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Bioadhesi dapat didefinisikan sebagai kemampuan sistem
BIOADHESION & MUCOADHESION
Importance of Bioadhesion in Drug
delivery
Teknik bioadhesi digunakan untuk mengoptimalkan
penghantaran obat lokal atau sistemik ke berbagai jalur
administrasi dengan cara:
a. Perpanjangan Waktu Kontak: memperpanjang waktu
kontak sistem penghantaran obat ke jaringan biologis
dapat memperbaiki terapi obat.
b. Lokalisir Sistem Pengiriman Obat: Beberapa obat lebih
mudah diabsorbsi di bagian tertentu "jendela untuk
absorbsi" misalnya besi, riboflavin, klorotiazida.
pembawa obat (sintetis atau biologis) untuk melekat pada
substrat biologis untuk jangka waktu yang lama.
Permukaan biologis bisa berupa jaringan epitel (kulit) atau
lapisan mukosa pada permukaan jaringan. Jika tempat
perlekatan adalah mukosa, fenomena tersebut disebut
sebagai mucoadhesion.
Transdermal bioadhesion
Transdermal bioadhesion (drug-in-glue patch- systems)
Keuntungan penghantaran transdermal:
- Mengurangi toksisitas sistemik dan efek
sampingnya.
- Minimalkan hilangnya obat, karena first pass
metabolisme
- Efek samping gastrointestinal dapat dihindari
- Mudah terminasi terapi
- Pelepasan obat bisa dikontrol
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Kekuatan ikatan film glutaraldehyde
crosslinked gelatin dengan jaringan
biologis disebabkan aldehida dalam
film GA-gelatin dan gugus amino
dari jaringan biologis.
Organogels yang diperoleh dengan
menambahkan sejumlah kecil air ke
larutan organik lesitin menghasilkan
gel lesitin sebagai pembawa
bioadhesive yang efisien untuk
transport transdermal berbagai
obat.
Harus permeabel terhadap uap air sampai
batas tertentu, eksudat lembab di bawah
sediaan dipertahankan tanpa genangan,
penyerapan cairan yang berlebih dan
penguapan menyebabkan pengeringan pada
luka.
Tidak boleh mengganggu proses normal
perbaikan alami, kompatibel dengan jaringan
tubuh, tidak beracun, tidak mengiritasi, tidak
antigenik dan tidak alergi.
Fibrinogen dan cyanoacrylates efektif dalam
face-to-face sealing atau penyembuhan luka.
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Hemostasis and Wound
Dressing Bioadhesion
Bioadhesives telah digunakan sebagai
agen penyembuhan hemostatik dan luka.
Persyaratan untuk polimer Bioadhesive yang baik untuk
penyembuhan hemostatik dan luka:
Memiliki kemampuan untuk menyebar di permukaan
jaringan
Harus secara cepat dan seragam menutup dan melekat
sesuai dengan topografi dan kontur luka untuk mencegah
pembentukan kantong udara atau cairan
Mencegah penyaluran perifer dari bakteri ke dalam luka
dan mendorong ikatan jaringan.
Chitosan dapat dilarutkan dalam asam organik, seperti
asam laktat dan asam asetat dan dicetak ke dalam cetakan
film yang membentuk perban luka bioadhesive yang
lembut, fleksibel dan lentur yang mampu mengikat dan
menggumpalkan beragam jenis sel mamalia secara efektif.
Cross-linked gelatin films terikat pada otot jantung dan
pleura paru dan parenkim, dengan menggunakan
pelepasan listrik dari argon beam radio-frequency
coagulator.
Protein terdenaturasi dari gelatin dan protein jaringan
membentuk keadaan terfluidisasi yang cepat bersatu.
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Dental Bioadhesion Pulmonary Bioadhesion (Airway Delivery)

Keuntungan: memperpanjang aksi obat dan mengurangi dosis
Adhesi pada gigi sulit dilakukan, karena permukaannya obat dapat dicapai dengan menggunakan Bioadhesion Paru.
biasanya tidak rata dan enamel eksternal dilapisi dengan Methyl cellulose (MC), Sodium carboxy methylcellulose
kutikula protein organik. (SCMC), Hydroxy propyl cellulose (HPC) adalah polimer yang
Perekat gigi, seperti asam poliakrilat, dapat melekat pada paling banyak digunakan.
email karena adanya kemampuan gugus karboksil bebas
untuk menggantikan ion fosfat dari matriks untuk
memastikan pembasahan yang baik.
Bahan yang menempel pada jaringan terkalsifikasi Powder inhalation in airway path for
pulmonary bioadhesion
membentuk khelat dengan kalsium sebagai poly (acrylic
acid) yang dianggap sebagai perekat gigi yang baik.

Ocular Bioadhesion
Beberapa polimer memiliki kapasitas untuk melekat di
lapisan mucin yang menutupi konjungtiva dan permukaan
Obat yang diberikan secara sistemik memiliki akses yang kornea mata sehingga memperpanjang waktu tinggal
buruk ke bagian dalam mata, karena adanya barrier blood- obat.
aqueous dan blood-retinal. Pada pH air mata fisiologis, jaringan lendir biasanya
Obat yang dioleskan secara topikal dengan cepat membawa muatan negatif yang signifikan karena adanya
dihilangkan dari area precorneal. Hilang dalam waktu 15- asam sialat dan residu sulfat.
30 detik karena refleks air mata dan drainase melalui
saluran nasolakrimal.
Kornea dianggap sebagai penghalang efektif untuk
penetrasi obat, karena epitel kornea memiliki sambungan
yang rapat yang benar-benar mengelilingi dan secara
efektif menutup sel epitel superfisial.

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Ophthalmic bioadhesives termasuk hidrogel seperti
carbopol, asam poliakrilat dan chitosan yang dapat
diformulasikan sebagai mucoadhesive erodible ocular
inserts, tablet mini, microspheres atau hidrogel.
Mechanism of mucoadhesion
Bentuk sediaan mukoadhesif harus:
tidak menyebabkan iritasi
cukup kecil dan fleksibel untuk bisa diterima oleh
pasien.
Persyaratan ini bisa dipenuhi dengan menggunakan
hidrogel.
Hidrogel: adalah matriks hidrofilik yang mampu
mengembang saat ditempatkan di media berair.
Seiring air diserap ke dalam hidrogel, terjadi relaksasi
rantai dan molekul obat dilepaskan melalui ruang atau
saluran di dalam jaringan hidrogel.
Matriks hidrogel meliputi gom alami dan turunan selulosa.
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MUCOADHESION
Konstituen utama mucus adalah mucin yaitu glikoprotein
dengan berat molekul tinggi, mucin juga memiliki densitas
muatan yang berbeda tergantung pH.
Untuk hidrogel bioadhesive yang baik, seperti
polycarbophil, penetrasi ke lapisan lendir bergantung pada
tekanan awal saat diaplikasikan.
Hidrogel berkekuatan bioadhesive yang moderat, misalnya
polymethacrylate, menunjukkan kemampuan untuk
terjerat dengan lapisan mucus.
Hidrogel yang berkekuatan bioadhesive rendah, seperti
polihidroksi etil metakrilat (PHEMA), menunjukkan sedikit
penetrasi ke dalam lapisan lendir.
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Theories of mucoadhesion, depending on the

chemical nature of adhesive/adherent
combinations :
1.Teori Difusi:
Teori difusi menggambarkan interpenetrasi mukoadesif
(polimer) dan substrat (mucin) sampai kedalaman yang
cukup dan pembentukan ikatan perekat semipermanen oleh
ikatan fisik yang bergantung pada berat molekul polimer dan
fleksibilitas dan mobilitas segmen rantai polimer mukoadesif

2. Teori Adsorpsi: Ini adalah kekuatan permukaan dimana Ikatan kimia sekunder: Ikatan hidrogen, kekuatan
molekul permukaan perekat dan pengikat bersentuhan. elektrostatik atau atraksi Van-der Waals cukup untuk
Menurut teori adsorpsi, sistem bioadhesive menempel pada berkontribusi pada sendi perekat.
jaringan karena pembentukan ikatan.
3. Teori Elektronik: menunjukkan bahwa transfer elektronik
Ikatan Kimia Primer
pada kontak polimer bioadhesive dan glikoprotein mucin,
Banyak bioadhesives dapat membentuk ikatan kovalen kimia yang menyebabkan pembentukan lapisan ganda muatan
dengan gugus fungsional pada mucin: listrik pada antarmuka bioadhesive.
Aldehida dan zat alkilasi dapat dengan mudah bereaksi
dengan gugus amino dan kelompok sulfhidril.
Agen asilasi bereaksi dengan gugus amino dan hidroksil
dari serin atau tirosin.

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4.Wetting Theory :
5. Teori Mekanik: adhesive mengalir ke dalam pori-pori dan
Kemampuan adhesive untuk menyebar pada mucin celah untuk membuat perekat tertanam, memadat dan
mempengaruhi kontak antara mucoadhesive & mucin, yang menjadi tidak dapat diekstraksi.
akibatnya mempengaruhi kekuatan mukoadhesif. Dengan
Teori mekanis bergantung pada irregularities permukaan
demikian kerja adhesi adalah fungsi dari tegangan
dan sifat cair dari adhesive yang mampu menembus celah
permukaan dari permukaan yang bersentuhan, serta
menciptakan perlekatan mekanis.
tegangan antarmuka. Jika tegangan antarmuka kecil berarti
lebih banyak kontak antara dua permukaan.

To generalize the mucoadhesion

phenomenon:
Langkah Pertama: (teori pembasahan)
Kontak yang dekat antara mukoadhesif dan yang dilekati
terjadi dengan pembasahan yang baik pada permukaan
mukoadhesif (lapisan mucin) dan pengembangan polimer
mukoadesif dengan penyebaran yang cukup untuk
memastikan kontak pada tingkat molekuler antara
mukoadesif dan membran.
Langkah Kedua: (Teori Mekanik dan Difusi)
Begitu kontak terbentuk, terjadi penetrasi mucoadhesive ke
celah-celah permukaan jaringan. Rantai polimer terhidrasi
bebas bergerak dan meregang dan menjadi terjerat atau
bengkok saat terjadi kontak yang dekat dengan substrat.

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FACTORS INFLUENCING BIOADHESION

Langkah Ketiga: (Adsorpsi dan Teori Elektronik) Nature of Polymer:
Setelah terjadi jeratan, bioadhesives bergabung dengan sisi Hydration of adhesives

Flexibility of adhesives
perekat aktif mereka yang ada di media untuk membentuk
ikatan perekat; atau molekul bebas terjerat membentuk Molecular weight and size of adhesives

ikatan kohesif. 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

Nature of Polymer: Hydration of Adhesives

A polymer characteristics are necessary for mucoadhesion: Many hydrocolloids, such as vegetable gums and hydrogels,
Strong hydrogen-bonding group (-OH, -COOH).
such as polycarbophil become adhesive after hydration.
Swelling state is an important factor for adhesiveness where
Strong ionic charges.
the swollen polymer allows the relaxation of the molecules,
High molecular weight. exposing their adhesive sites and facilitating interpenetration
Sufficient chain flexibility. to a sufficient depth in order to create adhesive bonds.
Surface energy properties favoring spreading onto However, there is an optimum water concentration for the
mucus. 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.
Molecular Weight and Size of Adhesives
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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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.
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 explain 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.
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 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
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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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.
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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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.
Buccal mucoadhesives
Advantages :
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
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
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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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 > buccal > palatal.
Oral cavity drug delivery is classified into:
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.
Local delivery
Drug delivery into the oral cavity has a number of
applications including, the treatment of toothaches, periodontal
diseases, aphthous and dental stomatitis.
Buccal delivery,
which is drug administration through the mucosal membranes
lining the cheeks (buccal mucosa).
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Oral Mucoadhesion
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.
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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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.
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.
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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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.
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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Transurethral Bioadhesion Nasal Mucoadhesion

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.
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

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.
Evaluation Of Bioadhesive
A prolonged residence time in the
nasal cavity may be achieved by using
Properties
bioadhesive polymers, as chitosan

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In-Vitro (Ex-Vivo) methods: In- Vivo methods:

Detachment force X-ray photography
Detachment weight method Scintigraphic method
Wash-off test
Electrical Conductance

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 penetrometer, Texture
adhesive extensions off the adhesive mass. Analyzer, can be used.
bioadhesive performance
test using one tissue layer was used for the bioadhesive
was determined by
characterization of solid dosage forms measuring the resistance
test using two tissue layers was used for the bioadhesive to withdraw the probe
characterization of semisolid dosage forms. represent the work
required for detachment
of the two systems.

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Detachment weight method
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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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
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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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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