JP4201771B2 - Frequent urine improving agent and pharmaceutical composition and food containing the same - Google Patents

Description

  The present invention relates to a drug, a pharmaceutical composition and a food for preventing or treating frequent urination.

  Frequent urination means a state in which the number of urinations has increased. Although there are individual differences in the number of urinations, the urine volume of healthy adults is around 1500 mL in 24 hours, and the capacity of the bladder when urinating is about 250-300 mL. About 6 times. Therefore, if urination occurs more than 10 times a day, it can be defined as frequent urination.

  Many people suffer from frequent urination due to various causes. This is especially true for older men.

  The first cause of frequent urination is a disease that increases urine output (polyuria). Polyuria can be caused by diabetes insipidus, diabetes, at certain times of renal failure, and by other drugs. In addition, there is a disease near the bladder, and frequent urination occurs when chronic stimulation is applied to the bladder. This applies to cancerous peritonitis, rectal cancer, uterine fibroids, etc. Sometimes pain such as back pain may irritate the bladder and cause frequent urination. Other frequent pollakiuria is often due to urinary disease. This includes renal droppings, urinary tract infections, atrophic bladder, and ureteral stones close to the bladder. Frequent urination associated with urinary tract infections occurs because, for example, acute cystitis associated with the growth of pathogenic bacteria stimulates urination, and urinary urination always involves urinary pain. In addition, there is psychogenic frequent urination.

  Because the cause of frequent urination is unclear, the frequent therapeutic problem is frequent urination in the elderly, and the most frequent is frequent urination associated with benign prostatic hyperplasia. Prostatic hypertrophy occurs with age. One of four men over the age of 60 suffers from this disease, such as difficulty in urinating, feeling of residual urine, and getting up in the bathroom many times in the night.

  Prostatic hypertrophy is a disease in which the urethra is compressed because the prostate surrounding the urethra is enlarged. Symptoms vary depending on the degree to which the urethra is compressed, but the main symptoms are dysuria and frequent urination, which makes it difficult for urine to leave the bladder. If anything, dysuria is the main cause, and frequent urination is accompanied by difficulty in urination. The cause of prostatic hypertrophy is not clear, but the balance between male and female hormones is thought to be a cause. Prostatic hypertrophy nodules, which is one of the aging phenomena commonly seen in men since their late 40s, is also considered to be a factor in hormonal imbalance.

  In the early stages of prostate cancer, dysuria appears, as with benign prostatic hyperplasia. When prostate cancer grows to a certain extent, the urethra is compressed, causing symptoms that are not related to benign prostatic hypertrophy, such as difficulty urinating, frequent urination, and residual urine sensation. Prostate cancer is the most common cancer in the United States, accounting for the top number of male cancer deaths. In Japan, the number of patients has increased rapidly in recent years due to changes in lifestyle habits, which has become a major medical problem. The onset of prostate cancer correlates with animal fat overdose and is said to be affected by lifestyle habits. People tend to think that prostate enlargement will progress to prostate cancer, but the two have little to do with each other.

  Regardless of the cause, frequent urination is an illness and treatment is essential because it reduces the quality of life (QOL).

  Table 1 shows drugs for treating frequent urination due to benign prostatic hyperplasia.

Current therapeutic drugs for pollakiuria are not satisfactory in terms of efficacy and safety. Among them, α ₁ blocker is frequently used and is frequently used. Its mechanism of action agent binds to adrenergic alpha ₁ receptor, based on inhibition of the action of the hormone. Since this series of drugs is produced as a by-product from the blood pressure lowering agent, side effects such as dizziness and dizziness due to blood pressure decrease occur.

  Anti-androgen drugs are used to treat androgen-sensitive prostate cancer. However, since side effects occur frequently, including liver dysfunction, QOL is lowered.

In contrast, herbal medicines and herbs, side effects are seldom, the effect when not take long is not expressed, and because of that potency weaker than the alpha ₁ blockers, application is limited.

  Antibiotics are effective in treating frequent urination associated with urinary tract infections. However, when pathogenic bacteria colonize the urinary tract and become chronic, it is difficult to sterilize with antibiotics alone. For this reason, infectious diseases recur due to various stimuli that lower the immune ability, such as cold stimuli, and frequent urination occurs. At present, there is no effective and appropriate measure against such urinary tract infections that recur.

  Lactoferrin is a glycoprotein having a molecular weight of about 80,000, which is mainly present in mammalian milk and is also found in neutrophils, tears, saliva, nasal discharge, bile, semen and the like. Lactoferrin belongs to the transferrin family because it binds iron. The physiological activities of lactoferrin include antibacterial action, iron absorption control, cell proliferation activation action, hematopoiesis action, anti-inflammatory action, antioxidant action, phagocytosis action, antiviral action, bifidobacteria growth promotion action, anticancer action Cancer metastasis inhibitory action, translocation inhibitory action, etc. are known. Thus, since lactoferrin is a multifunctional physiologically active protein that exhibits various functions, it is expected to be used for applications such as pharmaceuticals and foods. In fact, foods containing lactoferrin are already on the market. .

  However, no data specifically reporting that lactoferrin is effective in preventing or treating causative diseases such as benign prostatic hyperplasia and prostate cancer, frequent urination due to urinary tract infection, etc. has not been reported. That is, it has never been known that lactoferrin improves frequent urination.

Special table 2001-504447 JP-A-6-145068

  Frequent urination not only afflicts the sick but also results in enormous social and economic losses. Regardless of the cause, frequent urination significantly reduces the quality of life (QOL) due to troublesome frequent urination, stress due to difficulty in urination, lack of sleep due to interruption of sleep every time urination, and the like. Also, the medical costs spent on treating prostate hypertrophy, prostate cancer and urinary tract infections and improving frequent urination are enormous. Such medical costs are expected to be greatly reduced if these diseases or symptoms can be prevented.

  Therefore, the problem to be solved by the present invention is to provide a safe and highly effective treatment or prevention means for patients suffering from frequent urination, but it is not limited to this, and QOL is improved at the individual level. And reduction of medical costs at the social level.

The present invention
[1] An agent for improving frequent urination containing lactoferrin as an active ingredient;
[2] The frequent urination improving agent according to the above [1], wherein the frequent urination is caused by causes other than polyuria;
[3] The frequent urination improving agent according to the above [1] or [2], which improves urination difficulty together with frequent urination;
[4] A pharmaceutical composition for improving frequent urination , comprising the frequent urine improving agent according to any one of [1] to [3];
[5] The pharmaceutical composition for improving frequent urination according to the above [4], which is enteric;
I will provide a.

  According to the frequent urination improving agent, pharmaceutical composition, food and feed of the present invention (hereinafter sometimes referred to as frequent urination improving agent and the like), frequent urination can be relieved or cured, and chronic urinary tract infection can be achieved. Frequency can be prevented by suppressing recurrence of the disease. In addition, the lactoferrin contained as an active ingredient in the frequent urination improving agent of the present invention has a very high safety and a large amount or Even if administered or ingested continuously for a long period of time, no side effects will occur. Therefore, the frequent urination improving agent or the like of the present invention containing lactoferrin as an active ingredient is highly safe even after long-term use.

  Furthermore, since lactoferrin does not have any side effects even if it is administered for a long time, it is not necessary for the sick to go to a medical institution once every two weeks in order to receive the frequent urination drug. Thus, the sick can avoid time and economic losses and socially save huge medical costs.

  The agent for improving frequent urination etc. of the present invention not only prevents or treats (improves) frequent urine, but also resolves or improves various inconvenient situations accompanying it to the sick and medical institutions treating it. It also has the effect of improving the QOL of the sick. Furthermore, social costs associated with medical care can be reduced.

  Lactoferrin also has the effect of improving the inflammation of the prostate, so that the prostate surrounding the urethra is relaxed, and as a result, the pressure on the urethra is released. Therefore, according to the frequent urination improving agent and the like of the present invention, urination difficulty and frequent urination are simultaneously improved. On the other hand, since lactoferrin also has an action to improve inflammation of the bladder, according to the frequent urination improving agent of the present invention, it is possible to suppress the hypersensitive urination reaction based on cystitis.

  The lactoferrin used in the present invention is a natural lactoferrin molecule obtained from humans and various animals, such as cows, horses, pigs, sheep, goats, camels, etc. Any of recombinant lactoferrin produced based on a lactoferrin gene modified by genetic engineering technology, lactoferrin such as lactoferrin lactated by transgenic animals, and functional equivalents such as lactoferrin active fragments It may be. Therefore, the term “lactoferrin” in the context of the present invention is used to encompass these various lactoferrins unless otherwise indicated.

  In the present invention, one or more of these lactoferrins can be appropriately selected and used. From the viewpoints of availability, economy and the like, typically, bovine-derived lactoferrin, particularly lactoferrin isolated and purified from milk is conveniently used.

  The frequent urination improving agent of the present invention contains lactoferrin as the only essential component, but may optionally contain various components known in the pharmaceutical or food industry. For example, other pollakiuria improving substances can be included. In the present invention, “improvement” of frequent urination is used in the meaning including prevention and treatment (including remission and cure). Therefore, the frequent urination improving agent of the present invention can be aimed at either or both of prevention or treatment of frequent urination.

  The frequent urination improving agent of the present invention is a pharmaceutical composition obtained by adding excipients, disintegrating agents, lubricants and the like that are routinely used in the pharmaceutical industry as physiologically or pharmaceutically acceptable additives. It can be.

  For example, excipients include lactose, sucrose, glucose, sorbitol, lactitol and other monosaccharides or disaccharides, corn starch, potato starch and other starches, crystalline cellulose, and inorganic substances such as light silica gel, synthetic aluminum silicate, metasilicate aluminum Examples include magnesium acid and calcium hydrogen phosphate. However, reducing monosaccharides and disaccharides cause an aminocarbonyl reaction with the ε-amino group of lactoferrin to denature proteins. In particular, in the presence of moisture and iron ions, the rapid aminocarbonyl reaction proceeds, so it should be avoided. Examples of the disintegrant include starches, carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), carboxymethylcellulose sodium salt, and polyvinylpyrrolidone. As the lubricant, sucrose fatty acid ester, calcium stearate, magnesium stearate and the like can be used.

  Furthermore, the pharmaceutical composition of the present invention may contain a known pharmaceutically active ingredient.

  The pharmaceutical composition of this invention can be used as arbitrary dosage forms, such as a tablet, a granule, a capsule, a powder. The pharmaceutical composition of the present invention is particularly advantageous when it is in the form of an enteric preparation. Methods for producing such various preparations are well known to those skilled in the art. The term “pharmaceutical composition” in the context of the present invention includes not only those applied to humans but also those applied to animals veterinarily (veterinary medicine).

  Moreover, the frequent urination improving agent of the present invention can be added to foods and feeds, and can be ingested by humans or non-human target animals as foods or feeds. Such food or feed production methods are also known to those skilled in the art.

  The subject to be provided with the frequent urination improving agent of the present invention or a pharmaceutical composition, food or feed containing the same is various animals such as humans, mammals other than humans, and birds, such as cattle, Examples include livestock such as horses, pigs, sheep, goats and chickens, and pets such as poultry, dogs and cats.

Frequent urination for which frequent urination improving agent of the present invention is improved, preferably other than those caused by polyuria urinary frequency.

  The administration route of the frequent urination improving agent of the present invention may be any known route, and for example, any route such as oral, transdermal, injection, enteral, and rectal can be selected. Oral administration is preferred.

  The effective dosage of the frequent urination-improving agent according to the present invention varies depending on the type, age, weight, physical condition, etc. of the subject to be administered, and can be administered in an amount suitable for each. When administered to a mammal, the dose can be, for example, 0.001 to 10 g / kg / day, preferably 0.01 to 5 g / kg / day. When administered to humans, the amount of active ingredient is generally 50 mg to 15,000 mg, preferably 300 mg to 6,000 mg per day. Such daily doses can be administered once or divided to a subject in need of prevention, treatment or improvement of frequent urination with the frequent urination-improving agent of the present invention.

  The frequent urination improving agent of the present invention may be used in combination with other drugs. The above explanation regarding the administration route, dosage and the like applies similarly to the pharmaceutical composition for improving frequent urination of the present invention.

  EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto.

Example 1: Frequent urinary improving agent containing lactoferrin NLF Pharma Co., Ltd., manufactured by Japan Health Promotion Institute, Inc. Lactoferrin enteric preparation (86 mg contained in one tablet as pure lactoferrin) Was used as a pharmaceutical composition.

Improvement of frequent urination in pathological model animals A pathological model of acetic acid-induced cystitis was created using rats as experimental animals. This pathological model is a model of frequent urination caused by cystitis due to urinary tract infection because it exhibits frequent urinary symptoms due to hypersensitivity urination reflex enhancement due to cystitis. Using the number of urinations in this rat as an index, the effect of oral polluted lactoferrin on frequent urination was examined.

  Each dose (1, 0.3, 0.1, or 0.03 g / kg / day) of the above-mentioned pharmaceutical composition containing an agent for improving frequent urination was administered once each on day 0 and day 1 (total 2 times). ) After oral administration, 0.1% acetic acid was injected into the bladder and recovered 1 minute later to cause cystitis. The next morning (Day 2), lactoferrin was administered in the same manner, and after 10 hours of water shortly thereafter, 10 mL of water was forcibly administered orally, and the rats were housed one by one in a urine collection cage attached to a video monitor. The number of urinations and urine volume at 3 hours (equivalent to 24 to 27 hours after injecting acetic acid into the bladder) were measured. Regarding the number of urinations, the video taken was observed, the number of urinations at the individual level was measured, and the average value ± standard error was calculated for each group. On the next day (the third day), similarly to the second day, the number of urinations and the amount of urine were measured after lactoferrin administration. An outline of the experiment (experiment schedule) is shown in FIG.

  For comparison, the same measurements were performed on animals that did not cause cystitis (“healthy controls”) and animals that caused cystitis but did not receive lactoferrin (“controls”). In all groups, there were 5 rats per group.

  2 to 5 show the results of an experiment using a pathological model 24 hours and 48 hours after injecting acetic acid into the bladder. In the figure, “LF” means lactoferrin, and “*” and “**” indicate that there is a significant difference compared to the control group (“control”) (according to Student's t-test).

  At 24 hours after the onset of cystitis (FIG. 2), the number of urinations in the control group averaged 15 times within 3 hours of drinking water. In the lactoferrin administration group (lactoferrin was administered every day from 2 days before), the number of urinations was significantly reduced at all doses, and was suppressed to about the same as the healthy control group to about half of the control group.

  Such a frequent pollakiuria-inhibiting effect of lactoferrin was observed even 48 hours after the onset of cystitis as shown in FIG. The effect was more remarkable than 24 hours after the onset of cystitis, and the frequency of urination decreased to 1/3 to 1/2 of the control group in a dose-dependent manner.

  On the other hand, regarding the amount of urination within 3 hours of drinking water, there was no significant difference between the control group and the lactoferrin administration group (FIGS. 4 and 5). Therefore, it was found that the decrease in the number of urinations due to lactoferrin was not due to a decrease in the amount of urination.

  From the above results, it was confirmed that frequent urination due to cystitis was improved when lactoferrin was administered in advance. Moreover, since there was no significant difference in urinary excretion, it was found that lactoferrin improves frequent urination without affecting kidney function.

Confirmation of frequency urination improvement in humans 3 patients with benign prostatic hyperplasia (KA (71 years old), HS (62 years old), GK (47 years old)) and prostate cancer patients (SM (81 years old)) complaining of dysuria The effect of lactoferrin on frequent urination was examined. SM is a patient who has refused surgery due to her age and has been treated with drugs.

The above-mentioned lactoferrin enteric preparation (milk lactoferrin 86 mg / tablet) was taken orally for 4 weeks after breakfast and after dinner. Measurement of the average urinary flow rate was performed according to the following formula by urinating urine one day before the start of lactoferrin tablets and at 20:00 immediately after the end of the internal use, measuring the amount of urination and urination time.
Urination volume (mL) ÷ Urination time (seconds) = Average urine flow rate

  The results are shown in Table 2.

  As shown in Table 2, after one week of oral lactoferrin, the average urinary flow rate was improved in all subjects (P <0.01; according to Student paired t-test), indicating that dysuria was improved. .

  A questionnaire survey was conducted on subjective symptoms before and after taking lactoferrin tablets for these subjects. The results are shown in Table 3.

  Therefore, it was found that taking most of the patients improved the unpleasant symptoms such as difficulty in urination and feeling of residual urine by taking the pharmaceutical composition of the present invention.

FIG. 1 is a diagram for explaining an experimental schedule using a rat frequent urination condition model. FIG. 2 is a graph showing the relationship between lactoferrin administration and the number of urinations in a rat frequent urination state model (24 hours after inducing cystitis). FIG. 3 is a graph showing the relationship between the administration of lactoferrin and the number of urinations in a rat frequent urination condition model (48 hours after inducing cystitis). FIG. 4 is a graph showing the relationship between the administration of lactoferrin and the amount of urination in a rat frequent urination condition model (24 hours after inducing cystitis). FIG. 5 is a graph showing the relationship between the administration of lactoferrin and the amount of urination in a rat frequent urination condition model (48 hours after inducing cystitis).

Claims (5)

  An agent for improving frequent urination containing lactoferrin as an active ingredient.   The frequent urination agent according to claim 1, wherein the frequent urination is caused by causes other than polyuria.   The frequent urination improving agent according to claim 1 or 2, which improves dysuria together with frequent urination. The pharmaceutical composition for frequent urination improvement containing the frequent urination improving agent of any one of Claims 1-3. The pharmaceutical composition for improving frequent urination according to claim 4, which is enteric.

Images