Enteric Capsule Technologies to Help Fast-Track Pharmaceutical Drug Development. Eduardo Jule, PhD Director Pharmaceutical Business Development

Transcription

1 Enteric Capsule Technologies to Help Fast-Track Pharmaceutical Drug Development Eduardo Jule, PhD Director Pharmaceutical Business Development

2 Our Global Footprint 2

3 Product Range Key Services Capsugel Technology Platforms Bioavailability Enhancement Targeted Release Capsule Technologies / Encapsulation Specialized Applications Salt Screening / Selection Enteric / Delayed Release Capsule Gelatin Capsules (Coni-Snap) Taste-Masking Approaches Micronization Technologies Specialty Polymer Capsules Pediatric Applications Spray-Dried Dispersions Multi-particulate Technologies Vcaps Plus (HPMC) MP formulations Hot-Melt Extrusion Fluid-bed layering PlantCaps and OceanCaps Sprinkle Capsules Lipid-Based Formulations Liquid / Solvent-Based Formulations Nanotechnologies Nano-milling Nano-crystals Extrusion/Spheronization Lipid Multiparticulates (LMP) Mini-tabs Fixed Dose Combinations Bi/Tri Layer Matrix Capsule-in-Capsule Multiparticulates Extended / Controlled Release Osmotic / zero order release Enteric Capsules DRcaps Vcaps Enteric entrinsic DDT DPI Capsules (inhalation) Sprinkle Capsules Encapsulation Technologies Specialized Clinical Trial Capsules Biotherapeutics Bio-processing Bio-formulations Inhalation SD-based formulations Particle Engineering DPI capsules Abuse Deterrent Forms Matrix and MP / 1st order release Colonic Delivery / Liquid Fill Tech API Characterization / Pre-formulation Studies API-in-Capsule / Micro-dosing Evaluations Technology Selection Models / Methodologies Clinical Trial Material (CTM) Manufacture CTM Primary / Secondary Packaging & Distribution Commercial Manufacturing Specialized Handling (highly potent API, controlled substances, cold chain, hormones, probiotics, other) Drug Product Intermediate Hard Capsules Powder / Multi-particulate Filled Capsules Osmotic, Matrix, Orally Dissolving Tablets Liquid-filled Hard Capsules Soft Gelatin Capsules Sachet 3

4 Enteric Delivery and Limitations of Current Approaches 4

5 Why the need for enteric protection? Why enteric properties? APIs Stomach Intestine Sensitivity to Acid Sensitivity to Enzymes Local Toxicity Fast Intestinal Absorption Capsugel Research Small Molecules Biomolecules (peptides, proteins) Live organisms (bacteria, virus) Enteric protection / upper gastro-intestinal drug delivery targeting has historically been achieved primarily through functional coating. 5

6 Considerations for applying enteric coating Though enteric coating is routine and well understood, it still poses a few challenges: Functional coating is a complex process, adding 12-30% weight up to a 7-step preparation for enteric coating There are a number of key additional considerations: substrate (tablet) condition too soft = erosion too hard = poor adhesion proper balance in coat spray application coating distribution and drying sufficient protection of edges Coating defect potentials: Capping Chipping Picking Logo Bridging 6

7 Can we provide faster screening of NCE s with capsule technology? Reliance on functional coating may slow down product development 7

8 Benefits throughout the development Integrated enteric functionality in dosage form enables rapid development of prototypes for formulation screening Permits rapid testing of in vivo performance Removes need for process development and scale-up of enteric coat Minimizes scope of overall process development and validation program Obviates dependency between enteric functionality and coating process parameters and variability Minimizes risk of enteric performance changes on scale-up and stability 9 months potential savings through phase I and up to 14 months potential savings through phase III by eliminating enteric coating H2 Pharma Study 2015 Each day a drug is delayed from market, sponsors lose up to $8 million Beasely, "Recruiting"

9 Intrinsically enteric capsule technologies 9

10 A history of capsule development Gelatin Conisnap Composition Gelatin HPMC Dissolution ph dependance Vcaps Plus DRcaps Enteric HPMC HPMC + gelling agent Enteric HPMC No No Yes Yes Immediate Release Water content 13-16% Oxygen permeability Compatible with liquid or semisolid formulation Potential crosslinking issues Immediate Release <9% Can be customized Delayed release (1-hour resistance in acid medium) <9% Can be customized Enteric release (USP, EP compliant) 2-7% Yes Yes Yes Yes Yes No No No Target segment Pharma, H&N Pharma, H&N H&N Pharma 10

11 Vcaps Enteric capsule Product description Two-piece enteric hard capsule Manufactured with pharmaceutical grade of cellulosic enteric derivatives Immediate and full disintegration at ph 6.8 Sizes: Size #0 and #00 off-white available Regulatory Status Contains fully approved polymers (HPMCAS, HPMC) Complies with relevant European, Japanese and US Pharmacopeia monographs Water content: 2-7% Storage recommendations: C & 35 65% RH, in aluminium tight packaging 11

12 Vcaps Enteric: disintegration test performance Disintegration testing according to USP method Integrity of the Vcaps Enteric confirmed after 2 hours in gastric conditions ph 1.2 Capsules were not sealed (nor banded) to obtain such performance Vcaps Enteric capsules following 2-hours in gastric ph

13 % Reference API dissolved Vcaps Enteric: in vitro dissolution test performance Acetaminophen API dissolution test data Fully compliant and robust enteric release properties T = 0 3 months 40 C/75%RH open 3 months 40 C/75%RH closed Time (minutes) Method: spiral sinkers used for capsules (float w/o sinkers), 2-stage test with 2- hours gastric (750mL, HCl 0,1N) ph 1,2 then medium added at 2 hours to final: 1000mL phosphate buffer USP, ph 6.8; Acetaminophen UV detection l = 300nm; n=6. 13

14 In-vitro performance study: reducing gastric side effects Dimethyl Fumarate (TECFIDERA, Biogen) Treatment of adult patients with relapsing remitting multiple sclerosis Gelatin capsule containing enterically coated micro-tablets (anionic copolymers based on methacrylic acid and methyl methacrylate) DMF associated with flushing and stomach aches Formulation has been designed to allow to bypass the stomach and release DMF in the intestine DMF is rapidly metabolized at the level of the gastrointestinal tract to its primary, active metabolite Vcaps Enteric as potential alternative to enteric coated micro-tablets in capsule Test conditions (USP): Conditions: n=6 ; spiral sinkers 2-stage test with 2-hours gastric (750mL, HCl, 0,1N) then medium added at 2 hours to final: 1000mL 0.20M tribasic sodium phosphate, ph 6.8, 100 rpm, HPLC- UV DMF 240mg directly filled in Vcaps Enteric Grinded micro-tablets filled in Vcaps Enteric 14

15 In vitro performance study: delaying release to maximize absorption Budesonide (ENTOCORT, AstraZeneca) Corticosteroids used to treat the inflammation of the small bowel and the first part of the large bowel, known as Crohn s disease Gelatin capsule containing enterically coated saccharose based microgranules (anionic copolymers based on methacrylic acid and methyl methacrylate) Release in the ileum and ascending colon where the API is more favorably absorbed Vcaps Enteric as potential alternative to enteric coated microgranules in capsule Test Budesonide: Conditions: 9µgA/mL (9mg into 1L); n=6 ; spiral sinkers used for capsules (float w/o sinkers), 2-stage test with 2 hours gastric (500mL, 100mM HCl) then medium added at 2 hours to final: 1000mL 95mM phosphate buffer w/0.5% Kolliphor HS15, ph 6.8; 100 rpm, Test Ref: IRD (HPLC-UV) Budesonide pure API directly filled in Vcaps Enteric 15

16 In vitro performance study: allowing release on site of action Bisacodyl (DULCOLAX, Boehringer) Laxative used for relief of constipation (OTC) Enterically coated tablet (anionic copolymers based on methacrylic acid and methyl methacrylate) Local action stimulating colonic motility Vcaps Enteric as simple alternative to enteric coated tablet Test Bisacodyl: Conditions: 5µgA/mL (5mg into 1L); n=6 ; spiral sinkers used for capsules (float w/o sinkers), 2-stage test with 2- hours gastric (500mL, 100mM HCl) then medium added at 2 hours to final: 1000mL 95mM phosphate buffer w/0.5% SLS, ph 6.8; 100 rpm, Test Ref: 092 (HPLC-UV) Amorphous bisacodyl pure API directly filled in Vcaps Enteric 16

17 In vivo behavior of Vcaps Enteric Study synopsis (Center of Drug Absorption & Transport, University of Greifswald, DE) MR imaging study with 8 healthy volunteers in fasted state Vcaps Enteric capsules formulated with dry pineapple (opaque to MRI, used as tracer) Primary evaluation : Disintegration time and location In-vivo behavior of Vcaps Enteric Demonstration of gastro-resistance Disintegration occurs in ileum No evidence for influence of gastric residence time on intestinal disintegration time Variability of time to disintegration similar to coated enteric tablet 17

18 entrinsic Drug Delivery Technology Product description Two-piece enteric hard capsule Manufactured with 100% pharmaceutical grade of cellulosic enteric derivatives Size #0 & #3 standard (additional sizes upon request) White opaque standard for capsules (specific colors upon request) Regulatory Status Contains fully approved enteric polymers Complies with relevant European, Japanese and US Pharmacopeia monographs Water content: 2-7% Stability: After storage in HDPE bottles and blisters no change in dimensions and enteric 40 C/75%RH for 6 30 C/65%RH 12 5 C 9 20 C 9months 18

19 entrinsic enteric protection using highly acid sensitive drug Rationale Esomeprazole Magnesium Trihydrate selected as an acid labile model compound which can act as a model for peptides, nucleotides, vaccines, live biotherapeutics for which gastric stability is limited (acid and enzymes) Very fast degradation in acid medium with a solution becoming yellow/brown Nexium (gelatin capsules with enteric coated pellets) Acid stage HCl 0.1N No unit more than 10% Degradation of EMT No unit less than 80% (Q+5%) ph 6.8 Buffer stage OBSERVATIONS 1. Acid stage Quick dissolution of the gelatin capsules No dissolution of the pellets % EMT dissolved after 120 min (mean) = 0% 2. Buffer stage Complete dissolution of pellets % EMT dissolved after 30 min (mean) = 94% 19

20 % dissolved entrinsic enteric protection using highly acid sensitive drug Rationale Esomeprazole Magnesium Trihydrate selected as an acid labile model compound which can act as a model for peptides, nucleotides, vaccines, live biotherapeutics for which gastric stability is limited (acid and enzymes) Very fast degradation in acid medium with a solution becoming yellow/brown entrinsic filled with EMT layered uncoated pellets Average dissolution profile of entrinsic TM (N = 6 capsules, with SD interval) Acid stage HCl 0.1N Specification: No unit more than 10% No unit less than 80% (Q+5%) ph 6.8 Buffer stage Sampling time (min) In acid stage, the amount of Esomeprazole released is below the limit of quantification of the analytical method. entrinsic provides an effective protection of Esomeprazole content from acid degradation and therefore meets requirements of USP monograph for Esomeprazole delayed-release capsules. 20

21 entrinsic Technology Human Biostudy Protocol Randomized, open-label, single dose and crossover pharmacokinetic and gamma pharmacoscintigraphy study conducted using healthy volunteers under fasted state Radiolabeled pellets added to both entrinsic capsules and Nexium RLD capsules in order to detect location of capsule opening in the GI tract Study treatments entrinsic RLD Nexium One radiolabelled enteric capsule filled with layered uncoated pellets containing 40mg EMT given in fasted state (i.e. an overnight fast of at least 10 h) One radiolabelled Nexium gelatin capsule containing 40mg enteric-coated pellets of EMT given in fasted state (i.e. an overnight fast of at least 10 h) NEXIUM and the color purple as applied to the capsule are registered trademarks of the AstraZeneca group of companies Scintigraphy imaging (SI) Anterior & posterior images acquired at dosing + regular time points Pharmacokinetic study (PK) Blood sampling at pre-dose + regular time points post-dose 21

22 Scintigraphy studies on entrinsic capsule drug delivery technology Scintigraphy images Site of onset release entrinsic (n = 12) Esophagus 0 Stomach 0 Small intestine 11 Ileocaecal junction 1 No release and remain in stomach after 12h No release and remain in small intestine after 12h 0 0 Anterior scintigraphy images confirmed that, in fasted conditions, entrinsic capsules integrity in the stomach, with gastric emptying occurring within 60 min and followed by rapid opening of capsules and pellets release in duodenum 22

23 entrinsic Immediate Release for intestinal delivery: Esomeprazole Pharmacokinetic profile The high Esomeprazole plasma concentration confirmed that the drug was not degraded in stomach and achieved intact its absorption site in intestine The fast entrinsic capsule opening and pellets release in duodenum is also demonstrated by the fast onset of Esomeprazole in plasma, followed by a quick and complete Esomeprazole absorption Despite different dosage forms (monolithic entrinsic versus Nexium enteric coated pellets) human PK profiles of entrinsic and Nexium showed similar extent of drug absorption and Tmax in fasted state 23

24 Conclusions 24

25 Selecting the appropriate enteric solution for your product Protecting the stomach from aggressive APIs Delaying the release to achieve maximum absorption Protecting a sensitive molecule from acidic environment Vcaps Enteric EP/USP compliant enteric capsule Easy to implement solution for gastric-irritating actives or delayed release Ready to use capsule entrinsic Drug Delivery EP/USP compliant Full gastro protection and enteric release Enabling technology for oral delivery of heat and acid sensitive molecules DDT available under license Addressing needs of small molecules and biopharmaceuticals 25

26 Competitive Advantages Rapid Advancement Tool for NCEs & Biopharmaceuticals Easy to implement solution in early stages of development Eliminate coating process complexity Potential nine months cumulative savings in development Product Differentiation for Generic / 505b2 / CHC Efficient solution for tailored delayed or modified release profile (alone or in combination with multiparticulate approach) Powerful brand differentiation for CHC Potential IP circumventing tool Manufacturing efficiency through reduced process complexity QbD approach Compatible with high speed filling machine and continuous manufacturing Six Sigma Quality 26

27 Thank You! Questions? 27