CHALLENGES IN DEVELOPMENT OF COLON DRUG DELIVERY …

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Mittal et al. World Journal of Pharmacy and Pharmaceutical Sciences

CHALLENGES IN DEVELOPMENT OF COLON DRUG DELIVERY

SYSTEM WITH RESPECT TO DISSOLUTION STUDIES

Anchal Gaur1, Dr. Ashu Mittal*

2, Debaprasad Ghosh and Dr. Jagannath Sahoo

Department of Pharmaceutics, KIET School of Pharmacy, Ghaziabad.

ABSTRACT

Colon drug delivery has gained increased importance not only for the

treatment of local diseases associated with colon but also for its

potential for delivery of proteins and therapeutic peptides. Local

delivery allows topical treatment of inflammatory bowel disease,

Crohn‟s disease, Ulcerative colitis. However, treatment can be made

effective if drugs can be targeted directly into colon, thereby reducing

systemic side effects. New technologies have been developed for colon

targeting and to overcome the problem of previous methods. Oral

dosage forms are the most preferred delivery route for colonspecific

delivery due to their convenience. A broad range of in vitro systems is available, from static

monocompartmental to dynamic multicompartmental models. However, these models require

a compromise between technological complexity and biological significance. Further efforts

and technological innovations are still needed to improve in vitro models and meet growing

demands in the areas of health. This review highlights about the challenges in development of

colon drug delivery system with respect to dissolution studies. Oral delivery of drugs in the

colon is valuable in the treatment of diseases of colon where by high local concentration can

be achieved while minimizing side effects.

KEYWORDS: Colon targeted drug delivery, Dissolution, Colon products, Colon

technology.

INTRODUCTION

Colon targeted drug delivery has been the focus of numerous studies in recent years due to its

potential to improve treatment of local diseases affecting the colon, while minimizing

systemic side effects. Some examples of disease states which impact the colon include

Crohn‟s disease, Ulcerative colitis, Irritable Bowel Syndrome.[1,2]

The delivery of drugs to the

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.421

Volume 8, Issue 6, 1465-1491 Review Article ISSN 2278 – 4357

Article Received on

20 April 2019,

Revised on 10 May 2019,

Accepted on 31 May 2019,

DOI: 10.20959/wjpps20196-14051

*Corresponding Author

Dr. Ashu Mittal

Department of

Pharmaceutics, KIET School

of Pharmacy, Ghaziabad.


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colon via gastrointestinal tract requires protection of a drug from being released in stomach

and small intestine. Drugs, which are destroyed by stomach acid and metabolized by

pancreatic enzymes, are protected. Sustained release of drugs into colon can be useful in

treatment of certain diseases.

The colon is most suitable site for absorption of peptides and protein drugs for following

reasons:[3]

1. Less intensity of digestive enzymes.

2. Proteolytic activity of colon mucosa is less than that observed in small intestine, thus

colon targeted drug delivery system protect peptide and protein drugs from hydrolysis,

and enzymatic degradation in duodenum and jejunum, and releases drug into colon,

which leads to greater bioavailability.[4]

3. And finally, because colon has a long residence time which is up to 5 days and

responsible for enhancement of absorption.[5]

4. Oral route is most convenient and preferred route but other routes for CDDS may be used.

Rectal administration offers shortest route for targeting drugs to colon.[6]

5. The reactions carried out by this gut flora are azoreduction and enzymatic cleavage i.e.

glycosides.

1.1 ADVANTAGES

1. Colon is ideal site for delivery of agents to treat local diseases of colon.

2. Required small drug quantities due to locality targeting.

3. Reduces dosage frequency. Hence lower cost of expensive drugs.

4. Reduced incidence of side effects and drug interactions.

5. Colon is an attractive site where poorly absorbed drug molecules may have an improved

bioavailability.

6. Improve patient compliance.

7. Bypass first pass metabolism.

8. Reduce gastric irritation caused by many drugs like NSAIDS.

9. Flexibility in design.

10. Ulcerative colitis, and Crohn‟s disease are currently treated with glucocorticoids, and

other anti-inflammatory agents.

1.2 DISADVANTAGES

1. Multiple manufacturing steps.


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2. Incomplete release rate.

3. Bioavailability of drug is low.

4. Resident microflora could also affect colonic performance via metabolic degradation of

drug.

5. Dose loading is low.

6. Excipients are required in higher quantity.

7. Large no. of process variables.

8. Need of advanced technology.

9. Skilled personal needed for manufacturing of colonic drug delivery system.[7,8]

1.3 ANATOMY AND PHYSIOLOGY OF COLON

The digestive system is the collective name used to describe the alimentary canal, its

accessory organs and a variety of digestive process. The alimentary canal begins at the

mouth, passes through thorax, abdomen and pelvis and ends at the anus. The large intestine

extends from the distal end of the ileum to anus. Human large intestine is about 1.5 m long.

The colon is a cylindrical tube which is linked by moist, soft pink lining called mucosa. The

colon has four parts which are same structure and function.

a) Ascending colon: It is nearly 12.5 cm, in length. It extends from caecum to hepatic

flexure.

b) Transverse colon: The ascending colon further continues as the transverse colon, form

hepatic flexure to splenic future.

c) Descending colon: The transverse colon descends down to form descending colon.

d) Sigmoid colon: The descending colon continue as an S-shaped sigmoid colon,

terminating at rectum.

The physiology of the proximal and distal colon differs in severalrespects that have an effect

of drug absorption at each site. The physical properties of the luminal content of the colon

also change, from liquid in the caecum to semisolid in the distal colon.[9]


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Figure 1: Anatomy of Colon.

1.4 FUNCTIONS OF COLON

Create suitable environment for colonic microorganisms.

Storage reservoir of fecal matter.

Expulsion of the contents of the colon.

Absorption of potassium and water from the lumen.[10]

Table 1: Length of different parts in colon.

Sr.No. Large Intestine Length (cm)

1. Cecum 6-9

2. Ascending colon 20-25

3. Descending colon 10-15

4. Transverse colon 40-45

5. Sigmoid colon 35-40

6. Rectum 12

7. Anal Canal 3

2) COLON PRODUCTS IN MARKET

MARKETED pH DEPENDENT SYSTEMS

DRUG USED

DISEASE POLYMER USED

DOSAGE

FORM DISEASE

Tegaserod

maleate

Eudragit L 100, Eudragit

S 100 Tablet

IrritableBowel

Syndrome.[11]

Prednisolone Eudragit L 100, Eudragit

S 100 Tablet Ulcerative collitis.

[12]


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MARKETED TIME DEPENDENT SYSTEMS

DRUG POLYMER USED DOSAGE

FORM LAG TIME

Diltiazem

hydrochloride

Hydroxypropylmethylecellulo

se acetate succinate

(HPAMCAS)

Press coated

tablets

Lag time can be

upto 2-9h in pH

6.8.[13]

Mesalamine HPMCK-100M, HPMCK-4M,

HPMC E15, HPMC E15. Tablets Lag time of 10h.

[14]

MARKETED MICROBIALLY CONTROLLED SYSTEMS

DRUG USED POLYMER USED DOSAGE FORM DISEASE

Valdecoxib

Guar Gum and

Sodium Starch

Glycholate

Tablet Inflammatory

bowel disease.[15]

5- fluorouracil Pectin Tablet Colon cancer.[16]

Metronidazole Sesbania Gum Matrix Tablet Intestinal

Amoebiasis.[17]

NOVEL FORMS OF NATURAL POLYSACCHARIDES USED

DRUG POLYSACCHARIDE DOSAGE FORM

Diclofenac Sodium Chitosan Microspheres

Insulin Chitosan Capsules

Indomethacin Pectin Matrix Tablet

Dexomethasone Guar Gum Matrix Tablet

Indomethacin Chondroitin Sulphate Matrix Tablet

Theophylline Locust- BeanGum Film.[18]

MARKETED PRESSURE CONTROLLED RELEASE SYSTEM

DRUG USED POLYMER USED DOSAGE FORM DISEASE

Caffeine as test drug Ethyl Cellulose Capsule Healthy male

human volunteer

Glycyrrhizin PEG, labrasole Capsule To improve its

bioavailability.[19]

MARKETED HYDROGEL BASED SYSTEM

DRUG USED POLYMER USED APPROACH

USED

METHOD OF

PREPARATION

Satranidazole Chitosan pH sensitive Cross linking

method.[20]

5-fluorouracil

Hydroxyethylmethacrylate,

Methacryloyloxy

azobenzene (MAB)

Degradation by

azoreductase Polymerisation.

[21]


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MARKETED CODES BASED SYSTEM

DRUG USED POLYMER

USED

DOSAGE

FORM DISEASE

Mebeverine

Hydrochloride Eudragit E100 Tablets spasmolytic drug.

[22]

MICROSPHERES BASED COLON TARGETED SYSTEM

DRUG POLYMER

USED

METHOD OF

PREPARATION

DISEASE

Theophylline Ca-pectinate,

Eudragit S100

Ionotropic gelation

method

Anti-asthmatic

activity.[23]

Indomethacine Eudragit L-100,

Eudragit S-100

Solvent evaporation

method

Rheumatoid

disorders.[24]

Aceclofenac Guar gum Emulsification

methood

Rheumatoid

arithritis.[25]

3) TYPES OF COLON TECHNOLOGY

A. PRIMARY APPROACHES FOR CDDS

a) pH sensitive polymer coated drug delivery to colon

In the stomach pH ranges between 1 and 2 during fasting but increases after eating. The pH is

about 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 caecum. However, pH

values as low as 5.7 have been measured in the ascending colon in healthy volunteers. The

pH in the transverse colon is 6.6, in the descending colon 7.0. Use of pH dependent polymers

is based on these differences in pH levels.[26]

b) Microbial triggered drug delivery system

The various microflora of the colon are Bacteroides, Bifidobacteria, Eubacteria, Clostridia,

Enterococci, Enterobacteria, etc. This microflora of gut depends on fermentation of

undigested materials in the small intestine for their energy requirements. The microflora

performs fermentation by producing a large no. of enzymes like glucuronidase, xylosidase,

arabinosidase, galactosidase, and deaminase and urea dehydroxylase. These biodegradable

enzymes are capable of degrading the polymers used for targeting the drug delivery to colon.

Different polymers are used for preventing the release of drug in the stomach and small

intestine.

i. Prodrug approach for drug delivery to colon

Prodrug is the main approach of microbial triggered drug delivery system in which the drug

release from the formulation is triggered by the microflora present in the gut. Prodrug is the


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inactive form of an active parent drug that undergoes enzymatic transformation to release the

active drug. These prodrug molecules get hydrolysed in the presence of the enzymes released

by the microflora.

a) Azo bond conjugate

Sulfasalazine is used for treatment of Inflammatory Bowel Diseases. It is 5-amino salicylic

acid (5-ASA) prodrug. 85% of oral dose of Sulfasalazine reaches to colon unabsorbed, where

it is reduced by anaerobic environment into 5-ASA and Sulphapyridine. Various studies are

conducted on Sulphapyridine which lead to formation of other prodrug like Olsalazine, 4-

amino Benzoyl-beta-alanine. Mutual azo prodrug of 5-amino salicylic acid with histidine was

synthesized by coupling L-Histidine with Salicylic acid, for targeted drug delivery to

inflamed gut tissue.[27]

b) Glucuronide conjugate

Glucuronide and sulfate conjugation is major mechanisms for inactivation and preparation for

clearance of a variety of drugs. Bacteria of the lower gastrointestinal tract secrete

glucuronidase that glucouronidate a variety of drugs in the intestine. Since the

glucuronidation process results in the release of active drug and enables its reabsorption,

glucuronide prodrugs would be expected to be superior for colon targeted drug delivery.[28]

c) Cyclodextrin conjugates

The hydrophilic and ionisable Cyclodextrins can serve as potent drug carriers in the

immediate release and delayed release formulations, while hydrophobic cyclodextrins can

retard release rate. The hydrophilic and ionisable Cyclodextrins can serve as potent drug

carriers in the immediate of water. Methotrexate prodrugs of α- and γ-Cyclodextrins were

synthesized and result established the primary aim of masking the ulcerogenic potential of

free drug, by using 12-fold dose of the normal dose of methotrexate and equivalent doses of

the ester.[29]

c) Timed released systems

Time controlled release system 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 dosage

forms cannot be accurately predicted, resulting in poor colonical availability.[30]


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Disadvantages of this system are

(i) Gastric emptying time varies markedly between subjects or in a manner dependent on

typeand amount of food intake.

(ii) Gastrointestinal movement, especially peristalsis or contraction in the stomach would

resultin change in gastrointestinal transit of the drug.

(iii) Accelerated transit through different regions of the colon has been observed in patients

with the IBD, the carcinoid syndrome and diarrhea and the ulcerative colitis.

That is since the transit time of dosage forms in the small intestine is less variable i.e.about

3±1 hour. The time-release function (or timer function) should work more efficientlyin the

small intestine as compared the stomach.

Enteric coated time release press coated tablet

Enteric coated time release press coated tablets, are composed of three components, a drug

containing core tablet (rapid release function), press coated swellable hydrophobic polymer

layer (Hydroxy Propyl Cellulose layer), time-release function and an enteric coating layer

(acid resistance function). Tablet does not release the drug in the stomach due to the acid

resistance of the outer enteric coating layer. After gastric emptying, the enteric coating layer

rapidly dissolves and the intestinal fluid begins slowly erode the press coated polymer (HPC)

layer and when the erosion front reaches the core tablet, rapid drug release occurs since the

erosion process takes a long time there is no drug release period (lag phase) after gastric

emptying.[31]

B. PLATFORM TECHNOLOGIES FOR COLON TARGETED DRUG DELIVERY

SYSTEMS

Nowadays design of dosage form is becoming complex because there is a vast use of

technology in the dosage forms for controlling various aspects. Few examples are mentioned

in case of colon targeted drug delivery.

a) Pressure controlled delivery

Peristaltic motion causes the luminal pressure of large intestine to increase more than that of

small intestine because its contents are more viscous due to reabsorption of water. Takaya et

al. developed capsules that deliver a drug to colon based on luminal pressure. Although these

systems allow for drugs to be delivered to colon rather than small intestine due to higher


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colonic pressure, reabsorption of water from colon causes its content to be highly viscous

which may become an obstacle for site- specific delivery.[32]

b) Pulsatile colon targeted drug delivery

i. Pulsincap systems

The system consists of a water insoluble capsule body containing drug, a hydrogel plug

which seals opened end of this capsule body and a water soluble cap which covers the

hydrogel plug. Additionally, capsule is coated with an acid insoluble film coating which

prevents drug from being released in stomach. The hydrogel plug begins swelling when this

enteric coating dissolves in small intestine. The swelling of plug allows for a lag time before

drug is released and amount of lag time depends on length of plug and extent at which it is

inserted. Abraham et al. developed a pulsincap system in which they tested several polymers

as plug material. The formulations were tested at pH 1.2 for 2 hours to simulate gastric fluid,

pH 7.4 for 3 hours to simulate intestinal fluid, and pH 6.8 for 7 hours to simulate colon. It

was concluded that this modified pulsincap system can successfully target metronidazole to

the colon.[33]

ii. Port System

Port system consists of a gelatin capsule coated with a semi-permeable membrane (e.g.

cellulose acetate) housing an insoluble plug (e.g. lipidic) and an osmotically active agent

along with drug formulation. When in contact with aqueous medium, water diffuses across

the semi-permeable membrane, resulting in increased inner pressure that ejects plug after a

lag time.[34]

c) Osmotically controlled colon targeted drug delivery system

There are two OROS systems for colon drug delivery.

i. Osmet pump

It consists of an enteric coated semi permeable shell which encloses an osmotic layer along

with a central impermeable and collapsible reservoir filled with drug. The interior of this

compartment is connected with external environment through a delivery orifice at one end.

After dissolution of gastric- resistant film, water is allowed to penetrate through semi-

permeable membrane, thus raising pressure inside device, which cause inner reservoir to

shrinks and drug formulation to pump out.


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ii. Oros colon targeted drug delivery system

Immediately after ingestion, hard gelatin capsule shell dissolves. The push and pull unit is

prevented from absorbing water in acidic medium of stomach by enteric coating. The osmotic

pumping action results when coating dissolves in drug is delivered out of orifice at a rate

controlled by rate of water transport across membrane.[35]

d) Novel colon targeted delivery system (CODESTM)

CODESTM is an unique CDDS technology that was designed to avoid the inherent problems

associated with PH or time dependent systems. The system consists of a traditional tablet

core containing lactulose, which is over coated with and acid soluble material, Eudragit E,

and then subsequently overcoated with an enteric material, Eudragit L. The acid soluble

material coating then protects preparation as it passes through alkaline pH of the small

intestine. Once tablet arrives in colon, bacteria enzymatically degrade polysaccharide

(lactulose) into organic acid.[35]

e) Multiparticulate system based drug delivery

It includes pellets, microparticles, granules, nanoparticles. This system is more preferred over

single dosage forms as this system enables drug to reach colon quickly and retain for a

longerperiod of time. These systems pass through the GIT easily due to their smaller size.

Multiparticulate systems are dispersed more uniformly in the GIT resulting in more uniform

drug absorption.[36]

4) EVALUATION OF COLON TARGETED DRUG DELIVERY

In Vitro Evaluation

No standardized evaluation technique is available for evaluation of CDDS 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 and physical stress and these factors make it difficult to design a

slandered in vitro model. In vitro model used for CDDare.

In vitro dissolution test

Dissolution of controlled-release formulations used for colonspecific drug delivery are

usually complex, and the dissolution methods described in the USP cannot wholly 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.


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Parallel dissolution studies in different buffers may be undertaken to characterize the

behavior of formulations at different pH levels. Dissolution tests of a colonspecific

formulation in various media simulating pH conditions and times likely to be encountered at

various locations in the gastrointestinal tract. 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 ileal segment. Enteric-coated capsules for CDDS have been investigated in a

gradient dissolution study in three buffers. In vitro test for intactness of coatings and carriers

in simulated conditions of stomach and intestineDrug release study in 0.1 N HCl for 2 hours

(mean gastric emptying time) Drug release study in phosphate buffer for 3 hours (mean small

intestine transit time).

In-Vitro dissolution Studies

The in-vitro dissolution studies were carried out using USP dissolution apparatus type II in

different medium.

Preparation of reagents & solutions

Preparation of 0.1 N HCl

0.1N HCl was prepared by diluting 8.5 ml of concentrated hydrochloric acid to 1000 ml with

distilled water.

Preparation of pH-6.8 phosphate buffer

28.80 g of disodium hydrogen phosphate & 11.45g of potassium hydrogen phosphate were

dissolved in water & volume was made up to 1000 ml.

Preparation of pH-7.4 phosphate buffer

2.38 g of disodium hydrogen phosphate, 0.19 g of potassium dihydrogen phosphate & 8.0 g

of sodium chloride were dissolved in water & volume was made up to 1000 ml. Adjust the

pH if required.[37]

Preparation of pH 6.8 phosphate buffer with 4%w/v rat caecal contents

Male Wistar rats weighing 105-150 gm and maintained on a normal diet were used for the

study. Thirty minutes before the commencement of drug release studies, four rats were killed

by spinal traction. The abdomen were opened, the caecal were traced, ligated at both ends,

dissected and immediately transferred into pH-6.8 phosphate buffer, previously bubbled with

carbon dioxide gas. The caecal bags were opened; their contents were individually weighed,


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pooled and then suspended in pH-6.8 phosphate buffer to give 4%w/v dilution. As the

caecum is naturally anaerobic, all these operations were carried out under CO2 gas.[30]

In-

vitro dissolution study was performed by using USP Type II Apparatus (Basket type)

[Electrolab (ETC11L) Tablet Dissolution Tester] at 100 rpm for 2 h in 0.1 N HCl (900 ml).

Then the dissolution medium was replaced with pH 7.4 phosphate buffer (900 ml) and tested

for 3 h as the average transit time of small intestine is 3 h. After 5 h, the dissolution medium

was replaced with pH 6.8 phosphate buffer and tested for next 10 h. At the end of the time

period 10 ml of the sample were taken and analyzed for Nitrofurantoin content as described

previously. A 10 ml fresh and filtered dissolution medium (buffers) was added to make the

volume after each sample withdrawal.

In vitro enzymatic test

For this there are 2 tests:

1. Incubate carrier drug system in fermenter containing suitable medium for bacteria

(Streptococcus faccium or B.ovatus) amount of drug released at different time intervals

determined.

2. Drug release study is done in buffer medium containing enzymes (enzyme pectinase,

dextranase), or rat or guinea pig or rabbit cecal contents. The amount of drug released in

particular time is determined, which is directly proportional to the rate of degradation of

polymer carrier.

In Vivo Evaluation

A 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

the microflora of human GIT. While choosing a model for testing a CDDS, relative model for

the colonic diseases should also be considered. Eg. Guinea pigs are commonly used for

experimental IBD model. The distribution of azoreductase and glucouronidase activity in the

GIT of rat and rabbit is fairly comparable to that in the human. For rapid evaluation of CDDS

a novel model has been proposed. In this model the human fetal bowel is transplanted into a

subcutaneous tullel on the back of thymic nude mice, which vascularizes within 4 weeks,

matures and becomes capable of developing of mucosal immune system from the host.[38-42]

5) DISSOLUTION TESTING

Dissolution testing of poorly soluble compounds in immediaterelease (IR) solid dosage

forms poses many challenges. These challenges include developing and validating the test


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method, ensuring that the method is appropriately discriminatory, and addressing the

potential for anin vivo–in vitrorelationship (IVIVR) or correlation (IVIVC).

A broad range of in vitro systems is available, from static monocompartmental to dynamic

multicompartmental models. However, these models require a compromise between

technological complexity and biological significance. Further efforts and technological

innovations are still needed to improve in vitro models and meet growing demands in the

areas of health.[43]

Need ofin-vitrodissolution testing

a) Characterizing the drug-release mechanism by establishing anin vitrodissolution test

method (or an appropriate alternative method) to measure product performance is particularly

important for poorly soluble compounds.

b) Dissolution testing historically has been a key tool during the development stages of a

compound as well as for commercial manufacturing.

c) For a development compound, dissolution testing is used primarily to help develop and

evaluate new formulations by evaluating the rate of drug release from dosage forms,

evaluating the stability of these formulations, monitoring product consistency, assessing

formulation changes, and establishing IVIVRs or IVIVCs.

d) For a commercial product, dissolution testing is used primarily to confirm manufacturing

and product consistency, to evaluate the quality of the product during its shelf life, and to

assess postapproval changes and the need for bioequivalence studies.[44]

In vitro GSI models

a) Static monocompartmental models

Static models are the most widespread digestive systems. The gastric phase is reproduced by

a pepsin hydrolysis of homogenized food, under fixed pH and temperature, for a set period of

time (pH 1–2, 378℃, 1–3 h). This step may be followed, in the same bioreactor, by an

intestinal phase involving pancreatic enzymes with or without bile (pH 6–7). Most of these

models have been developed for specific applications and are cheap high-throughput tools,

particularly relevant for large prescreening approaches. The United States Pharmacopeia

(USP) apparatus also provides a static, closed environment, widely used to assess dosage

form disintegration and dissolution in a single medium reproducing digestive conditions, both

gastric (Simulated Gastric Fluid) and intestinal (Simulated Intestinal Fluid). However, in this


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approach, large volumes of media are often deployed and the mechanical forces (continuous

stirring) are not representative of complex peristaltic movements.[45]

b) Dynamic monocompartmental models

To overcome these limitations, several dynamic gastricmodels have been developed. One

model reproduces, based on in vivo data, the progressive acidification of gastric content by

HCl addition, the time course of pepsin flow rate and gastric emptying.[46]

The Dynamic

Gastric Model(DGM) was designed to take into account the regionspecificity of the stomach.

It is composed of two successive compartments.

(i) The „body‟ where gastric secretions are mixed with food.

(ii) The „antrum‟ where shear forces and stomach grinding are reproduced.

The gastricemptying is regulated by a valve that allows the smallest particles to leave the

stomach, whereas the bigger ones are refluxed into the top chamber to be further digested.

Despite its complexity, the DGM does not accurately reproduce the in vivo peristaltic

forces.[47,48]

The Human Gastric Simulator (HGS), composed of a latex chamber surrounded

by a mechanical driving system, more effectively emulates the peristaltic movements of the

stomach in amplitude, intensity, and frequency.[49]

c)Dynamic bi and multicompartmental models

The main bicompartmental models aim to simulate theluminal conditions of the stomach and

proximal smallintestine.[50,51]

Based on in vivo data, these computercontrolledsystems

reproduce the temperature, pH changesin the gastric and duodenal compartments, gastric

emptying, addition of pepsin, pancreatic juice and (or) bile, anddialysis of digestion end

products.[52]

Thesesystems have been mostly standardized and validatedfor specific

applications, such as the study of antacidactivity.[53]

or the survival of probiotics.[54]

To date, the TIM-1 (TNO gastro-Intestinal Model 1) isthe only GSI system characterized as

„full‟, that is, combining multi-compartmentalization and dynamism.[55]

This model is

composed of the stomach and the three parts of the small intestine, the duodenum, jejunum,

and ileum. It integrates key parameters of human digestion: temperature, kinetics of gastric

and intestinal pH, gastric and ileal deliveries, transit time, peristaltic mixing and transport,

sequential addition of digestive secretions, and passive absorption of water and small

molecules through a dialysis system. TIM-1 is so far the system that allows the closest


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simulation of in vivo dynamic events occurring within the human GSI lumen. It has been

applied in a large number of nutritional[56,57]

, toxicological[58,59]

, pharmaceutical[60,61]

, and

microbiological[62]

studies.

APPLICATIONS OF DISSOLUTION TESTING

1. In vitro dissolution testing is well established for solid oraldosage forms as both a quality

control test to assess batch-to batch consistency and to predict in vivo drug release profiles

for both immediate and modified release dosage forms.[63,64]

2. Many commonly used inhaled products such as metereddoseinhalers (MDIs), dry powder

inhalers (DPIs) and suspensionsfor nebulization deliver the active pharmaceutical

ingredient(API) to the lung in a solid form. A variety of competing mechanisms exist for the

clearance of aerosol particles after deposition in the airways.[65]

3. In vitro tools have been extensively used to determine thebioaccessibility of ingested

nutrients. Reported studies range from macronutrients[66,67]

to micronutrients such as

vitamins, minerals, or phytoconstituents.[68,69]

4. A variety of dissolution media, usually at pH=6.8–7.4, ranging from simple phosphate-

buffered saline (PBS) to simulated lung fluid (SLF) have been used for dissolution testing of

inhaled products.We use the term „simulated lung fluid‟, which has become customary in the

literature, with an understanding that SLF does not fully simulate the interstitial or epithelial

lung fluid (ELF) given that it will not contain protein components, mucus, etc.[70]

5. The in vitro dissolution of dysprosium lithium borate microspheres using simulated

synovial fluid used for treatment of Rheumatoid Arthritis.[71,72]

6. The synovial fluid was used to evaluate the in vitro bioactive behavior (in vitro bone-

bonding ability) of tissue-engineered osteochondral (bone-cartilage) composite used in the

treatment of lesions of the articular cartilage. The simulated synovial fluid was continuously

circulated in physiological conditions (pH 7.4 and 37 °C) using a peristaltic pump for up to

14 days with anavailable volume of 50 mL of fluid.[73]

7. Vertzoni et al. developed a simulated gastricmedium that more adequately reflects the

physiological conditions of the fasted state .This medium contains pepsin and low amounts of

bile salt and lecithin.[74]

8. The in vitro release ofbovine serum albumin from matrixes made of these modified

starches using the SCoF1.[75]

9. The in vitro release of metronidazole from modified Pulsincap dosage forms targeted to the

colon in a timedependent manner was evaluated using pH 6.8 phosphate buffer.[76]


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10. Development of a media simulatingthe physicochemical characteristics of the ascending

colon in the fasted and fed states.[77]

11. Development of a fluidto simulate the contents of the proximal colon. This medium was

used to predict the input profiles of extended-release products containing isosorbide-5-

mononitrate.[78]

12. SS 5 (300 mL) was used to monitor the release of salbutamol sulphate from oral fast

dissolving films using USP Apparatus 2 (paddles).[79]

13. The test method to characterize the dissolution properties of a multitude of formulation

types available for pulmonary delivery.[80]

14. SLF4 was used to evaluate the in vitro release of itraconazole from nebulized

nanoparticle dispersions.[81]

15. SLF5 was used to evaluate the dissolution oftitanium tritide particles used as components

of neutron generators. These particles may be released into the air as aerosols during

fabrication, assembling, and testing of components or in accidental or fugitive releases.[82]

16. The development of a simulated vaginal fluid(SVF1) (Table 12) that models the fluid

properties originating in the vagina, specifically the vaginal secretion found in healthy,

nonpregnant, premenopausal women.The volume of vaginal fluid can be measured in two

ways, the amount of fluid present at any one time or the amount of fluid produced over an

extended time interval.[83]

17. The in vitro release of clindamycin from bioadhesive gelwas performed using 15 mL of

SVF1 in a vertical diffusion cell.[84]

18. The swelling behavior, the mucoadhesion, and the invitro release of nystatin from a

mucoadhesive vaginal delivery were evaluated using SVF1.[85]

19. Simulated Tears 1 in the volume of 8 mL wasused to evaluate the in vitro release kinetic

of poly-anionic oligonucleotide macromolecules from cationic nanoemulsions with potential

use for age-related macular degeneration treatment.[86]

20. Simulated Tears 2 in the volume of 4 mL was used to evaluate drug-loadingefficiency and

in vitro release of pilocarpine fromhydrogels. These hydrogels behave as a drug-depot for

controlled-release applications.[87]

21. Development of in situ forming sodium alginate gels for the extended release of

indomethacin to the eye. They evaluated the in vitro gelation using Simulated Tears 2 and

Simulated Tears 3 and assessed the in vitro release using Simulated Tears 2 (200 mL/2 mL of

sample).[88]


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22. The in vitro release of fentanyl from transdermal systems was evaluated using 500 mL of

SSW(60) using USP Apparatus 5 (paddle over disk).[89]

23. Characterization of the corrosion layer of copper–nickel alloysin SSW2, with its pH

adjusted to 6.5 with ammonia.[90]

6) Limitations and challenges in colon targeted drug delivery[91-93]

1. One challenge in the development of colon-specific drug delivery systems is to establish an

appropriate dissolution testing method to evaluate the designed system in-vitro.

2. As a site for drug delivery, the colon offers a near neutral pH, reduced digestive enzymatic

activity, a long transit time and increased responsiveness to absorption enhancers; however,

the targeting of drugs to the colon isvery complicated.

3. Due to its location in the distal part of the alimentary canal, the colon is particularly

difficult to access.

4. In addition to that the wide range of pH values and different enzymes present throughout

the gastrointestinal tract, through which the dosage form has to travel beforereaching the

target site, further complicate the reliability and delivery efficiency.

5. Successful delivery through this site also requires the drug to be in solution form before it

arrives in the colon or, alternatively, it should dissolve in the luminal fluids of the colon, but

this can be a limiting factor for poorly soluble drugs as the fluid content in the colon is much

lower and itis more viscous than in the upper part of the GI tract.

6. In addition, the stability of the drug is also a concern and must be taken into consideration

while designing the delivery system.

7. The drug may potentially bind in a nonspecific way to dietary residues, intestinal

secretions, mucus or faecal matter.

8. The resident microflora could also affect colonic performance via metabolic degradation of

the drug. Lower surface area and relative „tightness‟ of the tight junctions in the colon can

also restrict drug transport across themucosa and into the systemic circulation.

9. The occurrence of physical and chemical interactionswithin and between the shell and fill

components. It is critical to understand these interactions to develop a softgel product that is

stable and provides desired in vitro and in vivo characteristics.[94]

10. USP Apparatus I and II arecommonly used for dissolution testing of commercially

available products of poorly soluble compounds, whereas other apparatus have been used

primarily for development.[95]


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11. USP evaluated the scientific rationale for in vitro dissolution tests for inhalation dosage

forms and concluded that there was no compelling evidence that dissolution was “kinetically

and/or clinicallycrucial for currently approved” OIPs.[96]

12. To simulate host responses more accurately, a combinatorialapproach involving in vitro

models and human intestinal cells in culturehas been proposed.[97]

13. Recent studies have also investigated the effectof in vitro digesta on intestinal cell

proliferation and inflammatory pathways to assess the potential anticarcinogenic or anti-

inflammatory properties of ingested substances.[98,99]

14. One of the major challenges in in vitro digestion is tosimulate as accurately as possible

the peristalsis and realistic shape and motility of GSI compartments. Interestingly, newly

developed GSI models should also reproduce the biphasic gastric emptying curves observed

in vivo, where emptying of solid food components presents a linear pattern starting after a lag

phase, whereas emptying of liquids begins immediately in an exponential manner.[100]

15. There are some technical challenges of measuring invitro dissolution of nanoparticles as

sub-micron particles can easily pass through a line filter, which may overestimate the

dissolution rate.[101]

CONCLUSION AND FUTURE SCOPE

A wide range of GSI models has been developed andapplied in many nutrition and health

studies.By usingin vitro dissolution tests, the industry generally seeks to establish in vivo–in

vitro relationships as opposed to invivo–in vitrocorrelations (IVIVCs), because the latter have

poorly defined validation requirements, challenges of predictability, and extensive added cost

with questionable benefit. Dissolution testing is most often used for the in vitroassessment of

the in vivo behavior of a pharmaceutical dosage form, both for development and quality

control. In vivo performance prediction is a valuable tool in drug developmentand regulatory

evaluation. As methods in modeling and simulation for predictions of bioavailability continue

to expand and improve, the role of predictive tools in drug development and review will

assume greater importance. Advisory Panel not to pursue the development of

standardizedmethods for possible compendial use, but will continue to maintain a watching

brief on the possible impact of dissolution- related effects associated with potential new

forms of OIPs, particularly those involving controlled release.

Establishing quantitative in vitro–in vivo relationships between dissolution data and PK, PD

or clinical data and Establishing quantitative in vitro–in vivo relationships between


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dissolution data and PK, giving consideration to the appropriate dissolution timescale relative

to mucocilary ormacrophage particulate clearance mechanisms and improving the robustness

and validation of the dissolution apparatus, particularly with regards to drug loading effects

and Using a truly predictive dissolution medium that correctlysimulates dissolution in the

lung and The use of experimental dissolution data within predictive pharmacokinetic models

[e.g., GastroPlus™ Simulations Plus Inc., Lancaster, CA pulmonary module data or the

published Hochhaus model data.

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