US 2016O199398A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0199398 A1 Gao (43) Pub. Date: Jul. 14, 2016
(54) COMPOSITIONS CONTAINING ENRICHED A61E36/752 (2006.01) NATURAL CROCIN AND/OR CROCETIN, A63L/01 (2006.01) AND THER THERAPEUTIC OR A61E36/45 (2006.01) NUTRACEUTICAL USES A613 L/353 (2006.01) A2.3L 2/52 (2006.01) (71) Applicant: Song Gao, East Brunswick, NJ (US) A63L/202 (2006.01) (52) U.S. Cl. (72) Inventor: Song Gao, East Brunswick, NJ (US) CPC ...... A6 IK3I/7024 (2013.01); A61 K3I/202 (2013.01); A61K 45/06 (2013.01); A61K 36/82 (21) Appl. No.: 14/934,260 (2013.01); A61 K3I/12I (2013.01); A61 K 3 I/05 (2013.01); A61K 36/258 (2013.01); (22) Filed: Nov. 6, 2015 A6 IK3I/385 (2013.01); A61 K3I/I64 Related U.S. Application Data (2013.01); A61 K36/87 (2013.01); A61K 36/41 (2013.01); A61K 36/16 (2013.01); A61K 36/28 (60) Provisional application No. 61/727.244, filed on Nov. (2013.01); A61 K36/752 (2013.01); A61 K 16, 2012. 31/01 (2013.01); A61K 36/45 (2013.01); A61 K 3 1/353 (2013.01); A23L I/30 (2013.01); A23L Publication Classification 2/52 (2013.01) (51) Int. Cl. (57) ABSTRACT A6 IK3I/7024 (2006.01) A6 IK 45/06 (2006.01) The invention relates to unique compositions containing A6 IK36/82 (2006.01) enriched and purified natural crocin and/or crocetin for pre A6 IK3I/2I (2006.01) vention and/or treatment of cancers and other conditions and A6 IK3I/05 (2006.01) diseases. Compositions comprise mainly enriched or purified A6 IK 36/258 (2006.01) natural crocin or crocetin or combination of both and possible A6 IK3I/385 (2006.01) other active phytochemicals. A composition is used as func A6 IK3I/64 (2006.01) tional food, drink, dietary supplement, or therapeutic dosage A6 IK36/87 (2006.01) to a human orally or through other appropriate way A6 IK 36/4I (2006.01) (parenteral, percutaneous, rectal, mucosal, intranasal or topi A6 IK 36/6 (2006.01) cal administration). A method of natural crocin and crocetin A6 IK 36/28 (2006.01) enriching and purification is revealed. Patent Application Publication Jul. 14, 2016 Sheet 1 of 3 US 2016/O199398 A1
Figure 1. Flow chart of crocin and crocetin purification
Gardenia Yellow GY 50 Sssssss 8% Esiasts WS' GY Stor Store at -10°C Crystašization : Sai Y actic grocit arid groceti in C-1 Solution i. ssoya is 88& Elias Regea Crystašizas: as-is. 3. $Sists Crocin and crocetis CC-2 or& C-2 solutioi insid asidads: i:S resis Roš: fán crossaiogag, systia Sakri Rious Res: isias: wish ais; a sad 3% asiatio ESS is 95% sha is High purity Crocis: Croceti x...Ito RiceState 3 dify ... Eits sittir Patent Application Publication Jul. 14, 2016 Sheet 2 of 3 US 2016/O199398 A1
Figure 2. HPLC Chromatogram of crocin after crystallization from gardenia yellow.
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Patent Application Publication Jul. 14, 2016 Sheet 3 of 3 US 2016/O199398 A1
Figure 3. Quantitative Nuclear Magnetic Resonance (QNMR). DMSO 400MHz
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COMPOSITIONS CONTAINING ENRICHED patients in the United States use complementary and alterna NATURAL CROCIN AND/OR CROCETIN, tive medicine, exclusively or concurrently with traditional therapeutic regime such as radiation therapy and/or chemo AND THER THERAPEUTIC OR therapy. It is ideal to develop drug or treatment from in fruits, NUTRACEUTICALUSES Vegetables, herbs and spices that are efficacious and without adverse side effect. Most preferably, a product or products CROSS-REFERENCE TO EARLIER FILED can be invented to prevent development of various cancers APPLICATIONS and other diseases. This invention relates to improvements in human nutrition and therapeutics involving providing unique 0001. This application is a continuation of U.S. patent compositions with enriched or purified natural crocin and application Ser. No. 14/072,998, filed on Nov. 6, 2013, which crocetin and/or other phytochemicals constituting anti-can claims priority to and the benefit of U.S. Provisional Appli cer compositions which can prevent, reduce and treat cancer cation No. 61/727,244, filed on Nov. 16, 2012, the full dis as well as prevent or treat other diseases and conditions, closures of which are incorporated herein by reference in its including age-related and neurodegenerative disorders such entirety for all purposes. as Alzheimer's and Parkinson's diseases, cardiovascular and cerebrovascular disease, digestive system diseases, toxin and FIELD OF THE INVENTION alcohol caused liver injuries. The compositions can be used alone against cancer and protect normal cells and organs, or 0002 The subject application relates to compositions con used in combination with other chemotherapy in a synergistic taining enriched or purified natural crocin and/or crocetin for fashion that serve as sensitizer to more effectively kill abnor enhancing health and preventing or treating cancers and other mal cells while protect normal cells and organs at lower diseases and health conditions. chemo dose, or in combination with radiotherapy against BACKGROUND OF THE INVENTION cancers and protect normal cells and organs undergoing radiation. 0003 Cancer is the leading cause of death in the world 0005 Crocin and crocetin exist in Crocus. They are the population. In 2008, there were an estimated 12.7 million new chemical components with antioxidative properties primarily cancer cases diagnosed and 7.6 million deaths from cancer responsible for the color of the Stigmas of Crocus sativus L. around the world according to
OH HO, US 2016/O 199398 A1 Jul. 14, 2016
0008 Chemical structure of Crocin-II (Crocetin-beta-D- gentiobiosyl-beta-D-glucosyl ester) is provided below:
0009 Chemical structure of Crocin-III (Crocetin-mono 0012 Another source of crocin and crocetin is the garde beta-D-gentiobiosyl ester) is shown below: nia fruit, Gardenia jasminoides Ellis or Gardenia augusta Merrill var. grandiflora Hort. Content of crocin in gardenia
fruits increases when ripening. Gardenia fruits have been used in China and Japan as traditional medicine for its OH antiphlogistic, diuretic, and cholagogic effects. Gardenia HOa - fruit is listed and approved in 1998 by Chinese government both as food and as medicine and listed in The Japanese w O Pharmacopoeia as crude drug and in the list of existing food HON O additives (Yoshiaki Kato 2000). Its extract, gardenia yellow, O N1s1's 1s1s1n 1s OH has also been listed as INS. 164 by JECFA (1989) as a food additive for colorant and widely used to give yellow color to O food products such as noodle, pasta, candy, beverage and pickled products in Japan. Gardenia yellow has almost the 0010 Saffron is used as coloring and flavoring agents in same crocin and crocetin derivatives as saffron, only different the preparation of food in different parts of the world and has in composition ratio of crocin and crocetin derivatives (Car been used since ancient times for strengthening digestion, mona M. 2006, Chen Y. & Zhang H. 2008). relieving coughs, Smoothing menstruation, relaxing muscle spasms, improving mood, calming anxiety, preventing 0013 Studies have shown saffron extracts have anti-can depression and enhancing men's sexual ability. Saffron is cer activities. The anticancer/antitumor properties of crude also used as health tonic. It is believed that regular intake of extracts of saffronhave been demonstrated invitro and in vivo saffron with milk helps to build resistance against common (Nair SC 1991, 1994, Abdullaev FI. 2002, 2003, Chryssanthi cold and asthma. In recent years, Saffron is reported to pos D G. 2007, Bakshi H. 2010). Crocin in saffron causes apop sess anti-oxidant and anti-cancer effects among a wide range tosis in different type cancer cells. It is of great interest that of pharmacological activities (Abdullaev FI. 2002, Cherma non-tumor cells in culture appear to be insensitive to the hini S.H. 2010, and Bhargavak V. 2011). effects of such extracts compared with tumor cells. Even 0011 Commercial saffron is produced in Azerbaijan, saffron extract was found to stimulate or Support in vivo France, Greece, India, Iran, Italy, Spain, China, Israel, growth of normal human lung cells (Abdullaev FI, 1992a,b). Morocco, Turkey, Egypt, and Mexico from dried Stigmas of 0014 Saffron aqueous extract rich in crocin was found cultivated Crocus sativus L. Each flower has only three small protect animal against genetic damage induced by anti-cancer stigmas. It takes about 75,000 flowers to produce one pound agents (Premkumar K. 2006). In this study, to ascertain the of saffron. Currently, Saffron is produced worldwide at an chemoprotective potential of saffron against the genotoxicity annual rate of about 300 tons and harvested by hand, making of three well-known anti-tumor drugs-cisplatin (CIS), cyclo Saffron an extremely expensive commodity with very limited phosphamide (CPH) and mitomycin C (MMC)-using comet supply. Saffron is safe to use. Saffron and saffron extracts assay, Three doses of saffron (20, 40 and 80 mg/kg b.w.) were have been safely used as spice, food coloring or for medicinal orally administered to mice for five consecutive days prior to purposes for hundreds of years. Saffron is regarded as a food the administration of anti-tumor drugs under investigation. by Joint FAO/WHO Expert Committee on Food Additives Pre-treatment with saffron significantly inhibited anti-tumor (TRS 733-JECFA 29/33) and listed as substance Generally drugs induced cellular DNA damage (strand breaks) as Recognized AS Safe (GRAS) by FDA CITE: 21CFR182.10, revealed by decreased comet tail length, tail moment and Revised as of Apr. 1, 2012. percent DNA in the tail. US 2016/O 199398 A1 Jul. 14, 2016
0015 Formation of toxic amyloid structures is believed to 2008). Quantification study of saffron also indicated a high be associated with various late-onset neurodegenerative dis amount of adulterant on the saffron market (Lechtenberg M. orders such as Alzheimer's and Parkinson's diseases. One 2008). Chemically synthesized crocetin and its salts are not human study (Akhondzadeh 2010) was carried out to inves natural and not identical to natural crocin and crocetin, and tigate Saffron may inhibit the aggregation and deposition of may possess very different biologically and pharmacologi amyloid? in the human brain and may therefore be useful in cally properties. Gardenia fruits, gardenia extracts, or gar Alzheimer's disease (AD). Fifty four patients were screened denia yellow provide a feasible source to enrich and purify for a 22-week, double-blind study of parallel groups of industrial scale of natural and high purity crocin and/or cro patients with mild to moderate AD. The psychometric mea cetin for wide applications. Enrich and purified crocin and/or Sures, which included AD assessment scale-cognitive Sub crocetin render means to quantitatively and consistently scale (ADAS-cog), and clinical dementia rating scale-sums deliver the actives in formulated products for preventing and of boxes, were performed to monitor the global cognitive and treating cancers and other diseases. clinical profiles of the patients. Patients were randomly 0019 Many other phytochemicals (organic chemicals assigned to receive capsule Saffron 30 mg/day (15 mg twice from plant source) also have extensive and variety of health per day) (Group A) or donepezil 10 mg/day (5 mg twice per benefits in preventing or treating diseases or cancers. A few day) for a 22-week study. Saffron at this dose was found to be examples are provided here. Resveratrol in grape has been effective similar to donepezil in the treatment of mild-to studied and reported to have anti-cancer effects, anti-inflam moderate AD after 22 weeks, while the donepezil group expe matory effects, cardiovascular benefits, anti-diabetes poten rienced significant frequency of Vomiting. tial, energy endurance enhancement, and protection against 0016 Alcohols or ethanol over consumption is known to Alzheimer's (Baur J A 2006). Curcuminoids, include cur impair learning and memory. The acute effects of an alcohol cumin, demethoxycurcumin, and bisdemethoxycurcumin, extract of Crocus sativus L (saffron) were studied on learning are polyphenolic pigments found in the spice turmeric. Cur and memory in step through and step down tests in normal as cumin has been widely studied and indicated to have antican well as in learning- and memory-impaired mice (Zhang cer, anti-inflammatory, antiviral, hypocholestrolemic and 1994). Saffron extract reduced the ethanol-induced impair break-up of beta-amyloid plaques in brain activities (Aggar ment of memory registration both in step through and step wal B. B. 2007). Tea polyphenols, including catechin, epicat down tests and the ethanol-induced impairment of memory echin, epicatechin gallate, epigallocatechin, epigallocatechin retrieval in step down test. Saffron extract decreased the gallate, theaflavin, theaflavin-3,3'-digallate, theaflavin-3-gal motor activity and prolonged the sleeping time induced by late, etc. and extracts have also been studied and showed hexobarbital. It was suggested that saffron extract amelio extensive health benefits including anticancer, cholesterol rates the impairment effects of ethanol on learning and lowing, anti-inflammatory, anti-aging, and against athero memory processes, and possesses a sedative effect. In behav Sclerosis and coronary heart disease, high blood cholesterol ioral and electrophysiological studies (Abe K. 2000), Saffron concentrations, and high blood pressure (Mukhtar H. 2000). extract improved ethanol-induced impairments of learning Anthocyanins are a category of phytochemicals in fruits and behaviors in mice, and prevented ethanol-induced inhibition vegetables that give them vivid red to blue. Based upon many of hippocampal long-term potentiation, a form of activity cell-line studies, animal models, and human clinical trials, dependent synaptic plasticity that may underly learning and Anthocyanins have been suggested possess anti-inflamma memory. This beneficial effect of saffron extract is attributed tory and anti-carcinogenic activity, cardiovascular disease to crocin (crocetin di-gentiobiose ester), but not crocetin. It prevention, obesity control, diabetes alleviation, and eye was indicated that Saffron extract or its active constituents, health promoting properties (He J 2010, Kalt W 2010). crocetin and crocin, could be useful as a treatment for neuro Human studies with diet rich in anthocyanins suggest it may degenerative disorders accompanying memory impairment. also protect against development of Parkinson's disease and 0017 Dietary saffron was found in animal study (Macca improve blood pressure (Cassidy J. 2011, Gao X. 2012). rone R. 2008) maintains morphology and function after expo 0020 Prior arts have been mostly focused on purify Sure to damaging light in mammalian retina. The photorecep shingle crocin component, either crocin-1 (alpha-crocin) or tor layer was largely preserved in Saffron-treated animals. crocetin. CN1025 16325 A revealed a method of producing Rate of photoreceptor death induced by the damaging bright crocin with higher than 95% purity from gardenia. The prior continuous light drastically reduced in Saffron treated ani art specifically produces one single crocin component, crocin mals. Saffron supplement was found to improve retinal flicker I (called crocin in prior art) to purity at least 95%. sensitivity in early age-related macular degeneration (AMD) WO2004078695 A1 revealed a method for purification of (Falsini B. 2010). Followed up clinical study in Italy and crocetin. Method in this prior art includes steps of hydrolysis Australia Supported Saffron Supplementation and indicated of crocin and then purification of crocetin. Prior arts also crocin and crocetin as key actives to provide Sustained ben include methods of extracting, changing profile of crocin and efits to central retinal function for AMD patients (Piccardi M. crocetin or improving recovery of Saffron colorant recovery. 2012) WO2010094745 A1 and US2010/0210572A1 revealed a 0018 Though saffron is reported to possess anti-oxidant method of producing hydrolysate of crocin, resulting in cro and anti-cancer effects among a wide range of pharmacologi cin related products with significant amount of crocetin mono cal activities, it is these main components, crocin and crocetin esters. WO2004.056201 A1 revealed a method of increased that were indicated to provide these pharmacological activi colorant (crocin and crocetin) recovery from Saffron raw ties. Due to the very limited source and expensiveness of material to 95%, while crocin and crocetin together having a saffron, it is unrealistic to produce large scale of highly pigment concentration of 15-24%. Crocetin and its salts have enriched crocin and crocetin from saffron. Saffron quality been chemically synthesized (WO2006104610 A2, U.S. Pat. and its content of crocin and crocetin vary significantly, range No. 7.351,844 B2). But these chemically synthesized croce from less than 1% to 20% (Alonso G. L. 2001, Lechtenberg M. tin and its salts are not natural and may not have the same US 2016/O 199398 A1 Jul. 14, 2016 biological and pharmacological properties. US20130156746 or normal cells, tissues, organs and patients from injury, dam A1 revealed a dietary Supplement composition which com age by other anti-cancer agents, toxins, chemotherapeutic prises saffron powder and resveratrol. Because saffron has agents, radiation. many different grades and varies in its crocin content, it is 0027. It is an object of the invention to provide composi very difficult to use Such a composition for products require tions and a means for improving/enhancing healthy aging and quality and efficacy consistency. US20110236481 A1 mental health, particularly responses in central nerve system revealed a composition contains Safranal and/or crocin and/or that slow, prevent, and mitigate neurodegenerative disorders picrocrocin from Saffron plant or saffron as Satiety agent for such as Alzheimer's and Parkinson's diseases; inhibit pro treatment of obesity. The active contents of safranal and/or ducing neurotoxins, inhibit acetylcholine breakdown, pre crocin and/or picrocrocin are used at low or diluted level by vent formation of toxic amyloid structures; enhance brain weight compare to saffron in products and showed to be function, have an effect of improved quality of life. effective in suppressing hungry (Gout B. 2010). 0028. It is an object of the invention to provide composi 0021 Applications of enriched and purified natural crocin tions and a means for improving/enhancing learning and and/or crocetin enable quality consistency and quantitative memory and cognitive abilities; reduce oxidative stress dam amount of crocin and/or crocetin in products. Its use alone or age to the hippocampus induced by chronic stress. use in combination with other health beneficial phytochemi 0029. It is an object of the invention to provide composi cals in nutraceutical or therapeutic composition is useful in tions and a means for improving/treating ethanol/alcohol preventing and treating many cancers and disease as well as induced impairments of learning and memory and cognitive enhancing health. Combinations of crocin and/or crocetin abilities; improve/treat neurodegenerative disorders accom with other phytochemicals also offer synergistic and broader panying memory impairment. benefits in preventing and treating cancers and diseases. The 0030. It is an object of the invention to provide composi invention is focused on crocin and/or crocetin that are tions and a means for protecting/improving/enhancing heart extracted, enriched or purified from natural source, gardenia function/structure/composition, particularly responses that fruits, gardenia extracts or gardenia yellow, to formation improve cardiac arrhythmia and antioxidant systems, prevent unique nutraceutical or pharmaceutical compositions with or the myocardial infarction and relieve myocardial stunning; without other health promoting phytochemicals, and their improve/enhance recovery of heart function. uses for(a) prevention or treatment of diseases and conditions 0031. It is an object of the invention to provide composi including cancers, neurodegenerative diseases, heart dis tions and a means for improving/enhancing human health, eases, liver diseases, kidney diseases, eye diseases, metabolic particularly responses that reduce chronic inflammation and syndrome, atherosclerosis, arthritis, inflammations, obesity, prevent inflammatory conditions; provide treatments that will or diabetes, etc.; (b) protection of liver, heart, kidney, and be simple and effective and will have little or no adverse side other normal organs from injuries or damages; (c) improve effects. ment or enhancement of learning/memory ability, immune 0032. It is an object of the invention to provide composi system, skin health, anti-aging, and over all health. tions and a means for improving/enhancing human health, particularly responses that improve and enhance immune sys SUMMARY OF THE INVENTION tem and, thereby, having an effect of regulating/boosting the 0022. Saffron provides many health benefits and has been health of human. safely used for thousand years, but quality of saffron and the 0033. It is an object of the invention to provide composi content of key actives, crocin and crocetin, vary significantly. tions and a means for improving/enhancing human health, Enriched and purified natural crocin and/or crocetin of this particularly responses that treat and reduce serum triglycer invention reduce or eliminate undesirable components in saf ide, total cholesterol, low density lipoprotein (LDL) choles fron or gardenia fruits. It provides means to deliver quantita terol and very low density lipoprotein (VLDL) cholesterol tively and consistently effective amount of crocin and/croce level. tin in compositions or formulated products for preventing 0034. It is an object of the invention to provide composi and/or treating cancers and other diseases as well as enhanc tions and a means for improving/enhancing liver function/ ing and improving health. High purity crocin and/or crocetin activities, particularly responses that protect, prevent liver is particular advantageous in a composition for injectable injury from alcohols, toxins, metal or heavy metal overdose; products. protect liver from chemo agent injury and damage. Maintain 0023. It is an object of the invention to provide composi and enhance recovery of liver function. tions and a means for improving/enhancing cancer preven 0035. It is an object of the invention to provide composi tion, treatment and reducing cancer risk as well as improving tions and a means for improving/enhancing liver health, par other conditions and diseases. ticularly responses that improve/enhance liver recovery from injury and shock, thereby, having an effect of maintaining/ 0024. It is an object of the invention to provide composi boosting health of human. tions and a means for improving/enhancing/restore cells, tis 0036. It is an object of the invention to provide composi Sues, and organ functions of cancer Suffer patients. Improve tions and a means for improving/enhancing kidney function/ and prolong life span. activities, particularly responses that protect, prevent kidney 0025. It is an object of the invention to provide composi injury and damage; maintain and enhance recovery of kidney tions and a means for improving/enhancing therapeutical function. effectiveness of other cancer drugs through synergistic effects 0037. It is an object of the invention to provide composi or as sensitizer or enhancer, reducing drug resistance. tions and a means for improving/enhancing eye health, par 0026. It is an objective of the invention to provide compo ticularly responses that slow/prevent/treat age related macu sitions and a means for improving/protecting non-cancerous lar degeneration; increase blood flow to the retina and US 2016/O 199398 A1 Jul. 14, 2016
choroid, also facilitate retinal function recovery thereby pre 0049. It is another object of one aspect of the invention to venting ischemic retinopathy and age related macular degen provide improvements of human nutrition by the combina eration. tions, in particular specially formulated with enriched or puri 0038. It is an object of the invention to provide composi fied natural crocin and/or crocetin to effectively enhance/ tions and a means for improving/enhancing human health, improve heart health, treat individuals with heart illness or particularly responses that improve diabetic benefits, inhibit Sub-normal conditions. insulin resistance or insensitivity induced by fat or various 0050. It is another object of one aspect of the invention to fatty acids or high Sugar diets; restore/maintain normal pan provide improvements of human nutrition by the combina creatic functions/orders, prevent glucose toxicity. tions, in particular specially formulated with enriched or puri 0039. It is an object of the invention to provide composi fied natural crocin and/or crocetin to effectively inhibit tions and a means for improving/enhancing human health, inflammations, chronic inflammations which may lead time particularly responses that prevent/treat obese and associated many health problems. diseases/conditions. 0051. It is another object of one aspect of the invention to 0040. It is an object of the invention to provide composi provide improvements of human nutrition by the combina tions and a means for improving/enhancing human health, tions, in particular specially formulated with enriched or puri particularly responses that reduce/prevent/treat atherosclero fied natural crocin and/or crocetin to enhance/improve sis, thereby, having an effect of regulating/boosting the car immune system. diovascular health and lowering cholesterol; prevent/treat 0052. It is another object of one aspect of the invention to coronary artery disease and peripheral vascular disease. provide improvements of human nutrition by the combina 0041. It is an object of the invention to provide composi tions, in particular specially formulated with enriched or puri tions and a means for improving/enhancing human health, fied natural crocin and/or crocetin to enhance/improve human particularly responses that improve sense of well-being and, circulation system, lower cholesterol, triglyceride and low thereby, having an effect of calming, prevent/improve depres density lipoprotein. 0053. It is another object of one aspect of the invention to S1O. provide improvements of human nutrition by the combina 0042. It is an object of the invention to provide composi tions, in particular specially formulated with enriched or puri tions and a means for improving/enhancing skin health and fied natural crocin and/or crocetin to enhance/improve liver appearance, particularly responses that improve skin condi health, protect/prevent liver injury/damage from alcohol/ tions in anti-aging, anti-wrinkle, anti-inflammation, anti-oxi ethanol, toxins, chemotherapeutic agent. Strengthen/restore dation, restore/prevent/treat skin damage and the signs of liver functions. aging of the skin. 0054. It is another object of one aspect of the invention to 0043. It is an object of the invention to provide specific provide improvements of human nutrition by the combina combinations of ingredients or formula containing enriched tions, in particular specially formulated with enriched or puri or purified natural crocin and/or crocetin that deliver bioac fied natural crocin and/or crocetin to effectively enhance/ tive components which directly, effectively prevent/treat/ improve eye health, prevent/slow/treat individuals with age benefit cancer/tumor patients. related illness or Sub-normal conditions. 0044. It is another object of one aspect of the invention to 0055. It is another object of one aspect of the invention to provide improvements of human nutrition by the combina provide improvements of human nutrition by the combina tions, in particular specially formulated to enhance bio-ac tions, in particular specially formulated with enriched or puri tives intakes. fied natural crocin and/or crocetin to enhance and benefit 0045. It is another object of one aspect of the invention to individuals with diabetes. provide improvements of human nutrition by the combina 0056. It is another object of one aspect of the invention to tions, in particular specially formulated with enriched or puri provide improvements of human nutrition by the combina fied natural crocin and/or crocetin to effectively prevent/pro tions, in particular specially formulated with enriched or puri tect risk of cancers, treat/benefit cancer/tumor patients. fied natural crocin and/or crocetin to enhance and benefit 0046. It is another object of one aspect of the invention to individuals with coronary artery disease and peripheral vas provide improvements of human nutrition by the combina cular disease; to prevent and reduce risk of coronary artery tions, in particular specially formulated with enriched or puri disease and peripheral vascular disease. fied natural crocin and/or crocetin to improve/protect non 0057 These and other objects are achieved by the inven cancerous or normal cells, tissues, organs and patients from tion, which provides food/dietary/therapeutic compositions/ injury/damage by other anti-cancer agents, toxins, chemo formula comprising unique combinations of enriched or puri therapeutic agents, radiation. fied natural crocin and/or crocetin and regimens employing 0047. It is another object of one aspect of the invention to them to enhance and maintain health and improve Sub-health provide improvements of human nutrition by the combina conditions. tions, in particular specially formulated with enriched or puri 0058. These and other objects are achieved by the inven fied natural crocin and/or crocetin to effectively prevent/treat/ tion, which provides therapeutic compositions/formula com benefit neurodegeneration patients; prevent/slow/treat prising unique combinations of enriched or purified natural Alzheimer's and Parkinson's diseases. crocin or crocetin alone or both in combination with other 0048. It is another object of one aspect of the invention to excipient or stabilizer to prevent or treat cancers/tumors. provide improvements of human nutrition by the combina 0059. These and other objects are achieved by the inven tions, in particular specially formulated with enriched or puri tion, which provides food/dietary/therapeutic compositions fied natural crocin and/or crocetin to effectively prevent/treat/ comprising unique combinations of natural enriched crocin benefit patients with impairment in learning and memory; and crocetin and possible other bio-actives, proteins, peptides improve/enhance learning and memory. and amino acids constituting immune system improving US 2016/O 199398 A1 Jul. 14, 2016 nutraceutical compositions and regimens employing them to and protecting them from oxygen radical stress, toxins, met reduce risks in individuals with Suppressed/abnormal als, alcohol/ethanol induced injury/damage/impairment. This immune systems. invention provides a safe and natural nutraceutical/therapeu 0060. These and other objects are achieved by the inven tic composition for enhancing/restoring in learning and tion, which provides food/dietary/therapeutic compositions memory. This invention prevents/improves/treats above men comprising unique combinations of natural enriched crocin tioned diseases and conditions by the use of a specific com and crocetin and possible other bio-actives, vitamins consti position or compositions of crocin and/or crocetin or combi nation of crocin and crocetin and possible selection of other tuting antioxidant nutraceutical compositions and regimens effective or health promoting phytochemicals, amino acids, employing them to reduce risks of diseases vitamins or minerals. The invention is also useful but not 0061 These and other objects are achieved by the inven limited to above mentioned diseases, disorders and Sub tion, which provides food/dietary/therapeutic/topical compo health conditions. These compositions can be considered as a sitions comprising unique combinations of natural enriched therapy. These compositions can also be considered as crocin and crocetin and possible other bio-actives, constitut improvements in human nutrition in that they present new ing antioxidant nutraceutical compositions and regimens combinations of phytochemicals, or amino acids, or vitamins employing them to reduce risks of radical damages, chemical useful in reducing above mentioned disease risks. damages and photo-damages to normal cells, tissues, organs, 0070 Crocin and other crocetinglycosides are major color (liver, skin, etc.). components and phytochemicals of the Stigmas of Saffron 0062. It is also an objective of this invention to provide a (Crocus sativus L.) and the fruits of gardenia (Gardenia method to enrich or purify crocin and/or crocetin from gar jasminoides Ellis). Both saffron and gardenia fruits have denia fruit, gardenia extract, gardenia yellow, or saffron. been traditionally used and listed as food additives. Crocin, crocetin and crocetin natural glycosides from Saffron orgar BRIEF DESCRIPTION OF THE FIGURES denia fruits are considered safe as extensive studies found 0063 FIG. 1 shows the flow diagram of crocin enriching crocin have no toxic effect on normal cells and protect normal and purification from gardenia yellow D500 as described in cells. Due to limitation of saffron source and its expensive Example 1. ness, it is cost forbidden to commercially enrich or purify crocin and/or crocetin from Saffron. Saffron quality variation 0064 FIG. 2 shows HPLC chromatograms of crocin and a high amount of adulterant on the Saffron market also obtained as described in Example 2. hinder its use in quality products. Enriching and purification 0065 FIG. 3 shows a QNMR chromatogram of crocin of crocin and crocetin from commercial gardenia yellow, obtained as described in Example 2. gardenia extract or directly from gardenia fruits provides affordable and high purity crocin and/or crocetin for quanti DETAILED DESCRIPTION OF INVENTION tative and amount consistent applications in this invention. 0066 While various embodiments of the present invention The enriched and purified crocin and/or crocetin of this inven about compositions are discussed below, it should be appre tion to be used in Supplements ortherapeutic products are safe ciated that the present invention provides some of many appli and effective for enhance health, protect, prevent and lower cable inventive concepts that can be embodied in a wide risk of above mentioned diseases and conditions. Use of variety of specific contexts. The specific embodiments dis enriched or purified natural crocin and/or crocetin in thera cussed herein are merely illustrative of a few specific ways to peutic compositions or formulations is essential in this inven make and use the invention and do not delimit the scope of the tion. Particularly an injectable requires high purity and high invention. quality crocin and/or crocetin. 0067. To facilitate the understanding of this invention, a (0071. The crocin and/or crocetin used in this invention is number of terms are defined below. Terms defined herein have the enriched or purified form with crocin and/or crocetin meanings as commonly understood by a person of ordinary content of at least 50%, preferably at least 80%, more pref skill in the areas relevant to the present invention. Terms such erably at least 90%, in particular cases at least 99%, manu as “a”, “an and “the are not intended to refer to only a factured under conditions to meet food or pharmaceutical singular entity, but include the general class of which a spe standards. Said the crocin can include Crocin-I (Crocetin-di cific example may be used for illustration. The terminology B-D-gentiobiosyl ester), Crocin-II (Crocetin-B-D-gentiobio herein is used to describe specific embodiments of the inven syl-B-D-glucosyl ester), Crocin-III (Crocetin-mono-f-D- tion, but their usage does not delimit the invention, except as gentiobiosyl ester), Crocin-IV (B-D-monoglucoside ester of outlined in the claims. monomethyl C-crocetin), Crocetin-di-(B-D-glucosyl) ester, 0068. This invention reveals nutraceutical/therapeutic Crocetin-mono-B-D-glucosyl ester, B-cis-crocetin di(B-D- compositions/formulations and/or regimens comprising gentiobiosyl) ester and B-cis-crocetin B-D-gentiobiosyl-3-d- unique combinations with meaningful, quantitative, and Suf glucosyl ester, etc. naturally existed crocetin derivatives in ficient amount of enriched or purified or high purity natural saffron or Gardenia fruits. crocin and/or crocetin and possible other health beneficial 0072 This invention has a number of advantages over the phytochemicals and/or extracts and/or vitamins and/or health use of saffron and saffron extracts. Because crocin and/or beneficial minerals. crocetin can be enriched and purified from an abundant and 0069. This invention to provide a safe and natural nutra safe source, gardenia yellow, gardenia fruit or gardenia ceutical/therapeutic composition for preventing, decreasing extract through a simple and effective method, the manufac and treating cancers, age-related neurodegenerating disease tured crocin and/or crocetin are highly enriched and purified (Alzheimer's and Parkinson's diseases), brain, heart, liver, in comparison to saffron. Processes described herein, without kidney diseases, eye and circulations diseases, diabetes, using toxic solvent or generating large amount of waste, are inflammations, skin damages, signs of aging of the skin and environmentally friendly. Enriched and purified crocin and/or other conditions. This invention provides a safe and natural crocetin with purity at least 50% up to 99% have significant nutraceutical/therapeutic composition for enhancing/restor reduced or no undesirable components provide safer prod ing function of brain, heart, liver, eye, kidney, pancreas, skin ucts. Unlike saffron which varies in crocin content, Crocin US 2016/O 199398 A1 Jul. 14, 2016
and/or crocetin described in compositions herein provide -continued quantitative, quality consistent and effective dosage for pre venting and treating cancers, neurodegenerative disorders Time (min) B% Such as Alzheimer's and Parkinson's diseases, age-related macular degeneration, and other diseases or conditions. High 1S.OO 100 purity crocin and/or crocetin described herein are particularly 2O.OO 100 useful in compositions for injection or infusion. Post run: 4.5 min 0073 Crocin and/or crocetin are typically analyzed and detected by HPLC at wavelength of 440 nm. However, if a 0080 Flow rate: 1 ml/min component or components in a saffron or gardenia extract I0081 Wave length: 440 nm possess no crocetin or carotenoid-like core structure. Such I0082 Column Temp: 40° C. components will not be detected at 440 nm. Hence, to deter I0083 Corresponding HPLC peak areas and concentra mine crocin purity in Saffron or gardenia extracts, it is essen tial to analyze the sample or samples with crocin standard at tions of crocin samples were listed in table 1: different concentrations to establish a linear line under the same conditions on a HPLC instrument. Preferably, crocin TABLE 1 purity determination can also be done by Quantitative Crocin Standards Peak area Conc (Ig/ml) Nuclear magnetic resonance (NMR) spectroscopy. Std. 1 3119.7 119 0074 An exemplary embodiment method of the invention Std. 2 2004.7 79.33 includes but is not limited, for example: Std. 3 1507.4 59.5 a. Purification of Crocin and/or Crocetin: Std. 4 735.6 29.75 0075 20 g of Commercial gardenia yellow D500 was St. S 168.8 7:44 weighed into a centrifuge bottle, add 3 times of 80% ethanol in volume ofgardenia yellow weight, cover the bottle and stir at 35° C. for 15 to 20 minutes in dark, separate soluble in I0084. A linear equation of y=26.361X-48.186 (R=0. supernatant after centrifugation at 10,000xg for 10 minutes, 9994) was obtained by calculation. Sample with crocin con Supernatant was collected in flask, repeat 5 times of the addi centration in the range of 7.44 ug/ml and 119 g/ml conforms tion of ethanol dissolution and separation of soluble Superna to the linear relation. tant, the collected and combined Supernatants was sealed and b. Analysis of Crystallization Sample: put into -10°C. freezer in dark for 15 to 20 days, then filter to I0085. Accurately weigh 18.8 mg crystallization sample in separate crystals from Solution and washed with acetone, 5.7 10 ml volumetric flask, add methanol and water (1:1) to g crocin was obtained, dissolve this crocin in 360 ml 80% dissolve sample and make to the scale resulting in 188 m/ml ethanol and recrystallize at -10° C. give purer crocin, wash (18.8 mg/10 ml) concentration, and accurately transfer 5 ml with acetone, dry to obtain about 4 g; high purity crocin is into another 10 ml volumetric flask, add methanol and water further obtained by column chromatography through com (1:1) to scale and make 94 ug/ml sample concentration; 50 of mon steps including dissolving the product in 30% ethanol, the prepared sample solution was injected to HPLC under passing the solution through a column filled with same conditions described in making standard linear equation macroporous resin A-5 to adsorb crocin with resin, washing (see FIG. 1); Calculate sample purity by using the formula of: with distilled water and 30% ethanol to remove impurities, Crocin Purity (100%)=Concentration of the solution eluting the column with 95% ethanol to desorb pure crocin under test Concentration of crocin samples* 100 from the resin, collecting the eluted crocin solution, concen I0086 Measured and calculated results by HPLC method trating and drying. A flow chart of crocin and/or crocetin are shown in table 2. purification is shown in FIG. 1. Analysis of Crocin by HPLC: TABLE 2 0076 Preparation of linear solution: Accurately weighed Sample Area C1 (g/ml) W (mg) C2 (g/ml) Purity % 11.9 mg Crocin I standard in 10 ml volumetric flask, add 1 3846.7 147.75 18.8 188 78.59 methanol and water (1:1) to dissolve crocin and make to the 2 1886 73.37 9.4 94 78.06 scale as mother Solution. Aliquot the prepared mother solu tion to make a series of diluted Standard Solutions. Standard c. Analysis of Crocin by QNMR: solutions were subjected to HPLC analysis to prepare stan I0087. Accurately weigh 5-10 mg of crystallization sample dard curve. 5uml of the prepared solution was injected into and maleic acid into NMR tube, add 0.6-1.0 ml of DMSO-d6 HPLC instrument. HPLC instrument is an Agilent 1260/6120 (>99% atom-% D) into the tube and shake to dissolve both and equipped with Agela Venusil XBPC18 column (4.6x150 sample and maleic acid. It is subjected to quantitative mm, 5um) and column temperature at 40°C. Other condi H-NMR analysis. NMR instrumentis Varian 400MR. Test for tions and elution gradient were listed below: measurement is set at Pulprog Zg45, d1 = 15, d2=19, and 0.077 Mobile Phase: A: 4 L H2O (with 1.5 ml TFA) int=16. 8 1.97 (12H) is selected as quantification peak; 8 6.25 (0078 B: 4 L Acetonitrile (with 0.75 ml TFA) is internal standard quantification peak (see FIG. 2). After 0079 Gradient: measurement, results are calculated by the formula:
Time (min) B. 90 O.O1 O I(a): Area of sample selected peak 10.00 60 I(b): Area of internal standard peak MW(a): Sample molecular weight US 2016/O 199398 A1 Jul. 14, 2016
MW(b): Internal standard molecular weight ginseng, astrgalus, rodiola, garcinia, ginger, ginkgo, citrus W(a): Sample weight fruit, grape skins, grape seeds, hawthorn, artichoke, broccoli, W(b): Internal standard weight broccoli seeds, apple, olive, orange, lemon, pepper, soybean, N(a): Number of proton of selected sample peak mango, tea leaves, tomato, turmeric, cabbage, purple corn, black rice, bitter lemon, Stevia, lohan, goji (wolfberry), sea N(b): Number of proton of selected internal standard peak buckthorn, kudzu, clove, hemp, Cassia, magnolia, nutmeg, A(b): Purity of internal standard jujube, honeysuckle, poria, bellflower, lotus, basil, Sesame, I0088. Measured and calculated results by QNMR method angelica, cimicifuga, epimedium, Schisandra, Salvia, lico are shown in table 3. rice, ligustrum, ophiopogonis, aloe, dodder, fenugreek, gotu kola, purslane, tribulus, etc. The above components of the TABLE 3 compositions of the invention should have, individually, Ratio of area of effective levels of purity to meet the objectives of the inven Sample Wt. Standard Wt. selected peak to Purity of tion. The components can be standardized for dosage level Test No. (mg) (mg) standards Sample based on purity and amount used. 1 9.7 6.2 0.795:1 77.30% 0091. The nutraceutical/pharmaceutical compositions can 2 9.4 6.9 O.871:1 81.10% further include one or more free amino acids or peptides, such Average 79.20% as arginine, lysine, methionine, histedin, leucine, isoluceine, alanine, phenyalanine, asparingine, aspartic acid, tryp 0089. The nutraceutical/pharmaceutical compositions tophane, proline, threonine, cysteine, selenocysteine, serine, with enriched or purified crocin and/or crocetin of the inven taurine, tyrosine, Valine, glycine, glutamine, glutamic acid, tion can be formed alone or in combination with one or more ornithine, carnosine, L-carnitine, glutathione. of health promoting phytochemicals or food extracts contain 0092. The nutraceutical/pharmaceutical compositions can ing effective amount of phytochemicals including: acteoside, further include one or more vitamins or minerals, including, aloenin, aloesin, aloin, alpinetin, atractylenolide, atractylo but not limited to, vitaminA, vitamin C, vitamin B1, vitamin din, aurantio-obtusin, cimigenol, cimifugin, cimiside, garci B2, vitamin 33, vitamin B6, vitamin B12, vitamin D, vitamin none, ascorbic acid, astragalin, quercetin, resveratrol, pteros E. Vitamin K (and derivatives), calcium, sodium, potassium, tilbene, curcumin, demethoxycurcumin, bis chromium, Vanadium, magnesium, manganese, selenium, demethoxycurcumin, theaflavin, theaflavin-3,3'-digallate, copper, molybdenum, boron, Vanadium, and/or iron (and theaflavin-3-gallate, theaflavin-3-gallate, L-theanine, antho derivatives)(preferably in amounts less than the RDA). cyanidins, anthocyanins, catechin, epicatechin, gallocat 0093. The nutraceutical/pharmaceutical composition of echin, epigallocatechin, epicatechin gallate, gallocatechin the invention may be administered in any route that is appro gallate, epigallocatechin gallate, procyanidin, chlorogenic priate, including but not limited to oral, parenteral (Intrave acid, cardamonin, arctigenin, arctiin, asiatic acid, asiatico nous, intramuscular, intraperitoneal, intrasternal. Subcutane side, bergamotin, bergapten, betaine, dioScin, galangin, ous, intraarticular injection and infusion), percutaneous, cimicifugoside, cinnamic acid, ferrulic acid, fumaric acid, rectal, mucosal, intranasal or topical (transdermal, as by pow C-lipoic acid, carnosine, L-carnitine, caffeic acid, ellagic ders, ointments, creams, sprays, drops or patches) adminis acid, maslinic acid, phenylethyl caffeate, caffeic acid phen tration. Ophthalmic formulation, ear drops, Solutions, and eye ethyl ester, theobromine, theophylline, caffeoylquinic acid, ointments are also contemplated as being within the scope of urSolic acid, allicin, gingerol, shogaol, ginkgolide, ginkgetin, this invention. The most Suitable route may depend upon the ginsenoside, astragaloside, cycloastragenol, danshensu, dan condition and disorder of the recipient. shenol, danshenxinkun, tanshinone, tanshindiol, rosmarinic 0094. In certain embodiments more than one dose com acid, dosmin, nobiletin, tangeretin, luteolin, lutein, B-lyco prising an effective amount of crocin and crocetin is admin pene, Zeaxanthin, tyrosol, hyperin, hyperoside, quercetin, istered to the human (e.g., two or more doses spaced over quercetrin, isoquercitrin, hydroxytyrosol, rosarin, B-rosas time, each dose comprising an effective amount of crocin and terol, rosavin, rosin, punicalagin, punicalin, myricetin, crocetin). The effective amount of crocin and crocetin can be myricitrin, kaempferol, dihydromyricetin, apigenin, narin in compositions in combination with one or more active com gin, maringenin, honokiol, magnolol, mangiferin, mangostin, ponents of phytochemicals and or amino acids or peptides hesperetin, hesperidin, lupeol, indole-3-carbinol, genistein, previously mentioned. genistin, daidzein, daidzin, cynarin, bilobalide, bilobetin, epi 0095. In some embodiments compositions comprise with medin, Sulforaphane, phloretin, phloretin-Xyloglucoside, one or more carbohydrate nutrients. For example, the carbo phloridzin, proanthocyanidins, procyanidin B1, procyanidin hydrate nutrient may be selected from the group consisting B2, procyanidin C1, silibinin, rutin, Wogonin, morin, of rice oligodextrin, amylase, amylopectin, glucose, Sucrose, morusin, mulberroside A, mulberroside B. glycyrrhizic acid, fructose; maltodextrin, maltose, isomalitulose, leucrose, tre glycyrrhetinic acid, linarin, protodioscin, protogracillin, Syn halulose, ribose, trehalose. ephrine, rebaudioside A, Stevioside, Vitexin, isovitexin, 0096. The applications and dosage forms of nutraceutical/ Vitexin-4, Vitexin-4'-O-glucoside, Vitexin-2'-O-rhamnoside, pharmaceutical compositions for oral administration can be Vitexin-4'-rhamnoside, alpha-tocopherol, beta-tocopherol, liquids, beverages, tablets, soft gels, capsules, pills, caplets, gamma-tocopherol, delta-tocopherol, etc. gums, dragees, granules, powders, or effervescent tablets, 0090. A food extract that should contain effective amount sprays, functional foods. of phytochemicals can come from one but not limited to the 0097. A solid nutraceutical/pharmaceutical composition following sources: bilberry, blueberry, cranberry, raspberry, for oral administration may optionally contain, in addition to cherry, mulberry, pomegranate, purple corn, Strawberry, the above enumerated nutraceutical/pharmaceutical compo grapes, blackberry, gooseberry, black currants, grape, cocoa sition ingredients or compounds: carrier materials such as beans, coffee beans, pine bark, cardamom, cinnamon bark, corn starch, acacia, gelatin, malt, tragacanth, microcrystalline US 2016/O 199398 A1 Jul. 14, 2016
cellulose, kaolin, dicalcium phosphate, calcium carbonate, agents, etc. The injectable compositions are sterilized in the Sodium chloride, alginic acid, lactose, glucose, Sucrose, and final formulation step or prepared by sterile procedure. The the like; disintegrators including, microcrystalline cellulose, nutraceutical/pharmaceutical composition of the invention alginic acid, and the like; binders including acacia, methyl may also be formulated into a sterile solid preparation, for cellulose, ethyl cellulose, sodium carboxymethylcellulose, example, by freeze-drying, and the sterile Solid preparation polyvinylpyrrolidone, hydroxypropyl methylcellulose, and can be dissolved in a solvent, sterile injectable water, inject the like; and lubricants such as magnesium Stearates, Stearic able saline or other sterile diluent(s), to form an injectable acid, silicone fluid, talc, oils, waxes, colloidal silica, and the Solution for immediate injection. like. In addition to active ingredients, an effervescent tablet 0101 A pharmaceutical composition solution for composition may contain mixtures of acids (like citric, tar parenteral administration may generally be prepared by dis taric, malic and fumaric acid or combination thereof) and Solving the compound in a medium, Subjecting the resulting carbonates like Sodium, potassium bicarbonate or carbonate solution to filtration for sterilization, filling the solution in that release carbon dioxide when dissolved in water and water vials or ampoules or glass bottles or Suitable plastic bags, and soluble binder (starches, natural gums, cellulose gums, sealing the vials or ampoules or bottles or bags. It is also microcrystalline cellulose, methylcellulose, cellulose ethers, possible to freeze-dry the composition and fill the resulted ethylcellulose, Sodium carboxymethylcellulose, gelatin, dex powder in vials, and then eliminate the moisture in vacuum to trose, lactose, Sucrose, Sorbitol, mannitol, polyethylene gly improve stability. Parenteral Suspensions can be prepared by col, polyvinylpyrrolidone, pectins, alginates, polyacryla Substantially the same method as that applied to Solutions for mides, polyvinyloxoazolidone, polyvinylalcohols and parenteral administration; however, the Suspensions can pref mixtures thereof) and lubricant (sodium benzoate, polyethyl erably be manufactured by Suspending the active ingredient ene glycol, L-leucine, adipic acid, and combinations thereof). in a medium, and then subjecting the result to sterilization by A composition can also include other ingredients including, using ethylene oxide or the like. Furthermore, surface active e.g., flavoragents, fillers, Surfactants, coloragents, and Sweet agents, moistening agents and so forth may also be added so eners. The usefulness of such excipients is well known in the that a uniform dispersion of the active ingredient can be art. A composition optionally comprises one or more addi obtained. tional coatings Surrounding the core and/or the control releas ing coat Such as moisture barrier coats, enteric coats or coat 0102 Compositions for rectal administration are prefer ings that affect the physical integrity and/or appearance of the ably Suppositories which can be prepared by mixing the nutraceutical composition. active components of this invention with suitable non-irritat 0098. In the case of capsules, tablets and pills, the dosage ing carriers such as cocoa butter, polyethylene glycol or a form may also comprise buffering agents. Solid compositions Suppository wax which are solid at ambient temperature but of a similar type may also be employed as fillers in Soft and liquid at body temperature and therefore melt in the rectum hard-filled gelatin capsules using lactose or milk Sugar as well and release the active compound. as high molecular weight polyethylene glycols and the like. 0103 Compositions for topical or transdermal administra 0099. A liquid nutraceutical composition for oral admin tion of this invention can be prepared as ointments, pastes, istration in connection with a method can be prepared in water creams, lotions, gels, powders, Solutions, sprays, inhalants or or other aqueous vehicles. In addition to the above enumer patches. The active component is admixed under sterile con ated nutraceutical/pharmaceutical composition ingredients ditions with a pharmaceutically acceptable carrier and any or compounds, a liquid nutraceutical/pharmaceutical compo needed preservatives or buffers as may be required. The oint sition can include Suspending agents such as, for example, ments, pastes, creams and gels may contain, in addition to an alginates, pectin, kelgin, carrageenan, acacia, methylcellu active compound of this invention, animal and vegetable fats, lose, polyvinyl alcohol, polyvinylpyrrolidone, and the like. oils, waxes, paraffins, starch, tragacanth, cellulose deriva The liquid nutraceutical/pharmaceutical compositions can be tives, polyethylene glycols, silicones, bentonites, silicic acid, in the form of a solution, emulsion, syrup, gel, powder or talc and Zinc oxide, or mixtures thereof. Powders and sprays elixir including or containing wetting agents, Sweeteners, and can contain, in addition to the compounds of this invention, coloring and flavoring agents. Various liquid and powder lactose, talc, silicic acid, aluminum hydroxide, calcium sili nutraceutical compositions can be prepared by conventional cates and polyamide powder, or mixtures of these Substances. methods. Sprays can additionally contain customary propellants such 0100. The nutraceutical/pharmaceutical compositions for as chlorofluorohydrocarbons. parenteral and percutaneous administration comprise phar 0104 Compositions of this invention may also be admin maceutically acceptable sterile aqueous or nonaqueous solu istered in the form of liposomes. AS is known in the art, tions, dispersions, Suspensions or emulsions and sterile pow liposomes are generally derived from phospholipids or other ders for reconstitution into sterile injectable solutions or lipid substances. Liposomes are formed by mono- or multi dispersions. Intravenous administration is likely one of the lamellarhydrated liquid crystals that are dispersed in an aque best routes in delivery of crocin and crocetin for most effec ous medium. Any non-toxic, physiologically acceptable and tive prevention and treatment of cancers and other diseases metabolizable lipid capable of forming liposomes may be and conditions. Examples of Suitable aqueous and nonaque used. The present compositions in liposome form may con ous carriers, diluents, solvents or vehicles include water, etha tain, in addition to the active components of this invention, nol, polyols (propylene glycol, polyethylene glycol, glycerol, stabilizers, preservatives, and the like. The preferred lipids and the like), suitable mixtures thereof, vegetable oils (such are the natural and synthetic phospholipids and phosphatidyl as olive oil) and injectable organic esters such as ethyl oleate. cholines (lecithins) used separately or together. Methods to Further, the injections may contain stabilizers, solubilizers, form liposomes are known in the art. See, for example, Pres Suspending agents, emulsifiers, Soothing agents, buffers, pre cott, Ed., Methods in Cell Biology, Volume XIV. Academic servatives, isotonic agents, antibacterial and antifungal Press, New York, N.Y., (1976), p 33 et seq. US 2016/O 199398 A1 Jul. 14, 2016
0105. In certain embodiments the amount of crocin or by no more than 25%. For therapeutic propose and treatment, crocetin or the combination of both is from about 1.0 mg to a dosage or multi-dosages of 1 g to 20 g per day is Sufficient about 7000 mg per dose, from about 50 mg to about 500 mg and effective for patients. per dose for prevention and protection, or from about 200 mg 0108. In yet another preferred form, a sterile injectable to about 2000 mg per dose, or from about 200 mg to 500 mg Solutions can be prepared by incorporating crocin and croce per dose. In certain embodiments the effective amount of tin prepared under pharmaceutical procedure in the required crocin and crocetin is from about 0.25 mg/kg bodyweight of amount in an appropriate solvent with one or a combination of the human to about 50 mg/kg bodyweight of the human per ingredients enumerated above, as required, followed by fil dose. The dose, and perhaps the dose frequency, can vary tered sterilization. Generally, dispersions are prepared by according to the age, body weight and conditions of indi incorporating the active compound into a sterile vehicle vidual patient. The purity of the ingredients and the presence which contains a basic dispersion medium and the required of added diluents, emulsifiers and other additives must be other ingredients from those enumerated above. In the case of taken into consideration in determining the dosage. sterile powders for the preparation of sterile injectable solu 0106. In a preferred form the invention provides a dietary tions, the preferred methods of preparation are vacuum dry Supplement composition wherein Supplement capsules are ing and freeze-drying which yields a powder of crocin and prepared by simply use of dry or Solid compositions as filler crocetin plus any additional desired ingredient from a previ in soft and hard-filled gelatin or vegetable capsules for oral ously sterile-filtered solution thereof. One example formula administration. Prepared capsules are orally administered as tion includes preparation of a solution with crocin and/or part of a prepared food. One example formula includes the crocetin, which is purified under pharmaceutical grade con following active ingredient presented in parts in weight: ditions, and cyclodextrin, or mannitol, or Sorbitol or maltitol, about 200 parts crocin and crocetin, about 150 parts green tea fill in glass vials with designated Volume/dosage and freeze extract, about 50 parts curcumin, about 50 parts resveratrol, dry to get powder form and aseptically seal the vials. An about 25 parts Panax ginseng extract, about 15 parts C-lipoic injectable solution is re-constituted with sterile injectable acid, and about 10 parts L-carnitine. A composition contain water or saline or 5% dextrin before injection. Dosage of ing this formula and carriers may be conventionally presented purified crocin and/or crocetin ranges from 10 mg to 5000 mg in unit dosage form and prepared by methods, fill in as cap per day, preferably 50 mg to 1000 mg per day, more prefer sules or press into tablets, well known in the art of supple ably 100 mg to 500 mg per days. ment. The total daily dose (in single or divided doses) ranges 0109. A topical formulation of this invention, one from about 100 mg per day to about 2000 mg per day, or about exampled composition contains a combination of crocin, cro 200 mg per day to about 4000 mg per day. In some embodi cetin, and one or more C-lipoic acid, a carnosine, and a ments, the total daily dose may range from about 50 mg to carnitine, is particularly advantageous because of the multi about 5000 mg per day. A powder mixture of this formula can pronged effect these ingredients have for addressing the aging also be used to prepare functional foods. More examples process. Each of C-lipoic acid, L-carnitine, and carnosine are provided later. produced by the body and their secretion generally decrease with age, and the topical application of these or related com 0107. In another preferred form the invention provides a pounds provides protection against loss due to age. These therapeutic composition wherein soluble effervescent tablets ingredients are also antioxidants. are prepared by compression. Compare to conventional tablet 0110. The topical formulation will preferably comprise and capsules, effervescent tablets have major advantage that crocin and/or crocetin thereof in an amount of from about the drug product is already in Solution at the time it is con 0.01 to 50% by weight, based on the total weight of the Sumed. The absorption is faster and active ingredients are composition, or more preferably in an amount of from about delivered to the stomach at a pH that is just right for absorp 0.1 to 7.0% by weight, based on the total weight of the tion. Because effervescent tablets dissolve fully in a buffered composition. The formulation will preferably comprise Solution, it prevents gastric acids from interacting with the L-carnitine thereofinanamount of from about 0.01 to 50% by active ingredients and reduces causes of stomach and esoph weight, based on the total weight of the composition, or more ageal upsets. Effervescent tablets also enhance the absorption preferably in an amount of from about 0.5 to 2.0% by weight, of a number of active ingredients, compared to conventional based on the total weight of the composition. The formulation formulations. This is because the carbon dioxide created by will preferably comprise carnosine thereof in an amount of the effervescent reaction can induce enhanced active-ingre from about 0.01 to 50% by weight, based on the total weight dient permeability due to an alteration of the paracellular of the composition, or more preferably in an amount of from pathway. The paracellular pathway is the primary route of about 0.1 to 5.0% by weight, based on the total weight of the absorption for hydrophilic active ingredients in which the composition. solutes diffuse into the intercellular space between epithelial cells. It is postulated that the carbon dioxide widens the 0111. Following examples are presented to further explain intercellular space between cells, which leads to greater and illustrate the invention and are not to be taken as limiting absorption of active ingredients. One exampled formula in any regard. Unless otherwise indicated, all parts and per includes: 1500 mg citric acid, 800 mg potassium bicarbonate, centages are by weight. 800 mg sodium bicarbonate, 160 mg sodium carbonate, 250 mg crocin and crocetin, 60 mg polyethylene glycol 6000, 50 COMPOSITION EXAMPLES mg aspartame, 30 mg flavorant. The material of this formula Example 1 can be blended and pressed into appropriate size of soluble effervescent tablets. For effective protection and prevention, 0112 This example provides a preferred, but not limited, a dosage unit of this formulation will preferably be from 0.5 dosage form of a composition of the invention. Gelatin or g to 10 g. The doses and these individual ingredients can be Vegan capsules are produced by preparing a mixture of the varied by up to 50% of the above values, preferably varying following ingredients with filler by grinding under a vacuum US 2016/O 199398 A1 Jul. 14, 2016 to assure intimate mixing and a dry character, and then filling Example 4 individual gelatin capsules with a total of 1000 mg as com prising of following: 0118. This example provides a preferred, but not limited, dosage form of a composition of the invention. Gelatin or Vegan capsules are produced by preparing a mixture of the 200 mg crocin and/or crocetin following ingredients with filler by grinding under a vacuum 150 mg green tea extract to assure intimate mixing and a dry character, and then filling 50 mg curcumin 50 mg resveratrol individual gelatin capsules with a total of 1000 mg as com 25 mg Panaxginseng extract prising of following: 15 mg C-lipoic acid, and 10 mg L-carnitine 250 mg crocin and/or crocetin 200 mg citrus extract (90% polymethoxylated flavones, nobiletin & tangeretin) 0113. These capsules are consumed in a regimen effective 100 mg curcumin to prevent or treat cancers and other conditions and diseases, 50 mg resveratrol preferably taking once in the morning and once in the evening. 0119 These capsules are consumed in a regimen effective for prevention and treatment of cancer and lowering risk of Example 2 cancers and other diseases or conditions, preferably taking once in the morning and once in the evening in the middle of 0114. This example provides another preferred, but not meal. limited, composition of this invention. Tablets are produced by preparing a mixture of the following ingredients with Example 5 excipient through steps by blending, dry granulating, milling, blending, compressing, and coating. A composition com 0.120. This example provides a preferred, but not limited, prises enriched and purified crocin and/or crocetin and other composition of this invention for eye health. Tablets are pre phytochemicals or extracts as following: pared by preparing a mixture of the following ingredients with excipient through steps by blending, dry granulating, milling, blending, compressing, and coating. A composition 200 mg crocin and/or crocetin comprises enriched and purified crocin and/or crocetin and 200 mg green tea extract 100 mg curcumin other phytochemicals or extracts as following: 100 mg Grape seed extract 50 mg Panaxginseng extract 50 mg Rhodioia rosea extract 200 mg crocin and/or crocetin 50 mg Ginkgo biloba extract 200 mg lycopene 100 mg beta-caroteine 100 mg bilberry extract 50 mg lutein 0115. A daily supplement dosage of 100 mg to 1000 mg is 25 mg zeaxanthin useful in preventing and delaying cancers and neurodegen erative diseases, enhancing brain and mental health, improv ing cognitive, learning and memory ability, protecting liver, I0121 These tablets are consumed in a regimen effective to heart, lung, kidney, eye, skin, nerves, normal cells. prevent and treat of age-related macular degeneration (AMD), increase blood circulation in retina, protect retina and brain from toxin- or light-induced stress, improve and Example 3 maintain eye sight and brain function, and lower risk of can 0116. This example provides a preferred, but not limited, cers and other diseases or conditions, preferably taking once dosage form of a composition of the invention. Gelatin or in the morning and once in the evening in the middle of meal. Vegan capsules are produced by preparing a mixture of the following ingredients with filler by grinding under a vacuum Example 6 to assure intimate mixing and a dry character, and then filling 0.122 This example provides a preferred, but not limited, individual gelatin capsules with a total of 1000 mg as com therapeutically injectable/infusion composition of this inven prising of following: tion. A sterile injectable/infusion composition is prepared in amber vials or bottles in lyophilized powder form by steps: quantitatively mixing 5 g high purity crocin and/or crocetin 200 mg crocin and/or crocetin 500 mg dihydromyricetin (at least a purity of 98%, preferably at least 99%) with 20g or 50 mg resveratrol 40g pharmaceutical grade mannitol, dissolving the mixture 50 mg artichoke leaf extract in a suitable solvent 400 ml or 800 ml distilled or injectable water, sterilizing by filtering the solution through 0.15-0.22 um sterilized filtration membrane, distributing into sterilized 0117 These capsules are consumed in a regimen effective amber vials or bottles, freeze-drying, sealing vials or bottles, to protect liver from injury and alcohol damage, or treat liver and labeling and packing to obtain the products. To inject or cancer and/or restore liver function, prevent and/or treat other infuse the product to a subject, a solution of the product is conditions and diseases, preferably taking once in the morn reconstituted by adding, shaking and dissolving in Suitable ing and once in the evening, or preferably taking prior to amount of injectable water or physiological (0.7% w/w) consume alcohol. saline Solution. US 2016/O 199398 A1 Jul. 14, 2016
0123 A. A Reconstituted Injection Lyophilized Vial Con Example 8 tains: I0128. This example provides a preferred, but not limited, dosage form of a composition of this invention for application 50 mg crocin and/or crocetin in food or drink. Powder of crocin and/or crocetin with rebau 200 mg mannitol dioside A, glycyrrhizic acid ammonium salt, and erythritol in 5 ml physiological (0.7% w/w) saline solution a ratio of 25:50:50:2875 by weight is mixed. The pre-mixed powder product can be directly used as powder form packed 0.124 B. A Reconstituted Infusion Lyophilized Bottle in Sachets or packets or a moisture and light shield container Contains: with a size pre-determined scoop. The pre-mixed powder can also be further formulated and processed as cubes, granules for use in Sachets or packets, and tablets. 2.5 grams of the 250 mg crocin and/or crocetin pre-mixed powder is added to a serving of non-fat and non 2000 mg mannitol Sugar yogurt (6 oz.) and followed with stirring to homog 50 ml physiological (0.7% w/w) saline solution enous. A nice yellow colored and sweetened yogurt with 25 mg crocin and/or crocetin but no extra calories is served. In 0.125. This injectable or infusion form of this invention is application to a drink, 2.5 grams of the pre-mixed powder or useful in treating various cancers, neurodegenerative disor formed cubes, granules or tablets, which are readily soluble, ders such as Alzheimer's and Parkinson's diseases, other is added to a serving (8 oz.) of water, or drink or juice. diseases and conditions. Flavoring can be added at user's choice or preference. Stir Example 7 with a spoon for 1 to 5 minutes. A drink with 25 mg crocin and/or crocetin but no extra calories is served. A composition 0126. This example provides a preferred, but not limited, list is provided as comprising of following: dosage form of a composition of this invention. Effervescent tablets are prepared by following steps: a. mix anhydrous citric acid with crocin and/or crocetin.b. make granulates by 100 mg crocin and/or crocetin adding 65% citric acid solution under agitation and Subse 200 mg rebaudioside A quently drying at low temperature to relative humidity of the 200 mg glycyrrhizic acid ammonium salt granule to less than 0.15%. c. mix granules at low humidity 9500 mg erythritol with anhydrous sodium bicarbonate, flavorant, aspartame, and polyethylene glycol (PEG) 6000. d. press to form the effervescent tablets and magnesium Stearate is used as an I0129. This composition in products is consumed daily in a external lubricant to avoid sticking during the tableting opera regimen effective for eye health and brain health, to preventor tion. Average size of the tablets is 3.85g with diameter of 23 delay age-related macular degeneration, to prevent or treat mm and thickness of 3.15 to 3.25 mm. e. pack 10 tablets in a mild-to-moderate Alzheimer's disease, to prevent and reduce re-sealable HDPE container. An exemplary effervescent risks of cancers and heart diseases, and to enhance overall composition comprises the following: health. 0.130. The above description is intended to enable the per son skilled in the art to practice the invention. It is not 200 mg crocin and/or crocetin 250 mg dihydromyricetin intended to detail all of the possible modifications and varia 5700 mg anhydrous citric acid tions which will become apparent to the skilled worker upon 12000 mg Sodium bicarbonate reading the description. It is intended, however, that all Such 300 mg PEG 6000 modifications and variations be included within the scope of 200 mg flavorant (lemon flavor) the invention which is seen in the above description and 200 mg aspartame otherwise defined by the following claims. The claims are meant to cover the indicated elements and steps in any 0127. A daily consumption of one tablet by dissolving the arrangement or sequence which is effective to meet the objec tablet in 6 oz. of water at room temperature and drinking is tives intended for the invention, unless the context specifi useful and effective for protecting liver from alcohol or over cally indicates the contrary. dose iron or other heavy metal caused damages, protecting lung from injury or cancers caused by Smoke or Smog, PATENT CITATIONS enhancing heart functions, preventing or treating cancers or other diseases or conditions. 0131)
Publication Cited Patent Filing date date Applicant Title Nov. 15, Jun. 27, 2012 Method for 2011 producing crocin with higher than 95% purity from gardenia WO2004O78695 Mar. 3, Sep. 16, 2004 Koichi Harada, Method for the A1 2004 Riken Vitamin Co, purification of Masahiro crocetin Takahashi US 2016/O 199398 A1 Jul. 14, 2016 13
-continued
Publication Cited Patent Filing date date Applicant Title WO2O10(O94745 Feb. 18, Aug. 26, 2010 Omnica Gmbh Hydrolysate of A1 2010 crocin US2O10O210572 Feb. 17, Aug. 19, 2010 Thomas Hydrolysate of A1 2010 Eidenberger crocin WO2004OS 6201 Dec. 19, Jul. 8, 2004 Shri Gopal Method for the A1 2002 Agarwal, Vilai preparation of Kant Agnihotri, Saffron pigment Council Scient Ind and flavor Res, Ghulam Nabi concentrate Qazi, Om Prakash Suri, Rajinder Kumar Thappa U.S. Pat. No. 7,351,844 B2 Feb. 25, Apr. 1, 2008 Diffusion Bipolar trans 2003 Pharmaceuticals carotenoid salts Llc and their uses US2O1301S6746 Aug. 25, Jun. 20, 2013 Persavita Ltd. Composition and A1 2011 method of manufacture US2O110236481 Jun. 9, Sep. 29, 2011 Cedric Bourges Use of saffron A1 2011 and/or safranal and/or crocin and/or picrocrocin and or derivatives thereofas a satiety agent for treatment of obesity
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0148. ZhangY. Shoyama Y. Sugiura M. Saito H. Effects of (2) at least one additional ingredient selected from the Crocus sativus L. on the ethanol-induced impairment of following: quercetin, resveratrol, pterostilbene, cur passive avoidance performances in mice. Biol Pharm Bull. cumin, theaflavin, theaflavin-3,3'-digallate, theaflavin 1994, 17 (2):217-21. 3-gallate, theaflavin-3-gallate, anthocyanidins, antho 0149. Abe K, Saito H. Effects of saffron extract and its cyanins, catechin, epicatechin, gallocatechin, constituent crocin on learning behaviour and long-term epigallocatechin, epicatechin gallate, gallocatechingal potentiation. Phytother Res. 2000, 14(3):149-52. late, epigallocatechingallate, nobiletin, tangeretin, C-li 0150. Maccarone R, Di Marco S. Bisti S. Saffron supple poic acid, L-carnitine, carnosine, astragaloside, cycloas ment maintains morphology and function after exposure to tragenol, lutein, B-lycopene, Zeaxanthin, rosarin, damaging light in mammalian retina. Invest Ophthalmol B-rosasterol, rosavin, rosin, dihydromyricetin, chloro Vis Sci. 2008, 49(3):1254-61. genic acid, glycyrrhizic acid ammonium salt, rebaudio 0151 Falsini B, Piccardi M, Minnella A, Savastano C, Capoluongo E. Fadda A, Balestrazzi E. Maccarone R. Bisti side A, green tea extract, black tea extract, bilberry S. Saffron supplementation improves retinal flicker sensi extract, ginseng extract, grape extract, grape seed tivity in early age-related macular degeneration. Invest extract, epimedium extract, Schisandra extract, astraga Ophthalmol Vis Sci. 2010, 51: 6118-6124. lus extract, rhodiola extract, citrus fruit extract, orange 0152 Piccardi M. Marangoni D, Minnella AM, Savastano extract, lemon extract, licorice extract, artichoke leaf MC, Valentini P. Ambrosio L. Capoluongo E. Maccarone extract, gotu kola extract, or Stevia extract, wherein the R. Bisti S, Falsini B. A longitudinal follow-up study of Selected at least one additional ingredient, in percentage Saffron Supplementation in early age-related macular by weight, 1-40%, wherein the composition having the degeneration: Sustained benefits to central retinal function. ingredient in amount, individually and/or combined, to Evid Based Complement Alternat Med. 2012, 2012: provide a nutraceutically or therapeutically significant 429 124. benefit to prevent or treat diseases/conditions. 0153. Alonso G. L. Salinas MR, Garijo.J. Sanchez-Fernan 2. The nutraceutical or therapeutic composition according deZ M A. Composition of crocins and picocrocin from Spanish saffron. J. Food Quality. 2001, 24:219-233. to claim 1, wherein said at least one additional ingredient is 0154 Lechtenberg M. Schepmann D. Niehues M. Hellen selected from the following: resveratrol, curcumin, nobiletin, brand N, Wünsch B, Hensel A. Quality and Functionality tangeretin, C.-lipoic acid, L-carnitine, carnosine, lutein, B-ly of Saffron: Quality Control, Species Assortment and Affin copene, Zeaxanthin, dihydromyricetin, glycyrrhizic acid ity of Extract and Isolated Saffron Compounds to NMDA ammonium salt, rebaudioside A, green tea extract, bilberry and O1 (Sigma-1) Receptors. Planta Med 2008: 74: 764 extract, ginseng extract, rhodiola extract, grape seed extract, 772. citrus fruit extract, or artichoke leaf extract, wherein the com (O155 Baur JA, Sinclair DA. Therapeutic potential of position having the ingredients in amount, individually and/ resveratrol: the in vivo evidence. Nature Reviews Drug or combined, to provide a nutraceutically or therapeutically Discovery. 2006, 5:493-506. significant benefit to prevent or treat diseases/conditions. 0156 Aggarwal BB, SurhYJ, Shoshodia S. The Molecu 3. The nutraceutical or therapeutic composition according lar Targets and Therapeutic Uses of Curcumin in Health to claim 1, wherein the enriched or purified crocin and/or and Disease. Advances in Experimental Medicine and crocetin is from Saffron orgardenia fruits or gardenia yellow. Biology. 2007, Volume 595. Published by Springer U.S. 0157 Mukhtar Hand Ahmad N. Tea polyphenols: preven 4. The nutraceutical or therapeutic composition according tion of cancer and optimizing health 1,2,3. Am J Clin Nutr to claim 2, wherein said at least one additional ingredient June 2000, 71(6): 1698-1702. comprises, in percentage by weight, 1-25% lutein and 1-10% 0158. He J, Giusti MM. Anthocyanins: Natural Colorants Zeaxanthin. with Health-Promoting Properties. Food Science and 5. The nutraceutical or therapeutic composition according Technology. 2010, 1: 163-187. to claim 2, comprises, in percentage by weight, 1-30% of 0159) Kalt W. HannekenA, Milbury P. Tremblay F. Recent crocin or crocetin or both, 1-30% of curcumin, 1-20% of Research on Polyphenolics in Vision and Eye Health. J. green tea extract, 1-20% grape seed extract, 1-15% of ginseng Agric. Food Chem., 2010, 58 (7): 4001-4007. extract, and 1-15% rhodiola extract. 0160 Cassidy A, O’Reilly E. J. Kay C, Sampson L. Franz 6. The nutraceutical or therapeutic composition according M, Forman J. P. Curhan G, Rimm E. B. Habitual intake of to claim 2, comprises, in percentage by weight, 1-30% of flavonoid subclasses and incident hypertension in adults. crocin or crocetin or both, 1-30% of curcumin, 1-20% of Am. J. Cli. Nutri. 2011, 93: 338-347. green tea extract, 1-20% grape seed extract, 1-15% of ginseng 0161 Gao X, Cassidy A, Schwarzschild MA, MD, Rimm extract, 1-15% rhodiola extract, and 1-15% ginkgo extract. EB, Ascherio A. Habitual intake of dietary flavonoids and risk of Parkinson disease. Neurology 2012 78(15); 1138 7. The nutraceutical or therapeutic composition according 1145. to claim 1, comprises, in percentage by weight, 1-50% of 0162 Gouta B, Bourges C. Paineau-Dubreuil S. Satiereal, crocin or crocetin or both, 10-75% of dihydromyricetin, 0.5- a Crocus sativus L. extract, reduces Snacking and increases 20% of resveratrol, and 0.5-20% of artichoke leaf extract satiety in a randomized placebo-controlled study of mildly wherein the artichoke leaf extract comprises, in percentage by overweight, healthy women. Nutrition Research. 2010, 30: weight, 10-30% of chlorogenic acid and 1-10% of cynarin. 305-313. 8. The nutraceutical or therapeutic composition according 1. A nutraceutical or therapeutic composition comprising: to claim 1, wherein said composition comprising, in percent (1) in percentage by 1-80%, of at least one of crocin and age by weight, 10-60% of citric acid, 5-40% of potassium crocetin, wherein crocin and/or crocetin is extracted, bicarbonate, 5-40% of sodium bicarbonate, 0.5-20% of enriched and/or purified from natural source to a purity sodium carbonate, 0.5-30% of crocins or crocetin or both, of at least 65%; and 0.2-10% of polyethylene glycol, 0.1-8% of aspartame, 0.1- US 2016/O 199398 A1 Jul. 14, 2016
5% of flavorant, wherein the ingredients of the composition 19. The method according to claim 11, said administering are blended and pressed into appropriate size of effervescent comprising administering said composition topically as pow tablets. ders, ointments, creams, sprays, drops or patches. 9. The nutraceutical or therapeutic composition according 20. The method according to claim 11, wherein said com to claim 1, wherein said composition in a porous lyophilized position is administered through ear drops, eye Solutions, or form comprising, in percentage by weight, 10-80% of crocin eye ointments, or through at least one of the following: rectal, or crocetin or both, and, in percentage by weight, 0.05-50% of mucosal, intranasal administration. L-carnitine, wherein the composition is capable of being 21. The method according to claim 11, wherein said com readily reconstituted into an injectable solution, or Suspen position protects/improves/enhances the function/condition sion or emulsion by mixing with water or saline or 5% dex of liver, wherein said composition protects/prevents or treats trose solution or 5% glucose solution or cyclodextrin or com liver injury from alcohols, toxins, shock, overdose of metal or bination thereof using mild agitation that does not require heavy metal, and/or protects liver from chemo agent injury machine processing. and damage. 10. The composition according to claim 1, wherein the 22. The method according to claim 11, wherein said com composition is formed as tablets, soft gels, capsules, pills, position protects/improves/enhances the function/condition caplets, dragees, granules, powders, or effervescent tablets, of kidney by at least one of the following: protecting kidney liquid, sprays, emulsion, injectable, functional foods, gums, chewing gum, gummi candy, taffy, caramel candy, fudge, from diseases and/or injury, preventing or treating kidney degradable thin films, nondegradable thin films, hard candy, diseases and injury. liquids, drinks, or beverages. 23. The method according to claim 11, wherein said com 11. A method of preventing, mitigating, or treating a dis position improves and enhances immune system. ease or condition in a Subject, comprising administering an 24. The method according to claim 11, wherein said com effective amount of the composition according to claim 1 to position has at least one of the following functions: slowS/ the subject in need thereof. prevents/treats age-related macular degeneration, increases 12. The method according to claim 11, wherein said subject blood flow to the retina and choroid, facilitates retinal func is a mammal. tion recovery thereby preventing ischemic retinopathy and 13. The method according to claim 12, wherein said subject age related macular degeneration, and/or improves/enhances is a human. eye health or treat eye conditions and diseases. 14. The method according to claim 11, wherein said subject 25. The method according to claim 11, wherein said com has at least one disease/condition selected from the following: position enhances/improves human circulation system by a cancer, a neurodegenerative disease/condition, a heart dis reducing level of cholesterol, triglyceride and low density ease/condition, a liver disease/condition, a kidney diseasef lipoprotein, and/or prevents, mitigates or treats coronary condition, memory loss, mental confusion, metabolic Syn artery diseases, atherosclerosis, cardiovascular diseases and drome, atherosclerosis, inflammation, obesity, diabetes; peripheral vascular diseases. 15. The method according to claim 11, wherein said com 26. The method according to claim 11, wherein said com position protects/improves/enhances the function/condition position prevents, mitigates or treats overweight or obese. of at least one of the following: liver, kidney, heart, lung, eye, 27. The method according to claim 11, wherein said com brain, skin, pancreas, stomach, esophagus, prostate, breast, position prevents, mitigates or treats depression, and/or ovarian, rectum, colon, bladder, and/or any other organ. improves/enhances well-being. 16. The method according to claim 11, wherein said com 28. The method according to claim 11, wherein said com position improves/enhances/restores cells, tissues, organ position improves/enhances skin health, conditions and/or functions of said Subject, and/or improves/prolongs life span, appearance, prevents/treats skin damage, or delayS/inhibits learning, memory and/or cognition of said Subject. signs of skin aging through anti-aging, anti-wrinkle, anti 17. The method according to claim 11, wherein said com inflammation and/or anti-oxidation. position prevents, mitigates or treats one of the following: Alzheimer's disease, Parkinson's disease, and other neuro 29. The method according to claim 11, wherein said com degenerative disorder/disease. Such as age-related macular position improves or treats peripheral neuropathy, muscle degenerated diseases. pain, nerve pain, muscle cramping, joint pain and combina 18. The method according to claim 11, said administering tions thereof. is done through at least one of the following: orally, transmu 30. The method according to claim 16, wherein adminis cosally, buccally, percutaneously, and parenterally via at least tering said composition via functional food product com one of the following: intravenous, intramuscular, intraperito prises one of the following: yogurt, sausage, sauce, cake, pie, neal, intrasternal, Subcutaneous, intraarticular injection, infu Soup, juice, ice cream, drink, energy drink, beverage, or Soda. S1O. k k k k k