• Journal of Pharmaceutical Investigation
• /
• 제6권3호
• /
• pp.58-69
• /
• 1976

It is well established that dissolution is freruently the rate limiting step in the gastrointestinal absorpton of a drug from a solid dosage from. The relationship between the dissolution rate and absorption is particularly distinct when considering drugs of low solubility. Consequently, numerous attempts have been made to modify the dissolution characteristics of poorly water soluble drugs. Since dissolution rate is directly proportional to surface area, one may increase the rate by decreasing the particle size of the drug. Levy has considered a number of methods by which a drug may be presented to the GI fludids in finely divided from. The direct method is the utilization of microcrystalline or micronized particles. A second method involves the administration of solutions from which, upon dilution with gastric fluids, the dissolved drug will precipitate in the form of very fine particles. A more unique way of obtaining microcrystalline dispersions of a drug has been ercently suggested by Sekiguchi et al. They have first proposed the formation of a eutectic mixture of a poorly water soruble drug with a physiologically inert, easily soluble carrier. When such systems are exposed to water or GI fluids, the soluble carrier will dissolve rapidly and the finely dispersed drug particles will then be released. It has been suggested by Shefter and Higuchi that the formation of crystalline solvate could be a powerful tool in affecting rapid disslution of highly insoluble substances. Goldberg et al. have noted that the formation of solid solution could reduce the particle size to a minimum and increase the dissolution rate as well as the solubility of the durgs. It has also been shown that the rates of solution of drugs were appreciably increased by coprectipitating the drug with soluble polymers. The increase was found to be sensitive to the method of preparation, the molecular weight of polymer and the particular ratio of drugs to polymer. Although several investigations have demontrated that the solubility and/or dissolution rates of drugs can be increased in this manner, little information is available in the literature related to the in vivo absorption pattern of drugs orally administered as PVP coprecipitates. Recently, however, it was demonstrated that both the rate and extent of absorption of the insoluble drug could be markedly enhanced when orally administered to rats in the form of a coprecipitate with PVP. The purpose of the present investigation was to ascertain the general appility of soluble polymer coprectation technique as a method for enhancing the in vitro dissolution rate of hydrophobic indomethacin. To accomplish this aim, the dissolution characteristics of pure indomethacin, indomethcin-polymer physical mixtures and indomethacin-polymer coprecipitates were quantitatively studied by comparing their relative dissolution rates. The solubility and dissolution behavior of these systems were also examined.

• Journal of Pharmaceutical Investigation
• /
• 제6권3호
• /
• pp.48-57
• /
• 1976

An enhancement in the dissolution rate of the drug should facilitate its GI absorption if the absorption process is dissolution rate limited. One of the need for the techniques that can potentially enhance the dissolution rate and extent of absorption of hydrophobic drugs is the formation of coprecipitates with pharmacologically inert, polymeric materials. The physicochemical modification offers the advantage of possibly enabling one to administer the drug orally in a form from which it is most available for GI absorption. Several $investigation^{1-15)}$ demonstrated that the formation of solid dispersions or coprecipitates of relatively water-insoluble drugs with various pharmacologically inert carriers can increase singnificantly their in vitro dissolution rates. However, little information is available in the literature related to the dissolution rate patterns of furosemide, a water-insoluble diurectices, with respect to the sort of copolymer and the ratio of coprecipitates as a function of time, respectively. The purpose of the present investigation was to ascertain, the general applicability of the copolymers to use fore more fast, enhanced dissolution techniques of furosemide. To accomplish the need for enhancement in the dissolution rate of furosemide, varying ratio coprecipitates with different water-soluble polymers, such as polyvinylpyrrolidone (PVP), polyethylene glycol 4000(PEG 4000), and polyethylene glycol 6000 (PEG 6000), were quantitatively studied by comparing their dissolution characteristics of furosemide. The dissolution patterns of pure furosemide, varying ratio furosemide-PVP coprecipitates, (1:2, 1:5, and 1:9(w/w)), furosemide-PEG 4000 coprecipitates (1:4, 1:9, and 1:19(w/w), furosemide-PEG 6000 coprecipitates(1:4, 1:9, and 1:19(w/w)), and the same ratio physical mixtures, respectively, were compared by the amount dissolved as a function of time.

• Archives of Pharmacal Research
• /
• 제8권1호
• /
• pp.7-14
• /
• 1985

Membrane-coated tablet of isonicotinic acid hydrazide (INAH) which releases INAH at the zero-order kinetics was deveoped. It consisted of a soluble tablet core surrounded by a porous membrane which controls the diffusion rate. Tablet cores were prepared by compressing granules of INAH and polyvinyl chloride (PVC) dissolved in methyl ethyl ketone in which micronized sucrose were suspended. Diffusion rate of INAH from the tablet through the membrane was constant until the loaded INAH in the core was almost released. The rate was independent of pH of the dissolution medium. Water-soluble sucrose particles behaved as a poreproducing material in the water-insoluble PVC film coat. The pH independency of the rate was probably due to the high solubility of INAH in the water of wide pH range. The diffusion rate of INAH could be controlled by chnaging the composition of the membrane or the coat weight. This membrane-coated INAH tablet seemed to be a powerful candidate for the controlled release drug delivery system (DDS) of INAH or other highly watersoluble drugs.

• 공업화학
• /
• 제17권1호
• /
• pp.106-110
• /
• 2006

약물입자들을 나노크기로 만들어 이용하면 기존 제형에 비해 효과적일 수 있다. 특히 생체 내 낮은 흡수율을 가진 난용성 약물들은 그 입자의 크기가 감소함에 따라 흡수율과 생체이용률이 높아질 수 있다. 본 연구에서는 난용성 약물인 이트라코나졸의 나노입자를 안정화시키기 위하여 폴리비닐피롤리돈(PVP)과 다양한 당을 안정화제로 사용하였다. 당으로 안정화된 이트라코나졸 나노입자는 5일 동안의 습식분쇄 공정으로 성공적으로 제조되었다. 그 후 얻어진 액상의 입자를 분무 건조하고 그 건조분말의 재분산성을 알아보았다. 분무 건조 시 가공 변수의 효과를 알아보기 위해 온도, 압력, 유속 등을 변화시켰다. 입자크기 분석을 통해 당을 함유한 나노입자 건조분산체가 그렇지 않은 경우보다 재분산도가 더 좋은 것을 알 수 있었다. 또한 주사전자현미경(SEM)과 원자현미경(AFM)을 이용하여 나노 결정입자들이 구형에 가까운 모양인 것을 확인하였다.

• Journal of Pharmaceutical Investigation
• /
• 제41권5호
• /
• pp.295-300
• /
• 2011

Paclitaxel is a well known anticancer agent and has been a pharmaceutical challenge because of its extremely poor water-solubility and susceptibility to the p-glycoprotein (p-gp)-mediated efflux in multi-drug resistant (MDR) cancer cells. Tributyrin (TB), a triglyceride with relatively short fatty acid chains, was chosen as solubilizing vehicle for paclitaxel based on the solubility study (26.6 mg/mL). Tributyrin (10%) o/w emulsion containing paclitaxel (5%), egg phosphatidylcholine (5%) and pegylated phospholipid (0.5%) was prepared by high pressure homogenization to obtain submicron-sized emulsion. The mean particle size of the resultant TB emulsion was 395.5 nm. Paclitaxel in TB emulsion showed higher anticancer activity against human breast cancer cell line, MCF-7, than free form delivered in DMSO solution. On the other hand, its anticancer activity was significantly reduced in MCF-7/ADR, a MDR variant cancer cell line of MCF-7, and recovered by the presence of verapamil, suggesting of the susceptibility to the p-gp mediated efflux even though paclitaxel was encapsulated into emulsion. The TB emulsion showed great potential as a promising vehicle for water-insoluble anticancer agent, paclitaxel.

• Bulletin of the Korean Chemical Society
• /
• 제33권12호
• /
• pp.4035-4040
• /
• 2012

Presented study describes the synthesis of photo cross-linkable and water soluble hydroxyethyl starch hydroxyethyl methacrylate (HESHEMA) samples with different degree of substitution (DS) by functionalization of hydroxyethyl starch (HES) with hydroxyethyl methacrylate (HEMA) or hydroxyethyl methacrylate carbonylimidazole (HEMACI) in DMSO using two different routes. It was revealed that the reaction time for HESHEMA synthesis can be reduced from 5 days to 24 h by conducting the reaction at $80^{\circ}C$ instead of at room temperature. Solubility of HESHEMA was found to be dependent on DS which in turn was dependent on ratio between HES and HEMA or HEMACI. HESHEMA samples with DS > 0.24 depicted insoluble in water, whereas the samples with DS < 0.05 did not form appreciable gel. HESHEMA samples with appropriate DS were converted into hydrogels by cross-linking polymer chains under UV radiations and resulting HESHEMA hydrogels showed swelling up to 1200%. Application of HESHEMA in controlled drug delivery was investigated by diffusion based encapsulation of Ondansetron, a serotonin 5-$HT_3$ receptor antagonist drug, mainly used for nausea and vomiting treatment.

• 환경위생공학
• /
• 제21권1호
• /
• pp.21-34
• /
• 2006

To investigate anti-HIV-1 activity of water soluble chitosans, sulfated chitosan derivatives were prepared in mild condition. Various sulfated chitosan derivatives (N-3,6-O-S-chitosan, N-desulfated 3,6-O-S-chitosan, 3,6-O-S-chitin, and 3,6-O-sulfated-N-(o-carboxybenzoyl) chitosan) were synthesized with sulfurtrioxidepyridene complex in pyridine solvent. Characterization of the sulfated chitosan derivatives was carried out by $^{13}C$ NMR and IR spectroscopies. To observe ionic reaction properties, pKas of the sulfated chitosan derivatives and chitosan of low molecular weight were estimated by potentiometric titration. The sulfated chitosan derivatives had high water solubility, pKas (pKa : 7.7) of N-3,6-O-S-chitosan and N-desulfated 3,6-O-S-chitosan were increased than pKa of water insoluble chitosan (pKa : 6.2), These results suggest the participation of electrostatic interaction of amino and sulfate groups on the sulfated chitosans. Anti-HIV-1 drugs, such as AZT, ddC, and ddI for anti-HIV activity had higher selective index compared with SCB-chitosan but N-3,6-O-S-chitosan has shown higher selective index compared with ddC and ddI as HIV drugs.. These results suggest that sulfated chitosan derivatives were expected as an anti-HIV drug with differential driving force mechanism against some nucleoside analogs drug in the future.

• Macromolecular Research
• /
• 제11권4호
• /
• pp.207-223
• /
• 2003

For last five years, we are developing the novel local drug delivery devices using biodegradable polymers, especially polylactide (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) due to its relatively good biocompatibility, easily controlled biodegradability, good processability and only FDA approved synthetic degradable polymers. The relationship between various kinds of drug [water soluble small molecule drugs: gentamicin sulfate (GS), fentanyl citrate (FC), BCNU, azidothymidine (AZT), pamidronate (ADP), $1,25(OH)_2$ vitamin $D_3$, water insoluble small molecule drugs: fentanyl, ipriflavone (IP) and nifedipine, and water soluble large peptide molecule drug: nerve growth factor (NGF), and Japanese encephalitis virus (JEV)], different types of geometrical devices [microspheres (MSs), microcapsule, nanoparticle, wafers, pellet, beads, multiple-layered beads, implants, fiber, scaffolds, and films], and pharmacological activity are proposed and discussed for the application of pharmaceutics and tissue engineering. Also, local drug delivery devices proposed in this work are introduced in view of preparation method, drug release behavior, biocompatibility, pharmacological effect, and animal studies. In conclusion, we can control the drug release profiles varying with the preparation, formulation and geometrical parameters. Moreover, any types of drug were successfully applicable to achieve linear sustained release from short period ($1{\sim}3$ days) to long period (over 2 months). It is very important to design a suitable formulation for the wanting period of bioactive molecules loaded in biodegradable polymers for the local delivery of drug. The drug release is affected by many factors such as hydrophilicity of drug, electric charge of drug, drug loading amount, polymer molecular weight, the monomer composition, the size of implants, the applied fabrication techniques, and so on. It is well known that the commercialization of new drug needs a lot of cost of money (average: over 10 million US dollar per one drug) and time (average: above 9 years) whereas the development of DDS and high effective generic drug might be need relatively low investment with a short time period. Also, one core technology of DDS can be applicable to many drugs for the market needs. From these reasons, the DDS research on potent generic drugs might be suitable for less risk and high return.

• Macromolecular Research
• /
• 제14권5호
• /
• pp.573-578
• /
• 2006

Three different, polymer-platinum conjugates (hydrogels, microparticles, and nanoparticles) were synthesized by complexation of cis-dichlorodiammineplatinum(II) (cisplatin) with partially succinylated glycol chitbsan (PSGC). Succinic anhydride was used as a linker to introduce cisplatin to glycol chitosan (GC). Succinylation of GC was investigated systematically as a function of the molar ratio of succinic anhydride to glucosamine, the methanol content in the reaction media, and the reaction temperature. By controlling the reaction conditions, water-soluble, partially water-soluble, and hydrogel-forming PSGCs were synthesized, and then conjugated with cisplatin. The complexation of cisplatin with water-soluble PSGC via a ligand exchange reaction of platinum from chloride to the carboxylates induced the formation of nano-sized aggregates in aqueous media. The hydrodynamic diameters of PSGC/cisplatin complex nano-aggregates, as determined by light scattering, were 180-300 nm and the critical aggregation concentrations (CACs), as determined by a fluorescence technique using pyrene as a probe, were $20-30{\mu}g/mL$. The conjugation of cisplatin with partially water-soluble PSGC, i.e., borderline between water-soluble and water-insoluble PSGC, produced micro-sized particles $<500{\mu}m$. Cisplatin-complexed PSGC hydrogels were prepared from water-insoluble PSGCs. All of the cisplatin-incorporated, polymer matrices released platinum in a sustained manner without any significant initial burst, suggesting that they may all be useful as slow release systems for cisplatin. The release rate of platinum increased with the morphology changes from hydrogel through microparticle to nanoparticle systems.

• Biomolecules & Therapeutics
• /
• 제8권3호
• /
• pp.269-275
• /
• 2000

Silibinin(silybin) is the active component of silymarin from Silybum marianum and has hepato-protective effect. It is water-insoluble and has low bioavailability. To improve its bioavailability, self-micro-emulsifying drug delivery system (SMEDDS) has been developed by Hanmi Pharmaceutical Company (Silyma $n^{R}$ 140 soft capsule). In this study, the pharmacokinetic profiles of Silyma $n^{R}$ were examined and compared it with a reference preparation, L Caps140 of B Pharmaceutical Company. This study was approved by Yonsei University Severance Hospital IRB(approval No. CR0004) and followed the bioequivalence test guideline of Korean FDA. Eighteen healthy adult volunteers were allocated based on 2$\times$2 Latin square cross-over design. They were given 2 capsules (each contains silymarin 140 mg (60 mg as silibinin)) of either drug at each period and crossed over after a week of drug-free washout period. Blood concentration of silibinin was measured by HPLC. The $C_{max}$ and AUC of the Silyma $n^{R}$ were 1542.0 $\pm$ 402.7 ng/ml and 3323.3 $\pm$ 824.7 ng.h/ml, respectively, and were significantly higher than those of reference preparation. The Tmax was 0.8 $\pm$ 0.3 h and significantly shorter than reference preparation. The $K_{e}$ and $T_{1}$2/ of both drugs were comparable. Percent differences in means against reference preparation were +88.3% for AUC, +222.6% for $C_{max}$, and -61.1% for $T_{max}$./.>././.>./.