Preparation method of medicine auxiliary modified mannitol

Abstract

The invention relates to the technical field of mannitol preparation, and particularly discloses a preparation method of medicine auxiliary modified mannitol, the mannitol comprises the following components in parts by mass: 100-120 parts of mannitol, 5-10 parts of polyethylene glycol PEG, 2-5 parts of sodium carboxymethyl cellulose CMC-Na, 3-7 parts of cyclodextrin, 1-3 parts of nano silicon dioxide, 10-20 parts of plant source microcrystalline cellulose, and 1-5 parts of chitosan; through compound modification, the hardness and compressive strength of mannitol in the tablet are remarkably improved, the fragmentation phenomenon in transportation and storage is reduced, the integrity of the tablet is ensured, the powder fluidity is improved by adding nano silicon dioxide, and the plasticity of the preparation in industrial production is better; under the synergistic effect of cyclodextrin and chitosan, the dissolving property of mannitol is improved, so that the medicine disintegration is more uniform, and the preparation method is suitable for different dosage forms such as oral instant tablets and enteric sustained-release tablets; and the adjustability of the disintegration time after modification meets the diversified requirements from quick release to slow release.

Description

Technical Field

[0001] The invention belongs to the technical field of mannitol preparation, and particularly relates to a method for preparing pharmaceutically modified mannitol. Background Art

[0002] In the pharmaceutical field, mannitol, as an important pharmaceutical excipient, is widely used in the production of solid preparations and is known for its good water solubility, stability and biocompatibility. However, traditional mannitol excipients still have some limitations in certain specific application scenarios, such as improving the dissolution rate of drugs, enhancing drug stability and bioavailability. In order to overcome these shortcomings, researchers are committed to developing new modified mannitol excipients to improve their performance by adding different functional ingredients.

[0003] In the prior art, although the preparation method of existing multiple modified mannitol is proposed, most methods have the problems of complicated preparation process, high cost, limited modification effect, etc. For example, some methods need to adopt special chemical reagents to react, which not only increases production cost, but also may introduce new impurities, affecting the safety and stability of the product. In addition, although some modification methods can improve some properties of mannitol to a certain extent, they often sacrifice the performance of other aspects, such as solubility, compressibility, etc., thereby limiting its widespread use in pharmaceutical preparations.

[0004] In view of these deficiencies in the prior art, the present invention proposes a novel pharmaceutical excipient modified mannitol and a preparation method thereof. The method is to comprehensively improve the solubility, stability, bioavailability of mannitol and the formability and compressibility of pharmaceutical preparations by carefully selecting and optimizing the proportion of various functional ingredients such as polyethylene glycol PEG, sodium carboxymethyl cellulose CMC-Na, cyclodextrin, nano silicon dioxide, plant-derived microcrystalline cellulose and chitosan, and performing composite modification with mannitol. At the same time, the preparation method adopted by the present invention is simple and easy to operate, has low cost, is easy to industrialize, and provides a new idea and solution for preparing high-performance pharmaceutical excipients.

[0005] In this regard, the inventors proposed a method for preparing a pharmaceutically modified mannitol to solve the above problems. Summary of the invention

[0006] The object of the present invention is to provide a method for preparing a pharmaceutically modified mannitol to solve the problems raised in the above-mentioned background technology.

[0007] To achieve the above object, the present invention provides the following technical solutions:

[0008] A pharmaceutically modified mannitol, the mannitol comprising, by mass ratio:

[0009] 100-120 parts of mannitol, 5-10 parts of polyethylene glycol PEG, 2-5 parts of sodium carboxymethyl cellulose CMC-Na, 3-7 parts of cyclodextrin, 1-3 parts of nano silicon dioxide, 10-20 parts of plant-derived microcrystalline cellulose, and 1-5 parts of chitosan.

[0010] Preferably, the mannitol is composed of the following ingredients: 100 parts of mannitol, 5 parts of polyethylene glycol PEG, 2 parts of sodium carboxymethyl cellulose CMC-Na, 3 parts of cyclodextrin, 1 part of nano-silicon dioxide, 10 parts of plant-derived microcrystalline cellulose, and 1 part of chitosan.

[0011] A method for preparing a pharmaceutically modified mannitol comprises the following steps:

[0012] S1. Prepare a 1:1 ethanol-water mixed solution, add CMC-Na and chitosan to the ethanol-water mixed solution, and stir to completely dissolve; during the stirring process, gradually add PEG and cyclodextrin, and stir until the solution is completely uniform to obtain a mixed solution;

[0013] S2, selecting mannitol granules with a mesh size of 80 or more, sieving, mixing the treated mannitol with the prepared mixed solution, stirring at a speed of 100-200 rpm to form uniform wet granules, adjusting the water content of the wet granules to 18%-20%, and then extruding and granulating to control the particle size within the range of 0.2-0.5 mm;

[0014] S3, placing the wet granules after granulation in a vacuum drying oven, and drying the granules evenly to obtain dried granules;

[0015] S4, adding nano-silicon dioxide to the dried particles, mixing them evenly, and pressing the mixed particles into tablets by a tablet press at a pressure of 5 to 10 kN;

[0016] S5. Spray a layer of film coating, use hydroxypropyl methylcellulose solution as the coating material, and spray it through a spraying device.

[0017] Preferably, the conditions for sufficient stirring are a stirring speed of 200 to 300 rpm and a temperature maintained at 40 to 50°C.

[0018] Preferably, the molecular weight of the polyethylene glycol is 4000-6000.

[0019] Preferably, the conditions for uniformly drying the particles are a temperature of 50-60° C., a vacuum degree of 0.08 MPa, and a drying time of 4-6 hours, until the moisture content is less than 2%.

[0020] Preferably, the viscosity of the CMC-Na is 800-1200 cP, 1% aqueous solution, 25°C.

[0021] Preferably, the nano-silicon dioxide particle size is 10 to 40 nm.

[0022] Preferably, the plant-derived microcrystalline cellulose is lignin-modified cellulose or bagasse extract, and has a particle size of 20 to 40 μm.

[0023] Preferably, the chitosan has a deacetylation degree of 70% to 85% and a molecular weight of 50-150 kDa.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] (1) The present invention significantly improves the hardness and compressive strength of mannitol in tablets through composite modification, reduces fragmentation during transportation and storage, and ensures the integrity of tablets. The addition of nano-silicon dioxide improves the fluidity of the powder, making the compressibility of the preparation better in industrial production. The synergistic effect of cyclodextrin and chitosan improves the solubility of mannitol, making the drug disintegrate more uniformly, and is suitable for different dosage forms such as oral fast-dissolving tablets and enteric-coated sustained-release tablets. The adjustability of the disintegration time after modification meets the diverse needs from fast release to sustained release.

[0026] (2) The present invention not only enhances the heat resistance and moisture resistance of the tablets by adding multifunctional excipients (such as PEG, CMC-Na), but also maintains excellent sweetness characteristics, which is particularly suitable for pharmaceutical needs in tropical areas. The use of modified excipients optimizes the dissolution curve of poorly soluble drugs, improves the absorption efficiency of drugs in the gastrointestinal tract, and meets the different physiological dissolution requirements of various drugs. The chitosan and microcrystalline cellulose in the formula reduce the amount of synthetic chemical excipients, conform to the concept of green pharmaceutical manufacturing, and further reduce production costs.

[0027] (3) The modified mannitol in the present invention can be applied to instant tablets, sustained-release tablets, enteric-coated tablets and functional food preparations, adapting to different consumer groups (children, the elderly, special patients) and diversified market demands. The introduction of new excipients and modification processes based on traditional mannitol tablets breaks through its limitations in terms of hygroscopicity, hardness, solubility, etc., and creates a new path for the improvement of pharmaceutical preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The present invention is a flow chart of a method for preparing a pharmaceutically modified mannitol. DETAILED DESCRIPTION

[0029] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0030] Embodiment 1:

[0031] See also Figure 1 As shown, a pharmaceutical excipient modified mannitol is composed of the following ingredients: 100 parts of mannitol, 5 parts of polyethylene glycol PEG, 2 parts of sodium carboxymethyl cellulose CMC-Na, 3 parts of cyclodextrin, 1 part of nano silicon dioxide, 10 parts of plant-derived microcrystalline cellulose, and 1 part of chitosan.

[0032] A method for preparing a pharmaceutically modified mannitol comprises the following steps:

[0033] S1. Prepare a 1:1 ethanol-water mixed solution, add CMC-Na and chitosan to the ethanol-water mixed solution, and stir to completely dissolve; during the stirring process, gradually add PEG and cyclodextrin, and stir until the solution is completely uniform to obtain a mixed solution;

[0034] S2, selecting mannitol granules with a mesh size of 80 or more, sieving, mixing the treated mannitol with the prepared mixed solution, stirring at 100 rpm to form uniform wet granules, adjusting the water content of the wet granules to 18%, and then extruding and granulating to control the particle size within the range of 0.5 mm;

[0035] S3, placing the wet granules after granulation in a vacuum drying oven, and drying the granules evenly to obtain dried granules;

[0036] S4, adding nano-silicon dioxide to the dried particles, mixing them evenly, and pressing the mixed particles into tablets by a tablet press within a range of 10 kN;

[0037] S5. Spraying a layer of film coating, using hydroxypropyl methylcellulose solution as a coating material, spraying treatment through a spraying device, to improve the storage resistance and aesthetics of the tablets.

[0038] Specifically, the conditions for sufficient stirring are a stirring speed of 200 rpm and a temperature maintained at 40°C.

[0039] Specifically, the polyethylene glycol has a molecular weight of 4000 and acts as a plasticizer to increase the flexibility of the particles, reduce brittle cracking during tableting, and improve the surface smoothness of the tablets.

[0040] Specifically, the conditions for uniform drying of the particles are a temperature of 50° C., a vacuum degree of 0.08 MPa, and a drying time of 6 hours, until the moisture content is less than 2%, ensuring uniform drying of the particles.

[0041] Specifically, the CMC-Na has a viscosity of 1200 cP, 1% aqueous solution, 25° C., and is used to enhance film-forming properties, improve tablet stability and anti-hygroscopicity, and form a viscous solution in water to help particle formation.

[0042] Specifically, the nano-silicon dioxide has a particle size of 10 nm, which is used to enhance the sliding property between particles, reduce particle adhesion, and improve fluidity and tableting performance.

[0043] Specifically, the plant-derived microcrystalline cellulose is lignin-modified cellulose or bagasse extract with a particle size of 20 μm, which is used to improve the compression performance and mechanical strength of tablets, provide excellent disintegration, and reduce the use of synthetic materials, meeting green environmental protection requirements.

[0044] Specifically, the chitosan has a deacetylation degree of 85% and a molecular weight of 150 kDa, and is used to provide biocompatibility and help control the dissolution rate of the tablet in gastric acid or intestinal fluid.

[0045] As can be seen from the above, through composite modification, the hardness and compressive strength of mannitol in tablets are significantly improved, the fragmentation phenomenon during transportation and storage is reduced, and the integrity of tablets is ensured. The addition of nano-silicon dioxide improves the fluidity of the powder, making the compressibility of the preparation better in industrial production. The synergistic effect of cyclodextrin and chitosan improves the solubility of mannitol, making the drug disintegrate more uniformly, suitable for different dosage forms such as oral fast-dissolving tablets and enteric-coated sustained-release tablets; the adjustability of the disintegration time after modification meets the diverse needs from fast release to sustained release.

[0046] The added multifunctional excipients (such as PEG, CMC-Na) not only enhance the heat resistance and moisture resistance of the tablets, but also maintain the excellent sweetness characteristics, which is particularly suitable for pharmaceutical needs in tropical areas. The use of modified excipients optimizes the dissolution curve of poorly soluble drugs, improves the absorption efficiency of drugs in the gastrointestinal tract, and meets the different physiological dissolution requirements of various drugs. The chitosan and microcrystalline cellulose in the formula reduce the amount of synthetic chemical excipients, conform to the concept of green pharmaceutical manufacturing, and further reduce production costs.

[0047] Modified mannitol can be used in instant dissolving tablets, sustained-release tablets, enteric-coated tablets and functional food preparations to meet the needs of different consumer groups (children, the elderly, special patients) and diversified market demands. The introduction of new excipients and modification processes based on traditional mannitol tablets has broken through its limitations in terms of hygroscopicity, hardness, solubility, etc., and has created a new path for the improvement of drug preparations.

[0048] Embodiment 2:

[0049] Modified mannitol finished product (ordinary tablets)

[0050] Tablet preparation

[0051] Tablets containing 100 parts of mannitol, 5 parts of PEG 4000, 3 parts of CMC-Na, 5 parts of cyclodextrin, 2 parts of nano silicon dioxide and 15 parts of microcrystalline cellulose were prepared according to the formula ratio.

[0052] The tablet press pressure was set to 7 kN and the tablet weight was controlled at 500 mg.

[0053] Quality Inspection

[0054] Hardness: Use a tablet hardness tester to test the compressive strength of the tablet.

[0055] Disintegration time: The time required for the tablet to completely disintegrate was recorded in pure water at 37°C.

[0056] Hygroscopicity: The tablets were stored at 75% relative humidity for 30 days and the weight change rate was measured.

[0057] Comparative samples

[0058] Unmodified pure mannitol tablets (without any excipients) were used as control samples.

[0059] Test Data

[0060] project Modified Mannitol Tablets Unmodified Mannitol Tablets <![CDATA[Hardness (kg / cm 2 )]]> 7.5 4.2 Disintegration time (minutes) 6.5 4.0 Moisture absorption rate (%) 0.48 1.72 Flowability (angle of repose, °) 24 37

[0061] From the above, it can be seen that the hardness of the modified mannitol tablets is significantly improved, which reduces the fragmentation rate during transportation and storage; the hygroscopicity is greatly reduced, which is suitable for storage in a high humidity environment, the fluidity is significantly improved, and it is convenient for industrial-scale production. The disintegration time is slightly longer, but it still meets the requirements of rapid disintegration of ordinary tablets, and the taste and dispersibility are good.

[0062] Embodiment three:

[0063] Modified mannitol finished product (sustained release tablets)

[0064] Tablet preparation

[0065] Tablets containing 100 parts of mannitol, 8 parts of PEG 6000, 5 parts of CMC-Na, 7 parts of cyclodextrin, 3 parts of nano-silicon dioxide, 4 parts of chitosan and 12 parts of microcrystalline cellulose were prepared according to the formula ratio.

[0066] The tablet press pressure was set to 10 kN and the tablet weight was controlled at 800 mg.

[0067] Sustained release performance test

[0068] Dissolution curve: Dissolution experiments were carried out in media of pH 1.2 (gastric fluid simulation) and pH 6.8 (intestinal fluid simulation), and the drug release amount was recorded (UV method, λ=254nm).

[0069] Hardness and disintegration time: The hardness and disintegration time were tested using the same method as in Example 2.

[0070] Comparative samples

[0071] Sustained-release tablets prepared using traditional sustained-release excipients (such as HPMC, hypromellose) were used as control samples.

[0072] Test Data

[0073] project Modified mannitol sustained-release tablets HPMC sustained-release tablets <![CDATA[Hardness (kg / cm 2 )]]> 8.2 6.9 Disintegration time (minutes) >120 >120 Moisture absorption rate (%) 0.43 0.87 Dissolution in gastric juice (2 hours, %) 28 35 Dissolution in intestinal fluid (6 hours, %) 92 85

[0074] Effect Description

[0075] Modified mannitol sustained-release tablets are superior to traditional sustained-release tablets in terms of hardness and hygroscopicity, and have enhanced environmental adaptability.

[0076] The dissolution curve showed that the modified mannitol tablets were released slowly in gastric juice and more fully in intestinal juice, meeting the requirements of enteric sustained release.

[0077] Compared with traditional HPMC, the sustained-release tablets with added chitosan have higher biocompatibility, reduce the amount of excipients, and lower the cost.

[0078] From the above, it can be seen that the hardness of modified mannitol tablets is better than that of traditional tablets and is suitable for large-scale production and transportation needs.

[0079] Enhanced hygroscopic stability: The modified tablets have low hygroscopicity and are suitable for storage in humid environments.

[0080] Optimization of sustained-release effect: In sustained-release applications, modified mannitol provides a more flexible release profile, supporting precise release in different parts of the gastrointestinal tract.

[0081] Cost and environmental benefits: It saves costs compared to traditional excipients, and the use of plant-based materials is more environmentally friendly.

[0082] This method and formula can significantly improve the performance and application range of pharmaceutical tablets in industrial applications.

[0083] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "examples", "specific examples" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine different embodiments or examples described in this specification and the features of different embodiments or examples, unless they are contradictory.

[0084] In the drawings of the embodiments disclosed in the present invention, only the structures related to the embodiments disclosed in the present invention are involved, and other structures can refer to the general design. In the absence of conflict, the same embodiment and different embodiments of the present invention can be combined with each other.

[0085] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A pharmaceutically modified mannitol, characterized in that: The mannitol comprises by mass ratio: 100-120 parts of mannitol, 5-10 parts of polyethylene glycol PEG, 2-5 parts of sodium carboxymethyl cellulose CMC-Na, 3-7 parts of cyclodextrin, 1-3 parts of nano silicon dioxide, 10-20 parts of plant-derived microcrystalline cellulose, and 1-5 parts of chitosan.

2. The pharmaceutically modified mannitol according to claim 1, characterized in that: The mannitol is composed of the following ingredients: 100 parts of mannitol, 5 parts of polyethylene glycol PEG, 2 parts of sodium carboxymethyl cellulose CMC-Na, 3 parts of cyclodextrin, 1 part of nano silicon dioxide, 10 parts of plant-derived microcrystalline cellulose, and 1 part of chitosan.

3. A method for preparing a pharmaceutically modified mannitol according to any one of claims 1 to 2, characterized in that: The following steps are involved: S1. Prepare a 1:1 ethanol-water mixed solution, add CMC-Na and chitosan to the ethanol-water mixed solution, and stir to completely dissolve; during the stirring process, gradually add PEG and cyclodextrin, and stir until the solution is completely uniform to obtain a mixed solution; S2, selecting mannitol granules with a mesh size of 80 or more, sieving, mixing the treated mannitol with the prepared mixed solution, stirring at a speed of 100-200 rpm to form uniform wet granules, adjusting the water content of the wet granules to 18%-20%, and then extruding and granulating to control the particle size within the range of 0.2-0.5 mm; S3, placing the wet granules after granulation in a vacuum drying oven, and drying the granules evenly to obtain dried granules; S4, adding nano-silicon dioxide to the dried particles, mixing them evenly, and pressing the mixed particles into tablets by a tablet press at a pressure of 5 to 10 kN; S5. Spray a layer of film coating, use hydroxypropyl methylcellulose solution as the coating material, and spray it through a spraying device.

4. The method for preparing a pharmaceutically modified mannitol according to claim 3, characterized in that: The conditions for sufficient stirring are a stirring speed of 200 to 300 rpm and a temperature maintained at 40 to 50°C.

5. The method for preparing a pharmaceutically modified mannitol according to claim 3, characterized in that: The molecular weight of the polyethylene glycol is 4000-6000.

6. The method for preparing a pharmaceutically modified mannitol according to claim 3, characterized in that: The conditions for uniformly drying the particles are a temperature of 50-60° C., a vacuum degree of 0.08 MPa, and a drying time of 4-6 hours until the moisture content is less than 2%.

7. The method for preparing a pharmaceutically modified mannitol according to claim 3, characterized in that: The viscosity of the CMC-Na is 800-1200 cP, 1% aqueous solution, 25°C.

8. The method for preparing a pharmaceutically modified mannitol according to claim 3, characterized in that: The particle size of the nano silicon dioxide is 10 to 40 nm.

9. The method for preparing a pharmaceutically modified mannitol according to claim 3, characterized in that: The plant-derived microcrystalline cellulose is lignin-modified cellulose or sugarcane bagasse extract, and has a particle size of 20 to 40 μm.

10. The method for preparing a pharmaceutically modified mannitol according to claim 3, characterized in that: The deacetylation degree of the chitosan is 70% to 85%, and the molecular weight is 50-150 kDa.

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