Use of saffron and/or safranal and/or crocin and/or picrocrocin and/or derivatives thereof as a sateity agent for treatment of obesity

Abstract

Use of saffron and its active ingredients, such as safranal and/or picrocrocin and/or crocin and/or derivatives thereof, for the production of an active satiation agent for the treatment of problems of overweight.

Claims

1. A method of treating an overweight or obese subject, comprising: orally administering to said subject a composition containing an effective amount of saffron stigmata solvent extract including a combination of picrocrocin, safranal and crocin, wherein said saffron stigmata solvent extract is obtained by: a.) isolating saffron stigmata; and b.) extracting the isolated saffron stigmata with a solvent, and wherein the effective amount of saffron stigmata solvent extract reduces fat-body mass while keeping lean-body mass and muscular mass stable.

2. The method according to claim 1, wherein, the composition further comprises at least one pharmaceutically and/or dietarily acceptable excipient or vehicle in the composition.

3. The method according to claim 1, wherein, the composition comprises a dose of the saffron stigmata solvent extract in an amount ranging from 60 mg to 150 mg.

4. The method according to claim 1, wherein, the composition is a solid form or a liquid form and the saffron stigmata extract is present in an amount of between 0.01 and 50% relative to the total weight of the solid form or relative to the volume of the liquid form.

5. The method according to claim 4, wherein the saffron stigmata extract is present in an amount of between 0.05 and 20% relative to the total weight of the solid form or relative to the volume of the liquid form.

6. The method according to claim 5, wherein the saffron stigmata extract is present in an amount of between 0.1 and 10% relative to the total weight of the solid form or relative to the volume of the liquid form.

7. The method according to claim 1, wherein the composition is in a form selected from the group consisting of a solution or an aqueous suspension in a glass ampoule, a spray, a beverage, a form suitable for a dropper bottle, one or more coated or uncoated tablets, one or more gel capsules, one or more capsules, powder, one or more effervescent tablets, granules, one or more strips, and one or more lozenges.

8. The method according to claim 1, wherein the saffron stigmata extract is extracted from saffron stigmata by hydrodistillation followed by liquid/liquid extraction.

9. The method according to claim 8, wherein the liquid/liquid extraction utilizes water and a solvent selected from the group consisting of ethanol, ethyl acetate, hexane, petroleum ether, acetone or methanol.

10. The method according to claim 9, wherein the liquid/liquid extraction utilizes water and ethanol.

11. The method according to claim 1, wherein the saffron stigmata extract includes a combination of picrocrocin, safranal and crocin.

12. The method according to claim 11, wherein said saffron stigmata is obtained from Safran Crocus sativus L.

13. A method of reducing or controlling caloric intake of calories consumed on a daily basis to regulate body weight in a subject in need thereof, comprising: orally administering to said subject a composition containing an effective amount of saffron stigmata solvent extract including a combination of picrocrocin, safranal and crocin, wherein said saffron stigmata solvent extract is obtained by: a.) isolating saffron stigmata; and b.) extracting the isolated saffron stigmata with a solvent, and wherein the effective amount of saffron stigmata solvent extract reduces hunger sensation, and wherein said subject is overweight or obese.

Description

(1) The invention will be better understood, and other objects, details, characteristics and advantages of the latter will emerge more clearly during the following detailed explanatory description of embodiments of the invention that are provided by way of purely illustrative and non-limiting examples, with reference to the accompanying figures, in which:

(2) FIG. 1 shows the mean changes in the sensation of hunger before the meal of 16 subjects having either received a placebo treatment for 28 days (group 1), or a composition that comprises a saffron stigmata extract according to this invention (group 2) between the end (day 28) and the beginning (day 0) of the experiment;

(3) FIG. 2 shows the mean changes of the sensation of hunger of group 1 and group 2 at the end of the meal during the experiment from day 0 to day 28;

(4) FIG. 3 shows the reduction in body mass by weight, by fat-body mass and by lean-body mass of group 1 and group 2 from day 0 to day 28.

(5) As indicated above, it was found, surprisingly enough, that the active ingredients of saffron, such as safranal (2,6,6-trimethyl-1,3-cyclohexadiene-1-carboxaldehdye) of the following formula:

(6) ##STR00001##
picrocrocin (4-(beta-D-glucopyranosyloxy)-2,6,6-trimethyl-1-cyclohexane-1-carboxaldehyde) and crocin (bis(6-O-beta-D-glucopyranosyl-beta-D-glycopyranosyl)8,8′diapo-psi,psi-carotenedioate) have proven effective in the treatment of weight problems of overweight individuals.

(7) According to the World Health Organization, a person is overweight when his body mass index (BMI), which is equal to the weight in kg/(size in meters),.sup.2 is between 25.0 and 29.9. If this index is above 30.0, the person is considered to be obese. This index thus makes it possible to estimate the nutritional state of a person and to know whether this person has excess fat in the body.

(8) The active ingredients of saffron are extracted from a plant, the Safran Crocus sativus L., and more particularly stigmata of this plant. It is also possible to extract these active ingredients from other plants, such as Yucca periculosa, Ditaxis heterantha, Cuminum cyminum, Gardenia jasminoides or Camelia Sinensis.

(9) The process that is used is known to one skilled in the art. It involves a first hydrodistillation stage, followed next by a second liquid/liquid extraction stage.

(10) The hydrodistillation is used to extract the essential oil from the water-immiscible plant. The essence is entrained by the vapor in the form of a heteroazeotrope. The boiling point of the mixture is less than 100°. A mixture of organic substances and water is thus recovered. It is also possible to use pulsed vacuum microwave hydrodistillation (VMHD).

(11) The liquid/liquid extraction is carried out by close contact of the solvent with the solution in equipment that is designed to mix the two phases (ampoules, columns, mixers). The separation of the phases is achieved by gravimetric decanting or centrifuging. The solvents that are used for the extraction are water and ethanol or else ethyl acetate, hexane, petroleum ether, acetone, or methanol.

(12) The extraction of safranal, as well as other natural active ingredients of saffron, can also be done using supercritical CO.sub.2, ideally at 100° C. and 20 MPa.

(13) A syrupy liquid product, deep garnet red in color with iridescent reflections, is obtained at ambient temperature. It may also come in the form of powder after the water evaporates after, for example, oven-drying or atomization.

(14) The thus extracted active ingredients: picrocrocin, safranal, and crocin also meet the ISO 3632 standards.

(15) The satiation agent comprises a content of safranal and/or picrocrocin and/or crocin and/or derivatives thereof between 0.01 and 50%—but preferably a content of between 0.1 and 10%, and more particularly from 1 to 5%—by weight, relative to the total weight of the satiation agent when the latter is in solid or liquid form.

(16) Other pharmaceutically and/or dietarily acceptable agents can be added to the satiation agent, such as bulking agents, fluidizing agents, natural extracts, vitamins, minerals, oligo elements, amino acids, fatty acids, anti-agglomerates, natural oils, aromas, dyes, acidifying agents, thickeners, preservatives and sweeteners.

(17) The feedstocks are advantageously microcrystalline cellulose, potato maltodextrin, and magnesium lactate.

(18) The thickener that is preferably used is potato starch, hydroxypropylmethyl cellulose, citrus pectin, guar gum, carob, agar-agar, konjac, hydrogenated oils, or beeswax.

(19) The fluidizing agents can be magnesium silicate, magnesium stearate, and colloidal silica.

(20) The anti-agglomerates are those usually used in the food industry, such as magnesium stearate and colloidal silica.

(21) The vitamins are selected from among, i.a., vitamins C, E, B.sub.6, B.sub.1, B.sub.2 and B.sub.3.

(22) The natural extracts in addition to the saffron stigmata extract can be extracts from green tea, cinnamon, guarana, Yerba Mate, fennel, queen of the meadow, corn, sage, bee balm, and caffeine.

(23) As acidifying agent, citric acid can be used in the composition of the satiation agent.

(24) The stabilizers used in the production of the satiation agent are those usually used in the agricultural industry, such as sorbitol.

(25) The aromas that can be used are varied, such as the aroma of coffee, lemon, apple, chocolate, vanilla, and strawberry.

(26) The sweeteners that are used are, i.a., xylitol, aspartame, glucose syrup, fructo-oligosaccharide syrup, maltitol in powder or in syrup form, acesulfame potassium, fructo-oligosaccharide, and sodium cyclamate.

(27) Fatty acids can also be added to the satiation agent, such as omega 3, omega 6, Galacto, lipids, but also minerals: chromium, boron, magnesium, calcium, iron, molybdenum and amino acids, such as tryptophan, leucine, arginine and glycine.

(28) Preservatives are useful so that the satiation agent is preserved over time. The preservatives that are used can be, for example, potassium sorbate, parabenes, sodium benzoate, or ascorbyl palmitate (anti-oxidant).

(29) All of these compounds in no way limit pharmaceutically and dietarily acceptable agents that can be added to the composition of the satiation agent for the treatment of overweight.

(30) The satiation agent that comprises, i.a., the active ingredients of saffron has the advantage of being easily usable and not restrictive. In addition, as the results below indicate, the content of active ingredients of saffron and more particularly safranal does not need to be very high to achieve the desired effect, i.e., an effect of satiation and therefore a very quick loss of weight of fat-body mass and in the circumference of the waist and hips. In contrast to satiation agents of the prior art, the saffron stigmata extract picked up in an ampoule or in a tablet does not have an odor, texture or taste that is disagreeable to the user. In addition, it is enough to take one or two daily doses, most often at breakfast and/or lunch so as to control or reduce the intake of calories during the day. Furthermore, as indicated above, the saffron stigmata extract can be combined with other active ingredients, such as vitamins, without this interacting with the effectiveness of the active ingredient. Finally, the satiation agent that is thus obtained is stable during its production and its storage.

(31) The use of the saffron extract to help the overweight individual reduce or control his daily calorie intake and/or to control his body weight and/or his physical appearance can be done in different ways. Actually, this active ingredient can be very simply added to any commonly consumed food (beverages, prepared meals, . . . ) or else be in the form of a dietary addition, dietary products, a medical device, or medications. In this latter case, the concentration of saffron stigmata extract within the medication will be increased so that the satiation effect is felt more strongly. For example, a dose of saffron stigmata extract ranging from 60 to 150 mg per medication will be suitable in particular for persons suffering from the disease of obesity.

(32) The following formulations (Tables 1 to 8) are provided by way of purely illustrative examples.

(33) 1) Size 12 Film-Coated Oval Tablet

(34) TABLE-US-00001 TABLE 1 Materials Dose in mg UNCOATED TABLET: Bulking agent: microcrystalline cellulose 150.00 Magnesium lactate 254.00 Saffron stigmata extract >2% safranal 30.00 Vitamin B6 2.00 Bee balm extract 10.00 Fluidizing agent: magnesium silicate 6.00 Potato starch 6.00 Magnesium stearate 5.00 Colloidal silica 2.00 TOTAL UNCOATED 465.00 FILM-COATING 18.60 Sepifilm LP014 11.16 Sepisperse dry 5221 7.44 TOTAL FILM-COATED 502.20

(35) 2) Size 1 Gel Capsule, Coating of Vegetable Origin

(36) TABLE-US-00002 TABLE 2 Ingredients Dose (mg) Bulking agent: potato maltodextrin 80.00 HPMC gel capsule 80.00 EGCG-rich green tea extract 60.00 Cinnamon bark extract 50.00 Saffron stigmata extract >2% safranal 20.00 Saffron stigmata powder 20.00 Vitamin B3 18.00 Chromium chloride 0.08 Vitamin E in 50% powder form (calculation 20.00 according to alpha-tocopherol LD 50%) Bulking agent: MCC cellulose 10.00 Anti-agglomerate: magnesium stearate 10.00 Fluidizing agent: colloidal silica 5.00 TOTAL 373.08

(37) 3) Soft Capsule

(38) TABLE-US-00003 TABLE 3 Ingredients mg/Capsule Wild fish oil with 30% omega 3 polyunsaturated 577.00 fatty acids 18% EPA, 12% DHA Saffron extract >2% safranal 40.00 Fish gelatin 130.07 Glycerol 61.00 Lemon aroma 1.93 TOTAL 810.00

(39) 4) Effervescent Tablet

(40) TABLE-US-00004 TABLE 4 mg of Ingredients Ingredient/Tablet Acidifying agent: citric acid (E330) 1070.00 Sodium bicarbonate 727.000 Saffron stigmata extract >2% safranal 60.000 20-30% catechin green tea leaf extract 220.000 Stabilizing agent: sorbitol 146.000 Vitamin C 72.000 12% guarana caffeine extract 70.000 Green lemon powder aroma 70.000 8% yerba-mate caffeine extract 42.500 Sweetener: aspartame 30.000 Yellow dye: tartrazine (E102) 0.210 Chromium chloride (19% chromium) 0.025 TOTAL 2507.735

(41) 5) 10 ml Glass Ampoule

(42) TABLE-US-00005 TABLE 5 Ingredients g/Ampoule Aqueous extract concentrated by hot 9.97 soaking of a mixture of plants: Fennel - bulb - 20% Queen of the meadow - flowered head 20% Corn - stigmata - 20% Green tea - leaf - 20% Guarana - nut - 20% Saffron stigmata extract >2% safranal 0.03 TOTAL 10.00

(43) 6) Beverage

(44) TABLE-US-00006 TABLE 6 Ingredients mg/50 ml Water Sufficient quantity for 50 ml Liquid saffron stigmata extract >2% safranal 50.00 Coffee aroma 146.40 Citric acid 111.44 Natural caffeine of coffee 96.00 Green tea leaf extract 51.00 Potassium sorbate 50.00 Sodium benzoate 50.00 Acesulfame potassium 3.76 Sodium cyclamate 3.76 TOTAL for 50 ml 50,000.00

(45) 7) Squared

(46) TABLE-US-00007 TABLE 7 Ingredients g/Squared Citrus pectin 3.600 Guar gum 2.258 Glucose syrup 1.660 Fructo-oligosaccharide 0.640 Maltitol syrup 0.670 Maltitol powder 0.500 Apple aroma 0.200 Powdered glycerol 0.190 TCM oil 0.136 Water 0.100 Saffron stigmata liquid extract >2% safranal 0.02 Citric acid 0.011 Soybean tocopherol (67-75%) 0.003 Ascorbyl palmitate 0.001 TOTAL/SQUARED 10.000

(47) 8) Granule

(48) TABLE-US-00008 TABLE 8 g/per 100 g Ingredients of Granules Citrus pectin 75.00 Microcrystalline cellulose 20.00 Sorbitol 4.97 Saffron stigmata extract >2% safranal 0.03 TOTAL 100.00

(49) Experimental tests have been performed so as to demonstrate the various actions of the satiation agent according to this invention:

(50) Dosage 1

(51) The effectiveness of the satiation agent that contains safranal has been tested on a panel of four persons for a duration of 20 days. These four persons have in no way modified their dietary habits nor their lifestyle during the period of the experiment. They have ingested 30 mg of saffron extract in a single dose daily at breakfast.

(52) They felt a very slight reduction of hunger at lunch and dinner. A loss of weight on average of 1 kg, as well as a reduction in the circumference of the waist by 1.2 cm and in the circumference of the hip by 0.5 cm for each person have been noted.

(53) This experimental test shows the surprising and unexpected effect of safranal on the regulation of hunger, whereas the saffron is usually used as an aroma or as a softener of the bitterness of certain foods.

(54) Dosage 2: Double-Blind Vs. Placebo Clinical Test

(55) A second clinical study was conducted so as to demonstrate the satiating effect of the active ingredients of saffron in 16 female subjects suffering from compulsive nibbling. The study was conducted over a period of four weeks. The healthy women were slightly overweight, i.e., a BMI of between 22 and 30.

(56) A randomization method was implemented so as to divide these 16 subjects into two groups of 8. A first group (group 1) took 2 placebo gel capsules each morning and mid-day, while the second group (group 2) took two gel capsules/day, also in the morning and at mid-day, of a composition containing a saffron stigmata extract, whereby the two groups each received dietary counseling.

(57) The composition that contains a saffron extract that was tested on group 2 comprised, i.a., gel capsules of 267 mg+/−10%; 90 mg of saffron stigmata extract stabilized on a microcrystalline cellulose substrate, and colloidal silica; and fatty acids rich in safranal, crocin and picrococin; 100 mg of maltodextrin; and 2 mg of magnesium stearate. More particularly, each gel capsule contained 0.9% picrocrocin (or 2.40 mg/gel capsule), 0.4% safranal (or 1.07 mg/gel capsule), and 0.3% crocin (or 0.80 mg/gel capsule).

(58) Various indicators of effectiveness, such as measurements of weight, fat-body mass, hydric mass and BMI, have been measured, accompanied by a self-evaluation of the sensation of hunger, amounts consumed during, between and after meals. This self-evaluation of the sensation of hunger was measured by means of a subjective evaluation established by a digital visual method known to one skilled in the art.

(59) First, as FIG. 1—which shows the demonstration of the sensation of hunger before meals between day 28 and day 0—illustrates, the subjects of group 2 felt a greater reduction of the sensation of hunger before lunch, continuing until dinner, while group 1 (placebo) felt an increase in the sensation of hunger.

(60) At the end of the meal, as FIG. 2 illustrates, group 2 has not felt a sensation of hunger at the end of the meal (no variations), while group 1 (placebo) felt an increase from day 0 to day 28.

(61) According to FIG. 3, which shows the reduction in body mass from day 0 to day 28, after 28 days of treatment of 2 gel capsules per day, one in the morning and one at mid-day, a loss of weight on average of −1.28 kg was noted in group 2 relative to a loss of weight on average of −0.50 kg within group 1; a loss of fat-body mass on average of −1.28 kg in group 2 relative to the placebo group 1 of −0.17 kg; and a loss of lean-body mass of 0 kg within group 2 relative to the placebo group that lost on average −0.33 kg.

(62) Thus, 100% of the women receiving gel capsules comprising the active ingredients of saffron, i.e., a composition according to this invention, attested to having perceived a reduction in their sensation of hunger at the time of lunch and dinner and declared having reduced their food intake during the study. In contrast, none of the women taking the placebo noted a reduction in their food intake.

(63) In addition, 25% of the women receiving the gel capsules according to this invention characterized their food intake as “much reduced” during the study.

(64) Furthermore, the most significant loss of weight (−3.5 kg) was measured in the woman who believed her food intake to be “much reduced” during the study.

(65) The reduction of the food intake in group 2 is thus connected to an increase in the sensation of fullness that, in contrast to the cognitive restriction, does not induce a sensation of frustration that increases the risk for regaining weight.

(66) In comparison to the placebo group (group 1), the supplementation with gel capsules containing a saffron extract and consequently safranal, crocin, and picrocrocin, promoted the loss of weight, the loss of physical fat-body mass while keeping the lean-body mass and therefore the muscular mass stable.

(67) The mean loss of weight is certainly modest, but it is probably clinically significant because of the absence of an associated low-calorie regimen, whereby the subjects have only received dietary counseling (for example, nibbling had been discouraged but not forbidden), and the short duration of the study relative to this problem.

(68) Within the scope of a low-calorie regimen: reducing the sensation of restriction could improve compliance with the regimen and associated loss of weight, as well as to reduce the risk of rebound, often linked to a slackening following the regimen period.

(69) In the long term (without an associated regimen), improving the ability of a subject to manage his dietary behavior can prove advantageous when he knows that avoiding an excess of 20 Kcal/day (or the equivalent of a piece of sugar) can prevent a weight gain of 1 kg of fat-body mass in 1 year (Ancellin, R., “Glucides et santé: état des lieux, évaluations et recommandations [Saccharides and Health: Assessments, Evaluations and Recommendations],” 2003).