JPWO2007018234A1 - Urinary pressure increasing agent - Google Patents

Abstract

An object of the present invention is to provide a novel agent for increasing urethral pressure. The present invention relates to a urethral pressure-increasing agent containing tramadol or a pharmaceutically acceptable salt thereof as an active ingredient, or a therapeutic or preventive agent for stress urinary incontinence. [Selection figure] None

Description

  The present invention relates to an agent for increasing intraurethral pressure, which contains tramadol or a pharmaceutically acceptable salt thereof as an active ingredient.

  Tramadol (generic name) has the chemical name (1R, 2R) and (1S, 2S) -2-[(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol and has an opioid action. It is generally known as a non-narcotic analgesic that exhibits an analgesic action by exerting a monoamine enhancing action, and is marketed in about 100 countries around the world.

  Moreover, since tramadol has an action of increasing bladder capacity, it is considered effective for urge urinary incontinence (see, for example, Patent Document 1). Optically active tramadol is also known to increase the bladder dose (see, for example, Patent Document 2).

  Urinary incontinence is a disease whose pathological condition is involuntary urination caused by low urethral pressure or detrusor overactivity (uninhibited contraction of bladder smooth muscle).

  An example of urinary incontinence caused by low urethral pressure can be stress urinary incontinence. Stress urinary incontinence is a pathological condition in which the urinary tract droops and the bladder pressure is higher than the urethral pressure when the abdominal pressure is applied, causing urine leakage without bladder contraction. Around the urethra, there are an internal urethral sphincter, an external urethral sphincter, and a pelvic floor muscle. By strengthening these muscle contractions with a drug, the pressure in the urethra can be increased to treat stress urinary incontinence. Drugs used to treat stress urinary incontinence include, for example, α-adrenergic receptor stimulants (eg, ephedrine), tricyclic antidepressants (eg, imipramine), β-adrenergic receptor stimulants (eg, clenbuterol) Examples include female hormone drugs (eg, estradiol).

On the other hand, examples of urinary incontinence caused by detrusor overactivity include urge urinary incontinence. Urgent urinary incontinence is an involuntary urinary leak with strong urinary intent. The treatment involves drugs that reduce the contractility of the detrusor (bladder smooth muscle), such as anticholinergic drugs (eg, oxybutynin, propiverine), tricyclic antidepressants (eg, imipramine), direct smooth muscle relaxants (eg, Flavoxate) is used.
International Publication No. 98/0462216 Pamphlet International Publication No. 01/024783 Pamphlet

  An object of the present invention is mainly to provide a novel agent for increasing urethral pressure.

  As a result of intensive studies, the present inventor has found that tramadol or a pharmaceutically acceptable salt thereof (hereinafter referred to as “tramadol etc.”) has an action of increasing the urethral pressure, and completed the present invention.

  The present invention is a urethral pressure-increasing agent containing tramadol or the like as an active ingredient, or an agent for preventing or treating stress urinary incontinence (hereinafter referred to as “tramadol pharmaceutical composition”). The present invention can also be said to be the use of tramadol or the like for producing an agent for increasing urethral pressure, or a preventive or therapeutic agent for stress urinary incontinence.

  The “urethral pressure-increasing agent” in the present invention refers to a drug effective for preventing or treating stress urinary incontinence, for example, showing an action of constricting the urethral sphincter or pelvic floor muscles to increase the urethral pressure.

  The present invention is described in detail below.

  Since tramadol is a basic compound, it can be used as a medicine as a free base, but can be used as a medicine in the form of a pharmaceutically acceptable salt by a known method.

  The “pharmaceutically acceptable salt” in the present invention is not particularly limited, and examples thereof include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, hydrofluoride and hydrobromide, and Carbonate, acetate, tartrate, lactate, propionate, glycolate, malonate, maleate, fumarate, tannate, succinate, alginate, benzoate, 2-phenoxy Benzoate, 2-acetoxybenzoate, cinnamate, mandelate, citrate, malate, salicylate, 3-aminosalicylate, ascorbate, embonate, nicotinate, iso Nicotinate, oxalate, amino acid salt, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, ethane-1,2-disulfonate, benzene Hong acid salts include 4-methylbenzenesulfonate, and organic acid salts such as naphthalene-2-sulfonate. In tramadol, the hydrochloride salt that is widely used as an analgesic for treatment is particularly preferred.

Tramadol and the like have an excellent urethral pressure-increasing action as shown in the following test examples, and are useful as, for example, preventive or therapeutic agents for stress urinary incontinence.
Tramadol or the like can be used to increase urethral pressure in animals including humans. Further, tramadol and the like can be used for prevention or treatment of stress urinary incontinence in animals including humans.

  The dose of tramadol and the like varies depending on the patient's condition such as body weight and age, administration route, nature and progression of the disease, etc., but generally ranges from 0.01 to 400 mg per day for adults. The inside is appropriate, preferably in the range of 0.1 to 200 mg, more preferably in the range of 1 to 100 mg. In some cases, less than this may be sufficient, and vice versa. Tramadol and the like can be used within the dose range usually used as an analgesic or within an equivalent range. In addition, for example, it can be administered divided into 2 to 5 times a day.

  The tramadol pharmaceutical composition comprises tramadol or the like as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example in the range of 0.01 to 99.5%, preferably 0.5 to 90%. It can be contained within the range.

  As the carrier, one or more solid, semi-solid, or liquid diluents, fillers, and other prescription auxiliary agents can be used. It is desirable to administer the tramadol pharmaceutical composition in dosage unit form. The tramadol pharmaceutical composition is a solid or liquid dosage unit, and is a powder, capsule, tablet, dragee, granule, powder, suspension, solution, syrup, elixir, troche, etc. Any form of parenteral preparations such as injections and suppositories can be used. It may be a sustained-release preparation. In particular, oral administration preparations such as tablets are preferred.

  The powder can be produced by making tramadol or the like fine. The powder can be produced by making tramadol or the like fine, and then mixing it with a finely divided pharmaceutical carrier such as edible carbohydrates such as starch and mannitol. A flavoring agent, a preservative, a dispersing agent, a coloring agent, a fragrance, and the like can be optionally blended.

  Capsules are first prepared by filling the powdered powder, powder or powder as described above into granules as described in the section of the capsule, for example, into capsule shells such as gelatin capsules. be able to. Lubricants and fluidizing agents such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol and the like can be mixed into a powdered state and then filled. Disintegrants and solubilizers such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium, calcium carbonate, sodium carbonate The effectiveness of the medicine can be improved. In addition, fine powders such as tramadol can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant and wrapped in a gelatin sheet to form a soft capsule.

  Tablets can be manufactured by adding excipients to make a powder mixture, granulating or slugging, then adding a disintegrant or lubricant and then tableting. The powder mixture is prepared by mixing an appropriately powdered substance with the above-mentioned diluent or base, and if necessary a binder (for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc.), Dissolution retarders (for example, paraffin), resorbents (for example, quaternary salts) and adsorbents (for example, bentonite, kaolin) can also be used in combination. The powder mixture can be first wetted with a binder such as syrup, starch paste, gum arabic, cellulose solution or polymer solution, stirred and mixed, dried and pulverized into granules. Instead of granulating the powder in this way, it is possible to first crush the tablet and then crush the resulting imperfectly formed slag into granules. The granules thus produced can be prevented from adhering to each other by adding stearic acid, stearate, talc, mineral oil or the like as a lubricant. Film coating or sugar coating can be applied to the uncoated tablets thus produced. In addition, tramadol or the like can be directly compressed after mixing with a fluid inert carrier without going through the steps of granulation and slag as described above. A transparent or translucent protective coating made of a shellac hermetic coating, a coating of sugar or polymer material, and a polishing coating made of wax can also be used.

  Other oral dosage forms, such as solutions, syrups, troches, elixirs, can also be in dosage unit form so that a given quantity contains a certain amount, such as tramadol. A syrup can be produced by dissolving tramadol or the like in an appropriate flavor aqueous solution, and an elixir can be produced by using a non-toxic alcoholic carrier. The suspension can be produced by dispersing tramadol or the like in a non-toxic carrier. Solubilizers and emulsifiers (eg, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavoring agents (eg, peppermint oil, saccharin) and others can also be added as needed. .

  If desired, dosage unit formulations for oral administration can be microencapsulated. The formulation can also provide extended action time or sustained release by coating or embedding in a polymer, wax or the like.

  A parenteral preparation can be prepared by using a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection, for example, a solution or suspension form. These are prepared by suspending or dissolving a certain amount of tramadol or the like in a non-toxic liquid carrier suitable for injection purposes, such as an aqueous or oily medium, and then sterilizing the suspension or solution. can do. Non-toxic salts and salt solutions can also be added to make the injection solution isotonic. Furthermore, stabilizers, preservatives, emulsifiers and the like can be used in combination.

  Suppositories are solids in which tramadol or the like is soluble or insoluble in water having a low melting point, such as polyethylene glycol, cacao butter, semi-synthetic fats and oils (for example, Witepsol, registered trademark), higher esters (for example, myristyl palmitate) And dissolved or suspended in a mixture thereof.

The present invention will be described in further detail below using test examples. However, it goes without saying that the present invention is not limited to the following test examples.
Test example 1
In the experiment, female SD rats (manufactured by SLC Japan, Inc.) having a body weight of 170 to 300 g were used. The animals were anesthetized by subcutaneous administration of urethane (900 mg / kg) and fixed in a dorsal position on a fixed table. After a midline incision was made in the lower abdomen, the bladder was exposed, the bladder was lightly pressed to drain the retained urine from the body, and then the ureters on both sides were cut.

  A 3-Fr microchip pressure transducer (SPC-330; manufactured by Millar Ltd) was inserted into the bladder through the mouth of the external urethra, and a urethral pressure measurement extraction device (KU-601G; manufactured by Nihon Kohden Co., Ltd.) and urethral pressure control module Using AU-601G (manufactured by Nihon Kohden Co., Ltd.), it was extracted from the bladder neck to the distal urethra about 15 mm and placed. The urethral pressure was amplified by a strain pressure amplifier (AP-620G; manufactured by Nihon Kohden Co., Ltd.) via a transducer control unit (TC-500; manufactured by Millar Ltd), and the output was then rectified (WT-685G; Japan). Recorded by Kodensha).

  In addition, the thigh skin was incised, and a tube was inserted into the femoral vein for administration of the test substance. After the intraurethral pressure was stabilized, the control substance and the test drug were administered intravenously. The administration dose was adjusted to 1 ml / kg at the time of use. As a test drug, tramadol hydrochloride 1 mg / kg, 3 mg / kg, 10 mg / kg dissolved in physiological saline was used. As a positive control substance, duloxetine hydrochloride (duloxetine hydrochloride 3 mg / kg dissolved in physiological saline containing 1% dimethyl sulfoxide), which is known to be effective for stress urinary incontinence due to the action of increasing urethral pressure, was used. As a negative control substance, a physiological saline solution (control substance 1) was used for the tramadol administration group, and a physiological saline solution containing 1% dimethyl sulfoxide (control substance 2) was used for the duloxetine administration group. The urethral pressure was recorded over time up to 30 minutes after administration of the control substance and the test drug. The urethral pressure immediately before administration and 5 minutes, 10 minutes, 20 minutes, and 30 minutes after administration and the urethral pressure with the greatest change (at peak) The urethral pressure was recorded.

  As the experimental results, the urethral pressure change value (ΔmmHg) from before administration and the difference between the pre-administration value and the peak urethral pressure (peak ΔmmHg) were obtained, and this was expressed as an average value ± standard error. In the case of multiple groups, Dunnett's multiple comparison is performed after a one-way analysis of variance between the control substance group and the test drug administration group in the case of multiple groups. In the case of two groups, t-test (equal variance) or Welch test (unequal variance) ) In any case, the case of P <0.05 was considered significant. Table 1 shows changes over time in urethral pressure change values (ΔmmHg) from before administration, and Table 2 shows changes in peak urethral pressure.

As shown in Table 1, in the intravenous administration of tramadol hydrochloride 3 mg / kg, the urethral pressure was significantly increased as compared with the control substance in the measurement at 5 minutes after administration. In addition, in the case of intravenous administration of 10 mg / kg of tramadol hydrochloride, the urethral pressure was significantly increased as compared with the control substance at 5 minutes, 10 minutes, and 20 minutes after the administration. In addition, duloxetine hydrochloride used as a positive control drug showed a significant increase in urethral pressure compared to the control substance 5 minutes after intravenous administration of 3 mg / kg.

  As shown in Table 2, the peak urethral pressure was significantly increased by intravenous administration of tramadol hydrochloride 3 mg / kg and 10 mg / kg.

From the above results, tramadol hydrochloride and the positive control drug duloxetine hydrochloride showed a similar increase in urethral pressure. Therefore, it is clear that tramadol hydrochloride is effective as a urethral pressure-increasing agent, or a preventive or therapeutic agent for stress urinary incontinence.

Formulation Example 1 Tablet (internal use)
100 mg of tramadol hydrochloride in 150 mg of 1 formulation
Corn starch 38 mg
Crystalline cellulose
10.5 mg
Magnesium stearate 1.5 mg
This proportion of the mixed powder is formed into tablets by a conventional method.

The compound of the present invention is useful not only as an analgesic but also as an agent for increasing urethral pressure, and can be applied to the prevention or treatment of stress urinary incontinence.

Claims (8)

An agent for increasing intraurethral pressure, containing tramadol or a pharmaceutically acceptable salt thereof as an active ingredient. An agent for preventing or treating stress urinary incontinence containing tramadol or a pharmaceutically acceptable salt thereof as an active ingredient. The agent for increasing intraurethral pressure according to claim 1, wherein the pharmaceutically acceptable salt of tramadol is tramadol hydrochloride. The agent for preventing or treating stress urinary incontinence according to claim 2, wherein the pharmaceutically acceptable salt of tramadol is tramadol hydrochloride. Use of tramadol or a pharmaceutically acceptable salt thereof for producing an agent for increasing urethral pressure. Use of tramadol or a pharmaceutically acceptable salt thereof for producing a preventive or therapeutic agent for stress urinary incontinence. Use according to claim 5, wherein the pharmaceutically acceptable salt of tramadol is tramadol hydrochloride. 7. Use according to claim 6, wherein the pharmaceutically acceptable salt of tramadol is tramadol hydrochloride.