DEVELOPMENT AND EVALUATION OF SUSTAINED RELEASE TABLETS OF INDAPAMIDE AND IMMEDIATE RELEASE BLEND OF RAMIPRIL IN CAPSULE
SYNOPSIS FOR
M.PHARM DISSERTATION
SUBMITTED
TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA.
BY
Ms. SREEDEVI.A
Ι M.PHARM(2010-2011)
DEPARTMENT OF PHARMACEUTICS,
M.E.S COLLEGE OF PHARMACY,
BANGALORE-560 064.
KARNATAKA.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR P.G. DISSERTATION
1. / NAME OF THE CANDIDATE AND ADDRESS(IN BLOCK LETTERS) / SREEDEVI.A
C/O B.R.NARAYANASWAMY ,
NO-16,CHIKKA AVALIAH BUILDUING, ANANDANILAYA,
RAJANUKUNTE POST,
BANGALORE NORTH-560 064
2. /
NAME OF THE INSTITUTION
/ M.E.S COLLEGE OF PHARMACYARADESHAHALLY GATE,
BANGALORE- 562 110
3. /
COURSE OF STUDY AND SUBJECT
/MASTER OF PHARMACY
IN
PHARMACEUTICS
4. /DATE OF THE ADMISSION
/ 30/09/20105.
6
\
7.
8.
/
TITLE OF THE TOPIC:
“DEVELOPMENT AND EVALUATION OF SUSTAINED RELEASE TABLETS OF INDAPAMIDE AND IMMEDIATE RELEASE BLEND OF RAMIPRIL IN CAPSULE’’
BRIEF RESUME OF THE INTENDED WORK6.1NEED FOR STUDY
Combinational therapy offer improved efficacy and response, as combination of Ramipril1 with other diuretic provides synergistic antihypertensive effect in controlling blood pressure Ramipril-diuretic combination. Among all diuretics, Indapamide has low dosage, high solubility, and short half life to treat hypertension. So, combination of Ramipril and Indapamide provide synergistic effects in treatment of mild to moderate hypertension2.
Ramipril has biological half life (3-16 hours) and its dose (2.5 & 5 mg / day) and long elimination phase (9-18 hours) suggest its immediate action for treating hypertension. Indapamide has short elimination half-life (3 to 7 hours). Frequent dosing is thus necessary to maintain reasonably stable plasma concentration.However,frequent dosing results in inconvenience to the patient and leads to poor compliance. Moreover, widely fluctuating plasma concentration of the drug also results in availability of erratic amount of drug and this makes Indapamide an ideal candidate for a Sustained-release formulation. So these two drugs are enclosed in capsules to obtain both relatively fast and quick onset of the therapeutic effect and maintenance of therapeutically active plasma concentration for relatively long period of time.
Ramipril, is an angiotensin-converting enzyme (ACE) inhibitor, used to treat hypertension and congestive heart failure. ACE inhibitors lower the production of angiotensin II, therefore relaxing arterial muscles while at the same time enlarging the arteries, allowing the heart to pump blood more easily, and increasing blood flow due to more blood being pumped into & through bigger passageways. Ramipril is a prodrug is converted to the active metabolite Ramipril at by liver esterase enzymes. Ramipril at is mostly excreted by the kidneys. The half-life of Ramipril at is variable (3-16 hours), & is prolonged by heart and liver failure, as well as kidney failure. It is white crystalline powder.
Indapamide is a mild diuretic and antihypertensive agent containing both a polar sulfamoyl chlorobenzamide moiety and a lipid soluble methylindoline-moiety which promote water loss from the body (diuretics). They inhibit Na+/Cl- reabsorption from the distal convoluted tubules in the kidneys. Indapamide can decrease the blood pressure without altering the diameter of brachial artery which supports the direct action of drug on vascular smooth muscle.
Indapamide is rapidly absorbed from gastro-intestinal tract and is widely distributed
throughout the body with an apparent volume of distribution 60 litres. It is extensively metabolized in the liver. Its elimination half-life is 3-7 hours.
6.2 REVIEW OF LITERATURE:
· The stability of Ramipril in the buffer solution with different pH and the influence of acid, alkaline and oxidative medium on Ramipril stability were studied. The Ramipril degradation products were determined by high- performance liquid chromatography (HPLC) method. Acetonitrile: sodium perchlorate was used as the mobile phase, at a flow rate of 1.0 ml/min (linear gradient elution). A Nucleosil 100-S 5 µm C18, 250 mm × 4.6 mm i.d. was utilized as stationary phase. More than 0.2% of impurity D (Ramipril–diketopiperazine) was detected in the buffer of pH 3 and pH 5. In the buffer of pH 8 there was detected more than 1% of impurity E(Ramipril–diacid). No peaks for degradation products appeared in the chromatograms above limit of quantification. The alkaline medium has the greatest effect on degradation of Ramipril into impurity E (more than 50%)3.
· To design a thermodynamically stable and dilutable nanoemulsion formulation of Ramipril, with minimum surfactant concentration that could improve its solubility, stability and oral bioavailability. The composition of optimized formulation was Sefsol 218 (20% w/w), Tween 80 (18% w/w), Carbitol (18% w/w) and standard buffer solution pH 5 (44% w/w) as oil, surfactant, cosurfactant and aqueous phase, respectively, containing 5 mg of Ramipril showing drug release (95%), droplet size (80.9 nm), polydispersity (0.271), viscosity (10.68 cP), and infinite dilution capability. The present study revealed that Ramipril nanoemulsion could be used as a liquid formulation for pediatric and geriatric patients and can be formulated
as self- nanoemulsifying drug delivery system (SNEDDS) as a unit dosage form4.
· sequential injection analysis/amperometric biosensor system is proposed for the enantioselective analysis of the S-enantiomer of enalapril, Ramipril and pentopril. The amperometric biosensor used as detector in the sequential injection analysis was designed by immobilization of L-amino acid oxidase in carbon paste. The proposed SIA system can be utilized reliably for the enantioanalysis of the S-enantiomer from the raw materials as well as from their pharmaceutical formulations, with a rate of 75 samples per hr R.S.D. values better than 0.1% (n = 10)5.
· The bioavailability of 20 mg lisinopril tablets (Sinopryl as test and an originator product as reference formulation;study1) and lisinopril/hydrochlorothiazide(20mg/12.5mg)(CAS83915-83-7/CAS 58-93-5) combined formulations study 2 was calculated. All the above values were within the acceptance ranges for bioequivalence studies. In the light of the present studies it can be concluded that Hsinopril as well as lisinopril/hydrochlorothiazide test formulations are bioequivalent to the respective reference formulations6.
· The efficiency of superdisintegrants in promoting tablet disintegration and drug dissolution under varied media pH was investigated. Significant reductions in the rate and extent of water uptake and swelling were observed for both sodium starch glycolate (Primojel) and croscarmellose sodium (Ac-Di-Sol) in an acidic medium (0.1 N HCl) but not for crospovidone NF (Polyplasdone XL10), a nonionic polymer. When Primojel and Ac-Di-Sol were incorporated in model formulations, a significant increase in tablet disintegration time was observed for slowly disintegrating tablets (lactose-based tablets) but not for the rapidly disintegrating tablets (dicalcium phosphate-based tablets). Water uptake and swelling were confirmed as 2 important functions of superdisintegrants. The reduced water uptake and swelling capacity of disintegrants containing ionizable substituents in an acidic medium can potentially jeopardize their efficiency in promoting tablet disintegration and the drug dissolution rate7.
· The Effect of hydroxypropyl cellulose (HPC) on dissolution rate of hydrochlorothiazide tablets was studied. Hydrochlorothiazide (HCTZ) 60 mg strength tablets containing commonly used excipients and hydroxypropyl cellulose, marketed as either Klucel-EF or HPC-L as a binder were manufactured using identical aqueous wet granulation process. These structural features make Klucel-EF less hydrophilic. Since the cloud point of Klucel-EF was similar to the dissolution medium temperature of 37(±2) °C, it may present a less viscous layer surrounding the HCTZ granules enabling faster dissolution of the drug8.
· The admixture of disintegrants in three different hydrochlorothiazide formulations with respect to tablet properties was studied. Sodiumcarboxymethyl starch, Na-CMS (Explotab, Primojel, Na-CMS AB-G.D.R.), cross-linked polyvinylpyrrolidone, CL PVP (Polyplasdone) and potato starch were applied. Considering the values of decomposition and compressive strength Polyplasdone XL has been proved to be the most effective disintegrant for the hydrochlorothiazide formulations investigated. Potato starch shows the worst results. There are only slight differences between the three Na-CMS9.
· The effect of dissolution medium variables, such as medium composition, ionic strength and agitation rate, on the swelling and erosion of Hypromellose matrices of different molecular weights was examined. Swelling and erosion of HPMC polymers was determined by measuring the wet and subsequent dry weights of matrices. The sensitivity of polymer erosion to the degree of agitation may influence the ability of these polymers to give reproducible, agitation-independent release, compared to more rigid non-eroding matrix materials, in the complex hydrodynamic environment of the gastrointestinal tract10.
· The use of Hypromellose in oral drug delivery. Hypromellose, formerly known as hydroxy propyl methyl cellulose (HPMC), is by far the most commonly employed cellulose ether used in the fabrication of hydrophilic matrices. Hypromellose provides the release of a drug in a controlled manner,
effectively increasing the duration of release of a drug to prolong its therapeutic effect. This review provides a current insight into the inclusion of drug-release modifiers within Hypromellose matrices, the effects of dissolution media and the influence of both the external environment and microenvironment pH within the gel matrix on the properties of the polymer is also discussed11.
· The water granulation mechanism of the hydrophilic matrix polymer HPMC in a high shear mixer and to relate the properties of the granules and tablets to the molecular weight and the degree of substitution for eight HPMC grades was investigated. The results of this study show that the properties of the granules and the tablets fall into two groups according to whether the molecular weight of the polymer is high or low. The dominant factors governing the properties are the molecular weight and, to lesser extent, the degree of substitution12.
· Novel Ramipril crystalline particles with improved stability and bioavailability. More particularly, the present invention is directed to individually coated, single Ramipril crystalline particles for pharmaceutical and biopharmaceutical applications in oral therapies that are stabilized against decomposition into degradation products, namely Ramipril-DKP and Ramipril-diacid, during formulation and storage conditions. In addition, they maintain consistent label Ramipril potency over extended shelf-life and provide reduced in vivo variability in the bioavailability of Ramipril among subjects when administered orally13.
· A stable, oral pharmaceutical effervescent formulation comprising the ACE-inhibitor ramipril and/or the pharmacologically acceptable salts and/or the pharmacologically acceptable esters thereof as active components, with a
weight ratio of acid to carbonate/bicarbonate of 0.6 to 1.3 and a weight ratio of ramipril to effervescent formulation of 0.004 to 0.01314.
· A stable oral pharmaceutical formulation comprising ramipril or its
pharmaceutically acceptable salt and a stabilizing amount of an aminomethacrylate in
a pharmaceutically acceptable carrier medium is described15.
6.1 OBJECTIVES OF THE STUDY:
ü Formulation of capsules with sustained release tablets of Indapamide and immediate release blend of Ramipril.
ü Evaluation of sustained release tablet.
ü Evaluation of immediate release blend.
ü Comparison with a marketed product.
ü Stability studies as per ICH guidelines.
ü Statistical analysis of all the results.
MATERIALS AND METHOD
7.1 SOURCE OF DATA
1. Library of M.E.S. college of Pharmacy
2. e-library of M.E.S.college of Pharmacy
3. The data will be collected from official books such as IP,BP,USP
4. Internet source
5. International and National pharmaceutical Journals.
7.2 MATERIALS AND METHODS:
1.Drug: Anti-hypertensive drugs: Ramipril & Indapamide.
2.Polymers: Hypromellose( Hydroxy propyl cellulose), Micro crystalline cellulose.
3. Excipients: Starch pregelatinised, Lactose monohydrate, Crospovidone, Magnesium stearate.
7.3 METHODS OF DATA COLLECTION:
1.Literature survey using internet and scientific Journals.
2.Data will be collected from experimental studies which includes:
§ Preformulation studies.
§ Formulation development and evaluation.
§ Optimization of the microspheres using suitable statistical designs.
§ Statistical analysis of all the results.
§ Stability studies as per ICH guidelines.
7.4 Does the study require any investigation or intervention to be conducted on patients or other human or animals?
-NO-
7.5 Has ethical clearance been obtained from your institute?
-NOT APPLICABLE-
REFERENCES:
1. Heidbreder D, Froer KL, Bauer B, Cairns V, Breitstadt A, Bender N, Combination of Ramipril and Hydrochlorothiazide in the treatment of mild to moderate hypertension- part 2: An open long term study of efficacy and safety, Clin Cardiol 1993 Jan;16(1):47-52.
2. Rang HP, Dale MM ,“Pharmacology”, 4th edition, Churchill Livingstone NY 1999;375.
3. Hanysova L , Vaclavkova M, Dohnal J and Klimes J, Stability of Ramipril in the solvents of different pH, Journal of Pharmaceutical and Biomedical Analysis 2005;37(5): 1179-1183.
4. Shafiq S, Shakeel F , Talegaonkar S, Ahmad FJ , Khar RK, Ali M, Development and bioavailability assessment of Ramipril nanoemulsion formulation European J Pharmactics and Biopharmaceutics Article in Press, Corrected Proof.
5. Stefan RI, Jacobus F. van Staden, Camelia Bala and Hassan Y. Aboul-Enein, On-line
assay of the S-enantiomer of enalapril, Ramipril and pentopril using a sequential injection
analysis / amperometric biosensor system, J Pharm and Biomed Analysis 2004;36(4): 889- 892.
6. Koytchev R, Ozalp Y, Erenmemisoglu A, van der Meer MJ, Alpan R .Effect of the combination of lisinopril and hydrochlorothiazide on the bioequivalence of tablet formulations, Arznei mittel forschung 2004 ; 54(9a):605-10.
7. Zhao N, Augsburger LL, The influence of swelling capacity of superdisintegrants in different pH media on the dissolution of hydrochlorothiazide from directly compressed tablets. Ame Asso Pharm Sci tech 2005 ;6(1):E120-6.
8. Desai D, Rinaldi F , Kothari S, Paruchuri S, Li D, Lai M, Fung S . Effect of hydroxypropyl cellulose (HPC) on dissolution rate of hydrochlorothiazide tablets, Int J Pharm 2006
308(1,2) 40-45.
9. Hennig D, Schubert E. The effect of selected disintegrants on the properties of three hydrochlorothiazide tablet formulations. Pharmazie 1987; 42 (11):725.
10. Kavanagh N, Corrigan O. Swelling and erosion properties of hydroxyl propyl methyl cellulose (Hypromellose) matrices--influence of agitation rate and dissolution medium composition. Int J Pharm. 2004 ; 279(1-2):141-52.
11. Li CL, Martini LG, Ford JL, Roberts M. The use of Hypromellose in oral drug delivery, J
Pharm Pharmacol 2005; 57 (5):533-46.
12. Herder J, Adolfsson A, LarssonA,.Initial studies of water granulation of eight grades of Hypromellose (HPMC). Inl J Pharm2006; 313( 1-2) 57-65.
13. Edward W (Us), Martin B (Us), inventor.King Pharmaceuticals Res & Dev (Us). Martin BW (Us),assignee. Stabilized Individually Coated Ramipril Particles, Compositions and Methods. 2006.
14. Karin K(De), Brigitte F(De), Alexandra H(De), inventor. Hexal Ag (De), assignee. Pharma Efferv Form containing Ramipril . 2003.
15. Dharmadhikari NB , Dhavse VV, inventor, Sun Pharm Industries Ltd , assignee. Stable Pharmaceutical Formulations.2006.