CN112121028B - Simvastatin solid nanoparticle preparation and preparation method thereof - Google Patents
Simvastatin solid nanoparticle preparation and preparation method thereof Download PDFInfo
- Publication number
- CN112121028B CN112121028B CN201910486460.2A CN201910486460A CN112121028B CN 112121028 B CN112121028 B CN 112121028B CN 201910486460 A CN201910486460 A CN 201910486460A CN 112121028 B CN112121028 B CN 112121028B
- Authority
- CN
- China
- Prior art keywords
- simvastatin
- preparation
- organic phase
- solid nanoparticle
- alpha
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- 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
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- 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
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- 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
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a simvastatin solid nanoparticle preparation and a preparation method thereof. The simvastatin solid nanoparticle preparation prepared by the invention has the advantages of long drug release period, good drug release characteristic, no drug burst release phenomenon, conformity with zero-order release characteristic, high entrapment rate of 96.39%, reduction of administration times, good treatment effect, simple preparation process, no use of any emulsifier and surfactant and high biological safety.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a simvastatin solid nanoparticle preparation and a preparation method thereof.
Background
Simvastatin is an HMG-CoA reductase inhibitor and is mainly used for reducing cholesterol and preventing cardiovascular diseases clinically at present, simvastatin has the advantages of simplicity, low price and the like, and is more and more researched, but simvastatin is insoluble in water, and after oral administration is metabolized by liver for the first time, the bioavailability is only 2.4%, and the exertion of drug effect and clinical application are severely restricted.
The novel drug delivery system such as liposome, micelle, nanoparticle, microsphere and the like can effectively improve the solubility of insoluble drugs and increase the adhesion on the intestinal surface and the capacity of cell bypass transportation and transmembrane transportation, thereby greatly improving the oral bioavailability of the drugs. The existing solid nanoparticle preparation generally uses PLGA or PLA as a carrier, which are FDA approved medicinal high polymer materials which can be safely used, and has the advantages of good biocompatibility, adjustable degradability and the like, but most of the preparations have obvious burst release phenomenon and can not reach zero-order release characteristic, so that the muscle toxicity and other toxic and side effects are caused, and the pain and economic burden of patients are increased; and the existing nanoparticle preparation is mostly prepared by an emulsification-solvent evaporation method, and a certain amount of surfactant and emulsifier are required to be used in the process, so that the safety of the medicine is reduced.
Chinese patent CN101511348B discloses a pharmaceutical composition containing statin-encapsulated nanoparticles, which takes PLGA, PEG-PLGA or PEG/CS-PLGA as a carrier, and the prepared statin-encapsulated nanoparticles have the curative effects of prolonging intracellular release and stimulating neoangiogenesis in specific tissues, have no potential side effects of rhabdomyolysis, liver injury and the like, but have an obvious burst release phenomenon at the initial release stage. Chinese patent CN100579524C and Chinese patent application CN108567762A respectively disclose a simvastatin-carrying sustained-release microsphere system and a lactic acid-based polymer disc-shaped drug-carrying particle and sustained-release preparation, and the lactic acid-based polymer is taken as a carrier, so that the phenomenon of drug burst release is avoided, but the encapsulation rate is lower and is respectively 40% and 68%. Chinese patent application CN104666270A discloses an osmotic pump controlled release preparation for controlling the whole release of nanoparticles and a preparation method thereof, firstly, insoluble drugs such as simvastatin with prescription dosage are prepared into nanoparticles, the nanoparticles are filled into capsules or tablets after being freeze-dried, and finally, the capsules are coated and laser-drilled, and the preparation process is complex and tedious, the technical threshold is high, and the time consumption is long. Chinese patent application CN103826615A discloses a method for preparing polymer particles with reduced initial burst, which reduces the internal voids of the particles and effectively reduces the burst phenomenon of the drug by contacting the polymer particles with an alcohol-water solution, but the temperature control is strict, and the emulsifier needs to be used for many times, otherwise the ideal effect cannot be achieved.
In view of this, there is a need for a simvastatin solid nanoparticle preparation with simple preparation process, no drug burst release, zero-order release characteristic and high encapsulation efficiency.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a simvastatin solid nanoparticle preparation and a preparation method thereof. According to the invention, Polyorthoester (POE) is used as a carrier material, and alpha-linolenic acid is added, so that the prepared simvastatin solid nanoparticle preparation has high encapsulation rate and long release period, solves the problem of burst release of common nanoparticles, has zero-order release characteristics, and is beneficial to improving the bioavailability and clinical curative effect of the medicine.
The inventor considers that the selection of a carrier is particularly important for solving the burst release problem of the drug-loaded nanoparticles, and firstly, the inventor takes the lactic acid polymer and the nanoliposome as the carrier, and the prepared simvastatin nanoparticle preparations have initial burst release problems of different degrees. The inventor finds that when degradable hydrophobic polymer POE is used as a carrier material, the prepared nanoparticle preparation has no obvious phenomenon of initial burst release of the medicine, but the encapsulation rate of the nanoparticle preparation does not reach an expected value, so the nanoparticle preparation is optimized.
POE is a biodegradable hydrophobic polymer material which is artificially synthesized, is not easy to swell in water, has good biocompatibility, can be degraded into small molecular compounds which are easy to metabolize in organisms, and is safe and reliable to organisms; alpha-linolenic acid is an omega-3 essential fatty acid forming the biomembrane structure of each tissue of a human body, has wide physiological activity and obvious pharmacological action, has the effects of regulating blood fat, reducing blood viscosity, inhibiting anaphylactic reaction and the like, is reported to be a potential antioxidant, but has no report on the effects of improving the drug encapsulation rate and the drug release characteristic in a drug-loaded nanoparticle preparation.
Specifically, the invention is realized by adopting the following technical scheme:
a simvastatin solid nanoparticle preparation comprises simvastatin, polyorthoester and alpha-linolenic acid.
Preferably, the polyorthoester has the formula:
wherein R is- (CH) 2 ) 6 -or
Molecular weight is 1000-10000; further preferably, R is
Preferably, the simvastatin solid nanoparticle preparation comprises 1 part of simvastatin, 10-20 parts of polyorthoester and 4-8 parts of alpha-linolenic acid.
More preferably, the simvastatin solid nanoparticle preparation comprises 1 part of simvastatin, 15 parts of polyorthoester and 7 parts of alpha-linolenic acid.
Meanwhile, the invention provides a preparation method of the simvastatin solid nanoparticle preparation, which comprises the following steps:
1) adding simvastatin and polyorthoester into a mixed solution of an organic solvent and alpha-linolenic acid in sequence, and stirring to dissolve the simvastatin and the polyorthoester to form an organic phase;
2) dropwise adding the organic phase obtained in the step 1) into the stirred purified water, stirring to solidify the organic phase, filtering to remove the uncoated medicine, and freeze-drying to obtain the medicine.
Preferably, the organic solvent in step 1) is one of acetone, tetrahydrofuran, acetonitrile and dichloromethane.
More preferably, the organic solvent in step 1) is acetone.
Preferably, the mass-to-volume ratio of the simvastatin to the organic solvent in the step 1) is 1: 0.5-2, mg/mL.
Preferably, the volume ratio of the organic solvent in the step 1) to the purified water in the step 2) is 1: 2-4.
Preferably, step 2) is performed by filtration through a 0.22 μm microporous membrane.
Preferably, the stirring rate of the purified water in step 2) is the rate at which nanoparticles can be formed after the organic phase is dropped into the purified water, such as 15000-20000 rpm. This process may be accomplished by a high shear homogenizing emulsifier or other device.
Preferably, the stirring speed of the stirring and curing process in the step 2) is 1000-1500 rpm.
In addition, the nanoparticle preparation can be directly injected and orally taken, and can also be further mixed with other pharmaceutically acceptable auxiliary materials to prepare preparations such as granules, tablets, pills, capsules and the like.
Compared with the prior art, the invention has the following advantages:
(1) the invention takes POE as a carrier and alpha-linolenic acid as an auxiliary, and the prepared simvastatin solid nanoparticle preparation has good drug release characteristics, has no drug burst release phenomenon, conforms to zero-order release characteristics, can reduce the toxic and side effects of drugs and improves the drug compliance of patients.
(2) The simvastatin solid nanoparticle has the advantages that the entrapment rate is 96.39%, the release period is long, the administration frequency is reduced, meanwhile, a good treatment effect is obtained, and the clinical requirements are fully met.
(3) The simvastatin solid nanoparticle preparation disclosed by the invention is simple in preparation process, higher in biological safety, and convenient for industrial production, and a large amount of emulsifier is avoided, and meanwhile, the production cost is saved.
Drawings
FIG. 1: example 2 in vitro release profile of nanoparticle formulation;
FIG. 2: comparative examples 1-6 in vitro release profiles of the nanoparticle formulations.
Detailed Description
The invention will be further described by the following description of specific embodiments, it being properly understood that: the examples of the present invention are provided for illustration only and not for limitation of the present invention. Therefore, simple modifications of the present invention in the process of the present invention are within the scope of the claimed invention. The polyorthoesters of the invention may be prepared by themselves, for example, in the development of poly (ortho esters) a historical overview (J. Heller, Biomaterials,1990, Vol 11, 659-. Other raw materials and reagents are commercially available unless otherwise specified.
The polyorthoesters used in examples 1-9,12-13, comparative example 3 and comparative example 6 below have the following structural formula:
wherein R is- (CH) 2 ) 6 -or
Molecular weight is 1000-10000. For writing inIn the invention, R is- (CH) 2 ) 6 The polyorthoester at-is named POE1, R is
The polyorthoester was named POE 2.
Example 1 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
POE1 100mg
40mg of alpha-linolenic acid.
The preparation method comprises the following steps:
1) simvastatin and POE1 with the prescription amount are sequentially added into a mixed solution of tetrahydrofuran (5ml) and alpha-linolenic acid, and stirred to be dissolved, so that an organic phase is formed;
2) dropwise adding the organic phase obtained in the step 1) into 10ml of purified water stirred at the rotating speed of 20000rpm, then stirring at the rotating speed of 1500rpm to solidify the organic phase, filtering by a 0.22-micron microporous filter membrane to remove the uncoated medicine, and freeze-drying to obtain the compound.
Example 2 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
POE2 150mg
Alpha-linolenic acid 70 mg.
The preparation method comprises the following steps:
1) the simvastatin and POE2 with the prescription amount are sequentially added into the mixed solution of acetone (10ml) and alpha-linolenic acid, and stirred to be dissolved to form an organic phase;
2) dropwise adding the organic phase obtained in the step 1) into 30ml of purified water stirred at the rotating speed of 18000rpm, then stirring at the rotating speed of 1200rpm to solidify the organic phase, filtering by using a 0.22-micron microporous filter membrane to remove the uncoated medicine, and freeze-drying to obtain the compound.
Example 3 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
POE2 200mg
Alpha-linolenic acid 80 mg.
The preparation method comprises the following steps:
1) simvastatin and POE2 with the prescription amount are sequentially added into a mixed solution of dichloromethane (20ml) and alpha-linolenic acid, and stirred to be dissolved, so that an organic phase is formed;
2) dropwise adding the organic phase obtained in the step 1) into 80ml of purified water stirred at the rotating speed of 15000rpm, then stirring at the rotating speed of 1000rpm to solidify the organic phase, filtering by using a 0.22-micron microporous filter membrane to remove the uncoated medicine, and freeze-drying to obtain the compound.
Example 4 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
POE1 120mg
Alpha-linolenic acid 70 mg.
The preparation method comprises the following steps:
1) simvastatin and POE1 with the prescription amount are sequentially added into a mixed solution of acetonitrile (5ml) and alpha-linolenic acid, and stirred to be dissolved to form an organic phase;
2) dropwise adding the organic phase obtained in the step 1) into 20ml of purified water stirred at the rotating speed of 16000rpm, then stirring at the rotating speed of 1300rpm to solidify the organic phase, filtering by a 0.22-micron microporous filter membrane to remove the uncoated medicine, and freeze-drying to obtain the compound.
Example 5 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
POE1 100mg
Alpha-linolenic acid 80 mg.
The preparation method comprises the following steps:
1) simvastatin and POE1 with the prescription amount are sequentially added into a mixed solution of tetrahydrofuran (20ml) and alpha-linolenic acid, and stirred to be dissolved to form an organic phase;
2) dropwise adding the organic phase obtained in the step 1) into 40ml of purified water stirred at the rotating speed of 20000rpm, then stirring at the rotating speed of 1000rpm to solidify the organic phase, filtering by a 0.22-micron microporous filter membrane to remove the uncoated medicine, and freeze-drying to obtain the compound.
Example 6 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
POE2 200mg
40mg of alpha-linolenic acid.
The preparation method comprises the following steps:
1) simvastatin and POE2 with the prescription amount are sequentially added into a mixed solution of tetrahydrofuran (5ml) and alpha-linolenic acid, and stirred to be dissolved, so that an organic phase is formed;
2) dropwise adding the organic phase obtained in the step 1) into 20ml of purified water stirred at the rotating speed of 15000rpm, then stirring at the rotating speed of 1500rpm to solidify the organic phase, filtering by using a 0.22-micron microporous filter membrane to remove the uncoated medicine, and freeze-drying to obtain the compound.
Example 7 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
POE1 170mg
Alpha-linolenic acid 50 mg.
The preparation method comprises the following steps:
1) simvastatin and POE1 with the prescription dose are sequentially added into a mixed solution of tetrahydrofuran (6.67ml) and alpha-linolenic acid, and stirred to be dissolved, so that an organic phase is formed;
2) dropwise adding the organic phase obtained in the step 1) into 20ml of purified water stirred at the rotating speed of 16000rpm, then stirring at the rotating speed of 1300rpm to solidify the organic phase, filtering by using a 0.22-micron microporous filter membrane to remove the uncoated medicine, and freeze-drying to obtain the medicine.
Example 8 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
POE1 150mg
Alpha-linolenic acid 70 mg.
The preparation method comprises the following steps:
1) the simvastatin and POE1 with the prescription amount are sequentially added into the mixed solution of acetone (40ml) and alpha-linolenic acid, and stirred to be dissolved to form an organic phase;
2) dropwise adding the organic phase obtained in the step 1) into 120ml of purified water stirred at the rotation speed of 18000rpm, then stirring at the rotation speed of 1200rpm to solidify the organic phase, filtering by using a 0.22-micron microporous filter membrane to remove the uncoated medicine, and freeze-drying to obtain the compound.
Example 9 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
POE1 150mg
Alpha-linolenic acid 70 mg.
The preparation method comprises the following steps:
1) simvastatin and POE1 with the prescription amount are sequentially added into a mixed solution of ethyl formate (10ml) and alpha-linolenic acid, and stirred to be dissolved to form an organic phase;
2) dropwise adding the organic phase obtained in the step 1) into 30ml of purified water stirred at the rotating speed of 18000rpm, then stirring at the rotating speed of 1200rpm to solidify the organic phase, filtering by using a 0.22-micron microporous filter membrane to remove the uncoated medicine, and freeze-drying to obtain the compound.
Example 10 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
Polyorthoesters 150mg
Alpha-linolenic acid 70 mg.
Wherein the polyorthoester is
R is- (CH) 2 ) 6 The molecular weight of the polyorthoester is 1000-10000.
The preparation method comprises the following steps:
1) simvastatin and polyorthoester with the prescription amount are sequentially added into a mixed solution of acetone (10ml) and alpha-linolenic acid, and stirred to be dissolved to form an organic phase;
2) dropwise adding the organic phase obtained in the step 1) into 30ml of purified water stirred at the rotating speed of 18000rpm, then stirring at the rotating speed of 1200rpm to solidify the organic phase, filtering by using a 0.22-micron microporous filter membrane to remove the uncoated medicine, and freeze-drying to obtain the compound.
Example 11 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
Polyorthoesters 150mg
Alpha-linolenic acid 70 mg.
Wherein the polyorthoester is
R is-CH 3 R' is- (CH) — (CH) 2 ) 4 The molecular weight of the polyorthoester is 1000-10000.
The preparation method comprises the following steps:
1) simvastatin and polyorthoester with the prescription amount are sequentially added into a mixed solution of acetone (10ml) and alpha-linolenic acid, and stirred to be dissolved to form an organic phase;
2) dropwise adding the organic phase obtained in the step 1) into 30ml of purified water stirred at the rotating speed of 18000rpm, then stirring at the rotating speed of 1200rpm to solidify the organic phase, filtering by using a 0.22-micron microporous filter membrane to remove the uncoated medicine, and freeze-drying to obtain the compound.
Example 12 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
POE2 150mg
Alpha-linolenic acid 20 mg.
The preparation method comprises the following steps:
1) simvastatin and POE2 with the prescription amount are sequentially added into a mixed solution of acetone and alpha-linolenic acid, and stirred to be dissolved to form an organic phase;
2) dropwise adding the organic phase obtained in the step 1) into 30ml of purified water stirred at the rotating speed of 18000rpm, then stirring at the rotating speed of 1200rpm to solidify the organic phase, filtering by using a 0.22-micron microporous filter membrane to remove the uncoated medicine, and freeze-drying to obtain the compound.
Example 13 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
POE2 150mg
130mg of alpha-linolenic acid.
The preparation method comprises the following steps:
1) the simvastatin and POE2 with the prescription amount are sequentially added into the mixed solution of acetone (10ml) and alpha-linolenic acid, and stirred to be dissolved to form an organic phase;
2) dropwise adding the organic phase obtained in the step 1) into 30ml of purified water stirred at the rotating speed of 18000rpm, filtering by using a 0.22-micron microporous filter membrane to remove the uncoated medicine, then stirring at the rotating speed of 1200rpm to solidify the organic phase, and freeze-drying to obtain the compound. Comparative example 1 simvastatin solid nanoparticle formulation
1) Dissolving 1.2g of PEG-PLGA (lactic acid/glycolic acid: 75/25, average molecular weight 22900, molecular weight of PEG moiety 6000) and 120mg of simvastatin in a mixed solution of 40mL of acetone and 20mL of ethanol to obtain a polymer solution;
2) dropwise adding the polymer solution obtained in the step 1) into 120mL of a continuously stirred (400rpm) 0.04% (weight ratio) chitosan (N- [ 2-hydroxy-3- (trimethylamino) propyl ] chitosan chloride) solution at a constant rate of 4mL/min at 40 ℃ to obtain a simvastatin-loaded PEG/CS-PLGA nanoparticle suspension;
3) and (3) decompressing the suspension obtained in the step 2) and continuously stirring the suspension at the speed of 100rpm for 2h at 40 ℃ to remove the organic solvent, then filtering the suspension by using a filter with the mesh size of 32 mu m, and finally freeze-drying the filtrate overnight to obtain the compound.
Comparative example 2 simvastatin solid nanoparticle formulation
Prescription:
the preparation method comprises the following steps:
1) placing soybean lecithin and polyethylene glycol-12-hydroxystearate in 20ml purified water, and uniformly dispersing in 70 + -1 deg.C water bath to obtain water phase;
2) heating cetyl palmitate and caprylic/capric glyceride in 70 + -1 deg.C water bath to melt, dispersing simvastatin into molten mixed lipid under stirring, and stirring to dissolve to obtain oil phase;
3) slowly dripping the water phase into the oil phase under magnetic stirring at 4000rpm, and continuously stirring for 20min to obtain primary emulsion;
4) and (3) carrying out ultrasonic treatment on the primary emulsion obtained in the step 3) for 5min (2.0 s of ultrasonic treatment, 2.0s of intermittent treatment and 400W of power) at the temperature of 70 +/-1 ℃ by using an ultrasonic cell crusher to obtain a light blue transparent colloidal solution, rapidly and fully cooling the colloidal solution in an ice-water bath, filtering the colloidal solution by using a 0.22-micron filter membrane, and carrying out freeze drying to obtain the product.
Comparative example 3 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
POE2 150mg。
The preparation method comprises the following steps:
1) the simvastatin and POE2 with the prescription amount are sequentially added into 10ml of acetone and stirred to be dissolved to form an organic phase;
2) dropwise adding the organic phase obtained in the step 1) into 30ml of purified water stirred at the rotating speed of 18000rpm, then solidifying the organic phase under the stirring at the rotating speed of 1200rpm, filtering the organic phase by using a 0.22-micron microporous filter membrane to remove the uncoated medicine, and freeze-drying to obtain the medicine.
Comparative example 4 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
PLGA (lactic/glycolic acid) ═ 75/25) 150mg
Alpha-linolenic acid 70 mg.
The preparation method comprises the following steps:
1) simvastatin and PLGA with the prescription dose are sequentially added into a mixed solution of acetone (10ml) and alpha-linolenic acid, and stirred to be dissolved, so that an organic phase is formed;
2) dropwise adding the organic phase obtained in the step 1) into 30ml of purified water stirred at the rotating speed of 18000rpm, then solidifying the organic phase under the stirring at the rotating speed of 1200rpm, filtering the organic phase by using a 0.22-micron microporous filter membrane to remove the uncoated medicine, and freeze-drying to obtain the compound.
Comparative example 5 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
Hydrogenated Soybean lecithin 150mg
Alpha-linolenic acid 70 mg.
The preparation method comprises the following steps:
1) the simvastatin and the hydrogenated soybean lecithin with the prescription amount are sequentially added into the mixed solution of acetone (10ml) and alpha-linolenic acid, and stirred to be dissolved to form an organic phase;
2) dropwise adding the organic phase obtained in the step 1) into 30ml of purified water stirred at the rotation speed of 18000rpm, then solidifying the organic phase under stirring at the rotation speed of 1200rpm, filtering the organic phase by using a 0.22-micron microporous filter membrane to remove the uncoated medicine, and freeze-drying to obtain the medicine.
Comparative example 6 simvastatin solid nanoparticle formulation
Prescription:
simvastatin 10mg
POE2 150mg
Linoleic acid 70 mg.
The preparation method comprises the following steps:
1) simvastatin and POE2 with the prescription dose are sequentially added into a mixed solution of acetone (10ml) and linoleic acid, and stirred to be dissolved, so that an organic phase is formed;
2) dropwise adding the organic phase obtained in the step 1) into 30ml of purified water stirred at the rotating speed of 18000rpm, filtering by using a 0.22-micron microporous filter membrane to remove the uncoated medicine, then solidifying the organic phase under the stirring at the rotating speed of 1200rpm, and freeze-drying to obtain the compound.
Verification example 1 encapsulation efficiency determination test
1. Test materials: examples 1-13 and comparative examples 1-6.
2. The test method comprises the following steps: the drug encapsulation rate of the nanoparticles is determined by adopting an organic solvent destructive extraction method, 5mg of a sample is added into 15mL of dichloromethane, the structure of the nanoparticles is destroyed and the drug is dissolved after water bath ultrasound for 10min, and the concentration of simvastatin is determined by taking the dichloromethane solution by using an HPLC method. Three replicates were performed and the results averaged.
Encapsulation efficiency (amount of drug encapsulated/total amount of drug encapsulated and unencapsulated in formulation) x 100%
3. And (3) test results: the results of the encapsulation efficiency measurements are shown in Table 1.
TABLE 1 results of simvastatin solid nanoparticle encapsulation efficiency assay
| Sample (I) | Encapsulation efficiency (%) |
| Example 1 | 93.06 |
| Example 2 | 96.39 |
| Example 3 | 95.02 |
| Example 4 | 92.51 |
| Example 5 | 92.35 |
| Example 6 | 94.95 |
| Example 7 | 92.41 |
| Example 8 | 91.46 |
| Example 9 | 92.07 |
| Example 10 | 90.82 |
| Example 11 | 91.04 |
| Example 12 | 94.51 |
| Example 13 | 94.28 |
| Comparative example 1 | 70.86 |
| Comparative example 2 | 81.30 |
| Comparative example 3 | 70.81 |
| Comparative example 4 | 59.47 |
| Comparative example 5 | 64.39 |
| Comparative example 6 | 69.09 |
Through experiments, the simvastatin solid nanoparticle prepared by the embodiment of the invention has an encapsulation rate of 96.39% (see table 1), which is significantly higher than that of the simvastatin solid nanoparticles prepared by the comparative examples 1-6. Compared with the embodiment 2, the comparative example 3 does not contain alpha-linolenic acid, the comparative example 6 replaces the alpha-linolenic acid with linoleic acid, and the difference of the encapsulation rate is large, so that the alpha-linolenic acid has the effect of improving the encapsulation rate of the simvastatin solid nanoparticle in the invention; in comparative examples 4 and 5, PLGA and hydrogenated soybean lecithin were used as carriers, respectively, and although the formula contained alpha-linolenic acid, the encapsulation rate was only 59.47%, thus the polyorthoester and alpha-linolenic acid have synergistic effect on the improvement of the encapsulation rate of the simvastatin solid nanoparticles.
Verification example 2 in vitro Release test
1. Test materials: examples 1-13 and comparative examples 1-6.
2. The test method comprises the following steps: referring to the chinese pharmacopoeia (2015 edition), the in vitro release behavior of simvastatin was examined using dialysis with a phosphate buffered solution containing 0.5% sodium dodecyl sulfate (pH 6.8). Precisely weighing 10mg of sample, dispersing the sample in 2mL of release medium, then placing the sample in a dialysis bag (80000-140000Da), placing the sample in the bottom of a paddle of a dissolution instrument after fastening two ends of the sample, and measuring 50mL of release medium and placing the sample in a 250mL dissolution cup. At a constant temperature of 37 +/-0.5 ℃ and 100rpm, 1mL of release medium (simultaneously supplemented with the same amount of release medium at the same temperature) is sucked at 0.5h, 2h, 12h, 24h, 48h, 120h and 240h respectively. Removed release mediumFiltering with 0.45 μm microporous membrane, determining simvastatin content by HPLC, calculating the accumulative release rate of simvastatin, and drawing accumulative release curve. Three times of parallel tests are carried out, the results are averaged, and simultaneously, the accumulated release degree of each sample is subjected to linear simulation, and the linear correlation coefficient R 2 Closer to 1, indicates a better linear relationship, with a zero order release profile.
3. And (3) test results: the test results are shown in table 2, fig. 1 and fig. 2.
TABLE 2 in vitro cumulative release of simvastatin
Through tests, the samples prepared by the embodiment of the invention have no initial burst release phenomenon, the release amount after 5 days is up to 99.82 percent, and the linear correlation coefficient R 2 Up to 0.9837, meeting the zero-order release profile (fig. 1). As can be seen from Table 2 and FIG. 2, comparative examples 1, 4 and 5 exhibited different degrees of initial burst, R 2 Relatively low, comparative examples 1, 2, 4, 5 released substantially completely on day 2 or day 4, respectively; although the burst release of the drugs of comparative examples 2, 3 and 6 was not significant, R was not observed 2 Significantly lower than the examples of the present invention.
Claims (7)
1. The simvastatin solid nanoparticle preparation is characterized by comprising 1 part of simvastatin, 10-20 parts of polyorthoester and 4-8 parts of alpha-linolenic acid; the polyorthoester has the following structural formula:
wherein R is
Or
Molecular weight is 1000-10000.
2. The simvastatin solid nanoparticle formulation according to claim 1, wherein R is
。
3. A method for preparing the simvastatin solid nanoparticle preparation of any one of claims 1-2, comprising the following steps:
1) adding simvastatin and polyorthoester into a mixed solution of an organic solvent and alpha-linolenic acid in sequence, and stirring to dissolve the simvastatin and the polyorthoester to form an organic phase;
2) dropwise adding the organic phase obtained in the step 1) into stirred purified water, stirring to solidify the organic phase, filtering to remove the uncoated medicine, and freeze-drying to obtain the medicine.
4. The preparation method of the simvastatin solid nanoparticle preparation according to claim 3, wherein the organic solvent in the step 1) is one of acetone, tetrahydrofuran, acetonitrile and dichloromethane.
5. The preparation method of the simvastatin solid nanoparticle preparation according to claim 4, wherein the organic solvent in the step 1) is acetone.
6. The preparation method of the simvastatin solid nanoparticle preparation according to claim 3, wherein the mass-to-volume ratio of the simvastatin to the organic solvent in the step 1) is 1: 0.5-2, mg/mL.
7. The preparation method of the simvastatin solid nanoparticle preparation according to claim 3, wherein the volume ratio of the organic solvent in the step 1) to the purified water in the step 2) is 1: 2-4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910486460.2A CN112121028B (en) | 2019-06-05 | 2019-06-05 | Simvastatin solid nanoparticle preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910486460.2A CN112121028B (en) | 2019-06-05 | 2019-06-05 | Simvastatin solid nanoparticle preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112121028A CN112121028A (en) | 2020-12-25 |
| CN112121028B true CN112121028B (en) | 2022-09-30 |
Family
ID=73849025
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910486460.2A Active CN112121028B (en) | 2019-06-05 | 2019-06-05 | Simvastatin solid nanoparticle preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112121028B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115381777B (en) * | 2021-05-21 | 2023-11-28 | 中国科学院上海药物研究所 | Nanoparticle for co-carrying patchouli alcohol and simvastatin, preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102861340A (en) * | 2012-03-15 | 2013-01-09 | 杨文莉 | Intelligent nano delivery system, preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG11201506366SA (en) * | 2013-02-13 | 2015-09-29 | Agency Science Tech & Res | A Polymeric System for Release of an Active Agent |
-
2019
- 2019-06-05 CN CN201910486460.2A patent/CN112121028B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102861340A (en) * | 2012-03-15 | 2013-01-09 | 杨文莉 | Intelligent nano delivery system, preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 聚原酸酯载药微球的制备及体外药物释放;魏民等;《中国生物医学工程学报》;19990630;第18卷(第2期);228-230页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112121028A (en) | 2020-12-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Pawar et al. | Engineered nanocrystal technology: in-vivo fate, targeting and applications in drug delivery | |
| USRE49741E1 (en) | Drug delivery system for administration of poorly water soluble pharmaceutically active substances | |
| JP5571380B2 (en) | Solid nanoparticle formulations of water-insoluble pharmaceutical substances with reduced Ostwald ripening | |
| US9855223B2 (en) | Compositions comprising a dendrimer-resveratrol complex and methods for making and using the same | |
| CN102302447B (en) | Novel taxol lipid microsphere injection and preparation method thereof | |
| US20150010616A1 (en) | Biocompatible Particles and Method for Preparing Same | |
| US8962017B2 (en) | Formulation of silymarin with high efficacy and prolonged action and the preparation method thereof | |
| WO2005070413A1 (en) | Retinoic acid-containing remedy for diabetes | |
| WO2018108164A1 (en) | Bortezomib pharmaceutical composition and applications thereof | |
| Mansour et al. | Intranasal versus intraperitoneal Myrj 59-stabilized cubosomes: A potential armamentarium of effective anti-diabetic therapy | |
| CN109730966B (en) | Chitosan oligosaccharide modified self-carried carrier-free nasal cavity nano preparation brain targeting delivery system and preparation method thereof | |
| US20080171687A1 (en) | Compositions And Methods For The Preparation And Administration Of Poorly Water Soluble Drugs | |
| CN112121028B (en) | Simvastatin solid nanoparticle preparation and preparation method thereof | |
| Nguyen et al. | Preparation of an oil suspension containing ondansetron hydrochloride as a sustained release parenteral formulation | |
| US8859001B2 (en) | Fenoldopam formulations and pro-drug derivatives | |
| Pandey | Solid lipid nanoparticles: a multidimensional drug delivery system | |
| WO2018108163A1 (en) | Talazoparib pharmaceutical composition and applications thereof | |
| CN100350912C (en) | Nanometer partical administration system of prostaglandin E1 coated with polyglycol derived phospholipid | |
| Seenivasan et al. | Lovastatin nanoparticle synthesis and characterization for better drug delivery | |
| US10835489B2 (en) | Modified release formulations of mycophenolate mofetil | |
| WO2019218305A1 (en) | Intramuscular depot of decoquinate compositions and method of prophylaxis and treatment thereof | |
| Gad et al. | Surfactants' Role in Nanovesicles Drug Delivery System | |
| CN108619525B (en) | Netupidem-mPEG-PLA nanoparticle and preparation method and application thereof | |
| CN114469878A (en) | Probucol dry emulsion composition and preparation method and application thereof | |
| CN115054578A (en) | Tumor-targeting norcantharidin nanostructured lipid carrier and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |