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 –‘‘Dragon’s 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 Basisof Modern Formulation

Professor Reinhard HuettenrauchVEB 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 systemsdelivery 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 againBiotech companies againaccounted for more new drugaccounted for more new drugapprovals by America’’s FDAapprovals by America’’s FDA

than did big pharmaceuticalthan did big pharmaceuticalcompaniescompanies

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 DeliveryAdvantages of Controlled Drug Delivery

Increase patient complianceIncrease patient compliance– Less frequent administrationLess frequent administration– Less invasiveLess invasive– Etc.Etc.

Employ less total drugEmploy less total drug– Minimize local and systemic side effectsMinimize local and systemic side effects– Decrease potentiation of drug activity with chronic useDecrease potentiation of drug activity with chronic use– Decrease drug accumulation with chronic useDecrease drug accumulation with chronic use

Improve efficiency in treatmentImprove efficiency in treatment– Cure or control condition more promptlyCure or control condition more promptly– Improve control by reduction in fluctuationImprove control by reduction in fluctuation– May improve bioavailabilityMay improve bioavailability– OtherOther

Many times economicalMany times economical– Considering cost of drug, hospitalization and lab tests for side effects, Considering cost of drug, hospitalization and lab tests for side effects,

etc.etc.

The Magic BulletThe Magic Bullet

Drug Targeting

DRUG DELIVERY SEGMENTSWORLDWIDE MARKET / GROWTH ($ IN BILLIONs)

TECHNOLOGY 2000 2005 GROWTH

CONTROLLED RELEASE 14.2 26.3 85%

PULMONARY, INHALATION 11.7 22.6 93%

TRANSNASAL DELIVERY 8.2 16.0 95%

TRANSMUCOSAL 2.4 6.5 171%

TRANSDERMAL DELIVERY 6.7 12.7 90%

INJECTABLE/IMPLANTABLE 3.8 7.2 89%

NEEDLE-LESS INJECTION 0.4 1 150%

RECTAL 0.5 1.2 140%

LIPOSOMAL 1.2 3.3 175%

CELL/GENE THERAPY 0 5 0%

MISCELLANEOUS 1.5 2.5 67%

TOTAL 50.6 104.3 106%

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

OROSPush-Pull Osmotic System

OROSPush-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

In vitro dissolution profiles of Propranolol HCl as time fuction

RELEASING PROFILE OF PROPRANOLOL HCL SUSTAINED RELEASE TABLET WITH FLOATING SYSTEM BY VARIATION CONCENTRATION

OF METHOCEL K15M AS MATRIX

(Proceeding International Conference)

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 PumpsExample: 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 Current Insulin Delivering Devices:Delivering Devices:– SyringesSyringes– Insulin PensInsulin Pens– Insulin jet injectorsInsulin jet injectors– Insulin pumpsInsulin pumps

Have a small reservoir, Have a small reservoir, syringe, programmable syringe, programmable hand padhand pad

Commonly used by Commonly used by Type I diabeticsType I diabetics

Glucowatch: case for continuous monitoring

Based on reverse iontophoresis:

Glucose pulled through the skin by charged moleculesThe ions migrate to the anode (+) and cathode (-)Glucose reacts with glucose oxidase to form hydrogen peroxideThe reaction produces an electrochemical measured by the AutoSensorReverse 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 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

Fast Dissolving Tablets

Paracetamol 250 mg

Chlorpheniramine maleate 1 mg, Dextromethorphan HBr 5 mg, Pseudoephedrine HCl 15 mg

Acetaminophen 160 mg, Dextromethorphan HBr USP 5 mg

Paracetamol 500 mg, Caffeine 65 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

Pool ofMedicationLeft by needle

Medication is Dispensed Uniformly in Spray Like Pattern

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 Generex’s 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)Transdermal permeation (percutaneous absorption)– The passage of substance from the outside of the skin The passage of substance from the outside of the skin

through its various layers into the bloodstreamthrough its various layers into the bloodstream

Advantages of transdermal delivery systemAdvantages of transdermal delivery system– The system avoids the chemically hostile GI environmentThe system avoids the chemically hostile GI environment– No Gi distress or other physiological contraindications of No Gi distress or other physiological contraindications of

the oral routethe oral route– Can provide adequate absorption of certain drugsCan provide adequate absorption of certain drugs– Increased patient complianceIncreased patient compliance– Avoids first-pass effectAvoids first-pass effect– Allows effective use of drugs with short biological half-lifeAllows effective use of drugs with short biological half-life– Allow administration of drugs with narrow therapeutic Allow administration of drugs with narrow therapeutic

windowswindows– Provides controlled plasma levels of very potent drugsProvides controlled plasma levels of very potent drugs– Drug input can be promptly interrupted when toxicity Drug input can be promptly interrupted when toxicity

occursoccurs

Disadvantages of TDSDisadvantages of TDS– Drug that require high blood levels cannot be Drug that require high blood levels cannot be

administeredadministered– Adhesive may not adhere well to all types of skinAdhesive may not adhere well to all types of skin– Drug or drug formulation may cause skin irritation Drug or drug formulation may cause skin irritation

or sensitizationor sensitization– Uncomfortable to wearUncomfortable to wear– May not be economicalMay not be economical

A schematic representation of the skin.

Types of transdermal delivery devices.Types of transdermal delivery devices.

Transdermal Controlled-Release Transdermal Controlled-Release Products and DevicesProducts and Devices

DrugDrug Trade NameTrade Name Type of Type of DevicesDevices

IndicationIndication

ScopolamineScopolamine Transderm-Transderm-ScopScop

ReservoirReservoir Motion Motion sicknesssickness

NitroglycerineNitroglycerine Transderm-Transderm-NitroNitro

ReservoirReservoir AnginaAngina

Nitro-DurNitro-Dur MonolithicMonolithic

NitrodiscNitrodisc MonolithicMonolithic

EstradiolEstradiol EstradermEstraderm Reservoir and Reservoir and ethanol ethanol enhancerenhancer

Hormone Hormone treatmenttreatment

Transdermal Products under Transdermal Products under DevelopmentDevelopment

DrugDrug Trade nameTrade name Producer-MarketerProducer-Marketer

MinocyclineMinocycline SunstarSunstar American Cyanamide, American Cyanamide, TakedaTakeda

Estradiol+NorEstradiol+Norethisteroneethisterone

Estracombi Estracombi TISTIS

Ciba-Geigy, AlzaCiba-Geigy, Alza

DHEADHEA PharmedicPharmedic

FentanylFentanyl

Triamcinolone Triamcinolone acetonideacetonide

Whitby Pharm.Whitby Pharm.

IontophoresisIontophoresisThe application of an electrical field to enhance the penetration of The application of an electrical field to enhance the penetration of the the

skin by ionic drugs. Examples: lidocaine, amino acids, peptides, skin by ionic drugs. Examples: lidocaine, amino acids, peptides,

steroids. Iontocaine recently approved.steroids. Iontocaine recently approved.– Major advantage; higher control of drug inputMajor advantage; higher control of drug input

– Disadvantage; low efficiency. Other ions such as Na+ and Cl- moving Disadvantage; low efficiency. Other ions such as Na+ and Cl- moving out of the body.out of the body.

– High Cost.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 contraceptiveRecently approved transdermal contraceptive

Recently (Nov 2001) approved by FDA (Ortho-McNeil)Recently (Nov 2001) approved by FDA (Ortho-McNeil)Once a week for three weeks, fourth week patch freeOnce a week for three weeks, fourth week patch free99 percent effective when used as directed99 percent effective when used as directedCombination estrogen and progestinCombination estrogen and progestinOne-and-three-quarter inch square applied to the lower One-and-three-quarter inch square applied to the lower abdomen, buttocks or upper body.abdomen, buttocks or upper body. Skin irritation or detachment reported in 2-5% of Skin irritation or detachment reported in 2-5% of patientspatients

PharmacologicPharmacologicLidoderm PatchLidoderm Patch

Lidoderm patch 5%Lidoderm patch 5%

(lidocaine)(lidocaine)

12 hrs on 12 hrs off12 hrs on 12 hrs off

Approved for PHNApproved for PHN

Off label use for Off label use for localized pain localized pain syndromes.syndromes.

Selected leading product utilizing Selected leading product utilizing Transdermal drug delivery systemTransdermal drug delivery system

Future Technologies : Future Technologies : Niche and emerging drug deliveryNiche and emerging drug delivery

Gene delivery : viral based vector and non-viral vector Gene delivery : viral based vector and non-viral vector (cationic lipid based).(cationic lipid based).

Pulmonary drug delivery : as a way to deliver gene Pulmonary drug delivery : as a way to deliver gene based therapies.based therapies.

Advance topical drug delivery : development of Advance topical drug delivery : development of improved absorption enhancer.improved absorption enhancer.

Implantable drug delivery : usage of bioerodible Implantable drug delivery : usage of bioerodible technology, iMEDD (nanoporous silicon membranes).technology, iMEDD (nanoporous silicon membranes).

‘‘Smart’ Microchips for controling release of Smart’ Microchips for controling release of therapeutic substancestherapeutic substances

Liposomal gene deliveyViral gene delivery

ChipRx

APLIKASI NANOPARTIKEL PADA INDUSTRI FARMASI

The next “Big Thing” is The next “Big Thing” is veryvery, , veryvery, , veryvery smallsmall!!

“ “Nanotechnology is an enabling Nanotechnology is an enabling technology that will change the technology that will change the nature of almost every human-nature of almost every human-made object in the next century.”made object in the next century.” --National Science and Technology Council -2000National Science and Technology Council -2000

This means… anything manufactured in Oklahoma will be This means… anything manufactured in Oklahoma will be impacted by nanotechnology and it is happening more impacted by nanotechnology and it is happening more quickly than most people might think!quickly than most people might think!

WHAT IS NANOTECHNOLOGY?WHAT IS NANOTECHNOLOGY?

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

Structures (e.g.materials)

Devices (e.g. sensors)

Systems (e.g. NEMS)

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

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 Products of nanotechnology are expected to revolutionize modern medicinemodern medicine

In pharmaceutics, ~90% of all medicines, the active In pharmaceutics, ~90% of all medicines, the active ingredient is in the form of solid particles. With the ingredient is in the form of solid particles. With the development in nanotechnology, it is now possible to development in nanotechnology, it is now possible to produce drug nanoparticles that can be utilized in a variety produce drug nanoparticles that can be utilized in a variety of innovative ways.of innovative ways.

New drug delivery pathways can now be used that can New drug delivery pathways can now be used that can increase drug efficacy and reduce side effects. For increase drug efficacy and reduce side effects. For example, in 2005, the U.S. Food and Drug Administration example, in 2005, the U.S. Food and Drug Administration approved intravenously administered 130-nm albumin approved intravenously administered 130-nm albumin nanoparticles loaded with paclitaxel (AbraxaneTM) for nanoparticles loaded with paclitaxel (AbraxaneTM) for cancer therapy, which epitomizes the new products cancer therapy, which epitomizes the new products anticipated based on nanoparticulate systems.anticipated based on nanoparticulate systems.

Medical and Pharmaceutical Medical and Pharmaceutical Applications of NanotechnologyApplications of Nanotechnology

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

Tissue regeneration, growth, repair

Material/technique Property Applications Timescale (to market launch)

Nanoparticles in the range of 50–100 nm

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

Cancer treatment. ?

Nanosizing in the range of 100–200 nm

Low solubility. More effective treatment with existing drugs.

?

Nanocapsules. Evading body’s immune system whilst directing a therapeutic agent to the desired site.

A Buckyball-based AIDS treatment is just about to enter clinical trials.

Early clinical.

Nanoporous materials.

Evading body’s immune system whilst directing a therapeutic agent to the desired site.

When coupled to sensors, drug-delivering implants could be developed.

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

‘Pharmacy-on-a-chip’ Monitor conditions and act as an artificial means of regulating and maintaining the body’s own hormonal balance.

E.g. diabetes treatment. More distant than ‘lab-on- a-chip’ technologies.

Application in drug delivery

http://www.azonano.com/details.asp?ArticleID=1078

Targeted delivery in cancer treatmentTargeted delivery in cancer treatment

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.

Multifunctional nanoparticle

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

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

PharmacogenomicsPharmacogenomics

Pharmaceuticals based on an Pharmaceuticals based on an

individuals genomeindividuals genome

““Individualizing drug therapy!”Individualizing drug therapy!”

>>>>> (Compounding)<<<<<>>>>> (Compounding)<<<<<

PharmacogenomicsPharmacogenomics

Based on the individuals human genomeBased on the individuals human genome

Better selection of drugsBetter selection of drugs

Better selection of doseBetter selection of dose

Better selection of excipientsBetter selection of excipients

Compounding may play a major role!Compounding may play a major role!

Thank YouThank You