The presence of cholesterol in human and other mammals is vitally important for the cell membrane function. However, an excessively high serum cholesterol concentration is a risk factor for cardiovascular diseases (CVD). In today’s world CVD is the leading cause of death in developed countries and is becoming one of the leading causes of death in developing countries as well. This means that despite the successful prevention of atherosclerosis, cardiovascular diseases are still responsible for one of every three cases of death. The combination of changed eating habits, the use of tobacco, and less physical activity are the main causes of the wide spread distribution of CVD. Genetic factors may also be a reason for enhanced serum cholesterol levels (Fuentes et al., 2000; Lind et al., 2002; Zuliani and Fellin, 2003). It has been demonstrated that a 10% decline in total cholesterol is associated with a 20% risk reduction of coronary heart disease at the age of 70 and even lowers the risk by 50% at the age of 40 (Law et al., 1994). Traditionally, high serum cholesterol levels have been normalised using cholesterol-lowering drugs. At the same time, the importance of dietary intake has been emphasised by the nutritionists.
Selective inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA or statins), the rate-controlling enzyme of cholesterol synthetic pathway, are effective drugs but a very expensive method to treat hypercholesterolemia. Statins (e.g. mevastatin, lovastatin, cerivastatin and simvastatin) are able to lower serum total cholesterol by decreasing low density lipoprotein (LDL) cholesterol by 20%, even up to 55% (Chong et al., 2001; Blasetto et al., 2003; Endo, 2004). Some statins have, however, lately caused severe side effects which have resulted in major estimated revenue decreases for the pharmaceutical industry (Clark, 2003; Jamal et al., 2004). In August 2001, Bayer AG had to withdraw their cholesterol-lowering drug Lipobay®/Baycol® (cerivastatin) worldwide due to reports of side effects involving muscular weakness (rhabdomyolysis) (Maggini et al., 2004;. In less than a month, Bayer’s share had lost over 42% of its value (Bloomberg Terminal, 2004). The FDA (Food and Drug Administration) has received reports of serious muscle toxicity of another statin drug, Crestor® (rosuvastatin) by AstraZeneca. At the moment the FDA is evaluating these reports and comparing the frequency of reports to the reports of other statins. The importance of looking for optional methods of lowering cholesterol is therefore imminent.
Studies of phytosterols, which are structurally related to cholesterol, date back to the 1950s, when large amounts of phytosterols (10-15 g/day) were administrated in the form of a powder (Pollack, 1953; Farquhar et al., 1956). The unpleasant texture of phytosterols and the poor solubility in oil or water has caused several problems in preparation and administration, and thus prevented their widespread use (Miettinen, 2001).
High-fat foods such as margarines and butters appear to be ideal vehicles for phytosterols and its saturated form phytostanol because of their strong hydrophobic nature (Mattson et al., 1982). Finnish science is at the forefront of development in sterols/stanols dietary products. The Raisio corporation launched the first commercialised phytostanol ester-containing cholesterol lowering margarine, Benecol®, in 1995 (Miettinen et al., 1995). High-fat foods are contradictory to the current approaches of maintaining healthy diets and a healthy lifestyle. Therefore, the attempt has been to incorporate phytosterols into lower-fat foods (St-Onge and Jones, 2003). Because of the hydrophobic nature of phytosterols, the cholesterol-lowering efficacy in low-fat foods was thought to be minor. Studies, however, show that the effect of low-fat foods have a significant cholesterol-lowering effect (Volpe et al., 2001; Nestel et al., 2001).
In the middle of the 1990s a new method was developed, to make the use of phytosterols more accessible. A microcrystalline suspension in oil allows incorporation of up to 30% of phytosterols into a food product without any chemical reactions or additives. The extent of cholesterol-lowering in vivo is similar to those examined using phytosterol or phytostanol esters dispersed in high fat spreads. In 2003, the European Union’s Novel Foods Regulator gave its approval to begin marketing this suspension (Diminicol®) throughout the EU. Diminicol® received GRAS status (Generally Recognised As Safe) earlier the same year in the US by the FDA. The FDA also granted products containing Diminicol® the right to use the approved sterol heart health claim. Functional foods have no precise, universally accepted definition in general, but they can be considered food components (being nutrient or not), which affects one or a limited number of function of the body in a positive way, providing a health benefit beyond traditional nutritional value (Roberfroid, 2000; Palou et al., 2003).
The combination of statins and sterols/stanols has only been tested on a small scale so far. It appears that for patients who are taking statins and are in need of additional cholesterol lowering, the addition of sterols/stanols into the diet is more effective than the increase of statin doses (Katan et al., 2003). A wide study carried out in Finland (FINRISK 2002) revealed that of all patients who were aware of their high cholesterol levels, 19% used cholesterol-lowering medicines, 11% used cholesterol-lowering bread spreads and 5% combined both therapies (de Jong et al., 2004).
CONTENTS
Table of contents
List of original publications
1 INTRODUCTION
2 REVIEW OF THE LITERATURE
2.1 Phytosterols as cholesterol-lowering agents
- 2.1.1 Composition, sources and consumption of phytosterols
2.1.2 Safety of phytosterols and phytostanols
2.1.3 Phytosterol absorption
2.1.4 Phytosterol mechanisms of action on intestinal cholesterol absorption
2.2 Theory of suspensions and crystal properties
- 2.2.1 Properties of solid particles
2.2.2 Properties of the dispersion medium
2.2.3 Formulation of a suspension
2.2.4 Crystal nucleation
2.2.5 Crystal growth.
2.2.6 Imperfections in crystals
2.2.7 Factors affecting crystal properties
2.2.8 Physical stability of suspensions
2.2.9 Methods for analysing suspensions
3 AIMS OF THE STUDY
4 EXPERIMENTAL
4.1 Materials
4.2 Preparation of phytosterol crystals (I)
4.3 Preparation of the suspensions (I-V)
4.4 Analysis of phytosterol crystals and suspensions
4.5 Dynamic in vitro lipolysis method (V)
5 RESULTS AND DISCUSSION
5.1 Crystal forms of phytosterol (I-IV)
5.2 Dehydration from phytosterol
- 5.2.1 Dehydration from hydrated phytosterol crystals (I)
5.2.2 Dehydration from phytosterol crystals in oil suspensions (IV)
5.3 Crystal habit and size distribution of phytosterol
- 5.3.1 The effect of the composition on crystal modifications (I,II)
5.3.2 The effects of process parameters on crystal modifications (I,II, III)
5.3.3 Changes in crystal size distribution and crystal habit during storage (II)
5.4 Effects on cholesterol solubilisation in vitro (V)
6 CONCLUSIONS
ACKNOWLEDGEMENTS
REFERENCES
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