In-Situ Gel-Based Nasal Drug Delivery of Oxymetazoline Hydrochloride:

A Mucoadhesive Approach

Shubham Sharma¹, Sunil Gupta²

¹School of Pharmacy, Mangalayatan University, Aligarh - 202146, India ORCID ID: 0000-0003-0295-7052.

²Mangalayatan Institute of Pharmaceutical Education and Research,

Mangalayatan University, Aligarh - 202146, India ORCID ID: 0000-0002-0383-6220.

*Corresponding Author E-mail: shubham.skdm@gmail.com

ABSTRACT:

Nasal mucosa has a high blood perfusion rate in the nasal cavity, which increases the drug's absorption and bioavailability in the systemic circulation compared to other routes. We need to apply a bio-compatible mucoadhesive polymer to increase the retention period of in-situ gel with nasal mucosa. However, the objective of the present study was to formulate and evaluate in-situ nasal gel of oxymetazoline hydrochloride. This drug delivery technology has the potential to bypass the initial metabolism of the medication and thereby enhance its bioavailability. A total 10 in situ nasal gels were created by combining hydroxypropyl methylcellulose (HPMC K-100) and xanthan gum in various polymeric ratios. All gel formulations that were produced (F1–F10) had pH values between 5.5±0.008 to 6.0±0.002. The gels' spreadability ranged from 10.1±0.24 to 6.7±0.67g/cm/sec. All prepared gel compositions were found to have gelling temperature ranged from 33.2±0.41°C to 34.8±0.36°C, gelling time ranged from 4.0±0.41 s to 10.1±0.16 seconds and gel strengths ranging from 51.16±0.66 to 62.14± 0.58. The range of 130.34±0.57 to 211.75±1.35 centipoises was found for the viscosity of the different prepared gels. All manufactured gel formulations were found to have a drug concentration ranging from 97.54±0.43 to 99.68±0.83 percent. Oxymetazoline hydrochloride nasal gels F9 have a 99.98 % drug release rate in their in vitro diffusion drug release. According to the release order kinetics, all of the formulations—from F1 to F10—followed the Higuchi diffusion model, as evidenced by the correlation coefficients R2=0.986 and 0.937, respectively. The drug release investigations conducted in a controlled laboratory environment shown that the formulated substances were capable of releasing the drug for a duration of 10hours. Furthermore, all of the formulations exhibited a consistent adherence to the Higuchi kinetics model. The accelerated stability investigations demonstrated that the gels remained stable throughout the six-month testing period. The Differential Scanning Calorimetry (DSC) and X-ray Diffraction (XRD) tests indicated the absence of any interaction between the medication and polymer. Based on these findings, it can be inferred that in situ nasal gels have the potential to be used as drug delivery systems for oxymetazoline HCl. This can help overcome first-pass metabolism and boost the bioavailability of the drug.

Graphical Abstract:

Development and evaluation of a mucoadhesive in-situ nasal gel of Oxymetazoline Hydrochloride.

KEYWORDS: In-situ, Gels, Oxymetazoline Hydrochloride, In-vitro diffusion, HPMC K-100, Xanthan gum.

1. INTRODUCTION:

An imidazoline derivative and sympathomimetic amine is oxymetazoline hydrochloride (6-tert-Butyl-3-(4,5- dihydro-1H-imidazol-2-ylmethyl)-2,4-dimethylphenol hydrochloride). For nearly 40 years, oxymetazoline has been sold as an over-the-counter intranasal medication in the United States. It is a vasoconstrictor that operates directly on nasal membranes¹. There are several justifications for exploring alternative means of administering nasal medications instead of relying on conventional approaches. The nasal route offers convenience due to its ease of use, fast onset of action, and lack of gastrointestinal degradation or first-pass metabolization. Due to the small size of the medications designed for it, this route has excellent bioavailability. In cases when the bioavailability is not naturally great, it can still be enhanced, making the nasal route highly desirable^2,3. It is authorized for the treatment of allergic rhinitis and common cold-related nasal congestion. The creation and assessment of oxymetazoline nasal gels is the primary goal of this investigation. to pass hepatic first pass metabolism and ensuing degradation in order to attain more consistent blood levels with smaller doses of medication^4-7. To lengthen the residence period and decrease the frequency of dose dumping. Drugs administered intranasal have long been used to treat nasal congestion and rhinitis. The hepatic first-pass impact and gastrointestinal side effects can be mitigated by intranasal delivery⁸. Moreover, the abundance of blood and lymphatic capillaries beneath the nasal mucosa improves drug absorption. Because of these characteristics, administering medications intranasally can significantly increase their bioavailability. It has been reported that intravenous and intranasal administration achieves similar blood concentrations⁹. Because the olfactory receptor cells are in direct contact with the central nervous system, nasal medication delivery also offers a means of accessing the brain that avoids the blood-brain barrier. The initial stage of medication absorption in the nasal cavity is mucus membrane crossing. because the mucus readily allows for the passage of tiny, uncharged particles. However, charged big molecules find it difficult to cross the mucous membrane.

The protein called mucin is found in the mucus layer and it binds to solutes to slow down diffusion and structural changes in the mucus layer that are also brought on by changes in the environment^10-12. Nowadays, sprays make up the majority of nasal medicines sold in stores. The short drug residence period (15–30min) on the human nasal mucosal surface caused by the scavenging action of nasal cilia has some bearing on clinical efficacy¹³. A physical state having characteristics halfway between those of solids and liquids is referred to as "gel." But it's frequently applied incorrectly to any fluid system that displays some degree of stiffness¹⁴.

2. MATERIALS AND METHODS:

2.1 Materials:

Received a free sample of oxymetazoline hydrochloride from CDH in Delhi, India. We bought xanthan gum, mannitol, polyethylene glycol (PEG), benzalkonium chloride, methanol, and hydroxypropyl methylcellulose (HPMC K 100) from SD Fine Chemicals in Bangalore, India. Analytical grade reagents and chemicals were all utilized.

2.2 Formulation of Oxymetazoline Hydrochloride In-situ Nasal Gels:

The process parameters were optimized using a factorial design. Table 1 displays the ingredients of several oxymetazoline hydrochloride in situ nasal gel formulations. Following the drug's dissolution in methanol, 10 millilitres of distilled water were added. Stirring continuously was used to mix the solution. Mannitol, PEG, and benzalkonium chloride were added to the medication solution mentioned above. The aforementioned mixture was thoroughly mixed with the polymeric solutions of HPMC K 100 and xanthan gum, which were made independently in distilled water. After 15minutes of magnetic stirring, the mixture was added to the Phosphate Buffer solution (PBS). Distilled water was added to the final volume to achieve the necessary amoun.^15,16. Table 1 describe the different formulation (F1-F10) of Oxymetazoline Hydrochloride in-situ gel.

2.3 Characterization of in-situ gel:

2.3.1 FT-IR studies for drug and excipients compatibilities: The pre-formulation investigation was completed before the dosage forms were developed¹⁷.IR spectrum investigations are primarily used to identify chemicals qualitatively, whether they are in their pure form or in combination with polymers and excipients. They also serve as a tool for determining the nature of chemical interactions. I.R. is associated with covalent bonding; hence the spectra can provide intricate details about the composition of molecules. Comparisons between the compounds' spectra and the pure compound were done to prove this conclusion^18,19.

Table: 1 Formulation data of different Oxymetazoline Hydrochloride in-situ Nasal gels

S. No.	Composition	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10
1	Oxymetazoline hydrochloride (%w/v)	0.07 %	0.07 %	0.07 %	0.07 %	0.07 %	0.07 %	0.07 %	0.07 %	0.07 %	0.07 %
2	HPMC K-100 (%w/v)	0.2	0.4	0.6	0.8	0.2	0.4	0.6	0.8	0.2	0.4
3	Mannitol (%w/v)	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5
4	Xanthan gum (%w/v)	0.10	0.10	0.10	0.15	0.15	0.15	0.20	0.20	0.20	0.25
5	PEG (%)	1.25	1.25	1.25	1.25	1.25	1.25	1.25	1.25	1.25	1.25
6	Benzalkonium chloride (%w/v)	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01
7	Methanol (mL)	5	5	5	5	5	5	5	5	5	5
8	PBS (pH 6.4) (mL)	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5
9	Distilled water (mL; QS)	25	25	25	25	25	25	25	25	25	25

2.3.2 Gelling temperature and gelling time:

The term "gelling temperature" describes the temperature at which, at 90°, the formulation's meniscus would no longer move. The method developed by Miller and Donovan was applied to ascertain the gelation investigations. By setting the test tube, which contained an adequate amount of the produced solutions, in a water bath at 4°C, the gelling temperature was ascertained. Every two minutes, the water bath's temperature was gradually raised by 1°C. Gelling time of formulations was calculated by applying the methods Miller and Donovan described^20,21. Prior to administration, the delivery systems are in the sol form; however, after administration, they go through gelation to become a gel. The moment at which gelation was initially detected was noted as the gelling time. By adding 2 millilitres of the manufactured formulation to a 10-milliliter test tube with a 1.0-centimeter diameter, the sol-gel transition temperature of the in-situ gel formulations was measured. The tube was kept in a water bath with circulation set at 37°C after being sealed with parafilm. Ten minutes were given for equilibration after each temperature setting. In order to assess the gelation and gauge the sample's condition, the test tube was lastly positioned horizontally²².

2.3.3 Viscosity of solution:

Using a Brookfield viscometer DV-II+ Pro connected to an S-94 spindle (Brookfield Engineering Laboratories Inc., MA, and USA), the viscosity of the in-situ gel systems was measured. The beaker was filled with the created gel compositions. The temperature was maintained at 37±0.5°C while the spindle was lowered perpendicularly into the gel at a speed of l00rpm. When the system was cooling, the viscosity was measured. Each measurement was carried out three times²³.

2.3.4 Rheological properties of in situ gels: Using a Brookfield LVDV-E Viscometer (Brookfield Engineering Laboratories, Inc., USA), the rheological characteristics of in situ gel compositions were examined. At first, the temperature was kept above 40 °C. By increasing the spindle rotational speed from 0.3 to 100rpm, the rheological parameters were examined and the viscosity (h), shear rate (g), and shear stress (t) were noted. Each measurement was carried out three times²⁴.

2.3.5 Determination of pH: A 10ml volumetric flask was filled with one millilitre of the produced gels, and the solution was thinned with distilled water. A digital pH meter (Shambhavi Impex, India) that had been previously calibrated using phosphate buffers at pH 4 and pH 7 was used to measure the pH of the resultant solution^25,26.

2.3.6 Drug content: One milliliter of the formulation was added to ten milliliters of volumetric flask, and it was then diluted with ten milliliters of distilled water. Once more, 10 milliliters of distilled water were used to dilute 1milliliter of this solution. Finally, using a UV visible spectrophotometer (Shimadzu 1800), the absorbance of the produced solution was measured at 217nm against a blank reagent. The tests were conducted in triplicate and the average data were recorded^27,28.

2.3.7 Gel strength: Sample (50g) was put into graduated cylinder (100ml). The formulations were gelled by placing them in a thermostat set to 37°C. The time it took for a 35g weight to sink 5cm in the gel was used to gauge the gel's strength^29,30.

2.3.8 Spreadability: A rectangular glass slide measuring 10 by 4cm was used to assess spreadability. A thread was used to secure the sheep's nasal mucosa from the serosal side to the slide's surface. The slide was maintained at 37°C in a hot air oven (Navyug Udyog, India), with a single gel drop positioned at a 120° angle on the mucosa. The spreadability of a liquid gel drop was measured in relation to its travel distance prior to gelation. Three readings on average were noted³¹. The spreadability was measured by using the following formula^32,33.

S = ML/T

S = Spreadability

M = Weight tide to upper slide

L = Length moved on the glass slide

T = Time taken to separate the slide completely from each other

2.3.9 Mucoadhesive strength: The force needed to separate the formulation from goat nasal mucosal tissue that was taken from the slaughterhouse was used to calculate the mucoadhesive potential of the created preparation. A portion of the goat nasal mucosa was placed in an inverted beaker, and one of the pans of the modified mucoadhesion test equipment was filled with the formulation to be tested. On the other side, the weight was increased until the two-mucosa separated from one another^34,35.

M = m* g/A

Where, M= mucoadhesive strength in dyne/cm2

m= weight in grams

g= gravitational force

A= area in cm2

2.3.10 In vitro drug release: Oxymetazoline hydrochloride in-situ nasal gel drug release was accomplished by employing a Franz diffusion cell with a dialysis membrane (mol. Wt. 12000 D) as a barrier. The dialysis membrane separated the donor compartment from the receptor compartment, which was filled with 2 ml of nasal in-situ xylometazoline hydrochloride gel after the assembly was assembled and the temperature was kept at 37±1°C. The pH 6.8 phosphate buffer was placed inside the receptor compartment. At regular intervals, 1 ml aliquots of the material were removed and replaced with a fresh receptor media of the same volume of phosphate buffer. The samples underwent spectrophotometric analysis at 217nm after being suitably diluted with phosphate buffer^36,37.

2.3.11 Accelerated stability studies: In situ gel formulation stability tests were conducted in compliance with the principles set forth by the International Conference on Harmonization. Enough in situ gel in nasal spray bottles was kept in a desiccator (Sabar Scientific, India) with a saturated sodium chloride solution (75±5% relative humidity (RH)). The samples were taken out of the desiccator after 1, 2, 3, 5, and 6 months of being kept in a hot air oven at 40±2°C. Investigations were conducted into alterations in the preserved formulations' appearance, drug content, gelling strength, and in vitro drug release³⁸. The three decisions' mean values were noted.

2.3.12 Differential scanning calorimetry: Thermograms of a particular formulation (F4) using differential scanning calorimetry (DSC) were acquired after it was kept for two months at 40±2 °C and 75±5% relative humidity. The samples were put in airtight aluminium pans and heated at a rate of 10°C per minute while being scanned between 30 and 200 °C³⁹.

2.3.13 X-Ray diffraction studies: Using a copper target at a voltage of 40 kV and a current of 30 mA, the Jeol JDX 8030 X-ray diffract meter (MTI Corporation, USA) was used to record the X-Ray diffraction studies (XRD) pattern of the chosen formulation (F4) for a defined quantity of pure medication. A range of 10–80 º in °2 θ was scanned^40-42.

3. RESULTS AND DISCUSSION:

3.1 Compatibility studies:

Fourier Transform Infrared Spectroscopy (FTIR) spectral analysis was used to characterize the drug and polymers to look for any physical or chemical changes to the drug's properties. The primary peaks of the Oxymetazoline Hydrochloride were found to be unchanged in the spectra of the drug-polymer mixture, indicating that there was no interference in the functional groups, according to the data. IR spectra of the pure drug (Oxymetazoline Hydrochloride) and Mixture of drug and polymer are shown in figure 1. FTIR was used to identify the specific functional groups found in pure drug and mixture of drug and polymer. The presence of IR bands at 2359.80 cm^-1, 2341.45 cm^-1and 1447.94 cm^-1 1361.25 cm^-1in FTIR spectrum of pure drug were assigned to C=C stretching vibration, NO₂ stretching vibration as shown in figure 1 (a). The presence of IR bands at 3248.34 cm^-1, 22.53.23 cm^-1 and 22169.79 cm^-1, 2147.67 cm^-1 in FTIR spectrum of mixture of drug and polymer were assigned to C=C stretching vibration, as shown in figure 1 (b).

Figure 1 (a): FTIR spectrum of Oxymetazoline Hydrochloride

Figure 1(b): FTIR spectra of mixture

Table 2: FTIR spectrum of observed and characteristic peak of pure Drug and Mixture of compounds

FTIR Spectrum	IR absorption bands (cm-1)		Bond	Functional group
FTIR Spectrum	Observed Peak	Characteristic Peak	Bond	Functional group
Oxymetazoline Hydrochloride	2359.80	2100-2660	C≡C	Alkynes
	2341.45	2100-2660	C≡C	Alkynes
	1447.94	1330-1540	NO₂	Nitro compounds
	1361.25	1220-1540	NO₂	Nitro compounds
Mixture	3248.34	3010-3300	C≡H	Alkynes
	2253.23	2100-2660	C≡C	Alkynes
	2169.79	2100-2660	C≡C	Alkynes
	2147.67	2100-2660	C≡C	Alkynes

3.2 Gelling temperature, gelling time, viscosity of solution, drug content and gel strength:

In this work, 2⁴ factorial designs were used to generate 10 formulations of in situ nasal gels. The basis polymers that were used were xanthan gum and HPMC K-100. Table 3 displays the gel strength, drug content, viscosity of solution, gelling temperature, and gelling time of the produced formulation.

In the solubility form, every formulation was visible. The in situ nasal gel that was generated had a gelling temperature that varied from 33.2±0.41°C to 34.8± 0.36°C. For thermo reversible nasal gel, the ideal gelling temperature is between 30 and 36°C. The term "gelation point" describes the temperature at which, after gradually raising the temperature to 90°, the formulation's meniscus would no longer move. Every formulation in the current analysis displayed a gelling temperature that fell within the range. On the other hand, when the temperature rises, the gelation does not occur at the nasal mucosa region, which results in rapid nasal clearance. The formulation's gelling time (s) varied from 4.0±0.41s to 10.1±0.16s. The gelling times for formulas F2, F4, F5 and F8 were found to be sufficient. The produced formulation's drug content varied from 97.54±0.43% to 99.68±0.83%. The formulation's viscosity varied from 130.34±0.57 to 211.75±1.35cP. When 0.8% of HPMC K-100 was added to the formulations together with concentrations of 0.10%, 0.15%, 0.20%, and 0.25% of xanthan gum, the viscosity increased. When HPMC K-100 was used in the formulations at concentrations of 0.2%, 0.4%, and 0.6%, a difference in viscosity was noted. The gel strength of formulation was ranges from 51.16±0.66 to 62.14±0.58 sec. The range of the mucoadhesive strength was 3010.89±1.21 to 6678.89±0.45. The strength of mucoadhesive material was directly correlated with the HPMC K-100 content. Fig. 2 shows the relationship between the viscosity of the gels and the polymer ratios (xanthan gum and HPMC ratios).

Table 3. Gelling temperature, gelling time, viscosity of solution, drug content, and gel strength of in situ nasal gel of Oxymetazoline Hydrochloride.

Formulation code	Appearance	Gelling temperature (°C) *	Gelling time (s)*	Viscosity of solution (cP)*	Drug content (%)*	Gel strength (s)*
F1		33.2 ± 0.41	10.1 ± 0.16	164.56 ± 0.68	99.35 ± 0.33	51.16 ± 0.66
F2		33.7 ± 0.34	4.1 ± 0.45	174.85 ± 0.36	98.10 ± 0.47	55.56 ± 0.73
F3		33.4 ± 0.45	6.2 ± 0.73	130.34 ± 0.57	98.27 ± 0.84	58.57 ± 0.45
F4		34.3 ± 0.79	4.5 ± 0.40	187.57 ± 0.96	99.37 ± 0.95	61.45 ± 0.76
F5	Transparent	34.8 ± 0.36	4.8 ± 0.30	186.68 ± 1.27	97.54 ± 0.43	57.57 ± 0.87
F6		33.6 ± 0.65	5.3 ± 0.54	195.47 ± 0.84	99.63 ± 0.28	54.46 ± 0.75
F7		34.4 ± 0.59	6.6 ± 0.36	192.47 ± 1.13	99.68 ± 0.83	58.26 ± 0.85
F8		33.9 ± 0.57	4.0 ± 0.41	211.75 ± 1.35	98.28 ± 0.75	62.14 ± 0.58
F9		34.5 ± 0.45	4.9 ± 0.76	175.55 ± 0.47	98.12 ± 0.23	55.16 ± 0.37
F10		33.6 ± 0.37	4.5 ± 0.37	156.32 ± 0.25	99.10 ± 0.87	54.37 ± 0.68

Fig. 2. The relation between the polymer ratios and the viscosity of the formulations (F1-F10).

2.3 Spreadability, pH, and mucoadhesive strength:

Table 4 displays the physicochemical characteristics, including pH, mucoadhesive strength, and Spreadability. The formulation's Spreadability varied from 10.1±0.24 to 6.7±0.67cm. The formulation's pH varied from 5.5± 0.008 to 6.0±0.002. These results showed that the formulations' pH values were within an acceptable range. The formulations' mucoadhesive strengths ranged from 3004.45±1.65to 6548.54±0.59 dyne/cm2.

Mucoadhesive drug delivery techniques extend the dosage's residence time at the application or absorption site by enabling quick drug dissipation in the circulatory system, which inhibits first-pass metabolism. In the current investigation, formulations made with a high HPMC K-100 concentration showed greater macro adhesion strength than formulations made with a lower concentration. Consequently, HPMC K-100's high concentration is more important to the formulation than xanthan gum.

2.4 In vitro drug release:

The produced formulations' in vitro drug release is displayed in (Fig. 4a, b). Maximum drug release was seen in the formulations F1 (99.91%), F2(99.97%), F3 (99.85%), and F9(99.98%) after 6 hours. Then, after 8 hours, the formulations F5(99.75%), F6(99.75%), F7 (99.93%) and F10(99.81%) showed maximum drug release. After ten hours, the medication was released from the remaining formulations, F4(99.88%) and F8 (99.76%).

The manufactured nasal gels may be preserving the drug in the matrix network and inhibit early release of the medication, according to in vitro drug release data. This allows the nasal gels to remain intact during the study time. Table 5 provides the R2, k, and n values.

Table 4. Mucoadhesive strength, Spreadability, and pH of different formulations of in situ nasal gel of oxymetazoline hydrochloride

Formulation code strength	Mucoadhesive strength	Spreadability (cm)*	pH*
F1	3004.45 ± 1.65	10.1 ± 0.24	5.6 ± 0.018
F2	4275.65 ± 0.55	8.9 ± 0.83	5.5 ± 0.008
F3	5877.93 ± 0.75	6.7 ± 0.67	5.9 ± 0.002
F4	6548.54 ± 0.59	7.6 ± 0.38	6.0 ± 0.002
F5	3248.53 ± 0.84	9.8 ± 0.57	5.9 ± 0.011
F6	4343.89 ± 0.67	8.3 ± 0.59	5.8 ± 0.001
F7	5846.94 ± 0.04	6.9 ± 0.38	5.9 ± 0.002
F8	6436.96 ± 0.24	7.8 ± 0.86	6.0 ± 0.001
F9	3456.65 ± 0.67	9.5 ± 0.46	5.8 ± 0.003
F10	4596.46 ± 0.98	8.8 ± 0.74	5.9 ± 0.003

*Averages of six determinations.

Table 5. Korsmeyer-Peppas model parameters for in vitro drug release from in situ nasal gel formulations.

Formulation Code	Higuchi r²	Higuchi y	Higuchi k	Korsmeyer-Peppas r²	Korsmeyer-Peppas y	Korsmeyer-Peppas n
F1	0.938	45.26x + 7.656	39.29	0.227	0.894x + 1.317	0.867
F2	0.937	43.76x + 7.37	40.78	0.234	0.904x + 1.315	0.906
F3	0.939	47.37x + 6.83	45.36	0.246	0.924x + 1.307	0.924
F4	0.956	28.95x + 9.635	25.99	0.329	0.775x + 1.253	0.775
F5	0.974	36.98x + 6.25	33.98	0.287	0.825x + 1.255	0.824
F6	0.978	39.45x + 7.254	35.46	0.284	0.836x + 1.267	0.836
F7	0.986	35.26x + 4.904	37.27	0.303	0.853x + 1.248	0.854
F8	0.979	25.37x + 9.257	26.87	0.327	0.774x + 1.254	0.778
F9	0.945	44.05x + 8.175	42.07	0.228	0.885x + 1.315	0.856
F10	0.979	37.37x + 4.507	38.36	0.313	0.875x + 1.243	0.878

Table 6. Accelerated stability studies of different formulations of in situ gel of oxymetazoline hydrochloride.

Evaluation Parameter	Formulation	1^stmonh	2^ndmonh	3^rdmonh	5^th month	6^th month
Drug content (mg)*	F2	99.12 ± 0.19	98.97 ± 0.11	98.62 ± 0.8	98.32 ± 0.13	97.89 ± 0.11
	F5	98.32 ± 0.12	98.12 ± 0.14	97.87 ± 0.22	97.36 ± 0.13	97.11 ± 0.12
	F7	98.56 ± 0.16	98.12 ± 0.15	97.98 ± 0.12	97.46 ± 0.18	96.99 ± 0.14
	F9	99.38 ± 0.32	99.12 ± 0.14	98.28 ± 0.13	98.12 ± 0.13	97.89 ± 0.13
Gelling strength (s)*	F2	60.12 ± 0.19	59.92 ± 0.32	59.42 ± 0.12	59.12 ± 0.32	58.22 ± 0.12
	F5	62.05 ± 0.12	61.76 ± 0.16	61.28 ± 0.32	61.14 ± 0.12	60.89 ± 0.18
	F7	64.14 ± 0.21	63.98 ± 0.14	63.48 ± 0.11	63.16 ± 0.21	62.99 ± 0.17
	F9	62.99 ± 0.16	62.67 ± 0.21	62.38 ± 0.18	62.14 ± 0.12	61.97 ± 0.16
*In vitro* drug release (%) *	F2	99.68 ± 1.4	99.12 ± 1.1	98.86 ± 2.1	98.98 ± 1.3	98.76 ± 1.4
	F5	99.52 ± 2.1	99.18 ± 1.8	98.92 ± 1.1	98.69 ± 1.1	98.18 ± 2.1
	F7	99.32 ± 2.2	99.08 ± 1.4	98.89 ± 1.2	98.47 ± 2.1	98.12 ± 2.2
	F9	99.12 ± 1.6	98.99 ± 2.1	98.62 ± 1.4	98.32 ± 2.1	98.12 ± 1.8
Appearance	F2	No change occurs	No change occurs	No change occurs	No change occurs	No change occurs
	F5	No change occurs	No change occurs	No change occurs	No change occurs	No change occurs
	F7	No change occurs	No change occurs	No change occurs	No change occurs	No change occurs
	F9	No change occurs	No change occurs	No change occurs	No change occurs	No change occurs

*Averages of six determinations.

2.7 X-Ray diffraction studies:

Figure 5 displays the XRD pattern of the chosen formulation (F5). Using an X-Ray diffractometer with Cu at 10-800/2θ intervals, the XRD patterns were found. At a scanning speed of 40/min, voltage of 40.0(kV), and current of 30.0(mA), the degree of diffraction was measured.

Fig. 5. X-ray diffraction pattern of selected F5 formulation

3. DISCUSSION:

This research effectively developed and assessed a mucoadhesive in situ nasal gel containing oxymetazoline hydrochloride utilizing combinations of HPMC K-100 and xanthan gum to enhance drug release, residence duration, and mucoadhesion in the nasal cavity. The thermosensitive and mucoadhesive properties of the gels facilitated improved nasal retention and decreased dosage frequency, which is essential for disorders such as nasal congestion and allergic rhinitis. The gelling temperature of all formulations was determined to be within the physiologically pertinent range (33.2±0.41°C to 34.8± 0.36°C), facilitating gelation upon contact with nasal mucosa. Gelling periods were swift (as low as 4.0±0.41 s), facilitating a prompt transition from sol to gel state following application. These outcomes are essential for guaranteeing formulation effectiveness and patient adherence. The concentration of HPMC K-100 and xanthan gum greatly affected viscosity and gel strength. Elevated concentrations resulted in augmented viscosity and gel strength, hence improving mucoadhesive strength while diminishing spreadability. This illustrates the necessity for a balanced polymer ratio to optimize all intended gel qualities. The pH of the formulations varied from 5.5 to 6.0, falling within the permissible physiological range for nasal applications, therefore minimizing irritation to the nasal mucosa. The drug content in all formulations surpassed 97%, demonstrating consistent drug distribution and great formulation accuracy. In vitro drug release experiments exhibited sustained release characteristics over 10hours for all formulations, with F9 displaying the highest release at 99.98%. The kinetics of drug release adhered to the Korsmeyer–Peppas model, with n values between 0.775 and 0.924, signifying anomalous transport, which encompasses both diffusion and erosion mechanisms. This behaviour is optimal for nasal formulations designed for extended efficacy. The Higuchi model demonstrated a strong correlation (R²>0.93), confirming that drug release is predominantly governed by diffusion through the polymeric matrix. Accelerated stability experiments validated the physical and chemical stability of the optimized formulations (F2, F5, F7, F9) over a six-month period, demonstrating no substantial degradation or changes in drug content, gelling strength, or appearance. Moreover, DSC and XRD tests indicated no substantial interactions between the medication and the polymers. The minor decrease in crystallinity detected through DSC and XRD indicated partial amorphization of the medication within the polymer matrix, potentially enhancing solubility and release kinetics while maintaining stability. The work emphasizes the significance of judicious polymer selection and optimization to attain a balance of mucoadhesion, gelation properties, and prolonged drug release.

4. CONCLUSION:

This study illustrates the effective creation of a thermosensitive, mucoadhesive in situ nasal gel for oxymetazoline hydrochloride, presenting a viable approach to circumvent first-pass metabolism and improve drug bioavailability. The improved formulations, specifically F5 and F9, demonstrated favourable physicochemical characteristics, quick gelation, robust mucoadhesive strength, prolonged in vitro drug release for up to 10 hours, and exceptional stability over a six-month duration. The use of HPMC K-100 and xanthan gum in suitable proportions facilitated regulated gel formation and drug release kinetics aligned with Korsmeyer-Peppas and Higuchi models. Furthermore, FTIR, DSC, and XRD tests validated the chemical compatibility and semi-crystalline characteristics of the final gel matrix, guaranteeing safety and stability. In summary, this mucoadhesive in situ gel formulation offers an efficient and patient-friendly nasal delivery mechanism for oxymetazoline hydrochloride. Nonetheless, in vivo investigations and clinical trials are necessary to comprehensively ascertain its therapeutic potential and confirm its efficacy under physiological settings.

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Received on 18.02.2025 Revised on 08.05.2025

Accepted on 10.07.2025 Published on 20.05.2026

Available online from May 25, 2026

Research J. Pharmacy and Technology. 2026;19(5):1986-1994.

DOI: 10.52711/0974-360X.2026.00284

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