WO2013117008A1

WO2013117008A1 - Composition comprising hawthorn and phytosterols

Info

Publication number: WO2013117008A1
Application number: PCT/CN2012/071019
Authority: WO
Inventors: Youyou ZHAO; Weiguo Zhang; Junkuan Wang; Ying Xia; Qiutao GAO; Olivier Ballevre; Peter J VAN BLADEREN; Hua Bai; Yangfeng HOU
Original assignee: Nestec S.A.
Priority date: 2012-02-10
Filing date: 2012-02-10
Publication date: 2013-08-15
Also published as: WO2013117732A1

Abstract

The composition comprising hawthorn and phytosterols for use in the treatment, alleviation or prevention of disorders associated with hypercholesterolemia and/or hyperlipidemia is described.

Description

COMPOSITION COMPRISING HAWTHORN AND PHYTOSTEROLS

The present invention generally relates to the field of health and wellness. In particular, the present invention addresses hyperlipidemia, hypercholesterolemia and disorders associated therewith. For example, the present invention describes a composition comprising phytosterols and hawthorn for use in the treatment, alleviation or prevention of disorders associated with hypercholesterolemia. Cardiovascular Diseases (CVDs) are the leading cause of death and disability globally. More people are severely affected annually by CVDs than from any other cause. From a WHO report, an estimated 17.3 million people died from CVDs in 2008, representing 30% of all global deaths. Of these deaths, an estimated 7.3 million were due to coronary heart disease and 6.2 million were due to stroke. By 2030, almost 23.6 million people will die from CVDs, mainly from heart disease and stroke. These are projected to remain the single leading causes of death. Hawthorn and phytosterols are well known to have beneficial health effects, however, both individual ingredients have their limitations.

Hawthorn a flowering shrub of the rose family, has an extensive history of use in cardiovascular diseases, dating back to the 1^st century. Hawthorn has been shown to have a promising effect on blood cholesterol reduction. However, to achieve a biologically significant effect, daily consumption of hawthorn juice frequently causes stomach discomfort due to its acidic taste. In addition, hawthorn has limited reducing effect on blood triglycerides, which is an important risk factor for cardiovascular disease among blood lipids.

Phytosterols are known to be able to reduce blood concentrations of total and LDL cholesterol by reducing cholesterol absorption in the gut. A daily intake of around 2.4 g of plant sterols (or its saturated form, stands) is associated with ci.n 8 "6 reduction of blood total cholesterol concentrations. However, phytosterols have unwanted side effects. For example, they inhibit alpha and beta carotene absorption. Beta carotene is an important source of Vitamin A. Vitamin A is essential for growth and development.

When administered at low dosages that avoid significant unwanted side effects or gut discomfort hawthorn or plant sterol have no statistical significant effect on blood lipids, or cholesterol reduction.

However, there is a clear need in the art for natural preparations that can be safely used without side effects and that allow reducing the risk for obtaining cardiovascular disorders.

The present inventors have addressed this need.

Consequently, it was the objective of the present invention to improve the state of the art and - in particular - to provide a natural composition that overcomes the problems of the prior art and addresses the needs described above.

The present inventors were surprised to see that the subject matter of the independent claim achieves the objective of the present invention. The subject matter of the dependant claims further develops the central idea of the present invention. In particular, the inventors have found in a hamster model that - when administered together - hawthorn and phytosterols act synergistically and allow reducing blood lipids and blood levels of LDL cholesterol statistically significantly, while keeping the individual dosages of phytosterols and hawthorn sufficiently low to avoid unwanted side effects and discomfort

Without wishing to be bound by theory, the present inventors believe that this beneficial effect is due to hawthorn and phytosterols simultaneously enhancing the cholesterol excretion and reducing the cholesterol absorption.

Consequently, the present invention relates in part to a composition comprising phytosterols and hawthorn for use in the treatment, alleviation or prevention of disorders associated with hyperlipidemia and/or hypercholesterolemia. The present invention also relates to the use of phytosterols and hawthorn in the preparation of a composition for treating, alleviating or preventing disorders associated with hyperlipidemia and/or hypercholesterolemia.

Disorders associated with hyperlipidemia and/or hypercholesterolemia are well known to those of skill in the art (see for example Bhatnagar D. et al . , BMJ 2008 ; 337 : a993, herewith incorporated by reference) . For example, hypercholesterolemia is one of the major causes of atherosclerosis or coronary heart diseases. Hyperlipidemia is characterized by abnormally elevated levels of any or all lipids and/or lipoproteins in the blood.

For example, disorders associated with hyperlipidemia and/or hypercholesterolemia may be cardiovascular disorders. Cardiovascular disorders are a group of disorders of the heart and blood vessels and include coronary heart disease, cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, deep vein thrombosis and pulmonary embolism, etc. "Cardiovascular disorders" generally refers to any disease that affects the cardiovascular system, and in particular refers to those disorders related to atherosclerosis (arterial disease) . These conditions usually have similar causes, mechanisms, and treatments.

Atherosclerosis is the buildup of fatty deposits (such as cholesterol) called plaque on the inside walls of arteries. By the time that heart problems are detected, atherosclerosis is usually quite advanced, having progressed for decades. Most commonly, the plaque suddenly ruptures which causing the formation of a thrombus that will rapidly block the blood flow, leading to death of the surrounding tissues only in 5 minutes. This catastrophic event is called an infarction. One of the most common recognized scenarios is called coronary thrombosis of a coronary artery, causing myocardial infarction (a heart attack) . The same process in an artery to the brain is commonly called stroke. Another common scenario in a very advanced disease state is claudication from insufficient blood supply to the legs, typically caused by a combination of both stenosis and aneurysmal segments narrowed with clots. The main cause of atherosclerosis is yet unknown, it is a syndrome affecting arterial blood vessels, a chronic inflammatory response in the walls of arteries, caused largely by the accumulation of macrophages and promoted by low-density lipoproteins (LDL, plasma lipoproteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the macrophages by functional high density lipoproteins (HDL) . It is commonly referred to as a hardening or furring of the arteries. This is caused by the formation of multiple plaques within the arteries.

Hyperlipidemia is the most important risk factor for atherosclerosis, which is the major cause of cardiovascular disease. Hyperlipidemias may also be classified directly into which types of lipids are elevated, that is hypercholesterolemia, hypertriglyceridemia or both in combined hyperlipidemia. Elevated levels of Lipoprotein (a) may also be classified as a form of hyperlipidemia. Today, people make great efforts to keep their cholesterol levels low. Typical measures to reduce cholesterol levels are reducing dietary cholesterol intake, administration of certain medications, and rarely other treatments even including surgery. The present invention now provides a convenient dietary way to reduce cholesterol levels.

Hence, the composition of the present invention may be used for lowering the plasma total cholesterol level, in particular the plasma level of LDL cholesterol.

A low LDL cholesterol concentration reduces the risk of cardiovascular disorders.

This effect is even more pronounced if a low LDL level is combined with a high HDL cholesterol level. Increasing HDL cholesterol levels can be achieved by weight loss and/or by exercise . Hence it is preferred if the composition of the present invention is administered in a caloric restriction regimen and/or to subject which exercise aerobically regularly. Typical cardiovascular disorders that can be prevented, ameliorated or treated with the composition of the present invention may be selected from the group consisting of artherosclerosis , myocardinal infarction, coronary heart disease, stroke, peripheral vascular diseases or combinations thereof .

Additionally or alternatively the compositions of the present invention may also be for use in treating or preventing high blood triglyceride levels and/or disorders linked thereto. One major field of public concern is heart health. With the effects that the present invention demonstrates for the compositions described herein, the compositions of the present invention may be for use in promoting heart health and/or in treating, alleviating or preventing an impaired heart health. In therapeutic applications, compositions are administered in an amount sufficient to at least partially cure or arrest the symptoms of a disease and/or its complications. An amount adequate to accomplish this is defined as "a therapeutically effective dose". Amounts effective for this purpose will depend on a number of factors known to those of skill in the art such as the severity of the disease and the weight and general state of the patient.

In prophylactic applications, compositions according to the invention are administered to a patient susceptible to or otherwise at risk of a particular disease in an amount that is sufficient to at least partially reduce the risk of developing a disease. Such an amount is defined to be "a prophylactic effective dose". Again, the precise amounts depend on a number of patient specific factors such as the patient's state of health and weight. The compositions of the present invention are effective following a dose-response curve. They may be administered in a therapeutically effective dose or a prophylactic effective dose. Skilled artesians will be able to determine such dosages appropriately.

However, generally the composition of the present invention may be to be administered in a daily dose corresponding to at least 0.5 g, 1 g, or 3 g hawthorn and at least 15 mg, 50 mg, or lOOmg phytosterols per kg body weight per day. For example, the composition of the present invention may comprise at least 0.5 g hawthorn and at least 15 mg phytosterols per kg body weight per day.

Alternatively, the composition of the present invention may comprise at least 1 g hawthorn and at least 50 mg phytosterols per kg body weight per day.

Further alternatively, the composition of the present invention may comprise at least 3 g hawthorn and at least 100 mg phytosterols per kg body weight per day.

To avoid unwanted side effects such as off-tastes or inhibitions of vitamin A absorptions, the dosages should be kept at a reasonably low level.

For example, the dosages of hawthorn may not exceed 2.5 g per kg body weight per day and the dosage of phytosterols may not exceed 40 mg per kg body weight per day. Hawthorn may be provided in any form suitable for administration to humans or animals. For example, hawthorn may be provided as fresh fruit, dried fruit, hawthorn leaf or as an extract thereof. Typical phytosterols that may be used for the purpose of the present invention may be selected from the group consisting of plant sterols, stands, or combinations thereof.

Examples are β-sitosterol , campesterol and/or stigmasterol . Phytosterols may be provided as chemically pure compounds. As such they may be purified from plant sources or synthesized chemically. This allows a very precise dosing.

It may also be preferred to provide phytosterols from natural sources or extracts thereof. As such the phytosterols may be dietary phytosterols. They may be provided as vegetable oils, nuts, cereal products, vegetables, fruit, berries or as extracts thereof.

The composition may be any composition that is suitable for human or animal consumption. As such the composition may be selected from the group consisting of a food product, a drink, a functional food, a nutraceutical , a food additive, a nutritional formula, and a pet food product.

As disorders associated with hyperlipidemia and/or hypercholesterolemia typically occur with ageing, the composition of the present invention may be to be administered to adults or the elderly.

For the purpose of the present invention a subject shall be considered as "elderly" if it has surpassed the first half of its average expected lifespan in its country of origin, preferably, if it has surpassed the first two thirds of the average expected lifespan in its country of origin, more preferably if it has surpassed the first three quarters of the average expected lifespan in its country of origin, most preferred if it has surpassed the first four fifths of the average expected lifespan in its country of origin.

For example, the composition of the present invention may be to be administered to people above the age of 45, 50, 55, 60, 65, 70, 75 or 80 years.

As disorders associated with hyperlipidemia and/or hypercholesterolemia not only occur in humans but also in animals the composition of the present invention may be to be administered to humans or animals, for example companion animals such as cats or dogs.

Based on guidelines provided by the American Heart Association, NIH and NCEP for fasting HDL levels and risk for heart disease a level of less than 40 mg/dL HDL cholesterol for men and less than 50 mg/dL HDL cholesterol for women causes a heightened risk for heart disease. An HDL cholesterol level of 60-50 mg/dL for women and of 60-40 mg/dL for men is considered normal .

Consequently, the composition of the present invention may be to be administered to people with a fasting HDL cholesterol level of below 60 mg/dL, of below 50 mg/dL or of below 40 mg/dL .

The American Heart Association, NIH, and NCEP have also provided a set of guidelines for fasting LDL-Cholesterol levels and risk for heart disease.

A fasting LDL-Cholesterol level of 100 to 129 mg/dL corresponds to a near optimal LDL level, corresponding to higher rates for developing symptomatic cardiovascular disease events . A fasting LDL-Cholesterol level of 130 to 159 mg/dL corresponds to a borderline high LDL level, corresponding to higher rates for developing symptomatic cardiovascular disease events . A fasting LDL-Cholesterol level of 160 to 199 mg/dL corresponds to a high LDL level, corresponding to much higher rates for developing symptomatic cardiovascular disease events

Finally, a fasting LDL-Cholesterol level of above 200 mg/dL corresponds to a very high LDL level, corresponding to highest increased rates of symptomatic cardiovascular disease events.

Consequently, the composition of the present invention may be to be administered to people with a fasting LDL cholesterol level of above 100 mg/dL, of above 130 mg/dL, of above 160 mg/dL or of above 200 mg/dL. Advantageously, the composition of the present invention may be consumed briefly before, with or briefly after the consumption of a high-fat or high LDL cholesterol meal.

A meal shall be considered high in fat if it contains more than 60%, more than 80% or more than 100% of the daily recommended fat intake.

Similarly, a meal shall be considered high in LDL cholesterol if it contains more than 60%, more than 80% or more than 100% of the daily recommended LDL cholesterol intake.

As such, the composition may be to be administered in the time frame from 1 hour before to 1 hour after a high fat and/or high LDL cholesterol meal. Those skilled in the art will understand that they can freely combine all features of the present invention described herein, without departing from the scope of the invention as disclosed. In particular, features described for the uses of the present invention may be applied to the composition of the present invention and vice versa.

Further advantages and features of the present invention are apparent from the following Examples and Figures.

Figure 1 shows that the combination treatment of hawthorn and plant sterol at the same dose significantly and synergistically reduced blood cholesterol compared to an HFD- placebo. Data were analyzed by one-way ANOVA followed by Tukey' s multiple comparison tests and unpaired student t test. MeanlSEM, n=8-12, *P<0.05, versus control; †P<0.05, versus HFD placebo.

Figure 2 shows that the combination treatment of hawthorn and plant sterols at the same dose significantly and synergistically reduced LDL cholesterol compared to an HFD- placebo. Data were analyzed by one-way ANOVA followed by Tukey' s multiple comparison tests and unpaired student t test. MeanlSEM, n=8-12, *P<0.05, versus control; †P<0.05, versus HFD placebo .

Figure 3 shows that the combination treatment of hawthorn and plant sterols at the same dose significantly and synergistically caused a robust reduction in blood triglyceride in HFD hamsters. Data were analyzed by one-way ANOVA followed by Tukey' s multiple comparison tests and unpaired student t test. MeanlSEM, n=8-12, *P<0.05, versus control; †P<0.05, versus HFD placebo. Examples 1. Synergistic effect of plant sterol (PS) and hawthorn (H) on 1.1 blood total cholesterol and 1.2 LDL-cholesterol reductions .

Background: Abnormal elevation of blood cholesterol level (hypercholesterolemia) especially with the higher concentration of LDL is strongly associated with cardiovascular disease because these promote atheroma development in arteries (atherosclerosis) . This disease process leads to myocardial infarction (heart attack) , stroke, and peripheral vascular disease.

1.1 Blood Total Cholesterol: After 6 weeks of treatment, a high fat diet (HFD) significantly elevated the blood cholesterol by 67mg/dL (Tablel.l, HFD-placebo vs. control) . Simultaneously treatment with plant sterol or hawthorn has no significant alteration on high blood cholesterol compared to HFD placebo (Figl, HFD-H, HFD-PS vs. control, *P<0.05; HFD-H, HFD-PS vs. HFD-Placebo, P>0.05) . Although two individual ingredients did not show the significant protection effect per se, the combination treatment of hawthorn and plant sterol at the same dose significantly and synergistically reduced blood cholesterol compared to an HFD-placebo (Fig. 1, HFD-PS/H vs. HFD placebo, †P<0.05) . In addition, the combination treatment showed synergistic reduction effect on high blood cholesterol versus individual treatments (Tablel.l) . Tablel.l. Blood total cholesterol (TC) reduction effect of Hawthorn (H) and Plant Sterol (PS) in high fat diet (HFD) hamster .

Control HFD-placebo HFD-H HFD-PS HFD-H/PS

TC

108.0+3.02 171.2+5.59* 187.2+6.10* 161.5+5.16* 145.3+5.67†

(mg/dL) 1.2 LDL Cholesterol: After 6 weeks of treatment, a high fat diet (HFD) significantly elevated LDL cholesterol by 27mg/dL (Tablel.2, HFD-placebo vs. control) . Simultaneously treatment with plant sterol or hawthorn had no significant alteration on high LDL cholesterol compared to HFD placebo (Figl, HFD-H, HFD-PS vs. control, *P<0.05; HFD-H, HFD-PS vs. HFD-Placebo, P>0.05) . Although two individual ingredients did not show the significant protection effect per se, the combination treatment of hawthorn and plant sterol at the same dose significantly and synergistically reduced LDL cholesterol compared to HFD-placebo (Fig.2, HFD-PS/H vs. HFD placebo, †P<0.05) . In addition, the combination treatment showed a synergistic reduction effect on LDL cholesterol versus individual treatments (Tablel.2) .

Tablel.2. LDL cholesterol reduction effect of Hawthorn (H) and Plant Sterol (PS) in high fat diet (HFD) hamster.

2. Synergistic effect of plant sterol (PS) and hawthorn (H) on blood triglyceride (TG) reduction.

Background: In medicine, hypertriglyceridemia denotes high (hyper-) blood levels (-emia) of triglycerides, the most abundant fatty molecule in most organisms. It has been associated with atherosclerosis, even in the absence of hypercholesterolemia (high cholesterol levels) . It can also lead to pancreatitis in excessive concentrations (i.e. when the triglyceride concentration is greater, and often very much greater, than 1000 mg/dl or 12 mmol/1) .

Blood Triglyceride: After 6 weeks of treatment, high fat diet significantly elevated the blood triglyceride by 126mg/dL (Table2, HFD-Placebo vs. control). Plant sterol alone showed robust reduction on blood triglyceride in HFD hamsters (Fig. 3, HFD-PS vs. control, P>0.05; HFD-PS vs. HFD-Placebo, †P<0.05). Although did not show the reduction effect alone, hawthorn has enhanced the blood triglyceride reduction effect of plant sterol by 8.8mg/dL.

Table2. Blood Triglyceride (TG) reduction effect of Hawthorn (H) and Plant Sterol (PS) in high fat diet (HFD) hamster.

Control HFD-placebo HFD-H HFD-PS HFD-H/PS

TG

131.3+17.0 257.2+23.2* 250.4+22.8* 171.7+12.8† 162.9+17.5†

(mg/dL)

Claims

Claims :

1. Composition comprising phytosterols and hawthorn for use in the treatment, alleviation or prevention of disorders associated with hypercholesterolemia and/or hyperlipidemia

2. Composition for use in accordance with claim 1 for use in lowering the plasma total cholesterol level.

3. Composition for use in accordance with one of the preceding claims for lowering the plasma level of LDL cholesterol.

4. Composition for use in accordance with one of the preceding claims wherein the disorders associated with hypercholesterolemia are cardiovascular disorders.

5. Composition for use in accordance with claim 4, wherein the cardiovascular disorder is selected from the group of artherosclerosis , coronary heart disease, myocardinal infarction, stroke, peripheral vascular diseases or combinations thereof.

6. Composition for use in accordance with one of the preceding claims for use in treating or preventing disorders linked to a high blood triglyceride levels.

7. Composition for use in accordance with one of the preceding claims for use in promoting heart health and/or in treating, alleviating or preventing an impaired heart health.

8. Composition for use in accordance with one of the preceding claims wherein the composition is to be administered in a daily dose corresponding to at least 0.5 g, 1 g, or 3 g hawthorn and at least 15 mg, 50 mg, or lOOmg phytosterols per kg body weight per day.

9. Composition for use in accordance with one of the preceding claims wherein hawthorn is provided as fresh fruit, dried fruit, hawthorn leaf or as an extract thereof.

10. Composition for use in accordance with one of the preceding claims wherein the phytosterols are selected from the group consisting of plant sterols and stands; for example β-sitosterol , campesterol and stigmasterol .

11. Composition for use in accordance with one of the preceding claims wherein the phytosterols are dietary phytosterols and are provided as vegetable oils, nuts, cereal products, vegetables, fruit and berries or as extracts thereof.

12. Composition for use in accordance with one of the preceding claims wherein the composition is selected from the group consisting of a food product, a drink, a functional food, a nutraceutical , a food additive, a nutritional formula, and a pet food product.

13. Composition for use in accordance with one of the preceding claims wherein the composition is to be administered to adults or the elderly.

14. Composition for use in accordance with one of the preceding claims wherein the composition is to be administered to humans or animals, for example companion animal such as cats or dogs.

15. Composition for use in accordance with one of the preceding claims wherein the composition is to be administered in the time frame from 1 hour before to 1 hour after a high fat and/or high LDL cholesterol meal.