Carrier cooperation system, application and preparation method of dihydrocodeine tartrate tablets

Abstract

The invention discloses a carrier cooperation system, application and a preparation method of a dihydrocodeine tartrate tablet, the carrier cooperation system comprises a mesoporous silica carrier and a hydroxypropyl trimethyl ammonium chloride chitosan modification layer, the surface of the mesoporous silica carrier is modified by silicon hydroxyl, and the hydroxypropyl trimethyl ammonium chloride chitosan modification layer is adsorbed in a pore channel of mesoporous silica. A mesoporous silica carrier modified by hydroxypropyl trimethyl ammonium chloride chitosan is formed; the silicon hydroxyl of the mesoporous silica carrier and the carboxyl of the active pharmaceutical ingredient form a hydrogen bond, and the quaternary ammonium group of the hydroxypropyl trimethyl ammonium chloride chitosan modified layer and the active pharmaceutical ingredient containing the tertiary amine group form an electrostatic complexing effect; according to the application of the carrier synergistic system in preparation of the abuse-preventing dihydrocodeine tartrate tablet, the tablet contains the carrier synergistic system, 6.67%-10.0% of dihydrocodeine tartrate and pharmaceutic adjuvants; the invention further discloses a specific preparation method, and the double effects of abuse prevention and slow release are synchronously achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a carrier collaborative system, application thereof, and a preparation method of dihydrocodeine tartrate tablets. Background Art

[0002] Existing opioid abuse-deterrent preparations mainly block alcohol extraction by adding gelling agents such as polyoxyethylene. However, this process has two major flaws. First, it cannot take into account the sustained-release function: abuse blocking relies on high doses of gelling agents, which can easily lead to excessive drug release and require frequent dosing; second, there is no spatial targeting: the drug is released prematurely in the stomach, increasing the risk of gastrointestinal side effects.

[0003] Conventional sustained-release technologies lack the synergistic design of pH responsiveness and abuse resistance. Therefore, there are currently no opioid preparations that simultaneously meet the dual functions of abuse resistance and sustained release. Summary of the Invention

[0004] The purpose of the present invention is to study an opioid preparation product that meets the dual functions of anti-abuse and sustained release. The present invention studies a preparation method of dihydrocodeine tartrate tablets.

[0005] The technical solution adopted by the present invention provides a carrier synergistic system. The key lies in that the above-mentioned carrier synergistic system includes a mesoporous silica carrier with a silanol-modified surface and a pore size of 6nm to 8nm and a hydroxypropyltrimethylammonium chloride chitosan modification layer. The above-mentioned hydroxypropyltrimethylammonium chloride chitosan modification layer is adsorbed in the pores of the mesoporous silica to form a hydroxypropyltrimethylammonium chloride chitosan modified mesoporous silica carrier; the silanol groups of the above-mentioned mesoporous silica carrier form hydrogen bonds with the carboxyl groups of the active pharmaceutical ingredients, and the quaternary ammonium groups of the above-mentioned hydroxypropyltrimethylammonium chloride chitosan modification layer form electrostatic complexation with the active pharmaceutical ingredients containing tertiary amine groups; the hydroxypropyltrimethylammonium chloride chitosan modified mesoporous silica carrier is referred to as HACC@MSN carrier.

[0006] The key to the application of the above-mentioned carrier synergistic system in the preparation of abuse-resistant dihydrocodeine tartrate tablets is that the dihydrocodeine tartrate tablets contain the above-mentioned carrier synergistic system, dihydrocodeine tartrate accounting for 6.67% to 10.0% of the tablet mass, and pharmaceutical excipients; the above-mentioned dihydrocodeine tartrate is loaded on the above-mentioned HACC@MSN carrier through hydrogen bonds between carboxyl groups and silanol groups, and electrostatic complexation between tertiary amine groups and quaternary ammonium groups.

[0007] 3. A method for preparing dihydrocodeine tartrate tablets, characterized in that the above preparation method includes S1 carrier construction, S2 drug loading, S3 inner coating, S4 outer coating and S5 mixed tableting, wherein the above S1 carrier construction is to adsorb hydroxypropyltrimethylammonium chloride chitosan and load it into the pores of mesoporous silica to obtain a HACC@MSN carrier; the above S2 drug loading is to load dihydrocodeine tartrate on the HACC@MSN carrier to obtain drug-loaded particles with a drug loading amount of 18% to 25%; the above S3 inner coating is to coat the drug-loaded particles with an ethyl cellulose solution to form an EC layer and then modify it with a triblock copolymer of polyethylene glycol-polypropylene glycol-polyethylene glycol to obtain a single-layer coated particle; the above S4 outer coating is to coat the drug-loaded particles with a poloxamer 407-PAA composite solution to obtain a double-layer coated particle; and the above S5 mixed tableting is to mix the double-layer coated particles with a diluent, a glidant, and a lubricant and then press them into tablets.

[0008] Specifically, in the construction of the S1 carrier, mesoporous silica was activated and then dispersed in an ethanol solution of hydroxypropyltrimethylammonium chloride chitosan; the mass ratio of the activated mesoporous silica to hydroxypropyltrimethylammonium chloride chitosan was 1:0.12-0.15; the ethanol used was an ethanol aqueous solution with a volume concentration of 80%-90%, and the concentration of hydroxypropyltrimethylammonium chloride chitosan in the hydroxypropyltrimethylammonium chloride chitosan solution was 1.5 mg / mL-2.5 mg / mL; in the construction of the S1 carrier, the loading method was vacuum adsorption, and during the vacuum adsorption process, the temperature was controlled at 40°C-50°C, and the vacuum degree was adjusted in stages. After the vacuum adsorption was completed, the HACC@MSN carrier was separated, washed, and dried at 40°C-60°C. The specific process of vacuum adsorption is: In the first stage, the vacuum degree is -0.085 MPa to -0.080 MPa, and the time is controlled at 50 min to 60 min; in the second stage, the vacuum degree is gradually reduced to -0.092 MPa to -0.090 MPa within 60 min to 80 min; in the third stage, the vacuum degree is maintained at -0.092 MPa to -0.090 MPa for 70 min to 110 min.

[0009] Furthermore, in the S2 drug loading step, the HACC@MSN carrier is dispersed in an ethanol solution of dihydrocodeine tartrate and vacuum adsorbed. After the vacuum adsorption, the drug-loaded particles are obtained by separation, ethanol elution, and drying. The mass ratio of the HACC@MSN carrier and dihydrocodeine tartrate is 1:0.3~0.4, and the mass concentration of dihydrocodeine tartrate in the ethanol aqueous solution of dihydrocodeine tartrate is 20mg / mL~30mg / mL. The conditions for vacuum adsorption are a temperature of 38°C~42°C and a vacuum degree of -0.092 MPa~-0.088MPa maintained for 230min~250min. The ethanol used is an ethanol aqueous solution with a volume concentration of 80%~90%.

[0010] Furthermore, in the S3 inner layer coating step, the drug-loaded particles are dispersed in an anhydrous ethanol solution of ethyl cellulose and coated using a fluidized bed. After the coating is completed, an ethanol solution of polyethylene glycol-polypropylene glycol-polyethylene glycol triblock copolymer is sprayed in, and the particles are heat-treated at 60° C. to 70° C. for 30 min to 60 min to obtain single-layer coated particles; the mass ratio of the drug-loaded particles to ethyl cellulose is 1:0.54 to 0.58, and the concentration of ethyl cellulose in the anhydrous ethanol solution of ethyl cellulose is 20 mg / mL to 40 mg / mL; The total molecular weight of the polyethylene glycol-polypropylene glycol-polyethylene glycol triblock copolymer is 4500Da to 6000Da, the concentration of the polyethylene glycol-polypropylene glycol-polyethylene glycol triblock copolymer in the ethanol solution is 45mg / mL to 55mg / mL, and the solvent is an ethanol aqueous solution with a volume concentration of 70% to 90% ethanol; The specific process of fluidized bed coating in the S3 inner layer coating step is as follows: controlling the inlet air temperature to 50°C to 60°C, the atomization pressure to 0.5MPa to 1.0MPa, the initial spray rate to 5g / min and maintaining it for 15min to 20min; increasing the spray rate by 3g / min every 5min to increase the spray rate to 20g / min and maintaining it for 30min to 35min; increasing the spray rate by 5g / min every 10min to increase the spray rate to 40g / min and maintaining it for 40min to 45min; increasing the spray rate by 2g / min every 2min to increase the spray rate to 50g / min and maintaining it for 10min to 15min.

[0011] Furthermore, in the S4 outer coating step, the single-layer coated particles are dispersed in a poloxamer 407-PAA composite solution and coated using a fluidized bed. After coating, they are matured in a fluidized bed to obtain double-layer coated particles; the mass ratio of the single-layer coated particles to poloxamer 407-PAA is 1:0.10-0.15.

[0012] Furthermore, the specific process of fluidized bed coating in the S4 outer coating step is as follows: the inlet air temperature is 30°C to 35°C, the atomization pressure is 0.8MPa to 1.2MPa, the initial spray rate is 5g / min and maintained for 10min to 15min; the spray rate is increased by 2g / min every 5min to increase the spray rate to 20g / min and maintained for 10min to 15min; the above-mentioned aging is carried out at a controlled temperature of 25°C to 28°C in the fluidized bed for 60min to 90min.

[0013] Preferably, the preparation method of the poloxamer 407-PAA composite solution is as follows: dissolving poloxamer 407 in water to prepare a poloxamer 407 solution with a mass concentration of 15% to 20%; adding acrylic acid to the poloxamer 407 solution, adding ammonium persulfate and N,N'-methylenebisacrylamide, stirring under the protection of inert gas, controlling the temperature at 38°C to 42°C to carry out a cross-linking reaction for 5h to 6h to form a cross-linked network to obtain a gel-like product; after the reaction is completed, Extraction, precipitation, suction filtration, ethanol washing, fine filtration, and drying are performed to obtain poloxamer 407-PAA dry powder; a poloxamer 407-PAA composite solution having a poloxamer 407-PAA dry powder concentration of 20 mg / mL to 40 mg / mL is prepared with water; and the mass ratio of acrylic acid, poloxamer 407, ammonium persulfate, and N,N'-methylenebisacrylamide is 1:1.5-2.5:0.005-0.01:0.0005-0.002.

[0014] Finally, in the inner coating step S3 or the outer coating step S4, a plasticizer is added to the coating solution; in the mixed tableting step S5, pharmaceutical excipients are added and mixed, and the tableting pressure is controlled to be 8kN to 12kN; the pharmaceutical excipients include diluents, glidants and lubricants.

[0015] Compared with the prior art, the present invention has the following beneficial effects: This invention, for the first time, uses the synergistic process of HACC@MSN carrier construction-EC inner layer coating modification-Poloxamer-PAA outer layer pH-responsive coating, requiring a HACC substitution degree of 0.5-0.8 and an EC coverage rate of 40%-45%, achieving a breakthrough in achieving the dual effects of anti-abuse and sustained release.

[0016] In a comparison of abuse prevention effects, the samples of the present invention met the FDA's abuse prevention standards under all three solvent conditions. In sustained-release studies, the present invention not only achieved sustained-release effects but also achieved integrated sustained-release targeting, resolving the functional fragmentation problem of traditional formulations.

[0017] Moreover, the present invention also improves the stability of the drug, with the content reduction rate of ≤2.5% in 6 months, which is far better than the reference product. It can be seen that the present invention provides a long-term stabilization solution for the industry.

[0018] In the present invention, a pharmaceutical excipient, i.e., the manufacture of poloxamer 407-polyacrylic acid dry powder, is also provided. Poloxamer 407-polyacrylic acid dry powder is a key pharmaceutical excipient for outer coating, which affects the anti-abuse effect and sustained-release targeted integrated function of the tablet product of the present invention, but there is currently no commercially available product. Therefore, the present invention needs to carry out research and manufacture of this new pharmaceutical excipient. The present invention uses poloxamer 407 and acrylic acid as raw materials, reacts under the action of an initiator and a cross-linking agent, and after the reaction is completed, extracts, precipitates, filtrates, washes, finely filters, and dries to obtain poloxamer 407-PAA dry powder. The method for manufacturing poloxamer 407-PAA dry powder of the present invention has a simple process, rapid reaction, and the quality of the obtained dry powder is stable, which can help achieve the purpose of the invention of the tablet of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0020] Figure 1 It is a content trend diagram under the accelerated test conditions of the present invention. DETAILED DESCRIPTION

[0021] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0022] It should be understood that the terms described herein are intended only to describe particular embodiments and are not intended to limit the present invention. In addition, for numerical ranges herein, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. The intermediate value within any stated value or stated range, and each smaller range between any other stated value or intermediate value within the stated range, is also encompassed within the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the scope.

[0023] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of any conflict with any incorporated document, the contents of this specification shall prevail.

[0024] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from the description of the invention. The description and examples are intended to be illustrative only.

[0025] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0026] If the specific conditions are not specified in the examples, the experiments can be carried out under conventional conditions; if the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased from the market.

[0027] Since the single-time measurement range of the laboratory-grade fluidized bed used in the examples is 50 g to 200 g, steps S1 to S4 in the examples are described at the 100-g level. The mass of the carrier will change during the activation, drug loading and coating processes, but for the convenience of description, the above steps are described based on 100 g of mesoporous silica, HACC@MSN carrier, drug-loaded particles, single-layer coated particles and double-layer coated particles. Example

[0028] This example takes 10 mg / tablet dihydrocodeine tartrate tablets as an example. The number of tablets for the tablet compression test is 200 tablets, and the weight of each tablet is 150 mg. The specific steps are as follows: S1 vector construction: S11. Activation of mesoporous silica: 100 g of mesoporous silica with silanol-modified surface and pore size of 7 nm was selected and vacuum dried at 155°C for 2.5 h to obtain activated mesoporous silica; S12, prepare HACC solution: 13.5 g of hydroxypropyl trimethyl ammonium chloride chitosan was dissolved in an ethanol aqueous solution with an ethanol volume concentration of 85% to obtain a HACC solution with a hydroxypropyl trimethyl ammonium chloride chitosan concentration of 2.0 mg / mL; S13, preparation of HACC@MSN carrier: The activated mesoporous silica was dispersed in the above-mentioned HACC solution, and vacuum adsorption was performed by adjusting the vacuum degree and controlling the time. The temperature during the vacuum adsorption process was controlled at 45°C. The staged process was as follows: the vacuum degree was -0.082 MPa in the first stage, and the time was controlled to be 55 minutes; the vacuum degree was gradually reduced to -0.091 MPa within 70 minutes in the second stage; and the vacuum degree was maintained at -0.091 MPa in the third stage for 90 minutes. After the vacuum adsorption, the HACC@MSN carrier was separated, washed, and dried at 50°C to obtain the HACC@MSN carrier sample 1.

[0029] S2 drug loading: S21. Prepare API solution: 35 g of dihydrocodeine tartrate was dissolved in an ethanol solution having a volume concentration of 85% ethanol to prepare an API solution having a mass concentration of 25 mg / mL of dihydrocodeine tartrate; S22, preparing drug-loaded particles: 100 g of HACC@MSN carrier was dispersed in the above API solution and vacuum adsorption was performed at low temperature of 40°C with a vacuum degree of -0.090 MPa maintained for 240 min. After vacuum adsorption, drug-loaded particles were obtained by separation, rapid elution with ethanol at 4°C, and drying. S23. Determination of drug loading: Sampling was performed by placing the drug-loaded particle sample in a 0.3% (v / v) formic acid methanol solution, vortex mixing for 1 minute, ultrasonic treatment at 40 kHz and 40°C for 30 minutes, and then shaking in a 60°C water bath for 1 hour. After centrifugation, the supernatant was collected and passed through a membrane. The mass of the loaded drug was measured and calculated using a high-performance liquid chromatography (HPLC). The drug loading was calculated using Equation 1. The drug loading in this example was 22.2%.

[0030] Drug loading (%) = (measured drug mass / drug-loaded particle sample mass) × 100% Formula 1.

[0031] S3 inner coating: S31. Prepare EC solution: 65 g of ethyl cellulose was dissolved in anhydrous ethanol solution, and triethyl citrate plasticizer was added at 20% of the mass of ethyl cellulose to prepare an EC solution with an ethyl cellulose concentration of 30 mg / mL; S32, prepare PEG-PPG-PEG solution: 11 g of a polyethylene glycol-polypropylene glycol-polyethylene glycol triblock copolymer with a total molecular weight of 5000 Da was selected to prepare a polyethylene glycol-polypropylene glycol-polyethylene glycol solution with a mass concentration of 50 mg / mL, referred to as PEG-PPG-PEG solution, and the solvent was an ethanol solution with a volume concentration of 80% ethanol, and the solution was set aside; S33, EC layer coating: 100 g of drug-loaded particles were dispersed in EC solution and coated using a fluidized bed. The inlet air temperature was controlled at 55°C, the atomizing pressure was 0.8 MPa, and the initial spray rate was 5 g / min and maintained for 18 min. The spray rate was increased by 3 g / min every 5 min to 20 g / min and maintained for 32 min. The spray rate was increased by 5 g / min every 10 min to 40 g / min and maintained for 43 min. The spray rate was increased by 2 g / min every 2 min to 50 g / min and maintained for 12 min. S34, EC layer modification: After coating, PEG-PPG-PEG solution was sprayed in and heat-treated at 65°C for 45 minutes to obtain single-layer coated particles, which were recorded as single-layer coated particles sample 1.

[0032] S4 outer coating: S41, preparation of poloxamer 407-polyacrylic acid dry powder: 20 g of poloxamer 407 was dissolved in deionized water to prepare a poloxamer 407 solution with a mass concentration of 18% at a temperature below 8° C. 10 g of acrylic acid was added to the poloxamer 407 solution, followed by 0.08 g of ammonium persulfate and 0.01 g of N,N'-methylenebisacrylamide. The mixture was stirred under inert gas at a temperature of 40° C. for a cross-linking reaction for 5.5 h. After the reaction, the reaction system was placed in an ice-water bath and poured into pre-cooled anhydrous ethanol. The mixture was stirred and allowed to stand to precipitate the polymer. The polymer was then filtered, washed, finely filtered, and dried to obtain a poloxamer 407-PAA dry powder. S42, prepare poloxamer 407-PAA composite solution: 12 g of poloxamer 407-PAA dry powder was dissolved in deionized water, and triethyl citrate plasticizer was added at 20% of the mass of the poloxamer 407-PAA dry powder to prepare a poloxamer 407-PAA composite solution with a concentration of 30 mg / mL of poloxamer 407-polyacrylic acid. S43, Poloxamer 407-PAA coating: 100 g of single-layer coated granules were dispersed in a poloxamer 407-PAA composite solution and coated using a fluidized bed. The inlet air temperature was controlled at 32°C, the atomization pressure was 1.0 MPa, and the initial spray rate was 5 g / min and maintained for 12 min. The spray rate was increased by 2 g / min every 5 min to 20 g / min and maintained for 13 min. After coating, the temperature in the fluidized bed was controlled at 27°C and matured for 85 min to obtain double-layer coated granules, which were recorded as double-layer coated granule sample 1.

[0033] S5 mixed tableting: S51. Material preparation: The number of tablets in this embodiment is 100, the weight of each tablet is 150 mg, and the specification is 10 mg / tablet. The mass of the required double-layer coated granules is calculated according to Formula 2, and the total mass of the required pharmaceutical excipients is calculated according to Formula 3: The mass of double-layer coated granules required = specification × total number of tablets / drug loading (Equation 2); The total mass of pharmaceutical excipients required = single tablet weight × total number of tablets - the mass of double-layer coated granules required (Formula 3); The calculation results are: The mass of the double-layer coated particles required is 9.01 g, and the total mass of the pharmaceutical excipients required is 20.99 g. The pharmaceutical excipients required include 63.0 mg of colloidal silicon dioxide, 105.0 mg of magnesium stearate, and other excipients are microcrystalline cellulose.

[0034] S52, material mixing: Weigh the above materials of the same type and mass, mix the double-layer coated granules and microcrystalline cellulose for 9 minutes, then add colloidal silicon dioxide and continue mixing for 3 minutes, then add magnesium stearate and mix for 2 minutes; S53, Tablet Compression: The rotary tablet press was controlled to have a pressure of 10 kN and a rotation speed of 20 rpm for tableting to prepare dihydrocodeine tartrate tablets, which were recorded as sample 1. Theoretically, the dihydrocodeine tartrate in sample 1 accounted for 6.67% of the tablet mass. Example

[0035] This example takes 15 mg / tablet dihydrocodeine tartrate tablets as an example. The number of tablets to be compressed is 100, and the weight of each tablet is 200 mg. The specific steps are as follows: S1 vector construction: S11. Activation of mesoporous silica: 100 g of mesoporous silica with silanol-modified surface and pore size of 6 nm was selected and vacuum dried at 160°C for 2 h to obtain activated mesoporous silica; S12, prepare HACC solution: 15 g of hydroxypropyl trimethyl ammonium chloride chitosan was dissolved in an ethanol aqueous solution with a volume concentration of 90% ethanol to obtain a HACC solution with a concentration of hydroxypropyl trimethyl ammonium chloride chitosan of 2.5 mg / mL; S13, preparation of HACC@MSN carrier: The activated mesoporous silica was dispersed in the above-mentioned HACC solution, and vacuum adsorption was performed by adjusting the vacuum degree and controlling the time. The temperature during the vacuum adsorption process was controlled at 50°C. The staged process was as follows: the vacuum degree was -0.085 MPa in the first stage, and the time was controlled to be 60 min; the vacuum degree was gradually reduced to -0.092 MPa within 60 min in the second stage; and the vacuum degree was maintained at -0.092 MPa for 110 min in the third stage. After the vacuum adsorption, the HACC@MSN carrier was separated, washed, and dried at 60°C to obtain the HACC@MSN carrier sample 2.

[0036] S2 drug loading: S21. Prepare API solution: 40 g of dihydrocodeine tartrate was dissolved in an ethanol solution having a volume concentration of 80% ethanol to prepare an API solution having a mass concentration of 30 mg / mL of dihydrocodeine tartrate; S22, preparing drug-loaded particles: 100 g of HACC@MSN carrier was dispersed in the above API solution and vacuum adsorption was performed at low temperature of 38°C with a vacuum degree of -0.088 MPa maintained for 250 min. After vacuum adsorption, drug-loaded particles were obtained by separation, rapid elution with ethanol at 4°C, and drying. S23. Determination of drug loading: Same as the “S23. Determination of drug loading” section of Example 1. The drug loading in this example is 24.6%.

[0037] S3 inner coating: S31. Prepare EC solution: 57.4 g of ethyl cellulose was dissolved in anhydrous ethanol solution, and triethyl citrate plasticizer was added at 25% of the mass of ethyl cellulose to prepare an EC solution with an ethyl cellulose concentration of 40 mg / mL; S32, prepare PEG-PPG-PEG solution: 13 g of a triblock copolymer of polyethylene glycol-polypropylene glycol-polyethylene glycol with a total molecular weight of 4500 Da was selected to prepare a PEG-PPG-PEG solution with a mass concentration of 55 mg / mL, and the solvent was an ethanol solution with a volume concentration of 90% ethanol, and the solution was set aside; S33, EC layer coating: 100 g of drug-loaded particles were dispersed in EC solution and coated using a fluidized bed. The inlet air temperature was controlled at 60 °C, the atomization pressure was 0.5 MPa, and the initial spray rate was 5 g / min and maintained for 15 min. The spray rate was increased by 3 g / min every 5 min to 20 g / min and maintained for 35 min. The spray rate was increased by 5 g / min every 10 min to 40 g / min and maintained for 40 min. The spray rate was increased by 2 g / min every 2 min to 50 g / min and maintained for 15 min. S34, EC layer modification: After coating, PEG-PPG-PEG solution was sprayed in and heat-treated at 70°C for 30 min to obtain single-layer coated particles, which were recorded as single-layer coated particles sample 2.

[0038] S4 outer coating: S41, preparation of poloxamer 407-polyacrylic acid dry powder: 15 g of poloxamer 407 was dissolved in deionized water to prepare a poloxamer 407 solution with a mass concentration of 20% at a temperature below 8° C. 10 g of acrylic acid was added to the poloxamer 407 solution, followed by 0.05 g of ammonium persulfate and 0.02 g of N,N'-methylenebisacrylamide. The mixture was stirred under inert gas at a temperature of 42° C. for a cross-linking reaction for 5 h. After the reaction, the reaction system was placed in an ice-water bath and poured into pre-cooled acetone. The mixture was stirred and allowed to stand to precipitate the polymer. The polymer was then filtered, washed, finely filtered, and dried to obtain a poloxamer 407-PAA dry powder. S42, prepare poloxamer 407-PAA composite solution: 10 g of poloxamer 407-PAA dry powder was dissolved in deionized water, and triethyl citrate plasticizer was added at 25% of the mass of the poloxamer 407-PAA dry powder to prepare a poloxamer 407-PAA composite solution with a concentration of 40 mg / mL of poloxamer 407-polyacrylic acid. S43, Poloxamer 407-PAA coating: 100 g of single-layer coated particles were dispersed in a poloxamer 407-PAA composite solution and coated using a fluidized bed. The inlet air temperature was controlled at 30°C, the atomization pressure was 1.2 MPa, and the initial spray rate was 5 g / min and maintained for 10 min. The spray rate was increased by 2 g / min every 5 min to 20 g / min and maintained for 10 min. After coating, the temperature in the fluidized bed was controlled at 25°C and matured for 90 min to obtain double-layer coated particles, which were recorded as double-layer coated particle sample 2.

[0039] S5 mixed tableting: S51. Material preparation: The number of tablets in this embodiment is 100, the weight of each tablet is 200 mg, and the specification is 15 mg / tablet. The calculation method is the same as that in the "S51, material preparation" section of Example 1.

[0040] The calculation results are: The mass of the double-layer coated particles required is 6.10 g, and the total mass of the pharmaceutical excipients required is 13.90 g. The pharmaceutical excipients required include 41.7 mg of colloidal silicon dioxide, 69.5 mg of magnesium stearate, and other excipients are microcrystalline cellulose.

[0041] S52, material mixing: Weigh the above materials of the same type and mass, mix the double-layer coated granules and microcrystalline cellulose for 10 minutes, then add colloidal silicon dioxide and continue mixing for 2 minutes, then add magnesium stearate and mix for 1 minute; S53, Tablet Compression: The rotary tablet press was controlled to have a pressure of 8 kN and a rotation speed of 15 rpm for tableting to prepare dihydrocodeine tartrate tablets, which were recorded as Sample 2. Theoretically, the dihydrocodeine tartrate in Sample 2 accounted for 7.50% of the tablet mass. Example

[0042] This example takes dihydrocodeine tartrate tablets with a specification of 10 mg / tablet as an example. The number of tablet compression tests is 200 tablets, and the weight of each tablet is 100 mg. The specific steps are as follows: S1 vector construction: S11. Activation of mesoporous silica: 100 g of mesoporous silica with silanol modification on the surface and a pore size of 8 nm was selected and vacuum dried at 150°C for 3 h to obtain activated mesoporous silica; S12, prepare HACC solution: 12 g of hydroxypropyl trimethyl ammonium chloride chitosan was dissolved in an ethanol aqueous solution with a volume concentration of 80% ethanol to obtain a HACC solution with a concentration of hydroxypropyl trimethyl ammonium chloride chitosan of 1.5 mg / mL; S13, preparation of HACC@MSN carrier: The activated mesoporous silica was dispersed in the above-mentioned HACC solution, and vacuum adsorption was performed by adjusting the vacuum degree and controlling the time. The temperature during the vacuum adsorption process was controlled at 40°C. The staged process was as follows: the vacuum degree was -0.080 MPa in the first stage, and the time was controlled to be 50 min; the vacuum degree was gradually reduced to -0.090 MPa within 80 min in the second stage; and the vacuum degree was maintained at -0.090 MPa in the third stage for 70 min. After the vacuum adsorption, the HACC@MSN carrier was separated, washed, and dried at 40°C to obtain the HACC@MSN carrier sample 3.

[0043] S2 drug loading: S21. Prepare API solution: 30 g of dihydrocodeine tartrate was dissolved in an ethanol solution having a volume concentration of 90% ethanol to prepare an API solution having a mass concentration of 20 mg / mL of dihydrocodeine tartrate; S22, preparing drug-loaded particles: 100 g of HACC@MSN carrier was dispersed in the above API solution and vacuum adsorption was performed at low temperature under controlled temperature of 42°C. The vacuum degree was maintained at -0.092 MPa for 230 min. After vacuum adsorption, the drug-loaded particles were separated, quickly rinsed with ethanol at 4°C, and dried. S23. Determination of drug loading: Same as the “S23. Determination of drug loading” section of Example 1. The drug loading in this example is 18.1%.

[0044] S3 inner coating: S31. Prepare EC solution: 58.2 g of ethyl cellulose was dissolved in anhydrous ethanol solution, and triethyl citrate plasticizer was added at 10% of the mass of ethyl cellulose to prepare an EC solution with an ethyl cellulose concentration of 20 mg / mL; S32, prepare PEG-PPG-PEG solution: 10 g of a triblock copolymer of polyethylene glycol-polypropylene glycol-polyethylene glycol with a total molecular weight of 6000 Da was selected to prepare a PEG-PPG-PEG solution with a mass concentration of 45 mg / mL, and the solvent was an ethanol solution with a volume concentration of 80% ethanol, and the solution was set aside; S33, EC layer coating: 100 g of drug-loaded particles were dispersed in EC solution and coated using a fluidized bed. The inlet air temperature was controlled at 50 °C, the atomizing pressure was 1.0 MPa, and the initial spray rate was 5 g / min and maintained for 20 min. The spray rate was increased by 3 g / min every 5 min to 20 g / min and maintained for 30 min. The spray rate was increased by 5 g / min every 10 min to 40 g / min and maintained for 45 min. The spray rate was increased by 2 g / min every 2 min to 50 g / min and maintained for 10 min. S34, EC layer modification: After coating, PEG-PPG-PEG solution was sprayed in and heat-treated at 60°C for 60 min to obtain single-layer coated particles, which were recorded as single-layer coated particles sample 3.

[0045] S4 outer coating: S41, preparation of poloxamer 407-polyacrylic acid dry powder: 25 g of poloxamer 407 was dissolved in deionized water to prepare a poloxamer 407 solution with a mass concentration of 15% at a temperature below 8° C. 10 g of acrylic acid was added to the poloxamer 407 solution, followed by 0.1 g of ammonium persulfate and 0.005 g of N,N'-methylenebisacrylamide. The mixture was stirred under inert gas at a temperature of 38° C. for a cross-linking reaction for 6 h. After the reaction, the reaction system was placed in an ice-water bath and poured into pre-cooled acetone. The mixture was stirred and allowed to stand to precipitate the polymer. The polymer was then filtered, washed, finely filtered, and dried to obtain a poloxamer 407-PAA dry powder. S42, prepare poloxamer 407-PAA composite solution: 15 g of poloxamer 407-PAA dry powder was dissolved in deionized water, and triethyl citrate plasticizer was added at 10% of the mass of the poloxamer 407-PAA dry powder to prepare a poloxamer 407-PAA composite solution with a concentration of 20 mg / mL of poloxamer 407-polyacrylic acid. S43, Poloxamer 407-PAA coating: 100 g of single-layer coated particles were dispersed in a poloxamer 407-PAA composite solution and coated using a fluidized bed. The inlet air temperature was controlled at 35°C, the atomization pressure was 0.8 MPa, and the initial spray rate was 5 g / min and maintained for 15 min. The spray rate was increased by 2 g / min every 5 min to 20 g / min and maintained for 15 min. After coating, the temperature in the fluidized bed was controlled at 28°C and matured for 60 min to obtain double-layer coated particles, which were recorded as double-layer coated particle sample 3.

[0046] S5 mixed tableting: S51. Material preparation: The number of tablets in this embodiment is 100, the weight of each tablet is 100 mg, and the specification is 10 mg / tablet. The calculation method is the same as that in the "S51, material preparation" section of Example 1.

[0047] The calculation results are: The mass of the double-layer coated particles required is 11.05 g, and the total mass of the pharmaceutical excipients required is 8.95 g. The pharmaceutical excipients required include 26.9 mg of colloidal silicon dioxide, 44.8 mg of magnesium stearate, and other excipients are microcrystalline cellulose.

[0048] S52, material mixing: Weigh the above materials of the same type and mass, mix the double-layer coated granules and microcrystalline cellulose for 8 minutes, then add colloidal silicon dioxide and continue mixing for 5 minutes, then add magnesium stearate and mix for 3 minutes; S53, Tablet Compression: The rotary tablet press was controlled to have a pressure of 12 kN and a rotation speed of 25 rpm to produce dihydrocodeine tartrate tablets, designated as Sample 3. Theoretically, the dihydrocodeine tartrate in Sample 3 accounted for 10.0% of the tablet mass.

[0049] Comparative Example 1 The implementation method is the same as Example 1, except that "S4 outer layer coating" is not performed. During "S5 mixed tableting", single-layer coated particles without poloxamer 407-PAA layer coating are used for material accounting and mixed tableting to prepare reference product 1.

[0050] Comparative Example 2 The implementation method is the same as Example 1, except that after "S3 inner layer coating" is not performed, in "S5 mixed tableting", single-layer coated particles without EC layer coating are used for material accounting and mixed tableting to prepare reference product 2.

[0051] Comparative Example 3 The implementation method is the same as Example 1, except that when performing "S3 inner layer coating", "S34, EC layer modification" is not performed, that is, PEG-PPG-PEG solution is not sprayed. The subsequent process is the same as Example 1 to prepare reference product 3.

[0052] Analysis and testing 1. Determination of the degree of substitution of hydroxypropyltrimethylammonium chloride chitosan The HACC@MSN carrier to be tested was taken and the degree of substitution of hydroxypropyltrimethylammonium chloride chitosan was determined by colloid titration method, expressed as HACC substitution degree. The results are shown in Table 1.

[0053] 2. Determination of EC layer coverage Take the single-layer coated particles to be tested and calculate the EC coverage rate according to Formula 4. The results are shown in Table 1.

[0054] EC coating rate = (EC feed amount × deposition efficiency) / single-layer coated particle mass × 100% Formula 4 The deposition efficiency in Formula 4 is the measured value of the fluidized bed under specific process parameters (including atomization pressure and spray velocity, etc.). The deposition efficiency of Example 1 is 75%; the deposition efficiency of Example 2 is 77%; and the deposition efficiency of Example 3 is 70%.

[0055] Table 1: Summary of HACC substitution degree and EC coverage results

[0056] From the results in Table 1, it can be seen that the HACC substitution degree of the present invention is in the range of 0.5 to 0.8, and the EC coverage is 40% to 45%.

[0057] Research on the degree of substitution of HACC revealed that excessively high HACC solution concentrations can lead to molecular chain entanglement, reducing the efficiency of substituent insertion, while low concentrations can result in insufficient adsorption. Furthermore, the ethanol concentration range employed in the present invention not only facilitates HACC dissolution but also prevents the folding of chitosan hydrophobic segments, reducing the exposure of active sites.

[0058] In the study on EC coverage rate, it was found that EC concentration and spray speed have a combined impact on the coverage rate. If the EC concentration is too high or the spray speed increases too quickly, the coverage rate will be too high; conversely, if the EC concentration is insufficient and the total amount of spray is small, the coverage rate will be insufficient.

[0059] 3. Quality Analysis of Dihydrocodeine Tartrate Tablets Because the present invention adopts an abuse-proof carrier, the inspection method for dihydrocodeine tartrate tablets recorded in Part II of the 2020 edition of the Chinese Pharmacopoeia cannot be directly used for quality determination.

[0060] 1. Comparison of anti-abuse effects The samples to be tested were ground into powders with a particle size of less than 500 μm, extracted using different solvent conditions, and the solubility of the samples and the reference substance was measured. The results are shown in Table 2.

[0061] Solvent condition 1: 40% ethanol + 0.5% Tween 80, 2 h; Solvent condition 2: acetone, 30 min; Solvent condition 3: 1 M HCl, 1 h.

[0062] Table 2: Comparison of anti-abuse effects

[0063] As can be seen from the results in Table 2, the dihydrocodeine tartrate tablet samples of the present invention can meet the anti-abuse standards in the three abuse solvents. This is the result of the synergistic effect of the double-layer coating and modification technology. The double-layer coating and modification steps are indispensable.

[0064] 2. Verification of sustained-release properties Because the present invention is still in the laboratory pilot stage and has not yet been tested on humans, an in vitro alternative scheme was used to verify the sustained-release properties.

[0065] The solution was treated with 0.1N HCl for 2 hours to simulate the gastric phase, and PBS (pH 6.8) for 10 hours to simulate the intestinal phase. During the in vitro simulation, the rotation speed was 100 rpm to simulate the peristaltic environment of the intestine. Samples were collected at 2 hours, 4 hours, 8 hours, and 12 hours for dissolution measurement. The results are shown in Table 3.

[0066] Table 3: Sustained release characteristics verification results

[0067] As shown in Table 3, the API release of the samples of the present invention in the gastric stage for 2 h was less than 30%, which met the requirement of sustained release. The API release at 12 h was greater than 80%, which met the requirement of complete release. However, the API release of Sample 3 was relatively low, which may be due to the low HACC substitution degree and insufficient carrier adsorption. There is still room for optimization and improvement.

[0068] 3. Intestinal targeting verification Because the present invention is still in the laboratory pilot stage and has not yet been tested on humans, an in vitro alternative approach is used to verify intestinal targeting.

[0069] For the gastric fluid stability test, refer to the experimental conditions and experimental results of the gastric stage in "2. Verification of sustained-release properties". If the API release of the sample of the present invention is ≤10%, it proves the protective effect in the stomach; The intestinal targeting efficiency test simulated conditions using PBS pH 6.8 + 0.5% bile salts. Acceptable criteria were an initial release time of 2 to 4 hours and a release of ≥60% at 2 hours. Meeting these acceptance criteria demonstrated that the drug could match the intestinal transit time and trigger release in the intestine. Results are shown in Table 4.

[0070] Table 4: Intestinal targeting efficiency test and initial release time results

[0071] As can be seen from the results in Table 4, the samples prepared in the present invention can swell under the simulated conditions of the intestinal targeting efficiency test and trigger a rapid release mechanism.

[0072] 4. Content analysis experiment Samples 1 to 3 and reference substances 1 to 3 were stored under accelerated test conditions (40°C, 75% RH) and the contents were determined using HPLC. The results are shown in Tables 5 and Figure 1 .

[0073] The preparation method of the test sample is as follows: the test sample is ground into a powder with a particle size of less than 100 μm, extracted with 0.5% SDS + 20% methanol aqueous solution, vortexed for 1 min, ultrasonicated at 40°C (40 kHz, 30 min), then shaken at 60°C for 1 h, centrifuged and filtered.

[0074] The specific HPLC method is: A Zorbax SB-C18 column was used, with acetonitrile-0.1% ammonium phosphate (30:70, pH 3.0) as the flow rate, a controlled flow rate of 1.2 mL / min, a column temperature of 40°C, and a detection wavelength of 284 nm.

[0075] Table 5: Assay results under accelerated test conditions

[0076] As shown in Table 5, under accelerated stability conditions, the content of the samples of the present invention is stable and significantly better than that of the control. This is because the poloxamer-PAA layer in the present invention isolates oxygen, the EC modified layer blocks water penetration, and the HACC@MSN carrier can inhibit the movement of API molecules.

[0077] The embodiments described above are merely descriptions of preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by persons skilled in the art should fall within the scope of protection defined by the claims of the present invention.

Claims

1. A carrier cooperative system, characterized in that: The carrier collaborative system includes a mesoporous silica carrier with a silanol modification on the surface and a pore size of 6nm to 8nm and a hydroxypropyltrimethylammonium chloride chitosan modification layer. The hydroxypropyltrimethylammonium chloride chitosan modification layer is adsorbed into the pores of the mesoporous silica to form a hydroxypropyltrimethylammonium chloride chitosan modified mesoporous silica carrier; the silanol groups of the mesoporous silica carrier form hydrogen bonds with the carboxyl groups of the active pharmaceutical ingredient, and the quaternary ammonium groups of the hydroxypropyltrimethylammonium chloride chitosan modification layer form an electrostatic complexation with the active pharmaceutical ingredient containing a tertiary amine group; the hydroxypropyltrimethylammonium chloride chitosan modified mesoporous silica carrier is referred to as HACC@MSN carrier.

2. Use of the carrier synergistic system according to claim 1 in the preparation of abuse-resistant dihydrocodeine tartrate tablets, characterized in that: The dihydrocodeine tartrate tablet comprises the carrier synergistic system according to claim 1, dihydrocodeine tartrate accounting for 6.67% to 10.0% of the tablet mass, and pharmaceutical excipients; the dihydrocodeine tartrate is loaded on the HACC@MSN carrier through hydrogen bonds between carboxyl groups and silanol groups, and electrostatic complexation between tertiary amine groups and quaternary ammonium groups.

3. A method for preparing dihydrocodeine tartrate tablets, characterized in that: The preparation method includes S1 carrier construction, S2 drug loading, S3 inner layer coating, S4 outer layer coating and S5 mixed tableting. The S1 carrier construction is to adsorb and load hydroxypropyltrimethylammonium chloride chitosan into the pores of mesoporous silica to obtain a HACC@MSN carrier; the S2 drug loading is to load dihydrocodeine tartrate on the HACC@MSN carrier to obtain drug-loaded particles with a drug loading amount of 18% to 25%; the S3 inner layer coating is to coat the drug-loaded particles with an ethyl cellulose solution to form an EC layer and then modify them with a triblock copolymer of polyethylene glycol-polypropylene glycol-polyethylene glycol to obtain single-layer coated particles; the S4 outer layer coating is to coat the drug-loaded particles with a poloxamer 407-PAA composite solution to obtain double-layer coated particles; and the S5 mixed tableting is to mix the double-layer coated particles with a diluent, a glidant and a lubricant and then press them into tablets.

4. The preparation method according to claim 3, characterized in that In the construction of the S1 carrier, mesoporous silica was activated and then dispersed in an ethanol solution of hydroxypropyltrimethylammonium chloride chitosan. The mass ratio of the activated mesoporous silica to hydroxypropyltrimethylammonium chloride chitosan was 1:0.12-0.

15. The ethanol used was an ethanol aqueous solution with a volume concentration of 80%-90%, and the concentration of hydroxypropyltrimethylammonium chloride chitosan in the hydroxypropyltrimethylammonium chloride chitosan solution was 1.5mg / mL-2.5mg / mL. In the construction of the S1 carrier, the loading method was vacuum adsorption. During the vacuum adsorption process, the temperature was controlled at 40°C-50°C, and the vacuum degree was adjusted in stages. After the vacuum adsorption, the HACC@MSN carrier was separated, washed, and dried at 40°C-60°C. The specific process of vacuum adsorption is: In the first stage, the vacuum degree is -0.085 MPa to -0.080 MPa, and the time is controlled at 50 min to 60 min; in the second stage, the vacuum degree is gradually reduced to -0.092 MPa to -0.090 MPa within 60 min to 80 min; in the third stage, the vacuum degree is maintained at -0.092 MPa to -0.090 MPa for 70 min to 110 min.

5. The preparation method according to claim 3, characterized in that In the S2 drug loading step, the HACC@MSN carrier is dispersed in an ethanol solution of dihydrocodeine tartrate and vacuum adsorbed. After the vacuum adsorption, the drug-loaded particles are obtained by separation, ethanol elution, and drying. The mass ratio of the HACC@MSN carrier and dihydrocodeine tartrate is 1:0.3-0.4, and the mass concentration of dihydrocodeine tartrate in the ethanol aqueous solution of dihydrocodeine tartrate is 20 mg / mL-30 mg / mL. The vacuum adsorption conditions are a temperature of 38°C-42°C and a vacuum degree of -0.092 MPa--0.088 MPa maintained for 230 min-250 min. The ethanol used is an ethanol aqueous solution with a volume concentration of 80%-90%.

6. The preparation method according to claim 3, characterized in that In the S3 inner layer coating step, the drug-loaded particles are dispersed in an anhydrous ethanol solution of ethyl cellulose and coated using a fluidized bed. After coating, an ethanol solution of polyethylene glycol-polypropylene glycol-polyethylene glycol triblock copolymer is sprayed in, and the particles are heat-treated at 60° C. to 70° C. for 30 to 60 minutes to obtain single-layer coated particles. The mass ratio of the drug-loaded particles to the ethyl cellulose is 1:0.54 to 0.58, and the concentration of the ethyl cellulose in the anhydrous ethanol solution is 20 mg / mL to 40 mg / mL. The total molecular weight of the polyethylene glycol-polypropylene glycol-polyethylene glycol triblock copolymer is 4500Da to 6000Da, the concentration of the polyethylene glycol-polypropylene glycol-polyethylene glycol triblock copolymer in the ethanol solution of the polyethylene glycol-polypropylene glycol-polyethylene glycol triblock copolymer is 45mg / mL to 55mg / mL, and the solvent is an ethanol aqueous solution with a volume concentration of 70% to 90% ethanol; The specific process of fluidized bed coating in the S3 inner layer coating step is as follows: controlling the inlet air temperature to 50°C to 60°C, the atomization pressure to 0.5MPa to 1.0MPa, the initial spray rate to 5g / min and maintaining it for 15min to 20min; increasing the spray rate by 3g / min every 5min to increase the spray rate to 20g / min and maintaining it for 30min to 35min; increasing the spray rate by 5g / min every 10min to increase the spray rate to 40g / min and maintaining it for 40min to 45min; increasing the spray rate by 2g / min every 2min to increase the spray rate to 50g / min and maintaining it for 10min to 15min.

7. The preparation method according to claim 3, characterized in that In the S4 outer coating step, the single-layer coated particles are dispersed in a poloxamer 407-PAA composite solution and coated using a fluidized bed. After coating, they are matured in a fluidized bed to obtain double-layer coated particles; the mass ratio of the single-layer coated particles to poloxamer 407-PAA is 1:0.10-0.

15.

8. The preparation method according to claim 7, characterized in that The specific process of fluidized bed coating in the S4 outer layer coating step is as follows: the inlet air temperature is 30°C to 35°C, the atomization pressure is 0.8MPa to 1.2MPa, the initial spray rate is 5g / min and maintained for 10min to 15min; the spray rate is increased by 2g / min every 5 minutes to increase the spray rate to 20g / min and maintained for 10min to 15min; the curing is carried out in a fluidized bed at a controlled temperature of 25°C to 28°C for 60min to 90min.

9. The preparation method according to claim 7, characterized in that The preparation method of the poloxamer 407-PAA composite solution is as follows: dissolving poloxamer 407 in water to prepare a poloxamer 407 solution with a mass concentration of 15% to 20%; adding acrylic acid to the poloxamer 407 solution, adding ammonium persulfate and N,N'-methylenebisacrylamide, stirring under the protection of inert gas, controlling the temperature at 38°C to 42°C to carry out a cross-linking reaction for 5h to 6h to form a cross-linked network to obtain a gel-like product, and extracting the product after the reaction. , precipitate, filter, wash with ethanol, fine filter, and dry to obtain poloxamer 407-PAA dry powder; prepare a poloxamer 407-PAA composite solution with a poloxamer 407-PAA dry powder concentration of 20 mg / mL to 40 mg / mL with water; the mass ratio of acrylic acid, poloxamer 407, ammonium persulfate and N,N'-methylenebisacrylamide is 1:1.5~2.5:0.005~0.01:0.0005~0.

002.

10. The preparation method according to claim 3, characterized in that In the inner coating step S3 or the outer coating step S4, a plasticizer is added to the coating solution; in the mixing and tableting step S5, pharmaceutical excipients are added and mixed, and the tableting pressure is controlled to be 8kN to 12kN; the pharmaceutical excipients include diluents, glidants and lubricants.

Images