Preparation method and application of deer skin glue microcapsule sustained-release tablet with honeycomb pore carrier structure

Abstract

The present application relates to a kind of preparation method and application of deerskin glue microcapsule sustained-release tablets with honeycomb pore carrier structure.The conventional deerskin glue preparation has the problems of fast in-vivo release speed, large blood concentration fluctuation, short action time and low bioavailability. By constructing honeycomb pore carrier structure, the bioavailability and action time of deerskin glue are effectively improved. Its preparation method includes deerskin glue enzymolysis, composite carrier solution configuration, emulsification crosslinking, pore-forming agent removal and tabletting steps. The materials used have no toxicity residues, are suitable for conventional equipment and do not require additional special equipment. The pore structure of the sustained-release tablets is controllable and has excellent sustained-release effect, and can be widely used in the field of pharmaceutical preparations.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a method for preparing and applying a deer hide gelatin microcapsule sustained-release tablet with a honeycomb porous carrier structure. Background Technology

[0002] Deer hide is a traditional Chinese medicine with a long history of medicinal use. As early as the *Compendium of Materia Medica*, it was recorded that deer hide "tonifies qi, astringes essence, and heals sores." The *Sichuan Materia Medica* also records that it "tonifies qi, astringes deficiency and lubrication, treats leukorrhea, metrorrhagia, kidney deficiency and seminal emission, and can be applied to all kinds of sores." The *Beijing Municipal Standards for Processing Traditional Chinese Medicine* describes deer hide glue as salty in taste, warm in nature, and entering the liver and kidney meridians. Its main functions are to tonify qi, astringe deficiency and lubrication, and strengthen muscles and bones. It can be used for emaciation, lower back pain, tinnitus, dizziness, chronic cough, hemoptysis, shortness of breath, irregular menstruation, metrorrhagia, and leukorrhea in women. Its warm nature allows it to tonify yang, nourish yin and blood, and stop bleeding. Deer hide glue is made from the hide of sika deer (Cervus nippon Temminck) or red deer (Cervus elaphus Linnaeus). Modern research shows that deer hide glue is rich in collagen and has the effects of tonifying blood, stopping bleeding, tonifying the kidneys, and nourishing yin. Traditional deer hide gelatin preparations are mostly in the form of ordinary tablets, capsules, or oral liquids, which have problems such as rapid release in vivo, large fluctuations in blood drug concentration, and short duration of action, requiring frequent administration. Furthermore, as a biological macromolecule, deer hide gelatin is easily degraded by gastrointestinal enzymes after oral administration, resulting in low bioavailability. Current research on deer hide gelatin as a microcapsule core material and sustained-release formulation carrier is still limited, and its potential in modern drug delivery systems remains to be explored. In modern drug delivery systems, oral sustained-release tablets are widely used due to their ability to reduce dosing frequency, maintain stable blood drug concentrations, and improve patient compliance. Traditional sustained-release tablets typically achieve slow drug release through matrix tablets or coating technology. However, these technologies often face several challenges: for example, for poorly soluble drugs, the dense tablet structure restricts the penetration of the dissolution medium, leading to incomplete drug dissolution and low bioavailability; some matrix tablets may experience a 'burst release' phenomenon during release, causing fluctuations in blood drug concentration. Furthermore, their manufacturing processes are complex, require high parameter control, and exhibit significant batch-to-batch variations. Microencapsulation technology is an advanced technique that encapsulates drugs (core material) within polymeric materials (encapsulation material) to form tiny particles, effectively protecting drug activity, masking unpleasant odors, and achieving controlled or sustained release. Microencapsulating drugs and then compressing them into tablets is a common strategy for developing sustained-release formulations. However, during conventional tableting, the microcapsules are compressed under high pressure, forming a dense core structure. This can also affect water penetration and drug dissolution, failing to fully realize the advantages of microencapsulation. Summary of the Invention The purpose of this invention is to overcome the shortcomings of existing technologies and provide a method for preparing deerskin glue microcapsule sustained-release tablets with a honeycomb porous carrier structure. The sustained-release tablets prepared by this method have a controllable pore structure and excellent sustained-release effect, effectively improving the bioavailability of deerskin glue and prolonging its duration of action. To achieve the above-mentioned objectives of this invention, the following technical solution is adopted: The core of the technical solution of this invention lies in the construction of a "honeycomb porous carrier structure", which specifically includes the following: This invention relates to a deerskin gelatin microcapsule sustained-release tablet with a honeycomb porous carrier structure, characterized by comprising an active core material, a composite carrier material, a controllable pore-forming agent, a crosslinking agent, an emulsifier, a pH adjuster, and tablet excipients, wherein the composite carrier material (rigid) is specifically at least one of 2-5 parts of chitosan and 1.5-4 parts of hydroxypropyl chitosan. Furthermore, the active core material is 10-18 parts of deer hide gum enzymatic hydrolysate. Furthermore, the composite carrier material (rigid) is chitosan and its derivatives, specifically at least one of 2-5 parts of chitosan or 1.5-4 parts of hydroxypropyl chitosan; the composite carrier material (flexible) is at least one of 3-7 parts of sodium alginate and 2-5 parts of carrageenan; and the composite carrier material (slow-release regulating component) is at least one of 1-3 parts of hydroxypropyl methylcellulose and 0.8-2.5 parts of povidone K30. The controllable pore-forming agent is at least one of the following: 2-6 parts of spherical ammonium bicarbonate, 3-7 parts of sodium citrate, 2.5-5.5 parts of polyethylene glycol, and 4-8 parts of lactose. This invention relates to a method for preparing and applying a chamois gelatin microcapsule sustained-release tablet with a honeycomb porous carrier structure. Traditional chamois gelatin formulations suffer from problems such as rapid in vivo release, large fluctuations in blood drug concentration, short duration of action, and low bioavailability. By constructing a honeycomb porous carrier structure, the bioavailability and duration of action of chamois gelatin are effectively improved. The preparation method includes steps such as enzymatic hydrolysis of chamois gelatin, preparation of a composite carrier solution, emulsification and cross-linking, removal of pore-forming agents, and tableting. The materials used are non-toxic and residue-free, compatible with conventional equipment, and require no additional specialized equipment. This sustained-release tablet has a controllable pore structure and excellent sustained-release effect, and can be widely used in the field of pharmaceutical formulation. The crosslinking agent is at least one of 0.1-0.3 parts of glutaraldehyde, 0.05-0.2 parts of genipin, and 0.3-0.6 parts of sodium tripolyphosphate. The emulsifier is at least one selected from Tween-80 (0.5-1.2 parts), Span-80 (0.3-0.8 parts), and polyglycerol fatty acid ester (0.4-1.0 parts). The pH adjuster is a 1 mol / L hydrochloric acid solution, a 1 mol / L sodium hydroxide solution, or an appropriate amount of sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution. The tablet excipients (disintegrants) are at least one of 3-6 parts microcrystalline cellulose and 1.5-4 parts crospovidone; the tablet excipients (lubricants) are at least one of 0.1-0.3 parts magnesium stearate, 0.15-0.35 parts sodium stearate fumarate, and 0.3-0.6 parts talc; and the tablet excipients (fillers) are at least one of 2-5 parts lactose and 1.5-4 parts mannitol. This invention also relates to a method for preparing the deerskin gelatin microcapsule sustained-release tablet with the honeycomb porous carrier structure, comprising: (1) Crush the deer hide glue block through an 80-mesh sieve, add 10-12 times the amount of deionized water, stir and dissolve at 50 ℃, adjust the pH to 7.5-8.5 (alkaline protease) or 6.0-7.0 (neutral protease), add the corresponding protease (enzyme-substrate ratio 1:100-1:120), enzymatically hydrolyze at 50-55 ℃ for 2-3 hours, inactivate the enzyme at 85-90 ℃ for 10-15 min, centrifuge at 5000-6000 rpm for 10-15 min, collect the supernatant, freeze dry at -40 ℃ (vacuum degree 0.08-0.1 MPa) to obtain a light yellow powder for later use; (2) Preparation of composite carrier solution: The rigid component is dissolved in the corresponding solvent chitosan / hydroxypropyl chitosan is dissolved in 1% hydrochloric acid solution, with a solid-liquid ratio of 1:40~1:60, and stirred at 25~30 ℃ for 1.5~2.5 h until completely dissolved to prepare a solution with a concentration of 2~5%; the flexible component and the slow-release regulating component are dissolved in deionized water (solid-liquid ratio of 1:30~1:50), and stirred at 30~35 ℃ for 2~3 h until completely dissolved to prepare a composite polysaccharide solution with a concentration of 4~8% for later use; (3) Add the deer hide gum hydrolysate powder to the complex polysaccharide solution, stir until dissolved, add emulsifier (used alone or in combination), homogenize at 1800~2200 rpm for 4~6 min to form an aqueous phase; add the controllable pore-forming agent to the rigid component solution, ultrasonically disperse at 180~220 W for 8~12 min (frequency 40 kHz) to ensure that the pore-forming agent is uniformly suspended and form an oil phase simulation system; (4) Slowly add the oil phase to the aqueous phase at a volume ratio of 1:2.5 to 1:3.5, stir and emulsify at 2800 to 3200 rpm for 12 to 18 minutes, adjust the pH to 4.8 to 5.5 with a pH adjuster, and react at a constant temperature of 35 to 38 °C for 0.8 to 1.2 hours to induce re-aggregation of the capsule wall; add the crosslinking agent and continue the reaction for 25 to 35 minutes to complete the crosslinking. (5) Remove the pore-forming agent by pyrolysis (ammonium bicarbonate: 60~70 ℃ for 25~35 min) or water washing (sodium citrate / PEG / lactose: soak in deionized water for 15~20 min) to form honeycomb pores; collect the microcapsules by centrifugation (4500~5500 rpm, 8~12 min), wash with deionized water 3~4 times, freeze dry at -40 ℃ to obtain deer skin glue microcapsule powder, with a particle size controlled at 50~250 µm and a porosity of 45~80%; (6) Mix the deer hide glue microcapsule powder with disintegrant, filler (optional) and lubricant for 12-18 min (mixing speed 18-22 rpm), compress the tablets using a rotary tablet press, and control the pressure at 7-11 MPa to make sustained-release tablets containing 80-120 mg of deer hide glue hydrolysate per tablet, with a tablet weight of 200-300 mg and a hardness of 8-12 kgf; The present invention has the following beneficial effects: (1) This invention is compatible with conventional equipment and does not require the addition of special equipment. Existing pharmaceutical or food production equipment such as homogenizers, centrifuges, and rotary tablet presses can be used, and enterprises do not need to invest additional equipment funds. (2) The materials have no toxic residues. All carrier materials and auxiliary reagents are pharmaceutical grade or food grade, and no unknown ingredients are added. Attached Figure Description Figure 1 Schematic diagram of honeycomb porous carrier microcapsule sustained-release tablet structure. Figure 2 Microcapsule size distribution diagram. Figure 3 : Schematic diagram of the preparation process. Detailed Implementation The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products. Example 1 Raw material composition (by weight): 15 parts of deer hide gum hydrolysate (alkaline protease hydrolysis), 4 parts of chitosan (degree of deacetylation ≥90%), 5 parts of sodium alginate (guluronic acid content ≥70%), 2 parts of HPMCK15M (hydroxypropyl methylcellulose), 5 parts of spherical ammonium bicarbonate (particle size 100~200 µm), 0.15 parts of genipin, 1.0 part of Tween-80, 5 parts of microcrystalline cellulose, and 0.2 parts of magnesium stearate. The preparation method is as follows: S1. Dissolve deer hide gelatin powder in 11 times the amount of water, adjust the pH to 8.0, add alkaline protease (0.8%), enzymatically hydrolyze at 53℃ for 2.5 h, inactivate the enzyme at 88℃ for 12 min, centrifuge at 5500 rpm for 12 min, collect the supernatant, and freeze-dry at -40℃ to obtain the enzymatic hydrolysate. S2. Chitosan was dissolved in 1% hydrochloric acid solution (solid-liquid ratio 1:50) and stirred at 28 ℃ for 2 h to prepare a 4% concentration solution; sodium alginate and HPMC K15M were dissolved in deionized water (solid-liquid ratio 1:40) and stirred at 32 ℃ for 2.5 h to prepare a 6% concentration solution. S3. Add the enzymatic hydrolysate to the complex polysaccharide solution, stir to dissolve, then add Tween-80 and homogenize at 2000 rpm for 5 min to form the aqueous phase; add ammonium bicarbonate to the chitosan solution and ultrasonically disperse at 200 W for 10 min to form the oil phase; slowly add the aqueous phase to the oil phase at a volume ratio of 1:3, stir and emulsify at 3000 rpm for 15 min, adjust the pH to 5.2 with hydrochloric acid / sodium hydroxide, react at 37 ℃ for 1 h, add genipin and continue the reaction for 30 min. S4. The reaction solution was heated to 65 °C and kept at that temperature for 30 min. The microcapsules were collected by centrifugation at 5000 rpm for 10 min, washed three times with deionized water, and freeze-dried to obtain microcapsules (particle size 100~200 µm, porosity 75%). Tableting: The microcapsules were mixed with microcrystalline cellulose and magnesium stearate for 15 min and compressed into tablets at 9 MPa. Each tablet weighed 250 mg and contained 100 mg of deer hide gum hydrolysate. Example 2 Raw material composition (by weight): 12 parts of deer hide gum hydrolysate (hydrolyzed by neutral protease), 3 parts of hydroxypropyl chitosan, 4 parts of carrageenan (κ-type), 2.5 parts of HPMC K4M, 6 parts of lactose (particle size 50~100 µm), 0.4 parts of sodium tripolyphosphate, 0.8 parts of polyglycerol fatty acid ester, 3 parts of crospovidone, 0.3 parts of sodium stearate fumarate, and 3 parts of mannitol. S1. Dissolve deer hide glue powder in 10 times its volume of water, adjust the pH to 6.5, add neutral protease (0.7%), enzymatically hydrolyze at 52℃ for 2.5 h, inactivate the enzyme at 85℃ for 15 min, centrifuge at 5000 rpm for 10 min, collect the supernatant, and freeze-dry to obtain the enzymatic hydrolysate; dissolve hydroxypropyl chitosan in 1% hydrochloric acid solution (solid-liquid ratio 1:45), stir at 25℃ for 2 h to prepare a 3% concentration solution; dissolve carrageenan and HPMC K4M in deionized water (solid-liquid ratio 1:35), stir at 30℃ for 2 h to prepare a 5% concentration solution. S2. The enzymatic hydrolysate was added to the complex polysaccharide solution, stirred and dissolved, and then polyglycerol fatty acid ester was added. The mixture was homogenized at 1900 rpm for 5 min to form an aqueous phase. Lactose was added to the hydroxypropyl chitosan solution and ultrasonically dispersed at 190 W for 10 min to form an oil phase. The oil phase was slowly added dropwise to the aqueous phase at a volume ratio of 1:3.2, and the mixture was stirred and emulsified at 2900 rpm for 16 min. The pH was adjusted to 5.0 with buffer solution, and the mixture was reacted at 36 ℃ for 1.1 h. Sodium tripolyphosphate was added and the reaction was continued for 32 min. S3. The microcapsules were soaked in deionized water for 18 min to remove lactose, centrifuged at 4800 rpm for 11 min, washed 4 times, and freeze-dried to obtain microcapsules (particle size 80~180 µm, porosity 50%). S4. The microcapsules were mixed with crospovidone, mannitol and sodium stearate for 16 min, and then compressed into tablets at 8 MPa. Each tablet weighed 280 mg and contained 90 mg of deer hide gum hydrolysate. Example 3 Raw material composition (by weight): 18 parts of deer hide gum hydrolysate, 5 parts of chitosan (degree of deacetylation ≥ 85%), 7 parts of sodium alginate (molecular weight 200~300 kDa), 2 parts of povidone K30, 5 parts of PEG6000, 0.25 parts of glutaraldehyde, 0.6 parts of Span-80, 4 parts of low-substituted hydroxypropyl cellulose, 0.5 parts of talc, and 5 parts of lactose. The steps are the same as in Example 1, except that the pore-forming agent is removed by water washing and the tableting pressure is 7.5 MPa.

Claims

1. A method for preparing deerskin gelatin microcapsule sustained-release tablets with a honeycomb porous carrier structure, characterized in that... Includes the following steps: (1) Crush the deer hide glue block and sieve it. Add deionized water, stir to dissolve, adjust the pH, add the corresponding protease, hydrolyze at constant temperature, inactivate the enzyme, centrifuge for 10-15 min, take the supernatant, freeze dry to obtain a light yellow powder. (2) The rigid component is dissolved in 1% hydrochloric acid solution with a solid-liquid ratio of 1:40~1:60 and stirred until completely dissolved. The flexible component and the slow-release regulating component are dissolved in deionized water with a solid-liquid ratio of 1:30~1:50 and stirred until completely dissolved to prepare a complex polysaccharide solution. (3) Add the deer skin gum hydrolysate powder to the complex polysaccharide solution, stir until dissolved, add emulsifier, and homogenize to form an aqueous phase; add the controllable pore-forming agent to the rigid component solution, and ultrasonically disperse to form an oil phase; slowly add the oil phase to the aqueous phase according to the volume ratio, stir to emulsify, adjust the pH value with pH adjuster, react at a constant temperature, add crosslinking agent, and continue the reaction to complete crosslinking; (4) The pore-forming agent was removed by pyrolysis to form honeycomb pores; the microcapsules were collected by centrifugation, washed with deionized water, and freeze-dried to obtain deerskin glue microcapsule powder with a particle size of 50~250 µm and a porosity of 45~80%; (5) Mix the deer hide glue microcapsule powder with disintegrant, filler and lubricant, and compress it into tablets using a rotary tablet press. The pressure is controlled at 7~11 MPa to make sustained-release tablets containing 80~120 mg of deer hide glue hydrolysate per tablet, with a tablet weight of 200~300 mg and a hardness of 8~12 kgf.

2. The preparation method according to claim 1, characterized in that: The active core material is deer hide gum enzymatic hydrolysate, and the dosage is 10-18 parts (by weight).

3. The preparation method according to claim 1, characterized in that: The composite carrier material includes 2-5 parts of chitosan or 1.5-4 parts of hydroxypropyl chitosan and 3-7 parts of sodium alginate or 2-5 parts of carrageenan, as well as 1-3 parts of hydroxypropyl methylcellulose or 0.8-2.5 parts of povidone K30.

4. The preparation method according to claim 1, characterized in that: The controllable pore-forming agent comprises 2-6 parts of spherical ammonium bicarbonate, 3-7 parts of sodium citrate, 2.5-5.5 parts of polyethylene glycol, or 4-8 parts of lactose.

5. The preparation method according to claim 1, characterized in that: The crosslinking agent includes 0.1-0.3 parts of glutaraldehyde, 0.05-0.2 parts of genipin, or 0.3-0.6 parts of sodium tripolyphosphate.

6. The preparation method according to claim 1, characterized in that: The emulsifier includes 0.5 to 1.2 parts of Tween-80, 0.3 to 0.8 parts of Span-80, or 0.4 to 1.0 parts of polyglycerol fatty acid ester.

7. The preparation method according to claim 1, characterized in that: The pH adjuster is 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide solution, or sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution.

8. The preparation method according to claim 1, characterized in that: The tablet excipients include 3-6 parts of microcrystalline cellulose or 1.5-4 parts of crospovidone, 0.1-0.3 parts of magnesium stearate, 0.15-0.35 parts of sodium stearate fumarate or 0.3-0.6 parts of talc, and 2-5 parts of lactose or 1.5-4 parts of mannitol.

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