HK1085131B - Solid drug for oral use - Google Patents

Description

Solid oral dosage form medicament

Technical Field

The present invention relates to solid medicaments in oral form for the treatment of dysuria. More particularly, the present invention relates to a solid oral dosage form medicament for treating dysuria comprising an indoline compound having an alpha as an active ingredient₁-adrenoceptor (hereinafter referred to as "alpha")₁-AR ") blocking activity, which can be represented by formula (I) (hereinafter referred to as" KMD-3213 "):

and a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, which are dissolved in a dissolution test for a period of 80% of time of not more than 60 minutes under the conditions of using water as a test medium and a paddle speed of 50rpm according to Japanese pharmacopoeia method 2 (paddle method).

The invention also relates to a solid oral dosage form medicament for the treatment of dysuria, said medicament comprising 1) KMD-3213, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, 2) at least one drug selected from alpha₁-adrenoceptor blockers, anticholinergicsAn anti-inflammatory agent and an antibacterial agent other than KMD-3213 as active ingredients, and their dissolution time of 85% in the dissolution test does not exceed 60 minutes under the conditions of using water as a test medium and a paddle speed of 50rpm according to Japanese pharmacopoeia method 2 (paddle method).

The invention also relates to solid oral dosage forms, medicaments and kits comprising:

1) a medicament for treating dysuria which comprises KMD-3213, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof as an active ingredient, which is dissolved in a dissolution test for 85% for not more than 60 minutes under the conditions of using water as a test medium and a paddle speed of 50rpm according to japanese pharmacopoeia method 2 (paddle method);

2) comprises at least one compound selected from alpha₁-drugs of adrenoceptor blockers, anticholinergics, anti-inflammatory agents and antibacterial agents other than KMD-3213 as active ingredients.

When the dissolution property of the solid oral dosage form drug for the treatment of dysuria according to the present invention was tested under the conditions of using water as a test medium and a paddle speed of 50rpm according to the dissolution test, japanese pharmacopoeia method 2 (paddle method), the time for the drug to dissolve 85% (hereinafter referred to as "T85%") was said to be not more than 60 minutes. More preferably, the T85% of the present drug is not more than 60 minutes when measured according to the japanese pharmacopoeia method 2 (paddle method) under the condition that the first fluid regulated in the japanese pharmacopoeia decomposition test (hereinafter referred to as "first fluid") is used as a test medium and the paddle speed is 50 rpm. More preferably, the T85% of the present drug does not exceed 30 minutes, most preferably 15 minutes, when measured under conditions using water or the first fluid according to japanese pharmacopoeia method 2 (paddle method).

The first fluid used in the dissolution test of the present invention means a first fluid adjusted in the japanese pharmacopoeia decomposition test, wherein the first fluid is prepared by: to 7.0mL of hydrochloric acid and water was added 2.0g of sodium chloride to prepare 1000mL of test medium.

Background

It is known that KMD-3213 as an active ingredient in the solid oral dosage form medicament for treating dysuria according to the present invention has a selective inhibitory activity on constriction of smooth muscle of urinary tract, and is a compound extremely useful as a medicament for treating dysuria without causing strong hypotensive action or orthostatic hypotension.

The following documents have hitherto been known about pharmaceutical compositions comprising KMD-3213, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof as an active ingredient.

In patent document 1, indoline compounds including KMD-3213 are disclosed, and several dosage forms as oral solid preparations are described. It is also reported therein as a summary that such dosage forms can be prepared by formulating indoline compounds according to conventional formulation procedures. However, patent document 1 does not disclose a specific preparation containing KMD-3213 as an active ingredient.

Patent document 2 discloses a method of preparing a₁KMD-3213, an AR blocker, is used as an active ingredient in a medicament useful for the treatment of lower urinary tract diseases, several dosage forms are described as oral solid preparations. It is also reported that such dosage forms can be prepared according to conventional formulation procedures with common pharmaceutical additives. However, patent document 1 does not disclose a specific pharmaceutical composition containing KMD-3213 as an active ingredient.

KMD-3213 is relatively unstable in light. Mixing several pharmaceutical additives with KMD-3213 resulted in incompatibility and degradation products. For example, KMD-3213 has poor compatibility with lactose, which is most commonly used as a filler, which leads to undesirable dissolution properties and unsatisfactory tablet hardness. In addition, KMD-3213 has a strong viscosity, and the use of a lubricant is inevitable when preparing tablets or capsules. On the contrary, the addition of such a lubricant causes a problem of delay in dissolution time. Thus, it is extremely difficult in practice to prepare a useful solid oral dosage form of a medicament comprising KMD-3213, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof as an active ingredient using conventional formulation methods.

Regarding these problems, patent documents 1 and 2 do not disclose or suggest any method of solving the problems. Patent document 2 discloses a method for producing a capsule containing tamsulosin hydrochloride or alfuzosin hydrochloride as an active ingredient. However, such a capsule pharmaceutical composition is completely different from the pharmaceutical composition of the present invention. In addition, the pharmaceutical composition of the present invention cannot be prepared by the method disclosed in patent document 2. Therefore, patent document 2 does not teach or suggest the effect of the present invention at all.

Patent document 1: japanese unexamined publication H06-2200151 (page 12, line 21)

Patent document 2: japanese unexamined publication No. 2001-288115 (page 3, lines 3-4)

Summary of The Invention

The present invention provides a practically usable solid oral dosage form medicament for treating dysuria without affecting blood pressure, which comprises KMD-3213, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof as an active ingredient, wherein the medicament has high content uniformity with high accuracy, good stability and excellent dissolution properties.

If a drug is orally administered, bioavailability of an active ingredient contained in the drug is very important, and stable efficacy is also required. For this reason, each batch of formulation needs to ensure homogeneity, i.e. bioequivalence. The pharmacopoeia prescribes procedures for testing the dissolution or dissolution properties of solid formulations to ensure stable quality and bioequivalence of the formulations. Thus, the drug is required to meet the specifications established by these tests.

Recently, dissolution test is considered as an important means for evaluating the efficacy or safety of drugs. Especially for poorly soluble drug substances, the dissolution properties are more critical than the dissolution properties for assessing the quality of a drug comprising such a substance.

The dissolution test is preferably carried out under various test conditions in terms of bioequivalence. However, it is difficult to determine the specifications of the dissolution test under various conditions, and therefore the dissolution test is usually performed under conditions where the drug is most likely to be non-bioequivalent. As the test medium in the dissolution test, a test medium having a physiological pH range, i.e., pH of 1 to 7, or water is usually used. Whereas the active ingredient in the test medium used is slowly released from the formulation, differences in the formulation can clearly be detected. Water is sensitive to changes in pH. Conversely, water is a test medium that can assess minor differences in formulation or manufacturing processes. Therefore, if water is used as a test medium in the dissolution test, it is preferable to use water in view of the effect of the test, economic efficiency and influence on the environment.

KMD-3213 has relatively high solubility in acidic media, but is poorly soluble in neutral media, such as water. Thus, water is the most suitable test medium for assessing non-bioequivalence of the dissolution test performed. In developing a solid oral dosage form formulation comprising KMD-3213 as an active ingredient, it is desirable to find a formulation having good dissolution properties in water. In the drug of the present invention, according to the japanese pharmacopoeia method 2 (paddle method), in the dissolution test performed under the condition of using water as a test medium and a paddle speed of 50rpm, T85% is preferably not more than 60 minutes, T85% is more preferably not more than 30 minutes, and T85% is most preferably not more than 15 minutes.

It is desirable that a solid oral dosage form drug exhibit good dissolution properties in the stomach unless the drug is enterically coated in an acidic environment. Since KMD-3213 is stable under acidic conditions, a solid oral dosage form drug comprising KMD-3213 as an active ingredient preferably shows good solubility in the first fluid of the dissolution test, which corresponds to gastric juice. Thus, in the solid oral dosage form formulation of the present invention, as in the dissolution test with water, the T85% preferably does not exceed 60 minutes, the T85% more preferably does not exceed 30 minutes, and the T85% most preferably does not exceed 15 minutes in the dissolution test with the first fluid.

Active ingredients contained in drugs generally exhibit biological activity in minute amounts of dosage. Therefore, in order to exert a stable efficacy, it is important to keep the content of the active ingredient at a stable level, and to reduce the content of the active ingredient to a minimum during storage. For this reason, it is desirable that the content be highly uniform for each batch of formulation and highly stable during storage.

KMD-3213, which is the active ingredient in the solid oral dosage form of the present invention, has strong adhesive and electrostatic properties. Especially when the formulation is prepared by a dry process, physical stimulation caused by processes such as pulverization, stirring, mixing, granulation, etc. generates static electricity, which in turn reduces the fluidity of the pulverized, mixed or granulated material, impairs handling properties, and reduces the accuracy of content uniformity of the active ingredient.

In the case of tablets or capsules, a lubricant is added in the step of filling or tableting in consideration of the handling property, the filling accuracy, and the like. KMD-3213 as an active ingredient in the solid oral dosage form of the present invention has a strong viscosity, and the use of a lubricant is inevitable. Conversely, the use of a lubricant delays the dissolution time.

In addition, KMD-3213, which is the active ingredient in the solid oral dosage form of the present invention, is not photo-stable and requires careful handling. In this case, the formulations are generally stored in light-resistant packages. However, opaque light-resistant packages are difficult to detect contamination by foreign matter. In addition, when a patient actually takes a light-resistant packaged preparation, the preparation is occasionally taken out of the light-resistant package and stored. Thus, there is a need for formulations that are highly stable to light, and that can be stored without the use of light-resistant packaging.

The present inventors have eagerly studied a solid dosage form drug comprising KMD-3213, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof as an active ingredient, which has highly precise content uniformity, excellent solubility in water or a first fluid, and good stability, and is extremely useful for treating dysuria.

As a result, the present inventors have found that the use of lactose, which is most commonly used as a filler, causes problems such as delay in dissolution time and reduction in tablet hardness. Therefore, the preferred formulations cannot be prepared using lactose as a filler. After further investigation of the bulking agent, the present inventors have found that the use of D-mannitol as a bulking agent provides highly preferred dissolution properties.

Further, the present inventors studied various methods for preparing formulations, and found that a formulation having satisfactory content uniformity, being not affected by electrostatic charge, having good stability and excellent solubility is prepared by wet granulation and adjustment of the amount of lubricant and mixing time. The present inventors have also found that, for capsules, by mixing a lubricant and another solid additive having a hydrophilic or surface active property in a specific ratio, a preparation excellent in solubility can be prepared. Further, the present inventors have studied a photostable preparation, and found that titanium dioxide can satisfactorily prevent the photodegradation of KMD-3213, and that a photostable preparation can be prepared by using a capsule containing titanium dioxide or a coating agent containing titanium dioxide. The present invention has been accomplished on the basis of these findings.

In many cases, the compound as an active ingredient is relatively unstable, and mixing such a compound with a pharmaceutical additive used for preparing a solid dosage form preparation often causes incompatibility such as discoloration, decomposition, and the like. However, it is difficult to estimate the compatibility between the pharmaceutical additive and the active ingredient in advance.

The present inventors first investigated the compatibility between KMD-3213, which is the active ingredient of the drug of the present invention, and various pharmaceutical additives used for the preparation of solid dosage form preparations, and then selected the pharmaceutical additives which do not cause discoloration or decomposition. Thereafter, the present inventors investigated whether or not selected pharmaceutical additives can be combined with each other without causing incompatibility and are suitable for manufacture.

As a result of the studies on fillers, lactose, which is most commonly used as a filler, does not cause incompatibility, but reduces solubility and hardness of tablets. For this reason, it is difficult to prepare a preferred formulation using lactose as a filler. The addition of crystalline cellulose improves the delay in dissolution time caused by lactose, but does not improve the tablet hardness. In addition, crystalline cellulose mixed with KMD-3213 caused incompatibility and produced degradation products. Thus, crystalline cellulose is not suitable for the preparation of the solid dosage form medicament of the present invention. After further investigating the bulking agent, the present inventors found that D-mannitol is suitable for compatibility and manufacturability, and provides excellent solubility, and thus is most suitable for use as a bulking agent.

Calcium carboxymethylcellulose and carboxymethylcellulose are not suitable for use as disintegrants because they cause most of the incompatibility, but starch, low-substituted hydroxypropylcellulose, partially pregelatinized starch, and the like are preferred. Examples of starches include corn starch and the like. Some of the pregelatinized starches include starch 1500 (registered trademark, Japan colorcon co., Ltd.), PCS (registered trademark, Asahi Chemical Industry co., Ltd), and the like.

Hydroxypropyl methylcellulose and hydroxypropyl cellulose are not suitable for use as binders because they cause little incompatibility.

Magnesium stearate, calcium stearate and talc do not cause incompatibility and are therefore preferred for use as lubricants.

macrogol (polyethylene glycol), polyethylene glycol (105), polypropylene glycol (5) and triethyl citrate are not suitable for use as surfactants because they cause most of the incompatibility.

Preferably the additives are selected according to the above findings. Then, the process for preparing the formulation according to the conventional method was investigated. First, if the formulation is prepared by a dry process, the powdery, mixed or granulated material prepared by the pulverizing, mixing or granulating process generates electrostatic charges, decreasing the fluidity of the material. Therefore, particularly in the preparation of capsules, handling during filling is impaired, and uniformity of filling volume and filling accuracy are impaired.

In order to improve the handling or filling accuracy, a lubricant is generally used in the filling of capsules or in the tableting of tablets. KMD-3213 naturally has a strong viscosity, and in particular generates electrostatic charges during dry preparation, and the fluidity of the mixed or granulated material is impaired, as described above, resulting in the use of a larger amount of lubricant. However, lubricants generally have water repellency, and the dissolution time is delayed with lubricants.

The present inventors have intensively studied the kind, combination or ratio of additives, the manufacturing process and the like, and found a highly practical preparation which has suitable handling property in the manufacturing process, high precision of content uniformity, excellent dissolution property, and is effective for exhibiting the biological activity of KMD-3213.

First, the present inventors found that delay in dissolution time can be prevented to some extent by reducing the amount of lubricant or shortening the mixing time. More specifically, good solubility can be achieved by reducing the amount of lubricant to no more than about 1%, more preferably between about 0.6-0.8%, and mixing immediately for about 3-5 minutes. Then, wet granulation is used instead of dry granulation, the dosage of the lubricant is not more than 1%, the mixing time is about 3 minutes, and the preparation with good fluidity of the mixed material, satisfactory carrying performance and high filling precision can be prepared.

However, KMD-3213, which is the active ingredient in the drug of the present invention, has a strong viscosity, and if a capsule is prepared with a lubricant in an amount of not more than 1%, there is a high risk of causing filling problems such as stickiness. In view of these problems, the present inventors studied a method of improving the dissolution time delay even if the amount of the lubricant is not more than 1%, and found that the dissolution time delay is remarkably improved by mixing a solid additive having hydrophilicity or surface activity, and thus a preparation having good solubility can be prepared.

The effect of improving the dissolution time delay with the above additives varies depending on the combination of the additives and the lubricant. For example, when magnesium stearate is used as a lubricant, sodium lauryl sulfate is most preferably used for the inhibitory effect, and sucrose esters of fatty acids, light anhydrous silicic acid and polyethylene glycol (105) polypropylene glycol (5) are unsatisfactory. For satisfactory improvement, the amount of sodium lauryl sulfate used is preferably about 0.1 to 2 parts, more preferably about 0.5 parts (based on 1 part of magnesium stearate), where solubility can be maintained at a desirable level.

The effect of improving the dissolution time delay with sodium lauryl sulfate varies greatly with the method of addition. For example, if sodium lauryl sulfate is dissolved in water and added together with water during granulation (hereinafter referred to as "addition during granulation"), the dissolution rate decreases at the point after the start of the dissolution test (5 minute value). Through further studies, the present inventors have found that a delay in the start of the rise can be prevented by adding sodium lauryl sulfate and a lubricant together after the granulation process (hereinafter referred to as "post-granulation addition").

KMD-3213 as the active ingredient in the solid oral dosage form of the present invention is photolithographically unstable, and the amount of the active ingredient decreases with time, with the rate of decrease depending on the storage conditions. Thus, KMD-3213 requires careful storage conditions and handling. In this case, the preparation is generally stored under light-resistant packaging, and opaque light-resistant packaging is difficult to detect contamination by foreign substances, so defective products are easily overlooked. In addition, when a patient actually takes a preparation wrapped with a light-resistant package, the preparation is occasionally drawn out of the light-resistant package for storage. Thus, there is a need for formulations that are stored without light-resistant packaging and are highly stable to light.

The present inventors have studied a light-shielding material preferably mixed with a capsule or a coating agent, and have found that titanium dioxide is most suitable as the light-shielding material. Capsules or tablets that are highly stable to light may be prepared with capsules comprising titanium dioxide or coatings comprising titanium dioxide.

The light stability was measured by the following method. The upper limit acceptance criterion of the amount (%) of each photodegradable material (hereinafter referred to as "related substance") and the total amount (%) of all the related substances is first determined, and then the photostability is judged by determining whether the amount of the related substance meets the criterion of being acceptable under standard illumination. According to the JIS (Japanese Industrial Standard) report, the standard illumination level of hospital pharmacy is 300-750 lux/hour, the average illumination time is about 8 hours/day, and the maximum storage period of the drug is 6 months. Thus, the standard illumination intensity is estimated to be about 120 million lux/hour, which is calculated considering a maximum illumination level of 750 lux/hour, an illumination time of about 8 hours per day, an illumination time of 180 days, an illumination corresponding to about 108 million lux/hour, and a measurement deviation thereof. In the guidelines for a qualified drug, the photostability test requires a total light exposure of not less than about 120 million lux/hour. Thus, in the photostability test, the qualified drug is stable under light of about 120 million lux/hour.

It has been determined that there are at least 6 related substances in KMD-3213 as the active ingredient in the solid oral dosage form of the present invention. A provisional specification determines that the content of the relevant substance a is not more than 4%, the content of each of the relevant substances b to f is not more than 1%, and the total amount of all relevant substances including trace amounts of other relevant substances is not more than 5%. The present inventors have studied light-resistant capsules or coatings that meet light exposure times of about 120 million lux/hour.

As a result, titanium dioxide is most preferable as a light-shielding material, and a solid drug highly stable to light can be prepared with a capsule containing titanium dioxide or a coating agent containing titanium dioxide.

The light shielding effect increases with the mixing amount of titanium dioxide, and the strength of the capsule decreases with the mixing amount of titanium dioxide. The preferred mixing amount can be determined appropriately according to the size of the drug. The amount of titanium dioxide to be blended is not less than about 3%, more preferably about 3.4 to 3.6% for exerting preferable light-shielding effect in the capsule. For the tablet, the blending amount of titanium dioxide is determined by the surface area of the tablet, the amount of the coating agent, and the like. The coating amount of titanium dioxide is usually not less than 0.5mg/cm for exerting preferable light-shielding effect²More preferably 1.1mg/cm²(based on the surface area of the tablet).

For a pharmaceutical composition comprising KMD-3213, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof as an active ingredient, only general descriptions are given in patent documents 1 and 2, and any specific pharmaceutical composition is not taught or suggested.

As described above, there are many problems to be solved in order to provide a practical oral drug comprising KMD-3213, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof as an active ingredient according to the conventional formulation method. Patent documents 1 and 2 do not disclose or suggest these problems and a method of solving these problems.

KMD-3213 as an active ingredient in the solid oral dosage form medicament of the present invention is a known compound, and can be prepared according to the procedure described in patent document 1.

Examples of the pharmaceutically acceptable salts of KMD-3213, which is the active ingredient in the solid oral dosage form of the present invention, include acid addition salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; acid addition salts with organic acids such as acetic acid, propionic acid, butyric acid, oxalic acid, citric acid, succinic acid, tartaric acid, fumaric acid, maleic acid, lactic acid, adipic acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, glutamic acid, aspartic acid and the like. Examples of the solvate include solvates with water, ethanol, and the like.

The solid oral dosage form of the present invention, such as a capsule, can be prepared as follows. KMD-3213, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, is mixed with a filler, preferably D-mannitol, and, if necessary, a suitable binder and a disintegrant. Then, an aqueous binder solution of an appropriate concentration is added, and the mixture is kneaded and, if necessary, sieved to prepare particles. Thereafter, a lubricant, preferably magnesium stearate, and a hydrophilic or surface-active solid additive, preferably sodium lauryl sulfate, are added to the granules. The amount of lubricant is 0.5-2.0%, and the ratio of solid additive and magnesium stearate is 1: 10-20: 10, preferably 5: 10-10: 10, and more preferably 5: 10. And then mixed and filled into a suitable capsule, preferably a capsule containing titanium dioxide, preferably a mixed amount of titanium dioxide of not less than about 3%, more preferably about 3.4 to 3.6%, to form a capsule.

The tablets can be prepared by the following method. The granules were prepared according to a procedure similar to that described for the preparation of capsules. A lubricant, preferably magnesium stearate, is then added to the granules in an amount not exceeding 1%, preferably from about 0.6 to about 0.8%, more preferably about 0.7%. The tablets are then blended and compressed by conventional means to form uncoated tablets. Thereafter, if desired, uncoated tablets may be sprayed with a coating solution prepared by dissolving or suspending the film-coating agent, the light-shielding material (preferably titanium dioxide), the plasticizing material, and if desired, a suitable lubricant, the polymerization inhibiting material, and the coloring agent in a suitable solvent. The amount of titanium dioxide is not less than 0.5mg/cm²It suffices that it is preferably 1.1mg/cm²(based on the surface area of the tablet).

KMD-3213 shows alpha₁AR blocks the activity with less influence on blood pressure, and is a compound extremely useful for treating dysuria associated with prostatic hypertrophy and the like. Reported to have alpha₁Prazosin hydrochloride and tamsulosin hydrochloride having AR-blocking activity are also used for the treatment of dysuria, such as bladder neck sclerosis, chronic prostatitis, neurogenic bladder, etc.

KMD-3213 is expected to be used for treating dysuria associated with urethral organized obstruction, such as prostatic hypertrophy, urethral stricture, urethral calculus, tumor, etc. (hereinafter, "prostatic hypertrophy, etc.), and dysuria associated with nerve disorder of urinary control, and dysuria associated with urethral functional obstruction, which are not included in any of the above dysuria, such as cervical sclerosis of bladder, chronic prostatitis, bladder instability, etc.

Dysuria associated with dysuria-controlling nervous disorders refers to dysuria caused by a controlling nervous disorder in the urinary tract or bladder, for example, brain diseases such as cerebrovascular diseases, brain tumors, etc., spinal diseases such as spinal cord injury, peripheral nervous diseases such as diabetes, lumbar spinal stenosis, etc. These diseases occur in both men and women, commonly referred to as neurogenic bladder.

Dysuria associated with urethral blockage of function but not accompanied by urethral organizing diseases and dysuria-controlling neurological disorders refers to bladder neck sclerosis, chronic prostatitis and unstable bladder and dysuria caused by dysuria, bladder neck block, urethral syndrome, detrusor-sphincter dyscoordination, chronic cystitis, prostadynia, Hinman syndrome, Fowler syndrome, psychological dysuria, drug-induced dysuria, senile dysuria, etc. These diseases are collectively referred to as lower urinary tract diseases.

The drug of the present invention has high content uniformity accuracy and excellent solubility, and thus can effectively exert the activity of KMD-3213. The medicament of the present invention is extremely useful for treating dysuria associated with urinary tract organic obstruction such as prostatic hypertrophy and the like; dysuria associated with micturition control neurological disorders such as neurogenic bladder; dysuria associated with urinary tract dysfunction is associated with urinary tract diseases such as the following.

Regarding the administration of the medicament of the present invention, the dose of the active ingredient is determined depending on the sex, age or body weight of the individual patient, the disease to be treated, etc., and is usually in the range of 1 to 50 mg/day/adult, preferably 4 to 20 mg/day/adult.

The medicament of the invention may also comprise at least one active ingredient chosen from: alpha is alpha₁-adrenoceptor blockers, anticholinergics, anti-inflammatory agents and antibacterial agents other than KMD-3213, and KMD-3213, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

The medicament of the present invention may be used in combination with a medicament comprising as an active ingredient at least one substance selected from the group consisting of: alpha is alpha₁-adrenoceptor blockers, anticholinergics, anti-inflammatory agents and antibacterial agents other than KMD-3213.

In these cases, the dosage and alpha of the pharmaceutically acceptable salt or pharmaceutically acceptable solvate of KMD-3213₁The dosages of the adrenoceptor blocker, anticholinergic agent, anti-inflammatory agent and antibacterial agent other than KMD-3213 may be suitably reduced.

Brief Description of Drawings

FIG. 1 shows the relationship between the mixing time of magnesium stearate and the delayed action of magnesium stearate on the dissolution time, where- ● -is formulation A, -O-is formulation B with a mixing time of 1min (formulation B/1min), - □ -is formulation B with a mixing time of 3min (formulation B/3min), -is formulation B with a mixing time of 7min (formulation B/7 min). The ordinate is the dissolution rate (%), and the abscissa is the time in minutes.

FIG. 2 shows the effect of various additives on the dissolution time delay caused by magnesium stearate, where- ● -is formulation A, - □ -is formulation B, -O-is formulation C, - ■ -is formulation D, -O-is formulation E, - Δ -is formulation F, -G. The ordinate is the dissolution rate (%), and the abscissa is time in minutes.

FIG. 3 shows the relationship between the mixing ratio of magnesium stearate and sodium lauryl sulfate and the solubility, wherein- ● -is formulation H, - □ -is formulation I, -A-is formulation J, -O-is formulation K and-diamond-solid-is formulation L. The ordinate is the dissolution rate (%), and the abscissa is time in minutes.

FIG. 4 shows the solubility of the formulations of examples 1-3, where-O-is the formulation of example 1, - ● -is the formulation of example 2, and- Δ -is the formulation of example 3. The ordinate is the dissolution rate (%), and the abscissa is time in minutes.

Fig. 5 shows the relationship between the amount of titanium dioxide mixed and the light stability in the capsules containing titanium dioxide, where- ● -is control (stored in a light-shielding container), -. DELTA. -is capsule a (containing 1.2% titanium dioxide), -. ■ -is capsule B (containing 2.4% ═ titanium oxide), -. largeis capsule C (containing 3.6% titanium dioxide). The ordinate is the total amount (%) of all relevant substances, and the abscissa is the amount of light (1000 lux/hour).

Best mode for carrying out the invention

The following examples and experimental examples further illustrate the present invention in detail.

Test example 1

Compatibility test

KMD-3213 was mixed with various pharmaceutical additives used to formulate oral solid dosage forms, and their compatibility with KMD-3213 was evaluated. Additives such as fillers, disintegrants and binders in large amounts are mixed with KMD-3213 in a ratio of 1: 1, while other additives in small amounts are mixed in a ratio of 10: 1. The mixture was stored under the following conditions 1 and 2, and a change in the mixture, i.e., incompatibility, was examined. Degradation products were detected by HPLC analysis according to the following HPLC conditions, and visually checked for appearance.

Storage conditions

Condition 1: 40 deg.C, 80% relative humidity for 3 weeks

Condition 2: 40 deg.C, 75% relative humidity for 4 weeks

Analytical method

The mixture of KMD-3213 and a pharmaceutically acceptable additive was accurately weighed, corresponding to about 5mg of KMD-3213. The mixture was dissolved in methanol and after sonication exactly 10mL of solution was obtained. Remove 4mL of solution with a pipette, add methanol, and prepare exactly 5mL of solution. The resulting solution was filtered with a membrane filter having a pore size of not more than 0.45. mu.m. This solution was used as a test solution.

mu.L of each test solution was taken and analyzed according to the following HPLC conditions. The ratio of the peak area of each related substance to the peak area of the solution except the peak area of the solvent was calculated by the area percentage method.

HPLC conditions:

wave length: 225nm

Column: capcell Pack C18 UG120(Shiseido Co., Ltd)

Column temperature: about 25 deg.C

Mobile phase: a mobile phase was prepared by dissolving 6.8g of potassium dihydrogen phosphate and 17.9g of disodium hydrogen phosphate dodecahydrate in water to prepare a 1000mL solution, and then mixing this solution with acetonitrile at a ratio of 7: 3

Flow rate: 1.0mL/min

Time interval of measurement: 40min

Tables 1 and 2 show the results of the tests under conditions 1 and 2, respectively.

As shown in tables 1 and 2, D-mannitol is most suitable as a filler, but microcrystalline cellulose is incompatible. Corn starch is most suitable as a disintegrant, whereas calcium carboxymethylcellulose is clearly incompatible with carboxymethylcellulose. As for the binder, hydroxypropylmethylcellulose and hydroxypropylcellulose are incompatible. As regards the surfactants, polyethylene glycol (105), polypropylene glycol (5) and triethyl citrate are clearly incompatible.

TABLE 1

Condition 1: 40 deg.C, 80% relative humidity for 3 weeks

Medicinal additive	Function(s)	Color change	Degradation product (%)
				D-mannitol	Filler	-	+0.44
Lactose	↓	-	+0.54
				Microcrystalline cellulose	↓	-	+1.01
Corn starch	Disintegrating agent	-	+0.23
				Low-substituted hydroxypropyl cellulose	↓	-	+0.55
Calcium carboxymethylcellulose	↓	+++	+3.57
				Carboxymethyl cellulose		+++	+8.24
Hydroxypropyl methylcellulose	Binder	-	+0.83
				Hydroxypropyl cellulose	↓	+	+0.76
Magnesium stearate	Lubricant agent	-	+0.92
				Calcium stearate	↓	-	+0.61
Talc	↓	-	+0.38
				Macrogol (polyethylene glycol)	Surface active agent	+	+1.55
Polyethylene glycol (105) polypropylene glycol (5)	↓	+	+0.73
				Citric acid acetate	Plasticizer	++	+2.37

TABLE 2

Condition 2: 40 deg.C, 75% relative humidity for 4 weeks

Medicinal additive	Function(s)	Color change	Degradation product (%)
				D-mannitol	Filler	-	+0.25
Lactose	↓	-	+0.47
				Microcrystalline cellulose	↓	-	+0.55
Corn starch	Disintegrating agent	-	+0.18
				Low-substituted hydroxypropyl cellulose	↓	-	+0.50
Calcium carboxymethylcellulose	↓	++	+2.31
				Carboxymethyl cellulose		+++	+3.31
Hydroxypropyl methylcellulose	Binder	-	+0.79
				Hydroxypropyl cellulose	↓	-	+0.44
Magnesium stearate	Lubricant agent	-	+0.32
				Calcium stearate	↓	-	+0.36
Talc	↓	-	+0.27
				Polyethylene glycol	Surface active agent	-	+0.51
Polyethylene glycol (105) polypropylene glycol (5)	↓	-	+0.32
				Citric acid acetate	Plasticizer	-	+0.79

Test example 2

Study of the relationship between magnesium stearate mixing time and dissolution time delay

The correlation between mixing time and dissolution time delay was studied using capsules containing D-mannitol as a filler, partially pregelatinized starch (starch 1500 (registered trademark), Japan colorcon co., Ltd) as a disintegrant, and about 1.0% magnesium stearate as a lubricant.

Each capsule was prepared according to the formulation shown in Table 3, and the dissolution time was measured.

Dissolution test method

The capsules were subjected to dissolution test according to dissolution test method 2 (japanese pharmacopoeia) using a sink and 500mL of water as a test medium at a paddle speed of 50 rpm. At 5, 10, 15, 20 and 30 minutes after the start of the test, 5mL of each of the dissolved solutions were taken and the same volume of test medium was immediately replenished. The solution withdrawn at each time point was filtered through a membrane filter having a pore size of not more than 0.45. mu.m. The first 4mL of filtrate was discarded, and the remaining filtrate was used as the test solution.

About 0.01g of KMD-3213 was accurately weighed and dissolved in water to prepare 100mL of a solution accurately. 8mL of the solution was pipetted and water was added to prepare exactly 100mL of the solution, which was used as a standard solution.

Each test solution and standard solution was tested at 100. mu.L each according to the following liquid chromatography conditions. The dissolution rate was calculated from the peak area of KMD-3213 in the test solution and the standard solution. In addition, the average dissolution rate of 6 samples per capsule was calculated.

HPLC conditions:

wave length: 270nm

Column: intertsil ODS-3(GL Science Co., Ltd)

Column temperature: about 25 deg.C

Mobile phase: sodium dihydrogen phosphate dihydrate 3.9g and 2.5mL of an aqueous phosphoric acid solution (1: 20) were dissolved in water to prepare 1000mL of a solution, which was then mixed with acetonitrile at a ratio of 5: 2 to prepare a mobile phase

Flow rate: 1.0mL/min

To prepare capsules of formulation B containing magnesium stearate, after mixing was initiated, the mixtures were pulled out at 1, 3, 5 and 7 minutes, respectively, and each mixture was filled manually into the capsule shell.

As shown in FIG. 1, formulation B (mixing time: 1 minute) was slightly delayed with respect to the dissolution time. Whereas for formulation B (mixing time: 3 minutes), the decomposition time was significantly delayed.

TABLE 3

Components	Preparation A	Preparation B
			KMD-3213	4.0	4.0
D-mannitol	169.2	169.2
			Partially pregelatinized starch (starch 1500)	10.0	10.0
Magnesium stearate		1.8
			Total weight of	183.2	185.0

Test example 3

Study of the Effect of pharmaceutical additives on the improvement of magnesium stearate-induced dissolution time delay

For the capsules, the improvement effect of various additives on the delay of dissolution time caused by the addition of 1% magnesium stearate was studied. Capsules were prepared by adding the same amount of test additive as the amount of magnesium stearate added to formulation B in test example 2. The dissolution time of the capsules was determined according to the same test method as described in test example 2.

To prepare capsules, granules were first prepared, and then the additive and magnesium stearate were added to the granules together and mixed for 5 minutes.

As shown in fig. 2, only sodium lauryl sulfate (formulation C) improved the delay in dissolution time, and formulation C dissolved immediately as formulation a without magnesium stearate.

TABLE 4

Preparation	A	B	C	D	E	F	G
								KMD-3213	4.0	4.0	4.0	4.0	4.0	4.0	4.0
D-mannitol	169.2	169.2	169.2	169.2	169.2	169.2	169.2
								Partially pregelatinized starch (starch 1500)	10.0	10.0	10.0	10.0	10.0	10.0	10.0
Magnesium stearate		1.8	1.8	1.8	1.8	1.8	1.8
								Sodium dodecyl sulfate			1.8
Sucrose ester of fat (stearic acid)				1.8
								Esters of fatty sucrose (palmitic acid)					1.8
Light anhydrous silicic acid						1.8
								Polyethylene glycol (105) polypropylene glycol (5)							1.8
Total weight of	183.2	185.0	186.8	186.8	186.8	186.8	186.8

Test example 4

Study of the Effect of magnesium stearate and sodium lauryl sulfate ratio on the dissolution time of capsules

The correlation between the ratio of magnesium stearate to sodium lauryl sulfate and the solubility of the capsules was investigated, wherein sodium lauryl sulfate has a good improving effect on the delay in dissolution time caused by the addition of magnesium stearate. Capsules were prepared according to the formulation shown in table 5, the dissolution time of which was measured according to japanese pharmacopoeia method 2 (paddle method) under conditions in which water was used as the test medium, the specific procedure being described in the test method below. HPLC conditions were the same as in test example 2.

Dissolution test method

The capsules were subjected to dissolution test according to dissolution test method 2 (japanese pharmacopoeia) using a sink and 500mL of water as a test medium at a paddle speed of 50 rpm. At 5, 10, 15, 20 and 30 minutes after the start of the test, 5mL of each of the dissolved solutions were taken and immediately supplemented with the same volume of test medium. The solution taken out at each time point was centrifuged at 3000rpm for 5 minutes or more, 10. mu.L of concentrated hydrochloric acid was added to the supernatant of the centrifuged solution, and the resulting solution was used as a test solution.

About 0.01g of KMD-3213 was accurately weighed and dissolved in 0.1N hydrochloric acid to prepare 100mL of a solution accurately. A pipette was used to remove 2mL of the solution, and 0.1N hydrochloric acid was added to prepare exactly 100mL of the solution, which was used as a standard solution.

To prepare capsules, granules were first prepared, and then the additive and magnesium stearate were added to the granules together and mixed for 5 minutes.

The average dissolution rate of 6 samples per capsule was calculated.

As shown in fig. 3, formulation I containing 10% sodium lauryl sulfate (based on magnesium stearate) has a good effect of improving solubility, almost improving the delay in dissolution time.

TABLE 5

Preparation	H	I	J	K	L
						Ratio of magnesium stearate to sodium lauryl sulfate	10∶1	10∶1	10∶3	10∶5	10∶10
KMD-3213	2.0	2.0	2.0	2.0	2.0
						D-mannitol	134.4	134.4	134.4	134.4	134.4
Partially pregelatinized starch (PCS)	26.0	26.0	26.0	26.0	26.0
						Partially pregelatinized starch (starch 1500)	9.0	9.0	9.0	9.0	9.0
Magnesium stearate	1.8	1.8	1.8	1.8	1.8
						Sodium dodecyl sulfate		0.18	0.54	0.9	1.8
Total weight of	173.2	173.38	173.74	174.1	175.0

Example 1

Capsule containing KMD-3213 2.0mg

2.0 parts of KMD-3213, 134.4 parts of D-mannitol, 26.0 parts of partially pregelatinized starch (PCS (registered trademark), Asahi Chemical Industry Co., Ltd.) and 9.0 parts of partially pregelatinized starch (starch 1500 (registered trademark), Japan Colorcon Co., Ltd.) were thoroughly mixed. Adding a proper amount of water, and granulating the mixture. The granules were dried with a fluid bed dryer at 60 ℃ inlet temperature until the exhaust temperature reached 40 ℃ and then sieved. A mixture of 1.8 parts magnesium stearate and 1.8 parts sodium lauryl sulfate was added to the sieved granules, mixed for 5 minutes, and the mixture was filled into capsule shells to prepare capsules containing 2.0mg KMD-3213.

Example 2

Capsule containing KMD-3213 4.0mg

4.0 parts of KMD-3213, 132.4 parts of D-mannitol, 26.0 parts of partially pregelatinized starch (PCS (registered trademark), Asahi Chemical Industry Co., Ltd.) and 9.0 parts of partially pregelatinized starch (starch 1500 (registered trademark), Japan Colorcon Co., Ltd.) were thoroughly mixed. Adding a proper amount of water, and granulating the mixture. The granules were dried with a fluid bed dryer at 60 ℃ inlet temperature until the exhaust temperature reached 40 ℃ and then sieved. A mixture of 1.8 parts magnesium stearate and 1.8 parts sodium lauryl sulfate was added to the sieved granules, mixed for 5 minutes, and the mixture was filled into capsule shells to prepare capsules containing 4.0mg KMD-3213.

Example 3

Tablet containing 4.0mg KMD-3213

4.0 parts of KMD-3213, 117.0 parts of D-mannitol and 7.0 parts of low-substituted hydroxypropylcellulose (L-HPC (registered trademark), Shin-Etsu Chemical Co., Ltd.) were thoroughly mixed. A 12% hydroxypropyl cellulose aqueous solution (4 parts hydroxypropyl cellulose and about 30 parts water) was added and the mixture was granulated. The granules were dried with a fluid bed dryer at 60 ℃ inlet temperature until the exhaust temperature reached 40 ℃, dried sieved and sieved. To the granules, 1.0 part of magnesium stearate was added and mixed for 3 minutes. The mixture was compressed and coated with a coating agent to prepare a tablet containing 4.0mg of KMD-3213.

Test example 5

Study of dissolution time

The capsules or tablets described in examples 1-3 were subjected to dissolution testing according to the following dissolution testing method. HPLC conditions were the same as in test example 2.

Dissolution test method

According to the dissolution test method 2 (Japanese pharmacopoeia), 1 tablet or 1 capsule was put into a sink, and a test was conducted under the condition that the paddle speed was 50rpm with 500mL of water as a test medium. After the start of the test, 5mL of each of the dissolved solutions were taken at 5, 10, 15, 20 and 30 minutes and immediately supplemented with the same volume of test medium. The solution removed at each time point was centrifuged at 3000rpm for more than 5 minutes. To the supernatant of the centrifuged solution, 10. mu.L of concentrated hydrochloric acid was added, and the resulting solution was used as a test solution.

About 0.01g of KMD-3213 was accurately weighed and dissolved in 0.1N hydrochloric acid to prepare 100mL of a solution accurately. For the dosage form containing 2mg of KMD-3213 in example 1, 2mL of the solution was pipetted and 0.1N hydrochloric acid was added to prepare exactly 100mL of the solution, which was used as a standard solution. For the dosage forms of examples 2 and 3 containing 4.0mg KMD-3213, 100mL of the solution was accurately prepared by pipetting 4mL of the solution and adding 0.1N hydrochloric acid, and this solution was used as a standard solution.

Each test solution and standard solution was tested at 100. mu.L each according to the following liquid chromatography conditions. The dissolution rate was calculated from the peak area of KMD-3213 in the test solution and the standard solution. In addition, the average dissolution rate of 6 samples per capsule was calculated.

HPLC conditions:

wave length: 270nm

Column: intertsil ODS-3(GL Science Co., Ltd)

Column temperature: about 25 deg.C

Mobile phase: sodium dihydrogen phosphate dihydrate 3.9g and 2.5mL of an aqueous phosphoric acid solution (1: 20) were dissolved in water to prepare 1000mL of a solution, which was then mixed with acetonitrile at a ratio of 5: 2 to prepare a mobile phase

Flow rate: 1.0mL/min

As shown in FIG. 4, all of the dosage forms of examples 1-3 had dissolution rates of no less than 90% at the start of the test and did not dissolve 85% for more than 10 minutes.

Test example 6

Photostability test of capsules containing titanium dioxide

The photostability test was performed on capsules prepared as described in example 1, which contained capsule shells of 1.2% (capsule a), 2.4% (capsule B) and 3.6% (capsule C), respectively, titanium dioxide. Further, the capsule prepared with a capsule shell containing 1.2% titanium dioxide was packed with a blister type packing material and an aluminum bag for the purpose of light-shielding. Capsules were also tested as blind controls.

The capsule contents were removed at the start of the test and their appearance and the amount of photodegradation products (related substances) were examined after illumination with total illumination of 67.2 ten thousand and 120 million lux/hour. The amount of photodegradation products was determined according to the following HPLC conditions, and the change in color was visually detected.

Determination of photodegradation products

The contents of 5 test capsules were removed and placed in a 50mL measuring flask. The empty capsules were washed 2 times with the mobile phase and the wash was poured into bottles. About 30mL of mobile phase was added to the bottle and the mixture was shaken for 15 minutes. Then, a mobile phase was added to prepare exactly 50mL of a solution, and the solution was filtered through a membrane filter having a pore size of not more than 0.45. mu.m. The first 2-3mL of filtrate was discarded, and the remaining filtrate was used as the test solution. 25 μ L of each test solution was used for the following HPLC analysis. The peak area of the solution is determined by an automatic integration method, and the ratio of the peak area of each related substance to the peak area of KMD-3213 is calculated by an area percentage method.

HPLC conditions:

wave length: 225nm

Column: intertsil ODS-3(GL Science Co., Ltd)

Column temperature: about 25 deg.C

Mobile phase: sodium dihydrogen phosphate dihydrate 3.9g and 2.5mL of an aqueous phosphoric acid solution (1: 20) were dissolved in water to prepare 1000mL of a solution, which was then mixed with acetonitrile at a ratio of 5: 2 to prepare a mobile phase

Flow rate: the retention time of KMD-3213 was adjusted to 7 minutes

Measuring time interval: 30 minutes

As shown in fig. 5 and table 6, capsule a, which contained 1.2% titanium dioxide, did not meet the specification for total amount after light exposure with respect to appearance and total illumination of all relevant material at about 67.2 mules/hour. Capsule B, containing 2.4% titanium dioxide, also did not meet the post-illumination specification for a total illumination of about 120 wallex/hour. In contrast, capsule C, which contained 3.6% titanium dioxide, was the most stable, meeting the specifications for appearance and total amount of all relevant materials.

TABLE 6

Sample (I)	Illuminance (million lux/hour)	Amount of related substance (%)								Appearance of the product
											a	b	c	d	e	F	Others	Total amount of
		Capsule A	0	0.13			0.04		0.04										0.07	0.28	White colour
0.672	2.28									0.31	0.31	0.50	0.99	0.04	0.42	4.85	Pale yellow and white
			1.248	3.52	0.49	0.52	0.68	1.61	0.04									0.68	7.54	Light yellow
Capsule B	0									0.15			0.02		0.04	0.07	0.28				White colour
		0.672	1.55	0.19	0.21	0.40	0.69	0.04	0.30									3.38	White colour
	1.248									2.38	0.33	0.35	0.54	1.10	0.04	0.40	5.14			Pale yellow and white
		Capsule c	0	0.15			0.02		0.04									0.07	0.28		White colour
0.672	1.29									0.16	0.16	0.35	0.54	0.04	0.23	2.77	White colour
			1.248	1.93	0.26	0.27	0.47	0.87	0.04									0.31	4.15	White colour
Control	0									0.13			0.04		0.04	0.07	0.28				White colour
		0.672	0.21			0.02		0.04	0.04									0.31	White colour
	1.248									0.16			0.02		0.04	0.04	0.26			White colour

Industrial applications

The solid oral dosage form drug of the present invention has good handling during the manufacturing process, good content uniformity and excellent solubility, and is particularly suitable for use as a solid oral dosage form drug for treating dysuria. The solid oral dosage form medicament has good carrying performance in the filling process of preparing capsules or the tabletting process of tablets, and has high precision of the content of active ingredients and good stability. Furthermore, the solid oral dosage form of the present invention shows a stable, excellent solubility in dissolution tests with water, the active ingredient is almost insoluble and the drug is most likely bioequivalent. Therefore, the solid oral dosage form medicament of the present invention is extremely suitable as a solid oral dosage form medicament for the treatment of dysuria.

Claims (11)

1. A capsule for treating dysuria, comprising (1) a granulated product comprising (a) a compound represented by the following formula as an active ingredient and (b) D-mannitol and (2) a combination of (c) a lubricant selected from magnesium stearate, calcium stearate or talc and (D) sodium lauryl sulfate,

according to the Japanese pharmacopoeia method 2, i.e., the paddle method, under the conditions that water is used as a test medium and the paddle speed is 50rpm, the time for which they are dissolved by 85% in the dissolution test is not more than 60 minutes.

2. The capsule according to claim 1, wherein they are dissolved in a dissolution test for a period of 85% not more than 60 minutes under the conditions of using the first fluid adjusted in the japanese pharmacopoeia disintegration test as a test medium and a paddle speed of 50rpm according to the japanese pharmacopoeia method 2, i.e., the paddle method.

3. A capsule according to claim 1 or claim 2, wherein 85% dissolution time is no more than 30 minutes.

4. The capsule of claim 3, wherein 85% dissolution time is no more than 15 minutes.

5. The capsule according to claim 1 or 2, wherein the lubricant is magnesium stearate.

6. The capsule according to claim 5, comprising 0.1-2 parts of sodium lauryl sulfate per part of magnesium stearate.

7. The capsule according to claim 5, comprising 0.5 to 1 parts of sodium lauryl sulfate per part of magnesium stearate.

8. The capsule of claim 5, the granulation further comprising a portion of pregelatinized starch.

9. The capsule according to claim 5, wherein the capsule is a light-resistant capsule.

10. The capsule according to claim 1 or 2, wherein the light-resistant capsule is a capsule comprising titanium dioxide.

11. A method of manufacturing a capsule comprising:

(1) wet granulating the compound of the following chemical formula and D-mannitol;

(2) mixing the granulation mass obtained in step 1 with a lubricant selected from magnesium stearate, calcium stearate or talc and sodium lauryl sulfate;

(3) filling into capsules.