CN111759807A - Cyclosporine liposome and preparation method thereof - Google Patents
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Abstract
The invention provides a cyclosporine liposome and a preparation method thereof, the cyclosporine liposome comprises the components of phospholipid, cholesterol, ethanol and cyclosporine, wherein the content of the cyclosporine is 0.01-5%, the content of the phospholipid is 0.1-1%, the content of the cholesterol is 0.01-5%, the content of the ethanol is 1-14%, and the preparation method of the cyclosporine liposome comprises the following steps: (1) putting phospholipid and cholesterol in a formula ratio into a container, and dissolving in preheated ethanol; (2) adding cyclosporine in the formula ratio to completely dissolve, adding normal saline with the same temperature as that in the step (1), homogenizing for a period of time by using a homogenizer to obtain colostrum, and cooling to room temperature. The method of the invention has simple operation and stable process, and is suitable for large-scale production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a cyclosporine liposome and a preparation method thereof.
Background
With the increasing frequency and the increasing time of the use of mobile phones, computers, tablets and other video terminals, and the popularization of air-conditioning facilities, the aggravation of environmental pollution, the increase of survival pressure and other factors, the incidence of dry eye diseases is on the rising trend year by year. Dry eye is one of the most common ocular surface diseases, and severe dry eyes can cause significant vision loss that affects work and life, and even causes blindness. By reviewing the data in recent years, the incidence rate of the xerophthalmia in China is about 3-5%, and the incidence rate tends to be low. Therefore, it is necessary to research drugs for relieving dry eye and improve the quality of life of people.
Cyclosporin (CsA) is a cyclic peptide isolated from filamentous fungus culture medium, is an immunosuppressant, and can be used for transplantation of heart, liver, kidney, lung and pancreas, etc., and treatment of autoimmune diseases. Cyclosporine plays a therapeutic role by reducing T lymphocyte infiltration, down-regulating inflammatory factors, and inhibiting apoptosis of lacrimal gland and conjunctival epithelial cells, and has become a hotspot of research in the field of dry eye prevention in recent years. The ciclosporin emulsion provides a more effective drug for treating dry eye than artificial tears, and is the first drug with therapeutic property in the aspect of dry eye treatment.
Most of the currently marketed cyclosporin preparations are oil-soluble preparations. When an oily preparation of cyclosporin is directly dropped onto the eye, irritation may occur to the eye due to the oily preparation and discomfort may be caused to the eye due to its stickiness, thereby possibly aggravating some ocular surface diseases. In addition, the eye drop residence time is short in view of the corneal surface residence time, and if the optimal treatment effect is achieved, patients need to take the cyclosporine eye drops for a long time and frequently, and treatment compliance can be affected. Therefore, the development of a long-acting cyclosporin eye drop free from oil-soluble components is particularly suitable.
Cyclosporin is highly lipid soluble and has a large molecular weight, readily passes through lipophilic epithelial layers, but does not readily permeate hydrophilic stromal layers to accumulate in the cornea, so oil-soluble formulations of cyclosporin can have a higher drug concentration in the cornea but lower concentrations in aqueous humor and other tissues. The liposome is made of phospholipid bimolecular membranes, is similar to biological membranes, is easy to biologically fuse, can easily enter corneal cells, can promote the wrapped medicine to penetrate the cornea, and ensures that the medicine has high medicine concentration on the cornea and the medicine concentration of aqueous humor and other eye tissues is obviously improved compared with common eye drops. Another reason liposomes promote ocular absorption of drugs is to increase the residence time of the drug in the cornea, thereby increasing intraocular absorption of the drug. The liposome has stronger affinity with the cornea, and can pass through the cornea more easily. The liposomes increase contact with the cornea without affecting the smooth concentration differential of the drug into the aqueous humor, ultimately increasing the intraocular drug concentration.
In addition, the existing cyclosporine liposome and preparation thereof have other problems, including complex preparation process, high cost, low encapsulation efficiency, poor stability and other defects. In order to overcome the defects, the invention develops the cyclosporine liposome which has small toxic and side effect, simple production process, low production cost, good stability, high encapsulation rate, good solubility and convenient storage and transportation and the preparation method thereof.
Disclosure of Invention
The invention aims to provide a cyclosporine liposome, which comprises the following raw materials in parts by weight:
cyclosporin (2): 0.01% to 5%, preferably 0.01% to 1%, more preferably 0.05%;
phospholipid: 0.1% to 1%, preferably 0.1% to 0.5%, more preferably 0.3%;
cholesterol: 0.01% to 5%, preferably 0.01% to 1%, more preferably 0.15%;
ethanol: 1% to 14%, preferably 4% to 10%, more preferably 4%.
The invention also provides a preparation method of the cyclosporine liposome, which comprises the following steps: (1) dissolving phospholipid and cholesterol in the formula ratio in preheated ethanol, and adding cyclosporine in the formula ratio; (2) slowly adding into physiological saline at the same temperature as the liposome material and cyclosporine, mixing, homogenizing with a homogenizer for a period of time to obtain suspension, and cooling to room temperature.
Further, the temperature of the preheating of the step is between 50 ℃ and 80 ℃, preferably between 60 ℃ and 70 ℃, and more preferably 70 ℃.
Further, the slow addition of the step is to suck the ethanol phase through a syringe to a position below the liquid level of the physiological saline, and then slowly add the ethanol phase.
Further, the fractional mixing in the step is that the vortex mixer shakes evenly, and the mixing is carried out once per drop.
Further, the rotating speed of the homogenizer in the step is 8000-15000 rpm, and the homogenizing time is 2-5 min.
The prepared liposome is suspension and is used for preparing eye drops.
The invention also aims to provide a ciclosporin liposome for treating eye diseases, wherein the ciclosporin and the lipid material are dissolved to prepare the drug-loaded liposome suspension for the eye preparation.
The invention has the beneficial effects that: the cyclosporine liposome adopts an ethanol injection method, and comprises the steps of adding phospholipid, liposome and cyclosporine and finally injecting normal saline. The cyclosporine liposome has high encapsulation rate, simple production process and good repeatability, and is suitable for industrial production. The ciclosporin liposome prepared by the method does not contain oil-soluble components, remarkably improves the stimulation effect of the ciclosporin oily preparation on eyes and the uncomfortable feeling of the eyes caused by the viscosity of the ciclosporin oily preparation, and avoids the stimulation of a preservative on the eyes.
Drawings
FIG. 1 is an HPLC chart of the cyclosporin content in example 1 of the present invention.
FIG. 2 is an HPLC chart of the cyclosporin content in example 2 of the present invention.
FIG. 3 is an HPLC chart of the cyclosporin content in example 3 of the present invention.
FIG. 4 is an HPLC chart of the cyclosporin content in example 4 of the present invention.
FIG. 5 is a graph showing particle sizes of examples 1, 2, 3 and 4 of the present invention.
FIG. 6 is a photograph taken under a microscope of examples 1, 2, 3 and 4 of the present invention.
FIG. 7 is a graph showing changes in particle size of examples 1, 2, 3 and 4 of the present invention stored for 0, 1 and 3 months.
FIG. 8 is a graph showing the change in the encapsulation efficiency of examples 1, 2, 3 and 4 of the present invention during storage for 0, 1 and 3 months.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that these examples are only for the purpose of the present invention and are not intended to limit the scope of the present invention. Unless defined or indicated otherwise, the scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
Example 1
First, preparation method
1. Weighing dipalmitoyl lecithin (DPPC)300mg, Cholesterol (CHO) -HP150mg in stoppered test tube, heating in circulating water bath to 70 deg.C, maintaining the temperature, and adding 4ml ethanol to dissolve lipid material completely;
2. cyclosporin 50mg was dissolved in the vessel in step 1. Heating 100ml physiological saline to the same temperature as liposome material, pouring ethanol phase into water phase, homogenizing with homogenizer at 10000rpm for 5min to obtain colostrum, and cooling colostrum.
The total amount of cyclosporin in the cyclosporin liposomes was measured by HPLC (see FIG. 1).
Second, determination of encapsulation efficiency of cyclosporine liposome
1. Summary of the process
The method comprises the steps of measuring by adopting a centrifugal method, namely measuring the different sedimentation speeds according to the different centrifugal forces borne by the liposome and the free drug with different specific gravities so as to achieve the purpose of separation, respectively measuring the content of the free cyclosporine and the content of the total cyclosporine by using a high performance liquid chromatography, processing data, and calculating to obtain the encapsulation efficiency of the cyclosporine liposome.
Reagent: acetonitrile: carrying out chromatographic purification; methanol: carrying out chromatographic purification; water: ultrapure water or redistilled water
Instruments and devices: high performance liquid chromatograph: a chromatographic workstation or integrator provided with an ultraviolet detector and data processing software; a mobile phase vacuum filtration degassing device; an ultrasonic oscillator; analytical balance: the sense of measurement is 0.001 g.
Chromatographic conditions are as follows: a chromatographic column: shimadzu C8(4.6 × 250mm 5 μm); mobile phase: methanol to water, 90 to 10 (volume ratio); detection wavelength: UV 220 nm; flow rate: 1.0 ml/min; column temperature: 50 ℃; sample introduction volume: 10 μ l
2. Analytical procedure
Determination of the content of free Cyclosporin
Sample pretreatment: taking 1000 mul of cyclosporine liposome sample, centrifuging at 12000rpm, taking supernatant, and filtering the supernatant by using a 0.45 mu m microporous filter membrane as an instrument detection sample.
Total cyclosporin content determination
Sample pretreatment: taking 1000 mul cyclosporine liposome sample, adding 5000 mul methanol for dissolving, and then filtering by using a 0.45 mu m microporous filter membrane as an instrument detection sample.
3. Presentation of results
The encapsulation efficiency of the cyclosporine liposome is calculated according to formula (1):
ER(％)＝(w1-w2)/w1*100％..............................(1)
in the formula:
ER- -encapsulation efficiency of the sample;
w1- -Total Cyclosporin content in sample;
w2- -free cyclosporin content in the sample;
4. measurement results
The content of cyclosporin liposome encapsulation efficiency in the final product was measured, and the results are shown in table 1.
TABLE 1 measurement results of encapsulation efficiency of cyclosporin liposomes in the final product
Example 2
1. Weighing dipalmitoyl lecithin (DPPC)200mg and Cholesterol (CHO) -HP 40mg, placing in a test tube with a stopper, heating in a circulating water bath to 70 deg.C, maintaining the temperature, and adding 14ml ethanol to dissolve lipid material completely;
2. cyclosporin 50mg was dissolved in the vessel in step 1. Heating 100ml physiological saline to the same temperature as liposome material, pouring ethanol phase into water phase, homogenizing with homogenizer at 10000rpm for 5min to obtain colostrum, and cooling colostrum.
3. HPLC method is adopted to determine cyclosporine in cyclosporine liposomeTotal volume (injection volume: 30. mu.l, see FIG. 2), by encapsulation (%) - (1-W)Swimming device/WGeneral assembly) × 100% and the results are shown in Table 2.
TABLE 2 measurement results of encapsulation efficiency of cyclosporin liposomes in the final product
Example 3
1. Weighing 300mg of distearoyl phosphatidyl glycerol (DSPC) and 150mg of CHO-HP, placing in a test tube with a plug, heating in a circulating water bath until the temperature is 70 ℃, maintaining the temperature, and adding 14ml of ethanol to completely dissolve the lipid material;
2. cyclosporin 50mg was dissolved in the vessel in step 1. Heating 100ml physiological saline to the same temperature as liposome material, pouring ethanol phase into water phase, homogenizing with homogenizer at 10000rpm for 5min to obtain colostrum, and cooling colostrum.
3. The total amount of cyclosporin in cyclosporin liposomes was measured by HPLC (injection volume: 30. mu.l, see FIG. 3) as the encapsulation efficiency (1-W)Swimming device/WGeneral assembly) × 100%, and the results are shown in Table 3.
TABLE 3 measurement of encapsulation efficiency of cyclosporin liposomes in the final product
Example 4
1. Weighing 200mg of DPPC and 66mg of CHO-HP, placing in a test tube with a plug, heating in a circulating water bath until the temperature is 70 ℃, maintaining the temperature, and adding 4ml of ethanol to completely dissolve the lipid material;
2. cyclosporin 50mg was dissolved in the vessel in step 1. Heating 100ml physiological saline to the same temperature as liposome material, pouring ethanol phase into water phase, homogenizing with homogenizer at 10000rpm for 5min to obtain colostrum, and cooling colostrum.
3. The total amount of cyclosporin in the cyclosporin liposomes (injection volume: 30. mu.l, see FIG. 4) was measured by HPLC method in terms ofEncapsulation efficiency (%) - (1-W)Swimming device/WGeneral assembly) × 100% and the results are shown in Table 4.
TABLE 4 measurement results of encapsulation efficiency of cyclosporin liposomes in the final product
Example 5
Particle size distribution determination and microscopic observation of cyclosporine liposome suspension
1ml of DPPC 2-CHO-CyA (prepared in example 1), DPPC5-CHO-CyA (prepared in example 2), DSPC2-CHO-CyA (prepared in example 3), and DPPC 3-CHO-CyA (prepared in example 4) were measured precisely in a 50ml volumetric flask and diluted with distilled water to the desired volume and shaken well. The particle size of the cyclosporine nanoliposome was measured in triplicate using a Sizemanozes 90 particle sizer and the results are shown in FIG. 5. The liposome morphology was observed under a 60-fold lens and photographed with a metallograph camera, see fig. 6.
In terms of particle size, the particle size of the four groups of cyclosporin liposome suspensions all showed a tendency to increase after storage at 4 ℃ for 1 month and 3 months, respectively. At 4 ℃, the speed of the particle sizes of four groups of cyclosporine liposome suspensions is from high to low in sequence: DPPC5-CHO-CyA, DSPC2-CHO-CyA, DPPC 3-CHO-CyA, DPPC 2-CHO-CyA. The particle size of DPPC5-CHO-CyA increased by more than 10 times (263nm → 2785nm), and the increase in PDI (Poly (lactic acid) index) was also large, indicating that the particle size of DPPC5-CHO-CyA increased with the increase in storage time, and the particle size distribution became nonuniform.
The particle size of DPPC 2-CHO-CyA is 361nm → 366nm, DSPC 765nm → 1225nm, and the particle size of DPPC 3-CHO-CyA is 397nm → 456nm, as shown in FIG. 7.
The liposome stored for 3 months is easier to aggregate than the liposome stored for 1 month as seen by LW200-3JT metallographic microscope, and the increase of the particle size measured by a zs90 nanometer particle size analyzer is also proved (367nm → 442 nm).
Under the same conditions, the particle size (125nm) of the liposome prepared from the lipid material DSPC is smaller than the particle size (195nm) of the liposome prepared from the lipid material DPPC, which indicates that the particle size of the prepared DSPC is smaller. The LW200-3JT metallographic microscope shows that the liposome prepared from the lipid material DSPC has a small particle size, and the particle size of the prepared DSPC is proved to be small.
The particle size of the liposomes (278nm) prepared with a phospholipid ratio of 5: 1 was smaller than the particle size of the liposomes (327nm) prepared with a phospholipid ratio of 3: 1, indicating an increased phospholipid ratio and a smaller particle size of the liposomes. The LW200-3JT metallographic microscope shows that the particle size of the liposome prepared from 5: 1 phospholipid is smaller than that of the liposome prepared from 3: 1 phospholipid, the increase of phospholipid ratio is proved, and the particle size of the prepared liposome is small.
Example 6
Determination of Cyclosporin liposome encapsulation efficiency
The encapsulation efficiency was determined by centrifugation. 1ml of DPPC 2-CHO-CyA (prepared in example 1), DPPC5-CHO-CyA (prepared in example 2), DSPC2-CHO-CyA (prepared in example 3), DPPC 3-CHO-CyA (prepared in example 4) was taken and measured in accordance with the method described in example 1.
The encapsulation efficiency (ER%) was calculated according to the formula. The change in encapsulation efficiency (ER%) at 0, 1 and 3 months of storage is shown in FIG. 8.
The results show that:
the four groups of cyclosporine liposome suspensions are stored for 0 month, 1 month and 3 months at the temperature of 4 ℃, and the encapsulation efficiency of the four groups of cyclosporine liposome suspensions is slightly changed. The entrapment rate is 85% after 3 months of DPPC 2-CHO-CyA, 84% after 3 months of DPPC5-CHO-CyA, 87% after 3 months of DSPC2-CHO-CyA and 86% after 3 months of DPPC 3-CHO-CyA 3. The entrapment rate of the 4 groups of cyclosporine liposome is not changed greatly during the storage period from 0 month to 3 months, the lipid framework material is stable, the medicine inclusion is complete, and the liposome is stable to store.
Claims (7)
1. The cyclosporine liposome is characterized by comprising the following components in percentage by weight:
cyclosporin (2): 0.01 to 5 percent of the total weight of the mixture,
phospholipid: 0.1 to 1 percent of the total weight of the mixture,
cholesterol: 0.01 to 5 percent of the total weight of the mixture,
ethanol: 1 to 14 percent.
2. Cyclosporine liposomes according to claim 1 characterised in that the phospholipid is dipalmitoyl lecithin or distearoyl phosphatidyl glycerol or dioleoyl phosphatidyl glycerol or egg yolk phosphatidyl glycerol or a mixture of more thereof.
3. A cyclosporin liposome according to claim 1, wherein the preparation is in the form of eye drop.
4. Liposomes employing cyclosporin according to claim 1, characterized in that the liposomes are formed spontaneously upon addition to an aqueous medium.
5. The method for preparing cyclosporine liposome according to claim 1, comprising the steps of: (1) dissolving phospholipid and cholesterol in the formula ratio in preheated ethanol, and adding cyclosporine in the formula ratio; (2) slowly adding into physiological saline with the same temperature as the liposome material and cyclosporine, mixing, homogenizing with a homogenizer to obtain suspension, and cooling to room temperature.
6. A process for the preparation of cyclosporin liposomes according to claim 5 wherein the preheated ethanol temperature is 50 ℃ to 80 ℃.
7. The method for preparing cyclosporine liposome of claim 5, wherein the homogenizer rotation speed is 8000rpm to 15000rpm, and the homogenization time is 2 to 5 min.
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| CN112472791A (en) * | 2020-11-16 | 2021-03-12 | 复旦大学 | Application of CsA liposome in preparation of anti-SARS-CoV-2 medicine |
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| CN1255057A (en) * | 1997-02-20 | 2000-05-31 | 方济各安吉利克化学联合股份有限公司 | Aqueous pharmaceutical composition comprising active ingredient which is highly insoluble in water |
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| CN112472791A (en) * | 2020-11-16 | 2021-03-12 | 复旦大学 | Application of CsA liposome in preparation of anti-SARS-CoV-2 medicine |
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