CN112663166A - Degradable subcutaneous implantation letrozole sustained-release electrospun fiber - Google Patents
Degradable subcutaneous implantation letrozole sustained-release electrospun fiber Download PDFInfo
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- CN112663166A CN112663166A CN202110021856.7A CN202110021856A CN112663166A CN 112663166 A CN112663166 A CN 112663166A CN 202110021856 A CN202110021856 A CN 202110021856A CN 112663166 A CN112663166 A CN 112663166A
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Abstract
The invention relates to the technical field of novel medicament forms, in particular to a degradable subcutaneously implanted letrozole sustained-release electrospun fiber, which is prepared by the following steps: s1, aliphatic polyester, a medicine and a surfactant are dissolved in dichloromethane together by an electrostatic spinning technology, the surfactant is compounded in the aliphatic polyester, the medicine is wrapped in the aliphatic polyester, S2 and the water-insoluble medicine which is solubilized and loaded in the aliphatic polyester are released into the dichloromethane together to obtain colorless, transparent and uniform solution to be electrospun, S3 electrostatic spinning is carried out under the action of high voltage electricity and runs to a receiving screen in a high-speed irregular spiral track, Poloxamer188 composite polyglycolic acid-co-L-lactic acid-co-alpha-hydroxy-L-butyric acid electrospun fiber can slowly release letrozole for 1 month, the release behavior conforms to the Peppas equation, and the system can completely release the loaded letrozole and is completely degraded within 3 months.
Description
Technical Field
The invention relates to the technical field of novel medicament forms, in particular to degradable subcutaneously implanted letrozole sustained-release electrospun fibers.
Background
The breast cancer is one of the most common diseases of women, in the modern society, the medicine for treating the breast cancer is not ideal, and people have certain defects when being administrated by oral administration and intravenous injection, such as: the oral administration is slow and irregular, the compliance is poor, or the patients with unconsciousness are difficult to administer, and the intravenous administration has the defects of larger irritation and the like. After intravenous injection and oral administration, the medicine can generate toxic and side effects on non-target parts, the targeting property of the medicine is improved, and the toxic and side effects are reduced for years.
For nearly half a century, aromatase inhibitors have been proposed and developed to organize the conversion of steroid structural molecules in the body to endogenous estrogens, i.e., to arrest the progression of breast cancer by reducing the estrogen concentration in the body. Of these, the aromatase inhibitors fadrozole, letrozole, anastrozole, and the like are typical drugs.
These drugs must be taken daily to achieve and maintain effective concentrations in the body, which greatly increases patient non-compliance. Whether a carrier capable of slowly releasing the aromatase inhibitor can be constructed or not is determined, so that the carrier can slowly release the drug for at least 1 month after one-time administration, and the carrier becomes a research direction of new dosage forms of the drug.
Disclosure of Invention
The invention aims to solve the defects in the prior art and provides a degradable subcutaneously implanted letrozole sustained-release electrospun fiber.
In order to achieve the purpose, the invention adopts the following technical scheme:
a degradable subcutaneous implantation letrozole slow-release electrospun fiber comprises the following preparation steps:
s1, dissolving aliphatic polyester, a drug and a surfactant into dichloromethane together by an electrostatic spinning technology, compounding the surfactant into the aliphatic polyester, and wrapping the drug in the aliphatic polyester;
s2, releasing the water-insoluble drug carried in the aliphatic polyester into dichloromethane together to obtain colorless, transparent and uniform solution to be electrospun;
s3, carrying out electrostatic spinning under the action of high voltage electricity, and moving the electrostatic spinning to a receiving screen in a high-speed irregular spiral track;
s4, adding a surfactant to reduce the surface tension of the aliphatic polyester solution and obtain a spinning solution with smooth spinning and uniform diameter;
s5, fixing the amount of the aliphatic polyester according to the difference of the chemical structures of the aliphatic polyester, the medicament and the surfactant, and adjusting the compounding amount of the medicament and the surfactant to obtain the letrozole sustained-release electrospun fiber.
Preferably, the spinning solution in S4 is a white felt with a thickness of about 0.5mm, which is formed by laminating fibers.
Preferably, the compound amount of the drug in S5 is 10%, 20% or 30% of polyester lactone, and the compound amount of the surfactant is 12.5%, 25%, 50%, 75% or 100%.
Preferably, the surfactant is poloxamer 188.
Compared with the prior art, the invention has the beneficial effects that:
1. the load of letrozole in the Poloxamer188 composite polyglycolic acid-co-L-lactic acid-co-alpha-hydroxy-L-butyric acid electrospun fiber can reach 30% of the mass of the polymer. Is the highest existing letrozole non-oral solid preparation.
2. The Poloxamer188 composite polyglycolic acid-co-L-lactic acid-co-alpha-hydroxy-L-butyric acid electrospun fiber can slowly release letrozole for up to 1 month, and the release behavior conforms to the Peppas equation. The system can completely release the loaded letrozole and completely degrade within 3 months.
3. In the nonionic surfactant compounded aliphatic polyester electrospun fiber system, the percentage release rate of the loaded drug is increased along with the increase of the compounding amount of the Poloxamer188, and one main function of the Poloxamer188 is to bind, wrap and solubilize the letrozole, the letrozole in the electrospun fiber is tightly bound with the Poloxamer188, and when the loading amount of the letrozole in the fiber is increased, the combination probability of the letrozole and the Poloxamer188 in the fiber is higher. That is, as the letrozole loading in the fiber increases, it consumes more Poloxamer188 for binding, encapsulation, and solubilization.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.
Fig. 1 is a schematic structural diagram of a degradable subcutaneously implanted letrozole sustained-release electrospun fiber provided by the invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments.
Example (b):
referring to fig. 1, aliphatic polyester, drug and surfactant are dissolved in dichloromethane together by a solvent electrospinning technology, the surfactant is compounded in electrospun fiber, and the drug is wrapped in the fiber.
Wherein the aliphatic polyester is not significantly degraded in aqueous medium and physiological medium within a short period of time and is insoluble in water, the surfactant can be released from the fiber, and simultaneously the water-insoluble drug solubilized in the fiber is released into the medium together.
Finally, colorless, transparent and uniform solution to be electrospun is obtained, electrostatic spinning is carried out under the action of high voltage electricity, and the solution moves to a receiving screen in a high-speed irregular spiral track.
In the prepared electrospun fiber, the surface tension of the aliphatic polyester solution is reduced by adding the surfactant, so that the spinning solution with smooth spinning and uniform diameter can be obtained.
After spinning, a white felt of about 0.5mm thickness is formed on the receiving screen by the deposition of fibers to reach the new drug delivery system.
According to the difference of chemical structures of the aliphatic polyester, the medicament and the surfactant, the amount of the aliphatic polyester polyglycolic acid-co-L-lactic acid-co-alpha-hydroxy-L-butyric acid is fixed, and the compounding amount of the medicament and the surfactant is adjusted, wherein the compounding amount of the medicament is 10%, 20% and 30% of polyester lactone, and the compounding amount of the surfactant is 12.5%, 25%, 50%, 75% and 100%.
15 different drug fibers were obtained. Characterization of the prepared electrospun fibers by scanning electron microscopy, X-ray diffraction, differential thermal analysis the release behavior of the fiber mats was investigated by in vitro release as follows:
1. scanning electron microscope, cutting off about 5mm × 5mm electrospun fiber, fixing on the conductive gel, dipping trace amount on the conductive gel when the sample is powder, and making the area of the sample area about 5mm × 5 mm. Then fixing the sample-carrying conductive adhesive on a metal sample stage, performing vacuum evaporation by using gold, and then placing under a scanning electron microscope for observation.
2. Weighing about 1g of electrospinning product by X-ray diffraction, uniformly paving the electrospinning product in a groove of a glass sheet, placing the glass sheet in a wide-angle X-ray diffractometer for testing at room temperature, and scanning the glass sheet in a scanning range: 5-80 DEG, scanning rate: 2o·min-1。
3. Differential thermal analysis weighing about 25mg of the electrospun product, placing the product into an alloy metal sample box for press sealing,placing in a differential thermal analyzer, raising the temperature from 25 ℃ to 400 ℃ under the protection of nitrogen flow, and raising the temperature rate: 5 ℃ min-1。
4. Releasing the fiber:
the samples were sheared into approximately 5cm by 5cm square strips so that each piece had a mass of approximately 50 + -5 mg, immersed in 10mL of pure water release medium. Placing in constant temperature air bath shaking table at 37 deg.C and 100r min-1Releasing by shaking under the condition. The entire release medium was removed at the set time point and the letrozole content was determined as under 2.3.1, after which 10ml of fresh release medium was added again to the release medium. The absolute and relative release percentages are plotted against time t and the resulting curves are fitted using the Korsmeyer-Peppas equation.
As a result:
1. the prepared fiber membrane is pure white soft thin felt in appearance, no bead structure appears in the obtained sample, the fiber surface is smooth, and no crystalline substance is separated out. The fiber diameter is relatively uniform.
2. According to an X-ray diffraction spectrum, as most of solid drugs, letrozole presents more characteristic peaks between 5 degrees and 40 degrees, Poloxamer188 has 2 obvious characteristic peaks at 19.5 degrees and 23.6 degrees, and polyglycolic acid-co-L-lactic acid-co-alpha-hydroxy-L-butyric acid has no obvious characteristic peak and is in an amorphous state. The diffraction pattern of any drug-loaded fiber has no characteristic peak of polyglycolic acid-co-L-lactic acid-co-alpha-hydroxy-L-butyric acid, which indicates that the semicrystalline substance is converted into an amorphous state after homogeneous solution spinning, which is probably the result of the plasticizing effect of the small molecular substance in the fiber on the polymer and reflects the good compounding of the small molecular substance and the polymer. When the Poloxamer188 composite content is higher, such as 50%, 75% and 100%, the characteristic peak of the surfactant appears on a diffraction pattern no matter how much the drug loading is. This phenomenon has been reported in other similar studies, and is attributed to the tendency of Poloxamer188 to distribute to the fiber surface until appearing in the form of its monomer when the compounding amount in the poly-L-lactic acid electrospun fiber is high, which may be a characteristic of the Poloxamer188 compounded poly-L-lactic acid electrospun fiber system.
3. The pure letrozole has 1 endothermic peak at 182 ℃, 1 endothermic peak at 57.8 ℃ of Poloxamer188 raw material, and 2 main endothermic peaks at 130-150 ℃ and 220-300 ℃ of polyglycolic acid-co-L-lactic acid-co-alpha-hydroxy-L-butyric acid raw material. The characteristic peaks of letrozole in the drug-loaded fiber disappear, which indicates that letrozole is well compounded in the fiber and exists in an amorphous state, and thus the letrozole is favorable for diffusion and release in a fiber matrix. It is worth noting that the X-ray diffraction results indicate that there is monomer deposition on the fiber surface, but the amount may be very small and may not be detected with the precision of differential thermal analysis. When the Poloxamer188 complex amount is 12.5% and 25%, the characteristic peak on the calorimetric curve is not obvious, and as the Poloxamer188 complex amount is increased to be more than 50%, the 2 characteristic peaks on the thermal analysis curve are all obvious. The X-ray diffraction results suggest that when the Poloxamer188 loading is increased above 50%, the monomers are present at the fiber surface. The 2 characteristic peaks on the thermal analysis curve show that the characteristic peak of Poloxamer188 on the surface of the fiber or the characteristic peak of Poloxamer188 inside the fiber matrix can not be determined yet.
4. At any point in time, the release medium was clear and transparent with no visible solid particles and tyndall and letrozole was detected in the release medium, indicating that the drug was released into the aqueous medium in a manner that was solubilized in the Poloxamer188 micelles. In general, three series of fiber drug release curves are provided with burst release, slow release phase and release platform phase. Poloxamer188 promotes letrozole release, which increases with increasing load of letrozole at the same time point, including burst and final sample point drug release, as the level of letrozole incorporation in the fiber increases.
The loading of letrozole itself also has a significant effect on its own release behavior. As the loading was gradually increased, the percent release of drug at the same time point was gradually decreased, including a smaller burst and a smaller release after 42 days. Taking the Poloxamer188 composite amount as 100 percent as an example, when the letrozole loading amount is 10 percent, the percentage release amounts of 0.5h and 42d are respectively 25 percent and 95 percent; when the letrozole loading was 20%, the percentage release at 0.5h and 42d was 20% and 90%, respectively; the percentage release at 0.5h and 42d was 15% and 85%, respectively, when the letrozole loading was 30%.
In the description of the present invention, it should be noted that, unless otherwise explicitly specified or limited, the terms "mounted," "connected," and "disposed" are to be construed broadly, e.g., as meaning either a fixed connection, a removable connection, or an integral connection; may be mechanically coupled, may be directly coupled, or may be indirectly coupled through an intermediary. To those of ordinary skill in the art, the specific meanings of the above terms in the present invention are understood according to specific situations. In the description herein, references to the description of "one embodiment," "an example," "a specific example" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
Claims (4)
1. A degradable subcutaneously implanted letrozole sustained-release electrospun fiber is characterized by comprising the following preparation steps:
s1, dissolving aliphatic polyester, a drug and a surfactant into dichloromethane together by an electrostatic spinning technology, compounding the surfactant into the aliphatic polyester, and wrapping the drug in the aliphatic polyester;
s2, releasing the water-insoluble drug carried in the aliphatic polyester into dichloromethane together to obtain colorless, transparent and uniform solution to be electrospun;
s3, carrying out electrostatic spinning under the action of high voltage electricity, and moving the electrostatic spinning to a receiving screen in a high-speed irregular spiral track;
s4, adding a surfactant to reduce the surface tension of the aliphatic polyester solution and obtain a spinning solution with smooth spinning and uniform diameter;
s5, fixing the amount of the aliphatic polyester according to the difference of the chemical structures of the aliphatic polyester, the medicament and the surfactant, and adjusting the compounding amount of the medicament and the surfactant to obtain the letrozole sustained-release electrospun fiber.
2. The degradable subcutaneously implantable letrozole slow-release electrospun fiber according to claim 1, wherein the spinning solution in S4 is a white felt with a thickness of about 0.5mm, which is formed by laminating fibers.
3. The degradable subcutaneously implantable letrozole slow-release electrospun fiber according to claim 1, wherein the drug in S5 is compounded in 10%, 20% and 30% of polyesterlactone, and the surfactant is compounded in 12.5%, 25%, 50%, 75% and 100%.
4. The degradable subcutaneously implantable letrozole sustained-release electrospun fiber according to claim 1, wherein the surfactant is poloxamer 188.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202110021856.7A CN112663166A (en) | 2021-01-08 | 2021-01-08 | Degradable subcutaneous implantation letrozole sustained-release electrospun fiber |
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| CN202110021856.7A CN112663166A (en) | 2021-01-08 | 2021-01-08 | Degradable subcutaneous implantation letrozole sustained-release electrospun fiber |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102251393A (en) * | 2011-05-18 | 2011-11-23 | 哈尔滨工程大学 | Surface modification method of aliphatic polyester electrospun fiber by using sodium alginate and gelatin |
| CN103356510A (en) * | 2012-03-30 | 2013-10-23 | 曼莉国际有限公司 | Methods for producing drug-containing bioabsorbable fibers |
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- 2021-01-08 CN CN202110021856.7A patent/CN112663166A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102251393A (en) * | 2011-05-18 | 2011-11-23 | 哈尔滨工程大学 | Surface modification method of aliphatic polyester electrospun fiber by using sodium alginate and gelatin |
| CN103356510A (en) * | 2012-03-30 | 2013-10-23 | 曼莉国际有限公司 | Methods for producing drug-containing bioabsorbable fibers |
Non-Patent Citations (1)
| Title |
|---|
| 黄佳娜等: "Poloxamer188复合聚L-乳酸电纺纤维中来曲唑的释放行为", 《沈阳药科大学学报》 * |
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Application publication date: 20210416 |