CN111202716B

CN111202716B - Theophylline sustained release tablet and preparation method thereof

Info

Publication number: CN111202716B
Application number: CN201811307588.XA
Authority: CN
Inventors: 肖宵; 张俊华; 江志强; 曹明达; 陈志华; 胡卫林
Original assignee: Guangzhou Baiyunshan Guanghua Pharmacy Co ltd
Current assignee: Guangzhou Baiyunshan Guanghua Pharmacy Co ltd
Priority date: 2018-11-05
Filing date: 2018-11-05
Publication date: 2021-10-26
Anticipated expiration: 2038-11-05
Also published as: CN111202716A

Abstract

The invention relates to a theophylline sustained release tablet and a preparation method thereof. The raw material components comprise the following components in percentage by mass: 20-50% of anhydrous theophylline; 5-15% of framework material; 3-7% of a lubricant; 2-6% of pore-foaming agent; 30-50% of a filler; 4-8% of a disintegrating agent; the framework material consists of ethyl cellulose and hydrogenated vegetable oil in a mass ratio of 1-3: 1; the preparation method comprises the following steps: (1) pulverizing anhydrous theophylline, skeleton material, pore-forming agent and 40-50% of lubricant, sieving, and mixing to obtain mixture; (2) carrying out hot melting and extrusion on the mixed material; (3) cooling, cutting into granules, and sieving; (4) adding the rest lubricant, filler and disintegrant, mixing, and making into tablet. The method combines the hot-melt extrusion technology with the skeleton type slow release technology, and obtains the preparation method of the theophylline slow release tablet with simple process, good slow release effect and high batch reproducibility through the selection of the raw materials and the proportion thereof and the selection of the preparation process.

Description

Theophylline sustained release tablet and preparation method thereof

Technical Field

The invention relates to the field of pharmaceutical preparations, in particular to a theophylline sustained-release tablet and a preparation method thereof.

Background

Bronchial asthma (short for asthma) is a common disease and frequently encountered disease. Currently, about 3 hundred million patients suffer from global asthma, and about 3000 ten thousand patients suffer from Chinese asthma. Asthma is an important disease affecting the physical and mental health of people. The treatment is untimely and irregular, asthma can be fatal, and the treatment method at present can lead to the excellent control of the disease of nearly 80 percent of asthma patients. Therefore, how to select a treatment mode which is easy to accept by the patient is an important method for ensuring the timely and standard treatment of the patient.

Sustained release formulations (SRPs) are formulations that provide better therapeutic effects by slowing the rate of release of the drug from the dosage form and reducing the rate of absorption of the drug into the body, but the rate of release of the drug from the formulation is affected by factors such as the PH of the environment. The regulation of Chinese pharmacopoeia indicates that the slow-release preparation is a preparation which is slowly released by oral medicines in a regulated release medium according to a requirement and at a non-constant speed, and compared with other corresponding ordinary preparations, the frequency of taking medicines every 24 hours is reduced from 3-4 times to 1-2 times. The oral sustained-release preparation is divided into a sustained-release preparation and a controlled-release preparation according to the first-order kinetics and the zero-kinetics equation in the drug release process. The sustained and controlled release preparation mainly comprises a skeleton type and a reservoir type. The slow release capability of the skeleton type slow controlled release preparation is slightly poorer than that of the reservoir type, and the process is simple; the depot type sustained-release agent has good sustained-release capability and complex preparation process, and the existence of blank particles in the film covering process can cause uneven film covering drug load, often cause poor reproducibility among batches and have high requirement on the preparation process.

Theophylline is a methylpurine medicine, and has effects of tonifying heart, promoting urination, dilating coronary artery, relaxing bronchial smooth muscle and exciting central nervous system. Theophylline is mainly used for treating bronchial asthma, emphysema, bronchitis, and cardiac dyspnea. The theophylline is prepared into a sustained release preparation, so that the fluctuation of blood concentration can be reduced, the toxic effect can be avoided, and the administration frequency can be reduced. The theophylline is taken as a representative medicine for treating asthma diseases, and the theophylline sustained release tablet is a very effective medicine for stably treating asthma and also has a good treatment effect. However, in terms of theophylline sustained release tablets in the current market, the difference of the release degree between tablets or between batches is large, and the difference of the release degree between the theophylline sustained release tablets of each batch is large, so that the theophylline sustained release tablets are not beneficial to stably playing the therapeutic effect of theophylline. The preparation has 2 main purposes, namely, the preparation is formed and has certain shape under the action of an excipient and equipment; secondly, modification is carried out, the properties of auxiliary materials or carriers are endowed to the preparation, so that the medicine has ideal in-vivo medicine release characteristics and technological characteristics. The common preparation process of theophylline sustained release tablets comprises high-speed wet granulation, extrusion and rounding, coating of a sustained release film coating layer and the like, and then mixing with certain auxiliary materials and compressing into tablets. However, the reproducibility between batches of high-speed wet granulation is poor, the extrusion and rounding, the coating process is long in time consumption, the continuous operation is not available, extra drying equipment is required, and the stability of the prepared particles is biased.

The hot melt extrusion technology is characterized in that materials are subjected to three stages of solid conveying, melting and melt conveying through screw extrusion equipment, and a molded product with high mixing dispersion is obtained under the action of strong shearing of a screw meshing area.

The hot-melt extrusion technology (HME) is mostly applied to the plastic preparation industry, and is gradually applied to the preparation of insoluble drugs and slow-control drugs in the pharmaceutical field in recent years, and compared with the common preparation technology, the preparation method has the advantages of continuous production, no dust generation, environmental friendliness, no organic solvent residue, large drug loading capacity, short heating time, high production efficiency and the like. How to combine the hot-melt extrusion technology with the traditional medicament preparation technology to obtain the sustained-release reagent with simple preparation technology, good sustained-release capability and high batch-to-batch reproducibility still has important significance.

Disclosure of Invention

Based on the above, the invention provides the preparation method of the theophylline sustained release tablet, which has the advantages of good sustained release capability, good batch-to-batch reproducibility and simple preparation process.

The specific technical scheme is as follows:

a preparation method of a theophylline sustained release tablet comprises the following raw material components in percentage by mass:

the framework material consists of ethyl cellulose and hydrogenated vegetable oil in a mass ratio of 1-3: 1;

the preparation method comprises the following steps:

(1) pulverizing anhydrous theophylline, skeleton material, pore-forming agent and 40-50% of lubricant, sieving, and mixing;

(2) carrying out hot melting and extrusion on the mixed material;

(3) cooling, cutting into granules, and sieving;

(4) adding the rest lubricant, filler and disintegrant, mixing, and making into tablet.

In some of these embodiments, the matrix material consists of ethyl cellulose and hydrogenated vegetable oil in a mass ratio of 1.5-2.5: 1.

In some of these embodiments, the temperature of the extrusion in step (2) is 160-180 ℃.

In some of these embodiments, the extruded speed of step (2) is 40-60 rpm.

In some of these embodiments, in step (1), the screened mesh is 40-100 mesh; in the step (3), the sieved mesh is 25-40 meshes.

In some of these embodiments, in step (4), the tablet has a hardness of 40-70N.

In some of the embodiments, the pore-forming agent is at least one of hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone; preferably polyvinylpyrrolidone.

In some of these embodiments, the filler is at least one of lactose, corn starch, microcrystalline cellulose, compressible starch; preferably a compressible starch.

In some of these embodiments, the disintegrant is at least one of croscarmellose sodium, low substituted hydroxypropyl cellulose, preferably croscarmellose sodium; the lubricant is at least one of hydrated silicon dioxide, talcum powder, superfine silica powder, calcium stearate and magnesium stearate, and preferably hydrated silicon dioxide.

The invention also aims to provide a theophylline sustained release tablet prepared by the method.

Compared with the prior art, the invention has the following beneficial effects:

the inventor finally obtains the preparation method of the theophylline sustained release tablet with simple preparation process, high batch-to-batch reproducibility and excellent sustained release effect by combining the hot melt extrusion technology with the skeleton type preparation process. The hot-melt extrusion technology can uniformly disperse theophylline and other auxiliary materials in the molten skeleton material under the action of mechanical acting force of an extruder and external heat of a machine barrel by one step, so that the medicine and a carrier are mixed at a molecular level, and the solubility and the dispersity of the medicine are improved; furthermore, the proportion of the theophylline, the framework material and other auxiliary materials is optimized by the inventor of the invention, and particularly, when the proportion of the ethyl cellulose and the hydrogenated vegetable oil in the framework material is 1-3:1, the obtained theophylline sustained-release tablet has a good sustained-release effect and good hardness and release stability. The theophylline sustained release tablet prepared by the method of the invention shows good batch reproducibility, overcomes the defect of poor batch reproducibility in the traditional technology, and is suitable for industrial amplification.

Furthermore, the invention further optimizes the technological parameters such as extrusion temperature, extrusion rotating speed, particle size and the like, and the finally obtained theophylline sustained-release tablet can achieve the same sustained-release effect as the reference preparation on the market.

Drawings

FIG. 1 is an in vitro dissolution profile of theophylline sustained release tablets prepared in three lots using the procedure of example 2;

Detailed Description

In order that the invention may be more readily understood, reference will now be made to the following more particular description of the invention, examples of which are set forth below. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. 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 invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

The present invention will be described in further detail with reference to specific examples.

The raw materials used in the embodiment of the invention are as follows:

the pore-forming agent is at least one of hydroxypropyl cellulose, polyethylene glycol and polyvinylpyrrolidone, and polyvinylpyrrolidone is selected in the following embodiment.

The filler is at least one of lactose, corn starch, microcrystalline cellulose and compressible starch. The following examples specifically select a compressible starch.

The disintegrant is at least one of croscarmellose sodium and low-substituted hydroxypropyl cellulose, and croscarmellose sodium is specifically selected in the following examples.

The lubricant is at least one of hydrated silicon dioxide, talcum powder, superfine silica powder, calcium stearate and magnesium stearate, and the hydrated silicon dioxide is specifically selected in the following embodiments.

Reference formulation information:

name of commodity	Theolong
		English name	Theolong Tablets 100mg
Specification of	100mg (calculated as anhydrous theophylline)
		Hold withHuman being	Japanese toilet paper

EXAMPLE 1 preparation of theophylline sustained-release tablets

(1) 40g of anhydrous theophylline, 9g of framework material (ethyl cellulose: hydrogenated oil 1:1), 1.5g of lubricant and 4g of pore-forming agent are sieved by a 80-mesh sieve, and the framework material and the lubricant are sieved by a 60-mesh sieve and are uniformly mixed to prepare a mixed material;

(2) setting the hot-melting extrusion temperature at 170 ℃, setting the rotating speed at 50rpm, adding the mixed material at a constant speed after the temperature is raised to a set value and is stable to obtain a strip-shaped extrudate, and cooling;

(3) granulating with a conical granulator, and sieving with a 30-mesh sieve to obtain sustained-release granules;

(4) 2g of lubricant, 38g of filling agent and 5.5g of disintegrating agent are added for total mixing; tabletting according to the weight of a given tablet of 250mg, and punching into a die with a circular concave-convex shape of 8mm, wherein the hardness of the tablet is controlled between 40 and 70N. The theophylline specification is 100 mg/tablet. Three batches of small samples were made in parallel.

Example 2

This example differs from example 1 in that, in step (1), the ratio of ethyl cellulose: the mass ratio of the hydrogenated oil is 2: 1. The raw material composition and other steps of this example were the same as in example 1.

Example 3

This example differs from example 2 in that, in step (1), the ratio of ethyl cellulose: the mass ratio of hydrogenated oil is 2.5: 1. The raw material composition and other steps of this example were the same as in example 2.

Example 4

This example differs from example 2 in that in step (2), the hot-melt extrusion temperature was 155 ℃.

The raw material composition and other steps of this example were the same as in example 2.

Example 5

This example differs from example 2 in that in step (2), the hot-melt extrusion temperature is 180 ℃.

Example 6

This example is different from example 2 in that the hot-melt extrusion rotation speed in step (2) was 30 rpm.

Example 7

This example is different from example 2 in that in step (2), the hot-melt extrusion rotation speed was 60 rpm.

Example 8

This example is different from example 2 in that in step (3), the mesh size of the sieve is 40 mesh. The raw material composition and other steps of this example were the same as in example 2.

Example 9

This example differs from example 2 in that in step (3), the mesh size of the sieve was 20 mesh. The raw material composition and other steps of this example were the same as in example 2.

Example 10

This example differs from example 1 in that in step (2), the hot-melt extrusion temperature was 155 ℃.

The raw material composition and other steps of this example were the same as in example 1.

Example 11

This example is different from example 1 in that the hot-melt extrusion rotation speed in step (2) was 30 rpm.

Comparative example 1

This comparative example is that of example 2, differing from example 2 in that: the ratio of ethyl cellulose to hydrogenated oil was: 1: 2; the raw material components and other steps of this comparative example were the same as in example 2.

Comparative example 2

This comparative example is that of example 2, differing from example 2 in that: the ratio of ethyl cellulose to hydrogenated oil was: 4: 1; the raw material components and other steps of this comparative example were the same as in example 2.

Comparative example 3

This comparative example is that of example 2, differing from example 2 in that: the anhydrous theophylline, the framework material and the lubricant in the step (1) do not have a screening step.

Comparative example 4 theophylline sustained-release tablet prepared by conventional wet method

The raw materials comprise:

the preparation method comprises the following steps:

(1) dissolving 4g of polyvinylpyrrolidone in an ethanol solution to prepare an alcohol solution;

(2) placing the sieved theophylline, the rest polyvinylpyrrolidone, the L-alanine, the alginic acid and the lactose in a particle stirrer for fully mixing, adding the solution obtained in the step (1), and fully mixing to obtain a soft material;

(3) drying the soft material, adding magnesium stearate as a lubricating glidant to obtain mixed powder, adding all the mixed powder into a multiphase motion mixer, and pressing into tablets after mixing;

(4) sieving pulvis Talci, mixing, adding into ethanol solution containing sodium carboxymethylcellulose and propylene glycol, stirring, and grinding to obtain coating solution;

(5) adding the plain tablets into a non-porous coating pan, adjusting the air intake, preheating the plain tablets, adding the coating liquid for coating, and obtaining the theophylline sustained release tablets.

Testing the dissolution performance of the theophylline sustained release tablet:

the release rates of the examples, comparative examples and reference preparations were measured according to the method (0931 second method of the general rule of the four divisions of the "chinese pharmacopoeia" 2015 edition), using 900ml of a phosphate buffer solution (1.70 g of potassium dihydrogen phosphate, 4.48g of disodium hydrogen phosphate, and 1000ml of water was added to dissolve them, and the pH value was adjusted to 6.8 with 2mol/L of sodium hydroxide solution) as a dissolution medium at 50rpm, and the solution was filtered at 10ml for 1 hour, 2 hours, 4 hours, 6 hours, 10 hours and 12 hours, and immediately supplemented with the dissolution medium at the same temperature and the same volume; taking appropriate amount of the subsequent filtrate, diluting with dissolution medium to obtain solution containing anhydrous theophylline about 7 μ g per l ml, measuring absorbance at wavelength of 271mn by ultraviolet-visible spectrophotometry (0401 in the four parts of the pharmacopoeia 2015), and calculating release degree.

TABLE 1 Process parameters of examples and comparative examples

TABLE 2 dissolution results for the examples, comparative examples and reference formulations

TABLE 3

In example 2, the theophylline sustained release tablet prepared by the method of the present invention exhibits good stable and slow release performance, no burst release occurs within 2 hours, the release rate is stabilized at about 50% in 4-6 hours, and the release rate is higher than 75% in 10 hours. The similarity factor of the theophylline sustained release tablet and the original ground reference preparation is more than 50 and reaches 64.65 percent, which shows that the theophylline sustained release tablet obtained in the example 2 has good fitting degree with the reference preparation.

As is clear from the results of table 1, the inventors of the present invention conducted intensive studies on the formulation process of a theophylline sustained-release tablet in which ethyl cellulose: the proportion of the hydrogenated vegetable oil, the hot-melt extrusion temperature, the hot-melt extrusion rotating speed and the mesh sieved after granulation have obvious influence on the slow release capability of the theophylline slow release tablet. The technological parameters of the method supplement each other, and when the technological parameters are matched with each other, the prepared theophylline sustained-release tablet can exert excellent sustained-release effect.

In comparative example 1, when the ratio of ethylcellulose: the ratio of the hydrogenated vegetable oil is 1:2, which is lower than the ratio range of the method, and the prepared theophylline sustained release tablet has quicker drug release; ethyl cellulose: the proportion of the hydrogenated vegetable oil is 4:1, the ratio is higher than the method, and the prepared theophylline sustained release tablet is too slow in drug release and cannot achieve the purpose of sustained release. Therefore, the proportion of the ethyl cellulose to the hydrogenated vegetable oil is one of the important factors influencing the performance of the theophylline sustained-release tablet. Comparative example 4 according to the conventional wet process, the release rate of the prepared product meets the Chinese pharmacopoeia standard, but the release rate is slow, and the batch-to-batch reproducibility is low. Therefore, the method combines the hot-melt extrusion technology with the skeleton type sustained release technology, and obtains the preparation method of the theophylline sustained release tablet with simple process, good sustained release effect and high batch reproducibility through the selection of the raw materials and the proportion thereof and the selection of the preparation process. Furthermore, the invention further optimizes the technological parameters of extrusion temperature, extrusion rotating speed, sieved meshes and the like, and the finally obtained theophylline sustained-release tablet can achieve the same sustained-release effect as the reference preparation on the market.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. The preparation method of the theophylline sustained release tablet is characterized by comprising the following raw material components in percentage by mass:

the pore-foaming agent is at least one of hydroxypropyl cellulose, polyethylene glycol and polyvinylpyrrolidone;

the filler is at least one of lactose, corn starch, microcrystalline cellulose and compressible starch;

the disintegrant is at least one of croscarmellose sodium and low-substituted hydroxypropyl cellulose;

the lubricant is at least one of hydrated silicon dioxide, talcum powder, superfine silica powder, calcium stearate and magnesium stearate;

the preparation method comprises the following steps:

(1) crushing 40-50% of the total amount of the anhydrous theophylline, the framework material, the pore-forming agent and the lubricant, sieving by a 40-100 mesh sieve, and uniformly mixing to obtain a mixed material;

(2) setting the hot-melting extrusion temperature at 160-180 ℃ and the rotating speed at 40-60rpm, and hot-melting and extruding the mixed material;

(3) cooling, cutting into granules, and sieving with 25-40 mesh sieve;

2. The process for preparing a theophylline sustained release tablet according to claim 1, wherein the temperature of the extrusion in step (2) is 170 ℃.

3. The process for preparing a theophylline sustained-release tablet according to claim 1, wherein the extrusion rotation speed in step (2) is 50 rpm.

4. The method for preparing a theophylline sustained release tablet according to claim 1, wherein the matrix material is composed of ethyl cellulose and hydrogenated vegetable oil at a mass ratio of 1.5-2.5: 1.

5. The process for preparing a theophylline sustained release tablet according to claim 1, wherein in the step (1), the mesh of the sieve is 60 mesh; in the step (3), the sieved mesh is 30 meshes.

6. The process for preparing a theophylline sustained-release tablet according to claim 1, wherein in step (4), the hardness of the tablet is 40 to 70N.

7. The method for preparing theophylline sustained release tablets according to any one of claims 1 to 6, wherein the pore-forming agent is polyvinylpyrrolidone.

8. The process for producing the theophylline sustained-release tablet according to any one of claims 1 to 6, wherein the filler is a compressible starch.

9. The process for producing the theophylline sustained-release tablet according to any one of claims 1 to 6, wherein the disintegrant is croscarmellose sodium; the lubricant is hydrated silica.

10. A theophylline extended release tablet prepared according to the method of any one of claims 1-9.