FORMULATION AND EVALUATION OF COLON PULSATILE DRUG DELIVERY SYSTEM
Synopsis for M. Pharm Dissertation submitted to the
Rajiv Gandhi University of Health Sciences Bengaluru, Karnataka.
Submitted By
Mr. MAMIDI NITHIN KUMAR
1st year M.Pharm.
Under the guidance of
Dr. B. A. VISHWANATH M. Pharm, Ph.D.,
HOD, DEPT. OF PHARMACEUTICS.
ADITYA BENGALURU INSTITUTE OF PHARMACY EDUCATION & RESEARCH
BENGALURU-64.
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BENGALURU.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1. / NAME OF THE CANDIDATEAND ADDRESS / Mr. MAMIDI NITHIN KUMAR
PRESENT ADDRESS:
ADITYA BENGALURU INSTITUTE FOR PHARMACY EDUCATION & RESEARCH
#12, KOGILU MAIN ROAD,
YELAHANKA , BENGALURU-64
PERMANENT ADDRESS:
KRS PLAZA, H.NO. G2,
SIVALAYAM STREET, OLD TOWN,
KAVALI, NELLORE (D), A.P 524201
2. /
NAME OF THE INSTITUTION
/ ADITYA BENGALURU INSTITUTE OF PHARMACY EDUCATION & RESEARCH, #12, KOGILU MAIN ROAD, BENGALURU-64.3. /
COURSE OF STUDY AND SUBJECT
/ MASTER OF PHARMACY IN PHARMACEUTICS.4. / DATE OF ADMISSION OF COURSE / 23rd July 2011.
5. / TITLE OF TOPIC
FORMULATION AND EVALUATION OF COLON PULSATILE DRUG DELIVERY SYSTEM
6.0
6.1
6.3
7.0
7.1
7.2
7.3
7.4
8.0 / BRIEF RESUME OF THE INTENDED WORK
Need for the study
The colon is a site where both local and systemic delivery of drugs can take place. Local delivery allows topical treatment of inflammatory bowel disease. However, treatment can be made effective if the drugs can be targeted directly into the colon, thereby reducing the systemic side effects.1
The colon is having high water absorption capacity, the colonic contents are considerably viscous and their mixing is not efficient, thus availability of most drugs to the absorptive membrane is low. These metabolic processes may be responsible for the metabolism of many drugs and may also be applied to colon-targeted delivery of peptide based macromolecules such as insulin by oral administration.2
Specific targeting of drugs to the colon is recognized to have several therapeutic advantages. Drugs, which are destroyed by the stomach acid and / or metabolized by pancreatic enzymes, are slightly affected in the colon, and sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis. Treatment of colonic diseases such as ulcerative colitis, colorectal cancer and Corn’s disease is more effective with direct delivery of vermicides and colonic diagnostic agents require smaller doses. Recent studies have revealed that diseases have predictable cyclic rhythms and that the timing of medication regimens can improve outcome in selected chronic conditions .There are many conditions that demand pulsatile release like
a) Many body functions that follow circadian biorhythm. e.g: Secretion of hormones, acid secretion in stomach, gastric emptying, and gastrointestinal blood transfusion.
b) Chronopharmacotherapy of diseases which shows circadian rhythms in their pathophysiology like bronchial asthma, myocardial infarction, angina pectoris, rheumatic disease, ulcer, and hypertension.
c) Drugs that produce biological tolerance demand for a system that will prevent their continuous presence at the biophase as this tends to reduce their therapeutic effect.
d) The lag time is essential for the drugs that undergo degradation in gastric acidic medium (e.g. peptide drugs) and irritate the gastric mucosa or induce nausea and vomiting.
All of these conditions demand for a time controlled therapeutic scheme releasing the right amount of drug at the right time. This requirement is fulfilled by Pulsatile Drug Delivery Systems which is of two type: a) Single pulse (Rupturable dosage form) b) Multiple pulse (Drug containing in a core, covered by swelling layer and an outer insoluble, but semipermeable polymer coating membrane.
At present, one of the most attractive systemic applications of colonic release is potentially connected with the oral delivery of peptide, protein, oligonucleotide, and nucleic acid drugs, from which great therapeutic benefits are expected, especially after the relevant large scale production has become feasible thanks to recent advances in biotech research. Even though their oral bioavailability is constrained by major stability, solubility, and permeability issues, such drugs have been recognized as less susceptible to biodegradation in the large bowel than in upper gastrointestinal regions, particularly because of a lower abundance of brush-border and luminal digestive enzymes. In addition, their colonic absorption might be aided by lymphoid follicles that are possibly involved in the uptake of macromolecules and a higher responsiveness to permeation enhancers, which can reach elevated concentrations in the close proximity of the mucosa owing to a combination of reduced dilution and slower progression of the contents.
For colon targeting purposes, a vast array of formulation stratergies has been described in the literature. Basically, all of them rely on selected physiological parameters that show typical variation patterns throughout the gastrointestinal tract. This is the case of composition of the microflora, pH of physiological media, intraluminal pressure generated by peristaltic contractions and, finally, time lapses needed for transit of individual compartments within the alimentary canal.4
pH sensitive system
In these system drugs can be formulated as solid dosage forms such as tablets, capsules, pellets and coated with pH sensitive polymers as enteric coating. The pH dependent system exploits the generally expectable view that the pH of human GIT increases progressively from the stomach pH 1-2 which increases to 4 during digestion and it increases to 7-8 in distal caecum.
The pH-dependent systems exploit the generally accepted view that pH of the human GIT increases progressively from the stomach (pH 1-2 which increases to 4 during digestion), small intestine (pH 6-7) at the site of digestion and it increases to 7-8 in the distal ileum. The coating of pH-sensitive polymers to the tablets, capsules or pellets provide delayed release and protect the active drug from gastric fluid. The polymers used for colon targeting, however, should be able to withstand the lower pH values of the stomach and of the proximal part of the small intestine and also be able to disintegrate at the neutral of slightly alkaline pH of the terminal ileum and preferably at the ileocecal junction. Widely used polymers are methacrylic resins (Eudragits), which are available in watersoluble and water-insoluble forms. Eudragit L and S are copolymers of methacrylic acid and methyl methacrylate. Colon targeted drug delivery systems based on methacrylic resins has described for insulin, prednisolone, quinolones, salsalazine, cyclosporine, beclomethasone dipropionate and naproxane14. In fact, the pH in the distal small intestine is usually around 7.5, while the pH in the proximal colon is closer to 6.0. These delivery systems therefore have a tendency to release their drug load prior to reaching the colon.5
Pulsatile drug delivery system
A pulsatile drug release, where the drug is released rapidly after a well defined lag-time, could be advantageous for many drugs or therapies. Pulsatile release systems can be classified in multiple-pulse and single-pulse systems. A popular class of single-pulse systems is that of rupturable dosage forms. Other systems consist of a drug-containing core, covered by a swelling layer and an outer insoluble, but semi permeable polymer coating or membrane. The lag time prior to the rupture is mainly controlled by:
(i) The permeation and mechanical properties of the polymer coating and
(ii) The swelling behavior of the swelling layer.
As it is frequently found in the living body, many vital functions are regulated by pulsed or transient release of bioactive substances at a specific site and time. Thus it is important to develop new drug delivery systems to achieve pulsed delivery of a certain amount of drugs in order to mimic the function of the living systems, while minimizing undesired side effects. Special attention has been given to the thermally responsive poly (N isopropylacrylamide) and its derivative hydrogels. Therefore, Pulsatile drug delivery is one such systems that, by delivering drug at the right time, right place and in right amounts, holds good promises of benefit to the patients suffering from chronic problems like arthritis, asthma, hypertension etc.
Various techniques are available for the Pulsatile delivery like pH dependent systems, time dependent systems, micro-flora activated systems etc.which can be designed as per the physiology of disease and properties of the drug molecule. The focus of the present review is primarily on the Pulsatile drug delivery methodologies and the upcoming technologies, which are being exploited on an industrial scale.6
Methodologies for Pulsatile drug delivery
Methodologies for the Pulsatile drug delivery system can be broadly classified into three classes;
1. Time controlled
2. Stimuli induced
3. Externally regulated
Recent advances in the Pulsatile drug delivery:
Nowadays Pulsatile drug delivery systems are gaining importance in various disease conditions specifically in diabetes where dose is required at different time intervals. Among these systems, multi-particulate systems (e.g. pellets) offer various advantages over single unit which include no risk of dose dumping, two components one is of immediate release type and other one is pulsed release which releases the drug in response to change in pH. In case of pH dependent system advantage has been taken of the fact that there exists different pH environment at different parts of the gastrointestinal tract.7
6.2 Review of the literature
Nitin saigal et al., site specific chronotherapeutic drug delivery system. The main objective of this study was to study about first order release in which the drug is released at a substantially steady rate of release per unit time. The Pulsatile drug delivery system can be classified into site specific system in which the drug is released at the desired site within the intestinal tract or time controlled devices in which the drug is released after a well defined time period. The delayed liberation of orally administered drugs has been achieved through a range of formulation approaches, including single or multiple unit system provided with release controlling coatings capsular devices and osmotic pumps.8
Najmuddin M et al., development and evaluation of Pulsatile drug delivery system of Flurbiprofen. The main objective of this study was to formulate oral colon specific Pulsatile drug delivery system of Flurbiprofen.The basic design consists of an insoluble hard gelatin capsule body filled with eudragit microsphere of Flurbiprofen and sealed with hydrogel plug. Different hydrogel polymers were used as plugs guar gum, HPMC, sodium alginate maintains a suitable lag period. Colon specific release has been achieved from a capsule device over a 2-15 hr period, consistent with the demands of chronotherapeutic drug delivery.9
Swati C. jagdale et al., design and evaluation of enteric press coated tablets for Pulsatile delivery of Atenolol. The main aim of current study was to investigate the In-vitro performance of compressed coated tablet of Atenolol. A novel colon targeted tablet formulation was developed by press coating rapidly disintegrating tablet of Atenolol with guar gum and eudragit L-100 as barrier layer. Different ratios of polymers were selected to achieve suitable lag time for the treatment of Angina Pectoris. In-vitro release studies for prepared tablets were carried out for 2 hr in 0.1N HCL, 3 hr in pH 7.4 phosphate buffer and 6 hr in simulated colonic fluid.6
Krunal patel M et al., described insoluble hard gelatin capsule body filled with ethyl cellulose microcapsules of Terbutaline sulphate and sealed with a hydrogel plug. The entire device was enteric coated so the variability of gastric time can be overcome and a colon specific release can be achieved.10
Shailendra Wasnik et al., the design of colon specific drug delivery system and different approaches to treat colon disesase. In oral colon drug delivery system the colon has a large amount of lymphoma tissue, negligible brush boarder membrane activity. Colon specific drug has gained increased importance not just delivery of drug for treatment of local disease. Different approaches are designed based on prodrug formulation, pH sensitivity, time dependency, microbial degradation and osmotic pressure etc to formulate the different dosage form like tablets, capsules, multiparticulates, microspheres, liposomes for colon targeting.11
Objectives of the study
v To develop, characterize, and optimize the Pulsatile colon target drug delivery system.
v To study the physical parameters of the dosage form.
v To estimate the drug content in the formulation.
v To study the drug release pattern using suitable In - vitro method.
v To retard the release of drug over extended period of time.
v To develop the effective dosage form to avoid patient compliance, to decrease frequency of dosing for better utilization of drug.
v To decrease local and systemic toxic effects.
MATERIALS AND METHODS
Drug : Anti-inflammatory drug.
Polymers : Polyethylene glycol, Hydroxypropylmethylcellulose (HPMC) different
grades, Eudragit different grades, Polyvinylpyrrolidone (PVP), HPC,
cellulose acetate phthalate, ethyl cellulose, etc.
Ingredients : Lactose, microcrystalline cellulose, magnesium stearate, colorant, etc.
Solvent like ethanol, dichloromethane etc.
Method : The Pulsatile colon targeted delivery can be prepared by using pH sensitive system. Tablets will be prepared by direct compression method.
Source of data
· The data will be obtained from the literature survey and internet source.
· The data will be obtained from the experimental work, which includes formulation of self micro emulsion, evaluation and stability studies.
Method of Collection of Data
· Data on drug and excipients are collected from the drug information centre, patents, reference books, text books, catalogs etc.
· Data will be collected from the prepared formulations, in-vitro dissolution studies and stability studies. In- vitro dissolution studies will be used as criteria for assessing the enhancement of oral bioavailability of poorly aqueous soluble drug.
Does the study require any investigation or intervention to be conducted on patients or Other humans or animals? If so, please mention briefly.
-NOT APPLICABLE-
Has ethical clearance been obtained from your institution in case of 7.3?
-NOT APPLICABLE-
LIST OF REFERENCES
1. Anil k philip, Betty philip.Colon targeted drug delivery systems: A review on primary and novel approches.Oman med j 2010;25(2):70-78.
2. Vinay kumar k, siva kumar T, Tamizh mani T.Colon targeted drug delivery system: A review on recent approches.Int j pharm biomed sci 2011;2(1):11-9.
3. Chourasia MK, Jain SK.Pharmaceutical approaches to colon targeted drug delivery systems. J Pharm Pharmaceut Sci 2003;6(1):33-66.