Controlled release preparation and preparation method thereof

Abstract

The invention discloses a controlled release preparation and a preparation method thereof. Specifically, the controlled release preparation comprises a drug crystal and a polymer coating wrapping the drug crystal, the preparation method of the controlled release preparation comprises the following steps: carrying out polymerization reaction on a monomer on the surface of a drug crystal to form a polymer coating, or carrying out cross-linking reaction on a polymer on the surface of the drug crystal to form the polymer coating. The controlled release preparation is high in drug loading capacity, long in drug release time, capable of achieving long-acting zero-order release of drugs, simple in preparation method and high in encapsulation efficiency.

Description

A controlled-release preparation and its preparation method

[0001] This application claims the benefit of Chinese Patent Application No. 2023102634617, filed on March 17, 2023. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0002] The present invention relates to the field of drug delivery, and in particular to a controlled-release preparation and a preparation method thereof. Background Art

[0003] Chronic diseases, such as cardiovascular and cerebrovascular diseases, diabetes, and cancer, are characterized by insidious onset, long and persistent course, and complex etiologies. They are characterized by high morbidity, low cure rates, and high mortality rates, often accompanied by serious complications. Chronic disease treatment often requires long-term, uninterrupted medication, severely impacting patients' quality of life and placing a heavy burden on their families. Long-acting, sustained-release drug formulations, which slowly release drugs from the body and maintain stable blood concentrations over time, are an effective treatment for chronic diseases.

[0004] High drug loading is a necessary condition for constructing long-acting sustained-release pharmaceutical preparations. In addition, drug carriers with high drug loading can reduce the frequency of drug administration, improve patient compliance, and reduce the use of materials / excipients and related side effects. However, due to compatibility issues between drug carriers and drugs, drug loading is usually limited, generally below 30wt%. Therefore, significantly increasing the drug loading of drug carriers remains a difficult problem.

[0005] Traditional drug carriers with first-order release properties struggle to effectively deliver some drugs with narrow therapeutic windows and short half-lives. To address these issues, zero-order release has emerged. This type of drug delivery system releases drugs at a constant rate. Assuming the clearance rate of the drug molecules in the body matches the release rate, zero-order release can maintain stable blood drug concentrations. Achieving zero-order release requires the following conditions: 1. The presence of an excess of undissolved drug within the drug carrier; 2. The drug dissolution rate is faster than the diffusion rate; and 3. The drug diffusion rate is relatively constant. Currently, most devices that achieve zero-order release properties are implantable devices, such as osmotic pumps, intravaginal rings, microchips, and microneedles. Designing an injectable drug carrier with zero-order release properties remains a significant challenge.

[0006] Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a controlled-release formulation and its preparation method in order to overcome the shortcomings of existing drug carriers, such as low drug loading capacity, short drug release time, and inability to achieve zero-order release. The controlled-release formulation of the present invention has an ultra-high drug loading capacity, a long drug release time, and can achieve long-term zero-order release of the drug. The preparation method is simple and the encapsulation efficiency is high.

[0008] The present invention solves the above technical problems through the following technical solutions.

[0009] The present invention provides a controlled-release preparation comprising drug crystals and a polymer coating wrapping the drug crystals.

[0010] The polymer is a polymer that can be formed by in situ polymerization of monomers on the surface of the drug crystal, or a polymer that can be adsorbed on the surface of the drug crystal and cross-linked, such as a dopa-modified polymer (i.e., a polymer containing a catechol (catechol) structure), preferably polydopamine, poly-levodopa, or mussel protein. The polymer coating is in the form of a polymer film.

[0011] The drug is any drug that can form crystals, such as human insulin, insulin analogs, glucagon-like peptide-1 (GLP-1), glucose-raising hormones or analgesics, preferably recombinant human insulin, insulin glargine, insulin detemir, insulin aspart, insulin lispro, insulin glulisine, recombinant human insulin containing oligosaccharide zinc, semaglutide, glucagon, tetracaine or bupivacaine.

[0012] The particle size of the drug crystals can be nanometer, micrometer, millimeter or centimeter level, depending on the specific drug crystal particle size, specifically 10nm-2cm, preferably 0.1μm-1000μm, more preferably 5μm-56μm.

[0013] In a preferred embodiment of the present invention, the drug is human insulin or an insulin analog (such as recombinant human insulin or insulin glargine), and the polymer is polydopamine or poly-levodopa.

[0014] In a preferred embodiment of the present invention, the drug is human insulin or an insulin analog (such as recombinant human insulin), and the polymer is mussel protein.

[0015] The mass ratio of the drug crystal to the polymer coating may be 1:(0.2-1.2), preferably 1:(0.2-0.8), and more preferably 1:0.4 or 1:0.2.

[0016] The thickness of the polymer coating may be 50-1000 nm, preferably 80-485 nm, and more preferably 161.54 nm.

[0017] Wherein, the controlled-release preparation is preferably composed of drug crystals and a polymer coating that wraps the drug crystals.

[0018] The controlled-release preparation may be a dosage form administered by any suitable route in the art, such as an injection dosage form (such as a subcutaneous injection), an oral dosage form, or an implantable device.

[0019] The drug loading of the controlled-release preparation is preferably 50%-99%, more preferably 60%-93%.

[0020] The encapsulation rate of the controlled-release preparation is preferably 60%-99.8%, more preferably 73.4%-99.8%.

[0021] The present invention also provides a method for preparing the above-mentioned controlled-release preparation, which comprises the following steps: polymerizing monomers on the surface of drug crystals to form a polymer coating.

[0022] The polymer can be formed by in-situ polymerization of monomers on the surface of the drug crystals. The polymerization reaction conditions can be selected according to the polymerization conditions required for the polymer. The polymerization reaction can be specifically performed by mixing the monomers with the drug crystals in a solvent and performing a polymerization reaction.

[0023] Wherein, the drug crystals are selected as described above.

[0024] The monomer is selected based on the monomer required to form the polymer. The mass ratio of the drug to the monomer can be 1:(0.2-1.2), preferably 1:(0.2-0.8), and more preferably 1:0.4.

[0025] The solvent is a solvent that makes the drug crystals insoluble. For example, a buffer solution that makes the drug crystals insoluble can be selected.

[0026] Wherein, according to polymerization requirements, the polymerization reaction can be carried out in the presence of a catalyst. When a catalyst is used, the preferred mixing order is to first mix the monomer and the drug crystals, and then mix them with the catalyst.

[0027] Wherein, the polymerization reaction is preferably carried out under stirring conditions.

[0028] The polymerization reaction time and number are selected based on the desired polymer coating thickness. When multiple polymerization reactions are required for multiple coatings, the specific operation is as follows: after a single polymerization reaction is completed, the resulting polymer-coated drug crystals are collected and then mixed with monomers for further polymerization until the desired polymer coating thickness is achieved.

[0029] The temperature of the polymerization reaction is selected based on the polymerization temperature required without affecting the activity of the drug.

[0030] In a preferred embodiment of the present invention, the drug is insulin or an insulin analog (such as recombinant human insulin or insulin glargine).

[0031] In this preferred embodiment, the monomer is preferably dopamine or levodopa. The mass ratio of the drug crystal to the monomer can be 1:(0.2-1.2), preferably 1:(0.4-0.8), and more preferably 1:0.4. The mass concentration of the monomer in the solvent can be 0.5-3 mg / mL, preferably 1-2 mg / mL, and more preferably 1 mg / mL.

[0032] In this preferred embodiment, the solvent is a buffer solution; the pH value of the buffer solution may be 4-9, preferably 5-8, and more preferably 7. The buffer solution may be sodium hydrogen phosphate-citrate buffer, Tris buffer, or PBS buffer. The concentration of the buffer solution may be 10-200 mM, preferably 10-182 mM, and more preferably 182 mM. Most preferably, the buffer solution is sodium hydrogen phosphate-citrate buffer with a concentration of 182 mM and a pH of 7.

[0033] In this preferred embodiment, the polymerization reaction is carried out in the presence of an oxidant. The oxidant is preferably a persulfate (e.g., ammonium persulfate), a divalent copper salt, a trivalent iron salt, a permanganate (e.g., potassium permanganate), or a periodate (e.g., sodium periodate), more preferably ammonium persulfate. The mass concentration of the oxidant in the solvent is 0.3-1.2 mg / mL, preferably 0.4-0.8 mg / mL, and more preferably 0.6 mg / mL.

[0034] In this preferred embodiment, the polymerization reaction time is preferably 2-12 hours, more preferably 2-8 hours, and most preferably 4 hours.

[0035] In this preferred embodiment, the polymerization reaction temperature may be room temperature, for example, 4-37°C, preferably 20-30°C.

[0036] According to routine, the preparation method may further include post-processing steps, such as centrifugation, washing (eg, washing with PBS) and drying (eg, freeze-drying).

[0037] The present invention also provides a method for preparing the above-mentioned controlled-release preparation, which comprises the following steps:

[0038] The polymer is cross-linked on the surface of the drug crystal to form a polymer coating.

[0039] The polymer is a polymer that can be adsorbed on the surface of the drug crystals and undergo cross-linking. The conditions for the cross-linking reaction can be selected according to the cross-linking conditions required for the polymer. The cross-linking reaction can be specifically performed by mixing the polymer with the drug crystals in a solvent and performing a cross-linking reaction.

[0040] Wherein, in the cross-linking reaction, the drug crystals are selected as described above.

[0041] In the cross-linking reaction, the solvent is a solvent that makes the drug crystals insoluble. For example, a buffer solution that makes the drug crystals insoluble can be selected.

[0042] Wherein, the cross-linking reaction can be carried out in the presence of a catalyst as needed. In the cross-linking reaction, when a catalyst is used, the preferred mixing order is to first mix the polymer and the drug crystals, and then mix them with the catalyst.

[0043] Wherein, the cross-linking reaction is preferably carried out under stirring conditions.

[0044] The time and number of cross-linking reactions are selected based on the desired polymer coating thickness. When multiple cross-linking reactions are required for multiple coatings, the specific operation is as follows: after a single cross-linking reaction is completed, the resulting polymer-coated drug crystals are collected and then mixed with the polymer for further cross-linking reactions until the desired polymer coating thickness is achieved.

[0045] The temperature of the cross-linking reaction is selected based on the cross-linking temperature that does not affect the activity of the drug.

[0046] In a preferred embodiment of the present invention, the drug is insulin or an insulin analog (such as recombinant human insulin); and the polymer is mussel protein.

[0047] The mass ratio of the drug crystal to the polymer may be 1:(0.2-1.2), preferably 1:(0.2-0.4), more preferably 1:0.2. The mass concentration of the polymer in the solvent may be 0.5-3 mg / mL, preferably 1-2 mg / mL, more preferably 1 mg / ml.

[0048] In this preferred embodiment, the solvent is a buffer solution; the pH value of the buffer solution may be 4-9, preferably 5-8, and more preferably 6. The concentration of the buffer solution may be 10-200 mM, preferably 20 mM. Most preferably, the buffer solution is a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer with a pH of 6 and a concentration of 20 mM.

[0049] In this preferred embodiment, the cross-linking reaction is carried out in the presence of an oxidizing agent. The oxidizing agent is preferably a persulfate (e.g., ammonium persulfate), a divalent copper salt, a trivalent iron salt, a permanganate (e.g., potassium permanganate), or a periodate (e.g., sodium periodate), more preferably ammonium persulfate. The mass concentration of the oxidizing agent in the solvent is 0.3-1.2 mg / mL, preferably 0.4-0.8 mg / mL, and more preferably 0.6 mg / mL.

[0050] In this preferred embodiment, the cross-linking reaction is preferably carried out overnight, for example, for 12 hours.

[0051] In this preferred embodiment, the temperature of the cross-linking reaction can be room temperature, for example, 4-37°C, preferably 20-30°C.

[0052] According to routine, the preparation method may further include post-processing steps, such as centrifugation, washing (eg, washing with PBS) and drying (eg, freeze-drying).

[0053] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0054] The reagents and raw materials used in the present invention are commercially available.

[0055] The positive progress of the present invention is that the controlled-release preparation of the present invention has an ultra-high drug loading capacity, a long release time, can achieve a long-term zero-order release of the drug, and has a simple preparation method and a high encapsulation rate. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] FIG1 is a schematic diagram of the preparation of the controlled-release preparation of the present invention and its long-lasting zero-order release.

[0057] Figure 2 shows scanning electron micrographs of recombinant human insulin crystals (a) and controlled-release preparation 1 (b) in Example 1, a transmission electron micrograph of a frozen section of controlled-release preparation 1 (c), and fluorescently labeled controlled-release preparation 1 (d).

[0058] Figure 3 is the scanning electron micrographs (a and b) of the insulin glargine crystals in Example 4 at different magnifications, and the scanning electron micrographs (c and d) of the controlled-release preparation 4 at different magnifications.

[0059] Figure 4 is a scanning electron micrograph of recombinant human insulin crystals (a) and controlled-release preparation 7 (b) in Example 7.

[0060] Figure 5 is a scanning electron micrograph of recombinant human insulin crystals (a) and controlled-release preparation 8 (b) in Example 8.

[0061] Figure 6 shows the cumulative release amounts of recombinant human insulin (a) in controlled-release formulations 1-3, insulin glargine (b) in controlled-release formulations 4-6, and recombinant human insulin (c) in controlled-release formulation 8 in Effect Example 2.

[0062] FIG7 is a blood glucose level curve of diabetic mice after subcutaneous injection of controlled-release preparations 1 and 4 in Effect Example 3. DETAILED DESCRIPTION

[0063] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0064] Example 1 Preparation of Controlled Release Formulation 1 (Polydopamine Coated Recombinant Human Insulin Crystals)

[0065] 1. Preparation

[0066] Step 1: Prepare sodium hydrogen phosphate-citrate buffer with a pH of 7 and a concentration of 182 mM;

[0067] Step 2: Prepare a 2 mg / mL dopamine solution and a 1.2 mg / mL ammonium persulfate solution using the above buffer;

[0068] Step 3: Add 10 mg of recombinant human insulin crystals to 2 mL of dopamine solution and stir magnetically.

[0069] Step 4: Add 2 mL of ammonium persulfate solution and continue stirring for 4 h;

[0070] Step 5: Centrifuge the precipitate to the bottom of the centrifuge tube, wash three times with PBS, and freeze-dry.

[0071] 2. Detection

[0072] Comparing the scanning electron microscopy images of recombinant human insulin crystals ( FIG. 2 a ) and controlled-release preparation 1 ( FIG. 2 b ), it can be seen that the surface of the recombinant human insulin crystals becomes rough after the in situ polymerization of dopamine.

[0073] Controlled-release preparation 1 was cryosectioned and observed under transmission electron microscopy. It can be seen that a uniform polymer film has formed on the surface of the recombinant human insulin crystals (Figure 2c). The thickness of the polymer film is 161.54 nm, indicating that the drug crystals are wrapped by the polymer film and the controlled-release preparation 1 is successfully prepared.

[0074] Example 2 Preparation of Controlled Release Formulation 2 (Polydopamine Coated Recombinant Human Insulin Crystals)

[0075] The same method as in Example 1 was used to prepare the controlled-release preparation 2, except that the number of coating times was adjusted to 2.

[0076] Example 3 Preparation of Controlled Release Formulation 3 (Polydopamine Coated Recombinant Human Insulin Crystals)

[0077] The same method as in Example 1 was used to prepare the controlled-release preparation 3, except that the number of coating times was adjusted to 3.

[0078] Example 4 Preparation of Controlled Release Formulation 4 (Polydopamine Coated-Insulin Glargine Crystals)

[0079] The same method as in Example 1 was used for preparation, except that the recombinant human insulin crystals were replaced with glargine insulin crystals.

[0080] Comparing Figures 3b and 3d, it can be seen that the surface of the insulin glargine crystals becomes rough after the in situ polymerization of dopamine, proving that the insulin glargine crystals are wrapped by the polydopamine film to form a controlled-release preparation 4.

[0081] Example 5 Preparation of Controlled Release Formulation 5 (Polydopamine Coated-Insulin Glargine Crystals)

[0082] The same method as in Example 4 was used to prepare the controlled-release preparation 5, except that the number of coating times was adjusted to 2.

[0083] Example 6 Preparation of Controlled Release Formulation 6 (Polydopamine Coated Insulin Glargine Crystals)

[0084] The same method as in Example 4 was used to prepare the controlled-release preparation 6, except that the number of coating times was adjusted to 3.

[0085] Example 7 Controlled Release Formulation 7 (Poly-L-Dopa-Recombinant Human Insulin Crystals)

[0086] The same method as in Example 1 was used to prepare the product, except that the dopamine solution was replaced by levodopa solution.

[0087] As can be seen from Figure 4b, the surface of the recombinant human insulin crystals became roughened after the in situ polymerization of L-dopa, proving that the recombinant human insulin crystals were successfully wrapped by the poly-L-dopa film to form a controlled-release preparation 7.

[0088] Example 8 Controlled Release Formulation 8 (Mussel Protein-Recombinant Human Insulin Crystals)

[0089] 1. Preparation

[0090] Step 1: Dissolve 1 mg of mussel protein and 5 mg of recombinant human insulin crystals in 1 mL of 20 mM sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, pH 6.0, and stir for 2 hours;

[0091] Step 2: Add 0.6 mg of ammonium persulfate and stir the reaction overnight;

[0092] Step 3: Centrifuge the precipitate to the bottom of the centrifuge tube, wash three times with PBS, and freeze-dry.

[0093] 2. Detection

[0094] Comparing the scanning electron micrographs of the recombinant human insulin crystals ( FIG. 5 a ) and the controlled-release preparation 8 ( FIG. 5 b ), it can be seen that the surface of the recombinant human insulin crystals becomes rough after the mussel protein is cross-linked, forming the controlled-release preparation 8 .

[0095] Effect Example 1 Determination of drug loading and encapsulation efficiency

[0096] The drug loading and encapsulation efficiency of the above controlled-release formulations 1-6 and 8 were tested.

[0097] Drug loading test method:

[0098] A certain mass of the controlled-release formulation was weighed and dispersed in a PBS buffer solution at pH 2. The recombinant human insulin or insulin glargine in the controlled-release formulation was dissolved. The concentration of the recombinant human insulin or insulin glargine in the PBS buffer solution was measured using a microplate reader using the Coomassie Brilliant Blue method (both at a detection wavelength of 595 nm), thereby calculating the mass of the recombinant human insulin or insulin glargine in the controlled-release formulation. The drug loading was calculated using formula (1).

[0099] The formula for calculating drug loading is:

[0100] The formula for calculating the encapsulation efficiency is:

[0101] Wherein, the total mass is the mass of recombinant human insulin crystals or insulin glargine crystals added during the preparation process; the unloaded mass is the mass of recombinant human insulin or insulin glargine in the buffer solution after centrifugation and precipitation, which is calculated by the recombinant human insulin concentration or insulin glargine concentration measured by the Coomassie Brilliant Blue method (Formula 2).

[0102] The drug loading and encapsulation efficiency data of controlled release formulations 1-6 and 8 are shown in the following table:

[0103] As can be seen from the above table, the controlled release preparations of the present application have ultra-high drug loading and encapsulation efficiency. Their drug loading decreases with the increase of the number of coatings, but is all greater than 60%. It is worth noting that when coated once, the drug loading is up to more than 90%. The encapsulation efficiency of controlled release preparations 1-3 decreases with the increase of the number of coatings, and is all greater than 70%. The encapsulation efficiency of controlled release preparations 4-6 remains constant substantially with the number of coatings, and is all higher than 99%. The drug loading and encapsulation efficiency of controlled release preparation 8 are both higher, being 82.7% and 94.4% respectively.

[0104] Effect Example 2 In vitro release experiment

[0105] The above-mentioned controlled-release preparations 1-6 and 8 were used to conduct release experiments in vitro. The specific procedures are as follows:

[0106] Disperse the controlled-release formulation in PBS buffer at a concentration of 5 mg / mL. Incubate on a shaker at 37°C. At the designated time points, aspirate 25 μL of the solution, centrifuge, and collect the supernatant. Measure the recombinant human insulin or insulin glargine concentration in the PBS buffer using a microplate reader using the Coomassie Brilliant Blue method (both detection wavelengths are 595 nm).

[0107] As shown in Figure 6, the polymer film effectively slows drug release after encapsulating the drug crystals, demonstrating zero-order release. The release rate decreases with increasing polymer coating thickness. Controlled-release formulation 3 maintained zero-order release behavior for 316 hours, with a cumulative release concentration of 2.74 mg / mL.

[0108] Effect Example 3: Release experiment in mice

[0109] Controlled-release formulation 1 and controlled-release formulation 4 were used to conduct in vivo release experiments in mice. The specific procedures were as follows:

[0110] Weigh 6 mg of the above controlled-release formulation and disperse it in 0.5 mL of PBS buffer. After anesthetizing five type 1 diabetic mice, inject 0.1 mL of the controlled-release formulation in PBS buffer subcutaneously into each diabetic mouse. Measure blood glucose levels at designated time points using a glucometer.

[0111] As shown in Figure 7, after the controlled-release preparation is injected into the subcutaneous part of diabetic mice, the in vivo release of insulin can be significantly slowed down. After the subcutaneous injection of recombinant human insulin controlled-release preparation, the blood sugar of diabetic mice can be maintained at normal levels (about 200mg / dL) for up to 10 days. After injecting the insulin glargine controlled-release preparation, blood sugar can be maintained at normal levels (about 200mg / dL) for up to 14 days. This shows that the controlled-release preparation of the present application can significantly prolong the blood sugar regulation time of recombinant human insulin or insulin glargine.

[0112] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A controlled release preparation, characterized in that: The invention comprises drug crystals and a polymer coating which wraps the drug crystals.

2. The controlled release preparation according to claim 1, characterized in that The polymer is a dopa-modified polymer, preferably polydopamine, poly-L-dopa or mussel protein; and / or, The drug is human insulin, insulin analogs, glucagon-like peptide-1, glucose-raising hormone or analgesic, preferably recombinant human insulin, glargine insulin, detemir insulin, aspart insulin, lispro insulin, glulisine insulin, low-protamine zinc recombinant human insulin, semaglutide, glucagon, tetracaine or bupivacaine.

3. The controlled release preparation according to claim 2, characterized in that It meets any of the following conditions: (1) The drug is human insulin or an insulin analog, such as recombinant human insulin or insulin glargine, and the polymer is polydopamine or poly-levodopa; Or, (2) the drug is human insulin or an insulin analog, such as recombinant human insulin, and the polymer is mussel protein.

4. The controlled release preparation according to any one of claims 1 to 3, characterized in that The controlled release preparation consists of drug crystals and a polymer coating that wraps the drug crystals.

5. The controlled release preparation according to any one of claims 1 to 3, characterized in that The controlled release formulation meets one or more of the following conditions: (1) The particle size of the drug crystal is 10 nm-2 cm, preferably 0.1 μm-1000 μm, and more preferably 5 μm-56 μm; (2) The mass ratio of the drug crystal to the polymer coating is 1:(0.2-1.2), preferably 1:(0.2-0.8), more preferably 1:0.4 or 1:0.2; (3) The thickness of the polymer coating is 50-1000 nm, preferably 80-485 nm, more preferably 161.54, 323.08 and 484.62 nm; (4) The drug loading of the controlled release preparation is 50%-99%, more preferably 60%-93%; and (5) The encapsulation efficiency of the controlled-release preparation is 60%-99.8%, preferably 73.4%-99.8%.

6. The method for preparing the controlled release preparation according to any one of claims 1 to 5, comprising the steps of: polymerizing the monomers on the surface of the drug crystals to form a polymer coating; The operation of the polymerization reaction is preferably as follows: in a solvent, the monomer is mixed with the drug crystal to carry out a polymerization reaction; Preferably, the polymerization reaction is carried out in the presence of a catalyst; When a catalyst is used, the mixing order is preferably to first mix the monomer and the drug crystals and then mix with the catalyst.

7. The preparation method according to claim 6, characterized in that: The drug is insulin or an insulin analog, such as recombinant human insulin or glargine insulin, The monomer is preferably dopamine or levodopa; The mass ratio of the drug crystal to the monomer is preferably 1:(0.2-1.2), more preferably 1:(0.4-0.8), and most preferably 1:0.4; The mass concentration of the monomer in the solvent is preferably 0.5-3 mg / mL, more preferably 1-2 mg / mL, and most preferably 1 mg / ml.

8. The preparation method according to claim 6, characterized in that: The solvent is a buffer solution, and the buffer solution satisfies one or more of the following conditions: (1) The pH value of the buffer solution is 4-9, preferably 5-8, and more preferably 7; (2) the buffer solution is sodium hydrogen phosphate-citrate buffer, Tris buffer or PBS buffer; and (3) The concentration of the buffer solution is 10-200 mM, preferably 10-182 mM, more preferably 182 mM; Preferably, the buffer solution is a sodium hydrogen phosphate-citrate buffer with a concentration of 182 mM and a pH of 7.

9. The preparation method according to claim 6, characterized in that: The catalyst is an oxidizing agent, The oxidant is persulfate, divalent copper salt, trivalent iron salt, permanganate or periodate, preferably ammonium persulfate, potassium permanganate or sodium periodate; and / or, The mass concentration of the oxidant in the solvent is 0.3-1.2 mg / mL, preferably 0.4-0.8 mg / mL, and more preferably 0.6 mg / ml.

10. The preparation method according to claim 9, characterized in that: The polymerization reaction time is 2-12 hours, preferably 2-8 hours, more preferably 4 hours; and / or, The polymerization reaction temperature is room temperature, for example, 4-37°C, preferably 20-30°C.

11. The method for preparing a controlled release preparation according to any one of claims 1 to 5, comprising the steps of: cross-linking a polymer on the surface of drug crystals to form a polymer coating; The cross-linking reaction is preferably carried out by mixing the polymer and the drug crystal in a solvent to carry out a cross-linking reaction; Preferably, the cross-linking reaction is carried out in the presence of a catalyst; When a catalyst is used, the mixing order is preferably to first mix the polymer and the drug crystals and then mix with the catalyst.

12. The preparation method according to claim 11, characterized in that: The drug is insulin or an insulin analog, such as recombinant human insulin, The polymer is preferably mussel protein; The mass ratio of the drug crystal to the polymer is preferably 1:(0.2-1.2), more preferably 1:(0.2-0.4), and most preferably 1:0.2; The mass concentration of the polymer in the solvent is preferably 0.5-3 mg / mL, more preferably 1-2 mg / mL, and most preferably 1 mg / ml.

13. The preparation method according to claim 11, characterized in that: The solvent is a buffer solution, and the buffer solution satisfies one or more of the following conditions: (1) The pH value of the buffer solution is 4-9, preferably 5-8, and more preferably 6; (2) the buffer solution is sodium dihydrogen phosphate-disodium hydrogen phosphate buffer; and (3) The concentration of the buffer solution is 10-200 mM, preferably 20 mM; Preferably, the buffer solution is a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer with a concentration of 20 mM and a pH of 6.

14. The preparation method according to claim 11, characterized in that: The catalyst is an oxidizing agent, The oxidant is persulfate, divalent copper salt, trivalent iron salt, permanganate or periodate, preferably ammonium persulfate, potassium permanganate or sodium periodate; and / or, The mass concentration of the oxidant in the solvent is 0.3-1.2 mg / mL, preferably 0.4-0.8 mg / mL, and more preferably 0.6 mg / ml.

15. The preparation method according to claim 11, characterized in that: The cross-linking reaction time is overnight, for example, 12 hours; and / or, The temperature of the cross-linking reaction is room temperature, for example, 4-37°C, preferably 20-30°C.

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