CN116077459A - Capsule of alpha 5-GABAA receptor modulator and preparation method thereof - Google Patents
Capsule of alpha 5-GABAA receptor modulator and preparation method thereof Download PDFInfo
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Abstract
The present application relates to a capsule of an alpha 5-GABAA receptor modulator and a method for preparing the same. The capsule of the alpha 5-GABAA receptor modulator comprises a capsule shell and contents contained in the capsule shell; the content comprises (2-10) drug particles and (0.1-1) a first disintegrating agent and a first lubricant in a weight ratio of 100; the drug particles comprise (5-25) alpha 5-GABAA receptor modulator solid dispersion, a second disintegrating agent and a first lubricant in a weight ratio of (0.1-1). The capsule of the alpha 5-GABAA receptor modulator has good stability in acceleration and long-term stability research, low content of related substances and good dissolution.
Description
Technical Field
The present application relates to pharmaceutical formulations, and in particular to capsules of an alpha 5-GABAA receptor modulator and methods of making the same.
Background
Alpha 5-GABAA receptor modulators have been studied to demonstrate utility in the treatment of pain, particularly Neuropathic Pain (NP), and as such alpha 5-GABAA receptor modulators are currently being studied in large numbers and have been synthesized in succession, e.g. as disclosed in Chinese patent application CN110256440AN-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2, 4)]Triazole [3,4-a ]]Phthalazin-6-yl) oxy) methyl) nicotinamide (structure is shown as the following formula1) Shown), intended for peripheral neuropathic pain.
At present, the current time of the process,N-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2, 4)]Triazole [3,4-a ]]Phthalazin-6-yl) oxy) methyl) nicotinamide is in the form of oral suspension used in phase I clinical trials, and has good bioavailability, but needs to be prepared at present, is inconvenient to use clinically and is not suitable for long-term administration. The granule and capsule have the advantages of simple production process, accurate dosage, stable quality, convenient use, long preservation time and the like, and can better solve the problem. However, the dosage forms of the capsules and the oral suspension have large differences, and how to ensure the quality standards such as dissolution rate of the capsules is a problem to be solved.
Disclosure of Invention
Based on the above, the present application provides a capsule of an α5-GABAA receptor modulator having a good dissolution rate and a method for preparing the same.
In a first aspect of the present application, there is provided a capsule of an α5-GABAA receptor modulator comprising a capsule shell and contents contained within said capsule shell;
the content comprises (2-10) drug particles and (0.1-1) a first disintegrating agent and a first lubricant in a weight ratio of 100;
the medicine particles comprise solid dispersion of alpha 5-GABAA receptor regulator, a second disintegrating agent and a second lubricant in a weight ratio of (5-25) to (0.1-1);
the alpha 5-GABAA receptor modulator has structural features represented by the following formula (1):
in one embodiment, the content comprises 100 (2-5) of drug particles, 0.3-0.7 of first disintegrating agent and first lubricant in a weight ratio.
In one embodiment, the drug particles comprise a solid dispersion of an alpha 5-GABAA receptor modulator, a second disintegrant, and a second lubricant in a weight ratio of 100 (10-20): (0.3-0.7).
In one embodiment, the first disintegrant is one or more of croscarmellose sodium, crospovidone, and sodium carboxymethyl starch, and further, the first disintegrant is croscarmellose sodium; and/or the number of the groups of groups,
the second disintegrating agent is one or more of croscarmellose sodium, crospovidone and carboxymethyl starch sodium, and further, the second disintegrating agent is croscarmellose sodium.
In one embodiment, the first lubricant is a combination of magnesium stearate and colloidal silica; and/or the number of the groups of groups,
the second lubricant is magnesium stearate.
In one embodiment, the first lubricant is a combination of magnesium stearate and colloidal silicon dioxide with a mass ratio of 1 (0.1-1).
In one embodiment, the solid dispersion of the α5-GABAA receptor modulator comprises the α5-GABAA receptor modulator and a carrier which is one or more of hydroxypropyl methylcellulose acetate succinate.
In one embodiment, the carrier is one or more of HPMCAS LG, HPMCAS MG and HPMCAS HG; further, the carrier is HPMCAS HG.
In one embodiment, the mass ratio of the alpha 5-GABAA receptor modulator to the carrier is 1 (2-8); further, the mass ratio of the alpha 5-GABAA receptor modulator to the carrier is 1 (4-8).
In a second aspect of the present application, there is provided a method for preparing a capsule of an α5-GABAA receptor modulator according to the first aspect, comprising the steps of:
mixing and granulating the solid dispersion of the alpha 5-GABAA receptor modulator, the second disintegrant and the second lubricant to prepare the drug granules;
mixing the drug particles with the first disintegrant, a first lubricant to prepare the content;
the contents are placed within the capsule shell.
In one embodiment, the conditions of the mixing granulation include:
the pressure of the press roller is 20-40 bar, the rotating speed of the press roller is 6-10 rpm, and the particle finishing speed is 80-120 rpm.
In one embodiment, in the process of preparing the content, the drug particles and the first disintegrating agent are mixed for 15 min-25 min under the condition of the rotation speed of 10 rpm-20 rpm, and then the first lubricating agent is added and mixed for 3 min-10 min under the condition of the rotation speed of 10 rpm-20 rpm.
In one embodiment, the method of preparing a solid dispersion of the α5-GABAA receptor modulator comprises:
mixing the alpha 5-GABAA receptor modulator, a carrier and a solvent to prepare a mixture;
and (3) carrying out spray drying on the mixture to prepare the solid dispersion of the alpha 5-GABAA receptor modulator.
In one embodiment, the solvent is a combination of at least two of dichloromethane, methanol, acetic acid, and acetone; further, the solvent is dichloromethane and methanol with the volume ratio of (1.0-3.0): 1.
The capsule of the alpha 5-GABAA receptor modulator is prepared by adding a part of the disintegrating agent and the lubricant into the drug particles, blending a part of the disintegrating agent and the lubricant with the drug particles, and reasonably controlling the weight ratio of each component.
In addition, it has been found during the course of the study that capsules of the above-described alpha 5-GABAA receptor modulator can achieve better bioavailability than conventional suspensions. In addition, the composition has good stability in acceleration and long-term stability research, and the content of related substances is low.
Detailed Description
The following describes in further detail the capsules of the α5-GABAA receptor modulator of the present application and the method of preparing the same, in conjunction with specific examples. This application may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the description of the application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.
The term "and/or," "and/or," as used herein, includes any one of two or more of the listed items in relation to each other, as well as any and all combinations of the listed items in relation to each other, including any two of the listed items in relation to each other, any more of the listed items in relation to each other, or all combinations of the listed items in relation to each other.
Herein, "one or more" refers to any one, any two, or any two or more of the listed items.
In this application, "first", "second", "third", "fourth", etc. are for descriptive purposes only and are not to be construed as indicating or implying a relative importance or quantity, nor as implying an importance or quantity of a technical feature being indicated. Moreover, the terms "first," "second," "third," "fourth," and the like are used for non-exhaustive list description purposes only, and are not to be construed as limiting the number of closed forms.
In the present application, the technical features described in an open manner include a closed technical scheme composed of the listed features, and also include an open technical scheme including the listed features.
In the present application, reference is made to numerical intervals, where the numerical intervals are considered to be continuous unless specifically stated, and include the minimum and maximum values of the range, and each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range description features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to include any and all subranges subsumed therein.
The percentage content referred to in the present application refers to mass percent for both solid-liquid and solid-solid phase mixing and volume percent for liquid-liquid phase mixing unless otherwise specified.
The percentage concentrations referred to in this application, unless otherwise indicated, refer to the final concentrations. The final concentration refers to the ratio of the additive component in the system after the component is added.
The temperature parameter in the present application is not particularly limited, and may be a constant temperature treatment or a treatment within a predetermined temperature range. The constant temperature process allows the temperature to fluctuate within the accuracy of the instrument control.
The room temperature in this application is generally 4 ℃ to 30 ℃, preferably 20+ -5 ℃.
An example of the present application provides a capsule of an α5-GABAA receptor modulator comprising a capsule shell and contents contained in the capsule shell;
the content comprises (2-10) drug particles and (0.1-1) a first disintegrating agent and a first lubricant in a weight ratio of 100;
the medicine particles comprise solid dispersion of alpha 5-GABAA receptor regulator, a second disintegrating agent and a second lubricant in a weight ratio of (5-25) to (0.1-1);
the alpha 5-GABAA receptor modulator has structural features represented by the following formula (1):
specifically, the weight ratio of the drug particles in the content to the first disintegrant and the first lubricant includes, but is not limited to: 100:2 (0.1-1), 100:3 (0.1-1), 100:4 (0.1-1), 100:5 (0.1-1), 100:6 (0.1-1), 100:7 (0.1-1), 100:8 (0.1-1), 100:9 (0.1-1), 100:10 (0.1-1), 100 (2-5) 0.1, 100 (2-5) 0.2, 100 (2-5) 0.3, 100 (2-5) 0.4, 100 (2-5) 0.5, 100 (2-5) 0.6, 100 (2-5) 0.7, 100 (2-5) 0.8, 100 (2-5) 0.9, 100 (2-5) 1.
Further, the content comprises (2-5) drug particles and (0.3-0.7) a first disintegrating agent and a first lubricant in a weight ratio of 100.
Specifically, the weight ratio of the solid dispersion of the α5-GABAA receptor modulator, the second disintegrant, and the second lubricant in the drug particles includes, but is not limited to: 100:5 (0.1-1), 100:7 (0.1-1), 100:10 (0.1-1), 100:12 (0.1-1), 100:15 (0.1-1), 100:17 (0.1-1), 100:20 (0.1-1), 100:22 (0.1-1), 100:25 (0.1-1), 100 (10-20) 0.1, 100 (10-20) 0.2, 100 (10-20) 0.3, 100 (10-20) 0.4, 100 (10-20) 0.5, 100 (10-20) 0.6, 100 (10-20) 0.7, 100 (10-20) 0.8, 100 (10-20) 0.9, 100 (10-20) 1.
Further, the drug particles comprise a solid dispersion of an alpha 5-GABAA receptor modulator, a second disintegrant and a second lubricant in a weight ratio of 100 (10-20): (0.3-0.7).
In some examples, the first disintegrant is one or more of croscarmellose sodium, crospovidone, and sodium carboxymethyl starch, and further, the first disintegrant is croscarmellose sodium.
In some examples, the second disintegrant is one or more of croscarmellose sodium, crospovidone, and sodium carboxymethyl starch, and further, the first disintegrant is croscarmellose sodium.
In some examples, the first lubricant is a combination of magnesium stearate and colloidal silica.
In some examples, the second lubricant is magnesium stearate.
In some examples, the first lubricant is a combination of magnesium stearate and colloidal silica in a mass ratio of 1 (0.1-1). Specifically, in the first lubricant, the mass ratio of magnesium stearate to colloidal silica includes, but is not limited to: 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.
In addition, the α5-GABAA receptor modulator is hardly soluble in water, has pH-dependent solubility, and has a good solubility in an acidic environment, but has a characteristic that the solubility is rapidly decreased with an increase in pH, and the solubility is high in the stomach, and precipitation may occur in the intestinal tract due to an increase in pH. Overall, therefore, α5-GABAA receptor modulators have poor solubility and dissolution and low bioavailability. Based on this, the present application further enables to further enhance the dissolution rate and bioavailability of the α5-GABAA receptor modulator by selecting an appropriate carrier to prepare a solid dispersion of the α5-GABAA receptor modulator.
In one example, the solid dispersion of the α5-GABAA receptor modulator includes the α5-GABAA receptor modulator and a carrier that is one or more of hydroxypropyl methylcellulose acetate succinate.
In one example, the carrier is one or more of HPMCAS LG, HPMCAS MG and HPMCAS HG. Further, the carrier is HPMCAS HG. By optimizing the type of carrier, better drug dissolution and higher bioavailability can be obtained.
In one example, the mass ratio of the alpha 5-GABAA receptor modulator to the carrier is 1 (2-8). Specifically, the mass ratio of the α5-GABAA receptor modulator to the carrier includes, but is not limited to: 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8. Further, the mass ratio of the alpha 5-GABAA receptor modulator to the carrier is 1 (4-8). By optimizing the mass ratio of the drug to the carrier, better drug dissolution and higher bioavailability can be obtained.
Another example of the present application provides a method for preparing a capsule of an α5-GABAA receptor modulator as described above, comprising the steps of:
mixing and granulating the solid dispersion of the alpha 5-GABAA receptor modulator, the second disintegrant and the second lubricant to prepare the drug granules;
mixing the drug particles with the first disintegrant, a first lubricant to prepare the content;
the contents are placed within the capsule shell.
In one example, the conditions of the mixing granulation include:
the pressure of the press roller is 20-40 bar, the rotating speed of the press roller is 6-10 rpm, and the particle finishing speed is 80-120 rpm.
Specifically, the nip roll pressure includes, but is not limited to: 20bar, 25bar, 30bar, 35bar, 40bar.
Specifically, the press roll rotational speeds include, but are not limited to: 6rpm, 7rpm, 8rpm, 9rpm, 10rpm.
Specifically, the particle finishing speeds include, but are not limited to: 80rpm, 90rpm, 100rpm, 110rpm, 120rpm.
In one example, in the process of preparing the content, the drug particles and the first disintegrating agent are mixed for 15 min-25 min under the condition of the rotating speed of 10 rpm-20 rpm, and then the first lubricating agent is added and mixed for 3 min-10 min under the condition of the rotating speed of 10 rpm-20 rpm.
In one example, the method of preparing a solid dispersion of the α5-GABAA receptor modulator comprises:
mixing an alpha 5-GABAA receptor modulator, a carrier and a solvent to prepare a mixture;
and (3) carrying out spray drying on the mixture to prepare the solid dispersion of the alpha 5-GABAA receptor modulator.
In one example, the solvent is a combination of at least two of dichloromethane, methanol, acetic acid, and acetone. Further, the solvent is dichloromethane and methanol with the volume ratio of (1.0-3.0): 1. By adopting a proper solvent, the dispersion and dissolution of the medicine in the solid dispersion are facilitated, the stability of the preparation process of the solid dispersion is ensured, and the solvent residue can be reduced.
In one example, the spray drying conditions include:
the temperature of the air inlet is 75-85 ℃, the atomization pressure is 0.1-0.15 mpa, and the temperature of the air outlet is 40-50 ℃.
Specifically, the intake vent temperature includes, but is not limited to: 75 ℃, 76 ℃, 77 ℃, 78 ℃, 79 ℃, 80 ℃, 81 ℃, 82 ℃, 83 ℃, 84 ℃, 85 ℃.
In particular, the atomization pressure includes, but is not limited to: 0.1Mpa, 0.11Mpa, 0.12Mpa, 0.13Mpa, 0.14Mpa, 0.15Mpa.
Specifically, the outlet temperature includes, but is not limited to: 40 ℃, 41 ℃, 42 ℃, 43 ℃, 44 ℃, 45 ℃, 46 ℃, 47 ℃, 48 ℃, 49 ℃, 50 ℃.
In one example, the spray drying conditions further include: the air intake is 2-6 m 3 And/min, wherein the peristaltic pump speed is 20-70 rpm.
In one example, the spray drying is followed by a drying step to provide a solvent residue of 600ppm or less. Further, the conditions of drying include: the temperature is not higher than 45 ℃ and the time is not lower than 4 hours.
The following are specific examples, and all materials used in the examples are commercially available products unless otherwise specified.
The drug substance (. Alpha.5-GABAA receptor modulator) used in the examples and comparative examples wasN-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2, 4)]Triazole [3,4-a ]]Phthalazin-6-yl) oxy) methyl) nicotinamide having the structure shown in formula (1) below:
crosslinked povidone was purchased from steker reddenemeal, model XL;
crosslinked sodium carboxymethylcellulose was purchased from Mingtai chemical;
sodium carboxymethyl starch was purchased from JRS;
colloidal silica was purchased from Grace GmbH;
gelatin empty capsules were purchased from su zhou capsules, model number 0.
Examples 1 to 6 and comparative examples 1 to 2
This example and comparative example provide capsules of an alpha 5-GABAA receptor modulator formulated (single capsule content of 30mg format) as shown in tables 1-2 below:
TABLE 1
TABLE 2
The capsule preparation procedure of example 1 was as follows:
(1) Preparing a dispersion:
1.1 adding 112.5mL of solvent (dichloromethane and methanol with volume ratio of 2:1) into a container, stirring uniformly, adding the raw material medicine, stirring and dissolving until the mixture is clear, then adding a carrier (HPMCAS HG), wherein the mass ratio of the raw material medicine to the carrier is 1g:5g, stirring and dissolving until the mixture is clear, and obtaining a mixture;
1.2 opening the spray drying apparatus, setting an air intake of 4m 3 After the isothermal stability, adding the mixture obtained in the step 1.1 into the mixture through a peristaltic pump with the speed of 50rpm for spray drying, and collecting the mixture;
1.3, vacuum drying the material collected in the step 1.2 at the temperature of less than or equal to 45 ℃ for more than or equal to 4 hours until the solvent residue meets the requirements, and dispersing;
(2) Mixing the dispersion prepared according to the step (1), croscarmellose sodium and magnesium stearate for dry granulation: adding the mixed powder obtained by mixing into a dry granulator for dry granulation, manually feeding, and setting a condensing temperature: 25 ℃, pressure of the press roll: 40bar, feed rate: 30rpm, press roll rotation speed: 8rpm, finishing speed: 100rpm, screen mesh size: 1.0mm round hole, dry granulating according to the above parameters, and sieving with 50 mesh sieve to obtain medicinal granule;
(3) Mixing the drug particles prepared in the step (2) with external crosslinked sodium carboxymethyl cellulose at a mixing speed of 14rpm for 20min, adding magnesium stearate and colloidal silicon dioxide, mixing at a mixing speed of 14rpm for 5min, and preparing a content;
(4) And (3) placing the content prepared in the step (3) into 1 capsule shell to obtain the capsule.
The procedure for the preparation of capsules of examples 1-4 and comparative examples 1-2 was the same as in example 1, except that the proportions of the components were varied according to tables 1 and 2.
The capsule preparation steps of examples 5 and 6 are the same as example 1, except that: and (2) replacing the croscarmellose sodium with the crospovidone and the carboxymethyl starch sodium in equal quantity.
Test example 1:
(1) Dissolution test:
the testing method comprises the following steps: the capsules prepared in examples and comparative examples were placed in 1000mL of sodium dihydrogen phosphate buffer solution at pH6.8, and stirred for 120min at 100rpm using a paddle method.
The test results are shown in table 3 below:
TABLE 3 Table 3
(2) Bioavailability test:
the testing method comprises the following steps: the capsules prepared in examples and comparative examples were administered in a single oral gavage at a dose of 1 grain/dog. The concentration of the drug substance in beagle plasma was quantitatively determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. Pharmacokinetic parameters were calculated using a non-compartmental model and bioavailability F was calculated. The calculation method of the bioavailability F is as follows:
F =(AUC 0-inf -PO/AUC 0-inf -IV mean)/Dose-PO/Dose-IV) 100%;
note that:
AUC 0-inf -PO: the area under the blood concentration-time curve from 0 to infinity time when administered orally;
AUC 0-inf -IV: the area under the blood concentration-time curve from 0 to infinity time when intravenous administration is performed;
Dose-PO: an orally administered dose;
Dose-IV: intravenous administration dose;
when AUC 0-inf If not available, AUC can be used 0-t F calculation (area under blood concentration-time curve over a period of time).
The test results are shown in table 4 below:
TABLE 4 Table 4
(3) Stability test:
the testing method comprises the following steps: the capsule prepared in the embodiment is prepared by taking 1 sample, placing at 60+/-2 ℃ for 10 days, and detecting related substances, content and dissolution, wherein the capsule is stable without obvious change.
The test results are shown in table 5 below:
TABLE 5
Examples 7 to 11 and comparative examples 3 to 9
Examples 7-11 provide solid dispersions of alpha 5-GABAA receptor modulators, the preparation steps of which are the same as step (1) in example 1, except that:
example 7: the adopted carrier is HPMCAS MG;
example 8: the adopted carrier is HPMCAS LG;
example 9: the mass ratio of the bulk drug to the carrier is 1g to 3g;
example 10: the mass ratio of the bulk drug to the carrier is 1g to 8g;
example 11: the solvent is acetic acid and acetone with volume ratio of 1:4, and the temperature of the air inlet is set at 124 ℃.
Comparative examples 3 to 8
Comparative examples 3-8 provide solid dispersions of alpha 5-GABAA receptor modulator, the preparation procedure being the same as in example 1, step (1), except that:
(D3) PEG6000, the mass ratio of the bulk drug to the carrier is 1g:3g;
(D4) Poloxamer 188, the mass ratio of the bulk drug to the carrier is 1g:3g;
(D5) HPMCP, the mass ratio of the bulk drug to the carrier is 1g to 3g;
(D6) HPMCP, the mass ratio of the bulk drug to the carrier is 1g:5g;
(D7) PVP S630, wherein the mass ratio of the bulk drug to the carrier is 1g to 5g;
(D8) PVP K30, the mass ratio of the bulk drug to the carrier is 1g:5g.
Test example 2:
(1) Solubility test:
the testing method comprises the following steps: 1.5mg of a sample to be measured (solid dispersion prepared in example 1, solid dispersion prepared in examples 7 to 10 and comparative examples 3 to 8) was weighed, 1.5mL of FaSSIF solution was added, shaking was conducted at 37℃for 0.5 hour, 0.5mL of the primary filtrate was removed by filtration, 400. Mu.L of the subsequent filtrate was taken, and diluted with 400. Mu.L of 50% acetonitrile. The sample solubility was calculated by analysis using High Performance Liquid Chromatography (HPLC).
The test results are shown in table 6 below:
TABLE 6
(2) Bioavailability test
The testing method comprises the following steps: samples to be tested (solid dispersion prepared in example 1, solid dispersion prepared in examples 7 to 10 and comparative examples 3 to 8) were filled into gelatin capsules, and the capsules were orally administered in a single dose of 1 capsule (the content of the single capsule is 30 mg)/dog dose, respectively. The concentration of the drug substance in beagle plasma was quantitatively determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. Pharmacokinetic parameters were calculated using a non-compartmental model and bioavailability F was calculated. The calculation method of the bioavailability F is as follows:
F =(AUC 0-inf -PO/AUC 0-inf -IV mean)/Dose-PO/Dose-IV) 100%;
note that: AUC (AUC) 0-inf -PO: the area under the blood concentration-time curve from 0 to infinity time when administered orally;
AUC 0-inf -IV: the area under the blood concentration-time curve from 0 to infinity time when intravenous administration is performed;
Dose-PO: an orally administered dose;
Dose-IV: intravenous administration dose;
when AUC 0-inf If not available, AUC can be used 0-t (during a certain period of time)Area under the inner plasma concentration-time curve) was subjected to F calculation.
The test results are shown in table 7 below:
TABLE 7
(3) Solvent residue test
The testing method comprises the following steps: the second method of the residual solvent determination method is carried out according to the four general rules 0861 of the 2015 edition of Chinese pharmacopoeia.
The test results are shown in table 8 below:
TABLE 8
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples merely represent a few embodiments of the present application, which facilitate a specific and detailed understanding of the technical solutions of the present application, but are not to be construed as limiting the scope of the claims. It should be noted that it would be apparent to those skilled in the art that various modifications and improvements could be made without departing from the spirit of the present application, which would be within the scope of the present application. It should be understood that those skilled in the art, based on the technical solutions provided in the present application, can obtain technical solutions through logical analysis, reasoning or limited experiments, all fall within the protection scope of the claims attached in the present application. The scope of the patent application is therefore intended to be indicated by the appended claims, and the description may be used to interpret the contents of the claims.
Claims (18)
1. A capsule of an alpha 5-GABAA receptor modulator comprising a capsule shell and a content contained in said capsule shell;
the content comprises (2-10) drug particles and (0.1-1) a first disintegrating agent and a first lubricant in a weight ratio of 100;
the medicine particles comprise solid dispersion of alpha 5-GABAA receptor regulator, a second disintegrating agent and a second lubricant in a weight ratio of (5-25) to (0.1-1);
the alpha 5-GABAA receptor modulator has structural features represented by the following formula (1):
2. the capsule of an α5-GABAA receptor modulator according to claim 1, wherein the content comprises 100 (2-5): 0.3-0.7 by weight of the drug particles, and the first disintegrant and the first lubricant.
3. The capsule of an alpha 5-GABAA receptor modulator according to claim 1, wherein the pharmaceutical granules comprise a solid dispersion of an alpha 5-GABAA receptor modulator in a weight ratio of 100 (10 to 20): (0.3 to 0.7), a second disintegrant and a second lubricant.
4. The capsule of an alpha 5-GABAA receptor modulator of claim 1, wherein the first disintegrant is one or more of croscarmellose sodium, crospovidone and sodium carboxymethyl starch; and/or the number of the groups of groups,
the second disintegrating agent is one or more of croscarmellose sodium, crospovidone and carboxymethyl starch sodium.
5. The capsule of an alpha 5-GABAA receptor modulator of claim 4, wherein said first disintegrant is croscarmellose sodium; and/or the number of the groups of groups,
the second disintegrating agent is croscarmellose sodium.
6. The capsule of an alpha 5-GABAA receptor modulator of claim 1, wherein said first lubricant is a combination of magnesium stearate and colloidal silicon dioxide; and/or the number of the groups of groups,
the second lubricant is magnesium stearate.
7. The capsule of an α5-GABAA receptor modulator according to claim 6, wherein the first lubricant is a combination of magnesium stearate and colloidal silica in a mass ratio of 1 (0.1 to 1).
8. The capsule of an α5-GABAA receptor modulator according to any one of claims 1 to 7, wherein the solid dispersion of the α5-GABAA receptor modulator comprises the α5-GABAA receptor modulator and a carrier, and the carrier is one or more of hydroxypropyl methylcellulose acetate succinate.
9. The capsule of an alpha 5-GABAA receptor modulator of claim 8, wherein the carrier is one or more of HPMCAS LG, HPMCAS MG and HPMCAS HG.
10. The capsule of an alpha 5-GABAA receptor modulator of claim 9, wherein the carrier is HPMCAS HG.
11. The capsule of an α5-GABAA receptor modulator according to claim 8, wherein the mass ratio of the α5-GABAA receptor modulator to the carrier is 1 (2 to 8).
12. The capsule of an α5-GABAA receptor modulator according to claim 11, wherein the mass ratio of the α5-GABAA receptor modulator to the carrier is 1 (4 to 8).
13. The method for preparing a capsule of an α5-GABAA receptor modulator according to any one of claims 1 to 12, comprising the steps of:
mixing and granulating the solid dispersion of the alpha 5-GABAA receptor modulator, the second disintegrant and the second lubricant to prepare the drug granules;
mixing the drug particles with the first disintegrant, a first lubricant to prepare the content;
the contents are placed within the capsule shell.
14. The method of preparing a capsule of an alpha 5-GABAA receptor modulator according to claim 13, wherein the conditions of the mixing granulation comprise:
the pressure of the press roller is 20-40 bar, the rotating speed of the press roller is 6-10 rpm, and the particle finishing speed is 80-120 rpm.
15. The method for preparing a capsule of an α5-GABAA receptor modulator according to claim 13, wherein in the process of preparing the content, the drug particles and the first disintegrant are mixed for 15min to 25min at a rotation speed of 10rpm to 20rpm, and then the first lubricant is added and mixed for 3min to 10min at a rotation speed of 10rpm to 20rpm.
16. The method for preparing a capsule of an α5-GABAA receptor modulator according to any one of claims 13 to 15, wherein the method for preparing a solid dispersion of the α5-GABAA receptor modulator comprises:
mixing the alpha 5-GABAA receptor modulator, a carrier and a solvent to prepare a mixture;
and (3) carrying out spray drying on the mixture to prepare the solid dispersion of the alpha 5-GABAA receptor modulator.
17. The method of preparing a capsule of an alpha 5-GABAA receptor modulator according to claim 16, wherein said solvent is a combination of at least two of dichloromethane, methanol, acetic acid and acetone.
18. The method for producing a capsule of an α5-GABAA receptor modulator according to claim 17, wherein the solvent is methylene chloride and methanol in a volume ratio of (1.0 to 3.0): 1.
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