前苏联专利SU1757472A3 Method for preparation of 7-isoprophydroxyisophlavone inclusion complexes

专利PDF首页>>前苏联专利

专利附录

专利说明

权利要求

类似技术

同族专利

引用文献

法律状态

优先权

专利摘要:
Usage: in medicine for the treatment of osteoporosis and osteomalacia. Essence: 7-isoproxyisoflavone is reacted with a "D and y-cyclodextrin, heptacs-2,6-0-dimethyl- or 2-heptacis-2,3,6-tri-0 -methyl- / 3 -cyclodextrin or cyclodextrin polymer with mol. 4000 in an aqueous or aqueous-organic medium. The molar ratio of the 7-isopropoxy-isoflavone cyclodextm component is 1.2-3.5. The desired product is isolated and dried. 6 tab.
公开号:SU1757472A3
申请号:SU864028162
申请日:1986-09-09
公开日:1992-08-23
发明作者:Штадлер Агнеш；Сейтли Йожеф；Вайсфайлер Виктор；Варгаи Золтан；Калон Каталин；Гергели Вера；Сютш Тамаш
申请人:Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Инопредприятие)；
IPC主号:

专利说明:

This invention relates to clathrate 7-isopropoxy-isoflavone (ipriflavone), which can be used in medicine for the treatment of osteoporosis and osteomalt.
Known preparations containing ipriflavone have insufficient therapeutic efficacy due to poor solubility and absorbability.
A known method for the preparation of the substance is hypoflavone.
Compound characteristics are as follows: mol. 280.3 m, so pl. 113-118 ° С, solubility in water at 25 ° С 1-42 mg / ml. It is slightly soluble in acetone, but good in chloroform and dimethylformamide.
It is known that the absorbability and solubility of pharmaceutical compositions with low solubility increases if they are ground with inert carriers. For example, grinding equal quantities of ipriflavone, aerosil (or activated carbon, activated clay, activated alumina) in a vibrating mill using steel balls allows to obtain compositions whose solubility is higher than the original pyriflavone. Thus, the product with aerosil has a solubility of 20.4 mg / ml in 50% aqueous methanol after 30 min at 37 ° C, while the solubility of the unground mixture is only 15.0 mg / ml, i.e. In vitro solubility increases 1.36 times. Analysis of the blood levels of dogs after oral administration shows that ipriflavon cannot be detected in the blood. Grinding with Aerosil increases the absorbability of the main metabolite from 0.152 Mpch / ml to 0.485 MPh / ml, which corresponds to an increase of 3.19 times.
Xi
SL vj 4 Yu

oz
The purpose of the invention is to obtain a substance containing 7-isopropoxy-isoflavone (ipriflavone) and having the ability of absorption in a pharmacologically active concentration,
This goal is achieved by the fact that according to the method for producing the inclusion complexes of 7-isopropoxy-isoflavone having the formula
CH3CH2-0
concluding that 7-isopropoxy-isoflavone is reacted with a, /, y-cyclodextrin, heptacis-2,6,0-dimethyl- or 2-heptacis -2,3,6-tri-0-methyl- / 3 - cyclodextrin, or cyclodextrin polymer with mol. 4000 in an aqueous or aqueous-organic medium, with a molar ratio of 7-isopropoxy-isoflavone and cyclodextrin component 1: 2-3.3, followed by isolation and drying of the target product.
It was established that the solubility of the obtained inclusion compound in vitro is 10 times higher than the solubility of ipriflavone administered by perse, and the blood level of the main metabolite is 15-20 times higher. Absorbency of pyriflavone was established in unchanged form and in a pharmaceutically effective concentration. One evidence of the formation of an inclusion compound is an increase in the solubility of hypoflavone in aqueous solutions.
The solubility of Ipriflavone in the obtained compounds of inclusion is given in Table 1.
An increase in solubility is observed with all the cyclodextrin components studied.
Summarize the results presented in table. 1, it is said that the solubility of the ipriflavone clathrate is 4 times higher relative to the active ingredient than the solubility of ipriflavone perse, and its absorbability after oral administration to rats is at least 10 times higher than the level in the blood measured after administration of the free active ingredient in that same dose. The constant level of ipriflavone is at least 25% of the total
the amount of material that is absorbed.
In the preparation of the proposed inclusion compound, the reaction process of the reactants is carried out in an aqueous-organic medium. Alcohol or ketone can be used as an organic solvent. Preferably a 50% ethanol solution is used. Selection of target products
occurs when cooling the reaction solutions. Crystalline products are obtained. It can be mixed in aqueous acetone at the same time as the solvent is evaporated using dimeb or trimeb
(dimethyl-cyclodextrin or trimethyl-cyclodextrin), or a soluble cyclodextrin polymer, a solid powdered product can be isolated from the reaction mixture by evaporation, drying, spraying,
drying at temperatures below 0 ° C, or in the case of dimeb by heating the solution.
Example 1. Obtaining Ipriflavon-β-cyclodextrin clathrate, having a molar ratio of 1: 2.
11.0 g (39.2 mmol) of ipriflavone and 114.3 g (338.3 mmol) of α-cyclodextrin with a moisture content of 12.36% are dissolved in 2.25 l of an aqueous solution of ethanol at 50% by volume, at 80 ° C, intensively mixing, and allowed to cool to room temperature. The precipitated crystalline product is filtered off and dried for 24 h at 60 ° C, which gives 96.4 g of product in the form of a loose white powder. The particle size is less than 90 / m. The content of ipriflavon is 10.8 May. % ipriflavon: / -cyclodextrin 1: 2, the yield relative to the active ingredient is 94.7% (the initial iproflafon: ft-cyclodextrin ratio is 1: 2.3).
In order to prove that the specified product is indeed a clathrate, various analyzes are carried out: thermoanalytical analysis, X-ray diffraction
rays and solubility analysis.
The thermoanalytical behavior of the mechanical mixture and the free components is almost the same, but the changes in the clathrate due to heating,
can be observed only simultaneously with the decomposition of cyclodextrin. When testing a mechanical mixture by differential scanning calorimetry (DSC) at 115 ° C, it is established that endothermic
the peak corresponds to the melting point of iproflavone, but there is no peak in the case of clathrate. The mechanical mixture shows continuous weight loss in accordance with the level of iproflavone between 130 ° C and 250 ° C, but
and in the case of clathrates, no loss in mass or release of organic matter is observed in the same temperature range (thermal expansion analysis, ATP).
The diagram obtained as a result of X-ray structural analysis of the powder of a mechanical mixture consists of additional sums of diagrams of the powder components. However, the clathrate powder chart contains fewer peaks and new peaks (2 6P 6.7; 7.8; 20.9), characteristic for the clathrate and different from the characteristic peaks of / -cyclodextrin (2 0 ° 4.5; 10.6;
12.3), while that of iproflavone is (2 6e 5.8; 11.5; 17.3; 22.0), indicating a new crystal structure and, thus, indirectly confirming the formation of cement.
In order to carry out the test, 250 ml of distilled water is placed in a 500 ml flask and heated to 37 ° C. Then, the product in an amount corresponding to 50 mg of the active ingredient is added, then the suspension thus obtained is stirred at 100 rpm using a magnetic stirrer. At certain intervals, samples of 2-6 ml samples are taken and filtered on a glass filter, and after dilution, the filtrates are examined photometrically in a mixture of water; ethanol in a 1: 1 ratio,
The results are shown in Table. 2
The dissolution of the free active ingredient is relatively slow, it reaches the saturation rate of ipriflavone {about 1.5 mg / ml) after 40-50 minutes. In the case of samples containing Ipriflavone-ft-cyclodextrin clathrate, the maximum concentration of dissolved Ipriflavon is obtained after 1 minute, i.e. the active ingredient dissolves immediately - instant dissolution also occurs and at the beginning the concentration of the active ingredient can be as high as double the level of saturation. The dissolution of the mixture of ipriflavone and / -cyclodextrin is slower, the concentration of the dissolved active ingredient reaches the value determined when the clathrate is dissolved, only after 30-40 minutes.
The solubility of the active ingredient is also determined at different pH levels. The obtained solubility curves at pH 1.3 (this corresponds to the acidity of the gastric juice, HCI) and at pH 7.6 (this corresponds to the intestinal pH value, phosphate buffer) do not significantly differ from the solubility values obtained in distilled water, and the solubility of the active ingredient does not depend on pH in the tested pH range.
Example 2. Obtaining Ipriflavon - / -cyclodextrin clathrate, having a molar ratio of 1: 2.
0.5 g (1.78 mmol) of ipriflavone is dissolved in 50 ml of 96% ethanol, and the solution thus obtained is added dropwise to a solution of 8.0 g (5.35 mmol) / 3 - moisture content cyclodextrin
13.3% in 50 ml of distilled water for 2 h, then the mixture is allowed to cool to room temperature. After stirring vigorously for another 16 h, the resulting product is filtered and dried for 24 h at 60 ° C to obtain 5.5 g of product.
Ipriflavon content: 7.9 wt.%, Molar ratio of Iprif Avon: p - cyclodextrin 1: 2.29. The output relative to the active ingredient 87%. The product also contains free cyclodextrin (the initial ratio of ipriflavon: y - cyclodextrin is 1: 3).
Example 3. Preparation of Ipriflavone-cyclodextrin clathrate having a molar ratio of 1: 2.
0.5 g (1.78 mmol) of ipriflavone is dissolved in 10 ml of acetone in a rotary mortar and 4.0 g (3.70 mmol) of a-cyclodextrin with a moisture content of 10% by weight and 2 ml of distilled water are added. The light suspension thus obtained is homogenized by trituration until the solvent is evaporated. Thereafter
the product thus obtained is dried for 24 hours at 60 ° C. It contains 11.1% of the active ingredient and also free α-cyclodextrin. The molar ratio of Ipriflavone to. A -cyclodextrin is 1: 1.1.
Examples of the form of production of pharmaceutical formulations containing Ipriflavone-cyclodextrin to Atrat as an active ingredient, and their biological
test
Example 4. Preparation of the inclusion complex of Ipriflavone-Dimeb with a molar ratio of 1: 2.
1.2 g (1.03 mmol) of dimeba are dissolved in
10 ml distilled water and add 0.1 g (0.37 mmol) of meflavone. The resulting suspension is shaken for 4 days, then filtered on a G4 filter and then dried, frozen out to obtain 1.25 g of product. It contains 5.67% active ingredient. The active component yield is 71% (molar ratio of ipriflavon: di- meb is 1: 2.8).
Example 5. Preparation of the inclusion complex Ipriflavone-Trimeb with a molar ratio of 1: 2.
2.03 g (1.73 mmol) of Trimeb is dissolved in 250 ml of 50% ethanol and 0.14 g (0.5 mmol) of meflavone is added. The resulting solution is stirred, then spray dried to obtain 1.96 g of product. It contains 6.9% active ingredient. The yield for the active component is 96.6%, the molar ratio of ipriflavon: trimeb is 1: 3.5).
Example 5. Preparation of an inclusion complex using Ipriflavone-cyclodextrin polymer with a molar ratio of 1: 2.
2 g (0.2 mmol) cyclodextrin polymer with an average mol. 4000 is dissolved in 250 ml of 50% ethanol, then proceed as in Example 2. The amount of the product obtained is 1.85 g, the content of active ingredient in it is 7.2%. The output of the active component is
95.1%.
Example 7. Compare the solubility of a known drug containing Ipriflavon-mbolan in tablets containing 200 mg of Ipriflavone (A), tablets containing 40 mg of Ipriflavone in the form of a / 3-cyclodextrin clathrate prepared according to Example 1, and tablets containing 200 mg of Ipriflavone and 330 mg -cyclodextrin at 37 ° C in 500 ml of gastric juice. A piece of the tablet is placed in the equipment and the amount of dissolved material is determined by spectrophotometry at 247 nm.
The compositions of the tested tablets are as follows: tablet A (known as tablet m-bolap, K-020484), mg: ipriflavon 200: amilum maxdis 36; lactose 60: PVP 13; Esma Sprang 30; talc 7; magnesium stearate 4.
Tablet B.
The proposed clathrate containing, mg: 40 mg of ipriflavone 370; PVP (polyvinylpyrrolidone) 15.
Tablet C, mg: ipriflavon 200, / -cyclodextrin 330; PVP 20.
The research results are summarized in table. 3
From the results it can be seen that only 0.62 mg of ipriflavone is dissolved from a conventional tablet, but in the case of a tablet containing one fifth of the active ingredient in the α-cyclodextrin clathrate form, compared to the amount of the active ingredient present in a conventional tablet, the amount of active ingredient doubles and the amount
the dissolved material is 30% higher than the maximum value obtained using conventional tablets after 2 minutes. In the case of a tablet that contains ipriflavone and a-cyclodextrin in the form of a mechanical mixture, the dissolution is somewhat slower, but even in this case, the amount of dissolved active ingredient is higher than with a conventional tablet.
In absorbability tests, male rats weighing 170–200 g are used. 16 hours after immobilization, 25 ml / kg (group A) of ipriflavone, ipriflavon / 3-cyclodextrin clathrate,
prepared according to example 1 (group B) and the ipriflavon- / 3-cyclodextrin mixture (group C) both contain / -cyclodextrin in an equimolar ratio with respect to the active ingredient, after
animals are given this food, for rats water (optional) ad libitum.
The test materials are mixed for 5 minutes in 2 ml of a 1% cellulose solution and introduced through a gastric tube.
Plasma samples collected after 10; 30 min and 1; 2 and 4 hours after treatment, using blood that flows out of Vena femoralis after it is cut in animals that are anesthetized with ether. Blood samples are placed in heparin tubes,
centrifuged, suction filtered and stored deep frozen in
ampoule until further use.
In order to take urine samples,
after treatment, animals are placed in separate metabolic tanks, and urine and feces are collected separately for 24 hours. Urine samples are stored until further use, subject to deep freezing. The concentration of unchanged Iproflavone and its major metabolites (7-hydroxyisoflavone) in urine and plasma samples is determined by high pressure liquid chromatography.
In order to carry out high pressure liquid chromatography, an RP-18 liquid chromatograph and a Lichrosorb reverse current column are used (the grain size in the case of plasma samples
10 mm and in the case of urine samples 5 // m). The flow rate of eluent1 is 1.5 ml / min, the wavelength of the UV detector is 254 nm, the speed of movement of the paper tape is 0.2 cm / min,
In the case of plasma samples, a mixture is used as eluent: 0.05 M acetate buffer (pH 3): acetonitrile - 60:40, and in the case of urine samples, acetate buffer: acetonitrile - 55:45. The internal standard is ethanol solution 2 -methyl-7-methoxy-4-nitroisoflavone (100 (lg / ml), and for calibration, solutions comprising 100 / g g / ml and 10 fi g / ml of 7-hydroxyisoflavone in methanol are used.
In order to analyze the plasma samples, 1 ml of plasma buffer (pH 5) and the enzyme glucuronidase (arylsulfonase) (100 FV) were added to 1 ml of plasma, diluted 10 times with 10 ml of distilled water, and incubated at 37 ° C. within 24 hours. After incubation, 50 ml of NaOH are added, the mixture is extracted with benzene and centrifuged. The organic phase is separated, the aqueous phase is acidified with 400 ml of 1N HCl, and after adding 50 ml of internal ethanol solution, it is extracted again with 8 ml of benzene. The organic phase is centrifuged, the residue is evaporated, dissolved in 100 pl of eluent, used for injection and measured 50 / and l of this solution
Calibration Curve Equation: y 8.2x
-0.08; correction factor 0,9999.
In order to analyze the urine sample, 0.5 rl of acetate buffer (pH 5) and 10 ml of fi -glucurinidase (arylsulfatase) enzyme (1000 FV) are added to 0.5 ml of urine and the mixture is extracted with 8 ml of benzene and centrifuged. The organic phase is separated, the aqueous phase is acidified by adding 400 ml of 1N HCl, and after adding 50 ml of internal ethanol solution, it is extracted with another 8 ml of benzene. The organic phase is centrifuged, evaporated and the residue is dissolved in 100 r of eluent and 10 ml of this solution is injected into the liquid chromatograph.
Calibration curve equation: 0.911x - 0.09; correction factor 0,9995.
In tab. 4 shows the concentration values of unchanged Iproflavone; in tab. five
- values of the concentration of the main metabolite, as determined in the blood of animals.
Group A is administered Ipriflavone per se, Group B, the proposed clathrate, and Group C, a mixture of Ipriflavone and cyclodextrin. At each time interval, unchanged Ipriflavone can be detected only in the case of group B and its amount is 50-500 ng / ml. In the case of group A, similarly to group C., unchanged ipriflavone can be detected only after some periods of time (after 2 and 4 hours). what
for the main metabolite, plasma levels are 10 to 20 times higher in each time interval in group A compared to the levels of groups A and C, which are determined
through the same period of time, i.e. Group B values are between 3 and 20 / Ar / ml, while for groups A and C, they range from 0.2 to 1.0 fi g / ml. In all cases, the second peak appears in
plasma curve after 2 h, which may be the result of an intensive enterohepatitic cycle and better absorption in the small intestine.
In tab. 6 shows the results of high pressure liquid chromatography of urine samples. In the range of 0-24 h in the urine samples can not detect a constant ipriflavon. However, the presence of the main metabolite can be traced (in all cases).
The average content of 7-hydroxy-isoflavone, which corresponds to a threefold increase compared with other groups. According to experience, the amount of the main metabolite is 5055% of the total amount of the metabolite, and therefore the total amount excreted in the urine is 2 times higher than the amount that is determined de facto.
So in the case of group B
40%, while in the case of groups A and So much of 10-14% of the administered dose is excreted in the urine.
After administration of the ipriflavon-3-cyclodextrin clathrate to rats, it is determined that an increase in plasma level can be achieved by a factor of 10 to 15 and a quantity of a substance excreted in the urine can be increased by a factor of 3 to 3 compared to the control group.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining the inclusion complexes of 7-isopropoxyisoflavone having the formula
45
SN Shigo50
pharmacologically active concentration, which is that 7-isopropoxy-zoflavone is reacted with a, (3, y-cyclodextrin. heptacis-2,6-0-dimethyl- or 2-heptacis-2,3,6 -tri-0-methyl-fi-cyclodextrin, or cyclodextrin polymer with a molecular weight of 4000 in water or
water-organic medium, with a molar ratio of 7-isopropoxyisoflavone and cyclodextrin component 1: 2-3.5 s
subsequent isolation and drying of the target product.
Table 1
Table 2
17
,five
k
LTD
ABOUT
about
about
about
about
about
0.078
about
0.095 0.041
oh oh oh oh
0.065 0.055 0.073 0.468
oh 14z
0.194 0.271 0.354 0.203 0.514 0.402 0.214 0.148
0.363
0.054
ABOUT
ABOUT
ABOUT
Table3
Table
0.479
ABOUT
ABOUT
ABOUT
ABOUT
ABOUT
ABOUT
ABOUT
ABOUT
0.081
oh oh oh oh oh oh
15
1757472
16 T a blitz 5
Table

类似技术:

公开号 | 公开日 | 专利标题

SU1757472A3|1992-08-23|Method for preparation of 7-isoprophydroxyisophlavone inclusion complexes

CA1234106A|1988-03-15|COMPOUNDS HAVING ANTIINFLAMMATORY ACTIVITY, OBTAINEDBY COMPLEXATION WITH .beta.-CYCLODEXTRIN, ANDPHARMACEUTICAL COMPOSITIONS CONTAINING THEM

US4565807A|1986-01-21|Medicinal composition containing pirprofen and cyclodextrin and a method of use

AU662986B2|1995-09-21|Novel inclusion complexes of clavulanic acid and of alkali salts thereof with hydrophilic and hydrophobic beta-cyclodextrin derivatives, a process for the preparation thereof and the use thereof

CA2027592C|1996-11-26|Solid pharmaceutical preparations of active form of vitamin d_ of improved stability

CN102510855B|2015-11-25|The crystalline form of N-[the fluoro-4-of 3-|-7-[| oxygen base]-quinolyl-4 } oxygen base) phenyl]-N '-| cyclopropane-1,1-diformamide

JP5757492B2|2015-07-29|Pharmaceutical core particles

US5079237A|1992-01-07|Inclusion complex of nicardipine or its hydrochloride with beta-cyclodextrin and a sustained release pharmaceutical preparation containing the same

EP0422497B1|1996-03-06|Inclusion complexes with silybinin, their preparation and pharmaceutical compositions containing them

US6444703B1|2002-09-03|Cyclohexane carbocyclic ester derivative and cyclodextrin complex and composition for treatment of helicobacter pylori infections

GB2170403A|1986-08-06|Anti-asthmatic composition and preparation thereof

US20220047498A1|2022-02-17|A sustained release composition comprising a methylcellulose

KR890003624B1|1989-09-28|Process for preparing piperacillin pivaloyloxymethyl ester

CN102085205A|2011-06-08|Medical compound preparation of eugenol aspirin ester and method for preparing same

KR101072698B1|2011-10-11|New metronidazole prodrug compound and pharmaceutical composition comprising the same

US4215143A|1980-07-29|Anti-ulcer pharmaceutical composition containing inositol hexasulfate aluminum or sodium aluminum salt as active ingredient

SK278519B6|1997-08-06|Water soluble inclusive complex of silybinine together with cyclodextrine, preparation method thereof and pharmaceutical composition contaning that complex

CN103724359A|2014-04-16|Amorphous cefotetan acid, method for preparing cefotetan disodium by amorphous cefotetan acid and pharmaceutical composition containing cefotetan disodium

EP0535269A1|1993-04-07|Pharmaceutical compositions containing thiazolidinedione derivatives

DE202007017517U1|2008-04-03|Fluvastatin sodium

CN101124231A|2008-02-13|Clopidogrel base suitable for pharmaceutical formulation and preparation thereof

CZ20032513A3|2004-02-18|Stable pharmaceutical preparation containing II torsemide modification

同族专利:

公开号 | 公开日

FI86958B|1992-07-31|

CN86106889A|1987-07-15|

PL261349A1|1987-06-29|

FI863652A0|1986-09-10|

HUT41759A|1987-05-28|

KR870002842A|1987-04-13|

JPS62103077A|1987-05-13|

FI86958C|1992-11-10|

JPH0688993B2|1994-11-09|

US5043326A|1991-08-27|

KR900000542B1|1990-01-31|

CS653586A3|1992-10-14|

US4826963A|1989-05-02|

FI863652A|1987-03-11|

DE3688114D1|1993-04-29|

HU199444B|1990-02-28|

CN1006889B|1990-02-21|

CA1288424C|1991-09-03|

CS276944B6|1992-10-14|

EP0214647A3|1987-09-30|

EP0214647A2|1987-03-18|

UA19813A|1997-12-25|

DD254939A5|1988-03-16|

EP0214647B1|1993-03-24|

AT87319T|1993-04-15|

RU2022970C1|1994-11-15|

引用文献:

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

US3949085A|1970-05-27|1976-04-06|Chinoin Gyogyszer-Es Vegyeszeti Termakek Gyara Rt|Anabolic-weight-gain promoting compositions containing isoflavone derivatives and method using same|

HU194858B|1982-12-03|1988-03-28|Chinoin Gyogyszer Es Vegyeszet|Process for producing dibenzo/b,d/pirane derivatives and pharmaceutical compositions containing them|

EP0129893B1|1983-06-28|1991-09-04|Takeda Chemical Industries, Ltd.|Ground mixture|US5221695A|1987-12-22|1993-06-22|Glaxo Group Limited|Aqueous formulation containing a piperidinylcyclopentylheptenoic acid derivative and beta-cyclodextrin|

SI8810082A8|1988-01-18|1995-12-31|Lek Tovarna Farmacevtskih|Process for preparing new inclusion complex of nicardipine or its hydrochloride with beta-cyclodextrine|

DE3809808A1|1988-03-23|1989-10-05|Hexal Pharma Gmbh & Co Kg|SOLIDS, ESPECIALLY FESTORAL AND RECTAL, ETOFENAMATE-CONTAINING MEDICINAL PRODUCTS|

MY106598A|1988-08-31|1995-06-30|Australian Commercial Res & Development Ltd|Compositions and methods for drug delivery and chromatography.|

EP0491812A4|1989-09-14|1992-11-04|Australian Commercial Research & Development Limited|Drug delivery compositions|

IT1241673B|1989-10-09|1994-01-27|Istituto Biochimico Italiano|INCLUSION COMPLEXES OF SILIBININ WITH CYCLODESTRINE, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM.|

WO1991013100A1|1990-03-02|1991-09-05|Australian Commercial Research & Development Limited|Cyclodextrin compositions and methods for pharmaceutical and industrial applications|

IT1241079B|1990-03-23|1993-12-29|Chiesi Farma Spa|PHARMACEUTICAL COMPOSITIONS CONTAINING IPRIFLAVONE, PROCEDURE FOR THEIR PREPARATION AND RELATED THERAPEUTIC USE|

US5221735A|1991-02-25|1993-06-22|Hoffmann-La Roche Inc.|Cyclodextrin-polyene inclusion complexes|

HU212932B|1993-08-02|1996-12-30|Chinoin Gyogyszer Es Vegyeszet|Parmaceutical composition containing ipriflavone, hydroxyapatit and tricalciumphosphate for treating lack of bones and process for producing the composition|

ZA949715B|1993-12-14|1996-06-06|Lilly Co Eli|Aqueous solution inclusion complexes of benzothiophene compounds with water soluble cyclodextrins and pharmaceutical formulations and methods thereof|

US5506211A|1994-05-09|1996-04-09|The Uab Research Foundation|Genistein for use in inhibiting osteroclasts|

US6298558B1|1994-10-31|2001-10-09|The Gillette Company|Skin engaging member|

WO1996040262A2|1995-06-07|1996-12-19|The Procter & Gamble Company|Process for preparing encapsulated water soluble beta-carotene|

US5847108A|1996-03-21|1998-12-08|Fujicco Co., Ltd.|Clathrate of isoflavone derivatives and edible composition comprising the same|

US6417224B1|1998-03-06|2002-07-09|Meiji Seika Kaisha, Ltd.|Prophylactic, therapeutic agent for osteoporosis|

JP4006133B2|1999-05-17|2007-11-14|松谷化学工業株式会社|Soluble isoflavone composition and method for producing the same|

US7182972B2|1999-12-17|2007-02-27|Quercegen Pharma, Llc|Water-soluble bean-based extracts|

JP4413464B2|1999-12-17|2010-02-10|光則小野|Water-soluble bean-based extract|

US6541062B2|1999-12-17|2003-04-01|Mitsunori Ono|Water-soluble soybean extracts|

JP4585074B2|2000-03-28|2010-11-24|ライオン株式会社|Method for producing pharmaceutical composition|

CA2304906A1|2000-04-07|2001-10-07|1411198 Ontario Limited|13-hode, a regulator of vascular biocompatibility and an inhibitor of cell hyperplasia|

DE10211192A1|2002-03-14|2003-09-25|Beiersdorf Ag|Composition for treatment of aged or greasy skin or acne or for wrinkle prevention contains an isoflavonoid compound as well as a cyclodextrin or derivative|

US6855359B2|2002-11-15|2005-02-15|Cargill, Incorporated|Soluble isoflavone compositions|

US7157446B2|2003-05-02|2007-01-02|Bristol Myers Squibb Company|Complex of ras-farnesyltransferase inhibitor, a cyclodextrin, and ethanol|

US6960300B2|2003-09-08|2005-11-01|Sami Labs Limited|Process for preparing water soluble diterpenes and their applications|

KR100847225B1|2003-10-24|2008-07-17|아모레퍼시픽|Method for extraction of isoflavone from plant material using molecular recognition function of cyclodextrin|

CN101528198A|2006-11-03|2009-09-09|玉米制品国际有限公司|Encapsulated soy extracts and process for preparing same|

JP4978209B2|2007-01-22|2012-07-18|株式会社イヅツみそ|Method for producing freeze-dried miso|

KR100929920B1|2007-09-05|2009-12-04|주식회사 마크로케어|Method for preparing clathrate containing hydrophobic physiologically active ingredient in cyclodextrin and derivatives thereof and use of clathrate prepared thereby|

EP2106786A1|2008-04-04|2009-10-07|Roewer, Norbert, Univ.-Prof. Dr. med.|Pharmaceutical preparation comprising permethylated cyclodextrin|

WO2010058242A1|2008-11-24|2010-05-27|Giovanni Nicolao Berta|New formulations with anti-neoplastic activity|

CN101757640B|2009-06-09|2011-08-31|东华大学|Preparation of clathrate compound containing isoflavone and cyclodextrin of chickpea|

WO2014075935A1|2012-11-15|2014-05-22|Sapiotec Gmbh|Delphinidin complex as an antiphlogistic or immunosuppressive active ingredient|

CA2893883A1|2012-12-11|2014-06-19|Sapiotec Gmbh|Delphinidin for combating melanoma cells|

US11234957B2|2017-01-09|2022-02-01|SciPharm S.à.r.l|Process for preparing water soluble forskolin|

法律状态:

优先权:

申请号 | 申请日 | 专利标题

HU853415A|HU199444B|1985-09-10|1985-09-10|Process for producing 7-isopropoxy-isoflavone-cyclodextrene inclusion complex and pharmaceutical compositions therefrom|

[返回顶部]