FORMULATION AND IN VITROEVALUATION OF SOLID DISPERSION

AND SUSTAINED RELEASE BEADS OF ATENOLOL FOR

ANTIHYPERTENSIVE THERAPY IN A SINGLE DOSAGE FORM (CAPSULE)

M.Pharm Dissertation Protocol Submitted to

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore– 560 041

By

Mr. SUPRATIK SAMANTA, B.Pharm

Under the Guidance of

Dr. DIVAKAR GOLI,M.Pharm, Ph.D

Department of Pharmaceutics,

Acharya & B.M. Reddy College of Pharmacy,

Soldevanahalli, Chikkabanavara (Post)

Hesaraghatta Main Road, Bangalore –560 090.

2011-2013

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE.

ANNEXURE - II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / Name of the Candidate
and Address / Mr. SUPRATIK SAMANTA
S/o Prof Sudhanshu Sekhar Samanta,
176 Shalgechia, PO:Tamluk-721636
DIST:Purbo Medinipur,
West Bengal.
2. /
Name of the Institution
/ ACHARYA & B.M. REDDY COLLEGE OF PHARMACY,
Soldevanahalli, Hesaraghatta Main Road,
Chikkabanavara Post.
Bangalore-560090
3. / Course of Study and Subject / M.Pharm
(Pharmaceutics)
4. /
Date of Admission
/
13-06-2011
5. TITLE OF THE PROJECT:-
FORMULATION AND IN VITRO EVALUATION OF SOLID DISPERSION AND SUSTAINED RELEASE BEADS OF ATENOLOL FOR ANTIHYPERTENSIVE THERAPY IN A SINGLE FORM (CAPSULE)
6.0
6.1
6.2
6.3
7.0
7.1
7.2
7.3

7.4
8.0 / BRIEF RESUME OF THE INTENDED WORK:
NEED FOR THE STUDY:
Solid dispersion will release drug immediately and immediate action will be achieved and sustained release dosage form (beads) will sustain the drug release for a long period of time (12hrs). This study is intended to formulate both immediate and sustained release formulations in a single dosage form (capsule).
SOLID DISPERSION:
Definition of solid dispersion: Theterm solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The matrix may be either crystalline or amorphous. The drug can dispersed in molecularly, in amorphous particles or in crystalline particles. According to molecular arrangements, solid dispersion can be classified in different types1.
“Dispersion involving the formation of eutectic mixtures with water soluble carriers by melting of their physical mixtures.”
Definition of sustained release dosage forms:
Sustained release dosage forms are designed to release the drugs at a predetermined rate in order to maintain a constant drug concentration for a specific period of time with minimum side effects2.
HYPERTENSION:
It is a chronic increase in arterial blood pressure. In general, if the diastolic pressure is more than 90 mm Hg and the systolic pressure more than 150mm Hg, the person is said to be hypertensive, though in the old age it is permissible as normal limit3.
Causes for blood pressure:
Many factors affect the blood pressure, including:
1)How much water and salt have in body
2)The condition of kidneys, nervous system, or blood vessels
3)The levels of different body hormones
The antihypertensive drug formulation is most common in the market; still it needs some modification in dosage forms.
Examples of some antihypertensive drugs: Hydrochlorothiazide(thiazides diuretic),captopril(ACE inhibitors),losartan(AT1 receptor blocker),verapamil(calcium channel blocker),propranolol(beta adrenergic blocker) and hydrazine(vasodilator).
Atenolol has low lipid solubility, sparingly soluble in water, protein binding 40-50%, plasma half-life 5-6 hours. After increase the solubility the protein binding and lipid solubility and drug release will be faster. The bioavailability can be increased by solid dispersion as it increases the solubility3. On the other hand, the sustained release dosage form going to minimize the blood pressure level for long period of the time.
A relatively selective beta-1 blocker having low lipid solubility.It is incompletely absorbed orally, but first pass metabolism is not significant.Side effects related to CNS action are less likely.No deleterious effect on lipid profile has been noted.Effective dosage for most individuals falls in a narrow range. It is commonly used beta blocker for hypertension and angina4.
REVIEW OF LITERATURE :
  • KaewnopparatN.et al., formulated Solid dispersions (SD) of curcumin polyvinylpyrrolidone in the ratio of 1:2, 1:4, 1:5, 1:6 and 1:8 to increase the solubility and dissolution of curcumin. Solid dispersion, Physical mixture and curcumin were evaluated for solubility, dissolution, powder X-ray diffraction, differential scanning calorimetry and fourier transform infrared spectroscopy. It was found that solubility and dissolution of solid dispersion were more than physical mixture and intact curcumin. It was found that the optimum weight ratio for curcumin: PVP K-30 is 1:6. The optimum formulation was still in amorphous form even after storing at ambient temperature for two years5.
  • Khirwadkar P.et al., worked on mouth dissolving tablets of Atenolol. Atenolol mouth dissolving tablets were formulated by effervescent method, superdisintegrant addition method, sublimation method, hot melt method and solid dispersion method by direct compression technique. Superdisintegrant addition method was found best after evaluating allthe five formulations for disintegration time, hardness and friability. Nine batches were prepared containing sodium starch glycolate and Ac-di-sol in differentconcentration. Various parameters like weight variation, hardness, friability, drug content, invitrodisintegration time were evaluated for all the formulations. The formulation having Sodium starch glycolate 4% and Ac-dic-sol 3% was found best based upon drug release6.
  • Deshmukh KR.et al., reviewed a article on the information about mouth dissolving tablets prepared by solid dispersion technique. Mouth dissolving tablets are being increasingly popular in the market over conventional tablets, because of their potential benefits.Solid dispersion is an innovative technique used for improving solubility. Formulation of solid dispersion as mouth dissolving tablets improves dissolution characteristics of drug and also provides ease of administration and quicker action. Various techniques used for the preparation of mouth dissolving tablet and solid dispersion are described in this article. Furthermore, the various characterization parameter evaluated for mouth dissolving tablets are modified disintegration time, wetting time, dissolution study, stability study etc7.
  • Bharate SS.et al., reviewed article on studies of active drug/excipient compatibility. Compatibility between pharmaceutical active ingredient and excipients represents an important phase in the preformulation stage of the development of all dosage forms. The physical and chemical interactionsbetween drugs and excipients can affect the chemical nature, stability and bioavailability of drugsand, finally, their therapeutic efficacy and safety. Examples of active drug/excipients interactions are transacylation, the Maillard browning reaction, acid base reactions and physical changes. Interaction between atenolol and PVP showed substantial changes in DSC thermograms of a drug-excipient binary mixture8.
  • Ostwal PP.et al., developed and evaluated tablet in capsule of nifedipine and atenolol. Delayed drug delivery system (DDS), zero-order DDS, and site-specific DDSare focuses of oral controlled-release solid dosage forms for researchers. Oral delayed DDS, which releases drugs after a programmable period of time, is used for treatment of diseases that depend on circadian rhythms. The system consists of a core and a coating. The core is coated with different polymeric barriers by film or compression. Until the polymeric shell is completely swollen or eroded, the drug release from core is prevented by coating. A multifunctional and multiple unit system for oral use were developed by filling versatile mini tablets in a hard capsule. Nifedipine was formulated as sustained release part and atenolol as immediate release part9.
  • Jia J.et al., worked on evaluation of pharmacokinetics and pharmacodynamics relationship of oral sustained release atenolol pellets in rats.This study was designed to evaluate the in vitro release, pharmacokinetics (PK), pharmacodynamics (PD) and PK-PD relationships of atenolol sustained-release pellets (AT-SRPs), compared with those of atenolol immediate-release pellets (AT-IRPs). Blood sampling for AT plasma concentration was performed in normal rats and blood pressure-lowering effects were recorded continuously in hypertensive rats (HRs) before and at 1, 4, 8, 12, 16 and 24 h after drug administration. The parameters were calculated using DAS1.0 program and WinNonlin software. The more favorable characteristics of SRPs would make it more appropriate as a potential dosage form for the treatment of hypertension10.
  • Jaiswal D et al., reported formulation and evaluation of oil entrapped floating alginate beads of RantidineHCl with the objective to develop a multi-unit gastro retentive sustained release dosage form of Ranitidine hydrochloride, from a completely aqueous
environment avoiding the use of organic solvent, which could cure peptic ulcer more efficiently by releasing the drug especially in stomach andalso for a prolonged duration of time. It was found that proper combination of alginate and pectin could provide sustain release of drug at gastric PH rather than sodium alginate alone11.
  • Karture AV et al., developed uv-spectrophotometric methodfor the estimation of atenolol and amlodipine besylate in tablets. The standard stock solutions of atenolol and amlodipine besylate as well as mixed standard solution were diluted appropriately. The absorption spectra of the resultant solutions of atenolol and mixed standard solution were obtained by scanning between 264 to 308 nm against solvent blank. The proposed analytic method was found to be accurate, precise and reproducible12.
  • Pawar DV et al., worked on formulation and evaluation of controlled release matrix tablet with solid dispersion. The study was aimed to develop once daily controlled release matrix tablet ofaceclofenac by applying solid dispersion technique for improving solubility. Thematrix tablets of aceclofenac solid dispersion granules were prepared by directcompression method using selected hydrophilic polymers like hydroxylmethyl cellulose (HPMC) and Carbopol 934(CP). From this study, it was clear that solid dispersion granules was one of the promising controlled release system applying solid dispersion technique for the poorly water soluble drug13.
  • Piyakulawat P. et al., prepared and evaluated chitosan (CS) and carrageenan (CR) for the controlled release of sodium diclofenac in the simulated gastrointestinal condition. They investigated various factors potentially influencing the drug release (ie, CS/CR proportion, DFNa content, types and amount of cross-linking agents). The optimal formulation was having CS/CR proportion of 2/1 and 5%(wt/vol) DFNa. This formulation was superior to other formulations for the controlled release of the drug and was able to maintain the release for almost 8 hours. The beads having cross-linking with glutaric acid and glutaraldehyde, were found to be more efficient for prolonged drug release than their non-cross-linking beads. The bead cross-linked with glutaraldehyde was able to control the release of the drug over 24 hours. The difference in the drug release behaviour can be due the differences in ionic interaction between the oppositely charged ions and to the concentrations of the drug within the beads, which depends on the compositions of the formulation and the pH of the dissolution medium. The release of drug was controlled by the mechanism of the dissolution of DFNa in the dissolution medium and the diffusion of DFNa through the hydrogel beads14.
  • Jain Set al, worked on sustained release tablets of furosemidefabricated using pectin, guar gum and xanthan gum.In-vitro release of drug was performed in phosphate buffer solution pH 7.2 for fifteen hours. All the physical characters of the fabricated tablet were within acceptable limits. The tablet with guar gum had greater swelling index and drug release than those with pectin and xanthan gum. From the dissolution profile of furosemide from matrix tablets prepared using different natural polymers, it was clear that drug release was retarded approx 15 hrs. The sustained release of used gums was found to be in order: guar gum> xanthan gum> pecin15.
  • Mohammed GAet al., researched on a new oral drug delivery system developed utilizing both the concepts ofcontrolled release and muco-adhesiveness, in order to obtain a unique drug delivery systemwhich would remain in stomach and control the drug release for longer period of time.Gastro-retentive beads of captopril were prepared by orifice ionicgelation method in 1:1 and 9:1 ratio of alginate along with mucoadhesive polymers viz;hydroxypropyl methyl cellulose, carbopol 934P, chitosan and cellulose acetate phthalate. The prepared beads were evaluated for various parameters like the percentage drug content, Photomicrographs, microencapsulation efficiency (89.7 percent), muco-adhesion. The in vitro release studies werecarried out in 0.1N hydrochloric acid and the release were found to be more sustained withAlginate-chitosan beads (9:1) than Alginate-Carbopol 934P (1:1) beads. The alginate-cellulose acetate phthalate beads exhibited the better sustained release as compared to all other alginatepolymercombinations. The drug release followed zero order kinetics in 0.1 N HCl (pH 1.2)16.
OBJECTIVE OF THE STUDY:-
The main objective of the present study was to formulate and evaluate solid dispersion and sustained release beads of Atenolol for antihypertensive therapy in a single dosage form (capsule).
The Plan of work is:
  1. Identification and confirmation of purity of drug by UV/HPLC.
  2. To carry out drug and polymer compatibility study by FTIR and DSC Studies.
  3. To carry out Preformulation studies.
  4. To carry out solubility studies for solid dispersion and beads.
  5. To carry out Entrapment efficiency of the beads.
  6. To formulate the sustain release and immediate release by solid dispersion of atenolol in single dosage form (capsule) and its release profile by in vitro study.
  7. To establish the reaction kinetics of the formulation.
  8. Stability study as per ICH guide line
MATERIALS AND METHODS:
SOURCE OF DATA:-
1)Review of literature from:
  1. Journals such as
  2. Pakistan Journal of Pharmaceutical Sciences
  3. International journal of Pharmacy and Technology
  4. International Journal of Research in Ayurveda and Pharmacy
  5. Journal of Excipients and Food chemicals
  6. Journal of Pharmaceutical and Biomedical Analysis
  7. International Journal of Pharmacy and Pharmaceutical Sciences
  8. International Journal of Pharmacy and Biological Sciences
  9. Indian Journal of Pharmaceutical Sciences
  10. Indian Journal of Novel Drug Delivery
  11. Journal of Current Pharmaceutical Research
  12. Research Journal of Pharmacy and Technology
  13. World Wide Web
  14. J-Gate@Helinet
materials and MethodS:
  1. To carry out preformulation studies
a)Drug-polymer interaction studies using FTIR and DSC.
b)Micrometric properties:
  • Angle of repose
  • Bulk density
  1. Preparation of sustained release beads.
  2. Preparation of solid dispersion by melting method.
  3. Characterization of sustained released beads and solid dispersion
a) Physicochemical properties:
  • General appearance
  • Particle size
  • Weight variation
  • Content uniformity
  • Solubility study
  • Entrapment efficiency(for Beads)
  • Swelling index(for Beads)
b) In-vitro dissolution studies
5.Evaluation of capsules for following parameters
a. In-vitro dissolution and release profile
b. weight variation test.
c. Disintegration test and assay
6. To carry out stability studies on the most satisfactory formulation as per ICH guidelines.
DOES THE STUDY REQUIRESANY INVESTIGATION OR INVESTIGATIONS TO BE CONDUCTED ON PATIENT OR OTHER HUMANS OR ANIMALS?
“NO”
HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION IN CASE OF 7.3?
“NOT APPLICABLE”
REFERENCES:
  1. Dhirendra K, Lewis S, Udupa N AND Atin K. solid dispersions: a review. Pak J PharmSci 2009;22(2):234-46.
  1. Sustained release dosage form. [online], [cited 2012 June 15]; [1 screen], Available from URL: release_dosage_form
  1. Gandhi TP, Goyal RK. Elements of human anatomy physiology and health education. 7th ed. Ahmedabad:B S Shah prakashan:1997-98.
  1. Tripati KD. Essentials of medical pharmacology.6thed. New Delhi:Jaypee Brothers medical publishers;2008.
  1. Natta kaewnoppratet al., Increased solubility, dissolution and physicochemical studies of curcumin-polyvinyl pyrrolidone K-30 solid dispersion. World academy Sci, Eng Tech. 2009;55(1):229-34.
  1. Khirwadkar P, Dashora K, Venkateswarlu BS. Formulation and evaluation of Mouth dissolving tablets of atenolol. Int JPharm Tech 2011;3(1):1876-88.
  1. Deshmukh KR, Patel V,VermaS,Panday AK,Dewangan P.A review on mouth dissolving tablet technique.Int J Pharm Res AyurPharm 2011;2(1):66-74.
  1. Bharte SS, Bharte SB and Bajaj AN. Interactions and incompatibities of Pharmaceutical excipients with active pharmaceutical ingredients: a comprehensive review. J Excipients Food Chem2010;1(3):3-26.
  1. Ostwald PP,Salunkhe PS, Jain MS, Jain SP. Development and evaluation for tablet in capsule of Nefidipne and Atenolol.Int J Pharmacy Bio Sci. 2011;1(4):468-73.
  1. Jia J, Dong C,Zhang W, Cui Y,Liu J. Evaluation of pharmacokinetics and pharmacodyanmics relationship for oral sustained-release atenolol pellets in rats.J Pharma Biomed 2011;55(2):342-8.
  1. Jaiswal D. et al.Formulation and evaluation of oil intrapped floating alginate beads of Rantidine Hydrochloride.Int J PharmPharmaceusci 2009;1(1):128-40.
  1. Karture A V, Ramteke Madhuri. Simultaneous UV spectrophotometric method for the estimation of atenolol and amlodipine besylate in combined dosage form.Ind J Pharmsci 2006;68(3):394-6.
  1. Pawar D V,MdSwarafaranet al. Solid dispersion technique the poorly water soluble drug.Ind J Novel drug Del 2010;2(3):109-13.
  1. Piyakulawat P, Praphairaksit N, Chantarasiri N, Muangsin N. Preparation and evaluation of chitosan/carrageenan beads for controlled release of Sodium diclofenac. AAPS PharmaSci Tech 2007;8(4)
  1. Jain S, Yadav SK,Patil UK. Preparation and evaluation of sustained release matrix tablets of furosemide using natural polymers. Res J Pharm Tech 2008;1(4):374-6.
  1. Mohammed GA, Satish K BP, Kiran K GB. Formulation and evaluation of gastric mucoadhesive drug delivery systems of captopril. J Cur Pharm Res 2010;2(1):26-32.

9 / Signature of the candidate:
10 / Remarks of the Guide: / The topic selected for dissertation is satisfactory. Adequate equipments and chemicals are available to carry out the project work.
11 / Name and Designation of:
11.1 / Institutional Guide: / Dr. Divakar Goli.M Pharm. Ph.D
Professor and Principal
11.2 / Signature:
11.3 / Co-Guide:
11.4 / Signature:
11.5 / Head of the Department: /
Dr. SHIVANAND KALYANAPPA
M.Pharm,Ph.D
Professor and H.O.D
Dept. of Pharmaceutics
Acharya & B.M. Reddy College of Pharmacy,
Bangalore-560 090.
11.6 / Signature
12 / 12.1 / Remarks of the Principal
12.2 / Signature /
Dr. Divakar GoliM.Pharm, Ph.D
Principal
Acharya & B.M.Reddy College of Pharmacy,
Bangalore.

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