Bioactive peptide-containing preparations

Abstract

The present invention provides a pharmaceutical composition containing a compound represented by formula (I), a salt thereof, or a solvate thereof. The present invention uses, as a disintegrant, a partially pregelatinized starch, carmellose calcium, a low-substituted hydroxypropyl cellulose, carmellose, and / or crospovidone, and uses D-mannitol as an excipient. As a result, it is possible to produce a pharmaceutical composition in which a change in contents, an increase in analogs, and a change in color tone occur less.

Description

[Technical field]

[0001] The present invention relates to a compound of formula (I): [ka] The present invention relates to a pharmaceutical composition comprising a compound represented by formula (I), a salt thereof, or a solvate thereof (hereinafter referred to as a compound represented by formula (I), etc.). More specifically, the present invention relates to a pharmaceutical composition comprising a compound represented by formula (I), etc., a disintegrant, and an excipient. [Background technology]

[0002] The compound represented by formula (I) and the like are described in Reference 1 as thyrotropin-releasing hormone (TRH) derivatives, and are described as exhibiting central nervous activation effects (acetylcholine-releasing effect, antireserpine effect, and spontaneous movement-increasing effect). The reference states that the compound represented by formula (I) and the like has excellent thermogenic and spontaneous movement-promoting effects due to activation of dopamine, norepinephrine, and acetylcholine neurons in the brain, and therefore can be used to treat various symptoms associated with the decline in function of these nervous systems. The reference also states that the compound represented by formula (I) and the like significantly activates cerebral cortical acetylcholine neurons, and therefore can also be used as a therapeutic agent for various symptoms associated with the decline in function of these systems (e.g., movement disorder, consciousness disorder, senile dementia, coma, attention deficit, speech disorder, etc.).

[0003] In addition, cited document 2 describes that the compound represented by formula (I) and the like are useful for treating spinocerebellar degeneration, and cited document 3 describes that the compound represented by formula (I) and the like are useful for treating Parkinson's disease. In addition, cited document 4 describes a dosing regimen for a therapeutic agent for ataxia in spinocerebellar degeneration. In addition, methods for producing the compound represented by formula (I) and the like are described in References 5 and 6. An enteric preparation containing the compound represented by formula (I) and the like is described in Reference 7, and is characterized by being coated with an enteric base. An oral preparation containing the compound represented by formula (I) and the like is described in Reference 8, and is characterized by containing a medium-chain fatty acid triglyceride. However, none of the cited documents discloses the formulation of the present invention. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO1998 / 008867 [Patent Document 2] WO2006 / 028277 [Patent Document 3] WO2002 / 017954 [Patent Document 4] WO2016 / 208045 [Patent Document 5] WO1999 / 045000 [Patent Document 6] WO2001 / 016117 [Patent Document 7] WO2002 / 004016 [Patent Document 8] WO1999 / 053941 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a pharmaceutical composition containing a compound represented by formula (I) and the like. [Means for solving the problem]

[0006] The present inventors conducted compatibility tests on various additives, checking the content, related substances, and changes in appearance, and found that clear color changes were observed in croscarmellose sodium, sodium carboxymethyl starch, and powdered sugar, and that particularly partially pregelatinized starch and D-mannitol showed little color change, and thus completed the pharmaceutical composition of the present invention containing the compound represented by formula (I), etc.

[0007] The present inventors have discovered a pharmaceutical composition comprising a compound represented by formula (I) and the like, as shown below. (1) Formula (I): [ka] A compound represented by the formula: Contains one or more disintegrants selected from the group consisting of partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropyl cellulose, carmellose and crospovidone; A pharmaceutical composition comprising D-mannitol as an excipient. (2) The pharmaceutical composition according to (1) above, wherein the disintegrant is partially pregelatinized starch. (3) The pharmaceutical composition according to (1) or (2) above, which contains a binder and / or a lubricant. (4) The pharmaceutical composition according to (3) above, which contains a binder, and the binder is povidone and / or hypromellose. (5) The pharmaceutical composition according to (4) above, wherein the binder is povidone. (6) The pharmaceutical composition according to any one of the above (3) to (5), which contains a lubricant, and the lubricant is magnesium stearate. (7) Formula (II): [ka] The pharmaceutical composition according to any one of (1) to (6) above, comprising a compound represented by the formula (II), a salt thereof, or a solvate thereof (hereinafter referred to as a compound represented by the formula (II), etc.). (8) The pharmaceutical composition according to (7) above, which contains a hydrate of the compound represented by formula (II). (9) Formula (I): [ka] a compound represented by the formula: Partially pregelatinized starch as a disintegrant, D-mannitol as an excipient Povidone as a binder, and A pharmaceutical composition comprising magnesium stearate as a lubricant. (10) Formula (II): [ka] The pharmaceutical composition according to the above (9), which contains a hydrate of the compound represented by the following formula: Effect of the Invention

[0008] The present invention provides a pharmaceutical composition containing a compound represented by formula (I) etc., which exhibits no change in content, a small amount of related substances and little change in appearance when stored over time. [Brief description of the drawings]

[0009] [Figure 1] 1 shows the results of a dissolution test of the pharmaceutical composition of the present invention. The vertical axis indicates the dissolution rate (unit: %), and the horizontal axis indicates time (unit: min). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The present invention will be described in detail below.

[0011] The present invention relates to a pharmaceutical composition containing a compound represented by formula (I) and the like. One embodiment of the present invention is a pharmaceutical composition comprising a compound of formula (I), a disintegrant and an excipient. Another embodiment of the present invention is a pharmaceutical composition comprising the compound represented by formula (II), a disintegrant and an excipient. Another embodiment of the present invention is a pharmaceutical composition comprising a hydrate of the compound represented by formula (II), a disintegrant and an excipient.

[0012] As the disintegrant, partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropyl cellulose, carmellose, crospovidone, croscarmellose sodium, carboxymethyl starch sodium, etc. can be used. Among these disintegrants, partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropyl cellulose, carmellose, crospovidone, croscarmellose sodium, carboxymethyl starch sodium are preferred. Partially pregelatinized starch is particularly preferred. The disintegrant can be used in an amount of 5 to 75% by weight, preferably 20 to 50% by weight, and particularly preferably 27 to 33% by weight, based on the total weight of the tablet.

[0013] Examples of excipients that can be used include lactose, refined white sugar, D-mannitol, xylitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, cornstarch, and powdered sugar. Among these excipients, lactose, refined white sugar, D-mannitol, xylitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, and cornstarch are preferred. D-mannitol is particularly preferred. The excipient can be used in an amount of 10 to 90% by weight, preferably 50 to 80% by weight, and particularly preferably 60 to 73% by weight, based on the total weight of the tablet.

[0014] One embodiment of the present invention is a pharmaceutical composition comprising a disintegrant and an excipient, such as a compound of formula (I), containing a binder and / or a lubricant.

[0015] Povidone, hypromellose, etc. can be used as the binder. Among these binders, povidone and hypromellose are preferred. Povidone is particularly preferred. The binder can be used in an amount of 0.1 to 5.0% by weight, preferably 0.5 to 2.0% by weight, and particularly preferably 0.8 to 1.0% by weight, based on the total weight of the tablet. As the lubricant, magnesium stearate and the like can be used. Among these lubricants, magnesium stearate is preferred. In particular, magnesium stearate is preferred. The lubricant can be used in an amount of 0.1 to 5.0% by weight, preferably 0.5 to 2.0% by weight, and particularly preferably 0.9 to 1.1% by weight, based on the total weight of the tablet.

[0016] The pharmaceutical composition of the present invention may contain additives used in the pharmaceutical field in addition to the above-mentioned disintegrants, excipients, binders, and lubricants, such as diluents, buffers, isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizers.

[0017] Examples of the salt of the compound represented by formula (I) or the compound represented by formula (II) include hydrochloride, sulfate, nitrate, acetate and the like. The solvates of the compound represented by formula (I) or its salt, or the compound represented by formula (II) or its salt include hydrates, ethanolates, etc. Preferred are hydrates, particularly preferred are monohydrates, trihydrates, and further trihydrates. In particular, the trihydrate of the compound represented by formula (II) is preferred. The method for producing the monohydrate is described in Reference 1, and the method for producing the trihydrate is described in Reference 2. The compound represented by formula (I) can be used in an amount of 0.5 to 10% by weight, preferably 1 to 5% by weight, and particularly preferably 1.7 to 2.0% by weight, based on the total weight of the tablet.

[0018] The method for producing the pharmaceutical composition of the present invention is a method of mixing the compound represented by formula (I) and additives such as a disintegrant and excipient to produce a mixed powder, and then granulating the mixed powder, preferably a wet granulation method in which water or water containing a binder or a solvent is added to granulate. The compound represented by formula (I) can be added to water or water containing a binder or a solvent. As a machine for mixing the compound represented by formula (I) and additives, a V-type mixer, a container blender, or an agitation granulator can be used. In addition, as a machine for granulation, a fluidized bed granulator or an agitation granulator can be used. The moisture content of the mixed powder during granulation is 10 to 70%, preferably 30 to 50%. Furthermore, this granule is mixed with a disintegrant and a lubricant, and the mixed granule is tableted with a tablet press. As a machine for mixing the granule with a disintegrant and a lubricant, a V-type mixer or a container blender can be used. As the tablet press, a single punch tablet press, a rotary tablet press, etc. can be used. The pharmaceutical composition of the present invention is preferably in the form of a tablet. The pharmaceutical composition of the present invention may contain, but is not limited to, 0.75 to 15 mg of the compound represented by formula (I). The amount is preferably 1.5 to 7.5 mg, and more preferably 2.25 to 3.0 mg. Particularly preferred is a pharmaceutical composition containing 2.4 mg of the compound represented by formula (I). In this case, the pharmaceutical composition contains 2.745 mg of the trihydrate of the compound represented by formula (II). The pharmaceutical composition of the present invention can be administered orally. Although not particularly limited, the compound represented by formula (I) can be administered at 0.1 to 10 mg / day. Preferably, it is 1 to 5 mg / day. Particularly preferably, it can be administered at 1.6 to 3.2 mg / day. The total weight of the pharmaceutical composition of the present invention is not particularly limited, but is 50 to 250 mg, more preferably 100 to 200 mg, and particularly preferably 150 mg. The pharmaceutical composition of the present invention can be used for the purposes described in any one of the cited documents 1 to 3. For example, it can be used for the prevention and / or treatment of central nervous system diseases such as spinocerebellar degeneration and Parkinson's disease. Another embodiment of the present invention is a pharmaceutical composition that does not have a coating layer. Another aspect of the present invention is a pharmaceutical composition with reduced color change. Reduction in color change can be confirmed under the storage conditions described in this specification. Another aspect of the present invention is a pharmaceutical composition in which an increase in related substances is reduced. The reduction in the increase in related substances can be confirmed under the storage conditions described in this specification. EXAMPLES

[0019] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to these examples.

[0020] Example 1 A compatibility test was carried out between the hydrate of the compound represented by formula (II) and each additive.

[0021] (A) Experimental materials The following reagents and additives were used in the experiment. (Disintegrant) Partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropyl cellulose, carmellose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch (Excipients) Lactose, refined white sugar, D-mannitol, xylitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, cornstarch, powdered sugar (Binding Agent) Povidone, Hypromellose (lubricant) Magnesium stearate

[0022] (B) Manufacturing equipment Ventilated dryer PMNo.TRV141

[0023] (C) Test method Loss on drying: Electronic moisture meter PMNo.AEH1122 (heating temperature 105℃) Content: HPLC method Column: Mightysil RP-18GP (150 mm x 4.6 mm) S-3 μm (Kanto Chemical) Column temperature: 40℃ Mobile phase: PIC B-5 (Low UV) / acetonitrile = 8 / 2 mixture Detection wavelength: 220nm Flow rate: approx. 1.0mL / min Injection volume: 100μL Pump: Waters 600 Injection device:Waters 717plus Detector: Waters 2487 Color difference: Spectroscopic altimeter SE-2000 (Nippon Denshoku) Field of view selection: Reflectance measurement Measurement conditions: 2 degree field of view, standard light Related substances: HPLC method

[0024] (D) Compatibility test specimens (D-1) Mixing ratio The compounding ratio of the additives was as follows: In order to obtain a compound represented by formula (II) of 1, a moisture correction was performed, and 1.15 of the hydrate of the compound represented by formula (II) was added. (Disintegrant) Compound represented by formula (II):additive=1:10 (Excipients) Compound represented by formula (II):additive=1:10 (Binding Agent) Compound represented by formula (II):additive=1:1 (lubricant) Compound represented by formula (II):additive=1:1

[0025] (D-2) Wet processing products All additives, except for the lubricant magnesium stearate, were wet processed and subjected to aging tests. (1) The compound represented by formula (II) : additive 10 or the compound represented by formula (II) : additive 1 were weighed out and mixed in an agate mortar, and purified water was gradually added and mixed. (2) Furthermore, the wet mixture was spread on a tray and dried through ventilation at 45° C. for 120 minutes.

[0026] (D-3) Physical mixture product Magnesium stearate was weighed out in a ratio of 1 part of the compound represented by the formula (II) to 1 part of the additive, and dry-mixed in an agate mortar.

[0027] (D-4) Time-lapse test The samples prepared for the compatibility test were weighed out and subjected to a time-course test under the conditions shown in Table 1.

[0028] [Table 1]

[0029] Preparation of compatibility samples The loss on drying of the wet-prepared compatibility test specimens is shown in Table 2.

[0030] [Table 2]

[0031] (result) A time-course test was carried out under the accelerated conditions shown in (D-4), and the content, related substances, and changes in appearance were confirmed. (Content) The change in content at the start and end of each test was confirmed. No significant decrease in content was observed for any of the additives. (Related substances) Changes in the amount of related substances at the start and end of each time-course test were confirmed. The amount of related substances at the start was about 0.02%, and at the end it was about 0.02-0.03%. There was a slight tendency for related substances to increase in carmellose, croscarmellose sodium, lactose, xylitol, anhydrous calcium hydrogen phosphate, powdered sugar, and hypromellose. (Appearance change) The color difference at the start and end of each aging test was confirmed. The color difference was expressed as ΔE. ΔE was calculated using the following formula, where L is lightness, a is chromaticity (+: redness, -: greenness), and b is chromaticity (+: yellowness, -: blueness). Table 3 shows the appearance evaluation criteria using a color difference meter. ΔE={(ΔL) 2 +(Δa) 2 +(Δb) 2} 1 / 2

[0032] [Table 3]

[0033] As a result of the test, clear color changes were observed in croscarmellose sodium, sodium carboxymethyl starch, and powdered sugar. In addition, in excipients with a high content in the formulation, color changes were observed in all excipients other than D-mannitol, although not as much as in powdered sugar. Among the excipients, D-mannitol showed the least color change. The results are shown in Table 4.

[0034] [Table 4]

[0035] Example 2 Based on the results of Example 1 above, a pharmaceutical composition containing a hydrate of the compound represented by formula (II) was prepared using partially pregelatinized starch as a disintegrant, D-mannitol as an excipient, povidone as a binder, and magnesium stearate as a lubricant. Partially pregelatinized starch and D-mannitol were mixed in an agitation granulator to produce a mixed powder. Then, in the agitation granulator, water containing the hydrate of the compound represented by formula (II) and povidone was added to the mixed powder, and wet granulation was performed to produce granules. Furthermore, the granules were mixed with partially pregelatinized starch and magnesium stearate in a container blender to produce mixed granules. The mixed granules were compressed in a rotary tablet press to produce tablets.

[0036] The contents of each ingredient in the pharmaceutical composition are shown in Table 5.

[0037] [Table 5]

[0038] Example 3 A stability test over time was carried out on the pharmaceutical composition of Example 2. As a result, no problems were found with respect to content, related substances, or changes in appearance.

[0039] Example 4 The disintegration time of the pharmaceutical composition of Example 2 was measured using a disintegration tester in accordance with the "Disintegration Test" of the Japanese Pharmacopoeia General Test Method. No auxiliary disk was used, and purified water was used as the test liquid. As a result of measuring six pharmaceutical compositions of Example 2, the disintegration time was 3 minutes 23 seconds to 4 minutes 5 seconds, indicating good disintegrability.

[0040] Example 5 A dissolution test was carried out on the pharmaceutical composition of Example 2. 900 mL of water was used as the test solution, and the test was carried out at 50 revolutions per minute by the paddle method. One pharmaceutical composition of Example 2 was taken, and the test was started. 4 mL of the dissolution solution was accurately taken 5, 10, 15, and 30 minutes later, and filtered through a membrane filter with a pore size of 0.45 μm. The first 2 mL of the filtrate was removed, and the next filtrate was used as the test solution. Separately, about 25 mg of the hydrate standard substance of the compound represented by formula (II) was precisely weighed, dissolved in water, and made exactly 50 mL. 5 mL of this solution was precisely weighed, and water was added to make 50 mL. 3 mL of this solution was precisely weighed, and water was added to make exactly 50 mL, making it the standard solution. 50 μL of each of the test solution and the standard solution was precisely taken, and the test was carried out by liquid chromatography under the following conditions, and the peak area of ​​each compound represented by formula (II) was measured. Test conditions Detector: Ultraviolet absorption photometer (measurement wavelength: 210 mm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 5 cm was packed with 3 μm octadecylsilylated silica gel for liquid chromatography (Develosil ODS-HG (Nomura Chemical) or equivalent). Column temperature: constant temperature around 45℃ Mobile phase: Water / acetonitrile for liquid chromatography (83:17) Liquid volume: adjusted so that the retention time of the compound represented by formula (II) was about 4 minutes. As a result of the above test, the pharmaceutical composition of the present invention exhibited a rapid dissolution behavior. The results are shown in Figure 1. [Industrial Applicability]

[0041] The pharmaceutical composition of the present invention is useful for the prevention and / or treatment of central nervous system diseases such as spinocerebellar degeneration and Parkinson's disease.

Claims

1. Formula (I): 【Chemistry 1】 A compound represented by the formula: Contains one or more disintegrants selected from the group consisting of partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropyl cellulose, carmellose and crospovidone; A pharmaceutical composition comprising D-mannitol as an excipient.

2. 2. The pharmaceutical composition according to claim 1, wherein the disintegrant is partially pregelatinized starch.

3. 10. The pharmaceutical composition of claim 1, further comprising a binder and / or a lubricant.

4. 4. The pharmaceutical composition according to claim 3, which contains a binder, the binder being povidone and / or hypromellose.

5. 5. The pharmaceutical composition of claim 4, wherein the binder is povidone.

6. 4. The pharmaceutical composition of claim 3, further comprising a lubricant, said lubricant being magnesium stearate.

7. Formula (II): 【Chemistry 2】 The pharmaceutical composition according to any one of claims 1 to 6, comprising a compound represented by the following formula (I):

8. 8. The pharmaceutical composition according to claim 7, comprising a hydrate of the compound of formula (II).

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