Bioadhesives in Drug Delivery Mucoadhesive drug delivery systems came into picture in the early 1980s and are one of the most studied novel delivery systems. Several researchers have focused on the investigations of the interfacial phenomena of mucoadhesion with the mucus. Tehran University of Medical Sciences Faculty of Pharmacy

1. Hajimiri SH, Payandemehr B and Soltani A
Students of Pharmacy
Tehran University of Medical Sciences

2.  The use of bioadhesives in drug delivery systems is by
no means new, although increased interest in its
unique applications in therapy is evidenced by the
recent spate of publications.

3. What is Bioadhesive?
 A bioadhesive can be defined as any substance that can
adhere to a biological substrate and is capable of being
retained on that surface for an extended period of time.

4.  Bioadhesives complement drug delivery systems
through increased residence time in the various routes
of administration.

5.  Prolonged contact time can offer very substantial
improvements in local drug therapy as well as
significant increases in bioavailability for some drugs.

6.  Drug delivery systems using bioadhesives usually
adhere to membrane surfaces or the mucin layer
coating such surfaces. The majority of the targeted
areas used in drug delivery have a coating of mucus,
and bioadhesive polymers that attach to this mucus
coating are generally called mucoadhesives.

7. History
Bioadhesive drug delivery formulations were
introduced in 1947 when gum tragacanth was
mixed with dental adhesive powder.
The aim was to deliver Penicillin into the oral
mucosa.

8. This later became Orabase®, a formulation used to
treat mouth ulcers. This product is available as a
paste which will stick to the wet surfaces of the
mouth and form a protective film over the mouth
ulcer.

9.  Their residence times on these surfaces are
controlled by whether the bioadhesive is water soluble
or insoluble.

10.  In the case of water-soluble bioadhesives, contact time
is generally only a few hours, depending on the
adhesive and flow of biological fluid at the site of drug
administration.
 Water-insoluble polymers, incontrast, remain in place
until the mucin or tissue replaces it self, typically a
period of about 4 to 72 hours.

11. Biological Substrate
 Mucus Layer
All external cavities of the body are lined with a
continuous, thick, gel-like structure called mucin.
This layer serves as a protective barrier between the
cell surface and its external surroundings.

12.  Mucin is secreted by goblet cells and can be considered
a natural bioadhesive capable of binding to the
underlying epithelial tissue.

13.  Mucus is a mixture of mucin glycoproteins, water,
electrolytes, enzymes, bacteria, and epithelial cells.

14.  Mucin glycoproteins are macromolecules linked
together by cross-linking disulfide bonds, physical
entanglement and secondary bonds to form a
continuous network.

15.  These glycoproteins have an abundance of
oligosaccharide side chains, with their terminal ends
usually being either sialic acid or L-fucose.
 The entire mucin network at physiological pH has a
net negative charge due to these sialic acid residues
(pKa=2.6) and additional sulfate residues.

16.  Since mucus is continually being formed, secreted,
and removed from these tissues, its turn over rate must
be taken into consideration when designing a
bioadhesive dosage form.

17. Biological Substrate
 Epithelial Surface
Most animal cell membrane surfaces are covered with
glycoproteins and glycolipids extending from the cell
exterior.

18.  Like mucus, the surface of cell membranes has a net
negative charge due to the presence of charged groups.

19.  Contact between the adhesive and the mucosal
membrane or its coating can be seen as a two step
process, the initial contact between the bioadhesive
and substrate and the subsequent formation of bonds
between the two surfaces.

20. Mechanisms of bioadhesion
Step 1 : Wetting and swelling of polymer
Step 2 : Interpenetration between the polymer chains
and the mucosal membrane
Step 3 : Formation of chemical bonds between the
entangled chains

21.  Success of the initial contact appears dependent on
similarity of physicochemical properties between the
adhesive and substrate and is often associated with
‘‘wetting’’ of the substrate surface.
 Formation of bonds, which can be electrostatic,
hydrophobic, or hydrogen bonds, permit the
bioadhesive to attach to the substrate.

22. Adherence of a drug delivery system to mucosal membrane
Disruption of the mucus layer
Penetration of bioadhesive in the mucin

23.  Disruption of the mucus layer can be by abrasion, cell
sloughing, chemical alterations by mucolytic agents, or
disease state of the tissue.

24. If such an interruption occurs, bioadhesives can serve to:
1- Maintain continuity of the mucus layer and
minimize the exposed area
2- Replace the mucus layer and provide a protective
covering for the underlying cell layers from physical
and chemical injury
3- Act as a platform for drug delivery to local tissues
and facilitate recovery of the damaged or diseased cell
layers

25. BIOADHESIVES
 The majority of work using bioadhesives in drug
delivery has been with a small number of water-
soluble and water-insoluble polymers.
 Bioadhesives can be natural or synthetic in origin, but
in drug delivery systems, non-biological
macromolecules are often used.

26. Examples of Bioadhesives
Water soluble Water insoluble
Cationic Anionic Neutral Cationic Anionic Neutral
Polylysine Alginic acid
Poly
ethelene
glycol
(PEG)
Gelatin Carbopol
Ethyl
cellulose
Polybrene Carrageena
n
Poly vinyl
pyrrolidone
(PVP)
Poly-
carbophil
Hydroxy
propyl
methyl
cellulose
Poly vinyl
methyl
imidazole
Carboxy
methyl
cellulose
Hydroxy
propyl
cellulose
Cross-
linked
polymethac
rylic acid
Poly methyl
methacrylat
e
Mucoadhesive polymers have been utilised in many different dosage forms in
efforts to achieve systemic delivery of drugs through the different mucosae.

27.  When both toxicity and bioadhesive properties are
considered, polyanionic polymers appear to be better
bioadhesives than polycations.
 Also, polyanions with carboxyl groups appear to be
better than those with sulfate groups when only
toxicity is considered.

28. Such polymers are sometimes referred to as
biological ‘glues’ because they are incorporated
into drugs to enable the drugs to bind to their
target tissues.

29. Physicochemical Criteria for Bioadhesion
 To serve as mucoadhesive polymers, the polymers
should possess some general physiochemical features
such as predominantly anionic hydrophilicity with
numerous hydrogen bond-forming groups, suitable
surface property for wetting mucus/mucosal tissue
surfaces and sufficient flexibility to penetrate the
mucus network or tissue crevices.

30.  In several studies the molecular weight of a compound
has been shown to be proportional to its bioadhesive
strength.
 For most polymers, increasing the molecular weight
means an increase in length of the molecule, which
can have an effect on the physical penetration and
subsequent entanglement of the polymer with the
substrate.

31.  The interactions between bioadhesives and their
substrates occur through covalent bonds, electrostatic
interactions, and hydrogen bond formation.

32.  Bioadhesive polymers often have numerous
hydrophilic functional groups such as carboxyl,
hydroxyl, amide, and sulfate groups which can form
hydrogen bonds with the biological substrates.
 These bonds may play a larger role in bioadhesion
than the electrostatic interactions mentioned above.

33.  The pH of the media can play a significant role in a
polymer’s bioadhesive strength, depending on the pKa
of the adhesive.
 Many polymers show significant bioadhesive strength
when they are not ionized.

34.  The degree of hydration of a polymer is pertinent to its
adhesive properties because sufficient water is needed
to properly hydrate and expand the adhesive.
 If insufficient amounts of solvent are available or
hydration is slow, the polymer is not fully hydrated and
this limits the flexibility and mobility of the polymer
chains, which is crucial to their diffusion and
penetration into a substrate.

35.  If a drug delivery system using bioadhesives is placed
in an aqueous medium, the polymer will absorb water.
This absorption of water leads to the formation of
aqueous channels and subsequent desorption of water
soluble drug.

36. How to control release of the drug?
 Controlling the swelling rate, the cross-linking density
of the polymer network, ionicity and pH of the media,
solubility of the active drug, and so on, of a drug
delivery system containing a bioadhesive can all be
manipulated to optimize release of the drug from the
delivery system to the targeted membrane.

37. Devices
 Bioadhesive dosage forms, such as laminated polymer
films, mucoadhesive tablets and patches, inserts, gels,
films, viscous liquids, gel forming liquids are currently
being investigated for sustained delivery of drugs.

38. APPLICATIONS
 Along with the physicochemical characteristics of the
bioadhesive and mucin–epithelium surface,
physiological events in the area in which adhesion
occurs must be addressed to optimize the drug
delivery system.

39.  Most delivery systems utilizing bioadhesives are
designed to be topically applied to a targeted tissue.
Drug delivery systems using bioadhesives can be
applied to many areas of the body, such as the oral
cavity, gastric, intestinal, rectal, vaginal, ocular, and
dermal areas.

40.  Each tissue type has its own unique properties which
can be exploited for the delivery of drugs.
 Each biological membrane has its own permeability,
enzym aticactivity, and immunology, which have to be
taken into consideration if both satisfactory
bioadhesion and improved bioavailability of drug are
to be achieved.

41. A. Gastrointestinal
 Most drug delivery systems are taken orally with the
absorption of the drug occurring mainly in the
proximal small intestine.

42.  To be effective either locally or systematically, a
bioadhesive drug delivery system must be able to
overcome the harsh gastric environment, motility of
the gastrointestinal (GI) tract, immunogenic
responses, enzymatic degradation, and dynamic
changes in localization of the drug.

43.  The intestinal route is a desirable one despite these
conditions because of its high absorptive
characteristics compared to other routes of
administration, which often need permeability
enhancement of the tissue to increase bioavailability
of the drug.

44.  This has been exploited in the use of an antiulcer drug
that can adhere to damaged gastric epithelial tissue.

45.  The antiulcer drug Sucralfate is used for the
treatment of peptic ulcers and has been shown to bind
to damaged gastric mucosa.
 Sucralfate polymerizes upon addition to acid and
forms a viscous mass that binds to the gastric mucosa.

46. Advantages
 Controlled intestinal release of drugs through the use
of bioadhesives has certain advantages due to the high
absorptivity and neutral pH of the intestinal lumen.
 The increased residence time in the lumen of the
intestine also increased the bioavailability of poorly
absorbed drugs.

47. Disadvantages
 Enzymatic and immunogenic degradation of both
drug and bioadhesive must be addressed in any route
of administration but seems to be very important in
the GI tract.
 Another drawback to the gastrointestinal route is that
drugs that enter the general circulation are subject to
first-pass metabolism as they pass through the
hepatic-portal system leading to lower systemic
availability.

48. B. Rectal
 Suppositories containing bioadhesives can reduce this
migration toward the upper rectum and hence
improve drug bioavailability.

49. Rectal Bioadhesive Formulations
 Anacal®
 Germoloids®
 Preparation H®

50.  Insulin (penetration enhancers)
 Antipyrine
 Theophylline (control released by cross-linked
hydroxyethyl methacrylate (HEMA) )

51.  The combination of permeability enhancement and
localization by bioadhesives has the potential to
increase drug bioavailability significantly via the rectal
route of administration.

52. C. Nasal
 This area provides an excellent route for drug
absorption because of its large surface area and
vascularity as well as a thin layer of mucus secreted
from local mucosal glands. Absorption into the
bloodstream via the nasal route also eliminates hepatic
first-pass metabolism.

53.  The nasal cavity is considered as an excellent route for
localized treatment (e.g., nasal inflammation and
allergic responses) as well as for systemic drug delivery.

54.  A suitable bioadhesive could then be hydrated by the
nasal mucus and form a viscous gel covering the nasal
cavity.

55.  Hydrophilic compounds that are normally poorly
absorbed in the nasal cavity can still be utilized using
penetration enhancers in conjunction with a retained
delivery system.

56.  Using degradable starch microspheres and a
penetration enhancer, the nasal absorption of
gentamicin was shown to be improved.
 Nasal administration of insulin and calcitonin has
been shown to be improved when administered with
penetration enhancers.

57.  Rhinocort®
Nasal spray is a powdered mixture of the steroid
Beclomethasone dipropionate(50μg) and 30mg of
Hydroxypropyl cellulose(HPC).
* Beconase®
* Nasacort®

58. D. Vaginal
 The vaginal and cervical route of administration is
unique from other routes in that the tissue
environment is subject to many changes throughout a
women’s life.
 Thus a vaginal bioadhesive delivery system geared to
women would need to address different conditions to
optimize drug availability.

59.  The patented use of a soluble hydroxypropyl cellulose
(HPC) cartridge for vaginal delivery of drugs has been
shown to release the drug for an extended period of
time.
 The anticancer drugs bleomycin, carbazilquinone, and
5-fluorouracil have been administered directly to the
cervix using disk- and rod-shaped dosage forms
containing a combination of HPC and Carbopol.

60.  Compared to vaginal suppositories, local side effects of
these dosage forms were reduced and stay in the
diseased area for a longer period of time.

61.  During a woman’s reproductive years, the vaginal
bacterial flora is capable of maintaining an acidic
environment which can reduce vaginal infection by
limiting the bacterial growth often associated with
other disease states.
 Maintenance of this slightly acidic pH is then crucial
for vaginal health, and thus drug delivery systems that
address this phenomenon have obvious therapeutic
benefits.

62. Vaginal bioadhesive formulations

63. E. Oral Cavity
 Drug administration to the oral cavity has many
advantages from both a patient and a therapeutic
point of view.
 Both local and systemic availability can be achieved
using bioadhesives in the oral cavity.
 Anesthetic, anti-inflammatory, and antimicrobial
agents can be administered locally for increased
residence time using bioadhesives.

64.  Systemic delivery of drugs through the mouth has
gained popularity in recent years.
 Drugs that are susceptible to degradation by the
harshness of the gastrointestinal route can be
administered via the mouth.
 This avoids first-pass metabolism of susceptible com-
pounds by the hepatic system and offers the patient a
more desirable route of administration than injection.

65.  Due to the limited area of the oral cavity, the delivery
system itself is restricted in size, and hence potent
compounds, such as proteins and peptides, are often
more suited to such delivery systems.

66. 3 distinct functional areas of oral cavity
The lining mucosa
(buccal, sublingal, and soft palate)
The masticatory mucosa
(hard palate and gingiva)
The specialized mucosa
(dorsal tongue)
The thickness and keratinization of the tissue differs between these regions and
hence the permeability of each is unique.

67.  The majority of the work with systemic delivery
systems using bioadhesives in the oral cavity has been
concentrated on the buccal (cheek) route of
administration because of its large surface area and
nonkeratinization.

68. Common conditions affecting the oral cavity
 Mouth ulcers
 Oral thrush
 Gingivitis

69. Oral Bioadhesive Formulations
 Corlan®
Corlan pellets are used in the treatment of mouth
ulcers to reduce the pain, swelling and
inflammation associated with mouth ulcers.
The active ingredient of the pellet is
Hydrocortisone succinate.

70.  Gelclair®
Is a gel that helps with the management of pain
associated with lesions and oral mucositis.

71.  Insulin( low bioavailability due to poor permeability)
 Treatment of cardiovascular disorders such as
angina and hypertension (nifedipine, nitroglycerin)

72. F. Ocular
 Drug delivery to the eyes is made difficult by dilution
of drug in the tears and the natural mechanisms of
blinking and high tear turnover rate, which protect
the eye from external contaminants.
 Bioavailability is severely limited for either local or
systemic therapy.

73. Some conditions of the eye
 Conjunctivitis
 Dry eye
 Glaucoma

74.  For a drug to be sustained in the eye, it must be
maintained in the precorneal area and deliver drug to
this area for an extended period of time.
 Ocular bioadhesive delivery systems could show a
sustained effect if they penetrate the aqueous tear film
and interact with the underlying mucin or cell layer. If
firmly attached to the surface, the dosage form could
remain in the preocular area longer than conventional
ocular dosage forms, and if dissolution of drug release
is controlled, utilization of water-soluble drug can be
increased significantly.

75.  Piloplex is a sustained-release product based on an
emulsion system of pilocarpine bound to a polymeric
carrier.
 The release of progesterone used as a model drug in an
ocular delivery system consisting of cross-linked
acrylic acid has been shown to be sustained. (4.2 times
increased bioavailability)
 Fuorometholone (1.7 times increased bioavailibility)

76. G. Topical
The drug delivery systems used in this case are
required to adhere to the skin for the purpose of:
• Collecting body fluids
• Protecting the skin
• Providing local or systemic drug delivery

77.  Voltarol® Emulgel
 Feldene®
 Evorel®

78. References
 Robinson R, Handbook of adhesive technology, 2nd
edition
 Mathiowits E, Bioadhesive drug delivery systems, 1999
 Jasti B, Recent Advances in Mucoadhesive Drug
Delivery Systems, Drug delivery polymers, 2003

79. Thanks for attention
