JPS61109730A - Drug useful for preventing or remedying stone occurring in urinary tract - Google Patents

Abstract

PURPOSE:The titled drug in granule or pill, obtained by extracting phytin, a chemical substance existing in rice bran, with hydrochloric acid, etc., neutralizing and precipitating it, and blending the prepared crystalline substance with a solid auxiliary substance. CONSTITUTION:Phytin(reaction formula), a chemical substance existing in rice bran, is extracted with a diluted aqueous solution of hydrochloric acid, etc., the extracted solution is neutralized and precipitated to give a crystalline substance, which is blended with a solid auxiliary substance, processed into granule or pill, to give a drug useful for preventing and remedying stone occurring in urinary tract. Phytin exists almost all the parts of plants, especially much in seeds, is much found in castor bean, peanut, flax seed, tobacco seed, wheat bran, etc., and rice bran contains twice - 5 times as much phytin as that in those. 80-90wt% total phosphorus and 75-90wt% total Mg and total Ca in rice bran exist as phytin derivatives. EFFECT:Excretion of excess Ca into urine found in people of abnormal constitution can be prevented, and necessary Ca is left in the body.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention provides a drug for preventing or treating stones occurring in the urinary tract. This will not only save the tens of thousands of people nationwide who suffer from kidney stone disease, but it will also help the many people who may suffer from such a disease in the future.
It is an extremely useful drug. It is a revolutionary new drug that can treat and prevent kidney stones by taking a small amount every day not only during hospitalization but also during outpatient visits.

(Prior Art) There are various types of stone diseases in the human body, including gallstones, urinary stones, Go stones, salivary stones, tonsil stones, bronchial stones, pancreatic stones, precious stones, stone stones, foreskin stones, and the like. The present invention aims to use drugs to cure and prevent kidney stones (urinary stones), which are the most common problem among patients and a worldwide problem for the medical community.

It is generally known that kidney stone disease is a disease in which stones form in the kidneys, but there are various causes and not all of them are clear. Kidney stones are generally found in the urine. Stones are formed when chemicals present in the renal papilla are deposited at the tip of the renal papilla, protrude into the solidified metanephric gland, and are separated and shed.

One of several stones, which have been shown to result from excessive metabolic production of substances such as uric acid or urate salts, is more common in gout patients. Calcium oxalate stones occur when there is a large amount of calcium in the diet, and calcium phosphate stones occur sometimes when there is enhanced parathyroid function and increased excretion of calcium, and other times when the solubility of calcium salts is reduced. It is more likely to occur when you are sleeping or when you ingest a large amount of milk.

Stones range in size from small sand-like stones to large stones called coral-like stones, and the number of stones is most often one to several, but sometimes there are more than 100. It occurs most often in young people in their prime working age, between the ages of 20 and 40.

Stones are harmless when they are small, with no pain or symptoms, but if they grow a little larger or increase in number (then they can erode the epithelium of the kidney, making it easier for bacteria to infect the kidneys, and they can cause problems in the urine stream). When a stone enters the ureter and the muscle M curves to expel it, an intense pain attack called renal pain occurs.

Although most stones cause pain, they can be expelled from the body by drinking large amounts of water and by stimulating the kidneys and ureters. However, for stones that cannot be excreted with such conservative treatment, surgical operations such as nephrolithotomy and nephrolithotomy, or in extreme cases, surgery to remove the kidney itself, must be performed.

Even if it can be cured through surgery, the mental and physical pain it causes is immeasurable, and it is a frightening disease with a high possibility of recurrence. The above is an overview of the causes, symptoms, and treatment of kidney stones, but to date, there are almost no drugs that can prevent or cure this troublesome stone disease, and this is the conventional stone countermeasure. The present invention is a drug that has been awaited not only by hundreds of thousands of patients nationwide and millions of patients worldwide, but also by the vast majority of people who may suffer from kidney stones.

(Problems to be solved by the invention) Although there are many unknowns about the mechanism by which kidney stones occur, there is no doubt that calcium plays some role as described above, and in fact, in patients with kidney stone disease, calcium An abnormally large amount of calcium is excreted.

If calcium is somehow involved in the development of kidney stones, and if too much calcium is the cause in many cases, then controlling the amount of calcium or removing unnecessary calcium can improve kidney stones. The present invention was the result of experiments conducted on the premise that stones could be prevented or treated.

So what kind of chemicals can be used to control calcium?
The problem is whether a derivative should be used, but the solution to this problem is a chemical substance or derivative that adsorbs calcium, namely a phytin preparation extracted from rice bran.

(Means for solving the problem) Phytin exists in almost all parts of the plant body, and is particularly abundant in seeds, but is also found in large quantities in castor, peanut, soybean/linseed, tobacco seed, wheat bran, etc. There are two of them in rice bran.
It contains phytin in an amount from 5 times to 5 times. It is recognized that 80 to 90% of the total phosphorus, 75 to 90% of the total magnesium and total calcium in rice bran exists as phytic forms.

The chemical formula of phytin is (CaH+gOz4Pi ” 3HzO)2CaMg
However, when extracting from rice bran as an insoluble colloidal precipitate, if caustic soda is used as a precipitant, some of the sodium will be substituted, and its chemical formula will be 'C6HhOz4PbMg*Ca+Naz' 2H
zOJ, and its structural formula is shown in FIG.

As can be seen from the structural formula in Figure 1, there are six phosphorus (P) atoms in rice bran phytin, and each P has four oxygen atoms (0
), and each of the four Ps has one magnesium (M
g), one calcium (Ca) is attached to one P, and two potassium (K) are attached to the remaining one P.

In the present invention, when the above-mentioned phytin is added to a solution with a high calcium concentration, each of the four Mg in FIG.
It focuses on the properties that can be replaced by a) and attempts to achieve the objective by utilizing those properties.

(Clinical progress leading to the invention) □ Case of rice bran □ As a result of continuing to administer rice bran containing high concentrations of phytin to patients at a Log dose per day, the inventors found that after 4 weeks, a significant amount of calcium was found in patients with high urinary calcium concentrations. A decrease in concentration was observed. This is Figure 2. Figure 3 shows 20g of rice bran per day.
The results show that the urinary calcium concentration significantly decreased after 4 weeks. In particular, when administering 20 g per day, the calcium concentration in all patients decreased after 4 weeks, regardless of the concentration in the patient's urine at the start of administration, which is different from administering 10 g per day.

Figure 4 shows what happens after a further 4 weeks when rice bran is continuously administered to a patient at a rate of 20 g per day and the administration is discontinued after 4 weeks have elapsed. As is clear from the figure, the calcium concentration in the urine increased immediately after discontinuing administration.

Figure 5 is the same as Figure 4, but shows the case where phytin extracted from rice bran was continued to be administered after 4 weeks, and the results were almost the same as in Figure 4.

In the case of Figure 4, before administration 4 weeks after administration urinary calcium 379 ±105 148 ± 43 (m
g/24 hours) 4 weeks after discontinuation of administration 276 ± 56 In the case of Figure 5, before administration 4 weeks after administration urinary calcium 407 ± 97 221 ± 72
4 weeks after change in administration: 298 ± 61 Detailed data such as those described above could also be recorded at the same time.

Next, we will show detailed figures on changes in biological trace elements in the body after two years of continuous administration of rice bran.

[Before administration] [One month later] (1) Patient number 7070 (2) Calcium (wag/24h) 332 ±80
235±91 (3) Phosphorus (〃) 906±
311 1000±314 (4) Magnesium (〃)
92±40 102±56 (5) Uric acid (-)
619±217 579±205 (6) Oxalate (
-) 44±2049±18 (7) Creatine (
〃) 1409±423 1291±300 (8) Urine volume (
ml/24h) 1933±699 1978±75
3 [6 months later] [12 months later] [24 months later] (1
) 30 23 B(2)
247±96 229±71 216±68
(3) 1108±375 1021±241
923±243 (4193±3490±41 101
±38(5) 642±255 604±175
575±120+6) 57±1959±2455
±13(7) 1408±346 1318±27
7 1231±262(8) 2101±679
1872 ±665 1761 ±470 As is clear from the table above, even if rice bran is administered over a long period of time, only the calcium concentration decreases and almost no changes are observed in other trace elements.

The component analysis of rice bran is as follows.

Phosphorus------3,7g Calcium---0,1g Magnesium---1,2g Crude fat---7,5g Crude fiber------ ---7.2g Starch ---80.3g (in 100g of rice*) □In the case of phytin□ Next, based on the data of a clinical experiment on pure phytin extracted from rice bran by the precipitation method, this book was published. Detailed description of the invention.

First, we measured the calcium concentration in the urine of men who had never had kidney stones (A) and men who had had kidney stones twice or more (B), and calculated the number of people who excreted excess calcium.

(A) 62.9% out of 20808 people) (B) 12 out of 47 people (25.5%) (C) 36 out of 75 people (48%) (a) 2 out of 50 people (4%) ( b) 4 out of 22 people (18.1%) (c) 5 out of 20 people (25%) From the above numbers, the percentage of women is slightly lower, but those with abnormal calcium excretion are those who have no history of kidney stones. It can be seen that the proportion of people with experience is abnormally high compared to

Figure 6 shows experimental data when rats were fed a high calcium diet. This is a graph showing the calcium concentration in the urine after 4 weeks in four groups of mice receiving only the high calcium diet, ■ high calcium diet + rice bran, ■ high calcium diet + phytin, and ■ normal diet.

FIG. 7 is a graph showing low calcium feed, low calcium + fucium concentration.

Figure 7 shows the cases in which low calcium feed, low calcium + phytin, low calcium + rice bran, and normal feed were fed.

As can be seen from the experimental data in Figures 6 and 7, the phytin-containing diet shows the values closest to normal diets, regardless of whether it is a high-calcium diet or a low-calcium diet. From this, the magnitude of the effect of taking phytin,
The smallness of the negative effects is clearly highlighted.

It can be seen how phytin adsorbs only excess calcium.

Figure 8 shows patient 23, who suffered from kidney stones for 45 years in addition to his annual income.
The study involved administering phytin to humans and observing the development of kidney stones for three years. It is a fact that people who have suffered from kidney stones for more than two years are sure to have a recurrence, and some patients have repeated episodes several times a year. Before administering phytin to the 23 patients, the number of kidney stones was 0.00 when evaluated based on the patient's total number of years.
However, after administration, only 2 out of 23 people developed kidney stones over a three-year period, and the number of kidney stones that occurred was only 0.048. Five people who have been taking the drug for more than three years have not developed any symptoms. The effects of phytin administration are clear.

Figures 9 and 10 show the results of an experiment on the binding force between phytin and calcium in a test tube. Figure 9 shows the binding strength measured in terms of calcium concentration, and Figure 10 shows the binding strength in terms of binding rate. In both cases, when the phytin concentration in the test tube was 0.2mM/L, the decrease was only about 20%, but at 2.0mM8, it bound to more than 90% of calcium, regardless of the initial calcium concentration. It's clear.

□In the case of phytic acid□ The chemical formula of phytic acid is shown in Figure 11, and how phytic acid acts on calcium will be clarified through experimental and clinical data.

Figures 12 and 13 are test tube experiments showing how chlorophytic acid binds to calcium.

In both cases, the sodium phytate (Na-phytate) concentration was 0.2mM/L, 0.5mM/L, and 1.0@IM.
The experiment was divided into four types: 2.0mM and 2.0mM.
Figure 12 shows the calcium concentration, and Figure 13 shows the probability of binding with calcium. Even at 0.2mM/L, calcium (Ca) decreased by 25-30%, but at 2.0mM/L, the reduction rate was almost 100%. That is, sodium phytate (Na-phytate
) was found to be strong enough to bind all calcium, regardless of the calcium concentration.

Figures 14 and 15 show sodium phytate (Na-phy
tate), magnesium phytate (Mg-phy
phytin preparations (phytin pha), phytin preparations (phytin pha
rm) and phytin, each with a concentration of 1.0 mM.
These are the experimental results when the concentration was increased to 2.0 mM and when the concentration was increased to 2.0 mM.

In the case of 1.0 mK in Figure 14, with sodium phytate, the calcium concentration is almost 100 mK even if the concentration is 5mM or 11mK.
% calcium, and in the case of the other three types, it was found that there is a limit to the binding strength when the calcium concentration becomes high.

In the case of the concentration of 2.0 mM in Figure 15, sodium phytate at a calcium concentration of 5 mM/L is approximately 100
% calcium, and even in the case of the other three types, 90%
It was found that the bonding strength was maintained at a certain level.

As a result of the experiments shown in Figures 1 to 15 above, sodium phytate (Na-phytate) has too strong a binding force with calcium, so calcium is not used to treat hypercalcemia, which is the cause of kidney stones. It may end up absorbing too much and be inaccurate.

In any case, the chemical logic by which rice bran phytin adsorbs and binds calcium is clear from the chemical structural formula in the attached drawing.
g) is carried out by replacing it with calcium (Ca). Therefore, the higher the calcium concentration, the lower the adsorption capacity, and the higher the phytin concentration, the greater the calcium adsorption capacity.

However, since calcium is an essential mineral for the human body, no matter how much kidney stones are prevented or treated, it is a health problem if all the calcium in the body is absorbed and excreted from the body. The biggest challenge was determining the appropriate amount of calcium to adsorb, and in order to solve this problem, we conducted a series of experiments like the one described above.

The results showed that sodium phytate adsorbed too much calcium, so magnesium phytate (Mg
-phytate) or phytin preparations are suitable. Usage, capacity, etc. will be described in Examples.

(Example) Although the method for producing phytic acid has been described, the following two types of methods for producing phytic acid can be considered.

First, phytic acid is heated with a 2% aqueous hydrochloric acid solution for one hour, filtered, concentrated under reduced pressure, passed through a cation exchange resin cylinder such as IR-110, and then evaporated and concentrated to obtain phytic acid. Second, 5% dilute phytic aqueous solution and calcium phytic are stirred together with filter aid and activated carbon in a dissolution tank, compressed and filtered, passed through an ion exchange resin cylinder, evaporated, and then mixed with filter aid and activated carbon again. This is a method in which an organic stabilizer is mixed in and compressed and filtered.

The pure phytic acid produced in this way can be combined with some kind of salt and administered to the patient as a powder, or it can be made into tablets, which is an arbitrary choice, and the type of oral medicine to be taken depends on the symptoms and other factors. Judge and decide.

In Example 1 of the present invention, phytin is pulverized and then granulated using a solid adjuvant and administered. The mechanism by which phytin preparations adsorb calcium in the body has not been completely elucidated, but when phytin preparations are administered into a body with high calcium concentrations, the calcium in the intestine is replaced by magnesium attached to the phosphate of the phytin preparation. It is thought that calcium is adsorbed. In general, calcium is very poorly absorbed into the body, and it is thought that when lactose is absorbed from the intestinal wall due to the supplementary effect of lactose contained in milk, etc., calcium is absorbed along with the intestinal wall in patients with kidney stones. It has been found that the calcium absorption capacity of

Phytin is characterized by the fact that it quickly binds to calcium that enters the body before it is absorbed through the intestinal wall, and if it binds after entering the blood, it will not be able to sufficiently prevent urinary stones.

Most patients with kidney stones have abnormal calcium levels in their urine, so phytin preparations must be adjusted so that phytin remains at a constant concentration in the body.

As a result, phytic acid was made into a phytic preparation, and 1
It has been found that it is possible to maintain the ideal phytin concentration in the body by administering 4g per person in 3 to 5 doses per day, and is currently administering it to approximately 150 patients in conjunction with a rice bran preparation. ing.

(Effect) The rice bran preparation and phytin preparation of the present invention were administered to patients in divided doses of 20 g per day for the former and 4 g per day for the latter, and as shown in Figure 8, the former was administered continuously for over 3 years. In some cases, there have been no cases of kidney stone disease.

The urine, which had previously shown abnormal calcium levels, now had approximately normal calcium levels. Minerals other than calcium also showed normal values. In the end, by administering these daily doses, the phytin concentration in the body was reduced to 1.0 mM/
L~2.0mM; It is thought that it was maintained at L.

The phytin preparation of the present invention is characterized in that its calcium removal rate is not 100%, and therefore the necessary calcium remains in the body, but the detailed chemical changes have not yet been fully elucidated.

As shown in Figure 1, there are 6 phosphorus in rice bran phytin, but one phosphorus is already bound to calcium.
Since the other phosphorus is combined with potassium, it ends up being 4
It is thought that the magnesium and calcium held by two phosphorus and the potassium and calcium held by one phosphorus replace each other, and this is due to the substitution rate of 100.
%, and only excess or unnecessary calcium is excreted and removed.

(Effects of the present invention) The effects of the present invention have been described in detail, but to summarize them here, firstly, it can prevent excretion of excess calcium into the urine, which is seen in people with abnormal constitutions. . Second, since the necessary calcium remains in the body, there is no need for calcium deficiency. Thirdly, there are almost no side effects even when used continuously over a long period of time.This lack of side effects is a major feature.The reason for this is that phytin preparations are based on phytin extracted from rice bran, which is very similar to natural products. This is due to the fact that it is a substance similar to that of phytin, and also because phytin itself is difficult to absorb through the intestinal wall, so phytin does not impregnate cells in the body as it is. Fourth, it is easy to take as it is sufficiently effective with just 4g per day. Fifth, phytin itself is tasteless and odorless, and can be formulated into powders, granules, and tablets. Sixth, phytin is extremely abundant in nature and can be produced at low cost.

Seventh, manufacturing is extremely simple.

As described above, the drug of the present invention, which is made from phytin, is expected to have immeasurable effects, and there is no doubt that it is an extremely ground-breaking invention that will bring good news to millions of patients with urinary tract stones around the world. However, since it is so simple and inexpensive to manufacture, there are many concerns about how the inventor's monopoly rights will be protected.

[Brief explanation of drawings]

FIG. 1 shows the chemical structural formula of rice bran phytin, which is the raw material of the present invention. Figures 2 and 3 are graphs of records obtained when rice bran was administered for 4 weeks. FIG. 4 is a record graph showing the state when rice bran administration was discontinued. FIG. 5 is a graph showing the state in which phytin was extracted from the rice bran being administered. FIG. 6 is a graph showing a state in which rats were fed food with a high calcium concentration and were also made to ingest phytin and rice bran at the same time. FIG. 7 is a graph showing a state in which rats were fed a diet with a low calcium concentration and were also made to ingest phytin and rice bran at the same time. FIG. 8 is a graph showing the administration of phytin to a patient who has suffered from kidney stones for many years. FIG. 9 and FIG. 1θ are graphs showing the binding state with calcium when the concentration of phytin is changed. FIG. 11 is the chemical structural formula of phytic acid. FIGS. 12 and 13 are graphs showing the binding state of phytic acid to calcium at various concentrations. FIGS. 14 and 15 are graphs showing the binding state of phytic acid and other calcium.

Claims (1)

[Claims] (1) Phytin, a chemical substance present in rice bran, is extracted by dissolving it in diluted water such as hydrochloric acid.The extract is neutralized and precipitated to form crystals, and then a solid auxiliary substance is mixed in to form granules. A drug used for the prevention or treatment of stones that occur in the urinary tract, which is in the form of a pill or pill.