Application of Polyvinyl Acetate as Release Controlling Agent in 17β-Estradiol Implant Matrices

AbstractObjective: To apply two different, low (113K) and high (500K), molecular weights polyvinyl acetate (PVAc) as the release controlling agent in 2% 17β-estradiol (E2) implant matrix system. Method: Two plasticizers, triethyl citrate (TEC, a water-soluble plasticizer or diethyl phthalate (DEP, a waterinsoluble plasticizer) were incorporated to alter the flexibility of the matrix. Polyvinylpyrrolidone (PVP K30) was used as the releasing modifier. Solid dispersion of E2 in polymer was prepared by solvent evaporation method and compressed in a mold to have an implant matrix of 2 mm in diameter and 10 mm in length. Results: The unplasticized PVAc of different molecular weights did not provide difference in E2 release rate in phosphate buffer pH 7.4, about 14% of E2 was gradually released from the matrices during 28 days. Implants using plasticized PVAc of different molecular weights gave different drug release rates. E2 released from implants increased with increasing weight percent of plasticizers and adding PVP K30 promoted more drug release. Release kinetic of the PVAc implant matrix was best described by Higuchi model which indicated drug release by diffusion process. Conclusion: PVAc could be applied in 17β-estradiol matrix implant for long term drug delivery.Keywords: 17β-estradiol, implant, polyvinylacetate, triethyl citrate, diethyl phthalate, polyvinylpyrrolidone บทคัดย่อวัตถุประสงค์: เพื่อทดสอบว่า polyvinyl acetate (PVAc) ทัง้ ชนิดน้ำหนักโมเลกุลต่ำ (113k) และสูง (500k) ในการเป็น release controlling agent ในระบบimplant matrix system ของ 2% 17β-estradiol (E2) วิธีการศึกษา: ใช้สารplasticizer สองชนิดคือ triethyl citrate (TEC) ซึ่งเป็นละลายน้ำ และ diethylphthalate (DEP) ซึ่งไม่ละลายน้ำ เพื่อเปลี่ยนค่าความยืดหยุ่นของเมทริกซ์ ใช้สารpolyvinylpyrrolidine เป็น releasing modifier ใช้วิธี solvent evaporation เพื่อเตรียม solid dispersion ของ E2 ในโพลิเมอร์ แล้วอัดในแม่พิมพ์ให้ได้ implantmatrix ขนาดเส้นผ่านศูนย์กลาง 2 มม. และยาว 10 มม. ผลการศึกษา: พบว่าPVAc ทัง้ ชนิดที่มีน้ำหนักโมเลกุลสูงหรือต่ำ เมื่อไม่ผสม plasticizer ให้อัตราการปลดปล่อย E2 ไม่ต่างกัน ใน phosphate buffer pH 7.4 โดยปลดปล่อย 14%ในช่วง 28 วัน ส่วน PVAc ที่ผสม plasticizer ให้อัตราการปลดปล่อย E2 ที่ต่างกันโดยการปลดปล่อย E2 เพิ่มขึ้นเมื่อสัดส่วน plasticizer เพิ่มขึ้น และเมื่อเติม PVPK30 พบว่าอัตราการปลดปล่อยเพิ่มขึ้น ลักษณะจลนศาสตร์การปลดปล่อย E2จาก implant matrix ที่มี PVAc เป็น release controlling agent สามารถอธิบายได้ด้วย Higuchi model ซึ่งอธิบายการปลดปล่อยด้วยกระบวนการแพร่ สรุป:สามารถใช้ PVAc ในระบบนำส่งยาแบบเนิ่นสำหรับ matrix implant ของยา 17β-estradiolคำสำคัญ: 17β-estradiol, implant, polyvinylacetate, triethyl citrate, diethylphthalate, polyvinylpyrrolidon

The influence of hydrophilic and hydrophobic additives on the formation and drug release from pellets prepared by extrusion/spheronization

The preparation of pharmaceutical pellets by the process of extrusion and spheronization usually relies on microcrystalline cellulose as a basic ingredient. The addition of other additives could influence the performance of the formulation of pellets, especially if an attempt is made to control the drug release from the pellets. The aim of this study was to investigate the influence of hydrophilic and hydrophobic additives on the ability to prepare spherical pellets by this process and on the characterization of in vitro drug release from the pellets produced. The study was carried out with the use of a ram extruder and a conventional spheronizer. The ability to form spherical pellets and the optimum quantity of binder liquid required were assessed by characterization of the extrusion force and the final product, in terms of size, size distribution, shape, density and porosity. An investigation of the extrudate diameter and the surface roughness of the extrudate and pellets was included for certain formulations. The influence of the additive on the in vitro drug release from pellets was assessed by the application of the statistical moment analysis. Spherical pellets containing paracetamol could be prepared by the addition of a wide range of potential drug release-controlling additives including the hydrophilic additives: 1-16% chitosan and/or 1-16% sodium alginate, 3% methylcellulose, 3% hydroxypropyl methylcellulose and 30% pregelatinized starch, and the hydrophobic additives: 30% methylcellulose, 15% solid of the aqueous dispersions of methylcellulose and acrylate co-polymers, 30-60% glyceryl monostearate, 30% cetyl alcohol and 30% carnauba wax. Pellets containing diclofenac sodium, ibuprofen, and indomethacin were also successfully formed with glyceryl monostearate at levels of 30-60%. For diclofenac sodium, glyceryl monostearate could fully replace microcrystalline cellulose in the formulation. Different glyceride-based waxes were also shown to form satisfactorily spherical pellets containing diclofenac sodium at a level of 30%. The presence of the additives in the formulations of pellets did influence the characteristics of the product and the in vitro drug release. It was not, however, possible to ensure sufficient retardation of drug release to provide a controlled release matrix pellet. This appeared to be in some way related to the fact that some additives caused the pellets to disintegrate when added to fluid. Identification of the mechanism of the control of drug release also provided an insight into the way the additives influenced the formulation

Asymmetric Crystal Growth of Resorcinol from the Vapor Phase: Surface reconstruction and conformational change are the Culprits.

NoThe growth of crystals of a-resorcinol from the vapor phase is asymmetric along the polar axis. By means of molecular-dynamics simulations, the slower growth at the (011) polar surface is traced back to conformational change of the molecule and to surface reconstruction, which may be a general phenomenon in polar crystals

An optimized force field for crystalline phases of resorcinol.

noThe two known crystalline phases of resorcinol and their phase transitions are of considerable interest. The crystals exhibit pyro- and piezo-electricity and, remarkably, the higher temperature phase is the denser phase. Furthermore, crystals of the phase, by virtue of having a polar axis, have played a crucial role in investigating fundamental issues of crystal growth. We report an optimized force field for the molecular simulation of crystalline phases of resorcinol. The hydroxyl groups of the resorcinol molecule have a torsional degree of freedom and the molecule adopts a different conformation in each of the two phases of resorcinol. The torsional barrier, therefore, was considered to be critical and has been characterized using ab initio methods. Although the atomic partial charges showed some dependence on the molecular conformation, a single set of partial charges was found to be sufficient in describing the electrostatic potential for all conformations. The parameters for the van der Waals interactions were optimized using sensitivity analysis. The proposed force field reproduces not only the static structures but also the stability of the crystalline phases in extended molecular dynamics simulations

The Molecular Mechanism of α-Resorcinol's Asymmetric Crystal Growth from the Melt

Polar crystals are characterized by an axis that has a nonzero dipole due to the nature of the molecular packing. For these crystals, the growth rates of the faces delineating the polar axis are generally expected to be equal. Recent experiments, however, have revealed a few exceptions where the growth of these faces from the vapor phase is asymmetric, a notable case being crystals of resorcinol. Here, we present the mechanics of resorcinol crystal growth from the melt for the hemihedral faces (011) and (01̅1̅) delineating the polar axis as revealed by molecular dynamics simulations. The simulations reveal asymmetric growth consistent with experiment. The asymmetry is attributed to the slow-growing (011) face being less able to direct the correct alignment of the oncoming molecules and the presence of an alternate resorcinol conformation that readily incorporates into the lattice at this surface, serving to poison and retard subsequent growth. Putting the issue of the rogue conformation aside, the identified factors that influence molecular recognition are considered to be applicable to other polar crystals, which suggest asymmetric growth along the polar axis to be a common feature