HK1084396B - Crystal for oral solid drug and oral solid drug for dysuria treatment containing the same - Google Patents

Description

Oral solid medicinal crystal and oral solid medicine containing the same for treating dysuria

Technical Field

The present invention relates to a crystal for oral administration of a solid drug. More particularly, the present invention relates to a crystal for an indoline oral solid pharmaceutical, the indoline being represented by the following general formula (hereinafter referred to as KMD-3213):

it functions as alpha₁-adrenoceptor (. alpha.)₁-AR) and as a therapeutic agent for dysuria; and to an oral solid medicine for treating dysuria comprising the crystal as an active ingredient.

The invention also relates to an oral solid medicine, which comprises KMD-3213 crystal and alpha selected from KMD-3213 except KMD-3213 as active ingredients₁-at least one of an AR blocker, an anticholinergic, a 5 α -reductase inhibitor, a sex hormone agent, an anxiolytic, a cholinergic, a cholinesterase inhibitor, an anti-inflammatory agent, and an antibacterial agent.

Furthermore, the present invention relates to a medicament for treating dysuria which comprises a medicament comprising as an active ingredient a crystal for KMD-3213 oral solid medicament and a crystal selected from the group consisting of alpha other than KMD-3213₁A pharmaceutical mixture of at least one of an AR blocker, an anticholinergic, a 5 alpha-reductase inhibitor, a sex hormone agent, an anxiolytic, a cholinergic, a cholinesterase inhibitor, an anti-inflammatory agent, and an antibacterial agent.

Background

KMD-33213 as an active ingredient in the oral solid medicine for treating dysuria according to the present invention is known to have a selective inhibitory effect on urethral smooth muscle contraction, and is a very useful pharmaceutical compound for treating dysuria, which does not cause a strong hypotensive effect or orthostatic hypotension. However, no specific preparation method and purification method thereof have been reported. Moreover, the physical properties of KMD-3213 have been reported on IR (infrared absorption spectrum), optical rotation and NMR (nuclear magnetic resonance spectrum) data, but appearance and crystalline polymorph thereof have not been reported. (see the following document 1)

That is, to date, no method for preparing KMD-3213 crystalline polymorph has been reported. Furthermore, there is no report or mention of what type of crystalline form exists, its preparation process and its properties, etc.

On the other hand, as for the pharmaceutical composition comprising the active ingredient KMD-3213 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, as a general description relating to all compounds represented by some general formulae (including KMD-3213), there have been enumeratedThese dosage forms. It is only said that these compositions can be prepared according to a general pharmaceutical method (see the following document 1). Furthermore, alpha is contained as an active ingredient for the treatment of lower urinary tract diseases₁In the general description of pharmaceutical compositions of AR blockers (including KMD-3213), oral solid dosage forms are exemplified. It has been described that the preferable preparation is a sustained-release pharmaceutical dosage form of a continuous-release type, and the preparation can be prepared according to a known method and an example of a pharmaceutical additive (see the following document 2).

That is, to date, the preferred crystalline form of KMD-3213 of the present invention for solid medicines and oral solid medicines containing it for treating dysuria have not been reported or mentioned at all.

Document 1: japanese unexamined patent publication H06-220015

Document 2: japanese unexamined patent publication No. 200₁-288115

Disclosure of Invention

The invention provides a better crystal for KMD-3213 oral solid medicine and an oral solid medicine for treating dysuria containing the same; the KMD-3213 is useful as a therapeutic agent for dysuria treatment and has less influence on blood pressure.

The invention also relates to a medicament for treating dysuria, which comprises KMD-3213 and alpha selected from KMD-3213 except KMD-3213 as active ingredients₁-at least one of an AR blocker, an anticholinergic, a 5 α -reductase inhibitor, a sex hormone agent, an anxiolytic, a cholinergic, a cholinesterase inhibitor, an anti-inflammatory agent, and an antibacterial agent.

Further, the present invention provides a medicament for treating dysuria which comprises a medicament comprising as an active ingredient a crystal for KMD-3213 oral solid medicament and a crystal selected from the group consisting of alpha other than KMD-3213₁-AR blockers, anticholinergics, 5 alpha-reductase inhibitors, sex hormone agents, anxiolytics, cholinomimetics, cholinesterasesA medicament comprising at least one of an inhibitor, an anti-inflammatory agent and an antimicrobial agent.

Brief Description of Drawings

Figure 1 is an X-ray powder diffraction pattern of form α of KMD-3213. The ordinate shows the intensity of the X-ray, expressed in Kcps; the abscissa shows 2 θ (°).

FIG. 2 is an X-ray powder diffraction pattern of crystalline form β of KMD-3213. The ordinate shows the intensity of the X-ray, expressed in Kcps; the abscissa shows 2 θ (°).

Figure 3 is an X-ray powder diffraction pattern of form gamma of KMD-3213. The ordinate shows the intensity of the X-ray, expressed in Kcps; the abscissa shows 2 θ (°).

BEST MODE FOR CARRYING OUT THE INVENTION

In the study of the case where an oral solid drug comprising KMD-3213 as an active ingredient, which is extremely useful for the treatment of dysuria, was used in the treatment of dysuria, the present inventors conducted extensive and intensive investigations on the preferred crystalline form of KMD-3213 for oral solid drugs. The present inventors have discovered a novel crystalline form suitable for oral administration of solid drugs. The present invention has been completed based on the finding.

The therapeutic agents are required to exhibit constant action and effect at all times. For this reason, the content of the active ingredient in the medicament must be substantially the same. In this case, the amount of crystal solvent or residual solvent such as adhesion solvent (adhesion) and the stability of the active ingredient are important. With regard to oral solid drugs, the solubility and specific volume of the active ingredient are also important factors.

In general, amorphous compounds are not generally suitable for oral solid drugs even though they show better solubility because of their poor stability, their specific volume is variable, and they are prone to solvent attachment or moisture absorption. On the other hand, crystalline compounds have low solubility, but are stable, compatible with excipients, or do not change over time. In addition, since it is not hygroscopic, its specific volume is approximately constant, and it is easy to control the amount of the active ingredient. Therefore, it is preferable to use a crystalline active ingredient for oral solid drugs as long as the crystal does not have a problem of solubility.

In addition, some compounds have many crystalline forms, i.e., polymorphism. Each crystal form exhibits different solubility or stability, which may affect hygroscopicity or drug efficacy. Therefore, when polymorphism of an active ingredient for a drug exists, it is required to confirm the characteristics of the polymorph used for the drug.

The present inventors have earnestly studied the polymorphic phenomenon of KMD-3213, which KMD-3213 is the most useful indoline compound for the treatment of dysuria as described in the above document 1. Thus, the present inventors have found that at least three crystalline forms exist, and preferably one of them is suitable for oral solid drugs.

That is, KMD-3213 has at least three crystal forms, as shown in the figure₁The powder X-ray diffraction pattern in (E) -3. Specifically, the present inventors have found that there are three crystal forms, (1) crystals having main peaks 2 θ of 5.5 ° ± 0.2 °, 6.1 ° ± 0.2 °, 9.8 ° ± 0.2 °, 11.1 ° ± 0.2 °, 12.2 ° ± 0.2 °, 16.4 ° ± 0.2 °, 19.7 ° ± 0.2 ° and 20.0 ° ± 0.2 ° (hereinafter referred to as crystal form α); (2) crystals having main peaks 2 θ of 7.0 ° ± 0.2 °, 12.5 ° ± 0.2 °, 18.5 ° ± 0.2 °, 19.5 ° ± 0.2 °, 20.7 ° ± 0.2 ° and 21.1 ° ± 0.2 ° (hereinafter referred to as crystalline form β); (3) crystals having main peaks 2 θ of 6.0 ° ± 0.2 °, 10.6 ° ± 0.2 °, 12.6 ° ± 0.2 °, 17.1 ° ± 0.2 °, 17.9 ° ± 0.2 °, 20.7 ° ± 0.2 ° and 23.7 ° ± 0.2 ° (hereinafter referred to as crystalline form γ). These crystalline forms can be prepared as follows.

The crystalline form α can be prepared as follows: the crude crystals are gradually precipitated by dissolving them in an appropriate amount of ethyl acetate, ethyl formate, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran or a mixed solvent (1: 1) of acetone and acetonitrile, preferably ethyl acetate, under heating and allowing to stand at room temperature.

The crystalline form β can be prepared as follows: the crystals are forcibly and suddenly precipitated by dissolving the crude crystals thereof in an appropriate amount of methanol under heating, adding petroleum as a poor solvent, and vigorously stirring the mixture. The crystalline form beta can also be obtained by dissolving the crude crystals thereof in ethanol or₁-propanol and rapidly cooling.

The crystalline form γ can be prepared as follows: the crystals are gradually precipitated by dissolving the crude crystals in an appropriate amount of toluene, a mixed solvent of acetonitrile and toluene (1: 4), or a mixed solvent of ethyl acetate and toluene (1: 19), preferably toluene, under heating, and allowing to stand at room temperature. The crystalline form γ can also be prepared by dissolving the crude crystals in 2-propanol, to which an appropriate amount of toluene is added to precipitate the crystals.

The stability and hygroscopicity of each crystalline form prepared above were measured. As a result, it was confirmed that the three crystal forms are more hygroscopic than the amorphous form, and there is little difference therebetween; the above amorphous form is prepared by dissolving the crystals in dioxane and lyophilizing the solution. Furthermore, it was also confirmed that there was no great difference in stability of the three crystal forms, however, the crystal form α was white, had little color in appearance, and was most stable. The present inventors have therefore found that crystalline form α is the best crystal for oral solid drugs in terms of stability and hygroscopicity.

Moreover, among the above crystalline forms of KMD-3213, crystalline form β has a problem of preparation in industrial production because it is prepared by adding a poor solvent to a warm solution as described above, and forcibly and abruptly precipitating the crystals. For example, equipment for industrial production becomes large, and it is difficult to produce crystals of constant quality. By dissolving in ethanol or₁In propanol and rapidly cooled to produce crystalline form β, there is a problem that different crystalline forms are easily mixed therein due to differences in cooling rate, temperature, degree of stirring, and the like, and thus yield and purity are not uniform.

The crystalline form γ is prepared by cooling the warm solution to cause the crystals to be precipitated stepwise and optionally according to a conventional recrystallization method, and therefore, the industrial equipment can be small, and uniform crystals can be easily prepared by controlling the amount of solvent, heating temperature, cooling rate, and the like. Therefore, there is no problem in industrial production. However, the recrystallization solvent of this form γ is toluene or a mixed solvent mainly of toluene. Therefore, this crystalline form γ has a problem that it is difficult to remove the solvent, and it is rather difficult to completely remove the residual solvent because the boiling point of toluene is high. As for the residual solvent in the crude material for pharmaceutical use, the upper limit of the amount has been determined depending on the kind of the solvent. The amount of toluene is required to be no more than 890 ppm. Thus, the crystalline form γ has a problem in this point.

On the other hand, the crystalline form α is industrially produced without the problems encountered in producing the crystalline form β and can be easily produced on a large scale regularly, and furthermore, without the problems of residual solvent encountered in the crystalline form γ. Therefore, the crystalline form α is preferably used for the oral solid pharmaceutical preparation in terms of industrial production process and quality.

Therefore, using the crystalline form α of KMD-3213 as an active ingredient allows the preparation of high-quality stable oral solid drugs for the treatment of dysuria, containing a constant content of the active ingredient, at low cost.

As mentioned above, the hygroscopicity and stability of crystalline forms β and γ of KMD-3213 are almost the same as those of said crystalline form α. The crystalline form β, the crystalline form γ and mixtures thereof may be used together as an active ingredient of the oral solid medicament of the present invention if the quality thereof (including residual solvent) is within an acceptable range. At this time, it is not a problem that the oral solid medicament for treating dysuria of the present invention contains other crystal forms other than the crystal form α as an active ingredient, and a mixture of the crystal form α and other crystal forms may be used as an active ingredient of the oral solid medicament of the present invention.

The oral solid medicine of the present invention can be prepared by conventional pharmaceutical procedures. For example, capsules are prepared by mixing form α of KMD-3213 or a mixture of form α and other forms and an excipient such as D-mannitol or lactose into water, kneading the mixture, screening and drying to prepare granules, and mixing the granules with a lubricant such as magnesium stearate, and filling the resulting mixture into suitable capsules.

Tablets are prepared by preparing granules in a manner similar to the capsules described above, mixing a lubricant such as magnesium stearate into the granules, pressing the mixture into tablets by conventional procedures, and coating with a suitable coating material.

Since KMD-3213 of the present invention represented by the above general formula (I) is relatively unstable to light, the content of the active ingredient decreases with the lapse of time depending on the preservation conditions. Therefore, for the capsule or tablet, a capsule filled with a light-shielding capsule or a tablet coated with a coating material having a light-shielding effect is preferable. As the light-screening capsules or coating materials having a light-screening effect, preferred are capsules containing titanium dioxide or coating materials containing titanium dioxide.

Heretofore, the indoline compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof and a pharmaceutical composition containing it as an active ingredient have been exemplified for these general dosage forms, and only those compositions which can be prepared according to a general or known method (for example, in the above documents 1 or 2) have been described.

As described above, the crystalline polymorph of KMD-3213 shown in the above formula (I) is contained as an active ingredient in the oral solid pharmaceutical of the present invention, which has not been studied at all, and therefore, there is no mention of what type of crystalline forms exist, how to prepare them and their properties. Furthermore, oral solid drugs comprising as an active ingredient each crystalline form of indoline of the above formula (I) of the present invention are not mentioned at all.

KMD-3213 represented by the above formula (I) is contained as an active ingredient in the oral solid medicine of the present invention, which is a known compound, and can be prepared, for example, according to the procedure described in the above document 1.

The KMD-3213 shown in the above formula (I) of the present invention functions as alpha₁The effect of the AR blocking agent has no effect on blood pressure, and is useful as a therapeutic agent for dysuria due to prostatic hypertrophy or the like. It is also expected that KMD-3213 shown by the above formula (I) of the present invention can be used as a therapeutic agent for dysuria associated with obstruction of urethral tissues other than prostatic hypertrophy (e.g., urethral stricture, urethral calculus and prostate cancer), dysuria associated with nerve disorder of urinary control and dysuria associated with functional obstruction of urethra (not included in any of the above dysuria such as bladder neck sclerosis, chronic prostatitis and unstable bladder).

Dysuria associated with dysuria-controlling nerve disorders refers to dysuria caused by dysuria-controlling nerve disorders in the urinary tract or bladder, for example, encephalopathy (encephathhy), such as cerebral vascular diseases and brain tumors, spinal diseases, such as spinal cord injury, and peripheral nerve diseases, such as diabetes and lumbar spinal stenosis. These diseases occur in both men and women, commonly referred to as the neurogenic bladder.

Dysuria associated with functional blockage of the urethra (which is not accompanied by urinary tract tissue diseases and dysuria-controlling nerve disorder) refers to dysuria caused by dysuria, bladder neck closure, urethral syndrome, detrusor-sphincter insufficiency, chronic cystitis, prostatodynia, hindman syndrome, Fowler syndrome, psychogenic dysuria, drug-induced dysuria, aging, and the like, in addition to bladder neck sclerosis, chronic prostatitis, and unstable bladder. These diseases are also commonly referred to as lower urinary tract diseases.

Since the drugs of the present invention have precise contents of active ingredients and good elution properties, they can effectively exhibit the effect of KMD-3213 shown in the above formula (I) of the present invention. Therefore, the drug of the present invention is very useful as an agent for treating dysuria associated with urethral tissue obstruction such as prostatic hypertrophy, urethral stricture, urethral calculus and prostatic cancer, dysuria caused by a neurologic disease for controlling urination (i.e., neurogenic bladder), and dysuria caused by functional obstruction of urethra (i.e., lower urinary tract disease).

When the actual medication using the above-mentioned drugs of the present invention is carried out, the dose of the active ingredient is determined approximately according to the sex, age or body weight of each patient, the condition to be treated, etc., and is approximately every adult per day₁-50mg, preferably 4-20 mg.

The medicament of the invention comprises alpha selected from KMD-3213 as another active ingredient₁-at least one of an AR blocker, an anticholinergic, an anti-inflammatory agent and an antibacterial agent.

The medicament of the present invention may also comprise an alpha selected from the group consisting of alpha other than KMD-3213₁-at least one of an AR blocker, an anticholinergic, a 5 α -reductase inhibitor, a sex hormone agent, an anxiolytic, a cholinesterase inhibitor, an anti-inflammatory agent, and an antibacterial agent is used together as a drug of an active ingredient. In the present invention, the drug for treating dysuria comprises a drug containing KMD-3213 crystal for oral solid drug as an active ingredient and a drug containing α selected from the group consisting of those other than KMD-3213₁A drug mixture of at least one of an AR blocking agent, an anticholinergic agent, a 5 alpha-reductase inhibitor, a sex hormone agent, an anxiolytic agent, a cholinesterase inhibitor, an anti-inflammatory agent and an antibacterial agent, which means a drug containing KMD-3213 as an active ingredient, which is prepared so as to be capable of being mixed with a drug containing an alpha selected from the group consisting of compounds other than KMD-3213₁-an AR blocker, an anticholinergic, a 5 alpha-reductase inhibitor, a sex hormone agent, an anxiolytic agent, a cholinergic agent, a cholinesterase inhibitor, an anti-inflammatory agent, and an antibacterial agent, and a kit comprising the same.

Under these conditions, the content of KMD-3213 represented by the above formula (I) and α other than KMD-3213 represented by the above formula (I)₁The content of the-AR blocker, anticholinergic agent, 5 α -reductase inhibitor, sex hormone agent, anxiolytic agent, cholinomimetic agent, cholinesterase inhibitor, anti-inflammatory agent and antibacterial agent can be suitably reduced.

Examples

The present invention is also illustrated in more detail by the following reference examples, examples and comparative examples

Example 1

Preparation of crystalline form alpha

To 1g of the crude crystals of KMD-3213 was added 3ml of ethyl acetate, and the mixture was heated to dissolve. After insoluble materials were filtered off, the filtrate was left to stand at room temperature. After the obtained crystals were completely precipitated, 10ml of ethyl acetate was added thereto. The resulting crystals were collected by filtration and dried under vacuum at 50 ℃ for 16 hours to give 930mg of form α.

Example 2

Preparation of crystalline form beta

To 1g of the crude crystals of KMD-3213 was added 0.4ml of methanol, and the mixture was heated to dissolve. After insoluble matter was filtered off, 20ml of petroleum ether was added thereto, and vigorously shaken. The resulting crystals were collected by filtration and dried under vacuum at 50 ℃ for 16 hours to give 930mg of form α.

Example 3

Preparation of crystalline form gamma

To 1g of the crude crystals of KMD-3213 was added 4ml of toluene, and the mixture was heated to dissolve. After insoluble materials were filtered off, the filtrate was left to stand at room temperature. After the obtained crystals were completely precipitated, 10ml of toluene was added thereto. The resulting crystals were collected by filtration and dried under vacuum at 50 ℃ for 16 hours to give 970mg of crystalline form α.

Test example 1

Stability test

Examples were determined after standing under the following conditions₁-3 appearance and purity of the individual crystals obtained and of the amorphous material obtained by lyophilization of KMD-3213 in dioxane. ToThe color and properties of the cosmetic were determined by visual inspection. Purity was determined by using integrated percentages of liquid chromatography.

Storage conditions are as follows:

condition 1: standing in a thermostatic device at 40 deg.C for 28 days;

condition 2: standing in a thermostatic device at 60 deg.C for 28 days;

condition 3: placing in a thermostatic device at 80 deg.C for 25 days;

condition 4: standing in a thermostatic apparatus at 40 deg.C and 75% relative humidity for 28 days;

liquid chromatography conditions:

a detector: ultraviolet absorption spectrometer (wavelength: 225nm)

A chromatographic column: intertsil ODS-3(GL Science, 5 μm, 4.6 mm. times.25 cm)

Temperature of the column: about 25 deg.C

Mobile phase: to 3.9g of sodium dihydrogen phosphate was added exactly 2.5ml of dilute phosphoric acid solution (1 → 20) and water was added, exactly 1000ml of solution was made. One resulting solution and a 5: 2 mixed solution of acetonitrile.

Flow rate: 1.0 ml/min

As a result, as shown in table 1, the crystal form α was extremely stable in terms of purity and appearance.

TABLE 1

Crystal	α		β		γ		Amorphous form
									Item	Appearance of the product	Purity (%)	Appearance of the product	Purity (%)	Appearance of the product	Purity (%)	Appearance of the product	Purity (%)
Initiation of	White powder	99.90	Light yellow powder	99.83	Light yellow powder	99.88	White powder	99.79
									Condition 1	White powder	99.84	Light yellow powder	99.73	Light yellow powder	99.85	White powder	99.66
Condition 2	White powder	99.84	Light yellow brown powder	99.57	Light yellow powder	99.84	Light yellow powder	99.56
									Condition 3	Light yellow powder	99.58	Light brown powder	98.42	Light yellow powder	99.64	Light yellow brown powder	99.53
Condition 4	White powder	99.85	Light yellow powder	99.69	Light yellow powder	99.85	White powder	99.71

Test example 2

Moisture absorption test

In the same manner as described in test example 1, examples were used₁-3 the resulting crystalline and amorphous material was tested. About 1g of the test substance is accurately weighed and placed in a sample vial. The weight change of the test substance was measured in an open-type constant temperature and humidity apparatus under the following conditions.

Storage conditions are as follows:

condition 1: placing in a constant temperature and humidity equipment with 25 deg.C and 60% relative humidity for 3 days;

condition 2: the mixture was placed in a constant temperature and humidity apparatus at 40 ℃ and 75% relative humidity for 3 days.

As a result, as shown in table 2, crystalline forms α, β, and γ showed almost no hygroscopicity, and were stable compared to amorphous.

TABLE 2

Crystal	Condition 1		Condition 2
					Starting weight (mg)	Change (%)	Starting weight (mg)	Change (%)
	α	947.78	-0.01	1010.59					-0.20
β					1000.51	+0.07	1090.14	-0.08
	γ	992.79	0.00	993.04					-0.19
Amorphous form					1001.09	+1.61	1005.69	+1.31

Example 4

Capsule 1

The formula is as follows:

crystalline form alpha 2.0g of KMD-3213

134.4g of D-mannitol

Part of alpha starch (PCS) 26.0g

Partial alpha starch (starch 1500) 9.0g

Magnesium stearate 1.8g

Sodium lauryl sulfate 0.2g

1000 capsules containing 2.0mg of KMD-3213 in the capsule were prepared by a conventional method according to the above formulation.

Example 5

Capsule 2

The formula is as follows:

crystalline form alpha 2.0g of KMD-3213

134.4g of D-mannitol

Part of alpha starch (PCS) 26.0g

Partial alpha starch (starch 1500) 9.0g

Magnesium stearate 1.8g

Sodium lauryl sulfate 0.5g

1000 capsules containing 2.0mg of KMD-3213 in the capsule were prepared by a conventional method according to the above formulation.

Example 6

Capsule 3

The formula is as follows:

crystalline form alpha 2.0g of KMD-3213

134.4g of D-mannitol

Part of alpha starch (PCS) 26.0g

Partial alpha starch (starch 1500) 9.0g

Magnesium stearate 0.9g

Sodium lauryl sulfate 1.8g

1000 capsules containing 2.0mg of KMD-3213 in the capsule were prepared by a conventional method according to the above formulation.

Example 7

Capsule 4

The formula is as follows:

crystalline form alpha 2.0g of KMD-3213

134.4g of D-mannitol

Part of alpha starch (PCS) 26.0g

Partial alpha starch (starch 1500) 9.0g

Magnesium stearate 1.8g

Sodium lauryl sulfate 1.8g

1000 capsules containing 2.0mg of KMD-3213 in the capsule were prepared by a conventional method according to the above formulation.

Example 8

Capsule 5

The formula is as follows:

crystalline form alpha 4.0g of KMD-3213

D-mannitol 132.4g

Part of alpha starch (PCS) 26.0g

Partial alpha starch (starch 1500) 9.0g

Magnesium stearate 1.8g

Sodium lauryl sulfate 1.8g

1000 capsules containing 4.0mg of KMD-3213 in the capsule were prepared by a conventional method according to the above formulation.

Example 9

Tablet formulation

The formula is as follows:

crystalline form alpha 4.0g of KMD-3213

D-mannitol 117.0g

Corn starch 7.0g

L-HPC 7.0g

HPC-SL 4.0g

Magnesium stearate 1.0g

1000 capsules containing 4.0mg of KMD-3213 in the tablet were prepared by a conventional method according to the above formulation.

Industrial applicability

In the present invention, the crystalline forms α, β and γ of KMD-3213 shown by the above formula (I) show almost no hygroscopicity and are stable. Since crystalline form α is very stable and has no problem in industrial production, it can be easily produced on a regular large scale. The crystalline form α is the best crystal in oral solid drugs. Moreover, the crystalline forms α, β and γ almost exhibit the same uniform hygroscopicity and stability with reduced purity, not appearance stability, so that a mixture of the crystalline form α and other crystalline forms can be used as an active ingredient for preparing the oral solid drug of the present invention.

Therefore, an oral solid medicament for treating dysuria can be prepared by containing crystalline form α or a mixture of crystalline form α and other crystalline forms as an active ingredient.

In particular, the oral solid medicament of the present invention comprising the crystalline form α active ingredient shows the constant content of the active ingredient, good stability and small decrease in the content during storage, and it is an excellent oral solid medicament for treating dysuria.

Claims (11)

1. A crystal of an indoline compound represented by the following general formula for an oral solid drug,

it is characterized in that in an X-ray powder diffraction pattern, the main peak 2 theta is 5.5 degrees +/-0.2 degrees, 6.1 degrees +/-0.2 degrees, 9.8 degrees +/-0.2 degrees, 11.1 degrees +/-0.2 degrees, 12.2 degrees +/-0.2 degrees, 16.4 degrees +/-0.2 degrees, 19.7 degrees +/-0.2 degrees and 20.0 degrees +/-0.2 degrees.

2. An oral solid medicament for treating dysuria, comprising the crystal of claim 1 as an active ingredient.

3. The pharmaceutical according to claim 2, comprising as another active ingredient α selected from the group consisting of indoline compounds represented by the following general formula₁At least one of an adrenoceptor blocker, an anticholinergic, a 5 alpha-reductase inhibitor, a sex hormone agent, an anxiolytic, a cholinergic, a cholinesterase inhibitor, an anti-inflammatory agent and an antibacterial agent

4. The medicament of claim 2 or 3, wherein the dosage form is a capsule or tablet.

5. The medicament of claim 4, wherein the capsule is filled in a light-shielding capsule or the tablet is coated with a coating material having a light-shielding effect.

6. The medicament of claim 5, wherein the light-blocking capsules are capsules comprising titanium dioxide.

7. The medicament according to claim 5, wherein the coating material having a light-screening effect is a coating material containing titanium dioxide.

8. A kit comprising the medicament of claim 2 and an α -peptide comprising an indoline compound selected from the group consisting of those represented by the following general formulae₁-at least one of an adrenoceptor blocker, an anticholinergic, a 5 alpha-reductase inhibitor, a sex hormone agent, an anxiolytic, a cholinergic, a cholinesterase inhibitor, an anti-inflammatory agent and an antibacterial agentA medicine as active ingredient

9. Use of the crystal of claim 1 for the preparation of a medicament for the treatment of dysuria.

10. The use of claim 9, wherein said dysuria is caused by dysuria associated with urethral tissue blockage, dysuria associated with dysuria-controlling neurological disorders, and dysuria associated with urethral functional blockage.

11. The use of claim 9, wherein the dysuria is caused by prostatic hypertrophy, urethral stricture, urethral calculus, prostate cancer, neurogenic bladder or lower urinary tract disease.