Sustained-release cellulose, preparation method thereof and oral sustained-release preparation

Abstract

The invention provides sustained-release cellulose, a preparation method thereof and an oral sustained-release preparation, and relates to the field of sustained-release preparation carriers. The preparation method of the slow-release cellulose comprises the following steps: mixing a hydrogen bond acceptor, a hydrogen bond donor and water, and forming a uniform and transparent eutectic solvent under heating and stirring conditions; wherein the hydrogen bond donor is carboxyl-containing organic acid, and the number of carboxyl groups in the carboxyl-containing organic acid is greater than or equal to 2; and adding a cellulose raw material into the eutectic solvent, reacting, carrying out solid-liquid separation on the reaction product, washing the solid obtained by solid-liquid separation with water until the solid is neutral, and drying to obtain the slow-release cellulose. The prepared slow-release cellulose has the pH response characteristic, the structure of the slow-release cellulose changes along with different environmental pH values, and when the slow-release cellulose serves as a carrier of a slow-release preparation, carboxyl of the slow-release cellulose is protonized in an acid environment, the structure is compact, and the slow-release cellulose has a slow-release effect; in a neutral / alkaline environment, carboxyl deprotonation and network swelling are realized, and targeted release of drugs is promoted.

Description

Technical Field

[0001] This application relates to the field of sustained-release formulation carriers, and more particularly to a sustained-release cellulose, a method for preparing the same, and an oral sustained-release formulation. Background Technology

[0002] Sustained-release formulations can extend the duration of drug action, reduce dosing frequency, improve patient compliance, and maintain stable blood drug concentrations by controlling the drug release rate. Due to their convenience, oral sustained-release formulations have become an important direction in drug delivery system development. However, oral administration presents many challenges for large biomolecules such as peptides and proteins, as well as certain small molecule drugs like nicotine. In particular, the harsh environment of the gastrointestinal tract (such as extreme pH and abundant hydrolytic enzymes) can lead to drug degradation and low absorption rates, making efficient and controllable oral delivery extremely difficult.

[0003] Carrier materials are one of the core factors determining the performance of sustained-release formulations. An ideal carrier should possess good biocompatibility, controllable drug release performance, stable physicochemical properties, and feasibility for large-scale production. However, existing oral sustained-release carriers generally lack intelligent responsiveness to the gastrointestinal physiological environment, making it difficult to achieve precise and efficient drug release at the target absorption site. This results in problems such as low oral bioavailability, large fluctuations in blood drug concentration, and high dosing frequency.

[0004] Therefore, it is necessary to improve the carriers used in oral sustained-release formulations. Summary of the Invention

[0005] The purpose of this application is to provide a sustained-release cellulose, a method for preparing the same, and an oral sustained-release formulation to solve the above-mentioned problems.

[0006] To achieve the above objectives, this application adopts the following technical solution: A method for preparing sustained-release cellulose, comprising: Hydrogen bond acceptor, hydrogen bond donor, and water are mixed and heated and stirred to form a homogeneous and transparent eutectic solvent; wherein the hydrogen bond donor is a carboxyl-containing organic acid, and the number of carboxyl groups in the carboxyl-containing organic acid is greater than or equal to 2. Cellulose raw material is added to the eutectic solvent to carry out the reaction; The reaction product was subjected to solid-liquid separation. The solid obtained from the solid-liquid separation was washed with water until neutral and dried to obtain slow-release cellulose.

[0007] According to embodiments of this application, the hydrogen bond acceptor includes at least one of choline chloride, betaine, L-carnitine, acetylcarnitine, taurine, L-arginine, choline derivatives, proline, alanine, and glycine. The carboxyl-containing organic acids include at least one of citric acid, succinic acid, malic acid, tartaric acid, sebacic acid, and fumaric acid.

[0008] According to embodiments of this application, the molar ratio of the hydrogen bond acceptor to the hydrogen bond donor is 1:9 to 9:1; And / or, the mass of water in the eutectic solvent accounts for 5%-50% of the total mass of the eutectic solvent.

[0009] According to an embodiment of this application, when preparing a eutectic solvent, the heating temperature is 60-100°C, the stirring speed is 100-300 rpm, and the heating time is 0.5-3 hours.

[0010] According to embodiments of this application, the cellulose raw material includes at least one of softwood pulp board and cotton linters; And / or, the mass ratio of the cellulose raw material to the eutectic solvent is 1:5 to 1:30.

[0011] According to an embodiment of this application, the reaction temperature is 80-150°C, and the reaction time is 1-4 hours; And / or, the reaction is carried out under stirring conditions of 400-1000 rpm.

[0012] According to an embodiment of this application, the drying temperature is 40-60°C, and the drying time is 24-48 hours.

[0013] This application also provides a sustained-release cellulose, which is prepared by the sustained-release cellulose preparation method described above.

[0014] This application also provides an oral sustained-release formulation comprising a carrier and an active ingredient loaded on the carrier, wherein the carrier is the sustained-release cellulose described above, and the active ingredient includes a polypeptide drug or a small molecule compound.

[0015] According to embodiments of this application, the polypeptide drug includes smegglutide, and the small molecule compound includes nicotine.

[0016] Compared with the prior art, the beneficial effects of this application include: 1. Intelligent and Precise Release Mechanism: This application utilizes a specific eutectic solvent system to functionalize and modify cellulose raw materials. The core mechanism lies in the chemical reaction between the acidic component containing at least two carboxyl groups in the eutectic solvent and the hydroxyl groups in the cellulose raw material, allowing the acidic component with free carboxyl groups to be grafted onto the cellulose backbone, forming sustained-release cellulose with a novel molecular structure. This material exhibits significant pH-responsive characteristics. When used as a carrier for oral sustained-release formulations, carboxyl groups are protonated in an acidic environment to make the structure dense, delaying drug release to achieve a protective effect. In a neutral to weakly alkaline environment, carboxyl groups are deprotonated to generate electrostatic repulsion, promoting continuous and targeted drug release. This simulates the physiological pH gradient to achieve autonomous and intelligent regulation of drug release behavior, providing an effective strategy based on carrier structure innovation for improving the bioavailability of poorly absorbed oral drugs.

[0017] 2. Green and efficient process: This application uses a eutectic solvent to achieve simultaneous deconstruction and carboxyl functionalization of cellulose raw materials. The process flow of this application is short, and the eutectic solvent is biodegradable and easy to recycle. The overall preparation process is environmentally friendly and avoids the risk of using toxic reagents in traditional chemical modification, which is in line with the development direction of green pharmaceuticals.

[0018] 3. Superior Formulation Performance: The oral sustained-release formulation of this application effectively protects the drug in the acidic environment of the stomach and can trigger and maintain stable drug release in the intestinal environment. This helps maintain stable blood drug concentrations, improves treatment safety, and reduces the incidence of side effects. Attached Figure Description

[0019] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments will be briefly described below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation on the scope of this application.

[0020] Figure 1 The Fourier transform infrared (FTIR) spectrum of the sustained-release cellulose prepared in Example 1 of this application is shown below. Figure 2 The X-ray diffraction (XRD) pattern of the sustained-release cellulose prepared in Example 1 of this application; Figure 3 Scanning electron microscope (SEM) image of the sustained-release cellulose prepared in Example 1 of this application at a low magnification; Figure 4 A scanning electron microscope (SEM) image of the sustained-release cellulose prepared in Example 1 of this application at a high magnification; Figure 5 BET specific surface area histograms of sustained-release cellulose in Examples 1 and 2 of this application; Figure 6BJH adsorption cumulative pore volume histograms of sustained-release cellulose in Examples 1 and 2 of this application; Figure 7 The in vitro release curves of the sustained-release semaglutide tablets of Example 1 of this application and the commonly available semaglutide tablets in simulated gastric juice are shown. Figure 8 The release curves of the sustained-release nicotine bag and the control nicotine bag in the simulated oral environment are shown in Example 2 of this application. Detailed Implementation

[0021] As used in this article: "Prepared from" is synonymous with "comprising". The terms "comprising", "including", "having", "containing", or any other variations thereof as used herein are intended to cover non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not necessarily limited to those elements, but may include other elements not expressly listed or elements inherent to such composition, step, method, article, or apparatus.

[0022] The conjunction "composed of..." excludes any unspecified elements, steps, or components. If used in a claim, this phrase makes the claim closed, excluding materials other than those described, except for associated conventional impurities. When the phrase "composed of..." appears in a clause of the body of a claim rather than immediately following it, it limits only the elements described in that clause; other elements are not excluded from the claim as a whole.

[0023] When a quantity, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range “1–5” is disclosed, the described range should be interpreted as including ranges “1–4”, “1–3”, “1–2”, “1–2 and 4–5”, “1–3 and 5”, etc. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range.

[0024] In these embodiments, unless otherwise specified, the portions and percentages are all by weight.

[0025] "Parts by mass" refers to the basic unit of measurement that expresses the mass ratio of multiple components. One part can represent any unit mass, such as 1g or 2.689g. If we say that component A has "a" parts by mass and component B has "b" parts by mass, it means the ratio of the mass of component A to the mass of component B is a:b. Alternatively, it can mean that the mass of component A is aK and the mass of component B is bK (where K is any number representing a multiplier). It is important to understand that, unlike parts by mass, the sum of the mass parts of all components is not limited to 100 parts.

[0026] "And / or" is used to indicate that one or both of the described situations may occur, for example, A and / or B includes (A and B) and (A or B).

[0027] Achieving efficient sustained release of oral medications, especially peptide drugs, is a key strategy for improving their clinical efficacy and patient compliance. Sustained-release formulations can precisely regulate drug release kinetics in the gastrointestinal tract, prolonging the duration of action while maintaining stable blood drug concentrations. This effectively reduces the frequency of dosing, lowers the risk of side effects caused by fluctuations in blood drug concentration peaks and troughs, and significantly improves the patient's medication experience. For example, peptide drugs are easily degraded and inactivated rapidly in the highly acidic and enzymatic environment of the stomach. However, existing oral sustained-release formulations often use non-responsive carriers, making it difficult for them to autonomously regulate release behavior according to the gastrointestinal pH environment. This leads to premature drug leakage in the stomach, resulting in low bioavailability.

[0028] To address the aforementioned technical problems, this application provides a method for preparing sustained-release cellulose, comprising: Hydrogen bond acceptor, hydrogen bond donor, and water are mixed and heated and stirred to form a homogeneous and transparent eutectic solvent; wherein the hydrogen bond donor is a carboxyl-containing organic acid, and the number of carboxyl groups in the carboxyl-containing organic acid is greater than or equal to 2. Cellulose raw material is added to the eutectic solvent to carry out the reaction; The reaction product was subjected to solid-liquid separation. The solid obtained from the solid-liquid separation was washed with water until neutral and dried to obtain slow-release cellulose.

[0029] This application utilizes a eutectic solvent treatment to achieve both physical decrystallization and chemical functionalization of cellulose raw materials. Carboxyl-containing organic acids interact with the cellulose raw materials, each containing at least two carboxyl groups. One carboxyl group reacts with a hydroxyl group in the cellulose raw material to form an ether bond, grafting the acidic component onto the cellulose backbone. The other free carboxyl group endows the sustained-release cellulose with pH-responsive release properties: protonation and contraction in acidic environments and deprotonation and swelling in neutral to alkaline environments. When used as a carrier, the sustained-release cellulose of this application not only provides a physical barrier to protect the drug from passing through the stomach but also achieves targeted and sustained release of the drug at the optimal absorption site in the intestine through intelligent response mechanisms (such as pH-dependent release). This fundamentally overcomes the bottleneck of low bioavailability in oral peptide formulations, providing a crucial technical pathway for developing efficient, safe, and convenient oral peptide therapies. Specifically, sustained-release cellulose undergoes structural contraction in acidic media due to protonation of the carboxyl group (-COOH), maintaining a dense structure to protect the drug in the acidic environment of the stomach. In alkaline media, the carboxyl group deprotonates to -COO. - Electrostatic repulsion is generated, and polymer network swelling is triggered by carboxyl deprotonation, enabling targeted and sustained drug release, thus forming a "molecular switch" for intelligent drug release.

[0030] According to embodiments of this application, the hydrogen bond acceptor includes at least one of choline chloride, betaine, L-carnitine, acetylcarnitine, taurine, L-arginine, choline derivatives, proline, alanine, and glycine. The number of carboxyl groups in the organic acid containing carboxyl groups in this application is greater than or equal to 2. For example, the number of carboxyl groups in the organic acid containing carboxyl groups can be 2, 3, 4, 5, 6 or any value greater than or equal to 2.

[0031] The carboxyl-containing organic acid includes at least one selected from citric acid, succinic acid, malic acid, tartaric acid, sebacic acid, and fumaric acid. The eutectic solvent system of this application can use a variety of carboxyl-containing organic acids, which can introduce carboxyl groups into the cellulose backbone during the reaction.

[0032] According to embodiments of this application, the molar ratio of the hydrogen bond acceptor to the hydrogen bond donor is 1:9 to 9:1; for example, the molar ratio of the hydrogen bond acceptor to the hydrogen bond donor is any value between 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 1:9 to 9:1.

[0033] The water content in the eutectic solvent is 5%-50% of the total mass of the eutectic solvent. By adjusting the amount of water added to the eutectic solvent, the viscosity, polarity, and reactivity of the eutectic solvent system can be adjusted.

[0034] For example, the mass of water in the eutectic solvent can be any value between 5%, 8%, 10%, 13%, 15%, 18%, 20%, 23%, 25%, 28%, 30%, 33%, 35%, 38%, 40%, 43%, 45%, 48%, 50%, or between 5% and 50% of the total mass of the eutectic solvent.

[0035] According to an embodiment of this application, when preparing a eutectic solvent, the heating temperature is 60-100°C, the stirring speed is 100-300 rpm, and the heating time is 0.5-3 hours.

[0036] For example, when preparing a eutectic solvent, the heating temperature is any value between 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, or 60-100°C; the stirring speed is any value between 100 rpm, 200 rpm, 300 rpm, or 100-300 rpm; and the heating time is any value between 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, or 0.5-3 hours.

[0037] According to the embodiments of this application, the cellulose raw material is a biomass material with high cellulose content, such as at least one of cotton linters and softwood pulp board; the cellulose raw material used in this application is inexpensive, which helps to reduce production costs.

[0038] The mass ratio of the cellulose raw material to the eutectic solvent is 1:5 to 1:30. For example, the mass ratio of the cellulose raw material to the eutectic solvent is any value between 1:5, 1:8, 1:10, 1:13, 1:15, 1:18, 1:20, 1:23, 1:25, 1:28, 1:30, or 1:5 to 1:30.

[0039] According to embodiments of this application, the reaction temperature is 80-150°C, and the reaction time is 1-4 hours. Thus, the eutectic solvent can penetrate and disrupt the crystalline structure of cellulose, increasing the proportion of amorphous regions and altering its surface properties and microstructure, thereby significantly improving its solubility, reactivity, and adsorption and loading properties as a material. Simultaneously, the carboxyl groups in the eutectic solvent can interact with the hydroxyl groups on the cellulose molecular chain, thereby introducing carboxyl functional groups onto the cellulose backbone to form new molecular structures.

[0040] For example, the reaction temperature is any value between 80℃, 90℃, 100℃, 110℃, 120℃, 130℃, 140℃, 150℃, or 80-150℃; the reaction time is any value between 1 hour, 2 hours, 3 hours, 4 hours, or 1-4 hours.

[0041] The reaction is carried out under stirring conditions of 400-1000 rpm. For example, the stirring speed of the reaction is any value between 400 rpm, 500 rpm, 600 rpm, 700 rpm, 800 rpm, 900 rpm, 1000 rpm, or 400-1000 rpm.

[0042] In some embodiments, after the reaction is complete, the residual eutectic solvent can be removed by washing the solid obtained from solid-liquid separation with water until neutral.

[0043] According to an embodiment of this application, the drying temperature is 40-60°C, and the drying time is 24-48 hours.

[0044] For example, the drying temperature is any value between 40°C, 50°C, 60°C, or 40-60°C; the drying time is any value between 24 hours, 26 hours, 28 hours, 30 hours, 32 hours, 34 hours, 36 hours, 38 hours, 40 hours, 42 hours, 44 hours, 46 hours, 48 ​​hours, or 24-48 hours.

[0045] In some embodiments, the carboxyl content in the sustained-release cellulose can be controlled by the composition of the eutectic solvent and the reaction conditions.

[0046] This application also provides a sustained-release cellulose, which is prepared by the sustained-release cellulose preparation method described above.

[0047] This application also provides an oral sustained-release formulation comprising a carrier and an active ingredient loaded on the carrier, wherein the carrier is the sustained-release cellulose described above, and the active ingredient includes a polypeptide drug or a small molecule compound.

[0048] The release mechanism of the oral sustained-release formulation of this application differs from that of traditional diffusion-controlled release: in the low pH environment of the stomach, the carrier structure is dense, and the overall drug release rate is slow, avoiding the huge drug effect caused by the release of the drug after primary pharmacokinetic.

[0049] According to embodiments of this application, the polypeptide drug includes semaglutide, and the small molecule compound includes nicotine. An oral sustained-release formulation containing semaglutide can be used for the treatment of type 2 diabetes; an oral sustained-release formulation containing nicotine can be used for the preparation of nicotine pouches.

[0050] In some embodiments, the oral sustained-release formulation may also include an absorption enhancer (e.g., SNAC for peptides), a lubricant (e.g., magnesium stearate), a filler (e.g., microcrystalline cellulose), etc.

[0051] Absorption enhancers include SNAC for peptides, lubricants include magnesium stearate, and fillers include microcrystalline cellulose.

[0052] Oral sustained-release formulations can be prepared using conventional formulation techniques, such as direct compression, wet granulation followed by tableting, or capsule filling, to produce a unit dose of oral sustained-release formulation.

[0053] The implementation schemes of this application will be described in detail below with reference to specific embodiments. However, those skilled in the art will understand that the following embodiments are only for illustrating this application and should not be regarded as limiting the scope of this application. Unless otherwise specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments used without specified manufacturers are all conventional products that can be purchased commercially.

[0054] Example 1 Example 1 provides a sustained-release cellulose, the preparation method of which includes: Step 1: Preparation of the eutectic solvent Weigh 70.00 g of choline chloride, 90.00 g of malic acid (molar ratio of choline chloride to malic acid is 1:1.3), and 40.00 g of deionized water into a 500 mL three-necked flask. Place the flask in an 80°C oil bath and stir at 200 rpm for 2 hours with a magnetic stirrer until a homogeneous, transparent, and colorless eutectic solvent is formed, wherein the mass of water accounts for 20% of the total mass of the eutectic solvent.

[0055] Step 2: Functionalization of cellulose 15 g of softwood pulp board was added to the eutectic solvent, with a mass ratio of softwood pulp board to eutectic solvent of 1:13.3. The reaction system was heated to 120°C and the stirring speed was increased to 600 rpm, and the reaction was continued under these conditions for 4 hours.

[0056] Step 3: Post-processing of the product After the reaction was complete, the mixture was cooled to room temperature and centrifuged at 3500 rpm for 15 minutes to separate the solid and liquid phases. The resulting solid was washed repeatedly with a large amount of deionized water five times until the washing liquid was neutral. The washed solid was then dried in a 50°C forced-air drying oven for 48 hours to obtain slow-release cellulose powder.

[0057] Example 2 Example 2 provides a slow-release cellulose, the preparation method of which includes: Step 1: Preparation of the eutectic solvent Weigh 70.00 g of choline chloride, 84.00 g of citric acid (molar ratio of choline chloride to citric acid is 1.1:1), and 46.00 g of deionized water into a 500 mL three-necked flask. Place the flask in an 80°C oil bath and stir at 200 rpm for 2 hours with a magnetic stirrer until a homogeneous, transparent, yellow eutectic solvent is formed, wherein the mass of water accounts for 23% of the total mass of the eutectic solvent.

[0058] Step 2: Functionalization of cellulose 15 g of softwood pulp board was added to the eutectic solvent, with a mass ratio of softwood pulp board to eutectic solvent of 1:13.3. The reaction system was heated to 110°C and the stirring speed was increased to 500 rpm, and the reaction was continued under these conditions for 3 hours.

[0059] Step 3: Post-processing of the product After the reaction was complete, the mixture was cooled to room temperature and centrifuged at 3500 rpm for 15 minutes to separate the solid and liquid phases. The resulting solid was washed repeatedly with a large amount of deionized water five times until the washing liquid was neutral. The washed solid was then dried in a 50°C forced-air drying oven for 48 hours to obtain slow-release cellulose powder.

[0060] Comparative Example 1 Comparative Example 1 uses a hydrogen bond donor that does not contain a carboxyl group. The hydrogen bond donor for Comparative Example 1 is glycerol.

[0061] The preparation method of sustained-release cellulose in Comparative Example 1 includes: Step 1: Preparation of the eutectic solvent Weigh 70.00 g of choline chloride, 90.00 g of glycerol (molar ratio of choline chloride to glycerol is 1:1.9), and 40.00 g of deionized water into a 500 mL three-necked flask. Place the flask in an oil bath at 80 °C and stir at 200 rpm for 2 hours to form a homogeneous, transparent eutectic solvent, wherein the mass of water accounts for 20% of the total mass of the eutectic solvent.

[0062] Step 2: Functionalization of cellulose 15 g of softwood pulp board was added to the above eutectic solvent, with a mass ratio of softwood pulp board to eutectic solvent of 1:13.3. The reaction system was heated to 120°C, the stirring speed was increased to 600 rpm, and the reaction was continued for 4 hours.

[0063] Step 3: Post-processing of the product After the reaction was completed, the mixture was cooled, centrifuged, washed with water until neutral, and dried at 50°C to obtain modified cellulose powder.

[0064] The sustained-release cellulose prepared in Comparative Example 1 did not show a carboxyl characteristic peak in the infrared spectrum and did not have a pH-responsive drug release effect.

[0065] Comparative Example 2 The preparation method of the sustained-release cellulose in Comparative Example 2 includes: Step 1: Preparation of the reaction mixture 15 g of softwood pulp board, 70.00 g of choline chloride, 90.00 g of malic acid, and 40.00 g of deionized water (the content of each component is the same as in Example 1) were added directly to the reactor. The step of preheating and stirring to form a homogeneous eutectic solvent was not performed.

[0066] Step Two: Reaction Process The solid-liquid mixture was directly heated to 120°C and reacted for 4 hours under stirring at 600 rpm.

[0067] In Comparative Example 2, uneven mixing of materials was observed during the reaction, with localized overheating in some areas and charring of malic acid. After the reaction, the product showed severe agglomeration, making it difficult to separate and purify by conventional water washing. The material prepared in Comparative Example 2 had an inhomogeneous structure and could not be used as a stable oral sustained-release carrier.

[0068] Comparative Example 3 Comparative Example 3 is unmodified softwood pulp board, without any treatment.

[0069] Unmodified softwood pulp boards have high crystallinity, small specific surface area, and lack functional groups, making them unsuitable as effective slow-release carriers and unable to achieve intelligent pH-responsive release.

[0070] FTIR analysis of sustained-release cellulose: 10 mg of the sustained-release cellulose powder prepared in Example 1 and 90 mg of potassium bromide were mixed and ground evenly, then pressed into tablets using a tableting mold. The prepared tablets were removed and placed on the sample holder of the FTIR spectrometer, ensuring the sample was within the effective detection region of the infrared path. The instrument parameters were set to a scanning range of 4000-400 cm⁻¹. -1 The number of scans was 32, and the resolution was 4cm. -1 First, perform a background scan (scanning without a sample to subtract environmental infrared interference). After subtracting the background, perform a sample scan. From Figure 1 Infrared spectral characteristic peak analysis shows that 3348 cm⁻¹ -1 The absorption peak at 2902 cm⁻¹ corresponds to the stretching vibration of the hydroxyl groups in the sustained-release cellulose molecule; -1 The absorption peak at 1738 cm⁻¹ originates from the CH stretching vibrations of the methylene and methine groups in the glucose unit; key evidence lies in the absorption peak at 1738 cm⁻¹. -1A distinct absorption peak appears at 1163 cm⁻¹, attributed to the stretching vibration of the C=O group in the carboxyl group, directly confirming the successful introduction of the carboxyl group. -1 1032 cm -1 The absorption peak at 897 cm⁻¹ corresponds to the stretching vibration of the ether bond (glycosidic bond) and the CO vibration of the sugar ring; -1 The absorption peak at that position is a characteristic absorption peak of the β-1,4 glycosidic bond. In summary, the sustained-release cellulose prepared in Example 1 successfully introduced carboxyl functional groups while maintaining the basic cellulose skeletal structure.

[0071] XRD analysis of sustained-release cellulose XRD analysis was performed on the sustained-release cellulose sample obtained in Example 1. Precise analysis was conducted using XRD peak fitting. Figure 2 The study confirmed that eutectic solvent treatment selectively destructured the cellulose crystal structure. XRD patterns showed that sustained-release cellulose exhibited characteristic diffraction peaks around 2θ of approximately 14.8°, 16.4°, and 22°, typical of cellulose crystal structure diffraction. Fitting results showed that the crystal plane diffraction peak (2θ ≈ 22.62°) remained sharp and had the highest intensity, indicating that the main framework of the cellulose Iβ crystal form was preserved. However, the relative intensity of the 14.8° and 16.4° crystal plane diffraction peaks decreased, and the full width at half maximum (FWHM) increased, suggesting that eutectic solvent treatment disrupted or weakened the ordered molecular chain stacking in specific directions within the cellulose microfibrils. This indicates that after eutectic solvent treatment, the crystallinity of cellulose decreased, and the proportion of amorphous regions significantly increased. This structural change facilitates the penetration of water molecules and drugs, providing a structural basis for pH-responsive swelling and controlled drug release.

[0072] SEM analysis of sustained-release cellulose SEM observation was performed on the samples obtained in Example 1. Figure 3 , Figure 4 At lower magnifications, the material exhibits a typical loose, interwoven three-dimensional network aggregate structure, forming abundant pores and channels. At higher magnifications, the surface morphology of individual cellulose units can be observed, showing a fibrous or sheet-like structure with clear surface texture, significantly roughened compared to the smooth surface of natural cellulose, and a significantly increased specific surface area. This porous microstructure with high specific surface area is highly conducive to drug adsorption and loading, and provides an ideal physical structure for subsequent pH-responsive swelling and drug diffusion.

[0073] Analysis of BET specific surface area and pore structure of sustained-release cellulose The specific surface area, pore volume, and pore size distribution of the sustained-release cellulose prepared in this application were determined and analyzed to evaluate its physical adsorption and loading potential as a drug carrier. A nitrogen adsorption-desorption method was used, and the surface area and pore size were measured using a specific surface area and pore size analyzer. Samples were degassed under vacuum at 105 °C for 6 hours before testing. Specific surface area was calculated using the BET (Brunauer-Emmett-Teller) model within a relative pressure (P / P0) range of 0.05–0.30. Pore volume and pore size distribution were calculated using the BJH (Barrett-Joyner-Halenda) model based on desorption isotherms. Figure 5 , Figure 6 As shown, the specific surface areas of the two slow-release celluloses (Example 1 and Example 2) prepared in this application are between 1.5 and 1.8 m². 2 Within the range of / g. This indicates that after treatment with a eutectic solvent, the microstructure of cellulose becomes coarser and more open, compared to the unmodified softwood pulp board of Comparative Example 3 (specific surface area of ​​1.0 m²). 2 Compared to (g), Examples 1 and 2 show an effective increase in specific surface area, providing more sites for the physical adsorption of the drug. This further demonstrates that the sustained-release cellulose prepared in this application possesses ideal physical characteristics as a highly efficient drug carrier.

[0074] Application Example 1 Take 430 mg of the sustained-release cellulose powder prepared in Example 1, 20 mg of smegglutide raw material, and 150 mg of absorption enhancer SNAC, and mix and grind them thoroughly in a mortar for 15 minutes. Using a single-punch tablet press, take 60 mg of the mixed powder, hold it under 1 ton of pressure for 5 seconds, and compress it into tablets with a diameter of 6 mm to obtain sustained-release smegglutide tablets.

[0075] Example 1 tested the release effects of sustained-release semaglutide tablets and commercially available semaglutide tablets in simulated gastric fluid (pH 1.2, 0.1 M hydrochloric acid solution). The detection method was as follows: First, the reaction system was prepared. The prepared sustained-release semaglutide tablets and commercially available semaglutide tablets were mixed with 1 mL of simulated gastric fluid, with 3 replicates per group, for a total of 6 systems. The systems were incubated in a constant temperature shaker at 37℃ and 100 rpm. At 0 min, 100 μL of supernatant was taken into a new tube, and 100 μL of simulated gastric fluid at the same temperature was added to the original tube. 300 μL of methanol was added to the supernatant, vortexed for 1 min, and centrifuged at 4℃ and 12000 rpm for 10 min. The supernatant was filtered through a 0.45 μm filter membrane to obtain the test solution. Samples were taken from the reaction system at different time points according to the above steps and post-processed. Further quantitative analysis was performed using HPLC. Each experiment was conducted in triplicate (n=3). Results are expressed as mean ± standard deviation and recorded on [the relevant file / record]. Figure 7 .

[0076] The results showed that the sustained-release semaglutide tablets prepared in this application and the commercially available semaglutide tablets had significant differences in release behavior: the commercially available semaglutide tablets exhibited rapid release characteristics in the early stage of the test (0-100 min), and the cumulative release percentage increased rapidly over time. The release process was fitted by a first-order release model, indicating that it followed the drug concentration-related first-order kinetic characteristics. In contrast, the sustained-release semaglutide tablets prepared in this application showed obvious delayed release characteristics. The release rate was extremely low in the early stage of the test (0-150 min), and the cumulative release amount was very small. Only after 150 min did it begin to show a continuous and gradual release trend, and its release process was more in line with the Korsmeyer-Peppas model.

[0077] Application Example 2 Take 50.0 g of the sustained-release cellulose powder prepared in Example 1 and 10.0 g of nicotine (calculated as free alkali), place them in a mixer, and mix at 30 rpm for 30 minutes until a uniform drug-containing powder is obtained. Using an automatic powder packaging machine, the above drug-containing powder is packaged into porous bags made of non-woven fabric and breathable film composite, with each bag containing 0.5 g. Heat-seal the bags to obtain sustained-release nicotine bags.

[0078] Following the same method for preparing sustained-release nicotine pouches, only the sustained-release cellulose powder was replaced with an equal mass of microcrystalline cellulose, while all other conditions remained identical, to prepare a control nicotine pouch.

[0079] The release rates of the sustained-release nicotine bag and the control nicotine bag in the simulated oral environment were tested according to Application Example 2. The test method included: placing the sustained-release nicotine bag and the control nicotine bag in release cups containing 5 mL of pH 6.8 phosphate buffer (simulating saliva, temperature 37.0 ± 0.5°C) to establish a release system; placing the system in a thermostatic dissolution apparatus with the impeller speed set to 25 rpm to simulate the low-shear environment of the oral cavity; continuously incubating the release system at 37°C, and taking samples at different time points. For each sample, 5 mL of release medium (with simultaneous addition of isothermal and equal-volume phosphate buffer) was precisely pipetted as the test sample at that time point; 100 μL of the test sample at each time point was taken, 300 μL of methanol solution was added, vortexed for 1 minute to ensure thorough mixing, centrifuged at 4°C for 10 minutes, and the supernatant was collected and subjected to 0.45... The sample was filtered through a μm organic filter membrane, and the filtrate was used as the test solution. Quantitative analysis of the test solution was performed using HPLC. The drug concentration in the release medium at each time point was calculated based on the nicotine peak area measured by HPLC, and the cumulative release percentage was then calculated. Each experiment was performed in triplicate (n=3). Results are expressed as mean ± standard deviation, and in vitro release curves were plotted and recorded. Figure 8 .

[0080] like Figure 8 Data shows that the sustained-release nicotine pouch prepared using the sustained-release cellulose of this application exhibits a significant sustained-release effect. Compared with the control nicotine pouch (90% release in 30 minutes), the sustained-release nicotine pouch only releases 64% in 30 minutes, with a significantly prolonged and smoother release process, reaching nearly complete release (98%) in approximately 660 minutes. This indicates that the sustained-release cellulose of this application can effectively delay the release rate of nicotine, and is expected to provide a more sustained and stable nicotine delivery during use, improving the user experience and reducing discomfort that may be caused by the initial shock release. This may be because small nicotine molecules can be embedded in the porous structure of the sustained-release cellulose, and in the weakly acidic environment of the oral cavity, the ionization of the carboxyl groups in the sustained-release cellulose induces moderate swelling of the cellulose network. The dual mechanisms work together to prolong the diffusion path of the active ingredient nicotine, thereby achieving a sustained-release effect.

[0081] Through the comparison of the above systematic embodiments and test cases, the sustained-release cellulose and its preparation method developed in this application have successfully solved the key problem of the lack of physiological environmental responsiveness in existing oral sustained-release systems, and provide an innovative, reliable and promising technical platform for the efficient and precise delivery of oral peptide drugs and small molecule compounds.

[0082] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

[0083] Furthermore, those skilled in the art will understand that although some embodiments herein include certain features included in other embodiments but not others, combinations of features from different embodiments are intended to be within the scope of this application and form different embodiments. For example, in the foregoing claims, any of the claimed embodiments can be used in any combination. The information disclosed in this background section is intended only to enhance the understanding of the general background of this application and should not be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

Claims

1. A method for preparing sustained-release cellulose, characterized in that, include: Hydrogen bond acceptor, hydrogen bond donor, and water are mixed and heated and stirred to form a homogeneous and transparent eutectic solvent; wherein the hydrogen bond donor is a carboxyl-containing organic acid, and the number of carboxyl groups in the carboxyl-containing organic acid is greater than or equal to 2. Cellulose raw material is added to the eutectic solvent to carry out the reaction; The reaction product was subjected to solid-liquid separation. The solid obtained from the solid-liquid separation was washed with water until neutral and dried to obtain slow-release cellulose.

2. The method for preparing sustained-release cellulose according to claim 1, characterized in that, The hydrogen bond acceptors include at least one of choline chloride, betaine, L-carnitine, acetylcarnitine, taurine, L-arginine, choline derivatives, proline, alanine, and glycine. The carboxyl-containing organic acids include at least one of citric acid, succinic acid, malic acid, tartaric acid, sebacic acid, and fumaric acid.

3. The method for preparing sustained-release cellulose according to claim 2, characterized in that, The molar ratio of the hydrogen bond acceptor to the hydrogen bond donor is 1:9 to 9:1; And / or, the mass of water in the eutectic solvent accounts for 5%-50% of the total mass of the eutectic solvent.

4. The method for preparing sustained-release cellulose according to claim 1, characterized in that, When preparing a eutectic solvent, the heating temperature is 60-100℃, the stirring speed is 100-300 rpm, and the heating time is 0.5-3 hours.

5. The method for preparing sustained-release cellulose according to any one of claims 1-4, characterized in that, The cellulose raw material includes at least one of softwood pulp board and cotton linters; And / or, the mass ratio of the cellulose raw material to the eutectic solvent is 1:5 to 1:

30.

6. The method for preparing sustained-release cellulose according to any one of claims 1-4, characterized in that, The reaction temperature is 80-150℃, and the reaction time is 1-4 hours; And / or, the reaction is carried out under stirring conditions of 400-1000 rpm.

7. The method for preparing sustained-release cellulose according to any one of claims 1-4, characterized in that, The drying temperature is 40-60℃, and the drying time is 24-48 hours.

8. A slow-release cellulose, characterized in that, The sustained-release cellulose is prepared by the method for preparing sustained-release cellulose according to any one of claims 1-7.

9. An oral sustained-release formulation, characterized in that, The product comprises a carrier and an active ingredient loaded on the carrier, wherein the carrier is the sustained-release cellulose of claim 8, and the active ingredient comprises a polypeptide drug or a small molecule compound.

10. The oral sustained-release formulation according to claim 9, characterized in that, The polypeptide drug includes smegglutide, and the small molecule compound includes nicotine.

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