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Drug permeability enhancement using cyclodextrins

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  1. 1. DRUGPERMEABILITYENHANCEMENTUSING CYCLODEXTRINS Presented by: Priyanka Gresess Anand M.Pharm Pharmaceutics Department of Pharmaceutics Integral University 1
  2. 2. CONTENTS • Introduction • Structure of cyclodextrin • Types of cyclodextrin • Cyclodextrin derivatives of pharmaceutical interest • Process for the manufacture of cyclodextrins • Cyclodextrins as permeability enhancers • Marketed products containing cyclodextrin • Conclusion • Case study 2
  3. 3. INTRODUCTION CYCLODEXTRINS • Cyclodextrins are cyclic oligosaccharides with a hydrophilic outer surface and a somewhat lipophilic central cavity • Cyclodextrins are able to form water-soluble inclusion complexes with many lipophilic water-insoluble drugs HISTORY • Cyclodextrins, as they are known today, were called "cellulosine" • The CD era began in the late 19th century when beautiful crystals were observed by the French scientist Villiers in alcohol waste left after the production of dextrins from starch with an impure bacterial culture* • Schardinger, in the early 20th century isolated and named the strain of bacteria, Bacillus macerans, responsible for CD synthesis* 3 (*Kurkov S.V. and Loftsson T., 2013. Cyclodextrins. Int. J. of Pharm. 453, 167-180)
  4. 4. STRUCTUREOFCYCLODEXTRIN • Formed by six to eight glucopyranose units • Glucopyranose units bound via - 1,4- glycosidic linkages • Able to include molecules in their cavity • Looks like a trucated cone with hydrophilic exterior wall • Inner wall is formed by hydrophobic carbon backbones of glucopyranose monomers • Inner wall is hydrophobic in nature • This structural feature predetermined the application of cyclodextrin as a solubilizer 6/2/2018 4 (Kurkov S.V. and Loftsson T., 2013. Cyclodextrins. Int. J. of Pharm. 453, 167-180)
  5. 5. TYPESOFCYLCODEXTRINS • α (alpha)-cyclodextrin: 6-membered sugar ring molecule, also known as Schardinger’s α-dextrin • β (beta)-cyclodextrin: 7-membered sugar ring molecule, also known as Schardinger’s β-dextrin • γ (gamma)-cyclodextrin: 8-membered sugar ring molecule, also known as Schardinger’s γ-dextrin 5Figure: Types of cyclodextrins (α, β and γ cyclodextrins)* (*Masson M. et al., 2002. J. Incl. Pharm. Macroc. Chem. 44, 213-218)
  6. 6. CYCLODEXTRINDERIVATIVESOFPHARMACEUTICAL INTEREST • RMβCD (Randomly methylated β-CD) • HPβCD (Hydroxy propyl β-CD) • HPγCD (Hydroxy propyl γ-CD) • DMβCD (2,4- dimethyl β-CD) • SBEβCD (Sulfobutylether β-CD) 6Figure: Relative distribution of cyclodextrins used in marketed medicines* (*Kurkov S.V. and Loftsson T., 2013. Cyclodextrins. Int. J. of Pharm. 453, 167-180)
  7. 7. PROCESSFORTHEMANUFACTUREOF CYCLODEXTRINS • Aqueous solution of starch is subjected to the action of an active cyclodextrin glycosyl transferase • Reaction mixture containing cyclodextrin, starch degradation products and active enzyme is continuously subjected to an ultra filtration process • Formed cyclodextrin passed through the membrane • Other starch degradation products and active enzyme retained over the membrane, permitting more cyclodextrin to be formed • Further formed cyclodextrin passes through the membrane • Aqueous solution collected and solid cyclodextrin recovered 7 Figure: Manufacturing plant of Cyclodextrins.
  8. 8. METHODSOFPREPARATIONOFCYCLODEXTRIN COMPLEXES • Physical mixing • Kneading • Co-precipitation • Dry mixing • Sealing • Slurry complexation • Neutralization • Spray drying • Freeze-drying • Solvent evaporation 8
  11. 11. CYCLODEXTRINSASPERMEABILITYENHANCERS • Drug delivery through biological membranes • Permeability enhancement of oral drugs • Permeability enhancement of sublingual formulation • Permeability enhancement of nasal formulations • Permeability enhancement of pulmonary drugs • Permeability enhancement of ophthalmic drugs • Permeability enhancement of dermal drugs 11
  12. 12. DRUGDELIVERYTHROUGHBIOLOGICAL MEMBRANES • Only negligible amounts of hydrophilic cyclodextrins and drug/cyclodextrin complexes are able to permeate lipophilic membranes such as skin and gastrointestinal mucosa1 • Only the free form of the drug, which is in equilibrium with the drug/cyclodextrin complex, is capable of penetrating lipophilic membranes • Cyclodextrins do not, in general, enhance permeability of hydrophilic water soluble drugs through lipophilic biological membranes • Numerous studies have shown that excess cyclodextrin will reduce drug permeability through biological membranes2 • Most biological membrane barriers (or biomembranes) are lipophilic with an aqueous exterior • Cyclodextrins can enhance drug bioavailability by stabilisation of drug molecules at the biomembrane surface 12 (1.Matsuda H. et al.,1999. Cyclodextrins in transdermal and rectal delivery. Adv. Drug Deliv. Rev. 36, 81-99) (2.Loftsson T. et al.,2001. Cyclodextrins in topical drug formulations: theory and practice. Int. J. Pharm. 225, 15-30)
  13. 13. 13 Figure: Mechanism of drug permeation from cyclodextrin complex across biological membrane* (*Loftsson T. et al., 2005. Cyclodextrin in drug delivery. Expert opinion drug delivery 2, 335-351) •For example, cyclodextrins have been shown to prevent insulin aggregation and to enhance insulin stability at the nasal mucosa •However, as cyclodextrins can both enhance and hamper drug delivery through biological membranes it is of utmost importance to optimize cyclodextrin-containing drug formulations with regard to drug delivery from the formulations* • Too much or too little cyclodextrin can result in less than optimum drug bioavailability
  14. 14. PERMEABILITYENHANCEMENTOF ORALDRUGS • The effect of cyclodextrins on oral drug absorption can be explained in the context of the Biopharmaceutics Classification System* • Class I drugs are relatively water soluble and their absolute bioavailability is ≥ 90% • Class II drugs have limited aqueous solubility, resulting in dissolution-rate limited oral absorption • Water-soluble cyclodextrin complexes of these drugs will enhance their diffusion to the mucosal surface leading to enhanced oral bioavailability • Class III drugs are water soluble, but do not easily permeate biological membranes due to, for example, their size and/or extent of hydration • Consequently, formation of hydrophilic drug/cyclodextrin complexes will not enhance their oral bioavailability, but will, if anything, reduce the ability of dissolved drug molecules to partition from the aqueous exterior into the gastrointestinal 14 (*Loftsson T. et al.,2004. Role of cyclodextrins in improving oral drug delivery. Am. J. Drug Deliv.2, 261-275)
  15. 15. • Class IV drugs are water insoluble and do not readily permeate lipophilic biological membranes • These can, for example, be water-insoluble zwitterions or relatively large lipophilic molecules • Hydrophilic water-insoluble compounds such as zwitterions do not readily form cyclodextrin complexes and, thus, hydrophilic cyclodextrins are not likely to improve their oral bioavailability • However, cyclodextrins are able to improve aqueous solubility of some large lipophilic molecules leading to increased drug availability at the mucosal surface • This will frequently lead to increased oral bioavailability 15 FDA class* Drug properties RDS to drug absorption¶ Effect of cyclodextrin complexation Aqueous solubility‡ Permeability§ I Highly soluble Highly permeable (Good bioavailability) Can decrease absorption II Poorly soluble Highly permeable Aqueous diffusion Can enhance absorption III Highly soluble Poorly permeable Membrane permeation Can decrease absorption IV Poorly soluble Poorly permeable Aqueous diffusion and membrane permeation Can enhance absorption (*Loftsson T. et al., 2005. Cyclodextrin in drug delivery. Expert opinion drug delivery 2, 335-351)
  16. 16. PERMEABILITYENHANCEMENTOFSUBLINGUAL FORMULATION • In sublingual formulations, the complexation of poorly water- soluble drugs with cyclodextrins has been shown to increase the bioavailability of various lipophilic drugs • For example, 2-hydroxypropyl-βcyclodextrin has been shown to increase the bioavailability of 17 β-oestradiol, androstenediol, clomipramine and danazol • In most studies, the increased bioavailability achieved by cyclodextrins is likely to be due to increased aqueous solubility and drug dissolution rate 16
  17. 17. PERMEABILITYENHANCEMENTOFNASAL FORMULATIONS • In nasal formulations, cyclodextrins are normally used to increase the aqueous solubility of lipophilic drugs • Methylated cyclodextrins in particular are efficient absorption enhancers and are the most commonly studied cyclodextrins in nasal drug delivery* • The first cyclodextrin-based nasal formulations contained steroidal hormones and peptides. • E.g. The bioavailability of progesterone is increased three fold compared with suspension of the same compound, methylated derivatives, as adjuvants used to improve the nasal absorption of insulin despite its administration as a suspension form • It has been suggested that cyclodextrin prevent insulin aggregation and enhanced insulin bioavailability after nasal administration and is partly due to this stabilising effect 17 (*Merkus F.W.H.M. et al.,1999. Cyclodextrin in nasal drug delivery. Adv. Drug Deliv. Rev. 36, 41-57)
  18. 18. PERMEABILITYENHANCEMENTOFPULMONARY DRUGS • Cyclodextrins can be of value in pulmonary delivery by increasing the solubility, stability and dissolution rate of water- insoluble and chemically unstable drugs • Cyclodextrins are more readily absorbed from the lungs than from the gastrointestinal tract and this limits the number of cyclodextrins that can be included in pulmonary formulations • The respirable fraction of salbutamol from Diskhaler® (GlaxoSmithKline) has been increased by complexation with γ- cyclodextrin and dimethyl-β cyclodextrin • The respirable fraction of beclomethasone dipropionate from Microhaler® has been increased by 2-hydroxypropyl-β- cyclodextrin complexation* 18 (*Leite P.J.M.C. et al.,1999. Beclomethasone/cyclodextrin inclusion complex for dry powder inhalation. S.T.P. Pharma. Sci. 9, 253-256)
  19. 19. PERMEABILITYENHANCEMENTOFOPHTHALMIC DRUGS • Through cyclodextrin solubilisation it is possible to increase the dose-to-solubility ratio, making it possible to apply drugs topically that previously could only be given by systemic delivery • For example, acetazolamide is a carbonic anhydrase inhibitor that is used to treat glaucoma with oral daily dose as high as 1000 mg • The aqueous solubility of acetazolamide in pure water is 0.7 mg/ml, but in 20% (w/v) aqueous 2-hydroxypropyl-β- cyclodextrin solution it is 7 mg/ml • Thus, it is possible to obtain topically effective acetazolamide eye drop solution through cyclodextrin solubilisation of the drug* 19 (*Loftsson T. et al.,1994.Topically effective ocular hypotensive acetazolamide and ethoxyzolamide formulations in rabbits. J. Pharm. Pharmacol. 46, 503-504)
  20. 20. PERMEABILITYENHANCEMENTOFDERMALDRUGS • Cyclodextrins enhance drug delivery through aqueous diffusion layers (i.e., aqueous diffusion barriers), but not through lipophilic barriers such as the stratum corneum • If the drug release is from an aqueous-based vehicle or if an aqueous diffusion layer at the outer surface of the skin is a rate- determining factor in dermal drug delivery, then cyclodextrins can act as penetration enhancers • However, if drug penetration through the lipophilic stratum corneum is the main rate-determining factor then cyclodextrins are unable to enhance the delivery • It appears that cyclodextrins do enhance hydrocortisone delivery from an unstirred aqueous donor phase through hair less mouse skin, but have no effect on hydrocortisone delivery from a well-stirred donor phase* 20 (*Shaker D.S. et al.,2003. Mechanistic studies of the effect of hydroxypropyl-βcyclodextrin on in vitro transdermal permeation of corticosterone through hairless mouse skin. Int. J. Pharm. 253, 1-11)
  21. 21. 21 Drug Administration route Trade name Market α-cyclodextrin Alprostadil (PGE1) CefotiamhexetilHcl IV Oral Prostavastin Pansporin T Ona (Japan) Japan β-cyclodextrin BenexateHcl Dexamethasone Nicotine Nimesulide Omeprazole Piroxicam Nitroglycerin Oral Dermal Sublingual Oral Oral Oral Sublingual Ulgut Glymesason Nicorette Nimedex Omebeta Brexin Nitropen Japan Japan Europe Europe Europe Europe Japan 2-Hydroxypropyl-β- cyclodextrin Indomethacin Itraconazole Hydrocortisone Mitomycin Eye drops Oral, IV Buccal IV Indocid Sporanox Dexocort Mitozytrex Europe Europe, USA Europe Europe Randomly methylatetd β-cyclodextrin 17β-Estadiol Chlorampenicol Nasal Spray Eye drops Aerodiol Clorocil Europe Europe Sulfobutylether β-cyclodextrin Voriconazole IV V fend Europe, USA 2-Hydroxypropyl-γ-cyclodextrin Diclofenac sodium Eye drops Voltaren Europe MARKETED PRODUCTS CONTAINING CYCLODEXTRIN Table: Example of marketed products containing cyclodextrins* (*Lofftsson T. et al, 2005. Expert Opin. Drug Del. 2, 335-351)
  22. 22. CONCLUSION • CDs are an important tool in pharmaceutical formulation to improve the solubility and permeability. • Worldwide there are currently about 30 different cyclodextrin- containing pharmaceutical products • In these products cyclodextrins are used to replace organic solvents in parenteral and topical formulations, to enhance oral bioavailability of Class II and some Class IV drugs, to reduce gastrointestinal irritation and to increase dermal availability of drugs • CDs use is not limited to oral drugs permeation only, it can also enhance the permeation of variety of drugs administered through different routes 22
  23. 23. CASESTUDY Evaluation of γ-cyclodextrin effect on permeation of lipophilic drugs: application of cellophane/fused octanol membrane • In this study, the permeation enhancing effect of γ-cyclodextrin (γCD) on saturated drug solutions containing hydrocortisone (HC), irbesartan (IBS), or telmisartan (TEL) was evaluated • This effect was evaluated using cellophane and fused cellulose- octanol membranes in a conventional Franz diffusion cell system • The membrane design is either a cellophane membrane, hydrophilic mono-membrane to represent UWL*, or a dual membrane consisting of a hydrophilic cellophane membrane (UWL) with a fused lipophilic octanol membrane • Drug permeation from aqueous bulk solution through lipophilic membrane is frequently hampered by the UWL • γ-cyclodextrin can enhance the diffusion of the drug through UWL 23 (*unstirred water layer)
  24. 24. METHOD • Materials- Hydrocortisone, Irbesartan, telmisartan, γ-cyclodextrin, diethyl ether, ethanol, n-octanol, mucin, nitrocellulose, cellophane membrane with MWCO* 12000-14000, franz diffusion cells • Preparation of fused octanol membrane- 24 Schematic diagram showing preparation of the fused n-octanol membrane (* Molecular weight cut off)
  25. 25. PERMEATIONSTUDY • Drug permeabilty investigated from aqueous γ-cyclodextrin solution using franz diffusion cell • Phosphate buffer solution (pH 7.4) containing 2% w/v γ- cyclodextrin for maintaining sink condition, used as receptor phase • Donor and receptor phases were separated by hydrophilic cellophane membrane • About 2ml of 20mM filtrate phosphate pH 7.4 buffer donor solution, containing 0% or 10% (w/v) γCD saturated with the drug to be tested was added to the donor chamber • Samples of 150ul were withdrawn from receptor phase at 30, 60, 90, 120, and 180 and 240 min • The drug content was quantified by HPLC • The steady state flux (J) and the apparent permeation coefficient (Papp) were calculated 25
  26. 26. RESULT • For the uncharged hydrocortisone (HC) molecule addition of γCD increased Papp from 2.91 ± 0.13*106 cm/s to 5.50 ± 0.29 *106 cm/s, suggesting that 10% (w/v) γCD was an optimal γCD concentration regarding transmembrane HC permeation • Papp was reduced from 9.05 ± 0.30 *106 cm/s to 7.47 ± 1.55 *106 cm/s and from 17.8 ± 7.43 *106 cm/s to 4.20 ± 0.56 *106 cm/s for irbesartan (IBS) and telmisartan (TEL), respectively. • A slight increase in flux and permeation coefficient was observed • The increase was most notable in the case of unionized HC flux while it was negligible in the case of IBS and TEL 26 Effect of γCD on drug flux and Papp through the hydrophilic membrane The influence of γCD concentration on the apparent permeation coefficient (Papp) from a donor phase saturated with drug containing 0% w/v (o) or 10% w/v γCD (•) on the permeation coefficient value of hydrocortisone (A), irbesartan(B), and telmisartan (C) (n=3–4)
  27. 27. EffectofγCDondrugfluxandingeneralPapp throughthedualmembrane • Papp of hydrocortison (HC) and irbesartan (IBS) was increased form 0.82 ± 0.49 *106 cm/s to 1.67 ± 0.38 *106 cm/s and 0.39 ± 0.03 *106 cm/s to 1.0 ± 0.09 *106 cm/s, respectively, indicating that γCD has the potential for promoting drug availability at the surface of the fused octanol membrane • In contrast, Papp was decreased for telmisartan (TEL), from 8.65 ± 2.95 *106 cm/s to 1.66 ± 0.68 *106 cm/s. This was also the case regarding telmisartan (TEL) permeation through simple hydrophilic cellophane membrane 27 The influence of γCD on permeation flux (J, ug/ml.h.cm2) of three model drugs and the flux enhancement ratio (JR) (n=3–4). The donor phase was saturated with the drug Muankaew C. et al., 2016. Pharmaceutical Devlop. And tech. res. art. 7450, 1083-1097
  28. 28. CONCLUSION • This study demonstrates the role of γCD on permeation behavior of three lipophilic drugs at physiological pH • The results reveal that, in general, addition of γCD to the aqueous donor solution saturated with the drug increased the drug flux • γCD solubilizes the poorly soluble drug in the aqueous donor solution and carries the drug molecules to the lipophilic membrane surface • The fused octanol membrane allowed estimation of how γCD in formulation affected drug penetration through biological membranes, whether γCD enhanced the drug permeation, had no effect or decreased it 28