VARIOUS DRUG DELIVERY SYSTEMS Ronny Martien

OCULAR DRUG DELIVERY SYSTEM

ROUTES OF OCULAR DELIVERY SYSTEMS
BARRIER
CORNEA AS A
BARRIER
 PRECORNEAL FACTORS
Loss of drug:
–spillage
•normal tear volume = 7 μl
•volume that can be accommodated without spillage = 30 μl
•estimated drop volume = 50 μl
•blinking > residual volume of ~10 μl

–removal by the naso-lacrimal duct

•takes place when reflex tearing causes volume to exceed 7-10 μl
•eventually goes to GI tract: Potential systemic effects, salty/ bitter
taste
•superficial absorption of drug through the conjunctiva: rapid
removal by peripheral blood vessels
 CORNEAL DRUG ABSORPTION
Drugs administered by instillation must penetrate the eye primarily
through cornea
Cornea provides a mechanical and chemical barrier for foreign
substances
Corneal epithelium is considered as a tight epithelium due to the
presence of tight junctions called ZONULA OCCLUDEN
Cornea is a lipid-water-lipid sandwich
Most effective penetration is obtained with drugs having both lipophilic
and hydrophilic properties
Presence of multidrug resistance efflux pumps on the cornea such as P-
gp, MRP and BCRP have also been proved to limit absorption of
topically applied drugs across the cornea
TRANSCLERAL DELIVERY: STATIC BARRIERS

1. Sclera
2. Choroid
3. Retinal pigment epithelium
(RPE)
Matrix composed of proteoglycans and collagen fibers
Permeability across sclera: dependence on molecular radius and
molecular weight
Increase in solute lipid solubility correlated to lower scleral
permeability
Hydrophilic molecules proposed to diffuse through in the aqueous
media of the proteoglycans
Charge also plays a role in scleral permeability: preferential lower
permeability of positively charged molecules due to negatively
charged proteoglycansfacilitating charge based interactions
RPE AS A BARRIER
TRANSCLERAL DELIVERY : DYNAMIC
BARRIERS
 APPLICATIONS
Intravitreal injections: Involves direct
injections of drugs into the vitreous
humor
High drug levels in retina
Endophthalmitis (retinal detachment)
Patient compliance
Development of glaucoma and cataract
 IMPLANTS
Scleral and vitreal implants have been attempted
Need for replacement every 6 months
Implants made from poly lactide/glycolide polymers
BUCCAL DRUG DELIVERY SYSTEM
•By pass hepatic first-pass metabolism
ADVANTAGES
•Improved patient compliance
•Sustained drug delivery
•A relatively rapid onset of action can be achieved relative to the oral
route, and the formulation can be removed if therapy is required to be
discontinued
•Increased ease of drug administration
•the buccal mucosa is well vascularized , and drugs can be rapidly
absorbed into the venous system underneath the oral mucosa.
•Transmucosal delivery occurs is less variable between patients, resulting
in lower intersubject variability
•The large contact surface of the oral cavity contributes to rapid and
extensive drug absorption
 LIMITATIONS
For local action the rapid elimination of drugs due to the flushing
action of saliva or the ingestion of foods stuffs may lead to the
requirement for frequent dosing.
The non-uniform distribution of drugs within saliva on release from a
solid or semisolid delivery system could mean that some areas of the
oral cavity may not receive effective levels.
For both local and systemic action, patient acceptability in terms of
taste, irritancy and ‘mouth feel’ is an issue.
 POTENTIAL APPLICATIONS INCLUDE THE DELIVERY OF

breath-freshening agents
nutriceuticals
vitamins
caffeine
pharmaceutical actives (from poorly soluble to highly soluble)
1. Sublingual delivery, consisting of administration through the
membrane of the ventral surface of the tongue and the floor of the
mouth.
2. Buccal delivery, consisting of administration through the buccal
mucosa, mainly composed of the lining of the cheeks
3. Local delivery, consisting of administration through all areas other
than former two region

These sites differ anatomically in their permeability to drugs, rate of drug

delivery, and ability to maintain a delivery system for the time required for drug
release out of the delivery apparatus and into the mucosa.
 STRUCTURE AND DESIGN OF BUCCAL DOSAGE FORM

Buccal Dosage form can be of

1. Matrix type: The buccal patch designed in a matrix configuration contains

drug, adhesive, and additives mixed together

1. Reserviour type: The buccal patch designed in a reservoir system contains a

cavity for the drug and additives separate from the adhesive.

An impermeable backing is applied to control the direction of drug delivery; to

reduce patch deformation and disintegration while in the mouth; and to prevent
drug loss

Additionally, the patch can be constructed to undergo minimal degradation in the

mouth, or can be designed to dissolve almost immediately
Transmucosal drug delivery systems can be :

1. bi-directional, patches release drug in both the mucosa and the mouth

2. Unidirectional, patches release the drug only into the mucosa

Drug + mucoadhesive matrix

bi-directional

Backing layer

Drug + mucoadhesive matrix

Unidirectional
STRUCTURE OF ORAL MUCOSA
• epithelium,
• basement membrane ,
• the lamina propria and
• submucosa.
• sensory receptors
• the taste receptors of the tongue.
 PERMEABILITY OF DRUGS THROUGH BUCCAL MUCOSA

There are 2 possible routes of drug absorption :

1. Transcellular (intracellular, passing through the cell)

2. Paracellular (intercellular, passing around the cell)

• Mainly by the paracellular route through the intercellular lipids produced by

membrane-coating granules

• passive diffusion is the main mechanism

• a potential site for the controlled delivery of hydrophilic macromolecular

therapeutic agents (biopharmaceuticals) such as peptides, oligonucleotides
and polysaccharides

• contains proteases that may degrade peptide-based drugs

• the salivary enzymes may also reduce stability

 BUCCAL DRUG DELIVERY AND
MUCOADHESIVITY
In the development of these Buccal drug delivery systems, mucoadhesion of the
device is a key element.

To serve as mucoadhesive polymers, the polymers should possess some general

physiochemical features such as :

• Suitable surface property for wetting mucus/mucosal tissue surfaces

• Sufficient flexibility to penetrate the mucus network or tissue crevices.

 POLYMER
Carboxymethyl cellulose, Thermally modified Starch,
Carbopol Pectin,
Polycarbophil, Polyvinyl pyrrolidone,
Poly(acrylicacid/ divinyl benzene), Acacia,
Sodium Alginate, Polyethylene glycol,
Hydroxyethyl cellulose, Psyllium
Hydroxypropyl methylcellulose,
Hyaluronic acid,
Gelatin, Guar Gum,
 NOVEL MUCOADHESIVE POLYMERS
Copolymer of PAA
PEG monoethylether monomethacrylate,
PAA complexed with PEGylated drug conjugate,
Hydrophilic pressure-sensitive adhesives (PSAs),
AB block copolymer of oligo(methyl methacrylate) and PAA ,
Polymers with thiol groups
 FACTORS AFFECTING DRUG
DELIVERY VIA BUCCAL ROUTE
Low solubility determines a small concentration gradient to the plasma
and the rate of diffusion is accordingly low.
Highly lipophilic compounds could permeate through the transcellular
route by partitioning into the lipids of the intercellular matrix while
hydrophilic compounds could diffuse through the paracellular pathway
Crystalline status and thermodynamic activity of a drug are
correlated with the diffusant concentration, thus affecting permeation.
Small molecules, <~100 Da, cross the mucosa rapidly; permeability
decreases as molecular size increases; high molecular weight drugs, such
as peptides, oligonucleotides and hormones, usually have low
permeability leading to a low bioavailability.
The pKa is indicative of the molecule degree of ionization and affects
permeability: maximum absorption occurs when molecules are not ionized
and absorption decreases as the degree of ionization increases. Most
drugs are weak acids or bases, and exist in solution as equilibrium
between the unionized and ionized forms. Only unionized nonpolar drugs
penetrate the membrane and, at equilibrium, the concentrations of the
unionized species are equal on both sides of the membrane. The
unionized form is assumed to be sufficiently lipophilic to cross membranes.
The fraction ionized is controlled by both the environmental pH and the
drug pKa.
 METHODS TO INCREASE DRUG
DELIVERY VIA BUCCAL ROUTE
Absorption enhancers
a) increasing the fluidity of the cell membrane,
b) extracting inter/intracellular lipids,
c) altering cellular proteins
d) altering surface mucin

Prodrugs
Administration of nalbuphine and naloxone in prodrug form caused no
adverse effects, with bioavailability ranging from 35 to 50%
showing marked improvement over the oral bioavailability of these
compounds
pH
permeability of acyclovir was found to be pH dependent with an increase influx
and permeability coefficient at both pH extremes (pH 3.3 and 8.8)

Patch design
the drug release pattern was different between single-layered and multi-layered patches
 TOXICITY AND IRRITANCY ASSOCIATED WITH
BUCCAL DRUG DELIVERY
Toxic effects can arise from the drug itself, the bioadhesive or from other
components of the formulation.

Carbomers have been reported to produce mucosal irritation believed to result

from a localised low pH,

lectins have been shown to be cytotoxic

absorption enhancers (e.g., sodium dodecyl sulfate) have also been reported to
be irritant.
 DRUG
Acitretin Nalbuphine
Metronidazole Cetyl Pyridinium chloride
Acyclovir Nicotine
Melatonin
Arecoline
Metoprolol tartrate
Buprenorpine
Morphine sulphate
Carbamazepine
VAGINAL DRUG DELIVERY SYSTEM
 ADVANTAGES
Easiness for administration
Auto administration
Hepatic first pass-effect by pass
Low systemic drug exposure
Increased permeability for some drug
Low enzymatic activities
Drug targeted to uterus (first uterine pass effect)
 DISADVANTAGES
Not seems to be feasible for most drug, ex. Steroids
Social taboos
Unawareness and gender specificity
Menstrual cycle associated vaginal change
Genital hygiene issues
Local site effect
Coitus interference and variable drug permeability
 DRUG DOSAGE FORM AND DELIVERY SYSTEM

Anatomical and physiological features of the vagina

Traditionally, liquids (solutions, emulsions or suspensions), vaginal
suppositories (also referred as pessaries or ovules), tablets, creams
and ointments.
Recently, gels and vaginal rings gained increased popularity due to
their unique advantages and women’s acceptance
Others, such as capsules, foams, vaginal films, and medicated
tampons, sponges or diaphragms
In progress, the use of mucoadhesive polymers, pH- or temperature-
sensitive delivery systems, nanocarriers, inserts, multiple emulsions or
modified saprophyte flora.
 USES
Treatment or management of local conditions, particularly those of
infectious nature, exp. local spermicides and cleansing products
Development of vaginal rings and other improved delivery systems
boosted the use of steroidal hormonal as contraceptives or in hormonal
substitution therapy
Emergency contraception, labor inducement, and abortion
Microbicides (vaginal products intended to protect from HIV and other
sexually transmitted infections),
mucosal vaccines
therapeutic proteins and peptides
Vaginal administration in animals (cattle fertility regulation purposes)
BLOOD BRAIN BARRIER (BBB)
BARRIERS
(1) tight junctions that seal the
pathway between the capillary
(endothelial) cells
(2) the lipid nature of the cell
membranes of the capillary wall
which makes it a barrier towater-
soluble molecules
(3), (4), and (5) represent some
of the carriers and ion channels;
(6) the 'enzymatic barrier'that
removes molecules from the blood
(7) the efflux pumps which
extrude fat-soluble molecules that
have crossed into the cells
STRATEGY
lipid-soluble pro-drug
Disruption of the BBB injecting mannitol
Intraventricular / Intra thecal delivery
Intra nasal drug delivery
The GLIADEL® wafer is a biodegradable
polymer loaded with the chemotherapeutic
agent for treatment of malignant brain
tumors
After surgical removal of the brain tumor,
GLIADEL® wafers are soaked with a
chemotherapy drug and are implanted in the
space where the tumor was. The wafers
destroy the remaining tumor cells.