**4. Fabrication of apatite microcapsules consisted of biomimetic porous bone-like apatite coatings by using apatite nuclei as precursors of apatite**

#### **4.1. Fabrication of microcapsule consisted of porous bone-like apatite**

Drug delivery system (DDS) is one of the most attractive techniques in the medical and pharmaceutical fields. DDS can contributes to chemotherapy that can achieve low side effects because it can achieve an efficient local or controlled release of pharmaceutical drugs. The microcapsules can be filled with pharmaceutical drugs. Hence, the DDS carriers consisted of microcapsules have a possibility to be applied in many kinds of pharmaceutical fields. Apatite has high bioaffinity because it forms bone-like apatite coatings consisted of needle-like fine crystallites on its surface in living body and can avoid immune reaction. From the above idea, it is thought that microcapsules possessing high biocompatibility can be obtained by applying apatite. The porous bone-like apatite microcapsules can be fabricated by the following process [46, 47]:


By this treatment, apatite formation is induced by the apatite nuclei and grows over the whole surface area of the core particles. As a result, porous bone-like apatite coats the whole surface of the particles and apatite microcapsules can be obtained (**Figure 10**). By this method, it is expected to encapsulate various kinds of functional particles or pharmaceutical drugs with apatite.

with 1.5 SBF, whose ion concentrations are 1.5 times in comparison with those of SBF, and apatite nuclei, thereafter, the mixture was treated by ultrasonic vibration to attach apatite nuclei on the surface of the oil droplets. After ethyl acetate was evaporated and removed from the mixture, the solution was kept at 36.5°C for 4 days. **Figure 11** shows SEM micrograph and EDX profile of thus-obtained microcapsules. Spherical particles consisted of needle-like crystals, which characterize bone-like apatite, were observed. In the EDX measurement, phosphorus and calcium, main consistent of apatite, were detected. It is suggested that the apatite nuclei attached on the oil droplets induced formation of bone-like apatite and then the crystal growth of apatite was caused on the surface of the oil droplets. **Figure 12** shows the powder X-ray diffraction (XRD) profile of the obtained apatite microcapsules. It can be seen that the peak positions of the apatite microcapsules corresponded to those of apatite, but shape of the pattern was broad. From this result, it was indicated that bone-like apatite covered the corn

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**4.4. Function of porous bone-like apatite microcapsules: drug release behavior**

The author evaluated the release behavior of ibuprofen contained in corn oil droplets. **Figure 13** shows the temporal change in the concentration of ibuprofen released from porous bone-like apatite microcapsules in phosphate buffer (pH 7.40 at 36.5°C) measured by high-performance liquid chromatography (HPLC). It can be seen that the concentration of

**Figure 11.** (a) SEM micrograph and (b) EDX profile of the porous bone-like apatite microcapsules encapsulating corn oil.

**Figure 12.** XRD profile of the porous bone-like apatite microcapsules encapsulating corn oil.

oil droplets during soaking in SBF.

The development of sustained-release of drug is expected to contribute to have effects of the drug without side effects and reduce the burdens of patients. Porous bone-like apatite formed in SBF has flake-like crystalline structure and porous body [46, 47]. Focusing on these features of porous bone-like apatite, the author has intended to fabricate porous bone-like apatite microcapsules encapsulating various kinds of substances such as PLLA [48], silver [48], silica gel [48, 49], magnetite [50], maghemite [51, 52], agarose gel [53, 54] and corn oil [55]. Among them, the author introduces the details of encapsulation of corn oil in the porous bone-like apatite microcapsules as representative cases in this chapter.

#### **4.2. Porous bone-like apatite microcapsules encapsulating corn oil**

By utilizing surfactant such as albumin, oil droplets in micrometer level can be stabilized in water phase or water droplets in micrometer level can be stabilized in oil phase. The microencapsulation techniques by forming oil or water droplets can achieve an intravenous injection of the droplets containing pharmaceutical drug. As described in this section, the author fabricated porous bone-like apatite microcapsules encapsulating corn oil droplets containing ibuprofen, hydrophobic drug and nonsteroidal anti-inflammatory drug and evaluated the temporal change in release of the ibuprofen in vitro.

#### **4.3. Preparation process of porous bone-like apatite microcapsules encapsulating corn oil**

#### *4.3.1. Fabrication of porous bone-like apatite microcapsules*

Corn oil and ibuprofen were mixed. In order to dissolve ibuprofen in corn oil sufficiently, ethyl acetate was added in the mixture. After albumin aqueous solution was poured, the mixture was treated by ultrasonic vibration, so emulsion was formed. The emulsion was mixed

**Figure 10.** Fabrication process of apatite microcapsules by using apatite nuclei.

with 1.5 SBF, whose ion concentrations are 1.5 times in comparison with those of SBF, and apatite nuclei, thereafter, the mixture was treated by ultrasonic vibration to attach apatite nuclei on the surface of the oil droplets. After ethyl acetate was evaporated and removed from the mixture, the solution was kept at 36.5°C for 4 days. **Figure 11** shows SEM micrograph and EDX profile of thus-obtained microcapsules. Spherical particles consisted of needle-like crystals, which characterize bone-like apatite, were observed. In the EDX measurement, phosphorus and calcium, main consistent of apatite, were detected. It is suggested that the apatite nuclei attached on the oil droplets induced formation of bone-like apatite and then the crystal growth of apatite was caused on the surface of the oil droplets. **Figure 12** shows the powder X-ray diffraction (XRD) profile of the obtained apatite microcapsules. It can be seen that the peak positions of the apatite microcapsules corresponded to those of apatite, but shape of the pattern was broad. From this result, it was indicated that bone-like apatite covered the corn oil droplets during soaking in SBF.

#### **4.4. Function of porous bone-like apatite microcapsules: drug release behavior**

• Apatite nuclei are attached to the surfaces of core particles.

apatite microcapsules as representative cases in this chapter.

temporal change in release of the ibuprofen in vitro.

*4.3.1. Fabrication of porous bone-like apatite microcapsules*

**Figure 10.** Fabrication process of apatite microcapsules by using apatite nuclei.

**corn oil**

**4.2. Porous bone-like apatite microcapsules encapsulating corn oil**

By this treatment, apatite formation is induced by the apatite nuclei and grows over the whole surface area of the core particles. As a result, porous bone-like apatite coats the whole surface of the particles and apatite microcapsules can be obtained (**Figure 10**). By this method, it is expected to encapsulate various kinds of functional particles or pharmaceutical drugs with apatite.

The development of sustained-release of drug is expected to contribute to have effects of the drug without side effects and reduce the burdens of patients. Porous bone-like apatite formed in SBF has flake-like crystalline structure and porous body [46, 47]. Focusing on these features of porous bone-like apatite, the author has intended to fabricate porous bone-like apatite microcapsules encapsulating various kinds of substances such as PLLA [48], silver [48], silica gel [48, 49], magnetite [50], maghemite [51, 52], agarose gel [53, 54] and corn oil [55]. Among them, the author introduces the details of encapsulation of corn oil in the porous bone-like

By utilizing surfactant such as albumin, oil droplets in micrometer level can be stabilized in water phase or water droplets in micrometer level can be stabilized in oil phase. The microencapsulation techniques by forming oil or water droplets can achieve an intravenous injection of the droplets containing pharmaceutical drug. As described in this section, the author fabricated porous bone-like apatite microcapsules encapsulating corn oil droplets containing ibuprofen, hydrophobic drug and nonsteroidal anti-inflammatory drug and evaluated the

**4.3. Preparation process of porous bone-like apatite microcapsules encapsulating** 

Corn oil and ibuprofen were mixed. In order to dissolve ibuprofen in corn oil sufficiently, ethyl acetate was added in the mixture. After albumin aqueous solution was poured, the mixture was treated by ultrasonic vibration, so emulsion was formed. The emulsion was mixed

• The microspheres are soaked in SBF.

22 Recent Advances in Porous Ceramics

The author evaluated the release behavior of ibuprofen contained in corn oil droplets. **Figure 13** shows the temporal change in the concentration of ibuprofen released from porous bone-like apatite microcapsules in phosphate buffer (pH 7.40 at 36.5°C) measured by high-performance liquid chromatography (HPLC). It can be seen that the concentration of

**Figure 11.** (a) SEM micrograph and (b) EDX profile of the porous bone-like apatite microcapsules encapsulating corn oil.

**Figure 12.** XRD profile of the porous bone-like apatite microcapsules encapsulating corn oil.

**Author details**

Takeshi Yabutsuka

University, Japan

**References**

79-92

Address all correspondence to: yabutsuka@energy.kyoto-u.ac.jp

1991;**74**(7):1487-1510. DOI: 10.1111/j.1151-2916.1991.tb07132.x

pp. 209-214. DOI: 10.1142/9781908977168\_0015

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10.1002/jbm.820270805

Department of Fundamental Energy Science, Graduate School of Energy Science, Kyoto

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**Figure 13.** Release behavior of ibuprofen from bone-like apatite microcapsules.

ibuprofen in the buffer did not increase rapidly in a short time but increased gradually. This profile suggested that the porous structure of bone-like apatite microcapsules can gradually release ibuprofen contained in corn oil through the micropores of the apatite coatings.

#### **4.5. Other types of porous bone-like apatite microcapsules**

As described in Section 4.1, this fabrication method for porous bone-like apatite microcapsules was applicable to other kinds of core materials such as encapsulating various kinds of substance such as PLLA [48], silver [48], silica gel [48, 49], magnetite [50], maghemite [51, 52] and agarose gel [53, 54] by optimizing the fabrication condition. In the case of silver, sustained release of silver was attained by existence of porous coatings of bone-like apatite. In the case of silica gel, sustained release of insulin was attained by conducting absorption of insulin solution into the silica-gel matrix [56]. In the case of magnetite, release of magnetite was inhibited in water by existence of the porous apatite coatings. In the case of agarose gel, sustained release of vitamin B12 was attained by conducting insertion of vitamin B12 solution in the apatite microcapsules [53]. In the case of maghemite, in addition, the author successfully achieved enzyme immobilization and collection by combination of bioaffinity of apatite with ferrimagnetism of maghemite.

#### **5. Conclusion**

In this chapter, the author introduced novel biomaterials utilizing porous bone-like apatite formation from apatite nuclei from a viewpoint of bioactive metals, bioactive organic polymers and apatite microcapsules. This methodology has high materials selectivity, and function of apatite nuclei enables us to impart bioactivity to various kinds of materials or to coat microparticles with porous bone-like apatite coating. It is expected that the porous bone-like apatite coating technique are promising methodology to be useful to fabricate novel medical, pharmaceutical and environmental materials by combination of bone-like apatite with various kinds of functional materials in micron scale.
