Clinical Relevance: Why Are Enteric Coatings Failing in Vivo?

Clinical relevance: Why are enteric coatings failing in vivo?

Daniela Amaral Silva [email protected] Ph.D. Student – University of Alberta Supervisor: Dr. Raimar Löbenberg Outline

• Background • Enteric coating and bicarbonate – the underlying science • Study with Canadian commercial products • Methods • Results • Conclusion

Background • Used since late 19th century to delay the onset of drug release in order to:

• Protect acid-labile API’s against degradation by gastric acid

Enteric coatings • Protect the gastric mucosa against the irritating effects of certain API’s

• Target the release of some API’s to particular intestinal segments

1946

- Enteric-coated ammonium chloride tablets passedCanadian unchanged Medical through the Association Journal GIT. Volume 55, Issue 5, - Low effective1946, absorptionPages 445-447 - Gelatin coated tablets – well absorbed 1950

Enteric-coated ammonium chloride tablets failing to disintegrate in the small intestine may become deposited in the large bowel and disturb the normal fecal flow causing fecal impaction.

The American Journal of Surgery Volume 79, Issue 1, January 1950, Pages 184-185  1964 1964

In vivo tests showed that an enteric coated aspirin tablet preparation which passed the USP tablet disintegration test was physiologically unavailable. Although one cannot generalize these findings to all enteric coated tablets, neither can one rely on the USP disintegration test as an index of physiologic availability. 1972 1972

1970

The author stressed the importance of definitive in vivo confirmation of the efficiency of an enteric-coating formulation.

1972

In the present study, delayed release of aspirin from enteric-coated tablets was demonstrated from the time course of the concentration of salicylic acid in saliva.

Journal of Pharmaceutical Sciences 1972, 61, (8), 1219-1222. Concentration of salicylic acid in saliva after administration of aspirin 1972 Hard gelatin capsules 3 subjects Enteric coated tablets - Rate and extent of absorption - Failure 1973

“…enteric-coated tablet of aminosalicylic acid was shown to pass all USP specifications in the FDA laboratories”.

Plasma samples of all eight subjects at each sampling time assayed “zero” for both drug and metabolite following oral administration of the enteric-coated tablet.

Journal of Pharmaceutical Sciences Volume 62, Issue 5, May 1973, Pages 859-860 1973

Tablet excreted in feces essentially intact (…) about 30 hr INTACT TABLET postingestion. BEFORE INGESTION The other tablet (…) large pieces were excreted in the same feces.

The essentially intact tablet  98% of labeled dose Fragments  48 % of labeled dose

CONCLUSION

It is obvious that an enteric-coated tablet that gave zero plasma levels of bioactive aminosalicylate and that was excreted in the feces would be clinically ineffective.

Essentially Large fragments intact tablet  1979

H.J. Pieniaszek, D. Resetarits, W. Wilferth, H. Blumenthal, T. Bates, J. Clin. Pharmacology. 19 (1) (1979) 39–45.

Commercial uncoated vs. enteric coated sulfasalazine tablets

Peak plasma concentration of uncoated tablets – 14 hours

Peak plasma concentration of enteric-coated tablets – 20 hours and only 50% of the attained from uncoated tablets.

These findings suggest that enteric-coated and uncoated tablets of sulfasalazine are not bioequivalent. It remains to be determined whether the clinical efficacy of sulfasalazine from enteric-coated tablets is affected.

1979

Sulfapyridine plasma concentration Sulfapyridine plasma concentration Fast acetylators Slow acetylators

- Extent of absorption Uncoated Uncoated

Uncoated Uncoated Enteric-coated Enteric-coated Enteric-coated Enteric coated 1989

…Patients“Enteric who coatedresponded tablets poorly to entericare-coated virtuallyCanadian ferrous Medical worthless sulfate preparationsAssociation. In each Journal case there was butVolume are 55,still Issue being 5, a prompt response1946, Pages to 445 non-447- enteric- coated preparations.market”.

Rudinskas L., et. al. CMAJ, 141 (1989), pp. 565-566 1991

PK of 4 commercially available aspirin formulations:

Immediate release: • No significant differences in tmax and AUC

EC formulations: • Significant prolonged tmax • Much lower AUC compared to IR tablets. • Aspirin detectable for up to 16 hours! • Greatest variability in plasma aspirin concentration vs. time profiles Clin. Pharmacokinet. 21:394–399, 1991. 1991

Enteric-coated Uncoated Enteric-coated

- Absorption rate - Extent of absorption

Clin. Pharmacokinet. 21:394–399, 1991. 1994

No salicylate in 33.8% of the patients!

Poor compliance was considered one of the reasons  Test repeated in a subgroup of 6 patients, and in 3 of the 6 patients (50%!) absence of plasma salicylate was confirmed.

A.P. Aihe, S.M. Halpern, P.J. Streete, P C. J R Soc Med. (1994). 87:183. 1994

BIOPHARMACEUTICS & DRUG DISPOSITION, VOL. 15, 775-788 (1994) Bioavailability of 4 EC diclofenac products:

Only one generic product was fully bioequivalent.

Several in vitro dissolution tests were conducted, however the European Pharmacopeia test did not detect any differences between the products. Comparative bioavailability and pharmacokinetics of investigational enteric- and film-coated formulations of flurbiprofen 100-mg tablets 2010

Film-coated CONCLUSIONS This small study found significant differences in the bioavailability and pharmacokinetic parameters of the Enteric-coated enteric- and film-coated flurbiprofen tablets. Thus, the 2 formulations could not be considered bioequivalent. Both formulations were well tolerated. - Absorption rate - Extent of absorption - Failure!

Clin. Ther. 32 (3) 607–613. 2013

Drug resistance to aspirin might” result in treatment failure”. “Specific phenotype of true pharmacological resistance to aspirin – genetic causes” !volunteers 400 Variable absorption caused a high frequency of apparent resistance to a single dose of 325-mg enteric coated aspirin (up to 49%) but not to immediate release aspirin (0%). The study assessed response (aggregation inhibition) – PD without PK

Apparent resistance to enteric coated aspirin We failed to find a single person who satisfied these Group 2: 49% at 4 hours criteria (genetic causes). By contrast, pseudoresistance, Group 3: 17% at 8 hours resulting from delayed and reduced drug absorption, was common after ingestion of enteric coated aspirin. 2017

Modified-release lipid-based aspirin

Objective: To determine if oral bioavailability mediates Plain aspirin nonresponsiveness. Compared with findings for plain aspirin and PL2200, this high EC aspirin rate of nonresponsiveness with EC aspirin was associated with lower exposure to acetylsalicylic acid

- Up to 70% lower Cmax and up to 82% lower AUC0–t , and up to 72% lower response (maximal decrease of TXB2), with marked interindividual variability.

Conclusions A high proportion of patients treated with EC aspirin failed to achieve complete inhibition of TXB2 generation due to incomplete absorption. Reduced bioavailability may contribute to “aspirin resistance” in patients with diabetes.

Enteric coating and bicarbonate buffer - the underlying How enteric coatings supposedly work…

Acid stage Buffer stage

H+ H2O H2O + + H H B- B- B- B- H+ B- B- H+

H+

- H+ B- B

H+ - + B- B + H H H+ - B- B

H+ H2O H2O

Unionized polymer  water insoluble Ionized polymer  Relaxes due to electrostatic repulsion Disentanglement  Swelling  Dissolution • Generally accepted concept: o An enteric polymer will quickly dissolve upon reaching an intestinal segment where the pH exceeds that of its dissolution pH threshold.

Dissolution pH • API release to the duodenum thresholds o Dissolution pH threshold of ∼5–5.5

• API release to the jejunum o Dissolution pH threshold of ∼6

• API release to the ileum and colon o Dissolution pH threshold of ∼7

〈711〉 DISSOLUTION

DELAYED-RELEASE DOSAGE FORMS Use Method A or Method B and the apparatus specified in the individual monograph. All test times stated are to be observed within a tolerance of ±2%, unless otherwise specified. ACID STAGE 0.1N Hydrochloric acid H H + H + + H H + + H + H + H + H H H + + + H +

BUFEER STAGE Buffer stage – 45 minutes Phosphate buffer 6.8

H2O H O - 2 B - - - B - B B B B-

Can be concluded in a shorter period of time if requirement for minimum B- B-

amount dissolved is met at an earlier B- B- time. B- B-

H2O H2O However, in bicarbonate buffer the situation is not quite the same…

Duodenum 2.7 – 15mM … Jejunum 2 – 20mM

Ileum 30±11 mM

The intestinal fluid is buffered by bicarbonate at molarities that are apparently not high. Bicarbonate buffer vs. phosphate buffer

Phosphate buffer

+ - H3PO4 (aq) ⇄ H (aq) + H2PO4 (aq) pKa1 = 2.12 - + -2 H2PO4 (aq) ⇄ H (aq) + HPO4 (aq) pKa2 = 7.21 -2 + -3 HPO4 (aq) ⇄ H (aq) + PO4 (aq) pKa3 = 12.44

Bicarbonate buffer

+ - H2CO3(aq) ⇄ H (aq) + HCO3 (aq) pKa: 3.55 Bicarbonate buffer vs. phosphate buffer

Phosphate buffer - + -2 H2PO4 (aq) ⇄ H (aq) + HPO4 (aq) pKa2 = 7.21

Bicarbonate buffer

+ - H2O(l) + CO2(aq) ⇄ H2CO3(aq) ⇄ H (aq) + HCO3 (aq) Bicarbonate buffer vs. phosphate buffer

Phosphate buffer - + -2 H2PO4 (aq) ⇄ H (aq) + HPO4 (aq) pKa2 = 7.21

Bicarbonate buffer

+ - H2O(l) + CO2(aq) ⇄ H2CO3(aq) ⇄ H (aq) + HCO3 (aq) pKa: 6.04 Bicarbonate buffer vs. phosphate buffer

Phosphate buffer - + -2 H2PO4 (aq) ⇄ H (aq) + HPO4 (aq) pKa2 = 7.21

Bicarbonate buffer

CO2(g)

+ - H2O(l) + CO2(aq) ⇄ H2CO3(aq) ⇄ H (aq) + HCO3 (aq) pKa: 6.04 Taking a closer look into bicarbonate buffer

 Cs  Escape of CO  2 (g) is too fast for CO2(g)  hydration and  h dehydration  reach ⇄   →  H2O(l) + CO2(aq) ← ⇄ H2CO3(aq)   BULK Taking a closer look into bicarbonate buffer

 Cs  Escape of CO  2 (g) is too fast for CO2(g)  hydration and  h dehydration reach  Bicarbonate⇄ has a lower   →  buffer capacityH2O(l) in + the CO 2(aq) H2CO3(aq)

← ⇄   BULK

boundary layer compared to + - the bulk solution. H (aq) + HCO3 (aq) i.e. the neutralization of the enteric coating occurs at a slowerEffective pKarate. in the boundary layer is lower than the apparent pKa of 6.04 in the bulk J. Al-Gousous, et. al. 2019. 2019 THE EFFECT OF A LOWER pKa AROUND Bicarbonate buffer Phosphate buffer THE POLYMER 5mM 15mM 50mM

ET: Eudragit L100-55

HP: Hypromellose phthalate

HS: Hypromellose acetate succinate

Duodenum 2.7 – 15mM

J. Al-Gousous, et. al. 2019. THE EFFECT OF A LOWER pKa AROUND Bicarbonate buffer Phosphate buffer THE POLYMER 5mM 15mM 50mM

ET: Eudragit L100-55

HP: Hypromellose phthalate

HS: Hypromellose acetate succinate

Duodenum 2.7 – 15mM

J. Al-Gousous, et. al. 2019. THE EFFECT OF A LOWER pKa AROUND Bicarbonate buffer Phosphate buffer THE POLYMER 5mM 15mM 50mM

ET: Eudragit L100-55

HP: Hypromellose phthalate Within the physiological ranges HS: Hypromellose of pH and acetate succinate bicarbonate molarity:

Dissolution is more likely to be bicarbonate molarity- Duodenum controlled rather 2.7 – 15mM than pH controlled

J. Al-Gousous, et. al. 2019. In vitro evidence • F. Liu, H.A. Merchant, R.P. Kulkarni, M. Alkademi, A.W. Basit Evolution of a physiological pH 6.8 bicarbonate buffer system: application to the dissolution testing of enteric coated products. Eur. J. Pharm. Biopharm., 78 (2011), pp. 151-157 • G. Garbacz, B. Kolodziej, M. Koziolek, W. Weitschies, S. Klein An automated system for The great discrepancy monitoring and regulating the pH of bicarbonate buffers. AAPS PharmSciTech, 14 (2013), pp. 517-522 between the typical in • F.J. Varum, H.A. Merchant, A. Goyanes, P. Assi, V. Zboranová, A.W. Basit Accelerating the dissolution of enteric coatings in the upper small intestine: evolution of a novel pH 5.6 vitro and the in bicarbonate buffer system to assess drug release. nt. J. Pharm., 468 (2014), pp. 172-177 • H.A. Merchant, A. Goyanes, N. Parashar, A.W. Basit Predicting the gastrointestinal behaviour of vivo buffers has been modified-release products: utility of a novel dynamic dissolution test apparatus involving the recognized: use of bicarbonate buffers. Int. J. Pharm., 475 (2014), pp. 585-591 • A. Goyanes, G.B. Hatton, H.A. Merchant, A.W. Basit Gastrointestinal release behaviour of modified-release drug products: dynamic dissolution testing of mesalazine formulations. Int. J. Pharm., 484 (2015), pp. 103-108 However, the • J. Al-Gousous, G.L. Amidon, P. Langguth Toward biopredictive dissolution for enteric coated dosage forms. Mol. Pharm., 13 (2016), pp. 1927-1936 compendial test with • H. Shibata, H. Yoshida, K. Izutsu, Y. Goda Use of bicarbonate buffer systems for dissolution characterization of enteric-coated proton pump inhibitor tablets. J. Pharm. phosphate buffer is Pharmacol., 68 (2016), pp. 467-474 • J. Al-Gousous, Y. Tsume, M. Fu, I.I. Salem, P. Langguth Unpredictable performance of pH- still the standard test dependent coatings accentuates the need for improved predictive in vitro test systems. Mol. Pharm., 14 (2017), pp. 4209-4219 for EC dosage forms. • F. Karkossa, S. Klein Assessing the influence of media composition and ionic strength on drug release from commercial immediate-release and enteric-coated aspirin tablets. J. Pharm. Pharmacol., 69 (2017), pp. 1327-1340

Study with Canadian commercial products 1

API Properties Does the BCS Class matter? Do Acid or Basic API characteristics influence the opening of the enteric coat? 1 2

API Properties Which enteric polymers are Does the BCS Class matter? affected? Do Acid or Basic API characteristics influence the opening of the enteric coat? ? 1 2 3

API Properties Which enteric polymers are What would be a suitable Does the BCS Class matter? affected? Quality Control Test? Do Acid or Basic API characteristics influence the opening of the enteric coat? Commercial products tested in both USP phosphate buffer (50mM) and bicarbonate buffer (5mM)

Dissolution pH Drug product BCS class pKa Coating polymer threshold

ASPIRIN Methacrylic acid I (Bayer Inc., LOT: Acid (3.41) and ethyl acrylate 5.5

NAA68A2) copolymer

ESOMEPRAZOLE II Basic Methacrylic acid (Apotex, LOT: 5.5 (4.77) copolymer type C NV2183)

Methacrylic acid – PANTOPRAZOLE Basic III ethyl acrylate 5.5 (Teva, LOT: 0691118) (3.55) copolymer

SULFASALAZINE IV Acid (3.23) Acryl resin 6 - 7 (PMS, LOT: 1037737) 100 ASPIRIN – BCS I - Acid 90 80 70

60 50

% Diss. % 40 30 20 10 0 0 50 100 150 200 250 300 350 PB BCB 100 ASPIRIN – BCS I - Acid ESOMEPRAZOLE – BCS II - Basic 90 100 80 70 80

60 60 50

% Diss. % 40 % Diss. % 40 30

20 20 10 0 0 0 50 100 150 200 250 300 350 0 50 100 150 PB BCB 100 ASPIRIN – BCS I - Acid ESOMEPRAZOLE – BCS II - Basic 90 100 80 70 80

60 60 50

% Diss. % 40 % Diss. % 40 30

20 20 10 0 0 0 50 100 150 200 250 300 350 0 50 100 150 PB 100 PANTOPRAZOLE – BCS III - Basic BCB 90 80 70

60 50

% Diss. % 40 30 20 10 0 0 50 100 150 Time (min) 100 ASPIRIN – BCS I - Acid ESOMEPRAZOLE – BCS II - Basic 90 100 80 70 80

60 60 50

% Diss. % 40 % Diss. % 40 30