Perifériás keringési elégtelenség (sokk)

• Particle size
parenteral
peroral
dosage
10-9
10-6
10-3 m
1nm
1μm
1mm
XXI.century
molecular systems
intelligent DDS
XX.century
colloidal
dosage forms
nanopreparations
microcapsules
biotechnological
preparations
emulsions,
suspensions
granules,
micropellets
tablets,
dragees
Types of preparations according to their dosage
– single unit systems
eg.: tablets, dragees
– multiple unit systems
eg.: microcapsules, micropellets, powders,
liposomes, nanocapsules
Conventional macro drug delivery systems are monolithic systems in
which all the active substance(s) are in one unit.
Multiparticulate preparations aren’t monolithic systems, differ from
macro systems in their size, structure, manufacturing technology and
mode of drug delivery as well. These contain the required amount of
active substance in several, individually controlled drug delivery units.
macro DDS
micro DDS
Sizes and types
micrometer
pills
minitablets
micropellets
microcapsules
nanometer
liposomes
cohleates
nanocapsules
dendrimers…
Multiparticulate micro-pharmaceutical preparations of the
micrometer scale are generally administered perorally.
After administration their particles, depending on control,
disperse in the GI tract before releasing active substance(s), and
then dissolution takes place with the same speed, in the same
place or at different times with different speeds in different
locations.
Multiparticulate nano-pharmaceutical preparations of the
nanometer scale are sufficiently small that they can be used
parenterally as well, apparently without any disadvantages..
Nanoparticles are able to achieve with success:
• tissue targeting of many drugs (antibiotics, cytostatics,
peptides and proteins, nucleic acids, etc.).
• protecting drugs against chemical and enzymatic
degradation
• reducing side effects of some active drugs.
1. homogeneous gastrointestinal distribution in the GI tract after administration,
2. local irritation can be reduced,
3. controlled drug delivery can be achieved,
4. It is possible to treat both the entire of GI tract or just certain parts of it,
5. bioavailability can be improved,
6. the biopharmaceutical properties of multiparticulate preparations are more
reproducible than those of conventional, monolithic preparations,
7. inter- and intrapersonal differences can be decreased,
8. safety of dosage can be increased, e.g. risks came from faulty coating of macro
preparations can be reduced, and the dissolution rate can be significantly
controlled (slower, not complete or too fast release) in multiparticulate systems
9. according to the newest therapeutical requirements the dissolution profile can be
modified by coating the active substance granules with different types of coating
inside the same preparation.
With
appropriately
small
compressing
machine
minitablets of 2-3 mm diameter can be produced as a
substitute for pellets. Minitablets (filmcoated, non-friable)
can be filled into capsules to produce specialized dosage
forms (spansules) or to separate incompatible
ingredients.
Pills are spherical solid multiparticulate dosage forms intended for
peroral administration. They are prepared by incorporating
medicinal agents with other materials to form a cohesive, plastic
mass, which is divided into the required number of portions. Pills
usually range in weight from 0.10 to 0.30 g.
1. Homogenization, wetting, kneading
2. Round formation of the pill mass
3. Stick formation
4. Stretching of the rod
till the required length
5. Cutting of the rod
6.Pill-chain after cutting
7. Rounding
8. Pills before wrapping
API
excipient
Definition
core
Pharmaceutcial micropellets are spherical solid particles of 0,52 mm diameter.
There are different micropellet structures.
API
(sugar) core
matrix
Advantages
• ideal spheric shape
Disadvantages
• expensive
• more uniform coating
• better flowability
• controllable drug liberation
• special equipments
• for the preparation
• for the examination
• rapid and sustained release can be
prepared in the same DDS
• sugar balls are very expensive
• targetted release at different
sites of the GI trackt
• dosing
• hard gelatin capsules
• tabletting
• The concomitant administration of
several materials
• incompatible compounds
Different types of
micropellets
a.
b.
c.
d.
without coat
with coat
inert core, without coat
inert core, with coat
Formation of
pellets
Mechanism of pelletizing with solvent,
binder or by sintering
The coating process
Mechanism of pellet coating
SUGLETS™, pharm-a-spheres ™
2016.03.09. 11:27
26
with core
coating pan
The coat application of the API
and the coating material:
coating with fluidisation
In pharmaceutical technology the following processes can be
used for the preparation of micropellets :
• rotating plate
• extrusion-spheronisation
• spray-drying
• spray-freeze-drying
• high shear pelletizing
• hot melt dispersion
Rotating pelletizer (rotating plate process)
In rotating plate methods the granulating liquid is fed to the powder
rotating on a plate. Centrifugal force rolls forming particles to the
border of the plate, which results in spherical shape. The end product
is easy to unload by swivelling the plate.
extrusion-spheronisation
Parts of the pelletizing operations
homogenisation
extrusion
spheronisation
drying
extrusion
substance
heating
product
extrusion
spheronization
Spheronizer
Spray drying (atomizing head, nozzle)
Feeding
pump
porlasztás
atomizing
suspension
szuszpendálás
drying
product
Suspension of the core in the
solution of the coat
Spray-freeze-drying with rotary atomizer
Feeding
pump
atomizing
szuszpendálás
Molten of
material of
the matrix
Suspension of the core in the
solution of the coat
drying
product
Spray-freeze-drying with rotary atomizer
Spray-freeze-drying with rotary atomizer
high-shear pelletizing
workspace
Feeding
pump
Procept pelletization process
High-shear pelletizing
Binder
Folyadék
addition
adagolás
Workspace
Munkatér
Aprító
Chopper
kések
Homogenizáló
Impelle
r
keverő
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40
High-shear pelletizing
Binder addition
Cutter
(chopper)
Stirring
paddle
(impeller)
high-shear pelletizing
Mean steps of the spheric agglomeration process
granulation
liquid
particles
wetting
liquid bridges
Growth of the agglomerates
pellet
Hot-melt dispersion process
Hot-melt dispersion process
BRACE technology
flowability
m
mérleg
mérleg
t (sec)
zárt
nyitott
m=at+b
Friability
F
erő mérő
log F
log F = a log d+ log b
log d
With naked eye
light microscope
shape
surface
SEM
surface
Pellet without coat
Coated pellet
Spansule
Dissolution from spansule
0. min
1. min
2. min
3. min
4. min
5. min
Definition
• Microcapsules are spherical particles with in range
1-1000 μm in which the API is in solid, liquid or
gaseous form.
core
shell
Aims of microencapsulation may be:
• Separation of incompatible components (vitamines)
• Incorporation of volatile components to avoid API loss (methyl-salicylate
• Taste and odour masking (erythromycine, cod liver oil)
• Protection of the API from the environment (vitamines, ASA, vitamine-A
palmitate)
• Solidification of liquids (vitamine A, E, D3, cod liver oil)
• Particle size reduction for enhancing solubility of the poorly soluble
drugs
• Reductance of the irritation of APIs (ASA)
• Sustained or controlled drug delivery
• Cell encapsulation
Excipients of microcapsulation
water soluble polymers
gelatine
acacia gum
starch
polyvinylpyrolidone
polyvinyl-alcohol
methylcellulose
carboxymethylcellulose
hydroxyethylcellulose
polyacrilic acid
water insoluble polymers
polyamide (i.e.: nylon)
polyethylene
polyethylene-vinyl-acetate
ethylcellulose
polymethacrylate
Bungenberg de Jong was the first who prescribed the
coacervation in 1932.
colloid poor phase
colloid rich phase
Amorf droplets
in the colloid
rich phase
1. Coacervation/Phase separation
1.1. in aqueous medium,
1.1.1. simple coacervation,
1.1.2. complex coacervation,
1.2. non-aqueous phase separation,
1.2.2. solvent evaporation,
1.2.3. solvent removal,
2. Interfacial polimerization,
3. Spray drying.
Coacervation
Steps of coacervation:
• formation of three immiscible phases (achieved by
dispersing the core particles in a polymer solution)
• formation of the coat, (phase separation)
• and deposition of the coat.
The core particles coated by the polymer are then separated
from the liquid phase by thermal, cross-linking, or desolvation
techniques leading to rigidization of the coat.
Coacervation is defined, as the separation of colloidal systems
into two liquid phases.
Coacervation
Accounting for different phase separation mechanisms,
coacervation can be subdivided into :
• Simplex:
• the polymer is salted out by electrolytes
(sodium sulfate)
• desolvated by the addition of a water miscible
non-solvent (ethanol)
• increase or decrease in temperature.
• Complex: driven by the attractive forces of oppositely
charged polymers
simple coacervation
Core is suspended or emulgeated in the liquid.
API
excipients
simple coacervation
API
excipients
Phase separation.
coacervates
simple coacervation
Confluence of the droplets.
API
excipients
Simple coacervation
API
excipients
Solidification
Filtration
Drying
API (core)
coat
Simple coacervation
Phase separation in aqueous medium.
polymer
(solution)
dispersion
Suspension
or emulsion
of the core
coacervation
pH,
salt,
solvent,
other polymer
oldat
Filtration and
drying
Simple coacervation
Simple coacervation can be ensured by the use of one type
of colloid and the desolvation, dehydration of the colloid.
Desolvation achived by:
- water-miscible non-solvent (e.g. ethanol, acetone,
propanol, isopropanol)
- inorganic salts (Na2SO4)
- temperature change
Gelatin, polyvinyl alcohol, methyl cellulose can be used as
coating materials.
Complex coacervation
Phase separation of the polymer solution
API
excipients
excipients
Droplets
Complex coacervation
Confluence of the droplets
complex coacervation
excipients
Solidification
Filtration
Drying
Core (API)
coat
API
excipients
Complex coacervation
Phase separation in aqueous medium.
gelatin
solution
dispersion
Suspension
or emulsion
of the core
coacervation
oldat
Filtration and
drying
Complex coacervation
Complex coacervation occurs in the solution of the two
opposite charged polymers.
The opposite charged polymers can adhere and neutralize
each other and form a continuous film on the surface of
the droplets or the suspended solid API.
For example: In the gelatin-gum arabic system, pH should
be below the isoelectric point of gelatin so that the gelatin
can maintain the positive charge. The positively charged
gelatin can bound to the negatvely charged gum arabic.
The particle size of the microparticles depends on :
• Preparation parameters
• stirring speed
• stirring time
• Excipients
• The size of the suspended or emulgeated
particles, droplets
Interfacial polymerisation (nylon)
n ClC(CH2)8CCl
+ n H2N(CH2)6NH2
Cl-[C(CH2)8C-NH(CH2)6NH]n-H + n HCl
Sebacic acid chloride + 1,6-hexane diamine
nylon 6-10
+ hydrochloric acid
NH2
hexane
NH2 Cl
Sebacic acid
Cl NH2
hexane
NH2
NH2
hexane
NH
Sebacic acid
NH
hexane
NH2
Interfacial polymerisation (nylon)
oil
dispersion
+ drug +
hexametile
n-diamin
suspension
or
emulsion
polymerization
oldat
Filtration and
drying
Interfacial polymerisation (nylon)
http://www.tam.uiuc.edu/publications/tam_reports/2003/1014.pdf
Spray drying (atomizer, nozzle)
Feeding
pump
porlasztás
atomizing
suspension
szuszpendálás
drying
product
Suspension of the core in the
solution of the coat
Spray drying (rotary atomizer)
Feeding
pump
atomizing
szuszpendálás
drying
product
Suspension of the core in the
solution of the coat
Spray drying with rotary atomizer
Suspension of
API
Atomized
droplets
spray drying
importance of spraying
Atomizer, nozzle
rotary atomizer
light microscope
particle size
http://www.univ-reims.fr/Labos/UPRESA6013/TECHNIE/Fonctionnalisees.html
scanning electron microscope (SEM)
Surface of
the microcapsule
Layers of the wall of
the microcapsule
http://www.csl.gov.uk/prodserv/rds/pesticide/micro.cfm
API
Excipient
Drug-dissolution
The wall is not soluble
breaking of
the wall
diffusion
Swelling and dissolution of the wall
(pH, enzymatic)
diffusion
Thank you for your attention
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