Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability

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This study aimed to develop NPH thermosensitive in situ gel to enhance its bioavailability by avoidance of first pass effect through rectal administration. Methods A cold method was employed to develop NPH thermosensitive rectal in situ gel utilizing various concentrations of poloxamer 407 (P 407) and poloxamer 188 (P188) alone or in mixture as thermosensitive polymers and hydroxypropyl methylcellulose K4M (HPMCK4M) as well as carboxymethyl cellulose (CMC) as mucoadhesive polymers. The achieved formulas were assessed for various in vitro constraints including: solution-gel temperature, gelation time, appearance, pH, gel strength, viscosity, in vitro drug release study. Furthermore, the optimized formula was evaluated for in vivo localization and permeability. Results The obtained outcomes demonstrated a direct correlation between solution-gelation temperatures and poloxamer 188 concentration as well as an inverse correlation with the concentration of both P407 and HPMCK4M. A direct correlation was perceived between the mucoadhesive forces and viscosity with HPMCK4M concentration. Additionally, an inverse correlation was observed between NPH released with HPMCK4M concentration. The optimal NPH gel formula (F8) (18% P407/2% P188 and 0.6%) presented a compatible pH value (7.2±0.35), an acceptable sol-gel T (35.4 °C), gel strength (39.54 ± 0.803), a mucoadhesion force of 6340.6 dyne/cm2 and sustained drug release of 85% at 8 hrs. Additionally it showed sufficient localization and a permeation flux of 0.0398 mg/cm2/h, and apparent permeability (Papp) of 1.99*10−3. Conclusions It was concluded that this drug delivery system may serve as a promising alternative to other dosage forms containing NPH, owing to avoidance of first-pass metabolism, enhanced bioavailability, non-invasiveness, and reduced adverse effects associated with other forms. 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F1000Research 2025, 14 :160 ( https://doi.org/10.12688/f1000research.159557.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability [version 1; peer review: 3 approved with reservations] Haydar Mahmood Ahmed https://orcid.org/0009-0009-2647-4793 1 , Iman Sabah Jaafar 1 Haydar Mahmood Ahmed https://orcid.org/0009-0009-2647-4793 1 , Iman Sabah Jaafar 1 PUBLISHED 04 Feb 2025 Author details Author details 1 Department of pharmaceutics, /College of Pharmacy/Mustansiriyah University, Baghdad, Iraq Haydar Mahmood Ahmed Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Iman Sabah Jaafar Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Background Nefopam hydrochloride (NPH) is a non-narcotic analgesic that is severely affected by its extensive hepatic metabolism resulting in low oral bioavailability. This study aimed to develop NPH thermosensitive in situ gel to enhance its bioavailability by avoidance of first pass effect through rectal administration. Methods A cold method was employed to develop NPH thermosensitive rectal in situ gel utilizing various concentrations of poloxamer 407 (P 407) and poloxamer 188 (P188) alone or in mixture as thermosensitive polymers and hydroxypropyl methylcellulose K4M (HPMCK4M) as well as carboxymethyl cellulose (CMC) as mucoadhesive polymers. The achieved formulas were assessed for various in vitro constraints including: solution-gel temperature, gelation time, appearance, pH, gel strength, viscosity, in vitro drug release study. Furthermore, the optimized formula was evaluated for in vivo localization and permeability. Results The obtained outcomes demonstrated a direct correlation between solution-gelation temperatures and poloxamer 188 concentration as well as an inverse correlation with the concentration of both P407 and HPMCK4M. A direct correlation was perceived between the mucoadhesive forces and viscosity with HPMCK4M concentration. Additionally, an inverse correlation was observed between NPH released with HPMCK4M concentration. The optimal NPH gel formula (F8) (18% P407/2% P188 and 0.6%) presented a compatible pH value (7.2±0.35), an acceptable sol-gel T (35.4 °C), gel strength (39.54 ± 0.803), a mucoadhesion force of 6340.6 dyne/cm 2 and sustained drug release of 85% at 8 hrs. Additionally it showed sufficient localization and a permeation flux of 0.0398 mg/cm 2 /h, and apparent permeability (Papp) of 1.99*10 −3 . Conclusions It was concluded that this drug delivery system may serve as a promising alternative to other dosage forms containing NPH, owing to avoidance of first-pass metabolism, enhanced bioavailability, non-invasiveness, and reduced adverse effects associated with other forms. READ ALL READ LESS Keywords Bioavailability, Liquid suppository, Mucoadhesive, Nefopam HCl, Poloxamer, Themosenstive. Corresponding Author(s) Haydar Mahmood Ahmed ( [email protected] ) Iman Sabah Jaafar ( [email protected] ) Close Corresponding authors: Haydar Mahmood Ahmed, Iman Sabah Jaafar Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Ahmed HM and Jaafar IS. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Ahmed HM and Jaafar IS. Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability [version 1; peer review: 3 approved with reservations] . F1000Research 2025, 14 :160 ( https://doi.org/10.12688/f1000research.159557.1 ) First published: 04 Feb 2025, 14 :160 ( https://doi.org/10.12688/f1000research.159557.1 ) Latest published: 04 Feb 2025, 14 :160 ( https://doi.org/10.12688/f1000research.159557.1 ) Introduction Pain mainly postoperative pain is a common condition that is the most frequent complaints of hospitalized patients. Even though the most effective analgesic in this situation is opioids, many serious side effects are related to them such as respiratory depression and sedation. 1 , 2 Nefopam hydrochloride (NPH) is a non-narcoticanalgesic that is frequently used to relieve moderate to severe postoperative pain. It acts by increasing neurotransmitter activity (serotonin, norepinephrine, and dopamine) which influences pain signaling in the brain and spinal cord. Additionally, it prevents glutamate release, which is known as a main neurotransmitter related to the pain signaling progression. 3 NPH is categorized as a class I drug in the biopharmaceutics classification system (BCS) with a molecular mass of 289.8, log P 3.4, and pKa 8.98. 4 NPH is administered orally, intramuscularly, and intravenously to avoid the multitude of side effects produced by opioid drugs and reduce their consumption by 30–40%. 5 , 6 After oral administration, NPH reaches peak plasma concentration by one to three hours with an elimination half-life of approximately four hours. NPH has a low bioavailability (about 36%) due to extensive hepatic metabolism and first pass effect which results in conversion into inactive metabolites that are primarily eliminated by urine. 7 , 8 Rectal administration could be an effective alternative to oral administration to overcome bioavailability issues related to first-pass degradation. Additionally, among the various noninvasive methods available, the rectal route is a safe substitute for oral and intravenous drug administration, especially for patients with swallowing difficulties, nausea, or vomiting, as well as for infants and elderly patients. 9 Upon insertion into the anus, a traditional solid suppository melts, dissolves, or softens in the rectal region to exert its effect. It has several drawbacks among them an alien feeling, pain sensation, anal leakage, low patient compliance, and patient discomfort which could result in patient rejection. 10 One of the novelties in rectal dosage forms is in situ liquid suppositories, which are fluid-liquid preparations that are transformed into gel inside the body upon insertion due to the effect of external stimuli for instance body temperature. 11 Poloxamer is the pillar of a thermosensitive in situ gelling system, a type of water-soluble, nonionic triblock copolymer. 12 Its thermosensitive properties and micellar formation are mainly related to its triblock structure, which combines hydrophilic and hydrophobic segments. In appropriate concentration poloxamer forms a gel at physiological body temperature, accordingly leakage prevention and extreme distribution in the rectum. 13 Additionally, mucoadhesive polymers are usually combined with thermosensitive polymers to exhibit an elevated level of retention at the site of application as well as provide a more sustained release pattern. 14 Consequently, an in situ thermoresponsive mucoadhesive gel has been considered to be more appropriate than a conventional solid suppository due to its simple administration to the rectum, safe to the rectal mucosal layers, adherence to the mucosal rectal tissue deprived of outflow and a foreign body feeling reduction. 9 The present work aimed to develop an in-situ thermos-gelling, mucoadhesive liquid suppository of NPH to improve the bioavailability and decrease the side effects associated with oral administration as the absorbed drug avoids the liver’s first-pass metabolism as well as avoid the drawbacks associated with solid suppositories. Methods This research was done at the Department of Pharmaceutics, College of Pharmacy, University of Mustansiriyah, Baghdad, Iraq (1 st of December 2023). Materials NPH was purchased from Targetmol Chemicals Inc., USA. Poloxamer 407 (P 407), poloxamer 188 (P188), and hydroxypropyl methylcellulose K4M (HPMC K4M) were purchased from Macklin Biochemical Co, Shanghai, China. Carboxymethylcellulose (CMC) was purchased from Shanghai Honest Chemicals, China. All chemical ingredients a reagent utilized were of analytical grade. Distilled water was purchased from SDI, Iraq. Laboratory animals The investigations were performed after approval by the ethical committee at Mustansiriyah University, College of Pharmacy (Approval No. 40 on 3/11/2024). We conducted the experiments following the guidelines established by the Committee for Control and Supervision of Experiments on Animals (CPCSEA). We applied methylated spirit as an antiseptic to prevent infection and used careful, gentle handling to minimize animal distress. Two animals were divided into two groups and housed in separated cages under optimal conditions of 25 ± 2°C, 50 ± 1% relative humidity (RH), and a 12-hour light/dark cycle, with regular access to water. Method of euthanasia According to AVMA guidelines for the euthanasia of animals 2020 edition, IV barbiturate was used as following steps: 1. Pre-Euthanasia Preparation: Ensure a calm and quiet environment to minimize stress for the rabbit and Gather necessary equipment and medications, including anesthetics and euthanasia solutions. 2. Sedation/Anesthesia: Administer a sedative or anesthetic, common combinations (Ketamine (20-40 mg/kg) and Xylazine (2-5 mg/kg) ‘given intramuscularly’). Then monitor the rabbit until it is adequately sedated and unconscious. This may take a few minutes, and sedation may be necessary to gain venous access for the administration of the euthanasia solution. 3. Euthanasia Solution: Once the rabbit is fully sedated, administer the euthanasia solution, typically an injectable solution containing pentobarbital sodium (barbiturate). - It is given by an IV (venous access could be obtained by ear). - The dose was 100-150 mg per 1 kg of body weight, as mentioned in the Handbook of Veterinary Anesthesia (William W Muir, John AE Hubbell.) 4. Confirmation of Death: Lack of breathing, palpable heartbeat, and a fixed dilated pupil are some of the easiest recognized indicators of death. Method of disposal of euthanized animals: Regardless of the euthanasia method chosen, animal remains must be handled appropriately and following state and local law. Preparation of NPH in situ gelling liquid suppository To identify the most suitable concentration of poloxamer that exhibited thermo-reversible properties below 37 °C (the temperature of the rectal cavity 37°C), an initial screening of different concentrations of P407 and P188 solutions was performed as shown in Table 1 . A dispersion of an accurately weighed amount of poloxamer (7.5-22.5%) in cold distilled water (100 ml) was prepared by slow continuous stirring (200-300 rpm) till complete desperation took place. Next, the prepared dispersions were reserved overnight in the refrigerator to confirm thorough dissolution and air bubble eradication. 15 Table 1. Preliminary formulas for screening the proper poloxamer concentration. Formula Code P407 % (w/v) P188 % (w/v) D.D.W q.s mL FP1 7.5 100 FP2 10 100 FP3 12.5 100 FP4 15 100 FP5 17.5 100 FP6 20 100 FP7 22.5 100 FP8 17 3 100 FP9 18 2 100 FP10 19 1 100 Formulas having appropriate gelation temperature (32-36 °C) were utilized for incorporation of NPH and mucoadhesive polymers (HPMC K4M and CMC) in different concentrations (0.4-1%) to formulate in situ gelling rectal suppositories utilizing the cold method and as shown in Table 2 . 16 Table 2. Composition of prepared NPH rectal in situ gel formulas. Formula Code NPH (Mg) P407%(w/v) P188 %(w/v) HPMC K4M %(w/v) CMC %(w/v) D.D.W q.s mL F1 200 17 3 100 F2 200 17 3 0.4 100 F3 200 17 3 0.6 100 F4 200 17 3 0.8 100 F5 200 17 3 1.0 100 F6 200 18 2 100 F7 200 18 2 0.4 100 F8 200 18 2 0.6 100 F9 200 18 2 0.8 100 F10 200 18 2 1.0 100 F11 200 18 2 0.4 100 F12 200 18 2 0.6 100 F13 200 18 2 0.8 100 F14 200 18 2 1.0 100 F15 200 19 1 100 F16 200 19 1 0.4 100 F17 200 19 1 0.6 100 F18 200 19 1 0.8 100 F19 200 19 1 1.0 100 F20 200 20 100 F21 200 20 0.4 100 F22 200 20 0.6 100 A precisely weighed amount of poloxamer (P407 and P188) for each formula was dissolved in a proper volume of distilled water at room temperature (25 °C). Consequently, the dispersion was sited inside an ice bath (4°) with continuous stirring for 30 min till a homogenous dispersion was acquired. The prepared dispersion was then kept overnight in a refrigerator to acquire a clear preparation. The accurate weight of mucoadhesive polymer (HPMC K4M or CMC) was dispersed in 30% of DW required for the formula and constantly stirred through a magnetic stirrer. Subsequently, both poloxamer and mucoadhesive polymer dispersions were blended constantly on an ice bath at 4° located on a magnetic stirrer. Characterization of prepared NPH in situ gel Determination of Sol-Gel transition temperature Ten milliliters of the liquid suppository were placed in a 20 mL transparent vial containing a magnetic bar. The vial then was placed in a thermostat water bath set at 25 °C and the liquid suppository was heated at a fixed rate (2 °C/min) with constant stirring (50 rpm). When the magnetic bar stopped moving due to gelation, the temperature was documented as the gelation temperature. 17 , 18 Gelation time (Gt) The reported approach was followed in determining the gelation time. In summary, a 30 mL universal tube containing 10 mL of the formulation was magnetically stirred at 100 rpm while the temperature was gradually raised (1°C/min). The gelation time was defined as the moment when the magnetic bead stopped rotating. 19 Appearance and pH determination The general appearance of formulated in situ gel was assessed by employing visual inspection for clarity and homogeneity under a white and black background. 20 The pH of the formulated in situ gel was evaluated utilizing a calibrated glass prob pH meter (Hanna Instruments, Italy). The pH meter probe was immersed in each formula and the average of three determinations for each formula was taken. 21 , 22 Measurement of gel strength Gel strength was determined in triplicate by weighing 5 g of each formula, which was placed in a 10 mL measuring cylinder using a temperature-controlled water bath; after the formula congealed at the gelation point, the gel was pressured using a 3.5 g weight via a circular cup. The time taken by weight of 3.5 g to penetrate 0.5 cm through the gel was recorded in seconds. 23 Drug content One mL of prepared formula equivalent to 2 mg of NPH was accurately taken and diluted to 10 mL by phosphate buffer (pH 7.4), the solution was filtered through a 0.45 μm pore size Millipore filter, The ultraviolet/visible spectrophotometer (Shimadzu ® , Japan) was used to analyze the resultant solution spectrophotometrically at 266 nm against phosphate buffer (pH 7.4) as a baseline. The concentration of the ingredient in the in-situ gelling liquid suppository formula was determined using a calibration curve that had been previously established. Drug content tests were conducted in triplicate. 24 Determination of the Mucoadhesive Force To measure the detachment force required to separate the developed liquid suppositories from fresh specimen of rectal sheep mucosal tissue, a modified mucoadhesive measuring apparatus was implemented. A tissue specimen from the mucosal side of the sheep rectum cavity was obtained from a nearby slaughterhouse and kept in normal saline. A piece of the rectum (surface area 3 cm* 3 cm) was cut and glued with cyanoacrylate adhesive on the ground surface of a tissue holder made of wood attached to the right arm of the balance. The measured amount (30 mL) of gel to be examined was added to the modified container located below the tissue holder. The tissue holders with rectal tissues and gel were subjected to uniform and constant pressure for 5 minutes (preload time) to promote adhesion bonding. Following a preload period, water was introduced into a pre-weighed container positioned on the left arm of the balance via an intravenous infusion set at a rate of one drop per second until the two adhered surfaces separated. The water in the container was subsequently measured and weighed. 25 The measured weight was transformed into the force required for detachment using the equation: (1) Detachment stress ( dynes / cm 2 ) = M ∗ G / A where M = Minimal weight required for separation of two vials in g, G = Gravitational acceleration (980 cm/s 2 ), and A = exposed tissue area. A newly rectal mucosal tissue was employed for each measurement. 26 Rheological study A Brookfield-DVE-USA viscometer was used to determine the viscosity of the formulated in situ gels. Initially, 20 mL of the prepared formula was placed in a small vial at room temperature (25 °C). The temperature of the prepared formula was then elevated to body temperature (37 °C) employing a water bath. Measurements were performed in triplicate for each prepared formula and recorded for 25 °C and 37 °C using spindle number 64. 27 In vitro release study A modified method was implemented to simulate an in vivo drug release from prepared in situ gel formulations. The study was conducted by using a USP type II dissolution apparatus (Vanguard Pharmaceutical Machinery, INC. USA). An accurately measured volume (10 mL) of in situ gel (containing 20 mg of NPH) was placed in a dialysis bag prepared from a previously soaked dialysis membrane (molecular weight of 8000-14000 Dalton) in PBS pH 7.4 for 24 hrs. The dialysis membrane was secured from one side using rubber bands prior to the placement of the gel. The other side of the bag was also secured post-gel settlement by the same method and then attached to the paddle firmly and immersed in a 350 mL phosphate buffer (PBS) pH 7.4, which was maintained at 37 ± 0.5°C and rotated at 50 rpm. Samples from the dissolution medium were withdrawn at scheduled times and replaced with fresh buffer medium to provide the sink condition and absorbance was measured with UV spectrophotometry at 266 nm. 28 , 29 Selection of optimum formula The selection of the NPH-loaded in situ gel formula was based on parameters such as gelation temperature, Gt, pH, gel strength, viscosity, mucoadhesive force, and in vitro drug release studies. The selected formula was then subject to further evaluation tests. Rectal in vivo localization of NPH thermosensitive in situ gel A modified method was employed to study the extent of localization of NPH thermosensitive in situ gel. The inclusion and exclusion criteria for animals encompassed parameters such as health status, age, weight, and sex. We divided two albino rabbits weighing 2–2.5 kg into two groups: Group I (control, formula 8 without mucoadhesive polymer) and Group II (formula 8). We caged them separately according to their groups, providing them with water and proper environmental conditions. Since the study did not identify a single primary outcome measure for hypothesis testing, we did not perform an a priori sample size calculation. Instead, we established the sample size based on existing literature. Prior to the experiment two male albino rabbits were fasted for 24 hours with free access to water to reduce the rectum fecal content. We used an electric clipper to remove the hair from the male albino rabbits’ abdominal surface (5*5 cm) without compromising the skin’s integrity. Then we applied methylated spirit as an antiseptic with cotton wool to the shaved area to prevent bacterial infection. Formula 8 (NPH-18% P407/2% P188/0.6 HPMCK4M) and control formula (NPH-18% P407 2% P188) (gelation temperature = 35.4 °C) were injected into the rectum 4 cm above the anus through a catheter which was affixed to a disposable syringe afterward incorporation of 1% methylene blue to each formula. At 30 minutes and 6 hours following administration, the rectum was sectioned, and the localization of the liquid suppository formulas in the rectum was identified by the blue color. 30 Animal handling and care during the experimental procedure adhered to the “Experimentation on Animals in the Course of Medical Research and Education” (CPCSEA) criteria and the AVMA 2020 guidelines. 31 The investigations were performed after approval by the ethical committee at Mustansiriyah University, College of Pharmacy (Approval No. 40 on 3/11/2024). In our animal studies, we employ several strategies to alleviate animal suffering. This involves ensuring a calm and quiet environment to minimize stress, modifying experimental procedures to minimize pain and distress by using less invasive techniques, improving housing conditions, and providing better care. Anesthesia during procedures helps alleviate suffering. Permeation study An ex vivo permeation study for the optimum selected formulation (F8) and control containing NPH aqueous solution (drug concentration 2 mg/mL) was implemented by Franz diffusion cell using a fresh specimen of a sheep rectum received from a local slaughterhouse. After thoroughly washing with PBS pH 7.4, the mucosal tissue was cut into sections measuring (2.5 cm * 2.5 cm). The prepared sections were placed in cooled PBS pH 7.4. The diffusion surface area was 2.5 cm 2 . The receptor compartment was filled with 28mL of PBS pH 7.4 and the cell was set at 37 ± 0.5 °C with the aid of a thermostatic bath and magnetic stirrer. 32 , 33 Formulation equivalent to 20 mg of drug was placed in the donor compartment which was in connection with the mucosal surface of the membrane. A portion of 1mL was withdrawn from the receptor compartment at suitable timing intervals (15,30,45,60,90,120,150,180, 210, 240, 270,300,330,360 and 480 min) and replaced with fresh buffer medium to maintain the sink condition and analyzed for drug concentration spectrophotometrically double beam UV-Vis spectrophotometer at lambda max. 34 The permeability coefficient was calculated at steady-state conditions by using the following equation 35 : (2) Peff = Jss / C0 Data statistical analysis Obtained data were analyzed via a one-way analysis of variance (ANOVA) test. Statistical dissimilarities are counted as significant when (p<0.05). 36 Results and discussion Solution - Gelation Temperature Solution-gelation temperature (sol-gel T) is the temperature at which the liquid phase makes a transition to gel. The temperature of the rectal mucosa is reported to be 37 °C as a body temperature. Consequently, the in situ gel formula is designed to have a sol-gel T in the range of 32–36 °C to maintain its liquid state at room temperature and readily transformed into a gel when it comes into contact with the rectal mucosa inside the body upon administration. 37 , 38 The sol-gel temperature of the prepared preliminary formulations was identified and the obtained results are revealed in Table 3 . Table 3. Sol-gel T of preliminarily prepared formulas. Formula Code P407 % (w/v) P188 % (w/v) Sol-gel T °C PF1 7.5 55 PF2 10 51 PF3 12.5 45 PF4 15 41 PF5 17.5 38 PF6 20 35 PF7 22.5 26.5 PF8 17 3 > 40 PF9 18 2 32.8 PF10 19 1 32 The obtained outcomes show that the sol-gel T decreased significantly (p < 0.05) as the concentration of P407 increased (PF1-PF7). This could be related to the availability of P407 chains for micelle formation and subsequently increases in the lattice packing order. Therefore, an increase in P407 concentration favored temperature-induced gelation and caused a lower gelation temperature. 39 A similar observation was obtained by Niyompanich J et al ., who developed gentamicin sulfate in situ gel thermosensitive gel for wound treatment. 40 Based on these findings P407 alone (PF1-PF7) could not provide the required sol-gel T. Consequently modulation of the sol-gel T was implemented and accomplished through the use of a combination of P407 and P188. 16 Up on implementing the combination an opposite result was obtained since increasing P188 concentration in the blend resulted in a significant (p < 0.05) increase in sol-gel T (PF8 - PF10). This outcome could be explained by the fact that P188 is more hydrophilic than P407 due to a higher ratio of polyethylene oxide/polypropylene oxide (PEO/PPO) group content compared to P407. Consequently, the addition of a minor amount of P188 to P407 changed the PEO proportion in the mixed polymer solutions since both had an equal proportion of PPO, leading to an increase in sol-gel T. Similar results were previously reported by Ibrahim E S et al. 41 Formulas (PF6, PF9, and PF10) that demonstrated an appropriate sol-gel T were subsequently selected for incorporation of NPH and various mucoadhesive polymers (HPMC K4M and CMC) in different concentrations (0.4-1%). The impact of various mucoadhesive polymers (HPMC and CMC) on sol-gel T of prepared formulas (F6-F22) is shown in Table 4 . Table 4. Physico-mechanical properties of NPH rectal in situ gel formulas. Formula Code Sol-gel T (°C) Gt (min) APP * pH Drug Content (%) Gel strength (sec) F1 >40 NA ++ NA NA NA F2 > 40 NA + NA NA NA F3 >40 NA + NA NA NA F4 39.8 NA + NA NA NA F5 39 NA + ppt. NA NA NA F6 36.2 4:17 ++ 6.76±0.05 97.79±0.32 6.24±0.946 F7 36 4:51 + 7.1±0.26 100.86±1.38 10.02 ± 0.012 F8 35.4 4:08 + 7.2±0.35 102.12±0.37 39.54 ± 0.803 F9 33.8 3:45 + 7.13±0.17 99.46±0.92 48.54 ± 0.515 F10 32.9 3:28 + ppt. 7.15 ± 0.1 99.19±1.30 59.72 ± 0.350 F11 > 40 NA + NA NA NA F12 39.8 NA + NA NA NA F13 38.6 NA + NA NA NA F14 37.1 NA + NA NA NA F15 36 3:38 ++ 6.8±0.07 98.420±0.928 31.31 ±1.05 F116 35.8 5:53 + NA NA NA F17 34.5 5:28 + NA NA NA F18 33.2 4:58 + 7.05 ± 0.1 98.26±0.98 1.06 min. ± 0.065 F19 32.4 4:26 + ppt 7 ± 0.1 99.12±0.95 1.32 min.± 0.117 F20 36.4 3:57 ++ 6.82±0.04 98.46±0.57 58.54±0.528 F21 33.8 3:33 + 6.8 ± 0.14 97.72±1.36 1.21min.±0.157 F22 32.6 2:55 + 6.85± 0.05 98.06±0.41 1.48min.±0.170 * (Cloudy -, Very Cloudy - -, Clear +, Transparent ++, Precipitate (ppt.)). The obtained result demonstrated a significant (p < 0.05) decline in the sol-gel T as the mucoadhesive polymer concentration increased (0.4 to 1% w/v). A similar observation was obtained by Thomas LM et al. in the preparation of lornoxicam in situ gelling liquid suppository. 42 This decline in sol-gel T could be explained by the polymer’s ability to attach to the polyoxyethylene chains in the molecules of poloxamer. Consequently, dehydration is facilitated, which improves the adjunct’s entanglement and significantly enhances intermolecular hydrogen bonding. As a result, gelation occurs at lower temperatures. 43 The obtained results also indicated that upon incorporation of NPH (PF9 and F6), the sol-gel T increased significantly (P < 0.05). This could be explained by the modification of the micellar association process of poloxamer solutions by water-soluble molecules, consequently increasing the sol-gel T. 44 Gelation time Gelation time is similarly essential as sol-gel T since the mixture must transform into a gel after installation and persist in a gel state for sufficient time to allow the drug to release. Consequently, liquid suppositories with ideal gel strength and a relatively short gelation time will stay in the suitable part of the rectum and will not leak out the anus. 45 The Gt of prepared in situ gel formulas is presented in Table 4 . The obtained outcomes demonstrated that as the concentration of mucoadhesive polymers increased as in formulas (F7-F10) and (F18-F22) a significant depletion (p < 0.05) in Gt was observed. These results could be justified by the development of hydrogen bonding concerning the poloxamer’s PEO chain and the mucoadhesive polymer and consequently a prompt growth of micellar structures. 46 The obtained results were in line with the results achieved by Rençber S et al. 47 Appearance and clarity A visual examination of selected formulas was done to assess for any incompatibilities resulting from an interaction between the excipients or between the excipients and the active pharmaceutical ingredient. The appearance of the prepared formulations is displayed in Table 4 . Formulas (F1-F10) and (F15-F22) were clear and revealed the formation of precipitate at the bottom of the container for formulas that contain the highest concentrations of HPMC K4M (1%). On the other hand, formulas (F11-F14) were clear and revealed the absence of any precipitation which indicates the absence of any interaction. 7 pH determination The pH of the rectum is normally neutral (7.2–7.4). Alterations in pH can cause discomfort or damage to the rectal mucosa, as well as affect formula stability. 48 The pH of developed liquid suppositories is shown in Table 4 . They were discovered to be between (6.76±0.05-7.2 ± 0.35) which is thought to be around the natural pH of the rectum and suitable for rectal administration with non-significant tissue irritation. 49 Gel strength In formulating a liquid suppository, the gel strength plays a crucial role in determining the ideal condition that permits the suppositories to be easily inserted and not leak out from the anus. 38 A liquid suppository with a gel strength of less than 10 seconds may lose its shape and leak out of the anus, whereas a liquid suppository with a duration of more than 50 seconds might be excessively hard and painful for the rectum. 50 In formulas with an optimum sol-gel T (F6-F10) and (F18 - F22), the obtained gel strength was from (6.24 ± 0.946 sec - 1.48 min.± 0.170), as shown in Table 4 . The obtained findings for formulas (F6, F15, and F20) and (F7, F18, and F21) demonstrated that the gel strength of formulas was significantly (P < 0.05) increased upon the addition of mucoadhesive polymer (HPMCK4M). Furthermore, the obtained results for formulas (F7-F10 and F20-F22) indicated that upon increasing the concentration of the mucoadhesive polymer (HPMC K4M), the gel strength of the poloxamer mixture increased significantly (p < 0.05) in a concentration-dependent manner. These results could be explained by the fact that HPMCK4M inclusion and increasing its concentration afford an increased viscosity as a result of a greater polymer chain cross-linking as well as the development of hydrogen bonds and Van der Waals between poloxamer and HPMCK4M, subsequently enhanced gel strength. 51 These results were in good accordance with the results obtained by Yong et al. 52 Drug content Drug content was determined to be (97.72 %-102.12 %) which is in the acceptable range according to the USP of all the formulations. 53 This suggests that the technique utilized could produce gels with homogenous drug content and low variability, 54 as displayed in Table 4 . Ex-vivo mucoadhesive strength The mucoadhesive force is a crucial physico-mechanical parameter for in situ gelling liquid suppositories because it prevents the formula from spreading to the upper part of the rectum, slows down rapid leakage, extends the formula’s residence duration, and prolongs drug release. 14 The obtained results as shown in Table 5 and Figure 1 demonstrated that formulas (F6, F15, and F20), which contain no mucoadhesive polymer showed minor mucoadhesive properties compared to formulas that contain mucoadhesive which reflected a limited residence time as well. Consequently, the implementation of bioadhesive polymers is crucial. 55 Table 5. Mucoadhesive characteristics for NPH rectal in situ gel formulas. Formula Code Bioadhesive strength (g) Mucoadhesive force (dyne/cm 2 ) F6 4.87 ± 0.417 1590.86 F7 12.46 ± 0.767 4070.27 F8 19.41 ± 0.884 6340.6 F9 20.85 ± 0.242 6811 F10 28.02 ± 0.395 9153.2 F15 3.46 ± 0.251 1130.26 F18 17.85 ± 0.639 5831 F19 22.34 ± 1.050 7297.7 F20 5.41 ± 0.364 1734.6 F21 13.39 ± 0.905 4374.1 F22 24.56 ± 0.919 8022.9 Figure 1. Mucoadhesive force of selected NPH rectal in situ gel formulas in the presence and absence of mucoadhesive polymer (HPMC K4M). (A) mucoadhesion force of F6-F10; (B) mucoadhesion force of F15, F18 and F19; (C) mucoadhesion force of F20-F22. The results indicated that the mucoadhesive force increased significantly (p<0.05) by raising the concentration of HPMCK4M across the range of 0.4-1% in formulas (F6-F9), (F15, F18-F19) as well as (F20-F22). Hence various mucoadhesive polymers (HPMCK4M and CMC) in different concentrations (0.4-1%) were incorporated and formulas with an optimum sol-gel T were then experimented for mucoadhesive force. The obtained outcomes revealed that none of the formulas went over the highest acceptable limit (10,000 dyne/cm 2 ) which indicates that the prepared formulas possess ideal mucoadhesion characteristics. 56 The achieved results declared a significant (p<0.05) enhancement in mucoadhesive force was obtained by the incorporation of mucoadhesive polymer (F7, F18, and F21) compared to (F6, F15, and F20) respectively. The presence of hydroxyl groups in HPMCK4M may contributed to this finding by improving the substance’s capacity to create hydrogen bonds with mucus which is considered an essential stage in the mucoadhesion process. 57 A comparable result was reported by Al Hablawi et al. 26 Furthermore, the results indicated that the mucoadhesive force increased significantly (p<0.05) by raising the concentration of HPMCK4M across the range of 0.4-1% in formulas (F6-F9), (F15, F18-F19) as well as (F20-F22). The abundance of secondary bond-forming groups in the mucoadhesive polymers explains the ability of mucoadhesive polymers to bind, via hydrogen bond, to the glycoprotein chains of the rectum mucus layer and result in enhancing the mucoadhesion in a concentration-dependent manner. Consequently increasing concentration will result in increasing the binding site available for adhesion. 58 , 59 Similar results were previously reported by Salman et al. 60 Rheological study The viscosity data of selected formulas (F6-F10), (F15, F18- F19), and (F21-F22) at liquid and gel phases under different shear rates (rpm) are shown in Figure 3 . All the prepared formulas showed quite low viscosity at room temperature while a significant increase (p < 0.05) in viscosity was obtained when the temperature increased to biological temperature as shown in Figure 2 . This could be explained by the fact that the gelation of in situ gel is mainly related to the breakage of aqua-phobic linkage covering the poloxamer molecule at low temperatures and the separation of the solvent component as the temperature increases. Accordingly, gel formation due to hydrophobic interaction that formed due to increased chain friction and entanglement in the polymer is responsible for the gelation of P407 15 Similar results were previously reported by previous literatures. 61 , 62 Figure 2. Viscosity measurement of prepared NPH rectal in situ gel formulas at room (25°C) and biological temperature (36°C). A significant increase (p < 0.05) in viscosity was obtained when the temperature increased to biological temperature. Figure 3. Rheogram profile for NPH rectal in situ gel formulas at 34 °C using spindle No. S64. The results of this study also demonstrated that the viscosity reduced significantly (p<0.05) as the rotation speed (shear rate) increased. The viscosity-temperature relationship deviates from the Arrhenius equation, which states that viscosity is inversely related to temperature. 63 The results correspondingly showed that the viscosity of in situ gelling liquid suppositories increased significantly (p<0.05) as the concentration of HPMC K4M increased (F7-F10). This could be justified by the hydrophilic ability of HPMC K4M to absorb water, which led to increased viscosity. 60 Additionally, the results of this study also demonstrated that the viscosity reduced significantly (p<0.05) as the rotation speed (shear rate) increased demonstrating the pseudoplastic (shear-thinning liquid) flow of the preparation. 64 This outcome is in agreement with what was reported previously. 65 In vitro release study The in vitro release profile of NPH from in situ rectal suppository formulations is shown in Figure 4 . Figure 4. In vitro release profile of NPH from in situ rectal suppositories in phosphate buffer (pH 7.4) (37°C). (A) NPH release profile for F6(HPMC K4M 0.0%), F15(HPMC K4M 0.0%) and F20(HPMC K4M 0.0%); (B) NPH release profile for F6, F7(HPMC K4M 0.4%), F8(HPMC K4M 0.6%), F9(HPMC K4M 0.8%) and F10(HPMC K4M 1.0%); (C) NPH release profile for F15, F18(HPMC K4M 0.8%) and F19(HPMC K4M 1.0%); (D) NPH release profile for F20, F21(HPMC K4M 0.4%) and F22(HPMC K4M 0.6%). A significant (P < 0.05) retardation in drug release was observed as the concentration of mucoadhesive polymer increased (F6-F10). The effect of the combination of mucoadhesive polymer (HPMCK4M) and its concentration is illustrated in B, C, and D. The obtained outcomes established that the maximum drug release was obtained by F6, (blend of 2%P188 and 18% P 407) where 92 % of NPH was released within 300 min, while a minimum drug was obtained by F19, (blend) of 1.0% HPMCK4M and 19% P 407 and 1% P188 where 60% of NPH was released within 480 min. The results also demonstrated that both P407 and P188 reduced NPH release in a concentration-dependent way as the release rate of NPH decreased significantly (P < 0.05) with increasing P407/P188 ratio (F6, F15, and F20) as shown in Figure 3A . This could be related to the ability of P407 molecules to form constricted gel arrangements by hydrogen bond formation in the aqueous media. Additionally, the hydrophilic nature of NPH facilitates its interaction with poloxamer, consequently interrupting the drug release profile. Thus, NPH release is reduced because of the postponement in both in situ gel dissolution and NPH diffusion. 66 Additionally, the achieved results revealed that the incorporation of mucoadhesive polymer (HPMCK4M) retard NPH release significantly (P < 0.05). This retardation in NPH release could be justified by the capability of mucoadhesive polymer to enhance the viscosity of the formula and subsequently affect the drug diffusion and release. 67 The obtained results are consistent with the results obtained by Özgüney I. et al. 68 Furthermore, a significant (P < 0.05) retardation in drug release was observed as the concentration of mucoadhesive polymer increased (F6-F10). These outcomes could be explained by an amplification of gel strength as well as a decrease in the number and size of the gel structure’s channels, consequently, limiting the drug’s release by reducing the penetration of the dissolution fluid and restricting the mobility of the drug molecule. 42 The effect of the combination of mucoadhesive polymer (HPMCK4M) and its concentration is illustrated in Figure 4 (B, C, and D) . Selection for optimum formula Based on results from gelation behavior, gel strength, mucoadhesion, in vitro drug release studies, and rheological evaluations, F8 containing P407/P1088/HPMC in 18%, 2%, and 0.6 %, respectively was selected for further ex vivo permeability evaluation. Rectal in vivo localization of NPH thermosensitive in situ gel The optimized NPH in situ liquid suppository (F8) and control were injected into rabbits’ rectums, and its localization was detected 30 min after administration. The blue color of the liquid suppository was noticed obviously in the rectum as shown in Figure 5A . Then 6 h post to administration, the blue tint of the liquid suppository in the rectum faded as shown in Figure 5B . Though, the formula’s position in the rectum did not change significantly over time and did not delocalize to the colon. These data revealed that the mucoadhesive force of the gel formula was sufficient to maintain it in the rectum for not less than 6 h permitting the in situ gel formula to persist in the lower part of the rectum and hence protecting NPH from extensive hepatic metabolism. These outcomes could be justified by the ability of the incorporated HPMCK4M to provide the required bonds for mucoadhesion with the chains of oligosaccharides of the mucous layer lining the rectum. Similar results were previously reported by Salem HF et al. 50 , 69 Figure 5. In vivo localization and retention of NPH liquid suppository (NPH-LS) in the rectum. (A) NPH-LS after 30 min; (B) NPH-LS after 6 hours. The blue color of the liquid suppository was noticed obviously in the rectum as shown in A. Then 6 h post to administration, the blue tint of the liquid suppository in the rectum faded as shown in B. Ex vivo permeability study The ex-vivo permeability study of the optimized in situ gel formula (F8) and the control result is shown in Figure 6 . A steady state, or linear profile, was monitored for eight hours, and the slope of the linear portion of the curve was identified by the application of linear regression. Figure 6. (A) Cumulative permeation of NPH from F8 and control through rectal mucosa; (B) Linear portion of permeation curve (steady state). The flux values at a steady state and effective permeability were calculated and are illustrated in Table 6 . Table 6. Ex-vivo permeation parameters for F8 and control formula. Formula No. Jss (mg/cm 2 min) P eff. (cm/min) control 0.0105 5.25 * 10 −4 F8 0.0398 1.99 * 10 −3 Permeation results revealed that the formula exhibited an initial rapid permeation and sustained drug permeation after 60 min. Such a delay in drug permeation may be explained by the presence of both thermosensitive polymers (P407 and P188) and mucoadhesive polymer (HPMCK4M) since the poloxamer has an improved micellar core and gel network with a mucoadhesive polymer that entraps the drug molecule and slows down the rate of drug release. 24 The findings also revealed that the F8 had greater Jss and Peff compared to the control formula. This difference can be attributed to either the impact of the mucoadhesive polymer by increasing the retention period or to the permeation-enhancing effect of HPMCK4M and thermosensitive polymers (P 407 and P188). 70 , 71 Conclusion According to the attained results, it was concluded that thermosensitive in situ rectal gel of NPH could be positively formulated employing poloxamer (P407, P188) and HPMCK4M. The optimal NPH in situ gel formula (18% P407/2% P188 and 0.6%) presented compatible pH value (7.2±0.35), an acceptable sol-gel T (35.4 °C), gel strength (39.54 ± 0.803), a mucoadhesion force of 6340.6 dyne/cm 2 and sustained drug release of 85% at 8 hrs. Additionally it showed sufficient localization at site of application without migration. These outcomes demonstrated that this drug delivery system could be an encouraging alternative to other dosage forms containing NPH due to avoidance of first-pass metabolism and enhanced bioavailability, non-invasiveness and reduction of side effects associated with them Ethical approval: Animal handling and care during the experimental procedure adhered to the “Experimentation on Animals in the Course of Medical Research and Education” (CPCSEA) criteria and the AVMA 2020 guidelines. The investigations were performed after approval by the ethical committee at Mustansiriyah University, College of Pharmacy (Approval No. 40 on the 3 rd of November 2024). Contributor role Conceptualization: Haydar Mahmood Ahmed, Iman Sabah Jaafar Data Curation: Haydar Mahmood Ahmed Formal Analysis: Haydar Mahmood Ahmed, Iman Sabah Jaafar Funding Acquisition: Haydar Mahmood Ahmed, Iman Sabah Jaafar Investigation: Haydar Mahmood Ahmed, Iman Sabah Jaafar Methodology: Haydar Mahmood Ahmed, Iman Sabah Jaafar Project Administration: Haydar Mahmood Ahmed Resources: Haydar Mahmood Ahmed, Iman Sabah Jaafar Software: Haydar Mahmood Ahmed, Iman Sabah Jaafar Supervision: Iman Sabah Jaafar Validation: Iman Sabah Jaafar Visualization: Haydar Mahmood Ahmed, Iman Sabah Jaafar Writing – Original Draft Preparation: Haydar Mahmood Ahmed Writing – Review & Editing: Haydar Mahmood Ahmed, Iman Sabah Jaafar Data availability Zenodo: Nefopam HCl in situ Mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability, https://doi.org/10.5281/zenodo.14218213 . 72 This project contains the following underlying data: • statistics.xlsx Data are available under Creative Commons Zero v1.0 Universal Extended data 1. Zenodo: Materials and calberation curve ‘Nefopam HCl in situ Mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability’, https://doi.org/10.5281/zenodo.14335091 . This project contains the following underlying data: • Materials and calberation curve.docx 2. Zenodo: figures and related data to ‘Nefopam HCl in situ Mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability’, https://zenodo.org/records/14334934 This project contains the following underlying data: • figures and related data.xlsx 3. Zenodo: information about Anesthetic and Euthanasia used ‘Nefopam HCl in situ Mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability’ https://doi.org/10.5281/zenodo.14335010 This project contains the following underlying data: • information about Anesthetic and Euthanasia used.pdf Creative Commons Zero v1.0 Universal Reporting guideline ARRIVE checklist for ‘Nefopam HCl in situ Mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability’. https://doi.org/10.5281/zenodo.14334832 . 73 Creative Commons Zero v1.0 Universal Acknowledgment The authors are sincerely grateful for the College of Pharmacy – Mustansiriyah University ( www.uomustansiriyah.edu.iq ), Baghdad, Iraq for its provision. References 1. Pirie K, Traer E, Finniss D, et al. : Current approaches to acute postoperative pain management after major abdominal surgery: a narrative review and future directions. Br. J. Anaesth. 2022; 129 : 378–393. 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Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 04 Feb 2025 ADD YOUR COMMENT Comment Author details Author details 1 Department of pharmaceutics, /College of Pharmacy/Mustansiriyah University, Baghdad, Iraq Haydar Mahmood Ahmed Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Iman Sabah Jaafar Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 04 Feb 2025, 14:160 https://doi.org/10.12688/f1000research.159557.1 Copyright © 2025 Ahmed HM and Jaafar IS. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Ahmed HM and Jaafar IS. Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability [version 1; peer review: 3 approved with reservations] . F1000Research 2025, 14 :160 ( https://doi.org/10.12688/f1000research.159557.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 04 Feb 2025 Views 0 Cite How to cite this report: Bhagwat DA. Reviewer Report For: Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability [version 1; peer review: 3 approved with reservations] . F1000Research 2025, 14 :160 ( https://doi.org/10.5256/f1000research.175305.r392428 ) The direct URL for this report is: https://f1000research.com/articles/14-160/v1#referee-response-392428 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 13 Aug 2025 Durgacharan A. Bhagwat , Bharati Vidyapeeth College of Pharmacy, Kolhapur, India Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.175305.r392428 Manuscript presents the development and evaluation of a thermosensitive in situ mucoadhesive liquid suppository for rectal delivery of Nefopam hydrochloride (NPH). The study is well-structured and explores both in vitro and ex vivo parameters relevant to bioavailability enhancement and formulation ... Continue reading READ ALL Manuscript presents the development and evaluation of a thermosensitive in situ mucoadhesive liquid suppository for rectal delivery of Nefopam hydrochloride (NPH). The study is well-structured and explores both in vitro and ex vivo parameters relevant to bioavailability enhancement and formulation optimization. But still need to clarify on following: 1) Add a discussion on how the in vitro release and ex vivo permeation correlate with in vivo retention/localization data. 2) Improve figure quality, add error bars where appropriate, and clarify units consistently across tables and figures. 3) The manuscript contains several minor typographical and grammatical errors. For example: "desperation" instead of "dispersion" (in methods) "Themosenstive" should be "thermosensitive" (keywords) "drug was obtained by F19, (blend)" - phrasing 4) Ensure all abbreviations (e.g., P407, HPMC K4M, CMC, Peff, Jss) are defined at first use and used consistently. 5) Suggest potential clinical implications and next steps (e.g., pharmacokinetics, human trials) in Conclusion section. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Formulation development of Novel drug delivery system, Solubility enhancement, SNEDDS, Cubosome, NLCs I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Bhagwat DA. Reviewer Report For: Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability [version 1; peer review: 3 approved with reservations] . F1000Research 2025, 14 :160 ( https://doi.org/10.5256/f1000research.175305.r392428 ) The direct URL for this report is: https://f1000research.com/articles/14-160/v1#referee-response-392428 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Castillo-Martinez NA. Reviewer Report For: Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability [version 1; peer review: 3 approved with reservations] . F1000Research 2025, 14 :160 ( https://doi.org/10.5256/f1000research.175305.r392420 ) The direct URL for this report is: https://f1000research.com/articles/14-160/v1#referee-response-392420 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 07 Aug 2025 Nydia Alejandra Castillo-Martinez , Facultad de Ciencias de la Salud, Autonomous University of Baja California, Tijuana, Baja California, Mexico Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.175305.r392420 This manuscript presents the development and evaluation of a thermosensitive, mucoadhesive in situ gel formulation of Nefopam HCl intended for rectal administration. The authors aim to overcome the limitations of oral bioavailability due to first-pass metabolism and enhance patient compliance ... Continue reading READ ALL This manuscript presents the development and evaluation of a thermosensitive, mucoadhesive in situ gel formulation of Nefopam HCl intended for rectal administration. The authors aim to overcome the limitations of oral bioavailability due to first-pass metabolism and enhance patient compliance by using a non-invasive delivery system. The study is well-designed with a comprehensive evaluation of physicochemical, rheological, in vitro, and ex vivo parameters. The formulation approach is scientifically sound, and the rationale for selecting specific polymers (P407, P188, HPMCK4M, and CMC) is appropriately justified. However, some areas require improvement to enhance the scientific rigor, clarity, and overall quality of the manuscript. The study addresses an important issue in drug delivery, the low bioavailability of Nefopam due to extensive hepatic metabolism. The rectal in situ gel approach is a novel and potentially valuable option for patients who are unable to tolerate oral or intravenous administration. The authors systematically evaluated multiple formulations, assessing sol-gel transition temperature, gelation time, mucoadhesive strength, drug release, viscosity, and in vivo localization, providing a thorough characterization. Data are generally well-organized, with appropriate tables and figures. The inclusion of standard deviations and triplicate measurements in the Excel file supports the reproducibility of findings. Major comments While ANOVA is mentioned, specific statistical outputs (e.g., F-values, p-values, confidence intervals) are missing or incomplete. Include complete statistical comparisons across groups where significance is claimed, especially for sol-gel temperature, mucoadhesive strength, and drug release. The in vivo rectal localization study includes only two rabbits. While this may be acceptable for a pilot study, this limitation should be acknowledged and addressed. Consider discussing how these preliminary results support future work with a larger sample size. Expand on the mechanistic explanation of drug release retardation due to polymer interactions. Include a comparison of the proposed formulation's performance with existing rectal or oral Nefopam formulations, if available. Ensure that all figures are high-resolution and include complete legends (e.g., units, sample sizes). Minor Comments The manuscript contains several grammatical and typographical errors that hinder clarity (e.g., "desperation" instead of "dispersion"). A professional language review or copyediting would significantly improve the readability. Define all abbreviations at first use (e.g., PBS, Gt, HPMCK4M). Indicate the number of replicates (n=3) explicitly in methods for each test. Avoid excessive repetition in figure captions and results text. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Antimicrobials I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Castillo-Martinez NA. Reviewer Report For: Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability [version 1; peer review: 3 approved with reservations] . F1000Research 2025, 14 :160 ( https://doi.org/10.5256/f1000research.175305.r392420 ) The direct URL for this report is: https://f1000research.com/articles/14-160/v1#referee-response-392420 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: J. Burgess D and Kulkarni R. Reviewer Report For: Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability [version 1; peer review: 3 approved with reservations] . F1000Research 2025, 14 :160 ( https://doi.org/10.5256/f1000research.175305.r366194 ) The direct URL for this report is: https://f1000research.com/articles/14-160/v1#referee-response-366194 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 03 Mar 2025 Diane J. Burgess , Department of Pharmaceutical Sciences, University of Connecticut, Storrs, USA Radha Kulkarni , Pharmaceutical Sciences, University of Connecticut School of Pharmacy, Storrs, Connecticut, USA Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.175305.r366194 The given manuscript is a good example of using a poloxamer based gelling system to prepare in situ gelling rectal suppositories. However, the given manuscript requires a few major revisions before it could be finalized and submitted. ... Continue reading READ ALL The given manuscript is a good example of using a poloxamer based gelling system to prepare in situ gelling rectal suppositories. However, the given manuscript requires a few major revisions before it could be finalized and submitted. There are a few grammatical errors in the manuscript which need to be corrected. For example, ‘narcoticanalgesic’ needs a space in between the two words. Certain procedures such as the in vivo study retention study in rabbits were not explained clearly. An ambiguity was found in the number of animals used in each group. Additionally, there is no definition/mention of bioadhesive strength in the muco-adhesion study, which should be explained with clarity. The selected (optimized) formulation (F8) was compared against a control formulation. But the composition of control formulation is not clearly mentioned. It is suggested to mention it in the formulation table. The formulae for different coefficients used must denote the definition of each variable. Overall, the manuscript requires additional clarity and explanations in the procedure and results and discussion section to reduce ambiguity. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Drug delivery: Specializing in long acting delivery. We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT J. Burgess D and Kulkarni R. Reviewer Report For: Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability [version 1; peer review: 3 approved with reservations] . F1000Research 2025, 14 :160 ( https://doi.org/10.5256/f1000research.175305.r366194 ) The direct URL for this report is: https://f1000research.com/articles/14-160/v1#referee-response-366194 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 18 Apr 2025 Haydar Mahmood Ahmed , Department of pharmaceutics, /College of Pharmacy/Mustansiriyah University, Baghdad, Iraq 18 Apr 2025 Author Response We sincerely thank the reviewer for the valuable and constructive comments. We have carefully addressed each point to improve the clarity and scientific value of the manuscript titled: “Nefopam HCl ... Continue reading We sincerely thank the reviewer for the valuable and constructive comments. We have carefully addressed each point to improve the clarity and scientific value of the manuscript titled: “Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability.” Below are our point-by-point responses: Comment 1 : There are a few grammatical errors in the manuscript which need to be corrected. For example, ‘narcoticanalgesic’ needs a space in between the two words. Response : Thank you for the observation. The manuscript has been carefully revised for grammar and spelling. All typographical and formatting issues, including the correction of “narcoticanalgesic” to “narcotic analgesic,” have been addressed to improve the overall language clarity. Comment 2 : Certain procedures such as the in vivo retention study in rabbits were not explained clearly. An ambiguity was found in the number of animals used in each group. Additionally, there is no definition/mention of bioadhesive strength in the muco-adhesion study, which should be explained with clarity. Response : We appreciate this important comment. Clarification has been added to the in vivo retention study section. A total of four rabbits (n = 4) were used, divided into two groups (n = 2): • Group 1 received the control 1 formulation •Group 2 received the optimized formulation (F8) Additionally, we have also clarified the bioadhesive strength by adding the following paragraph in the ex vivo mucoadhesive study: Bio-adhesion may be defined as the state in which two materials, at least one of which is biological in nature, are held together for extended periods by interfacial forces. In the pharmaceutical sciences, when the adhesive attachment is to mucus or a mucous membrane, the phenomenon is referred to as mucoadhesion. Bio-adhesive strength indicates the force required to separate the formulation from the rectal mucosa, reflecting the mucoadhesive characteristics of the system. Comment 3 : The selected (optimized) formulation (F8) was compared against a control formulation. But the composition of control formulation is not clearly mentioned. It is suggested to mention it in the formulation table. Response : Thank you for the observation. We have updated Table 2 in the manuscript to include the composition of the control formulations used in the study: • Control 1: Used in the in vivo localization study • Control 2: Used in the permeation study Each control formulation was designed appropriately for its corresponding experiment, and both are now clearly labeled and explained in the table to distinguish them from the optimized formulation (F8). Comment 4 : The formulae for different coefficients used must denote the definition of each variable. Response : We fully agree with the reviewer. In the revised manuscript, we have ensured that all mathematical equations now include a clear explanation of each variable. For example: Peff = Jss/C0 Where: • Peff: Effective permeability coefficient (cm/s) • Jss: Steady-state flux (µg/cm²/s) • C0: Initial drug concentration in the donor compartment (µg/mL) We sincerely thank the reviewer for the valuable and constructive comments. We have carefully addressed each point to improve the clarity and scientific value of the manuscript titled: “Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability.” Below are our point-by-point responses: Comment 1 : There are a few grammatical errors in the manuscript which need to be corrected. For example, ‘narcoticanalgesic’ needs a space in between the two words. Response : Thank you for the observation. The manuscript has been carefully revised for grammar and spelling. All typographical and formatting issues, including the correction of “narcoticanalgesic” to “narcotic analgesic,” have been addressed to improve the overall language clarity. Comment 2 : Certain procedures such as the in vivo retention study in rabbits were not explained clearly. An ambiguity was found in the number of animals used in each group. Additionally, there is no definition/mention of bioadhesive strength in the muco-adhesion study, which should be explained with clarity. Response : We appreciate this important comment. Clarification has been added to the in vivo retention study section. A total of four rabbits (n = 4) were used, divided into two groups (n = 2): • Group 1 received the control 1 formulation •Group 2 received the optimized formulation (F8) Additionally, we have also clarified the bioadhesive strength by adding the following paragraph in the ex vivo mucoadhesive study: Bio-adhesion may be defined as the state in which two materials, at least one of which is biological in nature, are held together for extended periods by interfacial forces. In the pharmaceutical sciences, when the adhesive attachment is to mucus or a mucous membrane, the phenomenon is referred to as mucoadhesion. Bio-adhesive strength indicates the force required to separate the formulation from the rectal mucosa, reflecting the mucoadhesive characteristics of the system. Comment 3 : The selected (optimized) formulation (F8) was compared against a control formulation. But the composition of control formulation is not clearly mentioned. It is suggested to mention it in the formulation table. Response : Thank you for the observation. We have updated Table 2 in the manuscript to include the composition of the control formulations used in the study: • Control 1: Used in the in vivo localization study • Control 2: Used in the permeation study Each control formulation was designed appropriately for its corresponding experiment, and both are now clearly labeled and explained in the table to distinguish them from the optimized formulation (F8). Comment 4 : The formulae for different coefficients used must denote the definition of each variable. Response : We fully agree with the reviewer. In the revised manuscript, we have ensured that all mathematical equations now include a clear explanation of each variable. For example: Peff = Jss/C0 Where: • Peff: Effective permeability coefficient (cm/s) • Jss: Steady-state flux (µg/cm²/s) • C0: Initial drug concentration in the donor compartment (µg/mL) Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 18 Apr 2025 Haydar Mahmood Ahmed , Department of pharmaceutics, /College of Pharmacy/Mustansiriyah University, Baghdad, Iraq 18 Apr 2025 Author Response We sincerely thank the reviewer for the valuable and constructive comments. We have carefully addressed each point to improve the clarity and scientific value of the manuscript titled: “Nefopam HCl ... Continue reading We sincerely thank the reviewer for the valuable and constructive comments. We have carefully addressed each point to improve the clarity and scientific value of the manuscript titled: “Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability.” Below are our point-by-point responses: Comment 1 : There are a few grammatical errors in the manuscript which need to be corrected. For example, ‘narcoticanalgesic’ needs a space in between the two words. Response : Thank you for the observation. The manuscript has been carefully revised for grammar and spelling. All typographical and formatting issues, including the correction of “narcoticanalgesic” to “narcotic analgesic,” have been addressed to improve the overall language clarity. Comment 2 : Certain procedures such as the in vivo retention study in rabbits were not explained clearly. An ambiguity was found in the number of animals used in each group. Additionally, there is no definition/mention of bioadhesive strength in the muco-adhesion study, which should be explained with clarity. Response : We appreciate this important comment. Clarification has been added to the in vivo retention study section. A total of four rabbits (n = 4) were used, divided into two groups (n = 2): • Group 1 received the control 1 formulation •Group 2 received the optimized formulation (F8) Additionally, we have also clarified the bioadhesive strength by adding the following paragraph in the ex vivo mucoadhesive study: Bio-adhesion may be defined as the state in which two materials, at least one of which is biological in nature, are held together for extended periods by interfacial forces. In the pharmaceutical sciences, when the adhesive attachment is to mucus or a mucous membrane, the phenomenon is referred to as mucoadhesion. Bio-adhesive strength indicates the force required to separate the formulation from the rectal mucosa, reflecting the mucoadhesive characteristics of the system. Comment 3 : The selected (optimized) formulation (F8) was compared against a control formulation. But the composition of control formulation is not clearly mentioned. It is suggested to mention it in the formulation table. Response : Thank you for the observation. We have updated Table 2 in the manuscript to include the composition of the control formulations used in the study: • Control 1: Used in the in vivo localization study • Control 2: Used in the permeation study Each control formulation was designed appropriately for its corresponding experiment, and both are now clearly labeled and explained in the table to distinguish them from the optimized formulation (F8). Comment 4 : The formulae for different coefficients used must denote the definition of each variable. Response : We fully agree with the reviewer. In the revised manuscript, we have ensured that all mathematical equations now include a clear explanation of each variable. For example: Peff = Jss/C0 Where: • Peff: Effective permeability coefficient (cm/s) • Jss: Steady-state flux (µg/cm²/s) • C0: Initial drug concentration in the donor compartment (µg/mL) We sincerely thank the reviewer for the valuable and constructive comments. We have carefully addressed each point to improve the clarity and scientific value of the manuscript titled: “Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability.” Below are our point-by-point responses: Comment 1 : There are a few grammatical errors in the manuscript which need to be corrected. For example, ‘narcoticanalgesic’ needs a space in between the two words. Response : Thank you for the observation. The manuscript has been carefully revised for grammar and spelling. All typographical and formatting issues, including the correction of “narcoticanalgesic” to “narcotic analgesic,” have been addressed to improve the overall language clarity. Comment 2 : Certain procedures such as the in vivo retention study in rabbits were not explained clearly. An ambiguity was found in the number of animals used in each group. Additionally, there is no definition/mention of bioadhesive strength in the muco-adhesion study, which should be explained with clarity. Response : We appreciate this important comment. Clarification has been added to the in vivo retention study section. A total of four rabbits (n = 4) were used, divided into two groups (n = 2): • Group 1 received the control 1 formulation •Group 2 received the optimized formulation (F8) Additionally, we have also clarified the bioadhesive strength by adding the following paragraph in the ex vivo mucoadhesive study: Bio-adhesion may be defined as the state in which two materials, at least one of which is biological in nature, are held together for extended periods by interfacial forces. In the pharmaceutical sciences, when the adhesive attachment is to mucus or a mucous membrane, the phenomenon is referred to as mucoadhesion. Bio-adhesive strength indicates the force required to separate the formulation from the rectal mucosa, reflecting the mucoadhesive characteristics of the system. Comment 3 : The selected (optimized) formulation (F8) was compared against a control formulation. But the composition of control formulation is not clearly mentioned. It is suggested to mention it in the formulation table. Response : Thank you for the observation. We have updated Table 2 in the manuscript to include the composition of the control formulations used in the study: • Control 1: Used in the in vivo localization study • Control 2: Used in the permeation study Each control formulation was designed appropriately for its corresponding experiment, and both are now clearly labeled and explained in the table to distinguish them from the optimized formulation (F8). Comment 4 : The formulae for different coefficients used must denote the definition of each variable. Response : We fully agree with the reviewer. In the revised manuscript, we have ensured that all mathematical equations now include a clear explanation of each variable. For example: Peff = Jss/C0 Where: • Peff: Effective permeability coefficient (cm/s) • Jss: Steady-state flux (µg/cm²/s) • C0: Initial drug concentration in the donor compartment (µg/mL) Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 04 Feb 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 1 04 Feb 25 read read read Diane J. Burgess , University of Connecticut, Storrs, USA Radha Kulkarni , University of Connecticut School of Pharmacy, Storrs, USA Nydia Alejandra Castillo-Martinez , Autonomous University of Baja California, Tijuana, Mexico Durgacharan A. Bhagwat , Bharati Vidyapeeth College of Pharmacy, Kolhapur, India Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Bhagwat D. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 13 Aug 2025 | for Version 1 Durgacharan A. Bhagwat , Bharati Vidyapeeth College of Pharmacy, Kolhapur, India 0 Views copyright © 2025 Bhagwat D. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Manuscript presents the development and evaluation of a thermosensitive in situ mucoadhesive liquid suppository for rectal delivery of Nefopam hydrochloride (NPH). The study is well-structured and explores both in vitro and ex vivo parameters relevant to bioavailability enhancement and formulation optimization. But still need to clarify on following: 1) Add a discussion on how the in vitro release and ex vivo permeation correlate with in vivo retention/localization data. 2) Improve figure quality, add error bars where appropriate, and clarify units consistently across tables and figures. 3) The manuscript contains several minor typographical and grammatical errors. For example: "desperation" instead of "dispersion" (in methods) "Themosenstive" should be "thermosensitive" (keywords) "drug was obtained by F19, (blend)" - phrasing 4) Ensure all abbreviations (e.g., P407, HPMC K4M, CMC, Peff, Jss) are defined at first use and used consistently. 5) Suggest potential clinical implications and next steps (e.g., pharmacokinetics, human trials) in Conclusion section. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Formulation development of Novel drug delivery system, Solubility enhancement, SNEDDS, Cubosome, NLCs I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Bhagwat DA. Peer Review Report For: Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability [version 1; peer review: 3 approved with reservations] . F1000Research 2025, 14 :160 ( https://doi.org/10.5256/f1000research.175305.r392428) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-160/v1#referee-response-392428 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Castillo-Martinez N. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 07 Aug 2025 | for Version 1 Nydia Alejandra Castillo-Martinez , Facultad de Ciencias de la Salud, Autonomous University of Baja California, Tijuana, Baja California, Mexico 0 Views copyright © 2025 Castillo-Martinez N. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This manuscript presents the development and evaluation of a thermosensitive, mucoadhesive in situ gel formulation of Nefopam HCl intended for rectal administration. The authors aim to overcome the limitations of oral bioavailability due to first-pass metabolism and enhance patient compliance by using a non-invasive delivery system. The study is well-designed with a comprehensive evaluation of physicochemical, rheological, in vitro, and ex vivo parameters. The formulation approach is scientifically sound, and the rationale for selecting specific polymers (P407, P188, HPMCK4M, and CMC) is appropriately justified. However, some areas require improvement to enhance the scientific rigor, clarity, and overall quality of the manuscript. The study addresses an important issue in drug delivery, the low bioavailability of Nefopam due to extensive hepatic metabolism. The rectal in situ gel approach is a novel and potentially valuable option for patients who are unable to tolerate oral or intravenous administration. The authors systematically evaluated multiple formulations, assessing sol-gel transition temperature, gelation time, mucoadhesive strength, drug release, viscosity, and in vivo localization, providing a thorough characterization. Data are generally well-organized, with appropriate tables and figures. The inclusion of standard deviations and triplicate measurements in the Excel file supports the reproducibility of findings. Major comments While ANOVA is mentioned, specific statistical outputs (e.g., F-values, p-values, confidence intervals) are missing or incomplete. Include complete statistical comparisons across groups where significance is claimed, especially for sol-gel temperature, mucoadhesive strength, and drug release. The in vivo rectal localization study includes only two rabbits. While this may be acceptable for a pilot study, this limitation should be acknowledged and addressed. Consider discussing how these preliminary results support future work with a larger sample size. Expand on the mechanistic explanation of drug release retardation due to polymer interactions. Include a comparison of the proposed formulation's performance with existing rectal or oral Nefopam formulations, if available. Ensure that all figures are high-resolution and include complete legends (e.g., units, sample sizes). Minor Comments The manuscript contains several grammatical and typographical errors that hinder clarity (e.g., "desperation" instead of "dispersion"). A professional language review or copyediting would significantly improve the readability. Define all abbreviations at first use (e.g., PBS, Gt, HPMCK4M). Indicate the number of replicates (n=3) explicitly in methods for each test. Avoid excessive repetition in figure captions and results text. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Antimicrobials I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Castillo-Martinez NA. Peer Review Report For: Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability [version 1; peer review: 3 approved with reservations] . F1000Research 2025, 14 :160 ( https://doi.org/10.5256/f1000research.175305.r392420) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-160/v1#referee-response-392420 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 J. Burgess D et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 03 Mar 2025 | for Version 1 Diane J. Burgess , Department of Pharmaceutical Sciences, University of Connecticut, Storrs, USA Radha Kulkarni , Pharmaceutical Sciences, University of Connecticut School of Pharmacy, Storrs, Connecticut, USA 0 Views copyright © 2025 J. Burgess D et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The given manuscript is a good example of using a poloxamer based gelling system to prepare in situ gelling rectal suppositories. However, the given manuscript requires a few major revisions before it could be finalized and submitted. There are a few grammatical errors in the manuscript which need to be corrected. For example, ‘narcoticanalgesic’ needs a space in between the two words. Certain procedures such as the in vivo study retention study in rabbits were not explained clearly. An ambiguity was found in the number of animals used in each group. Additionally, there is no definition/mention of bioadhesive strength in the muco-adhesion study, which should be explained with clarity. The selected (optimized) formulation (F8) was compared against a control formulation. But the composition of control formulation is not clearly mentioned. It is suggested to mention it in the formulation table. The formulae for different coefficients used must denote the definition of each variable. Overall, the manuscript requires additional clarity and explanations in the procedure and results and discussion section to reduce ambiguity. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Drug delivery: Specializing in long acting delivery. We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 18 Apr 2025 Haydar Mahmood Ahmed, Department of pharmaceutics, /College of Pharmacy/Mustansiriyah University, Baghdad, Iraq We sincerely thank the reviewer for the valuable and constructive comments. We have carefully addressed each point to improve the clarity and scientific value of the manuscript titled: “Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability.” Below are our point-by-point responses: Comment 1 : There are a few grammatical errors in the manuscript which need to be corrected. For example, ‘narcoticanalgesic’ needs a space in between the two words. Response : Thank you for the observation. The manuscript has been carefully revised for grammar and spelling. All typographical and formatting issues, including the correction of “narcoticanalgesic” to “narcotic analgesic,” have been addressed to improve the overall language clarity. Comment 2 : Certain procedures such as the in vivo retention study in rabbits were not explained clearly. An ambiguity was found in the number of animals used in each group. Additionally, there is no definition/mention of bioadhesive strength in the muco-adhesion study, which should be explained with clarity. Response : We appreciate this important comment. Clarification has been added to the in vivo retention study section. A total of four rabbits (n = 4) were used, divided into two groups (n = 2): • Group 1 received the control 1 formulation •Group 2 received the optimized formulation (F8) Additionally, we have also clarified the bioadhesive strength by adding the following paragraph in the ex vivo mucoadhesive study: Bio-adhesion may be defined as the state in which two materials, at least one of which is biological in nature, are held together for extended periods by interfacial forces. In the pharmaceutical sciences, when the adhesive attachment is to mucus or a mucous membrane, the phenomenon is referred to as mucoadhesion. Bio-adhesive strength indicates the force required to separate the formulation from the rectal mucosa, reflecting the mucoadhesive characteristics of the system. Comment 3 : The selected (optimized) formulation (F8) was compared against a control formulation. But the composition of control formulation is not clearly mentioned. It is suggested to mention it in the formulation table. Response : Thank you for the observation. We have updated Table 2 in the manuscript to include the composition of the control formulations used in the study: • Control 1: Used in the in vivo localization study • Control 2: Used in the permeation study Each control formulation was designed appropriately for its corresponding experiment, and both are now clearly labeled and explained in the table to distinguish them from the optimized formulation (F8). Comment 4 : The formulae for different coefficients used must denote the definition of each variable. Response : We fully agree with the reviewer. In the revised manuscript, we have ensured that all mathematical equations now include a clear explanation of each variable. For example: Peff = Jss/C0 Where: • Peff: Effective permeability coefficient (cm/s) • Jss: Steady-state flux (µg/cm²/s) • C0: Initial drug concentration in the donor compartment (µg/mL) View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern J. Burgess D and Kulkarni R. Peer Review Report For: Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability [version 1; peer review: 3 approved with reservations] . F1000Research 2025, 14 :160 ( https://doi.org/10.5256/f1000research.175305.r366194) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-160/v1#referee-response-366194 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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