Paracetamol formulation for intranasal administration

Abstract

The present invention relates to a pharmaceutical formulation comprising paracetamol that can be administered intranasally.

Description

[0001] PARACETAMOL FORMULATION FOR INTRANASAL ADMINISTRATION

[0002] Field of the Invention

[0003] The invention relates to a pharmaceutical formulation that can be administered intranasally.

[0004] In particular, the invention relates to a pharmaceutical formulation for intranasal administration comprising 0.25-10% paracetamol by weight and at least one pharmaceutically acceptable excipient.

[0005] State of the Art

[0006] Pain and painful symptoms are the complaints that immediately take the first place among the reasons for consulting a physician. There are many groups of drugs and forms of use that can be used in the treatment of such pains. The most commonly used analgesic drugs are classified as opioids (narcotics), adjuvant analgesics, nonopioid analgesics (non-narcotic analgesics), paracetamol and aspirin, NSAIDs.

[0007] Intranasal (IN) analgesia provides safe and timely relief of pain without discomfort and prevents delays in treatment with oral administration. With IN drug pharmacokinetics, reduction of drug absorption, therapeutic drug levels with minimal side effects and adequate analgesia are provided. IN drug administration is often used in place of parenteral opioids to provide analgesia in children. There are many studies showing the analgesic efficacy of ketamine administered perioperatively in the acute postoperative period. The maximum analgesic effect for intranasal ketamine spray begins approximately 3-4 minutes after reaching the maximum plasma concentration.

[0008] In a study conducted by the inventors, it was observed that intranasal ketamine administered for analgesia in pediatric patients following adenotonsiliectomy proved to be more effective than the analgesic effect of intravenous paracetamol at all time periods from 15 minutes postop to 24 hours postop. Side effects such as sedation, nausea, vomiting and respiratory depression can be seen in the use of ketamine. Intranasal fentanyl has been shown to be an effective, safe, and well-tolerated analgesia method for preoperative and postoperative pain control in pediatric patients, acute pain control in the emergency department in adults, and the management of attack pain in cancer patients. Fentanyl, on the other hand, is a morphine-derived drug and can be addictive in relation to the dose during use. Ketamine and fentanyl are green prescription drugs and there are dose limitations. Uncontrolled use outside the hospital may cause the emergence of unwanted side effects. For this reason, they could not be offered for sale as products in the market.

[0009] As seen above, although there are many different products, fentanyl, which is an opioid derivative, and ketamine are still not sufficient on their own for use as intranasal painkillers. The formulation of this invention is a new product that will serve as an answer to these problems.

[0010] Paracetamol is known as a therapeutic agent with analgesic activity and its chemical name is N- (2,3,5,6-tetradeuterio-4-hydroxyphenyl) acetamide as well as its chemical structure is as shown in Formula I.

[0011] Although its analgesic effect remains mild compared to new generation analgesics, the fact that it has almost no side effects in the gastrointestinal system, its reliability and its ability to be used by pregnant women ensures that paracetamol always remains at the forefront and is a classic analgesic.

[0012] The invention discloses a new product for intranasal use containing paracetamol.

[0013] As a result, due to the abovementioned disadvantages and the insufficiency of the current solutions regarding the subject matter, a development is required to be made in the relevant technical field.

[0014] Brief Description of the Invention

[0015] The invention relates to a pharmaceutical formulation comprising paracetamol that meets the above-mentioned requirements, eliminates all disadvantages and can be administered intranasally, which brings some additional advantages. The primary aim of the invention is to present a new pain reliever product that can be administered nasally and comprises paracetamol with minimal side effects.

[0016] Another aim of the invention is to provide an effective formulation for the nasal use of paracetamol to be used in relieving pain complaint (headache, toothache, abdominal pain, neck pain).

[0017] Another aim of the invention is to provide safe and rapid treatment of pain.

[0018] The invention aims to provide an analgesic nasal spray formulation that will provide an alternative treatment and easier application to patients in the pediatric age group who cannot swallow oral analgesics due to their underlying neurological problems or refuse to take oral analgesics and who have painful swallowing complaints after tonsillectomy.

[0019] The invention aims to provide a nasal administration of paracetamol for the treatment of pain with minimal side effects.

[0020] In order to fulfil the aforementioned aims, the invention is a pharmaceutical formulation that can be administered intranasally, comprising 0.25%-10.0% paracetamol by weight and at least one pharmaceutically acceptable excipient in the total formulation.

[0021] The structural and characteristic features and all the advantages of the invention will be understood more clearly due to the detailed description given below, and therefore the evaluation should be made while taking this detailed description into consideration.

[0022] Brief Description of the Figures

[0023] Figure 1 : In vitro release profiles of nasal spray formulations containing (A) diclofenac sodium, (B) ibuprofen and (C) paracetamol.

[0024] Figure 2: Liveliness of CCD-1079Sk cells incubated with various concentrations of diclofenac sodium, ibuprofen, and paracetamol for 1 , 6, and 24 hours (mean ± SD, n=3).

[0025] Figure 3: Analysis images of cells stained with AO / EB after 24 hours of treatment with Diclofenac Sodium, Ibuprofen and Paracetamol followed by green (living cells) and red (dead cells) using a fluorescent microscope. Figure 4: Analysis images of cells subjected to electrophoresis after 24 hours of treatment with Diclofenac Sodium, Ibuprofen and Paracetamol and stained with Ethidium Bromide followed up by fluorescent microscope imaging.

[0026] Detailed Description of the Invention

[0027] In this detailed description, the invention, which is a pharmaceutical formulation containing paracetamol, which can be administered intranasally, is described only for a better understanding of the subject and in a way that does not have any limiting effect.

[0028] The invention will provide an effective treatment due to a pharmaceutical formulation comprise paracetamol that can be administered intranasally, while also minimizing the side effects and dependencies that may occur during its use in the preferred nasal spray form.

[0029] According to an embodiment, the invention is a pharmaceutical formulation for intranasal administration, that comprises 0.25% -10.0% paracetamol by weight and at least one pharmaceutically acceptable excipient in the total formulation.

[0030] According to an embodiment, the invention is pharmaceutical formulation for intranasal administration, that comprises 1% paracetamol by weight in the total formulation.

[0031] According to an embodiment of the invention, due to the intranasal (IN) use of paracetamol, analgesia provides safe and timely relief of pain without discomfort and prevents delays in treatment with oral administration. With IN drug pharmacokinetics, reduction of drug absorption, therapeutic drug levels with minimal side effects and adequate analgesia are provided.

[0032] According to one embodiment of the invention, the pharmaceutical composition comprises at least one wetting agent, at least one flocculating agent, at least one suspension agent, at least one tonicity adjusting agent, at least one preservative agent, at least one buffering agent, or at least one pharmaceutically acceptable excipient selected from the group comprising the mixture thereof.

[0033] According to an embodiment of the invention, at least one wetting agent may be comprised, of but is not limited to, the following components; propylene glycol, polyethylene glycol, glycerin, hyaluronic acid, inositol, lactitol, maltitol, maltose, mannitol, mannose, potassium PCA, sodium PCA, sorbitol.

[0034] According to one embodiment of the invention, the wetting agent is sorbitol.

[0035] According to an embodiment of the invention, the total formulation preferably comprise 0.05%-10%, more preferably 1%-5% sorbitol by weight.

[0036] According to one embodiment of the invention, at least one flocculating agent may be comprised of, but is not limited to, the following components; non-ionic or anionic surfactants, hydrophilic polymers and some clay may be used for this purpose.

[0037] Typical examples of anionic surfactants include but are not limited to soaps, alkyl benzene sulfonates, alkane sulfonates, olefin sulfonates, alkyl ether sulfonates, glycerol ether sulfonates, alpha-methyl ester sulfonates, sulfolipid acids, alkyl sulfates, fatty alcohol ether sulfates, glycerol ether sulfates, fatty acid ether sulfates, hydroxy mixed ether sulfates, monoglycerides (ether) sulfates, fatty acid amide (ether) sulfates, mono and dialkyl sulfosuccinates, mono- and dialkyl sulfosuccinamates, sulfotriglycerides, amide soaps, ether carboxylic acids and their salts, fatty acid isethionates, fatty acid sarcosinates, fatty acid taurides, acyl lactylates, acyl tartrates, acyl glutamates and acyl aspartates, alkyl oliglucoside sulfates, protein, fatty acid condensates (especially wheat based plant products) and alkyl (ether) phosphates.

[0038] Typical examples of non-ionic surfactants include, but are not limited to, an ethoxylated surfactant, an ethoxylated alcohol, an ethoxylated alkyl phenol, an ethoxylated fatty acid, an ethoxylated monoalkalamide, an ethoxylated sorbitan ester, an ethoxylated fatty amino, an ethylene oxide propylene oxide copolymer, fatty alcohol polyglycol ethers, alkylphenol polyglycol ethers, fatty acid polyglycol esters, fatty acid amide polyglycol ethers, fatty amine polyglycol ethers, alkoxylated triglycerides, mixed ethers and mixed formals, optionally partially oxidized carbon numbered alk(en)yl oligo-glycosides or glucuronic acid derivatives, fatty acid N-alkyl glucamides, protein hydrolysates (especially wheat-based vegetable products), polyol fatty acid esters, sugar esters, sorbitan esters, polysorbates and amine oxides, Laureth-9, Laureth-4, Laureth-23, Ceteth-10, Ceteth-2, Ceteth-20, lsoceteth-20, Steareth-100, Steareth-2, Steareth-21 , Steareth-10, Steareth-20, Oleth-2, Oleth-10, Oleth-20, Ceteareth-17, Oleth-3, Oleth-5, Ceteth-2, Cetolet-10, Ceteareth-6, Ceteareth-25, Ceteareth-80, C12-13 Pareth-12, C12-13 Pareth-23, C12-13 Pareth-3, C12-13 Pareth-4, Steareth-200, Steareth-7, ethoxylated linear alcohol, lsodeceth-6, PEG-5 undecyl alcohol, Trideceth-10, Trideceth-3, Trideceth-5, PEG-35 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-7 hydrogenated castor oil, polyglyceryl-3 Distearate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan monopalmitate, sorbitan monooleate, polysorbate 65, polysorbate 20, sorbitan monolaurate, PEG-40 stearate, PEG-n stearate, POE-5 sorbitan monooleate, POE-20 sorbitan monolaurate, PEG-8 stearate, POE-20 sorbitan trioleate, POE-4 sorbitan monostearate, POE-20 sorbitan monopalmitate, POE-20 sorbitan Trioleate, POE-20 sorbitan tristearate, POE-4 sorbitan monolaurate, PEG-80 sorbitan laureate, polysorbate 80, POE-20 sorbitan monostearate, nonoxynol-40, nonoxynol-9, isoLauret-6, nonoxynol-4, C11-15 Pareth-9, octoxynol-40, octoxynol-9, glyceryl citrate and lactate and linoleate and oleate, caprylic / capric glycerides, polyglyceryl-3 polyricinoleate, glyceryl cocoate, glyceryl caprylate, glyceryl stearate, glyceryl oleate, glyceryl stearate citrate, glyceryl stearate, isostearyl diglyceryl succinate, oleyl macrogol-6 glycerides, PEG-8 beeswax, cetyl alcohol EP / NF and ceteth-20 and steareth-20 EP / NF, glycerol monostearate EP / NF and PEG-75 stearate NF / JPE, polyglyceryl-3 diisostearate NF, polyglyceryl-6 distearate, linoleoyl macrogol-6 glycerides EP, oleyl macrogol-6 glycerides EP, lauroyl macrogol-6 glycerides EP, PEG-6 stearate NF / JPE and ethylene glycol stearate EP / NF / JPE and PEG-32 stearate NF / JPE, propylene glycol monolaurate (type II), EP / NF, propylene glycol monocaprylate (type II) NF, propylene glycol monolaurate (type I) EP / NF, lauroyl macrogol-32 glycerides EP, Polyglyceryl-3 dioleate NF, tyloxapol and poloxamers.

[0039] Typical examples of hydrophilic polymers include, but are not limited to, arabic gum, xanthan gum, tragacanth gum, bentonite, aluminum-magnesium silicates, colloidal silica, acrylamide copolymers, agarose, amylopectin, bentonite, calcium alginate, carboxymethyl cellulose, carbomer, carboxymethyl chitin, cellulose gum, dextrin, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, magnesium alginate, methyl cellulose, microcrystal cellulose, pectin, various polyethylene glycols, polyacrylic acid, polymethacrylic acid, polyvinyl alcohol, various polypropylene glycols, sodium acrylate copolymer, sodium carrageenan, beta glucan.

[0040] According to one embodiment of the invention, the flocculating agent is polysorbate 80. According to one embodiment of the invention, the total formulation preferably comprises 0.001-1% polysorbate 80 by total weight, more preferably 0.1-0.5% polysorbate 80 by total weight.

[0041] According to one embodiment of the invention, at least one suspending agent may be comprised of, but is not limited to, the following components: methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose sodium, ethylcellulose, microcrystalline cellulose, chitosan and chitosan derivatives, starch, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylates, polyacrylamide, dextran, gellan gum, sodium alginate, gelatin, pectin, carrageenan, hyaluronic acid, poloxamer, polycarbophil or cellulose acetate phthalate.

[0042] According to one embodiment of the invention, the suspension agent is microcrystalline cellulose.

[0043] According to one embodiment of the invention, the total formulation preferably comprises 0.1%-10% microcrystalline cellulose by weight, more preferably 0.5% -1.5% microcrystalline cellulose by weight.

[0044] According to an embodiment of the invention, at least one tonicity adjusting agent may comprise, but is not limited to, the following components; sodium chloride, potassium chloride, mannitol, glucose, sorbitol, glycerol, propylene glycol.

[0045] According to one embodiment of the invention, the tonicity adjusting agent is sodium chloride.

[0046] According to an embodiment of the invention, the total formulation preferably comprises 0.1%-10% sodium chloride by weight, more preferably 0.5%-5% sodium chloride by weight.

[0047] According to an embodiment of the invention, as at least one preservative may be comprised of, but is not limited to, the following components; benzalkonium chloride, cetylpyridinium chloride / bromide, chlorobutanol, chlorhexidine acetate, chlorhexidine HCI, chlorhexidine digluconate, chlorocresol, methylparaben, propylparaben, butylparaben, phenoxyethanol, phenyl mercury salts, sorbic acid, thiomersal.

[0048] According to one embodiment of the invention, the preservative is benzalkonium chloride. According to one embodiment of the invention, the total formulation preferably comprises 0.001% -0.3% benzalkonium chloride by weight, more preferably 0.01%-0.05% benzalkonium chloride by weight.

[0049] According to one embodiment of the invention, as at least one buffering agent may be comprised of, but is not limited to, diethanolamine, lactic acid, monoethanolamine, triethanolamine, sodium hydroxide, sodium phosphate, citric acid, sodium citrate and semi-synthetic derivatives or combinations thereof.

[0050] According to one embodiment of the invention, the buffering agents are citric acid and sodium citrate.

[0051] According to an embodiment of the invention, the total formulation preferably comprises 0.05%-0.5% citric acid by weight, more preferably 0.1% citric acid by weight.

[0052] According to an embodiment of the invention, the total formulation preferably comprises 0.01 - 0.1% sodium citrate by weight, more preferably 0.03% sodium citrate by weight.

[0053] The pH value of the formulation of the invention is preferably between 4-7.4, more preferably between 5.5-6.5.

[0054] According to an embodiment of the invention which is a pharmaceutical formulation for intranasal administration, comprises paracetamol, polysorbate 80, microcrystalline cellulose, sorbitol, sodium chloride, benzalkonium chloride, sodium citrate, citric acid, water for injection. The formulation values of the preferred example of the invention are given in the table below.

[0055] Example 1 : Nasal spray formulation containing paracetamol

[0056] *100 ml to be completed

[0057] The experimental studies applied for a pharmaceutical formulation that can be administered intranasally, which is the subject of the invention, are provided below.

[0058] Experiment Procedure

[0059] Evaluation of Physicochemical Properties

[0060] Clarity Test

[0061] Visual inspection was conducted on the formulations to detect the presence of any foreign particles, and formulations containing such particles were discarded.

[0062] Determination of pH value

[0063] The pH values of the Diclofenac sodium, ibuprofen, and paracetamol nasal spray formulations were determined using a pH meter (Jenway 3040 Ion Analyze).

[0064] Drug Content

[0065] A content uniformity study was conducted to ascertain the drug content within various formulations. 100 pl of the formulations was dissolved and subsequently diluted using acetonitrile as the solvent. The resultant solution was then subjected to filtration through a 0.45 pm membrane filter. The quantification of total diclofenac sodium, ibuprofen, and paracetamol contents was achieved through a Reversed-Phase High-Pressure Liquid Chromatography (RP-HPLC) system (Shimadzu LC20-AT, Kyoto, Japan).

[0066] In vitro Release Studies

[0067] The in vitro drug release of the formulations was analyzed with the Franz diffusion cell (The Hanson Vertical Diffusion Cell) (13). A nylon membrane (MW cutoff 250 kDa, pore size 0.45 mm) was placed between the donor and the receiver compartment. The receiver compartment was filled with the g 0.5% sodium dodecyl sulfate in water to ensure sink condition. The receiver medium was continuously stirred at 400 rpm. Three puffs of the nasal spray formulations were sprayed on the membrane in the donor compartment. 0.5 mL of samples were withdrawn from the receptor phase at predetermined time intervals (0, 0.25, 0.5, 1 , 2, 3, 4, 5, and 6 hours) and replaced with an equal volume of fresh medium to ensure sink conditions. The amounts of active ingredients released were analyzed by a validated RP-HPLC method.

[0068] Stability Assessment of Formulations

[0069] To evaluate the stability of the optimized nasal spray formulations, the formulations were subjected to a three-month observation period. During this time, they were stored at a controlled temperature of 25±2eC and maintained under conditions of 60%±5% relative humidity. At predefined intervals throughout the three-month period, samples were taken from the formulations for analysis. These samples were then subjected to various tests including examination of physical appearance, pH levels, and drug content. The physical appearance of the formulations was visually inspected to detect any changes such as color alterations, phase separation, or particulate matter formation. pH measurements were taken to monitor potential variations in the formulations' acidity or alkalinity, which could impact their stability. Additionally, the drug content of the samples was quantitatively assessed to determine whether the formulations retained their intended drug concentrations over time.

[0070] Analytical Determination of Active Components

[0071] The amounts of diclofenac sodium, ibuprofen, and paracetamol using two different methods were analyzed by using a RP-HPLC system equipped with a UV-Vis detector (Shimadzu SPD-20A). Filtered and degassed phosphate buffer (pH 3.0): acetonitrile (40:60, v / v) for diclofenac sodium and phosphate buffer (pH 7.5): methanol (70:30, v / v) for ibuprofen and paracetamol were used as a mobile phase. The mobile phase was delivered isocratically at a flow rate of 1 mL / min through GL Sciences InertSustain C18 (250x4,6 mm, 5 pm) column maintained at 25‘C. The UV detector was s et at 210 nm for diclofenac sodium and 220 nm for ibuprofen and paracetamol detection.

[0072] The HPLC method for active ingredients was conducted based on the International Conference of Harmonization (ICH) Q2 (R1) guidelines. For linearity studies, the standard curves in the 0.05-10 pg / mL range prepared from the stock solution of diclofenac sodium, ibuprofen, and paracetamol were analyzed. The peak area correlated linearly with diclofenac sodium (r2=0.9993), ibuprofen (r2=0.9990), and paracetamol (r2=0.9994) concentrations in the range of 0.05-10 pg / ml. The examples obtained with free spray formulations did not demonstrate any interference with diclofenac sodium, ibuprofen, and paracetamol peaks, which results indicate the selectivity of the method. Furthermore, HPLC method validation was achieved on the accuracy, precision, and stability.

[0073] Cell Viability Assay

[0074] The possible cytotoxic effect of diclofenac sodium, ibuprofen, and paracetamol formulations was analyzed by the WST cell viability test (Roche, Germany), and non-toxic doses were determined. Briefly, 1 x104fibroblast cells were seeded to each well of 96-well plates and treated with different concentrations of nasal sprays (decided according to literature) for 1 , 6, and 24 hrs at 37eC. After the incubation period, 10 pL WST working solution was added to each well and incubated for 3 h at 37 G. The absorbance was then assessed at 440 nm using the microplate reader (Varioskan Flash Microplate Reader, Thermo Scientific, USA). The acquired data were averaged, and viability was calculated as a percentage relative to the non-treated control group, enabling the determination of a safe dosage. All experimental procedures were replicated three times for robustness and reliability.

[0075] Alkaline Single Cell Gel Electrophoresis Analysis

[0076] Possible genotoxic effects of 3 doses that do not show cytotoxic effects on fibroblast cells within 24 hours were evaluated by the alkaline single-cell gel electrophoresis analysis (Comet Analysis) method as described by Singh et al (15). Cells were seeded on a 6-well plate (approximately 2 x 105cells per well) and incubated for 24 hours with non-toxic doses. Cells were removed from the plates and mixed with low melting agarose (0.65%), then pipetted onto slides coated with agarose (1%). The slides were kept at 4 G for the gel to get solidified and then kept in the lysis buffer (2.5M NaCI, 100mM Na2EDTA, 10mM Tris-HCI, pH 10-10.5, 1% Triton X-100 and 10% DMSO added just before use) for at least 1 hour. The slides were rinsed with cold PBS and placed in fresh alkaline electrophoresis solution (300 mM NaOH, 1-mM EDTA-Na2, pH 13) to unwind the DNA for 20 min at 4 G. Then the cells were electrophoresed for 25 minu tes (25 V, 300 mA), and the gel was neutralized by 400 mM Tris-HCI buffer then stained with Ethidium Bromide (5 mg / ml) and examined by fluorescent microscope (Leica, Germany). One hundred cells on average were counted and scored for each concentration, and tail density (% tail) was calculated as DNA damage by using Comet Assay IV, Perceptive software (Suffolk, UK). Test Results

[0077] Clarity of Formulations

[0078] The view of the content of the nasal spray formulations was analyzed for all formulations. There is no change in color and clarity of the formulation as a showing of the product integrity in all formulations which was indicated in Table II. pH of the Formulations

[0079] The pH value of the nasal spray formulation is very significant primarily to prevent irritation of the nasal mucosa, to avoid the growth of pathogenic microorganisms and to maintain normal physiological ciliary movement. All formulations were determined at pH 5.5-6.2 so that the pH values of the prepared formulations were compatible with the pH value of the nasal mucosa.

[0080] The suitable pH for nasal sprays is 4-7.5 because the pH range of the human nasal mucosa is 5.5-6.5, which is slightly acidic. Therefore, newly formulated nasal medications containing diclofenac sodium, ibuprofen and paracetamol were studied primarily in terms of their physical and chemical characterization. In order for the pH values of the prepared formulations to be compatible with the pH value of the nasal mucosa, all formulations were determined at pH 5.5-6.2.

[0081] Drug Content

[0082] The content of diclofenac sodium, ibuprofen and paracetamol in the spray formulations was determined to analyze the loss of active components that may be seen during the preparation of nasal spray formulations. As a result of the studies, it was analyzed that the active components were recovered from the nasal spray formulation at a high rate ranging from 95.3 ± 0.5% to 98.2 ± 0.6% (Table 2).

[0083] Table 2. Characterization of nasal spray formulations

[0084] Parameter F1 -1 F1 -2 F1 -3 F2-1 F2-2 F2-3 F3-1 F3-2 F3-3

[0085] Clarity T T T T T T T T T pH 5.6 5.8 5.5 5.9 6.1 5.7 6.2 5.9 6.1

[0086] Drug content

[0087] (%) 98.2±0.6 97.3±1.1 98.5±0.8 96.2±1.3 97.4±0.4 95.3±0.5 97.2±1.9 96.1 ±1 .5 97.6±1 .3

[0088] Abbreviations: T: Transparent In vitro Drug Release of Nasal Spray Formulations

[0089] The drug release behavior of three different nasal spray formulations containing diclofenac sodium, ibuprofen and paracetamol, was determined by the diffusion method respectively. In vitro release studies were performed to select the appropriate formulations for cell culture studies. As shown in the in vitro release profiles given in Figure 1 , 77.56 ± 2.32% of the nasal spray formulations were released for diclofenac sodium (F1-1 ), 73.12 ± 3.05% for ibuprofen (F2-1) and 85.07 ± 1.12% for paracetamol (F3-1) within the first 2 hours. According to the in vitro release results, the increase in the polymer concentration in the spray formulations caused a slower release of the active components. Therefore, F1 -1 , F2-1 and F3-1 were selected from the nasal spray formulations prepared for cell culture studies.

[0090] Stability Studies

[0091] The stability analysis of the nasal spray formulations was conducted under controlled conditions, with the samples stored in a refrigerator at 25 ± 2eC and 60% ± 5% relative humidity for a span of 90 days. Throughout this period, several characterization parameters were monitored to assess the stability of the prepared spray formulations stored in appropriate conditions. Specifically, the physical appearance, pH, and drug content of selected formulations were analyzed at the outset and at various intervals. The results of these assessments were presented in Table III. Notably, no statistically significant variations were observed in the outcomes (p>0.05). The results achieved showed that the selected nasal spray formulations maintained their stability for 90 days.

[0092] Non-Toxic Doses of Diclofenac Sodium, Ibuprofen and Paracetamol Formulations

[0093] The formulations of the invention have been tested for in vitro toxicity. Non-toxic doses of the formulations were determined by performing cytotoxicity tests. The drug concentration in a nasal spray should not exceed 5 mg.

[0094] In this study, CCD-1079Sk human normal skin fibroblastic cells were used as a model of the progressive formation of cellular toxicity. For cytotoxicity studies, CCD-1079 cells were treated with nasal sprays at different concentrations for 1 hour, 6 hours, and 24 hours. The doses showing toxicity toxicity within 24 hours were eliminated. Safe doses were selected as 0.0625 mg / ml, 0.375 mg / ml and 1.25 mg / ml for diclofenac, ibuprofen and paracetamol respectively by not showing toxicity even at 24 hours (Figure 2). For later studies, concentrations around the non-toxic dose (0.0325 mg / ml and 0.125 mg / ml for Diclofenac; 0.25 mg / ml and 0.5 mg / ml for Ibuprofen; 0.625 mg / ml and 2 mg / ml for Paracetamol) were also studied for apoptosis and genotoxicity experiments.

[0095] Elimination of Possible Genotoxic Effect of the Formulations at Non-Toxic Doses

[0096] As is known, DNA damage is the abnormal chemical structure in DNA that prevents it from functioning and performing properly. The cell can either repair the damage or cause cell death if the damage is beyond repair. Since drugs can also cause DNA damage, three doses around the non-toxic doses of the new formulations were analyzed for any genotoxicity. The alkaline comet assay is a very common method for measuring DNA damage through the migration of DNA under conditions of electrophoresis. According to the results of the comet assay, no DNA damage was observed at the determined non- toxic doses of Diclofenac Sodium, Ibuprofen and Paracetamol formulations. The mean tail density values were similar to the untreated control group, although they showed an increasing pattern with increasing concentrations (Figure 3-4).

[0097] After 24 hours of treatment with Diclofenac Sodium, Ibuprofen and Paracetamol, the cells were stained with AO / EB and then analyzed as green (living cells) and red (dead cells) using fluorescence microscopy. (Figure 3) After 24 hours of treatment with Diclofenac Sodium, Ibuprofen and Paracetamol, the cells were electrophoresis and stained with Ethidium Bromide, and then analyzed using fluorescence microscopy and tail densities were calculated. (Figure 4)

[0098] Intranasal (IN) analgesic sprays are a safe analgesic method that shortens the onset of action time compared to oral painkillers. Intranasal drug administration instead of parenteral opioids can be used to provide analgesia in children. With our invention, an analgesic nasal spray formula that will serve as an alternative treatment and easier application to patients in the pediatric age group who cannot swallow oral analgesics due to their underlying neurological problems, refuse to take oral analgesics and complain of painful swallowing after tonsillectomy is provided.

[0099] With our invention, it has been shown that nonprescription paracetamol, ibuprofen and diclofenac sodium can be formulated as a nasal spray and their physical and chemical characterization is stable at 25±2eC for 90 days. Our invention is the first study to show that paracetamol, ibuprofen and diclofenac sodium can be formulated as nasal spray and applied as IN.

Claims

CLAIMS1. A pharmaceutical formulation that can be administered intranasally, characterized by comprising; 0.25%-10% paracetamol by weight and at least one pharmaceutically acceptable excipient in the total formulation.

2. The pharmaceutical formulation according to claim 1 , characterized by comprising;1% paracetamol by weight of the total formulation.

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