Formulation Approaches to Colon Delivery: an Overview

Transcription

1 ANDREA GAZZANIGA Formulation Approaches to Colon Delivery: an Overview Sezione di Tecnologia e Legislazione Farmaceutiche Maria Edvige Sangalli

2 number of pubblications publications year Formulation Approaches to Colon Delivery: an Overview Modified Release Systems generally intended for temporal and/or spatial control of release. potential of systems capable of delivering drugs to a specific site within the G.I. tract in particular to the colon

3 Traditionally interest tied up to local treatment of large bowel diseases need for high local drug concentrations /little or no drug absorption expected in the past, colon generally seen as a region with very poor absorption properties pharmacoscintigraphy enabling a correlation between the G.I. location of the dosage form and the plasma levels of the drug it has definitively been proved that a significant absorption can occur along the colon Presently local ---> systemic goals (IBD) Inflammatory Bowel Diseases Irritable Bowel Syndrome Adenocarcinoma Chemoprevention Degradation of residual -lactams Improvement in mucosal immune response 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

4 to recall some anatomical / physiological features of the Colon. begins from the ileo-caecal valve and the caecum and ends with the rectum approx 1.2 meter long 6-7 cm wide Transverse Colon Ascending Colon Caecum Ileo-Caecal valve Descending Colon Sigmoid Colon Rectum divided in.. A,T,D,S Colon 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

5 Proximal colon achievable only by oral route. Distal colon achievable in some cases also by rectal route.

6 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 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 stomach - microflora (quali-quantitative composition ) - ph of fluids - transit time small intestine colon possibility of exploiting their variations along the lumen preferred tools are polymeric materials

7 focus reservoir systems - enzymatically degraded - ph sensitive - time dependent classical innovative 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 on coated systems prepared through industrially scalable processes --- > for which data in humans are available

8 Oral cavity Stomach Duodenum Jejunum Ileum Ceacum Rectum Formulation Approaches to Colon Delivery: an Overview rationale - enzymatically degraded - ph sensitive - time dependent - pressure sensitive 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 Log number of selected bacterial species per g content of alimentary tract 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

9 Natural Polysaccharides Amylose Pectin Chitosan, Galactomannan Guar gum, Chondroitin sulphate as film forming agents.. although they undergo selective degradation in the colon, their overall important limitation is the solubility and/or swelling in the aqueous fluids. - enzymatically degraded - ph sensitive - time dependent - pressure sensitive.. 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... the suitability for colon delivery is therefore uncertain whereas the use of derivatives (salts, cross-linked compounds), polyelectrolyte complexes and/or physical mixtures with insoluble polymers has been proven advantageous preferred since their substrates are naturally-occurring polysaccharides mainly by glycosidases or azoreductases

10 Natural Polysaccharides Amylose - enzymatically degraded - ph sensitive - time dependent - pressure sensitive as film forming agent mixed film ---> insoluble polymer (EC) importantly - 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. - films formed from amylose alone do not prevent the release in upper GI fluids. - mixture of Amylose butanol complex with EC, applied as a water dispersion, provides a colon targeting coating A. W. Basit et al. (2009) ɣ scintigraphic study on 8 fasting volunteers 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 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) colon arrival of the systems

11 Natural Polysaccharides as film forming agent mixed film ---> insoluble polymer (EC) Y. Karrout et al., (2009) (2010) ( 2011) - enzymatically degraded - ph sensitive - time dependent - pressure sensitive 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

12 exploitation of the ph variation along the G.I. tract based on an assumed progressive ph increase from the stomach to the distal colon most commonly employed materials ---> acrylates copolymers designed to dissolve at intestinal ph - ph sensitive ---> many examples, used alone or in combination with other substances when used as such ---> generally applied as relatively thick films to prevent early failures in the SI ɣ-scintigraphy - 6 fasting volunteers W.A. Habib et al. (1999) sole Eudragit L soluble ph 5.5 not consistent results core: nisin tablets 7mm coat: Eudragit L30 D-55 analogous results 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 core : paracetamol capsules size 0 coat: Eudragit L30 D-55 E.T. Cole et al. (2002) amount of polymer applied - 8 mg/cm 2 spray coating / rotating pan 6 fasting volunteers (ɣ-scintigraphy) disintegration in the small intestine for all units

13 exploitation of the ph variation along the G.I. tract based on an assumed progressive ph increase from the stomach to the distal colon most commonly employed materials ---> acrylates copolymers designed to dissolve at intestinal ph - ph sensitive ---> many examples, used alone or in combination with other substances when used as such ---> generally applied as relatively thick films to prevent early failures in the SI ɣ-scintigraphy - 7 fasting volunteers M.Ashford et al. (1993) sole Eudragit S soluble ph 7.0 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 Authors conclusions due to the variability in the gastrointestinal tract conditions, ph dependent polymers may not provide the best method of targeting to the colon

14 stomach duodenum ---> caecum right colon left colon Formulation Approaches to Colon Delivery: an Overview exploitation of the ph variation along the G.I. tract based on an assumed progressive ph increase from the stomach to the distal colon ph profile in the G.I. tract assessed using a radio telemetric device ph 9 ---> ph drops to about 6.4 in the caecum D.F.Evans (1988) - ph sensitive 7 5 uncertainty location in which the ph-dependent formulations can start the release time (hours)

15 exploitation of the ph variation along the G.I. tract based on an assumed progressive ph increase from the stomach to the distal colon Asacol, Eudragit S (soluble ph 7.0) Salofalk, Claversal Eudragit L (soluble ph 5.5) Entocort, Budenofalk, Lialda Eudragit L /S - ph sensitive..nevertheless.. products for IBD on the market

16 exploitation of the ph variation along the G.I. tract based on an assumed progressive ph increase from the stomach to the distal colon Eudragit S coated prednisolone (10mg) tablets V.C. Ibekwe et al. (2006) 200 mg, 84 thickness, fluid bed 8 volunteers, ɣ-scintigraphy fasted condition Eudragit S aqueous dispersion- early break-up of all units in the proximal-to-mid SI - ph sensitive Eudragit S organic solution - 3 units fail to disintegrate, 2 ICJ and 6 AC disintegration V.C. Ibekwe et al. ( (2008) 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 Eudragit S organic solution fed: 3 units fail to disintegrate, 1 early break-up in the ileum, 3 ICJ and 1 AC disintegration summarizing ---> actual colon targeting was not consistently achieved --- > aqueous dispersions: early break-up of all units in the Small Intestine..more recently the disintegration behaviour of ph-dependent systems was in-depth investigated and the poorly reliable performance was confirmed --- > organic solutions: in all cases some units fail to break up Authors conclusions 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.

17 to overcome the possible issue of a break-up failure new colon delivery technology (two independent and complementary release mechanisms) V.C. Ibekwe et al.(2008) combination of: -ph-responsive polymer (Eudragit S) and -colonic microflora-degradable substrate (resistant starch) as the film coating matrix - ph sensitive ɣ-scintigraphy study on 24 volunteers fasted, fed, pre-feed conditions 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 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 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

18 to overcome the possible issue of a break-up failure another new colon delivery technology (hydrophilic substances to expedite the break-up of enteric films) R.C.A. Schellekens et al.(2010) combination of: -ph-responsive polymer (Eudragit S) and -disintegrants (crosscarmellose) - ph sensitive as the film coating matrix in vivo study on 12 fasted volunteers /indirect evaluation of site of release core: 13 C-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/cm 2 in 10 out of 11 subjects ---> complete release in the ileo-colonic region

19 exploitation of relatively constant small intestine transit time (SITT) rationale S.S Davis et al. (1986) Fasted 6 5 SITT (hours) Light breakfast Heavy breakfast Varied breakfast - time dependent 4 3 SITT practically independent [3h+1 s.e.] of dosage form characteristics and fed/fasted condition solutions pellets single -units

20 exploitation of relatively constant small intestine transit time (SITT) rationale The unit, following oral administration - time dependent stomach small intestine 1] is expected to remain intact in the stomach (the residence time is unpredictable) 2] should "know" that it has left the stomach entering the small intestine (triggering phase) 3] the delay phase (during which no release occurs) can start, lasting a period of 4-5 hours (time required to reach the colon) colon 4] release of the active (on the arrival into the colon)

21 exploitation of relatively constant small intestine transit time (SITT) rationale stomach - time dependent Trigger phase t = 0 small intestine LAG PHASE ( no release for 4-5 hours ) ph independent TIME colon ---> onset of release release t = 4-5 h

22 exploitation of relatively constant small intestine transit time (SITT) rationale - time dependent stomach Trigger phase relies on ph gradient between stomach and small ntestine small intestine LAG PHASE provided by a retarding mechanism based on solvent activation [dissolution, erosion, dispersion] of differing polymeric elementsmostly colon onset of release release release behaviour according to the features of the core unit

23 exploitation of relatively constant small intestine transit time (SITT) rationale as a general scheme ---> at least a two-layer coating is required drug containing core trigger layer lag phase layer stomach - time dependent Trigger phase gastroresistant film small intestine LAG PHASE slow dissolution, erosion and/or rupture of polymeric film colon onset of release release release behaviour according to the features of the core unit

24 amount released Formulation Approaches to Colon Delivery: an Overview exploitation of relatively constant small intestine transit time (SITT) A. Gazzaniga et al. (1994) - M.E.Sangalli et al. (2001) > Chronotopic System drug containing core Eudragit L medium viscosity HPMC - time dependent The gel layer progressively becomes permeable and/or erodes thus delaying the contact between the core and the aqueous fluids. following administration gastroresistant layer glassy rubbery drug particles Stage 0 - Dissolution of enteric film Stage 1 Slow interaction of HPMC layer Stage 2 Rapid release of the active ingredient ph change lag phase no release time

25 exploitation of relatively constant small intestine transit time (SITT) A. Gazzaniga et al. (1994) - M.E.Sangalli et al. (2001) Chronotopic System drug containing core Eudragit L medium viscosity HPMC - time dependent The gel layer progressively becomes permeable and/or erodes thus delaying the contact between the core and the aqueous fluids. following administration Stage 0 - Dissolution of enteric film Stage 1 Slow interaction of HPMC layer Stage 2 Rapid release of the active

26 exploitation of relatively constant small intestine transit time (SITT) A. Gazzaniga et al. (1994) - M.E.Sangalli et al. (2001) > Chronotopic System drug containing core γ- scintigraphy Placebo coated Tablet (6 mm mg) - thickness 1000 µm Retarding coat: Methocel E50 hydroalchoolic dispersion fluid bed Eudragit L medium viscosity HPMC - time dependent Transit and disintegration times (h) of placebo units 6 fasted volunteers - γ-scintigraphic Study Volunteers Gastric residence Small Instestine Transit Colon Arrival Break-up time after gastric emptying Break-up site Caecum/Ascending colon Ascending colon Caecum/Ascending colon Ascending colon Caecum/Ascending colon Ascending colon in all cases disintegration of the units in the proximal colon Mean (s.d.) 0.9 (0.5) 5.0 (1.1) 5.9 (1.3) 5.7 (0.8)

27 plasma concentration (ng/ml) Formulation Approaches to Colon Delivery: an Overview exploitation of relatively constant small intestine transit time (SITT) - time dependent 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 ME Sangalli et al. (2009) Pharmaco-scintigraphic study - 12 fasted/fed volunteers Transit and disintegration times of mesalazine coated tablets 300 subject #1 N-Acetylmesalazine 250 fasted state Mesalazine > Chronotopic System drug containing core γ- scintigraphy Mesalazine (400 mg) coated Tablet (11 mm mg) - thickness 1000 µm Retarding coat: Methocel E50 hydroalchoolic dispersion fluid bed Eudragit L medium viscosity HPMC time (h)

28 Glycaemia % Insulin (µg/ml) Formulation Approaches to Colon Delivery: an Overview exploitation of relatively constant small intestine transit time (SITT) - time dependent recently --> insulin single and multiple-unit formulations Chronotopic System A. Maroni al. (2009) M.D. Del Curto et al. (2009) M.D. Del Curto et al. (2011) even if we know that.. the best model for man is man! ---> in vivo study on diabetic rats-streptozotocin drug containing core S:S:Davis and I.R. Wilding (2001) Eudragit L medium viscosity HPMC insulin 0.4 mg 3 mm units University of Milan and Padua manuscript in preparation (2013) Colonic systems Uncoated cores Untreated rats Colonic systems Uncoated cores Untreated rats time (min) time (min)

29 Conclusions Irrespective of which formulation approach is relied on, the development of oral colon delivery systems involves unique/major challenges. 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. 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. there would be much more details in A. Maroni et al.int. J. Pharm. (2013 in press) this presentation will be uploaded on:

30 Acknowledgements the industrial side & the academic side Piero Iamartino Grazia Maffione Alessandra Maroni Cesare Busetti Matteo Cerea Luigi Moro Lucia Zema Luigi Bruschi Luca Palugan Carlo Vecchio Anastasia Foppoli Tiziano Crimella Mauro Serratoni MariaDorly del Curto Ferdinando Giordano Maria Edvige Sangalli there would be much more details in A. Maroni et al.int. J. Pharm. (2013 in press) this presentation will be uploaded on: