JPS6241217B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to Hypoxidaceae
It concerns active substances extracted from plants of the family. Plants of the Hypoxidaceae family belong to monocots,
Although it contains relatively few genera, it is widely distributed throughout the world, except in Europe and most of northern Asia.
Genera of the family Hypoxidaceae include, for example, Curculigo
Empodium, Hypoxis, Spiloxene, Rhodohypoxis,
Campynema, Campynemanthe, Pauridia and
There is Xiphidium. To date, relatively few reports have been published on plants of this family and the plants to which they belong. In these reports, members of this family mainly contain various sugars and sugar derivatives, such as mucilage hemicellulose, polysaccharides and certain sugars such as xylose, glucose, mannose, fructose, sucrose and glucuronic acid. There is. Phenolic compounds such as coumaric acid, caffeic acid, phenolic acid, ellagic acid and quercetin have also been detected. Furthermore, the existence of anthocyanidins has been suggested, and the existence of thieridonic acid has also been claimed, but these are still questionable. Although no alkaloids or saponins have been found in plants of this family, there are many reports on the presence of sterols, sterol glycosides, and steroid glycosides. To date, there have been no reliable reports of the presence of toxic substances in these plants. On the contrary, certain species appear to have been used in folk medicine and even as food in various countries, in times of famine or other emergencies. More recently, members of the Hypoxidaceae family have been shown to have surprising medicinal properties. For example, for the production of extracts of Hypoxis spp.
German Publication No. 2251695 and German Publication No. 2312285 and U.S. Patent No. 3933789
It is stated in the number. These patents state that the activity of the extracts depends on the sterol or steroid glycosides they contain and that these extracts are particularly active in the treatment of mild prostatic hyperplasia and its associated symptoms. It is said that there is. Regarding the production of extracts from Hypoxis species, German Publication No. 15877 is limited to extracting chopped fresh or pre-dried tubers or corms with water, ethanol or aqueous ethanol. On the contrary, DE 2251695 stipulates that the corms of the Hypoxis species used should be dried at a temperature not exceeding 40° C. before their extraction. According to the patent, extraction can be carried out, inter alia, with a mixture of water and lower alcohols. On the other hand, German Publication No. 2312295 states that it is absolutely necessary to destroy the sterolin-degrading enzymes in the corms by heating them to 60 degrees C before actually extracting them. There is. Furthermore, it has been shown that extracts particularly rich in sterolin can be obtained only by boiling the plant matter in water. Conversely, extraction with 60% ethanol gives an extract containing only trace amounts of sterolin and sterolin compounds. According to the present invention, it is surprising that fresh plant matter, whole or shredded, is heated to a temperature of at least 60 degrees Celsius or higher and has an ethanol content of 30 to 75 percent by volume. , a mixture of water and ethanol, and 60%
It has been found that extracts of plants of the family Hypoxidaceae, which are particularly effective as pharmaceuticals, can be obtained by extraction using a mixture of volume percentages at temperatures between 0 and the boiling point for periods ranging from several hours to 15 days. It was done. The extracts produced in this way show a particularly good effect in the treatment of various diseases, since the sterolin content of these extracts is substantially lower than that obtained according to DE 2312285. This is surprising. Therefore, besides sterolin and sterolin derivatives, other unidentified compounds were extracted with the above method and these compounds, either by themselves or acting cooperatively with sterolin,
It has become clear that it has a clear effect. However, compared to the method detailed in DE 2251695, the activity of the extract according to the invention is surprising. This is because, according to the method of the invention, it is absolutely necessary to heat the corms to a temperature of at least 60°C before extraction, whereas in the method described in DE 2251695, the corms are heated to a temperature of at least 40°C. This is because it requires drying to temperatures not exceeding 0.degree. C. or otherwise processing in the fresh state. According to the invention, freshly harvested plant material, in particular tubers or corms of plant species of the family Hypoxidaceae, are whole or comminuted and heated to at least 60° C. and preferably 80 to 100° C. as quickly as possible.
The extract is produced by heating to ℃. for example,
Heating can be carried out by steam, boiling water treatment or pasteurization. The duration of this heat treatment will vary depending on the particular plant material, its thickness and the medium used. It is necessary to heat the whole plant sufficiently to temperatures above 60°C so that the degrading enzymes are completely destroyed. Next, if the plant has not been shredded beforehand, shred the plant body and
75 and preferably aqueous ethanol containing 60 percent alcohol by volume, at temperatures between 0 and boiling point, preferably between 0 and 30°C,
Extract for 15 days. The time required varies with temperature and amount of extractant and can be completed in 7 days at 25°C. 40
Extraction is carried out at room temperature, as at temperatures of 0.degree. C. or higher, inert substances such as sugars and tannins are extracted too much. The various previously mentioned genera of Hypoxidaceae can be used as the material for extraction, as long as they contain sterolin compounds. It was confirmed that if sterolin was present, a compound that could be extracted with hydroalcohol but had not yet been identified was also present as an accompanying compound. Preferably, the extraction material used is a plant that is present in sufficient quantities to enable industrial processing. Among these, among others, hypoxia
and those of the genus curculigo. The extract thus produced can be used as is, such as in the fortification of foods for continuous administration for the treatment of specific diseases. However, preferably the resulting extract is concentrated under reduced pressure and then spray dried. The powder so obtained is incorporated into pharmaceutical products in already established manner. Clinical studies of the extracts so obtained have shown that doses of about 50 to 1000 mg of extract per day provide excellent efficacy in the treatment of most diseases. Usually 50 to 200 mg several times a day and preferably 100 mg three times a day. Furthermore, it is clear that sterol or steroid glycosides are not the only active materials;
No. 2312285, it was determined that when fresh Hypoxis corms were extracted with 60% ethanol for 3 days at ice-cold temperature, the sterol glycoside content was substantially reduced. For example 5.75mg for 100 grams,
In the preheat-treated Hypoxis corms, boiling water extraction gives 9.01 mg sterol glycosides per 100 g of extract, whereas under the above conditions only 0.23 mg sterol glycosides per 100 g.
The inventor's co-filed patent application “Sterolins and their uses” (corresponding to German Patent No. 2659466) further states that an advantageous effective dose of sterol glycosides is approximately 0.45 mg/day. ing. This dose is clearly higher than the advantageous doses of extracts according to the invention with a relatively low sterol content. When the extract produced according to the present invention is examined pharmaceutically, no toxic phenomena or organ changes are found in acute and chronic toxicity.
Furthermore, when the extract is clinically tested, there are no side effects. On the contrary, the extract of the invention is characterized by good drug resistance and high efficacy. In clinical studies, the extracts produced according to the invention were found to exhibit beneficial prophylactic and/or therapeutic effects against a number of pathological conditions. According to the results so far, it is applicable to the following diseases. (1) mild prostatic hyperplasia and its associated symptoms; (2) eczema edema; (3) dermatitis; (4) inflammation; and (5) arthritis and rheumatism. and the materials include, and consist essentially of, those indicated above. The present invention will be further explained in the following examples. Example 1 Preparation of extract Freshly washed corms of Hypoxis rooperi are treated with superheated steam at 120° C. for 20 minutes. Then cut directly into 12 liters of 60% aqueous ethanol. This mixture is left at 28° C. for 7 days and stirred twice a day for about 5 days. Take 12 liters of extract. If possible, let it pass. (a) Spray dry 6 liters of this extract to 180
gram of powder. This corresponds to a yield of 6%. This powder contains 2.5 mg of sterolin per 100 grams, calculated as cyststeryl β-D-glucoside. The dry extract obtained can be made into capsules, dragees, tablets, ointments, creams according to Examples 2 and 3. (b) Dilute the 6 liters with an additional 3 liters of 60% ethanol to give a solids content of 4%. After adjustment, pour into a bottle. The bottle should be labeled with instructions that the serving size is one teaspoon. One teaspoon has an average of 2.5
Contains cc liquid. This corresponds in this case to a Hypoxis extract content of 100 mg containing 0.0025 mg of sterolin. Example 2 The Hypoxis extract prepared as described in Example 1(a) is added to capsules, tablets and doulas in a known manner. (a) Manufacture of capsules The content of extract in one dose is 100 mg.
Usually, up to 100 mg of lactose or glucose is added as a carrier and 1 to 2 mg of
Add Aerosil or magnesium stearate as a disintegrant or lubricant. The final extract is mixed with additives and packed into plug capsules. (b) Manufacture of tablets 800 grams of Hypoxis extract, 752 grams of lactose (preferably with particle size not exceeding 0.15 mm) and 1400 grams of potato starch are intimately mixed. This mixture is granulated using a solution of 243.2 grams of gelatin, 4.8 grams of glycerin, and 2500 c.c. of water, and the granules are dried under vacuum at room temperature. The grains are then made into 8,000 tablets with a tablet weight of 400 mg. The tablets thus each contain 100 mg of Hypoxis extract, 94 mg of lactose, 175 mg of potato starch, 30.4 mg of gelatin and 0.6 mg of glycerin. (c) Preparation of Doulazia 420 grams of Hypoxis extract, 2310 grams of lactose and 420 grams of sucrose (both preferably with a particle size not exceeding 0.15 mm) are intimately mixed. This mixture is granulated with a solution containing 63 grams of gelatin in 2.1 liters of water. The resulting granules are dried under reduced pressure at 45°C and intimately mixed with 16.8 grams of magnesium stearate. This mixture (3125 grams) is molded into approximately 4000 pieces and coated with a suitably colored doulazier coating. Each Drazier contains 100mg of Hypoxis extract,
550mg lactose, 100mg sucrose, 15mg
of gelatin and 4 mg of magnesium stearate. Example 3 (a) Preparation of an ointment containing Hypoxis extract 90 grams of emulsifying cetyl-stearyl alcohol, 100 grams of viscous liquid paraffin and
Example 1a A molten mixture with 100 grams of white petrolatum (petroleum jelly) was heated to 60°C.
Add 30 grams of Hypoxis prepared according to
Contains 680 grams. Treat with the same warmed solution. The mixture is stirred until it reaches room temperature to form an ointment containing 3% Hypoxis extract. (b) Preparation of cream containing Hypoxis extract 500 grams of wool wax alcohol
Warm to
A similar treatment is carried out with a similarly warmed solution containing 30 grams of Hypoxis extract in 470 grams of water.
Stir the cream to bring it to room temperature, then replenish the evaporated water. This cream has 3%
Contains Hypoxis extract. Example 4 Pharmaceutical testing of the anti-inflammatory effect of the extract prepared in Example 1 Oral administration Twenty-four male Sprague-Dawley rats with an average body weight of 230 grams are habituated to the test conditions. The liquid extract is
Administer equal doses 48, 24 and 1 hour before administering the inflammatory drug. 1 c.c. or 2 c.c. of extract per 100 g body weight is administered orally by gavage. 0.9 of fresh chicken egg white, which is an inflammatory drug.
% NaCl to a concentration of 12.5% by volume and 0.1 cc of the resulting solution is injected into the heel area of the sole of the right foot. Half of the test animals are sacrificed after 5 hours to determine the presence of acute inflammation. The remaining animals were killed 24 hours later to determine any residual inflammatory effects. The residual edema is compared to the weight in the left sole injected with the same volume of the above saline solution as a control. The mean change in the group is compared to a control group that received only 10 c.c. of water per 100 g body weight instead of the test compound. The average percentage reduction in inflammatory response is shown in the following table, where edema formation in control animals is taken as 100%. 1 Decrease in acute inflammatory response 5 hours after administration of inflammatory drug 1c.c./100g 2c.c./100g 11% 17% 2 Decrease in residual inflammatory response 24 hours after administration of inflammatory drug 1c.c./100 grams 2c.c./100 grams 31.7% 33.6% Example 5 Chronic Toxicity Study Sprague-Dawley with an average initial weight of approximately 175 grams
Chronic toxicity was observed in white male rats. Both control and treatment groups consisted of 12 animals. The control group received pure water, and the test group received liquid extract-containing water prepared according to Example 1. In other words, one test group consisted of 25% extract;
One gives water containing 50% and the other 100% extract. The last one is actually
This means that the extract of the present invention was given instead of pure water. Examine all groups for 49 days. After the test, the test group of 100% extract and 1
All animals show normal weight gain and no macroscopic or microscopic changes are observed, except for the group where the head died of unknown causes. The results are summarized in the table below.

[Table] Example 6 Clinical trials Clinical trials are conducted on patients aged 52 to 89 (average age 69).
The study was conducted on 1,198 patients (aged 1 to 3 years old). Patient's symptoms: Diagnostic tests indicate mild benign prostatic hyperplasia (BPH)
The subjects were patients with the following hypersensitivity symptoms and disabling symptoms: (i) Frequency of hypersensitivity symptoms Urgent inability to urinate Continence at night Difficulty in urinating (ii) Disturbing symptoms in urination A weak urine flow that requires a long time is required. Drops of urine drop after urination. Insufficient sensation of emptying of the bladder (sensation of residual urine). Drug administration: 1 dose of the liquid extract prepared in Example 1(b) in an amount of 30 drops. Administer with 25 ml of water 3 times a day after meals or in the amount of 1 or 2 capsules (each capsule containing 100 mg of the extract of the invention) prepared in Example 2 (depending on the patient's condition). Administer by swallowing with water three times a day after meals. Administration Pattern: Drug administration was generally for several months, and in some cases for more than 1.5 years. Also, for some patients, antibiotics,
A combination of sulfonamides, furantoin, and cardiovascular drugs was administered, but almost no side effects were observed. Observations and Results: The following points (a), (b), (c), (d) and (e) were observed by a physician. However, patients with other etiologies or bladder outlet disorders such as the following are excluded from this observation: Bladder neck disorders Prostate tumors - adenocarcinomas, scaly cell carcinomas, endomas, etc. Duct disorders Insufficiency of urinary emptying Inflammation and Infectious symptoms - e.g. cystitis Prostatitis symptoms - e.g. acute and chronic prostatitis. The research was conducted as an open test. Although a statistical analysis of the results obtained was not possible, their medical evaluation was possible. The results of this medical evaluation indicate: (a) Residual urine volume (1) Residual urine volume of up to 100 c.c. was completely reduced in 100% of cases. (2) The residual urine volume between 100 and 200c.c.
In about 90% of cases, it decreased. (3) Residual urine volume from 200 to 500c.c.
decreased in 72%. 10% of these patients
One had 100 c.c. of residual urine and the other required surgery or electroresection. (b) Size of the prostate The gland was significantly reduced in 1150 cases on rectal examination. The colliculus spacing was measured and remained unchanged in only 4% of the cases examined, on average the spacing decreased by 0.6 to 0.8 cm. 4.2 to 3.2 cm in many cases, 3.2 to 2.4 cm in some cases
and in other cases from 3.0 to 2.0 cm. (c) Bladder pressure Measured using a manometer, an increase in urinary pressure due to the influence of the preparation was observed in 88% of the patients. from 40
The initial low value of 60 mmHg is 80 after 3 months of treatment.
It went from 100mmHg to 100mmHg. As a rule, the resistance pressure is
decreased by 10 to 20 mmHg. In 12% of the patients studied, there was no change in bladder pressure while on the medication. However, there was no further deterioration. (d) Urinary findings The improvement in urinary condition was reflected as a decrease in the number of white blood cells in the sediment. In other words, a large number of white blood cells were present before treatment, but only scattered white blood cells were observed at the end of treatment. A reduction in the number of white blood cells was obtained in 96% of all cases. In cases where the urinary tract infection was caused by Coli or Proteus, 863 patients (72% of the total) were negative at the end of the treatment period. 156 patients (13
%) did not have this remarkable result, but
The bacteriological condition was clearly improved. After treatment, only scattered bacteria were detected. The remainder of the infection was caused by Pyocyaneus and was unaffected by drug administration. No deterioration in the investigated parameters (sediments, bacteria) was observed even after long-term treatment. (e) X-ray image When a patient's enlarged prostate in the neck of the bladder makes it impossible to urinate through the bladder, residual urine usually remains and accumulates in the upper urethra, the ring ureter, the renal pelvis and the cup. The size becomes clearly larger. This can be observed on a separating urogram or an infusion urogram. Theoretically, these conditions should disappear once the bladder neck disorder is gone. In many cases, this can be demonstrated with appropriate X-ray images. In the X-ray images of 72 patients, the upper urethral obstruction caused by urinary obstruction at the bladder neck due to prostatic hypertrophy clearly degenerated. Clear regression has been observed in some cases at 4 to 6 weeks. In most cases, three months of treatment are required before clear degeneration is detected by X-ray. No radiographic enlargement of the upper urethra was observed in any of the patients treated with the preparation. Example 7 Clinical trial against rheumatoid arthritis Chronic polyarthritis, Morbus Reiter and various rheumatic diseases were treated with the 3 capsules of Example 1(a) and Example 2. A significant reduction in inflammation was observed in these cases. subjective relief from pain and objective decrease in symptoms of inflammation,
It was also observed in patients who had been taking anticorticosteroid hormones for many years and had no response to cortisone.
Similarly, administration of so-called palliative rheumatism drugs could also be discontinued.

Claims (1)

[Claims] 1. The heated material is first heated to a temperature of at least 60°C to inactivate any enzymes present, and then the heated material is heated to a temperature of at least 60°C.
Hypoxidaceae produced by extracting whole or freshly ground plants by extraction with aqueous alcohol containing ~75% ethanol by volume at 0 to 30°C for 1 to 15 days. A medicinally active extract of the plant. 2. Active extract according to claim 1, wherein the solution obtained after extraction is concentrated and spray-dried. 3. Plant material belonging to the family Hypoxidaceae is heated to at least 60° C., either as is or immediately after comminution, to inactivate the enzymes present, and the material is then treated with 30 to 75 percent by volume of ethanol. A medicinally active extract of a plant of the Hypoxidaceae family, produced by extracting the whole plant as it is or the plant immediately after being crushed, by extracting it with aqueous alcohol containing it for 1 to 15 days. Production method. 4. The method of claim 3, comprising the steps of concentrating the solution and spray drying. 5 First heat to a temperature of at least 60°C to inactivate any enzymes present and then heat the heated material to a temperature of at least 60°C.
Fresh or ground plants are extracted with aqueous alcohol containing ~75 volume percent ethanol at 0 to 30 °C for 1 to 15 days, optionally concentrating and spray drying the resulting solution after extraction. For the treatment of diseases such as benign prostatic hyperplasia and rheumatoid arthritis, which contains a medicinally active extract of a plant of the family Hypoxidaceae, prepared by extracting the plant immediately thereafter, in combination with a pharmaceutically acceptable carrier. Anti-inflammatory pharmaceutical compositions useful for treatment.