An in vitro evaluation of a chitosan-containing multiparticulate system for macromolecule delivery to the colon

A multiparticulate system of chitosan hydrogel beads has been investigated for colon-specific delivery of macromolecules using fluorescein isothiocyanate-labeled bovine serum albumin as a model protein. The hydrogel bead was formed by polyelectrolyte complexation of chitosan with its counterion, tripolyphosphate (TPP). The protein release experiments were carried out in vitro under different conditions to simulate the pH and times likely to be encountered during intestinal transit to the colon. The results show that the hydrogel beads were degraded by rat cecal and colonic enzymes, resulting in a marked acceleration in the release of protein. The ability of rat cecal and colonic enzymes to degrade chitosan hydrogel beads was independent of pretreatment conditions. A commercial beta-glucosidase preparation containing a chitinase did not have a similar effect on the chitosan bead, even though it has been found to mimic the degradation function of rat cecal and colonic enzymes in vitro for chitosan in solution. Degradation of the chitosan-TPP hydrogel beads in the presence of rat cecal and colonic enzymes indicates the potential of this multiparticulate system to serve as a carrier to deliver macromolecules specifically to the colon.     

Pulsatile multiparticulate drug delivery system for metoprolol succinate

Cardiovascular diseases and their treatment pose a great challenge. Many instances of cardiovascular disease occur in the early morning hours. Hence, the objective of this study was to develop a time-controlled release formulation of metoprolol succinate based on a pulsatile multiparticulate (pellets) drug delivery system. The formulation was intended to be administered in the evening at 22:00 hours to evaluate symptoms of cardiovascular disease that are experienced in the early morning hours (from 04:00 to 06:00). Drug layering followed by a swelling layer and finally by an insoluble coat application was done using a Sanmour fluid bed processor. Metoprolol succinate layered on sugar pellets (74% w/w) layered with 20% (w/w) ion doshion resin P-547 and coated with 15% (w/w) ethocel with the addition of 20% castor oil showed a lag time of 4 h and was then followed a sigmoidal release pattern with more than 95% drug having been released by the 10^th h.     

Design and development of multiparticulate system for targeted drug delivery to colon

A multiparticulate system combining pH-sensitive property and specific biodegradability for colon-targeted delivery of metronidazole has been investigated. Cross-linked chitosan microspheres were prepared from an emulsion system using liquid paraffin as the external phase and solution of chitosan in acetic acid as the disperse phase. The multiparticulate system was prepared by coating cross-linked chitosan microspheres exploiting Eudragit® L-100 and S-100 as pH-sensitive polymers. Morphology and surface characteristics of the formulations were determined by scanning electron microscopy. Particle size of the chitosan microspheres was determined by optical microscopy while that of coated microspheres was determined by particle size analyzer. In vitro drug-release studies were performed in conditions simulating stomach-to-colon transit in presence and absence of rat caecal contents. The size of the microspheres was small and they were efficiently microencapsulated within Eudragit® microspheres, forming a multireservoir system. By coating the microspheres with Eudragit® pH-dependant release profiles were obtained. No release was observed at acidic pH; however, when it reached the pH where Eudragit® starts solublizing there was continuous release of drug from the formulation. Further, the release of drug was found to be higher in the presence of rat caecal contents, indicating the susceptibility of chitosan matrix to colonic enzymes released from rat caecal contents.     

Development of pulsatile multiparticulate drug delivery system coated with aqueous dispersion Aquacoat ECD

The objective of this study was to develop and evaluate a pulsatile multiparticulate drug delivery system (DDS), coated with aqueous dispersion Aquacoat ECD. A rupturable pulsatile drug delivery system consists of (i) a drug core; (ii) a swelling layer, comprising a superdisintegrant and a binder; and (iii) an insoluble, water-permeable polymeric coating. Upon water ingress, the swellable layer expands, resulting in the rupturing of outer membrane with subsequent rapid drug release. Regarding the cores, the lag time was shorter, when 10% (w/w) theophylline was layered on sugar cores compared with cores consisting of 100% theophylline. Regarding swelling layer, the release after lag time was fast and complete, when cross-linked carboxymethyl cellulose (AcDiSol) was used as a swelling agent. In contrast, a sustained release was achieved after the lag time, when low-substituted hydroxypropyl cellulose (L-HPC) and sodium starch glycolate (Explotab) were used as swelling agents. The optimal level of AcDiSol to achieve a fast and complete release after the lag time was 26% (w/w) (based on the weight of the coated pellets) for poorly soluble theophylline and 48% (w/w) for highly soluble propranolol HCl. The lag time can be controlled by the coating level of an outer membrane and increased with increasing coating level of the outer membrane. Outer membrane, formed using aqueous dispersion Aquacoat ECD was brittle and ruptured sufficiently to ensure fast drug release, compared to ethylcellulose membrane formed using organic solution. The addition of talc led to increase brittleness of membrane and was very advantageous because of (i) reduced sensitivity of lag time on variations in the coating level and (ii) fast and complete drug release. Drug release starts only after rupturing of outer membrane, which was illustrated by microscopical observation of pellet during release.     

葛根素自微乳化释药系统的处方筛选与体外评价

目的筛选葛根素自微乳化释药系统（Pur-SMEDDS）的处方并进行体外评价。方法通过溶解度、处方配伍实验和伪三元相图的绘制,以色泽、乳化时间和乳化后粒径大小为指标,筛选油相、表面活性剂、助表面活性剂的处方配比。测定葛根素自微乳化释药系统的溶出度。结果处方选用油酸为油相,聚山梨酯80为表面活性剂,Transcutol P为助表面活性剂。自微乳化后的粒径为（49.8±4.7）nm,ξ电位为（4.8±0.8）mV。pH 6.8磷酸盐缓冲液中30 min累积溶出百分率〉85%,而葛根素片60 min的累积溶出百分率〈10%。结论通过处方研究确定了最优处方,研制了葛根素SMEDDS。     

Formulation and in vitro evaluation of transdermal drug delivery system for donepezil

The effects of different formulation variables on the transdermal absorption of donepezil were investigated. The permeation of donepezil from various pressure sensitive adhesive matrices was evaluated using flow-through diffusion cell system at 37°C. The penetration of donepezil from the matrices was found to be influenced by the nature of adhesives. 1:1 combination of acrylic rubber hybrid adhesives (Duro-Tak^? 87-503A and Duro-Tak^? 87-504A) provided good adhesion force and high flux of donepezil. Significant increase in flux was obtained using Brij^? 30, Brij^? 52, and their combination, as penetration enhancers. Manual assessment using thumb test revealed that patches containing combination of enhancers possessed good adhesive properties. The formulation containing combination of Brij^? 30 and Brij^? 52, each at the level of 5% v/w with 15% w/w drug load in 1:1 combination of Duro-Tak^? 87-503A and Duro-Tak^? 87-504A matrix was found to be the best. No significant alteration in morphology and assay values were observed during the physical and chemical stability tests conducted for the study period of 3?months.     

Development and in vitro evaluation of a drug delivery system protecting from trypsinic degradation

We have been developing a delivery system based on a novel polymer conjugate protecting perorally administered (poly)peptide drugs from trypsinic degradation. The trypsin inhibitor antipain was, therefore, covalently attached to the mucoadhesive polymer chitosan. The protective effect of resulting chitosan–antipain conjugates was quantified by an enzyme assay. In contrast to the unmodified polymer, chitosan–antipain conjugates exhibited a significant inhibitory effect towards enzymatic activity of trypsin (EC 3.4.21.4). Moreover, the mucoadhesive force of chitosan was not influenced by the slight modification. Based on a chitosan–antipain conjugate, a drug delivery system was generated using insulin as model drug. Tablets containing 5% polymer conjugate demonstrated after incubation with trypsin (180 spectrophotometric BAEE units/ml) for 1.5 h in lateral parts of the swelled dosage form a 13.3±2.3% (mean±S.D., n=3) minor proteolysis of matrix embedded insulin compared to tablets lacking the polymer conjugate. In the inner part of the swelled dosage form containing the conjugate proteolysis was completely inhibited, whereas in control tablets 11.3±9.5% (mean±S.D., n=3) insulin was degraded. Furthermore, a controlled drug release over a period of 6 h was guaranteed by the delivery system. According to these results, the novel chitosan–antipain conjugates shielding from luminal enzymatic attack may be a useful tool for the peroral administration of mainly trypsinic degraded peptide and protein drugs.     

Development of enteric-coated calcium pectinate microspheres intended for colonic drug delivery

Enteric-coated calcium pectinate microspheres (MS) aimed for colon drug delivery have been developed, by using theophylline as a model drug. The influence of pectin type (amidated or non-amidated) and MS preparation conditions (CaCl2 concentration and cross-linking time) was investigated upon the drug entrapment efficiency and its release behaviour. Drug stability and drug-polymer interactions were studied by Differential Scanning Calorimetry, thermogravimetry, X-ray diffractometry and FTIR spectroscopy. Enteric coating with Eudragit S100 enabled maintenance of MS integrity until its expected arrival to colon. The coating was also useful to improve the stability of MS during storage, avoiding morphologic changes observed for uncoated MS stored under ambient conditions. Entrapment efficiency increased by reducing cross-linking time, and (only in the case of non-amidated pectin) by increasing CaCl2 concentration. On the other hand, release tests performed simulating the gastro-intestinal pH variation evidenced an inverse relationship between CaCl2 concentration and drug release rate, whereas no influence of both pectin type and cross-linking time was found. Unexpectedly, addition of pectinolytic enzymes to the colonic medium did not give rise to selective enzymatic degradation of MS. Notwithstanding this unforeseen result, coated MS prepared at 2.5% w/v CaCl2 concentration were able to adequately modulate drug release through a mixed approach of pH and transit time control, avoiding drug release in the gastric ambient, and reaching the colonic targeting where 100% release was achieved within less than 24h.     

A novel propellant-free inhalation drug delivery system for cardiovascular drug safety evaluation in conscious dogs

INTRODUCTION: Estimation of possible cardiovascular side effects belongs to the safety assessment of every drug candidate. This paper describes a new strategy for treating conscious labrador dogs with drugs by inhalation using a specially designed mask and a novel inhaler device. METHODS: Labrador dogs (male or female) were used that had transducers implanted for the measurement of left ventricular and descending aortic blood pressures and an ECG for use together with a telemetry system. Administration by inhalation was achieved using a novel delivery device. The Respimat device is a propellant-free inhaler to deliver aerosols from solutions. The new system was evaluated using Formoterol with four dogs using a 4 x 4 Latin square design. Three doses of Formoterol (0.6, 1.2, and 2.4 microg/kg, dissolved in 60% ethanol) were administered by inhalation together with a vehicle (60% ethanol) treatment by applying three inhalations, each consisting of 10 microl solution. RESULTS: Formoterol increased HR, QRS-interval, QT-interval, and LVPdP/dtmax and dose-dependently decreased systolic and diastolic BP. This effect lasted up to 14 h. DISCUSSION: Drug administration by inhalation in the conscious labrador dog using the Respimat is a useful new model for safety pharmacology studies of new drug candidates that are intended to be given by inhalation in the clinic.     

A programmable drug delivery system for oral administration.

A programmable, controlled release drug delivery system has been developed. The device in the form of a non-digestible oral capsule (containing drug in a slowly eroding matrix for controlled release) was designed to utilize an automatically operated geometric obstruction that keeps the device floating in the stomach and prevents it from passing through the remainder of the GIT. Different viscosity grades of hydroxypropyl-methyl-cellulose were employed as model eroding matrices. The duration during which the device could maintain its geometric obstruction (caused by a built-in triggering ballooning system) was dependent on the erosion rates of the incorporated polymers (the capsule in-hosed core matrix). After complete core matrix erosion, the ballooning system is automatically flattened off so that the device retains its normal capsule size to be eliminated by passing through the GIT. In vitro long-term drug delivery from a prototype model was studied using levonorgestril as a model drug. Zero-order release could be maintained for periods ranging between 5 and 20 days before the geometric obstruction is triggered off. The rate of drug release was dependent on the nature, viscosity and ratios of polymer employed. Copyright     

Development of sustained release gastroretentive drug delivery system for ofloxacin: in vitro and in vivo evaluation

Sustained release (SR)-gastroretentive dosage forms (GRDF) enable prolonged and continuous input of the drug to the upper parts of the gastrointestinal (GI) tract and improve the bioavailability of medications that are characterized by a narrow absorption window. A new strategy is proposed for the development of gastroretentive dosage forms for ofloxacin preferably once daily. The design of the delivery system was based on the sustained release formulation, with floating and swelling features in order to prolong the gastric retention time of the drug delivery systems. Different polymers, such as psyllium husk, HPMC K100M, crospovidone and its combinations were tried in order to get the desired sustained release profile over a period of 24 h. Various formulations were evaluated for buoyancy lag time, duration of buoyancy, dimensional stability, drug content and in vitro drug release profile. It was found that dimensional stability of the formulation increases with the increasing psyllium husk concentration. It was also found that in vitro drug release rate increased with increasing amount of crospovidone due to the increased water uptake, and hence increased driving force for drug release. The optimized formulation was subjected to stability studies at different temperature and humidity conditions as per ICH guidelines. In vivo studies were carried out for the optimized formulation in 24 healthy human volunteers and the pharmacokinetic parameters of developed formulations were compared with the marketed once daily (Zanocin) formulation. Based on the in vivo performance in a parallel study design in healthy subjects, the developed formulation shows promise to be bioequivalent to the marketed product (Zanocin). The percent relative bioavailability of developed formulation was found to be 97.55%.     

Binders for colon specific drug delivery: an in vitro evaluation

In order to screen out an optimum complex for reducing the nephrotoxicity of cisplatin (CDDP), we investigated and compared CDDP–chondroitin sulfate complexes to CDDP in terms of in vivo pharmacokinetics and in vitro cytotoxicity. The polymeric carriers used in the study were chondroitin sulfate A (CSA, 4-sulfate) with mean molecular weights of 10 kDa (CSA-1) and 23 kDa (CSA-2), and chondroitin sulfate C (CSC, 6-sulfate) with mean molecular weights of 8 kDa (CSC-1) and 25 kDa (CSC-2). The resultant complexes (CDDP–CSA-1, CDDP–CSA-2, CDDP–CSC-1 and CDDP–CSC-2) were administered intravenously to rats. The obtained plasma concentration–time curves during the 3 h period studied for all complexes are biphasic. The plasma dispositions of complexes were dependent on the molecular sizes with urinary excretion as main elimination pathway. CDDP–CSA-1 and CDDP–CSC-1 were unable to effectively increase the plasma retention of platinum due to rapid renal excretion. Furthermore, CDDP–CSA-1 disappeared from plasma more quickly than CDDP–CSC-1. CDDP–CSA-2 and CDDP–CSC-2, with similar urinary excretion as CDDP, gave rise to approximately five and four-fold increase in AUC_{0–3 h} values, respectively, than that was achieved with native CDDP treatment. Biodistribution was compared between CDDP–CSA-2 and CDDP–CSC-2. Both complexes effectively suppressed the extensive distribution of CDDP into most tissues, especially kidney. However, CDDP–CSC-2 showed less reduction effect than CDDP–CSA-2. In addition, a significantly higher accumulation in tumor tissue was found with the administration of CDDP–CSA-2 than CDDP. Moreover, CSA complexes displayed an IC₅₀ of 6 μM Pt-equivalents against SW4800 human colon cancer cells, similar to that of CDDP, whereas CSC complexes were less active than CDDP. These studies indicate that the complex prepared with CSA, which is greater than 20 kDa of molecular size, is superior to that of CSC, exhibiting improved pharmacokinetics and similar pharmacological activity to the native drug.     

Development and evaluation of a gastroretentive drug delivery system for the low-absorption-window drug celecoxib

The objective of the present study is to develop microspheres for celecoxib to enhance its bioavailability by increasing its gastric residence time. Four different polymers-polyethylene oxide, Eudragit S, cellulose acetate, and Eudragit RL-were used to form the floating microspheres using an emulsion-solvent diffusion technique. The use of two different solvents (dichloromethane and ethanol) that differed in the rate of diffusion led to formation of a hollow core in the microspheres, which was partially responsible for the flotation ability. The formulation was optimized on the basis of in vitro buoyancy and in vitro release in simulated gastric fluid at pH 3. Scanning electron microscopy revealed differences between the formulations in terms of their topography. X-ray diffractometry and differential scanning calorimetry examination showed the amorphous nature of the drug. Microspheres prepared with polyethylene oxide:Eudragit S:celecoxib (2:2:1) gave the best in vitro percentage release and was taken as the optimized formulation. By fitting the data into zero order, first order, and Higuchi model, it could be concluded that the release followed first-order release kinetics. The correlation coefficient (R2 value) was obtained upon fitting the data to Higuchi equation, which signifies that the mechanism of release of celecoxib from the microspheres was diffusion rate-limited.     

负载连翘苷的外泌体递药系统制备及体外评价

目的:制备负载连翘苷(phil)的外泌体(exos)递药系统(phil-exos),并考察其对人肺上皮腺癌细胞A549迁移能力的影响.方法:采用差速-超高速离心法结合超滤法获取小鼠肺泡巨噬细胞(MHS)来源的外泌体,超声法制备phil-exos并测定其粒径及电位,采用透射电子显微镜观察其形态,蛋白质免疫印迹法鉴定标志蛋...     

四乙酰基葛根素自微乳化给药系统的制备及体外评价

目的筛选四乙酰基葛根素自微乳化给药系统的处方并进行体外评价。方法测定四乙酰基葛根素在各种油相、表面活性剂和助表面活性剂中的溶解度,对不同溶剂进行初步配伍研究,采用三元相图法考察不同油相、表面活性剂和助表面活性剂形成微乳的能力,绘制不同处方组成的三元相图,以微乳外观、乳化速度、乳滴粒径、载药量为指标,进一步优选处方,找出最佳的组合和处方配比,制备自微乳化液,测定四乙酰基葛根素自微乳化制剂的溶出度。结果最佳处方体系为Labrafil M1944 cs-Polyoxy 35 castor oil-Transultol P（30∶40∶30）和LauroglycolFCC-Tween 80-Transcutol P（30∶30∶40）,此处方体系能迅速乳化为外观澄清透明的微乳液,粒径分布为（21.6±5.1）、（20.2±9.8）nm,45 min内溶出度分别96.2%、96.7%。结论成功制备了四乙酰基葛根素自微乳化给药系统。     

紫杉醇纳米金刚石递药系统的构建及其体外评价

目的制备羧化纳米金刚石紫杉醇载药体系,单因素试验优化制备工艺,并进行体外评价。方法在混酸油浴下制备羧化纳米金刚石,以红外光谱进行结构确证。采用超声法包载紫杉醇,并以粒径大小为指标对制备工艺进行单因素考察,对优化后的纳米复合物进行制剂学和细胞毒性研究。结果通过红外图谱验证了羧化纳米金刚石的成功合成,优化纳米复合物呈均匀分散,平均粒径为(145.92±63.91)nm,Zeta电位为(-10.49±3.24)mV,体外释放具有更明显的缓释效果,细胞毒研究显示,羧化纳米金刚石紫杉醇载药系统对MCF-7肿瘤细胞的增殖具有更强的抑制作用,10μg·m L~(-1)可将细胞存活率控制在50%。结论羧化纳米金刚石具有更优的载药性质,减缓了药物的释放,用此载体载药可以提高紫杉醇的抗癌活性,羧化纳米金刚石是极具应用前景的抗肿瘤递药载体。     

吡罗昔康自微乳化药物传递系统的处方筛选与体外评价

筛选吡罗昔康自微乳化药物传递系统(SMEDDS)的处方并进行体外评价。考察了吡罗昔康在不同油相和表面活性剂中的溶解度；对不同油相和表面活性剂进行初步配伍研究；通过绘制三元相图研究处方中不同油相、表面活性剂和辅助表面活性剂形成微乳的能力和区域；对制剂粒径及溶出度进行考察。处方选用肉桂醇作为吡罗昔康的溶剂，以Labrafil M 1944CS为油相，Cremophor EL为表面活性剂，Transcotol P为辅助表面活性剂。所得3个处方乳化后的粒径及分布分别为(32.2±5.0)、(40.1±6.4)、(81.9±12.2)nm。制剂溶出速度快。通过处方研究确定了最优处方，研制了吡罗昔康SMEDDS。     

Preparation and in vitro evaluation of mebeverine HCl colon-targeted drug delivery system

Mebeverine HCl is a water soluble drug commonly used to treat irritable bowel syndrome by acting directly on the smooth muscles of the colon. This work was aimed at the formulation and in vitro evaluation of a colon-targeted drug delivery system containing mebeverine HCl. Matrix tablets were prepared using ethyl cellulose (EC), Eudragit RL 100 either solely or in combination by wet granulation technique. Dissolution was carried out in 0.1 N HCl for 2?h followed by pH 6.8 phosphate buffer for eight hours. Uncoated forms released more than 5% drug in 0.1 N HCl therefore, Eudragit L100 was used as a coat. The results indicated very slow release profile. As a result, single retardant was used to prepare the matrix and coated by Eudragit L 100. The matrix containing 7% Eudragit RL 100 and 6% of binder was subjected to further studies to assess the effect of different coats (Eudragit L 100-55 and cellulose acetate phthalate) and different binders (pectin and sodium alginate) on the release profile. Eudragit L 100 and pectin were the best coating agent and binder, respectively. The final formula was stable and it can be concluded that the prepared system has the potential to deliver mebeverine HCl in vivo to the colon.     

Novel preparation of enteric-coated chitosan-prednisolone conjugate microspheres and in vitro evaluation of their potential as a colonic delivery system.

After chitosan-succinyl-prednisolone conjugate (Ch-SP) was synthesized, conjugate microspheres (Ch-SP-MS), Eudragit L100-coated Ch-SP-MS and Eudragit S100-coated Ch-SP-MS, were prepared under novel preparative conditions. Namely, sonication was utilized to prepare finer Ch-SP-MS, and the addition ratio of Eudragit was reduced to yield Eudragit-coated Ch-SP-MS with higher drug content. Ch-SP-MS and Eudragit-coated Ch-SP-MS had mean sizes of 1.3microm and approximately 30microm, respectively, and showed prednisolone (PD) contents of 4.6% (w/w) and approximately 3% (w/w), respectively. Morphological changes of all the types of microparticles in different pH media were observed by scanning electron microscopy and confocal laser scanning microscopy. Both methods gave similar results. Both types of Eudragit-coated Ch-SP-MS protected Ch-SP-MS from morphological change at pH 1.2, and regenerated Ch-SP-MS fast at pH 6.8 and 7.4. For all types of microparticles, release of PD was suppressed at pH 1.2, but caused gradually at pH 6.8. These particle characteristics and in vitro behaviors demonstrated that the present Eudragit-coated Ch-SP-MS were considered potentially suitable for in vivo or practical application as a specific delivery system of PD to IBD sites.