INTRODUCTION:

Oral medication administration has been recognized for many years as the most popular mode of administration out of all the ways utilized for the central delivery of medications through a variety of pharmaceutical items in different dose form. One factor contributing to the oral route's appeal is how easy and uncomplicated it is to administer. The global oral solid-dosage pharmaceutical formulation market is expected to grow from 489.5 billion dollars in 2017 to 925.5 billion dollars by 2027, according to future industry trends.¹

Compared to oral liquids, capsules, solutions, or suspensions, solid tablets are the most durable oral dose form in terms of physical, chemical, and microbiological qualities.²

There are many different kinds of tablets available, and each has a unique set of disadvantages. Since slow absorption delays the onset of the action, it is a major disadvantage. This problem could be resolved by creating effervescent pills.³

Effervescent tablets are defined by the Indian Pharmacopoeia as tablets without a coating that include both carbonates and bicarbonates, which react fast in the presence of water to produce CO2, and approved flavouring additives. Before being delivered, they are meant to dissolve or be dispersed in water.⁴

Saline cathartics were the first effervescent formulations developed in the seventeenth century.^5,6Acids or acid salts, such as citric acid, tartaric acid, malic acid, or any other suitable acid or acid anhydride, and carbonates or bicarbonates, such as sodium, potassium, or any other suitable alkali metal carbonate or hydrogen carbonate, are commonly found in effervescent tablets. These substances react quickly with water by releasing carbon dioxide. Because of the release of CO2, API solubility in water and flavour masking are both enhanced.^3,7-11

In effervescent formulations, acid-base neutralization processes usually result in the release of CO2 effervescence and the production of buffered salt as a byproduct. The most common effervescent reaction is that which occurs when citric acid and the sodium bicarbonate salt mix. The reaction happens more quickly because water, even in little amounts, is present to catalyse it. Since water catalyses the reaction, all moisture-sensitive or effervescent goods are stored in a moisture-free environment.^9,12,13Because they're so simple to take, effervescent pills are seeing a rise in popularity in several sectors, including as the pharmaceutical and supplement industries.

When effervescent tablets come into contact with liquids like juice or water, they are meant to burst, which frequently results in the tablet dissolving into a solution.¹⁴These buoyant delivery systems make use of matrices made of effervescent substances like sodium bicarbonate and citric or tartaric acid, as well as swellable polymers like Methocel or polysaccharides like chitosan.¹⁵ or matrices with liquid chambers that gasify at room temperature^16,17

A floating chamber filled with air, vacuum, or an inert gas can be used to make a medication delivery system float in the stomach.¹⁸The volatilization of an organic solvent (such as ether or cyclopentane) or the CO2 created by an effervescent reaction between organic acids and carbonate-bicarbonate salts are two ways that gas can be introduced into the floating chamber.¹⁹The matrices are made in such a way that, when they enter the stomach, the acidity of the food releases carbon dioxide, which becomes trapped in the hydrocolloid that has gelled. As a result, the dose form moves upward and keeps its buoyancy. When the dose form's specific gravity drops, it floats on the chyme.^20,21Carbon tablets, often known as effervescent tablets, are made to dissolve in water and release carbon dioxide.^22-24

These are the results of compressing powdered component components into a dense mass, which is then sealed in a hermetically sealed container with a desiccant integrated into the cap or packaged in a blister pack. They are used by dissolving them in water to create a solution. Additionally, the powdered materials can be granulated and sold as effervescent granules, or they can be packaged and sold as effervescent powders. Before being formed into tablets, powdered components are often first ground into granules.^25-26

Fundamentals of effervescents:^27-28

A soluble organic acid and an alkali metal carbonate salt of which the API is frequently one combine to produce effervescence. When this mixture comes into contact with water, carbon dioxide is produced. The following are typical instances of acids and alkalis used:

· Sodium bicarbonate

· Sodium carbonate

· Sodium sesquicarbonate

· Potassium bicarbonate

· Potassium carbonate

· Citric acid

· Tartaric acid

· Malic acid

· Fumaric acid

· Adipic acid

Advantages of effervescent tablet:^29-32

· Quick start of the effect.

· Tablet swallowing not necessary.

· Excellent intestinal and stomach tolerance.

· Increased portability

· Better absorption: Effervescent formulations are designed to dissolve quickly in water16, which facilitates the active ingredients' easier absorption. This is done in order to increase the medication's surface area and distribute it more evenly throughout the effervescence phase, which will facilitate the body's absorption of the drug.

Disadvantages of effervescent tablet:^29-30

· Some of the active substances have a bad taste.

· Larger tablets necessitate specific packaging materials. Production of these tablets is rather expensive due to the enormous quantity of excipients, which can be costly, and the unique equipment needed.

· While a fine dispersion is now generally accepted, a clear solution is preferable for administration.

Benefits of effervescent tablet over simple tablets:

Simple Substitute for Regular Tablets: These can be an excellent option for people who are in pain, elderly people, or children who have trouble swallowing but still need to take supplements or medication on a regular basis. They can also be a great way to take medication for people with a variety of medical conditions that make swallowing difficult, and therefore are a viable alternative to taking regular tablets.³³

Effervescent tablets (et) are used to for this reasons:

1. Quick absorption: It dissolves in liquid quickly. This is an excellent way to take tablets since it provides quick and increased absorption, which is important because some oral tablets, like antacid, take longer to absorb in the stomach.

2. Increased intake of liquids: These tablets offer therapeutic benefits in addition to improving the absorption of liquids. When diarrhoea occurs, taking an effervescent tablet with water increases the amount of liquids consumed each day.

3. In the event of a swallowing difficulty: It offers an alternative for those experiencing swallowing difficulties.

4. Easy handling and precise dosage measurement: Tablets dissolve rapidly, enabling patients to get precise dosages.

In addition to the active component, these tablets also contain sodium bicarbonate (NaHCO3), citric acid, and tartaric acid. These substances react with water to release CO2, which causes effervescence and ultimately causes the breakdown of diclofenac. The salt version of diclofenac is sodium.

Fig No 1: Disintegration of Effervescent Tablet

Figure 1: Breakdown of the Carbonated Tablet Derivatives of benzene acetic acid and non-steroidal anti-inflammatory medications with analgesic (to relieve pain), antipyretic (to cure pyrexia, or elevated body temperature), and anti-inflammatory action (to lessen inflammation brought on by a variety of reasons) properties.³⁴

Diclofenac sodium:

The oral route is a highly favoured and popular method of administering medication. The oral administration method has been employed for both unique and standard medication delivery system. In the present day, persistent dose form for release is inhibiting the application of a traditional dose form.³⁵ Pharmacies that exhibit limited absorption, minimal aqueous solubility, instability at alkaline pH, and efficient stomach absorption are suitable options for gastro-retentive systems.³⁶ Among the appropriate candidates that can be created using delivery methods are aspirin, griseofulvin, p-nitro aniline, Ibuprofen, Ketoprofen, Piroxicam, Verapamil, Cholestyramine, Theophylline, Nifedipine, Nicardipine, Dipyridamole, Diclofenac, Indomethacin, Prednisolone, and Cinnarizine. ³⁷

In addition, novel production techniques that alter the active medicinal substance's particle size distribution have improved the oral drug products' solubility, bioavailability, and effectiveness.³⁸Diclofenac sodium is an anti-inflammatory medication that is used to treat posttraumatic and postoperative inflammatory diseases, rheumatoid arthritis, osteoarthritis, bursitis, spondylitis, toothache, dysmenorrhea, and renal calculi. It also helps to quickly relieve pain and wound edema.^37,39

Diclofenac sodium is a synthetic analgesic and anti-inflammatory nonsteroidal drug. the anti-inflammatory, antipyretic, and analgesic properties stem from the suppression of prostaglandin synthesis through cyclooxygenase (COX) inhibition. Diclofenac might be an exceptional NSAID as well. Diclofenac appears to block lipoxygenase pathways, which decreases leukotriene (also known as pro-inflammatory autacoids) synthesis, according to some data. Orally, it is well absorbed and exhibits 100% bioavailability, over 99% protein binding, metabolism, and excretion in both urine and bile, with a plasma half-life of 1.2-2 hours.^40-41

Diclofenac is used to treat gout attacks, musculoskeletal symptoms (particularly rheumatoid arthritis, osteoarthritis, spondylarthritis, and ankylosing spondylitis), and kidney and gallstone discomfort. Treating acute migraines is another indication. Diclofenac is used commonly to treat mild to moderate post-operative or post-traumatic pain, particularly when inflammation is also present, and is effective against menstrual pain.⁴²

It dissolves quickly in alkaline pH ranges of 5-8 and poorly in acidic pH ranges of 1-3 and water. In certain situations, regular doses is necessary to achieve therapeutic medication plasma levels because the drug's biological half-life is only 1-2 hours. Peptic ulcers, gastrointestinal bleeding, and gastrointestinal abnormalities are caused by long-term diclofenac administration. Therefore, a great deal of research is being done on novel drug delivery strategies to determine the best dosage schedule without sacrificing the medication’s therapeutic effectiveness. According to the study, when compared to single unit dosage forms, the gastro-retentive floating system exhibits more consistent medication absorption over an extended period of time and lowers the risk of local discomfort.⁴³

The purpose of this project was to use effervescent technology to build a novel diclofenac carrier based on controlled release gastro-retentive floating tablets. With the use of gastro-retentive floating tablets, an effort has been made to improve diclofenac's overall solubility, stability, and bioavailability. This approach also may help to eliminate the necessity for frequent dosing which in turn increases patient compliance and decreases the occurrence of adverse effects. ⁴⁴

Fig No 2: Diclofenac Sodium Tablet. I.P.

Advantages of diclofenac sodium:

· The flavour is getting better

· It absorbs quickly

· It has a higher bioavailability than other dose forms

· It doesn't require swallowing tablets

· It exhibits good absorption in the stomach and intestines.³³

Disadvantages of diclofenac sodium:

· Its size is larger

· Its production process is complex

· Its packing requires careful handling.⁴⁵

Combination of omeprazole and diclofenac sodium:

Several clinical studies have assessed the safety and effectiveness of co-administration of enteric-coated or extended-release sodium diclofenac with omeprazole in patients with osteoarthritis or rheumatoid arthritis who had developed gastric duodenal ulcers after long-term treatment with diclofenac or other NSAIDs, despite the fact that no fixed-dose combinations of diclofenac and proton pump inhibitors have been developed to date. There were no observed interactions between omeprazole and diclofenac. There was no discernible effect of omeprazole (20 mg/day) on the pharmacokinetic characteristics of enteric-coated, 50 mg tablets of diclofenac sodium.⁴⁶

Omeprazole co-administration decreased the likelihood of ulcer development.⁴⁷ and haemorrhaging due to recurring ulcers⁴⁸ and expedited healing of pre-existing ulcers in patients with a history of duodenal or stomach ulcers linked to long-term NSAID use. The majority of omeprazole's side effects were modest and fleeting, such as dry mouth and diarrhea.⁴⁹

Proton pump inhibitors are the primary acid-reducing medicine used to prevent ulcers associated to NSAIDs because of their effectiveness and high tolerability.⁵⁰ Nevertheless, the proton pump inhibitors offer no defence against harm to the lower gastrointestinal tract.^51-53

Drug and excipient profile:

Name: Diclofenac sodium

Molecular formula: C14H10CL12NNaO2

Synonyms: Diclofenac sodium, Salt sodium diclofenac etc

Structure:

Fig No 3: 3D Structure of diclofenac

Fig No 4: Structure of Diclofenac Sodium

Pharmacology:

· Anti-inflammatory activity:

Strong anti-inflammatory drugs like diclofenac sodium have been shown to work in carrageenan and kaolin paw oedema. Rat models with adjuvant arthritis treated for 18–21 days following. The injection of Freund’s adjuvant.^54-57The ED& many times lower than most anti-inflammatory NSAID’s and at least half that of indomethacin and naproxen.⁵⁸

· Inhibition of prostaglandin synthesis and platelet aggregation:

At 1.6 pmol/L, the medication is one of the most potent PGE synthetase inhibitors available. In rats, it significantly reduces platelet aggregation. 20 Diclofenac sodium was also investigated by Jobin and Gagnon, who discovered that it was a strong and partial inhibitor of the ADP- and collagen-induced aggregation of human platelets, respectively.⁵⁹

The medication prevents collagen aggregation and secondary aggregation caused by ADP and adrenaline (epinephrine) at low concentrations.^60-61

· Analgesic and anti-pyretic effects:

When mice and rats were given different irritants (p-benzoquinone and acetic acid) intraperitoneally, diclofenac was found to have a significantly stronger analgesic effect in the writhing condition than other NSAlDs that were examined. Rats with yeast-induced fevers likewise demonstrated the antipyretic effect.⁵⁹

Pharmacokinetics, metabolism of Diclofenac:

Absorption:

Research using oral and intravenous 50 mg dosages of 14C-labeled dic10fenac sodium show that oral administration of the drug results in nearly complete absorption (Kendall et al., 1979; John, 1979; Riess and Stierlin, 1978). Commercially available solutions that are given as single doses in the form of suppositories or as oral solution or enteric coated tablets absorb just as effectively (Riess and Stierlin, 1978). Peak plasma concentrations of the unchanged medication varied from 720 to II OOng/ml and were reached 1.5 to 2 hours after consumption following a single 25 mg dose given as enteric-coated tablets (Geiger et al., 1975). Kozatani et al. (J 972) observed that after 50 mg of unaltered diclofenac was given as film-coated tablets, the average peak plasma concentration was 700 ng/ml. The mean peak plasma levels in individuals under 22 years old and those over 62 years old Female individuals were 1500–1600 ng/ml after receiving 50 mg (enteric-coated) orally while fasting (Willis and Kendall, 1978). These values were acquired by applying the Geiger et al. (J 975). technique. Following oral treatment, diclofenac experiences "first-pass" metabolism, with roughly 60% of the medication entering the bloodstream undigested (John, 1979). The concurrent administration of therapeutic doses of aspirin results in a considerable drop in plasma concentrations (section 6). When compared to single doses, the pharmacokinetic behavior of diclofenac is not significantly altered by repeated administration (John, 1979).^62-65

Distribution:

Although there is a dearth of information regarding the distribution of diclofenac in humans, research conducted on rats using radiolabelled drug show that, aside from the liver, bile, and kidney, the largest quantities are found in the blood, which is followed by the heart and lung (Riess and Stierlin, 1978). Diclofenac sodium is highly (99.7%) bound to blood proteins, primarily albumin, as are the majority of other non-steroidal anti-inflammatory medications (Riess and Stierlin, I 978; Wagner and Sulc, 1979).⁶⁶

Elimination:

The main method of removing diclofenac sodium is metabolism (Stierlin et al., 1979). The glucuronide and sulphate conjugates of the metabolites are then excreted through the urine and biliary system (Stierlin et al., 1979).⁶⁶

Synovial fluid concentration:

Voltaren diffuses into the synovial fluid after penetrating the synovial membrane. Synovial levels of Voltaren are higher than comparable plasma levels between 4 and 24 hours post-dosage.⁶⁷

Tissue distribution:

After quick absorption, the medication is broadly disseminated, with the liver, kidney, and blood exhibiting the highest amounts in these elimination organs.⁶⁸

Therapeutic use of diclofenac:

· An FDA-approved medication called diclofenac is used to treat and manage both acute and chronic pain brought on by inflammatory diseases, particularly those that affect the musculoskeletal system. These consist of ankylosing spondylitis, rheumatoid arthritis, and osteoarthritis. Actinic keratosis can be treated topically using it.^69-70

· Off-label uses of diclofenac include the treatment of biliary colic, corneal abrasions, fever, gout, migraines, myalgia, and pain following episiotomy.⁷¹

· The medication is a non-steroidal anti-inflammatory that has anti-inflammatory (lower inflammation), analgesic (lower pain), and antipyretic (lower fever) properties.⁷²

· It is also used to treat rheumatoid arthritis and osteoarthritis.^73-75

Adverse events and drug–drug interactions:

Like other NSAIDs, diclofenac carries a higher risk of significant GI, CV, and renal adverse effects related to dosage.^76-81Reduced proteinoids' ability to secrete mucus and bicarbonate, which typically shield the stomach mucosa from harm, is the cause of GI adverse events.^82-83

In line with the hypothesis that NSAIDs that have the highest COX-1 selectivity are also more likely to raise the risk of gastrointestinal damage,^84-85Vascular endothelial cells use PGI2, a primary byproduct of COX-2-mediated metabolism of arachidonic acid, as a strong vasodilator and platelet inhibitor in physiological processes.⁸⁶Evidence from preclinical and clinical studies suggests that inhibiting PGI2 production raises the risk of thrombosis and hypertension.^87-89The degree to which NSAIDs partially inhibit COX-1 is a major factor in the varied risk of MI (myocardial infarction) caused by these medications.⁹⁰

Because of their unique method of action, NSAIDs are quite efficient as medicines, but they also frequently cause adverse effects, especially after oral administration. NSAIDs are thought to be the cause of between 21% and 25% of documented incidences of adverse drug reactions (ADRs). Functional problems of the digestive tract, kidneys, heart, and central nervous systems are the most common side effects of NSAID use, particularly when taken over an extended period of time. It has been demonstrated that nonsteroidal anti-inflammatory medication adverse effects, contraindications, and use limits might differ significantly.^91-95

Role of Diclofenac Sodium:

In injured nerves, COX-2 is potently increased in the area surrounding the injury. When a nerve is wounded, the expression of COX-1 and COX-2 is markedly elevated in Schwann cells and damaged nerve macrophages.⁹⁶Additionally, the Schwann cell product monocyte chemo attractant protein 1 (MCP-1) is activated in damaged neurons, causing blood-borne monocytes to move and differentiate into tissue macrophages. This suggests that MCP-1 increases the expression of COX-2.⁹⁷as well as PGE2 release⁹⁸invading other cells, including macrophages. Macrophages are important because they degrade axonal residues and produce and release growth factors, cytokines, eicosanoids, and nitric oxide (NO) as pro- or anti-inflammatory mediators in the wounded nerve.^99-100

In animal models of inflammatory demyelinating diseases, macrophages and Schwann cells express more COX-1 and COX-2.¹⁰¹

According to reports, COX inhibitors can block signals from myelin debris that negatively impact regeneration, which encourages axonal outgrowth in cultured neurons.¹⁰²Further evidence of the neurotoxic effects of glial cells and macrophages on neurons comes from decreased COX-2 inhibition in vitro.¹⁰³In rats, COX-2 has a direct impact on nerve regeneration.¹⁰⁴It has been demonstrated that the selective COX-2 inhibitor celecoxib can speed up functional recovery by promoting nerve regeneration in crush lesions created in experimental settings.¹⁰⁵The local injection of both selective and non-selective COX inhibitors has also been shown to reduce neuropathic pain resulting from nerve damage.¹⁰⁶

It is well established that DS works by inhibiting COX. Its ability to suppress COX-2 is 20 times stronger than that of COX-1¹⁰⁷.

CONCLUSION:

Compared to other medication delivery systems, effervescent tablets are a common dosage type that have various advantages. They have a quicker beginning of action and improved bioavailability since they dissolve easily in water and are absorbed by the body. They taste better and are more convenient for people who have trouble swallowing, which improves patient compliance. In addition to being more stable, effervescent pills are also easier to travel and store and can lessen gastrointestinal discomfort. Diclofenac sodium can effectively counteract the clinical signs and symptoms of inflammation by influencing a broad spectrum of mediators and cell processes connected to inflammation. Significant pain relief can be obtained quickly with diclofenac, and in some cases, this relief lasted for many days. The molecule that served as the model NSAID in terms of physicochemical and steric characteristics was the starting point for the creation of diclofenac medicinal products. An other strategy to improve GI tolerability was the creation of a fixed-dose combination of diclofenac sodium and a gastroprotective drug, misoprostol, a synthetic prostaglandin, or co-administration of a diclofenac enteric-coated tablet with proton pump inhibitors. Diclofenac Sodium's effervescent tablet form presents a viable substitute for traditional tablet forms. In treating acute pain and inflammatory diseases, this formulation improves the drug's solubility and absorption, which may result in a speedier beginning of action. Because it is easier to administer and more appealing, the effervescent version also increases patient compliance—especially for those who have trouble swallowing pills. Additionally, the effervescent pills reduce gastrointestinal discomfort, which is a typical adverse effect of oral NSAIDs.

REFERANCE:

1. Advankar A, Maheshwari R, Tambe V, Todke P, Raval N, Kapoor D, etal. Specialized tablets: Ancient history to modern developments. In: Drug Delivery Systems. Elsevier; 2019. p. 615-64. https://doi.org/10.1016/B978-0-12-814487-9.00013-2

2. Rudnic: Tablet dosage forms - Available from:https://scholar.google.com/scholar_lookup?title=Tablet%20dosage%20forms&author=E.M.%20Rudnic&publication_year=2002

3. İpci K, Öktemer T, Birdane L, Altıntoprak N, Bayar Muluk N, Passali D, et al. Effervescent tablets: a safe and practical delivery system for drug administration. ENT Updates. 2016 Apr 1; 46-50. https://doi.org/10.2399/jmu.2016001009

4. Viscosity. In: Indian Pharmacopoeia. The Indian Pharmacopoeia Commission, Indian Pharmacopoeia Laboratory, Govt. of India, Ministry of Health & Family Welfare; 2018. p. 2523.

5. Sendall:0 Effervescent tablets - Available from: https://scholar.google.com/scholar_lookup?title=Effervescent%20tablets&journal=Pharm.%20J.&volume=230&pages=289294&publication_year=1983&author=Sendall%2CF.%20E.%20J.&author=Staniforth%2CJ.%20N.&author=Rees%2CJ.%20E.&author=Leatham%2CM.%20 J.

6. Eichman Jonathan, Robinson Joseph. Mechanistic studies on effervescent-induced permeability enhancement. Pharm Res. 1998; 15(6):925-30. https://doi.org/10.1023/A:1011936901638

7. Rani R, Masoanl K, Sherry. A recent updated review on effervescent tablet. International journal of creative research thoughts. 2020; 8(4):3928-35. Available from: www.ijcrt.org

8. Patel SG, Siddaiah M. Formulation and evaluation of effervescent tablets: a review. Journal of Drug Delivery and Therapeutics. 2018 Nov 15; 8(6):296-303. https://doi.org/10.22270/jddt.v8i6.2021

9. Biranje S, More A, Shangrapawar TP, Bhosale PDEA A. A Review on Formulation and Evaluation of Effervescent Tablet. Int J Pharm Pharm Res. 2021; 21(3):476-86.

10. BG P, O M. Concept, Manufacturing and Characterization of Effervescent Tablets: A Review. SunText Review of Pharmaceutical Sciences. 2021; 02(01). https://doi.org/10.51737/2766-5232.2021.010

11. Rani Ms. Review on Introduction to Effervescent Tablets and Granules. Kenkyu Journal of Pharmacology. 2020; 6:1-11. https://doi.org/10.12928/pharmaciana.v11i2.20873

12. Juarez-Enriquez E, Olivas GI, Zamudio-Flores PB, Ortega-Rivas E, Perez-Vega S, Sepulveda DR. Effect of water content on the flowability of hygroscopic powders. J Food Eng. 2017 Jul 1; 205:12-7. https://doi.org/10.1016/j.jfoodeng.2017.02.024

13. Apostolopoulos D, Fusi R. Prediction of moisture barrier requirements for an effervescent single serve aspartame sweetened tablet. Development in food science. 1995; 37:1119-32. https://doi.org/10.1016/S0167-4501(06)80223-2

14. Agyilirah GA, Green M, DuCret R, Banker GS, Evaluation of the gastric retention properties of a cross-linked polymer coated tablet versus those of a non-disintegrating tablet, International Journal of Pharmaceutics, 1991; 75: 241–47.

15. Mohrle, R., Liberman, L, Schwartz L, Pharmaceutical Dosage Form, Vol. 1, Marcel Decker Inc., New York, 2005; 285- 292.

16. Lachman L, Liberman HA, Kanig JL. The theory and practice of industrial pharmacy. 3rd ed. Philadelphia: lea and febiger; 1986.

17. Swarbrick J, Boylan JC. Encyclopedia of pharmaceutical technology. New York: Marcel Dekker; 2002

18. Harald S, Effervescent Dosage, Pharmaceutical Technology Europe, 2003; 15(4): 25–28.

19. Srinath KR, “Formulation and Evaluation of Effervescent tablets of Paracetamol”, International Journal of Pharmaceutical Research & Development, 2011; 3(3):76-104.

20. Indian Pharmacopoeia, Government of India Ministry of Health and Family Welfare. Delhi: Controller of Publications 1996; 2: 35, 448, 554.

21. Howard CA, Lloyd A, Nocholas and Popovich, “Effervescent granules”8th edition “Pharmaceutical Dosage From and Drug Delivery” International Student Edition.-2000, 172-178.

22. Shimodaira S, Quality Verification of Dendritic Cell-Based Cancer Vaccine. Pharm Anal Acta, 2016; 7:467.

23. Hassali MA, Role of Pharmacists in Health Based Non-Governmental Organizations NGO: Prospects and Future Directions, Pharm Anal Acta. 2016; 7:467.

24. Vergeire DG, Usefulness of Cost Acta, 2016; 7:456.

25. Wang C, Application of In Vitro Models in Developmental Neurotoxicity and Pharmaceutics Research, Journal of Molecular Pharmaceutics & Organic Process Research, 2015;3:122-128..

26. Lyubchenko YL, Nanoimaging for Molecular Pharmaceutics of Alzheimer’s and other Neurodegenerative Disorders, Journal of Molecular Pharmaceutics & Organic Process Research, 2013;1:107-111.

27. Foldvari M, Nanopharmaceutics Innovations in Gene Therapy: Moving Towards Non-Viral and Non-Invasive Delivery Methods. J Nanomedine Biotherapeutic Discovery. 2014; 4:135.

28. Maurya SD, Rawal RK, Jha S, Chauhan PS, Kumar A, Drug Loaded Beads: Current Status, American Journal of PharmTech Research, 2013; 3 (1): 331-337.

29. Sallam A, Bioequivalence of Two Oral Formulations of Modafinil Tablets in Healthy Male Subjects under Fed and Fasting Conditions. Journal of Bioequivalence Availability. 2015; 7:63-67.

30. Agatonovic KS, Biorelevant Dissolution Studies of Pioglitazone HCL Immediate Release Tablets and the Determination of an In Vitro In Vivo Correlation, Journal of Bioequivalence Availability, 2015; 7:086-089

31. Prabhakar C, Krishna K. A review on efferevesent tablets. International Journal of Pharmacy and Technology. 2011; 3:704-12. Available from: https://www.researchgate.net/publication/286848680 A review on efferevesent tablets.

32. Vasim SM. Effervescent Mixture Based Solid Dispersion a Novel Approach for Solubility Enhancement. Research J Pharm and Tech. 2011; 4(11):1682-6.

33. Patel Salim G., Siddaiah M., Journal of Drug Delivery and Thera-peutics 2018; 8(6): 296-(303 Formulation and Evaluation of Effervescent tablets: A Review ISSN 2250-1177, Page No.299.

34. Lacheman or Liebermans 4th Edition the theory and practice of Industrial Pharmacy Published by CBS Publisher and Distributors PVT LTD. Page No. (468)

35. Dash RT, Verma P. Matrix: An approach towards oral extended release drug delivery. IJPPR. 2012; 2(2): 12-24

36. Kanwar N., Kumar R., Sarwal A. and Sinha V.R., Preparation and evaluation of floating tablets of pregabalin. Drug Development and Industrial Pharmacy, 42(4): 1-7, (2015)

37. Katariya C. and Roy A., Floating Drug Delivery System for Analgesic - A Review. International Journal of Pharmaceutical Sciences Review and Research, 43(2): 1-4, (2017)

38. Sun Z, Ya N, Adams RC, Fang FS. Particle size specifications for solid oral dosage forms: a regulatory perspective. Am PharmRev. 2010;13(4):70–3.

39. Manjunatha K.M., Ramana M.V. and D Satyanarayana D., Design and evaluation of diclofenac sodium controlled drug delivery system. Indian Journal of Pharmaceutical Science, 69(3): 384-389, (2007)

40. Tripathi K.D., Essentials of medical pharmacology, 6th edition, Jaypee brothers, medical publisher (P) Ltd., New Delhi, 2008, 184-206.

41. Rang H.P., De M.M., Ritter J.M., Flower R.J., Rang and Dale's pharmacology, 6thEdition, Churchill Livingstone Elsevier, 2007, 227-233.

42. Kornblurn S.S., Batopak S.W., J. Pharm Sci, 1993, 82 (1), 43-49.

43. Kouchak M. and Atyabi F., Ion-exchange, an Approach to Prepare an Oral Floating Drug Delivery System for Diclofenac. Iranian Journal of Pharmaceutical Research, 2: 93-97, (2004)

44. Swain R.P., Pendela S. and Panda S., Formulation and Evaluation of Gastro-bilayer Floating Tablets of Simvastatin as Immediate Release Layer and Atenolol as Sustained Release Layer. Indian Journal of Pharmaceutical Sciences, 78(4): 458-468, (2016)

45. Srinath KR, Chowdary C.P., Palanisamy P. Formulation and Evaluation of Effervescent tablets of Paracetamol., Int. J Pharma Research 2011; 3(3) 12 May 2011 et. Al, uprd 2011 Page No 77.

46. Andersson T, Bredberg E, Lagerstrom PO, Naesdal J, Wilson I.Lack of drug-drug interaction between three different non-steroidal anti-inflammatory drugs and omeprazole. Eur J ClinPharmacol. 1998;54(5):399–404.

47. Sugano K, Kinoshita Y, Miwa H, Takeuchi T, Esomeprazole NSAID Preventive Study Group. Safety and efficacy of long-term esomeprazole 20 mg in Japanese patients with a history of peptic ulcer receiving daily non-steroidal anti-inflammatory drugs. BMC Gastroenterol. 2013;13:54.

48. Chan FK, Lanas A, Scheiman J, Berger MF, Nguyen H, Goldstein JL. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet. 2010;376(9736):173–9.

49. Massimo Claar G, Monaco S, Del Veccho Blanco C, Capurso L, Fusillo M, Annibale B. Omeprazole 20 or 40 mg daily for healing gastroduodenal ulcers in patients receiving non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther.1998;12(5):463–8.

50. The Nonsteroidal Anti-Inflammatory Drugs: Treating Osteoarthritis and Pain Comparing Effectiveness, Safety, and Price 2013. Available from :https://www.consumerreports.org/health/resources/pdf/best-buy drugs/Nsaids2. pdf. Accessed 24 Mar 2014.

51. Davies NM, Anderson KE. Clinical pharmacokinetics of diclofenac. Therapeutic insights and pitfalls. Clin Pharmacokinet.1997;33(3):184–213.

52. Laine L, Connors LG, Reicin A, Hawkey CJ, Burgos-Vargas R, Schnitzer TJ, et al. Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use. Gastroenterology. 2003;124(2):288–92.

53. Wallace JL. Mechanisms, prevention and clinical implicationsof nonsteroidal anti-inflammatory drug-enteropathy. World J Gastroenterol. 2013;19(12):1861–76.

54. Adeyeye, C.M. and Li, P.K., 1990. Diclofenac sodium. In Analytical profiles of drug substances (Vol. 19, pp. 123-144). Academic Press.

55. Scholer, D.W., Ku, E.C., Boettcher, I. and Schweizer, A., 1986. Pharmacology of diclofenac sodium. The American journal of medicine, 80(4), pp.34-38.

56. Newbould BB: Chemotherapy of arthritis induced in rats by mycobacterial adjuvant. Br J Pharmacol 1963; 21: 127-136

57. Schweizer A, Brom R: Differentiation of peripheral and central effects of analgesic drugs. Int J Tissue React 1965; 7: 79-63.

58. H.L. White, and A.T. Glassman, Prostaglandins, L 123 (1 974)

59. Adeyeye, C.M. and Li, P.K., 1990. Diclofenac sodium. In Analytical profiles of drug substances (Vol. 19, pp. 123-144). Academic Press.

60. Todd, P.A. and Sorkin, E.M., 1988. Diclofenac sodium: a reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs, 35, pp.244-285.

61. Plavsic, F., & Culig, J. (1985) Human Toxicol. 4, 317-322

62. Shen TY: Synthesis and biological activity of some indomethacin analogs. In Garattini S, Dukes MNG, eds. International Symposium on Non-Steroidal Drugs, Milan, 1964. International congress series No. 82. Amsterdam: Excerpta Medica Foundation, 1985: 13.

63. Gund P, Shen TY: A model for the prostaglandin synthetase Cyclooxygenation site and its inhibition by anti-inflammatory Aryl acetic acids. J Med Chem 1977; 20: 1148-l 152.

64. Haas G, Rossi A: United States Patent 4057573 (to CIBAGEIGY), 1974.

65. Hobbs DC, Twomey TM: Piroxicam pharmacokinetics in man: Aspirin and antacid interaction studies. J Clin Pharmacol 1978; 19:. 270-281.

66. Brogden, R.N., Heel, R.C., Pakes, G.E., Speight, T.M. and Avery, G.S., 1980. Diclofenac sodium: a review of its pharmacological properties and therapeutic use in rheumatic diseases and pain of varying origin. Drugs, 20, pp.24-48.

67. P. D. Fowler, M. F. Shadforth, P. R. Crook, V. A. Euro, J. Clin. Pharmacol., i& 389 (1983).

68. W. Reiss, H. Sterlin, P. Degen, J. W. Faigle, A. Ge'rardin , J. Moppert, A. Sallman, K. Schmid, A. Schweizer, M. Sulc, W. Thesbald and J. Wagner, &and. J. Rheumafology, Supp 22: 17-29 (1978).

69. Pirard D, Vereecken P, Mélot C, Heenen M. Three percent diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses: a meta-analysis of the recent studies. Arch Dermatol Res. 2005 Nov;297(5):185-9.

70. Tampucci S, Carpi S, Digiacomo M, Polini B, Fogli S, Burgalassi S, Macchia M, Nieri P, Manera C, Monti D. Diclofenac-Derived Hybrids for Treatment of Actinic Keratosis and Squamous Cell Carcinoma. Molecules. 2019 May 09;24(9)

71. Standing JF, Savage I, Pritchard D, Waddington M. Diclofenac for acute pain in children. Cochrane Database Syst Rev. 2009 Oct 07;(4):CD005538.

72. Monita Thakare and Kamalinder K. Singh Preparation and Evaluation of diclofenac sodium controlled release tablets using spray drying technology in aqueous system, Indian Journal of Pharmaceutical Sciences.

73. Ahmed M. A. Masaad Formulation and Newly Effervescence diclofenac K tablet., Int-J Pharma Sci. Rev, 48 (January-February) 2018 article No.21 Page No.100

74. T. Comoglu, A. Dogan, S. Comoglu, N. Bascl Formulation and Evaluation of diclofenac potassium fast disintegrating tablets and their clinical application in migraine, Drug Dev Ind Pharma 2011 Mar. National library of medicine.

75. Francesco Cilurzo et al. Diclofenac fast-dissolving film: suppression of bitterness by a taste–sensing system; Drug Dev Ind Pharma 2011 Mar. National library of medicines national centre for biotechnology information.

76. Brater DC. Anti-inflammatory agents and renal function. Semin Arthritis Rheum. 2002;32(3 Suppl 1):33–42.

77. Kuo HW, Tsai SS, Tiao MM, Liu YC, Lee IM, Yang CY. Analgesic use and the risk for progression of chronic kidney disease. Pharmacoepidemiol Drug Saf. 2010;19(7):745–51.

78. Lewis SC, Langman MJ, Laporte JR, Matthews JN, Rawlins MD, Wiholm BE. Dose-response relationships between individual nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a meta-analysis based on individual patient data. Br J Clin Pharmacol. 2002; 54(3): 320–6.

79. Riera-Guardia N, Castellsague J, Calingaert B, Varas-Lorenzo C, Fourrier-Reglat A, Nicotra F, et al. The SOS Project: nonsteroidal anti-inflammatory drugs and upper gastrointestinal complications. Meta-analysis of epidemiological studies. In: International conference on pharmacoepidemiology. Brighton;2010.

80. Salvo F, Fourrier- Reglat A, Bazin F, Robinson P, Riera-Guardia N, Haag M, et al. Cardiovascular and gastrointestinal safety of NSAIDs: a systematic review of meta-analyses of randomized clinical trials. Clin Pharmacol Ther. 2011;89(6):855–66.

81. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population based controlled observational studies. PLoS Med. 2011;8(9):e1001098.

82. Sinha M, Gautam L, Shukla PK, Kaur P, Sharma S, Singh TP. Current perspectives in NSAID-induced gastropathy. MediatInflamm. 2013; 2013: 258209.

83. Miller TA. Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms. Am J Physiol. 1983;245(5 Pt 1):G601–23.

84. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivity for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci. 1999; 96(13):7563–8.

85. Patrignani P, Tacconelli S, Bruno A, Sostres C, Lanas A. Managing the adverse effects of nonsteroidal anti-inflammatory drugs. Expert Rev Clin Pharmacol. 2011;4(5):605–21.

86. Patrono C, Baigent C. Nonsteroidal anti-inflammatory drugs and the heart. Circulation. 2014;129(8):907–16.

87. Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769–79.

88. Yu Y, Ricciotti E, Scalia R, Tang SY, Grant G, Yu Z, et al. Vascular COX-2 modulates blood pressure and thrombosis in mice. Sci Transl Med. 2012;4(132):132ra54.

89. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006; 332(7553): 1302–8.

90. Garcia Rodriguez LA, Tacconelli S, Patrignani P. Role of dosepotency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population. J Am Coll Cardiol. 2008;52(20):1628–36.

91. Kowalski ML, Makowska JS, Blanca M. Hypersensivity to non-steroidal anti-inflammatory drugs (NSAIDs) – classification, diagnosis and management. Allergy 2011; 66: 818-829.

92. Lisowska B, Rell-Bakalarska M, Rutkowska-Sak L. Niesteroidowe leki przeciwzapalne – blaski i cienie. Reumatologia 2006; 44: 106-111.

93. Tatarkiewicz J. Farmakoterapia bólu: wybrane zagadnienia. Część I. Farm Pol 2004; 60: 1001-1006.

94. Zaremba M., Staniszewska A, Niewada M. Niesteroidowe leki przeciwzapalne – fakty, mity i kontrowersje dotyczące ryzyka sercowo-naczyniowego oraz ryzyka powikłań ze strony przewodu pokarmowego. Chor Serca Naczyń 2012; 9: 119-136.

95. Wełnicki M, Mamcarz A. Stosowanie niesterydowych leków przeciwzapalnych u pacjentów kardiologicznych – aktualny stan wiedzy. Kardiol Prakt 2012; 6: 33-37.

96. Ma, W., Quirion, R. Does COX-2-dependent PGE2 play a role in neuropathic pain? Neurosci. Lett. 2008; 437: 165–169.

97. Muja, N., DeVries, G.H. Prostaglandin E(2) and 6-keto-prostaglandin F(1alpha) production is elevated following traumatic injury to sciatic nerve. Glia. 2004; 46: 116–129.

98. Masuko-Hongo, K., Sato, T., Nishioka, K. Chemokines differentially induce matrix metalloproteinase-3 and prostaglandin E2 in human articular chondrocytes. Clin. Exp. Rheumatol . 2005; 23: 57–62

99. Barton, M.J., John, J.S., Clarke, M., Wright, A., Ekberg, J. The glia response after peripheral nerve injury: a comparison between Schwann cells and olfactory ensheathing cells and their uses for neural regenerative therapies. Int. J. Mol. Sci. 2017; 18: 287.

100. Wagner, R., Myers, R.R. Schwann cells produce tumor necrosis factor alpha: expression in injured and non-injured nerves. Neuroscience. 1996; 73: 625–629.

101. Shin, T., Lee, Y., Sim, K.B. Involvement of cyclooxygenase-1 and −2 in the sciatic nerve of rats with experimental autoimmune neuritis. Immunol. Invest. 2003; 32: 123–130.

102. Fu, Q., Hue, J., Li, S. Nonsteroidal anti-inflammatory drugs promote axon re-generation via RhoA inhibition. J. Neurosci. 2007; 27: 4154–4164.

103. Klegeris, A., McGeer, P.L. Cyclooxygenase and 5-lipoxygenase inhibitors protect against mononuclear phagocyte neurotoxicity. Neurobiol. Aging. 2002; 23: 787–794.

104. Mohammadi, R., Hirsaee, M.A., Amini, K. Improvement of functional recovery of transected peripheral nerve by means of artery grafts filled with diclofenac. Int. J. Surg. 2013; 11: 259–264.

105. Camara-Lemarroy, C.R., Guzman-de la Garza, F.J., Barrera-Oranday, E.A., Cabello-Garcia, A.J., Garcia-Tamez, A., Fernandez-Garza, N.E. Celecoxib accelerates functional recovery after sciatic nerve crush in the rat. J. Brachial Plex. Peripher Nerve Inj. 2008; 3: 25.

106. Syriatowicz, J.P., Hu, D., Walker, J.S., Tracey, D.J. Hyperalgesia due to nerve injury: role of prostaglandins. Neuroscience. 1999; 94: 587–594.

107. Cryer, B., Feldman, M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am. J. Med. 1998; 104: 413–421.

Received on 09.10.2024 Revised on 26.10.2024

Accepted on 09.11.2024 Published on 10.03.2025

Available online from March 21, 2025

Research J. Science and Tech. 2025; 17(1):89-98.

DOI: 10.52711/2349-2988.2025.00013

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.