Stabilized compositions of prasugre hydrochloride tablets

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

ISSN:2249-5347
IJSID
International Journal of Science Innovations and Discoveries An International peer
Review Journal for Science

Research Article Available online through www.ijsidonline.info
STABILIZED COMPOSITIONS OF PRASUGRE HYDROCHLORIDE TABLETS
Arunkanth Krishnakumar Nair*, Balla Srinivas, Venugopala Jayaramreddy, Chandrasekhar Sriram Kandi and Panyala

Aurobindo pharma Ltd, Hyderabad, Andhara Pradesh, India
Srinath Reddy

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

Currently available thienopyridines include clopidogrel and ticlopidine. Prasugrel is an
Received: 16.03.2012

orally bioavailable prodrug metabolized to an active adenosine diphosphate (ADP)
receptor antagonist, which is a potent inhibitor of platelet activation and aggregation
Accepted: 15.06.2012

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
*Corresponding Author

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
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
hydrochloride is used because of its better hydrolytic stability and because it provides a
better solubility at relevant physiological pHs. However, prolonged exposure of
prasugrel to air and moisture results in degradation. Hence, there is a need to develop a
Address: INTRODUCTION

composition, which improves the stability, shelf life and therefore long term efficacy of
Name:

individual doses of prasugrel. Due to prasugrel hydrochloride susceptibility to hydrolytic
Arunkanth Krishnakumar Nair
Place:

and oxidative degradation a dry manufacturing process was selected. Extensive
Aurobindo Pharma Ltd,

experiments have been conducted to ensure a robust manufacturing process.The
Hyderabad, India.
E-mail:

present study details about the stabilized pharmaceutical dosage forms of Prasugrel
arunkanthkr@yahoo.com INTRODUCTION

tablets prepared using Opadry AMB (PVA based coating system from M/s Colorcon) as
the film coating system.The formulations with moisture barrier coating shows better
stability in comparison to the normal hypromellose based coating system.
Keywords: Prasugrel, Opadry AMB, Stabilized compositions.

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

351


Prasugrel is a thienopyridine derivative, and an ADP receptor antagonist. Prasugrel is an inhibitor of platelet
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 hydrochloride has been shown to reduce the rate of a combined endpoint of cardiovascular death, nonfatal


myocardial infarction (MI), or nonfatal stroke compared to clopidogrel. The difference between treatments was driven
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
hours of initial presentation. In the clinical trial that established the efficacy of Effient, Effient and the control drug were not
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
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
of 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 and
molecular mass of 409.90

Fig. 1: Chemical structure of Prasugrel hydrochloride

Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite
Mechanism of Action

to the P2Y12 class of ADP receptors on platelets.

Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission
Pharmacodynamics

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 was about 70% following 3 to 5 days of dosing at 10 mg daily after a 60-mg loading dose of Effient. Platelet
aggregation 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 and
initiating prasugrel 10 mg with the next dose resulted in increased inhibition of platelet aggregation, but not greater than that
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.

Prasugrel is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites.
Pharmacokinetics

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.

Following oral administration, ≥ 79% of the dose is absorbed. The absorption and metabolism are rapid, with peak
Absorption and Binding

plasma concentrations (Cmax) of the active metabolite occurring approximately 30 minutes after dosing. The active
metabolite’s 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,
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%
to human serum albumin.

Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to a
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.

Fig 2-Metabolic pathway of Prasugrel
The estimates of apparent volume of distribution of prasugrel’s active metabolite ranged from 44 to 68 L and the
estimates 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 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.

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

efficacy and stability profiles compared to other salts and also compared to free base molecule. However, prolonged exposure
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
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
monoxide 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 gas
pressure, 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 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
formulations were stabilised by using inert gases/liquid pressure in packing. The present invention there by avoided the usage
of inert gases/liquid pressure in packing which is difficult to handle as used in the art to increase the stability.

The pharmaceutical composition of the present invention contains binders, diluents, disintegrants, lubricants and
MATERIALS AND METHODS

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. According to the invention, the diluent preferably used is mannitol and additionally
microcrystalline 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 choice
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
stability, with great organoleptic, non-cariogenic, sugar-free properties. Together with its versatile powder properties, it is the
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
polyvinylpyrrolidone ,croscarmellose sodium and low substituted hydroxy propyl cellulose.. According to the invention, the
disintegrant 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 major
disintegrant because of the following reasons,excellent compatibility with active ingredients and disintegration into smaller
particles 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 swelling
action causes tablets to quickly disintegrate.
Hypromellose (hydroxypropyl methycellulose, or HPMC), an excipient that is made up of water-souble, linear
polymers. 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 colloids
when dissolved in water.
The "lubricants" that may be used include but are not limited to, stearic acid, stearic acid metal salts such as
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
preferably used is Magnesium stearate . Lubricants generally decreases the ejection force and improves compressibility..The
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
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
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
require extreme moisture protection.
Another coating material available from M/s Colorcon ® are Opadry II.Offering short process times and a superior film
finish, the Opadry II product range consists of fully formulated dry blend systems for the aqueous film coating of
pharmaceutical and nutritional oral solid dosage forms. Opadry II is a water soluble, pH independent film coating system
which allows for immediate disintegration for fast, active release.Generally Opadry II film coating system contains Lactose,
Hypromellose,Titanium dioxide and triacetin.

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

dosage 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 then
compression-molding to produce a final dosage preparation. The evaluated composition contains the following excipients
Table 1-Excipient percentage range in both the formulations
S:No Ingredients Percentage content♠ Percentage content♠
(Formulation A) (Formulation B)

1 Prasugrel hydrochloride 5% 5%
Core

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%

7 Opadry AMB** 2-3% --
Film Coating

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, Titanium
dioxide and triacetin; # Evaporates during processing; ♠ Optimized composition was used for final evaluation

Prasugrel hydrochloride and all excipients were sifted through #40 mesh sieve and mixed thoroughly.
Manufacturing process

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
water till the desired weight build up was achieved. The tablets were analyzed for drug content and impurities before and
after storage at 40°C and 75% relative humidity conditions for one week (Open exposure studies).
Table 2-Comparative open exposure study data
Formulation A Formulation B

Condition Initial One week at Initial One week at 40°C/75%
Parameters 40°C/75% RH RH

Description White to Off white White to Off white White to Off white White to Off white tablets
tablets tablets tablets
Drug 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 formulations

Different literatures revealed that stored tablets containing prasugrel hydrochloride degrade by both hydrolytic and
RESULTS AND DISCUSSION

oxidative pathways. There are crossovers between these degradation pathways wherein intermediates or products of certain
steps in one pathway may interconvert or be kinetically accelerated or hindered by the concentration of product (or


356


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
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
moisture 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 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.

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

A ,shows better stability at accelerated storage conditions.As disclosed above the drug substance prasugrel hydrochloride
undergoes immediate degradation on exposure to air and moisture.The major degradation pathway for the product is by
hydrolysis. Hence the manufacturing process followed in this study is also by "direct compression method" , a method wherein
the raw material powders are directly subjected to mixing and then compressed to produce the final dosage form. Thus
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.

1. 1.Wiviott SD, Braunwald E, McCabe CH, et al. (2007). "Prasugrel versus clopidogrel in patients with acute coronary
REFERENCES

syndromes".N Engl J Med 357 (20): 2001–15
2. 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): 213‐229
3. 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): 1707‐26
4. Bhatt DL (2007). "Intensifying Platelet Inhibition — Navigating between Scylla and Charybdis". N Engl J Med 357 (20):
2078–81
5. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related
to active metabolite formation; American Heart Journal ,Volume 153, Issue 1 , Pages 66.e9-66.e16, January 2007
6. Prasugrel in Clinical Practice ;September 3, 2009;Bhatt D.L.;N Engl J Med 2009; 361:940-942
7. 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 Thiophene
Ring: Patrick M. Dansette*, Julien Rosi, Justine Debernardi, Gildas Bertho, and Daniel Mansuy; Chem. Res. Toxicol., Article
ASAP DOI: 10.1021/tx3000279,Publication Date (Web): April 6, 2012
9. Characterization of degradation products of amorphous and polymorphic forms of clopidogrel bisulphate under solid
state stress conditions ;
10. J Pharm Biomed Anal. 2010; 52: 332–344. http://dx.doi.org/10.1016/j.jpba.2009.05.001


357


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_8
12. Serebruany V, Makarov L. Prasugrel for arterial coronary thrombosis. Drugs Today. 2009; 45: 83–91.
http://www.ncbi.nlm.nih.gov/pubmed/19343228
13. http://www.rxlist.com/effient-drug.htm
14. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022307s002lbl.pdf
15. http://www.medicines.org.uk/emc/document.aspx?documentid=21504&docType=SPC
16. Summary basis of approval for Effient tablets
17. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR-
Public_assessment_report/human/000984/WC500021975.pdf


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