DESC:FIELD OF THE INVENTION:
The present invention relates to a pharmaceutical composition of nasal spray solution of corticosteroid to prevent inflammation due to allergic reactions and a method of preparation thereof. More particularly, the present invention relates to aqueous corticosteroid nasal spray solution that is capable of preventing inflammation due to allergic reactions and method thereof.

BACKGROUND OF THE INVENTION:
A nasal corticosteroid spray eases swelling and mucus in the nasal passageway. The sprays are effective in treating allergic rhinitis symptoms, such as congestion, runny nose, sneezing, itching, or swelling of the nasal passageway and nasal polyps, which are noncancerous (benign) growths in the lining of the nasal passage. One of the corticosteroids used for nasal spray preparation is Triamcinolone acetonide which is being widely researched for its efficacy.

The majority of the active pharmaceutical ingredients (API) used in nasal spray products are non-polar and hence the formulation is a suspension achieved through the use of surfactants and suspending agents. This requires that apart from testing parameters, one needs to carry out MDRS (Morphologically Directed Raman Spectroscopy) which differentiates between the particle size of API versus particle size of excipients such as Avicel used. This requires expensive instruments like Morphologically Directed Raman Spectroscopy, increasing the cost of analysis and batch release tests.

There are number of patents and non-patents literature which has been published in said domain. CN106074387B, a patent document titled “With thixotropic Triamcinolone acetonide nasal spray and preparation method thereof”, described thixotropic micronized triamcinolone acetonide suspension formulation method using suspending agent-microcrystalline cellulose and sodium carboxymethylcellulose, formed by weight 95: 5 - 60:40, wetting agent, osmotic pressure regulator, preservative-benzalkonium chloride, complexing agent and pH adjuster were dissolved in portions of de-ionized water. This shows that the number of excipients required for this formulation is more and hence the cost is high. Also, the requirement of MDRS makes the preparation expensive.

Another patent document, US20160220583A1, titled "Aqueous nasal spray composition of corticosteroids and antihistaminic agents”, describes an aqueous nasal spray solution containing Triamcinolone and utilizes chitosan as an adhesive and tween-80 as a solubilizing agent in the formulation. Cyclodextrin is comparatively safer than tween-80 because the latter shows developmental neurotoxicity when studied in animals as per a non-patent literature titled “Cyclodextrins” by Valentino et al., published in 2008. Hence the efforts were channelized to researching of use of cyclodextrins in this field.

Prior research shows that cyclodextrins have been used in combination with corticosteroids to prepare nasal aqueous solution. A patent document, RU2390330C2 titled “Inhalation formulation containing sulfoalkyl ether gamma-cyclodextrin and corticosteroid”, mentioned the use of sulfoalkyl ether gamma-cyclodextrin (SBE (6.1) -?-CD) for dissolution of corticosteroid (beclomethasone monopropionate/ budesonide/ flunisolide/ fluticasone propionate/ mometasone furoate/ triamcinolone acetonide/ fluticasosterone/ corticosterone). The ratio of the corticosteroid to Sulfoalkyl ether gamma-cyclodextrin was in the range of 1:2 to 1:10,000. The complex is stabilized by hydrophobic interactions and is not involved in the formation of any covalent bonds. As per the method, in citrate buffer, 0.01 % tween 80 and 12.5 % w/w SBE (6.1) -?-CD were mixed and excess of mometasone furoate added. The Samples were filtered using a 0.22 µm PVDF syringe filter and bottles stored at 25°C and 50°C. Control samples were stored at 5°C. Initially, HPLC analysis of the samples was performed (at time 0) and after 1, 2, and 3 months of storage. On the basis of HPLC samples were stable on 3 months storage. The method of preparation in this disclosure entails a long series of steps causing the time and cost to increase.

Another document, EP2173169B1, titled “Nasal delivery of aqueous corticosteroid solutions” disclosed the use of sulfobutyl ether ß-cyclodextrin (SAE-CD) for preparation of nasal and ophthalmic solution using corticosteroid selected from the group consisting of beclomethasone dipropionate, beclomethasone monopropionate, betamethasone, budesonide, ciclesonide, desisobutyryl-ciclesonide, dexamethasone, flunisolide, fluticasone propionate, fluticasone furoate, mometasone furoate, triamcinolone acetonide, and combinations thereof. It describes a metered dose device for nasal administration, wherein the device optionally emits 10 µl to 500 µl of the corticosteroid solution per unit dose. The aqueous liquid carrier comprised water, buffer, alcohol, organic solvent, glycerin, propylene glycol, poly (ethylene glycol), poloxamer, surfactant or a combination thereof; the aqueous liquid carrier comprises povidone, polyol or a combination thereof. The SAE-CD was present at a concentration of about 10 mg to about 500 mg of SAE-CD per mL of the corticosteroid solution and/or the SAE-CD was present in an amount of 100 µg to 1000 mg per unit dose. This composition and method involve numbers of excipients, a long series of steps of preparation method and a higher concentration of the cyclodextrin amounting to high costs.

It is seen from prior art that attempts have been made to replace SBE (6.1) -?-CD with hydroxy propyl ß-cyclodextrin as it is cheaper, easily available and required in lower quantity for solubilization purpose as compared with sulfobutyl ether ß-cyclodextrin. A patent document, CN108392638A, titled “A kind of Triamcinolone acetonide-cyclodextrin super molecule inclusion compound and the nasal spray containing it” mentioned the use of cyclodextrin (hydroxy propyl ß-cyclodextrin/ sulfobutyl ether ß-cyclodextrin) for the solubilization of Triamcinolone acetonide in ethanol water mixture (3h) followed by evaporation and lyophilization (12h). Herein it is seen that the preparation method includes use of one or more organic solvents which not only increases the number of excipients having an effect in increasing the cost but also entails larger number of steps consuming more time.

Therefore, there is a need of a safe and cost-effective pharmaceutical composition of aqueous nasal spray solution and a method of its formulation that is simple, requires less time for preparation, uses less amount of solubilizing agent, organic solvents, surfactants and suspending agents while requiring a smaller number of unit operations for formulation preparation compared to the methods in the state of the art.

Accordingly, the present invention discloses a formulation of corticosteroid aqueous nasal spray solution to prevent inflammation due to allergic reactions and a method of preparation of the said aqueous nasal spray.

OBJECT OF THE INVENTION:
The main object of the present invention is to provide a pharmaceutical composition of a corticosteroid in the form of an aqueous nasal spray solution that is capable of preventing inflammation due to allergic reactions.

Another object of the invention is to provide a method of preparation of a pharmaceutical composition of a corticosteroid aqueous nasal spray solution to relieve allergic rhinitis symptoms like sneezing, runny, stuffy, or itchy nose and itchy, watery eyes caused by hay fever or other allergies.

Yet another object of the invention is to provide a pharmaceutical composition of a corticosteroid aqueous nasal spray solution comprising corticosteroid, including but not limited to, Triamcinolone acetonide, mometasone furoate.
Yet another object of the invention is to provide a pharmaceutical composition of corticosteroid aqueous nasal spray solution and a method of preparation of the said aqueous nasal spray that is safe and cost effective.

Yet another object of the invention is to provide a pharmaceutical composition of a corticosteroid aqueous nasal spray solution and a method of preparation of the said aqueous nasal spray which is quick, involves lesser number of steps, is scalable and does not require MDRS studies for determining particle size of the API.

SUMMARY OF THE INVENTION:
Accordingly, the present invention relates to a pharmaceutical composition of a corticosteroid in the form of an aqueous nasal spray solution that is capable of preventing inflammation due to allergic reactions.

The invention provides a method of preparation of a pharmaceutical composition of a corticosteroid aqueous nasal spray solution to relieve allergic rhinitis symptoms like sneezing, runny, stuffy, or itchy nose and itchy, watery eyes caused by hay fever or other allergies.

The present invention relates a pharmaceutical composition of a corticosteroid aqueous nasal spray solution wherein said corticosteroid is selected from triamcinolone acetonide, mometasone furoate, fluticasone furoate, fluticasone propionate, aldosterone, ciclesonide, beclomethasone monopropionate, beclomethasone dipropionate betamethasone budesonide, cloprednol, kortivazol, deoksikorton, desonide, desoximetasone, diflucortolone, flukroloron, flumethasone, flunisolide, fluocinolone, flucinonide, flucortinbutyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, flunisolide, galcinonide, hydrocortisone, icomethasone, meprednisone, ikometazon enbutat, tixocortol 21-pivalate methyl prednisolone, parametasone, prednisone eponid,tixocortol, fluticasosterone/ corticosterone, aqueous nasal spray solution and a method of preparation thereof that is safe and cost effective. The method of this invention involves relatively lesser number of steps and does not require MDRS studies, thus saving expenses on analysis and batch release tests.

Cyclodextrins (CD) are cyclic oligosaccharides made up of a number of dextrose units of (a-1,4)-linked a-D glucopyranose. Cyclodextrins at high doses can increase drug permeability by direct action on mucosal membranes and enhance drug absorption and/or bioavailability. It is seen that nasal administration of highly water-soluble cyclodextrins complexes of steroid hormones provides a rapid rise of drug levels in systemic circulation, avoiding intestinal and hepatic first-pass metabolism of the drugs. ß-CD is generally regarded as safe (GRAS) list of the FDA for use as a food additive.

Cyclodextrins can be used in compositions for enhancing solubility, bioavailability, and chemical stability, for converting liquids and oils to free-flowing powders, for reducing evaporation and stabilizing flavors, for reducing odors and tastes and for releasing controls or protecting against oxidation.

The composition of the present invention comprises of corticosteroid and other excipients including but not limited to a cyclodextrin as solubilizing agent, a chelating agent and/or a stabilizer, an antimicrobial preservative, an antioxidant and / or binder, purified water and a solvent for increasing solubility and/ or stabilizing pH etc. The corticosteroid used in the present invention is selected from triamcinolone acetonide, mometasone furoate, fluticasone furoate, fluticasone propionate, aldosterone, ciclesonide, beclomethasone monopropionate, beclomethasone dipropionate betamethasone budesonide, cloprednol, kortivazol, deoksikorton, desonide, desoximetasone, diflucortolone, flukroloron, flumethasone, flunisolide, fluocinolone, flucinonide, flucortinbutyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, flunisolide, galcinonide, hydrocortisone, icomethasone, meprednisone, ikometazon enbutat, tixocortol 21-pivalate methyl prednisolone, parametasone, prednisone eponid,tixocortol, fluticasosterone/ corticosterone.

Solubilizing agents used in the invention is selected from cyclodextrins including but not limited to ß-cyclodextrins, a-cyclodextrins, ?-cyclodextrins, the amino acids selected from L-leucine, L-histidine,L-lysine, and L-glutamine along with L-arginine, meglumine, sodium chloride, phospholipids, polysorbate-80, polysorbate-20, sodium lauryl sulfate, propylene glycol, polyethylene glycol, carrageenans, sodium carbonate, acidic and basic buffers.

Said antimicrobial preservatives are selected from parabens, phenyl ethyl alcohol, quaternary ammonium antimicrobial agent benzalkonium chloride, EDTA and benzoyl alcohol.

The method of formulation requires less time for preparation, uses less amount of solubilizing agent with no utilization of organic solvents, surfactants or suspending agents, requires a smaller number of unit operations for formulation preparation compared with the state of the art. Also, the present method avoids the need to carry out MDRS (Morphologically Directed Raman Spectroscopy) analysis for the determination of particle size of API versus particle size of excipients such as Avicel used in case of suspension. The present invention avoids use of organic solvent, reduces process time and reduces number of unit operations for formulation preparation.

Thus, it can be said that the pharmaceutical composition of the present invention in the form of an aqueous nasal spray solution is a safe and cost-effective formulation for preventing inflammation due to allergic reactions and relieving the symptoms of many such diseases and disorders. It can be conclusively stated that the method of preparation of the formulation of the present invention requires minimal number of steps, is easy to prepare such that it saves time as well as expenses used in preparing the formulation and getting approvals.

Accordingly, a pharmaceutical composition of present invention in the form of an aqueous nasal spray solution prevents inflammation due to allergic reactions and relieves symptoms due to allergic rhinitis or many other related diseases or disorders.

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1 depicts the solubility of Triamcinolone acetonide in various solubilizing agents.
Figure 1a depicts the solubility of Triamcinolone acetonide (TA) in water, methanol and kleptose by UV method.
Figure 1b depicts the solubility of Triamcinolone acetonide (TA) in water, methanol and kleptose by HPLC estimation.
Figure 2a depicts the Plume geometry of Triamcinolone acetonide suspension formulation at 60 mm.
Figure 2b depicts the Plume geometry of Triamcinolone acetonide aqueous solution formulation at 60 mm.
Figure 3a depicts the Spray pattern of Triamcinolone acetonide suspension at 30 mm.
Figure 3b depicts the Spray pattern of Triamcinolone acetonide solution at 30 mm.
Figure 4a depicts the Spray pattern of Triamcinolone acetonide suspension at 60 mm.
Figure 4b depicts the Spray pattern of Triamcinolone acetonide solution at 60 mm.
Figure 5a depicts the HPLC chromatogram of diluent methanol.
Figure 5b depicts the HPLC chromatogram of standard Triamcinolone acetonide.
Figure 5c depicts the HPLC chromatogram of placebo.
Figure 5d depicts the HPLC chromatogram of freshly prepared Triamcinolone acetonide NS solution formulation.

DETAILED DESCRIPTION OF THE INVENTION:
Some embodiments of the present disclosure, illustrating all its features, will now be discussed in detail. It must also be noted that as used herein and in the appended claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

Various modifications to the embodiment will be readily apparent to those skilled in the art and the generic principles herein may be applied to other embodiments. However, one of ordinary skill in the art will readily recognize that the present disclosure including the definitions listed here below are not intended to be limited to the embodiments illustrated but is to be accorded the widest scope consistent with the principles and features described herein.

A person of ordinary skill in the art will readily ascertain that the illustrated steps detailed in the figures and here below are set out to explain the exemplary embodiments shown, and it should be anticipated that ongoing technological development will change the manner in which particular functions are performed. These examples are presented herein for purposes of illustration, and not limitation. Further, the boundaries of the functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternative boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed. Alternatives (including equivalents, extensions, variations, deviations, etc., of those described herein) will be apparent to persons skilled in the relevant art(s) based on the teachings contained herein. Such alternatives fall within the scope and spirit of the disclosed embodiments

The terminology used herein is for the purpose of describing particular example embodiments only and is not intended to be limiting. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which example embodiments belong. It will be further understood that terms, e.g., those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

The present invention discloses a pharmaceutical composition of a corticosteroid in the form of an aqueous nasal spray, that is capable of preventing inflammation due to allergic reactions and relieving allergic rhinitis symptoms like sneezing, runny, stuffy, or itchy nose and itchy, watery eyes caused by hay fever or other allergies. The method of preparing the said pharmaceutical composition is also disclosed herein.

The present invention discloses different trials for the solubility of triamcinolone acetonide as shown in Table 1 below.

Table 1: Solubility of triamcinolone acetonide using different solubilizing agents
Solubilizing agents % Solubility
Methanol 100.00
10 mM Kleptose 69.76
20 mM Kleptose 89.20
30 mM Kleptose 102.00
20 mM Methyl beta cyclodextrin 56.27
30 mM Methyl beta cyclodextrin 91.90
20 mM betadex sulfobutyl ether sodium 84.55
30 mM betadex sulfobutyl ether sodium 94.10
20 mM hydroxyl ethyl beta cyclodextrin 85.01
30 mM hydroxyl ethyl beta cyclodextrin 92.60
100 mM Megluamine 6.30
500 mM Megluamine 13.60

The aqueous nasal spray comprises of a corticosteroid, wherein said corticosteroid is selected from triamcinolone acetonide, mometasone furoate, fluticasone furoate, fluticasone propionate, aldosterone, ciclesonide, beclomethasone monopropionate, beclomethasone dipropionate betamethasone budesonide, cloprednol, kortivazol, deoksikorton, desonide, desoximetasone, diflucortolone, flukroloron, flumethasone, flunisolide, fluocinolone, flucinonide, flucortinbutyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, flunisolide, galcinonide, hydrocortisone, icomethasone, meprednisone, ikometazon enbutat, tixocortol 21-pivalate methyl prednisolone, parametasone, prednisone eponid,tixocortol, fluticasosterone/ corticosterone, more particularly, triamcinolone acetonide and mometasone furoate for preventing inflammation caused by allergic reactions, a cyclodextrin and hydroxy propyl ß-cyclodextrin (Kleptose) for enhancing absorption and bioavailability as the major components. The formulation also comprises of other excipients including but not limited to chelating agents and/or stabilizers, antimicrobial preservatives, antioxidants and/or binders, purified water and solvents for increasing solubility and/or stabilizing pH etc.

Said solubilizing agents used in the invention is selected cyclodextrins including but not limited to ß-cyclodextrins, a-cyclodextrins, ?-cyclodextrins, the amino acids selected from L-leucine, L-histidine,L-lysine, and L-glutamine along with L-arginine, meglumine, sodium chloride, phospholipids, polysorbate-80, polysorbate-20, sodium lauryl sulfate, propylene glycol, polyethylene glycol, carrageenans, sodium carbonate, acidic and basic buffers.

Said antimicrobial preservatives are selected from parabens, phenyl ethyl alcohol, quaternary ammonium antimicrobial agent benzalkonium chloride, EDTA and benzoyl alcohol.

Table 2 depicts the composition of the aqueous nasal spray per mL of the solution
Table 2: Composition of Triamcinolone acetonide nasal spray aqueous solution at pH 4-6:
Triamcinolone acetonide Solution NS Range of concentration
Sr No. Ingredients Unit quantity in mg/ml
(range of quantity) % %
1 Triamcinolone acetonide, USP 0.550 (0.27-1.1) 0.0550 0.027-0.11
2 Kleptose 46.24 (1-100) 4.62 0.1-10
3 Disodium ethylenediamine tetraacetate, USP 0.500 (0.25-1) 0.050 0.025-0.1
4 Benzalkonium chloride (BzCl) solution, 50 % of BzCl, NF 0.150 (0.075-0.3) 0.015 0.0075- 0.030
5 Dextrose (anhydrous), USP 50.000 (25-75) 5.000 2.5-7.5
6 Purified water, USP q.s q.s q.s
7 Diluted hydrochloric acid, NF q.s q.s q.s
8 0.1 N NaOH solution q.s. q.s. q.s
Total volume 100.00 -

The aqueous solution formulation is prepared by dissolving kleptose in 80 - 90 % water. To this aqueous kleptose solution, triamcinolone acetonide is dissolved at 50°C to 70°C with intermittent stirring for 15-20 min. and sonication for 15-20 min. at room temperature. EDTA dissolved in small portion of warm water and mixed with the kleptose-triamcinolone acetonide solution. This is followed by dissolving benzalkonium chloride and dextrose one after the other to the solution. NaOH and HCl were used to achieve formulation’s pH 4-6. Finally, the solution is filtered through nylon filter under vacuum and stored in nasal spray bottle having pump size 100 µL.

Solubility of Triamcinolone acetonide (TA) was checked in water, methanol and kleptose by UV spectrophotometric and HPLC estimation as shown in Fig. 1a and 1b.

The following UV spectrophotometric parameters were used for estimating the concentration of TA:
• Wavelength- 240 nm,
• Make of instrument- Shimadzu,
• Model- UV 1800,
• Software- UV probe,
• Detector- Silicon Photodiode,
• Source lamp- Deauterum, Tungesten-Halogen,
• Beam type- double,
• Wavelength range- 190-1100 nm.

The following HPLC parameters were used for estimating the concentration of TA:
• Mobile phase- Water: Acetonitrile: 68:32% V/V.
• Column temperature: 45°C,
• Sampler temperature: 15°C,
• Flow rate: 1.5 mL/ min.,
• Wavelength: 240 nm,
• Injection volume: 20 µL,
• Run time: 20 min.,
• Column: BakerBond, C18, 250X 4.6, 5 µm.
• Diluent: Methanol.

Table 3 below depicts the relative solubility of TA in water, methanol and kleptose.
Table 3: HPLC analysis of triamcinolone acetonide solution formulation:
Samples % Assay
Triamcinolone acetonide in methanol 102
Triamcinolone acetonide in water 2.51
Triamcinolone acetonide in solution formulation 100

Solubility of Triamcinolone acetonide in kleptose is estimated to be 100 %, which makes it an ideal choice for dissolving Triamcinolone acetonide. Kleptose (Hydroxy propyl ß-cyclodextrin) having 30 mM concentration is used for solubilizing Triamcinolone acetonide to make its aqueous solution formulation.

The Triamcinolone acetonide aqueous formulation is prepared in the form of aqueous solution using solubilizing agent hydroxy propyl ß-cyclodextrin. Said solution form has many advantages over the currently available suspension dosage form. Solution form is monophasic in nature, has more bioavailability, more stable and also there is no need to check the particle size of excipients in comparison with the suspension form.

Following physicochemical parameters are used to assess the suitability of the types of nasal sprays.
• Viscosity: refers to the state of being thick, sticky, and semi-fluid in consistency, due to internal friction. Viscosity of a nasal spray formulation is critical in retaining the drug in the nasal cavity for long enough to achieve sufficient absorption. It has an impact on spray characteristics such as droplet size, spray geometry and the nasal deposition. Low viscosity gives smaller droplet size and a wider plume angle. High viscosity causes the formation of larger droplets, a narrower spray plume and a smaller spray area.
• Surface Tension: It affects the spreading, distribution and absorption of drug. Increased surface tension decreases the droplet size.
• Average shot weight: refers to the weight of one shot of the spray. It shows the accuracy of nasal spray pump.
• Density: It is useful for examining the final state of a formulation.
• Osmolarity: denotes the solute concentration within a specific volume of the solvent. Osmolarity affects the permeability of the spray through the nasal mucosa.

Table 4 provides a comparative analysis of the physicochemical properties of the solution and the suspension.

Table 4: Comparison of Triamcinolone acetonide NS solution and suspension on the basis of physicochemical properties at the initial timepoint:
Parameters TA Nasal spray Suspension TA Nasal spray solution
Viscosity (cp) 21.5 1
Surface tension (mN/mtr) 60.36 77.76
Average shot weight (mg) 101.2 100.9
Osmolarity (mOsmol/L) 324.33 356.66
Density (g/cm3) 1 1

The nasal spray solution is less viscous than the suspension, as a result of which, the droplet size of the spray is relatively smaller, and the plume angle is wider for the solution. The average shot weight, osmolarity and density of the solution and suspension are similar for the suspension and solution. However, the surface tension of the solution is greater than the suspension, which improves the spreading, distribution and absorption of the pharmaceutical composition in the mucosal lining of the patient.

CHARACTERIZATION OF TRIAMCINOLONE ACETONIDE SOLUTION NASAL SPRAY AT THE INITIAL TIMEPOINT:
The Triamcinolone acetonide aqueous nasal spray was characterized on the basis of plume geometry, spray pattern and droplet size distribution. Spray pattern and plume geometry are important tests for orally inhaled and nasal drug product (OINDP) characterization.
(a) Plume geometry: refers to the spray angle and plume width. Spray angle is the angle of the emitted plume measured from the vertex of the spray cone and spray nozzle. Plume width is the width of the plume at a given distance from the spray nozzle. The plume geometry of the nasal spray was measured at 60 mm. with reference to plume width, plume height and plume angle. Plume geometry was checked for 14th, 15th and 16th number of sprays. Plume geometry data is provided in Table 5. Plume geometry has been diagrammatically represented in Fig. 2a and 2b.

Table 5: Characterization of Triamcinolone acetonide solution NS
based on Plume geometry
Plume geometry Unit life (Spray number) Plume width (mm) Plume height (mm) Plume angle (deg)
Lot: T1_Initial_60mm 14 59.63 60 52.9
15 57.97 60 51.6
16 59.97 60 53.1
Mean 59.19 60.00 52.53

(b) Spray Pattern: affects aerosolization, spray performance, and subsequent bioavailability of the delivered drug. Nasal cavity or internal nose of human beings is 60 to 70 mm long. It is important to check the spray pattern of the nasal spray at two points 30 mm and 60 mm in the instrument. Accordingly, the spray pattern was assessed at 30 mm and 60 mm, with reference to shortest and longest diameter (Dmin and Dmax) of the spray (Minimum and maximum diameter through the center of gravity), ovality ratio (ratio of Dmax to Dmin) and area of the spray. Spray pattern data is provided in Table 6a and 6b. The data has been diagrammatically depicted in Fig. 3a and 3b.

Table 6a: Characterization of Triamcinolone acetonide solution NS
based on Spray Pattern at 30 mm
Spray Pattern at 30 mm Unit life (Spray number) Dmin (mm) Dmax (mm) Ovality ratio Area (mm square)
Lot: T1_Initial_30 mm 6 33.09 36.43 1.101 914.3
7 32.67 36.34 1.112 907.3
8 32.64 36.36 1.114 909.6
Mean 32.80 36.38 1.11 910.40

Table 6b: Characterization of Triamcinolone acetonide solution NS
based on Spray Pattern at 60 mm.
Spray Pattern at 30 mm Unit life (Spray number) Dmin (mm) Dmax (mm) Ovality ratio Area (mm square)
Lot: T1_Initial_30 mm 6 33.09 36.43 1.101 914.3
7 32.67 36.34 1.112 907.3
8 32.64 36.36 1.114 909.6
Mean 32.80 36.38 1.11 910.40

c) Droplet Size: the droplet size distribution of the nasal spray was measured at 30 mm and 60 mm. Table 7a and 7b depict the droplet size distribution.
Table 7a: Droplet size distribution at 30 mm.
Batch no. and condition Unit life (Spray number) D10 (µm) D50 (µm) D90 (µm) % of Droplets <10 micron particles Span
Lot: T1_Initial_30 mm 20 14.54 33.82 76.01 2.65 1.818
21 14.7 33.85 76.46 2.409 1.824
22 14.79 34.1 76.3 2.423 1.804
Mean 14.68 33.92 76.26 2.49 1.82

Table 7b: Droplet size distribution at 60 mm.
Batch no. and condition Unit life (Spray number) D10 (µm) D50 (µm) D90 (µm) % of Droplets <10 micron particles Span
Lot: T1_Initial_60 mm 24 17.99 34.91 64.03 1.22 1.319
25 18.22 35.26 64.5 1.207 1.313
26 17.56 34.88 64.94 1.559 1.358
Mean 17.92 35.02 64.49 1.33 1.33

At 30 mm, 10 % of the particles were less than 14.68 µm in diameter, 50 % of the particles were less than 33.92 µm in diameter and 90 % of the particles were less than 76.26 µm in diameter. Similarly, at 60 mm, 10 % of the particles were less than 17.92 µm in diameter, 50 % of the particles were less than 35.02 µm in diameter and 90 % of the particles were less than 64.49 µm in diameter.

STABILITY OF THE NASAL SPRAY FORMULATION
Triamcinolone acetonide nasal spray solution formulation having 550 ppm concentration was filled in 15 mL polypropylene bottles and kept for stability studies at 2-8 ?, 25?, 40? for 1, 3 and 6 months. One formulation set which was stored at 40? for first 6 months and later it was stored for further 6 months at 30? (total 12 months of storage) and checked the stability.

The stability of Triamcinolone acetonide (TA) samples were tested based on the different characteristics such as % HPLC assay and pH, at every time point and all other characterizations were performed at initial and final timepoints.

Data reflecting the stability of TA samples kept for different time points such as one, three and six months under different conditions of temperature and relative humidity has been depicted in Table 8a, 8b and 8c. The formulation set which was stored at 40? for first 6 months and later it was stored for further 6 months at 30? (total 12 months of storage) has been depicted in Table 8d. The pH and % HPLC assay of TA samples remained almost same under different temperature and humidity.

Table 8a: HPLC and pH analysis of 1 month’s stability study Triamcinolone acetonide formulation samples stored in polypropylene bottles.
Samples (10 ppm) % HPLC assay of Triamcinolone acetonide pH
Standard TA 100 -
TA in formulation 1 month 2-8°C temp 97.6 5.06
TA in formulation 1 month 25°C temp, 60% RH 98.13 5.02
TA in formulation 1 month 40°C temp, 75 % RH 99.17 4.9

Table 8b: HPLC and pH analysis of 3 month’s stability study Triamcinolone acetonide formulation samples stored in polypropylene bottles.
Samples (10 ppm) % HPLC assay of Triamcinolone acetonide pH
Triamcinolone acetonide standard in methanol (freshly prepared) 100 -
Triamcinolone acetonide, 2-8°C, 3 months 98.13 4.95
Triamcinolone acetonide, 25°C, 60% RH, 3 months 96.73 4.87
Triamcinolone acetonide, 40°C, 75% RH, 3 months 97.95 4.6

Table 8c: HPLC analysis, pH and osmolarity of Triamcinolone acetonide formulation samples stored in polypropylene bottles and kept for 6 month’s stability study

Samples (10 ppm) % HPLC assay of Triamcinolone acetonide pH Osmolality
Triamcinolone acetonide formulation 100 - 356.66
Triamcinolone acetonide, 2-8°C, 6 months 99.31 4.96 354.66
Triamcinolone acetonide, 25°C, 60% RH, 6 months 99.43 4.79 359.66
Triamcinolone acetonide, 40°C, 75% RH, 6 months 99.81 4.49 361.33

Table 8 d: % HPLC assay of triamcinolone acetonide solution formulation stored in polypropylene bottles after 12 months (1st 6 M at 40°C and later at 30°C).

Samples (10 ppm) % HPLC assay of Triamcinolone acetonide in formulation pH
Triamcinolone acetonide standard in methanol (freshly prepared)
100
-
Triamcinolone acetonide, 30°C 101 4.63

Table 9: Triamcinolone acetonide solution formulation stored in polypropylene bottles 6 month’s stability under varying temperature
Parameters Solution (freshly prepared) Solution kept at 2-8 °C after 6 months Solution kept at 25 °C after 6 months Solution kept at 40 °C after 6 months
Viscosity (cp) 1 0.5 0.5 1
Surface tension (mN/mtr) 77.76 75.5 77.7 75.64
Osmolality (mOsmol/Kg) 356.66 354.66 359.66 361.33
Density (g/cm3) 1 1 1 1

TA formulation stored in polypropylene bottles was found to be stable on the basis of different parameters such as pH, % HPLC assay, viscosity, surface tension, osmolality, and density etc. Stability of TA formulation was also studied in HDPE bottles at 2-8?, 25?, 30? 40? for 1, 3 and 6 months to compare the data with formulation stored in polypropylene bottle.

Table 10a: HPLC analysis of 1 month’s stability study Triamcinolone acetonide formulation samples stored in High Density Polyethylene bottles (HDPE) bottles.
Triamcinolone acetonide (TA) samples (10 ppm) % HPLC Assay pH
Standard TA in methanol 100 -
TA in formulation 2-8°C temp 92 4.82
TA in formulation 25°C temp, 60% RH 106 4.69
TA in formulation 30°C temp, 75% RH 104 4.9
TA in formulation 1 month 40°C temp, 75 % RH 100.3 4.95

Table 10b: HPLC analysis of 3 month’s stability study Triamcinolone acetonide formulation samples stored in HDPE bottles.
Sample (10 ppm) % HPLC assay of Triamcinolone acetonide formulation pH
Triamcinolone acetonide standard in methanol (freshly prepared) -
Triamcinolone acetonide, 2-8°C 100 4.81
Triamcinolone acetonide, 25°C, 60% RH 102.7 4.94
Triamcinolone acetonide, 30°C, 75% RH 98.03 4.87
Triamcinolone acetonide, 40°C, 75% RH 100.3 4.69

Table 10c: HPLC analysis of 6 month’s stability study Triamcinolone acetonide formulation samples stored in HDPE bottles.
Sample (10 ppm) % Triamcinolone acetonide pH
Triamcinolone acetonide, 2-8°C 100 4.82
Triamcinolone acetonide, 25°C, 60% RH 102 4.85
Triamcinolone acetonide, 30°C, 75% RH 99 4.74
Triamcinolone acetonide, 40°C, 75% RH 106 4.62

Table 11: Stability studies of Triamcinolone acetonide aqueous solution stored in HDPE bottles formulation under different conditions.
Parameters Solution (freshly prepared) Solution kept at 2-8 °C after 6 months Solution kept at 25 °C after 6 months Solution kept at 40 °C after 6 months
Viscosity (cp) 1 0.5 0.5 1
Surface tension (mN/mtr) 77.76 75.5 77.7 75.64
Osmolality (mOsmol/Kg) 356.66 354.66 359.66 361.33
Density (g/cm3) 1 1 1 1

Stability of Triamcinolone acetonide aqueous solution formulation kept in HDPE bottles at different conditions such as 2-8°C, 25°C, 60% RH, 30°C, 75% RH, 25°C, 75% RH for 6 months was assessed on the basis of HPLC analysis, pH and osmolarity, viscosity, surface tension, density etc. Triamcinolone acetonide aqueous solution formulation kept in both polypropylene and HDPE bottles at different conditions was found to be stable.

As depicted in Table 12, the Triamcinolone acetonide solution formulation is comparable with that of suspension and also stable after 6 months of time period at different stability conditions based on characteristics such as spray pattern, plume geometry, and droplet size distribution.

Table 12: Stability studies of Triamcinolone acetonide aqueous solution formulation stored in Polypropylene bottles under different conditions.
Analytical parameter Triamcinolone acetonide suspension Initial Triamcinolone acetonide solution After 6 months TA solution at 2-8 °C After 6 months TA solution at 25°C After 6 months TA solution at 40°C Approximately Acceptable range
Avg. D10 at 30 mm (µm) 14.78 14.67 15.03 15.05 14.44 10-30 µm
Avg. D10 at 60 mm (µm) 18.95 17.92 18.09 17.49 17.44 10-30 µm
Avg. D50 at 30 mm (µm) 34.28 33.92 33.65 33.47 32.9 30-70 µm
Avg. D50 at 60 mm (µm) 36.75 35.01 34.86 34.47 35.08 30-70 µm
Avg. D90 at 30 mm (µm) 78.71 76.25 76.38 71.95 72.79 < 120
Avg. D90 at 60 mm (µm) 67.59 64.49 64.12 64.02 65.69 < 120
Span at 30 mm 1.865 1.815 1.83 1.7 1.77 <2
Span at 60 mm 1.323 1.33 1.32 1.35 1.383 <2
% Droplets <10 µm at 30 mm 3.039 2.494 2.032 2.56 3.084 As minimum as possible
% Droplets <10 µm at 60 mm 1.68 1.328 1.477 1.58 1.905 As minimum as possible
Plume angle (°) 46.26 52.53 50.63 50.43 50.5 45-90°
Ovality ratio at 30 mm 1.17 1.109 1.096 1.083 1.092 1-1.2- circular
Ovality ratio at 60 mm 1.25 1.175 1.25 1.152 1.192 1-1.2- circular

Table 13: Triamcinolone acetonide suspension NS at pH 4-6.
Ingredients Unit quantity (mg/ml) %
Triamcinolone acetonide, USP 0.550 0.0550
Mixture of microcrystalline cellulose and carboxymethylcellulose sodium, NF Avicel CL 611, NF 20.000 2.000
Polysorbate 80, NF surfactant 0.040 0.0040
Disodium ethylenediamine tetraacetate, USP 0.500 0.050
Benzalkonium chloride (BzCl) solution, 50 % of BzCl, NF 0.150 0.015
Dextrose (anhydrous), USP 50.000 5.000
Purified water, USP q.s q.s
Diluted hydrochloric acid, NF q.s q.s
0.1N NaOH solution q.s. q.s.
Total 100.00

The above table no. 13 depicts the list of ingredients for Triamcinolone acetonide suspension NS

Table 14: Triamcinolone acetonide solution NS at pH 4- 6.
Ingredients Unit quantity (mg/ml) %
Triamcinolone acetonide, USP 0.550 0.0550
Kleptose 46.24 4.62
Disodium ethylenediamine tetraacetate, USP 0.500 0.050
Benzalkonium chloride (BzCl) solution, 50 % of BzCl, NF 0.150 0.015
Dextrose (anhydrous), USP 50.000 5.000
Purified water, USP q.s q.s
Diluted hydrochloric acid, NF q.s q.s
0.1N NaOH solution q.s. q.s.
Total 100.00

The above table no. 14 depicts the list of ingredients for Triamcinolone acetonide solution NS. Triamcinolone acetonide aqueous solution formulation is prepared using solubilizing agent Hydroxypropyl ß-cyclodextrin. Solution dosage form has some advantages over the currently available suspension. Solution dosage form is monophasic in nature, has more bioavailability, more stable both in polypropylene and HDPE bottles and no need to check the particle size of excipients in comparison with the suspension form.

Characterization of Triamcinolone acetonide stored in Tarson tubes after 12 M was carried out. The result as obtained is shown in Table 15 (storage 1st 6 M at 40?C and next 6 M at 30?C)

Table 15: Characterization of Triamcinolone acetonide solution formulation stored in polypropylene bottles after 12 M.
Parameters Solution (freshly prepared) Solution 6 M Solution 12 M
Viscosity (cp) 1 1 0.5
Surface tension (mN/mtr) 77.76 77.76 72.00
Average shot weight (mg) 100.9 100.9 104.0
Osmolality (mOsmol/Kg) 356.66 356.66 373
Density (g/cm3) 1 1 1
pH 4-6 4-6

Inference: Physical parameters such as pH, density, osmolality, average shot weight, surface tension, viscosity for 12 month’s stability have been found to be considerably same when compared with the initial data.

Accordingly, the present invention provides a corticosteroid aqueous nasal spray solution which is stable, effective than the formulations available in the market and a method of preparation of the said aqueous nasal spray which is rapid, involves lesser number of steps, is scalable and does not require MDRS studies for determining particle size of the API.

EFFICACY STUDY OF TRIAMCINOLONE ACETONIDE SOLUTION FORMULATION USING IN-VITRO GLUCOCORTICOID RECEPTOR ASSAY

Table 16: Triamcinolone acetonide suspension

Sr. No. Samples % Binding activity of corticosteroid with NR3C1
1 Triamcinolone acetonide aqueous solution 0.045 % 39.71
2 Triamcinolone acetonide aqueous suspension 0.045 % No activity

Triamcinolone acetonide aqueous solution is showing 39.71 % binding activity with glucocorticoid receptor NR3C1. Whereas, Triamcinolone acetonide aqueous suspension is not showing the activity which might be due to its immiscibility with the assay mixture. This in-vitro glucocorticoid receptor assay confirms the efficacy of triamcinolone acetonide solution formulation to bind with the glucocorticoid receptor NR3C1 hence, ultimately showing the activity against the rhinitis.

ACUTE TOXICITY AND EFFICACY STUDIES OF AQUEOUS MOMETASONE FUROATE SOLUTION FORMULATION
Aqueous Mometasone furoate solution formulation has been prepared by dissolving it in 50 mM (7.71 %) hydroxypropyl ß-cyclodextrin and excipients. Its toxicity and efficiency have been checked by gills exposure in adult Zebra fish, Danio Rerio.
To obtain sufficient information on the test item thorough an acute toxicity study based on administration of the test item through gills to zebrafish. The test item is applied over gills at defined multiple concentrations. Absence or presence of test item related mortality of the fishes will determine the LD50 of the test item. The gills of fishes are exposed to the test item for the period of 96 hours. Mortalities are recorded at 24, 48, 72 and 96 hours and the lethal concentrations are determined. The study was done to evaluate the lethal and toxic concentration of Test item, Mometasone furoate in freshwater zebrafish, Danio rerio and to select the range of non-lethal doses for evaluation of innate cytokine responses by Mometasone furoate (Nasal Spray) in R848 respiratory mucosal challenged freshwater zebrafish model, Danio rerio.

Acute toxicity studies
Table 17: Test System
Species Danio rerio (Zebrafish)
Strain Wild –type
Sex Male and female (1:1)
Source Whizbang Bioresearch Pvt. Ltd.
Age at start of dosing 3 - 4 months post fertilization
Justification for the selection of test system Exploratory Efficacy studies are planned in this species in-line with 3R’s principle to reduce usage of rodents
Body weight range 0.415±0.100 g
Body length range 3.3±0.5 cm

Table 18: Grouping & Dosing
Group Concentration Dose
volume* Dose/fish Number of
fishes
Group 1 0 µg/mL 10 µL 0 6
Group 2 300 µg/mL 10 µL 3 µg 6
Group 3 150 µg/mL 10 µL 1.5 µg 6
Group 4 75 µg/mL 10 µL 0.75 µg 6
Group 5 37.5 µg/mL 10 µL 0.375 µg 6
Group 6 18.75 µg/mL 10 µL 0.188 µg 6
Note: *5 µL per gill/fish

Table 19: BEHAVIOURAL / VISIBLE ABNORMALITY AND OTHER CLINICAL SIGNS OF TOXICITY
Groups & Concentrations /
Observation Group I
(placebo) Group II
300 µg/mL Group II
150 µg/mL Group II
75 µg/mL Group II
37.5 µg/mL Group II
18.75 µg/mL
Time Interval
(Hours) No. of Fish observed 6 6 6 6 6 6

0 Continuous jerk of caudal fin 0 6 6 6 6 6
lack of movement 0 6 6 6 6 6
slow swimming 6 0 0 0 0 0
bottom settlement 6 6 6 6 6 6
Increased opercular movement 6 6 6 6 6 6
Increased movement of pectoral fins 6 6+ 6+ 6 6 6
0.5 Continuous jerk of caudal fin 0 6 5 4 4 4
Slow swimming 2 2 0 0 0 0
Bottom settlement- frequent 6 6 6 6 6 6
Increased in opercular movement 0 6 6 6 6 6
Increased movement of pectoral fins 0 6+ 2+ 0 0 0
2 Continuous jerk of caudal fin 0 6 4 2 2 2
Slow swimming 1 2 0 0 0 0
Bottom settlement- frequent 4 6 4 5 4 4
Increased in opercular movement 0 5 5 5 6 4
Increased movement of pectoral fins 0 5 2 0 0 0
24 Occasional jerk of caudal fin 0 6 3 1 0 0
Occasional erratic swimming 0 5 0 0 0 0
No Observable abnormality 6 0 3 5 6 6
48 No Observable abnormality 6 6 6 6 6 6
72 No Observable abnormality 6 6 6 6 6 6
96 No Observable abnormality 6 6 6 6 6 6
Note: + Vigorous movement of pectoral fins.
Table 20: Summary of Mortality
Groups Sample Mortality (%) at the end of 96 h
Group I Control (Placebo) 0%
Group II 300 µg/mL 0%
Group III 150 µg/mL 0%
Group IV 75 µg/mL 0%
Group V 37.5 µg/mL 0%
Group VI 18.75 µg/mL 0%

Table 21: Summary of Body weight & body length
Groups & concentration Group 1
(control)
Group 2
300 µg/mL
Group 3
150 µg/mL
Group 4
75 µg/mL
Group 5
37.5 µg/mL
Group 6
18.75 µg/mL

Observation
Time
Interval
(Hours)
Body weight (g) 0 0.446 0.352 0.369 0.430 0.490 0.400
96 0.396 0.377 0.359 0.417 0.417 0.397
Body length
(cm) 0 3.6 3.2 3.8 3.1 3.1 3.0
96 3.6 3.2 3.8 3.1 3.1 3.0

Conclusion:
The toxicity result shows the evidence that,
• No mortality was observed at any tested concentrations within 96 h after exposure.
• The clinical signs of toxicity and Behavioural abnormality recorded were, Jerk of caudal fin, lack of movement, slow swimming, bottom settlement, increased opercular movement, increased movement of pectoral fins, and erratic swimming. The signs of toxicity appeared in dose dependant manner.
• The clinical signs of toxicity and Behavioural abnormality at 150 µg/ mL was started reversing within first half hour as compared to 300 µg/mL where effects were persistent upto first 24 hour in 2/6 fish.
• No Mortality or test item related clinical signs of toxicity were observed in control group. Mild swimming behaviour abnormality was observed until 2 h of exposure, probably due to the route of administration of vehicle, which is insignificant.
• Based on lack of mortality at highest concentration 300 µg/mL within 96 hours after exposure, and reversal of the clinical signs of toxicity and Behavioural abnormality, the doses for efficacy study are proposed as High dose- 300 µg/mL, and low dose- 150 µg/ mL.
• As no mortality is seen at highest dose tested (maximum attainable concentration, no LD50 could be derived.
• LD50 of test item after gill exposure is considered >300 µg/mL.

EFFICACY STUDIES: EVALUATION OF INNATE CYTOKINE RESPONSES BY MOMETASONE FUROATE FORMULATION IN R848 RESPIRATORY MUCOSAL CHALLENGED ADULT ZEBRAFISH, DANIO RERIO BY GILLS EXPOSURE
Resiquimod
Table 22: Grouping & Dosing
Group Concentration Dose volume* Dose/ fish Number of fishes
Group 1 Placebo 0 µg/mL 5µL 0 10
Group 2 R848 alone 0.5 µg/mL 5µL 2.5 µg 10
Group 3 Marketed drug 500 µg/mL 5µL 2.5 µg 10
Group 4 MF- Low 150 µg/mL 5µL 0.75 µg 10
Group 5 MF- High 300 µg/mL 5µL 1.5 µg 10
*-5 µL per gill/fish

CONCLUSION
The result shows the evidence that,
• No mortality was observed at any tested concentrations within 8 hours after exposure.
• The clinical signs of toxicity and Behavioural abnormality were observed in all the test concentrations including placebo group, however incidence and severity was higher at R848 only, marketed drug and high dose of test item (300 µg/mL). The clinical signs of toxicity and Behavioural abnormality recorded were, continuous jerk of caudal fin with lack of movement & bottom settled, Vigorous movement of pectoral fins, and increase in opercular movement.
• Histopathological observation of gills revealed no significant inflammatory cells (neutrophil/lymphocyte) infiltration in induction group (R848), similarly the marketed drug and test item groups showed no inflammatory cells.
• Cytokine qPCR analysis supports following

Placebo (Group 1): Expected low expression with varying levels of variability.

Induction Group (Group 2): R848 (Resiquimod) is a known agonist of Toll like receptors (TLR7 and TLR8), which are involved in the innate immune response.
Activation of these receptors often leads to the production of inflammatory cytokines.

The high mean normalized expression in the induction group, coupled with the
mechanism of action of R848, supports the interpretation that this group signifies inflammatory cytokine expression. This is a typical outcome expected from the activation of TLR7/8 pathways by an agonist like R848, leading to an inflammatory response characterized by increased cytokine levels.

Marketed Drug (Group 3): provided consistent and moderate efficacy across
cytokines, serving as a reliable benchmark.

Low Dose Test Item (Group 4): shows higher cytokine expression than the • High Dose and marketed drug for TNF-a, INF-?, and IL-1ß, suggesting limited efficacy. However, for IL-6 and IFN, the results are more variable.

High Dose Test Item (Group 5): Shows significant efficacy compared to the low dose for TNF-a and IFN, but demonstrates significant efficacy for IL-1ß and IL-6. This suggests a non-linear dose-response relationship.

,CLAIMS:We claim:

1. A pharmaceutical nasal spray composition comprising of
a. Corticosteroid as active ingredient;
b. an additive for enhancing absorption and bioavailability;
c. an additive as chelating agents and/or stabilizers;
d. an additive for antimicrobial preservatives; and
e. purified water
wherein the composition is formulated to prevent inflammation due to allergic reactions

2. The composition as claimed in claim 1, wherein said corticosteroid is selected from triamcinolone acetonide, mometasone furoate, fluticasone furoate, fluticasone propionate, aldosterone, ciclesonide, beclomethasone monopropionate, beclomethasone dipropionate betamethasone budesonide, cloprednol, kortivazol, deoksikorton, desonide, desoximetasone, diflucortolone, flukroloron, flumethasone, flunisolide, fluocinolone, flucinonide, flucortinbutyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, flunisolide, galcinonide, hydrocortisone, icomethasone, meprednisone, ikometazon enbutat, tixocortol 21-pivalate methyl prednisolone, parametasone, prednisone eponid,tixocortol, fluticasosterone/ corticosterone.

3. The composition as claimed in claim 1, wherein said composition is in the form of aqueous nasal spray solution.

4. The composition as claimed in claim 1, wherein said the additive for enhancing solubility, absorption and bioavailability is selected from cyclodextrins including ß-cyclodextrins, a-cyclodextrins, ?-cyclodextrins, the amino acids selected from L-leucine, L-histidine,L-lysine, and L-glutamine along with L-arginine, meglumine, sodium chloride, phospholipids, polysorbate-80, polysorbate-20, sodium lauryl sulfate, propylene glycol, polyethylene glycol, carrageenans, sodium carbonate, acidic and basic buffers

5. The composition as claimed in claim 1, wherein said chelating agents are selected from alkali salt of metal such as magnesium, calcium and potassium having atleast one acidic group, alkali metal salt of Ethylene diamine tetra-acetic acid, in the form of mono, di, tri, or tetra sodium and Disodium ethylenediamine tetraacetate.

6. The composition as claimed in claim 1, wherein said antimicrobial preservatives are selected from parabens, phenyl ethyl alcohol, quaternary ammonium antimicrobial agent benzalkonium chloride, EDTA and benzoyl alcohol.

7. The pharmaceutical composition as claimed in claim 1, consisting of

Ingredient Concentration Range
(mg/ml)
Corticosteroid 0.027-0.11
Kleptose 0.1-10
Disodium ethylenediamine tetraacetate, USP 0.025-0.1
Benzalkonium chloride (BzCl) solution, 50 % of BzCl, NF 0.0075- 0.030
Dextrose (anhydrous), USP 2.5-7.5
Purified water, USP q.s
Diluted hydrochloric acid, NF q.s
0.1N NaOH solution q.s

8. A process for preparing a pharmaceutical nasal spray composition wherein the steps of said preparation comprise of:
a. dissolving kleptose in 80% to 90% of water to obtain aqueous kleptose solution
b. dissolving triamcinolone acetonide in the aqueous kleptose solution at suitable temperature with intermittent stirring followed by sonification
c. mixing aqueous solution of dissolved EDTA to the solution as obtained in step (b)
d. sequentially dissolving benzalkonium chloride and dextrose to the solution as obtained in step (c)
e. adjusting the pH of the solution between 4 to 6.0 with the addition of NaOH or HCl.
f. filtering the solution through nylon filter under vacuum and stored in nasal spray bottle
to obtain an aqueous nasal spray solution which is capable of preventing inflammation due to allergic reactions.

9. The process as claimed in claim 8, wherein said dissolution of step (b) is performed at 50°C to 70°C.

10. The process as claimed in claim 8, wherein said stirring is performed for 15-20 min and sonication is performed for 15-20 min at room temperature.

11. The process as claimed in claim 1, wherein the preparation time is minimized, resulting in a cost-effective formulation suitable for preventing inflammation due to allergic reactions and relieving symptoms of related diseases and disorders

12. The composition as claimed in claim 1 wherein said composition is an aqueous nasal spray solution to relieve allergic rhinitis symptoms like sneezing, runny, stuffy, or itchy nose and itchy, watery eyes caused by hay fever or other allergies.