CN115844856A

CN115844856A - Bicyclol solid preparation and preparation method thereof

Info

Publication number: CN115844856A
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: 2023-03-28
Anticipated expiration: 2043-01-06
Also published as: CN115844856B

Abstract

The embodiment of the application provides a bicyclol solid preparation and a preparation method thereof, wherein a quick-release micro-tablet and a sustained-release micro-tablet are both filled in a capsule cavity of a hard capsule body; the quick-release micro-tablet comprises the following components: bicyclol, a filling agent, a disintegrating agent and a multifunctional auxiliary material for improving the solubility of bicyclol; the sustained-release micro-tablet comprises the following components: a sustained-release coating layer which is used for adhering to the surface of the sustained-release micro-tablet core; the sustained release micro-tablet core comprises: bicyclol, a slow release skeleton and multifunctional auxiliary materials. The application provides a dicyclic alcohol solid preparation can reach the treatment window in the short time through quick release micro-tablet, realizes quick onset, reduces the patient because of the purpose of the uncomfortable sense that the disease produced. And the sustained-release mini-tablets are combined for use, so that the blood concentration of the bicyclol is controlled within a treatment window, and the treatment time of the medicament is prolonged to the greatest extent, thereby improving the treatment effect.

Description

Bicyclol solid preparation and preparation method thereof

Technical Field

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

Background

The aminotransferase can participate in the decomposition and synthesis of amino acids in human body, and is an essential 'catalyst' in the metabolic process of human body. Aminotransferases are mainly present in hepatocytes, and when the hepatocytes suffer from inflammation, necrosis, poisoning, etc., causing damage to the hepatocytes, the aminotransferases are released into the blood, which increases serum aminotransferases.

The existing medicine for treating the increase of aminotransferase caused by chronic hepatitis is a bicyclol tablet, and the preparation is an oral sustained-release preparation, and the blood concentration is difficult to control. That is, the maximum plasma concentration of the drug that can be reached within a certain time is above the therapeutic window; subsequently, the blood concentration drops rapidly below the therapeutic window for a short period of time, resulting in limited therapeutic efficacy.

Disclosure of Invention

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

In order to achieve the purpose, the technical scheme is as follows:

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

the capsule comprises a hard capsule body, at least one quick release micro-tablet and at least one sustained release micro-tablet, wherein each quick release micro-tablet and each sustained release micro-tablet 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 bicyclol, 0.1-0.2 part of filler, 0.2-0.4 part of disintegrant and 0.7-1.2 parts of multifunctional auxiliary material for improving the solubility of bicyclol;

the sustained-release micro-tablet comprises the following components in parts by mass: a sustained-release coating layer which is used for adhering to the surface of the sustained-release micro-tablet core;

the sustained release micro tablet core comprises: 1 part of bicyclol, 0.5-1.3 parts of slow-release skeleton and 0.5-0.7 part of multifunctional auxiliary material.

0.1 to 0.2 means any value in 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, in terms of parts by mass of the filler.

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 for parts by mass of the disintegrant.

0.7 to 1.2 means any value in the range of 0.7 to 1.2, for example, 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, 1.2 in terms of mass parts of the multifunctional excipient in the immediate release mini-tablet.

0.5 to 1.3 means any value in the range of 0.5 to 1.3, for example, 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, in terms of mass parts of the sustained-release matrix.

0.5 to 0.7 means any value in the range of 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, in terms of parts by mass of the multifunctional excipient in the sustained-release mini-tablet.

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-tablets and the slow-release micro-tablets to improve the solubility of the bicyclol, so that the drug release of the bicyclol is quicker, and the aim of improving the bioavailability is fulfilled.

Preferably, the slow release matrix 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 quick release micro tablet and each sustained release micro tablet contain 5mg of bicyclol.

Preferably, the proportion of the quick release micro-tablets to the slow release micro-tablets in each hard capsule body is 1:2.

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

In a second aspect, the present application provides a method for preparing a bicyclol solid preparation as shown in the first aspect, which specifically comprises:

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

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

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

mixing the first paste, 0.2-0.4 part of disintegrant and 0.1-0.2 part of filler to obtain a first wet mixture;

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

Specifically, in order to increase the solubility of bicyclol in the quick-release mini-tablets, anhydrous ethanol is firstly used as a solvent for dissolution treatment to obtain a first mixture of bicyclol and multifunctional auxiliary materials in a liquid form. And (3) carrying out reduced pressure evaporation treatment on the first mixture at the temperature of 40-50 ℃, and removing the absolute ethyl alcohol from the first mixture to obtain a first paste with the outer surface of the nano-scale bicyclol wrapped with the multifunctional auxiliary material. And uniformly mixing the first paste, the disintegrating agent and the filler, and then drying and tabletting to obtain the quick-release micro-tablets.

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

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

carrying out 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 skeleton to obtain a second wet mixture;

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

preparing a slow-release coating solution;

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

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

Specifically, in order to increase the solubility of bicyclol in the sustained-release micro-tablets, firstly absolute ethyl alcohol is used as a solvent to dissolve bicyclol and multifunctional auxiliary materials 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 the absolute ethyl alcohol in the second mixture and wrap the multifunctional auxiliary material on the outer surface of the nano-scale bicyclol to obtain a second paste. And mixing the second paste with the slow release skeleton to coat the slow release skeleton on the outer surface of the multifunctional auxiliary material, so as to reduce the dissolving speed of the bicyclol and control the drug release rate of the slow release micro-tablets. And drying and tabletting to obtain the sustained-release micro-tablet core. And finally, coating a coating layer on the outer surface of the tablet core of the sustained-release micro-tablet to obtain the sustained-release micro-tablet.

It is understood that the temperature at which the first mixture and the second mixture are evaporated under reduced pressure is 40 ℃ to 50 ℃ and any value in the range of 40 ℃ to 50 ℃ is meant, for example, 40 ℃, 42 ℃, 43 ℃, 44 ℃, 45 ℃, 46 ℃, 47 ℃, 48 ℃, 49 ℃ and 50 ℃.

When the sustained-release coating solution is prepared, ethyl cellulose and povidone are dissolved by using 80-100% ethanol solution to obtain the sustained-release coating solution with sufficient dissolution. With respect to the content of ethanol, 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 sustained-release coating liquid is coated on the outer surface of the sustained-release micro-tablet core, the liquid in the sustained-release coating liquid can volatilize, and the solid material in the sustained-release coating liquid can form the sustained-release coating layer on the outer surface of the sustained-release micro-tablet core.

Preferably, the disintegrant is corn starch.

Preferably, the filler is microcrystalline cellulose.

Preferably, the slow release matrix is ethyl cellulose.

According to the technical scheme, the application provides a bicyclol solid preparation and a preparation method thereof. The solid dicyclic alcohol preparation consists of fast releasing micro tablet and slow releasing micro tablet filled inside hard capsule. Wherein the quick-release micro-tablet consists of bicyclol, a filling agent, a disintegrating agent and a multifunctional auxiliary material. The sustained-release micro-tablet comprises a sustained-release micro-tablet core consisting of bicyclol, a sustained-release framework and a multifunctional auxiliary material, and a sustained-release coating layer adhered to the surface of the sustained-release micro-tablet core. Compared with the existing normal-release bicyclol tablets, the bicyclol solid preparation can achieve a treatment window in a short time through the quick-release micro-tablets, achieves the purposes of quickly taking effect and reducing discomfort of patients caused by diseases. And the sustained-release mini-tablets are combined for use, so that the blood concentration of the bicyclol is controlled within a treatment window, and the treatment time of the medicament is prolonged to the greatest extent, thereby improving the treatment effect.

Drawings

In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings needed to be used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present application, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.

FIG. 1 shows the results of examining the amount and type of a filler provided in test example 1 of the present application;

FIG. 2 shows the results of examining the amount and type of the disintegrant used in test example 2 of the present application;

FIG. 3 shows the results of examining the amount of a multifunctional excipient used in an immediate release mini-tablet provided in test example 3 of the present application;

FIG. 4 is a result of examining the amount of the multifunctional excipient in the sustained-release mini-tablet provided in test example 3 of the present application;

FIG. 5 shows the results of investigation of the amount and type of sustained-release matrix provided in test example 4 of the present application;

FIG. 6 is a result of investigation of the amount and kind of the coating layer provided in test example 5 of the present application;

FIG. 7 is a graph showing the particle size distribution of bicyclol at the nanometer scale as provided in test example 6 of the present application;

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

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

Detailed Description

In order to make those skilled in the art better understand the technical solutions in the embodiments of the present application, the technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all embodiments. All other embodiments obtained by a person of ordinary skill in the art based on the embodiments provided in the present application shall fall within the scope of protection of the embodiments of the present application.

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

Example 1

(1) Formula 1 of a bicyclic alcohol solid preparation is shown in the following table 1 in parts by mass:

TABLE 1

Example 2

(1) Formula 2 of a bicyclic alcohol solid preparation is shown in the following table 2 in parts by mass:

TABLE 2

Example 3

(1) Formula 3 of a bicyclol solid preparation is shown in the following table 3 in parts by mass:

TABLE 3

Example 4

(1) Formula 4 of a bicyclol solid preparation is shown in the following table 4 in parts by mass:

TABLE 4

Example 5

(1) Formula 5 of a bicyclic alcohol solid preparation is shown in the following table 5 in parts by mass:

TABLE 5

Example 6

(1) Formula 6 of a bicyclic alcohol solid preparation is shown in the following table 6 in parts by mass:

TABLE 6

Example 6 the samples were prepared as follows:

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

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

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

dissolving bicyclol and polyoxyethylene 40 hydrogenated castor oil with an appropriate amount of absolute ethanol to obtain a second mixture;

mixing the second paste with ethyl cellulose to obtain a second wet mixture;

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

coating the sustained-release micro-tablet core by using the sustained-release coating solution 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 the preparation principle of the sample of example 6, and is not described herein again.

Test example 1: examination of the amount and type of filler

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

TABLE 7

FIG. 1 shows the dissolution results of the immediate release mini-tablets in the investigation of the amount and type of the filler, with the abscissa representing the prescription name and the ordinate representing the dissolution rate.

In selecting the filler, the present application tried lactose and microcrystalline cellulose, respectively. When the dosage of the prescription 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 is not 85% in 45min, and the dissolution rate is not satisfactory. After the filling agent is replaced by microcrystalline cellulose from lactose, when the dosage of the prescription of the microcrystalline cellulose is 0.5mg and 0.8mg, the quick-release micro-tablets of the prescription 6 and the prescription 6-3 can meet the requirement that the dissolution rate reaches 85% in 45 min. Thus, the filler is selected to be microcrystalline cellulose.

Because the polyoxyethylene 40 hydrogenated castor oil is a paste, when the dosage of the prescription of the filler is less than 0.5mg, the dosage of the filler is less, and the sticky and sticky condition can occur when the quick-release micro-tablets of the prescription 6-1 and the prescription 6-2 are prepared, so that the tabletting can not be carried out. When the dosage of the filler is more than 2mg, the dissolution rate of the prescription 6-4 in 45min does not reach 85 percent, and the dissolution rate does not meet the requirement. And when the dosage of the prescription of the filler is more than 1mg, the volume of the quick-release micro-tablets is too large, so that the quick-release micro-tablets and the slow-release micro-tablets cannot be completely filled in the hard capsule body. When the dosage of the prescription of the filler is within the range of 0.5mg to 1mg, the dissolution rate of the quick-release micro-tablets can reach 85 percent in 45min, so the dosage of the prescription of the filler is defined as 0.5mg to 1mg.

Test example 2: examination of amount and type of disintegrant

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

TABLE 8

FIG. 2 shows the dissolution results of the immediate release mini-tablets in the study of the amount and type of disintegrant, the abscissa shows the name of the prescription, and the ordinate shows the dissolution rate.

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

The dosage of the disintegrant added in the quick-release micro-tablets of the prescriptions 6-7, 6-8 and 6-9 is less, so that the disintegration time of the quick-release micro-tablets is more than 15min, which can cause the quick-release micro-tablets not to be quickly disintegrated, thereby influencing the release of the medicine.

Although the quick release micro-tablets in the formulas 6 to 11 can be completely disintegrated within 15min, the quick release micro-tablets are easy to have lower hardness and are easy to be broken because of the excessive addition of the disintegrant.

In conclusion, because the corn starch is not used in the prescription 6-7, and the 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-tablets do not meet the requirements, the dosage of the prescription of the disintegrant is determined to be 1mg-2mg.

Test example 3: investigation of the amount of multifunctional adjuvants

In this test, the effect of the amount of the multifunctional excipient in the immediate release mini-tablets and the sustained release mini-tablets on dissolution was examined by using the formulation 6 of example 6 as a comparative formulation. The examination results of the multifunctional excipient for immediate release mini-tablets are shown in fig. 3, and the details thereof are shown in table 9. The examination result of the multifunctional auxiliary materials in the sustained-release micro-tablets is shown in fig. 4, and the specific examination contents are shown in table 10:

TABLE 9

FIG. 3 shows the cumulative dissolution rate of the immediate release mini-tablets in the dosage test of the multifunctional auxiliary materials, the abscissa is time, and the ordinate is the cumulative dissolution rate.

The dosage of the polyoxyethylene 40 hydrogenated castor oil in the quick-release microtablets of the prescriptions 6-13 and 6-14 is 0mg and 2.5mg respectively, and because the dosage of the polyoxyethylene 40 hydrogenated castor oil in the prescriptions is less, all the bicyclol cannot be wrapped into nano-scale small particles by the polyoxyethylene 40 hydrogenated castor oil when the quick-release microtablets are prepared, so that the cumulative dissolution rate of the two prescriptions in 45min is still less than 80%, the dissolution rate is slow, and the drug absorption is influenced.

The dosage of the polyoxyethylene 40 hydrogenated castor oil in the quick-release micro-tablets with the prescriptions 6-15, 6 and 6-16 is 3.5mg, 4mg and 6mg respectively. As shown in FIG. 3, the quick release mini-tablets of formula 6 and formula 6-16 have a cumulative dissolution rate of 85% or more at 45min, while the formulations 6-15 have a slow dissolution rate at the early stage, but have a uniform dissolution rate, and have a cumulative dissolution rate of 85% or more at 45 min. Therefore, the prescriptions 6-15, 6 and 16 can meet the drug release requirement without influencing the drug absorption.

The dosage of the polyoxyethylene 40 hydrogenated castor oil in the quick-release micro-tablets with the formulas 6 to 17 is 7.5mg, and the dosage is more, so that the situation that materials are sticky and flushed during tabletting is caused, and the tabletting effect is poor.

In conclusion, the dosage of the prescription of the polyoxyethylene 40 hydrogenated castor oil in the quick-release micro-tablets is 3.5mg-6mg.

Watch 10

Fig. 4 shows the cumulative dissolution of the sustained-release micro-tablets in the dosage study of the multifunctional auxiliary materials, wherein the abscissa is time and the ordinate is the cumulative dissolution.

The dosage of the polyoxyethylene 40 hydrogenated castor oil in the sustained-release microtablets of the formulas 6-18 and 6-19 is 0mg and 1mg respectively, and the dosage of the polyoxyethylene 40 hydrogenated castor oil in the formulas is less, so that all the bicyclol cannot be wrapped into nano-scale small particles by the polyoxyethylene 40 hydrogenated castor oil when the sustained-release microtablets are prepared, and the bicyclol particles are not uniform in size. The data between each time point is more different and the dissolution rate is more different as can be seen from the error bars in fig. 4. In conclusion, the non-uniform particle size of the bicyclol finally results in that the cumulative dissolution rate of the formulas 6-18 and 6-19 in 45min is lower than 70%, and the dissolution rate is slow, so that the drug absorption is influenced.

The dosage of the polyoxyethylene 40 hydrogenated castor oil in the sustained-release microtablets with the prescriptions 6-20, 6 and 21 is respectively 2.5mg, 3.25mg and 3.5mg. As shown in figure 4, the slow release micro tablets of the prescription 6-20, the prescription 6 and the prescription 6-21 can achieve the cumulative dissolution rate of more than 85% in 12 hours, and can slowly release the medicine at a uniform speed to achieve the purpose of slow release. Therefore, the prescriptions 6-20, 6 and 21 can meet the drug release requirements without affecting drug absorption.

The dosage of the polyoxyethylene 40 hydrogenated castor oil in the sustained-release micro-tablets with the formulas 6-22 is 5mg, and the dosage is more, so that the situation that materials are sticky and flushed during tabletting is caused, and the tabletting effect is poor. And the accumulated dissolution rate at 6h is about 80%, so that the medicament cannot be released for a long time and the aim of slow release cannot be fulfilled.

In conclusion, the dosage of the polyoxyethylene 40 hydrogenated castor oil in the sustained-release micro-tablets is determined to be 2.5mg-3.5mg.

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

In this test, the effect of dissolution on the amount and type of sustained-release matrix was examined by using the formulation 6 of example 6 as a comparative formulation, and the results are shown in fig. 5, and the details are shown in table 11:

TABLE 11

Fig. 5 shows the results of the dose and species investigation of the sustained-release matrix, with the abscissa representing time and the ordinate representing the cumulative dissolution rate.

In selecting a sustained release matrix in a sustained release mini-tablet, the present application has tried methylcellulose and ethylcellulose, respectively. When the dosage of the methylcellulose is 3mg and 5.5mg, the cumulative dissolution rates of the prescriptions 6-27 and 6-28 are about 80% in 8 hours, the drug release is relatively fast, and the slow release purpose cannot be met.

When methyl cellulose is removed from the sustained-release micro-tablets and no sustained-release skeleton is added, the prepared sustained-release micro-tablets have the accumulated dissolution rate of over 90 percent in 6 hours as shown in the prescription 6-23 of fig. 5, and the drug release speed is too high, so that the aim of stably and slowly releasing the drug cannot be fulfilled.

When the methyl cellulose in the sustained-release micro-tablets is replaced by ethyl cellulose, the dosage of the ethyl cellulose is respectively 2.5mg, 3mg and 4.5mg. As shown in figure 5, the slow release micro tablets of the prescription 6-24, the prescription 6 and the prescription 6-25 can slowly release the medicine at a uniform speed, and the cumulative dissolution rate reaches over 90 percent in 12 hours, so that the slow release purpose can be realized.

When the prescription dosage of the ethyl cellulose in the sustained-release micro-tablets is 5.5mg, the dosage of the sustained-release skeleton is too much, the cumulative dissolution rate of the prescription 6-26 is about 60% in 12 hours, and the drug release is too slow, so that the sustained-release requirement cannot be met.

In conclusion, the slow-release matrix of the application is selected from ethyl cellulose, and the dosage of the prescription is positioned at 2.5mg-4.5mg.

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

The test was conducted by taking formulation 6 of example 6 as a comparative formulation and examining the influence of the amount and type of the coating layer on the dissolution, and the results are shown in fig. 6, and the details are shown in table 12:

TABLE 12

FIG. 6 shows the results of the dose and species investigation of the coating layer, with time on the abscissa and the cumulative dissolution on the ordinate.

In the application, when the coating layer of the sustained-release micro-tablet is selected, ethyl cellulose, the 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 the formulas 6 (0.3 mg of ethylcellulose and 0.25mg of povidone K30), 6-30 (0.3 mg of ethylcellulose and 0.5mg of povidone K30) and 6-33 (0.3 mg of ethylcellulose and 0.25mg of povidone K30) in 12 hours is about 90% or more, which can meet the requirement of slow release of the drug.

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

As can be seen from FIG. 6, the cumulative dissolution rates of the samples of formulas 6 to 35 and 6 to 36 are relatively high in the first 4h and are relatively slow to release in the 4h to 10h, but the cumulative dissolution rate in 10h is about 90%, and the total drug release rate is relatively fast, so that the requirement of slow release cannot be met.

As can be seen from FIG. 6, the cumulative dissolution rate of the formulations 6-32 was faster than that of the formulation 6 in the first 4h, but the drug release rate decreased after 4h, and the cumulative dissolution rate was about 80% at 12h, and the overall drug release rate was slower. While the samples of the prescriptions 6-34 can release the drug at a constant speed in the first 6h, but the drug release speed is reduced after 6h, the cumulative dissolution rate in 12h is about 80%, the total drug release speed is slow, and the requirement of uniformly and slowly releasing the drug cannot be met.

In conclusion, the dosage of the hydroxypropyl methylcellulose is within the range of 0.5mg to 0.75mg, which cannot meet the requirement of slow release. The requirement of slow release cannot be met by only using the povidone K30 or only using the ethyl cellulose. And when the dosage of the ethyl cellulose is 0.25mg-0.45mg and the dosage of the povidone K30 is 0.25mg, the sustained release requirement can be met, so that the coating layer of the application is used by combining the ethyl cellulose and the povidone K30.

Test example 6: investigation of particle size

Fig. 7 is a graph of the particle size distribution of nano-sized bicyclol, on the abscissa, diameter and on the ordinate, percentage.

Figure 8 is a particle size distribution plot of micronized bicyclol on the abscissa for diameter and on the ordinate for percentage. It can be seen that the particle size of the micronized bicyclol is only up to 1000nm, in excess of the micron level.

The bicyclol in fig. 7 is prepared by the preparation method of the present application, that is, bicyclol and polyoxyethylene 40 hydrogenated castor oil are dissolved by using a proper amount of absolute ethanol, so that bicyclol and polyoxyethylene 40 hydrogenated castor oil can be uniformly distributed in the absolute ethanol, and the particle size of bicyclol can be in a nanometer level. Because the polyoxyethylene 40 hydrogenated castor oil is paste, the polyoxyethylene 40 hydrogenated castor oil can wrap the nano-level bicyclol while removing the excessive solvent 'absolute ethyl alcohol' through reduced pressure evaporation treatment. The particle size of the treated bicyclol becomes smaller and more uniform, which can make the bicyclol more soluble, and the conclusion can be drawn from fig. 4. As can also be seen from fig. 4, the amount of polyoxyethylene 40 hydrogenated castor oil has a large effect on dissolution, and when the amount is small, bicyclol cannot be completely wrapped, and nanoparticles cannot be formed, so that the dissolution is slow; and the bicyclol has uneven particle size, larger error line and uneven dissolution, so that the requirement of uniform and slow release cannot be met. When the amount of the polyoxyethylene 40 hydrogenated castor oil is large, the dissolution speed is too high, and the purpose of slow release cannot be achieved. Accordingly, the present application prescribes polyoxyethylene 40 hydrogenated castor oil in an amount of 2.5mg to 3.5mg.

In conclusion, the particle size of the bicyclol treated by the absolute ethyl alcohol and the polyoxyethylene 40 hydrogenated castor oil is about ten nanometers, while the particle size of the bicyclol treated by micronization is in a micron scale, which is hundreds of times different from the micron scale, and the nanometer-scale structural foundation has better uniformity and release efficiency.

Test example 7: pharmacodynamic examination

Fig. 9 is a graph of blood concentration of a commercial bicyclic alcohol tablet and prescription 6 sample.

As can be seen in fig. 9, the commercial bicyclic alcohol tablet reached a maximum drug concentration at about 3h, followed by a gradual decrease in drug concentration.

The formulation 6 sample comprises an immediate release micro-tablet and a slow release micro-tablet, the immediate release micro-tablet can be rapidly released in a short time, so that the formulation 6 sample can reach the highest drug concentration close to that of the commercial bicyclic alcohol tablet at 0.5h as can be seen from fig. 9. With the completion of the release of the quick-release mini tablet, the slow-release mini tablet starts to be released, and the blood concentration is momentarily reduced. But with the drug release of the sustained-release micro-tablets, the blood drug level rises again at 4h and then slowly decreases.

In summary, the drug concentration of the formulation 6 was generally reduced more slowly than that of the bicyclic alcohol tablet, so that high blood levels could 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 described by the phrase "comprising at least one of", does not exclude the presence of other identical elements in the process, method, article of manufacture, or apparatus that comprises the element.

The embodiments in the present specification are described in a progressive manner, and the same and similar parts among the embodiments are referred to each other, and each embodiment focuses on the differences from the other embodiments.

Finally, the above description is only an example of the present application, and is only used to illustrate the technical solution of the present invention, and is not used to limit the present application. Various modifications and changes may occur to those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the scope of the claims of the present application.

Claims

1. A bicyclol solid formulation comprising:

the sustained release micro-tablet core comprises: 1 part of bicyclol, 0.5-1.3 parts of slow release skeleton and 0.5-0.7 part of multifunctional auxiliary material.

2. The bicyclic alcohol solid preparation according to claim 1, wherein,

the filler is as follows: microcrystalline cellulose.

3. The bicyclic alcohol solid preparation according to claim 1, wherein,

the disintegrating agent comprises: corn starch.

4. The bicyclic alcohol solid preparation according to claim 1, wherein,

the multifunctional auxiliary material is polyoxyethylene 40 hydrogenated castor oil.

5. The solid bicyclic alcohol formulation as claimed in claim 1, wherein,

the slow release skeleton is ethyl cellulose.

6. The bicyclic alcohol solid preparation according to claim 1, wherein,

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.

7. The bicyclic alcohol solid preparation according to claim 1, wherein,

each quick release micro tablet and each sustained release micro tablet contain 5mg of dicyclic alcohol.

8. The solid bicyclic alcohol formulation as claimed in any one of claims 1 to 7, wherein,

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

9. a process for the preparation of a bicyclic alcohol solid formulation as claimed in any one of claims 1 to 8, characterized in that,

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

the sustained-release micro-tablets are prepared from the following components in parts by mass:

preparing a slow-release coating solution;

10. The method for preparing a bicyclic alcohol solid preparation according to claim 9,

the multifunctional auxiliary material is polyoxyethylene 40 hydrogenated castor oil;

and/or the presence of a gas in the gas,

the disintegrating agent is corn starch;

and/or the presence of a gas in the gas,

the filler is microcrystalline cellulose;

and/or the presence of a gas in the gas,

the slow release skeleton is ethyl cellulose;

and/or the presence of a gas in the gas,