CN116159031B

CN116159031B - Fluvoxamine maleate tablet and preparation method thereof

Info

Publication number: CN116159031B
Application number: CN202310149936.XA
Authority: CN
Inventors: 纪宇; 李亚栋; 张兴卫; 夏能斌; 刘烈强
Original assignee: Shanghai Guochuang Pharmaceutical Co ltd
Current assignee: Shanghai Guochuang Pharmaceutical Co ltd
Priority date: 2023-02-22
Filing date: 2023-02-22
Publication date: 2023-08-22
Anticipated expiration: 2043-02-22
Also published as: CN116159031A

Abstract

The invention provides a fluvoxamine maleate tablet and a preparation method thereof, belonging to the technical field of medicines, and comprising the following steps: preparing mesoporous hollow titanium dioxide nanospheres by adopting a sol-gel method, adding the nanospheres into magnesium aluminum silicate sol to prepare coated nanospheres, preparing fluvoxamine maleate into a self-emulsifying drug delivery system, dripping the self-emulsifying drug delivery system into the coated nanospheres, drying, sieving to prepare a solidified self-microemulsion system, uniformly mixing the solidified self-microemulsion system with auxiliary materials, and directly tabletting to prepare the fluvoxamine maleate tablets. The fluvoxamine maleate tablet prepared by the invention is prepared by adopting a direct tabletting method, so that the generation of impurities such as isomers and adducts in the fluvoxamine maleate in a humid or high-temperature environment is avoided, and meanwhile, the sustained-release tablet is prepared, so that the effective blood concentration is kept in a stable and durable state, the peak-valley concentration fluctuation phenomenon is reduced, the medication safety is improved, the adverse reaction phenomenon of the medicament is reduced or avoided, and the sustained-release tablet has a wide application prospect.

Description

Fluvoxamine maleate tablet and preparation method thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a fluvoxamine maleate tablet and a preparation method thereof.

Background

Fluvoxamine maleate (Fluvoxamine maleate) is (E) -5-methoxy-1- (4-trifluoromethylphenyl) -0- (2-amine hydroxamate) -1-pentanone maleate and has the following structural formula:

fluvoxamine maleate (fluvoxamine) is a 5-hydroxytryptamine reuptake inhibitor (SSRI) which is one of the most widely applied antidepressants clinically at present, and has the action mechanism of selectively inhibiting reuptake of 5-HT by a central nervous presynaptic membrane, increasing the 5-HT concentration at a synaptic cleft and achieving the purpose of antidepressant. Fluvoxamine maleate was originally marketed in europe in 1994, japan in 1999 and the united states in 2001. At present, only fluvoxamine maleate is sold in the domestic market as 'blue release' produced by the pharmaceutical production of thre in the netherlands and 'rui' produced by the pharmaceutical group company limited of lizhu. The active site of fluvoxamine maleate is 3 substituted fluoro groups on the phenyl ring, but 3 fluorine atoms also make fluvoxamine maleate very sensitive to water and temperature. In humid or high temperature environments, fluvoxamine maleate is prone to produce impurities such as isomers and adducts.

Therefore, in the process of fluvoxamine maleate preparation, the influence of factors such as temperature, humidity, auxiliary materials and the like on the stability of the fluvoxamine maleate preparation is required to be considered.

CN101332193B discloses a prescription of fluvoxamine maleate pharmaceutical composition and a preparation method thereof. The technology disclosed in the patent comprises the following steps: dry-pressing the mixed powder of fluvoxamine maleate, filler and disintegrating agent by a dry granulator, and granulating the obtained bars by a swinging granulator. Because the fluvoxamine maleate raw material is acicular or rod-shaped crystal, the fluvoxamine maleate raw material is easy to aggregate and difficult to mix uniformly in the dry granulation process, and therefore, the fluvoxamine maleate pharmaceutical composition disclosed in the patent has the defects of poor content uniformity and low stability.

JP2011088858A uses cyclodextrin as an auxiliary material to prepare fluvoxamine maleate tablets, and proves that the cyclodextrin can reduce the oral paralysis feeling generated when the fluvoxamine Sha Mingma maleate tablets are taken, but the patent does not disclose other auxiliary material components and proportions except the cyclodextrin, and does not relate to how to solve the stability problem of the fluvoxamine maleate tablets.

JP2011088858A uses a conventional wet granulation process. Wet granulation (Wet granulation) is a more traditional method of tableting, where multiple steps in the formulation process are Wet and hot, which is very detrimental to the stability of fluvoxamine maleate.

CN105832713B discloses a pharmaceutical composition containing fluvoxamine maleate and a preparation process thereof. In the patent, fluvoxamine maleate and pharmaceutically acceptable auxiliary materials are mixed and crushed into a mixture, and then the mixture is mixed with blank particles prepared in advance. The method partially solves the problem of unstable fluvoxamine maleate in the preparation method, so that the prepared fluvoxamine maleate pharmaceutical composition has the characteristics of good stability and low impurity growth rate compared with similar products of 'lanrelease' and 'relearn'. However, the preparation method involves preparing two parts, namely a "drug-containing part" and a "blank particle", respectively, and the preparation process is still relatively complicated.

The preparation methods described in the above patent documents all aim at solving the stability of the fluvoxamine maleate tablet, which uses different granulation processes or formulation prescriptions, but all suffer from this or that disadvantage. Thus, there remains a need in the art for a simple formulation process for preparing a fluvoxamine maleate pharmaceutical formulation of high stability.

Disclosure of Invention

The invention aims to provide a fluvoxamine maleate tablet and a preparation method thereof, wherein the fluvoxamine maleate tablet is prepared by adopting a direct tabletting method, does not need wet granulation, does not need humidification, heating and other processes, avoids the generation of isomer, addition product and other impurities in the fluvoxamine maleate in a humid or high-temperature environment, and simultaneously prepares a sustained-release tablet, so that the effective blood concentration is kept in a stable and durable state, the fluctuation of peak-valley concentration is reduced, the safety of medication is improved, the adverse reaction phenomenon of medicines is reduced or avoided, and the sustained-release tablet has wide application prospect.

The technical scheme of the invention is realized as follows:

the invention provides a preparation method of fluvoxamine maleate tablets, which comprises the following steps: preparing mesoporous hollow titanium dioxide nanospheres by adopting a sol-gel method, adding the nanospheres into magnesium aluminum silicate sol to prepare coated nanospheres, preparing fluvoxamine maleate into a self-emulsifying drug delivery system, dripping the self-emulsifying drug delivery system into the coated nanospheres, drying, sieving to prepare a solidified self-microemulsion system, uniformly mixing the solidified self-microemulsion system with auxiliary materials, and directly tabletting to prepare the fluvoxamine maleate tablets.

As a further improvement of the invention, the method comprises the following steps:

s1, preparing mesoporous hollow titanium dioxide nanospheres: dissolving tetrabutyl titanate and a lipophilic emulsifier in an organic solvent, adding an aqueous solution containing a mesoporous pore-forming agent and a hydrophilic emulsifier, mixing, emulsifying, centrifuging, washing and calcining to obtain mesoporous hollow titanium dioxide nanospheres;

preferably, the organic solvent is at least one selected from ethyl acetate, methyl acetate, butyl acetate and petroleum ether;

s2, preparing magnesium aluminum silicate sol: mixing the alkyl orthosilicate, the acid and the water uniformly to form gel, dropwise adding the aluminum salt and the magnesium salt solution, stirring and mixing uniformly, and dropwise adding ammonia water to prepare magnesium aluminum silicate sol;

s3, preparing the coated nanospheres: adding the mesoporous hollow titanium dioxide nanospheres prepared in the step S1 into the magnesium aluminum silicate sol prepared in the step S2, stirring and mixing uniformly, aging, washing, calcining, and ball milling to prepare coated nanospheres;

s4, preparation of a fluvoxamine maleate self-emulsifying drug delivery system: adding fluvoxamine maleate into a co-emulsifier Transcutol HP, then adding an oil phase Labrafil M1944CS and an emulsifier Cremophor EL, stirring to obtain a clear solution, and adding citric acid to obtain a fluvoxamine maleate self-emulsifying drug delivery system;

s5, curing the self-microemulsion: dropwise adding the fluvoxamine maleate self-emulsifying drug delivery system prepared in the step S4 into the coated nanospheres prepared in the step S3, stirring and mixing uniformly, drying and sieving to prepare a solidified self-microemulsion system;

s6, preparing auxiliary materials: uniformly mixing calcium hydrophosphate, microcrystalline cellulose, hydroxypropyl methylcellulose, lactose, compressible starch, sodium carboxymethyl starch and magnesium stearate to prepare auxiliary materials;

s7, preparing a slow release system: and (3) uniformly mixing the solidified self-microemulsion system prepared in the step (S5) and the auxiliary materials prepared in the step (S6), and directly tabletting to prepare the fluvoxamine maleate tablet.

As a further improvement of the present invention, the mesoporous porogen in step S1 is selected from at least one of cetyltrimethylammonium bromide, dodecyldimethylbenzyl ammonium chloride, octadecyldimethylbenzyl ammonium chloride, ethylene oxide-propylene oxide triblock copolymers PEO20-PPO70-PEO20, PEO106-PPO70-PEO106, preferably a mixture of cetyltrimethylammonium bromide and ethylene oxide-propylene oxide triblock copolymers PEO20-PPO70-PEO20, in a mass ratio of 3-5:2; the lipophilic emulsifier is at least one selected from span-20, span-40, span-60 and span-80; the hydrophilic emulsifier is at least one selected from Tween-20, tween-40, tween-60 and Tween-80; the mass ratio of the tetrabutyl titanate to the lipophilic emulsifier to the mesoporous pore-forming agent to the hydrophilic emulsifier is 10:0.1-0.3:0.5-1:0.2-0.4; the emulsifying condition is 12000-15000r/min, the time is 3-5min, the calcining temperature is 350-550 ℃ and the time is 2-3h.

As a further improvement of the invention, the alkyl orthosilicate in the step S2 is ethyl orthosilicate or methyl orthosilicate, and the mass ratio of the alkyl orthosilicate, the acid, the water, the aluminum salt and the magnesium salt is 10-15:0.5-1:30-50:3-5:1-3; the acid is hydrochloric acid or sulfuric acid with the concentration of 4-6 mol/L; the aluminum salt is at least one of aluminum chloride, aluminum sulfate and aluminum nitrate; the magnesium salt is at least one of magnesium chloride, magnesium nitrate and magnesium sulfate; the concentration of the ammonia water is 25-28wt%.

As a further improvement of the invention, in the step S3, the mass ratio of the mesoporous hollow titanium dioxide nanospheres to the magnesium aluminum silicate sol is 10:9-11, the aging time is 2-3h, the calcining temperature is 500-600 ℃ for 1-3h, and the ball milling time is 2-3h.

As a further improvement of the invention, the mass ratio of fluvoxamine maleate, co-emulsifier Transcutol HP, oil phase Labrafil M1944CS, emulsifier Cremophor EL and citric acid in the step S4 is 3-4:3-5:3-5:4-7:0.1-0.2.

As a further improvement of the invention, the mass ratio of the fluvoxamine maleate self-emulsifying drug delivery system to the coated nanospheres in the step S5 is 1:0.9-1.2; the mesh number of the sieving is 100-150 meshes.

As a further improvement of the invention, the mass ratio of the calcium hydrophosphate, the microcrystalline cellulose, the hydroxypropyl methylcellulose, the lactose, the compressible starch, the sodium carboxymethyl starch and the magnesium stearate in the step S6 is 7-10:12-15:15-20:5-10:3-5:4-6:0.1-0.2, wherein the hydroxypropyl methylcellulose is at least one selected from HPMC K4M, HPMC K15M, HPMC K100M and HPMC K100LV, preferably a mixture of HPMC K100M and HPMC K4M, and the mass ratio is 1:2-3.

As a further improvement of the invention, the mass ratio of the solidified self-microemulsion system to the auxiliary materials in the step S7 is 1:2-3.

The invention further provides the fluvoxamine maleate tablet prepared by the preparation method.

The invention has the following beneficial effects:

because depression patients and obsessive-compulsive patients generally need long-term medication, the fluvoxamine maleate is prepared into a slow release preparation, so that the frequency of taking the medicine by the patients can be reduced, and the compliance of the patients is improved; the effective blood concentration can be kept in a stable and durable state, and the phenomenon of peak-to-valley concentration fluctuation is reduced; meanwhile, the safety of medication is improved, and adverse reaction of the medication is reduced or avoided.

The calcium hydrophosphate is slightly dissolved in water, the calcium hydrophosphate is mixed into auxiliary materials and coated on the surface of the sustained-release tablet, after the sustained-release tablet is contacted with water or digestive juice, the calcium hydrophosphate is gradually dissolved, the calcium hydrophosphate is completely dissolved in about 2-4 hours, and a tiny pore canal is formed on a coating film so as to accelerate the entry of water and the outward diffusion of medicine solution, and further, the release curve of the sustained-release tablet can be adjusted. The release degree of the pellets can be adjusted by adding a proper amount of lactose, and after the lactose is slowly melted in water, a plurality of tiny pore channels are reserved in the hydroxypropyl methyl cellulose gel layer, so that the water is easy to permeate into the tablet, the dissolving process of the medicine in water is accelerated, the outward dissolving speed of the medicine through the gel layer is further accelerated, and the release of the fluvoxamine maleate in the tablet is more complete.

The hydroxypropyl methylcellulose with proper proportion is added to form a gel layer with proper thickness around the tablet, the speed of water entering the tablet layer is controlled, so that the dissolution speed is controlled, in addition, the effect of the hydroxypropyl methylcellulose on the release speed of the sustained and controlled release is larger, the higher the viscosity is, the slower the medicine diffuses to the periphery in the gel layer, the slower the medicine dissolves out to the outside, namely the longer the molecular chain forming the high polymer material is, the slower the dissolution speed of the gel by water or digestive juice is, the slow release effect is good, the hydroxypropyl methylcellulose with proper compound proportion and different viscosities is selected, and better hydrogen bonds are formed through the mixture of different molecular chain lengths, so that the release speed is further prolonged, the sustained and controlled release effect is improved, and the synergistic effect is realized.

The common domestic tablet preparation method is used for wet granulation, and in the process of wet granulation, the fluvoxamine maleate is contacted with water due to the wetting and drying processes, and meanwhile, the drug is unstable and byproducts are easy to generate due to the heating step. The invention adopts a direct powder tabletting method, does not need to be subjected to humidification and heating processes, greatly avoids the decomposition of raw materials and side reaction, improves the purity of the raw materials, reduces the generation of impurities and has better efficacy.

The coated nanospheres prepared by the invention take mesoporous hollow titanium dioxide nanospheres as a framework, a thicker magnesium aluminum silicate layer is coated and grown outside, the coated nanospheres have extremely large specific surface area and a porous structure, meanwhile, as the framework inner core is of a hollow structure, oily substances with 5-7 times of the self weight can be adsorbed, and meanwhile, high-quality tablets can be prepared under low pressure. Meanwhile, the fluvoxamine maleate can form a solid dispersion with the medicine, the dissolution rate of the medicine is improved, the fluvoxamine maleate exists in a partially crystalline form and is in a porous network structure of an aluminum magnesium silicate layer, intermolecular hydrogen bonding action possibly exists between the medicine and the carrier, and the dissolution rate of the solid dispersion is increased compared with that of a commercially available tablet. Meanwhile, the hardness of the tablet can be improved, the tabletability of the tablet can be improved, and the content uniformity of the low-dose medicine can be improved. Meanwhile, the titanium dioxide nanospheres are used as the framework, so that the whiteness of the tablet is improved, and the attractive effect is achieved.

The microcrystalline cellulose can play a certain role in disintegration, is beneficial to the diffusion of medicines in the sustained-release tablet, and simultaneously has a certain lubrication function by a self-microemulsion system, so that the microcrystalline cellulose has good powder properties and is beneficial to the tablet preparation by a powder direct compression method. The surface of the hydrophilic gel skeleton slow-release tablet is hydrated to form a gel layer after meeting water, the water continuously permeates into the tablet along with the time, the gel layer is continuously thickened, the release of the medicine from the tablet is stopped, and the purpose of controlling the release of the medicine is realized. Due to the interaction of the solidified self-microemulsion system and auxiliary materials, the binding force of the slow-release tablet powder is enhanced, the gaps among the powders are reduced, and the slow-release tablet is difficult to break through a gel layer formed after the material absorbs water. In addition, the pore canal of the coated nanospheres is deep and long, and the disintegrating agent needs to be added to enable the sustained-release tablet to absorb water and swell, so that the medicine in the pore canal is fully contacted with the release medium, and can be slowly released. The sodium carboxymethyl starch has remarkable water absorption expansion effect, and the expansion rate after water absorption is 290-320 times of the original volume, and is used as a disintegrating agent, thereby being beneficial to the release of the medicine.

The fluvoxamine maleate tablet prepared by the invention is prepared by adopting a direct tabletting method, does not need wet granulation, does not need humidification, heating and other processes, avoids the generation of isomer, addition product and other impurities in the fluvoxamine maleate in a moist or high-temperature environment, simultaneously prepares a sustained-release tablet, ensures that the effective blood concentration is kept in a stable and durable state, reduces the fluctuation of peak-valley concentration, improves the medication safety, reduces or avoids the occurrence of adverse reaction of the medicament, and has wide application prospect.

Drawings

In order to more clearly illustrate the embodiments of the invention or the technical solutions of the prior art, the drawings which are used in the description of the embodiments or the prior art will be briefly described, it being obvious that the drawings in the description below are only some embodiments of the invention, and that other drawings can be obtained according to these drawings without inventive faculty for a person skilled in the art.

Fig. 1 is a TEM image of the coated nanospheres produced in example 1.

Detailed Description

The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

The co-emulsifier Transcutol HP was diethylene glycol monoethyl ether, the oil phase Labrafil M1944CS was polyethylene glycol glyceride oleate, available from Gattefosse, france; the emulsifier Cremophor EL is polyoxyethylated 35 castor oil, available from BASF corporation, germany; hydroxypropyl methylcellulose (HPMC K100M, HPMC K4M), and compressible starch, purchased from Shanghai Chang as pharmaceutical adjuvants; microcrystalline cellulose is purchased from Shanghai Chang as a pharmaceutical adjuvant technology Co.

Example 1

The embodiment provides a preparation method of fluvoxamine maleate tablets, which comprises the following steps:

s1, preparing mesoporous hollow titanium dioxide nanospheres: dissolving 10 parts by weight of tetrabutyl titanate and 0.1 part by weight of span-20 in 70 parts by weight of ethyl acetate, adding 50 parts by weight of aqueous solution containing 0.5 part by weight of mesoporous pore-forming agent and 0.2 part by weight of tween-20, stirring and mixing for 15min, emulsifying for 3min 12000r/min, centrifuging for 15min 3000r/min, washing with clear water, and calcining at 350 ℃ for 2h to obtain mesoporous hollow titanium dioxide nanospheres;

the mesoporous pore-foaming agent is a mixture of hexadecyl trimethyl ammonium bromide and an oxyethylene-oxypropylene triblock copolymer PEO20-PPO70-PEO20, and the mass ratio is 3:2;

s2, preparing magnesium aluminum silicate sol: mixing 10 parts by weight of methyl orthosilicate, 0.5 part by weight of 4mol/L hydrochloric acid and 30 parts by weight of water, stirring for 15min to form gel, dropwise adding 25 parts by weight of solution containing 3 parts by weight of aluminum chloride and 1 part by weight of magnesium chloride, stirring and mixing for 15min, and dropwise adding 10 parts by weight of 25wt% ammonia water to prepare magnesium aluminum silicate sol;

s3, preparing the coated nanospheres: adding 10 parts by weight of the mesoporous hollow titanium dioxide nanospheres prepared in the step S1 into 9 parts by weight of the magnesium aluminum silicate sol prepared in the step S2, stirring and mixing for 15min, aging for 2h, washing with clear water, calcining for 1h at 500 ℃, and ball milling for 2h to prepare coated nanospheres; fig. 1 is a TEM image of the prepared coated nanospheres, which are hollow structures, and the periphery of the coated nanospheres is coated with a thick magnesium aluminum silicate layer, and the particle size is 400-700 nm.

S4, preparation of a fluvoxamine maleate self-emulsifying drug delivery system: 3 parts by weight of fluvoxamine maleate is added into 3 parts by weight of a co-emulsifier Transcutol HP, then 3 parts by weight of an oil phase Labrafil M1944CS and 4 parts by weight of an emulsifier Cremophor EL are added, the mixture is stirred into a clear solution, 0.1 part by weight of citric acid is added, and the stirring is carried out for 10 minutes, so that a fluvoxamine maleate self-emulsifying drug delivery system is prepared;

s5, curing the self-microemulsion: dropwise adding 10 parts by weight of fluvoxamine maleate self-emulsifying drug delivery system prepared in the step S4 into 9 parts by weight of coated nanospheres prepared in the step S3, stirring and mixing, naturally drying, and sieving with a 100-mesh sieve to prepare a solidified self-emulsifying system;

s6, preparing auxiliary materials: mixing 7 parts by weight of calcium hydrophosphate, 12 parts by weight of microcrystalline cellulose, 15 parts by weight of hydroxypropyl methylcellulose, 5 parts by weight of lactose, 3 parts by weight of compressible starch, 4 parts by weight of sodium carboxymethyl starch and 0.1 part by weight of magnesium stearate for 20 minutes, and stirring to prepare auxiliary materials;

the hydroxypropyl methylcellulose is a mixture of HPMC K100M and HPMC K4M, and the mass ratio is 1:2;

s7, preparing a slow release system: and (3) stirring and mixing 10 parts by weight of the curing self-microemulsion system prepared in the step (S5) and 20 parts by weight of the auxiliary materials prepared in the step (S6) for 30min, and directly tabletting to prepare the fluvoxamine maleate tablet.

Example 2

s1, preparing mesoporous hollow titanium dioxide nanospheres: dissolving 10 parts by weight of tetrabutyl titanate and 0.3 part by weight of span-60 in 100 parts by weight of methyl acetate, adding 60 parts by weight of aqueous solution containing 1 part by weight of mesoporous pore-forming agent and 0.4 part by weight of tween-60, stirring and mixing for 15min, emulsifying for 5min at 15000r/min, centrifuging for 15min at 3000r/min, washing with clear water, and calcining at 550 ℃ for 3h to obtain mesoporous hollow titanium dioxide nanospheres;

the mesoporous pore-foaming agent is a mixture of hexadecyl trimethyl ammonium bromide and an oxyethylene-oxypropylene triblock copolymer PEO20-PPO70-PEO20, and the mass ratio is 5:2;

s2, preparing magnesium aluminum silicate sol: 15 parts by weight of tetraethoxysilane, 1 part by weight of 6mol/L sulfuric acid and 50 parts by weight of water are mixed, stirred for 15 minutes to form gel, 25 parts by weight of solution containing 5 parts by weight of aluminum nitrate and 3 parts by weight of magnesium nitrate are dropwise added, stirred and mixed for 15 minutes, 10 parts by weight of 28wt% ammonia water is dropwise added, and magnesium aluminum silicate sol is prepared;

s3, preparing the coated nanospheres: adding 10 parts by weight of the mesoporous hollow titanium dioxide nanospheres prepared in the step S1 into 11 parts by weight of the magnesium aluminum silicate sol prepared in the step S2, stirring and mixing for 15min, aging for 3h, washing with clear water, calcining for 3h at 600 ℃, and ball milling for 3h to prepare coated nanospheres;

s4, preparation of a fluvoxamine maleate self-emulsifying drug delivery system: adding 4 parts by weight of fluvoxamine maleate into 5 parts by weight of a co-emulsifier Transcutol HP, then adding 5 parts by weight of an oil phase Labrafil M1944CS and 7 parts by weight of an emulsifier Cremophor EL, stirring to form a clear solution, adding 0.2 part by weight of citric acid, and stirring for 10min to prepare a fluvoxamine maleate self-emulsifying drug delivery system;

s5, curing the self-microemulsion: dropwise adding 10 parts by weight of fluvoxamine maleate self-emulsifying drug delivery system prepared in the step S4 into 12 parts by weight of coated nanospheres prepared in the step S3, stirring and mixing, naturally drying, and sieving with a 150-mesh sieve to prepare a solidified self-microemulsion system;

s6, preparing auxiliary materials: 10 parts by weight of calcium hydrophosphate, 15 parts by weight of microcrystalline cellulose, 20 parts by weight of hydroxypropyl methylcellulose, 10 parts by weight of lactose, 5 parts by weight of compressible starch, 6 parts by weight of sodium carboxymethyl starch and 0.2 part by weight of magnesium stearate are stirred and mixed for 20 minutes to prepare auxiliary materials;

the hydroxypropyl methylcellulose is a mixture of HPMC K100M and HPMC K4M, and the mass ratio is 1:3;

s7, preparing a slow release system: and (3) stirring and mixing 10 parts by weight of the curing self-microemulsion system prepared in the step (S5) and 30 parts by weight of the auxiliary materials prepared in the step (S6) for 30min, and directly tabletting to prepare the fluvoxamine maleate tablet.

Example 3

s1, preparing mesoporous hollow titanium dioxide nanospheres: dissolving 10 parts by weight of tetrabutyl titanate and 0.2 part by weight of span-80 in 85 parts by weight of butyl acetate, adding 55 parts by weight of aqueous solution containing 0.7 part by weight of mesoporous pore-forming agent and 0.3 part by weight of tween-80, stirring and mixing for 15min, emulsifying for 4min at 13500r/min, centrifuging for 15min at 3000r/min, washing with clear water, and calcining at 450 ℃ for 2.5h to obtain mesoporous hollow titanium dioxide nanospheres;

the mesoporous pore-foaming agent is a mixture of hexadecyl trimethyl ammonium bromide and an oxyethylene-oxypropylene triblock copolymer PEO20-PPO70-PEO20, and the mass ratio is 4:2;

s2, preparing magnesium aluminum silicate sol: mixing 12 parts by weight of tetraethoxysilane, 0.7 part by weight of 5mol/L hydrochloric acid and 40 parts by weight of water, stirring for 15min to form gel, dropwise adding 25 parts by weight of solution containing 4 parts by weight of aluminum sulfate and 2 parts by weight of magnesium sulfate, stirring and mixing for 15min, and dropwise adding 10 parts by weight of 27wt% ammonia water to prepare magnesium aluminum silicate sol;

s3, preparing the coated nanospheres: adding 10 parts by weight of the mesoporous hollow titanium dioxide nanospheres prepared in the step S1 into 10 parts by weight of the magnesium aluminum silicate sol prepared in the step S2, stirring and mixing for 15min, aging for 2.5h, washing with clear water, calcining at 550 ℃ for 2h, and ball-milling for 2.5h to prepare coated nanospheres;

s4, preparation of a fluvoxamine maleate self-emulsifying drug delivery system: adding 3.5 parts by weight of fluvoxamine maleate into 4 parts by weight of a coemulsifier Transcutol HP, then adding 4 parts by weight of an oil phase Labrafil M1944CS and 6 parts by weight of an emulsifier Cremophor EL, stirring to form a clear solution, adding 0.15 part by weight of citric acid, and stirring for 10min to prepare a fluvoxamine maleate self-emulsifying drug delivery system;

s5, curing the self-microemulsion: dropwise adding 10 parts by weight of fluvoxamine maleate self-emulsifying drug delivery system prepared in the step S4 into 10 parts by weight of coated nanospheres prepared in the step S3, stirring and mixing, naturally drying, and sieving with a 150-mesh sieve to prepare a solidified self-microemulsion system;

s6, preparing auxiliary materials: 8.5 parts by weight of calcium hydrophosphate, 13.5 parts by weight of microcrystalline cellulose, 17 parts by weight of hydroxypropyl methylcellulose, 7 parts by weight of lactose, 4 parts by weight of compressible starch, 5 parts by weight of sodium carboxymethyl starch and 0.15 part by weight of magnesium stearate are stirred and mixed for 20 minutes to prepare auxiliary materials;

the hydroxypropyl methylcellulose is a mixture of HPMC K100M and HPMC K4M, and the mass ratio is 1:2.5;

s7, preparing a slow release system: and (3) stirring and mixing 10 parts by weight of the curing self-microemulsion system prepared in the step (S5) and 25 parts by weight of the auxiliary materials prepared in the step (S6) for 30min, and directly tabletting to prepare the fluvoxamine maleate tablet.

Example 4

The difference compared to example 3 is that the mesoporous porogen is a single cetyltrimethylammonium bromide.

Example 5

The difference compared to example 3 is that the mesoporous porogen is a single ethylene oxide-propylene oxide triblock copolymer PEO20-PPO70-PEO20.

Example 6

The difference compared to example 3 is that the hydroxypropyl methylcellulose is a single HPMC K100M.

Example 7

The difference compared to example 3 is that the hydroxypropyl methylcellulose is a single HPMC K4M.

Comparative example 1

The difference compared to example 3 is that the mesoporous porogen is not added in step S1.

Comparative example 2

The difference from example 3 is that steps S1 and S3 are not performed.

Comparative example 3

The difference from example 3 is that aluminum sulfate is not added in step S2.

Comparative example 4

In comparison with example 3, the difference is that magnesium sulfate is not added in step S2.

Comparative example 5

In comparison with example 3, the difference is that aluminum sulfate and magnesium sulfate are not added in step S2.

Comparative example 6

The difference from example 3 is that steps S2 and S3 are not performed.

Comparative example 7

Compared with example 3, the difference is that steps S4 and S5 are not performed, and the fluvoxamine maleate and the coated nanospheres are uniformly mixed.

Comparative example 8

In comparison with example 3, the difference is that no hydroxypropyl methylcellulose was added in step S6.

Comparative example 9

The difference from example 3 is that no calcium hydrogen phosphate was added in step S6.

Comparative example 10

In comparison with example 3, the difference is that microcrystalline cellulose is not added in step S6.

Comparative example 11

In comparison with example 3, the difference is that sodium carboxymethyl starch is not added in step S6.

Comparative example 12

In comparison with example 3, the process is different in that step S7 is not performed, and wet granulation is performed and then tabletting is performed.

Test example 1

The fluvoxamine maleate tablets prepared in examples 1-7 and comparative examples 1-12, as well as commercially available products, were subjected to accelerated stability comparison experiments by being left for 90 days at 40℃under 75% RH conditions, and the impurity (addition product, isomer and fluvo Sha Mingtong) contents were measured at 0 month, 1 month and 3 months, respectively. The content detection method of the Z-isomer, the addition product and the fluvoxamine ketone comprises the following steps: the measurement is carried out according to the VD high performance liquid chromatography of the second appendix of Chinese pharmacopoeia.

The results are shown in Table 1.

TABLE 1

As shown in the table above, the Z-isomer, adduct and fluvoxamine maleate tablet prepared in examples 1-3 of the present invention have lower content of fluvoxamine ketone and lower growth rate than that of commercial product blue release, which indicates that the quality of the sample prepared by the optimized process and prescription of the present invention is superior to that of the original grinding medicine.

Test example 2

According to the first method (basket method) under the fourth rule 0931 of the pharmacopoeia of the people's republic of China, the release conditions of the fluvoxas maleate tablets prepared in examples 1-7 and comparative examples 1-12 under the condition of trough leakage are respectively examined by taking 0.4% Sodium Dodecyl Sulfate (SDS) solution or 250mL of distilled water as a release medium, the temperature (37.0+/-0.5) DEG C, the rotating speed is 100r/min, 3mL of the solution is respectively taken at 2, 6 and 12h, the equivalent release medium is immediately supplemented, the sample is diluted to 10mL, the release medium is taken as a blank control, the absorption degree is measured at 249nm, and the drug release percentage (%) is calculated.

The results are shown in Table 2.

TABLE 2

As shown in the table above, the fluvoxamine maleate tablets prepared in the examples 1-3 have a good sustained and controlled release effect, and the cumulative release rate of 12 hours is more than 90%.

Examples 4 and 5 in comparison with example 3, the mesoporous porogen was either a single cetyltrimethylammonium bromide or an oxyethylene-oxypropylene triblock copolymer PEO20-PPO70-PEO20. Comparative example 1 in contrast to example 3, the mesoporous porogen was not added in step S1. The slow release effect is reduced. The mesoporous pore-forming agent is used in a synergistic combination way, so that the pore canal of the prepared mesoporous hollow titanium dioxide nanospheres is deep and long, the disintegrating agent is required to be added to enable the sustained release tablet to absorb water and swell, and the medicine in the pore canal is fully contacted with a release medium, so that the sustained release tablet can be released slowly.

Examples 6 and 7 compared to example 3, the hydroxypropyl methylcellulose was either HPMC K100M or HPMC K4M alone. Comparative example 8 in contrast to example 3, no hydroxypropyl methylcellulose was added in step S6. The impurity content is improved, and the slow release effect is reduced. The hydroxypropyl methylcellulose with proper proportion is added to form a gel layer with proper thickness around the tablet, the speed of water entering the tablet layer is controlled, so that the dissolution speed is controlled, in addition, the effect of the hydroxypropyl methylcellulose on the release speed of the sustained and controlled release is larger, the higher the viscosity is, the slower the medicine diffuses to the periphery in the gel layer, the slower the medicine dissolves out to the outside, namely the longer the molecular chain forming the high polymer material is, the slower the dissolution speed of the gel by water or digestive juice is, the slow release effect is good, the hydroxypropyl methylcellulose with proper compound proportion and different viscosities is selected, and better hydrogen bonds are formed through the mixture of different molecular chain lengths, so that the release speed is further prolonged, the sustained and controlled release effect is improved, and the synergistic effect is realized.

Comparative example 2 compared with example 3, steps S1, S3 were not performed. In comparative examples 3 and 4, in comparison with example 3, aluminum sulfate or magnesium sulfate was not added in step S2. Comparative example 5 in comparison with example 3, no aluminum sulfate and no magnesium sulfate were added in step S2. Comparative example 6 compared with example 3, steps S2, S3 were not performed. The impurity content is improved, and the slow release effect is reduced. The coated nanospheres prepared by the invention take mesoporous hollow titanium dioxide nanospheres as a framework, a thicker magnesium aluminum silicate layer is coated and grown outside, the coated nanospheres have extremely large specific surface area and a porous structure, meanwhile, as the framework inner core is of a hollow structure, oily substances with 5-7 times of the self weight can be adsorbed, and meanwhile, high-quality tablets can be prepared under low pressure. Meanwhile, the fluvoxamine maleate can form a solid dispersion with the medicine, the dissolution rate of the medicine is improved, the fluvoxamine maleate exists in a partially crystalline form and is in a porous network structure of an aluminum magnesium silicate layer, intermolecular hydrogen bonding action possibly exists between the medicine and the carrier, and the dissolution rate of the solid dispersion is increased compared with that of a commercially available tablet. Meanwhile, the hardness of the tablet can be improved, the tabletability of the tablet can be improved, and the content uniformity of the low-dose medicine can be improved. Meanwhile, the titanium dioxide nanospheres are used as the framework, so that the whiteness of the tablet is improved, and the attractive effect is achieved.

Comparative example 7 in comparison with example 3, steps S4 and S5 were not performed, and fluvoxamine maleate was uniformly mixed with the coated nanospheres. The slow release effect is reduced. The self-microemulsion drug delivery system can improve the solubility of insoluble drugs, remarkably improve the dissolution and bioavailability of the drugs, and simultaneously has a certain lubrication effect when being solidified.

Comparative example 9 in contrast to example 3, no calcium hydrogen phosphate was added in step S6. The impurity content is improved, and the slow release effect is reduced. The calcium hydrophosphate is slightly dissolved in water, the calcium hydrophosphate is mixed into auxiliary materials and coated on the surface of the sustained-release tablet, after the sustained-release tablet is contacted with water or digestive juice, the calcium hydrophosphate is gradually dissolved, the calcium hydrophosphate is completely dissolved in about 2-4 hours, and a tiny pore canal is formed on a coating film so as to accelerate the entry of water and the outward diffusion of medicine solution, and further, the release curve of the sustained-release tablet can be adjusted. The release degree of the pellets can be adjusted by adding a proper amount of lactose, and after the lactose is slowly melted in water, a plurality of tiny pore channels are reserved in the hydroxypropyl methyl cellulose gel layer, so that the water is easy to permeate into the tablet, the dissolving process of the medicine in water is accelerated, the outward dissolving speed of the medicine through the gel layer is further accelerated, and the release of the fluvoxamine maleate in the tablet is more complete.

In comparative example 10, as compared with example 3, microcrystalline cellulose was not added in step S6. The slow release effect is reduced. The microcrystalline cellulose can play a certain role in disintegration, is beneficial to the diffusion of medicines in the sustained-release tablet, and simultaneously has a certain lubrication function by a self-microemulsion system, so that the microcrystalline cellulose has good powder properties and is beneficial to the tablet preparation by a powder direct compression method.

Comparative example 11 in contrast to example 3, sodium carboxymethyl starch was not added in step S6. The impurity content is improved, and the slow release effect is reduced. The sodium carboxymethyl starch has remarkable water absorption expansion effect, and the expansion rate after water absorption is 290-320 times of the original volume, and is used as a disintegrating agent, thereby being beneficial to the release of the medicine.

Comparative example 12 compared to example 3, step S7 was not performed, and wet granulation was used and tabletting was performed. The impurity content is obviously improved. The common domestic tablet preparation method is used for wet granulation, and in the process of wet granulation, the fluvoxamine maleate is contacted with water due to the wetting and drying processes, and meanwhile, the drug is unstable and byproducts are easy to generate due to the heating step. The invention adopts a direct powder tabletting method, does not need to be subjected to humidification and heating processes, greatly avoids the decomposition of raw materials and side reaction, improves the purity of the raw materials, reduces the generation of impurities and has better efficacy.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims

1. A method for preparing fluvoxamine maleate tablets, which is characterized by comprising the following steps:

the mesoporous pore-foaming agent is at least one selected from hexadecyl trimethyl ammonium bromide, dodecyl dimethyl benzyl ammonium chloride, octadecyl dimethyl benzyl ammonium chloride, ethylene oxide-propylene oxide triblock copolymer PEO20-PPO70-PEO20 and PEO106-PPO70-PEO 106; the lipophilic emulsifier is at least one selected from span-20, span-40, span-60 and span-80; the hydrophilic emulsifier is at least one selected from Tween-20, tween-40, tween-60 and Tween-80;

s2, preparing magnesium aluminum silicate sol: mixing the alkyl orthosilicate, the acid and the water uniformly to form gel, dropwise adding the aluminum salt and the magnesium salt solution, stirring and mixing uniformly, and dropwise adding ammonia water to prepare magnesium aluminum silicate sol; the mass ratio of the alkyl orthosilicate to the acid to the water to the aluminum salt to the magnesium salt is 10-15:0.5-1:30-50:3-5:1-3; the aluminum salt is at least one of aluminum chloride, aluminum sulfate and aluminum nitrate; the magnesium salt is at least one of magnesium chloride, magnesium nitrate and magnesium sulfate;

2. The preparation method according to claim 1, wherein the mesoporous pore-forming agent in the step S1 is a mixture of cetyltrimethylammonium bromide and an oxyethylene-oxypropylene triblock copolymer PEO20-PPO70-PEO20, and the mass ratio is 3-5:2; the mass ratio of the tetrabutyl titanate to the lipophilic emulsifier to the mesoporous pore-forming agent to the hydrophilic emulsifier is 10:0.1-0.3:0.5-1:0.2-0.4; the emulsifying condition is 12000-15000r/min, the time is 3-5min, the calcining temperature is 350-550 ℃ and the time is 2-3h.

3. The preparation method according to claim 1, wherein the alkyl orthosilicate in step S2 is ethyl orthosilicate or methyl orthosilicate, and the acid is 4-6mol/L hydrochloric acid or sulfuric acid; the concentration of the ammonia water is 25-28wt%.

4. The preparation method according to claim 1, wherein in the step S3, the mass ratio of the mesoporous hollow titanium dioxide nanospheres to the magnesium aluminum silicate sol is 10:9-11, the aging time is 2-3 hours, the calcining temperature is 500-600 ℃ for 1-3 hours, and the ball milling time is 2-3 hours.

5. The preparation method according to claim 1, wherein the mass ratio of fluvoxamine maleate, co-emulsifier Transcutol HP, oil phase Labrafil M1944CS, emulsifier Cremophor EL, citric acid in step S4 is 3-4:3-5:3-5:4-7:0.1-0.2.

6. The preparation method of claim 1, wherein the mass ratio of the fluvoxamine maleate self-emulsifying drug delivery system to the coated nanospheres in step S5 is 1:0.9-1.2; the mesh number of the sieving is 100-150 meshes.

7. The preparation method according to claim 1, wherein the mass ratio of calcium hydrogen phosphate, microcrystalline cellulose, hydroxypropyl methylcellulose, lactose, compressible starch, sodium carboxymethyl starch, magnesium stearate in step S6 is 7-10:12-15:15-20:5-10:3-5:4-6:0.1-0.2, wherein the hydroxypropyl methylcellulose is at least one selected from HPMC K4M, HPMC K15M, HPMC K100M and HPMC K100 LV.

8. The preparation method according to claim 7, wherein the hydroxypropyl methylcellulose is a mixture of HPMC K100M and HPMC K4M in a mass ratio of 1:2-3.

9. The preparation method according to claim 1, wherein the mass ratio of the solidified self-microemulsion system to the auxiliary materials in the step S7 is 1:2-3.

10. A fluvoxamine maleate tablet prepared by the process of any of claims 1 to 9.