CN110585170A - Sustained-release microsphere prepared by 3D printing and used for injection of terlipressin acetate and preparation method thereof - Google Patents
Sustained-release microsphere prepared by 3D printing and used for injection of terlipressin acetate and preparation method thereof Download PDFInfo
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- CN110585170A CN110585170A CN201910877928.0A CN201910877928A CN110585170A CN 110585170 A CN110585170 A CN 110585170A CN 201910877928 A CN201910877928 A CN 201910877928A CN 110585170 A CN110585170 A CN 110585170A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/095—Oxytocins; Vasopressins; Related peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
- B33Y10/00—Processes of additive manufacturing
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
- B33Y80/00—Products made by additive manufacturing
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Abstract
A terlipressin acetate sustained-release microsphere for injection prepared by 3D printing and a preparation method thereof relate to the technical field of medicine. The invention comprises 10-50 parts of adhesive formed by dissolving PLGA in dichloromethane, 50-90 parts of terlipressin acetate; (1) adding terlipressin acetate into a powder box of a 3D printing rapid forming machine; (2) loading the adhesive into the cartridge; (3) modeling according to preset parameters, and importing the parameters into a control system of a 3D printing rapid prototyping machine; (4) the control system outputs an instruction to control the 3D printing rapid forming machine to print the terlipressin acetate microsphere granules; (5) taking out after bonding and drying, and cleaning residual powder around; (6) crushing terlipressin acetate microsphere granules into microsphere particles smaller than or equal to 20 mu m by using low-temperature gas, and sieving and collecting microsphere powder smaller than 800 meshes to obtain the terlipressin acetate microsphere granules. The invention controls the impurities in the sustained-release microspheres within 5 percent; the initial burst release of the sustained release microspheres is reduced; the continuous release of the dosage is durable and stable.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a terlipressin acetate sustained-release microsphere for injection prepared by 3D printing and a preparation method thereof.
Background
The terlipressin acetate for injection is mainly used for treating liver cirrhosis complications (esophageal and gastric variceal bleeding, hepatorenal syndrome, ascites), is also suitable for treating urogenital tract and other abdominal organ bleeding, infectious shock, burn, acute liver failure, cardiac arrest and the like, but the terlipressin acetate is usually taken for a long time, frequent administration causes great psychological burden on patients, and the long-acting medicament prepared by adopting a slow release technology has practical significance.
At present, the preparation method of the sustained and controlled release preparation is mainly prepared by a solvent dissolution and dispersion method. For example, in the preparation of microcapsules disclosed in patent EP0052510A, and in the preparation of implants and microspheres disclosed in patent EP0058481A or US3976071A, it is a prerequisite that the degradable polymer is dissolved by an organic solvent. Although the active ingredient can be sufficiently dispersed in the polymer in this case, there are problems of solvent residue, formulation damage in therapeutic use, low toxicity of the organic solvent, complete removal of solvent residue, which tends to be expensive and complicated, and reduction in purity of the product.
However, as the active ingredient and the sustained-release ingredient are degraded by removing the organic solvent at high temperature, repeated experiments show that the problem of degradation of the active ingredient cannot be avoided by the sustained-release preparation of terlipressin acetate prepared under the melting temperature condition disclosed in CN1913924A, and when the conditions are applied for hot-melt extrusion, the organic impurities in the sustained-release preparation of terlipressin acetate are as high as about 10%, sometimes the organic impurities are even as high as 15%, so that the quality of the preparation is seriously reduced, and adverse reactions generated in clinical use of the medicine have a great relationship with the impurities in the medicine, so that the control of the content of the impurities is crucial in preparation of the preparation.
Disclosure of Invention
The invention aims to provide a terlipressin acetate sustained-release microsphere for injection prepared by 3D printing and a preparation method thereof aiming at the defects and the defects of the prior art, and the sustained-release microsphere for injection prepared by the process has low organic residue and impurities controlled within 5 percent.
In order to achieve the purpose, the invention adopts the following technical scheme: a terlipressin acetate sustained-release microsphere for injection prepared by 3D printing comprises the following formula: 10-50 parts of adhesive and 50-90 parts of terlipressin acetate.
The method for preparing the terlipressin acetate sustained-release microspheres for injection by adopting 3D printing comprises the following steps: (1) adding terlipressin acetate with the particle diameter of 0.01-0.1mm into a powder box of a 3D printing rapid forming machine;
(2) loading the adhesive into the cartridge;
(3) modeling according to preset parameters, and importing the parameters into a control system of a 3D printing rapid prototyping machine;
(4) the control system outputs an instruction to control the 3D printing rapid forming machine to print the terlipressin acetate microsphere granules;
(5) taking out after bonding and drying, and cleaning residual powder around;
(6) processing terlipressin acetate microsphere granules into microsphere particles smaller than or equal to 20 mu m by using a low-temperature gas pulverizer, and sieving and collecting microsphere powder smaller than 800 meshes to obtain the terlipressin acetate microsphere granules.
As used herein, the term "injectable sustained release microspheres" refers to minute particles, typically 20 μm in size, which are sized to pass through an 800 mesh screen, i.e., less than 800 mesh in size. Thus, the term "microsphere" herein is not limited to a geometric spherical particle, but may be other shapes obtained by pulverization, such as irregular geometric shapes, as long as it passes through a 800 mesh screen.
Preferably, the terlipressin acetate in the present invention is a pharmaceutically acceptable salt of terlipressin acetate, such as acetate, maleate, citrate, etc., most preferably its acetate, i.e. terlipressin acetate.
Research shows that the low-temperature crushing is helpful for preventing the dispersion of terlipressin acetate embedded in the poly (lactic-co-glycolic acid) (PLGA) which is possibly not completely coagulated in the interior, thereby further improving the encapsulation efficiency and reducing the aggregation and adhesion of microspheres. Therefore, in the first aspect of the present invention, the pulverization in the step (6) is carried out at a temperature of 0 ℃ to-50 ℃, preferably at a temperature of 0 ℃ to-20 ℃. Thus, the encapsulation efficiency of the finally prepared microspheres reaches more than 90 percent.
In a second aspect, the present invention is directed to sustained-release microspheres of terlipressin acetate prepared by the preparation method of the first aspect of the present invention. Preferably wherein the encapsulation efficiency of the microspheres reaches more than 90%. More preferably, the content of organic impurities in the sustained release microspheres of terlipressin acetate of the second aspect of the invention is less than 5%, preferably less than 4%, more preferably less than 3%, such as less than 2.5%. The organic impurity content can be determined by methods commonly used in the art, such as by HPLC.
In a third aspect, the present invention aims to provide a pharmaceutical preparation comprising the sustained-release microspheres of terlipressin acetate according to the second aspect of the present invention, preferably the pharmaceutical preparation is an injectable preparation. The sustained-release microspheres of terlipressin acetate according to the second aspect of the present invention may be formulated with a pharmaceutically acceptable carrier into a pharmaceutical preparation, preferably into an injection preparation, such as an injection needle or an injection powder, and a suitable pharmaceutically acceptable carrier is preferably, but not limited to, physiological saline, a pH buffer (such as phosphate buffer, Tris-HCl, etc.), and a protein protecting agent (such as albumin, glucose, etc.). Also preferably, the sustained-release microspheres of terlipressin acetate according to the second aspect of the invention, which are produced under sterile conditions, are directly mixed with physiological saline to prepare a suspension for direct injection.
After the technical scheme is adopted, the invention has the beneficial effects that: the problem of organic residue is reduced; controlling the impurities in the sustained-release microspheres within 5 percent; the initial burst release of the sustained release microspheres is reduced; the continuous release of the dosage is lasting and stable, thereby reducing the administration times and the administration pain.
Drawings
FIG. 1 is a graph comparing single release fit curves for example 1 and example 2 of the present invention.
FIG. 2 is a graph comparing cumulative release fit curves for example 1 and example 2 of the present invention.
Detailed Description
Examples preparation
The inexhaustible preparation examples of the invention can be found in the following description of the apparatus used. The general preparation method of the examples is as follows:
and (2) crushing PLGA for 2 minutes at-10 ℃, sieving and collecting particles below 70 meshes, and performing irradiation sterilization at 60 ℃ to obtain sterile PLGA particles. PLGA is dissolved in dichloromethane according to certain concentration to form a binder solution.
Pulverizing the terlipressin acetate freeze-dried powder at the temperature of minus 10 ℃ by a ball mill to 140 meshes, sieving, and collecting the terlipressin acetate with the granularity below 140 meshes and more than 1600 meshes.
Example 1: taking 20ml of 50:50 dichloromethane solution of polyglycolide-lactide copolymer and 4g terlipressin acetate, and setting the three-dimensional parameters of the 3D printing rapid forming machine as follows: the diameter is 2mm, the thickness is 0.2mm, the number of layers is 4, the layer height is 0.05mm, and the parameters of the adhesive are as follows: the spraying rate was 3.0nL × 12kz, and the number of spraying was 2. And (3) crushing the 3D printed microsphere particles by using a gas crusher at the temperature of-15 ℃ under the nitrogen condition, and collecting microsphere powder below 800 meshes.
The residual solvent, dichloromethane, was 0.8% as determined by residual solvent determination (first method 0861, fourth division of the pharmacopoeia of China 2015 edition); the total impurities are 1.1 percent and almost have no change before and after the preparation is processed according to the detection method of terlipressin acetate related substances.
Example 2: taking 40ml of 50:50 dichloromethane solution of polyglycolide-lactide copolymer and 1.5g terlipressin acetate, and setting the three-dimensional parameters of a 3D printing rapid forming machine as follows: the diameter is 1mm, the thickness is 0.2mm, the number of layers is 5, the layer height is 0.04mm, and the parameters of the adhesive are as follows: the spraying rate was 3.5nL × 10kz, and the number of spraying times was 3. And (3) crushing the 3D printed microsphere particles by using a gas crusher at the temperature of-10 ℃ under the nitrogen condition, and collecting microsphere powder below 800 meshes.
The residual solvent, dichloromethane, was 0.5% as determined by residual solvent determination (first method 0861, fourth division of the pharmacopoeia of China 2015 edition); the total impurities are 0.9 percent according to the detection method of terlipressin acetate related substances. The total impurities are almost unchanged before and after the preparation is processed.
Example 3: in vitro Release Curve determination
Taking the samples of the example 1 and the example 2, precisely weighing 10mg, adding release medium (weighing 34g of Tris base, 3g of Tris HCl, 5g of poloxamer (188) and 0.2g of sodium azide, adding 1000ml of water to dissolve, adjusting the pH value to 9.4 +/-0.1), carrying out vortex oscillation, then putting the mixture into a constant temperature oscillator (45 ℃) to oscillate (100 rpm), taking out the mixture at the 2h, 1d, 3d, 5d, 7d, 9d, 12d, 15d, 18d, 21d, 24d and 27d, centrifuging (6000 rpm, 4 ℃ and 5 min), sucking all release liquid (simultaneously precisely adding 1ml of release medium, placing the mixture into the constant temperature oscillator after vortex oscillation), filtering the mixture by using a 0.22 mu m microporous membrane, taking subsequent filtrate as sample solution, and preparing 6 parts by the same method; according to the chromatographic conditions of terlipressin acetate related substances, respectively and precisely measuring 20ul of the test solution to be tested, injecting the test solution into a liquid chromatograph, and recording the chromatogram. Taking a proper amount of terlipressin acetate reference substance, precisely weighing, adding water to dissolve and dilute to prepare a solution containing about 0.4mg in each 1ml, and measuring by the same method. Substituting the peak area of the terlipressin acetate in the test solution into a fitting equation (if the detection condition is changed, the fitting test of the in vitro degradation curve needs to be carried out again, and the degradation curve needs to be drawn again), and calculating the peak area before the terlipressin acetate is degraded; and calculating the single release degree and the cumulative release degree of the terlipressin acetate in the test sample by using the peak area according to an external standard method. As shown in fig. 1 and 2.
The above description is only for the purpose of illustrating the technical solutions of the present invention and not for the purpose of limiting the same, and other modifications or equivalent substitutions made by those skilled in the art to the technical solutions of the present invention should be covered within the scope of the claims of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (6)
1. The sustained-release microsphere for injection of terlipressin acetate prepared by 3D printing is characterized by comprising the following components: 10-50 parts of adhesive and 50-90 parts of terlipressin acetate.
2. The method for preparing the sustained-release microspheres for injection of terlipressin acetate prepared by 3D printing according to claim 1, which is characterized by comprising the following steps:
(1) adding terlipressin acetate with the particle diameter of 0.01-0.1mm into a powder box of a 3D printing rapid forming machine;
(2) loading the adhesive into the cartridge;
(3) modeling according to preset parameters, and importing the parameters into a control system of a 3D printing rapid prototyping machine;
(4) the control system outputs an instruction to control the 3D printing rapid forming machine to print the terlipressin acetate microsphere granules;
(5) taking out after bonding and drying, and cleaning residual powder around;
(6) processing terlipressin acetate microsphere granules into microsphere particles smaller than or equal to 20 mu m by using a low-temperature gas pulverizer, and sieving and collecting microsphere powder smaller than 800 meshes to obtain the terlipressin acetate microsphere granules.
3. The method for preparing the sustained-release microspheres for injection of terlipressin acetate prepared by 3D printing according to claim 2, wherein the method comprises the following steps: in the parameters of the step (4), the control parameters are as follows: the diameter is 0.5-2mm, the thickness is 0.1-0.3mm, the layer number is 2-5, the layer height is 0.02-0.15mm, and the parameters of the adhesive are as follows: the spraying rate is 3.0-4.0nL multiplied by 10-14kz, and the spraying times are 1-3.
4. The method for preparing sustained-release microspheres for injection of terlipressin acetate prepared by 3D printing according to claim 2, wherein the binder is a solution prepared by dissolving 0.1-1.0g of poly (glycolide-co-lactide) copolymer particles in 1ml of dichloromethane at a corresponding proportional concentration.
5. The method for preparing sustained-release microspheres for injection of terlipressin acetate prepared by 3D printing according to claim 4, wherein the ratio of PGA to PLA in the poly (lactide-co-glycolide) is 50: 50.
6. The method for preparing sustained-release microspheres for injection of terlipressin acetate prepared by 3D printing according to claim 2, wherein the diameter of the terlipressin acetate particles is 0.01-0.1 mm.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111249257A (en) * | 2020-03-27 | 2020-06-09 | 武汉大学 | 3D printing drug sustained-release capsule and preparation method and application thereof |
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2019
- 2019-09-17 CN CN201910877928.0A patent/CN110585170A/en active Pending
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111249257A (en) * | 2020-03-27 | 2020-06-09 | 武汉大学 | 3D printing drug sustained-release capsule and preparation method and application thereof |
| CN111249257B (en) * | 2020-03-27 | 2021-07-06 | 武汉大学 | 3D printing drug sustained-release capsule and preparation method and application thereof |
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Application publication date: 20191220 |