A kind of celecoxib solid self-microemulsification nanoparticles and its preparation method and application

Abstract

The invention discloses a celecoxib solid self-emulsifying nano-microsphere and a preparation method and application thereof. The celecoxib solid self-emulsifying nano-microsphere of the invention comprises an outer shell and an inner core arranged in the outer shell, wherein the raw materials for preparing the outer shell comprise: a polymer and a solvent; and the raw materials for preparing the inner core comprise: celecoxib, an oil phase, an emulsifier, an emulsifier and a precipitation inhibitor. The celecoxib solid self-emulsifying nano-microsphere has the advantages of good dispersibility, uniform particle size and large drug loading, and can be rapidly emulsified when encountering an aqueous environment of the gastrointestinal tract, significantly improving the dissolution rate and oral bioavailability of celecoxib. In addition, the preparation process of the invention is simple, there is no heating process, and the obtained product has stable quality, and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, and in particular to celecoxib solid self-microemulsification nanospheres and a preparation method and application thereof. Background Art

[0002] Celecoxib (CXB) has a molecular formula of C 17 H 14 F3N3O2S, with a molecular weight of 381.37, is a white or off-white powder with adhesive properties, but its bulk density and compressibility are very low, and its compressibility is poor and it is not easy to crush into smaller particles. Celecoxib, as a specific cyclooxygenase-2 (COX-2) inhibitor, can prevent the production of prostaglandins (PGs), thereby achieving anti-inflammatory, analgesic and anti-tumor effects, but celecoxib is almost insoluble in water, which brings many inconveniences to its oral drug delivery.

[0003] In the related art, in order to solve the solubility problem of drugs, new dosage forms are often used to improve the solubility of drugs. Common dosage forms include liposomes, solid dispersions, nano lipid carriers, self-microemulsions, etc. Self-microemulsion drug delivery systems (SMEDDS) are a thermodynamically stable system composed of drugs, oil phases, emulsifiers, and co-emulsifiers. The system can form water-in-oil microemulsions (particle size <100nm) after slight stirring in water or oral administration through gastrointestinal peristalsis at room temperature. SMEDDS can load drugs into mixed micelles well, by improving the solubility of poorly soluble drugs, increasing the permeability of cells, stimulating lymphatic transport, inhibiting the oral absorption-promoting mechanisms such as the efflux effect of the intestine, and thus improving the bioavailability of drugs. However, in related studies, the obtained celecoxib self-microemulsion still has the disadvantages of inconvenient storage, limited dosage forms, and poor stability.

[0004] Therefore, there is an urgent need to seek a celecoxib solid self-microemulsification nanosphere with good stability and simple preparation method. Summary of the invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the present invention provides a celecoxib solid self-microemulsification nano-microsphere and a preparation method and application thereof. The preparation method is simple and suitable for industrial production, and the prepared celecoxib solid self-microemulsification nano-microsphere has good stability and is easy to absorb.

[0006] The invention also provides a method for preparing celecoxib solid self-microemulsion nano-microspheres.

[0007] The present invention also provides an application of the celecoxib solid self-microemulsification nano-microspheres and the preparation method thereof in the preparation of sustained-release drugs.

[0008] In a first aspect of the present invention, there is provided a celecoxib solid self-microemulsification nanosphere, characterized in that it comprises an outer shell and an inner core arranged in the outer shell, wherein the raw materials for preparing the outer shell comprise: a high molecular polymer and a solvent;

[0009] The raw materials for preparing the inner core include: celecoxib, oil phase, emulsifier, co-emulsifier and precipitation inhibitor.

[0010] The celecoxib solid self-microemulsification nanospheres according to the embodiments of the present invention have at least the following beneficial effects:

[0011] (1) The celecoxib solid self-emulsified nanospheres prepared by the present invention have a round and smooth surface, good dispersibility, and a uniform particle size of about 200 to 300 nm. The average particle size of the microemulsion formed after emulsification is about 89 nm. Secondly, the celecoxib solid self-emulsified nanospheres prepared by the present invention have a large drug loading capacity, can be rapidly emulsified when encountering the aqueous environment of the gastrointestinal tract, and the dissolution rate is significantly higher than that of the raw material drug, and the oral bioavailability is significantly improved.

[0012] (2) The celecoxib solid self-microemulsion prepared by the present invention has good stability, is easy to store, and can be further prepared into other dosage forms. The properties are stable within 3 months, and the appearance, drug loading and in vitro release rate do not change significantly.

[0013] In some embodiments of the present invention, the mass volume ratio of the high molecular weight polymer to the solvent is 25-40 mg:1 mL.

[0014] Preferably, the mass volume ratio of the high molecular weight polymer to the solvent is 30 mg:1 mL.

[0015] In some embodiments of the present invention, the high molecular polymer is selected from at least one of acrylic resin RL100 and polyvinyl pyrrolidone;

[0016] Preferably, the high molecular polymer is acrylic resin RL100 and polyvinyl pyrrolidone;

[0017] Preferably, the high molecular polymer is selected from acrylic resin RL100 and polyvinyl pyrrolidone in a mass ratio of 4 to 6:1;

[0018] More preferably, the high molecular polymer is selected from acrylic resin RL100 and polyvinyl pyrrolidone in a mass ratio of 5:1.

[0019] In some embodiments of the present invention, the solvent is selected from at least one of methanol, isopropanol, ethanol, and water;

[0020] Preferably, the solvent is a mixture of isopropanol, ethanol and water;

[0021] Preferably, the volume ratio of isopropanol, ethanol and water is 5:3:1-3;

[0022] More preferably, the volume ratio of isopropanol, ethanol and water is 5:3:2.

[0023] In some embodiments of the present invention, the raw materials for preparing the inner core include, by mass percentage: 8% to 10% celecoxib, 10% to 40% oil phase, 30% to 60% emulsifier, 15% to 30% co-emulsifier and 2% to 4% precipitation inhibitor.

[0024] In some embodiments of the present invention, the raw materials for preparing the inner core include, by mass percentage: 8% to 10% celecoxib, 10% to 30% oil phase, 40% to 60% emulsifier, 15% to 30% co-emulsifier and 2% to 4% precipitation inhibitor.

[0025] In some embodiments of the present invention, the oil phase is selected from at least one of medium chain triglycerides, castor oil, oleic acid, ethyl oleate, isopropyl myristate, and triacetin;

[0026] Preferably, the oil phase is selected from at least one of medium chain triglycerides, isopropyl myristate, and triacetin;

[0027] More preferably, the oil phase is medium chain triglycerides.

[0028] In some embodiments of the present invention, the emulsifier is selected from at least one of Tween 80, Tween 20, polyoxyethylene 35 castor oil, and polyoxyethylene hydrogenated castor oil;

[0029] Preferably, the emulsifier is selected from at least one of polyoxyethylene 35 castor oil and polyoxyethylene hydrogenated castor oil;

[0030] More preferably, the emulsifier is polyoxyethylene 35 castor oil.

[0031] In some embodiments of the present invention, the co-emulsifier is selected from at least one of 1,2-propylene glycol, polyethylene glycol 400, polyethylene glycol 300, and diethylene glycol monoethyl ether;

[0032] Preferably, the co-emulsifier is selected from at least one of polyethylene glycol 400, polyethylene glycol 300, and diethylene glycol monoethyl ether;

[0033] More preferably, the co-emulsifier is diethylene glycol monoethyl ether.

[0034] In some embodiments of the present invention, the precipitation inhibitor is selected from at least one of PVPK60, PVPK90, hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (CMC-Na), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (soluplus);

[0035] Preferably, the precipitation inhibitor is selected from at least one of hydroxypropylmethylcellulose and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;

[0036] More preferably, the precipitation inhibitor is a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0037] In some embodiments of the present invention, the raw material volume ratio of the outer shell to the inner core is 1:1.4-2.0.

[0038] Preferably, the raw material volume ratio of the shell to the core is 1:1.6-2.0;

[0039] More preferably, the raw material volume ratio of the outer shell to the inner core is 1:1.6-1.8.

[0040] The second aspect of the present invention provides a method for preparing celecoxib solid self-microemulsion nanospheres, comprising the following preparation steps:

[0041] Step S1, mixing celecoxib, an oil phase, an emulsifier, a co-emulsifier and a precipitation inhibitor to obtain a celecoxib liquid self-microemulsion;

[0042] Step S2, dispersing the high molecular polymer in a solvent to obtain an electrostatic spray external axis solution;

[0043] Step S3, using the celecoxib liquid self-microemulsion as the electrostatic spray inner axis solution and the electrostatic spray outer axis solution for electrostatic spray granulation to obtain the celecoxib solid self-microemulsion nanospheres.

[0044] The preparation method according to the embodiment of the present invention has at least the following beneficial effects: the present invention adopts a coaxial electrostatic spraying process to prepare celecoxib solid self-emulsification nanospheres, and the process has the advantages of simple operation, high degree of industrialization, stable product quality, no heating process, and a wide range of applications. The celecoxib solid self-emulsification prepared by the process not only has the advantages of liquid self-emulsification, but also can improve the stability of the self-emulsification. The self-emulsification microspheres can be made into various solid dosage forms according to actual needs to meet the needs of dosage form development.

[0045] In some embodiments of the present invention, the specific method of mixing celecoxib, oil phase, emulsifier, co-emulsifier and precipitation inhibitor in step S1 comprises:

[0046] The emulsifier, oil phase, celecoxib and precipitation inhibitor are sequentially mixed with the co-emulsifier.

[0047] Preferably, the mixing temperature is 25° C. to 40° C., the mixing stirring rate is 100 rpm to 400 rpm, and the stirring time is 20 min to 40 min.

[0048] More preferably, the mixing temperature is 28° C. to 37° C., the mixing stirring rate is 250 rpm to 400 rpm, and the stirring time is 25 min to 35 min.

[0049] In some embodiments of the present invention, the electrostatic spray endo-axis solution is injected at a flow rate of 1.5 to 2.1 mL / h for electrostatic spray granulation;

[0050] The electrostatic spray external axis solution is injected at a flow rate of 2.7-3.4 mL / h to perform electrostatic spray granulation.

[0051] In some embodiments of the present invention, the inner diameter of the electrostatic spray nozzle is 0.25 mm to 0.84 mm;

[0052] Preferably, the inner diameter of the electrostatic spray nozzle is 0.40 mm to 0.6 mm;

[0053] Preferably, the inner diameter of the electrostatic spray nozzle is 0.45 mm to 0.48 mm.

[0054] In some embodiments of the present invention, the distance between the electrostatic spray nozzle and the receiving plate is 10 cm to 20 cm.

[0055] In some embodiments of the present invention, the working range of the electrostatic spray is 13 kV to 25 kV.

[0056] The third aspect of the present invention provides the use of celecoxib solid self-microemulsification nanospheres and the preparation method thereof in the preparation of sustained-release drugs.

[0057] The application according to the embodiment of the present invention has at least the following beneficial effects: the celecoxib solid self-emulsification nanospheres prepared by the present invention can significantly improve the oral absorption of celecoxib, and the polymer in the solid self-emulsion also has the effect of enhancing stability and promoting absorption.

[0058] Other features and advantages of the present invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] The present invention will be further described below with reference to the accompanying drawings and embodiments, wherein:

[0060] Figure 1 This is a transmission electron microscope observation image of the celecoxib liquid self-microemulsion in Example 1 of the present invention;

[0061] Figure 2 This is a SEM electron microscope image of the celecoxib solid self-microemulsion nanospheres of Example 1 of the present invention.

[0062] Figure 3 The dissolution curves of the celecoxib liquid self-microemulsion and celecoxib solid nanospheres of the present invention are shown.

[0063] Figure 4 The plasma drug-time curves of celecoxib, celecoxib liquid self-microemulsion and celecoxib solid self-microemulsion nanospheres of the present invention are shown. DETAILED DESCRIPTION

[0064] The following will be combined with the embodiments to clearly and completely describe the concept of the present invention and the technical effects produced, so as to fully understand the purpose, characteristics and effects of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative work are all within the scope of protection of the present invention.

[0065] In the description of the present invention, the description with reference to the terms "one embodiment", "some embodiments", "illustrative embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner.

[0066] If the specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. If the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0067] Example 1

[0068] This embodiment provides a celecoxib solid self-microemulsification nanosphere, and the raw materials for its preparation are shown in Table 1:

[0069] Table 1 Example 1 Celecoxib solid self-emulsified nanospheres preparation raw materials

[0070]

[0071] This embodiment also provides a method for preparing the above-mentioned celecoxib solid self-microemulsion nanospheres, which specifically comprises the following steps:

[0072] (1) Preparation of celecoxib liquid self-microemulsion: According to the content ratio in Table 1, 10 g of medium-chain triglycerides, polyoxyethylene 35 castor oil, and diethylene glycol monoethyl ether were weighed, mixed, and placed in a 37° C. water bath. After stirring for 30 min at a stirring speed of 400 r / min, 1 g of celecoxib was added and stirred until dissolved. Then, 200 mg of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer was added and stirred for 30 min to obtain a light yellow, clear and transparent celecoxib liquid self-microemulsion.

[0073] (2) Preparation of electrostatic spray inner and outer axis solutions: 10 mL of solvent (isopropanol: ethanol: water = 5:3:2, v / v) was measured, and 50 mg of acrylic resin RL100 and 250 mg of polyvinyl pyrrolidone were accurately weighed and added, and stirred for 2 h until the solution was uniform, thereby obtaining the electrostatic spray outer axis solution; 10 mL of celecoxib liquid self-microemulsion was measured, which was the electrostatic spray inner axis solution.

[0074] (3) Preparation of celecoxib solid self-emulsification microspheres: The electrostatic spray working liquid was placed in two syringes respectively, and the working liquid was slowly injected using a constant current pump to control the flow rate. The inner axis injection speed was 1.7 mL / h, and the outer axis injection speed was 2.8 mL / h. The electrostatic spray working voltage was 17 kV, the pinhole inner diameter was 0.48 mm, and the distance between the nozzle and the receiving plate was 18 cm. After the inner axis working liquid was sprayed out from the nozzle, it was wrapped by the outer axis working liquid and solidified into self-emulsification microspheres. Under the action of the electric field force, it was adsorbed on the receiving plate. The aluminum foil placed on the receiving plate was peeled off and scraped to obtain celecoxib solid self-emulsification microspheres.

[0075] Example 2

[0076] This embodiment provides a celecoxib solid self-microemulsification nanosphere, and the raw materials for its preparation are shown in Table 2:

[0077] Table 2 Example 2 Celecoxib solid self-emulsified nanospheres preparation raw materials

[0078]

[0079] This embodiment also provides a method for preparing the above-mentioned celecoxib solid self-microemulsion nanospheres, which specifically comprises the following steps:

[0080] (1) Preparation of celecoxib liquid self-microemulsion: According to the content ratio in Table 2, 10 g of medium-chain triglycerides, polyoxyethylene 35 castor oil, and diethylene glycol monoethyl ether were weighed, mixed, and placed in a 37° C. water bath. After stirring for 30 min at a stirring speed of 400 r / min, 1 g of celecoxib was added and stirred until dissolved. Then, 200 mg of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer was added and stirred for 30 min to obtain a light yellow, clear and transparent celecoxib liquid self-microemulsion.

[0081] (2) Preparation of electrostatic spray inner and outer axis solutions: 10 mL of solvent (isopropanol: ethanol: water = 5:3:2, v / v) was measured, and 50 mg of acrylic resin RL100 and 250 mg of polyvinyl pyrrolidone were accurately weighed and added, and stirred for 2 h until the solution was uniform, thereby obtaining the electrostatic spray outer axis solution; 10 mL of celecoxib liquid self-microemulsion was measured, which was the electrostatic spray inner axis solution.

[0082] (3) Preparation of celecoxib solid self-emulsification microspheres: The electrostatic spray working liquid was placed in two syringes respectively, and the working liquid was slowly injected using a constant current pump to control the flow rate. The inner axis injection speed was 2.1 mL / h, and the outer axis injection speed was 3.4 mL / h. The electrostatic spray working voltage was 24 kV, the pinhole inner diameter was 0.48 mm, and the distance between the nozzle and the receiving plate was 18 cm. After the inner axis working liquid was sprayed out from the nozzle, it was wrapped by the outer axis working liquid and solidified into self-emulsification microspheres. Under the action of the electric field force, it was adsorbed on the receiving plate. The aluminum foil placed on the receiving plate was peeled off and scraped to obtain celecoxib solid self-emulsification microspheres.

[0083] Example 3

[0084] This embodiment provides a celecoxib solid self-microemulsion nanosphere, and the raw materials for its preparation are shown in Table 3:

[0085] Table 3 Example 3 Celecoxib solid self-emulsified nanospheres preparation raw materials

[0086]

[0087] This embodiment also provides a method for preparing the above-mentioned celecoxib solid self-microemulsion nanospheres, which specifically comprises the following steps:

[0088] (1) Preparation of celecoxib liquid self-microemulsion: According to the content ratio in Table 3, 10 g of medium-chain triglycerides, polyoxyethylene 35 castor oil, and diethylene glycol monoethyl ether were weighed, mixed, and placed in a 37° C. water bath. After stirring for 30 min at a stirring speed of 400 r / min, 1 g of celecoxib was added and stirred until dissolved. Then, 200 mg of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer was added and stirred for 30 min to obtain a light yellow, clear and transparent celecoxib liquid self-microemulsion.

[0089] (2) Preparation of electrostatic spray inner and outer axis solutions: 10 mL of solvent (isopropanol: ethanol: water = 5:3:2, v / v) was measured, and 50 mg of acrylic resin RL100 and 250 mg of polyvinyl pyrrolidone were accurately weighed and added, and stirred for 2 h until the solution was uniform, thereby obtaining the electrostatic spray outer axis solution; 10 mL of celecoxib liquid self-microemulsion was measured, which was the electrostatic spray inner axis solution.

[0090] (3) Preparation of celecoxib solid self-emulsification microspheres: The electrostatic spray working liquid was placed in two syringes respectively, and the working liquid was slowly injected using a constant current pump to control the flow rate. The inner axis injection speed was 1.8 mL / h, and the outer axis injection speed was 3.0 mL / h. The electrostatic spray working voltage was 16 kV, the pinhole inner diameter was 0.48 mm, and the distance between the nozzle and the receiving plate was 18 cm. After the inner axis working liquid was sprayed out from the nozzle, it was wrapped by the outer axis working liquid and solidified into self-emulsification microspheres. Under the action of the electric field force, it was adsorbed on the receiving plate. The aluminum foil placed on the receiving plate was peeled off and scraped to obtain celecoxib solid self-emulsification microspheres.

[0091] Example 4

[0092] This embodiment provides a celecoxib solid self-microemulsification nanosphere, and the raw materials for its preparation are shown in Table 4:

[0093] Table 4 Example 4 Celecoxib solid self-emulsified nanospheres preparation raw materials

[0094]

[0095]

[0096] This embodiment also provides a method for preparing the above-mentioned celecoxib solid self-microemulsion nanospheres, which specifically comprises the following steps:

[0097] (1) Preparation of celecoxib liquid self-microemulsion: According to the content ratio in Table 4, 10 g of medium-chain triglycerides, polyoxyethylene 35 castor oil, and diethylene glycol monoethyl ether were weighed, mixed, and placed in a 37° C. water bath. After stirring for 30 min at a stirring speed of 400 r / min, 1 g of celecoxib was added and stirred until dissolved. Then, 150 mg of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer was added and stirred for 30 min to obtain a light yellow, clear and transparent celecoxib liquid self-microemulsion.

[0098] (2) Preparation of electrostatic spray inner and outer axis solutions: 10 mL of solvent (isopropanol: ethanol: water = 5:3:2, v / v) was measured, and 50 mg of acrylic resin RL100 and 250 mg of polyvinyl pyrrolidone were accurately weighed and added, and stirred for 2 h until the solution was uniform, thereby obtaining the electrostatic spray outer axis solution; 10 mL of celecoxib liquid self-microemulsion was measured, which was the electrostatic spray inner axis solution.

[0099] (3) Preparation of celecoxib solid self-emulsification microspheres: The electrostatic spray working liquid was placed in two syringes respectively, and the working liquid was slowly injected using a constant current pump to control the flow rate. The inner axis injection speed was 1.6 mL / h, and the outer axis injection speed was 2.7 mL / h. The electrostatic spray working voltage was 17 kV, the pinhole inner diameter was 0.48 mm, and the distance between the nozzle and the receiving plate was 18 cm. After the inner axis working liquid was sprayed out from the nozzle, it was wrapped by the outer axis working liquid and solidified into self-emulsification microspheres. Under the action of the electric field force, it was adsorbed on the receiving plate. The aluminum foil placed on the receiving plate was peeled off and scraped to obtain celecoxib solid self-emulsification microspheres.

[0100] Example 5

[0101] This embodiment provides a celecoxib solid self-microemulsion nanosphere, and the raw materials for its preparation are shown in Table 5:

[0102] Table 5 Example 5 Celecoxib solid self-microemulsion nanospheres preparation raw materials

[0103]

[0104]

[0105] This embodiment also provides a method for preparing the above-mentioned celecoxib solid self-microemulsion nanospheres, which specifically comprises the following steps:

[0106] (1) Preparation of celecoxib liquid self-microemulsion: According to the content ratio in Table 5, 10 g of medium-chain triglycerides, polyoxyethylene 35 castor oil, and diethylene glycol monoethyl ether were weighed, mixed, and placed in a 37° C. water bath. After stirring for 30 min at a stirring speed of 400 r / min, 1 g of celecoxib was added and stirred until dissolved. Then, 200 mg of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer was added and stirred for 30 min to obtain a light yellow, clear and transparent celecoxib liquid self-microemulsion.

[0107] (2) Preparation of electrostatic spray inner and outer axis solutions: 10 mL of solvent (isopropanol: ethanol: water = 5:3:2, v / v) was measured, and 50 mg of acrylic resin RL100 and 250 mg of polyvinyl pyrrolidone were accurately weighed and added, and stirred for 2 h until the solution was uniform, thereby obtaining the electrostatic spray outer axis solution; 10 mL of celecoxib liquid self-microemulsion was measured, which was the electrostatic spray inner axis solution.

[0108] (3) Preparation of celecoxib solid self-emulsification microspheres: The electrostatic spray working liquid was placed in two syringes respectively, and the working liquid was slowly injected using a constant current pump to control the flow rate. The inner axis injection speed was 1.7 mL / h, and the outer axis injection speed was 2.8 mL / h. The electrostatic spray working voltage was 17 kV, the pinhole inner diameter was 0.48 mm, and the distance between the nozzle and the receiving plate was 18 cm. After the inner axis working liquid was sprayed out from the nozzle, it was wrapped by the outer axis working liquid and solidified into self-emulsification microspheres. Under the action of the electric field force, it was adsorbed on the receiving plate. The aluminum foil placed on the receiving plate was peeled off and scraped to obtain celecoxib solid self-emulsification microspheres.

[0109] Example 6

[0110] This embodiment provides a celecoxib solid self-microemulsification nanosphere, and the raw materials for its preparation are shown in Table 6:

[0111] Table 6 Example 6 Celecoxib solid self-emulsified nanospheres preparation raw materials

[0112]

[0113]

[0114] This embodiment also provides a method for preparing the above-mentioned celecoxib solid self-microemulsion nanospheres, which specifically comprises the following steps:

[0115] (1) Preparation of celecoxib liquid self-microemulsion: According to the content ratio in Table 6, 10 g of medium-chain triglycerides, polyoxyethylene 35 castor oil, and diethylene glycol monoethyl ether were weighed, mixed, and placed in a 37° C. water bath. After stirring at a stirring speed of 400 r / min for 30 min, 1 g of celecoxib was added and stirred until dissolved. Then, 200 mg of sodium carboxymethyl cellulose was added and stirred for 30 min to obtain a light yellow, clear and transparent celecoxib liquid self-microemulsion.

[0116] (2) Preparation of electrostatic spray inner and outer axis solutions: 10 mL of solvent (isopropanol: ethanol: water = 5:3:2, v / v) was measured, and 50 mg of acrylic resin RL100 and 250 mg of polyvinyl pyrrolidone were accurately weighed and added, and stirred for 2 h until the solution was uniform, thereby obtaining the electrostatic spray outer axis solution; 10 mL of celecoxib liquid self-microemulsion was measured, which was the electrostatic spray inner axis solution.

[0117] (3) Preparation of celecoxib solid self-emulsification microspheres: The electrostatic spray working liquid was placed in two syringes respectively, and the working liquid was slowly injected using a constant current pump to control the flow rate. The inner axis injection speed was 1.5 mL / h, and the outer axis injection speed was 2.8 mL / h. The electrostatic spray working voltage was 21 kV, the pinhole inner diameter was 0.48 mm, and the distance between the nozzle and the receiving plate was 17 cm. After the inner axis working liquid was sprayed out from the nozzle, it was wrapped by the outer axis working liquid and solidified into self-emulsification microspheres. Under the action of the electric field force, it was adsorbed on the receiving plate. The aluminum foil placed on the receiving plate was peeled off and scraped to obtain celecoxib solid self-emulsification microspheres.

[0118] Example 7

[0119] This embodiment provides a celecoxib solid self-microemulsion nanosphere, and the raw materials for its preparation are shown in Table 7:

[0120] Table 7 Example 7 Celecoxib solid self-emulsified nanospheres preparation raw materials

[0121]

[0122]

[0123] This embodiment also provides a method for preparing the above-mentioned celecoxib solid self-microemulsion nanospheres, which specifically comprises the following steps:

[0124] (1) Preparation of celecoxib liquid self-microemulsion: According to the content ratio in Table 7, 10 g of medium-chain triglycerides, polyoxyethylene 35 castor oil, and diethylene glycol monoethyl ether were weighed, mixed, and placed in a 37°C water bath. After stirring at a stirring speed of 400 r / min for 30 min, 1 g of celecoxib was added and stirred until dissolved. Then, 200 mg of hydroxypropyl methylcellulose was added and stirred for 30 min to obtain a light yellow, clear and transparent celecoxib liquid self-microemulsion.

[0125] (2) Preparation of electrostatic spray inner and outer axis solutions: 10 mL of solvent (isopropanol: ethanol: water = 5:3:2, v / v) was measured, and 50 mg of acrylic resin RL100 and 250 mg of polyvinyl pyrrolidone were accurately weighed and added, and stirred for 2 h until the solution was uniform, thereby obtaining the electrostatic spray outer axis solution; 10 mL of celecoxib liquid self-microemulsion was measured, which was the electrostatic spray inner axis solution.

[0126] (3) Preparation of celecoxib solid self-emulsification microspheres: The electrostatic spray working liquid was placed in two syringes respectively, and the working liquid was slowly injected using a constant current pump to control the flow rate. The inner axis injection speed was 1.9 mL / h, and the outer axis injection speed was 3.4 mL / h. The electrostatic spray working voltage was 19 kV, the pinhole inner diameter was 0.48 mm, and the distance between the nozzle and the receiving plate was 17 cm. After the inner axis working liquid was sprayed out from the nozzle, it was wrapped by the outer axis working liquid and solidified into self-emulsification microspheres. Under the action of the electric field force, it was adsorbed on the receiving plate. The aluminum foil placed on the receiving plate was peeled off and scraped to obtain celecoxib solid self-emulsification microspheres.

[0127] Example 8

[0128] This embodiment provides a celecoxib solid self-microemulsification nanosphere, and the raw materials for its preparation are shown in Table 8:

[0129] Table 8 Example 8 Celecoxib solid self-emulsified nanospheres preparation raw materials

[0130] Preparation of raw materials content Celecoxib 1g Isopropyl myristate 2.5g Polyoxyethylene hydrogenated castor oil 5.625g Polyethylene glycol 300 1.875g Hydroxypropyl methylcellulose 200mg Polyvinylpyrrolidone 250mg Acrylic resin RL100 50mg Anhydrous ethanol 3ml Isopropyl alcohol 5ml Distilled water 2ml

[0131] This embodiment also provides a method for preparing the above-mentioned celecoxib solid self-microemulsion nanospheres, which specifically comprises the following steps:

[0132] (1) Preparation of celecoxib liquid self-microemulsion: According to the content ratio in Table 7, 10 g of isopropyl myristate, polyoxyethylene hydrogenated castor oil and polyethylene glycol 300 were weighed, mixed and placed in a 37°C water bath, stirred at a stirring speed of 400 r / min for 30 min, and then 1 g of celecoxib was added and stirred until dissolved. Then, 200 mg of hydroxypropyl methylcellulose was added and stirred for 30 min to obtain a light yellow, clear and transparent celecoxib liquid self-microemulsion.

[0133] (2) Preparation of electrostatic spray inner and outer axis solutions: 10 mL of solvent (isopropanol: ethanol: water = 5:3:2, v / v) was measured, and 50 mg of acrylic resin RL100 and 250 mg of polyvinyl pyrrolidone were accurately weighed and added, and stirred for 2 h until the solution was uniform, thereby obtaining the electrostatic spray outer axis solution; 10 mL of celecoxib liquid self-microemulsion was measured, which was the electrostatic spray inner axis solution.

[0134] (3) Preparation of celecoxib solid self-emulsification microspheres: The electrostatic spray working liquid was placed in two syringes respectively, and the working liquid was slowly injected using a constant current pump to control the flow rate. The inner axis injection speed was 1.9 mL / h, and the outer axis injection speed was 3.4 mL / h. The electrostatic spray working voltage was 19 kV, the pinhole inner diameter was 0.48 mm, and the distance between the nozzle and the receiving plate was 17 cm. After the inner axis working liquid was sprayed out from the nozzle, it was wrapped by the outer axis working liquid and solidified into self-emulsification microspheres. Under the action of the electric field force, it was adsorbed on the receiving plate. The aluminum foil placed on the receiving plate was peeled off and scraped to obtain celecoxib solid self-emulsification microspheres.

[0135] Comparative Example 1

[0136] This comparative example provides a celecoxib solid self-emulsification nanosphere and a preparation method thereof, which is different from Example 1 in that: polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (soluplus) is not added during the preparation of the celecoxib liquid self-emulsification in this comparative example, and the other conditions are the same.

[0137] During the preparation process, it was found that when polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer was not added, the amount of drug loaded in the solid self-emulsified nanospheres would be reduced, and the microemulsion formed by self-emulsification would show obvious drug crystallization after being left for a period of time.

[0138] Comparative Example 2

[0139] This comparative example provides a celecoxib solid self-microemulsification nanosphere and a preparation method thereof, which is different from Example 1 in that: the celecoxib liquid self-microemulsion of this comparative example is prepared by a conventional electrostatic spraying method, specifically comprising:

[0140] (1) Preparation of celecoxib liquid self-microemulsion: According to the content ratio in Table 1, 10 g of medium-chain triglycerides, polyoxyethylene 35 castor oil, and diethylene glycol monoethyl ether were weighed, mixed, and placed in a 37° C. water bath. After stirring for 30 min at a stirring speed of 400 r / min, 1 g of celecoxib was added and stirred until dissolved. Then, 200 mg of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer was added and stirred for 30 min to obtain a light yellow, clear and transparent celecoxib liquid self-microemulsion.

[0141] (2) Preparation of electrostatic spray liquid: 10 mL of solvent (isopropanol: ethanol: water = 5:3:2, v / v) was measured, and 50 mg of acrylic resin RL100 and 250 mg of polyvinyl pyrrolidone were accurately weighed and added. The mixture was stirred for 2 h until the solution was uniform. Then, 10 mL of celecoxib liquid self-microemulsion was added to obtain the electrostatic spray liquid.

[0142] (3) Preparation of celecoxib solid self-emulsification microspheres: The electrostatic spray liquid was placed in a syringe, and the working liquid was slowly injected using a constant current pump to control the flow rate. The injection rate was 2.0 mL / h, the electrostatic spray working voltage range was 17 kV, the inner diameter of the electrostatic spray nozzle was 5 mm, and the distance between the nozzle and the receiving plate was 18 cm. The working liquid was atomized into nanoparticles after being sprayed out of the nozzle. The particles were adsorbed on the receiving plate under the action of the electric field force. The aluminum foil placed on the receiving plate was peeled off and scraped to obtain the celecoxib solid self-emulsification microspheres.

[0143] An appropriate amount of the above-mentioned celecoxib solid self-microemulsion nanospheres was dissolved in water. The results showed that the particle size of the microemulsion formed by the solid self-microemulsion in water was relatively large, about 400 nm.

[0144] Test Example 1 Morphology and Particle Size Distribution of Celecoxib Liquid Self-Microemulsion

[0145] This test example tests the morphology and particle size distribution of the celecoxib liquid self-microemulsion prepared by the present invention. The celecoxib liquid self-microemulsion prepared in Example 1 was selected for performance characterization, and the celecoxib solid self-microemulsion nanospheres prepared in other examples have comparable performance to it.

[0146] (I) Appearance inspection

[0147] The celecoxib liquid self-microemulsion prepared in the embodiment was inspected for appearance, and the result showed that the celecoxib liquid self-microemulsion prepared in the present invention was a clear, transparent, viscous liquid, and after high-speed centrifugation at 10000rpm for 10min, there was no phase separation phenomenon, indicating that the celecoxib liquid self-microemulsion prepared in the present invention had good dynamic stability. Further, after adding an appropriate amount of water to the celecoxib liquid self-microemulsion for emulsification, a uniform, slightly blue-light transparent emulsion was formed, which was identified as an O / W type microemulsion by methylene blue and Sudan red solution dyeing.

[0148] (ii) Transmission electron microscopy observation

[0149] The celecoxib liquid self-microemulsion prepared in the example was diluted 100 times with 37°C distilled water, and dripped onto a copper mesh after passing through a 0.22 μm filter membrane, and the liquid was removed with filter paper after 10 minutes. The copper mesh was placed on a dyed droplet (10% phosphotungstic acid solution) for about 30 seconds, and the liquid was removed with filter paper after 5 minutes, and then observed under a transmission electron microscope.

[0150] The results are as follows Figure 1 As shown by Figure 1 It can be seen that the diameter of the emulsion droplets formed by the celecoxib liquid self-microemulsion prepared by the present invention and meeting water is about 20 nm, and the particle size distribution is uniform.

[0151] (III) Particle size determination

[0152] The celecoxib liquid self-microemulsification prepared in the example was diluted 100 times with 37° C. distilled water and then the PS and Zeta potential after emulsification were measured using a Zetasizer Nano ZS90 particle size analyzer.

[0153] The results show that the average particle size of the microemulsion formed by the celecoxib liquid prepared by the present invention after self-microemulsification is about 23 nm, the Zeta potential is 25.5 mv, and the polydispersity coefficient (PdI) is 0.201.

[0154] (IV) Influence of medium and dilution factor

[0155] The celecoxib liquid self-microemulsion prepared in the embodiment was added to three different types of dispersion media (hydrochloric acid with a pH value of 1.0, deionized water, and PBS buffer with a pH value of 6.8), and three different volumes of distilled water (50 times, 100 times, and 200 times), and gently stirred. Timing was started when the deionized water was added dropwise, and timing was stopped when the self-microemulsion was fully emulsified, and emulsification efficiency was evaluated with emulsification time and particle size.

[0156] The emulsification results of celecoxib liquid self-microemulsion in three different types of dispersion media are shown in Table 9.

[0157] Table 9: Effect of dispersion medium on emulsification effect

[0158] Dispersion medium pH 1.0 Hydrochloric acid Distilled water pH 6.8 PBS Emulsification time(s) 32’34’ 28’96’ 32’04’ Particle size (nm) 25.6 27.1 32.9 Particle size after 24h (nm) 25.1 28.2 30.4

[0159] The effects of different dilution multiples on the emulsification results of celecoxib liquid self-microemulsion are shown in Table 10.

[0160] Table 10: Effect of different dilution ratios on emulsification effect

[0161] Dilution multiple 50 100 200 Emulsification time 30’62’ 29’35’ 38’83’ Particle size (nm) 24.9 26.7 27.1 Particle size after 24h (nm) 25.5 26.3 26.5

[0162] The above test results show that: celecoxib liquid self-microemulsion can quickly form clear, transparent and slightly blue microemulsion in different dispersion media and different dilution multiples, and the particle size does not change after being placed for 24 hours.

[0163] Test Example 2 Morphology and Particle Size Distribution of Celecoxib Solid Self-emulsified Nanospheres

[0164] This test example tests the morphology and particle size distribution of the celecoxib solid self-emulsified nanospheres prepared by the present invention. The celecoxib solid self-emulsified nanospheres prepared in Example 1 were selected for performance characterization, and the celecoxib solid self-emulsified nanospheres prepared in other examples have comparable performance to them.

[0165] (I) SEM observation

[0166] An appropriate amount of the celecoxib solid self-microemulsion nanospheres prepared in the present invention is attached to a sample table, subjected to gold spraying treatment, and its structure is determined by SEM.

[0167] Test results see Figure 2 The results show that the celecoxib solid self-emulsification nanospheres prepared by the present invention are regular spherical and evenly distributed, and the particle size of the solid self-emulsification nanospheres is 200-300 nm.

[0168] (II) Particle size determination of solid self-emulsified nanospheres

[0169] The celecoxib solid SEM was diluted 100 times with 37°C distilled water and then its PS and Zeta potential after emulsification were determined using a Zetasizer Nano ZS90 particle size analyzer.

[0170] The results showed that the average particle size of celecoxib solid microemulsion formed by self-emulsification was about 89nm, with a normal distribution, a Zeta potential of 34.5mv, and a polydispersity coefficient (PdI) of 0.367.

[0171] Test Example 3 In vitro drug release experiment

[0172] In this test example, the celecoxib liquid self-microemulsion and celecoxib solid nanoparticles prepared in Example 1 were subjected to an in vitro drug release experiment.

[0173] This test uses the paddle method to test the in vitro dissolution rate, and the dissolution medium is pH 6.8 PBS. The specific steps are as follows: 900mL of dissolution medium is poured into the dissolution cup, the equilibrium dissolution temperature is 37±0.5℃, and the stirring paddle speed is set at 50rpm; then celecoxib raw material (CXB), celecoxib liquid self-microemulsion (CXB-L-SMEDDS), celecoxib solid self-microemulsion nanospheres (CXB-L-SMEDDS), each containing 100mg of celecoxib, are added into the dissolution cup according to the formula composition, 5mL of sample is drawn at selected time intervals (5, 10, 15, 20, 30, 45, 60, 90, 120 minutes), and 5mL of fresh medium is immediately added to the dissolution cup to make the amount of medium in the dissolution cup always maintained at 900mL. The sample was filtered using a 0.45 μm filter membrane, and the concentration of celecoxib was calculated based on the reference substance. The dissolution curve was drawn with the sampling time point as the horizontal axis and the cumulative dissolution of the drug as the vertical axis.

[0174] Its dissolution curve is as follows Figure 3 As shown in the figure, it can be seen that in the pH 6.8 PBS dissolution medium, the cumulative release of celecoxib raw material is 4.3%, which is almost no release; while the cumulative release of celecoxib liquid self-microemulsion is 98% and 72% respectively, indicating that the self-microemulsion technology can significantly increase the cumulative release of celecoxib in the dissolution medium.

[0175] Test Example 4 Pharmacokinetics test in rats

[0176] This test example respectively carries out the pharmacokinetic test in rats of the celecoxib liquid self-microemulsion and celecoxib solid self-microemulsion prepared in Example 1 and conventional celecoxib solution. It specifically comprises the following steps:

[0177] (1) Animal administration and blood sample processing: Fifteen healthy SD rats (180-220 g) were randomly divided into three groups (celecoxib solution group, celecoxib liquid self-microemulsion group, and celecoxib solid self-microemulsion nanosphere group). The rats in each group fasted for 12 h before administration (with free access to drinking water). According to the 40 mg / kg dose, 0.5 mL of blood was collected from the rats' orbits at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h, and 24 h after administration, and placed in an EP tube containing 1% sodium heparin solution and rotated at 10,000 r.min. -1 Centrifuge for 10 min, take the supernatant, process the sample, draw 20 μL of HPLC injection, and calculate the drug concentration at each time point.

[0178] (2) Draw the drug-time curve: Draw the plasma drug-time curves of celecoxib, celecoxib liquid self-microemulsion, and celecoxib solid self-microemulsion nanospheres.

[0179] Test results such as Figure 4 As shown, the results show that the MRT, Cmax, Tmax and AUC of the celecoxib solid self-emulsion nanospheres and celecoxib liquid self-emulsion prepared by the present invention are higher than those of the celecoxib solution group, indicating that the celecoxib liquid self-emulsion and celecoxib solid self-emulsion nanospheres prepared by the present invention can significantly improve the oral absorption of celecoxib, and the polymer in the solid self-emulsion also has the effect of enhancing stability and promoting absorption.

[0180] In summary, the present invention provides a celecoxib solid self-emulsification nanosphere and a preparation method and application thereof. The present invention adopts a coaxial electrostatic spraying process to prepare celecoxib solid self-emulsification nanosphere. The process has the advantages of simple operation, high degree of industrialization, stable product quality, no heating process, wide application range, etc. The celecoxib solid self-emulsification prepared by the process not only has the advantages of liquid self-emulsification, but also can improve the stability of self-emulsification. The self-emulsification microspheres can be made into various solid dosage forms according to actual needs to meet the needs of dosage form development.

[0181] In addition, the present invention conducts morphological and particle size distribution research and drug release kinetics analysis on the prepared celecoxib solid self-emulsification nano-microspheres, and the results show that the prepared celecoxib solid self-emulsification nano-microspheres have a round and smooth surface, good dispersibility, and a uniform particle size of about 200-300 nm. The average particle size of the microemulsion formed after emulsification is about 89 nm, and the diameter of the emulsion droplets formed after diluting 100 times with 37°C distilled water and passing through a 0.22μm filter membrane is about 20 nm. The celecoxib solid self-emulsification nano-microspheres have a large drug loading capacity, can be quickly emulsified when encountering the aqueous environment of the gastrointestinal tract, have a dissolution rate significantly higher than that of the raw material drug, and significantly improve oral bioavailability.

[0182] The above is a detailed description of the embodiments of the present invention, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge of ordinary technicians in the relevant technical field without departing from the purpose of the present invention. In addition, the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

Claims

1. A celecoxib solid self-microemulsification nanosphere, characterized in that: It comprises an outer shell and an inner core arranged in the outer shell, wherein the outer shell is prepared by raw materials consisting of a polymer and a solvent, wherein the polymer consists of acrylic resin RL100 and polyvinyl pyrrolidone in a mass ratio of 4 to 6:1; The raw materials for preparing the inner core are composed of 1g of celecoxib, 2.5g of medium chain triglycerides, 5.625g of polyoxyethylene 35 castor oil, 1.875g of diethylene glycol monoethyl ether and 0.2g of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; The celecoxib solid self-microemulsion nanospheres are prepared by the following preparation method: Step S1, mixing the raw materials for preparing the core to obtain a celecoxib liquid self-microemulsion; Step S2, dispersing the high molecular polymer in the solvent at a mass volume ratio of 25-40 mg: 1 mL to obtain an electrostatic spray external axis solution; Step S3, using the celecoxib liquid self-microemulsion as an electrostatic spray inner axis solution, and electrostatically spraying granulation with the electrostatic spray outer axis solution to obtain the celecoxib solid self-microemulsion nanospheres; The electrostatic spray inner axis solution is injected at a flow rate of 1.5-2.1 mL / h for electrostatic spray granulation; and the electrostatic spray outer axis solution is injected at a flow rate of 2.7-3.4 mL / h for electrostatic spray granulation.

2. The celecoxib solid self-microemulsion nanosphere according to claim 1, characterized in that: The solvent is selected from at least one of methanol, isopropanol, ethanol and water.

3. The celecoxib solid self-microemulsion nanospheres according to claim 1, characterized in that: The inner diameter of the electrostatic spray nozzle is 0.25mm~0.84mm.

4. The celecoxib solid self-microemulsion nanospheres according to claim 3, characterized in that: The distance between the electrostatic spray nozzle and the receiving plate is 10cm~20cm; 5. The celecoxib solid self-microemulsion nanospheres according to claim 3, characterized in that: The working range of the electrostatic spray is 13 kV~25 kV.

6. Use of the celecoxib solid self-microemulsification nanoparticles according to any one of claims 1 to 5 in the preparation of sustained-release drugs.

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