阅读说明：本技术 一种提高羟丙甲纤维素可压性的方法 (Method for improving compressibility of hypromellose ) 是由 孙敏捷 玛依努尔·艾沙 李菁 于 2021-08-30 设计创作，主要内容包括：本发明涉及一种提高羟丙甲纤维素可压性的方法。本发明采用部分溶胀法对羟丙甲纤维素进行改性,旨在提高其可压性,进而提高其粉末直压缓释性能。本发明改性的羟丙甲纤维素具有良好的可压性和流动性,其粉末直压缓释性能显著提升,可用于粉末直压工艺。本发明提高羟丙甲纤维素可压性的方法工艺简单、效果显著、环保且易于工业化大生产。(The invention relates to a method for improving compressibility of hypromellose. The invention adopts a partial swelling method to modify hydroxypropyl methylcellulose, and aims to improve the compressibility of the hydroxypropyl methylcellulose and further improve the direct-compression sustained-release performance of powder of the hydroxypropyl methylcellulose. The modified hydroxypropyl methylcellulose has good compressibility and fluidity, the powder direct-pressing slow release performance of the modified hydroxypropyl methylcellulose is obviously improved, and the modified hydroxypropyl methylcellulose can be used for a powder direct-pressing process. The method for improving the compressibility of the hydroxypropyl methylcellulose has the advantages of simple process, obvious effect, environmental protection and easy industrial mass production.)

1. A method for improving the compressibility of hypromellose, comprising the steps of:

step 1, dispersing hydroxypropyl methylcellulose in absolute ethyl alcohol, adding water to enable the hydroxypropyl methylcellulose to be in a partially swollen but insoluble state, and swelling for a period of time;

step 2, after swelling, adding absolute ethyl alcohol into the system, continuously stirring, standing at normal temperature to precipitate hydroxypropyl methylcellulose, pouring out supernatant, continuously adding absolute ethyl alcohol, repeating the operation for a plurality of times, and reducing the water content of the system;

and 3, removing absolute ethyl alcohol and water in the system by rotary evaporation, grinding and crushing the obtained powder, sieving with a 80-mesh sieve, drying in an oven, drying in a vacuum drying oven to reach a proper water content, and finally sieving with the 80-mesh sieve to obtain the hydroxypropyl methylcellulose powder with improved compressibility.

2. The method of claim 1, wherein: the hydroxypropyl methylcellulose is high-viscosity hydroxypropyl methylcellulose for a slow-release framework.

3. The method of claim 1, wherein: in the step 1, the mass ratio of the hydroxypropyl methylcellulose to the absolute ethyl alcohol is 1:1-1:20, the volume ratio of the absolute ethyl alcohol to the water is 1:1-20:1, and the swelling time is 1h-24 h.

4. The method of claim 1, wherein: in the step 2, the amount of the added absolute ethyl alcohol is 1-5 times of the volume of the system before the addition, the stirring time is 10min-5h, and the standing time is 10min-5 h.

5. The method of claim 1, wherein: in step 2, the number of repetition is 1-10.

6. The method of claim 1, wherein: in the step 3, the rotary evaporation temperature is 30-80 ℃, and the rotary evaporation speed is 40-100 rpm.

7. The method of claim 1, wherein: in the step 3, the drying temperature is 30-110 ℃, the drying time is 8-24 h, and the final water content is 1-10%.

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a method for improving compressibility of hypromellose.

Background

In the drug production process, compared with the traditional wet granulation process, the direct powder tabletting method can effectively avoid the granulation process, reduce the production procedures, shorten the production time and improve the production efficiency. The method has the advantages of low energy consumption, few processes, suitability for medicines with unstable damp heat and the like, and is widely concerned and favored by pharmaceutical enterprises in the production process. When the sustained-release matrix tablet is prepared by a powder direct compression process, 60% time and cost savings can be realized compared to a wet granulation process.

Hydroxypropyl methylcellulose (HPMC) is a semi-synthetic polymeric excipient, which is a non-ionic Cellulose ether in which a portion of the hydroxyls of Cellulose are replaced with methyl and hydroxypropyl groups. The molecular weight of the compound is 10000-1500000, the compound is white or white-like fibrous powder in a natural state, is odorless, tasteless and nontoxic, is insoluble in organic solvents such as absolute ethyl alcohol, ether, acetone and the like, has more hydroxyl groups in the structure, can form hydrogen bonds with water molecules, and can be dissolved and expanded into clear or slightly turbid colloidal solution in cold water but is insoluble in hot water. The sustained-release preparation has good biocompatibility, strong drug loading capacity and excellent biochemical inertia, and is widely applied to sustained-release preparations. Compared with the HPMC at home and abroad, the HPMC at home and abroad has late production start, few varieties, single variety and laggard production equipment, so that the physical and chemical properties of the HPMC at different manufacturers at home and abroad have differences, and the differences can potentially influence the in-vivo and in-vitro properties of the preparation. At present, domestic HPMC special for powder direct compression does not appear in China, so that HPMC for powder direct compression is monopolized by imported manufacturers. The main reason is that the domestic HPMC has poor compressibility, and the slow release performance is inferior to that of the imported HPMC when the powder direct compression process is adopted, so that the application of the domestic HPMC in the powder direct compression process is limited.

Powder Compressibility (Compressibility) refers to its ability to compress under a certain pressure into a tight association between particles to form a tablet with a certain strength. If the compressibility of the powder is poor, the compression force is removed after compression deformation, and the particles are elastically restored to release the elastic potential energy stored in the compression process, so that a large number of pores are generated inside the tablet, and the tensile strength of the tablet is further reduced. Powder compressibility is generally related to the bonding area and bonding strength of its particles when compressed, wherein the bonding area is related to the particle size, plasticity, specific surface area, porosity, surface roughness, brittleness, etc., and the bonding strength is related to the chemical structure of the auxiliary material and the amount of internal hydrogen bonds. The powder compressibility can be comprehensively evaluated by using its bonding strength and bonding area. If the powder is good in compressibility, the particle size is small, the plasticity, the brittleness, the specific surface area, the porosity and the surface are large, the prepared tablet is good in compactibility, high in tensile strength and small in porosity and elastic recovery. When the hydrophilic gel matrix tablet is prepared by adopting a powder direct compression process, the compressibility of the HPMC influences the tensile strength and porosity of the matrix tablet, and further influences the drug release rate of the matrix tablet.

Therefore, the method for improving the compressibility of the hydroxypropyl methylcellulose is designed, and has important significance for the application of domestic HPMC.

Disclosure of Invention

In view of the above problems, the present invention provides a method for improving the compressibility of hypromellose to prepare hypromellose for direct powder compaction.

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

a method for improving compressibility of hypromellose comprises the following steps:

step 1, dispersing hydroxypropyl methylcellulose in absolute ethyl alcohol, adding water to enable the hydroxypropyl methylcellulose to be in a partially swollen but insoluble state, and swelling for a period of time;

step 2, after swelling, adding absolute ethyl alcohol into the system, continuously stirring, then standing at normal temperature to precipitate hydroxypropyl methylcellulose, pouring out supernatant, continuously adding absolute ethyl alcohol, and repeating the operation for a plurality of times;

and 3, removing absolute ethyl alcohol and water in the system by rotary evaporation, grinding and crushing the obtained powder, sieving with a 80-mesh sieve, drying in an oven, drying in a vacuum drying oven to reach a proper water content, and finally sieving with the 80-mesh sieve to obtain the hydroxypropyl methylcellulose powder with improved compressibility.

Furthermore, the hydroxypropyl methylcellulose is high-viscosity hydroxypropyl methylcellulose for a slow-release framework, and the compressibility of the hydroxypropyl methylcellulose is low.

Further, in the step 1, the mass ratio of the hydroxypropyl methylcellulose to the absolute ethyl alcohol is 1:1-1:20, the volume ratio of the absolute ethyl alcohol to the water is 1:1-20:1, and the swelling time is 1h-24 h.

Further, in the step 2, the amount of the added absolute ethyl alcohol is 1-5 times of the volume of the system before the addition, the stirring time is 10min-5h, and the standing time is 10min-5 h.

Further, in step 2, the number of repetitions is 1 to 10.

Further, in the step 3, the rotary evaporation temperature is 30-80 ℃, and the rotary evaporation speed is 40-100 rpm.

Further, in the step 3, the drying temperature is 30-110 ℃, the drying time is 8-24 hours, and the final water content is 1-10%.

The method for improving the compressibility of the hydroxypropyl methylcellulose does not need excessively complicated operation and equipment, has simple process and low cost, and is easy for industrial mass production.

The microstructure of the hydroxypropyl methylcellulose powder obtained by the method is obviously changed, and the specific surface area is increased.

Respectively taking 300mg of HPMC before and after compressibility improvement, selecting 9mm punch, and setting the rotating speed of a single-punch tablet press to be 8 r.min^-1And directly tabletting under the same pressure to obtain HPMC plain tablets. The results show that, after improved compressibility, the hypromellose tablets have significantly increased tensile strength and significantly decreased porosity and elastic recovery.

Diclofenac sodium is used as a model drug, domestic HPMC before and after the compressibility is improved is used as a framework material, a powder direct compression process is adopted to prepare the diclofenac sodium sustained-release tablet, and the drug release result shows that the HPMC sustained-release performance is obviously improved after the compressibility is improved.

The method for improving the compressibility of the hydroxypropyl methylcellulose disclosed by the invention adopts a partial swelling method to modify the hydroxypropyl methylcellulose, and aims to improve the compressibility of the hydroxypropyl methylcellulose and further improve the direct-compression sustained-release performance of powder of the hydroxypropyl methylcellulose. The modified hypromellose obtained by the method has good compressibility and fluidity, the powder direct-compression slow-release performance of the hypromellose is obviously improved, and the hypromellose can be used for a powder direct-compression process. The method for improving the compressibility of the hydroxypropyl methylcellulose has the advantages of simple process, obvious effect, environmental protection and easy industrial mass production.

Drawings

FIG. 1 is a scanning electron micrograph of HPMC (A, a) before improving compactibility and HPMC (B, B) after improving compactibility of example 9 (A, B:. times.200; a, B:. times.1000).

Figure 2 is the specific surface area results for the HPMC powder before and after improved compactibility of example 9.

Figure 3 is the porosity results for the HPMC tablet before and after improved compressibility of example 9.

Figure 4 shows the results of the elastic recovery of the HPMC tablets of example 9 before and after improved compressibility.

Figure 5 shows the tensile strength of the HPMC tablet before and after improved compressibility of example 9.

FIG. 6 is the dissolution curve of the diclofenac sodium sustained-release tablet of example 16.

Detailed Description

The compressibility of HPMC from different manufacturers varies in performance due to differences in production conditions, production history, technical levels, etc. The invention has the advantages that the compressibility of the domestic HPMC is improved, the domestic HPMC can meet the limited requirement according to the limited index of the compressibility, but compared with the imported HPMC, the compressibility of the domestic HPMC is much lower, so that the slow release performance of the domestic HPMC is influenced. Therefore, the invention provides a method for improving the compressibility of HPMC, thereby expanding the application range of domestic HPMC.

The present invention will be further described with reference to specific examples, but it should be noted that the following examples are not intended to limit the present invention in any way.

HPMC used in the following examples was purchased from Shanhe, Anhui, pharmaceutical excipients Co., Ltd, and was HPMC K100M, lot number: 200104.

example 1

Step 1: 4g HPMC powder was dispersed in 40mL absolute ethanol and 2mL water was added to partially swell but not dissolve the HPMC, with a swelling time of 2 h.

Step 2: adding 100ml of absolute ethyl alcohol into the swelled system, continuously stirring for 30min, standing for 1h at normal temperature to precipitate HPMC powder, pouring out the supernatant, and continuously adding absolute ethyl alcohol to repeat the operation for 2 times.

And step 3: under the conditions that the temperature is 50 ℃ and the rotating speed is 40rpm, the anhydrous ethanol and the water in the system are removed by rotary evaporation, the obtained powder is ground and crushed and then passes through a 80-mesh sieve, the powder is dried in a 50 ℃ oven for 12 hours and then is dried in a vacuum drying oven until the water content is less than 5 percent, and finally the powder is filtered through the 80-mesh sieve, so that the water-soluble organic silicon material is obtained.

Examples 2 to 3

HPMC is improved in the same manner as in example 1, except that the mass ratio of hydroxypropyl methylcellulose to absolute ethyl alcohol in step 1 is respectively replaced by 1:5 and 1: 15;

examples 4 to 5

HPMC was improved in the same manner as in example 1 except that the volume ratio of absolute ethanol to water in step 1 was changed to 20:3, 20:6, respectively;

examples 6 to 7

HPMC was improved in the same manner as in example 1 except that the swelling time in step 1 was 6h and 10h, respectively.

Examples 8 to 9

HPMC was improved in the same manner as in example 1 except that the number of repetitions in step 2 was 1 and 3, respectively.

Examples 10 to 11

HPMC was modified in the same manner as in example 1 except that the temperatures of the roto-evaporation in step 3 were 40 deg.C, 60 deg.C and the rotational speeds were 60rpm and 80rpm, respectively.

Examples 12 to 13

HPMC was improved in the same manner as in example 1 except that the drying temperature in step 3 was changed to 40 ℃ and 60 ℃ respectively.

Examples 14 to 15

HPMC was improved in the same manner as in example 1 except that the final powder moisture control percentage in step 3 was 2%, 8%, respectively.

After the compressibility is improved by the method, 300mg of HPMC before and after improvement is respectively taken, a 9mm punch is selected, the rotating speed of a single-punch tablet machine is set to be 8 r.min < -1 >, and HPMC plain tablets are directly obtained by tabletting under the same pressure. The HPMC plain tablet hardness before and after compressibility improvement is shown in the table below:

EXAMPLE 16

Example 7 is used as a representative example, diclofenac sodium is used as a model drug, the HPMC with improved compressibility and the HPMC without improvement in compressibility in the example 4 are respectively used as sustained-release matrix materials, and a powder direct compression process is applied to prepare the diclofenac sodium sustained-release matrix tablets. The dissolution was measured in dissolution media at ph 6.8.

As shown in fig. 1 to 5, the microstructure of the hypromellose powder obtained by the method of the present invention is significantly changed, the specific surface area is increased, the tensile strength of the pressed hypromellose tablet is significantly improved, and the porosity and elastic recovery are significantly reduced. The dissolution results (fig. 6) show that the HPMC sustained release performance is significantly improved after improving compressibility.

While the embodiments of the present invention have been described in detail with reference to the drawings and the specific examples, the present invention is not limited to the embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art.