(ALA) SOURCE

TECHNICAL FIELD The present invention relates to use of an herbal formulation containing linseed oil (Oleum Lini) in the drug industry in the chemical industry.

In particular, the invention relates to use of an herbal formulation that is prepared with linseed oil being rich in alpha-linolenic acid which is a herbal fatty acid containing Omega 3; that is in the form of a capsule having an antioxidant property, on those who cannot use fish oil, particularly on vegetarians as a herbal omega 3 (ALA) source.

STATE OF THE ART Omega 3 is an essential fatty acid, it is a fatty acid that should be taken from outside to maintain the organism's life as other essential fatty acids and that cannot be synthesised in body. This essential fatty acid should be taken by means of nutrition and supplements into body. ALA being a sort of herbal Omega 3 fatty acid existing in the linseed oil structure and taken from outside into organism can be used on those who cannot use fish oil, particularly on vegetarians as a herbal omega 3 (ALA) source and thereby can be used as an adjuvant in regulating blood lipid (fat) levels and in the treatment of cardiovascular system diseases.

In the state of art; the products that are used as an adjuvant in regulating blood lipid (fat) levels and in the treatment of cardiovascular system diseases on those who cannot use fish oil, particularly on vegetarians as herbal omega 3 (ALA) source, contains synthetic substance or chemical substance in a certain amount. Use of synthetic and chemicals substances may badly affect the various systems of the body by causing various side effects in the organism.

Further, the products in most of the embodiments are in a liquid form. This complicates the administration of controlled dosing. Therefore, essential dosing cannot be achieved exactly and precisely. In the literature, one of the patents pertaining to this matter is the application numbered CN103099755. The invention mentions a shower foam prepared with various herbal materials including linseed that is natural and providing vitality and softness to skin. The application numbered CN105560646 mentions an herbal mixture comprising nanking cherry, tamarind, banana, dragon's tongue leaf, carageen, Russian bochniakia plant, Japanese dok roots, Nepal dok roots, radix Scrophulariae, radix lithospemi, coffee bean, senna, unripe Inula, orange, pakchoi plantlets, alopecia, senna and peach flowers as well as linseed so as to treat the symptoms such as constipation, irregular bowel movements, hard stool and pellet-like dry stool.

As a result, due to the aforementioned drawbacks and insufficiency of the existing solutions regarding the subject matter, the need for a development pertaining to use of linseed oil as a herbal omega 3 (ALA) source on those who cannot use fish oil, particularly on vegetarians in the related technical field has arisen.

OBJECTS OF THE INVENTION

Object of the invention is to use a formulation containing linseed oil on those who cannot use fish oil, particularly on vegetarians as an herbal omega 3 (ALA) source.

Due to the fact that the formulation contains a high herbal Omega-3 olinolenic acid (ALA, 18:3n-3), it can be both used as an omega 3 (ALA) source on those who cannot use fish oil, particularly on vegetarians and help with reducing LDL (low density lipoprotein) levels in blood. Furthermore, the formulation may assist in decreasing thrombosis incidence since it has the antithrombotic effects and the effects reducing aggregation of thromboses. These effects of linseed oil clarify the effects inhibiting the development of atherosclerosis and the effects regulating the blood lipid levels. Therefore, due to the fact that the formulation contains a high herbal Omega-3 olinolenic acid (ALA, 18:3n-3), it can be both used as an omega 3 (ALA) source on those who cannot use fish oil, particularly on vegetarians and again can be used as an adjuvant in regulating blood lipid (fat) levels and in the treatment of cardiovascular system diseases on said patients.

Another object of the invention is to provide a formulation containing no chemical substances, and being totally natural and herbal. No heat or chemical treatment is carried out even when the linseed oil used in the content of the formulation is obtained. Thus, active substances, nutritional values, vitamin and minerals in the plant are directly infused into the product without losing them. Another object of the invention is to ensure to minimize the side effects badly affecting the human health by means of the content formed without chemicals. The side effects affecting only gastro-entero system such as nausea, vomit, diarrhea resulting from the use of totally natural and herbal products is rarely observed.

Further object of the invention is to provide ease of use in terms of patient compliance through the fact that the formed formulation is in the form of capsule. Furthermore, it is advantageous in administrating the dosing in said indications by means of the formed capsule form.

DETAILED DESCRIPTION OF THE INVENTION

Preferred use of an herbal capsule formulation obtained by means of linseed oil so as to achieve the object of the invention is described solely for a better understanding of the subject without generating any restrictive effect.

Linseed Oil:

There are oil and lignans being rich in omega-3(ALA) in the linseed. Linseed among the oils obtained through seeds comes into prominence because it has highly olinolenic acid (ALA, 18:3n-3) and lignans. Linseed comprises oil rate of 35-45 percent whose ALA being a herbal Omega 3 rate is varying between 45-52 percent thereof. ALA is classified as Omega 3 group of essential fatty acids. Essential fatty acids (EYA) is crucial for human and the other mammals and it should be taken through diets since it cannot be synthesized in the body. EYA is poly unsaturated fatty acids that are vital for human and the other mammals. There are two type of EYA, namely Omega 3 (ω-3) and Omega 6 (ω-6), in the body, ω-3 consists of a-linolenic acid (ALA, 18:3) with 18- carbon and three double bond and ω-6 consists of cislinoleik acid (LA, 18:2) with 18-carbon and two double bond.

ω-3 and ω-6 fatty acids have good effects on various organs and diseases. EYA metabolism varies in the occurrence of obesity, hypertension, diabetes mellitus, coronary heart diseases, schizophrenia, Alzheimer's disease, atherosclerosis and cancer. Importance of Omega 3 (ω-3) fatty acids, in the first place, was realised through the studies carried out on the eskimos in Greenland. Although traditional foods contain high incidence of fat, it was observed that eskimos were resistant to heart and rheumatic diseases, asthma and various diseases seen frequently in the industrial countries. It was asserted that this is because they consume commonly fish meat containing unsaturated fats and fats of marine mammals. Omega 3 (ω-3) fatty acids exist in fish (menhaden, mackerel, sardine, trout and salmon) as animal source and in eggs in a low rate. As herbal sources, linseed oil, rapeseed oil, soybean oil, walnut, pumpkin seed, hemp seed oil and green-leafy vegetables such as purslane, legume and rape seed are rich in ALA. ω-3 fatty acids cause to reduce serum triglyceride and very low density lipoprotein (VLDL) levels on people with hyperlipidemic depending on the dose. In Lyon Diet Heart Study, 19 patients underwent myocardial infarction were monitored in terms of angina, cardiac insufficiency, seizure, lung or peripheral emboli, sudden cardiac death and nonfatal myocardial infarction for 4 years, and it was claimed that 4:1 omega 6: omega 3 rate obtained study group was protective and preventive. Yet, it was reported in both Mediterranean Diet Heart Study and GISSI-Prevenzione study that high ALA added in diet and applying omega 3 in the dose of 850 mg/day on the patients underwent myocardial infarction reduced the cardiovascular mortality. Further, ω-3 fatty acids suppress 3-hydroxy 3-methylglutaryl coenzyme A activity being the prostaglandin of the cholesterol synthesis. On the other hand, ω-3 fatty acids increase the endothelial NO production by stimulating enzyme synthesis taking place in the formation of nitric oxide (NO) having anti-inflammatory and anti-atherosclerotic properties.

Essential fatty acid insufficiency may play a role in causing inflammatory diseases, neurologic, neuropsychiatric diseases, cancer and chronic diseases (such as diabetes, arthritis, colitis) and it is observed that adding said fatty acids in the treatment protocols exhibits positive effects thereon.

Because of the above-mentioned effects; due to the fact that linseed oil in the formulation contains a high herbal Omega-3 olinolenic acid (ALA, 18:3n-3), it can be both used as an omega 3 (ALA) source on those who cannot use fish oil, particularly on vegetarians and again can be used as an adjuvant in regulating blood lipid (fat) levels and in the treatment of cardiovascular system diseases on said patients. Linseed oil exhibits various pharmacological effects due to ALA in its structure. Linseed oil causes serum total cholesterol levels to decrease by 15 percent. Use of linseed oil containing highly ALA decreases serum total cholesterol, LDL (low density lipoprotein) levels on people with hyperlipidemia. Further, LDL cholesterol levels are decreased on postmenopausal women. This effect is resulted from SDG (secoisolariciresinol diglucoside) composition being precursor of lignans named as enterodiol and enterolactone that is in breast isolated from linseed, and 33 percent decrease in serum total cholesterol and 73 percent decrease in plaque have been observed. These effects of linseed oil clarify the effects inhibiting the development of atherosclerosis and the effects regulating the blood lipid levels. Thus, the formulation can be used as adjuvant to the regulation of blood lipid (fat) levels and in the treatment of cardiovascular system diseases.

The linseed oil may assist in decreasing thrombosis incidence since it has the antithrombotic effects and the effects reducing aggregation of thromboses Therefore, the formulation can be also used as adjuvant in the treatment of cardiovascular diseases.

Linseed oil exhibits antioxidant effects due to ALA therein. Furthermore, ALA has suppressor effects on interleukin, TNF (Tumor necrosis factor), leukotriene B4 and polymorphonuclear leukocytes. These facts can explain the effects of linseed oil that can inhibit the development of inflammation.

It is known that linseed oil can increase calcium absorption. Along with said effect, it has supportive effects on bone health.

The linseed oil not only is a good nutritional source but also improve bowel movement in adults due to fibrous structure therein. Defecation frequency and continuity are regulated on those who uses the linseed oil. Therefore, the formulation can be used as adjuvant to the treatment of chronic constipation and mild gastrointestinal problems.

Because of the above-mentioned properties; the linseed oil is very important for adults who cannot use fish oil, particularly vegetarians within the scope of the fact that it is supportive in terms of herbal Omega 3.

Content of capsule formulation:

Linseed oil as active substance and dl otocopherol, dl otocopheril acetate, glycerin, purified water and gelatin as inactive substances are employed in the formulation, dl otocopherol and otocopheril acetate serve as preservative substance. Dl otocopherol and dl otocopheril acetate are added into the formulation in the ratio of ppm. Bovine gelatin is used so as to maintain the integrity of content. As an alternative to gelatin, other animal-originated and herbal gelatins can be used.

As is stated on Table 1 ; there exists 42,050 percent of linseed oil, 0,004 percent of dl o tocopherol; 0,021 percent of dl a-tocopheril acetate; 10,831 percent of glycerin; 23,547 percent of water; 23,547 percent of gelatin by weight in the content.

Table 1. Capsule Content and Percentage by weight

Production method of the capsule:

Production steps of capsule formulation follows as below: linseed oil, one of the raw materials, is subjected to sieving process. After sieving process, if necessary, breaking process is carried out. After carrying out said process and obtained desired size, the linseed oil is sent to cold pressing unit. By means of cold pressing method, extraction of oil from raw material is performed. In said method, it is not exceeded over 55 °C. The oil obtained through cold pressing unit is held in the mixing and settling tanks before filtering process. Thus, possible particles can be easily separated by means of mixing and settling processes. the extracted oil is fed to the filter unit indoor and at room temperature after mixing and settling tanks. Particles in the oil are filtered in the filter unit if there are. After filtering process, dl o tocopherol and dl α-tocopheril acetate as preservative substance are added into the obtained oil. Thus, the mixture of which content is formed, is obtained.

On the other hand, the gelatin is prepared in the gelatin preparing unit so as to maintain the integrity of capsule while carrying out these processes. After forming the mixture and preparing the gelatin, capsules in desired dosages are prepared by means of sending it to capsule producing unit. Said capsules are gelatin capsules.

After prepared the capsule, drying process is carried out. Dried capsules are packaged.

Instruction of Use of Capsule:

Therapeutic Indications: The capsule is rich in alpha-linolenic acid (ALA) being Omega 3 that is herbal. It is adjuvant to the treatment of patients with chronic constipation. Further, it is adjuvant to the treatment of cardio-vascular system diseases, regulating some blood lipid (fat) levels and mild gastrointestinal problems. The capsule can be used as a herbal Omega 3 (ALA) source on those who cannot use fish oil, particularly on vegetarians.

Dosing and Administration Method:

• Dosing administration frequency and period: As long as doctor recommends otherwise; the capsules are taken orally as 2-4 capsules (1250-2500 mg/day at dose) per day by adults (aged 18 and older). The capsule can be taken as 1 -2 capsules (625-

1250 mg/day) by children over 12 years of age.

• Administration Method: The capsules should be swallowed along with enough water, preferably on a full stomach without crushing and chewing them in mouth.

Additional Information on Special Populations:

• Renal/liver failure: The capsules should not be used on the patients with Renal and liver failure because sufficient safety study has not been performed.

• Pediatric population: It is not recommended to use the capsules on the children under 12 years of age because sufficient safety study has not been performed thereon.

• Geriatric population: No sufficient safety study has been performed on elders.

However, it is thought that dose adjustment is not necessary. Contraindications:

- Active substance Linseed or any component that the capsule contains should not be used on those who have allergic thereto;

- On pregnancy and lactation,

- On the patients with liver and renal failure,

- On those who have an unspecified rectal bleeding,

- On those who have defecation problems subsequent to laxatives use,

- On these patients that are observed to have sudden changes in bowel habits for a period more than two weeks,

- On these patients that have bowel paralysis, megacolon and ileus.

Special Warnings and Precautions for Use Each capsule contains 0,161 g of glycerin. It is not expected to appear any side effects resulting from the glycerin at this ratio.

Daily 3 g dosing should not be exceeded on the patient on oral anticoagulation therapy. The capsule should be carefully used in the course of the treatment of hormone-related tumors due to its oestrogen ic effect.

It should be used on the patients with bowel paralysis and ileus under the doctor control.

It is recommended that the capsule use should be maintained by consulting with your doctor if it takes longer than 1 week.

Pregnancy and Lactation

• Pregnancy period: The capsule should not be used because no study related to this matter has been performed.

· Lactation period: The capsule should not be used in the course of lactation because its safety in the lactation is not proven.

Undesirable Effects: · Gastrointestinal Diseases: Commonly meteorism and rarely hypersensitivity reactions similar to anaphylaxis can be observed along with the use of capsule. Further, nausea, vomit and diarrhea can be observed, however its frequency is not known.

Apart from these, no undesirable effect is reported. Overdose:

There is no reported overdose related to linseed oil. The linseed oil orally taken can be tolerated well. However, it is reported that if the linseed itself is taken orally, abdominal problems such as overdose-related gas and bloating may occur. If any findings occur subsequent to overdose, the treatment should be symptomatic and supportive. There is no specific antidote and elimination enhancement method.

Storage Conditions: Shelf life of the product is determined as 2 years.

Said capsule of which content and production methods are mentioned above has been licensed by Republic of Turkey Ministry of Health authorities as "Traditional Herbal Medical Product". Said license bearing the number 2016/856 and the date 02.12.2016 is called as a 625 mg soft capsule by the name "ZADE VITAL CORVITAL". According to the above listed Indications and Traditional Herbal Medicine Product Directive, it is a Traditional Herbal Medicine Product LICENSED by Republic of Turkey Ministry of Health. There are products containing numerous synthetic chemicals licensed for indications specified in the market. However, there is no traditional herbal medical product having such an indication licensed by health authorities in this area.

In the majority of current applications; while production in poor hygiene conditions is matter of concern, the related formulation is produced under GMP (Good Manufacturing Practices) norms, which the Ministry of Health requests from the pharmaceutical factories.

As known, it is a very difficult operation to provide standardization in herbal products. Within the related formulation;

• In its seed; pesticide, aflatoxin, heavy metal and active substances analysis, microbiological controls have been conducted.

· In cold press oil; method development, validation and microbiological controls for the analysis of active substances have been conducted. • In design; which product?, which indication?, what dose?, what dosage form? have been calculated.

• In the preformulation; which active substance/which analysis of the auxiliary substance?, which microbiological controls?, which quality control parameters, which stability studies to be done have been considered and a system has been developed accordingly.

• In the stability studies; stability studies have been proven which proves the conformity to specified specifications in the course of the anticipated shelf life; 24 months study under 25°C ± 2, 60±5% humidity and 6 months study under 40°C ± 2, 75% ± 5 humidity have been carried out. Validations and data pertaining to analytical test methods and package specifications, interactions, analysis and control methods related to analytical test methods have been determined.

• In preparation of capsule base and internal materials, content determination (oil component analysis), some viscosity and optical appearance control, etc. tests have been conducted.

• In the production procedure; qualitative and quantitative content determination, in-process controls and content determination such as optical control, microbiological analyzes, quality control procedures such as such optical control have been applied. Also, HPLC analysis of the active component and product sample was made and fatty acid compositions were calculated. Further, the calibration tables of the active substance have been prepared.

The processes described above are very important details in terms of standardization of herbal products and are carried out in detail in this product. This product has been licensed and approved for pharmacodynamic properties of a Traditional Herbal Medicine product by a health authority such as the Ministry of Health. This product has been approved by a health authority, such as the Ministry of Health, by licensing the SPI (Short Product Information-Prospectus) and Ul (Use Instructions) of a Traditional Herbal Medical product. This product has been approved by a health authority such as the Ministry of Health by standardizing and licensing the usage and dosing of a Traditional Herbal Medicinal product. In this sense, the traditional herbal medical product licensed by the Ministry of Health, dosing of which is stated in writing in compliance with the clinical studies has been officialised by obtaining the approval of health authorities and presented to the service of world medicine. REFERENCES

• Allman, M. A., Pena, M. M. and Pang, D. Supplementation with flaxseed oil versus sunflowerseed oil in healthy young men consuming a low fat diet: effects on platelet composition and function. Eur J Clin Nutr 1995; 49(3): 169-78.

• Axelson, M., Sjovall, J., Gustafsson, B. E. and Setchell, K. D. Origin of lignans in mammals and identification of a precursor from plants. Nature 1982; 298(5875): 659-60.

• Bhatty, R. S. Compositional analysis of laboratory-prepared and commercial samples of linseed meal and of hull isolated from flax. Journal of the American Oil Chemists Society 1995; 67: 79-84.

• Bloedon, L. T. and Szapary, P. O. Flaxseed and cardiovascular risk. Nutr Rev 2004; 62(1 ):

18-27.

• Care, A. D. Goitrogenic properties of linseed. Nature 1954; 173(4395): 172-3.

• Caughey, G. E., Mantzioris, E., Gibson, R. A., Cleland, L. G. and James, M. J. The effect on human tumor necrosis factor alpha and interleukin 1 beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil. Am J Clin Nutr 1996; 63(1 ): 1 16-22.

• Cohen, S. L, Moore, A. M. and Ward, W. E. Flaxseed oil and inflammation-associated bone abnormalities in interleukin-10 knockout mice. J Nutr Biochem 2005a; 16(6): 368-74.

• Cohen, S. L. and Ward, W. E. Flaxseed oil and bone development in growing male and female mice. J Toxicol Environ Health A 2005b; 68(21 ): 1861-70.

• Cunnane, S. C, Hamadeh, M. J., Liede, A. C, Thompson, L. U., Wolever, T. M., et al.

Nutritional attributes of traditional flaxseed in healthy young adults. Am J Clin Nutr 1995; 61 (1 ): 62-8.

• Djousse, L, Arnett, D. K., Carr, J. J., Eckfeldt, J. H., Hopkins, P. N., et al. Dietary linolenic acid is inversely associated with calcified atherosclerotic plaque in the coronary arteries: the National Heart, Lung, and Blood Institute Family Heart Study. Circulation 2005; 1 1 1 (22): 2921 -6.

• Djousse, L, Pankow, J. S., Eckfeldt, J. H., Folsom, A. R., Hopkins, P. N., et al. Relation between dietary linolenic acid and coronary artery disease in the National Heart, Lung, and Blood Institute Family Heart Study. Am J Clin Nutr 2001 ; 74(5): 612-9.

• Dorrell, D. G. Distribution of fatty acids in the seed of flax. Journal of Plant Science 1970;

50: 71-75. • Dupasquier, C. M., Dibrov, E., Kneesh, A. L, Cheung, P. K., Lee, K. G., et al. Dietary flaxseed inhibits atherosclerosis in the LDL receptor-deficient mouse in part through antiproliferative and anti-inflammatory actions. Am J Physiol Heart Circ Physiol 2007; 293(4): H2394-402.

· Dupasquier, C. M., Weber, A. M., Ander, B. P., Rampersad, P. P., Steigerwald, S., et al.

Effects of dietary flaxseed on vascular contractile function and atherosclerosis during prolonged hypercholesterolemia in rabbits. Am J Physiol Heart Circ Physiol 2006; 291 (6): H2987-96.

• EMEA (2006). ASSESSMENT REPORT ON LINUM USITATISSIMUM L, SEMEN.

· Francois, C. A., Connor, S. L., Bolewicz, L. C. and Connor, W. E. Supplementing lactating women with flaxseed oil does not increase docosahexaenoic acid in their milk. Am J Clin Nutr 2003; 77(1 ): 226-33.

• Freeman, T. P. S. o. f. I. F. i. H. N. (1995). Structure of flaxseed. . Flaxseed in Human Nutrition. Cunnane, S. C. a. T., L.H. Champaign, Illinois, AOCS Press: 1 1-25.

· Gebauer, S. K., Psota, T. L, Harris, W. S. and Kris-Etherton, P. M. n-3 fatty acid dietary recommendations and food sources to achieve essentiality and cardiovascular benefits. Am J Clin Nutr 2006; 83(6 Suppl): 1526S-1535S.

• Gopalan, C, Ramasastri, B. V. and Subramanian, S. C. (2007). Nutritive Value of Indian Foods. Hyderabad, India, National Institute of Nutrition.

· Harper, C. R., Edwards, M. C. and Jacobson, T. A. Flaxseed oil supplementation does not affect plasma lipoprotein concentration or particle size in human subjects. J Nutr 2006; 136(1 1 ): 2844-8.

• Hornstra, G., Haddeman, E. and ten Hoor, F. Fish oils, prostaglandins, and arterial thrombosis. Lancet 1979; 2(8151 ): 1080.

· KONUKOGLU, Dildar. Properties, functions of omega-3 and omega-6 fatty acids and relationship between essential fatty acids and cardiovascular diseases. Turkish Journal of Family Practice, 2008, 12.3: 121-129.

• Lee, P. and Prasad, K. Effects of flaxseed oil on serum lipids and atherosclerosis in hypercholesterolemic rabbits. J Cardiovasc Pharmacol Ther 2003; 8(3): 227-35.

· Madhusudhan, B., Wiesenborn, D., Schwarz, J., Tostenson., K. and Gillespie, J. A dry mechanical method for concentrating the lignan secoisolariciresinol diglucoside in flaxseed. Lebensmittel-Wissenschaft und Technologie 2000; 33: 268-275. • Nordoey, A. The Influence of Saturated Fat, Cholesterol, Corn Oil and Linseed Oil on the Adp-lnduced Platelet Adhesiveness in the Rat. Thromb Diath Haemorrh 1965; 13: 543-9.

• Odeleye, O. E. and Watson, R. R. Health implications of the n-3 fatty acids. Am J Clin Nutr 1991 ; 53(1 ): 177-8.

· Pan, A., Yu, D., Demark-Wahnefried, W., Franco, O. H. and Lin, X. Meta-analysis of the effects of flaxseed interventions on blood lipids. Am J Clin Nutr 2009; 90(2): 288-97.

• Patade, A., Devareddy, L., Lucas, E. A., Korlagunta, K., Daggy, B. P., et al. Flaxseed reduces total and LDL cholesterol concentrations in Native American postmenopausal women. J Womens Health (Larchmt) 2008; 17(3): 355-66. · Ramos, C. I., Andrade de Lima, A. F., Grilli, D. G. and Cuppari, L. The Short-Term Effects of Olive Oil and Flaxseed Oil for the Treatment of Constipation in Hemodialysis Patients. J Ren Nutr 2014.

• Richter, W. O., Jacob, B. G., Ritter, M. M. and Schwandt, P. Treatment of primary chylomicronemia due to familial hypertriglyceridemia by omega-3 fatty acids. Metabolism 1992; 41 (10): 1 100-5.

• Sacks, F. M., Stone, P. H., Gibson, C. M., Silverman, D. I., Rosner, B., et al. Controlled trial of fish oil for regression of human coronary atherosclerosis. HARP Research Group. J Am Coll Cardiol 1995; 25(7): 1492-8.

• Simopoulos, A. P. Essential fatty acids in health and chronic disease. Am J Clin Nutr 1999;

70(3 Suppl): 560S-569S.

• Simopoulos, A. P. Human requirement for N-3 polyunsaturated fatty acids. Poult Sci 2000;

79(7): 961-70.

• Singh, K. K., Mridula, D., Rehal, J. and Barnwal, P. Flaxseed: a potential source of food, feed and fiber. Crit Rev Food Sci Nutr 201 1 ; 51 (3): 210-22.

· Tzen, J., Cao, Y., Laurent, P., Ratnayake, C. and Huang, A. Lipids, Proteins, and Structure of Seed Oil Bodies from Diverse Species. Plant Physiol 1993; 101 (1 ): 267-276.

• Watkins, B. A., Li, Y., Lippman, H. E. and Seifert, M. F. Omega-3 polyunsaturated fatty acids and skeletal health. Exp Biol Med (Maywood) 2001 ; 226(6): 485-97.

• Weiler, H. A., Kovacs, H., Nitschmann, E., Bankovic-Calic, N., Aukema, H., et al. Feeding flaxseed oil but not secoisolariciresinol diglucoside results in higher bone mass in healthy rats and rats with kidney disease. Prostaglandins Leukot Essent Fatty Acids 2007; 76(5): 269-75. • Weiss, L. A., Barrett-Connor, E. and von Muhlen, D. Ratio of n-6 to n-3 fatty acids and bone mineral density in older adults: the Rancho Bernardo Study. Am J Clin Nutr 2005; 81 (4): 934-8.

• Zeybek U., Haksel M., Turkiye'de ve Dijnyada Onemli Tibbi Bitkiler ve Kullanimlari, 201 1 ;

1 16-121

• Williams, C. M. and Burdge, G. Long-chain n-3 PUFA: plant v. marine sources. Proc Nutr Soc 2006; 65(1 ): 42-50.

• Xu, J., Zhou, X., Chen, C, Deng, Q., Huang, Q., et al. Laxative effects of partially defatted flaxseed meal on normal and experimental constipated mice. BMC Complement Altern Med 2012; 12: 14.