International journal of Pharmaceutics 419 [2011)209—214
`
`
` It;
`
`Contents lists available at ScienceDirect
`
`International Journal of Pharmaceutics
`
`journal homepage: www.clseviercomllocatelijpharm
`
`hLSEVIER
`
`
`Influence of formulation variables in transdermal drug delivery system
`containing zolmitriptan
`
`Robhash Kusam Subedia, Je-Phil Ryoob, Cheol Moon '3', Hoo-Kyun Choi“
`‘ 3101‘ Project Team. College ofi’harmacy. Chosun University. 375 Seosuk—dong, Dong—git, Gwangi‘u 501—759. South Korea
`" NM Pharmaceuticals Ltd. Newjersey. USE
`
`ABSTRACT
`ARTICLE INFO
`
`
`Article history:
`Received 31 May 2011
`Received in revised form 24 Julyr 2011
`Accepted 2 August 201 1
`Available online 15 August 2011
`
`Keywords:
`Zolmitriptan
`Transdermal drug delivery
`Percutaneous penetration
`Chemical enhancers
`Polymorphism
`Crystallization inhibitor
`
`I. Introduction
`
`The effects ofdifferent formulation variables including pressure sensitive adhesive (PEA). thickness ofthe
`matrix. solvent system, inclusion ofcrystallization inhibitor, loading amount ofdrug and enhancers on
`the transdermal absorption of zolmitriptan were investigated. Acrylic adhesive with hydroxyl functional
`group provided good adhesion force and high flux of zolmitriptan. Pseudopolymorphs of zolmitriptan
`were found to possess different solid-state properties that affected the permeation rate. Polyoxyethylene
`alkyl ethers significantly increased the permeation ofzolmitriptan through hairless mouse skin. However.
`these enhancers induced crystallization of zolmitriptan. Kollidon"n 30 delayed the crystallization without
`altering the permeation profile 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.
`
`to 2011 Elsevier B.v. All rights reserved.
`
`
`Zolmitriptan is a potent and selective serotonin {S‘HTIBHDJ
`receptor agonist. It is a second-generation triptan and used in
`the acute treatment of migraine attacks with or without aura and
`cluster headaches. Zo] mitriptan has also shown efficacy in the treat-
`ment of persistent andlor 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 [Vyas et al.. 2005:
`Yates et al.. 2002 ). However. due to low bioavailability after oral
`administration (Seaber et al.. 1997) and inconveniences related 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 amounts of 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
`more patient friendly matrix system based transdermal drug deliv—
`
`"‘ Corresponding author.'1’el.: +82 62 230 636?; fax: +82 62 22B 3742.
`E—moil address: hgchoi@chosun.ac.kr (H,—K Choi ).
`
`0378—51735 — see front matter or 2011 Elsevier BM, All rights reserved.
`doi:10.1016lj.ijpharm.2011.08.002
`
`ery system (TDDS) fer zolmitriptan would be valuable in providing
`clinical benefit of prolonged pain-free response to patients. Based
`on the daily dose of 5mg and approximate bioavailabiiity of 40%
`(Seaber et al.. 1997). only about 2 mg is needed to be delivered
`transdermally.Although skin offers an important mode ofsystemic
`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 conducted to investigate the feasibility
`of developing TDDS for zolmitriptan. In vitm permeation studies
`were done to characterize permeation of zolmitriptan across hair-
`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-B oleate (Plurol olieque® CC497).
`propylene glycol mono laurate (Lauroglycol®), and polyoxy glyc-
`erate (Labrafil® 1944) were obtained from Masung Co. (Seoul.
`South Korea). PEG sorbitan monooleate [Tween® 80). sorbitan
`monooleate (Spanm 80). propylene glycol (PG) and oleyl alcohol
`were purchased from Junsei Chemicals (japan). lsopropyl palmi-
`
`Noven Pharmaceuticals, Inc.
`EX2020
`
`0001
`
`Mylan Tech, Inc. v. Noven Pharma, Inc.
`|PR201 8-01119
`
`

`

`210
`
`RX. Subedi et oi, / l'nternotionalj'oumol' ofPharmoceurfcs 419(20] l‘) 209—2 14
`
`tate(lPP), isopropyl myristate (IPM). PEG—1 2 palm kernel glycerides
`[Crovol® PK 40). and PEG—20 almond glycerides (Crovol® A 40)
`were obtained from Croda (Parsippany, NJ. USA). Lauryl alcohol
`(in). [R)—[+) limonene. polyoxyethylene lauryl ether (Brij® 30)
`and polyoxyethylene cetyl ether (Brij® 52) were purchased from
`Sigma Chemical (St. Louis, MO, USA). Acrylic and polyisobuty—
`lene (PIB) PSA solutions in organic solvents were obtained from
`National Starch and Chemical Company (Bridgewater. NJ. USA). Sil—
`icone PSA was obtained from Dow Corning (Midland. MI. USA).
`low substituted hydroxypropyl cellulose (HPC LH 11). Chitosan
`(low molecular weight) and B-cyclodextrin were purchased from
`Sigma—Ald rich [GmbH, Germany). Kollicoat® SR 30D and Kollidon®
`30 were obtained from BASF [Ludwigshafem Germany). All other
`chemicals were reagent grade or above and were used without
`further purification.
`
`2.2. Methods
`
`2.2.]. Preparation of patch 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 was stirred using teflon—coated magnetic bar
`to obtain homogeneous solution. The resulting drug—PEA solution
`was coated onto release liner. Silicone adhesive solution was cast
`
`on the release liner (ScotchPak® 1022. 3M, USA) that is coated with
`fluropolymer. After the solvent was removed, dried film was lam—
`inated with a polyester backing film [ScotchPak® 9732. BM. USA).
`The values of drug loading, excipients and enhancers are expressed
`as % with respect to the dry polymer weight.
`
`2.2.2. Drffiision study
`System comprising ofa multi channel peristaltic pump UPC-24.
`lsmatec. Switzerland). a fraction collector (Retriever IV. ISCO. NE,
`USA). a circulating water bath Ueio-Tech. South Korea) and flow-
`through diffusion cells were used. Each flow-through cell had two
`arms. which allowed the receiver cell medium pumped to a fraction
`collector. The diffusion cell temperature was maintained at 37 "C by
`circulating water through the outer part of jacketed receiver cell.
`Each of the flow—through diffusion cell components was connected
`via silicone rubber tubing with an internal diameter of 0.015 in.
`The surface area of receiver cell opening was 2 cm2. and its vol—
`ume was 5.5 mL Skin was excised from hairless mouse that was
`sacrificed with diethyl ether. Subcutaneous fat was removed with
`scissors and scalpel. The receiver cell was filled with pH 6.0 buffer
`solution and the media stirred by tellon—coated magnetic bar. The
`transdermal patch was placed on the stratum corneum and the
`excised skin was mounted onto each receiver cell. And O-ring and
`cell top were placed on the top of each skin. These components
`were then clamped. The samples were collected every 4 h for 24 h
`and analyzed by high performance liquid chromatography (HPLC).
`
`2.2.3. Analytical method
`Zolmitriptan was analyzed by an HPLC system (Shimadzu Sci-
`entific Instruments. MD). consisting of a UV detector {SPD—IDA),
`reversed—phase Cg column (4.6 mm x 150 mm. 5 pm, Luna). 3 pump
`(LC-IOAD). and an automatic injector [SIL—10A). The method pre-
`viously described (Vyas et al.. 2005) was slightly 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 p.L. The mobile phase consisted of acetoni-
`trilelSOmM phosphate buffer pH 7.5 (17.51825).
`
`2.2.4. Difierential scanning calorimetry (DSC)
`Thermal analysis was carried out using a BBC unit [Pyris 6 BBC.
`Perkin—Elmer, Netherlands). Indium was used to calibrate the tem—
`perature scale and enthalpic response. Samples were placed in
`
`aluminum pans and heated at a scanning rate of 10"Cimin from
`25 to 170 "C.
`
`2.2.5. X—ray diffraction study
`X—ray diffraction [XRD] patterns were obtained using an X—ray
`diffractometer (GMAX-1200. Rigaku Co.. Japan). The X-ray copper
`target tube was operated at 40 kV and 30 mA. The instrument geom—
`etry was reflection.The x-ray generator power was 2 kW. The scan
`time was 1" min“ and the step size was 0.03. The X-ray passed
`through 2° divergence slit. The diffracted radiation from the sam-
`ple passed through 0.43“ divergence slit and 0.30 mm receiving slit.
`The matrix sample was attached onto a glass holder.
`
`2.2.6. Release study
`Patch of 15 cm2 was held in position by attaching it to a sinker
`at the bottom of dissolution flask 500 mL of phosphate buffer (pH
`6.8) was used as dissolution medium, temperature was set at 32 "C
`and paddle speed of 50 rpm provided the agitation. 2 mL sample
`was withdrawn at 0.5 h, 1 h, 4 h, 3 h, 12 h. 24 h and 48 h post study.
`An equal volume of buffer was replaced after taking the sample.
`Samples were centrifuged at 13.000 rpm for 30 min and analyzed
`by HPLC. The study was performed in triplicate.
`
`3. Results and discussion
`
`3.1. Effect of adhesive matrix
`
`PSA is one of the most important components in fabricating a
`transdermal drug delivery system. The effect of PSA matrix on the
`permeation of zolmitriptan was investigated using silicone. PIB and
`acrylic adhesive matrices at 5% [w]w) drug loading As the first
`step to select appropriate PSA. solubility of the drug was evalu-
`ated in various PSA solutions. The solubility of zolmitriptan was
`found to be inadequate in silicone. SBS. and PIB adhesive solu-
`tions as the solutions were milky. and drug particles were formed
`in the adhesive matrix after drying. Based on higher solubility of
`zolmitriptan in acrylic adhesives. permeation of zolmitriptan from
`acrylic adhesives across the hairless mouse skin was investigated
`and the results are shown in Table 1. It has been reported that
`different functional groups in acrylic PSAs impart different physic—
`ochemical properties to the matrix (Venkatraman and Gale. 1998).
`which results in different permeation rates of the drugs (Hai et al..
`2008). The permeation rate was lowest in the adhesive contain—
`ing carboxyl functional group. This could be due to the interaction
`between amine group of zolmitriptan and carboxyl group of the
`adhesive. In previous study. low permeation rate of tacrine was
`observed due to the interaction between the amine group oftacrine
`and carboxyl group of acrylic adhesive [Kim et al.. 2000). Perme-
`ation rate of zolmitriptan in the acrylic adhesive matrix was highest
`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‘” 37—2510 and Duro—Tak‘D 87—2516
`
`matrixes as compared to Duro—Tak® 87—2287 matrix (Table 1).
`Therefore. both Duro—TakG’ 87—251 0 and Duro—Tak® 87—2516 were
`
`Table 1
`Penetration rate for zolmitriptan from different acrylic adhesive matrixcs at 5%
`(wj‘w) drug load (n = 3).
`
`Adhesive matrix
`Trade name
`Flux (pgfcmzih)
`Bum—Talk“ 833—4098
`6.16
`Without functional group
`Doro—Tali" SIP—2677
`0.22
`With carboxyl—functional group
`With hydroxyl—functional group
`Doro—Tali" SIP—25 l 0
`15.6
`Doro—Tali" 87—2287
`65
`
`Doro—Tali" SIP—2516 14.4
`
`0002
`
`

`

`RX, Suhedi et oi. f lnternotionol'journoi of Pharmaceutics 419 {201‘ L] 209—214
`
`2] I
`
`Pure drug
`Ethyl acetate
`...............
`—————— Ethyl methyl ketone
`_ _ ______
`2-propanol
`— — — Butanol
`— ————— Teb'ahydrofuran
`
`
`F._.._..—-— of
`
`a”
`
`x ________
`
`__- ...... "'-..‘—'——'—“"_""
`“e
`*"
`\g’
`
`x"r—..____.
`
`I
`f
`
`X
`
`\x
`
`_/
`
`,
`\J
`_//
`
`,-
`
`/
`
`
`
`300 -
`
`0-?
`5
`E 250 -
`E.
`E 200
`1
`
`0£
`
`150
`
`E,
`g
`a [00
`a;
`s
`g
`:r
`U
`
`50
`
`o
`
`+ 4“/ d
`rug
`0°
`—0— S/Bdrug
`
`__
`
`
`
`
`
`5
`—8
`E
`5
`E
`m
`
`
`
`..
`
`o
`
`5
`
`ll]
`
`,
`Time (h)
`
`.
`15
`
`20
`
`.
`25
`
`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].
`
`T“ — -— -— — _.-/
`
`I
`I
`I
`I
`I
`I
`I
`I
`I
`
`_
`_
`_
`_
`_
`consrdered for further study. Initial studies were performed 11']
`Duro—Takm’ 37—2510 matrix, as slightly higher flux of zolmitriptan
`was obtained from this matrix.
`
`20
`
`40
`
`so
`
`so
`
`100
`Temp("C)
`
`:20
`
`I40
`
`lot)
`
`130
`
`Fig. 3. DSC thermograms of different solvates of zolmitriptan prepared using ethyl
`acetate. butanol. 2-propanol. EMK and THF.
`
`ther increase in the thickness resulted in lower permeation rate.
`Therefore, the matrix thickness of 100 pm was selected for fur-
`ther studies with both Duro«Tak® 312510 and Duro«Tak® 87u2516
`matrices.
`
`3.3. Effect ofsoivent system
`
`Zolmitriptan exhibits polymorphism and seven different crys-
`talline forms were reported (Van Der Schaaf et al.. 2007). Different
`polymorphs. pseudopolymorphs or the amorphous form 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 Schaaf et 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-pr0panol, ethylmethyl
`ketone (EMK) and tetrahydrofuran [Tl-IF); followed by drying in
`vacuum oven for 24 h. 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 broadened in the case of each
`solvate. The DSC thermograms were also accompanied by addi-
`tional peak near 30"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 ditfractograrns
`of different solvates are given in Fig. 4. Each solvate possessed dis
`tinct crystalline pattern except the case of TH F where no crystal line
`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 these sol-
`vates also markedly differed in the physical properties. Notably.
`large rod shaped crystals were observed in formulation containing
`THF solvate after few hours of drying. X-ray diffractogram of the
`patch showed increase in crystallinity at 21.6 and 23.7 positions
`of 26 [data not shown). The crystal formation could be a result of
`
`3.2. Efiect ofdmg concentration and thickness
`
`The flux ofzolmitriptan did not change significantly as the drug
`loading in the Duro-Tak® 87-2510 matrix increased from 4% to
`10% [wfw) of the dry polymer weight. indicating that saturation
`of zolmitriptan within the PSA may be obtained at ca. 4% (wlw)
`(Fig. I J. The patch was clear at 4% (WM) drug load; however. milky
`appearance was observed in the patches containing 5% [wlw} or
`more drug load. Therefore. 4% (wiw) drug load was used for fur—
`ther study. In the case of Duro—Tak® 87-2516, 5% (wlw) drug load
`was used for further study as the patches were clear at this level of
`drug content.
`It has been reported that the thickness of the matrix may change
`the permeation rate of a drug across the skin (Kim and Choi. 2003}.
`The effect of thickness at 4% [wlw] drug load in Duro-Tak‘i' 87-
`2510 matrix was investigated to optimize the thickness (Fig. 2 ). The
`penetration rate of zolmitriptan increased when matrix thickness
`increased up to 95 pm and remained similar up to 130 pm. Fur-
`
`300 '
`
`+ 165 pm
`:f
`E 750 _ + 13:me
`E '
`+ 95pm
`E
`—*'—‘-— 60mm
`200
`E
`25 pm
`3O
`t:
`3 150
`
`EN 100
`D
`.2
`
`50
`0
`
`E g
`
`U
`
`
`
`::
`
`
`
`|
`
`Time (h)
`
`Fig. 2. Effect of thickness on the permeation of zolmitriptan from formulation
`containing 4% (wfw) drug in Duro—Tak'” 87—2510 matrix, Values are expressed as
`mean :I: standard deviation {:1 = 3).
`
`0003
`
`

`

`212
`
`RX. Sobedi er oi, / intemofionaij'oumoi ofPhormoceui‘ics 419(2011‘)209—214
`
`
`
`Butane]
`
`Z-Mpanol
`
`Ethyl methyl keione
`
`'
`
`- Temhydro fmn
`
`Ethyl acetate
`
`l—'—l—'—l—'—l—'—l—'—l—'
`0
`10
`20
`30
`40
`50
`Position [26]
`
`Fig. 4. X—ray dilfractogram of zolmitriptan solvates prepared using EMK. ethyl
`acetate. 2-propanol. butanol and '11-IF.
`
`unstable amorphous state of THF solvate. Furthermore. permeation
`study was conducted to evaluate whether there were any differ-
`ences among the solvates in terms of penetration characteristics.
`As clearly seen in Fig. 5, the highest permeation profile was obtained
`with EMK solvate and the least with THF solvate. The lowest flux
`obtained in case of THF solvate may be due to the rapid crystal-
`
`200 + Ethyl acetate
`
`—C>— Bulanol
`
`
`
`
`
`
`
`
`
`Table 2
`Solubility and dissolution of various zolmitriptan solvates (n = 3].
`
`Solvate
`Solubility {mgfmu
`Cumulative release 1%]
`No solvate
`12.9 :t 0.1
`—
`Ethyl acetate
`13.9 i 0.2
`73.1 i 2.3
`Ethyl methyl ketone
`19.9 i 0.6
`101.6 i 1.1
`
`15.6 :: 0.1
`2—Propanol
`97.6 :t 2.5
`15.7 i 0.3
`1—Butanol
`85.3 i 7.5
`Tetrahydrofuran
`24.7 i 0.3
`63.4 i 5.0
`
`1
`2
`3
`4
`5
`6
`
`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 butane] solvates possessed similar per-
`meation characteristics. In order to explore whether the solubility
`of zolrnitriptan solvates or release rate from PSA matrix had any
`correlation with the permeation rate. 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
`with the flux obtained [R2 = 0.005 J. Similarly. release ofthe solvates
`from the patches did not show significant correlation with the flux
`obtained (it2 = 0.214].
`The difference in crystalline property may not be the sole factor
`responsible for the difference in penetration properties observed.
`however. it certainly has been shown to be an important factor.
`These observations suggest that choice of appropriate solvent has
`some importance in designing the transdermal drug delivery sys-
`tem for drugs showing polymorphic behavior.
`
`3.4. Ejfect 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-Taktn 87-2510
`and Duro-Tak® 87-2516 matrices. Polyoxyethylene alkyl ethers
`
`Table 3
`Summary of en hancerscreening for zolmitriptan from Du ro—Tak‘n 87—2510 and Doro
`'l‘akm 37—25 16 matrices (n = 3).
`Enhancers
`Enhancement ratioa
`
`
`Doro—Taito 87—2510
`Dum—‘l’ako 87—2516
`1.00
`1.00
`0.68
`1.28
`0.63
`1.09
`0.66
`0.84
`0.98
`0.94
`0.35
`0.96
`1.37
`1.44
`1.15
`1.33
`0.77
`0.79
`1.39
`1.11
`0.54
`0.93
`1.02
`0.99
`0.70
`1.08
`0.58
`1.33
`0.56
`1.33
`0.40
`1.45
`0.43
`1.30
`1.13
`1.29
`0.98
`0.60
`
`Control
`Plurol olieque“ C0197
`Span" 80
`Tween” 80
`TranscutolG
`Oleyl alcohol
`Brijm 52
`Brij‘” 30
`Brijm 58
`Cineole
`ubrafil°1944
`Crovol" A40
`Crovol" PK40
`[PP
`[PM
`Lauryl alcohol
`[auroglycol
`Limonene
`Labrafacm PG
`Oleic acid
`0.39
`Labrafii" 2609
`0.72
`Brij" 72
`0.90
`an? s?
`0.30
`Brij" 700
`[ncrocaso 0.5]
`
`
`‘ Enhancement ratio = flux with enhanceriflux without enhancer.
`
`0004
`
`
`
`
`
`+ 2- Propanol
`—*'-‘-— Ethyl methyl ketone
`Teu'ahydroftuan
`
`
`
`150
`
`Cumulativeamountpenetrated(pgtcmz) 88
`
`Time (h)
`
`Fig. 5. Effect of solvent systems on the permeation of zolmitriptan at 4% (wi'w)
`drug load in Doro—TalcO 87—25 10 matrix. Different solvents were used to either dis—
`solve or disperse drug in the PSA matrix, prior to casting, Values are expressed as
`mean :1: standard deviation (n = 3].
`
`

`

`RX, Subedi er of. f lnrerno rionoljournal of Ph ormoceu tics 419 {20f l) 209—21'4
`
`213
`
`32:12: stability of zolmitriptan patch. formulated in DuromTalt‘a 87-2516 matrix. at elevated temperatures. Values are expressed as mean i standard deviation (n = 3).
`
`
`Assay
`Formulation
`1 month
`
`2 months
`3 months
`
`
`
`
`
`
`
` 40 "C 50"C 40"C 50 C 40C 50"C
`
`
`
`84.1 i 7.41
`92.8 i: 4.87
`84.3 i 5.67
`93.0 i 2.24
`93.9 i: 1.93
`96.3 i 4.06
`5.5% zolmitriptan. 5% cincole
`
`
`5.5% zolmitriptan.2.5% |imonene.2.5% cineole
`95.0 i— 1.80
`92.4 :: 1.11
`92.6 :: 3.25
`85.9 :t 1.99
`95.8 :l: 2.86
`88.5 4; 3.65
`
`
`
`'20”
`
`--
`
`4% drug and 5% Brij 52
`4%tlrug.5% Brij 52 and 5% Kollidon 30
`
`Counts
`
`| 000
`
`800
`
`600
`
`400
`
`200
`
`
`%
`
`5
`
`IO
`
`[5
`
`20
`
`25
`
`30
`
`Position (2 theta)
`
`the crystallization for more than a month and appearance of the
`patches containing Kollidon‘l" 30 was not satisfactory due to the
`precipitation of Kollidon® 30 in the PSA solution. To further inves-
`tigate inhibition ofcrystallization. various polymers were screened
`in combination with Kollidon® 30. Among the additives screened
`in the combination system. only BC 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—2515 matrix for more than a month.
`
`Fig. 6. X—ray diffractograms of patch containing 4% [wlw) drug and 5% (vlw) Brijo
`52. with or without 5% (wlw) Kollidon" 30, in Duro—Tak‘” 87—2510 matrix,
`
`3.6. Physical and chemical stability
`
`including Eirijfli> 30 and Brij® 52 significantly enhanced the flux of
`zolmitriptan at the level of5%{vlw). However.ctystals were formed
`shortly after the preparation. Additives used in the transdermal for-
`mulations are known to be an influential factor for crystallization
`ofdrug in acrylic PSA (Ma et al.. 1996]. Among the other enhancers
`screened. Plurol olieque® CC97. IPP. 1PM, lauroglycol. Iimonene and
`LA also significantly enhanced the flux of zolmitriptan from Doro-
`Takail 87-2515 matrix; however. crystals were formed as a matter
`of time. Only terpenes (cineole and limonene] provided higher flux
`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—Font et al.. 2005}.
`
`3.5. Effect of crystallization inhibitors
`
`In order to prevent crystallization of zolmitriptan in the
`patch containing Brij® 52. various crystallization inhibitors were
`screened at the level of 5% (wlw). with 4% (wlw) drug load in Duro-
`Tak® 87-2510 matrix. Among the excipients explored. Cremophor
`ELP®. HPC LH 11. chitosan. Carbomer® NF 971. 2-hydroxypropyl
`B-cyclodextrin. Kollicoat® SR30D. hydroxypropyl methylcellu-
`lose [HPMC). Lutrol‘D 127. Cremophor‘” RH 40. Eudragit® E100.
`Eudragit“D RL100. Eudragit® R5100 EC and PG could not inhibit the
`crystallization. Only in the formulation containing [{ollidon® 30.
`crystals were not observed for a period ofone month. Fig. 6 shows
`increase in crystallinity at various 29 positions in patches without
`Kollidonm 30. No such crystalline peak was seen in patches con-
`taining 5% (WM) Kollidon‘” 30. 5% MW) Brij‘” 52 and 4% [win
`drug. Kollidon® 30 has been frequently used as a drug crystal-
`lization inhibitor in pharmaceutical formulations (Ma et al.. 1996;
`Ziller and Rupprecht. 1988). Inhibitory effect of Kollidon‘m 30 on
`drug crystallization could be primarily attributed to the protective
`steric hindrance for crystallization ofdrug molecules. Kollidon® 30
`may also interact and adsorb onto the zolmitriptan nuclei or initial
`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.
`Appearance of 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 permeation rate. 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 patch at faster rate. Patches were stable at the storage condi—
`tion of 40“C for 2 months. However. spots appeared at 3rd month
`that developed into crystals. At 50 "C, spots appeared at 2nd month
`and the color of patch changed to 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 were visually
`monitored for appearance of crystals, and were found to be stable
`for the study period of6 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 management of migraine.
`
`0005
`
`

`

`214
`
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`0006
`
`