2024 Volume 72 Issue 12 Pages 1065-1072
Enteric-coated microcapsules can protect roxithromycin (ROX) from acid hydrolysis enhancing efficacy, solubility, and dissolution rate, representing a promising oral formulation for children and patients with swallowing difficulties. ROX-layered core particles were obtained with polyvinylpyrrolidone (PVP) K30 as the binder and Eudragit L30 D-55 as the coating material using the Wurster process in a fluidized bed processor. The enteric-coated microcapsules were characterized using powder X-ray diffraction, differential scanning calorimetry, and polarized optical microscopy. Enteric microcapsules with appropriate coating levels and particle sizes underwent dissolution tests, acid resistance tests. The weight ratio of PVP K30 to ROX was 1/2, and the average particle size of ROX-layered core particles was 130 µm. ROX molecule crystallinity in the layered core particles was inhibited. ROX was dispersed in PVP K30 with small particle size and high wettability. The average particle size of ROX enteric microcapsules with 60% coating level was approximately 155 µm. The acid resistance test showed that enteric microcapsules with a coating level of >50% and plasticizer contents of 20–25% can effectively protect ROX stability in simulated gastric fluid within 2 h. The dissolution experiment showed that the enteric microcapsules could protect ROX under acidic conditions of pH 1.2 and released >75% of ROX in the simulated intestinal fluid at pH 6.8 in 45 min. The enteric microcapsule of ROX using Wurster fluidized bed method can protect ROX from acid hydrolysis to ensure the efficacy, and has potential application in pharmaceutical industries, owing to its favorable dissolution.
Drug microcapsules are important development in the field of pharmaceutics in recent years and can provide necessary protection for the encapsulated materials from environmental influences of temperature, light, oxygen, and moisture. Furthermore, microcapsules can enhance the solubility of poorly water-soluble drugs, mask the unpleasant taste of active pharmaceutical ingredients (API), and provide specific drug delivery in pharmaceutical industries.1–4) An important step in formulation development in the pharmaceutical industry is masking the bitter or generally aversive taste of drugs, particularly for children.5–8) Most commercial formulations contain artificial sweeteners, such as saccharin and aspartame, to cover the bitter taste of drugs and exhibit poor taste-masking effects and the risk of toxic and allergic reactions.9–12) It has been suggested that such artificial flavors and sweeteners should be removed from dosage forms, particularly those for administration in children.13–15) In addition, oral solid formulations are superior to liquids in terms of taste-masking and are more convenient for packaging, transport, and use.16,17) However, common oral dosage forms such as tablets and capsules are unsuitable for children because of their poor swallowing ability. Thus, it is necessary to develop an oral solid dosage form with a taste-masking effect for children, such as microcapsules. In addition, the core-shell structure of microcapsules can provide various functions for expanding their application in pharmaceutical dosage form development.18,19) For example, enteric coating of microcapsules is reported to preserve API in the stomach and release the active substance in the intestine and is particularly useful for drugs that decompose easily under acidic conditions.20)
Roxithromycin (ROX) is a generation of macrolide antibiotics that mainly acts on Gram-positive bacteria, anaerobic bacteria, Chlamydia, and Mycoplasma.21,22) ROX is unstable in acidic solutions and easily decomposes, which limits its therapeutic capability.23,24) In vivo experiments using ROX have shown poor bioavailability owing to poor solubility and low residence time in stomach acid. Therefore, incorporating ROX into oral enteric formulations may protect against drug decomposition in the gastrointestinal tract and enable the drug to reach the small intestine with prompt release, allowing good oral absorption, enhancing the antibacterial effect, and providing a convenient dosage form for patients.25) Moreover, as ROX has a very bitter taste, children-oriented drugs, such as ROX-dispersible tablets and dry suspensions, need to mask the taste so that it is palatable for children. It has been reported that the preparation of ROX in enteric-coated pellets could increase its relative bioavailability and mask its bitter taste.26) This study used an enteric-coated microcapsule to prevent direct contact between ROX and the taste buds and decomposition in the stomach. Eudragit L30 D-55 composed of methacrylic acid and ethyl acrylate in a molar ratio of 1 : 1 is an anionic resin latex, which is often used for the coating of enteric formulations. The free carboxyl groups in Eudragit L30 D-55 were ionized above pH 5.5, and the coating film began to dissolve. In an acidic environment, the resin coating film does not dissolve, which can protect the drug from acid damage.27,28) In addition, acrylic resin enteric coatings are denser and have lower permeabilities than cellulose enteric coatings in acidic environments.29,30) Therefore, a low acrylic resin content is required to protect the drug.
Several methods are used to prepare microcapsules, which can be divided into chemical methods such as interfacial polymerization, physicochemical methods such as coacervation and phase separation, and physical methods such as spray drying and fluidized bed coating.31,32) Fluidized bed coating is an effective method for preparing microcapsules because of its versatility, convenience in industrial-scale production, and simple operation.33,34) The fluidized bed preparation of microcapsules involves the use of drug crystals or microparticles as the core and polymers as the coating material.35,36) The coating liquid is sprayed onto the core, and the rapid evaporation of the solvent aids in the formation of an outer layer on the core. Fluidized beds are divided into three types according to their spraying method: top spray, bottom spray, and rotating tangent spray. The latter two methods are commonly used to prepare microcapsules. The Wurster unit is a bottom-spray type frequently employed for coating and granulation.37,38) In addition, the poor water solubility of ROX is an obstacle that results in poor dissolution efficiency. Therefore, PVP and ROX were dissolved using an appropriate concentration of ethanol and then layered onto the core of calcium carbonate particles to prepare core particles containing amorphous drugs to improve the solubility of ROX. In order to achieve successful coating, plasticizers are commonly used to reduce the modulus, tensile strength, hardness and glass transition temperature of a polymer, which made coating easy for polymers.39) Triethyl citrate (TEC) is a traditional plasticizer, which is a triester of ethyl alcohol-citric acid and is a plasticizer of choice for aqueous system due to its water solubility.40) Herein, liquid plasticizer TEC was used in the coating process with respect to reducing the glass transition temperature (Tg) and increasing the mobility of coating polymer for further improving the fluidized bed coating process. Moreover, the release of drug from the coated products was influenced by the type and amount of plasticizer.41)
The primary objective of this study was to increase the acidic stability and dissolution rate of ROX; thus, the enteric polymer material Eudragit L30 D-55 containing of different amount of plasticizer TEC were used as the coating materials to optimize the formulation of enteric microcapsules using the fluidized bed method with a Wurster unit. Enteric microcapsules were characterized in terms of drug loading, encapsulation efficiency, size, and morphology. In addition, the dissolution characteristics and acid resistance of ROX enteric microcapsules were evaluated.
Roxithromycin (ROX, Merro Pharmaceutical Co., Ltd., Dalian, China), heavy calcium carbonate (Maruo Calcium Co., Ltd., Hyougo, Japan), PVP K30 (Nacalai Tesque, Inc., Kyoto, Japan), Eudragit L30 D-55 and Aerosil 200# (Evonik Degussa AG, Germany) were used in this study. The chemical structures of ROX and PVP K30 are shown in Fig. 1.
The ROX-layered core particles consisted of a calcium carbonate core of 53–63 µm were prepared by the Wurster process in a Grow Max 140 fluidized bed processor (Fuji Electric Co., Ltd., Tokyo, Japan). ROX and PVP K30 were dissolved in 70% ethanol at appropriate dosages. The formulations and operating conditions are listed in Table 1.
| Layering | ||
|---|---|---|
| Formulation 1 | Formulation 2 | |
| Formulation | ||
| Core : calcium carbonate (53–63 µm) (g) | 30 | 30 |
| Roxithromycin (g) | 60 | 60 |
| PVP K-30 (g) | 20 | 30 |
| Ethanol | 350 | 350 |
| Water | ad | ad |
| Total (mL) | 500 | 500 |
| Operation conditions | ||
| Inlet air temperature (°C) | 40 | 40 |
| Outlet air temperature (°C) | 25 | 25 |
| Inlet air flow rate (m3/min) | 0.10 | 0.10 |
| Liquid flow rate (mL/min) | 2.0 | 2.0 |
| Spray air flow rate (L/min) | 51 | 51 |
| Spray press (atm) | 2.3 | 2.3 |
| Products | ||
| Yield (%) | 78.3 | 91.5 |
Liquid Eudragit L30 D-55 latex was diluted with distilled water to obtain a solid content of 10%, and then an appropriate amount of TEC as a plasticizer was added under magnetic stirring to obtain solid contents relative to Eudragit L30 D-55 of 15, 20, and 25%. Subsequently, the solution was stirred for 30 min to completely disperse the TEC and obtain the coating solution. The coating process and conditions are listed in Table 2. At the end, the coated particles were dried under room temperature for 12 h, then dried at 30 °C for 48 h, the enteric microcapsules were obtained.
| Plasticizer ratio (w/w) | Coating | ||
|---|---|---|---|
| 15% | 20% | 25% | |
| Formulation | |||
| Drug-layered core particles (g) | 30 | 30 | 30 |
| Eudragit L30D-55 (dry weight) (g) | 18 | 18 | 18 |
| TEC | 2.7 | 3.6 | 4.5 |
| Water | ad | ad | ad |
| Total (mL) | 120 | 120 | 120 |
| Operation conditions | |||
| Inlet air temperature (°C) | 60 | 60 | 60 |
| Outlet air temperature (°C) | 32 | 31 | 32 |
| Inlet air flow rate (m3/min) | 0.18 | 0.18 | 0.18 |
| Liquid flow rate (mL/min) | 1.5 | 1.5 | 1.5 |
| Spray air flow rate (L/min) | 51 | 50 | 50 |
| Spray press (atm) | 2.3 | 2.3 | 2.3 |
| Products | |||
| Yield (%) | 90.5 | 89.8 | 88.1 |
The shapes of ROX-layered core particles and enteric microspheres were analyzed using a polarized optical microscope (OLYMPUS C-35; Olympus Corporation, Tokyo, Japan).
Particle Size Distribution MeasurementA hammer vibrating sieve (Iida-Seisakusho Japan Corporation, Tokyo, Japan) was used for particle size distribution analysis of drug-layered core particle or microcapsule samples. A set of sieves of sizes 75, 90, 105, 125, 150, 180, and 250 µm was used, weighed 20 g from the same sample and mixed with approximately 1% differential silica gel as an auxiliary sieving agent for each sieve, then shaken for 10 min, each sample underwent this experiment for one time. After shaking, the relationship between the weight percentage after sieving and size of the sieve aperture was plotted using a log-normal distribution method.
HPLC AnalysisEach sample was analyzed using a Shimadzu HPLC system consisting of an LC-6A pump and an SPD-6A UV detector (Shimadzu Corporation, Kyoto, Japan). Kaseisorb LC ODS Super (4.6 × 150 mm) was used for the analysis. Ultrapure water (500 mL) was added to 200 mL of ammonium dihydrogen phosphate solution, and the pH was adjusted to 5.3 with 2 mol/L sodium hydroxide. Subsequently, 500 mL of acetonitrile was added, and the mixed solution was used as the mobile phase. The flow rate was 1.0 mL/min and the detection wavelength was 205 nm. The injection volume was 20 µL.
Dissolution TestDissolution of the ROX-layered core particles was evaluated using the USP (26 version) paddle method with a dissolution tester NTR-VS3 (Toyama Sangyo Co., Ltd., Osaka, Japan). The dissolution medium was 500 mL of water, the paddles were rotated at 50 rpm, and the temperature was maintained at 37.0 ± 0.5 °C. A sample volume of 10 mL was withdrawn from the dissolution medium at the predetermined sampling points.
The dissolution of enteric microcapsules was performed using USP (26 version) method B for drug release from enteric microcapsules. An appropriate amount of vacuum dried enteric microcapsules was mixed with 1% differential silica gel, then heated to 60 °C for 24 h. Precisely weighed the heat treated enteric microcapsules containing 150 mg of ROX into 750 mL of 0.1 mol/L HCl solution (pH = 1.2), the paddles were rotated at 50 rpm, and the temperature was maintained at 37.0 ± 0.5 °C. After 2 h, 250 mL of 0.2 mol/L Na3PO4 solution was added. HCl solution (2 mol/L) or NaOH solution (2 mol/L) was used to adjust the pH to 6.8 when necessary. A sample volume of 10 mL was withdrawn from the dissolution medium at the predetermined sampling points.
All samples were filtered using a 0.22 µm microporous filter membrane and analyzed via HPLC, the dissolution tests were performed in triplicate.
Differential Scanning Calorimetry (DSC)DSC measurements were performed using a DSC-50 instrument (Shimadzu Corporation). The samples (approximately 5 mg) were placed in crimped aluminum pans. N2 was used as the purge gas at a flow rate of 50 mL/min and a heating rate of 5 °C/min.
Powder X-Ray Diffraction (PXRD) AnalysisThe PXRD measurements were performed using a Rigaku Miniflex diffractometer (Rigaku Corporation, Tokyo, Japan). The X-ray source was Cu-Kα radiation at 30 kV and 15 mA, and the scan rate was 4°/min.
Recovery StudiesAccording to the content determination method, recovery experiments were performed by adding 8 mg of ROX to 50 mg of ground enteric microcapsules. The percent analytical recovery was calculated by comparing the differential value between the total amount of the measured drug and the amount of drug contained in the microcapsule with the actual added pure drug. And the value was 98.43 ± 1.13%, n = 5.
Acid Resistance Test of Enteric MicrocapsulesA total of 50 mg of enteric microcapsules was added to a 20 mL volumetric flask and dissolved by 10 mL hydrochloric acid solution (pH = 1.2) and placed in a thermostatic water bath at 37.0 ± 0.5 °C with a constant shaking rate of 100 rpm for 120 min. Next, 1 mL of a mixing lye (containing 0.5 mol/L of Na2HPO4 and 0.1 mol/L of NaOH) were added to adjust the pH to approximately 6.8–7.4. Then 7 mL of ethanol solution was added, sonicated for 90 min, and stored for 60 min, the volume was made using water. Five milliliters of this solution were transferred to a 25 mL volumetric flask, and the volume was made with distilled water. The resulting solution was filtered through a 0.22 µm filter, and the concentration of ROX was determined by HPLC. ROX content A (%) was calculated using equation (1):
 | (1) |
All results are presented as means ± standard deviation (S.D.). Student’s t-test or one-way analysis of variance was used to evaluate significance.
ROX contains a large number of crystals with a size of 10–100 µm as shown in Fig. 2a. Heavy calcium carbonate was sifted out using molecular sieves with the size of 53 and 63 µm to unify the particle size within the range of 53–63 µm. Due to the large crystal size, these cannot be directly applied to calcium carbonate cores with a size of 53–63 µm (Fig. 2b). Therefore, ROX crystals must be crushed or dissolved before being layered onto the core particles. However, ROX easily decomposes during the crushing process; therefore, we selected the dissolution method. ROX is a poorly water-soluble drug,42,43) 70% ethanol was used to dissolve it. PVP K30, which is soluble in both water and ethanol,44) was used as the binder. A low inlet air temperature of 40 °C was selected because ethanol is volatile. When the weight ratio of PVP K30 to the total weight of the drug was 1 : 3, the yield of ROX-layered core particles was as low as 78%. A large amount of fine powder was observed on the filter bag at the air outlet; therefore, we concluded that the adhesive was not sufficiently viscous at high ethanol concentrations. When the weight ratio of PVP K30 to the total weight of the drug was increased to 1 : 2, the yield of the ROX-layered core particles increased to more than 90%. As shown in Fig. 3a, the roundness of the ROX-layered core particles was relatively high. The particle size distribution curve (Supplementary Fig. S1) shows that the average particle diameter of the obtained ROX-layered core particles was approximately 132 µm, and 99% of particles had a size less than 180 µm. Microscopy revealed that ROX-layered core particles with a particle size less than 150 µm were single particles. Composite particles containing 2–3 single particles with a particle size above 150 µm were also identified. Therefore, we considered that the weight of the aggregated particles was less than 10% indicating that the preparation conditions for the ROX-layered core particles were appropriate.
Addition of TEC was capable of decreasing the Tg of Eudragit L30 D-55, ensuring the film formation at relatively low curing temperature in the coating process (Supplementary Fig. S2). Hatch and Choate indicated that considerable information can be derived from the log-norma representation, such as geometric mean size, specific surface area, and volume.45) A mean size of the sieve opening corresponding to the 50% point of the distribution was used to calculate the average particle sizes.46) The average particle sizes of microcapsules with 60% coating level containing 15, 20, and 25% TEC were 158, 155, and 156 µm, respectively (Supplementary Fig. S1). This suggests that the amount of plasticizer added within this range had almost no effect on the average particle size of the microcapsules. Microscopy revealed a number of aggregated microcapsules visible when the particle size was greater than 180 µm, and the aggregation rate of the microcapsules was approximately 5–8% (Fig. 3b).
Dissolution Rate of ROX-Layered Core ParticlesThe dissolution properties of the ROX-layered core particles in water were evaluated using the paddle method (Fig. 4). The dissolution rate of ROX from the ROX-layered core particles was much higher than that of ROX. This suggests that the crystallization of ROX was successfully inhibited by combination with PVP K30 in the ROX-layered core particles. In general, it is expected that polymers are often used as inhibitors which could restrict crystallization or particle size of drug, and lead to an increase in dissolution rate.47) Moreover, hydrophilic polymers can increase the wettability of drugs, which can also enhance their dissolution rate.48) However, the ROX was not released completely, this could be due to the partial ROX crystalline residue which leaded to limited dissolution rate. The PVP K30 is a freely water-soluble polymer, and the absence of interaction between polymer and drug could also result the polymer rapidly dissolves in SIF while little drug retention.49) The detailed mechanism of ROX dissolution from layered core particles is not clear; thus, we investigated the state of ROX in the layered particles.
(n = 3, mean ± S.D.).
DSC was performed to assess the crystalline state of the active molecules and polymers in the ROX-layered core particles (Fig. 5). The DSC curves of ROX crystal exhibited an endothermic peak at 115.7 °C, which corresponds to its melting. PVP K30 showed a broad endotherm peak at 79.1 °C between 50 and 130 °C, which represents the evaporation of water because of the hygroscopic characteristics of this polymer.50) Physical mixtures of ROX and PVP K30 exhibited endothermic transitions expressing the melting of the drug and polymer, which ruled out any interactions between the drug and polymers.51) Conversely, the DSC curve of ROX-layered core particles showed a sharp endothermic peak at 108.5 °C, which might indicate the interaction between ROX and PVP K30 or the remaining of little crystalline ROX in its layered particles. Accordingly, to explain why ROX can quickly dissolve from the ROX-layered core particles, we evaluated the state of ROX in the ROX-layered core particles (Fig. 6). PXRD patterns of ROX intact, physical mixture of ROX and PVP K30 (molar ratio was 2 : 1), CaCO3, physical mixture of ROX, PVP K30 and CaCO3 (molar ratio was 2 : 1 : 1), ROX-layered core particles (stored for 6 months) and PVP are represented in Figs. 6A–F, respectively. A small number of diffraction peaks arising from the ROX crystals can be seen in the PXRD patterns of the ROX-layered core particles after storage at room temperature even after storing for six months. This demonstrated that ROX was embedded in the polymer matrix in the crystalline state. The crystallinity of the drug was inhibited by the formation of drug-layered core particle. This explains the fast dissolution behavior of ROX after 5 min. To further characterize the possible interactions between the drug and PVP K30 in the ROX-layered core particles, Fourier-transform FT-IR spectra were recorded (Supplementary Fig. S3). However, no differences were observed in the positions of the absorption bands in these spectra. It can be suggested that there were no changes in the bands corresponding to the functional groups of ROX or PVP K30 in drug-layered particles, indicating the absence of chemical changes in their structures. The FT-IR measurement showed that the ROX-layered particle had a good correlation with ROX bulk drug and polymer.
A: ROX intact; B: Physical mixture of ROX and PVP K30 (2 : 1); C: CaCO3; D: Physical mixture of ROX and PVP K30 and CaCO3 (2 : 1 : 1); E: ROX-layered core particles; F: PVP.
ROX is unstable in acidic medium.25,52) If the dissolution test is carried out according to the dissolution test method of enteric microcapsules in the US Pharmacopoeia,53) when dissolution is incomplete, it cannot be determined whether the reason for low dissolution is due to the degradation of the drug in the acidic medium or poor dissolution of the enteric microcapsules from the release medium. Therefore, the acid resistance of enteric microcapsules in simulated gastric fluid (SGF) should first be examined. As shown in Fig. 7, with an increase in the Eudragit L30 D-55 coating level, the drug residue also increased after the 2 h acid-resistance test in SGF. Moreover, the drug residual percentage increased in the order of TEC content of 15, 20, and 25% under the same coating level; thus, a higher amount of plasticizer could better protect the ROX.
(n = 3, mean ± S.D.).
The effect of thermal treatment time on the acid resistance of ROX in the microcapsules was also evaluated. The results of enteric microcapsules with a coating level of 60% after a 2 h acid-resistance test is shown in Fig. 8. The residual amount of ROX in the microcapsules with a TEC content of 15% without thermal treatment was less than 90%, while when the added amount of TEC was greater than 20%, the residual amount of ROX in the microcapsules exceeded 90% even without thermal treatment. It has been reported that the enhancement of acid resistance was attributed to the increased completeness of the coating level with relatively higher plasticizer content and longer curing time.39) Therefore, as the thermal treatment time and the amount of TEC increased, the acid resistance of all microcapsule samples improved. In particular, for the microcapsules with 15% TEC, the acid resistance significantly improved to more than 90%. It has been reported that coating formation is related to glass transition phenomena54,55) and the compatibility between polymer and plasticizer. However, the minimum film-forming temperature (MFT) for coating step with different amounts of TEC in enteric microcapsules formation is observed to be around 20 °C less than Tg,56) thus the inlet air temperature using in this study was much lower than the Tg value. Moreover, a longer curing time enables better fusing between polymer and plasticizer to ensure film formation while coating,57) even with relatively low content of plasticizer.
(n = 3, mean ± S.D.).
The effects of different coating levels and plasticizer dosages on the release of ROX from enteric microcapsules were investigated. The acid resistance test of the enteric microcapsules (described in Results of the Acid Resistance Test) showed that when the coating level was more than 50% and the plasticizer content was more than 20%, there was a smaller reduction in ROX content in the enteric microcapsules. Therefore, the dissolution of enteric microcapsules with coating levels of 50 and 60% and plasticizer contents of 20 and 25% was investigated (Fig. 9). The dissolution test was performed in SGF within the first 2 h, and phosphate buffer was added after 2 h to increase the pH of the dissolution medium to 6.8 as simulated intestinal fluid (SIF). All four types of enteric microcapsules were stable in SGF, whereas in SIF, ROX was released above 75% after 45 min, which meets the requirements of the US Pharmacopoeia53) of less than 10% within 2 h in SGF and more than 75% within 45 min in SIF. More than 90% of the enteric microcapsules with a coating level of 60% were released within 60 min. Microscopy revealed that the enteric microcapsules were slightly expanded; however, the capsule membranes remained intact after dissolution in SGF for 2 h (Fig. 10). The enteric microcapsules could not be seen in the microscopic observation image (Fig. 11) after 1 h of dissolution in SIF following dissolution in SGF for 2h; only calcium carbonate core particles were observed, indicating that ROX adhered to the core of the particles and PVP K30 was dissolved.58) However, the dissolution rate of enteric microcapsules was less than 100% at the end of the dissolution test because of the decomposition of small amounts of ROX in the SGF.
(n = 3, mean ± S.D.).
Enteric microcapsules containing ROX-layered core particles were successfully prepared using the fluidized bed method and showed uniform particle size, stability, and high drug-loading capacity. Additionally, the crystalline state of ROX was effectively inhibited by the formation of ROX-layered core particles with PVP K30 as a binder, and ROX was dispersed in PVP K30 with a small particle size and high wettability. Therefore, ROX dissolved faster in the layered core particles than in the crystalline drug. The dissolution test showed that the optimized microcapsules were able to protect ROX from decomposition in the simulated gastric fluid, while simultaneously allowing rapid drug release in the simulated intestinal fluid. Different coating levels, plasticizer dosages, and thermal treatment times were important factors affecting the acid resistance and dissolution behaviors of ROX enteric microcapsules. Moreover, the demonstrated fluidized-bed method can be easily scaled up and adapted to pH-sensitive or volatile drugs with subsequent product processing. It has been reported that there is already microencapsulation used as pediatric oral drug delivery. The layering with hydrophilic PVP and coated by Eudragit allowed manufacturing of a pH-dependent dosage form suitable for oral use in children.59,60) And some references reported that microcapsules already used as pediatric or patients with swallowing difficulties oral drug delivery formulation clinically.61) In addition, the polymer Eudragit possessed a good taste masking effect and also provided a favorable basis for the development of pediatric dosage forms such as dry suspension formulation.62) These results may provide guidelines for the development of potential formulations of ROX for use in pediatric oral medication, such as dry suspensions.
This work was supported by Higher Education Institutions of the Liaoning Provincial Department of Education (LJKZ0941), and Postdoctoral Research Foundation of China (2024M752159).
Nan Liu wrote, designed, and revised the manuscript; Ling-He Zang analyzed the data and revised the manuscript; Dong-Chun Liu designed the research, performed the experiments, and analyzed the data.
The authors declare no conflict of interest.
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