Oridonin-containing microspheres as well as preparation method and pharmaceutical preparation thereof

Abstract

The invention relates to an oridonin-containing microsphere as well as a preparation method and a pharmaceutical preparation thereof, and belongs to the field of oridonin pharmaceutical preparations. The oridonin sustained-release microsphere comprises the following components: oridonin, a water-soluble carrier and a sustained-release carrier, wherein the mass ratio of the oridonin to the water-soluble carrier to the sustained-release carrier is (1-10): (0-10): (3-11). The oridonin-containing microspheres are prepared by stirring and mixing the oil phase containing the oridonin and the sustained-release carrier and the water phase, the preparation operation is simple, and the obtained oridonin-containing microspheres are round in shape, high in entrapment efficiency and capable of better delaying drug release and have an internal net-shaped structure. The microspheres are prepared into oral tablets or capsules, and compared with common in-vivo implanted preparations, the oral tablets or capsules are simpler and more convenient to use, better in physicochemical property, low in production cost and convenient to take and carry.

Description

Technical Field

[0001] The invention belongs to the field of Rubescensine A pharmaceutical preparations, and particularly relates to Rubescensine A-containing microspheres, a preparation method thereof, and a pharmaceutical preparation. Background Art

[0002] Solid dispersion is an effective technology to improve the bioavailability of poorly soluble drugs. The drug is dispersed in a water-soluble carrier in the form of microcrystals, molecules or amorphous forms, which improves the dissolution of the drug to a certain extent. Solid dispersions generally exist as intermediate preparations. In traditional methods, they are prepared into conventional dosage forms through operations such as crushing, sieving, granulation and tableting.

[0003] A drug sustained-release carrier refers to a material that encapsulates and loads drugs, thereby slowly releasing and acting on the drugs to improve the long-term effect of the drugs. It itself is harmless to the human body and can participate in the body's metabolism, forming harmless substances and being excreted from the body.

[0004] Oridonin A is a tetracyclic diterpenoid compound of kaurene extracted and isolated from the genus Ipomoea in the Lamiaceae family. It has strong anti-tumor activity and is mostly used as a new anti-cancer drug and anti-cancer adjuvant in clinical practice. Oridonin A has poor water solubility and low bioavailability. It is a Class IV drug in the biopharmaceutics classification system. Its properties hinder its therapeutic potential and further clinical application. Therefore, it is necessary to develop new drug formulations to improve its bioavailability. Summary of the invention

[0005] In view of the above problems, the present invention provides oridonin-containing microspheres and a preparation method and a pharmaceutical preparation thereof. The present invention uses a sustained-release carrier as a carrier of oridonin to prepare microspheres containing oridonin and prepares a solid dispersion, thereby increasing the solubility of oridonin and effectively improving the bioavailability of oridonin.

[0006] The first object of the present invention is to provide oridonin-containing microspheres, wherein the components of the oridonin-containing microspheres include oridonin, a water-soluble carrier and a sustained-release carrier, and the mass ratio of the oridonin, the water-soluble carrier and the sustained-release carrier is 1-10:0-10:3-11, wherein the mass of the water-soluble carrier can be 0.

[0007] Preferably, the mass ratio of Rubescensine A, water-soluble carrier and sustained-release carrier is 3:6:10.

[0008] Furthermore, the particle size of the Rubescensine A-containing microspheres is 5-120 μm.

[0009] Furthermore, the encapsulation efficiency of the Rubescensine A-containing microspheres is 72-91.62%.

[0010] Furthermore, the in vitro release time of the Rubescensine A-containing microspheres is 20 days.

[0011] Furthermore, the water-soluble carrier is one of polyethylene glycols, poloxamer and povidone.

[0012] Furthermore, the sustained-release carrier is one or a combination of polylactic acid-glycolic acid copolymer and polylactic acid.

[0013] Preferably, the sustained-release carrier is polylactic acid-glycolic acid copolymer. Polylactic acid-glycolic acid copolymer, abbreviated as PLGA in English, is polymerized from two monomers, lactic acid and glycolic acid. It is a degradable functional polymer organic compound with good biocompatibility. As a drug carrier, it has the characteristics of controlling drug release, improving drug efficacy, and reducing drug toxicity. The degradation products of PLGA are lactic acid and glycolic acid, which can participate in the metabolism of the human body and eventually form carbon dioxide and water, which are excreted from the body. It can be used as a good sustained-release carrier material.

[0014] Furthermore, the molecular weight of the polylactic acid-glycolic acid copolymer is 10 to 40 kDa.

[0015] The molecular weight of the polylactic acid-glycolic acid copolymer is 10-15 kDa, 15-20 kDa, 20-25 kDa, 25-30 kDa, 30-35 kDa or 35-40 kDa.

[0016] The second object of the present invention is to provide a method for preparing Rubescensine A-containing microspheres, comprising:

[0017] Slowly injecting the oil phase containing Rubescensine A and the sustained-release carrier into the water phase, and stirring at a fixed temperature for a predetermined time to obtain a mixed phase;

[0018] The mixed phase is added to the diluent, followed by vacuum rotary evaporation, freeze centrifugation, washing and freeze drying to obtain Rubescensine A-containing microspheres.

[0019] Furthermore, the oil phase containing Rubescensine A and a sustained-release carrier is prepared by mixing Rubescensine A, a sustained-release carrier and a first organic solvent.

[0020] Furthermore, when the oil phase is prepared by mixing oridonin, a sustained-release carrier and a first organic solvent, the mass ratio of oridonin to the sustained-release carrier is 1-4:10.

[0021] Preferably, the mass ratio of Rubescensine A to the sustained-release carrier is 3:10.

[0022] Furthermore, the oil phase containing Rubescensine A and a sustained-release carrier is prepared by mixing a Rubescensine A solid dispersion, a sustained-release carrier and a first organic solvent.

[0023] Furthermore, when the oil phase is prepared by mixing the oridonin solid dispersion, the sustained-release carrier and the first organic solvent, the mass ratio of the oridonin solid dispersion to the sustained-release carrier is 1-4:10.

[0024] Preferably, the mass ratio of the Rubescensine A solid dispersion to the sustained-release carrier is 3:10.

[0025] Furthermore, the oridonin solid dispersion is prepared by ultrasonically dissolving oridonin and a water-soluble carrier in a second organic solvent, followed by rotary evaporation, vacuum drying, pulverization and sieving.

[0026] Furthermore, the mass ratio of Rubescensine A to the water-soluble carrier is 1:1-6.

[0027] Furthermore, the second organic solvent is one of methanol, ethanol and acetone.

[0028] Preferably, the second organic solvent is methanol.

[0029] Furthermore, the first organic solvent is a mixture of acetone, methanol and dichloromethane.

[0030] Furthermore, the volume concentration of dichloromethane in the oil phase is 0-10%.

[0031] Furthermore, the volume ratio of acetone in the oil phase to dichloromethane in the oil phase is 1:15-20.

[0032] Preferably, the volume ratio of acetone in the oil phase to dichloromethane in the oil phase is 1:19.

[0033] Furthermore, the volume concentration of methanol in the oil phase is 8-11%.

[0034] Furthermore, the mass concentration of the sustained-release carrier in the oil phase is 30-35 mg / mL.

[0035] Preferably, the mass concentration of the sustained-release carrier in the oil phase is 33 mg / mL.

[0036] Furthermore, the aqueous phase is a polyvinyl alcohol aqueous solution.

[0037] Preferably, the mass concentration of polyvinyl alcohol in the polyvinyl alcohol aqueous solution for the water phase is 1-3%.

[0038] Furthermore, the diluent is a polyvinyl alcohol aqueous solution, and the concentration of the polyvinyl alcohol aqueous solution used for the diluent is lower than that of the polyvinyl alcohol aqueous solution used for the water phase.

[0039] Preferably, the mass concentration of polyvinyl alcohol in the polyvinyl alcohol aqueous solution used as the diluent is 0.1%.

[0040] Furthermore, the fixed temperature is 10-20°C.

[0041] Illustratively, the fixed temperature is 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C or 20°C.

[0042] Furthermore, the predetermined time is 20-30 minutes.

[0043] For example, the predetermined time is 20 min, 21 min, 22 min, 23 min, 24 min, 25 min, 26 min, 27 min, 28 min, 29 min or 30 min.

[0044] Furthermore, the stirring speed is 6000-8000 r / min.

[0045] Illustratively, the stirring speed is 6000 r / min, 6500 r / min, 7000 r / min, 7500 r / min or 8000 r / min.

[0046] Furthermore, the rotation speed of the refrigerated centrifuge is 13000-14000r / min.

[0047] For example, the rotation speed of the refrigerated centrifuge is 13000 r / min, 13100 r / min, 13200 r / min, 13300 r / min, 13400 r / min, 13500 r / min, 13600 r / min, 13700 r / min, 13800 r / min, 13900 r / min or 14000 r / min.

[0048] Preferably, the rotation speed of the refrigerated centrifuge is 13500 r / min.

[0049] Furthermore, the time of the refrigerated centrifugation is 35-50 min.

[0050] For example, the time of the refrigerated centrifugation is 35 min, 36 min, 37 min, 38 min, 39 min, 40 min, 41 min, 42 min, 43 min, 44 min, 45 min, 46 min, 47 min, 48 min, 49 min or 50 min.

[0051] Preferably, the refrigerated centrifugation time is 40 min.

[0052] The third object of the present invention is to provide a pharmaceutical preparation containing Rubescensine A microspheres, wherein the Rubescensine A microspheres are the above-mentioned Rubescensine A microspheres.

[0053] Furthermore, the dosage form of the pharmaceutical preparation is one of tablets, capsules, granules, dry suspensions, and pills.

[0054] Furthermore, the pharmaceutical preparation comprises Rubescensine A microspheres and an excipient.

[0055] Furthermore, the excipients include fillers, disintegrants, binders and lubricants.

[0056] Furthermore, the pharmaceutical preparation comprises the following steps:

[0057] The oridonin-containing microspheres, fillers and disintegrants prepared by the above method are sieved and mixed evenly, a binder solution is added to make a soft material, sieved and granulated, granulated, dried, dry granulated, a lubricant is added and mixed evenly, and then tableted or filled into capsules.

[0058] Furthermore, each unit dose contains 20 mg of Rubescensine A.

[0059] Furthermore, the filler is selected from one of lactose, pregelatinized starch, and microcrystalline cellulose;

[0060] Furthermore, the disintegrant is selected from one of carboxymethyl cellulose, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose;

[0061] Furthermore, the adhesive is corn starch slurry, and its mass concentration ranges from 1% to 5%;

[0062] Furthermore, the lubricant is selected from one of magnesium stearate, silicon dioxide, and talc;

[0063] Further, the soft material is sieved through a 20-mesh sieve to obtain fine particles, dried at 40°C, and sieved through a 30-mesh sieve to obtain fine particles;

[0064] Further, the moisture content of the particles is controlled below 5%;

[0065] Furthermore, the mass percentage of the filler is 30-90%, and the mass percentage of the disintegrant is 15-30%.

[0066] Beneficial effects of the present invention:

[0067] The present invention discloses a Rubescensine A-containing microsphere, a preparation method thereof, and a pharmaceutical preparation. The Rubescensine A-containing microsphere is prepared by stirring and mixing an oil phase and an aqueous phase containing Rubescensine A and a sustained-release carrier. The preparation operation is simple, and the obtained Rubescensine A-containing microsphere has a rounded shape, an internal mesh structure, and a high encapsulation rate, and can better delay the release of the drug. The combination of the two preparation methods of solid dispersion and microsphere can not only increase the solubility of the drug, but also slowly release the drug, reduce the patient's compliance, effectively improve the bioavailability, and have a good sustained-release effect.

[0068] In addition, the present invention prepares the microspheres into oral tablets or capsules, which are simpler and more convenient to use than general in vivo implant preparations, have better physical and chemical properties, low production costs, and are easy to take and carry.

[0069] Other features and advantages of the present invention will be described in the following description, and partly become apparent from the description, or understood by practicing the present invention. The purpose and other advantages of the present invention can be realized and obtained by the structures pointed out in the description, claims and drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0070] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0071] Figure 1 shows the dissolution curves of dispersions prepared using different water-soluble carriers in Example 2 of the present invention;

[0072] Figure 2 The dissolution rates of dispersions prepared with different first drug-carrying ratios in Example 2 of the present invention are shown;

[0073] Figure 3 The scanning electron microscope image of Rubescensine A powder in Example 2 of the present invention is shown;

[0074] Figure 4 The scanning electron microscope image of the solid dispersion of Rubescensine A in Example 2 of the present invention is shown;

[0075] Figure 5 An optical microscope image of microspheres prepared when the oil phase is acetone according to Example 6 of the present invention is shown;

[0076] Figure 6 An optical microscope image of microspheres prepared when the content of dichloromethane in the oil phase is 5% according to Example 6 of the present invention is shown;

[0077] Figure 7 An optical microscope image of microspheres prepared when the content of dichloromethane in the oil phase in Example 6 of the present invention is 10% is shown;

[0078] Figure 8 The encapsulation efficiency of microspheres prepared with different second drug loading ratios in Example 7 of the present invention is shown;

[0079] Fig. 9 This is an in vitro cumulative release curve of Rubescensine A-containing microspheres according to Example 8 of the present invention;

[0080] Fig.10 This is a particle size distribution diagram of the microspheres containing Rubescensine A according to Example 10 of the present invention;

[0081] Fig.11 This is a scanning electron micrograph of the entire Rubescensine A-containing microspheres according to Example 10 of the present invention;

[0082] Fig.12 This is a scanning electron micrograph of a cross-section of the Rubescensine A-containing microspheres according to Example 10 of the present invention. DETAILED DESCRIPTION

[0083] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0084] Example 1

[0085] This embodiment provides a method for preparing a solid dispersion of Rubescensine A, which specifically comprises the following steps:

[0086] S1: weigh 4 g of Rubescensine A and 8 g of Poloxamer 188;

[0087] S2: dissolving the weighed Rubescensine A and Poloxamer 188 by ultrasonication in methanol to form an organic phase;

[0088] S3: heating the organic phase in a water bath at 40°C and removing the methanol by vacuum rotary evaporation to obtain a relatively wet solid dispersion;

[0089] S4: The solid dispersion was frozen in a -20°C refrigerator for 24 hours, and then dried in a 40°C vacuum drying oven for 3 days. The solid dispersion was crushed and passed through a 60-mesh sieve to obtain Rubescensine A solid dispersion.

[0090] Example 2

[0091] This example screens water-soluble carrier materials and specific drug-to-water-soluble carrier mass ratios according to the steps in Example 1 under the controlled variable method:

[0092] The water-soluble carrier material is selected from polyethylene glycol, poloxamer, and povidone. The effect of different water-soluble carrier materials on the dissolution rate of the dispersion is investigated. The results are as follows: Figure 1 shown.

[0093] from Figure 1 From the data, it can be seen that the dissolution rate of drug-containing dispersion prepared by poloxamer is the highest and the solubilization effect is more obvious. Therefore, poloxamer 188 is selected as the water-soluble carrier material.

[0094] Drug-carrier ratio screening: Drug-carrier and water-soluble carrier were prepared according to the mass ratio (hereinafter referred to as the first drug-carrier ratio) of (1:1) to (1:6) to prepare drug-containing dispersions, and the effect of different first drug-carrier ratios on the dissolution rate of drug-containing dispersions was investigated. The results are as follows: Figure 2 shown.

[0095] from Figure 2 From the data, it can be seen that the dissolution rate is best when the first drug loading ratio is 1:2, so the first drug loading ratio is selected as 1:2.

[0096] The results of observing oridonin and oridonin solid dispersion by scanning electron microscopy are as follows: Figure 3 , 4 shown.

[0097] from Figure 3 and Figure 4 From the data in , it can be seen that Rubescensine A is an obvious crystalline solid. When it is prepared into a drug-containing dispersion, its crystal structure disappears, indicating that Rubescensine A is amorphous in the dispersion.

[0098] Example 3

[0099] This embodiment provides a method for preparing microspheres containing Rubescensine A, which specifically comprises the following steps:

[0100] S1: Weigh 3 g of Rubescensine A and 10 g of PLGA (molecular weight 30-40 kDa), add 30 mL of dichloromethane, 30 mL of methanol and 240 mL of acetone, and dissolve by ultrasonication to obtain the oil phase;

[0101] S1: Weigh 9 g of the prepared Rubescens solid dispersion and 10 g of PLGA, add 30 mL of dichloromethane, 30 mL of methanol and 240 mL of acetone, and dissolve by ultrasonication to obtain the oil phase;

[0102] S3: The emulsion was poured into a 0.1 wt% PVA solution for dilution, and the organic reagent was removed by vacuum rotary evaporation. The solution was centrifuged at 4°C (13500 r / min) for 40 min, and washed with deionized water. The process was repeated three times, and the microspheres were obtained by freeze drying.

[0103] Example 4

[0104] A method for preparing microspheres containing Rubescensine A specifically comprises the following steps:

[0105] S1: Weigh 90 mg of Rubescensine A solid dispersion prepared according to the parameters in Example 2 and 100 mg of PLGA. Add 0.3 mL of dichloromethane, 0.3 mL of methanol and 2.40 mL of acetone, and dissolve by ultrasonication to obtain the oil phase;

[0106] S2: The oil phase was slowly injected into 5 mL of 2 wt% PVA solution and stirred at room temperature for 20 min (8000 r / min) to form an emulsion;

[0107] S3: The emulsion was poured into a 0.1 wt% PVA solution for dilution, and the organic reagent was removed by vacuum rotary evaporation. The solution was centrifuged at 4°C (13500 r / min) for 40 min, and washed with deionized water. The process was repeated three times, and the microspheres were obtained by freeze drying.

[0108] Example 5

[0109] This example screens the PVA concentration according to the steps in Example 4 under the control variable method:

[0110] The PVA concentration will affect the encapsulation efficiency and particle size of the drug-loaded microspheres. The higher the PVA concentration, the greater the viscosity, and the particle size of the prepared drug-loaded microspheres will also increase accordingly. In this embodiment, the PVA mass concentration (the PVA mass concentration in step S2) is set to 1wt% to 5wt% to prepare microspheres and investigate them. The effects of different PVA mass concentrations on the encapsulation efficiency and particle size of microspheres containing Rubescensine A were detected, and the results are shown in Table 1 (Table of particle size and encapsulation efficiency of microspheres prepared with different PVA concentrations).

[0111] Table 1

[0112] PVA mass concentration (wt%) Particle size (μm) Encapsulation rate (%) 1 7.49±2.51 72.63 2 41.67±3.48 89.63 3 55.96±2.97 74.68 5 59.60±2.84 78.82

[0113] From the data in Table 1, it can be seen that when the PVA concentration is 2wt%, the encapsulation rate is the largest and the particle size is moderate. Therefore, in step 2, 2wt% PVA solution is selected as the aqueous phase.

[0114] Example 6

[0115] This example screens the oil phase ratio according to the steps in Example 4 under the control variable method:

[0116] Because oridonin, poloxamer 188 and PLGA are all easily soluble in acetone, acetone is preferred as the organic reagent of the oil phase. When only acetone is used, a large volume is required to dissolve oridonin. Therefore, a small amount of methanol is reasonably added to improve its solubility and reduce the volume of the oil phase. When only acetone and methanol are used, the microspheres are easy to agglomerate and the balling effect is poor. The results are shown in Figure 5 ;

[0117] Therefore, we considered adding an appropriate amount of dichloromethane to improve the microsphere morphology, and investigated the morphology and encapsulation efficiency of the microspheres when the volume percentage of dichloromethane was 1% and 2%. Figure 6 and Figure 7 The particle size and encapsulation efficiency results are shown in Table 2. Wherein, encapsulation efficiency = measured oridonin content / (actual oridonin+actual water-soluble carrier content+actual PLGA content)×100%.

[0118] Table 2

[0119] Dichloromethane volume percentage (%) Particle size (μm) Encapsulation rate (%) 0 42.21±4.57 78.02 1％ 45.40±2.84 89.46 2％ 43.79±2.26 79.25

[0120] From Table 2 and Figure 6-Figure 7 It can be seen that when the volume percentage of dichloromethane is 1%, the encapsulation efficiency of the drug-loaded microspheres is the highest, and the morphology is uniform with less aggregation. Therefore, the volume percentage of dichloromethane in the oil phase is selected to be 1%.

[0121] Example 7

[0122] In this example, the mass ratio of Rubescensine A to PLGA (hereinafter referred to as the second drug loading ratio) was screened under the controlled variable method according to the steps in Example 4:

[0123] Both the content of Rubescensine A and the content of PLGA can affect the viscosity of the oil phase. When the content of Rubescensine A is low, the viscosity of the drug in the oil phase is not high, and Rubescensine A will transition from the oil phase to the water phase, resulting in a low encapsulation rate. When the content of Rubescensine A is too high, PLGA is difficult to completely encapsulate, and the encapsulation rate will not be high.

[0124] Therefore, choosing an appropriate second drug loading ratio is very important for the encapsulation efficiency. In the examples, the second drug loading ratios were set to 1 / 5, 3 / 10, and 2 / 5 to prepare microspheres. The encapsulation efficiency results are shown in Figure 8 It can be seen that when the drug loading ratio is 3 / 10, the encapsulation efficiency is the highest. Therefore, the second drug loading ratio is selected to be 3 / 10.

[0125] Example 8

[0126] In this example, the oridonin-containing microspheres prepared according to the process parameters obtained in Examples 6-7 were subjected to an in vitro release test:

[0127] Weigh 16 mg of the obtained drug-loaded microspheres into a 10 mL centrifuge tube, add 5 mL of PBS buffer and seal it tightly, oscillate at a constant temperature and speed of 100 rpm at 37°C, centrifuge for a set time, take 0.5 mL of the supernatant, add 0.5 mL of PBS and continue oscillating, determine the concentration by HPLC, and calculate the cumulative release rate. Fig. 9 shown.

[0128] from Fig. 9 It can be seen that the drug release rate is faster in the first 24 hours, and the rate gradually slows down after 24 hours until it reaches the release platform at 20 days. It can be seen that the microspheres prepared by the present invention have a good sustained release effect.

[0129] Example 9

[0130] In this example, the encapsulation efficiency and saturation solubility of the Rubescensine A-containing microspheres prepared in Example 3 (abbreviated as ORI-PLGA-MS) and the Rubescensine A-containing microspheres prepared according to the process parameters obtained in Examples 6-7 (abbreviated as ORI-SD-PLGA-MS) were tested:

[0131] The encapsulation efficiency and saturated solubility at 30 days of the Rubescensine A-containing microspheres prepared in Example 3 and the Rubescensine A-containing microspheres prepared according to the process parameters obtained in Examples 6-7 were determined by HPLC. The results are shown in Table 3.

[0132] Encapsulation efficiency in ORI-PLGA-MS = measured Rubescensine A content / (actual Rubescensine A content+actual PLGA content)×100%;

[0133] In ORI-SD-PLGA-MS, the encapsulation efficiency = measured Rubescensine A content / (actual Rubescensine A+actual water-soluble carrier content+actual PLGA content)×100%.

[0134] Table 3

[0135] Microsphere Type Encapsulation efficiency Saturation solubility ORI-PLGA-MS 85.06％ 0.841±0.004 ORI-SD-PLGA-MS 91.62％ 2.184±0.011

[0136] From the data in Table 3, it can be seen that the drug encapsulation efficiency of Rubescensine A solid dispersion prepared into microspheres is improved to a certain extent, and the solubility is also better, which can improve the bioavailability of Rubescensine A to a certain extent.

[0137] Example 10

[0138] In this example, the particle size of the oridonin-containing microspheres prepared according to the process parameters obtained in Examples 6-7 was measured using a laser particle size analyzer, and their morphology was observed using a scanning electron microscope. The results are as follows: Fig.10 , Fig.11 , Fig.12 shown.

[0139] from Fig.10 It can be seen that the particle size D50 of the prepared microspheres is 36.14 μm, the particle size is relatively uniform, and the number of microspheres formed is large; Fig.11 It can be seen that the prepared microspheres are generally round, and the cross section ( Fig.11 The results in middle b) show that the microspheres have a network structure inside to encapsulate the drugs, which can greatly improve the sustained-release effect of the microspheres.

[0140] Embodiment 11

[0141] The preparation method of the oridonin pharmaceutical preparation specifically comprises the following steps:

[0142] S1: Weigh 1.2g of Rubescensine A, 4g of lactose and 1.4g of sodium hydroxypropyl methylcellulose, and premix the three;

[0143] S2: add appropriate amount of 2% corn starch slurry, granulate, and pass through a 20-mesh sieve;

[0144] S3: drying at 40℃, sieve through 30 mesh;

[0145] S4: Add 1.5% of the prescribed amount of silicon dioxide and mix thoroughly;

[0146] S5: compressing the obtained granules into tablets or filling capsules, each granule containing about 20 mg of drug;

[0147] The tablet weight, hardness and capsule weight were investigated, and the results are shown in Table 4. The dissolution of the tablets and capsules was also investigated, and the results are shown in Table 5.

[0148] Table 4

[0149]

[0150] Table 5

[0151]

[0152] Example 12

[0153] The preparation method of the oridonin pharmaceutical preparation specifically comprises the following steps:

[0154] S1: weigh 3.6 g of Rubescensine A solid dispersion prepared according to the parameters in Example 2, 1.6 g of lactose and 1.4 g of sodium hydroxypropyl methylcellulose, and premix;

[0155] S2: add appropriate amount of 2% corn starch slurry, granulate, and pass through a 20-mesh sieve;

[0156] S3: drying at 40℃, passing through a 30-mesh sieve to size the particles;

[0157] S4: Add 1.5% of the prescribed amount of silicon dioxide and mix thoroughly;

[0158] S5: compressing the obtained granules into tablets or filling capsules, each granule containing about 20 mg of drug;

[0159] The tablet weight, hardness, and capsule weight were investigated, and the results are shown in Table 6. The dissolution of the tablets and capsules was also investigated, and the results are shown in Table 7.

[0160] Table 6

[0161]

[0162] Table 7

[0163]

[0164] Example 13

[0165] The preparation method of the oridonin pharmaceutical preparation specifically comprises the following steps:

[0166] S1: Weigh 4 g of Rubescensine A microspheres prepared in Example 3, 1.2 g of lactose and 1.4 g of sodium hydroxypropyl methylcellulose, and premix;

[0167] S2: add appropriate amount of 2% corn starch slurry, granulate, and pass through a 20-mesh sieve;

[0168] S3: drying at 40℃, passing through a 30-mesh sieve to size the particles;

[0169] S4: Add 1.5% of the prescribed amount of silicon dioxide and mix thoroughly;

[0170] S5: compressing the obtained granules into tablets or filling capsules, each granule containing about 10 mg of drug;

[0171] The tablet weight, hardness and capsule weight were investigated, and the results are shown in Table 8. Dissolution tests were also conducted, and the results are shown in Table 9.

[0172] Table 8

[0173]

[0174]

[0175] Table 9

[0176]

[0177] Embodiment 14

[0178] The preparation method of the oridonin pharmaceutical preparation specifically comprises the following steps:

[0179] S1: Weigh 4 g of Rubescensine A-containing microspheres prepared according to the process parameters obtained in Examples 6-7, 1.2 g of lactose and 1.4 g of sodium hydroxypropyl methylcellulose, and premix them;

[0180] S2: add appropriate amount of 2% corn starch slurry, granulate, and pass through a 20-mesh sieve;

[0181] S3: drying at 40℃, passing through a 30-mesh sieve to size the particles;

[0182] S4: Add 1.5% of the prescribed amount of silicon dioxide and mix thoroughly;

[0183] S5: compressing the obtained granules into tablets or filling capsules, each granule containing about 10 mg of drug;

[0184] Tablet weight, hardness and capsule weight were investigated, and the results are shown in Table 10. Dissolution tests were also conducted, and the results are shown in Table 11.

[0185] Table 10

[0186]

[0187] Table 11

[0188]

[0189] From the data in Tables 5, 7, 9 and 11, it can be seen that the Rubescensine A-containing microspheres prepared in Example 3 and the pharmaceutical preparation formed by the Rubescensine A-containing microspheres prepared according to the process parameters obtained in Examples 6-7 both have obvious sustained-release effects.

[0190] Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent substitutions for some of the technical features therein; and these modifications or substitutions do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A microsphere containing Rubescensine A, characterized in that: The components of the oridonin-containing microspheres include oridonin, a water-soluble carrier and a sustained-release carrier, and the mass ratio of the oridonin, the water-soluble carrier and the sustained-release carrier is 1-10:0-10:3-11.

2. The Rubescensine A-containing microspheres according to claim 1, characterized in that: The water-soluble carrier is one of polyethylene glycols, poloxamer and povidone.

3. The Rubescensine A-containing microspheres according to claim 1, characterized in that: The sustained-release carrier is one or a combination of polylactic acid-glycolic acid copolymer and polylactic acid.

4. The Rubescensine A-containing microspheres according to claim 3, characterized in that: The molecular weight of the polylactic acid-glycolic acid copolymer is 10-40 kDa.

5. A method for preparing microspheres containing Rubescensine A, characterized in that: The Rubescensine A-containing microspheres are the Rubescensine A-containing microspheres according to any one of claims 1 to 4, comprising: Slowly injecting the oil phase containing Rubescensine A and the sustained-release carrier into the water phase, and stirring at a fixed temperature for a predetermined time to obtain a mixed phase; The mixed phase is added to the diluent, followed by vacuum rotary evaporation, freeze centrifugation, washing and freeze drying to obtain Rubescensine A-containing microspheres.

6. The method for preparing Rubescensine A-containing microspheres according to claim 5, characterized in that: The oil phase containing Rubescensine A and a sustained-release carrier is prepared by mixing Rubescensine A, the sustained-release carrier and a first organic solvent.

7. The method for preparing Rubescensine A-containing microspheres according to claim 5, characterized in that: The oil phase containing Rubescensine A and a sustained-release carrier is prepared by mixing Rubescensine A solid dispersion, a sustained-release carrier and a first organic solvent.

8. The method for preparing Rubescensine A-containing microspheres according to claim 7, characterized in that: The oridonin solid dispersion is prepared by ultrasonically dissolving oridonin and a water-soluble carrier in a second organic solvent, followed by rotary evaporation, vacuum drying, pulverization and sieving; the second organic solvent is one of methanol, ethanol and acetone.

9. The method for preparing Rubescensine A-containing microspheres according to claim 7, characterized in that: The first organic solvent is a mixture of acetone, methanol and dichloromethane.

10. The method for preparing Rubescensine A-containing microspheres according to claim 9, characterized in that: The volume concentration of dichloromethane in the oil phase is 0-10%, the volume ratio of acetone in the oil phase to dichloromethane in the oil phase is 1:15-20, and the volume concentration of methanol in the oil phase is 8-11%.

11. The method for preparing Rubescensine A-containing microspheres according to claim 5, characterized in that: The mass concentration of the sustained-release carrier in the oil phase is 30-35 mg / mL.

12. The method for preparing Rubescensine A-containing microspheres according to claim 5, characterized in that: The aqueous phase is a polyvinyl alcohol aqueous solution; the mass concentration of polyvinyl alcohol in the polyvinyl alcohol aqueous solution is 1-3%.

13. The method for preparing Rubescensine A-containing microspheres according to claim 5, characterized in that: The diluent is a polyvinyl alcohol aqueous solution, and the concentration of the polyvinyl alcohol aqueous solution used for the diluent is lower than that of the polyvinyl alcohol aqueous solution used for the water phase.

14. The method for preparing Rubescensine A-containing microspheres according to claim 5, characterized in that: The fixed temperature is 10-20° C., the predetermined time is 20-30 min, and the stirring speed is 6000-8000 r / min.

15. A pharmaceutical preparation containing Rubescensine A microspheres, characterized in that: The Rubescensine A-containing microspheres are the Rubescensine A-containing microspheres according to any one of claims 1 to 4.

16. The pharmaceutical preparation containing Rubescensine A microspheres according to claim 15, characterized in that: The pharmaceutical preparation comprises Rubescensine A microspheres and excipients, wherein the excipients comprise a filler, a disintegrant, a binder and a lubricant.

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