Arunkanth Krishnakumar Nair et al.

, IJSID, 2012, 2 (3), 351-358

ISSN:2249-5347

IJSID

International Journal of Science Innovations and Discoveries

Research Article

An International peer Review Journal for Science

Available online through www.ijsidonline.info

STABILIZED COMPOSITIONS OF PRASUGRE HYDROCHLORIDE TABLETS

Arunkanth Krishnakumar Nair*, Balla Srinivas, Venugopala Jayaramreddy, Chandrasekhar Sriram Kandi and Panyala Srinath Reddy Aurobindo pharma Ltd, Hyderabad, Andhara Pradesh, India ABSTRACT Received: 16.03.2012 Accepted: 15.06.2012
*Corresponding Author

Currently available thienopyridines include clopidogrel and ticlopidine. Prasugrel is an orally bioavailable prodrug metabolized to an active adenosine diphosphate (ADP) receptor antagonist, which is a potent inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP receptor. Prasugrel hydrochloride is white to light brown crystalline solid, slightly hygroscopic and soluble to slightly soluble at pH 1-4, very slightly soluble at pH 5 and practically insoluble at pH 6-7. The pKa value of prasugrel hydrochloride 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 aqueous

Prasugrel is a member of the thienopyridine class of antiplatelet agents.

media, cleavage of the ester moiety forms the hydrolysis product, which exists as a mixture of diastereomers, and which are the precursors of theactive metabolite. The Address: Name: Arunkanth Krishnakumar Nair Place: Aurobindo Pharma Ltd, Hyderabad, India. E-mail: plnayak@reduffmail.com prasugrel to air and moisture results in degradation. Hence, there is a need to develop a hydrochloride is used because of its better hydrolytic stability and because it provides a better solubility at relevant physiological pHs. However, prolonged exposure of

INTRODUCTION

composition, which improves the stability, shelf life and therefore long term efficacy of individual doses of prasugrel. Due to prasugrel hydrochloride susceptibility to hydrolytic and oxidative degradation a dry manufacturing process was selected. Extensive present study details about the stabilized pharmaceutical dosage forms of Prasugrel stability in comparison to the normal hypromellose based coating system. Keywords: Prasugrel, Opadry AMB, Stabilized compositions. tablets prepared using Opadry AMB (PVA based coating system from M/s Colorcon) as experiments have been conducted to ensure a robust manufacturing process.The INTRODUCTION the film coating system.The formulations with moisture barrier coating shows better

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Arunkanth Krishnakumar Nair et al., IJSID, 2012, 2 (3), 351-358 INTRODUCTION activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets. It produces more potent platelet inhibition, a rapid onset of action and may provide a superior therapeutic alternative 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 percutaneous coronary 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 is a thienopyridine derivative, and an ADP receptor antagonist. Prasugrel is an inhibitor of platelet

myocardial infarction (MI), or nonfatal stroke compared to clopidogrel. The difference between treatments was driven

Prasugrel hydrochloride has been shown to reduce the rate of a combined endpoint of cardiovascular death, nonfatal

predominantly by MI, with no difference on strokes and little difference on CV death.It is generally recommended that antiplatelet therapy be administered promptly in the management of ACS because many cardiovascular events occur within administered to UA/NSTEMI patients until coronary anatomy was established. For the small fraction of patients that required urgent CABG after treatment with Effient, the risk of significant bleeding was substantial. Because the large majority of of bleeding in patients who do need to undergo urgent CABG. The chemical name of prasugrel hydrochloride molecular mass of 409.90 hours of initial presentation. In the clinical trial that established the efficacy of Effient, Effient and the control drug were not patients are managed without CABG, however, treatment can be considered before determining coronary anatomy if need for CABG is considered unlikely. The advantages of earlier treatment with Effient must then be balanced against the increased rate tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride corresponding to the molecular formula C20H20FNO3SHCl and is 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]4,5,6,7-

Mechanism of Action

Fig. 1: Chemical structure of Prasugrel hydrochloride

to the P2Y12 class of ADP receptors on platelets. Pharmacodynamics

Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite Prasugrel produces inhibition of platelet aggregation to 20 M or 5 M ADP, as measured by light transmission

aggregometry. Following a 60-mg loading dose of Effient, approximately 90% of patients had at least 50% inhibition of platelet

aggregation by 1 hour. Maximum platelet inhibition was about 80% (Figure 2). Mean steady-state inhibition of platelet aggregation gradually returns to baseline values over 5-9 days after discontinuation of prasugrel, this time course being a International Journal of Science Innovations and Discoveries, Volume 2, Issue 3, May-June 2012

aggregation was about 70% following 3 to 5 days of dosing at 10 mg daily after a 60-mg loading dose of Effient. Platelet

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Arunkanth Krishnakumar Nair et al., IJSID, 2012, 2 (3), 351-358 reflection of new platelet production rather than pharmacokinetics of prasugrel. Discontinuing clopidogrel 75 mg and typically produced by a 10 mg maintenance dose of prasugrel alone. The relationship between inhibition of platelet aggregation and clinical activity has not been established. Pharmacokinetics Prasugrel is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites.

initiating prasugrel 10 mg with the next dose resulted in increased inhibition of platelet aggregation, but not greater than that

The active metabolite has an elimination half-life of about 7 hours (range 2-15 hours). Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics. Absorption and Binding Following oral administration, 79% of the dose is absorbed. The absorption and metabolism are rapid, with peak

plasma concentrations (Cmax) of the active metabolite occurring approximately 30 minutes after dosing. The active metabolites exposure (AUC) increases slightly more than proportionally over the dose range of 5 to 60 mg. Repeated daily doses of 10 mg do not lead to accumulation of the active metabolite. In a study of healthy subjects given a single 15 mg dose, to human serum albumin. the AUC of the active metabolite was unaffected by a high fat, high calorie meal, but C max was decreased by 49% and Tmax was increased from 0.5 to 1.5 hours. Effient can be administered without regard to food. The active metabolite is bound about 98% Metabolism and Elimination thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to a

estimates of apparent clearance ranged from 112 to 166 L/hr in healthy subjects and patients with stable atherosclerosis. The International Journal of Science Innovations and Discoveries, Volume 2, Issue 3, May-June 2012

The estimates of apparent volume of distribution of prasugrels active metabolite ranged from 44 to 68 L and the

Fig 2-Metabolic pathway of Prasugrel

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Arunkanth Krishnakumar Nair et al., IJSID, 2012, 2 (3), 351-358 active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to human plasma proteins. Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolites. SCOPE

efficacy and stability profiles compared to other salts and also compared to free base molecule. However, prolonged exposure

The hydrochloride and maleate salt forms of prasugrel provide unexpected and unobvious improvements in their

of prasugrel to air and moisture results in degradation. Hence, there is a need to develop a composition, which improves the stability, shelf life and therefore long term efficacy of individual doses of prasugrel. International publication number WO monoxide atmosphere, to improve the stability and shelf life of prasugrel. pressure, to enhance the stability and shelf life of prasugrel. 2006/135605 describes a formulation comprising a therapeutically effective amount of prasugrel hydrochloride packaged in an air and moisture impervious blister package, with an inert gas like nitrogen, argon, neon, carbondioxide and carbon capsule, caplet or other solid form of prasugrel in an air and/or moisture impervious container under a positive liquid gas International publication number WO 2008/073759 describes a formulation comprising packaging prasugrel tablet, According to the invention, the pharmaceutical composition is in the form of a tablet, in which opadry AMB is being

used as a film coating material, provides a protective barrier layer against absorption of moisture. Further, the tablets are

packed in alu-alu cold packing which has no air gap in the pocket of aluminium blister preventing any moisture being present in the atmosphere around the tablet. There are inventions as disclosed in many of the literatures where in the Prasugrel of inert gases/liquid pressure in packing which is difficult to handle as used in the art to increase the stability. MATERIALS AND METHODS formulations were stabilised by using inert gases/liquid pressure in packing. The present invention there by avoided the usage The pharmaceutical composition of the present invention contains binders, diluents, disintegrants, lubricants and

coating materials. The "diluents" that may be used include but are not limited to, cellulose derivatives such as microcrystalline cellulose, phosphates such as dibasic calcium phosphate anhydrous, tricalcium phosphate anhydrous, mannitol and silicified microcrystalline cellulose also to enhance the tabletting proporties. microcrystalline cellulose. According to the invention, the diluent preferably used is mannitol and additionally for moisture sensitive drugs as it is non-hygroscopic. Unlike powdered mannitol, a DC-grade mannitol would provide good compaction characteristics and flowability.The PEARLITOL range offers a unique blend of exceptional physical and chemical key 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, crosslinked The mannitol range of diluent is selected from the commercially available brand Pearlitol. It is an excipient of choice

stability, with great organoleptic, non-cariogenic, sugar-free properties. Together with its versatile powder properties, it is the polyvinylpyrrolidone ,croscarmellose sodium and low substituted hydroxy propyl cellulose.. According to the invention, the 10%, more preferably from 5-10% of the disintegrant.The crosscarmallose sodium is being considered as the major particles leading to better dissolution.Crosscarmallose sodium is an effective disintegrant due to its swelling action in water. International Journal of Science Innovations and Discoveries, Volume 2, Issue 3, May-June 2012

disintegrant preferably used is Crosscarmallose sodium . The pharmaceutical preparation advantageously comprises from 1disintegrant because of the following reasons,excellent compatibility with active ingredients and disintegration into smaller

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Arunkanth Krishnakumar Nair et al., IJSID, 2012, 2 (3), 351-358 Crosscarmallose sodium is not soluble in water. However,it absorbs water and significantly expands in volume. This swelling action causes tablets to quickly disintegrate. polymers. In tablet and capsule formulations, hypromellose is primarily used as a wet or dry binder.Hypromellose is a solid, when dissolved in water. The "lubricants" that may be used include but are not limited to, stearic acid, stearic acid metal salts such as Hypromellose (hydroxypropyl methycellulose, or HPMC), an excipient that is made up of water-souble, linear

and is a slightly off-white to beige powder in appearance and may be formed into granules. The compound forms colloids magnesium 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 lubricant pharmaceutical 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/s preferably used is Magnesium stearate . Lubricants generally decreases the ejection force and improves compressibility..The Colorcon , Opadry AMB which contains partially hydrolyzed polyvinyl alcohol,talc,lecithin and xanthan gum. Opadry AMB is a film coating system specifically developed by Colorcon for the coating of oral solid-dosage forms that need to be protected require extreme moisture protection. from environmental moisture. Studies on moisture penetration and transmission rates have demonstrated that Opadry AMB provides unrivaled protection, making it the product of choice for immediate release tablets and multi-particulates that finish, the Opadry II product range consists of fully formulated dry blend systems for the aqueous film coating of which allows for immediate disintegration for fast, active release.Generally Opadry II film coating system contains Lactose, Hypromellose,Titanium dioxide and triacetin. PROCEDURE Another coating material available from M/s Colorcon are Opadry II.Offering short process times and a superior film

pharmaceutical and nutritional oral solid dosage forms. Opadry II is a water soluble, pH independent film coating system

dosage form which is more advantageous. The dry method of the present invention involves the direct compression method. compression-molding to produce a final dosage preparation. The evaluated composition contains the following excipients S:No 1 2 3 4 5 6 7 8 9 Ingredients Table 1-Excipient percentage range in both the formulations Percentage content (Formulation A) 5% 64%-76.5% 3-5% 5-10% 10-15% 0.5-1% Core Prasugrel hydrochloride Mannitol Hypromellose Crosscarmallose sodium Microcrystalline cellulose Magnesium stearate Film Coating Opadry AMB** Opadry II* Purified water# Percentage content (Formulation B) 5% 64%-76.5% 3-5% 5-10% 10-15% 0.5-1%

As the prasugrel and its salts are moisture sensitive, the present study utilizes the dry method for formulation of

The "direct compression method" is a method wherein the raw material powders are directly subjected to mixing and then

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2-3% -Quantity sufficient

-2-3% Quantity sufficient

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Arunkanth Krishnakumar Nair et al., IJSID, 2012, 2 (3), 351-358 ** contains partially hydrolyzed polyvinyl alcohol, talc, lecithin and xanthan gum; * contains Lactose, Hypromellose, Titanium dioxide and triacetin; # Evaporates during processing; Optimized composition was used for final evaluation Manufacturing 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. The

cores were aqueous coated in a coating pan using Opadry AMB for Formulation A and Opadry II for Formulation B in purified after storage at 40C and 75% relative humidity conditions for one week (Open exposure studies). Formulation A Table 2-Comparative open exposure study data One week at 40C/75% RH Initial

water till the desired weight build up was achieved. The tablets were analyzed for drug content and impurities before and Formulation B

Condition Parameters Description

Initial

One week at 40C/75% RH

Drug content Total impurities

White to Off white tablets 99.4 0.63%

White to Off white tablets 98.9 0.74%

White to Off white tablets 99.6 0.65%

White to Off white tablets 98.2% 1.34%

Figure -2: Graphical representation of degradation trend for both the formulations RESULTS AND DISCUSSION oxidative pathways. There are crossovers between these degradation pathways wherein intermediates or products of certain International Journal of Science Innovations and Discoveries, Volume 2, Issue 3, May-June 2012 Different literatures revealed that stored tablets containing prasugrel hydrochloride degrade by both hydrolytic and

steps in one pathway may interconvert or be kinetically accelerated or hindered by the concentration of product (or

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Arunkanth Krishnakumar Nair et al., IJSID, 2012, 2 (3), 351-358 intermediate), air or moisture from the environment or the other pathway.The above exposure study of two different formulations reveal the degradation tendency of the drug product in accelerated exposed conditions. Both the experimented moisture barrier poly vinyl alcohol based(Opadry AMB) film coating system. formulations have similar core composition and only varies in the final coating material. The formulation B which is having a normal hypromellose based aqueous film coating system shows more degradation trend in comparison to the product with Polyvinyl alcohol has excellent film forming and adhesive properties. It is also resistant to oil, grease and solvents. It is

odorless 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. The partially hydrolysed poly vinyl alcohol in Opadry AMB imparts the coating system better moisture barrier proporties and thus protecting the final dosage form. CONCLUSION

A ,shows better stability at accelerated storage conditions.As disclosed above the drug substance prasugrel hydrochloride

Based on the above revealed details it can be concluded that the product having moisture barrier coating, Formulation

undergoes immediate degradation on exposure to air and moisture.The major degradation pathway for the product is by Opadry AMB,a PVA based film coating can be used as the coating material for making stabilized pharmaceutical dosage forms of prasugrel hydrochloride tablets and thus improves the stability, shelf life and therefore long term efficacy of the product. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 1.Wiviott SD, Braunwald E, McCabe CH, et al. (2007). "Prasugrel versus clopidogrel in patients with acute coronary syndromes".N Engl J Med 357 (20): 200115 Baker WL, White CM. Role of Prasugrel, a Novel P2Y12 Receptor Antagonist, in the Management of Acute Coronary Syndromes. American Journal of Cardiovascular Drugs Aug 1,2009; 9 (4): 213229 Duggan ST, Keating GM. Prasugrel: A Review of its Use in Patients with Acute Coronary Syndromes UndergoingPercutaneous Coronary Intervention. Drugs Aug 20, 2009; 69(12): 170726 207881 Bhatt DL (2007). "Intensifying Platelet Inhibition Navigating between Scylla and Charybdis". N Engl J Med 357 (20): A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet Prasugrel in Clinical Practice ;September 3, 2009;Bhatt D.L.;N Engl J Med 2009; 361:940-942 to active metabolite formation; American Heart Journal ,Volume 153, Issue 1 , Pages 66.e9-66.e16, January 2007 inhibition is related

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the raw material powders are directly subjected to mixing and then compressed to produce the final dosage form. Thus

Review of prasugrel for the secondary prevention of atherothrombosis. J Manag Care Pharm. 2009 Jun;15(5):383-95. ASAP DOI: 10.1021/tx3000279,Publication Date (Web): April 6, 2012 state stress conditions ;

Metabolic Activation of Prasugrel: Nature of the Two Competitive Pathways Resulting in the Opening of Its Thiophene Characterization of degradation products of amorphous and polymorphic forms of clopidogrel bisulphate

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Arunkanth Krishnakumar Nair et al., IJSID, 2012, 2 (3), 351-358 11. Mousa SA, Jeske WP, Fareed J. Prasugrel: a novel platelet ADP P2Y(12) receptor antagonist. Methods Mol Biol. 2010; 663: 12. Serebruany V, Makarov L. Prasugrel for arterial coronary thrombosis. Drugs Today. 2009; 45: 8391. 13. http://www.rxlist.com/effient-drug.htm http://www.ncbi.nlm.nih.gov/pubmed/19343228 14. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022307s002lbl.pdf 16. Summary basis of approval for Effient tablets 17. http://www.ema.europa.eu/docs/en_GB/document_library/EPARPublic_assessment_report/human/000984/WC500021975.pdf 221228. http://dx.doi.org/10.1007/978-1-60761-803-4_8

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