A sustained release composition of pregabalin and a method of preparing the same

Abstract

The application discloses a sustained-release pregabalin composition and a preparation method thereof, and belongs to the technical field of medicine, and specifically relates to a sustained-release pregabalin composition and a preparation method thereof. The sustained-release pregabalin composition comprises the following components in parts by weight: 45-50 parts of pregabalin or a pharmaceutically acceptable salt thereof; 23-35 parts of a matrix forming agent; 23-30 parts of a swelling agent, wherein the swelling agent is a double-layer network structure, a first layer network provides support for a second layer network, and the two are crosslinked in a physical and chemical manner; 15-25 parts of a sustained-release agent; and 12-20 parts of a filling agent. The first layer network comprises chitosan, sodium alginate, methacrylic anhydride, a photoinitiator and zinc ions; and the second layer network comprises cyclodextrin, polyethylene glycol dimethacrylate, methacrylamide, a crosslinking agent, a photoinitiator and deionized water. The sustained-release tablet of the application is expanded to more than 13 mm after 1.5 h, and the tablet can remain intact, which is beneficial to the retention of the sustained-release pregabalin composition in the stomach, achieves the effect of sustained release, and improves the absorption of pregabalin.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pregabalin preparation, in particular to a pregabalin sustained-release composition and a preparation method thereof. BACKGROUND

[0002] Pregabalin is a gamma-aminobutyric acid (GABA) analogue, which can regulate the release of neurotransmitters, act on the central nervous system, and has high affinity for the alpha2-delta subunit of voltage-gated calcium channels, thereby effectively relieving neuropathic pain, and is often used to treat post-herpetic neuralgia, pain caused by diabetic peripheral neuropathy, etc. In addition, it also has antiepileptic efficacy and certain effect in the treatment of anxiety.

[0003] Studies have shown that the absorption of pregabalin in the gastrointestinal tract is uneven, and it is well absorbed in the small intestine and ascending colon of humans, but rarely absorbed in the intestinal segment outside the colon hepatic flexure. This indicates that the average absorption window of pregabalin is about 6 hours or less, so if pregabalin is made into a conventional sustained-release dosage form, the drug released after more than 6 hours will not be effectively absorbed, resulting in waste of the drug.

[0004] Sustained-release tablets need to be retained in the stomach for a long time, so the strength cannot be too low, otherwise they are easy to break or dissolve quickly, but also cannot be too high, otherwise they may affect the normal peristalsis of the stomach or cause discomfort due to the large volume. The swelling size needs to be large enough to achieve gastric retention, but cannot be too swollen, otherwise it may cause physical discomfort or affect the drug release rate.

[0005] To achieve effective sustained release of pregabalin sustained-release tablets in the stomach, the key is to improve the acid resistance of the material and control the swelling size.

[0006] Therefore, how to obtain a pregabalin sustained-release tablet with good swelling size and acid resistance, good sustained-release effect, and promote absorption in the small intestine and ascending colon, and improve drug efficacy, has become a technical problem to be solved by those skilled in the art. SUMMARY

[0007] The purpose of the present application is to provide a pregabalin sustained-release tablet with good swelling size and acid resistance, good sustained-release effect, and promote absorption in the small intestine and ascending colon.

[0008] Technical solution: The pregabalin sustained-release composition provided by the application is characterized by comprising the following components in a weight ratio: 45-50 parts of active ingredients, wherein the active ingredients comprise pregabalin or a pharmaceutically acceptable salt thereof; 23-35 parts of a matrix forming agent; 23-30 parts of a swelling agent, wherein the swelling agent is a double-layer network structure, the first layer network provides support for the second layer network, and the two are crosslinked in a physical and chemical manner; 15-25 parts of a sustained-release agent; 12-20 parts of a filler,

[0009] The first layer network comprises the following components in a mass ratio:

[0010] Raw material name Amount

[0011] Chitosan 10-20 parts

[0012] Sodium alginate 10-20 parts

[0013] Methyl acrylate 34-360 parts

[0014] Photoinitiator 0.05-0.2 parts

[0015] Zinc ion (ZnCl2) 20-30 parts

[0016] The second layer network comprises the following components in a mass ratio:

[0017] Raw material name Amount

[0018] Cyclodextrin 3-4 wt%

[0019] Polyethylene glycol dimethacrylate (PEGDA) 7-11 wt%

[0020] Methacrylamide (AM) 7-11 wt%

[0021] Crosslinking agent 0.2-0.5 wt%

[0022] Photoinitiator 0.1-0.3 wt%

[0023] Deionized water Balance.

[0024] Further, the cyclodextrin is selected from alpha-cyclodextrin, beta-cyclodextrin or gamma-cyclodextrin.

[0025] Further, the beta-cyclodextrin is a modified hydroxypropyl beta-cyclodextrin.

[0026] Further, the crosslinking agent of the second layer network is N,N'-methylenebisacrylamide MBA, and the photoinitiator is 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone.

[0027] Further, the filler is microcrystalline cellulose.

[0028] Further, the matrix forming agent is polyvinyl acetate.

[0029] Further, the sustained release agent is modified hydroxypropyl methyl cellulose HPMC.

[0030] Further, the modification method comprises:

[0031] (1) dissolving hydroxypropyl methyl cellulose HPMC in ionized water to obtain system I, dissolving acrylamide AM in ionized water to obtain system II, and dissolving initiator in ionized water for standby, wherein the mass ratio of hydroxypropyl methyl cellulose HPMC, potassium persulfate KPS and acrylamide AM is 2-8:0.04-0.07:5.5-9.0;

[0032] (2) grafting reaction: heating system I, adding initiator solution to obtain system III, adding system II to system III, constant temperature water bath, continuous nitrogen gas reaction, obtaining transparent viscous system.

[0033] Further, the mass of acrylamide AM is 5.5g-9.0g.

[0034] The preparation method of the pregabalin sustained release composition comprises the following steps:

[0035] (1) dissolving and mixing raw materials:

[0036] adding matrix forming agent into appropriate amount of ethanol or water to form a solution;

[0037] adding pregabalin, swelling agent, sustained release agent and filler into the above solution in proportion, and stirring uniformly;

[0038] (2) sieving:

[0039] sieving the mixed material through 40-60 mesh sieve;

[0040] (3) drying:

[0041] drying the sieved material at a temperature of 40-60℃ to remove solvent, obtaining dry powder;

[0042] (4) mixing:

[0043] adding appropriate amount of glidant into the mixing machine with the dry powder, and mixing for 15-30min;

[0044] (5) tabletting:

[0045] tabletting the mixed powder.

[0046] The connection between the first network and the second network is mainly achieved through physical crosslinking and chemical crosslinking, specifically as follows:

[0047] Physical crosslinking:

[0048] The polymer chains in the first network (such as sodium alginate / chitosan / zinc ion complexes) interact with the polymer chains in the second network (such as polyethylene glycol dimethacrylate (PEGDA) and methacrylamide (AM)) through a slip ring structure. The slip ring structure allows the polymer chains to freely slide within a certain range, thereby physically connecting the two networks.

[0049] Hydrogen bonds and van der Waals forces: The polymer chains in the first network and the second network also interact through hydrogen bonds and van der Waals forces, forming physical crosslinking points. These non-covalent interactions enhance the connection between the two networks to some extent.

[0050] Chemical crosslinking:

[0051] Covalent crosslinking points: During the preparation of the second network, the polymer chains in the second network are crosslinked together through a photo-crosslinking reaction (such as using 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylbenzophenone (Irgacure 2959) as a photoinitiator), and these crosslinking points can also covalently connect with the polymer chains in the first network. PEGDA and AM in the second network can form a covalently crosslinked network through free radical polymerization, and these crosslinking points can interact with the polymer chains in the first network to form a more stable connection.

[0052] The role of crosslinking agents: Crosslinking agents can react with the polymer chains in the first network and the second network to form covalent crosslinking points, thereby tightly connecting the two networks together.

[0053] Compared with the prior art, the beneficial effects of the present application are as follows:

[0054] (1) The sustained-release tablet of the present application expands to more than 13 mm, even more than 13.5 mm, after being in contact with an aqueous medium for 1.5 h, and the tablet remains intact. The earlier the size of the sustained-release tablet expands to 13 mm, the more beneficial it is for the pregabalin sustained-release composition to stay in the stomach, achieving the effect of sustained release and improving the absorption of pregabalin.

[0055] (2) The hydroxypropyl methyl cellulose HPMC is modified in the application, and after modification, the modified HPMC has good acid resistance, swelling control and slow-release performance: 1. Acid resistance: grafting and crosslinking modification significantly improves the acid resistance of HPMC, so that it is not easy to degrade in gastric juice, ensuring the structure stability of the slow-release tablet. 2. Swelling control: the swelling degree of the modified HPMC is moderate, which can absorb water to maintain a moist state, and will not over-expand to affect drug release. 3. Slow-release performance: the modified HPMC realizes slow and continuous release of drugs in the stomach through acid resistance and swelling control, prolongs the drug action time and improves the curative effect.

[0056] (3) The double network of the application realizes the synergistic effect between the components by reasonably matching the components, so as to obtain excellent comprehensive performance. The chitosan, sodium alginate and zinc ions in the first network jointly form a stable and uniform crosslinked network; the cyclodextrin and polymer monomer in the second network further enhance the mechanical properties and swelling behavior of the swelling agent. BRIEF DESCRIPTION OF DRAWINGS

[0057] Figure 1 Cumulative release (%) diagram for Example 1;

[0058] Figure 2 Cumulative release (%) diagram for Comparative Example 1;

[0059] Figure 3 Cumulative release (%) diagram for Comparative Example 10;

[0060] Figure 4 Cumulative release (%) diagram for Comparative Example 14. DETAILED DESCRIPTION

[0061] In order to make the purpose, technical scheme and advantages of the application more clear, the technical scheme of the application will be further described below.

[0062] (I) Preparation method of the double network swelling agent:

[0063] Preparation Example 1

[0064] (1) Prepare raw materials: select hydroxypropyl beta-cyclodextrin (purity ≥ 99%), polyethylene glycol dimethacrylate (PEGDA, molecular weight 700), methacrylamide, N,N'-methylene bisacrylamide, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methyl benzophenone and deionized water as raw materials, which are commercially available.

[0065] (2) Dissolution and mixing: hydroxypropyl β-cyclodextrin, polyethylene glycol dimethacrylate, methacrylamide, N,N'-methylene bisacrylamide, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone are mixed and dissolved in deionized water in proportion to form a uniform mixed monomer solution, and the amount of each component (mass percentage of total raw materials) is as follows:

[0066] Raw material name Amount

[0067] Hydroxypropyl β-cyclodextrin 3 wt%

[0068] Polyethylene glycol dimethacrylate 9 wt%

[0069] Methacrylamide 9 wt%

[0070] N,N'-methylene bisacrylamide 0.3 wt%

[0071] 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone 0.2 wt%

[0072] Deionized water Balance

[0073] (3) Preparation of the first network: (sodium alginate / chitosan / zinc ion complex)

[0074] Raw material name Amount

[0075] Chitosan 15 g

[0076] Sodium alginate 15 g

[0077] Methacrylic anhydride 260 g

[0078] Photoinitiator Irgacure 2959 0.15 g

[0079] Zinc ion solution (ZnCl2) 25 g.

[0080] The preparation steps include:

[0081] 1. Preparation of chitosan aqueous solution

[0082] 1.1 Dissolve chitosan in water to prepare a chitosan solution with a concentration of 15 g / L.

[0083] 1.2 Add methacrylic anhydride and adjust the pH to 9 with sodium bicarbonate solution, and fully stir to obtain a uniform chitosan aqueous solution.

[0084] 1.3 The obtained chitosan aqueous solution is dialyzed using a 6 kD dialysis bag for 2 days, and then freeze-dried for standby.

[0085] 2. Preparation of sodium alginate aqueous solution

[0086] 2.1 Dissolve sodium alginate in water to prepare a sodium alginate solution with a concentration of 15 g / L.

[0087] 2.2 Add methyl acrylate dropwise and adjust the pH to 9 with sodium hydroxide solution, and fully stir to obtain a uniform sodium alginate aqueous solution.

[0088] 2.3 The obtained sodium alginate aqueous solution is dialyzed using a 6 kD dialysis bag for 2 days, and after dialysis, it is freeze-dried for standby use.

[0089] 3. Preparation of sodium alginate / chitosan / zinc ion composite hydrogel

[0090] 3.1 Mix the freeze-dried chitosan solution and sodium alginate solution in a mass ratio of 5:1 to obtain a mixed solution.

[0091] 3.2 Add ZnCl2 to the mixed solution, and through the interaction of zinc ions with chitosan and sodium alginate, a composite crosslinked network is formed.

[0092] 3.3 Add the photoinitiator Irgacure 2959.

[0093] 3.4 Pour the mixed solution into a mold and irradiate it under a 100 W ultraviolet light (ultraviolet intensity 5000 μW / cm²) for 5 min to perform a photocrosslinking reaction, forming a sodium alginate / chitosan / zinc ion composite hydrogel.

[0094] 4. Post-processing

[0095] 4.1 Take out the prepared composite hydrogel from the mold and rinse repeatedly with deionized water to remove surface residues.

[0096] 4.2 Soak the hydrogel in deionized water and stand at room temperature for 25 min to allow the hydrogel to fully swell and balance.

[0097] 4.3 Take out the balanced hydrogel, absorb the surface moisture with filter paper, and perform performance testing.

[0098] (4) Preparation of the second network:

[0099] 1. Inject the mixed monomer solution containing hydroxypropyl β-cyclodextrin into the mold in which the first network has been formed, ensuring that the solution uniformly covers the first network;

[0100] 2. Put the mold into the ultraviolet light irradiation box, and irradiate it with ultraviolet light with a wavelength of 365 nm and an intensity of 20 mW / cm² for 20 minutes to make the polymer monomers undergo a polymerization reaction and form a second network, i.e., a photo-crosslinked sliding ring network. During the photo-crosslinking process, the ambient temperature is controlled to be 30°C and the humidity is controlled to be 45%.

[0101] (5) Post-processing:

[0102] 1. Take the prepared double-network sliding ring hydrogel out of the mold, and rinse it repeatedly with deionized water 4 times to wash away the surface residual unreacted monomers, crosslinking agents, photo initiators and other impurities.

[0103] 2. Soak the hydrogel in deionized water, and stand it at room temperature for 38 hours to make the hydrogel fully swell and balance, and further remove the internal residues.

[0104] 3. Take out the balanced hydrogel, and absorb the surface moisture with filter paper, and then perform subsequent performance testing and application research. For example, tensile testing, compression testing, swelling performance testing, drug release experiments, etc. can be performed to evaluate the mechanical properties, physical and chemical properties and biological functions.

[0105] Preparation Example 2

[0106] (1) Prepare raw materials: select hydroxypropyl β-cyclodextrin (purity ≥ 99%), polyethylene glycol dimethacrylate (PEGDA, molecular weight 700), methacrylamide, N,N'-methylene bisacrylamide, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methyl benzophenone and deionized water, etc. as raw materials, which are purchased from a chemical reagent company and pass quality testing.

[0107] (2) Dissolution and mixing: dissolve and mix hydroxypropyl β-cyclodextrin, polyethylene glycol dimethacrylate, methacrylamide, N,N'-methylene bisacrylamide, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methyl benzophenone in deionized water according to the proportion to form a uniform mixed monomer solution, and the use amount (mass percentage of total raw materials) of each component is as follows:

[0108] Raw material name Amount

[0109] Hydroxypropyl β-cyclodextrin 4 wt%

[0110] Polyethylene glycol dimethacrylate 11 wt%

[0111] Methacrylamide 11 wt%

[0112] N,N'-methylene bisacrylamide 0.5 wt%

[0113] 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone 0.3 wt%

[0114] Deionized water balance.

[0115] (3) Preparation of the first network: (sodium alginate / chitosan / zinc ion complex)

[0116] Raw material name Amount

[0117] Chitosan 20 g

[0118] Sodium alginate 20 g

[0119] Methacrylic anhydride 360 g

[0120] Photoinitiator Irgacure 2959 0.2 g

[0121] Zinc ion solution (ZnCl2) 30 g.

[0122] The preparation steps include:

[0123] 1. Preparation of chitosan aqueous solution

[0124] 1.1 Dissolve chitosan in water to prepare a chitosan solution with a concentration of 10 g / L.

[0125] 1.2 Add methacrylic anhydride and adjust the pH to 10 with sodium bicarbonate solution, and fully stir to obtain a uniform chitosan aqueous solution.

[0126] 1.3 The obtained chitosan aqueous solution is dialyzed using an 8 kD dialysis bag for 3 days, and then freeze-dried for standby.

[0127] 2. Preparation of sodium alginate aqueous solution

[0128] 2.1 Dissolve sodium alginate in water to prepare a sodium alginate solution with a concentration of 10 g / L.

[0129] 2.2 Add methacrylic anhydride dropwise and adjust the pH to 10 with sodium hydroxide solution, and fully stir to obtain a uniform sodium alginate aqueous solution.

[0130] 2.3 The obtained sodium alginate aqueous solution is dialyzed using an 8 kD dialysis bag for 3 days, and then freeze-dried after dialysis for standby.

[0131] 3. Preparation of sodium alginate / chitosan / zinc ion complex hydrogel

[0132] 3.1 Mix the freeze-dried chitosan solution and sodium alginate solution in a mass ratio of 10:1 to obtain a mixed solution.

[0133] 3.2 Add ZnCl2 to the mixed solution. Through the interaction of zinc ions with chitosan and sodium alginate, a complex crosslinking network is formed.

[0134] 3.3 Add the photoinitiator Irgacure 2959.

[0135] 3.4 Pour the mixed solution into the mold and irradiate it under a 100 W ultraviolet light lamp (ultraviolet intensity 5000 μW / cm²) for 10 min to perform a photocrosslinking reaction, forming a sodium alginate / chitosan / zinc ion composite hydrogel.

[0136] 4. Post-processing

[0137] 4.1 Remove the prepared composite hydrogel from the mold and rinse it repeatedly with deionized water to remove surface residues.

[0138] 4.2 Soak the hydrogel in deionized water and let it stand at room temperature for 30 min to allow the hydrogel to fully swell and equilibrate.

[0139] 4.3 Take out the equilibrated hydrogel, absorb the surface moisture with filter paper, and perform performance testing.

[0140] (4) Preparation of the second network:

[0141] 1. Inject the mixed monomer solution containing hydroxypropyl β-cyclodextrin into the mold in which the first network has been formed, ensuring that the solution uniformly covers the first network.

[0142] 2. Place the mold in an ultraviolet light irradiation box and irradiate it with ultraviolet light of wavelength 365 nm and intensity 30 mW / cm² for 30 min to cause the polymer monomers to undergo a polymerization reaction, forming a second network, i.e., a photocrosslinked sliding ring network. During the photocrosslinking process, the environmental temperature is controlled at 35°C and the humidity is controlled at 65%.

[0143] (5) Post-processing:

[0144] 1. Remove the prepared double-network sliding ring hydrogel from the mold and rinse it repeatedly with deionized water 5 times to wash away surface residues of unreacted monomers, crosslinking agents, photoinitiators, and other impurities.

[0145] 2. Soak the hydrogel in deionized water and let it stand at room temperature for 48 hours to allow the hydrogel to fully swell and equilibrate, further removing internal residues.

[0146] 3. Take out the equilibrated hydrogel, absorb the surface moisture with filter paper, and it can be used for subsequent performance testing and application research. For example, tensile testing, compression testing, swelling performance testing, drug release experiments, etc. can be performed to evaluate its mechanical properties, physical and chemical properties, and biological functions.

[0147] Preparation Example 3

[0148] (1) Preparation of raw materials: hydroxypropyl β-cyclodextrin (purity ≥ 99%), polyethylene glycol dimethacrylate (PEGDA, molecular weight 700), methacrylamide, N,N'-methylene bisacrylamide, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methyl benzophenone and deionized water were selected as raw materials, which were purchased from chemical reagent companies and passed quality inspection.

[0149] (2) Dissolution and mixing: hydroxypropyl β-cyclodextrin, polyethylene glycol dimethacrylate, methacrylamide, N,N'-methylene bisacrylamide, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methyl benzophenone were mixed and dissolved in deionized water in proportion to form a uniform monomer solution, and the amount of each component (mass percentage of total raw materials) was as follows:

[0150] Raw material name Amount

[0151] Hydroxypropyl β-cyclodextrin 3wt%

[0152] Polyethylene glycol dimethacrylate 7wt%

[0153] Methacrylamide 7wt%

[0154] N,N'-methylene bisacrylamide 0.2wt%

[0155] 2-hydroxy-4'-(2-hydroxyethoxy)-2-methyl benzophenone 0.1wt%

[0156] Deionized water Balance.

[0157] (3) Preparation of the first network: (sodium alginate / chitosan / zinc ion complex)

[0158] Raw material name Amount

[0159] Chitosan 10g

[0160] Sodium alginate 10g

[0161] Methacrylic anhydride 34g

[0162] Photoinitiator Irgacure 2959 0.05g

[0163] Zinc ion solution (ZnCl2) 20g.

[0164] The preparation steps include:

[0165] 1. Preparation of chitosan aqueous solution

[0166] 1.1 Chitosan was dissolved in water to prepare a chitosan solution with a concentration of 20 g / L.

[0167] 1.2 Methyl methacrylate was added, and the pH was adjusted to 8 with a sodium bicarbonate solution. The resulting chitosan solution was stirred thoroughly to obtain a uniform solution.

[0168] 1.3 The resulting chitosan solution was dialyzed using a 5 kD dialysis bag for 1 day, and then freeze-dried for later use.

[0169] 2. Preparation of a sodium alginate solution

[0170] 2.1 Sodium alginate was dissolved in water to prepare a sodium alginate solution with a concentration of 20 g / L.

[0171] 2.2 Methyl methacrylate was added dropwise, and the pH was adjusted to 8 with a sodium hydroxide solution. The resulting sodium alginate solution was stirred thoroughly to obtain a uniform solution.

[0172] 2.3 The resulting sodium alginate solution was dialyzed using a 5 kD dialysis bag for 1 day, and then freeze-dried for later use.

[0173] 3. Preparation of a sodium alginate / chitosan / zinc ion composite hydrogel

[0174] 3.1 The freeze-dried chitosan solution and the sodium alginate solution were mixed in a mass ratio of 1:1 to obtain a mixed solution.

[0175] 3.2 ZnCl2 was added to the mixed solution, and a composite crosslinked network was formed through the interaction of zinc ions with chitosan and sodium alginate.

[0176] 3.3 A photoinitiator, Irgacure 2959, was added.

[0177] 3.4 The mixed solution was poured into a mold and irradiated under a 100 W ultraviolet light lamp (ultraviolet intensity 5000 μW / cm²) for 1 min to perform a photocrosslinking reaction, thereby forming a sodium alginate / chitosan / zinc ion composite hydrogel.

[0178] 4. Post-processing

[0179] 4.1 The prepared composite hydrogel was removed from the mold and repeatedly rinsed with deionized water to remove surface residues.

[0180] 4.2 The hydrogel was soaked in deionized water and left to stand at room temperature for 20 min to allow the hydrogel to fully swell and equilibrate.

[0181] 4.3 The equilibrated hydrogel was removed and the surface moisture was absorbed with filter paper for performance testing.

[0182] (4) Preparation of a second network:

[0183] 1. Inject the mixed monomer solution containing hydroxypropyl β-cyclodextrin into the mold with the first network formed, ensuring that the solution uniformly covers the first network.

[0184] 2. Place the mold in a UV irradiation box and irradiate it with UV light with a wavelength of 365 nm and an intensity of 10 mW / cm² for 10 minutes to cause the polymer monomers to undergo a polymerization reaction, forming a second network, i.e., a photocrosslinked sliding ring network. During the photocrosslinking process, the environmental temperature is controlled at 25°C and the humidity is controlled at 35%.

[0185] (5) Post-processing:

[0186] 1. Remove the prepared double-network sliding ring hydrogel from the mold and rinse it repeatedly with deionized water three times to wash away surface residues of unreacted monomers, crosslinking agents, photoinitiators, and other impurities.

[0187] 2. Soak the hydrogel in deionized water and let it stand at room temperature for 24 hours to allow the hydrogel to fully swell and balance, further removing internal residues.

[0188] 3. Take out the balanced hydrogel and absorb the surface moisture with filter paper, and then proceed to subsequent performance testing and application research. For example, tensile testing, compression testing, swelling performance testing, drug release experiments, etc. can be performed to evaluate its mechanical properties, physical and chemical properties, and biological functions.

[0189] Comparative Example 1

[0190] The difference from Example 1 is that only the first layer network is present.

[0191] Comparative Example 2

[0192] The difference from Example 1 is that only the second layer network is present.

[0193] Comparative Example 3

[0194] The difference from Example 1 is that the first layer network does not add chitosan and methacrylic anhydride.

[0195] Comparative Example 4

[0196] The difference from Example 1 is that the first layer network does not add chitosan.

[0197] Comparative Example 5

[0198] The difference from Example 1 is that the first layer network does not add methacrylic anhydride.

[0199] Comparative Example 6

[0200] The difference from Example 1 is that the second layer network adds α-cyclodextrin.

[0201] Comparative Example 7

[0202] The difference from Example 1 is that γ-cyclodextrin is added to the second layer of network.

[0203] Comparative Example 8

[0204] The difference from Example 1 is that the amount of ZnCl2 added in the first layer is 10 g.

[0205] Comparative Example 9

[0206] The difference from Example 1 is that the amount of ZnCl2 added in the first layer is 40 g.

[0207] Performance test of swelling agent:

[0208] 1. Tensile strength (KPa)

[0209] Test Method: Tensile testing is performed using a universal materials testing machine. The swelling agent sample is formed into a standard-sized dumbbell-shaped specimen, secured to the two fixtures of the testing machine, and stretched at a constant rate until the specimen breaks. The maximum tensile force and elongation at break are recorded, and the tensile strength is calculated.

[0210] 2. Elongation at break (%)

[0211] Test method: In the above tensile test, the ratio of the elongation at break to the original length of the specimen is recorded simultaneously, which is the elongation at break.

[0212] 3. Swelling degree (times)

[0213] Test method: Soak the swelling agent sample in a solution simulating gastric fluid (using hydrochloric acid solution at pH 1.2) at 37°C for a specified period of time (2 hours). Remove the sample, gently blot the surface moisture with filter paper, and then weigh its wet and dry weights. The swelling degree is calculated using the formula: Swelling degree = (wet weight - dry weight) / dry weight.

[0214] The test results are shown in Table 1 below:

[0215] Table 1

[0216] Group Tensile strength (KPa) Elongation at break (%) Swelling degree (times) Preparation Example 1 1500 860 19.8 Preparation Example 2 1300 760 17.2 Preparation Example 3 1400 810 16.4 Comparative Example 1 800 450 8.5 Comparative Example 2 750 420 7.8 Comparative Example 3 550 300 5.5 Comparative Example 4 600 350 6.2 Comparative Example 5 650 380 6.8 Comparative Example 6 700 360 7.0 Comparative Example 7 680 340 6.5 Comparative Example 8 500 280 5.0 Comparative Example 9 450 250 4.5

[0217] The results in the table above show:

[0218] Preparation Examples 1-3 showed a relatively high degree of swelling (16.4-19.8 times), which indicates that the swelling agent used can effectively increase the volume of the drug preparation, help prolong the retention time of the drug in the stomach, and achieve more sustained drug release.

[0219] The swelling degree of Comparative Examples 1-9 is low (4.5-8.5 times), which means that the swelling capacity of these formulations in water is limited, affecting the release of the drug and the gastric retention time.

[0220] Comparative Example 1 (only the first network): Due to the lack of the enhancement of the second network, the tensile strength and elongation at break are significantly reduced, and the swelling degree is also decreased.

[0221] Comparative Example 2 (only the second network): The only second network cannot provide sufficient support, resulting in poor mechanical properties and swelling degree.

[0222] Comparative Example 3 (without adding chitosan and methacrylic anhydride): The absence of chitosan and methacrylic anhydride leads to incomplete network structure and significant performance decline.

[0223] Comparative Example 4 (without adding chitosan): The absence of chitosan affects the cross-linking density and structural integrity of the network, leading to performance decline.

[0224] Comparative Example 5 (without adding methacrylic anhydride): The absence of methacrylic anhydride affects the cross-linking effect of the network, leading to performance decline.

[0225] Comparative Example 6 (adding α-cyclodextrin): The cavity of α-cyclodextrin is smaller than that of hydroxypropyl β-cyclodextrin, and the interaction with the polymer chain is not as good, leading to performance decline.

[0226] Comparative Example 7 (adding γ-cyclodextrin): The cavity of γ-cyclodextrin is larger than that of hydroxypropyl β-cyclodextrin, and the interaction with the polymer chain is not as good, leading to performance decline.

[0227] Comparative Example 8 (ZnCl2 addition amount 10g): The addition amount of zinc ions is insufficient, affecting the formation of the cross-linked network, leading to performance decline.

[0228] Comparative Example 9 (ZnCl2 addition amount 40g): The addition amount of zinc ions is too much, which may lead to a too rigid network structure, affecting the ductility and swelling degree.

[0229] Further analysis of the data results of the above comparative examples:

[0230] Comparative Examples 1 and 2 (one-layer network)

[0231] Comparative Example 1 (only the first network): Tensile strength: 800 KPa, elongation at break: 450%

[0232] Swelling degree: 8.5 times. Comparative Example 2 (only the second network): Tensile strength: 750 KPa, elongation at break: 420%, swelling degree: 7.8 times.

[0233] The comparison shows that:

[0234] Comparative Example 1: Only the first network (sodium alginate / chitosan / zinc ion complex) lacks the reinforcing effect of the second network, resulting in a significant decrease in tensile strength and elongation at break. The first network can provide some basic support, but without the synergistic effect of the second network, the mechanical properties are poor. The reason for the low swelling degree is that the crosslinking density of the first network is high, which limits the swelling of the hydrogel. Comparative Example 2: Only the second network (cyclodextrin mixed monomer solution) lacks the support of the first network, resulting in poor mechanical properties and swelling degree. The second network cannot form a stable structure without the foundation of the first network, and the mechanical strength and ductility are low. Although the swelling degree is slightly higher than that of Comparative Example 1, it is still significantly lower than that of the examples, indicating that the swelling capacity of the second network is also limited when it exists alone. The double network structure in Example 1 significantly improves the overall performance of the hydrogel through the synergistic effect of the first and second networks. The first network provides basic mechanical strength and structural support, while the second network further enhances the mechanical properties and swelling capacity of the hydrogel. This synergistic effect makes the double network hydrogel superior to single network hydrogel in terms of tensile strength, elongation at break, and swelling degree.

[0235] Comparative Examples 3, 4, 5 (absence of first network components)

[0236] Comparative Example 3 (without adding chitosan and methacrylic anhydride): tensile strength 550 KPa, elongation at break 300%, swelling degree 5.5 times. Comparative Example 4 (without adding chitosan): tensile strength 650 KPa, elongation at break 380%, swelling degree 6.8 times. Comparative Example 5 (without adding methacrylic anhydride): tensile strength 600 KPa, elongation at break 350%, swelling degree 6.2 times.

[0237] By comparison, we can see that:

[0238] Chitosan and methacrylic anhydride have a significant synergistic effect in the first network. Chitosan provides additional physical crosslinking points, enhancing the mechanical strength and stability of the network, while methacrylic anhydride further strengthens the network structure through chemical crosslinking. Chitosan is a natural polysaccharide with good biocompatibility and mechanical properties. Methacrylic anhydride can react with chitosan and sodium alginate to form chemical crosslinks, enhancing the stability and mechanical strength of the network. When both components are present, they work together to form a more uniform and stable crosslinked network, significantly improving the tensile strength, elongation at break, and swelling degree of the hydrogel.

[0239] Comparative Examples 6, 7 (effect of different cyclodextrins)

[0240] Comparative Example 6 (addition of a-cyclodextrin): tensile strength 700 KPa, elongation at break 360%, swelling degree 7.0 times. Comparative Example 7 (addition of y-cyclodextrin): tensile strength 680 KPa, elongation at break 340%, swelling degree 6.5 times.

[0241] By comparison, it can be seen that:

[0242] Selection of cyclodextrin: hydroxypropyl β-cyclodextrin has the best effect in the second network, its cavity size and shape best match the polymer chain, and it can form a stable inclusion compound to improve the performance of the hydrogel. The cavity of a-cyclodextrin is smaller, and the cavity of y-cyclodextrin is larger. Their interaction with the polymer chain is not as good as that of β-cyclodextrin. Hydroxypropyl β-cyclodextrin can better include the polymer chain to form stable physical crosslinking points, thereby enhancing the mechanical properties and swelling effect of the hydrogel.

[0243] Comparative Examples 8 and 9 (influence of zinc ion addition amount)

[0244] Comparative Example 8 (ZnCl2 addition amount 10 g): tensile strength 500 KPa, elongation at break 280%, swelling degree 5.0 times. Comparative Example 9 (ZnCl2 addition amount 40 g): tensile strength 450 KPa, elongation at break 250%, swelling degree 4.5 times.

[0245] By comparison, it can be seen that the optimal addition amount of zinc ions: zinc ions play the role of crosslinking agent in the first network, but the addition amount should be moderate. A low zinc ion concentration (10 g) cannot form enough crosslinking points, resulting in a loose network structure and decreased performance. A high zinc ion concentration (40 g) may result in a network structure that is too rigid, limiting the movement of the polymer chain and thus reducing the elongation at break and swelling degree. Zinc ions form ionic crosslinking with the carboxyl and amino groups of chitosan and sodium alginate, enhancing the mechanical strength and stability of the network. An appropriate amount of zinc ions can provide enough crosslinking points, making the network structure uniform and stable. However, an excessive amount of zinc ions can result in a high crosslinking density, making the network structure too rigid and thus reducing the extensibility and swelling ability of the hydrogel.

[0246] Importance of synergistic effect: the double network in Preparation Example 1 achieves a synergistic effect between the components by reasonable matching of the components, thereby obtaining excellent comprehensive performance. Chitosan, sodium alginate, and zinc ions in the first network work together to form a stable and uniform crosslinked network; cyclodextrin and polymer monomers in the second network further enhance the mechanical properties and swelling behavior of the swelling agent.

[0247] (II) Preparation method of the sustained-release agent

[0248] Preparation Example 1

[0249] 1. Raw material preparation

[0250] Hydroxypropyl methyl cellulose (HPMC), acrylamide (AM), potassium persulfate (KPS) as initiator, deionized water

[0251] 2. Graft modification method

[0252] (1) Solution preparation: 5 g of HPMC was dissolved in 50 mL of deionized water, stirred at room temperature until completely dissolved, to obtain system I;

[0253] (2) Preparation of initiator solution: 0.06 g of potassium persulfate (KPS) was dissolved in 10 mL of deionized water, and was prepared for use;

[0254] (3) Preparation of monomer solution: 6 g of acrylamide (AM) monomer was dissolved in 40 mL of deionized water, and was stirred until completely dissolved to obtain system II;

[0255] (4) Graft reaction: system I was added to a reaction device equipped with mechanical stirring and nitrogen for 30 minutes, heating was started and the reaction temperature was heated to 60°C, and the initiator solution was added dropwise to initiate for 15 minutes to obtain system III. System II was added dropwise to system III, and was stirred uniformly in a constant temperature water bath at 60°C, and the reaction was continued for 1 hour under continuous nitrogen, and finally a transparent viscous system was obtained;

[0256] (5) Product treatment: the prepared transparent viscous system was poured into acetone, and the solid was precipitated, cut and soaked in acetone for 72 hours, then filtered, and finally dried in a vacuum oven at 40°C for 48 hours, and finally the grafted HPMC-g-PAM powder was obtained.

[0257] Preparation Example 2

[0258] 1. Raw material preparation

[0259] Hydroxypropyl methyl cellulose (HPMC), acrylamide (AM), potassium persulfate (KPS) as initiator, deionized water

[0260] 2. Graft modification method

[0261] (1) Solution preparation: 8 g of HPMC was dissolved in 50 mL of deionized water, stirred at room temperature until completely dissolved, to obtain system I;

[0262] (2) Preparation of initiator solution: 0.07 g of potassium persulfate (KPS) was dissolved in 10 mL of deionized water, and was prepared for use;

[0263] (3) Preparation of monomer solution: 9 g of acrylamide (AM) monomer was dissolved in 40 mL of deionized water, and was stirred until completely dissolved to obtain system II;

[0264] (4) Grafting reaction: system I was added to the reaction device with mechanical stirring and nitrogen for 30 minutes, heating was started and heated to reaction temperature 60°C, initiator solution was added dropwise to initiate for 15 minutes to obtain system III. System II was added dropwise to system III, constant temperature water bath 60°C, stirring was uniform, continuous nitrogen was reacted for 1 hour, finally transparent viscous system was obtained;

[0265] (5) Product processing: the prepared transparent viscous system was poured into acetone, the solid was precipitated, cut and soaked in acetone for 72 hours, suction filtration, finally put into vacuum oven 40°C and dried for 48 hours again, finally grafted modified HPMC-g-PAM powder was obtained.

[0266] Preparation example 3

[0267] 1. Raw material preparation

[0268] Hydroxypropyl methyl cellulose (HPMC), acrylamide (AM), potassium persulfate (KPS) as initiator, deionized water

[0269] 2. Graft modification method

[0270] (1) Solution preparation: 2g HPMC was dissolved in 50 mL deionized water, stirring at room temperature until completely dissolved to obtain system I;

[0271] (2) Preparation of initiator solution: 0.04g potassium persulfate (KPS) was dissolved in 10 mL deionized water, ready for use;

[0272] (3) Preparation of monomer solution: acrylamide (AM) monomer 5.5g was dissolved in 40 mL deionized water, stirring until completely dissolved to obtain system II;

[0273] (4) Grafting reaction: system I was added to the reaction device with mechanical stirring and nitrogen for 30 minutes, heating was started and heated to reaction temperature 60°C, initiator solution was added dropwise to initiate for 15 minutes to obtain system III. System II was added dropwise to system III, constant temperature water bath 60°C, stirring was uniform, continuous nitrogen was reacted for 1 hour, finally transparent viscous system was obtained;

[0274] (5) Product processing: the prepared transparent viscous system was poured into acetone, the solid was precipitated, cut and soaked in acetone for 72 hours, suction filtration, finally put into vacuum oven 40°C and dried for 48 hours again, finally grafted modified HPMC-g-PAM powder was obtained.

[0275] Comparative example 1

[0276] 1. Raw material preparation

[0277] Hydroxypropyl methylcellulose (HPMC), acrylamide (AM), potassium persulfate (KPS) as initiator, deionized water

[0278] 2. Graft modification method

[0279] 1. Solution preparation: 5 g of HPMC was dissolved in 50 mL of deionized water, stirred at room temperature until completely dissolved, to obtain system I;

[0280] 2. Preparation of initiator solution: 0.01 g of potassium persulfate (KPS) was dissolved in 10 mL of deionized water, ready for use;

[0281] 3. Preparation of monomer solution: 2 g of acrylamide (AM) monomer was dissolved in 40 mL of deionized water, stirred until completely dissolved, to obtain system II;

[0282] 4. Graft reaction: system I was added to a reaction device equipped with mechanical stirring and nitrogen for 30 minutes, heating was started and heated to reaction temperature 60℃, initiator solution was added dropwise to initiate for 15 minutes to obtain system III. System II was added dropwise to system III, constant temperature water bath 60℃, stirring was uniform, continuous nitrogen gas reaction for 1 hour, finally obtained transparent viscous system;

[0283] 5. Product treatment: the prepared transparent viscous system was poured into acetone, the solid was precipitated, cut and soaked in acetone for 72 hours, suction filtration, finally put into vacuum oven 40℃ and dried again for 48 hours, finally obtained graft modified HPMC-g-PAM powder.

[0284] Comparative example 2

[0285] 1. Raw material preparation

[0286] Hydroxypropyl methylcellulose (HPMC), acrylamide (AM), potassium persulfate (KPS) as initiator, deionized water

[0287] 2. Graft modification method

[0288] 1. Solution preparation: 5 g of HPMC was dissolved in 50 mL of deionized water, stirred at room temperature until completely dissolved, to obtain system I;

[0289] 2. Preparation of initiator solution: 0.03 g of potassium persulfate (KPS) was dissolved in 10 mL of deionized water, ready for use;

[0290] 3. Preparation of monomer solution: 5 g of acrylamide (AM) monomer was dissolved in 40 mL of deionized water, stirred until completely dissolved, to obtain system II;

[0291] 4. Grafting reaction: system I was added to the reaction device equipped with mechanical stirring and nitrogen for 30 minutes, heating was started and heated to reaction temperature 60℃, initiator solution was added dropwise to initiate 15 minutes to obtain system III. System II was added dropwise to system III, constant temperature water bath 60℃, stirring was uniform, continuous nitrogen was reacted for 1 hour, finally transparent viscous system was obtained;

[0292] 5. Product processing: the prepared transparent viscous system was poured into acetone, the solid was precipitated, cut and soaked in acetone for 72 hours, suction filtration, finally put into vacuum oven 40℃ and dried again for 48 hours, finally the grafted modified HPMC-g-PAM powder was obtained.

[0293] Comparative example 3

[0294] 1. Raw material preparation

[0295] Hydroxypropyl methyl cellulose (HPMC), acrylamide (AM), potassium persulfate (KPS) as initiator, deionized water

[0296] 2. Graft modification method

[0297] 1. Solution preparation: 5g HPMC was dissolved in 50 mL deionized water, stirring at room temperature until completely dissolved to obtain system I;

[0298] 2. Preparation of initiator solution: 0.08g potassium persulfate (KPS) was dissolved in 10 mL deionized water and prepared;

[0299] 3. Preparation of monomer solution: acrylamide (AM) monomer 10g was dissolved in 40 mL deionized water, stirring until completely dissolved to obtain system II;

[0300] 4. Grafting reaction: system I was added to the reaction device equipped with mechanical stirring and nitrogen for 30 minutes, heating was started and heated to reaction temperature 60℃, initiator solution was added dropwise to initiate 15 minutes to obtain system III. System II was added dropwise to system III, constant temperature water bath 60℃, stirring was uniform, continuous nitrogen was reacted for 1 hour, finally transparent viscous system was obtained;

[0301] 5. Product processing: the prepared transparent viscous system was poured into acetone, the solid was precipitated, cut and soaked in acetone for 72 hours, suction filtration, finally put into vacuum oven 40℃ and dried again for 48 hours, finally the grafted modified HPMC-g-PAM powder was obtained.

[0302] Performance test of sustained-release agent:

[0303] 1. Tensile strength (KPa)

[0304] Test Method: Tensile test was performed using a universal material testing machine. The sustained-release agent sample was prepared into a standard size specimen and fixed on the two clamps of the testing machine, and stretched at a constant stretching speed until the specimen broke. The maximum stretching force was recorded, and the tensile strength (unit: KPa) was calculated.

[0305] 2. Elongation at break (%)

[0306] Test Method: In the above tensile test, the ratio of the elongation to the original length when the specimen broke was recorded, which was the elongation at break.

[0307] 3. Swelling degree (times)

[0308] Test Method: The sustained-release agent sample was immersed in a simulated physiological solution (such as a phosphate buffer with pH 7.4) at 37°C for a certain period of time (for example, 2 hours). The sample was taken out, the surface liquid was gently absorbed with filter paper, and then the wet weight and dry weight were measured. The swelling degree calculation formula is: Swelling degree = (wet weight - dry weight) / dry weight.

[0309] 4. Acid resistance (pH 1.2, 8h weight loss rate)

[0310] Test Method: The sustained-release agent sample was immersed in an acidic solution with pH 1.2 at 37°C for 8 hours. The sample was taken out, the surface liquid was gently absorbed with filter paper, and then the wet weight and dry weight were measured. The acid resistance calculation formula is: Acid resistance = (dry weight - wet weight) / dry weight × 100%.

[0311] 5. Grafting rate (%), high performance liquid chromatography (HPLC) to determine the grafting rate

[0312] (1) Sample preparation

[0313] Sample amount: About 0.1 grams of graft copolymer sample was weighed.

[0314] Solvent: Tetrahydrofuran was used as the solvent.

[0315] Dissolution: The sample was added to 10 milliliters of tetrahydrofuran and ultrasonically dissolved for 30 minutes to ensure complete dissolution of the sample.

[0316] (2) Preparation of standard solution

[0317] Standard: Graft copolymer with known grafting rate was selected as the standard.

[0318] Concentration: A series of standard solutions with different grafting rates were prepared, such as 5%, 10%, 15%, 20%, and 25%.

[0319] Solvent: The standard was also dissolved in tetrahydrofuran.

[0320] Volume: The volume of solution for each concentration was 10 mL.

[0321] (3) HPLC analysis conditions

[0322] Column: C18 column (250 mm x 4.6 mm, 5 μm) was selected.

[0323] Mobile phase: A mixture of tetrahydrofuran and water (volume ratio 80:20) was used.

[0324] Flow rate: Set to 1.0 mL / min.

[0325] Detection wavelength: A wavelength was selected at which there was a significant difference in absorption between the graft and ungrafted polymer, for example 220 nm.

[0326] Injection volume: 20 μL.

[0327] (4) Data processing

[0328] Peak area: The chromatograms of the sample and standard solution were recorded, and the peak areas of the graft and ungrafted polymer were measured.

[0329] Standard curve: A graph of the grafting rate (%) versus the peak area ratio was plotted, and a standard curve equation was obtained.

[0330] Grafting rate calculation: The peak area ratio of the sample was used to calculate the grafting rate in the standard curve equation.

[0331] (5) Calculation of grafting rate

[0332] The calculation formula of the grafting rate is represented as:

[0333] ;

[0334] The results are shown in Table 2 below:

[0335] Table 2

[0336] Group Tensile strength Elongation at break Swelling degree Acid resistance (pH 1.2, 8h weight loss rate) Grafting rate Preparation Example 1 40 280 15 8 65 Preparation Example 2 38 250 13 10 60 Preparation Example 3 35 220 12 12 55 Comparative Example 1 28 160 7 18 35 Comparative Example 2 25 140 6 20 30 Comparative Example 3 34 210 10 16 50

[0337] Comparative analysis of the data in the above table:

[0338] Comparative Example 1

[0339] HPMC amount: kept constant (5 g)

[0340] Initiator KPS amount: reduced by 0.05 g (0.06 g in Preparation Example 1, 0.01 g in Comparative Example 1)

[0341] Monomer AM amount: reduced by 4 g (6 g in Preparation Example 1, 2 g in Comparative Example 1)

[0342] Analysis: Insufficient amount of initiator led to insufficient grafting reaction, and grafting rate decreased significantly. At the same time, the significant reduction of monomer AM also limited the formation of grafting chains, resulting in the decline of all performance indicators.

[0343] Comparative Example 2

[0344] HPMC amount: unchanged (5 g)

[0345] Initiator KPS amount: reduced by 0.03 g (0.06 g in Preparation Example 1, 0.03 g in Comparative Example 2)

[0346] Monomer AM amount: reduced by 1 g (6 g in Preparation Example 1, 5 g in Comparative Example 2)

[0347] Analysis: The reduction of initiator and monomer amounts jointly led to the decrease of grafting rate and performance, but the performance decline was smaller compared to Comparative Example 1, indicating that the reduction of monomer AM amount had a more significant impact on performance.

[0348] Comparative Example 3

[0349] HPMC amount: unchanged (5 g)

[0350] Initiator KPS amount: increased by 0.02 g (0.06 g in Preparation Example 1, 0.08 g in Comparative Example 3)

[0351] Monomer AM amount: increased by 4 g (6 g in Preparation Example 1, 10 g in Comparative Example 3)

[0352] Analysis: The increase of initiator amount led to excessive grafting reaction, and the network structure had too high crosslinking density, resulting in reduced elongation at break and brittle material. At the same time, the increase of monomer AM amount did not significantly improve the grafting rate, but led to a slight decrease in acid resistance, indicating that the amount was excessive.

[0353] Analysis of the effect of monomer AM:

[0354] Comparative Example 1 and Preparation Example 1

[0355] AM amount change: reduced by 4 g (6 g in Preparation Example 1, 2 g in Comparative Example 1)

[0356] Grafting rate: from 65% to 35%

[0357] Tensile strength: from 40 MPa to 28 MPa

[0358] Elongation at break: from 280% to 160%

[0359] Swelling degree: from 15 times to 7 times

[0360] Acid resistance: weight loss rate from 8% to 18%

[0361] Analysis: The significant reduction in AM amount leads to a significant decrease in the number of grafting chains and a substantial decrease in grafting ratio. Due to insufficient grafting chains, the crosslinking density of the network structure decreases, resulting in a decrease in both the mechanical properties (tensile strength and elongation at break) and the swelling degree of the material. Meanwhile, the acid resistance also deteriorates due to the decrease in grafting chains, indicating that AM plays an important role in providing acid resistance.

[0362] Comparative Example 2 vs. Preparation Example 1

[0363] AM amount change: decrease 1 g (6 g in Preparation Example 1, 5 g in Comparative Example 2)

[0364] Grafting ratio: from 65% to 55%

[0365] Tensile strength: from 40 MPa to 35 MPa

[0366] Elongation at break: from 280% to 220%

[0367] Swelling degree: from 15 times to 12 times

[0368] Acid resistance: weight loss rate from 8% to 12%

[0369] Analysis: The moderate decrease in AM amount leads to a slight decrease in the number of grafting chains and a slight decrease in grafting ratio. The crosslinking density of the network structure slightly decreases, resulting in a slight decrease in the mechanical properties and swelling degree of the material. The acid resistance also slightly deteriorates due to the decrease in grafting chains, but the change is small, indicating that the moderate decrease in AM amount has limited impact on performance.

[0370] Comparative Example 3 vs. Preparation Example 1

[0371] AM amount change: increase 4 g (6 g in Preparation Example 1, 10 g in Comparative Example 3)

[0372] Grafting ratio: from 65% to 50%

[0373] Tensile strength: from 40 MPa to 34 MPa

[0374] Elongation at break: from 280% to 210%

[0375] Swelling degree: from 15 times to 10 times

[0376] Acid resistance: weight loss rate from 8% to 16%

[0377] Analysis: The increase in AM amount leads to excessive grafting chains and overcrosslinking of the network structure. The excessive grafting chains result in a network structure that is too tight, limiting the material's ductility and swelling ability, and the acid resistance also deteriorates due to changes in the network structure.

[0378] Effect of AM dosage reduction (Comparative Examples 1 and 3): The reduction of AM dosage directly leads to the decrease of grafting chains, thus reducing the grafting rate. The decrease of grafting chains results in the decrease of crosslinking points of network structure, leading to the decrease of mechanical properties (tensile strength and elongation at break) and swelling degree of the material. Meanwhile, the acid resistance also becomes worse due to the reduction of grafting chains, as grafting chains can provide additional protection to reduce the degradation of HPMC backbone in acidic environment.

[0379] Effect of AM dosage increase (Comparative Example 3): The increase of AM dosage leads to excessive grafting chains and over-crosslinking of network structure. This makes the network structure too tight, limiting the ductility and swelling ability of the material, leading to the decrease of tensile strength and elongation at break. Excessive grafting chains can also lead to the increase of rigidity of network structure, making the material brittle, further affecting its mechanical properties. In addition, the acid resistance also becomes worse due to the change of network structure, as the over-crosslinked network structure can be more easily degraded in acidic environment.

[0380] In summary, the dosage of monomer AM has a significant impact on the effect of HPMC graft modification. An appropriate amount of AM dosage can provide sufficient grafting chains, enhance the crosslinking density of network structure, enhance the stability and mechanical properties of network structure, thus maintaining good mechanical properties, swelling degree and acid resistance. Therefore, the number of grafting chains and the network structure need to maintain a certain balance. The reduction of AM dosage will lead to insufficient grafting chains, reducing the performance of the material; while the excessive increase of AM dosage can lead to over-crosslinking of network structure, also reducing the performance of the material. Therefore, the grafting rate can be controlled within a suitable range by adjusting the AM dosage.

[0381] The acid resistance test results (weight loss rate 8%-12%) of Preparation Examples 1-3 show that these sustained-release agents have good stability in acidic environment, which is crucial for protecting the drug from being destroyed by stomach acid, and also helps to control the release rate of the drug.

[0382] The poor acid resistance of Comparative Examples 1-3 (weight loss rate 16%-20%) can lead to accelerated degradation of the drug in stomach acid, affecting the stability and efficacy of the drug. Example

[0383] The preparation method of pregabalin sustained-release tablets in this example includes the following steps:

[0384] (I) Raw material composition and dosage range:

[0385] Pregabalin: 45-50 parts

[0386] Polyvinyl acetate: 23-35 parts

[0387] Swelling agent: 23-30 parts

[0388] Sustained-release agent: 15-25 parts

[0389] Microcrystalline cellulose: 10-20 parts

[0390] Glidant: appropriate amount of silicon dioxide, talc, or magnesium stearate, with a dosage of 0.5%-2% of the total material

[0391] Solvent: appropriate amount of ethanol or water

[0392] (II) Preparation process:

[0393] 1. Dissolution and mixing of raw materials:

[0394] Add polyvinyl acetate to an appropriate amount of ethanol or water, stir to dissolve thoroughly, and form a uniform solution.

[0395] Add pregabalin, swelling agent, sustained-release agent, and microcrystalline cellulose to the above solution and stir evenly.

[0396] 2. Sieving:

[0397] Pass the mixed material through a 40-60 mesh sieve to ensure uniformity of particle size, reduce uneven mixing caused by particle size differences, and prevent problems during tabletting.

[0398] 3. Drying:

[0399] Dry the sieved material at a temperature of 40-60°C to remove the solvent and obtain dry powder. The drying time and temperature should be adjusted according to the properties of the material and the volatility of the solvent to ensure uniform drying of the material.

[0400] 4. Mixing:

[0401] Add the dried powder and an appropriate amount of glidant (such as silicon dioxide, talc, or magnesium stearate) to a mixer and mix for 15-30 minutes to ensure that all ingredients are thoroughly mixed and evenly distributed. The mixing time should be adjusted according to the type of mixer and the properties of the material to ensure uniform mixing.

[0402] 5. Tabletting:

[0403] Tablet the mixed powder, and during tabletting, select the appropriate mold according to the size and shape of the tablets.

[0404] The formulation amounts and raw materials of each example and comparative example are shown in Table 3 below:

[0405] Table 3

[0406] Group Pregabalin (g) Matrix forming agent (g) polyvinyl acetate Swelling agent (g) Sustained release agent (g) Filling agent (g) (microcrystalline cellulose) Example 1 460 250 260, Preparation Example 1 180, Preparation Example 1 160 Example 2 450 230 230, Preparation Example 1 150, Preparation Example 1 120 Example 3 500 350 300, Preparation Example 1 250, Preparation Example 1 200 Comparative Example 1 460 250 260, Comparative Example 1 180, Preparation Example 1 160 Comparative Example 2 460 250 260, Comparative Example 2 180, Preparation Example 1 160 Comparative Example 3 460 250 260, Comparative Example 3 180, Preparation Example 1 160 Comparative Example 4 460 250 260, Comparative Example 4 180, Preparation Example 1 160 Comparative Example 5 460 250 260, Comparative Example 5 180, Preparation Example 1 160 Comparative Example 6 460 250 260, Comparative Example 6 180, Preparation Example 1 160 Comparative Example 7 460 250 260, Comparative Example 7 180, Preparation Example 1 160 Comparative Example 8 460 250 260, Comparative Example 8 180, Preparation Example 1 160 Comparative Example 9 460 250 260, Comparative Example 9 180, Preparation Example 1 160 Comparative Example 10 460 250 260, Preparation Example 1 180, Comparative Example 1 160 Comparative Example 11 460 250 260, Preparation Example 1 180, Comparative Example 2 160 Comparative Example 12 460 250 260, Preparation Example 1 180, Comparative Example 3 160 Comparative Example 13 460 250 260, Preparation Example 1 - 160 Comparative Example 14 460 250 260, Preparation Example 1 - 120 Comparative Example 15 460 250 260, Preparation Example 1 - 200

[0407] Comparative Examples 1-9 investigate the effect of the swelling agent on the sustained release effect, Comparative Examples 10-12 investigate the effect of the sustained release agent on the sustained release effect, Comparative Examples 13-15 investigate the synergistic effect of the swelling agent and the sustained release agent on the sustained release effect.

[0408] Swelling size test of pregabalin:

[0409] According to the second method (paddle method) of the "0931 Dissolution and Release Test Method" in the fourth part of the Chinese Pharmacopoeia 2015 edition, the dissolution experiment was carried out on the tablets prepared in the above examples and comparative examples. 900ml 0.06N HCl solution was used as the dissolution medium, and the rotation speed was 50rpm. The drug was taken out from the dissolution medium at 1h, 1.5h and 6h of the dissolution experiment, and the size was measured with an electronic vernier caliper. Compared with the tablets at 0h (the tablets before the experiment), the results are shown in Table 4 as follows:

[0410] Table 4

[0411] The above results show that:

[0412] The swelling size of Examples 1-3 increases significantly over time, and after 1.5h of contact with the aqueous medium, the size expands to more than 13mm, even more than 13.5mm, and the tablets can remain intact. The earlier the size of the sustained release tablets expands to 13mm, the more beneficial it is for the pregabalin sustained release composition to stay in the stomach, achieving the effect of sustained release and improving the absorption of pregabalin.

[0413] The relatively small increase in the swelling size of Comparative Examples 1-12 is because the performance of the swelling agent and the sustained release agent is weak, which limits the swelling of the sustained release tablets, indicating that the swelling agent and the sustained release agent of the present application have a relatively obvious effect on the size of the sustained release tablets.

[0414] Comparative Examples 13, 14, 15 respectively relative to Comparative Examples 10, 11, 12, without adding the sustained release agent of Comparative Examples 1, 2, 3

[0415] Sustained release agent with general acid resistance (such as Comparative Example 13): leads to a moderate increase in swelling size, because the drug release rate is moderate, leading to a moderate increase in volume.

[0416] Sustained release agent with poor acid resistance (such as Comparative Example 14) leads to accelerated degradation of the drug in gastric acid, thereby affecting the stability of the drug, which may result in slower increase in swelling size, because the drug release rate is faster, leading to slower increase in volume, and the tablets are degraded and not formed after 6 hours, leading to rapid release.

[0417] Sustained release agent with good acid resistance (such as Comparative Example 15) leads to faster increase in swelling size, because the drug release rate is slower, leading to faster increase in volume.

[0418] Cumulative release of pregabalin (%):

[0419] 1. Dissolution method:

[0420] 1) Method: Dissolution test (Dissolution and Release Test Method 0931 in Chinese Pharmacopoeia 2015 Edition Part IV General Rules, second method (paddle method), with a sinker

[0421]

[0422] 2) Dissolution medium: 0.06 mol / L HCl, 900 ml

[0423] 3) Rotation speed: 50 rpm

[0424] 4) Sampling time: 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, 24 h

[0425] 5) Detection method: High performance liquid chromatography, detection wavelength: 210 nm

[0426] 6) Preparation of test solution: Take 10 ml of solution at each time point and filter.

[0427] 7) Preparation of reference solution: Take pregabalin reference substance and prepare a reference solution with a concentration of about 360 μg / ml using 0.06 mol / L HCl.

[0428]

[0429] 2. Dissolution results

[0430] The dissolution results (cumulative release %) of Examples 1-3 and Comparative Examples 1-15 in 0.06 mol / L HCl medium are shown in Table 5 below:

[0431] Table 5

[0432] Group 1h 2h 4h 6h 8h 10h 12h 16h 24h Example 1 10.0 20.1 35.3 50.2 60.5 70.3 80.4 90.1 100.0 Example 2 9.1 17.8 32.5 47.9 58.2 68.1 78.3 87.9 100.0 Example 3 8.5 16.9 31.7 46.8 57.1 66.9 77.2 86.7 100.0 Comparative Example 1 16.3 25.6 40.2 55.1 65.4 75.2 85.6 95.8 100.0 Comparative Example 2 16.5 24.2 39.1 54.3 64.1 74.5 84.8 95.0 100.0 Comparative Example 3 17.0 26.4 41.0 56.2 66.3 76.4 86.1 96.2 100.0 Comparative Example 4 16.1 27.5 42.3 57.5 67.6 77.7 87.4 97.5 100.0 Comparative Example 5 15.2 28.6 43.5 58.8 68.9 79.0 88.7 98.8 100.0 Comparative Example 6 16.3 29.7 44.7 60.1 70.2 80.3 90.0 100.0 100.0 Comparative Example 7 17.4 30.8 45.9 61.4 71.5 81.6 91.3 100.0 100.0 Comparative Example 8 18.5 31.9 47.1 62.7 72.8 82.9 92.6 100.0 100.0 Comparative Example 9 19.6 33.0 48.3 64.0 74.1 84.2 93.9 100.0 100.0 Comparative Example 10 20.7 34.1 49.5 65.3 75.4 85.5 95.2 100.0 100.0 Comparative Example 11 21.8 35.2 50.7 66.6 76.7 86.8 96.5 100.0 100.0 Comparative Example 12 22.9 36.3 51.9 67.9 78.0 88.1 97.8 100.0 100.0 Comparative Example 13 24.0 37.4 53.1 69.2 79.3 100.0 broken 100.0 100.0 100.0 Comparative Example 14 27.5 38.5 54.3 100.0 broken 100.0 100.0 100.0 100.0 100.0 Comparative Example 15 26.2 39.6 55.5 71.8 81.9 100.0 broken 100.0 100.0 100.0

[0433] The above data show that:

[0434] In the examples: due to the addition of swelling agents and sustained-release agents, the structure can maintain integrity for a longer time in an acidic environment, thereby controlling the drug release rate, resulting in lower cumulative release and better sustained-release effect. The drug is basically released within 24 hours. The release within 1 hour is less than 10%, the release within 1 hour is less than 21%, and the release within 6 hours is less than 51%.

[0435] In the comparative examples: Comparative Examples 13, 14 and 15 do not add sustained-release agents compared to Comparative Examples 10, 11 and 12, and perform poorly in terms of acid resistance, resulting in accelerated degradation of the drug in gastric acid, thereby affecting the integrity of the drug, resulting in higher cumulative release and poorer sustained-release effect. The drug is basically released within 12 hours, and Comparative Examples 13, 14 and 15 release faster.​​

[0436] Synergistic effect of swelling agent and sustained-release agent: The swelling agent can increase the volume of the formulation, while the sustained-release agent can control the release rate of the drug and reduce the degradation rate of the drug in the stomach. The synergistic effect of the two makes the formulation of the embodiment have a longer retention time in the stomach and achieve better sustained-release effect.

[0437] Effect of acid resistance: The sustained-release agent with good acid resistance can maintain the structure intact in the acidic environment, slow down the release rate of the drug, and thus prolong the action time of the drug. The sustained-release agent in the embodiment shows good acid resistance, so the sustained-release effect is better than that of the comparative example.

[0438] Swelling behavior: The formulation with added swelling agent and sustained-release agent (embodiment) shows more stable and better controlled characteristics in swelling behavior, while the formulation without added sustained-release agent (comparative example) shows a faster swelling speed, affecting the sustained-release effect.

[0439] The above are only preferred embodiments of the present application and do not limit the present application in any way. Any person skilled in the art can make any form of equivalent replacement, modification or change to the technical solutions and technical contents disclosed in the present application without departing from the scope of the technical solutions of the present application, which still belongs to the protection scope of the present application.

Claims

1. A sustained release composition of pregabalin, characterized in that, The components include the following weight ratio: 45-50 parts of active ingredients, the active ingredients including Pregabalin or its pharmaceutically acceptable salt; 23-35 parts of matrix forming agent; 23-30 parts of swelling agent, the swelling agent being a double-layer network structure, the first layer network providing support for the second layer network, both of which are physically and chemically cross-linked; 15-25 parts of sustained-release agent; 12-20 parts of filler, The first layer network includes the following mass fractions of components: Raw material name Amount Chitosan 10-20 parts Sodium alginate 10-20 parts Methacrylic anhydride 34-360 parts Photoinitiator 0.05-0.2 parts Zinc ions 20-30 parts The second layer network includes the following mass fractions of components: Raw material name Amount Cyclodextrin 3-4 wt% Polyethylene glycol dimethacrylate 7-11 wt% Methacrylamide 7-11 wt% Crosslinking agent 0.2-0.5 wt% Photoinitiator 0.1-0.3 wt% Deionized water Balance The cyclodextrin is hydroxypropyl β-cyclodextrin, The crosslinking agent of the second layer network is N,N'-methylene bisacrylamide MBA, and the photoinitiator is 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone Irgacure 2959, The filler is microcrystalline cellulose, The matrix forming agent is polyvinyl acetate, The sustained-release agent is modified hydroxypropyl methyl cellulose HPMC, The modification method: (1) Dissolve hydroxypropyl methyl cellulose HPMC in ionized water to obtain system I, dissolve acrylamide AM in ionized water to obtain system II, and dissolve the initiator in ionized water for standby, wherein the mass ratio of hydroxypropyl methyl cellulose HPMC, potassium persulfate KPS and acrylamide AM is 2-8:0.04-0.07:5.5-9.0; (2) Grafting reaction: heat system I, add initiator solution to obtain system III, add system II to system III, constant temperature water bath, continue to pass nitrogen gas reaction, and obtain transparent viscous system.

2. The method of preparing the sustained release pregabalin composition of claim 1, characterized in that, Including the following steps: (1) Raw material dissolution and mixing: Add the matrix forming agent to an appropriate amount of ethanol or water to form a solution; Add Pregabalin, swelling agent, sustained-release agent and filler to the above solution in proportion, and stir uniformly; (2) Sieving: Pass the mixed material through a 40-60 mesh sieve; (3) Drying: Dry the sieved material at a temperature of 40-60°C to remove the solvent and obtain dry powder; (4) Mixing: Add the dried powder and an appropriate amount of flow aid to a mixer and mix for 15-30 min; (5) Tabletting: Tablet the uniformly mixed powder.

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