CN116672312A - Tacrolimus-entrapped nano preparation and application thereof - Google Patents

Tacrolimus-entrapped nano preparation and application thereof Download PDF

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CN116672312A
CN116672312A CN202310851419.7A CN202310851419A CN116672312A CN 116672312 A CN116672312 A CN 116672312A CN 202310851419 A CN202310851419 A CN 202310851419A CN 116672312 A CN116672312 A CN 116672312A
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antioxidant
nano
tacrolimus
formulation
water
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游剑
郭雪萌
石美幸
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Zhejiang University ZJU
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P39/06—Free radical scavengers or antioxidants
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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Abstract

The invention provides a tacrolimus-entrapped nano preparation and application thereof. The oil phase is lecithin, medium chain triglyceride, fat-soluble antioxidant and tacrolimus, and the water phase is water-soluble antioxidant or deionized water. Aiming at the problems of large molecular weight of tacrolimus and low cornea permeability, the nano preparation provided by the invention improves local drug concentration and delivery efficiency, and simultaneously eliminates ROS accumulation in cells, relieves inflammatory reaction and protects cornea epithelial cells aiming at oxidative stress injury widely existing in xerophthalmia. The nano preparation provided by the invention can inhibit immune response and simultaneously relieve oxidative stress of eyes and reduce cell injury so as to achieve a more efficient treatment effect, has the characteristics of easiness in production and preparation, synergy and the like, and can be used for preparing tacrolimus antioxidant ophthalmic drugs. The invention has good biocompatibility and high safety, and has good industrialization prospect and wide application prospect in the ophthalmic preparation.

Description

Tacrolimus-entrapped nano preparation and application thereof
Technical Field
The invention belongs to the field of pharmacy, relates to a tacrolimus-entrapped nano preparation and application thereof, and relates to a tacrolimus-entrapped nano preparation with antioxidant activity, which can restore intracellular redox balance and reduce apoptosis while delivering medicines with high efficiency, and a construction method of the nano preparation and application thereof in ophthalmic diseases.
Background
The frequency of occurrence of ocular diseases is high and various, and if timely treatment is not available, the vision of a patient is generally affected. Among them, dry eye is a very common disease with prevalence between 5-30% and up to 75% in people over 40 years of age (Rouen and White 2018). Dry eye may be caused by an unstable tear film, resulting in increased evaporation and decreased tear volume, causing uncomfortable symptoms such as dryness, tearing, discomfort, foreign body sensation, and eye strain. If not treated in time, ocular inflammatory reactions, elevated tear osmotic pressure and unstable tear films can form a vicious circle, further worsening the patient's condition.
In the early stages of the disease, the integrity of the tear film is maintained by means of artificial tear supplementation in the clinic. However, when the disease goes into the middle and late stages, the inflammatory response is exacerbated and can only be treated locally with corticosteroids and immunosuppressants. However, the long-term use of corticosteroids causes a number of side effects, such as glaucoma, complications of cataracts, and secondary infections. In contrast, topical immunosuppressants have a higher safety profile. Tacrolimus and cyclosporin A are the two most commonly used immunosuppressants in ophthalmology. Although their mechanism of action is similar, tacrolimus is 10-100 times more potent than cyclosporine a. However, tacrolimus has a low ocular permeability due to its large molecular weight, high hydrophobicity, and direct delivery is difficult to effectively exert its effect. Currently, nano-delivery systems have played an important role in many ophthalmic diseases, including increasing target site concentration, increasing permeability, etc. Therefore, the use of nanocarriers is of great significance in improving the delivery problem of tacrolimus.
In dry eye, the "vicious circle" of oxidative stress is also a very important issue. Hyperosmotic stress of the cornea activates inflammatory signaling pathways, releasing inflammatory factors. Excessive amounts of inflammatory factors recruit activated immune cells, causing epithelial cell damage. During this process, a large amount of ROS also accumulates in the cells, exacerbating the inflammatory response. Thus, inhibition of excessive immune response and scavenging of accumulated ROS are both critical for dry eye treatment.
Disclosure of Invention
The invention aims to provide an antioxidant ophthalmic nano preparation of tacrolimus, which consists of an oil phase and a water phase, wherein the oil phase is: the water phase is 1:1000-1:2, w/w. The nanometer preparation has uniform and stable particle size of less than 200nm.
The nano preparation refers to a pharmaceutically acceptable carrier, including but not limited to nanoemulsion, liposome, micelle and lipid nanoparticle.
The oil phase comprises 5-80% of lecithin, 0-50% of medium chain triglyceride, 0.1-50% of fat-soluble antioxidant, 0.01-20% of tacrolimus and 0.w; the water phase is selected from water-soluble antioxidant 0.1-30%, w/w or deionized water.
Other oily components except fat-soluble antioxidants and tacrolimus in the oil phase can be replaced by phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, sphingomyelin, trimethyl-2, 3-dioleoyloxypropyl ammonium bromide (DOTAP), trimethyl-2, 3-dioleoyloxypropyl ammonium chloride (DOTMA), dimethyl Dioctadecyl Ammonium Bromide (DDAB), soybean oil, olive oil, castor oil, various medium-long chain fatty acid esters, cholesterol and squalane.
The fat-soluble antioxidants include natural vitamin E and its derivatives such as alpha-tocopherol, vitamin E acetate, vitamin E succinate, and vitamin E nicotinate; other antioxidants such as melatonin, polydopamine, glutathione, beta-carotene, astaxanthin, butylated Hydroxyanisole (BHA), curcumin, N-acetylcysteine (NAC), flavonoids (such as quercetin, kaempferol, catechin, epigallocatechin gallate EGCG), etc. can also be substituted. The fat-soluble antioxidant accounts for 0.1% -50% of the weight of the oil phase.
The water-soluble antioxidant accounts for 0.1-30% of the weight of the water phase. The water-soluble antioxidant comprises L-ascorbic acid, tea polyphenols, superoxide dismutase, glutathione peroxidase, glutathione reductase, etc.
The anti-oxidation nano preparation of the tacrolimus-coated drug can be constructed by the following method: the oil-in-water (O/W) drug-loaded nano-preparation is prepared by taking lecithin, medium-chain triglyceride, fat-soluble antioxidant and tacrolimus as oil phases, and taking aqueous solution or deionized water containing the water-soluble antioxidant as water phases.
The invention also aims to provide an application of the nano preparation in preparing tacrolimus antioxidant eye medicine, wherein the medicine is eye drops, and the preparation form is liquid preparation. The application is that the nano preparation can remove excessive ROS to maintain the redox balance steady state of cells of eyes, reduce inflammatory reaction of eyes and reduce apoptosis while inhibiting excessive immune reaction. The nanoformulations slow or eliminate the effects of oxidative stress on the eye in a prophylactic, blocking and repairing manner while delivering the drug.
The nanometer preparation of the invention takes common lipid materials with high biocompatibility, easy acquisition and low production cost as main components, and water-soluble or fat-soluble antioxidants are added, so that excessive ROS are removed to maintain the redox balance steady state of ocular cells while excessive immune response is inhibited, ocular inflammatory response is reduced, and apoptosis is reduced, and the combination of immunosuppressants and antioxidants enables the nanometer preparation to achieve the treatment effect of '1+1 & gt2' in dry eye treatment. The nanometer preparation has the advantages of convenient production, controllable cost, stable quality, high safety and good industrialization prospect and wide application prospect in the ophthalmic preparation due to the good biocompatibility of the used lipid material. The invention is innovative in that 1) the drug delivery efficiency is improved by the nano preparation aiming at the problems of large molecular weight and low cornea permeability of tacrolimus. 2) Aiming at the widely existing oxidative stress injury in xerophthalmia, the ROS accumulation in cells is eliminated, the inflammatory reaction is relieved, and the corneal epithelial cells are protected.
Drawings
Fig. 1 is the appearance of a drug-loaded nanoemulsion.
Fig. 2 is a graph of drug-loaded nanoemulsion particle size.
Fig. 3 is a transmission electron microscope image of the drug-loaded nanoemulsion.
Figure 4 is the particle size stability of blank and drug loaded nanoemulsions.
Figure 5 is blank and drug loaded nanoemulsion potential stability.
Figure 6 is free drug and drug loaded nanoemulsion 24h cytotoxicity.
Figure 7 ability of drug loaded nanoemulsions to scavenge ROS in HCEC cell lines.
Figure 8 retention of free drug and drug-loaded nanoemulsion after eye drops.
Figure 9 corneal sections after drug-loaded nanoemulsion treatment of dry eye in mice.
Figure 10 expression of ocular redox markers and inflammatory factors in mice following drug-loaded nanoemulsion treatment.
Figure 11 shows the inflammatory cell infiltration of the cornea of mice after drug-loaded nanoemulsion treatment.
Fig. 12 biological safety inspection of drug-loaded nanoemulsions.
Detailed Description
The invention is further described with reference to the drawings and examples of implementation.
Example 1 preparation of nanoemulsion and characterization of physicochemical Properties
Nanoemulsion formulation:
phosphatidylethanolamine 266.7mg
Triglycerides 66.3mg
Alpha-tocopherol 0.33mg
Tacrolimus FK 506.05 mg
1mL of water.
The oil-in-water emulsion was prepared using the high energy emulsification method according to the above recipe. Briefly, phosphatidylethanolamine, triglycerides, alpha-tocopherol, and FK506 were dissolved in a small amount of ethanol, followed by adding deionized water under high-speed stirring to obtain colostrum. And then the nanoemulsion is obtained by ultrasonic treatment of an ice bath probe. The prepared nanoemulsion is a white emulsion with good fluidity (see figure 1). The nanoemulsion prepared by the prescription is detected to have the particle size below 200nm by a dynamic light scattering method (see figure 2). The morphology of nanoemulsions was observed by Transmission Electron Microscopy (TEM) and exhibited a uniform and smooth-surfaced spherical structure (see fig. 3). The nanoemulsion was stable for at least 80 days at 4 ℃ without significant particle size change (see fig. 4) and potential change (see fig. 5).
EXAMPLE 2 cytotoxicity of drug-loaded nanoemulsions
Nanoemulsion formulation:
yolk lecithin 0.67mg
Olive oil 0.29mg
Alpha-tocopherol 0.27mg
FK506 0.11mg
1mL of water.
Since ocular topical administration generally requires a high frequency of administration, in order to determine that there is no safety risk in the local accumulation of nanoemulsions, a Human Corneal Epithelial Cell (HCEC) cell line was selected as a model to examine the safety of nanoemulsions prepared by the above formulation. The drug concentration gradient was set between 10-100 μg/mL. The nanoemulsion prepared in this example was almost non-toxic to ocular cells even at higher concentrations compared to the commercially available tacrolimus eye drops (tacrolimus) (see fig. 6). The nanoemulsion has good biological safety.
Example 3 investigation of antioxidant Capacity of drug-loaded nanoemulsion in vitro
Nanoemulsion formulation:
soybean lecithin 5mg
Castor oil 15mg
Vitamin E acetate 0.02mg
FK506 0.2mg
1mL of water.
Nanoemulsions were prepared using the above recipe. Addition of H to Human Corneal Epithelial Cells (HCEC) 2 O 2 In vitro, the oxidative stress condition is simulated, then the drug-loaded nanoemulsion is added for co-incubation for 30 minutes, DCFH-DA is used as an ROS indication probe, and a fluorescence enzyme-labeled instrument is used for detecting the ROS fluorescence signal intensity (see figure 7). Compared with the tacrolimus eye drops (tacrolimus) on the market, the drug-loaded nanoemulsion prepared in the invention can be obviously lightenedThe cell oxidative stress shows good in-vitro antioxidation capability.
EXAMPLE 4 investigation of ocular surface Retention after topical administration of drug-loaded nanoemulsions
Nanoemulsion formulation:
yolk lecithin 20mg
(2, 3-Dioleoyl-propyl) trimethylammonium chloride DOTAP 13.3mg
Soybean oil 66.3mg
Vitamin E acetate 166.7mg
Tacrolimus 66.7mg
1mL of water.
One of the problems to be solved in eye drops is the fast removal, usually the residence time of the free drug solution is only 1-5 minutes. To facilitate visualization of drug retention, fat-soluble fluorescent dye DIR labeling was used after nanoemulsion preparation according to the above recipe. The eyes of the rat on the administration side were removed 30min after the administration, and fluorescence section examination was performed after washing. As shown in fig. 8, the nanoemulsion prepared by the present invention has longer ocular surface retention than the free drug and can permeate to the corneal endothelial cell side. The nanoemulsion has stronger cornea penetration capacity.
Example 5 therapeutic Effect of antioxidant drug-loaded nanoemulsions in Dry eye models
Nanoemulsion formulation:
phosphatidylethanolamine 5mg
Phosphatidylserine 1mg
Curcumin 10mg
FK506 4mg
1mL of water.
A mouse dry eye model was made with long-term eye drops of 0.2% benzalkonium bromide. Dry eye is due to the disruption of tear film homeostasis, and tear evaporation accelerates. The long-term high osmotic pressure leads to an increased ocular surface inflammatory response and increased infiltration of immune cells, which in turn leads to an increased level of lipid peroxides (MDA) and inflammatory factors TNF-alpha and a decreased activity of cellular superoxide dismutase (SOD). Antioxidants in nanoemulsions can act synergistically with tacrolimus to suppress excessive immune response and reduce corneal cell damage (see figure 9). Compared with the pure tacrolimus, the nanoemulsion with the antioxidant function can reduce the cornea oxidative stress marker (see fig. 10), and the cornea inflammatory cell infiltration is remarkably reduced (see fig. 11).
Example 6 biological safety investigation of antioxidant drug-loaded nanoemulsions
Nanoemulsion formulation:
soybean lecithin 5mg
Castor oil 4mg
FK506 0.8mg
1mL of water (containing 4mg of L-ascorbic acid).
The drug-loaded nanoemulsion is prepared according to the prescription. The prepared nanoemulsion, the commercially available tacrolimus eye drops and PBS are instilled on the single-sided eyeball of the rat once daily. After the end of administration, the side eye ball was removed, and hematoxylin and eosin section was observed after PBS washing (see FIG. 12). No matter the nanoemulsion prepared by the invention and the commercially available tacrolimus eye drops, the nanoemulsion does not cause rat cornea hyperplasia after long-term administration. Proved by the invention, the nanoemulsion prepared by the method has good biological safety.
Example 7 preparation and application of an eye drug-carrying liposome having antioxidant function
Liposome formulation:
dioleoyl phosphatidylethanolamine 15mg
Phosphatidylinositol 5mg
Cholesterol 3mg
Astaxanthin 3mg
FK506 1mg
1mL of water.
The medicine carrying liposome with the antioxidation function is prepared by adopting a film dispersion method. Briefly, the lipids in the above formulation were completely dissolved in chloroform, and the solvent was removed by evaporation under reduced pressure using a rotary evaporator to form a uniform and complete film. To the lipid film obtained, ultrapure water was added, and hydration was carried out under water bath conditions at 45 ℃. And then, carrying out ice bath probe ultrasonic on the hydrated sample to obtain the drug-loaded liposome with uniform and stable particle size. In the liposome prepared by the invention, the astaxanthin can remove excessive ROS, and can inhibit ocular inflammatory reaction in cooperation with tacrolimus, thereby playing a good role in dry eye treatment.
Example 8 preparation and use of an eye drug-loaded micelle with antioxidant Properties
Micelle prescription:
distearoyl phosphatidylethanolamine (DSPE-PEG) 100mg
Epicatechin-3-gal (EGCG) 2.5mg
FK506 2.5mg
1mL of water.
The invention prepares DSPE-PEG micelle by a film hydration method. DSPE-PEG, EGCG and FK506 were first dissolved in chloroform solution and sonicated until completely dissolved. The organic phase is then removed by rotary evaporation to form a uniform lipid-containing film. And then adding pure water, stirring, and hydrating at 40 ℃ for 1h to obtain the drug-loaded micelle. EGCG can clear excessive ROS, alleviate ocular inflammatory reaction, protect corneal epithelial cells from injury, and inhibit ocular inflammatory reaction in cooperation with tacrolimus, and has good effect in dry eye treatment.
Example 9 preparation of lipid nanoparticles for eye use with antioxidant function
Solid lipid nanoparticle formulation:
glycerol monostearate 15mg
Melatonin 5mg
FK506 5mg
Tween 80 5-10mg
1mL of water.
The drug-loaded solid lipid nanoparticle is prepared by using an ultrasonic dispersion method. The prescribed amounts of glyceryl monostearate and FK506 were mixed and heated to melt to form an oil phase. Tween 80 was dissolved in water as the aqueous phase. The aqueous phase was slowly poured into the oil phase with stirring to obtain a primary emulsion. And then ultrasonic treatment is carried out for 3min, and solid lipid nanoparticles with uniform particle size are obtained after cooling at room temperature. The prepared nano particles can be taken up by corneal epithelial cells or can be remained on the surface of eyes through adhesion. The solid lipid nanoparticle can slowly release tacrolimus to inhibit excessive immune reaction, and simultaneously release melatonin to clear excessive ROS, so that the inflammatory circulation of xerophthalmia is broken, and a good treatment effect is exerted.

Claims (8)

1. The tacrolimus-entrapped antioxidant nano preparation is characterized by comprising a water phase and an oil phase, wherein the oil phase is 5-80% of lecithin, w/w of medium chain triglyceride, 0-50% of fat-soluble antioxidant, 0.1-50% of fat-soluble antioxidant and 0.01-20% of tacrolimus; the water phase is water-soluble antioxidant 0.1-30%, w/w or deionized water.
2. The antioxidant nano-formulation of claim 1, wherein the oil phase of the nano-formulation: the water phase is 1:1000-1:2, w/w.
3. The antioxidant nano-formulation according to claim 1, wherein the nano-formulation is a pharmaceutically acceptable carrier selected from nanoemulsions, liposomes, micelles or lipid nanoparticles.
4. The antioxidant nano-formulation of claim 1, wherein the resulting nano-formulation has a particle size of less than 200nm.
5. The antioxidant nano-formulation according to claim 1, wherein the fat-soluble antioxidant is selected from melatonin, polydopamine, glutathione, beta-carotene, astaxanthin, butylated hydroxyanisole, curcumin, N-acetylcysteine, quercetin, kaempferol, catechin or epigallocatechin gallate; the water-soluble antioxidant is selected from tea polyphenols, superoxide dismutase, glutathione peroxidase or glutathione reductase.
6. The antioxidant nano-formulation according to claim 1, wherein the oil phase of the nano-formulation is replaced by phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, sphingomyelin, trimethyl-2, 3-dioleoyloxypropylammonium bromide, trimethyl-2, 3-dioleoyloxypropylammonium chloride, dimethyl dioctadecyl ammonium bromide, soybean oil, olive oil, castor oil, various types of medium-long chain fatty acid esters, cholesterol or squalane, in addition to the lipid-soluble antioxidants and tacrolimus.
7. The use of the antioxidant nano-formulation according to claim 1 for preparing tacrolimus antioxidant ophthalmic drug, wherein the formulation of the drug is a liquid formulation.
8. The use of claim 7, wherein the use is to reduce or eliminate the effect of oxidative stress on the eye by reducing ocular inflammatory responses, reducing apoptosis, and blocking and repairing by the nano-formulation while suppressing excessive immune responses and scavenging excessive ROS to maintain ocular cellular redox equilibrium homeostasis.
CN202310851419.7A 2023-07-12 2023-07-12 Tacrolimus-entrapped nano preparation and application thereof Pending CN116672312A (en)

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