Transdermal Delivery Systems

Transdermal Drug Delivery

Passive
􀂄 Matrix (Oxytrol, Vivelle Dot)
􀂄 Reservior (Androderm,
Duragesic)

Active
􀂄 Iontophoresis
􀂄 Electroporation
􀂄 Sonophoresis
􀂄 Heat or thermal energy
􀂄 Microneedles
 TRANSDERMAL
Sistem Penghantaran Obat Transdermal :

Pengobatan yang diberikan secara topikal, menggunakan

bentuk sediaan patches (petcs) yang menghantarkan obat
untuk tujuan sistemik pada laju yang dapat ditentukan dan
dikendalikan.

Mekanisme Kerja Patch :

Obat dengan dosis tinggi diformulasikan dalam patch, obat

dilepaskan untuk menembus kulit dalam waktu yang
diperpanjang. Proses penembusannya secara difusi, melewati
kulit langsung ke pembuluh darah. Obat terdifusi di darah
dalam waktu yang lama sehingga menjaga konsentrasi obat
konstan dalam aliran darah.
Advantages
1.Avoid the risk and inconvenience of intravenous therapy
(noninvasive).

2.Avoidance of first pass hepatic metabolism (avoiding the

deactivation by digestive and liver enzymes) thus increasing
bioavailability and efficacy of drugs.

3.No gastrointestinal degradation (pH, enzymatic activity,

drug interaction with food, drink and other orally administered
drugs)

4.Substitute for oral administration of medication when that

route is unsuitable as with vomiting and diarrohea

5. Extended therapy avoiding frequent dose administration.

Advantages

6. Reduce side effect due to optimization of the

bloodconcentration time profile.

7. Greater patient compliance due to elimination of

multiple dosing intervals.

8. Enhance therapeutic efficiency.

9. Minimize inter and intra patient variations.

10. Reversibility of drug delivery which would allow

the removal of drug source.
Limitations of TDDS

1.Limited skin permeability.

2. Restricted to potent drug

3. Cannot use for large molecule (>500Dalton)

4. Significant lag time

5. Difficulty for adhesion.

6. The drug undergoes degradation in the skin.

7. Variation in absorption efficiency at different sites

of skin.
Potential Benefits of Transdermal Drug Delivery

􀂆 Therapeutic agent delivered at controlled rate through skin

into systematic circulation

􀂆 Maintain efficacious plasma levels of drug from 1 to 7 days

􀂆 Controlled delivery resulting in more reliable and predictable
blood levels
􀂆 Improved absolute bioavailability due to avoidance of first
pass hepatic and gastrointestinal metabolism
􀂆 More convenient and improved patient compliant dosing
regimen
􀂆 Providing added value by increasing efficacy and typically
decreasing toxicity level of drug when compared to oral
dosage forms.
Example Indications for Transdermal
Products :
􀂆 Hormone Replacement (testosterone, ERT, HRT)
􀂆 Angina (nitroglycerin)
􀂆 Pain relief (fentanyl)
􀂆 Hypertension (clonidine)
􀂆 Motion sickness (scopolamine)
􀂆 Smoking cessation (nicotine)
􀂆 Urge Incontinence (oxybutynin)
􀂆 Depression (selegiline)
􀂆 ADHD (methylphenidate)
Ideal properties drug for TDDS.

Half life <10hrs

Therapeutic index low
Oral bioavailability low
PH between 5-9
Skin permeability coefficient 0.5×10-3
(a)Physiochemical Properties

1. The drug should have are molecular weight less

than approximately 500 Daltons.

2. The drug should have affinity for both lipophilic

and hydrophilic phases.

Extreme partitioning characteristics are not

conductive to successful drug delivery via the
skin.

3. The drug should have a low melting point.

(b) Biological Properties
1. The drug should be potent with a daily dose of the
order of a few mg per day.
2. The half life ( t1/2) of the drug should be short.
3. The drug must not induce a cutaneous or allergic
response.
4. Drug which degrade in the G.I tract or inactivated
by hepatic first pass effect are suitable candidates for
transdermal delivery.
5. Tolerance to the drug must not develop under the
near zero order release profile of transdermal delivery.
6. Drugs which have to be administered for a long
period of time or which cause adverse effects to non-
target tissues can also be formulated for transdermal
delivery.
Kinetika Permeasi Transdermal

Pengetahuan kinetika permeasi kulit merupakan hal yang

menentukan keberhasilan pengembangan sistem terapi
transdermal.

Permeasi transdermal obat meliputi :

1. Sorpsi oleh stratum korneum

2. Penetrasi obat melalui epidermis
3. Masukan obat melalui jaringan kapiler dalam lapisan papila
dermal
Permeasi dapat terjadi hanya bila obat memiliki sifat fisiko-kimia
tertentu.
Rute Permeasi Obat Melalui Kulit

1. Rute Apendageal
Obat masuk melalui kelenjar sebasea, kel. Keringat,
folikel rambut
Hanya 0,1% luas total permukaan kulit (bukan jalur
utama)

2. Rute Transepidermal :
a. Jalur intraseluler, melintasi secara langsung lipid
kulit dan ruang internal korneosit.

b. Jalur interseluler, malalui matriks lipid interseluler

Jalur intraseluler
Skin Permeation

􀂆 Skin while being an effective barrier against

environmental assaults, is not completely
impermeable.
􀂆 Certain drugs are either inherently permeable, or
can be formulated to penetrate the skin.
􀂆 Outer most layer of skin (the stratum corneum) is
made up of dead epidermal cells (keratinocytes)
and is the primary barrier to drug delivery.
􀂆 Once this layer is penetrated, the feasibility of drug
delivery is greatly improved.
Schematic of Skin Absorption
Laju Permeasi Melewati Kulit :

dQ
------- = Ps ( Cd – Cr ) -------- ( persamaan 1 )
dt
Dimana :

Cd = konsentrasi penetran dalam kompartemen donor ( pada

permukaan stratum korneum)
Cr = konsentrasi penetran dalam kompartmen reseptor ( dlm
tubuh )
Ps = koefisien permeabilitas jaringan kulit terhadap penetran
 Ks Dss
Ps = -------------
hs

Ks = koefisien partisi mol. Penetran pd stratum korneum

Dss = tetapan difusitas mol. Penetran pd keadaan tunak,
melewati ketebalan jaringan kulit.
hs = ketebalan seluruh jaringan kulit
 Ks, Dss dan hs adalah di bawah kondisi tetap, maka Ps juga tetap,
sehingga dari persamaan 1 :

Bahwa laju permeasi obat dpt diperoleh hanya bila Cd >> Cr, maka
persamaan 1 menjadi :

dQ
------- = Ps Cd
dt
Artinya, laju permeasi kulit adalah konstan asalkan Cd sisa sepanjang
permeasi kulit, konstan.
Agar Cd sisa terjaga konstan, obat harus dilepaskan dari sistem dg laju
Rr konstan / lebih besar dr laju masukan obat ke kulit, Ra,  Rr
>>Ra
Rr >> Ra,  Cd terjaga pd tingkat yg sama / > kelarutan obat di
stratum korneum, Cs  Cd >> Cs
Maka laju maksimum permeasi kulit adalah :

(dQ/dt)m = Ps Cs

Jadi laju maksimumnya tergantung pd koefisien permeabilitas Ps dan

kelarutan dlm stratum korneum, Cs  Permeasi kulit sangat
dibatasi/ ditentukan oleh stratum korneum
Komponen Dasar Sistem Penghantaran Transdermal

1. Matriks / matriks polimer

2. Bahan Obat

3. Peningkat Permeasi/ penetrasi

4. Eksipien lainnya
1. Matriks Polimer

Fungsi : mengendalikan pelepasan obat dari sistem

(patch)

Polimer Alam :
derivat selulosa, gelatin, shellac, waxes, protein, gom
dan derivatnya, starch, karet

Elastomer sintetik :
polibutadiena, polisiloksan, silikon karet, akrilonitril

Polimer sintetik :
PVA, polivinil klorida, polietilen, polipropilen, poliakrilat,
PVP, polimetilmetrakilat, epoksi
2. Bahan Obat

Bahan Obat Harus dipilih

dg benar, mempunyai
sifat fisiko-kimia :

a. Bobot molekul
rendah
b. Mempunyai afinitas
terhadap fase
hidrofil maupun
lipofil
c. Mempunyai titik
leleh rendah
d. Obat poten, Waktu
paro rendah, Tidak
iritatif
Drug Properties for TDD Consideration

􀂆 Potency of the drug

Daily systemic dose should be ≤20 mg

􀂆 Drug must have adequate lipophilicity

The log P should be in the range 1 – 3

􀂆 Molecular Size
Drug molecular weight less than 500 Daltons

􀂆 Irritation
The drug should not be a direct irritant to the skin
􀂆 Melting point
Should be <200 ºC

􀂆 Immunogenicity
The drug should not stimulate an immune
reaction in the skin

􀂆 Other considerations
Pharmacokinetics
Indications
Metabolism
3. Peningkat Permeasi/ Penetrasi

Fungsi : senyawa yg dpt meningkatkan permeabilitas kulit

dg cara merubah sifat perintang kulit sehingga
obat/ molekul penetran mudah melewatinya.

a. Pelarut, senyawa yg dpt meningkatkan penetrasi dg

mengembangnya jalur polar &/ melarutkan lipid.

Contoh : air-alkohol: etanol, metanol; dimetil

sulfoksida, azone, propilen glikol,
gliserol, isopropil palmitat.
􀂆 Enhancers act on skin so that drug diffusivity or
drug solubility - or a combination of both – is
modified, leading to an increase in transport.

􀂆 Permeability can be enhanced by altering the

structure of the skin or by increasing the solubility
of the drug in the skin

􀂆 Drug transport through skin is the product of skin

permeability and drug concentration at saturation in
the skin
Two enhancer classes
􀂄Enhancers that alter the structure of the
skin lipids, decreasing their resistance to
diffusion
􀂄Those that enhance the solubility of the
diffusing drug within the skin
 b. Surfaktan, senyawa ini dapat meningkatkan transport
jalur polar untuk obat hidrofilik.
Kemampuan penetrasinya berhubungan dengan
gugus polar dan non-polarnya.
Surfaktan anionik : Na-lauril sulfat, dioktil
sulfosuksinat
Surfaktan non-ionik : span, tween, pluronik F 127

c. Bahan lain : urea, kalsium tioglikolat

4. Eksipien Lain
a. Adesif
b. Backing membrane
Sistem Transderm Scop
Tebal = 0,2 mm; Luas = 2,5 cm2; Isi = 1,5 mg skopolamin
Terdiri atas 4 lapis :
1. backing (lapis penahan), seleput poliester-aluminium
2. reservoir obat skopolamin, minyak mineral, poliisobutilen
3. membran polipropilen dg pori ukuran tertentu, pengatur pelepasan
obat ke permukaan kulit.
4. adesif (perekat-kulit), minyak mineral, poliisobutilen, skopolamin
200 μg
 Tipe Patches Transdermal

1. Single-layer Drugs in adhesive

Backing
Drug in adhesive
Liner

Obat dimasukkan dlm adesif yang kontak langsung dengan kulit

Laju pelepasan obat tergantung pd difusi obat melalui kulit
2. Multi-layer Drug-in-adhesive

Obat dimasukkan langsung ke adesif, dipisahkan oleh membran

pengendali pelepasan obat
3. Drug Reservoir-in-adhesive

Kompartemen cair yg berisi larutan obat/ suspensi, pelepasan

obat dikendalikan oleh membran semipermeabel dan adesif.
Adesif bertanggung jawab dlm peningkatan adesi dg kulit
Transdermal Reservoir Systems

􀂆 Typical systems consist of:

􀂄 Impermeable backing
􀂄 Reservoir of gel containing a drug, enhancer, and
antiirritants, and gelling agents.
􀂄 Membrane
􀂄 Adhesive
􀂆 Used when matrix systems cannot penetrate skin and
drugs require significant penetration enhancement
and/or high dosage levels
􀂆 Drug from reservoir slowly seeps into the membrane
and adhesive, allowing for constant release
4. Drug Matrix-in-Adhesive

Matriks semisolid yg mengandung larutan obat / suspensi yang

langsung kontak dg liner (pelapis luar).
Komponen yg bertanggung jawab untuk adesi – kulit dibuat
menyatu / melapisi matriks semisolid