CN102670483B - Electrostatic spinning fiber membrane preparation for treating hyperlipidemia and preparation method thereof - Google Patents
Electrostatic spinning fiber membrane preparation for treating hyperlipidemia and preparation method thereof Download PDFInfo
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- CN102670483B CN102670483B CN201210142467.0A CN201210142467A CN102670483B CN 102670483 B CN102670483 B CN 102670483B CN 201210142467 A CN201210142467 A CN 201210142467A CN 102670483 B CN102670483 B CN 102670483B
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Images
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an electrostatic spinning fiber membrane preparation for treating hyperlipidemia and preparation thereof. The electrostatic spinning fiber membrane preparation loaded with a statin medicament comprises an electrostatic spinning fiber membrane, wherein the electrostatic spinning fiber membrane consists of a statin medicament, a polymer and a medicinal oral preparation-acceptable surfactant; and the statin medicament is uniformly dispersed into the fiber membrane in an unformed state. In the electrostatic spinning fiber membrane preparation serving as a lipid-lowering medicament, the contained statin medicament is uniformly dispersed through the polymer and the surfactant. An electrostatic spinning fiber has high porosity and a large specific surface area, so that dissolution rate of the statin medicament can be increased remarkably, the apparent water solubility is increased, and the bioavailability after oral taking is improved. Meanwhile, specified space resistance is formed on the statin medicament which is dispersed in an unformed way under the actions of electrostatic spinning fibers with different fine structures, so that the reassembling and crystallization separation of the statin medicament can be effectively lowered, and a novel oral preparation of the statin medicament is formed.
Description
Technical Field
The invention relates to a preparation in the technical field of blood fat reducing medicines and a preparation method thereof, in particular to an electrostatic spinning fiber membrane preparation for treating hyperlipidemia and a preparation method thereof.
Background
Cardiovascular diseases are one of the diseases with the highest and fastest incidence worldwide in recent years, wherein the rise of blood fat/cholesterol and coronary heart disease, angina pectoris and myocardial infarction caused by the rise are the most common disease species. In the blood cholesterol metabolic pathway, HMG-CoA reductase becomes an important target for the research of cardiovascular disease treatment drugs. The statin drugs and HMG-CoA have similar structures, can be combined with HMG-CoA reductase, have the affinity which is thousands of times higher than that of HMG-CoA, and have stronger selective competitive inhibition effect on HMG-CoA reductase, so the statin drugs become important drugs for treating cardiovascular diseases and occupy more than 60 percent of market share in the global cholesterol drug field.
Most statins are high fat soluble drugs, are insoluble in water and have low absolute bioavailability when being orally absorbed. The literature research shows that the statins have better biomembrane permeability, and the low dissolution rate is the biggest obstacle to low oral bioavailability. According to the Noyes-Whitney law, the specific surface area is increased, the dissolution rate and apparent concentration of the drug can be obviously improved, and the intestinal absorption bioavailability can be effectively improved, wherein the nano-micro-crystal technology, the nano-solid dispersion technology, the nano-micro emulsion technology, the nano-capsule technology and the like are included.
The electrostatic spinning technology uses electrostatic force as traction force to prepare superfine fiber, namely charged polymer solution or melt is stretched under the action of electric field force in a high-voltage electrostatic field, when the electric field force is greater than the surface tension of polymer drops, the polymer forms a jet stream, solvent volatilization or molten polymer is solidified due to temperature reduction in the jetting process, and a non-woven fabric-shaped fiber felt can be obtained on a receiving net, wherein the basic device schematic diagram is shown in figure 1.
Since the nineties of the last century, the electrostatic spinning technology has attracted extensive attention of researchers, and successfully sprays spinning solutions such as polymer solutions or melts, dispersions, emulsions and the like under a high-voltage electric field to form ultrafine fibers with diameters ranging from nanometer to micrometer, and controls the morphology of the obtained electrostatic spinning fibers by adjusting the types and molecular weights of polymers, the characteristics of the spinning solutions such as the concentration, viscosity and solvents of the polymer dispersions, and process condition parameters such as external voltage, flow rate, shape and position of a receiving device. The electrostatic spinning fiber containing the drug or the drug combination can be prepared by dispersing or dissolving the needed drug or the drug combination in the spinning solution, and the non-woven fabric membrane formed by the superfine fiber has high porosity and specific surface area, thereby showing great potential in the research fields of drug delivery and the like. At present, it has been reported that small molecular drugs such as ibuprofen, tetracycline, Ambrisentan (Ambrisentan) and the like, and some biological macromolecular drugs of proteins all show good water solubility and controllable dissolution rate after electrostatic spinning drug loading. However, for loading different types of drugs, extensive formulation and screening of different polymers and pharmaceutically acceptable surfactants for oral formulation are required to form an optimized formulation.
Statins have a large market share, and many enterprises are internationally contemplating the development of new formulations thereof. The patent application WO2007100614-A2 describes a preparation method of amorphous atorvastatin salt through searching the prior art; patent application 201010172783.3 describes a liposomal formulation of atorvastatin and the like. Patent application 200810041039.2 describes the preparation of a nano-crystalline fiber mat of poorly water soluble drugs including anti-inflammatory analgesic drugs, anti-allergic drugs, anti-infective drugs, but not anti-cardiovascular drugs and statins. The electrostatic spinning drug loading of statins is not reported in the Chinese and foreign literatures.
The electrostatic spinning technology can prepare the fiber membrane preparation loaded with statins with different characteristics by designing a spinning solution formula and controlling the parameters of operating process conditions. In addition, the electrostatic spinning technology has simple equipment and high controllability of operation and process conditions, so that the prepared fiber membrane preparation loaded with statins has better industrial production prospect and huge market prospect.
Disclosure of Invention
The invention aims to provide an electrostatic spinning film preparation loaded with statins for treating hyperlipidemia and a preparation method thereof, wherein the electrostatic spinning film preparation can effectively improve the apparent solubility and dissolution rate of statins and reduce the reaggregation, crystallization and precipitation of statins, so that the oral bioavailability is increased, and a novel statin oral preparation is formed.
The electrostatic spinning fiber membrane preparation loaded with statins comprises an electrostatic spinning fiber membrane, wherein the electrostatic spinning fiber membrane consists of statins, polymers and surfactants acceptable for oral pharmaceutical preparations, and the statins are uniformly dispersed in the electrostatic spinning fiber membrane in an amorphous state. The electrostatic spinning fiber membrane is prepared by adopting a spinning solution system through an electrostatic spinning method.
The electrostatic spinning fiber membrane comprises the following components in percentage by mass: 1-45% of statins, 0.01-10% of acceptable surface active agents of oral pharmaceutical preparations and the balance of polymers.
Preferably, in the electrostatic spinning fiber membrane, the components and the corresponding mass percentage contents thereof are as follows: 1.0-20% of statins, 0.1-5% of acceptable surface active agents of oral pharmaceutical preparations and the balance of polymers.
Preferably, the electrospun fiber membrane is in the form of a fiber membrane, and the diameter of each individual fiber in the fiber membrane is between 10nm and 10 μm.
Preferably, the statin is selected from atorvastatin calcium, lovastatin, simvastatin, fluvastatin and sulvastatin.
Preferably, the polymer is a hydrophilic high molecular polymer, and the viscosity average molecular weight (Mw) of the polymer is more than 20 KDa. Preferably, the viscosity average molecular weight (Mw) of the hydrophilic high molecular polymer is 30 to 500 KDa.
Further, the hydrophilic high molecular polymer is polyethylene oxide (PEO), polyvinylpyrrolidone (PVP), carboxymethyl starch, polyvinyl alcohol (PVA), starch acetate, hydroxymethyl cellulose, carboxymethyl cellulose, polyhydroxyethyl methacrylate (PHEMA), Eudragit acrylic acidResin, and the like. Wherein, the proportion of each component in the hydrophilic high molecular polymers can be random. The acrylic resin is EsterqiAcrylic resin series products.
Preferably, the pharmaceutically acceptable surfactant for oral preparation is one or more of block polyether Pluronic F-68, Tween 80, Span 80, polyoxyethylene laurate, polyethylene glycol laurate, sucrose stearate, glyceryl monooleate, polyoxyethylene castor oil, hydrogenated castor oil and polyethylene glycol. The proportion of each component in the various surfactants can be random.
Further, the polyethylene glycol is selected from polyethylene glycol with the self-adhesive average molecular weight of PEG400-PEG2000 KDa.
Preferably, the spinning liquid system is an organic solvent solution comprising a statin, a polymer and a surfactant acceptable for pharmaceutical oral formulations; wherein the organic solvent is one or more mixed solvents selected from alcohol, acetone and tetrahydrofuran.
Wherein the mass percentage concentration of the statins in the spinning solution system is 0.01-10.0%; the mass percentage concentration of the surfactant acceptable for the pharmaceutical oral preparation is 0.0001-2%; the mass percentage concentration of the polymer is 1.0-30.0%.
Preferably, the mass percentage concentration of the statins in the spinning solution system is 0.01-1.0%; the mass percentage concentration of the acceptable surfactant of the pharmaceutical oral preparation is 0.1-1%; the mass percentage concentration of the polymer is 10.0-20.0%.
Further, the alcohol is one or more of methanol, ethanol, hexafluoroisopropanol and ethylene glycol.
The electrostatic spinning fiber membrane preparation loaded with statins can be widely applied to preparation of oral medicines for treating hyperlipidemia.
The invention also provides a preparation method of the electrostatic spinning fiber membrane preparation loaded with statins, which comprises the following steps:
1) fully dissolving the statins in a soluble organic solvent at room temperature according to the proportion of raw materials in the electrostatic spinning fiber membrane preparation loaded with the statins to obtain a solution of the organic solvent of the statins; dissolving a polymer and a surfactant acceptable for pharmaceutical oral preparations in water to obtain an aqueous solution in which the polymer and the surfactant are dissolved;
2) mixing a solution of an organic solvent of the statin medicine with an aqueous solution in which a polymer and a surfactant are dissolved, so that the statin medicine, the polymer and the surfactant are fully interacted, and forming a spinning solution after uniform mixing;
3) and (3) carrying out electrostatic spinning on the spinning solution by adopting electrostatic spinning equipment to obtain the electrostatic spinning fiber membrane, thus obtaining the electrostatic spinning fiber membrane preparation loaded with the statins.
Or,
1) fully dissolving the statins, the polymers and the surfactant acceptable for the pharmaceutical oral preparation into an organic solvent at room temperature according to the proportion of the raw materials in the electrostatic spinning fiber membrane preparation loaded with the statins, and uniformly mixing to obtain a spinning solution capable of electrostatic spinning;
2) and (3) carrying out electrostatic spinning on the spinning solution by adopting electrostatic spinning equipment to obtain the electrostatic spinning fiber membrane, thus obtaining the electrostatic spinning fiber membrane preparation loaded with the statins.
Or,
1) fully dissolving the statins in an organic solvent at room temperature according to the proportion of raw materials in the electrostatic spinning fiber membrane preparation loaded with the statins to obtain a solution of the first organic solvent of the statins; dissolving a polymer and a surfactant acceptable for pharmaceutical oral preparations in another organic solvent of the organic solvents to obtain a solution of the polymer and the surfactant in a second organic solvent;
2) mixing a solution of a first organic solvent of the statins with a solution of a second organic solvent in which a polymer and a surfactant are dissolved, so that the statins, the polymer and the surfactant are fully interacted, and uniformly mixing to form a spinning solution;
3) and (3) carrying out electrostatic spinning on the spinning solution by adopting electrostatic spinning equipment to obtain the electrostatic spinning fiber membrane, thus obtaining the electrostatic spinning fiber membrane preparation loaded with the statins.
Preferably, the mass percentage concentration of the statins in the spinning solution is 0.01-10.0%; the mass percentage concentration of the surfactant acceptable for the pharmaceutical oral preparation is 0.0001-2%; the mass percentage concentration of the polymer is 1.0-30.0%.
Preferably, the organic solvent is selected from the group consisting of alcohols, acetone and tetrahydrofuran. Wherein the alcohol is selected from methanol, ethanol, hexafluoroisopropanol, ethylene glycol and the like.
Preferably, when electrostatic spinning is carried out by adopting electrostatic spinning equipment, a 2ml syringe is adopted to suck spinning solution, the syringe is placed in a micro-injection pump push groove, the extrusion speed of the solution is adjusted to be 0.001-0.1ml/min, the spinning voltage is controlled to be 5-30KV, a nozzle is a metal needle head with the diameter of 0.1-1mm, aluminum foil is adopted as a collection plate, the collection distance is 5-30cm, the environmental temperature is kept at 10-40 ℃, and the environmental relative humidity is kept at 5-40%.
Preferably, when electrostatic spinning is carried out by adopting electrostatic spinning equipment, the extrusion speed of the solution is adjusted to be 0.04-0.09ml/min, the spinning voltage is controlled to be 10-20KV, aluminum foil is used as a collecting plate, the collecting distance is 10-25cm, the environmental temperature is kept at 20-40 ℃, and the environmental relative humidity is kept at 10-40%.
The electrostatic spinning fiber membrane preparation used as the blood fat reducing medicine of the invention contains the statins which are uniformly dispersed by polymer and surfactant acceptable by oral pharmaceutical preparations and is prepared by electrostatic spinning. According to the electrostatic spinning fiber membrane loaded with the statins prepared by the electrostatic spinning preparation method, the statins are uniformly dispersed in an amorphous state, the electrostatic spinning fiber membrane loaded with the statins has high porosity and large specific surface area, the dissolution rate of the statins can be improved, the apparent water solubility of the statins is increased, and the bioavailability after oral administration is improved.
The invention can prepare the electrostatic spinning fiber with different fine structures by controlling the components and the characteristics of the spinning solution system and the electrostatic spinning preparation process parameters, and form specific space resistance to the statins dispersed in the amorphous form, thereby effectively reducing the reaggregation and crystallization precipitation of the statins and forming a novel oral preparation of the statins.
Drawings
FIG. 1 schematic view of an electrospinning basic apparatus
FIG. 2 SEM picture of atorvastatin calcium-loaded electrostatic spinning drug-loaded fiber membrane
Figure 3 dissolution curves of atorvastatin calcium and electrospun drug loaded fiber membrane samples loaded with atorvastatin calcium. In the figure, 4% (w/w), 8% (w/w) and 16% (w/w) represent 4%, 8% and 16% of atorvastatin calcium in the fiber, respectively, based on the total mass of the fiber; unprocessed drug represents the dissolution profile of the pure drug atorvastatin calcium without any manufacturing operations; 4% (w/w) of the surfactant blocked polyether Pluronic F-68 is not contained, and the drug content in the fiber is 4% of the total mass of the fiber.
FIG. 4 XRD pattern of electrostatic spinning drug-loaded fiber membrane
Detailed Description
The present invention is further illustrated below with reference to specific examples, which are intended to be illustrative only and not to limit the scope of the invention.
Example 1
Fully dissolving a certain amount of 24mg of atorvastatin calcium in 0.2ml of methanol at room temperature to obtain a solution A; fully dissolving 600mg of polyvinylpyrrolidone (PVP K30, viscosity average molecular weight 40-60 KDa) and 6mg of block polyether Pluronic F-68 in 4.4g of ethanol to obtain a solution B; and mixing the solution A into the solution B to prepare the solution capable of electrostatic spinning.
Using electrostatic spinning equipment, sucking a spinning solution by using a 2ml syringe, placing the spinning solution in a micro-injection pump push groove, adjusting the extrusion speed of the solution to be 0.05ml/min, the spinning voltage to be 10KV, using a metal needle head with the diameter of 0.5mm as a nozzle, using aluminum foil as a collection plate, collecting the solution at the distance of 15cm, keeping the environmental temperature at 20-30 ℃, and controlling the environmental relative humidity at 20-25% to obtain the uniform electrostatic spinning drug-loaded fiber membrane, wherein the structure is shown in figure 2. The drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning (as shown in figure 2), and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 2
Fully dissolving a certain amount of 96mg of atorvastatin calcium in 0.5ml of methanol at room temperature to obtain a solution A; fully dissolving 600mg of polyvinylpyrrolidone (PVP) and 6mg of block polyether Pluronic F-68 in 4.2g of ethanol to obtain a solution B; and mixing the solution A into the solution B to prepare the solution capable of electrostatic spinning.
Using electrostatic spinning equipment, sucking a spinning solution by using a 2ml syringe, placing the spinning solution in a micro-injection pump push groove, adjusting the extrusion speed of the solution to be 0.09ml/min, the spinning voltage to be 13KV, using a metal needle with the diameter of 0.7mm as a nozzle, using aluminum foil as a collection plate, collecting the solution at a distance of 15cm, keeping the environmental temperature at 20-30 ℃, and controlling the environmental relative humidity at 20-25% to obtain the uniform electrostatic spinning drug-loaded fiber membrane.
Example 3
An electrospun solution was prepared by dissolving 12mg of lovastatin, 600mg of polyvinylpyrrolidone (PVP) and 6mg of the block polyether Pluronic F-68 in 4.0ml of methanol at room temperature.
Using electrostatic spinning equipment, sucking a spinning solution by using a 2ml syringe, placing the spinning solution in a micro-injection pump push groove, adjusting the extrusion speed of the solution to be 0.08ml/min, the spinning voltage to be 13KV, using a metal needle with the diameter of 0.3mm as a nozzle, using aluminum foil as a collection plate, collecting the solution at a distance of 15cm, keeping the environmental temperature at 20-30 ℃, and controlling the environmental relative humidity at 20-25% to obtain the uniform electrostatic spinning drug-loaded fiber membrane.
Example 4
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min.
Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in example 1, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml at 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the electrostatic spinning drug-loaded fiber membrane through a 0.45 mu m water film, and measuring the content of atorvastatin calcium by using a High Performance Liquid Chromatography (HPLC), wherein the result is shown in figure 3. As can be seen from fig. 3: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained from the uniform electrospun drug-loaded fibrous membrane product obtained in example 1 was detected, as shown in fig. 4, it can be seen from fig. 4 that the statin drug in the electrospun drug-loaded fibrous membrane preparation is dispersed in the fiber in an amorphous state.
Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in example 2, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml at 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium by a High Performance Liquid Chromatography (HPLC), wherein the result is that: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time. And the XRD spectrum shows that the statins in the electrostatic spinning drug-loaded fiber membrane preparation are dispersed in the fibers in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in example 3, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml at 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium by a High Performance Liquid Chromatography (HPLC), wherein the result is that: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Comparative example 1
Fully dissolving a certain amount of 24mg of atorvastatin calcium in 0.4ml of methanol at room temperature to obtain a solution A; dissolving 600mg polyvinylpyrrolidone (PVP K30, viscosity average molecular weight 40-60 KDa) in 4.0g water to obtain solution B; and mixing the solution A into the solution B to prepare the solution capable of electrostatic spinning.
Using electrostatic spinning equipment, sucking a spinning solution by using a 2ml syringe, placing the spinning solution in a micro-injection pump push groove, adjusting the extrusion speed of the solution to be 0.08ml/min, the spinning voltage to be 12KV, taking an aluminum foil as a collection plate, and obtaining a uniform electrostatic spinning drug-loaded fiber membrane without a surfactant acceptable for a pharmaceutical oral preparation, wherein the collection distance is 15 cm.
The dissolution rate is determined by adopting a basket method, according to the second part of Chinese pharmacopoeia 2010, the uniform electrostatic spinning drug-loaded fiber membrane without the surfactant acceptable for the oral drug preparation is determined by adopting the basket method, and the dissolution detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min.
Precisely weighing 10mg of electrostatic spinning drug-loaded fiber membrane without acceptable surfactant for oral pharmaceutical preparation, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml at 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the electrostatic spinning drug-loaded fiber membrane through a 0.45 mu m water film, and measuring the content of atorvastatin calcium by using a High Performance Liquid Chromatography (HPLC), wherein the result is shown as a 4% (w/w) without surfactants curve in figure 3. As can be seen from fig. 3: compared with the electrostatic spinning drug-loaded fiber membrane containing polymer and surfactant, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane is obviously reduced in the electrostatic spinning drug-loaded fiber membrane without the surfactant acceptable for the oral pharmaceutical preparation.
Comparative example 2
The dissolution rate is determined by adopting a basket method, according to the second part of Chinese pharmacopoeia 2010, the dissolution rate of untreated atorvastatin calcium is determined by adopting the basket method, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min.
10mg of untreated atorvastatin calcium was precisely weighed, placed in a dissolution measuring basket, 0.5ml of the atorvastatin calcium was sampled at 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtered through a 0.45 mu m water film, and the sample was subjected to High Performance Liquid Chromatography (HPLC) to measure the content of atorvastatin calcium, and the result is shown in the UnProcessed drug curve shown in FIG. 3. As can be seen from fig. 3: compared with the dissolution rate and the dissolution total amount of untreated atorvastatin calcium, the dissolution rate and the dissolution capacity of the electrostatic spinning drug-loaded fiber membrane containing the polymer and the surfactant are obviously improved, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane without the surfactant acceptable for the pharmaceutical oral preparation is slightly and slightly improved, and the dissolution total amount is almost equivalent to the untreated atorvastatin calcium.
Example 5
Fully dissolving a certain amount of 12mg of atorvastatin calcium into 0.2ml of hexafluoroisopropanol at room temperature to obtain a solution A; 600mg of polyethylene oxide (PEO, having a viscosity average molecular weight (Mw) of 30 to 500 KDa) and 6mg of polyoxyethylene laurate were sufficiently dissolved in 4.4g of ethanol to obtain a solution B; and mixing the solution A into the solution B to prepare the solution capable of electrostatic spinning.
Using electrostatic spinning equipment, sucking a spinning solution by using a 2ml syringe, placing the spinning solution in a micro-injection pump push groove, adjusting the extrusion speed of the solution to be 0.05ml/min, the spinning voltage to be 10KV, using a metal needle with the diameter of 0.1mm as a nozzle, using aluminum foil as a collection plate, collecting the solution at the distance of 10cm, keeping the environmental temperature at 20-30 ℃ and the environmental relative humidity at 30-40%, and obtaining the uniform electrostatic spinning drug-loaded fiber membrane.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 6
Fully dissolving a certain amount of 12mg of atorvastatin calcium in 0.2ml of ethylene glycol at room temperature to obtain a solution A; fully dissolving 600mg of polyvinyl alcohol (PVA with a viscosity average molecular weight (Mw) of 30-500 KDa) and 6mg of Tween 80 in 4.4g of methanol to obtain a solution B; and mixing the solution A into the solution B to prepare the solution capable of electrostatic spinning.
Using electrostatic spinning equipment, sucking a spinning solution by using a 2ml syringe, placing the spinning solution in a micro-injection pump push groove, adjusting the extrusion speed of the solution to be 0.05ml/min, the spinning voltage to be 20KV, using a metal needle with the diameter of 1mm as a nozzle, using aluminum foil as a collection plate, collecting the solution at the distance of 25cm, keeping the environmental temperature at 30-40 ℃ and the environmental relative humidity at 10-20%, and obtaining the uniform electrostatic spinning drug-loaded fiber membrane.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 7
Fully dissolving a certain amount of 12mg of atorvastatin calcium in 0.2ml of methanol at room temperature to obtain a solution A; fully dissolving 600mg of polyvinylpyrrolidone (PVP K30, viscosity average molecular weight (Mw) 40-60 KDa) and 6mg of block polyether Pluronic F-68 in 4.4g of water to obtain solution B; and mixing the solution A into the solution B to prepare the solution capable of electrostatic spinning.
Using electrostatic spinning equipment, sucking a spinning solution by using a 2ml syringe, placing the spinning solution in a micro-injection pump push groove, adjusting the extrusion speed of the solution to be 0.05ml/min, the spinning voltage to be 10KV, using a metal needle with the diameter of 0.5mm as a nozzle, using aluminum foil as a collection plate, collecting the solution at a distance of 15cm, keeping the environmental temperature at 20-30 ℃, and controlling the environmental relative humidity at 20-25% to obtain the uniform electrostatic spinning drug-loaded fiber membrane.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 8
The preparation steps of the uniform electrospun drug-loaded fiber membrane preparation of the present example were the same as those of example 1, except that the organic solvent was acetone, the polymer was carboxymethyl starch, and the surfactant was Span 80.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 9
The preparation steps of the uniform electrospun drug-loaded fiber membrane preparation of the present example were the same as those of example 1, except that the organic solvent was tetrahydrofuran, the polymer was starch acetate, and the surfactant was polyethylene glycol laurate.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 10
The preparation procedure for preparing the uniform electrospun drug-loaded fibrous membrane preparation of this example was the same as in example 1, except that the polymer was starch acetate and the surfactant was polyethylene glycol laurate.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 11
The procedure for preparing the uniform electrospun drug-loaded fibrous membrane preparation of this example was the same as example 1, except that the polymer was hydroxymethylcellulose and the surfactant was sucrose stearate.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 12
The preparation procedure for preparing the uniform electrospun drug-loaded fibrous membrane preparation of this example was the same as in example 1, except that the polymer was carboxymethylcellulose and the surfactant was glycerol monooleate.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 13
The procedure for preparing the uniform electrospun drug-loaded fibrous membrane preparation of this example was the same as in example 1, except that the polymer was Polyhydroxyethylmethacrylate (PHEMA) and the surfactant was polyoxyethylated castor oil.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 14
The procedure for preparing the uniform electrospun drug-loaded fibrous membrane formulation of this example was the same as example 1 except that the polymer was Eudragit acrylic resin and the surfactant was a mixture of hydrogenated castor oil and polyethylene glycol.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 15
The procedure for preparing the uniform electrospun drug-loaded fibrous membrane preparation of this example was the same as example 1, except that the statin was lovastatin.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 16
The procedure for preparing the uniform electrospun drug-loaded fibrous membrane preparation of this example was the same as in example 1, except that the statin was simvastatin.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 17
The procedure for preparing the uniform electrospun drug-loaded fibrous membrane preparation of this example was the same as in example 1, except that the statin was fluvastatin.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 18
The procedure for preparing the uniform electrospun drug-loaded fibrous membrane preparation of this example was the same as in example 1, except that the statin was sulvastatin.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 19
Fully dissolving a certain amount of 12mg of atorvastatin calcium in 0.25ml of methanol at room temperature to obtain a solution A; fully dissolving 240mg of polyvinylpyrrolidone (PVP K30, viscosity average molecular weight 40-60 KDa) and 6mg of block polyether Pluronic F-68 in 1000mg of ethanol to obtain a solution B; and mixing the solution A into the solution B to prepare the solution capable of electrostatic spinning.
Using electrostatic spinning equipment, sucking a spinning solution by using a 2ml syringe, placing the spinning solution in a micro-injection pump push groove, adjusting the extrusion speed of the solution to be 0.05ml/min, the spinning voltage to be 10KV, using a metal needle with the diameter of 0.5mm as a nozzle, using aluminum foil as a collection plate, collecting the solution at a distance of 15cm, keeping the environmental temperature at 20-30 ℃, and controlling the environmental relative humidity at 20-25% to obtain the uniform electrostatic spinning drug-loaded fiber membrane.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 20
Fully dissolving a certain amount of 12mg of atorvastatin calcium in 0.25ml of methanol at room temperature to obtain a solution A; fully dissolving 45mg of polyvinylpyrrolidone (PVP K30, viscosity average molecular weight 40-60 KDa) and 3mg of block polyether Pluronic F-68 in 1000mg of ethanol to obtain a solution B; and mixing the solution A into the solution B to prepare the solution capable of electrostatic spinning.
Using electrostatic spinning equipment, sucking a spinning solution by using a 2ml syringe, placing the spinning solution in a micro-injection pump push groove, adjusting the extrusion speed of the solution to be 0.05ml/min, the spinning voltage to be 10KV, using a metal needle with the diameter of 0.5mm as a nozzle, using aluminum foil as a collection plate, collecting the solution at a distance of 15cm, keeping the environmental temperature at 20-30 ℃, and controlling the environmental relative humidity at 20-25% to obtain the uniform electrostatic spinning drug-loaded fiber membrane.
The dissolution rate is determined by adopting a basket method, the dissolution rate of the electrostatic spinning drug-loaded fiber membrane loaded with atorvastatin calcium is determined by adopting the basket method according to the second part of Chinese pharmacopoeia 2010 edition, and the dissolution rate detection conditions are as follows: the dissolution medium is 600ml of ultrapure water, the temperature is 37 ℃, and the rotating speed is 100 r/min. Precisely weighing 10mg of the electrostatic spinning drug-loaded fiber membrane obtained in the embodiment, placing the electrostatic spinning drug-loaded fiber membrane in a dissolution measuring basket, sampling 0.5ml in 5 th, 15 th, 30 th, 60 th, 90 th and 120 th minutes, filtering the sample through a 0.45 mu m water film, and measuring the content of atorvastatin calcium in the sample by using a High Performance Liquid Chromatography (HPLC), wherein the result is as follows: compared with the dissolution rate of pure medicines and the total dissolution amount of medicines, the electrostatic spinning fibrous membrane medicinal preparation is remarkably improved; the content of the drug in the fiber is inversely related to the dissolution rate of the drug; the addition of the surfactant can obviously improve the dissolution rate of the medicament, and the total dissolution amount of the medicament is improved by about 1 time.
The XRD spectrum of the electrospun drug-loaded fibrous membrane obtained by detecting the uniform electrospun drug-loaded fibrous membrane product obtained in this example shows that the statin drug in the electrospun drug-loaded fibrous membrane preparation is uniformly dispersed in the fiber in an amorphous state. In addition, the drug molecules are combined with the hydrophilic polymer through weak bond acting forces such as hydrogen bonds and the like, a certain spatial structure is formed and fixed after spinning, and the resistance on spatial migration is inevitably caused to the crystallization and aggregation of the drug, so that the stability of the preparation is improved.
Example 21
Preparing 10 g of an electrostatic spinning drug-loaded fiber membrane sample according to the preparation method of the embodiment 2, crushing, sieving with a 80-mesh sieve, respectively sieving microcrystalline cellulose and lactose with a 80-mesh sieve, and preparing the electrostatic spinning drug-loaded fiber membrane according to the following steps: microcrystalline cellulose: the lactose is mixed evenly in a weight ratio of 100:100:50 and filled into empty capsules to obtain capsules with a dosage of 250 mg each.
In addition, the electrospun drug-loaded fiber membranes obtained in examples 1 and 3-20 can also be prepared into corresponding capsules by the preparation method of the capsules.
Claims (8)
1. An electrostatic spinning fiber membrane preparation loaded with statins comprises an electrostatic spinning fiber membrane, wherein the electrostatic spinning fiber membrane consists of statins, polymers and surfactants acceptable for oral pharmaceutical preparations, the statins are uniformly dispersed in the electrostatic spinning fiber membrane in an amorphous state, and the electrostatic spinning fiber membrane comprises the following components in percentage by mass: 1.0-20% of statin drugs, 0.1-5% of acceptable surface active agents of oral drug preparations and the balance of polymers; the polymer is a hydrophilic high molecular polymer, and the viscosity average molecular weight of the polymer is more than 20 KDa; the acceptable surface active agent of the medicine oral preparation is block polyether Pluronic F-68; the hydrophilic high molecular polymer is one or a combination of polyethylene oxide, polyvinylpyrrolidone, carboxymethyl starch, polyvinyl alcohol, starch acetate, hydroxymethyl cellulose, carboxymethyl cellulose, polyhydroxyethyl methacrylate and acrylic resin; the statin is atorvastatin calcium.
2. The statin-loaded electrospun fibrous membrane formulation of claim 1 wherein the electrospun fibrous membrane is in the form of a fibrous membrane and the individual fibers in the fibrous membrane have a diameter of between 10nm and 10 μm.
3. A statin-loaded electrospun fibrous membrane preparation according to any of claims 1-2 wherein said statin-loaded electrospun fibrous membrane preparation is a capsule.
4. A method of preparing a statin-loaded electrospun fiber membrane formulation according to any of claims 1-3, comprising the steps of:
1) fully dissolving the statins in an organic solvent at room temperature according to the proportion of raw materials in the electrostatic spinning fiber membrane preparation loaded with the statins to obtain a solution of the organic solvent of the statins; dissolving a polymer and a surfactant acceptable for pharmaceutical oral preparations in water to obtain an aqueous solution in which the polymer and the surfactant are dissolved;
2) mixing a solution of an organic solvent of the statin medicine with an aqueous solution in which a polymer and a surfactant are dissolved, so that the statin medicine, the polymer and the surfactant are fully interacted, and forming a spinning solution after uniform mixing;
3) carrying out electrostatic spinning on the spinning solution by adopting electrostatic spinning equipment to obtain the electrostatic spinning fiber membrane, thus obtaining the electrostatic spinning fiber membrane preparation loaded with statins;
or,
1) fully dissolving the statins, the polymers and the surfactant acceptable for the pharmaceutical oral preparation into an organic solvent at room temperature according to the proportion of the raw materials in the electrostatic spinning fiber membrane preparation loaded with the statins, and uniformly mixing to obtain a spinning solution capable of electrostatic spinning;
2) carrying out electrostatic spinning on the spinning solution by adopting electrostatic spinning equipment to obtain the electrostatic spinning fiber membrane, thus obtaining the electrostatic spinning fiber membrane preparation loaded with statins;
or,
1) fully dissolving the statins in one of organic solvents at room temperature according to the proportion of raw materials in the electrostatic spinning fiber membrane preparation loaded with the statins to obtain a solution of the first organic solvent of the statins; dissolving a polymer and a surfactant acceptable for pharmaceutical oral preparations in another organic solvent of the organic solvents to obtain a solution of the polymer and the surfactant in a second organic solvent;
2) mixing a solution of a first organic solvent of the statins with a solution of a second organic solvent in which a polymer and a surfactant are dissolved, so that the statins, the polymer and the surfactant are fully interacted, and uniformly mixing to form a spinning solution;
3) and (3) carrying out electrostatic spinning on the spinning solution by adopting electrostatic spinning equipment to obtain the electrostatic spinning fiber membrane, thus obtaining the electrostatic spinning fiber membrane preparation loaded with the statins.
5. The method for preparing the statin-loaded electrospun fiber membrane preparation according to claim 4, wherein the mass percentage concentration of the statin in the spinning solution is 0.01-10.0%; the mass percentage concentration of the surfactant acceptable for the pharmaceutical oral preparation is 0.0001-2%; the mass percentage concentration of the polymer is 1.0-30.0%.
6. The method of claim 4, wherein the organic solvent is selected from the group consisting of alcohols, acetone, and tetrahydrofuran.
7. The method of preparing a statin-loaded electrospun fiber membrane formulation according to claim 6 wherein the alcohol is selected from the group consisting of methanol, ethanol, hexafluoroisopropanol and ethylene glycol.
8. The method for preparing an electrospun fiber membrane preparation loaded with statin drugs according to claim 4, wherein when electrospinning is carried out using electrospinning equipment, a 2ml syringe is used to suck the spinning solution, the syringe is placed in a push tank of a micro-injection pump, the extrusion speed of the solution is adjusted to 0.001-0.1ml/min, the spinning voltage is controlled to 5-30KV, the nozzle is a metal needle with a diameter of 0.1-1mm, aluminum foil is used as a collection plate, the collection distance is 5-30cm, and the ambient temperature is kept at 10-40 ℃ and the ambient relative humidity is kept at 5-40%.
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