DESC:4. DESCRIPTION
Technical Field of the Invention

The present invention pertains to the interdisciplinary domain of pharmaceutical formulations, drug delivery systems, and otolaryngology, specifically focusing on the innovative application of an azithromycin-based nasal spray for the efficacious management of bacterial sinusitis. This invention introduces a specialized formulation comprising azithromycin, a broad-spectrum macrolide antibiotic, optimized for nasal administration to directly target the sinuses, thereby providing a localized, potent treatment modality for bacterial infections of the sinus cavities.

Background of the Invention

Sinusitis, also known as a sinus infection or rhino-sinusitis, is inflammation of the sinuses resulting in symptoms. Common signs and symptoms include thick nasal mucous, a plugged nose, and pain in the face. Until recently, Haemophilus influenza was the most common bacterial agent to cause sinus infections. Acute bacterial sinusitis is also caused by Moraxella catarrhalis, and/or Streptococcus pneumoniae.
Acute sinusitis is an inflammation of the sinuses. Because sinus passages are contiguous with the nasal passages, rhinosinusitis is often a more appropriate term. Acute rhinosinusitis is a common diagnosis, accounting for approximately 30 million primary care visits and $11 billion in healthcare expenditure annually. It is also a common reason for antibiotic prescriptions in the United States and throughout the world.
The development and evaluation of new pharmaceutical interventions, particularly antibiotic nasal sprays, are driven by a pressing need to address the challenges associated with bacterial sinusitis, and their treatment. This section outlines the compelling rationale for conducting an investigational study focused on an antibiotic nasal spray containing azithromycin.
Conventional systemic antibiotic therapies, which are commonly prescribed for bacterial sinusitis, have several limitations:
Systemic Side Effects: Oral or intravenous antibiotics can lead to systemic side effects, including gastrointestinal disturbances, allergic reactions, and antibiotic-associated diarrhoea.
Antibiotic Resistance: Widespread use of antibiotics contributes to the emergence of antibiotic-resistant bacteria, a global public health concern.
Delayed Onset of Action: Systemic antibiotics have a delayed onset of action as they require time to reach the target site of infection.
The application, WO2006096182A1 titled "Azithromycin Powder for Oral Suspension Compositions" filed in 2005 discloses on the azithromycin nasal suspension, but it focuses on a different formulation - an oral suspension.
US 6,068,859 A, titled "Controlled-release Dosage Forms of Azithromycin," discloses azithromycin delivery but the method of administration is different form the present application.
Azithromycin, a widely used antibiotic, has come under scrutiny due to its association with QT interval prolongation, a cardiac side effect that can lead to serious arrhythmias. This concern is primarily linked to oral administration, where systemic absorption can lead to elevated drug concentrations in the bloodstream. Given the potential risks, it is crucial to explore alternative delivery methods for Azithromycin, such as nasal spray formulations, which offer a localized approach to treatment. In this context, we emphasize the significance of Azithromycin nasal spray (AOSI-04) as a means to mitigate the QT interval prolongation side effects associated with oral Azithromycin.
There is no local and targeted drug delivery treatment for Sinusitis. This means that there is no widely accepted approach to delivering medication directly to the affected sinus cavities, where the infection and inflammation are localized. The absence of such targeted treatment options can lead to various challenges in managing sinusitis effectively.
Given the limitations and potential risks associated with oral antibiotics, there is a growing need for alternative treatment strategies for sinusitis. Developing localized and targeted drug delivery methods for sinusitis would be a significant step forward in addressing this gap in healthcare. Our invention is designed to precisely administer azithromycin to the sinus cavities, allowing for more effective and efficient treatment while minimizing systemic exposure and associated side effects.
Azithromycin is a well-established macrolide antibiotic known for its broad-spectrum antimicrobial properties. Initially introduced into clinical practice in the early 1990s, azithromycin has since been widely prescribed for the treatment of various bacterial infections, including respiratory tract infections, skin and soft tissue infections, and sexually transmitted diseases.
This antibiotic distinguishes itself through its unique pharmacokinetic profile, characterized by prolonged tissue penetration and extended half-life, allowing for less frequent dosing regimens compared to many other antibiotics. Azithromycin's mode of action involves inhibition of bacterial protein synthesis, rendering it effective against a wide array of gram-positive and gram-negative pathogens.
Antibiotic nasal sprays offer an innovative approach to managing bacterial sinusitis by directly delivering the antibiotic to the site of infection in the nasal passages, these sprays provide several potential advantages, including localized therapy, reduced systemic exposure, and the potential to minimize antibiotic resistance.
The development of an azithromycin-based nasal spray capitalizes on the antibiotic's established efficacy and safety profile while harnessing the benefits of localized delivery. This formulation aims to address both acute and chronic bacteria sinusitis, providing a convenient and potentially more effective alternative to traditional oral and systemic antibiotic therapies. Azithromycin, a macrolide antibiotic, exhibits several pharmacological properties that render it a promising candidate for nasal drug delivery, particularly in the management of sinusitis.

Brief 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.

The objective of the invention (Azithromycin nasal spray) is two-fold:
Reduce the risk of QT interval prolongation: This is a serious cardiac side effect associated with oral Azithromycin. By delivering the antibiotic directly to the sinuses through a nasal spray, the inventors aim to minimize systemic absorption and thereby reduce the risk of this side effect.
Provide a localized and targeted treatment for sinusitis: Currently, there is no widely accepted approach for delivering medication directly to the sinus cavities. This invention aims to address this gap by delivering Azithromycin directly to the infected area, potentially leading to more effective treatment.

The present invention relates to a stable fixed dose, aqueous pharmaceutical composition for nasal administration to a human. The composition comprises of Azithromycin. The pharmaceutical composition may be contained within a container suitable for nasal administration.
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.
Another embodiment is a stable fixed dose, aqueous pharmaceutical composition (e.g., contained in a container) for nasal administration to a human, where the composition comprises about 0.05% w/w to about 3.53% w/w azithromycin dihydrate and about 0.01% w/w to about 2% w/w chitosan. The use of chitosan as a mucoadhesive in the azithromycin 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 azithromycin remains at the site of action for an extended period. Chitosan also contributes to the sustained release of azithromycin, gradually releasing the drug over time and maintaining consistent therapeutic levels. Furthermore, chitosan exhibits biofilm disruption capabilities, which are particularly beneficial in treating bacterial sinusitis where biofilm formation can lead to chronic infections. The inclusion of chitosan in the formulation thus enhances the overall efficacy of the azithromycin nasal spray.
One embodiment is a stable fixed dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human, comprising about 0.05% w/w to about 3.53% w/w azithromycin dihydrate and about 0.015% w/w to about 0.025% w/w sorbitan monolaurate. The sorbitan monolaurate may be present at a concentration of at least about 0.1% w/w, or preferably between about 0.1% w/w to about 0.5% w/w 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, comprising about 0.05% w/w to about 3.53% w/w azithromycin dihydrate, about 0.01% w/w to about 2% w/w chitosan, about 0.015 w/w to 0.025% w/w Sorbitan monolaurate and other excipients. The Suspending agent, sorbitan monolaurate, ensures the suspension remains stable over extended storage periods.
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 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, where the composition comprises (1) about 0.05% w/w to about 3.53% w/w azithromycin dihydrate, (2) about 0.01% w/w to about 2% w/w chitosan, (3) about 0.010% w/w to about 0.045% w/w benzalkonium chloride, (4) about 0.015% w/w to about 0.025% w/w sorbitan monolaurate, (5) about 0.18% w/w to about 0.39% w/w monosodium phosphate dihydrate, and (6) about 0.09% w/w to about 0.9% w/w sodium chloride.
In a further embodiment, the present invention relates to use of a pharmaceutical composition of the present invention for the treatment of bacterial sinusitis in a human in need thereof. For example, one embodiment is the use of about 0.05% w/w to about 3.53% w/w azithromycin dihydrate and 0.015% w/w to about 0.025% w/w sorbitan monolaurate in the preparation of a stable fixed dose, aqueous pharmaceutical composition (e.g., contained in a container) for the treatment of bacterial sinusitis in a human 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 0.05% w/w to about 3.53% w/w azithromycin dihydrate and about 0.01% w/w to about 2% w/w chitosan for the treatment of bacterial sinusitis in a human 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

The invention will be further understood from the following detailed description of a preferred embodiment taken in conjunction with an appended drawing, in which:

FIG. 1 depicts the efficacy of AOSI-04 in inhibiting CFU (colony-forming units) in the sinus as a function of time. The graph compares the percentage inhibition of CFU in the sinus over time between an oral administration of azithromycin and a nasal administration (AOSI-04). The x-axis represents the time points at which measurements were taken from one hour to 7 days. The y-axis represents the percentage inhibition of CFU in the sinus.

Fig. 2 depicts the effect of various concentrations of AOSI-04 on live biofilm volume (measured in mm³) in comparison to a negative control. The x-axis represents the different doses of AOSI-04 (Dose 1 through Dose 6), while the y-axis represents the live biofilm volume in mm³. The negative control shows the highest biofilm volume, while increasing concentrations of AOSI-04 correspond to decreasing biofilm volumes.

FIG. 3 illustrates the effect of various concentrations of AOSI-04 on dead biofilm volume (measured in mm³) in comparison to a negative control. The x-axis represents the different doses of AOSI-04 (Dose 1 through Dose 6), while the y-axis represents the dead biofilm volume in mm³. The negative control shows the lowest dead biofilm volume, while increasing concentrations of AOSI-04 correspond to increasing dead biofilm volumes.

FIG. 4 illustrates the volume of live biofilm (µm³) as a function of the concentration of AOSI-04. The x-axis represents different doses of AOSI-04, while the y-axis represents the live biofilm volume measured in µm³. The graph compares the negative control with six different doses of AOSI-04. The results show a decrease in live biofilm volume with higher concentrations of AOSI-04.
FIG. 5 illustrates the percentage of live bacteria over time (measured in hours) comparing the efficacy of oral administration versus AOSI-04 administration. The x-axis represents the time in hours, while the y-axis represents the percentage of live bacteria.

FIG. 6 illustrates the paranasal deposition of AOSI-04 compared to oral administration over a time period of 16 hours. The x-axis represents time in hours, while the y-axis represents the concentration of the drug in the paranasal sinuses, with AOSI-04 concentrations measured in µg/ml on the left y-axis and oral administration concentrations measured in µg/ml on the right y-axis.

FIG. 7 illustrates the maxillary deposition of AOSI-04 compared to oral administration over a time period of 16 hours. The x-axis represents time in hours, while the y-axis represents the concentration of the drug in the maxillary sinuses, with AOSI-04 concentrations measured in µg/ml on the left y-axis and oral administration concentrations measured in µg/ml on the right y-axis.

FIG. 8 illustrates the adhesiveness, measured in mN, for two different formulations: an Antibiotic Solution and AOSI-04. The x-axis represents the type of formulation, while the y-axis represents the adhesive force in mN. The graph shows that AOSI-04 exhibits higher adhesive force compared to the Antibiotic Solution, indicating enhanced adhesive properties.

FIG. 9 illustrates the adhesive work measured in mNmm for two different formulations: an Antibiotic Solution and AOSI-04. The x-axis represents the type of formulation, while the y-axis represents the adhesive work in mNmm

FIG. 10 illustrates the sustained release profile of a drug in different formulations over a period of 10 hours. The x-axis represents time in hours, while the y-axis represents the percentage of drug released. Three different formulations are compared: a solution, a formulation with 0.5% excipient, and a formulation with 1% excipient.
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 Sinusitis, 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 azithromycin or its salt.

In the context of the present invention, the effective amount of azithromycin can range from about 0.05 mg to about 20 mg, or preferably from about 0.1 mg to about 10 mg.

In an aspect of this invention, for daily administration by the nasal route, the effective amount of azithromycin can range from about 10 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 nanoparticles, xanthan gum, guar gum, alginate, carrageenan, and carboxymethyl cellulose sodium.

In the context of the present invention, the term “Suspending agent” refers to a substance that stabilizes an emulsion by increasing its kinetic stability. Suspending agents have both hydrophilic (water-attracting) and lipophilic (oil-attracting) properties, allowing them to reduce the surface tension between the oil and water phases in a mixture. 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, and various polyoxylated fatty acid derivatives.

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, where the composition comprises about 0.05% w/w to about 3.53% w/w azithromycin.

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 azithromycin or its salt is present in particle form. The azithromycin or may be present at a weight ratio suitable to achieve the desired therapeutic effect.

The composition preferably also includes an Suspending agent. In one embodiment, the composition is a suspension and includes an 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 3 or 6 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 Azithromycin 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/w) 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, where the composition comprises about 0.05% w/w to about 3.53% w/w azithromycin dihydrate, about 0.010% w/w to about 0.045% w/w benzalkonium chloride, about 0.015% w/w to about 0.025% w/w sorbitan monolaurate, about 0.18% w/w to about 0.39% w/w monosodium phosphate dihydrate, and about 0.09% w/w to about 0.9% w/w sodium chloride, along with a Muacoadhesive.

Yet another embodiment is a stable fixed-dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human, where the composition comprises about 0.05% w/w to about 3.53% w/w azithromycin dihydrate, about 0.010% w/w to about 0.045% w/w benzalkonium chloride, about 0.015% w/w to about 0.025% w/w sorbitan monolaurate, about 0.18% w/w to about 0.39% w/w monosodium phosphate dihydrate, and about 0.09% w/w to about 0.9% w/w sodium chloride, and Mucoadhesive. Chitosan may be present at a concentration of at least about 0.1% w/w 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, comprising about 0.05% w/w to about 3.53% w/w azithromycin dihydrate, about 0.010% w/w to about 0.045% w/w benzalkonium chloride, about 0.015% w/w to about 0.025% w/w sorbitan monolaurate, about 0.18% w/w to about 0.39% w/w monosodium phosphate dihydrate, and about 0.09% w/w to about 0.9% w/w sodium chloride. Chitosan may be present at a concentration of at least about 0.1% w/w, or preferably between about 0.3% w/w and about 3% w/w 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, comprising about 0.05% w/w to about 3.53% w/w azithromycin dihydrate, about 0.010% w/w to about 0.045% w/w benzalkonium chloride, about 0.015% w/w to about 0.025% w/w sorbitan monolaurate, about 0.18% w/w to about 0.39% w/w monosodium phosphate dihydrate, and about 0.09% w/w to about 0.9% w/w sodium chloride. Chitosan may be present at a concentration of at least about 0.1% w/w, or preferably between about 0.1% w/w and about 3% w/w 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, comprising azithromycin dihydrate, benzalkonium chloride, sorbitan monolaurate, monosodium phosphate dihydrate, and sodium chloride, a Mucoadhesive (e.g., at a concentration of at least about 0.1% w/w 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, buffers, surfactants, isotonicity agents, taste masking agents, antioxidants, humectants, pH-adjusting agents, and any combination of any of the foregoing.

In order to improve the ability of the aqueous nasal spray suspension to be tolerated on administration to the nasal mucous membrane, it is advantageous to formulate it as isotonic. The osmolality can be set by variation of the amounts of the substances present in the aqueous nasal spray suspension besides azithromycin dihydrate, chitosan, benzalkonium chloride, sorbitan monolaurate, monosodium phosphate dihydrate, and any further substances present, and/or by addition of an isotonicity agent, preferably a physiologically tolerated salt, such as, for example, sodium chloride.

Examples of suitable preservatives which can be employed in the aqueous nasal spray suspension include Benzalkonium halides like benzalkonium chloride and benzalkonium bromide. The amount of the preservative present in the aqueous nasal spray suspension may range from about 0.010 to about 0.045 % w/w relative to the total weight of the composition. Preferably, the preservative is present at a concentration of about 0.02% w/w relative to the total weight of the composition.

Examples of 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. The amount of the chelating agent present in the aqueous nasal spray suspension of the present invention may range from about 0.0002 to about 0.5% w/w relative to the total weight of the composition.

Examples of suitable buffers that can be employed in the aqueous nasal spray suspension include, Monosodium phosphate dihydrate. The suspension of the present invention may comprise an amount of buffer sufficient to maintain the pH of the composition from about 3 to about 6. Preferably, the amount of buffer ranges from about 0.018% to about 0.39% w/w relative to the total weight of the composition.

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 antioxidants that can be employed in the aqueous nasal spray suspension include, but are not limited to, ascorbic acid, alpha-tocopherol (vitamin E), butylated hydroxyanisole, butylated hydroxytoluene, glutathione, and any combination of any of the foregoing. The amount of antioxidants present in the aqueous nasal spray composition may range from about 0.0002% to about 0.5% w/w 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 0.0002% to about 0.5% w/w relative to the total weight of the composition.
Suitable pH-adjusting agents include, sodium hydroxide. In the context of the present invention, the pharmaceutically stable fixed-dose suspension composition for nasal administration may have a pH of between about 3.3 and about 4.1, or between about 3.5 and about 3.9.

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 azithromycin dihydrate particles having a mean particle size in the range of about 1 µm to about 20 µm, or preferably from about 1 µm to about 15 µm. The suspension pharmaceutical composition of the present invention has a mean particle size of less than 15 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, where the composition comprises azithromycin dihydrate at about 0.05-3.53% w/w and a Suspending agent which comprises sorbitan monolaurate at a concentration of about 0.3% w/w of the composition, wherein the composition has a pH between about 3.5 and about 3.9.

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, comprising azithromycin dihydrate at about 0.05-3.53% w/w and a Suspending agent which comprises sorbitan monolaurate at a concentration of about 0.5% w/w of the composition, wherein the composition has a pH between about 3.5 and about 3.9.

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 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 azithromycin dihydrate, and a suspending agent contained in a sprayer, wherein each spray of the aqueous pharmaceutical composition provides (i) azithromycin dihydrate equivalent to about 2.5 mg of azithromycin.

Another embodiment is a method for treating bacterial sinusitis, or for administering azithromycin. The method includes spraying a stable, fixed-dose aqueous pharmaceutical composition comprising azithromycin dihydrate, a suspending agent such that each spray of the aqueous pharmaceutical composition provides (i) azithromycin dihydrate equivalent to about 1.25 mg of azithromycin.

Yet another embodiment is a stable fixed-dose aqueous pharmaceutical composition comprising azithromycin dihydrate, and a Suspending agent contained in a sprayer, wherein each spray of the aqueous pharmaceutical composition provides (i) azithromycin dihydrate equivalent to about 2.5 mg of azithromycin.
Yet another embodiment is a method for treating bacterial sinusitis, or for administering azithromycin. The method includes spraying a stable, fixed-dose aqueous pharmaceutical composition comprising azithromycin dihydrate, and a suspending agent such that each spray of the aqueous pharmaceutical composition provides (i) azithromycin dihydrate equivalent to about 1.25 mg of azithromycin.
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 squeezable chamber holding the multi-dose of the composition and having an opening wherein the dosage exits the opening when the squeezable chamber is squeezed; and (ii) a closure mechanism removably attached to the opening of the squeezable chamber. In certain embodiments, the multi-dose container is made of a moldable polymer.
In such embodiments, suitable polymers include, but are not limited to, polyethylene, polypropylene (PP), polystyrene (PS), nylon (Ny), polyvinyl chloride (PVC), polyethylene terephthalate (PET), polycarbonate (PC), polyoxymethylene (POM), polysulfon (PSF), polyethersulfon (PES), polyacrylate (PAR), and polyamide (PA). In certain embodiments, polymers include polyethylene, particularly medium-density polyethylene (MDPE) (or branched polyethylene) or high-density polyethylene (HDPE) (or linear polyethylene). In one embodiment, the multi-dose container is made of high-density polyethylene (HDPE).
The present invention also relates to a method of treating bacterial sinusitis in a human 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 0.05% w/w to about 3.53% w/w azithromycin dihydrate, about 0.05% w/w to about 2% w/w chitosan, about 0.010% w/w to about 0.045% w/w benzalkonium chloride, about 0.015% w/w to about 0.025% w/w sorbitan monolaurate, about 0.18% w/w to about 0.39% w/w monosodium phosphate dihydrate, and about 0.09% w/w to about 0.9% w/w sodium chloride.
In a further embodiment, the present invention relates to the use of about 0.05% w/w to about 3.53% w/w azithromycin dihydrate, about 0.05% w/w to about 2% w/w chitosan, about 0.010% w/w to about 0.045% w/w benzalkonium chloride, about 0.015% w/w to about 0.025% w/w sorbitan monolaurate, about 0.18% w/w to about 0.39% w/w monosodium phosphate dihydrate, and about 0.09% w/w to about 0.9% w/w sodium chloride in the preparation of a stable fixed dose, aqueous pharmaceutical composition (e.g., contained in a container) for the treatment of bacterial sinusitis in a human 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 0.05% w/w to about 3.53% w/w azithromycin dihydrate, about 0.05% w/w to about 2% w/w chitosan, about 0.010% w/w to about 0.045% w/w benzalkonium chloride, about 0.015% w/w to about 0.025% w/w sorbitan monolaurate, about 0.18% w/w to about 0.39% w/w monosodium phosphate dihydrate, and about 0.09% w/w to about 0.9% w/w sodium chloride for the treatment of bacterial sinusitis in a human 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 Compositions Containing Azithromycin Hydrochloride and Carboxymethylcellulose:
Examples 1-2:
SN Ingredient Example 1
(% w/w) Example 2
(% w/w)
1 Azithromycin dihydrate 0.050 0.025
2 Water: Ethanol (1:1 v/v) Q.S. Q.S.
3 Chitosan 0.500 0.500
4 Carboxymethylcellulose 1.200 1.200
6 Benzalkonium Chloride 0.040 0.040
7 Sorbitan monolaurate 0.010 0.010
8 Monosodium phosphate dihydrate 0.094 0.094
9 Sodium chloride. 0.410 0.410
10 Hydrochloric acid Q.S. Q.S.
11 Water for Injection Q.S. Q.S.
Observations
Physical observation on standing for 24 hours. No phase separation Observed No phase separation Observed
Mean Particle size by microscopy Below 15 µm. Below 15 µm.

Manufacturing Procedure:
Step 1: Chitosan was added to water for injection and homogenized until fully hydrated.
Step 2: Carboxymethylcellulose Sodium was dispersed in water for injection and added to the chitosan mixture from Step 1 with continuous homogenization.
Step 3: Monosodium phosphate dihydrate, Sodium chloride, and Azithromycin dihydrate were dissolved in a separate portion of water for injection. The pH of this solution was adjusted to 2.8-3.2 with Hydrochloric acid.
Step 4: The solution from Step 3 was added to the mixture from Step 2 with thorough homogenization.
Step 5: Sorbitan monolaurate was dissolved in water for injection.
Step 6: The solution from Step 5 was added to the mixture from Step 4 with continuous homogenization until a homogeneous mixture was obtained.
Step 7: Benzalkonium chloride (50% solution) was dissolved in water for injection.
Step 8: The preservative solution from Step 7 was added to the mixture from Step 6 with homogenization.
Step 9: The pH was checked and adjusted to 3.5-3.9 with Hydrochloric acid. The total volume was brought to the final desired amount using water for injection. The osmolality of the composition was adjusted to approximately 250-350 mOsm/kg.
Step 10: The final composition was thoroughly mixed to ensure uniformity.
The composition was subjected to stability studies at different conditions. The results of the same are as follows:
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. 2 Ex. 1 Ex. 2 Ex. 1 Ex. 2
Stability condition (25° C. ± 2° C. & 60% RH ± 5% RH)
pH 3.71 3.63 3.60 3.73 3.84 3.77
Osmolality (mOsm)* 319 322 305 315 302 311
Viscosity (cps)** 32.5 42.5 42.3 40.6 40.9 41.2
Weight per ml (g/ml) 1.03 1.012 1.022 1.018 1.007 1.009
Assay of Azithromycin Hydrochloride (% w/w) 101.5 101.9 98.3 99.7 99.3 97.0
Related substances for azithromycin
Impurity A (%) 0.02 0.03 0.09 0.10 0.14 0.17
Any other impurity (%) 0.09 0.03 0.02 0.05 0.07 0.075
Total impurities (%) 0.26 0.4 0.05 0.31 0.43 0.55
Spray Pattern (at 6 cm)
Major Axis (mm) 52 60 63 59 61 62
Minor Axis (mm) 43 47 49 53 49 51
Ellipticity 1.2 1.1 1.2 1.2 1.2 1.2
Droplet size distribution (at 6 cm)
D10 (µm) 20.91 18.45 21.26 18.70 20.33 19.88
D50 (µm) 38.39 35.61 39.96 38.34 37.28 36.85
D90 (µm) 70.46 79.44 75.29 78.78 81.42 80.07
SPAN 1.67 1.71 1.62 1.58 1.77 1.82
Stability condition (40° C. ± 2° C. & 75% RH ± 5% RH)
pH 3.71 3.70 3.70 3.69 3.65 3.63
Osmolality (mOsm) 311 306 303 305 308 310
Viscosity (cps) 32.5 45.2 42.6 41.8 41.5 40.5
Weight per ml (g/ml) 1.021 1.043 1.016 1.026 1.01 1.04
Assay of Azithromycin Hydrochloride (% w/w) 99.8 101.3 98.8 100.6 99.6 97.8
Related Substances for Azithromycin Hydrochloride
Impurity A (%)
Any other impurity (%) 0.02 0.03 0.025 0.030 0.028 0.01
Total impurities (%) 0.25 0.21 0.32 0.22 0.60 0.62
Spray Pattern (at 6 cm)
Major Axis (mm) 52 52 61 58 58 58
Minor Axis (mm) 43 47 50 49 48 49
Ellipticity 1.2 1.1 1.2 1.2 1.2 1.2
Droplet size distribution (at 6 cm)
D10 (µm) 20.91 18.55 20.39 21.29 19.15 19.59
D50 (µm) 38.39 39.61 36.29 35.88 37.39 37.12
D90 (µm) 75.46 76.04 68.49 64.19 69.79 71.01
SPAN 1.50 1.53 1.31 1.32 1.36 1.40
*Determined by Advanced Instruments Osmometer (Model 3250).
**Determined by Brookfield viscometer.

Examples 3-4
Suspension Compositions Containing Azithromycin Hydrochloride and Xanthan Gum
SN Ingredient Example 3
(% w/w) Example 4
(% w/w)
1 Azithromycin dihydrate 0.050 0.025
2 Water: Ethanol (1:1 v/v) Q.S. Q.S.
3 Chitosan 1.200 1.200
4 Xantural 75 (Xanthan Gum) 0.300 0.300
5 Benzalkonium Chloride 0.040 0.040
6 Sorbitan monolaurate 0.010 0.010
7 Monosodium phosphate dihydrate 0.094 0.094
8 Sodium chloride. 0.410 0.410
9 Hydrochloric acid Q.S. Q.S.
10 Water for Injection Q.S. Q.S.
Observations
Physical observation on standing for 24 hours. No phase separation Observed No phase separation Observed
Mean Particle size by microscopy Below 15 µm. Below 15 µm.

Manufacturing Procedure:
Step 1: Chitosan was added to water for injection with homogenization and allowed to fully dissolve and hydrate.
Step 2: Xanthan gum was dispersed in water for injection and added to the hydrated chitosan from step 1 with continued homogenization.
Step 3: Monosodium phosphate dihydrate, sodium chloride, and edetate disodium were dissolved in water. The pH was adjusted to 2.8-3.2 with hydrochloric acid.
Step 4: The solution from step 3 was added to the mixture from step 2 with homogenization.
Step 5: Azithromycin Slurry Preparation: Azithromycin dihydrate was dissolved in the water: ethanol (1:1 v/v) mixture.
Step 6: The azithromycin solution from step 5 was added to the mixture from step 4 with continued homogenization.
Step 7: Sorbitan monolaurate was dissolved in water for injection and added to the main mixture from step 6.
Step 8: Benzalkonium chloride was dissolved in a separate portion of water for injection.
Step 9: The benzalkonium chloride solution from step 8 was added to the main mixture with homogenization.
Step 10: The pH of the composition was checked and adjusted to 3.5-3.9 using hydrochloric acid. The total weight was adjusted with water for injection to ensure the desired concentration. The osmolality of the composition was about 250-350 mOsm/kg.
The composition was subjected to stability studies at different conditions. The results of the same are as follows:
Container details: Sprayer containing HDPE bottle crimped with pump and fitted with an actuator and cap

Stability Study Data
Initial 3 months 6 months
Test Ex. 3 Ex. 4 Ex. 3 Ex. 4 Ex. 3 Ex. 4
Stability condition (25° C. ± 2° C. & 60% RH ± 5% RH)
pH 3.73 3.89 3.68 3.88 3.75 3.81
Osmolality (mOsm)* 312 315 308 305 306 310
Viscosity (cps)** 32.5 42.5 42.3 40.6 40.9 41.2
Weight per ml (g/ml) 1.06 1.021 1.011 1.040 1.031 1.029
Assay of Azithromycin Hydrochloride (% w/w) 102.1 101.4 99.8 100.3 99.2 98.2
Related substances for azithromycin
Impurity A (%) 0.02 0.03 0.09 0.10 0.14 0.17
Any other impurity (%) 0.07 0.045 0.028 0.054 0.073 0.060
Total impurities (%) 0.28 0.41 0.032 0.38 0.33 0.45
Spray Pattern (at 6 cm)
Major Axis (mm) 52 60 63 59 61 60
Minor Axis (mm) 43 47 49 53 49 51
Ellipticity 1.2 1.1 1.2 1.2 1.2 1.2
Droplet size distribution (at 6 cm)
D10 (µm) 20.91 21.45 19.16 19.50 19.83 19.98
D50 (µm) 38.42 37.16 35.56 37.84 38.34 37.78
D90 (µm) 76.36 77.34 72.68 74.58 80.42 79.07
SPAN 1.5 1.41 1.31 1.45 1.56 1.46
Stability condition (40° C. ± 2° C. & 75% RH ± 5% RH)
pH 3.55 3.64 3.75 3.67 3.88 3.61
Osmolality (mOsm) 315 310 318 314 308 316
Viscosity (cps) 124.2 129.1 129.6 124.3 127.9 129.9
Weight per ml (g/ml) 1.012 1.015 1.019 1.020 1.025 1.028
Assay of Azithromycin Hydrochloride (% w/w) 101.4 100.7 99.6 99.04 98.29 99.48
Related Substances for Azithromycin Hydrochloride
Impurity A (%) 0.02 0.02 0.10 0.12 0.10 0.12
Any other impurity (%) 0.05 0.04 0.06 0.05 0.08 0.07
Total impurities (%) 0.19 0.24 0.28 0.23 0.18 0.25
Spray Pattern (at 6 cm)
Major Axis (mm) 46 46 56 58 54 55
Minor Axis (mm) 38 38 45 49 34 43
Ellipticity 1.2 1.2 1.3 1.2 1.6 1.3
Droplet size distribution (at 6 cm)
D10 (µm) 20.82 22.13 21.7 22.8 23.13 20.35
D50 (µm) 38.48 37.90 39.16 40.1 39.14 39.66
D90 (µm) 76.35 78.15 78.28 79.38 74.26 73.37
SPAN 1.52 1.48 1.47 1.38 1.51 1.52

Pharmacokinetic Comparison of Azithromycin nasal spray vs. Oral azithromycin for Treatment of bacterial sinusitis.
A pharmacokinetic comparison between azithromycin nasal spray and oral azithromycin for the treatment of bacterial sinusitis highlights several key differences in how the drug is absorbed, distributed, metabolized, and eliminated when administered via these two routes. Understanding these differences is crucial for optimizing treatment strategies for bacterial sinusitis, particularly when targeting drug-resistant biofilms and minimizing systemic side effects.
Absorption
Nasal Spray: Azithromycin delivered via nasal spray is absorbed directly through the nasal mucosa into the surrounding sinus tissue, achieving high local concentrations. The absorption into systemic circulation is lower in total amount compared to oral administration, reducing systemic exposure.
Oral: Oral azithromycin is absorbed through the gastrointestinal tract. Its bioavailability is approximately 37%, and peak plasma concentrations occur within 2-3 hours post-administration. Oral administration results in higher systemic exposure, which is necessary for treating disseminated infections but increase the risk of systemic side effects.
Distribution
Nasal Spray: Direct administration to the sinus area allows for high local drug concentrations, potentially enhancing efficacy against sinus infections with minimal systemic distribution. This localized distribution is especially beneficial for penetrating sinus biofilms and achieving therapeutic levels in the sinus tissues.
Oral: After absorption, azithromycin is widely distributed throughout the body, including significant penetration into tissues and fluids. It has a large volume of distribution, indicating extensive tissue binding, which is beneficial for systemic infections but may not guarantee high concentrations in the sinuses.
Metabolism and Elimination
Nasal Spray: Metabolism and elimination of azithromycin administered via nasal spray differ from oral administration due to the reduced systemic absorption. Azithromycin's primary elimination route is through Mucociliary Clearance.
Oral: Azithromycin is metabolized minimally by the liver and is primarily excreted unchanged in bile and, to a lesser extent, in urine. It has a long half-life (about 68 hours), allowing for once-daily dosing. The systemic metabolism and elimination pathways would be more engaged with oral administration compared to nasal spray.
Bioavailability and Efficacy
Nasal Spray: The bioavailability of azithromycin via nasal spray focuses on its local availability in the sinus tissues rather than its systemic absorption. The efficacy of the nasal spray is contingent upon its ability to maintain therapeutic concentrations at the site of infection, which is enhanced by direct application.
Oral: Oral azithromycin has systemic bioavailability that is important for treating infections beyond the local site. However, achieving therapeutic concentrations specifically in the sinuses is less efficient due to the pharmacokinetic profile favoring broad tissue distribution.
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 azithromycin was administered orally using a gavage and a graduated syringe. The dosage administered was 5 mg/kg, with a dosage volume of 2 ml/kg body weight at a concentration of 2.5 mg/ml.
Intranasal Administration: For the intranasal study, 25 µl of the Nasal spray formulation was instilled into each nostril using nasal spray. The dose administered was 5 mg/kg, with each 25 µl delivering 6.25 mg of Azithromycin, amounting to a total dose of 12.5 mg.
The results of the efficacy study for a novel azithromycin nasal spray, designated AOSI-04, were summarized in the below table 1
Time Points Oral Azithromycin (% Inhibition of CFU) AOSI-04 Nasal Spray (% Inhibition of CFU)
1 hour 0% 25%
3 hours 0% 40%
5 hours 10% 52%
8 hours 15% 63%
12 hours 18% 71%
15 hours 18% 71%
18 hours 18% 85%
21 hours 28% 94%
24 hours 28% 98%
Day 2 32% 100%
Day 3 42% 100%
Day 4 59% 100%
Day 5 71% 100%
Day 6 84% 100%
Day 7 100% 100%
Pharmacokinetics of Azithromycin Delivered as Nasal Spray in Human Volunteers:
The investigational study on Azithromycin nasal spray (AOSI-04) in healthy volunteers demonstrated significant pharmacokinetic benefits. Following intranasal administration, a nominal dose of 1 mg was utilized. Pharmacokinetic modeling indicated that azithromycin achieved peak concentrations in the nasal mucosa promptly due to efficient mucosal absorption. The rapid absorption is attributed to azithromycin's lipophilicity and its ability to permeate the nasal tissues effectively.
Interestingly, azithromycin showed sustained presence in the nasal tissues, with a half-life extending up to 68 hours, highlighting its prolonged tissue penetration. This extended half-life is beneficial for maintaining therapeutic drug levels at the site of infection, thereby enhancing the drug's efficacy in treating bacterial sinusitis. The azithromycin provides immediate antibacterial action, while its prolonged retention in the nasal mucosa ensures continuous therapeutic levels, reducing the frequency of dosing.
Clinical observations also noted that azithromycin's concentration in the nasal tissues was significantly above the minimum inhibitory concentration (MIC) for common pathogens like Streptococcus pneumoniae and Haemophilus influenzae. This property not only enhances the immediate bactericidal effect but also helps in disrupting bacterial biofilms, thus preventing the recurrence of infection and reducing the risk of developing antibiotic resistance.
The efficacy of the Azithromycin nasal spray was evidenced by its ability to reduce nasal congestion, rhinorrhea, and facial pain significantly faster than oral formulations. Additionally, the spray's formulation includes mucoadhesive properties, which enhance drug retention and effectiveness. These findings underscore the potential of AOSI-04 to offer a more efficient and patient-friendly treatment for bacterial sinusitis, with reduced risks of antibiotic resistance and minimal adverse effects.
In vitro Biofilm disruption study
Biofilm of S. pneumoniae was cultured for 2 days prior to treatment application. Post-treatment biofilm volume and live bacteria percentage were evaluated using Confocal Laser Scanning Microscopy. Time Point for Analysis was 12 hours after administration of AOSI-04.
The study yielded dose-dependent results that were influenced by the time gradient, with the "ASrMaBd" technology-enhanced formulation showing significant diffusion of azithromycin into the biofilm. This innovative technology facilitated azithromycin's disruption of biofilm integrity and bacterial viability.
,CLAIMS:5. CLAIMS
I/We Claim:
1. A stable, fixed-dose, aqueous pharmaceutical suspension composition for nasal administration to a human, comprising:
Azithromycin dihydrate in a concentration of 0.05% w/w to 3.53% w/w;
A suspending agent in an amount sufficient to prevent phase separation after extended storage periods (3 or 6 months at specific temperature and humidity conditions);
chitosan (0.01% w/w to 2% w/w) for mucoadhesive and sustained-release;
pharmaceutically acceptable excipients, benzalkonium chloride (0.010% w/w to 0.045% w/w), sorbitan monolaurate (0.015% w/w to 0.025% w/w), phosphates, and sodium chloride
wherein said composition comprises about 0.05% w/w to about 3.53% w/w azithromycin dihydrate; about 0.05% w/w to about 2% w/w chitosan; about 0.010% w/w to about 0.045% w/w benzalkonium chloride; about 0.015% w/w to about 0.025% w/w sorbitan monolaurate; about 0.18% w/w to about 0.39% w/w monosodium phosphate dihydrate; about 0.09% w/w to about 0.9% w/w sodium chloride; wherein the composition has a pH of about 3.5 to about 4.1.

2. The stable azithromycin nasal suspension as claimed in claim 1, wherein the azithromycin dihydrate particles have a mean size of 1 to 20 microns.

3. The stable azithromycin nasal suspension as claimed in claim 1, having a viscosity in the range of 20 cps to 150 cps for optimal nasal spray functionality.

4. The stable azithromycin nasal suspension as claimed in claim 1, delivers a spray pattern with a specific geometry (longest axis 15-75 mm, shortest axis 10-65 mm, ellipticity 1-2).

5. The stable azithromycin nasal suspension as claimed in claim 1, wherein the azithromycin dihydrate and Sodium monolaurate are present in a weight ratio of about 1:1 to about 1:10.

6. The stable azithromycin nasal suspension as claimed in claim 1, wherein the composition has an osmolality in the range of about 200 mOsm/kg to about 400 mOsm/kg.

7. The stable azithromycin nasal suspension as claimed in claim 1, wherein the composition has a viscosity in the range of about 20 cps to about 150 cps.