JP2013035833A - Composition for treating urinary frequency - Google Patents

Abstract

The present invention provides an excellent pharmaceutical composition for preventing and / or treating lower urinary tract symptoms having high efficacy and few side effects.
An agent for the prevention and / or treatment of lower urinary tract symptoms, comprising loxoprofen sodium or a hydrate thereof, and one or more amino acids selected from the group consisting of L-glutamic acid or a salt thereof and glycine. Pharmaceutical composition.
[Selection figure] None

Description

  The present invention relates to a pharmaceutical composition containing loxoprofen sodium or a hydrate thereof for preventing and / or treating lower urinary tract symptoms (LUTS) such as frequent urination.

  As Japan's aging progresses, an increasing number of patients complain of various symptoms related to urination. Recently, symptoms related to urination have been classified into three categories: urinary storage symptoms, urination symptoms, and post-urination symptoms, and these symptoms are collectively referred to as lower urinary tract symptoms (LUTS). Yes. Lower urinary tract symptoms include symptoms such as frequent urination, urgency, urinary incontinence, delayed urination, and residual urine. If there are underlying diseases (prostatic hypertrophy, hypertension, etc.) that can cause any of these symptoms, they are first treated. Medicine may be added. However, anticholinergic drugs are known to be highly effective but have a high incidence of side effects such as dry mouth and constipation.

  Loxoprofen sodium or a hydrate thereof is known as a non-steroidal antipyretic analgesic that inhibits cyclooxygenase, has excellent efficacy and safety, and is widely used clinically. In addition, loxoprofen sodium has been reported to have an effect of reducing the number of urinations for the treatment of nocturnal enuresis and nocturia (for example, see Patent Document 1 and Non-Patent Documents 1 to 3).

Glycine, a kind of amino acid, is known to have an effect as an antacid, in addition to being used as a component of a mixed amino acid preparation. Similarly, L-glutamic acid, which is a kind of amino acid, is produced as an intermediate of sodium L-glutamate, which is a component of the seasoning, and is also used as a component of mixed amino preparations. Furthermore, any component is also used as a pharmaceutical additive in applications such as a corrigent.
On the other hand, anti-edema action of amino acids is expected, glycine, glutamic acid and alanine-containing composition is administered to patients with benign prostatic hyperplasia, urination difficulty due to urinary retention due to the disease, frequent urination, residual urinary sensation, nocturia, etc. It has been reported that slight improvement was observed (see, for example, Non-Patent Document 4). However, the composition indirectly improves urethral pressure improvement by enlargement of the prostate using the anti-edema action of amino acids and dysuria such as residual urine sensation based on the enlargement of the prostate, by reducing edema. There is no report on the effect of suppressing frequent urination and urine volume in patients without urinary retention.

Although specific data is not disclosed, it is described that glycine suppresses gastric mucosal damage caused by loxoprofen sodium or its hydrate (for example, see Patent Document 2).
However, there is no report or suggestion about the anti- frequent urination effect when loxoprofen sodium or a hydrate thereof is used in combination with glycine or glutamic acid.

US Pat. No. 7,547,688 JP 2006-52210 A

Clinical Medicine Vol. 21, No. 1, 89-95 2005 Acta. Med. Okayama, 2004, Vol. 58 (1), 45-49 Acta. Med. Okayama, 2008, Vol. 62 (6), 373-378 New drugs and clinical medicine Vol.18 No.5 123-125 1969

  As described above, existing therapeutic agents for lower urinary tract symptoms based on anticholinergic effects are widely used and highly effective, but there is a problem that the incidence of side effects is as high as 20.9 to 54.6%. . That is, an object of the present invention is to provide an excellent pharmaceutical composition for preventing and / or treating lower urinary tract symptoms having high effectiveness and few side effects.

  As a result of intensive studies to solve the above problems, the present inventors use loxoprofen sodium or a hydrate thereof, and one or more amino acids selected from L-glutamic acid or a salt thereof and glycine in combination. Thus, it was found that an excellent effect on lower urinary tract symptoms was obtained, and the present invention was completed.

That is, the present invention provides the following (1) to (5).
(1) A pharmaceutical for the prevention and / or treatment of lower urinary tract symptoms, comprising loxoprofen sodium or a hydrate thereof, and one or more amino acids selected from the group consisting of L-glutamic acid or a salt thereof and glycine Composition.
(2) The pharmaceutical composition according to (1), wherein loxoprofen sodium or a hydrate thereof is loxoprofen sodium dihydrate.
(3) The blending ratio of loxoprofen sodium or its hydrate and glycine is 0.5 to 500 parts by weight of glycine with respect to 1 part by weight converted to loxoprofen sodium anhydride, as described in (1) or (2) Pharmaceutical composition.
(4) The mixing ratio of loxoprofen sodium or a hydrate thereof and L-glutamic acid or a salt thereof is 0.5 to 200 parts by weight of L-glutamic acid or a salt thereof relative to 1 part by weight converted to loxoprofen sodium anhydride. The pharmaceutical composition according to (1) or (2).
(5) The pharmaceutical composition according to any one of (1) to (4), which is for oral administration.

  According to the present invention, an excellent pharmaceutical composition for preventing and / or treating lower urinary tract symptoms can be provided.

  “Loxoprofen sodium or a hydrate thereof” in the present invention includes loxoprofen sodium, loxoprofen sodium monohydrate, and loxoprofen sodium dihydrate. In the present invention, loxoprofen sodium dihydrate is preferred, and such loxoprofen sodium dihydrate is listed in the 15th revised Japanese Pharmacopoeia and is readily available.

  “Glycine” in the present invention is listed in the 15th revised Japanese Pharmacopoeia, and a commercially available product is easily available.

  Examples of “L-glutamic acid or a salt thereof” in the present invention include L-glutamic acid, sodium L-glutamate, potassium L-glutamate, and L-glutamic acid hydrochloride. As “L-glutamic acid or a salt thereof” in the present invention, L-glutamic acid is preferable. L-glutamic acid and salts of L-glutamic acid are described in the Pharmaceutical Additives Encyclopedia 2005, and commercial products are easily available.

  In the pharmaceutical composition of the present invention, the content ratio of loxoprofen sodium or a hydrate thereof and glycine is usually 0.1 to 1000 weights as a content ratio of glycine with respect to 1 part by weight converted to loxoprofen sodium (anhydride). Part, preferably 0.5 to 500 parts by weight, more preferably 1 to 200 parts by weight.

  In the pharmaceutical composition of the present invention, the content ratio of loxoprofen sodium or a hydrate thereof and L-glutamic acid or a salt thereof is 1 part by weight converted to loxoprofen sodium (anhydride) as a content ratio of L-glutamic acid, Usually, it is 0.1-1000 weight part, 0.5-200 weight part is preferable and 1-100 weight part is more preferable.

  The pharmaceutical composition of the present invention is used for the prevention and / or treatment of lower urinary tract symptoms. Lower urinary tract symptoms include frequent urination, urinary incontinence (urinary leakage), urgency, and urination symptoms include weakness of urine, delayed urination, and abdominal pressure urination. Symptoms include feeling of residual urine. The pharmaceutical composition of the present invention is preferably used for the prevention and / or treatment of urinary storage symptoms and post-urination symptoms, and is suitable for the prevention and / or treatment of frequent urination, urinary incontinence, urgency, and residual urine sense. More preferably, it is used particularly preferably for the prevention and / or treatment of frequent urination.

The pharmaceutical composition of the present invention may be for oral or parenteral use, but is preferably for oral use. When the pharmaceutical composition of the present invention is for oral use, its dosage form is not particularly limited, but a solid preparation is preferred.
When the dosage form of the pharmaceutical composition of the present invention is a solid preparation, specific examples include granules, powders, capsules, tablets, or pills described in the 15th revised Japanese Pharmacopoeia. . The dosage form of the pharmaceutical composition of the present invention is preferably a granule, powder, capsule or tablet, more preferably a tablet. Such tablets include orally disintegrating tablets, chewable tablets, lozenges, and the like.

  Pharmaceutical additives used in producing the pharmaceutical composition of the present invention include pharmaceutically acceptable carriers such as excipients, binders, disintegrants, disintegration aids, lubricants, Fluidizers, brighteners, foaming agents, moisture-proofing agents, surfactants, stabilizers, emulsifiers, antioxidants, fillers, preservatives, preservatives, sweeteners, flavoring agents, cooling agents, fragrances, fragrances Agents, colorants, coating agents, dispersants, antifoaming agents and the like.

  Further, as the granule or tablet of the present invention, those in which the preparation is coated with a water-soluble polymer and those in which the tablet is coated with sugar are also suitable. That is, film-coated granules, film-coated tablets, sugar-coated tablets and the like can be mentioned as preferred granule and tablet embodiments.

Although the manufacturing method of the formulation of the pharmaceutical composition of this invention is not specifically limited, For example, it can manufacture using the method as described in the 15th revision Japanese Pharmacopoeia formulation general rules.
If the dosage form of the pharmaceutical composition of the present invention is a tablet, the active ingredient and the pharmaceutical additive are granulated together to produce a granule, and if necessary, the pharmaceutical additive is added and mixed before tableting Thus, a tablet may be manufactured. Loxoprofen sodium or a hydrate thereof and one or more amino acids selected from L-glutamine or a salt thereof and glycine may be produced so as to be contained in the same granule, or may be contained in another granule. May be manufactured.

  In order to describe the present invention in more detail, examples are described below, but the present invention is not limited thereto.

(Test example) Examination of urination frequency change and urine volume change by combined use of loxoprofen sodium and L-glutamic acid or glycine

1. Test substance Loxoprofen sodium dihydrate was manufactured by Daiichi Sankyo Co., Ltd., glycine was manufactured by Peptide Institute, Ltd., and L-glutamic acid was manufactured by Wako Pure Chemical Industries, Ltd. Each test substance was prepared by weighing the required amount and dissolving in 0.5% tragacanth rubber aqueous solution.

2. Selection of Eligible Rats SD male rats (7 weeks old, Charles River) were housed in a metabolic gauge, and about 30 minutes before extinction, 4.0 mL / body of vehicle (0.5% tragacanth gum aqueous solution) was orally administered. A digital balance was installed under the gauge, and only the excreted urine was accumulated in a container on the balance, and the weight change was recorded on a personal computer via PowerLab (registered trademark) (manufactured by ADI Instruments Pty. Ltd.). The amount of urination (weight), the number of urinations, and the time of urination (time after administration) were calculated by analyzing 8 hours after administration. During the measurement, free drinking and free eating were used. Based on the calculated individual rat data, the suitability for use in the test drug evaluation test was judged and selected as a qualified rat. After administration when the test substance or vehicle described below is administered to the same individual (rat) based on the values of urination volume (weight) and the number of urinations up to 4 hours after administration of the medium in each individual rat selected The numerical values of urination volume (weight) and urination frequency for up to 4 hours are obtained using the following formulas 1 and 2 to determine the rate of change in urination frequency (%) and rate of urination rate (%) for each individual (rat). The average was calculated as the rate of change (%) for each administration group.

3. Assignment of administration group Eligible rats selected in the above screening are assigned to the group shown in Table 1 on the next day of the above screening, and then placed in a metabolic cage, and the test substance is dissolved or dissolved in the medium about 30 minutes before extinction. Suspended and administered orally.

  A digital balance was placed under the metabolic cage containing the rats, and only excreted urine was accumulated in a container on the balance, and the weight change was recorded on a personal computer via PowerLab (registered trademark). The measurement was conducted overnight, and the amount of urination (weight), the number of urinations and the time of urination (time after administration) were calculated 4 hours after administration. During the measurement, free drinking and free eating were used. The change in the number of urinations and the change in the urination amount were calculated by the following formula 1 or 2.

4). Selection of Loxoprofen dosage in combination study Confirmation of the effect of loxoprofen alone on micturition kinetics, and the study was conducted to select the dose to be used in the combination study, vehicle administration group (vehicle → vehicle) and loxoprofen alone Table 2 shows the results of measuring the influence on the urination dynamics during the control with the administration group (vehicle → loxoprofen 1 mg / kg, 3 mg / kg, 10 mg / kg).

As shown in Table 2, the cumulative number of urinations and cumulative urination volume up to 4 hours after administration decreased in a dose-dependent manner by loxoprofen monotherapy. When the change in the vehicle administration group was 100%, the cumulative urination frequency was suppressed by about 20% to 60% in the 1 mg / kg, 3 mg / kg, and 10 mg / kg groups. Similarly, the cumulative urination volume was about 30%. Reduced by ~ 60%.
In each administration group, a significant decrease in the number of cumulative urination was observed in the group of 3 mg / kg or more, and the amount of cumulative urination in the group of 1 mg / kg or more was significantly decreased with respect to the control. In general, in the case of non-steroidal antipyretic analgesics, the decrease in the number of urination first decreases the amount of urination, and it is assumed that the effect increases as the degree increases, so loxoprofen is 1 mg / kg. It was considered that the effect was clearly manifested. Therefore, a significant decrease in cumulative urination volume was observed, but 1 mg / kg, which did not show a significant decrease in cumulative urination frequency, was used, and a combined study was conducted with the cumulative urination frequency at the time of combination as the primary endpoint. .

5. Confirmation test 1
The test was performed in two steps. The first study was conducted in the vehicle administration group, the loxoprofen single administration group (1 mg / kg), the loxoprofen (1 mg / kg) + L-glutamic acid combination administration group, and the loxoprofen + glycine combination administration group. Group, L-glutamic acid single administration group, and glycine single administration group. The test results are shown in Tables 3 and 4.

As shown in Table 3 and Table 4, the number of urinations in the loxoprofen single administration group (1 mg / kg), the glycine single administration group, and the L-glutamic acid single administration group was respectively compared with the vehicle administration group (100%). 95.9%, 81.5%, and 114.0%. Therefore, when loxoprofen sodium dihydrate 1 mg / kg alone, L-glutamic acid or glycine was administered alone, there was no change compared to the change in the number of urinations in the vehicle administration group. Or showed only a very small effect of reducing the number of urinations.
On the other hand, in the group administered with 1 mg / kg of loxoprofen and L-glutamic acid (loxoprofen + L-glutamic acid combined administration group) in which loxoprofen alone was not effective, the dose was 66.compared with the vehicle administration group (100%). In the group administered with 3% and 1 mg / kg loxoprofen and glycine (loxoprofen + glycine combined administration group), the number of urinations was significantly reduced to 56.4% compared with the vehicle administration group (100%). . Especially when loxoprofen and glycine were used in combination, the number of urinations decreased to less than half. From this, it was found that the number of urinations was significantly reduced by using loxoprofen sodium or a hydrate thereof together with L-glutamic acid or glycine.
Moreover, in the amount of urination, as shown in Table 3 and Table 4, compared with the loxoprofen single administration group, in the loxoprofen + L-glutamic acid combination administration group and the loxoprofen + glycine combination administration group, the urination amount was clearly decreased. . This change in the amount of urination was a significant reduction effect compared to the group administered with L-glutamic acid or glycine alone.

6). Confirmation test 2
In the vehicle administration group, the loxoprofen (3 mg / kg) + glycine (5 mg / kg) combined administration group, and the loxoprofen (3 mg / kg) + glycine (500 mg / kg) combined administration group, the same effect as the confirmation test 1 of the above combination effect The confirmation test of the combined use effect was carried out by the method.
The test results are shown in Table 5.

  As shown in Table 5, in the group in which loxoprofen 3 mg / kg and glycine 5 mg / kg or 500 mg / kg were used in combination, an excellent decrease in the number of urinations and a decrease in the amount of urination were observed. These effects were excellent even when compared with the loxoprofen 3 mg / kg single administration group shown in Table 1.

  From the above results, L-glutamic acid or glycine is administered in combination with loxoprofen sodium or its hydrate, so that an effect superior to single administration of loxoprofen sodium or its hydrate for lower urinary tract symptoms, particularly frequent urination, is expected. On the other hand, it was found that even when loxoprofen sodium was reduced, the combined effect was exhibited.

  INDUSTRIAL APPLICABILITY The present invention can be used as a pharmaceutical composition for prevention and / or treatment having both efficacy and safety for patients with lower urinary tract symptoms.

Claims (5)

  A pharmaceutical composition for preventing and / or treating lower urinary tract symptoms, comprising loxoprofen sodium or a hydrate thereof, and one or more amino acids selected from the group consisting of L-glutamic acid or a salt thereof and glycine.   The pharmaceutical composition according to claim 1, wherein loxoprofen sodium or a hydrate thereof is loxoprofen sodium dihydrate.   The pharmaceutical composition according to claim 1 or 2, wherein the blending ratio of loxoprofen sodium or a hydrate thereof and glycine is 0.5 to 500 parts by weight of glycine with respect to 1 part by weight in terms of loxoprofen sodium anhydride.   The compounding ratio of loxoprofen sodium or a hydrate thereof and L-glutamic acid or a salt thereof is 0.5 to 200 parts by weight of L-glutamic acid or a salt thereof with respect to 1 part by weight in terms of loxoprofen sodium anhydride. The pharmaceutical composition according to 1 or 2.   The pharmaceutical composition according to any one of claims 1 to 4, which is for oral administration.