Preparation of disintegration tablet using Cucurbita maxima pulp powder as disintegration
The tablet is the widely used dosage form because of its convenience in terms of self-administration, low cost and ease in formulation. However, geriatric and pediatric patients experience difficulty in swallowing conventional tablets, which leads to poor patient compliance. “Mouth dissolve (MD)” tablets are novel types of tablets that disintegrate/ dissolve/disperse in saliva within 15 to 60 s, without the need of water. This characteristic advantage leads to their suitability for geriatric and pediatric patients at anytime, anywhere. The benefits, in terms of patient compliance, rapid onset of action, increased bioavailability, and good stability make these tablets popular as a dosage form of choice in the current market. Different technological techniques, such as freeze drying, moulding, direct compression, are currently employed to prepare the formulations of this type present in the pharmaceutical market. Beta vulgaris (Chenopodiaceae) is an important plant found in India. Pulp powder of this plant was used to prepare fast dispersible tablet. This type of natural plants plays an important role as pharmaceutical excipient. These are easily available, biodegradable and having low cost. Bio compatibility of these natural polymers promotes their use as in pharmaceutical formulations.
Present work used direct compression technique to prepare tablets. In present study Diclofenac sodium, a non-steroidal anti-inflammatory drug was selected as model drug. It is an acetic acid nonsteroidal antiinflammatory drug (NSAID) with analgesic and antipyretic properties. Diclofenac sodium is used to treat pain, dysmenorrhea, ocular inflammation, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and actinic keratosis.
Extraction and Characterization of Polymer
Preparation of Beta vulgaris pulp powder:
Beta vulgariswas purchased from local market of Meerut (Uttar Pradesh) India. The fruit was clean with water to remove dust from surface and further peel was removed. Pulp was cut into small pieces and put into grinder to form paste. This was further lyophilized to get solid porous mass. Size reduction was done and powder was collected. The collected powder was passed through 80 # sieve and stored in the air tight container for further study.
Profile of Diclofenac
Generic name: Diclofenac Sodium, Misoprostol
Brand Names: Voltaren, Cataflam, Voltaren-XR
· Small Molecule
IUPAC Name: 2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid
Chemical Formula: C14H11Cl2NO2
Average Molecular Weight: 296.148 g/mol
Melting Point: 280°C
Solubility: Soluble in water
Drug Category: Anti-inflammatory, pain relief
Indication:Diclofenac is used for musculoskeletal complaints, especially arthritis, rheumatoid arthritis, polymyositis, dermatomyositis, osteoarthritis, dental pain, TMJ, spondylarthritis, ankylosing spondylitis, gout attacks,and pain managementin cases of kidney stones and gallstones. An additional indication is the treatment of acute migraines. 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 and endometriosis.
Diclofenac suppositories:As long-term use of diclofenac and similar NSAIDs predisposes for peptic ulcer, many patients at risk for this complication are prescribed a combination (Arthrotec) of diclofenac and misoprostol, a synthetic prostaglandin analogue, to protect the gastric mucosa. An external, gel-based formulation containing 3% of diclofenac (Solaraze) is available for thetreatment of facial actinic keratosiswhich is caused by over-exposure to sunlight. Some countries have also approved the external use of diclofenac 1% gel to treat musculoskeletal conditions.Over-the-counter use against minor aches and pains and fever associated with common infections is also licensed in some countries, such as Australia and New Zealand. In many countries eye-drops are sold to treat acute and chronic non-bacterial inflammations of the anterior part of the eyes (e.g. postoperative states). A common brand name is Voltaren-ophta.
Mechanism of Action:
The exact mechanism of action is not entirely known, but it is thought that the primary mechanism responsible for its anti-inflammatory, antipyretic, and analgesic action is inhibition of prostaglandinsynthesis by inhibition of cyclooxygenase(COX). It also appears to exhibit bacteriostatic activity by inhibiting bacterial DNA synthesis.Inhibition of COX also decreases prostaglandinsin the epithelium of the stomach, making it more sensitive to corrosion by gastric acid. This is also the main side effect of diclofenac. Diclofenac has a low to moderate preference to block the COX2-isoenzyme (approximately 10-fold) and is said to have therefore a somewhat lower incidence of gastrointestinal complaints than noted with indomethacin and aspirin. The action of one single dose is much longer (6 to 8 hours) than the very short half-life that the drug indicates. This could be partly because it persists for over 11 hours in synovial fluids. Diclofenac may also be a unique member of the NSAIDs. There is some evidence that diclofenac inhibits the lipoxygenase thus reducing formation of the leukotrienes(also pro-inflammatory autacoids). There is also speculationthat diclofenac may inhibit phospholipase A2as part of its mechanism of action. These additional actions may explain the high potency of diclofenac it is the most potent NSAID on a broad basis. Pharmacology of Diclofenac Sodium. Am J of Medicine Volume 80 April 28, 1986There are marked differences among NSAIDs in their selective inhibition of the two subtypes of cyclo-oxygenase, COX-1and COX-2. Much pharmaceutical drug design has attempted to focus on selective COX-2 inhibition as a way to minimize the gastrointestinal side effects of NSAIDs like aspirin. In practice, use of some COX-2 inhibitorswith their adverse effects has led to massive numbers of patient family lawsuits alleging wrongful death by heart attack, yet other significantly COX-selective NSAIDs such as diclofenac have been well-tolerated by most of the population
Half Life: 1-2 hour
Hypersensitivity against diclofenac
History of allergic reactions (bronchospasm, shock, rhinitis, urticaria) following the use of Aspirin or another NSAID
Active stomach and/or duodenal ulceration or gastrointestinal bleeding
Inflammative intestinal disorders such as Crohn's disease or ulcerative colitis
Severe insufficiency of the heart (NYHA III/IV)
Recently, a warning has been issued by FDA not to use to treat patients recovering from heart surgery
Severe liver insufficiency (Child-Pugh Class C)
Severe renal insufficiency (creatinine clearance <30 ml/min)
Caution in patients with preexisting hepatic porphyria, as diclofenac may trigger attacks
Caution in patients with severe, active bleeding such as cerebral hemorrhage
NSAIDs in general should be avoided during dengue fever.
Investigationaluses: Diclofenac is often used to treat chronic pain associated with cancer, particularly if inflammation is also present
Ø Fever due to malignant lymphogranulomatosis (Hodgkin's lymphoma) often responds to diclofenac. Treatment can be terminated as soon as the usual treatment with radiation and/or chemotherapy causes remission of fever.
Ø Diclofenac may prevent the development of Alzheimer's disease if given daily in small doses during many years.
Ø Diclofenac has been found to increase the blood pressure in patients with Shy-Drager syndrome and Diabetes Mellitus
Ø .Diclofenac has been found to be effective against all strains of multi drug resistant E. coli.
Ø Diclofenac has the capacity to treat uncomplicated urinary tract infections (UTI) caused by E. coli.
Ø Effective In treating Salmonella infections in mice and is under investigation for the treatment of tuberculosis
Ø Diclofenac is an antiuricosuric
• Following the identification of increased risks of heart attacks with the selective COX-2 inhibitor rofecoxib in 2004, attention has focused on all the other members of the NSAIDs group, including diclofenac. Research results are mixed with a meta-analysis of papers and reports up to April 2006 suggesting a relative increased rate of heart disease of 1.63 compared to non-users. Professor Peter Weissberg, Medical Director of the British Heart Foundation said, "However, the increased risk is small, and many patients with chronic debilitating pain may well feel that this small risk is worth taking to relieve their symptoms". Only Aspirin was found not to increase the risk of heart disease; however, this is known to have a higher rate of gastric ulceration than diclofenac.
A subsequent large study of 74,838 users of NSAIDs or coxibs, published in May 2006, found no additional cardiovascular risk from diclofenac use. A very large study of 1,028,437 Danish users of various NSAIDs or coxibs, published online on June 8, 2010, found that "Use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death (odds ratio, 1.91; 95% confidence interval, 1.62 to 2.42; and odds ratio, 1.66; 95% confidence interval, 1.06 to 2.59 respectively), with a dose-dependent increase in risk." .
• Diclofenac has similar COX-2 selectivity to celecoxib. Perhaps related to this selectivity, a review of this constantly-changing topic by FDA Medical Officer David Graham concluded in September, 2006 that diclofenac does increase the risk of myocardial infarction.
• Gastrointestinal complaints are most often noted (see above). The development of ulceration and/or bleeding requires immediate termination of treatment with diclofenac. Most patients receive an ulcer-protective drug as prophylaxis during long-term treatment (misoprostol, ranitidine 150 mg at bedtime or omeprazole 20 mg at bedtime).
• Liver damage occurs infrequently, and is usually reversible. Hepatitis may occur rarely without any warning symptoms and may be fatal. Patients with osteoarthritis more often develop symptomatic liver disease than patients with rheumatoid arthritis. Liver function should be monitored regularly during long-term treatment. If used for the short term treatment of pain or fever, diclofenac has not been found to be more hepatotoxic than other NSAIDs.
• As of 12/2009 Endo, Novartis and FDA notified healthcare professionals to add new warnings and precautions about the potential for elevation in liver function tests during treatment with all products containing diclofenac sodium.
• Cases of drug-induced hepatotoxicity have been reported in the first month, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.
• Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac.
• Studies in Pakistan showed that diclofenac caused acute kidney failure in vultures when they ate the carcasses of animals that had recently been treated with it (see below at Ecological problems). Species and individual humans that are drug sensitive are initially assumed to lack genes expressing specific drug detoxification enzymes.
• NSAIDs "are associated with adverse renal [kidney] effects caused by the reduction in synthesis of renal prostaglandins" in sensitive persons or animal species, and potentially during long term use in non-sensitive persons if resistance to side effects decreases with age. Unfortunately this side effect can't be avoided merely by using a COX-2 selective inhibitor because, "Both isoforms of COX, COX-1 and COX-2, are expressed in the kidney... Consequently, the same precautions regarding renal risk that are followed for nonselective NSAIDs should be used when selective COX-2 inhibitors are administered." However, diclofenac appears to have a different mechanism of renal toxicity.
• Bone marrow depression is noted infrequently (leukopenia, agranulocytosis, thrombopenia with/without purpura, aplastic anemia). These conditions may be life-threatening and/or irreversible, if detected too late. All patients should be monitored closely. Diclofenac is a weak and reversible inhibitor of thrombocytic aggregation needed for normal coagulation.
• Induces warm antibody hemolytic anemia by inducing antibodies to Rh antigens, Ibuprofen also does this.
• Diclofenac may disrupt the normal menstrual cycle
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