1. An intranasal in situ gel delivery system comprising: caffeic acid as the active pharmaceutical ingredient; and a pharmaceutically acceptable, ion-sensitive polysaccharide gum, wherein the formulation undergoes a sol-to-gel transition upon contact with nasal physiological conditions, enabling direct nose-to-brain delivery via the olfactory and trigeminal pathways for the management of Alzheimer’s disease; and wherein the formulation demonstrates mucoadhesive properties that prolong nasal residence time and reduce mucociliary clearance.

2. The delivery system as claimed in claim 1, wherein the pharmaceutically acceptable, ion-sensitive polysaccharide gum is selected from the group consisting of gellan gum, xanthan gum, guar gum, locust bean gum, carrageenan, or combinations thereof

3. The delivery system as claimed in claim 1, wherein the pharmaceutically acceptable, ion-sensitive polysaccharide gum is gellan gum.

4. The delivery system as claimed in claim 1, further comprising one or more pharmaceutically acceptable excipients selected from stabilizers, penetration enhancers, buffering agents, isotonic agents, preservatives, or antioxidants.

5. The delivery system as claimed in claim 1, wherein in vivo administration results in higher drug permeation coefficient and enhanced brain uptake compared to pure caffeic acid.

6. The delivery system as claimed in claim 1, formulated as a non-invasive, patient-compliant nasal dosage form suitable for repeated administration.

7. A method for treating Alzheimer’s disease in a subject in need thereof, comprising administering a therapeutically effective amount of the in situ nasal gel delivery system as claimed in claim 1.

8. The delivery system as claimed in claim 1, wherein the formulation is used for the management of neurodegenerative disorders selected from Parkinson’s disease, Huntington’s disease, dementia, or other central nervous system disorders.

9. A method for preparing an intranasal in situ gel formulation as claimed in claim 1, wherein the method comprising, (i) dissolving a pharmaceutically acceptable, ion-sensitive polysaccharide gum in distilled water at a concentration of about 0.2% to 0.5% w/w to obtain a solution; (ii) heating the solution to 90 °C ± 2 °C under continuous stirring until complete dissolution is achieved followed by cooling the heated solution to ambient temperature in the range of 20 ℃ to 35 ℃ to obtain gum solution; (iii) dissolving caffeic acid in PEG at a concentration of about 3–5% v/v to obtain caffeic acid solution; (iv) mixing the caffeic acid solution with the gum solution in equal proportion; (v) adding, methyl paraben at about 0.2% w/v and glycerol at about 2% w/v, to the resultant solution obtained in step (iv); and (vi) storing the final formulation in a sealed container at room temperature, wherein the formulation exhibits sol-to-gel transition upon contact with simulated nasal fluid at about 34 ± 2 °C; and wherein the final formulation demonstrates mucoadhesive properties that prolong nasal residence time and reduce mucociliary clearance.

10. The method as claimed in claim 9, wherein said pharmaceutically acceptable, ion-sensitive polysaccharide gum is selected from the group consisting of gellan gum, xanthan gum, guar gum, locust bean gum, carrageenan, or combinations thereof

11. The method as claimed in claim 9, wherein said pharmaceutically acceptable, ion-sensitive polysaccharide gum is gellan gum.

Description:FIELD OF INVENTION:
The present invention relates to the field of pharmaceutical drug delivery systems. Particularly, the present invention relates to a nasal in situ gel formulation incorporating caffeic acid, a plant-derived bioactive compound, for improved nose-to-brain delivery bypassing the blood–brain barrier for the management of neurological disorders, particularly Alzheimer’s disease. More particularly, it relates to a nasal in situ gel delivery system comprising caffeic acid, for direct nose-to-brain targeting in the management of Alzheimer’s disease.

BACKGROUND OF THE INVENTION:
Alzheimer’s disease is a progressive neurological condition marked by cognitive deterioration, memory impairment, and behavioral disturbances. Alzheimer disease (AD) is a progressive degenerative brain disorder responsible for around 60-70% of dementia cases. Clinically, it’s hallmark include decline or irreversible loss of cognitive function across multiple areas like memory, language and executive function along with visuospatial ability, personality, and behavioral change.
The continuous aggregation of amyloid beta peptides and hyperphosphorylated Tau protein leading to remodeling of central cholinergic system is responsible for clinical symptoms. Practically, 10 million newly diagnosed cases of dementia across the globe every year according to WHO are making it the seventh leading cause of death. The incurability of AD imposes remarkable social and economic implications. Therefore, precise diagnosis, proactive measures and targeted therapeutic strategies are crucial to deal with symptoms and slow down the progressing debilitating condition.
Cholinesterase inhibitors (donepezil, galantamine, rivastigmine), NMDA antagonist, memantine, and anti-amyloid monoclonal antibodies (aducanumab, lecanemab, and donanemab) are current USFDA approved treatments for AD. The available medications help to manage only symptoms by increasing acetylcholine level or regulating glutamate activity respectively instead of modifying the underlying neurodegenerative processes.
Furthermore, available therapies also induce serious side effects like psychosis, agitation, convulsion, tremors, brain edema and intracerebral bleeding etc. Promising progress in the prevention and treatment of AD has been achieved in recent years. A viable approach to AD intervention is to lower neurotoxic amyloid-beta (Aβ) amount in brain by curtailing Aβ aggregation or encouraging the disintegration of mature fibrils into less toxic or nontoxic forms.
Caffeic acid, a polyphenolic organic acid, possess a spectrum of biological activity including antioxidant, anti-ischemia reperfusion, anti-thrombosis, cardioprotective, anti-hypertension, anti-diabetic, antiviral, neuroprotectant, antibacterial, hepatoprotective and anticancer activity. Caffeic acid also demonstrates significant anti-amyloidogenic activity by inhibiting the aggregation of Aβ₁₋₄₂, the most neurotoxic and aggregation-prone isoform of amyloid-β and by promoting the disassembly of preformed fibrils. These effects have been observed in both aqueous and lipid-rich settings, supporting caffeic acid’s potential as a therapeutic candidate for Alzheimer’s disease.
KR20210056265A discloses a brain delivery technology by nasal administration, and more particularly, the present invention is for a central nervous system brain disease by nasal administration of a pH-sensitive bio reducible PPA polymer that can be used as a drug delivery system and effectively delivering it to the brain, provides an effect used in the diagnosis, prevention or treatment of neurodegenerative diseases or brain tumors.
Nose to Brain Drug Delivery System: A Comprehensive Review, Pankaj et al. discloses that nose to brain drug delivery system is an interesting approach to deliver a drug directly in the brain through the nose. Intranasal drug delivery is very beneficial because it avoids first-pass metabolism and achieves a greater concentration of drugs in the central nervous system (CNS) at a low dose. This delivery system is used for the treatment of various neurological disorders such as Parkinson's disease, Alzheimer's disease, schizophrenia, dementia, brain cancer, etc. To treat such types of diseases, different formulations like nanoparticles (NPs), microemulsions, in situ gel, etc. can be used depending on the physiochemical properties of the drug.
US11458203B2 relates to pharmaceutical compositions comprising caffeic acid chelates, kits, and methods for using such compounds and pharmaceutical compositions. Particularly, relates to caffeic acid chelates for use as an antiviral agent that is effective against Herpes Simplex Virus (HSV), Ebola Viruses and vaccinia. The caffeic acid chelates of the present disclosure are believed to inhibit the virus attachment to the cell and thus reduce viral infection of cells. These viruses bind cells via a heparin-sulfate proteoglycan receptor. This active constituent is believed to bind proteins on the surface of the virion thereby blocking interaction with the cellular receptor.
Caffeic acid, a naturally occurring phenolic compound with strong antioxidant, neuroprotective, and anti-inflammatory properties, has been proposed as a potential therapeutic candidate. However, its low solubility and bioavailability, instability, lack of specificity, and rapid systemic clearance contribute to insignificant therapeutic effect, thereby restricting its clinical application. Therefore, a need exists to develop a novel carrier system capable of enhancing the therapeutic effectiveness and stability of caffeic acid.
Intranasal administration offers a convenient and non-invasive route of drug delivery that bypasses first-pass metabolism, gastrointestinal degradation, and BBB limitations, while also providing a highly vascularized surface area for absorption. Direct nose-to-brain delivery enables quicker onset of action, enhanced local bioavailability, lower dosing requirements, and reduced systemic side effects.
However, conventional intranasal formulations such as solutions, suspensions, and emulsions suffer from drawbacks including mucociliary clearance, enzymatic degradation, and short residence time in the nasal cavity, which impede efficient brain targeting.
Mucoadhesive in situ gelling systems have emerged as an effective approach to overcome these limitations by combining the advantages of solutions and gels. These systems are administered as free-flowing liquids and undergo sol-to-gel transition upon exposure to physiological stimuli such as pH, temperature, or ionic strength. This transition enhances nasal retention, reduces mucociliary clearance, and allows for sustained release, thereby improving bioavailability and reducing dose frequency.
In recent years, in situ gelling formulations have attracted significant attention in both academia and the pharmaceutical industry due to their potential to improve intranasal drug delivery. Among available polymers, an anionic polysaccharide, is particularly suitable for nasal in situ gel systems owing to its ability to undergo cation (Na⁺ or Ca²⁺) responsive sol–gel transformation in nasal fluid. This property enhances mucosal adhesion and enables controlled drug release, thereby optimizing absorption and minimizing patient discomfort.
Till date, no report exists in the literature on caffeic acid-loaded intranasal in situ gel systems. Therefore, the present invention aims to design and evaluate a smart polymeric in situ nasal gel system of caffeic acid utilizing a pharmaceutically acceptable, ion-sensitive polysaccharide gum, with the aim of achieving direct nose-to-brain delivery and establishing its in vivo effectiveness for the management of Alzheimer’s disease.

OBJECT OF THE INVENTION
To address the foregoing problems, in whole or in part, and/or other problems that may have been observed by persons skilled in the art, the present disclosure provides formulation and method as described by way of example as set forth below.
Accordingly, the main object of the present invention is to provide a smart polymeric in situ nasal gel delivery system of caffeic acid employing a pharmaceutically acceptable, ion-sensitive polysaccharide gum for enhanced brain targeting in the management of Alzheimer’s disease.
Another object of the present invention is to provide a novel nasal in situ gel formulation incorporating caffeic acid, a plant-derived active pharmaceutical ingredient that is optimized for enhanced brain targeting bypassing blood brain barrier.
Yet another object of the present invention is to overcome the limitations of conventional intranasal formulations such as poor stability, rapid clearance, and short residence time.
Yet another object of the present invention is to develop a nasal formulation with prolonged nasal residence time by employing mucoadhesive in situ gelation.
Yet another object of the present invention is to provide a safe, non-invasive, and patient-friendly delivery platform for the treatment of neurodegenerative disorders, particularly Alzheimer’s disease.

SUMMARY OF THE INVENTION:
This summary is intended to introduce, in simplified form, a selection of concepts that are further described in the detailed description. This summary is merely presented as a brief overview of the subject matter described and claimed herein and does not aid in determining the scope of the claimed subject matter.
Accordingly, the present invention provides a novel intranasal in situ gel delivery system of caffeic acid utilizing a pharmaceutically acceptable, ion-sensitive polysaccharide gum for enhanced brain targeting in the management of Alzheimer’s disease. Caffeic acid, a plant-derived polyphenolic compound, is limited in its clinical utility due to poor solubility, low bioavailability, instability, and high systemic clearance, which collectively result in negligible therapeutic effects.
In one aspect, the present invention employs mucoadhesive in situ gel technology, wherein the formulation remains in liquid state prior to administration and undergoes sol-to-gel transition upon exposure to nasal physiological conditions. A pharmaceutically acceptable, ion-sensitive polysaccharide gum particularly, an anionic polysaccharide that enables ion-responsive gelation in the presence of cations in nasal fluid, thereby enhancing mucosal adhesion, prolonging residence time, and facilitating sustained drug release.
In an embodiment, the ion-sensitive polysaccharide gum is Gellan gum.
In yet another aspect, the present invention provides an in situ nasal gel system that not only addresses the limitations of the pure drug but also maximizes its therapeutic potential by offering controlled release, improved mucosal adhesion, and targeted delivery to the brain which are the factors essential for effectively reducing oxidative stress in neurodegenerative conditions.
In yet another aspect, the present invention provides smart polymeric system ensuring direct nose-to-brain delivery via olfactory and trigeminal pathways, thereby bypassing the gastrointestinal degradation, hepatic first-pass metabolism, and blood-brain barrier restrictions commonly associated with conventional routes of administration.
In yet another aspect, the present invention discloses that in situ nasal gel formulation of caffeic acid is prepared by dissolving an appropriate quantity of a pharmaceutically acceptable, ion-sensitive polysaccharide gum in distilled water with heating and continuous stirring until complete dissolution is achieved. The polymeric solution is then cooled to room temperature. Separately, caffeic acid is dissolved in a pharmaceutically acceptable solvent and subsequently mixed with the gum solution. Preservatives and humectants are incorporated to improve stability and patient compliance. The final formulation is stored in sealed containers under ambient conditions and evaluated for physicochemical parameters.
Trial formulations may be prepared by varying the concentration of polymer and co-solvent, and the minimum concentration required for in situ gelation is determined on the basis of gel strength upon interaction with simulated nasal fluid at physiological temperature.
In yet another aspect, in vivo evaluations demonstrate that the caffeic acid-loaded in situ nasal gel exhibits superior mucoadhesive strength, optimal gelation properties, higher drug permeation coefficient, and significantly enhanced brain uptake compared to pure caffeic acid. The formulation thus provides a safe, non-invasive, and effective delivery platform for improving therapeutic outcomes in Alzheimer’s disease and potentially other neurodegenerative disorders.

BREIF DESCRIPTION OF DRAWINGS:
Fig. 1 illustrates the FTIR spectrum of caffeic acid, gellan gum (GG), sodium chloride (NaCl), potassium chloride (KCl), calcium chloride (CaCl2), PEG 400, physical mixture of caffeic acid, GG, NaCl, KCl, CaCl2, PEG 400 respectively.
Fig. 2 illustrates the influence of different formulation compositions on (A) spreadability, (B) gel strength, (C) water retention capacity and (D) viscosity of liquid formulation and after conversion to gel on exposure with simulated nasal fluid (SNF) respectively.
Fig. 3 illustrates (A) In vitro and (B) ex vivo release profile of optimized nasal gel formulation and free drug respectively.
Fig. 4 illustrates the viscosity of (A) optimized liquid formulation (B) optimized formulation on exposure to SNF stored at different storage conditions after 3 months respectively.
Fig. 5 illustrates impact of various interventions on (A) latency time of entry in preferred arm, (B) percentage spontaneous alteration and (C) Time spent in preferred arm respectively
Fig. 6 illustrates influence of various interventions on (A) time taken to discover the position of the hidden platform, (B) escape latency, (C) percentage of time spent in the target quadrant and (D) frequency of crossing of platform respectively.
Fig. 7 illustrates impact of various treatments on oxidative stress biomarkers (A) LPO, (B) MPO, (C) SOD, (D) GSH, (E) NO and (F) catalase activity of brain tissues respectively.

DETAILED DESCRIPTION OF THE INVENTION:
Accordingly, the present invention provides a novel intranasal in situ gel delivery system of caffeic acid utilizing a pharmaceutically acceptable, ion-sensitive polysaccharide gum for enhanced brain targeting in the management of Alzheimer’s disease. Caffeic acid, a plant-derived polyphenolic compound, is limited in its clinical utility due to poor solubility, low bioavailability, instability, and high systemic clearance, which collectively result in negligible therapeutic effects.
The present disclosure can be understood more readily by reference to the following description, taken in conjunction with the accompanying Figures and Examples, all of which form a part of this disclosure.
At the very outset of the detailed description, it may be understood that the ensuing description only illustrates a particular form of the invention covered in the present disclosure. However, such a particular form is only an exemplary embodiment, and without intending to imply any limitation on the scope of the invention. Accordingly, the description is to be understood as an exemplary embodiment and teaching of invention and not intended to be taken restrictively.
Before the present disclosure or methods of the present disclosure are described in greater detail, it is to be understood that the specific products, methods, processes, conditions or parameters, are not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the methods. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the methods. Certain ranges are presented herein with numerical values being preceded by the term “about.” The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. For example, "about" can mean within one or more standard deviations, or within ± 30%, 25%, 20%, 15%, 10% or 5% of the stated value.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.
It is appreciated that certain features of the methods, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the methods, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace operable processes and/or composites/scaffolds.
The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.
As used herein, the term "comprises", "comprising", or “comprising of” is generally used in the sense of include, that is to say permitting the presence of one or more features or components. The term "comprises", "comprising", or “comprising of” when placed before the recitation of steps in a process or method means that the process or method encompasses one or more steps that are additional to those expressly recited, and that the additional one or more steps may be performed before, between, and/or after the recited steps.
Reference throughout this specification to “certain embodiments”, “further embodiments”, “specific embodiments”, “further specific embodiment”, “one embodiment”, “a non-limiting embodiment”, “an exemplary embodiment”, “some instances”, or “further instances”, means that a particular feature, structure or characteristic described in connection with the embodiment may be included in at least one embodiment of the present disclosure.
As used herein, the terms ‘include’, ‘have’, ‘comprise’, ‘contain’ etc. or any form of said terms such as ‘having’, ‘including’, ‘containing’, ‘comprising’ or ‘comprises’ are inclusive and will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
The use of any and all examples, or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illustrate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed.
As used herein, the term “invention”, “present invention”, “disclosure” or “present disclosure” as used herein is a non-limiting term and is not intended to refer to any single embodiment of the particular invention but encompasses all possible embodiments as described in the specification.
The terms “process(es)” and “method(s)” are considered interchangeable within this disclosure.
For convenience, certain terms used in the specification and examples are collected in this section below:
AD: Alzheimer disease
Aβ: Amyloid-beta Aβ
Aβ₁₋₄₂: Amyloid-β peptide (1-42)
CA: Caffeic acid
PEG: Polyethylene Glycol
Kp: Permeation coefficient
J: Flux
LPO: Lipid peroxidation
SOD: Superoxide dismutase
MPO: Myeloperoxidase activity
NO: Nitric oxide
GSH: Glutathione peroxidase
In one specific embodiment, the present invention provides a novel intranasal in situ gel delivery system of caffeic acid utilizing a pharmaceutically acceptable, ion-sensitive polysaccharide gum for enhanced brain targeting in the management of Alzheimer’s disease. Caffeic acid, a plant-derived polyphenolic compound, is limited in its clinical utility due to poor solubility, low bioavailability, instability, and high systemic clearance, which collectively result in negligible therapeutic effects.
In another embodiment, the present invention provides a novel intranasal in situ gel formulation of caffeic acid for enhanced brain targeting through direct transport via the olfactory and trigeminal neural pathways. The formulation is designed to overcome the inherent limitations of caffeic acid, such as poor aqueous solubility, low stability, rapid systemic clearance, and poor permeability across the blood–brain barrier.
In yet another embodiment, the present invention discloses that mucoadhesive strength plays a key role in enhancing nasal residence time. A stronger mucoadhesive force helps the gel to adhere better to the nasal lining, making it less likely to leak out through the nostrils or slide down the nasopharynx. However, excessive mucoadhesion may risk damaging the nasal epithelium, emphasizing the need for an optimal balance.
In yet another embodiment, the present study effectively revealed the prospective of in-situ nasal gel of caffeic acid with special emphasis on management of Alzheimer. Caffeic acid loaded in-situ nasal gel showed superior mucoadhesive behavior, ease of spreadability with good gel strength and higher average drug permeation coefficient compared to pure drug. Superior in vivo performance relative to pure drug indicates that formulation can serve as promising drug delivery platform for management of neurological disorders like Alzheimer.
In yet another embodiment, the optimized caffeic acid-based intranasal in situ gel formulation was subjected to preclinical evaluation to assess its neuroprotective and anti-Alzheimer potential. Behavioral studies demonstrated significant improvements in learning ability, cognitive function, and memory enhancement in treated groups compared to controls. Further, biochemical assessments confirmed the antioxidant and anti-inflammatory activity of the formulation, showing marked restoration of oxidative balance. These results indicate that the developed in situ gel formulation of caffeic acid provides a promising, non-invasive therapeutic approach for the effective management of Alzheimer’s disease.
In yet another embodiment, the formulation of present invention was evaluated for physicochemical properties like mucoadhesiveness, in vitro release, ex-vivo permeability, and stability to ensure its suitable delivery through nasal route.
In yet another embodiment, the present invention discloses that in situ nasal gel formulation of caffeic acid is prepared by dissolving an appropriate quantity of a pharmaceutically acceptable, ion-sensitive polysaccharide gum in distilled water with heating and continuous stirring until complete dissolution is achieved. The polymeric solution is then cooled to room temperature. Separately, caffeic acid is dissolved in a pharmaceutically acceptable solvent and subsequently mixed with the gum solution. Preservatives and humectants are incorporated to improve stability and patient compliance. The final formulation is stored in sealed containers under ambient conditions and evaluated for physicochemical parameters.
In yet another embodiment, humectant maintains moisture and improve patient comfort. Suitable humectants, but are not limited to, glycerol, propylene glycol, sorbitol, or polyethylene glycol.
In yet another embodiment, preservative is used to enhance stability and prevent microbial growth. Suitable preservatives include, but are not limited to, methyl paraben, propyl paraben, or sodium benzoate.
In yet another embodiment, caffeic acid is dissolved in a pharmaceutically acceptable solvent prior to mixing with the polymeric solution. Suitable solvents include, but are not limited to, polyethylene glycol, propylene glycol, ethanol, or water-miscible co-solvents.
In yet another embodiment, the in-situ nasal gel formulation comprises a pharmaceutically acceptable gum as the polymeric base to enable sol–gel transition upon administration. The gum may be selected from the group consisting of gellan gum, xanthan gum, guar gum, locust bean gum, carrageenan, or combinations thereof.
In yet another embodiment, a pharmaceutically acceptable, ion-sensitive polysaccharide gum is gellan gum due to its ion-sensitive gelation behavior in the presence of cations such as sodium or calcium ions naturally present in nasal fluid.
In yet another embodiment, trial formulations can be prepared by varying the concentration of polymer and co-solvent, and the minimum concentration required for in situ gelation is determined on the basis of gel strength upon interaction with simulated nasal fluid at physiological temperature.
In yet another embodiment, the present invention discloses a method for preparing an intranasal in situ gel formulation as claimed in claim 1, wherein the method comprising:
dissolving a pharmaceutically acceptable, ion-sensitive polysaccharide gum in distilled water at a concentration of about 0.2% to 0.5% w/w to obtain a solution;
heating the solution to 90 °C ± 2 °C under continuous stirring until complete dissolution is achieved followed by cooling the heated solution to ambient temperature in the range of 20 ℃ to 35 ℃ to obtain gum solution;
dissolving caffeic acid in PEG at a concentration of about 3–5% v/v to obtain caffeic acid solution;
mixing the caffeic acid solution with the gum solution in equal proportion;
adding, methyl paraben at about 0.2% w/v and glycerol at about 2% w/v, to the resultant solution obtained in step (iv); and
storing the final formulation in a sealed container at room temperature,
wherein the formulation exhibits sol-to-gel transition upon contact with simulated nasal fluid at about 34 ± 2 °C.
In an embodiment of the method of the present disclosure, the ion-sensitive polysaccharide gum may be selected from the group consisting of gellan gum, xanthan gum, guar gum, locust bean gum, carrageenan, or combinations thereof.
In an example of the method of the present disclosure, the ion-sensitive polysaccharide gum is Gellan gum.
It is found that the optimized formulation having optimal pH (5.5-6.5), optimal viscosity of liquid formulation, mucoadhesive property (55.51± 6.84 %) which made the formulation best suited for nasal delivery.
From the result of in vitro release studies, it is found that nearly 86% of drug get released in 12 h, which denoted sustained release of drug from the formulation. Similarly, ex- vivo permeation studies also demonstrated that optimized formulation showed ~13- fold greater permeation compared to free drug along with sustained release of drug through nasal route of administration. Preclinical studies also demonstrated significant neuroprotective and anti-alzheimer effect.
Even though we have explained the invention of the present disclosure using specific examples, this explanation is not meant to limit how you understand it. People who are skilled in this field may think of various changes and different versions of the invention after reading this description. We expect that such changes can be made without straying from the main idea or purpose of the invention as defined in the claims.
The present disclosure is further described with reference to the following examples, which are only illustrative in nature and should not be construed to limit the scope of the present disclosure in any manner.

EXAMPLES
Evaluation of in situ nasal gel formulation
Compatibility study
The structural information of the functional groups and chemical bonds of components of formulation was obtained using FT-IR spectra. Spectrum of caffeic acid showed characteristic peak at 1642 cm-1 due to C=C stretch of nonconjugated alkene, at 3743 cm-1 and 3216 cm-1 due to O-H and C-H stretching of carboxylic acid, respectively. Spectrum of gellan gum (GG) exhibited characteristic peaks at 3386 cm-1 due to O-H stretching, 2903 cm-1 as a result of C-H stretching vibration of CH2 group, strong peak at 1645 cm-1 indicated asymmetric stretching of carboxylate groups, 1424 cm-1 corresponded to symmetric stretching of carboxylate groups, 1072 cm-1 indicated C-O stretching for alkyl ether and the bending vibration of C-H was observed at 809 cm−1. The characteristic peaks of caffeic acid at 3744 cm-1 and 3209 cm-1 due to aromatic O-H and C-H stretching of carboxylic acid respectively along with peak at 1642 cm-1 due to C=C stretching of nonconjugated alkene are present in the physical mixture of caffeic acid, GG and PEG 400. The characteristic peaks of caffeic acid has not showed substantial shift implying chemical inertness between caffeic acid and polymers. FTIR spectrum of gellan gum with components of simulated nasal fluid, i.e., sodium chloride and potassium chloride revealed no remarkable alteration compared to pure gellan gum. However, FTIR spectrum with calcium chloride exhibited characteristic peak at 1758.24 cm–1 revealed the interaction of carboxylate ion with calcium ion. The results are shown in figure 1.
Caffeic Acid loaded nasal gel formulation
To better understand the gelation process, in vitro studies were conducted to observe hydrogel formation. In situ gelling systems are primarily characterized by two critical attributes: suitable viscosity and efficient gelling capacity. The formulation must possess an initial viscosity that enables easy administration as a liquid, followed by a rapid sol–gel transition upon contact with physiological ions. As illustrated in Figure 2, gel formation occurred at 34 ± 1°C on interaction with SNF pH (6.4 ± 0.1) mimicking nasal physiological conditions indicating that ionic interactions at the microscale level are sufficient to trigger gelation, which supports the likelihood of rapid in vivo gel formation.
The pH of all formulations prepared was observed to be within the range of 5.44 to 5.88 (Table 1), (pH of formulations was measured utilizing digital pH meter (Equip-Tronics, India)) aligning well with the nasal mucosal pH levels, which typically ranges between 5.5- 6.4. The acceptable pH range of formulation too confirms that formulation will not cause local irritation to nasal mucosa and accompanying changes.
Formula-tion Code Gellan Gum (% w/v) PEG 400
(% v/v) Visual Remark Refractive Index pH % Drug Content % Muco-adhesive strength

Fr1 0.2 4 No firm gel formation 1.33± 0.01 5.64± 0.02 98.22± 3.31 54.06± 7.02
Fr2 0.3 4 Firm gel formation 1.33± 0.01 5.50± 0.01 101.05±3.83 56.41± 3.30
Fr3
0.4 4 Thick gel formation 1.33± 0.01 5.65± 0.01 97.10± 5.13 55.51± 6.84
Fr4 0.5 4 Thick gel formation 1.33± 0.01 5.88± 0.02 97.70± 4.33 52.26± 6.71
Fr5 0.3 3 Gel formation 1.33± 0.02 5.44± 0.01 97.10± 4.62 46.90± 4.03
Fr6 0.3 5 Firm gel formation 1.33± 0.01 5.20± 0.05 99.56± 4.66 61.29± 3.41
Table 1: Effect of different composition on visual appearance, refractive index, pH, % drug content and % mucoadhesive strength of batches prepared.

Appearance and clarity
Various batches prepared were estimated for appearance by visual assessment using black and white background contrast by inverting sample under sufficient light. Moreover, samples were examined for any particulate matter and evolution of turbidity. The clarity of formulations prior to gelation was estimated in terms of refractive index of liquid formulations utilizing Abbey refractometer (RS12-1, Rajdhani, India). The values of refractive index of different batches prepared were close to 1.33 i.e., refractive index of water which confirmed that all formulations were clear in appearance (Table 1).
Drug content
Briefly, formulation (1 ml) was mixed with solvent system composed of ethanol and purified water in 4:6 ratio (10 ml) and stirred for 2.5 h. Subsequently, solution was centrifuged for 15 min at 15000 rpm at 4 ℃. Supernatant collected was analyzed after suitable dilution using UV-Visible spectrophotometer (Shimadzu-1900, Japan) at 321 nm. The percent drug content of formulations was found within the range of 97-101%, which indicates content uniformity
Viscosity
The viscosity of formulations was measured using Brookfield Viscometer DV-II+ PRO fitted with an S-94 spindle (Brookfield Engineering Laboratories Inc., MA, USA) at 25°C and after interaction with simulated nasal fluid at 34±2 °C at angular velocity of 200 rpm. All the measurements were performed in triplicates. The results are shown in figure 2A.
Upon mixing the prepared sols with SNF, a viscous gel was instantly developed confirming the ion-responsive gelation behavior of formulation. In determining the optimal concentration of the gelling agent, a balance was necessary ensuring sufficient gel strength for effective drug delivery while maintaining viscosity that allows for ease of administration via nasal spray/ instillation. The viscosity of the formulations showed proportional increase with the concentration of gellan gum (0.2 - 0.5% w/v), indicating a strong dependency on polymer content. A notable rise in viscosity was recorded during the sol–gel transition at lower deacetylated gellan gum concentrations (0.2% and 0.3%). On the contrary, the initial solution of higher concentration (0.5% w/v) already had substantial viscosity, resulting in minimal change after gelation (Figure 2). This behavior is likely due to increased proximity and interaction between polymer chains at higher concentrations, resulting in a more compact and structured three-dimensional gel network. These preliminary evaluations indicated that 0.3% w/v gellan gum provided optimal gelation. This concentration was therefore selected for subsequent trials to assess the influence of PEG 400 on the viscosity of the formulation, tested within a range of 3-5% v/v. Increase in PEG 400 concentration increased the viscosity of formulation (Table 1).
Water retention capacity
Initially, weight of empty centrifuge tubes was recorded (W1). Subsequently, liquid formulation (1ml) was gently mixed with simulated nasal fluid (0.25 ml) and loaded into preweighed empty centrifuge tube and weighed again (W2). The unbound water was separated and decanted carefully after centrifuging the sample at 10,000 rpm for 10 min. The weight of the tube with the retained gel was then estimated (W3). Water holding capacity of in-situ gel was determined utilizing formula:
%Water retention capacity=((W3-W1))/((W2-W1) )*100 ------ (i)
The results are shown in figure 2B.
To exhibit effective mucoadhesive behavior, in situ gels must demonstrate efficient hydration and substantial water-retention capacity. A strong positive correlation existed between gellan gum concentration and water-holding capacity. As shown in Figure 2, formulations containing gellan gum at concentrations above 0.3% (w/v) consistently retained more than 40% of water. However, no statistically remarkable improvement (p > 0.05) in water-holding capacity was seen beyond the 0.3% concentration, indicating a plateau effect in hydration performance at higher gellan gum levels.
During the sol-to-gel phase transition, in-situ gels may undergo slight volumetric expansion, potentially leading to discomfort in the confined space of the nasal cavity. Therefore, evaluating the expansion coefficient is crucial to ensure patient comfort. The expansion coefficient of caffeic acid loaded in-situ gel formulations containing 0.2% gellan gum remained below 5% following mixing with simulated nasal fluid. Specifically, the formulation with 0.3% gellan gum exhibited an expansion of approximately 5%, which is minimal and unlikely to cause any physical discomfort upon intranasal administration.
Spreadability
Spreadability refers to the area traversed in a given time (cm²/min) by gel formulation. A 1ml graduated syringe was positioned vertically on the stand in a manner that syringe tip was held 2 cm above the surface of Whatman filter paper (0.45 µm) immersed in simulated nasal fluid. Formulation was dropped on the filter paper to determine surface area covered by the gel formulation in 20 s to estimate spreadability.
An essential characteristic of an effective in situ nasal gel is adequate spreadability, which ensures ease of administration and uniform distribution over the nasal mucosa without the risk of leakage post-application. Among different formulations, Fr2 exhibited the highest spreadability, as evidenced by its ability to cover a larger surface area on the filter paper, indicating better potential for mucosal coverage upon nasal application. Spreadability studies revealed an inverse relationship with viscosity. Higher polymer concentrations, while improving mucoadhesiveness, reduced the gel's ability to spread, potentially affecting ease of application (Figure 2). The spreadability results are shown in figure 2C.
Gel strength determination
Forty grams of solution was dispensed in measuring cylinder and gelled utilizing sufficient amount of simulated nasal fluid in a water bath with thermostat control at 34 ± 2 °C. A 5g weight was gently placed on the top of gelled solution. The gel strength was estimated by measuring the time in second needed by the weight to invade 5 cm deeper the gel at physiological condition. The results are shown in figure 2D. Time taken by reference weight object to travel across gel indicates rigidity of gel (Figure 2D). Gel strength between 25-50 s is usually regarded adequate. Gels with strength below 25 s may compromise their structural integrity and erode rapidly, whereas those exceeding 50 s may be too rigid and can trigger discomfort by mucosal irritation. Therefore, an ideal formulation should exhibit sufficient gel strength for retention without compromising spreadability or causing leakage.
Ex-vivo mucoadhesive strength
Concisely, 5 ml of porcine mucin suspension and 2 ml of prepared placebo in situ nasal gel formulation were mixed and incubated for 60 min at 37 ⁰C in an orbital incubator. Subsequently, samples were centrifuged at 15000 rpm and supernatant collected was analyzed by UV Visible spectrophotometry at 253 nm and % mucin binding efficiency of nasal formulation was estimated as follows
%Mucinbinding efficiency=((Total mucin-Free mucin)/(Total mucin))*100 (iv)
Mucoadhesive strength plays a key role in enhancing nasal residence time. Increase in concentration of PEG400 from 3 % to 5% simultaneously increased the mucoadhesive strength of formulations prepared (Table 1). A stronger mucoadhesive force helps the gel to adhere better to the nasal lining, making it less likely to leak out through the nostrils or slide down the nasopharynx. However, excessive mucoadhesion may risk damaging the nasal epithelium, emphasizing the need for an optimal balance.
Fr2 formulation was accounted as customized formulation for further studies depending upon various parameters including appearance, mucoadhesion, viscosity in situ, water holding capacity, spreadability and gel strength.
In vitro permeation studies
The initial burst release from in-situ hydrogel system might be attributed to excessive swelling of hydrogel during initial exposure. Later, substantial sustained drug release was observed due to enhanced gel network density (Figure 3A). Since gellan gum undergoes ionic crosslinking in a cationic environment, primarily through interactions between divalent ions present in simulated nasal fluid and the carboxylate groups on glucuronic acid residues. Therefore, optimized formulation containing 0.3% w/v gellan gum and 4% PEG400 showed controlled and prolonged drug release i.e., ~ 91% drug release in 24 h along with favorable rheological properties while pure drug diffused very slowly (Figure 3A). Furthermore, a comparative evaluation of regression coefficients (R2) of zero order (R2=0.816), first order (R2=0.939), Higuchi model (R2=0.947), and Korsmeyer-Peppas equation (R2=0.969) suggested best fit to Korsmeyer-Peppas equation. The value of the diffusion coefficient (n=0.61), confirmed non-Fickian diffusion pattern i.e., anomalous dissolution and diffusion-controlled drug release.
Ex vivo permeation studies
Ex vivo permeation study of pure drug and in situ gel was performed utilizing modified Franz diffusion cell. The freshly excised nasal mucosa of goat collected from local slaughter house was washed thrice with saline solution to remove debris. Goat nasal mucosa was mounted onto donor compartment of diffusion cell. Simulated nasal fluid was filled in receptor compartment (pH 6, 7 ml) and maintained at 34 ± 1 °C with constant stirring at 50 rpm. Aliquots were withdrawn at predestined time interval until 6h with subsequent replenishment with an equal amount of simulated nasal fluid to ensure sink conditions. Samples were diluted appropriately, filtered and estimated spectrophotometrically at 321 nm using UV-Visible spectrophotometer. Data collected was further utilized to determine cumulative amount of drug permeated across nasal mucosa (Q), permeation coefficient (Kp) and flux (J) respectively. The average steady state flux (J) was determined by the equation described below.
J=(ⅆQ)/dtA (ii)
Where A is skin surface area skin exposed and dQ/dt is amount of drug permeated with respect to time.
Kp=J/ΔC (iii)
Where ΔC is drug concentration difference between the donor and receptor at a given time.
The permeation of CA across sheep nasal membrane was ~78 % and ~12% from optimized formulation and free drug respectively for 10 h at a flux rate of 77.92 µg/cm2/h and 11.59 µg/cm2/h respectively (Figure 3B). Increased flux rate with optimized formulation is also coupled with reduction of time period needed to attain stable diffusion flow of drug. The average permeability co-efficient of optimized formulation was observed to be ~13 time higher than amount of free caffeic acid. The outcomes of study clearly indicated that in-situ nasal gel formulation remarkably enhanced nasal permeation compared to pure drug. The increased interaction of optimized formulation with nasal mucosal layer due to its mucoadhesiveness as well as hydrogel property of formulation facilitated the development of higher concentration gradient of caffeic acid which might be major factor driving enhanced penetration of caffeic acid.
Stability study
Stability study was performed in accordance of ICH guidelines at accelerated (40 ± 2 ⁰C/ 75 ± 5% RH), room temperature (25 ± 2 ⁰C/ 60 ± 5% RH), and cool temperature (4 ± 1°C/ 75 ± 5% RH) storage conditions for 3 months. Formulation were analyzed for parameters like appearance, refractive index, pH, viscosity, drug content and mucoadhesive strength over a period of stability study.
The results of analyzed parameters like appearance, refractive index, viscosity, drug content, pH, mucoadhesive strength etc. of samples stored at different storage conditions according to ICH guidelines are represented in Table 2 and Figure 4. The optimized formulation remained stable in terms of appearance, clarity indicated by their refractive index, pH, drug content and release profile when stored for 3 months at 4 ± 1°C/75 ± 5% RH, 25 ± 2°C/60 ± 5% RH, and 40 ± 2°C/75 ± 5% RH, although a slight decrease in viscosity was noted under elevated storage conditions (Figure 4).
Table 2: Stability study of CA loaded nasal gel
Storage condition Duration (month) Visual appearance Refractive index pH % Drug content % Muco-adhesive strength

4 ± 1°C/ 75 ± 5% RH 1 Clear colorless 1.33±0.01 5.55±0.01 99.4± 3.26 52.36± 5.21
3 Clear colorless 1.33±0.01 5.74±1.85 98.2± 2.14 51.27± 6.47
25 ± 2⁰C/60 ± 5% RH 1 Clear colorless 1.33±0.01 5.81±0.01 100.33± 2.78 52.22± 4.62
3 Clear colorless 1.33±0.01 5.75±0.01 99.66± 2.47 50.66± 3.19
40 ± 2⁰C/ 75 ± 5% RH 1 Clear colorless 1.33±0.01 5.48±0.01 97.22± 5.18 49.74± 4.41
3 Clear colorless 1.33±0.01 5.87±0.01 91.26± 3.25 42.57± 5.39

Statistical analysis
All data in the experiment were assessed statistically using GraphPad Prism version 5.00 (GraphPad Software, San Diego, CA, USA) and displayed as mean ± SD (n=3) deviation. Comparisons between data from multiple groups were performed using one-way ANOVA. p< 0.05 was considered as statistically significant in all studies.
Behavioral Studies
In Vivo studies
Preclinical studies were performed in compliance with the protocol sanctioned by IAEC Banasthali Vidyapith. Swiss albino mice weighing 25-30 g were kept at 25± 2 ⁰C, RH 60 ± 5% with 12 h light and dark cycle as per Good Laboratory Practice mentioned in CPCSEA guidelines.
After 2 weeks of acclimatization under controlled environment, a screening test was conducted to select healthy animals for reliable study outcomes. Animals were placed in a circular water pool (150x60 cm; containing water at 24±2 °C) partitioned into 4 equal quadrants with a hidden escape platform (10x10 cm, 1 cm below the water surface) in the center of quadrant II. Animals were having 60 s to find the platform and those who could not locate it after two attempts were not included in the study. Subsequently, selected healthy mice were randomly assigned to 5 groups (n=5/ group) and received treatment intranasally. Group 1 (näive) and 2 (control) received equivalent volume of normal saline respectively; Group 3 received pure caffeic acid dispersed in normal saline at a dose of 25 mg/kg; Group 4 received formulation equivalent to dose 25 mg/kg of caffeic acid; Group 5 (positive control) received donepezil (5mg/kg) orally. The cognitive impairment model of Alzheimer’s disease was established by administering scopolamine (3mg/kg,i.p.) after 30 min of intranasal treatment in respective group. The treatment duration was set for two weeks with daily administration, with mice euthanized on day 15. Animals were observed for any prominent clinical symptoms or fatalities during study. The ameliorative effect of different treatments on spatial short and long-term memory in scopolamine induced memory impaired mice was determined using Y-maze and Morris water maze test respectively.
Y maze Test
The Y-maze test was conducted on day 1, 3 and 7 following administration of scopolamine in different test groups respectively. During the habituation phase, animals were placed in the Y-maze to familiarize with the apparatus for a period of 5 minutes. The first arm chosen by the animal was noted preferred arm and the other noted discriminated arm. During the acquisition phase, 24 h later, the discriminated arm by the animal was closed, and the food was placed in the preferred arm. The mouse was placed in the starting arm and allowed to move to the open arm. This exercise was done for 5 minutes for each mouse. During the retention phase, after 30 min of scopolamine administration, mice were introduced one after the other into the Y-maze for a period of 5 minutes. After each passage, the apparatus was cleaned with alcohol (70% ethanol), in order to eliminate as much as possible the odorous traces left by the previous mouse. The latency time to choose the preferred arm, the time spent in the different arms of the Y-maze (preferred and discriminated) and the number of entries in the different arms (preferred and discriminated) were recorded. The percent (%) alternation was determined using formula
% Alternation=(Numberofalternations/[Totalnumberofarmentries-2] )*100 ------- (vi)
The impact of caffeic acid and optimized formulation on short-term memory was estimated utilizing Y-maze test for shift in behavior patterns on day 1, 3 and 7. The control group showed significantly higher latency time of entry in preferred arm along with lower time spent in preferred arm and higher spontaneous alteration relative to naïve group (p<0.05) confirming memory loss on scopolamine administration. However, donepezil, CA and optimized formulation treated mice exhibited remarkably lower latency time and spontaneous alteration rates and higher time spent in preferred arm in contrast to control group (Figure 5). Our findings suggest that caffeic acid and optimized formulation administration effectively inhibited spatial memory impairment (p<0.05).
However, significant decrease in latency time and spontaneous alteration rates and time spent in preferred arm for animals receiving formulation compared to caffeic acid after 24 h and on day 7 was observed (Figure 5). The results are in compliance with in vitro dissolution study and validated that prolonged and controlled delivery of caffeic acid from nasal gel prolonged the therapeutic potential of optimized formulation.
Morris water maze task
The Morris water maze test was conducted from day 7 to day 14 following administration of respective treatment. Morris water maze test setup was having a circular water pool (150x60 cm; containing water at 24±2˚C) divided into 4 equally spaced quadrants containing various prominent visual cues. An invisible escape platform (10x10 cm, 1 cm below the water surface) was hidden in the center of quadrant II to allow animal to rest for 30s during the training period and removed at the time of the probe task. During training, mouse was carefully placed into one of four randomized quadrant with maximum search duration of 60 s. The mouse was allowed to swim freely and time taken to successfully locate and reach circular platform was recorded. Memory training was initiated twice a day for 5 days. On day 14, platform was removed and probe trial was run for 60 s to record the time to reach target quadrant and number of crosses at previous platform location. The escape latency, time taken to reach the escape platform, time spent in the target quadrant, and the number of times the animal crossed the previous location of the platform was measured.
The outcomes of investigation remarkably indicated dementia-like behavior in scopolamine treated mice with raised escape latency to platform and substantial decline in the frequency of crossing times in the Morris water maze (Figure 6). However, optimized formulation treated mice promptly discovered the position of the hidden platform after the training compared to caffeic acid treated group (Figure 6). This indicated that optimized formulation significantly decreased the escape latency compared to control group (scopolamine) and pure drug treated group confirming improved long term spatial memory and learning abilities. Similarly, % target quadrant occupancy and number of crossings in optimized formulation-treated mice was notably greater than pure drug treated and control mice (Figure 6). The results indicated that optimized formulation appreciably upgraded the spatial memory of AD mice due to prolonged drug release behavior of formulation. Overall, the findings align with prior investigations that caffeic acid retards the impact of scopolamine on learning and memory processes. Overall, the intranasal formulation effectively mitigated learning and memory impairment induced by scopolamine due to sustained drug release behavior and improved drug absorption facilitated by improved nasal residence time of formulation by in-situ gel formation.
Biochemical and histopathological evaluation
Animals were euthanized after completion of behavioral investigation. Immediately brain was removed, cleaned, minced and centrifuged to prepare tissue homogenate 10,000 rpm/min at 4° C for 15 min to collect supernatant for biochemical analysis. Various biochemical tests like lipid peroxidation (LPO), superoxide dismutase (SOD), myeloperoxidase activity (MPO), nitric oxide (NO), glutathione peroxidase (GSH) and catalase activity were performed to estimate the potential of different treatments on oxidative stress.
Oxidative stress markers and antioxidant enzyme level: Oxidative stress exhibits a crucial contribution to progression of neurodegenerative diseases and is typically characterized by elevated levels of LPO, MPO, NO, and diminished operation of key antioxidant defense enzymes like SOD, catalase, and reduced GSH. Intranasal administration of caffeic acid and optimized formulation has significantly reduced the levels of LPO and MPO, both of which are indicators of cellular membrane damage and inflammation, respectively (Figure 7). Concurrently, both pure drug and optimized formulation helped in lowering excessive nitric oxide production, which when dysregulated, contributes to nitrosative stress and neuronal injury. However, in-situ gel provided significantly higher reduction in oxidative stress markers compared to caffeic acid (p<0.05) (Figure 7).
Importantly, standard drug (donepezil), caffeic acid and optimized formulation treatment was associated with a notable enhancement in endogenous antioxidant enzyme activity. The upregulation of SOD and catalase suggests improved neutralization of reactive oxygen species, while the restoration of GSH levels indicates strengthened cellular redox balance (Figure 7). These combined effects contribute to the mitigation of oxidative damage and preservation of neuronal function. Thus, intranasal delivery of caffeic acid offers a promising non-invasive strategy to modulate oxidative stress markers and potentially slow the progression of oxidative stress-mediated neurodegeneration.
In contrast, optimized formulation showed superior efficacy in reducing oxidative stress markers statistically (p<0.05) (Figure 7) by extending retention period on the nasal mucosa, allowing prolonged contact and absorption across the olfactory and respiratory epithelium. Thus, in situ nasal gel system not only addresses the limitations of the pure drug but also maximizes its therapeutic potential by offering controlled release, improved mucosal adhesion, and targeted delivery to the brain—factors essential for effectively reducing oxidative stress in neurodegenerative conditions.
The present study effectively revealed the prospective of in-situ nasal gel of caffeic acid with special emphasis on management of Alzheimer. Caffeic acid loaded in-situ nasal gel showed superior mucoadhesive behavior, ease of spreadability with good gel strength and higher average drug permeation coefficient compared to pure drug. Superior in vivo performance relative to pure drug indicates that formulation can serve as promising drug delivery platform for management of neurological disorders like Alzheimer.
, Claims:We claim
1. An intranasal in situ gel delivery system comprising:
caffeic acid as the active pharmaceutical ingredient; and
a pharmaceutically acceptable, ion-sensitive polysaccharide gum,
wherein the formulation undergoes a sol-to-gel transition upon contact with nasal physiological conditions, enabling direct nose-to-brain delivery via the olfactory and trigeminal pathways for the management of Alzheimer’s disease; and
wherein the formulation demonstrates mucoadhesive properties that prolong nasal residence time and reduce mucociliary clearance.

2. The delivery system as claimed in claim 1, wherein the pharmaceutically acceptable, ion-sensitive polysaccharide gum is selected from the group consisting of gellan gum, xanthan gum, guar gum, locust bean gum, carrageenan, or combinations thereof

3. The delivery system as claimed in claim 1, wherein the pharmaceutically acceptable, ion-sensitive polysaccharide gum is gellan gum.

4. The delivery system as claimed in claim 1, further comprising one or more pharmaceutically acceptable excipients selected from stabilizers, penetration enhancers, buffering agents, isotonic agents, preservatives, or antioxidants.

5. The delivery system as claimed in claim 1, wherein in vivo administration results in higher drug permeation coefficient and enhanced brain uptake compared to pure caffeic acid.

6. The delivery system as claimed in claim 1, formulated as a non-invasive, patient-compliant nasal dosage form suitable for repeated administration.
7. A method for treating Alzheimer’s disease in a subject in need thereof, comprising administering a therapeutically effective amount of the in situ nasal gel delivery system as claimed in claim 1.

8. The delivery system as claimed in claim 1, wherein the formulation is used for the management of neurodegenerative disorders selected from Parkinson’s disease, Huntington’s disease, dementia, or other central nervous system disorders.

9. A method for preparing an intranasal in situ gel formulation as claimed in claim 1, wherein the method comprising,
(i) dissolving a pharmaceutically acceptable, ion-sensitive polysaccharide gum in distilled water at a concentration of about 0.2% to 0.5% w/w to obtain a solution;
(ii) heating the solution to 90 °C ± 2 °C under continuous stirring until complete dissolution is achieved followed by cooling the heated solution to ambient temperature in the range of 20 ℃ to 35 ℃ to obtain gum solution;
(iii) dissolving caffeic acid in PEG at a concentration of about 3–5% v/v to obtain caffeic acid solution;
(iv) mixing the caffeic acid solution with the gum solution in equal proportion;
(v) adding, methyl paraben at about 0.2% w/v and glycerol at about 2% w/v, to the resultant solution obtained in step (iv); and
(vi) storing the final formulation in a sealed container at room temperature,
wherein the formulation exhibits sol-to-gel transition upon contact with simulated nasal fluid at about 34 ± 2 °C; and
wherein the final formulation demonstrates mucoadhesive properties that prolong nasal residence time and reduce mucociliary clearance.
10. The method as claimed in claim 9, wherein said pharmaceutically acceptable, ion-sensitive polysaccharide gum is selected from the group consisting of gellan gum, xanthan gum, guar gum, locust bean gum, carrageenan, or combinations thereof
11. The method as claimed in claim 9, wherein said pharmaceutically acceptable, ion-sensitive polysaccharide gum is gellan gum.