Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.
Scientific Reports volume 14, Article number: 28512 (2024 ) Cite this article effervescent tablet packaging machine
Metoclopramide is an antiemetic agent prescribed for motion sickness, cancer chemotherapy, and pregnancy. The present work aimed to design a metoclopramide-loaded halloysite nanotubes (HNTs) drug-in-adhesive transdermal drug delivery system. Four formulations F1, F2, and F3 with different ratios of HNTs to metoclopramide and a F4 without HNTs were developed using acrylic adhesive DURO-TAK 387–2510 by the solvent casting method. These formulated patches were thoroughly evaluated and in-vitro release and permeation studies were performed. The optimized formulation was analyzed using skin irritation, SEM, DSC, and FTIR studies. The GASTROPLUS TCAT model was used to predict the in-vivo performance. HNT-based formulations exhibited controlled drug release, achieving approximately 60% in 4 h, compared to over 80% release in the same period from the formulation without HNT. The optimized formulation (F3) demonstrated a lag time of 1.802 h with a flux of 0.103 mg/cm2/hr. The shelf life was 19.279 months at 5 ± 3 °C. The Cmax, Tmax, AUCt, and AUCinf were predicted as 40.84 ng/mL, 6.32 h, 561.51 ng/mL×h and 599.61 ng/mL×h for a 30 mg patch. The study demonstrated that metoclopramide can be effectively loaded into HNTs and proved safe and effective in drug-in-adhesive type transdermal systems using HNTs as a drug carrier.
Metoclopramide is a dopamine D2 antagonist and antiemetic agent. It is widely used in the management of nausea and vomiting associated with cancer chemotherapy, early stage of pregnancy, and motion sickness. It is generally available in oral and parenteral dosage forms1,2. The orally administered metoclopramide passes through hepatic first-pass metabolism, resulting in irregular bioavailability (32–100%) and adverse effects such as drowsiness, fatigue, and restlessness. In comparison, parenteral forms have resulted in low acceptance among patients due to their invasive nature2,3. Its physicochemical properties, such as molecular weight (354.3 Daltons), water solubility (0.02 g/100 ml), melting point (146.5–148 °C), and partition coefficient (2.667) make it a suitable candidate for transdermal delivery3.
The transdermal route of drug administration offers multiple advantages over conventional drug delivery systems, like avoiding intestinal irritation of orally administered drugs, providing painless delivery and preventing needle phobia of intravenous drugs, avoiding first-pass intestinal and hepatic metabolism, and increasing drug bioavailability4. Additionally, sustained drug delivery reduces dosing frequency, ensures a uniform pharmacokinetic profile, minimizes the risk of side effects, and enhances patient compliance5,6,7. Transdermal patches are designed to deliver a drug in a controlled manner through the skin by either loading the drug into a polymer mixture or storing it in a reservoir8. Different polymers have been used to obtain a sustained-release transdermal delivery system for metoclopramide9,10. In addition, due to the presence of lipid bilayer and proteins and its compact nature, the stratum corneum layer of the skin acts as a barrier for drug delivery from the transdermal system. The use of permeation enhancers in the transdermal formulation is one of the methods used to reduce the skin barrier properties to some extent8. These chemicals promote drug movement and enhance drug flux across the skin. Studies reported using chemical permeation enhancers to improve metoclopramide permeation from transdermal formulations. Specifically, dimethyl sulfoxide (DMSO) and liquid paraffin, each at a minimum concentration of 10% v/v, have been used to facilitate the delivery of metoclopramide through the skin2,9. The DMSO is a byproduct of the wood and paper industries. It is one of the most extensively studied compounds used as a penetration enhancer in pharmaceuticals due to its safe and low toxicity profile11. Similarly, the liquid paraffin is obtained from crude mineral oils, which are reported to be safe, non-allergic, and compatible with various drugs and excipients12,13.
Halloysite nanotubes (HNTs) are a natural clay material comprising 600 to 900 nm long 10 to 15 rolls of double layers of alumina-silica nanotubes with 50 nm inner and 15 nm outer diameters, respectively14. Structurally, it consists of a 1:1 ratio of octahedral aluminum hydroxide (Al–OH) and tetrahedral siloxane (Si–O–Si) layers14,15,16. It possesses a negative charge on the outer surface due to the presence of a siloxane layer and a positive charge on the inner surface because of the aluminum hydroxide layer14. This unique property of HNTs allows them to effectively load and adsorb drug molecules. Additionally, HNTs are economical, abundant in nature, biocompatible, and non-toxic14,15,16,17,18. It is a useful release retarding agent for several drugs such as tetracycline HCl, propranolol HCl, diltiazem HCl, diclofenac sodium, fentanyl and 5-aminosalicylic acid19. Recently, it has been studied for topical and transdermal applications20,21. However, it has not been studied as a drug carrier in the formulation of drug-in-adhesive type transdermal drug delivery systems.
The present study aimed to evaluate the use of HNTs as a drug carrier in the transdermal delivery of metoclopramide HCl. These transdermal patches were evaluated for weight and thickness, folding endurance, moisture content, moisture uptake, drug content characteristics, metoclopramide release, and permeation performance. The impact of permeation enhancers (DMSO and liquid paraffin) on the permeation of metoclopramide was evaluated, along with the structural, thermal, and surface properties of the optimized formulation. An in-silico model was employed to predict the in-vivo characteristics of metoclopramide from the formulation. Additionally, the stability of the formulation was assessed at various temperatures.
HNTs were gifted by China Clays Limited (New Zealand). Metoclopramide HCl was kindly provided by Nabiqasim Industries Private Limited (Karachi, Pakistan), Dichloromethane and Hydrochloric acid was purchased from Riedel-De Haen, Laborchemikalien GmbH (Seelze, Germany), Methanol from TEDIA (Fairfield, USA), Ethanol from BDH (Poole, England), Ethyl oleate from AVONCHEM (Cheshire, England), Propylene glycol, Potassium phosphate monobasic anhydrous from SIGMA-ALDRICH (St. Louis, Missouri, USA), sodium hydroxide, orthophosphoric acid, potassium dihydrogen phosphate, sodium chloride and formaldehyde solution from Merck (Darmstadt, Germany). The patch components, including adhesive (DURO-TAK 387–2510), were gifted by Henkel Corporation (Bridgewater, Belgium), while the backing layer (3 M COTRAN 9720) and release liner (3 M SCOTCHPAK 9755) by 3 M (St. Paul, USA).
Male albino mice (weighing 21 to 27 g) used in the skin irritation test were obtained from the animal house, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi. The ethical approval of the study was granted and approved by the Institutional Bioethics Committee (IBC), University of Karachi (Approval no: IBC KU-106-B/2020). The study followed all ARRIVE guidelines for the care and use of laboratory animals and guidelines of the National Research Council’s Guide for the Care and Use of Laboratory Animals for the welfare of the laboratory animals22,23.
Halloysite nanotubes were loaded with metoclopramide using the method reported by Levis and Deasy after slight modification24. Briefly, a 5% w/v drug solution was prepared in water. Halloysite clay was mixed with the solution in halloysite: drug ratios of 1:1 (F1), 0.5:1 (F2), and 2:1 (F3) and subjected to a vacuum (∼ 30 mm Hg)) for 30–60 s until all gas was removed. The process was repeated three times to allow all the drugs to displace the air within and between the nanotubes. The mixture was shaken for 24 h at 250 rpm on a flat orbital shaker (KS 260 B, Industrial, and Automotive Equipment, Germany) and filtered through 0.22 μm membrane filter paper using a vacuum filtration assembly. The filtered mixture was dried overnight at 50 °C in a hot air-circulating oven (YCO-N01, Gemmy Industrial Corporation, Taiwan). The percentage yield of the drug-loaded halloysite nanotubes and the drug loading efficiency were determined using Eqs. 1 and 2:
The solvent evaporation method was used to produce the drug in an adhesive matrix-type transdermal patch of metoclopramide-loaded halloysite nanotubes6. A 0.5 g of adhesive (DURO-TAK 387–2510) was dissolved in 20 mL methanol and dichloromethane solvent mixture (1:9). The drug-loaded halloysite samples (F1-F3) were added to the adhesive solution and spread on the backing film such that each 1 cm2 patch contained 10 mg metoclopramide. The patches were dried at room temperature for 15 min, followed by oven drying at 60 °C for 10 min. In addition, a patch of a simple drug-in-adhesive was also formulated (F4) as a control.
The prepared patches were assessed for the impact of permeation enhancers, dimethyl sulfoxide (DMSO), and liquid paraffin. For this, 0.5 g of adhesive was first dissolved in a 20 mL methanol and dichloromethane solvent mixture (1:9). The drug-loaded halloysite samples from optimized formulation (F3) along with 10%v/v DMSO or liquid paraffin were incorporated into the adhesive solution. The mixture was spread onto the backing film, left to air dry at room temperature for 15 min, and then oven-dried at 60 °C for an additional 10 min.
The prepared transdermal patches were evaluated for weight and thickness uniformity, folding endurance, moisture content, moisture uptake, and content uniformity. Accordingly, ten patches of 1 cm2 size from each formulation were selected for each test.
The patches of 1 cm2 size were weighed individually on an analytical balance (SARTORIUS CP 224 S, Gottingen, Germany), and their thickness was determined using a digital vernier caliper (SEIKO Brand, China). The mean and standard deviation of the readings were calculated, and thickness and weight variation among the patches were determined25,26.
The folding endurance was determined to measure the capability of a transdermal patch to resist rupture or maintain physical integrity with general skin folding27. The patches were folded repeatedly manually at the same place, and the number of folds required to produce visible cracks was recorded28.
The physical stability of the patches was evaluated by determining the moisture content test. The patches were weighed initially on an analytical balance and placed at room temperature for 24 h in a desiccator containing a saturated calcium chloride solution. The weight was measured after 24 h, and the percentage moisture content was calculated using Eq. 329.
The ability of the patches to absorb moisture from the environment was assessed through the moisture uptake test. The patches were placed at room temperature for 24 h in a desiccator containing a saturated calcium chloride solution. The weight was measured after 24 h, and the percentage moisture uptake was calculated by using Eqs. 430,31.
The pharmaceutical assay method for metoclopramide tablets was adopted from USP-44 for content assay in the patches32. Samples were prepared in triplicate. Sample preparation comprised of sonication of a patch (1 cm2 size) into 30 ml methanol in a volumetric flask (50 ml) for 30 min. The volume was made up, and the samples were analyzed using the HPLC method. The L1 column (SYMMETRY C-18, 4.6 mm x 15 cm, Waters Corporation, Milford, USA) was used with a mobile phase containing a mixture of sodium acetate in distilled water and tetra-methylammonium hydroxide in methanol. An equal volume of acetonitrile (ACN) and buffer in a ratio of 1:1 was used to make the final composition of the mobile phase further adjusted with glacial acetic acid to pH 6.5. The flow rate was set at 1.5 ml/min on an isocratic pump (LC-20AD, SHIMADZU, Kyoto, Japan), and detection was made on a UV-VIS detector (SPD-20 A, SHIMADZU, Kyoto, Japan) at 215 nm. Data was acquired with LABSOLUTION software (version 1.0.6249, Shimadzu, Kyoto, Japan).
The drug release studies from transdermal matrix patches (F1-F4) were performed using the USP dissolution apparatus V, i.e. Paddle over disk method (ERWEKA DT-600, Huesenstamm, Germany). A patch of 1 cm2 size was cut from each formulation and fixed on the disc assembly (90 mm diameter, 17′′ mesh) (LABECX, Santa Clarita, California, USA), consisting of 125 μm stainless steel mesh, watch glass, and clips, having adhesive portion faces upward. The test was carried out without a barrier membrane. The disc assembly was placed into the baskets of the dissolution apparatus containing phosphate buffer solution pH 7.4 (500 ml) at 32 ± 1°C and rotated at 50 rpm. Samples (5 ml) were withdrawn at 0.25, 0.5, 1, 2, 4, 6, 8, and 12 h and replaced immediately with fresh medium to maintain the sink condition. The samples were subsequently assayed using a double-beam UV-Vis. Spectrophotometer (UV-1800, SHIMADZU Corporation, Kyoto, Japan) at 272 nm wavelength. The experiment was repeated in triplicate33,34.
The drug release kinetics were determined using different drug release kinetic models such as Zero Order, First Order, Higuchi, and Korsmeyer-Peppas (Eq. 5 to 8) using the Microsoft Excel add-in program DDSOLVER35,36.
Q1 and Q0 are the amounts of drug dissolved at a particular time t and the amount of the drug present at time zero in the dissolution media, respectively. K0 is the zero-order rate constant.
Q1 and Q0 are the amounts of the drug in the dissolution media at time t and zero, respectively. K1 is the first-order rate constant.
Q1 is the dissolved amount of the drug in the dissolution media at time t, t1/2 is the square root of time (t), and KH is the rate constant for the Higuchi model.
a is a constant that depends on the geometric and structural characteristics of the dosage form. n is the release exponent indicating the mechanism of drug release.
The permeation test was conducted with the help of Franz Diffusion Cell (PERMEGEAR V9-CB, USA) using dialysis tubing (500 MWCO) as a barrier membrane37. Transdermal patches of 1 cm2 size were placed over the dialysis tubing between the donor and acceptor compartment. The acceptor compartment was filled with phosphate buffer pH 7.4 (5 mL), and the temperature was set at 37 ± 1°C. Samples (0.5 mL) were collected in triplicate at 0.25, 0.5, 1, 2, 4, 6, 8, and 12 h and replaced immediately with fresh medium to maintain the sink condition30. The samples were diluted with an appropriate volume of the same buffer and the absorbance of the drug in each sample was determined using a double-beam UV-Vis. Spectrophotometer at 272 nm wavelength. The amount of the drug diffused through the barrier membrane at different time intervals was calculated. Permeation profiles were obtained by plotting a graph between the amount of drug permeated (µg/cm2) versus time. Various permeation parameters such as flux, permeation coefficient, lag time, and diffusion coefficient were also determined using the method stated by Ubaidulla in 200738. The flux (J) was calculated as the slope of the graph plotted between the linear portion of the cumulative amount of drug permeated and time. The lag time (L) was determined by extrapolating the line of the same graph to the abscissa. The partition coefficient (P) and the diffusion coefficient (D) were calculated using Eqs. 9 and 1039,40.
P is the partition coefficient, J is the flux, and Cd is the amount of drug in the donor compartment.
Where D is the diffusion coefficient, h is the thickness of the membrane, and L is the lag time.
In addition, one-way ANOVA and 1-sample t-test were applied with a significance level (α) of 0.05 to compare the means of permeation data and lag times using the Minitab Statistical Software version 20.2, 2021. A p-value greater than 0.05 was considered indicative of no significant difference, while a p-value less than 0.05 was considered indicative of a significant difference.
The FTIR study was performed to determine the compatibility of metoclopramide with the excipients in the optimized formulation. The FTIR spectroscopy was conducted on NICOLET AVATAR 330, ThermoFisher Scientific, USA at a wavelength range of 4000 –600 cm− 1 ref41. The FTIR spectra of the pure drug and optimized patch were obtained and compared for any possible interaction.
A DSC analysis of pure metoclopramide powder and components of the optimized transdermal patch was carried out to analyze the thermal behavior. The study was performed using the DSC 250, TA instruments, DE, USA. The samples were heated at a scanning rate of 10 °C /min over a temperature range of 30 °C to 240 °C21. The thermograms obtained were compared for any change in the thermal behavior of the samples.
Scanning Electron Microscopy of the HNTs, metoclopramide-loaded HNTs, and optimized formulation was performed using SEM, JEOL JSM 6380-A, Tokyo, Japan, to analyze its surface morphology. The analysis was done at an accelerating voltage of 20 kV. An automated sputter coater (JEOL FC-1500) was used to carry out the sputter coating of the samples with gold up to 250°A.
The skin irritation study was performed in accordance with the National Research Council’s Guide for the Care and Use of Laboratory Animals42. The selected animals (n = 6) were placed in the cage at normal room temperature before the test for seven days with free access to food and water to acclimatize to the environment. The dorsal part of the skin of the animal’s abdomen was shaved using an electric clipper (KM-6330, Kemei, China). The optimized patch was applied to the animal skin as a test (n = 3), while 0.8% formalin solution was used as a control (n = 3). The patch was removed after twenty-four hours, and the symptoms of sensitivity reactions, such as redness or erythema to the skin, were visually examined, as reported by Singh, A. and A. Bali43.
The program GASTROPLUS (version 9.8.3, Simulations Plus Inc., Lancaster, CA, USA) was used to predict the systemic disposition of metoclopramide transdermal patches using the Transdermal Compartmental Absorption & Transit Module (TCAT module). Different physicochemical, physiological, formulation, and pharmacokinetic parameters (logP, pKa, blood: plasma ratio, unbound fraction in plasma, effective permeability) obtained from the literature and ADMET predictor (Simulations Plus Inc., Lancaster, CA, USA) module were incorporated as shown in Table 1 ref44,45,46,47. The initial validation of the model was performed using experimental plasma profiles for intravenous and oral routes48,49. The pharmacokinetics parameters were calculated after processing and modeling (compartmental modeling) from the metoclopramide plasma concentration-time profile. PKPLUS module in GASTROPLUS was applied to examine compartmental modeling and obtain compartmental parameters. The relative accuracy between predicted PK parameters against the observed PK parameters was calculated by comparing the fold error (FE) between the observed and predicted values according to Eq. 1150:
where P is the permeability coefficient (cm/s) obtained from the in-vitro permeation study, h is the thickness of the membrane (cm), and K is the partition coefficient predicted by the in-silico TCAT module for the drug between the membrane and water. Diffusivity values in the viable epidermis and dermis were predicted using the in-silico method present in GASTROPLUS. The simulated plasma concentration of the optimized (F3) metoclopramide patch (10 mg) after transdermal administration was compared to the plasma concentration after the oral administration of the 10 mg dose.
The transdermal patch (containing the metoclopramide HCl, adhesive, and HNTs) was subjected to stability studies as per ICH stability evaluating conditions52. In the stability testing, the patches from the optimized formulation were placed in the refrigerator (5 ± 3 °C), at room temperature (25 ± 2 °C, 60 ± 5%RH), and accelerated temperature (40 ± 2 °C, 75 ± 5%RH) in a stability chamber (NUAIRE, Plymouth, MN, USA). These samples were evaluated for any change in morphology and metoclopramide content uniformity at different times during six months of storage. The shelf life was also calculated using MINITAB Statistical Software version 20.2, 2021.
The results of the different evaluation tests, including weight, thickness, folding endurance, moisture content, moisture uptake, drug content, the yield of the drug-loaded halloysite nanotubes, and drug loading efficiency, are presented in Table 2. The weight and thickness of the transdermal patches ranged between 0.065 ± 0.011 to 0.081 ± 0.014 g and 0.167 ± 43 to 0.25 ± 0.0245 mm, the value of folding endurance was > 300 folds, the moisture content ranged from 0.2 ± 0.421 to 1.8 ± 0.567% while the uptake of moisture ranged from 9.1 ± 1.852 to 17.7 ± 1.494%, the average percent amount of metoclopramide in all formulations ranged 102.419 ± 4.401 to 106.914 ± 2.553%, and the average percentage yield and loading efficiency of halloysite nanotube obtained from three different loading experiments were ranging from 68.066 ± 4.812 to 71.555 ± 5.058 and 6.933 ± 0.642 to 11.333 ± 0.763% respectively.
The in-vitro drug release profiles of the patches are presented in Fig. 1. The dissolution rate of the drug in the formulation without HNTs (F4) was highest (> 80% in 4 h). The release was found to be controlled (≈ 60% in 4 h) in the patches with HNTs loaded with metoclopramide. The patches with HNT: drug ratio of 1:1 (F1) and 2:1 (F3) showed almost similar and more controlled release effects compared to 0.5:1 (F2). An initial burst effect was also observed in all the formulations within 15 min.
Percentage release of metoclopramide from the transdermal patches.
The release behavior of the formulations was subjected to different release kinetic models, including zero order, first order, Higuchi, and Korsmeyer-Peppas; the results are shown in Table 3. Korsmeyer-Peppas model was found to best fit on the release data with an r2 value of 0.995 to 0.999. The release of metoclopramide from patches presented concentration dependency and followed first-order release with an r2 value of > 0.8. Moreover, the Fickian and the non-Fickian behavior of patches were assessed using the Korsemeyer-Peppas model. The values of n were < 0.5, indicating Fickian law of diffusion was followed.
The amount of metoclopramide permeation per unit area from transdermal patches is shown in Table 4; Fig. 2, along with permeation parameters in Table 5. The rate of permeation of metoclopramide was comparable among the formulations (p = 0.975). However, the permeation flux was higher for patches with pure drug (0.112 ± 0.0016 mg/cm2hr) and a greater ratio of drug to HNTs (0.113 ± 0.0031 mg/cm2/hr). In addition, formulation F3, containing 2:1 HNT to drug ratio, provided the lowest lag time, 1.802 ± 0.1257 h, with a p-value of 0.002, 0.032, and 0.017 for F1, F2, and F4, respectively.
Amount of metoclopramide permeated from the transdermal patches.
The rate of metoclopramide permeated per unit area is presented in Fig. 3, along with permeation parameters in Table 5. The permeation results showed that the addition of permeation enhancers, DMSO and liquid paraffin, resulted in higher flux (0.121 ± 0.0009 mg/cm2hr and 0.119 ± 0.0017 mg/cm2hr) and shorter lag time (1.517 ± 0.1487 h and 1.702 ± 0.1322 h).
Permeation profile of metoclopramide in the presence of permeation enhancers.
The FTIR spectra of optimized patch components (metoclopramide HCl, DURO-TAK 387–2510 [adhesive], CoTran 9720 [backing layer], and halloysite nanotubes) and the optimized patch at 4000 to 600 cm− 1 scanning range are presented in Fig. 4 and Figure S2. The characteristic peaks of the drug (metoclopramide HCl), such as O-H, HN2, and C = O stretching at 3440 cm− 1, 3390 cm− 1, and 1593 were found intact in the optimized patch material. In the case of Duro-Tak 387–2510, the polymeric asymmetric C-H stretching was observed between 2930 cm− 1 and 2860 cm− 1 and a little shifted towards 2920 cm− 1 and 2850 cm− 1 in the optimized patch. The characteristic peaks of the halloysite, appearing at 9780 cm− 1 and 9100 cm− 1, corresponding to Si-O-Si, asymmetric, and in-plane stretching, respectively, were also found intact in the optimized patch.
FTIR spectra of pure drug (metoclopramide HCl) powder, optimized patch and its components.
The DSC thermograms of metoclopramide HCl, DURO-TAK 387–2510 [adhesive], COTRAN 9720 [backing layer], halloysite, and the optimized patch are shown in Fig. 5 and Figure S3. The thermogram of pure metoclopramide HCl presented a sharp endotherm at ~ 93–94 °C and at ~ 93 °C in the transdermal patch. Among other patch components, the CoTran 9720 backing layer showed a sharp endotherm at around 107 °C with a broad peak starting from ~ 80 °C to 113 °C.
DSC thermogram of pure drug (metoclopramide HCl) powder, optimized patch and its components.
SEM images of the HNTs, metoclopramide-loaded HNTs, and optimized formulation at X10000 magnification with a scale bar of 1 μm are presented in Fig. 6a, b, c. Varying sizes of HNT nanotubules are visible with lengths in the nanometer range (Fig. 6a). In the metoclopramide-loaded HNTs sample (Fig. 6b), the nanotubules are not visible but are covered with drug particles, indicating the successful loading of metoclopramide onto the HNTs (Fig. 6b). Additionally, a uniform distribution of the metoclopramide-loaded HNTs can be seen within the optimized patch (Fig. 6c).
SEM images of (a) HNTs, (b) metoclopramide HCl loaded HNTs and (c) optimized formulation
The optimized patch was evaluated for skin irritation after application to the mice’s skin, as shown in Fig. 7. The formulation was found non-irritant and safe, as no redness or erythema was observed.
7 Skin irritation study of the optimized metoclopramide patch on mice (a) patch applied on the shaved skin (b) skin after the patch removed (c) skin after treated with formalin (control).
The prediction of the systemic disposition for the optimized metoclopramide transdermal patch was carried out using the TCAT model. The two-compartmental model was selected with the help of the PKPLUS module considering the intravenous administration of 10 mg to simulate the systemic disposition in individuals with an average weight of 70 kg as a comparison parameter53. The pharmacokinetics parameters for the intravenous and oral routes calculated with PKPLUS and reported literature were: clearance = 0.16 L/h/kg, half-life (t1/2) = 6.8 h, and volume of distribution (Vd) = 3.5 L/kg. The model was initially validated by comparing the fold error of 10 mg IV and oral routes. The values of fold error were found to be between 0.5 and 1.5 (see Table 6). After testing different metoclopramide application areas and dosage values, the model integrated pharmacokinetic parameters and TCAT model for the metoclopramide patch (F3) using values of a dose of 10 mg and 20 cm2 as the application surface area. The mean pharmacokinetic parametric values, as shown in Table 6, for the optimized formulation of transdermal patches were calculated as 13.50 ng/mL (Cmax), 6.32 h (Tmax), 185.13 ng/mL×h (AUCt) and 197.85 ng/mL×h (AUCinf). Similarly, the predicted parametric values for a 30 mg patch designed (see Fig. 8) for once-daily dosing are 40.84 ng/mL (Cmax), 6.32 h (Tmax), 561.51 ng/mL×h (AUCt), and 599.61 ng/mL×h (AUCinf).
Predicted and observed plasma concentration of metoclopramide for once-daily dosing from (a) an intravenous administration (b) oral administration (c) from a 10 mg of drug patch and (d) from a 30 mg of drug patch.
The stability study of the optimized transdermal patch was carried out in a refrigerator, at room temperature, and in accelerated conditions. The physical characteristics and metoclopramide content were determined at different time intervals, as shown in Table 7. The morphology of the patches was found to be satisfactory, and no significant change was observed in the physical appearance. Similarly, the content of metoclopramide HCl was found to be 98.96 ± 0.90% in the refrigerator, 96.15 ± 1.81% at room temperature, and 95.45 ± 0.89% at accelerated temperature, respectively. Furthermore, the shelf life of metoclopramide HCl patches was calculated as 19.27 months at 5 ± 3 °C, 8.22 months at 25 ± 2 °C and 7.22 months at 40 ± 2 °C (Figure S4).
The present study reports using HNTs as a drug carrier in the transdermal delivery of metoclopramide HCl. Initially, the metoclopramide HCl was loaded in the HNTs with different ratios, and then the drug-in-adhesive type transdermal patches of metoclopramide-loaded HNTs were developed using the solvent evaporation method. In addition, DMSO and liquid paraffin were also incorporated as permeation enhancers in optimized formulation (F3) to assess their impact on the permeation of metoclopramide HCl. The patches were subjected to different evaluation or characterization tests, in-vitro release and permeation performance, in-silico absorption prediction, and stability study as described above. A low SD value among the weight and thickness of patches from the same formulation (Table 2) indicates the uniformity of the patches28. The variations in weight and thickness among the patches from different formulations may be due to differences in HNT-to-drug ratios. Also, a high value of folding endurance (> 300 folds) indicates that the patches can retain their physical stability and withstand skin folding during application27. Moreover, the low moisture content observed in the formulations is considered favorable as it reduces the chances of microbial contamination and enhances stability54. The high moisture uptake observed in the formulations is regarded as an essential property for the diffusion of drugs across the skin. When applied on the skin, the patch uptakes water from cells and the environment and thereby helps the active substance diffuse easily through the skin55. In addition, the average percent of metoclopramide in all formulations (Table 2 and Figure S1) ranged to meet the official compendia limit (90 to 110%) for the drug content32. Furthermore, the loading efficiency was directly related to the amount of halloysite in sample56. Therefore, the highest percent yield and loading efficiency in F3 (Table 2) could be due to the higher availability of halloysite in the sample for metoclopramide loading.
The release of metoclopramide HCl from the patches in the presence of HNTs was controlled along with a burst release in the initial minutes (Fig. 1). It was found that the amount of HNTs in the formulation was directly related to the controlled release of metoclopramide from the patches. The decrease in the release rate of metoclopramide in the presence of HNTs is considered to occur due to the loading of the drug into the lumen of HNTs or strong ion interaction between the drug and HNTs57. The burst effect in the formulations was supposed to happen due to the adsorbed drug on the surface and the low concentration of adhesive58,59. In a study conducted by Sharif, S., et al., a similar burst effect of metoclopramide HCl was observed from the halloysite nanotubes, and about 50% of the drug was released in the first 3 h60. The kinetic models applied on the release profile were found to best fit the Korsmeyer-Peppas model with Fickian behavior and the first-order model. Similarly, the release of drugs from the HNTs was also found to best fit with the same models in other studies21,58,60,61. In addition, O. Eraga et al. have also reported the Fickian diffusion mechanism for metoclopramide from polymeric transdermal patches and found first-order and Korsmeyer-Peppas as the best-fitted model with r2 > 0.9 2 (Table 3).
The permeation study revealed that the permeation flux was higher in patches with a high drug ratio (Fig. 2), possibly due to the high availability of drugs at the permeation site. Similarly, Liu et al. found that acrylic adhesives, due to their high thermodynamic activity and low interaction potential with the drug, cause high drug permeation62. Furthermore, it is believed that the amount of drug permeation from a drug in an adhesive-type transdermal patch depends on the percentage of drug released from the patch63. Although the rate of metoclopramide permeation was comparable among all the formulations, formulation F3 provided the lowest lag time (Table 4). The nano-size structure of HNTs might be responsible for the decrease in lag time by increasing the rate of metoclopramide penetration across the barrier membrane15,64. Therefore, based on the physicochemical properties, in-vitro metoclopramide release, and permeation results, the formulation F3 was selected as the optimized formulation, and it was further evaluated for the effect of permeation enhancers, skin irritation, chemical interaction, surface morphology, and stability.
The permeation of metoclopramide from the optimized formulation was found to increase with the addition of DMSO and liquid paraffin (Fig. 3). A study conducted by Amin, S., et al., where matrix patches of metoclopramide were formulated using Eudragit, also observed an increase in permeation and flux in the presence of 10% v/v DMSO as permeation enhancer9. The DMSO is known to expand the barrier membrane and thus help the diffusivity of drug substances across it65. Similarly, O. Eraga et al. reported a more than 30% increase in the diffusion rate of metoclopramide from the patches formulated with liquid paraffin2.
The FTIR study revealed that the characteristic peaks of the drug (metoclopramide HCl), such as O-H, HN2, and C = O stretching along with various bending peaks in the region of 1500 –1000 cm− 1, were found intact in the optimized patch material (Fig. 4), suggesting that no chemical interaction has taken place between the drug and the various components of the patch. Similarly, the peaks of the halloysite were also found intact in the optimized patch, suggesting no chemical interaction of the clay material with the drug and polymeric matrix.66,8. Moreover, the shifting of C-H stretching of the Duro-Tak 387–2510 in the optimized patch indicates the presence of the drug in the polymeric matrix as well with the consequent stretch in the C-H67.
The sharp endothermic peak in the DSC thermogram of pure metoclopramide HCl (Fig. 5) is suggestive of the melting of the monohydrate form of the drug68. The sharp endotherm with a broad peak observed in the CoTran 9720 backing layer was due to the melting of the backing layer. In the optimized transdermal patch, the melting of the drug was evident at ~ 93 °C, suggesting that the drug remained in the crystalline form of monohydrate salt after being loaded in the HNTs and formulated into patches. Similarly, the melting of the backing layer was also evident in the patch at the same temperature range, indicating no significant change in the form of any ingredient, if any21,69.
The SEM images showed HNTs nanotubules with lengths in nanometers, adsorbed drug particles on the HNTs surfaces, and a uniform distribution of metoclopramide-loaded HNTs within the patch (Fig. 6). These observations confirm the successful loading of drug particles onto the HNTs and ensure uniform drug throughout the patch.
Skin irritation was not observed when the metoclopramide-loaded HNT patch was applied to the mice skin in our study (Fig. 7). Although mild and tolerable irritation has been reported previously on rabbit skin9.
The values of pharmacokinetic parameters from the in-silico absorption model were predicted to be in agreement with observed values, indicating a reliable in-silico model (Table 6). Compared to intravenous administration, where plasma drug concentration decreases abruptly, there can be expected to be a gradual increase in the plasma levels of metoclopramide patch since the appearance of the drug in plasma depends on drug dissolution from the matrix and its permeation through skin barriers. According to Batemane et al. (1979), after a bolus of 10 mg through an intravenous injection, the plasma levels of metoclopramide decreased from 140 ng/mL to less than 20 ng/mL in one hour70; this enables us to understand that there would be a drastic change in the fold error values of Cmax and Tmax (Table 6) confirming the slow and controlled release of drug from the transdermal route. The plasma concentration of metoclopramide administered by a transdermal route was observed to equal the plasma concentration after administration by an intravenous route after 6–7 h. The most important feature of transdermal patches is that they deliver an effective concentration of the drug for an extended period through slower dermal absorption. Thus, based on the in silico pharmacokinetic model, it was possible to observe the viability of formulating transdermal patches using halloysite as a drug carrier as an alternative to oral administration thereby avoiding GI disturbances and possible hepatic elimination.
The morphology of the patches was found satisfactory in different environmental conditions during the stability study, and the metoclopramide HCl content was also observed to be within the limit, indicating the patches were relatively stable. However, a comparably higher shelf life was obtained at refrigerator temperature (Figure S4). Therefore, it can be proposed that the prepared patches should be stored at 5 ± 3 °C temperature.
Data is already available in the manuscript and the raw data will be available from the corresponding author upon reasonable request.
Metoclopramide pharmacology and clinical application. Ann. Intern. Med. 98, 86–95. (1983).
Eraga, O., Arhewoh, S. I., Meko, A. & M. & Evaluation of transdermal formulations of metoclopramide prepared using arachis oil and liquid paraffin as permeation enhancers. Pharma Biomed. Res. 6, 213–222 (2020).
Meko, O. A., Eraga, S. & Arhewoh, M. Transdermal delivery of metoclopramide using eucalyptus oil and shea butter. 12, 208–216 (2020).
Prausnitz, M. R., Mitragotri, S. & Langer, R. Current status and future potential of transdermal drug delivery. Nat. Rev. Drug Discov. 3, 115–124 (2004).
Article CAS PubMed Google Scholar
Mo, L., Lu, G., Ou, X. & Ouyang, D. Formulation and development of novel control release transdermal patches of carvedilol to improve bioavailability for the treatment of heart failure. Saudi J. Biol. Sci. 29, 266–272. https://doi.org/10.1016/j.sjbs.2021.08.088 (2022).
Article CAS PubMed Google Scholar
Imtiaz, M. S. et al. Formulation development and evaluation of drug-in-adhesive-type transdermal patch of metoclopramide HCl. Polym. bull. 79, 1187–1200. https://doi.org/10.1007/s00289-021-03559-3 (2022).
Alkilani, A. Z., McCrudden, M. T. & Donnelly, R. F. Transdermal drug delivery: innovative pharmaceutical developments based on disruption of the barrier properties of the stratum corneum. Pharmaceutics 7, 438–470. https://doi.org/10.3390/pharmaceutics7040438 (2015).
Article CAS PubMed Google Scholar
Kahali, N., Khanam, J. & Ghosh, N. An attempt to enhance solubility of metoclopramide base by solid dispersion strategy and its application on development of transdermal device. Brazilian J. Pharma Sci. 57 (2021).
Amin, S., Mir, S., Kohli, K. & Ali, A. Novel polymeric matrix films for transdermal delivery of metoclopramide. Int. J. Pharma Front. Res. 2, 48–60 (2012).
Saxena, M., Mutalik, S. & Reddy, M. Formulation and evaluation of transdermal patches of metoclopramide hydrochloride. Indian Drugs. 43, 740–745 (2006).
Marren, K. Dimethyl sulfoxide: an effective penetration enhancer for topical administration of NSAIDs. Phys. Sportsmed. 39, 75–82. https://doi.org/10.3810/psm.2011.09.1923 (2011).
Chuberre, B., Araviiskaia, E., Bieber, T. & Barbaud, A. Mineral oils and waxes in cosmetics: an overview mainly based on the current European regulations and the safety profile of these compounds. J. Europ Acad. Dermatol. Venereol. 33, 5–14. https://doi.org/10.1111/jdv.15946 (2019).
Jayvadan, P. & Rupal, J. Enhancing effect of natural oils as permeation enhancer for transdermal delivery of diltiazem hydrochloride through Wistar rat skin. Int. J. Pharm. Sci. Rev. Res. 36, 9–16 (2016).
Setter, O. P. & Segal, E. Halloysite nanotubes–the nano-bio interface. Nanoscale 12, 23444–23460 (2020).
Fizir, M. et al. Halloysite nanotubes in analytical sciences and in drug delivery: a review. Microchim. Acta. 185, 1–33 (2018).
Massaro, M., Noto, R., Riela, S. & Past Present and Future perspectives on Halloysite Clay minerals. Molecules 25, 4863 (2020).
Article CAS PubMed PubMed Central Google Scholar
Ahmed, F. R. et al. In-vitro assessment of cytotoxicity of halloysite nanotubes against HepG2, HCT116 and human peripheral blood lymphocytes. 135, 50–55 (2015).
Ahmed, F. R. et al. Clay nanotubes as a novel multifunctional excipient for the development of directly compressible diclofenac potassium tablets in a SeDeM driven QbD environment. Eur. J. Pharma Sci. 133, 214–227. https://doi.org/10.1016/j.ejps.2019.03.028 (2019).
Article ADS CAS Google Scholar
Krejčová, K., Deasy, PB & Rabišková, M. Optimization of Diclofenac Sodium Profile from Halloysite nanotubules. Ceska words. Pharmacy: Cas in Czech Pharmaceutical Society Slovak Pharmaceutical Society. 62, 71–77 (2013).
Borrego-Sánchez, A., Sainz-Díaz, C. I., Perioli, L. & Viseras, C. Theoretical study of retinol, niacinamide and glycolic acid with halloysite clay mineral as active ingredients for topical skin care formulations. Molecules (Basel Switzerland). 26, 4392. https://doi.org/10.3390/molecules26154392 (2021).
Article CAS PubMed Google Scholar
Sikandar, M. et al. Nanoclay-based composite films for transdermal drug delivery: development, characterization, and in silico modeling and simulation. Int. J. Nanomed. 17, 3463–3481. https://doi.org/10.2147/ijn.s367540 (2022).
Percie du Sert. The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLOS Biol. 18, e3000410. https://doi.org/10.1371/journal.pbio.3000410 (2020).
Article CAS PubMed PubMed Central Google Scholar
Council, N. R. Guide for the care and use of laboratory animals. (2010).
Levis, S. R. & Deasy, P. B. Use of coated microtubular halloysite for the sustained release of diltiazem hydrochloride and propranolol hydrochloride. Int. J. Pharm. 253, 145–157. https://doi.org/10.1016/S0378-5173(02)00702-0 (2003).
Article CAS PubMed Google Scholar
Al Hanbali, O. A. et al. Transdermal patches: design and current approaches to painless drug delivery. Acta Pharm. 69, 197–215 (2019).
Article CAS PubMed Google Scholar
Prabhu, P., Shah, S. & Gundad, S. Formulation development and investigation of domperidone transdermal patches. Int. J. Pharm. Investig. 1, 240–246. https://doi.org/10.4103/2230-973X.93008 (2011).
Article CAS PubMed PubMed Central Google Scholar
Mohd, F., Bontha, L., Bontha, V. & Vemula, S. Formulation and evaluation of transdermal films of ondansetron hydrochloride. MOJ Bioequiv Availab. 3, 00039 (2017).
Nair, R. S., Ling, T. N., Shukkoor, M. S. A. & Manickam, B. Matrix type transdermal patches of captopril: ex vivo permeation studies through excised rat skin. J. Pharm. Res. 6, 774–779 (2013).
Arora, P. & Mukherjee, B. Design, development, physicochemical, and in vitro and in vivo evaluation of transdermal patches containing diclofenac diethylammonium salt. J. Pharm. Sci. 91, 2076–2089. https://doi.org/10.1002/jps.10200 (2002).
Article CAS PubMed Google Scholar
Amnuaikit, C., Ikeuchi, I., Ogawara, K., Higaki, K. & Kimura, T. Skin permeation of propranolol from polymeric film containing terpene enhancers for transdermal use. Int. J. Pharm. 289, 167–178 (2005).
Article CAS PubMed Google Scholar
David, S. R. N., Rajabalaya, R. & Zhia, E. S. Development and in vitro evaluation of self-adhesive matrix-type transdermal delivery system of ondansetron hydrochloride. Trop. J. Pharm. Res. 14, 211–218 (2015).
Akram, M. R., Ahmad, M., Abrar, A., Sarfraz, R. M. & Mahmood, A. Formulation design and development of matrix diffusion controlled transdermal drug delivery of glimepiride. Drug Des. Dev. Ther. 12, 349–364. https://doi.org/10.2147/DDDT.S147082 (2018).
Wamorkar, V., Manjunath, S. Y. & Varma, M. Development and validation of UV spectroscopic method for determination of metoclopramide hydrochloride in bulk and tablet formulation. Int. J. Pharm. Pharm. Sci. 3, 171–174 (2011).
Zhang, Y. et al. DDSolver: an add-in program for modeling and comparison of drug dissolution profiles. AAPS J. 12, 263–271. https://doi.org/10.1208/s12248-010-9185-1 (2010).
Article CAS PubMed PubMed Central Google Scholar
Ali, F. R. et al. Design, Development, and Optimization of Dexibuprofen Microemulsion Based Transdermal Reservoir Patches for Controlled Drug Delivery. BioMed. Res. Int. 4654958, doi: (2017). https://doi.org/10.1155/2017/4654958 (2017).
Haney, P., Herting, K. & Smith, S. Molecular weight cut-off (MWCO) specifications and rates of buffer exchange with Slide-A-Lyzer dialysis devices and snakeskin dialysis tubing. Protein Biol. Resour. Libr. ThermoFisher Sci. Waltam (2013).
Ubaidulla, U., Reddy, M. V. S., Ruckmani, K., Ahmad, F. J. & Khar, R. K. Transdermal therapeutic system of carvedilol: Effect of hydrophilic and hydrophobic matrix on in vitro and in vivo characteristics. AAPS PharmSciTech. 8, E13–E20. https://doi.org/10.1208/pt0801002 (2007).
Article PubMed Central Google Scholar
Kunta, J. R., Goskonda, V. R., Brotherton, H. O., Khan, M. A. & Reddy, I. K. Effect of menthol and related terpenes on the percutaneous absorption of propranolol across excised hairless mouse skin. J. Pharm. Sci. 86, 1369–1373. https://doi.org/10.1021/js970161+ (1997).
Article CAS PubMed Google Scholar
Adrian, C. Williams. in Aulton’s Pharmaceutics - The design and manufacture of medicine Vol. 1 (ed Micheal F. Aulton and Kevin M. G. Taylor) Ch. 40, 715–738 (Elsevier, 2018).
Kumar De, P. et al. Optimization of in - vitro permeation pattern of ketorolac tromethamine transdermal patches. Iran. J. Pharm. Res. 10, 193–201 (2011).
ADS PubMed PubMed Central Google Scholar
Council, N. R. Guide for the care and use of Laboratory Animals: Eighth Edition (National Academies, 2011).
Singh, A. & Bali, A. Formulation and characterization of transdermal patches for controlled delivery of duloxetine hydrochloride. J. Anal. Sci. Technol. 7 https://doi.org/10.1186/s40543-016-0105-6 (2016).
Kasim, N. A. et al. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol. Pharm. 1, 85–96 (2004).
Article CAS PubMed Google Scholar
Bateman, D., Kahn, C., Mashiter, K. & Davies, D. Pharmacokinetic and concentration-effect studies with intravenous metoclopramide. Br. J. Clin. Pharmacol. 6, 401–407 (1978).
Article CAS PubMed PubMed Central Google Scholar
Stosik, A. et al. Biowaiver monographs for immediate release solid oral dosage forms: Metoclopramide hydrochloride. J. Pharm. Sci. 97, 3700–3708 (2008).
Article CAS PubMed Google Scholar
Webb, D., Buss, D., Fifield, R., Bateman, D. & Routledge, P. The plasma protein binding of metoclopramide in health and renal disease. Br. J. Clin. Pharmacol. 21, 334–336 (1986).
Article CAS PubMed PubMed Central Google Scholar
Hasan, E. I., Amro, B. I., Arafat, T. & Badwan, A. A. Assessment of a controlled release hydrophilic matrix formulation for metoclopramide HCl. Eur. J. Pharm. Biopharm. 55, 339–344. https://doi.org/10.1016/S0939-6411(03)00022-5 (2003).
Article CAS PubMed Google Scholar
Ross-Lee, L., Eadie, M., Hooper, W. & Bochner, F. J. E. Single-dose pharmacokinetics of metoclopramide. J. O C P. 20, 465–471 (1981).
Kuemmel, C. et al. Consideration of a credibility assessment framework in model-informed drug development: potential application to physiologically‐based pharmacokinetic modeling and simulation. CPT: Pharmacometrics Syst. Pharmacol. 9, 21–28 (2020).
Ellison, C. A. et al. Partition coefficient and diffusion coefficient determinations of 50 compounds in human intact skin, isolated skin layers and isolated stratum corneum lipids. Toxicol. Vitro. 69, 104990. https://doi.org/10.1016/j.tiv.2020.104990 (2020).
GuidelineI. H. T. Stability testing of new drug substances and products. Q1A (R2). current step 4, 1–24 (2003).
Schuppan, D., Schmidt, I. & Heller, M. [Preliminary pharmacokinetics of metoclopramide in humans. Plasma levels following a single oral and intravenous dose (author’s transl)]. Arzneimittelforschung 29, 151–154 (1979).
Mutalik, S. & Udupa, N. Glibenclamide transdermal patches: physicochemical, pharmacodynamic, and pharmacokinetic evaluations. J. Pharm. Sci. 93, 1577–1594. https://doi.org/10.1002/jps.20058 (2004).
Article CAS PubMed Google Scholar
Patel, K. N., Patel, H. K. & Patel, V. A. Formulation and characterization of drug in adhesive transdermal patches of diclofenac acid. Int. J. Pharm. Pharm. Sci. 4, 296–299 (2012).
Husain, T. et al. Investigating Halloysite nanotubes as a potential platform for oral modified delivery of different BCS class drugs: characterization, optimization, and evaluation of drug release kinetics. Int. J. Nanomed. 2021, 1725–1741. https://doi.org/10.2147/IJN.S299261 (2021).
Biddeci, G., Spinelli, G., Colomba, P., Di Blasi, F. & Nanomaterials A review about Halloysite nanotubes, properties, and application in the Biological Field. Int. J. Mol. Sci. 23, 11518 (2022).
Article CAS PubMed PubMed Central Google Scholar
Abdouss, M. et al. Fabrication of Bio-nanocomposite based on HNT-Methionine for controlled release of Phenytoin. Polymers 13 https://doi.org/10.3390/polym13152576 (2021).
Yang, D., Wan, X., Quan, P., Liu, C. & Fang, L. The role of carboxyl group of pressure sensitive adhesive in controlled release of propranolol in transdermal patch: quantitative determination of ionic interaction and molecular mechanism characterization. Eur. J. Pharm. Sci. 115, 330–338. https://doi.org/10.1016/j.ejps.2018.01.038 (2018).
Article CAS PubMed Google Scholar
Sharif, S. et al. Mucoadhesive micro-composites: Chitosan coated halloysite nanotubes for sustained drug delivery. Colloids Surf. B Biointerfaces. 184, 110527 (2019).
Article CAS PubMed Google Scholar
Mohebali, A., Abdouss, M. & Afshar Taromi, F. Fabrication of biocompatible antibacterial nanowafers based on HNT/PVA nanocomposites loaded with minocycline for burn wound dressing. Mater. Sci. Eng. C. 110, 110685. https://doi.org/10.1016/j.msec.2020.110685 (2020).
Liu, C., Hui, M., Quan, P. & Fang, L. Drug in adhesive patch of palonosetron: effect of pressure sensitive adhesive on drug skin permeation and in vitro-in vivo correlation. Int. J. Pharm. 511, 1088–1097 (2016).
Article CAS PubMed Google Scholar
Parhi, R. & Padilam, S. In vitro permeation and stability studies on developed drug-in-adhesive transdermal patch of simvastatin. Bull. Fac. Pharm. Cairo Univ. 56, 26–33 (2018).
Roberto Díaz-Torres. in. CURRENT TECHNOLOGIES TO INCREASE THE TRANSDERMAL DELIVERY OF DRUGS Vol. 1 (ed José Juan Escobar-Chávez) Ch. 7, 121 (Bentham Science, 2010).
Robinson, J. & Lee, V. H. Controlled drug Delivery: Fundamentals and Applications (CRC, 1987).
Husain, T. et al. Investigating Halloysite nanotubes as a potential platform for oral modified delivery of different BCS class drugs: characterization, optimization, and evaluation of drug release kinetics. Int. J. Nanomed. 16, 1725–1741. https://doi.org/10.2147/ijn.S299261 (2021).
Savaşer, A., Taş, Ç., Bayrak, Z., Özkan, C. K. & Özkan, Y. Effect of different polymers and their combinations on the release of metoclopramide HCl from sustained-release hydrophilic matrix tablets. Pharm. Dev. Technol. 18, 1122–1130. https://doi.org/10.3109/10837450.2012.710240 (2013).
Article CAS PubMed Google Scholar
Mitchell, A. G. Polymorphism in metoclopramide hydrochloride and metoclopramide. J. Pharm. Pharmacol. 37, 601–604. https://doi.org/10.1111/j.2042-7158.1985.tb05093.x (1985).
Article CAS PubMed Google Scholar
Joussein, E. et al. Halloysite clay minerals—a review. J. C m. 40, 383–426 (2005).
Bateman, D., Kahn, C., Mashiter, K. & Davies, D. J. B. J. o. C. P. Pharmacokinetic and concentration-effect studies with intravenous metoclopramide. 6, 401–407 (1978).
Khalid, S., Rasool, M.F., Masood, I. et al. Application of a physiologically based pharmacokinetic model inpredicting captopril disposition in children with chronic kidney disease. Sci. Rep. 13, 2697 (2023).
The authors thank the Department of Pharmaceutics and Bioavailability and Bioequivalence Research facility for their support. Furthermore, it is an academic research project that has no external funding.
Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi, Karachi, 75270, Pakistan
Monica Parkash, Muhammad Harris Shoaib, Muhammad Sikandar, Rabia Ismail Youssuf, Muhammad Talha Saleem, Farrukh Rafiq ahmed & Faad Siddique
Bioavailability and Bioequivalence Research Facility, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi, Karachi, 75270, Pakistan
Muhammad Harris Shoaib & Fahad Siddiqui
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
All authors contributed equally in this project.
Correspondence to Muhammad Harris Shoaib.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Below is the link to the electronic supplementary material.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Parkash, M., Shoaib, M.H., Sikandar, M. et al. Formulation development, characterization, and mechanistic PBPK modeling of metoclopramide loaded halloysite nanotube (HNT) based drug-in-adhesive type transdermal drug delivery system. Sci Rep 14, 28512 (2024). https://doi.org/10.1038/s41598-024-80089-8
DOI: https://doi.org/10.1038/s41598-024-80089-8
Anyone you share the following link with will be able to read this content:
Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative
Scientific Reports (Sci Rep) ISSN 2045-2322 (online)
pharma capsule filling machine Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.