CN115844856B

CN115844856B - Dicyclo alcohol solid preparation and preparation method thereof

Info

Publication number: CN115844856B
Application number: CN202310015180.XA
Authority: CN
Inventors: 杨玉莹; 檀华进; 罗四海; 毕珊珊; 王登才; 郑晓军; 杨玲
Original assignee: Beijing Zhongkelihua Pharmaceutical Research Institute Co ltd
Current assignee: Beijing Zhongkelihua Pharmaceutical Research Institute Co ltd
Priority date: 2023-01-06
Filing date: 2023-01-06
Publication date: 2023-05-16
Anticipated expiration: 2043-01-06
Also published as: CN115844856A

Abstract

The embodiment of the application provides a dicyclo alcohol solid preparation and a preparation method thereof, wherein a quick-release microchip and a slow-release microchip are filled in a capsule cavity of a hard capsule body; the quick release micro tablet comprises the following components: the pharmaceutical composition comprises bicyclo-ethanol, a filler, a disintegrating agent and multifunctional auxiliary materials for improving the solubility of the bicyclo-ethanol; the sustained-release microchip comprises the following components: a slow release microchip core and a slow release coating layer adhered to the surface of the slow release microchip core; the sustained-release microchip core comprises: bicyclic alcohol, slow release skeleton and multifunctional auxiliary materials. The dicyclo alcohol solid preparation provided by the application can reach a treatment window in a short time through the quick-release microchip, so that the purpose of quick acting and reducing uncomfortable feeling of a patient caused by diseases is realized. And then, by the combined use with the sustained-release microchip, the treatment time of the medicine is prolonged to the greatest extent while controlling the blood concentration of the bicyclic alcohol to be positioned in the treatment window, so that the treatment effect is improved.

Description

Dicyclo alcohol solid preparation and preparation method thereof

Technical Field

The application relates to the field of medicines, in particular to a bicyclo-ethanol solid preparation and a preparation method thereof.

Background

Aminotransferase can participate in the decomposition and synthesis of human amino acids, and is an indispensable 'catalyst' in the metabolic process of human body. Aminotransferase is mainly present in liver cells, and when liver cells are damaged due to inflammation, necrosis, poisoning, etc., transaminase is released into blood to raise serum transaminase.

The existing medicines for treating the aminotransferase elevation caused by chronic hepatitis are dicyclo alcohol tablets, and the preparations are oral sustained release preparations, so that the blood concentration is not easy to control. That is, the maximum blood concentration that the drug may reach over a period of time is above the therapeutic window; subsequently, the blood concentration drops rapidly below the therapeutic window for a short period of time, thus limiting the therapeutic effect.

Disclosure of Invention

In view of the above, the present application provides a bicyclo-ethanol solid preparation and a preparation method thereof, so as to at least partially solve the above problems.

In order to achieve the above purpose, the present application is realized by the following technical scheme:

in a first aspect, the present application provides a bicyclol solid formulation comprising:

at least one quick-release microchip and at least one slow-release microchip, wherein each quick-release microchip and each slow-release microchip are filled in a capsule cavity of the hard capsule body;

the quick-release micro tablet comprises the following components in parts by mass: 1 part of bicyclo-ethanol, 0.1-0.2 part of filler, 0.2-0.4 part of disintegrating agent and 0.7-1.2 parts of multifunctional auxiliary material for improving the solubility of bicyclo-ethanol;

the sustained-release microchip comprises the following components in parts by mass: a slow release microchip core and a slow release coating layer adhered to the surface of the slow release microchip core;

the sustained-release microchip tablet core comprises: 1 part of bicyclo-ethanol, 0.5-1.3 parts of slow-release framework and 0.5-0.7 part of multifunctional auxiliary materials.

The term "0.1 to 0.2" means any value within the range of 0.1 to 0.2, for example, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 and 0.2, with respect to the mass part of the filler.

The term "0.2 to 0.4" means 0.2, 0.22, 0.24, 0.25, 0.28, 0.3, 0.32, 0.34, 0.36, 0.38 and 0.4 based on the mass of the disintegrating agent.

For the mass parts of the multifunctional auxiliary materials in the quick-release micro tablet, 0.7-1.2 refers to any value ranging from 0.7 to 1.2, such as 0.7, 0.72, 0.74, 0.76, 0.78, 0.8, 0.82, 0.84, 0.88, 0.9, 0.92, 0.94, 0.96, 0.98, 1.0, 1.02, 1.04, 1.06, 1.08, 1.1, 1.12, 1.14, 1.16, 1.18 and 1.2.

By mass of the slow release matrix, 0.5-1.3 is meant any value in the range of 0.5 to 1.3, such as 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.1, 1.15, 1.2, 1.25, and 1.3.

For the mass parts of the multifunctional auxiliary materials in the sustained-release microchip, 0.5-0.7 refers to any value ranging from 0.5 to 0.7, for example, 0.5, 0.52, 0.54, 0.56, 0.58, 0.6, 0.62, 0.64, 0.66, 0.68 and 0.7.

Preferably, the filler is: microcrystalline cellulose.

Preferably, the disintegrant comprises: corn starch.

Preferably, the multifunctional auxiliary material is polyoxyethylene 40 hydrogenated castor oil.

Specifically, the polyoxyethylene 40 hydrogenated castor oil is added into the quick-release micro tablet and the slow-release micro tablet to improve the solubility of the bicyclo-ethanol, so that the medicine of the bicyclo-ethanol is released more rapidly, and the aim of improving the bioavailability is achieved.

Preferably, the slow release skeleton is ethyl cellulose.

Preferably, the slow release coating layer comprises the following components in parts by mass: 0.05-0.1 part of ethyl cellulose and 0.05 part of povidone K.

Preferably, each of the immediate release mini-tablets and each of the sustained release mini-tablets contains 5mg of dicyclo alcohol.

Preferably, the ratio of the quick release micro tablet to the slow release micro tablet in each hard capsule body is 1:2.

specifically, the proportion of the quick-release micro tablet to the slow-release micro tablet in each hard capsule is 1:2, when the content of the bicyclo-ethanol in each quick-release micro tablet and each slow-release micro tablet is 5mg, the content of the bicyclo-ethanol in each hard capsule can be 75mg-150mg. The diameters of each quick-release micro tablet and the slow-release micro tablet are 2-3mm.

In a second aspect, the present application provides a method for preparing a solid preparation of a bicyclo-ethanol as shown in the first aspect, which specifically includes:

(1) The quick-release micro tablet is prepared by the following components in parts by mass:

dissolving 1 part of dicyclo alcohol and 0.7-1.2 parts of multifunctional auxiliary materials for improving the solubility of dicyclo alcohol by using absolute ethyl alcohol to obtain a first mixture;

performing reduced pressure evaporation treatment on the first mixture to obtain a first paste;

mixing the first paste, 0.2-0.4 part of disintegrating agent and 0.1-0.2 part of filling agent to obtain a first wet mixture;

and (3) drying and tabletting the first wet mixture to obtain quick-release micro tablets.

Specifically, in order to increase the solubility of the bicyclo-ethanol in the quick-release microchip, absolute ethyl alcohol is used as a solvent for dissolution treatment to obtain a first mixture of the bicyclo-ethanol in a liquid form and the multifunctional auxiliary materials. And (3) carrying out reduced pressure evaporation treatment on the first mixture at the temperature of 40-50 ℃ to remove the absolute ethyl alcohol from the first mixture, thereby obtaining a first paste which is coated with the multifunctional auxiliary materials on the outer surface of the nano-scale bicyclo-ethanol. Uniformly mixing the first paste, the disintegrating agent and the filler, and then drying and tabletting to obtain the quick-release micro tablet.

(2) The sustained-release micro tablet is prepared by the following components in parts by mass:

dissolving 1 part of dicyclo alcohol and 0.5-0.7 part of multifunctional auxiliary materials for improving the solubility of dicyclo alcohol by using absolute ethyl alcohol to obtain a second mixture;

performing reduced pressure evaporation treatment on the second mixture to obtain a second paste;

mixing the second paste with 0.5-1.3 parts of slow-release framework to obtain a second wet mixture;

drying and tabletting the second wet mixture to obtain a slow-release microchip core;

preparing a slow-release coating liquid;

coating the sustained-release microchip core by using the sustained-release coating liquid to obtain a sustained-release microchip with a sustained-release coating layer adhered on the surface of the sustained-release microchip core;

and filling the quick-release microchip and the slow-release microchip into a capsule cavity of the hard capsule body.

Specifically, in order to increase the solubility of the bicyclo-ethanol in the sustained-release microchip, the bicyclo-ethanol and the multifunctional auxiliary materials are dissolved by using absolute ethanol as a solvent to obtain a second mixture. And then carrying out reduced pressure evaporation treatment on the second mixture at the temperature of 40-50 ℃ to remove absolute ethyl alcohol in the second mixture, and wrapping the multifunctional auxiliary materials on the outer surface of the nano-scale bicyclo-ethanol to obtain a second paste. And mixing the second paste with a slow-release skeleton to wrap the slow-release skeleton on the outer surface of the multifunctional auxiliary material so as to reduce the dissolution rate of the bicyclo-ethanol and control the drug release rate of the slow-release micro tablet. And then the slow-release microchip tablet core can be obtained after drying and tabletting treatment. Finally, the outer surface of the sustained-release microchip core is coated with a coating layer to obtain the sustained-release microchip.

It is understood that the temperature at which the first mixture and the second mixture are evaporated under reduced pressure means any value ranging from 40 to 50 c, such as 40 c, 42 c, 43 c, 44 c, 45 c, 46 c, 47 c, 48 c, 49 c and 50 c.

When the slow-release coating liquid is prepared, the ethyl cellulose and the povidone are dissolved by using 80% -100% ethanol solution, so that the slow-release coating liquid with sufficient dissolution is obtained. For ethanol content, 80% -100% refers to any value in the range of 80% to 100%, such as 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98% and 100%.

It can be understood that after the slow-release coating liquid is coated on the outer surface of the slow-release micro tablet core, the liquid in the slow-release coating liquid volatilizes, and the solid materials in the slow-release coating liquid can form a slow-release coating layer on the outer surface of the slow-release micro tablet core.

Preferably, the disintegrant is corn starch.

Preferably, the filler is microcrystalline cellulose.

Preferably, the slow release skeleton is ethyl cellulose.

According to the technical scheme, the application provides a dicyclo alcohol solid preparation and a preparation method thereof. The bicyclol solid preparation comprises quick-release micro tablets and slow-release micro tablets which are filled in a hard capsule body. Wherein, the quick release micro tablet is composed of bicyclo-ethanol, filler, disintegrating agent and multifunctional auxiliary materials. The sustained-release microchip comprises a sustained-release microchip core composed of a bicyclo-ethanol, a sustained-release skeleton and multifunctional auxiliary materials, and a sustained-release coating layer adhered on the surface of the sustained-release microchip core. Compared with the existing normal-release bicyclic alcohol tablet, the bicyclic alcohol solid preparation can reach a treatment window in a short time through the quick-release microchip, achieves quick effect, and reduces uncomfortable feeling of patients due to diseases. And then, by the combined use with the sustained-release microchip, the treatment time of the medicine is prolonged to the greatest extent while controlling the blood concentration of the bicyclic alcohol to be positioned in the treatment window, so that the treatment effect is improved.

Drawings

In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, and it is obvious that the drawings in the following description are some embodiments of the present application, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.

FIG. 1 is a graph showing the results of examining the amounts and types of fillers used in test example 1 of the present application;

FIG. 2 is a view showing the examination results of the amounts and types of disintegrants provided in test example 2 of the present application;

FIG. 3 is a view showing the results of examining the amounts of the multifunctional auxiliary materials in the immediate release microtablets provided in test example 3 of the present application;

fig. 4 is a result of examining the amount of the multifunctional auxiliary material in the sustained-release microchip provided in experimental example 3 of the present application;

FIG. 5 is a view showing the results of examining the amounts and types of the sustained-release matrix provided in test example 4 of the present application;

FIG. 6 is a view showing the results of examining the amounts and types of coating layers provided in test example 5 of the present application;

FIG. 7 is a graph of the particle size distribution of a nano-scale bicyclo-alcohol as provided in test example 6 of the present application;

FIG. 8 is a graph showing the particle size distribution of micronized bicyclol provided in test example 6 of the present application;

fig. 9 is a graph of the blood concentration provided in test example 7 of the present application.

Detailed Description

In order to better understand the technical solutions in the embodiments of the present application, the following description will clearly and completely describe the technical solutions in the embodiments of the present application with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are only some embodiments of the present application, but not all embodiments. All other embodiments obtained by a person of ordinary skill in the art based on the embodiments provided herein shall fall within the scope of the embodiments of the present application.

The present application is further described below with reference to specific examples.

Example 1

(1) Prescription 1 of a solid formulation of a bicyclo-ethanol, expressed in parts by mass as shown in the following table 1:

TABLE 1

Example 2

(1) Prescription 2 of the dicyclo alcohol solid preparation is shown in the following table 2 in parts by mass:

TABLE 2

Example 3

(1) Prescription 3 of the dicyclo alcohol solid preparation is shown in the following table 3 in parts by mass:

TABLE 3 Table 3

/>

Example 4

(1) Prescription 4 of the dicyclo alcohol solid preparation is shown in the following table 4 in parts by mass:

TABLE 4 Table 4

Example 5

(1) Prescription 5 of the dicyclo alcohol solid preparation is shown in the following table 5 in parts by mass:

TABLE 5

Example 6

(1) Prescription 6 of the dicyclo alcohol solid preparation is shown in the following table 6 in parts by mass:

TABLE 6

The preparation method of the sample of example 6 is as follows:

dissolving dicyclo alcohol and polyoxyethylene 40 hydrogenated castor oil with a proper amount of absolute ethyl alcohol to obtain a first mixture;

evaporating the first mixture under reduced pressure to obtain a first paste;

mixing the first paste, corn starch and microcrystalline cellulose to obtain a first wet mixture;

drying and tabletting the first wet mixture to obtain quick-release micro tablets;

dissolving dicyclo alcohol and polyoxyethylene 40 hydrogenated castor oil with a proper amount of absolute ethyl alcohol to obtain a second mixture;

evaporating the second mixture under reduced pressure to obtain a second paste;

mixing the second paste with ethylcellulose to obtain a second wet mixture;

uniformly mixing ethyl cellulose and povidone by using 80% ethanol solution to obtain a slow-release coating liquid;

coating the sustained-release micro tablet core by using the sustained-release coating liquid to obtain a sustained-release micro tablet with a sustained-release coating layer adhered on the surface of the sustained-release micro tablet core;

The preparation method of the samples of examples 1 to 5 is the same as that of the sample of example 6, and will not be described here again.

Test example 1: examination of the amount and types of fillers

In this test, the effect of the amount and type of the filler on the dissolution rate was examined using the formulation 6 of example 6 as a comparative formulation. The results of examination of the amount and type of filler are shown in FIG. 1. The specific examination is shown in table 7:

TABLE 7

FIG. 1 shows the dissolution results of immediate release microtablets in examination of the amount and type of filler, with the abscissa indicating the name of the prescription and the ordinate indicating the dissolution rate.

The present application attempts lactose and microcrystalline cellulose, respectively, when selecting fillers. When the prescription dosage of lactose is 0.8mg and 1.5mg, the dissolution rate of the quick-release micro tablets of the prescription 6-5 and the prescription 6-6 can not reach 85% in 45min, and the dissolution rate is not satisfactory. After the filling agent is changed from lactose to microcrystalline cellulose, when the prescription dosage of microcrystalline cellulose is 0.5mg and 0.8mg, the quick-release microchip of prescription 6 and prescription 6-3 can meet the requirement that the dissolution rate reaches 85% in 45 min. Therefore, the filler is selected to be microcrystalline cellulose.

Because the polyoxyethylene 40 hydrogenated castor oil is pasty, when the prescription dosage of the filling agent is less than 0.5mg, the filling agent dosage is less, and the sticking and flushing situations can occur during the preparation of the quick release micro tablets of the prescription 6-1 and the prescription 6-2, so that tabletting cannot be performed. When the dosage of the filler is more than 2mg, the dissolution rate of the prescription 6-4 at 45min is less than 85%, and the dissolution rate is not satisfactory. And when the prescription dosage of the filler is more than 1mg, the volume of the quick-release microchip is overlarge, so that the quick-release microchip and the slow-release microchip cannot be completely filled in the hard capsule body. When the prescription dosage of the filling agent is in the range of 0.5mg-1mg, the dissolution rate of the quick-release micro tablet can reach 85% in 45min, so that the prescription dosage of the filling agent is 0.5mg-1mg.

Test example 2: investigation of the amount and type of disintegrant

In this test, the effect of the amount and type of the disintegrant on the disintegration time was examined using the formulation 6 of example 6 as a comparative formulation. The results of examination of the disintegrants are shown in figure 2. Specific examination is shown in table 8:

TABLE 8

Fig. 2 shows the dissolution results of the immediate release micro-tablets in the examination of the amount and type of the disintegrating agent, wherein the abscissa indicates the prescription name and the ordinate indicates the dissolution rate.

When the disintegrating agent is selected, corn starch and sodium carboxymethyl starch are tried respectively, and when the prescription dosage of the corn starch is within 1.5mg and 1.25mg, the quick-release micro tablets of the prescription 6 and the prescription 6-10 can be completely disintegrated within 15min, so that the aim of quickly releasing the medicine in a short time can be fulfilled. When the filling agent is changed from corn starch to sodium carboxymethyl starch and the prescription dosage of the sodium carboxymethyl starch is 1.5mg, the quick-release micro tablets of the prescription 6-12 cannot be completely disintegrated within 15min, and the sodium carboxymethyl starch cannot realize quick release of the medicine within a short time.

The dosage of the disintegrating agent added in the quick-release micro tablets of the prescription 6-7, the prescription 6-8 and the prescription 6-9 is small, so that the disintegration time limit of the quick-release micro tablet is more than 15 minutes, which can lead to the quick-release micro tablet not being rapidly disintegrated, thereby affecting the drug release.

The immediate release micro-tablets of the prescription 6-11 can be completely disintegrated within 15min, but the immediate release micro-tablets have lower hardness and the tablets are fragile due to the excessive addition of the disintegrant.

In summary, since corn starch is not used in the prescription 6-7, when the prescription dosage of the prescription 6-8, the prescription 6-9 and the prescription 6-11 is respectively 0.25mg, 0.5mg and 2.5mg, the disintegration time limit or the tablet quality of the quick-release micro tablet are not satisfactory, so the prescription dosage of the disintegrating agent is 1mg-2mg.

Test example 3: inspection of the amount of multifunctional auxiliary Material

In the test, the effect of the dosage of the multifunctional auxiliary materials in the quick-release micro tablet and the slow-release micro tablet on dissolution is examined by taking the prescription 6 of the example 6 as a comparison prescription. The investigation results of the multifunctional auxiliary materials of the quick-release microchip are shown in fig. 3, and the specific investigation contents are shown in table 9. The investigation result of the multifunctional auxiliary materials in the sustained-release microchip is shown in fig. 4, and the specific investigation content is shown in table 10:

TABLE 9

Fig. 3 shows the cumulative dissolution of the immediate release microchip in the multifunctional adjuvant amount investigation, with time on the abscissa and the cumulative dissolution on the ordinate.

The dosage of the polyoxyethylene 40 hydrogenated castor oil in the quick-release micro tablets of the prescription 6-13 and the prescription 6-14 is respectively 0mg and 2.5mg, and because the dosage of the polyoxyethylene 40 hydrogenated castor oil in the prescription is less, the polyoxyethylene 40 hydrogenated castor oil can not wrap all the dicyclo alcohol into nano-scale small particles when the quick-release micro tablets are prepared, so that the accumulated dissolution rate of the two prescriptions at 45min still can not reach more than 80%, the dissolution speed is lower, and the drug absorption is affected.

The dosage of polyoxyethylene 40 hydrogenated castor oil in the immediate release micro-tablets of prescription 6-15, prescription 6 and prescription 6-16 is 3.5mg, 4mg and 6mg respectively. As shown in fig. 3, the immediate release microchip of prescription 6 and prescription 6-16 can have a cumulative dissolution rate of 85% or more at 45min, and the immediate release microchip of prescription 6-15 can have a uniform dissolution rate although the dissolution rate is slow in the early stage, and the cumulative dissolution rate of 85% or more at 45 min. Therefore, prescriptions 6-15, 6 and 6-16 can meet the drug release requirements without affecting drug absorption.

The dosage of the polyoxyethylene 40 hydrogenated castor oil in the quick-release micro tablet of the prescription 6-17 is 7.5mg, and the dosage is more, so that the condition of sticky materials during tabletting is caused, and the tabletting effect is poor.

In summary, the prescription dosage of the polyoxyethylene 40 hydrogenated castor oil in the immediate-release micro tablet is 3.5mg-6mg.

Table 10

Fig. 4 shows the cumulative dissolution rate of the sustained-release microchip in the multifunctional adjuvant amount investigation, wherein the abscissa represents time, and the ordinate represents the cumulative dissolution rate.

The dosage of the polyoxyethylene 40 hydrogenated castor oil in the sustained-release micro-tablets of the prescription 6-18 and the prescription 6-19 is 0mg and 1mg respectively, and the polyoxyethylene 40 hydrogenated castor oil in the prescription has small dosage, so that all the dicyclo alcohol cannot be wrapped into nano-scale small particles when the sustained-release micro-tablets are prepared, and the dicyclo alcohol particles are uneven in size. From the error bars in fig. 4, it can be seen that the data between each time point is greatly different and the dissolution rate is greatly different. In conclusion, due to the uneven particle size of the bicyclo-ethanol, the accumulated dissolution rate of the prescription 6-18 and the prescription 6-19 at 45min is lower than 70%, and the dissolution speed is low, so that the drug absorption is affected.

The dosage of polyoxyethylene 40 hydrogenated castor oil in the sustained-release micro-tablets of prescription 6-20, prescription 6 and prescription 6-21 is 2.5mg, 3.25mg and 3.5mg respectively. As shown in fig. 4, the sustained-release micro tablets of the prescription 6-20, the prescription 6 and the prescription 6-21 can reach over 85% of accumulated dissolution rate at 12h, and can release medicine slowly at uniform speed, thereby achieving the purpose of sustained release. Therefore, prescription 6-20, prescription 6-21 can meet the drug release requirement without affecting drug absorption.

The dosage of the polyoxyethylene 40 hydrogenated castor oil in the sustained-release microchip of the prescription 6-22 is 5mg, and the dosage is more, so that the material is sticky and rushed during tabletting, and the tabletting effect is poor. And the accumulated dissolution rate at 6 hours is about 80%, so that the medicine cannot be released for a long time and the aim of slow release cannot be achieved.

In summary, the prescription dosage of the polyoxyethylene 40 hydrogenated castor oil in the sustained-release microchip is set to be 2.5mg-3.5mg.

Test example 4: investigation of the amount and type of sustained-release matrix

In the test, the formulation 6 of example 6 is taken as a comparison formulation, the dissolution effect is examined according to the amount and type of the slow-release skeleton, the examination result is shown in fig. 5, and the specific examination contents are shown in table 11:

TABLE 11

FIG. 5 shows the results of examining the amount and type of the slow-release matrix, wherein the abscissa represents time and the ordinate represents the cumulative dissolution rate.

In the present application, methylcellulose and ethylcellulose were tried separately in selecting a slow-release matrix in a slow-release microchip. When the dosage of the methylcellulose is 3mg and 5.5mg, the accumulated dissolution rate of the prescription 6-27 and the prescription 6-28 is about 80% in 8 hours, the drug release is relatively quick, and the slow release purpose cannot be met.

When methylcellulose is removed from the sustained-release microchip and no sustained-release skeleton is added, the prepared sustained-release microchip has an accumulated dissolution rate of more than 90% at 6h as shown in the prescription 6-23 of fig. 5, and the drug release speed is too high to meet the purpose of stably and slowly releasing the drug.

When the methyl cellulose in the sustained-release microchip is replaced by ethyl cellulose, the prescription dosage of the ethyl cellulose is 2.5mg, 3mg and 4.5mg respectively. As shown in fig. 5, the sustained-release micro tablets of prescription 6-24, prescription 6 and prescription 6-25 can release the medicine slowly and uniformly, and the accumulated dissolution rate reaches more than 90% in 12 hours, so that the sustained-release purpose can be realized.

When the prescription dosage of the ethylcellulose in the sustained-release microchip is 5.5mg, the dosage of the sustained-release skeleton is excessive, the accumulated dissolution rate of the prescription 6-26 is about 60% when 12h, and the drug release is too slow to meet the sustained-release requirement.

In summary, the slow release skeleton of the application is selected as ethylcellulose, and the dosage of the prescription is 2.5mg-4.5mg.

Test example 5: investigation of the amount and type of coating layer

In this test, the effect of the amount and type of the coating layer on dissolution was examined using the formulation 6 of example 6 as a comparative formulation, the examination results are shown in fig. 6, and the specific examination contents are shown in table 12:

table 12

FIG. 6 shows the results of examining the amount and type of coating layer, the abscissa represents time, and the ordinate represents the cumulative dissolution rate.

In the application, when a coating layer of a sustained-release micro tablet is selected, ethyl cellulose, a combination of ethyl cellulose and povidone K30, povidone K30 and hydroxypropyl methyl cellulose are respectively tried.

As can be seen from FIG. 6, the cumulative dissolution rate of the samples of prescription 6 (0.3 mg of ethyl cellulose, 0.25mg of povidone K30), prescription 6-30 (0.3 mg of ethyl cellulose, 0.5mg of povidone K30) and prescription 6-33 (0.3 mg of ethyl cellulose, 0.25mg of povidone K30) at 12 hours was about 90% or more, and the requirement of slow drug release could be met.

As can be seen from FIG. 6, the samples of prescriptions 6-29 and 6-31 have a cumulative dissolution rate of about 90% at 8 hours, and the drug release rate is high, which cannot meet the slow release requirement.

As can be seen from FIG. 6, the samples of prescriptions 6-35 and 6-36 have relatively high accumulated dissolution rate in the first 4 hours and release slowly in the 4 th-10 hours, but the accumulated dissolution rate in the 10 th is about 90%, so that the overall drug release rate is relatively high, and the slow release requirement cannot be met.

As can be seen from FIG. 6, the samples of formulas 6-32 had a faster cumulative dissolution rate than that of formula 6 for the first 4 hours, but the drug release rate was reduced after 4 hours, and the cumulative dissolution rate was about 80% at 12 hours, with a slower overall drug release rate. The samples of the prescriptions 6-34 can release the medicine at a constant speed in the first 6 hours, but the medicine release speed is reduced after 6 hours, the accumulated dissolution rate is about 80% in 12 hours, and the overall medicine release speed is lower, so that the requirement of uniformly and slowly releasing the medicine can not be met.

In conclusion, the use amount of the hydroxypropyl methylcellulose is within the range of 0.5mg to 0.75mg, and the slow release requirement cannot be met. Either povidone K30 alone or ethylcellulose alone cannot meet the slow release requirements. The dosage of the ethyl cellulose is 0.25mg-0.45mg, and the dosage of the povidone K30 is 0.25mg, so that the slow release requirement can be met, and the coating layer of the application adopts the combination of the ethyl cellulose and the povidone K30.

Test example 6: particle size investigation

FIG. 7 is a graph of the particle size distribution of a bicyclol on a nano scale, with diameter on the abscissa and percentage on the ordinate.

FIG. 8 is a graph showing the particle size distribution of micronized bicyclol with diameter on the abscissa and percentage on the ordinate. It can be seen that the particle size of the micronized bicyclic alcohol can only reach 1000nm, exceeding the micron level.

The bicyclo-ethanol in fig. 7 is prepared by the method of the present application, that is, dissolving the bicyclo-ethanol and polyoxyethylene 40 hydrogenated castor oil with an appropriate amount of absolute ethanol can make the bicyclo-ethanol and polyoxyethylene 40 hydrogenated castor oil uniformly distributed in the absolute ethanol, and the particle size of the bicyclo-ethanol can be in nano scale. Because the polyoxyethylene 40 hydrogenated castor oil is pasty, the polyoxyethylene 40 hydrogenated castor oil can wrap nano-scale bicyclic alcohol while removing the redundant solvent of absolute ethyl alcohol through decompression evaporation treatment. The particle size of the treated bicyclo-alcohol becomes smaller and more uniform, which can lead to better solubility, as can be seen from figure 4. As can be seen from fig. 4, the amount of the polyoxyethylene 40 hydrogenated castor oil has a large influence on dissolution, and when the amount is small, the polyoxyethylene 40 hydrogenated castor oil cannot completely encapsulate the bicyclic alcohol and cannot form nano particles, so that the dissolution is slow; and the particle size of the dicyclo alcohol is uneven, the error line is larger, the dissolution is uneven, and the requirement of uniform and slow release cannot be met. When the amount of the polyoxyethylene 40 hydrogenated castor oil is large, the dissolution rate is too high, so that the aim of slow release cannot be achieved. Thus, the present application prescribes a polyoxyethylene 40 hydrogenated castor oil in an amount of 2.5mg to 3.5mg.

In conclusion, the particle size of the dicyclo alcohol treated by the absolute ethyl alcohol and the polyoxyethylene 40 hydrogenated castor oil is about ten nanometers, and the particle size of the dicyclo alcohol treated by micronization is in the micron order, which are different by hundred times, so that the nanoscale structural basis has better uniformity and release efficiency.

Test example 7: pharmacodynamic investigation

FIG. 9 is a graph of blood concentration of commercially available bicyclol tablets and samples of prescription 6.

As can be seen from fig. 9, the commercially available bicyclo-ethanol tablet reached the maximum drug concentration at about 3 hours, followed by a gradual decrease in drug concentration.

The sample of prescription 6 includes immediate release microtablets and sustained release microtablets, which are rapidly released in a short time, so it can be seen from fig. 9 that the sample of prescription 6 can reach a maximum drug concentration approaching that of the commercial bicyclic alcohol tablet at 0.5 h. The slow release micro tablet starts to release after the quick release micro tablet finishes releasing the medicine, and the blood concentration can be reduced temporarily. However, with the drug release of the sustained-release mini-tablets, the blood concentration increased again at 4 hours and then decreased slowly.

In summary, the overall decrease rate of drug concentration in the sample of prescription 6 is slower than that of the bicyclo-ethanol tablet, so that a higher blood level of drug concentration can be maintained for a longer period of time.

It should also be noted that the term "comprises," "comprising," or any other variation thereof is intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising at least one of the elements" does not exclude the presence of additional identical elements in a process, method, article or apparatus that comprises the element.

In this specification, each embodiment is described in a progressive manner, and identical and similar parts of each embodiment are all referred to each other, and each embodiment mainly describes differences from other embodiments.

Finally, it should be noted that the foregoing description is only an example of the present application, and is merely for illustrating the technical solution of the present invention, not for limiting the present application. Various modifications and changes may be made to the present application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc. which are within the spirit and principles of the present application are intended to be included within the scope of the claims of the present application.

Claims

1. A bicyclol solid formulation comprising:

the quick-release micro tablet comprises the following components in parts by mass: 1 part of bicyclo-ethanol, 0.1-0.16 part of filler, 0.25-0.3 part of disintegrating agent and 0.7-1.2 parts of multifunctional auxiliary materials for improving the solubility of the bicyclo-ethanol;

the sustained-release microchip tablet core comprises: 1 part of bicyclo-ethanol, 0.5-0.9 part of slow-release framework and 0.5-0.7 part of multifunctional auxiliary materials;

the filler is as follows: microcrystalline cellulose;

the disintegrant comprises: corn starch;

the multifunctional auxiliary material is polyoxyethylene 40 hydrogenated castor oil;

the slow-release framework is ethyl cellulose;

the slow-release coating layer comprises the following components in parts by mass: 0.05-0.09 part of ethyl cellulose and 0.05 part of povidone K.

2. The solid formulation of claim 1, wherein the solid formulation comprises a bicyclic alcohol,

each of the quick-release micro tablets and the slow-release micro tablets contains 5mg of dicyclo alcohol.

3. The solid preparation of bicyclol according to claim 1 or 2, characterized in that,

the proportion of the quick release micro tablet to the slow release micro tablet in each hard capsule body is 1:2.

4. a process for the preparation of a solid formulation of a bicyclol as claimed in any one of claims 1 to 3,

the quick-release micro tablet is prepared by the following components in parts by mass:

mixing the first paste, 0.25-0.3 part of disintegrant and 0.1-0.16 part of filler to obtain a first wet mixture;

the sustained-release micro tablet is prepared by the following components in parts by mass:

mixing the second paste with 0.5-0.9 part of slow-release framework to obtain a second wet mixture;

preparing a slow-release coating liquid;