CN115837027A - Ophthalmic dexamethasone pharmaceutical composition - Google Patents
Ophthalmic dexamethasone pharmaceutical composition Download PDFInfo
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- CN115837027A CN115837027A CN202211427732.XA CN202211427732A CN115837027A CN 115837027 A CN115837027 A CN 115837027A CN 202211427732 A CN202211427732 A CN 202211427732A CN 115837027 A CN115837027 A CN 115837027A
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Abstract
The invention discloses a dexamethasone pharmaceutical composition for eyes. The raw materials of the ophthalmic dexamethasone pharmaceutical composition comprise: dexamethasone, hydroxypropyl-gamma-cyclodextrin, a polymer stabilizer and water. The invention effectively solves the technical problem that the dexamethasone/gamma-cyclodextrin suspension eye drops are degraded under the condition of severe high temperature by using the solubilizing cyclodextrin and the aggregating cyclodextrin together, and obtains the ophthalmic dexamethasone pharmaceutical composition which is easier to realize by process amplification and has satisfactory stability and higher bioavailability.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel aqueous eye drop composition, wherein the active ingredient of the composition is dexamethasone.
Background
Moderate to severe visual acuity with increasing aging populationThe number of physical disabilities and blindness has risen dramatically. Posterior segment diseases of the eye, such as age-related macular degeneration, diabetic retinopathy, uveitis, and macular edema, are the leading causes of impaired vision in the aging population of developed countries. The current modes of drug delivery in the posterior segment of the eye are primarily intravitreal and suprachoroidal. The intravitreal route is considered to be one of the most effective routes for drug delivery to the retina, and current posterior segment diseases involving pathological angiogenesis and vascular permeability changes are usually treated by intravitreal administration, but intravitreal injection or implant administration carries risks of complications and puts extremely high demands on clinical practice, and the number and frequency of clinically practical injections are lower than those of clinical trials, thereby affecting the curative effect. The suprachoroidal route, which injects the drug into the suprachoroidal space primarily through microneedles, bypasses the sclera, provides higher bioavailability than the peripheral route, and currently has drug approval to market
For the treatment of macular edema associated with uveitis, safer and less risk of side effects than the intravitreal route, but there is still an invasive procedure with low patient compliance. The local administration on the ocular surface is safer and easier to use, and the treatment scheme can be customized according to the specific condition of a patient, but the difficulty of local administration to the posterior segment tissues of the eye is very large, and the current conventional technology cannot obtain the drug treatment level. Accordingly, there is an increasing need to treat chronic blinding retinal diseases with non-invasive drug delivery systems.
Dexamethasone is one of the most globally prescribed drugs in corticosteroids for the treatment of ocular diseases, for the treatment of various ocular diseases, including anterior segment inflammation (such as keratitis, blepharitis, allergic conjunctivitis, anterior uveitis, and dry eye) and posterior segment inflammation (such as intermediate uveitis, choroiditis, panuveitis, and macular edema), and for the reduction of inflammation after various ocular surgeries; dexamethasone is commonly used as an immunosuppressive agent for the postoperative management and prevention of corneal graft rejection. Dexamethasone has been marketed in various dosage forms for treating ocular diseases, and is currently used as a food drug in the United statesDexamethasone single-component ophthalmic precursor preparation approved by Food and Drug Administration (FDA) on the market is useful as suspension eye drops for treating anterior segment steroid responsive inflammatory diseases
Intravitreal implants for treatment of macular edema and posterior segment uveitis>
Intra-ocular injection of suspensions for post-operative inflammation>
And implants for post-operative inflammation and ocular itching>
Effective treatment with dexamethasone requires that therapeutic concentrations be achieved and maintained at the target site. Topical administration can reach the anterior segment of the eye, but due to poor permeability to the cornea, it is estimated that less than 3% of the administered dose reaches the aqueous humor; dexamethasone has an aqueous half-life of about 3-6 hours and thus requires frequent administration (up to 6 times per day). The current marketed products deliver dexamethasone to the posterior segment of the eye using only invasive methods of intravitreal implantation.
Dexamethasone has a structure formula shown in formula (formula C) 22 H 29 FO 5 Molecular weight 392.47)
Due to the complex and unique anatomical and physiological features of the eye, drug delivery from the ocular surface to posterior segment tissues is hampered by multiple barriers, including drug solubility in tears, tear drainage, ocular surface mucus, membrane barriers, and other barriers, reaching intraocular tissues with no more than 5% drug, reaching the retina with no more than 0.01% drug, and is even more challenging to deliver to the posterior segment of the eye. In order to overcome the obstacles of ocular Drug delivery and improve Drug bioavailability, novel Drug Delivery Systems (DDS) have been developed, such as emulsions, nanomicelles, in situ gels, liposomes, nanoparticles, layered double hydroxides, dendrimers, cyclodextrin aggregates, etc. (Wang Y, xu X, gu Y, et al, recent advance of nanoparticle-based targeted Drug delivery to the spatial segment of the eye. Extra Option Drug delivery Deliv.2018;15 (7): 687-701.). While these new DDSs overcome some of the limitations of conventional DDSs in ocular disease management, there is currently no success in clinical trials with drugs delivered to the posterior segment of the eye by ocular surface topical administration using other formulation technology means other than cyclodextrin aggregate technology.
Hydroxyl groups at the edges of the cyclodextrin cavity can form intermolecular hydrogen bonds of cyclodextrin, resulting in self-assembly of dissolved cyclodextrin molecules to form cyclodextrin aggregates. The suspension eye drops are prepared by utilizing the tendency that cyclodextrin and an inclusion compound thereof form particle aggregates in a self-assembly manner, the ocular surface retention time of the drug can be prolonged after the ocular surface administration, the metastable particles can be decomposed into nanoparticles adhered to a mucus layer, and the drug is continuously released along with the dilution of tears, so that the ocular surface can keep higher drug concentration for a longer time. Dexamethasone/gamma-cyclodextrin suspension eye drops developed by Oculis company by using a cyclodextrin aggregate technology have two indications, and phase III clinical tests are carried out to respectively evaluate the effectiveness and the safety of the dexamethasone/gamma-cyclodextrin suspension eye drops on diabetic macular edema (the clinical test registration number is NCT 05066997) and evaluate the effectiveness and the safety of the dexamethasone/gamma-cyclodextrin suspension eye drops on cataract postoperative ocular inflammation and pain (the clinical test registration number is NCT 05147233); the results of a completed phase II clinical trial (clinical trial accession number: eudraCT No.2017-001172-36, NCT04130802) preliminarily demonstrated the feasibility of the cyclodextrin aggregation technique in delivering drugs to the posterior segment of the eye.
A dexamethasone/gamma-cyclodextrin suspension eye drop process developed by Oculis company relates to the process operation of heating a raw material and auxiliary material aqueous suspension at 121 ℃ for 20min (Tanito M, hara K, takai Y, et al. Topical dexameso-cyclodextrine microparticle eye drops for metabolic macromolecular eye ema. Invest Ophthalmol Vis Sci.2011;52 (11): 7944-7948.), and dexamethasone can be degraded to a certain extent under severe high temperature conditions; the operation has high requirements on production equipment, special large suspension sterilization equipment is required, the conventional eye drops production is not available at present, and the existing equipment is difficult to meet. Meanwhile, in the already-developed human-related tests for dexamethasone/γ -cyclodextrin suspension eye drops (Ohira A, hara K, johannesson G, et al. Acta Ophthalmol.2015;93:610-615.Shulman S, johannesson G, stefansson E, et al.2015 93:411-415.Krag S, hessellund A.2014 92. E689-e 690.), the number of administrations for treating posterior segment diseases of the eye is 3-4 times per day, and the frequency of administration is still high. Therefore, the bioavailability of dexamethasone to the eye needs to be further improved.
Although there have been reports of the use of both γ -cyclodextrin and hydroxypropyl- γ -cyclodextrin to increase dexamethasone solubility (Jansook P, ritthidej GC, ueda H, et al. γ CD/HP γ CD mixures as solubilizer: solid-state chromatography and sample dexamethasone eye drop administration. J Pharm Sci.2010;13 (3): 336-350.), these previous studies still used a process operation of sterilization at 121 ℃ for 20 minutes and stability was not fully studied, nor did it further increase ocular drug delivery of dexamethasone in vivo.
Thus, there remains a strong need for ophthalmic pharmaceutical compositions comprising dexamethasone that are more easily scaled up, have satisfactory stability and higher bioavailability.
Disclosure of Invention
The invention aims to provide an ophthalmic medicine composition containing dexamethasone as an active ingredient, which has good use compliance of patients, is easier to realize process amplification, and has satisfactory stability and higher bioavailability.
In order to achieve the purpose, the invention adopts the following technical scheme:
an ophthalmic dexamethasone pharmaceutical composition comprises the following raw materials:
(1) An ophthalmically effective dexamethasone;
(2) Hydroxypropyl-gamma-cyclodextrin in an amount effective to form a water-soluble complex with said dexamethasone;
(3) Gamma-cyclodextrin in an amount effective to form dexamethasone/hydroxypropyl-gamma-cyclodextrin complex aggregates;
(4) A polymer stabilizer; and
(5) Water;
1.0-w/v-2.0-w/v% of dexamethasone, about 3-w/v-12.5-w/v% of hydroxypropyl-gamma-cyclodextrin, about 4.25-w/v-12.75-w/v% of gamma-cyclodextrin, about 0.1-w/v-2.5-w/v% of polymer stabilizer.
The ophthalmic dexamethasone pharmaceutical composition, wherein the solid pharmaceutical portion comprises dexamethasone/cyclodextrin aggregate particles having a diameter of about 0.5 μm to about 50 μm. In one embodiment, the ophthalmic pharmaceutical composition, the solid drug portion thereof, comprises dexamethasone/cyclodextrin particles having a diameter (D90) of 3 μm to 10 μm. In one embodiment, the ophthalmic pharmaceutical composition, the solid drug portion thereof, comprises dexamethasone/cyclodextrin particles having a diameter (D90) of 3 μm to 6 μm.
In one embodiment, the total concentration of dexamethasone is about 1.25% w/v-1.75% w/v, the total concentration of hydroxypropyl- γ -cyclodextrin is about 5% w/v-12.5% w/v, the total concentration of γ -cyclodextrin is about 6% w/v-10% w/v, the total concentration of polymeric stabilizing agent is about 0.25% w/v-2.5% w/v.
In a specific embodiment, the total concentration of dexamethasone is about 1.5% w/v, the total concentration of hydroxypropyl- γ -cyclodextrin is about 6.5% w/v-12.5% w/v, the total concentration of γ -cyclodextrin is about 8% w/v-10% w/v, the total concentration of polymeric stabilizer is about 1% w/v-2.5% w/v.
In one embodiment, the polymeric stabilizer is selected from poloxamer, hypromellose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol or hyaluronic acid, preferably poloxamer, hypromellose or sodium carboxymethylcellulose, more preferably poloxamer.
In one embodiment, the ophthalmic pharmaceutical composition further comprises a pH adjusting agent selected from at least one of hydrochloric acid, sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, citric acid, and sodium citrate. Preferably the pH adjusting agents are disodium hydrogen phosphate and citric acid.
In one embodiment, the ophthalmic pharmaceutical composition further comprises an isotonicity adjusting agent selected from the group consisting of sodium chloride, glucose, or mannitol. Preferably the isotonicity adjusting agent is sodium chloride.
In one embodiment, the ophthalmic pharmaceutical composition further comprises a metal ion chelate, wherein the metal ion chelate is edetate disodium or edetate calcium sodium. Preferably the metal ion chelating agent is edetate disodium.
In one embodiment, the ophthalmic pharmaceutical composition further comprises a bacteriostatic agent which is benzalkonium chloride, benzalkonium bromide, methyl paraben, or propyl paraben. Preferably the bacteriostatic agent is benzalkonium chloride.
The ophthalmic dexamethasone pharmaceutical composition can be prepared by performing step-by-step ultrasonic treatment on hydroxypropyl-gamma-cyclodextrin, gamma-cyclodextrin and dexamethasone. In particular, for aqueous suspension eye drops, the following preparation method can be employed: subjecting the aqueous suspension of the polymer stabilizer, hydroxypropyl-gamma-cyclodextrin and dexamethasone to ultrasound, adding a gamma-cyclodextrin solution to ultrasound, and shaking.
Some embodiments of the above ophthalmic dexamethasone pharmaceutical composition further provide a preparation method of the aqueous suspension eye drop: and (3) carrying out ultrasonic treatment on the aqueous suspension of the polymer stabilizer, the hydroxypropyl-gamma-cyclodextrin and the dexamethasone, adding a gamma-cyclodextrin solution, stirring and shaking.
The application of the ophthalmic dexamethasone pharmaceutical composition in preparing the medicine for treating and/or preventing the diseases related to the posterior segment of the eye. The diseases related to the posterior segment of the eye are diseases related to the retina of the posterior segment of the eye, such as diabetic macular edema, age-related macular degeneration, cystoid macular edema and uveitis.
The medicament can be in the form of solution, suspension, gel, emulsion, etc., and particularly can be aqueous suspension eye drops.
The inventor unexpectedly discovers that the dexamethasone/gamma-cyclodextrin suspension eye drops are prepared by adopting a process of sterilizing at 121 ℃ for 20 minutes, so that dexamethasone is degraded under the condition of severe high temperature; and the operation has high requirements on production equipment, and the conventional eye drop production equipment is difficult to meet. In addition, the administration frequency of the dexamethasone/gamma-cyclodextrin suspension eye drops in human body tests which are already carried out is 3-4 times per day, and the administration frequency is higher.
Through further experimentation, the inventors unexpectedly found that: in the ophthalmic dexamethasone pharmaceutical composition, the solubilizing cyclodextrin and the aggregating cyclodextrin are used together, for example, hydroxypropyl-gamma-cyclodextrin and gamma-cyclodextrin are used together, and the ophthalmic dexamethasone pharmaceutical composition is prepared by using an ultrasonic inclusion process, so that the problems can be effectively solved, and the ophthalmic dexamethasone pharmaceutical composition with easier realization of process amplification, satisfactory stability and higher bioavailability is obtained. Based on this finding, the present invention provides an ophthalmic pharmaceutical composition comprising dexamethasone.
The process amplification of the dexamethasone ophthalmic medicine composition is easier to realize. The dexamethasone ophthalmic medicine composition can realize medicine inclusion only by ultrasonic operation, does not need to adopt the operation of sterilizing at 121 ℃ for 20 minutes, does not need to use large-scale special suspension sterilizing equipment, and is easy to produce and amplify.
The dexamethasone ophthalmic medicine composition has satisfactory stability. The stability investigation result shows that the dexamethasone ophthalmic medicine composition has good stability after being placed for 6 months under the accelerated test condition and the long-term test condition.
The dexamethasone ophthalmic medicine composition can avoid adverse reactions caused by invasive operation and realize higher bioavailability of eyes. The results of in vivo ocular tissue distribution test data show that compared with the comparative dexamethasone/gamma-cyclodextrin suspension eye drops for ocular surface local administration, the ophthalmic pharmaceutical composition for dexamethasone provided by the invention for ocular surface local administration has the advantages that the drug concentration in each ocular tissue is obviously increased within 2 hours after single administration, and the AUC (oral administration coefficient) of cornea, conjunctiva, aqueous humor, sclera and choroid-retina is remarkably increased 0-12h Respectively 1.95, 1.41, 1.65, 1.46 and 1.41 times of the comparative examples, further improves the bioavailability of the medicament, and has the advantages of improved bioavailabilityThe potential of reducing the frequency of administration in one step, and the eye surface local administration improves the compliance and the medication convenience of patients.
Drawings
FIG. 1 is a phase solubility curve for dexamethasone in various aqueous cyclodextrin solutions of example 1.
FIG. 2 is a phase solubility curve (different inclusion processes) for dexamethasone in aqueous gamma-cyclodextrin solution according to example 2.
Fig. 3 is a graph of drug concentration of dexamethasone in rabbit eye tissue after a single administration of example 8 and comparative example 1 (Mean ± SD, n =3, x indicates that limit of detection was not reached,. P <0.05, with significant difference from comparative example 1 group).
Detailed Description
The invention discloses a pharmaceutical composition of ophthalmic dexamethasone, in particular to an aqueous ophthalmic preparation, which can be realized by appropriately improving process parameters or formula proportion by a person skilled in the art by taking the contents of the invention as reference and combining the principle of pharmacy.
The following examples are presented in detail by way of illustration only and should not be construed to be limiting in spirit or scope; all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention. While the invention has been described in terms of preferred embodiments, those skilled in the art will recognize that the invention can be practiced and applied with modification, alteration, or combinations of the methods and applications described herein without departing from the spirit and scope of the invention.
Example 1
The influence of different cyclodextrin species on the solubility of dexamethasone in water was studied, and the inclusion efficiency (CE) and the inclusion constant (K) of different cyclodextrin species with dexamethasone were determined 1:1 ). Weighing excessive dexamethasone, adding into pure water and different cyclodextrin water solutions (alpha-cyclodextrin: 1%, 3%, 5%, 7%, 10%, 14%; gamma-cyclodextrin: 0.5%, 1%, 2%, 3%, 5%, 7%, 9%, 12%, 15%, 20%; hydroxypropyl-beta-cyclodextrin) with different concentrations (w/v)Refining: 1%, 3%, 5%, 10%, 15%, 20%, 25%; hydroxypropyl- γ -cyclodextrin: 1%, 3%, 5%, 10%, 15%, 20%, 25%; methyl- β -cyclodextrin: 1%, 3%, 5%, 10%, 15%, 20%, 25%), sealing, performing ultrasound at 50 ℃ for 1h, cooling to room temperature, and shaking in a constant-temperature water bath shaker at 25 ℃ for 7 days (100 rpm). Each sample was filtered using a 0.45 μm PES filter and the filtrate was taken off to determine the concentration of dexamethasone.
The dexamethasone concentration determination method comprises the following steps: high performance liquid chromatography; octadecylsilane chemically bonded silica was used as a filler (150X 4.6mm,5 μm); mobile phase: acetonitrile-water (28; flow rate: 1.0mL/min; column temperature: 40 ℃; detection wavelength: 240nm.
The phase solubility curves were plotted with cyclodextrin concentration (mM) as the X-axis and drug concentration (mM) as the Y-axis, and CE and K were calculated according to the following formula 1:1 。
Wherein S is 0 Is the inherent solubility of dexamethasone; slope is the Slope of the linear regression of the phase solubility curve.
The results are shown in Table 1.
TABLE 1 CE and K of dexamethasone with different cyclodextrins 1:1
| CD | Slope | R 2 | K 1:1 (M -1 ) | CE |
| Alpha-cyclodextrin | 0.0445 | 0.9998 | 228.67 | 0.05 |
| Hydroxypropyl-beta-cyclodextrin | 0.2955 | 0.9981 | 2059.50 | 0.42 |
| Hydroxypropyl-gamma-cyclodextrin | 0.5471 | 0.9979 | 5931.30 | 1.21 |
| Methyl-beta-cyclodextrin | 0.4261 | 0.9964 | 3645.53 | 0.74 |
| Gamma-cyclodextrin | 0.6667 | 0.9998 | 9821.57 | 2.00 |
* Note: the fit calculation was performed only for the linear segments (0.5-2% w/v) of the γ -cyclodextrin.
As can be seen from FIG. 1, the phase solubility curve of gamma-cyclodextrin is B S In the type, the dissolved dexamethasone is linearly increased along with the increase of the concentration of the gamma-cyclodextrin in the front section part, so that the maximum solubility of the dexamethasone is reached; with the continuous increase of the concentration of the gamma-cyclodextrin, the inclusion compound self-assembles to form an aggregate, precipitates out from the solution, and the concentration of the dissolved dexamethasone gradually decreases. Therefore, the dexamethasone-cyclodextrin suspension eye drops are formulated with the gamma-cyclodextrin selected to form aggregates. The concentration of the dissolved dexamethasone linearly increases along with the increase of the concentration of other screened cyclodextrins, and the solubility curves of the phases belong to A L And (4) molding. From the phase solubility diagram and K in Table 1 1:1 The value shows that the solubilization capacity of the hydroxypropyl-gamma-cyclodextrin to the dexamethasone is the strongest.
Example 2
The effect of different inclusion processes on phase solubility was investigated. The phase solubility of dexamethasone in the series of gamma-cyclodextrin solutions was examined using a sterile inclusion process and compared to the phase solubility results obtained using the ultrasonic inclusion process as measured in example 1. Weighing excessive dexamethasone, adding into gamma-cyclodextrin water solution (0.5%, 1%, 2%, 3%, 5%, 7%, 9%, 12%, 15%, 20%) with different concentrations (w/v), sealing, sterilizing at 121 deg.C for 20min, cooling to room temperature, and shaking in constant temperature water bath shaker at 25 deg.C for 7 days (100 rpm). Filtering each sample with 0.45 μm PES filter membrane, measuring dexamethasone concentration in the subsequent filtrate, and calculating CE and K 1:1 。
Research results show that the K of the dexamethasone is subjected to inclusion by adopting the gamma-cyclodextrin determined by adopting ultrasonic inclusion at 50 ℃ for 1h and sterilization at 121 ℃ for 20min 1:1 The values are respectively 9821.57M -1 And 9050.85M -1 The phase solubility curve is shown in FIG. 2. Therefore, the two inclusion processes adopted have no obvious influence on the inclusion behavior of the gamma-cyclodextrin. Thus, the inclusion process has no critical effect on the inclusion capacity of the cyclodextrin.
Example 3
The preparation with different dosage of hydroxypropyl-gamma-cyclodextrin and dosage of gamma-cyclodextrin is prepared, and the specific preparation method comprises the following steps: adding poloxamer 407 and hydroxypropyl-gamma-cyclodextrin with a formula accounting for 1% (w/v) into purified water with a total volume of 50%, stirring to dissolve, adding dexamethasone with a formula accounting for 1.5% (w/v), and performing ultrasonic treatment at 50 deg.C for 30min; adding water solution of gamma-cyclodextrin, ultrasonic treating at 50 deg.C for 30min, adding purified water to desired volume, stirring, mixing, and shaking at 25 deg.C for 7 days (100 rpm). The formulation ratios of hydroxypropyl-gamma-cyclodextrin and gamma-cyclodextrin for the different formulations are shown in table 2.
TABLE 2 hydroxypropyl-gamma-cyclodextrin dosages and gamma-cyclodextrin dosages for the different formulations
| Preparation | Hydroxypropyl-gamma-cyclodextrin prescription ratio (w/v) | Gamma-cyclodextrin prescription ratio (w/v) |
| F1 | 12.5％ | 12.75％ |
| F2 | 12.5％ | 8.5％ |
| F3 | 12.5％ | 4.25％ |
| F4 | 12.5％ | 2.55 |
| F5 | ||
| 9％ | 12.75 | |
| F6 | ||
| 9％ | 8.5 | |
| F7 | ||
| 9％ | 4.25 | |
| F8 | ||
| 9％ | 2.55％ | |
| F9 | 6.5％ | 12.75％ |
| F10 | 6.5％ | 8.5％ |
| F11 | 6.5％ | 4.25％ |
| F12 | 6.5％ | 3.4％ |
| F13 | 6.5％ | 2.55 |
| F14 | ||
| 5％ | 8.5 | |
| F15 | ||
| 4％ | 8.5％ | |
| F16 | 3％ | 8.5％ |
The particle size of the sample is measured according to a particle size and particle size distribution measuring method (a third method of 0982 of the four general rules of the 2020 edition of Chinese pharmacopoeia), and the specific operation is as follows: taking a proper amount of fully re-dispersed samples, taking pure water as a dispersion medium, adding the suspension into the dispersion medium under the stirring state of the dispersion speed of 2000rpm, diluting to enable the shading ratio displayed by an instrument to be between 10% and 20%, dispersing for 30-120s to enable the suspension to be uniformly dispersed, measuring for 20s, and recording D10, D50 and D90.
The solid drug fraction is used for evaluating the proportion of dexamethasone in the solid cyclodextrin microparticle aggregates, and the specific determination steps are as follows: measuring a sample, centrifuging at 8000rpm for 10min, and measuring the concentration of dexamethasone in the supernatant; and (4) taking a fully redispersed sample to determine the concentration of dexamethasone, thus obtaining the total drug concentration. The calculation formula is as follows:
TABLE 3 measurement results of various formulations
From the test results in table 3, it can be seen that the formulations F2, F6, F9, F10, F11, F14, F15, and F16 all gave a pale milky to milky suspension with a particle size (D90) in the range of about 3-25 μm and a solid drug fraction in the range of 3% -70%, which can be used for ocular administration, and by using the suspension form, the retention time of the drug on the ocular surface was increased, the ocular surface loss was reduced, and the sustained release of the drug with the dilution of the tear fluid resulted in a higher drug concentration on the ocular surface over a longer period of time. At this time, the prescription ratio of hydroxypropyl-gamma-cyclodextrin is in the range of 3% -12.5%, and the prescription ratio of gamma-cyclodextrin is in the range of 4.25% -12.75%. Within this range, the larger the amount of the γ -cyclodextrin used, the larger the particle size of the aggregates formed, and the larger the solid drug fraction.
Example 4
The preparation containing different polymer stabilizers is prepared by the following specific preparation method: adding a polymer stabilizer and hydroxypropyl-gamma-cyclodextrin into purified water with the total volume of 50%, stirring to dissolve, adding dexamethasone, and performing ultrasonic treatment at 50 ℃ for 30min; adding water solution of gamma-cyclodextrin, ultrasonic treating at 50 deg.C for 30min, adding purified water to desired volume, stirring, mixing, and shaking at 25 deg.C for 7 days (100 rpm). Formulations containing different types of polymeric stabilizers are shown in Table 4.
TABLE 4 formulation (w/v) containing different types of polymeric stabilizers
TABLE 5 measurement results of various formulations
From the test results in table 5, it is clear that when no polymer stabilizer is added to the formulation (F17, F18, F19), the sample properties are significantly layered and difficult to redisperse, failing to meet the requirements of ophthalmic preparations. Poloxamer was used as the polymer stabilizer in example 3; in this embodiment, polyvinylpyrrolidone, hypromellose, sodium carboxymethylcellulose, polyvinyl alcohol, and hyaluronic acid may also be added as a polymer stabilizer to prepare a preparation meeting the ophthalmic requirements.
Example 5
The preparation containing different dosages of poloxamer 407 is prepared, and the specific preparation method comprises the following steps: adding poloxamer 407 and hydroxypropyl-gamma-cyclodextrin into purified water with a total volume of 50%, stirring to dissolve, adding dexamethasone, and performing ultrasound treatment at 50 deg.C for 30min; adding water solution of gamma-cyclodextrin, ultrasonic treating at 50 deg.C for 30min, adding purified water to desired volume, stirring, mixing, and shaking at 25 deg.C for 7 days (100 rpm). Formulations containing different amounts of poloxamer 407 are shown in table 6.
TABLE 6 formulation (w/v) containing different poloxamer 407 amounts
| Preparation | Dexamethasone | Hydroxypropyl-gamma-cyclodextrin | Gamma-cyclodextrin | Poloxamer 407 |
| F29 | 1.5％ | 12.5％ | 8.5％ | 1.75％ |
| F30 | 1.5％ | 9％ | 8.5％ | 1.75％ |
| F31 | 1.5％ | 6.5％ | 8.5％ | 1.75％ |
| F32 | 1.5％ | 12.5％ | 8.5％ | 2.5％ |
| F33 | 1.5％ | 9％ | 8.5％ | 2.5％ |
| F34 | 1.5％ | 6.5％ | 8.5％ | 2.5％ |
TABLE 7 measurement results of various formulations
From the test results in table 7 in combination with the test results in table 3 in example 3, it can be seen that the amount of poloxamer as the polymer stabilizer is in the range of 1% to 2.5%, and suspension formulations meeting the ophthalmic requirements can be obtained.
Example 6
TABLE 8 prescription composition of eye drops
| Components | Ratio (%) | Dosage (100 mL) |
| Dexamethasone | 1.5 | 1.5g |
| Hydroxypropyl-gamma-cyclodextrin | 12.5 | 12.5g |
| Gamma-cyclodextrin | 8.5 | 8.5g |
| Poloxamer 407 | 1 | 1.0g |
| Benzalkonium chloride | 0.02 | 20mg |
| Edetate disodium | 0.1 | 100mg |
| Na 2 HPO 4 ·12H 2 O | 0.39 | 0.39g |
| Citric acid | Proper amount of | Adjusting pH to 5.0-6.0 |
| Sodium chloride | 0.28 | 280mg |
| Purified water | Proper amount of | Adding to 100mL |
According to the prescription in Table 8, the edetate disodium and Na are prescribed 2 HPO 4 ·12H 2 Adding purified water with the total volume of 50% into O, benzalkonium chloride, sodium chloride, poloxamer 407 and hydroxypropyl-gamma-cyclodextrin, stirring for dissolving, and adjusting pH to 5.0-6.0 with 0.1mol/L citric acid solution. Adding dexamethasone with the prescription amount, and performing ultrasonic treatment at 50 ℃ for 30min; then adding the gamma-cyclodextrin aqueous solution with the prescription amount, carrying out ultrasonic treatment at 50 ℃ for 30min, fixing the volume of purified water, stirring and mixing uniformly, and shaking for 5 days (100 rpm) at 25 ℃.
Example 7
TABLE 9 prescription composition of eye drops
| Components | Percentage of occupation (%) | Amount (100 mL) |
| Dexamethasone | 1.5 | 1.5g |
| Hydroxypropyl-gamma- |
9 | 9g |
| Gamma-cyclodextrin | 8.5 | 8.5g |
| Poloxamer 407 | 1 | 1.0g |
| Benzalkonium chloride | 0.02 | 20mg |
| Edetate disodium | 0.1 | 100mg |
| Na 2 HPO 4 ·12H 2 O | 0.39 | 0.39g |
| Citric acid | Proper amount of | Adjusting pH to 5.0-6.0 |
| Sodium chloride | 0.33 | 330mg |
| Purified water | Proper amount of | Adding to 100mL |
According to the prescription in Table 9, the edetate disodium and Na are prescribed 2 HPO 4 ·12H 2 Adding O, benzalkonium chloride, sodium chloride, poloxamer 407 and hydroxypropyl-gamma-cyclodextrin into 50% of purified water, stirring to dissolve, and adjusting pH to 5.0-6.0 with 0.1mol/L citric acid solution. Adding dexamethasone with the prescription amount, and carrying out ultrasonic treatment at 40 ℃ for 30min; then adding the gamma-cyclodextrin aqueous solution with the prescription amount, stirring to be clear, fixing the volume of the purified water, stirring and mixing uniformly, and shaking for 5 days (100 rpm) at 25 ℃.
Example 8
TABLE 10 prescription composition of eye drops
| Components | Ratio (%) | Dosage (1000 mL) |
| Dexamethasone | 1.5 | 15g |
| Hydroxypropyl-gamma-cyclodextrin | 6.5 | 65g |
| Gamma-cyclodextrin | 8.5 | 85g |
| Poloxamer 407 | 1 | 10g |
| Benzalkonium chloride | 0.02 | 200mg |
| Edetate disodium salt | 0.1 | 1g |
| Na 2 HPO 4 ·12H 2 O | 0.39 | 3.9g |
| Citric acid | Proper amount of | Adjusting pH to 5.0-6.0 |
| Sodium chloride | 0.41 | 4.1g |
| Purified water | Proper amount of | Adding to 1000mL |
According to the prescription in Table 10, the edetate disodium and Na are prescribed 2 HPO 4 ·12H 2 Adding purified water with the total volume of 50% O, benzalkonium chloride, sodium chloride, poloxamer 407 and hydroxypropyl-gamma-cyclodextrin, stirring for dissolving, adjusting pH to 5.0-6.0 with 0.5mol/L citric acid solution, and filtering with 0.22 μm microporous membrane. Adding dexamethasone with the prescription amount, and performing ultrasonic treatment at 30 ℃ for 30min; then adding the gamma-cyclodextrin aqueous solution with the prescription amount filtered by a 0.22 mu m microporous membrane, stirring to clarify, fixing the volume by using purified water, stirring and mixing uniformly, and shaking for 5 days (100 rpm) at 25 ℃.
Comparative example 1
Samples were prepared according to the recipe (Table 11) and procedures mentioned in the literature (Tanito M, hara K, takai Y, et al. Focal demethanine-cyclic microparticles eye drop for diagnostic laboratory edima. Invest Ophthalmol Vis Sci.2011;52 (11): 7944-7948.) and their quality characteristics were determined.
TABLE 11 COMPARATIVE EXAMPLE 1 prescription
| Composition (I) | Amount of the composition | Ratio (%) |
| Dexamethasone | 1.50g | 1.5 |
| Gamma-cyclodextrin | 14g | 14 |
| Benzalkonium chloride | 20mg | 0.02 |
| Edetate disodium | 100mg | 0.1 |
| Poloxamer 407 | 2.5g | 2.5 |
| Sodium chloride | 570mg | 0.57 |
| Are prepared into | 100mL | —— |
The preparation method comprises the following steps: suspending dexamethasone and gamma-cyclodextrin in a prescribed amount in an aqueous solution containing benzalkonium chloride, edetate disodium, poloxamer 407, and sodium chloride, autoclaving the resulting suspension in a sealed container at 121 deg.C for 20min, cooling to room temperature, and shaking at 25 deg.C for 7 days (100 rpm).
Method for measuring substance concerned
Measuring by high performance liquid chromatography (China pharmacopoeia 2020 edition four-part general regulation 0512). The chromatographic conditions are as follows: and (3) chromatographic column: octadecylsilane chemically bonded silica as a filler (250X 4.6mm,5 μm); mobile phase: acetonitrile-water (28; flow rate: 1.0mL/min; column temperature: 40 ℃; detection wavelength: 240nm; sample introduction amount: 20 μ L.
TABLE 12 comparison of test results
As can be seen from Table 12, the samples of examples 6, 7 and 8 prepared by the ultrasonic process had significantly lower substances than the sample of comparative example 1 prepared by the sterilization process at 121 ℃.
Example 9
Stability study
Example 8 samples were tested in samples taken at 1 month, 2 months, 3 months and 6 months under accelerated conditions (temperature 40 ℃ C. + -. 2 ℃ C., relative humidity 75% + -. 5%) and prolonged conditions (temperature 25 ℃ C. + -. 2 ℃ C., relative humidity 60% + -. 5%), respectively.
Method for measuring viscosity
The viscosity of the product is measured by a rotational viscometer according to the third method of the general rules of the four departments of the 2020 edition of Chinese pharmacopoeia 0633. Setting the rotation speed at 60rpm (No. 1 rotor), placing a proper amount of fully redispersed samples in a beaker, maintaining the temperature of the samples at 25 ℃, leveling the liquid mark of the rotor with the liquid level for measurement, and displaying the reading by a recording instrument.
Redispersibility measurement method: the sample was a suspension, and the content of 1 drop of the suspension after redispersion was determined in order to evaluate its redispersibility, and three portions were determined in parallel.
TABLE 13 results of accelerated condition stability examination of samples of example 8 (40 ℃. + -. 2 ℃, 75%. + -. 5% RH)
TABLE 14 Long term stability test results for samples of example 8 (25 ℃. + -. 2 ℃, 60%. + -. 5% RH)
As can be seen from the study results in tables 13 and 14, the sample of example 8 has good stability under accelerated and long-term conditions for 6 months, the key quality attributes do not change significantly, and all the items meet the proposed quality standards.
Example 10
Animal tissue distribution comparison study of dexamethasone Mixed Cyclodextrin aggregate eye drops (example 8) and dexamethasone Single Cyclodextrin aggregate eye drops (comparative example 1)
Materials and methods
Experimental animals: new Zealand white rabbit (Lefu farm in Putou, nanjing), 2.0-2.5kg, male, quality certificate number: no.202212467.
And (3) testing a sample: example 8 sample, comparative example 1 sample
The experimental method comprises the following steps:
36 male rabbits were randomly divided into 12 groups of 3 animals each. After the rabbits were fixed, 50 μ L of the sample of example 8 or the sample of comparative example 1 was administered in a single dose into the lower conjunctival sac of the left eye of each group of rabbits, and the right eye was left as a blank without any treatment. After administration, the eyelids were allowed to close freely and the nasolacrimal duct was pressed 60s. Killing the corresponding rabbits by adopting an ear edge intravenous injection air method at 0.5, 1, 2, 4, 8 and 12 hours after single administration, taking conjunctival tissues from the surfaces of eyeballs, then quickly picking the eyeballs, removing blood clots and redundant hoof tissues on the surfaces of the eyeballs, and washing the eyeballs clean by using normal saline. The micro-injector is penetrated into the eyeball to collect aqueous humor, and then the cornea is cut along the edge of the cornea and collected; the sclera was cut open, the vitreous fluid was removed sufficiently, the choroidal-retinal scraping was collected, and then the sclera was collected. Each tissue was placed in a sampling tube and weighed. The dexamethasone concentration in each eye tissue sample was determined by appropriate treatment of the sample.
The experimental results are as follows:
TABLE 15 pharmacokinetic parameters of rabbit eye tissue after single administration (Mean + -SD, n = 3)
* p <0.05, compared to comparative example 1
The drug concentrations in the rabbit eye tissues for the example 8 sample and the comparative example 1 sample are shown in FIG. 3. The pharmacokinetic parameters associated with the drug in each eye tissue were calculated using pksolver2.0 pharmacokinetic software, and the results are shown in table 15. The drug concentration in each tissue was higher for the sample of example 8 than for the sample of comparative example 1 (p < 0.05) within 2h after a single topical administration to rabbit eyes. Example 8 AUC of samples in cornea, conjunctiva, aqueous humor, sclera and choroid-retina 0-12h The bioavailability of the drug is further improved by 1.95, 1.41, 1.65, 1.46 and 1.41 times of the sample of comparative example 1. Dexamethasone was reported to have an activation potency of 3nM (i.e., 1.2 ng/mL) for the glucocorticoid receptor (believed to be primarily responsible for the anti-inflammatory effects of corticosteroids) in HeLa cells (Whitcup SM, cidlowski JA, csaky KG, et al. Pharmacology of corticosteriods for diabetic maular diet. Invest Ophthalmol Vis Sci.2018;59 (1): 1-12.), this cellLayered dexamethasone activation efficacy in dexamethasone implants
Also confirmed in the FDA pharmacological review report. Example 8 the drug concentrations measured in the posterior segment of the eye at 12h after a single administration of the sample were all higher than the effective concentration of dexamethasone. Compared with the dexamethasone/gamma-cyclodextrin suspension eye drop sample in the comparative example 1, the bioavailability of the suspension eye drop is improved, and the administration frequency can be further reduced. />
Claims (10)
1. An ophthalmic dexamethasone pharmaceutical composition, comprising: the raw materials comprise: dexamethasone, hydroxypropyl-gamma-cyclodextrin, a polymeric stabilizer, and water;
the dosage of the dexamethasone is 1.0% w/v-2.0% w/v, the dosage of the hydroxypropyl-gamma-cyclodextrin is 3% w/v-12.5% w/v, the dosage of the gamma-cyclodextrin is 4.25% w/v-12.75% w/v, and the dosage of the polymer stabilizer is 0.1% w/v-2.5% w/v.
2. The ophthalmic dexamethasone pharmaceutical composition according to claim 1, wherein: the dosage of the dexamethasone is 1.25% w/v-1.75% w/v, the dosage of the hydroxypropyl-gamma-cyclodextrin is 5% w/v-12.5% w/v, the dosage of the gamma-cyclodextrin is 6% w/v-10% w/v, and the dosage of the polymer stabilizer is 0.25% w/v-2.5% w/v.
3. The ophthalmic dexamethasone pharmaceutical composition according to claim 1, wherein: the dosage of the dexamethasone is 1.5% w/v, the dosage of the hydroxypropyl-gamma-cyclodextrin is 6.5% w/v-12.5% w/v, the dosage of the gamma-cyclodextrin is 8% w/v-10% w/v, and the dosage of the polymer stabilizer is 1% w/v-2.5% w/v.
4. The ophthalmic dexamethasone pharmaceutical composition according to claim 1, wherein: the polymer stabilizer is selected from poloxamer, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol or hyaluronic acid, preferably poloxamer, hydroxypropyl methylcellulose or sodium carboxymethylcellulose, and more preferably poloxamer.
5. The ophthalmic dexamethasone pharmaceutical composition according to claim 1, wherein: the raw material also comprises a pH regulator, and the pH regulator is at least one selected from hydrochloric acid, sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, citric acid or sodium citrate.
6. The ophthalmic dexamethasone pharmaceutical composition according to claim 1, wherein: the raw material also comprises an isoosmotic adjusting agent, and the isoosmotic adjusting agent is selected from sodium chloride, glucose or mannitol.
7. The ophthalmic dexamethasone pharmaceutical composition according to claim 1, wherein: the raw material also comprises a metal ion chelate, and the metal ion chelate is disodium edetate or calcium sodium edetate.
8. The ophthalmic dexamethasone pharmaceutical composition according to claim 1, wherein: the raw materials also comprise bacteriostatic agents which are benzalkonium chloride, benzalkonium bromide, methyl paraben or propyl paraben.
9. Use of an ophthalmic dexamethasone pharmaceutical composition according to any one of claims 1-8 in the manufacture of a medicament for the treatment and/or prevention of diseases related to the posterior segment of the eye.
10. Use according to claim 9, characterized in that: the disease related to the posterior segment of the eye is a disease related to the retina of the posterior segment of the eye.
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