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IJPCBS 2013, 3(2), Rehnasalim et al. ISSN: 2249-9504

INTERNATIONAL JOURNAL OF PHARMACEUTICAL, CHEMICAL AND BIOLOGICAL SCIENCES

Available online at www.ijpcbs.com Review Article

BIOWAIVER MONOGRAGHS OF DEXIBUPROFEN Rehnasalim, R. Sivakumar, Krishnapillai, C. Sajeeth and Haribabu Grace College of Pharmacy, Palakkad, Kerala, India.

ABSTRACT

Literature data are reviewed on the properties of dexibuprofen related to thebiopharmaceutics classification system (BCS). Dexibuprofen was assessed to be a BCS classII drug.This article summarizes the main pharmacological effects, therapeutical applications, adverse drug reactions drug-drug interactions,pharmacokinetic properties, physicochemical properties and BCS classification of dexibuprofen. Dexibuprofen is derivatives.It is the active dextrorotatory of .

Keywords: Dexibuprofen, Drug -drug interaction, Physicchemical properties.

INTRODUCTION ibuprofen. Most ibuprofen formulations A monograph based on literature data is contain a of dexibuprofen presented on dexibuprofen concerning its [(+)-ibuprofen] and (−)-ibuprofen. S(+) properties related to the biopharmaceutics Ibuprofen is over 100‐fold more potent an classification system (BCS).. In brief, it is to inhibitor of ‐I than Dexibuprofen data available from literature R‐Ibuprofen2. Dexibuprofen shows an sources about dexibuprofen. Dexibuprofen equipotency with half of the racemic is the most commonly used and most ibuprofen dose, and the introduction of frequently prescribed NSAID. It is a non- dexibuprofen (Seractil) permits the selective inhibitor of cyclo-oxygenase-1 prescription of lower doses3. (COX-1) and Cyclooxygenase-2 (COX-2). It has a prominent and antipyretic role. Its effects are due to the inhibitory actions on cyclo-oxygenases, which are involved in the synthesis of . Prostaglandins have an important role in the production of pain, inflammation and fever.

LITERATURE DATA Fig. 1: Structure Of Dexibuprofen General Characteristics Dexibuprofen chemical name is(2S)-2-[4- (2-methylpropyl)phenyl] propanoic acid Clinical Pharmacology of Dexibuprofen (and its structure shown in Figure Dexibuprofen is supplied as tablets with a 1.S+Ibuprofen can form salts with bases potency of 200 to 400 mg4. The usual dose such as basic aminoacids, examples are is 600 to 900 mg three times a day5. It is lysine and arginine. The lysine part almost insoluble in water having pKa of enhances, solubility of the ibuprofen in 4.656.It is well absorbed orally; peak serum water and gastric solution(Dexibuprofen) concentrations are attained in 1 to 2 hours obtained with half the dose racemic after oral administration. It is rapidly bio- ibuprofen formulation1. It is the transformed with a serum half life of 1.8 to active dextrorotatory enantiomer of

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3.5 hours. The drug is completely dose of ibuprofen. Greater peak analgesia eliminated in 24 hours after the last dose was also seen with. It is indicated and eliminated through metabolism7,8. The dexibuprofen for the relief of sign and drug is more than 99% protein bound, symptoms of osteoarthritis, rheumatoidal extensively metabolized in the liver and disorders such as osseous rheumatism, little is excreted unchanged9. ankylosing sodalities, juvenile arthritis, Although highly bound to plasma proteins muscular rheumatism and degenerative (90-99%), displacement interactions are joint disease. It is also used for the acute not clinically significant, hence the dose of symptomatic treatment of painful oral anti-cogulants and oral hypoglycemic menstruation, symptomatic treatment needs not be altered11. More than 90% of an muscle pain, head ache and dental ingested dose is excreted in the urine as pain.Dexibuprofen has equal efficacy and metabolites or their conjugates, the major comparable safety andtolerability19 with metabolites are hydroxylated and in the treatment of the carboxylated compounds4,10. osteoarthritis18.Dexibuprofen shows Renal impairment also has no effect on the excellent tolerability, safety than other kinetics of the drugs, rapid elimination still NSAIDlike sodium, dexibuprofen occur as a consequence of metabolism12.The has stronger pain reducingeffect than administration of ibuprofen tablets either racemic ibuprofen. Maximum Daily Dose of under fasting conditions or immediately 3200mg18(adult) of Ibuprofen racemate is before meals yield quiet similar serum required, but dose required concentrations-time profile. When it is fordexibuprofen lysinate is 2692.5 mg of administered immediately after a meal, S+Ibuprofen lysinateequivalent to 1500mg there is a reduction in the rate of absorption of dexibuprofen 200‐300mg every 4‐6 hrs but no appreciable decrease in the extent of forthe relief of pain. S(+) Ibuprofen is absorption. superior in anti‐inflammatoryaction but equal to reacemic ibuprofen in analgesic Therapeutic Applications action. A low dose ibuprofen is as effective as Dexibuprofen is the single and for the indications pharmacologically effective enantiomer of normally treated with over the counter rac-ibuprofen. Racibuprofen and medications13. It is widely used as an dexibuprofen differ in their physico- analgesic, an anti inflammatory and an chemical properties, in terms of their antipyretic agent14-15. Recemic ibuprofen pharmacological properties and their and S(+) enantiomer are mainly used in the metabolic profiles. Several clinical trials and treatment of mild to moderate pain related post-marketing surveillance studies were to dysmenorrhea, headache, migraine, performed to broaden the findings on postoperative dental pain, management of dexibuprofen. In the last 5 years 4836 spondylitis, osteoarthritis, rheumatoid patients have been exposed to dexibuprofen arthritis and soft tissue disorder16. A in clinical trials and PMS trials. Only in 3.7% number of other actions of NSAIDs can also of patients adverse drug reactions have be attributed to the inhibition of been reported and 3 serious adverse drug prostaglandins (PGs) or reactions (0.06%) were observed. In the synthesis, including alteration in platelet dose ratio of 1 : 0.5 (rac-ibuprofen vs. function (PGI2 and Thromboxane), dexibuprofen) at least equivalent efficacy prolongation of gestation and labor (PGE2, was proven in acute mild to severe somatic PGF2A), gastrointestinal mucosal damage and visceral pain models. Dexibuprofen has (PGI2 and PGE2), fluid and electrolyte proven at least comparable efficacy to imbalance (renal PGs), premature closure of diclofenac, and celecoxib and has ductus arteriosus (PGE2) and bronchial shown a favourable tolerability. The results asthma (PGs)17. The advantages of include suggest that dexibuprofen processed in a greater dexibuprofen clinical efficacy, ease special crystal form is a safe and effective in dose optimization, less variability in treatment for different pain conditions. therapeutic effects, all of these at half the

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Indication to 1% with placebo and 12.5% with Dexibuprofen is indicated for the treatment aspirin24. Ibuprofen was a potential cause of of Pain and inflammation caused by GI bleeding25,26,increasing the risk of gastric osteoarthritis ulcers and damage, renal failure, epistaxis27- Acute symptomatic treatment of pain 30,apoptosis31, heart failure, during menstrual bleeding (Primary hyperkalaemia32, confusion and dysmenorrhoea)Mild to moderate pain, bronchospasm33.It has been estimated that such as pain in the muscles and joints and 1 in 5 chronic users (lasting over a long toothaches. It may be used as an antipyretic period of time) of NSAIDs will develop to reduce fever. gastric damage which can be silent34. Other adverse effects of ibuprofen have Contra-indications been reported less frequently. They include Dexibuprofen should not be administered thrombocytopenia, rashes, headache, to Patients with hypersensitivity dizziness, blurred vision and in few cases toDexibuprofen or other non-steroidal anti- toxic amblyopia, fluid retention and edema. inflammatory drugs, Patients with active or Patients who develop ocular disturbances suspected gastrointestinal ulcer or history should discontinue the use of of recurrent gastrointestinal ulcer,Patients dexibuprofen35. Effects on kidney (as with who have gastrointestinal bleeding or other all NSAIDs) include acute renal failure, active bleedings or bleeding disorders, interstitial nephritis, and nephritic Patients with active Crohn's disease or syndrome, but these very rarely occur36. active ulcerative colitis, Patients with severe renal dysfunction (GFR < Drug-Drug Interactions 30ml/min),Patients with severely impaired Dexibuprofen has established drug hepatic function, Patients with hemorrhagic interactions with NSAIDs which are both diathesis and other coagulation disorders, pharmacokinetic or pharmacodynamic in or patients receiving anticoagulant therapy, origin(37,38). The most potentially serious From the beginning of 6th month of interactions include the use of NSAIDs with pregnancy. lithium, warfarin, oral hypoglycemics, high dose methotrexate, antihypertensives, Precautions angiotensin converting inhibitors, Symptoms or history of gastro-intestinal β-blockers, and diuretics. Anticipation and disease, asthma, impaired hepatic, cardiac care full monitoring can often prevent or renal function. NSAID may mask serious events when these drugs are used infections or temporarily inhibit platelet concomitantly39. aggregation. In late pregnancy, as with Observational studies and in-vivo other NSAIDs, it should be avoided as it may experiments have raised concerns that the cause premature closure of ductus cardio protective effects of arteriosus. Dexibuprofen should be used taking aspirin are blocked by ibuprofen with caution in nursing mothers. which competitively inhibits aspirin’s binding sites on platelets(41-43). The Adverse Reactions pharmacodynamic interactions of aspirin NSAIDs are widely used, frequently taken and ibuprofen may not have a significant inappropriately and potentially impact on patient outcomes45.Palmer et al. dangerously20. Nevertheless, dexibuprofen in 2003 suggested that NSAIDs interfere exhibits few adverse effects21. The major with certain antihypertensive therapies. adverse reactions include the affects on the Dexibuprofen caused a significant increase gastrointestinal tract (GIT), the kidney and in systolic and diastolic blood pressure the coagulation system22. Based on clinical compared to placebo46. A case of life- trial data, serious GIT reactions prompting threatening hypotension due to sinus arrest withdrawal of treatment because of was described in a patient in whom hematemesis, peptic ulcer,23 and severe exercise-induced hyperkalemia developed gastric pain or vomiting showed an during a stable regimen that included incidence of 1.5% with ibuprofen compared verapamil, propranolol, and

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ibuprofen47. Similar to other NSAIDs, greater response to ibuprofen-caffeine ibuprofen is likely to decrease the diuretic treatment of headaches.59 and anti hypertensive actions of thiazides, Gemfibrozil moderately increases the AUC furosemide and β-Blockers11. of R-ibuprofen and prolongs its t (1/2), Hence the administration of dexibuprofen indicating that R-ibuprofen is partially caused a significant decrease in urinary metabolised by Cytochrome P2C8 output, inulin clearance, sodium excretion, (CYP2C8). The interconversion of R- to S- osmolar clearance, free water clearance and ibuprofen can explain the small effect of urinary PGE2 clearance89.Many overdose gemfibrozil on the t (1/2) of S-ibuprofen. experiences have been reported in medical However, the gemfibrozil-ibuprofen literature48. Ibuprofen may cause serious interaction is of limited clinical toxicity when overdosed, mainly in children significance.60 on ingestion of 400 mg/kg or St. John’s wort is a popular herbal moreMaximum Daily Dose of supplement that has been involved in 3200mg18(adult) of Ibuprofen racemate is various herb-drug interactions. St. John’s required, but dose required wort treatment appears to significantly fordexibuprofen lysinate is 2692.5 mg of reduce the mean residence time of S- S+Ibuprofen lysinateequivalent to 1500mg ibuprofen, no ibuprofen dose adjustments of dexibuprofen 200‐300mg every 4‐6 hrs appear warranted when the drug is forthe relief of pain. S+ Ibuprofen is administered orally with St. John’s wort, superior in anti‐inflammatoryaction but due to the lack of significant changes equal to reacemic ibuprofen in analgesic observed in ibuprofen area under the curve action.Dexibuprofen has a low acute toxicity (AUC) and maximum concentration C (max) and patients have survived after single for either enantiomer.61 doses as high as 54 g of racemic ibuprofen. The effects of the antifungals voriconazole Most overdoses have been asymptomatic. and fluconazole on the pharmacokinetics of There is a risk of symptoms at doses>80 - S-(+) - and R-(-)-ibuprofen were studied by 100 mg/kg racemic ibuprofen.The Hynninen et al. A reduction of ibuprofen symptoms of high dose include seizures, dosage should be considered when apnea, and hypertension, as well as renal ibuprofen is coadministered with and hepatic dysfunction48-51 Ibuprofen has voriconazole or fluconazole, especially been implicated in elevating the risks of when the initial ibuprofen dose is high due myocardial infarction, particularly among to the inhibition of the cytochrome P450 those chronically using high doses52-55. 2C9-mediated metabolism of S-(+)- Desmopressin and NSAIDs should not be ibuprofen.62 used in combination in patients with The competitive binding characteristics of bleeding disorders.56Coadministration ibuprofen and naproxen with respect to the of thiopurines and various NSAIDs binding site on bovine serum albumin (BSA) (, dexibuprofen and ibuprofen) were studied. Ibuprofen displaced naproxen may lead to drug interactions.57 and vice versa from its high affinity binding It has been observed that caffeine improves site (site II) and the displaced drug rebound antinociceptive efficacy of some non- to its low affinity binding site (site I) on BSA steroidal anti inflammatory drugs (NSAIDs) molecule.63 in several experimental models, however, Anandamide, an endocannabinoid, is these effects have been questioned in degraded by the enzyme fatty acid amide humans. Caffeine is able to potentiate the hydrolase which can be inhibited by antinociceptive effect of ibuprofen. This nonsteroidal anti-inflammatory drugs effect was greater than the maximum (NSAIDs). The antinociceptive interaction produced by in the experimental between anandamide and ibuprofen was conditions.58 Caffeine also enhances the synergistic. The combination of anandamide effectiveness of most , including with ibuprofen produced synergistic ibuprofen. Comparison of the cumulative antinociceptive effects involving both 64 response scores revealed a trend toward a cannabinoid CB1 and CB2 receptors. A study by Kaminski et al. in 1998 showed

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that all NSAIDs enhanced the protective Use in Elderly Patients activity of valproate magnesium against It is recommended to start the therapy at maximal electroshock-induced seizures. the lower end of the dosage range. The Only ibuprofen and enhanced the dosage may be increased to that anticonvulsive activity of recommended for general population only diphenylhydantoin. Ibuprofen also after good general tolerance has been decreased the effective dose 50 (ED50value) ascertained. of valproate (for the induction of motor impairment). Thus, NSAIDs could enhance Use in Patients with Hepatic dysfunction: the protective activity of antiepileptics.65 Patients with mild to moderate hepatic dysfunction should start therapy at reduced Posology and method of administration doses and be closely monitored. The dosage should be adjusted to the Dexibuprofen should not be used in severity of the disorder and the complaints patients with severe hepatic dysfunction. of the patient. During chronic administration, the dosage should be Use in Patients with Renal dysfunction adjusted to the lowest maintenance dose The initial dosage should be reduced in that provides adequate control of patients with mild to moderate impaired symptoms. renal function.Dexibuprofen should not be used in patients with severe renal Adults dysfunction. The recommended dosage is 600 to 900 mg dexibuprofen daily, divided in up to three Over Dosage single doses.For the treatment of mild to Dexibuprofen has a low acute toxicity and moderate pain, initially single doses of 200 patients have survived after single doses as mg and daily Alpha 10 doses of 600 mg high as 54 g of racemic ibuprofen. Most dexibuprofen are recommended. The overdoses have been asymptomatic. There maximum single dose is 400 mg is a risk of symptoms at doses>80 - 100 dexibuprofen The dose may be temporarily mg/kg racemic ibuprofen. increased up to 1200 mg dexibuprofen per day in patients with acute conditions or Storage exacerbations. The maximum daily dose is Dexibuprofen should be kept in a tightly 1200 mg. closed container, and out of reach of For dysmenorrhoea a daily dose of 600 to children. It should be stored in a cool, dry 900 mgAlpha 10, divided in up to three area and must be properly labeled. single doses, is recommended. The maximum single dose is 300 mg; the Physicochemical properties maximum daily dose is 900 mg. (S)-(＋)-Ibuprofen (dexibuprofen) is one of the of racemic ibuprofen Children which is a non-steroidal anti-inflammatory Dexibuprofen has not been studied in drug (NSAID), and it has a pharmaceutical children and adolescents (< 18 years): activity in racemic compound. According to Safety and efficacy have not been the literature, (S)-(＋)-Ibuprofen has a established and therefore it is not solubility twice as high as that of the recommended in these age groups. racemate, and its crystal structure,optical properties, thermodynamic properties are 100mg/5ml Solution also different from the racemate.66 Table 3.1 Children and adolescents Dose:10 to was the comparison between 15mg/kg daily in 2 to 4 divided doses dexibuprofen and racemic ibuprofen.Its molecular weight 206.29, melting point is of 52 °C.

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Table: Physicochemical property of (S)-(＋)-Ibuprofen.67 Properties Dexibuprofen Racemic Ibuprofen Space group P21/C P21 Density (g/cm3) 1.098 1.110 Melting point (°C) 52.1±0.3 75.3±0.3 Heat of fusion (J/g) 91±1 125±2 11.8 4.8 Solubility in water at 37 °C (mg/100ml)

Solubility in HCl at pH 1.5 and 37 °C 9.6 1 4. (mg/100ml)

Solubility classification requires data onthe solubility Dexibuprofen is practically insoluble in at 37ᵒC, these values were water, but it is readily soluble in most experimentallydetermined, for each media organic solvents like methanol, methylene in triplicate.Dexibuprofen drug substance chloride, and acetone, and is soluble in was suspended inmedium and stirred for 24 aqueous solution of alkali hydroxides and h at 37ᵒC and thenstored for a further 24 h carbonates. It is slightly soluble in a buffer without agitation. In eachcase sediment on medium of pH 6.8 and very slightly soluble the bottom of the flask was observed.The in a buffer medium of pH 4.5. dexibuprofen concentration in the Solubility values are shown in Table 1. In clearsupernatant was determined by UV- theliterature only data at 20ᵒC or room analysis. temperaturewere found10,11. BCS These results are also shown in Table no:2.

Solubility in Solubility in 400mg/250ml at Medium /pH mg/ml at 37°C±0.5°C( as per 37°C±0.5°C BCS) Purified water 0.06 7 1.2 buffer 0.03 4 4.5 acetate buffer 0.13 27 6.8 phosphate buffer 3.44 400 7.2 phosphate buffer 5.32 400

The equilibrium solubilites of dexibuprofen decreased by 9.7%.which is likely due to in pH 1.2 and pH 7.2 were reported to be food induced pH elevation in the stomach 0.03 and 5.32gm/ml respectively. Also it resulting in earlier in vivo dissolution of exhibitsthe pH dependent solubility. ibuprofen68. Rapid and complete absorption suggests a high permeability through the GI Partition coefficient membrane.69,70 Scintigraphic studies with Calculation of then-octanaol-acid buffer sustained release products in humans distribution coefficient gave log P values at indicate that ibuprofen absorption occurs pH value1.2. throughout the GI tract following oral administration, which again supports a high pKa permeability.70 Rapid and complete The pKa of dexibuprofen is in the range of absorption of ibuprofen was also reported 4.65. from enteric coated microcapsules in humans administered as an oral PHARMACOKINETICES PROPERTIES suspension.71 Similar to other NSAIDs, high Absorption and Permeability permeability of ibuprofen and its Absorbed primarily from the small intestine enantiomers has been observed in rats, with maximum concentration (tmax) of where increased GI permeability was approximately 2 hours after oral observed because NSAIDs promote their administration.Food intake also affects the own transport.72,73This observation may absorption rate of dexibuprofen,No Effect possibly explain the GI side effects and the on AUC, tmax delayed by 0.7 hours, Cmax damage of the GI membrane following oral

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administration of high doses or upon long any of the DSC thermograms and XRD term oral usage of ibuprofen. High patterns. permeability of ibuprofen and its enantiomers has been also observed in BCS Classification Caco-2 cell cultures. According to the present regulations, dexibuprofen is a BCS class II drug, showing Invitro dissolution studies high permeability and pH-dependent The invitro dissolution studies of different solubility, that is, a high solubility according formulations of Dexibuprofen- β-CD to BCS requirements only above a certain complexes were performed using USP XXII pH value. The assignment of dexibuprofen rotating basket method (USP,2005). The to BCS Class II is supported by an observed samples were placed in a hard gelatin in vitro in vivo correlation (IVIVC) where a capsules.900ml of 0.1N Hcl was used as rank order was found between dissolution dissolution media at37o±0.5oc and characteristics and the rate of absorption, maintaining stirring speed at 50rpm. The since IVIVC’s are predicted for BCS Class II samples were withdrawn and replaced with drugs.74 Other worker classified same volume offresh dissolution media at dexibuprofen as BCS Class II also. One different time intervals and estimated at research group based its classification on 220nm by U.V. Spectrophotometer. The solubility values, measured by the dissolution profile of Dexibuprofen in saturation-flask method, at different pH- 0.1NHcl at 120min showed 43.09%. The values, and absorption permeability inclusion complexes prepared by kneading literature data; another research group method showed 78.15% and 88.01% for 1:1 based its classification on the solubility of and 1:2 molar ratios respectively whereas ibuprofen in water, without taking into freeze dried showed 95.03% and 96.05% account the pH dependency, and calculated for 1:1 and 1:2 molar ratios respectively at partition coefficients; the latter were shown 120 min. The freeze dried product of1:2 to correlate with human intestinal showed marked increases in drug release permeability. Both of the current BCS compared with other methods. Guidances allow the possibility for a biowaiver exclusively for BCS class I drugs. Polymorphism Study The limited solubility of dexibuprofen Polymorphism was a behavior that a solid biowaiver criteria. However, at pH values had different molecular arrangements in a near neutral, the solubility of dexibuprofen longrange order. Therefore, the interactions is sufficient to comply with criterion for among molecules were different in a high solubility: a dose solubility quotient of different polymorph. When Form less than 250 mL. As these pH values are transformation occurs, energy was needed closer to those at the absorption sites in the for the re-arrangement of the molecules. So small intestine they are therefore more polymorphism could be identified by DSC. relevant in terms of systemic absorption of Besides, different polymorph gives different dexibuprofen. Accordingly, ibuprofen may d-spacing in Bragg law, and PXRD could also fit in the newly proposed ‘‘intermediate characterize it. According to the literature, solubility class’’ suggested for acids and S-Ibu had a melting point at about 49 to 53 bases that are highly soluble at either °C, and the DSC analysis of solid re- physiologically relevant pH 1.2 or 6.8. crystallize by all good solvents showed that Current publications also suggest pH- the peaks were in this arrange. This showed dependent soluble, highly permeable, weak that S-Ibu re crystallized from good solvents acidic ionizable drug compounds should be by temperature cooling was isomorphism. handled like BCS class I drugs. This Both S-Ibu and solid re crystallized had an evaluation is supported by Rinaki et al.75 endothermal peak in the range of 49 to 53 who emphasized the dynamic character of °C. Besides DSC data, PXRD was also an the absorption process, as drug dissolution evidence of isomorphism to S-Ibu. The is promoted by high permeability for highly different solvents used only changed the permeable acidic NSAIDs like ibuprofen. aspect ratios and no new peaks appeared in

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