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    FORMULASI DAN TEKNOLOGI

    SEDIAAN FARMASI

    Modul matrikulasi UKAI

    1

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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

    3

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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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    21

    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

    81

    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

    82

    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.

    89

    P b t ti t ik

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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.

    90

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    94

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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)

    101

    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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    107

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    Perbedaan potensial elektrik SC dgn dosage form. Pelepasan/penolakan kation dr anodal dan anion

    dr katodal ke dlm kulit.108

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    109

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    110

    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.

    111

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    Manajemen dosis berdasarkan durasi iontophoresis

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    114

    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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    116

    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

    117

    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.

    118

    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

    119

    B. Electroporation

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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)

    120

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    121

    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

    122

    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.

    123

    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.

    124

    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

    125

    Jenis jarum(b h )

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    (bahan)

    126

    Hollowi dl

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    micro-needle

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    Contoh aplikasi

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    128

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    E. Vesicle

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    130

    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.

    131

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    Fungsi vesikel

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    g

    Pembawa utk obat yg terikat ataumenembus kulit

    Depot untuk pelepasan terkontrol

    Preparat kosmetik

    133

    Evaluasi sediaan transdermal

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    Fisika Kimia

    Mikrobial

    Studi permeasi in vitro Studi permeasi in vivo

    134

    Evaluasi fisikokimia

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    Ketebalan Bobot % moisture content % moisture uptake

    Flatness Tensile strength

    Folding enduranceAdhesive test

    Drug content Uji disolusi/pelepasan obat

    135

    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.

    137

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    Alat uji : sel difusiada 3 tipe:

    Side-by-side diffusion cells

    Franz diffusion cells Flow-through diffusion cells

    139

    Alat uji : sel difusi

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    140

    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.

    142

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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)

    143

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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.

    144

    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

    145

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