College Papers

For and crotonic acid. In order to improve

For patient conveniency and their acceptance tablets are
often coated, also to protect drug from gastric acid etc but the tendency of
formulations to adhere can be affected by coatings themselves. The result of
using isolated oesophageal preparations in In vitro studies is that the hard
gelatin capsules had greatest tendency to adhere. While the film coated
tablets, uncoated tablets, sugar coated tablets show minimum adhesion.Calculations
show that the tendency of adhesion of hard gelatin capsules is 6 times than the
tendency of sugar coated tablets and when calculated per unit area it is 1.5
times than that of soft gelatin capsules.

Normally, human studies do not accept the difference of hard
and soft gelatin capsules in their tendency to adhere.Though there is shorter
oesophageal passage time of coated tablets 
than plain tablets but it take longer for them to break, if they do
lodge. Coatings having low tendency to adhere are made up from cellulose
acetate phthalate, shellac, methacrylate copolymer and a copolymer composed
from of vinyl acetate and crotonic acid.

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In order to improve 
the adhesion  tendency of
hydroxypropylmethylcellulose, sucrose is incorporated which helps to reduce the
surface stickness; while the addition of titanium oxide, lactose and talc
increases the tendency to adhere. On the other hand , greatest tendency to
adhere is shown by polyethylene glycol 6000 coating .A variety of studies in
humans show  that capsules get stuck  in the oesophagus with a much higher rate
than tablets. Hard gelatin capsule can become adherent to mucosa by absorbing sufficient
water, if its passage through the oesophagus is hindered for more than two
minutes. Besides gelatin, cellulose derivatives and guargum are materials that
become sticky as hydrated. According to recent studies,guargum when transformed
into a slimming product hydrated and developed a large sticky mass which was
enough to cause oesophageal barrier.

Not only the pharmaceuticals dosage forms get stuck into the
oesophagus but neutraceuticals can also cause this hazard as reported by recent
researches where an anhydrous protein health food tablet get stuck to the
oesophagus so strongly that it had to be removed by endoscopy.

With the newly developed Dosage forms there will be no need
of drinking water for swallowing . although these dose forms are retained in
mouth and oesophagus yet saliva is needed for clearance.

One of the example of quickly disintegrating solid dosage
forms is the Zydis® formulation (Scherer DDS Ltd) that can be taken without
water.the fast dissolving dosage forms can be cleared through buccal cavity by
either of two methods; to clear with the help of several swallows after
dissolving or to pass the whole through oesophagus.

SIGNIFICANCES
OF ADHESION OF DOSAGE FORMS

lag in
drug absorption

Drug absorption can be delayed due to withholding of dosage
form in oesophagus and thus the commencement of action.it becomes difficult for
drugs to pass through the strarified squamous epithelium of oesophageal mucosa.
Disintegration time of the unit in oesophagus is the factor on which the  passage of the drug into the stomach and
through  the small intestine depends.

Oesophageal
damage

oesophageal injury can occur due to the adhesion of dosage
form releasing concentrated solution of drug to a very small area of mucosa.Dysphagia
is the result of repeated insult to the mucosa; and even rebuke formation, both
of them intensify the original problem. Enteric coated formulations given as an
alternative of gastric mucosal irritant drug can result into the failure if
units chalet into the oesophagus having pH near in 19701, first medication
induced oesophageal injury was  reported
and in 198323 it was reviewed.

Afterall there have been numerous reports in the literature,
due to 26 different medications 221 cases were reported in the time period
between 1960 and 1983.

Numerous drugs like emepronium bromide, theophylline,
doxycycline monohydrate and bisphosphonates26 
have been reported as to account for half of the reported cases
including antibiotics, regardless of brand. Although this has not been studied
but various proportion of drugs which are prescribed may be reflected through
it . According to endoscopic surveillance studies in healthy volunteer we can
detect oesophagitis in 20% of subjects having non-steroidal anti-inflammatories
(NSAIDs). Oesophageal stricture can be caused in patients with gastro-oesophageal
reflux due to NSAIDs caustic or acidic effects, hyperosmotic effect, heat
production, gastro-oesophageal reflux, impaired oesophageal clearance of acid
and accumulation within the basal layer of the epithelium are the range of
mechanisms through which drug can cause local injury, moreover to other toxic
effects caused by the drug.

Physiological
Pharmaceutics

An erosion about the size of a coin,  a deep ulcer or redness and friability of
mucosa are determined by endoscopy. Sometimes particles of the drug get adhered
to the mucosa.The aortic arch or slightly above it is the area where majority
of abrasion are located. mostly  in
bedridden patients, lesions are found higher in oesophagus the lower third of
the oesophagus, just above the gastro-oesophageal junction is the area where
lesions have also been reported. stricture may result in severe cases. There
are many patients that are ostensibly healthy but suddenly hit by the symptoms
of oesophageal injury. Such patients are between 9 and 98 years of age, both
men and women alike are affected according to the literature.

If the patient takes the tablets/capsules without water and
just  before retiring to bed, this single
dosage form can cause problems. This results in severe retrosternal pain after
waking up few hours later or inmorning and it cant be reassured by drinking or
eating. As swallowing becomes painful, patient avoids it.In this situation
doctor will avert  the heart disease and
prescribe an analgesic or antacid, if medical approach is made .This can only
rissolve when the patient  changes his
method of taking medications otherwise pain will continue.

 

EFFECT
OF AGEING

In ageing population, one of the major health care problem
with advancing age is loss of the ability to swallow. Radiological studies
shows the presence of a normal pattern of of deglutition in only 16%
individuals out of 56 patients with a mean age 83 years . 63% of the cases were
noted having Oral abnormalities, such as having trouble in controlling and
transporting  a bolus followed by
ingestion to the oesophagus. Although minor changes of structure and function
are directly related to ageing, however neoplasms, strictures and diverticula
are structural abnormalities that cause oesophageal dysphagia therefore, during
a swallow trouble occurs in relation with the coordination of tongue,
oropharynx and upper oesophagus associated with neurological mechanisms.

Oesophageal
transit

Even small tablets (4 mm) get adhered to the oesophagus as a
result of weakened swallowing in elderly.According to reports aminobisphosphonates
which is  used to inhibit bone
resorption, along with the other low dose tablets are cause of ulceration.Such
medications should be consumed with 240 ml water and after administration the
subject should remain vertical for 30 minutes as according to FDA
recommendation. By sticking on the roof of oropharynx, coadministered dosage
forms which float on the water can also present problems to the elderly.

PATIENT
PREFERENCE AND EASE OF SWALLOWING

Due to smooth surface and shape which support swallowing,
Patients prefer to take capsules rather than large oval or round tablets
comparatively. After the age of 60 years when up to 60% of healthy subjects may
show  a problem, the difficulty rate to
swallow large round tablets increases. There is a tendency amongst these
patients have tendency either  to open
the capsule and dissolve the pills in food or a drink or to chew tablets and
capsules. Due to this there is an unknown loss of dose amount. Sustained or
controlled release formulations that are designed to be swallowed complete are
effected by chewing formulations and also the integrity of any surface coating
is destroyed by chewing formulations. Surface area available for drug
termination is increased by chewing and it also destroy matrix structures.

EFFECT
OF DISEASED STATES ON TRANSIT

Oropharyngeal dysphagia or achalasia are diseased states that
can effect oesophageal transportation. A common problem, oral pharyngeal
dysphagia in the elderly can be responsible for a significant injury/disease
and mortality. The commonest cause of Oral-pharyngeal dysphagia could be
neurogenic dysfunction with stroke it can also be due to local structural
injuries. due to local structural abrasions including inability of lower
oesophageal sphincter to relax and reduced transportation by an oesophageal
stricture, achalasia is caused.it results as the oesophageal maintainance of
food

.Although the abnormality of the oesophagus is not essential
for adhesion of dosage forms,however chronic alcoholism, scleroderma and
diabetes mellitus are the diseases which cause abnormalities in oesophageal
function.

drugs such as theophylline may show an increased rate of
adhesion because  studies have shown that
oesophageal dysfunction is more common in 
asthmatics subjects as compare to the normal ones.

Oesophagitis produced as a result of injury to the
oesophageal mucosa due to reflux of gastric contents can lead to stricture.
Doxycycline monohydrate are the drugs which are poorly water soluble and should
produce little damage under normal conditions, however oesophageal damage
produced by such drugs can intensify the acid reflux.  Highly ulcerogenic hydrochloride can be
produced from monohydrate, due to the occurrence of gastrooesophagesal reflux
of acid. Since delayed transport is linked with hiatus hernia and gastro
oesophageal reflux with normal clearance time of 50s as compare to 9.5 in
normal, this problem would be compounded in humans.

The possibility of further damage increases due to an
existing stricture caused by reflux or previous ‘pill-induced’ damage.For
stricture and non-sricture groups, risk factors are associated with age,
posture and formulation.

TARGETING
THE OESOPHAGUS

Reproducible smooth and rapid oesophageal transit was focused
in the past attention. Delivery of drugs to the oesophageal mucosa would be
desirable in some cases, for example curing oesphageal damage or oesophageal
cancer from gastrooesophageal reflux. According to reports, In 1990, to treat
oesophageal cancer, ultrafine ferrite (Fe2O3), utilising a dye and polymer as
an release controlling delivery system was used. For this use, recently  poly (oxyethylene-b-oxypropylene-boxyethylene)-g-poly
(acrylic acid) which is made up of polyacrylic acid and a block copolymer of
ethylene oxide and propylene oxide has been discovered. At body temperature
this material undergoes reverse thermal gelation and shows great mucoadhesive
characteristics. Observations show that ten minutes after the administration,
about ten percent of the formulation was there.

CONCLUSIONS

Although oesophageal adhesion can cause problems like
local  ulceration or late drug
absorption, yet these dosage forms are surprisingly common. Size of dosage
form, its shape, position of subject, volume of water with which the dosage
form is administrated and suface properties of dosage form are some of the
important factors which prepare a formulation to adhere. Mainly in high risk
group, it is important to use correct method of swallowing the tablets. In
order to treat disorders of oesophagus, new technologies are developing to
deliver drugs locally.