qd diffucaps drug delivery systems for weakly basic ... · qd diffucaps® drug delivery systems for...

1

QD Diffucaps® Drug Delivery Systems forWeakly Basic Pharmaceutical Actives

Abstract

Lack of compliance to dosing regimens is widespread largely dueto complicated regimens (e.g., too many medications, too frequentdosing) and swallowing difficulties. Eurand’s Diffucaps® technologyenables the development of once-daily controlled-release (CR) capsules or patient-compliant orally disintegrating tablet formulations(ODT – CR) comprising immediate-release (IR), sustained-release(SR), timed pulsatile-release (TPR) or timed sustained-release (TSR)bead populations multicoated with a weakly basic drug, an organicacid or an alkaline buffer, and a solid-solution and then furthercoated with one or more functional polymers.

Introduction

• Complicated regimens (too many medications, too frequent dosing) and physical difficulties in complying (e.g., handlingsmall tablets, swallowing difficulties, timely accessibility todrinks) are often cited as factors responsible for non-complianceor lack of adherence to dosing regimens, which has become amajor medical problem in America costing billions of dollars.

• Drug delivery systems such as sustained-release (SR) multi-particulate capsule or matrix tablet formulations, amorphous/nanocrystalline or solid solution formulations, and organicacid- or effervescent-containing formulations have been developed to enhance absorption of the drug throughoutthe human digestive tract to reduce the frequency of dosing.

• Many pharmaceutical actives are weakly basic and exhibitpH-dependent solubility profiles. Further, in the human digestive track, a drug will experience varying pHs (for example,

stomach: pH 1.2–3.5, duodenum: pH 4.6–6.0, small intestine:pH 4.7–6.5, large intestine: pH 7.5–8.0); varying fluid volumes(for example, 45 mL vs. 686 mL in the stomach, 105 mL vs.54 mL in the small intestine, and 13 mL vs. 11 mL in the largeintestine in the fasted vs. fed states); surface area (stomach:0.1–0.2 square meter (sq-m), small intestine: 4,500 sq-m, largeintestine: 0.5–1 sq-m); and transit times (stomach: 0.25–3 hrs,duodenum: 1–2 hrs, small intestine: 1–10 hrs, large intestine:4–20 hrs) that depend on factors such as dosage form andfasted/fed conditions1–4. The drug must be released fromthe dosage form in solution form; otherwise, it is generallynot absorbed. Consequently, the ability to apply enhanced absorption systems to develop controlled-release (CR) products has been limited.

• Eurand’s Diffucaps® technology allows development and commercialization of weakly basic drugs with varying pH-dependent solubility profiles (e.g., ondansetron, carvedilol,EUR-1057, nifedipine) based on lag-time coating and (1) useof solubility-enhancing organic acids, (2) solubility-retardingalkaline buffers, and/or (3) use of crystallization-inhibitingpolymers (solid-solution approach).

• Eurand’s Diffucaps® technology allows development and commercialization of drug delivery systems of weakly basicdrugs with varying but pH-independent solubility profiles (e.g.,methylphenidate, propranolol, cyclobenzaprine) for customizeddelivery as needed, i.e., to deliver drugs in quantities whenneeded to mimic circadian rhythm variations of disease states.

G. Venkatesh1, J. Lai1, N.H. Vyas1, P.J. Stevens1, M. Gosselin1, J. Clevenger1, P. Percel1, P. Gatti2, C. Strollberg2, F. Fabiani2,L. Boltri2, L. Mapelli2, and I. Colombo2

1. Eurand Inc., Vandalia, OH 45377 (USA); 2. Eurand S.p.A., Pessano con Bornago, Milan (Italy)

For more information about our portfolio of proprietary pharmaceutical technologies,please visit www.AptalisPharmaceuticalTechnologies.com.

Aptalis Pharmaceutical Technologies, formerly Eurand Pharmaceutical Technologies

Diffucaps®

2

Experimental Methods

• Eurand’s Diffucaps® technology involves (1) the preparation of drug-containing cores such as immediate-release (IR) beads, pellets ormicrotablets (e.g., typically 2 mm or less in diameter) obtained by (1) layering drug on inert cores, extrusion-spheronization, controlledspheronization, or granulation-compression, (2) applying one or more coatings with proprietary functional polymers, and (3) combiningone or more coated, spherical, multi-layered bead populations (Fig. 1) into hard gelatin or hydroxypropyl methylcellulose (HPMC) capsules2 or blending with rapidly dispersing granules and compressing into orally disintegrating tablets (ODTs)5 (Fig. 1).

• In case of weakly basic drugs requiring an organic acid to solubilize the drug prior to its release into the intestine, a drug-containingcore (e.g., an acid crystal or an inert core layered with the acid) is coated with a water-insoluble polymer to sustain the acid releaseand to prevent the acid from coming into contact with the weakly basic drug. The SR acid-cores are coated with the drug as well asone or more polymer membranes to produce CR capsules containing IR and/or timed pulsatile-release (TPR) bead populations6.

• A weakly basic drug and a crystallization-inhibiting/solubility-enhancing polymer are dissolved in a solvent mixture and coated ontoinert cores. The polymer inhibits the drug from returning to crystalline form while maintaining it in the thermodynamically activated(i.e., amorphous) state7.

• IR beads containing extremely soluble drugs, such as EUR-1057, are coated with an alkaline buffer prior to coating with functionalpolymers to create an alkaline pH microenvironment that retards drug release. The polymer-coated beads are further coated with acompressible coating to eliminate/minimize membrane fracture during compression8.

Results and Discussion

• Cyclobenzaprine, freely water-soluble, is a novel centrally acting drug administered to relieve skeletal muscle spasm of local origin.Cyclobenzaprine is well absorbed after oral administration with a relatively long half-life, but with a suspected short pharmacologicalactivity. Amrix® is the first and only FDA-approved, once-daily skeletal muscle relaxant (Fig. 2) providing significant reduction in patient-rated daytime drowsiness9–11.

Fig. 1: Diffucaps® CR beads in capsules or in ODT - CR

Inert Core

Drug + Binder

CR CapsulesSeal Coat

ODT - CR

Functional Polymer Coating

= Amrix® 30 mg= Cyclobenzaprine 10 mg TID= Therapeutic cyclobenzaprine level

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• Stimulant therapy of school-going children with attention-deficit/hyperactivity disorder (ADHD) with a scheduled drug such asmethylphenidate requires the development of a modified-release dosage form to avoid dispensing the drug during the school hours.Metadate CD®, a capsule formulation containing 30% of the dose as IR for rapid onset of action upon dosing at breakfast and the remaining 70% of the dose for continued action until bedtime, is compared with Concerta®, an expensive osmotic device that usesthe OROS® technology, in Fig. 312,13.

• InnoPran XL®, a chronotherapeutic dosage form designed to be dosed at bedtime, provides therapeutically effective concentrations inthe morning hours to prevent or minimize target organ damage from morning cardiovascular events (Fig. 4)14,15.

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Fig. 2: Plasma Profiles of cyclobenzaprine from Flexeril® (10 mg IR) dosed 3 times daily vs. Amrix® (ER capsule) dosed once daily

Fig. 3: Plasma Profiles of Metadate CD® compared to expensive Concerta®

– Amrix® with reduced sedation is better tolerated compared to Flexeril®

– Metadate CD® containing a scheduled CNS stimulant was initially developed to avoid medication of children with ADHD during school hours as it allows medicating just once daily at breakfast

– The extended-release capsules comprise 30% of the dose as immediate-release (IR) beads for rapid onset of action and 70% of the dose as extended-release (ER) beads for extended effect during the day until bedtime

Fig. 4: Plasma Profiles of InnoPran XL vs. Inderal LA

InnoPran ®XL

Chronot cifically designed to coincide with me catecholamine levelsAd4 hour delayed release to achieve Cmax in the early morning hours

during the night when less is neededSuperior bioavailability to Inderal LA®.

InnoPran ®XL®

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• Ondansetron, a serotonin receptor antagonist, is freely soluble < pH 3.0 and is practically insoluble > pH 6.0, thereby making it difficultto develop once-daily (q.d.) formulations. By creating an acidic pH microenvironment within the polymer-coated bead to solubilize thedrug prior to its release into the hostile pH environment, the formulation has demonstrated its suitability for a q.d. dosing regimen(Fig. 5)8,16,17.

• Maximizing the surface area and optimizing the drug load and polymer-coating composition while maintaining the drug in the amorphousstate dramatically shifts the poorly soluble drug’s solubility/absorption kinetics, enabling the development of q.d. dosage forms of poorlysoluble drugs (e.g., nifedipine)7.

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Ondansetron QD Test Formulations Ratios)

EUR-1025 provides consistent therapy by elitrough in PK curve

(hours ~5–10) between doses of

IR Zofran

Zofran® IR, BID

Fig. 5: Plasma Profiles of Ondansetron QD (EUR-1025) vs. Reference (Zofran® IR) Dosed BID

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– Chronotherapeutic release formulation specifically designed to coincide with daytime catecholamine levels – Administration at bedtime – 4 hour delayed release to achieve Cmax in the early morning hours – Lower plasma concentration during the night when less is needed – Superior bioavailability to Inderal LA®

– EUR-1025 achieved similar plasma concentration at 24 hours post dosing v. BID dosing of IR product • N = 12 healthy subjects

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• EUR-1057, an atypical antipsychotic agent, is extremely soluble in the physiological pH range (e.g., > 700 mg/mL), thereby insufficientlyextending drug release/absorption from coated beads under 500 µm to provide patient-compliant, once-daily, orally disintegrating tabletformulations. By creating an alkaline pH microenvironment at the drug-alkaline buffer interface within the polymer-coated bead, therebyretarding drug’s solubility/release, Eurand could develop alternate bioequivalent dosage forms – CR capsules and ODT CR (Fig. 6 &7)8,18.

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Fig. 6: Release Profiles for EUR-1057 Once-daily ODT-CR and CR Capsules

– Patient-friendly once-daily ODT CR also developed to improve patient compliance – EUR-1057 CR beads are provided with a compressible coating to minimize membrane fracture during tableting

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• For a CR ODT, the most critical parameter is being able to develop a product with reproducible dissolution profiles. Coated beads aretypically rigid and encounter breakage issues upon compression into ODTs. The Diffucaps® beads are coated with a compressiblecoating to eliminate/minimize membrane fracture during tabletting (Fig. 7).

Conclusion

• Combining one or more Diffucaps® bead populations into CR dosage forms provides therapeutically effective plasma concentrationprofiles suitable for q.d. dosing regimens.

REFERENCES:

1. Davis SS, Hardy JG, Fara JW. Transit of pharmaceutical dosage forms through the small intestine. Gut. 1986 Aug; 27(8): 886–92.

2. Chawla G, et al. Gastroretention: A means to address regional variability in intestinal drug absorption. Pharm Technol. 2003; July: 50–68.

3. Schiller C, et al. Intestinal fluid volumes and transit of dosage as assessed by magnetic resonance imaging. Aliment Pharmacol Ther.2005; 22: 971–979.

4. Gupta PK, Robinson JR. Oral controlled release delivery, In: Kydonieus A (ed). Treatise on controlled drug delivery. Marcel Dekker, Inc.New York; 1992; 255–313.

5. Venkatesh G. Diffucaps technology for controlled release drug delivery. In: Youan BC (ed). Chronotherapeutics: Science and Technologyfor Biological Rhythm Guided Therapy and Prevention of Diseases. New York: John Wiley & Sons; 2009: 122–142.

6. Ventakesh GM. Drug delivery systems comprising weakly basic drugs and organic acids. United States Patent 20070190145, August 23,2007.

7. Ventakesh G, Boltri L, Colombo I, et al. Drug delivery systems comprising solid solutions of weakly basic drugs. United States Patent20080069878. March 20, 2008.

8. Ventakesh GM, Stevens PJ, Lai JW. Compositions comprising melperone. United States Patent 20100151021. June 17, 2010.

9. Ventakesh G, Clevenger JM. Modified release dosage forms of skeletal muscle relaxants. United States Patent 7, 387,793, US 7,544,372,US 7,790,199.

Fig. 7: Plasma Profiles for EUR-1057 QD, 50 mg vs. 25 mg Syrup

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ndly once-daily ODT-CR1 and CR capsules are bioequivalent

Cmax of 50 mg ODT-CR1 and CR capsules comparable to that of 25 mg Syrup

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Conclusion


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Conclusion


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– Patient-friendly once-daily ODT-CR1 and CR capsules are bioequivalent

– Cmax of 50 mg ODT-CR1 and CR capsules comparable to that of 25 mg Syrup

7

10. Darwish M, Chang S, Hellriegel ET. A pharmacokinetic comparison of single doses of once-daily cyclobenzaprine extended-release 15mg and 30 mg: a randomized, double-blind, two-period crossover study in healthy volunteers. Clin Ther. 2009; 31(1): 108–14.

11. Malanga GA, et al. Cyclobenzaprine ER for muscle spasm associated with low back and neck pain: two randomized, double-blind,placebo-controlled studies of identical design. Curr Med Res Opin. 2009; 28: 1179–1196.

12. Battman MJ, Percel PJ, Hensley DL, Vishnupad KS, Ventakesh GM. Methylphenidate modified release formulations. US 6,344,215.

13. Swanson JM. A comparison of once-daily extended-release methylphenidate formulations in children with attention-deficit/hyperactivitydisorder in the laboratory school (the Comacs Study). 2004; 113 (3part 1): e206–216.

14. Percel PJ, Vishnupad KS, Ventakesh GM. Timed sustained release systems for propranolol. US 6,500,454.

15. Sica D, Frishman WH, Manowitz N. Pharmacokinetics of propranolol after single and multiple dosing with sustained release propranololor propranolol CR (innopran XL), a new chronotherapeutic formulation. Heart Dis. 2003 May–Jun; 5(3): 176–81.

16. Ventakesh G, Lai J, Vyas NH, Purohit V. Drug delivery systems comprising weakly basic drugs and organic acids. United States patent20090232885. September 17, 2009.

17. Ventakesh G, Perrett S, Thieroff-Eherdt R. Methods of treating PDNV and PONV with extended release ondansetron compositions.United States Patent Application Ser. No. 12/688,493 filed on July 6, 2010.


1

QD Diffucaps® Drug Delivery Systems forWeakly Basic Pharmaceutical Actives

Abstract

Lack of compliance to dosing regimens is widespread largely dueto complicated regimens (e.g. too many medications, too frequentdosing) and swallowing difficulties. Eurand’s Diffucaps® technologyenables the development of once-daily controlled-release (CR) capsules or patient-friendly orally disintegrating tablet (ODT) CRcomprising immediate-release (IR), sustained-release (SR), timedpulsatile-release (TPR) or timed sustained-release (TSR) bead populations multicoated with a weakly basic drug, an organicacid, and a solid-solution and then further coated with one ormore functional polymers.

Introduction

• Complicated regimens (too many medications, too frequent dosing) and physical difficulties in complying (e.g. handlingsmall tablets, swallowing difficulties, timely accessibility todrinks) are often cited as factors responsible for non-complianceor lack of adherence to dosing regimens, which has become amajor medical problem in America costing billions of dollars.

• Drug delivery systems such as sustained-release (SR) multi-particulate capsule or matrix tablet formulations, amorphous/nanocrystalline or solid solution formulations, and organicacid- or effervescent-containing formulations have been developed to enhance absorption of the drug throughoutthe human digestive tract to reduce the frequency of dosing.

• Many pharmaceutical actives are weakly basic and exhibit pH-dependent solubility profiles. Further, in the human digestivetract, a drug will experience varying pHs (e.g., from pH 1.0 in

the stomach under fasted conditions to pH ~7.4 in the large intestine) and transit times that depend on factors such asdosage form and fasted/fed conditions1. The drug must be released from the dosage form in solution form; otherwise,it is generally not absorbed. Consequently, the ability to applyenhanced absorption systems to develop controlled-release(CR) products has been limited.

• Eurand’s Diffucaps® technology allows development and commercialization of weakly basic drugs with varyingpH-dependent solubility profiles (e.g., cyclobenzaprine, propranolol, ondansetron, carvedilol, nifedipine, EUR-1057)based on (1) lag-time coating, (2) use of solubility-enhancingorganic acids, and/or (3) use of crystallization-inhibiting polymers (solid-solution approach).

Experimental Methods

• Eurand’s Diffucaps® technology involves (1) the preparationof drug-containing cores such as immediate-release (IR) beads,pellets or microtablets (e.g., typically 1.5 mm in diameter) obtained by layering drug on inert cores, (2) controlled spheronization or granulation-compression using one ormore coatings with proprietary functional polymers, and(3) combining one or more coated, spherical, multi-layeredbead populations (Fig. 1) into hard gelatin or hydroxypropylmethylcellulose (HPMC) capsules2 or blending with rapidlydispersing granules and compressing into orally disintegratingtablets (ODTs) (Fig. 2).

G. Venkatesh1, J. Lai1, N.H. Vyas1, P.J. Stevens1, M. Gosselin1, J. Clevenger1, P. Percel1, P. Gatti2, C. Strollberg2, F. Fabiani2,L. Boltri2, L. Mapelli2, and I. Colombo2

1. Eurand Inc., Vandalia, OH 45377 (USA); 2. Eurand S.p.A., Pessano con Bornago, Milan (Italy)

For more information about our portfolio of proprietary pharmaceutical technologies,please visit www.AptalisPharmaceuticalTechnologies.com.

Aptalis Pharmaceutical Technologies, formerly Eurand Pharmaceutical Technologies

qd diffucaps drug delivery systems for weakly basic ... · qd diffucaps® drug delivery systems for...

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