International Journal of Pharmaceutics 419 (2011) 209—214
`
`
`journal homepage: www.e|seviencomilocatefijpharm
` A;
`
`Contents lists available at ScienceDirect
`
`International Journal of Pharmaceutics
`
`ELSEVIER
`
`Influence of formulation variables in transdermal drug delivery system
`containing zolmitriptan
`
`Robhash Kusam Subedi 3. Je-Phil Ryoob, Cheol Moon b, Hoo-Kyun Choi at
`" 3K2} Project Team. College ofi’hormocy. Chosun University. 375 Sensuk—dong. Dong—go. Gwangiu 501—759. South Korea
`h NAL Pharmaceuticois Ltd. Newjersey. USA
`
`
`ABSTRACT
`ARTICLE INFO
`
`
`Article history:
`Received 31 May 2011
`Received in revised form 24July 2011
`Accepted 2 August 2011
`Available online 15 August 201 1
`Keywords:
`Zolmitriptan
`Transdermal drug delivery
`Percutaneous penetration
`Chemical enhancers
`Polymorphism
`Crystallization inhibitor
`
`
`I. Introduction
`
`The effects of different formulation variables including pressure sensitive adhesive [PSAL thickness of the
`matrix. solvent system. inclusion of crystallization inhibitor. loading amount of drug and enhancers on
`the transdermal absorption ofzolmitriptan 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. |(ollidonD 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.
`
`e: 2011 Elsevier By. All rights reserved.
`
`
`Zolmitriptan is a potent and selective serotonin {S-HTIBJHD)
`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 shown efficacy in the treat—
`ment of persistent andior 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.Tel.: +82 62 230 6367: fax: +82 62 228 3742.
`Email address: hgchoi®chosun.ac.kr [H.mK. Choi}.
`
`0378-51235 — see front matter © 2011 Elsevier BM. All rights reserved.
`doi:10.l016fj,ijpharm.2011.08.002
`
`ery system [TDDS] for zolmitriptan would be valuable in providing
`clinical benefit of prolonged pain-free response to patients. Based
`on the daily dose of 5 mg and approximate bioavailabiiity of 40%
`[Seaber et al.. 1997). only about 2mg 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 vitro 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—3 oleate (Plurol olieque® C0197).
`propylene glycol mono laurate (Lauroglycol‘i’), and polyoxy glyc-
`erate [Labrafil‘g’ 1944) were obtained from Masung Co. (Seoul.
`South Korea). PEC. sorbitan monooleate (Tween® 80). sorbitan
`monooleate (Span® 80]. propylene glycol (PG) and oleyl alcohol
`were purchased from Junsei Chemicals Uapan). lsopropyl palmi—
`
`Noven Pharmaceuticals, Inc.
`EX2020
`
`0001
`
`Mylan Tech., Inc. v. Noven Pharma, Inc.
`lPR2018—00174
`
`

`

`210
`
`KK. Subedi et al. [international Journal of Pharmaceutics 419(2011J209—214
`
`aluminum pans and heated at a scanning rate of 10"C1min 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 (20.. 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"n1in—‘ and the step size was 0.03. The X—ray passed
`through 2° divergence slit. The diffracted radiation from the sam-
`ple passed through 0.48" 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. 8 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 zolmitri ptan was investigated using silicone. PIB and
`acrylic adhesive matrices at 5% (wlw) 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. 535. 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—“l‘ak‘D 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
`
`tate (lPP). isopropyl myristateUPM). 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. polyoxyethyiene 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).
`bow substituted hydroxypropyl cellulose (HPC LH 11). Chitosan
`(low molecular weight] and B-cyclodextrin were purchased from
`Sigma—Alt] rich (GmbH. Germany]. Kollicoat® SR 30D and Kollidon®
`30 were obtained from BASF {Ludwigshafen Germany). All other
`chemicals were reagent grade or above and were used without
`further purification.
`
`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 was stirred using teflon-coated magnetic bar
`to obtain homogeneous solution. The resulting drug-PSA solution
`was coated onto release liner. Silicone adhesive solution was cast
`
`on the release liner (Scotchl’ak® 1022, BM. USA} that is coated with
`fluropolymer. After the solvent was removed. dried film was lam-
`inated with a polyester backing film (ScotchPak“D 9732. 3M. USA).
`The values ofdrug loading. excipients and enhancers are expressed
`as % with respect to the dry polymer weight.
`
`2.22. Daffusion study
`System comprising ofa multichannel peristaltic pump UPC-24.
`lsmatec. Switzerland). a fraction collector (Retriever lV. lSCO. NE.
`USA). a circulating water bath (Jeio-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 2cm2. 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 teflon-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 (HPbC).
`
`2.2.3. Analytical method
`Zolmitriptan was analyzed by an HPLC system (Shimadzu Sci-
`entific Instruments. MD). consisting ofa UV detector {SPD-10A),
`reversed-phase C3 column(4.6 mm x 150 mm. 5 pm. Luna). a 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 mLimin, and
`injection volume was 10 p.L The mobile phase consisted ofacetoni-
`trile.-‘50 mM phosphate buffer pH 7.5 (17.51825).
`
`2.2.4. Differential 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 enthal pic response. Samples were placed in
`
`Table 1
`Penetration rate for zolmitriptan from different acrylic adhesive matrixes at 5%
`(wfw) drug load (it = 3].
`Adhesive matrix
`
`Trade name
`Du rD—Ta k‘“I 87—4098
`Duro—Tak'” Sit—26??
`Duro—Tak'” 811—2510
`Duro—Tak'm Sit—2287
`Duro-Tak'” 812516
`
`Flux [p.gi'cm2 Ih)
`6.16
`0.22
`15.6
`6.5
`14.4
`
`Without functional group
`With carboxyl—functional group
`With hydroxyl—functional group
`
`0002
`
`

`

`ELK. Snbed'i ct til. 3‘ international journal of Pharmaceutics 41’!) {201' I) 209—2 I4
`
`2] I
`
`3m —
`
`”E
`~31] 250 —
`£-
`"3
`g 200 _
`tscD
`t:
`E 150 -
`
`Ea 100 -
`fl)
`.2
`E:I
`:I
`E
`u
`
`50
`
`_
`
`o o
`o
`
`—o— 4% drug
`—o— 5% drug
`+ 15% drug
`o
`—£‘-— lU/odrug
`
`__
`--
`
`
`
`
`
`5
`
`[0
`
`15
`
`20
`
`Time (h)
`
`.
`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 :l: standard deviation (n = 3}.
`
`considered for further study. Initial studies were performed in
`Duro—Takm’ 87—2510 matrix, as slightly higher flux of zolmitriptan
`was obtained from this matrix.
`
`3.2. Efl‘ect of drug 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% (WM) of the dry polymer weight. indicating that saturation
`of zolmitriptan within the PSA may be obtained at ca. 4% [wfwj
`(Fig. 1 J. The patch was clear at 4% (wfw) drug load: however. milky
`appearance was observed in the patches containing 5% [wfw} or
`more drug load. Therefore. 4% (wlw) drug load was used for fur-
`ther study. In the case of Doro-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 ofthe matrix may change
`the permeation rate of a drug across the skin (Kim and Choi. 2003}.
`The effect of thickness at 4% (mm drug load in Duro-Tak® 87-
`2510 matrix was investigated to optimize the thickness (Fig. 2]. The
`penetration rate of zolmitriptan increased when matrix thickness
`increased up to 95 um and remained similar up to 130 um. Fur-
`
`30‘0 '
`
`Pure drug
`Ethyl acetate
`Ethyl methyl ketone
`2-propanol
`Butanol
`Tetrahydrofiaran
`
`Endothen'n
`
`down
`
`
`
`Fig. 3. DSC thermograms of different solvates ofzolmitriptan prepared using ethyl
`acetate. butanol. 2—propano]. EMK and THF.
`
`ther increase in the thickness resulted in lower permeation rate.
`Therefore. the matrix thickness of 100 um was selected for fur-
`ther studies with both Duro—Tak® 37-2510 and Duro—Tak® 87-2516
`matrices.
`
`3.3. Efiect ofsolvent 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 melti ng 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-propanol, ethylmethyl
`ketone (EMKJ and tetrahydrofuran (THF); 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 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 dilfractograms
`of different solvates are given in Fig. 4. Each solvate possessed dis-
`tinct crystalline pattern except the case ofTHF where no crystalline
`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
`
`.r.“
`+ 165 um
`E 250 _
`—0— 130 pm
`E
`+ 95 run
`2;
`—*'-‘-— 60 pm
`E 200 — + 25m
`I:D
`I:
`E 150 -
`
`100 -
`
`_
`
`50
`
`0 .
`0
`
`3 §
`
`fl.)
`.2
`E:I
`:I
`E
`U
`
`
`
`
`
`I:
`
`
`
`
`
`
`I
`IS
`
`I
`20
`
`I
`25
`
`5
`
`10
`
`Time (h)
`
`Fig. 2. Effect of thickness on the permeation of zolmitriptan from formulation
`containing 4% (WM) drug in Doro-Tait" 87-2510 matrix. Values are expressed as
`
`mean :: standard deviation (:1 = 3).
`
`0003
`
`

`

`212
`
`R.i(. Subedi er ol. / lntemetionaljotrmol of Pharmaceutics 419(201 1 J 209—2 14
`
`
`
`Butanol
`
`2-Pmpanol
`
`Ethyl melhyl ketone
`
`- Ten'ahydm fur-an
`
`Ethyl acetate
`
`'——|—1—|—r—|—1—1—I—|—|
`0
`1 El
`20
`30
`40
`50
`Position [29}
`
`Fig. 4. X-ray dittractogram 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.
`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 + Ethylacctalc
`
`—O— Butane]
`
`—-r— 2— Propanol
`—o— Ethyl methyl kclonc
`Ten'ahydrofiiran
`
`
`
`
`
` Otmulativepenetrated(pgfcm2) aeamount
`
`Table 2
`Solubility and dissolution of various zolmitriptan solvates (n = 3}.
`Soivatc
`Solubility (mgimL)
`Cumulative release {‘36)
`No solvate
`12.9 i 0.1
`—
`Ethyl acetate
`13.9 i 0.2
`23.] :: 2.3
`Ethyl methyl ketone
`19.9 i 0.6
`101.5: 1.1
`2—Propanol
`15.5 i 0.1
`92.15:: 2.5
`l—Butanol
`15.? t 0.3
`85.31 7.5
`Tetrahydrofuran
`24.7Ir i 0.3
`68.4 :: 5.0
`
`1
`2
`3
`4
`5
`5
`
`
`
`lization in the PSA matrix. The drug Clystals 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 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). Similarly. release of the solvates
`from the patches did not show significant correlation with the flux
`obtained (R2 =o.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. 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 enhancer screening for zolmitriptan from Du ro-Tak" 82-2510 and Duro
`Talc" 82-2515 matrices (n = 3].
`Enhancers
`
`Enhancement ratioa
`
`Duro-Takm 87-2510
`Doro-Talc" 87-2516
`
`Control
`1.00
`1.00
`Plurol oliequeU (I49?
`0.58
`1.28
`Span“ 80
`0.63
`1.09
`Tweenm 80
`0.66
`0.84
`Transcutol"
`0.98
`0.94
`Oleyl alcohol
`0.35
`0.96
`Brij” 52
`1.3?
`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
`0.20
`1.08
`IPP
`0.58
`1.33
`IPM
`0.55
`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" 93
`0.30
`Brij‘” 300
`
`lncrocas" 0.51
`
`" Enhancement ratio= flux with enhancerlflux without enhancer.
`
`0004
`
`
`
`
`
`150
`
`
`
`
`
`Time (h)
`
`Fig. 5. Effect of solvent systems on the permeation of zolmitriptan at 4% (wfw)
`drug load in Duro~Taktn 8332510 matrix. Different solvents were used to either dism
`solve or disperse drug in the PSA matrix. prior to casting. Values are expressed as
`mean 1 standard deviation [n = 3).
`
`

`

`RK. Subedi er al. 3‘ internationalJournal of Pharmaceutics 419 (201' 1‘) 209—2 14
`
`213
`
`:71:i:i:al stability ofzolmitn’ptan patch, formulated in Duro—Tak" 87—2516 matrix, at elevated temperatures. Values are expressed as mean 1 standard deviation [11:3].
`
`
`Assay
`Formulation
`1 month
`
` 40"C 501: 40 C 50C 40 C 50"C
`
`
`
`2 months
`3 months
`
`
`
`
`
`
`
`84.i i 7.4]
`92.8 d: 4.8?
`84.3 d: 5.6?
`93.9 d: 1.93
`96.3 i 4.06
`5.5% zolmitriptan. 5% cincole
`93.0 :: 2.74
`
`5.5% zolmitriptan.2.5% Iimonene. 2.5% cineole 88.5 t 3.65 95.0 i 1.80 97.4 .+. 1.1] 92.6 d: 3,26 85.9 i 1.99 96.8 d: 2.36
`
`
`
`
`
`
`
`
`'200 _ --
`
`--
`
`-
`
`4% drug and 5% Brij 52
`-- 4% drug. 5% Brij 52 and 5% Kollidon 30
`
`Counts
`
`“300 —
`
`800 -
`
`600 -
`
`
`400 -
`
`200 z
`
`9 '
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Position [2 theta)
`
`the crystallization for more than a month and appearance of the
`patches containing Kollidon‘In 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 EC was compatible with [{ollidon®
`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® 87-2515 matrix. The combined crystallization
`inhibitory system with EC and Kollidon® 30 was employed using
`Duro—Tak® 87—251 6 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.
`
`Fig. 6. X—ray diffractograms of patch containing 4% (MW) drug and 5% (viw) Brij“
`52, with or without 5% (wj'w) Kollidon‘” 30. in Duro—Tak" 87—25 10 matrix,
`
`3.6. Physical and chemical stability
`
`including Brij® 30 and Brij‘fi’ 52 significantly enhanced the flux of
`zolmitriptan at the level of5%{vlw). However. crystals were formed
`Shortly after the preparation. Additives used in the transdermal for—
`mulations are known to be an influential factor for crystallization
`of drug in acrylic PSA (Ma et al.. 1995). Among the other enhancers
`screened. Plurol olieque® CC97. IPP. IPM. lauroglycol. Iimonene and
`LA also significantly enhanced the flux of zolmitriptan from Duro—
`Tak® 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 of5% (wiw). with4% (wlw) drug load in Doro-
`Tak® 87-2510 matrix. Among the excipients explored. Cremophor
`ELP®. HPC LH 11. chitosan. Carbomer® NF 97]. 2-hydroxypropyl
`B—cyclodextrin. Kollicoat® SRBOD. hydroxypropyl methylcellu—
`lose [HPMC). Lutrollm 127. Cremophor‘m RH 40. Eudragit® E100.
`Eudragit“D RL100. Eudragit® R5100 EC and PG could not inhibit the
`crystallization. Only in the formulation containing Kollidon® 30.
`crystals were not observed for a period of one month. Fig. 5 shows
`increase in crystallinity at various 29 positions in patches without
`Kollidon® 30. No such crystalline peak was seen in patches con-
`taining 5% [wiw] Kollidon‘m 30. 5% (viw) Brij® 52 and 4% (Wm)
`drug. Kollidon® 30 has been frequently used as a drug crystal-
`lization inhibitor in pharmaceutical formulations [Ma et al.. 1995:
`Ziller and Rupprecht. 1988). Inhibitory effect of Kollidon® 30 on
`drug crystallization could be primarily attributed to the protective
`steric hindrance for crystallization of drug molecules. Kollidon® 30
`may also interact and adsorb onto the zolmitriptan nuclei or initial
`crystals. delaying crystal growth. Kollidon‘i’ 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 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 management of migraine.
`
`0005
`
`

`

`214
`
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