Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Transdermal drug delivery system of lidocaine hydrochloride based on dissolving gelatin/sodium carboxymethylcellulose microneedles

Transdermal drug delivery system of lidocaine hydrochloride based on dissolving gelatin/sodium... Introduction number of drugs can be administered via TDDs (molecu- The skin is the largest organ of the body that provides a lar weight less than 500 Da) (Bos and Meinardi 2000). convenient and accessible route for drug delivery (Han To overcome these limitations, an innovative and Das 2015; Cevc and Chopra 2016). Transdermal drug microneedle (MN) approach aimed at developing safe delivery (TDD) demonstrates an attractive approach to and efficient means for delivering medications through systemic drug delivery and avoids pre-systematic metab- the skin has attracted the attention of many scien- olism (destruction in the gastrointestinal tract or by the tists (Hao Y et  al. 2017;  Kochhar et  al. 2016; Migdadi liver), the possibility of controlled drug delivery for a and Donnelly 2019; Ahmad et  al. 2020; Bonfante et  al. long time, and an alternative solution for oral dosing in 2020; Liu et  al. 2022; Dugam et  al. 2021). DMNs pen- patients with anesthesia or nausea and direct access to etrate the SC and dissolve in the interstitial tissue and the site or disease, for example, treatment of skin disor- release encapsulated drugs into the epidermal layer (He ders such as fungal infections and psoriasis (Prausnitz X et  al. 2019;  Bonfante et  al. 2020; Ma and Wu 2017; MR and  Langer R 2008; Jeong et  al. 2021; Wang et  al. Yang et al. 2020; Lee et al. 2020; Zhang et al. 2021; Xing 2021). Most importantly, since TDD is a noninvasive and et al. 2021). The evolution of these MNs has led to more almost painless administration method, it increases the innovative designs (Vecchione R. et  al. 2014:  Dugam acceptance of patients, especially children and the elderly et  al. 2021; Vora et  al. 2022; Roy et  al. 2022; Shah and (Inamuddin and Mohammad 2018; Zhu et al. 2001; Don- Choudhury 2017; Zhang et al. 2021). Hydrogel-forming nelly et  al. 2012). However, there are several challenges MN or swellable MN can be used as a method devel- to TDDs that have not yet fully achieved their poten- oped from the “poke and release” approach for drug tial as an alternative to hypodermic injections, mucosal delivery (Liu et al. 2022; Li et al. 2018; Dash et al. 2013) administration, and oral delivery. First, the physicochem- due to their high water content, biodegradability, bio- ical properties of the skin create a barrier to drug deliv- compatibility, and renewability (Bao et  al. 2019; Ge ery through the outermost layer of the skin epidermis et  al. 2018). Among the local anesthetics, lidocaine called the stratum corneum (SC) (Jeong et al. 2021; Wang is a frequently used medication for the treatment of et  al. 2021; Pastore et  al. 2015). Second, only a limited chronic pain and acute (Zempsky WT 2008; Kochhar Bahmani  et al. AAPS Open (2023) 9:7 Page 3 of 15 Fig. 1 The GEL/NaCMC hydrogel synthesis of schematic et al. 2013; Gomes et al. 2016; Houck and Sethna 2005; cellulose (NaCMC) are biopolymers with bioavailability Martell et  al. 2017); lidocaine must get through a skin properties that can deliver therapeutic drugs transder- barrier to reach the nerve system in order to provide a mally as well as in combination with the composition local anesthetic (Gudin and Nalamachu 2020). Inject- of DNM (Nayak et  al. 2013). GEL is a biodegradable able Lido solution in either basic (lidocaine) or acidic protein that is naturally amphoteric due to the presence forms (LidoHCl) has the mechanism of action antago- of both acidic and basic functional groups in the struc- nism of nerve signals in cells by inhibiting the influx of ture (Xing et  al. 2014; Hajzamani et  al. 2020). The low sodium ions through the sodium channels of the bio- thermal and mechanical stability of GEL hydrogels has logical cell membrane, which response to temporary constrained their use in a variety of applications. How- pain blockage on the skin surface (Rasool et  al. 2020; ever, by mixing GEL with other natural polymers such Cepeda et al. 2015; Abdellatif and Ibrahim 2020). How- as NaCMC, and also using crosslinking agents such as ever, using syringes can cause anxiety, pain, and infec- glutaraldehyde (GTA), its thermal and mechanical sta- tion that lead to poor patient compliance and require bility can be improved (Khan and Anwar 2021; Liu et al. a prescription by experienced medical personnel (Shin 2022; Favatela et al. 2021). GEL/NaCMC hydrogels can et  al. 2017; Donnelly et  al. 2010). Topical anesthetic be modified according to the ratio of polymers and gels and creams provide a simple, painless way to apply the amount of GTA for drug delivery under interstitial anesthesia. Nevertheless, these procedures lead to pas- fluid conditions (pH = 5.5 and T = 37 °C). GEL/NaCMC sive diffusion in the outer layer of the skin, resulting hydrogel synthesis representation is given in Fig.  1. As in slow-onset times of 30 to 60  min (Lee et  al. 2020). the protein and polysaccharides utilized in this research This delayed onset is a major obstacle to the widespread include abundant amino and carboxyl groups, they use of local anesthetics for intravenous access meth- generate a pH-sensitive hydrogel network. As per the ods (Donnelly et  al. 2010; Spierings et  al. 2008). To literature, the interstitial fluid of the skin has a mildly overcome this limitation, the MN has been studied to acidic environment (Wagner et al. 2003; Proksch 2018; deliver drugs through the transdermal route for a fast Ali and Yosipovitch 2013). onset time. The literature review showed that there are not enough The use of biopolymers like polysaccharides and pro - studies about dissolving microneedles for anesthetics teins for the crosslinking structure with the functional drug delivery systems. Here, a DMN transdermal drug role of trapping drugs and with the goal of optimiz- delivery system is proposed for the delivery of an anes- ing skin permeation pharmacokinetics has attracted thetic drug. GEL/NaCMC hydrogels in different mix - the attention of many investigators (Santos LF et  al. ing ratios were prepared and loaded with LidoHCl and 2018; Edgar et al. 2021; Jeong et al. 2021; Mustafa Kamal crosslinked with glutaraldehyde. The structural charac - et  al. 2020). Gelatin (GEL) and sodium carboxymethyl teristics of the DMN were determined by FTIR and XRD Bahmani et al. AAPS Open (2023) 9:7 Page 4 of 15 to confirm the lack of chemical interactions between the Table 1 Formulation MNs drug and comprehend the polymers and the formation of Sample codes Mixing ratio Polymer/GTA ratio LidoHCl crosslinking structure between GEL/NaCMC. The effect GEL/NaCMC (wt/wt) content (wt/wt) (%) of varying concentrations of polymers, crosslinker, and amount of drug on swelling, solubility, gel fraction, drug MN1 3:1 1.5 10 release behavior, and mechanical strength was also evalu- MN2 4:1 1.5 10 ated. So, considering the highest swelling in skin condi- MN3 5:1 1.5 10 tions, we believed that the development of GEL/NaCMC MN4 5:1 2.5 10 hydrogels with MN morphology via a manner of “poke MN5 5:1 3.1 10 and release” is a promising approach for TDDs, and MN6 5:1 1.5 20 this strategy can be used for pain relief as well as before MN7 5:1 1.5 40 minor skin surgery, such as the removal of moles, warts, and verrucas. ratio) was poured into the positive mold, and the proce- Materials and methods dure was completed by placing it in a vacuum oven over- Materials night. The last negative silicone mold was used to create GEL type A (300 bloom), NaCMC (Mw 250 kDa, DS: 0.9), MN from hydrogels (Fig. 2). GTA solution (25% in water), and acetic acid were sup- −1 plied from Sigma-Aldrich. LidoHCl (Mw 288.81 g  mol ) Scanning electron microscopy studies was provided by Darou Pakhsh Pharma Chem. Co.. All The surface morphology of the DMN arrays was inves - chemicals were used without further purification. tigated using SEM (Vegall, Tescan). DMN samples were mounted on an aluminum mount and sputtered with a Methods thin layer of gold. The samples were then placed into the Preparation of hydrogels SEM vacuum chamber and observed at various angles using an accelerating voltage of 15  kV. ImageJ software • Solution A: The clear gelatin solution was obtained was used to measure the dimensions. by dispersing the required amount of GEL at 40  °C (Bello et al. 2020; Ivone et al. 2021) while stirring, and FT‑IR spectroscopic analysis then, the required amount of LidoHCl was loaded FTIR spectral data were taken with the Infrared Bruker into it (Table  1), and its pH was adjusted to 3.8–4.2 −1 Tenso II instrument (at a resolution of 4  cm and aver- by adding acetic acid (0.1 M). aged 16 scans) to confirm the structure and also to find • Solution B: NaCMC was separately dispersed in dis- the chemical stability of the drug in the hydrogels. Gela- tilled water and gently heated (~ 50 °C) to accelerate tin, NaCMC, and LidoHCl were each separately finely dissolution. Subsequently, solution B was added to grounded with KBr and thus kept ready for taking spec- solution A and stirred until a viscous solution was tra. Also, for the GEL/NaCMC DMN and drug-loaded obtained. The total concentration of polymers in the DMN, ATR spectroscopy was performed with an EQUI- solution was constant at 15 (w/v%) for all prepared NOX device from Bruker, Germany. samples. After cooling to 25  °C, the crosslinking agent (GTA) was added slowly under continuous stir- X‑ray diffraction (XRD) analysis ring (400 rpm speed for 20 min). X-ray pattern of LidoHCL, drug-loaded, and unloaded DMN was analyzed using Inel X-ray Diffractometer (EQUINOX 3000). This analysis was run at a current of Molding 30 mA and voltage of 40 kV with Cu Ka radiation. Microneedle molds were made by a two-step “print and fill” method, using 3D printing (Krieger et al. 2019; Nejad Swelling, solubility, and gel fraction et  al. 2018). First, the positive template was designed The swelling behavior of hydrogels in different pH values of using 3Design software. Then, by examining the effects 1.2, 5.5, 6.5, and 7.5 of USP phosphate buffers at 37 ± 0.1 °C of MN mold geometry, the parameters of needle height was monitored (Khan and Anwar 2021). Typically, a certain (500 ± 10 µm), needle angle (35°), tip radius (40 ± 10 µm), amount (40 to 50 mg) of DMNs, dried to constant weight, and tip-to-tip distance (960 ± 10  µm) were optimized. The optimized design was printed using a 3D printer (DLP ). Afterward, it was washed with hot water and dried. The molding silicone resin with hardener (in a 10:1 Direct light processing Bahmani  et al. AAPS Open (2023) 9:7 Page 5 of 15 Fig. 2 MN mold. a Positive template fabricated by the 3D printer. b Obtained negative silicone mol Release study of LidoHCl in vitro was placed in a pouch made of nylon cloth, weighted, The in vitro drug release from LidoHCl-DMN was stud - and left to swell by immersing into a beaker containing ied in PBS buffer (pH = 5.5) by dissolution analysis. the swelling media. At regular intervals, the pouch was For this purpose, the paddle-over disk method (Fig.  3) removed from the solvent, after blotting with tissue paper was used to examine the transdermal delivery systems to remove excess solvent on the surface, and was weighed (USP38/NF33 2015; Jesús et al. 2022; Price et al. 2020). using an electronic microbalance (Sartorius 313, accuracy First, 500  ml of the buffer solution was poured into of ± 0.01  mg) and then returned to the medium. The per - the vessel, and then, the DMN assembled on a disk was centage of swelling determined at the time (t) was calcu- placed at the end of the vessel and stirred at 50  rpm. At lated using Eq. (1) (Saraswathy et al. 2020; Khan and Anwar predetermined time intervals, 2  ml of the solution was 2021): taken and replaced with a fresh one, and all samples were Ws − Wd tested in triplicate. Sink conditions were maintained WR % = × 100 ( ) (1) Ws throughout the experiment, with the concentration of the LidoHCl in the release medium being less than 10% where W and W are the weights of swollen hydrogels s d of the saturated solubility and constant temperature of at t, and dried hydrogels, respectively. The experiments 37 ± 0.5 °C. The concentration of LidoHCL in the release were repeated three times and reported as a mean value. media was determined by UV–Vis spectrophotometer The gel fraction was determined by weighing the (PerkinElmer, LAMBDA 365, USA) at λ of 263 nm. To max unwashed DMNs before drying them in an oven at 40  °C determine the reproducibility and the accuracy of the UV (M ). To remove non-crosslinked polymer, the samples test, the RSD percentage was calculated, and it was deter- were immersed in deionized water as a solvent for 24  h. mined to be less than 5%. Also, UV spectroscopy was After that, DMNs were dried in a vacuum oven at 40  °C performed for each of the ingredients of the formulation. until a constant weight was obtained (M ). The percentage Solution samples were tested separately, and PBS buffer of gel fraction was calculated using Eq.  (2) (Favatela et  al. (pH = 5.5) was the reference. 2021): Mf Calibration curve of LidoHCl GF (%) = ( ) × 100 (2) Mi A calibration curve is required to determine the rate of drug release from the samples (Pandit et al. 2016; Kumar Solubility analysis was performed to determine the et  al. 2012) Specified concentrations of LidoHCL (5, 10, quantity of partial dissolution or the percentage of mass 15, 20, 30, and 40  µg/ml) in the buffer (pH = 5.5) were lost. The DMNs were weighed before (M ) and after (M ) i f scanned in the range of 200–400 nm by using a UV–Vis being placed in 100-ml buffer (PBS pH 5.5) at 37  °C for spectrophotometer, and a prominent peak was observed 48  h, and then, weight loss was inspected. The samples at 263 ± 1 (nm). The absorbance values were recorded solubility was calculated based on Eq. (3) (Esteghlal et al. at 263  nm with the corresponding concentrations, the 2018): calibration curve was plotted, and the line equation was Solubility (%) = (M − M /M ) × 100 i f i (3) obtained with R = 0.9953. Using Eq.  4, the drug release rate was obtained by knowing its absorbance. Bahmani et al. AAPS Open (2023) 9:7 Page 6 of 15 Fig. 3 Paddle over disk for dissolution test fitted at the end of the falcon tube, and then, the hydro - Absorbance = 0.0181 Concentration (μg/ml) + 0.0258 gels were added and centrifuged for 5 min at 5000 rpm. (4) The centrifugal force caused the hydrogels to enter the microcavities of the MN mold (Fig.  5e). The molds Mechanical properties containing the hydrogel were then placed in a vacuum The evaluation of the mechanical strength of the oven to dry for 6  h. Finally, the DMN hydrogels were LidoHCl-DMN was measured using a SANTAM- STM20 instrument with a 6 N load cell as it allowed for sensitive measurements within an accuracy level of 0.4%. LidoHCl-DMNs containing 5 × 5 needle arrays were fixed on a platform surface under the vertically moving mechanical sensor using a double-sided adhe- sive tape. Then, the probe moved downward vertically −1 at a speed of 0.5  mm  s as shown in Fig.  4. Subse- quently, the varying force and sensor displacement were recorded during the test to obtain the axial force that causes the fracture of DMN. Antibacterial analysis The antimicrobial activities of the prepared MN were investigated using the diffusion method. One-hundred milliliters of gram-negative bacterial Escherichia coli and Staphylococcus aureus with a concentration of 0.5 × 10 was cultured, and it is used to test antibacterial activity by agar diffusion assay. The bacterial plates were placed in an incubator at 37  °C for 24  h. After 24  h, the plate was checked from the zone of inhibition by calculating the diameter of the inhibition section, and a picture was taken (Xue et al. 2013). Results Fabrication of MN The polymer mixture was cast into the negative mold Fig. 4 Schematic of the mechanical test machine by centrifuged force. The negative silicon mold was first Bahmani  et al. AAPS Open (2023) 9:7 Page 7 of 15 separated from the mold and washed three times with absorption of the microneedle was observed. The distilled water (40  °C) to remove unreacted materials. amount of glutaraldehyde had an inverse relation with The dried DMN hydrogels were placed in a vacuum- swelling. In other words, increasing the crosslinker equipped desiccator until further usage. concentration forms a strong structure that declines the swelling. Macrostructure Gel fraction and solubility study Figure 5a, b, and c indicated the surface morphology of The effects of the LidoHCl-DMN contents on the DMN arrays. The DMN arrays in this study had a sur - gel fraction are presented in Table  2. To scrutinize face area of 25 (mm ) and contained 25 MN equally the effect of the amount of crosslink agent on GF%, distributed in a 5 × 5 arrangement (Fig.  5e, f ). It was three samples (MN3, MN4, and MN5) were studied observed that SEM micrographs of the DMN arrays with different amounts of polymer/GTA ratio (3.1, sample contain slightly rough surfaces. The structure of 2.5, and 1.5), while the ratio of polymers and the individual needles was evident at increased magnifica - amount of drug are constant. These results show tion (Fig. 5a). that increasing the amount of crosslink agent leads to an increase in the percentage of GF. To elaborate the effect of polymers ratio on GF of DMN, three Structure investigation samples (MN1, MN2, and MN3) were prepared with The ATR-FTIR analysis confirmed the successful varying rates of GEL: NaCMC (3:1, 4:1, and 5:1) and crosslinking of GEL and NaCMC chains. The spectra keeping the amount of GTA and LidoHCl constant. of GEL, NaCMC, GEL/ NaCMC DMN, LidoHCl, and This is because increasing the concentration of GTA LidoHCl-loaded GEL/NaCMC DMN are presented leads to an increase in active sites for the crosslink- in Fig.  6. As shown, the stretching vibrations of the ing reaction. Thus, the crosslinking density between O–H and N–H in the GEL/NaCMC hydrogel spectrum GEL and NaCMC increases, which leads to an shifted gently to lower wavelengths. In addition, the increase in the mechanical strength of the hydrogel −1 amide I band shifted from 1654 to 1656  cm . These and a higher percentage of GF. indicated that the anionic groups in NaCMC with the cationic ones in GEL were coupled. On the other hand, In vitro drug release the new bands in the range of 1150 to 1070 are attrib- In vitro release studies were performed to under- uted to the C–O–C stretching vibrations, which con- stand drug release from LidoHCl-DMNs in the condi- firmed the crosslinking of the polymers. tions of skin pH. The selectivity results revealed that Figure  7 shows the diffractograms of LidoHCl, Gel/ in the λ of LidoHCl, each of the ingredients of the max NaCMC, and drug-loaded samples. As illustrated, formulation had no significant absorption. As shown LidoHCl has shown numerous characteristic sharp in Fig.  5g, h, and i, the tips of the needles swell after peaks due to its highly crystalline nature. The XRD 5  min, and a significant amount of needles dissolve pattern of blank GEL/NaCMC hydrogel (MNB sam- after 10 min. Figure 8 illustrates the effects of the ratio ple) exhibits a broad peak, which represented the of the polymer, the amount of crosslinker, and the amorphous state. The diffractogram achieved by the amount of medication on drug release at pH = 5.5. drug-loaded GEL/NaCMC DMN (MN3, MN6, MN7) indicated the same amorphous state at 2 = θ 21°. The Mechanical properties appearance of peaks following LidoHCl loading at 14° An axial compression force was applied to the MN and 26° indicates an increase in the crystallinity of the arrays to see whether they had adequate mechanical hydrogel samples. strength to penetrate the skin (Chen et  al. 2021). As reported in the force/needle results of DMNs (Table 2), Eec ff ts of pH, the ratio of polymers, and polymer/GTA ratio all MN arrays have the sufficient mechanical strength on swelling to penetrate the skin. The swelling behavior of GEL/NaCMC hydrogels is influenced by the pH of the immersed media, the ratio Antimicrobial activity of the two polymers, and the amount of the crosslinking The prepared sample was applied to bacterial E.coli and agent. Table  2 demonstrates the extent of the swelling S.aureus which results in antibacterial activity as shown of DMNs. The highest value of swelling was observed in Fig.  9. MN7 proved to be antibacterial in nature. The in acidic pH. Also, by raising the gelatin content in the average diameter of the zone of inhibition is 0.88 cm. microneedle composition, an increment in the water Bahmani et al. AAPS Open (2023) 9:7 Page 8 of 15 Fig. 5 LidoHCl DMNs. a Hydrogel-filled silicon mold. b and c Synthesized samples. d SEM at 280 × , e 500 × , f 80 × magnifications. g 0, h 5, and i 10 min after exposure to pH 5.5. j Before and k after the force application Bahmani  et al. AAPS Open (2023) 9:7 Page 9 of 15 Fig. 6 FTIR spectra of the LidoHCL, NaCMC, GEL/NaCMC DMN, and drug-loaded DMN Fig. 7 XRD pattern of LidoHCl, MNB, MN3, MN6, and MN7 samples Table 2 The results of swelling, GF, solubility, and mechanical strength tests Sample codes Degree of swelling (%) GF (%) Solubility (%) Force/ needle pH (1.2) pH (5.5) pH (6.5) pH (7.5) (N) MN1 346 298 165 86 73 53 0.23 MN2 540 467 303 101 68.4 65 0.19 MN3 610 553 333 120 64.2 73 0.15 MN4 330 263 111 86 76.1 45 0.34 MN5 160 123 103 74 84.5 40 0.45 MN6 646 555 340 135 57 85 0.14 MN7 650 560 350 150 58.3 89 0.16 Bahmani et al. AAPS Open (2023) 9:7 Page 10 of 15 Fig. 8 Eec ff t of a GTA, b polymer ratio, and c the amount of LidoHCl on in vitro release profile Bahmani  et al. AAPS Open (2023) 9:7 Page 11 of 15 NaCMC showed a strong absorbance band at −1 3368  cm was assigned to the O–H stretching vibra- −1 tion. The shoulder at 2918  cm indicated aliphatic C–H −1 stretching vibrations, while the strong peak at 1625  cm −1 and medium peak at 1425  cm were due to the asym- metric and symmetric stretching of the carboxylate group. The intense peak of C–O stretching vibration for ethers was ascribed to the significant absorption peaks at −1 1000–1160  cm . These findings are in good accord with findings from previous investigations (Devi and Maji 2009). The main absorption peaks of LidoHCl powder were −1 observed at 3382, 3011, 1654, and 1470  cm . These bands were assigned as N–H stretching, C–H stretching, amide I (C = O), and amide II (C–N), respectively. FTIR spectra were also used to affirm the chemical stability of LidoHCL in samples. As observed in Fig.  6, the posi- tion of these bonds in drug-containing hydrogels almost remained unchanged, indicating there was no significant Fig. 9 Antimicrobial activity of MN7 chemical interaction between the drug and the GEL/ NaCMC hydrogels. It may be noted that in the case of −1 drug-containing DMNs, the band observed at 1654  cm Discussion overlapped with the GEL amide band, so XRD analy- Dissolving and hydrogel-forming MN with the “poke and sis was performed to confirm the stability of Lido in the release” approach are a novel method of TDDs in which hydrogel. drugs can be loaded and released when the MN dissolves The intensity of XRD peaks was more noticeable for the after insertion (Liu et al. 2022), also reducing onset time MN7 sample than for the MN3 and MN6 samples, indi- and improving permeability (Ma and Wu 2017; Yang cating a higher amount of drug. These results are consist - et  al. 2020). In this study, a mixture of a polysaccha- ent with the in vitro drug release data. ride (NaCMC) and a protein (GEL) was used to create a The study of swelling results showed that acidic media drug delivery carrier with microneedle morphology. The is due to the protonation of the free amino groups of dimensions of the prepared microneedle were needle GEL, which leads to electrostatic repulsions between height 450  µm, tip radius 30  µm, and tip-to-tip distance them and thus expands the polymer network, whereas 960 µm. Examining the different dimensional parameters free carboxylic groups with hydroxyl groups of NaCMC of the microneedle, it was found that needles with an may lead to a contraction of the network by intense input height of 300 to 600 µm are not of sufficient qual - hydrogen interactions or by intermolecular lactonization ity for molding, and higher heights may cause pain in the (Khan and Anwar 2021; Tataru et  al. 2011). As the pH patient (Krieger et al. 2019; Nejad et al. 2018). increases towards the basic medium, carboxylic groups The ATR-FTIR spectrum of samples clearly showed of CMC become ionized, and GEL owns COO − groups, the absorption bands of the crosslinked mixture of poly- and the electrostatic repulsion between the carboxy- mers. In the spectrum of GEL, a sharp absorbance band −1 late groups expands the polymer network. Due to the was observed at 3420  cm due to N–H stretching vibra- −1 higher weight ratio of GEL in hydrogels, its effect on tion. The medium peak at 1558  cm belonged to the the degree of swelling was superior to NaCMC; hence, N–H bending vibration. The absorption bands appearing −1 the maximum swelling was observed in acidic pHs (1.2, at 1654 and 1330  cm indicated the type 1 amide band 5.5). Similar findings were presented by Khan and Taturo, and the C–N band stretching vibrations, respectively, and that the swelling ratio increases with increasing GEL which are the most significant peaks for FTIR analysis content (Khan and Anwar 2021; Tataru et  al. 2011). As of the gelatin structure (Khan and Anwar 2021; Buhus −1 shown in Table  2, hydrogels containing higher amounts et  al. 2009). The medium peak at 1239  cm belonged of GEL (MN3) showed a higher degree of swelling than to the type 3 amide, and the weak peak that appeared at −1 formulations containing lower amounts of gelatin (MN1, 1525  cm was assigned to the type 2 amide. The band −1 MN2). The swelling data of crosslinked hydrogels showed appearing at 1440  cm indicated aliphatic C–H bend- that by increasing the amount of GTA in the polymer ing vibrations, while aliphatic C–H stretching vibrations −1 hydrogel from 3.1 to 2.5 (wt/wt), the swelling decreases were observed at 2923  cm . Bahmani et al. AAPS Open (2023) 9:7 Page 12 of 15 significantly from 553 to 263%. This was owing to the elaborate the effect of drug loading on in  vitro release hydrogel’s mechanical strength increasing as a result of profiles, three DMN samples (MN3, MN6, and MN7) crosslinking and the formation of a more compact wall. were prepared with varying concentrations of LidoHCl Also, it is observed that MN5 has the highest GF with (10, 20, and 40%) and kept the concentration polymers more crosslinker. Similar findings were reported that and GA constant. This indicates that an increase in drug GF is directly related to crosslinking density (Khan and concentration causes an increase in the release rates of Anwar 2021). The GEL/NaCMC ratio of 5:1 showed a drugs (Fig.  8c). Also, MN7 exhibited excellent antibacte- lower gel fraction compared to the ratio of 3:1 and 4:1. rial activity. According to previous studies, in the short This is consistent with the results of Kreua-Ongarjnukool contact time and low concentration of glutaraldehyde, et  al. (2020) who concluded that at constant concentra- the adverse effect on the skin does not remain (Ballan - tions of GTA, the gel fraction decreases with increasing tyne and Jordan 2001). polymer concentration, meaning that polymer chains DMN array failure force is presented in Table 2. Accord- have less crosslinking. Also, there was no significant ing to the literature, the insertion force required to over- difference between MN7 and MN6, indicating that the come the barrier of the skin and deliver the drug efficiently −1 amount of drug did not affect GF. MN5 with the high - into the skin is 0.058 (N needle ) (Davis et al. 2004). For est amount of GTA showed the lowest dissolution. Other MN3, MN4, and MN5 DMNs, failure force increased authors have achieved similar results in examining the with an increasing amount of GTA. This dependence is crosslinks of GEL/NaCMC (Khan and Anwar 2021; expected because increasing the crosslinker quantity leads Favatela et  al. 2021). They argued that increasing the to a rigid network structure. Comparing the mechani- crosslink density increases the mechanical strength of the cal strength of neat GEL and GEL/NaCMC DMN arrays hydrogel, which in turn leads to a decrease in the solubil- showed that the addition of NaCMC to GEL greatly ity of the hydrogel and reduces the water-uptake capacity increases the mechanical properties. However, pure GEL of the polymer network. From data in Table  2, it is evi- DMN arrays exhibit compression forces at the end (low dent that the solubility at the 5:1 (MN3) ratio of polymers stress at fracture) of 0.051 (N), while mechanical strength was higher than the ratio of 3:1 (MN1) which is in good for GEL/NaCMC DMN arrays reached 0.162 ± 0.01 N. agreement with the results of swelling. Similar findings Liu et  al. (2022) deduced that the addition of cellulose were presented by Tataro et  al. (Tataru et  al. 2011) that nanofibrils to GEL could effectively improve the strength as the amount of gelatin increased, more electrostatic and toughness of the composite hydrogels. They found repulsion was generated, leading to the relaxation of the that when the composite hydrogel is under stress, the load polymer network. In MN3, MN6, and MN7 samples, the can be transferred efficiently between the GEL matrix and effect of drug amount on solubility was investigated. The cellulose nanofibrils. As shown in Table  2, the mechanical MN7 sample showed the highest percentage of solubil- strength of MN1 with a polymer ratio of 3:1 has higher ity. At a constant ratio of polymers and the amount of mechanical strength than MN3 and MN2. However, there crosslinker, the solubility increases with the increasing was no significant difference in the mechanical strength of amount of drug. This may be due to increased electro - various amounts of the drug (MN3, MN6, and MN7). The static repulsion between the polar groups of GEL and shape of the synthesized DMN before and after applying LidoHCl. the force is shown in Fig. 5j and k. According to these results, during the first 10  min of release, a burst release effect was observed, and then, its Conclusion value increased slightly for a while and was fixed after Dissolving microneedles loaded lidocaine based on natu- 60  min. Effects of various ratios of polymers in formu - ral polymers GEL and NaCMC were synthesized using lations MN1, MN2, and MN3 on release rates are pre- GTA as the crosslinking agent. Prepared DMN can replace sented in Fig.  8b. The MN3 formulation showed higher conventional anesthetic delivery methods such as injec- release rates than MN2. Similarly, MN2 revealed a higher tions and topical creams, due to their dissolution in skin release rate than MN1. Drug release experiments agreed pH, rapid onset time, and ability to cross the SC layer with the study of swelling; as the rate of GEL versus and deliver the sufficient drug to the skin. FTIR was used NaCMC increases, the swelling increases, which in turn to corroborate the formation of crosslinked hydrogels causes the higher release of drug (Fig.  8b). The effect of between GEL and NaCMC. Also, XRD analysis indicated GTA content in MN3, MN4, and MN5 formulations on that the LidoHCl remained crystalline in the hydrogels. In drug release rate is shown in Fig. 8a. The drug release rate addition, the shape of the DMN was shown on scanning was higher in the case of MN3 than in MN4 and MN5. electron microscopy micrographs. The synthesized DMN This is because increasing the concentration of GTA showed excellent swelling and solubility at skin pH. The leads to the formation of a rigid network structure. To results of the drug release study demonstrated that it was Bahmani  et al. AAPS Open (2023) 9:7 Page 13 of 15 Bonfante G, Lee H, Bao L, Park J, Takama N, Kim B (2020) Comparison of poly- directly related to the ratio of polymers and the amount mers to enhance mechanical properties of microneedles for bio-medical of drug and inversely to the amount of crosslinker. It was applications. Micro Nano Syst Lett 8(1):1–3. https:// doi. org/ 10. 1186/ also observed that all samples presented a burst release in s40486- 020- 00113-0. Springer Singapore Bos JD, Meinardi MMHM (2000) The 500 Dalton rule for the skin penetration of the first 10  min. Mechanical properties data revealed that chemical compounds and drugs. Exp Dermatol 9:165–9. https:// doi. org/ all synthesized DMNs were able to cross the skin barrier. 10. 1034/j. 1600- 0625. 2000. 00900 3165.x In this study, MN7 was considered the ideal DMN with the Buhus G, Popa M, Desbrieres J (2009) Hydrogels based on carboxymethylcel- lulose and gelatin for inclusion and release of chloramphenicol. J Bioact highest drug release rate and sufficient mechanical strength Compat Polym 24:525–545 to penetrate the skin. It can be concluded that DMN loaded Cepeda MS, Tzortzopoulou A, Thackrey M, Hudcova J, Arora Gandhi P, LidoHCl based on GEL/NaCMC hydrogels have the poten- Schumann R (2015) Adjusting the pH of lidocaine for reducing pain on injection. Cochrane Database Syst Rev 5:CD006581. pp 1–65 tial to be used as transdermal drug delivery devices. They Cevc G, Chopra A (2016) Deformable ( Transfersome ) vesicles for improved can dissolve well in skin pH and are a good clinical tool in drug delivery into and through the skin. In: Percutaneous penetration the field of local anesthesia and management of periopera - Enhanc Chem methods penetration Enhanc. Springer, Berlin, Heidelberg. p 39–59. https:// doi. org/ 10. 1007/ 978-3- 662- 47862-2_3 tive pain and chronic pain as well as before minor skin sur- Chen X, Yu H, Wang L, Wang N, Zhang Q, Zhou W et al (2021) Preparation of gery, such as the removal of moles, warts, and verrucas. phenylboronic acid-based hydrogel microneedle patches for glucose- dependent insulin delivery. J Appl Polym Sci 138:1–11 Acknowledgements Dash R, Foston M, Ragauskas AJ (2013) Improving the mechanical and thermal Not applicable. properties of gelatin hydrogels cross-linked by cellulose nanowhiskers. Carbohydr Polym 91:638–45. https:// doi. org/ 10. 1016/j. carbp ol. 2012. 08. Authors’ contributions 080. Elsevier Ltd. The authors read and approved the final manuscript. Davis SP, Landis BJ, Adams ZH, Allen MG, Prausnitz MR (2004) Insertion of microneedles into skin: measurement and prediction of insertion force Funding and needle fracture force. J Biomech 37:1155–1163 No funding body has provided funding for this research. Devi N, Maji TK (2009) Preparation and evaluation of gelatin/sodium carboxy- methyl cellulose polyelectrolyte complex microparticles for controlled Availability of data and materials delivery of isoniazid. AAPS PharmSciTech 10:1412–1419 All data generated or analyzed during this study are included in this published article. Donnelly RF, Raj Singh TR, Woolfson AD (2010) Microneedle-based drug delivery systems: microfabrication, drug delivery, and safety. Drug Deliv 17(4):187–207. https:// doi. org/ 10. 3109/ 10717 54100 36677 98 Declarations Donnelly RF, Singh TRR, Garland MJ, Migalska K, Majithiya R, McCrudden CM et al (2012) Hydrogel-forming microneedle arrays for enhanced transder- Competing interests mal drug delivery. Adv Funct Mater 22:4879–4890. Wiley Online Library The authors declare that they have no competing interests. Dugam S, Tade R, Dhole R, Nangare S (2021) Emerging era of microneedle array for pharmaceutical and biomedical applications: recent advances Author details and toxicological perspectives. Futur J Pharm Sci 7:1–26. Future Journal of Department of Polymer Engineering, Faculty of Engineering, Islamic Azad Pharmaceutical Sciences University, South Tehran Branch, P.O. Box: 11365/4435, Tehran, Iran. Depar t- Edgar AC-M, Guadalupe M-M, Gonzalo V (2021) Interactions of the molecular ment of Polymer and Textile, Islamic Azad University, South Tehran Branch, assembly of polysaccharide-protein systems as encapsulation materi- P.O. Box: 11365/4435, Tehran, Iran. Department of Polymer Processing, Iran als. A review, Advances in Colloid and Interface Science, vol 295, ISSN Polymer and Petrochemical Institute (IPPI), P.O. Box: 14965-112, Tehran, Iran. 0001–8686. https:// doi. org/ 10. 1016/j. cis. 2021. 102398. https:// www. scien Department of Medical, Tehran Medical Sciences Branch Islamic Azad Univer- cedir ect. com/ scien ce/ artic le/ pii/ S0001 86862 10003 97 sity, P.O. Box: 19395/1495, Tehran, Iran. Esteghlal S, Niakousari M, Hosseini SMH (2018) Physical and mechanical prop- erties of gelatin-CMC composite films under the influence of electrostatic Received: 23 December 2022 Accepted: 27 February 2023 interactions. Int J Biol Macromol 114:1–9. https:// doi. org/ 10. 1016/j. ijbio mac. 2018. 03. 079. Elsevier B.V. Favatela F, Horst MF, Bracone M, Gonzalez J, Alvarez V, Lassalle V (2021) Gelatin/ cellulose nanowhiskers hydrogels intended for the administration of drugs in dental treatments: study of lidocaine as model case. J Drug Deliv Sci Tech- References nol 61:101886. https:// doi. org/ 10. 1016/j. jddst. 2020. 101886. Elsevier B.V. Abdellatif MK, Ibrahim TH (2020) Intraoperative infusion of lidocaine 2% Ge S, Li M, Ji N, Liu J, Mu H, Xiong L et al (2018) Preparation of a strong gelatin- reduces postoperative fentanyl requirements for pain control in renal short linear glucan nanocomposite hydrogel by an in situ self-assembly transplantation surgery. Ain-Shams J Anesthesiol 12(1):1–6 process. J Agric Food Chem 66:177–186 Ahmad Z, Khan MI, Siddique MI, Sarwar HS, Shahnaz G, Hussain SZ, Bukhari NI, Gomes C, Glass M, Kieffer J, Chiforeanu M, Philippe P (2016) Topical anaesthetic Hussain I, Sohail MF (2020). Fabrication and Characterization of Thiolated solutions for pain free suture of lacerations in the emergency Dr Sylvie Martus, Chitosan Microneedle Patch for Transdermal Delivery of Tacrolimus. AAPS Laurence Poncin • lacerations = frequent in a paediatric emergency room • PharmSciTech 21(2):68. https:// doi. org/ 10. 1208/ s12249- 019- 1611-9 usually: local anaesthesia by injection of Lidocaine – But: pain, fear and a Ali SM, Yosipovitch G (2013) Skin pH: from basic science to basic skin care. Acta Gudin J, Nalamachu S (2020) Utility of lidocaine as a topical analgesic and Derm Venereol 93:261–267 improvements in patch delivery systems. Postgrad Med 132:28–36. Ballantyne B, Jordan SL (2001) Toxicological, medical and industrial hygiene https:// doi. org/ 10. 1080/ 00325 481. 2019. 17022 96. Taylor & Francis aspects of glutaraldehyde with particular reference to its biocidal use in Hajzamani D, Shokrollahi P, Najmoddin N, Shokrolahi F (2020) Eec ff t of engi- cold sterilization procedures. J Appl Toxicol 21:131–151. England neered PLGA-gelatin-chitosan/PLGA-gelatin/PLGA-gelatin-graphene Bao Z, Xian C, Yuan Q, Liu G, Wu J (2019) Natural polymer-based hydrogels three-layer scaffold on adhesion/proliferation of HUVECs. Polym Adv with enhanced mechanical performances: preparation, structure, and Technol 31:1896–1910 property. Adv Healthc Mater 8:1–11 Han T, Das DB (2015) Potential of combined ultrasound and microneedles for Bello AB, Kim D, Kim D, Park H, Lee S-H (2020) Engineering and functionaliza- enhanced transdermal drug permeation: a review. Eur J Pharm Biopharm. tion of gelatin biomaterials: from cell culture to medical applications. 89:312–28. https:// doi. org/ 10. 1016/j. ejpb. 2014. 12. 020. Elsevier B.V. Tissue Eng Part B Rev 26:164–80. United States Bahmani et al. AAPS Open (2023) 9:7 Page 14 of 15 Hao Y, Li W, Zhou X, Yang F, Qian Z (2017) Microneedles-based transdermal Pandit AP, Pol VV, Kulkarni VS (2016) Xyloglucan based in situ gel of lidocaine drug delivery systems: a review. J Biomed Nanotechnol 13:1581–1597 HCl for the treatment of periodontosis. J Pharm 2016:1–9 He X, Sun J, Zhuang J, Xu H, Liu Y, Wu D (2019) Microneedle system for Pastore MN, Kalia YN, Horstmann M, Roberts MS (2015) Transdermal patches: transdermal drug and vaccine delivery: devices, safety, and prospects. history, development and pharmacology. Br J Pharmacol 172:2179–2209 Dose-Response 17:1–18 Prausnitz MR, Langer R (2008) Transdermal drug delivery. Nat Biotechnol Houck CS, Sethna NF (2005) Transdermal analgesia with local anesthetics in 26:1261–1268. Nature Publishing Group children: review, update and future directions. Expert Rev Neurother Price R, Shur J, Ganley W, Farias G, Fotaki N, Conti DS et al (2020) Development 5:625–634. Taylor & Francis of an aerosol dose collection apparatus for in vitro dissolution measure- Inamuddin A, Mohammad A (2018) Applications of nanocomposite materials ments of orally inhaled drug products. AAPS J 22:47. United States in drug delivery Proksch E (2018) pH in nature, humans and skin. J Dermatol 45:1044–1052 Ivone R, Yang Y, Shen J (2021) Recent advances in 3D printing for parenteral Rasool A, Ata S, Islam A, Rizwan M, Azeem MK, Mehmood A et al (2020) applications. AAPS J 23:87. https:// doi. org/ 10. 1208/ s12248- 021- 00610-z Kinetics and controlled release of lidocaine from novel carrageenan and Jeong WY, Kwon M, Choi HE, Kim KS (2021) Recent advances in transdermal drug alginate-based blend hydrogels. Int J Biol Macromol 147:67–78. https:// delivery systems: a review. Biomater Res 25:1–15. Biomaterials Researchdoi. org/ 10. 1016/j. ijbio mac. 2020. 01. 073. Elsevier B.V. Jesús P-P, Montserrat M-C, Dolors P-DM, Ramon T-GJ, Antonio B-M (2022) Roy G, Garg P, Venuganti VVK (2022) Microneedle scleral patch for minimally Release of ropinirole in acrylate transdermal patches: mutual interactions invasive delivery of triamcinolone to the posterior segment of eye. Int between formulation variables. AAPS PharmSciTech 23:82. United States J Pharm 612:121305. https:// doi. org/ 10. 1016/j. ijpha rm. 2021. 121305. Khan S, Anwar N (2021) Gelatin/carboxymethyl cellulose based stimuli-respon- Elsevier B.V. sive hydrogels for controlled delivery of 5-fluorouracil, development, Santos LF, Correia IJ, Silva AS, Mano JF (2018) Biomaterials for drug delivery in vitro characterization, in vivo safety and bioavailability evaluation. patches. Eur J Pharm Sci 118:49–66. https:// doi. org/ 10. 1016/j. ejps. 2018. Carbohydr Polym 257:117617. https:// doi. org/ 10. 1016/j. carbp ol. 2021. 03. 020. Elsevier B.V. 117617. Elsevier Ltd Saraswathy K, Agarwal G, Srivastava A (2020) Hyaluronic acid microneedles- Kochhar JS, Lim WXS, Zou S, Foo WY, Pan J, Kang L (2013) Microneedle laden collagen cryogel plugs for ocular drug delivery. J Appl Polym Sci integrated transdermal patch for fast onset and sustained delivery of 137:1–14 lidocaine. Mol Pharm 10:4272–4280. ACS Publications Shah V, Choudhury BK (2017) Fabrication, Physicochemical Characterization, Kochhar JS, Tan JJY, Kwang YC, Kang L (2019) Microneedle patch for fast onset and Performance Evaluation of Biodegradable Polymeric Microneedle and long-lasting delivery of painkillers. In: Microneedles Transdermal Patch System for Enhanced Transcutaneous Flux of High Molecular Drug Deliv. p 67–80 Weight Therapeutics. AAPS PharmSciTech 18(8):2936–2948. https:// doi. Kreua-Ongarjnukool N, Niyomthai ST, Sarodom K, Lothong T, Soomherun N org/ 10. 1208/ s12249- 017- 0774-5 (2020) Hybrid gelatin/carboxymethyl cellulose hydrogel loaded copper Shin CI, Jeong SD, Rejinold NS, Kim Y-C (2017) Microneedles for vaccine deliv- (II) ion for medical applications. Mater Sci Forum 1009 MSF:3–8 ery: challenges and future perspectives. Ther Deliv 8:447–60. Available Krieger KJ, Bertollo N, Dangol M, Sheridan JT, Lowery MM, O’Cearbhaill ED from: https:// www. future- scien ce. com/ doi/ 10. 4155/ tde- 2017- 0032 (2019) Simple and customizable method for fabrication of high-aspect Spierings ELH, Brevard JA, Katz NP (2008) Two-minute skin anesthesia through ratio microneedle molds using low-cost 3D printing. Microsystems Nano- ultrasound pretreatment and iontophoretic delivery of a topical anes- eng 5(1):42. https:// doi. org/ 10. 1038/ s41378- 019- 0088-8. Springer US thetic: a feasibility study. Pain Med 9:55–9. Available from: https:// acade Kumar BK, Rajan VST, Begum NT (2012) Analytical method development and mic. oup. com/ painm edici ne/ artic le- lookup/ doi/ 10. 1111/j. 1526- 4637. validation of lidocaine in ointment formulation by UV spectrophotomet-2007. 00281.x ric method. Int J Pharm Pharm Sci 4:610–4. Available from: http:// www. Tataru G, Popa M, Desbrieres J (2011) Microparticles of hydrogel type based ijpps journ al. com/ Vol4I ssue2/ 3568. pdf on carboxymethylcellulose and gelatin for controlled release of water Lee B-M, Lee C, Lahiji SF, Jung U-W, Chung G, Jung H (2020) Dissolving soluble drugs. Rev Roum Chim 56:399–410 microneedles for rapid and painless local anesthesia. Pharmaceutics USP38/NF33 (2015) Validation of compendial methods section. United State 12:366. Multidisciplinary Digital Publishing Institute Pharmacopeial/National Formul, p 2256. The United States Pharmaco- Li W, Terry RN, Tang J, Feng MR, Schwendeman SP, Prausnitz MR (2018) Sus- peial Convention 12601 Twinbrook Parkway, Rockville, MD 20852. tained release of a contraceptive. Nat Biomed Eng. Springer US. https:// Vecchione R, Coppola S, Esposito E, Casale C, Vespini V, Grilli S et al (2014) doi. org/ 10. 1038/ s41551- 018- 0337-4 Electro-drawn drug-loaded biodegradable polymer microneedles as a Liu Q, Liu J, Qin S, Pei Y, Zheng X, Tang K (2020) High mechanical strength gela- viable route to hypodermic injection. Adv Funct Mater 24:3515–3523 tin composite hydrogels reinforced by cellulose nanofibrils with unique Vora D, Garimella HT, German CL, Banga AK (2022) Microneedle and ionto- beads-on-a-string morphology. Int J Biol Macromol 164:1776–84. https:// phoresis mediated delivery of methotrexate into and across healthy and doi. org/ 10. 1016/j. ijbio mac. 2020. 08. 044. Elsevier B.V. psoriatic skin. Int J Pharm 618:121693. https:// doi. org/ 10. 1016/j. ijpha rm. Liu B, Yi X, Zheng Y, Yuan Z, Yang J, Yang J et al (2022) A review of nano/micro/2022. 121693. Elsevier B.V. milli needles fabrications for biomedical engineering. Chinese J Mech Wagner H, Kostka KH, Lehr CM, Schaefer UF (2003) pH profiles in human skin: Eng (English Ed) 35(1):106. https:// doi. org/ 10. 1186/ s10033- 022- 00773-6. influence of two in vitro test systems for drug delivery testing. Eur J Springer Nature Singapore Pharm Biopharm 55:57–65 Ma G, Wu C (2017) PT NU SC. J Control Release. Elsevier B.V. https:// doi. org/ 10. Wang M, Luo Y, Wang T, Wan C, Pan L, Pan S et al (2021) Artificial skin percep - 1016/j. jconr el. 2017. 02. 011 tion. Adv Mater 33:1–20 Martell B, Kushner H, Richardson E, Mize A, Mayer P (2017) Pharmacokinetics Xing Q, Yates K, Vogt C, Qian Z, Frost MC, Zhao F (2014) Increasing mechani- of lidocaine and its metabolites following vaginal administration of lido- cal strength of gelatin hydrogels by divalent metal ion removal. Sci Rep caine gel to healthy female subjects. Clin Pharmacol Drug Dev 6:27–35 4:1–10 Migdadi EM, Donnelly RF (2019) Microneedles for transdermal drug delivery. Xing M, Wang X, Zhao L, Zhou Z, Liu H, Wang B et al (2021) Novel dissolving In: Imaging Technol. Transdermal Deliv. Ski. Disord microneedles preparation for synergistic melasma therapy: combined Mustafa Kamal NA, Tuan Mahmood TM, Ahmad I, Ramli S (2020) Improving effects of tranexamic acid and licorice extract. Int J Pharm 600:120406. rate of gelatin/carboxymethylcellulose dissolving microneedle for trans-https:// doi. org/ 10. 1016/j. ijpha rm. 2021. 120406. Elsevier B.V. dermal drug delivery. Sains Malays 49:2269–2279 Xue X, Chen X, Mao X, Hou Z, Zhou Y, Bai H et al (2013) Amino-terminated Nayak A, Das DB, Vladisavljevi GT (2013) Microneedle-assisted permeation of generation 2 poly(amidoamine) dendrimer as a potential broad-spec- lidocaine carboxymethylcellulose with gelatine co-polymer hydrogel trum, nonresistance-inducing antibacterial agent. AAPS J 15:132–142 Nejad HR, Sadeqi A, Kiaee G, Sonkusale S (2018) Low-cost and cleanroom-free Yang H, Kang G, Jang M, Um DJ, Shin J, Kim H et al (2020) Development of fabrication of microneedles. Microsystems Nanoeng 4:1–7. https:// doi. lidocaine-loaded dissolving microneedle for rapid and efficient local org/ 10. 1038/ micro nano. 2017. 73. The Author(s) anesthesia. Pharmaceutics 12:1067. Multidisciplinary Digital Publishing Nejad HR, Sadeqi A, Kiaee G, Sonkusale S (2018) Low-cost and cleanroom-free Institute. Available from: https:// www. mdpi. com/ 1999- 4923/ 12/ 11/ 1067 fabrication of microneedles. Microsyst Nanoeng 4:1–7. Nature Publishing Zempsky WT (2008) Pharmacologic approaches for reducing venous access Group pain in children. Pediatrics 122(Suppl 3):S140–S53 Bahmani  et al. AAPS Open (2023) 9:7 Page 15 of 15 Zhang L, Guo R, Wang S, Yang X, Ling G, Zhang P (2021) Fabrication, evaluation and applications of dissolving microneedles. Int J Pharm 604:120749. https:// doi. org/ 10. 1016/j. ijpha rm. 2021. 120749 Zhang L, Li Y, Wei F, Liu H, Wang Y, Zhao W, Dong Z, Ma T, Wang Q 2020 Trans- dermal Delivery of Salmon Calcitonin Using a Dissolving Microneedle Array: Characterization, Stability, and In vivo Pharmacodynamics. AAPS PharmSciTech 22(1):1. https:// doi. org/ 10. 1208/ s12249- 020- 01865-z Zhu Y, Carragher B, Potter CS (2001) Automated filament finding and selection from cryo electron micrographs. Microsc Microanal 7:986–987 Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AAPS Open Springer Journals

Transdermal drug delivery system of lidocaine hydrochloride based on dissolving gelatin/sodium carboxymethylcellulose microneedles

Loading next page...
 
/lp/springer-journals/transdermal-drug-delivery-system-of-lidocaine-hydrochloride-based-on-8XFgcHttY0

References (79)

Publisher
Springer Journals
Copyright
Copyright © The Author(s) 2023
eISSN
2364-9534
DOI
10.1186/s41120-023-00074-9
Publisher site
See Article on Publisher Site

Abstract

Introduction number of drugs can be administered via TDDs (molecu- The skin is the largest organ of the body that provides a lar weight less than 500 Da) (Bos and Meinardi 2000). convenient and accessible route for drug delivery (Han To overcome these limitations, an innovative and Das 2015; Cevc and Chopra 2016). Transdermal drug microneedle (MN) approach aimed at developing safe delivery (TDD) demonstrates an attractive approach to and efficient means for delivering medications through systemic drug delivery and avoids pre-systematic metab- the skin has attracted the attention of many scien- olism (destruction in the gastrointestinal tract or by the tists (Hao Y et  al. 2017;  Kochhar et  al. 2016; Migdadi liver), the possibility of controlled drug delivery for a and Donnelly 2019; Ahmad et  al. 2020; Bonfante et  al. long time, and an alternative solution for oral dosing in 2020; Liu et  al. 2022; Dugam et  al. 2021). DMNs pen- patients with anesthesia or nausea and direct access to etrate the SC and dissolve in the interstitial tissue and the site or disease, for example, treatment of skin disor- release encapsulated drugs into the epidermal layer (He ders such as fungal infections and psoriasis (Prausnitz X et  al. 2019;  Bonfante et  al. 2020; Ma and Wu 2017; MR and  Langer R 2008; Jeong et  al. 2021; Wang et  al. Yang et al. 2020; Lee et al. 2020; Zhang et al. 2021; Xing 2021). Most importantly, since TDD is a noninvasive and et al. 2021). The evolution of these MNs has led to more almost painless administration method, it increases the innovative designs (Vecchione R. et  al. 2014:  Dugam acceptance of patients, especially children and the elderly et  al. 2021; Vora et  al. 2022; Roy et  al. 2022; Shah and (Inamuddin and Mohammad 2018; Zhu et al. 2001; Don- Choudhury 2017; Zhang et al. 2021). Hydrogel-forming nelly et  al. 2012). However, there are several challenges MN or swellable MN can be used as a method devel- to TDDs that have not yet fully achieved their poten- oped from the “poke and release” approach for drug tial as an alternative to hypodermic injections, mucosal delivery (Liu et al. 2022; Li et al. 2018; Dash et al. 2013) administration, and oral delivery. First, the physicochem- due to their high water content, biodegradability, bio- ical properties of the skin create a barrier to drug deliv- compatibility, and renewability (Bao et  al. 2019; Ge ery through the outermost layer of the skin epidermis et  al. 2018). Among the local anesthetics, lidocaine called the stratum corneum (SC) (Jeong et al. 2021; Wang is a frequently used medication for the treatment of et  al. 2021; Pastore et  al. 2015). Second, only a limited chronic pain and acute (Zempsky WT 2008; Kochhar Bahmani  et al. AAPS Open (2023) 9:7 Page 3 of 15 Fig. 1 The GEL/NaCMC hydrogel synthesis of schematic et al. 2013; Gomes et al. 2016; Houck and Sethna 2005; cellulose (NaCMC) are biopolymers with bioavailability Martell et  al. 2017); lidocaine must get through a skin properties that can deliver therapeutic drugs transder- barrier to reach the nerve system in order to provide a mally as well as in combination with the composition local anesthetic (Gudin and Nalamachu 2020). Inject- of DNM (Nayak et  al. 2013). GEL is a biodegradable able Lido solution in either basic (lidocaine) or acidic protein that is naturally amphoteric due to the presence forms (LidoHCl) has the mechanism of action antago- of both acidic and basic functional groups in the struc- nism of nerve signals in cells by inhibiting the influx of ture (Xing et  al. 2014; Hajzamani et  al. 2020). The low sodium ions through the sodium channels of the bio- thermal and mechanical stability of GEL hydrogels has logical cell membrane, which response to temporary constrained their use in a variety of applications. How- pain blockage on the skin surface (Rasool et  al. 2020; ever, by mixing GEL with other natural polymers such Cepeda et al. 2015; Abdellatif and Ibrahim 2020). How- as NaCMC, and also using crosslinking agents such as ever, using syringes can cause anxiety, pain, and infec- glutaraldehyde (GTA), its thermal and mechanical sta- tion that lead to poor patient compliance and require bility can be improved (Khan and Anwar 2021; Liu et al. a prescription by experienced medical personnel (Shin 2022; Favatela et al. 2021). GEL/NaCMC hydrogels can et  al. 2017; Donnelly et  al. 2010). Topical anesthetic be modified according to the ratio of polymers and gels and creams provide a simple, painless way to apply the amount of GTA for drug delivery under interstitial anesthesia. Nevertheless, these procedures lead to pas- fluid conditions (pH = 5.5 and T = 37 °C). GEL/NaCMC sive diffusion in the outer layer of the skin, resulting hydrogel synthesis representation is given in Fig.  1. As in slow-onset times of 30 to 60  min (Lee et  al. 2020). the protein and polysaccharides utilized in this research This delayed onset is a major obstacle to the widespread include abundant amino and carboxyl groups, they use of local anesthetics for intravenous access meth- generate a pH-sensitive hydrogel network. As per the ods (Donnelly et  al. 2010; Spierings et  al. 2008). To literature, the interstitial fluid of the skin has a mildly overcome this limitation, the MN has been studied to acidic environment (Wagner et al. 2003; Proksch 2018; deliver drugs through the transdermal route for a fast Ali and Yosipovitch 2013). onset time. The literature review showed that there are not enough The use of biopolymers like polysaccharides and pro - studies about dissolving microneedles for anesthetics teins for the crosslinking structure with the functional drug delivery systems. Here, a DMN transdermal drug role of trapping drugs and with the goal of optimiz- delivery system is proposed for the delivery of an anes- ing skin permeation pharmacokinetics has attracted thetic drug. GEL/NaCMC hydrogels in different mix - the attention of many investigators (Santos LF et  al. ing ratios were prepared and loaded with LidoHCl and 2018; Edgar et al. 2021; Jeong et al. 2021; Mustafa Kamal crosslinked with glutaraldehyde. The structural charac - et  al. 2020). Gelatin (GEL) and sodium carboxymethyl teristics of the DMN were determined by FTIR and XRD Bahmani et al. AAPS Open (2023) 9:7 Page 4 of 15 to confirm the lack of chemical interactions between the Table 1 Formulation MNs drug and comprehend the polymers and the formation of Sample codes Mixing ratio Polymer/GTA ratio LidoHCl crosslinking structure between GEL/NaCMC. The effect GEL/NaCMC (wt/wt) content (wt/wt) (%) of varying concentrations of polymers, crosslinker, and amount of drug on swelling, solubility, gel fraction, drug MN1 3:1 1.5 10 release behavior, and mechanical strength was also evalu- MN2 4:1 1.5 10 ated. So, considering the highest swelling in skin condi- MN3 5:1 1.5 10 tions, we believed that the development of GEL/NaCMC MN4 5:1 2.5 10 hydrogels with MN morphology via a manner of “poke MN5 5:1 3.1 10 and release” is a promising approach for TDDs, and MN6 5:1 1.5 20 this strategy can be used for pain relief as well as before MN7 5:1 1.5 40 minor skin surgery, such as the removal of moles, warts, and verrucas. ratio) was poured into the positive mold, and the proce- Materials and methods dure was completed by placing it in a vacuum oven over- Materials night. The last negative silicone mold was used to create GEL type A (300 bloom), NaCMC (Mw 250 kDa, DS: 0.9), MN from hydrogels (Fig. 2). GTA solution (25% in water), and acetic acid were sup- −1 plied from Sigma-Aldrich. LidoHCl (Mw 288.81 g  mol ) Scanning electron microscopy studies was provided by Darou Pakhsh Pharma Chem. Co.. All The surface morphology of the DMN arrays was inves - chemicals were used without further purification. tigated using SEM (Vegall, Tescan). DMN samples were mounted on an aluminum mount and sputtered with a Methods thin layer of gold. The samples were then placed into the Preparation of hydrogels SEM vacuum chamber and observed at various angles using an accelerating voltage of 15  kV. ImageJ software • Solution A: The clear gelatin solution was obtained was used to measure the dimensions. by dispersing the required amount of GEL at 40  °C (Bello et al. 2020; Ivone et al. 2021) while stirring, and FT‑IR spectroscopic analysis then, the required amount of LidoHCl was loaded FTIR spectral data were taken with the Infrared Bruker into it (Table  1), and its pH was adjusted to 3.8–4.2 −1 Tenso II instrument (at a resolution of 4  cm and aver- by adding acetic acid (0.1 M). aged 16 scans) to confirm the structure and also to find • Solution B: NaCMC was separately dispersed in dis- the chemical stability of the drug in the hydrogels. Gela- tilled water and gently heated (~ 50 °C) to accelerate tin, NaCMC, and LidoHCl were each separately finely dissolution. Subsequently, solution B was added to grounded with KBr and thus kept ready for taking spec- solution A and stirred until a viscous solution was tra. Also, for the GEL/NaCMC DMN and drug-loaded obtained. The total concentration of polymers in the DMN, ATR spectroscopy was performed with an EQUI- solution was constant at 15 (w/v%) for all prepared NOX device from Bruker, Germany. samples. After cooling to 25  °C, the crosslinking agent (GTA) was added slowly under continuous stir- X‑ray diffraction (XRD) analysis ring (400 rpm speed for 20 min). X-ray pattern of LidoHCL, drug-loaded, and unloaded DMN was analyzed using Inel X-ray Diffractometer (EQUINOX 3000). This analysis was run at a current of Molding 30 mA and voltage of 40 kV with Cu Ka radiation. Microneedle molds were made by a two-step “print and fill” method, using 3D printing (Krieger et al. 2019; Nejad Swelling, solubility, and gel fraction et  al. 2018). First, the positive template was designed The swelling behavior of hydrogels in different pH values of using 3Design software. Then, by examining the effects 1.2, 5.5, 6.5, and 7.5 of USP phosphate buffers at 37 ± 0.1 °C of MN mold geometry, the parameters of needle height was monitored (Khan and Anwar 2021). Typically, a certain (500 ± 10 µm), needle angle (35°), tip radius (40 ± 10 µm), amount (40 to 50 mg) of DMNs, dried to constant weight, and tip-to-tip distance (960 ± 10  µm) were optimized. The optimized design was printed using a 3D printer (DLP ). Afterward, it was washed with hot water and dried. The molding silicone resin with hardener (in a 10:1 Direct light processing Bahmani  et al. AAPS Open (2023) 9:7 Page 5 of 15 Fig. 2 MN mold. a Positive template fabricated by the 3D printer. b Obtained negative silicone mol Release study of LidoHCl in vitro was placed in a pouch made of nylon cloth, weighted, The in vitro drug release from LidoHCl-DMN was stud - and left to swell by immersing into a beaker containing ied in PBS buffer (pH = 5.5) by dissolution analysis. the swelling media. At regular intervals, the pouch was For this purpose, the paddle-over disk method (Fig.  3) removed from the solvent, after blotting with tissue paper was used to examine the transdermal delivery systems to remove excess solvent on the surface, and was weighed (USP38/NF33 2015; Jesús et al. 2022; Price et al. 2020). using an electronic microbalance (Sartorius 313, accuracy First, 500  ml of the buffer solution was poured into of ± 0.01  mg) and then returned to the medium. The per - the vessel, and then, the DMN assembled on a disk was centage of swelling determined at the time (t) was calcu- placed at the end of the vessel and stirred at 50  rpm. At lated using Eq. (1) (Saraswathy et al. 2020; Khan and Anwar predetermined time intervals, 2  ml of the solution was 2021): taken and replaced with a fresh one, and all samples were Ws − Wd tested in triplicate. Sink conditions were maintained WR % = × 100 ( ) (1) Ws throughout the experiment, with the concentration of the LidoHCl in the release medium being less than 10% where W and W are the weights of swollen hydrogels s d of the saturated solubility and constant temperature of at t, and dried hydrogels, respectively. The experiments 37 ± 0.5 °C. The concentration of LidoHCL in the release were repeated three times and reported as a mean value. media was determined by UV–Vis spectrophotometer The gel fraction was determined by weighing the (PerkinElmer, LAMBDA 365, USA) at λ of 263 nm. To max unwashed DMNs before drying them in an oven at 40  °C determine the reproducibility and the accuracy of the UV (M ). To remove non-crosslinked polymer, the samples test, the RSD percentage was calculated, and it was deter- were immersed in deionized water as a solvent for 24  h. mined to be less than 5%. Also, UV spectroscopy was After that, DMNs were dried in a vacuum oven at 40  °C performed for each of the ingredients of the formulation. until a constant weight was obtained (M ). The percentage Solution samples were tested separately, and PBS buffer of gel fraction was calculated using Eq.  (2) (Favatela et  al. (pH = 5.5) was the reference. 2021): Mf Calibration curve of LidoHCl GF (%) = ( ) × 100 (2) Mi A calibration curve is required to determine the rate of drug release from the samples (Pandit et al. 2016; Kumar Solubility analysis was performed to determine the et  al. 2012) Specified concentrations of LidoHCL (5, 10, quantity of partial dissolution or the percentage of mass 15, 20, 30, and 40  µg/ml) in the buffer (pH = 5.5) were lost. The DMNs were weighed before (M ) and after (M ) i f scanned in the range of 200–400 nm by using a UV–Vis being placed in 100-ml buffer (PBS pH 5.5) at 37  °C for spectrophotometer, and a prominent peak was observed 48  h, and then, weight loss was inspected. The samples at 263 ± 1 (nm). The absorbance values were recorded solubility was calculated based on Eq. (3) (Esteghlal et al. at 263  nm with the corresponding concentrations, the 2018): calibration curve was plotted, and the line equation was Solubility (%) = (M − M /M ) × 100 i f i (3) obtained with R = 0.9953. Using Eq.  4, the drug release rate was obtained by knowing its absorbance. Bahmani et al. AAPS Open (2023) 9:7 Page 6 of 15 Fig. 3 Paddle over disk for dissolution test fitted at the end of the falcon tube, and then, the hydro - Absorbance = 0.0181 Concentration (μg/ml) + 0.0258 gels were added and centrifuged for 5 min at 5000 rpm. (4) The centrifugal force caused the hydrogels to enter the microcavities of the MN mold (Fig.  5e). The molds Mechanical properties containing the hydrogel were then placed in a vacuum The evaluation of the mechanical strength of the oven to dry for 6  h. Finally, the DMN hydrogels were LidoHCl-DMN was measured using a SANTAM- STM20 instrument with a 6 N load cell as it allowed for sensitive measurements within an accuracy level of 0.4%. LidoHCl-DMNs containing 5 × 5 needle arrays were fixed on a platform surface under the vertically moving mechanical sensor using a double-sided adhe- sive tape. Then, the probe moved downward vertically −1 at a speed of 0.5  mm  s as shown in Fig.  4. Subse- quently, the varying force and sensor displacement were recorded during the test to obtain the axial force that causes the fracture of DMN. Antibacterial analysis The antimicrobial activities of the prepared MN were investigated using the diffusion method. One-hundred milliliters of gram-negative bacterial Escherichia coli and Staphylococcus aureus with a concentration of 0.5 × 10 was cultured, and it is used to test antibacterial activity by agar diffusion assay. The bacterial plates were placed in an incubator at 37  °C for 24  h. After 24  h, the plate was checked from the zone of inhibition by calculating the diameter of the inhibition section, and a picture was taken (Xue et al. 2013). Results Fabrication of MN The polymer mixture was cast into the negative mold Fig. 4 Schematic of the mechanical test machine by centrifuged force. The negative silicon mold was first Bahmani  et al. AAPS Open (2023) 9:7 Page 7 of 15 separated from the mold and washed three times with absorption of the microneedle was observed. The distilled water (40  °C) to remove unreacted materials. amount of glutaraldehyde had an inverse relation with The dried DMN hydrogels were placed in a vacuum- swelling. In other words, increasing the crosslinker equipped desiccator until further usage. concentration forms a strong structure that declines the swelling. Macrostructure Gel fraction and solubility study Figure 5a, b, and c indicated the surface morphology of The effects of the LidoHCl-DMN contents on the DMN arrays. The DMN arrays in this study had a sur - gel fraction are presented in Table  2. To scrutinize face area of 25 (mm ) and contained 25 MN equally the effect of the amount of crosslink agent on GF%, distributed in a 5 × 5 arrangement (Fig.  5e, f ). It was three samples (MN3, MN4, and MN5) were studied observed that SEM micrographs of the DMN arrays with different amounts of polymer/GTA ratio (3.1, sample contain slightly rough surfaces. The structure of 2.5, and 1.5), while the ratio of polymers and the individual needles was evident at increased magnifica - amount of drug are constant. These results show tion (Fig. 5a). that increasing the amount of crosslink agent leads to an increase in the percentage of GF. To elaborate the effect of polymers ratio on GF of DMN, three Structure investigation samples (MN1, MN2, and MN3) were prepared with The ATR-FTIR analysis confirmed the successful varying rates of GEL: NaCMC (3:1, 4:1, and 5:1) and crosslinking of GEL and NaCMC chains. The spectra keeping the amount of GTA and LidoHCl constant. of GEL, NaCMC, GEL/ NaCMC DMN, LidoHCl, and This is because increasing the concentration of GTA LidoHCl-loaded GEL/NaCMC DMN are presented leads to an increase in active sites for the crosslink- in Fig.  6. As shown, the stretching vibrations of the ing reaction. Thus, the crosslinking density between O–H and N–H in the GEL/NaCMC hydrogel spectrum GEL and NaCMC increases, which leads to an shifted gently to lower wavelengths. In addition, the increase in the mechanical strength of the hydrogel −1 amide I band shifted from 1654 to 1656  cm . These and a higher percentage of GF. indicated that the anionic groups in NaCMC with the cationic ones in GEL were coupled. On the other hand, In vitro drug release the new bands in the range of 1150 to 1070 are attrib- In vitro release studies were performed to under- uted to the C–O–C stretching vibrations, which con- stand drug release from LidoHCl-DMNs in the condi- firmed the crosslinking of the polymers. tions of skin pH. The selectivity results revealed that Figure  7 shows the diffractograms of LidoHCl, Gel/ in the λ of LidoHCl, each of the ingredients of the max NaCMC, and drug-loaded samples. As illustrated, formulation had no significant absorption. As shown LidoHCl has shown numerous characteristic sharp in Fig.  5g, h, and i, the tips of the needles swell after peaks due to its highly crystalline nature. The XRD 5  min, and a significant amount of needles dissolve pattern of blank GEL/NaCMC hydrogel (MNB sam- after 10 min. Figure 8 illustrates the effects of the ratio ple) exhibits a broad peak, which represented the of the polymer, the amount of crosslinker, and the amorphous state. The diffractogram achieved by the amount of medication on drug release at pH = 5.5. drug-loaded GEL/NaCMC DMN (MN3, MN6, MN7) indicated the same amorphous state at 2 = θ 21°. The Mechanical properties appearance of peaks following LidoHCl loading at 14° An axial compression force was applied to the MN and 26° indicates an increase in the crystallinity of the arrays to see whether they had adequate mechanical hydrogel samples. strength to penetrate the skin (Chen et  al. 2021). As reported in the force/needle results of DMNs (Table 2), Eec ff ts of pH, the ratio of polymers, and polymer/GTA ratio all MN arrays have the sufficient mechanical strength on swelling to penetrate the skin. The swelling behavior of GEL/NaCMC hydrogels is influenced by the pH of the immersed media, the ratio Antimicrobial activity of the two polymers, and the amount of the crosslinking The prepared sample was applied to bacterial E.coli and agent. Table  2 demonstrates the extent of the swelling S.aureus which results in antibacterial activity as shown of DMNs. The highest value of swelling was observed in Fig.  9. MN7 proved to be antibacterial in nature. The in acidic pH. Also, by raising the gelatin content in the average diameter of the zone of inhibition is 0.88 cm. microneedle composition, an increment in the water Bahmani et al. AAPS Open (2023) 9:7 Page 8 of 15 Fig. 5 LidoHCl DMNs. a Hydrogel-filled silicon mold. b and c Synthesized samples. d SEM at 280 × , e 500 × , f 80 × magnifications. g 0, h 5, and i 10 min after exposure to pH 5.5. j Before and k after the force application Bahmani  et al. AAPS Open (2023) 9:7 Page 9 of 15 Fig. 6 FTIR spectra of the LidoHCL, NaCMC, GEL/NaCMC DMN, and drug-loaded DMN Fig. 7 XRD pattern of LidoHCl, MNB, MN3, MN6, and MN7 samples Table 2 The results of swelling, GF, solubility, and mechanical strength tests Sample codes Degree of swelling (%) GF (%) Solubility (%) Force/ needle pH (1.2) pH (5.5) pH (6.5) pH (7.5) (N) MN1 346 298 165 86 73 53 0.23 MN2 540 467 303 101 68.4 65 0.19 MN3 610 553 333 120 64.2 73 0.15 MN4 330 263 111 86 76.1 45 0.34 MN5 160 123 103 74 84.5 40 0.45 MN6 646 555 340 135 57 85 0.14 MN7 650 560 350 150 58.3 89 0.16 Bahmani et al. AAPS Open (2023) 9:7 Page 10 of 15 Fig. 8 Eec ff t of a GTA, b polymer ratio, and c the amount of LidoHCl on in vitro release profile Bahmani  et al. AAPS Open (2023) 9:7 Page 11 of 15 NaCMC showed a strong absorbance band at −1 3368  cm was assigned to the O–H stretching vibra- −1 tion. The shoulder at 2918  cm indicated aliphatic C–H −1 stretching vibrations, while the strong peak at 1625  cm −1 and medium peak at 1425  cm were due to the asym- metric and symmetric stretching of the carboxylate group. The intense peak of C–O stretching vibration for ethers was ascribed to the significant absorption peaks at −1 1000–1160  cm . These findings are in good accord with findings from previous investigations (Devi and Maji 2009). The main absorption peaks of LidoHCl powder were −1 observed at 3382, 3011, 1654, and 1470  cm . These bands were assigned as N–H stretching, C–H stretching, amide I (C = O), and amide II (C–N), respectively. FTIR spectra were also used to affirm the chemical stability of LidoHCL in samples. As observed in Fig.  6, the posi- tion of these bonds in drug-containing hydrogels almost remained unchanged, indicating there was no significant Fig. 9 Antimicrobial activity of MN7 chemical interaction between the drug and the GEL/ NaCMC hydrogels. It may be noted that in the case of −1 drug-containing DMNs, the band observed at 1654  cm Discussion overlapped with the GEL amide band, so XRD analy- Dissolving and hydrogel-forming MN with the “poke and sis was performed to confirm the stability of Lido in the release” approach are a novel method of TDDs in which hydrogel. drugs can be loaded and released when the MN dissolves The intensity of XRD peaks was more noticeable for the after insertion (Liu et al. 2022), also reducing onset time MN7 sample than for the MN3 and MN6 samples, indi- and improving permeability (Ma and Wu 2017; Yang cating a higher amount of drug. These results are consist - et  al. 2020). In this study, a mixture of a polysaccha- ent with the in vitro drug release data. ride (NaCMC) and a protein (GEL) was used to create a The study of swelling results showed that acidic media drug delivery carrier with microneedle morphology. The is due to the protonation of the free amino groups of dimensions of the prepared microneedle were needle GEL, which leads to electrostatic repulsions between height 450  µm, tip radius 30  µm, and tip-to-tip distance them and thus expands the polymer network, whereas 960 µm. Examining the different dimensional parameters free carboxylic groups with hydroxyl groups of NaCMC of the microneedle, it was found that needles with an may lead to a contraction of the network by intense input height of 300 to 600 µm are not of sufficient qual - hydrogen interactions or by intermolecular lactonization ity for molding, and higher heights may cause pain in the (Khan and Anwar 2021; Tataru et  al. 2011). As the pH patient (Krieger et al. 2019; Nejad et al. 2018). increases towards the basic medium, carboxylic groups The ATR-FTIR spectrum of samples clearly showed of CMC become ionized, and GEL owns COO − groups, the absorption bands of the crosslinked mixture of poly- and the electrostatic repulsion between the carboxy- mers. In the spectrum of GEL, a sharp absorbance band −1 late groups expands the polymer network. Due to the was observed at 3420  cm due to N–H stretching vibra- −1 higher weight ratio of GEL in hydrogels, its effect on tion. The medium peak at 1558  cm belonged to the the degree of swelling was superior to NaCMC; hence, N–H bending vibration. The absorption bands appearing −1 the maximum swelling was observed in acidic pHs (1.2, at 1654 and 1330  cm indicated the type 1 amide band 5.5). Similar findings were presented by Khan and Taturo, and the C–N band stretching vibrations, respectively, and that the swelling ratio increases with increasing GEL which are the most significant peaks for FTIR analysis content (Khan and Anwar 2021; Tataru et  al. 2011). As of the gelatin structure (Khan and Anwar 2021; Buhus −1 shown in Table  2, hydrogels containing higher amounts et  al. 2009). The medium peak at 1239  cm belonged of GEL (MN3) showed a higher degree of swelling than to the type 3 amide, and the weak peak that appeared at −1 formulations containing lower amounts of gelatin (MN1, 1525  cm was assigned to the type 2 amide. The band −1 MN2). The swelling data of crosslinked hydrogels showed appearing at 1440  cm indicated aliphatic C–H bend- that by increasing the amount of GTA in the polymer ing vibrations, while aliphatic C–H stretching vibrations −1 hydrogel from 3.1 to 2.5 (wt/wt), the swelling decreases were observed at 2923  cm . Bahmani et al. AAPS Open (2023) 9:7 Page 12 of 15 significantly from 553 to 263%. This was owing to the elaborate the effect of drug loading on in  vitro release hydrogel’s mechanical strength increasing as a result of profiles, three DMN samples (MN3, MN6, and MN7) crosslinking and the formation of a more compact wall. were prepared with varying concentrations of LidoHCl Also, it is observed that MN5 has the highest GF with (10, 20, and 40%) and kept the concentration polymers more crosslinker. Similar findings were reported that and GA constant. This indicates that an increase in drug GF is directly related to crosslinking density (Khan and concentration causes an increase in the release rates of Anwar 2021). The GEL/NaCMC ratio of 5:1 showed a drugs (Fig.  8c). Also, MN7 exhibited excellent antibacte- lower gel fraction compared to the ratio of 3:1 and 4:1. rial activity. According to previous studies, in the short This is consistent with the results of Kreua-Ongarjnukool contact time and low concentration of glutaraldehyde, et  al. (2020) who concluded that at constant concentra- the adverse effect on the skin does not remain (Ballan - tions of GTA, the gel fraction decreases with increasing tyne and Jordan 2001). polymer concentration, meaning that polymer chains DMN array failure force is presented in Table 2. Accord- have less crosslinking. Also, there was no significant ing to the literature, the insertion force required to over- difference between MN7 and MN6, indicating that the come the barrier of the skin and deliver the drug efficiently −1 amount of drug did not affect GF. MN5 with the high - into the skin is 0.058 (N needle ) (Davis et al. 2004). For est amount of GTA showed the lowest dissolution. Other MN3, MN4, and MN5 DMNs, failure force increased authors have achieved similar results in examining the with an increasing amount of GTA. This dependence is crosslinks of GEL/NaCMC (Khan and Anwar 2021; expected because increasing the crosslinker quantity leads Favatela et  al. 2021). They argued that increasing the to a rigid network structure. Comparing the mechani- crosslink density increases the mechanical strength of the cal strength of neat GEL and GEL/NaCMC DMN arrays hydrogel, which in turn leads to a decrease in the solubil- showed that the addition of NaCMC to GEL greatly ity of the hydrogel and reduces the water-uptake capacity increases the mechanical properties. However, pure GEL of the polymer network. From data in Table  2, it is evi- DMN arrays exhibit compression forces at the end (low dent that the solubility at the 5:1 (MN3) ratio of polymers stress at fracture) of 0.051 (N), while mechanical strength was higher than the ratio of 3:1 (MN1) which is in good for GEL/NaCMC DMN arrays reached 0.162 ± 0.01 N. agreement with the results of swelling. Similar findings Liu et  al. (2022) deduced that the addition of cellulose were presented by Tataro et  al. (Tataru et  al. 2011) that nanofibrils to GEL could effectively improve the strength as the amount of gelatin increased, more electrostatic and toughness of the composite hydrogels. They found repulsion was generated, leading to the relaxation of the that when the composite hydrogel is under stress, the load polymer network. In MN3, MN6, and MN7 samples, the can be transferred efficiently between the GEL matrix and effect of drug amount on solubility was investigated. The cellulose nanofibrils. As shown in Table  2, the mechanical MN7 sample showed the highest percentage of solubil- strength of MN1 with a polymer ratio of 3:1 has higher ity. At a constant ratio of polymers and the amount of mechanical strength than MN3 and MN2. However, there crosslinker, the solubility increases with the increasing was no significant difference in the mechanical strength of amount of drug. This may be due to increased electro - various amounts of the drug (MN3, MN6, and MN7). The static repulsion between the polar groups of GEL and shape of the synthesized DMN before and after applying LidoHCl. the force is shown in Fig. 5j and k. According to these results, during the first 10  min of release, a burst release effect was observed, and then, its Conclusion value increased slightly for a while and was fixed after Dissolving microneedles loaded lidocaine based on natu- 60  min. Effects of various ratios of polymers in formu - ral polymers GEL and NaCMC were synthesized using lations MN1, MN2, and MN3 on release rates are pre- GTA as the crosslinking agent. Prepared DMN can replace sented in Fig.  8b. The MN3 formulation showed higher conventional anesthetic delivery methods such as injec- release rates than MN2. Similarly, MN2 revealed a higher tions and topical creams, due to their dissolution in skin release rate than MN1. Drug release experiments agreed pH, rapid onset time, and ability to cross the SC layer with the study of swelling; as the rate of GEL versus and deliver the sufficient drug to the skin. FTIR was used NaCMC increases, the swelling increases, which in turn to corroborate the formation of crosslinked hydrogels causes the higher release of drug (Fig.  8b). The effect of between GEL and NaCMC. Also, XRD analysis indicated GTA content in MN3, MN4, and MN5 formulations on that the LidoHCl remained crystalline in the hydrogels. In drug release rate is shown in Fig. 8a. The drug release rate addition, the shape of the DMN was shown on scanning was higher in the case of MN3 than in MN4 and MN5. electron microscopy micrographs. The synthesized DMN This is because increasing the concentration of GTA showed excellent swelling and solubility at skin pH. The leads to the formation of a rigid network structure. To results of the drug release study demonstrated that it was Bahmani  et al. AAPS Open (2023) 9:7 Page 13 of 15 Bonfante G, Lee H, Bao L, Park J, Takama N, Kim B (2020) Comparison of poly- directly related to the ratio of polymers and the amount mers to enhance mechanical properties of microneedles for bio-medical of drug and inversely to the amount of crosslinker. It was applications. Micro Nano Syst Lett 8(1):1–3. https:// doi. org/ 10. 1186/ also observed that all samples presented a burst release in s40486- 020- 00113-0. Springer Singapore Bos JD, Meinardi MMHM (2000) The 500 Dalton rule for the skin penetration of the first 10  min. Mechanical properties data revealed that chemical compounds and drugs. Exp Dermatol 9:165–9. https:// doi. org/ all synthesized DMNs were able to cross the skin barrier. 10. 1034/j. 1600- 0625. 2000. 00900 3165.x In this study, MN7 was considered the ideal DMN with the Buhus G, Popa M, Desbrieres J (2009) Hydrogels based on carboxymethylcel- lulose and gelatin for inclusion and release of chloramphenicol. J Bioact highest drug release rate and sufficient mechanical strength Compat Polym 24:525–545 to penetrate the skin. It can be concluded that DMN loaded Cepeda MS, Tzortzopoulou A, Thackrey M, Hudcova J, Arora Gandhi P, LidoHCl based on GEL/NaCMC hydrogels have the poten- Schumann R (2015) Adjusting the pH of lidocaine for reducing pain on injection. Cochrane Database Syst Rev 5:CD006581. pp 1–65 tial to be used as transdermal drug delivery devices. They Cevc G, Chopra A (2016) Deformable ( Transfersome ) vesicles for improved can dissolve well in skin pH and are a good clinical tool in drug delivery into and through the skin. In: Percutaneous penetration the field of local anesthesia and management of periopera - Enhanc Chem methods penetration Enhanc. Springer, Berlin, Heidelberg. p 39–59. https:// doi. org/ 10. 1007/ 978-3- 662- 47862-2_3 tive pain and chronic pain as well as before minor skin sur- Chen X, Yu H, Wang L, Wang N, Zhang Q, Zhou W et al (2021) Preparation of gery, such as the removal of moles, warts, and verrucas. phenylboronic acid-based hydrogel microneedle patches for glucose- dependent insulin delivery. J Appl Polym Sci 138:1–11 Acknowledgements Dash R, Foston M, Ragauskas AJ (2013) Improving the mechanical and thermal Not applicable. properties of gelatin hydrogels cross-linked by cellulose nanowhiskers. Carbohydr Polym 91:638–45. https:// doi. org/ 10. 1016/j. carbp ol. 2012. 08. Authors’ contributions 080. Elsevier Ltd. The authors read and approved the final manuscript. Davis SP, Landis BJ, Adams ZH, Allen MG, Prausnitz MR (2004) Insertion of microneedles into skin: measurement and prediction of insertion force Funding and needle fracture force. J Biomech 37:1155–1163 No funding body has provided funding for this research. Devi N, Maji TK (2009) Preparation and evaluation of gelatin/sodium carboxy- methyl cellulose polyelectrolyte complex microparticles for controlled Availability of data and materials delivery of isoniazid. AAPS PharmSciTech 10:1412–1419 All data generated or analyzed during this study are included in this published article. Donnelly RF, Raj Singh TR, Woolfson AD (2010) Microneedle-based drug delivery systems: microfabrication, drug delivery, and safety. Drug Deliv 17(4):187–207. https:// doi. org/ 10. 3109/ 10717 54100 36677 98 Declarations Donnelly RF, Singh TRR, Garland MJ, Migalska K, Majithiya R, McCrudden CM et al (2012) Hydrogel-forming microneedle arrays for enhanced transder- Competing interests mal drug delivery. Adv Funct Mater 22:4879–4890. Wiley Online Library The authors declare that they have no competing interests. Dugam S, Tade R, Dhole R, Nangare S (2021) Emerging era of microneedle array for pharmaceutical and biomedical applications: recent advances Author details and toxicological perspectives. Futur J Pharm Sci 7:1–26. Future Journal of Department of Polymer Engineering, Faculty of Engineering, Islamic Azad Pharmaceutical Sciences University, South Tehran Branch, P.O. Box: 11365/4435, Tehran, Iran. Depar t- Edgar AC-M, Guadalupe M-M, Gonzalo V (2021) Interactions of the molecular ment of Polymer and Textile, Islamic Azad University, South Tehran Branch, assembly of polysaccharide-protein systems as encapsulation materi- P.O. Box: 11365/4435, Tehran, Iran. Department of Polymer Processing, Iran als. A review, Advances in Colloid and Interface Science, vol 295, ISSN Polymer and Petrochemical Institute (IPPI), P.O. Box: 14965-112, Tehran, Iran. 0001–8686. https:// doi. org/ 10. 1016/j. cis. 2021. 102398. https:// www. scien Department of Medical, Tehran Medical Sciences Branch Islamic Azad Univer- cedir ect. com/ scien ce/ artic le/ pii/ S0001 86862 10003 97 sity, P.O. Box: 19395/1495, Tehran, Iran. Esteghlal S, Niakousari M, Hosseini SMH (2018) Physical and mechanical prop- erties of gelatin-CMC composite films under the influence of electrostatic Received: 23 December 2022 Accepted: 27 February 2023 interactions. Int J Biol Macromol 114:1–9. https:// doi. org/ 10. 1016/j. ijbio mac. 2018. 03. 079. Elsevier B.V. Favatela F, Horst MF, Bracone M, Gonzalez J, Alvarez V, Lassalle V (2021) Gelatin/ cellulose nanowhiskers hydrogels intended for the administration of drugs in dental treatments: study of lidocaine as model case. J Drug Deliv Sci Tech- References nol 61:101886. https:// doi. org/ 10. 1016/j. jddst. 2020. 101886. Elsevier B.V. Abdellatif MK, Ibrahim TH (2020) Intraoperative infusion of lidocaine 2% Ge S, Li M, Ji N, Liu J, Mu H, Xiong L et al (2018) Preparation of a strong gelatin- reduces postoperative fentanyl requirements for pain control in renal short linear glucan nanocomposite hydrogel by an in situ self-assembly transplantation surgery. Ain-Shams J Anesthesiol 12(1):1–6 process. J Agric Food Chem 66:177–186 Ahmad Z, Khan MI, Siddique MI, Sarwar HS, Shahnaz G, Hussain SZ, Bukhari NI, Gomes C, Glass M, Kieffer J, Chiforeanu M, Philippe P (2016) Topical anaesthetic Hussain I, Sohail MF (2020). Fabrication and Characterization of Thiolated solutions for pain free suture of lacerations in the emergency Dr Sylvie Martus, Chitosan Microneedle Patch for Transdermal Delivery of Tacrolimus. AAPS Laurence Poncin • lacerations = frequent in a paediatric emergency room • PharmSciTech 21(2):68. https:// doi. org/ 10. 1208/ s12249- 019- 1611-9 usually: local anaesthesia by injection of Lidocaine – But: pain, fear and a Ali SM, Yosipovitch G (2013) Skin pH: from basic science to basic skin care. Acta Gudin J, Nalamachu S (2020) Utility of lidocaine as a topical analgesic and Derm Venereol 93:261–267 improvements in patch delivery systems. Postgrad Med 132:28–36. Ballantyne B, Jordan SL (2001) Toxicological, medical and industrial hygiene https:// doi. org/ 10. 1080/ 00325 481. 2019. 17022 96. Taylor & Francis aspects of glutaraldehyde with particular reference to its biocidal use in Hajzamani D, Shokrollahi P, Najmoddin N, Shokrolahi F (2020) Eec ff t of engi- cold sterilization procedures. J Appl Toxicol 21:131–151. England neered PLGA-gelatin-chitosan/PLGA-gelatin/PLGA-gelatin-graphene Bao Z, Xian C, Yuan Q, Liu G, Wu J (2019) Natural polymer-based hydrogels three-layer scaffold on adhesion/proliferation of HUVECs. Polym Adv with enhanced mechanical performances: preparation, structure, and Technol 31:1896–1910 property. Adv Healthc Mater 8:1–11 Han T, Das DB (2015) Potential of combined ultrasound and microneedles for Bello AB, Kim D, Kim D, Park H, Lee S-H (2020) Engineering and functionaliza- enhanced transdermal drug permeation: a review. Eur J Pharm Biopharm. tion of gelatin biomaterials: from cell culture to medical applications. 89:312–28. https:// doi. org/ 10. 1016/j. ejpb. 2014. 12. 020. Elsevier B.V. Tissue Eng Part B Rev 26:164–80. United States Bahmani et al. AAPS Open (2023) 9:7 Page 14 of 15 Hao Y, Li W, Zhou X, Yang F, Qian Z (2017) Microneedles-based transdermal Pandit AP, Pol VV, Kulkarni VS (2016) Xyloglucan based in situ gel of lidocaine drug delivery systems: a review. J Biomed Nanotechnol 13:1581–1597 HCl for the treatment of periodontosis. J Pharm 2016:1–9 He X, Sun J, Zhuang J, Xu H, Liu Y, Wu D (2019) Microneedle system for Pastore MN, Kalia YN, Horstmann M, Roberts MS (2015) Transdermal patches: transdermal drug and vaccine delivery: devices, safety, and prospects. history, development and pharmacology. Br J Pharmacol 172:2179–2209 Dose-Response 17:1–18 Prausnitz MR, Langer R (2008) Transdermal drug delivery. Nat Biotechnol Houck CS, Sethna NF (2005) Transdermal analgesia with local anesthetics in 26:1261–1268. Nature Publishing Group children: review, update and future directions. Expert Rev Neurother Price R, Shur J, Ganley W, Farias G, Fotaki N, Conti DS et al (2020) Development 5:625–634. Taylor & Francis of an aerosol dose collection apparatus for in vitro dissolution measure- Inamuddin A, Mohammad A (2018) Applications of nanocomposite materials ments of orally inhaled drug products. AAPS J 22:47. United States in drug delivery Proksch E (2018) pH in nature, humans and skin. J Dermatol 45:1044–1052 Ivone R, Yang Y, Shen J (2021) Recent advances in 3D printing for parenteral Rasool A, Ata S, Islam A, Rizwan M, Azeem MK, Mehmood A et al (2020) applications. AAPS J 23:87. https:// doi. org/ 10. 1208/ s12248- 021- 00610-z Kinetics and controlled release of lidocaine from novel carrageenan and Jeong WY, Kwon M, Choi HE, Kim KS (2021) Recent advances in transdermal drug alginate-based blend hydrogels. Int J Biol Macromol 147:67–78. https:// delivery systems: a review. Biomater Res 25:1–15. Biomaterials Researchdoi. org/ 10. 1016/j. ijbio mac. 2020. 01. 073. Elsevier B.V. Jesús P-P, Montserrat M-C, Dolors P-DM, Ramon T-GJ, Antonio B-M (2022) Roy G, Garg P, Venuganti VVK (2022) Microneedle scleral patch for minimally Release of ropinirole in acrylate transdermal patches: mutual interactions invasive delivery of triamcinolone to the posterior segment of eye. Int between formulation variables. AAPS PharmSciTech 23:82. United States J Pharm 612:121305. https:// doi. org/ 10. 1016/j. ijpha rm. 2021. 121305. Khan S, Anwar N (2021) Gelatin/carboxymethyl cellulose based stimuli-respon- Elsevier B.V. sive hydrogels for controlled delivery of 5-fluorouracil, development, Santos LF, Correia IJ, Silva AS, Mano JF (2018) Biomaterials for drug delivery in vitro characterization, in vivo safety and bioavailability evaluation. patches. Eur J Pharm Sci 118:49–66. https:// doi. org/ 10. 1016/j. ejps. 2018. Carbohydr Polym 257:117617. https:// doi. org/ 10. 1016/j. carbp ol. 2021. 03. 020. Elsevier B.V. 117617. Elsevier Ltd Saraswathy K, Agarwal G, Srivastava A (2020) Hyaluronic acid microneedles- Kochhar JS, Lim WXS, Zou S, Foo WY, Pan J, Kang L (2013) Microneedle laden collagen cryogel plugs for ocular drug delivery. J Appl Polym Sci integrated transdermal patch for fast onset and sustained delivery of 137:1–14 lidocaine. Mol Pharm 10:4272–4280. ACS Publications Shah V, Choudhury BK (2017) Fabrication, Physicochemical Characterization, Kochhar JS, Tan JJY, Kwang YC, Kang L (2019) Microneedle patch for fast onset and Performance Evaluation of Biodegradable Polymeric Microneedle and long-lasting delivery of painkillers. In: Microneedles Transdermal Patch System for Enhanced Transcutaneous Flux of High Molecular Drug Deliv. p 67–80 Weight Therapeutics. AAPS PharmSciTech 18(8):2936–2948. https:// doi. Kreua-Ongarjnukool N, Niyomthai ST, Sarodom K, Lothong T, Soomherun N org/ 10. 1208/ s12249- 017- 0774-5 (2020) Hybrid gelatin/carboxymethyl cellulose hydrogel loaded copper Shin CI, Jeong SD, Rejinold NS, Kim Y-C (2017) Microneedles for vaccine deliv- (II) ion for medical applications. Mater Sci Forum 1009 MSF:3–8 ery: challenges and future perspectives. Ther Deliv 8:447–60. Available Krieger KJ, Bertollo N, Dangol M, Sheridan JT, Lowery MM, O’Cearbhaill ED from: https:// www. future- scien ce. com/ doi/ 10. 4155/ tde- 2017- 0032 (2019) Simple and customizable method for fabrication of high-aspect Spierings ELH, Brevard JA, Katz NP (2008) Two-minute skin anesthesia through ratio microneedle molds using low-cost 3D printing. Microsystems Nano- ultrasound pretreatment and iontophoretic delivery of a topical anes- eng 5(1):42. https:// doi. org/ 10. 1038/ s41378- 019- 0088-8. Springer US thetic: a feasibility study. Pain Med 9:55–9. Available from: https:// acade Kumar BK, Rajan VST, Begum NT (2012) Analytical method development and mic. oup. com/ painm edici ne/ artic le- lookup/ doi/ 10. 1111/j. 1526- 4637. validation of lidocaine in ointment formulation by UV spectrophotomet-2007. 00281.x ric method. Int J Pharm Pharm Sci 4:610–4. Available from: http:// www. Tataru G, Popa M, Desbrieres J (2011) Microparticles of hydrogel type based ijpps journ al. com/ Vol4I ssue2/ 3568. pdf on carboxymethylcellulose and gelatin for controlled release of water Lee B-M, Lee C, Lahiji SF, Jung U-W, Chung G, Jung H (2020) Dissolving soluble drugs. Rev Roum Chim 56:399–410 microneedles for rapid and painless local anesthesia. Pharmaceutics USP38/NF33 (2015) Validation of compendial methods section. United State 12:366. Multidisciplinary Digital Publishing Institute Pharmacopeial/National Formul, p 2256. The United States Pharmaco- Li W, Terry RN, Tang J, Feng MR, Schwendeman SP, Prausnitz MR (2018) Sus- peial Convention 12601 Twinbrook Parkway, Rockville, MD 20852. tained release of a contraceptive. Nat Biomed Eng. Springer US. https:// Vecchione R, Coppola S, Esposito E, Casale C, Vespini V, Grilli S et al (2014) doi. org/ 10. 1038/ s41551- 018- 0337-4 Electro-drawn drug-loaded biodegradable polymer microneedles as a Liu Q, Liu J, Qin S, Pei Y, Zheng X, Tang K (2020) High mechanical strength gela- viable route to hypodermic injection. Adv Funct Mater 24:3515–3523 tin composite hydrogels reinforced by cellulose nanofibrils with unique Vora D, Garimella HT, German CL, Banga AK (2022) Microneedle and ionto- beads-on-a-string morphology. Int J Biol Macromol 164:1776–84. https:// phoresis mediated delivery of methotrexate into and across healthy and doi. org/ 10. 1016/j. ijbio mac. 2020. 08. 044. Elsevier B.V. psoriatic skin. Int J Pharm 618:121693. https:// doi. org/ 10. 1016/j. ijpha rm. Liu B, Yi X, Zheng Y, Yuan Z, Yang J, Yang J et al (2022) A review of nano/micro/2022. 121693. Elsevier B.V. milli needles fabrications for biomedical engineering. Chinese J Mech Wagner H, Kostka KH, Lehr CM, Schaefer UF (2003) pH profiles in human skin: Eng (English Ed) 35(1):106. https:// doi. org/ 10. 1186/ s10033- 022- 00773-6. influence of two in vitro test systems for drug delivery testing. Eur J Springer Nature Singapore Pharm Biopharm 55:57–65 Ma G, Wu C (2017) PT NU SC. J Control Release. Elsevier B.V. https:// doi. org/ 10. Wang M, Luo Y, Wang T, Wan C, Pan L, Pan S et al (2021) Artificial skin percep - 1016/j. jconr el. 2017. 02. 011 tion. Adv Mater 33:1–20 Martell B, Kushner H, Richardson E, Mize A, Mayer P (2017) Pharmacokinetics Xing Q, Yates K, Vogt C, Qian Z, Frost MC, Zhao F (2014) Increasing mechani- of lidocaine and its metabolites following vaginal administration of lido- cal strength of gelatin hydrogels by divalent metal ion removal. Sci Rep caine gel to healthy female subjects. Clin Pharmacol Drug Dev 6:27–35 4:1–10 Migdadi EM, Donnelly RF (2019) Microneedles for transdermal drug delivery. Xing M, Wang X, Zhao L, Zhou Z, Liu H, Wang B et al (2021) Novel dissolving In: Imaging Technol. Transdermal Deliv. Ski. Disord microneedles preparation for synergistic melasma therapy: combined Mustafa Kamal NA, Tuan Mahmood TM, Ahmad I, Ramli S (2020) Improving effects of tranexamic acid and licorice extract. Int J Pharm 600:120406. rate of gelatin/carboxymethylcellulose dissolving microneedle for trans-https:// doi. org/ 10. 1016/j. ijpha rm. 2021. 120406. Elsevier B.V. dermal drug delivery. Sains Malays 49:2269–2279 Xue X, Chen X, Mao X, Hou Z, Zhou Y, Bai H et al (2013) Amino-terminated Nayak A, Das DB, Vladisavljevi GT (2013) Microneedle-assisted permeation of generation 2 poly(amidoamine) dendrimer as a potential broad-spec- lidocaine carboxymethylcellulose with gelatine co-polymer hydrogel trum, nonresistance-inducing antibacterial agent. AAPS J 15:132–142 Nejad HR, Sadeqi A, Kiaee G, Sonkusale S (2018) Low-cost and cleanroom-free Yang H, Kang G, Jang M, Um DJ, Shin J, Kim H et al (2020) Development of fabrication of microneedles. Microsystems Nanoeng 4:1–7. https:// doi. lidocaine-loaded dissolving microneedle for rapid and efficient local org/ 10. 1038/ micro nano. 2017. 73. The Author(s) anesthesia. Pharmaceutics 12:1067. Multidisciplinary Digital Publishing Nejad HR, Sadeqi A, Kiaee G, Sonkusale S (2018) Low-cost and cleanroom-free Institute. Available from: https:// www. mdpi. com/ 1999- 4923/ 12/ 11/ 1067 fabrication of microneedles. Microsyst Nanoeng 4:1–7. Nature Publishing Zempsky WT (2008) Pharmacologic approaches for reducing venous access Group pain in children. Pediatrics 122(Suppl 3):S140–S53 Bahmani  et al. AAPS Open (2023) 9:7 Page 15 of 15 Zhang L, Guo R, Wang S, Yang X, Ling G, Zhang P (2021) Fabrication, evaluation and applications of dissolving microneedles. Int J Pharm 604:120749. https:// doi. org/ 10. 1016/j. ijpha rm. 2021. 120749 Zhang L, Li Y, Wei F, Liu H, Wang Y, Zhao W, Dong Z, Ma T, Wang Q 2020 Trans- dermal Delivery of Salmon Calcitonin Using a Dissolving Microneedle Array: Characterization, Stability, and In vivo Pharmacodynamics. AAPS PharmSciTech 22(1):1. https:// doi. org/ 10. 1208/ s12249- 020- 01865-z Zhu Y, Carragher B, Potter CS (2001) Automated filament finding and selection from cryo electron micrographs. Microsc Microanal 7:986–987 Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations.

Journal

AAPS OpenSpringer Journals

Published: Apr 3, 2023

Keywords: Dissolving microneedles; Sodium carboxymethylcellulose/gelatin hydrogels; Lidocaine hydrochloride

There are no references for this article.