Non-biodegradability of the GI Tract. Although the use of

Non-biodegradability is one of the defect or
limitation of pH sensitive polymers. Because of this limitation polymers made
up of non-biodegradable polymers are discharged from body after use. The non-biodegradability
is no longer a complication in certain applications such as in oral drug
delivery but it becomes a serious restriction in other applications such as the
development of implantable drug, attention has been focused on the development
of biodegradable, pH sensitive hydrogels based on peptides, proteins and
polysaccharides.

Dextran was activated with 4-aminobutyric acid for
crosslinking with 1, 10 diaminodecane and also combined with carboxylic groups.
The modified dextran hydrogels have shown a faster and higher extent of
swelling at high pH conditions and changing the pH between 7 and 2 resulted in
cyclic swelling- de-swelling. Dextran hydrogels may not be actually biodegradable,
since the body or certain sites may not have the enzyme to degrade dextran
molecules. The natural polysaccharides are not usually biodegradable in human
body.

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!


order now

Synthetic polypeptides are also used in the synthesis
of biodegradable hydrogels because of their more structured arrangement and
less versatile amino acid residues than those derived from the natural
proteins. Poly aspartic acid, poly L-lysine and poly glutamic acid are the
examples of synthetic polypeptide hydrogels.

Enteric coated systems

Enteric-coated formulations are suitable vehicles to
improve the release of active substances at specific target areas in the
gastrointestinal tract and preventing its release in stomach. The principle
cause of enteric coating is the protection of drugs that are sensitive or
unstable at acidic ph. This is particularly vital for drugs such as enzymes and
proteins because these macromolecules are immediately hydrolyzed and
inactivated in acidic medium. Macrolide antibiotics such as erythromycin are
rapidly degenerated by gastric juices. Acidic drugs like NSAID’s are also
enteric coated to prevent local irritation of the mucosa.

Another purpose of enteric coating is drug targeting for
example in case of 5-aminosalicylic acid or the prodrugs sulfasalazine. In
these cases, enteric coating is administered such that the drug concentration
is enhanced in the lower parts of the GI Tract. Although the use of enteric
coating to improve modified drug release is known for long but it has always
been criticized as to its true value of providing protection and targeted
release of coated active agents.

Schematic
representation of Enteric coated system

Dosage Forms

In general, film coated dosage forms can be divided
into two forms multiple unit and single unit dosage forms. Single unit dosage
form contains tablets, film coated capsules and other forms. Multiple units
contains granules, capsules, pellets and compressed film coated particles.

Drug in enteric coated form can produce aqueous
dispersions and suspensions. The enteric coated time clock system comprising of
tablet core that is coated with a mixture of hydrophobic material and
surfactant is applied as an aqueous dispersion. The drug release from the core
is occurring at a predetermined lag time. The lag time is insensitive of GI pH
and depends on the thickness of hydrophobic layer.

Tablets

Tablets can be easily enteric coated and a wide
variety of products are in the market for example naproxen, acetyl salicylic
acid , diclofenac they have increased bioavailability , improved patient
compliance and the formulation stability due to coating process.

Capsules

Extra precautions are required during coating as
capsule shells become brittle during storage. To ensure proper coating of the
capsule closure the thickness of the film coating layer has to be increased.
Enteric coating of hard gelatine capsules containing acetaminophen showed good
stability. Soft gelatine capsules containing thin transparent film coating also
showed good stability.

Multiple units

A widely used method of producing multiple units has
been the formulation of sachets containing film coated granules. Capsules
filled with enteric coated particles is of common use. In addition to the
flexible polymers for coating, suitable larger sized fillers-binders and stable
strong pellet cores are also considered for the enteric dosage form designs.
Only methacrylic acid copolymers seem to have these qualities necessary to
produce these dosage forms.

Example: Small microcapsules of
ibuprofen were film coated with cellulose acetate phthalate and dispersed in
water before administering, plasma levels didn’t differ from the conventional
enteric coated tablet as expected.

PH sensitive gels

Many poly-anionic materials are pH sensitive and the
extent of swelling of such polymers can be changed by changing pH. An
application of such technology is used in the development of biomimetic
secretary granules for drug delivery system.

The polymer network, containing biological mediators
such as histamine exist in a collapsed state as a result of internal pH and
ionic content that is maintained by the lipid surrounding the membrane.
Histamine release from granule is initiated by the fusion of the granule with
the cell membrane revealing the poly-anionic internal matrix to the
extracellular environment. Hence the change in pH and ionic strength results in
ion exchange and swelling of the poly-anionic network that causes the release
of mediators

                

Schematic
diagram showing the release of drug from a biomimetic secretory granule on
disruption of the external lipid bilayer

Application

The use of this system in conjunction with temperature
sensitive lipids provide potential to target drugs to the areas of inflammation
or to reach site specific, pulsatile drug delivery through the localized
external application of ultrasound or heating to distort the lipid bilayers.

PH-Sensitive Liposomes

PH-Sensitive liposomes are stable at physiological pH,
under acidic conditions they destabilize leaking to the release of their
aqueous contents. In addition, they appear to destabilize or combine with the
membranes of endosomes in which they are internalized allowing even
macromolecular liposomes contents to enter the cytoplasm. Following binding to
cells, liposomes are internalized through the endocytotic pathway. Liposomes
are retained in early endosomes that mature into late endosomes. The potential
of pH sensitive liposomes lies in their ability to undergo destabilization at
this stage thus stopping their degradation at the lysosomal level and therefore
increasing access to nuclear targets.

Intracellular
delivery of oligonucleotides by pH-sensitive liposomes

Applications

Hyper-branched poly glycidal (HPG) derivatives were
formulated as a new type of pH sensitive polymer used in modification of
liposomes. They have shown stronger interaction with the membrane than the
linear polymers show. Thus liposomes modified with HPG derivatives show better
results.

PH sensitive nanoparticles

Particles in the size range of 40-120nm are
translocated both transcellularly and paracellularly. In addition to enhancing
drug bioavailability, particulate oral drug delivery systems can protect reactive
macromolecules from stomach acid and first pass effect in the GIT. The use of
pH sensitive polymers like hydroxypropyl methyl cellulose phthalate for
encapsulating proteins or antigens for oral administration, these particles are
matrix-type dispersed systems. At a specific pH highly dispersed drugs release
within the GIT close to the absorption window of the drug thus increasing the
probability to maximum absorption and to minimize first pass metabolism.
Methods to prepare polymeric nanoparticles are ionic gelation, solvent
evaporation, salting-out/emulsification diffusion and polymerization.

 

Application

PH-Sensitive nanoparticles are used for antitumor
evaluation

Advantages of PH Sensitive Drug Delivery System

Following are the advantages

1.      Drug
directly available at the target site

2.      Decreased
dose to be administered

3.      Reduced
side effects

4.      Improved
drug utilization

5.      Enhanced
patient compliance

6.      Lower
daily cost to the patient as fewer dosage units are required by the patient in
therapy

7.      Mucosa
protection from irritating drugs

8.      Extensive
drug pass metabolism for prevention of drug loss

 Disadvantages of
PH Sensitive Drug Delivery System

1.      In
order to get fast response the size should be smaller and thinner in hydrogels
but this makes hydrogels very fragile hence compromising their mechanical
strength which is one of the main characteristics necessary for biomedical
applications.

2.      Non-biodegradability
is limitation in pH sensitive polymers in certain cases

Example of Novel Drugs

Example 1

PH-sensitive hydrogels comprises of polyethylene
glycol and methacrylic acid (MAA) macromonomer (PEGMEMA) entrapping diliazem
HCL were synthesized inside soft gelatine capsules for use as a new dosage form
for oral drug administration. For the assessment of their swelling and release
behaviour in two media, different monomers were used at pH 7 stimulating the
higher pH environment of the intestine while at low pH stimulating the acid pH
of the stomach. DIL-HCL release and swelling both processes are dependent on PH
and composition of monomer. Hydrogels with intermediate formations showed
diminished DIL·HCl release at pH 1.2. Similar shaped release profiles were
found for the four hydrogels compositions at pH 7. At this neutral pH slow
protonation of the carboxylate groups of MAA led to the swelling front and a
dry core that is detected using MRI. As a result of this swelling, release
curves presented a long period of zero order kinetics. So, this shows that the
system could be a suitable candidate for developing a zero order release dosage
form for oral administration of DIL-HCL. The processes of dissolution and
swelling were analysed by using different mathematical approaches.

Example 2

The development of a novel colon-specific drug delivery system using
methacrylate derivatives of 5-ASA properties of drug release and PH sensitive
swelling. 5-ASA film coated tablets were developed for colon specific delivery.
During this process 5-ASA core tablets were initially made then coated with
dispersion containing Eudragit RS and dessterrifed pectin,
polygalacturonicacidor its sodium and potassium salts. During the first five
hours negligible drug release occurred where the coated tablets were in small
intestine and stomach. After that, 5-ASA release from coated tablets released
linearly as a function of time because of pectinolytic enzymes action.