1.0 Brief resume of intended work:

1.1 Need for study:

The goal of any therapy is to maintain the plasma drug concentration in a therapeutically effective and non toxic level for an extended period of time. This rather is achieved by the modification of dosage form in such that it releases the desired amount of drug over an extended time period. Modified release systems continuously releasedrug over an extended period of time after administration of single dose. Products of this type have been formulated for oral, injectable and topical use and inserts for placement in body cavities.1

Modified release dosage forms have several advantages over the conventional formulations like less frequency of drug administration, patient compliance is improved, blood level oscillation characteristics of multiple dosing of conventional dosage form is reduced, total amount of drug administration can be reduced1 and many more.

Hypertension is one of the most common cardiovascular disease affecting a large proportion of population. It means abnormally elevated arterial blood pressure causing pathological changes in the vasculature and hypertrophy of the left ventricle.2 Systemic hypertension characterized by a major risk factor coronary artery disease and its attendant complication myocardial infraction, ischemic and hemorrhagic stroke and sudden cardiac death, renal insufficiency and dissecting aneurysm of the aorta.2

The treatment of hypertension requires repeated administration of anti-hypertensive drugs. A section of patients requires regular administration of antihypertensive agents often b.i.d or t.i.d. This necessitates development of a dosage form which increases patient convenience. Modified release dosage forms of antihypertensive drugs provide convenient dosing frequency in comparison to conventional tablets while providing nearly constant serum level of medication over prolong period and improving delivery of medication, which reduces side effect.3

In the present study, Metoprololan antihypertensive drugis selected as model drug. Metoprolol is a β1 selective adrenergic receptor blocking agent. The half life ofmetoprolol is about 4 h, the oral dose of metoprolol is 50-100mg.4-5

1.2 Review of the literature:

Varshosazet al5developed a controlled release formulation of memetoprolol in a solid dispersion system using Eudragit RSPO. Two methods, melting method and solvent methods, were used to prepare the solid dispersion of the drug in carrier systems. The formulations were characterized by XRD, DSC, IR and dissolution studies. The resultsshowed that the drug release from the dosage form was slower than pure drug.

Ragnarssonet al6developeda new multi unit controlled release metoprolol product. The effect of several physicochemical properties of drug on release profile was investigated. Based on the release profile, it was concluded that the salt form has significant effect on drug release from the carrier. The pharmacokinetic study was done for a selected formulation in vivo.

Goldsteinet al7studiedmetoprolol CR/ERrelese in patient with severe heart failure analysis of experience in MERIT-HF study.The results concluded that the patient with severe heart failure receive a similar mortality benefit and similar reduction in hospitalization for worsening heart failure with metoprolol CR/XL treatment.

Quintenet al8prepared a matrix tablet formulation by injection moulding. The influence of the type of the carrier, salt form of the drug and formulation variables on drug release pattern was investigated. It was observed that the salt form of the drug had plasticizer effect on hydrophilic carrier. The pharmacokinetic parameters were dependent on high drug loading in formulations.

Almeida et al9prepared and evaluated hot-melt extruded matrices based on ethylene vinyl acetate and polyethylene oxide for sustained release of antihypertensive drug. The prepared formulations were characterized by DSC, XRD, FTIR and raman spectroscopy along with dissolution properties. The drug release was dependent on on VA content, PEO molecular weightand content, matrix porosity as well as pore size distribution.

Dadarwalet al10developed a tablet formulation for delayed release of metoprolol using compression coating method. The formulations were evaluated for physicochemical properties and drug release pattern. The optimized formulation showed a lag time of 6 h for drug release and duration extended upto 24 h.

1.3 Objectives of the study:

1. Preparation of modified release formulation for selected model drug using a suitable method.

2. Investigation of effect of type and amount of carrier and excipients dissolution rate.

3. Evaluation of the physical characteristics and invitro release studies of formulation.

4.Stability studies on selected batch as per ICH guidelines.

2.0 Materials and methods:

2.1 Source of data:

Preliminary data required for the experimental study would be obtained from scientific journals, books available at college library.

2.2 Method of collection of data:

Data on drug and excipient will be collected from the information center, books, catalogs etc. On the basis of extensive preformulation trials on the drug and excipient, the final formulation will be developed.

I Materials:

The material required for the study like anti-hypertensive drug (e.g., Metoprolol),hydrophilic carriers and suitable excipients will be procured from commercial suppliers.

II Methodology:

Modified release dosage forms will be prepared by wet granulation, direct compression or by other innovative methods using either hydrophilic or hydrophobic polymer. The matrix forming materials is selected based on the incompatibility studies and preformulation parameters.

Evaluation of the prepared formulations:

The prepared formulations will be evaluated for various physicochemical and physicomechanical properties like friability, hardness, and dissolution studies.

2.3Does the study require any investigation or interventions to be conducted on patients or other humans or animals?

No studies are intended to be performed on humans or animals.

2.4. Has ethical clearance been obtained from you in case of 2.3?

Not applicable.

3.0REFERENCES:

1. Longer AM. Robinson RJ. Sustained release drug delivery system.In: Remington’s pharmaceutical sciences. 17th Edn, Mack publishing company,Easton:1985:1645.

2. Hoffman BB. Therapy of hypertension. In: Brunton LL, Lazo JS, Parker KL, editors. The pharmacological basis of therapeutics. 11thedn,New York:Mcgraw-Hill, 2001.

3. Hui Hw, Lee VHL, Robinson JR. Design and fabrication of oral controlled release drug delivery systems. In: Robinson RJ, Vincent HL, editors. Controlled drug delivery- Fundamentals and applciations. 2nd edn, InformaHealh, New York 2005:373-421.

4. Benowitz NL. Antihypertensive agents. In: Katzung BG, Masters SB, Trevor AJ, editors. Basicand clinical pharmacology. 11thEdn New York: Mcgraw-Hill, 2001.

5. Varshosaz J, Faghihian H, Rastgoo K. Preparation and characterization of metoprololcontrolled release in solid dispersion.Drug Deliv.2006;13:295-302.

  1. Ragnarsson G, Sandberg A, Jonson UE,Sjogren J.The development of new controlled release Metoprolol product.Drug DevInd Pharm.1987;13:1495-509.
  2. Goldstein S, Fagerberg B,Hjalmarson A, Kjekshus J, Waagstein F, Wedel H, Wikstrand J. The metoprolol CR/ER in patient with several heart failure analysis of experience in MERIT-HF study. J Am CollCardiol. 2011;38:932-8.
  3. Quinten T, Andrew GP, Beer TD, Saerenes L, Bouquet W, Jones DS et al. Preparation and evaluation of sustained release matrix tablets based on metoprolol and an acrylic carrier using injection moulding. AAPS PharmSciTech. 2012;13:1197-1211.
  4. Almeida A, Brabant L, Sipmann F, Beer T,Bouquet W,Hoorebeke L, Siepmann,Remon JP, Vervaet C.Sustained release from hot-melt extruded matrices based on ethylene vinyl aceatate and polyethylene oxide. EurJPharm. 2012;10:1016.
  5. Dadarwal S, Madan S, Agrwal S.Formulation and evaluation of delayed-onset extended-release tablets of metoprololtartrate using hydrophilic-swellable polymers. Acta Pharm. 2012; 62:105-14.

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