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FORMULASI DAN TEKNOLOGI
SEDIAAN FARMASI
Modul matrikulasi UKAI
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Pustaka
Allen, L.V., and Ansel, H.C., 2005, Ansels Pharmaceutical DosegeForms and Drug Delivery Systems, 10thEd., Lippiincott Williams &Wilkins, Philadelphia
Dollas RT, Roshmani A, Bhandari A., Kuma B, Somvanshi S, 2011,Novel Sustained Release Gastro Retentive Drug Delivery System,International Journal of Pharmaceutical Research and Development Vol
2 (11), India. Khachane, K.N., Bankar, V.H., Gaikwad, P.D., 2011, Novel Sustained
Release Drug Delivery System, International Journal of PharmaceuticalResearch and Development, India.
Potts, R.O., and Guy, R.H., 1997,Mechanism of Transdermal DrugDelivery, Vol. 83, Marcel Dekker, New York, pp 291-338.
Roberts, M. S dan Walters, K. A. (Eds.), Dermal Absorption andToxicological Assessment, Marcel Dekker, New York, pp 162-165.
Swarbrick, J. (Ed.), Encyclopedia of Pharmaceutical Technology, Vol.1,3rdEd., Informa Healthcare Inc., USA
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SISTEM PELEPASAN OBAT
TERMODIFIKASI(MODIFIED RELEASE DOSAGE FORM)
Definisi :
THE DRUG RELEASE CHARACTERISTICS OF TIME, COURSE, AND / ORLOCATION ARE CHOSEN TO ACCOMPLISH THERAPEUTIC ORCONVENIENCE OBJECTIVES NOT OFFERED BY CONVENTIONALDOSAGE FORMS
Solid oral modified release dosage form
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MACAM SISTEM PELEPASAN OBAT
TERMODIFIKASI :
1. DELAYED RELEASE
2. EXTENDED RELEASE
- SUSTAINED RELEASE
- PROLONGED ACTION
3. TARGETED RELEASE
- SITE-SPECIFIC TARGETING
- RECEPTOR TARGETING
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Delayed Release
Designed to release the drug at a timeother than promptly after administration.
The delay may be time based or based on
the influence of environmental conditions,like gastrointestinal pH.
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Enteric-coated tablets or capsules designed to passthrough the stomach unaltered, later to releasetheir medication within the intestinal tract.
The purpose :- may be to protect a drug destroyed by gastric
fluids,
- to reduce gastric distress caused by drugs
particularly irritating to the stomach, or
- to facilitate gastrointestinal transit for drugs that
are better absorbed from the intestines.
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The enteric coating may be :
pH dependent, breaking down in the less
acidic environment of the intestine;
time dependent, eroding by moisture overtime during gastrointestinal transit; or
enzyme dependent, deteriorating as a
result of the hydrolysis-catalyzing actionof intestinal enzymes.
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Among the many agents used for entericcoating of tablets and capsules are fats,
fatty acids, waxes, shellac, and cellulose
acetate phthalate.
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Extended Release
Designed to release their medication in acontrolled manner, at a predeterminedrate, duration, and location to achieve and
maintain optimum therapeutic bloodlevels of drug.
The drug and the therapeutic indication
must be considered jointly in determiningwhether or not to develop an extended-release dosage form.
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To be a successful extended-release product,the drug must be :
released from the dosage form at a
predetermined rate, dissolved in the gastrointestinal fluids, maintained at sufficient gastrointestinal
residence time, and absorbed at a rate that will replace the
amount of drug being metabolized andexcreted.
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KEUNTUNGAN
1. MENGONTROL DOSIS TERAPI
2. MENJAGA KONSENTRASI KONSTAN PADA DOSIS TERAPI DALAMWAKTU LAMA
3. MEMAKSIMALKAN HUBUNGAN EEKTIVITASDOSIS4. MENGURANGI EFEK SAMPING
5. MENGURANGI FREKUENSI PENGGUNAAN OBAT
6. MENINGKATKAN KEPATUHAN PASIEN
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KERUGIAN
1. BIAYA LEBIH MAHAL
2. ADANYA DOSE DUMPING
3. KORELASI IN VITROIN VIVO YANG JELEK
4. MENGURANGI FLEKSIBILITAS PEMBERIAN DOSIS
5. EFEKTIVITAS PELEPASAN OBAT TERGANTUNG DARI LAMA TINGGALDI SALURAN CERNA
6. KESULITAN PENGELUARAN OBAT DALAM KONDISI KERACUNAN
ATAU ALERGI
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Drug Candidates
Administered in relatively small doses.
Possess a good margin of safety /
therapeutic index.
- very narrow are poor candidates for ER because
high risk of dose dumping.
Used in the treatment of chronic rather
than acute conditions.
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MACAM SEDIAAN ORAL MODIFIED
RELEASE
MATRIKS TABLET :
- hidrofilik dan hidrofobik matrik tablet
FILM COATING TABLETS
- diffusion-controlled membranes
- enteric coating
MULTIPLE UNIT TABLETS
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SISTEM MATRIKS
BANYAK DIGUNAKAN DALAM FORMULASI MODIFIED
RELEASE
DIGUNAKAN POLIMER DENGAN BERBAGAI VARIASI TIPE
- MATRIKS HIDROFOBIK
- MATRIKS HIDROFILIK
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Plastic/Hydrophobic Matrix System
The drug is granulated with an inert plastic materialsuch as polyethylene, polyvinyl acetate, orpolymethacrylate, ethyl cellulose, and the granulationis compressed into tablets.
The drug is slowly released from the inert plastic
matrix by diffusion. The compression creates the matrix or plastic form
that retains its shape during leaching of the drug andduring its passage through the alimentary tract.
An immediate release portion of drug may be
compressed onto the surface of the tablet. The inert tablet matrix, expended of drug, is excreted
with the feces.
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Hydrophilic Matrix System
The drug substance is combined and madeinto granules with an excipient material thatslowly erodes in body fluids, progressively
releasing the drug for absorption. The effectiveness of these hydrophilic matrix
systems is based on the successive processesof hydration of the cellulosic polymer, gelformation on the polymer's surface, tableterosion, and the subsequent and continuousrelease of drug.
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Hydrophilic cellulose polymers arecommonly used (Eg. HPMC)
Tablets are prepared by thoroughly
distributing HPMC in the formulation,preparing the granules by wet granulation
or roller compaction, and manufacturing
the tablets by compression. the rate of drug release is controlled by
diffusion and tablet erosion.
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SCHEMATIC REPRESENTATION OF MORPHOLOGICAL CHANGES
OCCURING IN HYDROPHILIC MATRIX STRUCTURE WITH TIME
IN AN AQUEOUS MEDIUM
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1/3/
2016
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DIFFUSION CONTROL OF DRUG RELEASE BY A PARTIALLY WATERSOLUBLE POLYMER
(Eg. Ethyl cellulose, methylcellulose)
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1. GRANUL COATED PRODUCTS- Drugs coated with a slowly dissolving wax orpolymer coat of varying thickness
2. MICROENCAPSULATION- It can be used to encase particles of liquids,solids to encapsulate materials
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Type ofcoating
Material suitabledosage forms
Example Probablerelease
mechanism
Properties
Barriercoating(includesmicroencapsulation)
1. Film-coatedtablets
2. Film coated pelletsor granules placedin gelatin capsules
3. Compressedtablets containingmixtures ofbarrier-coatedparticles with fillerparticles
4. Compressed
tablets containingonly barrier-coated particlesforming a matrix
1. Shellacs2. Gllyeryl mono
stearate3. Ethyl cellulose4. Acrylic resins
5. Celluloseacetatebutyrate
6. Polyvinylchloride
7. Sodiumcarboxy-
methylcellulose8. Starch9. Polyvinyl
pyrrolidone10.Gelatin
1. Diffusionand dialysis
2. Somedesintegration
3. Dissolution
1. Slow orincompleterelease
2. Coating issubject to
fractureduringcompression
3. Releasedepends onsolubility ofthe drug and
porestructure ofthemembrane
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Type of
coating
Material
suitable dosageforms
Example Probable
releasemechanism
Properties
Embedmentinto a fattycoating
1.Compressedgranules madein to a tablet
2.Compressedgranules placedin a gelatincapsule
3.Multilayeredtablets
4.Compression -coated tablets
1.Beeswax2.Glycowax3.Castor wax
4.Carnaubawax5.Glyceryl
mono-stearat
6. Stearyl
alcohol
1.Erosion ofthe coat
2.Coating
may containportion ofthe dose forquickrelease withsubsequent
slow releasefromerosion of acore
1.Slow orincompleterelease
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Type ofcoating
Materialsuitable
dosage forms
Example Probablerelease
mechanism
Properties
Repeatactioncoatings
1.Sugar coatingof an enteric-coated coretablet
2.Compressedcoating of anenteric-coatedcore tablet
3.Multiayeredtablets
4.Compression -coatedtablets
1.Celluloseacetatphtalate
1.pHdependentdissolutionandenzymaticbreakdown
1.Variationsdue tochangingstomach-emptyingtimes
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Menggunakan membran semipermeabel di
sekeliling tablet, partikel atau larutan obat
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METHODS USING OSMOTIC PRESSURE
Example : Procardia XL
(Nifedipine)
push-pull osmotic pump
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High Density SystemsBioadhesive Systems
Swelling andExpanding Systems
Floating Systems
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(Dolas, 2011)
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EXCIPIENTS
ARE USED TO BRING DRUG(S) IN THE MOST SUITABLE
DOSAGE FORMS
THEY SHOULD IMPROVES THE PROPERTIES OF THEDRUG IN THE DOSAGE FORMS
TO BRING THE DRUG IN THE MOST APPROPRIATE FORMTO THE OPTIMAL PLACE ABSORPTION AT THE RIGHTTIME AND THE RIGHT DOSE ( INCUDING DRUGTARGETING )
TO IMPROVE DRUG STABILITY
TO MASK BITTER TASTE
TO IMPROVE PATIENT COMPLIANCE
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Solubilizing agent
Non swellable solubilizing agents are classified intothree groups:
Agents that inhibits crystal formation of thedrugs or otherwise act by complexation of drug(e.g., PVP, PEG, and cyclodextrins)
A high HLB micelle forming surfactant,particularly anionic surfactants (e.g., Tween 20,60, 80, poly oxy ethylene or polyethylenecontaining surfactants and other long chain
anionic surfactants such as SLS).Citrate esters and their combinations with anionic
surfactants (e.g., alkyl esters particularly triethylcitrate)
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Plasticizer
Elasticity of membranes can be increased byadding plasticizer, which increases the waterdiffusion coefficient.
Examples: dialkyl pthalates, trioctyl phosphates,
alkyl adipates, triethyl citrate and other citrates,propionates, glycolates, glycerolates, myristates,benzoates, sulphonamides and halogenatedphenyls.
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Semipermeable membran
Semipermeable membrane must possess certain performancecriteia: It must have sufficient wet strength and water permeability.
It should be selectively permeable to water and biocompatible.
Cellulose acetate is a commonly employed semipermeablemembrane for the preparation of osmotic pumps.
Some other polymers such as agar acetate, amylosetriacetate, betaglucan acetate, poly (vinylmethyl) ethercopolymers, poly (orthoesters), poly acetals, poly (glycolicacid) and poly (lactic acid) derivatives.
The unique feature of semipermeable membrane utilized for
an osmotic pump is that it permits only the passage of waterinto the unit, thereby effectively isolating the dissolutionprocess from the gut environment.
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Evaluation
Drug release Uniformity of dosage units
IVIVC (in vitro-in vivo correlations)
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2. Uniformity of dosage forms
Uniformity of dosage units may bedemonstrated by either of two methods,weight variation or content uniformity.
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3 categories IVIVC :
Level A : using entire data of in vitro dissolutionand in vivo response time courses. mostcommon.
Level B : using summary parameters thatcharacterize the in vitro and in vivo timecourses, eg. : the mean.
Level C : using the amount dissolved in vitro ata particular time or fixed doses (e.g., T50) and asummary parameter that characterizes the invivo time course (e.g., Cmax or AUC).
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The most common process for developing an
IVIVC model (level A) is to :
develop formulations with different releaserates
obtain in vitro dissolution profiles and in vivoplasma concentration profiles for theseformulations, and
estimate the in vivo absorption or dissolutiontime course for each formulation and subjectusing appropriate mathematical approaches.
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Kendala rute peroral
Degradasi/metabolisme di usus dan hati Absorpsi rendah
Iritasi saluran cerna
Fluktuasi Cp
Sistem penghantaran terkontrol
Transdermalalternatif rute penghantaran
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Sesuai untuk penghantaran obat yang :
- waktu paruh eliminasi singkat
- jendela terapi sempit
- absorpsi peroral tidak baik
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Kerugian
Tidak semua obat dapat diformulasikanuntuk SP transdermal
Jumlah produk masih terbatas
cth : skopolamin, nikotin, nitrogliserin,klonidin, estradiol, testosteron, fentanil.
Ada barrier transpor yang kuat
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Struktur kulit
Epidermis- non-viable epidermis : stratum corneum
- viable epidermis : stratum lucidum, granulosum,
spinosum,dan basale Dermis
mulai ada pembuluh darah kapiler
Subkutan
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Absorpsi/permeasi melalui kulit
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Absorpsi perkutan terjadi scr difusi pasif, mengikutihukum Fickspertama.
(dC/dt) = (D.A.C)/h
(dC/dt) = kecepatan absorpsi obat (jumlah/waktu)
D = koefisien difusi obat
A = luas permukaan membran
h = ketebalan membranC = gradien konsentrasi
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Faktor yang mempengaruhi absorpsi
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Faktor yang mempengaruhi absorpsiperkutan
Konsentrasi obat
Luas area aplikasi
Atraksi fisikokimia obat ke kulit > dalam
pembawatergantung kelarutan dan log P obat
BM obat
Hidrasi kulit, sifat oklusif Ketebalan kulit
Lama kontak obat dgn kulit
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Kriteria sifat obat
Poten dlm dosis kecil ( 20 mg) BM kecil (< 500 Da)
Lipofilik (log P 1-3)
Titik lebur < 200
C Koefisien permeabilitas > 0,5 x 10-3cm/jam
Tidak mengiritasi kulit dan tidak merangsang
reaksi imun di kulit
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Sistem penghantaran transdermal
Fungsi kulitbarrier kuatmencegah masuknya senyawa
asing ke dalam tubuh
Perlu peningkatan
kecepatan transpormenembus kulit
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Teknik peningkatan permeasi
Mengubah sifat fisikokimia obat / prodrug Penggunaan chemical penetration enhancer
Bentuk transdermal aktif
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J SP d l
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Jenis SP transdermal
Pasiftranspor terjadi karena gradien
konsentrasi
AktifSelain gradien konsentrasi juga dibantu
oleh energi/faktor eksternal
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SP T d l P f
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SP Transdermal Pasif
Patchsediaan farmasi yang lentur denganukuran bervariasi, mengandung satu atau
lebih zat aktif, ditujukan untuk diaplikasikan
pada kulit yang sehat (tidak terluka) untukmenghantarkan zat aktif menuju sirkulasi
sistemik setelah melalui barrierkulit.
Menggunakan matriksatau membranuntuk mengontrol kecepatan pelepasan
obat ke kulit dan masuk sirkulasi sistemik
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P h
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Patch
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Matriks berisi sejumlah tertentu senyawa obatyang terdispersi homogen dalam polimer matriks
dan akan dihantarkan melewati kulit. Jumlah obat dlm matriks berlebihmenjamin
steady-state conc. gradient di SC.
Pelepasan obat diatur oleh komponen polimerdalam matriks.
Mekanisme difusi obat dalam matriks :
1. difusi melalui pori yang terbentuk dari
polimer yang larut dlm pelarut (hidrofilik).2. partisi obat dalam matriks diikuti difusi
sepanjang segmen polimer.
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Pelepasan obat tidak mengikuti kinetika ordenol, karena pelepasan obat dipengaruhi olehjarak molekul obat dalam matriks terhadapkulit. Obat yang paling dekat dengan kulit akan
terlepaskan terlebih dahulu.
Karena bentuknya yang lebih tipis danlebih kecil dibanding tipe reservoir, tipeini dapat meningkatkan kepatuhanpasien.
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Pembuatan tipe matriks
Obat, polimer, dan adhesive dilarutkanatau dicampurkan bersamamatriks
Dikeringkan dlm bentuk lembaran/silinder
dalam satu unit dosis.Assembled betweenbacking and release
liner.
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3. Pressure-sensitive adhesivemenjaga kontak dgn kulit selama aplikasi sediaan
ada 2 jenis : peripheral adhesive danface adhesive
tidak boleh mengiritasi, mudah dilepaskan, tidak
mengganggu flux, kompatibel dgn komponen lain.
cth : polybutyl acrylate
4. Release liner
dilepaskan sebelum aplikasi
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Persyaratan enhancers yg baik
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Persyaratan enhancersyg baik
Tidak berefek farmakalogis Stabilitas baik
Predictable and repeatable results
Kompatibel dgn komponen lain Tidak menimbulkan dermal toxicity
(iritasi/alergi)
Dpt dilepaskan dr sediaan Karakter umum baik (bau, warna, harga)
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Mekanisme
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Mekanisme
Meningkatkan permeabilitas dgn merusakscr reversibel atau merubah sifatfisikokimia alami kulit (stratum korneum)untuk mengurangi resistensinya.
Perubahan bisa dgn meningkatkan hidrasiSC, atau merubah struktur lipid ataulipoprotein mll solvent action atau
denaturasi. Bisa juga dgn meningkatkan partisi zat
aktif
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SP Transdermal Aktif
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SP Transdermal Aktif
Iontophoresis Electroporation
Micro-needle
Sonophoresis Vesicle
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Perbedaan potensial elektrik SC dgn dosage form. Pelepasan/penolakan kation dr anodal dan anion
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C h b l d k d k
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Cth obat : lidokain, deksametason,
verapamil, propanolol, asam amino,
peptida, insulin.
Kemungkinan transpor peptida BM
besar dan ionik sulit menembus kulit
iontophoresis-enhanced TDDS.
Cth aplikasi klinik transdermal
iontophoresislihat buku Potts and Guy
hal 304-306.
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Manajemen dosis berdasarkan durasi iontophoresis
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Produk pengembangan
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Produk pengembangan
Sediaan patch yg dilengkapi dgn mini-circuit power supply menggunakan mini
battery.
Ada komponen patch yang disposable(patch) dan ada yg reusable (battery).
Cth : E-trans Fentanyl (ALZA) dan Vyteris
Lidocaine (Vyteris)
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Faktor formulasi
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Faktor formulasi
pH larutan obat dlm patch Konsentrasi obat dlm patch
sebagian besar obat ada batas nilai optimum
Kekuatan arus listrikmanajemen titrasi dosis sesuai kebutuhan
pasien
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Kelebihan iontophoresis
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Kelebihan iontophoresis
Profil Cp vs t mendekati profil infus IV Memungkinkan manajemen dan titrasi
dosis yg fleksibel berdasarkan kekuatan
arus listrik yg digunakan Tingkatan transpor menembus sawar kulit
lebih tinggi dibanding transdermal pasif.
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Kekurangan iontophoresis
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Kekurangan iontophoresis
Batasan maksimum kekuatan arus listrikyang aman bagi manusia utk mencegah
iritasi, burning, kemerahan, dan efek
samping lain pd kulit.
Pembuatan dan teknologi deviceyg relatif
mahal
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B. Electroporation
Aplikasi voltage tinggi (0,1-1 kV) dengandurasi pendek (0,0001-1 detik).
Perubahan fungsi sawar SC yang intensif
dlm waktu sangat pendek. Melalui pembentukan pori scr teoritis
lebih efektif dlm menghantarkan molekul
obat berukuran besar (cth: protein,makromolekul)
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Kombinasi
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Kombinasi
Electroporation- membuka pori sawar SC
- memberi loading dosesteady state
flux pada level tertentu Iontophoresis
- meningkatkan level transpor utk mencapai
level terapi- maintanance dose
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Aplikasi klinis
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p as s
Msh terbatas dalam skala riset Pembuatan deviceyg relatif lbh kompleks
Faktor keamanan dlm aplikasi voltage
sangat tinggi msh mjd perdebatan.
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C. Transdermal Micro-needle
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Penggabungan antara penggunaantransdermal patchdgn micro-needle(jarum
berukuran micrometer).
Mekanisme : pembukaan pori pd SC scrmekanik menggunakan micro-needle.
Memungkinkan peningkatan penetrasi
obat/makromolekul menembus kulit.
Tidak mencapai sistem syaraf shg tidak
menimbulkan rasa sakit/nyeri.
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Jarum, terbuat dr bahan silikon, logam, atau
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J , , g ,biodegradable polymer.
Biodegradable polymerpaling amanjikaterdapat patahan jarum di kulit akan dptdidegradasi scr aman oleh tubuh.
Ujung jarum dpt bersifat:
- massive:
- tanpa lubang
- efektif untuk meningkatkan permeabilitas
- hollow :- dengan lubang
- sesuai untuk convective/microinfusion delivery
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Jenis jarum(b h )
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(bahan)
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Hollowi dl
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micro-needle
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Contoh aplikasi
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E. Vesicle
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Struktur koloidal bulat berongga tersusun
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ggdari molekul- molekul amfifilik.
- hidrofilikhead-group- lipofilik tail-group
Biodegradable, toksisitas rendah, non-imunogenic.
Variasi jenis lipid dan surfaktan
- fosfolipidliposome
- non-ionic surfactantniosome
Faktor fisiko-kimia (ukuran, muatan,lamelaritas, elastisitas) faktor penting dlmpenghantaran obat.
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Fungsi vesikel
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g
Pembawa utk obat yg terikat ataumenembus kulit
Depot untuk pelepasan terkontrol
Preparat kosmetik
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Evaluasi sediaan transdermal
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Fisika Kimia
Mikrobial
Studi permeasi in vitro Studi permeasi in vivo
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Evaluasi fisikokimia
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Ketebalan Bobot % moisture content % moisture uptake
Flatness Tensile strength
Folding enduranceAdhesive test
Drug content Uji disolusi/pelepasan obat
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Uji disolusi/pelepasan
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j p p
Paddle-over-disk apparatus (usp apparatus5)
Cylinder apparatus (usp app 6)
Reciprocating holder apparatus (usp app7)
Diffusion cells
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Studi permeasi in vitro
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p
Subjek uji : jaringan kulit manusia atauhewan (whole skin, dermis, atau epidermis)
Human skinsulit pengadaan,
penyimpanan, mahal, dan variasi permeasi.Animal skinvariasi permeasi, lebih
permeabel dr human skin.
cth : tikus, mencit, babi, ular, anjing, marmut.
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Alat uji : sel difusiada 3 tipe:
Side-by-side diffusion cells
Franz diffusion cells Flow-through diffusion cells
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Alat uji : sel difusi
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Sel difusi :
2 h b /k t
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2 chamber/kompartemen :
- donor chambersediaan uji- aseptor chamberlarutan aseptor
Larutan aseptor :
- Phosphate buffered saline(PBS) pH 7,4- jika kelarutan obat dalam lar. aseptor
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Membran kulit atau sintetik barrierdifusi,diletakkan di antara 2 kompartemen.
Persiapan membran/kulit uji.
Hidrasi membran dalam lar. aseptor sebelumperlakuan.
Suhu pengujian32 1C Gelembung udara di bawah membran
dihilangkan.
Pengadukan lar. aseptor selama pengujian.
Sampling lar. aseptor scr periodik danpenggantian lar. setiap sampling.
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Difusi obat/kecepatan permeasi melaluimembran ditentukan dgn uji drug content
di larutan aseptor tiap waktu sampling.
Analisa drug content di membran
kecepatan permeasi dan retensi kulit.
Hasil uji permeasiflux(J)jumlah
obat tertanspor menuju fase aseptor
(dXA(t)) per satuan luas membran (S) per
satuan waktu (dt)
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Asumsi uji permeasi in vitro : kompartemen aseptor dalam keadaan sink
terjadinya penurunan jumlah pada
kompartemen donor diabaikan membran yang digunakan merupakan bagian
yang homogen.
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Studi penetrasi in vivo
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Tujuan :- verifikasi dan kuantifikasi BA
- melihat hubungan Cp dgn efek terapetik sistemik
- melihat BE- determinasi resiko toksisitas sistemik
Subjek uji :
- manusia (paling relevan)
- animal models (prediksi respon pd manusia),
cth : tikus, babi, kera
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