Modified hydroxypropyl methyl cellulose for capsule shell wall material and preparation method of modified hydroxypropyl methyl cellulose

Abstract

The invention provides modified hydroxypropyl methyl cellulose for a capsule shell wall material and a preparation method of the modified hydroxypropyl methyl cellulose, and belongs to the technical field of pharmaceutic adjuvants. The preparation method comprises the following steps: modifying hydroxypropyl methyl cellulose prepared from straws through KH560 to prepare silane modified hydroxypropyl methyl cellulose, mixing the silane modified hydroxypropyl methyl cellulose with modified enzymolysis starch prepared through enzymolysis and silane coupling agent modification, adding the mixture into water, adding gelatin, stirring and mixing uniformly to form a glue solution, adding EDC, and stirring and reacting to prepare the modified hydroxypropyl methyl cellulose for the capsule shell wall material. The prepared modified hydroxypropyl methyl cellulose for the capsule shell wall material has better stability, film-forming property, water and oxygen resistance and mechanical strength, is green and non-toxic, is low in cost, also has low allergy and chemical stability, has proper drug dissolution rate and bioavailability, has biodegradability and good biocompatibility, and can be used for preparing the capsule for treating the hyperplasia and hyperplasia of the hyperplasia and hyperplasia of the hyperplasia and hyperplasia of the hyperplasia and hyperplasia of the hyperplasia and hyperplasia. The capsule shell material is a good capsule shell material and has a wide application prospect.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical excipients, and in particular to modified hydroxypropyl methylcellulose for capsule shell material and a preparation method thereof. Background Art

[0002] The capsule shell material of capsules is usually gelatin. The production process of gelatin capsule shell is simple, but there are some problems and phenomena such as poor protection of moisture and oxygen sensitive drugs, reduced drug solubility, and delayed disintegration of the capsule shell during storage. Therefore, hydroxypropyl methylcellulose is used as a substitute for gelatin capsule material in the preparation of capsules, which improves the capsule manufacturing formability and use effect, and has been widely promoted at home and abroad. Podczeck et al. (Podczeck F, Jones BE. The invitrodissolution of the ophylline from different types of hard shell capsules [J]. Drug Dev Ind Pharm, 2002, 28 (9): 1163.) used theophylline as a control drug and found that the drug dissolution rate of the capsule shell using hydroxypropyl methylcellulose was greater than that of the gelatin capsule shell. The reason for the analysis is that the disintegration of HPMC is the simultaneous disintegration of the entire capsule shell, while the disintegration of the gelatin capsule shell is first disintegration at the reticular structure, and then the disintegration of the entire capsule shell, so the HPMC capsule shell is more suitable for the capsule shell of the rapid release preparation. Chiwele et al. (Chiwele I, Jones BE, Podczeck F. The shell dissolution of various empty hard capsules [J]. Chem Pharm Bull (Tokyo), 2000, 48 (7): 951.) also reached a similar conclusion and compared the dissolution of three types of capsule shells: gelatin, gelatin / polyethylene glycol and HPMC. The results showed that the HPMC capsule shell dissolved very quickly under different pH conditions, while the gelatin capsule shell was greatly affected by different pH conditions. Tang Yue et al. (Tang Yue, Zhu Jiabi, Gan Li. The effect of HPMC capsule shell on the performance of dry powder inhaler [J]. Journal of China Pharmaceutical University, 2004, 35 (1): 32.) screened a new type of capsule shell for a small-dose drug blank dry powder inhaler carrier system. The capsule shell of hydroxypropyl methylcellulose and gelatin were compared to investigate the stability of the capsule shell and the properties of the powder inside the shell under different conditions, and a friability test was conducted. The results showed that compared with gelatin capsules, HPMC capsule shells were superior in stability and powder protection, had stronger moisture resistance, and had lower brittleness than gelatin capsule shells. Therefore, HPMC capsule shells were more suitable for use as capsules for dry powder inhalers.

[0003] As we all know, the gelatin used in the capsule processing is food grade gelatin, and food grade products cannot meet the requirements of pharmaceutical grade to a certain extent. As the state's supervision and requirements for drug production become increasingly strict, the use of food grade gelatin to produce capsule materials will be restricted. Therefore, the use of commonly used pharmaceutical excipients hydroxypropyl methylcellulose HPMC as the raw material of capsule materials will increase market strength. With the increasing depletion of oil resources, the research and development of hydroxypropyl methylcellulose using cellulose as raw material will be of great significance. Summary of the invention

[0004] The purpose of the present invention is to provide a modified hydroxypropyl methylcellulose for capsule shell material and a preparation method thereof, which has good stability, film-forming property, water and oxygen barrier property and mechanical strength, is green and non-toxic and has low cost, is low in allergy and chemical stability, has suitable drug solubility and bioavailability, is biodegradable and has good biocompatibility, is a better capsule shell material, and has broad application prospects.

[0005] The technical solution of the present invention is achieved in this way:

[0006] The invention provides a method for preparing modified hydroxypropyl methylcellulose for capsule shell materials. Hydroxypropyl methylcellulose prepared from straw is modified with KH560 to obtain silane-modified hydroxypropyl methylcellulose, which is mixed with modified enzymatic starch prepared by enzymatic hydrolysis and modification with a silane coupling agent and added into water, gelatin is added, stirred and mixed evenly to form a glue solution, EDC is added, stirred and reacted, and the modified hydroxypropyl methylcellulose for capsule shell materials is obtained.

[0007] As a further improvement of the present invention, the following steps are included:

[0008] S1. Add hydroxypropyl methylcellulose to methanol, stir and disperse evenly, add silane coupling agent KH560, heat and stir to react, filter, wash, and dry to obtain silane-modified hydroxypropyl methylcellulose;

[0009] S2. Add starch to water, add amylase to hydrolyze, inactivate the enzyme, add ethanol to precipitate, filter, wash, and dry to obtain enzymatic starch;

[0010] S3. The enzymatic starch was added to acetonitrile, stirred and dispersed evenly, a composite silane coupling agent was added, heated and stirred to react, filtered, washed, and dried to obtain a modified enzymatic starch;

[0011] S4. Add gelatin into water, heat to dissolve, add silane-modified hydroxypropyl methylcellulose and modified enzymatic starch, stir and mix evenly to form a gelatin solution, add EDC, stir to react, and dry to obtain modified hydroxypropyl methylcellulose for capsule shell material.

[0012] As a further improvement of the present invention, the preparation method of hydroxypropyl methylcellulose in step S1 is as follows:

[0013] T1. Wash the straw, dry it, crush it, add it to the alkali mixture for pretreatment, filter it, wash it, and dry it to obtain pretreated straw powder;

[0014] T2. The pretreated straw powder was added to the acid solution, heated to reflux for extraction, filtered, washed, and dried to obtain straw cellulose;

[0015] T3. Adding straw cellulose to alkali solution, heating and stirring the reaction, filtering, washing, and drying to obtain alkali cellulose;

[0016] T4. Add alkali cellulose to an organic solvent, add methyl chloride and propylene oxide, heat for etherification reaction, filter, wash and dry to obtain hydroxypropyl methylcellulose.

[0017] As a further improvement of the present invention, the straw in step T1 is selected from at least one of wheat straw, corn straw, rice straw, and sorghum straw, the alkaline mixture is an aqueous solution containing 10-15wt% NaOH, 3-5wt% urea, and 2-3wt% thiourea, the pretreatment temperature is 40-50°C, and the time is 1-3h; the solid-liquid ratio of the pretreated straw powder and the acid solution in step T2 is 1:10-15g / mL, the heating reflux extraction time is 2-3h, and the acid solution is 1-3mol / L nitric acid solution.

[0018] As a further improvement of the present invention, the alkali solution in step T3 is an aqueous solution containing 7-10wt% NaOH, 10-20wt% isopropanol and 7-12wt% ethanol, the temperature of the heating and stirring reaction is 55-65°C, and the time is 1-2h; the mass ratio of alkali cellulose, methyl chloride and propylene oxide in step T4 is 10:14-17:2-3, the temperature of the heating etherification reaction is 60-70°C, and the time is 1-3h, and the organic solvent is a mixed solvent of toluene and isopropanol, and the volume ratio is 4-6:3.

[0019] As a further improvement of the present invention, in step S1, the mass ratio of hydroxypropyl methylcellulose to silane coupling agent KH560 is 10:2-3, the temperature of the heating and stirring reaction is 40-50° C., and the time is 2-4 hours.

[0020] As a further improvement of the present invention, the mass ratio of starch to amylase in step S2 is 40-60:3-5, the temperature of the enzymatic hydrolysis is 35-40°C, the time is 1-3h, and the amylase is α-amylase and β-amylase, with a mass ratio of 3-5:2.

[0021] As a further improvement of the present invention, the mass ratio of the enzymatic starch and the composite silane coupling agent in step S3 is 12-15:3-4, the composite silane coupling agent is selected from at least two of KH550, KH602, and KH792, preferably, a mixture of KH602 and KH792, with a mass ratio of 3-5:2-3, and the temperature of the heating and stirring reaction is 40-50°C, and the time is 1-3h.

[0022] As a further improvement of the present invention, in step S4, the mass ratio of gelatin, silane-modified hydroxypropyl methylcellulose, modified enzymatic starch, and EDC is 10:12-15:3-6:0.1-0.2, the heating is to 60-70° C., and the stirring reaction time is 2-4 h.

[0023] The present invention further protects a modified hydroxypropyl methylcellulose for capsule shell material obtained by the above-mentioned preparation method.

[0024] The present invention has the following beneficial effects:

[0025] The natural high molecular substances in straw are cellulose, hemicellulose and lignin. These three components are interlocked in straw to form the cell wall of plants, and the highest content is cellulose. Straw is not only a natural raw material that is safe and friendly to the environment, but also has the excellent properties of being cheap, easy to obtain, and resistant to mildew and antibacterial, and is widely used as a raw material for synthetic materials. The preparation method of hydroxypropyl methylcellulose prepared by extracting cellulose from straw and modifying it is simple, with mild process conditions, high yield, low cost, and easy to realize industrial production. The prepared hydroxypropyl methylcellulose has good emulsification, dispersion, thickening, bonding, water retention and glue retention properties, is soluble in water and most polar solvents, and its aqueous solution has high transparency and excellent stability. The capsule shell prepared has the advantages of low allergy and chemical stability.

[0026] Capsule shell is an oral solid pharmaceutical excipient with good drug targeting, can mask the bad smell of drugs, can contain drugs and protect them from external influences. Directly using hydroxypropyl methylcellulose as a capsule shell material also has some disadvantages, such as poor mechanical strength, high cost, poor oxygen barrier properties, resulting in degradation of some oxygen-sensitive drugs during storage.

[0027] Starch has great potential in the preparation of pharmaceutical excipients due to its wide source, green and non-toxic, and low price. However, natural starch has the disadvantages of easy aging and regeneration, poor solubility and freeze-thaw stability, which limit its application in various fields to a certain extent. The present invention modifies starch by enzymatic hydrolysis, greatly improves its solubility and stability, and significantly enhances its film-forming property, water and oxygen barrier property, and strength.

[0028] Gelatin as a capsule shell material has biodegradability, good biocompatibility and film-forming properties, but because of cross-linking reactions in itself and the outside world, the drug solubility and bioavailability are reduced; high temperature, high humidity and light will also promote its cross-linking; it is easy to stick in a humid environment and easy to lose water and harden in a low humidity environment; the addition of some excipients, such as preservatives, colorants, and sunscreens, will affect the cross-linking of the capsule shell. Therefore, its application is greatly limited.

[0029] The present invention prepares hydroxypropyl methylcellulose prepared from straw by modifying it with a silane coupling agent KH560, so that the surface of the hydroxypropyl methylcellulose has epoxy groups, and the hydroxypropyl methylcellulose is mixed with starch modified by enzymatic hydrolysis and a silane coupling agent with an amino group, so that the two are easily reacted, thereby realizing self-crosslinking, and gelatin is further added, and under the action of EDC, the carboxyl groups in the gelatin molecules are activated, so that the carboxyl groups can react with the amino groups of the gelatin molecules and the modified starch, and the crosslinking is further strengthened, so that the prepared modified hydroxypropyl methylcellulose for capsule shell material has good comprehensive performance.

[0030] The modified hydroxypropyl methylcellulose for capsule shell material prepared by the present invention has good stability, film-forming property, water and oxygen barrier property and mechanical strength, is green and non-toxic and has low cost, is low in allergy and chemical stability, has suitable drug solubility and bioavailability, is biodegradable and has good biocompatibility, is a better capsule shell material, and has broad application prospects. DETAILED DESCRIPTION

[0031] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0032] α-amylase, 40,000 U / g, β-amylase, 70,000 U / g, purchased from Xiasheng (Beijing) Biotechnology Development Co., Ltd. Starch was corn starch, with a content of >99%, purchased from Henan Julong Starch Industry Co., Ltd.

[0033] EDC, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, is commercially available.

[0034] Preparation Example 1 Preparation of Hydroxypropyl Methylcellulose

[0035] Here’s how:

[0036] T1. Wash, dry, and crush 2 g corn stalks, add them to 100 mL of an alkali mixture, heat them to 40 ° C for 1 h, filter, wash, and dry them to obtain pretreated stalk powder;

[0037] The alkaline mixture is an aqueous solution containing 10wt% NaOH, 3wt% urea, and 2wt% thiourea;

[0038] T2. Add 2 g of pretreated straw powder to 20 mL of 1 mol / L nitric acid solution, heat and reflux for 2 h, filter, wash, and dry to obtain straw cellulose;

[0039] T3. Add 1 g of straw cellulose to 100 mL of alkali solution, heat to 55°C, stir and react for 1 h, filter, wash and dry to obtain alkali cellulose;

[0040] The alkali solution is an aqueous solution containing 7wt% NaOH, 10wt% isopropanol and 7wt% ethanol;

[0041] T4. Add 10 g of alkali cellulose to 200 mL of organic solvent, add 14 g of methyl chloride and 2 g of propylene oxide, heat to 60°C, etherify for 1 h, filter, wash, and dry to obtain hydroxypropyl methylcellulose;

[0042] The organic solvent is a mixed solvent of toluene and isopropanol in a volume ratio of 4:3.

[0043] Preparation Example 2 Preparation of Hydroxypropyl Methylcellulose

[0044] Here’s how:

[0045] T1. Wash 2 g wheat straw, dry it, crush it, add it to 100 mL of alkali mixture, heat it to 50 ° C for 3 h, filter it, wash it, and dry it to obtain pretreated straw powder;

[0046] The alkaline mixture is an aqueous solution containing 15wt% NaOH, 5wt% urea, and 3wt% thiourea;

[0047] T2. Add 2 g of pretreated straw powder to 30 mL of 3 mol / L nitric acid solution, heat and reflux for extraction for 3 h, filter, wash, and dry to obtain straw cellulose;

[0048] T3. Add 1 g of straw cellulose to 100 mL of alkali solution, heat to 65 ° C, stir and react for 2 h, filter, wash and dry to obtain alkali cellulose;

[0049] The alkali solution is an aqueous solution containing 10wt% NaOH, 20wt% isopropanol and 12wt% ethanol;

[0050] T4. Add 10 g of alkali cellulose to 200 mL of organic solvent, add 17 g of methyl chloride and 3 g of propylene oxide, heat to 70 ° C, etherify for 3 hours, filter, wash, and dry to obtain hydroxypropyl methylcellulose;

[0051] The organic solvent is a mixed solvent of toluene and isopropanol in a volume ratio of 6:3.

[0052] Preparation Example 3 Preparation of Hydroxypropyl Methylcellulose

[0053] Here’s how:

[0054] T1. Wash 2 g wheat straw, dry it, crush it, add it to 100 mL of alkali mixture, heat it to 45 ° C for 2 h, filter it, wash it, and dry it to obtain pretreated straw powder;

[0055] The alkaline mixture is an aqueous solution containing 12wt% NaOH, 4wt% urea, and 2.5wt% thiourea;

[0056] T2. Add 2 g of pretreated straw powder to 25 mL of 2 mol / L nitric acid solution, heat and reflux for extraction for 2.5 h, filter, wash, and dry to obtain straw cellulose;

[0057] T3. Add 1 g of straw cellulose to 100 mL of alkali solution, heat to 60°C, stir and react for 1.5 h, filter, wash and dry to obtain alkali cellulose;

[0058] The alkali solution is an aqueous solution containing 8wt% NaOH, 15wt% isopropanol and 10wt% ethanol;

[0059] T4. Add 10 g of alkali cellulose to 200 mL of organic solvent, add 15.5 g of methyl chloride and 2.5 g of propylene oxide, heat to 65 ° C, etherify for 2 h, filter, wash, and dry to obtain hydroxypropyl methylcellulose;

[0060] The organic solvent is a mixed solvent of toluene and isopropanol in a volume ratio of 5:3.

[0061] Comparative Preparation Example 1

[0062] Compared with Preparation Example 3, the difference is that step T1 is not performed.

[0063] The details are as follows:

[0064] T1. Add 2g wheat straw to 25mL 2mol / L nitric acid solution, heat and reflux for 2.5h, filter, wash and dry to obtain straw cellulose;

[0065] T2. Add 1 g of straw cellulose into 100 mL of alkali solution, heat to 60°C, stir and react for 1.5 h, filter, wash and dry to obtain alkali cellulose;

[0066] The alkali solution is an aqueous solution containing 8wt% NaOH, 15wt% isopropanol and 10wt% ethanol;

[0067] T3. Add 10 g of alkali cellulose to 200 mL of organic solvent, add 15.5 g of methyl chloride and 2.5 g of propylene oxide, heat to 65 ° C, etherify for 2 h, filter, wash, and dry to obtain hydroxypropyl methylcellulose;

[0068] The organic solvent is a mixed solvent of toluene and isopropanol in a volume ratio of 5:3.

[0069] Comparative Preparation Example 2

[0070] Compared with Preparation Example 3, the difference is that step T2 is not performed.

[0071] The details are as follows:

[0072] T1. Wash 2 g wheat straw, dry it, crush it, add it to 100 mL of alkali mixture, heat it to 45 ° C for 2 h, filter it, wash it, and dry it to obtain pretreated straw powder;

[0073] The alkaline mixture is an aqueous solution containing 12wt% NaOH, 4wt% urea, and 2.5wt% thiourea;

[0074] T2. Add 1 g of pretreated straw powder into 100 mL of alkali solution, heat to 60 ° C, stir and react for 1.5 h, filter, wash, and dry to obtain alkali cellulose;

[0075] The alkali solution is an aqueous solution containing 8wt% NaOH, 15wt% isopropanol and 10wt% ethanol;

[0076] T3. Add 10 g of alkali cellulose to 200 mL of organic solvent, add 15.5 g of methyl chloride and 2.5 g of propylene oxide, heat to 65 ° C, etherify for 2 h, filter, wash, and dry to obtain hydroxypropyl methylcellulose;

[0077] The organic solvent is a mixed solvent of toluene and isopropanol in a volume ratio of 5:3.

[0078] Test Example 1

[0079] The hydroxypropyl methylcellulose prepared in Preparation Example 1-3 and Comparative Preparation Example 1-2 was dissolved in water, heated to a viscosity of 200±10mPa·s, defoamed, and evenly spread in a plastic culture dish by casting, dried, and cut into a rectangular film of 15mm×30mm and 0.08-0.10mm in thickness. According to the national standard GB / T1040.1-2018, an electronic universal tensile testing machine was used to measure the elongation at break and tensile strength of the film, with the initial clamping distance set to 40mm and the tensile speed set to 10mm / s. The results are shown in Table 1.

[0080] Table 1

[0081] Group Tensile strength(Mpa) Elongation at break (%) Preparation Example 1 11.5 103 Preparation Example 2 11.8 105 Preparation Example 3 11.9 108 Comparative Preparation Example 1 9.1 84 Comparative Preparation Example 2 9.4 88

[0082] It can be seen from the above table that the hydroxypropyl methylcellulose prepared in Preparation Examples 1-3 of the present invention has good mechanical properties.

[0083] Example 1

[0084] This embodiment provides a method for preparing modified hydroxypropyl methylcellulose for capsule shell material, comprising the following steps:

[0085] S1. 10 g of hydroxypropyl methylcellulose prepared in Preparation Example 1 was added to 200 mL of methanol, stirred and dispersed at 500 r / min for 10 min, 2 g of silane coupling agent KH560 was added, heated to 40 ° C, stirred and reacted for 2 h, filtered, washed, and dried to obtain silane-modified hydroxypropyl methylcellulose;

[0086] S2. Add 40 g of starch to 1 L of water, add 3 g of amylase, hydrolyze at 35 ° C for 1 h, inactivate the enzyme, add ethanol until the ethanol content of the system is 80 wt%, precipitate for 1 h, filter, wash, and dry to obtain enzymatic starch;

[0087] The amylases are α-amylase and β-amylase, with a mass ratio of 3:2;

[0088] S3. 12 g of enzymatic starch was added to acetonitrile, stirred and dispersed at 500 r / min for 10 min, 3 g of composite silane coupling agent was added, heated to 40 ° C, stirred for 1 h, filtered, washed, and dried to obtain modified enzymatic starch;

[0089] The composite silane coupling agent is a mixture of KH602 and KH792, with a mass ratio of 3:2;

[0090] S4. Add 10g gelatin into 500mL water, heat to 70°C, stir to dissolve, add 12g silane-modified hydroxypropyl methylcellulose and 3g modified enzymatic starch, stir and mix for 15min to form a gelatin solution, add 0.1g EDC, stir and react for 2h, and dry to obtain modified hydroxypropyl methylcellulose for capsule shell material.

[0091] Example 2

[0092] This embodiment provides a method for preparing modified hydroxypropyl methylcellulose for capsule shell material, comprising the following steps:

[0093] S1. 10 g of hydroxypropyl methylcellulose prepared in Preparation Example 2 was added to 200 mL of methanol, stirred and dispersed at 500 r / min for 10 min, 3 g of silane coupling agent KH560 was added, heated to 50 ° C, stirred and reacted for 4 h, filtered, washed, and dried to obtain silane-modified hydroxypropyl methylcellulose;

[0094] S2. Add 60 g of starch to 1 L of water, add 5 g of amylase, hydrolyze at 40 ° C for 3 h, inactivate the enzyme, add ethanol until the ethanol content of the system is 80 wt%, precipitate for 1 h, filter, wash, and dry to obtain enzymatic starch;

[0095] The amylases are α-amylase and β-amylase, with a mass ratio of 5:2;

[0096] S3. 15 g of enzymatic starch was added to acetonitrile, stirred and dispersed at 500 r / min for 10 min, 4 g of composite silane coupling agent was added, heated to 50 ° C, stirred for 3 h, filtered, washed, and dried to obtain modified enzymatic starch;

[0097] The composite silane coupling agent is a mixture of KH602 and KH792, with a mass ratio of 5:3;

[0098] S4. Add 10g of gelatin into 500mL of water, heat to 80°C, stir to dissolve, add 15g of silane-modified hydroxypropyl methylcellulose and 6g of modified enzymatic starch, stir and mix for 15min to form a gelatin solution, add 0.2g of EDC, stir and react for 4h, and dry to obtain modified hydroxypropyl methylcellulose for capsule shell material.

[0099] Example 3

[0100] This embodiment provides a method for preparing modified hydroxypropyl methylcellulose for capsule shell material, comprising the following steps:

[0101] S1. 10 g of hydroxypropyl methylcellulose prepared in Preparation Example 3 was added to 200 mL of methanol, stirred and dispersed at 500 r / min for 10 min, 2.5 g of silane coupling agent KH560 was added, heated to 45 ° C, stirred for 3 h, filtered, washed, and dried to obtain silane-modified hydroxypropyl methylcellulose;

[0102] S2. Add 50 g of starch to 1 L of water, add 4 g of amylase, hydrolyze at 37 ° C for 2 h, inactivate the enzyme, add ethanol until the ethanol content of the system is 80 wt%, precipitate for 1 h, filter, wash, and dry to obtain enzymatic starch;

[0103] The amylases are α-amylase and β-amylase, with a mass ratio of 4:2;

[0104] S3. 13 g of enzymatic starch was added to acetonitrile, stirred and dispersed at 500 r / min for 10 min, 3.5 g of composite silane coupling agent was added, heated to 45 ° C, stirred for 2 h, filtered, washed, and dried to obtain modified enzymatic starch;

[0105] The composite silane coupling agent is a mixture of KH602 and KH792, with a mass ratio of 4:2.5;

[0106] S4. Add 10 g of gelatin to 500 mL of water, heat to 75°C, stir to dissolve, add 14 g of silane-modified hydroxypropyl methylcellulose and 4.5 g of modified enzymatic starch, stir and mix for 15 minutes to form a gelatin solution, add 0.15 g of EDC, stir and react for 3 hours, and dry to obtain modified hydroxypropyl methylcellulose for capsule shell material.

[0107] Example 4

[0108] Compared with Example 3, the difference is that the amylase is a single α-amylase.

[0109] Example 5

[0110] Compared with Example 3, the difference is that the amylase is a single β-amylase.

[0111] Comparative Example 1

[0112] Compared with Example 3, the difference is that the hydroxypropyl methylcellulose is prepared by Comparative Preparation Example 1.

[0113] Comparative Example 2

[0114] Compared with Example 3, the difference is that the hydroxypropyl methylcellulose is prepared by Comparative Preparation Example 2.

[0115] Comparative Example 3

[0116] Compared with Example 3, the difference is that step S1 is not performed.

[0117] The details are as follows:

[0118] S1. Add 50g starch to 1L water, add 4g amylase, enzymatically hydrolyze at 37°C for 2h, inactivate the enzyme, add ethanol until the ethanol content of the system is 80wt%, precipitate for 1h, filter, wash, and dry to obtain enzymatically hydrolyzed starch;

[0119] The amylases are α-amylase and β-amylase, with a mass ratio of 4:2;

[0120] S2. 13 g of enzymatic starch was added to acetonitrile, stirred and dispersed at 500 r / min for 10 min, 3.5 g of composite silane coupling agent was added, heated to 45 ° C, stirred for 2 h, filtered, washed, and dried to obtain modified enzymatic starch;

[0121] The composite silane coupling agent is a mixture of KH602 and KH792, with a mass ratio of 4:2.5;

[0122] S3. Add 10 g of gelatin to 500 mL of water, heat to 75°C, stir to dissolve, add 14 g of hydroxypropyl methylcellulose prepared in Preparation Example 3 and 4.5 g of modified enzymatic starch, stir and mix for 15 minutes to form a gelatin solution, add 0.15 g of EDC, stir and react for 3 hours, and dry to obtain modified hydroxypropyl methylcellulose for capsule shell material.

[0123] Comparative Example 4

[0124] Compared with Example 3, the difference is that step S2 is not performed.

[0125] The details are as follows:

[0126] S1. 10 g of hydroxypropyl methylcellulose prepared in Preparation Example 3 was added to 200 mL of methanol, stirred and dispersed at 500 r / min for 10 min, 2.5 g of silane coupling agent KH560 was added, heated to 45 ° C, stirred for 3 h, filtered, washed, and dried to obtain silane-modified hydroxypropyl methylcellulose;

[0127] S2. 13 g of starch was added to acetonitrile, stirred and dispersed at 500 r / min for 10 min, 3.5 g of composite silane coupling agent was added, heated to 45 ° C, stirred and reacted for 2 h, filtered, washed, and dried to obtain modified starch;

[0128] The composite silane coupling agent is a mixture of KH602 and KH792, with a mass ratio of 4:2.5;

[0129] S3. Add 10g gelatin into 500mL water, heat to 75°C, stir to dissolve, add 14g silane-modified hydroxypropyl methylcellulose and 4.5g modified starch, stir and mix for 15min to form a gelatin solution, add 0.15g EDC, stir and react for 3h, and dry to obtain modified hydroxypropyl methylcellulose for capsule shell material.

[0130] Comparative Example 5

[0131] Compared with Example 3, the difference is that step S3 is not performed.

[0132] The details are as follows:

[0133] S1. 10 g of hydroxypropyl methylcellulose prepared in Preparation Example 3 was added to 200 mL of methanol, stirred and dispersed at 500 r / min for 10 min, 2.5 g of silane coupling agent KH560 was added, heated to 45 ° C, stirred for 3 h, filtered, washed, and dried to obtain silane-modified hydroxypropyl methylcellulose;

[0134] S2. Add 50 g of starch to 1 L of water, add 4 g of amylase, hydrolyze at 37 ° C for 2 h, inactivate the enzyme, add ethanol until the ethanol content of the system is 80 wt%, precipitate for 1 h, filter, wash, and dry to obtain enzymatic starch;

[0135] The amylases are α-amylase and β-amylase, with a mass ratio of 4:2;

[0136] S3. Add 10g gelatin into 500mL water, heat to 75°C, stir to dissolve, add 14g silane-modified hydroxypropyl methylcellulose and 4.5g enzymatic starch, stir and mix for 15min to form a gelatin solution, add 0.15g EDC, stir and react for 3h, and dry to obtain modified hydroxypropyl methylcellulose for capsule shell material.

[0137] Comparative Example 6

[0138] Compared with Example 3, the difference is that gelatin is not added in step S4.

[0139] The details are as follows:

[0140] S4. Add 14 g of silane-modified hydroxypropyl methylcellulose and 4.5 g of modified enzymatic starch into 500 mL of water, stir and mix for 15 min to form a gel solution, add 0.15 g of EDC, stir and react for 3 h, and dry to obtain modified hydroxypropyl methylcellulose for capsule shell material.

[0141] Comparative Example 7

[0142] Compared with Example 3, the difference is that EDC is not added in step S4.

[0143] The details are as follows:

[0144] S4. Add 10 g of gelatin into 500 mL of water, heat to 75°C, stir to dissolve, add 14 g of silane-modified hydroxypropyl methylcellulose and 4.5 g of modified enzymatic starch, stir and mix for 15 minutes to form a gelatin solution, dry, and obtain modified hydroxypropyl methylcellulose for capsule shell material.

[0145] Test Example 1

[0146] The capsule shell material prepared in Examples 1-5 and Comparative Examples 1-7 was added to water with modified hydroxypropyl methylcellulose, adjusted to a viscosity of 200-210 mPa·s, defoamed, and evenly spread in a plastic culture dish by casting, dried, and cut into a rectangular film of 15 mm×30 mm and a thickness of 0.08-0.10 mm. The film was placed in a relative humidity of 50% for 24 hours, and the tensile strength at break was measured on a microcomputer-controlled electronic universal testing machine with a clamping distance of 20 mm and a stretching rate of 100 mm / min. The results are shown in Table 2.

[0147] Table 2

[0148] Group Membrane tensile strength (MPa) Example 1 24.65 Example 2 25.04 Example 3 25.12 Example 4 23.05 Example 5 23.16 Comparative Example 1 22.75 Comparative Example 2 22.37 Comparative Example 3 21.94 Comparative Example 4 22.39 Comparative Example 5 21.17 Comparative Example 6 18.48 Comparative Example 7 20.37

[0149] It can be seen from the above table that the modified hydroxypropyl methylcellulose used for capsule shell materials prepared in Examples 1-3 of the present invention has good mechanical properties.

[0150] The film prepared above was placed in a drying oven at a humidity of 10% and a temperature of 25°C for drying, and taken out after 24 hours, and weighed, which was recorded as W0. It was then placed in a closed desiccator filled with a saturated NaNO3 solution and a humidity of 75%, and taken out after 24 hours, and its mass was weighed until the mass was constant, which was recorded as W, and the moisture content (%) was calculated. The results are shown in Table 3.

[0151] Moisture content (%) = (W-W0) / W0×100%

[0152] Table 3

[0153] Group Moisture content (%) Example 1 4.5 Example 2 4.3 Example 3 4.0 Example 4 6.5 Example 5 6.9 Comparative Example 1 5.5 Comparative Example 2 5.2 Comparative Example 3 6.8 Comparative Example 4 8.5 Comparative Example 5 7.4 Comparative Example 6 8.9 Comparative Example 7 8.1

[0154] It can be seen from the above table that the water absorption rate of the modified hydroxypropyl methylcellulose used for the capsule shell material prepared in Examples 1-3 of the present invention is relatively low.

[0155] Test Example 2

[0156] The capsule shell materials prepared in Examples 1-5 and Comparative Examples 1-7 were added to water with modified hydroxypropyl methylcellulose, adjusted to a viscosity of 200-210 mPa·s, defoamed, and prepared into hollow capsules. After the drug was filled, the capsules were sealed by a capsule sealing machine at a sealing speed of 75 rpm, and placed in a constant temperature incubator at a temperature of 40°C for stability investigation, and the drug volatilization rate was calculated. The results are shown in Table 4.

[0157] Table 4

[0158] Group Drug volatilization rate (%) Example 1 12.09 Example 2 11.88 Example 3 11.75 Example 4 14.35 Example 5 14.87 Comparative Example 1 13.45 Comparative Example 2 13.09 Comparative Example 3 16.37 Comparative Example 4 16.85 Comparative Example 5 17.85 Comparative Example 6 19.27 Comparative Example 7 18.62

[0159] It can be seen from the above table that the capsule shell materials prepared in Examples 1-3 of the present invention have low drug volatility after being encapsulated with modified hydroxypropyl methylcellulose and have good stability.

[0160] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing modified hydroxypropyl methylcellulose for capsule shell material, characterized in that: Hydroxypropyl methylcellulose prepared from straw is modified with KH560 to obtain silane-modified hydroxypropyl methylcellulose, which is mixed with modified enzymatic starch obtained by enzymatic hydrolysis and modification with a silane coupling agent and added into water, gelatin is added, and the mixture is stirred to form a gelatin solution, and EDC is added, stirred to react, and modified hydroxypropyl methylcellulose for capsule shell material is obtained.

2. The preparation method according to claim 1, characterized in that: The following steps are involved: S1. Add hydroxypropyl methylcellulose to methanol, stir and disperse evenly, add silane coupling agent KH560, heat and stir to react, filter, wash, and dry to obtain silane-modified hydroxypropyl methylcellulose; S2. Add starch to water, add amylase to hydrolyze, inactivate the enzyme, add ethanol to precipitate, filter, wash, and dry to obtain enzymatic starch; S3. The enzymatic starch was added to acetonitrile, stirred and dispersed evenly, a composite silane coupling agent was added, heated and stirred to react, filtered, washed, and dried to obtain a modified enzymatic starch; S4. Add gelatin into water, heat to dissolve, add silane-modified hydroxypropyl methylcellulose and modified enzymatic starch, stir and mix evenly to form a gelatin solution, add EDC, stir to react, and dry to obtain modified hydroxypropyl methylcellulose for capsule shell material.

3. The preparation method according to claim 2, characterized in that: The preparation method of hydroxypropyl methylcellulose described in step S1 is as follows: T1. Wash the straw, dry it, crush it, add it to the alkali mixture for pretreatment, filter it, wash it, and dry it to obtain pretreated straw powder; T2. The pretreated straw powder was added to the acid solution, heated to reflux for extraction, filtered, washed, and dried to obtain straw cellulose; T3. Adding straw cellulose to alkali solution, heating and stirring the reaction, filtering, washing, and drying to obtain alkali cellulose; T4. Add alkali cellulose to an organic solvent, add methyl chloride and propylene oxide, heat for etherification reaction, filter, wash and dry to obtain hydroxypropyl methylcellulose.

4. The preparation method according to claim 3, characterized in that: The straw in step T1 is selected from at least one of wheat straw, corn straw, rice straw and sorghum straw, the alkaline mixed solution is an aqueous solution containing 10-15wt% NaOH, 3-5wt% urea and 2-3wt% thiourea, the pretreatment temperature is 40-50°C and the time is 1-3h; the solid-liquid ratio of the pretreated straw powder and the acid solution in step T2 is 1:10-15g / mL, the heating reflux extraction time is 2-3h, and the acid solution is a 1-3mol / L nitric acid solution.

5. The preparation method according to claim 3, characterized in that: The alkali solution in step T3 is an aqueous solution containing 7-10wt% NaOH, 10-20wt% isopropanol and 7-12wt% ethanol, and the temperature of the heating and stirring reaction is 55-65°C and the time is 1-2h; the mass ratio of alkali cellulose, methyl chloride and propylene oxide in step T4 is 10:14-17:2-3, the temperature of the heating etherification reaction is 60-70°C and the time is 1-3h, and the organic solvent is a mixed solvent of toluene and isopropanol in a volume ratio of 4-6:

3.

6. The preparation method according to claim 2, characterized in that: In step S1, the mass ratio of hydroxypropyl methylcellulose to silane coupling agent KH560 is 10:2-3, the temperature of the heating and stirring reaction is 40-50° C., and the time is 2-4 hours.

7. The preparation method according to claim 2, characterized in that: In step S2, the mass ratio of starch to amylase is 40-60:3-5, the temperature of the enzymatic hydrolysis is 35-40°C, the time is 1-3h, and the amylase is α-amylase and β-amylase, with a mass ratio of 3-5:

2.

8. The preparation method according to claim 2, characterized in that: In step S3, the mass ratio of the enzymatic starch and the composite silane coupling agent is 12-15:3-4, the composite silane coupling agent is selected from at least two of KH550, KH602, and KH792, preferably, a mixture of KH602 and KH792, with a mass ratio of 3-5:2-3, and the temperature of the heating and stirring reaction is 40-50° C., and the time is 1-3h.

9. The preparation method according to claim 2, characterized in that: In step S4, the mass ratio of gelatin, silane-modified hydroxypropyl methylcellulose, modified enzymatic starch and EDC is 10:12-15:3-6:0.1-0.2, the heating temperature is 60-70° C., and the stirring reaction time is 2-4 hours.

10. A modified hydroxypropyl methylcellulose for capsule shell material obtained by the preparation method according to any one of claims 1 to 9.