formulation approaches to colon delivery: an...

Formulation Approaches to Colon Delivery: an Overview

Sezione di Tecnologia e Legislazione Farmaceutiche Maria Edvige Sangalli

ANDREA GAZZANIGA

in particular to the colon potential of systems capable of delivering drugs to a specific site within the G.I. tract

0

10

20

30

40

50

60

num

ber

of p

ubbl

icat

ions

year

num

ber

of p

ublica

tion

s

Modified Release Systems


generally intended for

temporal and/or spatial control of release.

need for high local drug concentrations /little or no drug absorption expected

Traditionally interest tied up to local treatment of large bowel diseases

in the past, colon generally seen as a region with very poor absorption properties


… it has definitively been proved that a significant absorption can occur along the colon

pharmacoscintigraphy enabling a correlation between the G.I. location of the dosage form and the plasma levels of the drug

Improvement in the oral bioavailability of peptides and proteins (less hostile environment in the colon - more than 50

different types of peptidases in the small intestine

(IBD) Inflammatory Bowel Diseases Irritable Bowel Syndrome

Adenocarcinoma Chemoprevention Degradation of residual -lactams

Improvement in mucosal immune response

local ---> systemic goals Presently

Caecum

Ileo-Caecal valve

Rectum

Ascending Colon

Transverse Colon

Descending Colon

Sigmoid Colon

… begins from the ileo-caecal valve and the caecum and ends with the rectum

1.2 meter long 6-7 cm wide

… divided in .. A,T,D,S Colon

approx


segmentation contractions peristaltic/antiperistaltic waves (movements)

the first part of the meal reaches the caecum in about 4 h

… as much as 25 % of the residue of test meal

may still be in the rectum after 72 h

transit of dosage forms ranges from 6-7 to 20 hours

..drained by mesenteric veins and lymphatic vessels

… to recall … … some anatomical / physiological

features of the Colon….


Distal colon achievable in some

cases also by rectal route.

Proximal colon

achievable only by oral route.

small intestine

stomach

colon

… any possible formulation strategies for selective release into the colon require a sophisticated approach based on the anatomical and physiological features of the entire GI tract

possibility of exploiting their variations along the lumen

polymeric materials preferred tools are

- microflora (quali-quantitative composition )

- pH of fluids

- transit time


… system capable of passing without releasing through the stomach and the small bowel provided a suitable mechanism that allows the release when the colon is reached

- enzymatically degraded

- pH sensitive

- time dependent

classical

innovative

--- > for which data in humans are available

i.e. films based on well-established coating agents and process conditions

i.e. films based on novel coating agents (materials not used before) and/or newly set up process conditions


film coatings

… on coated systems prepared through industrially scalable processes

focus

reservoir systems


- pH sensitive

- time dependent

- pressure sensitive Ora

l ca

vity

Sto

mac

h

Duo

den

um

Jej

unum

Ileu

m

0

2

3

4

5

6

7

8

9

10

11

Log number of selected bacterial species per g content of alimentary tract

Cea

cum

Rec

tum

Enterococci

Veillonellae

Bacteroides

Lactobacilli

Coliform bacteria

Bifidobacteria

Clostridium perfrigens

Eubacteria

Anaerobic streptococci

Adapted from T. Mitsuoka (1978)

Microflora polulation INCREASES DOWNWARDS IN THE G.I.TRACT – q.q. abundance in the colon

… use of either natural or synthetic film forming substances selectively degraded in the colon by differing enzymes,

mainly by glycosidases or azoreductases

Exploitation of the selective/unique presence in the colon of bacterial species capable of catalyzing a large number of enzymatic reactions

on substances that are not degradable in the upper GI tract rationale

film coatings



- pH sensitive

- time dependent

- pressure sensitive

….. the suitability for colon delivery is therefore uncertain

as film forming agents

….. when used as the sole film forming agent the

resulting coats might fail to prevent drug

release prior to colon arrival of the dosage form.

preferred since their substrates are naturally-occurring polysaccharides

mainly by glycosidases or azoreductases

.. although they undergo selective degradation in

the colon, their overall important limitation is

the solubility and/or swelling in the aqueous

fluids.

as film forming agents

Chitosan,

Guar gum,

Amylose

Natural Polysaccharides


Chondroitin sulphate

film coatings

Pectin

Galactomannan

… whereas the use of derivatives (salts, cross-linked compounds), polyelectrolyte complexes and/or physical mixtures with insoluble polymers has been proven advantageous


- pH sensitive

- time dependent


as film forming agent

Amylose


film coatings

- films formed from amylose alone do not prevent the release in upper GI fluids.

- linear polymeric component of starch,

- in a glassy amorphous state it escapes digestion by pancreatic a-amylase in the small intestine and is degraded by bacteria within the large bowel.

mixed film ---> insoluble polymer (EC)

Prednisolone-containing formulation (derived from these studies) COLAL-PRED ---> for the local therapy of ulcerative colitis ---> has reached a late pharmaceutical development stage (phase III)


- mixture of Amylose butanol complex with EC, applied as a water dispersion, provides a colon targeting coating

… importantly

core : theophylline pellets - E/S coat: Amylose:EC 1:3 by weight ratio- spray coating fluid bed

amount of polymer applied - w. g. 20%

---> drug plasma levels detected only after

colon arrival of the systems

ɣ scintigraphic study on 8 fasting volunteers

A. W. Basit et al. (2009)


- pH sensitive

- time dependent


as film forming agent


film coatings

mixed film ---> insoluble polymer (EC)


Y. Karrout et al., (2009) (2010) ( 2011)

high amylose maize starch, unmodified peas

starch and a number of starch derivatives

(Nutriose) are under extensive investigation

with the aim of identifying film compositions

that would undergo enzymatic breakdown in

the lower intestine even in the presence of

IBD-related alterations of the microflora

- pH sensitive

sole Eudragit® L soluble pH 5.5

not consistent results

exploitation of the pH variation along the G.I. tract

most commonly employed materials ---> acrylates copolymers designed to dissolve at intestinal pH

when used as such ---> generally applied as relatively thick films to prevent early failures in the SI

based on an assumed progressive pH increase from the stomach to the distal colon

core : paracetamol capsules size 0 coat: Eudragit®L30 D-55 E.T. Cole et al. (2002)

amount of polymer applied - 8 mg/cm2 spray coating / rotating pan

6 fasting volunteers (ɣ-scintigraphy) disintegration in the small intestine for all units


film coatings ---> many examples, used alone or in combination with other substances

analogous results

ɣ-scintigraphy - 6 fasting volunteers

core: nisin tablets 7mm coat: Eudragit®L30 D-55 fluid bed

evaluation of the influence of film thickness ---> 400 -1,300

- for units ---> 400 film thickness: disintegration started in the small intestine - for units --->900 film thickness: too long time needed for complete disintegration

W.A. Habib et al. (1999)

- pH sensitive

sole Eudragit® S soluble pH 7.0

… due to the variability in the gastrointestinal tract conditions, pH dependent polymers may not provide the best method of targeting to the colon

exploitation of the pH variation along the G.I. tract

most commonly employed materials ---> acrylates copolymers designed to dissolve at intestinal pH

when used as such ---> generally applied as relatively thick films to prevent early failures in the SI

based on an assumed progressive pH increase from the stomach to the distal colon

Authors’ conclusions


film coatings ---> many examples, used alone or in combination with other substances

ɣ-scintigraphy - 7 fasting volunteers core: biconvex placebo tablets 10 mm coat: Eudragit®S organic solution / weight gain: 5 % pan coating triacetin

- lack of site specificity : in vivo disintegration extremely variable in

terms of time (5-15 h) and position

M.Ashford et al. (1993)

pH profile in the G.I. tract assessed using a

radio telemetric device

- pH sensitive

exploitation of the pH variation along the G.I. tract based on an assumed progressive pH increase from the stomach to the distal colon


film coatings

D.F.Evans (1988)

pH

time (hours)

left

col

on

righ

t co

lon

caec

um

duo

den

um

stom

ach

5

7

9

1 3 5 7 9 11 13 15 17 19

--->

pH drops to about 6.4 in the caecum

--->

uncertainty

location in which the pH-dependent formulations can start the release

..nevertheless..

products for IBD on the market

•Salofalk®, Claversal® Eudragit® L (soluble pH 5.5)

•Asacol®, Eudragit® S (soluble pH 7.0)

•Entocort®, Budenofalk® , Lialda® Eudragit® L /S

- pH sensitive



film coatings

- pH sensitive

fasted condition

Eudragit®S aqueous dispersion- early break-up of all units in the proximal-to-mid SI

Eudragit®S organic solution - 3 units fail to disintegrate, 2 ICJ and 6 AC disintegration

V.C. Ibekwe et al. ( (2008)


V.C. Ibekwe et al. (2006)

Eudragit®S organic solution

fasted: 1 unit fails to disintegrate, 1 ICJ and 6 AC disintegrations

pre-feed: 3 units fail to disintegrate, 4 ICJ and 1 AC disintegration

fed: 3 units fail to disintegrate, 1 early break-up in the ileum, 3 ICJ and 1 AC disintegration


film coatings

Eudragit®S coated prednisolone (10mg) tablets

… the behaviour of pH-responsive dosage forms in vivo is much more complex than may have been

previously anticipated and the efficacy and reproducibility of treatment with these systems cannot be assumed.

Authors’ conclusions

200 mg, 84 thickness, fluid bed 8 volunteers, ɣ-scintigraphy

organic solutions: in all cases some units fail to break up

… summarizing

--- >

aqueous dispersions: early break-up of all units in the Small Intestine

---> actual colon targeting was not consistently achieved

--- >

the disintegration behaviour of pH-dependent systems was in-depth investigated and the poorly reliable performance was confirmed

..more recently…

V.C. Ibekwe et al.(2008)

- pH sensitive

combination of: -pH-responsive polymer (Eudragit®S) and

-colonic microflora-degradable substrate (resistant starch)

as the film coating matrix

core: placebo tablet 8mm diameter

coat: mixture of Eudragit®S (ethanolic solution) and Eurylon® VII (aqueous dispersion) – (3:7 solids)

method : bottom spray fluid bed w.g. or tickness: not reported

ɣ-scintigraphy study on 24 volunteers – fasted, fed, pre-feed conditions


film coatings

new colon delivery technology (two independent and complementary release mechanisms)

to overcome the possible issue of a break-up failure

… for coatings that dissolve at pH 7 there is a reasonable possibility that

the dosage form may start releasing in the ileum rather than in the colon

2) … if the unit remains intact/fails to disintegrate in the small intestine, no release is

likely to take place while it moves along the ascending colon where the pH is below 7

in most cases the disintegration of the dosage form occurred in the colon irrespective of the feeding conditions, 4 units broke up at the ICJ

- pH sensitive

combination of: -pH-responsive polymer (Eudragit®S) and

-disintegrants (crosscarmellose)

as the film coating matrix

in 10 out of 11 subjects


film coatings

R.C.A. Schellekens et al.(2010)

another new colon delivery technology

(hydrophilic substances to expedite the break-up of enteric films)

to overcome the possible issue of a break-up failure

core: 13C-urea capsule size 2

coat: suspension of Ac-di-sol® in Eudragit®S acetone/water (7:3 solids)

method : Capsule Spray Coater, Labo Tech /curing tickness: 9.1 mg/cm2

“in vivo” study on 12 fasted volunteers /indirect evaluation of site of release

---> complete release in the ileo-colonic region

- time dependent

solutions pellets single -units

6

0

1

2

3

4

5

SITT (hours)

Fasted

Light breakfast

Heavy breakfast

Varied breakfast

SITT practically independent [3h+1 s.e.]

of dosage form characteristics and fed/fasted condition

rationale S.S Davis et al. (1986) rationale

exploitation of relatively constant small intestine transit time (SITT)


film coatings

- time dependent

stomach

small intestine

colon

The unit, following oral administration

2] should "know" that it has left the stomach entering the small intestine (triggering phase)

4] release of the active (on the arrival into the colon)

1] is expected to remain intact in the stomach (the residence time is unpredictable)

3] the delay phase (during which no release occurs) can start, lasting a period of 4-5 hours (time required to reach the colon)

rationale rationale



film coatings

- time dependent

stomach

small intestine

colon

t = 0

TIME

release

onset of release

Trigger phase

t = 4-5 h

LAG PHASE ( no release for 4-5 hours ) pH independent

rationale rationale



film coatings --->

- time dependent

stomach

small intestine

colon release

onset of release

Trigger phase

LAG PHASE

provided by a retarding mechanism based on solvent activation [dissolution,

erosion, dispersion] of differing polymeric elements- mostly film coatings

release behaviour according to the features of

the core unit

rationale

relies on pH gradient between stomach and

small ntestine

rationale



film coatings

- time dependent

stomach

small intestine

colon release

onset of release

Trigger phase

LAG PHASE

slow dissolution, erosion and/or rupture of

polymeric film

gastroresistant film

release behaviour according to the features of

the core unit

rationale



film coatings

drug containing

core

trigger layer

lag phase layer

as a general scheme ---> at least a two-layer coating is required

- time dependent

Stage 0 - Dissolution of enteric film Stage 1 – Slow interaction of HPMC layer Stage 2 – Rapid release of the active ingredient

following administration gastroresistant layer

glassy

rubbery

drug particles

am

ou

nt

rele

as

ed

time

pH change

• • • • •

• • •

• • • •

• •

no release

lag phase

The gel layer progressively becomes permeable and/or erodes thus delaying the contact between the core and the aqueous fluids.

A. Gazzaniga et al. (1994) - M.E.Sangalli et al. (2001)



film coatings

medium viscosity HPMC

Eudragit L drug

containing core

Chronotopic® System

------->

- time dependent

Stage 0 - Dissolution of enteric film Stage 1 – Slow interaction of HPMC layer Stage 2 – Rapid release of the active

following administration




film coatings


Eudragit L drug

containing core


The gel layer progressively becomes permeable and/or erodes thus delaying the contact between the core and the aqueous fluids.

- time dependent




film coatings


Eudragit L drug

containing core


------->

5.7

(0.8)

5.9

(1.3)

5.0

(1.1)

0.9

(0.5) Mean (s.d.)

Ascending colon 6.0

6.0 5.5 0.5 6

Caecum/Ascending colon 5.0 5.5 4.5 1.0 5

Ascending colon 5.5 5.0 4.5 0.5 4


Ascending colon 6.0 7.0 5.0 2.0 2


Break-up site

Break-up time after gastric

emptying

Colon Arrival

Small Instestine

Transit

Gastric residence

Volunteers

Transit and disintegration times (h) of placebo units 6 fasted volunteers - γ-Scintigraphic Study

in all cases disintegration of the units in the proximal colon

γ- scintigraphy Placebo coated Tablet (6 mm - 160 mg) - thickness 1000 µm Retarding coat: Methocel E50 hydroalchoolic dispersion fluid bed

time (h)

300

0

50

100

150

200

250

plas

ma

conc

ent

rati

on (

ng/m

L)

0 3 6 9 12 15 18 21 24

Mesalazine N-Acetylmesalazine

- time dependent



film coatings


Eudragit L drug

containing core

Chronotopic® System ME Sangalli et al. (2009)

------->

subject #1 fasted state Individual (subject #1) mesalazine and N-

acetylmesalazine plasma levels after administration of the Chronotopic® system in the fasted state.

Red, blue, and green lines indicate gastric, small intestine, and colon residences of the device. Disintegration is indicated as the grey line.

in all cases disintegration of the units in the proximal colon

Pharmaco-scintigraphic study - 12 fasted/fed volunteers Transit and disintegration times of mesalazine coated tablets

γ- scintigraphy Mesalazine (400 mg) coated Tablet (11 mm - 550 mg) - thickness 1000 µm Retarding coat: Methocel E50 hydroalchoolic dispersion fluid bed



film coatings


Eudragit L drug

containing core

- time dependent


even if we know that.. … the best model for man is man ! S:S:Davis and I.R. Wilding (2001)

-1

0

1

2

3

4

5

0 10 20 30 40 50 60

Insulin

(µ

g/m

l)

time (min)

Colonic systems

Uncoated cores

Untreated rats

20

40

60

80

100

120

Gly

caem

ia

%

Colonic systems

Uncoated cores

Untreated rats

01

0 12 24 36 48 60

time (min)

---> in vivo study on diabetic rats-streptozotocin

insulin 0.4 mg – 3 mm units University of Milan and Padua –manuscript in preparation (2013)

recently --> insulin single and multiple-unit formulations

A. Maroni al. (2009) – M.D. Del Curto et al. (2009) – M.D. Del Curto et al. (2011)

Moreover, the behaviour of the colonic formulations is to be assessed by means of imaging studies in volunteers:

- pharmacokinetic methods would fail to directly point out the site of drug release, and

- no animal models exhibit GI anatomy and physiology characteristics that may suitably mimic the human ones.

Indeed, all approaches suffer from the variability that affects intrinsic biological parameters.

This is particularly true under pathological conditions, i.e. when the local delivery of bioactive molecules is needed.

Conclusions


Irrespective of which formulation approach is relied on, the development of oral colon delivery systems involves unique/major challenges.

… details in A. Maroni et al.Int. J. Pharm. (2013 in press)

http://users.unimi.it/gazzalab/ … this presentation will be uploaded on:

… there would be much more…


Piero Iamartino

Grazia Maffione

Cesare Busetti

Luigi Moro

Luigi Bruschi

Carlo Vecchio

Tiziano Crimella

… the industrial side & the academic side Acknowledgements

Alessandra Maroni

Matteo Cerea

Lucia Zema

Luca Palugan

Anastasia Foppoli

Mauro Serratoni

MariaDorly del Curto

Ferdinando Giordano

Maria Edvige Sangalli

… details in A. Maroni et al.Int. J. Pharm. (2013 in press)

http://users.unimi.it/gazzalab/ … this presentation will be uploaded on:

… there would be much more…

formulation approaches to colon delivery: an...

Documents