Biofarmasi Sediaan melalui Kulit/Perkutan

Anatomi Kulit

Struktur epidermis & Matriks lipid intraselular

Kandungan SC:
• Protein (tonofibril, keratohialin, keratin,
dll.)
• Lipida (asam lemak, fosfolipida, skualen,
Sasaran pengobatan perkutan kolesterol)
• Air
✓ Lokal (anti-infeksi, anti-inflamasi, anti-histamin, dll.)
✓ Sistemik (nitrogliserin)
Formulasi/Sediaan

Klasifikasi Sediaan Perkutan (Lokal dan Transdermal)

Contoh

Proses transdermal delivery dari formulasi suspensi

Pemilihan sediaan topical dan transdermal berdasarkan pertimbangan
halangan/barrier melalui kulit
Contoh komposisi formula pd sediaan perkutan
 | 13

Pemilihan pembawa
› Skin condition
▪ Restore hydratation to normal level
▪ ‘Wet on wet, fat on dry’
- Wetting skin: liquid dermatics
- Dry skin: semi-solid dermatics with fat content
› Location on the body
▪ Hairy skin: washable
▪ Skin folds: avoid inclusion
› Acceptability for user
▪ No extremely fat vehicle during day time
› Compatibility of constituents vehicle with drug substance
 | 14

Sifat Fisik Pembawa

› Can be used to optimise therapy

› Cooling and/or drying due to presence of volatile solvent

▪ Water, ethanol
› Drying and protecting by dispersed indifferent substances
▪ Zinc oxide, talcum, starch
› Counteracting dehydratation using hydrophobic ingredients
▪ Paraffin, petrolatum, vegetable oil, glycerin
 | 15

Faktor (Patho)physiological
› Also determine efficacy dermal preparations

› Penetration rate of drug higher when applied on thin skin

than on thick skin
▪ Behind ear, on eyelid or scrotum versus palm of hand, sole of foot
› Penetration rate of drug into damaged skin higher than into
intact skin
› Penetration rate of drug intro hydrated skin higher than into
dry skin
 | 17

Dosing dermatics
› Physical action
▪ Ample application
▪ As frequent as necessary, ≥ 2x per day

› Pharmacological action
▪ Thin application
▪ 1-2 x per day
 |

FTU
› ‘Fingertip unit’: practical aid for dosing dermatics

› 1 FTU: dash cream or ointment with length distal bone

forefinger adult

› 1 FTU ≈ 0.5 g
▪ Covers 300 cm2 skin

› Depending on part of body one or more FTU used

 |

FTU-dosing (ointment, cream)

Head and Arm and Leg and foot Trunk (front) Back and
neck hand bottom

Age Number of FTU per application

3-12 months 1 1 1½ 1 1½

1-2 years 1½ 1½ 2 2 3
3-5 years 1½ 2 3 3 3½
6-10 years 2 2½ 4½ 3½ 5
Adult 2½ 4* 8** 7 7

*For only one hand adult 1 FTU is required

**For only one foot of adult 2 FTU are required
 |

Quantities required
› Adults, two times daily, one week treatment

Part of the body Cream / ointment / Liquid preparation

paste
Face 1 – 15 g 100 mL
Hand 15 – 50 g 200 mL
Arm 50 – 150 g 200 mL
Leg 100 – 300 g 200 mL
Trunk 200 – 500 g 500 mL
Whole body 500 – 1500 g 500 mL
 |

Pengembangan Sediaan
› Transdermal patches
▪ Clinical applications
› Iontophoresis
▪ Applications still limited
▪ Transdermal administration of charged molecules
› Microneedles / micropores
▪ Both technologies not yet widely applied
▪ Enable neutral or bulky molecules to pass the skin barrier
▪ Seen as potential approach to administer proteins
Transdermal
patches
 Transdermal patches | 79

› ‘Controlled’ dose
› Drug release is passive process
› Applied for several days to one week
› Circumvention of first pass effect
› Applications include
▪ Nicotine (to quit smoking)
▪ Hormones (treatment of menopausal problems, anticonceptives)
▪ Analgesics (fentanyl)
▪ Scopolamine (motion sickness)
▪ Nitroglycerin (angina pectoris)
 | 80

Transdermal fentanyl
› Fentanyl more potent
analgesic than
morphine
› Very lipophilic
› Patch with fentanyl in
case of severe chronic
pain
› Unsuitable to treat
acute pain
› Skin acts as depot
Iontophoresis | 81

› Controlled dose per unit of time

› Influence absorption rate by selection of voltage

› Applied for several days (week is not exceptional)
› Circumvents first pass effect
› Needs charged compounds (relation to pH in the skin)

› Needs potent drugs

Microneedles |
 Micropores
Microporation: rapid application of thermal energy to a small
area of skin to create ‘pores’ in the epidermis
Currently implemented with a small diameter wire that is
heated by passing a short duration current pulse (0.003 sec)
through it (hot wire technique)
Pore depth and width depends on
▪ Pulse duration
▪ Wire diameter
▪ Wire temperature
Temperature at site of contact 550°C; 30 µm deeper: 45°C
 Biofarmasi Sediaan
Waktu laten pada penyerapan perkutan

2 e = tebal membran
e
T1 = D = tetapan difusi molekul dalam struktur kulit
6D
Jumlah senyawa yang diserap
per satuan waktu (dQ/dt)

dQ
= Kp.S .(C1 − C2 ) Rute penetrasi. A. penetrasi interselular, B. Penetrasi folikular,
dt C. Penetrasi transelular
Kp = tetapan permeabilitas
S = luas permukaan membran
C1-C2 = perbedaan konsentrasi pada kedua sisi
membran
Persamaan Higuchi:

dQ Km.D.S .(C1 − C2 )
=
dt e
Km = koefisien partisi senyawa dalam kulit dan
pembawa
D = tetapan difusi
S = luas permukaan membran
C1-C2 = perbedaan konsentrasi pada kedua sisi
membran
e = tebal membran Transport obat melalui kulit
Tetapan permeabilitas: Permeabilitas kulit:

km.D
Kp = Kmc .Dc
e Kp = Kc =
ec
Kp = tetapan permeabilitas
Km = koefisien partisi
D = tetapan difusi
e = tebal membran
Faktor fisiologik yang mempengaruhi
penyerapan perkutan
 Keadaan dan umur kulit
 Aliran darah
 Tempat pengolesan
 Kelembaban dan suhu
Optimasi ketersediaan hayati sediaan
per kutan
 Tetapan difusi
 Konsentrasi zat aktif dalam sediaan
 Koefisien partisi
 Pembawa
 Surfaktan
 Peningkat penembusan zat aktif (DMSO, DMA, DMF, dll.)
 Ionoforesis (untuk ion)
Tetapan difusi (Hukum Stokes-Einstein)

k '.T
D=
6 .r.
Evaluasi biofarmasetik sediaan perkutan

 Studi difusi in vitro (difusi dalam gel, difusi melalui membran)

 Studi penyerapan (penentuan sisa obat dalam sediaan, penentuan obat yang
masuk ke dalam darah, yang diekskresi)
 Pengamatan efek biologik (pelebaran/ penyempitan pembuluh darah, dll.)
 Histologik
Uji In vitro
Uji in vitro sel franz

Contoh pengerjaan:
https://www.youtube.com/watch?v=BDoHqrnSFPg
https://www.youtube.com/watch?v=cxeCmb_gTow