Controlled Release from Ordered Microstructures Formed by

Chapter 34

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Controlled Release from Ordered Microstructures Formed by Poloxamer Block Copolymers Lin Yang and Paschalis Alexandridis Department of Chemical Engineering, State University of New York at Buffalo, Buffalo, NY 14260-4200

The in vitro release kinetics of a low molecular weight hydrophilic drug from hydrogels consisting of Poloxamer poly(ethylene oxide)-poly(propylene oxide) block copolymer spherical micelles, and from tablets formulated from bulk (water-free) Poloxamer are reported. Sustained drug release has been achieved. Our experiments showed the drug release kinetics to depend on two contributions: (i) diffusion of the drug molecules through the water channels present in the gel microstructure (~Vt), and (ii) release concurrent with the erosion/ dissolution of the Poloxamer gel matrix (~t). The drug release profiles determined experimentally for Poloxamer hydrogels were fitted to an equation which included both a diffusion and an erosion term. The two contributions were quantified and were correlated to the apparent diffusion coefficient of the drug in the gel matrix and to the erosion rate of the gel matrix. The matrix erosion rate was measured independently, and the drug released due to the erosion effect was thus estimated. The release of hydrophilic drug from Poloxamer tablets followed closely the erosion mechanism (zero order release kinetics), however, the diffusion mechanism was still active due to the formation of a thin hydrogel layer at the tablet surface. The interplay between the self-assembled microstructures present in Poloxamer block copolymer hydrogels and the drug molecules can be utilized in controlled delivery applications.

Poloxamers (also known as Pluronics®) are triblock copolymers consisting of poly(ethylene oxide) (PEO) and polypropylene oxide) (PPO) blocks. PEO is watersoluble (hydrophilic) while PPO is sparsely soluble in water (hydrophobic). Poloxamers are thus amphiphilic and, when present in aqueous solutions above a certain concentration (CMC: critical micellization concentration) and/or temperature (CMT: critical micellization concentration), they tend to self-assemble into spherical micelles having a hydrophobic PPO core which is "protected" by a hydrophilic PEO

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© 2000 American Chemical Society

In Controlled Drug Delivery; Park, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.


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corona (1). At high (e.g., >20%) concentrations, and/or above a certain temperature, Poloxamers can form hydrogels. It is now known that these "gels" are lyotropic liquid crystals and have different microstructures (based on, e.g., spherical, cylindrical or planar micelles), depending on the Poloxamer molecular weight, PEO/PPO block ratio, and Poloxamer concentration, the temperature, and the presence of additives (2). The ability to form micelles and hydrogels renders Poloxamers useful in a variety of applications (3). A number of Poloxamers have been approved for pharmaceutical use. Poloxamer micelles can be used, e.g., as drug delivery vehicles, with the drug molecules solubilized in the hydrophobic PPO core. Encouraging results have been reported where the entrapment of peptide and protein drugs into Poloxamer micellar microcontainers reduces toxicity, prolongs their residence time, and protects them against degradation (4,5). Poloxamer hydrogels have also been used as an artificial barrier in transdermal drug delivery, taking advantage of their reverse thermal gelation property (i.e., a gel forms from a liquid solution upon increasing the temperature) and the improved diffusivity of the drug in the Poloxamer gel due to the presence in the gel microstructure of continuous water channels (6,7). Sustained release and improved bioavailability have been reported in Poloxamer-based ocular or intranasal delivery systems, resulting from their strong bioadhesiveness and prolonged clearance time (8). The kinetics of drug release from the Poloxamer matrix is a central issue in all applications of Poloxamers in drug delivery systems. In vitro zero-order (i.e., linear function of time) release of both small-molecule (9) and protein (4) drugs from Poloxamer hydrogels into aqueous surroundings has been reported. At the same time, drug release which is linear to the square root of time (10) has been observed in many studies which utilized isopropylmyristate (IPM), a solvent used to emulate the properties of skin, as the receptor phase. It has been recognized that the drug release kinetics can be affected by the physicochemical properties (such as pKa) of the drug, as well as by the properties of the Poloxamer gel (such as the Poloxamer concentration and the presence of additives (77)). However, very few investigations have addressed the mechanism of drug release from Poloxamer gels, taking into account the fact that these gels are well organized lyotropic liquid crystals, and recognizing that this microstructure can affect the drug release. We have carried out extensive studies characterizing the formation of Poloxamer micelles (72), the solubilization in such micelles (13), and the microstructure of Poloxamer gels under equilibrium conditions (14), and have recently examined the kinetics of Poloxamer gel formation and dissolution (75). In this context, we have observed that, following the penetration of water in bulk Poloxamer, the block copolymer molecules self-assemble into different lyotropic liquid crystalline structures according to the water concentration gradient; these hydrogels swell with water linearly to the square root of time (75). Water-soluble drug molecules present in Poloxamer hydrogels (or in bulk Poloxamer tablets) can be released in the aqueous solution via diffusion through the free water channels present in the gel, or via the erosion (dissolution) of the Poloxamer gel matrix (16). While physico-chemical properties of the drug, such as solubility, partition coefficient, and size, always play an important role on the apparent release kinetics, we expect the gelation and dissolution properties of the Poloxamer to contribute to, and even control the release kinetics.


366 In the present study we report the in vitro release kinetics of a low molecular weight hydrophilic model drug, caffeine, from Poloxamer hydrogels and from tablets formulated from bulk (initially water-free) Poloxamer. The contributions to the release kinetics of the diffusion of the drug molecules out of the gel and of the erosion (dissolution) of the Poloxamer matrix have been quantified. The release characteristics of the gels are contrasted to those of the tablets.


Materials and Methods Materials The Pluronic F127 (Poloxamer 407) poly(ethylene oxide)-poly(propylene oxide)poly(ethylene oxide) block copolymer was a gift from BASF Corp. Pluronic F127 has a nominal molecular weight of 12600 and 70% PEO content. The polymer is available as flakes (part of the PEO is in crystalline form at room temperature). Ethyl acetate, acetone, and cobalt nitrate 6-hydrate were purchased from J. T. Baker, and Ammonium thiocyanate from Fisher Scientific. Caffeine (of purity more than 99.9%) was purchased from Sigma. Water of Milli-Q quality was used in all experiments. Preparation of Poloxamer Hydrogels An appropriate amount of caffeine was dissolved in water at room temperature. Bulk Pluronic F127 was then mixed with the aqueous caffeine solution to obtain the desired Poloxamer weight percentage. The mixture was left in a refrigerator (4 °C) for two days (with occasional stirring) until a clear homogeneous liquid solution was obtained. The caffeine-loaded aqueous Poloxamer solution was then poured into a cylindrical mold with a 0.68 cm height and a 1.17 cm radius. A strong gel formed in less than 5 minutes when the Poloxamer water solution was placed into a chamber thermostated at 37 °C. The microstructure of this hydrogel consists of spherical block copolymer micelles (of radius of about 10 nm) packed in a cubic lattice (17). Preparation of Poloxamer Tablets A homogeneous mixture of caffeine and Pluronic F127, with 20 wt% dispersed caffeine loading and a total Poloxamer + caffeine weight of about 1 g, was placed into a tablet mold with a 1.3 cm radius, and was compressed using a manual press under 2500 pounds of pressure for 2 minutes. The height of the resulting tablet was about 0.75 cm. The density of the tablet was approximately 0.97 g/mL (for comparison, the density of the bulk block copolymer is 1.04 g/mL). Release Experiments In vitro release studies of caffeine from Poloxamer hydrogels or tablets were conducted in beakers containing 300 mL water for the gels (and 500 mL water for the tablets) at 37 °C. The stirring rate was 20 rpm, controlled by a Barnant series 20 mixer located 2 cm above the gel (or tablet) surface. The Poloxamer gels/tablets were fixed at the bottom of the dissolution cell with only one side exposed to the aqueous medium. 10 mL samples of the solution were removed at certain time intervals (to


367


determine the caffeine concentration), and equal amounts of water were added (to keep the total solution volume constant). The amount of caffeine present in the aqueous solution was detected at 272.5 nm using a Beckman DU-70 spectrophotometer. Assay of Poloxamer Concentration (18) A series of Pluronic F127 aqueous solutions were prepared, with Poloxamer concentrations ranging from 0.01 to 0.08 wt%. A cobalt thiocyanate reagent (dye solution) was prepared by dissolving 4.6 g of cobalt nitrate 6-hydrate and 20 g of ammonium thiocyanate in 100 mL water. 0.5 mL of a Pluronic F127 solution, 0.5 mL cobalt thiocyanate dye solution, and 1.5 mL ethyl acetate were mixed well in a 14 mL centrifuge tube, and were then centrifuged for 10 min at 12000 rpm, using a Sorvall RC-5B Refrigerated Superspeed Centrifuge, DuPont Instruments. After the centrifugation, the upper two layers were aspirated by a pipette, without disturbing the pellet that was formed by the Pluronic and dye complex. The pellet and the centrifuge tube were washed with about 5 mL ethyl acetate and were then centrifuged for 4 min at 10500 rpm. This washing-centrifugation process was repeated five times, until the aspirated ethyl acetate became colorless. The pellet was then dissolved in 1.5 mL acetone and the absorbance was measured at 333 nm using a Beckman DU-70 spectrophotometer. A calibration curve of absorbance vs Pluronic F127 concentration was thus obtained. The Pluronic F127 concentrations of the samples withdrawn during the release experiments were measured following the above procedure. Measurement of Caffeine Partition Coefficient in Poloxamer Micelles (19) The partition coefficient of caffeine between the F127 micellar (Sm) and aqueous phases (Sw) was determined from the ratio of the caffeine solubility in a micellar solution to that in an aqueous solution. In this study, excess amount of caffeine was added to pure water and to a series of aqueous Pluronic F127 solutions with F127 concentrations ranging from 0.01 to 15 wt% at 23 °C. Following an equilibration period of about one month, the undissolved caffeine was separated from the saturated solution by filtering twice with paper filter. The solubility of caffeine in the saturated solutions was measured by UV at 272.5 nm.

Results and Discussion Partition Coefficient of Caffeine in Pluronic F127 Caffeine is a non-charged low-molecular weight (194.19) molecule with relatively good water solubility, 1 g in 46 mL water at room temperature (20). The release of drug from the hydrogel can be a result of diffusion of the drug molecules through the aqueous domains present in the hydrogel structure, or a consequence of the erosion (dissolution) of the gel matrix. Therefore, the location of the caffeine molecules in the Poloxamer hydrogel will affect the drug release mechanism. If the majority of the caffeine molecules were to partition into the hydrophobic core of the Poloxamer micelles, then the diffusion mechanism would be insignificant due to the very small


368


amount of caffeine dissolved in the water channels occurring between adjacent micelles in the Poloxamer hydrogel. In this case, the caffeine would be released in the solution primarily due to the erosion of the Poloxamer gel matrix. On the other hand, if most caffeine molecules were present (dissolved) in the water channels of the Poloxamer gel and the partition of caffeine in the micelles was negligible, then the release mechanism of caffeine would be controlled both by the diffusion of caffeine molecules though the water channels, and by the release of caffeine concurrent with the erosion of Poloxamer gel matrix (see Figure 1).

Figure 1. Schematic of diffusion (left) and erosion (right) release mechanisms hydrophilic drug from Poloxamer hydrogels.

In order to elucidate the above, we measured the solubility of caffeine in aqueous Pluronic F127 solutions and compared it to the caffeine solubility in plain water. From Figure 2, where the caffeine solubility is plotted vs the F127 concentration, we can see that the caffeine solubility remained almost independent of the F127 concentration, up to about 12 wt% F127. When the F127 concentration was increased further to 15%, the caffeine solubility decreased to some extent. This is most likely a result of the decrease in the amount of water available for solvation of the drug. As shown in Figure 1 (fdled circles), when the caffeine solubility is expressed in terms of only the water present in the solution, then the solubility values at high F127 content approach those observed at low F127 contents. From the fact that the caffeine solubility in the Pluronic F127 solution remained independent of the F127 concentration, we can conclude that the partition of caffeine into the hydrophobic micellar core is negligible. Therefore, both diffusion and erosion mechanisms need to be considered in the release of caffeine from the Poloxamer hydrogels.


369


101

1

1

1

1

I

1 h

I ι ι

0

ι ι ι I ι ι

5

10

Pluronic F127

15

c o n c e n t r a t i o n , wt

20 %

Figure 2. Caffeine solubility vs Pluronic F127 concentration: (o) caffeine solubility in aqueous F127 solution expressed in terms of the overall (caffeine + water) solution content; (·) caffeine solubility expressed in terms of only the water amount.

Diffusion and Erosion Mechanisms of Controlled Release In order to describe the release of caffeine from the Poloxamer gei, and to ascribe our observations to the diffusion and erosion mechanisms, we utilized the following expression (16): A = M, + M 1

1 / 2

2

+M 1 3

(1)

Here, A is the amount of caffeine (per unit area) released from the gel matrix, and Mj, M and M are constants. In this model, the first term accounts for the retardation of the drug release due to the induction time needed for the polymer disentanglement. The second term describes the Fickian-type (first order) diffusion of drug from the Poloxamer hydrogel. The third term results from the (zero order) release of the drug upon the erosion/dissolution of the gel matrix. According to a model proposed by Higuchi (23), the constant of the diffusion term, M , can be expressed as: 2

3

2

M = 2C (D 2

0

a p p

/7t)


(2)

370

where C is the initial caffeine concentration in the gel matrix, and D is the apparent diffusion coefficient of caffeine in the gel matrix. The erosion/dissolution term of Equation 1, M , can be related to the dissolution rate of gel matrix, and can be expressed as: 0

app

3

M =C */C 3

(3)

p 0

where C is the initial caffeine concentration in the gel matrix, C is the Poloxamer concentration in the gel matrix, and k is the dissolution rate constant of the gel matrix, k can be obtained independently from the caffeine release, by measuring the change of Poloxamer concentration in the dissolution medium. 0


0

p 0

Controlled Release of Caffeine from Poloxamer Hydrogel Representative data for the release of caffeine from Poloxamer hydrogels are shown in Figure 3, where the amount of released caffeine per unit area is plotted vs time for a 20 wt% Pluronic F127 gel with 2.2% caffeine dissolved. The drug release achieved was almost immediate (Mi~0). In the Poloxamer hydrogel, the block copolymer molecules are already solvated and arranged in spherical micelles that actually repel each other. So, given the opportunity (i.e., the driving force originating from the concentration gradient), these micelles are immediately released in the solution, together with the accompanying drug. The caffeine release profile in the experiment shown in Figure 3 obviously deviates from the zero-order kinetics. The microstructure of the Poloxamer hydrogels which we studied is based on block copolymer micelles arranged in a liquid crystalline lattice which allows domains of free water to be present between adjacent micelles (2). This lyotropic liquid crystalline structure makes it possible for small drug molecules with relatively high water solubility, such as caffeine, to diffuse out from the gel matrix. As a result, diffusion is an important mechanism and manifests itself in the release profile of Figure 3. Meanwhile, the solvated block copolymer micelles which make up the hydrogel can dissolve into the aqueous solution. Caffeine present in the gel matrix will then be released concurrently with the disintegration of gel matrix. Consequently, in the release of low molecular weight hydrophilic drugs from Poloxamer hydrogels we expect to have both diffusion and erosion. The caffeine release profile obtained from the experiment of Figure 3 can be fitted nicely (R = 0.9999) to Equation 1 which considers both diffusion and erosion effects. The dissolution rate constant (k) of 20 wt% F127 gel containing 2.2% dissolved caffeine was obtained by determining the concentration of Pluronic F127 in the dissolution medium over the course of the dissolution experiment. The amount of caffeine released due to the dissolution of F127 matrix was estimated from Equation 3, under the assumption that the caffeine amount in the gel matrix remained constant during the dissolution process. The caffeine release profile which can be attributed to the erosion of the gel matrix is also plotted in Figure 3. The amount of caffeine released due to the F127 gel matrix erosion is up to 40% smaller than the measured



371 overall caffeine release. This result indicates that during the release process of caffeine from a Poloxamer hydrogel, the diffusion of caffeine from the gel matrix through the water channels is an active mechanism and makes significant contributions. Moreover, with the diffusion of caffeine from the gel matrix, the caffeine concentration remaining in gel matrix will decrease with time. Thereby, the assumption of constant caffeine concentration would lead to an over-estimation of the erosion contribution, especially at the later stages of the gel matrix dissolution process (where from the two curved shown in Figure 3 it appears that the erosion becomes more dominant).

0

50

100

150

200

250

300

350

time (min)

Figure 3. Caffeine release profilefrom20 wt% Pluronic F127 hydrogel with 2 wt% dissolved caffeine. Fitting of the caffeine release data to Equation 1 results in expression: A = - 0.0008 + 0.000655 t ' + 0.00001171. 1 2

The apparent diffusion coefficient of caffeine in the 20 wt% F127 hyrogel matrix was obtained from the fitting of the caffeine release profile to Equation 1, and then from relating the constant M to the apparent diffusion coefficient, based on Equation 2. The caffeine diffusion coefficient is thus estimated to 1.15 10" cm /s. This result is much higher than the 8.2 10" cm /s caffeine diffusion coefficient reported for ethyl cellulose dry film with 20% plasticizer (24). The high caffeine diffusion coefficient observed in the Poloxamer hydrogel matrix can be attributed to the high (80%) water content and to the well defined liquid crystalline structure which allows the free dissolved caffeine to diffuse out more easily. The 1.15 10" em /s diffusion coefficient measured in this study for caffeine is comparable to the 0.755 10" cm /s diffusion coefficient reported for diclofenac sodium in a 20 wt% F127 hydrogel (6). 2

5

10

2

2

5

2

5

2


372 It is notable that, under our experimental conditions, it took more than 5 hours to totally release all of the caffeine loaded in 1 gram of 20 wt% F127 hydrogel. This shows the potential of Poloxamer hydrogels as a sustained drug delivery system.


Controlled Release of Caffeine from Poloxamer Tablet An alternative formulation of caffeine involves its compounding with water-free flake-like Poloxamer. A representative release profde of caffeine from such a tablet formed by bulk Pluronic F127 is shown in Figure 4. The overall release profde follows closely zero order kinetics, indicating the dominance of the erosion mechanism in the drug release process. However, Equation 1, which includes a diffusion term, still provides the best fit to the experimental data. 0.12 ι

1

1

1

1

1

1

1

1

1

ι

1

1

1

1

1

1

1

1

1

ι

t i m e (min)

Figure 4. Caffeine release profile from Pluronic F127 tablet loaded with 20 wt% dispersed caffeine. Fitting of the caffeine release data to Equation 1 results i expression: A = - 0.0024 + 0.00051 t + 0.000062 t. m

When a Poloxamer water-free tablet is placed into an aqueous solvent, water penetrates into the bulk block copolymer, the PEO and PPO blocks of the block copolymer segregate (one being water-soluble and the other not), and the block copolymers self-organize into regions of different lyotropic liquid crystal microstructure which if a function of the local water concentration (14,15). A Poloxamer hydrogel layer is thus formed in situ, and simultaneously dissolves into water. From our previous static dissolution studies (15), we found that the gel layers



373 became more extensive with the progress of dissolution time, and their widths were proportional to the square root of time. The development of these gel layers is controlled by two competing factors: (i) the dissolution (erosion) of the gel matrix adjacent to the solution, which consumes the gel layer, and (ii) the transfer of Poloxamer from the bulk water-free state into the hydrogel, which causes the hydrogel layer to grow to the expense of the bulk polymer. Under conditions of stirring, the dissolution of the gel matrix is accelerated, thereby the thickness of the gel layer in the current tablet experiments is smaller than what we had observed in the static dissolution experiments (75). The near-zero order release from the Poloxamer tablet shown in Figure 4 results from the dominant erosion effect of the Poloxamer gel matrix in the presence of the solvent. The diffusion mechanism is still present, but becomes less important due to the thinner gel layer; thereby smaller amounts of caffeine are available for the diffusion process.

Conclusions Sustained drug release can be achieved from formulations based on Poloxamer poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymers which can form hydrogels consisting of close-packed spherical, cylindrical or planar micelles. The release of a hydrophilic low-molecular weight drug from Poloxamer lyotropic liquid crystalline hydrogels or from bulk (initially water-free) Poloxamer tablets is based on the combination of two contributions: (i) diffusion of the drug molecules through the water channels present in the hydrogel structure, which is a linear function of Vt, and (ii) release of the drug concurrent to the erosion/dissolution of the Poloxamer gel matrix, which is a linear function of t. The release profile of such drugs fits very well to the model proposed in Equation 1 which includes both a diffusion term and an erosion term. By comparing the caffeine released due to matrix erosion to the overall amount of caffeine released, we provide evidence that the diffusion of caffeine from the Poloxamer hydrogels has an important contribution to the overall release process. In the Poloxamer tablet formulation, the diffusion contribution becomes less important due to the much thinner gel layer formed during the tablet dissolution process. The release kinetics of caffeine from Poloxamer tablets are almost zero-order (erosion controlled). This study aims in understand the drug release from block copolymer lyotropic liquid crystal structures in the context of the diffusion and erosion mechanisms. Hydrophilic or hydrophobic drugs, small or big molecules, and colloidal particles such as proteins and peptides, are expected to have different release profiles due to the different contributions of these two mechanisms. The dissolution conditions, such as temperature, solvent and stirring/shear rate, also have important effects on the release of drug from Poloxamer formulations. These subjects are currently under investigation in our laboratory. The aim is to utilize the interplay between the drug molecules and the self-assembled microstructures into controlled delivery applications.


374 Literature Cited


1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

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Controlled Release from Ordered Microstructures Formed by

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