A zuogui pill and a preparation method thereof

Abstract

The present application relates to the field of traditional Chinese medicine pills, and discloses a Zuogui pill and a preparation method thereof. The Zuogui pill comprises a pill core and a coating covering the pill core; the pill core comprises medicinal material powder; and the coating comprises modified controlled-release coating material, which is controlled-release coating material connected with an o-benzene diol group through a polypeptide chain. The Zuogui pill of the present application can make the medicinal material powder without extraction release the medicinal effective components more fully in the digestive tract, improve the bioavailability of the medicine, and avoid the long retention time of the Zuogui pill on the mucosa of the digestive tract, thereby causing gastrointestinal discomfort.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine pills, and in particular to a Zuogui pill and its preparation method. Background Technology

[0002] Zuogui Pill was modified by Zhang Jingyue, a physician specializing in warming and tonifying medicine in the Ming Dynasty, based on Liuwei Dihuang Pill and Jinkui Shenqi Pill. It mainly consists of Rehmannia glutinosa, Achyranthes bidentata, Cuscuta chinensis, Dioscorea opposita, Cornus officinalis, Lycium barbarum, tortoise shell glue, and deer antler glue. It can be used for symptoms such as deficiency of true yin and kidney water, deficiency of essence and marrow, and depletion of body fluids. Volume Five of the *Medical Essentials* states: "The formula uses Rehmannia glutinosa (Shu Di Huang) to tonify the kidneys as the chief ingredient; Dioscorea opposita (Shan Yao) to tonify the spleen; and Cornus officinalis (Shan Zhu Yu) to tonify the liver as the assistant ingredients; combined with Lycium barbarum (Gou Qi) to tonify essence, Achyranthes bidentata (Chuan Xi) to tonify blood, Cuscuta chinensis (Tu Si Zi) to tonify the qi of the kidneys, and deer antler glue and tortoise shell glue to tonify the original qi of the Du and Ren meridians. Although it is called Zuo Gui (Left Returning to the Source), it actually tonifies all three Yin meridians, a formula that harmonizes water and fire." Recent experimental studies have also shown that it has effects such as delaying aging, repairing damage to the nervous system, regulating endocrine and immune systems, improving bone metabolism, and promoting reproductive development. Currently, it is widely used clinically to treat various diseases such as senile chronic bronchitis, hypertension, senile dementia, chronic nephritis, lumbar muscle strain, and infertility.

[0003] Currently, Zuogui Pills are often made from medicinal extracts. For example, patents CN201510043415.1 and CN201610703802.8 describe methods for obtaining medicinal extracts, namely decoction and supercritical CO2 extraction, which are then processed into nano-sustained-release microspheres or pills. While this method can accelerate the absorption of the active ingredients, the extraction process is complex and can lead to the loss of active ingredients. Conversely, if the medicinal materials are pulverized and directly made into Zuogui Pills without extraction, although the loss during the extraction process can be avoided, the slow rate at which the powdered medicinal materials release the active ingredients in the body results in limited absorption of the active ingredients in the digestive tract and a low bioavailability. Summary of the Invention

[0004] To address the technical problem that the extraction process leads to the loss of active pharmaceutical ingredients, while not extracting the ingredients results in low bioavailability of the active ingredients in Zuogui Pills, this invention provides a Zuogui Pill. This Zuogui Pill, by adding a special modified controlled-release coating material to the coating, enables the unextracted medicinal powder to release its active pharmaceutical ingredients more fully in the digestive tract, improving bioavailability. Simultaneously, it avoids prolonged retention of the Zuogui Pill on the digestive tract mucosa, thus preventing gastrointestinal discomfort.

[0005] The specific technical solution of this invention is as follows:

[0006] First, the present invention provides a Zuogui Pill, comprising a pill core and a coating covering the pill core; the pill core comprises medicinal powder; the coating comprises a modified controlled-release coating material, wherein the modified controlled-release coating material is a controlled-release coating material with catechol groups linked by polypeptide chains.

[0007] Upon entering the gastrointestinal tract, the controlled-release coating material does not dissolve rapidly, preventing the Zuogui Pill from disintegrating. The grafted polypeptide chains—catechol groups—remain within the coating. Because the catechol groups have strong adhesion to the digestive tract mucosa, utilizing these groups in the coating prolongs the retention time of the Zuogui Pill in the digestive tract. This allows the powdered medicine more time to decompose and release its active ingredients under the action of digestive juices, thus improving the bioavailability of the drug in the Zuogui Pill.

[0008] Furthermore, because Zuogui Pills are relatively large, prolonged adhesion to the gastrointestinal mucosa can easily cause gastrointestinal discomfort. In this invention, the catechol groups and the controlled-release coating material are bridged by polypeptide chains. Since polypeptide chains can be degraded by digestive tract proteases, over time within the digestive tract, the catechol groups separate from the coating along with the polypeptide chains. This gradually weakens the adhesion of Zuogui Pills to the digestive tract mucosa, causing them to detach and preventing prolonged retention of Zuogui Pills on the mucosa, thus avoiding gastrointestinal discomfort.

[0009] Preferably, the coating further includes an elastic material and a gastrosoluble coating material; the pellet core further includes a disintegrant.

[0010] While the coating containing the modified controlled-release coating material of this invention can prolong the retention time of Zuogui Pill in the gastrointestinal tract, it also hinders the contact between the medicinal powder in the pill core and digestive juices, thereby slowing down the release of the active pharmaceutical ingredient and limiting the improvement of drug bioavailability. To address this, this invention adds a gastrointestinal-soluble coating material and an elastic material to the coating, along with a disintegrant in the pill core, achieving the following effects: When Zuogui Pill enters the stomach, the gastrointestinal-soluble coating material dissolves, creating more pores within the coating. This accelerates the entry of digestive juices into the pill core, allowing them to contact the medicinal powder and promoting the decomposition and release of the active pharmaceutical ingredient under the action of the digestive juices. Furthermore, when the pill core contains a disintegrant, the increased pores in the coating in the stomach promote swelling of the disintegrant upon contact with digestive juices. Simultaneously, the elastic material allows Zuogui Pill to expand under the action of the disintegrant, facilitating the entry of digestive juices into the pill core and accelerating the release of the active pharmaceutical ingredient within.

[0011] Preferably, the raw materials for the core of the pill include the following components in parts by weight: 200 parts of Rehmannia glutinosa, 90-110 parts of Cuscuta chinensis, 70-80 parts of Achyranthes bidentata, 95-105 parts of tortoise shell glue, 95-105 parts of deer antler glue, 95-105 parts of Dioscorea opposita, 95-105 parts of Cornus officinalis, 95-105 parts of Lycium barbarum, 0-70 parts of honey, 0-25 parts of lubricant, and 90-110 parts of disintegrant.

[0012] Preferably, the lubricant comprises pharmaceutical charcoal and talc in a mass ratio of 3.5 to 4.5:1.

[0013] Preferably, the disintegrant includes sodium carboxymethyl starch.

[0014] Preferably, the polypeptide chain is poly-L-glutamic acid composed of L-glutamic acid residues linked by α-amide bonds; the controlled-release coating material is cellulose acetate.

[0015] Poly-L-glutamic acid, which is composed of L-glutamic acid residues linked by α-amide bonds, is sensitive to digestive tract proteases and has a suitable decomposition rate under the action of digestive tract proteases. When used to bridge catechol groups and controlled-release coating materials, it can not only improve the bioavailability of Zuogui Pill to a large extent, but also avoid the excessive retention time of Zuogui Pill on the digestive tract mucosa.

[0016] Preferably, the preparation method of the modified controlled-release coating material includes the following steps:

[0017] (I) Grafting an aminosilane coupling agent onto cellulose acetate to obtain amino-modified cellulose acetate;

[0018] (II) By ring-opening polymerization, the anhydride in the N-carboxyl ring of 5-benzyl glutamic acid is grafted onto the product of step (I) to obtain cellulose acetate grafted with poly-L-glutamic acid-5-benzyl ester.

[0019] In the N-carboxyl ring anhydride of 5-benzyl glutamic acid, the γ-carboxyl group of glutamic acid is protected by benzyl (benzyl esterification). Using the amino group in aminated cellulose acetate as an initiator, the N-carboxyl ring anhydride of 5-benzyl glutamic acid undergoes a ring-opening polymerization reaction, thereby branching polyglutamic acid onto aminated cellulose acetate. In the obtained product, the γ-carboxyl group in the polyglutamic acid chain is still protected by benzyl, and there is a free carboxyl group at the end of the chain.

[0020] (III) Dopamine is grafted onto the product of step (II) by amidation reaction to obtain cellulose acetate grafted with poly(L-glutamic acid-5-benzyl ester) and catechol groups.

[0021] In step (II), the free carboxyl groups at the ends of the polyglutamic acid chains in the product undergo an amidation reaction with the amino groups in dopamine, thereby grafting catechol groups onto the polyglutamic acid chains.

[0022] (IV) Remove the benzyl group from the product of step (III) to obtain the modified controlled-release coating material.

[0023] Preferably, the preparation method of the modified controlled-release coating material specifically includes the following steps:

[0024] (I) Disperse cellulose acetate in solvent I, add an aminosilane coupling agent to it, carry out a hydrolysis-condensation reaction, separate the product, and obtain aminoated cellulose acetate.

[0025] (II) Dissolve the product of step (I) in solvent II, add the N-carboxyl anhydride of 5-benzyl glutamic acid under inert gas protection, carry out ring-opening polymerization reaction, separate the product, and obtain cellulose acetate grafted with poly-L-glutamic acid-5-benzyl ester.

[0026] (III) Mix the product of step (II), the carboxyl activator and solvent III, add dopamine hydrochloride to it, carry out an amidation reaction, separate the product, and obtain cellulose acetate grafted with poly-L-glutamic acid-5-benzyl ester and catechol groups.

[0027] (IV) The product from step (III) is mixed with solvent IV, and a hydrobromic acid-acetic acid solution is added to carry out a debenzylation reaction to separate the product and obtain the modified controlled-release coating material.

[0028] Preferably, in step (I), the mass ratio of cellulose acetate to aminosilane coupling agent is 1:0.03 to 0.06.

[0029] Preferably, in step (I), the hydrolysis-condensation reaction is carried out at a temperature of 100–110°C for 3–5 hours.

[0030] Preferably, the molar ratio of the aminosilane coupling agent in step (I) to the N-carboxylic acid anhydride in step (II) is 1:5 to 10.

[0031] Preferably, in step (II), the ring-opening polymerization reaction is carried out at a temperature of 20–30°C for 9–15 hours.

[0032] Preferably, in step (III), the pH is adjusted to 5.0–6.0 before adding dopamine hydrochloride; the amidation reaction is carried out at a temperature of 20–30°C for 15–24 hours.

[0033] Preferably, the molar ratio of the aminosilane coupling agent in step (I) to the dopamine hydrochloride in step (III) is 1:1 to 1.5.

[0034] Preferably, in step (IV), the debenzylation reaction is carried out at a temperature of 20–30°C for a time of 1.5–3.5 h.

[0035] Preferably, the mass ratio of the modified controlled-release coating material, the elastic material, and the gastrointestinal coating material is 1:0.4-1.0:0.03-0.08.

[0036] Preferably, the elastic material includes a silicone elastomer.

[0037] Preferably, the gastric-soluble coating material includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinyl alcohol.

[0038] Second, the present invention provides a method for preparing Zuogui Pill, comprising the following steps: dispersing a coating material, including a modified controlled-release coating material, in water to prepare a coating solution; spraying the pill core with the coating solution and then drying it to obtain Zuogui Pill.

[0039] Preferably, the method for preparing the pellet core includes the following steps:

[0040] (1) Pulverization: Pulverize and mix Rehmannia glutinosa, Cuscuta chinensis, Achyranthes bidentata, Dioscorea opposita, Cornus officinalis and Lycium barbarum to obtain medicinal powder;

[0041] (2) Melting: Mix tortoise shell glue and deer antler glue with water, heat and stir to melt the tortoise shell glue and deer antler glue to obtain glue solution;

[0042] (3) Preparation of soft material: Mix the medicinal powder, disintegrant, glue, honey and water to prepare soft material;

[0043] (4) Making wet pellets: After the soft material is pelletized, ethanol is sprayed in for powdering, and lubricant is sprayed in during the process. Then it is polished to obtain wet pellets.

[0044] (5) Drying: Dry the wet pellets to obtain pellet cores.

[0045] Preferably, in step (1), before pulverizing, Rehmannia glutinosa, Cuscuta chinensis, Achyranthes bidentata, Dioscorea opposita, Cornus officinalis, and Lycium barbarum are sterilized. The specific sterilization process includes the following steps: mixing Rehmannia glutinosa, Cuscuta chinensis, Achyranthes bidentata, Dioscorea opposita, Cornus officinalis, and Lycium barbarum with 88-92 vol% alcohol, keeping warm at 55-75°C for no less than 2 hours, then evacuating to a vacuum degree of no less than 0.07 MPa, adding 88-92 vol% alcohol, and cooling for no less than 12 hours.

[0046] Preferably, in step (2), the mass of the water is 1 to 1.5 times the total mass of the tortoise shell glue and deer antler glue.

[0047] Preferably, in step (4), the weight of the wet pills is 1.1 to 1.3 g / 10 pills.

[0048] Preferably, in step (5), the drying is carried out by microwave vacuum drying, with a microwave power of 12-24kW, a drying temperature of 50-60℃, and a drying time of 30-40min.

[0049] Compared with the prior art, the present invention has the following advantages:

[0050] (1) By adding modified controlled-release coating material to the coating, the present invention can achieve better adhesion, so that Zuogui Pill can adhere better to the digestive tract mucosa, thereby effectively improving the bioavailability of the drug, and can also avoid the long retention time of Zuogui Pill on the digestive tract mucosa, which may cause gastrointestinal discomfort.

[0051] (2) By adding gastrosoluble coating material and elastic material to the coating and combining it with the disintegrant in the core of the pill, the present invention can accelerate the decomposition and release of the active ingredients of the medicinal powder under the action of digestive fluid, which is beneficial to improving the bioavailability of the medicine in Zuogui Pill. Attached Figure Description

[0052] Figure 1 The blood drug concentration-time curves of Zuogui Pill after administration are obtained according to the steps of Examples 1 and 4 and Comparative Examples 1 and 2.

[0053] Figure 2 The blood drug concentration-time curve of Zuogui Pill after administration, prepared according to the steps of Example 2;

[0054] Figure 3 The blood drug concentration-time curve after administration of Zuogui Pill prepared according to the steps of Example 3 is shown. Detailed Implementation

[0055] The present invention will be further described below with reference to embodiments.

[0056] General Implementation Examples

[0057] A Zuogui Pill includes a pill core and a coating covering the pill core; the pill core includes medicinal powder; the coating includes a modified controlled-release coating material, wherein the modified controlled-release coating material is a controlled-release coating material with catechol groups linked by polypeptide chains.

[0058] In one specific embodiment, the coating further includes an elastic material and a gastrointestinal coating material, wherein the mass ratio of the modified controlled-release coating material, the elastic material, and the gastrointestinal coating material is 1:0.4-1.0:0.03-0.08; the pellet core further includes a disintegrant.

[0059] In the above specific embodiments, optionally:

[0060] The elastic material includes a silicone elastomer;

[0061] The gastrointestinal coating material includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinyl alcohol.

[0062] In one specific embodiment, the polypeptide chain is poly-L-glutamic acid formed by L-glutamic acid residues linked by α-amide bonds; the controlled-release coating material is cellulose acetate.

[0063] As one specific embodiment, the preparation method of the modified controlled-release coating material includes the following steps:

[0064] (I) Disperse cellulose acetate in solvent I, add an aminosilane coupling agent to it, wherein the mass ratio of cellulose acetate to aminosilane coupling agent is 1:0.03-0.06, carry out hydrolysis and condensation reaction at 100-110°C for 3-5 hours, separate the product, and obtain aminoated cellulose acetate.

[0065] (II) Dissolve the product of step (I) in solvent II, and add glutamic acid 5-benzyl ester N-carboxyl ring anhydride under inert gas protection. The molar ratio of the aminosilane coupling agent to glutamic acid 5-benzyl ester N-carboxyl ring anhydride is 1:5-10. Carry out the ring-opening polymerization reaction at 20-30°C for 9-15 hours, separate the product, and obtain cellulose acetate grafted with poly-L-glutamic acid-5-benzyl ester.

[0066] (III) Mix the product of step (II), the carboxyl activator, and solvent III, adjust the pH to 5.0-6.0, add dopamine hydrochloride, wherein the molar ratio of the aminosilane coupling agent to dopamine hydrochloride is 1:1-1.5, and carry out an amidation reaction at 20-30°C for 15-24 h, and separate the product to obtain cellulose acetate grafted with poly(L-glutamic acid-5-benzyl ester) and catechol groups; (IV) Mix the product of step (III) and solvent IV, add hydrobromic acid-acetic acid solution, and carry out a debenzylation reaction at 20-30°C for 1.5-3.5 h, and separate the product to obtain a modified controlled-release coating material.

[0067] In one specific embodiment, the raw materials of the core pill include the following components in parts by weight: 200 parts of Rehmannia glutinosa, 90-110 parts of Cuscuta chinensis, 70-80 parts of Achyranthes bidentata, 95-105 parts of tortoise shell glue, 95-105 parts of deer antler glue, 95-105 parts of Dioscorea opposita, 95-105 parts of Cornus officinalis, 95-105 parts of Lycium barbarum, 0-70 parts of honey, 0-25 parts of lubricant, and 90-110 parts of disintegrant.

[0068] In the above specific embodiments, optionally:

[0069] The lubricant comprises pharmaceutical charcoal and talc in a mass ratio of 3.5 to 4.5:1;

[0070] The disintegrant includes sodium carboxymethyl starch.

[0071] A method for preparing Zuogui Pills includes the following steps: dispersing a coating material, including a modified controlled-release coating material, in water to prepare a coating solution; spraying the pill core with the coating solution and then drying it to obtain Zuogui Pills.

[0072] As one specific embodiment, the method for preparing the pellet core includes the following steps:

[0073] (1) Sterilization: Mix Rehmannia glutinosa, Cuscuta chinensis, Achyranthes bidentata, Dioscorea opposita, Cornus officinalis and Lycium barbarum with 88-92 vol% alcohol, keep warm at 55-75℃ for no less than 2 hours, then evacuate to a vacuum degree of no less than 0.07 MPa, add 88-92 vol% alcohol, and cool for no less than 12 hours.

[0074] (2) Pulverization: Sterilized Rehmannia glutinosa, Cuscuta chinensis, Achyranthes bidentata, Dioscorea opposita, Cornus officinalis and Lycium barbarum are pulverized and mixed to obtain medicinal powder;

[0075] (3) Melting: Mix tortoise shell glue and deer antler glue with 1 to 1.5 times their weight of water, heat and stir to melt the tortoise shell glue and deer antler glue, and obtain glue solution;

[0076] (4) Preparation of soft material: Mix the medicinal powder, disintegrant, glue, honey and water to prepare soft material;

[0077] (5) Making wet pellets: After the soft material is pelletized, ethanol is sprayed in for powdering, and lubricant is sprayed in during the process. Then it is polished to obtain wet pellets with a weight of 1.1 to 1.3 g / 10 pellets.

[0078] (6) Drying: The wet pellets are dried by microwave vacuum drying method. The microwave power is 12-24kW, the drying temperature is 50-60℃, and the time is 30-40min to obtain pellet cores.

[0079] Example 1

[0080] Cellulose acetate-PGlu-DA was prepared by the following steps:

[0081] (I) Take 1000g of cellulose acetate, add 20 times its weight of n-butanol, stir evenly, then add 50g of silane coupling agent KH550, control the temperature at 105±5℃, and stir for 3-5 hours. Then remove the solvent by rotary evaporation under reduced pressure, wash with water and ethanol successively, and dry to obtain cellulose acetate-NH3.

[0082] (II) Take the cellulose acetate-NH3 obtained in step (1), add 30 times its mass of N,N-dimethylformamide (DMF), stir to dissolve, replace the air with nitrogen, add 400g of glutamic acid 5-benzyl ester N-carboxylate anhydride, and stir at room temperature (26±2℃) for 10h. Then add purified water for precipitation, wash the separated precipitate with water and ethanol in sequence, and dry to obtain cellulose acetate-PBLG.

[0083] (III) Take the cellulose acetate-PBLG obtained in step (II), add 50 times its weight of DMF, stir to dissolve, add 30g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) and 15g of N-hydroxysuccinimide (NHS), stir well, adjust the pH to 5.5, then add 50g of dopamine hydrochloride, and stir at room temperature (26±2℃) for 20h. Then add purified water for precipitation, wash the separated precipitate with water and ethanol successively, and dry to obtain cellulose acetate-PBLG-DA.

[0084] (IV) Take the cellulose acetate-PBLG-DA obtained in step (III), add 30 times its mass of dichloroacetic acid, stir well, then add 15 times its mass of 30wt% hydrobromic acid-acetic acid solution, and stir at room temperature (26±2℃) for 2 hours. Then add purified water for precipitation, wash the separated precipitate with water and ethanol in sequence, and dry to obtain cellulose acetate-PGlu-DA.

[0085] The cellulose acetate-PGlu-DA obtained in this embodiment was used to prepare Zuogui Pills. The specific steps are as follows:

[0086] (1) Sterilization: Take 1000g of Rehmannia glutinosa, 500g of Cuscuta chinensis, 375g of Achyranthes bidentata, 500g of Dioscorea opposita, 500g of Cornus officinalis and 500g of Lycium barbarum and put them into an MQ-6 type ethanol gas sterilizer. Add 170mL of 90vol% alcohol and control the temperature at 65℃±10℃. Keep warm for 2h. Then, evacuate to a vacuum degree of 0.08MPa, add 170mL of 90vol% alcohol, and let it cool naturally for 12h. After the process is completed, transfer the materials to the intermediate station, hang the status mark, and set them aside for use.

[0087] (2) Place the sterilized medicinal materials from step (1) into a pulverizer and pulverize them. After passing them through a 100-mesh sieve and mixing for 30 minutes, obtain the medicinal material powder and put it into a clean container for later use.

[0088] (3) Melting: Take 500g of tortoise shell glue and 500g of deer antler glue and place them in a tilting jacketed kettle. Add purified water equal to their total mass, heat to boiling, and stir until completely melted without any hard lumps to obtain the glue solution. Keep it at about 60℃ to prevent coagulation.

[0089] (4) Preparation of soft material: Take the medicinal powder obtained in step (2) and 535g sodium carboxymethyl starch and place them in a tank mixer, add the glue obtained in step (3), 338g honey and purified water, stir and mix for 10 minutes to obtain soft material.

[0090] (5) Making wet pellets: Place the soft material obtained in step (4) into a fully automatic pelleting machine and make pellets using a pellet mold with a diameter of 6.1 mm. Weigh the pellets at least once at the beginning and middle of each pelleting process to control the weight of the wet pellets to 1.1-1.3 g / 10 pellets. Spray an appropriate amount of ethanol into the wet pellets and send them to a powder sprinkler. Sprinkle 21.5 g of talc powder and 86 g of medicinal charcoal to prevent the pellets from sticking together. Place them in a polishing machine and roll them until the surface is round.

[0091] (6) Drying: The wet pellets obtained in step (5) are pushed into a microwave vacuum dryer. The microwave power is set to 20kW and the drying temperature is set to 55℃. The pellets are dried for 35 minutes to obtain pellet cores.

[0092] (7) Sizing: Place the dried pellet cores from step (6) into a pelletizing machine and screen out irregularly shaped pellets such as those with different diameters or those that are stuck together.

[0093] (8) Preparation of coating solution: Take 700g cellulose acetate-PGlu-DA, 420g silicone elastomer, 35g hydroxypropyl methylcellulose and 40g triethyl citrate, add 2.5 times the total mass of purified water, stir evenly to obtain coating solution, and set aside.

[0094] (9) Coating: The pill core after being shaped in step (7) is placed in a coating machine and coated with the coating liquid prepared in step (8). Then it is dried at 55°C for 30 minutes. The weight of the coated pill increases by about 6%.

[0095] (10) Drying the pills: Spread the coated pills from step (9) onto a stainless steel sieve lined with a clean cloth, place them in a drying room, and dry for 6 hours.

[0096] Example 2

[0097] Cellulose acetate-PGlu-DA was prepared by the following steps:

[0098] (I) Take 1000g of cellulose acetate, add 20 times its weight of n-butanol, stir evenly, then add 30g of silane coupling agent KH550, control the temperature at 105±5℃, and stir for 3-5 hours. Then remove the solvent by rotary evaporation under reduced pressure, wash with water and ethanol successively, and dry to obtain cellulose acetate-NH3.

[0099] (II) Take the cellulose acetate-NH3 obtained in step (1), add 30 times its mass of DMF, stir to dissolve, replace the air with nitrogen, add 330g of glutamic acid 5-benzyl ester N-carboxyl ring anhydride, and stir at room temperature (26±2℃) for 15h. Then add purified water for precipitation, wash the separated precipitate with water and ethanol in sequence, and dry to obtain cellulose acetate-PBLG.

[0100] (III) Take the cellulose acetate-PBLG obtained in step (II), add 50 times its weight of DMF, stir to dissolve, add 30g EDC and 15g NHS, stir well, adjust the pH to 5.5, then add 26g dopamine hydrochloride, and stir at room temperature (26±2℃) for 15h. Then add purified water for precipitation, wash the separated precipitate with water and ethanol in sequence, and dry to obtain cellulose acetate-PBLG-DA.

[0101] (IV) Take the cellulose acetate-PBLG-DA obtained in step (III), add 30 times its mass of dichloroacetic acid, stir well, then add 15 times its mass of 30wt% hydrobromic acid-acetic acid solution, and stir at room temperature (26±2℃) for 1.5 h. Then add purified water for precipitation, wash the separated precipitate with water and ethanol in sequence, and dry to obtain cellulose acetate-PGlu-DA.

[0102] The cellulose acetate-PGlu-DA obtained in this embodiment was used to prepare Zuogui Pills. The specific steps are as follows:

[0103] (1) The same steps as in Example 1 were used to prepare the pellet core and perform pelletizing;

[0104] (2) Preparation of coating solution: Take 700g cellulose acetate-PGlu-DA, 280g silicone elastomer, 21g hydroxypropyl methylcellulose and 40g triethyl citrate, add 2.5 times the total mass of purified water, stir evenly to obtain coating solution, and set aside.

[0105] (3) Coating: The core of the whole pill is placed in a coating machine and coated with the coating liquid prepared in step (2). Then it is dried at 55°C for 30 minutes. The weight of the coated pill increases by about 6%.

[0106] (4) Drying the pellets: Same as in Example 1.

[0107] Example 3

[0108] Cellulose acetate-PGlu-DA was prepared by the following steps:

[0109] (I) Take 1000g of cellulose acetate, add 20 times its weight of n-butanol, stir evenly, then add 60g of silane coupling agent KH550, control the temperature at 105±5℃, and stir for 3-5 hours. Then remove the solvent by rotary evaporation under reduced pressure, wash with water and ethanol successively, and dry to obtain cellulose acetate-NH3.

[0110] (II) Take the cellulose acetate-NH3 obtained in step (1), add 30 times its mass of DMF, stir to dissolve, replace the air with nitrogen, add 360g of glutamic acid 5-benzyl ester N-carboxyl anhydride, and stir at room temperature (26±2℃) for 9h. Then add purified water for precipitation, wash the separated precipitate with water and ethanol in sequence, and dry to obtain cellulose acetate-PBLG.

[0111] (III) Take the cellulose acetate-PBLG obtained in step (II), add 50 times its weight of DMF, stir to dissolve, add 30g EDC and 15g NHS, stir well, adjust the pH to 5.5, then add 76.5g dopamine hydrochloride, and stir at room temperature (26±2℃) for 24h. Then add purified water for precipitation, wash the separated precipitate with water and ethanol in sequence, and dry to obtain cellulose acetate-PBLG-DA.

[0112] (IV) Take the cellulose acetate-PBLG-DA obtained in step (III), add 30 times its mass of dichloroacetic acid, stir well, then add 15 times its mass of 30wt% hydrobromic acid-acetic acid solution, and stir at room temperature (26±2℃) for 3.5 h. Then add purified water for precipitation, wash the separated precipitate with water and ethanol in sequence, and dry to obtain cellulose acetate-PGlu-DA.

[0113] The cellulose acetate-PGlu-DA obtained in this embodiment was used to prepare Zuogui Pills. The specific steps are as follows:

[0114] (1) The same steps as in Example 1 were used to prepare the pellet core and perform pelletizing;

[0115] (2) Preparation of coating solution: Take 700g cellulose acetate-PGlu-DA, 700g silicone elastomer, 56g hydroxypropyl methylcellulose and 40g triethyl citrate, add 2.5 times their total mass of purified water, stir evenly to obtain coating solution, and set aside.

[0116] (3) Coating: The core of the whole pill is placed in a coating machine and coated with the coating liquid prepared in step (2). Then it is dried at 55°C for 30 minutes. The weight of the coated pill increases by about 6%.

[0117] (4) Drying the pellets: Same as in Example 1.

[0118] Example 4

[0119] The cellulose acetate-PGlu-DA of this embodiment was prepared using the same steps as in Example 1.

[0120] The cellulose acetate-PGlu-DA obtained in this embodiment was used to prepare Zuogui Pills. The specific steps are as follows:

[0121] (1) The same steps as in Example 1 were used to prepare the pellet core and perform pelletizing;

[0122] (2) Preparation of coating solution: Take 700g of cellulose acetate-PGlu-DA and 40g of triethyl citrate, add 2.5 times the total mass of purified water, stir evenly to obtain coating solution, and set aside.

[0123] (3) Coating: The core of the whole pill is placed in a coating machine and coated with the coating liquid prepared in step (2). Then it is dried at 55°C for 30 minutes. The weight of the coated pill increases by about 6%.

[0124] (4) Drying the pellets: Same as in Example 1.

[0125] Comparative Example 1

[0126] The Zuogui Pill of this comparative example was prepared according to the steps in Example 1. The only difference between this comparative example and Example 1 is that it is not coated, that is, steps (8) to (9) are not performed.

[0127] Comparative Example 2

[0128] Cellulose acetate-DPA is prepared through the following steps:

[0129] (I) Take 1000g of cellulose acetate, add 20 times its weight of n-butanol, stir evenly, then add 50g of silane coupling agent KH550, control the temperature at 105±5℃, and stir for 3-5 hours. Then remove the solvent by rotary evaporation under reduced pressure, wash with water and ethanol successively, and dry to obtain cellulose acetate-NH3.

[0130] (II) Take the cellulose acetate-NH3 obtained in step (1), add 50 times its weight of DMF, stir to dissolve, add 30g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) and 15g of N-hydroxysuccinimide (NHS), stir well, then add 48g of 3,4-dihydroxyphenylpropionic acid, and stir at room temperature (26±2℃) for 20h. Then add purified water for precipitation, wash the separated precipitate with water and ethanol in sequence, and dry to obtain cellulose acetate-DPA.

[0131] The cellulose acetate-DPA obtained in this comparative example was used to prepare Zuogui Pills. The specific steps are as follows:

[0132] (1) The same steps as in Example 1 were used to prepare the pellet core and perform pelletizing;

[0133] (2) Preparation of coating solution: Take 700g cellulose acetate-DPA, 420g silicone elastomer, 35g hydroxypropyl methylcellulose and 40g triethyl citrate, add 2.5 times the total mass of purified water, stir evenly to obtain coating solution, and set aside.

[0134] (3) Coating: The core of the whole pill is placed in a coating machine and coated with the coating liquid prepared in step (2). Then it is dried at 55°C for 30 minutes. The weight of the coated pill increases by about 6%.

[0135] (4) Drying the pellets: Same as in Example 1.

[0136] Test Example 1: Intestinal Retention Time Test

[0137] Zuogui pills prepared according to the steps of Examples 1-3 and Comparative Example 2 were soaked in artificial gastric fluid (prepared according to the Chinese Pharmacopoeia) for 2 hours and then removed. Small intestines of rats were taken and everted into intestinal sacs. Physiological saline was instilled into the intestinal sacs. After the everted intestinal sacs were upright, the Zuogui pills soaked in artificial gastric fluid were deposited on the surface of the small intestinal mucosa. The everted intestinal sacs were then upright and immersed in artificial small intestinal fluid (prepared according to the Chinese Pharmacopoeia). The shedding of substances from the surface of the small intestinal mucosa was observed. The time when 90% of the Zuogui pills detached was recorded as their retention time on the small intestinal mucosa. Each example and comparative example was tested three times, and the average value was taken. The results are shown in Table 1.

[0138] Table 1

[0139] Dwell time / h Example 1 6.50 Example 2 7.00 Example 3 6.25 Comparative Example 2 10.25

[0140] Test Example 2: Pharmacokinetic Test

[0141] Adult rats were randomly divided into 6 groups (n=6 per group, half male and half female) and administered Zuogui Pills prepared according to the steps of Examples 1-3 and Comparative Examples 1-2 by gavage at a dose of 18 g / kg. Blood samples were collected from the portal vein at 0 h, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 7 h, 9 h, 12 h, and 24 h after administration to detect the blood concentration of loganin. Blood concentration-time curves were plotted, and the results are shown below. Figures 1-3 .

[0142] From Table 1 and Figures 1-3 It can be seen that:

[0143] (1) Compared with Comparative Example 1, the peak blood drug concentration in Example 1 is increased, and the blood drug concentration can be maintained at a high level for a longer period of time. This is because: Example 1 has the coating of the present invention on the surface of Zuogui Pill. The catechol group in the coating can make Zuogui Pill adhere better to the digestive tract mucosa, thereby prolonging its retention time in the digestive tract, so that the medicinal powder has a longer time to decompose and release the active ingredients of the drug under the action of digestive juice.

[0144] (2) Although the drug absorption in Comparative Example 2 was increased compared to Example 1, the retention time on the small intestinal mucosa was too long. This indicates that when the catechol group is directly grafted onto cellulose acetate without using polypeptide chain bridging, the retention time of Zuogui Pill in the intestine is too long. This is because the polypeptide chain can be degraded by digestive tract proteases. Therefore, in the digestive tract, over time, the catechol group separates from the coating along with the degradation of the polypeptide chain, and the adhesion strength of Zuogui Pill on the digestive tract mucosa gradually weakens, causing it to detach from the digestive tract mucosa.

[0145] (3) Compared with Example 4, the peak blood drug concentration in Example 1 is increased, and the blood drug concentration can be maintained at a high level for a longer period of time. This is because: In Example 1, a gastrointestinal coating material and an elastic material were added to the coating. When Zuogui Pill enters the stomach, the gastrointestinal coating material dissolves, creating more pores in the coating, which can accelerate the entry of digestive juice into the pill core, contact with the medicinal powder inside, and cause the disintegrant in the pill core to swell. At the same time, the elastic material allows Zuogui Pill to expand under the action of the disintegrant, which is conducive to the entry of digestive juice into the pill core. In this way, the medicinal powder in the pill core can be decomposed and released under the action of digestive juice to release the active ingredients of the drug.

[0146] Unless otherwise specified, the raw materials and equipment used in this invention are all commonly used in the field; unless otherwise specified, the methods used in this invention are all conventional methods in the field.

[0147] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications, alterations, and equivalent transformations made to the above embodiments based on the technical essence of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A method for preparing Zuogui Pill, characterized in that, include: S1: Grafting an aminosilane coupling agent onto cellulose acetate yields aminated cellulose acetate. The product is then subjected to ring-opening polymerization to graft N-carboxylic acid 5-benzyl ester anhydride onto the product to obtain cellulose acetate grafted with poly-L-glutamic acid-5-benzyl ester. Dopamine is then grafted onto the product via amidation to obtain cellulose acetate grafted with poly-L-glutamic acid-5-benzyl ester and catechol groups. Debenzylation yields a modified controlled-release coating material. S2: Prepared Rehmannia glutinosa, Cuscuta chinensis, Achyranthes bidentata, Dioscorea opposita, Cornus officinalis, and Lycium barbarum are pulverized and mixed to obtain medicinal powder; tortoise shell glue and deer antler glue are mixed with water, heated and stirred to dissolve the tortoise shell glue and deer antler glue to obtain a glue solution; medicinal powder, disintegrant, glue solution and water are mixed to obtain a soft material; after the soft material is made into pills, ethanol is sprayed in to sprinkle powder, then polished and dried to obtain pill cores; S3: Disperse the coating material in water to prepare a coating solution. The coating material includes modified controlled-release coating material, elastic material and gastrointestinal coating material in a mass ratio of 1:0.4~1.0:0.03~0.

08. Spray the core of the pill with the coating solution and dry it to obtain Zuogui Pill.

2. The preparation method according to claim 1, characterized in that, In step S2, honey is mixed in during the process of mixing the herbal powder, disintegrant, gel, and water.

3. The preparation method according to claim 1, characterized in that, In step S2, lubricant is sprayed in during the powdering process of spraying ethanol.

4. The preparation method according to claim 1, characterized in that, In step S2, the raw materials for the core of the pill include the following components in parts by weight: 200 parts of Rehmannia glutinosa, 90-110 parts of Cuscuta chinensis, 70-80 parts of Achyranthes bidentata, 95-105 parts of tortoise shell glue, 95-105 parts of deer antler glue, 95-105 parts of Dioscorea opposita, 95-105 parts of Cornus officinalis, 95-105 parts of Lycium barbarum, 0-70 parts of honey, 0-25 parts of lubricant, and 90-110 parts of disintegrant.

5. The preparation method according to claim 1 or 4, characterized in that, In step S2, the disintegrant includes sodium carboxymethyl starch.

6. The preparation method according to claim 1, characterized in that, Step S1 specifically includes the following steps: (I) Disperse cellulose acetate in solvent I, add an aminosilane coupling agent to it, carry out a hydrolysis and condensation reaction, separate the product, and obtain aminoated cellulose acetate; (II) Dissolve the product of step (I) in solvent II, add the N-carboxyl anhydride of 5-benzyl glutamic acid under inert gas protection, carry out ring-opening polymerization reaction, separate the product, and obtain cellulose acetate grafted with poly-L-glutamic acid-5-benzyl ester. (III) Mix the product of step (II), the carboxyl activator and solvent III, add dopamine hydrochloride to it, carry out an amidation reaction, separate the product, and obtain cellulose acetate grafted with poly(L-glutamic acid-5-benzyl ester) and catechol groups. (IV) The product from step (III) is mixed with solvent IV, and a hydrobromic acid-acetic acid solution is added to carry out a debenzylation reaction to separate the product and obtain the modified controlled-release coating material.

7. The preparation method according to claim 1, characterized in that, The mass ratio of the modified controlled-release coating material, the elastic material, and the gastrointestinal coating material is 1:0.6:0.

05.

8. The preparation method according to claim 1, characterized in that, The mass ratio of the modified controlled-release coating material, the elastic material, and the gastrointestinal coating material is 1:0.4:0.

03.

9. The preparation method according to claim 1, characterized in that, The mass ratio of the modified controlled-release coating material, the elastic material, and the gastrointestinal coating material is 1:1.0:0.08.

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