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Development and Evaluation of
Colon Targeted Multi-Particulate Drug Delivery
Systems (MPDDS) of Diclofenac Sodium by
Pulsincap Drug Delivery System
Literature Review
Submitted To
Department of Pharmacy,
Kathmandu University
Submitted By
Bibek Singh Mahat, Roll No.: 07
M. Pharm. (Industrial Pharmacy Group)
Kathmandu University
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TABLEOFCONTENTS
1. MultiparticulateDrugDeliverySystem(MPDDS) 3
1.1 Reasons for formulating a drug as a multiparticulate system 3
1.2 Drug safety vs. MPDDS 3
1.3 Multiparticulate Preparation Methods 4
1.4 Purpose of Designing MPDDS 4
1.5 Mechanism of Drugrelease from MPDDS 4
1.6 Novel Drug Delivery System based on MPDDS 5
2. ColonTargetedDrugDeliverySystems(CDDS) 12
2.1 Advantages of CDDS over Conventional Drug Delivery 12
2.2 Criteria for Selection of Drug for CDDS 14
2.3 Approaches used for Site Specific Drug Delivery to Colon 15
2.4 Approaches used for the evaluation of Drug Delivery to Colon 24
3. PulsatileTechnology(PDS) 25
3.1 Diseases targeted for pulsatile technology 26
3.2 Methodologies for PDDS 26
3.3 Time controlled Pulsatile release on Capsular system 27
3.4 Marketed Technologies 28
4. ChronobiologyandChronotherapyofArthriticDiseases 29
4.1 Rheumatoid Arthritis 29
4.2 Biological rhythms in experimental inflammation 31
4.3 Cortisol and melatonin regulated circadian cytokine production 32
4.4 Cortisol and melatonin effects on circadian rhythms in rheumatoid arthritis 33
4.5 Conclusions of circadian symptoms in patients with RA 36
5. HardGelatinCapsulesandCross LinkingTechnology 37
5.1 Gelatin and Hard Gelatin Capsules 37
5.2 Reaction between the Proteins and Formaldehyde 38
6. DesigningoftheDevice 42
7. MaterialsandMethod 45
8. WorkDescriptionandTimeSchedule 48
9. References 49
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1. Multiparticulate DrugDeliverySystem(MPDDS)
Pharmaceutical invention and research are increasingly focusing on delivery systems which
enhance desirable therapeutic objectives while minimizing side effects. Recent trends indicate
that multiparticulate drug delivery systems (MPDDS) are especially suitable for achievingcontrolled or delayed release oral formulations.
Multi-particulate drug delivery systems are mainly oral dosage forms consisting of a multiplicity
of small discrete units, each exhibiting some desired characteristics. In these systems, the dosage
of the drug substances is divided on a plurality of subunit, typically consisting of thousands of
spherical particles with diameter of 0.05-2.00mm. To deliver the recommended total dose, these
subunits are filled into a sachet or encapsulated or compressed into a tablet.1
1.1Reasons for formulating a drug as a multiparticulate system:- 1
a) To facilitate disintegration in the stomach,
b) To provide a convenient, fast disintegrating tablet that dissolves in water before swallowing
which can aid compliance in older patients and children.
c) Multiparticulate systems show better reproducible pharmacokinetic behavior than
conventional (monolithic) formulations.
d) After disintegration within a few minutes, the individual subunit particles pass rapidly
through the GI tract.
e) If these subunits have diameters of less than 2mm, they are able to leave the stomach
continuously, even if the pylorus is closed.
f) These results in lower intra and inter individual variability in plasma levels andbioavailability.
1.2Drug safety vs. MPDDS:- 1
Drug safety may also be increased by using multiparticulate dosage forms, particularly for
modified release systems. If the film coat of a single-unit (monolithic) enteric coated tablet is
damaged, the complete dose will be released into the stomach where it may cause pain or
ulceration or reduced efficacy, depending on the reason for choosing the protection of the enteric
coating. If there is damage to the film coating of a monolithic tablet with a sustained release
formulation, this can lead to dose dumping and result in dramatic side effects. Inmultiparticulate formulation, the release characteristics are incorporated into every single subunit
and any damage only affects the release behavior of the subunit involved, which represents a
small part of the total dose, reducing the likelihood of safety problems.
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1.3Multiparticulates Preparation Methods:-
Multiparticulates may be prepared by several methods. Different methods require different
processing conditions and produce multiparticulates of distinct qualities. Some of these methods
may be broadly classified as:- Pelletization, Granulation,Spray drying,Spray congealing, Drug
particles may be entrapped within the multiparticulates , Drug particles may be layered aroundthem. These multiparticulates may be modified in many ways to achieve the desired drug release
profile. One approach to the modification of drug release profile in multiparticulates is to coat
them.
1.4Purpose of Designing MPDDS:- 1
To develop a reliable formulation that has all the advantages of a single unit formulations and
also devoid of the danger of alteration in drug release profile and formulation behavior due to,
Unit to unit variation, Change in gastro luminal pH and Enzyme population.
Multiparticulate systems perform better in vivo than single unit system, as they spread out
through the length of the intestine cause less irritation, enjoy a slower transit through the colon
and give a more reproducible drug release. Incorporating an existing medicine into a novel drug
delivery system (NDDS) can significantly improve its performance in terms of efficacy, safety
and improved patient compliance. In the form of a Multiparticulate NDDS, an existing drug
molecule can get new life, thereby increasing its market value and competitiveness and even
extending patent life.
1.5Mechanism of Drug-release from MPDDS:-
The mechanism of drug release can occur in the following ways:
a) Diffusion: - On contact with aqueous fluids in the gastrointestinal tract (GIT), water diffuses
into the interior of the particle. Drug dissolution occurs and the drug solutions diffuse across
the release coat to the exterior.
b) Erosion: - Some coatings can be designed to erode gradually with time, thereby releasing
the drug contained within the particle.
c) Osmosis: - In allowing water to enter under the right circumstances, an osmotic pressure canbe built up within the interior of the particle. The drug is forced out of the particle into the
exterior through the coating.
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1.6 Novel Drug Delivery System based on MPDDS:-
a) Intestinal Protective Drug Absorption System (IPDAS)
Intestinal protective drug absorption system (IPDAS) is a multiparticulate tablet technology that
has been developed to enhance the gastric tolerability of potentially irritant or ulcerogenic drugssuch as the NSAIDs. It consists of high density controlled release beads that are compressed into
a tablet form. The beads may be manufactured by techniques such as extrusion-spheronization.
Controlled release mechanism can be achieved with the use of different polymer systems to coat
the resultant beads.
Once an IPDAS tablet is ingested, it rapidly disintegrates and disperses beads containing the
drug in the stomach which subsequently pass into the duodenum and along the gastrointestinal
tract in a controlled and gradual manner, independent of the feeding state.Release of active
ingredient from the multiparticulates occurs through a process of diffusion either through the
polymeric membrane and /or the micro matrix of the polymer/active.
Figure 1: IPDAS technology
Naprelan, which is marketed in the United States, employs IPDAS technology. This
innovative formulation of naproxen sodium is a unique controlled release formulation indicated
both for acute and chronic pain. The desired pharmacodynamic activity of a once-daily dosage
form of naproxen requires: rapidly available naproxen for a prompt onset of analgesic activity, as
well as a prolonged phase of absorption to provide 24-hour analgesic/anti-inflammatory activity.
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b) Spheroidal Oral Drug Absorption Systems (SODAS)
SODAS
(Spheroidal Oral Drug Absorption System) is Elan Drug Technologies
multiparticulate drug delivery system. It is a multiparticulate technology that enables the
production of customized dosage forms and responds directly to individual drug candidate needs.
This technology is based on the production of uniform spherical beads of 1-2 mm in diametercontaining drug plus excipients and coated with product specific controlled release polymers.
Benefits offered by the SODAS
technology include:
i. Controlled absorption with resultant reduction in peak to trough ratios
ii. Targeted release of the drug to specific areas within the gastrointestinal tract
iii. Absorption independent of the feeding state
iv. Suitability for use with one or more active drug candidate
v. Facility to produce combination dosage forms
vi. Sprinkle dosing by administrating the capsule contents with soft food
vii. Once or twice daily dose resembling multiple daily dose profiles
SODAS can provide a number of tailored drug release profiles, including:-
i. Immediate release of drug followed by sustained release to give rise to a fast onset of action,
which is maintained for 24 hours.
ii. Alternatively the opposite scenario can be achieved where drug release is delayed for a
number of hours.
iii. An additional option is pulsatile release, where a once daily dosage form can resemble
multiple daily doses by releasing drug in discrete bursts throughout the day.
Figure 2: SODAS technology
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Products marketed using the SODAS
Technology:-
i) Diltiazem Once and Twice Daily
Diltiazem has a short half and was originally administered three or four times daily. The twice
daily product was first launched in the US in 1986, followed by the once daily product in 1991.Elan Drug Technologies diltiazem is now marketed in many international markets including the
U.S., Europe and Asia.
ii) Verapamil Once Daily
Verapamil, a calcium channel blocker, indicated for the treatment of hypertension was originally
administered three times daily. Once daily formulation was unique in that it represented the first
verapamil controlled release formulation in which the extent or rate of absorption was not
affected by food intake. In addition, the capsule could be opened and the beads sprinkled on soft
food for those patients unable to swallow traditional dosage forms.This verapamil is now
marketed in many international markets including the U.S. and Europe.
c) Programmable Oral Drug Absorption System (PRODAS)
Programmable Oral Drug Absorption System (PRODAS
Technology) is a multiparticulate
technology, which is unique in that it combines the benefits of tableting technology within a
capsule. The PRODAS
delivery system is presented as a number of mini-tablets combined in a
hard gelatin capsule, to target the profile of a candidate drug. It is possible to incorporate
different mini-tablets, each one formulated individually and designed to release drug at different
sites so that higher dose loading is possible within the gastrointestinal tract.
Figure 3: PRODAS technology
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f) Stabilized Pellet Delivery System:-
The active drug is incorporated in multiparticulate dosage forms such as DIFFUCAPS or Eurand
MINITABS, which are then subsequently coated with pH dependent/independent polymeric
membranes that will deliver the drug to the desired site. These are then filled into hard gelatin
capsules. This technology is designed specifically for unstable drugs and incorporates a pelletcore of drug and protective polymer outer layer(s).
g) Pelletised tablet:-
Pelletised tablet (Peltab) system utilizes polymer-coated drug pellets or drug crystals, which
are compressed into tablets. In order to provide a controlled release, a water insoluble polymer is
used to coat discrete drug pellets or crystals, which then can resist the action of fluids in the GIT.
This technology incorporates a strong polymer coating enabling the coated pellets to be
compressed into tablets without significant breakage.
h) Multi-particle Drug Dispersing Shuttle:-
Multiparticle drug dispersing shuttle (Multipart) consists of a tablet carrier for the delivery of
controlled release beads or pellets through the GIT which preserves the integrity and release
properties of the beads. The distribution of the beads is triggered by the disintegration of the
tablet carrier in the stomach. Drug release from the beads is triggered by super disintegration of
the tablets. It can be pH-activated or pH-independent and can occur by disintegration or osmosis.
The beads can be formulated to produce first or zero order release.
i) Eurands Orbexa technology:-
Eurands Orbexa technology produces beads of a controlled size and density using granulation
spheronization, and extrusion techniques. These beads provide high drug concentrations and can
be coated with functional polymer membranes for additional release rate control. Orbexa beads
can be filled into capsules or single-dose sachets.
Figure 6: ORBEXA
technology
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2.ColonTargetedDrugDeliverySystems
Targeted drug delivery into the colon is highly desirable for local treatment of a variety of bowel
diseases such as ulcerative colitis, Crohns disease, amebiosis, colonic cancer, local treatment of
colonic pathologies, and systemic delivery of protein and peptide drugs. The colon specific drugdelivery system (CDDS) should be capable of protecting the drug en route to the colon i.e. drug
release and absorption should not occur in the stomach as well as the small intestine, and neitherthe bioactive agent should be degraded in either of the dissolution sites but only released and
absorbed once the system reaches the colon.2
The colon is believed to be a suitable absorption site for peptides and protein drugs for thefollowing reasons: -
2
a) Less diversity, and intensity of digestive enzymes,
b) Comparative proteolytic activity of colon mucosa is much less than that observed in the smallintestine, thus CDDS protects peptide drugs from hydrolysis, and enzymatic degradation induodenum and jejunum, and eventually releases the drug into ileum or colon which leads to
greater systemic bioavailability.
c) And finally, because the colon has a long residence time which is up to 5 days and is highlyresponsive to absorption enhancers.
Oral route is the most convenient and preferred route but other routes for CDDS may be used.Rectal administration offers the shortest route for targeting drugs to the colon. However,
reaching the proximal part of colon via rectal administration is difficult. Rectal administration
can also be uncomfortable for patients and compliance may be less than optimal.2
Because of the high water absorption capacity of the colon, the colonic contents are considerably
viscous and their mixing is not efficient, thus availability of most drugs to the absorptivemembrane is low. The human colon has over 400 distinct species of bacteria as resident flora, a
possible population of up to 1010 bacteria per gram of colonic contents. Among the reactions
carried out by these gut flora are azoreduction and enzymatic cleavage i.e. glycosides. These
metabolic processes may be responsible for the metabolism of many drugs and may also beapplied to colon-targeted delivery of peptide based macromolecules such as insulin by oral
administration.2
2.1Advantages of CDDS over Conventional Drug Delivery :- 2,3
Chronic colitis, namely ulcerative colitis, and Crohns disease are currently treated with
glucocorticoids, and other anti-inflammatory agents. Administration of glucocorticoids namely
dexamethasone and methyl prednisolone by oral and intravenous routes produce systemic sideeffects including adenosuppression, immunosuppression, cushinoid symptoms, and bone
resorption. Thus selective delivery of drugs to the colon could not only lower the required dose
but also reduce the systemic side effects caused by high doses.
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Figure 8: Comparison of conventional and Colon Targeted dosage forms
Target sites Disease conditions Drug and active agents
Topicalaction
Inflammatory Bowel Diseases,Irritable bowel disease and Crohns disease.
Chronic pancreatitis
Hydrocortisone, Budenoside,Prednisolone, Sulfaselazine,
Olsalazine, Mesalazine,Balsalazide.
Local action Pancreatactomy and cystic fibrosis,Colorectal cancer
To prevent gastric irritation
Digestive enzymesupplements
5-Flourouracil.
Systemicaction
To prevent first pass metabolismof orally ingested drugsOral delivery of peptidesOral delivery of vaccines
NSAIDSSteroidsInsulin
Typhoid
Table 1: Colon targeting diseases, drugs and sites
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2.2Criteria for Selection of Drug for CDDS4,5,6:-
The best Candidates for CDDS are drugs which show poor absorption from the stomach orintestine including peptides. Thedrugs used in the treatment of IBD, ulcerative colitis, diarrhea,
and colon cancer are ideal candidates for local colon delivery. Drug Carrier is another factor
which influences CDDS. The selection of carrier for particular drugs depends on thephysiochemical nature of the drug as well as the disease for which the system is to be used.Factors such as chemical nature, stability and partition coefficient of the drug and type of
absorption enhancer chosen influence the carrier selection. Moreover, the choice of drug carrier
depends on the functional groups of the drug molecule. For example, aniline or nitro groups on adrug may be used to link it to another benzene group through an azo bond.
Criteria Pharmacologicalclass
Non-peptide drugs Peptide drugs
Drugs used for local
effects in colonagainst GIT diseases
Anti-inflammatory
drugs
Oxyprenolol, Metoprolol,
Nifedipine
Amylin,
Antisenseoligonucleotide
Drugs poorly absorbedfrom upper GIT
Antihypertensive andantianginal drugs
Ibuprofen, Isosorbides,Theophylline
Cyclosporine,Desmopressin
Drugs for colon cancer Antineoplastic drugs Pseudoephedrine Epoetin,Glucagon
Drugs that degrade instomach and small
intestine
Peptides and proteins Bromophenaramine,5-Flourouracil, Doxorubicin
Gonadoreline,Insulin,
Interferons
Drugs that undergoextensive first pass
metabolism
Nitroglycerin andcorticosteroids
Bleomycin, Nicotine Protirelin,sermorelin,
Saloatonin
Drugs for targeting Antiarthritic andAntiasthamatic drugs
Prednisolone,hydrocortisone,
5-Amino-salicylic acid
Somatropin,Urotoilitin
Table 2: Criteria for selection of drugs for CDDS
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2.3Approaches used for Site Specific Drug Delivery to Colon (CDDS):-
a) Primary Approaches for CDDS:i) pH Sensitive Polymer Coated Drug Delivery to the Colon8:-
In the stomach, pH ranges between 1 and 2 during fasting but increases after eating. The pH isabout 6.5 in the proximal small intestine and about 7.5 in the distal small intestine. From the
ileum to the colon, pH declines significantly. It is about 6.4 in the cecum. However, pH values as
low as 5.7 have been measured in the ascending colon in healthy volunteers. The pH in thetransverse colon is 6.6 and 7.0 in the descending colon. Use of pH dependent polymers is based
on these differences in pH levels.
The polymers described as pH dependent in colon specific drug delivery are insoluble at low pH
levels but become increasingly soluble as pH rises. Although a pH dependent polymer can
protect a formulation in the stomach, and proximal small intestine, it may start to dissolve in the
lower small intestine, and the site-specificity of formulations can be poor. The decline in pHfrom the end of the small intestine to the colon can also result in problems, lengthy lag times at
the ileo-cecal junction or rapid transit through the ascending colon which can also result in poor
site-specificity of enteric-coated single-unit formulations.
ii) Delayed (Time Controlled Release System) Release Drug Delivery to Colon8:-
Time controlled release system (TCRS) such as sustained or delayed release dosage forms are
also very promising drug release systems. However, due to potentially large variations of gastric
emptying time of dosage forms in humans, in these approaches, colon arrival time of dosageforms cannot be accurately predicted, resulting in poor colonical availability. The dosage forms
may also be applicable as colon targeting dosage forms by prolonging the lag time of about 5 to6 h. However, the disadvantages of this system are:
a. Gastric emptying time varies markedly between subjects or in a manner dependent on typeand amount of food intake.
b. Gastrointestinal movement, especially peristalsis or contraction in the stomach would resultin change in gastrointestinal transit of the drug.
c. Accelerated transit through different regions of the colon has been observed in patients withthe IBD, the carcinoid syndrome and diarrhea, and the ulcerative colitis.
Therefore, time dependent systems are not ideal to deliver drugs to the colon specifically for the
treatment of colon related diseases. Appropriate integration of pH sensitive and time releasefunctions into a single dosage form may improve the site specificity of drug delivery to the
colon. Since the transit time of dosage forms in the small intestine is less variable i.e. about 31hr. The time-release function (or timer function) should work more efficiently in the small
intestine as compared the stomach. In the small intestine drug carrier will be delivered to the
target side, and drug release will begin at a predetermined time point after gastric emptying. On
the other hand, in the stomach, the drug release should be suppressed by a pH sensing function(acid resistance) in the dosage form, which would reduce variation in gastric residence time.
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Figure 9: Human GIT with lag time and pH change range
Enteric coated time-release press coated (ETP) tablets, are composed of three components, a
drug containing core tablet (rapid release function), the press coated swellable hydrophobicpolymer layer (Hydroxy propyl cellulose layer (HPC), time release function) and an enteric
coating layer (acid resistance function). The tablet does not release the drug in the stomach due
to the acid resistance of the outer enteric coating layer. After gastric emptying, the entericcoating layer rapidly dissolves and the intestinal fluid begins to slowly erode the press coatedpolymer (HPC) layer. When the erosion front reaches the core tablet, rapid drug release occurs
since the erosion process takes a long time as there is no drug release period (lag phase) after
gastric emptying. The duration of lag phase is controlled either by the weight or composition ofthe polymer (HPC) layer.
Figure 10: Design of enteric coated timed-release press coated tablet (ETP Tablet)
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iii) Microbially Triggered Drug Delivery to Colon8:-
The microflora of the colon is in the range of 1011 -1012 CFU/ mL, consisting mainly ofanaerobic bacteria, e.g. bacteroides, bifidobacteria, eubacteria, clostridia, enterococci,
enterobacteria and ruminococcus etc. This vast microflora fulfills its energy needs by fermenting
various types of substrates that have been left undigested in the small intestine, e.g. di- and tri-saccharides, polysaccharides etc. For this fermentation, the microflora produces a vast number ofenzymes like glucoronidase, xylosidase, arabinosidase, galactosidase, nitroreductase,
azareducatase, deaminase, and urea dehydroxylase. Because of the presence of the biodegradable
enzymes only in the colon, the use of biodegradable polymers for colon-specific drug deliveryseems to be a more site-specific approach as compared to other approaches. These polymers
shield the drug from the environments of stomach and small intestine, and are able to deliver the
drug to the colon. On reaching the colon, they undergo assimilation by micro-organism, ordegradation by enzyme or break down of the polymer back bone leading to a subsequent
reduction in their molecular weight and thereby loss of mechanical strength. They are then
unable to hold the drug entity any longer.
iv) Prodrug Approach for Drug Delivery to Colon8:-
Prodrug is a pharmacologically inactive derivative of a parent drug molecule that requiresspontaneous or enzymatic transformation in vivo to release the active drug. For colonic delivery,
the prodrug is designed to undergo minimal hydrolysis in the upper tracts of GIT, and undergo
enzymatic hydrolysis in the colon there by releasing the active drug moiety from the drug carrier.Metabolism of azo compounds by intestinal bacteria is one of the most extensively studied
bacterial metabolic processes.
A number of other linkages susceptible to bacterial hydrolysis especially in the colon have beenprepared where the drug is attached to hydrophobic moieties like amino acids, glucoronic acids,
glucose, glactose, cellulose etc.
Limitations of the prodrug approach are that, it is not a very versatile approach as its formulationdepends upon the functional group available on the drug moiety for chemical linkage.
Furthermore, prodrugs are new chemical entities, and need a lot of evaluation before being used
as carriers.
v) Azo-Polymeric Prodrugs8:-
Newer approaches are aimed at the use of polymers as drug carriers for drug delivery to the
colon. Both synthetic as well as naturally occurring polymers have been used for this purpose.
Sub synthetic polymers have been used to form polymeric prodrug with azo linkage between thepolymer and drug moiety. These have been evaluated for CDDS. Various azo polymers have also
been evaluated as coating materials over drug cores. These have been found to be similarlysusceptible to cleavage by the azo-reducatase in the large bowel. Coating of peptide capsules
with polymers cross linked with azo-aromatic group have been found to protect the drug from
digestion in the stomach and small intestine.
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vi) Polysaccharide Based Delivery Systems8:-
The use of naturally occurring polysaccharides is attracting a lot of attention for drug targetingthe colon since these polymers of monosaccharides are found in abundance, have wide
availability are inexpensive and are available in a verity of a structures with varied properties.
They can be easily modified chemically, biochemically, and are highly stable, safe, nontoxic,hydrophilic and gel forming and in addition, are biodegradable. These include naturallyoccurring polysaccharides obtained from plant (guar gum, inulin), animal (chitosan, chondrotin
sulphate), algal (alginates) or microbial (dextran) origin. The polysaccrides can be broken down
by the colonic microflora to simple saccharides.24 Therefore, they fall into the category ofgenerally regarded as safe (GRAS).
b) Newly Developed Approaches for CDDS
i) Pressure Controlled Drug-Delivery Systems8:-
As a result of peristalsis, higher pressures are encountered in the colon than in the small intestine.Takaya et al. developed pressure controlled colon-delivery capsules prepared using
ethylcellulose, which is insoluble in water. In such systems, drug release occurs following the
disintegration of a water-insoluble polymer capsule because of pressure in the lumen of thecolon. The thickness of the ethyl cellulose membrane is the most important factor for the
disintegration of the formulation. The system also appeared to depend on capsule size and
density. Because of re-absorption of water from the colon, the viscosity of luminal content ishigher in the colon than in the small intestine. It has therefore been concluded that drug
dissolution in the colon could present a problem in relation to colon-specific oral drug delivery
systems. In pressure controlled ethyl cellulose single unit capsules the drug is in a liquid. Lagtimes of three to five hours in relation to drug absorption were noted when pressure-controlled
capsules were administered to humans.
ii) Novel Colon Targeted Delivery System (CODESTM) 8:-
CODESTM is a unique CDDS technology that was designed to avoid the inherent problems
associated with pH or time dependent systems. CODESTM is a combined approach of pHdependent and microbially triggered CDDS. It has been developed by utilizing a unique
mechanism involving lactulose, which acts as a trigger for site specific drug release in the colon.
The system consists of a traditional tablet core containing lactulose, which is over coated withand acid soluble material, Eudragit E, and then subsequently overcoated with an enteric material,
Eudragit L.
The premise of the technology is that the enteric coating protects the tablet while it is located in
the stomach and then dissolves quickly following gastric emptying. The acid soluble materialcoating then protects the preparation as it passes through the alkaline pH of the small intestine.
Once the tablet arrives in the colon, the bacteria enzymetically degrade the polysaccharide
(lactulose) into organic acid. This lowers the pH surrounding the system sufficient to affect the
dissolution of the acid soluble coating and subsequent drug release.
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Figure 11: Schematics of the conceptual design of CODES
iii) Osmotic Controlled Drug Delivery (ORDS-CT) 8:-
The OROS-CT can be used to target the drug locally to the colon for the treatment of disease or
to achieve systemic absorption that is otherwise unattainable. The OROS-CT system can be a
single osmotic unit or may incorporate as many as 5-6 push-pull units, each 4 mm in diameter,encapsulated within a hard gelatin capsule. Each bilayer push pull unit contains an osmotic push
layer and a drug layer, both surrounded by a semipermeable membrane. An orifice is drilled
through the membrane next to the drug layer.
Figure 12: Cross-Section of the OROS-CT colon targeted drug delivery system
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Immediately after the OROS-CT is swallowed, the gelatin capsule containing the push-pull units
dissolves. Because of its drug-impermeable enteric coating, each push-pull unit is prevented
from absorbing water in the acidic aqueous environment of the stomach, and hence no drug isdelivered. As the unit enters the small intestine, the coating dissolves in this higher pH
environment (pH >7), water enters the unit, causing the osmotic push compartment to swell, and
concomitantly creates a flowable gel in the drug compartment.
Swelling of the osmotic push compartment forces drug gel out of the orifice at a rate precisely
controlled by the rate of water transport through the semipermeable membrane. For treating
ulcerative colitis, each push pull unit is designed with a 3-4 h post gastric delay to prevent drugdelivery in the small intestine. Drug release begins when the unit reaches the colon. OROS-CT
units can maintain a constant release rate for up to 24 hours in the colon or can deliver drug over
a period as short as four hours.
c) Systems with Capsular Structures
Several single unit pulsatile dosage forms with a capsular design have been developed. Mostconsist of an insoluble capsular body, which contains the drug, and a plug, which is removed
after a predetermined lag time because of swelling, erosion or dissolution.
Linkwitz et al. described the delivery of agents from osmotic systems based on an expandable
orifice technology. The system is in the form of a capsule from which the drug is delivered by
the capsules osmotic infusion of moisture from the body. The delivery orifice opensintermittently to achieve a pulsatile delivery effect. The orifice forms in the capsule wall, which
is constructed of an elastic material, preferably elastomer (e.g. styrene-butadiene copolymer),
which stretches under a pressure differential caused by the pressure rise inside the capsule as theosmotic infusion progresses.
9
The orifice is small enough that, when the elastic wall is relaxed, the flow rate of drug through
the orifice is substantially zero; however, when the elastic wall is stretched, because of thepressure differential across the wall exceeding a threshold, the orifice expands sufficiently to
allow the release of the drug at a physiologically required rate. This osmotically driven delivery
device can be used as an implant in the anal-rectal passageway, in the cervical canal, as anartificial gland, in the vagina, as a ruminal bolus and so on.
Niwa et al. prepared a novel capsule made from ethyl cellulose for the time-controlled release ofdrugs in the colon. Initially, the capsule was prepared using a gelatin capsule with ethyl
cellulose, followed by dissolution of the gelatin in water. The thickness of the ethyl cellulose
capsule body was varied and the effect of the wall thickness on the release of the drugs in thecapsules was investigated. The ethyl cellulose capsules contained a large number of
mechanically made micropores (400 m) at the bottom. A swellable layer, consisting of low-substituted hydroxypropyl cellulose (L-HPC), was also located in the bottom of the capsule
body. Above the swellable layer was the drug reservoir, which contained a mixture of the model
drug, fluorescein and a bulking agent, such as lactose or starch.9
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The capsule was then capped and sealed with a concentrated ethyl cellulose solution. After
administration of the drug containing capsule, water molecules penetrated the capsule through
the micropores in the bottom of the capsule body. Hydration and swelling of the L-HPC inducedan increase in the internal osmotic pressure, which resulted in the explosion of the capsule and
a burst-like drug release was observed. The lag time of the drug release could be altered by
altering the thickness of the capsule.
Figure 13: Capsular Drug Delivery Systems
The Pulsincap
system consists of a water-insoluble capsule body, which is filled with the drugformulation. The capsule is closed at the open end with a swellable hydrogel plug. The
dimensions and the position of the plug can control the lag time prior to drug release. In order to
ensure rapid release of the drug, effervescent agents or disintegrants can be included in the drugformulation, in particular with water-insoluble drugs.
9
Figure 14: The Pulsincap Systems
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This system is coated with an enteric layer, which dissolves upon reaching the higher pH region
of the small intestine. This system comprises insoluble capsules and plugs. The plugs consisteither of swellable materials, which are coated with insoluble but permeable polymers (e.g.
polymethacrylates), or of erodible substances, which are compressed (e.g. HPMC, polyvinyl
alcohol, polyethylene oxide) or prepared by congealing melted polymers (saturatedpolyglycolated glycerides or glyceryl monooleate). The erosion of the plug can also be controlledenzymatically; a pectin plug can be degraded by incorporating pectinolytic enzymes directly into
the plug.
Insoluble Body Enteric Outer Layer Drug Release
Soluble Cap Cap dissolves Plug Erosion
Figure 15: The working principle of Pulsincap Systems
Another group of researchers developed a Chronopharmaceutical capsule using an ethyl-
cellulose-coated gelatin capsule as the insoluble shell and high swelling L-HPC excipients,which was found to be a more reliable expulsion system than effervescent agents.
Pulsatile systems based on multiparticulates for oral administration are described by Percel.The delivery system can be a capsule or tablet composed of a large number of pellets consisting
of two or more particle populations. Each pellet has a core that contains the therapeutic drug and
a water-soluble osmotic agent (e.g. NaCl). A waterpermeable, water-insoluble polymer film
encloses each core. A hydrophobic water-insoluble agent that alters permeability (e.g. wax, fattyacid or salts of fatty acids) is incorporated into the polymer film. The rate at which water passes
from the film coating through to the core differs for each pellet population in the dosage form.
The osmotic agent dissolves in water, which causes the pellets to swell and thereby regulates therate of diffusion of the drug from the dosage form. The effect of each pellet releasing its drug
into the environment sequentially provides a series of pulsatile administrations of the drug from a
single dosage form. The coating thickness may also vary among pellet populations.
US Patent 20010046964 describes a capsule capable of delivering therapeutic agents into the
body in a time-controlled or position-controlled pulsatile release fashion; it is composed of amultitude of multicoated particulates (beads, pellets, granules etc.). Each of these beads, except
an immediate-release bead, has at least two coated membrane barriers. One is composed of a
mixture of a water-insoluble polymer and an enteric polymer. The composition and the thickness
of the polymeric membrane barriers determine the lag time and the duration of the drug releasefrom each of the bead populations.
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US Patent 6627223B2 describes a capsule having the capability of delivering therapeutic agents
into the body in a time-controlled or position-controlled pulsatile release fashion. The dosageform comprises a multitude of multicoated particulates. The time-controlled series of pulses
occurs several hours after oral administration, with or without immediate release. One of the
coating membranes is composed of an enteric polymer and the second membrane barrier iscomposed of a mixture of a water-insoluble polymer and an enteric polymer. The compositionand the thickness of the polymeric membranes determine the lag time and the duration of drug
release from each of the bead populations. In other preparations, an organic acid, such as fumaric
acid, citric acid, succinic acid, tartaric acid or malic acid, is included and a maleic-acid-containing membrane may be provided between the first and second membrane layers to provide
for the time-separated pulses. The acids in between the membranes may delay the dissolution of
the enteric polymer in the inner layer, thereby increasing the lag time as well as decreasing therate of release of the active ingredient from the coated microparticulates. The enteric coating
membrane is generally incorporated in the innermost layer to have the drugs released in the
lower intestine. One of the membrane layers is made of plasticized enteric polymer whereas the
other may be a mixture of a water-insoluble polymer and a plasticized water-soluble/dispersibleenteric polymer.
US Patent 7048945B2 provides a method for manufacturing a multiparticulate dosage formhaving a time-controlled series of pulses occurring several hours after oral administration, with
or without an immediate-release pulse upon oral administration. The dosage form consists of an
active core, a first membrane of an enteric polymer and a second membrane of a mixture ofwater-insoluble and enteric polymers.
US Patent 6531152B1 describes a delivery system for targeted delivery with burst release withinthe gastrointestinal tract. The delivery system contains a core and a coating. The core contains a
drug in combination with a career material. The career material has the property of swelling uponcontact with an aqueous medium. The core has the ability to absorb larger quantities of fluid and
disintegrates faster in that fluid. The career material comprises a water-insoluble polymer (e.g.calcium pectinate, calcium alginate etc.), which swells considerably but does not form a strong
gel, a disintegrant (e.g. crospovidone) and a hardness enhancer (e.g. microcrystalline cellulose).
This type of delivery system allows the controlled introduction of water from the surroundingmedium into the device. When an aqueous medium comes in contact with particulate matter, the
particulate matter swells. The particles eventually form channels from the outer part of the
device to the core containing the drug. The core imbibes fluid and then swells, breaks the coatingand disintegrates, and all or most of the drug is released with a burst effect.
A time-controlled explosion systemis described in
US Patent 4871549. In this system, a drug iscoated on to the seed along with the swelling agent, and the finished pellets are then coated with
water-insoluble materials. Drug release is time controlled by the breakage of the external water-insoluble membrane, which is caused by the explosive swelling effect of the swelling agent. The
coating thickness of the particles is increased to delay release of the drug. However, this system
has the drawback of failing to release the drug if the swelling agent fails to rupture the water-
insoluble coating. Further, it lacks the flexibility of enabling various delivery patterns becausethe thickness of the coating determines the release of the drug.
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2.4Approaches used for the evaluation of Drug Delivery to Colon (CDDS):-
For in vitro evaluation, not any standardized evaluation technique is available for evaluation ofCDDS because an ideal in vitro model should posses the in-vivo conditions of GIT such as pH,
volume, stirring, bacteria, enzymes, enzyme activity, and other components of food. Generally,
these conditions are influenced by the diet, physical stress, and these factors make it difficult todesign a standard in-vitro model. In vitro models used for CDDS are:
a) In vitro dissolution test 8Dissolution of controlled-release formulations used for colon-specific drug delivery are usuallycomplex, and the dissolution methods described in the USP cannot fully mimic in vivo
conditions such as those relating to pH, bacterial environment and mixing forces. Dissolution
tests relating to CDDS may be carried out using the conventional basket method. Paralleldissolution studies in different buffers may be undertaken to characterize the behavior of
formulations at different pH levels. Dissolution tests of a colon-specific formulation in various
media simulating pH conditions and times likely to be encountered at various locations in the
gastrointestinal tract have been studied.
The media chosen were, for example, pH 1.2 to simulate gastric fluid, pH 6.8 to simulate the
jejunal region of the small intestine, and pH 7.2 to simulate the ileum segment. Enteric-coatedcapsules for CDDS have been investigated in a gradient dissolution study in three buffers. The
capsules were tested for two hours at pH 1.2, then one hour at pH 6.8, and finally at pH 7.4.
b) In vitro enzymatic tests 8Incubate carrier drug system in fermenter containing suitable medium for bacteria (strectococcus
faccium and B. Ovatus). The amount of drug released at different time intervals are determined.Drug release study is done in buffer medium containing enzymes (ezypectinase, dextranase), or
rat or guinea pig or rabbit cecal contents. The amount of drug released in a particular time isdetermined, which is directly proportional to the rate of degradation of polymer carrier.
c) In vivo evaluation 8A number of animals such as dogs, guinea pigs, rats, and pigs are used to evaluate the delivery of
drug to colon because they resemble the anatomic and physiological conditions as well as themicroflora of human GIT. While choosing a model for testing a CDDS, relative model for the
colonic diseases should also be considered. Guinea pigs are commonly used for experimental
IBD model. The distribution of azoreductase and glucouronidase activity in the GIT of rat andrabbit is fairly comparable to that in the human.
d) Drug Delivery Index (DDI) and Clinical Evaluation of CDDS
8
DDI is a calculated pharmacokinetic parameter, following single or multiple dose of oral colonic
prodrugs. DDI is the relative ratio of RCE (Relative colonic tissue exposure to the drug) to RSC(Relative amount of drug in blood i.e. that is relative systemic exposal to the drug). High drug
DDI value indicates better colon drug delivery.
Absorption of drugs from the colon is monitored by colonoscopy and intubation. Currently,
gamma scintigraphy and high frequency capsules are the most preferred techniques employed toevaluate colon drug delivery systems.
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3.PulsatileTechnology:
The oral controlled-release system shows a typical pattern of drug release in which the drug
concentration is maintained in the therapeutic window for a prolonged period of time, therebyensuring sustained therapeutic action.
However, there are certain conditions for which such a release pattern is not suitable. These
conditions demand release of drug after a lag time. In other words, it is required that the drug
should not be released at all during the initial phase of dosage form administration. Such a
release pattern is known as pulsatile release.10
Recent studies have revealed that diseases have a predictable cyclic rhythm and that the timing
of medication regimens can improve the outcome of a desired effect. This condition demands
release of drug as a "pulse" after a time lag and such system has to be designed in a way that
complete and rapid drug release should follow the lag time. Such systems are known as pulsatile
drug delivery systems (PDDS), time-controlled systems, or sigmoidal release systems (Fig 16).10
Figure 16: Schematic representation of different drug delivery systems where
(a) = sigmoidal release after lag time, (b) = delayed release after lag time, (c) = sustained
release after lag time, (d) = extended release without lag time.
PDDS have been developed in close connection with emerging chronotherapeutic views. In this
respect, it is well established that the symptoms of many pathologies, as well as the
pharmacokinetic and pharmacodynamic profiles of most drugs, are subject to circadian variation
patterns.
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3.3Time controlled Pulsatile release on Capsular system:-
Different single-unit capsular PDDS have been developed. A general -design of such systems
consists of an insoluble capsule body housing a drug and a plug. The plug is removed after a
predetermined time lag due to swelling, erosion, or dissolution.10
The Pulsincap system is an example of such a system that is made up of a water-insoluble
capsule body filled with drug formulation. The body is closed at the open end with a swellable
hydrogel plug. Upon contact with dissolution medium or gastro-intestinal fluids, the plug swells,
pushing itself out of the capsule after a time lag. This is followed by a spontaneous release of the
drug (Fig 17).10
The time lag can be controlled by manipulating the dimension and the position of the plug. For
water insoluble drugs, a spontaneous release can be ensured by inclusion of effervescent agents
or disintegrants. The plug material consists of insoluble but permeable and swellable polymers
(e.g.:polymethacrylates), erodible compressed polymers (e.g: hydroxypropylmethyl cellulose,polyvinyl alcohol, polyethylene oxide), congealed melted polymers (e.g: saturated
polyglycolated glycerides, glycerylmonoole and enzymatically controlled erodible polymer
e.g:pectin).
These formulations are well tolerated in animals and healthy volunteers, and there have been no
reports of gastro-intestinal irritation. However, there was a potential problem of variable gastric
residence time, which was overcome by enteric coating the system to allow its dissolution only
in the higher pH region of small intestine.
Figure 17: Time controlled Pulsatile release on Capsular system
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3.4Marketed Technologies:-
CODAS (Chronotherapeutic Oral Drug Absorption System) is one of Elan Drug Technologies,
multiparticulate drug delivery systems. The CODAS technology is designed to allow a 4-5 h
delay for onset following administration of drug. This delay in release is introduced by the level
of release-a controlling polymer applied to the drug-loaded beads. Applying the CODAStechnology to Verapamil Hydrochloride, Verelan PM complimented the circadian pattern of
hypertension and helped to minimize the risk of early morning cardiovascular events.11
Penwest Pharmaceuticals and Co., USA, considered to be top runner in drug delivery
technologies with patented products such as TIMERx , Geminex and SyncroDose TM The
TIMERx oral drug delivery system achieves a variety of release profiles (First order, Zero order,
BurstCR, etc.) for a wide range of drugs, accommodating even the most difficult actives.
TIMERx enabled Penwest to meet the significant challenges of today's pharmaceutical
marketplace head-on with 32 US issued patents and 178 patents worldwide. Alza Corporationuses OROS (Osmotic Release Oral Systems) drug delivery platform with marketed products such
as Covera-HS and Procardia XL . Eurand Pharmaceuticals DIFFUCAPS technology is a
multiparticulate system that provides optimal release profiles for either single drugs or for a
combination of drugs.11
Table 3: The marketed technologies of Pulsatile delivery systems
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4.ChronobiologyandChronotherapyofArthriticDiseases
Chronobiology is the science concerned with the biological mechanism of the diseases according
to a time structure and chronopharmacology is the science concerned with the variations in the
pharmacological actions of various drugs over a period of time of the day, and based upon this,chronotherapeutics is the discipline concerned with the delivery of drugs according to inherentactivities of a disease over a certain period of time.
12
Circadian rhythms are self-sustaining, endogenous oscillations that occur with a periodicity ofabout 24 hours. Normally, circadian rhythms are synchronized according to internal biologic
clocks related to the sleep-wake cycle1. Most people sleep at night and rise in the morning. Innight-shift workers (who typically sleep during the day), most circadian rhythms are shifted to
match their sleep-wake cycle.12
The goal of chronotherapeutics is to match the timing of treatment with the intrinsic timing of
illness. Theoretically, optimum therapy is more likely to result when the right amount of drug isdelivered to the correct target organ at the most appropriate time. 14
Figure 18: Circadian Rhythms of Diseases (Peak Time of Event/Variable)13
Arthritic diseases such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and gout
exhibit profound circadian rhythms in the manifestation and intensity of symptoms.14
4.1Rheumatoid Arthritis
Rheumatoid arthritis is a chronic inflammatory autoimmune disorder. The cardinal signs of
rheumatoid arthritis are stiffness, swelling and pain of one or more joints of the body
characteristically most severe in the morning. Rheumatoid arthritis shows a marked circadian
variation in its symptoms.
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A group of British volunteers self-assessed the pain and stiffness of affected finger joints every 2
to 3 hours daily for several consecutive days. They also measured the circumference of the
arthritic joints to gauge the amount of their swelling, and they performed grip strength tests to
determine the effect of the arthritic condition on the hands. Ratings of the severity of joint pain
swelling and stiffness were about 3 times higher between 08:00 and 11:00 than at bedtime. In
contrast, hand strength was lower by as much as 30% in the morning than at night.15
Figure 19: Diagram of chronological biological processes in rheumatoid arthritis (RA)
compared with those in healthy controls.15
It is well known that some clinical signs and symptoms of rheumatoid arthritis (RA) vary within
a day and between days, and the morning stiffness seen in patients with RA has become one ofthe diagnostic criteria of the disease.
16
Figure 20: Clinical signs and symptoms in RA depend on the time of day16
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Clinical signs and symptoms of articular inflammation in patients with RA change consistentlyas a function of the hours of the day. Pain and joint stiffness are greater after waking up in the
morning than in the afternoon or evening. Among the clinical signs of joint inflammation inpatients with RA, the intensity of pain changes consistently as a function of the hours of the day.
Pain is greater after waking up in the morning than in the afternoon or evening. In patients with
RA circadian variations are also found in joint swelling and finger size and these symptoms arein phase with the circadian rhythm of pain. The RA rhythms differ in phase by about 12 hoursfrom the circadian changes of left and right hand grip strength. Greater grip strength is seen
when joint circumferences and the subjective ratings of stiffness and pain are least and vice
versa. Therefore, clinical signs and symptoms in RA show a rhythm that seems driven by a
biological clock.16
4.2Biological rhythms in experimental inflammation
Biological rhythms have been seen in different models of inflammation, and maximal
inflammation occurred during the activity period of the animals, that is, between midnight and
8.00 am. Biological rhythms with a periodicity longer than 24 hours have also been detected, anda circaseptan rhythm (almost seven days) of paw oedema, over a period of 30 days, was
observed, with peak of inflammation every 67 days.16
Furthermore, circannual variations have been identified in different models of inflammationshowing that maximal articular oedema was significantly larger in spring and lowest in winter.
A time dependent change of blood flow at the inflammatory site may also explain the circadian
variations in experimental oedema; some studies in rat models showed that the blood flow was
greater in the night and lower in the morning.16
The mechanisms of the time dependent variations of the inflammatory reaction are complex and
include several systems of mediators (that is, histamine, bradikinin, prostaglandin, and mainly,pro- and anti-inflammatory cytokine production). However, the circadian changes in themetabolism or secretion of endogenous corticosteroids are certainly implicated in the time
dependent changes seen during the inflammatory response. This assumption is supported by data
showing that adrenalectomy abolished the circadian variation in the rate of formation of
experimental oedema and that this was restored by hydrocortisone administration.16
More recently, melatonin (MLT), another circadian hormone that is the secretory product of the
pineal gland, has been found to be implicated in the time dependent inflammatory reaction, witheffects opposite to those of cortisol. In several species, pinealectomy or any other experimental
procedure that inhibits MLT synthesis and secretion induces a state of immunodepression, which
is counteracted by MLT replacement.
16
In general, MLT displays an immunoenhancing effect. MLT can activate T lymphocytes,
monocytes, NK cells, and even neutrophils, activates antibody dependent cellular cytotoxicity,and enhances antibody responses in vivo. In animal models, as well as in human and in vitro
experiments, MLT enhances inflammatory cytokine and nitric oxide production. In addition, the
in vitro effects exerted by glucocorticoids on the immune function seem modulated by MLT in
physiological to pharmacological concentrations.16
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4.3Cortisol and melatonin regulated circadian cytokine production
In adult primates, only visible light (400700 nm) is received by the retina. This photic energy is
then transduced and delivered to the visual cortex and, by an alternative pathway, to the
suprachiasmatic nucleus, the hypothalamic region that directs circadian rhythms. Visible light
exposure also modulates the pituitary and pineal glands, leading to neuroendocrine changes.MLT, norepinephrine, and acetylcholine decrease with light activation, whereas cortisol,
serotonin, -aminobutyric acid, and dopamine levels increase.16
Therefore, ocular light seems to be the predominant modulator and major determinant ofcircadian rhythm for many neurohormones, with cortisol and MLT showing an opposite response
to the light. The light conditions in the early morning have a strong impact on the morning
cortisol peak, whereas direct inhibitory effects of light on pineal activity may contribute tophasing of the onset and termination of MLT production in a strictly nocturnal pattern.
Melatonin counteracts the effects of cortisol. Recently, a diurnal rhythmicity in healthy humans
between cellular (Th1 type) or humoral (Th2 type) immune responses has been found and related
to immunomodulatory actions of cortisol and MLT.
16
Figure 21: A diurnal rhythmicity in healthy humans between cellular (Th1 type) or
humoral (Th2 type) immune responses has been found and related to the
immunomodulatory effects exerted by cortisol and melatonin, respectively.
In particular, the production of the interferon (IFN; type 1) and interleukin 10 (IL10; type 2)in human whole blood stimulated with lipopolysaccharide or tetanus, as well as the IFN/IL10
ratio, exhibited a significant diurnal rhythmicity. The IFN/IL10 ratio peaked during the earlymorning and correlated negatively with plasma cortisol and positively with plasma MLT; the
IFN/IL10 ratio decreased by >70% after the administration of oral cortisone acetate (25 mg).
Therefore, these findings support the concept that plasma cortisol and possibly MLT seem to
regulate diurnal variations of cytokine production.
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In normal subjects,
a) MLT peaks at about 3 am, whereas cortisol peaks at about 4 am.b) Interestingly, IL1, IL6, and soluble IL2 receptors peak at 14 am and are low throughout the
day.
c) MLT stimulates IL1 and IFN production by human monocytes, and serum IL2 increasesduring the night concomitantly with the rise in MLT;
d) MLT also seems to enhance IL2 immunomodulating effects.e) In addition, MLT increases the production of IL12 and nitric oxide by cultured human
synovial macrophages, enhances IL2, IL6, and IFN production by human circulating CD4+
lymphocytes, and up regulates the level of gene expression of tumour necrosis factor (TNF) and macrophage-colony stimulating factor.
f) On the contrary, cortisol was found to be negatively correlated with the IFN/IL10 ratio, andcortisone administration markedly reduced this ratio with a clear causal relationship.
g) Furthermore, similarly to IFN and IL1, TNF and IL12 also exhibit distinct diurnal rhythmsthat peak in the early morning, and these changes are inversely related to the rhythm of
plasma cortisol.h) In conclusion, because IFN and IL10 might be considered markers of cellular (type 1) andhumoral (type 2) immunity, respectively, these circadian studies suggest that there is a bias
towards cellular immunity during the night and early morning (peak of MLT) when the
IFN/IL10 ratio is high and, conversely, a relative bias towards humoral (type 2) immunityduring the rest of the day.
4.4Cortisol and melatonin effects on circadian rhythms in rheumatoid arthritis
The inflammatory cytokines (that is, IL6, IL1, TNF), as soluble products of the activatedimmune system, stimulate in the central nervous system, the production of corticotrophin
releasing hormone (CRH) in the hypothalamus: CRH release leads to pituitary production ofadrenocorticotrophic hormone (ACTH), followed by glucocorticoid secretion by the adrenal
cortex. These components constitute the hypothalamic-pituitary-adrenocortical axis (HPA).
Recently, intact ACTH secretion, but impaired cortisol response in patients with active RA has
been described and this observation was consistent with a relative adrenal glucocorticoidinsufficiency. HPA axis function is a normal response to the stress of inflammation and may be
mediated by central and peripheral actions of circulating cytokines.
Besides IL1 and TNF, IL6 seems to be a major factor mediating interactions between the
activated immune system and both the anterior pituitary cells (central) and the adrenal
(peripheral) steroidogenesis.16
However, recent studies in patients with RA have shown that the overall activity of the HPA axis
remains inappropriately normal (or low) and is apparently insufficient to inhibit ongoing
inflammation, at least in patients with early untreated arthritis. In particular, in the early morninghours, an earlier surge of plasma ACTH and cortisol was seen in patients with RA, who at the
same time had significantly increased IL6 levels and a pronounced circadian variation of plasma
levels in comparison with healthy subjects.16
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In addition, in the patients with RA, a positive temporal correlation was found between plasma
IL6 levels and ACTH/cortisol, with raised levels of IL6 before the increases of ACTH and
cortisol by one and two hours, respectively. In the same patients, a negative effect of cortisolupon IL6 was found, exerted with a delay of five hours, confirming that the HPA axis in RA is
apparently insufficient to inhibit ongoing inflammation.
Recent studies have evaluated MLT levels in patients with RA, together with an analysis of
circadian variations. Interestingly, MLT serum levels at 8 pm and 8 am were found to besignificantly higher in patients with RA than in controls (p60 years) than in the younger ones. Both in patients with RA
and healthy subjects, MLT levels progressively increased from 8 pm to the early hours of themorning, but reached a peak in patients with RA at 12 pm, at least two hours before those in
controls. Subsequently, in patients with RA, MLT concentrations reached a plateau, lasting 23
hours; this effect was not evident in the controls. After 2 am, MLT levels decreased similarlyboth in patients with RA and healthy subjects. The results of the study confirm the existence of a
nocturnal rhythm of MLT also in patients with RA. However, the peak appears earlier in the
night and lasts longer in the early morning than in healthy controls.
16
Figure 22: A lower than expected cortisol secretion as seen during testing in patients with
RA, should be clearly regarded as a relative adrenal insufficiency in the setting of a
sustained inflammatory process (that is, high IL6 serum levels).16
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As previously discussed, IFN and IL2, as well as IL1, IL6, IL12, and TNF production (Th1cytokines) reach peak levels during the night and in the early morning, when MLT serum levels
are highest and plasma cortisol levels are lowest.
Therefore, MLT may play a part in the induction of a more active inflammatory response during
the night, at least in patients with RA, because the disease is considered to be a Th1-cytokinedriven immune disease. At that time; the lower than expected levels of cortisol seen in patients
with RA; are less efficient in counteracting the effects of MLT. Recently, MLT has been found ata rather high concentration in the synovial fluids of patients with RA, and binding sites for MLT
have been detected in synovial macrophages.16
Figure 23: IFN, IL2, as well as IL1, IL6, IL12, and TNF production (Th1 cytokines)
reach a peak during the night and early morning, when MLT serum levels are highest and
plasma cortisol levels the lowest.16
Therefore, MLT may be implicated in a more active inflammatory response during the night, andthe clinical symptoms follow this rhythm in patients with RA.
16
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4.5Conclusions of circadian symptoms in patients with RA
An altered functioning of the HPA axis and of the pineal gland seems to be an important factor in
the perpetuation of clinical circadian symptoms in patients with RA. The clinical symptoms
show a circadian variation, with joint stiffness and pain being more prominent in the early
morning. Consistently, human pro-inflammatory cytokine production exhibits a diurnalrhythmicity, with peak levels during the night and early morning when plasma cortisol level is
lowest and MLT level is highest.
In particular, Th1 type cytokines that are mainly involved in RA, significantly increase, with anearlier peak in relation to altered peaking of both cortisol and MLT. An inappropriate low
secretion of cortisol is a typical feature of the inflammatory disease in patients with RA.
On the contrary, the nocturnal rhythm of MLT shows an earlier peak and longer peak duration inthe early morning in patients with RA than in normal subjects. Therefore, an imbalance between
anti-inflammatory effects exerted by cortisol and proinflammatory effects exerted by MLT
during the night seems evident in patients with RA and suggests that this imbalance may have acrucial pathogenic role in RA, and may also drive the circadian rhythm of the clinical symptoms
that is, morning stiffness and pain.
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5.HardGelatinCapsulesandCross LinkingTechnology
5.1Gelatin and Hard Gelatin Capsules
Gelatin is a generic term for a mixture of purified protein fractions obtained either by partial acidhydrolysis (type A gelatin) or by partial alkaline hydrolysis (type B gelatin) of animal collagen
obtained from cattle and pig bone, cattle skin (hide), pigskin, and fish skin. Gelatin may also be amixture of both types. The protein fractions consist almost entirely of amino acids joined
together by amide linkages to form linear polymers, varying in molecular weight from 20,000
200,000.18
Gelatin is an amphoteric material and will react with both acids and bases. It is also a protein and
thus exhibits chemical properties characteristic of such materials; for example, gelatin may be
hydrolyzed by most proteolytic systems to yield its amino acid components. Gelatin will alsoreact with aldehydes and aldehydic sugars, anionic and cationic polymers, electrolytes, metal
ions, plasticizers, preservatives, and surfactants. It is precipitated by alcohols, chloroform, ether,
mercury salts, and tannic acid. 18
Gelatin is widely used in a variety of pharmaceutical formulations, including its use as a
biodegradable matrix material in an implantable delivery system, although it is most frequentlyused to form either hard or soft gelatin capsules. Gelatin capsules are unit-dosage forms designed
mainly for oral administration. Soft capsules on the market also include those for rectal and
vaginal administration. Gelatin is soluble in warm water (>30C), and a gelatin capsule will
initially swell and finally dissolve in gastric fluid to release its contents rapidly.18
Hard capsules are manufactured in two pieces by dipping lubricated stainless steel mold pins into
a 4555C gelatin solution of defined viscosity, which depends on the size of the capsules andwhether cap or body are to be formed. The gelatin is taken up by the pins as a result of gelation,
and the resulting film thickness is governed by the viscosity of the solution. The capsule shells
are passed through a stream of cool air to aid setting of the gelatin, and afterwards they areslowly dried with large volumes of humidity controlled air heated to a few degrees above
ambient temperature and blown directly over the pins. The capsule halves are removed from
their pins trimmed and fitted together.18
Gelatin that is used to produce hard capsules may contain various coloring agents and
antimicrobial preservatives. Surfactants may be present in small quantities in the shells being a
residue of the pin lubricant. However, the use of preservatives is no longer encouraged in linewith current GMP principles. Capsule shells may be treated with formaldehyde to make them
insoluble in gastric fluid.18
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5.2Reaction between the Proteins and Formaldehyde
A study of the literature relating to the reaction between the proteins and formaldehyde suggeststhat some divergence of opinion exists.
a) Harris and Birch in 1930 showed that the titration of amino acids, with hydrochloric acid inthe presence of formaldehyde, is not affected, while the titration with sodium hydroxide is
markedly affected. Harris explained this phenomenon as the repression of acidic groups upon
acid titration and the repression of basic groups upon alkaline titration.19
b) Tomiyama believes the anionic form of the amino acid reacts with the formaldehyde. He alsoconsiders the protein-formaldehyde reaction in terms of the electronic theory. He pictures theformaldehyde as a dipolar molecule and since the amino or imino group of the anionic form
of the amino acid has unshared electrons, the two components react to give the
accompanying formula.
19
c) Levy and Silberman have shown mathematically from their studies that 2 molecules of
formaldehyde combine with 1 molecule of amino acid. Bergmann et al. have isolated atriformyl compound and further shown that the triformyl derivative changes to the
monoformyl upon addition of alkali. Reiner and Marton postulated the following reactionbetween protein and formaldehyde,
19
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d) The aldehyde being held to the amino group by secondary valence. Einhour showed that theacid amides fix formaldehyde and suggested the following reaction,
19
R-CONH2 + CH2O + R-CONH.CH2OH
e) Cherbuliez and Bergmann found that diketopiperazines react with formaldehyde, taking up 2molecules of the aldehyde.
19
f) Levy and Silberman have taken exception to the interpretations of Tomiyama, maintainingthat he made no distinction between amino and imino groups. Balson and Lawson have
suggested that the number of formaldehyde groups which can be introduced corresponds to
the number of hydrogen atoms attached to the nitrogen atom and have therefore proposed
Reactions 1, 2, and 3.19
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g) Stiasny has suggested that formaldehyde reacts with gelatin in possibly two ways, in one,with the basic groups, changing them to neutral ones, and in the other, with the imino groupsof the peptide linkage. He suggests that the first reaction proceeds through an intermediate
formation of a triformyl derivative which then changes to the monoformyl. In the secondreaction, Stiasny postulates a binding of the formaldehyde with the weakly basic iminogroups, forming methyol compounds,
19
h) Stiasny further suggests that the free amino groups of the gelatin react rapidly, while thepeptide groups only do so gradually. He believes that the action of the formaldehyde on the
basic groups is such that not only the acid and base fixation capacity is influenced but also
that of the fixation of tanning materials and dyes.19
i) It was suggested by Meyer and Kinzel that the tanning and hardening effect of formaldehydeon proteins might be ascribed to the formation of methylene cross-links. The work of
Custavson and Hadorn included experimental evidence and indicated that free amino groupswere essential for the cross-linking. Proteins containing appreciable amounts of amino and
also phenol or imidazole groups bound considerably more formaldehyde in a manner
irreversible by acid hydrolysis than did derivatives in which the amino groups had beenselectively acetylated.
20
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