INTRODUCTION:

The nose is an ideal site for medication absorption due to its large surface area and the numerous microvilli on its epithelial surface. The subepithelial layer is highly vascularized, allowing venous blood from the nose to enter the systemic circulation directly, thus avoiding first-pass metabolism in the liver^1,2.

This leads to lower required dosages, faster achievement of therapeutic blood levels, and quicker onset of pharmacological action. Additionally, this method results in fewer side effects. The nose also offers a significant total circulation per cm³, a porous endothelial basement membrane, and easy accessibility. Moreover, it enables drug delivery to the brain via the olfactory nerves³.

In situ gelation is the process by which gel forms at the site of action after the formulation is applied. A liquid pharmaceutical formulation is used in the in-situ gel effect, and it is then converted into an opaque mucous sticky key reservoir^4,5,6. The basic principle of in-situ gelling with nasal formulation is applying in nasal fluid. After being delivered, the medicine solution in this treatment turns into a gel within the nasal cavity^7.8. The nasal cavity offers an extended duration of drug occupancy, requiring fewer administrations of the medication. This method prevents the drug from being metabolized by stomach acid or enzymes, resulting in higher bioavailability. Additionally, it reduces both local and systemic negative effects^9,10.

Meningitis is defined as inflammation of the fluid-filled space (subarachnoid gap) between the meninges, which are the coats of tissue that envelop the brain and spine cord themselves^11,12,13. Moxifloxacin HCl is a strong, broad-spectrum fluoroquinolone antibiotic that effectively treats a variety of bacterial illnesses by inhibiting key bacterial enzymes involved in transcription and DNA replication. Its broad spectrum of action and superior tissue penetration make it a valuable therapy option for infections^14,15,16.

MATERIALS AND TECHNIQUES:

A generous gift sample of Moxifloxacin HCl was received from INTAS Pharmaceuticals in Ahmedabad, India. We bought carbopol 940, HPMC K4M, and xanthan gum from Modern Industries in Nashik. All other reagents used for the assessment, as well as analytical grade organic solvents, were supplied by Thermo Fisher Scientific India Pvt. Ltd.

Procedure for preparation of in-situ nasal gel:

In the cold method, HPMC and Carbopol were continuously mixed with hot distilled water (60°C) to permit swelling. In a different container, xanthan gum was slowly dissolved in 4°C cold distilled water while being stirred constantly in an ice bath^17,18,19. Using an ice bath to keep the temperature at roughly 4°C, the initial solution of HPMC and Carbopol was combined with the xanthan gum solution while being continuously agitated at 200 rpm. Stirring for 1 hour produced a 4°C polymeric solution. After that, Moxifloxacin HCl was dissolved at room temperature in a DMSO, PEG, and Bch combination. To get the right volume, this medication solution was combined with the previous polymer solution and cold distilled water was added. An in-situ gel was produced by stirring this mixture with a magnetic stirrer for four hours at 200 rpm and 4°C. A transparent gel was obtained by refrigerating the final combination for an entire night^20,21,22.

Formulation of in-situ nasal gel by using 3² factorial design:

A 3² factorial design was used in the development of the Moxifloxacin HCl in-situ gel²³. The nine Moxifloxacin HCl in-situ gel batches shown in Table 2 were formulated using HPMC K4M (X1) and Xanthan gum (X2) in the different ratios shown in Table 1, along with Moxifloxacin HCl. These batches were produced using a factorial design and were based on the percent CDR, viscosity, and mucoadhesive strength, with three levels: low, medium, and high. Additionally, carbopol was used as a gelling agent, benzalkonium chloride (Bch) as a preservative, PEG 400 as a penetration enhancer, dimethyl sulfoxide as a co-solvent, and water as a solvent^24,25.

Table 1: Dependent and independent factors in 3²factorial design

Dependent Factors	Levels		Independent Factors
HPMC K4M	Low	0.3	Viscosity Mucoadhesive strength % CDR
	Medium	0.6
	High	0.9
Xanthan gum	Low	0.05	Viscosity Mucoadhesive strength % CDR
	Medium	0.10
	High	0.15

CHARACTERIZATION OF IN SITU NASAL MUCOADHESIVE GEL:

The in-vitro examination of the in-situ gels included measurements of pH, rheology, spreadability, bioadhesive strength as a percentage of API concentration, gelling temperature, gelling time, and ex-vivo perfusion trials. The purpose of these experiments was to determine the optimal batch by using selected findings as an independent factor for optimization, and to examine the stability and other aspects of in-situ gels^26,27.

pH Measurement:

The pH of every formulation was measured with a digital pH meter. Phosphate buffer solution was used for pH meter calibration²⁸.

Table 2: Optimization batches developed by 3² factorial design

Composition (%w/v)	F1	F2	F3	F4	F5	F6	F7	F8	F 9
Moxifloxacin HCl	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
HPMC K4M	0.3	0.3	0.3	0.6	0.6	0.6	0.9	0.9	0.9
Xanthan Gum	0.05	0.10	0.15	0.05	0.10	0.15	0.05	0.10	0.15
Carbopol 940	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1
PEG-400	10	10	10	10	10	10	10	10	10
Bch	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01
DMSO	2	2	2	2	2	2	2	2	2
Distilled water (q.s)	100	100	100	100	100	100	100	100	100

Viscosity Measurement:

To evaluate the viscosity of the in-situ gels, a Brookfield viscometer DV-1 with spindles #61, #62, #63, and #64 was used. The container was filled with the prepared gel solutions. The gel was held at 25±0.5°C when the spindle was immersed in it. The viscosity test was repeated three times, each time using a spindle that rotated at 100 revolutions per minute. Examined were the rheological characteristics of in-situ gel formulations. Similarly, viscosity was measured in triplicate at an ambient temperature of 37 +0.5°C for the nose, and the mean was recorded. To ascertain the rheological characteristics, the average viscosity was noted^29,30.

Gelation Time:

Gelation time refers to the period needed for a thermoreversible solution to transition from a sol form to a gel form at a specific gelling temperature. This was measured by continuously stirring an in-situ gel at its gelling temperature with a magnetic stirrer. The precise moment when the liquid completely gelled and the magnetic bead stopped rotating was recorded³¹.

Gelation Temperature:

The temperature at which a solution's characteristics transition from those of a sol to those of gel is known as the gelation temperature. A gelation temperature measurement carried out by taking a 10 ml container having an in-situ gel solution was placed in an ice bath at 4°C. The temperature was increased in steps of 2°C, and after 5 minutes at each new temperature, the container was tilted to see the gelation. When the solution stopped moving when the container tilted to a 90° angle, gelation was said to have occurred. The test was administered three times, and the average outcome was noted³².

Mucoadhesive Gel Strength:

To measure the ex-vivo muco-adhesive strength, fresh sheep nasal mucous layer was used. The mucosa was exposed by removing surrounding fatty and free tissues and cleaned thrice with distilled water and phosphate buffer (pH 6)³³. A polypropylene polymer "T" mould was hung in place of the left pan of an analytic balance. The sample was placed in a watch glass, with the second strong mould positioned upside down under the top beaker's bottom mould. A centimetre-long piece of sheep nasal tissue was cut and adhered to the watch glass. The gel mixture was applied to the membrane, and the top mould was lowered. Weights were gradually added to the left pan until the top mould separated from the specimen. The muco-adhesive strength, measured in dynes/cm², was determined by the weight required for separation^34,35.

Drug Content:

A dual-beam UV-VIS spectrophotometer (Shimadzu UV-1800) was used in triplicate to assess the formulations' percentage drug content. One gram of gel was transferred to a 10 ml volumetric flask, diluted with distilled water, and the volume adjusted to10 ml. 1 ml of this stock solution was further diluted to 10 ml using pure water. The drug content % was then determined by measuring the absorbance of the resulting solution at 221 and 289 nm with the UV-VIS spectrophotometer³⁶.

Ex-Vivo Study:

A freshly harvested sheep nasal membrane was utilised to test the drug's in vivo perfusion using the Franz-diffusion equipment (Orchid Scientific). The donor's and recipient's chambers were joined by the treated nasal tissue³⁷. A 20 ml pH 6 phosphate buffer solution was added to the receiver chamber, which was then agitated at 200 rpm and maintained at 37°C. The nasal membrane was covered with the gel samples, and the chambers were shut firmly. At 15, 30, 60, 120, 240, 360, 480, 600, and 720-minute intervals, samples were collected. Fresh phosphate buffer was added to the receiver chamber after 1 ml aliquots were taken out. Following the proper dilutions, the aliquots were examined for perfusion at 221 and 289 nm^38,39.

Accelerated Stability Procedure:

In compliance with ICH requirements, a three-month stable test was conducted on an optimal batch (F5) of in-situ gel. A suitable quantity of in-situ gel was kept at 40 + 2°C, 75±5% relative humidity, and elevated room temperature 25±3°C at room temperature and 25 +2°C at 60 +5% relative humidity, respectively. Aliquots taken at 0, 1, 2, and 3 months were used to evaluate the physiological properties, content homogeneity, gel-forming ability, and in-vitro API release of the preparation under study. A published average of three measurements was obtained⁴⁰.

RESULT AND DISCUSSION:

Solubility Study:

The solubility tests of Moxifloxacin HCl were carried out in a range of solvents, including ethanol, DMSO, DMF, phosphate buffer (pH 6), and distilled water. It was discovered that the moxifloxacin was virtually insoluble in acetone, sparingly soluble in water (24 mg/ml), DMSO (88 mg/ml), and somewhat soluble in ethanol (1 mg/ml).

Structural Elucidation:

The drug's FTIR spectra were used to perform the structural elucidation (FTIR Bruker Alpha-II). The drug's primary functional components are emphasized with in spectrums (Figures1). The FTIR values of the major functional groups seen in the drug's FTIR plots.

Table 3: pH, viscosity, gelation time, and temperature of batches

Batches	Results of Various Parameters
	pH	Viscosity		Gelation Time (mins)	Gelation Temp. (°C)
	pH	25°C	37°C	Gelation Time (mins)	Gelation Temp. (°C)
F1	5.6±0.02	128.2±3.11	253.3±3.22	7±0.2	34.5±0.3
F2	5.9±0.02	131.6±4.21	276.4±3.47	6.5±0.4	34±0.5
F3	5.8±0.02	145.3±3.42	289.5±6.11	6±0.3	33.5±0.6
F4	6.2±0.02	158.4±6.24	312.8±4.58	5±0.2	32.5±0.2
F5	6.1±0.02	165.8±6.77	326.7±5.67	3±0.3	32±0.4
F6	5.7±0.02	172.8±5.51	344.6±3.52	3.5±0.4	31.5±0.3
F7	6.4±0.02	183.7±7.53	361.6±5.53	4±0.3	31±0.5
F8	6.3±0.02	196.1±4.36	386.8±5.41	2.5±0.2	30.5±0.4
F9	6.5±0.02	208.2±3.18	422.7±6.73	1.5±0.2	30±0.3

Spreadability Study:

Spreadability is a measure of a semisolid's robustness. It was found that the F1 to F9 samples had a spreadability of 25 ±0.8 to 33.5 ±0.5 gm.cm/sec (Table 4).

Mucoadhesive Strength:

Table 4 shows that the gel's bioadhesive ability rises in direct proportion to the increase in the amount of the bioadhesive component, while it is inversely correlated with the gelling temperature and gelling time. Therefore, batches containing greater amounts of HPMC K4M or Xanthan gum had lower gelation temperatures and longer gelation times, as well as stronger mucoadhesive gels.

Drug Content:

The % API concentrations of all intranasal in-situ gel formulations were determined. For Moxifloxacin HCl, these % ranged from 95.8±0.3 to 98.3±0.3 % (Table 4).

Table 4: Spreadability, gel strength, and % drug content of F1 to F9 batches

Batches	Results of various Parameters
Batches	Spreadability (gm.cm/sec)	Gel strength (dyne/cm²)	Drug content (%)
F1	33.5±0.3	3593±88.3	96.14±
F2	33±0.4	3762±72.6	97.33±
F3	32±0.6	4012±118.6	97.49±
F4	30.5±0.4	4591±105.7	97.85±
F5	30±0.5	4901±123.7	98.35±
F6	29.5±0.4	5042±112.9	97.78±
F7	29±0.3	5118±143.4	97.11±
F8	28±0.6	5246±112.5	96.52±
F9	26±0.7	5479±153.8	95.88±

Perfusion/Ex-Vivo Study:

Drug permeation through the nasal mucosa was monitored and found to be 98.35% at the end of the 12th hour. This permeation exhibited a synergistic relationship with the in vitro drug release. Table 5, illustrates the in vitro permeation profile of the optimized formulation.

Kinetic study data of optimized (F5) batch of in-situ gel:

The figure indicates that, with n values of 0.6147, the Korsmeyers-Peppas models were determined to be the Non-Fickian models for optimized (F5) in-situ gel (Figure 3).

Figure 3: Korsmeyer-Peppas plot of kinetic study data

ANOVA

ANOVA To compare two models, one uses the Analysis of Variance. It is helpful when looking at two or more variables, generally speaking. ANOVA is typically used to compare the average outcomes at various factor levels.

ANOVA for Linear Model

Response 1: Viscosity

Table 5: % Cumulative drug release of Moxifloxacin HCl in perfusion study

Time (min)	F1	F2	F3	F4	F5	F6	F7	F8	F9
0	0	0	0	0	0	0	0	0	0
15	9.8	11.5	14.8	17.8	21.5	10.6	8.5	5.3	2.1
30	16.3	19.4	24.7	26.7	29.6	13.7	11.5	7.8	7.9
60	21.3	27.8	32.6	35.7	38.4	25.3	19.8	15.4	14.7
120	33.8	33.9	38.3	42.5	43.9	28.7	26.1	22.5	21.3
240	40.9	46.9	52.7	54.3	56.9	42.8	37.9	33.7	31.7
360	53.6	58.3	60.2	63.8	65.7	50.1	46.8	43.8	42.7
480	62.8	67.2	69.3	73	76.8	60.5	53.7	56.2	55.3
600	78.4	79.4	82.8	84.6	88.9	71.9	68.9	66.8	61.9
720	83.6	87.5	92.3	95.4	98.3	82.7	80.4	77.8	72.8

Figure 4: 3D Viscosity Surface plot in cp, Plotting of the Viscosity Contour, and Plot of the Viscosity Perturbation

The three-dimensional surface plot and contour map (Figure 3) show that the effects of Xanthan gum and HPMC K4M on viscosity are the same since there are similar amounts of green and blue hues. Additionally, the perturbation plot revealed an interaction between the two lines, indicating that the effects of Xanthan gum and HPMC K4M on viscosity were equivalent. Desirability in this instance, which helped determine the proper formulation for the study and emerged as a means of meeting the fundamental condition, should be less than 1.

Response 2: % CDR

Figure 5: 3D Cumulative drug release (CDR) surface plot in percentage, Plotting of the CDR Contour, and Plot of the CDR perturbation

In the 3D surface plot and contour plot (Figure 4), orange was more visible than green, indicating that HPMC K4M has a greater impact on the percentage of cumulative drug release than Xanthan gum. The perturbation plot, where the green line represents Factor A, or HPMC K4M, displayed more interaction behaviour than the blue line representing Factor B, or Xanthan gum, provided more proof that HPMC K4M had a greater impact on percent CDR than Xanthan gum.

Response3: Mucoadhesive Strength

Figure 6: 3D Mucoadhesive strength (MS) Surface plot in dyne/cm², Plotting of the MS Contour, and Plot of the MS Perturbation

In the 3D surface plot and contour plot (Figure 4), orange was more visible than blue, indicating that HPMC K4M has a stronger impact on the mucoadhesive strength than Xanthan gum. The perturbation plot, where the green line represents Factor A, or HPMC K4M, showed more interaction behaviour than the blue line representing Factor B, or Xanthan gum, provided more proof that HPMC K4M had a greater effect on mucoadhesive strength than Xanthan gum.

Stability Study:

Three months were spent verifying the stability of the optimised in-situ gel (F5). The preparation's pH, gelation parameters, bioadhesive capacity, rheological and physiological properties, content homogeneity, and ex-vivo penetration were all discovered to be unchanged throughout that time.

CONCLUSION:

Nasal transport of medicines is a rapidly growing field for delivering APIs that face challenges like enzyme-mediated degradation, first-pass metabolism, and poor gastrointestinal absorption. Thermoresponsive and bioadhesive polymers improve drug absorption, extend controlled release, and provide non-invasive, targeted brain delivery. A thermoreversible bioadhesive in-situ nasal gel containing moxifloxacin was developed to bypass the blood-brain barrier and prevent enzymatic or first-pass destruction. Ex-vivo research indicates its potential for nasal-to-brain antibacterial delivery. While promising for quick treatment initiation and effective drug delivery, further in-vivo studies are needed to confirm these results. In-situ gel formulations hold significant potential for novel drug delivery systems.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors express their sincere thanks to INTAS Pharmaceuticals, Ahmedabad, India for supplying gift samples of Moxifloxacin HCl as an Active Pharmaceutical Ingredient. The authors are thankful to GES’s Sir Dr. M. S. Gosavi College of Pharmaceutical Education and Research, Nashik, India for providing the facility to carry out the research work.

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Received on 05.07.2024 Revised on 07.12.2024

Accepted on 14.03.2025 Published on 01.10.2025

Available online from October 04, 2025

Research J. Pharmacy and Technology. 2025;18(10):5003-5010.

DOI: 10.52711/0974-360X.2025.00723

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Solubility Study:

Structural Elucidation:

Compatibility Study: