DESC:4. FIELD OF THE INVENTION
The present invention relates to formulation comprising Amoxicillin, a broad-spectrum ß-lactam antibiotic, in combination with Clavulanate, a ß-lactamase inhibitor, optimized for nasal cavity.
BACKGROUD OF THE INVENTION
Amoxicillin clavulanate is a well-established antibiotic combination known for its broad-spectrum antimicrobial properties. Initially introduced into clinical practice in the early 1980s, amoxicillin clavulanate has since been widely prescribed for the treatment of various bacterial infections, including respiratory tract infections, urinary tract infections, and skin and soft tissue infections.

This antibiotic combination distinguishes itself through its ability to overcome beta-lactamase-mediated resistance, enhancing its efficacy against a wide range of gram-positive and gram-negative pathogens. Amoxicillin Involves inhibition of bacterial cell wall synthesis by binding to penicillin-binding proteins, disrupting peptidoglycan cross-linking, and causing cell lysis. However, beta-lactamase enzymes can degrade amoxicillin. Clavulanate, a beta-lactamase inhibitor, prevents this by binding to the enzyme's active site, preserving amoxicillin's efficacy. This combination broadens the spectrum of bacteria that can be effectively targeted.

Post-surgical nasal infections are a common and potentially serious complication following nasal surgeries. These infections occur when bacteria colonize the surgical site, taking advantage of the disrupted mucosal barriers and exposed tissues. The nasal cavity, due to its rich vascular supply and close proximity to the sinuses and respiratory tract, is particularly susceptible to infection following surgical interventions.

Post-surgical nasal infections are commonly caused by pathogenic organisms, primarily Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Pseudomonas species and others. These microorganisms are frequently identified as the major contributors to post-operative complications in nasal surgeries.
Conventional systemic or oral antibiotic therapies for post-surgical nasal infections face several limitations, including the development of antibiotic-resistant bacteria due to widespread use, which can lead to prolonged infections and complications when resistant strains fail to respond to standard treatments like oral amoxicillin-clavulanate. Additionally, these therapies often cause systemic side effects, such as gastrointestinal disturbances, allergic reactions, and antibiotic-associated diarrhea, which can hinder patient recovery in the post-surgical context. The delayed therapeutic action of systemic antibiotics, which must traverse the bloodstream to reach the nasal cavity, can allow infections to worsen, while the inadequate local concentration of antibiotics may fail to eradicate infections, especially in the presence of biofilms. These biofilms act as barriers, protecting bacteria from antibiotics and contributing to chronic infections that may require further surgical interventions. While drug-eluting stents show promise, their long-term efficacy remains under investigation, and they are costly and not universally suitable, further limiting the available treatment options.
A targeted solution for post-surgical nasal infections offers several advantages over conventional treatments. By enabling direct delivery of antimicrobial agents to the infection site, such as through a nasal spray, it ensures high local drug concentrations while minimizing systemic exposure, reducing side effects like gastrointestinal disturbances and allergic reactions. This localized approach enhances effectiveness against infections, particularly in the complex nasal anatomy, and improves biofilm penetration, ensuring thorough eradication of resistant bacterial colonies. Use of these targeted agents can significantly lower the risk of post-operative infections, especially in high-risk surgeries, improving patient outcomes, accelerating recovery, and reducing the need for additional interventions. Furthermore, resistance management strategies, such as the use of novel antimicrobials or combination therapies, help mitigate the risk of antibiotic resistance, enhancing long-term treatment efficacy while reducing overall healthcare costs.
The patent, US8106040B2 titled "Stable Amoxicillin-Clavulanate Formulation for Treatment of Bacterial Infections" filed in 2007, discloses an oral formulation. It focuses on a stable pharmaceutical suspension for oral administration, lacking the specific mucoadhesive properties and targeting capabilities found in the Amoxicillin clavulanate nasal spray formulation.

The application, WO2013173803A2 titled "Pharmaceutical Compositions Comprising Amoxicillin and Clavulanate" filed in 2013, discloses a paediatric pharmaceutical composition for oral administration that includes amoxicillin and clavulanate which is different from the Amoxicillin clavulanate formulation that is specifically developed as a nasal spray for nasal cavity and leveraging mucoadhesive properties.

Currently, there are limited options for delivering antibiotics directly to the nasal cavities, often resulting in suboptimal treatment outcomes. This invention aims to address this gap by delivering Amoxicillin Clavulanate directly to the nasal passages, ensuring a higher concentration of the antibiotic at the site of infection. Additionally, the formulation incorporates mucoadhesive properties to prolong the residence time of the antibiotic in the nasal cavity. This mucoadhesion helps the antibiotic adhere to the mucosal surfaces, allowing for sustained release of the active ingredients over an extended period. This targeted and prolonged approach enhances the efficacy of the treatment, leading to faster infection resolution, minimizing the need for systemic antibiotics, and providing effective localized therapy.

OBJECTIVE OF THE INVENTION

The primary objective of the invention is to provide a composition comprising Amoxicillin Clavulanate nasal spray to prevent post-surgical nasal infections in individuals who have undergone nasal surgery.

The objective of the invention (Amoxicillin Clavulanate Nasal Spray) is two-fold, to provide a localized and targeted treatment for post-surgical nasal infections. Post-surgical nasal infections require effective and direct treatment at the site of infection, and then combat antibiotic resistance through biofilm disruption.

SUMMARY OF THE INVENTION
The following presents a simplified summary of the disclosure in order to provide a basic understanding to the reader. This summary is not an extensive overview of the disclosure and it does not identify key/critical elements of the invention or delineate the scope of the invention. Its sole purpose is to present some concepts disclosed herein in a simplified form as a prelude to the more detailed description that is presented later.

This invention relates to a novel and improved composition for nasal cavity. The composition focuses on a stable, fixed-dose, aqueous suspension of Amoxicillin Clavulanate specifically formulated for nasal cavity. Furthermore, the formulation exhibits mucoadhesive properties, adhering to the nasal mucosa to prolong drug contact time and enhance absorption.
A key feature of this technology is its ability to disrupt bacterial biofilms, making the infection more susceptible to treatment and reducing the risk of antibiotic resistance.
The composition includes Amoxicillin Clavulanate as the core antibiotic combination, along with Chitosan, a mucoadhesive agent with biofilm disruption properties.
The invention also provides a application of Amoxicillin Clavulanate nasal spray to prevent post-surgical nasal infections in patients who have undergone nasal surgery. By administering the nasal spray immediately following surgery and during the post-operative recovery period, this approach aims to prevent bacterial colonization and the development of subsequent infections. This targeted post-surgical treatment is designed to ensure that the surgical site remains free from infection, thereby reducing the need for systemic antibiotics and minimizing the risk of complications associated with post-surgical infections. By maintaining high local concentrations of the antibiotic directly at the site of surgery, this approach supports faster healing and improved overall patient outcomes.

The pharmaceutical composition may be contained within a container suitable for nasal administration, ensuring ease of use and accurate dosing. The composition preferably includes a suspending agent, ensuring that the formulation remains stable over time. In one embodiment, the composition is a suspension that includes a suspending agent in a sufficient amount to prevent phase separation (i.e., separation of the particles and solution) after 3 or 6 months of storage at 25±2°C and 60%±5% relative humidity (RH) or at 40±2°C and 75%±5% RH. In another embodiment, the aqueous pharmaceutical composition is a single-phase suspension that remains stable as a single-phase suspension even after 12 or 24 months of storage under the same conditions.

Another embodiment is a stable fixed dose, aqueous pharmaceutical composition (e.g., contained in a container) for nasal administration to a human and/or an animal, where the composition comprises about 0.001% w/v to about 4.87% w/v amoxicillin, about 0.001 w/v to 2.13% w/v Clavulanate and about 0.5% w/v to about 2% w/v chitosan. The use of chitosan as a mucoadhesive in the amoxicillin clavulanate nasal spray formulation provides additional benefits, including sustained release, and biofilm disruption properties. The mucoadhesive property of chitosan enhances the retention time of the formulation on the nasal mucosa, allowing for prolonged contact and improved drug absorption. This results in a more effective therapeutic outcome by ensuring that the amoxicillin clavulanate remains at the site of action for an extended period. Chitosan also contributes to the sustained release of amoxicillin clavulanate, gradually releasing the drug over time and maintaining consistent therapeutic levels. Furthermore, chitosan exhibits biofilm disruption capabilities, which are particularly beneficial in treating Post-surgical nasal infections where biofilm formation can lead to chronic infections. The inclusion of chitosan in the formulation thus enhances the overall efficacy of the amoxicillin clavulanate nasal spray.

In one embodiment, the composition comprises amoxicillin as the active pharmaceutical ingredient in one or more of its approved salt forms, including amoxicillin trihydrate, amoxicillin sodium, and amoxicillin potassium. These salts are selected based on their stability, solubility, and compatibility in a suspension formulation. In a preferred example, amoxicillin trihydrate is utilized due to its excellent stability in aqueous environments, non-irritating nature, and suitability for long-term storage. Alternatively, amoxicillin sodium can be employed in formulations designed for rapid therapeutic action, while amoxicillin potassium may be considered for its specific compatibility with other components in the formulation. These salts ensure optimal antibacterial activity and uniformity in the nasal spray suspension.

In one embodiment, the composition further comprises clavulanate, a ß-lactamase inhibitor, in one or more of its approved salt forms, including potassium clavulanate, clavulanate sodium, and clavulanate magnesium. Among these, potassium clavulanate is preferred for its superior solubility and stability in aqueous formulations, making it ideal for nasal spray suspensions. Alternatively, clavulanate sodium may be employed in formulations requiring rapid action against ß-lactamase-producing bacteria, while clavulanate magnesium is a viable option for specific applications where additional stability or solubility advantages are desired. These salts ensure that the amoxicillin component is protected from enzymatic degradation, thereby enhancing the efficacy of the formulation in treating upper respiratory tract infections.

One embodiment is a stable fixed dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human and/or an animal, comprising about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate and about 0.5% w/v to about 2% w/v polyvinyl alcohol. The polyvinyl alcohol may be present at a concentration of at least about 0.5% w/v, or preferably between about 0.5% w/v to about 2% w/v of the composition.

One embodiment is a stable fixed dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human and/or an animal, comprising about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate and about 0.1% w/v to about 0.5% w/v EDTA. The EDTA may be present at a concentration of at least about 0.1% w/v, or preferably between about 0.1% w/v to about 0.5% w/v of the composition.

One embodiment is a stable fixed dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human and/or an animal, comprising about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate and about 1% w/v to about 2% w/v Poloxamer 407. The Poloxamer 407 may be present at a concentration of at least about 1% w/v, or preferably between about 1% w/v to about 2% w/v of the composition.

Another embodiment is a stable fixed dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human and/or an animal, comprising about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate and about 0.1% w/v to about 1% w/v carbopol. The carbopol may be present at a concentration of at least about 0.1% w/v, or preferably between about 0.1% w/v to about 1% w/v of the composition.

Another embodiment is a stable fixed dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human and/or an animal, comprising about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate, about 0.5% w/v to about 2% w/v chitosan, about 0.5 w/v to 0.2% w/v Polyvinyl alcohol, about 0.1% w/v to about 0.5% w/v and other excipients. The Suspending agents, polyvinyl alcohol, Xantham gum ensures the suspension remains stable over extended storage periods.

Another embodiment is a stable fixed dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human and/or an animal, comprising about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate, about 0.5% w/v to about 2% w/v chitosan, about 0.5 w/v to 0.2% w/v Polyvinyl alcohol, about 0.1% w/v to about 0.5% w/v and other excipients. The Xantham gum may be present at a concentration of at least about 0.1 w/v, or preferably between about 0.1% to about 0.5% w/v.
Another embodiment is a stable fixed dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human and/or an animal, comprising about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate and about 0.1% w/v to about 1% w/v carbopol. The carbopol may be present at a concentration of at least about 0.1% w/v, or preferably between about 0.1% w/v to about 1% w/v of the composition.

Another embodiment is a stable fixed dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human and/or an animal, comprising about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate and about 1% w/v to about 5% w/v Glycerine. The glycerine may be present at a concentration of at least about 1% w/v, or preferably between about 1% w/v to about 5% w/v of the composition.

Another embodiment is a stable fixed dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human and/or an animal, comprising about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate and about 0.05% w/v to about 0.1% w/v Citric acid. The citric acid may be present at a concentration of at least about 1% w/v, or preferably between about 1% w/v to about 5% w/v of the composition.

In a further embodiment, the stable fixed dose, aqueous pharmaceutical composition is contained in a sprayer, and on delivering a spray of the composition to a human and/or an animal nose results in a spray pattern having a longest axis of 15-75 mm, a shortest axis of 10-65 mm, and an ellipticity of 1-2.

In an embodiment, the present invention relates to a stable fixed dose pharmaceutical aqueous suspension composition (e.g., contained in a container) for nasal administration to a human and/or an animal, where the composition comprises (1) about 0.001% w/v to about 4.87% w/v amoxicillin, (2) 0.001% w/v to about 2.13% w/v clavulanate, (3) about 0.5% w/v to about 2% chitosan, (4) about 0.5 w/v to 0.2% w/v Polyvinyl alcohol (5) about 0.1% w/v to about 0.5% w/v EDTA, (6) about 0.1% w/v to about 1% w/v Polysorbate 80, (7) about 1% w/v to about 2% w/v Poloxamer 407, (8) about 0.1% w/v to about 1% w/v carbopol, (9) about 0.1-0.5% w/v Xanthan gum, (10) about 1% w/v to about 5% w/v Glycerine, (11) about 0.05% w/v to about 0.1% w/v Citric acid.

In a further embodiment, the present invention relates to use of a pharmaceutical composition of the present invention for the treatment of post-surgical nasal infections in a human and/or an animal in need thereof. For example, one embodiment is the use of about about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate and about 0.1% w/v to about 1% w/v Polysorbate 80, in the preparation of a stable fixed dose, aqueous pharmaceutical composition (e.g., contained in a container) for the treatment of post-surgical nasal infections in a human and/or an animal in need thereof.

In a further embodiment, the present invention relates to a stable fixed dose, aqueous pharmaceutical composition (e.g., contained in a container) for nasal administration comprising about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate, about 0.5% w/v to about 2% w/v chitosan, for the treatment of Post-surgical nasal infections in a human and/or an animal in need thereof.

In a further embodiment, the present invention relates to a kit comprising a stable fixed dose, aqueous pharmaceutical composition contained in a container, for nasal administration and a package insert containing instructions about the use of the pharmaceutical composition.

Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, the detailed description and specific examples, while indicating preferred embodiments of the invention, will be given by way of illustration along with complete specification.

BRIEF SUMMARY OF THE DRAWINGS
Fig.1. The graph represents the sustained release and deposition of drug over a period of 12 hours for different doses and standard (Oral amoxicillin clavulanate).
Fig.2. The graph represents the Adhesive work across different groups with adhesive work increasing progressively from the Dose 1 to Dose 3 in a Porcine Mucin Model.
Fig.3. The graph represents the Adhesive force across different groups with adhesive force increasing progressively from the Dose 1 to Dose 3 in a Porcine Mucin Model.
Fig.4. The graph represents the live biofilm volume across different groups with live biofilm decreasing progressively from the Dose 1 to Dose 3 in New Zealand rabbit model.
Fig.5. The graph represents the dead biofilm volume across different groups with dead biofilm increasing progressively from the Dose 1 to Dose 3 in New Zealand rabbit model.
Fig.6. The graph represents the wound mean defect size reduction over 5 postoperative weeks, with Dose 3 achieving the smallest defect size, indicating the most effective healing in an experimental rabbit model of mucosal injury.
Fig.7. The graph represents the mean Epithelial thickness index (ETI) over five postoperative weeks, with Dose 3 consistently achieving higher ETI values, indicating greater epithelial thickening in an experimental rabbit model of mucosal injury.
Fig.8. The graph represents the Tissue epidermal growth factor levels in different groups with dose 3 achieving similar tissue epidermal growth factor to the control in rats.
Fig.9. The graph represents the colony forming units of bacterial in different groups with dose 3 achieving higher bacterial eradication.
DETAILED DESCRIPTION OF THE INVENTION

The present disclosure emphasises that its application is not restricted to specific details of construction and component arrangement, as illustrated in the drawings. It is adaptable to various embodiments and implementations. The phraseology and terminology used should be regarded for descriptive purposes, not as limitations.

The terms "including," "comprising," or "having" and variations thereof are meant to encompass listed items and their equivalents, as well as additional items. The terms "a" and "an" do not denote quantity limitations but signify the presence of at least one of the referenced items. Terms like "first," "second," and "third" are used to distinguish elements without implying order, quantity, or importance.

The term “effective amount” when used in connection with an active ingredient denotes an amount of the active ingredient that, when administered to a subject for treating Post-surgical nasal infections, produces an intended therapeutic benefit in a subject. The term “active ingredient” (used interchangeably with “active” or “active substance” or “drug”) as used herein includes Amoxicillin Clavulanate or its salt.

The present invention relates to a stable fixed-dose, aqueous pharmaceutical composition for nasal administration to a human and/or an animal. This composition is specifically formulated with Amoxicillin Clavulanate and is designed for the targeted treatment of nasal infections. By delivering the antibiotic directly to the nasal cavities, the invention aims to optimize therapeutic outcomes and minimize systemic absorption, thereby reducing the risk of systemic side effects commonly associated with oral or intravenous administration of Amoxicillin Clavulanate. The formulation is designed to fight against antimicrobial resistance by disrupting bacterial biofilms.

Provided herein are, for example, pharmaceutical spray formulations of Amoxicillin and Clavulanate.

In the context of the present invention, the effective amount of amoxicillin clavulanate can range from about 0.001 mg to about 10 mg, or preferably from about 0.1 mg to about 4.87 mg.

In an aspect of this invention, for daily administration by the nasal route, the effective amount of Amoxicillin Clavulanate can range from about 530 mcg to about 5000 mcg, or preferably from about 20 mcg to about 3000 mcg.

By “pharmaceutically acceptable excipients”, it is meant any of the components of a pharmaceutical composition other than the active ingredients and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.

As used herein, the term “average particle size” (or synonymously, “mean particle size”) refers to the distribution of particles, wherein about 50 volume percent of all the particles measured have a size less than the defined average particle size value and about 50 volume percent of all particles measured have a particle size greater than the defined average particle size value. This can be identified by the term “D50” or “d(0.5)”. The average particle size can be measured using various techniques such as microscopy, laser diffraction, photon correlation spectroscopy (PCS), and Coulter's principle.

In the context of the present invention, the term “mucoadhesive” refers to the ability of a substance to adhere to the mucosal surfaces of the body, such as the nasal mucosa. This property enhances the retention time of a pharmaceutical formulation at the site of administration, allowing for prolonged contact and improved drug absorption. Mucoadhesive agents can form strong non-covalent bonds with mucin and epithelial cells, leading to an increased local concentration of the active pharmaceutical ingredient, improved therapeutic efficacy, and potentially reduced dosing frequency. Non-limiting examples of chitosan-related polymers that can be used include trimethyl chitosan, glycol chitosan, carboxymethyl chitosan, chitosan oligosaccharides, hydroxypropyl chitosan, chitosan hydrochloride, chitosan glutamate, N-succinyl chitosan, quaternized chitosan, and chitosan, xanthan gum, guar gum, alginate, carrageenan, and carboxymethyl cellulose sodium. (Xanthan gum mentioned as mucoadhesive in the reference but it is mentioned as suspension stabiliser in this formulation)

In the context of the present invention, the term “Suspending agent” refers to a substance that stabilizes a suspension by increasing its kinetic stability. Suspending agents are used to increase the viscosity of a liquid, helping to stabilize suspensions by keeping insoluble particles evenly distributed and preventing them from settling. This results in a stable dispersion of small droplets of one phase within the other, preventing the phases from separating. Suspending agents are commonly used in pharmaceutical compositions to ensure uniform distribution of active ingredients and enhance the consistency and stability of the formulation. Non-limiting examples of Suspending agents include polysorbates (e.g., polysorbate 80), sorbitan esters (e.g., sorbitan monolaurate), lecithin, xanthum gum, and various polyoxylated fatty acid derivatives, cellulose derivatives like microcrystalline cellulose and sodium carboxymethylcellulose (Avicel RC-591), hydroxypropyl methylcellulose (HPMC), and methylcellulose. Polysaccharides such as xanthan gum and carrageenan, along with natural gums like acacia and tragacanth, are also prevalent. Synthetic polymers like carbomers (Carbopol) and polyvinyl compounds such as polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) are employed for their stabilizing properties. Inorganic agents like colloidal silicon dioxide and magnesium aluminum silicate are sometimes used for additional stabilization. Surfactants such as polysorbates (e.g., Polysorbate 80)

As used herein, the term “container” refers to a single unit-dose container or multi-dose container. Suitable single unit-dose containers or multi-dose containers include, but are not limited to, glass, aluminum, polypropylene, or high-density polyethylene, for example, high-density polyethylene containers produced using a blow-fill-seal manufacturing technique. In one embodiment, the container is a sprayer which delivers the pharmaceutical composition in the form of a fine mist. A sprayer generally includes a container containing a pharmaceutical composition, a pump sealed (e.g., hermetically engaged) with the container, an actuator removably receiving a top portion of the pump, and a cap removably engaged with the container and the actuator.

The present invention relates to a stable fixed dose, aqueous pharmaceutical composition (e.g., contained in a container) for nasal administration to a human and/or an animal, where the composition comprises about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate.

The Amoxicillin Clavulanate nasal spray formulation described herein can also be utilized as a method to treat not only for post surgical wound healing, but also for other nasal infections including but not limited to sinusitis, Rhinitis, Rhinosinusitis, Nasal Vestibulitis, Furunculosis (Nasal Furuncles), Septal Abscess. The recommended administration involves applying the nasal spray to the nasal cavity both before and after surgical procedures to create an antimicrobial environment that reduces the risk of infection. The sustained release and mucoadhesive properties of the formulation ensure prolonged contact with the nasal mucosa, providing effective protection during the critical post-operative period. This use is particularly advantageous in surgeries known to have high infection rates.

The pharmaceutical composition may be in the form of a solution or a suspension, but preferably the composition is in the form of a suspension (more preferably, a single-phase suspension), wherein Amoxicillin Clavulanate or its salt is present in particle form. The Amoxicillin Clavulanate or may be present at a weight ratio suitable to achieve the desired therapeutic effect.

The composition preferably also includes a Suspending agent. In one embodiment, the composition is a suspension and includes a Suspending agent in a sufficient amount to prevent phase separation (i.e., separation of the particles and solution) after 3 or 6 months of storage at 25±2°C and 60%±5% relative humidity (RH) or at 40±2°C and 75%±5% RH. In one embodiment, the aqueous pharmaceutical composition is a single-phase suspension which remains a single-phase suspension even after 12 or 24 months of storage at 25±2°C and 60%±5% RH or at 40±2°C and 75%±5% RH.

The term "stable" as used in connection with aqueous suspensions refers to a composition that, when shaken and then stored for at least 24 hours at ambient condition, does not show phase separation on visual inspection. Preferably, such stable composition does not show phase separation for a period of at least 3 days, or at least 5 days, or at least 7 days. In one aspect, the "stable" composition of the present invention shows, upon shaking (e.g., for 1 minute) and visual inspection, no lump formation and a total impurity content of no more than 1.0% after storage at ambient conditions (at about 25°C and a relative humidity of about 60%) for a period of at least 6 months.

In the context of the present invention, the drug content and impurities can be determined by various analytical techniques such as HPLC, LC-MS, TLC and the like.

It was observed that when various pharmaceutical compositions for nasal administration comprising Amoxicillin Clavulanate were prepared, the compositions generally showed physical separation in the suspension composition. This physical instability further leads to lack of dose uniformity. Surprisingly, it was found that addition of a Suspending agent at certain concentrations (e.g. at a concentration of at least about 0.1% w/v) mention in the suspension composition yielded a physically stable composition (with no separation) suitable for nasal administration.

Another embodiment is a stable fixed-dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human and/or an animal, where the composition comprises (1) about 0.001% w/v to about 4.87% w/v amoxicillin, (2) 0.001% w/v to about 2.13% w/v clavulanate, (3) about 0.5% w/v to about 2% w/v chitosan, (4) about 0.5 w/v to 0.2% w/v Polyvinyl alcohol (5) about 0.1% w/v to about 0.5% w/v EDTA, (6) about 0.1% w/v to about 1% w/v Polysorbate 80, (7) about 1% w/v to about 2% w/v Poloxamer 407, (8) about 0.1% w/v to about 1% w/v carbopol, (9) about 0.1-0.5% w/v Xanthan gum, (10) about 1% w/v to about 5% w/v Glycerine, (11) about 0.05% w/v to about 0.1% w/v Citric acid.

Yet another embodiment is a stable fixed-dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human and/or an animal, where the composition comprises about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate, about 0.5 w/v to 0.2% w/v Polyvinyl alcohol, about 0.1% w/v to about 0.5% w/v EDTA, about 0.1% w/v to about 1% w/v Polysorbate 80, about 1% w/v to about 2% w/v Poloxamer 407, about 0.1% w/v to about 1% w/v carbopol, about 0.1-0.5% w/v Xanthan gum, about 1% w/v to about 5% w/v Glycerine, about 0.05% w/v to about 0.1% w/v Citric acid.

Yet another embodiment is a stable fixed-dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human and/or an animal, comprising about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate, about 0.5 w/v to 0.2% w/v Polyvinyl alcohol, about 0.1% w/v to about 0.5% w/v EDTA, about 0.1% w/v to about 1% w/v Polysorbate 80, about 1% w/v to about 2% w/v Poloxamer 407, about 0.1% w/v to about 1% w/v carbopol, about 0.1-0.5% w/v Xanthan gum, about 1% w/v to about 5% w/v Glycerine, about 0.05% w/v to about 0.1% w/v Citric acid. Chitosan may be present at a concentration of at least about 0.5% w/v, or preferably between about 0.5% w/v and about 2% w/v of the composition.

Yet another embodiment is a stable fixed-dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human and/or an animal, comprising about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate, about 0.5 w/v to 0.2% w/v Polyvinyl alcohol, about 0.1% w/v to about 0.5% w/v EDTA, about 0.1% w/v to about 1% w/v Polysorbate 80, about 1% w/v to about 2% w/v Poloxamer 407, about 0.1% w/v to about 1% w/v carbopol, about 0.1-0.5% w/v Xanthan gum, about 1% w/v to about 5% w/v Glycerine, about 0.05% w/v to about 0.1% w/v Citric acid. Chitosan may be present at a concentration of at least about 0.5% w/v, or preferably between about 0.5% w/v and about 1% w/v of the composition.

Yet another embodiment is a stable fixed-dose aqueous pharmaceutical composition in the form of suspension (e.g., contained in a container) for nasal administration to a human and/or an animal, comprising Amoxicillin, Clavulanate, Polyvinyl alcohol, EDTA, Polysorbate 80, Poloxamer 407, Carbopol, Xanthan gum, Glycerine, Citric acid, a Mucoadhesive (e.g., at a concentration of at least about 0.5% w/v of the composition), and a pharmaceutically acceptable excipient.

It will also be appreciated by the skilled artisan that in order to improve the physical properties, appearances, or smells of the composition of the present invention, one or more further pharmaceutically acceptable excipients may be added as desired. Suitable pharmaceutically acceptable excipients include, but are not limited to, chelating agents, preservatives, surfactants, suspending agents, humectants, pH-adjusting agents, and any combination of any of the foregoing.

Edetate disodium (EDTA) is included in the formulation primarily as a chelating agent due to its ability to bind divalent metal ions such as calcium and magnesium, which play a critical role in stabilizing bacterial cell walls and biofilm structure. In addition to its chelating properties, EDTA also exhibits a significant biofilm-disrupting activity, effectively breaking down the extracellular polymeric substances (EPS) that form the structural matrix of bacterial biofilms. This dual functionality enhances the overall antimicrobial efficacy of the nasal spray formulation by improving penetration and activity of the active pharmaceutical ingredients against biofilm-embedded bacteria. The concentration of EDTA in the aqueous nasal spray suspension ranges from approximately 0.1% w/v to 0.5% w/v, relative to the total weight of the composition, ensuring optimal performance without compromising the safety or stability of the formulation. Examples of such suitable chelating agents which can be employed in the aqueous nasal spray suspension include, but are not limited to, edetate disodium (EDTA), edetate trisodium, edetate tetrasodium, and diethyleneamine pentaacetate, preferably EDTA.

Examples of suitable sweetener/taste masking agents that can be employed in the aqueous nasal spray suspension include, but are not limited to, sucralose, thaumatin (e.g., Talin(R)), sucrose, saccharin (including salt forms such as sodium and calcium salts), fructose, glucose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, neotame, mannitol, eucalyptus oil, camphor, and natural or artificial flavors or flavoring agents (for example, menthol, mints, vanilla, orange, etc.), or combinations of two or more of such agents. A particularly preferred taste-masking agent is sucralose. The amount of the sweetener/taste masking agent present in the aqueous nasal spray suspension may range from about 0.01% to about 1% w/w relative to the total weight of the composition.

Examples of suitable Biofilm disrupting agents that can be employed in the aqueous nasal spray suspension include Chitosan, EDTA, Polysorbate 80, Glycerin, Citric acid.

Examples of suitable pH adjusting agent that can be employed in the aqueous nasal spray suspension include, Citric acid. The suspension of the present invention may comprise an amount of pH adjusting agent sufficient to maintain the pH of the composition from about 6.1 to about 7.1. Preferably, the amount of buffer ranges from about 0.05% to about 1% w/v relative to the total weight of the composition.

Examples of suitable Surfactants include Polysorbate 80. The amount of surfactant present in the aqueous nasal spray composition may range from about 0.1% w/v to about 1% w/v relative to the total weight of the composition.

Examples of suitable humectants that can be employed in the aqueous nasal spray suspension include, but are not limited to, glycerin, sorbitol, polyethylene glycol, propylene glycol, or mixtures thereof, which are mixed with a suitable humectant vehicle such as water. The amount of humectant present in the aqueous nasal spray suspension may range from about 1% to about 5% w/v relative to the total weight of the composition

Suitable pH-adjusting agents include, Citric acid. In the context of the present invention, the pharmaceutically stable fixed-dose suspension composition for nasal administration may have a pH of between about 5.5 and about 7.1, or between about 5.5 and about 6.7.

The osmolality of the composition may range between about 200 mOsm/kg and about 400 mOsm/kg, or about 250 mOsm/kg and about 350 mOsm/kg. The viscosity of the composition may be about 10 cps to about 200 cps, or preferably from about 20 cps to about 150 cps.

In yet another aspect, the pharmaceutical composition in the form of suspension contains Amoxicillin Clavulanate particles having a mean particle size in the range of about 10 µm to about 100 µm, or preferably from about 10 µm to about 50 µm. The suspension pharmaceutical composition of the present invention has a mean particle size of less than 50 µm when determined by microscopy technique.

In yet another aspect, the pharmaceutical composition, when delivered as a nasal spray, has a spray pattern with a longest axis of about 15–75 mm, a shortest axis of about 10-65 mm, and an ellipticity of about 1-2.

In the context of the present invention, the viscosity can be determined by various known instruments, such as a dynamic stress rheometer or Brookfield viscometer. In a preferred embodiment, the viscosity is determined by a Brookfield viscometer by measuring torque transmission through a sample using a rotating spindle.

In another embodiment, the present invention relates to a stable, fixed-dose, aqueous pharmaceutical composition (e.g., contained in a container) for nasal administration to a human and/or an animal, where the composition comprises about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate, and a Suspending agent which comprises Polyvinyl alcohol at a concentration of about 0.5% w/v to about 2% w/v of the composition, wherein the composition has a pH between about 5.5 and about 7.1.

Yet another embodiment is a stable fixed-dose pharmaceutical composition in the form of suspension (e.g., contained in a container) for nasal administration to a human and/or an animal, comprising Amoxicillin at about 0.05-3.53% w/v and Clavulanate at about 0.001%- 2.13% and a Suspending agent which comprises Polyvinyl alcohol at a concentration of about 0.5%-2% w/v of the composition, wherein the composition has a pH between about 5.5 and about 7.1..

Preferably, the suspensions of the present invention have only one phase (i.e., they are preferably a single-phase suspension).

In a further embodiment, the present invention relates to a kit comprising a stable fixed-dose, aqueous pharmaceutical composition of the present invention contained in a container for nasal administration and a package insert containing instructions about the use of said pharmaceutical composition. In one preferred embodiment, the container is part of a sprayer which has an actuator. When the actuator is actuated, the composition is delivered in the form of a spray.

In a further embodiment, the pharmaceutical composition is contained in a sprayer and has, upon delivery, a spray of the composition to a human and/or an animal nose, a spray pattern having a longest axis of 15–75 mm, a shortest axis of 10-65 mm, and an ellipticity of 1-2.

In the context of the present invention, the pharmaceutical composition, when delivered as a nasal spray using a sprayer, yields a specific spray pattern and spray droplet size. The spray pattern can be determined by various known techniques, such as with an ADSA with NSPUA set up (Innova System) and the spray droplet size distribution can be determined by various known techniques, such as with a Malvern Spraytec with NSPUA set up (Innova System).

The following describes a typical procedure for characterizing droplet size distribution of the spray: The sprayer is loaded with a composition as described above and primed by an actuating pump via an actuator until a fine mist appears out of the nozzle of the sprayer. A commercially available laser diffraction instrument is arranged so that the nozzle is about 3 cm or 6 cm below the laser beam of the laser diffraction instrument. The pump is actuated with a conventional mechanical actuator using a constant force. The resulting spray of the composition crosses the laser beam. Data are collected for D10, D50, D90, SPAN, and % Volume <10 µm. The average values for each of these parameters for three sprays are calculated.

One embodiment is a stable fixed-dose aqueous pharmaceutical composition comprising Amoxicillin Clavulanate, and a suspending agent contained in a sprayer, wherein each spray of the aqueous pharmaceutical composition provides (i) Amoxicillin equivalent to about 2.5 mg and Clavulanate equivalent to about 0.8 mg.

Another embodiment is a method for treating post-surgical nasal infections, or for administering amoxicillin clavualanate. The method includes spraying a stable, fixed-dose aqueous pharmaceutical composition comprising Amoxicillin Clavulanate, a suspending agent such that each spray of the aqueous pharmaceutical composition provides Amoxicillin equivalent to about 1.25 mg and Clavulanate equivalent to about 0.6 mg.

Yet another embodiment is a stable fixed-dose aqueous pharmaceutical composition comprising Amoxicillin Clavulanate, and a Suspending agent contained in a sprayer, wherein each spray of the aqueous pharmaceutical composition provides Amoxicillin equivalent to about 0.8 mg and Clavulanate equivalent to about 0.35 mg.

Yet another embodiment is a method for treating post-surgical nasal infections, or for administering amoxicillin clavulanate. The method includes spraying a stable, fixed-dose aqueous pharmaceutical composition comprising Amoxicillin Clavulanate, and a suspending agent such that each spray of the aqueous pharmaceutical composition Amoxicillin equivalent to about 0.4 mg and Clavulanate equivalent to about 0.175 mg.

The aqueous nasal spray suspension can be administered as a drop or in any other form suitable for topical administration. The composition may also be administered using a nasal tampon or a nasal sponge.

In a preferred embodiment, the aqueous suspension is provided in the form of nasal spray, wherein the suspension is administered in a single unit-dose container or multi-dose container. Suitable single-unit-dose containers or multi-dose containers include, but are not limited to, glass, aluminum, polypropylene, or high-density polyethylene. For example, high-density polyethylene containers are produced using a blow-fill-seal manufacturing technique.

In certain additional embodiments, the invention provides a multi-dose composition of matter, comprising: (a) a multi-unit dosage of a pharmaceutical composition of the present invention; and (b) a container comprising: (i) a chamber holding the multi-dose of the composition and having an opening wherein the dosage exits the opening unpon actuation; (ii) actuator and (iii) a closure mechanism removably attached to the opening of the chamber. In certain embodiments, the multi-dose container is made of a moldable polymer.

The present invention also relates to a method of treating post-surgical nasal infections and other nasal infections in a human and/or an animal in need thereof, comprising administering by the nasal route a stable fixed dose of the aqueous pharmaceutical composition of the present invention. For example, the pharmaceutical composition that may be contained in a container comprises about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate, about 0.5% w/v to about 2% w/v chitosan, about 0.5 w/v to 0.2% w/v Polyvinyl alcohol, about 0.1% w/v to about 0.5% w/v EDTA, about 0.1% w/v to about 1% w/v Polysorbate 80, about 1% w/v to about 2% w/v Poloxamer 407, about 0.1% w/v to about 1% w/v carbopol, about 0.1-0.5% w/v Xanthan gum, about 1% w/v to about 5% w/v Glycerine, about 0.05% w/v to about 0.1% w/v Citric acid.

In a further embodiment, the present invention relates to the use of about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate, about 0.5% w/v to about 2% w/v chitosan, about 0.5 w/v to 0.2% w/v Polyvinyl alcohol, about 0.1% w/v to about 0.5% w/v EDTA, about 0.1% w/v to about 1% w/v Polysorbate 80, about 1% w/v to about 2% w/v Poloxamer 407, about 0.1% w/v to about 1% w/v carbopol, about 0.1-0.5% w/v Xanthan gum, about 1% w/v to about 5% w/v Glycerine, about 0.05% w/v to about 0.1% w/v Citric acid, in the preparation of a stable fixed dose, aqueous pharmaceutical composition (e.g., contained in a container) for the treatment of Post-surgical nasal infections in a human and/or an animal in need thereof. Any pharmaceutical composition described herein may be used.

In a further embodiment, the present invention relates to a stable fixed-dose, aqueous pharmaceutical composition (e.g., contained in a container) for nasal administration comprising about 0.001% w/v to about 4.87% w/v amoxicillin, 0.001% w/v to about 2.13% w/v clavulanate, about 0.5% w/v to about 2% w/v chitosan, about 0.5 w/v to 0.2% w/v Polyvinyl alcohol, about 0.1% w/v to about 0.5% w/v EDTA, about 0.1% w/v to about 1% w/v Polysorbate 80, about 1% w/v to about 2% w/v Poloxamer 407, about 0.1% w/v to about 1% w/v carbopol, about 0.1-0.5% w/v Xanthan gum, about 1% w/v to about 5% w/v Glycerine, about 0.05% w/v to about 0.1% w/v Citric acid for the treatment of Post-surgical nasal infections in a human and/or an animal in need thereof.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore, the above description should not be construed as limiting but merely as exemplifications of preferred embodiments. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention.

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.
Suspension Composition Containing Amoxicillin clavulanate and Chitosan:
Formulation 1:
SN Components Concentration (w/v)
1 Amoxicillin 0.001-4.87%
2 Clavulanate 0.001-2.13%
3 Chitosan 0.5-2% w/v
4 Polyvinyl Alcohol 0.5-2% w/v
6 EDTA 0.1-0.5% w/v
7 Polysorbate 80 0.1-1% w/v
8 Poloxamer 407 1-2% w/v
9 Carbopol 0.1-1% w/v
10 Xanthan Gum 0.1-0.5% w/v
11 Glycerin 1-5% w/v
12 Citric acid 0.05-0.1% w/v
13 Purified water q.s. to 100%
Observations
Physical observation on standing for 24 hours. No phase separation Observed
Mean Particle size by microscopy between 10 – 100 µm.

SN Components Mild Infection (mg/100 µL) Moderate Infection (mg/100 µL) Severe Infection (mg/100 µL)
1 Amoxicillin 0.53 mg 0.8 mg 1.2 mg
2 Clavulanate 0.27 mg 0.4 mg 0.6 mg
3 Chitosan 1.0 mg 1.0 mg 1.0 mg
4 Polyvinyl Alcohol 1.5 mg 1.5 mg 1.5 mg
5 EDTA 0.2 mg 0.2 mg 0.2 mg
6 Polysorbate 80 0.5 mg 0.5 mg 0.5 mg
7 Poloxamer 407 1.5 mg 1.5 mg 1.5 mg
8 Carbopol 0.3 mg 0.3 mg 0.3 mg
9 Xanthan Gum 0.3 mg 0.3 mg 0.3 mg
10 Glycerin 2.0 mg 2.0 mg 2.0 mg
11 Citric Acid 0.075 mg 0.075 mg 0.075 mg
12 Purified Water q.s. to 100 µL q.s. to 100 µL q.s. to 100 µL

Manufacturing Steps:
1. Preparation of Chitosan Solution:
o Dissolve the required amount of chitosan (1.0 mg) in a small volume of purified water (acidified to pH 5.0 with citric acid) under gentle stirring.
o Allow the solution to hydrate for 2–3 hours or until fully dissolved.
2. Preparation of Polymer and Viscosity Enhancer Solution:
o In a separate vessel, dissolve polyvinyl alcohol (1.5 mg), poloxamer 407 (1.5 mg), carbopol (0.3 mg), and xanthan gum (0.3 mg) in a portion of purified water under constant stirring.
o Heat the solution to 50–60°C to ensure complete dissolution of the polymers.
o Cool the solution to room temperature before proceeding.
3. Preparation of Buffer and Stabilizing Solution:
o Dissolve citric acid (0.075 mg) and EDTA (0.2 mg) in a separate portion of purified water.
o Adjust the pH of the solution to 6.5–7.5 using sodium hydroxide or hydrochloric acid as needed.
4. Preparation of Surfactant Solution:
o Dissolve polysorbate 80 (0.5 mg) and glycerin (2.0 mg) in purified water under gentle stirring.
5. Incorporation of Active Pharmaceutical Ingredients (APIs):
o Add amoxicillin (0.53 mg) and clavulanate (0.27 mg) to the polymer-viscosity enhancer solution (from Step 2) under stirring until fully dissolved.
6. Combination of Solutions:
o Gradually combine the chitosan solution (Step 1), buffer solution (Step 3), and surfactant solution (Step 4) into the API-polymer solution (Step 5).
o Use a high-shear homogenizer for 5–10 minutes to ensure a uniform suspension.
7. Filtration:
o Pass the combined solution through a 0.22 µm sterile filter to remove any particulate matter and ensure sterility.
8. Filling into Nasal Spray Devices:
o Fill the sterile filtered suspension into pre-sterilized metered-dose nasal spray devices under a laminar flow hood.
o Each spray is calibrated to deliver 100 µL per actuation.
9. Final Checks:
o Perform pH and viscosity measurements to ensure the formulation is within specified ranges.
o Check for uniformity and absence of phase separation by visual inspection.
o Perform microbiological testing to confirm sterility.
Stability Studies: The composition was subjected to stability studies under different conditions. The results were documented.
Container Details: The final product was packaged in a sprayer containing an HDPE bottle, crimped with a pump, and fitted with an actuator and cap.

Stability Study Data
Initial 3 months 6 months
Test Ex. 1 Ex. 1 Ex. 1
Stability condition (25° C. ± 2° C. & 60% RH ± 5% RH)
pH 6.5 6.5 6.5
Osmolality (mOsm)* 302 305 310
Viscosity (cps)** 35.5 40.3 40.2
Weight per ml (g/ml) 1.04 1.025 1.011
Assay of Amoxicillin Clavulanate (% w/w) 101.6 100.4 99.5
Related substances for Amoxicillin Clavulanate
Impurity A (%) 0.021 0.04 0.12
Any other impurity (%) 0.08 0.03 0.06
Total impurities (%) 0.101 0.180
Spray Pattern (at 6 cm)
Major Axis (mm) 58 68 62
Minor Axis (mm) 55 63 57
Ellipticity 1 1.1 1.1
Droplet size distribution (at 6 cm)
D10 (µm) 18.81 20.18 19.35
D50 (µm) 39.37 38.36 38.28
D90 (µm) 74.33 80.02 76.11
SPAN 1.41 1.56 1.48
Stability condition (40° C. ± 2° C. & 75% RH ± 5% RH)
pH 6.5 6.5 6.5
Osmolality (mOsm) 301 302 300
Viscosity (cps) 36.5 40.3 41.15
Weight per ml (g/ml) 1.011 1.018 1.012
Assay of Amoxicillin Clavulanate 99.7 99.8 99.8
Related Substances for Amoxicillin Clavulanate
Impurity A (%)
Any other impurity (%) 0.02 0.022 0.028
Total impurities (%) 0.25 0.31 0.60
Spray Pattern (at 6 cm)
Major Axis (mm) 52 61 56
Minor Axis (mm) 48 56 50
Ellipticity 1.2 1.2 1.2
Droplet size distribution (at 6 cm)
D10 (µm) 21.91 21.39 20.15
D50 (µm) 39.19 38.39 37.29
D90 (µm) 76.46 71.49 69.21
SPAN 1.2 1.2 1.3
*Determined by Advanced Instruments Osmometer (Model 3250).
**Determined by Brookfield viscometer.

Suspension Composition Containing Amoxicillin Clavulanate and Hydroxypropyl Methylcellulose:
Formulation 2:
SN Ingredient Concentration (w/v)
1 Amoxicillin 0.001-4.87%
2 Clavulanate 0.001-2.13%
3 Hydroxypropyl Methylcellulose (HPMC) 0.5%-2%
4 Magnesium Stearate 0.1%-0.3%
6 Polysorbate 80 0.05%-0.1%
7 N-Acetylcysteine (NAC) 0.1%-0.5%
8 Glycerine 2%-5%
9 Citric acid 0.1%-0.3%
10 Purified Water Q.S. to 100%
Observations
Physical observation on standing for 24 hours. No phase separation Observed
Mean Particle size by microscopy between 10 – 100 µm.

Manufacturing Procedure:
• Preparation of HPMC Solution:
• Gradually disperse HPMC (0.5–2% w/v) into purified water under stirring to avoid clumping.
• Heat the mixture to 60–70°C to dissolve the polymer completely.
• Allow the solution to cool to room temperature.
• Preparation of Stabilizer and Buffer Solution:
• Dissolve citric acid (0.1–0.3% w/v) and N-acetylcysteine (0.1–0.5% w/v) in a separate portion of purified water under gentle stirring.
• Incorporation of Surfactant:
• Add polysorbate 80 (0.05–0.1% w/v) to the stabilizer solution while stirring continuously to ensure uniform dispersion.
• Preparation of API Solution:
• Dissolve amoxicillin (0.001–4.87% w/v) and clavulanate (0.001–2.13% w/v) in purified water.
• Add the API solution to the buffer-stabilizer solution (from Step 2) under continuous stirring.
• Incorporation of Magnesium Stearate:
• Disperse magnesium stearate (0.1–0.3% w/v) into the HPMC solution (Step 1) using a high-shear homogenizer to ensure even distribution.
• Combination of Solutions:
• Gradually combine the API-buffer solution (Step 4) and the HPMC-magnesium stearate solution (Step 5).
• Mix using a high-shear homogenizer for 10–15 minutes to form a uniform suspension.
• Adjustment of Viscosity and pH:
• Add glycerine (2–5% w/v) to the combined solution and adjust the pH to 6.5–7.5 using sodium hydroxide or hydrochloric acid as required.
• Filtration:
• Pass the final formulation through a 0.22 µm sterile filter to ensure sterility and remove particulates.
• Filling into Nasal Spray Devices:
• Under a laminar flow hood, fill the sterile filtered suspension into pre-sterilized metered-dose nasal spray devices.
• Each spray should deliver 100 µL per actuation.

Container Details: The final formulation was packaged in a sprayer containing an HDPE bottle, crimped with a pump, and fitted with an actuator and cap.

Stability Study Data
Initial 3 months 6 months
Test Ex. 3 Ex. 3 Ex. 3
Stability condition (25° C. ± 2° C. & 60% RH ± 5% RH)
pH 6.5 6.5 6.5
Osmolality (mOsm)* 303 306 308
Viscosity (cps)** 34.5 40.3 41.9
Weight per ml (g/ml) 1.08 1.021 1.026
Assay of Amoxicillin Clavulanate 100.1 99.9 99.52
Related substances for Amoxicillin Clavulanate
Impurity A (%) 0.01 0.08 0.11
Any other impurity (%) 0.06 0.031 0.052
Total impurities (%) 0.07 0.11 0.16
Spray Pattern (at 6 cm)
Major Axis (mm) 55 61 56
Minor Axis (mm) 48 55 52
Ellipticity 1.2 1.2 1.2
Droplet size distribution (at 6 cm)
D10 (µm) 19.81 19.26 20.83
D50 (µm) 39.42 36.56 39.34
D90 (µm) 78.36 74.68 81.42
SPAN 1.48 1.51 1.54
Stability condition (40° C. ± 2° C. & 75% RH ± 5% RH)
pH 3.65 3.74 3.84
Osmolality (mOsm) 310 315 318
Viscosity (cps) 124.2 129.6 127.9
Weight per ml (g/ml) 1.015 1.017 1.015
Assay of Amoxicillin Clavulanate (% w/w) 100.4 99.8 98.79
Related Substances for Amoxicillin Clavulanate
Impurity A (%) 0.03 0.18 0.12
Any other impurity (%) 0.06 0.07 0.07
Total impurities (%) 0.09 0.25 0.19
Spray Pattern (at 6 cm)
Major Axis (mm) 48 54 54
Minor Axis (mm) 40 48 44
Ellipticity 1.2 1.3 1.6
Droplet size distribution (at 6 cm)
D10 (µm) 12.22 12.67 13.1
D50 (µm) 36.48 39.88 39.34
D90 (µm) 80.33 77.18 78.16
SPAN 1.8 1.6 1.6

Suspension Composition Containing Amoxicillin Clavulanate and Sodium hyaluronate:
Formulation 3:
SN Ingredient Concentration(w/v)
1 Amoxicillin 0.001-4.87%
2 Clavulanate 0.001-2.13%
3 Sodium Hyaluronate 0.1%-0.5%
4 Xantham Gum 0.2%-0.4%
6 N-Acetylcysteine 0.1%-0.5%
7 Magnesium Stearate 0.1%-0.3%
8 Polysorbate 80 0.05%-0.1%
9 Calcium chloride 0.05%-0.1%
10 Citric acid 0.1%-0.3%
11 Sodium Chloride 0.5%-0.9%
12 Purified water Q.S. to 100%
Observations
Physical observation on standing for 24 hours. No phase separation Observed
Mean Particle size by microscopy between 10 – 100 µm.

1. Preparation of Stabilizer Solution:
o Dissolve citric acid (0.1–0.3% w/v), sodium chloride (0.5–0.9% w/v), and calcium chloride (0.05–0.1% w/v) in purified water under gentle stirring.
2. Preparation of Mucoadhesive and Thickening Agents:
o Gradually add sodium hyaluronate (0.1–0.5% w/v) and xanthan gum (0.2–0.4% w/v) to a separate portion of purified water under constant stirring to avoid clumping.
o Allow the mixture to hydrate for 1–2 hours until fully dissolved and homogenous.
3. Incorporation of N-Acetylcysteine (NAC):
o Dissolve NAC (0.1–0.5% w/v) into the stabilizer solution (from Step 1) while stirring gently.
4. Addition of Surfactant and Lubricant:
o Add polysorbate 80 (0.05–0.1% w/v) and magnesium stearate (0.1–0.3% w/v) to the mucoadhesive-thickener solution (from Step 2).
o Homogenize the solution using a high-shear homogenizer for 10 minutes to ensure uniform dispersion.
5. Incorporation of Active Ingredients (APIs):
o Dissolve amoxicillin (0.001–4.87% w/v) and clavulanate (0.001–2.13% w/v) in purified water under stirring.
o Combine the API solution with the stabilizer-thickener mixture under continuous stirring.
6. Combination of All Solutions:
o Gradually combine the API-stabilizer mixture (Step 5) with the surfactant-thickener solution (Step 4).
o Homogenize the final mixture for 10–15 minutes to form a uniform suspension.
7. Adjustment of pH:
o Measure the pH of the suspension and adjust it to 6.5–7.5 using sodium hydroxide or hydrochloric acid, as required.
8. Sterile Filtration:
o Pass the final suspension through a 0.22 µm sterile filter to ensure sterility and remove any particulate matter.
9. Filling into Nasal Spray Devices:
o Fill the sterile suspension into pre-sterilized metered-dose nasal spray devices under a laminar flow hood.
o Each spray should deliver 100 µL per actuation.

Pharmacokinetic Comparison of Amoxicillin Clavulanate Nasal Spray vs. Oral Amoxicillin Clavulanate for Treatment of Post-Surgical Nasal Infections
A pharmacokinetic comparison between amoxicillin clavulanate nasal spray and oral amoxicillin clavulanate for the treatment of post-surgical nasal infections highlights significant differences in drug absorption, distribution, metabolism, and elimination when administered via these two routes. Understanding these differences is crucial for optimizing treatment strategies, particularly for targeting localized infections in the nasal cavity while minimizing systemic side effects.

Absorption
· Nasal Spray: Amoxicillin clavulanate nasal spray is designed to target localized infections in the nasal cavity, particularly those occurring post-surgery. The absorption process is enhanced by the wound affinity and wound adhesion properties, which allow the drug to remain in close contact with the affected tissues. This localized application minimizes systemic absorption, thereby reducing the risk of systemic side effects. The nasal mucosa provides a rapid absorption route directly into the affected area, leading to higher local drug concentrations where needed most.
· Oral: Oral amoxicillin clavulanate is absorbed through the gastrointestinal tract, with an approximate bioavailability of 60-70% for amoxicillin and 30-40% for clavulanate. Peak plasma concentrations are reached within 1-2 hours post-administration. Oral administration results in higher systemic exposure, which is necessary for treating widespread infections but increases the risk of systemic side effects, including gastrointestinal disturbances.

Distribution
· Nasal Spray: The distribution of amoxicillin clavulanate administered via nasal spray is highly localized, primarily concentrated within the nasal cavity at the site of Infection. The formulation is designed to ensure that the drug remains concentrated at the site of wound and infection, thereby maximizing its efficacy for treating post-surgical nasal infections. Due to the nasal spray's localized application, systemic distribution is minimal, which further reduces the likelihood of systemic side effects. This targeted distribution is particularly advantageous for managing infections where high local drug concentrations are required to effectively combat pathogens within the nasal passages.
· Oral: After absorption, amoxicillin and clavulanate are widely distributed throughout the body, with significant penetration into tissues and fluids. However, this broad distribution may not guarantee high concentrations in the nasal and sinus tissues specifically, potentially limiting its efficacy in treating localized post-surgical infections.

Metabolism and Elimination
· Nasal Spray: The elimination of amoxicillin clavulanate when administered via nasal spray is primarily localized, with minimal systemic absorption leading to reduced engagement of the body's systemic elimination pathways. The drug is largely retained within the nasal cavity and sinus tissues, where it can be metabolized locally or cleared through the mucociliary system. This localized elimination minimizes the burden on renal and hepatic systems, which is beneficial in reducing potential side effects associated with systemic drug clearance. The lower systemic absorption also means that less of the drug is available for excretion in urine or feces, making this route more suitable for localized infections that do not require widespread systemic treatment.
· Oral: Amoxicillin, when taken orally, is minimally metabolized and is primarily excreted unchanged in the urine, reflecting its systemic absorption and distribution. Clavulanate, on the other hand, undergoes some hepatic metabolism and is excreted in both urine and feces. The oral administration of amoxicillin clavulanate involves systemic metabolism and elimination, which is effective for treating widespread infections but may not be ideal for localized post-surgical nasal infections. The systemic elimination pathways are more engaged in oral administration, potentially leading to higher systemic side effects and less localized therapeutic effect within the nasal cavity.

Bioavailability and Efficacy
· Nasal Spray: The bioavailability of amoxicillin clavulanate in a nasal spray formulation is tailored for localized delivery, focusing on achieving high concentrations at the site of infection rather than in the systemic circulation. The bioavailability in this context is more about the efficiency of drug deposition and retention within the nasal cavity and surrounding tissues. Due to the wound affinity and wound adhesion, the drug remains in contact with the infected area for an extended period, which enhances local efficacy. While systemic bioavailability is lower compared to oral administration, this is an advantage for minimizing systemic side effects and focusing the therapeutic effect where it is most needed.
· Oral: Oral amoxicillin clavulanate has a systemic bioavailability that is crucial for treating infections that may extend beyond the local site. The bioavailability of amoxicillin is approximately 60-70%, and for clavulanate, it is around 30-40%. This systemic absorption is important for addressing infections in multiple body tissues, but it is less efficient in achieving therapeutic concentrations specifically within the nasal cavity. The broad tissue distribution of the oral formulation may dilute the drug's presence in the nasal tissues, potentially reducing its effectiveness for localized infections like those that occur post-surgery in the nasal area.

In Vivo Efficacy Study:
In a controlled in vivo study using New Zealand White rabbits, animals were fasted overnight before the experiment. The following day, two treatment groups were administered medications via different routes:
· Oral Administration: A solution of oral amoxicillin clavulanate was administered orally using a gavage and a graduated syringe. The dosage administered was 20 mg/kg (amoxicillin) + 5 mg/kg (clavulanate), with a dosage volume adjusted to ensure accurate delivery of both components.
· Intranasal Administration: For the intranasal study, 25 µl of the Amoxicillin Clavulanate Nasal Spray formulation was instilled into each nostril using a nasal spray. The dose administered was equivalent to 2.5 mg/kg (amoxicillin) + 1mg/kg (clavulanate), ensuring that each 25 µl delivered the appropriate amount of both components for effective local treatment.
This comparison demonstrates the potential advantages of using amoxicillin clavulanate nasal spray for treating post-surgical nasal infections, particularly in achieving high local drug concentrations with reduced systemic exposure.

Pharmacokinetics of Amoxicillin clavulanate Delivered as Nasal Spray in Human Volunteers:
The investigational study on amoxicillin clavulanate nasal spray in healthy volunteers demonstrated significant pharmacokinetic advantages for treating post-surgical nasal infections. Following intranasal administration, a dose of 0.53 mg was employed. This nasal spray was given as a treatment to prevent post-surgical nasal infections, aiming to reduce the incidence and severity of infections following nasal surgery.
The study revealed that amoxicillin and clavulanate achieved peak concentrations in the nasal mucosa swiftly due to the formulation's optimized properties for mucosal absorption. The rapid absorption can be attributed to the synergistic interaction of amoxicillin and clavulanate, coupled with the formulation's design to ensure effective permeation of the nasal tissues.
Notably, amoxicillin clavulanate exhibited sustained presence at the site of infection (wound), with an extended release and deposition upto 12 hours, indicating prolonged tissue penetration and retention. This extended half-life is particularly advantageous for maintaining therapeutic drug levels at the site of infection(wound), enhancing the efficacy of the spray in treating post-surgical nasal infections. The immediate antibacterial action of amoxicillin, combined with the extended retention facilitated by the mucoadhesive properties of the spray, ensures continuous therapeutic levels, reducing the need for frequent dosing.
Clinical observations indicated that the concentrations of amoxicillin and clavulanate in the nasal tissues were significantly above the minimum inhibitory concentration (MIC) for common pathogens associated with post-surgical infections, such as Staphylococcus aureus and Streptococcus pyogenes. This property not only enhances the immediate bactericidal effect but also aids in the disruption of bacterial biofilms, thereby preventing the recurrence of infection and reducing the likelihood of developing antibiotic resistance.
The efficacy of the amoxicillin clavulanate nasal spray was further evidenced by its ability to alleviate post-surgical symptoms such as nasal congestion, discharge, and pain more rapidly compared to systemic formulations. The formulation's mucoadhesive properties significantly enhanced drug retention within the nasal cavity, contributing to its effectiveness. These findings underscore the potential of amoxicillin clavulanate nasal spray to offer a more efficient and patient-friendly treatment for post-surgical nasal infections, with reduced risks of antibiotic resistance and minimal systemic side effects.
In vivo evaluation of sinonasal epithelial wound healing in New Zealand Rabbits:
The sinonasal epithelial wound healing was evaluated in rabbits. Circular wounds of uniform size were created on the sinonasal epithelium using a biopsy punch. The rabbits were divided into groups, including a control group, a standard treatment group(Oral amoxicillin clavulanate), a negative control, and groups treated with Dose 1, Dose 2, and Dose 3 of the amoxicillin-clavulanate nasal spray. The percentage of wound closure was calculated at defined intervals by imaging the wounds and analyzing the epithelial migration. Dose 3 demonstrated accelerated and superior wound healing compared to lower doses and the standard treatment(Oral amoxicillin clavulanate), emphasizing its therapeutic potential in sinonasal epithelial repair.
Invitro Evaluation of Wound Healing and Epithelial Regeneration in an Experimental Rabbit Model:
This procedure evaluates sinonasal epithelial wound healing by tracking morphological defect indices (MDI, MTI, ETI) over time under various conditions. The parameters were monitored to compare the efficacy of different treatments, including a control group, a standard treatment group, a negative control with inhibited healing, and three experimental doses of the amoxicillin-clavulanate nasal spray. Samples were analyzed over sequential time points to assess their effectiveness in reducing wound defects. The graph depicts a reduction in defect indices across time, with experimental doses showing comparable or improved healing outcomes relative to the (Oral amoxicillin clavulanate) treatment, and the negative control exhibiting slower progress. This highlights the potential of the nasal spray in promoting epithelial wound closure.

In vitro Evaluation of Wound Healing, Mucosal Thickness, and Ciliated Cell Index in an Experimental Rabbit Model:
The efficacy of various treatments in promoting sinonasal wound healing and tissue regeneration in an experimental rabbit model of mucosal injury was evaluated. Rabbits underwent mucosal injury induction, followed by the administration of a control, standard treatment(Oral amoxicillin clavulanate), or experimental doses of an amoxicillin-clavulanate nasal spray. The wound healing process was assessed over five postoperative weeks through the measurement of three key parameters:
Mean Defect Size Reduction (MDI): Dose 3 achieved the smallest defect size, indicating the most effective healing.
Mean Mucosal Thickness Index (MTI): Dose 3 consistently showed higher MTI values, signifying superior mucosal thickening.
Epithelial thickness index (ETI): Dose 3 consistently achieving higher ETI values, indicating greater epithelial thickening in an experimental rabbit model of mucosal injury.
Ciliated Cell Index (CCI): Dose 3 exhibited the highest values, reflecting enhanced epithelial regeneration and thickening.
Data were collected at weekly intervals to monitor the healing trajectory, emphasizing the potential of Dose 3 in accelerating wound closure, restoring mucosal integrity, and enhancing epithelial repair compared to control and standard treatment (Oral amoxicillin clavulanate).

In vivo evaluation of Tissue Epidermal Growth Factor Levels in Rats:
In this experimental setup, rats were used to assess tissue EGF levels as a marker of wound healing and epithelial regeneration. Various groups, including a control, a standard treatment (Oral amoxicillin clavulanate), a negative control, and experimental doses of the amoxicillin-clavulanate nasal spray, were tested. Dose 3 demonstrated tissue EGF levels comparable to the control group, indicating effective epithelial repair. The procedure likely involved administering treatments intranasally, followed by tissue extraction and EGF quantification using methods immunohistochemistry. Time points were selected to capture the dynamics of tissue healing, enabling comparative analysis of treatment efficacy in promoting EGF normalization.

In vitro Biofilm disruption study in New Zealand rabbit:
The In Vitro Biofilm Disruption Study graph evaluates the efficacy of an amoxicillin-clavulanate formulation enhanced with "ASrMaBd" technology in disrupting biofilms of S. pneumoniae. Biofilms were cultured for two days before treatment, and their live volume and bacterial viability were assessed 12 hours after administering Amoxicillin clavulanate nasal spray. The study revealed dose-dependent effects, with higher doses (Dose 1 to Dose 3) progressively reducing live biofilm volume and increasing dead biofilm volume in a New Zealand rabbit model. The technology-enhanced formulation facilitated deeper diffusion of amoxicillin-clavulanate into the biofilm, significantly compromising its structural integrity and bacterial survival. These results highlight the formulation's potential in targeting resistant biofilms effectively.
In Vivo Biofilm Disruption Study in New Zealand Rabbits:
The In Vivo Biofilm Disruption Study graph illustrates the effectiveness of treatments in reducing biofilm thickness in S. pneumoniae-infected New Zealand rabbit sinusitis models. The study compared oral azithromycin with the experimental Amoxicillin clavulanate nasal spray. Post-infection, rabbits were treated, and sputum samples were collected at hourly intervals to monitor biofilm formation and bacterial viability. Confocal Laser Scanning Microscopy (CLSM) was employed to measure biofilm thickness
The graph indicates a progressive decrease in biofilm thickness from Dose 1 to Dose 3 in the Amoxicillin clavulanate nasal spray group, highlighting its superior ability to disrupt biofilms compared to azithromycin. This demonstrates the nasal spray’s potential as an effective targeted treatment for bacterial sinusitis, promoting enhanced bacterial eradication in the infected sinus.

In vivo Sustained release study in New Zealand rabbits:
The sustained release profile of an amoxicillin-clavulanate nasal spray over a 12-hour period, tested in a New Zealand Rabbit model. This study involves 4 groups: Standard (Oral amoxicillin clavulanate), and three varying doses (Dose 1, 2, and 3) of the test product, with five animals per group. The experimental design incorporates comparative analysis of different doses of test product (amoxicillin clavulanate nasal spray) against Oral amoxicillin clavulanate nasal spray and to evaluate drug release dynamics in vivo. Nasal fluid samples were collected from rodents at predetermined intervals over 12 hours to measure drug concentration and release rate. The results highlight a gradual and sustained release across time, with higher doses demonstrating superior release profiles compared to the standard group. This model underscores the product's potential for effective and prolonged nasal drug delivery.

Invitro Mucoadhesion study in porcine model:
The study evaluates the mucoadhesive properties of Amoxicillin clavulanate Nasal Spray using an in vitro Porcine Mucin Model. Two parameters, Adhesive Work (Fig. 8) and Adhesive Force (Fig. 9), were analyzed across 4 groups: Standard(Amoxicillin plain spray) and Test Groups 1–4 (n=5 per group). The experiment employed a texture analyzer, where a 2500 mN preload was applied to the nasal spray sample for 3 minutes. Following this, a cylinder probe with the Amoxicillin clavulanate nasal spray was lifted at a speed of 2.5 mm/min to detach the sample from the mucin surface. The results show a progressive increase in adhesive work and adhesive force from Dose 1 to Dose 3, demonstrating dose-dependent mucoadhesion. These findings underline the strong binding capability of Amoxicillin clavulanate nasal spray, which could enhance retention in nasal applications.

In vivo deposition study in New Zealand rabbits:
The deposition study for Amoxicillin-Clavulanate Nasal Spray was conducted to evaluate its efficacy in enhancing drug deposition in the paranasal and maxillary sinuses. This in vivo experiment utilized New Zealand White (NZW) rabbits (n=6) as the test species. The nasal spray formulation was administered intranasally, and drug deposition in the sinuses was assessed over a time course of 0 to 12 hours. Deposition levels were determined using high-sensitivity liquid chromatography-tandem mass spectrometry (LC-MS/MS). The experimental design included comparative groups: the amoxicillin-clavulanate nasal spray and standard(Oral amoxicillin clavulanate). The study aimed to measure and compare the drug concentration achieved in the wound tissues, hypothesizing a statistically significant increase in deposition with the amoxicillin-clavulanate formulation compared to the standard. This approach highlights the potential of the nasal spray to improve localized antibiotic delivery effectively.

,CLAIMS:5. CLAIMS
I/We Claim:

1. A nasal spray pharmaceutical formulation comprising:
amoxicillin: 0.001–4.87% w/v
clavulanate: 0.001–2.13% w/v
chitosan: 0.5–2% w/v
polyvinyl alcohol: 0.5–2% w/v
EDTA: 0.1–0.5% w/v
polysorbate 80: 0.1–1% w/v
poloxamer 407: 1–2% w/v
carbopol: 0.1–1% w/v
xanthan gum: 0.1–0.5% w/v
glycerin: 1–5% w/v
citric acid: 0.05–0.1% w/v
purified water: q.s. to 100%.
2. A nasal spray pharmaceutical formulation comprising between about 0.40 mg and about 4.8 mg of amoxicillin and 0.05 mg and about 2.1 mg of clavulanate, or a respective salts thereof, in a multi-dose of the nasal spray pharmaceutical formulation.
3. The nasal spray pharmaceutical formulation of claim 1, wherein intranasal administration of a single dose of the nasal spray pharmaceutical formulation to a subject provides amoxicillin clavulanate concentration that is efficacious for eliminating nasal bacterial infections.
4. The nasal spray pharmaceutical formulation as claimed in claim 1, wherein the composition has a pH in the range of 5.1 to about 7.1.

5. The nasal spray pharmaceutical formulation as claimed in claim 1, wherein the composition is stable for at least 12 months at 25°C and 60% relative humidity.

6. The nasal spray pharmaceutical formulation as claimed in claim 1, wherein the composition is formulated as a nasal spray.

7. The nasal spray pharmaceutical formulation as claimed in claim 1, wherein the intranasal administration of a single dose of the nasal spray pharmaceutical formulation to a subject provides amoxicillin clavulanate concentration that is efficacious for the eliminate nasal bacterial infections.
8. The nasal spray pharmaceutical formulation as claimed in claim 1, wherein a dose of the formulation is about 100 µl.
9. The nasal spray pharmaceutical formulation as claimed in claim 1, wherein mucoadhesive polymer chitosan enhances drug retention in the nasal cavity upon administration.
10. The nasal spray pharmaceutical formulation as claimed in claim 1 has a viscosity of 1,000–3,000 cps, ensuring optimal deposition in the nasal cavity.
11. The nasal spray pharmaceutical formulation as claimed in claim 1disrupts bacterial biofilms in the sinus cavity through the combined action of amoxicillin, clavulanate, and chitosan.
12. The nasal spray pharmaceutical formulation as claimed in claim 1is dispensed as droplets with a particle size between 10–20 µm, suitable for effective nasal deposition and sinus penetration.
13. The nasal spray pharmaceutical formulation as claimed in claim 1, is an aqueous suspension suitable for targeted drug release at the sinus infection site.
14. The nasal spray pharmaceutical formulation as claimed in claim 1, wherein the inclusion of poloxamer 407 and carbopol enables sustained release of the active pharmaceutical ingredients for a duration of 8 to 24 hours.
15. The nasal spray pharmaceutical formulation as claimed in claim 1, wherein the inclusion of mucoadhesive polymer chitosan increases the residence time of the formulation in the nasal cavity by at least 30% compared to a non-mucoadhesive formulation.
16. The nasal spray pharmaceutical formulation as claimed in claim 1, wherein the combination of amoxicillin, clavulanate, and chitosan disrupts bacterial biofilms by penetrating the biofilm matrix and inhibiting bacterial adhesion within the sinus cavities.
17. The nasal spray pharmaceutical formulation as claimed in claim 1, wherein the dosage is tailored for:
Mild Infections: 0.53 mg/100 µL of amoxicillin and 0.27 mg/100 µL of clavulanate;
Moderate Infections: 0.8 mg/100 µL of amoxicillin and 0.4 mg/100 µL of clavulanate;
Severe Infections: 1.2 mg/100 µL of amoxicillin and 0.6 mg/100 µL of clavulanate.
18. A method of treating a post-surgical nasal infection in a human or animal, comprising:
(a) providing an aqueous pharmaceutical suspension comprising: (i) about 0.001% w/v to about 4.87% w/v amoxicillin; (ii) about 0.001% w/v to about 2.13% w/v clavulanate; (iii) chitosan; (iv) polyvinyl alcohol; (v) EDTA; (vi) polysorbate 80; (vii) poloxamer 407; (viii) carbopol; (ix) xanthan gum; (x) glycerin; and (xi) citric acid;
(b) administering said suspension nasally to the subject in an amount effective to treat the post-surgical nasal infection.

19. The method of claim 18, wherein the post-surgical nasal infection is selected from the group consisting of sinusitis, rhinitis, rhinosinusitis, nasal vestibulitis, furunculosis, and septal abscess.

20. A method for preparing a nasal spray formulation comprising:
providing a chitosan solution comprising chitosan dissolved in an aqueous acidic solution;
providing a polymer solution comprising polyvinyl alcohol, poloxamer 407, carbopol, and xanthan gum dissolved in water;
providing a buffer solution comprising citric acid and EDTA dissolved in water, wherein the pH of the buffer solution is adjusted to between 6.5 and 7.5;
providing a surfactant solution comprising polysorbate 80 and glycerin dissolved in water;
providing an active pharmaceutical ingredient (API) solution comprising amoxicillin and clavulanate potassium dissolved in the polymer solution;
combining the chitosan solution, polymer solution, the buffer solution, and the surfactant solution with the API solution;
homogenizing the combined solution using a high-shear homogenizer;
filtering the homogenized solution through a 0.22 µm sterile filter; and
filling the sterile filtered solution into metered-dose nasal spray devices.

21. Use of the composition of any one of claims 1-20 for the manufacture of a medicament for the treatment of post-surgical nasal infections in a human or animal.

22. A kit comprising:
a) a container containing the composition of any one of claims 1-18; and
b) instructions for use of the composition.

6. DATE AND SIGNATURE

Dated this 29th day of December 2024
Signature

(Mr. Srinivas Maddipati)
IN/PA 3124
Agent for Applicant.