Materi

Pengantar Bentuk Sediaan (Dosage Form) Transforming art into science in dosage form design Controlled Drug Delivery

Oral Controlled Drug Delivery Inplantable Terapeutics Innovative Dosage Form

Oral Disintegrating Tablet Fast Dissolving Tablet Soluble Film Technology Injectable Drug Delivery

Transdermal Drug Delivery System

Referensi

Banker D, Rhodes C., 2002, Modern Pharmaceutics, 4 th ed, Marcel Dekker Inc Ghosh, T., Pfister W, 2005, Drug Delivery to Oral Cavity, Taylor & Francis Group, LLC Guy R, Hadgraff, 2003, Transdermal Drug Delivery, 2 nd ed, Marcel Dekker Inc Ranade V, Holinger, M., 2004, Drug Delivery System, 2 nd ed, CRC Press Siswantoro, PA., 2007, Perkembangan Industri Farmasi, pengaruhnya terhadap Pendidikan Tinggi farmasi Indonesia, Makalah APTFI, Yogyakarta. York, P, 2007, Transforming art into science in dosage form design achievements and challenges, Institut of Pharmaceutical Innovation, Amsterdam. -----------------, Injex Needle Free injection System, Injex Presentation

Transforming art into science in dosage form design

Materia Medica

Materia Medica (Latin - -matters medical) body of knowledge about the therapeutic properties of any substance used for healing (pengobatan) Term used from the period of the Roman Empire to 20th century Used by Dioscorides (1st century AD) in is book De Materia Medica with details of over 600 medicinal plants; remained in use to 1600s Galen (130 -200 AD) principles of preparing and compounding medicines ruled western world for 1500 years

The art of dosage form design

Drug substances from botanical and mineral origins Galenical preparations skills and recipes of the apothocaries Dosage forms liquids, suspensions, topical preparations Secundum artum!!

Pharmacy magic Dragons Blood

Resin from fruit of species of Deamanorops( (Dragon Tree), ), originally from the Yemen Mild astringent Reputed to be a charm to restore love!!

Appeared in the British Pharmaceutical Codex until 1934!!!

Era of Medicinal Chemistry

Primarily plant and mineral sources for therapeutics up to 19th century Start of medicinal chemistry at end of 19th Century Synthesis of acetyl salicylic acid in 1897 Patented as aspirin by Bayer in 1899

Aspirin the dawn (awal) of the medicinal chemistry revolution

Molecular Pharmaceutics
Molecular Pharmaceutics as the Basis of Modern Formulation
Professor Reinhard Huettenrauch VEB Jenapharm , Jena, GDR
(Acta Pharm. Tech. Supp 6, 55- -127 (1978))

Molecular Pharmaceutics

Enabled the introduction of molecular scientific thinking into dosage form design and concept of drug delivery systems

Drug Delivery Systems

Drug delivery systems

delivery of therapeutic agent in an amount which will modulate the receptor/pathway appropriately
deliver with the timing to match the chronotherapeutic requirements of the disease deliver at the site required

Controlled Release: Advantage for the Patient

Drivers of Innovation

Biotech companies again accounted for more new drug approvals by Americas FDA than did big pharmaceutical companies

Economist, Jun 2nd 2005

Strategi pengembangan penghantaran obat baru :

Mencari tempat pemasukan baru (entry point)

Transdermal, pulmonal, transnasal

Mencoba memanfaatkan lokasi di saluran cerna yang selama ini dianggap kurang prospektif Mengembangkan sistem penghantaran koloidal

Mis. Liposom, niosom, nanopartikel, mikroemulsi

Mengembangkan sistem penghantaran yang terkait dengan pulse (pulsatile release system) Mengembangkan sistem penghantaran yang responsif terhadap rangsang (termal, cahaya, magnetik, listrik) Mengendalikan sistem penghantaran sesuai dengan keperluan dan keinginan terapi

Advantages of Controlled Drug Delivery

Increase patient compliance
Less frequent administration Less invasive Etc.

Employ less total drug

Minimize local and systemic side effects Decrease potentiation of drug activity with chronic use Decrease drug accumulation with chronic use

Improve efficiency in treatment

Cure or control condition more promptly Improve control by reduction in fluctuation May improve bioavailability Other

Many times economical

Considering cost of drug, hospitalization and lab tests for side effects, etc.

The Magic Bullet

Drug Targeting

DRUG DELIVERY SEGMENTS WORLDWIDE MARKET / GROWTH ($ IN BILLIONs)

TECHNOLOGY CONTROLLED RELEASE PULMONARY, INHALATION TRANSNASAL DELIVERY TRANSMUCOSAL TRANSDERMAL DELIVERY INJECTABLE/IMPLANTABLE NEEDLE-LESS INJECTION RECTAL LIPOSOMAL CELL/GENE THERAPY MISCELLANEOUS TOTAL

2000 14.2 11.7 8.2 2.4 6.7 3.8 0.4 0.5 1.2 0 1.5 50.6

2005 26.3 22.6 16.0 6.5 12.7 7.2 1 1.2 3.3 5 2.5 104.3

GROWTH 85% 93% 95% 171% 90% 89% 150% 140% 175% 0% 67% 106%

Osmotic Pumps
Tablet core
drug layer and push layer

Semi-permeable membrane with small hole Water enters through membrane/dissolves drug
Increase in osmotic pressure Forces drug solution out through orifice

Examples:
Ditropan XL,Glucotrol XL

Procardia XL

OROS Push-Pull Osmotic System

OROS Push-Pull Osmotic System

Hydrodynamic Balanced System (HBS)

Matrix system designed to float in stomach Hydrocolloid swells upon contact with water Forms barrier layer that gradually erodes
progressive erosion

Example: Valrelease (Roche)

capsule shell dissolves blood levels equivalent to 5mg valium TID

Approaches to Achieving Gastric Retention Floating systems

Low density (i.e. HBS) Effervescent/CO2 producing

Sinking systems Adhesion

Swelling and Expansion

Magnetic

RELEASING PROFILE OF PROPRANOLOL HCL SUSTAINED RELEASE TABLET WITH FLOATING SYSTEM BY VARIATION CONCENTRATION OF METHOCEL K15M AS MATRIX (Proceeding International Conference)

In vitro dissolution profiles of Propranolol HCl as time fuction

Buoyancy studies at initial time

Buoyancy studies after 3 hours

Drug Coated onto Beads Non-pareil beads Coated with drug/polymer mixture Coated with rate-controlling membrane Filled into capsules or compressed into tablets

Prilosec

Eryc

PCE

Eroding Matrix
Drug combined with matrix material:
lipid/cellulosic/polymeric

Processed into tablets

slowly erode in body fluids

Combined with regular granulated drug

immediate release + prolonged release filled in capsules or compressed in tablets

Ex: Slow-K, Sinemet CR

Hydrophilic Matrix System

(K-type Methocel)

Implantable vaginal rings

Available since 2002 (NuvaRing, Organon) Ethylene vinyl acetate copolymer 54 mm in diameter Cross-sectional diameter 4 mm. Systemic control for 1 month 0.120 mg of etonogestrel & 0.015 mg of ethinyl estradiol per day over 3 weeks (21 days)

Responsive Drug Delivery Systems

Example: Insulin Pumps
An insulin reservoir (like a regular syringe) A small battery operated pump A computer chip for control Infusion set- a thin plastic tube to deliver insulin to the body Pump therapy A basal rate & bolus insulin Combination with Glucose sensors

Current Insulin Delivering Devices:

Syringes Insulin Pens Insulin jet injectors Insulin pumps
Have a small reservoir, syringe, programmable hand pad Commonly used by Type I diabetics

Glucowatch: case for continuous monitoring

Based on reverse iontophoresis:

Glucose pulled through the skin by charged molecules The ions migrate to the anode (+) and cathode (-) Glucose reacts with glucose oxidase to form hydrogen peroxide The reaction produces an electrochemical measured by the AutoSensor Reverse iontophoresis: future insulin delivery method in response to glucose?

INNOVATIVE DOSAGE FORM

Oral Drug Delivery Inhaled Drug Delivery Injectable Drug Delivery Transmucosal Drug Delivery Transdermal Drug Delivery Future Tech : Gene Delivery & Nanotech

Slide from Pre Agusta Siswantoro (Kalbe)

Orally Disintegrating Tablet ?

sediaan yang cepat larut, meleleh atau hancur dalam rongga mulut (tanpa dikunyah), dapat dikonsumsi tanpa air minum, kapanpun dan dimanapun saat gejala muncul disintegration time < 1 menit

Keistimewaan/Feature : ODT
penggunaan mudah dan praktis --> tanpa air meningkatkan kepatuhan penggunaan obat (compliance) Praktis dibawa dana lebih stabil (Solid) kemudahan untuk pasien yang sukar menelan (anak-anak atau orang tua) dan untuk travelling patients Rasa lebih enak
Pharma technology trend

Fast Dissolving Tablets

Fast dissolve (< 1 minute, without water), good taste Target :
children, elderly and patients who have difficulty swallowing tablets or liquids patients with persistent nausea, vomit, who are traveling or who have no access to water

Fast Dissolving Tablets

Paracetamol 250 mg

Paracetamol 500 mg, Caffeine 65 mg

Chlorpheniramine maleate 1 mg, Acetaminophen 160 mg, Dextromethorphan HBr USP 5 mg Dextromethorphan HBr 5 mg, Pseudoephedrine HCl 15 mg

Pharma technology trend

Soluble Film Technology

Good prospect in the nutraceutical industry Watson Foods, West Haven (expertise in soluble film technology): wide range of film technologies, from quick dissolve strips to slower dissolving strips (up three hours) Great application: pain relief diet product contained an ingredient providing satiation & also made mouth feel fresh

Soluble Film Technology

Seamless Mini Capsules

Breath freshener

mint, cinnamon, spearmint, alpine splash

Injectable Drug Delivery

Injectable DDS is the only viable drug delivery method for large molecular weight compounds of low potency (e.g. monoclonal antibodies).

Injectable Formulation :
Needleless injection Long acting/sustained release injection (matrix, PEGylation, depot) Liposomal injection

Major therapeutic Applications :

anti-infectives, anti-cancer, anesthetics

How Injex Penetrates the Skin

Needle Syringe

Needle-Free Injection
Medication is Dispensed Uniformly in Spray Like Pattern

Pool of Medication Left by needle

Application
Dental

Application
Diabetes

Application
Local Anaesthesia

Selected leading product utilizing injectable drug delivery system

Transmucosal Drug Delivery

Advantages : avoiding hepatogastrointestinal clearance, increased bioavailability compared with transdermal drug delivery, ability to start and stop administration quickly. Transmucosal formulations : buccal, nasal, pulmonary, rectal, vaginal. Exciting innovations in buccal delivery is Generexs system, a drug is administered via metered dose oral spray for absorption through the mucous membranes. Oralin is the first transoral insulin to be launched. The development of nasal vaccines is a promising approach to the prevention of infectious disease.

Selected leading product utilizing Transmucosal drug delivery system

Transdermal permeation (percutaneous absorption)

The passage of substance from the outside of the skin through its various layers into the bloodstream

Advantages of transdermal delivery system

The system avoids the chemically hostile GI environment No Gi distress or other physiological contraindications of the oral route Can provide adequate absorption of certain drugs Increased patient compliance Avoids first-pass effect Allows effective use of drugs with short biological half-life Allow administration of drugs with narrow therapeutic windows Provides controlled plasma levels of very potent drugs Drug input can be promptly interrupted when toxicity occurs

Disadvantages of TDS Drug that require high blood levels cannot be administered Adhesive may not adhere well to all types of skin Drug or drug formulation may cause skin irritation or sensitization Uncomfortable to wear May not be economical

A schematic representation of the skin.

Types of transdermal delivery devices.

Transdermal Controlled-Release Products and Devices

Drug Scopolamine
Nitroglycerine

Trade Name TransdermScop

TransdermNitro Nitro-Dur Nitrodisc

Type of Devices Reservoir

Reservoir Monolithic Monolithic Reservoir and ethanol enhancer

Indication Motion sickness

Angina

Estradiol

Estraderm

Hormone treatment

Transdermal Products under Development

Drug Trade name Producer-Marketer

Minocycline
Estradiol+Nor ethisterone DHEA Fentanyl Triamcinolone acetonide

Sunstar
Estracombi TIS

American Cyanamide, Takeda Ciba-Geigy, Alza

Pharmedic

Whitby Pharm.

Iontophoresis
The application of an electrical field to enhance the penetration of the skin by ionic drugs. Examples: lidocaine, amino acids, peptides, steroids. Iontocaine recently approved.
Major advantage; higher control of drug input Disadvantage; low efficiency. Other ions such as Na+ and Cl- moving out of the body. High Cost.

A charged drug delivery electrode (positive or negative) repels(mengusir) the drug ions into the underlying tissue.

Schema of molecular transport during iontophoresis.

Recently approved transdermal contraceptive

Recently (Nov 2001) approved by FDA (Ortho-McNeil) Once a week for three weeks, fourth week patch free 99 percent effective when used as directed Combination estrogen and progestin One-and-three-quarter inch square applied to the lower abdomen, buttocks or upper body. Skin irritation or detachment reported in 2-5% of patients

Pharmacologic Lidoderm Patch

Lidoderm patch 5% (lidocaine) 12 hrs on 12 hrs off Approved for PHN Off label use for localized pain syndromes.

Selected leading product utilizing Transdermal drug delivery system

Future Technologies : Niche and emerging drug delivery

Gene delivery : viral based vector and non-viral vector (cationic lipid based). Pulmonary drug delivery : as a way to deliver gene based therapies.

Advance topical drug delivery : development of improved absorption enhancer.

Implantable drug delivery : usage of bioerodible technology, iMEDD (nanoporous silicon membranes). Smart Microchips for controling release of therapeutic substances

ChipRx

Viral gene delivery

Liposomal gene delivey

APLIKASI NANOPARTIKEL PADA INDUSTRI FARMASI

The next Big Thing is very, very, very

small

Nanotechnology is an enabling technology that will change the nature of almost every humanmade object in the next century.
-National Science and Technology Council -2000
This means anything manufactured in Oklahoma will be impacted by nanotechnology and it is happening more quickly than most people might think!

WHAT IS NANOTECHNOLOGY?
Nanotechnology is the manipulation of matter at the nanometer* scale to create novel structures, devices and systems.

Structures (e.g.materials)

Devices (e.g. sensors)

Systems (e.g. NEMS)

* 1 millimeter = 1,000 micrometers; 1 micrometer = 1,000 nanometers Source: "Nanotech: The Tiny Revolution" by CMP Cientfica (November 2001)

EFEK UKURAN PADA SIFAT-SIFAT MATERIAL

Mengapa reduksi ukuran material dalam skala nanometer menjadi begitu penting? Sifat-sifat material yang meliputi sifat fisis, kimiawi, maupun biologi berubah begitu dramatis ketika dimensi material masuk ke dalam skala nanometer. Yang lebih menarik lagi adalah sifat-sifat tersebut ternyata bergantung pada ukuran,kemurnian permukaan, maupun bentuk/topologi material. Para ilmuwan percaya bahwa setiap sifat memiliki skala panjang kritis. Ketika dimensi material lebih kecil dari panjang kritis tersebut maka sifat-sifat fisis fundamental mulai berubah. Sebagai contoh, nanopartikel tembaga yang memiliki diameter 6 nm memperlihatkan kekerasan lima kali lebih besar daripada tembaga ukuran besar (bulk). Contoh lain, keramik yang umumnya kita kenal mudah pecah dapat dibuat menjadi fleksibel jika ukuran bulir (grain) direduksi ke dalam orde nanometer.

HOW SMALL

Nanobatteries are 200 nm in diameter

2 billion could fit on the surface of a nickel

http://www.interdisciplines.org/interfaces/papers/1

Nanotechnology impact in pharmaceutics and medicines

Products of nanotechnology are expected to revolutionize modern medicine In pharmaceutics, ~90% of all medicines, the active ingredient is in the form of solid particles. With the development in nanotechnology, it is now possible to produce drug nanoparticles that can be utilized in a variety of innovative ways. New drug delivery pathways can now be used that can increase drug efficacy and reduce side effects. For example, in 2005, the U.S. Food and Drug Administration approved intravenously administered 130-nm albumin nanoparticles loaded with paclitaxel (AbraxaneTM) for cancer therapy, which epitomizes the new products anticipated based on nanoparticulate systems.

Medical and Pharmaceutical Applications of Nanotechnology

Biosensors and Biolabels - Fluorescent nanoparticles for cell labeling - Magnetic nanoparticles as sensor Diagnostics and Imaging - Early detection of disease - Improved imaging performance Targeted Drug Delivery the most promising aspects of nanotechnology in
pharmaceuticals & medicines

Tissue regeneration, growth, repair

Application in drug delivery

Material/technique
Nanoparticles in the range of 50100 nm

Property
Larger particles cannot enter tumour pores while nanoparticles can easily move into a tumour.

Applications
Cancer treatment.

Timescale (to market launch)

?

Nanosizing in the Low solubility. range of 100200 nm

Nanocapsules. Evading bodys immune system whilst directing a therapeutic agent to the desired site. Evading bodys immune system whilst directing a therapeutic agent to the desired site.

More effective treatment with existing drugs.

A Buckyball-based AIDS treatment is just about to enter clinical trials. When coupled to sensors, drug-delivering implants could be developed.

?
Early clinical.

Nanoporous materials.

Pre-clinical: an insulin- delivery system is being tested in mice.

Pharmacy-on-a-chip Monitor conditions and act as E.g. diabetes treatment. More distant than an artificial means of lab-on- a-chip regulating and maintaining the technologies. bodys own hormonal balance. http://www.azonano.com/details.asp?ArticleID=1078

Targeted delivery in cancer treatment

Multifunctional nanoparticle

Multicomponent targeting strategies: Nanoparticles extravasate into the tumour stroma through the fenestrations of the angiogenic vasculature, demonstrating targeting by enhanced permeation and retention. The particles carry multiple antibodies, which further target them to epitopes on cancer cells, and direct antitumour action. Nanoparticles are activated and release their cytotoxic action when irradiated by external energy.

Impian Nano

Nanobot; swimming to the injury site, sensing, diagnosing, then activating therapeutic systems and even cellular repair

www.nanobot.blogspot.com/ 2004_04_01_archive.html

Pharmacogenomics
Pharmaceuticals based on an individuals genome

Individualizing drug therapy! >>>>> (Compounding)<<<<<

Pharmacogenomics
Based on the individuals human genome Better selection of drugs Better selection of dose Better selection of excipients

Compounding may play a major role!

Thank You