CN113559059B - Cationic nano suspension and preparation method and application thereof - Google Patents
Cationic nano suspension and preparation method and application thereof Download PDFInfo
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- A61P27/02—Ophthalmic agents
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Abstract
The invention relates to a cationic nano suspension and a preparation method and application thereof, wherein the preparation method comprises the following steps: weighing and preparing an aqueous solution of a cationic surfactant, a nonionic surfactant and a high molecular polymer as a stabilizer aqueous solution; weighing pure drug particles, dissolving the pure drug particles by an organic solvent, injecting the pure drug particles into the aqueous solution of the stabilizer prepared in the step S1 by using a syringe under the stirring condition, continuously stirring, and removing the organic solvent by rotary evaporation to obtain crude nano suspension; finally, regulating the pH value to 6-8 to obtain the cationic nano suspension. Compared with the prior art, the invention uses pure drug particles as a core, uses cationic surfactant, nonionic surfactant and high molecular polymer as stabilizers, forms a submicron particle colloidal dispersion system, and the prepared cationic nano suspension can increase the biological adhesiveness of eyes and prolong the retention time of ocular surfaces, thus being a more effective ocular drug delivery system.
Description
Technical Field
The invention relates to the technical field of ophthalmic nanosuspensions, in particular to a cationic nanosuspension, a preparation method and application thereof.
Background
Ocular administration is affected by many drug delivery barriers and clearance systems due to the unique anatomical and physiological characteristics of the eye. Such as reflex blinking, tear film regeneration, tear circulation, etc., result in poor bioavailability, typically less than 5%, for topical ocular administration. For various ocular surface and intraocular diseases, such as xerophthalmia, glaucoma, uveitis, macular degeneration, etc., steroid or non-steroid anti-inflammatory drugs are mostly used clinically, and they are insoluble drugs. Because these drugs themselves have the characteristics of strong lipophilicity and poor water solubility,
in recent years, for such poorly soluble drugs, several lipid nanocarrier formulations such as nanoemulsions, liposomes, nanomicelles, and the like have emerged. Because of the limitation of lipid carrier, the entrapment rate and drug-loading rate are limited, and the toxic and side effects such as irritation and the like are wide in clinic.
Therefore, research on a novel ophthalmic drug delivery system is needed, and the novel ophthalmic drug delivery system has important clinical significance in not only increasing the bioavailability of drugs in eyes, but also greatly reducing the irritation of eyes.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a cationic nano suspension, a preparation method and application thereof, which are used for effectively delivering drugs in eyes.
The aim of the invention can be achieved by the following technical scheme:
firstly, the technical scheme has a meticulous conception, a definite research and development direction is established based on a research and development basis, and the unique composition form of the nanosuspension is adopted in the invention, so that the nanosuspension becomes a very promising eye drug delivery system. Compared to nanolipid carrier formulations, ophthalmic nanosuspensions have the following advantages:
(1) The eye irritation is reduced without increasing the drug concentration by means of high-concentration surfactant, so that the problems of eye redness, stinging, burning, tear flow rate reduction and other irritation caused by the fact that a large amount of oil phase and surfactant in the nano lipid carrier preparation damage the integrity of cornea cells can be well solved, the safety of the ophthalmic preparation is improved, and the irritation is reduced.
(2) Increase corneal adhesiveness and prolong ocular surface residence time.
(3) Promoting cornea penetration and improving eye bioavailability. The huge specific surface area of the nano suspension can obviously increase the saturation solubility and dissolution speed of the medicine in tear fluid, can enable the medicine to be released more quickly and completely in a shorter time, can quickly reach higher medicine concentration on the surface of cornea, forms a certain concentration gradient, improves the medicine cornea permeation, and promotes the transportation of medicine molecules from tear fluid to eye tissues.
As the core of the conception in the technical proposal: the ocular surface mucus layer is composed of mucins and tears, the negatively charged properties of which combine with positively charged drug ions, thereby increasing the retention of the cationic drug delivery system on the ocular surface.
A first object of the present application is to protect a method for preparing a cationic nanosuspension, comprising the steps of:
s1: weighing and preparing an aqueous solution of a cationic surfactant, a nonionic surfactant and a high molecular polymer as a stabilizer aqueous solution;
s2: weighing pure drug particles, dissolving the pure drug particles by an organic solvent, injecting the pure drug particles into the aqueous solution of the stabilizer prepared in the step S1 by using a syringe under the stirring condition, continuously stirring, and removing the organic solvent by rotary evaporation to obtain crude nano suspension;
s3: finally, regulating the pH value to 6-8 to obtain the cationic nano suspension.
Furthermore, the nano suspension prepared in the step S3 takes pure drug particles as a core, and takes cationic surfactant, nonionic surfactant and high molecular polymer as stabilizers, so that a submicron particle colloidal dispersion system is formed, and the prepared cationic nano suspension can increase the biological adhesiveness of eyes and prolong the residence time of the surfaces of eyes, so that the nano suspension is a more effective eye drug delivery system.
Further, the average particle size of the nanosuspension prepared in S3 is less than 1 μm, and the Zeta potential is-15- +90mV.
Further, the pure drug particles are cyclosporin a.
Further, the addition amount of the cationic surfactant is 0.0001 to 0.01 weight percent of the cationic nanosuspension;
the dosage of the nonionic surfactant is 0.01 to 4 weight percent of the cationic nano suspension;
the dosage of the high molecular polymer is 0.01 to 4 weight percent of the cationic nano suspension.
The dosage of the pure drug particles is adjusted according to actual requirements.
Further, the cationic surfactant is one or a combination of more of cetammonium chloride (CKC), benzalkonium chloride (BKC), benzalkonium bromide (BDB), cetyltrimethylammonium chloride (1631), octadecyltrimethylammonium chloride (1831) and chitosan.
Further, the nonionic surfactant is one or more of poloxamer 407 (P407), poloxamer 188 (P188), TPGS (CAS number 9002-96-4), tween 80 and PEG 400.
Further, the high molecular polymer is one or more of polyvinyl alcohol (PVA), povidone (PVP), HPMC-hydroxypropyl methylcellulose (HPMC) and Hyaluronic Acid (HA).
A second object of the present application is to protect a cationic nanosuspension prepared by the method described above.
A third object of the present application is to protect the use of a cationic nanosuspension as described above in ophthalmic medicine.
Compared with the prior art, the invention has the following technical advantages:
(1) The cationic nano suspension prepared by the invention has the advantages of small auxiliary material consumption, small irritation, positive charge of the drug particles due to the addition of the cationic surfactant, high bioadhesion, long residence time on the ocular surface and high in vivo bioavailability, and can be combined with mucin with negative charges on the ocular surface.
(2) The cationic nano suspension prepared in the invention can reach effective drug treatment concentration (10-20 mug/g) in cornea, and is an effective ophthalmic cyclosporin nano delivery system.
(3) The cationic nanosuspension prepared in the invention has higher bioavailability in the eye compared with mucus penetrating particles and common nanosuspensions.
Drawings
Fig. 1: transmission electron microscopy of cationic nanosuspensions.
Fig. 2: x-ray powder diffraction pattern of cationic nanosuspensions.
Fig. 3: the potential change results after the cationic cyclosporine nanosuspension is reacted with mucin at different concentrations.
Fig. 4: experimental results of the binding rate of cyclosporine nanosuspension to mucin over time.
Fig. 5: concentration of cyclosporin in cornea after topical administration of cyclosporin nanosuspension.
Detailed Description
The invention will now be described in detail with reference to the drawings and specific examples.
The invention adopts an antisolvent precipitation method to prepare the nanometer suspension. The drug is dissolved in an organic solvent and then rapidly injected into an isotonic aqueous solution containing a stabilizer under magnetic stirring.
The invention provides a positive-charge cationic nanosuspension, wherein the cationic nanosuspension takes nonionic surfactants comprising poloxamer 407, poloxamer 188, TPGS, tween 80, PEG400 and cationic surfactants comprising ceto ammonium chloride (CKC), benzalkonium chloride (BKC), benzalkonium bromide (BDB), cetyltrimethylammonium chloride (1631), octadecyl trimethylammonium chloride (1831) and chitosan as stabilizers, wherein the nonionic surfactants act as steric stabilization, and the cationic surfactants adsorb on the surfaces of particles to enable the particles to have positive charges to form electrostatic repulsion, and the steric stabilization and the electrostatic repulsion jointly maintain the stability of the particles.
Examples 1 to 9
Prescription composition, see Table 1
(1) Precisely weighing the prescribed amount of stabilizer, placing in a beaker, adding purified water, and performing ultrasonic treatment to completely dissolve the stabilizer.
(2) Accurately weighing the cyclosporine A with the prescription amount, adding a proper amount of organic solvent into a small beaker for dissolution, injecting the cyclosporine A into the aqueous solution containing the stabilizer by using a syringe under the condition of the magnetic stirring speed of 100-900 rpm, continuously stirring, and then rotationally evaporating for 2-3h to remove the organic solvent to obtain the crude nano suspension.
(3) Finally, regulating the pH value to 6-8 to obtain the final cyclosporine A nanometer suspension.
TABLE 1
In examples 1-9, 9 different stabilizers, HA, PVP, PVA and HPMC, which are high molecular weight polymers, were used; p88, P407, TPGS, tween 80 belong to nonionic surfactants; SDS belongs to ionic surfactants. The particle size sequence of the formed nano suspension is as follows: SDS < P188 < P407 < TPGS < Tween 80 < PVA < HPMC, wherein HA and PVP cannot form a uniform nano suspension, but white flocculent precipitate appears.
After 2 days of standing at 25 ℃, the particle sizes of the nanosuspensions formed in the examples 4 and 5 by using PVA and P407 as stabilizers are basically unchanged, and other particle sizes are obviously changed, so that the PVA and P407 have better effects as stabilizers.
Examples 10 to 23
Preparation of nanosuspension:
similar to examples 4 and 5, the nanosuspensions were prepared using different concentrations of high molecular weight polymer and ionic surfactant.
TABLE 2
Comparing the examples, it is apparent that the particle size decreases significantly with increasing stabilizer amount, and the rate of particle size decrease decreases with increasing stabilizer amount.
Examples 10-16 significantly reduced PVA compared to examples 17-23, mainly because P407 is an amphiphilic surfactant with a shorter hydrophilic chain than PVA, which is a high molecular polymer, has a larger molecular weight, has a longer hydrophilic chain, and has a stronger steric acting force.
The data from the 14 day particle size and particle size distribution change at 25℃show that the particle sizes of examples 14 and 21 do not substantially increase and that the stability is good.
Examples 24 to 29.
Prescription composition: see table 3.
A preparation method of a nanometer suspension, which comprises the following steps:
similar to examples 14 and 21, except that a combination of polymeric, nonionic and cationic surfactants was used as a complex stabilizer to prepare nanosuspensions.
TABLE 3 Table 3
Comparison of examples 24-26 shows that the nanosuspension prepared by combining PVA and TPGS shows good stability, which indicates that the stabilizer of both PVA and TPGS has good compatibility, because TPGS is an amphiphilic surfactant with a lipophilic head and a hydrophilic tail, and the lipophilic chain has strong affinity with the liposoluble drug particles, so that the absorption of TPGS on the surface of the nanosuspension is promoted, while the relatively short hydrophilic chain does not affect the further absorption of PVA, so that the stable coverage of the surface of the drug particles is more complete, and good stability is shown.
The comparative examples 27-19 show that the nanosuspensions prepared after the combination of TPGS and P407 are poor in stability, which means that the compatibility of TPGS and P407 is poor, mainly because both TPGS and P407 belong to amphiphilic surfactants, both have lipophilic chains, and the adsorption on the surfaces of the liposoluble drug particles is competitive, so that the adsorption of the drug particle surface stabilizer is incomplete, and a thicker hydration layer cannot be formed, and the spatial three-dimensional barrier effect is weak, so that the formed nanosuspensions are not stable enough.
Compared with other examples, the nano suspension prepared after adding CKC in example 25 and example 27 has good stability, mainly because the addition of CKC makes the surface of the nano particle have higher positive charge, forms stronger electrostatic repulsion, and further enhances the stability of the nano suspension.
Examples 30 to 40
Prescription composition: see table 4.
A preparation method of a nanometer suspension, which comprises the following steps:
examples 25 and 27 are similar, except that different types of cationic surfactants are used to prepare nanosuspensions.
TABLE 4 Table 4
Examples 41 to 50
Prescription composition: see table 5.
A preparation method of a nanometer suspension, which comprises the following steps:
similar to examples 32 and 35, the difference was that different concentrations of cationic surfactant were used to prepare nanosuspensions.
TABLE 5
Comparing the examples, it can be seen that the Zeta potential of the nanosuspension increases with increasing amounts of cationic surfactant. Comparing examples 40-45 and examples 46-50, it can be seen that when the same concentration of cationic surfactant is used, the Zeta potential of the nanosuspension prepared with the surfactant as the primary stabilizer is higher than the Zeta potential of the nanosuspension prepared with the polymer as the stabilizer.
Application examples
The in vitro physicochemical properties of the nanosuspensions according to the present invention were characterized by the use of the nanosuspensions according to example 21, example 25, example 26 and example 27, and the in vitro adhesion, mucous penetration and ocular tissue distribution were evaluated.
After dilution in water, particle size, PDI and potential were determined for the different nanosuspensions using a malvern particle sizer. See table 6.
TABLE 6
The physicochemical properties of the 4 different CsA nanosuspensions, the average particle sizes of example 25 and example 26 were (181.9 nm) and (197.5 nm), respectively, significantly greater than those of example 27 (115.7 nm) and example 21 (117.9 nm). This is because the main stabilizer PVA used in example 25 and example 26 is a high molecular polymer, and the main stabilizer used in example 27 and example 21 is P407 is a surfactant. P407 belongs to an amphiphilic surfactant, the hydrophilic chain of the surfactant is shorter than that of PVA, and the PVA belongs to a high-molecular polymer, has larger molecular weight and longer hydrophilic chain, and forms a larger hydration layer on the surface of a medicine crystal, so that the particle size of the formed nano particles is larger.
1. Cationic cyclosporin nanosuspension and potential change after action of mucin at different concentrations
The test steps are as follows:
(1) 100mg mucin is weighed in a mortar, a small amount of deionized water is added to grind for 1 hour, deionized water is added to dilute to obtain 1mg/mL mucin solution, then the mucin solution is stirred overnight at a stirring speed of 300rpm by a magnetic stirrer to be fully hydrated, then the mucin solution is reserved at 4 ℃, and then the mucin solution is diluted to different concentrations to prepare 0.1mg/mL, 0.2mg/mL, 0.3mg/mL, 0.4mg/mL, 0.5mg/mL, 0.75mg/mL and 1mg/mL mucin solution.
(2) Samples were added to the above mucin solutions of different concentrations (1 mL sample solution+10 mL mucin solution) at a ratio of 1:10, and the mixture was left to stand for 15min after being mixed on a mixer for 30s, and the zeta potential changes before and after mixing were compared.
The experimental results are shown in FIG. 3. As the mucin concentration increases, the Zeta potential gradually decreases and then approaches zero, which eventually results in the charge of the drug nanoparticle changing from positive to negative as the mucin concentration is further increased. This is probably because the negatively charged mucin adsorbs on the surface of the positively charged CsA nanoparticle body, thereby reducing the surface charge. Furthermore, we have found that the Zeta potential of both final example 15 and example 13 is reversed to around-15 mV at mucin concentrations of 0.3mg/ml and 1mg/ml, respectively. The above results indicate that the electrostatic force between example 3 (+31 mV) and mucin is stronger than example 13 (+11 mV), mainly because example 15 has a larger positive charge than example 13, and the larger the Zeta absolute value, the stronger the electrostatic force.
2. Binding rate of nanosuspension to mucin
The test steps are as follows:
(1) 100mg of mucin was weighed in a mortar, ground with a small amount of pure water for 1 hour, diluted with water to obtain 1mg/ml mucin solution, and then stirred overnight with a magnetic stirrer at a stirring speed of 300rpm to be completely hydrated and then stored at 4 ℃.
(2) Adding a sample into the mucin solution (1 mg/ml) in a ratio of 1:10, uniformly mixing for 30 seconds on a mixing machine, standing for 5min, 10min, 30min and 60min respectively, centrifuging (16000 rpm,10 min), taking supernatant, diluting by 10 times with deionized water, measuring absorbance at the maximum absorption wavelength of mucin by using an ultraviolet spectrophotometer, and obtaining the concentration of free mucin, thereby calculating the binding rate of the sample and mucin. The higher the bonding rate, the stronger the adhesion.
The results are shown in FIG. 4. The adsorption was completely equilibrated after 60min incubation of examples 25 and 26 with mucin solution, whereas the equilibration was achieved after only 10min incubation of examples 27 and 21. This is probably because the stabilizers used in examples 25 and 26 are high molecular polymer PVA, which has a long hydrophilic chain and mucin and may have a hydrogen bond or a physical entanglement process in addition to electrostatic interactions. The process of physical entanglement is not as fast as the electrostatic interaction, resulting in a longer time for example 25 and example 26 to reach equilibrium. The binding rate of example 25 to mucin was lower than that of example 27 in the first 20min, but after 60min, the binding rate of final example 25 (61%) to mucin was higher than that of example 27 (50.2%), for the same reason.
It can be seen from the figures that the binding rate of example 25 (61%) and example 27 (50.2%) to mucin is significantly higher than that of example 26 (29.9%) and example 21 (10.2%). This is probably because examples 25 and 27 are positively charged and interact more strongly with negatively charged mucins. The results show that the binding efficiency of the drug nano particles and the mucin can be promoted through electrostatic interaction and physical winding, but the speed of the electrostatic interaction is faster than that of the physical winding, the electrostatic interaction can be completed in a few minutes, and the binding rate of the mucin can reach more than 50%. It can be seen that the electrostatic interaction of positive and negative charges is a major factor affecting the binding rate of nanocrystals to negatively charged mucins, followed by the storage of hydrophilic chains by PVA.
3. In vitro mucous penetrability experiment of nanosuspension
The test steps are as follows:
the penetration of CsA nanosuspensions in mucus was studied using a Transwell cell to simulate the structure of the ocular mucus layer in vivo, the Transwell cell permeation device consisting essentially of a donor cell and an acceptor cell, the bottom of the donor cell being coated with a special polycarbonate semipermeable membrane having a pore size of 0.4 μm which allows drug particles to pass freely into the receiving cell, but the mucus is impermeable. 100. Mu.L of mucin solution with the concentration of 1mg/mL was added to the above-mentioned 12-well Transwell cell (0.4 μm) semipermeable membrane, 1.5mL of artificial tear was added to the receiving chamber, 500. Mu.L of four kinds of cyclosporin nanosuspension solutions with the same concentration were respectively added to the upper chamber, the temperature of the thermostatic shaker was set to 35.+ -. 0.1 ℃ and the shaking shaker rotation speed was set to 100rpm in order to simulate the dynamic environment in vivo, the above-mentioned Transwell cell permeation apparatus was cultured for 3 hours under this condition, 200. Mu.L of sample solution was taken in the receiving chamber below with a pipette, and the drug concentration was measured by HPLC sample introduction.
The experimental results are shown in Table 5. Example 25 (1.01X10-6 cm.s) -1 ) And example 27 (0.43X10-6 cm. S) -1 ) The Papp value of (2) is significantly lower than that of the implementationExample 26 (3.44X10) -6 cm.s -1 ) And example 21 (4.94X10-6 cm.s) -1 ). This result shows that since example 25 and example 27 are both positively charged, a strong electrostatic interaction with mucin occurs, thus exhibiting a higher affinity with mucin, being captured by mucin in mucus, and thus having a low apparent permeability coefficient. In addition, although example 26 and example 21 were both negatively charged, example 21 (4.94X10-6 cm. S) -1 ) The Papp value of (C) is significantly higher than that of example 26 (3.44X10-6 cm. S) -1 ). This is because the stabilizer used in example 21 is surfactant P407, and the molecular structure of P407 has 2 hydrophilic PEG chains, and the PEG hydrophilic chains are covered on the CsA surface to form a coating with mucous penetrability, and the example 21 forms a particle (MPP) with mucous penetrability, which can evade the capture of mucin, so the apparent permeability coefficient is higher. These findings indicate that MPP technology may help drug particles overcome the ocular mucus barrier, achieving higher drug concentrations to the corneal surface.
TABLE 7
4. Ocular tissue distribution test
The test steps are as follows:
(1) Tissue sample preparation. The healthy male New Zealand white rabbits with the equivalent body weight of each group are fixed on an experimental operation table, 50 mu L of cyclosporin nanosuspension is dripped into conjunctival sac of each rabbit eye (4 times daily, 2 hours each time and 5 days each time are used for continuous administration), and eyelid of each rabbit eye is gently closed for 1 minute after each administration, so that the overflow and the loss of the medicine are prevented. After 1h of the last administration, 20mL of air was injected intravenously to the ear margin, the eyes were rapidly picked up and placed in a surface dish by embolism sacrifice, then rapidly dissected, the cornea was completely taken out, and placed in a different tissue grinder for grinding, and a cornea tissue homogenate was prepared.
(2) And (5) sample pretreatment. Treatment of rabbit cornea samples: tissue homogenization was performed by adding 500. Mu.L of physiological saline, respectively. Then, the mixture was placed on a shaker for 1 hour at 35.+ -. 0.1 ℃ and 100rpm to allow the drug to be sufficiently eluted from the corneal tissue. Then 400 mu L of the homogenized cornea tissue homogenate is placed in a 5mL centrifuge tube by a pipetting gun, 100 mu L of cyclosporin D (CsD) internal standard solution with the concentration of 1 mu g/mL is added into the centrifuge tube, 2mL of diethyl ether solution is added for extraction, after the mixed solution is uniformly mixed, the mixture is centrifuged on a centrifuge for 1min (3000 r/min), the upper organic phase is transferred into another centrifuge tube, the organic solution is blow-dried by nitrogen in a ventilation kitchen under the condition that the water bath temperature is 40 ℃, 500 mu L of methanol-water solution (70% methanol) is added into the centrifuge tube to fully dissolve residues, after the uniform mixing, 500 mu L of fat-soluble impurities in n-heptane extraction solution are added, after the mixed spinning is carried out for 30s, the mixture is centrifuged for 1min (3000 r/min), the lower solution is taken out for sample injection, and the drug concentration is measured by LC-MS.
The experimental results are shown in table 7 and fig. 5. Tissue distribution experiments showed that the drug content in cornea reached effective drug treatment concentration (10-20 μg/g) both for positively charged cationic nanosuspensions with higher adhesion example 27 (13641.10 ng/g) and example 25 (11912.58 ng/g) and for example 21 with stronger mucus penetration (11436.073 ng/g). Whereas example 26 (8471.47 ng/g), which is not very penetrating and adhesive, has significantly lower drug content in the cornea than the other three groups. The surface of the drug particles is modified to have mucous penetrability or adhesiveness, so that the bioavailability of the drug in local administration of the eye can be effectively improved. In addition, the higher positively charged example 27 has a higher drug concentration in the cornea than example 21, demonstrating that increasing mucus adhesiveness by electrostatic action has a greater impact on drug bioavailability in the eye than increasing mucus penetration to overcome the mucus barrier.
TABLE 8
In summary, cyclosporin nanosuspensions with mucus penetration and mucus adhesion both increase drug bioavailability at the cornea, while cationic nanosuspensions have higher bioavailability, which is a more effective ocular drug delivery system.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the present disclosure, should make improvements and modifications without departing from the scope of the present invention.
Claims (2)
1. A method for preparing cationic nanosuspension, comprising the steps of:
s1: weighing and preparing an aqueous solution of a cationic surfactant, a nonionic surfactant and a high molecular polymer as a stabilizer aqueous solution;
s2: weighing pure drug particles, dissolving the pure drug particles by an organic solvent, injecting the pure drug particles into the aqueous solution of the stabilizer prepared in the step S1 by using a syringe under the stirring condition, continuously stirring, and removing the organic solvent by rotary evaporation to obtain crude nano suspension;
s3: finally, regulating the pH value to 6-8 to obtain cationic nano suspension;
the nanometer suspension prepared in the S3 is a submicron particle colloidal dispersion system formed by taking pure drug particles as cores and taking cationic surfactant, nonionic surfactant and high molecular polymer as stabilizers;
the average grain diameter of the nano suspension prepared in the step S3 is smaller than 1 mu m, and the Zeta potential is minus 15 to plus 90mV;
the addition amount of the cationic surfactant is 0.0001-0.01-wt% of the cationic nano suspension;
the dosage of the nonionic surfactant is 0.01wt% -4 wt% of that of the cationic nanosuspension;
the dosage of the high molecular polymer is 0.01wt% -4 wt% of cationic nano suspension;
the pure drug particles are cyclosporine A;
the cationic surfactant is one or more of cetammonium chloride (CKC), benzalkonium chloride (BKC), benzalkonium bromide (BDB), cetyltrimethylammonium chloride (1631), octadecyl trimethylammonium chloride (1831) and chitosan;
the nonionic surfactant is one or more of poloxamer 407, poloxamer 188, TPGS, tween 80 and PEG 400;
the high polymer is one or more of polyvinyl alcohol (PVA), povidone (PVP), HPMC-hydroxypropyl methylcellulose (HPMC) and Hyaluronic Acid (HA).
2. A cationic nanosuspension prepared by the method of claim 1.
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| US8796222B2 (en) * | 2011-11-15 | 2014-08-05 | Allergan, Inc. | Suspensions of cyclosporin A form 2 |
| CN105708844A (en) * | 2014-12-05 | 2016-06-29 | 成都青山利康药业有限公司 | Tobramycin and dexamethasone nanosuspension eye drop and preparation method thereof |
| CN107998399A (en) * | 2017-12-22 | 2018-05-08 | 北京诺康达医药科技有限公司 | A kind of cyclosporine compound eye drops and preparation method thereof |
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| US8796222B2 (en) * | 2011-11-15 | 2014-08-05 | Allergan, Inc. | Suspensions of cyclosporin A form 2 |
| CN105708844A (en) * | 2014-12-05 | 2016-06-29 | 成都青山利康药业有限公司 | Tobramycin and dexamethasone nanosuspension eye drop and preparation method thereof |
| CN107998399A (en) * | 2017-12-22 | 2018-05-08 | 北京诺康达医药科技有限公司 | A kind of cyclosporine compound eye drops and preparation method thereof |
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