Drug elution device
By designing a drug elution device and method, the release process of drug-loaded corneal lenses in the human body was simulated, overcoming the shortcomings of existing drug release measurement methods and realizing accurate prediction and quality control of drug release.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Utility models(China)
- Current Assignee / Owner
- SHANGHAI MODERN PHARMACEUTICAL ENGINEERING RESEARCH CENTER CO LTD
- Filing Date
- 2025-04-24
- Publication Date
- 2026-04-21
AI Technical Summary
Existing technologies lack methods for measuring drug release from drug-loaded corneal contact lenses that can accurately predict drug release in vivo, and cannot establish the correlation between in vitro and in vivo drug release, which affects the quality control and prediction of drug release.
A drug elution device was designed, including a base and a cover. The base and cover simulate the release process of a drug-loaded corneal lens in the human body through an arc-shaped space formed by protrusions and grooves. Specific gaps and flow paths are set to simulate the drug elution process.
This device can accurately predict the release kinetics of drugs from drug-eluting corneal lenses, improving the accuracy of predicting drug release in vivo and serving as an effective means of quality control to ensure drug quality.
Smart Images
Figure CN224152470U_ABST
Abstract
Description
Technical Field
[0001] This utility model relates to a drug elution device. Background Technology
[0002] Litahistine is a novel small-molecule integrin inhibitor and lymphocyte function-associated antigen 1 (LFA-1) antagonist that blocks the interaction between LFA-1 and its homologous ligand, intercellular adhesion molecule-1 (ICAM-1), thus interfering with the overexpression of ICAM-1 in the cornea and conjunctiva, which causes dry eye syndrome. Litahistine contact lenses are drug-release contact lenses. The lenses are soaked in a drug-eluting solution to retain drug molecules, allowing for high drug loading and sustained release into the eye. After wearing, the drug is released from the lens and further penetrates various tissues to exert its effect. However, different materials and preparation methods may affect the loading and retention of the drug within the contact lens, leading to variations in drug release. Therefore, studying the kinetics of drug release from drug-eluting contact lenses is crucial for quality control and predicting in vivo drug release.
[0003] However, there is currently no universal method for measuring drug release from medicated corneal contact lenses; and the relevant research methods reported in the literature have failed to establish the correlation between in vitro and in vivo drug release, and therefore cannot be used to predict in vivo drug release. Utility Model Content
[0004] To address the lack of existing methods for determining the drug release curve of drug-loaded corneal contact lenses that effectively correlates with in vivo drug release, this invention provides a drug elution device and method. The drug elution device and method of this invention can not only accurately predict in vivo drug release but also serve as an effective means of quality control to ensure drug quality.
[0005] The present invention solves the above-mentioned technical problems through the following technical solutions.
[0006] This utility model provides a drug elution device, which includes a base and a cover;
[0007] The base includes a first fixing body and a groove disposed inside the first fixing body;
[0008] The cover includes a second fixed body, a protrusion, a liquid inlet channel, and a liquid outlet channel; the liquid inlet channel and the liquid outlet channel are arranged parallel to each other in the second fixed body and are adjacent to both sides of the protrusion, respectively; the liquid inlet channel is used to introduce the eluent, and the liquid outlet channel is used to discharge the eluted liquid;
[0009] The first fixing body and the second fixing body are detachably connected; when the first fixing body and the second fixing body are connected, the groove can accommodate the protrusion, and there is an arc-shaped space between the groove and the protrusion, the arc-shaped space is used to accommodate the drug-eluting corneal lens; the difference between the radius of curvature of the groove and the radius of curvature of the protrusion is the same as the depth of the arc-shaped space; the width of the protrusion is smaller than the width of the groove;
[0010] The inlet channel, the arc-shaped space, and the outlet channel are connected in sequence to form the flow path of the eluent.
[0011] In this invention, the protrusions and grooves are provided and the gap formed therein is used to accommodate the drug-eluting corneal lens. The thickness of the gap and the width of the protrusions and the width of the grooves are set in a specific way to better simulate the release process of the drug-eluting corneal lens in the human body, so that the kinetics of the eluted drug are more matched with the release process in the human body.
[0012] In this invention, the depth of the arc-shaped space is defined as the perpendicular distance between the tangent of the groove at a point in the vertical cross-section and the tangent of the protrusion at a point in the vertical cross-section, along the same radial direction.
[0013] In this invention, preferably, the ratio of the radius of curvature of the groove to the radius of curvature of the protrusion is (1-1.5):1, more preferably (1.04-1.25):1.
[0014] In this invention, preferably, the radius of curvature of the groove is 9-14 mm, more preferably 10-13 mm.
[0015] In this invention, preferably, the radius of curvature of the protrusion is 8-12 mm, more preferably 9-11 mm.
[0016] In this invention, preferably, the depth of the arc-shaped space is 0.5-2mm, more preferably 0.5-1.5mm, for example 0.8mm.
[0017] In this invention, preferably, the ratio of the width of the protrusion to the width of the groove is (0.5-1):1, more preferably (0.7-0.9):1.
[0018] In this invention, preferably, the difference between the width of the protrusion and the width of the groove is 2-4 mm, for example, 3 mm.
[0019] In this invention, preferably, the width of the protrusion is 11-15mm, more preferably 12-14mm, for example 13.7mm.
[0020] In this invention, preferably, the width of the groove is 13-19mm, more preferably 14-18mm, for example 16.7mm.
[0021] In this invention, preferably, the diameter ratio of the inlet channel to the outlet channel is 1:(1-3), for example, 1:1.
[0022] In this invention, preferably, the diameter of the liquid inlet channel is 0.5-1.5 mm.
[0023] In this invention, preferably, the diameter of the liquid outlet channel is 0.5-1.5 mm.
[0024] In some specific embodiments of this utility model, the vertical projection surface of the protrusion is circular, and the vertical projection surface of the groove is circular.
[0025] In some specific embodiments of this utility model, the drug elution device further includes a fixing connection component, which is connected to the base and the cover respectively to realize the connection between the base and the cover.
[0026] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of this utility model.
[0027] The reagents and raw materials used in this invention are all commercially available.
[0028] The positive and progressive effects of this utility model are as follows:
[0029] The drug elution device of this invention can be used to study the kinetic behavior of simulated drug release from drug-loaded corneal contact lenses into the body. When applied to the drug elution method of this invention, the drug elution device can predict the in vivo and in vivo release of drug-loaded corneal lenses with high accuracy. It can be effectively used to study the release of drugs in drug-loaded corneal contact lenses.
[0030] Meanwhile, the similarity factors among the embodiments of this utility model are high, all exceeding 50, indicating that the drug elution device of this utility model has good durability.
[0031] The drug elution device of this invention can also serve as an effective means of quality control to ensure the quality of drugs. Attached Figure Description
[0032] Figure 1 This is a cross-sectional schematic diagram of the drug elution device in Example 1.
[0033] The attached figures are labeled as follows:
[0034] 1-First fixing body; 2-Groove; 3-Second fixing body; 4-Protrusion; 5-Inlet channel; 6-Outlet channel; 7-Fixed connecting component.
[0035] Figure 2 This is the drug release curve for Example 2.
[0036] Figure 3 The in vivo release curve of the drug-loaded corneal lens in rabbits in Example 2 is shown.
[0037] Figure 4 The drug concentration curve in rabbit tears for the drug-loaded corneal lens in Example 2 is shown.
[0038] Figure 5 The image shows the absorption fraction curve of rabbit tears in Example 2.
[0039] Figure 6 This is a comparison chart of the in vivo predicted values and the actual in vivo release values in rabbits in Example 2.
[0040] Figure 7 This is a comparison graph of the predicted in vivo values and the measured values of tear absorption fraction in rabbits in Example 2.
[0041] Figure 8 This is a comparison chart of the in vivo predicted values and the actual in vivo release values in rabbits in Example 3.
[0042] Figure 9 This is a comparison graph of the predicted in vivo values and the measured values of tear absorption fraction in rabbits in Example 3.
[0043] Figure 10 This is a comparison chart of the in vivo predicted values and the actual in vivo release values in rabbits in Example 4.
[0044] Figure 11 This is a comparison graph of the predicted in vivo values and the measured values of tear absorption fraction in rabbits in Example 4.
[0045] Figure 12 This is a comparison chart of the in vivo predicted values and the actual in vivo release values in rabbits in Example 5.
[0046] Figure 13 This is a comparison graph of the predicted in vivo values and the measured values of tear absorption fraction in rabbits in Example 5. Detailed Implementation
[0047] The present invention is further illustrated below by way of embodiments, but these embodiments do not limit the present invention to the scope of the embodiments described. Experimental methods in the following embodiments that do not specify specific conditions are performed according to conventional methods and conditions, or as selected according to the product instructions.
[0048] Example 1
[0049] The drug elution device of Example 1 includes a base and a cover;
[0050] The base includes a first fixing body 1 and a groove 2 disposed inside the first fixing body 1;
[0051] The cover includes a second fixed body 3, a protrusion 4, a liquid inlet channel 5, and a liquid outlet channel 6; the liquid inlet channel 5 and the liquid outlet channel 6 are arranged parallel to each other in the second fixed body 3 and are adjacent to the two sides of the protrusion 4 respectively; the liquid inlet channel 5 is used to introduce the elution solution, and the liquid outlet channel 6 is used to discharge the eluted liquid; the diameter of the liquid inlet channel 5 and the liquid outlet channel 6 is 1 mm.
[0052] The first fixing body 1 and the second fixing body 3 are detachably connected; when the first fixing body 1 and the second fixing body 3 are connected, the groove 2 can accommodate the protrusion 4, and there is an arc-shaped space between the groove 2 and the protrusion 4, which is used to accommodate the drug-eluting corneal lens; the difference between the radius of curvature of the groove 2 and the radius of curvature of the protrusion 4 is the same as the depth of the arc-shaped space; the radius of curvature of the groove 2 is 10.8mm, the radius of curvature of the protrusion 4 is 10mm, and the depth of the arc-shaped space is 0.8mm.
[0053] The vertical projection surface of protrusion 4 is circular, the vertical projection surface of groove 2 is circular, the width of protrusion 4 is 13.7mm, and the width of groove 2 is 16.7mm.
[0054] The inlet channel 5, the arc-shaped space, and the outlet channel 6 are connected in sequence to form a flow path for the eluent.
[0055] The drug elution device also includes a fixing connection component 7, which is connected to the base and the cover respectively to realize the connection between the base and the cover.
[0056] Example 2
[0057] This embodiment uses the drug elution device from Example 1.
[0058] Drug-eluting corneal lenses:
[0059] The listatin-loaded corneal lens of this embodiment is self-made. The specific self-made method is as follows: Take 1 mL of drug-containing solution (listatin concentration of 0.6 mg / mL, excipients of 1.28% (w / v) boric acid, 0.38% (w / v) borax, 0.4% (w / v) sodium chloride, 0.3% (w / v) sodium thiosulfate and water for injection) into a glass bottle, put one unloaded corneal contact lens into the glass bottle, seal it with a chlorobutyl rubber stopper covered with polytetrafluoroethylene / ethylene copolymer film, and sterilize it by heating at 115°C for 2 hours.
[0060] The prepared drug-loaded corneal lens has a base arc radius of curvature of 8.5 mm, a circular vertical projection surface, a diameter of 14.2 mm, a center thickness of 0.1 mm, and a drug loading of 0.3 mg per lens.
[0061] Artificial tears:
[0062] Sodium chloride, sodium bicarbonate, calcium chloride dihydrate, and water are mixed to form artificial tears, which include 0.67% (w / v) sodium chloride, 0.22% (w / v) sodium bicarbonate, 0.006% (w / v) calcium chloride, and 0.14% (w / v) potassium chloride.
[0063] The drug elution method in this embodiment includes the following steps:
[0064] The eluent artificial tears were introduced into the drug elution device through the inlet channel at a flow rate of 0.15 mL / min, and the drug-loaded corneal lens was eluted at 25°C. After elution, the solution was discharged through the outlet channel.
[0065] The method for testing the concentration of the eluted solution includes the following steps:
[0066] 1. Preparation of control solution: Weigh out literal amounts of rituximab, and record the value as m. s The control solution was prepared by dissolving and diluting with artificial tears to a concentration of 4 μg / mL, and its volume was V. s The purity of the drug in the control solution was 98% when it was prepared; this value is calculated as W. s ;
[0067] 2. Using the above-described drug elution method, samples were taken from the eluted solutions at 30 min, 60 min, 120 min, 180 min, 240 min, 360 min, and 480 min, respectively. The samples were filtered through a 0.22 μm polyethersulfone membrane and used as the test solution. The volume of the eluted solution obtained from 0-30 min was recorded as V1, the volume of the eluted solution obtained from 30-60 min as V2, and so on, to obtain the volume V of the test solution at different sampling time points. i ;
[0068] 3. High-performance liquid chromatography (HPLC) was used to test the control solution and the test solution, respectively, and A was obtained. x and A s The drug release amount of the test solution was calculated using the external standard method to obtain the drug release curve. The chromatographic conditions were as follows: octadecylsilane-bonded silica gel as the stationary phase; 0.05% trifluoroacetic acid-acetonitrile (60:40) as the mobile phase; flow rate 1.0 mL / min; detection wavelength 254 nm; column temperature 40 °C; injection volume 30 μL.
[0069] Drug concentration C i The calculation formula is as follows:
[0070]
[0071] Cumulative release Q i The formula for calculating ' is as follows:
[0072]
[0073] In the formula:
[0074] C i - The concentration of the test solution at different sampling times;
[0075] V i - The volume of the test solution obtained at different sampling time periods;
[0076] A x - Peak area of the test sample solution;
[0077] A s - The average peak area of the control solution;
[0078] W s - The purity of the drug when the control solution was prepared;
[0079] m s - The weight of the drug when preparing the control solution;
[0080] V s - Volume of the control solution;
[0081] Q i -Cumulative release (%)
[0082] L c - This is the labeled amount (mg / piece), which is the amount of drug loaded in each drug-eluting corneal lens, i.e., 0.3 mg / piece.
[0083] The drug release curve of Example 2 is as follows: Figure 2 As shown.
[0084] Example 3
[0085] This embodiment uses the drug elution device from Example 1.
[0086] Drug-eluting corneal lenses:
[0087] The listatin-loaded corneal lens of this embodiment is self-made. In the self-made method, the concentration of listatin in the drug-containing solution is adjusted to 0.4 mg / mL, and the types and contents of excipients are the same as in Example 2, so that the listatin-loaded corneal lens has a drug loading of 0.2 mg per lens, and the preparation process is the same as in Example 2.
[0088] The only difference between this embodiment and Example 2 is that the drug-loaded corneal lens has the same conditions as in Example 2, except that the drug loading per lens is 0.2 mg.
[0089] The conditions for the drug elution method in this embodiment are the same as in Embodiment 2.
[0090] In the method for testing the concentration of the eluted solution, step 2 involves sampling the eluted solution at 1h, 2h, 3h, 4h, 6h, and 8h, respectively, with the remaining steps and conditions the same as in Example 2.
[0091] Example 4
[0092] This embodiment uses the drug elution device from Example 1.
[0093] Drug-eluting corneal lenses:
[0094] The listatin-loaded corneal lens of this embodiment is self-made. In the self-made method, the concentration of listatin in the drug-containing solution is adjusted to 1.2 mg / mL, and the types and contents of excipients are the same as in Example 2, so that the listatin-loaded corneal lens has a drug loading of 0.6 mg per lens, and the preparation process is the same as in Example 2.
[0095] The only difference between this embodiment and Example 2 is that the drug-loaded corneal lens has a drug loading of 0.6 mg per lens. All other conditions for the drug-loaded corneal lens are the same as in Example 2.
[0096] The conditions for the drug elution method in this embodiment are the same as in Embodiment 2.
[0097] In the method for testing the concentration of the eluted solution, step 2 involves sampling the eluted solution at 1h, 2h, 3h, 4h, 6h, and 8h, respectively, with the remaining steps and conditions the same as in Example 2.
[0098] Example 5
[0099] This embodiment uses the drug elution device from Example 1.
[0100] Drug-eluting corneal lenses:
[0101] The listatin drug-eluting corneal lens in this embodiment is self-made, and the self-making method is the same as in Example 2.
[0102] The only difference between this embodiment and Example 2 is that the drug-loaded corneal lens has the same conditions as in Example 2, except that the drug loading amount per lens is 0.3 mg.
[0103] In the drug elution method of this embodiment, the eluent artificial tears are introduced into the drug elution device through the inlet channel at a flow rate of 0.3 mL / min, and the other conditions are the same as in Example 2.
[0104] The conditions for testing the concentration of the eluted solution are the same as in Example 2.
[0105] Example 6
[0106] This embodiment uses the drug elution device from Example 1.
[0107] Drug-eluting corneal lenses:
[0108] The listatin-loaded corneal lens of this embodiment is self-made. In the self-made method, the concentration of listatin in the drug-containing solution is adjusted to 0.4 mg / mL, and the types and contents of excipients are the same as in Example 2, so that the listatin-loaded corneal lens has a drug loading of 0.2 mg per lens, and the preparation process is the same as in Example 2.
[0109] The only difference between this embodiment and Example 2 is that the drug-loaded corneal lens has the same conditions as in Example 2, except that the drug loading per lens is 0.2 mg.
[0110] In the drug elution method of this embodiment, the eluent artificial tears are introduced into the drug elution device through the inlet channel at a flow rate of 0.5 mL / min, and the other conditions are the same as in Example 2.
[0111] The conditions for testing the concentration of the eluted solution are the same as in Example 2.
[0112] Example 7
[0113] This embodiment uses the drug elution device from Example 1.
[0114] Drug-eluting corneal lenses:
[0115] The listatin drug-eluting corneal lens in this embodiment is self-made, and the self-making method is the same as in Example 2.
[0116] The only difference between this embodiment and Example 2 is that the drug-loaded corneal lens has the same conditions as in Example 2, except that the drug loading amount per lens is 0.3 mg.
[0117] In the drug elution method of this embodiment, the eluent is an aqueous solution of sodium chloride with a concentration of 0.9% (w / v), and the other conditions are the same as in Example 2.
[0118] The conditions for testing the concentration of the eluted solution are the same as in Example 2.
[0119] Example 8
[0120] This embodiment uses the drug elution device from Example 1.
[0121] Drug-eluting corneal lenses:
[0122] The listatin-loaded corneal lens of this embodiment is self-made. In the self-made method, the concentration of listatin in the drug-containing solution is adjusted to 0.4 mg / mL, and the types and contents of excipients are the same as in Example 2, so that the listatin-loaded corneal lens has a drug loading of 0.2 mg per lens, and the preparation process is the same as in Example 2.
[0123] The only difference between this embodiment and Example 2 is that the drug-loaded corneal lens has the same conditions as in Example 2, except that the drug loading per lens is 0.2 mg.
[0124] In the drug elution method of this embodiment, the drug-loaded corneal lens is eluted at 34°C, and the other conditions are the same as in Example 2.
[0125] The conditions for testing the concentration of the eluted solution are the same as in Example 2.
[0126] Example 9
[0127] This embodiment uses the drug elution device from Example 1.
[0128] Drug-eluting corneal lenses:
[0129] The listatin-loaded corneal lens of this embodiment is self-made. In the self-made method, the concentration of listatin in the drug-containing solution is adjusted to 0.4 mg / mL, and the types and contents of excipients are the same as in Example 2, so that the listatin-loaded corneal lens has a drug loading of 0.2 mg per lens, and the preparation process is the same as in Example 2.
[0130] The only difference between this embodiment and Example 2 is that the drug-loaded corneal lens has the same conditions as in Example 2, except that the drug loading per lens is 0.2 mg.
[0131] In the drug elution method of this embodiment, the drug-loaded corneal lens is eluted at 40°C, and the other conditions are the same as in Example 2.
[0132] The conditions for testing the concentration of the eluted solution are the same as in Example 2.
[0133] Example 10
[0134] This embodiment uses the drug elution device from Example 1.
[0135] Drug-eluting corneal lenses:
[0136] The listatin-loaded corneal lens of this embodiment is self-made. In the self-made method, the concentration of listatin in the drug-containing solution is adjusted to 1.2 mg / mL, and the types and contents of excipients are the same as in Example 2, so that the listatin-loaded corneal lens has a drug loading of 0.6 mg per lens, and the preparation process is the same as in Example 2.
[0137] The only difference between this embodiment and Example 2 is that the drug-loaded corneal lens has a drug loading of 0.6 mg per lens. All other conditions for the drug-loaded corneal lens are the same as in Example 2.
[0138] In the drug elution method of this embodiment, the drug-loaded corneal lens is eluted at 20°C, and the other conditions are the same as in Example 2.
[0139] The conditions for testing the concentration of the eluted solution are the same as in Example 2.
[0140] Comparative Example 1
[0141] This comparative example uses the drug elution apparatus of Example 1.
[0142] Drug-eluting corneal lenses:
[0143] The listatin drug-eluting corneal lens used in this comparative example was prepared in-house using the same method as in Example 2.
[0144] The only difference between this comparative example and Example 2 is that the drug-loaded corneal lenses containing listatin have the same conditions as those in Example 2, except that the drug loading per lens is 0.3 mg.
[0145] In this comparative example of drug elution method, the eluent artificial tears are introduced into the drug elution device through the inlet channel at a flow rate of 2 mL / min, and the other conditions are the same as in Example 2.
[0146] The conditions for testing the concentration of the eluted solution are the same as in Example 2.
[0147] Comparative Example 2
[0148] This comparative example uses the drug elution apparatus of Example 1.
[0149] Drug-eluting corneal lenses:
[0150] The listatin drug-eluting corneal lens used in this comparative example was prepared in-house using the same method as in Example 2.
[0151] The only difference between this comparative example and Example 2 is that the drug-loaded corneal lenses containing listatin have the same conditions as those in Example 2, except that the drug loading per lens is 0.3 mg.
[0152] In this comparative example, the eluent is an aqueous solution of sodium chloride with a concentration of 0.9% (w / v). The eluent is introduced into the drug elution device through the inlet channel at a flow rate of 1 mL / min, and the drug-loaded corneal lens is eluted at 60°C. The other conditions are the same as in Example 2.
[0153] The conditions for testing the concentration of the eluted solution are the same as in Example 2.
[0154] Comparative Example 3
[0155] This comparative example uses vials.
[0156] Drug-eluting corneal lenses:
[0157] The listatin drug-eluting corneal lens used in this comparative example was prepared in-house using the same method as in Example 2.
[0158] The only difference between this comparative example and Example 2 is that the drug-loaded corneal lenses containing listatin have the same conditions as those in Example 2, except that the drug loading per lens is 0.3 mg.
[0159] In this comparative example, the drug elution method used 50 mL of artificial tears as the eluent and the elution temperature was 34°C. The specific steps are as follows:
[0160] The drug-eluting corneal lens was placed in a vial containing 50 mL of artificial tears, sealed with a rubber stopper, and placed in a constant-temperature air bath shaker at 34°C and 200 rpm. 2 mL samples were taken at 30 min, 60 min, 120 min, 240 min, and 480 min, and the volume was replenished with an equal amount of artificial tears. The resulting solutions were filtered through a 0.2 μm polyethersulfone membrane and used as the test solution. The drug release from the test solution was calculated using high-performance liquid chromatography (HPLC) according to the external standard method to obtain the drug release curve. The chromatographic conditions were the same as in Example 2.
[0161] Example 1
[0162] 1. Determine the in vivo release curve of drug-eluting corneal lenses in rabbits.
[0163] Specific testing methods:
[0164] 12-14 rabbits were randomly selected (ensuring that 4 rabbits' eyes were sampled at each specified time point). The drug-eluting corneal lenses of each embodiment and comparative example were worn on the rabbits' eyes for a specified time (the specified time points correspond to the sampling time points of different embodiments; for example, for Embodiment 2, the specified time points are 0.5h, 1h, 2h, 3h, 4h, 6h, and 8h; for Embodiment 3, the specified time points are 1h, 2h, 3h, 4h, 6h, and 8h). At each time point, 4 drug-eluting corneal lenses were obtained. After removing and drying the lenses, the residual drug in the lenses was extracted using a solvent (60mL artificial tears, extracted three times, 20mL each time; the artificial tears are the same as in Embodiment 2) as the test solution. After the above test, four sets of test solutions were obtained at each time point.
[0165] The preparation method of the control solution was the same as in Example 2; and the drug release of the test solution was calculated by liquid chromatography using the external standard method. The chromatographic conditions were: octadecylsilane-bonded silica gel as the stationary phase; 0.05% trifluoroacetic acid-acetonitrile (60:40) as the mobile phase; flow rate 1.0 mL / min; detection wavelength 254 nm; column temperature 40 °C; injection volume 30 μL. The in vivo release curve of the drug-loaded corneal lens in rabbits was obtained based on the above tests.
[0166] The calculation formula for the external standard method is as follows:
[0167]
[0168]
[0169]
[0170] In the formula:
[0171] C i - The concentration of the test solution at different sampling times;
[0172] A x - Peak area of the test sample solution;
[0173] A s - The average peak area of the control solution;
[0174] W s - The purity of the drug when the control solution was prepared;
[0175] m s - The weight of the drug when preparing the control solution;
[0176] V s - Volume of the control solution;
[0177] V i - The volume of the extraction solvent is 60 mL;
[0178] Q i ''- Cumulative release in rabbits (%)
[0179] m i - The amount of drug remaining in the drug-eluting corneal lens (μg);
[0180] L c - This is the labeled amount (mg / piece), which represents the amount of drug loaded per drug-eluting corneal lens in each example.
[0181] Based on the above calculations, four cumulative release amounts in rabbits will be obtained at each time point. The average of these four cumulative release amounts in rabbits will be calculated as the cumulative release amount in rabbits at each time point. The curve of the average cumulative release amount in rabbits versus time will be plotted, which is the in vivo release curve of the drug-loaded corneal lens in rabbits.
[0182] 2. Determine the drug concentration curve and tear absorption fraction curve of rabbits with drug-eluting corneal lenses.
[0183] Specific testing methods:
[0184] Three rabbits were randomly selected, and the drug-eluting corneal lenses of each embodiment or comparative example were worn on the rabbits' eyes for a specified time (the specified time points correspond to the sampling time points of different embodiments; for example, for embodiment 2, the specified time points are 0.5h, 1h, 2h, 3h, 4h, 6h, and 8h; for embodiment 3, the specified time points are 1h, 2h, 3h, 4h, 6h, and 8h). Tear samples were collected using Whatman filter paper strips, and the drug concentration in the tear samples was determined by LC-MS / MS.
[0185] The method for processing tear samples is as follows:
[0186] The tear sample was dried at room temperature, and 10 μL of internal standard working solution (500 μg / mL resmetiro methanol solution) was added and dried again. Then 1 mL of 50% methanol was added, vortexed for 10 min, centrifuged at 10000 rpm for 10 min, filtered, and injected into the chromatogram for testing.
[0187] The LC-MS / MS chromatographic conditions were as follows:
[0188] Chromatographic column: Agilent ZORBAX SB-C8 column, 4.6×50mm, 3.5μm;
[0189] Mobile phase: A: 0.5% formic acid-water; B: 0.5% formic acid-methanol; A:B = 40:60;
[0190] Flow rate: 0.2 ml / min.
[0191] After the above tests and calculations, the drug concentration of rabbit tears in each eye at various time points was obtained, and the curves of rabbit tear drug concentration versus time at various time points were plotted, thereby calculating the tear absorption fraction of each eye at each time point.
[0192] Rabbit tear absorption fraction Q t Calculation of (%):
[0193]
[0194] In the formula:
[0195] AUC 0→t - The area under the drug concentration curve in rabbit tears from 0 to the specified time t (mg / g∙h).
[0196] AUC 0→∞ - The area under the drug concentration curve in rabbit tears from time 0 to infinity (mg / g∙h).
[0197] Q t(%) - Rabbit tear absorption fraction.
[0198] At each time point, six rabbit tear drug concentrations were obtained. The average of these six rabbit tear drug concentrations was calculated as the rabbit tear drug concentration at each time point, and a curve of the average rabbit tear drug concentration versus time was plotted, which is the rabbit tear drug concentration curve.
[0199] After the above tests and calculations, six rabbit tear absorption fractions were obtained at each time point. The average of these six rabbit tear absorption fractions was calculated as the rabbit tear absorption fraction at each time point. A curve of the average rabbit tear absorption fraction versus time can be plotted, which is the rabbit tear absorption fraction curve.
[0200] 3. Linear correlation r test: The drug release curves obtained from each example and comparative example, the in vivo release curve of the drug-loaded corneal lens in rabbits obtained from the above test, and the tear absorption fraction curve of rabbits were subjected to correlation analysis. The specific calculation method was linear regression using the least squares method.
[0201] Linear regression using least squares:
[0202] Linear regression was performed using the least squares method based on the obtained drug release curve, in vivo release curve in rabbits, and tear absorption fraction curve in rabbits.
[0203] (1) In vitro-in vivo linear correlation r1: The drug release amount in the drug release curve and the rabbit in vivo release amount in the rabbit in vivo release curve at the same time point were obtained. The drug release amount in the drug release curve was used as the x-axis and the rabbit in vivo release amount in the rabbit in vivo release curve was used as the y-axis to perform linear regression and obtain the linear regression equation and R. 2 The R 2 This is the in vitro-in vivo linear correlation r1.
[0204] Based on the linear regression equation described above, the drug release amount from the drug release curves at different time points is substituted into x in the equation to calculate the predicted value y. A curve of y versus time is then plotted to obtain the in vivo predicted value. This in vivo predicted value is then compared with the measured in vivo release value in rabbits to obtain a comparison graph of the in vivo predicted value and the measured in vivo release value in rabbits.
[0205] (2) In vitro-in vivo linear correlation r2: The drug release amount in the drug release curve and the rabbit tear absorption fraction in the rabbit tear absorption fraction curve were obtained at the same time point. The drug release amount in the drug release curve was used as the x-axis and the rabbit tear absorption fraction in the rabbit tear absorption fraction curve was used as the y-axis. Linear regression was performed to obtain the linear regression equation and R. 2 The R 2This is the in vitro-in vivo linear correlation r2.
[0206] Based on the linear regression equation described above, the drug release amount from the drug release curves at different time points was substituted into x in the equation to calculate the predicted value y. A curve of y versus time was then plotted to obtain the in vivo predicted value. This in vivo predicted value was then compared with the measured value of the tear absorption fraction in rabbits, resulting in a comparison graph between the in vivo predicted value and the measured value of the tear absorption fraction in rabbits.
[0207] 4. Similarity factor f2 test:
[0208] Based on the drug release curves of the two embodiments, a similarity factor f2 between the two embodiments was obtained. Taking the calculation of the similarity factor between Embodiment 6 and Embodiment 3 as an example, the drug release amount R at different time points was obtained based on the drug release curve of Embodiment 6. t When t is 1, it is the first sampling time point (1 hour). When t is 1, R t This refers to the cumulative drug release over the period of 0-1 hour. When t = 2, it represents the second sampling time point (2 hours). The R value at t = 2 is... t This refers to the cumulative drug release over the 0-2 hour time period, and so on, where n is the number of sampling time points. The drug release amount T at different time points was obtained based on the drug release curve from Example 3. t When t is 1, it is the first sampling time point (1 hour). When t is 1, T t This refers to the cumulative drug release over the period of 0-1 hour. When t = 2, it represents the second sampling time point (2 hours). The time T when t = 2 is... t This refers to the cumulative drug release over a period of 0-2 hours, and so on, where n is the number of sampling time points.
[0209] The specific calculation formula is as follows:
[0210]
[0211] The similarity factor f2 is calculated using the formula above.
[0212] The test results are as follows:
[0213] The drug release curve of Example 2 is as follows: Figure 2 As shown, the in vivo release curve of the drug-loaded corneal lens in rabbits in Example 2 is as follows. Figure 3 As shown, the drug concentration curve of the drug-loaded corneal lens in rabbit tears in Example 2 is as follows. Figure 4 As shown, the absorption fraction curve of rabbit tears in Example 2 is as follows. Figure 5 As shown in the figure, the comparison between the in vivo predicted value and the measured in vivo release value in rabbits in Example 2 is as follows. Figure 6 As shown in the figure, the comparison between the predicted in vivo value and the measured value of the rabbit tear absorption fraction in Example 2 is as follows. Figure 7 As shown.
[0214] The comparison graph of the in vivo predicted value and the measured in vivo release value in rabbits in Example 3 is shown below. Figure 8 As shown in the figure, the comparison between the predicted in vivo value and the measured value of the tear absorption fraction in rabbits in Example 3 is as follows. Figure 9 As shown.
[0215] The comparison graph of the in vivo predicted value and the measured in vivo release value in rabbits in Example 4 is shown below. Figure 10 As shown in the figure, the comparison between the predicted in vivo value and the measured value of the tear absorption fraction in rabbits in Example 4 is as follows. Figure 11 As shown.
[0216] The comparison graph of the in vivo predicted value and the measured in vivo release value in rabbits in Example 5 is shown below. Figure 12 As shown in the figure, the comparison between the predicted in vivo value and the measured value of the tear absorption fraction in rabbits in Example 5 is as follows. Figure 13 As shown.
[0217] according to Figures 6-13 As can be seen from the comparison chart, the in vivo predicted values and the measured in vivo release values of rabbits in Examples 2-5 are highly similar, as are the in vivo predicted values and the measured values of tear absorption fraction in rabbits. This indicates that when the drug elution device of this invention is used in a drug elution method, it can accurately simulate the in vivo release kinetics and in vivo release kinetics of drugs.
[0218] The linear correlation and similarity factor data obtained from the above tests are listed in Table 1:
[0219] Table 1
[0220]
[0221] The results show that the drug release curves obtained using the drug elution device and method of this invention have a high correlation with the in vivo release curves and tear absorption fraction curves in rabbits, both not lower than 0.97. Furthermore, the in vivo and in vivo predicted values obtained from the drug release curves show high similarity to the measured values. This indicates that the drug elution device and method of this invention can predict the in vivo and in vivo release of drug-loaded corneal lenses with high accuracy, and can be effectively used to study the release of drugs in drug-loaded corneal contact lenses.
[0222] Meanwhile, the similarity factors among the embodiments of this utility model are high, all exceeding 50, indicating that the drug elution device and drug elution method of this utility model have good durability.
Claims
1. A drug elution device, characterized in that, It includes a base and a cover; The base includes a first fixing body and a groove disposed inside the first fixing body; The cover includes a second fixed body, a protrusion, a liquid inlet channel, and a liquid outlet channel; the liquid inlet channel and the liquid outlet channel are arranged parallel to each other in the second fixed body and are adjacent to both sides of the protrusion, respectively; the liquid inlet channel is used to introduce the eluent, and the liquid outlet channel is used to discharge the eluted liquid; The first fixing body and the second fixing body are detachably connected; when the first fixing body and the second fixing body are connected, the groove can accommodate the protrusion, and there is an arc-shaped space between the groove and the protrusion, the arc-shaped space is used to accommodate the drug-eluting corneal lens; the difference between the radius of curvature of the groove and the radius of curvature of the protrusion is the same as the depth of the arc-shaped space; the width of the protrusion is smaller than the width of the groove; The inlet channel, the arc-shaped space, and the outlet channel are connected in sequence to form the flow path of the eluent.
2. The drug eluting device of claim 1, wherein, The drug elution device satisfies one or more of the following conditions: (a) The ratio of the radius of curvature of the groove to the radius of curvature of the protrusion is (1-1.5):1; (b) The ratio of the width of the protrusion to the width of the groove is (0.5-1):
1.
3. The drug eluting device of claim 2, wherein, The drug elution device satisfies one or more of the following conditions: (a) The ratio of the radius of curvature of the groove to the radius of curvature of the protrusion is (1.04-1.25):1; (b) The ratio of the width of the protrusion to the width of the groove is (0.7-0.9):
1.
4. The drug eluting device of claim 1, wherein, The drug elution device satisfies one or more of the following conditions: (a) The difference between the width of the protrusion and the width of the groove is 2-4 mm; (b) The diameter ratio of the inlet channel to the outlet channel is 1:(1-3); (c) The vertical projection surface of the protrusion is circular, and the vertical projection surface of the groove is circular.
5. The drug eluting device of claim 4, wherein, The drug elution device satisfies one or more of the following conditions: (a) The difference between the width of the protrusion and the width of the groove is 3 mm; (b) The diameter ratio of the inlet channel to the outlet channel is 1:
1.
6. The drug eluting device of claim 1, wherein, The drug elution device satisfies one or more of the following conditions: (a) The depth of the arc-shaped space is 0.5-2 mm; (b) The width of the protrusion is 11-15 mm; (c) The width of the groove is 13-19 mm.
7. The drug eluting device of claim 6, wherein, The drug elution device satisfies one or more of the following conditions: (a) The depth of the arc-shaped space is 0.5-1.5 mm; (b) The width of the protrusion is 12-14 mm; (c) The width of the groove is 14-18 mm.
8. The drug eluting device of claim 7, wherein, The drug elution device satisfies one or more of the following conditions: (a) The depth of the arc-shaped space is 0.8 mm; (b) The width of the protrusion is 13.7 mm; (c) The width of the groove is 16.7 mm.
9. The drug elution apparatus as described in claim 1, characterized in that, The drug elution device satisfies one or more of the following conditions: (a) The radius of curvature of the groove is 9-14 mm; (b) The radius of curvature of the protrusion is 8-12 mm; (f) The diameter of the liquid inlet channel is 0.5-1.5 mm; (g) The diameter of the liquid outlet channel is 0.5-1.5 mm.
10. The drug elution apparatus as described in claim 9, characterized in that, The drug elution device satisfies one or more of the following conditions: (a) The radius of curvature of the groove is 10-13 mm; (b) The radius of curvature of the protrusion is 9-11 mm.