Solving the solubility challenge: A key success factor of pharmaceutical formulations
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1 Solving the solubility challenge: A key success factor of pharmaceutical formulations ExcipientFest Americas, April 28 th - 29 th 2015
2 Agenda 1 A formulator s strategies to overcome bioavailability issues 2 Silica for drug delivery and solving the solubility challenge 3 Case studies 4 Summary 2
3 Agenda 1 A formulator s strategies to overcome bioavailability issues 2 Silica for drug delivery and solving the solubility challenge 3 Case studies 4 Summary 3
4 High failure rates in R&D: Insufficient bioavailability is a big issue Drugs in Preclinical Stage Why do they fail? High Toxicity 11% Adverse Effects 10% Molecules promoted from preclinical to phase I 25% N = 3,900 Molecules failed in preclinical 75% Low Efficacy 30% Others 10% Poor Bioavailability 39% Bioavailability enhancement will help to reduce the failure rate and R&D expenses 4 A. Pandit, GlobalData 2009
5 Low bioavailability because of low solubility 25% 5% 20% 10% III III Drugs in in pipeline IV IV Marketed drugs II 30% 5% I II I 35% 70% Marketed drugs: BCS class II and IV account for 40% of all drugs Drugs in pipeline: BCS class II and IV account for 90% of all drugs Permeability BCS: Biochemical classification system Class I High solubility High permeability Class III High solubility Low permeability Permeability = how API gets into the blood stream Class II Low solubility High permeability Class IV Low solubility Low permeability Solubility Source: David Hauss, Oral Lipid based Drug Delivery, Marcel Dekker
6 A formulator s strategies Bioavailability enhancement Speed up Liberation Increase Absorption Influence Distribution Reduce Metabolism Postpone Elimination Type of dosage form Disintegration time Solubility Chemical approaches Salt formation Prodrug formation Permeability Administration route Permeation enhancers API lipophilicity Tissue targeting Protein binding other Efflux (P-gp) API stability Avoid the first pass effect Reduce enzymatic biotransformation Increase circulating lifetime Increase size Physical approaches Particle size reduction Solubilization Complexation Drug carriers Solid form modification Solid dispersion 6
7 A formulator s strategies Bioavailability enhancement Speed up Liberation Increase Absorption Influence Distribution Reduce Metabolism Postpone Elimination Type of dosage form Disintegration time Solubility Permeability Tissue targeting Protein binding other Avoid the first pass effect Reduce enzymatic biotransformation Increase circulating lifetime Increase size Chemical approaches Salt formation Prodrug formation Administration route Permeation enhancers API lipophilicity Efflux (P-gp) API stability Physical approaches Particle size reduction Solubilization Complexation Drug carriers Solid form modification Solid dispersion 7
8 Agenda 1 A formulator s strategies to overcome bioavailability issues 2 Silica for drug delivery and solving the solubility challenge 3 Case studies 4 Summary 8
9 Why silica for drug delivery? The high surface of porous silica particles acts as drug carrier The drugs are distributed homogeneously on surface and within pores, in amorphous or nanocrystalline state Resulting in enhanced dissolution rate and/or solubility, bioavailability, drug stability Safe and inert inorganic material (GRAS = Generally Recognized As Safe) with EP/USP monographs Adsorption Controlled Release Drug = 9
10 Pharmacopoeial monographs Parteck SLC is not a novel excipient Monographs two main types: Fumed Silica: very fine particulate or colloidal form of SiO 2. Prepared by burning SiCl 4 in an oxygen rich flame Precipitated Silica: typically prepared by acidification of sodium silicate solutions Silica = SiO 2 10
11 Specific surface area (S BET ) 10 g porous SiO 2 offer a surface area of approx m² 11
12 Development Steps: Silica for Drug Delivery What Carrier (Silica ) API properties API solubility Loading Analytical methods Success of carrier load Theta Absolute Intenity Dissolution Formulation 12
13 Agenda 1 A formulator s strategies to overcome bioavailability issues 2 Silica for drug delivery and solving the solubility challenge 3 Case studies 4 Summary 13
14 Case study I: Poorly soluble API fenofibrate Solid state of model API fenofibrate after loading on Parteck SLC Pure Fenofibrate Porous silica + Fenofibrate Pure Fenofibrate Porous silica + Fenofibrate Absolute Intensity Theta Model API fenofibrate is present in its amorphous form 14
15 Case study I: Poorly soluble API fenofibrate Where is the API located? EDS-measurement after microtome sectioning 50 µm Pure silica carrier 50 µm Si marker for silica carrier 50 µm S marker for the resin 50 µm Cl marker for API homogeneous API deposition across entire particle surface of carrier 15
16 Case study I: Poorly soluble API fenofibrate Fenofibrate (FEN) In-vitro dissolution in FeSSIF In-vitro dissolution: 30% FEN + 70% silica (equal to 48mg API) 16 Amount Fenofibrate Dissolved (%) Dissolution of fenofibrate-containing formulations reported in "percent drug dissolved" (n=3) in 900 ml FeSSIF, 75 RPM Silica Formulation Nano-Milled Material Fenofibrate Time (min) Nanomilled API 48mg tablets Scale (mg/tab) 48mg Material name Fenofibrate (nanomilled) Polyvinyl alcohol Soybean Lecithin, Hypromellose Formulation with Parteck SLC shows an improved dissolution performance in comparison to best performing marketed formulation Docusate Sodium Sodium Lauryl Sulfate Lactose Monohydrate Silicified Microcrystalline Cellulose Crospovidone Magnesium Stearate
17 Case study I: Fenofibrate PK study in rats Dose Form AUC/Dose tmax mg/kg µg/mlxh/ mg/kg TriCor (Nanomilled)* 4.2 solid (tablet in capsule) Lipidil -TER (Micronized)* 4.2 solid (tablet in capsule) EMD silica 4.2 solid (Silica in capsule) h n=6 rats, gastric probe, plasma levels determined as fenofibric acid Status: In-vivo FEN-EMD Silica is comparable to the "gold standard" formulations on the market marketed formulation (nanomilled) EMD silica + fenofibrate marketed formulation (micronized) pure fenofibrate (crystalline) 17 Time [h] *TriCor a d Lipidil - TER are registered trademarks of AbbVie Inc. (N. Chicago, IL, USA) and Abbott Laboratories (Abbott Park, IL, USA), respectively
18 Case study I: Poorly soluble API fenofibrate Comparison: Parteck SLC or "ordered mesopores"? Simulated Gastric Fluid (SGF), 0.1 wt.% sodium dodecyl sulfate (SDS) (USP II at 75 rpm, 1000 ml vessel) 18 Amount of Fenofibrate Releaesed (%) Ordered and granulated types Silica Parteck SLC shows 1.6 fold AUDC after 2 hours against best ordered or granulated types silica Merck EMD Silica Bimodal Aeroperl Granulated 300type MCM-41 SBA-15 x-fold vs pure Fenofibrate Mean AUDC Formulation (ug/ml min) 30% FEN/ Parteck SLC % FEN/ MCM % FEN/ SBA Time (min) 30% FEN/ Granulated Colloidal Silica Fenofibrate
19 Case study I: Poorly soluble API fenofibrate In-vitro stability data Study was performed including four batches Conditions tested: Refrigerator / 25 C and 60% r.h. / 30 C and 65% r.h./ 40 C and 75% r.h./ 40 C and 75% (open) week DSC XRD NMR (RS) TGA KF PSD BET dp HG REM Dissolution Assay Purity Solubility 0 x x x x x x x x x x x x x 4 x x - x x - x x x x x x - 8 x x - x x - x x x x x x - 13 x x - x x - x x x x x x - 26 x x - x x x x x x x x x x Example: 40 C and 75% (open) Fenofibrate 19
20 Case study I: Poorly soluble API fenofibrate Fenofibrate (FEN) In-vitro dissolution stability data In-vitro dissolution: 30% FEN + 70% silica (equal to 48mg API) Dissolution [%] Time [min] t=0 weeks t= 4 weeks t= 8 weeks t= 12 weeks t= 16 weeks t= 20 weeks t= 24 weeks Stable for 6 months even at 40 C+75% RH even in open vi als! Simulated Gastric Fluid (SGF), 0.1 wt.% sodium dodecyl sulfate (SDS) (USP II at 75 rpm, 1000 ml vessel) 20
21 Case study I: Poorly soluble API fenofibrate Chemical Stability of Fenofibrate After Loading on Parteck SLC Purity [%] Weeks open Fenofibrate 21 Open containers stored at 40 C/75% RH
22 Drug Loading: 1kg batch loading Fenofibrate: Homogeneity 100 Batch: Silica Loading % Test 1 31 Test 2 30 Test 3 32 Test 4 31 Test 5 31 SD % / RSD 0.71 / 2.3 Dissolved [%] SGF % SDS (USP apparatus II at 75 rpm ml vessel. 37 C) time [min] Test 1 Test 2 Test 3 Test 4 Test 5 Fenofibrate pure 48mg Fenofibrate 50 mg 5 batch samples show good intra-batch homogeneity 1. Dry powder 2. Impregnation 3. Vacuum dried powder 22 repeated impregnation
23 Case study II: Poorly soluble API itraconazole Itraconazole (ITZ) Drug Loading 30% ITZ + 70% Silica Pure silica Pure ITZ Pure Itraconazole Porous silica + Itraconazole Pure Itraconazole Absolute Intensity Porous silica + Itraconazole Drug loaded Silica Theta
24 Case study II: Poorly soluble API itraconazole Itraconazole (ITZ) In-vitro dissolution Dissolution rate [%] Scale (mg/cap) Simulated gastric fluid (SGF), 0.1 wt.% sodium dodecyl sulfate (SDS) (USP II at 75 rpm, 1000 ml vessel) BP048a_imp1 Silica + Itraconazole Sporanox Capsules Itraconazole Crystalline Itraconazole (pure) Time [min] Comparator: Sporanox 100mg Capsules* 3 layer pellets (US Patent 5,633,015) Material name Itraconazole (used as pellets) Empty HardGelatine Capsules, Size 0 Sugar Spheres Hypromellose Polyethylene Glycol Cornstarch Sucrose Titanium Dioxide *Sporanox is a registered trademark of Janssen Pharmaceuticals, Inc. (Titusville, NJ, USA)
25 Case study II: Poorly soluble API itraconazole Itraconazole (ITZ) In-vitro dissolution stability data 30% ITZ + 70% silica (equal to 50mg API) Released amount of API [%] BP48b_ITZ_imp_00 Porous silica + Itraconazole start BP48b_ITZ_imp_4075_04 Porous silica + Itraconazole 4 weeks BP48b_ITZ_imp_4075_08 Porous silica + Itraconazole 8 weeks BP48b_ITZ_imp_4075_13 Porous silica + Itraconazole 13 weeks BP48b_ITZ_imp_40/75_26 Porous silica + Itraconazole 26 weeks Itraconazole (original) Pure Itraconazole [crystalline] Time [min] Stable for 6 months at 40 C+75% RH even in open vials! Simulated gastric fluid (SGF), 0.1 wt.% sodium dodecyl sulfate (SDS) (USP II at 75 rpm, 1000 ml vessel) 25
26 Case study II: Poorly soluble API itraconazole Chemical Stability of Itraconazole After Loading on Parteck SLC Purity [%] Weeks open Itraconazole Open containers stored at 40 C/75% RH 26
27 Case study III: Tablet formulation with ibuprofen Goal Develop a 25 mg ibuprofen tablet with the following specifications: Tablet Weight: 333 mg ± 5% Tablet Hardness: > 40 N Disintegration: < 90 seconds Friability: < 1.0% The powder blend was compressed on a tablet press EK0 (Korsch AG, Berlin, Germany) Die Size: 11 mm Compression Force: 30 kn Results Tablet Weight: mg ± 2.25% Tablet Hardness: 42.8 N Disintegration: 14 sec Friability: 0.11% Component % Ibuprofen loaded Parteck SLC 25 Hypromellose 10 Parteck M Microcrystalline Cellulose 53 Parteck CCS 2 27 Parteck LUB MST 0.5
28 Case study III: Tablet formulation Dissolution profile of ibuprofen loaded Parteck SLC mg API ml SGFsp (ph 1.2) 75 rpm 80 Dissolution [%] Time [min] 28
29 Important Considerations for Parteck SLC Solubility considerations Drug must be soluble in an acceptable solvent Solvent properties: Low boiling point, high vapor pressure, acceptable tox. profile API concentrations of mg/ml ideal, a lower concentration is possible Loading procedure considerations Loading should be carried out as to not over-saturate the silica Good experience with ~ 30 % w/w for fully amorphous state Drying is needed to remove residual solvents Drying temperature should be selected based on solvent boiling point and drug melting point/t g Formulation considerations Loading capacity: ~ 30 % API Tabletting capacity: up to 30 % Silica Tablet size: depending on intended API dose: up to 1000 mg API dose: up to 120 mg 29
30 Agenda 1 A formulator s strategies to overcome bioavailability issues 2 Silica for drug delivery and solving the solubility challenge 3 Case studies 4 Summary 30
31 Summary High bioavailability is essential for the product performance Bioavailability enhancement will be a driving force in the development of new drugs Parteck SLC is an innovative and promising technology to help enhance the bioavailability and performance of your active... by increasing the aqueous solubility and/or dissolution rate compared to the crystalline form by using straight-forward processes with typically available equipment for NCE s or life cycle management of established compounds Adsorption Controlled Release 31 Drug =
32 EMD Millipore: We provide solutions! Solubility enhancement Dissolution rate Solubility enhancement Reduce enzymatic biotransformation Increase circulating lifetime Increase size Activated PEGs Solubility enhancement Avoid the first pass effect Solubility enhancement Parteck SLC API Modification PVA PEGs Parteck M Drug Carriers Solid Dispersions Parteck ODT Parteck M PVA Controlled Release Current Portfolio Counter Ions Dissolution rate Liposomes Hydrogels Lipids PEG-Lipids Solubilizers PVA PEGs API stability Increase circulating half time Cyclodextrin HPB Tween PEGs Tissue targeting Solubility enhancement API stability Administration route Dissolution rate Meglumine 32 API stability Solubility enhancement Tween is a registered trademark of Uniqema Americas LLC, Delaware, USA
33 EMD Millipore, the M-Logo, EMPROVE and Parteck are registered trademarks of Merck KGaA, Darmstadt, Germany. All other trademarks pertain to their respective proprietors. 33
7. SUMMARY, CONCLUSION AND RECOMMENDATIONS
211 7. SUMMARY, CONCLUSION AND RECOMMENDATIONS Drug absorption from the gastro intestinal tract can be limited by various factors with the most common one being poor aqueous solubility and poor permeability
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