Biopharmaceutics of Non Oral Medications
Possible routes of drug administration are
divided into two classes :
1- Enteral
2- Parenteral
Enteral include , Sublingual or buccal, oral and
rectal administration .
Parenteral routes include, I.V, I.M, Subutaneous
injections and topical application to the eyes
or certain mucous membrane.
Skin and dermatological preparation
Dermatological preparation are those which
intended to act locally in the treatment of skin
disorders.
It is applied to the skin for systemic absorption to
decrease some side effect of drugs such as
topical application of glucocorticoids
dramatically decrease their side effects.
Anti- inflammatory drugs that have irritant effect
on the stomach mucosa can be used topically on
the skin for systemic absorption with decreasing
its side effect .
Anatomy of Human Skin
1- Epidermis 2- Dermis 3- subcutaneous Fat
The most superfacial layer of epidermis is the
stratum corneum which is composed of several
layers of dead keratinized cells.
The Dermis or true skin is highly vascular region
Drugs penetrating to this region are likely to
reach the systemic circulation .
Per cutaneous Absorption
Route of penetration:
The molecules move from the environment to the
intact skin of the living person through :
-- folecular region Sweat glands Unbroken
stratum corneum between these appendages .
Hair follicles play a distinguished part in the
penetration of particular substances.
It found that absorption of hydrocortisone is rapid
in region with large or numerous hair follicles ,as
in scalp and forehead.
Absorption is decreased in in some region of skin
having thickened stratum corneum e.g. the foot.
Cuts ,diaper rash , inflammation, mild burns or any
other condition in which the stratum corneum is
injured promotes the absorption of drugs
through the skin.
Factors affecting the skin penetration :
1- Physicochemical properties of the drug.
2- Vehicle, PH and concentration.
3- Different physiological variation .
Among these variables are :
a- Condition of skin ,intact or injured.
b- skin age c- The area of skin treated .
d- The thickness of skin barrier phase.
e- Species variation F- Hydration state of skin
• Chemical form of drug and the vehicle in which
the drug is incorporated can have an important
influence on percutaneous absorption .
• Example the efficacy of flucinolon eacetonide in
inflammatory dermatosis (eczema and psoriasis
Strongly depend on the vehicle .
Cream containing 0.1% of hydrocortisone is more
effective than several other commercial
formulation containing 1% hydrocortisone .
The percutaneous absorption of betamethzone
17-benzoate is more greater from gel than from
cream.
• Incorporation of certain chemicals ,such as DMSO
(dimethylsulfoxide ) into topical formulation has been
advocated to enhance penetration and percutaneous
absorption of drugs .
• Possibly by producing structural change of the skin
,such as swelling of stratum corneum .
• Possibly by replacement of water as the continuous
membrane phase of the skin barrier.
• Absorption of hydrocortisone is increased during
repeated administration whether it was applied in an
acetone vehicle or an emulsion ointment base.
• Long term aplication of hydrocortisone may alter the
percutaneous barrier ,resulting in inhanced
penetration.
• Hexachlorophane and gama benzene
hexachloride are absorbed from the skin.
• The topical application of drugs intended for
systemic absorption may be useful for :
• 1- Drugs with low bioavailability after oral
administration due to first pass effect.
• 2- It may be useful for short acting drugs since
percutaneous absorption tend to be slow and
prolonged effect may be realized.
• E.g. nitroglycerin ointment has longer duration of
action when compared with sublingual one , it
can be used as prophylactic in certain cases of
angina . Ointment has slower onset of action
than buccal medication so it is not used for acute
attack .Nitroglycerin ointment is available in 0.2%
strength in lanoline petrolatum base.
• Rectal Administration
• Suppositories are more frequently used in children
than in adult.
• Rectal administration of drugs intended for systemic
effect is usually limited to those situation in which
oral administration is difficult or contraindicated.
There are many drugs that can be administered by this
route ,e.g,aspirin ,acetaminophen, theophyllin,
chlorpromazine ,promethazine,indomethacin and
certain barbiturates.
The drug absorption from rectum is often slow ,as
rectum is devoid from villi and has a relatively small
surface area but rectum has a good blood supply.
• The following are general principles with respect
to drug absorption following rectal
administration to human:
• 1- Absorption from rectum is more rapid and
efficient when drugs are given in solution
form(microenema ) than in suppository form .
• 2- Absorption is more variable when drugs are
administered in solution form rectally than orally.
• 3- the presence of fecal matter in rectum retards
absorption .so absorption is more rapid and
efficient if a cleansing enema preceds drug
administration.
• 4- Some suppository base ,such as PEG are irritant to
human rectum and to promote defecation and loss of
drug.
• 5- Bioavailability from suppositories may be poor
because the drug is not released or is slowly released .
• The extent of absorption of theophyllin after rectal
administration of aqueous solution of drug was about
90% that found after oral administration.
• Attempts to develop rectal dosage forms of tetracyclin
and penicillin G have been unsuccessful because of
poor absorption of these drugs across rectal mucosa .
• The extent of absorption of rectal solution of antibiotic
lincomycin in children and adults was only 50% that
observed after oral administration of a syrup of a drug and
was more variable., and only about one third that found
with capsule given orally.
• Rectal suppositories of acetaminophen produce an
antipyretic effect almost equal to an oral elixir in febrile
children ,ranging in age from 3 months to 6 years .
• The absorption of non steroidal anti- inflammatory and
analgesic drug naproxin after rectal suppositories
• Is rapid and complete as after commercial oral tablets.
• Indomethacin given orally as capsules or rectally as
suppositories are equally effective in relieving morning
symptoms inpatient with rheumatoid arthiritis.
• It was found that bioavailability of diazepam from
rectal suppositories is better than from I.V.
injection and absorption of it from rectal solutions
is far better than from suppositories, and the rate
of absorption of drug from rectal solution is
greater than from oral tablets .
• So rectal solution of diazepam may be a suitable
alternative to I.V. injection of convulsive disorders
in young children.
• Rectal suppositories of oxymorphone has been
compared with I.V. injection of the drug in
patients with postoperative pain ,rectal
administration resulted in lower and delayed
peak of analgesia and a slightly longer duration of
effect than I.M injection. Rectal oxymorphone
was found to be one tenth as potent as I.M.form.
However since I.M oxymorphone is 9 to 10 times
as potent as morphine 5 to 10 mg of
oxymorphone by suppositories may be as
effective as the usual injected doses of narcotic
analgesics.
• Rectal administration of analgesic meptazinol in healthy
subjects resulted in more rapid and complete absorption
than after oral administration .
• The more rapid absorption may be the result of avoiding
the gastric emptying seen after oral administration of the
drug . The more complete absorption suggests that at least
part of the rectal dose was absorbed directly into systemic
circulation and not subject to pre systemic hepatic
metabolism.
• The mean bioavailability of lidocaine was considerably
higher after rectal than after oral administration. This is due
to the fact that about half of the rectal dose by passes the
liver during absorption.
Intranasal Application
• There is interest in the intranasal route for the
systemic administration of drugs as:
• 1- the nasal mucosa appear to be more
permeable to drugs than the GIT mucosa .
• 2- No local metabolism is known.
• 3- dugs absorbed through the nasal mucosa go
directly to blood stream and are not subject to
first pass hepatic metabolism.
• E.G. propranolol, Nitroglycerin(NTG).
• NTG is rapidly absorbed when given
intranasally ,it provide a safe , simple and
effective method to attenuate the
hypertensive response to laryngoscopy and
tracheal intubation.
• Factors Affecting absorption of the drug from
the nasal mucosa:
• 1- Lipid solubility of the drug .
• 2- Molecular weight of the drug .
• 3- Effect on the movement of the nasal cilia .
• Posterior pituitary hormones and other
related compounds such as oxytocin and
desmopressin . Oxytocin is available as a nasal
solution to stimulate lactation .
• Desmopressin is a synthetic polypeptide , its
acetate salt nasal solution is indicated for the
prevention or control of polydipsia , polyuria
and dehydration associated with diabetes
insipidus caused by insufficient antidiuretic
hormone.
• Intranasal administration of buserelin in the
treatment of patients with metastatic prostatic
cancer was used in the form of a nasal spray
delivering 100 ug of drug per inhalation .
• Intranasal buserelin is an effective ,simple and
safe way to achieve androgen deprivation in the
treatment of advanced prostatic cancer . This
treatment neither causes the psychological
problems of castration nor is associated with
morbidity of estrogen administration .
• Nasal spray of this drug is more acceptable to
patients than daily subcutaneous injection
• The nasal absorption of other hormones such
as insulin and calcitonin is limited and not
sufficiently reproducible.
• Nasal administration of insulin with promoter
such as bile salts improves bioavailability .
• Administration of insulin in a solution
containing 5% sodium glycocholate increased
absorption of the drug but this bile salt is
clinically unacceptable .Why?
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Buccal or Sublingual Administration
Buccal or sublingual route appears ideal for ;
1- Lipid – soluble drug .
2- Those drugs that are metabolized in the
gastrointestinal or liver during absorption. Why?
• The pH of saliva is usually about 6. Increasing
the pH of fluid in the cavity promote the
absorption of weak bases but reduces the
absorption of weak acids. WHY?
• Although similarities exist between
gastrointestinal and buccal absorption of
drugs , some important differences must also
exist.
• 1- A higher degree of lipid solubility may be
required for good absorption from the buccal
cavity than from the gastrointestinal tract.
• 2- there are storage compartment in the
buccal membrane .
• This phenomenon may be responsible for the
slow absorption of buprenorphine after buccal
administration.
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The main advantages of sublingual nitroglycerin:
1- A lack of tolerance. 2- Ease of administration
3- Rapid ,consistent and complete absorption.
Nitroglycerine levels were variable after
sublingual administration . The low and variable
absorption of it may be related to :
• 1- The patient inability to maintain the dose in
the mouth without swallowing.
• 2- Inadequate moisture in the mouth . As the
sublingual mucosa must be sufficiently moist to
facilitate the dissolution of sublingual tablets of
nitroglycerin.
• An oral nitroglycerine aerosol spray is marketed
for the prevention and treatment of angina
pectoris.It is sprayed onto or under tongue. Its
effect appear after 2 min after use of spray.
• There are many advantages of nitroglycerin
spray over sublingual tablets :
• 1- It is easier to use spray than a small sublingual
tablets .
• 2- Dry mouth can delay the dissolution of
sublingual nitrate tablets .
• 3- The aerosol droplets may be better absorbed
in some patients.
• 4- The spray has shelf life 3-years, so it is more
stable than sublingual tablets which have a shelf
life of one year under ideal conditions.
• Rapid and effective bronchodilator (fenoterol)was
obtained by directing the jet of the aerosol onto the
buccal mucosa .This technique could prove useful in
the treatment of young children who can not use an
aerosol dosage in the recommended manner .
• Alprazolam is an anxiolytic agent for the treatment
of panic disorder . Sublingual administration may be
a useful alternative for panic disorder patients who
can not swallow tablets or those who do not have
access to water .Its absorption is rapid after
sublingual administration and may prove to be
preferable to oral administration of alprazolam after
a meal ,when gastric emptying is prolonged and the
rate of absorption is reduced.
• Nicotine gum was developed as substitution
therapy to help people stop smoking .
• The preparation consists of nicotine bound to an
ion exchange resin and incorporated into a gum
base .The gum also contain a bicarbonate buffer
to enhance the buccal absorption of nicotine .
• Nicotine is well absorbed from buccal cavity
during gum chewing but rather slowly
• The absorption of methylesterone from
sublingual tablets is high with the avoidance of
presystemic metabolism.
Prolonged-Release Medication
Pharmacokinetic Theory :
The duration of drug effect is a function of the
pharmacokinetic of the drug molecule in an
individual patient.
The degree of persistence of the molecule in the
body is determined by clearance and apparent
volume of distribution of a drug .This persistence is
characterized in term of half life or mean residence
time (MRT). Because the duration of drug action is
related to the distribution and elimination kinetics of
a drug ,the frequency of dosing must have some
relation to the drug,s half life or MRT .
• Drug absorption and duration effect.
• Prolonged release medication is a dosage form
containing more drug than a conventional
dosage form but releasing the drug far more
slowly over a period of hours or even days.
• We seek a situation where the duration of
drug action is determined by the duration of
drug release from the dosage form rather than
the drug molecule,s pharmacokinetics
properties .
• Steady State Concentration and Release Rate
• Reducing the absorption rate of a drug by
controlling its release rate from the dosage form
can dramatically affect drug concentration at
steady state . For a given dose regimen the slower
the release rate of drug the smaller is the ratio of
maximum to minimum drug concentration at
steady state .
• Under these conditions we can give larger doses at
less frequent interval and still stay within the
therapeutic concentration range of the drug .This is
the rationale for prolonged release medication.
• Zero Order Release
The only way to achieve constant blood level is to
administer the drug at a constant rate over the entire
dosing interval( zero order).
The concentration of drug at steady state is given by the
following equation :
Css= ko/cl
Ko is the zero order delivery or release rate of drug
Cl is the clearance of the drug .
Today there are dosage forms intended for oral ,ocular ,
intravaginal or intramuscular administration that
release the drug in zero order or near zero order
fashion.
Oral medication
The ultimate criteria for evaluating prolonged
release dosage forms are :
1- The amount of the drug intended to be
absorbed is indeed absorbed in a predictable
and consistent manner.
2- The steady –state ratio of maximum to
minimum drug concentration is no greater than
or,optimally, less than that produced by more
frequently administered conventional dosage
form.
• A wide variety of techniques have been used to
develop prolonged release oral dosage forms.
1- the use of drug substance of decreased solubility
or dissolution rate ,accomplished by :
a- Increasing particle size
b- the use of less soluble salt or complexes .
c- Ion exchange resin to bind the drug substance.
2- Porous, non disintegrating, inert carriers as
matrices for the drug .
3- Slowly eroding coatings or matrices and coatings
that serve as membranes for drug diffusion.
• Most oral prolonged release dosage forms are
either subdivided or single units.
• Subdivided PRD forms exemplified by Spansules.
• Several kinds of beads are found in the hard
gelatin capsule ,some releasing the drug rapidly,
• Others releasing the drug over a period of several
• Hours ,still others releasing the drug at
intermediate rates. These beads of drug are
slowly dissolving and releasing the drug at
different rates.
Phenothiazine ,antihistamines,iron and many drugs are
available in this kind of dosage form.
The single unit prolonged release dosage form remain more
or less intact throughout the GIT releasing the drug
continuously during its passage down the tract. An example
of this dosage form is
The inert plastic matrix ,the drug is mixed with inert insoluble
powdered matrix consisting of plastic resin and other
ingredient and compressed .In the GIT drug particles from
the surface of the matrix system dissolve and leave pores
through which the drug from within the tablet leaches out
.The matrix retain its shape during the leaching process and
is eliminated in the feces . The release rate of drug
decreases with time , and in this sense , resemble a first
order process.
• Zero Order Release:
A system termed Elementary osmotic Pump (EOP)
Is now available to achieve this goal.
The EOP tablet contain a solid core of drug and
adjuvants coated with a polymeric membrane
,permeable to water and interrupted only by a single
small orifice with a diameter of 0.1 to 0.4 mm . After
the tablet is swallowed the membrane selectively
admits water from the GHT , drug within the
membrane is gradually dissolved the internal
pressure produced by entry of the water forces the
drug solution out of the orifice.Since the volume of
the system is fixed ,constant rate of release is
achieved.
The depleted membrane is excreted intact .Drug
release is independent of pH or motility .
The duration of drug delivery is controlled by :
The permeability of the membrane
Composition of the core .
At a given rate of drug delivery ,the duration of
controlled release is determined by the amount
of drug in the core.
Generic Osmotic Pumps :
Thy are available as experimental tools for animal or
clinical studies .
They are useful for but not limited to oral
administration .
The reservoir is filled with a drug solution . The wall
of the reservoir is inert ,impermeable and flexible.
A sleeve of osmotically active agent is placed
between the reservoir wall and the rigid semi
permeable membrane .
Water from the surroundings is imbibed through
the outer membrane into the osmotic sleeve at a
rate controlled by:
the permeability of membrane and the osmotic
pressure difference across the membrane .
The incoming water squeezes the reservoir and the
drug solution is expelled at a constant volume per
unit time. Delivery of drug solution continues at a
constant rate until the drug reservoir is
completely collapsed.
Limitations of Prolonged Release Medication
1- The limited residence time of the dosage form
in the small intestine.
2- Drugs having a biological half life of 8 hours or
more should not be used in prolonged release
preparation.
3- Drugs that are efficiently absorbed only in the
proximal intestine .e.g. riboflavin,as there is no
release of the drug in this absorbing area.
4- The drug that is metbolised in G.I. barrier during
absorption. E.g. Chlorpromazine ( extensive first
pass clearance).
5- Drugs administered in slow release dosage
form are subjected to metabolism by bacteria in
the lower intestine .This is of particular concern
for drug molecules that can be biochemically
reduced such as those containing nitro group .
Bacterial metabolism can affect bioavailability or
result in the formation of toxic metabolites.
6- Drugs whose precision (accuracy ) of dosage is
important e.g. digitalis glycosides should not be
administered in prolonged release D.F.
7- Drugs with slow intrinsic absorption rates .
8- Drugs such as warfarin ,where pharmacological
effect is delayed relative to its wood profile .
9- Low or slow solubility drug
10- Extensive first pass clearance.
There are some exceptions:
Nitroglycerin has a short half life ,less than 0.5 hour ,it
is rapidly metabolized in the liver and is considered
to be poorly absorbed, but the low circulating level
of it obtained from these products appear to provide
adequate prophylaxis against anginal attack.
Some drugs have biological half life 8 hrs and given
as prolonged release .These products may
reduce toxic effects by preventing the sharp
peak in circulating drug levels .
Implants
Numerous devices have been described for the
diffusion through silicon rubber e.g. contraceptive
devices in the form of silicon rubber capsules
containing progesterone have been implanted
subcutaneously.
silicon rubber capsules containing ethinyl estradiol have
been used in the treatment of patients with prostate
cancer .
Certain disorders of male reproductive function can be
treated with long acting implants of testosterone .
Sub dermal silastic implants containing
levonorgestrel have been described. The
capsules are implanted into a women upper or
lower arm with hypodermic needle.
The capsules are to be effective for 5 years .
Generic osmotic pump is a useful implant for
experimental drug study in animals .
Commercially available pumps permit constant
rate delivery over one or two weeks .
Refillable implant have also described .These
devices have been used in patients prone to
thrombophlebitis and pulmonary embolism
who require heparin . One refillable implant
deliver heparin solution continuously over
45days before refilling is necessary .
These implants are also used to provide an intraarterial infusion of 5- fluorouracil for the
treatment of hepatoma and primary liver
cancer.
Portable Infusion Pump(PIP):
The most important application of it is the
programmed delivery of insulin to provide strict
control of blood glucose levels in diabetes .
Recently developments of PIP provide light
,portable devices for use by out patients requiring
chronic parenteral therapy but need not be
hospitalized.
Typically the hormones can infused S.C by a
catheter leading from the portable pump.
There many advantages of Insulin Pump Therapy:
1- Can improve and stabilize eye and kidney
function in insulin dependent diabetic patients.
2- A good and efficient glucose control is achieved
by using it.
Ocular Medication
Drug effect in the eye tend to be short lived
because of the eye,s efficient mechanism to
maintain homeostasis . Ocular insert (ocusert)
intended to release the drug slowly in a
controlled fashion ,offer the potential benefit
of 1-dramatic decrease in the frequency of
dosing.
2- more uniform clinical response.
3-decrease in adverse effect.
Ocusert containing pilocarpine is used for lowering
elevated ocular pressure .The insert is placed
under the eye lid where it remains seven days
slowly and continuously delivering pilocarpine.
Ocusert consists of the drug enclosed by a dense
membrane . Pilocarpine is dissolved in the
membrane and diffuses slowly to the eye .
N.B the total dose delivered by a single ocusert
over its 7 days lifetime is one eighth of the
amount provided by the usual 2% eye drops of
pilocarpine.
Advantages of pilocarpine ocusert :
1- Less effect on accomodation
2- therapeutic effectiveness.
3- Less miosis.
4- convenient to patients.
Disadvantages :
1-Occasional discomfort .
2- High cost.
3- the need for instruction and encouragement of
the patient.
Intrauterine device:
Intrauterine progesterone drug delivery system
( progestasert)
It slowly release an average of 60 ug of
progesterone per day for a period of one year
after insertion.
The continuous release of progesterone into the
uterine cavity provide a local rather than systemic
action .
Intrauterine device contain 38 mg of progesterone .
The device is replaced annually for the
maintenance of contraception.
Progestasert is a T shaped ,polymeric
progesterone containing device that
continuously delivered 60 ug of drug per day
for one year.
It has the advantages of :
1- Using natural hormone .
2- No estrogen.
3- using a T- shaped delivery device to ensure
comfort ,safety and retention ,minimizing
mechanically- induced irritation.
4- hormonal action is confined to the uterus.
Progestasert is a device contain 38mg of
progesterone suspended in silicon oil , Barium
sulphate is added to make it radio opaque.
EVA(ethylene vinyl acetate )membrane that
surround the drug core control the rate of drug
release.Titanium dioxide is added o the EVA for
a white color.At the end of the year the device
will contain 14 mg of drug .this excess is
required to maintain the thermodynamic
activity of the drug reservoir.
Vaginl Insert
Vaginal administration of drugs especially
hormones has many advantages:
1- Self insertion and removal and continuous
drug administration at effective dose level and
better patient compliance.
2- continuous release and local absorption of
drug minimizes systemic toxicity that may
result from oral peak and valley drug
administration.