Oral Drug Delivery: Formulation Selection Methods & Novel Delivery Technologies

ORAL DRUG DELIVERY: FORMULATION SELECTION METHODS & NOVEL DELIVERY TECHNOLOGIES

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www.ondrugdelivery.com “Oral Drug Delivery: Formulation Selection Approaches CONTENTS & Novel Delivery Technologies”

This edition is one in the ONdrugDelivery series of pub- No Longer a Hit-or-Miss Proposition: lications from Frederick Furness Publishing. Each issue focuses on a specific topic within the field of drug deliv- Once-Daily Formulation for Drugs with ery, and is supported by industry leaders in that field. pH-Dependent Solubility Gopi Venkatesh, Director of R&D & Anthony Recupero, EDITORIAL CALENDAR 2011: Senior Director, Business Development June: Injectable Drug Delivery (Devices Focus) Aptalis Pharmaceutical Technologies 4-8 July: Injectable Drug Delivery (Formulations Focus) September: Prefilled Syringes A possible approach for the desire to innovate October: Oral Drug Delivery Brian Wang, CEO & Dr Junsang Park, CSO November: Pulmonary & Nasal Drug Delivery (OINDP) GL PharmTech 10-13 December: Delivering Biotherapeutics

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“Oral Drug Delivery: Formulation Selection Approaches Solumer™ Technology: a Viable Oral Dosage & Novel Delivery Technologies” is published by Form Option for BCS Class II Molecules Frederick Furness Publishing. Dr Robert Lee, Vice-President, Pharmaceutical Development & Dr Amir Zalcenstein, CEO Copyright © 2011 Frederick Furness Publishing. SoluBest, Ltd 26-29 All rights reserved Controlled Drug Release: Novel Time-Delayed Formulations and their Clinical Evaluation Dr Carol Thomson, Chief Operating Officer Drug Delivery International Ltd 30-32

Liquid-Fill Hard Two-Piece Capsules: The Answer to Many Product Development Issues The views and opinions expressed in this issue are those of the authors. Mr Gary Norman, Product Development Manager Due care has been used in producing this publication, but the publisher Encap Drug Delivery 34-36 makes no claim that it is free of error. Nor does the publisher accept liability for the consequences of any decision or action taken (or not taken) as a result of any information contained in this publication. Multi-Tip Tooling: A Guide

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NO LONGER A HIT-OR-MISS PROPOSITION: ONCE-DAILY FORMULATION FOR DRUGS WITH PH-DEPENDENT SOLUBILITY

In this article, Dr Gopi Venkatesh, Director of R&D, and Dr Anthony Recupero, Senior Director, Business Development, both of Aptalis Pharmaceutical Technologies (formerly Eurand), describe a specific application of Diffucaps® technology, which allows the creation of once-daily oral formulations of weakly basic active pharmaceutical ingredients, previously extremely difficult to achieve, but with significant benefits to patient adherence.

MEDICATION ADHERENCE tion is important for the kinetics of drug absorption. The dosage form and hence the pharma- It is estimated that 33-69% of all medication- ceutical ingredient (API) is subjected to varying related hospital admissions in the US are due pH levels during GI transit.13-16 Specifically, pH to poor medication adherence, with a resultant varies from a minimum of about 1.2 to a maxi- cost of approximately US$100 billion a year.1-6 mum of around 7.4 (stomach pH: 1.2-2.5, which Taking medications exactly as prescribed and increases to 3.5-6.1 upon consumption of food; following appropriate lifestyle recommenda- bile pH: 7.0-7.4; pH 5.0-6.0 in small intestine; tions is highly beneficial and may reduce the and pH: 6 to 7 in the large intestine). Gopi Venkatesh, PhD impact of side effects. GI fluid volume and agitation can vary sig- Director of R&D Practitioners should always assess adher- nificantly, which has substantial impact on drug ence to therapy and may improve adherence by dissolution and absorption.17 Moreover, transit emphasising the value of a patient’s regimen, time may vary significantly in individual parts making the regimen as simple as possible, and of the GI tract, depending on individual size and customising the regimen to the patient’s life- prevailing local conditions.18 style.7 Simple dosing (one pill, once daily) can Truly once-daily dosage forms of many weak- help maximise adherence, particularly when ly basic drugs are not commercially available. combined with reinforcing visits / messages Several attempts have been made in the past from healthcare practitioners, despite the fact at developing once-daily delivery systems of that 10-40% of patients on simple regimens weakly basic drugs, such as carvedilol, ondanse- Anthony Recupero, PhD continue to have imperfect dosing adherence.8,9 tron, and dipyridamole, with limited success.19-22 Senior Director, Business This is largely because the absorption of a weakly Development T: +1 267 759 9346 WHY AREN’T ONCE-DAILY ORAL basic drug is critically affected by its solubility E: [email protected] DOSAGE FORMS AVAILABLE FOR and the required total daily dose. The ability to ALL DRUGS? maintain these drugs in a soluble form as the drug Aptalis Pharmaceutical passes through the GI tract throughout the day has Technologies As the orally administered pharmaceutical been a substantial challenge for oral formulators. 790 Township Line Road dosage form passes through the human gastro- Suite 250 intestinal (GI) tract, drug should be released SOLUBILITY ENHANCEMENT BY Yardley, PA 19067 United States from the dosage form and be available in solu- ORGANIC ACIDS tion at or near the optimal site for drug absorp- www.AptalisPharmaceutical tion to occur.10-12 The rate at which the drug is The solubility-enhancing property of Technologies.com released from a dosage form and goes into solu- organic acids23 is exploited during the manu-

4 www.ondrugdelivery.com Copyright © 2011 Frederick Furness Publishing Figure 1: Diffucaps®– Customised Drug Release Bead (A) soaked in pH 1.2 or resident in the stomach and (B) soaked in pH 6.8 or in transit in the intestinal tract. facture of customised-release (CR) dosage During dissolution testing in two-stage dis- DEVELOPMENT OF ONCE-DAILY forms using Diffucaps® technology. The solution media (first two-hour dissolution test- DOSAGE FORMS OF WEAKLY potential for in situ formation of acid addition ing in 700 mL of 0.1N HCl and thereafter BASIC DRUGS compounds24 is averted by using a sustained- testing in 900 mL of pH 6.8 buffer obtained release (SR) coating membrane between the by adding 200 mL pH modifier) or upon oral Below is shown the method for the prepara- inner organic acid layer and the weakly basic administration, water or body fluid is blocked tion25 of CR drug delivery systems comprising drug layer. The SR-coating membrane thus from imbibing into the core as the polymeric one or more IR, SR, TPR/TSR, Delayed-Release applied, precisely controls the release of the system is impermeable in the acidic medium (DR) bead populations, themselves containing organic acid ensuring drug is not retained in or gastric fluid. When the pH of the medium a weakly basic, nitrogen moiety-containing API the dosage form for lack of solubilising acid is changed to 6.8 or following exit from the such as ondansetron, carvedilol, dypiramidole, in the Diffucaps® formulation. stomach, the penetrating dissolution medium or lamotrigine or iloperidone, which is moderately intestinal fluid selectively dissolves the enteric soluble at pH <4, but it is practically insoluble at DIFFUCAPS® TECHNOLOGY polymer molecules or molecular clusters start- a pH >6, and at least one pharmaceutically accept- ing from the outermost membrane layer, thereby able organic acid as a solubiliser (see the schemat- Diffucaps® technology in its simplistic creating tortuous nanopore channels for dis- ics of SR organic acid bead & TPR/TSR bead form (see Schematic of the Time Pulsatile solved drug to pass through.23 containing a weakly basic drug shown in Figure 2). Release / Time Sustained Release (TPR/TSR) The tortuosity increases with increasing The method comprises the following steps: bead shown in Figure 1) involves the prepara- coating thickness and/or decreasing enteric a) layering an organic acid on 25-30 mesh sugar tion of: polymer content, and consequently, the drug spheres; (1) drug-containing cores by drug-layering on release from the TPR beads having no barrier b) applying an SR coating on acid-layered beads inert particles coat becomes sustained with increasing thick- with a water-insoluble polymer to control the (2) customised release (CR) beads by coating ness of the TPR coating. rate of release of the acid; immediate release (IR) particles with one or more functional dissolution rate controlling polymers or waxes (3) combining one or more functional polymer coated Diffucaps® bead populations into hard gelatin or hydroxypropyl methylcel- lulose (HPMC) capsules.24

MECHANISM OF DRUG RELEASE FROM TPR/TSR BEADS

The water-insoluble and enteric polymers are dissolved in a common solvent mixture and the solution is sprayed onto drug particles. These two polymers may exist as molecularly dispersed or as molecular clusters in the lag- time coating membrane applied on the drug Figure 2: Diffucaps®: Customised Drug Release Bead for pH-sensitive Drugs cores (Figure 1). (e.g. Ondansetron HCl).

Modified release (MR), once-daily dosage forms of ondansetron HCl dihydrate using Diffucaps® technology Pharmacokinetic/biopharmaceutical modeling and simulation of possible plasma profiles based on available pharmacokinetic data as a guide in the design of customised-release (CR) dosage forms in order to be suitable for a once- daily dosing regimen is typically performed using WinNonlin® and/or GastroPlus™ computer simulation and modeling techniques. The CR capsule product was designed to comprise appropriate amounts of both IR and TPR components wherein the TPR component used SR-coated organic acid beads as inert cores to design multiple TPR bead populations with different lag times.33 The use Figure 3: Pilot PK Study - Ondansetron QD versus Ondansetron IR (Zofran®). of such methods resulted in reduced feasibility development time and enhanced the probability c) preparing IR beads by layering the weakly Nausea and vomiting very often occur together of success of the program. basic nitrogen moiety-containing API and but can also occur independently. RINV and For the IR component of the formulation, applying a protective seal-coat with a water- CINV during cancer therapy can have a direct rapid release (RR) granules comprising ondan- soluble polymer; and significant impact on adherence to primary setron, mannitol, and organic acid were devel- d) preparing SR beads by applying a barrier therapy. Some of the most highly prescribed anti- oped, which are designed to release the drug (SR) coating of a water-insoluble polymer emetics suffer from a short-half life requiring mul- faster than, or similar to, Zofran® IR tablets even on the IR beads to sustain the drug release tiple daily doses for control of emesis. Between under alkaline pH conditions.33 over several hours (if needed); doses, the plasma levels of the anti-emetic can Ondansetron HCl CR capsules were e) preparing TPR beads by applying a lag-time drop well below efficacious levels increasing designed to comprise appropriate amounts of coating on IR beads or SR beads (called the risk for breakthrough nausea and vomiting, both RR granules and TPR beads. Three CR TSR beads) comprising water-insoluble and particularly when subsequent doses are not taken formulations were prepared for pharmacokinetic enterosoluble polymers for a weight gain exactly as scheduled. Proper control of acute and (PK) testing in healthy volunteers.33 sufficient to achieve a lag time (a time period breakthrough nausea and vomiting therefore can A randomised, four-way crossover pilot PK of less than 10% drug release) of 2-6 hours be achieved with a higher probability and a higher study was conducted that included 12 healthy followed by a sustained-release profile; and level of confidence with a customised-release male volunteers, aged 18-55 years, with a wash- f) filling into a capsule a mixture of IR beads (CR) dosage form for oral administration, prefer- out period of seven days. Each volunteer was and one or more TPR bead populations at ably administered prior to the procedure. dosed with one of three test formulations of appropriate amounts to achieve a target phar- Ondansetron MR at 0800h, or two Zofran® (8 macokinetics profile suitable for a once-daily Weakly basic ondansetron HCl dihydrate mg) at 0800h and 1630h after an overnight fast. dosing regimen. Ondansetron HCl dihydrate, the API in the Figure 3 shows the mean plasma concentration- branded product, Zofran® Tablets (4 and 8 mg time profiles achieved. The relative bioavail- The following examples demonstrate how base equivalent) and Zofran® Oral Solution, ability compared with 8 mg IR bid reference Aptalis Pharmaceutical Technologies utilised marketed by GlaxoSmithKline, is a selective was approximately 0.85 for all test formulations the above process to formulate once-daily dos- serotonin 5-HT3 blocking agent (an antiemetic). (Test Formula 1, 2, and 3) at the end of 24 hours. age forms of ondansetron and iloperidone. The API in Zofran® ODTs (orally disintegrating Based on these results, Test Formula 3, given tablets, 4 and 8 mg) is ondansetron base. All the product code EUR1025, was advanced into NAUSEA AND VOMITING products are immediate release (IR) formulations. pivotal PK studies which have been completed.34 FOLLOWING CHEMOTHERAPY, Ondansetron is indicated for the prevention of In these trials, single and repeated oral adminis- RADIATION THERAPY, OR SURGERY nausea and vomiting associated with radiotherapy trations of 24 mg EUR1025 resulted in similar (adults: 8 mg tid) and/or chemotherapy (adults: rate and extent of exposure as 8 mg Zofran® tid. Radiotherapy-induced nausea and vomit- 8 mg bid to tid) and prevention of postoperative Steady-state concentrations of Treatment 2 (8 mg ing (RINV), chemotherapy-induced nausea and nausea and/or vomiting (adults: 8 mg bid). Zofran® bid) and Treatment 3 (8 mg Zofran® tid) vomiting (CINV), and postoperative nausea and Ondansetron is a weakly basic drug having a are equivalent to that of single administrations of vomiting (PONV) remain the most common and pKa of 7.4 and an elimination half-life averag- two and three 8 mg Zofran®, respectively.34 The distressing challenges facing patients receiving ing approximately 3.8±1 hours. It is practically total exposure of ondansetron (AUC0-24) from these cancer therapies or following surgical pro- insoluble in the pH environment of the intestinal EUR1025 on day six was approximately 13% cedures under general anaesthesia (occurring in tract. However, there is a dramatic increase higher than that observed on day one, suggesting up to 80% of cases).25-33 in solubility in aqueous organic acid solution, minor accumulation following repeated dosing.

6 www.ondrugdelivery.com Copyright © 2011 Frederick Furness Publishing The total exposure of Treatment 1 (24 mg incompatible actives or actives requiring dif- 6. Horwitz RI, Horwitz SM. Adherence to treat- EUR 1025) appears to be nearly equivalent to fering target plasma profiles ment and health outcomes. Arch Intern Med that of Treatment 3 (8 mg Zofran® tid) at steady • Capability to create micro-environments: 1993;153:1863-8. state. The product is now ready to enter Phase III – Create a sustainable acidic pH micro-envi- 7. Osterberg, L, and Blaschke, T. Adherence to clinical development.34 ronment within coated bead to solubilise Medication. N Engl J Med 2005; 353:487-97. the weakly basic drug (which is practically 8. Greenberg RN. Overview of patient compli- ILOPERIDONE TPR BEADS AND insoluble at pH 6.0 or above) in order to ance with medication dosing: a literature RELEASE PROFILES extend its release into the GI tract review. Clin Ther 1984;6:592-9. – Create a sustainable alkaline pH micro- 9. Eisen SA, Miller DK, Woodward RS, The Diffucaps® organic acid approach used environment within coated bead to moder- Spitznagel E, Przybeck TR. The effect of with ondansetron is applicable to any weakly ate the solubility of a weakly basic drug prescribed daily dose frequency on patient basic drug, which is at least slightly soluble at a (which is extremely soluble in the entire medication compliance. Arch Intern Med pH≤3, but is poorly soluble or practically insolu- physiologically relevant pH range of 1.0 to 1990;150:1881-4. ble above pH 6. Iloperidone, the API in Fanapt®, 8.0) to avoid dose dumping 10. P.K. Gupta, J.R. Robinson, “Oral controlled is a weakly basic, dopamine and serotonin recep- • Improve patient adherence due to reduced fre- release delivery”, in: “Treatise on controlled tor antagonist exhibiting antipsychotic activities. quency of dosing, ease of oral administration, drug delivery”, Kydonieus, A. (ed.), Marcel Iloperidone (12 mg) is dosed twice daily. reduction in incidence of adverse events, and/ Dekker, New Jersey (1992) 255-310. The incidence of adverse effects in or improved safety profile 11. R.E. Notari, “Biopharmaceutics and clini- patients treated with Fanapt® 20-24 mg/day • Additional product patent protection cal pharmacokinetics”, Marcel Dekker, were twice that occurring in patients treated Inc., New York, 1987. with Fanapt® 10-16 mg/day indicating an MR, CONCLUSIONS 12. D.J. Greenblatt, L.L. van Moltke, once-daily formulation may improve the side J.J. Harmatz, and R.I. Shader, effect profiles of iloperidone. Initial studies Adherence to oral medication regimens, Pharmacokinetics, pharmacody- indicate that by combining IR and TPR bead and therefore effective therapy, is a common namics, and drug disposition”, In: populations at appropriate quantities (as deter- issue for patients across multiple indications. “Neuropsychopharmacology”, K.L Davis, mined by simulation and modeling) to provide Although simple dosing regimens (one pill, D. Charney, J.T. Coyle, and C. Nemerof desired in vitro release profiles, it would be once daily) as provided by extended release (eds), Lippincott, Williams & Wilkins, possible to achieve target plasma profiles suit- (ER) formulations for a number of products Philadelphia, (2002) 507-524. able for a once-daily dosing regimen. are available, there are still many drugs for 13. G. Chawla, P. Gupta, V. Koradia, and which an ER, once-daily form has proven to A.K. Bansal, “A means to address regional ADVANTAGES OF CR DIFFUCAPS® be exceptionally challenging to develop. These variability in intestinal drug absorption”, DRUG DELIVERY SYSTEMS challenging molecules frequently have water Pharm. Technol., July 2003, 50-68. solubility issues which may also be complicated 14. Davis, S.S., 1987. Evaluation of the gas- Controlled-release drug delivery systems by limited molecule half-life. trointestinal transit and release charac- consisting of coated multiparticulates, particu- The Diffucaps® technology is one approach teristics of drugs. in. Johnson, P., Lloyd- larly based on Diffucaps® technology, which that effectively overcomes such challenges, Jones, J.G. (Eds), Drug Delivery systems typically have a particle size in the range of 200- allowing for straightforward development of [Fundamentals and techniques]. Ellis 600 μm, exhibit characteristic target in vitro ER, once-daily formulations that help to improve Harwood, Chichester, pp. 164-179. profiles, as well as target plasma concentration- adherence, which can result in improved effi- 15. J.B. Dressman, R.R. Berardi, L.C. time profiles to be suitable for a once-daily cacy and patient quality of life. Dermentzoglou, T.L. Russell, S.P. dosing regimen. Schmaltz, J.L. Barnett, K.M. Jarvenpaa, Multiparticulate drug delivery systems, such REFERENCES Upper gastrointestinal (GI) pH in young as Diffucaps®, offer the following advantages healthy men and women, Pharm. Res. 7 over conventional controlled-release monolithic 1. McDonnell PJ, Jacobs MR. Hospital admis- (1990) 756–761. dosage forms such as matrix or coated tablets sions resulting from preventable adverse reac- 16. C. Schiller, C.P. Prohlicht, T. Giessmann, including osmotic delivery systems: tions. Ann Pharmacother 2002; 36:1331-6. W.,Siegmund, H. Monnikess, and N. • Dispersed along the GI Tract for more effec- 2. Senst BL, Achusim LE, Genest RP, et al. Hosten, “Intestinal fluid volume and transit tive delivery Practical approach to determining costs of dosage forms as assessed by magnetic • Predictable and consistent GI transit time and frequency of adverse drug events in a resonance imaging”, Aliment. Pharmacol. thereby minimising food effect healthcare network. Am J Health Syst Pharm Ther., 22 (2005) 871-879. • Low probability of dose dumping 2001; 58:1126-32. 17. Davis, S.S., Hardy, J.G., Taylor, M.J., • Reduced inter- and intra-subjectvariability 3. Levy G, Zamacona MK, Jusko WJ. Developing Whalley, D.R., Wilson, C.G., 1984. A com- • Easy adjustment of multiple dose strengths compliance instructions for drug labeling. parative study of the gastrointestinal transit Clin Pharmacol Ther 2000;68:586-91. of a pellet and tablet formulation. Int. J. In addition, the Diffucaps® technology offers 4. Berg JS, Dischler J, Wagner DJ, Raia JJ, Pharm. 21, 167-177. incremental advantages: Palmer-Shevlin N. Medication compliance: 18. W. Eisert and P. Gruber, “US 6,015,577 • Easy adjustment of target plasma profiles a healthcare problem. Ann Pharmacother B1: Pharmaceutical compositions con- including combining bead populations exhibit- 1993;27:Suppl 9:S1-S24. taining dipyridamole or mopidamol and ing differing release profiles 5. LaRosa JC. Poor compliance: the hidden risk acetylsalicylic acid or the physiologically • Ability to create combination products of factor. Curr Atheroscler Rep 2000;2: 1-4. acceptable salts thereof; processes for

Copyright © 2011 Frederick Furness Publishing www.ondrugdelivery.com 7 preparing them and their use in treat- 25. J.L. Parlow, A.T. Meikle, J. v. Vlymen, N. Singla, H. Minkowitz, A.S. Habib, J. ing clot formation”, assigned to Dr. Karl “Post discharge nausea and vomiting after Knighton, A.D. Carides, H. Zhang, K.J. Thomae GmbH. ambulatory laparoscopy is not reduced by Horgan, J.K. Evans, F.C. Lawson, and 19. G.K. Jain, O. Anand, and A. Rampal, “WO promethazine prophylaxis”, Can. J. Anesth. The Aprepitant-PONV Study Group, “A 2004/096182 A1: Extended release matrix 46 (1999) 719-724. randomzed, double-blind comparison of the tablets of carvedilol”, assigned to Ranbaxy 26. T.J. Gan, R. Franiak, J. Reeves, NK1 antagonist, Aprepitant, versus ondan- Laboratories Limited. “Ondansetron orally disintegrating tablet setron for the prevention of postoperative 20. V. Andronis, K. A. Lamey, and C.K. Oh, versus placebo for the prevention of post- nausea and vomiting”, Anesth. Analg. 104 “US 20040019096 A1: Novel formulations discharge nausea and vomiting after ambu- (2007) 1082-1089. of carvedilol”, assigned to SmithKline latory surgery”, Anesth. Analg. 94 (2002) 31. P.C. Feyer, E. Maranzano, A.M. Beecham Corporation. 1199-1200. Molassiotis, F. Roila, R.A. Clark-Snow, 21. February 6, 2007 at 3:00 PM: (Business 27. F. Roila, P.J. Hesketh, J. Herrstedt, and K. Jordan, Radiotherapy induced nau- Wire) Scolr Pharma announces positive “Antiemetic Subcommittee of the sea and vomiting (RINV): MASCC/ESMO results from its Second 24 Hour CDT Multinational Association of Supportive guideline for antiemetics in radiotherapy: Ondansetron Trial at http://www.scolr.com. Care in Cancer. Prevention of chemo- Update 2009”, Support Care Cancer 22. G. Venkatesh, “US 20070196491 A1: Drug therapy and radiotherapy induced emesis: Published online: 10 August 2010, DOI delivery systems comprising weakly basic results of the 2004 Perugia International 10.1007/s00520-010-0950-6. drugs and organic acids”, assigned to Antiemetic Consensus Conference, Ann. 32. B. Nevidjon and R. Chaudhary, Controlling Eurand, Inc. Oncol. 17 (2006) 20-28. emesis: Evolving challenges, novel strate- 23. G. Venkatesh, “Diffucaps® technology 28. T.J. Gan. “Risk factors for postoperative gies”, The J. Support. Oncol. 8 (2010) 1-10. for controlled release drug delivery”, In. nausea and vomiting” Anesth. Analg. 102 33. G. Venkatesh, J.-W. Lai, N.H. Vyas, and V. Chronotherapeutics”, B.-B.C.Youan (Ed.), (2006) 1884-98. Purohit, “US 20090232885 A1: Drug deliv- John Wiley & Sons, New York (2009) 29. D.S. Wagner, V. Gauger, D. Chiravuri, ery systems comprising weakly basic drugs 121-144. and K. Faust, “Ondansetron oral disinte- and organic acids”, assigned to Eurand, Inc. 24. R. Sun, K.W. Klein, and P.F. White, grating tablet for the prevention of post- 34. G. Venkatesh, S. Perrett, and R. Thieroff- “The effect of timing of ondansetron operative vomiting in children undergoing Ekerdt, “US 20090232885 A1: Methods administration in outpatients undergoing strabismus surgery”, Ther. Clin. Risk of treating PDNV and PONV with ER Otolaryngologic surgery”. Anesth. Analg. Manag. 3 (2007) 691-694. Ondansetron compositions”, assigned to 84 (1997) 331-6. 30. T.J. Gan, C.C. Apfel, A. Kovac, B.K. Philip, Eurand, Inc.

A POSSIBLE APPROACH FOR THE DESIRE TO INNOVATE

Here, Hunsik (Brian) Wang, Chief Executive Officer, and Junsang Park, PhD, Chief Scientific Officer, both of GL PharmTech, introduce GLARS, a novel concept extended-release triple- layered tablet delivery technology for delivery to the intestine and colon.

How did you feel when you heard your brand drug delivery products captured about 10% of product was easily copied by a generic company the top 200 product sales, which reportedly after the expiration of its new chemical entity reached US$14.5 billion. patent? And what about the case when someone from sales & marketing came and complained UNDER PRESSURE FOR of setbacks in developing a pre-defined refor- REFORMULATION mulation product?... For various reasons, with which readers As product developers using oral drug deliv- will already be familiar, individuals working ery technology, GL PharmTech is constantly in pharmaceutical product development and considering what gaps innovators want to fill in formulation have been under significant pres- their currently marketed products. What should sure for some time. This pressure may have be the factor to drive reformulation? made possible various kinds of open-innovation There are many reasons why currently mar- by prompting the adoption of technologies or keted products could be reformulated. These products from outside. can originate from aspects of marketing, manu- The drug delivery industry has been work- facturing, regulation, generic competition, and even sometimes a purely scientific basis. These various rea- “HOW DID YOU FEEL sons can come alone, together, or complicatedly combined. WHEN YOU HEARD YOUR BRAND Therefore, a single outside PRODUCT WAS EASILY COPIED technology or reformulated product could not fill all the gaps BY A GENERIC COMPANY AFTER or cover possible voids the inno- Hunsik (Brian) Wang vator did not feel compelled to Chief Executive Officer T: +82 31 739 5220 (Ext. 102) THE EXPIRATION OF ITS NEW address at one time. This might F: +82 31 739 5034 CHEMICAL ENTITY PATENT?” be the driving force for why E: [email protected] innovative pharma companies have their departments of devel- Dr Junsang Park Chief Scientific Officer ing as an innovator and excellent partner over opment review outside technology as often as T: +82 31 739 5220 (extension 301) the past 30 years, providing technologies that possible and compile it in their databases. F: +82 31 739 5220 have enabled brand pharmaceutical compa- Whenever we imagine someone at an inno- E: [email protected] nies to take new steps. This is surely one rea- vator company trying to align all the variables son why the number of reformulated products to find a fit for their molecules or products GL PharmTech reached about triple that of new chemical with outside drug delivery technologies, the 138-6 Sangdaewon Jungwon entities (NCEs) in 2009 (75 versus 26).1 As picture gives a strong feeling that a new drug Seongnam Republic of Korea (South Korea) a player in the oral drug delivery field, we at delivery player might be what is required to GL PharmTech were pleased to note that oral make every thing click together.

NEEDS FOR MEETING A NEW CONCEPT IN ORAL EXTENDED RELEASE

This situation could be particularly true in the field of oral extended-release dosage forms. ® The first big successes – OROS from Alza Figure 2: Morphological changes in GLARS upon water contact (now Johnson & Johnson, New Brunswick, NJ, US) and Geomatrix® from Skyepharma Praf T®. Mirabegron has been in Phase III clini- structure. As long as the surrounding water (London, UK) – had a large impact in the field cal trials in various countries. penetrates into the tablet core, it can perform its of oral extended-release drug delivery technol- The reformulated OCAS tamsulosin product role to diffuse outward from the core. During ogy. However, there has not since been a other was reported to show not only higher night-time the diffusion process the water can also move strong player showing a comparable, remark- maintenance of plasma concentrations during upwards and downwards, and this additional able success, and the platform patents of both but also no food effects upon its pharmacoki- diffusion, together with the diffusion of GI fluid technologies have expired. In addition, the rela- netic profiles.5, 6 present outside the tablet, allows the upper and tively short gastro-intestinal transit time cannot lower layers to be quickly swollen and gelled, expectedly or unexpectedly give a new start GLARS: A NOVEL INTESTINAL AND at the same time. to blockbuster products, even by applying the COLONIC EXTENDEND-RELEASE As is already recognised in the field, a already-existing technologies. In other words, TECHNOLOGY conventional matrix sustained-release tablet the molecule candidates on the market or under has its own erosion, diffusion, swelling front, development must have a suitable half-life for The focus of GL PharmTech over the past and un-swollen intact core. Achieving com- those technologies to be applied. ten years has been on developing a technol- plete swelling of a tablet without an intact Recently, a novel oral extended release tech- ogy named GLARS (Geometrically Long core before considerable erosion during normal nology was presented. Astellas Pharma (Tokyo, Absorption Regulated System). The system gastro-intestinal transit time has appeared to be Japan; formerly Yamanouchi Pharma) suggest- entraps more gastro-intestinal fluid into the dos- challenging. From this standpoint the insertion ed a possible cause for limited absorption in the age form at early dissolution time to give further of a highly water-penetrating middle layer into colon and developed a new dosage form capable extended absorption in the colon. GLARS was a radical approach. of dragging and retaining gastro-intestinal fluid We have now reached a remarkable milestone. Another feature of this system is rapid into the dosage form itself, which could, in turn, During the course of our work, we fabricated a enclosing of the tablet’s lateral side with the act as drug-releasing media in the colon.3, 4 triple-layered tablet, where the drug and very upper and lower layers in a relatively short time. They found another main reason for mal- hydrophilic excipients are incorporated into the As shown in Figure 3, after closing, drug release absorption in the colon to be that there was middle layer while highly water-retaining and is mainly demonstrated through the enclosed no additional surrounding fluid present for swellable materials are embedded in the upper lateral side, where the orange colour (from the active substance in dosage form to be released and lower layers (see Figure 1). incorporated colourant) in the middle layer is from, and described how this limitation could After oral administration, the surrounding much thicker than on the other sides. be overcome to some degree by incorporating GI fluid can penetrate very quickly into the highly water-retaining polymers into the dosage middle layer, thus the upper and lower layers PROOF OF CONCEPT form. They named this technology OCAS (Oral concurrently swell rapidly. These rapidly swol- Controlled Absorption System). len upper and lower layers enclose the lateral Tamsulosin Up until now, Astellas has applied this tech- side of the middle layer in quick-time (as shown The first target for determining whether this nology to at least two products, according to the in Figure 2). system could actually operate was the block- literature, including tamsulosin, a global lead- The amount of water drawn into the tablet buster molecule, tamsulosin.8 Marketed under ing drug for anti-benign prostatic hyperplasia reaches about 3-5 times the weight of the tablet the name Harnal®, as well as Flomax®, this (BPH), and mirabegron, an anti-incontinence itself and it can function, in turn, as additional product was originally formulated into enteric- drug. The reformulated tamsulosin product has media which enables further later drug release out matrix granules in a hard gelatin capsule. In been on sale in European regions under various of the dosage form when it passes into the colon.7 Asia, including Japan and Korea, a normal local brand names such as Alna OCAS®, Omnic The key feature of GLARS is the middle dose is 0.2 mg, compared with 0.4 mg in the OCAS®, Flomaxtra XL®, Urolosin OCAS® and layer, where it horizontally divides the tablet Americas and Europe.

Copyright © 2011 Frederick Furness Publishing www.ondrugdelivery.com 11 Tianeptine Another proof on concept study was carried out with tianeptine, an anti-depressant, developed and marketed under the name Stablon® by Servier (Neuilly-sur-Seine, France). The purpose of the application was to determine whether the system could reduce the number of daily administrations for better patient compliance. Figure 5 represents the results of the pharmacokinetic study, where the total amount of the API was the same, 37.5 mg. In terms of the pharmacokinetic parameters, no large difference was shown between Tianeptine GLARS (GX-2903) once daily, and three-times-daily administration of the immediate-release dosage form. Of course, this should be further evaluated to determine whether this kind of plasma profile Figure 3: Schematic representation of rapid water penetration through middle layer as is clinically effective and comparable with the well as swelling and enclosing of upper and lower layers performance of existing immediate-release dosage forms. As presented in Figure 4, Tamsulosin the very close relationship of peak concentra- GLARS, including a double amount of the API tion versus adverse effects, for which extended CREATING EARLY PARTNERSHIPS (0.4mg), showed a nearly similar peak con- release dosage forms are desired. centration to Harnal® containing only 0.2 mg Another finding in the application was that Several oral drug delivery technologies have of the API. Nonetheless, the extent of absorp- the therapeutic concentration was persistent come and gone, and new systems still emerge tion, AUC, was not reduced but, instead, nearly even during the night. Considering reports that even today. However, their fates appear to be doubled. nocturia is a key worry frequently raised by very similar to those of NCEs. Approximately When considering normal cases of most BPH patients, longer duration of action at night five years is needed to demonstrate any phar- types of drug product with dose proportionality could be a very meaningful step for meeting maceutical or clinical evidence of one technol- – the greater the dose administered, the propor- patients’ ongoing needs.9 ogy. In addition, reformulated products must be tionally higher the pharmacokinetic parameters The relatively rigid swollen matrix structure exclusively marketed for at least ten years.

Cmax and AUC. However, the GLARS system of GLARS formulations allows drug release to Then, we, as drug delivery industry workers, demonstrated a proportionally higher extent of be unaffected by surrounding mechanical flux, have only five years between showing evidence absorption without a remarkable increase in the which can provide relatively consistent in vivo and launching a product into market. rate of absorption. This result suggests that the drug release irrespective of the degree of gastro- Another aspect to be considered is that system can be applied to types of drugs with intestinal motility. there comes a time when additional innovative pharmaceutical applications are needed over the previously much-used simple matrix-type sustained release form. When exclusivity expires, there is the likely tendency of copying by generic companies in a very short time. Considering both aspects in combination, the marriage of the NCE with the drug delivery system, through a partnership between pharma company and drug delivery company, should be created as early as possible. Early partnering would represent a great step towards securing more valuable next-generation reformulated products.

REFERENCES:

1. Rekhi GS. “Advances in solid dose oral Product Cmax (ng/mL) AUCt (hr ng/mL drug delivery.” ONdrugDelivery: Oral drug ® Harnal (0.2mg; qd) 5.16±0.97 69.6±22.3 Delivery & Advanced Excipients, 2010, 14-18. GLPT’s GLARS (0.4mg; qd 6.60±2.70 114.34±39.9 2. Bossart J .“Oral drug delivery: the numbers behind the business.” Figure 4: Pharmacokinetic profiles of Tamsulosin GLARS, which shows doubled extent ONdrugDelivery: Oral drug Delivery & of absorption without a dose-proportional increase of peak concentration Advanced Excipients, 2010, 4-6.

12 www.ondrugdelivery.com Copyright © 2011 Frederick Furness Publishing tion rate of control-release acetaminophen tablets containing polyethylene oxide and colonic drug release in dogs.” Pharm Res, 1996, 13(4), 594-598. 5. Michel MC et al. “The pharmacokinetic profile of Tamsulosin oral controlled absorption system(OCAS®).” Eur. Urol. Suppl. 2005, 4, 15-24 6. Djavan B et al. “The impact of Tamsulosin oral controlled absorption system(OCAS) on nocturia and the quality of sleep: pre- liminary results of a pilot study.” Eur Urol Suppl, 2005, 4, 61-68. 7. Park JS et al. “A novel three-layered tablet for extended release with various layer formulations and in vitro release profiles.” Product Cmax (ng/mL) AUCt (hr ng/mL Drug Devel Ind Pharm, 2011, 37 (in press). 8. Park JS et al. “Formulation variation and Stablon® (12.5mg x tid) 335±107.6 2705.3±601.8 in vitro-in vivo correlation for a rapidly GLPT’s GLARS (37.5mg qd 359.2±74.2 2849.7±622.9 swellable three-layered tablet of Tamsulosin HCl.” Chem Pharm Bull, 2011, 59 (in Figure 5: Pharmacokinetic profiles of Tianeptine GLARS, which shows the possibility of press). once daily administration 9. Schulman CC et al. “The impact of nocturia on health status and quality of 3. Sako K et al. “Influence of physical fac- the 6th Conference of the Academy of life in patients with lower urinary tract tors in gastrointestinal tract on acetami- Pharmaceutical Science and Technology, symptoms suggestive of benign prostatic nophen release from controlled-release Japan. 1990, 30-31. hyperplasia(LUTS/BPH).” Eur Urol Suppl, tablets in fasted dogs.” Proceedings of 4. Sako K et al. “Relationship between gela- 2005, 4, 1-8.

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ous drug delivery technologies. The in-market sion and marumerisation to form a drug sales of products developed at the Salisbury, core with a polymer coat. Australia facility using its technologies are in • The second process is known as spheroni- excess of US$500 million per year. sation, where the drug particles are fixed to the outside of a seed core (typically a sugar Mayne Pharma’s drug delivery systems sphere). This process provides a very tight include: size distribution of pellets. Drug potencies up to 60% are possible. A leading pharmaceutical organisation built Technology to control drug release on a heritage of 160 years of industry excel- To enable pulsed release, extended release, For both of the processes above, the desired lence, Mayne Pharma International is a and delayed release profiles (pellet/bead drug release profile is achieved by coating market-driven company offering a range of formulations produced using extrusion and these particles with an appropriate polymer. drug delivery technologies. Mayne Pharma marumerisation, or spheronisation processes, Mayne Pharma International has particular International offers contract development see below). Pellets may be tabletted or encap- expertise in polymer selection and process- and commercial manufacture for oral and sulated. This technology is very flexible and ing. The company can also work with a wide topical pharmaceutical products. it can be adapted to the specific formulation range of solvent systems. needs of a particular drug substance. Mayne Pharma International has comprehen- SUBA™ sive experience in the solid oral Drug Delivery Technology to improve oral bioavailability System (DDS) market, encompassing develop- Particularly for insoluble drugs (SUBA™ SUBATM is a novel technology for enhanc- ment and manufacture of these products. technology, see below). ing the bioavailability of poorly water soluble drugs utilising a solid dispersion of drug The company has: Technology to taste mask liquids and tablets in various polymers. To improve palatability and aid swallowing • more than 30 years’ experience in suc- (Cleantaste™ technology, see below). SUBATM has been shown to double the cessfully developing DDS products for the oral bioavailability of itraconazole when global market TECHNOLOGY TO CONTROL compared with the innovator product • a dedicated product development facility DRUG RELEASE (Sporanox®). which meets cGMP standards, and includes pilot-scale plant equipment; this allows a Pellet (or bead) technology allows a vari- CLEANTASTE™ scale-up pathway from small clinical trial ety of different drug delivery profiles to be batches to full commercial manufacture achieved by coating drug and excipient with Cleantaste™ technology allows a polymer • proven ability to develop and successfully various polymers. The drug cores are gener- coat to be applied to very small particles transfer manufactured product and technol- ally spheroidal in shape and have a diameter (25-150 μm diameter) to improve taste. It ogy to other sites around the world in the range of 300-1,700 μm. Pellets can be is also possible to use this technology to • intellectual property and formulation presented in capsule or tablet dosage forms. improve stability or to deliver sustained capabilities to help with product life cycle release characteristics. The fine, non-gritty management. Two types of process are used to generate texture of product produced by this tech- the spheroidal particles (see diagram): nology lends itself to being used in orally Mayne Pharma International has been grant- • The first of these processes, which allows dispersible tablet and liquid formulations, as ed, or applied for, patents that protect its vari- drug potencies up to 90%, utilises extru- well as encapsulated products. Cleantaste™ acetaminophen and ambroxol have been commercialised and launched in Australia, the US and Japan.

SERVICES SUMMARY

Mayne Pharma International can develop and manufacture oral and topical formulations for clinical trials and commercial supply. Mayne Pharma International can provide:

• Tablets (immediate, extended, delayed or pulsed release and taste masked) • Capsules (powder, pellets (beads) Pellet technology used for controlled release formulations. • Liquids and Creams

14 www.ondrugdelivery.com Copyright © 2011 Frederick Furness Publishing Placebo formulations can be provided to contract development and manufacturing • 9 patent families match client specifications or innovator company for oral and topical pharmaceuti- • 48 registered patents product. Packaging and labelling can be cal products. • 14 pending applications completed to customer requirements. Mayne Pharma international competes in Mayne Pharma International is located at In addition to its drug delivery technologies, the oral drug delivery, branded, generic and Salisbury (Adelaide), South Australia. There Mayne Pharma International offers a number value-added API markets. The oral pharma- is 12,000 m2 of manufacturing space on a of specialty services: ceutical business at Salisbury, Australia, is a 19-hectare site. Mayne Pharma International GMP facility. is a wholly owned subsidiary of Mayne • Formulation Development Pharma Group Ltd, an Australian public Annual production capacity: company listed on the ASX. Provide solutions to a range of common formulation challenges such as poor solubil- • 2,500 million capsules and tablets ity, poor bioavailability, short half life, low • 100 tonnes of bulk product Cmax, poor powder flow, non-uniform crys- • 16 million units of liquids and creams Mayne Pharma International tal size and scale-up issues. PO Box 700 The site is approved by all major regulatory Salisbury ABOUT MAYNE PHARMA authorities: South Australia 5108 Australia

A leading pharmaceutical organisation • FDA: United States built on a heritage of 160 years of • MHRA: UK T: +61 8 8209 2604 F: +61 8 8281 6998 industry excellence, Mayne Pharma • TGA: Australia E: [email protected] International is a market-driven company • TPD: Canada offering a range of drug delivery technolo- Mayne Pharma International has generated www.maynepharma.com gies. Mayne Pharma International offers numerous patents in the drug delivery field.

Making the right choice of formulation for the first-into-human studies of a product candidate is extremely important and has significant time and cost implications for the development programme. Here, Robert Harris, PhD, Director, Early Development at Molecular Profiles, describes various formulation options available and suggests methods that can be used to select the best formulation option for a new orally delivered drug substance.

A new experimental drug substance shows molecules based on certain molecular attributes. great promise from pre-clinical studies for the The BCS has proved a useful tool to formu- treatment of a disease which afflicts millions of lators for classifying drug substances, but its patients worldwide. What is the best strategy for primary purpose is for establishing criteria for testing the drug in man for the first time? This biowaivers, and alternative ‘developability’ clas- is a question that all companies developing new sification systems have recently been proposed.3,4 drugs face on a regular basis. How well a drug is absorbed into the blood- Entering Phase I clinical trials is a key stream from the gastro-intestinal tract (GIT) is milestone in any drug development project and governed predominantly by (i) drug solubility in to reach this stage as quickly as possible is of the gastric and intestinal fluids and (ii) perme- paramount importance – especially for those ability through cell lipid bilayers. BCS Class I with limited budgets. Of equal importance is to drugs are freely soluble in GIT fluids and perme- ensure that the new drug substance is adminis- ate easily through lipid bilayers. These drugs are tered in a form that will give it the best chance well absorbed when given orally and present the of success in early clinical assessment. A poor easiest task when choosing a formulation strat- choice of formulation strategy can lead to poor egy. BCS Class IV drugs on the other hand are clinical data – which can lead to re-formulation defined as poorly soluble (in GIT fluids) and per- and a prolonged Phase I clinical programme, or meate poorly across lipid bilayers. Consequently, even termination of the project. these drugs exhibit poor oral bioavailability and So how do you decide what is the best for- pose the formulator the greatest challenge. Dr Robert Harris mulation for a new drug, assuming at this stage Director, Early Development that it is intended for oral administration? Additional physicochemical and biological fac- T: +44 115 871 8883 F: +44 115 871 8889 tors which can challenge formulators are: E: [email protected] KNOW YOUR DRUG SUBSTANCE • Drug instability: – during processing or in the formulation (e.g. Molecular Profiles Ltd From preclinical studies, there should be apomorphine) 8 Orchard Place sufficient information to be able to define the – in the GIT (e.g. when drug is acid labile, as Nottingham Business Park drug according to its water-solubility and per- with omeprazole). Nottingham meability characteristics in accordance with the • Narrow absorption window in the intestine NG8 6PX United Kingdom biopharmaceutics classification system (BCS).1 (e.g. acyclovir, captopril). Also, Lipinski’s “Rule of Five” 2 is a useful tool • Drug metabolism and/or efflux within the www.molprofiles.com in predicting the oral bioavailability of drug intestinal wall (e.g. cyclosporin A).

Drug absorption and metabolism can vary ing a drug-in-capsule/bottle approach, it should Particle size reduction between animal species and therefore it is not be considered with caution if the compound is Increasing the overall surface area of a solid always possible to predict the influence of bio- not BCS Class I. If a drug substance does not can lead to more rapid dissolution of the drug sub- logical factors (e.g. pre-systemic metabolism) wet easily or if its solubility in water is poor the stance. Micronising equipment (e.g. fluid energy on drug uptake in humans from preclinical drug may be poorly absorbed from the GIT and mills) can reduce particle size down to 2-10 animal studies. hence exhibit poor bioavailability. If there is a μm. Taking the principle of size reduction even known history of poor or variable absorption in further, there are now technologies available to DECIDE ON A FORMULATION animal models then a formulation strategy to produce submicron ‘nanocrystals’ through pre- STRATEGY enhance water-solubility of the drug substance cipitation (bottom up) or wet milling (top down) should be considered. techniques.7,8 Following particle size reduction For first-into-human studies it is usual to Two basic principles for enhancing water- the drug substance can be dispensed into capsules, administer the drug either as powder-in-bottle solubility of the drug substance are (i) reduction either as drug alone or as a powder blend (with (for reconstitution prior to administration) or in of the particle size of the drug substance and (ii) excipients), depending on the required dose and capsules, which offer the greatest flexibility for use of solubility-enhancing vehicles. flow properties of the milled drug substance. dose adjustment. Choosing a formulation will Brief descriptions of typical solubility- depend on the properties of the drug substance enhancing formulation strategies are given Solubility-enhancing vehicles and the target dose. Decision trees can be very below. Regardless of the formulation strategy For each of the strategies described below effective tools in helping select the most appro- chosen, it is vital to assess drug solubility fol- the resulting formulation can be filled into priate formulation strategy.5,6 Figure 1 is an lowing dilution of the test formulations in capsule shells for administration. Capsule fill- example of a decision tree which can be used to aqueous media. The dissolution test procedures ing machines which are suitable for this pur- select a suitable formulation strategy for first- used should simulate both gastric and intestinal pose include the IN-CAP® (Dott. Bonapace, into-human clinical trials. conditions (in terms of pH, fluid volume, etc). Limbiate, Italy), suitable for powders or liq- The simplest formulation strategy is not to uids/semi-solids, and the CFS 1200 (Capsugel) formulate – just administer the drug substance which is suitable for liquids/semi-solids. with no additional excipients. In this case the required quantity of drug active is added directly Solution/semi-solid capsule formulations: to a container (for reconstitution with a suitable If the drug can be dissolved in a suitable liquid prior to ingestion) or to a capsule. This pharmaceutically acceptable vehicle then it may approach is widely used within the industry as be appropriate to consider preparation of a solu- it significantly reduces the time and cost for tion of the drug which can be filled into cap- progressing to first-into-man studies. For small sules. The main benefit of this approach is that quantities of units the active is weighed into pre-dissolving the compound overcomes the each capsule or bottle by hand. For large quanti- initial rate limiting step of particulate dissolu- ties of capsules or where the required dose is tion in the aqueous environment within the GIT. < 10 mg, capsule filling can be achieved accu- However, a potential problem is that the rately by use of specialised precision powder drug may precipitate out of solution when dosing equipment (for example, Xcelodose® the formulation disperses in the GIT, par- (Capsugel, Peapack, NJ, US), as shown in ticularly if the solvent is miscible with water Figure 2). (e.g. polyethylene glycol). If the drug is suf- The ‘drug-in-capsule/bottle’ approach is par- ficiently lipophilic to dissolve in a lipid vehicle ticularly suited for BCS Class I compounds, there is less potential for precipitation on dilu- which are absorbed easily from the GIT. Figure 2: Xcelodose® precision powder tion in the GIT, as partitioning kinetics will Although there are obvious benefits in adopt- dispenser. favour the drug remaining in the lipid drop-

Copyright © 2011 Frederick Furness Publishing www.ondrugdelivery.com 17 physical stability of such formulations needs to be assessed using techniques such as differential scanning calorimetry (DSC) and X-ray crystallography. For formulations in which the drug is to be dissolved (in liquid or solid vehicles) miscibility of the drug substance with the vehicle is a key requirement – to maximise water-solubility of the drug and to maintain the physical stability of the formulation (i.e. prevent drug precipitation). A comparison of the solubility parameters for drug and excipients can be used to predict miscibility of the drug the excipients.13,14,15 The closer together the solubility parameters are between drug and excipient the higher the probability of the drug and excipient being miscible. An example of how this information can be used to gauge miscibility of drug with excipients is illustrated in Figure 3. The graph shows that the polymer with the closest spatial proximity to acetaminophen is HPMC and we would therefore expect there to be a high probability that the drug will be miscible in this polymer.

PVP= polyvinyl pyrrolidone PEG= polyethylene glycol EC= ethyl cellulose SOLID DISPERSIONS HEC= hydroxyethyl cellulose PEO= polyethylene oxide HPMC= hydroxypropylmethyl cellulose Solid dispersions are similar to solid solu- Figure 3: Comparison of acetaminophen and polymer excipients according to their tion formulations, except that the drug exists in Hansen partial solubility parameters. the form of discrete particles dispersed within a polymer or wax matrix. lets. Also, lipidic vehicles are generally well 1. Conversion of the drug material into its amor- absorbed from the GIT and in many cases this phous state – generally, a drug substance is MELT EXTRUSION approach alone can significantly improve the easier to dissolve when in the amorphous oral bioavailability 9,10 compared with admin- state compared with the crystalline state, due This technique 16,17 is an extension of the istration of the solid drug substance, but there to absence of ordered intermolecular bonds ‘solid solution’ approach described previously. may be significant inter and intra-subject vari- 2. Incorporation of the amorphous drug sub- It consists of extruding a co-melt of the drug ation in drug uptake, depending on the capac- stance in a hydrophilic polymeric matrix – a substance and a polymer through a heated screw ity of individuals to digest these lipid-based number of hydrophilic, polymeric materi- to produce a solid extrudate which can then be formulations. als have been used as solubility-enhancing milled to produce granules (for encapsulation In recent years there have been significant matrices for drug substances. For example, or compression into tablets). As with the solid advances in the use of lipidic excipients and sur- polyvinyl pyrrolidone (PVP) and polyethyl- solution approach, the production of a melt factants to produce self-emulsifying drug deliv- ene glycol (PEG 6000) have been used for extruded drug/polymer matrix is an effective ery systems (SEDDS) and self-micro-emulsi- preparing solid solutions containing poorly method of increasing the water solubility of a fying drug delivery systems (SMEDDS) for soluble drugs. poorly water-soluble drug substance. The effec- oral drug delivery.11 These formulations form tiveness of this approach depends on miscibility emulsions or micro-emulsions spontaneously Solid solutions can be prepared by dis- of drug and polymer substances and on the drug on contact with aqueous media. Both SEDDS solving both the drug compound and the substance and the polymer exhibiting similar and SMEDDS use pharmaceutically acceptable polymer in a suitable volatile solvent. On melting points. surfactant excipients to achieve self-emulsifica- removing the solvent (e.g. by spray drying) tion, therefore eliminating the reliance on the an amorphous drug-polymer complex is pro- MELT GRANULATION gastro-intestinal secretions (such as bile salts) to duced. On cooling, the drug is then trapped in emulsify the lipids in the formulation. an amorphous state within the water-soluble With this approach a water soluble polymer polymer matrix, thus enhancing the water- is used as a binding agent in a powder mixture Solid solutions solubility of the drug. to produce a granule blend. The blend is heated Solid solutions 12 (also sometimes described One potential problem with this type of to a temperature at which the polymer bind- as solid dispersions) are molecular dispersions formulation is that the drug may favour a more ing agent softens (without completely melting) of the drug molecules in a polymer matrix. This thermodynamically stable crystalline state, which results in formation of aggregates com- approach combines two principles to enhance which can result in the drug compound crys- prised of the drug and excipients. The granule water solubility of a drug: tallising in the polymer matrix. Therefore the mass is then cooled, sieved and is then suitable

18 www.ondrugdelivery.com Copyright © 2011 Frederick Furness Publishing for either encapsulation or compression into tab- ment project. This rational approach to formu- Adv. Drug Deliv. Rev. (2007), 59: 667–676. lets. This technique has proved to be effective in lation development offers obvious advantages 10. O’Driscoll, CM & Griffin, BT. enhancing water-solubility of several drugs.18,19 in reducing time for project completion and “Biopharmaceutical challenges associated maximising the effectiveness of formulations with drugs with low aqueous solubility – INCLUSION COMPLEXES SUCH AS for Phase I studies. the potential impact of lipid-based formula- CYCLODEXTRINS tions.” Adv. Drug Deliv. Rev. (2008), 60: REFERENCES 617–624. Cyclodextrins 20 are doughnut-shaped mole- 11. Pouton, CW & Porter, CJH. “Formulation cules with a lipophilic surface on the inside ring 1. FDA Guidance for Industry. “Waiver of in of lipid-based delivery systems for oral and a hydrophilic surface on the outer surface vivo bioavailability and bioequivalence stud- administration: Materials, methods and of the ring. The principle behind this strategy is ies for immediate-release solid oral dosage strategies.” Adv. Drug Deliv. Rev. (2008), that the poorly soluble drug molecule fits into forms based on a biopharmaceutics classifi- 60: 625–637. the inner ring and the outer hydrophilic surface cation system.” (August, 2000). 12. Vasconcelos, T, et al. “Solid dispersions as of the cyclodextrin holds the complex in solu- 2. Lipinski, CA et al. “Experimental and com- strategy to improve oral bioavailability of tion. The inclusion complex can be prepared putational approaches to estimate solubility poor water soluble drugs.” Drug Discovery by dissolving the drug and cyclodextrin in a and permeability in drug discovery and Today (2007), 12: 1068-1075. common solvent or by solid-state mixing of the development settings.” Adv. Drug Deliv. 13. Greenhalgh, DJ, et al. “Solubility param- materials using a high-attrition technique, such Rev. (1997), 23: 3-25. eters as predictors of miscibility in solid as ball milling. 3. Wu, CY & Benet, LZ. “Predicting drug dis- dispersions.” J. Pharm. Sci. (1999), 88: position via application of BCS: transport/ 1182-1190. CONCLUSION absorption/elimination interplay and devel- 14. Adamska, K, et al. “Selection of solubility opment of a biopharmaceutics drug disposi- parameters for characterization of phar- In conclusion, a number of factors need to tion classification system.” Pharm. Res. maceutical excipients.” J. Chromatogr. A be taken into consideration in deciding how (2005), 22: 11-23. (2007), 1171: 90-97. best to take a new drug entity into first-into-man 4. Butler, JM and Dressman, JB. “The devel- 15. Albers, J, et al. “Evaluation of predictive studies. The drug-in-capsule approach is often opability classification system: application models for stable solid solution formation.” seen as a cost effective and time saving option of biopharmaceutics concepts to formulation J. Pharm. Sci. (2011): 100: 667-680. for testing a drug in Phase I studies. Indeed, it development.” J. Pharm. Sci. (2010), 99: 16. Crowley, MM, et al. “Pharmaceutical significantly reduces the complexity of early 4940-4954. applications of hot-melt extrusion: Part stage development and progression from drug 5. Brachu. S, et al. “A decision-support tool 1.” Drug. Dev. Ind. Pharm. (2007), 33: substance to a Phase I clinical trial can be for the formulation of orally active, poorly 909-926 achieved within weeks. However, if the drug soluble compounds.” Eur. J. Pharm. Sci. 17. Repka, MA, et al. “Pharmaceutical appli- substance has known solubility/bioavailability (2007), 32: 128-139. cations of hot-melt extrusion: Part 2.” limitations (as is the case for more than 40% of 6. Hariharan, M, et al. “Reducing the time to Drug. Dev. Ind. Pharm. (2007), 33: 1043- NCEs) then due consideration should be given develop and manufacture formulations for 1057 to formulation strategies which can enhance first oral dose in humans.” Pharm. Tech., 18. Yang, D, et al. “Effect of the melt granula- drug solubility in the GIT. October 2003, 68-84. tion technique on the dissolution charac- Developing a suitable drug formulation 7. Kesisoglou, F, et al. “Nanosizing — Oral teristics of griseofulvin.” Int. J. Pharm. for first-into-human studies can be prob- formulation development and biopharma- (2007), 329: 72-80. lematic and time consuming, especially for ceutical evaluation.” Adv. Drug Deliv. Rev. 19. Passerini, N, et al. “Preparation and char- poorly water-soluble drugs. By predicting (2007), 59: 631–644. acterisation of ibuprofen–poloxamer 188 drug-excipient miscibility (through compari- 8. Eerdenbrugh, BV, et al. “Top-down produc- granules obtained by melt granulation.” son of solubility parameters) and subsequently tion of drug nanocrystals: Nanosuspension Eur. J. Pharm. Sci., (2002), 15: 71–78. using a decision tree approach for choosing an stabilisation, miniturization and transforma- 20. Brewster, ME & Loftsson, T. appropriate formulation strategy, it is possible tion into solid products.” Int. J. Pharm. “Cyclodextrins as pharmaceutical solubi- to eliminate a significant proportion of trial (2008), 364: 64-75. lizers.” Adv. Drug Deliv. Rev., (2007), 59: and error from a drug formulation develop- 9. Hauss, DJ. “Oral lipid-based formulations.” 645–666.

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In this article, Camille Rivail, Business Development Analyst, and Jean Chatellier, PhD, Vice-President, Alliance Management, both of Flamel Technologies, describe the company’s LiquiTime technology, which enables liquid formulations that are palatable, can incorporate various modified-release profiles, and are stable with long shelf-lives. The technology meets the need for liquid oral formulations in the large and growing number of patients who have difficulty swallowing conventional tablets and capsules, including the young and the elderly.

Paediatric and geriatric drug delivery are major adding sweeteners and flavors to mask the The multiparticulate nature of the dosage form challenges in drug development: it is estimated taste is often not sufficient. minimises inter- and intra-individual variation as that 50% of the population have difficulties in • A lack of enteric or modified drug delivery tech- compared with conventional tablets or capsules. swallowing solid oral dosage forms. This is espe- nologies as compared with tablets and capsules. cially true among children under 12 years and the • Stability issues of drugs in liquid form. elderly; there is a real need for age-adapted formulations to promote better treatment compliance. LiquiTime, Flamel Technologies’ innovative Indeed, patients have been found to break delivery platform, meets these different challenges. tablets into fragments in order to facilitate Based on a multi-microparticles approach, administration or to adapt the dose, generating LiquiTime allows stable, controlled-release, ready- major risks such as inaccurate dosing, or stabil- to-use liquid oral suspensions, with good “mouth ity issues of the residual fragments. feel”, of one or several combined drugs over time. Liquid formulations are thus one of the most The microparticles (shown in Figure 1) appropriate dosage forms for these subpopula- are composed of a drug core coated with a Camille Rivail tions, as they allow better compliance compared proprietary multifunctional diffusion film. The Business Development Analyst with classic tablets or capsules as well as better expertise developed by Flamel in coating in dose adaptability (age- and weight-dependent). fluidised beds allows accurate and reproducible However, a number of challenges are related coating on very small drug cores to manufacture to the use of liquid formulations: microparticles with narrow size distribution and • The palatability or taste of the solution, which final particle diameters below 200 μm. must be sufficiently agreeable in flavour to be The microparticles size and the narrow consumed. With respect to bitter-tasting drugs, distribution optimise mouth-feel, generating a smooth, liquid formulation with the possibility to adjust the flavour using aroma agents. The encapsulation of the active within the microparticles allows taste-masking, even for the most Dr Jean Chatellier Vice-President, Alliance unpleasant-tasting drugs. Management LiquiTime enables tailoring and accurate fit- ting of any release profile, especially zero-order Flamel Technologies SA kinetics, to optimise pharmacokinetics (Figure 2) 33 avenue du Dr Georges Levy for a wide range of therapeutic applications and 69693 Vénissieux Cedex drugs (unlike ion exchange resin-complex tech- France nology, which is limited solely to ionic drugs). T: +33 472 783 434 Other benefits may also be obtained, such 200µm F: +33 472 783 446 as the possibility to mix immediate-release and E: [email protected] extended-release kinetics for fast onset and Figure 1 : Flamel Technologies’ extended release, or the possibility of mixing www.flamel.com LiquiTime-based coated microparticles have an average diameter <200 µm. different drugs with different release kinetics.

20 www.ondrugdelivery.com Copyright © 2011 Frederick Furness Publishing Regarding stability, one of the main techni- 110 cal hurdles related to liquid forms is to maintain 100 the performance of the drug over time to pro- 90 vide an acceptable shelf-life. Due to its unique 80 approach, LiquiTime has demonstrated long- 70 term physical and performance stability of over 24 months of storage. 60 Prototype I The physical properties of LiquiTime, such as 50 viscosity, density, have been optimised to ensure 40 Prototype II precise and reproducible sampling to be delivered 30 with existing marketed dosing devices (for exam- 20 ple, plastic syringes), allowing flexible and accu- released % cumutalive 10 rate dose titration adapted to individual patients. Development time of LiquiTime formulations 0 02 4 6 8 1012141618202224 has been optimised through the use of cutting-edge Time (hours) equipment and the skill and experience of the Flamel development team. Beyond the lab, cGMP Figure 2: This graph illustrates the different zero-order release profiles achieved for manufacturing of clinical trial material and scale- LiquiTime-based formulations (easily tailored to obtain the appropriated targeted up to commercial size can be rapidly executed at product profile). Flamel’s US FDA-approved industrial plant. LiquiTime is protected by a strong IP portfo- MICROPUMP Medusa enables the controlled delivery from lio, including several granted patents in territo- one day up to 14 days of non-modified drugs ries including the US, EU and Japan. The Micropump micro-encapsulation oral that remain fully active (as opposed to protein drug delivery platform, for the formulation engineering or chemical modification approach- KEY BENEFITS OF LIQUITIME and the controlled release of chemical drugs, is es). It may be used to develop Biobetters with designed to increase absorption time, particular- potentially improved efficacy, reduced toxic- • Easy to swallow, good mouth feeling, taste ly for drugs only absorbed in the small intestine, ity and enhanced patient compliance. Several masked and to deliver the drug to specific sites in the Medusa-based products are at various clinical • Liquid formulations stable over 24 months gastro-intestinal tract. Micropump allows tailor- stages of development. Flamel’s lead internal • Applicable to a wide range of drugs, not lim- ing the exact kinetics required to optimise the Medusa-based product candidate IFN-a XL ited to ionic drugs as with resin-complex based final product and offers the advantage of easily (long-acting interferon alpha-2b) is currently technology and accurately mixing microparticles with dif- the subject of a Phase II trial in HCV patients. • Zero-order kinetics ferent release kinetics, in different ratios, with DeliVax*, Medusa’s vaccine application, • Combination of immediate-release and extend- every individual particle performing indepen- permits the efficient formulation of vaccines. ed-release kinetics possible dently. A single Micropump formulation can be These versatile drug delivery platforms may • Combination in the same formulation of differ- presented in various dosage forms such as cap- be used to address threshold formulation prob- ent drugs with different release kinetics possible sule, tablet, sachet or oral suspensions without lems such as poor solubility, aggregation and • Use GRAS materials to warrant safety affecting the release rate. instability for both chemical and biological • Rapid development time under cGMP conditions Flamel has developed US FDA- and drugs. Flamel’s innovative delivery platforms • Ease to scale-up to industrial scale EMA-approved products and manufactures are used for the lifecycle management of mar- • Clinical Proof of Concept achieved in humans Micropump-based microparticles. keted products, including Biobetters, and the for a liquid suspension of an undisclosed drug development of new compounds with many for treatment of children TRIGGER LOCK™ unique competitive advantages: • Broad and strong IP protection In addition to Micropump and LiquiTime, • Improvement of drug characteristics such as ABOUT FLAMEL TECHNOLOGIES Flamel has developed another oral drug delivery efficacy, bioavailability and pharmacokinetics technology, Trigger Lock™, which provides • Improvement of the drug safety profile with a Flamel Technologies SA (NASDAQ: FLML) controlled release of narcotic and opioid analge- noticeable diminution of peak dose concentra- is a leading drug delivery company focused on the sics while deterring tampering (particles cannot tions, which in turn allows administration of goal of developing safer, more efficacious formu- be crushed to extract the active). higher effective doses and potentially greater lations of drugs that address unmet medical needs. efficacy Flamel Technologies has collaborations MEDUSA • Potential improvement of patient compliance with a number of leading pharmaceutical and due to reduced side-effects and greater con- biotechnology companies, including Baxter, Medusa is a proprietary injectable nanogel venience GlaxoSmithKline (Coreg CR®, carvedilol phos- platform for the formulation and/or the extended • Protection of market position through patent phate), Merck Serono and Pfizer. release of a broad range of biologics (including extension and/or product differentiation Its product development pipeline includes proteins, antibodies, peptides and vaccines) • Extension of market to new indications and biological and chemical drugs formulated with and of small molecules. The nanogel has been new patient populations. the Micropump®, Medusa® and other propri- proven to be safe and biodegradable (DMF filed etary platforms. with the FDA in February 2011). * pending trademarks

Oral thin films were first launched in 2004 for systemic drug delivery and are now widely accepted. In this article, Scott Barnhart, MS, Technical Director, and Martha Sloboda, MBA, Business Manager, both of ARx, LLC, detail the latest formulation and manufacturing techniques for oral thin films and describe how novel forms with, for example, controlled- release capabilities are emerging.

Rapidly dissolving oral thin films (OTFs; see selection and absorption rate are all considered Figure 1) are widely accepted by patients and so that an equivalent or an improved product caregivers for their ease-of-delivery, portability profile may be produced over existing liquids, and accurate dosing. Since the first commercial capsules and tablets. The robustness of thin-film launch of OTFs for systemic drug delivery in dosage forms has been demonstrated through 2004, 1 the platform has evolved as more phar- 24-month ICH stability studies. maceutical researchers evaluate ways to apply Ongoing research is extending the dissolv- the benefits of this technology across more able film technology to more complicated markets and therapeutic classes for localised systems for modified or controlled release. and systemic drug delivery. This also includes applications for topical As a result of these efforts, new applications delivery. In some cases, there is convergence are emerging. Advances in chemistries and the with transdermal technology that enables manufacturing processes used in the formula- films to have more tangible adhesive prop- tion and scale-up of this technology play a sig- erties such as increased dwell time in the nificant role in advancing the potential of OTFs mouth or other alternative delivery sites. This Martha Sloboda beyond immediate-release oral applications. work relies on a strong understanding of the Business Manager T: +1 717 227 3326 suitability, compatibility, and availability of E: [email protected] OTF FORMULATION material sets.

The chemistry and art behind formulating EXCIPIENTS OTFs draws on polymer expertise derived from traditional solid, buccal and transdermal Robust OTFs are developed using current dosage forms. By understanding these formats commercially available generally regarded as and leveraging their similarities, formulators safe (GRAS) excipients. Most major excipient can effectively deliver unique and compliant suppliers of solid oral dosage forms materials products within a shortened product develop- now offer excipients that are appropriate for ment timeframe. use in OTFs and potentially enhance disinte- The formulation flexibility of the OTF gration properties. Dr Scott Barnhart platform enables formulators to evaluate a The majority of film formulations are first Technical Director T: +1 717 227 3206 broad range of excipients and active pharma- compounded as a liquid prior to being cast into E: [email protected] ceutical ingredient (API) forms when embark- films. A host of water, solvents, and combina- ing on new product development initiatives. tions of both exist as process aides. Based on ARx, LLC This formulation flexibility may also increase the solubility and compatibility of the API, P.O. Box 100 a programme’s chance for success by present- a formulator can choose to develop a 100% 100 Seaks Run Road ing chemists with a wider range of available water-based system; or in the event that the Glen Rock, PA 17327 material sets to produce both an acceptable API degrades in water, other pharmaceutically- United States and stable product. acceptable organic solvents can be selected. www.arglobal.com When selecting an OTF to replace an exist- Solvent selection can also be used to enhance ing product, the film’s dissolution rate, material manufacturing efficiency based on the relative

22 www.ondrugdelivery.com Copyright © 2011 Frederick Furness Publishing Figure 1: Rolls of dissolvable films (left) and film being wound on a roll (right). energy required to remove the volatile liquid compound particle size distributions fall within each thin film drug product. API concentra- during the film casting process. typical OTF production requirements. tions are typically limited to 50% of the final A number of taste-masking options exist and unit mass. However, the size of the final unit RELEASE LINERS have been used in the development of OTFs. strip is adjustable to deliver the proper dose. This includes sophisticated masking technology Thicker OTFs can be produced to yield higher Significant research and expertise derived specifically designed for highly bitter materials strengths. In this case, it is up to the formulator from the transdermal arena has resulted in a with an affinity for the oral cavity. Key consid- to determine at what point the thickness of the wide range of release liner technologies that erations in selecting any taste-masking approach product detracts from the desired disintegra- may be used as processing aids in the manu- beyond palatability include cost, impact to API tion profile. Furthermore, a formulator can facture of OTFs. These materials are comprised particle size or mass and solvent compatibility. elect to produce multiple formulas to obtain of a plastic film or paper substrate coated with Researchers have some latitude in both multiple strengths for a specific API, or pro- silicone or non-silicone chemistries for a clean how much API can be incorporated and how duce a single formula that is cut into multiple release of the film when appropriate in the con- other product attributes can be tailored for strengths based on the size of the unit area. For version process. By coating a compounded liquid formulation to a continuous web of release liner material, film manufacturers are able to 30 mm maintain the integrity of the OTF film product throughout the manufacturing process because this component provides added strength, sup- 15 mm port and environmental protection to wound rolls of OTF film prior to finishing. Release liners can be incorporated strictly as a processing aide that is removed in the film finishing stage, 20 mm 20 mm or as seen in new product launches, this component can remain affixed to the OTF to aid in dispensing and administering the drug product.

ACTIVE INGREDIENTS

OTFs can integrate most available forms of APIs, including micronised, granulated, salt, and free-base forms. Both soluble and insoluble drugs have been successfully compounded into High Dose Low Dose solutions, emulsions, or dispersions that have subsequently resulted in the launches of the OTF 30 mm x 20 mm strip 15 mm x 20 mm strip products currently available in the market today. 10 mg 5 mg Larger particle size compounds do present some constraints in regards to the final OTF’s thick- Figure 2: Formulators can choose to produce a single OTF formula that is cut into ness, but in general, most APIs and nutritional multiple strengths based on the size of the unit area.

Mix API + Coat Slit and Convert Final Receive excipients and dry metal and package inspection Solution incoming raw solution detect into final and Emulsion materials into roll stock product release Dispersion bulk roll

Figure 3: The manufacturing techniques for oral thin films are well understood and lend themselves to holding exceptionally tight tolerances throughout the process. example, 10 mg strength of a given formula tronics market for enabling multi-lane simul- ABOUT ARX, LLC could become a 5 mg strength dose by halving taneous coating. 3 By applying this technique the unit size with no additional formulary work to OTF manufacturing, the potential exists ARx, LLC, a wholly owned subsidiary of required (see Figure 2). to coat incompatible materials, or synergistic Adhesives Research, Inc (AR), was created in Looking forward, the use of micronised and chemistries, side-by-side without triggering any 2005 to address the growing global need for nano particle APIs in OTFs opens the door for pre-dose reaction. innovative delivery of active drug-containing potentially more effective drug delivery methods. Packaging has commonly been a single- systems. This was a natural extension of AR’s With the increased surface area of the API and unit dosage format that accommodates one or 20+ years of experience manufacturing pressure- the larger direct-contact surface area of the film, two strips per pouch and enables portability of sensitive adhesives and components for transder- there is the possibility to improve bioavailability the product. It also allows for multiple-count mal and other pharmaceutical applications. and to increase uptake from the mucosal surface. options to accommodate dispensing needs and ARx is dedicated to developing and manufac- By modifying the residence time of the OTF on regional requirements. However, a number of turing innovative pharmaceutical products, includ- the mucosal tissue in conjunction with the micro- new, stable formats are emerging that maintain ing adhesive laminates and dissolvable films, nised or nano-API, early stage work suggests that dose integrity while also offering a more cost- for customised drug delivery platform technolo- this type of system has the potential to effectively effective dispensing option that complies with gies. As part of this commitment, in 2007, ARx deliver drugs in a shorter timeframe. stability and regulatory requirements. opened a new, state-of-the-art 25,000 square-foot The manufacturing flexibility of OTFs (2,323 m2) pharmaceutical manufacturing facil- OTF MANUFACTURE reduces capital requirements and capacity con- ity designed to manufacture dissolvable film, sumption. It also enables formulators to con- transdermal, and buccal drug delivery systems for Based on precision adhesive coating technol- sider new options for delivery. Because these over-the-counter, prescription and biopharmaceu- ogies used for decades in the transdermal indus- manufacturing approaches are also well under- tical products. The globally-compliant facility tri- try, the manufacturing techniques for OTFs are stood and controlled, robust, efficient develop- ples ARx’s manufacturing capacity and laboratory well-understood and lend themselves to holding ment can occur from bench to commercial scale. space to support the rapid growth in the industry. exceptionally tight tolerances throughout the process. The precision-coating techniques derived THE FUTURE OF OTFS REFERENCES from transdermal production are now used for producing OTF base chemistries into final The application of OTFs now extends beyond 1. “Novartis launches first systemic OTC in film individual doses with unit tolerances as tight as traditional immediate release oral dosage forms. strip format.” Available at: http://www.in-phar- ± 2.5% around the potency target.2 Specialised Development of topical films, probiotic strips,4 matechnologist.com/Materials-Formulation/ coat-weight monitoring systems and liquid dep- and controlled-release OTF products are new Novartis-launches-first-systemic-OTC-in-film- osition techniques enable any OTF product to forms made possible through this delivery for- strip-format. Accessed October 1, 2009. hold and maintain consistent cross and down- mat’s flexibility, proven robustness and stability. 2. Van Arnum, P. “Pediatric Formulations: stream uniformity during manufacture. This The future of OTF formulation and process- Technical and Regulatory Considerations: continuous process monitoring also lends itself ing is a direct reflection of evolving healthcare A Roundtable.” Pharm. Tech 2009. 33 (8) to process analytical technology (PAT) initia- needs. Demographically, most established mar- Outsourcing Resources suppl. s58-s67. tives and identifying any processing variability kets have aging populations that benefit from 3. Greb, E. “Are Orally Dissolving Strips Easy in real time (Figure 3). simple, easy-to-dispense and dose products. for Manufacturers to Swallow?” Available at: Coating technology from other markets con- As emerging markets require flexibility in the http://pharmtech.findpharma.com/pharmtech/ tinues to advance OTF production and cost- number of units dispensed at any given time and article/articleDetail.jsp?id=615617&sk=& effectiveness. Multi-functional mixers drawn providers continue to look for options that can date=&pageID=3. Accessed October 5, 2009. from the food industry enable multiple products increase compliance, minimise dosage levels 4. “Ganeden Biotech Introduces the First to be manufactured out of the same process and frequency, and reduce costs. OTFs have Probiotic Thin Strip.” Available at: http:// footprint. New approaches in coating techniques increasingly become the solution to satisfy all news.prnewswire.com/ViewContent. are leading to more sophisticated OTF construc- of these needs. In addition development teams aspx?ACCT=109&STORY=/www/story/09- tions. An example of this can be seen in the are able to capitalise on the flexibility of OTFs 15-2009/0005094056&EDATE=. Accessed adhesive coating techniques utilised in the elec- by adapting the technology for their program. September 28, 2009.

SOLUMER™ TECHNOLOGY: A VIABLE ORAL DOSAGE FORM OPTION FOR BCS CLASS II MOLECULES

In this article, Mark Mitchnick, MD, Chief Executive Officer, and Robert Lee, PhD, Vice- President, Pharmaceutical Development, both of Particle Sciences, and Amir Zalcenstein, PhD, Chief Executive Officer, SoluBest, introduce Particle Sciences’ formulaic DOSE™ system for dosage form development and drug delivery technology selection, and discuss one such technology, Solubest’s Solumer™, a scalable solid dispersion approach based on spray drying that is suitable for BCS Class II APIs and NCEs.

In the lifecycle management of pharmaceuti- Increasingly, solid dispersions are being cal products, novel drug delivery technolo- looked at as a viable solution to this pervasive gies that offer positive differentiation over issue. Although only a few solid dispersions first-generation products provide an important are currently marketed, the approach has some means for staying competitive in today’s busi- inherent advantages over other approaches. ness environment. Presence of an active compound as a molecular Dr Robert Lee Many existing active pharaceutical ingredi- or nanoparticle dispersion combines the ben- Vice-President, Pharmaceutical Development ents (APIs) and new chemical entities (NCEs) efits of decreasing crystal lattice energy and T: +1 610 861-4701 are poorly water soluble and subsequently have maximising surface area, thus facilitating better E: [email protected] low oral bioavailability if formulated in their contact with dissolution media. Fortuitously, unmodified forms. Traditional approaches to many of the carriers that can be employed for Particle Sciences, Inc 3894, Courtney Street overcoming this include: the production of solid dispersions are gener- Bethlehem, PA 18017 ally recognised as safe (GRAS) and are already United States • Improvement of water miscibility by employ- extensively used as excipients in marketed ing self-emulsification,1 lipid-based tech- products, easing the regulatory burden. www.particlesciences.com niques,2 solubilisation into micellar cores,3 or Particle Sciences has developed DOSE™, a formulaic approach to dosage form development that rapidly narrows “THIS METHODICAL ITERATIVE in on the drug delivery technology of choice. When solid dispersions APPROACH ALLOWS ONE TO RAPIDLY are called for, Particle Sciences NARROW IN ON THE FORMULATION has a number of approaches. One of them, thorough its partner- APPROACHES MOST LIKELY TO ship with SoluBest, is to use the Solumer™ technology,8 a unique YIELD THE DESIRED RESULTS.” Dr Amir Zalcenstein solid dispersion technology that Chief Executive Officer significantly improves the dissolu- T: +972 8 940 3023 x102 alternatively complexation with cyclodextrins.4 tion and bioavailability of poorly soluble drugs. E: [email protected] • Reduction of particle size to nano-scale via The technology has been proven in human trials SoluBest, Ltd mechanical milling or high-shear processing and has been scaled to commercial levels. Weizmann Science Park accompanied by particle stabilisation.5 Under Particle Sciences’ DOSE™ system, 18 Einstein Street • Impacting crystal lattice energy using poly- APIs are first extensively characterised as to Ness Ziona 74140 Israel morphs or co-crystals,6 or through the crea- their physicochemical properties, including a tion of solid dispersions of drug in inert proprietary solubility screen. Then, after excipi- www.solubest.com carriers or matrices.7 ent compatibility studies, formulation prototypes

26 www.ondrugdelivery.com Copyright © 2011 Frederick Furness Publishing are screened for their impact on solubility and SOLUMER FINGERPRINTS permeability. This methodical iterative approach Formulating lipophilic crystalline drugs results in a self-assembled drug-polymer complex. allows one to rapidly narrow in on the formulation This provides two features that are required for improved bioavailability: approaches most likely to yield the desired results. • Depression of melting temperature and energy • Formation of colloidal dispersions upon contact with aqueous media THE CHALLENGE API Formulation

An increasing number of compounds com- Tmelt (ºC) ΔHmelt (J/g) Tmelt (ºC) ΔHmelt Particle size (J/g ) nm ing out of discovery are poorly soluble. By drug some estimates 40-70% of new lead com- Reservatrol 267.4 253.6 199.1 14.0 1224 pounds in development fall into this cat- Hesperetin 231.0 166.2 No peak of melting 1310 egory.9,10 Additionally many new compounds Nifedipine 172.4 113.4 140.9 8.4 749 also exhibit poor permeability. In 1993, the Fenoﬁbrate 81.5 74.3 64.4 9.3 669 Biopharmaceutical Classification System Tacrolimus 135.0 60.5 118.0 52.0 836 (BCS) 11,12,13,14 was proposed as a way to facili- Clarithromycin 227.6 70.2 207.9 40.1 1190 tate the marketing of generic drugs. The system Albendazole 215.2 209.7 161.4 31.2 555 classifies a given compound by its aqueous Fenbendazole 239.2 166.3 203.7 8.9 892 solubility and gut permeability. Itraconazole 169.7 84.4 155.6 21.9 910 Beyond its regulatory use, the BCS provides a very useful framework in which to evalu- Particle Sciences ate APIs and chart a logical course to achieve the desired pharmacokinetics (PK), including Figure 1: Comparative Thermodynamic Characteristics (Melting Temperatures and greater bioavailability. For BCS II and IV mol- Melting Energies) of Various Unformulated APIs and their Corresponding Solumer™ ecules, where solubility is the main or largely Formulations. contributing limiting property, there are a number of approaches including increasing surface a BCS Class I molecule, the prototypical formula- in water. The drug and polymer solutions are then area through particle size reduction, surface tion could be a simple powder-filled capsule. For mixed and spray dried. The exact compositions of morphology modification and solid solutions. a poorly water-soluble molecule, BCS Class II or the feed stocks are determined in an extensive, yet IV, such a simple system is unlikely to provide efficient, preformulation phase utilising Design ONE POSSIBLE SOLUTION: any commercially helpful data, speed develop- of Experiment (DoE) methodology, when appro- SOLUMER™ TECHNOLOGY ment or bring to light clinically relevant findings. priate. Key drivers include the APIs solubility Therefore, a FIH formulation designed to deliver in various organic solvents, the APIs molecular Generating human data as quickly as possible the drug in a commercially viable way is, in our weight, the solubilities of the polymeric excipi- is a goal of every drug developer and there are view, important. For drugs with limited aqueous ents, and the compatibility of the API and poly- several philosophies as to how best to achieve first solubility, one such approach is Solumer™, a meric excipients in the spray drying solution. in human (FIH) dosing. It has been estimated that patented dual polymer system utilising GRAS In the context of the Solumer technology, 3-6 formulation changes occur from FIH to com- excipients and traditional processing techniques. amphiphilic polymers are defined as soluble mercialisation.15 At Particle Sciences, we believe In this approach, the API is solubilised in an both in organic solvents and in water. that FIH experience should be in a formulation organic solvent, usually ethanol. An amphiphilic Examples of amphiphilic polymers suitable that will provide useful developmental data. For and a hydrophilic polymer are separately mixed for use with Solumer include but are not lim-

Solu-Naproxen

Naproxen

Figure 2: Comparason of X-ray Diffraction Patterns of Figure 3: Differential Scanning Calorimetry of Naproxen API Naproxen API (Naproxen) and Naproxen processed (Raw Naproxen) and Naproxen processed using the Solumer™ using the Solumer™ Technology (Solu-Naproxen). Technology (SoluNaproxen 294-153).

Copyright © 2011 Frederick Furness Publishing www.ondrugdelivery.com 27 ited to polyethylene oxides (PEO, also com- patented process, Solumer™ technology monly referred to as polyethylene glycol or results in stable crystalline constructs that PEG), PEO derivatives, PEO copolymers increase bioavailability by increasing the such as PEO/polypropylene glycol (PPG) solubility of the API. To date the technology copolymers, PEG-modified starches, polox- has been demonstrated in more than a dozen amers, poloxamines, polyvinylpyrrolidones, compounds and is currently being scaled for hydroxypropyl cellulose, hypromellose and Phase III commercialisation. esters thereof, vinyl acetate/vinylpyrrolidone random copolymers, polyacrylic acid, and REFERENCES polyacrylates. Hydrophilic polymers are defined as those soluble in water or in a 1 Kohli K, Chopra S, Dhar D, Arora S, mixture of organic solvent and water, but not Khar RK. “Self-emulsifying drug delivery soluble in organic solvent alone. Examples systems: an approach to enhance oral bio- of hydrophilic polymers include but are not availability.” Drug Discov Today. 2010 limited to starch, sodium carboxymethyl- Nov;15(21-22):958-65. cellulose, hydroxyethylcellulose, polyvinyl 2 Rahman MA, Harwansh R, Mirza MA, alcohol, sodium alginate, chitosan, and carra- Hussain MS, Hussain A. “Oral Lipid geenan. Notably, Solumer formulations utilise Based Drug Delivery System (LBDDS): only FDA-approved polymers. Formulation, Characterization and The use of hydrophilic polymers that Application: A Review.” Curr Drug Deliv. ionise at different pH allows for the design of 2011 Apr 1. formulations targeted either to the stomach or 3 Kadam Y, Yerramilli U, Bahadur A, the intestine. For example, chitosan, which is Bahadur P. “Micelles from PEO-PPO- ionised at low pH, promotes drug release in PEO block copolymers as nanocontainers the stomach, while sodium carboxymethyl for solubilization of a poorly water soluble cellulose and sodium alginate, ionised at Figure 4: Dissolution Profiles and Porcine drug hydrochlorothiazide.” Colloids Surf neutral conditions, facilitate release in the Pharmacokinetic Data for Fenofibrate B Biointerfaces. 2011 Mar 1;83(1):49-57. small intestine. 4 Kanwar JR, Long BM, Kanwar RK. “The The resulting powder is free flowing and will melting temperature and enthalpy of melting is Use of Cyclodextrins Nanoparticles for contain 25% or more API. Characteristics of the clearly demonstrated. It is believed that these Oral Delivery.” Curr Med Chem. 2011 drug product include: thermal property alterations are responsible for Apr 26. the drastic increase in solubility provided by 5 Peltonen L, Hirvonen J. “Pharmaceutical • Solubilised drug homogeneously interwoven the technology. nanocrystals by nanomilling: critical process into a polymer matrix Figure 4 shows the dissolution profiles and parameters, particle fracturing and stabiliza- • Formation of crystalline drug within the poly- porcine pharmacokinetic data for fenofibrate. tion methods.” J Pharm Pharmacol. 2010 mer matrix (A: dissolution profiles of raw API, commer- Nov;62(11):1569-79. • Modified thermal behavior demonstrating cial product, and Solumer™ fenofibrate (Solu- 6 Miroshnyk I, Mirza S, Sandler N. depressed melting temperature and enthalpy of Fenofibrate); and B: porcine PK data for com- “Pharmaceutical co-crystals-an opportunity melting of the drug (see Figure 1) mercial product versus Solu-Fenofibrate). for drug product enhancement.” Expert Opin • Spontaneous formation of nanocolloidal dis- Figure 5 shows the dissolution profiles and Drug Deliv. 2009 Apr;6(4):333-41. persions upon contact with aqueous media porcine pharmacokinetic data for albendazole 7 Janssens S, Van den Mooter G. “Review: • Enhanced dissolution rate/solubility of the (A: dissolution profiles of raw API and Solu- physical chemistry of solid dispersions.” J drug in aqueous media as well as prolonged Albendazole in 0.05 M SLS; B: dissolution pro- Pharm Pharmacol. 2009 Dec;61(12):1571-86. supersaturation in relevant biological fluids, files of raw API and Solu-Albendazole in fasted 8 Zalcenstein, A. “SoluBest’s Solumer and GI site-targeted release of the drug. simulated intestinal fluid; C: porcine PK data for Solubilising Platform: An All-in-One commercial product versus Solu-Albendazole; Technology.” ONdrugDelivery, Oral Drug CHARACTERISATION and D: efficacy in porcine model of commercial Delivery & Advanced Excipients, April 2010, product versus Solu-Albendazole). 27-30. Comparing X-Ray diffraction patterns of 9 Hauss DJ. “Oral lipid-based formulations.” a model API, naproxen, with its correspond- CONCLUSION Adv Drug Deliv Rev. 2007 Jul 30;59(7):667- ing Solumer™ formulation, shows that in the 76. Solumer™ formulation, the drug (naproxen) is Drug product formulation development will 10 Dubin CH. “Formulation strategy for present in its crystalline form (see Figure 2). In become increasingly sophisticated over time. poorly soluble drugs.” Drug Del Technol contrast to some systems dependent on amor- Whether reformulating an existing compound or 2006;6(6):34–38. phous forms, this technology results in very working with an NCE, the ability to understand 11 Yu LX, Amidon GL, Polli JE, Zhao H, stable constructs since the drug is present in its and manipulate those factors within our control Mehta MU, Conner DP, Shah VP, Lesko most thermodynamically favoured state. that dictate PK behavior is key. For compounds LJ, Chen ML, Lee VH, Hussain AS. Several commercial compounds have been with low solubility, we have presented one “Biopharmaceutics classification system: thoroughly evaluated using this technology. approach to oral dosage form development. the scientific basis for biowaiver exten- In Figure 3, the impact of the technology on Using GRAS ingredients and a readily scaled, sions.” Pharm Res. 2002 Jul;19(7):921-5.

28 www.ondrugdelivery.com Copyright © 2011 Frederick Furness Publishing 12 Chen ML, Amidon GL, Benet LZ, Lennernas H, Yu LX. “The BCS, BDDCS, and Regulatory Guidances.” Pharm Res. 2011 Apr 14. 13 Tsume Y, Amidon GL. “The biowaiver extension for BCS class III drugs: the effect of dissolution rate on the bioequivalence of BCS class III immediate- release drugs predicted by computer simulation.” Mol Pharm. 2010 Aug 2;7(4):1235-43. 14 Takagi T, Ramachandran C, Bermejo M, Yamashita S, Yu LX, Amidon GL. “A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan.” Mol Pharm. 2006 Nov- Dec;3(6):631-43. 15 Hussain AS. “Quality by Design: Integration of prior knowledge and pharmaceutical development into CMC submission and review: FDA Perspective.” AAPS Workshop, Oct. 2005. Figure 5: Dissolution Profiles and Porcine Pharmacokinetic Data for Albendazole.

Drug Delivery International Ltd has developed oral drug delivery preparations that provide a range of drug-release profiles that can be developed for single- or multiple-drug delivery. The profiles can combine separate pulse releases, or an initial release combined with delayed, sustained release. Here, Carol Thomson, PhD, Chief Operating Officer, Drug Delivery International, explains how the preparations’ behaviour in man has been demonstrated using the nuclear imaging technique, gamma scintigraphy. Dr Thomson outlines how potential applications in sleep maintenance, pain management and cardiovascular disease have been demonstrated in this way, although the formulations are not limited to these therapeutic areas; indeed, they could be applied to a broad range of drugs and disease groups.

There are many benefits offered by controlled particularly beneficial for drugs with a narrow drug delivery systems. For example, sustained- therapeutic window. release technologies allow prolonged delivery Further, there is an expanding body of of a therapeutic dose, thus reducing the number evidence concerning the relationship between of times that a patient needs to take their medi- circadian rhythms and the responsiveness of the cation while maintaining a steady state of drug body to drugs. As a consequence of this rela- in the bloodstream, and time-delayed release tionship, the absorption, distribution, metabo- introduces a lag time before dose release, lism and elimination of a drug and its subse- providing pulsatile delivery of drug to specific quent therapeutic efficacy and/or toxicity can sites, such as the colon, or at a specific time. vary considerably with the circadian cycle. Temporal control of drug release has par- Drug Delivery International (DDi) is a start- ticular advantages in the treatment of disor- up formulation development company that spe- ders that demonstrate a circadian pattern, such cialises in providing solutions for “difficult” as cardiovascular disorders, asthma, anxiety formulations, such as those for drugs with poor solubility, poor bioavailability or other properties that “THE ABSORPTION, DISTRIBUTION, prevent APIs from reaching the market or achieving their full METABOLISM AND ELIMINATION therapeutic potential. DDi has an OF A DRUG AND ITS SUBSEQUENT expanding intellectual property portfolio, providing licensing or Dr Carol Thomson Chief Operating Officer collaborative research opportu- THERAPEUTIC EFFICACY AND/OR T: +44 141 552 0126 nities in controlled release and E: [email protected] TOXICITY CAN VARY CONSIDERABLY chronopharmaceutics. DDi has developed a series WITH THE CIRCADIAN CYCLE.” Drug Delivery International Ltd of novel delivery systems, based Basement Medical Block on compressed tablet technol- Glasgow Royal Infirmary and hypercholesterolemia. In such cases, the ogy, that can be readily configured to provide 84 Castle Street development of controlled-release formulations immediate, biphasic (two pulses of drug(s) Glasgow, G4 0SF United Kingdom that deliver the payload at an optimal time separated by a defined delay) or time-delayed can greatly enhance the therapeutic effects of sustained release patterns of one or more drugs www.drugdeliveryinternational.com the drug and reduce the dose required. This is for a wide range of medical applications. The

• Widespread applicability to different drugs and dosages • High degree of flexibility in manipulating drug release profiles • Simple assembly and production processes • Formulations are not pH-sensitive.

These formulations have been developed for three therapeutic areas: sleep maintenance; cardiovascular disease; and pain management. Formulations have been clinically evaluated using the non-invasive imaging technique of gamma scintigraphy to visualise the release of the drug. The gamma scintigraphy work was carried Figure 1: Time delayed in vitro release of zolpidem out by Bio-Images Research Ltd (Glasgow, UK), a complete clinical research services company and in the small intestine in the remaining sub- the six subjects, indicating robustness of the which, with a high level of expertise in drug ject. Complete release was noted in the stomach formulation in providing accurate time-delayed delivery systems, provides clients with early- for four subjects and in the small intestine for release. The physiological effects of the sleep stage guidance in the drug development process. two. Figure 2 shows scintigraphic images of key tablet coincided with the scintigraphic confir- events in the GI transit of a tablet in Subject 001. mation of release. SLEEP MAINTENANCE Almost immediately after radiolabel release was confirmed by scintigraphy, the subjects CARDIOVASCULAR Sleep maintenance insomnia is characterised reported feeling drowsy and fell asleep. No by frequent and prolonged nocturnal awaken- clinically significant deviations from normal Hypertension has been shown to follow a ings, typically in the second half of the night. blood pressure and pulse ranges were noted. circadian pattern. Specifically, both heart rate It is a common problem which has increased The formulated tablet proved successful in and blood pressure blood pressure peak early in incidence with age and detrimentally impacts delivering the drug after a predicted time delay. the morning and in many people with hyperten- on the quality of life of individuals. Difficulty in The release parameters were comparable among sion there is a marked rise in blood pressure resuming sleep has been associated with reduced sleep quality, leading to anxiety, mood disorders and consequently daytime impairment.1 DDi has developed a time-delayed hypnotic formulation that provides a two-hour-delayed release of zolpidem for the treatment of sleep maintenance insomnia. Gamma scintigraphy and pharmacokinetic analysis was used to monitor the in vivo performance of the formulation. In vitro validation was carried out by stand- ard dissolution studies. The mean time to onset Figure 2: Scintigraphic images of Subject 001 at various times post-dose: 0 min of radiolabel release was 95 min (n=3) post- (immediately post-dose); 97.5 min (onset of 99mTc release); and 157.5 min (complete dose and the mean time to completion of 99mTc release). Outline of the stomach is drawn for visualisation only. radiolabel release was 171.7 ±15.3 min (n=3) post-dose (see Figure 1). Clinical evaluation was carried out using gamma scintigraphy in six healthy male volunteers. The mean time to onset of radiolabel release was 98 ±10 min post-dose and the mean time to completion of radiolabel release was 153 ±8 min post-dose. This gave a mean time of 55 ±16 min for complete dispersion, from onset to completion. These data correlate with the in vitro results and show the tablet’s barrier layer to prevent drug release successfully until close to the target Figure 3: Scintigraphic images of a healthy volunteer at various times post-dose: time of two hours post dose. Onset of radiolabel 0 min (immediately post-dose); 172.5 min (onset of 99mTc release); and 262.5 min release occurred in the stomach in five subjects (complete 99mTc release). Outline of the stomach is drawn for visualisation only.

Copyright © 2011 Frederick Furness Publishing www.ondrugdelivery.com 31 upon awakening called “the a.m. surge”.2,3 DDi formulation strategies have previously been hours will successfully target the colon. has developed a formulation for the delivery proposed for the delivery of drugs to the colon: We have successfully used this strategy for of anti-hypertensive drugs in the middle of the the development of a range of colon-targeting night, prior to wake-up, when the risk of fatal 1. The use of pH-sensitive coatings that dis- versions of time-delayed dosage forms. heart attack is greatest. solve at specific pHs in the small intestine. Drug Delivery International Ltd and Bio- The formulation provides a delayed release 2. The use of microbial flora of the colon to selec- Images Research Ltd are part of the Bio-Images of verapamil. In vitro, around 20% of the drug tively metabolise a portion of the coating.5-8 Group – providing integrated pharmaceutical is released 3-5 hours after administration, with development solutions. the remainder of the drug being released in a Before employing such strategies it is sustained manner over the following 4-5 hours, important to consider the environment in the REFERENCES thereby covering the pre-wake-up period of small intestine and colon in the disease state greatest cardiovascular risk. This ensures that as the pH and microbial organisms may dif- 1. Ohayon MM. “Difficulty in resuming or peak plasma levels of verapamil are achieved fer from that understood to be present in the inability to resume sleep and the links to during the night in a targeted manner consist- healthy population. daytime impairment: definition, prevalence ent with the chronopharmacological nature of and comorbidity.” J Psychiatr Res. 2009 cardiovascular disease. DDI COLON DELIVERY Jul;43(10):934-40. E-pub 2009 Mar 3. This formulation was validated clinically TECHNOLOGY 2. White WB. “Circadian variation in blood using gamma scintigraphic imaging in six pressure.” Blood Press Monit. 1997;2:46-51 healthy male volunteers, demonstrating delayed DDi has developed patented technology for 3. Millar-Craig MW, Bishop CN, Raftery EB. sustained release of verapamil in vivo (see time-delayed formulations based on a detailed “Circadian variation of blood pressure.” Figure 3 on previous page). understanding of the erosion of dosage forms in Lancet. 1978;1:795-797. the GI tract. The barrier layers developed by DDi 4. Yazici, Y; Pincus, T; Kautiainen, H; Sokka, PAIN THERAPY operate independently of pH and are relatively T (2004). “Morning stiffness in patients with unaffected by agitation conditions, leading to early rheumatoid arthritis is associated more People with rheumatoid arthritis suffer sig- excellent in vitro/in vivo correlation of erosion strongly with functional disability than with nificant problems with pain and stiffness upon performance. However, gastric residence is a joint swelling and erythrocyte sedimentation awakening, severely impacting on their normal very variable event in a population and depends rate.” J Rheumatol. (2004) 31 (9): 1723–6. daily functions.4 DDi has developed a formu- significantly on the fed state of the subject. In the 5. Stevens HNE. “Pulsincap Technology with lation that provides an immediate night-time presence of food, gastric emptying is delayed. Special Reference to Colon Targeting.” release of diclofenac, followed by a seven-hour Since the dietary habit of patients is virtually Progress in Drug Delivery Systems II. delay before pulsatile release of a second dose uncontrollable, gastric emptying will be very pp. 31-45, Pub. Biomedical Research of the drug. This formulation offers immediate variable in a patient population. This means that Foundation Tokyo, Japan (1993). pain relief at night time, allowing pain-free employing time-delay alone is not a useful tech- 6. Binns JS, Stevens HNE, Bakshaee M and sleep, and subsequently provides delivery of nique for the delivery of drugs to the colon, since Wilson CG. “Colon Targeted Release Using pain-relief prior to waking. This will be particu- gastric residence will be variable and will result the Pulsincap Delivery System.” Proceed. larly useful in the treatment of patients suffering in delivery to a range of intestinal sites. Intern. Symp. Control. Rel. Bioact. Mater., from chronic pain that has a significant inflam- The addition of a gastroresistant coating 21, 260-261 (1994). matory component. to a DDi time-delay formulation successfully 7. Pecek D, Sime KA, Ronaldson VE, Connolly The formulation has been demonstrated in eliminates the variability of gastric emptying. SM, Hodges LA, McInnes FJ, Stevens HNE. vitro to be highly reproducible. Further studies The erosion of the time-delay layer only begins “Development of a capsule systems for site are being carried out to validate the formula- following dissolution of the gastroresistant coat- specific drug delivery.” Proceed. Intern. Symp. tion in vivo. ing, which can only occur in the higher pH Control. Rel. Bioact. Mater (2010). environment in the small intestine, following 8. Pecek D, Sime KA, Ronaldson VE, Connolly COLON TARGETING gastric emptying. Since small intestine transit SM, Hodges LA, McInnes FJ, Stevens HNE. time is very reproducible, at around 3-4 hours, “Validation of a targeted release capsule Colon targeting is desirable for treatment of it follows that an enteric coated time-delayed using scintigraphic methods.” AAPS, New diseases specific to the large intestine.5-8 Two dosage form with a time-delay of around three Orleans, 2010.

IN WHICH EDITION SHOULD YOUR COMPANY APPEAR? WWW.ONDRUGDELIVERY.COM

LIQUID-FILL HARD TWO-PIECE CAPSULES: THE ANSWER TO MANY PRODUCT DEVELOPMENT ISSUES

In this article, Gary Norman, Product Development Manager, Encap Drug Delivery, gives an overview of the various processes and technologies the company employs for the development of capsule-based formulations. Particular advantages of these formulations over traditional presentations are described.

Liquid-fill formulation is one of the fastest grow- with aqueous media. An example of a marketed appropriate vehicles which are suitable for filling sectors of the drug delivery market, increas- product that uses a SMEDDS type formulation ing into hard shell capsules. ing at a rate of 30% per annum. This is due to the is Neoral, an oral formulation of cyclosporine number of highly potent chemical and biological from Novartis (Basel, Switzerland). TARGETED DELIVERY drugs moving through development pipelines In addition, Encap can offer the possibility today particularly for cancer treatments. to explore formulation screening for this type In addition to the liquid-filled capsule technol- of formulation using excipients from a range ogy Encap has other complimentary technologies BIOAVAILABILITY ENHANCEMENT of manufacturers including Gattefossé (Saint- such as targeted delivery of capsules. Targeted Priest, France). Encap has experience of a wide delivery could be as simple as enteric coating. For drugs with low solubility or bioavailabil- range of functional “bioavailability-enhancer” However, for targeted delivery of capsules to the ity, Encap Drug Delivery has a range of formu- excipients which are fully approved from a reg- colon our ENCODE® technology is utilised. lation options and technologies which will give ulatory perspective and include the screening of ENCODE is Encap Drug Delivery’s umbrel- drugs the best chance of success. These include such excipients during pre-formulation studies. la trademark for technologies that deliver cap- solid solutions and solid suspensions of drugs A formulation strategy for poorly soluble in polymeric vehicles, emulsions and self emul- drugs is the use of solid solutions, which are sifying lipidic systems. Liquid and semi-solid molecular dispersions of drug molecules in a filled hard capsule lipidic formulations are also polymer matrix. This conversion of the drug into ideally suited to compounds with low aqueous the amorphous state produces material which solubility, poor permeability and consequently dissolves more rapidly than the corresponding low or variable bioavailability. crystalline drug substance. The incorporation of Formulations which increase the solubility the drug substance into hydrophilic polymeric of the active or indeed present the drug as a materials such as polyvinylpyrollidone (PVP) solution can have a significant impact on the and polyethylene glycol (e.g. PEG6000) can bioavailability of such drugs. Lipidic vehicles produce additional solubility enhancing effects. Mr Gary Norman are generally well absorbed from the GI tract Solid solutions can be prepared by dis- Product Development Manager T: +44 1506 448 080 and in many cases this approach can significant- solving the drug and the polymer in a suitable F: +44 1506 448 081 ly improve the oral bioavailability compared volatile solvent. On removing the solvent (by E: [email protected] with administration of the solid drug substance. spray drying) an amorphous drug/polymer Encap has expertise in the use of self- complex is formed. In some cases it is possible Encap Drug Delivery emulsifying vehicles and has developed a num- to dissolve the drug in the molten polymer and Units 4, 5 & 6 ber of self-emulsifying drug delivery systems fill directly into hard capsules. On cooling, the Oakbank Park Way (SEDDS) and self-microemulsifying drug deliv- drug is entrapped in an amorphous state within Livingston West Lothian, EH53 0TH ery systems (SMEDDS) for the oral admin- the water-soluble matrix. United Kingdom istration of drugs with poor water solubility. In many cases, improvements in drug disso- These are formulations which form emulsions lution and bioavailability can also be achieved www.encapdrugdelivery.com or micro-emulsions spontaneously on contact using dispersions or suspensions of drugs in

Figure 1: DuoCap: Examples of various fills. sules to the colon. One such technology in this for either new indications or extending the shelf idly to progress clinical candidates through the area is ENCODEpHloral, a specialised patented life due to patents lapsing. development process. The use of powder fill colonic target coating. capsules without formulation using equipment

ENCODEPHloral is a dual-trigger mechanism, DELIVERY OF BIO-MOLECULES such as the Xcelodose (Capsugel, Peapack, NJ, utilising pH and the microbiota in the colon, for US) has been very well accepted by the industry delivery of the drug accurately and consistantly to Delivering therapeutically active large mol- for first-in-man studies. This has been a valu- the colon, either for topical delivery such as anti- ecules by the oral route has been a challenge and a able innovation. However, a draw-back is that inflammatory drugs for ulcerative colitus / Crohn’s goal for several decades. The oral route of admin- the capsule output makes it difficult to support disease. For certain drugs, systemic delivery may istration for these substances is problematic for larger-scale trials without the need for long be achieved via the colon with increased bioavail- many reasons: proteolysis by gastric and pancre- manufacturing campaigns running into many ability due to lower expression of the PGP efflux atic enzymes; high acidity in the stomach; and lim- days for a single batch. Liquid-fill encapsulation mechanism and/or due to the absence of certain ited absorption through the GI tract for instance. provides an alternative route to rapidly progress enzymes in the colon, such as CYP 3A4, which However the benefits of oral delivery are clear, simple formulations of actives into the clinic may degrade a drug if it is a CYP3A4 substrate. with the ease of administration and improved which is capable of accommodating batch-to- patient compliance being the major advantages. batch variations in API (particle size, shape, DUOCAP TECHNOLOGY density and flow characteristics) and can scale Encap can employ a number of strategies: easily from bench to high speed machines. DuoCapTM is a single, oral-dosage unit that • Formulation is designed for optimal biomol- comprises a capsule-in-a-capsule and offers ecule chemical and conformational stability WHY CONSIDER A LIQUID FILL broad therapeutic applications. The inner and in a part aqueous environment which is still FORMULATION FOR A FIRST-IN- outer capsules may contain the same active compatible with capsules MAN STUDY? drug providing multiple release profiles from • Avoid exposure to stomach and targeted deliv- the dosage unit, for exampe, an immediate- ery to small intestine using enteric coating For the oral dosing route of administration, release formulation from the outer capsule • Targeted delivery to colon using ENCODE there are several dosage form options generally and a controlled-release formulation from the technologies used for first-in-human studies: API in bottle; inner capsule. • As well as delivery of proteins and peptides, powder in bottle; API into capsule; and tradi- In addition to modifying the release profiles our approach can also be used for domain tional formulations of tablets/capsules. Each it is also possible to target the inner and outer antibodies, oligonucleotides and oral vaccines. approach has associated advantages and disad- capsule to different areas of the GI tract (small vantages. In many instances a liquid-filled hard intestine or colon), with the appropriate coating Case Study: capsule may be a more appropriate formulation as discussed earlier. Alternatively, the capsules A water-soluble protein which is stable in for numerous reasons including: may contain different actives for use with com- an aqueous environment, was provided as a bination therapies or actives that are incompat- concentrate in an aqueous buffer (phosphate • Best chance bioavailability for API ible in a single capsule. buffer solution (PBS)), which was diluted to the • Protects hygroscopic and oxidation sensitive Combination therapies are currently of sig- required concentration with water. The diluted compounds including proteins and peptides nificant interest, demonstrated by the recent protein/buffer solution was then incorporated • Ideal for cytotoxic APIs launches of CombodartTM (GlaxoSmithKline) into a novel formulation containing 28% water. • Removes issues caused by API variability and VimovoTM (Pozen/AstraZeneca). A hard-shell gelatine capsule was then filled (particle size, shape, crystal habit, density, The inner capsule may contain liquid, semi- with the formulation and the capsule was closed polymorphic form or moisture) solid, powder or pellet formulations and the and banded. After stability testing, the capsule • Eliminates compatability issues between shell outer capsule contains liquid or semi-solid for- was found to remain stable without softening and API mulations (see Figure 1). or cracking after three months stability storage, • Provides a scalable formulation that may be Combination drugs have not been as common and the formulation retained its protein concen- suitable up to Proof of Concept and beyond. in the industry as one may think. This may be due tration and activity. This therefore provided a to stability issues between the actives. The advent viable route for the formulation of proteins (and ENHANCED STABILITY of capsule-in-capsule technology allows both peptides) in stable aqueous media for adminis- API’s to be kept distinctly separate. Therefore, tration in capsule form. The chemical stability of oxygen-, mois- it is likely that combination drugs may become ture- and light-sensitive drugs can be signifi- more common in the Pharmaceutical industry. FAST CLINICAL DEVELOPMENT cantly improved by using liquid or semi-solid Fewer new drugs are being discovered and devel- capsule products. By dissolving the drug in oped and current drugs seem to be getting more Liquid-fill encapsulation can provide a valu- non-aqueous vehicles which are compatible of the spotlight in terms of being re-formulated able tool to enable drug developers more rap- with capsules, this problem of instability can be

Copyright © 2011 Frederick Furness Publishing www.ondrugdelivery.com 35 Category Examples release profile, formulated from excipients chosen to provide the best deterrence to potential Opioids and Morphine Derivatives Vicodin, OxyContin, Demerol, Percodan routes of abuse. The objective is to provide a Depressants Xanax, Librium, Valium useful pharmaceutical to the patient whilst providing resistance to abuse by others. Stimulants Ritalin, Adderall, Dexedrine Release profiles can be tailored to give immediate (e.g. 100% in 30 minutes), con- Anabolic Steroids Anadrol, Oxandrin trolled, delayed or sustained release (e.g. 100% Figure 2: Prescription Drugs of abuse. release in 40+ hours). The release profiles can be manipulated by selecting the appropriate reduced or eliminated. Similarly, the amount of ABUSE RESISTANCE excipients, size of the capsule and the active moisture present in tablet- or powder-based concentration formulations can be 10-100 times greater than There is an increasing interest from pharma in the oil- or lipid-based formulations used at companies and regulators in the development The abuse resistance can be achieved Encap. This can have a significant impact in of abuse resistant formulations. Prescription through use of: improving drug stability. drug abuse is prevalent globally. Figure 2 pro- • High melting excipients to prevent melting Vancomycin is one product that was suc- vides examples of drugs commonly abused, in and injection cessfully developed as a liquid-fill capsule various categories. In the US there are about • Waxy materials, which prevent powdering at product in order to achieve acceptable stability. six million users of prescription drugs for room temperature and resistance to snorting non-medical use. Within that six million, the • Unpleasant tasting excipients + taste modifiers HIGH POTENTCY PRODUCTS majority of the abuse is of pain relievers; about • Thickening agents which make it difficult to 4.4 million abusers. There are over 500,000 extract and inject active Liquid-fill, hard-capsule technology is becom- emergency-room incidents per year. Since 1998 • Capsule banding. ing an increasingly attractive approach for both there has been a >100% increase in abuse of high-potency products and for anticancer agents. controlled prescription drugs. This represents IP PROTECTION Technically, it offers processing convenience in a far greater increase than that in marijuana, minimising hazards of cross-contamination, mini- cocaine and heroin use. In 2007, 5.2% of 12th- One other often overlooked advantage of mises the need for complex and expensive plant grade students reported to have abused oxyco- liquid-filled hard capsule formulations is that of and assures product uniformity. The approach done, and 9.6% abused Vicodin (hydrocodone patent protection or patent avoidance. has also become more attractive commercially + paracetamol). Various products have been manufactured with the availability of contract facilities with the Methods of abuse tend to be snorting, injec- using a LFHC formulation avoiding current IP relevant specialized full-scale GMP plant . tion, ingestion (melting or extracting), dose protection. As an example a patent may specify Low dosage products (under 10mg) can often dumping by chewing , abuse of others (covert a certain particle size distribution for an active. give rise to low content uniformity. For tablet administration). Using an array of solubilisers this issue is and powder formulations it is often very difficult The abuse potential of dosage forms such as avoided by solubilising the active. to achieve an acceptable uniformity. Liquid-fill tablets, capsules (powder fill) and soft gelatin formulations, as solutions or suspensions, rou- capsule is significant. CONCLUSION tinely provide better dose homogeneity and fill accuracy compared with powder-fill capsules, or Tablets: Liquid-filled, hard two-piece capsule for- tablets. They are often the formulation of choice • Most popular oral form mulations are an excellent choice to overcome for low-dose products. In addition, liquid-fill • Can be crushed easily to give a high surface area various technical and patent issues that arise in capsules generally require less API and excipient • Ideal for fast release, extraction, snorting, dose the formulation development of a drug product. compared with other formulations, thus minimis- dumping and possibly dissolution and injection ing API requirements in both the early stages of Benefits Summary: drug product development and clinical manufac- Powder filled capsules: • Enhanced Bio-availability ture. These formulations are also very scalable • Already has a high surface area • Enhanced Stability ensuring a smooth and speedy transition from • Can contain high-melting-point solids • Targeted Delivery bench scale to commercial scale when required. • Waxy or sticky materials cannot be used • Fast to Clinic formulations Encap has considerable experience of • Similar abuse potential to tablets • Abuse Resistance formulations developing uniform, formulations for doses as • Low dose /potent API Uniformity low as 250 μg. Soft gels: • Oral Bio-molecule delivery Drug products that are intended for use in low • Contain liquids or near liquid • IP avoidance. doses are generally difficult to produce in a solid • Maximum fill temperature of about 35°C. oral dosage form. The highly potent nature of such • Contents can thus be liquefied near body Encap is no novice when it comes to the drugs (cytotoxic agents, hormones, etc) means that temperature, extracted, dose dumped or development and commercial manufacture of they carry increased risks of cross contamination directly injected. liquid-filled, hard two-piece capsule (LFHC) and can expose operators to harmful dust during technology. In fact, Encap, with over 20 manufacture. Incorporating these APIs into a dust- Encap’s Abusolve™ technology is the years’ experience and more than 60 dedicated free liquid or semi-solid formulation is a valid application of hard-shell liquid-fill techniques staff, is the number one in the liquid-fill alternative which protects against these risks. to produce a dosage unit tailored to the required hard-capsule field.

Exploit the potential of your lipid-based formulations for poorly soluble compounds ) Fill and seal up to 1,500 capsules per hour with the CFS 1500 C system and 1,200/hr with the CFS 1200 system ) Ideal for clinical trials – Pre-clinical, Phase I and Phase II ) Suitable for dosing API solutions, self-emulsifying liquids, micro-emulsions and hot melt formulas ) Allows easy integration into a suitable containment system (CFS 1500 C system) CFS 1500 C and CFS 1200 ) Records weight of each capsule ﬁlled (CFS 1500 C system) liquid ﬁlling and sealing systems

Fast, ﬂexible, precision powder ﬁlling ) Fills single receptacles or 600+ capsules per hour (depending on system chosen) ) Repeatable dispensing of any dry powder with doses as low as 100μg with an RSD of ˜1-2% ) Fills most formulated (blend) powders without segregation ) Dispense into a variety of receptacles (capsules, vials, tubes, beakers, etc.) ) Ideal for clinical trials – Pre-clinical, Phase I and Phase II ) Fill up to 600 capsules per hour

Xcelodose® 600 S precision powder micro-dosing system and Xcelolab™X carousel option for batch ﬁlling Xcelolab™ powder dispenser increasesin throughput. NEW Xceloprotect™X isolator for ﬁlling potent compounds.

Call +44 1304 644791, email ptg@pﬁzer.com or visit www.capsugel.com

In this piece, Dale Natoli, Vice-President, Natoli Engineering Company, Inc, provides a brief overview of multi-tip tooling for tablet presses, and provides some guidelines for selecting the most appropriate equipment.

Multi-tip tooling isn’t new to the pharmaceuti- The solid multi-tip configuration (Figure 2), cal industry; the unique tool configuration has which is machined from a single piece, is becom- been used for more than 150 years. At the start ing more popular. It requires no disassembly for of the tablet compression industry, single-sta- cleaning, eliminating reassembly and ensuring tion tablet presses were used in production and proper alignment of punch tips in the die. However, were commonly outfitted with multi-tip tooling it allows fewer punch tips in relation to tablet size. to increase tablet production and reduce labour, Before investing in multi-tip tooling, verify maintenance, energy, space requirements and that your tablet press has turret punch guides the number of presses. When the high-speed and die sockets that are in good condition, with Figure 1: Assembly configuration 16-station rotary tablet press was introduced no excessive wear. Worn guides and/or worn comprising the punch body, cap, and in the late 1800s, the single-station press and die pockets can create punch-tip misalignment, individual punch tips. multi-tip tooling lost popularity. which in turn causes premature tip wear, exces- Soon after the introduction of the rotary tablet sive head and cam wear, and tool binding in the press, the industrial, confectionery, and food indus- punch guide and tip binding in the die. You can tries implemented multi-tip tooling, and today the easily check the condition of the turret with a pharmaceutical industry is following suit. turret inspection kit, which is available from Multi-tip tooling is available in two common most tooling manufacturers. Inspect the turret for configurations: assembly (or multi-piece), and wear periodically, regardless whether single-tip solid. When choosing the configuration, con- or multi-tip tools are used. Inspection will alert sider the tool type, tablet size, and the number you to premature tool wear and tooling failure. of tips per punch. Also consider tool handling For tablet presses with tablet rejection sys- Figure 2: Solid configuration, machined practices, cleaning, and inspection. The sup- tems, many companies use validation punches, from a single piece. plier will help you decide which configuration which are identical to the other punches except is best. Most tooling suppliers have selection for a slight deviation in their working and guidelines for each tool type. overall lengths. The validation punch verifies The assembly configuration consists of the the operation of the reject system by produc- punch body, cap, and individual punch tips (see ing tablets of different hardness, thickness, and Figure 1). The biggest advantage of the assembly weight. While some pharmaceutical companies is the removable punch tips. If one of the punch are turning to multi-tip tooling, other companies tips is damaged, it can easily be replaced so the are more reticent, investigating the effect on punch can return to service. If a punch tip on product flow, compression and ejection forces, the solid configuration (Figure 2) is damaged, and tablet reject systems, among others. the entire tool must be replaced, which is costly. But multi-tip tooling can definitely pay Dale Natoli Vice-President Cleaning and sanitising the assembly con- off. For example, a US pharmaceutical com- figuration requires disassembling the punch pany I worked with produced approximately T: +1 636.926.8900 tips from the punch body, cleaning and drying 8,540 pellets per minute using single-tip tooling. F: +1 636.926.8910 each component, and reassembling. Although When they switched to nine-tip tooling, produc- E: [email protected] reassembly should be quick and easy, if any tion reached approximately 76,860 pellets per of the mating parts become damaged or even minute. That’s an 800 percent increase without Natoli Engineering Company, Inc nicked, or if a slight amount of debris or corro- additional personnel or equipment! 28 Research Park Circle St Charles, MO 63304 sion interferes, the punch tips won’t align. If the Is your product a candidate for multi-tip United States punch tips don’t align properly and the punch is tooling? Check with your supplier. In today’s returned to service, the tooling may fail prema- economy, increasing tablet production while www.natoli.com turely or damage the press. cutting operating costs is especially attractive.

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