracurium and beta-cyclodextrin derivatives. (Machine-translation by Google Translate, not legally binding)
CN108289832A (en) * 2015-11-06 2018-07-17 卡利努法姆股份有限公司 For carrying out the Levosimendan of intravenously administrable with infusion or injection form and being transfused the improvement formula of concentrate
US11097023B1 (en) 2020-07-02 2021-08-24 Par Pharmaceutical, Inc. Pre-filled syringe containing sugammadex
WO2023275157A1 (en) 2021-07-02 2023-01-05 Fresenius Kabi Austria Gmbh Aqueous, room-temperature stable rocuronium composition

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WO2005065649A1 (en) * 2003-12-31 2005-07-21 Cydex, Inc. Inhalant formulation containing sulfoalkyl ether ϝ-cyclodextrin and corticosteroid

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US6153746A (en) * 1997-07-01 2000-11-28 Pfizer Inc. Process for making a cyclodextrin
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WO2013189800A1 (en) * 2012-06-22 2013-12-27 Farmhispania S.A. Cisatracurium and beta-cyclodextrin derivative compositions
EP2712611A1 (en) 2012-09-27 2014-04-02 B. Braun Melsungen AG Stabilized aqueous compositions of neuromuscular blocking agents
KR101803857B1 (en) 2013-07-01 2017-12-04 마루이시세이야쿠가부시키가이샤 Rocuronium preparation with improved vascular pain, method for producing same, and method for suppressing and relieving vascular pain using same
US10821119B2 (en) 2013-07-01 2020-11-03 Maruishi Pharmaceutical Co., Ltd. Rocuronium preparation causing less pain, method for producing the same, and method for reducing and/or alleviating vascular pain to be induced using the same
AU2014285324B2 (en) * 2013-07-01 2019-05-23 Maruishi Pharmaceutical Co., Ltd. Rocuronium preparation causing less pain, method for producing the same, and method for reducting and/or alleviating vascular pain to be induced using the same
RU2680405C2 (en) * 2013-07-01 2019-02-21 Маруиси Фармасьютикал Ко., Лтд. Rocuronium preparation with improved vascular pain, method for producing same, and method for suppressing and/or relieving vascular pain which may be caused by use thereof
EP3017817A4 (en) * 2013-07-01 2017-03-22 Maruishi Pharmaceutical Co., Ltd. Rocuronium preparation with improved vascular pain, method for producing same, and method for suppressing and relieving vascular pain using same
AU2014398349B2 (en) * 2014-06-26 2020-08-06 Maruishi Pharmaceutical Co., Ltd. Rocuronium preparation with improved stability
KR101692884B1 (en) 2014-06-26 2017-01-04 마루이시세이야쿠가부시키가이샤 Rocuronium preparation with improved stability
KR20160086953A (en) 2014-06-26 2016-07-20 마루이시세이야쿠가부시키가이샤 Rocuronium formulation with improved stability
WO2015198456A1 (en) * 2014-06-26 2015-12-30 丸石製薬株式会社 Rocuronium formulation with improved stability
JP5684954B1 (en) * 2014-06-26 2015-03-18 丸石製薬株式会社 Rocuronium formulation with improved stability
US10869876B2 (en) 2014-06-26 2020-12-22 Maruishi Pharmaceutical Co., Ltd. Rocuronium preparation with improved stability
CN113350274A (en) * 2014-06-26 2021-09-07 丸石制药株式会社 Rocuronium bromide formulations with improved stability
CN108289832A (en) * 2015-11-06 2018-07-17 卡利努法姆股份有限公司 For carrying out the Levosimendan of intravenously administrable with infusion or injection form and being transfused the improvement formula of concentrate
ES2658115A1 (en) * 2016-05-10 2018-03-08 Farmhispania S.A. Compositions of cisatracurium and beta-cyclodextrin derivatives. (Machine-translation by Google Translate, not legally binding)
US11097023B1 (en) 2020-07-02 2021-08-24 Par Pharmaceutical, Inc. Pre-filled syringe containing sugammadex
WO2023275157A1 (en) 2021-07-02 2023-01-05 Fresenius Kabi Austria Gmbh Aqueous, room-temperature stable rocuronium composition

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