Drug Delivery System

and Modified Release

Oral Delivery

1
2
.

3
Region of the Length, Internal Volume, Surface pH Average
GIT cm diameter, ml area, cm2 residence
cm time
Entire GIT 530-870 3-9 2 x 106 1.5-7 Up to 38 h
Mouth cavity 15-20 10 700
Esophagus 20 2-4 200
Stomach
•Fasted state 25 15 25-50 1.4-2.1 0.5-1.5 h
•Fed state 1000-1600 2-5 2-6 h

Small intestine 370-630 3-5 2.1-5.9 x 106 4.4-7.4 3±1h

➢Duodenum 20-30 3-5 0.113- 4.9-6.4 3-10 min
➢Jejunum 150-260 3-5 0.283x106 4.4-6.4 0.5-2 h
➢Ileum 200-350 3-5 0.27-0.75x106 6.5-7.4 0.5-2.5 h
0.36-1.05x106
Large intestine 150 3-9 15,000 5.5-7.4 Up to 27 h
Caecum 7 7 500 5.5-7
Rectum 90-150 3-9 15,000 7.4
11-16 2.5 150 7

4
 .
Drug Delivery
Definition
– The appropriate administration of drugs through
various routes in the body for the purpose of
improving health
– It is highly interdisciplinary
– It is not a young field
– It has recently evolved to take into consideration
Drug physico-chemical properties
Body effects and interactions Controlled
Improvement of drug effect Drug Delivery
Patient comfort and well being

5
 Drug Delivery

Conventional Controlled

Enteral Sustained

Extended
Parenteral
Site-specific
Other
Pulsatile
6
 Oral Administration
Advantages Disadvantages
– Patient: Convenience, – Unconscious patients
not invasive, higher cannot take dose
compliance – Low solubility
– Manufacture: well – Low permeability
established processes, – Degradation by GI
available infrastructure enzymes or flora
– First pass metabolism
– Food interactions
– Irregular absorption

7
 Oral Administration
Traditional oral
delivery systems
– Tablets
– Capsules
– Soft gelatin capsules
– Suspensions
– Elixirs

8
 Buccal/Sublingual
Advantages Traditional delivery
– By-pass First pass system/devices
metabolism – Tablets
– Rapid absorption – Chewing gum
– Low enzymatic activity
Disadvantages
– Discomfort during
dissolution
– Probability of swallowing-
lost of effect
– Small doses

9
.
SISTEM PENGHANTARAN OBAT
(DRUG DELIVERY SYSTEMS)

ASPEK TEMPORAL
ASPEK SPASIAL

•KOMPLEKSITAS PENGHANTARAN
•OPTIMASI OBAT SAMPAI LOKASI TARGET

10
SOME EXAMPLES OF DRUG DELIVERY
SYSTEMS

11
12
 History of Controlled Drug
Delivery

◼ Wurster technique 1949

◼ Coacervation (liquid encapsulation) 1953

◼ Microencapsulation 1960’s
◼ 65% of all current drugs use some form of micro-encapsulation
◼ Implants 1970’s
◼ Transdermal 1980’s
◼ Site directed systems 1990’s

13
 How is entrapment or
encapsulation obtained?
The physical entrapment and encapsulation of
drugs within a polymer is complete via one of
five techniques
1. Wurster
2. Coacervation
3. Spray drying (or precipitation)
4. Coextrustion
5. Self-assembly methods

14
 Wurster processing (1949)
◼ The Wurster process is essentially a coating
process applied after a drug core is formed.
◼ The polymer shell is applied via spraying while the
drug cores (liquid or solid) is suspended and
recirculated in a gas stream
Drug
Polymer Drug
Polymer

Gas
Gas
15
 Coacervation Technique
STEP #1:

Polymer/Oil

Drug/H20
◼
◼ Polymer dissolved in a solvent (or oil)
◼ Drug dissolved in water
◼ STEP #2:
◼ 2 liquids are rapidly mixed
◼ water droplets form within the solvent

H20
◼ STEP # 3:
◼ Emulsion from step #2 is mixed rapidly with
fresh water
◼ Oil droplets within the fresh water phase
◼ Oil droplets contain original dispersed
water/drug phase
◼ Oil diffuses into the fresh water phase
precipitating the polymer & entrapping the
drug 16
Supercritical fluid precipitation
Solvent- polymer
solution f rom
pump

CO2
from
pump Flow straightener
He at e xchanger

Nozzle
Nozzle
contraction

Pr ecipitate

Back pressure
re gulator
Poly(l-lactide) ~1-mm diameter
particles formed by PCA processing
Gas outlet
0.2µm
filte r 17
 Co-extrusion processing
• There are numerous co-extrusion processes
but they all share one feature – the
polymer shell is flowed concentrically
around a pipe containing the drug
formulation
Syringe pump

◼ These concentric
Drug
cylinders then
breakup into
individual packets Polymer
Neg.

either driven by air HV

supply
flow, electrostatic or
mechanical vibration 18
 Self-assembling delivery systems

The next advance was to construct

materials/polymers that would self assemble with
drugs to create controlled drug delivery vehicles

• Self assembly is typically approach via one of

two methods:
1. Using a molecule that has a hydrophilic
head and hydrophobic tail to form a shell,
or
2. Electrostatic interaction to entrap drug
molecules 19
 Micelles & Bilayers
Polar Head
Group
(hydrophilic)
◼ Entrapment by micelle or bilayer
formation can be obtained using
lipids, surfactants and block Fatty Tail
copolymers (hydrophobic)

Lipid entrapment or liposomes are

the most common
•Small unilamellar
(10 to 50nm)
•Large unilamellar
(50nm to 1um) monlayer
•Large multilamellar
(100nm to 20mm)
micelle

Bilayer 20
 Liposome Formation
◼ Liposome are typically formed by:
◼ Fissure homogenization
◼ High pressure homogenization
◼ Extrusion through polycarbonate membranes

◼ Large multilamellar liposomes are prepared by hydration of

a dry lipid film by an aqueous solution.
◼ Thickness of the film, temperature, lipid composition effect lipid size
◼ Large unilamellar liposomes are prepared by vigorous
agitation (fissure or high pressure) during the hydration
process
◼ Mixing strength, lipid and surfactant control lipid size
◼ Small unilamellar liposomes are typically prepared by taking
LUV suspensions and passing them through fine matrix
polycarbonate membrane.
◼ Membrane pore size largely controls the resulting SML size 21
 Electrostatic entrapment
• Ionic attraction between dissimilar charged
molecules can be used to attach a molecule to
the drug OH
NH
• The resulting complex may provide protection
HO
CH Cl
by containing the drug molecule on the interior
3

or simply inactive the drug

Aqueous Phase l-PhenylephrineHydrochloride
OH Dodecyl Sodium Sulfate
NH
HO OH
CH3 Cl CH3 [CH2]11 OSONH Na
HO 3

CH3 CH3 [CH2]11 OSO3

Na Cl
l-PhenylephrineHydrochloride
Aqueous Phase l -Phenylephrine-Dodecyl Sulfate Complex

OHDodecyl Sodium Sulfate

HO NH Organic Phase
CH3 [CH2]11CH
OSO 3 3 Na
3 CH [CH2]11 OSO3
22
 Aqueous Phase • Complexes are prepared
OH Dodecyl Sodium Sulfate
by vigorously mixing
HO
NH
aqueous solutions of the
CH3 Cl CH3 [CH2]11 OSO3 Na
surfactant and drug.
• The complex either
Na Cl
l-PhenylephrineHydrochloride precipitates as a solid or
can be separated by
OH
partitioning to an organic
HO NH Organic Phase
CH3 CH3 [CH2]11 OSO3

l -Phenylephrine-Dodecyl Sulfate Complex

Dissolution M echanism
Phase Change Reverse Ion Pairing Process
k1 k2
(T  S)s (T  S)aq (T  S) aq + NaCl (T  Cl) aq + (Na  S)
• Unpairing
happens
naturally in the D iss olved Tacrine-S urfactan t (T •S) a q NH 2

presents of salts
NH2

Na Cl Cl
CH3 CH2 OSO3
11 N
N
Na Cl CH3 CH 2 OSO 3
11 Na
S olid Tacrine-Surfactant (T• S) s
Na Cl F ree Tacrine (T•C l) aq
an d Su rfactant (N a• S)
23
More than protection and release:
targeting a site
◼ The coating or matrix surrounding the
therapeutic molecule can also be used to
direct the particle to a targeted site.
◼ Such systems include:
1. Liposomes
2. Surfactant
3. Nanoparticles
4. Antibodies, enzymes and other proteins
5. Viral vectors

24
25
 Factors Influencing the Selection of
the Delivery Route

◼ Drug physico-chemical properties

◼ Drug molecular size (molecular weight)
◼ Half-life
◼ Chemical stability
◼ Loss of biological activity in aqueous
solution
◼ Proteins
◼ Denaturation, degradation

26
Factors Influencing the Selection
of the Delivery Route
◼ Solubility in aqueous solution
(hydrophobicity/hydrophilicity)
◼ pH
◼ pKa - ionization
◼ Temperature
◼ Concentration
◼ Crystalinity
◼ Particle size
◼ State of hydration

27
 Factors Influencing the Selection
of the Delivery Route
◼ Drug biological interactions
◼ Sensitive to FPM
◼ Low membrane permeability
◼ Efflux pumps (MRP, MDR) – cancer drugs
◼ Hydrophilicity
◼ High-density charge
◼ Enzymatic degradation
◼ Bacterial degradation
◼ Half-life
◼ Side effects
◼ Irritation
28
 Factors Influencing the Selection
of the Delivery Route
◼ Desired pharmacological effect
◼ Local
◼ topical, vaginal
◼ Systemic
◼ oral, buccal, IV, SC, IM, rectal, nasal
◼ Immediate response
◼ IV, SC, IM, nasal
◼ Dose size
◼ Drug molecular size
29
 Implications of PK and PD in
Drug Delivery
◼ The PK and PD of a drug may be affected
when administered via different routes
◼ Examples
◼ Proteins – oral vs. intramuscular
◼ Morphine – oral vs. intramuscular
◼ The PK and PD of a drug delineates its
therapeutic window
◼ Degree of absorption
◼ Degree of elimination and/or metabolism
◼ Example
◼ Tetracycline (infection) – given 6 to 8 hours
◼ Digoxin (cardiac failure)– given daily
30
Where to Find PD and PK
Information
◼ United States Pharmacopeia
◼ www.usp.org
◼ It is also paper published
◼ Provides standards, chemical properties,
and protocols to perform pharmacological
experiments
◼ Federal Drug Administration – if it has
already being approved
◼ www.fda.org
31
Drug Delivery Systems

container
+ body
drug

32
 Manufacture of Classical Oral
Delivery Systems
◼ Formulation – combination of active
ingredients with the appropriate excipients
◼ Excipients – inactive ingredients employed
for the purpose of dilution, protection, stability,
controlled release, taste, fillers, coloring,
disintegration, etc

The conventional dosage forms, such as tablets

and capsules, composed of drugs with traditional
excipients, continue today as the vast majority of
formulations available for drug administration. 33
Manufacture Process
for Tablets Blending
and Capsules

Wet Granulation Dry

Milling

Compression

Coating

Labeling

Packing 34
 PENENTUAN BENTUK SEDIAAN
UNTUK SPO KONVENSIONAL

Suatu obat perlu dikaji:

•Sifat fisikokimia
•Perilaku fisiologis terhadap sifat fisikokimia

Contoh Obat:
PROGABIDA – suatu obat anti konvulsan

Progabide
35
 Systematic (IUPAC) name

4-[(4-chlorophenyl)-(5-fluoro-2-hydroxy-phenyl)-methylidene]aminobutanamide

Clinical data

Pregnancy cat. ?

Legal status Prescription only

Routes Oral

Pharmacokinetic data

Bioavailability 60%

Protein binding 95%

Metabolism Hepatic

Half-life 4 hours

Excretion Renal

Chemical data

Formula C17H16ClFN2O2

Mol. mass 334.772 g/mol

36
Profil Preformulasi Progabida pada suhu 37oC

pKa 3,41

Koefisien partisi 933

Kelarutan (mg/ml) 9093, pH 2,2

44, pH 6,3

Stabilitas obat 18, pH 2,2

(t1/2, menit) 130, pH 6,3

Kecepatan absorpsi 0,0859, t1/2 abs= 8,1 menit

(ka, menit-1) Penambahan asam salisilat memberikan ka= 0,101
dengan t1/2 abs= 6,9 menit

37
Bioavailabilitas Progabida setelah diberikan pada
manusia secara oral dengan dosis 600 mg, n=6

Formulasi Ukuran Partikel AUC (mg/ml/jam)

Kapsul Mikron 9836 ± 2950

Bioavailabilitas Progabida setelah diberikan pada manusia
secara oral dengan dosis 600 mg, n=6
Kapsul Kasar 4508 ± 655

Tablet Micron 8607 ± 819

Tablet enterik Micron 4590 ± 1393

38
Progabide is an analog and prodrug of gamma-aminobutyric acid.
It is commonly used in the treatment of epilepsy. It has agonistic
activity for both the GABAA and GABAB receptors.
Progabide has been investigated for many diseases besides epilepsy,
including Parkinson's disease, schizophrenia, clinical depression and
anxiety disorder with varying success.

Pharmacology:
Progabide, a fatty acid derivative, is a GABA receptor agonist used to
treat the symptoms of epilepsy.
Mechanism of action:
Progabide binds to both GABAA and GABAB receptors located on the
terminals of primary afferent fibers.
Binding to GABAA results in an increased affinity of the GABA
receptor for the amino acid, an augmented flux of chloride ions
across the terminal membrane, and an increase in the amount of
presynaptic inhibition.
Activation of the GABAB receptors retards the influx of calcium ions
into the terminals, thereby reducing the evoked release of excitatory
amino acids and possibly other transmitters.

Drug type: Approved. Small Molecule

Drug category: Anticonvulsants, Antidepressants.
39
Antidepressive Agents, Antidyskinetics.
Concept of Modified Release DDS
◼ Controlled drug delivery is one
which delivers the drug at a
predetermined rate, for locally or
systemically, for a specified period
of time.

◼ Continuous oral delivery of drugs at

predictable & reproducible kinetics
for predetermined period
throughout the course of GIT.

40
 TERMINOLOGY OF MODIFIED RELEASE DDS

Sustained-release:
Any dosage form that provides medication over extended time
Controlled-release:
The system is able to provide some actual therapeutic control;
be of a temporal nature, spatial nature, or both.
The system attempts to control drug concentration in the
target tissue.
Delayed-release
Enteric coated tablets
Site-specific systems
Targeted-delivery systems

41
Plasma concentration time profile

42
 Challenges in Oral
Drug Delivery

◼ Development of drug delivery system

Delivering a drug at therapeutically effective rate to
desirable site.

◼ Modulation of GI transit time

Transportation of drug to target site.

◼ Minimization of first pass elimination

43
DDS types
◼ Monolithic devices: matrix systems
◼ Reservoir devices: rate controlling
membranes
◼ Degradable systems: polymers
degrade due to chemical action
◼ Etc.

44
45
46
Diffusion in monolithic and
reservoir devices

http://www.devicelink.com/mpb/archive/97/11/003.html
47
Controlled Release Oral Drug
Delivery System
Advantages

▪ Total dose is low.

▪ Reduced GI side effects.

▪ Reduced dosing frequency.

▪ Better patient acceptance and compliance.

▪ Less fluctuation at plasma drug levels.

▪ More uniform drug effect

▪ Improved efficacy/safety ratio.

48
Disadvantages

◼ Dose dumping.

◼ Reduced potential for accurate dose adjustment.

◼ Need of additional patient education.

◼ Stability problem.

49
 Oral – controlled release

◼ Formulation system:

→ Modification of drug substance:

e.g. low solubility salt;
drug polymer complex

→ Modification of delivery :
1. Multiple unit : e.g. coated pellets
2. Single unit: e.g. osmotic pump

50
 Materials Used as Components in
Controlled Release

Enteric coatings
◼ Cellulosic

◼ Cellulose acetate phthalate (CAP)

◼ Hydroxypropylmethylcellulose phthalate (HPMCP)

Noncellulosic
◼ Methacrylic acid polymers

◼ Polyvinylacetate phthalate (PVAP)

◼ Shellac

51
Materials Used as Components in
Controlled Release
Non-enteric coatings
Cellulosic
◼ Ethylcellulose (EC)
◼ Hydroxyethylcellulose (HEC)
◼ Hydroxypropylmethylcellulose (HPMC)
◼ Methylcellulose (MC)
◼ Sodium carboxymethylcellulose (Na CMC)

52
Materials Used as Components in
Controlled Release

Non-enteric coatings
Non-cellulosic
◼ Carnauba wax
◼ Castor oil
◼ Cetyl alcohol
◼ Ethylene vinyl acetate copolymer
◼ Hydrogenated vegetable oils
◼ Polyvinyl alcohol
◼ Silicon-based polymers

53
Mechanism aspects of Oral drug
delivery formulation

1.Dissolution : 1.Matrix
2.Encapsulation

2.Diffusion : 1.Matrix
2.Reservoir

3.Combination of both dissolution & diffusion.

4.Osmotic pressure controlled system

54
 Several physicochemical factors controlling the
delivery of a bioactive agent to the host:
.

◼ Local pH of the host site

◼ Hydrophilic or hydrophobic nature of the active
agent
◼ Solubility of the active in the delivery matrix
◼ Permeability of the delivery matrix to water
◼ Solubility of the active in the local
environment
◼ Permeability of the delivery matrix to the
active agent
◼ Bio-stability of the delivery matrix

55
 POLYMER FOR CONTROLLED-
RELEASE DELIVERY
There are several important factors to consider in selecting or
developing a polymer for controlled delivery:
◼ Biocompatibility and toxicology
◼ Regulatory acceptance or concerns
◼ Degradation rate and degradation products and their
biocompatibility and toxicology, if biodegradable
◼ Cost
◼ Chemical, physical, and mechanical properties
◼ Suitable solvents
◼ Processing requirements
◼ Compatibility limits of the active agent with the polymer
◼ Required sterilization methods
◼ Thermal transition temperatures

56
 Dissolution Definition:
◼ Solid substances solubilizes in a given solvent.

◼ Mass transfer from solid to liquid.

◼ Rate determining step:

Diffusion from solid to liquid.

◼ Several theories to explain dissolution –

Diffusion layer theory (imp)
Surface renewal theory
Limited solvation theory.

57
 Noyes Whitney Equation

dc/dt = kD.A (Cs – C )

dc/dt = D/h A. (Cs – C)

dc/dt = Dissolution rate.

k= Dissolution rate constant (1st order).
D = Diffusion coefficient/diffusivity
Cs = Saturation/ maximum drug solubility.
C =Con. of drug in bulk solution.
Cs-C=concentration gradient.
h =Thickness of diffusion layer.

58
 Matrix Type
◼ Also called as Monolith dissolution
controlled system. Soluble drug

◼ Controlled dissolution by:

1.Altering porosity of tablet.
2.Decreasing its wettability.
3.Dissolving at slower rate.
Slowly
dissolving
◼ First order drug release.
matrix

◼ Drug release determined by

dissolution rate of polymer.

◼ Examples: Dimetane extencaps,

Dimetapp extentabs.

59
 Encapsulation
◼ Called as Coating dissolution
controlled system. Soluble drug

◼ Dissolution rate of coat depends

upon stability & thickness of
coating.
Slowly
◼ Masks colour,odour,taste, dissolving
minimising GI irritation. or erodible
coat
◼ One of the microencapsulation
method is used.

◼ Examples: Ornade spansules,

Chlortrimeton Repetabs

60
Diffusion

◼ Major process for absorption.

◼ No energy required.

◼ Drug molecules diffuse from a region of higher

concentration to lower concentration until equilibrium is
attainded.

◼ Directly proportional to the concentration gradient

across the membrane.

61
 Matrix Diffusion Types
◼ Rigid Matrix Diffusion
Materials used are insoluble plastics such as PVP &
fatty acids.
◼ Swellable Matrix Diffusion
1. Also called as Glassy hydrogels.
Popular for sustaining the release of highly water
soluble drugs.
2. Materials used are hydrophilic gums.
Examples : Natural- Guar gum,Tragacanth.
Semisynthetic -HPMC,CMC,Xanthum gum.
Synthetic -Polyacrilamides.

Examples: Glucotrol XL, Procardia XL

62
Matrix system

Rate controlling
step:
Diffusion of
dissolved drug in
matrix.

63
 Higuchi Equation

Q = DE/T (2A.E Cs) Cs. t)1/2

Where ,
Q=amt of drug release per unit surface area at time t.
D=diffusion coefficient of drug in the release medium.
E=porosity of matrix.
Cs=solubility of drug in release medium.
T=tortuosity of matrix.
A=concentration of drug present in matrix per unit
volume.

64
 Reservoir System
◼ Also called as Laminated matrix device.
◼ Hollow system containing an inner core surrounded
in water insoluble membrane.
◼ Polymer can be applied by coating or micro
encapsulation.
◼ Rate controlling mechanism - partitioning into
membrane with subsequent release into surrounding
fluid by diffusion.
◼ Commonly used polymers - HPC, ethyl cellulose &
polyvinyl acetate.
◼ Examples: Nico-400, Nitro-Bid

65
Reservoir System
Rate controlling
steps :
Polymeric content in
coating, thickness of
coating, hardness of
microcapsule.

66
Use Fick’s law to design drug release

67
 Dissolution & Diffusion
Controlled Release system
◼ Drug encased in a partially
soluble membrane. Insoluble
membrane
◼ Pores are created due to
dissolution of parts of
Entry of
membrane.
dissolution
◼ It permits entry of aqueous fluid
medium into core & drug Drug
dissolution. diffusion

◼ Diffusion of dissolved drug out

of system.
Pore created by
◼ Ex- Ethyl cellulose & PVP dissolution of
mixture dissolves in water & soluble fraction of
create pores of insoluble ethyl membrane
cellulose membrane.
68
 METODE ION EXCHANGE
Resin yang tidak larut dalam air
Resin bermuatan positif atau negatif

◼
.
Resin + obat ---agar terjadi kontak lama :
resin dan larutan obat dicampur
◼ resin dalam kolom dan larutan obat dilewatkan resin secara berulang-ulang
◼ obat-resin dicuci dan dikeringkan untuk membuat partikel atau butiran-butiran
(beads)
Pelepasan obat:
◼ Resin-(NCH3) X + Z- → Resin-(NCH3) Z + X-
Resin-(SO3) A + B+ → Resin-(SO3) B + A+
X dan A adalah molekul obat

Batasan metode ion exchange:

◼ memerlukan adanya ion dalam larutan, tidak dapat digunakan pada semua tempat
dalam tubuh; misal: kulit
◼ biodegradasi yang lama dari resin exchange
◼ adanya variabilitas ionic dari isi GIT
◼ cocok untuk implan dan IM

69
“smart materials”, mechanism of action

70
http://www.devicelink.com/mpb/archive/97/11/003.html
Diabetes

71
From Chien, Novel Drug Delivery Systems. Figure 30, pg 35.
 “Smart
materials”
designed
based on
external cues

72
http://www.devicelink.com/mpb/archive/97/11/003.html
Biodegradable systems
Drug delivery from:
(a)bulk-eroding and
(b) surface-eroding biodegradable
systems

http://www.devicelink.com/mpb/archive/97/11/003.html 73
Biodegradable PLA and PEG
PLA = poly(lactic) acid

74
 ASPEK
FARMAKOKINETIKA
◼ Agar konsentrasi obat dalam darah tetap, maka
◼

◼ Rate in = Rate out

◼

◼ Absorpsi:
◼ Log (Ao – X) = Log Ao - Ka . t / 2,303
◼

◼ Ao = obat mula-mula dalam saluran cerna

◼ X = obat yang telah diabsorpsi
◼ Ka = konstante kecepatan absorpsi
◼

◼ Obat diabsorpsi dengan kinetika orde I

◼

◼ 75
ASPEK
FARMAKOKINETIKA
◼ Eliminasi:
◼ Log (Bo – E) = Log Bo - Kel.t / 2,303
◼

◼ Bo = obat mula-mula dalam badan

◼ E = obat yang telah dieliminasi
◼ Kel = konstante eliminasi
◼

◼ Eliminasi obat mengikuti kinetika orde I

76
◼ ABSORPSI = ELIMINASI
. RATE IN = RATE OUT
◼

◼ D(Ao – X)/dt = d (Bo - E)/dt

◼

◼ -Ka (Ao – X) = - Kel (Bo – E)

◼

◼ Untuk menjaga agar obat dalam darah konstan maka sediaan

harus memberikan obat dengan kecepatan yang konstan pula
◼

◼ R = d (Ao – X)/ dt = Kel (Bo – E)

◼

◼ R = rate of delivery
Dalam proses absorpsi, kecepatan pembatas adalah
pelepasan obat dari bentuk sediaan 77
 SEDIAAN OBAT HIPOTETIS

◼ D* = dosis diperlukan untuk mendapatkan konsentrasi obat

◼ Dalam darah pada konsentrasi puncak
◼ B* = obat dalam badan pada waktu konsentrasi puncak
D* = 100 mg
B* = 80 mg
Kel = 0,023 jam-1

◼ R = Kel B*
◼ R = (0,023)(80) mg/jam = 1,84 mg/jam

◼ Obat harus diabsorpsi dari pool-nya dengan kecepatan 1,84

mg/jam

78
◼ Agar obat dalam darah konstan maka obat yang masuk
darah harus sama dengan kecepatan obat dieliminasi
◼

◼
.
R = Kel B* = Ka D ;
◼ D = Jumlah obat dalam pool untuk diabsorpsi
◼

◼ Biasanya, obat tidak diabsorpsi 100% tetapi obat hanya

sebagian yang diabsorpsi (F); Misal F = 0,8
◼

◼ Ka F D = Kel B*
◼

◼ Ka D = Kel B* / F
◼

◼ R = 1,84/ 0,8 mg/jam = 2,3 mg/jam

79
 Cp(steady state) = F D / V Kel Ƭ = F D / Cl Ƭ
.
◼

◼ D / Ƭ = Cp Cl / F
◼

◼ V = volume distribusi
◼ Ƭ = interval pemberian obat
◼ Cl = klirens
◼

◼ R = D/ Ƭ = 2,3 mg/jam

80
 ◼ Jika waktu yang diperlukan untuk pelepasan
terkontrol (sustaining time) = 10 jam, maka
dosis keseluruhan yang diperlukan selama 10
.
jam adalah:
◼

◼ Dm = R h ; Dm = maintaining dose;
◼ h = sustaining time
◼

◼ Dm = (2,3 mg/jam)(10 jam) = 23 mg

◼

◼ Dt = D* + Dm ; Dt = total dose
◼ Dt = 100 mg + 23 mg = 123 mg

81
.
◼ SOAL

◼ Buatlah sediaan lepas terkontrol untuk

pemakaian oral suatu obat A!
◼ Diketahui: obat A mempunyai waktu paro
eliminasi 3 jam sedangkan MEC = 10 ug/ml
dan MTC = 20 ug/ml.
Volume distribusi A = 50 liter. Obat A
diabsorpsi dari saluran cerna dengan F = 0,8.

◼ Bagaimana anda mendesain sediaan itu?

82
Osmotic Pressure Controlled
Drug Delivery System

◼ Definition

◼ Procedure

◼ Diagram

◼ Modifications

83
 Osmosis
- Movement of solvent from lower to higher concentration.
- The passage of solvent into a solution through
semipermeable membrane.

Semipermeable Membrane
Molecules are permitted only to one component
(Water).

Osmotic pressure
It is the hydrostatic pressure produced by a solution
in a space divided by a semipermeable membrane
due to difference in concentration of solutes.
84
 Osmotic Pressure Controlled
System
◼ Provides zero order release
◼ Drug may be osmotically active, or combined with
an osmotically active salt (e.g., NaCl).
◼ Semipermeable membrane usually made from
cellulose acetate.
◼ More suitable for hydrophilic drug.

◼ Examples: Glucotrol XL, Procardia XL,

85
Equation

(Q/t) z = Pw Am/ hm (πs-πe )

(Q/t)= Rate of zero order drug release.

Pw, Am & hm= water permeability, effective
surface area & thickness of
semipermeable membrane.
πs= osmotic pressure of saturated solution of
osmotically active drug or salt in system.
πe = osmotic pressure of GI fluid.

86
Osmotic Pressure Controlled
System

87
Osmotic Pressure Controlled
System

88
Modifications

- Immediate release system.

- Osmotically active compartment system

89
 Immediate Release System

◼ Activation of system is done.

◼ Dividing a dose into two parts.
◼ One third immediate release.
◼ Two third controlled release.
◼ Encapsulated into semipermeable
membrane.
e.g. : Phenylpropanolamine.

90
 Osmotically active system

◼ Two compartments Delivery orifice

separated by movable
partition.
◼ Osmotically active Drug compartment
compartment absorbs Movable
water from GIT. partition
Osmotically active
◼ Creates osmotic compartment
pressure.
◼ Partition moves upward
& then drug releases.
◼ Ex: Nifedipine.

91
Two-compartment osmotic
(commercial) pump

92
Some Popular Brand names used
for OCDDS
◼ Spansule capsule ( SK & F )
◼ Sequal capsule (Lederle )
◼ Extentab tablets ( Robins )
◼ Timespan tablet ( Roche )
◼ Dospan tablet ( Merrell Dow )
◼ Chronotab tablet ( Schering )
◼ Plateau capsule ( Marion )
◼ Tempule capsule ( Armour )

93
 Some Examples of OCDDS

◼ Propranolol (Inderal LA)

◼ Methyiphenidate HCl (RitalinSR)
◼ Iron (Slow-Fe)
◼ GITS-Prazosin (Minipress)
◼ Morphine sulfate (Roxanol SR)
◼ Decongestant & antihistamine (Resaid SR, Novafed SR
Dristan)
◼ Pseudoephedrine HCI (Sudafed SA)
◼ Potassium (Micro-K, Slow-K, Klotrix)
◼ Antitussive combinations (Rescap, Ornade Spansules)
◼ Chlorpheniramine maleate (ChlorTrimeton)
◼ Decongestant, antihistamine and anticholinergic
(Dallergy, Supres)
94
 Recent Trends : Extended release
formulation of Bupropion
◼ Bupropion is used in the treatment of major
depressive disorder.

◼ Conventional formulation has to be administered 3

times daily

◼ Initially 150 mg ER formulation was introduced for

bid regimen

Later on 300 mg ER formulation was introduced for

once daily regimen

◼ For ER formulation provide similar Cmax and AUC

values as compared to immediate release
formulation at steady state.

95
Recent Trends : Extended release
formulation of Bupropion

96
 Recent Trends: OROS
Technology (ALZA corporation)
ELEMENTARY OSMOTIC PUMP
◼ Single layer tablet: Drug
core (water soluble drug
with or without excipients)
◼ Semipermeable membrane
with a drilled orifice
◼ Water imbibition by the core
because of osmotic action
results in drug dissolution,
which is released at a
controlled rate through the
orifice
◼ Not suitable for water insoluble drugs.
◼ Examples: Sudafed 24 hours (Pseudoephedrine);
Volmax (Salbutamol)
97
 Recent trends: Geomatrix® (SKY Parma)

Products in market:
Cordicant -uno®
Madopar DR
SULAR ER

This technology Controls amount,

timing and location of release in
body.

-Formulation with predictable and

reproducible drug release profile.
-Controls rate of drug diffusion
throughout release process,
ensuring 100% release Products

98
99
 References
➢ Novel drug delivery system , volume 50,
Y.W.Chien

➢ The theory & practice of industrial pharmacy,

Leon Lachman , Herbert A.Lieberman,
Joseph L.Kanig,3 rd edition.

➢ The Eastern pharmacist, november 1993.

Sustained release drugs, V R.Gudsoorkar & D.Rambhau
page 27-32

➢ Biopharmaceuitics & pharmacokinetics,

D M.Brahmankar & Sunil B. Jaiswal.

www.google.com
100
Thank you

101