A COMPOSITION CONTAINING AN EXTRACT OBTAINED BY A WATERCONTAINING ORGANIC SOLVENT, AND A PROCESS FOR PREPARING THE SAME

Abstract: A composition containing an extract obtained by a water-containing organic solvent, comprising: (a) an extract containing active ingredients almost insoluble in water, said extract being obtained from plant tissues by extraction with a water-containing organic solvent, and at least one of (b) a water-soluble high-molecular substance and (c) a fatty acid ester of polyglycerol. This composition can be formulated into preparations not containing ethanol, i.e. solid preparations including tablets, granules, and powder preparations, or non-­ alcoholic liquid preparations such as drinkable preparations and syrups, in such a way that the extract contained is well absorbed through the digestive tract.

Description: This invention relates to a composition containing an extract obtained by extraction with a water-containing organic solvent, which has a high bioavailability and can be formulated into various preparations including tablets, granules, powder preparations, drinkable preparations, and syrups, and also to a process for preparing said composition. In France, Germany, etc., remedial preparations containing, as active ingredient, an extract obtained from plant tissues such as ginkgo leaves by extraction with a water-containing organic solvent have hitherto been used widely for the purpose of improving metabolism of cerebral circulation. It is known that the above extract obtained by extraction with a water-containing organic solvent has such pharmacological actions as relaxation of smooth muscles of blood vessels contracted owing to stress, tension, etc., thereby reducing resistance in peripheral arteries and cerebral circulatory system; and vasodilation and increasing of blood flow velocity, thereby increasing blood flow in the pacillary tissues. Said extract is also known to have a pharmacological action of lowering viscosity of the blood in the arteries and veins, thereby smoothing the blood flow, with the result that disorder in the peripheral blood vessels and cerebral blood vessels is improved. In order to administer the above extract obtained by extraction with a water-containing organic solvent to elderly people, or minors, or to patients with liver diseases, it is desirable to formulate it into preparations not containing ethanol. That is to say, it is necessary to formulate it into solid preparations including tablets, granules, and powder preparations, or liquid preparations such as drinkable preparations and syrups, in such a way that no ethanol is used, yet the extract contained is well absorbed through the digestive tract. However, the above-mentioned extract obtained by extraction with a water-containing organic solvent has such property that it is soluble in water-containing organic solvents such as water-containing acetone, water-containing methyl ethyl ketone, water-containing methanol and water-containing ethanol, but practically insoluble in water. Thus, it is possible to formulate the extract into liquid preparations such as tinctures, spirits, and elixirs, as ethanol is used in these preparations as one of the solvents. However, it has been impossible to formulate it into non-alcoholic liquid preparations such as non-alcoholic drinkable preparations and syrups. When the above extract obtained by extraction with a water-containing organic solvent is used in easy-to-take solid preparations such as tablets, granules and powder preparations, the absorption becomes poor. The reason is that, to have the active ingredients of the extract absorbed into the human body, it is necessary for the active ingredients to be dissolved or emulsified in the digestive tract. In making this invention, the above problems were taken into consideration, and thus the purpose of this invention is to provide a composition which contains an extract obtained by extraction with a water-containing organic solvent and which has a high bioavailability and can be formulated into various forms of preparations including tablets, granules, powder preparations, drinkable preparations and syrups. Another purpose of this invention is to provide a process for preparing said composition containing an extract obtained by extraction with a water-containing organic solvent. The Composition of this invention is one containing an extract obtained from Gingko leaves by a water-containing organic solvent. In the extract from Gingko leaves, there are contained flavone glycoside, biflavone as active ingredients almost insoluble in water. Further, the composition containes gum arabic or guar gum. The above mentioned extracts are obtained from said Gingko leaves by extraction in a conventional manner with a water-containing solvent such as water-containing methanol, water-containing ethanol, water-containing acetone, and water-containing methyl ethyl ketone, and from which the water-containing solvent has been distilled off. In addition, the composition of the invention preferably comprises a fatty acid ester of polyglycerol such as the monostearate, monooleate or monolaurate of decaglycerin; monostearate, monooleate or monolaurate of hexaglycerin; and monolaurate of tetraglycerin, provided HLB of the ester is 10 or higher. To prepare the composition of this invention, an extract obtained as above by extraction with a water-containing organic solvent, and gum arabic or guar gum and possibly a fatty acid ester of polyglycerol are mixed first. When, in this process, the two (or three) components are first dissolved and evenly mixed in a water-containing lower alcohol, and then the solvent (water-containing lower alcohol) is distilled off, followed by drying, there is obtained a composition whose active ingredients have an improved solubility and a very high bioavailability. As a water-containing lower alcohol to be used in this process, it is desirable to use an aqueous solution of alcohol with 20 - 45 v/v % content of lower alcohol. As lower alcohol, there are exemplified methanol, ethanol, isopropanol, etc., of which ethanol is especially preferable. Concrete methods of preparation include the following: (1) An extract obtained by extraction with a water-containing organic solvent is dissolved in a water-containing lower alcohol. To this are added gum arabic or guar gum and a fatty acid ester of polyglycerol, and then water to make a solution or an emulsion. After that, the solvent in the solution (or emulsion) is distilled off by a publicly-known method such as spray-drying method or ventilation-drying method. (2) A method in which the extract obtained by extraction with a water-containing organic solvent is structurally modified by coating the surface of the extract with gum arabic or guar gum and a fatty acid ester of polyglycerol with use of a surface modification apparatus for fine particle. (3) Gum arabic or guar gum and a fatty acid ester of polyglycerol, and water are added to a solution of an extract obtained by extraction with a water-containing organic solvent in a water containing lower alcohol. Then, the solution (or emulsion) obtained is adsorbed to an excipient or excipients in a fluidized bed, and then dried. Next, the mixture, prepared as above, of an extract obtained by extraction with a water-containing organic solvent, and gum arabic or guar gum and possibly a fatty acid ester of polyglycerol is mixed with a publicly-known excipient or excipients, and then a binder is added. The mixture thus prepared is then granulated in a fluidized bed, whereby granules of the composition of this invention are obtained. The granules can also be tableted after adding a suitable lubricant. Gum arabic or guar gum may be used with or without a fatty acid ester of polyglycerol but when used together, better results are obtained in many cases as compared with the use of only gum arabic or guar gum. The solid preparations, made as above, of the composition of this invention are soluble in water or dispersible in water in fine particles, thereby making it easy to be absorbed into the digestive tract, and as a result, a bioavailability equal to that of conventional alcohol-containing liquid preparations is obtained. In addition to excipient, binder, lubricant, and disintegrator, there may be added to the composition of this invention other additives generally accepted for foods and pharmaceuticals. These include sweetener and perfume which are used to improve taste, and surfactant used to stabilize dispersion. The product may also be coated. The composition of this invention can also be dissolved or emulsified in water without the use of ethanol or with the use of a very small amount (1%) of ethanol, thereby making it possible to formulate it into liquid preparations having a good absorbency in the digestive tract. To the liquid preparations thus made, there may also be added sweeteners such as saccharose, glucose, sorbitol, maltitol, stevia, and aspartame, and preservatives such as sodium benzoate, and p-hydroxy benzoate. The following Examples and accompanying drawings are given to further illustrate this invention. Fig. 1 shows, by graph, the results of dissolution tests of the compositions each containing an extract obtained with a water-containing organic solvent, which are shown in Examples of this invention, Example 1: The following Compositions 1 - 5, with components as mentioned below, each containing an extract obtained by extraction with a water-containing organic solvent were prepared: (1) Composition 1 , containing an extract obtained by extraction with a water-containing organic solvent: In 1 l of a water-containing ethanol with 30 v/v % alcohol content, were dissolved 100 g of an extract obtained from ginkgo leaves by extraction with a water-containing organic solvent, and 100 g of gum arabic, and after that, the solvent in the solution was distilled off the spray-drying method, whereby a composition in powder form was obtained. (2) Composition 2 , containing an extract obtained by extraction with a water-containing organic solvent: In 1 l of a water-containing ethanol with 30 v/v % alcohol content, were dissolved 100 g of an extract obtained from Gingko leaves by extraction with a water-containing organic solvent and 100 g of guar gum, and after that, the solution was dried by the ventilation-drying method. The resultant lumps were crushed by hammer mill, whereby a compostion in powder form was obtained. (3) Composition 3 , containing an extract obtained by extraction with a water-containing organic solvent: A mixture of 100 g of an extract from ginkgo leaves by extraction with a water-containing organic solvent and 200 ml of a 10 v/v % aqueous solution of gum arabic was subjected to fine disintegrating and coating with a surface modification apparatus for fine particle, to obtain a composition in powder form. (4) Composition 4 , containing an extract obtained by extraction with a water-containing organic solvent: A mixture of the solution in water-containing ethanol prepared in (1) above and 1.8 kg of lactose was granulated in a fluidized bed, whereby a composition in granules was obtained. By adding a suitable quantity of a lubricant, the granules could be made into tablets by the direct tableting method. (5) Composition 5 , containing an extract obtained by extraction with a water-containing organic solvent: The procedure of (1) above (Composition 1) was followed except for using 80 g of gum arabic and 50 g of decaglycerin monooleate in place of 100 g of gum arabic. Next, to 20 mg each of above Compositions 1 - 3, and 5 were added 375 mg of lactose, and 5 mg of a fatty acid ester of sucrose as lubricant. Then, each mixture was tableted, whereby 400 mg of tablets was obtained respectively. As for Composition 4, it was tableted, without adding anything, to obtain 400 mg of tablets. (6) Comparison Example 1 : To 10 mg of an extract obtained from ginkgo leaves by extraction with a water-containing organic solvent were added 385 mg of lactose and 5 mg of a fatty acid ester of sucrose, and the mixture was tableted to obtain 400 mg of tablets. (7) Comparison Example 2 : An extract obtained from ginkgo leaves by extraction with a water-containing organic solvent was tableted, without adding anything, to obtain 400 mg of tablets. However, the tablets obtained were not soluble in water. Dissolution test A dissolution test was performed, by the method and with the apparatus described in the Japanese Pharmacopoeia, for each lot of tablets obtained from Compositions 1 - 3, and 5, and Comparison Example 1. In this test, the paddle method was used, under the following conditions: Purified water 500 ml, 3 tab., wavelength (λ max) 266 nm, number of revolutions of spindle 100 rpm, and temperature of water 37 °C. Results obtained are shown in Fig. 1. As is clear from these results, the tablets from Comparison Example 1 were slightly soluble, while the tablets from Compositions 1 - 3 and 5 each showed a good dispersibility in water. The "dissolution rate" includes both what was dissolved into solution and what came into emulsion, the term being used in the same way hereafter. Clinical Experiment. A double blind experiment was performed using tablets made from Compostions 1 and 5 and tablets of Comparison Example 1, covering 120 patients with disturbances in cerebral circulation. The tablets were given orally (before meal: 4 tablets at a time; 3 times / day). As a result of adiministration for one month, improvement was seen, as compared with the conditions before administration, in 29 patients (67.4%)out of 41 receiving tablets of Composition 1 and in 17 patients (73.9%) outof 23 receiving tablets of Composition 5. On the other hand, in the group receiving tablets of Comparison Example 1, improvement was seen in 13 patients (32.5%)out of 40. Thus, as compared with the tablets of Comparison Example 1, excellent results were seen in tablets of Composition 1 with + 34.9 % and in tablets of Composition 5 with + 41.4 %, showing that each of these compositions has a high bioavailability. Dissolution test A dissolution test was performed, in the same manner as in Example 1, for each of the podwders of Compositions 7 and 8. It is to be noted that the dissolution rate for Composition 8 shows the dissolution rate of total alkaloids. The powders of Compositions 7 - 8 each showed better dispersibility in water as compared with powders of Scopolia or Platycodon obtained by spray drying of a 15 w/v % extracts. As mentioned above, the solid preparations, such as tablets, granules and powder prepapration; and non-alcoholic liquid preparations such as drinkable preparations and syrups, which are made from the compositions of this invention are well absorbed into the digestive tract and thus show a high bioavailability, although no alcohol is contained. Therefore, these preparations are most suitable for the treatment of disorder in cerebral circulation in the elderly people and minors, and also in patients with liver diseases.

Claims: A composition containing an extract obtained from Ginkgo leaves by a water-containing organic solvent, characterized in that the composition comprises: a.) an extract comprising flavone glycoside and biflavone as active ingredients almost insoluble in water, b.) gum arabic or guar gum. A composition as set forth in claim 1, wherein said composition further comprises a fatty acid ester of polyglycerol. A composition as set forth in claim 2, wherein HLB of the fatty acid ester of polyglycerol is 10 or higher. A process for preparing a composition as claimed in claim 1 comprising extracting Ginkgo leaves with a water-containing organic solvent, dissolving the extract obtainied and gum arabic or guar gum in a water-containing lower alcohol, and then, distilling off said water-containing lower alcohol. A process for preparing a composition as claimed in claim 1 comprising extracting Ginkgo leaves with a water-containing organic solvent, dissolving the extract obtained, gum arabic or guar gum, and a fatty acid ester of polyglycerol in a water-containing lower alcohol, and then distilling off said water-containing lower alcohol.

Inventors: MOTOYAMA, SHIMESU, SAITO, YUKIHIRO, UMEDA, SEIICHI
Applicants: FREUND INDUSTRIAL CO., LTD.
Application year: 1989
Main classification: A61K35
IPC codes: A61K36, A61K47, A23L2, A23L1