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Lecithin-Based Microemulsions for Pharmaceutical use - Phase behavior and Solution Structure

von Corswant, Christian LU (1998)
Abstract (Swedish)
Popular Abstract in Swedish

Många nya läkemedel har en mycket låg löslighet i vatten vilket medför att det behövs stora mängder vatten (ibland 10 tals liter) för att lösa upp en tillräcklig mängd av läkemedlet. Detta gör det till exempel omöjligt att ge medicinen som en injektion direkt i blodet. En möjlig lösning på detta problem är att lösa upp läkemedlet i en s. k. mikroemulsion istället. En mikroemulsion är en blandning av olja, vatten och ett ytaktivt ämne. Det är en helt klar och stabil lösning och eftersom mikroemulsionen innehåller stora mängder olja så räcker det ofta med några milliliter för att lösa en tillräcklig dos av det svårlösliga läkemedlet. I avhandlingen presenteras mikroemulsionssystem som lämpar sig... (More)
Popular Abstract in Swedish

Många nya läkemedel har en mycket låg löslighet i vatten vilket medför att det behövs stora mängder vatten (ibland 10 tals liter) för att lösa upp en tillräcklig mängd av läkemedlet. Detta gör det till exempel omöjligt att ge medicinen som en injektion direkt i blodet. En möjlig lösning på detta problem är att lösa upp läkemedlet i en s. k. mikroemulsion istället. En mikroemulsion är en blandning av olja, vatten och ett ytaktivt ämne. Det är en helt klar och stabil lösning och eftersom mikroemulsionen innehåller stora mängder olja så räcker det ofta med några milliliter för att lösa en tillräcklig dos av det svårlösliga läkemedlet. I avhandlingen presenteras mikroemulsionssystem som lämpar sig för farmaceutiskt bruk. Huvudbeståndsdelarna är växtfett (liknande de som finns i matolja) och det ytaktiva ämnet lecitin som utvinns bland annat från sojabönor. Både lecitin och fett finns naturligt i kroppen och är därför inte giftiga vilket är en förutsättning för att det skall kunna användas i farmaceutiska sammanhang.



En stor del av avhandlingen beskriver hur mikroemulsionerna ser ut på mikroskopisk, molekylär nivå. Det visar sig att trots att mikroemulsionerna för ögat ser ut som en klar lösning så är olje och vatten molekylerna inte fullständigt blandade utan de återfinns antingen som små, små droppar eller stora tredimensionella nätverk separerade av en mycket tunn film av det ytaktiva ämnet. Exempel ges på hur mikrostrukturen förändras om man byter olja, blandar i ytterligare ett ytaktivt ämne, eller löser upp ett läkemedel i mikroemulsionen. Det beskrivs också vad som händer när mikroemulsionen späds ut med vatten.



Slutligen visas att det är möjligt att ge upp till 1.5 ml/kg av mikroemulsionen till råttor utan att de får några biverkningar. Lösligheten av felodipin (den verksamma beståndsdelen i Plendil som är ett läkemedel mot högt blodtryck) förbättrades c:a 10000 gånger i denna mikroemulsion jämfört med lösligheten i rent vatten. (Less)
Abstract
Microemulsions are thermodynamically stable, transparent solutions of water, oil and amphiphile(s). It is possible to incorporate large amounts of oil in microemulsions, which makes them interesting for use as a drug delivery vehicle for water insoluble drugs. A prerequisite for pharmaceutical use, however, is a low toxicity of the composition. The aim of this thesis has thus been to characterize microemulsion systems based on the pharmaceutically acceptable components lecithin (soybean phosphatidylcholine), medium-chain and long-chain triglycerides and isopropyl myristate (IPM). An analysis was made of the microstructure of these systems and their phase behavior determined. The effect of the addition of hydrophilic amphiphiles (the IPM... (More)
Microemulsions are thermodynamically stable, transparent solutions of water, oil and amphiphile(s). It is possible to incorporate large amounts of oil in microemulsions, which makes them interesting for use as a drug delivery vehicle for water insoluble drugs. A prerequisite for pharmaceutical use, however, is a low toxicity of the composition. The aim of this thesis has thus been to characterize microemulsion systems based on the pharmaceutically acceptable components lecithin (soybean phosphatidylcholine), medium-chain and long-chain triglycerides and isopropyl myristate (IPM). An analysis was made of the microstructure of these systems and their phase behavior determined. The effect of the addition of hydrophilic amphiphiles (the IPM system) and of two drug compounds, felodipine and BIBP3226 was also analyzed. Felodipine, being practically insoluble in water and slightly soluble in MCT, was found to act as a non-penetrating oil with only a slight influence (decrease) on the curvature of the amphiphilic film. BIBP3226, on the other hand, being practically insoluble in MCT but slightly soluble in the aqueous phase, had an affinity for the lecithin monolayer which significantly increased both the solubility and the spontaneous curvature of the film. At the point of saturation, approximately 60 percent of the drug molecules were located in the film.



A microemulsion system suitable for intravenous administration is presented. It is composed of a medium-chain triglyceride as the oil, soybean phosphatidylcholine and polyethylene glycol(660)-12-hydroxystearate as amphiphiles, and polyethylene glycol 400 and ethanol as cosolvents. The microstructure of this microemulsion was found to be of a bicontinuous nature, even at high oil concentrations. When diluted with water, the microemulsion spontaneously formed an oil-in-water emulsion with a mean droplet diameter between 60 and 200 nm depending on the oil content of the microemulsion. It was possible to administer up to 1.5 ml/kg of the microemulsion intravenously to conscious rats without causing any permanent changes in the hemodynamic parameters studied. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Prof Strey, Reinhard, Institut für Physikalische Chemie, Universität zu Köln, Köln, Germany
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Food and drink technology, felodipine, solubilization, drug delivery, self-diffusion NMR, alkylmaltoside, microstructure, isopropyl myristate, triglyceride, soybean phosphatidylcholine, Microemulsion, lecithin, Livsmedelsteknik
pages
57 pages
publisher
Department of Food Technology, Lund University
defense location
Lecture hall A, Center for Chemistry and Chemical Engineering, Lund
defense date
1998-11-21 13:15
external identifiers
  • Other:ISRN: LUTKDH/TKL0-1034/1-57
language
English
LU publication?
yes
id
ef6063e9-d3c0-475e-beca-a2c9ff497af3 (old id 39076)
date added to LUP
2007-10-14 17:48:25
date last changed
2016-09-19 08:45:01
@misc{ef6063e9-d3c0-475e-beca-a2c9ff497af3,
  abstract     = {Microemulsions are thermodynamically stable, transparent solutions of water, oil and amphiphile(s). It is possible to incorporate large amounts of oil in microemulsions, which makes them interesting for use as a drug delivery vehicle for water insoluble drugs. A prerequisite for pharmaceutical use, however, is a low toxicity of the composition. The aim of this thesis has thus been to characterize microemulsion systems based on the pharmaceutically acceptable components lecithin (soybean phosphatidylcholine), medium-chain and long-chain triglycerides and isopropyl myristate (IPM). An analysis was made of the microstructure of these systems and their phase behavior determined. The effect of the addition of hydrophilic amphiphiles (the IPM system) and of two drug compounds, felodipine and BIBP3226 was also analyzed. Felodipine, being practically insoluble in water and slightly soluble in MCT, was found to act as a non-penetrating oil with only a slight influence (decrease) on the curvature of the amphiphilic film. BIBP3226, on the other hand, being practically insoluble in MCT but slightly soluble in the aqueous phase, had an affinity for the lecithin monolayer which significantly increased both the solubility and the spontaneous curvature of the film. At the point of saturation, approximately 60 percent of the drug molecules were located in the film.<br/><br>
<br/><br>
A microemulsion system suitable for intravenous administration is presented. It is composed of a medium-chain triglyceride as the oil, soybean phosphatidylcholine and polyethylene glycol(660)-12-hydroxystearate as amphiphiles, and polyethylene glycol 400 and ethanol as cosolvents. The microstructure of this microemulsion was found to be of a bicontinuous nature, even at high oil concentrations. When diluted with water, the microemulsion spontaneously formed an oil-in-water emulsion with a mean droplet diameter between 60 and 200 nm depending on the oil content of the microemulsion. It was possible to administer up to 1.5 ml/kg of the microemulsion intravenously to conscious rats without causing any permanent changes in the hemodynamic parameters studied.},
  author       = {von Corswant, Christian},
  keyword      = {Food and drink technology,felodipine,solubilization,drug delivery,self-diffusion NMR,alkylmaltoside,microstructure,isopropyl myristate,triglyceride,soybean phosphatidylcholine,Microemulsion,lecithin,Livsmedelsteknik},
  language     = {eng},
  pages        = {57},
  publisher    = {ARRAY(0xc357530)},
  title        = {Lecithin-Based Microemulsions for Pharmaceutical use - Phase behavior and Solution Structure},
  year         = {1998},
}