Stabilized compositions of prasugre hydrochloride tablets

Arunkanth Krishnakumar Nair et al., IJSID, 2012, 2 (3), 351-358

International Journal of Science Innovations and Discoveries, Volume 2, Issue 3, May-June 2012

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STABILIZED COMPOSITIONS OF PRASUGRE HYDROCHLORIDE TABLETS

Arunkanth Krishnakumar Nair*, Balla Srinivas, Venugopala Jayaramreddy, Chandrasekhar Sriram Kandi and Panyala

Srinath ReddyAurobindo pharma Ltd, Hyderabad, Andhara Pradesh, India

INTRODUCTION

INTRODUCTION

ISSN:2249-5347IJSID

International Journal of Science Innovations and Discoveries An International peerReview Journal for Science

Research Article Available online through www.ijsidonline.info

Received: 16.03.2012

Accepted: 15.06.2012

*Corresponding Author

Address:

Name:Arunkanth Krishnakumar NairPlace:Aurobindo Pharma Ltd,Hyderabad, India.E-mail:[email protected]

ABSTRACTPrasugrel is a member of the thienopyridine class of antiplatelet agents.Currently available thienopyridines include clopidogrel and ticlopidine. Prasugrel is anorally bioavailable prodrug metabolized to an active adenosine diphosphate (ADP)receptor antagonist, which is a potent inhibitor of platelet activation and aggregationmediated by the P2Y12 ADP receptor. Prasugrel hydrochloride is white to light browncrystalline solid, slightly hygroscopic and soluble to slightly soluble at pH 1-4, veryslightly soluble at pH 5 and practically insoluble at pH 6-7. The pKa value of prasugrelhydrochloride was 5.1. It shows polymorphism. It is obtained as a racemic mixture;therefore, it shows no optical rotation.Prasugrel hydrochloride is a prodrug. In aqueousmedia, cleavage of the ester moiety forms the hydrolysis product, which exists as amixture of diastereomers, and which are the precursors of theactive metabolite. Thehydrochloride is used because of its better hydrolytic stability and because it provides abetter solubility at relevant physiological pHs. However, prolonged exposure ofprasugrel to air and moisture results in degradation. Hence, there is a need to develop acomposition, which improves the stability, shelf life and therefore long term efficacy ofindividual doses of prasugrel. Due to prasugrel hydrochloride susceptibility to hydrolyticand oxidative degradation a dry manufacturing process was selected. Extensiveexperiments have been conducted to ensure a robust manufacturing process.Thepresent study details about the stabilized pharmaceutical dosage forms of Prasugreltablets prepared using Opadry AMB (PVA based coating system from M/s Colorcon) asthe film coating system.The formulations with moisture barrier coating shows betterstability in comparison to the normal hypromellose based coating system.Keywords: Prasugrel, Opadry AMB, Stabilized compositions.



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INTRODUCTIONPrasugrel is a thienopyridine derivative, and an ADP receptor antagonist. Prasugrel is an inhibitor of plateletactivation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors onplatelets. It produces more potent platelet inhibition, a rapid onset of action and may provide a superior therapeuticalternative to clopidogrel. Prasugrel hydrochloride is indicated to reduce the rate of thrombotic cardiovascular (CV) events(including stent thrombosis) in patients with acute coronary syndrome (ACS) who are to be managed with percutaneouscoronary intervention (PCI) as follows: Patients with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI). Patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI.Prasugrel hydrochloride has been shown to reduce the rate of a combined endpoint of cardiovascular death, nonfatalmyocardial infarction (MI), or nonfatal stroke compared to clopidogrel. The difference between treatments was drivenpredominantly by MI, with no difference on strokes and little difference on CV death.It is generally recommended thatantiplatelet therapy be administered promptly in the management of ACS because many cardiovascular events occur withinhours of initial presentation. In the clinical trial that established the efficacy of Effient, Effient and the control drug were notadministered to UA/NSTEMI patients until coronary anatomy was established. For the small fraction of patients that requiredurgent CABG after treatment with Effient, the risk of significant bleeding was substantial. Because the large majority ofpatients are managed without CABG, however, treatment can be considered before determining coronary anatomy if need forCABG is considered unlikely. The advantages of earlier treatment with Effient must then be balanced against the increased rateof bleeding in patients who do need to undergo urgent CABG.The chemical name of prasugrel hydrochloride is 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride corresponding to the molecular formula C20H20FNO3S•HCl andmolecular mass of 409.90

Fig. 1: Chemical structure of Prasugrel hydrochlorideMechanism of ActionPrasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metaboliteto the P2Y12 class of ADP receptors on platelets.PharmacodynamicsPrasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmissionaggregometry. Following a 60-mg loading dose of Effient, approximately 90% of patients had at least 50% inhibition of plateletaggregation by 1 hour. Maximum platelet inhibition was about 80% (Figure 2). Mean steady-state inhibition of plateletaggregation was about 70% following 3 to 5 days of dosing at 10 mg daily after a 60-mg loading dose of Effient. Plateletaggregation gradually returns to baseline values over 5-9 days after discontinuation of prasugrel, this time course being a



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reflection of new platelet production rather than pharmacokinetics of prasugrel. Discontinuing clopidogrel 75 mg andinitiating prasugrel 10 mg with the next dose resulted in increased inhibition of platelet aggregation, but not greater than thattypically produced by a 10 mg maintenance dose of prasugrel alone. The relationship between inhibition of plateletaggregation and clinical activity has not been established.PharmacokineticsPrasugrel is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites.The active metabolite has an elimination half-life of about 7 hours (range 2-15 hours). Healthy subjects, patients with stableatherosclerosis, and patients undergoing PCI show similar pharmacokinetics.Absorption and BindingFollowing oral administration, ≥ 79% of the dose is absorbed. The absorption and metabolism are rapid, with peakplasma concentrations (Cmax) of the active metabolite occurring approximately 30 minutes after dosing. The activemetabolite’s exposure (AUC) increases slightly more than proportionally over the dose range of 5 to 60 mg. Repeated dailydoses of 10 mg do not lead to accumulation of the active metabolite. In a study of healthy subjects given a single 15 mg dose,the AUC of the active metabolite was unaffected by a high fat, high calorie meal, but Cmax was decreased by 49% and Tmax wasincreased from 0.5 to 1.5 hours. Effient can be administered without regard to food. The active metabolite is bound about 98%to human serum albumin.Metabolism and EliminationPrasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to athiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesserextent by CYP2C9 and CYP2C19.

Fig 2-Metabolic pathway of PrasugrelThe estimates of apparent volume of distribution of prasugrel’s active metabolite ranged from 44 to 68 L and theestimates of apparent clearance ranged from 112 to 166 L/hr in healthy subjects and patients with stable atherosclerosis. The



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active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactivemetabolites are highly bound to human plasma proteins. Approximately 68% of the prasugrel dose is excreted in the urine and27% in the feces as inactive metabolites.SCOPE The hydrochloride and maleate salt forms of prasugrel provide unexpected and unobvious improvements in theirefficacy and stability profiles compared to other salts and also compared to free base molecule. However, prolonged exposureof prasugrel to air and moisture results in degradation. Hence, there is a need to develop a composition, which improves thestability, shelf life and therefore long term efficacy of individual doses of prasugrel. International publication number WO2006/135605 describes a formulation comprising a therapeutically effective amount of prasugrel hydrochloride packaged inan air and moisture impervious blister package, with an inert gas like nitrogen, argon, neon, carbondioxide and carbonmonoxide atmosphere, to improve the stability and shelf life of prasugrel.International publication number WO 2008/073759 describes a formulation comprising packaging prasugrel tablet,capsule, caplet or other solid form of prasugrel in an air and/or moisture impervious container under a positive liquid gaspressure, to enhance the stability and shelf life of prasugrel.According to the invention, the pharmaceutical composition is in the form of a tablet, in which opadry AMB is beingused as a film coating material, provides a protective barrier layer against absorption of moisture. Further, the tablets arepacked in alu-alu cold packing which has no air gap in the pocket of aluminium blister preventing any moisture being presentin the atmosphere around the tablet. There are inventions as disclosed in many of the literatures where in the Prasugrelformulations were stabilised by using inert gases/liquid pressure in packing. The present invention there by avoided the usageof inert gases/liquid pressure in packing which is difficult to handle as used in the art to increase the stability.

MATERIALS AND METHODSThe pharmaceutical composition of the present invention contains binders, diluents, disintegrants, lubricants andcoating materials. The "diluents" that may be used include but are not limited to, cellulose derivatives such as microcrystallinecellulose, phosphates such as dibasic calcium phosphate anhydrous, tricalcium phosphate anhydrous, mannitol and silicifiedmicrocrystalline cellulose. According to the invention, the diluent preferably used is mannitol and additionallymicrocrystalline cellulose also to enhance the tabletting proporties.The mannitol range of diluent is selected from the commercially available brand Pearlitol. It is an excipient of choicefor moisture sensitive drugs as it is non-hygroscopic. Unlike powdered mannitol, a DC-grade mannitol would provide goodcompaction characteristics and flowability.The PEARLITOL® range offers a unique blend of exceptional physical and chemicalstability, with great organoleptic, non-cariogenic, sugar-free properties. Together with its versatile powder properties, it is thekey to a wide range of oral applications, and for use in different processes (wet or dry granulation, direct compression).The "disintegrants" that may be used are, selected from the group consisting of starch, starch glycolates, crosslinkedpolyvinylpyrrolidone ,croscarmellose sodium and low substituted hydroxy propyl cellulose.. According to the invention, thedisintegrant preferably used is Crosscarmallose sodium . The pharmaceutical preparation advantageously comprises from 1-10%, more preferably from 5-10% of the disintegrant.The crosscarmallose sodium is being considered as the majordisintegrant because of the following reasons,excellent compatibility with active ingredients and disintegration into smallerparticles leading to better dissolution.Crosscarmallose sodium is an effective disintegrant due to its swelling action in water.



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Crosscarmallose sodium is not soluble in water. However,it absorbs water and significantly expands in volume. This swellingaction causes tablets to quickly disintegrate.Hypromellose (hydroxypropyl methycellulose, or HPMC), an excipient that is made up of water-souble, linearpolymers. In tablet and capsule formulations, hypromellose is primarily used as a wet or dry binder.Hypromellose is a solid,and is a slightly off-white to beige powder in appearance and may be formed into granules. The compound forms colloidswhen dissolved in water.The "lubricants" that may be used include but are not limited to, stearic acid, stearic acid metal salts such asmagnesium stearate or calcium stearate; talc; colloidal silica; waxes such as bee's wax or spermaceti; boric acid; adipic acid;sulfates such as sodium sulfate glycol; tumeric acid; sodium steryl fumerate. According to the invention, the lubricantpreferably used is Magnesium stearate . Lubricants generally decreases the ejection force and improves compressibility..Thepharmaceutical preparation advantageously comprises from 0.05 to 1%, more preferably from 0.5 to 1% of the lubricant.As the "coating agents" used, is the commercially available grade of moisture protecting coating material from M/sColorcon® , Opadry AMB which contains partially hydrolyzed polyvinyl alcohol,talc,lecithin and xanthan gum. Opadry AMB is afilm coating system specifically developed by Colorcon® for the coating of oral solid-dosage forms that need to be protectedfrom environmental moisture. Studies on moisture penetration and transmission rates have demonstrated that Opadry AMBprovides unrivaled protection, making it the product of choice for immediate release tablets and multi-particulates thatrequire extreme moisture protection.Another coating material available from M/s Colorcon® are Opadry II.Offering short process times and a superior filmfinish, the Opadry II product range consists of fully formulated dry blend systems for the aqueous film coating ofpharmaceutical and nutritional oral solid dosage forms. Opadry II is a water soluble, pH independent film coating systemwhich allows for immediate disintegration for fast, active release.Generally Opadry II film coating system contains Lactose,Hypromellose,Titanium dioxide and triacetin.PROCEDUREAs the prasugrel and its salts are moisture sensitive, the present study utilizes the dry method for formulation ofdosage form which is more advantageous. The dry method of the present invention involves the direct compression method.The "direct compression method" is a method wherein the raw material powders are directly subjected to mixing and thencompression-molding to produce a final dosage preparation. The evaluated composition contains the following excipients

Table 1-Excipient percentage range in both the formulationsS:No Ingredients Percentage content♠

(Formulation A)Percentage content♠

(Formulation B)Core1 Prasugrel hydrochloride 5% 5%2 Mannitol 64%-76.5% 64%-76.5%3 Hypromellose 3-5% 3-5%4 Crosscarmallose sodium 5-10% 5-10%5 Microcrystalline cellulose 10-15% 10-15%6 Magnesium stearate 0.5-1% 0.5-1%

Film Coating7 Opadry AMB** 2-3% --8 Opadry II* -- 2-3%9 Purified water# Quantity sufficient Quantity sufficient



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** contains partially hydrolyzed polyvinyl alcohol, talc, lecithin and xanthan gum; * contains Lactose, Hypromellose, Titaniumdioxide and triacetin; # Evaporates during processing; ♠ Optimized composition was used for final evaluationManufacturing process

Prasugrel hydrochloride and all excipients were sifted through #40 mesh sieve and mixed thoroughly. Prasugrel hydrochloride was mixed with 1 :1 proportion of mannitol Step 2 blend was cosifted with microcrystalline cellulose, and Crosscarmallose sodium Step 3 blend along with hypromellose was mixed in a blender for fixed time The step 4 blend was then lubricated with Magnesium stearate in a suitable blender.The final lubricated blend was then subjected to compression on suitable compression machine to make tablets. Thecores were aqueous coated in a coating pan using Opadry AMB for Formulation A and Opadry II for Formulation B in purifiedwater till the desired weight build up was achieved. The tablets were analyzed for drug content and impurities before andafter storage at 40°C and 75% relative humidity conditions for one week (Open exposure studies).

Table 2-Comparative open exposure study dataFormulation A Formulation BConditionParameters

Initial One week at40°C/75% RH

Initial One week at 40°C/75%RH

Description White to Off whitetablets White to Off whitetablets White to Off whitetablets White to Off white tabletsDrug content 99.4 98.9 99.6 98.2%Total impurities 0.63% 0.74% 0.65% 1.34%

Figure -2: Graphical representation of degradation trend for both the formulationsRESULTS AND DISCUSSIONDifferent literatures revealed that stored tablets containing prasugrel hydrochloride degrade by both hydrolytic andoxidative pathways. There are crossovers between these degradation pathways wherein intermediates or products of certainsteps in one pathway may interconvert or be kinetically accelerated or hindered by the concentration of product (or



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intermediate), air or moisture from the environment or the other pathway.The above exposure study of two differentformulations reveal the degradation tendency of the drug product in accelerated exposed conditions. Both the experimentedformulations have similar core composition and only varies in the final coating material. The formulation B which is having anormal hypromellose based aqueous film coating system shows more degradation trend in comparison to the product withmoisture barrier poly vinyl alcohol based(Opadry AMB) film coating system.Polyvinyl alcohol has excellent film forming and adhesive properties. It is also resistant to oil, grease and solvents. It isodorless and nontoxic. It has high tensile strength and flexibility, as well as high oxygen and moisture barrier properties.However these properties are dependent on humidity, in other words, with higher humidity more water is absorbed. Thepartially hydrolysed poly vinyl alcohol in Opadry AMB imparts the coating system better moisture barrier proporties and thusprotecting the final dosage form.CONCLUSIONBased on the above revealed details it can be concluded that the product having moisture barrier coating, FormulationA ,shows better stability at accelerated storage conditions.As disclosed above the drug substance prasugrel hydrochlorideundergoes immediate degradation on exposure to air and moisture.The major degradation pathway for the product is byhydrolysis. Hence the manufacturing process followed in this study is also by "direct compression method" , a method whereinthe raw material powders are directly subjected to mixing and then compressed to produce the final dosage form. ThusOpadry AMB,a PVA based film coating can be used as the coating material for making stabilized pharmaceutical dosage formsof prasugrel hydrochloride tablets and thus improves the stability, shelf life and therefore long term efficacy of the product.REFERENCES1. 1.Wiviott SD, Braunwald E, McCabe CH, et al. (2007). "Prasugrel versus clopidogrel in patients with acute coronarysyndromes".N Engl J Med 357 (20): 2001–152. Baker WL, White CM. Role of Prasugrel, a Novel P2Y12 Receptor Antagonist, in the Management of Acute CoronarySyndromes. American Journal of Cardiovascular Drugs Aug 1,2009; 9 (4): 213‐2293. Duggan ST, Keating GM. Prasugrel: A Review of its Use in Patients with Acute Coronary SyndromesUndergoingPercutaneous Coronary Intervention. Drugs Aug 20, 2009; 69(12): 1707‐264. Bhatt DL (2007). "Intensifying Platelet Inhibition — Navigating between Scylla and Charybdis". N Engl J Med 357 (20):2078–815. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is relatedto active metabolite formation; American Heart Journal ,Volume 153, Issue 1 , Pages 66.e9-66.e16, January 20076. Prasugrel in Clinical Practice ;September 3, 2009;Bhatt D.L.;N Engl J Med 2009; 361:940-9427. Review of prasugrel for the secondary prevention of atherothrombosis. J Manag Care Pharm. 2009 Jun;15(5):383-95.8. Metabolic Activation of Prasugrel: Nature of the Two Competitive Pathways Resulting in the Opening of Its ThiopheneRing: Patrick M. Dansette*, Julien Rosi, Justine Debernardi, Gildas Bertho, and Daniel Mansuy; Chem. Res. Toxicol., ArticleASAP DOI: 10.1021/tx3000279,Publication Date (Web): April 6, 20129. Characterization of degradation products of amorphous and polymorphic forms of clopidogrel bisulphate under solidstate stress conditions ;10. J Pharm Biomed Anal. 2010; 52: 332–344. http://dx.doi.org/10.1016/j.jpba.2009.05.001



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11. Mousa SA, Jeske WP, Fareed J. Prasugrel: a novel platelet ADP P2Y(12) receptor antagonist. Methods Mol Biol. 2010; 663:221–228. http://dx.doi.org/10.1007/978-1-60761-803-4_812. Serebruany V, Makarov L. Prasugrel for arterial coronary thrombosis. Drugs Today. 2009; 45: 83–91.http://www.ncbi.nlm.nih.gov/pubmed/1934322813. http://www.rxlist.com/effient-drug.htm14. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022307s002lbl.pdf15. http://www.medicines.org.uk/emc/document.aspx?documentid=21504&docType=SPC16. Summary basis of approval for Effient tablets17. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR-Public_assessment_report/human/000984/WC500021975.pdf

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