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MODIFIED RELEASE PER ORAL DOSAGE FORM s2 oke.pptx.pdf
- 1. MODIFIED RELEASE PERORAL DOSAGE FORM Agus Siswanto
- 2. CHAPTER CONTENT • Maintenanceof Therapeutic drug concentration by MR per oral dosage form • Design of peroral modified-release drug delivery system • Formulation of modified-release dosage form • Membrane-controlled drug delivery systems
- 3. A. MAINTENANCE OFTHERAPEUTIC DRUG CONCENTRATION
- 4. Ideal dosage regimen Therapeuticconcentation of drug at the site (s) of action is attained immediately and is then maintained constant for the desire duration therapeutic 'steady-state' plasma concentrations of a drug by the repetitive administration of conventional peroral dosage forms provided dose size frequency of administration are correct
- 7. Conventional per oraldosage form • Complete dose of drug contained is immediately released rapidly following administration • Available for absorption into the sistemic circulation
- 8. Limitation of conventionalper oral dosage form • Drug conc. in plasma and at site(s) of action: fluctuates over dosing interval → not possible to maintain constant • Fluctuation → patient being over – or undermedicated for periods of time if Cmin & Cmax rise or fall, beyond the therapeutic range • Drug with short biological half-lives → frequent doses → forgotten doses & overnight no-dose period → therapeutic inefficiency or failure
- 9. Modified-release Dosage Form •MR will be used to describe peroral dosage forms that continously release drugs at rates which are sufficiently controlled to provide periods of prolonged therapeutic action following each administration of a single dose • A variety of terms was used to describe this system: – Delayed-release - Extended-release – Repeat action - Controlled-release – Prolonged-release - Modified-release – Sustained-release
- 10. • Delayed release🡪 obat tdk segera dilepaskan stlh diberikan tp stlh beberapa waktu kemudian (enteric-coated) • Repeat action 🡪 suatu dosis individual dilepaskan dg segera stlh pemberian dan dosis kedua/ ketiga dilepaskan pd interval waktu tertentu • Prolonged release 🡪 obat tersedia selama periode absorpsi yg lebih panjang dibandingkan bentuk konvensional (onset lambat) • Sustained release 🡪 suatu pelepasan awal obat cukup memberikan dosis terapi dan kemudian memberikan pelepasan bertahap dlm periode yg lama
- 11. • Extended release🡪 melepaskan obat dg lambat shg konsentrasi obat dlm plasma dipertahankan pd kadar terapetik dlm periode tertentu (8-12 jam) • Controlled release 🡪 melepaskan obat pd kec konstan dan memberikan konsentrasi obat yg tetap dlm plasma pd setiap waktu • Modified release 🡪 bentuk sediaan dg karakter waktu dan tempat pelepasan obatnya dipilih utk mendapatkan tujuan terapi
- 12. Repeat action vsmodified released
- 13. Disain MR product 1.Dg segera memberikan konsentrasi obat pada plasma dan tetap konstan pd interval nilai terapetik (kurva A) MR products are generally designed to provide... 2. Mencapai konsentrasi plasma meskipun tdk konstan dan menurun secara lambat dlm kadar plasma (kurva B)
- 14. Metode formulasi MRproduct • Initial priming dose dapat dilepaskan dengan cepat – Terpisah dari maintenance dose – Terletak dipermukaan porous wax atau plastic matrix • Maintenance dose dilepaskan secara lambat dalam durasi yang diinginkan → memerlukan barrier baik secara fisik atau kimia – Coating – Embedding of drug in a wax or plastic matrix – Microencapsulation – Chemical bindering to ion exchange resin – Incorporation in an osmotic pump
- 15. Kinetic pattern ofdrug release required for the ideal modified controlled-release per oral dosage form
- 16. Penentuan dosis modified-releaseproduct • kr = konstanta kec pelepasan • ka = konstanta kec absorpsi • ke = konstanta kec eliminasi • Rate limiting step → kr (kr << ka) • Idealnya banyaknya obat yg dilepaskan tdk tergantung konsentrasi obat dlm sediaan – Zero order – Laju pelepasan yg konstan Dosage form GI tract Blood Urine kr ka ke
- 17. Kecepatan pelepasan ygdiharapkan • Asumsi farmakokinetika obat mengikuti model 1 kompartemen terbuka • Utk mempertahankan kadar obat dlm darah konstan maka jml obat yg dikeluarkan (eliminasi) harus sama dg pelepasan obat dari sediaan (rate out = rate in) Rate out = kr = Ct x Ke x Vd Rate in = W = Di + (kr x h) – W = total dosis – Di = initial dose – h = durasi efek – Vd = volume distribusi – Ct = kadar obat dalam darah (MEC – MTC) – Ke = konstanta kec eliminasi – Kr = konstanta kec pelepasan obat dari sediaan
- 18. Contoh 1 • Buatlahsediaan lepas terkontrol untuk pemakaian oral obat teofilin! Diketahui parameter farmakokinetika sbb: Di = 100 mg, ke = 0,085/jam, Ct = 10 μg/mL, dan Vd = 35 L. • Hitung berapa dosis total yg diperlukan selama 12 jam! (asumsi F = 100%)
- 19. Jawab 1. Rate in= rate out = kr = Ct x ke x Vd = 10μg/mL x 0,085/jam x 35000 mL = 29750 μg/jam 2. W = Di + (kr x h) = 100 000 μg + (29750 μg/jam x 12 jam) = 457000 μg = 457 mg/ tablet
- 20. KEUNTUNGAN MR PRODUCT •Mengurangi fluktuasi kadar obat dalam darah • Mengurangi frekuensi pemberian • Meningkatkan kepuasan dan kenyamanan pasien • Mengurangi efek samping yang merugikan • Mengurangi biaya pemeliharaan kesehatan
- 21. Keterbatasan MR Product •Efektifitas pelepasan obat dipengaruhi dan dibatasi oleh lama waktu tinggal di saluran cerna • Kemungkinan adanya dose dumping – sejumlah besar obat dari sediaan yg dilepaskan dengan cepat • Sering mempunyai korelasi in vitro-in vivo yang jelek • Biaya produksi lebih mahal dibanding sediaan konvensional • Tidak dapat digunakan untuk obat dengan dosis besar (500 mg)
- 22. B. DESIGN OFPERORAL MODIFIED RELEASE DRUG DELIVERY SYSTEMS Factors influencing design strategy 1. The physiology of the gastrointestinal tract and drug absorption 2. Physicochemical properties of the drug 3. Choice of the dosage form 4. Drug-release mechanisms
- 23. 1. The physiologyof the gastrointestinal tract and drug absorption • the residence time of a dosage form in the gastrointestinal tract is influenced by both stomach emptying time and intestinal transit time – • solution and pellets (<2 mm) leave the stomach rapidly – • single dose units (>7 mm) can stay in the stomach for up to 10 hours if the delivery system is taken with a heavy meal – • the transit time through the small intestine is approximately 3 hours
- 24. 2. Physicochemical propertiesof the drug Kandidat zat aktif untuk MR Product • Solubility (> 1 mg/mL) • Permeability (> 0,5x 10-6 mm/detik) • Biological half life antara 2-6 jam – Tidak terjadi akumulasi dalam tubuh • Dosis obat yang rendah (125-325 mg) → keterbatasan ukuran sediaan • Stabilitas yang baik – Tdk mengalami first pass effect metabolism – Tdk rusak akibat pengaruh enzim dan cairan saluran cerna
- 25. Biopharmaceutical Classification System • highsolubility and high permeability (best case) • high solubility and low permeability • low solubility and high permeability • low solubility and low permeability (worst case) A drug that is highly soluble at intestinal pH and absorbed by passive diffusion (i.e. not site-specific absorption) would probably present the ideal properties for inclusion in an MR dosage form
- 26. • More than90% absorption in vivo may be expected for compounds with permeability, P, values > 4 x 10-6 mm s-1 , whereas less than 20% absorption is expected when P is <0.5 x 10-6 mm s-1
- 27. 3. Choice ofthe dosage form • Active ingredient – Single unit system: tablet, coated tablet, matrix tablet, capsule – Multiple unit system: granule, beads, capsule, microcapsule • MR dosage form – Monolithic or matrix system – Reservoir or membrane-controlled system – Osmotic pump system • The selection of the appropriate dosage form – will need to take account of an acceptable level of variability of performance – the influence of GI tract structure and function on the delivery system, and the release mechanism and release profile of the dosage form
- 28. 4. Mekanisme pelepasanobat (1) The two basic mechanisms controlling drug release dissolution of the active drug component 🡪diffusion of dissolved or solubilized species 1. Pembasahan bentuk sediaan Misal: hidrokoloid → mengembang (sweeling) channeling agent → larut 2. Difusi air ke dalam bentuk sediaan 3. Disolusi obat 4. Difusi zat aktif keluar bentuk sediaan Keempat proses tersebut tidak saling tergantung (dpt terjadi secara bersamaan atau berurutan)
- 29. 4. Mekanisme pelepasanobat (2) Drug delivery systems can be designed to have either • Constant release – ideal MR system – should provide and maintain constant drug plasma concentrations 🡪 release drugs at a constant rate 🡪 zero-order release diffusion of the drug or osmosis • Declining release – first-order kinetics – Cannot maintain a constant plasma drug concentration but can provide sustained release • Bimodal release – a dosage form that provides a rapid initial delivery of drug followed by a slower rate of delivery and then an increased rate at a later time
- 30. C. FORMULATION OF MODIFIED-RELEASEDOSAGE FORMS • Components of a modified-release delivery system • Monolithic matrix delivery systems • Membrane-controlled drug delivery systems • Delivery systems for targeting to specific sites in the gastrointestinal tract
- 31. MODIFIED RELEASE DOSAGEFORM A. Monolithic or matrix system B. Reservoir or membrane-controlled system C. Osmotic pump system a basic principle that governs all these systems In a solution, drug diffusion will occur from a region of high concentration to a region of low concentration 🡪 Water diffuses into the system in an analogous manner
- 32. Component of aMR delivery system • Active drug • Release-controlling agent(s): matrix former, membrane former • Matrix or membran modifier – Channeling agent for wax matrices – Wicking agent for hydrophilic matrices • Solubilizer, pH modifier, density modifier • Lubricant and glidant – Biasanya bersifat hidrofob – Dpt mempengaruhi pelepasan (mg stearat, as stearat)
- 34. A. Monolithic matrix deliverysystem 1. Matrik koloid hidrofilik – Partikel obat didispersikan dalam suatu matrik yg larut – Obat dilepaskan ketika matrik terlarut atau mengembang – Kec disolusi tergantung pelarutan matrik 2. Matrik lipid atau polimer yg tidak larut – Partikel obat didispersikan dalam suatu matrik yg tidak larut – Obat dilepaskan ketika pelarut masuk ke dalam matrik dan melarutkan obat – Ada 2 matrik 🡪 lipid matrix system dan Insoluble polymer matrix system
- 35. 1. Lipid matrixsystem • Zat aktif dicampur dengan eksipien yang bersifat hidrofobik • Manufacturing: direct compression, roller compaction or hot-melt granulation • Formulasi – Zat aktif – Wax matrix former – Channeling agent – Solubilizer and pH modifier – Antiadherent/glidant – Lubricant
- 36. Formulasi Lipid matrixsystem • Zat aktif • Matrix former – Hydrophobic material (padat pada suhu ruangan dan tidak meleleh pada suhu tubuh) – Contoh: carnauba wax, microcrystalline wax, cottonseed oil, soya oil – Jumlah 20-40 % • Channeling agent – Larut dalam saluran pencernaan → lepas dari sediaan → terbentuk matrik yang berpori – Partikel obat berdifusi keluar melewati pori dlm matrik yg dibentuk oleh channeling agent – Contoh: NaCl, gula, polyol (20-30 %) • Solubilizer & pH modifier – Utk meningkatkan kelarutan zat aktif – Misal: PEG, surfaktan, polyol • Antiadhernt/glidant – 0,5-1 % colloidal silicon dioxide – 4-6 % talk
- 37. Mekanisme pelepasan zataktif dari lipid matrix system 1. Air berdifusi ke dalam matriks 2. Pelarutan channeling agent 3. Pelarutan zat aktif 4. Zat aktif yg larut mengisi kapiler/kanal chaneling agent keluar dari matriks Kontrol pelepasan obat ditentukan oleh jumlah dan panjang channeling agent yg terbentuk
- 38. 2. Insoluble polymermatrix system • Drug is embedded in an inert polimer which is not soluble in the gastrointestinal fluids • Drug release from inert matrices = leaching from sponge • Release rate depends on drug molecules in aquous solution diffusing through a network of capillaries formed between compacted polymer particles • Release rate can be modified by changes with: – The addition of pore forming hydrophilic salt – Compression force – The particle size of the insoluble matrix – Solubility of active compound • Insoluble polymer matrix: ethylcellulose
- 39. Pengaruh eksipien thdpelepasan obat dari Insoluble polymer matrix system • Eksipien larut air – ↑Pembasahan matrik – ↑ Porositas • Eksipien tidak larut – ↓Pembasahan matrik – ↓Penetrasi medium disolusi • Ukuran partikel insoluble matrix components mempengaruhi kec pelepasan – Partikel besar →struktur matrik lebih terbuka →↗ kec disolusi
- 40. Drug release frominsoluble matrices a. Obat dlm bentuk larutan dlm matriks → Obat berdifusi lewat membran dlm bentuk larutan b. Obat terdispersi padat dlm matriks → setelah obat terdisolusi maka terdifusi dlm bentuk larutan c. Obat dlm bentuk larutan dlm matriks→ difusi melalui pori matriks (channeling agent) d. Obat terdispersi padat dlm matriks→ setelah obat terdisolusi maka difusi terjadi melalui air yg mengisi pori2 dlm matriks
- 41. 3.Hydrophilic Colloid matrixsystem • Obat dicampur dengan water-swellable hyrophilic polymer • The system → swelling → gel formation erosion & dissolution in aqueous media • Matrik kontak dg air → matrik koloid hidrofilik mengembang (swelling) → membentuk lapisan yg bersifat sticky → pengontrol disolusi zat aktif • Mekanisme pelepasan obat → air masuk ke dalam sediaan shg melarutkan obat dlm matrik → zat aktif keluar melalui lapisan koloid hidrofilik
- 42. Keuntungan matrik hidrofilik •Sederhana • Harga matrik lebih murah • High drug loading • Erodible shg secara perlahan2 matrik keluar dari tubuh • Mudah diproduksi (cetak langsung, granulasi basah, roller compaction) • Profil pelepasan obat dpt mengikuti: zero order, first order, etc.
- 43. Keterbatasan matrik hidrofilik •Pelepasan obat tergantung pada 2 proses difusi: penetrasi air melalui hydrated matrix ke dalam sediaan & difusi obat yg terlarut melalui hydrated matrix • Jika lapisan luar matrik mengalami erosi maka profil pelepasan lebih kompleks • Problem pada scale-up: konsistensi antar batch • Untuk zat aktif yang berbeda maka need optimal rate-controlling polymers
- 44. Formulasi Hydrophilic Colloidmatrix system • Zat aktif • Koloid hidrofilik • Matrix modifier → optional • Solubilizer and/or pH modifier → optional • Compression aid • Lubricant • Glidant → optional
- 45. Koloid hidrofilik • Matrix-formingagent • 20-80 % of the mass. Actual amount – depends on drug & desired release characteristics • + air → a hydrated gel → sebaiknya tetap utuh agar dpt mengontrol pelepasan obat • Contoh: NaCMC, HPMC, alginat, Xanthan gum, carbopol
- 46. Gel modifier • Untukmemodifikasi karakter difusi lapisan gel hidrofilik – Hidrasi koloid hidrofil lebih seragam – Mempercepat hidrasi koloid hidrofilik • Misal: gula, polyols, soluble salts
- 47. Solubilizer & pHmodifiers • Solubilizing agent – PEG – Polyols – Surfactans
- 48. Pelepasan obat dari matrikkoloid hidrofilik Matriks dalam medium air • Air melarutkan obat (water soluble) dipermukaan untuk dosis awal • Polimer hidrofilik terhidrasi & membentuk outer gel layer • Gel layer berfungsi sbg barrier terhadap masuknya air dan transfer obat • Pelepasan obat (soluble) terjadi melalui difusi melalui lapisan gel • Pelepasan obat (insoluble) terjadi melalui erosi
- 49. B. Membrane-controlled drugdelivery system Membrane • Sebagai pengontrol pelepasan obat dari sediaan • Lapisan yg mengendalikan kecepatan air yg masuk dan pelepasan obat • Permeable – Dpt dilewati air (cairan GI) – Dpt dilewati oleh obat • Tidak mengembang • Tidak mengalami erosi • Terdapat dipermukaan sediaan Drug reservoir • Tablet atau multiparticulate pellet yg disalut dg membran • Obat sebaiknya tdk berdifusi dlm bentuk padat, meskipun membran dpt dimuati obat utk initial dose • Air dpt masuk ke sistem → fase kontinyu → awal difusi obat & pelepasan
- 50. Formula sistem membran Core(inti) • Active drug • Filler or substrate • (solubilizer) • Lubricant/glidant Membran (coating) • Membran polymer – Misal : ethyl cellulose, acrylic copolymers (Eudragit) • Plasticizer – Memudahkan pelarutan obat dlm membran – Sbg pelentur →↓ kemungkinan pecahnya membran saat dikempa – Misal: dibutyl phthalate, citric acid ester utk ethyl cellulose (10-25% dari polimer) • (membrane modifier) • (colour/opacifier)
- 51. 1. Single unitsystem (tablet) • Tablet cetak • Inti tablet tidak hancur namun dapat melepaskan obat • Memungkinkan air dapat berpenetrasi & melarutkan obat shg terjadi difusi zat aktif melewati membran • Bahan pengisi : laktosa, MCC, dektrosa, sukrosa, polyols (mannitol, sorbitol, xylitol) • Buffer: surfaktan, polyols, PEG
- 52. 2. Multiple-unit systems •Terdapat lebih dari 1 unit individual – Misal: granul atau pellet yg disalut • Coated spheroids (pellet dg diameter 1 mm) • Dimasukkan dalam kapsul keras atau dikempa dalam bentuk tablet (jarang dilakukan krn bisa merusak membran)
- 53. 2. Multiple-unit systems(2) • Formulasi: 1. Penggunaan pellet yg berisi gula, lalu disalut dg obat (berada dipermukaan pellet), kemudian dilapisi membran 2. Formulasi utk small spheroids yg mengandung obat dengan metode extrusion/spheronization • Pelepasan obat terjadi dari bagian per bagian tergantung permeabilitas membran : – Ketebalan membran – Jenis material coating
- 54. C. Osmotic pumpsystems • Another form of membrane-controlled release drug (terdapat hole sebagai pintu keluarnya obat) • Obat (water soluble) dimasukkan tablet inti • Tablet inti disalut dengan membran yg bersifat semipermiable – Air masuk ke dalam tablet inti melewati membran – Zat aktif dlm tablet inti terlarut (suspensi/ larutan) – ↗ tekanan hidrostatik – Pemompaan larutan obat (atau suspensi) melewati hole • Kecepatan pelepasan obat ditentukan oleh – Kecepatan penetrasi air ke dalam tablet inti – Kecepatan obat keluar melalui hole membran
- 55. Formulasi Osmotic pumpsystems Tablet inti • Active drug • Filler • (viscosity modifier) • (solubilizer) • Lubricant/glidant Coating • Membran polymer • Plasticizer • (membrane modifier) • (colour/opacifier) Catatan: Membran bersifat semipermiable Harus ada hole dlm membran utk tempat keluarnya obat Air melarutkan obat dlm tablet inti (jika obat kurang larut maka + solubilizer)
- 56. Delivery systems fortargeting to specific sites in the gastrointestinal tract • Gastric retentive systems • Colonic delivery systems
- 57. Gastric retentive systems •reduced variability of drug release, local drug delivery and action • enhanced bioavailability for those drugs with a restricted absorption window in the gastrointestinal tract
- 58. Methods to achievegastric retention • • the addition of passage-delaying agents, – such as food material, for example triethanolamine myristate, or drugs, for example propantheline; • • the use of high-density materials: – high-density particles (>2.5g/cm3) have prolonged gastric residence times. This can be achieved by the addition of materials such as barium sulphate • • modification of the size/shape of delivery system – by the use of unfolding polymer sheets, swelling hydrogel balloons, or polymer units that are too large to pass through the pyloric sphincter. • • bioadhesive systems. – Systems have been used which will adhere to surfaces such as the mucosa. The problems when these systems are used for gastrointestinal delivery are that first, high local concentrations of drug may result, and second, there is a turnover of mucosa, leading to detachment of the delivery system; • the use of floating dosage forms. – These systems resist gastric emptying by floating on the stomach contents. They should not alter the intrinsic emptying rate of the stomach and their specific gravity should be less than that of the stomach contents. Systems used are (a) hydrodynamically balanced systems; (b) carbon dioxide-generating systems; (c) freeze-dried systems.
- 59. Colonic delivery systems •Applications for these systems include local delivery for the treatment of inflammatory diseases, infections, and diarrhoea; and systemic delivery.
- 60. Design principles forthese delivery systems make use of: • the specific pH of the colon – pH-sensitive polymers are used in their manufacture, e.g. combinations of Eudragit 100-55 (pH 5.5) with Eudragit S (pH 7.0). – The principle is that drug is released at a specific pH environment • small-intestine transit time – These depend on timed release of the active drug
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