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Controlled poorly soluble drug release from solid self-microemulsifying formulations with high viscosity hydroxypropylmethylcellulose
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 3 4 ( 2 0 0 8 ) 274–280
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/ejps
Controlled poorly soluble drug release from solid self-microemulsifying formulations with high viscosity hydroxypropylmethylcellulose Tao Yi, Jiangling Wan, Huibi Xu, Xiangliang Yang ∗ College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, China
a r t i c l e
i n f o
a b s t r a c t
Article history:
The objective of this work was the development of a controlled release system based
Received 4 March 2008
on self-microemulsifying mixture aimed for oral delivery of poorly water-soluble drugs.
Received in revised form
HPMC-based particle formulations were prepared by spray drying containing a model drug
18 April 2008
(nimodipine) of low water solubility and hydroxypropylmethylcellulose (HPMC) of high vis-
Accepted 30 April 2008
cosity. One type of formulations contained nimodipine mixed with HPMC and the other
Published on line 4 May 2008
type of formulations contained HPMC and nimodipine dissolved in a self-microemulsifying system (SMES) consisting of ethyl oleate, Cremophor® RH 40 and Labrasol® . Based on inves-
Keywords:
tigation by transmission electron microscopy (TEM), scanning electron microscopy (SEM),
Controlled release
differential scanning calorimetry (DSC) and X-ray powder diffraction, differences were found
Self-microemulsifying
in the particle structure between both types of formulations. In vitro release was performed
Poorly soluble drugs
and characterized by the power law. Nimodipine release from both types of formulations
Spray drying
showed a controlled release profile and the two power law parameters, n and K, correlated
Hydroxypropylmethylcellulose
to the viscosity of HPMC. The parameters were also influenced by the presence of SMES. For the controlled release solid SMES, oil droplets containing dissolved nimodipine diffused out of HPMC matrices following exposure to aqueous media. Thus, it is possible to control the in vitro release of poorly soluble drugs from solid oral dosage forms containing SMES. © 2008 Elsevier B.V. All rights reserved.
1.
Introduction
In recent years, increasing attention has been focused on solid self-emulsifying formulations (S-SEF) (Newton et al., 2001, 2007; Nazzal et al., 2002; Attama et al., 2003; Franceschinis et al., 2005; Abdalla and Mader, 2007), which were prepared by incorporating a liquid self-emulsifying formulation (SEF) into a solid dosage form, combining the advantages of SEF with those of a solid dosage form and overcoming the shortcomings of liquid formulations (Nazzal and Khan, 2006). S-SEF reported in the literature typically could release a poorly soluble drug from the solid formulation in an imme-
∗
Corresponding author. Tel.: +86 27 87794520; fax: +86 27 87794517. E-mail address: [email protected] (X. Yang). 0928-0987/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2008.04.010
diate release pattern, which may be not fit for poorly soluble drugs that require frequent dosing. While S-SEF has shown a reasonable success in improving oral bioavailability of poorly soluble drugs (Kim et al., 2001; Tuleu et al., 2004), the utility of such a system in controlling the release rate of poorly soluble drugs needs to be studied further. Only few investigations were reported that combine the characteristics of controlled release and SEF. Nazzal and Khan (2006) reported that a eutectic-based self-nanoemulsified formulation of ubiquinone was incorporated into a tablet dosage form and the drug release from this tablet dosage form could be controlled by the addition of microcrystalline cellulose of
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 3 4 ( 2 0 0 8 ) 274–280
finer particle size and colloidal silicates. Another most recent study prepared pellets containing self-emulsifying mixtures by extrusion/spheronization and subsequently coated the pellets with a polymer film to control the release rate of drugs (Serratoni et al., 2007). In our previous study, it has been shown that it is possible to prepare a solid self-microemulsifying formulation for oral poorly water-soluble drug by spray drying, using a watersoluble solid carrier, and that this formulation was equally bioequivalent in rabbits to the same drug SEF administered as a liquid dosage form. It was also suggested that different solid carrier resulted in different droplet size of reconstituted microemulsions, which has been shown to have an important influence on the drug release from S-SEF (Kim et al., 2001). Thus, it could be surmised that spray-dried S-SEF using solid carrier material with different effect on controlling the drug release could behave differently in the drug release pattern. Hydroxypropylmethylcellulose (HPMC) is the most important hydrophilic carrier material used widely as matrices for oral controlled-release formulations (Colombo, 1993; Li et al., 2005). Upon contact with aqueous media, hydration takes place and HPMC matrices form a gel layer to achieve controlled drug release. Nimodipine is a dihydropyridine calcium antagonist, with a strong antispastic action on cerebral arteries used in the treatment of cerebrovascular spasm, stroke and migraine (Langley and Sorkin, 1989). Nimodipine occurs in two polymorphic forms. The intrinsic solubilities of both modifications are 0.86 and 0.44 g/ml at 37 ◦ C, respectively (Grunenberg et al., 1995). Due to lower oral bioavailability and frequent dosing, nimodipine could be considered a good candidate for controlled-release self-microemulsifying drug delivery. The objective of the present study was therefore to develop controlled-release S-SEF by spray drying, using different viscosity HPMC as solid carriers and nimodipine as the model drug. Reconstitution properties of the spray-dried powders were investigated by transmission electron microscopy (TEM), and the surface characterization and inner physical structure of the powders were performed by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction. Based on these results, potential structures of the S-SEF particle and the HPMC particle without self-emulsifying mixtures were supposed. Furthermore, the in vitro release of the model drug from the S-SEF was compared with that from the corresponding HPMC particle formulations without self-emulsifying ingredients. All the in vitro release profiles were characterized by the power law (Korsmeyer et al., 1983; Siepmann and Peppas, 2001) to explore the underlying mechanisms.
2.
Materials and methods
2.1.
Materials
275
Ludwigshafen, Germany) and Labrasol® (saturated polyglycolysed C6 –C14 glycerides, where C8 is 58.1% and C10 is 39.8%, from Gattefosee Corp., France) (63:30:7, w/w). HPMC of three viscosity grade (Methocel® K4M Premium CR EP, K15M Premium CR EP, and K100M Premium CR EP) were Dow Chemicals products and kindly gifted by Shanghai Colorcon Corp., Ltd. Other chemicals were of HPLC or analytical grade.
2.2.
Methods
2.2.1. Preparation of S-SEF and HPMC particle formulations Aqueous solutions containing different viscosity HPMC as the matrix material were prepared. Nimodipine was dispersed into the mixture of oil and surfactants by gentle stirring and vortex mixing at 37 ◦ C until completely dissolved. Nimodipine dissolved in SEF or pure nimodipine powders were then added to the HPMC solution respectively with constant stirring using a high-speed stirrer (Model 1001, Shanghai Weiyu Corp., China) for 20 min at 6000 rpm. The mixtures obtained ¨ were spray dried with a Buchi mini spray dryer B-191 appara¨ tus (Buchi, Switzerland) under the following conditions: inlet temperature, 150 ◦ C; outlet temperature, 70 ◦ C; aspiration, 85%; drying air flow, 500 nl/h; feeding rate of the emulsion, 10 ml/min. The formulations before spray drying are given in Table 1.
2.2.2.
Reconstitution properties of S-SEF
S-SEF (100 mg) were dispersed with 20 ml of distilled water and incubated at 37 ◦ C for 2 h. Then samples were withdrawn and investigated by the transmission electron microscope (TEM, Tecnai G2 20, FEI, The Netherlands). TEM was conducted with negative staining of phosphotungstic acid (PTA) solution (1%, w/v) and dried in air at room temperature before loaded in the microscope.
2.2.3.
Surface characterization of S-SEF
The surface morphologies of the S-SEF particle (formulation C) and the HPMC particle without self-emulsifying mixtures (formulation F) were examined by SEM with a FEI Sirion-200 scanning electron microscope (FEI, the Netherlands), operating at 5 kV. Prior to microscopy, every sample was coated with a thin layer of gold.
2.2.4. Characterization of inner physical structure of S-SEF 2.2.4.1. DSC. The physical states of nimodipine in the six formulations were investigated by the differential scanning calorimetry thermogram analysis (DSC822e , METTLER TOLEDO, Switzerland). Each sample (about 4.00 mg) was placed in standard aluminum pans, and dry nitrogen was used as effluent gas. All samples were scanned at a temperature ramp speed of 5 ◦ C/min and the heat flow from 0 to 150 ◦ C.
2.2.4.2. X-ray powder diffraction. To further verify the physiNimodipine was purchased from Kaifeng Pharmaceutical Corp. (Henan, China). Based on previous researches (Tu et al., 2005), the liquid SEF consisted of ethyl oleate (Shanghai Chemical Reagent Corporation, Shanghai, China), Polyoxyl 40 hydrogenated castor oil 40 (Cremophor® RH 40, BASF Corp.,
cal state of nimodipine in the six formulations, X-ray powder scattering measurements were performed with an X’Pert PRO diffractometer (PANalytical, The Netherlands). A voltage of 40 kV and a current of 40 mA for the generator were employed with Cu as the tube anode material. The powders were
276
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 3 4 ( 2 0 0 8 ) 274–280
Table 1 – Composition of HPMC/SEF particle formulations before spray drying Formulation
Ingredients (g) Nimodipine
A B C D E F
0.4 0.4 0.4 0.4 0.4 0.4
SEF 7.6 7.6 7.6 – – –
HPMC K4M 10 – – 10 – –
exposed to a Cu K radiation, over a range of 2 angles from 10◦ to 90◦ , at an angular speed of 2◦ (2)/min, a sampling interval of 0.02◦ .
2.2.5.
HPMC K15M
HPMC K100M
– 10 – – 10 –
Water
– – 10 – – 10
1000 1000 1000 1000 1000 1000
kinetic constant in the incorporating structure and geometric characteristics of the release device, and n is the release exponent characterizing the mechanism of drug release.
In vitro release test
Release tests were performed with Chinese Pharmacopoeia (2005 ED.) Method II, paddle method, in 900 ml of pH 4.5 acetate buffer containing 0.05% (w/v) of sodium dodecyl sulfate (SDS), at 37 ◦ C with the paddle rotating at 75 rpm (He et al., 2004). 5 ml of samples for analysis was collected at specific time intervals through filters and an equal volume of blank medium was added to keep constant volume. The concentration of nimodipine was determined by reversed phase HPLC (Agilent 1100 series, Agilent, USA). The column was a Lichrospher C18 column (5 m, 4.6 mm i.d. × 25 cm). A mobile phase consisted of acetonitrile and 0.05 mol/l ammonium acetate (65:35, v/v). The flow rate was 1 ml/min, and the effluents were monitored at 360 nm. The spray-dried formulations containing a constant quantity of nimodipine were filled into hard gelatin capsules for release test, respectively. All release tests were performed in triplicates. All the in vitro release profiles were characterized by the power law (Eq. (1)) (Korsmeyer et al., 1983; Siepmann and Peppas, 2001). Release parameters, the time of 10% (T0.1 ), 50% (T0.5 ) and 80% (T0.8 ) drug release, were also calculated from this equation: Mt = Ktn M∞
(1)
where Mt and M∞ are the cumulative amounts of drug released at time t and infinite time, respectively, K is the
3.
Results and discussion
3.1.
Reconstitution properties of S-SEF
TEM micrograph (Fig. 1) shows that the reconstituted microemulsions were released from S-SEF when exposed to aqueous media. The microemulsions from S-SEF using different viscosity HPMC as solid carriers had shown a similar droplet size, less than 100 nm, regardless of the viscosity of HPMC. Thus, it seemed that the S-SEF preserved the selfemulsification performance of the liquid SEF and that the viscosity of HPMC had no remarkable effect on the droplet size of reconstituted microemulsions.
3.2.
Surface characterization of S-SEF
Fig. 2 shows the scanning electron micrographs of the S-SEF particle (formulation C) and the HPMC particle without selfemulsifying mixtures (formulation F). While both types of the particles showed a satisfactory regular spherical shape, on the particle surface of the former there were deep and abundant dents (Fig. 2a) and the particle surface of the latter was smoother (Fig. 2c). Moreover, on the particle surface of the former there were plenty of micropores, which size was less than 100 nm (Fig. 2b). However, these micropores were not seen on the particle surface of the latter (Fig. 2d). It was probably due
Fig. 1 – TEM micrographs of the reconstituted microemulsions released from formulation A (a), formulation B (b), and formulation C (c), with negative staining of phosphotungstic acid (bar = 200 nm).
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 3 4 ( 2 0 0 8 ) 274–280
277
Fig. 2 – Scanning electron microphotographs of formulation C (a: whole particle; b: surface) and formulation F (c: whole particle; d: surface).
to the only presence of oil and surfactants in the former formulation.
3.3. S-SEF
Characterization of inner physical structure of
DSC curves of pure nimodipine powder and all the formulations are shown in Fig. 3. Nimodipine crystallizes in two polymorphic forms (Grunenberg et al., 1995). Modification I
Fig. 3 – DSC curves of pure nimodipine powder and formulation A–F.
melts at 124 ◦ C and crystallizes as the racemic compound. Modification II melts at 116 ◦ C and is a conglomerate of two pure enantiomers. The mixture of the two modifications usually shows three endothermic peaks (Fig. 3, curve nimodipine). These endothermic peaks disappeared in the curves of formulations A–C (curves A–C). However, the non-selfmicroemulsifying HPMC particle formulations (formulations D–F) exhibited peaks for nimodipine (curves D–F). It might be explained that self-microemulsifying ingredients inhibited the crystallization of nimodipine. It was further verified by X-ray powder diffractograms in Fig. 4. No peaks representing crystals of nimodipine were seen for formulations A–C (curves A–C), and a few peaks from nimodipine appeared in formulations D–F (curves D–F). It was suggested that nimodipine existed in amorphous state in the S-SEF after fabrication, whereas there were a certain amount of nimodipine in a crystalline state in the non-self-microemulsifying HPMC particle formulations. From the results above (Figs. 1–4), it was possible to suppose potential structures of the S-SEF particle and the HPMC particle without self-emulsifying mixtures (Fig. 5). For the former, nimodipine of amorphous state may be dissolved in oil droplets, which were dispersed in HPMC matrix. Because of absence of the self-microemulsifying ingredients, the latter particle consisted of nimodipine dispersed in HPMC matrix and was without microspores on the surface. These differences in the particle structure could be an explanation for
278
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 3 4 ( 2 0 0 8 ) 274–280
Fig. 4 – X-ray powder diffractometry of pure nimodipine powder and formulation A–F.
Fig. 5 – Potential structures of (a) the spray-dried controlled-release S-SEF particle and (b) the spray-dried HPMC particle without self-emulsifying mixtures.
the difference in the following in vitro release results between both types of formulations.
3.4.
In vitro release test
In order to evaluate the effect of the interaction of HPMC and SEF, nimodipine release from the self-microemulsifying HPMC particle formulations and the non-self-microemulsifying HPMC particle formulations was compared. The in vitro release profiles are given in Fig. 6. Power law correlation results and release parameters of nimodipine (T0.1 , T0.5 and T0.8 ) are reported in Table 2. Despite the differences in the power law parameters and release parameters, nimodipine release from both types of formulations showed a controlled release profile. Because HPMC particles of higher viscosity grades swell slower and produce swollen particles of smaller volumes (Panomsuk et al., 1995), matrices made of HPMC with higher viscosity grades will show slower release rates than those made of HPMC with lower viscosity grades (Campos-Aldrete
Fig. 6 – Experimental nimodipine release data (symbols) and the power law fitting (lines).
279
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 3 4 ( 2 0 0 8 ) 274–280
Table 2 – Power law correlation and release parameters of nimodipine from HPMC/SEF particle formulations Formulation
Power law Time span (h)
A B C D E F
0.5–5 0.5–8 0.5–8 0.5–12 1–12 1–12
Release parameters
K (S.E.)
n (S.E.)
r
T0.1 (h)
T0.5 (h)
T0.8 (h)
0.5125 (0.0121) 0.3507 (0.0141) 0.1120 (0.0087) 0.0544 (0.0054) 0.0515 (0.0085) 0.0486 (0.0120)
0.4213 (0.0204) 0.5066 (0.0251) 0.9616 (0.0437) 0.8732 (0.0442) 0.8489 (0.0752) 0.8391 (0.1129)
0.9928 0.9907 0.9938 0.9941 0.9843 0.9596
0.02 0.08 0.89 2.01 2.19 2.36
0.94 2.01 4.74 >12 >12 >12
2.88 5.09 7.72 >12 >12 >12
and Villafuerte-Robles, 1997), as has been observed in this study for the non-self-microemulsifying HPMC particle formulations (formulations D–F) with K values decreasing by increasing viscosity grade of HPMC. The same relationship was found with the self-microemulsifying HPMC particle formulations (formulations A–C). However, K values of the self-microemulsifying HPMC particle formulations were much bigger than those of the corresponding formulations without self-emulsifying ingredients. As K is a constant reflecting structure and geometric characteristics of HPMC matrix and the particle of both types of formulations showed the same spherical shape, the increased K value was probably due to the presence of the self-microemulsifying ingredients resulting in change in the particle structure (see Fig. 5). Diffusion, swelling and erosion are the most important drug release mechanisms of controlled release products like HPMC matrices (Langer and Peppas, 1983). Regarding a poorly soluble drug, its release from the HPMC matrices was controlled by mechanism of erosion (Ford et al., 1987; Tahara et al., 1996), which was verified in the present study for the non-selfmicroemulsifying HPMC particle formulations (formulations D–F) with n values ranging from 0.83 to 0.88. In contrast, n values of formulation A and B were 0.4213 and 0.5066, respectively. It was also probably due to the differences in the particle structure. In the case of the non-self-microemulsifying HPMC particle formulations, dissolved and non-dissolved nimodipine coexisted within HPMC matrices. As non-dissolved drug was not available for diffusion (Siepmann and Peppas, 2001), nimodipine release rate was slower than that of the selfmicroemulsifying HPMC particle and the main rate limiting factor for the nimodipine release was erosion of HPMC matrix. In the case of the self-microemulsifying HPMC particle formulations, it was possible that oil droplets containing dissolved nimodipine diffused out of HPMC matrices following exposure to aqueous media. For the formulation C, n value of 0.9616, near to 1.0, showed an approximately zero-order release. It might be the subsequence of retardarce of HPMC with the highest viscosity grade (Methocel® K100M). In addition, plenty of micropores on the particle surface could expedite the imbibitions of water and the diffusion of oil droplets. Thus, lag time (T0.1 ) values of the self-microemulsifying HPMC particle formulations were smaller than those of the formulations without self-microemulsifying ingredients.
4.
Conclusion
This investigation has shown that it is possible to control the release of a poorly water-soluble drug from the solid self-
microemulsifying formulation by employing high viscosity HPMC as solid carrier to modify the drug release. The in vitro release tests showed a controlled release profile and the power law parameters correlated to the viscosity of HPMC. TEM micrographs illustrated that the S-SEF could release reconstituted microemulsions when contact with water. From results of SEM, DSC and X-ray powder diffraction, it was possible to suppose potential structures of the S-SEF particle and the nonself-emulsifying HPMC particle. The differences in the particle structures between both types of formulations resulted in the differences in the in vitro release results. The power law parameters (n and K) were influenced by the presence of SEF. It was possible that oil droplets containing dissolved nimodipine diffused out of HPMC matrices following the controlled release solid SEF exposure to aqueous media. Thus, this formulation approach provides the possibility of combining the characteristics of controlled release and self-emulsifying formulations for the biopharmaceutical requirements of oral poorly water-soluble drugs. In the future, further investigations are necessary to evaluate the bioavailability of such formulations.
Acknowledgements This work was supported by National Basic Research Program of China (Grant No. 2007CB935800). The authors are grateful to BASF for the generous gift of Cremophor® RH 40 and to Shanghai Colorcon Corp., Ltd., for kindly providing HPMC.
references
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available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/ejps
Controlled poorly soluble drug release from solid self-microemulsifying formulations with high viscosity hydroxypropylmethylcellulose Tao Yi, Jiangling Wan, Huibi Xu, Xiangliang Yang ∗ College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, China
a r t i c l e
i n f o
a b s t r a c t
Article history:
The objective of this work was the development of a controlled release system based
Received 4 March 2008
on self-microemulsifying mixture aimed for oral delivery of poorly water-soluble drugs.
Received in revised form
HPMC-based particle formulations were prepared by spray drying containing a model drug
18 April 2008
(nimodipine) of low water solubility and hydroxypropylmethylcellulose (HPMC) of high vis-
Accepted 30 April 2008
cosity. One type of formulations contained nimodipine mixed with HPMC and the other
Published on line 4 May 2008
type of formulations contained HPMC and nimodipine dissolved in a self-microemulsifying system (SMES) consisting of ethyl oleate, Cremophor® RH 40 and Labrasol® . Based on inves-
Keywords:
tigation by transmission electron microscopy (TEM), scanning electron microscopy (SEM),
Controlled release
differential scanning calorimetry (DSC) and X-ray powder diffraction, differences were found
Self-microemulsifying
in the particle structure between both types of formulations. In vitro release was performed
Poorly soluble drugs
and characterized by the power law. Nimodipine release from both types of formulations
Spray drying
showed a controlled release profile and the two power law parameters, n and K, correlated
Hydroxypropylmethylcellulose
to the viscosity of HPMC. The parameters were also influenced by the presence of SMES. For the controlled release solid SMES, oil droplets containing dissolved nimodipine diffused out of HPMC matrices following exposure to aqueous media. Thus, it is possible to control the in vitro release of poorly soluble drugs from solid oral dosage forms containing SMES. © 2008 Elsevier B.V. All rights reserved.
1.
Introduction
In recent years, increasing attention has been focused on solid self-emulsifying formulations (S-SEF) (Newton et al., 2001, 2007; Nazzal et al., 2002; Attama et al., 2003; Franceschinis et al., 2005; Abdalla and Mader, 2007), which were prepared by incorporating a liquid self-emulsifying formulation (SEF) into a solid dosage form, combining the advantages of SEF with those of a solid dosage form and overcoming the shortcomings of liquid formulations (Nazzal and Khan, 2006). S-SEF reported in the literature typically could release a poorly soluble drug from the solid formulation in an imme-
∗
Corresponding author. Tel.: +86 27 87794520; fax: +86 27 87794517. E-mail address: [email protected] (X. Yang). 0928-0987/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2008.04.010
diate release pattern, which may be not fit for poorly soluble drugs that require frequent dosing. While S-SEF has shown a reasonable success in improving oral bioavailability of poorly soluble drugs (Kim et al., 2001; Tuleu et al., 2004), the utility of such a system in controlling the release rate of poorly soluble drugs needs to be studied further. Only few investigations were reported that combine the characteristics of controlled release and SEF. Nazzal and Khan (2006) reported that a eutectic-based self-nanoemulsified formulation of ubiquinone was incorporated into a tablet dosage form and the drug release from this tablet dosage form could be controlled by the addition of microcrystalline cellulose of
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 3 4 ( 2 0 0 8 ) 274–280
finer particle size and colloidal silicates. Another most recent study prepared pellets containing self-emulsifying mixtures by extrusion/spheronization and subsequently coated the pellets with a polymer film to control the release rate of drugs (Serratoni et al., 2007). In our previous study, it has been shown that it is possible to prepare a solid self-microemulsifying formulation for oral poorly water-soluble drug by spray drying, using a watersoluble solid carrier, and that this formulation was equally bioequivalent in rabbits to the same drug SEF administered as a liquid dosage form. It was also suggested that different solid carrier resulted in different droplet size of reconstituted microemulsions, which has been shown to have an important influence on the drug release from S-SEF (Kim et al., 2001). Thus, it could be surmised that spray-dried S-SEF using solid carrier material with different effect on controlling the drug release could behave differently in the drug release pattern. Hydroxypropylmethylcellulose (HPMC) is the most important hydrophilic carrier material used widely as matrices for oral controlled-release formulations (Colombo, 1993; Li et al., 2005). Upon contact with aqueous media, hydration takes place and HPMC matrices form a gel layer to achieve controlled drug release. Nimodipine is a dihydropyridine calcium antagonist, with a strong antispastic action on cerebral arteries used in the treatment of cerebrovascular spasm, stroke and migraine (Langley and Sorkin, 1989). Nimodipine occurs in two polymorphic forms. The intrinsic solubilities of both modifications are 0.86 and 0.44 g/ml at 37 ◦ C, respectively (Grunenberg et al., 1995). Due to lower oral bioavailability and frequent dosing, nimodipine could be considered a good candidate for controlled-release self-microemulsifying drug delivery. The objective of the present study was therefore to develop controlled-release S-SEF by spray drying, using different viscosity HPMC as solid carriers and nimodipine as the model drug. Reconstitution properties of the spray-dried powders were investigated by transmission electron microscopy (TEM), and the surface characterization and inner physical structure of the powders were performed by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction. Based on these results, potential structures of the S-SEF particle and the HPMC particle without self-emulsifying mixtures were supposed. Furthermore, the in vitro release of the model drug from the S-SEF was compared with that from the corresponding HPMC particle formulations without self-emulsifying ingredients. All the in vitro release profiles were characterized by the power law (Korsmeyer et al., 1983; Siepmann and Peppas, 2001) to explore the underlying mechanisms.
2.
Materials and methods
2.1.
Materials
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Ludwigshafen, Germany) and Labrasol® (saturated polyglycolysed C6 –C14 glycerides, where C8 is 58.1% and C10 is 39.8%, from Gattefosee Corp., France) (63:30:7, w/w). HPMC of three viscosity grade (Methocel® K4M Premium CR EP, K15M Premium CR EP, and K100M Premium CR EP) were Dow Chemicals products and kindly gifted by Shanghai Colorcon Corp., Ltd. Other chemicals were of HPLC or analytical grade.
2.2.
Methods
2.2.1. Preparation of S-SEF and HPMC particle formulations Aqueous solutions containing different viscosity HPMC as the matrix material were prepared. Nimodipine was dispersed into the mixture of oil and surfactants by gentle stirring and vortex mixing at 37 ◦ C until completely dissolved. Nimodipine dissolved in SEF or pure nimodipine powders were then added to the HPMC solution respectively with constant stirring using a high-speed stirrer (Model 1001, Shanghai Weiyu Corp., China) for 20 min at 6000 rpm. The mixtures obtained ¨ were spray dried with a Buchi mini spray dryer B-191 appara¨ tus (Buchi, Switzerland) under the following conditions: inlet temperature, 150 ◦ C; outlet temperature, 70 ◦ C; aspiration, 85%; drying air flow, 500 nl/h; feeding rate of the emulsion, 10 ml/min. The formulations before spray drying are given in Table 1.
2.2.2.
Reconstitution properties of S-SEF
S-SEF (100 mg) were dispersed with 20 ml of distilled water and incubated at 37 ◦ C for 2 h. Then samples were withdrawn and investigated by the transmission electron microscope (TEM, Tecnai G2 20, FEI, The Netherlands). TEM was conducted with negative staining of phosphotungstic acid (PTA) solution (1%, w/v) and dried in air at room temperature before loaded in the microscope.
2.2.3.
Surface characterization of S-SEF
The surface morphologies of the S-SEF particle (formulation C) and the HPMC particle without self-emulsifying mixtures (formulation F) were examined by SEM with a FEI Sirion-200 scanning electron microscope (FEI, the Netherlands), operating at 5 kV. Prior to microscopy, every sample was coated with a thin layer of gold.
2.2.4. Characterization of inner physical structure of S-SEF 2.2.4.1. DSC. The physical states of nimodipine in the six formulations were investigated by the differential scanning calorimetry thermogram analysis (DSC822e , METTLER TOLEDO, Switzerland). Each sample (about 4.00 mg) was placed in standard aluminum pans, and dry nitrogen was used as effluent gas. All samples were scanned at a temperature ramp speed of 5 ◦ C/min and the heat flow from 0 to 150 ◦ C.
2.2.4.2. X-ray powder diffraction. To further verify the physiNimodipine was purchased from Kaifeng Pharmaceutical Corp. (Henan, China). Based on previous researches (Tu et al., 2005), the liquid SEF consisted of ethyl oleate (Shanghai Chemical Reagent Corporation, Shanghai, China), Polyoxyl 40 hydrogenated castor oil 40 (Cremophor® RH 40, BASF Corp.,
cal state of nimodipine in the six formulations, X-ray powder scattering measurements were performed with an X’Pert PRO diffractometer (PANalytical, The Netherlands). A voltage of 40 kV and a current of 40 mA for the generator were employed with Cu as the tube anode material. The powders were
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Table 1 – Composition of HPMC/SEF particle formulations before spray drying Formulation
Ingredients (g) Nimodipine
A B C D E F
0.4 0.4 0.4 0.4 0.4 0.4
SEF 7.6 7.6 7.6 – – –
HPMC K4M 10 – – 10 – –
exposed to a Cu K radiation, over a range of 2 angles from 10◦ to 90◦ , at an angular speed of 2◦ (2)/min, a sampling interval of 0.02◦ .
2.2.5.
HPMC K15M
HPMC K100M
– 10 – – 10 –
Water
– – 10 – – 10
1000 1000 1000 1000 1000 1000
kinetic constant in the incorporating structure and geometric characteristics of the release device, and n is the release exponent characterizing the mechanism of drug release.
In vitro release test
Release tests were performed with Chinese Pharmacopoeia (2005 ED.) Method II, paddle method, in 900 ml of pH 4.5 acetate buffer containing 0.05% (w/v) of sodium dodecyl sulfate (SDS), at 37 ◦ C with the paddle rotating at 75 rpm (He et al., 2004). 5 ml of samples for analysis was collected at specific time intervals through filters and an equal volume of blank medium was added to keep constant volume. The concentration of nimodipine was determined by reversed phase HPLC (Agilent 1100 series, Agilent, USA). The column was a Lichrospher C18 column (5 m, 4.6 mm i.d. × 25 cm). A mobile phase consisted of acetonitrile and 0.05 mol/l ammonium acetate (65:35, v/v). The flow rate was 1 ml/min, and the effluents were monitored at 360 nm. The spray-dried formulations containing a constant quantity of nimodipine were filled into hard gelatin capsules for release test, respectively. All release tests were performed in triplicates. All the in vitro release profiles were characterized by the power law (Eq. (1)) (Korsmeyer et al., 1983; Siepmann and Peppas, 2001). Release parameters, the time of 10% (T0.1 ), 50% (T0.5 ) and 80% (T0.8 ) drug release, were also calculated from this equation: Mt = Ktn M∞
(1)
where Mt and M∞ are the cumulative amounts of drug released at time t and infinite time, respectively, K is the
3.
Results and discussion
3.1.
Reconstitution properties of S-SEF
TEM micrograph (Fig. 1) shows that the reconstituted microemulsions were released from S-SEF when exposed to aqueous media. The microemulsions from S-SEF using different viscosity HPMC as solid carriers had shown a similar droplet size, less than 100 nm, regardless of the viscosity of HPMC. Thus, it seemed that the S-SEF preserved the selfemulsification performance of the liquid SEF and that the viscosity of HPMC had no remarkable effect on the droplet size of reconstituted microemulsions.
3.2.
Surface characterization of S-SEF
Fig. 2 shows the scanning electron micrographs of the S-SEF particle (formulation C) and the HPMC particle without selfemulsifying mixtures (formulation F). While both types of the particles showed a satisfactory regular spherical shape, on the particle surface of the former there were deep and abundant dents (Fig. 2a) and the particle surface of the latter was smoother (Fig. 2c). Moreover, on the particle surface of the former there were plenty of micropores, which size was less than 100 nm (Fig. 2b). However, these micropores were not seen on the particle surface of the latter (Fig. 2d). It was probably due
Fig. 1 – TEM micrographs of the reconstituted microemulsions released from formulation A (a), formulation B (b), and formulation C (c), with negative staining of phosphotungstic acid (bar = 200 nm).
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277
Fig. 2 – Scanning electron microphotographs of formulation C (a: whole particle; b: surface) and formulation F (c: whole particle; d: surface).
to the only presence of oil and surfactants in the former formulation.
3.3. S-SEF
Characterization of inner physical structure of
DSC curves of pure nimodipine powder and all the formulations are shown in Fig. 3. Nimodipine crystallizes in two polymorphic forms (Grunenberg et al., 1995). Modification I
Fig. 3 – DSC curves of pure nimodipine powder and formulation A–F.
melts at 124 ◦ C and crystallizes as the racemic compound. Modification II melts at 116 ◦ C and is a conglomerate of two pure enantiomers. The mixture of the two modifications usually shows three endothermic peaks (Fig. 3, curve nimodipine). These endothermic peaks disappeared in the curves of formulations A–C (curves A–C). However, the non-selfmicroemulsifying HPMC particle formulations (formulations D–F) exhibited peaks for nimodipine (curves D–F). It might be explained that self-microemulsifying ingredients inhibited the crystallization of nimodipine. It was further verified by X-ray powder diffractograms in Fig. 4. No peaks representing crystals of nimodipine were seen for formulations A–C (curves A–C), and a few peaks from nimodipine appeared in formulations D–F (curves D–F). It was suggested that nimodipine existed in amorphous state in the S-SEF after fabrication, whereas there were a certain amount of nimodipine in a crystalline state in the non-self-microemulsifying HPMC particle formulations. From the results above (Figs. 1–4), it was possible to suppose potential structures of the S-SEF particle and the HPMC particle without self-emulsifying mixtures (Fig. 5). For the former, nimodipine of amorphous state may be dissolved in oil droplets, which were dispersed in HPMC matrix. Because of absence of the self-microemulsifying ingredients, the latter particle consisted of nimodipine dispersed in HPMC matrix and was without microspores on the surface. These differences in the particle structure could be an explanation for
278
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Fig. 4 – X-ray powder diffractometry of pure nimodipine powder and formulation A–F.
Fig. 5 – Potential structures of (a) the spray-dried controlled-release S-SEF particle and (b) the spray-dried HPMC particle without self-emulsifying mixtures.
the difference in the following in vitro release results between both types of formulations.
3.4.
In vitro release test
In order to evaluate the effect of the interaction of HPMC and SEF, nimodipine release from the self-microemulsifying HPMC particle formulations and the non-self-microemulsifying HPMC particle formulations was compared. The in vitro release profiles are given in Fig. 6. Power law correlation results and release parameters of nimodipine (T0.1 , T0.5 and T0.8 ) are reported in Table 2. Despite the differences in the power law parameters and release parameters, nimodipine release from both types of formulations showed a controlled release profile. Because HPMC particles of higher viscosity grades swell slower and produce swollen particles of smaller volumes (Panomsuk et al., 1995), matrices made of HPMC with higher viscosity grades will show slower release rates than those made of HPMC with lower viscosity grades (Campos-Aldrete
Fig. 6 – Experimental nimodipine release data (symbols) and the power law fitting (lines).
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Table 2 – Power law correlation and release parameters of nimodipine from HPMC/SEF particle formulations Formulation
Power law Time span (h)
A B C D E F
0.5–5 0.5–8 0.5–8 0.5–12 1–12 1–12
Release parameters
K (S.E.)
n (S.E.)
r
T0.1 (h)
T0.5 (h)
T0.8 (h)
0.5125 (0.0121) 0.3507 (0.0141) 0.1120 (0.0087) 0.0544 (0.0054) 0.0515 (0.0085) 0.0486 (0.0120)
0.4213 (0.0204) 0.5066 (0.0251) 0.9616 (0.0437) 0.8732 (0.0442) 0.8489 (0.0752) 0.8391 (0.1129)
0.9928 0.9907 0.9938 0.9941 0.9843 0.9596
0.02 0.08 0.89 2.01 2.19 2.36
0.94 2.01 4.74 >12 >12 >12
2.88 5.09 7.72 >12 >12 >12
and Villafuerte-Robles, 1997), as has been observed in this study for the non-self-microemulsifying HPMC particle formulations (formulations D–F) with K values decreasing by increasing viscosity grade of HPMC. The same relationship was found with the self-microemulsifying HPMC particle formulations (formulations A–C). However, K values of the self-microemulsifying HPMC particle formulations were much bigger than those of the corresponding formulations without self-emulsifying ingredients. As K is a constant reflecting structure and geometric characteristics of HPMC matrix and the particle of both types of formulations showed the same spherical shape, the increased K value was probably due to the presence of the self-microemulsifying ingredients resulting in change in the particle structure (see Fig. 5). Diffusion, swelling and erosion are the most important drug release mechanisms of controlled release products like HPMC matrices (Langer and Peppas, 1983). Regarding a poorly soluble drug, its release from the HPMC matrices was controlled by mechanism of erosion (Ford et al., 1987; Tahara et al., 1996), which was verified in the present study for the non-selfmicroemulsifying HPMC particle formulations (formulations D–F) with n values ranging from 0.83 to 0.88. In contrast, n values of formulation A and B were 0.4213 and 0.5066, respectively. It was also probably due to the differences in the particle structure. In the case of the non-self-microemulsifying HPMC particle formulations, dissolved and non-dissolved nimodipine coexisted within HPMC matrices. As non-dissolved drug was not available for diffusion (Siepmann and Peppas, 2001), nimodipine release rate was slower than that of the selfmicroemulsifying HPMC particle and the main rate limiting factor for the nimodipine release was erosion of HPMC matrix. In the case of the self-microemulsifying HPMC particle formulations, it was possible that oil droplets containing dissolved nimodipine diffused out of HPMC matrices following exposure to aqueous media. For the formulation C, n value of 0.9616, near to 1.0, showed an approximately zero-order release. It might be the subsequence of retardarce of HPMC with the highest viscosity grade (Methocel® K100M). In addition, plenty of micropores on the particle surface could expedite the imbibitions of water and the diffusion of oil droplets. Thus, lag time (T0.1 ) values of the self-microemulsifying HPMC particle formulations were smaller than those of the formulations without self-microemulsifying ingredients.
4.
Conclusion
This investigation has shown that it is possible to control the release of a poorly water-soluble drug from the solid self-
microemulsifying formulation by employing high viscosity HPMC as solid carrier to modify the drug release. The in vitro release tests showed a controlled release profile and the power law parameters correlated to the viscosity of HPMC. TEM micrographs illustrated that the S-SEF could release reconstituted microemulsions when contact with water. From results of SEM, DSC and X-ray powder diffraction, it was possible to suppose potential structures of the S-SEF particle and the nonself-emulsifying HPMC particle. The differences in the particle structures between both types of formulations resulted in the differences in the in vitro release results. The power law parameters (n and K) were influenced by the presence of SEF. It was possible that oil droplets containing dissolved nimodipine diffused out of HPMC matrices following the controlled release solid SEF exposure to aqueous media. Thus, this formulation approach provides the possibility of combining the characteristics of controlled release and self-emulsifying formulations for the biopharmaceutical requirements of oral poorly water-soluble drugs. In the future, further investigations are necessary to evaluate the bioavailability of such formulations.
Acknowledgements This work was supported by National Basic Research Program of China (Grant No. 2007CB935800). The authors are grateful to BASF for the generous gift of Cremophor® RH 40 and to Shanghai Colorcon Corp., Ltd., for kindly providing HPMC.
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