A nano-micelle preparation of flucoridine and its preparation method and use

Abstract

The present invention provides a flucoridine nano-micelle preparation, which comprises flucoridine and a polymer excipient. The present invention also provides a method for preparing the nano-micelle preparation. The flucoridine nano-micelle preparation has the advantage of high bioavailability.

Description

Technical Field

[0001] The invention relates to a flucortidine nano-micelle preparation, a preparation method and application of the preparation, and belongs to the field of medicine. Background Art

[0002] Flucoratine is a new effective monomer obtained through structural optimization based on accolade. Its structural formula is shown in the following formula (A):

[0003]

[0004] Patent application number 201210573072.6 discloses a compound of formula A and claims that the compound has the potential to treat tumors such as breast cancer, colon cancer, endometrial cancer, leukemia, liver cancer, lymphoma, lung cancer, prostate cancer, gastric cancer, or pancreatic cancer. However, during the research and development process, the applicant discovered that flucoridine has poor solubility in both water and oil, making it difficult to prepare a solvent.

[0005] Patent publication number WO2016127925 discloses a pharmaceutical composition of flavonoid compounds, including a pharmaceutical composition of a compound of formula A. This pharmaceutical composition overcomes the problem that existing flavonoid compounds are difficult to dissolve in water and oil. The compound of formula A is made into a self-emulsifying dosage form, thereby fully improving the bioavailability of the flavonoid compound in animals.

[0006] However, the applicant has found that the self-emulsifying property of the compound of formula A has the disadvantage of poor safety during administration to animals. Therefore, it is necessary to develop a formulation with high safety and high bioavailability. Summary of the Invention

[0007] One object of the present invention is to provide a flucoridine nano-micelle preparation having the advantage of high bioavailability.

[0008] Another object of the present invention is to provide a method for preparing the flucoridine nanomicelle preparation of the present invention.

[0009] In one aspect, the present invention provides a flucoridine nano-micelle preparation, which comprises flucoridine and a polymer excipient.

[0010] Preferably, the preparation is an oral preparation.

[0011] Preferably, the preparation is a liquid preparation or a solid preparation.

[0012] Preferably, when the preparation is a solid preparation, it contains, by mass: 1 part of flucoridine and 1-20 parts of polymer excipients.

[0013] More preferably, the preparation contains, by mass: 1 part of flucoridine and 4 parts of polymer excipients.

[0014] Preferably, when the preparation is a liquid preparation, it contains, by mass: 1 part of flucoridine, 2-20 parts of polymer excipients and 20-500 parts of water.

[0015] Preferably, when the preparation is a liquid preparation, it contains, by mass: 1 part of flucoridine, 4 parts of polymer excipients and 250 parts of water.

[0016] Preferably, when the preparation is a solid preparation, the flucoridine therein exists in an amorphous state.

[0017] Preferably, the X-ray powder diffraction pattern of the flucoridine nano-micelle preparation when it is a solid preparation is as follows: Figure 3 shown.

[0018] Preferably, the polymer excipient is selected from one or more of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone VA64, polyethylene glycol 4000, sodium carboxymethyl cellulose, polyvinyl pyrrolidone K25, polyvinyl pyrrolidone K30, polyvinyl pyrrolidone K90, poloxamer 188, poloxamer 407, tocopherol polyethylene glycol succinate and polyethylene glycol-15 hydroxystearate.

[0019] Another aspect of the present invention provides a method for preparing the flucoridine nanomicelle preparation of the present invention, the method comprising the following steps:

[0020] A) first dissolving flucoridine in a solvent capable of dissolving flucoridine to form a flucoridine solution;

[0021] B) dissolving the polymer excipient in a solvent capable of dissolving the excipient to form a polymer solution;

[0022] C) adding the flucoridine solution to the polymer solution to form a suspension;

[0023] D) Centrifuge the suspension, remove the precipitate, and collect the supernatant;

[0024] E) The supernatant is concentrated to produce micellar concentrate.

[0025] Preferably, after step E, the method further comprises step E': adding one or more of a flavoring agent, a preservative and a defoaming agent to the flucoridine micelle concentrate and mixing them uniformly to obtain a flucoridine nano-micelle liquid preparation.

[0026] Preferably, the method further comprises the following steps:

[0027] F) adding lyophilization excipients to the micellar concentrate and lyophilizing to prepare lyophilized tablets;

[0028] Preferably, the lyophilized excipient is one or more selected from mannose, dextran, lactose, sucrose, glucose, glycine, trehalose and polyvinylpyrrolidone 10K, and the lyophilized excipient accounts for 1-50% of the total mass of flucoratine and the lyophilized excipient in the micellar concentrate.

[0029] More preferably, the freeze-dried excipient is 2-20% of the total mass of flucoridine and the freeze-dried excipient in the micellar concentrate.

[0030] Preferably, the solvent capable of dissolving flucoridine includes tetrahydrofuran, methanol, ethanol, acetone, N,N-dimethylformamide or an aqueous alkali solution, wherein the aqueous alkali solution includes sodium hydroxide, potassium hydroxide, calcium hydroxide or an aqueous sodium carbonate solution.

[0031] Preferably, the solvent capable of dissolving the auxiliary material includes petroleum ether, n-hexane, water, hydrochloric acid, sulfuric acid, nitric acid, sulfurous acid or an aqueous solution of phosphoric acid.

[0032] Preferably, the flavoring agent includes a sweetener and a fragrance, the sweetener is a non-sugar sweetener, the sweetener accounts for 0.01-1% of the mass of the flucoridine nano-micelle liquid preparation, and the fragrance accounts for 0.01-5% of the mass of the flucoridine nano-micelle liquid preparation.

[0033] Preferably, the preservative accounts for 0.01-1% of the mass of the flucoridine nano-micelle liquid preparation, and the defoaming agent accounts for 0.01-1% of the mass of the flucoridine nano-micelle liquid preparation.

[0034] Preferably, in step C), the polymer solution is stirred at a speed of 20-2000 rpm and flucoridine is added thereto; and in step D), the suspension is centrifuged at a speed of 1000-20000 rpm.

[0035] Preferably, in step E), the concentration of the concentrated solution is 5-50 mg flucoridine / mL.

[0036] Preferably, the freeze-drying temperature is -10 to -80°C.

[0037] Preferably, the non-sugar sweetener is selected from one or more of sucralose, steviol glycosides, steviol, mannitol, lactitol, maltitol, alitame, aspartame, saccharin, saccharin sodium, saccharin calcium, acesulfame potassium and thaumatin.

[0038] Preferably, the aroma is selected from one or more of cherry, lemon, lime, orange, tangerine, mandarin, mint, strawberry, caramel, peach, raspberry, grapefruit, vanilla, cream, chocolate and grape aromas.

[0039] Preferably, the preservative is selected from one or more of parabens, chlorobutanol, propionic acid and sorbate.

[0040] Preferably, the defoaming agent is selected from one or more of mineral oils, alcohols, fatty acids, fatty acid esters, amides, phosphates, silicones, polyethers and polyether-modified polysiloxanes.

[0041] The present invention provides a nano-micelle preparation of flucoridine and a method for preparing the nano-micelle preparation. Because the micelles in the nano-micelle preparation of flucoridine are amorphous and have nanometer-scale particle sizes, they exhibit high bioavailability. Compared to an oral preparation containing a flucoridine solid dispersion tablet, the bioavailability is increased by 1.9 times, and the maximum blood concentration in animals is increased by nearly 1.7 times. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 The figure shows the scanning electron microscope image of the flucoridine nanomicelles of the present invention.

[0043] Figure 2 The particle size distribution diagram of the flucoridine nanomicellar solution of the present invention is shown.

[0044] Figure 3 The figure shows the X-ray powder diffraction pattern of the freeze-dried powder of flucoridine nanomicelles according to Example 2 of the present invention.

[0045] Figure 4 The differential scanning calorimetry spectrum of the flucoridine solid nanomicelle freeze-dried powder according to Example 2 of the present invention is shown.

[0046] Figure 5 The graph shows the concentration-time curves of flucoridine nanomicelle oral solution and flucoridine solid dispersion tablets in beagle dogs. DETAILED DESCRIPTION

[0047] Unless otherwise specified, the term "nano micelle" herein refers to the formation of flucoratine formulations in a liquid state, including freeze-dried formulations in a state where water is added, in which flucoratine and its polymer excipients are observed under a scanning electron microscope to form an association of an external hydrophilic polar portion and an internal hydrophobic portion. This association is called a micelle, and under scanning electron microscope observation, the association has spherical, lamellar and rod-like shapes, and the diameter or width of each association ranges from tens of nanometers to hundreds of nanometers.

[0048] Unless otherwise specified, the term "solid preparation" herein includes both the nanomicelle lyophilized preparation of the present invention and the solid preparation obtained by drying the nanomicelle liquid preparation of the present invention.

[0049] Unless otherwise specified, the term "amorphous state" herein refers to a flucortidine nanomicelle solid preparation, including a liquid preparation after drying. When measured using Cu-Ka radiation, X-ray powder diffraction shows a diffuse peak in the 2θ value range of 0-40°, and thus the flucortidine in the preparation exists in an amorphous form.

[0050] Unless otherwise specified, the term "polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer" herein is purchased from BASF under the trade name Soluplus.

[0051] Unless otherwise specified, the term "copovidone VA64" herein refers to a water-soluble copolymer of N-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 60:40. Copovidone VA64 is purchased from BASF under the trade names Kollidon VA 64 and Kollidon VA 64 Fine.

[0052] Unless otherwise specified, the term "polyethylene glycol 4000" in this article refers to a high molecular weight polymer formed by the polycondensation of ethylene oxide and water, with the molecular formula HO(CH2CH2O) n H represents, where n represents the average number of oxyethylene groups, and n in polyethylene glycol 4000 is about 4000.

[0053] Unless otherwise specified, the term "sodium carboxymethylcellulose" herein is purchased from Ashland and has a molecular weight of 250,000-720,000.

[0054] Unless otherwise specified, the term "polyvinylpyrrolidone K25" herein refers to a polymer of vinylpyrrolidone, where the K value represents the average molecular weight range of the vinylpyrrolidone polymer. The K value is actually a characteristic value related to the relative viscosity of a PVP aqueous solution. Viscosity, in turn, is a physical quantity related to the molecular weight of the polymer. Therefore, the K value can be used to characterize the average molecular weight of PVP. Generally, a higher K value indicates a higher viscosity and stronger adhesion. Polyvinylpyrrolidone K25 herein is purchased from Ashland under the trade name Plasdone PVP K25.

[0055] Unless otherwise specified, the term "polyvinylpyrrolidone K30" herein is defined with reference to polyvinylpyrrolidone K25. Polyvinylpyrrolidone K30 herein is purchased from Ashland under the trade name Plasdone PVP K30.

[0056] Unless otherwise specified, the term "polyvinylpyrrolidone K90" herein is defined with reference to polyvinylpyrrolidone K25. Polyvinylpyrrolidone K90 herein is available from Ashland under the trade name Plasdone PVP K90.

[0057] Unless otherwise specified, the term "Poloxamer 188" herein, also known as Pluronic F68, refers to a PEO-PPO-PEO triblock copolymer composed of polyoxyethylene, polyoxypropylene, and polyoxyethylene, with oxyethylene units comprising 75-85% and oxypropylene units 25-30%. The average molecular weight is 7680-9510. The trade name is Kolliphor P188.

[0058] Unless otherwise specified, the term "Poloxamer 407" herein is composed of about 70% ethylene oxide and 30% propylene oxide, with an average molecular weight of 9840 to 14600. The trade name is Kolliphor P407.

[0059] Unless otherwise specified, the term "tocopheryl polyethylene glycol succinate and 2-hydroxyethyl 12-hydroxy-18-phosphate" herein is referred to as TPGS, with the CAS number being 9002-96-4 and the trade name being Kolliphor TPGS.

[0060] Unless otherwise specified, the term "polyethylene glycol-15 hydroxystearate" herein is referred to as "Solutol HS15" with the CAS number of 70142-34-6.

[0061] Unless otherwise specified, the term "flavoring agent" in this article refers to a pharmaceutical excipient used in medicines to improve or mask the unpleasant smell and taste of the medicine, making it difficult for the patient to detect the strong bitter taste (or other odors such as spicy, irritating, etc.) of the medicine.

[0062] Unless otherwise specified, the term "sweetener" herein refers to a pharmaceutical additive that imparts a sweet taste to the formulations of the present invention.

[0063] Unless otherwise specified, the term "fragrance" herein refers to a pharmaceutical additive that imparts olfactory aroma to the formulations of the present invention.

[0064] Unless otherwise specified, the term "simethicone" herein is purchased from Guangzhou Biaomei Pharmaceutical Excipients Co., Ltd., CAS No. 8050-81-5, and is used as a defoaming agent in the present invention.

[0065] Unless otherwise specified, the term "Span 85" herein, also known as "sorbitan trioleate", is purchased from Xi'an Jinxiang Pharmacy Co., Ltd., product number 18091874298, and is used as a defoaming agent in the present invention.

[0066] Unless otherwise specified, the term "lyophilization excipient" herein is also referred to as a lyophilization support agent or lyophilization excipient, and refers to an excipient that maintains the state and stability of the preparation and has good resolubility after the drug is lyophilized.

[0067] Unless otherwise specified, the term "AUC" in this article last "AUC represents the area between the blood drug concentration curve and the time axis from the start of drug administration to the last point. last ” is also often called “drug exposure”.

[0068] Unless otherwise specified, the term "AUC" in this article INF ” represents the area enclosed by the blood drug concentration curve and the time axis from 0 to infinity.

[0069] Example 1

[0070] Preparation of Flucoridine Nanomicelle Oral Solution

[0071] 2.4 g of flucoratine raw material was dissolved in 120 mL of 0.2 mol / L sodium hydroxide solution. 4.8 g of poly(vinyl caprolactam)-poly(vinyl acetate)-poly(ethylene glycol) graft copolymer and 4.8 g of poloxamer 407 were dissolved in 480 mL of 0.05 mol / L hydrochloric acid solution. Under high-speed stirring at 1000 rpm, the sodium hydroxide solution mixed with flucoratine was added to the polymer-hydrochloric acid solution via a peristaltic pump. Stirring was continued for 20 minutes. The solution was then centrifuged at 10,000 rpm for 20 minutes to remove the precipitate. The supernatant was the flucoratine micellar solution. The flucoratine concentration was 3.6 mg / mL. The resulting solution was ultrafiltered using a regenerated cellulose membrane (100 kDa) in an ultrafiltration cup to obtain a higher concentration of flucoratine micellar solution, reaching a flucoratine concentration of 30 mg / mL.

[0072] The obtained flucortidine mixed solution was placed in a transparent test bottle, and a beam of light was passed through the solution. From the direction perpendicular to the incident light, a bright "pathway" was observed in the solution. Therefore, the flucortidine mixed solution exhibited a Tyndall effect, forming a mixed micellar solution of flucortidine.

[0073] The flucoridine micelle solution was examined by electron microscopy (10KV, scanning electron microscope) to obtain Figure 1 The electron microscope images shown are from Figure 1 By comparison with the ruler, it can be seen that the particle size distribution of the flucoridine micelle particles is at the nanometer level, with the particle size being within 200 nanometers.

[0074] The micelle solution obtained in Example 1 was analyzed by a dynamic light scattering laser particle size analyzer (Malvern Master size Nano ZS) to obtain Figure 2 Particle size distribution diagram. Figure 2 The particle size distribution curve shows that the flucoridine micelles are a monodisperse system with an average particle size of about 80 nm.

[0075] Example 2

[0076] Preparation of Flucoridine Micellar Concentrate

[0077] 2 g of flucoridine raw material was dissolved in 140 mL of acetone, and 20.0 g of polyethylene glycol 15-hydroxystearate and 5.0 g of tocopheryl polyethylene glycol succinate were dissolved in 500 mL of purified water. The flucoridine acetone solution was added dropwise to the polyethylene glycol 15-hydroxystearate and tocopheryl polyethylene glycol succinate solutions using a peristaltic pump at 1000 rpm. Stirring was continued for 20 minutes after the addition was complete. The reaction solution was then placed in a ventilated area and stirred at 200 rpm to evaporate the acetone for at least 36 hours until the acetone was completely evaporated. The remaining solution was centrifuged at 12,000 rpm at 20°C for 20 minutes to remove the precipitate. The supernatant was the flucoridine micellar solution. The flucoridine concentration was 6 mg / mL. The solution was concentrated by membrane filtration using a regenerated cellulose membrane (100 kDa) to obtain a 12 mg / mL flucoridine micellar solution.

[0078] Example 3

[0079] Preparation of Flucoridine Micellar Concentrate

[0080] 1.0 g of flucoridine was dissolved in 70 mL of acetone, and 20.0 g of polyethylene glycol 15-hydroxystearate and 0.25 g of sodium lauryl sulfate were dissolved in 200 mL of purified water. The flucoridine acetone solution was added dropwise to the polyethylene glycol 15-hydroxystearate and sodium lauryl sulfate solution using a peristaltic pump under high-speed stirring at 1000 rpm. Stirring was continued for 10 minutes. The reaction solution was then placed in a ventilated area and stirred at 300 rpm to evaporate the acetone for at least 24 hours until the acetone was completely evaporated. The remaining solution was centrifuged at 20°C and 12,000 rpm for 20 minutes to remove the precipitate. The supernatant was the flucoridine micellar solution. The flucoridine concentration was 5 mg / mL. Membrane filtration and concentration using a regenerated cellulose membrane (100 kDa) yielded a 45 mg / mL flucoridine micellar solution.

[0081] Example 4

[0082] Preparation of Flucoridine Micellar Concentrate

[0083] 1.2 g of flucoridine raw material was dissolved in 60 mL of 0.2 mol / L sodium hydroxide solution. 2.4 g of tocopheryl polyethylene glycol succinate and 1.2 g of poloxamer 188 were dissolved in 240 mL of 0.05 mol / L hydrochloric acid solution. Under high-speed stirring at 1000 rpm, the sodium hydroxide solution mixed with flucoridine was added to the polymer-hydrochloric acid solution via a peristaltic pump. Stirring was continued for 20 minutes. The mixture was then centrifuged at 10,000 rpm for 20 minutes to remove the precipitate. The supernatant was the flucoridine micellar solution. The flucoridine concentration was 3.8 mg / mL. The resulting solution was ultrafiltered using a regenerated cellulose membrane (100 kDa) in an ultrafiltration cup to obtain a higher concentration of flucoridine micellar solution, with a flucoridine concentration of 20 mg / mL.

[0084] Example 5

[0085] Preparation of Flucoridine Micellar Concentrate

[0086] 2.4 g of flucoridine raw material was dissolved in 60 mL of 0.4 mol / L sodium hydroxide solution, and 9.6 g of copovidone VA64 was dissolved in 240 mL of 0.1 mol / L hydrochloric acid solution. Under high-speed stirring at 1000 rpm, the sodium hydroxide solution mixed with flucoridine was added to the polymer solution in hydrochloric acid solution via a peristaltic pump. Stirring was continued for 20 minutes. The mixture was then centrifuged at 5000 rpm for 20 minutes to remove the precipitate. The supernatant was the flucoridine micellar solution. The flucoridine concentration was 7.8 mg / mL. The resulting solution was ultrafiltered using a polyphenylene ether sulfone membrane (100 kDa) in an ultrafiltration cup to obtain a higher concentration of flucoridine micellar solution, with a flucoridine concentration of 28 mg / mL.

[0087] Example 6

[0088] Preparation of Flucoridine Micellar Oral Solution

[0089] The flucoridine micellar concentrated solution was prepared according to the method of Examples 1 to 3. Other components were added according to the prescription composition. As shown in the following table:

[0090] <![CDATA[ Prescription composition ]]> <![CDATA[ Prescription 1 ]]> <![CDATA[ Prescription 2 ]]> <![CDATA[ Prescription 3 ]]> Flucoridine micellar concentrate 30mg / ml 12mg / ml 45mg / ml Simethicone 0.20g <![CDATA[ / ]]> <![CDATA[ / ]]> Strawberry flavor / 0.40g 0.40g Vanilla flavor 0.80g / 0.80g Sucralose 0.30g 0.10g 0.45g Methylparaben 0.45g 0.45g 0.45g Disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution <![CDATA[ pH=6.8 ]]> <![CDATA[ pH=6.8 ]]> <![CDATA[ pH=6.8 ]]> Total volume <![CDATA[ 400ml ]]> <![CDATA[ 400ml ]]> <![CDATA[ 400ml ]]>

[0091] While stirring continuously, the defoaming agent simethicone, strawberry flavor, vanilla flavor, sucralose, and methylparaben were added to the solutions of Examples 1-3 in the prescribed amounts and proportions, respectively. The pH was then adjusted to 6.8 with a disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution. The mixture was thoroughly stirred and filtered. The resulting solution was then sealed and stored in an amber glass bottle.

[0092] Example 7

[0093] Preparation of Flucoridine Micellar Oral Solution

[0094] A flucoridine micellar concentrated solution was prepared according to the method of Examples 4 and 5. Other components were added according to the prescription composition, as shown in the following table:

[0095] Prescription composition Prescription 4 Prescription 5 Flucoridine micellar concentrate 20mg / ml 28mg / ml Simethicone 0.10g / Span 85 / 0.20g Strawberry flavor 0.40g / Vanilla flavor 0.40g 0.80g Sucralose 0.20g 0.30g Methylparaben 0.45g 0.30g Propylparaben / 0.20g Disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution pH=6.0 pH=6.0 Total volume 400ml 400ml

[0096] While stirring continuously, add the defoaming agent simethicone, Span 85, strawberry flavor, vanilla flavor, sucralose, methylparaben, and propylparaben to the solutions of Examples 1-3 in the prescribed amounts and proportions, in that order. Then, adjust the pH to 6.0 with a sodium dihydrogen phosphate / sodium dihydrogen phosphate buffer solution and stir thoroughly.

[0097] After filtration, the prepared solution was placed in an amber glass bottle and sealed for storage.

[0098] Example 8

[0099] The concentrated micelle solution of Example 2 was added with flucoridine and sucrose (5% by weight of sucrose), mixed and stirred evenly, and the micelle solution was divided into portions. Placed in 10 ml glass bottles (3 mL / bottle), freeze-dried for 48 h to form a freeze-dried powder of flucoridine nano-micelles. The freeze-dried powder was identified by XRPD diffraction pattern, and the attached Figure 3 The spectrum shown in the attached Figure 3 It can be seen that there are diffuse peaks on the X-ray powder diffraction pattern. Figure 4 The differential scanning calorimetry analysis curves of the lyophilized powder of the flucoratine nanomicelles and the anhydrous flucoratine crystalline form of this example are curve b and curve a, respectively. Curve b is a flat curve, and no heat change occurs in the entire temperature range of 38-388°C. Curve a is the curve of the anhydrous flucoratine crystalline form, and a clear melting endothermic peak appears at approximately 260°C. This shows that the lyophilized powder of the flucoratine solid nanomicelles obtained by the method of this example no longer contains flucoratine crystals, but rather an amorphous state of flucoratine.

[0100] Example 9 Preparation of Flucoratine Freeze-dried Tablets

[0101] A flucoridine micellar concentrated solution was prepared according to the method of Example 1. Other components were added according to the prescription composition, as shown in the following table:

[0102] <![CDATA[ Prescription composition ]]> <![CDATA[ prescription ]]> <![CDATA[ Flucoridine micellar concentrate ]]> <![CDATA[ 3mL, 20mg / mL ]]> <![CDATA[ Simethicone ]]> <![CDATA[ 0.03g ]]> <![CDATA[ Vanilla flavor ]]> <![CDATA[ 0.15g ]]> <![CDATA[ Stevioside ]]> <![CDATA[ 0.03g ]]> <![CDATA[ sucrose ]]> <![CDATA[ 0.1g ]]> Disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution <![CDATA[ pH=6.8 ]]>

[0103] To the flucoridine micellar concentrated solution, simethicone, essence, steviol glycoside and sucrose were added in order according to the prescribed amount, and the mixture was stirred evenly. Disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution was added to adjust the pH to 6.8.

[0104] The solution was filled into a double aluminum packaging mold, transferred to a freeze-drying device for freeze-drying, and freeze-dried tablets were prepared.

[0105] Comparative Example Preparation of Flucoridine Soft Capsules

[0106] Flucortidine anhydrous crystalline solids with a purity exceeding 97% were ground through a 170-mesh sieve. For the preparation of the flucortidine raw material, refer to the description in 201710565804.X. Testing revealed that the ground flucortidine had a particle size of less than 90 μm. 0.4 g of beeswax and 15 g of corn oil were heated to 70°C and dissolved and mixed uniformly. Flucortidine was added to the corn oil and beeswax solution, and the resulting oil-soluble product was added to soft capsules to produce flucortidine oil-soluble soft capsules. Each flucortidine soft capsule contained 100 mg of flucortidine.

[0107] Example 10

[0108] In vivo pharmacokinetic study in beagle dogs

[0109] Male beagle dogs (aged 2-3 years, weighing approximately 8-10 kg) were purchased from Beijing Marshall Biotechnology Co. Ltd. They were housed in a room at 23 ± 2°C and 55 ± 10% humidity, with a 12-hour day / night cycle, and were allowed free access to food and water. They were fasted for 24 hours before dosing. The beagle dogs were administered the flucoridine nanomicelle oral solution described in Example 1 and the flucoridine soft capsules described in the comparative example, both at a dose of 20 mg flucoridine / kg body weight. Blood samples were collected from a peripheral vein at 0, 0.167, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours. Plasma was obtained by centrifugation at 4000 rpm for 10 minutes at 2-8°C. The plasma was then transferred to -75 ± 15°C for storage. The flucoridine nanomicelle oral solution was assigned to Group 1, and the flucoridine soft capsules were assigned to Group 2.

[0110] To evaluate whether Group 1 can improve the oral bioavailability of flucoratine compared to Group 2, a pharmacokinetic study was conducted in beagle dogs because the pharmacokinetic parameters in beagle dogs are different from those in mice but relatively close to those in humans. Four beagle dogs were used for Group 1 and six beagle dogs were used for Group 2. The pharmacokinetic parameters and comparative values ​​are listed in Table 1. The blood concentration curves throughout the experiment are shown in Figure 5 After oral administration, the maximum concentration of flucoridine in group 1 was C max was 595±350ng / mL, which was 9.5 times higher than that in group 2 (p<0.05); the AUC of group 1 last The concentration of flucoridine in group 1 was 3592±2267 h*ng / mL, which was 14.9 times higher than that in group 2 (p<0.05). These results show that the nanomicelle formulation in group 1 can significantly improve the absorption of flucoridine. This is because the solubility and permeability of flucoridine in group 1 are higher than those in group 2, which leads to the maximum concentration of flucoridine C max and AUC last There has been significant improvement.

[0111] Pharmacokinetic parameters following oral administration of Group 1 and Group 2 to beagle dogs.

[0112] Table 1

[0113] PK parameters Group 1 (n=4) Group 2 (n=6)

[0114] <![CDATA[T max (hours)]]> 1.25±0.50 1.42±0.66 <![CDATA[C max (ng / mL)]]> 595±350 62.7±14.3 <![CDATA[ T 半衰期 (hours)]]> NA 2.04±0.32 <![CDATA[AUC last (hr*ng / mL)]]> 3592±2267 241±283 <![CDATA[AUC INF (hr*ng / mL)]]> NA 245±293

[0115] NA: Unable to report a value.

Claims

1. A flucoridine nano-micelle preparation, comprising: Flucoridine and polymer excipients. When the preparation is a solid preparation, the flucoridine therein exists in an amorphous state. The X-ray powder diffraction pattern of the flucoridine nanomicelle preparation when it is a solid preparation is shown in Figure 3. The polymer excipients are polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and poloxamer 407.

2. The preparation according to claim 1, characterized in that This preparation is for oral administration.

3. The preparation according to claim 2, characterized in that The preparation is a liquid preparation or a solid preparation.

4. The preparation according to claim 1 or 3, characterized in that When the preparation is a solid preparation, the preparation contains, by mass, 1 part of flucoridine and 1-20 parts of polymer excipients.

5. The preparation according to claim 4, comprising, by mass, 1 part of flucoridine and 4 parts of polymer excipients.

6. The preparation according to claim 1 or 3, characterized in that When the preparation is a liquid preparation, it contains, by mass, 1 part of flucoridine, 2-20 parts of polymer excipients and 20-500 parts of water.

7. The preparation according to claim 6, when the preparation is a liquid preparation, contains, by mass: 1 part of flucoridine, 4 parts of polymer excipients and 250 parts of water.

8. A method for preparing the flucoridine nanomicelle preparation according to any one of claims 1 to 7, comprising the following steps: A) first dissolving flucoridine in an aqueous solution of sodium hydroxide to form a flucoridine solution; B) dissolving the polymer excipient in an aqueous solution of hydrochloric acid to form a polymer solution; C) adding the flucoridine solution to the polymer solution to form a suspension; D) centrifuging the suspension, removing the precipitate, and collecting the supernatant; E) The supernatant is concentrated to prepare micellar concentrate.

9. The method according to claim 8, characterized in that After step E, the method further comprises step E': adding one or more of a flavoring agent, a preservative and a defoaming agent to the flucoridine micelle concentrate and mixing them uniformly to obtain a flucoridine nano-micelle liquid preparation.

10. The method according to claim 8 or 9, characterized in that The method further comprises the following steps: F) adding freeze-drying excipients to the micelle concentrate and freeze-drying to prepare freeze-dried tablets.

11. The method according to claim 10, characterized in that The freeze-dried auxiliary material is selected from one or more of mannose, dextran, lactose, sucrose, glucose, glycine, trehalose and polyvinylpyrrolidone 10K, and the freeze-dried auxiliary material accounts for 1-50% of the total mass of flucoridine and the freeze-dried auxiliary material in the micelle concentrate.

12. The method according to claim 11, wherein the freeze-dried excipient accounts for 2-20% of the total mass of flucoratine and the freeze-dried excipient in the micellar concentrate.

13. The method according to claim 9, characterized in that The flavoring agent includes a sweetener and an aromatic. The sweetener is a non-sugar sweetener, the sweetener accounts for 0.01-1% of the mass of the flucoridine nano-micelle solid preparation, and the aromatic accounts for 0.01-5% of the mass of the flucoridine nano-micelle solid preparation.

14. The method according to claim 9, characterized in that The preservative accounts for 0.01-1% of the mass of the flucoridine nano-micelle solid preparation, and the defoaming agent accounts for 0.01-1% of the mass of the flucoridine nano-micelle solid preparation.

15. The method according to claim 8, wherein in step C), the flucoridine solution is added to the polymer solution while stirring at a speed of 20-2000 rpm; and in step D), the suspension is centrifuged at a speed of 1000-20000 rpm.

16. The method according to claim 8, characterized in that In step E), the concentration of flucoridine in the concentrated solution is 5-50 mg / mL.

17. The method according to claim 10, wherein: The freeze-drying temperature is -10 to -80°C.

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