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Journal of Controlled Release 104 (2005) 497 – 505 Controlled release of lidocaine hydrochloride from the Zhijian Wua,b, Hyeonwoo Joob, Tai Gyu Leeb, Kangtaek Leeb,T aCollege of Materials Science and Engineering, Huaqiao University, Quanzhou 362011, PR China bDepartment of Chemical Engineering, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-749, Korea Received 23 August 2004; accepted 28 February 2005 We investigate the controlled release of lidocaine hydrochloride from the doped silica-based xerogels. In the xerogel preparation, tetraethoxysilane (TEOS), methyltriethoxysilane (MTES), and propyltriethoxysilane (PTES) are used asprecursors, and a nonionic surfactant Igepal CO 720 is used as a dopant. The experimental results suggest that the releaseof lidocaine hydrochloride can be easily controlled by partially substituting TEOS with the organosilanes, and/or by adding thedopant. Adding the organosilane precursors lowers the release of both the drug and the surfactant in the order of TEOS, MTES/TEOS, and PTES/TEOS xerogels. The release from the PTES/TEOS xerogels is much lower than that from the other xerogels.
The release of lidocaine hydrochloride is obviously suppressed by the addition of Igepal CO 720, while the release of Igepal CO720 is slightly promoted by the addition of the drug. The overall release process is found to be diffusion-controlled, and therelease behaviors can be well explained by considering the effects of the textual properties of the xerogels and the interactionsamong the drug, the surfactant, and the xerogel matrices.
D 2005 Elsevier B.V. All rights reserved.
Keywords: Lidocaine hydrochloride; Igepal CO 720; Hybrid xerogel; Diffusion; Hydrophobic interaction; Mutual effect microscopic porosity. It is also convenient to preparegel membrane by the sol–gel technique. After Sol–gel derived silica xerogels have been inves- gelation, the drugs in silica sols become uniformly tigated as carrier materials for controlled drug delivery distributed within the porous silica xerogel networks These materials are room temperature pre- that are biocompatible in vivo These materials pared, silica-based, and amorphous, and have a high cause no adverse tissue reactions and degrade in thebody to silicic acid, i.e. Si(OH)4, which is eliminatedthrough the kidney Drug-release behavior from silica xerogels can be T Corresponding author. Tel.: +82 2 2123 2760; fax: +82 2 312 affected to some extent by changing the sol–gel E-mail address: (K. Lee).
synthesis parameters (i.e. pH, the water/alkoxide ratio 0168-3659/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jconrel.2005.02.023 Z. Wu et al. / Journal of Controlled Release 104 (2005) 497–505 temperature, type or concentration of the catalyst ) as well as drying and heating conditions.
Drug release, though, is generally known to be diffusion controlled and relatively fast in simpleTEOS-based xerogels without dopants It may be The xerogels were prepared through a two-step sol– helpful for an easy control of drug release to take gel process. Tetraethoxysilane (TEOS; Aldrich), or the advantage of the various interactions by partially mixture of TEOS and organosilane, i.e. methyltrie- replacing the TEOS with organosilanes and/or by thoxysilane (MTES; Aldrich) or propyltriethoxysilane adding dopants, usually surfactants.
(PTES; Aldrich), ethanol, 0.050 M lidocaine hydro- In the drug release systems, matrix/dopant inter- chloride (Sigma) in water, 1.71 mM Igepal CO 720 (a actions may cause dramatic changes in the solubility nonionic surfactant; Aldrich) in ethanol, doubly dis- and diffusivity of the drug and the rheological tilled and deionized water, and 0.010 M HCl solution properties of the matrix. In consequence, incorpora- were mixed and stirred to get uniform sols. All the sols tion of the dopant opens a possibility for the were hydrolyzed in a covered beaker for one day at development of the controlled drug delivery systems room temperature before 1.0 M ammonia was added.
The mutual effect of the drug and the dopant, For the preparation of all the xerogels, the final molar though, has not been clearly demonstrated to date.
ratio was (TEOS + organosilane):water:ethanol:drug: Lidocaine hydrochloride is the most commonly surfactant:HCl:NH3 =1:6:8:8 Â 10À4 : 8 Â 10À 4 : 8 Â used local anesthetic in intradermal infiltration, topical 10À 5 : 6 Â 10À 3, where TEOS:organosilane = 4 : 1.
anesthesia, and peripheral nerve blocks It After gelation the gels were dried at room temperature presents a short duration, thus a long-action single- for three days, and at 50 8C for one day. The irregular- dose treatment would be of clinical importance shaped xerogels with a diameter between 1 and 2 mm For such purpose, lidocaine hydrochloride has been were used for the release experiments. The sol used in the forms of skin bioadhesive films composition, gel time, and drug content in the final hydrochloride is chosen as a model drug. We controlthe drug/matrix/dopant interactions by using different 2.2. Determination of the textural properties of the types of oragnosilane precursors and nonionic surfac- tant Igepal CO 720, and attempt to understand theeffect of the various interactions on the drug release Textural properties of the xerogels were estimated rate. This study should give insights on the design of using nitrogen sorption experiments. The adsorption/ carrier materials in the controlled drug delivery by the desorption isotherms of nitrogen at 77 K were measured with an automated Micromeritics ASAP Table 1Composition of the sols used in the experiments The concentration of HCl solution is 0.01 M; the concentration of ammonia solution is 1.0 M; the concentration of drug in water is 0.050 mM;the concentration of surfactant in ethanol is 1.71 mM.
Z. Wu et al. / Journal of Controlled Release 104 (2005) 497–505 Table 2Gel time, drug content, and the textural properties of the gels 2020 apparatus. Prior to the measurements, the drug and the surfactant concentration. Then, the xerogels were degassed for 2 h at 160 8C. The xerogels and the supernatant were transferred back specific surface area was calculated from the BET into the original vials for further release experiments.
equation and the average pore size was calculated by The UV-160A UV-visible spectrophotometer was BJH method based on the desorption branch of the used to determine the concentrations of lidocaine isotherms. The textural properties of the xerogels are hydrochloride and surfactant in solution: i) the concentration of surfactant was measured at 284 nmbecause the lidocaine hydrochloride does not have absorption at 284 nm; ii) the concentration oflidocaine hydrochloride was determined directly at Half a gram of xerogel was mixed with 10 ml of 262 nm for the xerogels without the surfactant, or by 0.050 M phosphate buffer solutions at pH 7.4 which is subtracting the surfactant absorbance from the total the pH used for lidocane hydrochloride release absorbance of the drug and the surfactant at 262 nm experiments The mixtures were stirred at 80 for the xerogels doped with both the drug and the rpm in closed vials at 37 8C using a BS-06 shaking surfactant (All the release experiments were water bath. At different intervals, the aliquot of the solution was centrifuged for 3 min at 10,000 rpm andthe supernatant was used for the determination of the The textural properties of the xerogels are listed in It is shown that the addition of the organo- silane precursors affects the textural properties of the xerogels. The PTES/TEOS xerogels (Gels 3, 6, 9)exhibit the lowest surface area and the smallest average pore size, while the textural properties of TEOS gels (Gels 1, 4, 7) are similar to those of the Fig. 1. UV spectra of the solutions (1: 0.050 M phosphate buffer solution at pH 7.4; 2: 0.748 mM lidocaine hydrochloride inphosphate buffer solution; 3: 0.520 mM Igepal CO 720 in phosphate The fraction of drugs released (F) is shown as a buffer solution; 4: 0.748 mM lidocaine hydrochloride and 0.520mM Igepal CO 720 in phosphate buffer solution).
function of time in The fraction released Z. Wu et al. / Journal of Controlled Release 104 (2005) 497–505 Fig. 2. Release of lidocaine hydrochloride from the gels without Fig. 4. Release of Igepal CO 720 from the gels without lidocaine glycol (PEG) was also found to lower the release organosilane precursors clearly lowers the release of both lidocaine hydrochloride and Igepal CO 720 inthe order of TEOS, MTES/TEOS and PTES/TEOSgels. Note that the release from the PTES/TEOS gels (Gels 3, 6, 9) is much lower than that from the othergels. These results are consistent with the work by Matrix swelling, matrix dissolution, and the dif- Kortesuo et al. in which partial substitution of the fusion of the drug are the most important rate- TEOS with tri-or dialkoxysilane reduced the release controlling mechanisms of the commercially available controlled release products Matrix swelling is acommon phenomenon in the organic hydrogels. The 3.3. Mutual effect of lidocaine hydrochloride and inorganic gels, however, are reported to be difficult to swell Furthermore, in the hybrid silicaxerogels used in this study, there are no organic demonstrates that the release of lidocaine groups incorporated into the siloxane bone structures hydrochloride is suppressed by the addition of (but the organic groups exist only as end Igepal CO 720 in the xerogels, while the release groups. Thus, it is reasonable to assume that the of Igepal CO 720 is slightly promoted by the swelling of xerogels is negligible in this study.
addition of the drug. It has been shown that In aqueous solutions, silica solubility is known to surfactants can be used to give a prolonged release increase rapidly at pH N 10 This can cause the from gels through the partition of nonionized drugs dissolution of the xerogels, thereby leading to a to micelles For the release of toremifene decrease in surface area and the increase in pore size citrate from silica xerogel, addition of polyethylene Because the pH of the release medium is fixed at Fig. 3. Release of lidocaine hydrochloride from the gels doped with Fig. 5. Release of Igepal CO 720 from the gels doped with lidocaine Z. Wu et al. / Journal of Controlled Release 104 (2005) 497–505 from poly(d,l-lactic acid) nanospheres at low load- ings and the release of nifedipine trypsin inhibitor and dexmedetomidine from silicaxerogels. For the release of metoprolol tartrate from hydroxypropyl methylcellulose-based tablets, the release was found to be diffusion-controlled with theexponent n ranging from 0.46 to 0.59 and the investigated formulation and processing variables did not alter the drug release mechanism Overall processes in this study may involve the Fig. 6. Comparison of the fraction released for lidocaine hydro- following steps: i) initially water rapidly enters the chloride and Igepal CO 720 after 54 h.
xerogels because of the steep water concentrationgradients at the xerogel/water interface; ii) due to the 7.4 in our experiments and the hybrid gels dissolve concentration gradients lidocaine hydrochloride and even more slowly than the pure silica gels the Igepal CO 720 dissolve upon contact with water and dissolution of the xerogels is negligible and would not diffuse out of the xerogels; iii) the diffusivity of the affect drug release. Thus, we expect that the release drug and the surfactant increases substantially with would not be controlled by the xerogel swelling and increasing water content iv) textural properties dissolution. Next, we test the diffusion-controlled of the xerogels affect the release of the drug and the surfactant; (v) the interactions among the drug, thesurfactant, and the xerogel matrices affect the release of the drug and the surfactant. Thus, one can expectthat the differences in release behavior come mainly from the textural properties and the interactions.
is used to test the diffusion-controlled releasemechanism: 4.2. Effect of the textural properties of the xerogels onthe release rate Here, F is the fraction of the drug released at time t; k shows that the PTES/TEOS gels (Gels 3, 6, is a constant incorporating structural and geometric 9) have the lowest surface area and the smallest feature of the xerogels; n is the release exponent average pore size, while the textural properties of the which is indicative of the release mechanism. In the TEOS gels (Gels 1, 4, 7) are similar to those of the diffusion-controlled release, n = 0.5, 0.45, and 0.43 forslab, cylinder, and sphere; in swelling-controlled release, n = 1.0, 0.89, and 0.85 for slab, cylinder, and sphere Thus, for irregular-shaped samples, n is expected to be between 0.43 and 0.5 for diffusion- ( CH CH ) OH
controlled release; between 0.85 and 1.0 for swelling- The fitting results using the above model are listed in In all cases, the release exponent for both the drug and the surfactant lies between 0.30 and 0.67, suggesting diffusion-controlled release. Furthermore, matrix swelling and dissolution are negligible as discussed above. Thus, our results suggest that the Fig. 7. Schematic diagram of the interactions between lidocaine release appears to be diffusion-controlled regardless cation, Igepal CO 720, and the xerogel matrix in Gel 9 (A: Igepal of precursor types and surfactant. Diffusion-controlled CO 720; B: lidocaine cation; (1) electrostatic attraction; (2) release was also found for the release of lidocaine hydrogen bonding; (3) hydrophobic attraction).
Z. Wu et al. / Journal of Controlled Release 104 (2005) 497–505 MTES/TEOS gels (Gels 2, 5, 8). According to 11 the xerogel surface in our experiments is 3, the release constant k of TEOS and MTES/TEOS negatively charged at pH 7.4. In aqueous solutions xerogels is always larger than that of PTES/TEOS of pH near 7, though, lidocaine hydrochloride exists xerogels, which suggests a faster release of the drug mainly as lidocaine cations (proton ions may and the surfactant from the TEOS and MTES/TEOS associate with one of the two nitrogen atoms as in gels. Thus, lowering the surface area and the average pore size suppress the release of the drug and the attraction between the drug and the surface of the Since there are more silanol groups and the silanols 4.3. Effect of the interactions on the release rate are more acidic in pure silica xerogels (Gels 1, 4, 7), itis expected that the pure silica xerogels are more There can be three types of interactions that can negatively charged at pH 7.4. Therefore, there should affect the release rate: 1) electrostatic interactions; 2) be a stronger electrostatic attraction between the hydrogen bonding; 3) hydrophobic interactions.
lidocaine cations and the pure silica xerogel surface Schematic of these interactions among the drug, than that between the cations and the hybrid xerogel the surfactant, and the xerogel matrices is given in surface. However, the release experimental results show that the release of drug is higher from the puresilica xerogels than from the hybrid xerogels, suggest- ing that the electrostatic attraction is not as important Bulk silica xerogels consist of siloxane units as the other interactions and the textural properties of joined together in a tetrahedral lattice. Different functional groups can be present at the surface,depending on the preparation method of the xerogels and (if in solution) the nature of medium.
Hydrogen bonding is a more common interaction.
Functional groups commonly associated with the There exists a hydrogen bonding among the drug, the silica surface are silanol groups and organic groups surfactant, and all the xerogel matrices (Since if organosilane precursors are used. The two-step there are more silanol groups in pure silica xerogels, it xerogels are reported to have higher contribution of is expected that the drug and the surfactant have a silanol groups than the acid-catalyzed single-step stronger hydrogen bonding with pure silica xerogels xerogels Charge on the silica surface changes than with hybrid xerogels. The release experimental as the silanol groups on the surface are protonated results, though, show that there is more drug released or deprotonated depending mainly on the solution from the pure silica xerogels than from the hybrid pH. Since the density of negative charges on the xerogels. This suggests that hydrogen bonding is also xerogel surface remains low until the solution pH not important compared with the other interactions reaches 6, but increases sharply between pH 6 and and the textural properties of the gels.
Z. Wu et al. / Journal of Controlled Release 104 (2005) 497–505 importance of the hydrophobic interactions was also Hydrophobic interactions which represent a ten- proved by the reactivity of acid-base indicators in dency of nonpolar groups to associate in aqueous silica xerogels the release of organic dye from solutions commonly occur in aqueous solutions of hybrid silica xerogels and the organic dye low-molecular organic substances as well as of biological macromolecules The association is accompanied by little change in enthalpy, but it is electrostatic and hydrophobic interactions with governed mainly by the entropic effects. Because any surfactants and hybrid xerogels. By using hybrid association (or dissociation) of systems is directly xerogels, the release rate of the drugs can by related to a negative (or positive) entropy change, this reduced by the hydrophobic interactions between entropy change is associated with the ordering of the drugs and the organic groups on the hybrid molecules that surround the hydrocarbon residues in xerogel surface. By including a surfactant in the formulation, the release rate can be further reduced There are hydrophobic interactions among the since hydrophobic interactions can take place drug, the surfactant, and the hybrid xerogel surface between the drug and both the gel matrix and the surfactant is suppressed by partially replacing TEOSwith organosilanes, which may be caused by boththe textural property changes and the hydrophobic interactions. Organic groups linked to the xerogelnetwork by covalent bonds can provide a modified We have designed the doped hybrid xerogels for hydrophobicity that can reduce the release of the the controlled release of lidocaine hydrochloride to drug. There have been several reports that support understand the effects of the textural properties of the the role of the hydrophobic interactions on the drug xerogels and the drug/matrix/dopant interactions on release. According to Kortesuo et al. increasing the release rate. The experimental results can be the number or length of the organic groups attached to silicon reduced the release rate of dexmedetomi-dine from monoliths. In addition to drugs with low (1) The release of lidocaine hydrochloride can molecular weight, the release of macromolecules easily be controlled by partially substituting such as heparin was also suppressed from an alkyl- TEOS with the organosilanes and/or by adding substituted silica xerogel matrix In our experi- the dopant. With the addition of the organo- ments, the pure silica and the MTES/TEOS xerogels silane precursors, the release of both the drug have similar textural properties, but the fraction and the surfactant decreases in the order of released from the pure silica xerogels is always TEOS, MTES/TEOS and PTES/TEOS xerogels.
higher than that from the MTES/TEOS xerogels, The release from the PTES/TEOS xerogels is confirming the importance of the hydrophobic always much smaller than that from the other (2) The release of lidocaine hydrochloride is obvi- obviously suppressed by the addition of the surfac- ously suppressed by the addition of Igepal CO tant, while the surfactant release is slightly promoted 720 in the xerogels, while the release of Igepal by the addition of the drug. It is suspected that this CO 720 is slightly promoted by the addition of may also be partly caused by the hydrophobic interaction between the drug and the surfactant. By (3) PTES/TEOS xerogels have the lowest surface adding the micelle-forming surfactants in the for- area and the smallest average pore size, while mulation of some polymer gels, Paulsson et al.
the textural properties of TEOS xerogels are observed a reduction in the diffusivity of similar to those of the MTES/TEOS xerogels.
drug molecules because of the hydrophobic inter- (4) The overall release process is diffusion-con- actions between the drug and the micelle. The trolled for both of the drug and the surfactant.
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