Bioactive peptide-containing formulation

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

Bioactive peptide-containing preparations

[0001] The present invention relates to a compound of formula (I): The present invention relates to a pharmaceutical composition containing 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 containing a compound represented by formula (I), etc., a disintegrant, and an excipient.

[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 system activating effects (acetylcholine-releasing effect, antireserpine effect, and locomotor activity-increasing effect). The reference also describes that the compound represented by formula (I) and the like have excellent thermogenic and locomotor activity-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 decreased function of these nervous systems. The reference also describes 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 decreased function of these systems (e.g., movement disorders, consciousness disorders, senile dementia, coma, attention deficit, speech disorders, etc.).

[0003] Furthermore, Patent Document 2 describes that the compound represented by formula (I) and the like are useful for treating spinocerebellar degeneration, and Patent Document 3 describes that the compound represented by formula (I) and the like are useful for treating Parkinson's disease. Furthermore, Patent Document 4 describes a dosing regimen for a therapeutic agent for ataxia in spinocerebellar degeneration. Furthermore, methods for producing the compound represented by formula (I) and the like are described in Patent Documents 5 and 6. Furthermore, an enteric-coated formulation containing the compound represented by formula (I) and the like is described in Patent Document 7, which is characterized by being coated with an enteric base. Furthermore, an oral formulation containing the compound represented by formula (I) and the like is described in Patent Document 8, which is characterized by containing a medium-chain fatty acid triglyceride. However, neither of these documents discloses the formulation of the present invention.

[0004] WO1998 / 008867WO2006 / 028277WO2002 / 017954WO2016 / 208045WO1999 / 045000WO2001 / 016117WO2002 / 004016WO1999 / 053941

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

[0006] The present inventors conducted compatibility tests on various additives, checking the content, related substances, and changes in appearance, and found that a clear change in color was observed in croscarmellose sodium, carboxymethyl starch sodium, and powdered sugar, and that a small change in color was observed in particularly partially pregelatinized starch and D-mannitol, 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 containing a compound represented by formula (I) shown below. (1) Formula (I): A pharmaceutical composition comprising a compound represented by the formula (II): The pharmaceutical composition according to any one of (1) to (6) above, containing a compound represented by formula (II), a salt thereof, or a solvate thereof (hereinafter referred to as a compound represented by formula (II), etc.). (8) The pharmaceutical composition according to (7) above, containing a hydrate of a compound represented by formula (II). (9) A pharmaceutical composition according to formula (I): (10) A pharmaceutical composition comprising a compound represented by formula (II): The pharmaceutical composition according to (9) above, which contains a hydrate of the compound represented by the formula:

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

[0009] 1 shows the results of a dissolution test of the pharmaceutical composition of the present invention. The vertical axis represents dissolution rate (unit: %), and the horizontal axis represents time (unit: minutes).

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

[0012] Disintegrants that can be used include partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropyl cellulose, carmellose, crospovidone, croscarmellose sodium, and carboxymethyl starch sodium. Of these disintegrants, partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropyl cellulose, carmellose, crospovidone, croscarmellose sodium, and carboxymethyl starch sodium are preferred. Particularly, partially pregelatinized starch is 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 sucrose, D-mannitol, xylitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, cornstarch, and powdered sugar. Of these excipients, lactose, refined sucrose, 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 aspect 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 lubricant.

[0015] Povidone, hypromellose, etc. can be used as the binder. Of 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 based on the total weight of the tablet. Preferably, it is 0.5 to 2.0% by weight. Particularly preferred, it is 0.8 to 1.0% by weight. Magnesium stearate, etc. can be used as the lubricant. Of these lubricants, magnesium stearate is preferred. Particularly preferred, magnesium stearate is preferred. The lubricant can be used in an amount of 0.1 to 5.0% by weight based on the total weight of the tablet. Preferably, it is 0.5 to 2.0% by weight. Particularly preferred, it is 0.9 to 1.1% by weight.

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

[0017] Salts of the compound represented by formula (I) or the compound represented by formula (II) include hydrochloride, sulfate, nitrate, acetate, etc. 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 even more preferred are trihydrates. The trihydrate of the compound represented by formula (II) is particularly preferred. A method for producing the monohydrate is described in Reference 1, and a method for producing the trihydrate is described in Reference 2. The compound represented by formula (I) or the like can be used in an amount of 0.5 to 10 wt% based on the total tablet weight. Preferably, it is 1 to 5 wt%. Particularly preferred is 1.7 to 2.0 wt%.

[0018] The method for producing the pharmaceutical composition of the present invention involves 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, water containing a binder, or a solvent is added to form granules. The compound represented by formula (I) and additives can be added to water, water containing a binder, or a solvent. A V-type mixer, container blender, or agitator granulator can be used as a machine for mixing the compound represented by formula (I) and additives. Furthermore, a fluidized bed granulator or agitator granulator can be used as a machine for granulation. The moisture content of the mixed powder during granulation is 10 to 70%, preferably 30 to 50%. Furthermore, a disintegrant and a lubricant are mixed with the granules, and the mixed granules are compressed into tablets using a tablet press. A V-type mixer or container blender can be used as a machine for mixing the granules with the disintegrant and lubricant. Furthermore, a single punch tablet press, a rotary tablet press, or the like can be used as the tablet press. Tablets are preferred as the pharmaceutical composition of the present invention. The pharmaceutical composition of the present invention can contain, but is not limited to, 0.75 to 15 mg of the compound represented by formula (I). Preferably, it is 1.5 to 7.5 mg, and even more preferably, 2.25 to 3.0 mg. 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 a dose of 0.1 to 10 mg / day. Preferably, it is 1 to 5 mg / day. Particularly preferably, it can be administered at a dose of 1.6 to 3.2 mg / day. The total weight of the pharmaceutical composition of the present invention is, but is not particularly limited to, 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 applications described in any of 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 embodiment of the present invention is a pharmaceutical composition that is reduced in color change.Under the storage conditions described herein, a reduction in color change can be confirmed. Another aspect of the present invention is a pharmaceutical composition in which an increase in related substances is reduced. Under the storage conditions described herein, a reduction in an increase in related substances can be confirmed.

[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 Compatibility tests were carried out between the hydrate of the compound represented by formula (II) and various additives.

[0021] (A) Experimental Materials The following reagents and additives were used in the experiment: (Disintegrants) Partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropyl cellulose, carmellose, crospovidone, croscarmellose sodium, carboxymethyl starch sodium (Excipients) Lactose, refined sucrose, D-mannitol, xylitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, corn starch, powdered sugar (Binders) Povidone, hypromellose (Lubricant) Magnesium stearate

[0022] (B) Manufacturing equipment Ventilation dryer PM No. TRV141

[0023] (C) Test Methods Loss on drying: Electronic moisture meter PM No. AEH1122 (heating temperature 105°C) Content: HPLC method Column: Mightysil RP-18GP (150 mm x 4.6 mm) S-3 μm (Kanto Chemical) Column temperature: 40°C Mobile phase: PIC B-5 (Low UV) / acetonitrile = 8 / 2 mixture Detection wavelength: 220 nm Flow rate: Approximately 1.0 mL / min Injection volume: 100 μL Pump: Waters 600 Injector: Waters 717plus Detector: Waters 2487 Color difference: Spectrophotometer SE-2000 (Nippon Denshoku) Field of view selection: Reflected light measurement Measurement conditions: 2-degree field of view, standard light Related substances: HPLC method

[0024] (D) Samples for Compatibility Test (D-1) Blending Ratios The blending ratios of the additives were as follows. To make the compound represented by formula (II) equal to 1, a water content 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 (Excipient) Compound represented by formula (II): additive = 1:10 (Binder) Compound represented by formula (II): additive = 1:1 (Lubricant) Compound represented by formula (II): additive = 1:1

[0025] (D-2) Wet-processed product The additives, except for the lubricant magnesium stearate, were wet-processed and subjected to a time-course test. (1) The compound represented by formula (II) 1:10 additives or the compound represented by formula (II) 1:1 additive were weighed out and mixed in an agate mortar, followed by gradual addition of purified water and further mixing. (2) The wet kneaded product was then spread on a tray and aerated and dried at 45°C for 120 minutes.

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

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

[0028]

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

[0030]

[0031] (Results) Time-course tests were conducted under the accelerated conditions shown in (D-4), and changes in content, related substances, and appearance were confirmed. (Content) Changes in content were confirmed between the start and end of each time-course test. No significant content decrease was observed for any of the excipients. (Related Substances) Changes in the amount of related substances between the start and end of each time-course test were confirmed. The amount of related substances at the start was approximately 0.02%, and was approximately 0.02-0.03% at the end. A slight increase in related substances was observed in carmellose, croscarmellose sodium, lactose, xylitol, anhydrous calcium hydrogen phosphate, powdered sugar, and hypromellose. (Appearance Changes) Color differences were confirmed between the start and end of each time-course test. Color differences were 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 criteria for determining appearance using a color difference meter. ΔE = {(ΔL) 2 +(Δa) 2 +(Δb) 2} 1 / 2

[0032]

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

[0034]

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

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

[0037]

[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 regard to the 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 Method" in the Japanese Pharmacopoeia General Test Method. No auxiliary disc 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 conducted on the pharmaceutical composition of Example 2. Using 900 mL of water as the test solution, the test was conducted by the paddle method at 50 revolutions per minute. One pharmaceutical composition of Example 2 was taken, and the test was initiated. At 5, 10, 15, and 30 minutes, 4 mL of the dissolution solution was accurately taken and filtered through a membrane filter with a pore size of 0.45 μm. The first 2 mL of filtrate was discarded, and the next filtrate was used as the test solution. Separately, approximately 25 mg of the hydrate standard substance of the compound of formula (II) was precisely weighed and dissolved in water to make exactly 50 mL. 5 mL of this solution was accurately weighed, and water was added to make exactly 50 mL. 3 mL of this solution was accurately weighed, and water was added to make exactly 50 mL to make the standard solution. 50 μL of each of the test solution and the standard solution was accurately taken and tested by liquid chromatography under the following conditions, and the peak areas of each compound of formula (II) were 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 packed with 3 μm octadecylsilylated silica gel for liquid chromatography (Develosil ODS-HG (Nomura Chemical) or equivalent) Column temperature: a constant temperature of around 45° C. Mobile phase: water / acetonitrile solution 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 showed a rapid dissolution behavior. The results are shown in FIG. 1.

[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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