Porous Inorganic Excipients as Carriers for Amorphous Solid Dispersions

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1 Porous Inorganic Excipients as Carriers for Amorphous Solid Dispersions Irina Kazakevich, PhD Merck & Co., Inc. AAPS 2014 San Diego November 6, 2014

2 Outline Introduction How are insoluble molecules formulated? Current Formulation Approaches Enabled formulations overview Innovative Alternatives to Existing Formulation Platforms: Porous inorganic excipients as carriers Case studies Summary Acknowledgments 2

3 Introduction Solubility of Marketed Products VERY SOLUBLE 76 FREELY SOLUBLE 340 SOLUBLE SPARINGLY SOLUBLE SLIGHTLY SOLUBLE VERY SLIGHTLY SOLUBLE 122 PRACTICALLY INSOLUBLE Source: Impact: Inability to achieve target exposure in safety studies Low exposure and variable PK in clinical studies Greater potential for food effect and PPI effect High pill burden for patients 3

4 Formulation Approaches to Overcome Dissolution- Limited Absorption of BCS II/IV Compounds Dissolution-Limited Absorption: How to Improve Dissolution Rate Noyes-Whitney Equation: dm dt = DS(Cs C)/h S Cs S Cs where: D-diffusion coefficient S-surface area of exposed solid h-the thickness of the diffusion layer Cs- solubility of the solute C-concentration of the solute in bulk solution at time t Source: C.McKelvey et al., Harvard Advanced Materials Pharmaceutical Symposium, Nov.28-30,

5 Alternative Carriers For Solid Dispersions TO PRODUCE STABLE AMORPHOUS DISPERSION WE CURRENTLY USE Organic Polymers Inorganic Porous Excipients: Silicon Dioxide Magnesium Alumosilicate Anhydrous Calcium Phosphate Calcium Carbonate Well developed. Many commercial products Research area, no commercial products available yet

6 6 Silica has multiple forms and applications

7 History of Silica Used in Drug Delivery 1977 Rupprecht et al., first reported the use of silica beads as a drug carrier. Codeine was utilized as a model drug and the silica gel beads had pores in the size of 1-5 micron suitable for sustained release 1992 MCM-41 ( Mobile Composition of Matter, No.41), first synthesized ordered amorphous silica gel 2-5 nm pore size; spec. surface area ~1000 m 2 /g for particle size 1996 SBA-15 (Santa Barbara Amorphous) developed at University of California, Santa Barbara, ordered amorphous silica gel: 8-11 nm pore size; spec. surface area ~600 m 2 /g; particle size: 1-2 um Early 2000 s Mesoporous silicates first looked at for delivery of poorly water soluble API s, and after that Source: S.Kucera, Parteck SLC, Merck KGaA, An Innovative Solution for Bioavailability Enhancement, June 5, 2014

8 Not all silicon dioxides are the same Source: Syloid FP Customer Presentation, Grace, 2012 Commercially available silica for pharmaceutical applications: Syloid ( 244, 72, and AL1) FP Silica, from W.R.Grace &Co,-Conn. Aeroperl, Sipernat, and Aerosil, from Evonik Parteck SLC 500&800, from EMD Millipore Neusilin US2, Fuji Chemical Industry Co., LTD.

9 General Characteristics of Commercially Available Porous Silica-Based Excipients Porous Excipient Parteck SLC 500 Description Morphology PSD*, µm Source D 10 D 50 D 90 Silica gel EMD Millipore Neusilin US2 Aeroperl 300 Granulated magnesium aluminosilicate Granulated fumed silica Fuji Chemical Evonik Syloid 244FP Silica gel Grace * - PSD data were generated internally at Merck by Sympatec HELOS Particle size Analysis, except Parteck SLC 500 9

10 Nitrogen Adsorption Isotherm as a Powerful Tool to Characterize the Surface Properties of Porous Excipients BET equation P P0 a 1 P P 0 = 1 n m C + C 1 n m C P P 0 S = 16.4 [Å 2 ]. n m a adsorption P/P 0 relative pressure n m monolayer capacity C k 1 exp H a L RT H a Heat of adsorption L Heat of N 2 condensation Approximate ranges of C-constant: hydrophobic surface aromatic, or polarizable 80 and higher polar typical silica Porous structure Cylinders; corpuscular, slit-type slit flakes From S.J.Gregg, K.S.W.Sing, Adsorption, Surface Area and Porosity, AP 1982, London

11 Material Surface Chemistry Characterization by Nitrogen Adsorption/Desorption Isotherms Adsorption, mmol/g Pore Size Distribution Nitrogen adsorption data Surface Area C (BET) constant Pore volume Pore diameter max. average m 2 /g ml/g Å Å Parteck SLC Neusilin US Aeroperl Syloid 244FP Parteck SLC500 Neusilin US2 Aeroperl 300 Syloid 244FP Pore diameter, (Å) Parteck SLC500 Neusilin US2 Aeroperl 300 Syloid 244FP Material Characteristics from Nitrogen Adsorption/Desorption Isotherms: Porous morphology differs significantly for all studied excipients. All excipients demonstrate comparable high surface area. Surface Energy (C-constant), calculated from BET equation, reflects highly hydroxylated silica surface Relative Pressure, P/Po

12 How to Load Crystalline Drug Substance onto Porous Excipients to Produce Amorphous Solid Dispersion? Inorganic porous excipient based amorphous solid dispersions can be produced via co-milling (solid-solid), wet impregnation/melt adsorption (liquid-solid), spontaneous amorphization ( vapor-solid). Commercial scale-up information is not available, however, many lab and pilot-plant batches were manufactured by: Fluid Bed Impregnation (Plamen Grigorov et al., Rutgers) Spontaneous evaporation and sublimation ( Ken Qian et al.) Spray Drying (Abhijit Gokhale, Patheon, and Dina Zhang, Merck) Hot-Melt Extrusion ( Jenifer Maclean at al., Amgen) Co-Milling ( Dr. Robin Bogner, UConn, and multiple groups within Merck) Wet Impregnation/Solvent Deposition ( Michiel van Speybroeck et al. Formac., Sean Kucera at al., EMD Millipore; and many others)

13 Case Study: Improving Bioperformance of CNS Drug by Co-Milling with Neusilin US2 Solubility, mg/ml Problem Statement: CNS drug has significantly decreased bioavailability when coadministered with proton pump inhibitors. Goal: Develop PPI resistant formulation 13 Formulation Screening Results: (i) Conventional formulation has shown a significant PPI effect; ( ii) Enabled formulations such as nano, SP and HME, have demonstrated low POS due to the intrinstic properties of the molecule such as phdependent solubility, high melting point, low solubility in SD solvents at ambient temperature, and low solubility in LFC solubilizing vehicles Aqueous Solubility of MK-XX ph Alternative Formulation Approach: Co-milling with Neusilin US2 to produce amorphous solid dispersion. Form pk a 5.7 Melting point 256 C T g 74 C Log P 2.3 Aqueous Solubility (µg/ml) BCS Crystalline Free Base SGF: 162.5; FaSSIF: 1.96; FeSSIF: 5.95 II

14 Case Study: Improving Bioperformance of CNS Drug by Co-Milling with Neusilin US2 Experimental Design: Blending MK-A, Neusilin US2, Excipient Co-Milling Encapsulation Bioperformance: Formulation AUC 0-8 C max (µm) (µm*hr) Conventional tablet (famotidine) ± ± Conventional tablet predissolved in SGF (famotidine) ± ± Neusilin based dry blend capsule (famotidine) ± ± Physical stability: up to 1 month at 40C/75%RH, up to 1 year at ambient conditions Conclusion: PPI-resistant formulation was developed for PK Safety studies in dogs at lab scale (50 g). No line of sight to commercialization due to the absence of commercially available pharmaceutical milling equipment. 14

15 Case Study: Itraconazole/Parteck SLC 500 Amorphous Dispersion by Wet Impregnation Source.: Sean Kucera, Parteck SLC An Innovative Solution for Bioavailability Enhancement, Merck KGaA

16 How Processing Route and the Nature of Solid Carrier Affect the Properties of Amorphous Solid Dispersions. Merck/UConn Scientific Collaboration. Model compound: Itraconazole (ITR) Melting Point 178 C Solubility: 0.1N HCl water pka, weak base 3.7 BCS Class 4-6 µg/ml 1-4 ng/ml Composition: ITR/Excipient II Neusilin US2 Veegum-F A-TAB Description Mesoporous amorphous magnesium aluminosilicate Non-porous magnesium aluminosilicate Macro porous crystalline anhydrous calcium phosphate Processes: Solvent Deposition (SD) Co- Milling (CM)

17 Surface Properties of Itraconazole Amorphous Dispersions and Corresponding Excipients NEUSILIN SD milled 17

18 Excipient Loading Capacity by Solvent Deposition of Itraconazole Loading capacity [%] 50 > 10 > 6 Neusilin US2 > A-TAB > Veegum F PXRD patterns of ITR, Neusilin US2, Veegum F and A-TAB and ITR solvent-deposited in/on the three excipients at loading levels above and below the apparent amorphization capacity are shown below: ATR-FTIR scans of crystalline and amorphous ITR, and ITR solvent-deposited using Neusilin US2, A-TAB, and Veegum F along with scans of the neat excipients. Note: Neat amorphous ITR shows band broadening, but no other significant differences from the crystalline form. No spectral shifts are observed suggesting the presence of hydrogen bonding between the drug and excipients. 18

19 Amorphization Rate of Itraconazole by Co-Milling with Excipients of Different Nature Amorphization time (or time to disrupt the crystalline state) by co-milling at a single level of ITR (30%) are in the order of : ITR:Neusilin US2 < ITR:A-TAB < ITR:Veegum F < ITR crystalline 19

20 Effect of Milling on Surface Properties and Loading Capacity of Neusilin US2 Nitrogen adsorption isotherms of Neusilin original (blue), Neusilin milled for 30 min (red), and Neusilin milled for 60 min (green). PXRD patterns of (a) crystalline ITR and 30% ITR solventdeposited on Neusilin US2 where the Neusilin was (b) unmilled or previously milled for (c) 30 min or (d) 60 min. a b c d SSA, m 2 /g of milled Neusilin by BET: 397 > 152 > 57 As is > 30 min > 60 min Milling affects significantly the porosity of the material, decreases the surface area of Neusilin US2 and, subsequently, its loading capacity.

21 Dissolution Enhancement of Itraconazole Dissolution profiles of crystalline ITR and ITR deposited on/into excipient. ITR crystalline (black squares); ITR melt-quneched (black circles); 6% ITR:Veegum (red); 10% ITR:ATAB (blue); 30% ITR:Neusilin US2 (green). Dissolution profiles of a crystalline ITR and 30% ITR co-milled with excipient. ITR crystalline (black squares); neat ITR milled 3 hours (black circles); 30% ITR:Veegum (red); 30% ITR:ATAB (blue); 30% ITR:Neusilin US2 (green). 21 Dissolution conditions: USP Type 2 Apparatus, SGF ph 1.2 at 37 C, 500 ml, 250 rpm, 30 mg ITR

22 Physical Stability of Itraconazole Amorphous Dispersions Solvent deposition Ball milled Stability at 40 C/0% RH of the dissolutioneof Itraconazole by Neusilin at 3 Loading Levels using (a) co-milling or (b) solvent-deposition for amorphization Formulation Neat ball milled Itraconazole Neat melt quenched Itraconazole Storage time [month] Initial/0 2 3 Concentration (μg/ml) % Itraconazole : Neusilin US2 40% Itraconazole : Neusilin US2 50% Itraconazole : Neusilin US2 30% Itraconazole : Neusilin US % Itraconazole : Neusilin US2 50% Itraconazole : Neusilin US

23 Physical Stability of Itraconazole Amorphous Dispersion at 50%DL by XRPD XRPD of 50% ITR solvent-deposited on Neusilin US2 and stored at 40 C/0%RH and 40 C/75%RH for 2 months. 23

24 Merck/UConn Collaboration Summary Dry milling is a very attractive green approach which allows to remove the solvent from the process to produce amorphous solid dispersion. However, it is a very complex process where the excipient plays a part in the transfer of mechanical energy to the drug, creates mechanical barriers and, in some cases, intermolecular bonds to prevent drug s recrystallization in solid state and serves as stabilizer of amorphous form upon dissolution. Among three evaluated excipients Neusilin US2 has demonstrated superior amorphization potential and stabilization of amorphous form in solid dispersions produced by milling. Wet impregnation loading approach is widely used for producing amorphous solid dispersions on lab scale. The unique characteristics of porous excipients such as high surface area and large pore volume provide significant benefits in drug loading capacity and stabilization of amorphous form by confinement in narrow pores. With wet impregnation it was possible to achieve 50% ITR DL on Neusilin US2, compare to 10% on A-TAB, and 6% on Veegum F, non-porous excipients. 24

25 Conclusions Numerous research groups in academia and the pharmaceutical Industry are working on innovative applications of porous excipients to produce stable amorphous dispersions via multiple processing routes. Advantages of using porous excipients as alternative carriers for solid amorphous dispersions include well defined pharmaceutical safety profile, commercial availability, enhanced dissolution profile, good flowability, and compactibility of final blend. The mechanism of amorphization and stabilization of porous inorganic carrier-based amorphous solid dispersions is depend upon the loading process and interfacial interactions between an adsorbed drug and the surface of the porous carrier. A complete understanding of surface chemistry is required prior to the use of porous carriers for producing amorphous dispersions. 25

26 Acknowledgments Merck Research Laboratories: Dina Zhang, PhD Louis Crocker, PhD John Higgins, PhD David Dubost, PhD Steven Wang, PhD Anthony Leone, PhD Michiel Van Speybroeck, PhD, Formac Pharmaceuticals University of Connecticut: Dr. Robin Bogner and her research group EMD Millipore: Sean Kucera, PhD Thomas Brennan Ken Qian, PhD, NIST Janine Sink, Grace Michael Greene, Mutchler 26

27 27 Thank You!