“FORMULATION AND EVALUATION OF PULSATILE DRUG DELIVERY SYSTEM CONTAINING INDOMETHACIN USING NATURAL POLYMERS”
MASTER OF PHARMACY DISSERTATION PROTOCOL
SUBMITTED TO THE
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE.
BY
KAMAT AKSHAY RAMESH
M.PHARM – I
Under The Guidance of
Dr. A.R. SHABARAYA M. Pharm., Ph.D.
DEPARTMENT OF PHARMACEUTICS.
SRINIVAS COLLEGE OF PHARMACY, VALACHIL, MANGALORE – 574143
2011-2013
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1. / Name of the Candidate and Address: / MR. KAMAT AKSHAY RAMESH.1stYEAR M.PHARM, DEPT. OF
PHARMACEUTICS,
SRINIVAS COLLEGE OF PHARMACY,
VALACHIL, MANGALORE-574143.
2. / Name of the Institution: / SRINIVAS COLLEGE OF PHARMACY,
VALACHIL, FARANGIPETE POST, MANGALORE-574143.
3. / Course of Study and Subject: / MASTER OF PHARMACY
(PHARMACEUTICS)
4. / Date of Admission: / 09 MAY 2011
5. / Title of the Project:
FORMULATION AND EVALUATION OF PULSATILE DRUG DELIVERY SYSTEM CONTAINING INDOMETHACIN USING NATURAL POLYMERS.
6.
7.
8. / Brief Resume of the intended work:
6.1 Need of the study:
Oral controlled release drug delivery systems offer a number of advantages over the conventional immediate release delivery preparations. These systems are designed to deliver the drugs at a controlled and predetermined rate thus maintaining their therapeutically effective concentration in systemic circulation for prolonged periods. On the other hand, for certain therapies a pulsatile drug release pattern, where the drug is released after well-defined lag time, exhibits significant advantages. It is well documented that most of the body functions display circadian rhythms, e.g. heart rate, stroke volume, blood pressure, blood flow, body temperature and gastric-pH. Moreover, in a number of organs their functions vary with the time of the day. It is increasingly recognized that there are
rhythmic and temporal patterns in the manifestation of many disease states. The symptoms for a number of diseases, such as bronchial asthma, myocardial infraction, angina pectoris, hypertension, rheumatic diseases, etc. follow a circadian rhythm1.
Circadian rhythms are self-sustaining, endogenous oscillations that occur with a periodicity of about 24 hours2. Interestingly, the term circadian is derived from the Latin circa which means “about” and dies which can be defined as “a day”. Normally, circadian rhythms are synchronized according to internal biologic clocks related to the sleep-wake cycle. Our circadian rhythm is based on sleep-activity cycle and is influenced by our genetic makeup and thereby affects our body’s function throughout day and night (24-hours period). Circadian rhythm regulates many body functions in humans like metabolism, physiology, behavior, sleep pattern and hormone production3. As many conditions show circadian pattern, advantage could be taken by timing and adjusting the administration of drugs according to the circadian rhythm of the disease.
In a number of reports it is documented that there are day-night variations in blood pressure of the Hypertensive patient4, 5. Francesco Portaluppi and Ramón C. Hermida reported that all established determinants of cardiac arrhythmias like imbalanced autonomic tone, circulating levels of catecholamines, increased heart rate and blood pressure show circadian variations and underlie the genesis of the circadian pattern of cardiac arrhythmias6. Gwen S. Skloot reported a sharp increase in the incidence of asthamatic attacks during early morning hours7.
Based on these findings drug delivery and therapy should be modified to achieve an effective drug level at the required time. This can be achieved by adapting a pulsatile drug delivery system of a suitable drug. Consequently, the administration of a drug formulated in such a delivery system, i.e. taken at bedtime with a programmed start of drug release in early morning hours, could offer a more effective therapy than a typical controlled release drug delivery system, provided that the most appropriate drugs are administrated.
Oral pulsatile administration could be useful for the treatment of certain diseases, such as asthma, gastric ulcer, hypertension, ischemic heart disease, arthritis, etc. which exhibit circadian rhythms. A pulsatile release profile is characterized by a lag time followed by rapid and complete drug release. Most pulsatile systems are reservoir systems and usually covered with a barrier. This barrier can be dissolved, eroded or removed at a predetermined period of time after which the drug is dissolved and rapidly released.
Morning stiffness associated with pain at the time of awakening is a diagnostic criterion of the rheumatoid arthritis and these clinical circadian symptoms are supposed to be outcome of altered functioning of hypothalamic-pitutary-adrenocortical axis8. Chronopharmacotherapy for rheumatoid arthritis has been recommended to ensure that the highest blood levels of the drug coincide with peak pain and stiffness. A pulsatile drug delivery system that can be administered at night (bed time) but that release drug in early morning would be a promising chronopharmaceutic system.
Indomethacin is a low dose, sparingly soluble in aqueous media is one of the most widely used non-steroidal anti-inflammatory drug and is being used successfully for the treatment of rheumatoid arthritis and other joint pains; hence, was used as a model drug.
In the present study, attempt is made to formulate press-coated pulsatile release tablets to treat rheumatoid arthritis. The press-coated pulsatile release tablets to be formulated and to be investigated in present study will consist of rapid release core tablet which is to be press-coated with different compositions of suitable hydrophilic and hydrophobic natural polymers, to be prepared by dry blending-direct compression method and by wet granulation method. The purpose of study is to design the simple, single pulse technique and to investigate the effect of type and amount of hydrophilic and hydrophobic natural polymer mix together in outer coating on drug release.
6.2 – Review of literature:
· Arora S, Ali J, Ahuja A, Baboota S, Qureshi J3 have developed pulsatile drug delivery system as an approach for controlled drug delivery system. From the study it has been concluded that this system can provide increased therapeutic benefits to patients in chronic problems like ulcer, asthma, hypertension, arthritis, etc.
· Anils K, Anal9 have reviewed time controlled pulsatile delivery systems for bioactive compound. This review describes the recent patents related to preprogrammed delivery system such as, system with eroding soluble or rupturable barrier coating and system with the capsular structure. With these formulations less frequent drug administration is possible and lower plasma peak concentration can be obtained to avoid adverse effect and patient complaints correspondingly be improved.
· Patel HK, Nagle A, Murthy RSR10 have done characterization of calcium alginate beads of 5-fluorouracil for colon delivery. From the study it has been concluded that the results of the study clearly indicate that there is a great potential in designing site-specific delivery of 5-fluorouracil which may reduce side effects of the drug caused by it’s absorption from the upper part of the GI tract when given in conventional dosage from.
· Januguade B. U, Patel S. S, Patel S. V, Lade P. D11 have developed oral press-coated Montelukast Sodium tablets by using direct compression and wet granulation method to achieve the predetermined lag time. From the study it has been concluded that press-coated tablet coated by dry mixing and by wet granulation showed variation in the lag time. As compared to dry mix blend method, the wet granulation method gives less lag time.
· Patel Krunal M, Karna Nabin, Biswal Biswajit, Patel Janki12 have prepared and evaluated pulsatile drug delivery system containing Terbutaline Sulphate, they investigated oral colon specific pulsatile device to achieve time or site specific release of Turbutaline Sulphate, design consist of an insoluble gelatine capsule body, filled with ethyl cellulose microcapsules of Terbutaline Sulphate and sealed with a hydro gel plug. The microcapsules were prepared by varing the drug to polymer ratio and evaluated for drug content and in-vitro release profile. From the study it has been concluded that as the concentration of the ethyl cellulose was increased the % yield of the microcapsule was increased.
· Viral Shah, Manish Patel, Naresh Rajgor13 have developed a formula which is a multiple unit based pulsatile delivery of Salbutamol Sulphate which can offer a solution for exhibiting chronopharmacological behaviour of asthma, extensive first-pass metabolism and necessity of night-time dosing. Five batches of % cellulose acetate phthalate and % ethyl cellulose were prepared. From the study it has been concluded that batch containing 4% cellulose acetate phthalate and 2% ethyl cellulose showed maximum release of drug and was the accurate batch for nocturnal asthma according to pulsatile drug delivery system.
· Sadaphal K. P, Thakare V. M, Gandhi B. R, Tekade B. W14 have prepared and evaluated pulsatile drug delivery system for chronological disorder: Asthma. They developed the pulsatile drug delivery system to mimic the cicardian rhythm of the disease by releasing the drug with a predetermined lag time of 6 hours, the design consisted of a rapid release core tablet and a controlled release tableted coat. From the study it has been concluded that the lag time can be controlled by adjusting the percent weight gain as well as the superdisintegrant concentration.
· J. Kausalya, J. Lakshmi Eswari, S. Padma Priya, Kumaravel Rajan, V. Vaijayanthi, Anusha Rupenagunta, S. Senthilnathan et al15 have prepared and evaluated pulsatile drug delivery system of Flurbiprofen microspheres. They developed the pulsatile drug delivery system for site-specific release to the colon. The design consisted of drug-loaded cellulose acetate cores, which were prepared by solvent evaporation technique in an oily phase at different drug:polymers ratios (1:1, 2:1 and 3:1). These cores were successfully microencapsulated with Eudragit S-100 following the same technique at the core: coat ratio of 1:5. From the study it has been concluded that the cellulose acetate cores effectively controlled the drug release for a period of 12 hours in pH 7.4.
· N. Kanaka Durga Devi, B. Sai Mrudula, A. Prameela Rani16 have prepared and evaluated chronomodulated drug delivery system of Montelukast Sodium. They developed the pulsatile drug delivery system to overcome disadvantages of Montelukast Sodium such as first-pass metabolism and differences in absorption at different sites. The design consisted of core tablet formulations (F1-F9) containing primojel, Ac-di-sol and polyplasdone XL 10 as swelling polymers. And barrier layer formulations (X1-X2) consisted of Xanthan gum, ethyl cellulose T10, Tamarind seed polysaccharide. From the study it has been concluded that F8 formulation with 7.5% polyplasdone XL 10 as the best immediate release core tablet and X12 was found to show single pulse drug delivery with considerable drug release for 2 hours after maintaining the pre expected 5 ½ hours lag time.
· Swati C. Jagdale, Monali S. Sali, Ajay L. Barhate, Janardan N. Loharkar, Aniruddha R. Chabukswar17 have prepared and evaluated enteric press-coated tablet for colon-specific pulsatile delivery of Atenolol. They developed the pulsatile drug delivery system to achieve suitable lag time for the treatment of angina pectoris. The design consisted of rapidly disintegrating tablet of Atenolol which was press-coated with different ratios of polymers, Gaur gum and Eudragit L-100 and formulations F1-F6 were prepared. From the study it has been concluded that colon-specific release has been achieved from tablet of F4 formulation (50:50) which meet demand of chronotherapeautic drug delivery.
· Fukui Eiji, Katsuji Uemura, Masso Kobayashi18 have prepared press-coated tablets containing diltiazem hydrochloride. The press-coated tablets consisted of core tablet containing diltiazem hydrochloride and coated with hydroxypropylcellulose as the outer shell. Various types of press-coated tablets were prepared using a rotary tabletting machine and their diltiazem dissolution behaviour was evaluated by the JP paddle method. From the study it has been concluded that tablets with the timed-release function could be prepared, and that the lag times were prolonged as the viscosity of hydroxypropylcellulose and the amount of the outer shell were increased.
6.3 – Objectives of the study:
1. To formulate press-coated pulsatile release tablets of Indomethacin by dry blending-direct compression and by wet granulation method using different compositions of hydrophilic and hydrophobic natural polymers.
2. To evaluate the formulated press-coated pulsatile release tablets with respect to various physical parameters.
3. To evaluate the formulated press-coated pulsatile release tablets with respect to drug-excipients interaction studies.
4. The formulated press-coated pulsatile release tablets will be subjected to accelerated stability studies as per ICH guidelines.
Materials and Methods:
Materials:
1. Drug: Indomethacin.
2. Superdisintegrants: Plantago ovata Mucilage, Modified Agar, etc.
3. Polymers: Xanthan Gum, Karaya Gum, Damar Gum, Copal Gum, etc.
4. Excipients: Microcrystalline Cellulose (Avicel PH- 102), Starch, Polyvinylpyrrolidone K 90, Magnesium Stearate, etc.
Methods:
The press-coated pulsatile release tablets will be formulated by reservoir system with rupturable polymeric coating. The press-coated pulsatile release tablet consist of rapid release core tablet of Indomethacin, the rapid release core tablet contain natural superdisintegrant and than the rapid release core tablet is press-coated with different compositions of suitable hydrophilic and hydrophobic natural polymers.
7.1 Source of data:
Review of literature from
a) Journals such as
Ø International Journal of Drug Delivery
Ø Indian Journal of Pharmaceutical Sciences
Ø Scholars Research Library
Ø International Journal of Pharmaceutical Sciences Review and Research
Ø International Journal of Pharmacy and Pharmaceutical Sciences
Ø Journal of Pharmacy Research
Ø Current Research and Information on Pharmaceutical Sciences
Ø International Research Journal of Pharmacy
Ø International Journal of Current Pharmaceutical Research
Ø Indian Journal of Pharmaceutical Education and Research
Ø International Journal of Drug Discovery
Ø Journal of Chemical and Pharmaceutical Research
Ø International Journal of Pharmaceutical Technology and Research
Ø International Journal of Pharmaceutical World Research
b) Internet Browsing.
c) Laboratory based studies.
7.2 – Method of Collection of Data:
1. An Overview of Pulsatile Drug Delivery System.
2. Formulation of the Pulsatile dosage form.
3. Evaluation of the developed Pulsatile dosage form as, follows: