Doi:10.1016/j.jconrel.2005.04.017

Journal of Controlled Release 106 (2005) 88 – 98 SMGA gels for the skin permeation of haloperidol L. Kanga, X.Y. Liub, P.D. Sawantb, P.C. Hoa, Y.W. Chanc, S.Y. Chana,* aDepartment of Pharmacy, National University of Singapore, Republic of Singapore bDepartment of Physics, National University of Singapore, Republic of Singapore cDepartment of Anesthesiology, Singapore General Hospital, Republic of Singapore Received 24 May 2004; accepted 2 April 2005 Small molecule gelling agent (SMGA) gels were developed using the gelator GP-1 in the solvents, namely, isostearyl alcohol (ISA) and propylene glycol (PG), to deliver haloperidol through the skin. The concentrations of the drug, haloperidol,the enhancer, farnesol and the gelator, GP-1 are 3 mg/ml, 5% (w/v) and 5% (w/v), respectively. The study employed a three-factor full factorial statistical design to investigate the influence of factor level changes on the permeability coefficient andpermeation lag-time of haloperidol. Gels were prepared by raising temperature to 120 8C, followed by natural cooling underroom temperature of 22 F 1 8C. The rheological properties of the gels were examined with a strain-controlled dynamicmechanical method. The in vitro permeation study was conducted with automated flow-through type cells. The gelssuccessfully incorporated the drug and enhancer without losing their aesthetic properties. The in vitro human skin permeationstudy showed the permeation of the drug in ISA-based gels reached the pseudo steady state faster than PG-based gels and wereless affected by gelator. PG-based gels delivered the drug at a faster rate with the incorporation of the enhancer. GP-1 did notinfluence the drug permeation rate but it increased permeation lag-time. The co-existence of gelator or enhancer increased thelag-time to a larger extent than when used separately. The novel SMGA gels are suitable for topical or transdermal delivery.
D 2005 Published by Elsevier B.V.
Keywords: Organogel; Gelator; GP-1; SMGA; Skin; Transdermal drug delivery; Factorial design; Gels; Permeation enhancer less than 3000, can form supramolecular networks andimmobilize water or organic solvents to yield SMGA Small molecule gelling agents (SMGA) or low- gels The gelators for organic solvent are clas- mass gelling agents (LMGA), of molecular weights sified into five categories: fatty acids, steroids andtheir derivatives, anthracene derivatives, cyclo-(dipep-tides), and sorbitols Hydrogelators consist main- * Corresponding author. Department of Pharmacy, Faculty of ly of four classes: conventional amphiphiles, bola Science, National University of Singapore, 18 Science Drive 4, amphiphiles, Gemini surfactants and sugar-based sys- Singapore 117543, Republic of Singapore. Tel.: +65 6874 3096; tems. SMGA can be used as gelling agents for almost E-mail address: [email protected] (S.Y. Chan).
all kinds of polar and non-polar liquids. The inherent 0168-3659/$ - see front matter D 2005 Published by Elsevier B.V.
doi:10.1016/j.jconrel.2005.04.017 L. Kang et al. / Journal of Controlled Release 106 (2005) 88–98 physicochemical properties of gels, such as hardness, copolymers with relatively low molecular weights elasticity, clarity, and liquid-carrying capacity, depend and narrow molecular-weight distributions possess on the microstructure of the fiber network structure of self-assembly property, but their molecular weights SMGA, which in turn is determined by the mutual are generally two magnitude higher than the range of interactions between SMGA molecules and solvent, the degree of supersaturation, and branching agents self-assembled three-dimensional fibrous network The thermomechanical processing conditions structures are formed by interconnecting nanosized such as the stress, strain, and temperature, also have fibers. The strands of SMGA gels are organized influence on the microstructure formation and macro- through noncovalent interaction, one of the reasons scopic properties of the gels The gelation process that make them thermoreversible. Apart from this, in is controlled by a crystallographic mismatch branch- the area of colloidal and nanoscale physics, the net- ing that leads to the formation of the Caley fractal-like works of aggregations are often found to have fractal interconnecting fiber network structures in the liquid These networks form highly porous superstruc- These supramolecular materials find many appli- tures and immobilize a large volume of liquid effi- cations in various fields, such as nanomaterials, ciently via capillary and other related forces. It is lithography, biomaterial processing, tissue engineer- known that a SMGA can form a gel in one solvent, but may fail to form a gel in other isomeric solvents, fields of drug delivery, however, SMGA gels remain or if formed, the network structure and properties may largely unexplored. The few cases that have been reported so far were briefly reviewed as follows. It The gels are prepared by dissolving or dispersing is reported that a non-ionic surfactant, sorbitan the gelator in the organic solvent to prepare the sol monostearate, can gelate biodegradable oils and the phase which, on cooling, sets to the gel state. Cool- SMGA gels formed may be suitable for a depot ing the sol phase results in a self-assembly of the preparation for intramuscular administration gelator molecules into 3-D permanent interconnect- Another study shows that l-alanine derivatives, as ing nanocrystal fibrous networks, which immobilize the gelling agent, immobilized soybean oil and me- the organic solvent. In contrast, systems consisting dium-chain triglycerides, which can lead to in situ of nonpermanent or transient interconnecting fibers formation of an implant The most remarkable or needles can only form weak and viscous paste at study is that the antibiotic, vancomycin, is deriva- low concentrations. The resultant organic gels are tized into a hydrogelator by adding a pyrene group opaque or transparent in some cases, and thermo- to its molecule. The modified vancomycin, 11-fold reversible in nature. On heating, the gel normally more powerful than vancomycin, can dissolve in melts to the sol phase with an increase in the water to form a gel without additional heating.
solubility of the gelator, but in some cases, com- The novel mechanism of targeted delivery based plexes between gelator and solvent form at low on this argued that these gelator-antibiotic molecules temperature and the resulting solution will gelate formed a lethal layer of SMGA gel encapsulating with rising temperature The transition is ther- the bacteria through self-assembly. The results could have opened a new area of drug design and delivery SMGA gels are intrinsically different from micro- emulsions or polymeric gels. The essential compo- For topical or transdermal applications, only nents of microemulsion are oil, water and surfactant, microemulsion-based organic gels have been previ- which form circular units, stabilized by surfactant, dispersed in the leftover water or oil, i.e., the con- gels in transdermal drug delivery is thus investigated for the first time, to our best knowledge. Two achieved by strong mechanical forces. Polymers im- SMGA gels are prepared by dissolving a small mol- mobilize bulk solvents by forming networks with ecule gelling agent, N-lauroyl-l-glutamic acid di-n- their covalently connected long chains, such as the butylamide (GP-1), into propylene glycol (PG) or organogels formed by PG and Carbopol Some isostearyl alcohol (ISA). While the ISA gels have L. Kang et al. / Journal of Controlled Release 106 (2005) 88–98 already been extensively studied, PG is found to be process are evaluated by means of in vitro skin gelated by GP-1 for the first time. Its rheological permeation study, via a factorial design.
properties were studied by a rheological expansionsystem. The organogels are employed as the matrixto deliver a lipophilic drug, haloperidol, which is a suitable transdermal candidate, through human skinIt is a hydrophobic molecule with low molec- ular weight (The only long-lasting formula-tion is its ester, the haloperidol decanoate, for Haloperidol, dl-lactic acid, antibiotic antimycotic intramuscular injection, which, however, has such solution (100X), PG and sodium di-hydrogen phos- disadvantages as injection pain, marked inter-individ- phate monohydrate were purchased from Sigma ual variation and complex administration regime Chemical Company. ISA was purchased from Kishi- . Therefore, it is important to develop an moto Sangyo Asia Ltd (Singapore) and GP-1 (95%) alternative for its maintenance therapy to prevent from Ajinomoto Co (Japan). Farnesol (96.6%) was the relapse of psychosis. A skin penetration enhanc- obtained from TCI (Japan). All other chemical er, farnesol, is also incorporated. The effects of reagents were of at least reagent grade and all materi- enhancer, gelator and solvent on skin permeability als were used as supplied. The molecular structures of N-lauroyl-L-glutamic acid di-n-butylamide (GP-1) (MW=453.70, Log P=5.02) Propylene glycol (MW=76.09, Log P=-0.81) Isostearyl Alcohol (ISA) (MW=270.49, Log P=7.19) Fig. 1. The molecular structures of haloperidol, farnesol, GP-1, PG and ISA. The log P values were given by ChemDraw UltraR.
L. Kang et al. / Journal of Controlled Release 106 (2005) 88–98 the chemicals are shown in Water purified by of 22 F 1 8C, the solution became a white, opaque or translucent organogel. For the 4 solution formulae,PG or ISA was heated to 60 8C to accelerate the dissolution of haloperidol and the solution was vor-texed till haloperidol dissolved completely. Haloper- A 23 full factorial design is used to study the effect idol is photosensitive but very stable in solution of three factors, i.e., the permeation enhancer, the gelator and the solvent, each at two levels, on the in done in darkness. The first-order rate constant of vitro permeation profiles of the drug in solutions/gels, its degradation is 0.0248 dayÀ 1 at 110 8C So with specific focus on the permeability coefficient Kp only 0.0517% of the drug decomposed within the 30 and lag-time Lt. For enhancer and gelator, the high level indicates their presence in the formulation andlow level indicates their absence from the formula.
2.4. Strain-controlled dynamic mechanical spectros- The high and low levels of solvent are ISA and PG, respectively. Eight formulations were generated fol-lowing the Yate’s order (Concentra- A strain-controlled dynamic mechanical spectrom- tions of haloperidol are 3 mg/ml in all the eter with a temperature range from À 150 to 8 formulations, respectively. The concentrations of 600 F 0.1 8C (ARES, Rheometric Inc., US) was farnesol or GP-1 are 5% (w/v), respectively, when applicable in the formulations. Data were analyzed by the statistical software MinitabR.
used to control the cooling rate and the temperature.
The sample was placed between two circular plates 2.3. Preparation of the solutions and gels of diameter 25 mm having a gap of 1.5 mm between,and then subjected to sinusoidal oscillations by mov- Farnesol is easily miscible with PG or ISA. Clear ing both the upper and lower plates. The frequency solutions were obtained at 37 8C for all the formulae was set to 0.1 Hz. The amplitude of the oscillations without GP-1 (For the 4 gel formulae, GP- was controlled to obtain a 0.1% maximum strain in 1 was weighed into a test tube and the organic the sample. Under this strain limit, the structure of solvent PG or ISA was added. The mixture was supramolecular materials would not be destroyed by heated to 120 8C in an oven to dissolve GP-1 the measurements. The instant measurement of the Upon dissolution haloperidol or farnesol was added applied stress and the resultant strain allowed the and the solution was vortexed until haloperidol was calculation of the storage modulus GV and the loss completely dissolved, normally within 30 min at modulus GW, and consequently the complex modulus pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi about 60–120 8C. On cooling at room temperature Table 1The formulae of the 8 solutions/gels, the permeability coefficient Kp and the lag-time Lt of the drug haloperidol Factor A refers to farnesol and factor B refers to GP-1. The plus sign stands for presence (high level) and minus sign for absence (low level). Thelow and high levels of factor C are propylene glycol (PG) and isostearyl alcohol (ISA), respectively. (n = 3 or 4).
L. Kang et al. / Journal of Controlled Release 106 (2005) 88–98 solution was thoroughly degassed to prevent the for-mation of bubbles beneath the membrane. Antibacte- Drug concentrations were determined by a reversed rial and antimycotic solution was added to receptor phase HPLC method (C18 column, Waters Corpora- solutions to maintain the integrity of the skin through- tion) at 254 nm Mobile phase consisted of 0.05 out the experiment and to minimize the microbial M phosphate buffer pH adjusted to 3 and acetonitrile contamination in samples during the analysis. One with a ratio of 50 : 50. Droperidol was used as an milliliter of the solutions/gels was added to the internal standard. Flow rate was 1.3 ml/min and in- donor compartment and covered with parafilm to jection volume was 100 Al. Retention times of the minimize the contamination of the solution. Ambient internal standard and drug were approximately 4 and temperature of the cells (PermeGear, US) was 6.5 min, respectively. Mean peak area ratios of the controlled at 37 8C by a heater/circulator (Haake, drug and internal standard in 0.03% (v/v) lactic acid Germany). The receptor solution is pumped by a 16- were linearly related to the drug concentrations for the channel peristaltic cassette pump (Ismatec, Switzer- land) continuously through the receptor compartment and received by the tubes sitting in a fraction collector(ISCO Retriever IV, US). Cumulated receptor liquid samples were taken at 6-h intervals for HPLC assay.
Chinese female skin was obtained from a plastic 2.8. Permeation parameters and nonlinear regression surgery patient with informed consent at the Singa-pore General Hospital, Singapore. Epidermis was The following nonlinear model was used to esti- prepared by immersing the whole skin in 60 8C mate the permeability coefficient Kp and the lag-time water for 2 min, followed by careful removal of the Lt, from which Kp = KVDV and Lt = 1 / (6 DV) epidermis from the connective tissues. Samples were stored in plastic bags at À 80 8C until use Prior to permeation experiments, membranes with stratum corneum side up were floated over 0.9% (w/v) sodi-um chloride solution containing antibacterial antimy- The parameters are Q, cumulative amount of per- cotic solution (1 in 100 dilution) at 22 F 1 8C for 2 h meated drug; A, the area of permeation; KV or DV, the intermediate parameters defined by K, the partitioncoefficient between skin and donor solution, D, the 2.7. In vitro permeation study with human epidermis diffusion coefficient and l, path length of diffusion,(KV = Kl and DV = D/l2, respectively); C0, the concen- Flow-through type diffusion cells were used for tration of the drug; and time t. Nonlinear regression analysis was carried out with the statistical software, mounted between donor and receptor compartments and excessive skin at the sides was trimmed off tominimize lateral diffusion. Stratum corneum facedtowards the donor compartment and the circular skin area for permeation was 0.785 cm2. Since the solubil-ity of HP in 0.03% (v/v) lactic acid solution is ap- proximately 1 mg/ml, 500 ml of 0.03% (v/v) lacticacid solution containing 1% (v/v) antibacterial anti- The PG gels start to gelate almost immediately mycotic solution was placed in the reservoir bottle as after the ambient temperature changed from 120 8C the receptor solution, which flows through the recep- to room temperature (22 F 1 8C) whereas the ISA tor compartment at 0.75 ml/h The pH of the formulation began to gel an hour later and the process receptor solution was approximately 3 but that did not was much slower than for the PG gels. For both ISA affect the integrity of the epidermis Receptor and PG gels, the formulae without farnesol gelated L. Kang et al. / Journal of Controlled Release 106 (2005) 88–98 faster than those with farnesol. Flake-like white spots strain the mesh-like micro/nanostructure is intact and appear ubiquitously in the clear solution and intensify slowly until a uniform gel was formed. The PG gels(formula dbT and dabT) are opaque and white in color while the ISA gels are translucent, indicating that PGgels possess thicker fibers and a lower degree of The original permeation data are shown in network branching than the ISA gels. The improved The estimated values of Kp and Lt are given in clarity of ISA gels is due to the formation of thinner 1, and as the response variables for the three factors, fibers and more densely branched three dimensional their changes in response from low levels to high levels of the factors were analyzed with a statistical The structure of interconnecting fiber networks is directly associated with the rheological properties. As For the permeability coefficient Kp, factor A and C shown in where the moduli were recorded as a are significant, which indicates the enhancer and sol- function of time, the elastic and viscous moduli gels vent exerted their influences upon Kp when changing formed at 0.01% of strain, 20 8C and 1 Hz frequency from low level to high level, but the gelator did not.
and are almost parallel to each other; therefore the gels The effect of enhancer farnesol is positive, showing it possess the mesh-like interconnecting networks of can increase Kp when present in the formula. The micro/nano structures. shows the change of factor C, solvent, shows a negative effect, which the moduli of the gels as functions of various oscil- indicates that when the solvent changed from low lating strain amplitudes, c. The strain corresponds to level (PG) to high level (ISA), the permeability coef- the deformation of the networks caused by the applied ficient Kp decreased. Therefore PG delivered haloper- shear stress. The storage modulus, GV, remains stable idol at a faster rate than ISA on average. One of the under small strains and decreases abruptly when c two-way interactions, A*C, also showed significant exceeds a certain value c0, which corresponds to the negative effect. This can be explained that the enhanc- breakage of the junctions in the networks. The gels er is less effective in ISA than in PG. The three-way can withstand up to 0.25% of the strain. Below this interaction term is not significant.
Fig. 2. Dependence of the storage modulus GV, the loss modulus GW, and the complex modulus G* on time. Time sweep method for formuladabT gel at 20 8C.
L. Kang et al. / Journal of Controlled Release 106 (2005) 88–98 G`
103 G``
Fig. 3. Dependence of the storage modulus GV, the loss modulus GW, and the complex modulus G* on strain. Dynamic strain method forformula dabT gel at 20 8C.
Cumulative amount of permeated drug (microgram).
Fig. 4. Time course of mean cumulative amounts of haloperidol permeated through 1 cm2 of human epidermal membrane in the solutions/gelsformulated according to Each point represents mean F SD (n = 3 or 4).
L. Kang et al. / Journal of Controlled Release 106 (2005) 88–98 enced by the three factors and their interaction terms, The effects and significance levels of the factors and their interac- all of which are estimated in the factorial design as The factor A, a skin penetration enhancer, may increase Kp by modifying the lipid compositions and structures. The factor C is the solvent. PG is an established solvent for transdermal delivery, miscible with water. It can dissolve many essential oils, but is immiscible with fixed oils. ISA is a saturated fatty alcohol, clear and viscous. It is a biocompatible sol- vent widely used in cosmetic industry. Factor B is the gelator, the SMGA, also being used for cosmetics, The results were confirmed by ANOVA tests ( p b 0.05*).
such as lipstick, eyeliner, deodorant and makeuplotions It may retard the permeation process Unlike Kp, the lag-time Lt, is sensitive to all the three by its steric supramolecular structure, reducing the factors, as well as their combinations. The enhancer permeation area on the skin and by Fick’s law this and gelator can increase lag-time, while ISA de- creased the lag-time compared to PG. The positive On average, however, as the results have shown, the two-way interaction term shows that when the gelator gelator did not influence Kp significantly as it did with is present, the enhancer will increase lag-time to a Lt. This is also shown in where the curve daT is larger extent than when there is no gelator in the well above curve dabT, but the slopes of their linear formula and vice versa. The other two negative two- parts are quite similar to each other. The definitions of way interactions show ISA can counteract the elon- permeability coefficient and lag-time are Kp ¼ K Dl gation effect of the enhancer or the gelator on drug and Lt ¼ l2 , respectively The partition coef- permeation. The three-way interaction is negative, for ficient between the donor solution and the top layer of which the most intuitive explanation is that when the the stratum corneum, K, is hard to define since there is solvent is ISA, the A*B interaction is not as strong as no distinct interface in terms of lipids as the solvent when the solvent is PG, therefore the enhancer/gelator vehicles pass through the stratum corneum. If K is will not increase the lag-time much more than when assumed to remain constant with the introduction of the gelator/enhancer is absent, respectively.
the gelator to the delivery system, an explanation isthat both the diffusion path length, l, and diffusioncoefficient, D, increased while their ratio remains constant. The lipophilic gelator GP-1 (MW = 453.70,Log P = 5.02) could have posed some extra spatial The gels can accommodate both the drug and the hindrance to propylene glycol (MW = 76.09, Log permeation enhancer while still retaining their rheo- P = À 0.81), which literally increased the path length.
logical and aesthetic properties, which showed that The increased D could be due to the synergistic effect SMGA gels have potential for delivery of drugs between the enhancer, farnesol (MW = 222.37, Log through the skin. In vitro permeation study was, P = 2.47), and the gelator, both lipids in nature. As therefore, conducted to evaluate the performance of for the other solvent, ISA, the scenario is partially the gels for the transdermal delivery of the drug, different as the gelator in it did not affect either Kp or Lt significantly. As shown in compared with The permeability coefficient, Kp, and the lag-time, formula dacT, the presence of the gelator in formula Lt, defined a permeation curve of the cumulative dabcT did not cause any significant effect on the per- permeated drug against time with all the other para- meation profile (two-sample t-test, p = 0.05). The sol- meters kept constant. Pseudo-steady permeation with vent ISA (MW = 270.49, Log P = 7.19) is similar to a flux of KpC0 is expected after a transitional period GP-1 structurally as well as sizably, and they are both of 3 times Lt Both parameters can be influ- lipophilic. The aliphatic long-chain gelator, GP-1, thus L. Kang et al. / Journal of Controlled Release 106 (2005) 88–98 presented a lesser permeation barrier to ISA than to teristically aesthetic and rheological properties with PG. This ISA-controlled permeation was in line with the incorporation of the drug and enhancer. These in the statistical result that ISA could significantly coun- vitro human skin permeation studies showed the gels teract the delayed effect of the enhancer or gelator on possessed desirable properties for topical or transder- mal delivery. The translucent lipophilic gels based on Some other interaction effects among the three solvent ISA were stable and the permeation of the factors were also revealed by the statistical analysis, drug reached the pseudo steady state in less time of which the most prominent one is that the enhancer compared to the PG-based gel. The latter, opaque performed much better in PG than in ISA, judging by white in color, delivered the drug at a faster rate Kp. In fact, the enhancer in ISA did not exert any with the addition of the enhancer. The gelator, GP-1, significant effect (two-sample t-test, p = 0.05). Since did not influence the drug permeation rate but it the main barriers are caused by the stratum corneum intercellular lipids, the penetration of PG is retarded,to some extent, due to its hydrophilicity Thesituation was changed with the addition of farnesol, which bridged the lipids and PG so that the solutionsmoved faster as a whole through the lamella of inter- The authors would like to thank Dr. Shenghua Kelly Fan, Department of Statistics and Applied Prob- The main components of these intercellular lipids, ability, National University of Singapore, for her in- i.e., cholesterol, free fatty acids and ceramides are spiring comments on the experimental design.
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