DEVELOPMENT OF MODIFIED PECTIN BASED EXTENDED RELEASE TABLETS OF NIFEDIPINE

SYNOPSIS FOR

M.PHARM DISSERTATION

SUBMITTED TO

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES, KARNATAKA

BY

MURALI KRISHNA REDDY. P

I M.PHARM (2010-11)

Department of Pharmaceutics

M.S.RamaiahCollege of Pharmacy

BANGALORE- 560 054.

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCESBANGALORE, KARNATAKA

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECT FOR P.G DISSERTATION

1. / NAME OF THE CANDIDATE AND ADDRESS(IN BLOCK LETTERS) / MURALI KRISHNA REDDY.P
S/O P. ANANDHA REDDY
# 1/ 141, KARLAPUDI (VIL),
SIDDAVARAM (PO),
KOTA (M), NELLORE (DIST)
A.P - 524411
2. /

NAME OF THE INSTITUTION

/ M.S.RAMAIAHCOLLEGE OF PHARMACY
M.S.R.I.T. POST
M.S.RAMAIAH NAGAR
BANGALORE-560 054.
3. /

COURSE OF THE STUDY AND SUBJECT

/

M.PHARM

PHARMACEUTICS

4. /

DATE OF THE ADMISSION

/ 19.11.2010
5. / TITLE OF THE TOPIC
DEVELOPMENT OF MODIFIED PECTIN BASED
EXTENDED RELEASE TABLETS OF NIFEDIPINE

6. BRIEF RESUME OF THE INTENDED WORK

6.1 NEED FOR THE STUDY

Drug dosage forms contain many excipients in addition to the active pharmaceutical ingredient(s) to assist in the manufacturing process as well as to optimize drug delivery. They may be natural or synthetic which directly or indirectly influence the extent and/or rate of drug release and absorption. But today, the whole world is increasingly interested in natural drugs and excipients. Natural materials have advantages over synthetic materials because they are non-toxic, less expensive and freely available. Furthermore, they can be modified to obtain tailor made materials for drug delivery systems allowing them to compete with the synthetic products that are commercially available.

Polymers have been successfully employed in the formulation of solid, liquid and semi-solid dosage forms and are specifically useful in the design of modified release drug delivery systems. Both natural and synthetic polymers have been investigated extensively for this purpose, but the use of natural polymers for pharmaceutical applications is attractive because they are economical, readily available, non-toxicand capable of chemical modifications, potentially biodegradable and with few exceptions also biocompatible.

The increasing importance for the use of natural polymers is due to the fact that the plant resources are renewable and if cultivated or harvested in a sustainable manner, they can provide a constant supply of raw material.

The specific application of plant-derived polymers in pharmaceutical formulations include their use in the manufacture of solid monolithic matrix systems, implants, films, beads, microparticles, nanoparticles, inhalable and injectable systems as well as viscous liquid formulations. Within these dosage forms, polymeric materials have fulfilled different roles such as binders, matrix formers or drug release modifiers, film coating formers, thickeners or viscosity enhancers, stabilisers, disintegrants, solubilisers, emulsifiers, suspending agents, gelling agents and bioadhesives. Thus the use of plant-derived polymers and their semi-synthetic derivatives as excipients in the design of novel dosage forms such as modified release matrix type tablets has increased day-by-day1.

Pectin, a naturally occurring polysaccharide, in recent years gained increased importance. The benefits of natural pectin are also appreciated by scientists and consumer due to its biodegradability. Pectin is the methylated ester of polygalacturonic acid and it is commercially extracted from citrus peels and apple pomace under mildly acidic conditions.

Pectin possesses several requisite characteristics to be used as polymer in drug development and release kinetics and itis a family of complex polysaccharides present in the cell walls that surround growing and dividing plant cells and is present in most of the higher plants. It is also present in the junctional zone between cells within secondary cell walls including xylem and fiber cells in woody tissue. Pectin is an essential component in the initial growth and ripening process of fruit and is often a waste material from the food and fruit processing industry with a consequent high availability. It is extracted from different sources, e.g. apple, grapes or citrus and is commercially available as a white to light brown powder.

Structure of Pectin

It consists of linear chain of 1-4 linked α-D-galacturonic acid residues with varying degrees of methyl ester substituents.2The galacturonic acid polysaccharides are rich in neutral sugars such as rhamnose, arabinose, galactose, xylose and glucose.

Cross-linking of pectin with calcium ions inhibits the release of the incorporated drug from pectin tablets by suppressing both the dissolution and swelling of these systems. Depending on the type and structure of the pectin molecule, pectins can gel in various ways. Gelling can be induced by acid or cross-linking with calcium ion or by reaction with alginate. When a pectin solution is titrated with acid, the ionization of carboxylate groups on pectins is repressed causing pectin molecules to no longer repel each other over their entire chains. The pectins can thus associate over a portion of their chains to form acid-pectin gels. Gel forming systems have been investigated widely for sustained drug delivery. Hencerecently, pectin has gained increasing research interest in gastroenterological medicine, for use in drug carriers for oral drug delivery3.

Pectin has high potential as a hydrophilic polymeric material for controlled release matrix drug delivery systems, but its aqueous solubility contributes to undesirable, premature and fast release of the drug from these polysaccharide matrices. One of the options to reduce the high solubility of pectin in aqueous medium is through chemical modification without affecting favourable biodegradability properties4. Pectins can be chemically modified by saponification catalysed by mineral acids, bases, salts of weak acids, enzymes, concentrated ammonium systems and primary aliphatic amines5.

Patients with chronic diseases are increasingday by day. This situation necessitates the useof drugs for a longer period and taking a lot ofmedicines simultaneously, which may lead to adecrease in patient compliance. This problem isserious for drugs with short biological half- livesbecause they must be taken more frequently. Inthis condition controlled release formulationbecomes beneficial for reducing dosingfrequency and thus increase patientcompliance6.

Nifedipine is a calcium-channel antagonist that is widely used in the treatment of angina pectoris and systemic hypertension. It is a poorly water soluble drug and its absorption from gastrointestinal tract (GIT) is rate limited. Its biological half-life is about 2 h. and it shows a low and irregular bioavailability of about 50% after oral administration with a high first pass effect.

When administrated orally via immediate-release solid dosage forms, absorption of nifedipine is poor7.

Clinical experiences gained with oral nifedipine formulations with immediate-release (IR) characteristics clearly show that a steep rise in the drug plasma concentration results in an increase in heart rate and drug-specific side effects. Therefore, it has been generally accepted that extended-release (ER) formulations are most efficient for routine hypertension therapy with nifedipine8.

Hence in the present research work, chemical modification of pectin and its use in the release retardant effect of nifedipine from the developed tablet dosage form would be carried out.

6.2 REVIEW OF LITERATURE

Literature review for understanding the concepts was done by referring to published articles in various national, international journals, official books and websites.

Studies on the effects of different formulation variables upon the characteristics of pectinate microparticles (MPs) prepared by ionotropic gelation technique for colonic delivery of mesalazine using pectin derivatives was reported. It was observed that maximum entrapment of mesalazine (86.1 %) and strength of gel network zinc pectinate gel microparticles was achieved in cross-linking solution of pH 1.6. Furthermore scintigram studies showed the residence of microparticles (filled in enteric coated capsule) in colon for more than 9 hr. and delivery of almost all the drug loading dose in colon2.

Studies on the chemical modification of pectin by acetylation process along with the effect on the release pattern of Ibuprofen formulated as tablets using chemically modified pectin was reported. Drug dissolution studies were carried out in buffers of pH 1.2 and 6.8 and the system was designed based on the total GIT transit time concept. It was observed that optimum concentrations of the modified pectin in such a system protected the tablet for 10–12 hr. throughout the gastrointestinal tract3.

Studies on the chemical modification of pectin by acetylation process using various strengths of 20%, 40% and 60% v/v acetyl chloride in ethanol and the impact on drug release of matrix tablets of Tramadol formulated using various strengths of modified pectins in different concentrations were studied. Physico-chemical characteristic studies like solubility, gelling studies, acid value, saponification value and ester value were carried out. Furthermore FTIR studies were carried out to confirm the chemical modification of pectin. It was observed that the optimized tablet formulation sustained the drug release over a period of 8hr. as comparable to the marketed product4.

Development and evaluation of in-situ gel of Salbutamol sulphate using pectin as a crosslinking agent and the in-vitro release studies in acidic medium followed by basic medium for about 8 hr.was reported. The stability studies were carried out for 3 months and the pH, drug content, viscosity were also carried out. It was observed that the solutions contained calcium ions in complex form, which on release in the acidic environment of the stomach caused gelation of the pectin. Furthermore in-vitro gelation capacity of the formulated sols was examined and it was proved that the formulations were homogenous liquid when administered orally and became gel at the contact site6.

Development of pH-sensitive controlled release formulation of clarithromycin in oil-entrapped calcium pectinate microgel bead was reported. Pectin-based oil-entrapped microgel beads were prepared by ionic gelation technique. The gel beads were formed instantly after adding the liquid formulation mixture dropwise into calcium chloride solution. Also the beads were optimized by coating with ethylcellulose solution and then evaluated for their diameter, floating lag time, encapsulation efficiency and drug release. It was observed that the particle size, encapsulation efficiency and buoyancy were significantly affected by the concentration of the pectin and calcium chloride and the formulations exhibited sustained release profile. It was found that ethylcellulose-coated formulation batch, was the most suitablecontrolled formulation with drug release of 65 -70 % in 8 h9.

Studies on in-vitro dissolution properties of matrix, multilayer and compression coated tablets of Mesalamine to reach the colon intact, using pectin as a carrier was reported. Multilayered tablets were formulated using pectin as release controlling layers on either side of mesalamine matrix tablets and mesalamine core tablets were prepared and compression coated with pectin and the effect of the incorporation of different percentages of chitosan in the pectin coat on drug release was investigated. It was found that matrix and multilayer tablets failed to control the drug release in the physiological environment of stomach and small intestine whereas compression coated formulations were able to protect the tablet core from premature drug release but at high pectin coat:core ratios of 4: 1 and 5: 1 and also inclusion of chitosan 3% and 5% w/w in the pectin coat offered better protection at a lower coat: core ratio (3: 1). Furthermore, it was revealed that selective delivery of Mesalamine to the colon could be achieved using a Pectin or Pectin/Chitosan mixture in the form of compression coated tablets10.

Studies on the chemical modification of citrus pectin with a low degree of methyl esterfication (LMP) and its deesterified form potassium pectate (KP), modified using a low amount of UV-absorbing substituents were reported. For this purpose, two different substitution reactions were used (a) alkylation of hydroxyl groups with p-carboxybenzyl bromide in aqueous alkali and (b) alkylation of the carboxylate group with benzyl bromide in the DMSO/TBAI/catalyst system. Furthermore, the hydrodynamic properties were assessed by analytical ultracentrifugion, viscometry etc. It was observed that the introduction of small amounts of p-carboxybenzyl ether groups had no effect on the hydrodynamic properties in the case of KP, whereas it was accompanied with a decrease of molecular mass. Also the results confirmed that LMP is susceptible to chain cleavage due to β-elimination during both modification reactions. However, KP seems to be more tolerant of the reaction conditions11.

Studies on the effect of two formulation variables, the pectin type (with different degrees of esterification [DEs]) and the amount of calcium, on drug release from pectin-based matrix tablets of indomethacin was reported.The in-vitro release studies in phosphate buffer indicated that the lower the DE, the greater the time for 50% of drug release (T50). This was probably because of the increased binding capacity of pectin to calcium. However, when the calcium was excluded, the pectins with different DEs showed similar release pattern with insignificant difference of T50. When the amount of calcium acetate was increased from 0 to 12 mg/tablet, the drug release was significantly slower. However, a large amount of added calcium (i.e. 24 mg/tablet) produced greater drug release because of the partial disintegration of tablets. Hence it was observed that both pectin type and added calcium affect the drug release from the pectin-based matrix tablets12.

6.3 OBJECTIVES OF THE STUDY

  • Synthesis of modified pectins by suitable chemical modification technique to reduce the polarity of the polymer.
  • To study the physico-chemical and hydro-dynamic characteristics of modified pectins.
  • To formulate and evaluate modified pectin based extended release tablets of nifedipine.
  • To evaluate the formulated dosage form for various un-official and official tests.
  • To study the in-vitro drug release studies and the rate release kinetics of the formulated tablets.
  • To compare drug release profile of the optimized modified pectin based nefidipine tablet with the available marketed formulation.
  • To study the drug : polymer compatibility studies using suitable analytical techniques
  • Shelf life prediction of the optimized dosage form by conducting stability studies as per the ICH guide lines.

7. MATERIALS AND METHODS

7.1 SOURCE OF DATA

1)Library: M.S.RamaiahCollege of Pharmacy.

2)e-library: M.S.RamaiahCollege of Pharmacy.

3)Official books (IP, BP and USP).

4)Internet.

5)RGUHS Library, Bangalore (J-Gate, Helinet).

6)Micromedex® Health care series. Drug Information Centre: M.S.RamaiahCollege of Pharmacy.

7)International and National Pharmaceutical Journals.

8)Lab based studies.

MATERIALS

1)Drug selection: Classical anti- hypertensive Nifedipine,poorly water soluble drug having shorter biological half -life of 2 hr. is selected for the study.

2)Polymer: Natural polymerPectin will be subjected to chemicalmodification byalkylation , acetylation or saponification process.

3)Organic acids: Acetyl chloride, Phenyl acetyl chloride, Thionyl chloride, Phenyl acetic acid, Hydrochloric acid etc. will be used.

4)Organic solvents: Ethanol, Methanol, Chloroform etc. will be used.

5)Other materials: potassium hydroxide, phenolphthalein, pumice powder etc. will be used.

All other chemicals and solvents used will be of A.R & L.R grade procured from reliable sources.

7.2 METHODS OF COLLECTION OF DATA

Data will be collected from the experimental work which includes:

1) PRE-LABORATORY WORK

The drug nifedipine purchased from Yarrow Chemical Products, Mumbai. Pectin, organic acids, chemicals , reagents and solvents required will be procured from the reputed chemical suppliers like S.D.Fine Chemicals, Merck etc.

2) LABORATORY WORK

Chemical modification of natural polymer pectin by using suitable techniques will be performed.

Physico-chemical characterization studies of modified pectins includes:

a)Solubility studies.

b)Gelling or swelling studies.

c)Determination of acid value.

d)Determination of saponification value.

e)Determination of ester value.

f)Polymer compatibility studies.

Formulation of the modified pectin based extended release tablets of Nifedipineby using different strengths of modified pectin at varying ratios and combinations of drug to polymer will be carried out.

Drug – Excipient compatibility studies like FT-IR, XRD and DSC will be carried out.

Pre-compression studies of the dosage formlike Angle of Repose, Carr’s index, Hausner’s ratio etc.

Post compression studies:

  • The compressed modified pectin based Nifedipinetablets will be subjected to unofficial test like Hardness test and official tests like Weight uniformity test, Drug content, Friability, Disintegration test and the in-vitro drug release studies.
  • Comparative in-vitro drug release profile of the optimized formulation with the available marketed product.
  • The in-vitro data will be analyzed statistically and kinetics of drug release will be predicted using the Software PCP Disso V3.

Stability studiesof the optimized formulations will be performed as per the ICH guidelines.

7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTION TO BE

CONDUCTED ON PATIENTS OR OTHER HUMAN OR ANIMALS?

- NO –

7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED BY YOUR INSTITUTE?

- NOT APPLICABLE –

8. LIST OF REFERENCES

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Molecules2009; 14: 2602-20.

  1. Kawadkar J, Chauhan MK, Ram A.Evaluation of potential of Zn-pectinate gel

microparticles containing mesalazine for colonic drug delivery. DARU 2010;18(3):

211-20.

  1. LinShu L, Marshall L, Fishman, Kevin B, Hicks, Meir K. Interaction of various pectin formulations with porcine colonic tissues. Biomaterials 2005; (26): 5907–16.
  1. Manish BS, Rameshwar D, Praffula C, Neela BM. Chemical modification of pectins,

characterization and evaluation for drug delivery. Scientia Pharmaceutica 2008; 76: 775-84.

  1. Harika Puppala SK, Bharath S, Basavaraj BV, Deveswaran R, Madhavan V. Chemical modification and characterization of pectin as a potential drug release retardant. Int J Res Ayu Pharm 2011; 2(2): 640-47.
  1. Hetangi R, Vishnu P, Dushyant S. Pectin based insitu gelling system of salbutamol for oral sustained drug delivery. Int J Pharm Res Dev 2011; 3(1):53-58.
  1. Bhavin P, Piyush P, Ashok B, Shrawaree H, Swati M, Ganesh C. Evaluation of Tamarind Seed Polysaccharide (TSP) as a Mucoadhesive and sustained release component of nifedipine buccoadhesive tablet & Comparison with HPMC and Na CMC. Int J PharmTech Res 2009; 1(3): 404-410.
  1. Grzegorz G, Henning B, Werner W. Investigation of the DissolutionCharacteristics of Nifedipine Extended-Release Formulations Using USP Apparatus 2 and a Novel Dissolution Apparatus. Dissolution Technologies 2009; 7-13.
  1. Tripathi GK, Singh S. Formulation and In Vitro Evaluation of pH-Sensitive Oil-entrapped buoyant beads of clarithromycin. Trop J PharmRes 2010; 9(6): 533-39.
  1. Nirav PV, Jayvadan P K, Shreeraj SH, Jagruti P J. Design, development and in vitro evaluation of mesalamine tablets containing pectin and chitosan for colon- specific drug delivery. Int JPharm Pharma Sci2010; 1(2): 94-102.
  1. Gordon MA, Zdenka H, Anna E, Anna M, Juraj A, Stephen HE. Modification of pectin with UV-absorbing substituents andits effect on the structural and hydrodynamic properties of the water-soluble derivatives. Carbohydrate Polymers. 2002; 48: 351-59.
  1. Sungthongjeen S,Sriamornsak P,Pitaksuteepong T,Somsiri A, Puttipipatkhachorn S.

Effect of degree of esterification of pectin and calcium amount on drug release from