Application of hemoglobin in drugs for improving nocturnal urination

Abstract

The present invention provides the use of heme in a pharmaceutical for ameliorating nocturnal urination. Specifically, the present invention provides the use of heme, its derivatives, its analogs, and its pharmaceutically acceptable salts for preparing pharmaceutical compositions and formulations for (a) treating or ameliorating nocturnal urination; and (b) ameliorating symptoms associated with nocturnal urination. The pharmaceutical compositions or formulations of the present invention not only rapidly and effectively improve nocturnal urination, but also are easily absorbed orally, have high bioavailability, convenient administration routes, and good safety.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and more particularly to application of hemoglobin in medicines for improving nocturnal urination. Background Art

[0002] Frequent urination at night in middle-aged and elderly people refers to urinating more than once at night. Excluding organic diseases, middle-aged and elderly women are often accompanied by autonomic dysfunction, mental and psychological disorders. Frequent urination at night in middle-aged and elderly men is generally attributed to hypertrophy caused by chronic non-bacterial prostatitis. The initial manifestation of prostatic hypertrophy is increased urination frequency, ranging from 2-3 times at night to 5-6 times at night, and prolonged urination time. As the prostate further proliferates, urine obstruction becomes more and more severe, and the urine flow becomes thinner, causing urine to be stored in the bladder and unable to be discharged. Over time, the bladder's compensatory ability gradually decreases and is lost. Prostatic hypertrophy increases the risk of bladder or kidney infections, leading to serious life-threatening consequences. Increased nocturnal urination is an early manifestation of prostatic hypertrophy. For middle-aged and elderly men, early intervention is of great significance.

[0003] Therefore, there is an urgent need in the art to develop a drug that has a quick effect and few toxic and side effects to improve frequent urination. Summary of the Invention

[0004] The purpose of the present invention is to provide a medicine for improving nocturnal urination with rapid effect, significant therapeutic effect and small toxic and side effects.

[0005] In the first aspect of the present invention, there is provided a use of hemoglobin, its derivatives, its analogs, and pharmaceutically acceptable salts thereof for preparing pharmaceutical compositions and preparations, wherein the pharmaceutical compositions and preparations are used for (a) treating or improving nocturnal urination; (b) improving symptoms associated with nocturnal urination.

[0006] In another preferred embodiment, the improvement of nocturnal urination means that after taking the drug for 1-56 days, more than 40%, preferably more than 50% of the subjects have their nocturnal urination improved.

[0007] In another preferred embodiment, the subject is selected from the following groups: patients with untreated nocturnal frequent urination and patients with ineffective drug treatment.

[0008] In another preferred embodiment, the drug is selected from the following group: diuretics, antidiuretic hormones, anticholinergic drugs, α1 receptor blockers, β3 receptor agonists, 5α reductase inhibitors, etc.

[0009] In another preferred embodiment, the heme has a structure shown in Formula A:

[0010]

[0011] In another preferred embodiment, the heme is hemin chloride.

[0012] In another preferred embodiment, the symptoms associated with frequent urination at night are selected from the following group: urgency, pain when urinating, frequent urination, hematuria, thin urine stream, difficulty urinating, small amount of urination, poor sleep, fever, fatigue, night sweats, back pain, tinnitus, dry mouth and throat, bitter taste in the mouth, pale complexion, accompanied by autonomic nervous system dysfunction, depression, psychological disorders and their combinations.

[0013] In another preferred embodiment, the pharmaceutical composition or preparation contains 0.001-99 wt%, preferably 0.1-90 wt%, and more preferably 1-80 wt% of hemoglobin, its derivatives, its analogs, its solvates, and its pharmaceutically acceptable salts, based on the total weight of the composition or preparation.

[0014] In another preferred embodiment, the pharmaceutical composition or preparation contains 0.001-99 wt% of hemin.

[0015] In another preferred embodiment, the pharmaceutical composition or preparation contains 0.1-90 wt%, preferably 1-80 wt%, more preferably 5-60 wt%, and most preferably 20-50 wt% of hemin.

[0016] In another preferred embodiment, the pharmaceutical composition or preparation may further contain other active pharmaceutical ingredients and pharmaceutically acceptable carriers.

[0017] In another preferred embodiment, the carrier is selected from the following group: diluent, excipient, filler, binder, wetting agent, disintegrant, absorption enhancer, sweetener, flavoring agent.

[0018] In another preferred embodiment, the pharmaceutical composition or preparation can be prepared into a dosage form selected from the group consisting of tablets, powders, capsules, granules, oral liquids, ointments, injections, aerosols, pills, pastes, and suppositories.

[0019] In another preferred embodiment, the dosage form is any dosage form that allows hemoglobin to effectively enter the body.

[0020] In another preferred embodiment, the pharmaceutical composition or preparation may further contain other trace elements, such as zinc, calcium, selenium, etc.

[0021] In another preferred embodiment, the pharmaceutical composition or preparation may further contain other excipients, such as lactose, sorbitol, etc.

[0022] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0023] After extensive and intensive research, the inventors have discovered for the first time that heme (structure shown in Formula I) can significantly improve nocturnal urination and symptoms associated with it. Experiments have shown that the pharmaceutical composition of the present invention not only quickly and effectively improves nocturnal urination, but also is easily absorbed orally, has high bioavailability, convenient administration routes, and good safety. This is the basis for the completion of the present invention.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, when used in reference to a specific recited value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0025] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

[0026] Active ingredients

[0027] The present invention provides a compound hemoglobin, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, and derivatives and analogs thereof for improving nocturnal urination.

[0028] In a preferred embodiment of the present invention, the compound hemoglobin for improving nocturnal urination according to the present invention as an active ingredient has a structure of formula A:

[0029]

[0030] The present invention also includes pharmaceutically acceptable salts of the compound of formula A. The term "pharmaceutically acceptable salt" refers to a salt formed by the compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is the salt formed by the compound of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0031] The compounds of formula A of the present invention can be prepared by methods well known to those skilled in the art, and there are no particular restrictions on the reaction parameters of each step. In addition, the typical compounds of the present invention can also be obtained through commercial means.

[0032] In the body, heme (structure shown in Formula A above) serves as a cofactor in substances such as hemoglobin, myoglobin, and cytochromes, capable of binding oxygen and transferring electrons. Heme products, as iron supplements, offer advantages such as high bioavailability, no rusty taste, and no gastrointestinal irritation. Heme is widely recognized as the preferred iron and blood supplement for infants, young children, and pregnant women.

[0033] Studies have shown that heme can induce HO-1 expression in the body, increasing blood levels of CO, bilirubin, and biliverdin, thereby slowing the progression of heart failure and chronic renal failure. Heme can also protect vascular endothelial cells and reduce apoptosis. Therefore, heme has potential applications in organ and cell protection. However, there are currently no reports on heme improving nocturnal urination.

[0034] Compositions and methods of administration

[0035] The present invention provides a composition for improving nocturnal urination, including (but not limited to): a pharmaceutical composition, a dietary supplement, a beverage composition, and the like.

[0036] In the present invention, the pharmaceutical composition can be directly used for treating diseases, for example, for treating nocturnal frequent urination.

[0037] The present invention also provides a pharmaceutical composition comprising a safe and effective amount of a compound of the present invention and a pharmaceutically acceptable carrier or excipient. Such carriers include (but are not limited to) saline, buffer, glucose, water, glycerol, ethanol, powders, and combinations thereof. The pharmaceutical formulation should be compatible with the route of administration.

[0038] Taking pharmaceutical compositions as an example, the compositions of the present invention can be prepared in the form of injections, for example, using physiological saline or an aqueous solution containing glucose and other adjuvants by conventional methods. Pharmaceutical compositions such as tablets and capsules can be prepared by conventional methods. Pharmaceutical compositions such as injections, solutions, tablets, and capsules are preferably manufactured under sterile conditions. The pharmaceutical combination of the present invention can also be prepared as a powder for aerosol inhalation.

[0039] The dosage of the active ingredient is a therapeutically effective amount, for example, about 1 μg / kg body weight to about 5 mg / kg body weight per day. In addition, the hemoglobin, its derivatives and analogs of the present invention can also be used in combination with other therapeutic agents.

[0040] The pharmaceutical composition of the present invention can be administered to a desired subject (such as a human or non-human mammal) in a conventional manner. Representative administration methods include (but are not limited to): oral administration, injection, aerosol inhalation, and the like.

[0041] When using a pharmaceutical composition, a safe and effective amount of the drug is administered to a mammal, wherein the safe and effective amount is generally at least about 10 μg / kg body weight and, in most cases, does not exceed about 8 mg / kg body weight. Preferably, the dose is about 10 μg / kg body weight to about 1 mg / kg body weight. Of course, the specific dose will also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.

[0042] The main advantages of the present invention include:

[0043] 1) Hemoglobin can effectively improve various types of frequent urination caused by different reasons;

[0044] 2) Hemoglobin can effectively improve nocturnal urination in all kinds of people;

[0045] 3) Hemoglobin has no toxic side effects on the human body;

[0046] 4) Hemoglobin is an oral drug that has been used in clinical practice, with a convenient administration route and good safety.

[0047] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0048] Example 1.

[0049] This example observes and evaluates the effects of the following preparations on middle-aged and elderly people suffering from nocturnal urination.

[0050] 1.1 Sample

[0051] Take hemin as the test sample, 175 mg / portion.

[0052] 1.2 Subjects

[0053] 220 middle-aged and elderly people with nocturnal frequent urination and no other diseases.

[0054] 1.3 Criteria for inclusion of tasters

[0055] Voluntary subjects suffering from nocturnal urinary frequency were selected.

[0056] 1.4 Excluding food tasters

[0057] 1.4.1 Complications of important organs such as heart, liver, and kidney;

[0058] 1.4.2 Patients with other serious primary diseases;

[0059] 1.4.3 Incomplete data make it impossible to accurately determine the efficacy;

[0060] 1.5 Tasting Method

[0061] The test subjects included 60 women and 160 men, aged 38-85 years. They took the test substance in 1.1 once a day for 8 consecutive weeks.

[0062] 2. Effectiveness Observation

[0063] 2.1 Symptom Observation

[0064] The main record is whether the subjects' frequent urination at night is improved before and after the test.

[0065] 2.2 Safety Observation

[0066] Observe for any side effects such as allergies, poisoning, and gastrointestinal reactions.

[0067] 2.3 Effectiveness judgment criteria

[0068] 1) The treatment is effective if the frequency of nocturnal urination is reduced and sleeping conditions are improved.

[0069] 2) Number of people whose nocturnal frequent urination was effectively improved.

[0070] 2.4 Test results

[0071] 1) Subjects' conditions before the trial

[0072] A total of 190 subjects completed the study, including 48 females and 142 males.

[0073] Table 1-1 General situation before tasting

[0074]

[0075] 2) Comparison of nocturnal urination before and after the trial

[0076] The efficacy of the test subjects was recorded and graded. The grading standards are shown in Table 1-2. The total number of effective cases is the sum of the number of cases with significant effect and improvement.

[0077] Table 1-2 Efficacy grading standards

[0078]

[0079] After four weeks of treatment, both groups experienced significant improvement in their nocturnal urination, with the number of participants experiencing the condition significantly reduced compared to before the trial (see Tables 1-3). Of the 48 female participants, 22 (45.83%) experienced marked improvement, while 20 (41.67%) showed improvement, for an overall effective rate of 87.50%. Of the 142 male participants, 53 (37.32%) achieved marked improvement, while 37 (26.06%) showed improvement, for an overall effective rate of 63.38%.

[0080] After 8 weeks of treatment, among the 48 female subjects, 30 (62.50%) achieved significant effects, 14 (29.17%) improved, and the total effective rate reached 91.67%; among the 142 male subjects, 71 (50.00%) achieved significant effects, 50 (35.21%) improved, and the total effective rate was 85.21%.

[0081] No allergic, poisoning or other adverse reactions were observed during the tasting.

[0082] Table 1-3 Nocturnal urination after feeding (examples)

[0083]

[0084] in conclusion

[0085] Hemoglobin can effectively improve nocturnal urination caused by different reasons and has no toxic side effects on the human body.

[0086] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. Use of hemin in the preparation of a pharmaceutical preparation for treating or improving nocturnal urination.

2. The use according to claim 1, characterized in that The pharmaceutical preparation contains 0.001-99 wt% of hemin.

3. The use according to claim 1, characterized in that The pharmaceutical preparation also contains a pharmaceutically acceptable carrier.

4. The use according to claim 1, wherein The pharmaceutical preparation can be prepared in a dosage form selected from the group consisting of tablets, capsules, granules, oral liquids, and pills.

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