Paraben free syrup compositions

Abstract

The present invention relates to a syrup composition comprising paracetamol (I), chlorpheniramine (II), ascorbic acid (III) and one or more pharmaceutically acceptable excipient wherein the syrup composition is particularly free of paraben.

Description

[0001]DESCRIPTION PARABEN FREE SYRUP COMPOSITIONS Field of Invention The present invention relates to a syrup composition comprising paracetamol, 5 chlorpheniramine, ascorbic acid and one or more pharmaceutically acceptable excipient wherein the syrup composition is particularly free of paraben. Background of the Invention Paracetamol's origins date back to the late 19th century. It was first synthesized by 10 Harmon Northrop Morse in 1877. It was introduced into clinical practice in the 1950s, following the recognition of its efficacy and safety profile. In 1955, it was marketed in the United States under the brand name Tylenol by McNeil Laboratories. Today, paracetamol is one of the most commonly used medications for pain and fever relief, included in various formulations, from tablets and capsules to syrups and suppositories. Its role in 15 medicine continues to be vital due to its efficacy, safety profile when used as directed, and versatility in treating a wide range of common ailments. Paracetamol 20 Paracetamol (Acetaminophen) also commonly known as Tylenol, is the most commonly taken analgesic worldwide and is recommended as first-line therapy in pain conditions by the World Health Organization (Ennis, Z. N., Dideriksen, D., Vaegter, H. B., Handberg, G., & Pottegård, A. (2016). Acetaminophen for Chronic Pain: A Systematic Review on Efficacy. 25 Basic & clinical pharmacology & toxicology, 118(3), 184–189). It is effective in treating mild to moderate pain, such as headaches, menstrual cramps, toothaches, and musculoskeletal pain, as well as in reducing fever. Unlike nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol does not have significant anti-inflammatory effects, making it a preferred choice for individuals who need pain relief without the gastrointestinal side effects often associated with NSAIDs. Chlorpheniramine is an antihistamine used to relieve symptoms of allergy, hay fever, and 5 the common cold. These symptoms include rash, watery eyes, itchy eyes / nose / throat, cough, runny nose, and sneezing. Chlorpheniramine works by blocking histamine, a substance in the body that causes allergic symptoms. It also has mild sedative effects due to its action on the central nervous system. 10 Chlorpheniramine Chlorpheniramine was developed in the 1940s as part of the efforts to create effective antihistamines. It was among the first generation of antihistamines synthesized. It was introduced into the market in the 1950s. It quickly gained acceptance due to its 15 effectiveness in treating allergic reactions and its relatively mild sedative effects compared to other antihistamines available at the time. Ascorbic acid, commonly known as vitamin C, is a vital nutrient that plays several crucial roles in the body. It is an antioxidant, helping to protect cells from damage caused by free 20 radicals. Additionally, it is essential for the synthesis of collagen, the absorption of iron from plant-based foods, and the proper functioning of the immune system. Ascorbic Acid (Vitamin C) 25 Ascorbic acid was first isolated in 1928 by the Hungarian scientist Albert Szent-Györgyi, who received the Nobel Prize in Physiology or Medicine in 1937 for his work. The chemical structure of ascorbic acid was determined by Norman Haworth in the early 1930s, and he, along with Szent-Györgyi, successfully synthesized it in the laboratory, furthering its availability for widespread use. initially used to prevent and treat scurvy among sailors and others with limited access to fresh fruits and vegetables, ascorbic acid quickly became recognized as an essential nutrient. Its use expanded to include 5 supplementation for general health, especially for its antioxidant properties and immune support. Paracetamol, chlorpheniramine, and ascorbic acid are often combined in medications designed to treat symptoms of the common cold and flu. This combination leverages the 10 analgesic and antipyretic effects of paracetamol, the antihistamine properties of chlorpheniramine, and the immune-supporting benefits of ascorbic acid. Combination products comprising paracetamol, chlorpheniramine, and ascorbic acid available in worldwide. These products are formulated to relieve symptoms of the 15 common cold and flu, offering analgesic, antihistamine, and immune-support benefits. They are available in various forms, comprising tablets and syrups, and are distributed in multiple countries with different packaging options and dosage recommendations. In view of the foregoing, there is a need to improve microbial stability and high patient 20 compliance in syrup compositions comprising paracetamol, chlorpheniramine, ascorbic acid. The present invention provides a solution to these problems by providing novel compositions comprising paracetamol, chlorpheniramine, ascorbic acid, and one or more pharmaceutically acceptable excipient wherein the syrup composition is free of paraben. These solutions will be described in detail. 25 Brief Description of the Invention The present invention provides a syrup composition comprising paracetamol, chlorpheniramine or pharmaceutically acceptable salt thereof, ascorbic acid and one or more pharmaceutically acceptable excipient wherein the composition is free of paraben. 30 The composition of present invention can be comprising diluents, diluents, lubricants, glidants, binders, disintegrants, antioxidants, solubility increasing agents, preservatives, buffering agents, solvents, flavoring agent, stabilizers, sweetening agent or mixtures thereof as a pharmaceutically acceptable excipient. The syrup composition of the present invention comprises below: Table 1: Paracetamol- Chlorpheniramine -Ascorbic Acid compositions Ingredients % weight Paracetamol1.00%-7.00%Chlorpheniramine or pharmaceutically acceptable salt thereof 0.001% - 0.1% Ascorbic acid 0.10% - 5.00% Sweetening agents 9.50% - 45.00% Viscosity enhancer 0.10% - 5.00% Solubility increasing agent 4.00%-10.00% Buffering agents 0.10%-5.00% Flavoring agent 1.00%-2.50% Preservatives 0.1% - 3.00% At least one solvent 40.00% - 90.00% Coloring agent 0.0001% - 0.1% Total 100.00% In other embodiment preservative can be benzoic acid derivative or non-benzoic acid derivative. 5 In further embodiment preservative can be non-benzoic acid derivative. In preferred embodiment the non-benzoic acid derivative can be potassium sorbate. In other aspect of the present invention a process for preparing syrup composition can be comprises below steps: 10 a. Adding viscosity enhancer into solvent, then stir until completely dissolved, b. Adding solubility increasing agent to step a mix, then stir until completely dissolved, c. Adding buffering agent and sweetening agent to step b mix, then stir until completely dissolved d. Adding chlorpheniramine or pharmaceutically acceptable salt thereof to step c mix, 15 then stir until completely dissolved e. Adding sweetening agent to step d mix, then stir until completely dissolved, f. Adding solvent to step e mix, then stir until completely dissolved, g. Adding paracetamol to step f mix, then stir until completely dissolved, h. Adding sweetening agent to step g mix, then stir until completely dissolved, i. Adding preservatives to step h mix, then stir until completely dissolved j. Adding coloring agent and flavoring agent to step i, then stir until completely 5 dissolved, k. Packing the prepared mixture. In other aspect of a syrup composition of the present invention for use in the treatment of headache, fever, body aches, runny or stuffy nose, sneezing, itching, watery eyes, and sinus 10 congestion caused by allergies. Detailed Description of the Invention The aspects and disclosures according to the present invention, in particular the syrup compositions, methods and uses, refer to the paracetamol chlorpheniramine or pharmaceutically acceptable salt thereof, ascorbic acid, viscosity enhancer and one or more pharmaceutically 15 acceptable excipient defined hereinbefore and hereinafter. Preferably, the amount of paracetamol can be between 1.00-7.00% by weight of the total composition of the present invention. 20 Preferably, the amount of chlorpheniramine or pharmaceutically acceptable salt thereof can be between 0.001-0.10% by weight of the total composition of the present invention. Preferably, the amount of ascorbic acid can be between 0.10-5.00% by weight of the total composition of the present invention. 25 As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound that does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. 30 In other embodiment of the present invention chlorpheniramine or pharmaceutically acceptable salt thereof can be chlorpheniramine maleate. Excipients used in a formulation may adversely affect physicochemical and pharmacokinetic properties. These excipients can interact with the active ingredient. For this reason, while 35 developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected. Preferably, the present invention relates to the syrup composition comprising paracetamol chlorpheniramine or pharmaceutically acceptable salt thereof, ascorbic acid, at least one viscosity enhancer and one or more pharmaceutically acceptable excipient, wherein the excipients are selected from the group including, but are not limited to diluents, lubricants, glidants, binders, 5 disintegrants, antioxidants, solubility increasing agents, preservatives, buffering agents, solvents, flavoring agent, stabilizers, sweetening agent, mixtures thereof. and other materials known to one of ordinary skill in the art and the mixtures thereof. Preferably, the amount of viscosity enhancer can be between 0.10-5.00% by weight of the total 10 composition of the present invention. Preservatives play a crucial role in syrup compositions, ensuring their stability and extending their shelf life by inhibiting microbial growth and spoilage. Among the preservatives commonly utilized are benzoic acid derivative preservatives and non-benzoic acid derivative preservatives. 15 Preservatives play a crucial role in syrup compositions, ensuring their stability and extending their shelf life by inhibiting microbial growth and spoilage. Among the preservatives commonly utilized are benzoic acid derivative preservatives and non-benzoic acid derivative preservatives. 20 Suitable benzoic acid derivative preservatives include, but are not limited to, benzyl alcohol, benzoic acid or mixtures thereof. Suitable non-benzoic acid derivative preservatives for this innovative formulation include, but are not limited to ethyl alcohol, ethyl alcohol / propylene glycol, propionic acid, potassium sorbate, 25 sorbic acid or mixtures thereof. Non-benzoic acid derivative preservatives, especially potassium sorbate, serve as alternatives for those seeking options beyond benzoates. Sorbic acid derivatives function similarly to benzoates, exhibiting potent antimicrobial activity and aiding in the preservation of syrup formulations. 30 Careful consideration of preservative selection is pivotal, balancing efficacy with regulatory compliance and consumer safety standards to ensure the syrup remains microbiologically stable and safe for consumption throughout its intended shelf life. Potassium sorbate is a suitable preservative for this choice. Preferably, the amount of potassium sorbate can be between 0.10- 3.00% by weight of the total composition of the present invention. 35 The inventors have found that the paraben-free syrup compositions comprising paracetamol, chlorpheniramine or pharmaceutically acceptable salt thereof, ascorbic acid and one or more pharmaceutically acceptable excipient, improves syrup compositions chemical and physical stability. The inventors surprisingly have found that the paraben-free syrup compositions comprising 5 paracetamol, chlorpheniramine or pharmaceutically acceptable salt thereof, ascorbic acid, potassium sorbate as a non-benzoic acid derivative preservative and one or more pharmaceutically acceptable excipient, improves syrup compositions chemical physical and microbial stability, increase patient compliance. 10 Suitable viscosity enhancers for this innovative formulation include, but are not limited to, hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, and carboxymethyl cellulose. Preferably viscosity enhancer can be selected from hydroxyethyl cellulose, hydroxyetyhlmethyl cellulose, hydroxypropyl cellulose, hypromellose, methyl cellulose or mixtures thereof. Preferably, the amount of viscosity enhancers 15 can be between 0.10-5.00% by weight of the total composition of the present invention. Sweetening agents can also be utilized in the formulation process. Sweetening agents are incorporated to enhance the palatability of the composition, making it more acceptable and pleasant for consumption. These agents mask the undesirable taste of certain active 20 pharmaceutical ingredients, thereby improving patient compliance, especially in pediatric and geriatric populations. Most sweetening agents have good solubility in water, allowing them to effectively distribute and impart sweetness throughout the formulation. Suitable sweetening agents for this innovative formulation can be selected from the group, but are 25 not limited to, aspartame, acesulfame potassium, saccharin, sucralose, stevia, xylitol, sorbitol, mannitol, saccharin sodium, sodium chloride, maltitol, fructose, dextrose, and sucrose, as well as other materials known to one of ordinary skill in the art. A combination of the aforementioned sweetening agents can also be used. The preferred sweetening agents are sucralose, sorbitol, saccharin sodium, sucralose. Preferably, the amount of sweetening agents can be between 9.50- 30 45.00% by weight of the total composition of the present invention. Solubility increasing agents, also known as solubilizers, are essential in pharmaceutical formulations to enhance the solubility of poorly soluble active pharmaceutical ingredients (APIs). These agents work by various mechanisms, such as reducing particle size, altering the crystalline 35 structure, or increasing the wettability of the drug, thereby improving its dissolution rate and bioavailability. Preferably, the amount of solubility increasing agents can be between 4.00- 10.00% by weight of the total composition of the present invention. Buffering agents are critical components in syrup compositions, ensuring the stability and effectiveness of the active ingredients by maintaining an optimal pH range. Buffering agents help to resist changes in pH when the syrup is diluted or when it comes into contact with different biological environments, such as the acidic conditions of the stomach or the more neutral 5 environment of the intestines. Suitable buffering agents for syrup formulations include, but are not limited to, citric acid, sodium citrate, phosphoric acid, sodium phosphate, potassium phosphate, sodium citrate dihydrate tartaric acid, sodium bicarbonate, and various combinations thereof. Preferably buffering agent10 can be sodium citrate dihydrate. Preferably, the amount of buffering agents can be between 0.10- 5.00% by weight of the total composition of the present invention. Flavoring agents play a crucial role in syrup compositions, enhancing the palatability and overall patient acceptance of the formulation. These agents mask the unpleasant tastes of active 15 pharmaceutical ingredients and other excipients, making the medication more agreeable, especially for pediatric and geriatric patients. Suitable flavoring agents can be selected from natural and synthetic sources, including but not limited to, fruit flavors such as cherry, orange, banana, grape, orange aroma liquid, and raspberry, 20 as well as mint, vanilla, chocolate, and butterscotch. Preferably flavoring agent can be orange aroma liquid. Preferably, the amount of flavoring agents can be between 1.00-2.50% by weight of the total composition of the present invention. Solvents are a crucial component in the formulation of syrup compositions, as they serve as the 25 medium in which active ingredients and other excipients are dissolved or suspended. The selection of an appropriate solvent ensures the stability, efficacy, and palatability of the syrup. Suitable solvents for this inventive formulation can be selected from the group, but are not limited to, purified water, ethanol, glycerol, propylene glycol, and polyethylene glycol. A combination of 30 the aforementioned solvent can also be used. The preferred sweetening agents are purified water and glycerol. Preferably, the amount of solvent can be between 40.00-90.00% by weight of the total composition of the present invention. Coloring agents are an essential component in syrup formulations, providing visual appeal and 35 aiding in product identification. These agents can enhance the overall aesthetic quality of the syrup, making it more attractive to consumers, especially in pediatric populations. Suitable coloring agents for this inventive formulation can be selected from a variety of FDA- approved food dyes and natural colorants, but are not limited to, FD&C Red No.40, FD&C Yellow No.6, FD&C Blue No.1, caramel color, sunset yellow, annatto extract, beet juice powder, beta- carotene, and chlorophyllin-copper complex. Preferably coloring agent can be sunset yellow. 5 Preferably, the amount of coloring agents can be between 0.0001-0.10% by weight of the total composition of the present invention. The syrup composition of the present invention comprises below: Table 2: Paracetamol- Chlorpheniramine -Ascorbic Acid compositions Ingredients % weight Paracetamol1.00%-7.00%Chlorpheniramine or pharmaceutically acceptable salt thereof 0.001% - 0.1% Ascorbic acid 0.10% - 5.00% Sweetening agents 9.50% - 45.00% Viscosity enhancer 0.10% - 5.00% Solubility increasing agent 4.00%-10.00% Buffering agents 0.10%-5.00% Flavoring agent 1.00%-2.50% Preservatives 0.1% - 3.00% At least one solvent 40.00% - 90.00% Coloring agent 0.0001% - 0.1% Total 100.00% 10 In other aspect of the present invention a process for preparing syrup composition can be comprises below steps: a. Adding viscosity enhancer into solvent, then stir until completely dissolved, b. Adding solubility increasing agent to step a mix, then stir until completely dissolved, 15 c. Adding buffering agent and sweetening agent to step b mix, then stir until completely dissolved d. Adding chlorpheniramine or pharmaceutically acceptable salt thereof to step c mix, then stir until completely dissolved e. Adding sweetening agent to step d mix, then stir until completely dissolved, f. Adding solvent to step e mix, then stir until completely dissolved, 5 g. Adding paracetamol to step f mix, then stir until completely dissolved, h. Adding sweetening agent to step g mix, then stir until completely dissolved, i. Adding preservatives to step h mix, then stir until completely dissolved j. Adding coloring agent and flavoring agent to step i, then stir until completely dissolved, 10 k. Packing the prepared mixture. In other aspect of a syrup composition of the present invention for use in the treatment of headache, fever, body aches, runny or stuffy nose, sneezing, itching, watery eyes, and sinus congestion caused by allergies. 15 Experiments Stability Results The stability of the product was monitored under the following three conditions. During the stability period, the product was found to meet the specifications. 20 25°C ± 2°C / %60 RH ± %5 RH 30°C ± 2°C / %65 RH ± %5 RH 40°C ± 2°C / %75 RH ± %5 RH In vitro Tests 25 Experiments were conducted with the same composition using different preservatives. In experiments conducted with benzoic derivative preservatives (benzoic acid) and non- benzoic derivatives preservatives (ethyl alcohol, ethyl alcohol / propylene glycol, propionic acid, potassium sorbate, sorbic acid). 30 Experiments with benzoic acid resulted in turbidity of the syrup composition and visual problems. Experiments with potassium sorbate are observed most chemically, physically and microbial stability and patient compliance syrup compositions.

Claims

CLAIMS 1. A syrup composition comprising paracetamol, chlorpheniramine or pharmaceutically acceptable salt thereof, ascorbic acid and at least one pharmaceutically acceptable excipient characterized in that syrup composition is free of paraben. 5 2. The syrup composition according to claim 1, characterized in that said excipient is selected from, diluents, lubricants, glidants, binders, disintegrants, antioxidants, solubility increasing agents, preservatives, buffering agents, solvents, flavoring agent, stabilizers, sweetening agent or mixtures thereof.

3. The syrup composition according to claim 2, wherein said composition comprises: ^ 1.00% - 7.00% by weight paracetamol, ^ 0.001% - 0.1% by weight chlorpheniramine or pharmaceutically acceptable salt thereof, ^ 0.10% - 5.00% by weight ascorbic acid, ^ 9.50% - 45.00% by weight sweetening agent, ^ 0.10% - 5.00% by weight viscosity enhancer, ^ 4.00%-10.00% by weight solubility increasing agent, ^ 0.10%-5.00% by weight buffering agents, ^ 1.00%-2.50% by weight flavoring agent, ^ 0.1% - 3.00% by weight preservative, ^ 40.00% - 90.00% by weight at least one solvent, ^ 0.0001% - 0.1% by weight coloring agent.

4. The syrup composition according to claim 3, characterized in that said preservative is benzoic acid derivative or non-benzoic acid derivative preservative.

5. The syrup composition according to claim 4, characterized in that preservative is non-benzoic acid derivative preservative.

6. The syrup composition according to claim 5, characterized in that non-benzoic acid derivative preservative is potassium sorbate.

7. A process for preparing syrup composition according to claim 3, comprising the steps of a. Adding viscosity enhancer into solvent, then stir until completely dissolved, b. Adding solubility increasing agent to step a mix, then stir until completely dissolved,c. Adding buffering agent and sweetening agent to step b mix, then stir until completely dissolved d. Adding chlorpheniramine or pharmaceutically acceptable salt thereof to step c mix, then stir until completely dissolved 5 e. Adding sweetening agent to step d mix, then stir until completely dissolved, f. Adding solvent to step e mix, then stir until completely dissolved, g. Adding paracetamol to step f mix, then stir until completely dissolved, h. Adding sweetening agent to step g mix, then stir until completely dissolved, i. Adding preservatives to step h mix, then stir until completely dissolved j. Adding coloring agent and flavoring agent to step i, then stir until completely dissolved, k. Packing the prepared mixture.

8. A syrup composition according to claims 1 to 7, for use in the treatment of headache, fever, body aches, runny or stuffy nose, sneezing, itching, watery eyes and sinus congestion caused by allergies.

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