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Available on line at : International Journal of Pharmaceutical and Phytopharmacological Research
ISSN (Online) 2249 – 6084
ISSN (Print) 2250 – 1029
Int.J.Pharm.Phytopharmacol.Res. 2013, 2(4): 259-262 (Research Article)
Design and Evaluation of Chronopharmaceutical Drug Delivery System for Asthma Using Natural
Prashant S. Malpure*, Avinash B. Gangurde, Dr. P. Perumal, Dr. R. Sambathkumar
J. K. K. Nataraja College of Pharmacy, Komarapalayam, Dist-Namakkal (TN), India Received on: 05/02/2013 Accepted on: 20/02/2013
A new oral chronopharmaceutical drug delivery system for asthma was developed by using press-coating technology. Tablets
composed of an outer shell made up of different natural gums and their combination and core tablet containing Montelukast
sodium as a model drug. Press coated tablets with different weight ratio of Xanthan Gum (XG) and Locust Bean Gum (LBG); as
an outer coating shell and Starlac as filler binder in core tablet were examined for change in time lag and release pattern of
Montelukast sodium. Press coated tablets were evaluated for thickness, hardness, friability, weight variation and in vitro
dissolution test. The study showed different release pattern with changing the coating composition. The results also showed that
press coated tablets, comprising of a core tablet containing drug, an outer shell of different combinations of natural polymers,
showed acid resistance and time-released functions on in vitro dissolution study.

Key Words:
Chronopharmaceutical drug delivery system; Xanthan Gum (XG); Locust Bean Gum (LBG); Press-coated tablet,
TIMERxR technology.


biological requirement of a given disease therapy. Ideally, Chronobiology is the study of biological rhythms and their chronopharmaceutical drug delivery systems (ChrDDS) mechanisms. Biological rhythms are defined by a number of should embody time-controlled and site-specific drug characteristics1. The term ‘‘circadian’’ was coined by Franz delivery systems4. Advantages are safer, more effective and Halberg from the Latin circa, meaning about, and dies, reliable therapeutic effect taking into account advances in meaning day2. Oscillations of shorter duration are termed chronobiology and chronopharmacology, system biology ‘‘ultradian’’ (more than one cycle per 24 h). Oscillations and nanomedicine5,6. For example, it has recently been that are longer than 24 h are ‘‘infradian’’ (less than one demonstrated that it is possible to perform a continuous cycle per 24 h) rhythms. Ultradian, circadian, and infradian label-free detection of two cardiac biomarker proteins rhythms coexist at all levels of biologic organization1. (creatin kinase and myoglobin) using an array of Pharmaceutics is an area of biomedical and pharmaceutical microfabricated cantilevers functionalized with covalently sciences that deals with the design and evaluation of anchored anti-creatin kinase and anti-myoglobin antibodies pharmaceutical dosage forms (or drug delivery systems) to by antigen–antibody molecular recognition7. Clinical assure their safety, effectiveness, quality and reliability applications of such nanotechnological approach lie in the (Figure-1). Traditionally, drug delivery has meant getting a field of early and rapid diagnosis and even design of simple chemical absorbed predictably from the gut or from ChrDDS against acute myocardial infarction. Evidence the site of injection. A second-generation drug delivery goal suggests that an ideal ChrDDS should: (i) be non-toxic has been the perfection of continuous, constant rate (zero- within approved limits of use, (ii) have a real-time and order) delivery of bioactive agents. However, living specific triggering biomarker for a given disease state, (iii) organisms are not ‘‘zero-order’’ in their requirement or have a feed-back control system (e.g. self-regulated and response to drugs. They are predictable resonating dynamic adaptative capability to circadian rhythm and individual systems, which require different amounts of drug at patient to differentiate between awake–sleep status), (iv) be predictably different times within the circadian cycle in biocompatible and biodegradable, especially for parenteral order to maximize desired and minimize undesired drug administration, (v) be easy to manufacture at economic cost, and (vi) be easy to administer in to patients in order to chronopharmaceutics is a branch of pharmaceutics devoted enhance compliance to dosage regimen. To our knowledge to the design and evaluation of drug delivery systems that such ideal ChrDDS is not yet available on the market. The release a bioactive agent at a rhythm that ideally matches the majority of these features may be found at the interface of Prashant S. Malpure et al.Int.J.Pharm.Phytopharmacol.Res. 2013, 2(4): 259-262
chronobiology, chronopharmacology, system biology and minutes. The resulting powder mixtures were compressed into tablets (average tablet weight 75 mg) using a rotary
tablet machine equipped with 6 mm concave faced punch.
Sufficient pressure was applied to keep the hardness 5
kg/cm2. The core tablets were evaluated for tablet weight
variation, thickness and diameter, hardness and friability etc.
Preparation of press - coated tablets
The Press-Coated tablet was prepared according to the
method of Fukui E10. All the powder mixtures were
previously passed through the sieve No. 44 and 200 mg of
the powder mixture was used for the upper and lower shell.
The press coating of tablets was performed using a rotary
tablet machine. A half amount of the powder was filled into
the die to make a powder bed, on the center of which was
placed the core tablet manually. Then, the remaining half of
the coating material filled in the die, and the contents were
compressed under a sufficient compression force, using a
concave punch 10 mm in diameter to keep the hardness of coated tablet 10 kg/cm2. The total amount of upper and Figure-1: Key steps to be well-integrated for successful
lower shell was 200 mg constant for all formulations. In Vitro evaluation of timed-release press coated tablets TIMERxR TECHNOLOGY
The test was carried out in a USP dissolution apparatus The TIMERxR technology (hydrophilic system)8 combines (Type II Paddle; Model-DT 60, Veego, India) at 100 rpm primarily xanthan and locust bean gums mixed with and temperature 37 ± 0.50C. 1.2 pH phosphate buffer (1st fluid; simulated gastric fluid) was used as dissolution components works to form a strong, binding gel in the medium for first 2 hr and 6.8 pH phosphate buffer (2nd fluid; presence of water. Drug release is controlled by the rate of simulated intestinal fluid) was used as dissolution media up water penetration from the gastrointestinal tract into the to drug release. Aliquots of dissolution fluid were removed TIMERxR gum matrix, which expands to form a gel and at specified time intervals and analyzed for the amount of subsequently releases the active drug substance. This system Montelukast sodium released by a spectrophotometer (UV can precisely control the release of the active drug substance 1700, Shimadzu, Japan) at a wavelength of 283.6 nm. in a tablet by varying the proportion of the gums, together with the third component, the tablet coating and the tablet RESULTS AND DISCUSSION
manufacturing process. A chronotherapeutic version of this technology platform is being tested in clinical trial with a Effect of Ac-Di-Sol® and Crosspovidone Level on Drug
bioactive agent known as AD 121 against rheumatoid Release Profile from Core Tablets11,12
arthritis. Potential application of this technology is the The core compositions for one tablet are reported in Table
development of an oral, CR opioid analgesic oxymorphone9. 1. In order to perform different release patterns; depending
upon different release mechanism involved, effect of Ac-Di- MATERIALS AND METHODS
Sol® and Crosspovidone level on drug release profile from uncoated tablet (Formulations C1, C2, C3 and C4) were Materials
determined. The formulation containing highest amount of Ac-Di-Sol® (C1) showed fast disintegration and fast release Pharmaceuticals Ltd, Pune and used as a model drug. because of swellable disintegrant present in it. Ac-Di-Sol® is Starlac, Ac-Di-Sol®, Crosspovidone, Xanthan Gum (XG) one of the best super disintegrant having excellent and Locust Bean Gum (LBG) were supplied from Lucid disintegrating ability. It swells to a large when it come in Colloids; aerosil, magnesium stearate was supplied from S. contact with water to disintegrate tablets and has a fibrous D. Fine Chemicals Mumbai, India and Quinolline yellow nature that allows intra particulate as well as extra was supplied from Colorcon Asia Ltd. Goa, India. All other particulate wicking of water even at low concentration. chemicals and solvents were of analytical reagent grade. Formulation C2 shows delayed in drug release as compared to formulation C1 because of less amount of Ac-Di-Sol®. Methodology
The formulation C3 and C4 containing Crosspovidone and these are also shows same release pattern as that of The inner core tablet was prepared by direct compression formulation C1 and C2. The Crosspovidone is water method using rotary tablet machine (Karnawati Rimek insoluble tablet disintegrant used at 2-5% concentration in Minipress II) in order to perform different release pattern, tablet prepared by direct compression / wet and dry depending upon different release mechanism involved. The granulation methods. It rapidly exhibits high capillary powder mixture of Montelukast sodium, starlac®, Ac-Di- activity and pronounced hydration capacity with little Sol®, and qunolline Yellow were dry blended first for 20 tendency of crosspovidone strongly influence disintegration minutes followed by the addition of magnesium stearate and of tablets. Larger particles provide a faster disintegration aerosil®. The powder mixture was further blended for 10 than smaller particles. Crosspovidone can also be used as a solubility enhancer with the technique of co-evaporation. It Prashant S. Malpure et al.Int.J.Pharm.Phytopharmacol.Res. 2013, 2(4): 259-262
can be also used to enhance the solubility of poorly soluble Table-1: Composition of Core Tablets.
drugs. The drug is adsorbed on to crosspovidone in the presence of a suitable solvent and the solvent is then evaporated. This technique results in faster dissolution rate. Formulation
1, C2, C3 and C4 containing starlac® as a filler binder which is a co processed excipients consist of lactose and maize starch (85:15) produced by spray drying. As lactose is water soluble in nature and starch contains disintegrant property, upon contact with dissolution medium formulations containing Ac-Di-Sol® with Starlac® get easily erodes, rather than swelling of Ac-Di-Sol® in core tablet. The effect Ac-Di-Sol® level on drug release profile from Total Weight
uncoated tablet C1 and C2 and effect of crosspovidone level on drug release profile from uncoated tablet C3 and C4 are Table-2: Effect of gellable material (Xanthan Gum)
showed in Figure-2. All the formulation C1, C2, C3 and C4 combined with gellable material (Locust Bean Gum) in showed similar release pattern so only formulation C1 was Formulation
In Vitro Dissolution Profile of Drugs from Timed-
Coating Material
Release Press Coated Tablets
Effect of gellable material Xanthan Gum (XG) combined with gellable material Locust Bean Gum (LBG) in the outer 1 to F5 shows increase in lag time and decrease in Montelukast Sodium release rate with increase in weight ratio of Xanthan Gum/Locust Bean Gum. Formulation F1 to 5 contains Xanthan Gum/Locust Bean Gum weight ratio of 00:100, 25:75, 50:50, 75:25 and 100:00 respectively. The formulation F1 having outer layer of xanthan gum,
which showed the lag time upto 10 hrs, the initial increase in
drug release rate on increasing the concentration of xanthan
gum can be explained on the basis that a higher binder
concentration led to an increase in hardness of the tablet,
while the porosity and capillary pore sizes were reduced13.
This in turn reduced the wicking of water into the tablet and
consequently the swelling and drug release rates are slowed.
Xanthan gum is a polysaccharide consisting of a cellulose
backbone and Trisaccharide side chains containing
glucuronic acids that give this polymer a negative charge.
Although primarily used as a suspending agent, xanthan
gum has been reported to function as a matrix retardant in
solid dosage forms14-18. This in turn reduced the wicking of water into the tablet and consequently the swelling and drug Figure-2: Effect of Ac-Di-Sol® level on Drug Release
release rates are slowed. These tablets showed a considerable swelling at a pH of 6.8 and the drug was dispersed in the swollen matrix formed by the
The formulation F5 having outer layer of locust bean gum,
which showed the lag time upto 4 hrs, Locust bean
galactomannan were found to be soluble in water. Cross-
linked galactomannan however led to water-insoluble film
microflora19. However, dissolution study performed on theophylline tablets coated with cross-linked galactomannan showed the mechanical instability of these coatings in the dissolution media20 thereby suggesting the non suitability of such films as colon carriers. The lag time and drug release profile of Montelukast Sodium from dry-coated tablets using different weight ratio of Xanthan Gum: Locust Bean Gum mixture are given in Figure-3: Effect of gellable material (Xanthan Gum)
combined with gellable material (Locust Bean Gum) in the Prashant S. Malpure et al.Int.J.Pharm.Phytopharmacol.Res. 2013, 2(4): 259-262
15) Dhopeshwarkar, V., Zatz, J. L., “Evaluation of Smolensky M.H., D’Alonzo G.E., Biologic rhythms xanthan gum in the preparation of sustained release and medicine, Am. J. Med. 1988, 85: 34– 46. matrix tablets”, Drug Develop. Ind. Pharm. 1993, 19, M. Moore-Ede, C. Fuller, F. Sulzman, The Clocks That Time Us, Havard University Press, Boston, “Evaluation of xanthan gum as a hydrophilic matrix Hrushesky W.J., Tumor chronobiology, J. Control. for controlled release dosage form preparations”, Drug Develop. Ind. Pharm. 1993, 19, 1037-1046. Bussemer T., Otto I., Bodmeier R., Pulsatile drug- 17) El- Gazayerly, O. N., “Release of pentoxifylline from delivery systems, Crit. Rev. Ther. Drug. Carrier Syst. xanthan gum matrix”, Drug Develop. Ind. Pharm. Kitano H., Systems biology: a brief overview, 18) Mu, X., Tobyn, M. J., Staniforth, J. N., “Influence of physiological variables on the in vitro drug release Freitas R., Drexler K., Nanomedicine: Basic behavior of a polysaccharide matrix controlled Capabilities, Landes Bioscience, Georgetown, TX, release system”, Drug Develop. Ind. Pharm., 2003, Arntz Y., Seelig J.D., Lang H.P., Zhang J., Hunziker 19) Bauer, K.H., Kesselhut, J.F., Novel pharmaceutical P., Ramseyer J.P., Meyer E., Hegner M., Gerber C., excipients for colon targeting. S.T.P. Pharm. Sci. Label-free protein assay based on a nanomechanical cantilever array, Nanotechnology, 2003,14:86– 90. 20) Hirsch, S., Binder, V., Schehlmann, V., Kolter, K., Baichwal A., Staniforth J., Penwest Pharmaceuticals Bauer, K.H., Lauroyldextran and cross-linked galactomannan as coating materials for site-specific Oxymorphone-Endo/Penwest: EN 3202, EN 3203, drug delivery to the colon. Eur. J. Pharm. Biopharm. Drugs in R and D. 2003,4 (3) : 204– 206. 10) Fukui E, Uemura K, Kobayashi M (2000) “Studies on Applicability of Press-Coated Tablets using *Corresponding Author:
Hydroxypropylcellulose (HPC) in the Outer Shell for Timed-Release Preparations” J. Control. Release.68: Komarapalayam, Dist-Namakkal (TN) , India 11) Rowe R. C., Sheskey P. J., Weller P. J., Croscarmellose sodium Handbook of Pharmaceutical Excipients; 4th edition; Pharmaceutical press: 2000; 181-183. 12) Weller P. J., Sheskey P. J., Rowe R. C.; Handbook of Pharmaceutical Excipients; Fourth Edition; Pharmaceutical Press, London; 2003; 184-185. 13) Upadarshka, S. M., Katikaneni, P. R., Nuessle, N. O., “Chitosan as a tablet binder”, Drug. Dev. Ind. Pharm., 1992, 18: 1701-1708. 14) Rowe, R. C., Sheskey, P. J., Weller, P. J., “Xanthan Gum” Handbook of Pharmaceutical Excipients; 4th edition; Pharmaceutical press, 2000, 691-693.


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