JP2013060427A - Composition for pollakiuria treatment containing loxoprofen and pepper mint extraction - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition for preventing and/or treating lower urinary tract symptoms having high effectiveness and few side effects.SOLUTION: The composition is provided for preventing and/or treating lower urinary tract symptoms containing loxoprofen sodium or a hydrate thereof and a pepper mint extraction.

Description

  The present invention relates to a composition for preventing or treating lower urinary tract symptoms (LUTS) such as frequent urination, which contains loxoprofen sodium or a hydrate thereof.

  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, while anticholinergic drugs are highly effective, they have a problem of high incidence of side effects such as dry mouth and constipation.

  Loxoprofen sodium is known as a non-steroidal antipyretic analgesic that inhibits cyclogeoxygenase, 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).

  Peppermint is a perennial flowering plant belonging to the family Lamiaceae and is widely cultivated at home and abroad for collecting its perfume oil. Peppermint extract (peppermint oil) obtained from the ground part of peppermint is mainly used as a fragrance, and is used for many symptoms such as cold symptoms, severe abdominal pain, headache, indigestion, joint pain, nausea ( For example, Non-Patent Document 4).

  However, it is not known about the anti- frequent urination effect when loxoprofen sodium and peppermint extract are used in combination.

US Pat. No. 7,547,688

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 Catherine E. Wulb Hirito et al. Herbs & Supplements Sansei Publishing Co., Ltd. Published January 10, 2007

  As described above, existing therapeutic agents for lower urinary tract symptoms based on anticholinergic effects are widely used and have a high effective rate, but have a problem that the side effect rate 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-mentioned problems, the present inventors can obtain an excellent effect on lower urinary tract symptoms by using loxoprofen sodium or a hydrate thereof and peppermint extract in combination. As a result, the present invention has been completed.
That is, the present invention provides the following (1) to (3).
(1) A composition for the prevention and / or treatment of lower urinary tract symptoms, comprising loxoprofen sodium or a hydrate thereof and peppermint extract.
(2) The composition for prevention and / or treatment of lower urinary tract symptoms according to (1) above, wherein the loxoprofen sodium or hydrate thereof is loxoprofen sodium dihydrate.
(2a) The lower part according to (1) or (2) above, wherein the mixing ratio of loxoprofen sodium or a hydrate thereof and peppermint extract is 0.01 to 100 parts by weight as 1 part by weight of loxoprofen sodium anhydride A composition for preventing and / or treating urinary tract symptoms.
(3) The composition for prevention and / or treatment of lower urinary tract symptoms according to any one of (1), (2), and (2a), which is for oral administration.

  According to the present invention, it is possible to provide a composition for preventing and / or treating lower urinary tract symptoms having both effectiveness and safety.

  “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.

The “peppermint extract” in the present invention is obtained by extracting ground parts such as peppermint leaves and stems with water, alcohol or a mixture thereof. The “peppermint extract” includes a product obtained by further extracting commercially available peppermint oil with water, alcohol or a mixture thereof, or a product obtained by further extracting peppermint leaves, stems or their extracts by steam distillation. The peppermint extract is listed in the Pharmaceutical Additives Encyclopedia 2005 as peppermint essence or peppermint powder, and is readily available because it is commercially available.
Moreover, you may use the peppermint extract processed beforehand as a mint flavor. Mint flavors are listed in the Pharmaceutical Additives Encyclopedia 2005 and are readily available because they are commercially available.
The “peppermint extract” in the present invention is preferably a commercially available mint flavor, peppermint essence, or peppermint powder. As components contained in these “peppermint extracts”, those listed in the following (1) to (7) are known.
(1) As hydrocarbons, (1-a) monoterpenes α-pinene, β-pinene, limonene, menthene, ferrandlene, sabinene, myrcene, cis-osimene, ρ-cymene, terpinolene, α-terpinene, γ-terpinene, ( 1-b) Sesquiterpenes β-caryophyllene, trans-β-farnesene, α-murolene, Germacrene D, γ-kadinene, β-ballbonene;
(2) As alcohols, (2-a) monoterpenols such as menthol, isomenthol neo-menthol, piperitol, piperitenol, isopiperitenol, α-terpineol, linalool, terpinen-4-ol, (2-b ) Visidiflorol of sesquiterpenols, 10-α-casinoal, (2-c) 3-octanol of other alcohols;
(3) Mentone, iso-menton, neo-menton, piperitone, isopiperitone, pulgon as ketones;
(4) As oxides, 1,8-cineole, mentfuran, piperithenone, trans-piperitone oxide, caryophyllene oxide;
(5) As esters, menthyl acetate, neomenthyl acetate, isomenthyl acetate, menthyl butyrate, menthyl isovalerate;
(6) As coumarins, esculetin;
(7) As other components, mentfuran Among the above components, menthol (L-menthol), menthone (L-menthol), menthyl acetate, 1,8 as components contained in "Peppermint extract" at high content -Cineol, neo-menthol, iso-mentholone, mentofuran, limonene, β-caryophyllene, pulgon, etc. can be mentioned, but the "peppermint extract" of the present invention is limited only to those containing these high content components Is not to be done.

The content ratio of loxoprofen sodium or a hydrate thereof and peppermint extract in the composition of the present invention is usually 0.001 to 1 as a content ratio of peppermint extract per part by weight converted to loxoprofen sodium (anhydrous). It is the range of 1000 weight part, The range of 0.01-100 weight part is preferable, and 0.1-20 weight part is more preferable.
Furthermore, the composition of the present invention contains a component having an effect of preventing or treating lower urinary tract symptoms other than loxoprofen sodium or its hydrate and peppermint extract, such as glycine, glutamic acid or a salt thereof, and the like. Is also possible.

  The 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 composition of the present invention is preferably used for the prevention or treatment of urinary storage symptoms and post-urination symptoms, and is used for the prevention or treatment of frequent urination, urinary incontinence, urgency, residual urine sensation. More preferably, it is particularly preferably used for the prevention and / or treatment of frequent urination.

  The composition of the present invention may be for oral or parenteral use, but is preferably for oral use. When the 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 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 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 such formulations include pharmaceutically acceptable carriers such as lactose, mannitol, hydroxypropylcellulose and other excipients; crystalline cellulose and other binders; croscarmellose sodium; Disintegrants such as crospovidone, lubricants such as magnesium stearate, and talc can be added. Add additives, stabilizers, emulsifiers, antioxidants, fillers, preservatives, preservatives, sweeteners, flavoring agents, cooling agents, fragrances, fragrances, colorants, dispersants, defoamers Can do.

  In addition, when the dosage form of the composition of the present invention is a granule or a tablet, a granule or tablet coated with a water-soluble polymer or the like and a coating agent such as hypromellose or a tablet coated with sugar Is also suitable. That is, film-coated granules, film-coated tablets, sugar-coated tablets and the like are preferable granule and tablet embodiments.

Although the manufacturing method of the formulation of the 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.
Also, when the dosage form of the pharmaceutical composition of the present invention is a tablet, the active ingredient and the pharmaceutical additive are granulated together, and if necessary, the pharmaceutical additive is added and mixed, and then tableted to produce a tablet. May be. Loxoprofen sodium or a hydrate thereof and peppermint extract may be produced so as to be contained in the same granule, or may be produced so as to be contained in separate granules so as not to contact each other.

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

(Test example) Examination of urination frequency change and urine output change Test substance Loxoprofen sodium dihydrate was manufactured by Daiichi Sankyo Co., Ltd. Hereinafter, the dose of loxoprofen sodium dihydrate is shown in terms of loxoprofen sodium anhydride. As the peppermint extract, mint flavor (Mint Flavor HQ-3230) manufactured by Takasago Fragrance Co., Ltd. containing 0.5% as peppermint oil was used as the “mint flavor aqueous solution”. The medium used was a 0.5% tragacanth rubber aqueous solution.
Each of the following loxoprofen administration groups weighed loxoprofen sodium dihydrate converted to the amount of loxoprofen sodium anhydrous and dissolved or suspended it in a calculated amount of 0.5% tragacanth gum aqueous solution.

2. Qualifying Rat Selection Screen 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 a vehicle (0.5% tragacanth gum aqueous solution) was 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 data of the calculated individual rats, the suitability of the implementation was judged, and the rats judged to be eligible were selected. 4 hours after administration of the following test substances 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 of selected rats Using the following (Equation 1) and (Equation 2), the urination rate change rate (%) and urination rate change rate (%) of each individual (rat) The average change rate (%) for each administration group was calculated.

3. Measurement by administration of test substance Eligible rats selected in the above screening are allocated to the groups shown in Table 1 on the next day of the above screening, and then placed in metabolic cages. Was administered.

A digital balance was installed under the cage, 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 rate of change in the number of urinations and the rate of change in urination amount were calculated by the following equations.

4). Selection of Loxoprofen Dose in Combination Tests In order to confirm the rate of change due to loxoprofen dose, vehicle administration group, loxoprofen single administration group (1 mg / kg, 3 mg / kg, 10 mg / kg; respectively, loxoprofen sodium anhydride equivalent amount) As). The test results are shown in Table 2. As shown in Table 2, when loxoprofen was administered at 3 mg / kg, both the rate of change in urination (%) and the change in urine output (%) had an inhibitory effect of about 30% or more on the solvent administration group. At about 10 mg / kg, an inhibitory effect of about 60% was observed. On the other hand, in the 1 mg / kg administration group of loxoprofen, the inhibitory effect compared with the vehicle administration group was weak, so the dose of loxoprofen for confirming the effect of the combination test was set to 1 mg / kg.

5. Confirmation test of combined effect 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), and the loxoprofen (1 mg / kg) + peppermint extract combined administration group. In the second study, the vehicle administration group, peppermint extract alone This was performed in the administration group. The results are shown in Tables 3 and 4.

As shown in Tables 3 and 4, the rate of change in urination frequency in the loxoprofen single administration group and the peppermint extract single administration group was 96% and 98%, respectively, compared with the vehicle administration group. Loxoprofen sodium 2 water The single administration of each drug of Japanese and peppermint extract was not different from the vehicle group.
On the other hand, the rate of change in urination frequency in the loxoprofen + peppermint extract combined administration group was 79%, and an inhibitory effect of about 20% or more was observed. From this, it was found that the number of urinations was significantly reduced by using loxoprofen sodium and peppermint extract in combination.
As for urinary output, urinary output was clearly decreased in the loxoprofen + peppermint extract combined administration group compared to the loxoprofen single administration group. This change in the amount of urination was found to be further reduced compared to the group to which the peppermint extract was administered alone.
From the above results, it can be expected that loxoprofen sodium alone is administered to loxoprofen sodium in combination with loxoprofen sodium alone for lower urinary tract symptoms, particularly frequent urination. Furthermore, it was speculated that even when the amount of loxoprofen sodium was reduced, the same effect as that of single administration could be realized with higher safety.

  INDUSTRIAL APPLICABILITY According to the present invention, it can be used as a therapeutic composition having both efficacy and safety for patients with lower urinary tract symptoms.

Claims (3)

  A composition for the prevention and / or treatment of lower urinary tract symptoms, comprising loxoprofen sodium or a hydrate thereof and a peppermint extract.   The composition for prevention and / or treatment of lower urinary tract symptoms according to claim 1, wherein loxoprofen sodium or a hydrate thereof is loxoprofen sodium dihydrate.   The composition for prevention and / or treatment of lower urinary tract symptoms according to claim 1 or 2, which is for oral administration.