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SISTEM PENGHANTARAN OBAT
MELALUI MATA
ANITA LUKMAN
PENDAHULUAN
• Bola mata merupakan salah satu organ yang bisa
digunakan untuk pemberian obat namun sangat
terlindung terhadap zat asing melalui berbagai
barrier.
• Hal ini menjadi salah satu kendala untuk
pengembangan formulasi preparat mata
• Sediaan konvensional seperti salep, suspensi
atau tetes mata relatif tidak efisien dalam
pengobatan mata
Structure of Eye
•
The eye is composed of two components
1. anterior segment: consists of front one-third of eye that mainly
includes pupil, cornea, iris, ciliary body, aqueous humor, and lens
2. posterior segment: consists of the back two-thirds of the eye that
includes vitreous humor, retina, choroid, macula, and optic nerve
• For the treatment of the anterior segment of the
eye (cornea, conjunctiva, sclera, anterior uvea),
usually topical ocular eye-drops are used.
• An eye-drop, irrespective of the instilled volume,
often eliminates rapidly within five to six
minutes after administration, and only a small
amount (1–3%) of an eye-drop actually reaches
the intraocular tissue.
• Thus, it is difficult to provide and maintain an
adequate concentration of drug in the precorneal
area.
• More than 75% of applied ophthalmic solution is
lost via nasolachrymal drainage and absorbed
systemically via conjunctiva, hence ocular drug
availability is very low.
• To increase ocular bioavailability and prolong
the retention time on the ocular surface,
numerous ophthalmic vehicles such as viscous
solutions, suspensions, emulsions, ointments,
aqueous gels, and polymeric inserts, have been
investigated for topical application to the eye.
Routes of drug administration
• Topical Administration
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▫
Drops
Perfusion
Sprays
Ointments
Particulates
• Intraocular drug delivery
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▫
▫
▫
Liposomes
Microparticulates and nanoparticles
Intraocular devices
Iontophoresis
Drops
• The most common form of topical administration is the eye drop. It is
apparently easy to use, relatively inexpensive and does not impair
vision.
• The major problems with these types of formulation are their inability
to sustain high local concentrations of drug and they only have a short
contact time with the eye
• Contact time between the vehicle and the eye can be increased by the
addition of polymers such as polyvinyl alcohol and methylcellulose
• Drainage from the eye may also be reduced by punctual occlusion or
simple eyelid closure, which prolongs the contact time of the drug with
the external eye.
Perfusion
• Continuous and constant perfusion of the eye with drug solutions
can be achieved by the use of ambulatory motor driven syringes that
deliver drug solutions through fine polyethylene tubing positioned
in the conjunctival sac
• The flow rate of the perfusate through a minipump can be adjusted
to produce continuous irrigation of the eye surface (3– 6 ml/min) or
slow delivery (0.2 ml/min) to avoid overflow
• This system allows the use of a lower drug concentration than used
in conventional eye-drops, yet will produce the same potency. Side
effects are reduced and constant therapeutic action is maintained
Sprays
• Spray systems produce similar results to eye-drops in terms of duration
of drug action and side effects. Sprays have several advantages over eyedrops:
1. a more uniform spread of drug can be achieved
2. precise instillation requiring less manual dexterity than for eye-drop
administration and is particularly useful for treating patients with
unsteady hand movements
3. contamination and eye injury due to eye-drop application are avoided
4. spray delivery causes less reflex lacrimation.
5. Can be used by patients who have difficulty bending their neck back
to administer drops.
Ointments
• Ointments are not as popular as eye drops since vision is blurred
by the oil base, making ointments impractical for daytime use
• They are usually applied for overnight use or if the eye is to be
bandaged. They are especially useful for pediatric use since small
children often wash out drugs by crying.
• Ointments are generally non-toxic and safe to use on the exterior
of the surface of the eye. However, ointment bases such as
lanolin, petrolatum and vegetable oil are toxic to the interior of
the eye, causing corneal oedema, vascularization and scarring
Poin Penting Untuk Optimasi
Penghantaran Obat Melalui Mata
• 1. Meningkatkan waktu kontak ocular
• 2. Meningkatkan permeabilitas kornea
• 3. Meningkatkan pencapaian obat ke tempat
spesifik
Mekanisme Absorpsi Melalui Mata
1. Non-corneal absorption
- Penetrasi melalui sclera dan conjungtiva
untuk masuk kedalam jaringan mata
2. Corneal absorption
- Outer epithelium : hanya bisa untuk ion kecil
dan molekul lipofilik
- Trans cellular transport : Transport antara
epitelium cornea dan stroma
Faktor-faktor yang mempengaruhi
bioavailabilitas intraocular
1. Pemasukan dan pengeluaran dari Lacrimal
fluids
2. Efisiensi pengeringan naso-lacrimal
3. Ikatan obat dengan protein dari lacrimal-fluids
4. Pengenceran dengan air mata
Peran polimer pada ODDS
1. Meningkatkan viskositas
2. Mengurangi pengeringan larutan
3. Pembawa polimer mucoadhesif : Tertahan di
mata melalui ikatan non kovalen dengan
conjungtival mucine
Klasifikasi bentuk sediaan melalui
mata
1. Berdasarkan rute pemberian
- Topical solution : Multiple dose container
with preservatives
- Intraocular solution : for surgery, single dose
, without preservatives
- Ophthalmic solution injection : Intraocular
injection, diberikan pada jaringan mata,
tanpa pengawet
Retinal Disease
Diabetic retinopathy
2. Berdasarkan bentuk fisik
- Larutan
- Suspensi
- Salep
- Gels
- Eye lotions
- Solid inserts
Preparat Mata
Diaplikasikan secara topikal melalui kornea, atau
ditanamkan diantara bola mata dan kelopak mata bawah
- Larutan
Diencerkan dengan air mata, dan diberikan berkali-kali
- Suspensi
Waktu kontak lebih lama, berpotensi menyebabkan
iritasi akibat ukuran partikel obat
- Salep
- Waktu kontak lebih lama, stabilitas penyimpanan lebih
besar, menghasilkan lapisan film menutupi mata dan
mengaburkan pandangan
- Emulsi
Memperpanjang pelepasan obat dan mengaburkan
pandangan, pasien tidak nyaman
- Gel
Nyaman digunakan, sedikit mengaburkan
pandangan tetapi kekurangannya kelopak mata
menjadi berkerut serta tidak dapat mengontrol
kecepatan difusi obat
- Sistem penghantaran terkontrol
Kecepatan pelepasan obat konstan pada waktu
yang lama, meningkatkan absorpsi kornea, efek
samping obat yang tidak serius atau dapat
ditoleransi pasien
Keuntungan
1. Meningkatkan kontak pada mata sehingga
meningkatkan bioavailabilitas.
2. Memungkinkan tersedianya obat dengan
pelepasan yang diperpanjang sehingga efek
lebih baik
3. Efek samping pada mata dan sistemik lebih
rendah
4. Meningkatkan usia simpan untuk sediaan
larutan
5. Pengecualian
dari
pengawet
sehingga
mengurangi resiko reaksi sensitif
6. Memungkinkan untuk mencapai jaringan
internal ocular melalui rute non-kornea
7. Mengurangi pemberian yang berulang sehingga
penerimaan pasien lebih baik
8. Dosis pemberian pada mata akurat yang dapat
mempertahankan secara penuh pada tempat
pemberian sehingga terapi lebih baik
Klasifikasi
•
•
•
•
•
•
•
•
•
Bentuk sediaan mucoadhesive
Ocular inserts
Pelindung kolagen
Hydrogel tipe kontak lens
Ocular iontophoresis
Larutan polimer
Peningkat penetrasi ocular
Sistem fase transisi
Sistem partikulat seperti microspheres dan
nanopartikel
• Vesicular sistem seperti liposom, niosom,
phamacosome dan discomes
Bentuk Sediaan Mucoadesif
• Sistem ini secara signifikan memperpanjang
waktu tinggal obat.
• Polimer mucoadesif biasanya merupakan
makromolekul hidrokoloid
Polimer Mucoadhesif Ocular
• Non-ionik : HPMC
• Polikationik : Chitosan, Dextran
Polianionik : Derivat Polyacrylic acid
(Carbopol, Polycarbophils, CMC)
Faktor yang mempengaruhi kekuatan
mucoadhesif
•
•
•
•
Fleksibilitas rantai
BM
pH
Kekuatan ion
Ophthalmic Inserts
• Merupakan polymeric ocular controlled drug
delivery system
• Obat dalam bentuk dispersi atau larutan dalam
polimer yang sesuai
• Merupakan preparat steril dengan konsistensi padat
atau semipadat dan ukuran serta bentuknya khusus
dirancang untuk penggunaan pada mata
• Tujuannya adalah untuk meningkatkan waktu
kontak untuk pengobatan topikal/sistemik untuk
pelepasan tertunda/terkontrol pada jaringan
konjungtiva
Klasifikasi Ophthalmic Inserts
1. Soluble
2. Insoluble (osmotic, diffusion, contact lens)
3. Bioerodible
Soluble Opthalmic Inserts
• Alat larut air yang berbentuk oval kecil
• Tidak membutuhkan untuk dilepaskan setelah
diaplikasikan
• Sejumlah obat yang dilepaskan akan tergantung
pada jumlah agent pengikat, konsentrasi dari
larutan obat
• Dalam 10-15 detik berbentuk softlens
• Dalam 10-15 menit akan menjadi cairan kental
• Setelah 30-60 menit menjadi larutan polimer
• Jenis
- Berdasarkan polimer alami seperti kolagen
- Berdasarkan polimer semi sintetik atau sintetik
Faktor yang mempengaruhi pelepasan obat
1. Penetrasi dari cairan
2. Pengembangan matriks
3. Disolusi obat dan polimer
4. Relaksasi polimeric chain
• Komponen soluble inserts
1. Polimer sintetis larut air
- Derivat selulosa (HPMC, MC, HEC, HPC)
- PVA, Ethylene vinylacetate co-polymer
2. Bahan tambahan
- Plasticizer (PEG, Glyserin, Propilen glikol)
- Polimer salut enteric (HPMC phtalate)
- Agen pengompleks ( PVP)
- Bioadhesiva (Polyacrylic acids)
• Keuntungan
1. Menggantikan 4-12 kali pemberian obat tetes
mata
2. Menggantikan 3-6 kali pemakaian ointment
Intraocular devices
• The administration of medications by implants or depot devices is a very
rapidly developing technology in ocular therapeutics. These overcome the
potential hazards associated with repeated intravitreal injection such as
clouding of the vitreous humor, retinal detachment and endophthalmitis
• Implantable devices have been developed that serve two major purposes.
First, to release of drug at zero order rates, thus improving the
predictability of drug action, and second, to release of the drug over
several months, reducing dramatically the frequency of administration.
• Vitrasert® is a commercially available sustained release intraocular
device for ganciclovir approved for use in-patients suffering from
cytomegalovirus
Vitrasert® intraocular device
Osmotics Inserts
• Komponen
1. Water permeable matrix : Ethylene- vinyl ester
copolymers, Polyethylene
2. Membran semipermeabel : Derivat selulosa asetat,
ethyl vinyl acetat, poliester acrylic, asam
methacrylic
3. Osmotic agents
- Inorganic : MgSO4, NaCl, K2PO4, Na2SO4
- Organik : Ca Lactat, Mg Suksinat, asam tartrat
- Karbohidrat : Sorbitol, Manitol, Glukosa,
Sukrosa
Insoluble Ophthalmic Inserts
• Diffusion Inserts ( Central reservoir,
Microporous membran)
• Contacs Lens
• Controlled ocular drug delivery systems
meningkatkan efisiensi obat dengan mengurangi
wastage dan dengan meningkatkan absorpsi
dengan meningkatnya waktu kontak obat
• Meningkatkan kepatuhan pasien dengan
berkurangnya frekwensi dosis
• Mengurangi
dosis
sehingga
juga
akan
mengurangi efek samping obat
• Kelemahannya
kurang
popular
karena
pemakaian dengan meletakkan dan melepaskan
sediaan dari kelopak mata bawah secara
periodik
• Kurang nyaman pada mata
Iontophoresis
• Iontophoresis (see transdermal lecture notes) facilitates drug
penetration through the intact corneal epithelium
• The solution of the drug is kept in contact with the cornea in an eyecup
bearing an electrode. A potential difference is applied with the
electrode in the cup having the same charge as the ionized drug, so that
the drug flux is into the tissue
• This method of administration is very rarely used, except under
carefully controlled conditions. Iontophoresis allows penetration of
antibiotics that are ionised and therefore do not penetrate by other
methods, for example, polymyxin B used in the local treatment of
infections
• Commonly reported toxic effects
include slight retinal and choroidal
burns and retinal pigment epithelial
and choroidal necrosis, corneal
epithelial oedema, persistent corneal
opacities and polymorphonuclear cell
infiltration. Other disadvantages of
iontophoresis include side effects
such as itching, erythema and general
irritation
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