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Drug/cyclodextrin nanoparticles for topical drug delivery to the posterior segment of the eye Thorsteinn Loftsson, Ph.D. Faculty of Pharmaceutical Sciences University of Iceland [email protected] September 20th 2016, 11:30-12:00 Cyclodextrins Bacterial digestion But cyclodextrins are able to form inclusion complexes: Cyclodextrins are oligosaccharides and share many of the physicochemical and biological properties of the linear oligosaccharides, including their toxicological and pharmacokinetic properties. αCD βCD γCD Cyclodextrins and their derivatives Usage in pharmaceutical products: 1. Solubilizers 2. Stabilizers (can increase both chemical and physical stability) 3. Penetration enhancers 4. As nanoparticle building blocks etc. Can be found in about 40 marketed drug products. Aggregation of cyclodextrin complexes + Transmission electron microscopic (TEM) image of hydrocortisone/HPβCD aggregates. Hydrocortisone flux through semipermeable cellophane membrane with MWCO 15 kDa (8 complexes). Cyclodextrin (CD) aggregation - some observations: • The natural αCD, βCD and γCD do form aggregates by themselves in pure aqueous CD solutions but the aggregation is very low with much less than 1% of dissolved CD present in the form of aggregates. • Formation of drug/CD inclusion complexes increases the aggregation, both in the case of the natural CDs and in the case of the randomly substituted CD derivatives. • The diameter of the complex aggregates depends on the drug/CD properties as well as the concentration of drug/CD inclusion complexes, increasing with increasing availability of drug/CD complexes. • The degree of aggregation depends on the availability of drug/CD complexes in the aqueous solution, increasing with increasing availability of drug/CD complexes. • Addition of organic solvents such as ethanol that are known to decrease the complexation will reduce the aggregation. Also, heating of aqueous CD solutions will result in decreased aggregation. • In aqueous solutions drug/CD complex aggregates are in dynamic equilibrium with un-aggregated (i.e., free) complexes. Aggregates are constantly being formed and dissembled. • The complex aggregates are unstable and dissemble up on media dilution (and filtration). • Complexes of the natural αCD, βCD and γCD have limited solubility in water and tend to precipitate in aqueous solutions as solid drug/CD complex aggregates. Their complexes are frequently less soluble than the CDs themselves. Topical drug delivery to the eye I. Barriers to Ocular Drug Delivery: Aqueous drug solubility. Limited solubility of lipophilic drugs in aqueous eye drops and tear film. The short contact time. The normal tear fluid is only about 8 µl and the average tear secretion is 1.2 μl/min. The lipid membrane barrier. In general, the passive drug permeation through the lipid membrane barrier, i.e. cornea or conjunctiva/sclera, is very slow. II. Conventional eye drops: The aqueous tear fluid. About 50% is replaced every 3 to 4 minutes. Less than 5% of the dose permeates into the eye. III. Tasks to improve eye drop delivery: Increase aqueous solubility of lipophilic molecules. Sustained high drug conc. in tear film. Enhanced drug partition into eye wall. Most of the dose is absorbed into the systemic blood circulation mainly via the nasal cavity. Nanoparticulate drug/γCD delivery system The system consists of aqueous eye drops containing nanosuspension of drug/γCD complexes. Microparticles, 50 to 90% of the drug is in small microparticles with diameter of 1 to 10 μm. The dimeter depends on the preparation method and excipients (e.g., polymers) used. The microparticle increase the drug contact time from few minutes to several hours and provide for high and sustained concentration of dissolved dexamethasone in the tear fluid. Water is about 85% of the eye drops. Nanoparticles, 10 to 50% of the drug is present as drug/γCD nanoparticles with diameter of 100 to 300 nm. The nanoparticles increase the contact time with the mucus layer that results in enhanced drug delivery through the tear film (i.e. the unstirred water layer) to the membrane surface. Drug/γCD complexes enhance the aqueous drug solubility. In case of dexamethasone the enhancement is 30-fold but it can be as high as couple of hundred fold for very poorly soluble drugs. This increases the drug concentration gradient over the membrane barrier and, consequently, drug permeation into the eye. + The free drug permeates into the eye but the carrier, γCD, is metabolized to maltose and glucose by α-amylase that can be found in the tear fluid and in the GI tract. The result is increased ocular bioavailability from less than 5% to about 50% and decreased systemic drug delivery (5-fold decrease in case of dexamethasone). γ-Cyclodextrin and its derivatives are basically the only cyclodextrins metabolized by human α-amylase (found in the tear fluid, saliva, etc.). Michaelis–Menten parameters of the γ-cyclodextrin, 2-hydroxypropyl-γcyclodextrin and sulfobutylether γ-cyclodextrin degradation by porcine pancreatic α-amylase. Vmax (mM/min) γCD 17.01 KM (mM) 0.54 Vmax/KM (min-1) 31.5 t½ 1.3 s HPγCD 0.07 88 8.0∙10-4 14.4 h SBEγCD 0.57 134 4.3∙10-3 2.7 h Lumholdt, L.R., Holm, R., Jorgensen, E.B., Larsen, K.L., In vitro investigations of α-amylase mediated hydrolysis of cyclodextrins in the presence of ibuprofen, flurbiprofen, or benzo[a]pyrene. Carbohydrate Research 362, 56-61 (2012). Lumholdt, L., Pipkin, J.D., Antle, V., Reaction between α-amylase and CAPTISOL® and other SBEcyclodextrins (poster presentation), 4th European Conference on Cyclodextrins, October 6th-9th, 2015, Lille, France. Drug Delivery Mechanism (on the eye surface) Tear fluid Microparticle Mucus (unstirred water layer) Nanoparticle Single complex + Unbound drug molecule Glucose Maltose Washed down into the lacrimal duct to be further metabolized in the GI tract. Lipophilic membrane Inner layers Advantages over “normal” nanoparticles Normal Nanoparticles (NP): Limited increase in aqueous solubility of lipophilic drug molecules. Sustained low concentration of dissolved drug in tear film. Do not increased drug concentration gradient or result in only limited increase. Solubilizing Nanoparticles (SNP): Increase aqueous solubility of lipophilic drug molecules. Give sustained high concentration of dissolved drug in tear film. Increase drug concentration gradient enhanced drug permeation into the eye. Dorzolamide O H3C S H O O H3C S SO2NH2 H pKa = 6.4 NHCH2CH3 H+ Molecular weight Melting point Calculated logP(octanol/water) Solubility in water at 25°C O S O H3C S H SO2NH2 H NHCH2CH3 Dorzolamide 324.4 Da 283-285°C pKa = 8.5 O S S SO2NH - H H NHCH2CH3 Dorzolamide hydrochloride 359.9 Da 264°C 1.7 (at pH 7.4) 6.7 mg/ml (at pH 7.4) P. Jansook, E. Stefánsson, M. Thorsteinsdóttir, B. B. Sigurdsson, S. S. Kristjánsdóttir, J. F. Bas, H. H. Sigurdsson, T. Loftsson, „Cyclodextrin solubilization of carbonic anhydrase inhibitor drugs: formulation of dorzolamide eye drop microparticle suspension”, Eur. J. Pharm. Biopharm. 76, 208-214 (2010). Dorzolamide concentration (g/ml) in aqueous humor after topical administration to rabbits (mean SD; n=6-8) Aqueous humor 14-fold (0-24h) SEM image of the dorzolamide eye drop 3% dorzolamide eye drop formulation containing 18% w/v CD (○); and Trusopt(●) that contains 2% dorzolamide in soln. Dorzolamide/γCD eye drops in humans (mean SD; n=7) DorzSNP once per day Trusopt® three times per day B. S. Gudmundsdottir, D. Petursdottir, G. M. Asgrimsdottir, M. S. Gottfredsdottir, S. H. Hardarson, G. Jóhannesson, S. V. Kurkov, P. Jansook, T. Loftsson, E. Stefansson: γ-Cyclodextrin nanoparticle eye drops with dorzolamide. Effect on intraocular pressure in man, J. Ocul. Pharmacol. Ther. 30, 35-41 (2014). Dexamethasone Molecular weight Melting point Calculated logP(octanol/water) Solubility in water at 25°C H-bond acceptors H-bond donors 392.5 Da 262-264°C 2.03 35 µg/ml 5 3 Concentration of dexamethasone in the tear film after topical application of 1 drop Rabbits Humans DexSNP DexSNP Maxidex® Maxidex® ● Maxidex® (dexamethasone alcoholic suspension 1 mg/ml) ○ aqueous dexamethasone/γCD nanoparticle eye drop suspension (15 mg/ml) Dexamethasone/γCD Nanosuspension Clinical trials of the DexSNP eye drops Diabetic macular edema (DME): Swelling of the retina in diabetes mellitus due to leaking of fluid from blood vessels within the retina. Uveitis is inflammation of the uvea, that is the pigmented layer between the inner retina and the outer fibrous layer composed of the sclera and cornea. Both DME and uveitis phase II studies show promising clinical effect. The trials in DME demonstrate very good efficacy of the eye drops and the results are comparable to intravitreal injected drugs. A. Ohira, K. Hara, G. Jóhannesson, M. Tanito, G.M. Ásgrímsdóttir, S.H. Lund, T. Loftsson, E. Stefánsson, Topical dexamethasone γ-cyclodextrin nanoparticle eye drops increase visual acuity and decrease macular thickness in diabetic macular oedema. Acta Ophthalmol. 93, 610-615 (2015). S. Shulman, G. Jóhannesson, E. Stefánsson, A. Loewenstein, A. Rosenblatt, Z. Habot-Wilner, Topical dexamethasone-cyclodextrin nanoparticle eye drops for non-infectious Uveitic macular oedema and vitritis – a pilot study. Acta Ophthalmol. 93, 411-415 (2015). S. Krag, A. Hessellund, Topical dexamethasone-cyclodextrin microparticle eye drops for uveitic macular oedema. Acta Ophthalmol. 92(8), e689-90 (2014). M. Tanito, K. Hara, Y. Takai, Y. Matsuoka, N. Nishimura, P. Jansook, T. Loftsson, E. Stefánsson, A. Ohira, Topical dexamethasone-cyclodextrin nanoparticle eye drops improve visual acuity and reduce retinal thickness in diabetic macular edema, Invest. Ophthalmol. Vis. Sci. 52, 7944-7948 (2011). DexNP | Clinical Trials DME* DexNP compares favourably with current standard of care Macular thickness on OCT 50 12 10 8 6 4 2 0 0 -2 • 1 2 3 4 5 6 7 Months 8 9 10 11 12 Mean change in CRT from baseline Mean change in BCVA letter score from baseline Visual acuity 0 0 1 2 3 4 5 6 7 8 9 10 11 12 -50 -100 -150 -200 -250 Months Short term data for DexNP compares favorably with ranibizumab (Lucentis), both in terms of vision (BCVA) and central retinal thickness (CRT). BCVA: Best Corrected Visual Acuity; OCT: Optical Coherence Tomography *Ohira et al. 2015; Tanito et al 2011; Massin et al. 2010 (RESOLVE); Mitchell et al 2011 (RESTORE) DexNP| Clinical Trials DME Change in BCVA - Comparing different clinical trials (mean improvement) Time point (months) eye drops 5.5 – 7.5 1-2 Ozurdex® implant 0.4 – 4.1 39 Iluvien® implant 3.7 – 5.2 24 Lucentis® intravitreal inj. 7.9 24 Eylea® intravitreal inj. 9.4 – 11.1 24 ETDRS letters Non-invasive DexSNP Invasive Laser 2.5 BCVA: Best Corrected Visual Acuity; ETDRS: Early Treatment Diabetic Retinopathy Study Unstable self-assembled nanoparticles. Fall apart upon dilution and even during filtration. Same toxicologic profile as γ-cyclodextrin itself. Targeted drug delivery. Behaves similar to nanoparticles and liposomes. Increased drug contact time with the eye surface. The eye drops provide sustained release over several hours compared to a few minutes with conventional eye drops. Increases concentration of dissolved drug in the tear fluid. Gives higher drug concentration gradient. The carrier, γ-cyclodextrin, is metabolized in the tear fluid. About 10-fold increase in drug bioavailability. The eye drops deliver 30-50% of the drug into the eye compared to 3-5% for conventional eye drops. 22 Thank you From left: Thorsteinn Loftsson, André Rodrigues Sá Couto (PhD student from Portugal), Alexey Ryzhakov (Postdoc from Russia), Blanca Lorenzo Veiga (PhD student from Spain), Chutimon Muankaew (PhD student from Thailand), Pitsiree Praphanwittaya (PhD student from Thailand), Phennapha Saokham (PhD student from Thailand), Zoltán Fülöp (Oculis Scientist from Hungary), Sunna Jóhannesdóttir (PhD student from Iceland), and Agnieszka Popielec (PhD student from Poland).