Sandwich effervescent tablet for cleaning contact lenses and preparation method thereof

Abstract

The invention belongs to the field of contact lens care, and particularly relates to a sandwich effervescent tablet for cleaning contact lenses and a preparation method of the sandwich effervescent tablet. The outer layer is prepared from the following raw materials: citric acid, sodium bicarbonate, disodium ethylene diamine tetraacetate, a surfactant, polyvinylpyrrolidone, microcrystalline cellulose and colloidal silicon dioxide; the middle layer is prepared from the following raw materials in parts by weight: sodium percarbonate, tetraacetylethylenediamine, phosphate buffer salt, a surfactant, anhydrous sodium carbonate, microcrystalline cellulose and colloidal silicon dioxide; the inner core is prepared from the following raw materials in parts by weight: catalase, a stabilizer, hydroxy propyl cellulose K4M, ethyl cellulose, microcrystalline cellulose and sodium bicarbonate. According to the invention, citric acid / bicarbonate is matched with an active agent to weaken a biological membrane in the outer layer, and a permeation channel is opened preferentially; the H2O2 platform is formed by matching middle-layer sodium percarbonate; and the inner core adopts HPMC / EC controlled-release catalase to realize hysteresis-burst release neutralization.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of contact lens care, and particularly relates to a sandwich effervescent tablet for cleaning contact lenses and a preparation method thereof. BACKGROUND

[0002] Contact lenses are in direct contact with the cornea and tear film for a long time, and the lens surface is easy to adsorb proteins, mucin and lipids and form a biofilm, resulting in blurred vision, dryness and foreign body sensation, and increased risk of infection. Soft materials represented by silicone hydrogel have high oxygen permeability, but are inherently hydrophobic and have poor wettability, and are more prone to deposition and interface instability, thus requiring higher requirements for cleaning, disinfection and end-point compatibility.

[0003] Existing care solutions mainly include multifunctional care solutions containing preservatives and disinfection systems represented by hydrogen peroxide. The former relies on bacteriostatic ingredients such as PHMB and quaternary ammonium salt, and sensitive people are prone to irritation; and the cleaning-rinsing-storage steps in the single bottle process are greatly affected by user operation. The latter has strong disinfection, but needs to use catalyst discs / neutralization caps to complete the decomposition of hydrogen peroxide. If neutralization is too early or not enough, it will cause insufficient Ct (concentration-time integral) or residual irritation; at the same time, there is a compatibility and stability contradiction between oxidizing agents and functional components such as proteases in the same system, and it is difficult to balance deep decontamination and high-efficiency disinfection. The effervescent or enzyme tablets on the market are mostly single-function, lacking gradient control of bubble breaking, oxidative disinfection and safe neutralization reset, and the end-point pH and osmotic pressure are often difficult to stabilize and return to the physiological friendly interval. At the manufacturing level, although complex processes such as film coating and fluidized bed can partially achieve separation, the equipment and cost pressure are large, and the oxidizing agents / enzymes sensitive to moisture and heat are prone to inactivation during storage and transportation. In summary, it is extremely necessary to develop a sequential care cleaning technology that realizes rapid bubble breaking and wetting in the early stage, stable oxidative disinfection in the middle stage, and rapid neutralization and return to physiological pH / osmotic pressure in the final stage under the premise of simplifying the process, in order to improve the removal efficiency of biofilm and deposition, increase disinfection efficiency, and reduce end-point irritation, while ensuring long-term compatibility with lens materials such as silicone hydrogel and use safety. SUMMARY

[0004] In view of the defects of the prior art, the purpose of the present application is to provide a sandwich effervescent tablet for cleaning contact lenses and a preparation method thereof. In order to solve the problems of irritation of existing care solution preservatives, complexity of hydrogen peroxide system process, and premature neutralization, and simple enzyme washing does not equal to disinfection, the present application proposes a layered sandwich effervescent tablet. The outer layer uses citric acid / bicarbonate to instantaneously foam, cooperates with EDTA and mild non-ionic / two-surfactants to weaken the metal bridge of biological membrane, reduce the interfacial tension, and preferentially open the penetration channel. The middle layer uses sodium percarbonate to form a moderate intensity H2O2 platform in a small volume lens box, and takes into account sterilization and material compatibility. The inner core uses HPMC / EC controlled release of catalase to realize lagging-burst neutralization, fully retains the disinfection efficacy in the front section, and quickly reduces H2O2 to near zero at the end and swings the pH back to neutral or weakly alkaline.

[0005] The technical effect of the present application is realized by the following technical scheme: a sandwich effervescent tablet for cleaning contact lenses, which is composed of 42-46% outer layer, 45-48% middle layer and 8-10% inner core; Preferably, the outer layer is composed of the following components by weight parts: 25-30 parts of citric acid, 40-48 parts of sodium bicarbonate, 1-1.6 parts of ethylenediaminetetraacetic acid disodium, 2-3 parts of surfactant, 3-5 parts of polyvinylpyrrolidone, 18-24 parts of microcrystalline cellulose and 0.2-0.4 parts of colloidal silicon dioxide; Preferably, in the outer layer, the surfactant is any one of poloxamer, cocamidopropyl betaine, lauryl betaine and sodium cocoyl glutamate; Preferably, the middle layer is composed of the following components by weight parts: 82-87 parts of sodium percarbonate, 1-4 parts of tetraacetyl ethylenediamine, 2-3 parts of phosphate buffered salt, 2-3 parts of surfactant, 2-3 parts of anhydrous sodium carbonate, 5-8 parts of microcrystalline cellulose and 0.2-0.4 parts of colloidal silicon dioxide; Preferably, in the middle layer, the surfactant is any one of poloxamer, tetra butyl phenol, lauryl glucoside and decyl glucoside; Preferably, the inner core is composed of the following components by weight parts: 7-12 parts of catalase, 30-45 parts of stabilizer, 30-40 parts of hydroxypropyl cellulose K4M, 2-5 parts of ethyl cellulose, 10-18 parts of microcrystalline cellulose and 3-6 parts of sodium bicarbonate.

[0006] Preferably, in the inner core, the stabilizer is any one or several of mannitol, trehalose and sodium alginate; further preferably, mannitol and trehalose are prepared in a 1:1 ratio; Another aspect of the present application is to provide a preparation method of a sandwich effervescent tablet for cleaning contact lenses, which specifically comprises the following steps: S1: citric acid, 75% by weight of microcrystalline cellulose, polyvinylpyrrolidone, surfactant, ethylenediaminetetraacetic acid disodium and colloidal silicon dioxide are mixed in a high-speed mixer at 200-300 rpm for 2-4 min; another 200-300 rpm is used to pre-mix sodium bicarbonate and the remaining microcrystalline cellulose for 2-4 min; then the two mixed powders are combined and mixed at 250-300 rpm for 60-90 s to obtain the outer layer of the pre-mixed powder; S2: sodium percarbonate, tetraacetyl ethylenediamine, anhydrous sodium carbonate and colloidal silicon dioxide are mixed at 150-200 rpm for 2 min; then the surfactant, phosphate buffer salt and microcrystalline cellulose are added and mixed for another 2-3 min, and the temperature is controlled at 25°C throughout the process to obtain the middle layer of the pre-mixed powder; S3: catalase, mannitol, trehalose, microcrystalline cellulose, hydroxypropyl cellulose K4M, ethyl cellulose, sodium bicarbonate are mixed at 150 rpm for 2 min; a small die is used to dry-press the micro-chip on the tablet press to obtain the inner core chip; S4: the inner core chip of step S3 is placed in the die cavity of the tablet press; the middle layer of the pre-mixed powder of step S2 is added and lightly pressed once to form a middle layer blank; the outer layer of the pre-mixed powder of step S1 is added and main-pressed to form a tablet; the formed tablet is dried at a low temperature of 30-35°C until the weight loss is less than 0.5%, and then placed in a drying room for 12-24 h to balance, to obtain a sandwich effervescent tablet; Preferably, in step S3, the tablet press micro-chip parameters are: main pressure 120-200 MPa, turret speed 15-25 rpm, main pressure dwell time 80-120 ms; Preferably, in step S4, the light pressure parameters are: pressure 25-50 MPa, turret speed 15-25 rpm, dwell time 40-60 ms; Preferably, in step S4, the main pressure parameters are: pressure 120-180 MPa, turret speed 15-25 rpm, dwell time 60-100 ms.

[0007] The beneficial effects of the present application are as follows: The outer layer of the sandwich effervescent tablet of the present application is instantaneously foamed by citric acid / sodium bicarbonate, and is matched with the simultaneous release of nonionic / amphoteric surfactant and ethylenediaminetetraacetic acid disodium (EDTA-2Na), and the micro-bubbles convectively thin the lens surface diffusion boundary layer, reduce the interfacial tension and chelate Ca 2+ / Mg 2+Bridge, protein / lipid deposition and biological membrane pre-destabilization, penetration channel is opened; followed by solid sodium percarbonate in the small volume mirror box to form a stable medium intensity H2O2 platform, with the help of the interface modification and biological membrane destabilization effect, oxidant is more easily contact and destroy the bacterial / fungal cell outer polymer and cell membrane structure, to achieve the efficient killing of common pathogenic bacteria and yeast-like fungi; At the same time, trace anhydrous sodium carbonate and phosphate buffer in the middle layer will maintain the system in a range friendly to the silica hydrogel material, not only to inhibit the decomposition of sodium percarbonate (SPC) due to moisture, but also to avoid the adverse effects of early pH fluctuations on the surface treatment layer of the lens; Finally, the inner core is constructed by hydroxypropyl cellulose K4M / a small amount of ethyl cellulose to build a low swelling diffusion barrier to achieve the release of catalase in a lag - burst mode, and the effective disinfection stage is not weakened by continuous neutralization, and once the release is triggered, the residual H2O2 is quickly decomposed into water and oxygen, and a small amount of carbonate is used to return the end point pH to neutral or weakly alkaline, and the osmotic pressure returns to isotonic, which significantly reduces the risk of irritation and improves the compatibility and initial wetness of the silica hydrogel material (polyvinylpyrrolidone / hydroxypropyl cellulose terminal adsorption further improves the wetting angle). On the process, complex film coating and fluidized bed coating are not used, but a simplified route of grouping formula - low humidity granulation - layering tabletting is adopted, and the water content and particle size of the outer layer, middle layer and inner core are optimized respectively to avoid the early contact of acid / base / oxidant and enzyme, and the disinfection platform time - neutralization starting point - end point pH three curves are solidified into the tablet structure, and the stable time window and end point safety boundary are reproduced without film / catalyst cap. BRIEF DESCRIPTION OF DRAWINGS

[0008] Figure 1 The biocompatibility test results chart of the sandwich effervescent tablets prepared for the examples 1-3 and comparative examples 1-3 of the present application; Figure 2 The staphylococcus aureus sterilization test results chart of the sandwich effervescent tablets prepared for the examples 1-3 and comparative examples 1-3 of the present application; Figure 3 The pseudomonas aeruginosa sterilization test results chart of the sandwich effervescent tablets prepared for the examples 1-3 and comparative examples 1-3 of the present application; Figure 4 The candida albicans sterilization test results chart of the sandwich effervescent tablets prepared for the examples 1-3 and comparative examples 1-3 of the present application; Figure 5 The H2O2 content results chart of the sandwich effervescent tablets prepared for the examples 1-3 and comparative examples 1-3 of the present application; Figure 6 The pH change results chart of the sandwich effervescent tablets prepared for the examples 1-3 and comparative examples 1-3 of the present application. DETAILED DESCRIPTION

[0009] The technical solutions of the present application will be clearly and completely described below in combination with the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments; without special description, the raw materials involved in the present application are purchased through conventional commercial channels; the experimental methods without specific conditions are conventional methods and conventional conditions familiar to the field, or according to the conditions recommended by the instrument manufacturer.

[0010] Example 1: a sandwich effervescent tablet for cleaning contact lenses, which is composed of 45% outer layer, 47% middle layer and 8% inner core; The raw materials for composing the outer layer include the following components by weight parts: 28 parts of citric acid, 44 parts of sodium bicarbonate, 1.4 parts of disodium ethylenediaminetetraacetate, 2.5 parts of surfactant, 4 parts of polyvinylpyrrolidone, 21 parts of microcrystalline cellulose and 0.3 parts of colloidal silicon dioxide; The raw materials for composing the middle layer include the following components by weight parts: 85 parts of sodium percarbonate, 2.5 parts of tetraacetyl ethylenediamine, 2.5 parts of phosphate buffered salt, 2.5 parts of surfactant, 2.5 parts of anhydrous sodium carbonate, 7 parts of microcrystalline cellulose and 0.3 parts of colloidal silicon dioxide; The raw materials for composing the inner core include the following components by weight parts: 9 parts of catalase, 40 parts of stabilizer, 35 parts of hydroxypropyl cellulose K4M, 3 parts of ethyl cellulose, 13 parts of microcrystalline cellulose and 4 parts of sodium bicarbonate.

[0011] The preparation of the sandwich effervescent tablet for cleaning contact lenses includes the following steps: S1: citric acid, 75% by weight of microcrystalline cellulose, polyvinylpyrrolidone, poloxamer, disodium ethylenediaminetetraacetate and colloidal silicon dioxide are mixed in a high-speed mixer at 250 rpm for 3 min; sodium bicarbonate and the remaining amount of microcrystalline cellulose are premixed at 250 rpm for 3 min; then the two mixed powders are combined and short-mixed at 280 rpm for 75 s to obtain the outer layer premixed powder; S2: sodium percarbonate is mixed with tetraacetyl ethylenediamine, anhydrous sodium carbonate, colloidal silicon dioxide at 180 rpm for 2 min; poloxamer, phosphate buffered salt and microcrystalline cellulose are added and mixed for another 2.5 min, with the whole process controlled at a material temperature of 25℃ to obtain the middle layer premixed powder; S3: the stabilizer prepared by mixing catalase, mannitol and trehalose in a ratio of 1:1, microcrystalline cellulose, hydroxypropyl cellulose K4M, ethyl cellulose, sodium bicarbonate are mixed at 150 rpm for 2 min; a small die is used to dry-press into a microchip on a tablet press, with the parameters being main pressure 160 MPa, turntable speed 20 rpm, main pressure residence time 100 ms; the inner core chip is obtained; S4: put the core tablet of step S3 into the die of the tablet press; add the middle layer premix powder of step S2 and lightly press once to form a middle layer blank with a small pressure, parameters are, pressure 40 MPa, rotation speed of the turntable 20 rpm, and residence time 50 ms; add the outer layer premix powder of step S1 and main-press to form a tablet, parameters are, pressure 150 MPa, rotation speed of the turntable 20 rpm, and residence time 80 ms; the formed tablet is dried at a low temperature of 32°C until the weight loss is less than 0.5%, and then is put into a drying room for 18 hours of balancing, to obtain the sandwich effervescent tablet.

[0012] Example 2: a sandwich effervescent tablet for cleaning contact lenses, which is composed of 42% outer layer, 48% middle layer and 10% core; The outer layer is composed of the following components by weight parts: 25 parts of citric acid, 40 parts of sodium bicarbonate, 1 part of disodium ethylenediaminetetraacetate, 2 parts of surfactant, 3 parts of polyvinylpyrrolidone, 18 parts of microcrystalline cellulose and 0.2 parts of colloidal silicon dioxide; The middle layer is composed of the following components by weight parts: 82 parts of sodium percarbonate, 1 part of tetraacetyl ethylenediamine, 2 parts of phosphate buffer salt, 2 parts of surfactant, 2 parts of anhydrous sodium carbonate, 5 parts of microcrystalline cellulose and 0.2 parts of colloidal silicon dioxide; The core is composed of the following components by weight parts: 7 parts of catalase, 30 parts of stabilizer, 30 parts of hydroxypropyl cellulose K4M, 2 parts of ethyl cellulose, 10 parts of microcrystalline cellulose and 3 parts of sodium bicarbonate.

[0013] The preparation of the sandwich effervescent tablet for cleaning contact lenses comprises the following steps: S1: mix citric acid, 75% by weight of microcrystalline cellulose, polyvinylpyrrolidone, cocamidopropyl betaine, disodium ethylenediaminetetraacetate and colloidal silicon dioxide in a high-speed mixer at 300 rpm for 2 min; separately mix sodium bicarbonate and the remaining amount of microcrystalline cellulose at 300 rpm for 2 min; then combine the two mixed powders and short-mix at 300 rpm for 60 s to obtain an outer layer premix powder; S2: mix sodium percarbonate with tetraacetyl ethylenediamine, anhydrous sodium carbonate, colloidal silicon dioxide at 150 rpm for 2 min; add butylated hydroxytoluene, phosphate buffer salt and microcrystalline cellulose, and mix for another 2 min, with the whole process being controlled at a material temperature of 25°C, to obtain a middle layer premix powder; S3: mix catalase, mannitol, microcrystalline cellulose, hydroxypropyl cellulose K4M, ethyl cellulose and sodium bicarbonate at 150 rpm for 2 min; use a small punch to dry-press into a micro tablet on a tablet press, parameters are, main pressure 120 MPa, rotation speed of the turntable 15 rpm, and main pressure residence time 80 ms; to obtain a core tablet; S4: Put the core tablet of step S3 into the die of the tablet press; add the middle layer premix powder of step S2 and lightly press once to form a middle layer blank with a small pressure, parameters are, pressure 25 MPa, rotation speed of the turntable 15 rpm, and residence time 40 ms; add the outer layer premix powder of step S1 and main press to form a tablet, parameters are, pressure 120 MPa, rotation speed of the turntable 15 rpm, and residence time 60 ms; dry the formed tablet at a low temperature of 30°C until the weight loss is less than 0.5%, then put it into a drying room for 12 hours to balance, and obtain the sandwich effervescent tablet.

[0014] Example 3: A sandwich effervescent tablet for cleaning contact lenses, which is composed of 46% outer layer, 45% middle layer and 9% core; The outer layer is composed of the following components by weight parts: 30 parts of citric acid, 48 parts of sodium bicarbonate, 1.6 parts of disodium ethylenediaminetetraacetate, 3 parts of surfactant, 5 parts of polyvinylpyrrolidone, 24 parts of microcrystalline cellulose and 0.4 parts of colloidal silicon dioxide; The middle layer is composed of the following components by weight parts: 87 parts of sodium percarbonate, 4 parts of tetraacetyl ethylenediamine, 3 parts of phosphate buffered salt, 3 parts of surfactant, 3 parts of anhydrous sodium carbonate, 8 parts of microcrystalline cellulose and 0.4 parts of colloidal silicon dioxide; The core is composed of the following components by weight parts: 12 parts of catalase, 45 parts of stabilizer, 40 parts of hydroxypropyl cellulose K4M, 5 parts of ethyl cellulose, 18 parts of microcrystalline cellulose and 6 parts of sodium bicarbonate.

[0015] The preparation of the sandwich effervescent tablet for cleaning contact lenses comprises the following steps: S1: Mix citric acid, 75% by weight of microcrystalline cellulose, polyvinylpyrrolidone, lauryl betaine, disodium ethylenediaminetetraacetate and colloidal silicon dioxide in a high-speed mixer at 200 rpm for 4 min; separately mix sodium bicarbonate with the remaining amount of microcrystalline cellulose at 200 rpm for 4 min; then combine the two mixed powders and short mix at 250 rpm for 90 s to obtain an outer layer premix powder; S2: Mix sodium percarbonate with tetraacetyl ethylenediamine, anhydrous sodium carbonate, colloidal silicon dioxide at 200 rpm for 2 min; add lauryl glucoside, phosphate buffered salt and microcrystalline cellulose, and mix for another 3 min, with the whole process controlled at a material temperature of 25°C, to obtain a middle layer premix powder; S3: Mix catalase, trehalose, microcrystalline cellulose, hydroxypropyl cellulose K4M, ethyl cellulose and sodium bicarbonate at 150 rpm for 2 min; use a small die to dry-press into a micro tablet on a tablet press, parameters are, main pressure 200 MPa, rotation speed of the turntable 25 rpm, and main pressure residence time 120 ms; obtain a core tablet; S4: Put the core tablet of step S3 into the die cavity of the tablet press; add the middle layer premix powder of step S2 and lightly press once to form a middle layer blank with a small pressure, parameters are: pressure 50 MPa, rotation speed of the turntable 25 rpm, and residence time 60 ms; add the outer layer premix powder of step S1 and main-press to form a tablet, parameters are: pressure 180 MPa, rotation speed of the turntable 25 rpm, and residence time 100 ms; dry the formed tablet at a low temperature of 35°C until the weight loss is less than 0.5%, and then put it into a drying room for 24 h of balancing, to obtain the center-encased effervescent tablet.

[0016] Comparative Example 1: The operation process of Comparative Example 1 is basically the same as that of Example 1, the main difference is that in step S202 of Comparative Example 1, the addition of EDTA-2Na is cancelled, and an equal amount of microcrystalline cellulose is used to replace it to keep the tablet weight consistent; the rest of the operation process parameters remain the same.

[0017] Comparative Example 2: The operation process of Comparative Example 2 is basically the same as that of Example 1, the main difference is that in step S3 of Comparative Example 2, catalase is directly added into the middle layer premix powder of step S2 in an equal amount and mixed, and the core is cancelled; the rest of the operation process parameters remain the same.

[0018] Comparative Example 3: The operation process of Comparative Example 3 is basically the same as that of Example 1, the main difference is that in step S3 of Comparative Example 3, catalase is replaced by the chemical reducing agent Na2S2O3·5H2O; the rest of the operation process parameters remain the same.

[0019] Performance test: Biocompatibility test: Take one piece of the center-encased effervescent tablet prepared in Examples 1-3 and Comparative Examples 1-3, add it into 10 mL of isotonic base solution, run to the neutralization endpoint in 6 h, take the supernatant as the mother liquor, mix the mother liquor with complete culture medium (DMEM+10% fetal bovine serum+1% penicillin-streptomycin) to make the final equivalent extraction ratio 0.2 g / mL, continue to extract at 37°C with slight shaking for 24 h; sterilize the extract liquid with a 0.22 μm filter membrane for standby, select human corneal epithelial cells HCE-T for CCK-8 cell viability detection and fluorescent live / dead staining; the negative control is blank complete culture medium, the positive control is complete culture medium containing 10% DMSO, and a cell-free blank well is set for background subtraction, the cell survival rate (%) is calculated according to the following formula: survival rate (%)=(sample group OD-positive control OD) / (negative control OD-positive control OD)×100%, each batch of samples is tested three times independently, and the average value is taken as the result, and the test results are shown in Table 1. Figure 1

[0020] Based on the above Figure 1 ​Result analysis, the effervescent tablets prepared in the embodiments of the application have excellent biocompatibility, the hydrogen peroxide used in the application is rapidly decomposed into water and oxygen by catalase at the end point, no reducing byproducts with high ionic strength are produced, the surfactant dose in the formula is low and most of them are non-ionic, the membrane phase disturbance after entering the extracellular environment is extremely weak. Based on the result analysis of Example 1 and Comparative Example 1, after the removal of EDTA in Comparative Example 1, the influence on biocompatibility is weak; based on the result analysis of Example 1 and Comparative Example 2, the hydrogen peroxide enzyme is placed in the oxidation layer in advance in Comparative Example 2, which leads to neutralization at the beginning of the process, although this weakens the disinfection platform, but for the end point extraction liquid, it means that it is also close to neutral, low residue, low surfactant exposure; a small amount of free protein entering the culture system usually does not cause adverse effects on HCE-T, on the contrary, it can act as an inert protein to buffer the interface, therefore, its cell survival rate is comparable to that of the embodiment, showing good end point biocompatibility; based on the result analysis of Example 1 and Comparative Example 3, in Comparative Example 3, the enzyme catalysis is replaced by core chemical reduction (Na2S2O3·5H2O), the neutralization depends on stoichiometry and diffusion, it is easier to leave reducing ions such as thiosulfate / sulfite or their oxidation products in the end point solution, and introduce higher ionic strength and pH fluctuation, these factors cause the osmotic pressure deviation and the imbalance of the reduction-oxidation microenvironment of the extracellular environment, which causes mild inhibition to the mitochondrial metabolism and membrane integrity of epithelial cells, resulting in decreased survival rate and increased batch-to-batch variation.

[0021] Bactericidal efficiency test: one piece of the sandwich effervescent tablets of Examples 1-3 and Comparative Examples 1-3 was placed in 10 mL of isotonic base liquid, and the tablets were placed according to the instructions, and the bactericidal efficiency was evaluated at three contact time points of 30 min, 120 min and 360 min; the test strains were selected as Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans, and the pre-prepared bacterial suspension was 10 7 CFU / mL, a certain amount of bacterial liquid was added to each mirror box to make the initial load 10 6 CFU / mL; at the predetermined time point, 1 mL of reaction solution was immediately removed and added into an equal volume of high-activity peroxidase neutralization liquid for neutralization for 1 min, then ten-fold serial dilution was carried out and plated on TSA (bacteria) / SDA (fungi) plates, respectively, and cultured at 37°C (bacteria) / 30°C (fungi) for 48 h to count the number of bacteria; the bactericidal rate (%) = (bacterial CFU before inoculation-bacterial CFU after inoculation) / bacterial CFU before inoculation x 100%, the results are shown in Figure 2 、 Figure 3 and Figure 4 .

[0022] Based on Figure 2 、 Figure 3 and Figure 4Analysis, the prepared effervescent tablets of the embodiment of the application have excellent sterilization performance; based on the results of Example 1 and Comparative Example 1, it is found that in Comparative Example 1, EDTA is removed, and obvious lag occurs at 30-120 min, and it is basically caught up at 360 min, which may be due to the lack of chelation and membrane rupture, Ca 2+ / Mg 2+ The maintained EPS / LPS bridge is not effectively destabilized, the boundary layer on the lens surface is thicker and the deposition is more compact, resulting in a decrease in the effective contact area and penetration rate of the oxidant and the microorganism; with the passage of time, the total Ct accumulates and the end point approaches the embodiment; based on the results of Example 1 and Comparative Example 2, it is found that in Comparative Example 2, the enzyme is placed in the middle layer, and the starting point is neutralized, and the sterilization rate is significantly lower at 30-120 min, and it approaches the qualified level at 360 min, which may be due to the fact that the continuous competition compresses the platform period of hydrogen peroxide, so that the front Ct is greatly reduced; although the final solution approaches neutral earlier and the residual is low, the disinfection window is sacrificed, and the logarithmic reduction of Staphylococcus aureus / Candida albicans in the early and middle stages falls behind obviously; based on the results of Example 1 and Comparative Example 3, it is found that in Comparative Example 3, the core chemical Na2S2O3·5H2O is reduced, which is close to the embodiment at 30-120 min, but the sterilization rate of Pseudomonas aeruginosa in the middle and late stages is slightly lower, which may be due to the fact that the diffusion leakage and metering consumption of the chemical reducing agent gradually remove the hydrogen peroxide, causing the Ct in the latter half to be consumed unstably; at the same time, the slight drift of the reduction byproduct and pH / ionic strength weakens the activation of TAED and the oxidation efficiency, resulting in a slightly poor end point killing of gram-negative bacteria with higher resistance.

[0023] Neutralization test: take one piece of the sandwich effervescent tablets of Examples 1-3 and Comparative Examples 1-3 and place them in 10 mL of isotonic base solution, and run at 25°C; sample at 0, 10, 30, 60, 120, 180, 240, 300 and 360 min to evaluate the neutralization process; at each time point, 100 µL of reaction solution is diluted with sterile water according to the predetermined multiple (high concentration stage 1:500 for 0-60 min in the early stage, 1:100 for 60-240 min in the middle stage, and original solution for 240-360 min in the late stage), and the H2O2 concentration is determined by hydrogen peroxide colorimetry, and the pH is determined by calibrated pH meter; set blank base solution control and method validation holes (add high activity catalase after sampling to confirm that the measurement method is not disturbed by residual interference); define the time point corresponding to H2O2 residual ≤10 ppm as the T 90 neutralization time, and the pH returns to 7-7.4 at 6h as the end point safety criterion; the results are shown by H2O2-time curve and pH-time curve, and the results are shown in Figure 5 and Figure 6 .

[0024] Based on Figure 5 and Figure 6Result analysis, the effervescent tablets prepared in the embodiment of the present application show a release curve with obvious high platform-hysteresis-bursting zeroing, a stable H2O2 platform is maintained for 0-240 min, a rapid drop is observed after 300 min, and the pH returns to 7-7.3 at 6 h with small batch-to-batch fluctuation. Based on the result analysis of Comparative Example 1 and Example 1, after removing the outer layer EDTA in Comparative Example 1, the neutralization curve and pH return are generally overlapped, but the early bactericidal and deposition removal performance lags behind: the lack of chelation membrane rupture makes Ca 2+ / Mg 2+ The bridged biofilm and protein deposition are more difficult to loosen, CO2 disturbance and surface activity wetting are present, but the penetration channel is not fully opened, resulting in a decrease in effective Ct utilization rate under the same platform concentration, which shows low logarithmic killing, weak protein removal rate and light transmittance recovery for 30-120 min; based on the result analysis of Comparative Example 2 and Example 1, Comparative Example 2 places the catalase in the middle layer, resulting in continuous neutralization at the beginning, and the H2O2-time curve decreases to ≤10 ppm for 60-120 min, which can ensure the safety at the end point and the stability of pH, but significantly compresses the effective oxidation window, making the early Ct insufficient; this may be due to the fact that the enzyme and the peroxide are not spatially isolated, and the competitive kinetics continuously consumes H2O2; based on the result analysis of Comparative Example 3 and Example 1, Comparative Example 3 uses Na2S2O3·5H2O chemical reduction in the core instead of enzyme catalysis, and the neutralization and pH curves show obvious batch-to-batch drift: H2O2 decay is affected by particle size, water content and diffusion path, and individual samples are still >10 ppm at 6 h, and the pH shows a fluctuation of 6.6-7.6 in the middle and late stages due to the coupling effect of reduction by-products and buffer capacity.

[0025] Although embodiments of the present application have been shown and described, it is to be understood that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the present application, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A sandwich effervescent tablet for cleaning contact lenses, characterized in that, It consists of 42-46% outer layer, 45-48% middle layer and 8-10% kernel; The outer layer consists of the following components by weight: 25-30 parts citric acid, 40-48 parts sodium bicarbonate, 1-1.6 parts disodium ethylenediaminetetraacetate, 2-3 parts surfactant, 3-5 parts polyvinylpyrrolidone, 18-24 parts microcrystalline cellulose, and 0.2-0.4 parts colloidal silica. The intermediate layer composition includes the following components by weight: 82-87 parts sodium percarbonate, 1-4 parts tetraacetylethylenediamine, 2-3 parts phosphate buffer, 2-3 parts surfactant, 2-3 parts anhydrous sodium carbonate, 5-8 parts microcrystalline cellulose, and 0.2-0.4 parts colloidal silica. The core components include the following components by weight: 7-12 parts catalase, 30-45 parts stabilizer, 30-40 parts hydroxypropyl cellulose K4M, 2-5 parts ethyl cellulose, 10-18 parts microcrystalline cellulose, and 3-6 parts sodium bicarbonate.

2. The sandwich effervescent tablet for cleaning contact lenses according to claim 1, characterized in that, In the outer layer, the surfactant is any one of poloxamer, cocamidopropyl betaine, lauryl betaine, and sodium cocoamphoacetate.

3. The sandwich effervescent tablet for cleaning contact lenses according to claim 2, characterized in that, In the middle layer, the surfactant is any one of poloxamer, tetrabutylphenol, lauryl glucoside, and decyl glucoside.

4. The sandwich effervescent tablet for cleaning contact lenses according to claim 3, characterized in that, In the core, the stabilizer is any one or more of mannitol, trehalose, and sodium alginate.

5. A method for preparing a sandwich effervescent tablet for cleaning contact lenses according to any one of claims 1-4, characterized in that, Specifically, the following steps are included: S1: Citric acid, microcrystalline cellulose, polyvinylpyrrolidone, surfactant, disodium EDTA and colloidal silica are mixed in a high-speed mixer; sodium bicarbonate is premixed with the remaining microcrystalline cellulose; then the two mixed powders are combined and briefly mixed to obtain the outer premixed powder; S2: Sodium percarbonate is mixed with tetraacetyl ethylenediamine, anhydrous sodium carbonate, and colloidal silica under low shear; surfactant, phosphate buffer and microcrystalline cellulose are added, and then mixed again, with the material temperature controlled at room temperature throughout the process to obtain the middle layer premixed powder; S3: Mix catalase, mannitol, trehalose, microcrystalline cellulose, hydroxypropyl cellulose K4M, ethyl cellulose, and sodium bicarbonate; dry press the mixture into microchips using a small die on a tablet press to obtain the core chip; S4: Place the core chip from step S3 into the mold cavity of the tablet press; add the intermediate premixed powder from step S2 and press it lightly once with low pressure to form an intermediate preform; add the outer premixed powder from step S1 and press it into shape; place the formed tablet in a low-temperature drying chamber and then put it into a drying room for equilibration to obtain sandwich effervescent tablets.

6. A method for preparing a sandwich effervescent tablet for cleaning contact lenses according to claim 5, characterized in that, In step S3, the microchip parameters of the tablet press are: main pressure 120-200MPa, turntable speed 15-25rpm, and main pressure dwell time 80-120ms.

7. A method for preparing a sandwich effervescent tablet for cleaning contact lenses according to claim 6, characterized in that, In step S4, the light pressure parameters are: pressure 25-50 MPa, turntable speed 15-25 rpm, and dwell time 40-60 ms.

8. A method for preparing a sandwich effervescent tablet for cleaning contact lenses according to claim 7, characterized in that, In step S4, the main pressure parameters are: pressure 120-180MPa, turntable speed 15-25rpm, and dwell time 60-100ms.

Images