- Email: [email protected]
Development of amorphous solid dispersion formulations of a poorly water-soluble drug, MK-0364
Accepted Manuscript Title: Development of Amorphous Solid Dispersion Formulations of a Poorly Water-Soluble Drug, MK-0364 Authors: S. Sotthivirat C. McKelvey J. Moser B. Rege W. Xu D. Zhang PII: DOI: Reference:
S0378-5173(13)00338-4 http://dx.doi.org/doi:10.1016/j.ijpharm.2013.04.037 IJP 13279
To appear in:
International Journal of Pharmaceutics
Received date: Revised date: Accepted date:
20-8-2012 10-3-2013 15-4-2013
Please cite this article as: Sotthivirat, S., McKelvey, C., Moser, J., Rege, B., Xu, W., Zhang, D., Development of Amorphous Solid Dispersion Formulations of a Poorly Water-Soluble Drug, MK-0364, International Journal of Pharmaceutics (2013), http://dx.doi.org/10.1016/j.ijpharm.2013.04.037 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Formulation preparation by solvent casting
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Physical characterization Dissolution
MK-0364 solid dispersion candidates HME
Dissolution testing
SD
Physical characterization
In vivo study
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Development of Amorphous Solid Dispersion Formulations of a Poorly
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Water-Soluble Drug, MK-0364
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S. Sotthivirat *, C. McKelvey, J. Moser, B. Rege, W. Xu, and D. Zhang *
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Departments of Product Value Enhancement, Formulation Sciences, and Analytical Sciences,
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Merck & Company, Inc., West Point, PA 19486, USA
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Merck & Company, Inc., Summit, NJ 07901, USA
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* Correspondence
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S. Sotthivirat
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Merck & Company, Inc.
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770 Sumneytown Pike
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West Point, PA 19486
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USA
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Telephone: (215) 652-0924
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E-mail: [email protected]
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and D. Zhang
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Merck & Company, Inc.
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556 Morris Avenue
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Summit, NJ 07901
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USA
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Telephone: (908) 473-2305
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E-mail: [email protected]
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Abstract
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The goal of this study was to demonstrate that MK-0364 solid dispersions can be developed as a
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means to increase the solubility and bioavailability of a poorly water-soluble drug, MK-0364.
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The potential solid dispersions would enable an oral solid dosage form as a monotherapy or
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combination product of MK-0364. Preliminary screening included sample preparation via a
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solvent casting method, physical characterization, and in vitro dissolution testing. Lead
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formulations were subsequently manufactured using hot melt extrusion (HME) and spray-drying
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(SD). All HME (without polyvinyl pyrrolidone) and SD formulations exhibit characteristics of a
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single phase glass including an amorphous halo when analyzed with X-ray powder diffraction
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(XRPD), a single glass transition temperature (Tg) measured with differential scanning
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calorimetry (DSC), and supersaturation when dissolved in dissolution media. The oral
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absorption of MK-0364 from selected HME and SD formulations in monkeys results in
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marginally greater exposure with a consistently longer Tmax relative to a liquid filled capsule
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reference. Based on the processability, physical characterization, in vitro dissolution, and animal
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pharmacokinetic results, copovidone- and hydroxypropyl methylcellulose acetate succinate
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(HPMCAS)-based solid dispersion formulations are viable product concepts. The physical
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stability of both the solid dispersion formulations was also evaluated for 54 weeks under
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different conditions. The copovidone-based solid dispersion requires protection from moisture.
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Keywords: MK-0364, copovidone, HPMCAS, solid dispersion, hot melt extrusion, spray drying,
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dissolution, bioavailability
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1. Introduction Drugs with poor aqueous solubility have low or erratic absorption and, consequently, poor and variable bioavailability. Several common formulation approaches to increase
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the drug solubility/bioavailability include the use of cosolvents, surfactants, cyclodextrins
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(Loftsson and Brewster, 1996; Rajewski and Stella, 1996; Stella and Rajewski, 1997),
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salt formation, pH adjustment, particle size reduction, or lipid-based formulations. Solid
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dispersions or, more specifically, solid solutions of drugs in polymers as alternatives can
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be produced using cost effective manufacturing technologies adapted from other
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industries (e.g., extrusion and spray drying), enable solid products directly suitable for
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fixed dose combinations, and do not require prohibitively expensive excipients (e.g.,
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hydroxypropyl-beta-cyclodextrin).
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Solid dispersions have been used for dissolution or bioavailability enhancement since
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the 1960s. Solid dispersions are defined as the solid state dispersions of one or more
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compounds in an inert matrix (Chiou and Riegelman, 1971). Early solid dispersions
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using low molecular weight matrices such as urea and succinic acid increased the
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dissolution and absorption of sulfathiazole (Goldberg et al., 1965; Sekiguchi and Obi,
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1961), chloramphenicol (Goldberg et al., 1965), griseofulvin (Chiou and Niazi, 1976;
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Goldberg et al., 1966b), and acetaminophen (Goldberg et al., 1966a). More recent solid
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dispersions using high molecular weight matrices such as polyethylene glycols, cellulose
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derivatives, acrylics (polyacrylates, polymethacrylates), and polyvinyl-based polymers
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not only enhanced the dissolution and bioavailability but also provided good physical
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stability of several compounds (Al-Obaidi and Buckton, 2009; Andrews et al., 2010;
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Andrews et al., 2009; Curatolo et al., 2009; Dong et al., 2008; Friesen et al., 2008;
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Kennedy et al., 2008; Konno et al., 2008; Leuner and Dressman, 2000; Serajuddin, 1999).
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Additionally, solid dispersions are suitable for the production of a wide variety of solid oral dosage forms. For example, the melted drug/matrix can be extruded and
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shaped as films, sticks, granules, pellets, powders, or individual unit dosage forms (e.g.,
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injected molds). Alternatively, solid dispersions can be used as intermediates to be
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further processed into conventional tablets as immediate or modified release
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formulations. Several commercially available products are based on solid dispersions
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such as Gris-PEG (griseofulvin/PEG), Certican (everolimus/HPMC), Isoptin-SRE
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(verapamil/HPC/HPMC), ProGraf (tacrolimus/HPMC), Cesamet (nabilone/PVP), and
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Kaletra (lopinavir/ritonavir/copovidone).
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The research described here involves the development of amorphous solid dispersion
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formulations of a poorly water-soluble drug, MK-0364, to increase its solubility and
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bioavailability. The potential solid dispersions would enable an oral solid dosage form as
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a monotherapy or combination product of MK-0364. The evaluation of this system
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included initial preparation via solvent casting, physical characterization, and in vitro
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dissolution testing prior to identifying lead formulations for further development via hot
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melt extrusion (HME) and spray-drying (SD). During HME and SD formulation
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development, physical characterization, in vitro dissolution testing, and in vivo evaluation
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were conducted to select the best candidates for subsequent physical stability studies.
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2. Materials and Methods
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2.1 Materials
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All chemicals were analytical grade or ACS reagents. MK-0364 was obtained from Merck & Co., Inc. Polysorbate 80 (Tween 80™, Croda, Inc., Edison, NJ), sorbitan
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monooleate (Span 80®, Uniqema, New Castle, DE), polyvinyl pyrrolidone (PVP or
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Plasdone® K-29/32, ISP Corporation, Wayne, NJ), methacrylic acid copolymer
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(Eudragit L100-55, Evonik Degussa Corporation, Piscataway, NJ), caprylic/capric
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glycerides (Imwitor® 742, Sasol North America, Inc., Westwood, NJ), acetone, methanol,
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hydrochloric acid, and water were used as received. D--tocopheryl polyethylene glycol
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1000 succinate (vitamin E TPGS) and butylated hydroxylanisole (BHA) were purchased
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from Eastman Chemical Company (Kingsport, TN). Hydroxypropyl methylcellulose
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(HPMC, Pharmacoat grade 606), hydroxypropyl methylcellulose phthalate (HPMCP HP-
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55) and hydroxypropyl methylcellulose acetate succinate (HPMCAS-LF) were purchased
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from Shin-Etsu Chemical Co., Ltd., Japan. Copovidone (Kollidon® VA 64), poloxamer
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407 (Lutrol F 127), polyoxyl 35 castor oil (Cremophor EL), and sodium lauryl sulfate
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(Texapon K 12 P PH) were purchased from BASF Corporation (Florham Park, NJ).
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2.2 Preparation of Solvent Cast (SC) Formulations The SC formulations (Table 1) were prepared by dissolving 2 g of solids in 15 mL of
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a suitable organic solvent according to the solubility. The solutions were spread into a
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thin layer in a foil-protected aluminium or stainless steel pan for drying in a vacuum
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oven. Samples were dried for approximately 30 min at 110C/>30 in Hg, transferred
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from pans to glass vials, and dried for an additional 16 hours at 40C/ambient.
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2.3 Preparation of Hot Melt Extrusion (HME) Formulations
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Prior to the HME process, all components listed in Table 2 were pre-blended in a Bohle high shear granulator (model BMG, L.B. Bohle, Germany). Polysorbate 80 and
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sorbitan monooleate were first mixed to obtain a homogeneous solution, whereas vitamin
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E TPGS was melted in a water bath set at 40-45C. Copovidone and MK-0364 were
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blended in the high shear granulator for 3-5 min with an impeller speed of 300-500 rpm.
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The surfactants were then added to the granulator over a period of 3-8 min using 300-500
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rpm impeller and 1000 rpm chopper speeds, followed by a 2-5 min additional mixing.
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The wet granulated sample was introduced into a Thermo Scientific 16 mm 25:1 L/D
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corotating twin-screw extruder (Thermo Fisher Scientific, Inc., Waltham, MA) set at 130-
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160C using a Brabender Technologie single-screw FlexWall feeder (20% drive
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command in volumetric mode). The twin-screw extruder screw designs are illustrated in
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Figure 1. The resulting extrudate was ambiently cooled and ground in a mortar with a
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pestle for physical characterization.
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2.4 Preparation of Spray-Drying (SD) Formulations
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The SD formulations listed in Table 3 were prepared using a Niro SD-Micro spray
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dryer (GEA Processing Engineer, Inc., Columbia, MD). A feed solution at 5% solids was
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prepared by dissolving polymers, surfactants, and MK-0364 in a suitable solvent.
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Acetone was used in SD 1, whereas methanol was used for the remainder. After
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dissolving completely, the feed solution was atomized into a spray of droplets. The spray
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dryer experiments were designed to achieve a specific target nitrogen gas outlet
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temperature (50-60C for SD 1 and 60-70C for others). The resulting spray-dried
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particles were collected in a cyclone and bag filter. The solution feed rate (1-10 mL/min)
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was controlled by an external peristaltic pump. The atomizing nitrogen and processing
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nitrogen rates were 1-5 Kg/hr and 10-30 Kg/hr, respectively.
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2.5 In vitro MK-0364 Dissolution Studies for Solid Dispersion Formulations
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The MK-0364 dissolution testing on all solid dispersion formulations except SC 1, SC 2, SC 3, and SD 1 was performed in a 250 mL 0.1 N HCl solution using the USP
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paddle (II) method at 37C (100 rpm, n=3). For SC 1, SC 2, SC 3, and SD 1, MK-0364
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release was performed in a 250 mL 25 mM buffer solution (pH 6.85) using the same USP
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method as described above due to the solubility of these enteric coating polymers at pH
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5.5 or above. Dissolution samples were withdrawn via a 35 µm flow through filter at
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predetermined intervals and assayed by HPLC using a Vydac C18 (250 x 4.6 mm, 5 µm
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particle size) column. The method used a gradient mobile phase consisting of methanol
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and 0.1% phosphoric acid at a flow rate of 1.5 mL/min, and the effluent was monitored at
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220 nm.
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2.6 Physical Characterization of Solid Dispersion Formulations
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All solid dispersion samples were evaluated and characterized using differential
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scanning calorimetry (DSC, model Q2000, TA Instruments, Inc., New Castle, DE),
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thermogravimetric analysis (TGA, model G5000, TA Instruments, Inc., New Castle, DE),
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X-ray powder diffraction (XRPD, Panalytical X'pert Pro diffractometer, Spectris plc,
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England), and optical microscopy (Olympus BX51, Olympus America, Inc., Center
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Valley, PA). Dry Tg data were obtained by heating a sample in an aluminium pan at a
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constant rate of 10C/min following the removal of solvent via an initial heating cycle.
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In addition, glass transition temperatures (Tg) of certain samples stored under different
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conditions (30C/65%RH, 40C/ambient, 40C/75%RH, and 60C/ambient) were
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determined as a function of water content using a modulated DSC (mDSC) where a
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sample was initially equilibrated at 10C and then modulated at 0.5C every 60 sec with a
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ramp rate of 2.5C/min to 100C. Water content was determined using TGA by heating a
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sample at 10°C/min to 190C under nitrogen flow. XRPD spectra were collected on the
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Panalytical X'pert Pro diffractometer with Cu Ka1 radiation of 1.5406Å in the
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transmission mode at ambient conditions. Samples were scanned between a two theta
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range of 2º and 40º at a step size of 0.0167º and a scan rate of 2.4º/min. A few samples
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were also analyzed at a scan rate of 0.02º/min within a narrower two theta range (15º to
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22º) to improve the detection limit for crystalline drug. The tube power used was 45 kV
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and 40 mA.
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2.7 Evaluation of Pharmacokinetic (PK) Parameters Following the Oral Administration
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of HME and SD Formulations in Rhesus Monkeys
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HME and SD samples were prepared in capsules with 6 mg MK-0364 and drug X, as
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shown in Table 4. These formulations were administered orally in rhesus monkeys (n=6)
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in a crossover design and compared to coadministration of MK-0364 LFC and drug X
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formulations as a reference, to evaluate their potential differences in oral absorption. The
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MK-0364 LFC formulation was prepared by dissolving MK-0364 in caprylic/capric
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glycerides/ polysorbate 80 (1:1, w/w) and placed in a capsule while the drug X
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formulation was prepared by blending of drug X with other excipients and compressed
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into a tablet. All the monkeys were fasted for 16 hours prior to dosing. The capsules
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were given orally via a gavage tube, followed immediately by water (20 mL). After
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dosing, water and food were returned at 1 hour and 4 hours, respectively. Blood was
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drawn via venipuncture using a butterfly needle inserted into the saphenous vein at
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predose and predetermined time intervals postdose. The plasma was separated by
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centrifugation and analyzed using liquid chromatography/electrospray ionization tandem
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mass spectrometry(LC/ESI-MS/MS). The chromatography was performed on a Aquasil
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C8 (100 x 2 mm, 5µm particle size) column, using 75% acetonitrile and 25% 25mM
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ammonium formate buffer (pH 3.0). PK parameters including area under the curve
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(AUC0-24 hr), observed maximum plasma concentration (Cmax), and time of Cmax (Tmax)
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were calculated using noncompartmental analysis in WinNonlin. All studies were
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conducted under a protocol approved by Merck Institutional Animal Care and Use
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Committee (Merck IACUC), in accordance with USDA guidelines.
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2.8 Physical Stability Studies of HME and SD Formulations Lead formulations were chosen based on the in-vivo and dissolution results. The
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physical stability of the lead formulations was performed up to 54 weeks as a function of
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relative humidity and temperature (5C with desiccants, 25C/ambient, 30C/65%RH,
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40C/ambient, 40C/75%RH, and 60C/ambient). Physical characterization of stressed
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samples was performed using the techniques listed previously. In addition, a water
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sorption/desorption isotherm of HME 1 was determined at 25C from 5% to 95% RH
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using a dynamic vapor sorption analyzer (VTI model SGA-100, TA Instruments, Inc.,
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New Castle, DE) with an integrated microbalance system to measure the uptake and loss
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of water. Weight measurements were taken over a 180-min equilibration period at each
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RH level studied.
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Results and Discussion
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3.1 Physicochemical and Biopharmaceutical Properties of MK-0364
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MK-0364 (Figure 2), a cannabinoid receptor type 1 (CB-1) inverse agonist, is
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available as a crystalline form with its solubility less than 0.4 µg/mL at pH 1-10. No
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stable salt was successfully discovered due to its very low pKa of the pyridine nitrogen,
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but improved solubility with lipid-based vehicles and surfactants was reported (Table 5).
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The in vitro permeability of MK-0364 through a Caco-2 cell monolayer in the apical to
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basolateral direction was found to be 0.91 ± 0.07 x 10-6 cm/s, which is much less than
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that of metoprolol used as a reference. Therefore, it is classified as a BCS class IV drug
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with a dose number (Amidon et al., 1995; Rohrs, 2006) of 60 based on a 6 mg dose. In
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animal studies, MK-0364 absorption from a traditional wet granulation of MK-0364 with
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sodium lauryl sulfate was less than 20% of that obtained from the liquid filled capsule
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(LFC) formulation containing caprylic/capric glycerides/ polysorbate 80 (1:1, w/w). The
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absorption observed from LFC formulations led to the development of MK-0364 LFC
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formulations for the treatment of obesity as monotherapy.
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The glass-forming tendency, defined as the ratio of Tg to Tm (both temperatures are in
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kelvin), is used to suggest how easy the glassy state can be obtained (Zallen, 1983). The
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Tg/Tm ratio of MK-0364 is greater than 0.7, suggesting MK-0364 is an "excellent glass
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former" (the Tg and Tm of MK-0364 are 41C and 104C, respectively, resulting in a
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Tg/Tm ratio of 0.83). Overall, MK-0364 appears to be a good candidate for a solid
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dispersion approach because of its poor aqueous solubility and anticipated behavior as an
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"excellent glass former".
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3.2 Preliminary Screening Using a Solvent Casting Approach
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Formulations with various polymer/surfactant combinations at a fixed drug loading
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were first prepared using a solvent casting technique (Table 1), and several surfactants
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were evaluated based on the solubility data in Table 5. The formulations were
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subsequently characterized using XRPD, DSC, optical microscopy, and in vitro
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dissolution testing (Table 6 and Figures 3a-b). No crystallinity was detected in the
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formulations listed in Table 6 except SC 8 using XRPD and optical microscopy. SC 8
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showed some crystallinity, which is due to the semicrystalline nature of poloxamer. It
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should be noted that the presence of MK-0364 with a Tg of 41C may contribute to
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considerable Tg depression in the formulations, and, therefore, high Tg polymers such as
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Eudragit L100-55, HPMC HP-55, HPMCAS-LF, and copovidone may be beneficial to
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improve the physical stability of MK-0364 (e.g., prevent recrystallization or phase
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separation of MK-0364). During the screening of the high Tg polymers, the relatively
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high Tg values of the binary polymer/MK-0364 systems were observed for SC 1-4 (Table
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6). For the copovidone-based formulations, the effect of surfactants present in SC 5 and
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SC 6 on Tg was apparent, as compared to SC 4, but SC 6 had the lowest Tg due to the
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presence of vitamin E TPGS at high levels.
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Among the binary dispersions without surfactants (Figure 3a), the HPMCAS system
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(SC 3) showed the best sustained supersaturation for 60 min. MK-0364 precipitation was
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observed in both the HPMCP (SC 2) and Eudragit (SC 1) samples, however, which is
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consistent with the reduced area under the dissolution curve of MK-0364. In addition,
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there was relatively higher variability in MK-0364 released from SC 1 and SC 2 than SC
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3. The high variability is likely caused by variability in the drug crystallization rate
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among the samples (n=3) of SC 1 and SC 2 during the dissolution testing. It is not
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untypical for nucleation or crystal growth to proceed at different rates in different
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dissolution vessels. Although the 30 min data points for SC 1 and SC 2 appear to be
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inconsistent with the rest of the data, the rank order for dissolution performance among
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SC 1, SC 2, and SC 3 is still very clear. It is apparent that HPMCAS (SC 3) provides the
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best dissolution enhancement (sustained supersaturation) compared to HPMCP (SC 2)
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and Eudragit (SC 1). The supersaturation is attributed to the ability of polymers to
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inhibit nucleation and/or crystallization. HPMCAS has been shown to promote
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supersaturation during in vitro dissolution for several compounds due to the amphiphilic
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nature of HPMCAS (Dhirendra et al., 2009; Friesen et al., 2008; Ilevbare et al., 2012;
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Kennedy et al., 2008; Konno et al., 2008). It is believed that the hydrophobic regions of
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the polymer allow drug molecules to interact with the polymer and form amorphous
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drug/polymer nanostructures, whereas the negative charges of the succinate groups of
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HPMCAS help the nanostructures remain as stable colloids in solution (Friesen et al.,
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2008).
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The dissolution of MK-0364 from the copovidone-based formulations was evaluated
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and found to be profoundly influenced by surfactants such as polysorbate 80/ sorbitan
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monooleate, vitamin E TPGS, polyoxyl 35 castor oil, and poloxamer. The impact of
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surfactants on supersaturation behavior in the copovidone system was ranked as follows:
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SC 10 << SC 7 < SC 8 SC 9 < SC 6 < SC 5 (Figure 3b). This is also consistent with
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studies in which the dissolution rate and saturation solubility of tested drugs were
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enhanced with the presence of surfactants in copovidone (Ghebremeskel et al., 2006). On
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the one hand surfactants may stabilize the solid dispersion by increasing drug solubility
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and homogeneity in the polymer. However, on the other hand surfactants can destabilize
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the system by acting as plasticizers to lower the Tg and increasing water uptake
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(Ghebremeskel et al., 2006, 2007). Therefore, it is critical to determine the optimal
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surfactant level to ensure physical stability without compromising any supersaturation
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characteristics or formulation processing.
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based formulations with either polysorbate 80/ sorbitan monooleate or vitamin E TPGS
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and the HPMCAS-based formulation appear to be the beset candidates. Copovidone has
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been commonly used in HME formulations owing to a relatively low Tg and good
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thermal stability, whereas processing HPMCAS with extrusion is generally more
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challenging (Dong and Choi, 2008; Schenck et al., 2010). Therefore, the copovidone-
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based formulations with either polysorbate 80/ sorbitan monooleate or vitamin E TPGS
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were chosen for HME development, whereas the HPMCAS-based formulation was
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chosen for SD development.
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3.3 HME Formulations: Processing, Physical Characterization, and Dissolution
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Following the preliminary screening indicating surfactants required for the
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copovidone system, specific formulations (Table 2) were manufactured using hot melt
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extrusion to produce material for further study and to assess potential challenges with
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extrusion processing. HME 1 and HME 2 are two different copovidone-based HME
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formulations with polysorbate 80/ sorbitan monooleate and vitamin E TPGS,
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respectively, whereas HME 3, HME 4, and HME 5 were modified from HME 1. BHA
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used as an antioxidant was evaluated in HME 3 to improve the chemical stability of MK-
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0364 if necessary. In addition, PVP was evaluated in HME 4 and HME 5 as an
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additional polymer to increase the physical stability of HME formulations. The
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surfactant quantity was chosen based on prior experience. Surfactants listed in HME 1
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and HME 2 in Table 2 were reduced by half (as compared to SC 5 and SC 6 in Table 1)
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because of the processing issues such as poor flow properties and inhomogeneity of
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polysorbate 80/ sorbitan monooleate and vitamin E TPGS (data not shown). It is
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noteworthy that supersaturation behavior was not compromised with the reduced
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surfactants (Figure 3c). During the processing of all the formulations listed in Table 2,
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the feed rate was set at 20% of maximum speed, but the actual rate was much lower and
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variable due to poor flow properties of the wet granulated samples. The flow related
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issues can be minimized by roller compacting material following wet granulation, using a
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gravity feeder, or directly adding the liquid surfactant as a separate feed stream.
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Crystallinity was not detected in samples HME 1, HME 2, and HME 3 using XRPD,
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optical microscopy, and thermal characterization. In addition, a single Tg in the range of
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85-90C was observed (Table 7), indicating single phase behavior of amorphous or
315
undetectable levels of phase separation. All the extrudate strand samples except HME 4
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and HME 5 were clear and slightly yellow. The extrudate strand samples of HME 4 and
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HME 5 were grainy and opaque even though the processing temperature was increased to
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160-170C. No crystallinity was detected in both HME 4 and HME 5 using XRPD, but
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at least two distinct Tg events were observed in HME 5 using mDSC. In addition, the
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presence of different levels of PVP in HME 4 and HME 5 did not have any impact on dry
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Tg. Based on visual observation, it is likely that HME 4 is heterogeneous even though it
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was not possible to detect multiple glass transition temperatures with DSC. Additionally,
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the presence of BHA as an antioxidant in HME 3 slightly reduced Tg without any
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detected crystallization.
Based on initial process development evaluation and physical characterization, HME
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1 and HME 2 were further evaluated in dissolution and animal studies. Dissolution
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profiles of HME 1 and HME 2 were similar, as shown in Figure 3c. However, in animal
328
studies HME 1 showed slightly greater bioavailability than HME 2 in both AUC and Cmax
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(see more detail in Section 3.5). HME 1 was, therefore, selected as a HME lead for
330
subsequent physical stability studies.
333
M
3.4 SD Formulations: Physical Characterization and Dissolution
te
332
d
331
an
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326
Besides the above HME formulations, SD formulations as shown in Table 3 were prepared and then characterized using XRPD, DSC, and optical microscopy (Table 8).
335
HPMCAS was identified as a good SD candidate based on the preliminary screeening,
336
whereas HPMC, which has a relatively high Tg and low degradation temperature, was
337
evaluated to understand the potential benefit of cellulosic polymers in comparison to
338
hydrophilic polymers such as copovidone. No significant crystallinity was detected in
339
any SD formulations using XRPD (Figure 4) and optical microscopy (Table 8). In
340
addition, a single Tg of each formulation was observed. As expected, the Tg values of all
341
the SD formulations ranged from 99C to 116C (Table 8). Wide and weak Tg patterns
342
were noted for SD 2 and SD 3 due to the typical characteristics of HPMC. All the
Ac ce p
334
15
Page 16 of 49
343
physical characterization results indicate single phase behavior of amorphous or
344
undetectable levels of phase separation for all the SD formulations. In addition, MK-0364 dissolution of all the SD formulations was determined using
346
either a 0.1N HCl or phosphate buffer medium. All the SD samples showed sustained
347
supersaturation profiles due to amorphous drug being stabilized by the presence of
348
polymers and/or surfactants, as discussed previously in Section 3.2 for HPMCAS. This is
349
also consistent with other findings for solid dispersions using HPMC in several
350
compounds (Ghebremeskel et al., 2006). The initial dissolution rate of SD 2 was faster
351
than that of SD 3 in a 0.1N HCl media while both reached a comparable plateau (Figure
352
5). Interestingly, disparate dissolution profiles were observed between SD 1 and SC 3
353
(Figure 6) despite the same composition. Experimental evidence does not exist to explain
354
such differences. However, prior investigators have reported that varying drying kinetics
355
can lead to differences in morphology and porosity (Handscomb et al., 2009) or spatial
356
composition of chemical components (Vehring et al., 2007). This can lead to differences
357
in dissolution rate. Although SD 1 and SD 2 showed favorable results in animal studies
358
(Section 3.5), SD 1 with a Tg of 99C was selected as a SD lead because of the reduced
359
hygroscopicity of HPMCAS as compared to HPMC (6-7% water for HPMCAS vs. 10%
360
water for HPMC at 25C and 75% RH (Friesen et al., 2008; McGinity, 1997; Rumondor
361
et al., 2010)).
Ac ce p
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345
362 363 364 365
3.5 Evaluation of Solid Dispersion Formulations in Rhesus Monkeys HME 1, HME 2, SD 1, and SD 2 were selected for evaluation of oral absorption in rhesus monkeys. The formulations were administered as a combination product with
16
Page 17 of 49
drug X where the same drug X formulation was directly blended with each MK-0364
367
formulation (Table 4). Drug X bioavailability results were similar in all the formulations,
368
compared to that of the MK-0364 LFC/drug X coadministration as a reference, and
369
thereby only PK parameters of MK-0364 are summarized in Table 9. According to the
370
crossover monkey studies, all the formulations had promising exposures of MK-0364 that
371
exceeded the exposure of the reference. All MK-0364 Cmax ratios ranged from 0.51 to
372
1.13 with a significant increase in Tmax, when compared to that of the reference. The
373
longer Tmax may possibly be attributed to the different dissolution mechanisms of these
374
formulations where polymers have to dissolve in GI fluids before MK-0364 is released.
375
However, the MK-0364 LFC formulation is readily emulsified, thereby facilitating the
376
dissolution/release of MK-0364. In addition, HME 1 had slightly greater bioavailability
377
than did HME 2. Nonetheless, SD 1 and SD 2 showed similar AUC ratios with a higher
378
Cmax ratio for SD 1.
381
cr
us
an
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d te
380
3.6 Physical Stability of Lead Solid Dispersion Formulations
Ac ce p
379
ip t
366
Polymers selected for solid dispersions should not only improve dissolution profiles
382
via inhibiting crystallization and/or forming nanoparticles but also ensure MK-0364
383
physical stability against recrystallization in solid state under storage conditions. The
384
physical stability of HME 1 was evaluated as a function of water content using mDSC
385
and XRPD (Table 10) after storage under different conditions.
386
As expected, Tg decreased with an increase in water content due to the plasticizing
387
effect of water. All HME 1 samples stored under different conditions for 1 week showed
388
no detected crystallinity by XRPD. HME 1 was, however, hygroscopic at > 60% RH
17
Page 18 of 49
(Figure 7), which is related to the water uptake behavior of copovidone (Taylor et al.,
390
2001). The hygroscopicity of HME 1 at relatively high humidities may reflect the high
391
water content of 13.2% in the sample stored under 40C/ 75%RH conditions (Table 10).
392
As a result, the Tg of the sample is depressed (Tg /T <1), and the sample is changed into a
393
super-cooled liquid. This leads to increased mobility and, therefore, potential
394
recrystallization.
cr
In addition, HME 1 and SD 1 physical stability was evaluated for 54 weeks and found
us
395
ip t
389
to be different. By using XRPD with a regular scan mode, no crystallinity of MK-0364
397
was detected in HME 1 stored under all conditions after 54 weeks (Figure 8a). However,
398
only minor crystalline MK-0364 was detected in HME 1 stressed at 40C/ 75%RH using
399
a slow scan mode (Figure 8a with detected peaks in circles), which is supported by the
400
increased mobility and potential recrystallization due to the high water content of the
401
40C/ 75%RH sample. Unlike HME 1, the physical stability of SD 1 was excellent.
402
Neither crystalline MK-0364 nor phase separation was detected in any of stressed SD 1
403
samples for 54 weeks using mDSC and XRPD (with both regular and slow scan modes)
404
as shown in Figure 8b. This indicates that SD 1 is not as sensitive to moisture as HME 1.
405
This is also consistent with the fact that HPMCAS is significantly less hygroscopic than
406
copovidone.
M
d
te
Ac ce p
407
an
396
Based on the above findings, HME 1 must be protected from moisture for acceptable
408
shelf-life stability. However, SD 1 may not require protection from moisture due to the
409
excellent physical stability for 54 weeks.
410 411
4. Conclusions
18
Page 19 of 49
412
MK-0364 solid dispersions were successfully developed and significantly improve the solubility and bioavailability of MK-0364, a poorly water-soluble drug, while
414
maintaining acceptable physical stability. During the preliminary assessment via a
415
solvent casting technique, physical characterization tools and dissolution testing were
416
implemented to identify lead formulations including copovidone- and HPMCAS-based
417
formulations. Both the formulations provide amorphous characteristics and dissolution
418
enhancement in spite of different composition. The copovidone system requires the
419
addition of surfactants for dissolution enhancement while the same is not true for the
420
HPMCAS system in this specific study. These lead formulations were further developed
421
using HME and SD approaches. All HME (without PVP) and SD formulations have
422
amorphous characteristics, single Tg, and supersaturation profiles. The bioavailability
423
results of MK-0364 from selected HME and SD formulations in rhesus monkeys are
424
promising with a trend of slower onset than that of a liquid filled capsule reference.
425
Based on the processability, physical characterization, in vitro dissolution, and animal PK
426
data, HME 1 (copovidone-based HME) and SD 1 (HPMCAS-based SD) appear to be the
427
best candidates. HME 1 has worse 54-week-physical stability than SD 1, requiring
428
protection from moisture to achieve acceptable shelf-life stability.
430 431
cr
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429
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413
Acknowledgements
The authors would like to thank Wei Xia and Brian Hill for generating dissolution
432
data, Sarah Geers and Varaporn Treemaneekarn for their assistance with physical
433
characterization, and Huizhi Xie for generating PK data. We would like to specially
19
Page 20 of 49
434
thank Laman Alani, Soumojeet Ghosh, Ian Hardy, Larry Rosen, and Ron Smith for
435
providing their comments and encouragement during the preparation of this manuscript.
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437
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438
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ip t
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441
Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product
442
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Andrews, G.P., AbuDiak, O.A., Jones, D.S., 2010. Physicochemical characterization of hot melt extruded bicalutamide-polyvinylpyrrolidone solid dispersions. J. Pharm.
445
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Andrews, G.P., Jones, D.S., Abu Diak, O., Margetson, D.N., McAllister, M.S., 2009. Hot-melt extrusion: an emerging drug delivery technology. Pharm. Technol. Eur.
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te
Chiou, W.L., Niazi, S., 1976. Pharmaceutical applications of solid dispersion systems:
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Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS) for Initiation and
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Maintenance of Drug Supersaturation in the GI Milieu. Pharm. Res. 26, 1419-
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Dhirendra, K., Lewis, S., Udupa, N., Atin, K., 2009. Solid dispersions: a review. Pak. J. Pharm. Sci. 22, 234-246. Dong, Z., Chatterji, A., Sandhu, H., Choi, D.S., Chokshi, H., Shah, N., 2008. Evaluation
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solvent co-precipitation. Int. J. Pharm. 355, 141-149.
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Dong, Z., Choi, D.S., 2008. Hydroxypropyl methylcellulose acetate succinate: potential drug-excipient incompatibility. AAPS PharmSciTech 9, 991-997.
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Friesen, D.T., Shanker, R., Crew, M., Smithey, D.T., Curatolo, W.J., Nightingale, J.A.S., 2008. Hydroxypropyl Methylcellulose Acetate Succinate-Based Spray-Dried
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Dispersions: An Overview. Mol. Pharm. 5, 1003-1019. Ghebremeskel, A.N., Vemavarapu, C., Lodaya, M., 2006. Use of Surfactants as
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Plasticizers in Preparing Solid Dispersions of Poorly Soluble API: Stability
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Testing of Selected Solid Dispersions. Pharm. Res. 23, 1928-1936.
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Ghebremeskel, A.N., Vemavarapu, C., Lodaya, M., 2007. Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: Selection of polymer-surfactant combinations using solubility parameters and testing the processability. Int. J. Pharm. 328, 119-129.
Goldberg, A.H., Gibaldi, M., Kanig, J.L., 1965. Increasing dissolution rates and
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gastrointestinal absorption of drugs via solid solutions and eutectic mixtures. I.
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Theoretical considerations and discussion of the literature. J. Pharm. Sci. 54,
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Goldberg, A.H., Gibaldi, M., Kanig, J.L., 1966a. Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures. II.
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Experimental evaluation of a eutectic mixture: urea-acetaminophen system. J.
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Goldberg, A.H., Gibaldi, M., Kanig, J.L., 1966b. Increasing dissolution rates and
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Experimental evaluation of griseofulvin-succinic acid solid solution. J. Pharm.
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Handscomb, C.S., Kraft, M., Bayly, A.E., 2009. A new model for the drying of droplets
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containing suspended solids after shell formation. Chem. Eng. Sci. 64, 228-246. Ilevbare, G.A., Liu, H., Edgar, K.J., Taylor, L.S., 2012. Understanding Polymer
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Properties Important for Crystal Growth Inhibition-Impact of Chemically Diverse
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Polymers on Solution Crystal Growth of Ritonavir. Cryst. Growth Des. 12, 3133-
493 494 495 496 497
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Kennedy, M., Hu, J., Gao, P., Li, L., Ali-Reynolds, A., Chal, B., Gupta, V., Ma, C., Mahajan, N., Akrami, A., Surapaneni, S., 2008. Enhanced Bioavailability of a Poorly Soluble VR1 Antagonist Using an Amorphous Solid Dispersion Approach: A Case Study. Mol. Pharm. 5, 981-993.
Konno, H., Handa, T., Alonzo, D.E., Taylor, L.S., 2008. Effect of polymer type on the
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dissolution profile of amorphous solid dispersions containing felodipine. Eur. J.
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Dekker, New York.
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dispersions. Eur. J. Pharm. Biopharm. 50, 47-60.
Rajewski, R.A., Stella, V.J., 1996. Pharmaceutical applications of cyclodextrins. 2. in
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Leuner, C., Dressman, J., 2000. Improving drug solubility for oral delivery using solid
vivo drug delivery. J. Pharm. Sci. 85, 1142-1169.
Rohrs, B.R., 2006. Biopharmaceutics Modeling and the Role of Dose and Formulation on
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Oral Exposure, in: Borchardt, R.T., Kerns, E.H., Hageman, M.J., Thakker, D.R.,
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Stevens, J.L. (Eds.), Optimizing the “Drug-Like” Properties of Leads in Drug
511
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513 514 515 516
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Rumondor, A.C.F., Konno, H., Marsac, P.J., Taylor, L.S., 2010. Analysis of the moisture
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sorption behavior of amorphous drug-polymer blends. J. Appl. Polym. Sci. 117, 1055-1063.
Schenck, L., Troup, G.M., Lowinger, M., Li, L., McKelvey, C., 2010. Achieving a hot melt extrusion design space for the production of solid solutions, in: am Ende,
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519
Sekiguchi, K., Obi, N., 1961. Absorption of eutectic mixtures. I. A comparison of the behavior of a eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in
521
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522
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Serajuddin, A.T., 1999. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci. 88, 1058-1066.
524
Stella, V.J., Rajewski, R.A., 1997. Cyclodextrins: their future in drug formulation and
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us
delivery. Pharm. Res. 14, 556-567.
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523
Taylor, L.S., Langkilde, F.W., Zografi, G., 2001. Fourier transform Raman spectroscopic study of the interaction of water vapor with amorphous polymers. J. Pharm. Sci.
528
90, 888-901.
531 532 533 534
d
drying. J. Aerosol Sci 38, 728-746.
te
530
Vehring, R., Foss, W.R., Lechuga-Ballesteros, D., 2007. Particle formation in spray
Zallen, R., 1983. The formation of amorphous solids, The physics of amorphous solids.
Ac ce p
529
M
527
John Wiley & Sons, Inc., New York.
25
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Figure legends
536
Figure 1: Extrusion screw design. Two conventional mixing zones were employed each
537
consisting of 5 forward 30 degree offset paddles, 5 forward 60 degree offset paddles and
538
5 neutral 90 degree offset paddles. Bilobed intermeshing screws were used with the
539
exception of the single flight conveying elements at the die end of the extruder (a
540
customary ThermoPrism design element). All other conveying sections employed a pitch
541
of 1 revolution per diameter length (i.e., 1 D pitch). An ambient vent was placed just
542
downstream of the second mixing zone to facilitate the removal of water vapor prior to
543
the die and feeding was by gravity from the top.
544
Figure 2: Chemical structure of MK-0364.
545
Figure 3a: Dissolution of MK-0364 from SC samples without surfactants (● SC 1, ○ SC
546
2, and ▼ SC 3) in a 250 mL 25 mM buffer solution (pH 6.85) was determined using the
547
USP paddle (II) method at 37C and 100 rpm.
548
Figure 3b: Dissolution of MK-0364 from copovidone-based formulations (● SC 4, ○ SC
549
5,▼ SC 6, SC 7, ■ SC 8, □ SC 9, and SC 10) using copovidone with different
550
surfactants in a 250 mL 0.1 N HCl solution was determined using the USP paddle (II)
551
method at 37C and 100 rpm.
552
Figure 3c: Dissolution of MK-0364 from HME samples (● HME 1 and ○ HME 2) in a
553
250 mL 0.1 N HCl solution was determined using the USP paddle (II) method at 37C
554
and 100 rpm.
555
Figure 4: X-ray powder diffraction (XRPD) patterns of SD samples (SD 1, SD 2, and SD
556
3) at initial.
Ac ce p
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535
26
Page 27 of 49
Figure 5: Dissolution of MK-0364 from SD samples (● SD 2 and ○ SD 3) in a 250 mL
558
0.1 N HCl solution was determined using the USP paddle (II) method at 37C and 100
559
rpm.
560
Figure 6: Dissolution of MK-0364 from solid dispersion samples of HPMCAS prepared
561
via SD and SC approaches (● SD 1 and ○ SC 3) in a 250 mL 25 mM buffer solution (pH
562
6.85) was determined using the USP paddle (II) method at 37C and 100 rpm.
563
Figure 7 : Water sorption/desorption isotherm of HME 1 (■ water sorption and □ water
564
desorption) at 25C.
565
Figure 8a: X-ray powder diffraction (XRPD) patterns of HME 1 stored at 5C with
566
desiccants, 25C/ambient, 30C/65%RH, 40C/ambient, 40C/75%RH, and
567
60C/ambient for 54 weeks using a regular scan mode. The top two patterns were
568
obtained using a slow scan mode.
569
Figure 8b: X-ray powder diffraction (XRPD) patterns of SD 1 stored at 5C with
570
desiccants, 40C/ambient, 40C/75%RH, and 60C/ambient for 54 weeks using a regular
571
scan mode. The top two patterns were obtained using a slow scan mode.
cr
us
an
M
d
te
Ac ce p
572
ip t
557
27
Page 28 of 49
Ac
ce
pt
ed
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i
Figure 1
Page 29 of 49
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pt
ed
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i
Figure 2
Page 30 of 49
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pt
ed
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i
Figure 3a
Page 31 of 49
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ed
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cr
i
Figure 3b
Page 32 of 49
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ed
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i
Figure 3c
Page 33 of 49
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ed
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i
Figure 4
Page 34 of 49
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ed
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i
Figure 5
Page 35 of 49
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ed
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Figure 6
Page 36 of 49
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ed
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i
Figure 7
Page 37 of 49
Ac ce p
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cr
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Figure 8a
250
Intensity (counts/sec)
200
150
60C/amb Slow Scan 40C/75%RH Slow Scan
60C/amb. 40C/75%RH 40C/amb. 30C/65%RH 25C/amb.
100
5C/des 50
Crystalline MK-0364 0 5
10
15
20
Diffraction angle (2θ)
25
30
Page 38 of 49
35
Ac ce p
te
d
M
an
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cr
ip t
Figure 8b
Intensity (counts/sec)
200
150
60C/amb Slow Scan 40C/75%RH Slow Scan
100 60C/amb. 40C/75%RH 40C/amb. 5C/des
50
0
Crystalline MK-0364 5
10
15
20
Diffraction angle (2θ)
25
30
Page 39 of 49 35
SC 1
SC 2
SC 3
SC 4
SC 5
SC 6
SC 7
SC 8
SC 9
SC 10
%
%
%
%
%
%
%
%
%
%
MK-0364
10
10
10
10
10
10
10
10
10
10
Polysorbate 80
NA
NA
NA
NA
3
NA
NA
NA
NA
NA
Sorbitan monooleate
NA
NA
NA
NA
3
NA
NA
NA
NA
NA
Vit E TPGS
NA
NA
NA
NA
NA
10
Poloxamer 407
NA
NA
NA
NA
NA
Polyoxyl 35 castor oil
NA
NA
NA
NA
Sodium lauryl sulfate
NA
NA
NA
Eudragit L100-55
90
NA
NA
HPMCP HP-55
NA
90
NA
HPMCAS-LF
NA
NA
Copovidone
NA
NA
M
Table 1: Summary of MK-0364 SC formulations
cr
ip t
Component
NA
NA
NA
NA
10
15
NA
NA
NA
NA
NA
NA
6
NA
NA
NA
NA
NA
NA
NA
10
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
an
us
NA
NA
NA
NA
NA
NA
NA
NA
NA
90
84
80
80
75
84
80
Ac ce
pt
ed
90
Page 40 of 49
Table 2: Summary of MK-0364 HME formulations
HME 1
HME 2
HME 3
HME 4
HME 5
%
%
%
%
%
Function Active
10
10
10
10
10
Polysorbate 80
Surfactant
1.5
NA
1.5
1.5
1.5
Sorbitan monooleate
Surfactant
1.5
NA
1.5
1.5
1.5
Vit E TPGS
Surfactant
NA
5
NA
NA
NA
BHA
Antioxidant
NA
NA
0.83
NA
NA
PVP
Polymer
NA
NA
NA
10
20
Copovidone
Polymer
87
77
67
an
us
cr
MK-0364
86.17
Ac ce
pt
ed
M
85
ip t
Component
Page 41 of 49
Table 3: Summary of MK-0364 SD formulations SD 2 % 10 1.5 1.5 NA 87 NA
SD 3 % 10 NA NA 5 85 NA
Ac ce
pt
ed
M
an
us
cr
MK-0364 Polysorbate 80 Sorbitan monooleate Vit E TPGS HPMC HPMCAS-LF
SD 1 % 10 NA NA NA NA 90
ip t
Component
Page 42 of 49
Table 4: Summary of MK-0364 formulations used in PK studies in rhesus monkeys HME 1
HME 2
SD 1
SD 2
%
%
%
%
MK-0364
1.5
1.5
1.5
1.5
Drug X
32.1
32.1
32.1
Polysorbate 80
0.2
NA
NA
Sorbitan monooleate
0.2
NA
NA
Vit E TPGS
NA
0.7
NA
Copovidone
13.1
12.8
HPMCAS-LF
NA
NA
HPMC
NA
Other excipients
52.9
ip t
Component
32.1
us
cr
0.2
0.2
NA NA
13.5
NA
an
NA
NA
13.1
52.9
52.9
52.9
Ac ce
pt
ed
M
NA
Page 43 of 49
Table 5: Solubility of MK-0364 in different surfactants and lipid-based vehicles Solubility of MK-0364 (mg/mL) 0.08
2.5% Polysorbate 80
0.40
0.1% Vit E TPGS
0.03
1% Vit E TPGS
0.30
cr
0.5% Polysorbate 80
0.1% Poloxamer 407
0.005
1% Poloxamer 407
us
0.004
0.1% Polyoxyl 35 castor oil
0.02 0.23
an
1% Polyoxyl 35 castor oil 0.1% Sodium lauryl sulfate 1% Sodium lauryl sulfate
0.002 0.41 184*
Polysorbate 80
104*
M
Caprylic/capric glycerides/ polysorbate 80 (1:1, w/w)
ed
Sorbitan monooleate Polyoxyl 35 castor oil
ip t
Vehicle
45* 131*
Ac ce
pt
Note: * is the solubility of MK-0364 in mg per g of the listed vehicles.
Page 44 of 49
Table 6: Physical characterization of selected SC samples of MK-0364 using XRPD, DSC, and optical microscopy Optical microscopy amorphous amorphous amorphous amorphous amorphous amorphous partially crystalline (poloxamer)
ip t
Dry Tg , C 91 86 99 89 81 56 NA
cr
XRPD amorphous amorphous amorphous amorphous amorphous amorphous partially crystalline (poloxamer)
Ac ce
pt
ed
M
an
us
SC samples SC 1 SC 2 SC 3 SC 4 SC 5 SC 6 SC 8
Page 45 of 49
Table 7: Physical characterization of HME samples of MK-0364 using XRPD, DSC, and optical microscopy Optical microscopy amorphous amorphous amorphous amorphous amorphous
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Average Dry Tg (SD), C 89.6 (0.5) 84.5 87.6 (0.8) 89.0 (0.8) 88.9 (0.4)
XRPD amorphous amorphous amorphous amorphous amorphous
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Formulation HME 1 HME 2 HME 3 HME 4 HME 5
Page 46 of 49
Table 8: Physical characterization of SD samples of MK-0364 using XRPD, DSC, and optical microscopy Average Dry Tg (SD), C 98.6 (0.5) 116.4 (1.5) 109.2 (1.8)
XRPD amorphous amorphous amorphous
Optical microscopy amorphous amorphous amorphous
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Formulation SD 1 SD 2 SD 3
Page 47 of 49
Table 9: MK-0364 PK parameters following the oral administration of listed formulations in monkeys (n=6) Cmax (µM)
Tmax (hr)
AUC0-24 hr ratioa
Cmax ratiob
MK-0364 LFC
2.16 ± 0.28
0.409 ± 0.05
1.8 ± 0.5
1.00
1.00
HME 1
2.65 ± 0.47
0.292 ± 0.07
4.3 ± 0.3
1.23
HME 2
2.35 ± 0.37
0.208 ± 0.05
3.3 ± 0.7
1.09
SD 1
2.68 ± 0.52
0.462 ± 0.14
3.3 ± 0.4
1.24
SD 2
2.62 ± 0.66
0.333 ± 0.13
3.7 ± 0.5
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Formulation
AUC0-24 hr (µM*hr)
0.71
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0.51
1.21
1.13
0.81
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Note: a and b are AUC and Cmax ratios of the tested formulations to the reference, respectively.
Page 48 of 49
Table 10: Glass transition temperature (Tg) and water content measurements of HME 1 as a function of temperature and relative humidity and their physical states under different conditions % Water content 7.9 13.2 1.8 0.7
Tg /T 1.02 0.93 1.09 1.06
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All Tg values are within 2C.
State of samples super-cooled liquid/glass super-cooled liquid glass glass
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Tg (C) a 36 18 69 81
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Condition (T/%RH) 30ºC/65%RH 40C/75%RH 40C/amb 60C/amb
Page 49 of 49
S0378-5173(13)00338-4 http://dx.doi.org/doi:10.1016/j.ijpharm.2013.04.037 IJP 13279
To appear in:
International Journal of Pharmaceutics
Received date: Revised date: Accepted date:
20-8-2012 10-3-2013 15-4-2013
Please cite this article as: Sotthivirat, S., McKelvey, C., Moser, J., Rege, B., Xu, W., Zhang, D., Development of Amorphous Solid Dispersion Formulations of a Poorly Water-Soluble Drug, MK-0364, International Journal of Pharmaceutics (2013), http://dx.doi.org/10.1016/j.ijpharm.2013.04.037 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Formulation preparation by solvent casting
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Physical characterization Dissolution
MK-0364 solid dispersion candidates HME
Dissolution testing
SD
Physical characterization
In vivo study
Page 1 of 49
1
Development of Amorphous Solid Dispersion Formulations of a Poorly
2
Water-Soluble Drug, MK-0364
3
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S. Sotthivirat *, C. McKelvey, J. Moser, B. Rege, W. Xu, and D. Zhang *
4
Departments of Product Value Enhancement, Formulation Sciences, and Analytical Sciences,
6
Merck & Company, Inc., West Point, PA 19486, USA
7
Merck & Company, Inc., Summit, NJ 07901, USA
8
----------------------------------------------
9
* Correspondence
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S. Sotthivirat
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Merck & Company, Inc.
12
770 Sumneytown Pike
13
West Point, PA 19486
14
USA
15
Telephone: (215) 652-0924
16
E-mail: [email protected]
17
and D. Zhang
18
Merck & Company, Inc.
19
556 Morris Avenue
20
Summit, NJ 07901
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USA
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Telephone: (908) 473-2305
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E-mail: [email protected]
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Abstract
25
The goal of this study was to demonstrate that MK-0364 solid dispersions can be developed as a
26
means to increase the solubility and bioavailability of a poorly water-soluble drug, MK-0364.
27
The potential solid dispersions would enable an oral solid dosage form as a monotherapy or
28
combination product of MK-0364. Preliminary screening included sample preparation via a
29
solvent casting method, physical characterization, and in vitro dissolution testing. Lead
30
formulations were subsequently manufactured using hot melt extrusion (HME) and spray-drying
31
(SD). All HME (without polyvinyl pyrrolidone) and SD formulations exhibit characteristics of a
32
single phase glass including an amorphous halo when analyzed with X-ray powder diffraction
33
(XRPD), a single glass transition temperature (Tg) measured with differential scanning
34
calorimetry (DSC), and supersaturation when dissolved in dissolution media. The oral
35
absorption of MK-0364 from selected HME and SD formulations in monkeys results in
36
marginally greater exposure with a consistently longer Tmax relative to a liquid filled capsule
37
reference. Based on the processability, physical characterization, in vitro dissolution, and animal
38
pharmacokinetic results, copovidone- and hydroxypropyl methylcellulose acetate succinate
39
(HPMCAS)-based solid dispersion formulations are viable product concepts. The physical
40
stability of both the solid dispersion formulations was also evaluated for 54 weeks under
41
different conditions. The copovidone-based solid dispersion requires protection from moisture.
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Keywords: MK-0364, copovidone, HPMCAS, solid dispersion, hot melt extrusion, spray drying,
44
dissolution, bioavailability
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46 47
1. Introduction Drugs with poor aqueous solubility have low or erratic absorption and, consequently, poor and variable bioavailability. Several common formulation approaches to increase
49
the drug solubility/bioavailability include the use of cosolvents, surfactants, cyclodextrins
50
(Loftsson and Brewster, 1996; Rajewski and Stella, 1996; Stella and Rajewski, 1997),
51
salt formation, pH adjustment, particle size reduction, or lipid-based formulations. Solid
52
dispersions or, more specifically, solid solutions of drugs in polymers as alternatives can
53
be produced using cost effective manufacturing technologies adapted from other
54
industries (e.g., extrusion and spray drying), enable solid products directly suitable for
55
fixed dose combinations, and do not require prohibitively expensive excipients (e.g.,
56
hydroxypropyl-beta-cyclodextrin).
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Solid dispersions have been used for dissolution or bioavailability enhancement since
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the 1960s. Solid dispersions are defined as the solid state dispersions of one or more
59
compounds in an inert matrix (Chiou and Riegelman, 1971). Early solid dispersions
60
using low molecular weight matrices such as urea and succinic acid increased the
61
dissolution and absorption of sulfathiazole (Goldberg et al., 1965; Sekiguchi and Obi,
62
1961), chloramphenicol (Goldberg et al., 1965), griseofulvin (Chiou and Niazi, 1976;
63
Goldberg et al., 1966b), and acetaminophen (Goldberg et al., 1966a). More recent solid
64
dispersions using high molecular weight matrices such as polyethylene glycols, cellulose
65
derivatives, acrylics (polyacrylates, polymethacrylates), and polyvinyl-based polymers
66
not only enhanced the dissolution and bioavailability but also provided good physical
67
stability of several compounds (Al-Obaidi and Buckton, 2009; Andrews et al., 2010;
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Andrews et al., 2009; Curatolo et al., 2009; Dong et al., 2008; Friesen et al., 2008;
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Kennedy et al., 2008; Konno et al., 2008; Leuner and Dressman, 2000; Serajuddin, 1999).
70
Additionally, solid dispersions are suitable for the production of a wide variety of solid oral dosage forms. For example, the melted drug/matrix can be extruded and
72
shaped as films, sticks, granules, pellets, powders, or individual unit dosage forms (e.g.,
73
injected molds). Alternatively, solid dispersions can be used as intermediates to be
74
further processed into conventional tablets as immediate or modified release
75
formulations. Several commercially available products are based on solid dispersions
76
such as Gris-PEG (griseofulvin/PEG), Certican (everolimus/HPMC), Isoptin-SRE
77
(verapamil/HPC/HPMC), ProGraf (tacrolimus/HPMC), Cesamet (nabilone/PVP), and
78
Kaletra (lopinavir/ritonavir/copovidone).
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The research described here involves the development of amorphous solid dispersion
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formulations of a poorly water-soluble drug, MK-0364, to increase its solubility and
81
bioavailability. The potential solid dispersions would enable an oral solid dosage form as
82
a monotherapy or combination product of MK-0364. The evaluation of this system
83
included initial preparation via solvent casting, physical characterization, and in vitro
84
dissolution testing prior to identifying lead formulations for further development via hot
85
melt extrusion (HME) and spray-drying (SD). During HME and SD formulation
86
development, physical characterization, in vitro dissolution testing, and in vivo evaluation
87
were conducted to select the best candidates for subsequent physical stability studies.
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2. Materials and Methods
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2.1 Materials
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All chemicals were analytical grade or ACS reagents. MK-0364 was obtained from Merck & Co., Inc. Polysorbate 80 (Tween 80™, Croda, Inc., Edison, NJ), sorbitan
93
monooleate (Span 80®, Uniqema, New Castle, DE), polyvinyl pyrrolidone (PVP or
94
Plasdone® K-29/32, ISP Corporation, Wayne, NJ), methacrylic acid copolymer
95
(Eudragit L100-55, Evonik Degussa Corporation, Piscataway, NJ), caprylic/capric
96
glycerides (Imwitor® 742, Sasol North America, Inc., Westwood, NJ), acetone, methanol,
97
hydrochloric acid, and water were used as received. D--tocopheryl polyethylene glycol
98
1000 succinate (vitamin E TPGS) and butylated hydroxylanisole (BHA) were purchased
99
from Eastman Chemical Company (Kingsport, TN). Hydroxypropyl methylcellulose
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(HPMC, Pharmacoat grade 606), hydroxypropyl methylcellulose phthalate (HPMCP HP-
101
55) and hydroxypropyl methylcellulose acetate succinate (HPMCAS-LF) were purchased
102
from Shin-Etsu Chemical Co., Ltd., Japan. Copovidone (Kollidon® VA 64), poloxamer
103
407 (Lutrol F 127), polyoxyl 35 castor oil (Cremophor EL), and sodium lauryl sulfate
104
(Texapon K 12 P PH) were purchased from BASF Corporation (Florham Park, NJ).
106 107
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2.2 Preparation of Solvent Cast (SC) Formulations The SC formulations (Table 1) were prepared by dissolving 2 g of solids in 15 mL of
108
a suitable organic solvent according to the solubility. The solutions were spread into a
109
thin layer in a foil-protected aluminium or stainless steel pan for drying in a vacuum
110
oven. Samples were dried for approximately 30 min at 110C/>30 in Hg, transferred
111
from pans to glass vials, and dried for an additional 16 hours at 40C/ambient.
112 113
2.3 Preparation of Hot Melt Extrusion (HME) Formulations
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Prior to the HME process, all components listed in Table 2 were pre-blended in a Bohle high shear granulator (model BMG, L.B. Bohle, Germany). Polysorbate 80 and
116
sorbitan monooleate were first mixed to obtain a homogeneous solution, whereas vitamin
117
E TPGS was melted in a water bath set at 40-45C. Copovidone and MK-0364 were
118
blended in the high shear granulator for 3-5 min with an impeller speed of 300-500 rpm.
119
The surfactants were then added to the granulator over a period of 3-8 min using 300-500
120
rpm impeller and 1000 rpm chopper speeds, followed by a 2-5 min additional mixing.
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The wet granulated sample was introduced into a Thermo Scientific 16 mm 25:1 L/D
122
corotating twin-screw extruder (Thermo Fisher Scientific, Inc., Waltham, MA) set at 130-
123
160C using a Brabender Technologie single-screw FlexWall feeder (20% drive
124
command in volumetric mode). The twin-screw extruder screw designs are illustrated in
125
Figure 1. The resulting extrudate was ambiently cooled and ground in a mortar with a
126
pestle for physical characterization.
129
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2.4 Preparation of Spray-Drying (SD) Formulations
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The SD formulations listed in Table 3 were prepared using a Niro SD-Micro spray
130
dryer (GEA Processing Engineer, Inc., Columbia, MD). A feed solution at 5% solids was
131
prepared by dissolving polymers, surfactants, and MK-0364 in a suitable solvent.
132
Acetone was used in SD 1, whereas methanol was used for the remainder. After
133
dissolving completely, the feed solution was atomized into a spray of droplets. The spray
134
dryer experiments were designed to achieve a specific target nitrogen gas outlet
135
temperature (50-60C for SD 1 and 60-70C for others). The resulting spray-dried
136
particles were collected in a cyclone and bag filter. The solution feed rate (1-10 mL/min)
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was controlled by an external peristaltic pump. The atomizing nitrogen and processing
138
nitrogen rates were 1-5 Kg/hr and 10-30 Kg/hr, respectively.
139
141
2.5 In vitro MK-0364 Dissolution Studies for Solid Dispersion Formulations
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The MK-0364 dissolution testing on all solid dispersion formulations except SC 1, SC 2, SC 3, and SD 1 was performed in a 250 mL 0.1 N HCl solution using the USP
143
paddle (II) method at 37C (100 rpm, n=3). For SC 1, SC 2, SC 3, and SD 1, MK-0364
144
release was performed in a 250 mL 25 mM buffer solution (pH 6.85) using the same USP
145
method as described above due to the solubility of these enteric coating polymers at pH
146
5.5 or above. Dissolution samples were withdrawn via a 35 µm flow through filter at
147
predetermined intervals and assayed by HPLC using a Vydac C18 (250 x 4.6 mm, 5 µm
148
particle size) column. The method used a gradient mobile phase consisting of methanol
149
and 0.1% phosphoric acid at a flow rate of 1.5 mL/min, and the effluent was monitored at
150
220 nm.
152
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2.6 Physical Characterization of Solid Dispersion Formulations
153
All solid dispersion samples were evaluated and characterized using differential
154
scanning calorimetry (DSC, model Q2000, TA Instruments, Inc., New Castle, DE),
155
thermogravimetric analysis (TGA, model G5000, TA Instruments, Inc., New Castle, DE),
156
X-ray powder diffraction (XRPD, Panalytical X'pert Pro diffractometer, Spectris plc,
157
England), and optical microscopy (Olympus BX51, Olympus America, Inc., Center
158
Valley, PA). Dry Tg data were obtained by heating a sample in an aluminium pan at a
159
constant rate of 10C/min following the removal of solvent via an initial heating cycle.
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In addition, glass transition temperatures (Tg) of certain samples stored under different
161
conditions (30C/65%RH, 40C/ambient, 40C/75%RH, and 60C/ambient) were
162
determined as a function of water content using a modulated DSC (mDSC) where a
163
sample was initially equilibrated at 10C and then modulated at 0.5C every 60 sec with a
164
ramp rate of 2.5C/min to 100C. Water content was determined using TGA by heating a
165
sample at 10°C/min to 190C under nitrogen flow. XRPD spectra were collected on the
166
Panalytical X'pert Pro diffractometer with Cu Ka1 radiation of 1.5406Å in the
167
transmission mode at ambient conditions. Samples were scanned between a two theta
168
range of 2º and 40º at a step size of 0.0167º and a scan rate of 2.4º/min. A few samples
169
were also analyzed at a scan rate of 0.02º/min within a narrower two theta range (15º to
170
22º) to improve the detection limit for crystalline drug. The tube power used was 45 kV
171
and 40 mA.
174
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2.7 Evaluation of Pharmacokinetic (PK) Parameters Following the Oral Administration
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of HME and SD Formulations in Rhesus Monkeys
175
HME and SD samples were prepared in capsules with 6 mg MK-0364 and drug X, as
176
shown in Table 4. These formulations were administered orally in rhesus monkeys (n=6)
177
in a crossover design and compared to coadministration of MK-0364 LFC and drug X
178
formulations as a reference, to evaluate their potential differences in oral absorption. The
179
MK-0364 LFC formulation was prepared by dissolving MK-0364 in caprylic/capric
180
glycerides/ polysorbate 80 (1:1, w/w) and placed in a capsule while the drug X
181
formulation was prepared by blending of drug X with other excipients and compressed
182
into a tablet. All the monkeys were fasted for 16 hours prior to dosing. The capsules
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Page 9 of 49
were given orally via a gavage tube, followed immediately by water (20 mL). After
184
dosing, water and food were returned at 1 hour and 4 hours, respectively. Blood was
185
drawn via venipuncture using a butterfly needle inserted into the saphenous vein at
186
predose and predetermined time intervals postdose. The plasma was separated by
187
centrifugation and analyzed using liquid chromatography/electrospray ionization tandem
188
mass spectrometry(LC/ESI-MS/MS). The chromatography was performed on a Aquasil
189
C8 (100 x 2 mm, 5µm particle size) column, using 75% acetonitrile and 25% 25mM
190
ammonium formate buffer (pH 3.0). PK parameters including area under the curve
191
(AUC0-24 hr), observed maximum plasma concentration (Cmax), and time of Cmax (Tmax)
192
were calculated using noncompartmental analysis in WinNonlin. All studies were
193
conducted under a protocol approved by Merck Institutional Animal Care and Use
194
Committee (Merck IACUC), in accordance with USDA guidelines.
196
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2.8 Physical Stability Studies of HME and SD Formulations Lead formulations were chosen based on the in-vivo and dissolution results. The
198
physical stability of the lead formulations was performed up to 54 weeks as a function of
199
relative humidity and temperature (5C with desiccants, 25C/ambient, 30C/65%RH,
200
40C/ambient, 40C/75%RH, and 60C/ambient). Physical characterization of stressed
201
samples was performed using the techniques listed previously. In addition, a water
202
sorption/desorption isotherm of HME 1 was determined at 25C from 5% to 95% RH
203
using a dynamic vapor sorption analyzer (VTI model SGA-100, TA Instruments, Inc.,
204
New Castle, DE) with an integrated microbalance system to measure the uptake and loss
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of water. Weight measurements were taken over a 180-min equilibration period at each
206
RH level studied.
208
3
Results and Discussion
209
3.1 Physicochemical and Biopharmaceutical Properties of MK-0364
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MK-0364 (Figure 2), a cannabinoid receptor type 1 (CB-1) inverse agonist, is
211
available as a crystalline form with its solubility less than 0.4 µg/mL at pH 1-10. No
212
stable salt was successfully discovered due to its very low pKa of the pyridine nitrogen,
213
but improved solubility with lipid-based vehicles and surfactants was reported (Table 5).
214
The in vitro permeability of MK-0364 through a Caco-2 cell monolayer in the apical to
215
basolateral direction was found to be 0.91 ± 0.07 x 10-6 cm/s, which is much less than
216
that of metoprolol used as a reference. Therefore, it is classified as a BCS class IV drug
217
with a dose number (Amidon et al., 1995; Rohrs, 2006) of 60 based on a 6 mg dose. In
218
animal studies, MK-0364 absorption from a traditional wet granulation of MK-0364 with
219
sodium lauryl sulfate was less than 20% of that obtained from the liquid filled capsule
220
(LFC) formulation containing caprylic/capric glycerides/ polysorbate 80 (1:1, w/w). The
221
absorption observed from LFC formulations led to the development of MK-0364 LFC
222
formulations for the treatment of obesity as monotherapy.
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The glass-forming tendency, defined as the ratio of Tg to Tm (both temperatures are in
224
kelvin), is used to suggest how easy the glassy state can be obtained (Zallen, 1983). The
225
Tg/Tm ratio of MK-0364 is greater than 0.7, suggesting MK-0364 is an "excellent glass
226
former" (the Tg and Tm of MK-0364 are 41C and 104C, respectively, resulting in a
227
Tg/Tm ratio of 0.83). Overall, MK-0364 appears to be a good candidate for a solid
10
Page 11 of 49
228
dispersion approach because of its poor aqueous solubility and anticipated behavior as an
229
"excellent glass former".
231
3.2 Preliminary Screening Using a Solvent Casting Approach
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230
Formulations with various polymer/surfactant combinations at a fixed drug loading
233
were first prepared using a solvent casting technique (Table 1), and several surfactants
234
were evaluated based on the solubility data in Table 5. The formulations were
235
subsequently characterized using XRPD, DSC, optical microscopy, and in vitro
236
dissolution testing (Table 6 and Figures 3a-b). No crystallinity was detected in the
237
formulations listed in Table 6 except SC 8 using XRPD and optical microscopy. SC 8
238
showed some crystallinity, which is due to the semicrystalline nature of poloxamer. It
239
should be noted that the presence of MK-0364 with a Tg of 41C may contribute to
240
considerable Tg depression in the formulations, and, therefore, high Tg polymers such as
241
Eudragit L100-55, HPMC HP-55, HPMCAS-LF, and copovidone may be beneficial to
242
improve the physical stability of MK-0364 (e.g., prevent recrystallization or phase
243
separation of MK-0364). During the screening of the high Tg polymers, the relatively
244
high Tg values of the binary polymer/MK-0364 systems were observed for SC 1-4 (Table
245
6). For the copovidone-based formulations, the effect of surfactants present in SC 5 and
246
SC 6 on Tg was apparent, as compared to SC 4, but SC 6 had the lowest Tg due to the
247
presence of vitamin E TPGS at high levels.
248
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Among the binary dispersions without surfactants (Figure 3a), the HPMCAS system
249
(SC 3) showed the best sustained supersaturation for 60 min. MK-0364 precipitation was
250
observed in both the HPMCP (SC 2) and Eudragit (SC 1) samples, however, which is
11
Page 12 of 49
consistent with the reduced area under the dissolution curve of MK-0364. In addition,
252
there was relatively higher variability in MK-0364 released from SC 1 and SC 2 than SC
253
3. The high variability is likely caused by variability in the drug crystallization rate
254
among the samples (n=3) of SC 1 and SC 2 during the dissolution testing. It is not
255
untypical for nucleation or crystal growth to proceed at different rates in different
256
dissolution vessels. Although the 30 min data points for SC 1 and SC 2 appear to be
257
inconsistent with the rest of the data, the rank order for dissolution performance among
258
SC 1, SC 2, and SC 3 is still very clear. It is apparent that HPMCAS (SC 3) provides the
259
best dissolution enhancement (sustained supersaturation) compared to HPMCP (SC 2)
260
and Eudragit (SC 1). The supersaturation is attributed to the ability of polymers to
261
inhibit nucleation and/or crystallization. HPMCAS has been shown to promote
262
supersaturation during in vitro dissolution for several compounds due to the amphiphilic
263
nature of HPMCAS (Dhirendra et al., 2009; Friesen et al., 2008; Ilevbare et al., 2012;
264
Kennedy et al., 2008; Konno et al., 2008). It is believed that the hydrophobic regions of
265
the polymer allow drug molecules to interact with the polymer and form amorphous
266
drug/polymer nanostructures, whereas the negative charges of the succinate groups of
267
HPMCAS help the nanostructures remain as stable colloids in solution (Friesen et al.,
268
2008).
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The dissolution of MK-0364 from the copovidone-based formulations was evaluated
270
and found to be profoundly influenced by surfactants such as polysorbate 80/ sorbitan
271
monooleate, vitamin E TPGS, polyoxyl 35 castor oil, and poloxamer. The impact of
272
surfactants on supersaturation behavior in the copovidone system was ranked as follows:
273
SC 10 << SC 7 < SC 8 SC 9 < SC 6 < SC 5 (Figure 3b). This is also consistent with
12
Page 13 of 49
studies in which the dissolution rate and saturation solubility of tested drugs were
275
enhanced with the presence of surfactants in copovidone (Ghebremeskel et al., 2006). On
276
the one hand surfactants may stabilize the solid dispersion by increasing drug solubility
277
and homogeneity in the polymer. However, on the other hand surfactants can destabilize
278
the system by acting as plasticizers to lower the Tg and increasing water uptake
279
(Ghebremeskel et al., 2006, 2007). Therefore, it is critical to determine the optimal
280
surfactant level to ensure physical stability without compromising any supersaturation
281
characteristics or formulation processing.
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Based on the above physical characterization and dissolution results, the copovidone-
an
282
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based formulations with either polysorbate 80/ sorbitan monooleate or vitamin E TPGS
284
and the HPMCAS-based formulation appear to be the beset candidates. Copovidone has
285
been commonly used in HME formulations owing to a relatively low Tg and good
286
thermal stability, whereas processing HPMCAS with extrusion is generally more
287
challenging (Dong and Choi, 2008; Schenck et al., 2010). Therefore, the copovidone-
288
based formulations with either polysorbate 80/ sorbitan monooleate or vitamin E TPGS
289
were chosen for HME development, whereas the HPMCAS-based formulation was
290
chosen for SD development.
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292
3.3 HME Formulations: Processing, Physical Characterization, and Dissolution
293
Following the preliminary screening indicating surfactants required for the
294
copovidone system, specific formulations (Table 2) were manufactured using hot melt
295
extrusion to produce material for further study and to assess potential challenges with
296
extrusion processing. HME 1 and HME 2 are two different copovidone-based HME
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Page 14 of 49
formulations with polysorbate 80/ sorbitan monooleate and vitamin E TPGS,
298
respectively, whereas HME 3, HME 4, and HME 5 were modified from HME 1. BHA
299
used as an antioxidant was evaluated in HME 3 to improve the chemical stability of MK-
300
0364 if necessary. In addition, PVP was evaluated in HME 4 and HME 5 as an
301
additional polymer to increase the physical stability of HME formulations. The
302
surfactant quantity was chosen based on prior experience. Surfactants listed in HME 1
303
and HME 2 in Table 2 were reduced by half (as compared to SC 5 and SC 6 in Table 1)
304
because of the processing issues such as poor flow properties and inhomogeneity of
305
polysorbate 80/ sorbitan monooleate and vitamin E TPGS (data not shown). It is
306
noteworthy that supersaturation behavior was not compromised with the reduced
307
surfactants (Figure 3c). During the processing of all the formulations listed in Table 2,
308
the feed rate was set at 20% of maximum speed, but the actual rate was much lower and
309
variable due to poor flow properties of the wet granulated samples. The flow related
310
issues can be minimized by roller compacting material following wet granulation, using a
311
gravity feeder, or directly adding the liquid surfactant as a separate feed stream.
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312
Crystallinity was not detected in samples HME 1, HME 2, and HME 3 using XRPD,
313
optical microscopy, and thermal characterization. In addition, a single Tg in the range of
314
85-90C was observed (Table 7), indicating single phase behavior of amorphous or
315
undetectable levels of phase separation. All the extrudate strand samples except HME 4
316
and HME 5 were clear and slightly yellow. The extrudate strand samples of HME 4 and
317
HME 5 were grainy and opaque even though the processing temperature was increased to
318
160-170C. No crystallinity was detected in both HME 4 and HME 5 using XRPD, but
319
at least two distinct Tg events were observed in HME 5 using mDSC. In addition, the
14
Page 15 of 49
presence of different levels of PVP in HME 4 and HME 5 did not have any impact on dry
321
Tg. Based on visual observation, it is likely that HME 4 is heterogeneous even though it
322
was not possible to detect multiple glass transition temperatures with DSC. Additionally,
323
the presence of BHA as an antioxidant in HME 3 slightly reduced Tg without any
324
detected crystallization.
Based on initial process development evaluation and physical characterization, HME
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325
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320
1 and HME 2 were further evaluated in dissolution and animal studies. Dissolution
327
profiles of HME 1 and HME 2 were similar, as shown in Figure 3c. However, in animal
328
studies HME 1 showed slightly greater bioavailability than HME 2 in both AUC and Cmax
329
(see more detail in Section 3.5). HME 1 was, therefore, selected as a HME lead for
330
subsequent physical stability studies.
333
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3.4 SD Formulations: Physical Characterization and Dissolution
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332
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331
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Besides the above HME formulations, SD formulations as shown in Table 3 were prepared and then characterized using XRPD, DSC, and optical microscopy (Table 8).
335
HPMCAS was identified as a good SD candidate based on the preliminary screeening,
336
whereas HPMC, which has a relatively high Tg and low degradation temperature, was
337
evaluated to understand the potential benefit of cellulosic polymers in comparison to
338
hydrophilic polymers such as copovidone. No significant crystallinity was detected in
339
any SD formulations using XRPD (Figure 4) and optical microscopy (Table 8). In
340
addition, a single Tg of each formulation was observed. As expected, the Tg values of all
341
the SD formulations ranged from 99C to 116C (Table 8). Wide and weak Tg patterns
342
were noted for SD 2 and SD 3 due to the typical characteristics of HPMC. All the
Ac ce p
334
15
Page 16 of 49
343
physical characterization results indicate single phase behavior of amorphous or
344
undetectable levels of phase separation for all the SD formulations. In addition, MK-0364 dissolution of all the SD formulations was determined using
346
either a 0.1N HCl or phosphate buffer medium. All the SD samples showed sustained
347
supersaturation profiles due to amorphous drug being stabilized by the presence of
348
polymers and/or surfactants, as discussed previously in Section 3.2 for HPMCAS. This is
349
also consistent with other findings for solid dispersions using HPMC in several
350
compounds (Ghebremeskel et al., 2006). The initial dissolution rate of SD 2 was faster
351
than that of SD 3 in a 0.1N HCl media while both reached a comparable plateau (Figure
352
5). Interestingly, disparate dissolution profiles were observed between SD 1 and SC 3
353
(Figure 6) despite the same composition. Experimental evidence does not exist to explain
354
such differences. However, prior investigators have reported that varying drying kinetics
355
can lead to differences in morphology and porosity (Handscomb et al., 2009) or spatial
356
composition of chemical components (Vehring et al., 2007). This can lead to differences
357
in dissolution rate. Although SD 1 and SD 2 showed favorable results in animal studies
358
(Section 3.5), SD 1 with a Tg of 99C was selected as a SD lead because of the reduced
359
hygroscopicity of HPMCAS as compared to HPMC (6-7% water for HPMCAS vs. 10%
360
water for HPMC at 25C and 75% RH (Friesen et al., 2008; McGinity, 1997; Rumondor
361
et al., 2010)).
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362 363 364 365
3.5 Evaluation of Solid Dispersion Formulations in Rhesus Monkeys HME 1, HME 2, SD 1, and SD 2 were selected for evaluation of oral absorption in rhesus monkeys. The formulations were administered as a combination product with
16
Page 17 of 49
drug X where the same drug X formulation was directly blended with each MK-0364
367
formulation (Table 4). Drug X bioavailability results were similar in all the formulations,
368
compared to that of the MK-0364 LFC/drug X coadministration as a reference, and
369
thereby only PK parameters of MK-0364 are summarized in Table 9. According to the
370
crossover monkey studies, all the formulations had promising exposures of MK-0364 that
371
exceeded the exposure of the reference. All MK-0364 Cmax ratios ranged from 0.51 to
372
1.13 with a significant increase in Tmax, when compared to that of the reference. The
373
longer Tmax may possibly be attributed to the different dissolution mechanisms of these
374
formulations where polymers have to dissolve in GI fluids before MK-0364 is released.
375
However, the MK-0364 LFC formulation is readily emulsified, thereby facilitating the
376
dissolution/release of MK-0364. In addition, HME 1 had slightly greater bioavailability
377
than did HME 2. Nonetheless, SD 1 and SD 2 showed similar AUC ratios with a higher
378
Cmax ratio for SD 1.
381
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380
3.6 Physical Stability of Lead Solid Dispersion Formulations
Ac ce p
379
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366
Polymers selected for solid dispersions should not only improve dissolution profiles
382
via inhibiting crystallization and/or forming nanoparticles but also ensure MK-0364
383
physical stability against recrystallization in solid state under storage conditions. The
384
physical stability of HME 1 was evaluated as a function of water content using mDSC
385
and XRPD (Table 10) after storage under different conditions.
386
As expected, Tg decreased with an increase in water content due to the plasticizing
387
effect of water. All HME 1 samples stored under different conditions for 1 week showed
388
no detected crystallinity by XRPD. HME 1 was, however, hygroscopic at > 60% RH
17
Page 18 of 49
(Figure 7), which is related to the water uptake behavior of copovidone (Taylor et al.,
390
2001). The hygroscopicity of HME 1 at relatively high humidities may reflect the high
391
water content of 13.2% in the sample stored under 40C/ 75%RH conditions (Table 10).
392
As a result, the Tg of the sample is depressed (Tg /T <1), and the sample is changed into a
393
super-cooled liquid. This leads to increased mobility and, therefore, potential
394
recrystallization.
cr
In addition, HME 1 and SD 1 physical stability was evaluated for 54 weeks and found
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395
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389
to be different. By using XRPD with a regular scan mode, no crystallinity of MK-0364
397
was detected in HME 1 stored under all conditions after 54 weeks (Figure 8a). However,
398
only minor crystalline MK-0364 was detected in HME 1 stressed at 40C/ 75%RH using
399
a slow scan mode (Figure 8a with detected peaks in circles), which is supported by the
400
increased mobility and potential recrystallization due to the high water content of the
401
40C/ 75%RH sample. Unlike HME 1, the physical stability of SD 1 was excellent.
402
Neither crystalline MK-0364 nor phase separation was detected in any of stressed SD 1
403
samples for 54 weeks using mDSC and XRPD (with both regular and slow scan modes)
404
as shown in Figure 8b. This indicates that SD 1 is not as sensitive to moisture as HME 1.
405
This is also consistent with the fact that HPMCAS is significantly less hygroscopic than
406
copovidone.
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396
Based on the above findings, HME 1 must be protected from moisture for acceptable
408
shelf-life stability. However, SD 1 may not require protection from moisture due to the
409
excellent physical stability for 54 weeks.
410 411
4. Conclusions
18
Page 19 of 49
412
MK-0364 solid dispersions were successfully developed and significantly improve the solubility and bioavailability of MK-0364, a poorly water-soluble drug, while
414
maintaining acceptable physical stability. During the preliminary assessment via a
415
solvent casting technique, physical characterization tools and dissolution testing were
416
implemented to identify lead formulations including copovidone- and HPMCAS-based
417
formulations. Both the formulations provide amorphous characteristics and dissolution
418
enhancement in spite of different composition. The copovidone system requires the
419
addition of surfactants for dissolution enhancement while the same is not true for the
420
HPMCAS system in this specific study. These lead formulations were further developed
421
using HME and SD approaches. All HME (without PVP) and SD formulations have
422
amorphous characteristics, single Tg, and supersaturation profiles. The bioavailability
423
results of MK-0364 from selected HME and SD formulations in rhesus monkeys are
424
promising with a trend of slower onset than that of a liquid filled capsule reference.
425
Based on the processability, physical characterization, in vitro dissolution, and animal PK
426
data, HME 1 (copovidone-based HME) and SD 1 (HPMCAS-based SD) appear to be the
427
best candidates. HME 1 has worse 54-week-physical stability than SD 1, requiring
428
protection from moisture to achieve acceptable shelf-life stability.
430 431
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413
Acknowledgements
The authors would like to thank Wei Xia and Brian Hill for generating dissolution
432
data, Sarah Geers and Varaporn Treemaneekarn for their assistance with physical
433
characterization, and Huizhi Xie for generating PK data. We would like to specially
19
Page 20 of 49
434
thank Laman Alani, Soumojeet Ghosh, Ian Hardy, Larry Rosen, and Ron Smith for
435
providing their comments and encouragement during the preparation of this manuscript.
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437
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438
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Andrews, G.P., AbuDiak, O.A., Jones, D.S., 2010. Physicochemical characterization of hot melt extruded bicalutamide-polyvinylpyrrolidone solid dispersions. J. Pharm.
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Dhirendra, K., Lewis, S., Udupa, N., Atin, K., 2009. Solid dispersions: a review. Pak. J. Pharm. Sci. 22, 234-246. Dong, Z., Chatterji, A., Sandhu, H., Choi, D.S., Chokshi, H., Shah, N., 2008. Evaluation
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Dong, Z., Choi, D.S., 2008. Hydroxypropyl methylcellulose acetate succinate: potential drug-excipient incompatibility. AAPS PharmSciTech 9, 991-997.
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Friesen, D.T., Shanker, R., Crew, M., Smithey, D.T., Curatolo, W.J., Nightingale, J.A.S., 2008. Hydroxypropyl Methylcellulose Acetate Succinate-Based Spray-Dried
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Dispersions: An Overview. Mol. Pharm. 5, 1003-1019. Ghebremeskel, A.N., Vemavarapu, C., Lodaya, M., 2006. Use of Surfactants as
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Ghebremeskel, A.N., Vemavarapu, C., Lodaya, M., 2007. Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: Selection of polymer-surfactant combinations using solubility parameters and testing the processability. Int. J. Pharm. 328, 119-129.
Goldberg, A.H., Gibaldi, M., Kanig, J.L., 1965. Increasing dissolution rates and
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Goldberg, A.H., Gibaldi, M., Kanig, J.L., 1966a. Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures. II.
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Experimental evaluation of griseofulvin-succinic acid solid solution. J. Pharm.
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Handscomb, C.S., Kraft, M., Bayly, A.E., 2009. A new model for the drying of droplets
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containing suspended solids after shell formation. Chem. Eng. Sci. 64, 228-246. Ilevbare, G.A., Liu, H., Edgar, K.J., Taylor, L.S., 2012. Understanding Polymer
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Properties Important for Crystal Growth Inhibition-Impact of Chemically Diverse
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Leuner, C., Dressman, J., 2000. Improving drug solubility for oral delivery using solid
vivo drug delivery. J. Pharm. Sci. 85, 1142-1169.
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Stevens, J.L. (Eds.), Optimizing the “Drug-Like” Properties of Leads in Drug
511
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513 514 515 516
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Rumondor, A.C.F., Konno, H., Marsac, P.J., Taylor, L.S., 2010. Analysis of the moisture
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519
Sekiguchi, K., Obi, N., 1961. Absorption of eutectic mixtures. I. A comparison of the behavior of a eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in
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524
Stella, V.J., Rajewski, R.A., 1997. Cyclodextrins: their future in drug formulation and
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523
Taylor, L.S., Langkilde, F.W., Zografi, G., 2001. Fourier transform Raman spectroscopic study of the interaction of water vapor with amorphous polymers. J. Pharm. Sci.
528
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531 532 533 534
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drying. J. Aerosol Sci 38, 728-746.
te
530
Vehring, R., Foss, W.R., Lechuga-Ballesteros, D., 2007. Particle formation in spray
Zallen, R., 1983. The formation of amorphous solids, The physics of amorphous solids.
Ac ce p
529
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527
John Wiley & Sons, Inc., New York.
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Figure legends
536
Figure 1: Extrusion screw design. Two conventional mixing zones were employed each
537
consisting of 5 forward 30 degree offset paddles, 5 forward 60 degree offset paddles and
538
5 neutral 90 degree offset paddles. Bilobed intermeshing screws were used with the
539
exception of the single flight conveying elements at the die end of the extruder (a
540
customary ThermoPrism design element). All other conveying sections employed a pitch
541
of 1 revolution per diameter length (i.e., 1 D pitch). An ambient vent was placed just
542
downstream of the second mixing zone to facilitate the removal of water vapor prior to
543
the die and feeding was by gravity from the top.
544
Figure 2: Chemical structure of MK-0364.
545
Figure 3a: Dissolution of MK-0364 from SC samples without surfactants (● SC 1, ○ SC
546
2, and ▼ SC 3) in a 250 mL 25 mM buffer solution (pH 6.85) was determined using the
547
USP paddle (II) method at 37C and 100 rpm.
548
Figure 3b: Dissolution of MK-0364 from copovidone-based formulations (● SC 4, ○ SC
549
5,▼ SC 6, SC 7, ■ SC 8, □ SC 9, and SC 10) using copovidone with different
550
surfactants in a 250 mL 0.1 N HCl solution was determined using the USP paddle (II)
551
method at 37C and 100 rpm.
552
Figure 3c: Dissolution of MK-0364 from HME samples (● HME 1 and ○ HME 2) in a
553
250 mL 0.1 N HCl solution was determined using the USP paddle (II) method at 37C
554
and 100 rpm.
555
Figure 4: X-ray powder diffraction (XRPD) patterns of SD samples (SD 1, SD 2, and SD
556
3) at initial.
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Page 27 of 49
Figure 5: Dissolution of MK-0364 from SD samples (● SD 2 and ○ SD 3) in a 250 mL
558
0.1 N HCl solution was determined using the USP paddle (II) method at 37C and 100
559
rpm.
560
Figure 6: Dissolution of MK-0364 from solid dispersion samples of HPMCAS prepared
561
via SD and SC approaches (● SD 1 and ○ SC 3) in a 250 mL 25 mM buffer solution (pH
562
6.85) was determined using the USP paddle (II) method at 37C and 100 rpm.
563
Figure 7 : Water sorption/desorption isotherm of HME 1 (■ water sorption and □ water
564
desorption) at 25C.
565
Figure 8a: X-ray powder diffraction (XRPD) patterns of HME 1 stored at 5C with
566
desiccants, 25C/ambient, 30C/65%RH, 40C/ambient, 40C/75%RH, and
567
60C/ambient for 54 weeks using a regular scan mode. The top two patterns were
568
obtained using a slow scan mode.
569
Figure 8b: X-ray powder diffraction (XRPD) patterns of SD 1 stored at 5C with
570
desiccants, 40C/ambient, 40C/75%RH, and 60C/ambient for 54 weeks using a regular
571
scan mode. The top two patterns were obtained using a slow scan mode.
cr
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Ac ce p
572
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557
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Figure 1
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Figure 2
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Figure 3a
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Figure 3b
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Figure 3c
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Figure 4
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Figure 5
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Figure 6
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Figure 7
Page 37 of 49
Ac ce p
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Figure 8a
250
Intensity (counts/sec)
200
150
60C/amb Slow Scan 40C/75%RH Slow Scan
60C/amb. 40C/75%RH 40C/amb. 30C/65%RH 25C/amb.
100
5C/des 50
Crystalline MK-0364 0 5
10
15
20
Diffraction angle (2θ)
25
30
Page 38 of 49
35
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Figure 8b
Intensity (counts/sec)
200
150
60C/amb Slow Scan 40C/75%RH Slow Scan
100 60C/amb. 40C/75%RH 40C/amb. 5C/des
50
0
Crystalline MK-0364 5
10
15
20
Diffraction angle (2θ)
25
30
Page 39 of 49 35
SC 1
SC 2
SC 3
SC 4
SC 5
SC 6
SC 7
SC 8
SC 9
SC 10
%
%
%
%
%
%
%
%
%
%
MK-0364
10
10
10
10
10
10
10
10
10
10
Polysorbate 80
NA
NA
NA
NA
3
NA
NA
NA
NA
NA
Sorbitan monooleate
NA
NA
NA
NA
3
NA
NA
NA
NA
NA
Vit E TPGS
NA
NA
NA
NA
NA
10
Poloxamer 407
NA
NA
NA
NA
NA
Polyoxyl 35 castor oil
NA
NA
NA
NA
Sodium lauryl sulfate
NA
NA
NA
Eudragit L100-55
90
NA
NA
HPMCP HP-55
NA
90
NA
HPMCAS-LF
NA
NA
Copovidone
NA
NA
M
Table 1: Summary of MK-0364 SC formulations
cr
ip t
Component
NA
NA
NA
NA
10
15
NA
NA
NA
NA
NA
NA
6
NA
NA
NA
NA
NA
NA
NA
10
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
an
us
NA
NA
NA
NA
NA
NA
NA
NA
NA
90
84
80
80
75
84
80
Ac ce
pt
ed
90
Page 40 of 49
Table 2: Summary of MK-0364 HME formulations
HME 1
HME 2
HME 3
HME 4
HME 5
%
%
%
%
%
Function Active
10
10
10
10
10
Polysorbate 80
Surfactant
1.5
NA
1.5
1.5
1.5
Sorbitan monooleate
Surfactant
1.5
NA
1.5
1.5
1.5
Vit E TPGS
Surfactant
NA
5
NA
NA
NA
BHA
Antioxidant
NA
NA
0.83
NA
NA
PVP
Polymer
NA
NA
NA
10
20
Copovidone
Polymer
87
77
67
an
us
cr
MK-0364
86.17
Ac ce
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85
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Component
Page 41 of 49
Table 3: Summary of MK-0364 SD formulations SD 2 % 10 1.5 1.5 NA 87 NA
SD 3 % 10 NA NA 5 85 NA
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M
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MK-0364 Polysorbate 80 Sorbitan monooleate Vit E TPGS HPMC HPMCAS-LF
SD 1 % 10 NA NA NA NA 90
ip t
Component
Page 42 of 49
Table 4: Summary of MK-0364 formulations used in PK studies in rhesus monkeys HME 1
HME 2
SD 1
SD 2
%
%
%
%
MK-0364
1.5
1.5
1.5
1.5
Drug X
32.1
32.1
32.1
Polysorbate 80
0.2
NA
NA
Sorbitan monooleate
0.2
NA
NA
Vit E TPGS
NA
0.7
NA
Copovidone
13.1
12.8
HPMCAS-LF
NA
NA
HPMC
NA
Other excipients
52.9
ip t
Component
32.1
us
cr
0.2
0.2
NA NA
13.5
NA
an
NA
NA
13.1
52.9
52.9
52.9
Ac ce
pt
ed
M
NA
Page 43 of 49
Table 5: Solubility of MK-0364 in different surfactants and lipid-based vehicles Solubility of MK-0364 (mg/mL) 0.08
2.5% Polysorbate 80
0.40
0.1% Vit E TPGS
0.03
1% Vit E TPGS
0.30
cr
0.5% Polysorbate 80
0.1% Poloxamer 407
0.005
1% Poloxamer 407
us
0.004
0.1% Polyoxyl 35 castor oil
0.02 0.23
an
1% Polyoxyl 35 castor oil 0.1% Sodium lauryl sulfate 1% Sodium lauryl sulfate
0.002 0.41 184*
Polysorbate 80
104*
M
Caprylic/capric glycerides/ polysorbate 80 (1:1, w/w)
ed
Sorbitan monooleate Polyoxyl 35 castor oil
ip t
Vehicle
45* 131*
Ac ce
pt
Note: * is the solubility of MK-0364 in mg per g of the listed vehicles.
Page 44 of 49
Table 6: Physical characterization of selected SC samples of MK-0364 using XRPD, DSC, and optical microscopy Optical microscopy amorphous amorphous amorphous amorphous amorphous amorphous partially crystalline (poloxamer)
ip t
Dry Tg , C 91 86 99 89 81 56 NA
cr
XRPD amorphous amorphous amorphous amorphous amorphous amorphous partially crystalline (poloxamer)
Ac ce
pt
ed
M
an
us
SC samples SC 1 SC 2 SC 3 SC 4 SC 5 SC 6 SC 8
Page 45 of 49
Table 7: Physical characterization of HME samples of MK-0364 using XRPD, DSC, and optical microscopy Optical microscopy amorphous amorphous amorphous amorphous amorphous
ip t
Average Dry Tg (SD), C 89.6 (0.5) 84.5 87.6 (0.8) 89.0 (0.8) 88.9 (0.4)
XRPD amorphous amorphous amorphous amorphous amorphous
Ac ce
pt
ed
M
an
us
cr
Formulation HME 1 HME 2 HME 3 HME 4 HME 5
Page 46 of 49
Table 8: Physical characterization of SD samples of MK-0364 using XRPD, DSC, and optical microscopy Average Dry Tg (SD), C 98.6 (0.5) 116.4 (1.5) 109.2 (1.8)
XRPD amorphous amorphous amorphous
Optical microscopy amorphous amorphous amorphous
Ac ce
pt
ed
M
an
us
cr
ip t
Formulation SD 1 SD 2 SD 3
Page 47 of 49
Table 9: MK-0364 PK parameters following the oral administration of listed formulations in monkeys (n=6) Cmax (µM)
Tmax (hr)
AUC0-24 hr ratioa
Cmax ratiob
MK-0364 LFC
2.16 ± 0.28
0.409 ± 0.05
1.8 ± 0.5
1.00
1.00
HME 1
2.65 ± 0.47
0.292 ± 0.07
4.3 ± 0.3
1.23
HME 2
2.35 ± 0.37
0.208 ± 0.05
3.3 ± 0.7
1.09
SD 1
2.68 ± 0.52
0.462 ± 0.14
3.3 ± 0.4
1.24
SD 2
2.62 ± 0.66
0.333 ± 0.13
3.7 ± 0.5
ip t
Formulation
AUC0-24 hr (µM*hr)
0.71
us
cr
0.51
1.21
1.13
0.81
Ac ce
pt
ed
M
an
Note: a and b are AUC and Cmax ratios of the tested formulations to the reference, respectively.
Page 48 of 49
Table 10: Glass transition temperature (Tg) and water content measurements of HME 1 as a function of temperature and relative humidity and their physical states under different conditions % Water content 7.9 13.2 1.8 0.7
Tg /T 1.02 0.93 1.09 1.06
pt
ed
M
an
us
cr
All Tg values are within 2C.
State of samples super-cooled liquid/glass super-cooled liquid glass glass
Ac ce
a
Tg (C) a 36 18 69 81
ip t
Condition (T/%RH) 30ºC/65%RH 40C/75%RH 40C/amb 60C/amb
Page 49 of 49