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Universita’ degli Studi di Milano
Prof. Andrea Gazzaniga
Rilascio Modificato via Orale – Sito-Specifico (Colon)
Corso di Laurea Magistrale in Chimica eTecnologia Farmaceutiche
Chimica Farmaceutica Applicata - 8 CFU
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Sistemi per il rilascio modificato per via orale
-Introduzione generale-Teoria Trasporto di Massa -Rilascio Prolungato
-Fast (?) release -Rilascio Ritardato -Rilascio Sito-Specifico
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Sistemi a Rilascio Modificato per via Orale
Controllo spaziale del rilascio
sito diminuzione della velocità di transito G.I.
(es. sistemi bioadesivi)
rilascio in specifiche regioni del tratto G.I.(es. sistemi per il rilascio al colon e sistemi gastroretentivi )
Controllo del rilascio
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Colonic Drug Delivery
Nowadays
Traditionally
local or systemic therapies
interest tied up to local treatment of large bowel diseases
colon generally seen as a region with very poor absorption properties
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When and why the colon has been reconsidered as a possible site of absorption ?
Small intestine: known as a good site of absorption
Colon: known as unsuitable for absorption
- reduced surface area
- wider lumen
- low volume of dissolution fluids
- poor permeability of the mucosa
- higher viscosity of the content
- pharmacoscintigraphy enabling a correlation between the G.I.location of the dosage form and the plasma levels of the drug.
- once and twice-a-day oral prolonged-release systems.
With the development of:
It has definitively been proved that a significant absorption can occur along the whole colon.
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…since peptidases are generallybelieved to be less concentrated in the large
bowel, the colon has also been suggested as a sitefor selective delivery of drugs having peptidic structure.
…furthermore …
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Local goals
Colon Targeting
Improvement in the oral bioavailability of peptides and proteins (less hostile environment in the colon - more than 50 different typesof peptidases in the small intestine)
Systemic goals
(IBD) Inflammatory Bowel Disease - ulcerative colitis, Crohn’s Disease
Adenocarcinoma
Irritable Bowel Syndrome. . . . .
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The Digestive System… Colon ….
… begins from the ileo-caecalvalve and the caecum and
ends with the rectum
Caecum
Ileo-Caecalvalve
Rectum
… approx. 1.2 meter long
6-7 cm wide
AscendingColon
TransverseColon
DescendingColon
… divided in .. A,T,D,S Colon
SigmoidColon
..the wall consists of 4 layers
mucosasubmucosamuscularis
serosa
..the fibers of the muscularisexterna are collected into 3
longitudinal bands
teniae coli
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The Digestive System
Movements:segmentation contractions
peristaltic/antiperistaltic waves.
Absorption:..drained by mesenteric veins and
lymphatic wessels… enterocytes with brush border
and tight junctionsthe barrier can be crossed via
transcellular or paracellular pathway.
Transit:the first part of the meal reaches
the caecum in about 4 hAs much as 25 % of
the residue of test mealmay still be in the rectum after 72 h
… Colon ….
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Proximalcolonachievable only by oral route.
Oral Colon Targeting
Distal colonachievable in somecases also by rectal
route.
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system able to move intact through the stomachand the small bowel provided a suitable mechanismthat triggers release when the colon is reached
Oral Colon Targeting
smallintestine
stomach
colon
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Oral Colon Targeting
spatial and/or temporal parameters(i.e. bacterial count, pH, intralumenal pressure and time taken by the unit to transit the digestive tract)
possibility of exploiting their increase along the G.I. tract
… any possible formulation strategies require a
sophisticated approach based on the anatomical
and physiological features of the region.
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smallintestine
stomach
colon
b a c t e r i a l c o u n t
p H t i m e
i n t r a l u m e n a l p r e s s u r e
INCREASE
Oral Colon Targeting
possibility of exploiting their increase along the G.I. tract
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Oral Colon Targeting
- polymeric coating which dissolves at specific pH- devices capable of exploiting the relatively constant SITT
- Chemical / microbiological approach
-Technological / physiological approach
Variety of mixed strategies includingthe use of:
- prodrugs and polymeric matrices/coatings degraded by enzymaticactivity of colonic bacteria
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Chemical / Microbiological Approach Microbially-Controlled Drug Delivery Systems
Exploitation of the selective presence in thecolon of bacterial species capable of catalyzing
enzymatic reactions on substances which have notbeen degraded in the upper G.I. tract
Use of either natural or synthetic compoundsselectively degraded in the colon
Quali Quantitative Microflora Composition along the Human G I Tract
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O r a l
c a v i t y
S t o
m a c h
D u o d
e n u m
J e
j u n u m
I l e u m
R
e c t u m
Quali-Quantitative Microflora Composition along the Human G.I. Tract Adapted from Mitsuoka T., Intestinal Bacteria and Health, Harcourt Brace Jovanovich, Tokjo, 1978
Enterococci
Veillonellae
Bacteroides
Lactobacilli
Coliform bacteria
Bifidobacteria
Clostridium perfrigensEubacteria
Anaerobic streptococci
0
2
3
4
5
6
7
8
9
10
11
Log number of selected bacterial species per g content of alimentary tract
O r a l
c a v i t y
S t o
m a c h
D u o d
e n u m
J e
j u n u m
I l e u m
C e a c u m
R
e c t u m
Microflora population INCREASES PROCEEDING DOWNWARDS IN THE G.I.TRACT – q.q. abundance in the colon
significant gradientbetween small and
large intestine
> 400 bacterial species identified in the colon
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> 400 bacterial species identified in the colon
Enzymatic Reactions Catalyzed by Colonic Microflora
•
hydrolysis of glycosides• hydrolysis of -CO-NH c.• hydrolysis of esters• dehydroxylation• C- dehydroxylation• N- dehydroxylation• decarboxylation• dealkylation• O-demethylation• N- demethylation
•
dehalogenation• reduction of double bonds• reduction of nitro-groups• reduction of azo-groups• reduction of aldehydes• reduction of ketones•
reduction of alcohols• deamination• nitrosamine formation• acetylation• esterification
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Prodrugs
Chemical / Microbiological Approach
Undegradable and negligibly absorbed as such in the upperG.I. tract
selectively activated in the colonic microbial environment
Polymeric excipients for colonic delivery systems
Undegradable and insoluble in the upper G.I. tract
selectively degraded in the colonic microbial environment
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N
N
NH-SO 2 N=N
COOH
OHSulphasalazine
NH-SO 2 NH 2 + OH
COOH
H 2 N
Sulphapyridine5-aminosalicylic acid (5-ASA)
Bacterial azoreductases
Reduction of Azo-Groupscatalyzed by bacterial azoreductases
Sulphasalizine is a prodrug which prevents 5-ASA from being absorbed in the upper G.i>. tract
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Olsalazine
N
COOH
OHN
HOOC
HO
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Polymeric carrier
NO2
NH
SO2+
COOH
NH2
OH
Anaerobic Bacteria
Lower bowel
COONa
OH
N
N
SO2
NH
Brown J.P. et al., J. Med. Chem. 23, 1300 (1983)
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Saffran M. et al., Science, 233, 1081-1084
(1986)
A New Approac h to the Oral Administration ofInsulin and Other Peptide Drugs
Insulin -containing pellets coated by azoaromatic polymer (styrene and hydroxyethyl methacrylate
copolymer cross-linked by divinyl azobenzene)administered to rats made diabetic with streptozocin
Azopolymers for Colon Delivery Systems
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30
40
50
60
70
80
90
100
110
g l u c o s e l e v e l ( % )
0 1 2 3 4 5 6 7 8 9 10
time (hours)
Adapted from Saffran M. et al., Science, 233, 1081 (1986)
Effect on the blood glucose levels of the oral administration of an azoaromatic
polymer-coated pellet containing 1 IU (about 28 nmol/Kg body weight) of insulinto two rats made diabetic with streptozocin. Initial blood glucose levels were400 and 290 mg/100 ml, respectively.
The fall in blood glucose became significant 3 hrs post-dose .
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Hydrolysis of Glycosidic Bonds
Cathartic action of glycosidic derivativescontained in senna and cascara sagrada
catalyzed by bacterial -glycosidases
The aglycone is responsible for the therapeutic effect after
enzyme-dependent cleavage of the glycosidic bond in the colon
The saccharidic moiety, due to its hydrophilicity prevents themolecule (glycosidic compound) from absorption in the upper G.I.
Historical background
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O
O
F
HO OH
CH3
C O
O
OH
HOOH
OHdexamethasone-21,D-glycoside
Friend D.R. et al., J. Pharm. Pharmacol. 43(5), 353 (1991)
Natural Polysaccharides for Colon Delivery Systems
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Natural Polysaccharides for Colon Delivery Systems
Pectin
Chondroitin sulphate
Guar gum
Lehmann K.O.R. and Dreher K.D., Proceed. Int.’l Symp. Control. Rel. Bioact. Mater. 18, 331 (199Amylose
D-galacturonic acid and methyl ester polysaccharide, cell wall constituent . Used asa compression coat as well as a matrix forming agent in the form of calcium salt ormethoxylated derivative, or else blended with ethylcellulose, Eudragit ® RS, chitosan
Ashford M., Fell J.T. et al., J. Control. Rel. 26(3), 213 (1991)
.Mucopolysaccharide contained in the dietary meat. Used as a matrix forming agenafter cross-linking. Rubinstein A. et al., Pharm. Res. 9(2), 276 (1992)
Galactomannan. Used as a matrix forming agent in blends with acrylic resins
(Eudragit®RS, RL, NE).
D-glucose polymer constituent of starc h with amylopectin. Used in the glassy formwhich is pancreatic amylase resistant, blended with ethylcellulose (1:4) for aqueousfilm-coating. Tested in vivo by pharmacoscintigraphy, the coating mixture applied on5-ASA containing pellets was demonstrated suitable for colon delivery
Milojevic S., Newton J.M. et al., STP Pharma Sci. 5, 47 (1995ChitosanHigh molecular cationic polysaccharide obtained by chitin (shellfish exoskeletonconstituent) N-deacetylation. Used as a coating agent or capsule forming materialAcid-soluble, requires gastric resistant coating. Absorption enhancer
Rubinstein A. et al., Pharm. Res. 9(2), 276 (1992
Natural Polysaccharides for Colon Delivery Systems
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Chondroitin sulphate
Pectin
Guar gumAmylose
Chitosan
.. although these materials havedemonstrated to undergo selectiveenzyme degradation in the colon, theiroverall important limitation is thesolubility in the aqueous fluids.
….. when used as such or in physical mixtures within theformulation, they would likely fail to prevent drugrelease prior to colon arrival of the dosage form.
….. the suitability as coating or matrix-forming agents for colon delivery istherefore rather uncertain
Natural Polysaccharides for Colon Delivery Systems
… whereas the use of derivatives (salts, cross-linked compounds) or coatingformulations consisting of blend with film forming insoluble polymers , such as
EC or Acrylic resins, may be useful
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• Great efforts [time and costs] required fordevelopment and approval of new chemical
entities (NCE) [both new prodrugs and polymers]
• Limited reproducibility in enzymatic activity
Limits to the Chemical / MicrobiologicalApproach
Oral Colon Targeting
l l
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Oral Colon Targeting
- polymeric coating which dissolves at specific pH- devices capable of exploiting the relatively constant SITT
- Chemical / microbiological approach
-Technological / physiological approach
Variety of mixed strategies includingthe use of:
- prodrugs and polymeric matrices/coatings degraded by enzymaticactivity of colonic bacteria
l l
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Exploitation of:
pH variation along the G.I. tract
relatively constant small intestine transittime (SITT)
classical
innovative
-Technological / physiological approach
Oral Colon Targeting
Technological / physiological approach
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Initial hypothesis:
Systems devised as drug reservoirs coated by polymers or polymeric blends soluble at pH>6-7
progressive pH increase fromthe stomach to the
distal colon
pH-Controlled Colon Delivery Systems
Several examples
conflicting results
Technological / physiological approach
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pH
time
(hours)
l e f t c o l o n
r i g h t c o l o n
c a e c u m
d u o d e n u m
s t o m a c h
1
3
5
7
9
1 3 5 7 9 11 13 15 17 19
pH-Controlled Colon Delivery Systems
pH profile in the G.I. tractassessed using a radio
telemetric deviceAdapted from Evans D.F., Gut 29, 1035 (198
steep rise betweenstomach and small
intestinepH about 6.4
pH gradually increases to > 7 in
transverse and left colon
pH increases withspikes to about 7.5 in
the terminal ileum
pH drops toabout 6.4 inthe caecum
Technological / physiological approach
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pH-Controlled Colon Delivery Systems
Uncertainty
location
..Nevertheless..
products on themarket
•Salofalk®, Claversal® Eudragit®L (soluble pH 5.5)
•Asacol® Eudragit®S (soluble pH 7.0)
in which the pH-dependentformulations can start the release
pH-Controlled Colon Delivery Systems
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Development and In Vitro / In Vivo Evaluation of aColonic Release Capsule of Vasopressin
Vasopressin -containing hard gelatin minicapsules coatedwith a mixture of Eudragit ® S100 and Eudragit ® NE 30 D
(3:7) and by an external cellulose acetate phthalate film.
Rao S.S. and Ritschel W.A., Int. J. Pharm. 86, 35 (1992)
pH Controlled Colon Delivery Systems
Significant and long lasting decrease in the urine output following
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1 2 4 6 9 10 12 14 22 24 27 360
20
40
60
80
100
Urine output (% of baseline)
Adapted from Rao S.S. and Ritschel W.A., Int. J . Pharm. 86, 35 (1992)
gn f n n ng ng n u n u pu f w ngadministration to rats with diabetes insipidus.
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Colonic drug delivery via the use of pH-dependent polymers, an in vitro investigation.
The effect of a model, pH dependent polymer coating, EUDRAGIT S, onthe release of drug from standard, rapidly disintegrating tablets underconditions likely to be incurred in vivo during mouth to colonic transit hasbeen investigated systematically.
Dissolution is affected by pH, buffer system and strength of thedissolution medium. pH profiles constructed to mimic extremes ofconditions in vivo indicate that tablet disintegration may commence in theduodenum or not occur at all.
Therefore, due to variability in the gastrointestinaltract conditions, pH dependent polymers may not provide the best method of targeting to the colon .
M. Ashford et al., Proceed. 6th Intern. Confer. on Pharmaceutical Technology, II, 59-65 (1992)
Technological / physiological approach
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pH variation along the G.I. tractclassical
relatively constant small intestinetransit time (SITT) innovative
Small Intestine Transit Adapted from Davis S.S et al., Gut 27, 886 (1986)
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solutions pellets single units
6
0
1
2
3
4
5
S m a l l i n t e s
t i n a l t r a n s i t t i m e
( h o u r s )
Fasted
Light breakfast
Heavy breakfast
Varied breakfast
practically independent [3h + 1
s.d.] of dosage formcharacteristicsand fed/fasted
condition
relatively constant small intestinetransit time (SITT) of dosage forms
Time-Controlled Colon Delivery Systems
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T r a n s i t t i m e ( h )
LB: light breakfast
HB: heavy breakfastFA: fastedSM: standard meal
S M ( a )
L B
L B
L B
L B
L B
L B
S M ( a )
S M ( a )
S M ( a )
F A
F A
F A
F A
H B
H B
H B
Solution PelletsOsmoticpumps
OsmoticpumpsPelletsSolution
Gastric emptying Small intestine transit
Redrawn from S.S. Davis, J. Control. Release, 2 (1985) 27-38.
need to zero its influence
y y
high variability in gastric emptying
Time-Controlled Colon Delivery Systems
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stomach
smallintestine
colon
The unit, following oral administration
3] the delay phase (during whichno release occurs) can start , lastinga period of 3-4 hours (time
required to reach the colon).
2] should "know" that it has leftthe stomach entering the small
intestine ( triggering phase )
1] is expected to remain intact inthe stomach
4] release of the active
Time-Controlled Colon Delivery Systems
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t = 0
t = 3-4 h
TIME
stomach
smallintestine
colon
LAG PHASE ( no release for 3-4 hours )
release
pH independent
onset of release
Trigger phase
phase of unpredictable duration in the stomach
Differents steps:
Time-Controlled Colon Delivery Systems
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stomach
smallintestine
colon
LAG PHASE ( no release for 3-4 hours )
onset of release
release
relies on pH gradientbetween stomach andintestine environments
release behaviour according tothe design and features
of the core unit
retarding mechanism basedon solvent activation [dissolution, erosion,
dispersion] of differing polymericor non polymeric elements
Trigger phase
Time-Controlled Colon Delivery Systems
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Lag phase
Trigger phase
…in principle, all systems able to provide a lag phase prior torelease, i.e. delayed/pulsatile delivery devices, are potentiallysuitable for Time-Controlled Colon Delivery
Time-Controlled Colon Delivery Systems
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Capsular devices with release-controlling plugs
Pulsincap®
PORT (Programmable Oral Release Technologies) system
Osmotic pumps
Oros-CT ®
Reservoir systems with release-controlling coatings
TES (time-Controlled Explosion System)
Time-Clock® systemCTDC (Colon-Targeted Delivery Capsule)
EDP (Enteric Coated Timed-Release Press-Coated Tablets)
Chronotopic system
Capsular device with release-controlling plugs
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water-soluble cap
hydrogel plug
water-insoluble rigid body
drug formulation
enteric film
McNeil M.E. et al., Intern. Patent WO 90/09168 (1990)Wilding I.R. et al., Pharm. Res. 9(5), 654-657 (1992)
Binns J.S. et al., Proceed. Int’l. Symp. Control. Rel. Bioact. Mater. 20, 226 (1993)Wilson C.G. et al., Drug Delivery 4, 201-206 (1997)
Pulsincap
Capsular device with release-controlling plugs
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Drug released
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
•
• •
•
• •
• •
• •
• •
• •
• •
Stage 0 - Dissolution of enteric filmStage 1 - Dissolution of the capStage 2 - Swelling of the plug [plug removal, and then lag phase, depends on its size and position within the capsule body]
Stage 3 - Rapid release of the active
Pulsincap
Swollenejected plug
Capsular device with release-controlling plugs
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Gastrointestinal transit and plug separation times (h)
SubjectGastric
residenceSmall
intestinetransit
Colonarrival
Plugseparation post-dose
Plug
separation post-
gastricemptying
Ascendingcolon
residence
1 0.19 3.31 3.50 3.68 3.49 6.33
2 0.56 3.38 3.94 4.52 3.96 5.14
3 0.86 2.77 3.63 5.07 4.21 7.73
4 0.27 3.33 3.60 4.13 3.86 2.63
5 0.81 3.07 3.88 4.50 3.69 6.03
6 0.26 3.32 3.58 (10.48) (10.22) 8.20Mean 0.49 3.20 3.69 5.40 4.91 6.01
SD 0.30 0.24 0.18 2.53 2.62 2.00
Adapted from C.G. Wilson et al., Drug Delivery 4, 201-206 (1997
Pulsincap
Reservoir systems with release-controlling coatings
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General scheme at least two-layer coatings
Trigger layer
Lag phase layer
Drug-containing core
[retarding layer]
Reservoir systems with release-controlling coatings
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- Dispersible hydrophobic polymeric coatings
- Internal pH-mediated soluble polymeric coatings
- Erodible/dissolving hydrophilic swellable polymeric coatings
General scheme at least two-layer coatings
Lag phase layer
Time-Clock ® Systemfollowing administration
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Enteric film
Wax and surfactant mixture
Core (tablet)
Stage 0 - Dissolution of enteric filmStage 1 – Erosion/dispersion of the wax layerStage 2 - Rapid release of the active
fo ow ng a m n strat on
Pozzi F. et al., J. Control. Release 31(1), 99 (1994)Wilding I.R.. et al., Int. J. Pharm. 111, 99-102 (1994)Steed K.P. et al., J. Control. Release 49, 115 (1997)
Adapted from Wilding I.R. et al., Int. J. Pharm. 111, 99-102 (1994Time-Clock ® System
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Transit and disintegration times (min) of placebo units6 fed (light breakfast) volunteers
SubjectGastric
emptying
Smallintestinaltransit
Colon
arrivalTablet
dispersionPosition ofdispersion
1 103 248 351 655 caecum
2 251 168 419 656 proximal colon3 154 267 421 655 caecum
4 123 186 319 593 proximal colon
5 87 163 250 523 descending colon
6 201 251 452 575 proximal colonMean 153 261 369 610
SE 27 19 31 23
Colon-Targeted Delivery Capsule (CTDC)following administration
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gelatin capsule
drug
organic acid
three-layered coating
enteric layer
intermediate hydrophilic layer
acid soluble permeable layer
HPMC-AS
HPMC Low Viscosity Grade
Eudragit® E 100
Stage 0 - Dissolution of outer enteric and intermediate hydrophilic filmsStage 1 – External fluids diffuse into the capsule trough the permeable Eudragit® E layer Stage 2 - Ionization of organic acid and subsequent dissolution of the Eudragit® E layer Stage 3 – The capsule content is fully exposed to the external fluids
Colon-Targeted Delivery Capsule (CTDC)
CTDC O i h F
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subjectInitial disintegration Complete disintegration
min post-dose min post-GEAnatomical position
min post-doseAnatomical position
1 371 324 ICJ 422 AC
2 310 282 AC 421 AC
3 304 241 ICJ 514 AC4 298 272 DC 469 DC
5 385 349 AC 495 AC
6 663 590 AC 685 AC
7 240 201 AC 301 AC
8283 270 AC 502 TC
mean 357 316 476
SD 132 120 109
Redrawn from T. Ishibashi et al., J. Pharm. Sci. 87(5), 531-535 (1998
CTDC Disintegration Profile after an Overnight Fast
Chronotopic™ SystemGazzaniga A. et al., Boll. Chim. Farm. 132(2), 66 (1993)Sangalli M E et al J Control Release 73(1) 103 (2001)
Gazzaniga A. et al., Eur. J. Pharm. Biopharm. 40(4), 246 (1994)Gazzaniga A. et al., Int. J. Pharm. 108(1), 77 (1994)Gazzaniga A. et al., S.T.P. Pharma Sci. 5(1), 83 (1995)
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Stage 0 - Dissolution of enteric filmStage 1 – Swelling/Dissolution/Erosion of the polymeric layerStage 2 – Rapid/Slow release of the active
Enteric film
Hydrophilic swellable polymeric layer(HPMC, different viscosity grades)
Drug-containing core [single/multiple unit]
following administration
Sangalli M.E. et al., J. Control. Release 73(1), 103 (2001)Sangalli M.E. et al., Eur. J. Pharm. Sci. 22(5), 469 (2004)
h i l h i l h t i tiLag phaseChronotopic™ System Adapted from Gazzaniga A. et al.- Eur.J. Pharm. Biopharm. 40(4), 246 (199
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gastroresistant layer
glassy
rubbery
drug particles
a m o u n t r e l e a s e d
time
pH change
• •
• • • • •
• • •
• • •
•
physical-chemical characteristicsand coating level of the retarding layer
Lag phase
no releaselag phase
Chronotopic™ System
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Chronotopic ™ System
Model drug: Antipyrine (50 mg)
Disintegrating core: 6 mm, 158 mg
Retarding layer: Methocel ® E50 (thickness 325, 575 and 1020 µm)
Spraying equipment: Fluid bed (Uniglatt, Glatt GmbH)
Volunteers: 4 healthy male (age 36-45, weight 70-80Kg)
Sampling Antipyrine was quantified in saliva by HPLC
in vivo study on Antipyrine-containing units
saliva and blood concentrations of Antipyrine are known to be consistent
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Chronotopic™ System
Two-layer units (gastroresistant- Eudragit® L)
Adapted from Sangalli M.E. et al., J. Control. Release 73, 103 (2001)
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Chronotopic ®
units : Samarium oxide containing core,diameter = 6 mm, weight = 160 mg.
Retarding layer: Methocel ® E50 (thickness 1000 µm).
Enteric layer: Eudragit ® L,
Volunteers: 6 healthy male, aged 30-48 years (70-85Kg)
Images: 30 min intervals
PLACEBO units γ -Scintigraphic Study
Two layer units (gastroresistant Eudragit L)
Chronotopic™ System
Two-layer units (gastroresistant- Eudragit® L)
Adapted from Sangalli M.E. et al., J. Control. Release 73, 103 (2001)
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Two layer units (gastroresistant Eudragit L)
γ-Scintigraphic Data
Chronotopic™ System
Two-layer units (gastroresistant- Eudragit ® L)
Adapted from Sangalli M.E. et al., J. Control. Release 73, 103 (2001)
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5.7(0.8)
5.5
(1.3)
5.0(1.1)
0.9 (0.5)
Mean(s.d.)
Ascending colon6.06.05.50.56
Caecum/Ascending colon5.05.54.51.05
Ascending colon5.55.04.50.54
Caecum/Ascending colon4.54.03.50.53
Ascending colon6.07.05.02.02
Caecum/Ascending colon7.08.07.01.01
Break-up siteBreak-up
time after gastric
emptying (h)
ColonArrival
(h)
SmallInstestine
Transit time
(h)
Gastricresidence
(h)
Volunteers
γ Scintigraphic Data
core: placebo tablet, 6 mm, 160 mg; coating: low-viscosity HPMC (Methocel ® E50),coating thickness 1000 µm; 6 healthy volunteers, fasted state
wo ay r un ts (gastror s stant Eu rag t L)
Adapted from Sangalli M.E. et al., J. Control. Release 73, 103 (2001)Ch
ronotopic™ System
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Model drug: Mesalazine [5-aminosalicylic acid] (400 mg)Disintegrating core: 11 mm, 550 mg
Retarding layer: Methocel ® E50 (weight gain 50%, thickness~1000 µm)
Enteric layer: Eudragit ® L
Spraying equipment: Fluid bed (Uniglatt, Glatt GmbH)Volunteers: 6 healthy male (age 29-39)
Images: 1 h intervals in the 0-12 h post-dose period, andthen at 24 h.
Pharmaco-scintigraphic study on 5-ASA
containing Chronotopic™ systems
Chronotopic™ System fasted state
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Individual mesalazine and N-acetylmesalazine plasma levels after administrationof the Chronotopic® system in the fasted state. Gastric , small intestine , andlarge bowel residences of the device are indicated as red , yellow , and green lines; disintegration is indicated as the blue line.
time (h)
300
0
50
100
150
200
250
p l a s m a
c o n c e n t r a t i o n ( n
g / m L )
0 3 6 9 12 15 18 21 24
Sangalli M.E. et al., Unpublished Results
MesalazineN-Acetylmesalazine
Chronotopic™ System fed state
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Individual mesalazine and N-acetylmesalazine plasma levels after administration ofthe Chronotopic® system in the fed state. Gastric , small intestine , and large bowel residences of the device are indicated as red , yellow , and green lines; disintegration is indicated as the blue line.
Sangalli M.E. et al., Unpublished Results
50
100
150
200
250
300
p l a s m a
c o n c e n t r a t i o n
( n
g / m L )
0 3 6 9 12 15 18 21 24
MesalazineN-Acetylmesalazine
0time (h)
Chronotopic™ System
… some criticisms are addressed
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… however, the achievements reportedin literature, in connection with many differentformulations
and devices,seem to confirm that, through
time-controlled systems,colon delivery can be attained .
Colon elivery… some criticisms are addressedto time-dependent approachto colon targeting,
particularlywith respect toSITT reproducibility
Chronotopic™ Technology Platform
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Colon eliveryHard and soft
gelatin capsules as the core
Line extension
Possibility of incorporating active principles in liquid or semisolid
formulations (suspensions, emulsions, microparticles, microemulsions, pro- liposomes, SMEDDS , SLN …)
oral delivery of peptides and proteinsimportant
Colon-targeting
Technological problems of the coating process of gelatine capsules
Chronotopic™ Technology Platform
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capsules stickinginteraction of the gelatinsubstrate with the aqueous
solvent
volume increase / shrinkingof gelatin shells
operating temperatures
… TO PREVENT…
soft gelatin capsules as cores
Chronotopic™ Technology Platform
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soft gelatin capsules as cores
Chronotopic™ Technology Platform
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Zema L et al., 4th APGI/APV Meeting, Firenze, 8-11 April 2002
w.g. 13% - 170 µm w.g 21% - 315 µm
w.g. 51% - 650 µm w.g. 83% - 950 µm w.g. 103% - 1135 µm
hard gelatin capsules as cores
Chronotopic™ Technology Platform
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In vitro release profiles of Acetaminophen from uncoated cores and units coatedwith increasing amounts of Methocel ® E50 (CV<15%)
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90 100
time (min)
d r
u g r e l e a s e d ( % )
uncoated cores
coated units (287mm) coated units (576 mm)coated units (763 mm)
Sangalli M.E. et al., submitted
hard gelatin capsules as cores
Chronotopic™ Technology Platform
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Acetaminophen saliva concentration versus time after oral administration of uncoated cores andunits coated with increasing amounts of Methocel ® E50 (increasing retarding layer thickness)
Sangalli M.E. et al., submitted
0,0
0,5
1,0
1,5
2,0
2,5
3,0
0 1 2 3 4 5 6 7 8
time (h)
s a l i v a c o n c e n t r a t i o n ( m i c r o g / m l )
0,0
0,5
1,0
1,5
2,0
2,5
3,0
0 1 2 3 4 5 6 7 8
time (h)
s a l i v a c o n c e n t r a t i o n ( m i c r o g / m l )
0,0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
4,0
0 1 2 3 4 5 6 7 8
time (h)
s a l i v a c o n c e n t r a t i o n ( m i c r o g / m l )
0,0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
4,0
0 1 2 3 4 5 6 7 8
time (h)
s a l i v a c o n c e
n t r a t i o n ( m i c r o g / m l )
In vivo lag time = 1.08 h (± 0.16)
In vivo lag time = 2.04 h (±0.57) In vivo lag time = 3.27 h (±
0.34)
uncoated cores
(thickness 576 mm)(thickness 763 mm)
(thickness 287 mm)
hard gelatin capsules as cores
Chronotopic™ Technology Platform240
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Relationship between in vivo t 10% (time to 10% C max ) and coating thickness for hard gelatincapsule-based systems.
coating thickness (µm)
in vivo lag time T 10% (min)
Sangalli M.E. et al., submitted
y = 0,2304x - 6,7897 R 2 = 0,9775
0
60
120
180
0 100 200 300 400 500 600 700 800 900 coating thickness (µm)
i n v i v o t 1 0 %
( m i n )
240
hard gelatin capsules as cores
Chronotopic™ Technology Platform
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Relationship between in vitro t 10% (time to 10% release of drug labelled content)and in vivo t 10% (time to 10% of C max ) for hard gelatin capsule cores and relevantsystems with increasing coat thickness. [ bars represent s.d.]
y = 3.0341x - 3.7945
R 2
= 0.9902
0
60
120
180
240
0 10 20 30 40 50 60 70
Sangalli M.E. et al., submitted
in vitro lag time t10% (min)
in vivo lag time T 10% (min)
hard gelatin capsules as cores
Chronotopic™ Technology Platform
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0,0
0,5
1,0
1,5
2,0
2,5
3,0
0 1 2 3 4 5 6 7 8time (h)
s a l i v a c o n c e n t r a t i o n ( m i c r o
g / m l )
Acetaminophen saliva concentration versus time after oral administration ofcoated capsules (retarding layer thickness, 763 mm)
in vivo lag time = 3.27 h (± 0.34)
Sangalli M.E. et al., submitted
Colon-targeting
hrono a ™ Novel Capsular Pulsatile Device
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p
-Versatility(ready to use systems with pre-defined performance)
-Reduced time for pharmaceutical development(limited compatibility and stability study
A Novel Injection-Molded Capsular Device for Oral Pulsatile Delivery Based onSwellable/Erodible Polymers. A. Gazzaniga, et al.- AAPS PharmSciTech 12, 295-303 (2011)
hrono a ™ Novel Capsular Pulsatile Device
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2.0
0 2 4 6 8 10 12 14 16 18 20 22 24
1.0
3.0
0.0
in vivo lag time = 3.42 h (± 0.44)
Acetaminophen saliva concentration versus time after oral administration ofChronoCap™
units (shell thickness, 1000 µm)
[C] (µg /mL)
Time (hours)
Time-based ColonDelivery System
p