WO2004054574A1 - 経口固形医薬 - Google Patents
経口固形医薬 Download PDFInfo
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- WO2004054574A1 WO2004054574A1 PCT/JP2003/015837 JP0315837W WO2004054574A1 WO 2004054574 A1 WO2004054574 A1 WO 2004054574A1 JP 0315837 W JP0315837 W JP 0315837W WO 2004054574 A1 WO2004054574 A1 WO 2004054574A1
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- 230000001107 psychogenic effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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Classifications
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Definitions
- the present invention relates to an oral solid medicine for treating dysuria. Specifically, as an active ingredient, it has an adrenergic receptor (hereinafter referred to as —AR) blocking action, and the formula (I):
- AR adrenergic receptor
- KMD — 3213 An indoline compound represented by the following formula (hereinafter referred to as KMD — 3213), its prodrug, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
- the drug for the treatment of micturition disorders contains 85% dissolution time in a dissolution test using water as a test solution and 50 revolutions in the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method). It is related to an oral solid medicine that is 60 minutes or less.
- the present invention also provides, as an active ingredient, KMD-3213, a prodrug thereof, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof.
- a drug for the treatment of micturition disorders containing at least one selected from the group consisting of i-adrenergic receptor blockers other than KMD—3213, anticholinergic drugs, anti-inflammatory drugs and antibacterial drugs.
- i-adrenergic receptor blockers other than KMD—3213 i-adrenergic receptor blockers other than KMD—3213
- anticholinergic drugs anti-inflammatory drugs
- antibacterial drugs antibacterial drugs.
- the present invention further comprises KMD-3213, a prodrug thereof, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof as an active ingredient.
- KMD-3213 a prodrug thereof, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof as an active ingredient.
- Dyuria which is based on the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method) in a dissolution test in which water is used as a test solution and the number of revolutions is 50 times Z minutes.
- Elution time is 60 minutes or less, and at least selected from the group consisting of adrenergic receptor blockers, anticholinergics, anti-inflammatory drugs and antibacterial drugs other than KMD-321
- the present invention relates to an oral solid drug which can be used in combination with a drug containing at least one as an active ingredient, and a kit drug comprising the combination.
- the oral solid drug for treating micturition disorder of the present invention has a concentration of 85% in a dissolution test using water as a test solution and a rotation speed of 50 times / min according to the Japanese Pharmacopoeia dissolution test method 2 (paddle method).
- the elution time (hereinafter, referred to as T85%) may be 60 minutes or less, but the test solution is the first solution of the Japanese Pharmacopoeia Disintegration Test Method (hereinafter, referred to as the first solution) and the number of rotations is 5 It is desirable that the 85% in the dissolution test at 0 times is also 60 minutes or less, and the water or the first solution is used as the test solution and the rotation speed is 50 times / minute. More preferably, 85% is 30 minutes or less, and most preferably, 85% is 15 minutes or less.
- the first solution of the test solution used in the dissolution test of the present invention means the first solution of the Japanese Pharmacopoeia Disintegration Test Method, and 2.0 ml of sodium chloride is added with 7.0 ml of hydrochloric acid and water. This is a test solution made up to 100 ml.
- KMD-3213 contained as an active ingredient in the oral solid medicine for treating dysuria of the present invention has a selective urethral smooth muscle contraction inhibitory action, and induces a strong blood pressure lowering action or orthostatic hypotension. It is known that the compound is a very useful compound as a therapeutic agent for dysuria without the need to perform it.
- Patent Document 1 does not specifically disclose a preparation containing KMD-3 2 13 as an active ingredient. W
- KMD—3 2 13 is relatively unstable to light, and depending on the type of excipient, can easily change its composition to produce degraded products. In addition, it is the most commonly used excipient. It has poor compatibility with lactose, and when lactose is used, it has problems that it is difficult to obtain good dissolution characteristics and the hardness of tablets becomes low. In addition, KMD-3213 has strong adhesion, and a lubricant is indispensable in the production of tablets or capsules. However, there is a problem that the addition of the lubricant tends to delay the dissolution time. ing.
- oral solid pharmaceuticals containing KMD-3213 or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof may not be practically used depending on a usual production method. It is difficult to produce a formulation that can be used.
- Patent Literature 1 and Patent Literature 2 do not report or suggest any of these problems nor a method for solving them. Further, Patent Document 2 describes a method for producing a capsule containing musculin hydrochloride or alfuzosin hydrochloride as an active ingredient, but the composition is completely different from the pharmaceutical composition of the present invention. Therefore, the medicament of the present invention cannot be obtained by the production method, and a person skilled in the art cannot make the present invention based on the invention.
- Patent Document 1 Japanese Patent Application Laid-Open No. 6-220015 (page 12, column 21)
- Patent Document 2 Japanese Patent Application Laid-Open No. 2000-128815 (page 3) , Columns 3-4) [Disclosure of the Invention]
- An object of the present invention is to provide KMD-3213, a prodrug thereof, a pharmacologically acceptable salt thereof, or a pharmacology thereof, which has little effect on blood pressure and is extremely useful as a therapeutic agent for dysuria.
- the Pharmacopoeia stipulates a test method for disintegration and dissolution of solid dosage forms as a standard for managing a certain level of quality and bioequivalence, and pharmaceuticals are set based on those tests. It is required to conform to the standard.
- dissolution tests have become important as a means of predicting efficacy and safety. Particularly for poorly soluble drugs, dissolution is considered to be a more important quality characteristic than disintegration.
- test solution for the dissolution test a pH test solution ( ⁇ ⁇ 1 to 7) or water in a physiological fluctuation range is used, but a test solution having a slow dissolution rate, that is, a test solution with poor dissolution is usually used between the preparations. Difference is easy to detect.
- water has the disadvantage that pH is easily fluctuated, but it is a test solution that is sensitive to differences in formulation and manufacturing method.If water can be tested, use water as much as possible. It is recommended from the viewpoint of economy, environment and so on.
- KMD-3213 is relatively soluble in acidic liquids, but hardly soluble in neutral water. I can say. Therefore, as for an oral solid preparation containing KMD-3213 as an active ingredient, a preparation with good dissolution characteristics in water is required.
- at least T85% is 60 minutes in a dissolution test in which water is used as a test solution and the number of rotations is 50 times according to the Japanese Pharmacopoeia dissolution test method 2 (paddle method).
- T85% is less than or equal to 30 minutes, more preferably T85% is less than or equal to 15 minutes.
- KMD—3 2 13 is stable against acids
- KMD—3 2 13 It is desirable that the oral solid preparation containing the active ingredient be good in the dissolution test in the first liquid corresponding to gastric juice. Specifically, in the dissolution test for the first liquid, as in the dissolution test for water, at least T85% is desirably 60 minutes or less, and T85% is 30 minutes or less. Is more desirable, and most preferably, T85% is 15 minutes or less.
- the active ingredient contained in pharmaceuticals generally exerts a strong effect in a small amount, in order to always exert a certain effect, it is needless to say that the content of the active ingredient is constant. It is important to minimize the decrease in the content of the active ingredient during storage. For this reason, it is required that there is no variation in the content between lots of the preparation and that the storage stability is high.
- KMD-3213 contained as an active ingredient in the oral solid pharmaceutical preparation of the present invention has a strong adhesive property and is easily charged with static electricity. Easily charged by physical stimulus in the operation of granulation, etc., the fluidity of the milled material, mixture or granulated material is reduced, the operability is poor, and the filling amount varies, and the accuracy of the active ingredient content is low. Problems easily occur.
- a lubricant is added in the filling step or the tableting step in view of operability and filling accuracy.
- KMD-3213 which is contained as an active ingredient in the oral solid pharmaceutical preparation of the present invention, has a strong adhesive property, so that the addition of a lubricant is indispensable. Is generated.
- KMD-3213 which is contained as an active ingredient in the oral solid drug of the present invention, is relatively unstable to light, so care must be taken when handling it.
- opaque light-shielding packaging it is difficult to determine the presence of foreign matter, and it is expected that patients who actually take the medicine will be taken out of the light-shielding packaging and stored.
- a highly photostable formulation that does not require light-shielding packaging is desired.
- KMD-321 a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, which is extremely useful as a therapeutic agent for dysuria.
- a drug that contains a substance as an active ingredient has a high accuracy of content, and has excellent elution characteristics in water or water and the first liquid, and is stable Intensive research to develop oral solid medicines with high quality.
- lactose which is commonly used as an excipient, tends to delay the dissolution time and has many problems, such as low tablet hardness, and when lactose is used as an excipient, It has been found that it is difficult to obtain a suitable preparation.
- the present inventors have made intensive studies on excipients, and as a result, have found that the use of D-mannitol as an excipient can ensure extremely good elution characteristics.
- the present inventors further studied the method of manufacturing the preparation, prepared granules by a wet method, and adjusted the amount of the lubricant added and the mixing time to reduce the variation in the filling amount due to electrostatic charging. It is possible to obtain a stable and excellent dissolution property of the preparation without causing any problem.
- a solid hydrophilic or surfactant additive and a lubricant are mixed at a specific ratio. Titanium oxide has a very good inhibitory effect on the photodegradability of KMD-3 2 13 with regard to the photostability of the drug product. Using a capsule containing titanium or a coating agent containing titanium oxide, a formulation having high photostability can be obtained, and the present invention has been accomplished.
- KMD-3 2 13 contained as an active ingredient in the medicament of the present invention was subjected to a confirmation test for the interaction with various pharmaceutical excipients used in the production of solid preparations, and discoloration or decomposition, etc. Pharmaceutical excipients that did not cause harm were selected, and then their combinations and their suitability for production were further investigated.
- lactose which is the most commonly used, does not change the formulation, but tends to lower the dissolution characteristics, and furthermore has a number of problems, such as lower tablet hardness. It was difficult to obtain a suitable formulation.
- starch for example, corn starch, and as partially pregelatinized starch, for example, "Starch 150 (registered trademark)” (manufactured by Nippon Colorcon Co., Ltd.), "PCS (registered trademark)” (manufactured by Asahi Kasei Corporation), etc. Can be mentioned.
- hydroxypropylmethylcellulose and hydroxypropylcellulose both undergo some degree of formulation change and are not preferred.
- magnesium stearate, calcium stearate and talc can be used without any particular change in formulation.
- macrogol polyethylene glycol
- polyoxyethylene [105] polyoxypropylene [5] glycol and triethyl citrate are unsuitable because of their large change in blending.
- a lubricant is used in order to improve operability and filling accuracy in the capsule filling step or tablet tableting step.
- KMD—3 2 13 has inherently strong adhesion, and in the case of the dry method, it is also charged with static electricity as described above, and the fluidity of the mixture or granulated material is further reduced. Although more is required, this lubricant generally causes a delay in dissolution time due to water repellency.
- the delay of the elution time due to the lubricant can be improved to some extent by reducing the amount of the lubricant used and shortening the mixing time.
- the amount of the lubricant used can be reduced to about 1% or less, It has been found that good dissolution characteristics can be maintained by mixing preferably in a short period of time, preferably in a range of about 3 to about 5 minutes, preferably to about 0.6 to about 0.8%. Therefore, granulation is performed by replacing the dry method with the wet method, the amount of lubricant used is reduced to about 1% or less, and the mixing time is reduced to about 3 minutes, so that the fluidity of the mixture is good and the operability is improved. It was possible to manufacture a preparation with good filling accuracy.
- KMD-3213 which is contained as an active ingredient in the drug of the present invention, has a strong adhesive property, and particularly in the case of capsules, when the lubricant is suppressed to about 1% or less, such as stateing, etc.
- the potential for filling problems is high, and keeping lubricants below about 1% can be dangerous.
- further investigation was conducted to find a method that could improve the elution time delay even when about 1% or more of a lubricant was added.As a result, the elution time was increased by adding a solid hydrophilic or surface active additive. It has been found that the delay in the dissolution is remarkably suppressed, and a formulation having good dissolution characteristics can be produced.
- the effect of the additive on improving the elution time delay differs depending on the combination with the lubricant.
- sodium lauryl sulfate is most preferred, sucrose fatty acid esters, light anhydrous
- the effect is weak with keic acid, polyoxyethylene [105] polyoxypropylene [5] glycol, etc.
- Sodium lauryl sulfate can exert a sufficient improvement effect by adding about 2 to about 0.1 part, preferably about 0.5 part with respect to 1 part of magnesium stearate, and maintain good dissolution characteristics. it can.
- KMD-3213 contained as an active ingredient in the oral solid pharmaceutical preparation of the present invention is relatively unstable to light, and the content of the active ingredient decreases over time depending on the storage method. Careful handling is required. Therefore, in the case of ordinary preparations, storage in light-shielding packaging is essential, but in opaque packaging, it is difficult to determine the inclusion of foreign substances, etc., and there is a high risk of impairing the inspection of defective products. However, it is expected that patients who actually take the medicine will be kept in a state where they are removed from light-shielding packaging.
- titanium oxide is most preferred as the light-shielding substance, and a capsule containing titanium oxide or a core containing titanium oxide is preferred. It has been found that the use of a thickening agent makes it possible to produce extremely good capsules or tablets having high light stability.
- the amount (%) of each photodegradation product (related substance, hereinafter referred to as “related substance”) and the total amount (%) of all related substances. Is determined to be less than or equal to the set standard.
- the standard of light for hospital pharmacies is set at 300 to 750 lux / hour in the JIS standard.
- the irradiation time is considered to be about 8 hours per day on average, and the storage period of the drug is considered to be a maximum of 6 months.Therefore, the standard exposure light amount is set to the maximum value of 7500 lux / hour.
- the irradiation time per day is about 8 hours, about 180,000 lux, equivalent to 180 days of light exposure, and about 120,000 lux / hour, taking into account measurement errors, the amount of exposure for Z hours It is said that.
- the guidelines for ethical drugs specify that the total light intensity of 120,000 lux Z hours or more should be used as the light exposure in the photostability test. Therefore, in the case of ethical drugs, it is required to be stable in a stability test at an exposure of about 120,000 lux Z hours.
- KMD-3213 contained as an active ingredient in the oral solid pharmaceutical preparation of the present invention.
- provisional specifications have been tentatively set, and the largest related substance a is 4 1% or less, other related substances b to f are each 1% or less, and the total amount of all related substances including other trace amounts of related substances is 5% or less.
- a study was conducted to produce capsules or coating agents having a light-shielding property that can be adapted to the amount of exposure light over time.
- titanium oxide is most suitable as a light-shielding substance, and that a solid drug having high light stability can be produced by using a capsule or a coating agent containing titanium oxide.
- blending amount of titanium oxide the higher the light-shielding property.
- the greater the blending amount the lower the strength of the capsule.
- a suitable amount is appropriately determined depending on the size of the preparation and the like. For example, in the case of a capsule, about 3% or more, preferably about 3.4
- a suitable light-shielding property can be exhibited by adding up to 3.6%.
- it is determined by the surface area of the tablet, the amount of the coating agent, etc.
- the surface area of the tablet should be at least 0.5 mgZcm2, preferably at least 1.1 mgZcm2. Thereby, more suitable light shielding properties can be exhibited.
- compositions containing KMD-3213, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof as an active ingredient have been disclosed, for example, in Patent Documents.
- Patent Document 1 or Patent Document 2 only a very general description is made, and no specific report is made.
- oral solid pharmaceuticals containing KMD-3213, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof as an active ingredient are generally used.
- Patent Document 1 or Patent Document 2 does not report or suggest any of these problems nor any method for solving them.
- KMD-3213 contained as an active ingredient in the oral solid pharmaceutical preparation of the present invention is a known compound, and can be produced by a method described in a literature, for example, a method described in Patent Document 1.
- the pharmacologically acceptable salts of KMD-3213 contained as an active ingredient in the oral solid pharmaceutical preparation of the present invention include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphorus Acid addition salts with mineral acids such as acids, acetic acid, propionic acid, butyric acid, oxalic acid, citric acid, succinic acid, tartaric acid, fumaric acid, malonic acid, maleic acid, malic acid, lactic acid, adipic acid, benzoic acid, salicylic acid , Methanesulfonic acid, benzenesulfone Acid addition salts with organic acids such as acid, p-toluenesulfonic acid, glutamic acid, and aspartic acid can be mentioned.
- the solvate include a solvate with water or ethyl alcohol.
- the oral solid medicine of the present invention for example, a capsule can be produced as follows. That is, an excipient, preferably D-mannitol, is added to KMD-321, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and If necessary, an appropriate binder and disintegrant are added, an aqueous solution of an appropriate concentration of the binder is added, and the mixture is kneaded, and if necessary, sieved to produce granules.
- an excipient preferably D-mannitol
- magnesium stearate and a solid hydrophilic or surface active additive preferably sodium lauryl sulfate, in a ratio of 10: 1 to 1; L0: 20, more preferably 10: 5 to; L0: 10, still more preferably in a ratio of 10: 5, and mix with appropriate capsules, preferably titanium oxide, at about 3% or more, more preferably about 3. It is manufactured by filling into a force capsule with 4 to 3.6%.
- Tablets can be manufactured as follows. That is, a granule is prepared in the same manner as a capsule, and a lubricant, preferably magnesium stearate, is used in an amount of 1% or less, preferably about 0.6 to about 0.8%, more preferably about 0%. Add 7%, mix and compress by standard methods to produce uncoated tablets. Further, a film-coating agent, a light-shielding agent, preferably titanium oxide, and a plasticizer are added to an appropriate solvent, and if necessary, an appropriate lubricant, an anti-agglomeration agent, and a coloring agent are added, and then dissolved or dissolved. Disperse to produce a coating solution, which is spray-coated on plain tablets to produce. It is sufficient that the amount of titanium oxide is at least 0.5 mgZ square cm, preferably at least 1.1 mgZ square cm, based on the surface area of the tablet.
- a lubricant preferably magnesium stearate
- ⁇ 10-3 2 13 is an extremely effective compound as a therapeutic agent for dysuria due to benign prostatic hyperplasia, which has an effect of blocking AR and has little effect on blood pressure.
- prazosin hydrochloride and muscoscine hydrochloride which have an AAR blocking effect, are effective for urinary disorders such as bladder neck sclerosis, chronic prostatitis, and neurogenic bladder.
- KMD-3 2 1 3 can be used for prostatic hypertrophy, urethral stenosis, urethral stones, tumors, etc.
- urinary disorders due to organic obstruction of the urethra hereinafter referred to as benign prostatic hyperplasia
- urinary disorders due to abnormalities in the urinary nervous system and none of them, bladder neck sclerosis, chronic It can be expected as a therapeutic agent for urinary disorders due to functional obstruction of the urethra such as prostatitis and unstable bladder.
- Urinary disturbances associated with abnormalities of the urinary nerves include nervous system disorders such as cerebrovascular disorders and brain tumors, spinal cord disorders such as spinal cord injury, and peripheral nerve disorders such as diabetes and lumbar spinal canal stenosis. It is urinary dysfunction caused by dysfunction, which occurs in both genders, and is collectively called neuropathic bladder.
- dysuria associated with functional obstruction of the urethra includes the above-mentioned bladder neck sclerosis, chronic prostatitis, unstable bladder, dysuria, Bladder neck obstruction, urethral syndrome, detrusor-sphincter dysfunction, chronic cystitis, prostate pain, Hinman syndrome, Fowler syndrome, psychogenic voiding, drug-induced voiding, aging It is a dysuria and is generally called lower urinary tract disease.
- the medicament of the present invention has a high precision of the content of the active ingredient, and is excellent in dissolution characteristics, and can effectively exert the action of KMD-3213. Therefore, the medicament of the present invention can be used for neuropathic bladder or urinary dysfunction caused by functional obstruction of the urethra due to urinary dysfunction due to abnormal urinary nervous system, such as prostatic hypertrophy due to organic urethral obstruction. It is extremely useful as a therapeutic agent for urinary tract diseases.
- the dose of the active ingredient is appropriately determined according to the sex, age, weight, degree of disease, etc. of the patient. It is administered in a dose of 50 mg, preferably in the range of 4 to 20 mg.
- the medicament of the present invention contains, as an active ingredient, KMD-3213, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof.
- a t other than 3 2 1 3 may contain at least one selected from the group consisting of AR blockers, anticholinergics, anti-inflammatory drugs and antibacterial drugs.
- the medicament of the present invention is further combined with a medicament containing at least one selected from the group consisting of an AR blocker other than KMD-3213, an anticholinergic agent, an anti-inflammatory agent and an antibacterial agent as an active ingredient. May be used.
- FIG. 1 is a diagram showing the mixing time and dissolution time delay effect of magnesium stearate.
- Prescription A is Prescription A
- 110 is Prescription B for 1 minute mixing time (Prescription B ⁇ 1 minute)
- 1 Bit is Prescription B for 3 minutes mixing time (Prescription B ⁇ 3 minutes)
- 101 Indicates formulation B (formulation B ⁇ 7 minutes) with a mixing time of 7 minutes
- the vertical axis indicates dissolution rate (%)
- the horizontal axis indicates time (minutes).
- FIG. 2 is a graph showing the effect of various additives on the elution time delay of magnesium stearate.
- -Hataichi is prescription A
- bite one is prescription B
- - ⁇ one is prescription (
- one ⁇ one is prescription D
- - ⁇ one is prescription E
- one ten is prescription F
- one is prescription G.
- the vertical axis shows the dissolution rate (%)
- the horizontal axis shows time (minutes).
- FIG. 3 shows the relationship between the mixing ratio of magnesium stearate and sodium lauryl sulfate and the dissolution characteristics.
- prescription H is prescription H
- bite one is prescription I
- one is prescription J
- one is prescription K:
- one is prescription L
- the vertical axis is the dissolution rate (%).
- the horizontal axis indicates time (minutes).
- FIG. 4 is a diagram showing dissolution characteristics of each preparation of Examples 1 to 3.
- 1-1 is the preparation of Example 1
- 1 is the preparation of Example 2
- 1-1 is the preparation of Example 3
- the vertical axis shows the dissolution rate ()
- the horizontal axis shows time. (Minutes).
- FIG. 5 is a graph showing the relationship between the amount of titanium oxide and the photostability in the titanium oxide compounding force cell.
- ⁇ refers to the control (preserved in a light-shielded container)
- ⁇ refers to capsule A (containing 1.2% titanium oxide)
- ⁇ refers to capsule B (containing 2.4% titanium oxide)
- ⁇ refers to Capsule C (containing 3.6% of titanium oxide)
- the vertical axis shows all related substances i (%)
- the horizontal axis shows exposure light (1,000 lux Z hours).
- the most used excipients, disintegrants and binders are 1: 1 and the other less used excipients are 10: After mixing at a ratio of 1 and storing under the following storage conditions (1) and (2), a change in the composition was confirmed.
- the decomposition products were quantified by the following HP LC analysis method, and the discoloration was performed by visual observation.
- a mixed powder equivalent to 5 mg of KMD-3213 was taken, dissolved in 10 mL of methanol, and shaken for 10 minutes using a shaker. 4 mL of this solution was taken, and methanol was added to make 5 mL. The solution was filtered through a membrane filter having a pore size of 0.45 m, and the filtrate was used as a sample solution.
- HPLC measurement was carried out under the following conditions with a sample solution of 5 zL, and the percentage of each related substance peak area to the total peak area excluding the solvent peak was determined.
- Mobile phase 6.8 g of potassium dihydrogen phosphate and disodium hydrogen phosphate monobasic ⁇ 12 hydrates A mixture of 17.9 g of water to make a total volume of 100 OmL, and a 7: 3 mixed solution with acetonitrile .
- D-mannitol was the most preferred excipient, and crystalline cellulose was unsuitable due to a change in formulation.
- starch corn starch
- calcium carboxymethylcellulose and carboxymethylcellulose were unsuitable because of a large change in the composition.
- the binders hydroxypropylmethylcellulose and hydroxypropylcellulose both changed the formulation to some extent and were not very good.
- Surfactant macrogol, polyoxyethylene [105] polyoxypropylene [5] glycol, triethyl citrate, and the like were largely unsuitable for compounding.
- Temperature 40 ° (:, relative humidity 75%, change in formulation after storage for 4 months
- D-mannitol was selected as an excipient, and partially pregelatinized starch “Starch 1500 (registered trademark)” (manufactured by Nippon Colorcon Co., Ltd.) was selected as a disintegrating agent. Magnesium stearate as a lubricant was added at about 1%. The correlation between the mixing time and the elution time delay upon addition was confirmed.
- Capsules were manufactured according to the formulation shown in Table 3, and the dissolution time was measured by the following dissolution test method.
- test preparation was placed in a sinker and submerged in the center of the container. Using 50 OmL of purified water as the test solution, the number of rotations was 50 times by the Japanese Pharmacopoeia dissolution test method 2 (paddle method). 5 minutes, 10 minutes, 15 minutes, 20 minutes, and 30 minutes after the start of the test 5 mL of the eluate was collected, and immediately supplemented with the same volume of the test solution. The collected eluate was filtered with a 0.45 / zm membrane filter, and the remaining 1 mL of filtrate except 4 mL of the first filtrate was used as a sample solution.
- KMD-3213 standard was precisely weighed and dissolved in purified water to make exactly lOOmL. 8 mL of this solution was accurately measured, and purified water was added to make exactly 10 OmL, which was used as a standard solution.
- Liquid chromatography was performed under the following conditions at 10 O L of the sample solution and the standard solution, and the elution rate was calculated from the KMD-3213 peak areas of the sample solution and the standard solution.
- the dissolution rate was determined by randomly extracting 6 samples from each formulation, conducting tests, and taking the average.
- Mobile phase Sodium dihydrogen phosphate dihydrate 3.9 g and dilute phosphoric acid aqueous solution (1 ⁇ 20) 2.
- a 5 2 mixed solution of a solution obtained by adding water to 5 mL to make a total volume of 100 OmL, and acetonitrile
- the mixing time was 1 minute (Formulation B ⁇ 1 minute), 3 minutes (Formulation B ⁇ 3 minutes) and 7 minutes (Formulation B ⁇ 7 minutes). Each mixture was removed and filled into capsules. The capsule was filled by hand.
- Capsules were prepared by adding (Table 4) the same amounts of various additives as magnesium stearate to Formulation B in 2, and the dissolution time was measured by the same dissolution test method as in Test Example 2.
- Each additive was prepared by a late addition method in which the granules were added together with magnesium stearate after production.
- the mixing time was 5 minutes.
- test preparation was placed in a sinker and submerged in the center of the container. Using 90 O mL of purified water as the test solution, the number of revolutions was 50 min.
- Japanese Pharmacopoeia dissolution test method 2 (paddle method). After 5 minutes, 10 minutes, 15 minutes, 20 minutes and 30 minutes after the start of the test, 5 mL of the eluate was collected, and the same volume of the test solution was immediately supplemented. The collected eluate was subjected to centrifugal separation (30000 times, Z minutes, 5 minutes or more), and 10 L of concentrated hydrochloric acid was added to the supernatant to obtain a sample solution.
- about 0. Olg of KMD-3213 standard was precisely dissolved in 0. IN hydrochloric acid to make exactly lOOmL. 2 mL of this solution was accurately adjusted to exactly 10 OmL by adding 0.1 IN hydrochloric acid, and used as a standard solution.
- each additive was a late addition method in which the granules were added together with magnesium stearate after the production of the granules, and the mixing time was 5 minutes.
- the dissolution rate was determined by randomly extracting six samples from each formulation and conducting a test, and taking the average. '
- the granulated product was dried with a fluidized bed granulating dryer at an air supply of 60 ° C and an exhaust of 40 ° C, dried, ground, sized, and sieved to produce granules. To this is added 1.0 part of magnesium stearate, mixed for 3 minutes, compressed into tablets, coated with a coating agent, and coated with a coating agent. 4. Tablets containing Omg KMD-3213 in 1 tablet Made. Test example 5
- the dissolution time of the preparations of Examples 1 to 3 was measured by the following dissolution test method. W
- test preparation Place one test preparation as it is for tablets, put it in a sinker for capsules, sink it in the center of the container, and use 90 OmL of purified water as the test solution.
- the test was carried out at 50 revolutions / minute according to the method described above, and 5 mL, 10 minutes, 15 minutes, 20 minutes, and 30 minutes after the start of the test, 5 mL of the eluate was collected, and the same volume of the test solution was immediately supplemented.
- the collected eluate was centrifuged (3000 times / min, 5 minutes or more), and 1 OL of concentrated hydrochloric acid was added to the supernatant to prepare a sample solution.
- KMD-3213 standard was precisely weighed and dissolved in 0.1 N hydrochloric acid to make exactly 10 mL.
- Example 1 (2 mg formulation), accurately weigh 2 mL of this solution, and for the formulations of Examples 2 and 3 (4 mg formulation), accurately weigh 4 mL of this solution, and add 0.1 N hydrochloric acid each. In addition, it was adjusted to exactly 10 OmL, and used as a standard solution.
- HPLC HPLC was measured under the following conditions for 100 ⁇ L of the sample solution and standard solution, and the elution rate was calculated from the peak area of KMD-3213 of the sample solution and standard solution.
- the dissolution rate was determined by randomly extracting 6 samples from each formulation and conducting the test, and taking the average. HP LC measurement conditions
- Liquid volume 1. OmL / min
- Flow rate Adjust the retention time of KMD-3213 to about 7 minutes.
- capsule A containing 1.2% titanium oxide
- the capsule B containing 2.4% titanium oxide
- the exposure limit is incompatible with the specified limit or non-conformity.
- Capsule C containing 3.6% titanium oxide
- the oral solid pharmaceutical preparation of the present invention is a practical solid oral treatment preparation for treating urinary disorders, which has no manufacturing problems such as operability and content variation in the production process, and has excellent dissolution characteristics.
- the oral solid medicine of the present invention has good operability in a capsule or tablet filling step or tableting step, high filling accuracy, a constant active ingredient content, and good stability. Extremely good dysuria treatment with constant and good dissolution characteristics in dissolution tests in water with little change in the active ingredient content and in water that is the least soluble and most easily biologically non-equivalent It is an oral solid preparation for use.
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Priority Applications (19)
Application Number | Priority Date | Filing Date | Title |
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YU20050470A RS58025B1 (sr) | 2002-12-16 | 2003-12-11 | Lekovi u čvrstom stanju za oralnu upotrebu |
MEP-108/08A MEP10808A (en) | 2002-12-16 | 2003-12-11 | Solid drug for oral use |
ES03780719.5T ES2544560T3 (es) | 2002-12-16 | 2003-12-11 | Fármaco sólido para uso oral |
MEP-2008-108A ME00076B (me) | 2002-12-16 | 2003-12-11 | Lijek u čvrstom obliku za oralnu primjenu |
CA2507002A CA2507002C (en) | 2002-12-16 | 2003-12-11 | Solid drug for oral use |
MXPA05006513A MXPA05006513A (es) | 2002-12-16 | 2003-12-11 | Farmaco solido para uso oral. |
US10/538,514 US20060018959A1 (en) | 2002-12-16 | 2003-12-11 | Solid drug for oral use |
NZ540664A NZ540664A (en) | 2002-12-16 | 2003-12-11 | Solid drug for oral use |
BR0317349-6A BR0317349A (pt) | 2002-12-16 | 2003-12-11 | Droga sólida para uso oral |
EA200500985A EA008196B1 (ru) | 2002-12-16 | 2003-12-11 | Твердая лекарственная форма для перорального применения |
EP03780719.5A EP1574215B1 (en) | 2002-12-16 | 2003-12-11 | Solid drug for oral use |
JP2004560618A JP4633469B2 (ja) | 2002-12-16 | 2003-12-11 | 経口固形医薬 |
AU2003289320A AU2003289320C1 (en) | 2002-12-16 | 2003-12-11 | Solid drug for oral use |
IL169040A IL169040A (en) | 2002-12-16 | 2005-06-07 | A capsule containing granules obtained with wet granulation and a lubricant and method of obtaining it |
HRP20050544AA HRP20050544B1 (hr) | 2002-12-16 | 2005-06-14 | Čvrsti oblik za oralnu upotrebu |
IS7929A IS7929A (is) | 2002-12-16 | 2005-07-01 | Lyf á föstu formi til inntöku um munn |
NO20053467A NO20053467L (no) | 2002-12-16 | 2005-07-15 | Fremgangsmate ved biotransformasjon av kolkionforbindelser til de tilsvarende 3-glykosyl-derivater |
HK06105339A HK1085131A1 (en) | 2002-12-16 | 2006-05-08 | Solid drug for oral use |
US13/288,348 US20120064154A1 (en) | 2002-12-16 | 2011-11-03 | Solid drug for oral use |
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JP2002364238 | 2002-12-16 | ||
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EP (2) | EP2402010A1 (ja) |
JP (1) | JP4633469B2 (ja) |
KR (2) | KR101072909B1 (ja) |
CN (2) | CN100339078C (ja) |
AU (1) | AU2003289320C1 (ja) |
BR (1) | BR0317349A (ja) |
CA (1) | CA2507002C (ja) |
EA (1) | EA008196B1 (ja) |
ES (1) | ES2544560T3 (ja) |
HK (2) | HK1085131A1 (ja) |
HR (1) | HRP20050544B1 (ja) |
IL (1) | IL169040A (ja) |
IS (1) | IS7929A (ja) |
ME (2) | ME00076B (ja) |
MX (1) | MXPA05006513A (ja) |
NO (1) | NO20053467L (ja) |
NZ (1) | NZ540664A (ja) |
PL (1) | PL220457B1 (ja) |
RS (1) | RS58025B1 (ja) |
TW (2) | TWI382838B (ja) |
UA (2) | UA85359C2 (ja) |
WO (1) | WO2004054574A1 (ja) |
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- 2003-12-11 AU AU2003289320A patent/AU2003289320C1/en active Active
- 2003-12-11 CN CNB2003801062486A patent/CN100339078C/zh not_active Ceased
- 2003-12-11 JP JP2004560618A patent/JP4633469B2/ja not_active Expired - Lifetime
- 2003-12-11 RS YU20050470A patent/RS58025B1/sr unknown
- 2003-12-11 NZ NZ540664A patent/NZ540664A/en not_active IP Right Cessation
- 2003-12-11 BR BR0317349-6A patent/BR0317349A/pt not_active Application Discontinuation
- 2003-12-11 KR KR1020057010977A patent/KR101072909B1/ko active IP Right Grant
- 2003-12-11 UA UAA200809667A patent/UA85359C2/ru unknown
- 2003-12-11 EA EA200500985A patent/EA008196B1/ru unknown
- 2003-12-11 ME MEP-2008-108A patent/ME00076B/me unknown
- 2003-12-11 WO PCT/JP2003/015837 patent/WO2004054574A1/ja active Application Filing
- 2003-12-11 CA CA2507002A patent/CA2507002C/en not_active Expired - Lifetime
- 2003-12-11 CN CN2007100840362A patent/CN101069685B/zh not_active Expired - Lifetime
- 2003-12-11 ME MEP-108/08A patent/MEP10808A/xx unknown
- 2003-12-11 EP EP03780719.5A patent/EP1574215B1/en not_active Revoked
- 2003-12-11 UA UAA200507046A patent/UA84694C2/ru unknown
- 2003-12-11 MX MXPA05006513A patent/MXPA05006513A/es active IP Right Grant
- 2003-12-11 US US10/538,514 patent/US20060018959A1/en not_active Abandoned
- 2003-12-11 PL PL377495A patent/PL220457B1/pl unknown
- 2003-12-11 KR KR1020107026925A patent/KR101077061B1/ko active IP Right Grant
- 2003-12-11 ES ES03780719.5T patent/ES2544560T3/es not_active Expired - Lifetime
- 2003-12-15 TW TW098121810A patent/TWI382838B/zh not_active IP Right Cessation
- 2003-12-15 TW TW092135358A patent/TWI325318B/zh not_active IP Right Cessation
-
2005
- 2005-06-06 ZA ZA200504613A patent/ZA200504613B/en unknown
- 2005-06-07 IL IL169040A patent/IL169040A/en active IP Right Grant
- 2005-06-14 HR HRP20050544AA patent/HRP20050544B1/hr not_active IP Right Cessation
- 2005-07-01 IS IS7929A patent/IS7929A/is unknown
- 2005-07-15 NO NO20053467A patent/NO20053467L/no not_active Application Discontinuation
-
2006
- 2006-05-08 HK HK06105339A patent/HK1085131A1/xx not_active IP Right Cessation
- 2006-05-08 HK HK08101016.0A patent/HK1107768A1/xx not_active IP Right Cessation
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2011
- 2011-11-03 US US13/288,348 patent/US20120064154A1/en not_active Abandoned
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2005085195A1 (ja) | 2004-03-05 | 2005-09-15 | Kissei Pharmaceutical Co., Ltd. | 神経障害に伴う過活動膀胱の予防または治療用医薬組成物 |
JPWO2006038611A1 (ja) * | 2004-10-05 | 2008-05-15 | キッセイ薬品工業株式会社 | 下部尿路閉塞疾患に伴う蓄尿障害の予防及び/又は治療剤 |
JP2010521416A (ja) * | 2007-03-13 | 2010-06-24 | 武田薬品工業株式会社 | 2−[[6−[(3r)−3−アミノ−1−ピペリジニル]−3,4−ジヒドロ−3−メチル−2,4−ジオキソ−1(2h)−ピリミジニル]メチル]−4−フルオロベンゾニトリルを含む固形製剤 |
JP2013049653A (ja) * | 2011-08-31 | 2013-03-14 | Chiba Univ | 女性の排尿障害の治療剤 |
WO2014157137A1 (ja) | 2013-03-26 | 2014-10-02 | キッセイ薬品工業株式会社 | シロドシンの苦味をマスキングした経口投与製剤 |
JP2017031103A (ja) * | 2015-08-03 | 2017-02-09 | 大原薬品工業株式会社 | 光安定性が向上した、プラミペキソール製剤包装体 |
JP2020117476A (ja) * | 2019-01-25 | 2020-08-06 | 日本ジェネリック株式会社 | シロドシン含有固形組成物及びその製造法 |
JP7262005B2 (ja) | 2019-01-25 | 2023-04-21 | 日本ジェネリック株式会社 | シロドシン含有固形組成物及びその製造法 |
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