WO2005123063A1

WO2005123063A1 - Compositions for urinary dysfunction and edema containing decursin and/or decursinol angelate, or angelica extract containing decursin and /or decursinol angelate

Info

Publication number: WO2005123063A1
Application number: PCT/KR2005/001932
Authority: WO
Inventors: Sang-Pil Han; Eui-Jae Yoo; Soon-Ok Choi; Yong-Chan Kim; Paeck-Hi Choi; Hee-Jun Lee; Young-Deuk Choi; Ik-Hwan Kim
Original assignee: HANSSEM HEALTH CO Ltd
Current assignee: HANSSEM HEALTH CO Ltd
Priority date: 2004-06-22
Filing date: 2005-06-22
Publication date: 2005-12-29
Anticipated expiration: 2006-12-22
Also published as: EP1781281A4; KR101072175B1; JP2008503566A; CN1976695A; EP1781281A1; KR20050121324A

Abstract

The present invention relates to compositions for urinary dysfunction and edema containing decursin and /or decursinol angelate , or angelica extract containing decursin and /or decursinol angelate. In case of using the compositions for urinary dysfunction and edema containing decursin and /or decursinol angelate, or angelica extract containing decursin and /or decursinol angelate, it would be possible to provide therapeutics, subsidiary agent and health subsidiary foods, which having excellent effects for urinary dysfunction and edemas representing BPH and urinary incontinence, being safe without any side effects despite long term use, additionally improving mi- crocosmic functions

Description

Description COMPOSITIONS FOR URINARY DYSFUNCTION AND EDEMA CONTAINING DECURSIN AND/OR DECURSINOL ANGELATE, OR ANGELICA EXTRACT CONTAINING DECURSIN AND /OR DECURSINOL ANGELATE Technical Field

[1] The present invention relates to composition for urinary dysfunction and edema containing decursin and/or decursinol angelate , or angelica extract containing decursin and /or decursinol angelate. Background Art

[2] The urinary dysfunction means symptoms accompanying any difficulty of normal urination due to some primary factors. Excluding significant factors such as in particular, operation, use of specific drug and the like, Benign Prostatic Hyperplasia (BPH) for the male and urinary incontinence for the female or male may be typical causal diseases.

[3] The BPH is one of very frequent benign enlargement developed among the male after middle age. Aging and Hormone imbalance due to androgen are recognized to be two biggest primary factors. As the BPH is not a fatal dieses, cases developing into serious symptom are few. However, prevalence rate is so high that 60% of sixties of the male may have. So urinary dysfunction such as nocturnal, residual urine, urgency, uretic defect and the like are accompanied not only leading to the difficulty of daily life, but also to develop secondary problems such as edema, renae functional disorder , somnipathy , sexual life, depression and the like, by which living quality is considerably reduced. Therefore, most patients suffered BPH are to be cured to eliminate the urinary dysfunction.

[4] As for pharmacological therapy for the BPH, -adrenergic antagonist like prazosin and terazosin etc eliminating urination troubles by relaxing muscles near the urethra leading to expanding it, 5-α reductase inhibitors represented finasteride, antiandrogens may be cited. However, there were problems, wherein it took long time to confirm the therapeutic effect (2-3 weeks to six months longer), led to the efficacy decrease thereof or the frequent side effects of headache, tachycardia, erectile dysfunction and the like.

[5] Furthermore, efforts for applying herb medicines have been tried to minimize such side effects. As for the interested ones Saw Palmetto and β-Sitosterol are available. Even if they have a lower rate leading to the side effects of erectile dysfunction and the like for medical actions comparing over said medical therapy, those pharmaceutical actions had not been sufficiently verified. Furthermore, those medical effects are recognized to be unsatisfactory.

[6] The Urinary incontinence is a symptom which is urinated to wet one s underwear regardless of his intention. About 40% of total middle aged women suffer from such symptom. This is a disease having a prevalence rate matching to the BPH for the male and reducing quality of life, which both man and woman experience.

[7] In particular, for the woman, there are two typical symptoms which is the abdominal cavity pressurized - urinary incontinence in case she is pressed therein during her daily life due to the dislocated vesial or weakening urethra, and the imminent urinary incontinence feeling an urge to urinate and becoming unbearable at the moment are. Even in the case of the male, a urinary incontinence develops due to the residual urine accompanied by the weakening urethra and BPH owing to aging. As for therapeutics, even if pharmacotherapeutics for stabilizing smooth muscles and increasing the urethra is available, the effect is temporary and insufficient. Thus, recently it is common to choose operation, pelvis muscular training and the like.

[8] Over Active Bladder as a conception recognized to be a common symptom said BPH and urinary incontinence is a recent term called a phenomenon of imminent or wetting urine accompanied by aging regardless of sex. In the case of female, it is mostly due to deteriorating urethra, and in the case of the male, due to the BPH. In particular, it is known that the case accompanying Over Active Bladder, in particular as for the BPH reaches 20 to 41%.

[9] As of today highly interested in aging and of the quality of life for the aged, it is considered that the medicines which are effective and side effects is minimized for the BPH and the urinary incontinence of high prevalence rate representing the urinary dysfunction are highly required.

[10] As for the medical actions of decursin, decursinol angelate, decursinol and/or angelica extract containing more than 2 kinds of those; active components of Korean Angelica gigas Nakai, a numerous studies have been carried out. Among them, studies finding out effective one for leukemia cancer cell(Korean patent registration announcement No.2001-0080265), effective one for alleviating pain(Korean patent registration announcement No.l0-0397950),effective one for lung cancer, lever cancer and the like(Korean patent registration announcement No.10-0187881), and active inhibitory component for kidney toxicity during applying anti-cancer medicine(patent registration announcement No. 2000-0026683)are remarkable. Observing that decursin and /or decursinol angelate, or angelica extract containing decursin and /or decursinol angelate having preventive kidney toxicity and protective action of kidney function activate Protein Kinase-C (PKC), this materials may have a similar action to that of αl-adrenergic antagonist from which view point, a positive effect relating to the urinary dysfunction and edema would be shown, the inventors of the present invention presumed. However, as a result of searching for the related references up to now, any actions for urination and anti-edema regarding to decursin and/or decursinol angelate, or angelica extract containing decursin and/or decursinol angelate had not been found, and there were no applied examples to the urinary dysfunction disease and diseases with edema like BPH or urinary incontinence. Disclosure of Invention Technical Solution

[11] In accordance with said object, the present invention provides a composition of therapeutics for the urinary dysfunction and the edema containing decursin as shown in the following chemical formula 1 or angelica extract containing decursin as shown in the following chemical formula 1 as an effective component.

[12] [13]

(i)

[14] Furthermore, the present Invention provides a composition of therapeutics for the urinary dysfunction and the edema containing decursinol angelate as shown in the following chemical formula 2, or angelica extract containing decursinol angelate as shown in the following chemical formula 2 as effective components.

[15]

(2)

[16] Furthermore, the composition according to the present invention may comprise one or more selected from a group consisting of decursinol as shown in the following chemical formula 3 in addition to said decursin and/ or decursinol angelate or angelica extract decursin and or decursinol angelate as effective components.

[17]

(3)

[18] Said urinary dysfunction disease includes all the primary and secondary ones known to develop the urine dysfunction, out of which prostantomegaly or urinary incontinence obtains the most desirable effect. Furthermore, Over Active Bladder, juvenile urine adjustment has a desirable therapeutic effect. It is effective to the secondary symptom known to be accompanied by the disease or symptom as indicated in the example but is not limited thereto.

[19] Said edemas include all the primary and secondary edema induced diseases known to develop edema symptoms out, of which leg edema developed after operation, anti- cancer chemotherapy or radiotherapy obtain the most desirable effect. Said decursin, decursinol angelate or decursinol are obtainable from the Angelica gigas, which are extracted, separated and purified. The specified methods for extracting and purifying thereof are described in references(JiHyungjoon etc, Biochemical Journal, 1, 25-32(1970) and Korean Phaπnacogn., 21, 64-68(1990)) and Patent registration No.10-2385092, but are not limited thereto. Any extracting methods obtainable from said decursin, decursinol angelate or decursinol may be allowable even if solvent, the conditions of extracting and the like are different therefrom.

[20] Besides said decursin, decursinol angelate or decursinol said angelica extracts may comprise additionally all the salts, organic salts, complexes and the like of those known to be accompanied by the extracting process.

[21] Said decursin, decursinol angelate or decursinol may be used by synthesizing them, which detailed methods are described in the references (Tetsuhiro Nemoto etc., Tetrahedron Letters, 41, 9569-9574(2000); Lan Xie etc., J. Med. Chem., 42, 2662-2672(1999); patent application No.2000-25749; and patent registration No.10-0417624), but not limited thereto, and any one of synthesizing method which may obtain decursin, decursinol angelate or decursinol may be used. [22] In case using the synthetic decursin, decursinol angelate or decursinol as the component of composition for said urinary dysfunction and edema, all the inorganic salts, organic salts, complexes of those known to be accompanied during composing said materials may be further comprised.

[23] Said chemical compounds may be formed of pharmaceutically allowable inorganic salts selected from the group consisting of sodium salts, potassium salts, magnesium salts, calcium salts or organic salts selected from the group consisting of lysine, ethanolamine, N,N -dibenzyl ethylene diamine and the like.

[24] Furthermore, according to the present invention, therapeutics for urinary dysfunction and edema comprising decursin and/or decursinol angelate or angelica extracts containing decursin and/or decursinol angelate as effective components, further comprising pharmaceutically acceptable carriers or pharmaceutical additives are provided.

[25] Furthermore, according to the present invention, subsidiary therapeutics and subsidiary foods comprising decursin and/or decursinol angelate or angelica extract containing decursinol angelate as effective components, further comprising pharmaceutically acceptable carriers or food additives which are supportive for the urinary dysfunction and edema are provided.

[26] The composition comprising decursin and or decursinol angelate or angelica extract containing decursin and/or decursinol angelate as effective components used by the present invention may be applied by changing a dosage depending on the objective diseases, objects and the conditions for the patients. In general, it is preferable to dose 1 to lOOmg as for the decursin per 1kg by body weight, more preferably, 3 to 30mg per one time, 1 to 3 times per day. Furthermore, said dosage may be dosed by forming for oral administration or non-oral use.

[27] Furthermore, during the process of clinical trials made by the inventors it was verified that the composition containing decursin and or decursinol angelate or angelica extract containing decursinol angelate as effective components had their respective improving effects for pimple, good looking healthy face color tone, contraction of thyroid nodule, urolithiasis, hemoturia, dysuria and the like, for ischemic angiopathy and peripheral vascular disease, for impotence, the developing physical strength, of hair growth, curative value for cystitis after radiotherapy or for vesial dysfunction. As for those effects, deep studies are being under progress by the present inventors.

[28] Further details of the present invention are described by the following embodiments. However, The embodiments do not restrict the scope of the present invention. Best Mode for Carrying Out the Invention

[29] <Subject>

[30] Clinical trials for 32 patients for the benign prostatic hypertrophy, 15 for the urinary incontinence and 14 for every kind of edema oriented evaluations of effects for the composition according to the present invention were carried out.

[31] Table 1

[32] Detailed profiles for said patients for the edema are as follows: [33] 3 cases: patients for systemic edema with body diabetes, hypertension, fatty liver or the like.

[34] 11 cases: 1 case of each leg edema after each operation for coronary, cerebral vascular or , heart disease 3 case of operation for prostate carcinoma cancer

[35] 1 case of perennial region-leg edema after operation for bladder cancer [36] 1 case of leg edema and multiple mass for thyroid gland after operation of uterine cancer (same patient)

[37] 1 case of multiple mass in axillary region [38] 2 cases of edema after radiotherapy [39] <Dosing method> [40] By using decursin and decursinol angelate obtained from cultivating and extracting a local angelica extract according to the method as described in patent registration No.10-0385092, each one sack for 300mg of decursin, 300mg of decursinol angelate and 300mg of mixture of decursin and decursinol angelate were prepared.

[41] The subjects were allowed to take them one time per day for 3 weeks to 10 months together with about 50ml of potable water around nine o clock every day.

[42] <Diagnosis> [43] The following items were diagnosed and the result was shown in Table 2. [44] Inquiry [45] Examination for voiding speed(speed examination for 5 seconds before urination, 10 to 15 seconds during urination) [46] Examination for urine

[47] Rectal digital examination [48] Ultrasonic examination(excluding PSA positive patients) [49] Table 2

[50] As for said BPH patients, the scores of each effective improvement were decided based on IPSS (International Prostatic Symptom Score) as followed.

[51] Good : Effect shown within one day after dosage. [52] Normal(effective) : Effect shown within 2 to 3 days after dosage. [53] No effect : No effect shown even in 3 to 5 days after dosage. [54] Industrial Applicability

[55] Comparing 1-adrenergic antagonist known to be 50 to 60% of improvement effect based on International Prostatic Symptom Score(IPSS) in 2 to 3 weeks after dosage, 91% of the patients showed the improvement effect within 1 to 2 days after dosing the composition according to the present invention. The finding result of showing poor improvements of the symptoms were each case for too narrow urinary tract, tumor in the prostate gland, overdrinker, potential patient for bladder disease and excessive glycosuria.

[56] As for the urinary incontinence, except each case for the long term patients or other related potential diseases, it showed a favorable effect with effective rate of 90%, in particular, the case of 13 years old boy wetted mattress twice or three times every day due to poor adjustment of the urination had shown the result of complete recovery by twice doses.

[57] In the case of edema patients, the curing effect for the BPH by the action for α 1-adrenergic antagonist being verified, a curing effect for the edema by the same mechanism was expected, but unexpected curing effect which relieving action of the edema for all the patients joined the experiment was verified was obtained. As for the patients for the vascular disease such as diabetes, hypertension, fatty liver and the like, for some of them complaining the systemic edema, the clinical numerical values of decreased blood sugar level with considerable reduced weight and the like after dosage were improved and resulted in the loss of multiple mass for thyroid gland or axillary region. In particular, as for a group of patients showing leg edemas such as coronary and the like after operation and those of edema after radio therapy, specifically, showing the effect of relieving edema, one alternative thereof without any clear means of therapy until now, after operation/anti-cancer therapy may be expected.

[58] Furthermore, in any case, even one case of side effects which α 1-adrenergic antagonist, 5-α reductase inhibitors or every kind of edema cures develop, and any other effects were not reported for 10 months. Thus, the possibility as excellent safe therapeutics for urinary dysfunction and edema was verified. Some improved points by dosing the composition according to the present invention for the impotence known to effect seriously on the quality of life for the patient due to side effects accompanied by the BPH, in particular, deteriorated during curing androgen would be especially noteworthy by dosing the composition according to the present invention.

[59]

Claims

[1] A composition for treating urinary dysfunction and edema comprising decursin as shown in the following chemical formula 1 or angelica extract containing decursin as shown in chemical formula 1 as an effective component.

(i)

[2] A composition for treating urinary dysfunction and edema comprising decursinol angelate as shown in the following chemical formula 2 or angelica extract containing decursinol angelate as shown in chemical formula 2 as an effective component.

(2)

[3] The composition for treating urinary dysfunction and edema as described in Claim 1 further comprising decursinol angelate as shown in said chemical formula 2.

[4] The composition for treating urinary dysfunction and edema as described in any one of Claims 1 to 3 further comprising decursinol as shown in the following chemical formula 3.

(3)

[5] The composition for treating urinary dysfunction as described in any one of Claims 1 to 3 wherein said urinary dysfunction is benign prostatic hypertrophy or urinary incontinence.

[6] The composition for treating edema as described in any one of Claims 1 to 3 wherein said edema is leg edema developed after operation, anti-cancer chemotherapy or radio therapy.

[7] The composition for treating urinary dysfunction and edema as described in any one of Claims 1 to 3 wherein the angelica extract further comprises inorganic salts, organic salts and complex thereof known to be accompanied by during extracting process in addition to said decursin, decursinol angelate or decursinol.

[8] The composition for treating urinary dysfunction and edema as described in any one of Claims 1 to 3 wherein said decursin and decursinol angelate are synthetics, and further comprises inorganic salts, organic salts and complex thereof known to be accompanied by during synthesis.

[9] The composition for treating urinary dysfunction and edema as described in any one of Claims 1 to 3 wherein said decursin and decursinol angelate are the forms of pharmaceutically acceptable salts.

[10] The composition for treating urinary dysfunction and edema as described in Claim 9 wherein said salts are inorganic salts selected from the group consisting of sodium salts, potassium salts, magnesium salts and calcium salts.

[11] The composition for treating urinary dysfunction and edema as described in Claim 9 wherein said salts are organic salts selected from the group consisting of lysine, ethanolamine and N,N-dibenzylethylenediamine.

[12] A therapeutics for treating urinary dysfunction and edema comprising decursin and/or decursinol angelate or angelica extract containing decursin and/or decursinol angelate as effective components and pharmaceutically acceptabse carriers or additives.

[13] A subsidiary therapeutics and subsidiary foods containing decursin and/or decursinol angelate or angelica extract containing decursin and/or decursinol angelate as effective components and pharmaceutically acceptable carriers or food additives which are supportive for the treating the urinary dysfunction and the edema.