AJPS - Author Template
AJPS - Author Template
AJPS - Author Template
Dear Editor ,
It has not been published elsewhere and that it has not been submitted simultaneously for
publication elsewhere.
Yours Sincerely,
E-mail: zhhundds@163.com
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prolonged period of time both in vitro and in vivo.
2
a
Shenyang Pharmaceutical University, Shenyang 110016, China
b
Gifu Pharmaceutical University, Gifu 502, Japan
*Corresponding author.
Tel.: +86-24-23986353
Acknowledgements
devoted to improving the dissolution rate of the drug and then the controlled release of drug
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from the microspheres. Eu E100 and Aerosil were employed as a solid dispersion base for the
immediate release microspheres, while HP55 and aerosil were employed as a solid dispersion
base for the sustained release microspheres, while ethyl cellulose (EC) was selected as a
1. Introduction
Solid dispersion is one of the most efficient techniques to improve the dissolution rate of
formulations. At present, the solvent method and the melting method are widely used in the
liquid system which was developed by Kawashima in the 1980s [1]. In this system,
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beginning, the spherical crystallization technique was mainly used in direct tabletting
flowability, packability and compressibility [2, 3]. Later on, functional drug devices such as
microspheres [4], microcapsules [5], microballoons [6], and biodegradable nanospheres [7]
crystallization techniques involving the introduction of a functional polymer into the system.
In previous studies we have designed sustained release mirospheres for a water soluble drug
[8], a water insoluble drug [9] and an oily drug [10] using this technique.
Nimodipine (Shandong Xinhua Pharmaceutical Co. Ltd. China) was used as a model
phthalate (HPMCP, Shinetsu Chemical Co. Ltd. Japan) were selected as a dispersion base,
aerosol (pass 400 mesh, Qingdao Ocean Chemical Co. Ltd. China) as a absorbent was added
to promote drug dispersion and increase the mass for compact consolidation of the resultant
microspheres. Ethylcellulose (EC 10 cp, Shanghai Colorcon Co. Ltd. China) was used as a
retarding agent to control the drug release. Acetone was selected as a good solvent, distilled
water was used as a poor solvent, and dichloromethane (Shenyang Chemical Co. Ltd.) was
chosen as a bridging agent due to its good wettability with regard to both the drug and
polymers, and its immisciblity with the poor solvent. A small amount of surfactant, such as
poloxamer (F188, Shenyang Pharmaceutical Factory, China), was added to the poor solvent
in order prevent sticking to the baffle or the agitator. NimotopTM (Bayer com., Germany) was
selected as a reference formulation for the relative bioavailability test. All solvents used were
of analytical grade.
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Nimodipine (0.6 g) and Eu E100 (1.2, 2.4 and 3.6 g) were dissolved in a mixture of good
solvent (acetone, 10 ml) and bridging liquid (dichloromethane, 2.5 ml), and the dispersion
agent (aerosol, 1.2, 2.4 and 3.6 ml) was added to the drug-polymer solution system. The poor
solvent (distilled water, 150 ml) containing poloxamer (4%, 3 ml) was placed in a 500 ml
flask fitted with three baffles to improve agitation during the agglomeration process. When
the drug-polymer solution was added to the poor solvent at a temperature of 25 C and 400–
600 r/min stirring with a propeller type agitator, the drug-polymer solution immediately
dispersed as droplets to form a quasi o/w emulsion, and the emulsion droplets gradually
solidified along with the diffusion of the good solvent from the droplets into the poor solvent.
Finally, the coprecipitated microspheres of the drug-polymer were filtered and dried in oven
at 50 C for more than 6 h to reduce the residual solvent in accord with the tolerance given in
Ch.P.
In the preparation of the sustained release microspheres, the process and the equipment was
the same as that used for the immediate release microspheres. The formulations were as
follows: Nimodipine: HP55: aerosol: EC = 1: 2: 7: (0.5, 0.625 and 0.75) were dissolved in the
mixture of good solvent (acetone, 11 ml) and bridging liquid (dichloromethane, 7 ml), then
the drug-polymer solution was poured into the poor solvent (distilled water, 200 ml) with the
temperature controlled at 15–20 C under stirring at 700 r/min. After agitating the system for
20–40 min, the emulsion droplets gradually solidified through coacervated droplets, and the
resulting microspheres were filtered and dried using the same method as for the immediate
release microspheres.
In this study, acetone and dichloromethane, in which nimodipine is readily soluble, were
used as a good solvent and bridge liquid to dissolve the drug and pH- dependent polymers,
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and distilled water containing 4% (w/v) poloxamer was used as a poor solvent to precipitate
both nimodipine and the pH-dependent polymers. Gradually, the emulsion droplets solidified
along with diffusion of the good solvent, e.g., drug and polymers were coprecipitated in the
liquid was commixed with the good solvent, and when the good solvent in the droplets
diffused into the poor solvent, the residual dichloromethane in the droplets bridged the
aerosil, coprecipitated drug and polymer to form agglomerates. The aerosil acts as a
dispersing agent and mass compactor, because coacervation droplets formed from the drug-
polymer droplets during the solidifying period were very sticky and readily coalesced, while
microspheres. In addition, the aerosol also dramatically improved the drug dispersion,
As discussed above, the mean particle size (D50) or size distribution of the microspheres
was mainly controlled by the agitation speed. The average diameter of the microspheres was
controlled mainly by the agitation speed during the formation of quasi-emulsion droplets
during the initial stage. Fig. 2 shows the change in the D50 of the microspheres with regard to
the stirring speed, i.e., increasing the agitation speed reduced the particle size. It was found
that the temperature of the solvent system also affected the properties of the resulting
particle size, and tended increase the sphericity. In this study, under the optimum conditions
for producing immediate release microspheres, which were determined by the orthogonal
design method, the total recovery was 97%. The micromeritic properties of the resultant
4. Conclusion
By combination of a polymeric crystallization technique and a solid dispersion
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technique, the immediate and sustained release microspheres could be successfully produced
in a solid dispersion state. Aerosil as a drug dispersion agent and fillers helped prevent the
coalescence of sticky polymer droplets during the preparation process, the method was highly
Conflicts of interest
The authors report no conflicts of interest. The authors alone are responsible for the
References
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Figure and Table legends
Fig. 1. Pathological features of specimens of the: (A) anterior mediastinum and (B) hepatic
tumors demonstrate similar morphology as described in the text. (C, D) he key stains for CD5
Figures:
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Fig. 1. Characterizations of formulations: (A) IR spectra; (B) DSC curves; (C) XRD
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Figure samples
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Tables:
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Table 1 Pharmacokinetic parameters of nimodipine after oral administrations in dogs
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