High-content 5-aminolevulinic acid sustained-release pellet and preparation method thereof

Abstract

The invention relates to a high-content 5-aminolevulinic acid sustained-release pellet, which comprises the following components: 5-aminolevulinic acid phosphate; microcrystalline cellulose (MCC PH-102); hydroxypropyl cellulose (HPC-SL); 2-5% of pregelatinized starch; sodium carboxymethyl starch (CMS-Na); sucrose; the drug loading capacity is 60 + / -2%, and the bulk density is 0.65-0.75 g / cm < 3 >.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a high-content 5-aminolevulinic acid sustained-release microsphere and its preparation method. Background Technology

[0002] 5-Aminolevulinic acid (5-ALA) is an oxygen- and nitrogen-containing organic compound. It is a common precursor for the biosynthesis of all porphyrin compounds. It is a non-protein amino acid that is widely found in living organisms such as bacteria, fungi, animals, and plants. It is a naturally occurring, essential, and metabolically active physiological substance in plants.

[0003] 5-Aminolevulinic acid has important applications in multiple fields:

[0004] In the agricultural field, 5-aminolevulinic acid acts as a plant biostimulant, which can promote the growth of crops, fruit trees, vegetables, garden plants, etc., increase yield, and improve quality. The yield increase effect of crops can reach 10-60%, and it is also easy to degrade in the environment without leaving any residue.

[0005] In the feed industry, it can improve anemia and enhance the immunity of poultry and livestock.

[0006] In medicine, 5-aminolevulinic acid can be used as a new generation of photodynamic drugs for cancer diagnosis and treatment;

[0007] 5-Aminolevulinic acid can also be used as an additive in cosmetics and health foods, and can also be used in biochemical research.

[0008] However, the current application of 5-aminolevulinic acid has problems:

[0009] Conventional 5-ALA formulations (tablets / powders) suffer from severe photosensitivity degradation, with a significant decrease in content during storage;

[0010] It is unstable in the gastric acid environment after oral administration and has low bioavailability, reported in the literature as <15%.

[0011] In applications such as high-dose photodynamic therapy, conventional formulations require frequent administration, resulting in poor patient compliance.

[0012] This leads to a technological bottleneck:

[0013] 5-ALA has strong hygroscopicity, and conventional drug loading (≤30%) is insufficient to meet high-dose requirements;

[0014] Existing microcapsule excipients (such as single MCC) cannot simultaneously solve the problems of drug protection and release control.

[0015] Therefore, it is necessary to provide a high-content 5-aminolevulinic acid sustained-release microsphere and its preparation method to solve the above problems. Summary of the Invention

[0016] The purpose of this invention is to provide a high-content sustained-release microsphere of 5-aminolevulinic acid and its preparation method.

[0017] One of the technical solutions is as follows:

[0018] A high-content sustained-release microsphere containing 5-aminolevulinic acid has the following composition:

[0019] 5-Aminolevulinic acid phosphate;

[0020] Microcrystalline cellulose (MCC PH-102);

[0021] Hydroxypropyl cellulose (HPC-SL);

[0022] 2-5% pregelatinized starch; sucrose;

[0023] The charge loading is 60±2%, and the bulk density is 0.65-0.75 g / cm³. 3 .

[0024] Furthermore, the degree of substitution of hydroxypropyl cellulose is 0.60-0.70, and the viscosity grade of 8% aqueous solution at 20°C is 2-3 mPa·s; the particle size of sucrose is D90≤30μm.

[0025] Furthermore, sucrose 5-aminolevulinic acid phosphate is co-dispersed in a porous framework formed by MCC with a porosity of 15-25%; a continuous outer hydrophobic membrane formed by HPC has a thickness of 10-20 μm.

[0026] Furthermore, under 4500 Lux illumination for 24 hours, the degradation rate of 5-aminolevulinic acid phosphoric acid was ≤5%;

[0027] Under accelerated testing at 40℃ / RH75% for 1 month, the content of 5-aminolevulinic acid phosphoric acid decreased by ≤3%; in hydrochloric acid medium at pH 1.2: the release rate was 30-40% after 0.5 hours and 80-85% after 2 hours.

[0028] Technical Solution Two:

[0029] A method for preparing high-content 5-aminolevulinic acid sustained-release microspheres includes the following steps:

[0030] 1) Dry powder mixing: Place 5-aminolevulinic phosphate, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, and sucrose powder in a high-speed shear mixer and mix at 1200-1500 rpm for 10-15 minutes.

[0031] 2) Wet granulation: Spray in a binder solution, wherein the binder is an ethanol-water solution of HPC-SL, and the amount used is 22-25% of the total weight of the dry powder, and the wetting time is controlled to be ≤90 seconds;

[0032] 3) Extrusion-rounding: Extruder screen aperture 0.8±0.05mm, extrusion rate 20-30rpm; rounding machine speed 1100-1300rpm, rounding time 7-9 minutes;

[0033] 4) Drying: The fluidized bed drying temperature is 35-40℃, until the moisture content is ≤2%.

[0034] Furthermore, the sphericity of the microspheres during the rounding step is ≥0.85 (according to USP). <905> The particle size distribution of the dried microspheres is 500-800 μm, of which 90% of the microspheres fall within the range of 600±100 μm.

[0035] Furthermore, the high-content 5-aminolevulinic acid sustained-release microspheres obtained were used in the preparation of tumor photodynamic therapy drugs, with a single dose of 15-20 mg / kg, administered once daily; peak blood drug concentration was reached 2-4 hours after administration.

[0036] Furthermore, the high-content 5-aminolevulinic acid sustained-release microspheres were prepared and applied as agricultural biostimulants: loaded onto the surface of fertilizer granules in the form of coating, with a 5-ALA content of 0.1-0.5 wt%; the sustained-release period is ≥72 hours in a soil pH environment of 4.0-8.0.

[0037] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0038] Breaking through drug loading limits: The MCC-sucrose porous structure achieves a drug loading of 60%, far exceeding the industry standard of ≤30%;

[0039] It has a triple protection mechanism: HPC film formation blocks light, sucrose fills micropores to reduce moisture absorption, and MCC skeleton buffers gastric acid erosion;

[0040] Clinical advantages: The single dose is reduced by 40%, and the number of doses required for photodynamic therapy is reduced from 3 to 1. Detailed Implementation

[0041] Example 1:

[0042] This embodiment demonstrates a high-content 5-aminolevulinic acid sustained-release microsphere, with the following composition:

[0043] 5-Aminolevulinic acid phosphate 58-62%;

[0044] Microcrystalline cellulose (MCC PH-102) 20-30%;

[0045] Hydroxypropyl cellulose (HPC-SL) 5-10%;

[0046] Pregelatinized starch 2-5%; sucrose 1-3%;

[0047] The charge loading is 60±2%, and the bulk density is 0.65-0.75 g / cm³. 3 .

[0048] Furthermore, the degree of substitution of hydroxypropyl cellulose is 0.60-0.70, and the viscosity grade of 8% aqueous solution at 20°C is 2-3 mPa·s; the particle size of sucrose is D90≤30μm.

[0049] Furthermore, sucrose 5-aminolevulinic acid phosphate is co-dispersed in a porous framework formed by MCC with a porosity of 15-25%; a continuous outer hydrophobic membrane formed by HPC has a thickness of 10-20 μm.

[0050] Furthermore, under 4500 Lux illumination for 24 hours, the degradation rate of 5-aminolevulinic acid phosphoric acid was ≤5%;

[0051] Under accelerated testing at 40℃ / RH75% for 1 month, the content of 5-aminolevulinic acid phosphoric acid decreased by ≤3%; in hydrochloric acid medium at pH 1.2: the release rate was 30-40% after 0.5 hours and 80-85% after 2 hours.

[0052] The preparation steps are as follows:

[0053] 1) Dry powder mixing: Place 5-aminolevulinic phosphate, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, and sucrose powder in a high-speed shear mixer and mix at 1200-1500 rpm for 10-15 minutes.

[0054] 2) Wet granulation: Spray in a binder solution, wherein the binder is an ethanol-water solution of 8-10% HPC-SL, with an ethanol:water ratio of 7:3, and the amount used is 22-25% of the total weight of the dry powder, and the wetting time is controlled to be ≤90 seconds;

[0055] 3) Extrusion-rounding: Extruder screen aperture 0.8±0.05mm, extrusion rate 20-30rpm; rounding machine speed 1100-1300rpm, rounding time 7-9 minutes;

[0056] 4) Drying: The fluidized bed drying temperature is 35-40℃, until the moisture content is ≤2%.

[0057] The sphericity of the microspheres during the rounding process is ≥0.85 (according to USP). <905> The particle size distribution of the dried microspheres is 500-800 μm, of which 90% of the microspheres fall within the range of 600±100 μm.

[0058] Example 1:

[0059] The high-content 5-aminolevulinic acid sustained-release microspheres were prepared and used in the preparation of tumor photodynamic therapy drugs. The single dose was 15-20 mg / kg, and the drug was administered once daily. The peak blood concentration was reached 2-4 hours after administration.

[0060] Example 2:

[0061] The high-content 5-aminolevulinic acid sustained-release microspheres prepared are used as agricultural biostimulants: they are loaded onto the surface of fertilizer granules in the form of coating, with a 5-ALA content of 0.1-0.5 wt%; the sustained-release period is ≥72 hours in soil pH 4.0-8.0 environment.

[0062] The optimization effect of this solution can be clearly shown in the table below:

[0063]

[0064] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0065] Breaking through drug loading limits: The MCC-sucrose porous structure achieves a drug loading of 60%, far exceeding the industry standard of ≤30%;

[0066] It has a triple protection mechanism: HPC film formation blocks light, sucrose fills micropores to reduce moisture absorption, and MCC skeleton buffers gastric acid erosion;

[0067] Clinical advantages: The single dose is reduced by 40%, and the number of doses required for photodynamic therapy is reduced from 3 to 1.

[0068] For those skilled in the art, various modifications and improvements can be made without departing from the inventive concept of this invention, and these all fall within the protection scope of this invention.

Claims

1. A high-content sustained-release microsphere containing 5-aminolevulinic acid, characterized in that: The composition is as follows: 5-Aminolevulinic acid phosphate; Microcrystalline cellulose (MCC PH-102); Hydroxypropyl cellulose (HPC-SL); 2-5% pregelatinized starch; sucrose; Sodium carboxymethyl starch (CMS-Na) The charge loading is 60±2%, and the bulk density is 0.65-0.75 g / cm³. 3 .

2. The high-content 5-aminolevulinic acid sustained-release microspheres according to claim 1, characterized in that: The degree of substitution of hydroxypropyl cellulose is 0.60-0.70, and the viscosity grade of 8% aqueous solution at 20℃ is 2-3 mPa·s; the particle size of sucrose is D90≤30μm.

3. The high-content 5-aminolevulinic acid sustained-release microspheres according to claim 1, characterized in that: 5-Aminolevulinic acid sucrose is co-dispersed in a porous framework formed by MCC with a porosity of 15-25%; a continuous outer hydrophobic membrane is formed by HPC with a thickness of 10-20 μm.

4. The high-content 5-aminolevulinic acid sustained-release microspheres according to claim 1, characterized in that: Under 4500 Lux light for 24 hours, the degradation rate of 5-aminolevulinic acid phosphoric acid is ≤5%; under accelerated testing at 40℃ / RH75% for 1 month, the content of 5-aminolevulinic acid phosphoric acid decreases by ≤3%; in hydrochloric acid medium at pH 1.2: the release rate is 30-40% after 0.5 hours, and the release rate of 5-aminolevulinic acid phosphoric acid after 2 hours is 80-85%.

5. A method for preparing high-content 5-aminolevulinic acid sustained-release microspheres, characterized in that: The preparation steps are as follows: 1) Dry powder mixing: Place 5-aminolevulinic phosphate, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, and sucrose powder in a high-speed shear mixer and mix at 1200-1500 rpm for 10-15 minutes. 2) Wet granulation: Spray in a binder solution, wherein the binder is an ethanol-water solution of HPC-SL, and the amount used is 22-25% of the total weight of the dry powder, and the wetting time is controlled to be ≤90 seconds; 3) Extrusion-rounding: Extruder screen aperture 0.8±0.05mm, extrusion rate 20-30rpm; rounding machine speed 1100-1300rpm, rounding time 7-9 minutes; 4) Drying: The fluidized bed drying temperature is 35-40℃, until the moisture content is ≤2%.

6. The method for preparing high-content 5-aminolevulinic acid sustained-release microspheres according to claim 5, characterized in that: The sphericity of the microspheres during the rounding process is ≥0.85 (according to USP). <905> The particle size distribution of the dried microspheres is 500-800 μm, of which 90% of the microspheres fall within the range of 600±100 μm.

7. The method for preparing high-content 5-aminolevulinic acid sustained-release microspheres according to claim 5, characterized in that: The high-content 5-aminolevulinic acid sustained-release microspheres were prepared and used in the preparation of tumor photodynamic therapy drugs. The single dose was 15-20 mg / kg, and the drug was administered once daily. The peak blood concentration was reached 2-4 hours after administration.

8. The method for preparing high-content 5-aminolevulinic acid sustained-release microspheres according to claim 7, characterized in that: The high-content 5-aminolevulinic acid sustained-release microspheres prepared are used as agricultural biostimulants: they are loaded onto the surface of fertilizer granules in the form of coating, with a 5-ALA content of 0.1-0.5 wt%; the sustained-release period is ≥72 hours in soil pH 4.0-8.0 environment.

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