BIOADHESION

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BIOADHESION
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BIOADHESION

• Bioadhesion can be defined as the ability of a
  drug carrier system (synthetic or biological) to
  adhere to a biological substrate for an extended
  period of time.
• The biological surface can be epithelial tissue
  (skin) or the mucous coat on the surface of a
  tissue.
• If the adhesive attachment is to a mucous coat,
  the phenomenon is referred to as mucoadhesion.

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Importance of Bioadhesion in Drug delivery

• Bioadhesion technique used to optimize either
  local or systemic drug delivery for various
  routes of administration by
• Extension of Contact Time
• prolong contact time of a drug delivery system to
  biological
• tissue can improve drug therapy.
• b. Localization of Drug Delivery System
• Some drugs are preferentially absorbed in a
  specified region "window for absorption". e.g.,
  iron, riboflavin, chlorothiazide.

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Mucoadhesion

• mucoadhesive dosage forms should be
• not cause irritation
• small and flexible enough to be accepted by the
  patient.
• These requirements can be met by using hydrogels.
• Hydrogels are hydrophilic matrices that are
  capable of swelling when placed in aqueous media.
• As water is absorbed into hydrogels, chain
  relaxation occurs and drug molecules are released
  through the spaces or channels within the
  hydrogel network.
• Hydrogels matrices include natural gums and
  cellulose derivatives.

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Mechanism of mucoadhesion

• The major constituents of mucus is mucin are the
  high molecular
• weight glycoproteins, Mucin also has different
  charge density
• Depending on the pH.
• For a good bioadhesive hydrogel , such as
  polycarbophil, the penetration into the mucus
  layer is dependent on the initial applied
  pressure.
• A moderately bioadhesive hydrogel, like
  polymethacrylate, shows a capability to entangle
  with the mucus layer.
• A poor bioadhesive hydrogel, like polyhydroxy
  ethyl methacrylate (PHEMA), shows little
  penetration into the mucus layer.

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The interaction of mucoadhesive hydrogels with
the mucus layer
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Theories of mucoadhesion, depending on the
chemical nature of adhesive/adherent combinations

1. Diffusion Theory The diffusion theory
describes interpenetration of the mucoadhesive
(polymer) and substrate (mucin) to a sufficient
depth and creation of a semipermanent adhesive
bond by physical entanglement which is dependent
on the molecular weight of the polymer and
flexibility and chain segment mobility of the
mucoadhesive polymer
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• 2. Adsorption Theory
• It is a surface force where surface molecules of
  adhesive and adherent are in contact.
• According to adsorption theory, bioadhesive
  systems adhere to tissue due to bond formation.
• Primary Chemical Bonds
• Many bioadhesives can form primary chemical
  covalent bonds with functional chemical groups in
  mucin
• Aldehydes and alkylating agents can readily react
  with
• amino groups and sulfhydryl groups.
• Acylating agents react with amino and hydroxyl
  groups of
• serine or tyrosine.

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Secondary chemical bonds Hydrogen bonding,
electrostatic forces or Van-der Waals attractions
are sufficient to contribute adhesive joints.
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3. Electronic Theory indicate that electronic
transfer on contact of the bioadhesive polymer
and the mucin glycoprotein, which lead to the
formation of a double layer of electrical charge
at the bioadhesive interface. 4. Wetting
Theory the ability of the adhesive to spread on
mucin influences the contact between the
mucoadhesive mucin, that consequently
influences mucoadhesive strength. Thus work of
adhesion is a function of the surface tensions of
surfaces in contact, as well as the interfacial
tension. A small interfacial tension means more
contact between the two surfaces.
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5. Mechanical Theory the adhesive flow into the
pores and interstices to create mechanical
embedding embedded adhesive solidifies and
becomes inextractable. The mechanical theory
depends on irregularities of the surface and
Highly fluid adhesives which are able to
penetrate into the cracks and crevices of the
adherent create mechanical embedding.
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To generalize the bioadhesion phenomenon The
First Step (wetting theory) A close contact
between the mucoadhesive and adherent occur by a
good wetting of the mucoadhesive surface (mucin
layer) and the swelling of the mucoadhesive
polymer with a sufficient spreading to assure a
contact at the molecular level between the
mucoadhesive and the membrane.
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The Second Step (Mechanical and diffusion
Theories) Once contact is established,
penetration of the mucoadhesive into the crevices
of the tissue surface. Hydrated polymer chains
are free to move and stretch and become entangled
or twisted when become into close contact with
the substrate. The Third Step (Adsorption and
Electronic Theories) Once entangled is
established, the bioadhesives match their active
adhesive sites with those on the substrate to
form an adhesive bond or the free entangled
molecules form cohesive bonds.
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Evaluation Of Bioadhesive Properties

• The test methods for bioadhesion measurements
  can be classified into two categories
• A. In-Vitro (Ex-Vivo) methods
• Detachment force
• Detachment weight method
• Wash-off test
• Electrical Conductance
• B. In- Vivo methods
• X-ray photography
• Scintigraphic method

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A. In-Vitro (Ex-Vivo) methods

• 1. Detachment force
• It is useful technique for adhesive
  characterization of bioadhesive solid and
  semisolid dosage forms.
• The adhesive force is determined by the work to
  break adhesive extensions off the adhesive mass.
• test using one tissue layer was used for the
  bioadhesive characterization of solid dosage
  forms
• test using two tissue layers was used for the
  bioadhesive characterization of semisolid dosage
  forms.

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penetrometer, Texture Analyzer, can be
used. bioadhesive performance was determined by
measuring the resistance to withdraw the probe
represent the work required for detachment of the
two systems.
TA-XT2i-Texture Analyzer
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2. Detachment weight method
Bioadhesive force is determined by the following
equation Detachment stress (dyne/cm2) x 102
m g / A Where m The minimal weight
added to the balance cause detach (g).
g Acceleration due to gravity (980 cm/sec 2).
A Area of tissue exposed (p r2
). Force of adhesion (N) Bioadhesive strength X
9.81
1000
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• 3. Wash-off test
• The method is used for the evaluation of
  mucoadhesion properties of microparticles
• Pieces of mucosal tissue were mounted onto glass
  slide.
• About 100 microparticles, with mucoadhesive
  polymer are spread onto wet tissue specimen. hold
  onto the arm of a USP tablet-disintegration
  tester, permitting a slow, regular up and down
  movement (30 min) in a test fluid kept at 37C.
• Mucoadhesive force of the tested polymer
  Resistant to hydrodynamic shear

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• 4. Electrical Conductance
• In the presence of adhesive material, the
  conductance was comparatively low.
• As the adhesive was removed, the value increased
  to a maximum value corresponding to the
  conductance of the saliva, which indicated the
  absence of adhesion.

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B. In- Vivo methods Based on the measurement of
the residence time of bioadhesives at the
application site. 1. X-ray photography Barium
sulfate (BaSO4) matrix dosage form, containing
the polymer whose bioadhesive properties want to
be tested, can be administered to the volunteer,
who is subjected to X-ray studies. X-ray
photographs show the extent of mucoadhesion of
the polymeric dosage form.
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2. Scintigraphic method
The gastrointestinal transit times of
bioadhesives have been examined using
radioisotopes as 55Cr-labeled bioadhesive
material was inserted in the stomach and the
radioactivity was measured at time intervals.
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FACTORS INFLUENCING BIOADHESION

• Nature of Polymer
• Hydration of adhesives
• Flexibility of adhesives
• Molecular weight and size of adhesives
• Function Groups of Adhesives
• Charge Sign of the Adhesives
• Charge density of adhesives
• Physiological Variables
• Hydration of Biological Substrates
• Turnover of Adherent
• Nature of Surrounding Media
• pH of the Surrounding Media

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Nature of Polymer
A polymer characteristics are necessary for
mucoadhesion (i) Strong hydrogen-bonding
group (-OH, -COOH). (ii) Strong ionic
charges. (iii) High molecular weight. (iv)
Sufficient chain flexibility. (v) Surface
energy properties favoring spreading onto mucus.
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• Hydration of Adhesives
• Many hydrocolloids, such as vegetable gums and
  hydrogels, such as polycarbophil become adhesive
  after hydration.
• Swelling state is an important factor for
  adhesiveness where the swollen polymer allows the
  relaxation of the molecules, exposing their
  adhesive sites and facilitating interpenetration
  to a sufficient depth in order to create adhesive
  bonds.

• However, there is an optimum water concentration
  for the hydrocolloid particles to develop maximum
  adhesive strength where excessive water may cause
  slippery nonadhesive mucilage.

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• Flexibility of Adhesives
• There is a relationship between structure and
  adhesion
• of mucoadhesive polymers where bioadhesives
  should
• possess optimal flexibility , to allow
  interpenetration of
• polymer and mucus to take place, that permit the
  adhesive
• to conform to the adherent.
• The flexibility of a polymer backbone is
  influenced by the
• steric effect of substituent side groups.
• As the size of the substituted side group becomes
  larger, chain flexibility is decreased.

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• If side chains are flexible, they give internal
  plasticization to the whole polymer structure
  with suitable adhesiveness.
• Increased cross-linking reduces chain flexibility
  that decreases bioadhesive performance
• As acrylic acid hydrogels (as Carbopol) contain
  coiled macromolecules, unable to form an elastic
  polymer network as a result of the repulsion of
  negative charges and many of the adhesively
  active groups are shielded inside the coils and
  do not actively participate in the adhesion
  process.

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• Thus, it is necessary to neutralize the produced
  anionic liquid gels to help in the formation of
  an expanded gel network.
• triethanolamine was preferred as neutralizing
  agent, since relatively higher viscosity could be
  obtained using organic amines than using
  inorganic bases (as sod. Hydroxide) where cations
  generated by amines, resulting in greater steric
  expansion of the polymer molecules than the
  smaller sodium cations which leads to lower
  hydration of the polymer.

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• Molecular Weight and Size of Adhesives
• Higher molecular weight leads to higher cohesive
  strength and reduces creep (move), due to the
  greater degree of chain entanglement resulting
  from longer chains.
• Adhesive force increases as polymer molecular
  weight increases, until a plateau value is
  reached.
• At higher than optimum molecular weight, adhesion
  may be reduced due to reduced penetration of the
  adherent surface by adhesive polymers due to
  their low mobility.

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• Function Groups of Adhesives
• For mucoadhesion to occur, polymers must have
  functional groups that are able to form hydrogen
  bonds, that explaine the excellent performance of
  adhesives, containing phenolic or aliphatic
  hydroxyl groups with polar substrates.
• Also charged carboxylated polyanions are good
  potential bioadhesives for drug delivery.

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• Charge Sign of the Adhesives
• Polymers commonly used can be classified as
  following
• Non-ionic polymers as Hydoxypropyl cellulose
  (HPC) and hydoxypropyl methylcellulose (HPMC).
• Polycationic polymers as Chitosan.
• Polyanionic polymers as Polyacrylic acid
  (PAA)
• derivatives, e.g., carbopols (CP) and
  polycarbophils

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• Cationic and anionic polymers bind more
  effectively with the epithelium than the neutral
  polymers.
• Positively charged polymeric hydrogels have
  additional molecular-attractive forces due to the
  electrostatic interactions with negatively
  charged mucosal surfaces
• Also anionic polymers with sulphate groups bind
  more effectively than those with carboxylic
  groups.

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• Charge Density of Adhesives
• It explain the mechanism whereby negative charge
• polymers can bind to a mucus surface of the same
  charge
• sign by the increase in the number of carboxyl or
  sulfonate
• groups on the surface, which cause increase in
  wettability.
• The reason for the excellent bioadhesive
  property of Polycarbophil or Carbopol is due to
  that, they are both polyanions with high charge
  density.

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Physiological Variables
Hydration of Biological Substrates
Effective adhesion can only occur, when an
adhesive and adherent are brought into molecular
contact. The presence of water and other fluids
on the surface of adherent may prevent full
effective interactions at appropriate interfaces
,Due to greatest disruptive effect of water on
adhesive bonds occur with polymer systems,
which depend primarily on hydrogen bonding.
The dehydration theory of mucoadhesion
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• Turnover of Adherent
• Mucus covering epithelial cells in the GIT ,
• Nasal or eye is continuously secreted and
  eliminated.
• The continuous renewal of the adherent as in soft
  tissue bioadhesion , allow failure of a strong
  adhesive bond.
• Thus bioadhesives which bind to this mucus layer
  are expected to be removed at the same time when
  mucin turnover regardless of the adhesive
  strength.

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Nature of Surrounding Media
pH of the Surrounding Media

• Mucous has a different charge density, depending
  on pH, due to differences in dissociation of
  functional groups on the carbohydrate in the
  amino acids of polypeptide backbone.
• As the pH of the adherent medium increased,
  charge repulsion is increase with decrease in
  adhesion.
• The absorption of water by a polymer and its
  swelling, depends on the pH.
• The interaction of polycarbophil with
  intestinal tissue was negligible compared to that
  with stomach tissue due to the difference in pH.

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Applications of bioadhesion
Mucoadhesion

• Transmucosal routes of drug delivery (i.e.,
  the mucosal linings of the eyes, nasal, rectal,
  vaginal and buccal cavities) offer advantages for
  systemic drug delivery include
• Bypass of first pass effect,
• avoidance of presystemic elimination within the
  gastrointestinal tract.

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1. Buccal mucoadhesives

• Advantages Of Buccal Adhesive Drug Delivery
  Systems
• The mucosa is relatively permeable (4-4000) times
  greater than that of the skin with a rich blood
  supply that render buccal adhesive drug delivery
  systems gained interest in systemic delivery of
  drugs undergoing hepatic first-pass metabolism
  within the gastrointestinal tract.
• Drug can be easily applied and localized to the
  application site and can be removed.
• Buccal cavity is highly acceptable by patients.

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Disadvantages Of Buccal Adhesive Drug Delivery
Systems

1. the environmental factors such as the exposure of
   the oral mucosa to salivary flow, shearing forces
   of tongue movement and swallowing which can act
   to displace and wash away an adhering vehicle

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There are considerable differences in
permeability between different regions of the
oral cavity, because of the varied structures and
functions of the different oral mucosa. The
permeabilities of the oral mucosa decrease in the
order of sublingual gt buccal gt palatal.
This rank order is based on the relative
thickness and degree of keratinization of these
tissues, with the sublingual mucosa being
relatively thin and non-keratinized, the buccal
thicker and non-keratinized and the palatal
intermediate in thickness but keratinized.
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• Thus, oral cavity drug delivery is classified
  into
• (i) Sublingual delivery
• Which is systemic delivery of drugs through the
  mucosal membranes lining the floor of the mouth.
• Give rapid absorption with acceptable
  bioavailability of many drugs.

(ii) Local delivery Drug delivery into the
oral cavity has a number of applications
including, the treatment of toothaches,
periodontal diseases, aphthous and dental
stomatitis. (iii) Buccal delivery, which is
drug administration through the mucosal membranes
lining the cheeks (buccal mucosa).
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• 2. Oral Mucoadhesion
• to localize a drug and increase its residence
  time at a certain site in the GIT.
• Oesophageal Mucoadhesion
• Oesophageal mucoadhesion is used for prolonged
  retention of drugs within the oesophagus for
  treatment of upper gastro-oesophageal disorders.
  
• Alginate solution can form a coat for
  localization of drugs within the oesophageal
  tissue for prolonged periods of time.

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• Gastric Mucoadhesion
• Gastric residence of a conventional dosage form
  is typically short and transit rapidly through
  the small intestine. This diminish the extent of
  absorption of many drugs.
• The Gastric mucoadhesive most commonly used
  system for prolonged residence time in stomach
  to improve the efficacy of antibiotics to
  penetrate through the gastric mucus layer in
  cases of gastritis, gastric ulcer and gastric
  carcinoma due to Helicobacter pylori.

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• Potential drug candidates for gastro-mucoadhesive
  
• a. Drugs that have absorption windows in the
  upper part of the gastrointestinal tract.
• b. All drugs that are intended for local action
  on the gastro-duodenal wall, as in case of
  ulcerous diseases.
• Carbomers and HPMC have good properties with the
• gastric mucoadhesion.
• Mucoadhesive chitosan microspheres interact with
  
• sialic acid in the gastric mucus by
  electrostatic
• interaction that improve the gastric
  residence time of a
• drug. Also provide pH-responsive release
  profile by swelling in acidic environment of the
  gastric fluid.

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• Intestinal Mucoadhesion
• Mucoadhesive microspheres applied into the
  intestine using Chitosan as a cationic
  mucoadhesive polymers can resist hydrodynamic
  shear leading to in vivo absorption enhancement
  of orally administered drugs.
• Chitosan microspheres can be used for the oral
  delivery of vaccines, based on its bioadhesive
  properties and biodegradability.
• Polycarbophyl beads, as an anionic bioadhesive
  are washed-off very rapidly.

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• Colon Mucoadhesion
• Colon mucoadhesion tablets remain intact in the
  stomach due to the enteric coat (EudragitL100).
• In small intestine, with alkaline pH, the enteric
  coat will dissolve
• Upon entry into the colon, the azo-networks of
  HPMC degrade by microbial azo reductase present
  in the colon to produce a structure, capable of
  developing mucoadhesive interactions with the
  colonic mucosa.

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• 3. Rectal Bioadhesion
• Anatomically, the upper part of the rectal
  venous drainage is connected with the portal
  system, while the lower part directly with the
  general circulation.
• solid suppository have hepatic first-pass
  elimination of the drugs following rectal
  administration.
• Liquid suppositories containing mucoadhesive
  polymers were administered intrarectally to
  avoiding first-pass hepatic elimination of the
  drug and avoid the hepatotoxicity of some drugs
  as antifungal ketoconazole.

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• Mucoadhesive polymers sodium alginate were added
  to liquid suppository bases Poloxamers (pluronic
  407 and P 188) to exhibit great mucoadhesive
  characterization with no irritation of the rectal
  mucosal membrane and diminish the migration
  distance of the suppository in rectum without
  leakage after administration.

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• 4. Vaginal Bioadhesion
• Vaginal delivery is useful for systemic drug
  absorption as well as local action.
• A numbers of factors including changes in
  vaginal environment cause some problems for
  drugs. Bioadhesive systems of sodium alginate and
  Chitosan may overcome these problems by yielding
  safe vaginal delivery systems as contraceptive
  vaginal formulations.

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• 5. Transurethral Bioadhesion
• The most common treatment method for carcinoma of
  the bladder is known as the transurethral
  resection (TUR).
• to obtain desired attachment onto the bladder
  wall for pharmacotherapy after TUR, mucoadhesive
  chitosan carrier was prepared in the form of
  cylindrical geometry.

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6.Nasal Mucoadhesion

• The nasal cavity can be used as a site
• for systemic drug delivery.
• chronic application of nasal dosage forms cause
  irreversible damage to the ciliary action of the
  nasal cavity
• the large intra- and inter-subject variability
  in mucus secretion of the nasal mucosa, could
  significantly affect drug absorption from this
  site.

1. Lower region for air way 2. Middle region for
systemic way 3. Upper region for olfactory way
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• Advantages
• intranasal drug delivery is ease of
  administration
• rapid drug absorption
• avoidance of hepatic first-pass metabolism.
• The richly supplied vascular nature of the nasal
  mucosa with its high drug permeation, makes the
  nasal route of administration attractive for many
  drugs.

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• The most efficient area for drug absorption
  through nasal mucosa is the lateral wall of the
  nasal cavity.
• The mucociliary clearance is inversely related to
  the residence time and the absorption of drugs
  administered.
• A prolonged residence time in the nasal cavity
  may be achieved by using bioadhesive polymers, as
  chitosan

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• 7. Pulmonary Bioadhesion (Airway Delivery)
• Advantege
• prolonging drug action and reducing drug dosage
  can be ashieved by using Pulmonary Bioadhesion .

Methyl cellulose (MC), Sodium carboxy
methylcellulose(SCMC) Hydroxy propyl cellulose
(HPC) are most commonly used polymers.
Powder inhalation in airway path for pulmonary
bioadhesion
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• 8. Ocular Bioadhesion
• Drugs administered systemically have poor access
  to the inside of the eye, because of the
  blood-aqueous and blood-retinal barriers.

• Topically applied drugs are rapidly eliminated
  from the precorneal area. lost within 15-30 sec.
  due to reflex tearing and drainage via the
  nasolacrimal duct.
• The cornea is considered as an effective barrier
  to drug penetration, since the corneal epithelium
  has tight junctions which completely surround and
  effectively seal the superficial epithelial cell.

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• Some polymers have the capacity to adhere to the
  mucin coat covering the conjunctiva and the
  corneal surface of the eye prolonging the
  residence time of a drug.
• At physiological pH of tears, the mucus network
  usually carries a significant negative charge
  because of the presence of sialic acid and
  sulfate residues.

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• Ophthalmic bioadhesives including hydrogels like
  carbopols, polyacrylic acids and chitosan which
  can be formulated as mucoadhesive erodible ocular
  inserts, minitablets, microspheres or hydrogels.

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• 9. Hemostasis and Wound Dressing Bioadhesion
• Bioadhesives have been used as
• haemostatic and wound healing agents.
• Requirements for good Bioadhesive polymers
• for haemostatic and wound healing.
• Have the ability to spread on tissue surfaces
• Must be rapidly and uniformly adhere and conform
  to wound bed topography and contour to prevent
  air or fluid pocket formation.
• Prevents peripheral channeling into the wound by
  bacteria and promotes bonding to tissues.

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• Must be Permeable to water vapor to the extent,
  that moist exudates under the dressing is
  maintained without pooling, but excess fluid
  absorption and evaporation leading to desiccation
  of the wound bed.
• Must not interfere with normal progress of
  natural repair process, compatible with body
  tissues, be nontoxic, non irritant, non-antigenic
  and non-allergenic.
• Fibrinogen and cyanoacrylates are effective in
  face-to-face sealing of tissues or wound healing.

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• Chitosan could be dissolved in organic acids,
  such as lactic acid and acetic acid and casted
  into films forming soft, flexible and pliable
  bioadhesive wound healing bandages able to
  effectively bind and agglutinate a wide variety
  of mammalian cell types.
• Cross-linked gelatin films were bonded to heart
  muscle and to lung pleura and parenchyma, using
  the electrical discharge of an argon beam
  radio-frequency coagulator.
• denatured protein constituents of both gelatin
  and tissue protein chains create a fluidized
  state that rapidly coalesced.

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Dental Bioadhesion

• Adhesion to a tooth substance is difficult,
• because the surface is not usually smooth and the
  external enamel is coated with an organic
  proteinaceous cuticle.
• Dental adhesives, such as polyacrylic acid, to
  enamel explained by the ability of free carboxyl
  groups to displace phosphate ions from the
  apatite matrix to ensure excellent wetting.
• Materials that adher to calcified tissue forming
  chelate with calcium as poly (acrylic acid)
  considered as good dental adhesives.

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Transdermal bioadhesion

• Transdermal bioadhesion (drug-in-glue patch-
  systems)
• Advantages of Transdermal delivery
• Reduce the systemic toxicity and side effect.
• Minimize the loss of drug, due to first pass
  metabolism
• Gastrointestinal adverse effects can be avoided
• Easily termination of therapy
• Release of the drug is controllable

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• The bonding strength of glutaraldehyde
  crosslinked gelatin films with biological tissue
  is due to aldehyde in the GA-gelatin films and
  the amino groups of the natural tissue.

• Organogels obtained by adding small amounts of
  water to organic solution of lecithin produce
  lecithin gels as efficient bioadhesive vehicles
  for transdermal transport of various drugs