Dacrotamide sustained-release microsphere and preparation method thereof

Abstract

The invention relates to the technical field of drug sustained-release microspheres, and particularly provides a dalotamide sustained-release microsphere which is of a structure composed of an inner layer and an outer layer, and the inner layer is coated with the outer layer; the inner layer is prepared from the following raw material components: first PLGA and dalotamide; the outer layer is prepared from the following raw material components: second PLGA, dalotamide dispersed particles and a release regulator; the dalotamide dispersed particles are prepared from the dalotamide and Soluplus; the release regulator is selected from a hydrophilic substance and / or a pore-foaming agent. According to the microspheres disclosed by the invention, the programmed release effect of'early-stage quick release-medium-stage stable release-long-term slow release 'of the dalotamide can be realized, and the stability of the dalotamide is good.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical microspheres, specifically providing dalotamide sustained-release microspheres and their preparation method. Background Technology

[0002] Darolactone is a nonsteroidal anti-androgen drug used to treat non-metastatic castration-resistant prostate cancer. It inhibits prostate cancer cell growth by competitively binding to the androgen receptor (AR), blocking AR activation. Darolactone is poorly soluble in water and aqueous media, limiting its absorption in the intestine and resulting in low bioavailability. Currently, darolactone is only available in oral tablet form, requiring twice-daily oral administration for 2-5 days to reach steady state, which is inconvenient for patients.

[0003] Drug microspheres, as a novel drug delivery system, can achieve effects such as long-lasting release, improved bioavailability, and enhanced patient compliance. However, when dallotamine is prepared into dallotamine sustained-release microspheres, there are still shortcomings in terms of drug stability, dissolution, and long-lasting release. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides dalotamide sustained-release microspheres and a method for their preparation.

[0005] The technical solution of the present invention is as follows: A dalotatamine sustained-release microsphere having a structure consisting of an inner layer and an outer layer, wherein the outer layer covers the inner layer; The raw material components of the inner layer include a first PLGA and dallotamine; The outer layer of raw material components includes a second PLGA, dalotamiamine dispersion particles, and a release regulator; The dallotamine dispersion particles are composed of dallotamine and Soluplus; The release regulator is selected from hydrophilic substances and / or porogens.

[0006] Preferably, the weight ratio of the inner layer to the outer layer is 1:0.5-1.

[0007] Preferably, the molar ratio of LA to GA in the first PLGA is 70:30-85:15; The molar ratio of LA to GA in the second PLGA is 50:50-65:35.

[0008] Preferably, the dallotamine accounts for 10-30% by weight of the raw material components in the inner layer; The dallotamine in the raw material components of the inner layer is micronized dallotamine; The weight percentage of daloltadine in the daloltadine dispersion particles is 10-30%; The daloltadine dispersion particles, calculated as daloltadine, are in a weight ratio of 1:2-4 to the second PLGA.

[0009] Preferably, the raw material components of the inner layer further include a pH adjuster, which adjusts the pH of the inner layer to 8-9.

[0010] Preferably, the hydrophilic substance is selected from one or a combination of two or more of polyethylene glycol, polyvinylpyrrolidone, and polyvinyl alcohol; The hydrophilic substance accounts for 1-10% of the weight of the raw material components in the outer layer.

[0011] Preferably, the pore-forming agent is selected from mannitol and / or trehalose; The pore-forming agent accounts for 5-25% by weight of the raw material components in the outer layer.

[0012] A method for preparing dalotamide sustained-release microspheres according to any of the above embodiments, comprising the steps of: A W / O emulsion containing the raw material components of the inner layer in the oil phase is prepared, and the organic solvent is removed to obtain the inner layer microspheres; The raw material components of the outer layer are dissolved or dispersed in a coating solvent to form a coating solution; the coating solution coats the inner microspheres to form coated microspheres. The coated microspheres are then subjected to freeze-drying with a lyophilization protective solution to obtain the dalotahamine sustained-release microspheres.

[0013] Preferably, the coating solvent is selected from one or a combination of two or more of acetone, ethyl acetate, butyl acetate, isopropanol, and anhydrous ethanol; The weight-to-volume ratio of the raw material components of the outer layer to the coating solvent is 0.5-1.2g:5ml.

[0014] Preferably, the freeze-drying protective solution contains mannitol and / or sucrose; The freeze-drying includes pre-freezing and subsequent low-temperature drying. The pre-freezing is maintained at -5~0℃ for 20-60 minutes, and the low-temperature drying is maintained at -30~-40℃ for 4-6 hours.

[0015] The beneficial effects of this invention are: (1) The present invention adopts a double-layer coating structure consisting of an inner layer and an outer layer, forming a better physical barrier to effectively isolate the effects of light, oxygen and moisture on the stability of daloltadine. Both the inner and outer layers of the double-layer structure contain daloltadine, which overcomes the defects of the single-layer microsphere drug release mode and realizes a programmed release curve of "initial rapid release - mid-term stable release - long-term sustained release". This not only improves the dissolution performance of poorly soluble drugs, but also maintains steady-state blood drug concentration and significantly improves bioavailability.

[0016] (2) Adding a pH adjuster to the inner layer can inhibit the hydrolysis reaction of dalotamiamine. The amorphous structure of the outer solid dispersion reduces the risk of dalotamiamine crystal transformation and improves the stability of dalotamiamine. Attached Figure Description

[0017] Figure 1 This is a SEM image of the dalotamide sustained-release microspheres from Example 1.

[0018] Figure 2 The following is a trend of blood drug concentration changes in vivo for the dalotamide sustained-release microspheres of Example 7. Detailed Implementation

[0019] The technical solution of the present invention will be further explained and described below through specific embodiments.

[0020] On the one hand, the present invention proposes a dalotamide sustained-release microsphere having a structure consisting of an inner layer and an outer layer, with the outer layer covering the inner layer; The inner layer's raw material components include first PLGA and dalotamide; The outer layer of raw material components includes a second PLGA, dalotamide dispersion particles, and a release modifier; Daroltadine dispersion particles are composed of daroltadine and Soluplus; The release regulator is selected from hydrophilic substances and / or porogens.

[0021] The dalotartamine sustained-release microspheres of the present invention consist of an inner layer and an outer layer, both of which contain dalotartamine and a biodegradable polymer (PLGA). As the second PLGA and the first PLGA gradually degrade, a programmed release microsphere structure of "initial rapid release - mid-term stable release - long-term sustained release" is constructed, which improves the sustained-release effect. Moreover, the bilayer structure of the microspheres provides a good physical barrier for the stability of dalotartamine, thereby improving the stability of dalotartamine in the microspheres.

[0022] In this invention, both the inner and outer layer raw material components use PLGA as the matrix polymer. PLGA has good biodegradability and a fast degradation rate, promoting initial drug release. There are no particular limitations on the intrinsic viscosity of the first and second PLGA; for example, the intrinsic viscosity can be 0.2-0.8 dL / g. Considering that the first PLGA needs to degrade slowly while the second PLGA needs to degrade rapidly, the intrinsic viscosity of the first PLGA can be higher than that of the second PLGA. For example, the intrinsic viscosity of the first PLGA can be 0.6-0.8 dL / g, and the intrinsic viscosity of the second PLGA can be 0.2-0.5 dL / g.

[0023] In some embodiments, the weight ratio of the inner layer to the outer layer is 1:0.5-1. For example, the weight ratio of the inner layer to the outer layer can be any value or any value in between, such as 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, etc., without any particular limitation.

[0024] In some embodiments, the molar ratio of LA to GA in the first PLGA is 70:30-85:15; The molar ratio of LA to GA in the second PLGA is 50:50-65:35.

[0025] PLGA is a copolymer of lactic acid (LA) and glycolic acid (GA). It has good biocompatibility and is non-toxic. The degradation rate of PLGA can be adjusted by regulating the molar ratio of LA to GA. The higher the proportion of LA in PLGA, the slower the degradation rate; the lower the proportion of LA, the faster the degradation rate. In this invention, the first PLGA in the inner layer has a higher molar proportion of LA, resulting in a slower degradation rate, while the second PLGA in the outer layer has a lower molar proportion of LA, resulting in a faster degradation rate. That is, the molar proportion of LA in the first PLGA is greater than that in the second PLGA. The second PLGA in the outer layer undergoes rapid degradation first, achieving rapid release of dalotamidine in the initial stage. The first PLGA in the inner layer undergoes slow degradation in the later stage, achieving slow release of dalotamidine in the later stage, thus achieving a sustained-release effect of "rapid release in the initial stage - stable release in the middle stage - sustained release in the long stage".

[0026] For example, the molar ratio of LA to GA in the first PLGA can be any value or any value in between, such as 70:30, 75:25, 80:20, 85:15, etc., without any particular restriction. Similarly, the molar ratio of LA to GA in the second PLGA can be any value or any value in between, such as 50:50, 55:45, 60:40, 65:35, etc., without any particular restriction.

[0027] In some embodiments, dallotamine accounts for 10-30% by weight of the raw material components in the inner layer; The dallotamine in the inner layer is micronized dallotamine; The weight percentage of daloltadine in daloltadine dispersion particles is 10-30%; The weight ratio of dalolactamine dispersion particles to the second PLGA is 1:2-4, based on dalolactamine.

[0028] The use of micronized dalolactamine in the inner layer of raw material components is beneficial for improving release rate and bioavailability. The average particle size of micronized dalolactamine can be 1-10 μm. There are no particular restrictions on the preparation method of micronized dalolactamine; for example, it can be prepared by air jet milling.

[0029] For example, the weight percentage of darotamide in the raw material components of the inner layer can be any value or any value between 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, 30%, etc., without any particular restrictions.

[0030] For example, the weight percentage of dalolactamine in the dalolactamine dispersion particles can be any value or any value between 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, 30%, etc., without any particular restriction. The weight ratio of dalolactamine dispersion particles (based on dalolactamine) to the second PLGA can be any value or any value between 1:2, 1:2.5, 1:3, 1:3.5, 1:4, etc., without any particular restriction.

[0031] There are no particular limitations on the preparation method of dalolactamine dispersion particles. One method is to mix dalolactamine and Soluplus with an appropriate amount of water to obtain a mixture; the mixture is then melt-blended in a hot melt extruder at 150-180℃ and extruded. After the extruded strips are cooled, they are ground and sieved to obtain solid dispersion particles with a particle size of 1-10 μm.

[0032] In some embodiments, the raw material components of the inner layer further include a pH adjuster, which adjusts the pH of the inner layer to 8-9.

[0033] The present invention employs the following two measures to improve the stability of daloltadine: (1) Soluplus (polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) is used as a dispersion carrier in the outer layer to reduce the risk of daloltadine crystal transformation; (2) A pH adjuster is added to the inner layer to adjust the pH of the internal raw material components to a weakly alkaline state (8-9), thereby inhibiting the deliquescence and / or hydrolysis of daloltadine during storage. There are no particular limitations on the pH adjuster; it can be an inorganic base and / or an organic base, such as one or a combination of two or more of disodium hydrogen phosphate, trisodium phosphate, dipotassium hydrogen phosphate, sodium carbonate, sodium hydroxide, and potassium hydroxide.

[0034] In some embodiments, the hydrophilic material is selected from one or a combination of two or more of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and polyvinyl alcohol (PVA); The weight percentage of hydrophilic substances in the raw material components of the outer layer is 1-10%.

[0035] Adding hydrophilic substances to the outer layer of raw material components can improve the hydrophilicity of dalotamide sustained-release microspheres, which is beneficial for the wetting and penetration of microspheres by in vivo fluids, accelerating the degradation of PLGA and the dissolution of dalotamide. For polyethylene glycol, the molecular weight can be 200-10000 g / mol. For polyvinyl alcohol, the degree of alcoholysis can be 80-95%. For example, the weight percentage of the hydrophilic substance in the outer layer of raw material components can be any value or any value between 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, etc., without any particular restriction.

[0036] In some embodiments, the pore-forming agent is selected from mannitol and / or trehalose; The weight percentage of the pore-forming agent in the raw material components of the outer layer is 5-25%.

[0037] A porogen is added to the outer layer of the raw material components. Under the influence of in vivo fluid (e.g., dissolution), the porogen can form micropores in the outer layer of the dallotamine sustained-release microspheres, facilitating fluid penetration and accelerating the degradation of the second PLGA and the dissolution of dallotamine in the outer layer. The formation of micropores in the outer layer also accelerates the wetting of the inner layer of the microspheres by the in vivo fluid and its degradation of the first PLGA, further accelerating the dissolution of dallotamine in the inner layer.

[0038] On the other hand, the present invention also provides a method for preparing dalotamide sustained-release microspheres according to any of the above embodiments, the steps of which include: A W / O emulsion containing the inner layer of the raw material components in the oil phase was prepared, and the organic solvent was removed to obtain the inner layer microspheres; The outer layer of raw material components is dissolved or dispersed in a coating solvent to form a coating solution; the coating solution coats the inner layer of microspheres to form coated microspheres. Add a freeze-drying protective solution to the coated microspheres and then freeze-dry them to obtain darotamide sustained-release microspheres.

[0039] This invention first prepares inner-layer microspheres via emulsification, and then coats the outer layer onto the surface of the inner-layer microspheres using a coating method, thereby obtaining dalotamidine sustained-release microspheres with a bilayer structure. For the method of preparing a W / O emulsion in which the oil phase contains the inner-layer feed component, existing techniques can be followed. For example, the inner-layer feed component is dissolved or dispersed in an organic solvent to form an oil phase, which is then dispersed in an aqueous phase containing an emulsifier to form a W / O emulsion. The organic solvent is removed from the W / O emulsion, and the precipitate yields the inner-layer microspheres.

[0040] In some embodiments, the coating solvent is selected from one or a combination of two or more of acetone, ethyl acetate, butyl acetate, isopropanol and anhydrous ethanol; The weight-to-volume ratio of the outer layer raw material components to the coating solvent is 0.5-1.2g:5ml.

[0041] For example, the weight-to-volume ratio of the outer raw material component to the coating solvent can be 0.5g:5ml, 0.7g:5ml, 0.8g:5ml, 1g:5ml, 1.2g:5ml, etc.

[0042] In some embodiments, the lyophilization protectant contains mannitol and / or sucrose; the concentration of mannitol and / or sucrose may be 5 wt%; Freeze-drying includes pre-freezing and subsequent low-temperature drying. Pre-freezing involves maintaining a temperature of -5 to 0°C for 20-60 minutes, and low-temperature drying involves maintaining a temperature of -30 to -40°C for 4-6 hours. There are no particular limitations on the cooling rate during pre-freezing (0.5-2°C / min) or low-temperature drying (0.5-2°C / min). This freeze-drying method, combining pre-freezing and low-temperature drying, maintains the integrity of the microsphere structure and prevents microsphere collapse and dallotamine leakage.

[0043] The technical solution of the present invention will be further described and illustrated below with reference to various embodiments. Unless otherwise specified, the parts mentioned in the following embodiments are parts by weight.

[0044] Example 1 Preparation of dalolactamine solid dispersion: 0.3 g dalolactamine and 0.7 g Soluplus were added to 2 g water and stirred until homogeneous to obtain a mixture. The mixture was then melt-blended in a hot melt extruder at 150 °C and extruded. After cooling, the extruded strips were ground and sieved to obtain solid dispersion particles with an average particle size of 6 μm.

[0045] Preparation of micronized darolactamine: Darolactamine was coarsely pulverized, passed through a 40-mesh sieve, and then micronized using an air jet milling method, with an average particle size of 3 μm.

[0046] Preparation of inner layer microspheres: 1.0 g of first PLGA (LA:GA=75:25, intrinsic viscosity 0.65 dL / g), 0.3 g of micronized dallotamine, and 0.05 g of dipotassium hydrogen phosphate (adjusted to pH 8-8.5) were dissolved in 10 mL of dichloromethane as the oil phase; the oil phase was added dropwise to 100 mL of aqueous phase containing 1 wt% PVA, and high-speed shear emulsification was carried out at 10000 rpm for 3 minutes to form a primary emulsion; the primary emulsion was stirred at room temperature for 6 hours, the dichloromethane was evaporated to remove it, the wet microspheres were collected by centrifugation, and the inner layer microspheres were obtained after washing.

[0047] Outer coating: 0.5g of second PLGA (LA:GA=50:50, intrinsic viscosity 0.23 dL / g), 0.2g of dalolatadine solid dispersion (calculated as dalolatadine), 0.025g of PEG-4000 and 0.075g of mannitol were dissolved in 5mL of acetone to prepare the coating solution; the coating solution coated the inner microspheres to form a microsphere suspension.

[0048] Freeze-drying: The above microsphere suspension was added to a freeze-drying protective solution containing 5% mannitol and freeze-drying was carried out in stages: first, the temperature was lowered to 0℃ at 1℃ / min and held for 30 min, then the temperature was lowered to -40℃ at 0.5℃ / min and held for 4 h.

[0049] After freeze-drying, the following temperature-increasing drying process was performed: (1) primary drying, maintained at -10℃ for 25 hours, with a vacuum of 0.1 mbar; (2) secondary drying, heated to 45℃ at 0.5℃ / min and maintained for 8 hours, with a vacuum of 0.05 mbar; (3) tertiary drying, heated to 50℃ at 0.5℃ / min and maintained for 3 hours, with a vacuum of 0.05 mbar. Darlotamine sustained-release microspheres were obtained after the temperature-increasing drying process.

[0050] The SEM images of the dalotamide sustained-release microspheres in this embodiment are attached. Figure 1 As shown, it has a distinct microsphere structure.

[0051] Comparative Example 1 The inner layer microspheres in Example 1 were dried according to the freeze-drying steps in Example 1 to obtain dalotamid sustained-release microspheres.

[0052] Comparative Example 2 The difference between this comparative example and Example 1 is that in Example 1, the dalolactamine solid dispersion was replaced with 0.2g of micronized dalolactamine from Example 1 during the outer coating process. The remaining steps remained unchanged.

[0053] Example 2 The difference between this embodiment and Embodiment 1 is that in Embodiment 1, dipotassium hydrogen phosphate was not added when preparing the inner layer microspheres. The remaining steps remain unchanged.

[0054] Example 3 The difference between this embodiment and Embodiment 1 is that in Embodiment 1, PEG-4000 was not added during the outer coating process. The remaining steps remain unchanged.

[0055] Example 4 The difference between this embodiment and Embodiment 1 is that in Embodiment 1, mannitol was not added during the outer coating process. The remaining steps remain unchanged.

[0056] Comparative Example 3 The difference between this embodiment and Embodiment 1 is that in Embodiment 1, PEG-4000 and mannitol were not added during the outer coating process. The remaining steps remained unchanged.

[0057] Example 5 The difference between this embodiment and Embodiment 1 is that in Embodiment 1, when preparing the inner layer microspheres, the first PLGA was replaced with an equal weight of the second PLGA. The remaining steps remain unchanged.

[0058] Example 6 The difference between this embodiment and Embodiment 1 is that in Embodiment 1, during the outer layer coating, the second PLGA is replaced with an equal weight of the first PLGA from Embodiment 1. The remaining steps remain unchanged.

[0059] The performance of the darotahide sustained-release microspheres of Examples 1-6 and Comparative Examples 1-3 is shown in Table 1 below.

[0060] D90 particle size: measured using a laser particle size analyzer.

[0061] Cumulative release determination: Refer to the release determination method in (General Chapter 0931, Part IV, Chinese Pharmacopoeia 2025 Edition) to determine the cumulative release rate (%) of darotamid sustained-release microspheres at 2h, 28h and 72h.

[0062] Drug content determination: Dichloromethane was used to fully demulsify the PLGA sustained-release microspheres. Methanol was added and the mixture was sonicated to fully dissolve dallotamine. The supernatant was collected by centrifugation and filtered as the test solution. The dallotamine content was determined by high-performance liquid chromatography (HPLC). Encapsulation efficiency was calculated as the ratio of encapsulated drug amount to the total amount of encapsulated drug in the microsphere formulation. This indicator directly reflects the drug loading efficiency and actual drug content level of the microspheres.

[0063] Stability: Daroltadine sustained-release microspheres were stored at (40±2)℃ and (75±5)% relative humidity for 6 months. The drug content of daroltadine in the sustained-release microspheres was determined by high performance liquid chromatography.

[0064] Table 1

[0065] Therefore, comparing Example 1 and Comparative Example 1, it can be seen that the dalotartamine sustained-release microspheres of the present invention, with dalotartamine distributed in both the inner and outer layers, achieve a release effect of "initial rapid release - mid-term stable release - long-term sustained release." In contrast, in Comparative Example 1, the initial release was too rapid, and the later release was slower, with incomplete release after 72 hours, and the stability of dalotartamine in the microspheres was relatively poor. Comparing Examples 1, 3, 4, and Comparative Example 3, it can be seen that adding hydrophilic substances and / or porogens to the outer layer can significantly improve the initial release rate and release completeness. In Comparative Example 3, without the addition of hydrophilic substances and porogens, the release rate was significantly slower, and the release completeness was also poor. Comparing Examples 1 and 2, adding a pH adjuster to adjust the pH to 8-9 in the inner layer can significantly improve the stability of the drug. Comparing Examples 1 and 5-6, the release rate of the microspheres is more suitable when the degradation rate of PLGA in the inner layer is slower and the degradation rate of PLGA in the outer layer is faster.

[0066] Example 7 Preparation of dalolactamine solid dispersion: 0.2 g dalolactamine and 0.8 g Soluplus were added to 2.5 g water and stirred until homogeneous to obtain a mixture. The mixture was then melt-blended in a hot melt extruder at 160 °C and extruded. After cooling, the extruded strips were ground and sieved to obtain solid dispersion particles with an average particle size of 4 μm.

[0067] Preparation of micronized darolactamine: Darolactamine was coarsely pulverized, passed through a 30-mesh sieve, and then micronized using an air jet milling method, with an average particle size of 2 μm.

[0068] Preparation of inner layer microspheres: 1.0 g of first PLGA (LA:GA=70:30, intrinsic viscosity 0.65 dL / g), 0.2 g of micronized dallotamine, and 0.05 g of disodium hydrogen phosphate (adjusted to pH 8.5-9) were dissolved in 10 mL of dichloromethane as the oil phase. The oil phase was added dropwise to 100 mL of aqueous phase containing 1 wt% PVA, and high-speed shear emulsification was carried out at 10000 rpm for 5 minutes to form a primary emulsion. The primary emulsion was stirred at room temperature for 6 hours, and the dichloromethane was evaporated to remove it. The wet microspheres were collected by centrifugation and washed to obtain the inner layer microspheres.

[0069] Outer coating: 0.5g of second PLGA (LA:GA=55:45, intrinsic viscosity 0.25 dL / g), 0.25g of daloltadine solid dispersion (calculated as daloltadine), 0.04g of PVP K-30 and 0.12g of trehalose were dissolved in 5mL of acetone to prepare the coating solution; the coating solution coated the inner microspheres to form a microsphere suspension.

[0070] Freeze-drying: The above microsphere suspension was added to a freeze-drying protective solution containing 5% mannitol and freeze-drying was carried out in stages: first, the temperature was lowered to 0℃ at 1.5℃ / min and held for 30 min, and then the temperature was lowered to -40℃ at 1℃ / min and held for 4 h.

[0071] After freeze-drying, the following temperature-increasing drying process was performed: (1) primary drying, maintained at -10℃ for 25 hours, with a vacuum of 0.1 mbar; (2) secondary drying, heated to 45℃ at 0.5℃ / min and maintained for 8 hours, with a vacuum of 0.05 mbar; (3) tertiary drying, heated to 50℃ at 0.5℃ / min and maintained for 3 hours, with a vacuum of 0.05 mbar. Darlotamine sustained-release microspheres were obtained after the temperature-increasing drying process.

[0072] Example 8 The difference between this embodiment and Embodiment 7 is that in Embodiment 7, when preparing the inner layer microspheres, the ratio of LA:GA in the first PLGA was adjusted from 70:30 to 80:20. The remaining steps remain unchanged.

[0073] Example 9 The difference between this embodiment and Embodiment 7 is that in Embodiment 7, when preparing the inner layer microspheres, the first PLGA was adjusted from 0.65 dL / g to 0.8 dL / g, while the weight remained unchanged. The remaining steps remained the same.

[0074] Example 10 The difference between this embodiment and Embodiment 7 is that in Embodiment 7, during the outer coating process, the second PLGA was adjusted from 0.25 dL / g to 0.35 dL / g, while the weight remained unchanged. The remaining steps remained the same.

[0075] Example 11 The difference between this embodiment and Embodiment 7 is that in Embodiment 7, the amount of PVP K-30 used for the outer coating was adjusted from 0.04g to 0.01g. The remaining steps remain unchanged.

[0076] Example 12 The difference between this embodiment and Embodiment 7 is that in Embodiment 7, the amount of trehalose used for the outer coating was adjusted from 0.12g to 0.025g. All other steps remained unchanged.

[0077] The cumulative release performance of the dalotamide sustained-release microspheres in Examples 7-12 is shown in Table 2 below.

[0078] Table 2 Cumulative Release Rate / %

[0079] As shown in Table 2 above, the lower the degradation rate of the first and second PLGA, the slower the release of daloltadine from the microspheres. Reducing the amount of hydrophilic substances and pore-forming agents in the inner layer also reduces the release rate of daloltadine from the microspheres. However, the daloltadine sustained-release microspheres of Examples 7-12 can still generally achieve the release effect of "initial rapid release - mid-term stable release - long-term sustained release".

[0080] Comparative Example 4 The difference between this comparative example and Example 7 is that in Example 7, citric acid was added to the inner layer to adjust the pH to 2-2.5. The remaining steps remain unchanged.

[0081] Comparative Example 5 The difference between this comparative example and Example 7 is that in Example 7, citric acid was added to the inner layer to adjust the pH to 5.5-6. The remaining steps remained unchanged.

[0082] Comparative Example 6 The difference between this comparative example and Example 7 is that in Example 7, citric acid was added to the inner layer to adjust the pH to 6.5-7. The remaining steps remained unchanged.

[0083] The dalotatamide sustained-release microspheres of Examples 7 and Comparative Examples 4-6 were placed at (40±2)℃ and (75±5)% relative humidity for 6 months, and the changes in the appearance and morphology of the microspheres and the changes in the dalotatamide drug content were observed. The results are shown in Table 3 below.

[0084] Table 3

[0085] As shown in Table 3, adjusting the pH of the inner layer of dalotatamide sustained-release microspheres to a weakly alkaline state (8-9) significantly improves the stability of the microspheres, and also enhances the stability of dalotatamide. When the pH of the inner layer is neutral, the solubility of dalotatamide is poor, the drug content in the microspheres is low, and the stability is also poor.

[0086] In vivo release assay: Beagle dogs were used as experimental animals. Darlottadine sustained-release microspheres from Example 7 were used as the test sample, which were reconstituted with physiological saline to obtain the test sample solution. The drug was administered subcutaneously every 4 weeks for a total of 6 injections. Serum samples were collected at different time points, and the concentration of darlottadine in the serum was determined by liquid chromatography after centrifugation. Drug concentration-time curves were plotted. Results are attached. Figure 2 As shown, the concentration of darotamide in the body reaches a relatively stable level starting from 3-4 days, and only needs to be taken once every 4 weeks.

[0087] Therefore, the dalotatamine sustained-release microspheres of the present invention overcome the problems of low encapsulation rate, unstable release, and poor drug stability when dalotatamine is prepared into microspheres, which are of great significance for improving the efficacy of dalotatamine.

[0088] As described above, the basic principles, main features, and advantages of the present invention have been shown and described. Those skilled in the art should understand that the present invention is not limited to the above embodiments, which are merely preferred embodiments and should not be construed as limiting the scope of the invention. All equivalent changes and modifications made in accordance with the scope of the patent and the description should still fall within the scope of the present invention. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A dalotactic acid sustained-release microsphere, characterized in that, It has a structure consisting of an inner layer and an outer layer, wherein the outer layer covers the inner layer; The raw material components of the inner layer include a first PLGA and dallotamine; The outer layer of raw material components includes a second PLGA, dalotamiamine dispersion particles, and a release regulator; The dallotamine dispersion particles are composed of dallotamine and Soluplus; The release regulator is selected from hydrophilic substances and / or porogens.

2. The dalotartamine sustained-release microspheres according to claim 1, characterized in that, The weight ratio of the inner layer to the outer layer is 1:0.5-1.

3. The dalotamide sustained-release microspheres according to claim 1, characterized in that, The molar ratio of LA to GA in the first PLGA is 70:30-85:15; The molar ratio of LA to GA in the second PLGA is 50:50-65:

35.

4. The dalotartamine sustained-release microspheres according to claim 1, characterized in that, The weight percentage of dallotamine in the raw material components of the inner layer is 10-30%. The dallotamine in the raw material components of the inner layer is micronized dallotamine; The weight percentage of daloltadine in the daloltadine dispersion particles is 10-30%; The daloltadine dispersion particles, calculated as daloltadine, are in a weight ratio of 1:2-4 to the second PLGA.

5. The dalotamide sustained-release microspheres according to claim 1, characterized in that, The raw material components of the inner layer also include a pH adjuster, which adjusts the pH of the inner layer to 8-9.

6. The dalotamide sustained-release microspheres according to claim 1, characterized in that, The hydrophilic substance is selected from one or a combination of two or more of polyethylene glycol, polyvinylpyrrolidone, and polyvinyl alcohol; The hydrophilic substance accounts for 1-10% of the weight of the raw material components in the outer layer.

7. The dalotamide sustained-release microspheres according to claim 1, characterized in that, The pore-forming agent is selected from mannitol and / or trehalose; The pore-forming agent accounts for 5-25% by weight of the raw material components in the outer layer.

8. A method for preparing dalotamide sustained-release microspheres according to any one of claims 1-7, characterized in that the step... include: A W / O emulsion containing the raw material components of the inner layer in the oil phase is prepared, and the organic solvent is removed to obtain the inner layer microspheres; The raw material components of the outer layer are dissolved or dispersed in a coating solvent to form a coating solution; the coating solution coats the inner microspheres to form coated microspheres. The coated microspheres are then subjected to freeze-drying with a lyophilization protective solution to obtain the dalotahamine sustained-release microspheres.

9. The method for preparing dalotartamine sustained-release microspheres according to claim 8, characterized in that, The coating solvent is selected from one or a combination of two or more of acetone, ethyl acetate, butyl acetate, isopropanol, and anhydrous ethanol; The weight-to-volume ratio of the raw material components of the outer layer to the coating solvent is 0.5-1.2g:5ml.

10. The method for preparing dalotamide sustained-release microspheres according to claim 8, characterized in that, The freeze-drying protective solution contains mannitol and / or sucrose; The freeze-drying includes pre-freezing and subsequent low-temperature drying. The pre-freezing is maintained at -5~0℃ for 20-60 minutes, and the low-temperature drying is maintained at -30~-40℃ for 4-6 hours.

Images