Composition

Abstract

The present invention relates to a solid oral composition comprising red yeast rice fermented rice stabilized by the addition of CaCO3.

Description

[Technical field]

[0001] The present invention relates to a solid oral composition based on red yeast rice fermented standardized with monacolin K (MK) and using the addition of calcium carbonate to improve the stability of monacolin K. [Background technology]

[0002] Red yeast rice (RYR), also known as red yeast rice, has traditionally been used for centuries as a natural food colorant and as a food preservative for meat and fish. It has become a popular dietary supplement in recent years due to the discovery that many of its bioactive components, including the series of active pharmaceutical compounds monacolins (shown as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors), can lower serum cholesterol levels (Lin et al., Appl Microbiol Biotechnol 2008;77,965-973).

[0003] Among the bioactive compounds found in red yeast rice, monacolins are well known for their pharmacological effects in controlling hyperlipidemia. Monacolin K is considered to be the most effective compound in lowering plasma cholesterol. It is structurally identical to lovastatin and mevinolin (Klimek, Wang, and Ogunkanmi, P&T 2009,34 No6,313-316).

[0004] It is well known that monacolin K has poor stability in red yeast rice and in pharmaceutical formulations. Stability analysis has shown that monacolin K was unstable during long-term storage of red yeast rice powder, especially under atmospheric storage conditions and at high temperatures (40-50°C) (Sani Jirasatid et al., Journal of Food Engineering 116(2013)436-443).

[0005] Further studies have revealed that monacolins are significantly reduced under high temperature and humidity (75% relative humidity, 60°C) and sunlight conditions. Monacolin K and its hydroxy acid forms are dehydrated and converted to dehydromonacolin K at high temperature (80°C), while monacolins K, J, and L are converted to the corresponding hydroxy acid forms under high humidity conditions (92.5% RH, 25°C). This observation indicates that monacolins in red yeast rice powder are photosensitive and thermosensitive (Yong-Guo Li, Journal of Pharmaceutical and Biomedical Analysis 39(2005)82-90).

[0006] It is therefore an object of the present invention to provide monacolin K in a red yeast rice formulation that exhibits increased stability. Summary of the Invention

[0007] The present invention provides a composition comprising red yeast rice and CaCO3.

[0008] Surprisingly, applicants have found that a composition comprising red yeast rice and CaCO3 improved stability, which showed a statistically significant effect.

[0009] [Definition] The percentages of the various components of the combination are defined relative to the other components. The weight percent (wt%) of a particular component based on the other components is the weight (mass) of the particular component divided by its weight (mass) based on the weight of the composition multiplied by 100, i.e.:

number

[0010] Red yeast rice or red yeast rice is a traditional Chinese preparation of cooked white rice that has been fermented with Monascus purpureus at room temperature for several days, resulting in a red color.

[0011] The red yeast rice used in connection with the present invention may be standardized with monacolin K to 0.5-2.0% (w / w).

[0012] Red yeast rice standardized to 1.75% monacolin K is particularly preferred. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present invention provides a composition comprising red yeast rice and CaCO3 (calcium carbonate).

[0014] In one embodiment, the present invention provides a composition comprising red yeast rice standardized with monacolin K to 1.75% w / w and CaCO3 in a weight ratio of 1:5 to 5:1.

[0015] Preferably, the present invention provides a composition comprising red yeast rice standardized with monacolin K to 1.75% w / w and CaCO3 in a weight ratio of 2:1.

[0016] More preferably, the present invention provides a composition comprising red yeast rice standardized with monacolin K to 1.75% w / w and CaCO3 in a weight ratio of 1:2.

[0017] More preferably, the present invention provides a composition comprising red yeast rice standardized with monacolin K to 1.75% w / w and CaCO3 in a weight ratio of 2:3.

[0018] In further embodiments, the aforementioned compositions may additionally comprise Berberis aristata, phytosterols and / or phytostanols, Cynara cardunculus extract, Citrus bergamia extract, Allium sativum, Salvia miltiorrhiza, policosanol, Camellia sinensis extract, Melannurca campana extract, Curcuma longa, and one or more ingredients selected from curcuminoids, spirulina, chitosan, beta-glucan, glucomannan, coenzyme Q10, astaxanthin, folic acid, and orthosiphon.

[0019] [Use of the present invention] The present invention also provides the use of the compositions disclosed herein for use in the treatment or prevention of hypercholesterolemia or hyperlipidemia.

[0020] The present invention provides the use of a composition disclosed herein for the manufacture of a medicament for the treatment or prevention of hypercholesterolemia or hyperlipidemia.

[0021] The present invention also provides a method for the treatment or prevention of hypercholesterolemia or hyperlipidemia, comprising administering to a patient in need thereof a composition disclosed herein.

[0022] Hypercholesterolemia (and hyperlipidemia) is a well-known risk factor for coronary artery disease, cerebrovascular disease, and peripheral arterial disease. In fact, every reduction in basal plasma cholesterol levels correlates with a proportional reduction in the incidence of cardiovascular complications (myocardial infarction, stroke, peripheral occlusive arterial disease). This correlation exists already before the first clinical event associated with primary prevention, and also before the first post-clinical cardiovascular event associated with secondary prevention.

[0023] [Dosage] The compositions of the present invention are useful for treating or preventing hypercholesterolemia and hyperlipidemia.

[0024] The compositions are generally administered to a subject in need thereof, such as a human or animal, typically a human.

[0025] The compositions are typically administered in a therapeutically or prophylactically useful amount.

[0026] The compositions may be administered over an extended period of time to maintain beneficial therapeutic effects, or may be administered for only a short period of time.

[0027] Typical daily doses of each component of the combination can be in the range 100 pg to 100 mg per kg of body weight, more typically 5 ng to 25 mg per kg of body weight, more usually 10 ng to 15 mg per kg of body weight (e.g., 10 ng to 10 to 20 mg, more typically 1 μg per kg to 20 mg per kg, e.g., 1 μg to 10 mg per kg), although higher or lower doses may be administered if necessary.

[0028] The composition may be orally administered within a dosage range of, for example, 0.1 to 1000 mg, 1 to 800 mg, 5 to 700 mg, 10 to 500 mg, 25 to 400 mg, or 50 to 350 mg.

[0029] Particular examples of daily doses of the composition are 100, 200, 300, 600, 900, 1200, 1500, and 1800 mg.

[0030] For a red yeast rice composition standardized to 1.75 w / w% monacolin K, this dosage range typically corresponds to a daily dose of 0.2 mg to about 35 mg of monacolin K.

[0031] The daily dose may be administered in multiple doses throughout the day, such as once a day, twice a day, or three times a day.

[0032] [formulation] In one embodiment, the red yeast rice composition, e.g., pharmaceutical composition, according to the invention is provided in an oral dosage form, including tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers, or patches, such as buccal patches.

[0033] Thus, in one embodiment of the present invention, the red yeast rice composition according to the invention is presented in a tablet.

[0034] Typically, tablets contain one or more pharma- ceutically acceptable excipients, which may be selected from, for example, carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents, fillers or extenders, granulating agents, coating agents, release control agents, binders, disintegrants, lubricants, preservatives, antioxidants, buffers, suspending agents, thickeners, flavoring agents, sweeteners, taste masking agents, stabilizers, or any other excipients conventionally used in pharmaceutical compositions.

[0035] Preferably, the compositions of the present invention are formulated with one or more pharma- ceutically acceptable fillers or bulking agents.

[0036] Examples of excipients include magnesium stearate, silicon dioxide, carboxymethylcellulose, crospovidone, as well as hydroxypropylcellulose and maltodextrin.

[0037] In one embodiment, the red yeast rice composition is provided in a capsule.

[0038] Typically, the capsule comprises one or more pharma- ceutically or nutraceutical acceptable excipients, which may be selected, for example, from carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents, fillers or extenders, granulating agents, coating agents, release control agents, binders, disintegrants, lubricants, preservatives, antioxidants, buffers, suspending agents, thickeners, flavoring agents, sweeteners, taste masking agents, stabilizers, or any other excipients conventionally used in pharmaceutical compositions.

[0039] Examples of excipients include magnesium stearate, silicon dioxide, maltodextrin, carboxymethylcellulose, crospovidone, and hydroxypropylcellulose. Examples of formulations [Table 1] EXAMPLES

[0040] [Stability analysis of red yeast rice composition] The objective of the stability study was to compare the effect of different ratios of RYR to CaCO3 on the stability profile of a composition containing monacolin K.

[0041] The preparation of tablets was carried out in the usual manner.

[0042] The following tablet compositions were analyzed: A 2:3 ratio of RYR / CaCO3 B RYR / CaCO3 in a ratio of 2:1 C RYR / CaCO3 in a ratio of 1:2 D RYR / CaHPO4 in a ratio of 1:2

[0043] The storage conditions were 25°C, 65% RH, 30°C, 75% RH, and 40°C, 75% RH.

[0044] Samples were analyzed after 0, 3, 6, 12, 18, and 24 months.

[0045] [result] [Table 2] JPEG2024546526000004.jpg31123

[0046] The results show that the composition containing RYR and CaCO3 has improved stability with respect to monacolin K concentration compared to the composition containing RYR and CaHPO4.

[0047] Particularly stable are compositions containing RYR and CaCO3 in ratios of 2:3 and 1:2.

Claims

1. Red yeast rice and CaCO ３ A composition comprising:

2. The red yeast rice and CaCO ３ The composition according to claim 1, characterized in that the ratio of is 1:5 to 5:

1.

3. The red yeast rice and CaCO ３ 2. The composition according to claim 1, characterized in that the ratio of

4. The red yeast rice and CaCO ３ 2. The composition according to claim 1, characterized in that the ratio of

5. The red yeast rice and CaCO ３ 2. The composition according to claim 1, characterized in that the ratio of

6. The composition according to claims 1 to 5, characterized in that the red yeast rice is standardized with monacolin K to 0.5 to 2.0 w / w%.

7. A composition according to claims 1 to 6, characterized in that the red yeast rice is standardised with monacolin K to 1.75 w / w%.

8. The composition according to any one of claims 1 to 7 for use in the treatment or prevention of hypercholesterolemia or hyperlipidemia.

9. 9. The composition of any one of claims 1 to 8, further comprising Berberis aristata, phytosterols and / or phytostanols, Cynara cardunculus extract, Citrus bergamia extract, Allium sativum, Salvia miltiorrhiza, policosanol, Camellia sinensis extract, Melannurca campana extract, Curcuma longa, and one or more components selected from curcuminoids, spirulina, chitosan, beta-glucan, glucomannan.

10. The composition according to any one of claims 1 to 9, further comprising one or more components selected from coenzyme Q10, astaxanthin, folic acid, and orthosiphon.

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