糖类交联明胶微球的制备及其释药特性研究

目的:以生物相容性的糖作交联剂制备明胶药物载体并研究其释药特性。方法:用葡萄糖、葡聚糖、氧化葡萄糖、氧化葡聚糖作交联剂制备明胶盘和微球,测定其溶胀动力学,分别以阿司匹林和牛血清白蛋白为药物模型,紫外分光光度法测定药物包裹率、载药率,并检测明胶微球在模拟体内条件下药物的释放速率。结果:葡萄糖、氧化葡萄糖、葡聚糖、氧化葡聚糖作交联剂制备的凝胶溶胀率分别为204%、246%、166%、233%;4种阿司匹林和牛血清白蛋白明胶微球平均载药率分别为8.73%和4.05%,平均包封率分别为62.55%和31.40%;2h药物释放百分率依次为30%、14%、76%、73%和97.2%、86.6%、60.8%、50.1%。结论:上述4种糖均可以取代化学交联剂制备明胶微球;天然糖交联微球缓释效果优于氧化糖。     

Effect of fill weight, capsule shell, and sinker design on the dissolution behavior of capsule formulations of a weak acid drug candidate BMS-309403

Two strengths of BMS-309403 capsules were developed from a common stock granulation. Dissolution testing of the capsules was conducted utilizing the USP apparatus 2 (paddle) with a neutral pH dissolution medium. Unexpectedly, the lower-strength capsules exhibited slower dissolution than the higher-strength capsules filled with the same stock granulation. Higher variability was also observed for the lower-strength capsules. This was found to be mainly caused by a low fill weight in a relatively large size hard gelatin capsule shell. Instead of bursting open, some gelatin capsule shells softened and collapsed onto the granulation, which delayed the release of the active drug. The problem was aggravated by the use of coil sinkers which hindered the medium flow around the capsules. Switching from the gelatin capsule shells to the HPMC (hydroxypropyl methylcellulose) shells reversed the dissolution rate ranking between the two capsule strengths. However, both dissolved at a slower rate initially than the gelatin capsules due to the inherent dissolution rate of the HPMC shells at pH 6.8. Notably, the HPMC shells did not occlude the granulation as observed with the gelatin shells. The study demonstrated that the dissolution of capsule formulations in neutral pH media was significantly affected by the fill weight, sinker design, and capsule shell type. Careful selection of these parameters is essential to objectively evaluate the in vitro drug release.     

Dissolution of theophylline from film-coated slow release mini-tablets in various dissolution media

The dissolution of an experimental formulation of film-coated slow release theophylline mini-tablets has been investigated using the USP paddle apparatus in test media at pH 1.2 (hydrochloric acid), pH 5.4 and 7.4 (phosphate buffers) at 37 degrees C. Monitoring of in-vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in less than 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in-vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasize the usefulness of an animal model for assessment of in-vivo drug release and subsequent absorption, during the development of modified release dosage forms.     

Polyacrylate resin microcapsules for taste masking of antibiotics

Abstract

Various microencapsulated dosage forms were prepared to limit the release of an antibiotic in solution for up to 3 days and in the oral cavity following per oral administration. An experimental antibiotic, clarithromycin (TE-031), was used in these studies. The drug was first encapsulated in gelatin followed in some cases by crosslinking with glutaraldehyde. The gelatin microcapsules were then coated with acrylic resins (Eudragit®), whose solubility properties vary according to pH. A non-solvent coacervation technique was used to apply the Eudragit resins. It was found that crosslinking the gelatin retarded release of TE-031 somewhat relative to that from uncrosslinked gelatin microcapsules in a 72 h release experiment conducted at room temperature. Coating the gelatin microcapsules with Eudragit resins L100, S100, or E100 slowed the release of TE-031 further still; less TE-031 was released over 72 h from the Eudragit-coated formulations prepared with crosslinked gelatin compared with formulations prepared with uncrosslinked gelatin. The Eudragit ElOO-coated crosslinked gelatin microcapsule formulation was most effective in preventing release of the TE-031 under simulated conditions of storage in an aqueous solution.     

Polyacrylate resin microcapsules for taste masking of antibiotics.

Various microencapsulated dosage forms were prepared to limit the release of an antibiotic in solution for up to 3 days and in the oral cavity following per oral administration. An experimental antibiotic, clarithromycin (TE-031), was used in these studies. The drug was first encapsulated in gelatin followed in some cases by crosslinking with glutaraldehyde. The gelatin microcapsules were then coated with acrylic resins (Eudragit), whose solubility properties vary according to pH. A non-solvent coacervation technique was used to apply the Eudragit resins. It was found that crosslinking the gelatin retarded release of TE-031 somewhat relative to that from uncrosslinked gelatin microcapsules in a 72h release experiment conducted at room temperature. Coating the gelatin microcapsules with Eudragit resins L100, S100, or E100 slowed the release of TE-031 further still; less TE-031 was released over 72 h from the Eudragit-coated formulations prepared with crosslinked gelatin compared with formulations prepared with uncrosslinked gelatin. The Eudragit E100-coated crosslinked gelatin microcapsule formulation was most effective in preventing release of the TE-031 under simulated conditions of storage in an aqueous solution.     

Effect of Fill Weight,Capsule Shell,and Sinker Design on the Dissolution Behavior of Capsule Formulations of a Weak Acid Drug Candidate BMS‐309403

Two strengths of BMS‐309403 capsules were developed from a common stock granulation. Dissolution testing of the capsules was conducted utilizing the USP apparatus 2 (paddle) with a neutral pH dissolution medium. Unexpectedly, the lower‐strength capsules exhibited slower dissolution than the higher‐strength capsules filled with the same stock granulation. Higher variability was also observed for the lower‐strength capsules. This was found to be mainly caused by a low fill weight in a relatively large size hard gelatin capsule shell. Instead of bursting open, some gelatin capsule shells softened and collapsed onto the granulation, which delayed the release of the active drug. The problem was aggravated by the use of coil sinkers which hindered the medium flow around the capsules. Switching from the gelatin capsule shells to the HPMC (hydroxypropyl methylcellulose) shells reversed the dissolution rate ranking between the two capsule strengths. However, both dissolved at a slower rate initially than the gelatin capsules due to the inherent dissolution rate of the HPMC shells at pH 6.8. Notably, the HPMC shells did not occlude the granulation as observed with the gelatin shells. The study demonstrated that the dissolution of capsule formulations in neutral pH media was significantly affected by the fill weight, sinker design, and capsule shell type. Careful selection of these parameters is essential to objectively evaluate the in vitro drug release.     

Sustained release of water-soluble drug from directly compressed alginate tablets

The release of acetyl salicylic acid from directly compressed alginate tablets was investigated. The effect of the amount and type of alginate on the drug release rate was evaluated in different formulations. Four different grades of alginate were used. The in vitro release studies were carried out using the apparatus II (paddle) equipment as described in the USP 23/NF dissolution monograph. Dissolution medium was 0.1 M HCl for 2 h followed by phosphate buffer pH 6.8; both at 37 degrees C. Sustained drug release up to 16 h was achieved using sodium alginate in combination with dibasic calcium phosphate.     

Crosslinked gelatin matrices: release of a random coil macromolecular solute

The purpose of this investigation was to evaluate the effect of matrix crosslinking and solute size on release of a random coil macromolecular solute from crosslinked gelatin matrices. Gelatin hydrogel matrices crosslinked with different molar ratios of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC):epsilon-amino groups on gelatin (1:1, 4:1, and 10:1) were prepared containing dextran of molecular weights 12, 20, and 77 kDa, and hydrodynamic diameters 54, 74, and 133 A, respectively. The extent of matrix crosslinking was determined quantitatively and used to calculate the molecular weight between crosslinks (Mc). The Mc parameter and equilibrium swelling ratio (Qm) were used to calculate an estimated matrix mesh size (xi). The in vitro release of incorporated dextran was evaluated at 37 degrees C in PBS at pH 7.4 for approximately 80 h. The one-, four- and 10-fold molar ratios of crosslinking agent EDC yielded 24, 41, and 78% of gelatin matrix crosslinking, respectively. The calculated average matrix mesh size ranged from 338 to 90 A. The effect of matrix crosslinking varied with solute size, from retarding diffusional release of the dextran to completely entrapping it inside the crosslinked matrices. These results support the threshold concept of solute size relative to matrix mesh size for release of a flexible, random coil macromolecular solute from a hydrogel.     

Diisocyanate mediated polyether modified gelatin drug carrier for controlled release

Gelatin is an extensively studied biopolymer hydrogel drug carrier due to its biocompatibility, biodegradability and non-toxicity of its biodegraded products formed in vivo. But with the pristine gelatin it is difficult to achieve a controlled and desirable drug release characteristics due to its structural and thermal lability and high solubility in aqueous biofluids. Hence it is necessary to modify its solubility and structural stability in biofluids to achieve controlled release features with improved drug efficacy and broader carrier applications. In the present explorations an effort is made in this direction by cross linking gelatin to different extents using hitherto not studied isocyanate terminated poly(ether) as a macrocrosslinker prepared from poly(ethylene glycol) and isophorone diisocyanate in dimethyl sulfoxide. The crosslinked samples were analyzed for structure by Fourier transform-infrared spectroscopy, thermal behavior through thermogravimetric analysis and differential scanning calorimetry. The cross linked gelatins were biodegradable, insoluble and swellable in biofluids. They were evaluated as a carrier for in vitro drug delivery taking theophylline as a model drug used in asthma therapy. The crosslinking of gelatin decreased the drug release rate by 10–20% depending upon the extent of crosslinking. The modeled drug release characteristics revealed an anomalous transport mechanism. The release rates for ampicillin sodium, 5-fluorouracil and theophylline drugs in a typical crosslinked gelatin carrier were found to depend on the solubility and hydrophobicity of the drugs, and the pH of the fluid. The observed results indicated that this material can prove its mettle as a viable carrier matrix in drug delivery applications.     

Crosslinking studies in gelatin capsules treated with formaldehyde and in capsules exposed to elevated temperature and humidity

Incomplete in vitro capsule shell dissolution and subsequent drug release problems have recently received attention. A modified USP dissolution method was used to follow capsule shell dissolution, and a 2,4,6-trinitrobenzenesulfonic acid (TNBS) assay was used to follow loss of epsilon-amino groups to study this shell dissolution problem postulated to be due to gelatin crosslinking. The dissolution problems were simulated using hard gelatin capsule (HGC) shells previously treated with formaldehyde to crosslink the gelatin. These methods were also used to study the effect of uncrosslinked HGC stored under stressed conditions (37 degrees C and 81% RH) with or without the presence of soft gelatin capsule shells (SGC). A 120 ppm formaldehyde treatment reduced gelatin shell dissolution to 8% within 45 min in water at 37 degrees C. A 200 ppm treatment reduced gelatin epsilon-amino groups to 83% of the original uncrosslinked value. The results also support earlier reports of non-amino group crosslinking by formaldehyde in gelatin. Under stressed conditions, HGC stored alone showed little change over 21 weeks. However, by 12 to 14 weeks, the HGC exposed to SGC showed a 23% decrease in shell dissolution and an 8% decrease in the number of epsilon-amino groups. These effects on the stressed HGC are ascribed to a volatile agent from SGC shells, most likely formaldehyde, that crosslinked nearby HGC shells. This report also includes a summary of the literature on agents that reduce gelatin and capsule shell dissolution and the possible mechanisms of this not-so-simple problem.     

Preparation and characterization of spray-dried valsartan-loaded Eudragit® E PO solid dispersion microparticles

The purpose of this study was to develop the immediate release stomach-specific spray-dried formulation of valsartan (VAL) using Eudragit^® E PO (EPO) as the carrier for enhancing dissolution rate in a gastric environment. Enhanced solubility and dissolution in gastric pH was achieved by formulating the solid dispersion using a spray drying technique. Different combinations of drug–polymer–surfactant were dissolved in 10% ethanol solution and spray-dried in order to obtain solid dispersion microparticles. Use of the VAL–EPO solid dispersion microparticles resulted in significant improvement of the dissolution rate of the drug at pH 1.2 and pH 4.0, compared to the free drug powder and the commercial product. A hard gelatin capsule was filled with the VAL–EPO solid dispersion powder prior to the dissolution test. The increased dissolution of VAL from solid dispersion microparticles in gastric pH was attributed to the effect of EPO and most importantly the transformation of crystalline drugs to amorphous solid dispersion powder, which was clearly shown by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and powder X-ray diffraction (P-XRD) studies. Thus, VAL, a potential antihypertensive drug in the form of a solid dispersion microparticulate powder, can be effectively delivered in the immediate release dosage form for stomach-specific drug delivery.     

Development and in vitro evaluations of gelatin A microspheres of ketorolac tromethamine for intranasal administration

Gelatin A microspheres (MS) of ketorolac tromethamine (KT) for intranasal systemic delivery were developed with the aim to avoid gastro-intestinal complications, to improve patient compliance, to use as an alternative therapy to conventional dosage forms, to achieve controlled blood level profiles, and to obtain improved therapeutic efficacy in the treatment of postoperative pain and migraine. Gelatin A microspheres were prepared using the emulsification-crosslinking technique. The drug was dispersed in polymer gelatin and formulated into a w/o emulsion with liquid paraffin, using glutaraldehyde as a crosslinking agent. The formulation variables were drug loading and the concentrations of polymer (gelatin), co-polymer (chitosan) and the crosslinking agent. All the prepared microspheres were evaluated for physical characteristics, such as particle size, incorporation efficiency, swelling ability, in vitro bioadhesion on rabbit small intestine and in vitro drug release characteristics in pH 6.6 phosphate buffer. All the microspheres showed good bioadhesive properties. Gelatin A and chitosan concentrations, percentage of the crosslinking agent and also the drug loading affected significantly the rate and extent of drug release. The data indicated that the KT release followed Higuchi's matrix model.     

Release characteristics of salmon calcitonin from dextran hydrogels for colon-specific delivery.

Biodegradable dextran hydrogels were synthesized by crosslinking dextran (T-70) with epichlorohydrin (ECH) for the in vitro colon-specific delivery of salmon calcitonin (sCT). Crosslinking reaction was performed in 2.8 M NaOH solution both in the presence and absence of ethanol at 10 and 23 degrees C. Biodegradation kinetics of dextran hydrogels were studied and, in the presence of 0.7 IU ml-1 dextranase, dextran discs lost 71.0% and 56.5% of their dry weight within 80 h at pH 5.5 and 7.0, respectively. sCT was derivatized with the fluorescamine (FSM) at borate buffer (pH 9.0) and the quantitative determinations were performed using spectrofluorimetric method (lambdaex: 390 nm, lambdaem: 475 nm). In vitro release studies for the hydrogels prepared in the presence of ethanol were carried out in simulated gastrointestinal fluids. Results indicated that 84.9% of the loaded-sCT was released for 17 h and dextran hydrogel prepared in the presence of ethanol may be a good delivery device for the colon-specific delivery of other peptide-type drugs as well as sCT.     

Application and use of isothermal calorimetry in pharmaceutical development

Magnetic micro- and nanoparticles based on ferrofluid (maghemite) were elaborated by inverse emulsion crosslinking of sodium salt of carboxymethylcellulose (CMCNa) and gelatin. Crosslinking was carried out with glutaric aldehyde within aqueous droplets dispersed into toluene in presence of surfactants. The influence of parameters such as the ratio of polymers and maghemite in the initial mixture on the composition, size, size dispersity, particle swelling and their ability for drug inclusion was studied. The ability to take-up drugs is directly correlated with the degree of swelling and gelatin content within the particles. Particle size is between tens of nanometers and a few microns. The magnetic properties of particles are demonstrated from saturation magnetization (between 43 and 44 emu g(-1)) when their superparamagnetic character was shown by the absence of hysteresis on the magnetization curve. Polymer-drug systems elaborated under particles keep their bactericide activity for at least 48 h. The absence of toxicity, associated with the bactericide activity, make these systems potential drug carriers.     

Chitosan sponges as sustained release drug carriers

Chitosan sponges as sustained release drug carriers were prepared by freeze-drying partially N-acetylated chitosan gels and crosslinked chitosan solutions. Micronized triamcinolone acetonide was used as a model drug. N-acetylchitosan sponges were prepared from 2.5% chitosan solutions acetylated with 10.58 mmol of acetic anhydride per gram of chitosan. Crosslinked chitosan sponges were prepared from 2.5% chitosan solution crosslinked with 1.33% glutaraldehyde in respect to chitosan mass. Drug content in both N-acetylated and crosslinked chitosan sponges were uniform. Scanning electron microscopy (SEM) photos show a leaflet- or a platelet-like structure of both chitosan sponges. The incorporated drug was found in a crystalline form. The water uptake ability of both chitosan sponges was more than 20 times of their weight. The pH of dissolution media and the drug content of the sponges affected the release rate of the drug. The drug release at pH 1.2 was faster than at pH 7.4. The drug release at pH 7.4 was a function of square root of time over 52 h from the N-acetylchitosan sponges and over 36 h from the crosslinked chitosan sponges. With increasing the drug content a slower drug release was found. The delayed drug release was due to the decreased chitosan solubility by either N-acetylation or crosslinking.     

The influence of agitation intensity, particle size and pH of dissolution fluid on the in-vitro release of drug from hard gelatin capsules

The influence of agitation intensity on the in-vitro release of controlled particle size fractions of acetylsalicylic acid from hard gelatin capsules into buffered dissolution fluids has been investigated employing a dissolution technique. The value of T50 decreased as the stirring rate increased from 120 to 320 rev min-1 for all particle size fractions and pH values. A further increase in the stirring rate had a limited effect on the value of T50 and the changes were particle size dependent. The influence of the drug solubility, induced by changing the pH of the dissolution fluid, was decreased by increased agitation. When the capsules were filled at bulk densities above the maximum tapped bulk density, the value of T50 was increased, the extent of increase being greater the smaller the particle size of the drug. The kinetics of the solution process were influenced by agitation intensity and particle packing.     

Chemical and Swelling Evaluations of Amino Group Crosslinking in Gelatin and Modified Gelatin Matrices

Purpose. To determine the extent of amino group crosslinking in gelatin matrices by chemical assay, and to compare these results to crosslinking evaluations from swelling measurements. Methods. Matrices crosslinked with a water soluble carbodiimide (EDC/G), glutaraldehyde (GTA/G), as well as a GTA crosslinked matrix prepared from gelatin modified to contain 230% greater crosslinking sites (GTA/Mod) were evaluated. Crosslinking extent, X _c, was determined by a UV assay of uncrosslinked amino groups before and after crosslinking, and was used to obtain crosslinking densities. Equilibrium swelling ratios, Q _m at 37°C in isotonic pH 7.4 were used to calculate crosslinking degree from the Flory equation for swelling of ionic polymers for comparison to the chemically determined crosslinking densities. Results. Of the original 33 × 10^–5 moles -amino groups/g gelatin, 91 to 95% were crosslinked in EDC/G and GTA/G. GTA/Mod lost 95% of the original 108 × 10^–5 moles amino groups/g gelatin. Crosslinking densities were 4.1 × 10^–4 and 4.2 × 10^–4 moles/mL for EDC/G and GTA/G, respectively. The value for GTA/Mod increased to 14.2 × 10^–4 moles/mL. Values of Q _m followed the same trend. The Flory crosslinking degrees for both gelatin matrices were 12 × 10^–4 and 13 × 10^–4 moles/mL, respectively. The value for the more extensively crosslinked GTA/Mod was 280 × 10^–4moles/mL. Conclusions. The swelling and chemical evaluations of crosslinking are in general agreement for matrices with the lower of two crosslinking levels. The chemical determination appears suitable for evaluating amino group crosslinking in gelatin and it may be suitable for other proteinaceous materials.     

Swellable matrices for the controlled-release of diclofenac sodium: formulation and in vitro studies

Oral administration has been the most usual and convenient employed route of drug delivery systems. Particularly, oral sustained-release systems for the delivery of drugs by a process of continuous swelling of the polymeric carrier have been investigated. Thus, the goal of this study was to evaluate the effects of hydroxypropyl methylcellulose (HPMC) and carboxypolymer (Carbopol 934) on the release behavior of diclofenac sodium (DS) from a swellable matrix tablet system. Nine different DS controlled-released tablets were compressed by using the wet-granulation technology. The influence of the polymer content, the polymer ratio, the polymeric swelling behavior, and the pH changes on the release rate of DS was investigated. There was no significant difference in drug release when total polymer concentration was 10%. When the tablets were formulated having 20% or 30% of HPMC/carbomer, it was observed that a more rapid release of DS occurred as the carboxypolymer ratio within the matrices increased. In agreement with previous results, the dissolution studies demonstrated that the combination of these two polymeric matrix formers resulted in near zero-order release rate of DS. The DS release from all these matrix tablets was pH dependent, being markedly reduced at lower pH, and could be attributed to the poor solubility of DS at this pH value. In HCl 0.1 N solution, HPMC controlled drug release because the carbomer has a low solubility at this pH. As the pH increased, the carbomer became ionized, being able to interact with HPMC to control the drug release.     

pH-sensitive hydrogels based on bovine serum albumin for oral drug delivery

pH-sensitive bovine serum albumin (BSA) hydrophilic microspheres were prepared by free radical polymerization of methacrylate derivatized BSA and methacrylic acid sodium salt. Incorporation of both monomers in hydrogels was confirmed by Fourier transform infrared spectroscopy. Morphological analysis by scanning electron microscopy showed spherical shape and porous surface of all prepared samples. The microspheres showed high water affinity at neutral pH values and a narrow dimensional distribution. Network density of hydrogels depends on derivatization degree (DD%) of BSA and/or concentration of modified BSA in the polymerization feed. In order to employ the prepared samples such as pH-sensitive hydrogels, in vitro release studies, in media simulating biological fluids, were performed using diflunisal (DF) and beta-propranolol (PR) as model drugs. Experimental data showed that the release profiles depend on drug-matrix interactions and diffusional limitation awardable to crosslinking degree of microparticles. beta-Propranolol is quickly released at pH 1.0 and a complete release after 1 h at pH 6.8 was observed. In the case of diflunisal pH-sensitive release was observed. At pH 1.0 low amounts of drug were released (w/w<10% after 2 h). When the pH is 6.8, the diflunisal release increased in the amount (w/w>75% after 24 h).     

Development of novel gastroretentive floating particulate drug delivery system of gliclazide

The objective of present project was to improve the dissolution profile of gliclazide by developing floating alginate beads using various biodegradable polymers like gelatin, pectin and hydroxypropylmethylcellulose (HPMC). The floating beads were prepared by a simple ionotropic gelatin method using calcium carbonate as gas generating agent. The developed beads were characterized by Fourier transform infrared spectroscopy analysis, differential scanning calorimetry, X-ray diffraction analysis and scanning electron microscopy (SEM). The prepared beads showed good in vitro floatation, which was dependent on the concentration of gas-forming agent. SEM photomicrographs confirmed that the developed beads were spherical in shape and had particle size in the range of 730 to 890 μm. The incorporation efficiency was found to be in the range of 59.96 to 85.1%. The cumulative percent drug release from the beads after 10 h dissolution study at pH 1.2 and pH 5.8 was in the range of 33 to 46% and 82 to 95% respectively. The concentration of the gas generating agent was found to influence the release rate. The mechanism of drug release was Fickian diffusion with swelling. The in vivo sub-acute hypoglycemic study in high fat diet induced diabetic C57BL/6J mice demonstrated significant (p < 0.05) hypoglycemic effect over a period of 12 h and 24 h, respectively, with HPMC and pectin beads. A significant (p & 0.05) reduction in fasting and non-fasting blood glucose levels, reduction in fasting plasma insulin level and a significant improvement in glucose tolerance were observed in animals treated with formulations. The developed beads were suitable carriers for improving the systemic absorption of gliclazide and maintaining reduced blood glucose levels.