International Journal of Pharmaceutics 419 (2011) 209-214
`
`
` International Journal of Pharmaceutics
`
`Contentslists available at ScienceDirect
`
`wt
`ELSEVIER
`journal homepage: www.elsevier.com/locate/ijpharm
`
`
`
`
`Influence of formulation variables in transdermal drug delivery system
`containing zolmitriptan
`
`Robhash Kusam Subedi®, Je-Phil Ryoo, Cheol Moon®, Hoo-Kyun Choi?*
`4 BK21 Project Team, College ofPharmacy, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju 501-759, South Korea
`» NAL Pharmaceuticals Ltd., NewJersey, USA
`
`ABSTRACT
`ARTICLE INFO
`
`
`Article history:
`Received 31 May 2011
`Received in revised form 24 July 2011
`Accepted 2 August 2011
`Available online 16 August 2011
`
`
`Keywords:
`Zolmitriptan
`Transdermal drug delivery
`Percutaneous penetration
`Chemical enhancers
`Polymorphism
`Crystallization inhibitor
`
`1. Introduction
`
`Theeffects of different formulation variables including pressure sensitive adhesive (PSA), thickness of the
`matrix, solvent system, inclusion of crystallization inhibitor, loading amount of drug and enhancers on
`the transdermal absorption of zolmitriptan were investigated. Acrylic adhesive with hydroxylfunctional
`group provided good adhesion force and high flux of zolmitriptan. Pseudopolymorphs of zolmitriptan
`were found to possessdifferent solid-state properties that affected the permeation rate. Polyoxyethylene
`alkyl ethers significantly increased the permeation ofzolmitriptan through hairless mouse skin, However,
`these enhancersinducedcrystallization of zolmitriptan. Kollidon® 30 delayed the crystallization without
`altering the permeationprofile of zolmitriptan. Stability studies suggested that terpenes did not induce
`crystallization of zolmitriptan in the patch and stable formulations could be produced by using cineole
`and limonene,or their combination.
`
`© 2011 Elsevier B.V.All rights reserved.
`
`
`Zolmitriptan is a potent and selective serotonin (5-HTjg/1p)
`receptor agonist. It is a second-generation triptan and used in
`the acute treatment of migraine attacks with or without aura and
`cluster headaches. Zolmitriptan has also shownefficacy in the treat-
`ment of persistent and/or recurrent migraine headache (Dowson
`and Charlesworth, 2002). It is generally well tolerated, with most
`adverse events being mild-to-moderate, transient and resolv-
`ing without intervention or the need for treatment withdrawal.
`However, orally delivered triptan drugs may produce gastroin-
`testinal disturbances (Cipolla et al., 2001). As an improved way
`of drug delivery, intranasal spray and mucoadhesive microemul-
`sion formulations for zolmitriptan were studied (Vyaset al., 2005;
`Yates et al., 2002). However, due to low bioavailability after oral
`administration (Seaber et al., 1997) and inconveniencesrelated to
`intranasal dosing, the development of new mode of zolmitriptan
`delivery is required. Recently, transdermal iontophoretic delivery
`of zolmitriptan was reported (Patel et al., 2009). It was claimed in
`the report that therapeutic amountsof zolmitriptan were obtained
`at a faster rate than the existing dosage forms. Despite the poten-
`tial of this electrically assisted system for zolmitriptan, simpler and
`morepatient friendly matrix system based transdermal drug deliv-
`
`* Corresponding author. Tel.: +82 62 230 6367; fax: +82 62 228 3742.
`E-mail address: hgchoi@chosun.ac.kr (H.-K. Choi).
`
`0378-5173/$ - see front matter © 2011 ElsevierB.V. All rights reserved.
`doi:10,1016/j.ijpharm.2011.08,002
`
`ery system (TDDS) for zolmitriptan would be valuable in providing
`clinical benefit of prolonged pain-free responseto patients. Based
`on the daily dose of 5mg and approximate bioavailability of 40%
`(Seaberet al., 1997), only about 2mg is needed to be delivered
`transdermally. Although skin offers an important modeof systemic
`drug delivery, the barrier properties of stratum corneum limit the
`permeation of drug molecules. Significant effort has been devoted
`to develop strategies for overcoming the impermeability of intact
`human skin. Among them, penetration enhancers are widely used
`to reversibly decrease the resistance (Williams and Barry, 2004).
`The present study was conductedto investigate the feasibility
`of developing TDDS for zolmitriptan. In vitro permeation studies
`were done to characterize permeation of zolmitriptan acrosshair-
`less mouse skin from various PSA based formulations, containing
`different chemical enhancers and crystallization inhibitors.
`
`2. Materials and methods
`
`2.1. Materials
`
`Zolmitriptan was obtained from Gaobo Pharm-Chemicals
`(Beijing, China). Polyglyceryl-3 oleate (Plurol olieque® CC497),
`propylene glycol monolaurate (Lauroglycol®), and polyoxy glyc-
`erate (Labrafil® 1944) were obtained from Masung Co. (Seoul,
`South Korea). PEG sorbitan monooleate (Tween® 80), sorbitan
`monooleate (Span® 80), propylene glycol (PG) and oleyl alcohol
`were purchased from Junsei Chemicals (Japan). Isopropyl palmi-
`
`Noven Pharmaceuticals, Inc.
`EX2020
`Mylan Tech., Inc. v. Noven Pharma., Inc.
`IPR2018-001 74
`
`0001
`
`

`

`210
`
`R.K. Subedi et al. / International Journal of Pharmaceutics 419 (2011) 209-214
`
`aluminum pans and heated at a scanning rate of 10°C/min from
`25 to 170°C.
`
`tate (IPP), isopropyl myristate (IPM), PEG-12 palm kernel glycerides
`(Crovol® PK 40), and PEG-20 almond glycerides (Crovol® A 40)
`were obtained from Croda (Parsippany, NJ, USA). Lauryl alcohol
`(LA), (R)-(+) limonene, polyoxyethylene lauryl ether (Brij® 30)
`2.2.5. X-ray diffraction study
`and polyoxyethylene cetyl ether (Brij® 52) were purchased from
`X-ray diffraction (XRD) patterns were obtained using an X-ray
`Sigma Chemical (St. Louis, MO, USA). Acrylic and polyisobuty-
`diffractometer (GMAX-1200, Rigaku Co., Japan). The X-ray copper
`lene (PIB) PSA solutions in organic solvents were obtained from
`target tube was operatedat 40 kV and 30 mA, The instrument geom-
`National Starch and Chemical Company(Bridgewater, NJ, USA). Sil-
`etry wasreflection. The X-ray generator power was 2 kW.The scan
`icone PSA was obtained from Dow Corning (Midland, MI, USA).
`time was 1° min! and the step size was 0.03. The X-ray passed
`Low substituted hydroxypropyl cellulose (HPC LH 11). Chitosan
`through 2° divergenceslit. The diffracted radiation from the sam-
`(low molecular weight) and B-cyclodextrin were purchased from
`ple passed through 0.48°divergenceslit and 0.30 mm receivingslit.
`Sigma-Aldrich (GmbH, Germany). Kollicoat® SR 30D and Kollidon®
`The matrix sample was attached ontoaglass holder.
`30 were obtained from BASF (Ludwigshafen, Germany). All other
`chemicals were reagent grade or above and were used without
`further purification.
`
`2.2.6. Release study
`Patch of 15 cm? washeldin position by attaching it to a sinker
`at the bottom ofdissolution flask. 500 mL of phosphate buffer (pH
`6.8) was used as dissolution medium, temperature was set at 32°C
`and paddle speed of 50rpm provided the agitation. 2 mL sample
`was withdrawnat 0.5h, 1h, 4h, 8h, 12h, 24h and 48h poststudy.
`An equal volume of buffer was replaced after taking the sample.
`Samples were centrifuged at 13,000rpm for 30 min and analyzed
`by HPLC. The study was performedin triplicate.
`
`3. Results and discussion
`
`3.1. Effect of adhesive matrix
`
`2.2. Methods
`
`2.2.1, Preparation ofpatch containing zolmitriptan
`Drug solution was prepared by dissolving zolmitriptan in suit-
`able organic solvent. After adding enhancer and PSA to the drug
`solution, the mixture wasstirred using teflon-coated magnetic bar
`to obtain homogeneoussolution. The resulting drug-PSA solution
`wascoated ontoreleaseliner. Silicone adhesive solution was cast
`on therelease liner (ScotchPak® 1022, 3M, USA) that is coated with
`fluropolymer. After the solvent was removed, dried film was lam-
`inated with a polyester backingfilm (ScotchPak® 9732, 3M, USA).
`The valuesof drug loading, excipients and enhancers are expressed
`as % with respect to the dry polymer weight.
`
`PSA is one of the most important componentsin fabricating a
`transdermal drug delivery system. The effect of PSA matrix on the
`permeation of zolmitriptan wasinvestigated usingsilicone, PIB and
`2.2.2, Diffusion study
`acrylic adhesive matrices at 5% (w/w) drug loading. As the first
`System comprising of a multi channel peristaltic pump (IPC-24,
`step to select appropriate PSA, solubility of the drug was evalu-
`Ismatec, Switzerland), a fraction collector (Retriever IV, ISCO, NE,
`ated in various PSA solutions. The solubility of zolmitriptan was
`USA), a circulating water bath (Jeio-Tech, South Korea) and flow-
`found to be inadequate in silicone, SBS, and PIB adhesive solu-
`through diffusion cells were used. Each flow-throughcell had two
`tions as the solutions were milky, and drug particles were formed
`arms, which allowed the receiver cell medium pumpedtoafraction
`in the adhesive matrix after drying. Based on higher solubility of
`collector. The diffusion cell temperature was maintained at 37 °C by
`zolmitriptan in acrylic adhesives, permeation of zolmitriptan from
`circulating water through the outer part of jacketed receivercell.
`acrylic adhesives across the hairless mouse skin was investigated
`Each of the flow-throughdiffusion cell components was connected
`and the results are shown in Table 1. It has been reported that
`via silicone rubber tubing with an internal diameter of 0.015 in.
`different functional groupsin acrylic PSAs impartdifferent physic-
`The surface area of receiver cell opening was 2cm?, andits vol-
`ochemical properties to the matrix (Venkatraman and Gale, 1998),
`ume was 5.5 mL. Skin was excised from hairless mouse that was
`whichresultsin different permeation rates of the drugs (Hai etal.,
`sacrificed with diethyl ether. Subcutaneous fat was removed with
`2008). The permeation rate was lowest in the adhesive contain-
`scissors and scalpel. The receiver cell wasfilled with pH 6.0 buffer
`ing carboxyl functional group. This could be dueto the interaction
`solution and the media stirred by teflon-coated magnetic bar. The
`between amine group of zolmitriptan and carboxy! group of the
`transdermal patch was placed on the stratum corneum and the
`adhesive. In previous study, low permeation rate of tacrine was
`excised skin was mounted onto each receiver cell. And O-ring and
`observed due to the interaction between the aminegroup oftacrine
`cell top were placed on the top of each skin, These components
`and carboxyl group of acrylic adhesive (Kim et al., 2000). Perme-
`were then clamped. The samples werecollected every 4h for 24h
`ation rate of zolmitriptan in the acrylic adhesive matrix was highest
`and analyzed by high performanceliquid chromatography (HPLC).
`with acrylic adhesive containing hydroxyl functional group. Further
`study on different kinds of acrylic adhesives containing hydroxyl
`functional group revealed that more than 2 fold flux could be
`obtained with both Duro-Tak® 87-2510 and Duro-Tak® 87-2516
`matrixes as compared to Duro-Tak® 87-2287 matrix (Table 1).
`Therefore, both Duro-Tak® 87-2510 and Duro-Tak® 87-2516 were
`
`2.2.3. Analytical method
`Zolmitriptan was analyzed by an HPLC system (Shimadzu Sci-
`entific Instruments, MD), consisting of a UV detector (SPD-10A),
`reversed-phase Cg column(4.6 mm x 150mm,5 1m, Luna),a pump
`(LC-10AD), and an automatic injector (SIL-10A). The method pre-
`viously described (Vyas et al., 2005) wasslightly modified. Briefly,
`the wavelength of the UV detector was 229 nm, the column tem-
`perature was maintained at 30°C, the flow rate was 1 mL/min, and
`injection volume was 10 wL. The mobile phase consisted ofacetoni-
`trile/SO mM phosphatebuffer pH 7.5 (17.5/82.5).
`
`2.2.4, Differential scanning calorimetry (DSC)
`Thermal analysis was carried out using a DSC unit (Pyris 6 DSC,
`Perkin-Elmer, Netherlands). Indium wasusedto calibrate the tem-
`perature scale and enthalpic response. Samples were placed in
`
`Table 1
`Penetration rate for zolmitriptan from different acrylic adhesive matrixes at 5%
`(w/w) drug load (n=3).
`
`Adhesive matrix
`Withoutfunctional group
`With carboxyl-functional group
`With hydroxyl-functional group
`
`Trade name
`Duro-Tak® 87-4098
`Duro-Tak® 87-2677
`Duro-Tak® 87-2510
`Duro-Tak® 87-2287
`Duro-Tak® 87-2516
`
`Flux (wg/cm?/h)
`6.16
`0.22
`15.6
`6.5
`14.4
`
`0002
`
`

`

`R.K. Subediet al. / International Journal of Pharmaceutics 419 (2011) 209-214
`
`211
`
`
`25
`
`300 7
`
`“p
`g, 250 4
`&
`3
`2 200 4
`oavo
`= 150 4
`
`a z3
`
`vo
`
`2 ==
`
`100 4
`
`4
`
`50
`
`Zz
`
`=3
`
`0°
`0
`
`—e— 4%drug
`—o— 5%drug
`—y— 7.5% drug
`0,
`—+— 10% drug
`
`os
`4
`7
`
`
`
`1
`
`Time(h)
`
`Fig. 1. Effect of drug concentration on the permeation of zolmitriptan from
`different formulations in Duro-Tak® 87-2510 matrix. Values are expressed as
`mean + standard deviation (n=3).
`
`considered for further study. Initial studies were performed in
`Duro-Tak® 87-2510 matrix, as slightly higher flux of zolmitriptan
`was obtained from this matrix.
`
`Temp (°C)
`
`Fig. 3. DSC thermograms ofdifferent solvates of zolmitriptan prepared using ethyl
`acetate, butanol, 2-propanol, EMK and THF.
`
`Pure drug
`Ethyl acetate
`Ethyl methyl ketone
`2-propanol
`Butanol
`Tetrahydrofuran
`
` Endotherm
`
`down
`
`
`
`ther increase in the thickness resulted in lower permeation rate.
`Therefore, the matrix thickness of 100,.m wasselected for fur-
`ther studies with both Duro-Tak® 87-2510 and Duro-Tak® 87-2516
`matrices.
`
`3.3. Effect ofsolvent system
`
`Zolmitriptan exhibits polymorphism and seven different crys-
`talline forms were reported (Van DerSchaafet al., 2007). Different
`polymorphs, pseudopolymorphs or the amorphousform differ in
`their physical properties such as melting point and solubility. These
`parameters can appreciably influence pharmaceutical properties
`of the drug. It was reported that when zolmitriptan was crys-
`tallized using various solvents, different solvates having distinct
`XRD pattern were formed (Van Der Schaafet al., 2007). During
`the preparation of transdermal patch, drug substance may encap-
`sulate solvent molecules in the process of drying. To investigate
`this phenomenon, drug solution was prepared using various sol-
`vents including ethyl acetate, butanol, 2-propanol, ethylmethyl
`ketone (EMK) and tetrahydrofuran (THF); followed by drying in
`vacuum oven for 24h, The dried crystalline forms of zolmitriptan
`were subjected to DSC analysis for the characterization of solid-
`state property. As seen in Fig. 3, the melting peak of zolmitriptan
`at around 140°C was reduced and broadenedin the case of each
`solvate. The DSC thermograms were also accompanied by addi-
`tional peak near 80°C that corresponded to the boiling points of
`each solvent used except butanol. With THF solvate, no clear peak
`was observed. XRD studies were also conducted to have a better
`insight into the crystallinity of the solvates. X-ray diffractograms
`ofdifferent solvates are given in Fig. 4. Each solvate possessed dis-
`tinct crystalline pattern except the case ofTHF where nocrystalline
`peak was observed. The absence of characteristic peaks for THF
`solvate in DSC thermogram and X-ray diffractogram implied that
`it might exist as amorphous form. Patches made using thesesol-
`vates also markedly differed in the physical properties. Notably,
`large rod shaped crystals were observedin formulation containing
`THF solvate after few hours of drying. X-ray diffractogram of the
`patch showed increasein crystallinity at 21.6 and 23.7 positions
`of 24 (data not shown). The crystal formation could be a result of
`
`3.2. Effect of drug concentration and thickness
`
`The flux of zolmitriptan did not change significantly as the drug
`loading in the Duro-Tak® 87-2510 matrix increased from 4% to
`10% (w/w) of the dry polymer weight, indicating that saturation
`of zolmitriptan within the PSA may be obtained at ca. 4% (w/w)
`(Fig. 1). The patch wasclear at 4% (w/w)drug load; however, milky
`appearance was observed in the patches containing 5% (w/w) or
`more drug load. Therefore, 4% (w/w) drug load was used for fur-
`ther study. In the case of Duro-Tak® 87-2516, 5% (w/w) drug load
`wasusedfor further study as the patches wereclearat this level of
`drug content.
`It has been reported that the thickness of the matrix may change
`the permeationrate of a drug across the skin (Kim and Choi, 2003).
`The effect of thickness at 4% (w/w) drug load in Duro-Tak® 87-
`2510 matrix wasinvestigated to optimize the thickness(Fig. 2). The
`penetration rate of zolmitriptan increased when matrix thickness
`increased up to 95,.m and remained similar up to 130 zm.Fur-
`
`300 4
`
`
`
`
`—e 165 um
`—o— 130 um
`—r— 95 um
`—— 60 um
`25 um
`
`Tt
`
`
`
`
`
`
`5
`
`10
`
`15
`
`20
`
`1
`25
`
`DS
`5 5a -
`B
`3
`z 200
`auo
`= 150 4
`
`a 8=
`
`o= 3a
`
`100 4
`
`z
`a
`oO
`
`50
`
`0
`
`4
`
`0
`
`Time (h)
`
`Fig. 2. Effect of thickness on the permeation of zolmitriptan from formulation
`containing 4% (w/w) drug in Duro-Tak® 87-2510 matrix. Values are expressed as
`
`mean +standard deviation (n= 3).
`
`0003
`
`

`

`212
`
`R.K. Subedi et al. / International Journal of Pharmaceutics 419 (2011) 209-214
`
`
`
`Table 2
`Solubility and dissolution of various zolmitriptan solvates (n= 3).
`Solvate
`Solubility (mg/mL)
`Cumulative release (%)
`No solvate
`12.9 + 0.1
`=
`Ethyl acetate
`13.9 + 0.2
`73.1423
`Ethyl methyl ketone
`19.9 + 0.6
`101.64 1.1
`2-Propanol
`15.6 + 0.1
`97.6425
`1-Butanol
`15.7 + 0.3
`85.3475
`Tetrahydrofuran
`24.7403
`68.4+45.0
`
`1
`2
`3
`4
`5
`6
`
`
`
`Butanol
`
`2-Propanol
`
`Ethyl methyl ketone
`
`4 Tetrahydro furan
`
`Ethyl acetate
`
`lization in the PSA matrix. The drug crystals should first dissolve
`and then be released from the system in order to be permeated
`across the skin and the dissolution process is usually rate limit-
`ing and tends to affect delivery rate (Subedi et al., 2010). Ethyl
`acetate, 2-propanol and butanol solvates possessed similar per-
`meation characteristics. In order to explore whether the solubility
`of zolmitriptan solvates or release rate from PSA matrix had any
`correlation with the permeationrate, solubility and release rate of
`the solvates were measured in pH 6.8 phosphate buffer (Table 2).
`However, solubility of the solvates in pH 6.8 buffer did not correlate
`withthe flux obtained (R? = 0.005). Similarly, release ofthe solvates
`from the patches did not showsignificant correlation with the flux
`obtained (R? = 0.214).
`Thedifference in crystalline property may notbe the sole factor
`responsible for the difference in penetration properties observed,
`however, it certainly has been shownto be an importantfactor.
`These observations suggest that choice of appropriate solvent has
`some importance in designing the transdermal drug delivery sys-
`tem for drugs showing polymorphic behavior.
`
`|0
`
`10
`
`20
`
`30
`Position (2)
`
`40
`
`50
`
`Fig. 4. X-ray diffractogram of zolmitriptan solvates prepared using EMK, ethyl
`acetate, 2-propanol, butanol and THF.
`
`unstable amorphous state ofTHF solvate. Furthermore, permeation
`study was conducted to evaluate whether there were any differ-
`ences among the solvates in terms of penetration characteristics.
`Asclearly seenin Fig. 5, the highest permeation profile was obtained
`with EMK solvate and the least with THF solvate. The lowestflux
`obtained in case of THF solvate may be due to the rapid crystal-
`
`3.4. Effect of penetration enhancers
`
`To reversibly overcome the barrier properties of stratum
`corneum, penetration enhancers are commonly employed in the
`transdermal systems (Williams and Barry, 2004). Table 3 gives the
`summary of enhancer screening with both Duro-Tak® 87-2510
`and Duro-Tak® 87-2516 matrices. Polyoxyethylene alkyl ethers
`
`Table 3
`Summary of enhancerscreeningfor zolmitriptan from Duro-Tak® 87-2510 and Duro
`Tak® 87-2516 matrices (n=3).
`Enhancers
`
`Enhancementratio#
`
`Duro-Tak® 87-2510
`Duro-Tak® 87-2516
`
`Control
`1.00
`1.00
`Plurol olieque® CC497
`0.68
`1.28
`Span® 80
`0,63
`1,09
`Tween® 80
`0.66
`0.84
`Transcutol®
`0.98
`0.94
`Oleyl alcohol
`0.35
`0.96
`Brij® 52
`1.37
`1.44
`Brij® 30
`1.15
`1.33
`Brij® 58
`0.77
`0.79
`Cineole
`1.39
`1.11
`Labrafil®1944
`0.54
`0.93
`Crovol® A40
`1.02
`0.99
`Crovol® PK40
`0.70
`1,08
`IPP
`0.58
`1.33
`IPM
`0.56
`1.33
`Lauryl alcohol
`0.40
`1.45
`Lauroglycol
`0.43
`1.30
`Limonene
`1.13
`1.29
`Labrafac® PG
`0.98
`Oleic acid
`0.60
`0.39
`Labrafil® 2609
`0.72
`Brij® 72
`0.90
`Brij® 97
`0.30
`Brij® 700
`
`Incrocas® 0.51
`
`@ Enhancementratio= flux with enhancer/flux without enhancer.
`
`0004
`
`200
`
`
`
`
`
`
`
`
`
`—*— Ethyl acetate
`—o— Butanol
`—*— 2- Propanol
`—‘— Ethyl methyl ketone
`Tetrahydrofuran
`
`
`
`Cumulativeamountpenetrated(g/cm?) g3
` aS$
`
`Time(h)
`
`Fig. 5. Effect of solvent systems on the permeation of zolmitriptan at 4% (w/w)
`drug load in Duro-Tak® 87-2510 matrix. Different solvents were used to eitherdis-
`solve or disperse drug in the PSA matrix, prior to casting. Values are expressed as
`mean + standard deviation (n=3).
`
`

`

`R.K. Subediet al. / InternationalJournal of Pharmaceutics 419 (2011) 209-214
`
`213
`
`Chemical stability ofzolmitriptan patch, formulated in Duro-Tak® 87-2516 matrix, at elevated temperatures. Values are expressed as mean + standard deviation (n=3).
`
`
`Assay
`Formulation
`1 month
`
` 40°C 50°C 40°C 50°C 40°C 50°C
`
`
`
`2 months
`3 months
`
`
`
`
`
`
`
`84.1 + 7.41
`92.8 + 4.87
`84.3 + 5.67
`93.9 + 1.93
`96.3 + 4.06
`5.5% zolmitriptan, 5% cineole
`93.0 + 2.74
`
`5.5% zolmitriptan, 2.5% limonene, 2.5% cineole 88.5 + 3.65 95.0 + 1.80 97.4+ 1.11 92.6 + 3.26 85.9 + 1.99 96.8 + 2.86
`
`
`
`
`
`
`1200 y
`
`1000 -
`
`800 5
`
`600 5
`
`200
`
`Counts
`
`
`
`4% drug and 5%Brij 52
`~ 4% drug, 5% Brij 52 and 5% Kollidon 30
`
`
`400
`
`the crystallization for more than a month and appearance of the
`patches containing Kollidon® 30 was not satisfactory due to the
`precipitation of Kollidon® 30 in the PSA solution. To further inves-
`tigate inhibition of crystallization, various polymers were screened
`in combination with Kollidon® 30. Among the additives screened
`in the combination system, only EC was compatible with Kollidon®
`30, to form a homogenous film. However, similar with the case of
`Kollidon® 30, even in the combined system,crystallization could
`not be delayed for more than a month.
`Since, satisfactory results were not obtained with Duro-Tak®
`87-2510 based formulations, further studies were performed
`with Duro-Tak® 87-2516 matrix. The combined crystallization
`inhibitory system with EC and Kollidon® 30 was employed using
`Duro-Tak® 87-2516 matrix. Nevertheless, Brij® 52 induced crystal-
`lization of zolmitriptan could not be prevented in the Duro-Tak®
`87-2516 matrix for more than a month.
`
`§-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Position (2 theta)
`
`Fig. 6. X-ray diffractogramsof patch containing 4% (w/w) drug and 5% (v/w)Brij®
`52, with or without 5% (w/w) Kollidon® 30, in Duro-Tak® 87-2510 matrix.
`
`3.6. Physical and chemicalstability
`
`including Brij® 30 and Brij® 52 significantly enhanced theflux of
`zolmitriptan at the level of 5% (v/w). However,crystals were formed
`shortly after the preparation. Additives used in the transdermalfor-
`mulations are known to be aninfluential factorfor crystallization
`of drug in acrylic PSA(Ma etal., 1996). Among the other enhancers
`screened,Plurol olieque® CC97,IPP, IPM, lauroglycol, limonene and
`LA also significantly enhanced theflux of zolmitriptan from Duro-
`Tak® 87-2516 matrix; however, crystals were formed as a matter
`of time. Only terpenes (cineole and limonene) provided higherflux
`of zolmitriptan than the control without inducing crystallization
`in the PSA matrix, It was also reported in the literature that ter-
`pene (limonene) in solution formulation increased the diffusivity
`of triptan (sumatriptan) across the skin (Femenia-Fontetal., 2005).
`
`3.5. Effect of crystallization inhibitors
`
`In order to prevent crystallization of zolmitriptan in the
`patch containing Brij® 52, various crystallization inhibitors were
`screenedat the level of 5% (w/w), with 4% (w/w) drug load in Duro-
`Tak® 87-2510 matrix. Amongthe excipients explored, Cremophor
`ELP®, HPC LH 11, chitosan, Carbomer® NF 971, 2-hydroxypropyl
`B-cyclodextrin, Kollicoat® SR30D, hydroxypropyl methylcellu-
`lose (HPMC), Lutrol® 127, Cremophor® RH 40, Eudragit® E100,
`Eudragit® RL100, Eudragit® RS100 EC and PG couldnotinhibit the
`crystallization. Only in the formulation containing Kollidon® 30,
`crystals were not observed for a period of one month.Fig. 6 shows
`increase in crystallinity at various 20 positions in patches without
`Kollidon® 30. No such crystalline peak was seen in patches con-
`taining 5% (w/w) Kollidon® 30, 5% (v/w) Brij® 52 and 4% (w/w)
`drug. Kollidon® 30 has been frequently used as a drug crystal-
`lization inhibitor in pharmaceutical formulations (Maetal., 1996;
`Ziller and Rupprecht, 1988). Inhibitory effect of Kollidon® 30 on
`drug crystallization could be primarily attributed to the protective
`steric hindrancefor crystallization ofdrug molecules. Kollidon® 30
`mayalso interact and adsorb onto the zolmitriptan nucleiorinitial
`crystals, delaying crystal growth. Kollidon® 30 could not inhibit
`
`Since the use of crystallization inhibitors was not successful,
`enhancers that would not cause crystallization were examined,
`Appearanceof crystals was visually monitored. Among the formu-
`lations studied, the ones containing terpenes as enhancer remained
`clear with time. Permeation studies with aged samples (2 months in
`RT) did not show any reduction in permeationrate, indicating that
`the matrix might be physically stable. Patches containing terpenes
`were also observed for any change in morphology orcrystals at vari-
`ous temperatures.Crystallization was found to be dependent on the
`storage temperature. At elevated temperatures crystals appeared
`in the patchat faster rate. Patches werestable at the storage condi-
`tion of 40°C for 2 months. However, spots appeared at 3rd month
`that developedinto crystals. At 50°C, spots appeared at 2nd month
`and the color of patch changedto yellowish at the 3rd month, Other
`investigations have also reported that temperature is a critical fac-
`tor governing the induction time of crystallization (Kim and Choi,
`2002). Chemical stability was also evaluated at various tempera-
`tures. The drug content in patches stored at 40°C did not change
`for 3 months (Table 4). At 50°C, drug content started to decline
`after 2 months. Patches stored at room temperature werevisually
`monitored for appearanceof crystals, and were foundto be stable
`for the study period of 6 months.
`
`4. Conclusions
`
`Zolmitriptan was formulated into a transdermal patch in an
`attempt to present a better mode of drug delivery. Permeation of
`zolmitriptan from the matrix was influenced by different formu-
`lation variables like the nature of adhesive, enhancer, thickness of
`matrix, drug load and the solvent system used. Solvent systems,
`associated with different polymorphs, were found to influence the
`permeation rate. Crystallization was primarily dependent on the
`temperature and enhancers used. Stable formulations were iden-
`tified through stability testing. The present study suggests that,
`matrix based transdermal dosage form of zolmitriptan could be
`explored for the managementof migraine.
`
`0005
`
`

`

`214
`
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`0006
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`