A compound acetaminophen and amantadine preparation and its preparation method

Abstract

This application belongs to the field of pharmaceutical formulation technology and discloses a compound acetaminophen and amantadine preparation and its preparation method. This technical solution uses quaternized montmorillonite-modified polylactic acid-glycolic acid copolymer (modified PLGA) to load the active ingredient of the compound acetaminophen and amantadine preparation, and then coats the modified PLGA loaded with the active ingredient with N,N,N-trimethyl chitosan. After mixing excipients, tableting, and drying, the compound acetaminophen and amantadine preparation is obtained. The layered structure of the modified PLGA can hinder rapid drug diffusion, and the N,N,N-trimethyl chitosan forms a dense barrier to further reduce initial burst release, achieving sustained release. This method also enhances drug adhesion and absorption in the digestive tract. The compound acetaminophen and amantadine preparation prepared by this method achieves a cumulative drug release rate of over 72% within 24 hours, significantly improves burst release within 5 hours, and maintains blood drug concentration within the effective and safe range for a long period, reducing the risk of side effects and improving drug utilization.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a compound acetaminophen and amantadine preparation and its preparation method. Background Technology

[0002] Compound acetaminophen and amantadine preparations are commonly used compound cold medicines in clinical practice, mainly used to relieve various symptoms caused by the common cold and influenza. The development of compound acetaminophen and amantadine preparations is based on the complexity of the pathological mechanisms of the cold and the technological trend of cold medicines moving from single-symptom treatment to multi-effect combinations. Single ingredients, such as acetaminophen alone, can only relieve fever and pain, but cannot solve problems such as nasal congestion, runny nose, or viral replication. Compound preparations, through the combination of antipyretic, analgesic, antihistamine, and antiviral components, can simultaneously cover multiple symptoms, reducing the inconvenience of patients needing to take multiple medications. This is the core technological requirement for the development of compound cold medicines.

[0003] Acetaminophen has excellent antipyretic and analgesic effects with minimal gastrointestinal irritation, making it the most commonly used antipyretic and analgesic ingredient in compound acetaminophen and amantadine preparations. Amantadine hydrochloride was a classic early antiviral ingredient and is a common choice for adjuvant antiviral treatment in compound cold medicines. Chlorpheniramine maleate is a first-generation antihistamine widely used to relieve allergy-like symptoms of colds. Caffeine can counteract the drowsiness side effect of chlorpheniramine maleate while slightly enhancing the analgesic effect. Artificial bezoar has antipyretic, sedative, and anti-inflammatory effects.

[0004] Chinese patent application CN105920043A discloses a compound acetaminophen and amantadine tablet and its preparation method. This compound acetaminophen and amantadine tablet includes acetaminophen, amantadine hydrochloride, caffeine, chlorpheniramine maleate, artificial bezoar, and excipients. This compound acetaminophen and amantadine tablet is a rapid-release tablet, its advantage being rapid disintegration and instantaneous release after entering the body, with peak blood concentration reaching an effective therapeutic level within 1-2 hours. Its advantage lies in rapidly relieving acute symptoms and addressing sudden onset. However, due to metabolism, the effective concentration can only be maintained for 4-6 hours, resulting in a short duration of action, requiring frequent dosing, and leading to recurring symptoms. Furthermore, the rapid-release tablet exhibits a sudden rise and fall in blood concentration, with significant issues of excessively high peak values ​​and excessively low trough values, which directly increases the probability of side effects or exacerbates discomfort.

[0005] Therefore, developing a sustained-release compound acetaminophen and amantadine preparation that can be released evenly and slowly in the body, and whose blood drug concentration can be maintained in an effective and safe range for a long time, while maintaining a stable blood drug concentration and reducing the risk of side effects, has become a technical problem that urgently needs to be solved. Summary of the Invention

[0006] To address the aforementioned problems, this invention provides a compound acetaminophen and amantadine preparation and its preparation method. This application uses modified PLGA (modified polylactic acid-glycolic acid copolymer) to load the active ingredient of the compound acetaminophen and amantadine, and then coats the modified PLGA with N,N,N-trimethyl chitosan. The resulting compound acetaminophen and amantadine preparation exhibits pH-responsive drug release, efficiently releasing the active ingredient in the digestive tract environment. The N,N,N-trimethyl chitosan coating can mitigate the rapid disintegration of PLGA and release of the active ingredient, alleviate gastrointestinal irritation caused by the drug, and effectively adhere to the digestive tract, promoting intestinal absorption of the activated ingredient and improving drug utilization.

[0007] To achieve the above objectives, this application adopts the following technical solution:

[0008] In a first aspect, this application provides a method for preparing a compound acetaminophen and amantadine preparation, comprising:

[0009] Step S1: Mix acetaminophen, amantadine hydrochloride, caffeine, chlorpheniramine maleate and artificial bezoar, and disperse them in ethanol to obtain an active ingredient solution;

[0010] Step S2: Disperse the modified PLGA in a solvent, add the active ingredient solution, mix to obtain the oil phase, disperse polyvinyl alcohol in deionized water, add N,N,N-trimethyl chitosan solution, mix to obtain the aqueous phase;

[0011] Step S3: Add the oil phase to 1 / 3 of the aqueous phase, stir for the first time to obtain an emulsion, add the emulsion to the remaining aqueous phase, stir for the second time, solidify, and centrifuge to collect the modified PLGA loaded with the drug.

[0012] Step S4: The modified PLGA loaded with the drug is washed with deionized water, dispersed in a lyophilization protectant solution, sonicated, freeze-dried, sieved, and then a flow aid, filler, lubricant, and disintegrant are added. The mixture is then sieved through an 80-100 mesh screen, tableted, and vacuum-dried to obtain the compound acetaminophen and amantadine preparation.

[0013] Preferably, in step S1, the mass ratio of acetaminophen, amantadine hydrochloride, caffeine, artificial bezoar, chlorpheniramine maleate and anhydrous ethanol is 1:(0.2~0.4):(0.04~0.06):(0.02~0.04):(0.008~0.02):(4~6).

[0014] Preferably, in step S2, the modified PLGA preparation method includes:

[0015] Step A1: Disperse sodium montmorillonite in deionized water, sonicate to obtain sodium montmorillonite suspension, add hexadecyltrimethylammonium bromide solution, and stir to obtain quaternized montmorillonite dispersion;

[0016] Step A2: Let the quaternized montmorillonite dispersion stand overnight, discard the supernatant, wash, dry, and grind through a 200-mesh sieve to obtain quaternized montmorillonite;

[0017] Step A3: Disperse PLGA in a solvent, add quaternized montmorillonite, stir, and dry to obtain modified PLGA.

[0018] Preferably, in step A1, the mass ratio of sodium montmorillonite to deionized water is 1:99.

[0019] Preferably, in step A1, the mass ratio of hexadecyltrimethylammonium bromide to deionized water in the hexadecyltrimethylammonium bromide solution is 1:(20~25).

[0020] Preferably, in step A1, the mass ratio of the sodium montmorillonite suspension to the hexadecyltrimethylammonium bromide solution is 1:(0.3~0.5).

[0021] Preferably, in step A1, the stirring temperature is 50~60℃ and the stirring time is 4~5h.

[0022] Preferably, in step A2, the solvent used for washing is deionized water.

[0023] Preferably, in step A2, the drying temperature is 50~60℃ and the drying time is 20~24h.

[0024] Preferably, in step A3, the solvent is dichloromethane; the mass ratio of PLGA, solvent and quaternized montmorillonite is 1:20:(0.1~0.25).

[0025] Preferably, in step A3, the stirring time is 30-60 minutes.

[0026] Preferably, in step A3, the drying temperature is 40~50℃ and the drying time is 20~24 h.

[0027] Preferably, in step S2, the solvent is dichloromethane; the mass ratio of the modified PLGA, solvent and active ingredient solution is 1:(20~25):(13~19).

[0028] Preferably, in step S2, the solvent in the N,N,N-trimethyl chitosan solution is deionized water, and the mass ratio of N,N,N-trimethyl chitosan to deionized water is 1:(20~25).

[0029] Preferably, in step S2, the mass ratio of the polyvinyl alcohol, deionized water and N,N,N-trimethyl chitosan solution is 1:(75~100):(5~10).

[0030] Preferably, in step S3, the mass ratio of the oil phase to the water phase is 1:(10~15).

[0031] Preferably, in step S3, the first stirring speed is 800~1000 rpm, and the first stirring time is 10~20 min.

[0032] Preferably, in step S3, the second stirring speed is 300~500 rpm, and the second stirring time is 1~3 hours.

[0033] Preferably, in step S4, the freeze-drying protectant solution is any one or more of sucrose solution, mannitol solution, and polyvinylpyrrolidone.

[0034] Preferably, in step S4, the concentration of the freeze-drying protectant solution is (2~10) g / L.

[0035] Preferably, in step S4, the freeze-drying operation is as follows: the temperature is lowered to -30 to -40°C at a rate of 5 to 10°C / h and held for 2 to 4 hours; the temperature is raised to -20 to -10°C at a rate of 2 to 3°C / h and held for 6 to 10 hours; the shelf temperature is raised to 20 to 40°C at a rate of 3 to 5°C / h and held for 8 to 10 hours.

[0036] Preferably, in step S4, the flow aid is talc.

[0037] Preferably, in step S4, the lubricant is magnesium stearate.

[0038] Preferably, in step S4, the filler is any one or more of microcrystalline cellulose or lactose.

[0039] Preferably, in step S4, the disintegrant is any one or more of sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose.

[0040] Preferably, in step S4, the mass ratio of the drug-loaded PLGA, gliding agent, filler, lubricant, and disintegrant is 1:(0.01~0.05):(0.001~0.005):(0.001~0.005):(0.005~0.02).

[0041] Preferably, in step S4, the parameters for tablet compression are: pressure of 25~30MPa and holding pressure for 20~30s.

[0042] Preferably, in step S4, the vacuum drying temperature is 40~50℃ and the vacuum drying time is 2~3h.

[0043] Secondly, this application provides a compound acetaminophen and amantadine preparation prepared by the preparation method described in the first aspect.

[0044] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0045] This application utilizes PLGA modified with quaternized montmorillonite to load the active ingredient of compound acetaminophen and amantadine, and then coats the PLGA loaded with the active ingredient with N,N,N-trimethyl chitosan. The resulting compound acetaminophen and amantadine formulation exhibits pH-responsive release, adheres to the digestive tract environment, and can slowly release the active ingredient, significantly improving drug utilization and absorption. Specifically:

[0046] (1) In this application, quaternized montmorillonite is used to modify PLGA in order to increase the loading of PLGA.

[0047] Firstly, quaternization modification of montmorillonite solved the interfacial compatibility problem between montmorillonite and PLGA. Montmorillonite's layered structure consists of alternating stacks of silicon-oxygen tetrahedral and aluminum-oxygen octahedral sheets, with exchangeable cations between the layers. Its surface is strongly hydrophilic due to hydroxyl groups and interlayer cations. PLGA, on the other hand, is a polyester polymerized from lactic acid and glycolic acid. Its molecular chains are mainly composed of hydrophobic methylene and methine groups, with only a small amount of hydroxyl groups at the end groups, making it hydrophobic. This hydrophilic-hydrophobic interfacial contradiction is the fundamental reason for the low loading capacity of traditional systems. Quaternization modification, through ion exchange reactions, removes Na+ from the interlayer of montmorillonite. + The quaternary ammonium salt cations are replaced with long-chain alkyl quaternary ammonium salt cations. The long-chain alkyl groups of these cations are hydrophobic and are oriented on the surface and between layers of the montmorillonite sheets, transforming the originally hydrophilic montmorillonite surface into a hydrophobic one. This allows the quaternized montmorillonite to match the hydrophobic PLGA matrix, significantly reducing interfacial tension and preventing aggregation caused by interfacial repulsion. Simultaneously, the quaternary ammonium nitrogen in the quaternary ammonium salt cations carries a positive charge, forming electrostatic interactions with the hydroxyl groups at the end of the PLGA molecular chains. The carbon-carbon bonds of the long-chain alkyl groups form van der Waals forces with the carbon-carbon bonds and ester groups of the PLGA molecular chains. These two interfacial binding forces ensure that the quaternized montmorillonite is tightly bonded to the PLGA matrix, rather than dispersed in a free state, providing a stable interfacial basis for high loading.

[0048] Secondly, the layered structure of montmorillonite provides a spatial basis for high dispersion capacity, thereby increasing the loading capacity. In quaternized montmorillonite, the long-chain quaternary ammonium salt cations expand the interlayer spacing, forming an intercalated composite material with PLGA. This interlayer containment mode avoids direct aggregation of quaternized montmorillonite sheets, meaning each quaternized montmorillonite sheet can function as an independent dispersion unit, significantly increasing the loading capacity per unit volume of PLGA.

[0049] (2) The long-chain alkyl groups on the surface of quaternized montmorillonite-modified PLGA are tightly bonded to the hydrophobic segments of the PLGA molecular chain through van der Waals forces, preventing the quaternized montmorillonite from agglomerating in the PLGA matrix. The ester groups in the PLGA molecular chain are bonded to the N in the hexadecyltrimethylammonium cation. + The formation of weak polar ion interactions further enhances interfacial bonding, reduces interfacial delamination during degradation or stress in the composite material, and ensures the formation of uniform drug diffusion channels on the carrier, laying the structural foundation for subsequent sustained release. The drug achieves efficient loading through electrostatic adsorption or interlayer trapping. During release, the drug must first overcome the interlayer barrier of quaternized montmorillonite and then diffuse through the channels formed by PLGA degradation. The quaternized montmorillonite-modified PLGA surface is denser and smoother, which facilitates the formation of a uniform and continuous coating layer of N,N,N-trimethyl chitosan on the surface. The release rate is dually regulated, reducing the bursting effect of drug release from PLGA and thus achieving sustained release.

[0050] (3) This application uses N,N,N-trimethyl chitosan to coat quaternized montmorillonite modified PLGA loaded with active ingredients to form a synergistic effect of dual barrier, pH-responsive release and bidirectional anchoring, thereby optimizing the sustained release effect from four key aspects: inhibiting drug leakage, pH-responsive release, delaying matrix degradation and regulating drug dissolution.

[0051] While quaternized montmorillonite-modified PLGA can reduce burst release, the tiny pores on the PLGA surface can lead to rapid dissolution of free drug from the carrier surface. The N,N,N-trimethyl chitosan coating layer forms a second dense barrier, further enhancing the inhibition of drug diffusion. N,N,N-trimethyl chitosan is a cationic polysaccharide whose molecular chains form a dense film structure through hydrogen bonds and electrostatic repulsion. This film can directly cover the pores on the surface of the quaternized montmorillonite-modified PLGA core loaded with the active ingredient, physically blocking the direct diffusion path of free drug from the core to the external environment, further reducing the initial burst release rate.

[0052] N,N,N-Trimethyl chitosan-coated quaternized montmorillonite-modified PLGA, loaded with active ingredients, enhances drug immobilization and reduces free dissolution. The quaternary ammonium cations between the quaternized montmorillonite layers can adsorb negatively charged drugs via electrostatic interactions or fix them through hydrogen bonds, effectively locking the drug inside the PLGA. The -N... + (CH3)3 forms a strong electrostatic interaction with the negatively charged groups of the drug molecule. Even if a small amount of drug diffuses from the core to the surface, it will be adsorbed and fixed by the N,N,N-trimethyl chitosan layer and cannot be dissolved quickly. At the same time, the hydroxyl groups of N,N,N-trimethyl chitosan form hydrogen bonds with the amino groups of the drug, further enhancing the anchoring effect on the drug.

[0053] Chitosan, a natural cationic polymer, is a widely studied biomaterial for drug delivery. It enhances drug absorption by adhering to mucosal surfaces. However, chitosan is only soluble in acidic environments, making it unsuitable for neutral and alkaline conditions, such as oral administration to the intestines, skin / mucous membranes, or ocular sites. N,N,N-Trimethylchitosan, a chemically modified derivative of chitosan, overcomes the problems of poor water solubility, narrow pH range, and limited functionality of chitosan. N,N,N-Trimethylchitosan is stably soluble in acidic (pH 2-6), neutral (pH 6-8), and weakly alkaline (pH 8-10) environments, with a much higher solubility than chitosan. Its quaternary ammonium salt groups carry a positive charge, enabling efficient drug delivery into cells through a mechanism of charge adsorption-membrane perturbation-endocytosis, thus improving drug absorption in the digestive tract. Attached Figure Description

[0054] Figure 1 This is a flowchart of the preparation process for a compound acetaminophen and amantadine formulation.

[0055] Figure 2 The drug release trend diagrams of the compound acetaminophen and amantadine preparations prepared in Examples 4 to 6 within 24 hours are shown.

[0056] Figure 3 The drug release trend diagrams within 24 hours are for the compound acetaminophen and amantadine preparations prepared in Example 6 and Comparative Examples 1 to 2. Detailed Implementation

[0057] The following embodiments are only used to illustrate the technical solutions of the present invention more clearly, and should not be used to limit the scope of protection of the present invention.

[0058] The main compounds used in the examples and comparative examples were all commercially available products and were not subjected to any further purification treatment.

[0059] Example 1

[0060] A modified PLGA, the preparation method of which includes:

[0061] Step A1: Disperse 1g of sodium montmorillonite in 99g of deionized water, sonicate to obtain sodium montmorillonite suspension, add 30g of cetyltrimethylammonium bromide solution (1.4g cetyltrimethylammonium bromide, the remainder is deionized water), stir at 50℃ for 5h to obtain quaternized montmorillonite dispersion.

[0062] Step A2: Let the quaternized montmorillonite dispersion stand overnight, discard the supernatant, wash 5 times with deionized water, dry at 50℃ for 24 hours, grind and pass through a 200-mesh sieve to obtain quaternized montmorillonite.

[0063] Step A3: Disperse 5g of PLGA in 100g of dichloromethane, add 0.5g of quaternized montmorillonite, stir at 100rpm for 30min, and dry at 40℃ for 24h to obtain modified PLGA.

[0064] Example 2

[0065] A modified PLGA, the preparation method of which includes:

[0066] Step A1: Disperse 1g of sodium montmorillonite in 99g of deionized water, sonicate to obtain sodium montmorillonite suspension, add 40g of cetyltrimethylammonium bromide solution (1.55g cetyltrimethylammonium bromide, the remainder is deionized water), stir at 55℃ for 4h to obtain quaternized montmorillonite dispersion.

[0067] Step A2: Let the quaternized montmorillonite dispersion stand overnight, discard the supernatant, wash 6 times with deionized water, dry at 50℃ for 22 hours, grind and pass through a 200-mesh sieve to obtain quaternized montmorillonite.

[0068] Step A3: Disperse 5g of PLGA in 100g of dichloromethane, add 1g of quaternized montmorillonite, stir at 100rpm for 40min, and dry at 50℃ for 22h to obtain modified PLGA.

[0069] Example 3

[0070] A modified PLGA, the preparation method of which includes:

[0071] Step A1: Disperse 1g of sodium montmorillonite in 99g of deionized water, sonicate to obtain sodium montmorillonite suspension, add 50g of cetyltrimethylammonium bromide solution (2g cetyltrimethylammonium bromide, the remainder is deionized water), stir at 60℃ for 4h to obtain quaternized montmorillonite dispersion.

[0072] Step A2: Let the quaternized montmorillonite dispersion stand overnight, discard the supernatant, wash 4 times with deionized water, dry at 60℃ for 20 hours, grind and pass through a 200-mesh sieve to obtain quaternized montmorillonite.

[0073] Step A3: Disperse 5g of PLGA in 100g of dichloromethane, add 1.25g of quaternized montmorillonite, stir at 100rpm for 60min, and dry at 40℃ for 20h to obtain modified PLGA.

[0074] Example 4

[0075] A compound acetaminophen and amantadine preparation and its preparation method, such as Figure 1 As shown, it includes:

[0076] Step S1: Mix 25g acetaminophen, 5g amantadine hydrochloride, 1g caffeine, 0.5g artificial bezoar and 0.2g chlorpheniramine maleate, and disperse them in 100g anhydrous ethanol to obtain an active ingredient solution.

[0077] Step S2: Disperse 10g of the modified PLGA prepared in Example 1 in 200g of dichloromethane, add all the above-mentioned active ingredient solutions, mix to obtain an oil phase, disperse 20g of polyvinyl alcohol in 1500g of deionized water, add 100g of N,N,N-trimethyl chitosan solution (4.76g of N,N,N-trimethyl chitosan, the remainder being deionized water), mix to obtain an aqueous phase.

[0078] Step S3: Add all the oil phase to 540g of aqueous phase, stir at 800rpm for 20min to obtain an emulsion, add the emulsion to the remaining 1080g of aqueous phase, stir at 300rpm for 3h to solidify, centrifuge at 1000rpm to collect, and obtain 42.6g of drug-loaded modified PLGA.

[0079] Step S4: Wash 42.6g of drug-loaded PLGA four times with deionized water, disperse it in a sucrose solution (2g sucrose, the remainder is deionized water, prepared in 1L), sonicate, place it in a freeze dryer, cool it to -30℃ at a rate of 5℃ / h, keep it at that temperature for 4h, heat it to -10℃ at a rate of 2℃ / h, keep it at that temperature for 10h, then heat it to 20℃ at a rate of 3℃ / h, keep it at that temperature for 10h, sieve it through a 90-mesh sieve, add 0.426g talc, 0.0426g microcrystalline cellulose, 0.0426g magnesium stearate and 0.213g sodium carboxymethyl starch, mix, sieve it through a 90-mesh sieve, hold it at 25MPa for 30s, vacuum dry it at 40℃ for 3h to obtain the compound acetaminophen and amantadine preparation.

[0080] Example 5

[0081] A compound acetaminophen and amantadine preparation and its preparation method, such as Figure 1 As shown, it includes:

[0082] Step S1: Mix 25g acetaminophen, 8g amantadine hydrochloride, 1.5g caffeine, 0.75g artificial bezoar and 0.3g chlorpheniramine maleate, and disperse them in 120g anhydrous ethanol to obtain an active ingredient solution.

[0083] Step S2: Disperse 10g of the modified PLGA prepared in Example 2 in 250g of dichloromethane, add all the above-mentioned active ingredient solutions, mix to obtain an oil phase, disperse 20g of polyvinyl alcohol in 1700g of deionized water, add 150g of N,N,N-trimethyl chitosan solution (6.52g of N,N,N-trimethyl chitosan, the remainder being deionized water), mix to obtain an aqueous phase.

[0084] Step S3: Add all the oil phase to 623g of aqueous phase, stir at 900rpm for 15min to obtain an emulsion, add the emulsion to the remaining 1247g of aqueous phase, stir at 400rpm for 2h to solidify, centrifuge at 1000rpm to collect, and obtain 45.5g of drug-loaded modified PLGA.

[0085] Step S4: Wash 45.5g of drug-loaded modified PLGA 6 times with deionized water, disperse it in mannitol solution (7.5g mannitol, the remainder is deionized water, prepared in 1L), sonicate, cool to -40℃ at a rate of 10℃ / h, keep at this temperature for 3h, heat to -15℃ at a rate of 3℃ / h, keep at this temperature for 8h, then heat to 30℃ at a rate of 4℃ / h, keep at this temperature for 9h, sieve through 80 mesh, add 1.365g talc, 0.1365g lactose, 0.1365g magnesium stearate and 0.455g low-substituted hydroxypropyl cellulose, mix, sieve through 80 mesh, hold at 30MPa for 20s, vacuum dry at 45℃ for 2h to obtain compound acetaminophen and amantadine preparation.

[0086] Example 6

[0087] A compound acetaminophen and amantadine preparation and its preparation method, such as Figure 1 As shown, it includes:

[0088] Step S1: Mix 25g acetaminophen, 10g amantadine hydrochloride, 1g caffeine, 1g artificial bezoar and 0.5g chlorpheniramine maleate, and disperse them in 150g anhydrous ethanol to obtain an active ingredient solution.

[0089] Step S2: Disperse 10g of the modified PLGA prepared in Example 3 in 200g of dichloromethane, add all the above-mentioned active ingredient solutions, mix to obtain an oil phase, disperse 20g of polyvinyl alcohol in 2000g of deionized water, add 200g of N,N,N-trimethyl chitosan solution (7.7g of N,N,N-trimethyl chitosan, the remainder being deionized water), mix to obtain an aqueous phase.

[0090] Step S3: Add the oil phase to 740g of the aqueous phase, stir at 1000rpm for 10min to obtain an emulsion, add the emulsion to the remaining 1480g of the aqueous phase, stir at 500rpm for 1h to solidify, centrifuge at 1000rpm to collect, and obtain 47.2g of drug-loaded PLGA.

[0091] Step S4: Wash 47.2g of drug-loaded modified PLGA five times with deionized water, disperse it in polyvinylpyrrolidone (10g polyvinylpyrrolidone, the remainder is deionized water, prepared in 1L), sonicate, cool to -40℃ at a rate of 5℃ / h, hold for 2h, heat to -20℃ at a rate of 3℃ / h, hold for 6h, then heat to 40℃ at a rate of 5℃ / h, hold for 8h, sieve through 100 mesh, add 2.36g talc, 0.236g microcrystalline cellulose, 0.236g magnesium stearate and 0.944g sodium carboxymethyl starch, mix, sieve through 100 mesh, hold at 30MPa for 30s, dry at 50℃ for 2h to obtain the compound acetaminophen and amantadine preparation.

[0092] Comparative Example 1

[0093] A compound acetaminophen and amantadine preparation and its preparation method are disclosed, which differ from Example 6 in that PLGA is used in step S2 instead of the modified PLGA prepared in Example 3.

[0094] Comparative Example 2

[0095] A compound acetaminophen and alkylamine preparation and its preparation method are disclosed, which differ from Example 6 in that N,N,N-trimethylchitosan solution is not added in step S2.

[0096] Drug sustained-release effect evaluation experiment:

[0097] A 0.1 mol / L hydrochloric acid solution preheated to 37±0.5℃ was used to simulate the gastric environment, and a phosphate buffer solution with pH 6.8 preheated to 37±0.5℃ was used to simulate the small intestinal environment. A rotation speed of 50 rpm was used to simulate gastric peristalsis.

[0098] The compound acetaminophen and amantadine preparations obtained in Examples 4-6 and Comparative Examples 1-2 were placed in beakers containing the above-mentioned hydrochloric acid solution and stirred at 50 rpm for 2 hours. Samples of 5 mL were taken at 0.5 h, 1 h, and 2 h, and 5 mL of hydrochloric acid solution at the same temperature and pH was added back simultaneously. After filtration, 1 mL of the filtrate was accurately measured and placed in a 50 mL graduated cylinder. 0.1 mol / L sodium hydroxide solution was added to the mark. The absorbance at 257 nm was measured using spectrophotometry (Appendix IV A, Part II of the 2010 edition of the Chinese Pharmacopoeia) to calculate the drug release.

[0099] Two hours later, the medium containing the tablets was switched to phosphate buffer solution preheated to 37±0.5℃ with a pH of 6.8. Stirring continued at 50 rpm. Samples (5 mL) were taken at 3h, 5h, 10h, 14h, 18h, 20h, 22h, and 24h, and 5 mL of hydrochloric acid solution at the same temperature and pH was added simultaneously. After filtration, 1 mL of the filtrate was accurately measured and placed in a 50 mL graduated cylinder. 0.1 mol / L sodium hydroxide solution was added to the mark. The absorbance at 257 nm was measured using spectrophotometry (Appendix IV A, Part II of the 2010 edition of the Chinese Pharmacopoeia) to calculate the drug release. The experimental results are as follows: Figure 2 and Figure 3 As shown.

[0100] Figure 2 This is a release trend diagram of the compound acetaminophen and amantadine preparations prepared in Examples 4-6 within 24 hours, based on... Figure 2 As shown, in Example 4, the cumulative release was 12.36% within 2 hours, 19.86% within 10 hours, 62.13% within 20 hours, and reached 76.45% within 24 hours. In Example 5, the release was 14.52% within 2 hours, 20.25% within 10 hours, 63.24% within 20 hours, and reached 72.96% within 24 hours. In Example 6, the release was 11.52% within 2 hours, 16.85% within 10 hours, 58.77% within 20 hours, and reached 78.25% within 24 hours. The overall release patterns of Examples 4 to 6 were similar. Compared with Comparative Examples 1 and 2, the burst release within 5 hours was significantly improved, and the drug release showed a continuous upward trend from 10 to 24 hours.

[0101] Figure 3 This is a release trend diagram of the compound acetaminophen and amantadine preparations prepared in Example 6 and Comparative Examples 1-2 within 24 hours, based on... Figure 3As shown, the compound acetaminophen and amantadine preparation prepared in Comparative Example 1 had a cumulative release of 13.25% in the first 2 hours, 34.52% in 10 hours, only 48.85% in 20 hours, and 52.33% in 24 hours. The total cumulative release within 24 hours was significantly lower than that in Example 6. In the compound acetaminophen and amantadine preparation prepared in Comparative Example 1, modified PLGA was used to load the active ingredient. That is, the PLGA did not have the support of quaternized montmorillonite, which means that a large number of active ingredients were not stably bound by the pores, hydrogen bonds, or hydrophobic interactions inside the PLGA matrix, but were attached to the surface or near-surface area of ​​the PLGA in a free state. Therefore, the loading was relatively low, and the loading of active ingredients was significantly lower than that in Example 6. The PLGA loaded with the active ingredient was coated with N,N,N-trimethyl chitosan, and the sustained-release effect was better than that of Comparative Example 2. However, the PLGA did not have the support of quaternized montmorillonite, and the N,N,N-trimethyl chitosan coating layer had micro-cracks and discontinuous defects. Therefore, the active ingredient in Comparative Example 1 was more likely to dissolve from the PLGA and dissolve rapidly in the medium. Even though the loaded active ingredient was less, the release rate of Comparative Example 1 before 18 hours was higher than that of Example 6 compared to the release trend of Example 6.

[0102] The compound acetaminophen and amantadine preparation prepared in Comparative Example 2 achieved a cumulative release of 32.65% within the first 2 hours, significantly higher than Comparative Example 1 and Example 6. The cumulative release reached 70.12% after 10 hours, but the upward trend in release slowed significantly after 10 hours. Therefore, Comparative Example 2 exhibited a more pronounced burst release phenomenon in the initial stage of drug release. In the compound acetaminophen and amantadine preparation prepared in Comparative Example 2, quaternized montmorillonite-modified PLGA was used to load the active ingredient, with an active ingredient loading comparable to Example 6. However, it did not use N,N,N-trimethyl chitosan for coating, resulting in a faster initial release rate.

[0103] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a compound acetaminophen and amantadine preparation, characterized in that, include: S1. Mix acetaminophen, amantadine hydrochloride, caffeine, chlorpheniramine maleate and artificial bezoar, and disperse them in anhydrous ethanol to obtain an active ingredient solution. S2. Disperse the modified PLGA in a solvent, add the active ingredient solution, and mix to obtain the oil phase. Disperse polyvinyl alcohol in deionized water, add N,N,N-trimethyl chitosan solution, and mix to obtain the aqueous phase. S3. Add the oil phase to 1 / 3 of the aqueous phase, stir for the first time to obtain an emulsion, add the emulsion to the remaining aqueous phase, stir for the second time, solidify, and centrifuge to collect the drug-loaded modified PLGA. S4. The drug-loaded modified PLGA was washed with deionized water, dispersed in a lyophilization protectant solution, sonicated, lyophilized, sieved, and then a flow aid, filler, lubricant, and disintegrant were added. The mixture was then sieved through an 80-100 mesh screen, tableted, and vacuum dried to obtain the compound acetaminophen and amantadine preparation.

2. The method for preparing a compound acetaminophen and amantadine preparation according to claim 1, characterized in that, In S1, the mass ratio of acetaminophen, amantadine hydrochloride, caffeine, artificial bezoar, chlorpheniramine maleate and anhydrous ethanol is 1: (0.2~0.4): (0.04~0.06): (0.02~0.04): (0.008~0.02): (4~6).

3. The method for preparing a compound acetaminophen and amantadine preparation according to claim 1, characterized in that, In step S2, the method for preparing the modified PLGA includes: A1. Disperse sodium montmorillonite in deionized water, sonicate to obtain sodium montmorillonite suspension, add hexadecyltrimethylammonium bromide solution, stir to obtain quaternized montmorillonite dispersion; A2. The quaternized montmorillonite dispersion was left to stand overnight, the supernatant was discarded, washed, dried, and ground through a 200-mesh sieve to obtain quaternized montmorillonite. A3. Disperse PLGA in a solvent, add quaternized montmorillonite, stir, and dry to obtain modified PLGA.

4. The method for preparing a compound acetaminophen and amantadine preparation according to claim 3, characterized in that, In step A1, the mass ratio of sodium montmorillonite to deionized water is 1:99; in the hexadecyltrimethylammonium bromide solution, the mass ratio of hexadecyltrimethylammonium bromide to deionized water is 1:(20~25); the mass ratio of sodium montmorillonite suspension to hexadecyltrimethylammonium bromide solution is 1:(0.3~0.5); the stirring temperature is 50~60℃, and the stirring time is 4~5h; in step A2, the washing solvent is deionized water; the drying temperature is 50~60℃, and the drying time is 20~24h.

5. The method for preparing a compound acetaminophen and amantadine preparation according to claim 3, characterized in that, In A3, the solvent is dichloromethane; the mass ratio of PLGA, solvent and quaternized montmorillonite is 1:20:(0.1~0.25); the stirring time is 30~60 min; the drying temperature is 40~50℃ and the drying time is 20~24 h.

6. The method for preparing a compound acetaminophen and amantadine preparation according to claim 1, characterized in that, In step S2, the solvent is dichloromethane; the mass ratio of the modified PLGA, solvent, and active ingredient solution is 1:(20~25):(13~19); in the N,N,N-trimethyl chitosan solution, the solvent is deionized water, and the mass ratio of N,N,N-trimethyl chitosan to deionized water is 1:(20~25); the mass ratio of the polyvinyl alcohol, deionized water, and N,N,N-trimethyl chitosan solution is 1:(75~100):(5~10).

7. The method for preparing a compound acetaminophen and amantadine preparation according to claim 1, characterized in that, In step S3, the mass ratio of the oil phase to the water phase is 1:(10~15); the first stirring speed is 800~1000 rpm, and the first stirring time is 10~20 min; the second stirring speed is 300~500 rpm, and the second stirring time is 1~3 h.

8. The method for preparing a compound acetaminophen and amantadine preparation according to claim 1, characterized in that, In step S4, the freeze-drying protectant solution is any one or more of sucrose solution, mannitol solution, and polyvinylpyrrolidone; the concentration of the freeze-drying protectant solution is (2~10) g / L; the freeze-drying operation is as follows: the temperature is lowered to -30~-40℃ at a rate of 5~10℃ / h and held for 2~4h; the temperature is raised to -20~-10℃ at a rate of 2~3℃ / h and held for 6~10h; the temperature is raised to 20~40℃ at a rate of 3~5℃ / h and held for 8~10h.

9. The method for preparing a compound acetaminophen and amantadine preparation according to claim 1, characterized in that, In step S4, the gliding agent is talc; the lubricant is magnesium stearate; the filler is any one or more of microcrystalline cellulose or lactose; the disintegrant is any one or more of sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose; the mass ratio of the drug-loaded PLGA, gliding agent, filler, lubricant, and disintegrant is 1:(0.01~0.05):(0.001~0.005):(0.001~0.005):(0.005~0.02); the tableting parameters are: pressure of 25~30 MPa, holding pressure for 20~30 s; the vacuum drying temperature is 40~50℃, and the vacuum drying time is 2~3 h.

10. A compound acetaminophen and amantadine preparation prepared by the method of any one of claims 1-9.

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