CN113876701A - Dexamethasone in-situ liquid crystal gel preparation for treating diabetic retinopathy, preparation method and application - Google Patents
Dexamethasone in-situ liquid crystal gel preparation for treating diabetic retinopathy, preparation method and application Download PDFInfo
- Publication number
- CN113876701A CN113876701A CN202111295366.2A CN202111295366A CN113876701A CN 113876701 A CN113876701 A CN 113876701A CN 202111295366 A CN202111295366 A CN 202111295366A CN 113876701 A CN113876701 A CN 113876701A
- Authority
- CN
- China
- Prior art keywords
- dexamethasone
- liquid crystal
- crystal gel
- diabetic retinopathy
- situ liquid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- 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
- A61K9/08—Solutions
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Diabetes (AREA)
- Ophthalmology & Optometry (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A dexamethasone in-situ liquid crystal gel preparation for treating diabetic retinopathy, a preparation method and application thereof, belonging to the technical field of medicaments for treating diabetic retinopathy. The injection is prepared from 60-70 mg of lipid material, 0.01-3 mg of dexamethasone, 25-35 mg of cosolvent and 0-5 mu L of injection water. Heating lipid material in water bath at corresponding melting temperature to obtain oil phase, heating dexamethasone, cosolvent and water for injection in water bath until dexamethasone is dissolved to obtain water phase; adding the water phase into the oil phase, and quickly vortexing to colorless and transparent after adding to obtain the final product. The invention realizes the high-efficiency eye application of dexamethasone, has the characteristics of convenient administration, rapid gelation after being dropped into eyes, safety, no stimulation, good biological adhesiveness and long eye retention time, thereby reducing the administration frequency, improving the bioavailability of the medicament and enhancing the curative effect of the dexamethasone on treating diabetic retinopathy.
Description
Technical Field
The invention belongs to the technical field of medicines for treating diabetic retinopathy, and particularly relates to a dexamethasone in-situ liquid crystal gel preparation for treating diabetic retinopathy, a preparation method and application.
Background
With the continuing increase in the prevalence of diabetes worldwide, diabetic retinopathy remains a major cause of visual loss in patients in many developed countries. Diabetic retinopathy is the most common and severe ocular disease caused by diabetes. It is well documented that about one third of diabetic patients have signs of diabetic retinopathy, one third of which may have vision threatening retinopathy, defined as severe retinopathy or macular edema. Diabetic retinopathy not only affects vision, but also increases the risk of vascular complications.
Diabetic retinopathy is divided into two stages, an early non-proliferative diabetic retinopathy stage and a late proliferative diabetic retinopathy stage. The nonproliferative diabetic retinopathy stage is characterized by enhanced production of various inflammatory mediators in the retina, such as tumor necrosis factor alpha, nuclear factor kappa B, and intercellular adhesion molecule 1. Proliferative diabetic retinopathy develops from nonproliferative diabetic retinopathy and is characterized by enhanced secretion of angiogenic mediators and vascular endothelial growth factors. The production of inflammatory and angiogenic mediators can cause a stress response in retinal glial cells, leading to increased production of glial fibrillary acidic proteins, impaired photoreceptor cell function or photoreceptor cell death, and ultimately blindness. The pathogenesis of diabetic retinopathy is related to inflammatory mediators and neovascular mediators. Therefore, drugs with anti-inflammatory or anti-angiogenic activity have been widely used to alleviate diabetic retinopathy and its associated complications.
Dexamethasone is a corticosteroid that has proven effective in non-proliferative diabetic retinopathy and proliferative diabetic retinopathy due to its anti-inflammatory, anti-angiogenic, anti-apoptotic, and neuroprotective properties. Is an effective anti-inflammatory agent for treating acute and chronic posterior segment diseases of eyes such as uveitis. The cornea is the primary route of drug absorption, but the lipophilicity and tight association of corneal epithelium make it the main obstacle to drug absorption, whereas in clinically common sodium phosphate eye drops, dexamethasone exists in a hydrophilic ionized form and cannot effectively penetrate lipophilic corneal epithelium.
Clinically, injection of dexamethasone into the vitreous body is used for treating diabetic retinopathy, but injection into the vitreous body is invasive and can cause various complications such as intraocular hemorrhage, pain discomfort, poor patient compliance and the like. In addition, frequent intravitreal injections may lead to vitreous hemorrhage and retinal detachment. In order to improve the bioavailability to the eye, several ophthalmic drug delivery systems have been proposed, such as cyclodextrin-drug complexes, liposomes and nanoparticles. However, these methods have a short half-life and all drugs are released within a few hours. Therefore, it is urgent to search for a non-invasive route of administration.
Lyotropic liquid crystal systems are receiving increasing attention from many researchers due to their non-toxicity, good mucosal adhesion, good biocompatibility, and other characteristics. The internal structure of lyotropic liquid crystal can be divided into lamellar (L alpha) and cubic (Q) phaseII) Hexagonal phase (H)II). The cubic phase (Pn3m) can be used as a carrier for hydrophilic, lipophilic or amphoteric drugs, the hydrophilic drugs being located near the polar head of the lipid or in the water channel, while the lipophilic drugs will be loaded in the lipid bilayer, the amphiphilic drugs being at the interface. In contrast to the cubic phase, the water channels in the hexagonal phase are closed and the distribution of the drug in the hexagonal phase is similar to the distribution in the cubic phase. In addition, they have a chemical bond withLiving cell membranes have similar chemical and structural properties and have a high affinity between them. Thus, the system may be referred to as a competent and promising drug delivery strategy.
An in situ gel is a solution for administration and then converted to a gel in the eye. It combines the advantages of solution and gel, not only is convenient for administration, but also prolongs the detention time in eyes and improves the bioavailability of the eyes. More specifically, the in situ gel is a preparation which can effectively prevent the drug from being removed from the target part due to the drainage of the nasolacrimal duct, thereby improving the bioavailability, reducing the administration frequency and certainly improving the compliance of patients.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel administration mode for treating diabetic retinopathy by using a dexamethasone in-situ liquid crystal gel preparation, prolong the corneal residence time, reduce the administration times and ensure that patients take the medicine more conveniently. Meanwhile, the invention provides a preparation method of the dexamethasone in-situ liquid crystal gel.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a dexamethasone in-situ liquid crystal gel preparation for treating diabetic retinopathy is prepared from 60-70 mg of lipid material, 0.01-3 mg of dexamethasone, 25-35 mg of cosolvent and 0-5 mu L of injection water.
As a preferred technical scheme, the dexamethasone in-situ liquid crystal gel preparation is prepared from 65mg of lipid material, 1mg of dexamethasone, 30mg of cosolvent and 5 mu L of water for injection.
Preferably, the lipid material is one or more of Phytantriol (PHYT), Glyceryl Monooleate (GMO), Monoglyceride (MO) and Sorbitol Monooleate (SMO).
As a preferred technical scheme, the cosolvent adopts one or more of PEG400, Tween 80, propylene glycol, glycerol and any other substance which can be tolerated by eyes physiologically.
A preparation method of a dexamethasone in-situ liquid crystal gel preparation comprises the following steps:
(1) precisely weighing lipid material, heating in water bath at corresponding melting temperature to obtain oil phase;
(2) precisely weighing dexamethasone, cosolvent and water for injection, and heating in water bath until dexamethasone is dissolved as water phase;
(3) and adding the water phase into the oil phase, and quickly swirling to be colorless and transparent after adding to obtain the dexamethasone in-situ liquid crystal gel preparation.
Compared with the prior art, the invention has the beneficial effects that:
(1) the dexamethasone in-situ liquid crystal gel preparation disclosed by the invention is convenient to administer and has good biological adhesiveness, the corneal residence time is prolonged, the administration frequency is reduced, the side effect of the medicine is reduced, and the compliance of a patient is improved.
(2) The liquid crystal gel has similar structure to biological membrane and good biocompatibility, and can enhance corneal penetration and improve bioavailability of medicine.
(3) The amphiphilic lipid material and the cosolvent adopted by the in-situ liquid crystal gel preparation are safe, non-toxic and good in biocompatibility, so that the preparation has the advantages of safety, no stimulation and the like.
(4) The invention has simple manufacturing process and high long-term stability.
Drawings
FIG. 1 is a polarization microscope photograph (picture magnification 100 times) of dexamethasone in-situ liquid crystal gel, wherein a is before phase inversion of the dexamethasone in-situ liquid crystal gel, and b is after phase inversion of the dexamethasone in-situ liquid crystal gel.
FIG. 2 is a graph of the small angle X-ray scattering curve of dexamethasone in situ liquid crystal gel.
Figure 3 is the ex vivo corneal penetration results (n-3).
FIG. 4 is a histological photograph (original magnification 200 times) of dexamethasone in situ liquid crystal gel. In the figure, EP: an epithelial layer; ST: a substrate layer; EN: an inner skin layer; ONL: an outer core layer; INL: an inner core layer; GCL: ganglion cell layer.
FIG. 5 is a photograph comparing the results of ocular residence time for dexamethasone in situ liquid crystal gel and eye drops.
Figure 6 is an aqueous humor pharmacokinetic profile after topical administration of dexamethasone in situ liquid crystal gel (n-3).
Detailed Description
The invention is further described in detail below with reference to the figures and examples.
Example 1
A method for preparing a dexamethasone in-situ liquid crystal gel preparation comprises the following steps:
(1) 65mg of phytantriol was precisely weighed and heated in a water bath at 60 ℃ as an oil phase.
(2) 1mg of dexamethasone, 30mg of PEG400 and 5 mu L of water for injection are precisely weighed and heated under the condition of water bath until the dexamethasone drug is dissolved to be used as a water phase.
(3) And adding the water phase into the oil phase, and quickly swirling to be colorless and transparent after adding to obtain the dexamethasone in-situ liquid crystal gel preparation. The liquid crystal gel is liquid and semi-solid gel before and after in-situ (phase transition).
Example 2
Dexamethasone in situ liquid crystal gel phase inversion properties
Minimum volume of phase inverted artificial tear (V)m) And time (T)g)
Experiments were conducted on the phase inversion properties of the dexamethasone in situ liquid crystal gel prepared in example 1. Determination of V of the formulation Using tube inversion methodmAnd Tg. Accurately weighing 200mg of dexamethasone in-situ liquid crystal gel in a centrifuge tube, placing a sample in a water bath at 37 ℃ to simulate a human body environment, sequentially adding 20 mu L of artificial tears, quickly swirling, and inclining the sample by 90 degrees to observe whether the sample is gelatinized. When no flow was observed, it was confirmed that the sample had completely gelled. When the formulation had completely gelled, the total amount of artificial tears added at the end of the experiment was recorded as VmRecording gel formation time Tg。
When the precursors are exposed to artificial tears, they undergo a phase change due to the presence of an aqueous environment, and the precursor solution gradually changes to a gel state. Multiple experiments show that the phase inversion occurs after 75 plus or minus 5 mu L of artificial tears is added into 200mg of preparation, and the phase inversion time is about 1.4 plus or minus 0.3 s. A rapid solution-gel phase transition will attenuate the side effects caused by an undesirably high drug concentration in the blood circulation system.
Example 3
Polarizing microscope observation of dexamethasone in situ liquid crystal gel
The dexamethasone in-situ liquid crystal gel prepared in example 1 was observed by a polarizing microscope. To examine the internal morphology of the gel, a small sample was placed on a glass slide and covered with a cover glass, and then observed at room temperature by a polarizing microscope, as shown in FIG. 1, with a dark field before and after the dexamethasone liquid crystal gel in situ (phase transition).
Example 4
Drawing of small-angle X-ray scattering curve of dexamethasone in-situ liquid crystal gel
The dexamethasone in-situ liquid crystal gel prepared in the example 1 is taken to carry out a small-angle X-ray scattering test, and the internal structure of the preparation after phase inversion can be further observed through the small-angle X-ray scattering test. The samples were tested using an X-ray source at 40kV and 50mA for 10 minutes. And (3) plotting the scattering intensity and the scattering vector (q) of the Bragg peak, and determining the structure according to the ratio of the scattering vectors corresponding to the scattering peaks of the sample.
The scattering pattern of the prepared formulation can be seen in fig. 2. These results indicate that the relative positions of the bragg peaks of example 1 are √ 2: √ 3: √ 4 from left to right, and thus it can be determined that the lattice type is a cubic phase liquid crystal.
Example 5
In vitro corneal penetration assessment of dexamethasone in situ liquid crystal gel
In vitro corneal penetration studies were performed on dexamethasone in situ liquid crystal gel prepared in example 1. Using an effective diffusion area of 0.5024cm2Modified Franz-type diffusion cells corneal penetration experiments were performed. The formulation (50mg) was placed in the donor compartment and dexamethasone sodium phosphate eye drops served as a control. The receptor compartment was 5mL PBS buffer (pH 7.4, 37 ℃) to maintain sink conditions. The cornea is placed on the recipient chamber with the outer surface of the cornea facing upwards (convex), the donor chamber is placed on top of the cornea, and the two half-chambers are clamped together. At specific time intervals (30, 60, 90, 120, 150, 180, 240, 300 and 360 minutes) 400. mu.L of sample solution was removed from the receptor chamber and replaced with the sameVolume of PBS buffer. The data obtained were analyzed using the following formula:
wherein Δ Q/Δ t represents the slope of the linear portion of the curve of dexamethasone (Q/μ g) content in the receptor compartment versus time, C0Initial drug concentration in the donor compartment (μ g/mL) is indicated, A represents the effective surface area of the cornea (0.5024 cm)2) And 60 is the unit conversion from minutes to seconds.
To evaluate the irritation of the formulations on the cornea, the corneal Hydration Level (HL) was measured after an in vitro corneal penetration test. At the end of the in vitro penetration study, each cornea was rinsed with saline to remove residual formulation on the corneal surface and then weighed (Wt). After drying at 70. + -. 0.5 ℃ for 12h, the sample (Wd) is weighed again. The HL% value was calculated using the following formula:
table 1 ex vivo corneal penetration parameters and corneal hydration values (n ═ 3)
*p<0.05, compared with eye drops, the eye drop has significant difference;
the results of the ex-corneal penetration test of example 1 and dexamethasone sodium phosphate eye drops are shown in FIG. 3. It is shown that example 1 shows faster and more stable penetration rate in the first 150 minutes than eye drops and sustained release over the next 3.5 hours. Compared with eye drop group, the in-situ liquid crystal gel has better corneal permeability. P of example 1appIs 5.45 times of the eye drop group, which shows that the in situ liquid crystal gel has the function of enhancing the corneal permeability.
Corneal hydration levels were evaluated after in vitro corneal penetration tests. Generally, the HL value of a healthy cornea is 76-80%, and the cornea hydration value exceeding 83% indicates that the cornea is damaged to a certain extent. In this example, the cornea of example 1 had a corneal hydration level of 77.4. + -. 0.57% and the eye drops were 81.2. + -. 0.47%, respectively, indicating that the cornea was not significantly irritated or damaged throughout the experiment. By comparison, the cornea hydration value of the example 1 is better than that of dexamethasone sodium phosphate eye drops.
Example 6
Histological examination of dexamethasone in situ liquid crystal gel
The dexamethasone in situ liquid crystal gel prepared in example 1 was taken for histological examination. A total of 6 rabbits (2.0-3.0kg) were used in this experiment and divided into two groups. Dexamethasone in-situ liquid crystal gel and dexamethasone sodium phosphate eye drops are dripped into the conjunctival sac under the right eye 3 times per day, and physiological saline (50 mu L) is dripped into the contralateral eye to serve as a negative control. One week after the experiment, the rabbits were euthanized, the eyeballs were removed, and then the eyeballs were fixed in 4% paraformaldehyde fixing solution. Subsequently, paraffin-embedded sections were performed and H & E staining was performed, and changes of cornea, iris and retina were observed with an optical microscope and photographed.
The results of histological examination of dexamethasone in situ liquid crystal gel are shown in fig. 4, and the structures of corneal epithelial cells and stroma layers of the in situ liquid crystal gel and eye drop group are not obviously changed. Meanwhile, the eye mask has no obvious stimulation to the iris and the retina. Therefore, the in-situ liquid crystal gel is considered to have good biocompatibility and can be used for eye medicines.
Example 7
Irritation evaluation of dexamethasone in situ liquid Crystal gel
Eye irritation examination was performed using the dexamethasone in situ liquid crystal gel prepared in example 1. Eye irritation test (Draize test) the aim was to determine the safety of the formulation. A total of 9 female New Zealand albino rabbits (2.0-3.0kg) were divided into three groups of three rabbits each. 50mg of dexamethasone in-situ liquid crystal gel and 100 mu L of eye drops are dripped into the conjunctival sac under the right eye, and physiological saline (0.9% NaCl) is dripped into the left eye to serve as a negative control. The rabbits were examined for any signs of redness, congestion, and secretions using a slit lamp at 1, 2, 4, 12, 24, 48, and 72 hours. The long-term stimulation test was identical to the single-dose eye stimulation test, but lasted 7 days.
The Draize test results after application of dexamethasone in situ liquid crystal gel in rabbit eyes show that the formulation has excellent ocular tolerance. Although conjunctival congestion was observed in the in situ liquid crystal gel group, there was no significant difference from the eye drop group. The total score for all formulations was between 0 and 3 in single dose or long term eye irritation tests (table 2). These results indicate that the in situ liquid crystal gel is less irritating and that dexamethasone in situ liquid crystal gel can be considered as a safe ophthalmic administration.
TABLE 2 modified Draize test results (n ═ 3)
Example 8
Corneal residence time investigation of dexamethasone in situ liquid Crystal gel
The dexamethasone in situ liquid crystal gel prepared in example 1 was used for the corneal residence time examination. The low bioavailability of eye drops is mainly due to normal physiological activities such as blinking and tear turnover. Thus, the bioavailability of the drug can be increased by extending the residence time of the drug on the ocular surface. The fluorescein-loaded in situ liquid crystal gel was formed by adding an amount of fluorescein (1%, w/w) to the aqueous phase of the formulation. Meanwhile, a fluorescein-loaded solution with 1 wt% was used as a control. Finally, the intensity of the fluorescein was detected at a predetermined time using a fluorescent lamp.
The result of the cornea retention time of the dexamethasone in-situ liquid crystal gel is shown in fig. 5, and the retention time of the dexamethasone in-situ liquid crystal gel in rabbit eyes exceeds 4 hours, which is far longer than the eye retention time of eye drops.
Example 9
Study on aqueous pharmacokinetics of dexamethasone in situ liquid crystal gel
The dexamethasone in situ liquid crystal gel prepared in example 1 was taken for the study of aqueous pharmacokinetics. Six healthy New Zealand white rabbits (2.0-3.0kg) were used as animal models to evaluate the pharmacokinetics of drugs in aqueous humor. Rabbits were randomly divided into 2 groups of 3 rabbits each. The 50mg formulation and 100 μ L of eye drops were applied to the lower conjunctival sac of the rabbit eye. To allow the drug to sufficiently contact the cornea, the eyelid was gently closed for 10 seconds after the administration. 100 μ L aqueous humor samples were collected from the eye using a 1mL syringe at predetermined time points (0.17, 0.33, 0.50, 0.75, 1, 2, 4, 6, 8, 10 and 12 hours).
The aqueous humor was mixed with 300. mu.L acetonitrile, vortexed for 1 minute to remove protein, and then centrifuged at high speed for 10 minutes (4000 rpm/min). The DEX concentration in the room water was analyzed using HPLC techniques. All pharmacokinetic data analyses were performed using DAS 2.0.
Table 3 aqueous humor pharmacokinetic parameters after topical administration (n ═ 3)
*p<0.05, compared with eye drops, has significant difference,**p<0.01, compared with eye drops, has significant difference
The concentration-time curve of dexamethasone in rabbit aqueous humor is shown in fig. 6, and the pharmacokinetic parameters are summarized in table 3. The eye drops reach C within 0.5 hourmaxThere was no significant change in drug concentration after 4 hours. The bioavailability is low and the treatment effect is limited. However, the first 4h of the formulation group is a rapid accumulation process, CmaxIs 1.78 times of eye drops. The results showed that the Mean Retention Time (MRT) (4.435 + -0.24 h) of the formulation group was 1.72 times that of the eye drops (2.568 + -0.33 h), demonstrating that the liquid crystal gel could be released continuously. AUC of dexamethasone in situ liquid crystal gel0→12hThe value is 5.26 times that of dexamethasone sodium phosphate eye drops, which possibly indicates that the dexamethasone in-situ liquid crystal gel has higher bioavailability.
Example 10
The dexamethasone in situ liquid crystal gel preparation comprises 62mg of glyceryl monooleate, 0.5mg of dexamethasone, 27mg of Tween 80 and 3 mu L of water for injection. The preparation steps are as follows:
(1) 62mg of glycerol monooleate was precisely weighed and heated in a water bath at 37 ℃ as an oil phase.
(2) 0.5mg of dexamethasone, 27mg of tween 80 and 3 mul of water for injection are precisely weighed and heated under the condition of water bath until the dexamethasone medicine is dissolved to be used as a water phase.
(3) And adding the water phase into the oil phase, and quickly swirling to be colorless and transparent after adding to obtain the dexamethasone in-situ liquid crystal gel preparation.
Example 11
The dexamethasone in-situ liquid crystal gel preparation comprises 68mg of monoglyceride, 1.5mg of dexamethasone, 35mg of glycerol and 5 mu L of water for injection. The preparation steps are as follows:
(1) 68mg of monoglyceride was precisely weighed and heated in a water bath at 58 ℃ as an oil phase.
(2) 1.5mg of dexamethasone, 35mg of glycerol and 5 microliter of water for injection are precisely weighed and heated under the condition of water bath until the drug dexamethasone is dissolved to be used as a water phase.
(3) And adding the water phase into the oil phase, and quickly swirling to be colorless and transparent after adding to obtain the dexamethasone in-situ liquid crystal gel preparation.
In conclusion, the invention adopts the amphiphilic lipid material capable of self-assembling to form stable lyotropic liquid crystal, realizes the high-efficiency eye application of dexamethasone, has the characteristics of convenient administration and rapid gelation after being dropped into eyes, and simultaneously has the advantages of safety, no stimulation, good biological adhesiveness and long eye retention time, thereby reducing the administration frequency, improving the bioavailability of the medicament and enhancing the curative effect of the dexamethasone on treating diabetic retinopathy.
The foregoing is merely exemplary and illustrative of the principles of the present invention and various modifications, additions and substitutions of the specific embodiments described herein may be made by those skilled in the art without departing from the principles of the present invention or exceeding the scope of the claims set forth herein.
Claims (6)
1. A dexamethasone in-situ liquid crystal gel preparation for treating diabetic retinopathy is prepared from 60-70 mg of lipid material, 0.01-3 mg of dexamethasone, 25-35 mg of cosolvent and 0-5 mu L of injection water.
2. The dexamethasone in situ liquid crystal gel formulation for use in the treatment of diabetic retinopathy according to claim 1, wherein the formulation is prepared from 65mg of lipid material, 1mg of dexamethasone, 30mg of co-solvent and 5 μ L of water for injection.
3. The dexamethasone in situ liquid crystal gel formulation for use in the treatment of diabetic retinopathy according to claim 1 or claim 2, wherein the lipid material employs one or more of phytantriol, glycerol monooleate, monoglyceride and sorbitol monooleate.
4. The dexamethasone in situ liquid crystal gel formulation for use in the treatment of diabetic retinopathy according to claim 1 or claim 2, wherein the co-solvent employs one or more of PEG400, tween 80, propylene glycol and glycerol.
5. A method for preparing the dexamethasone in-situ liquid crystal gel formulation as claimed in any one of claims 1 to 4, comprising the steps of:
(1) precisely weighing lipid material, heating in water bath at corresponding melting temperature to obtain oil phase;
(2) precisely weighing dexamethasone, cosolvent and water for injection, and heating in water bath until dexamethasone is dissolved as water phase;
(3) and adding the water phase into the oil phase, and quickly swirling to be colorless and transparent after adding to obtain the dexamethasone in-situ liquid crystal gel preparation.
6. The use of the dexamethasone in situ liquid crystal gel formulation according to any one of claims 1 to 4 for the treatment of diabetic retinopathy.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111295366.2A CN113876701A (en) | 2021-11-03 | 2021-11-03 | Dexamethasone in-situ liquid crystal gel preparation for treating diabetic retinopathy, preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111295366.2A CN113876701A (en) | 2021-11-03 | 2021-11-03 | Dexamethasone in-situ liquid crystal gel preparation for treating diabetic retinopathy, preparation method and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113876701A true CN113876701A (en) | 2022-01-04 |
Family
ID=79016380
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111295366.2A Pending CN113876701A (en) | 2021-11-03 | 2021-11-03 | Dexamethasone in-situ liquid crystal gel preparation for treating diabetic retinopathy, preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113876701A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101502485A (en) * | 2009-03-20 | 2009-08-12 | 中国药科大学 | Nano cubic liquid crystal dexamethasone preparation for eye and preparation method thereof |
| WO2011006079A2 (en) * | 2009-07-10 | 2011-01-13 | Lyotropoic Therapeutics, Inc. | Ophthalmic formulations of reversed liquid crystalline phase materials and methods of using |
| CN108078955A (en) * | 2016-11-21 | 2018-05-29 | 广州中大南沙科技创新产业园有限公司 | Novel lipid nano cubic liquid crystal pharmaceutical carrier |
-
2021
- 2021-11-03 CN CN202111295366.2A patent/CN113876701A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101502485A (en) * | 2009-03-20 | 2009-08-12 | 中国药科大学 | Nano cubic liquid crystal dexamethasone preparation for eye and preparation method thereof |
| WO2011006079A2 (en) * | 2009-07-10 | 2011-01-13 | Lyotropoic Therapeutics, Inc. | Ophthalmic formulations of reversed liquid crystalline phase materials and methods of using |
| CN108078955A (en) * | 2016-11-21 | 2018-05-29 | 广州中大南沙科技创新产业园有限公司 | Novel lipid nano cubic liquid crystal pharmaceutical carrier |
Non-Patent Citations (1)
| Title |
|---|
| 蒲一民等: "糖尿病视网膜病变药物治疗的研究进展", 《国际眼科杂志》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Yadav et al. | Glaucoma: current treatment and impact of advanced drug delivery systems | |
| JP5583310B2 (en) | Ophthalmic formulation for prevention and treatment of ocular symptoms | |
| Kwon et al. | Potential therapeutic usage of nanomedicine for glaucoma treatment | |
| ES2952677T3 (en) | Ocular implant containing a tyrosine kinase inhibitor | |
| Soni et al. | Design and evaluation of ophthalmic delivery formulations | |
| WO2011063606A1 (en) | Ophthalmic gel of gatifloxacin and preparation method thereof | |
| JP6768780B2 (en) | Topical ophthalmic preparations of endothelin receptor antagonists and their use | |
| JP2004538056A (en) | Inserts for dry eye treatment | |
| RU2561585C2 (en) | Local eye peptide composition | |
| US20220192980A1 (en) | Cationic hyaluronic acid coated spanlastics and preparation and application thereof | |
| US11045352B2 (en) | Methods for treatment of dry eye and other acute or chronic inflammatory processes | |
| RU2581495C1 (en) | Method of treating dry eye syndrome | |
| CN115315250A (en) | Mucoadhesive solid or semi-solid ocular delivery systems based on pre-activated thiolated polymers | |
| WO2014142469A2 (en) | Eye drop composition for treating ocular inflammatory disease and preparation method therefor | |
| JP6213560B2 (en) | Drug delivery system and method for treating open angle glaucoma and ocular hypertension | |
| CN112891326B (en) | Natamycin-loaded alginic acid gel medicine film and preparation method thereof | |
| CN113876701A (en) | Dexamethasone in-situ liquid crystal gel preparation for treating diabetic retinopathy, preparation method and application | |
| JP2023547607A (en) | Intraocular implants containing active agents | |
| Kaul et al. | An insight into ocular insert | |
| Nair et al. | Current trends in ocular drug delivery systems and its applications | |
| JP7504125B2 (en) | Cationized hyaluronic acid modified niosome vesicles and their production and use | |
| KR102125256B1 (en) | Eye drop carrier, pharmaceutical composition having the same, and method of pharmaceutical composition | |
| Chang | Recent advances in ophthalmic drug delivery | |
| Soni et al. | Innovation In Ocular Drug Delivery System | |
| US20220183969A1 (en) | Ocular insert containing a glucocorticoid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |