Solubilisation of drugs within liposomal bilayers: alternatives to cholesterol as a membrane stabilising agent

M Habib Ali, Daniel J Kirby, Afzal R Mohammed, Yvonne Perrie

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

OBJECTIVES: The aim of this work was to investigate the effect of cholesterol on the bilayer loading of drugs and their subsequent release and to investigate fatty alcohols as an alternative bilayer stabiliser to cholesterol.

METHODS: The loading and release rates of four low solubility drugs (diazepam, ibuprofen, midazolam and propofol) incorporated within the bilayer of multilamellar liposomes which contained a range of cholesterol (0-33 mol/mol%) or a fatty alcohol (tetradecanol, hexadecanol and octadecanol) were investigated. The molecular packing of these various systems was also investigated in Langmuir monolayer studies.

KEY FINDINGS: Loading and release of drugs within the liposome bilayer was shown to be influenced by their cholesterol content: increasing cholesterol content was shown to reduce drug incorporation and inclusion of cholesterol in the bilayer changed the release profile of propofol from zero-order, for phosphatidyl choline only liposomes, to a first-order model when 11 to 33 total molar % of cholesterol was present in the formulation. At higher bilayer concentrations substitution of cholesterol with tetradecanol was shown to have less of a detrimental impact on bilayer drug loading. However, the presence of cholesterol within the liposome bilayer was shown to reduce drug release compared with fatty alcohols. Monolayer studies undertaken showed that effective mean area per molecule for a 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC):cholesterol mixture deviated by 9% from the predicted area compared with 5% with a similar DSPC:tetradecanol mixture. This evidence, combined with cholesterol being a much more bulky structure, indicated that the condensing influence of tetradecanol was less compared with cholesterol, thus supporting the reduced impact of tetradecanol on drug loading and drug retention.

CONCLUSIONS: Liposomes can be effectively formulated using fatty alcohols as an alternative bilayer stabiliser to cholesterol. The general similarities in the characteristics of liposomes containing fatty alcohols or cholesterol suggest a common behavioural influence for both compounds within the bilayer.

LanguageEnglish
Pages1646-1655
Number of pages10
JournalJournal of Pharmacy and Pharmacology
Volume62
Issue number11
DOIs
Publication statusPublished - 30 Nov 2010

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Excipients
Cholesterol
Membranes
Fatty Alcohols
Pharmaceutical Preparations
Liposomes
Propofol
Phosphorylcholine
Ibuprofen
Midazolam
Diazepam
Phosphatidylcholines
Solubility

Keywords

  • chemistry, pharmaceutical
  • cholesterol
  • drug delivery systems
  • excipients
  • fatty alcohols
  • liposomes
  • membranes
  • pharmaceutical preparations
  • phosphatidylcholines
  • solubility

Cite this

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title = "Solubilisation of drugs within liposomal bilayers: alternatives to cholesterol as a membrane stabilising agent",
abstract = "OBJECTIVES: The aim of this work was to investigate the effect of cholesterol on the bilayer loading of drugs and their subsequent release and to investigate fatty alcohols as an alternative bilayer stabiliser to cholesterol.METHODS: The loading and release rates of four low solubility drugs (diazepam, ibuprofen, midazolam and propofol) incorporated within the bilayer of multilamellar liposomes which contained a range of cholesterol (0-33 mol/mol{\%}) or a fatty alcohol (tetradecanol, hexadecanol and octadecanol) were investigated. The molecular packing of these various systems was also investigated in Langmuir monolayer studies.KEY FINDINGS: Loading and release of drugs within the liposome bilayer was shown to be influenced by their cholesterol content: increasing cholesterol content was shown to reduce drug incorporation and inclusion of cholesterol in the bilayer changed the release profile of propofol from zero-order, for phosphatidyl choline only liposomes, to a first-order model when 11 to 33 total molar {\%} of cholesterol was present in the formulation. At higher bilayer concentrations substitution of cholesterol with tetradecanol was shown to have less of a detrimental impact on bilayer drug loading. However, the presence of cholesterol within the liposome bilayer was shown to reduce drug release compared with fatty alcohols. Monolayer studies undertaken showed that effective mean area per molecule for a 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC):cholesterol mixture deviated by 9{\%} from the predicted area compared with 5{\%} with a similar DSPC:tetradecanol mixture. This evidence, combined with cholesterol being a much more bulky structure, indicated that the condensing influence of tetradecanol was less compared with cholesterol, thus supporting the reduced impact of tetradecanol on drug loading and drug retention.CONCLUSIONS: Liposomes can be effectively formulated using fatty alcohols as an alternative bilayer stabiliser to cholesterol. The general similarities in the characteristics of liposomes containing fatty alcohols or cholesterol suggest a common behavioural influence for both compounds within the bilayer.",
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Solubilisation of drugs within liposomal bilayers : alternatives to cholesterol as a membrane stabilising agent. / Ali, M Habib; Kirby, Daniel J; Mohammed, Afzal R; Perrie, Yvonne.

In: Journal of Pharmacy and Pharmacology, Vol. 62, No. 11, 30.11.2010, p. 1646-1655.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Solubilisation of drugs within liposomal bilayers

T2 - Journal of Pharmacy and Pharmacology

AU - Ali, M Habib

AU - Kirby, Daniel J

AU - Mohammed, Afzal R

AU - Perrie, Yvonne

N1 - © 2010 The Authors. Journal compilation © 2010 Royal Pharmaceutical Society of Great Britain.

PY - 2010/11/30

Y1 - 2010/11/30

N2 - OBJECTIVES: The aim of this work was to investigate the effect of cholesterol on the bilayer loading of drugs and their subsequent release and to investigate fatty alcohols as an alternative bilayer stabiliser to cholesterol.METHODS: The loading and release rates of four low solubility drugs (diazepam, ibuprofen, midazolam and propofol) incorporated within the bilayer of multilamellar liposomes which contained a range of cholesterol (0-33 mol/mol%) or a fatty alcohol (tetradecanol, hexadecanol and octadecanol) were investigated. The molecular packing of these various systems was also investigated in Langmuir monolayer studies.KEY FINDINGS: Loading and release of drugs within the liposome bilayer was shown to be influenced by their cholesterol content: increasing cholesterol content was shown to reduce drug incorporation and inclusion of cholesterol in the bilayer changed the release profile of propofol from zero-order, for phosphatidyl choline only liposomes, to a first-order model when 11 to 33 total molar % of cholesterol was present in the formulation. At higher bilayer concentrations substitution of cholesterol with tetradecanol was shown to have less of a detrimental impact on bilayer drug loading. However, the presence of cholesterol within the liposome bilayer was shown to reduce drug release compared with fatty alcohols. Monolayer studies undertaken showed that effective mean area per molecule for a 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC):cholesterol mixture deviated by 9% from the predicted area compared with 5% with a similar DSPC:tetradecanol mixture. This evidence, combined with cholesterol being a much more bulky structure, indicated that the condensing influence of tetradecanol was less compared with cholesterol, thus supporting the reduced impact of tetradecanol on drug loading and drug retention.CONCLUSIONS: Liposomes can be effectively formulated using fatty alcohols as an alternative bilayer stabiliser to cholesterol. The general similarities in the characteristics of liposomes containing fatty alcohols or cholesterol suggest a common behavioural influence for both compounds within the bilayer.

AB - OBJECTIVES: The aim of this work was to investigate the effect of cholesterol on the bilayer loading of drugs and their subsequent release and to investigate fatty alcohols as an alternative bilayer stabiliser to cholesterol.METHODS: The loading and release rates of four low solubility drugs (diazepam, ibuprofen, midazolam and propofol) incorporated within the bilayer of multilamellar liposomes which contained a range of cholesterol (0-33 mol/mol%) or a fatty alcohol (tetradecanol, hexadecanol and octadecanol) were investigated. The molecular packing of these various systems was also investigated in Langmuir monolayer studies.KEY FINDINGS: Loading and release of drugs within the liposome bilayer was shown to be influenced by their cholesterol content: increasing cholesterol content was shown to reduce drug incorporation and inclusion of cholesterol in the bilayer changed the release profile of propofol from zero-order, for phosphatidyl choline only liposomes, to a first-order model when 11 to 33 total molar % of cholesterol was present in the formulation. At higher bilayer concentrations substitution of cholesterol with tetradecanol was shown to have less of a detrimental impact on bilayer drug loading. However, the presence of cholesterol within the liposome bilayer was shown to reduce drug release compared with fatty alcohols. Monolayer studies undertaken showed that effective mean area per molecule for a 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC):cholesterol mixture deviated by 9% from the predicted area compared with 5% with a similar DSPC:tetradecanol mixture. This evidence, combined with cholesterol being a much more bulky structure, indicated that the condensing influence of tetradecanol was less compared with cholesterol, thus supporting the reduced impact of tetradecanol on drug loading and drug retention.CONCLUSIONS: Liposomes can be effectively formulated using fatty alcohols as an alternative bilayer stabiliser to cholesterol. The general similarities in the characteristics of liposomes containing fatty alcohols or cholesterol suggest a common behavioural influence for both compounds within the bilayer.

KW - chemistry, pharmaceutical

KW - cholesterol

KW - drug delivery systems

KW - excipients

KW - fatty alcohols

KW - liposomes

KW - membranes

KW - pharmaceutical preparations

KW - phosphatidylcholines

KW - solubility

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U2 - 10.1111/j.2042-7158.2010.01090.x

DO - 10.1111/j.2042-7158.2010.01090.x

M3 - Article

VL - 62

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EP - 1655

JO - Journal of Pharmacy and Pharmacology

JF - Journal of Pharmacy and Pharmacology

SN - 0022-3573

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