Patent Application
20240024399
Liver as organ is most important in detoxification of the body, elimination of toxins and waste products, taking part in production of proteins which are required for immunity. Because of obesity and diabetes about one third of the people with modern life style are getting affected with one form or other liver diseases, which are affecting over all health and becoming economic burden to individuals, family and also society.
In the United States, 64 million people are estimated to have NAFLD; of which, 6.65 million have NASH. There were estimated 232,000 cases of incident NASH reported in 2017 in the United States.3 In a smaller study conducted in Manitoba, Canada, incidence of NASH was reported to be between 28 and 36%. Prevalence of NAFLD in South America is 30.4%, with up to a third of these individuals progressing to NASH. Depending on the country, the prevalence of NAFLD varies from as low as 13% in Peru to as high as 30% in Brazil. Most of these studies used abdominal ultrasound and transaminases to estimate the prevalence of NAFLD. Prevalence of NAFLD diagnosed by ultrasound and liver enzymes in Italy was noted to be 23%, the Netherlands 34%, Hungary 23%, and Finland about 41%.7 Prevalence of NAFLD seem to be more in UK (46.2%) among all European countries compared to Germany (about 30%), Romania 20%, and Spain 25.8%. As per recent estimates, prevalence of NAFLD in the United States based on liver ultrasound in general population is around 24%. (from Ref:4)
Younossi et al. reviewed data from 86 studies and reported a global prevalence of NAFLD as 25.2%. The prevalence was highest in the Middle East (31.8%) and South America (30.5%) and lowest in Africa (13.5%). The prevalence of NAFLD in Asia was 27.4%, which was not lower than that in Europe (23.7%) and North American (24.1%).(from Ref:5)
Asia is a vast continent including countries with different lifestyle habits and economic development. In the same meta-analysis by Younossi et al., the prevalence of NAFLD in Asia ranged from 14.8% in Taiwan to 43.9% in China. It is important to remember that the included studies differ in research setting, study population, the method of diagnosis and the year of investigation. Studies at hospital clinics tend to report a higher prevalence of NAFLD than true general population studies. The prevalence was also higher in recent than old studies. The latter suggests that NAFLD is increasingly common in Asia. In one of the few secular trend studies, Kojima et al. reported that the prevalence increased from 12.6% in 1989 to in 1998 in Japan. Similarly, a meta-analysis of studies from China also showed an increase in NAFLD prevalence from 18.2% in 2000-2006 to 20.7% in 2010-2013.(From Ref: 5).
Above two articles indicates severity of liver diseases which need better working product besides requirement of immediate life style changes before it reaches to NASH. Fatty liver, NAFLD can be reversed with life style changes besides medication. Once it touches NASH, inflammation becomes major issues which leads to liver fibrosis, liver cirrohosis and liver cancers which cannot be reversed. This invention trying to address these issues with a innovation in the product from the existing knowledge or processes to bring out better working product with better safety profile.
Silybum marianum (Milk thistle, Silybum marianum L. Gaernt) is being used from ancient times for treatment of liver dysfunctions, gallbladder disorders. References can be found in the Old Testament (Genesis 3:18). In ancient Greece, Indian and Chinese medicines used Silybum marianum for liver and gallbladder problems. Due to its hepatoprotective use, silymarin, an extract of Silybum marianum fruits, classified by WHO as an official medicine with hepatoprotective properties.(from Ref:1)
Silymarin represents 1.5-3% of the fruit's dry weight and is an isomeric mixture of unique flavonoid complexes—flavonolignans. The main representatives of this group presented in silymarin are silybin, isosilybin, silychristin, isosilychristin, silydianin, and silimonin. The chemical composition of milk thistle fruit besides flavonolignans also include other flavonoids (such as taxifolin, quercetin, dihydrokaempferol, kaempferol, apigenin, naringin, eriodyctiol, and chrysoeriol), 5,7-dihydroxy chromone, dehydroconiferyl alcohol, fixed oil (60% linoleic acid; 30%, oleic acid; 9% palmitic acid), tocopherol, sterols (cholesterol, campesterol, stigmasterol, and sitosterol), sugars (arabinose, rhamnose, xylose, and glucose), and proteins. However, the highest concentration, comprising approximately 50-70% of the extract, is silybin, which is the major bioactive component of extract, which has been confirmed in various studies. The silybin concentrations typically found in common pharmaceutical products containing a silymarin range of 20-40%. Besides the hepatoprotective action, silybin has strong antioxidant properties and modulates a variety of cell-signaling pathways, resulting in the reduction of pro-inflammatory mediators. Silybin is also studied as a potential anticancer and chemo-preventive agent. Research performed last year demonstrates that silybin is able to inhibit serine proteases involved in the blood coagulation process, as well as reduce blood platelets' response to physiological agonists.(from Ref:1)
Silybum marianum is being sold as powder, for making tea, tincture, standardised Silymarin extract for human consumption for liver protection, diseases and disorders. Normal content of Silymarin is 1.5-3%, which they process and standardise with up to 95%.
Silymarin was first isolated in 1968 by German scientists at the University of Munich and then described and patented by the German herbal medicine manufacturer Madaus as a specific treatment “against liver diseases”. The first commercial preparation of silymarin was developed by Rottapharm/Madaus (Cologne, Germany) and complies with the analytical specifications reported in the European Pharmacopoeia January/2005 under “Milk Thistle fruit.” It is registered as a drug for liver diseases in many countries in Europe, Asia, America, Africa and Australia. Different forms, including capsules and tablets, are available with different dosages; the recommended daily dosage (depending on the commercial formulation used) is between 420 and 600 mg, and the majority of clinical trials have been conducted with a dosage of 140 mg three times a day.(From Ref:2)
Crude silymarin extract is lipophilic and poorly soluble in water, so only about 20-50% is absorbed from the gastrointestinal tract after ingestion. For this reason, formulation scientists have endeavored to improve the oral bioavailability and solubility of silymarin preparations, but the commercially available silymarin-containing products differ significantly in their content, dissolution and oral bioavailability of the active ingredient silibinin. In 1995, Rottapharm/Madaus invented a co-precipitation processing method that produced a high-quality silymarin (90-96% purity; approximately 60% of the content being silibinin) with an enhanced dissolution profile (>90% of silibinin liberated by the co-precipitate); this advanced processing method was subsequently patented in 2014 under the trade name Eurosil 85®. Most of the published clinical research on silymarin has used this standardized pharmaceutical preparation.(From Ref:2)
Dorata (From ref 3) mentioned Pressurised liquid extraction (PLE) parameters under study were solvent type (methanol, acetone and ethyl acetate), temperature (50, 75, 100, 125 and 1508 C), time (5, 10, 15 and 20 min) and the number of extraction cycles (1-5). For the PLE defatting process, n-hexane was applied as solvent, and parameters under study were temperature (50 and 1008 C) and time (5 and 10 min) of lipids removal. Acetone and ethyl acetate extracts were evaporated to dryness under vacuum and redissolved in methanol before chromatographic analysis. Still it uses multiple solvents including polar solvents and high temperatures for PLE.
In the present processes of Silymarin extraction it undergoes defatting, then extract silymarin and standardise. In that process they do multiple extractions at high temperatures with non-polar and polar solvents. Though they standardise the silymarin, this high exposure of heat and solvents could be reducing the efficacy of the product. Crude dry powders, crude extract & tinctures by polar solvents is considered less palatable due to its oily & bitter taste. Also those contain glucosides and glycosides which are polar soluble.
Present invention is to address following drawbacks of Silybum marianum extract:
With this invention, inventor would like to bring additional benefit by:
Inventor is anticipating and claiming following in the present invention:
Inventor has used similar processes for other products, but not for Silybum marianum. Due to shorter produce time and higher availability of Silybum marianum, this invention will be beneficial to the needy, who are presently about 20 pct of western elderly population who are suffering with one or other form of liver diseases or disorders, and aging.
Following are some of the examples/embodiments of improved extraction process. Any modifications, improvements to this invention done by persons who has skill and art will be in the scope and spirit of this invention and the same are anticipated.
Extract thus collected is in semisolid condition, sent for testing and formulation in controlled conditions.
Extract thus collected sent for testing and formulation in controlled conditions.
Wherever it is mentioned as SS in this application, it is understood that it meant seeds and/or fruits of Silybum marianum (Milk thistle, Silybum marianum L. Gaernt). Wherever it is mentioned for present invention as extract it is understood that it is lipophilic extract as claimed.
Processes described above also can be used for extraction of other plant materials like, but not limited to, Curcuma species (including turmeric), Coptis Root and Cortex Phellodendri (including Berberine), plants of Panax genus including Ginseng, genus Zingiber (Ginger) and other medicinal plants which are known for liver protection, immunity and anti-inflammatory activity and the same are within the scope and spirit of this invention.
Description/Specifications/Claims and variations described above are feasible by persons skilled in the art to make minor modifications and use as innovation without real added benefit to humans or animals and the same are within the scope and spirit of this invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2021/058777 | 9/27/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63084714 | Sep 2020 | US |
