DDS 개발과 약물의 생체내 동태 : Polyanhydride 이식제의 약물 방출 기전

박은석(Park Eun Seok),(Jaymin C . Shah) 한국약제학회 1997 과학의 달 기념 심포지움 Vol.- No.9

Influence of physicochemical properties of model compounds on their release from biodegradable polyanhydride devices

Park, Eun-Seok,Maniar, Manoj,Shah, Jaymin C. 성균관대학교 약학연구소 1997 成均藥硏論文集 Vol.9 No.1

A new class of fatty acid dimer-based polyanhydride, polycfatty acid dimer-sebacic acid) (P(FAD-SA)), was reported to have desired physicochemical and mechanical properties for a biodegradable device and believed to undergo pure surface erosion. The objectives of this study were to determine if P(FAD-SA) undergoes pure surface erosion, and to identify the factors governing the release characteristics and mechanism from polyanhydride devices at various pHs. Three model compounds, mannitol (small M_w, highly water soluble), inulin (large M_w, moderately water soluble) and stearic acid (medium M_w, extremely lipophilic) were incorporated at 10% w/w in disk-shaped P(FAD-SA, 50:50 w/w) devices and the release of the compounds studied from pH 1-9. All the three model compounds were released faster at alkaline pH than at acidic pH (pH 9>pH 7.4>pH 1-5), suggesting that the release of model compounds was dependent on the catalyzed erosion of polyanhydride. However, erosion was not the sole release rate controlling mechanism for these model compounds. Highly water soluble mannitorl and inulin were released rapidly at acidic pH, when erosion of polyanhydride is negligible. Mannitol released faster than inulin, which was released faster than lipophilic stearic acid at all pH, suggesting that the hydrophilic/hydrophobic nature of the loaded compound influenced its release significantly. the observed release profiles were significantly higher, and did not match the release profiles predicted from erosion rates of the mannitol and inulin devices, however they were closer for stearic acid devices. Althoug inulin was released rapidly in the initial phase (40-50%), only 60-70% inulin was released over a 6-week period compared to 100% release of mannitol. The large molecular size of inulin may have hindered its diffusion through water-filled pores and channels observed in the devices during release, which may have resulted in the majority of inulin being still trapped in the devices. Although various contributing factors in overall release were identified, a single release kinetic model could not explain the release profiles of all the loaded compounds under the different pH conditions. The complete release profiles could be decribed by first order kinetics, however the initial release profiles of all the model compounds were described very well by zero order kinetics. The release rates of mannitol and inulin were influenced by both the erosion rates and the intrinsic dissolution rates unlike release rates of stearic acid which correlated closely with erosion rates. This may be due to the fact that different release machanisms, such as diffusion, dissolution and erosion all play a significant role in overall release of compound from this newly developed P(FAD-SA) device. However, the contribution of each process to overall release may vary as a function of pH, the nature of the compound and polymer erosion. In conclusion, the results suggest that P(FAD-SA, 50:50 w/w) is undergoing bulk erosion rather than the desired surface erosion. If it did undergo surface erosion, release characteristics would be independent of the physicochemical nature of the incorporated compound and release kinetics would be zero order from disk-shaped devices irrespective of the nature of the loaded compound.

Biodegradable polyanhydride devices of cefazolin sodium, bupivacaine, and taxol for local drug delivery : preparation, and kinetics and mechanism of in vitro release

Park, Eun-Seok,Manoj Maniar,Shah, Jaymin C. 성균관대학교 약학연구소 1998 成均藥硏論文集 Vol.10 No.1

The overall objective was to design and evaluate biodegradable implants for local drug delivery in clinical conditions and/or diseases described below, which are currently treated with systemic administration of drugs. Local delivery of cefazolin is desired in conditions such as osteomyelitis, soft-tissue infection and for prevention of post-surgical infections. Similarly, implanting a biodegradable device loaded with taxol in the cavity created by tumor resection will provide high local concentrations of taxol killing the malignant cells which may have survived the surgery, thus preventing metastasis and regrowth of the tumor and also prevent the systemic side effects of taxol. Prolonged reversible nerve blockade required in a number of clinical situations involving acute or chronic pain such as post-surgical pain following herniorrhaphy and thoracotomy can be achieved with local delivery of bupivacaine. Therefore, disk-shaped implants of polyanhydride, P(FAD-SA, 50:50 w/w), loaded with 10% w/w of cefazolin sodium, taxol and bupivacaine were prepared and evaluated for content uniformity and in vitro release characteristics for the above mentioned local drug delivery applications. All of cefazolin sodium was released in 14 days while 90% bupivacaine was released in 35 days. In striking contrast, taxol was released very slowly, and only 15% taxol was released in 77 days. The overall release appeared to be following first order kinetics, and the initial linear profile was fitted to zero order kinetics to obtain release parameters. Since cefazolin is highly water soluble and bupivacaine is moderately water soluble, compared to taxol which is extremely lipophilic, the aqueous solubility of the incorporated drug appeared to influence its release characteristics. Very good correlation was observed between release parameters (A_0, K_0) and the solubility and intrinsic dissolution rate (IDR) of drugs suggesting that the hydrophilic/hydrophobic nature of the drug influences its release from polyanhydride devices. Since polyanhydrides are believed to undergo pure surface erosion, release of the incorporated drug should be independent of its physicochemical properties, however the results presented in this study suggest otherwise. Therefore, P(FAD-SA, 50:50 w/w) may not be undergoing surface erosion, and that diffusion and dissolution properties of the drug in addition to erosion characteristics of the polyanhydride appear to play a role in drug release. Implants prepared and evaluated in this study released cefazolin, bupivacaine and taxol for a prolonged duration of time; however, depending upon the desired duration of release, an appropriate polyanhydride will have to be selected. For example, taxol was released so slowly that a more hydrophilic polyanhydride may have to be selected to release all the drug in a shorter period of time to be of any therapeutic use. Cefazolin implants released the drug for a sufficient duration for osteomyelitis and soft-tissue infection but the release was more prolonged than required for prevention of post-surgical wound infection.

Water uptake in to polyanhydride devices : kinetics of uptake and effects of model compounds incorporated, and device geometry on water uptake

Park, Eun-Seok,Maniar, Manoj,Shah, Jaymin 성균관대학교 약학연구소 1996 成均藥硏論文集 Vol.8 No.1

Polyanhydrides are known as surface eroding biodegradable polymers since they are hydrophobic, which is believed to prevent penetration of water into the bulk and hence only the labile bonds on the surface are hydrolyzed. We wanted to test the hypothesis that polyanhydrides, specifically poly(fatty acid dimer-sebacic acid; FAD-SA) undergo pure surface erosion. If P(FAD-SA) does indeed undergo pure surface erosion, very little water should be present in the device since the polymer is hydrophobic and hydrolyzed on contact with water. An understanding of water uptake is also necessary to predict the stability and release of the incorporated drug. The specific aims of this study were to establish the rate of water uptake into P(FAD-SA) devices of cylinder and disk shapes at various pH conditions, and to study the effect of loaded model drug compounds (having different molecular size, aqueous solubility and dissolution rate) on water uptake. The model compounds included: mannitol, inulin and stearic acid, loaded at 10%(w/w) in disk-shaped devices. Water uptake was estimated from the amount of tritiated water found in the devices after they were soaked and gently mixed with buffers (pH 1-9) containing tritiated water (1μCi/ml) at various time intervals. The results showed that water uptake by the devide is a function of pH (pH 9>pH 7.4≫pH 1-5). Significantly higher amount of water was taken up at pH 7.4 and 9.0 (8-9% (v/v) for cylindrical devices, 15-25% (v/v) for disk-shaped device in 2 weeks), compared to less than 5% (v/v) uptake between pH 1 and 5. Disk-shaped devices showed a faster uptake rate compared to cylinder-shaped devices due to their higher surface area to volume ratio. The loaded compounds had no significant effect on either the water uptake profile or water uptake kinetics at all pH values examined. From the large amount of water (up to 20% (v/v)) found in the devices at pH 7.4 and pH 9.0, it appears that P(FAD-SA) does not undergo pure surface erosion. The photomicrographs of the devices at various stages of water uptake showed channels on the rough surface indicative of bulk erosion rather than pure surface erosion.