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Loratadine is a drug to treat allergies, which is a second generation non-sedating H1 anti-histamine drug to treat seasonal allergies. It is accessible as a generic drug.Â It is commercially available in the market asÂ Claritin-DÂ or Clarinase and in some 88 countries; including the United States it is available as CLARITINB. The other polycyclic histamine H1 antagonists is capable with lipophilic properties, loratadine are considered to be effective in invitro models of allergic reactions(Church 1980; Daniels 1986). Loratadine is revealed to decrease platelet activating factor (PAF)-induced bronchospasm to a limited but significant extent(Kreutner 1987). Loratadine reduces the immunologically induced release of sulfidopeptide leukotrienes from human bronchi in vitro, that does not affect the bronchoconstriction(Ornella Letari 1993). It is an antihistamine which is indicated for the relief of nasal and non-nasal symptoms of seasonal allergic rhinitis (Watkins PB 1985; Haria M 1994). Metabolism studies on the loratadine in laboratory animals showed that the drug is well absorbed, but undergoes extensive first pass metabolism (Katchen B 1985). Older histamine, (Hi) receptor antagonists contain moderate and transient bronchodilatory action(VT. 1977; Nogrady SG 1978). Newer H1 blockers, is recommended for the treatment of rhinitis and treatment of asthma (Townley RG 1989; Wasserfallen JB 1993; Spector SL 1995). Loratadine is a potent and selective H1 receptor antagonist that acts as a mast-cell stabilizing agent and reduces the intracellular adhesion molecule-l expression on mucosal surfaces(Greiff L 1995; Vignola AM 1995). Loratadine inhibits eosinophil chemotaxis, hence reducing eosinophil accumulation in target organs. Other anti-inflammatory properties include its ability to inhibit P-selectin expression and histamine-induced production of interleukin-6 and interleukin-8(Molet S 1997). These antiallergic properties of loratadine are effective in the treatment of asthma(Ciprandi G 1995). Claritin is available in the form of tablets and syrup (www.rxlist.com/claritin-drug.htm). It helps to cure anxiety and nervousness. Loratadine is off white -powder which is not soluble in water but it is soluble in alcohol,acetone and chloroform(Menardo, Horak et al. 1997). Loratadine can be taken orally. It can be of tablet form or the syrup form(See.S 2003).
Loratadine / Claritin are introduced to the world originally by Schering- Plough organization as the prescription medication in 1988 in the place called Belgium. In the year 1990, in Canada the Loratadine was first introduced as the non-prescription product. Loratadine is the drug which was developed by the Schering-Plough a pharmaceutical company as a part of a quest for a potential drug a non sedating antihistamine. However by the time the company submitted the drug to U.S. Food and Drug Administration (FDA) for its approval, the agency had already approved another non-sedating antihistamine drug called Terfenadine (Seldane- the trade name), hence loratadine was at the last priority(Hall 2001). Later loratadine was approved by FDA in the year 1993. In the year 1993, the U.S. approved for the prescription use for the seasonal allergies and in September 1995 for CIU (chronic idiopathic urticaria). Schering's sales accounted for about 28% in total. For many years, the Claritin is available in many countries as counter drug. In some countries the drug Claritin is available without the prescription. In the year 27 November 2002, Claritin was approved in the U.S. The FDA had to decide for the approval upon the condition that the consumers diagnose and manage on their own with help of medication. Without the help of the direct supervision of the physician it had to be safe for the consumers use. The company had to give complete explanation of the adverse effects and the directions to use the particular drug in simple understandable language on the label. In most countries loratadine is available as a non-prescription product; it is indicated for allergic rhinitis, allergic skin disorders, and hives. In some countries, including the United Kingdom, Canada, and Australia, loratadine is available OTC -over the counter (i.e., purchased without pharmacist intervention). Loratadine is currently approved and is available under prescription in the U.S. for the relief of nasal and non-nasal symptoms of seasonal allergic rhinitis and for the treatment of chronic idiopathic urticaria in patients 2 years of age and older. Schering has developed the desloratadine (Clatinex), which is an active metabolite of loratadine(Charles E. Lee 26 March 2002 ).
C:\Users\Aishwarya\Documents\structure of L.JPG
The structural formula of loratadine is shown in the figure 1(Roman and Danzig 1993).
Loratadine (SCH 2981, clarityneÂ®, LisinoÂ®), is a non-classical selective, peripheral H1 receptor antagonist antihistamine (figure1) is structurally related to azatidine. It is active oral administration and can be consumed only once daily as dosage. Loratadine is devoid of important central and autonomic nervous system effects, and extensive clinical investigation and it has confirmed Loratadine's safety and efficacy for the treatment of allergic symptoms(Roman and Danzig 1993). Structurally, it is closely related to tricyclic antidepressants, such asÂ imipramine, and is distantly related to the atypicalÂ antipsychoticÂ quetiapine (Kay and Harris 1999). Loratadine's IUPAC name is Ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[l,2-b]pyridin-11-yliden)-1-piperidinecarboxylate (Watkins PB 1985; Haria M 1994). The empirical formula of loratidine is C22H23ClN2O2 and molecular weight is 382.89(Menardo, Horak et al. 1997).
Mechanism of action:
Loratadine competes with free histamine and exhibits activity which is specific, selective peripheral H1 antagonistic activity. It can block the action of endogenous histamine. The wild-type human histamine H1 receptor in SV40 resulted in an agonist-independent elevation of the basal levels of the second messenger. More than a few histamine H1 receptor antagonists, including the therapeutically used loratadine reduced the constitutive histamine H1 receptor activity. Contrary agonism that is stabilization of an inactive conformation of the human histamine H1 receptor and hence it is a key component of the anti-allergic mechanism of action of clinically used antihistamine. H1 antihistamines are inverse agonists but not receptor antagonists (Bakker, Wieland et al. 2000).The active and inactive states of H1 receptor are in equilibrium or balanced state when histamine or antihistamine are present. Usually the histamine combines with active form of receptor to stabilize and transfer the balance towards the activated state and stimulates the cell (Figure 2)(Leurs R 2002).
Figure 2: Simplified two state compartment model of histamine H1 receptor (Leurs R 2002).
The shifting of the equilibrium in the opposite direction is done by antihistamines by stabilizing the inactive form. Hence the balance of the histamine and H1 antihistamines depends on the balance between the amounts of histamine induced stimulation of the cells or tissues. Pain, headache, tachycardia, flushing, vasodilation and vascular permeability are the histamine effects which are stimulated by H1 receptor and stimulation of vagal afferent nerves and cough receptors which will decrease artioventricular -node conduction. Even though most of the effects of histamine in allergic diseases are mediated by H1 receptor, certain effects like hypotension, tachycardia, flushing, itching and nasal congestion are mediated by both H1 and H2 receptors(Lorenz W 1994). The effects of histamine exerts through H1 receptors include cycle of sleep and waking, food intake emotion, memory, learning, thermal regulation, locomotion and aggressive behavior in the central nervous system. The H1 histamines such as diphenyldramine, hydrazine and promethazine penetrate into the brain, which occupies 50-90% of the H1 receptors in the first generation(Tagawa M 2001). The result of this is CNS sedation. In contrast, the H1 antihistamines penetrate the CNS weakly, as they are actively pumped out by P-glycoprotein which is an organic anion transporting protein that can be expressed on the surface of the luminal of vascular endothelial cells in the blood vessels that represent the blood brain barrier in the second generation(Chishty M 2001). The tendency to occupy H1 receptors in the central nervous system varies from 0% for fexofenadine to 30% for cetirizine. Hence H1 antihistamines are relatively free of sedating effects in the second generation. Through H1 receptor receptors histamine has many effects on the immune system, including the maturation of dendritic cells and balance of modulation of helper T-cells type1 (Th1) and Th2 towards Th1. Histamine induces the release of pro-inflammatory cytokines(Bakker, Wieland et al. 2000). Since the Histamine has several effects on allergic inflammation and the immune system, treatment with H1 antihistamines decrease the expression of pro-inflammatory cell adhesion molecules and the accumulation of inflammatory cells like neutrophils and eosinophils. Main clinical effects of H1 antihistamines are observed in suppression of the early response to allergen in the conjunctiva, lower airway, skin and nose.
Formulation and preparation of loratadine chewable tablets:
Loratadine is a piperidine derivative and it is a long acting selective peripheral H1 antagonist which lacks CNS depressant effects used in the treatment of allergic skin disorder like atopic dermatitis and urticaria, allergic rhinitis, acute coryza, ocular allergies at the dose of 10 mg once a day in adult and 5 mg or 10 mg in 2 - 12 years children(Kay GG 1999) .The easy way to administer drug is by the oral route which is common and easiest way. But it is difficult in the children who do not have learnt to swallow tablets. Hence it was decided to make Loratadine chewable tablet to improve the conformity in children. Chewable tablets help in rapid release and more rapid absorption of active ingredients and supply quick onset of action. The main objectives of this study were to formulate and evaluate Loratadine chewable tablet dosage form at the dose of 5 mg and to study the various formulation variables that affect the drug release.
Materials and methods:
Chemicals used are as follows Loratadine (Urolabo, Spain), Microcrystalline cellulose 70% and guar gum 30% (Avicel CE 15 - FMC Biopolymer), Lactose monohydrate (Pharmatose-200M - DMV Fonterra), Mannitol (Pearlitol-25C - Roquette), Ethyl cellulose (Ethocel std 10FP - Colorcon), Maize starch (Universal), Povidone K 30 (PVP K 30 - Signet), D&C Yellow No.6 (Colorcon), Citric acid (Kinsun), Raspberry flavour (Givaudan), Aspartame (Manus aktteva), Sodium starch glycolate (Signet), Colloidal silicon dioxide (Aerosil - Cabot) and Magnesium stearate (Ferro).
By wet granulation method chewable tablets containing 5 mg of Loratadine were prepared with a total tablet weight of 550 mg. Quantity of Loratadine and excipients are given in Table 1. Loratadine and other required excipients were sieved and mixed at a slow speed in "Rapid Mixer Granulator" to get a dry mix. To get binder Povidone K 30 and D&C Yellow were dissolved in purified water. To get starch paste Maize starch and D&C Yellow were dissolved in purified water. Dry mix was added to either binder or starch paste, granulated and the obtained wet mass were dried in "Fluidized bed dryer" at 60 degree C. By the help of #20 mesh dried granules were sieved. Excipients like lubricant and flavouring agents were then added to get a blend which was assessed for its flow properties. Blend with good flow property was compressed by using 12 mm standard flat punches with plain surface on both sides to get chewable tablets(K Kathiresan 2010).
Clinical trials of Claritin Tablets involved over 10,700 patients, 12 years of age and older, who received either Claritin Tablets or another antihistamine and placebo in double-blind randomized controlled studies. In placebo-controlled trials, 10 mg once daily of Claritin tablets was better to placebo and comparable to clemastine (1 mg BID) or terfenadine (60 mg BID) in effects on nasal and non-nasal symptoms of allergic rhinitis. In these studies, somnolence occurred less often with Claritin tablets than with clemastine and at the same frequency as terfenadine or placebo. In studies with Claritin tablets at doses two to four times higher than the recommended dose of 10 mg, a dose-related increase in the amount of somnolence was observed. Hence some patients, mainly those with hepatic or renal impairment and the elderly, or those on medications that impair clearance of loratadine and its metabolites, may experience somnolence. In addition, 188 pediatric patients with seasonal allergic rhinitis aged 6 to 12 years, three placebo-controlled, double-blind; 2-week trials were conducted at doses of Claritin Syrup up to 10 mg once daily. In a double-blind, 60 pediatric patients between 2 and 5 years of age placebo-controlled study, the safety of 5 mg loratadine, administered in 5 ml of Claritin Syrup. No unexpected adverse events were observed. Clinical trials of Claritin Reditabs (loratadine rapidly-disintegrating tablets) involved over 1300 patients who received Claritin Reditabs (loratadine rapidly-disintegrating tablets), Claritin Tablets, or placebo. In placebo-controlled trials, one Claritin Reditabs (loratadine rapidly-disintegrating tablets) once daily was higher to placebo and alike to Claritin Tablets in effects on nasal and non-nasal symptoms of seasonal allergic rhinitis. Among those patients involved in double-blind, randomized, forbidden studies of Claritin Tablets, approximately 1000 patients (age 12 and older), and were enrolled in studies of chronic idiopathic urticaria. In placebo-controlled clinical trials, Claritin Tablets 10 mg once daily were superior to placebo in the administration of chronic idiopathic urticaria, as demonstrated by decrease of associated itching, erythema, and hives. In these clinical trials, the occurrence of somnolence seen with Claritin Tablets was alike to that seen with placebo. In a study in which Claritin Tablets were administered to adults at four times the clinical dose for 90 days, no clinically significant increase in the QTc was seen on ECGs. In a single-rising dose study in which doses up to 160 mg (16 times the clinical dose) were studied, loratadine did not cause any clinically important changes on the QTc interval in the Eco cardio graph(Kenilworth 1997,1998,1999,2000).In 1989, Boner and colleagues compared the efficacy and safety of loratadine to standard therapy with a first-generation antihistamine in 40 children with allergic rhinitis(Boner AL 1989). Patients were allowed to receive either loratadine (2.5 or 5 mg once daily,equivalent to 0.11-0.24 mg/kg, once daily) or dexchlorpheniramine (0.1-0.23 mg/kg every 8 hours) for 14 days. Nasal discharge, congestion, and nasal itching, itching, burning, or watery eyes and itching of the ears or palate were observed at days 3, 7, and 14. Both drugs considerably reduced nasal and ocular symptoms compared to baseline throughout the duration of the study .While both drugs were well tolerated in general, only the children in the dexchlorpheniramine group experienced drowsiness. These investigators published another pediatric loratadine study in 1992, comparing loratadine (5 or 10 mg once daily) and astemizole (0.2 mg/kg once daily)(Boner AL 1992). Forty-one children (6-14 years of age) were participated in the 14-day blinded study. Significant growth in allergy symptoms was reported in both groups, with a response of excellent or good in 83.3% of the loratadine patients and 58.8% of the astemizole group. Lutsky and colleagues compared loratadine and terfenadine in an international study of 96 3-6 year old children with allergic rhinitis(Lutsky BN 1993). Patients were randomized to receive loratadine (5 or 10 mg once daily) or terfenadine (15 mg twice daily) for 14 days. Mean scores for nasal and non-nasal allergy symptoms were considerably reduced from baseline in both groups (p < 0.05) at days 3, 7, and 14. Non-nasal symptoms were well improved with loratadine (p < 0.05). Therapeutic response was rated as excellent or good in 82% of the loratadine patients and 60% of the terfenadine group. The first published report of desloratadine in children was a tolerability study conducted by the producer. Bloom and colleagues performed a double-blind, placebo-controlled trial in 111 children between 2 and 5 years of age and 129 children 6 to 11 years of age(Bloom M 2004). Desloratadine doses were given as 1.25 mg in the younger group and 2.5 mg in the older children. There were no major differences in the incidence of minor adverse effects between active drug and placebo in either age group. No severe or serious adverse effect was reported. Electrocardiogram (ECG) results showed no significant changes. In 2005, Rossi and coworkers described the first clinical efficacy trial of desloratadine in children(Rossi GA 2005). Total of 54 children (6-12 years of age) participated in their 4-week open-label trial. The patients consumed 2.5 mg desloratadine syrup once daily. Rhinorrhea, sneezing, nasal congestion, cough, ocular symptoms, and itching were considerably reduced during the study. In the children with underlying asthma, the use of short-acting beta2-adrengergic agonists reduced. Only the adverse effects were reported with one case each of insomnia and diarrhea. The safety of desloratadine was evaluated in children 6 months to 2 years of age by Prenner and colleagues in 2006(Prenner B 2006). Two hundred and fifty-five children were randomized to either desloratadine (1 or 1.25 mg once daily, depending on age) or placebo for 15 days. The most commonly reported poor effects were somnolence (in 5.3% of desloratadine and 7.3% of controls), diarrhea (6.1% and 2.4%, respectively), and irritability (6.9% and 5.6%, respectively). There were no major changes in ECG parameters and no severe or serious adverse effects. In 2007, Dizdar and colleagues compared regular and intermittent "as needed" desloratadine administration in 37 adolescents (ages 12-18 years) with allergic rhinitis(Dizdar EA 2007). Patients were randomized to a routine of 10 mg desloratadine each morning for 4 weeks or 10 mg daily on needed basis. There were no differences between the groups in symptom control. Inflammatory markers and nasal flow measurements were also no different. Albuterol use was lower in the regular desloratadine group during the fourth week of the study, when pollen counts were high. No unfavourable effects were reported. The authors concluded that intermittent administration was adequate for most children with allergic rhinitis, but that regular administration may suggest better control for children with airway reactivity.
Manufacturing of Loratadine and its intermediates:
Accordingly, the discovery objectives are:
The present objective aims to provide a process, which results to produce the product which is increased in yield and higher purity.
Other objective is that the process is simple to operate, do not require strict conditions and special infrastructure.
Another objective is to provide a process that eliminates through hazardous chemicals and strict operating conditions.
The main aim of the process is that it is environmental friendly, easy to scale up with industrial manufacture with good quality of the title product, economical and easily reproducible (Suri 2006).
The process contains:
Subjecting the benzyl halide that is substituted to cyanation in a biphasic system using water immiscible solvents with any method that is known.
Condensing in situ the phenyl acetonitrile hence obtained with nicotinic ester in presence of alkali metal alkoxide and water immiscible organic solvent to produce ketonitrile.
Hydrolyzing by decarboxylating the ketonitrile in situ to particular ketone in acid environment below 60 degree C.
Subjecting the ketone obtained to reduction by N-oxidation, cyanation, and hydrolysis by known method to generate picolinic acid.
Cyclising the picolinic acid to tricyclic ketone by conventional methods.
Treating the tricyclic ketone with organometallic compound containing Mg will produce carbonil.
Purifying the carbonil with purifying agent from polar water miscible organic solvent followed by dehydrating with sulphuric acid at the temperature of 50 degree C, to produce N-methyl product (olefin), and subjecting olefin to N-carbethoxylation to produce loratadine. Loratadine is prepared by treating cyano compound with organomettalic compound with Mg to give a ketone followed by cyclizing in prescence of a mixture of suphuric acid and boric acid to get N-methyl product and converting to loratadine by N-carbethoxylation. The process is explained as shown below (Suri 2006).
Figure 3:Process of loratadine production(Suri 2006)
Drugs that slow down the activity of CYP3A4, such as erythromycin, cimetidine, and ketoconazole, delay the metabolism of loratadine and desloratadine. As a result, plasma concentrations may increase drastically. Administration of ketoconazole 200 mg every 12 hours produced a 307% increase in loratadine plasma concentrations, measured as the area under the concentration-time curve over 24 hours, and a 39% increase in desloratadine concentrations. In spite of the increase in plasma concentrations, studies conducted in healthy adult volunteers have not exposed a change in vital signs, electrocardiographic measurements of the QTc interval, laboratory tests, or other adverse effects. Azithromycin and fluoxetine may also increase loratadine or desloratadine concentrations, but to a lesser degree(Marcia L. Buck 2001).
Pharmacokinetics of loratadine:
H1-receptor antagonists are well absorbed from the gastrointestinal tract after oral administration. And their reaction starts within 1-3 hours and the duration of action varies from few hours to 24 hours (second-generation drugs being generally around 24 hours)(Middleton E 2006). First and second generation antihistamines agents are oxidatively metabolized by the hepatic cytochrome P450 system, the exception being levocetirizine, cetirizine, and fexofenadine. Levocetirizine and cetirizine are largely excreted in urine and fexofenadine is excreted majority in the faeces but less in the urine(Devillier P 2008). Hepatic metabolism has many implications: prolongation of the serum half-life in patients with hepatic dysfunction and those getting associated cytochrome P450 inhibitors, such as ketoconazole and erythromycin. The older patients who have reduced liver function which results in longer duration of action. In such persons there are more chances of precipitating unwanted cardiac or CNS effects. Such adverse effects usually occur in the first generation antihistamines. Related administration of probenicid reduces the total body and renal clearance of fexofenadine(Liu S 2008). The bioavailability of fexofenadine can be changed by instantaneous consumption of grapefruit juice (reduced rate and absorption of the drug by almost 30%)(Banfield C 2002) .However, the grapefruit juice does not affect the absorption of other second-generation antihistamines. Even though topical intranasal and ophthalmic H1 antihistamines differ in their pharmacokinetics, most of the topical arrangements need to be administered twice daily because of the washout from the nasal mucosa or conjunctiva. Loratadine was rapidly absorbed following the oral administration of 10 mg tablets, once daily for 10 days to healthy adult participants with times to maximum concentration (Tmax) of 1.3 hours for loratadine and 2.5 hours for major active metabolite, descarboethoxyloratadine. Based on a cross-study contrast of single doses of loratadine syrup and tablets given to healthy adult participant the plasma concentration profile of descarboethoxyloratadine for the two formulations was almost similar. The pharmacokinetics of loratadine and descarboethoxyloratadine are independent of dose over the dose range of 10 mg to 40 mg and are not changed by the duration of treatment. In a singledose study, food increased the systemic bioavailability (AUC) of loratadine and descarboethoxyloratadine by approximately 40% and 15%, respectively. The time to peak of plasma concentration (Tmax) of loratadine and descarboethoxyloratadine was postponed by 1 hour. Food did not affect the peak plasma concentrations (Cmax). Pharmacokinetic studies results that Claritin Reditabs (loratadine rapidly-disintegrating tablets) provide plasma concentrations of loratadine and descarboethoxyloratadine comparable to those achieved with Claritin Tablets. Following administration of 10 mg loratadine once daily for 10 days with each dosage form in a randomized crossover comparison in 24 normal adult subjects, similar mean exposures (AUC) and peak plasma concentrations (Cmax) of loratadine were observed. Claritin Reditabs (loratadine rapidly-disintegrating tablets) mean AUC and Cmax were 11% and 6% greater than that of the Claritin Tablet respectively. Descarboethoxyloratadine bioequivalence was established between the two formulations. After 10 days of continuous dosing, mean peak plasma concentrations was reached at 1.3 hours and 2.3 hours (Tmax) for parent and metabolite, respectively. In a single-dose study with Claritin Reditabs (loratadine rapidly-disintegrating tablets), food increased the AUC of loratadine by approximately 48% and did not majorly affect the AUC of descarboethoxyloratadine. The times to peak plasma concentration (Tmax) of loratadine and descarboethoxyloratadine were delayed by approximately 2.4 and 3.7 hours, respectively, Claritin Reditabs (loratadine rapidly-disintegrating tablets) were consumed before the food administration. The parent and metabolite peak concentration (Cmax) was not affected by food. In a single-dose study with Claritin Reditabs (loratadine rapidly-disintegrating tablets) in 24 subjects, the AUC of loratadine was increased by 26% when administered without water compared to administration with water, while Cmax was not considerably affected. The bioavailability of descarboethoxyloratadine was not different when administered without water(Kenilworth 1997,1998,1999,2000).
Loratadine is the major class of drugs used in the treatment of allergic disorder, allergic rhinoconjunctivitis and urticaria in particular.
Allergic rhinoconjunctivitis: Patients with allergic rhinitis (AR) both first- and second-generation H1 antihistamines have showed thatextremely effective in relieving sneezes, itching, and nasal discharge but not nasal blockage. First-generation H1antihistamines have aninsufficient benefit-to-risk measure in allergic rhinoconjunctivis. The evidence base for the use in seasonal and perennial rhinitis is small. In seasonal AR, there is a huge use of second-generation oral H1 antihistamines such as cetirizine, desloratadine, fexofenadine, loratadine(Howarth PH 1999; Van Cauwenberge P 2000). In perennial AR, the second-generation H1 antihistamines are used in growing and the efficacy of cetirizine, desloratadine, fexofenadine, loratadine, and levocetirizine(W 1996; Ciprandi G 2001; Simons FER 2003) H1 antihistamines provide relief for allergic rhinitis and are generally found to be less potent than intranasal corticosteroids in the treatment of AR symptoms. Eye drops such as azelastine, ketotifen, levocabastine and olopatadine are used during the allergic conjunctivitis(A 2000).
Asthma: In asthma, there are no evidences updated which does not support the use of antihistamines for treatment. The second-generation antihistamines are used to reduce symptoms of allergic asthma and exacerbation of asthma with AR. The improvement produced by H1 antihistamines in asthma is modest(Group 2001).
Use in pregnancy and lactation: The use of the new antihistamines during pregnancy, loratadine are considered relatively safe for use during pregnancy (FDA category B)(Seto A 1997). H1 antihistamines are excreted in small amounts in breast milk .The infant which is breast-fed by the motherswho are ingested by first-generation antihistamines may experience irritability, drowsiness or respiratory depression(S 2000).
The adverse effects of first-generation H1 antihistamines, occurs mainly on the CNS causing drowsiness, impaired driving performance, fatigue, lassitude, and dizziness. Other side-effects are dry mouth, urinary retention, gastrointestinal upset and appetite stimulation. Even though the new-generation antihistamines are relatively free of serious CNS effects, a small number of individuals may experience sedation with the agents. Minor side-effects such as nausea, lightheadedness, drowsiness, headaches, agitation may occur with new antihistamines. Weight gain has been observed in some patients treated with cetirizine. Hypersensitivity reactions, including skin rashes and angio-oedema may occur. In suggested dosages, the new antihistamines are generally safe. Toxicity associated with the new anthistamines is usually related to increased drug levels (due to overdosage or impaired metabolism). Symptoms of overdosage include drowsiness and agitation (especially in children). First-generation H1 antihistamines may cause tachycardia, supraventricular arrhythmia, and prolongation of the QT interval in a dose-dependent delivary. In second- generation antihistamines, astemizole and terfenadine, were inhibited from the market because of their cardiac toxic effects. Cetirizine, levocetirizine fexofenadine, loratadine and desloratadine appear to be free from cardiac toxicity even more than recommended doses(Craig-McFeely PM 1888; Yap YG 2002). Both the loratadine and desloratadine were well tolerated in children (Boner AL 1989; Lutsky BN 1993; Salmun LM 2000; Bloom M 2004) . Loratadine's adverse effects were observed in premarketing trials which involed around 300 children between 6 and 12 years of age, with abdominal pain fatigue, hyperkinesia, malaise, nervousness and wheezing, and conjunctivitis, dysphonia, and upper respiratory tract infection .Sixty children between 2 and 5 years of age were studied in the second week double-blinded, placebo-controlled clinical trial. The most common adverse effects were diarrhea and epistaxis , pharyngitis, earache, fatigue, influenza-like symptoms, rash, stomatis, tooth disorder, and concomitant viral infection. Diarrhea may be caused with loratadine or desloratadine solutions due the presence of sorbitol in the products.
The adverse effects of desloratadine were considered by the manufacturer in three placebo-controlled clinical trials of 246 children between 6 months and 11 years of age. In the oldest children (those between 6 and 11 years of age), the adverse effect was not more it was 2% of patients. In the 2-5 year old group, the most common reactions were fever, urinary tract infection and concomitant varicella infection. In the children between 12 and 23 months of age, the most frequent adverse effects were fever diarrhea, upper respiratory tract infections, coughing, increased appetite, and emotional lability, epistaxis, parasitic infection, pharyngitis, and rash. In infants, the most common reactions were upper respiratory tract infections, diarrhea, fever, irritability, coughing, somnolence, bronchitis, otitis media, vomiting, anorexia, pharyngitis, insomnia, rhinorrhea, erythema and nausea. Not any of the patients had a major change in ECG measurements. Only one patient was in necessary for the discontinuation of treatment(Marcia L. Buck 2001).
Marketing sales and Patent:
Loratadine /Claritin is marketed by Schering-Plough. The overall retail pharmacy sales of loratadine were $2.25 billion in 2001.It ranked number 11, representing approximately 1.2% of total community pharmacy prescription drug sales. The total prescription antihistamine market was approximately $4.69 billion for that year, with loratadine accounting for nearly 50%. Two other second-generation antihistamines, fexofenadine (Allegra) and cetirizine (Zyrtec), accounted for 24.8% and 20.8%, respectively, of this market (Patricia Harrington 2002).
Expenses on loratadine drugs in the United States continue to increase faster than any other medical service sector .In the past several years, loratadinedrug spending has risen by more than 15% per annum. These rising costs have attracted significant attentionfrom consumer protection groups and the health care industry. In the year 2000, U.S. consumers were estimated to spend $19.1 billion on OTC drugs. The OTC market has expanded significantly in the last 10 years, from an estimated $10.2 billion in 1991(Figure 4) (Patricia Harrington 2002).
The Reasons behind for this increase in OTC sales include
â€¢ Growing emphasis on individual autonomy in health care,
â€¢ A trend toward prescription drug deregulation in the United States,
â€¢ Cost-containment efforts by health care organizations,
â€¢ Profit interests of the pharmaceutical industry, and
â€¢ A steady increase in the number of OTC products.
Figure 4: The Growth of U.S. OTC Retail loratadine Drug Sales over a 10-Year Period(Patricia Harrington 2002)
Some of the US Patent details listed below(Asotra 2010):
Â In 1981 Schering obtained a patent on loratadine (Claritin), which became a widespread antihistamine medication. Schering applied and got 46 months of patent extensions owing to regulatory review time and changes in patent laws, and gave nearly 21 years of patent protection, which exceeds the standard 20-year time frame. During that time the manufacturer sought numerous other ways to extend its market exclusivity even further, including patenting the compound desethoxycarbonyl-loratadine (DCL), which is formed in the body during the normal metabolism of loratadine. The patent was challenged in court and was eventually inverted because DCL was "necessarily and inevitably" formed in every patient, and generic loratadine was ultimately marketed in 2002. However, the court noted that its decision did not spread to every metabolite of a pharmaceutical product, suggesting that " the metabolite may be claimed in its pure and isolated form or as a pharmaceutical composition for example with a pharmaceutically acceptable carrier(Kesselheim 2007). In Canada, Mexico, the U. S, the U.K and many other countries loratadine is available over the counter which are second generation antihistamines. Only in presence of pharmacist the drug can be sold in the U.K.