Development of Biodegradable Starch Microspheres for Intranasal Delivery

Domperidone microspheres for intranasal administration were prepared by emulsification crosslinking technique. Starch a biodegradable polymer was used in preparation of microspheres using epichlorhydrine as cross-linking agent. The formulation variables were drug concentration and polymer concentration and batch of drug free microsphere was prepared for comparisons. All the formulations were evaluated for particle size, morphological characteristics, percentage drug encapsulation, equilibrium swelling degree, percentage mucoadhesion, bioadhesive strength, and in vitro diffusion study using nasal cell. Spherical microspheres were obtained in all batches with mean diameter in the range of above 22.8 to 102.63 μm. They showed good mucoadhesive property and swelling behaviour. The in vitro release was found in the range of 73.11% to 86.21%. Concentration of both polymer and drug affect in vitro release of drug.     

Evaluation of snail mucin motifs as rectal absorption enhancer for insulin in non-diabetic rat models

The use of snail mucin motifs as rectal absorption enhancer for insulin has been evaluated. The mucin motifs were extracted from the giant African snail Archachatina marginata by differential precipitation with acetone. The mucin motifs were found to have a molecular weight of 5780 Da and an isoelectric point of 3.4. At the concentrations evaluated, the mucin exhibited rectal absorption enhancing property for the administration of insulin in rats. The % basal blood glucose level of the rats that received the batch of suppositories containing no mucin were consistently above 100% except at the ninetieth minute when it came down slightly to 97.2%. Rats dosed with the batch containing 7%w/w suppositories showed the greatest blood glucose reduction with mean % basal blood glucose concentration of 61.2%. Batches of the suppository containing 5% and 7% mucin showed more marked and consistent lowering in blood glucose concentration than the other batches containing lower amounts of the rectal absorption enhancer. The batch with 7% mucin reduced the basal glucose level to 44% within 2 h of administration of the glycero-gelatin suppository loaded mucin.     

Formulation and evaluation of chitosan microspheres of aceclofenac for colon‐targeted drug delivery

The objective of this investigation was to develop novel colon specific drug delivery. Aceclofenac, a NSAID, was successfully encapsulated into chitosan microspheres. Various formulations were prepared by varying the ratio of chitosan, span‐85 and stirring speed and the amount of glutaraldehyde. The SEM study showed that microspheres have smooth surfaces. Microspheres were characterised by Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) to confirm the absence of chemical interactions between drug and polymer and to know the formation of microspheres structure. The microspheres were evaluated for particle size, encapsulation efficiency, drug loading capacity, mucoadhesion studies, stability studies, in vitro and in vivo drug release studies. Particle sizes, as measured by the laser light scattering technique, were of an average size in the range 41–80 µm. The swelling index was in the range 0.37–0.82 and the entrapment efficiency range was 51–75% for all the formulations. The optimised batch ACM₁₃ released 83.6% at 8 h and 104% at 24 h in SCF containing rat caecal content. Eudragit coated chitosan microspheres prevented the release of the aceclofenac in the physiological environment of the stomach and small intestine and released 95.9±0.34% in the colon. With regard to release kinetics, the data were best fitted with the Higuchi model and showed zero order release with non‐Fickian diffusion mechanism. The in vivo findings suggest that aceclofenac microspheres exhibit a prolonged effect of aceclofenac in rats and produce a significant anti‐inflammatory effect. The findings of the present study conclusively state that chitosan microspheres are promising for colon targeting of aceclofenac to synchronise with chronobiological symptoms of rheumatoid arthritis. Copyright © 2010 John Wiley & Sons, Ltd.     

Preformulation experiences and in vitro model studies with spironolactone-containing suppositories

The optimal suppository base for the formulation of rectal suppositories containing diuretic spironolactone was selected experimentally. Model studies were carried out about the effect of solubility-increasing additives on the release of the drug from the suppositories. During the in vitro examinations acceptor phases of different pH values were used, and both diffusion time and the number of samplings were changed. Among the lipophilic and hydrophilic suppository bases studied the hydrophilic Macrogolum 1540 was found to be optimal. The release and diffusion of spironolactone was the most favourable from these suppositories. During storage these suppositories remained stable and the values of release did not decrease significantly (p < 0.05).     

Development and characterisation of levosulpiride-loaded suppositories with improved bioavailability in vivo

The purpose of this study was to develop and characterize levosulpiride loaded liquid suppository with improved bioavailability. The content of levosulpiride-loaded liquid suppositories were optimized in a series of experiments using various weight ratios of P188, P407, Tween 80, and drug. The suppositories were liquid at room temperature, however, when rectally administered, they became gel at body temperature. Their rheological properties and release characteristics were determined in vitro while pharmacokinetic study was performed after its rectal administration in rats and compared with drug suspension. Poloxamer 188 and Twee 80 decreased the gelation temperature and gelation time, but increased the gel strength and mucoadhesive force of liquid suppositories. Liquid suppository composed of [Levosulpiride/P 188/P 407/Tween 80 (1/15/17/3%)] with a gelation temperature of about 30.7?°C remained liquid at 25?°C, but converted to gel at 30–36.5?°C, resulting in easy administration and rapid gelation inside the body. This liquid suppository gave a considerably increased dissolution rate reflected in a meaningfully higher plasma concentration and 7.1-fold AUC values of levosulpiride in rats as compared to the drug suspension. Hence, liquid suppository system could be used for enhanced bioavailability of levosulpiride-loaded pharmaceutical products.     

Pharmacokinetics and anti-hypertensive effect of metoprolol tartrate rectal delivery system

The main aim of this work was to develop rectal suppositories for better delivery of metoprolol tartrate (MT). The various bases used were fatty, water soluble and emulsion bases. The physical properties of the prepared suppositories were characterized such as weight variation, hardness, disintegration time, melting range and the drug content uniformity. The in vitro release of MT from the prepared suppositories was carried out. The evaluation of the pharmacological effects of MT on the blood pressure and heart rate of the healthy rabbits after the rectal administration compared to the oral tablets was studied. Moreover, the formulation with the highest in vitro release and the highest pharmacological effects would be selected for a further pharmacokinetics study compared to the oral tablets. The results revealed that the emulsion bases gave the highest rate of the drug release than the other bases used. The reduction effect of the emulsion MT suppository base on the blood pressure and heart rate was found to be faster and greater than that administered orally. The selected emulsion suppository base (F11) showed a significant increase in the AUC (1.88-fold) in rabbits as compared to the oral tablets. From the above results we can conclude that rectal route can serve as an efficient alternative route to the oral one for systemic delivery of MT which may be due to the avoidance of first-pass effect in the liver.     

挤出滚圆法制备马来酸曲美布汀胃黏附微球

目的利用适合于工业化生产的方法制备具有较好生物黏附能力和适宜缓释效果的马来酸曲美布汀胃黏附微球。方法通过挤出滚圆法制备马来酸曲美布汀胃黏附微球 ;以动物体内外胃黏膜表面滞留程度 ,考察CP的含量和微球粒径对微球黏附能力的影响 ;以体外释药速率评价热处理 ,CP的含量 ,CP、SA与EC间的比例 ,TM含量 ,微球粒径对微球缓释效果的影响 ;以镇痛效果考察最终处方的药效。结果CP比例增加 ,微球的黏附性增强 ,药物缓释效果降低 ,呈现负相关 ;TM含量增加 ,微球的黏附性降低 ,缓释效果降低 ;微球粒径增大 ,微球的黏附性降低 ,缓释效果增加 ;最佳处方的作用时间延长 ,作用强度增强。结论载药量在 2 0 % (w)以下 ,粒径为 5 0 0～ 90 0 μm,CP含量为 1 3 3 0 % (w)的TM微球在胃黏膜表面具有良好的黏附特性 ,且药物缓释可达 8h。     

Effects of absorption enhancers in chloroquine suppository formulations: I. In vitro release characteristics.

The need to develop chloroquine suppository formulations that yield optimal bioavailability of the drug has been emphasized. This study demonstrates the effects of incorporation of known absorption-enhancing agents (nonionic surfactants and sodium salicylate) on the in vitro release characteristics of chloroquine from polyethylene glycol (1000:4000, 75:25%, w/w) suppositories. The release rates were determined using a modification of the continuous flow bead-bed dissolution apparatus for suppositories. Results showed that the extent of drug release from suppositories containing any of three surfactants (Tween 20, Tween 80 and Brij 35) was 100%, whereas 88% release was obtained with control formulation (without enhancer) (P<0.05). However, Tween 20 was more effective than Brij 35 and Tween 80 in improving the drug release rate. There was a concentration-dependent effect with Tween 20, and 4% (w/w) of this surfactant was associated with the highest increase in the rate of drug release from the suppositories. Sodium salicylate at a concentration of 25% (w/w) also significantly enhanced the drug release rate, but a higher concentration of the adjuvant markedly reduced both the rate and extent of drug release. Combined incorporation of Tween 20 and sodium salicylate did not significantly modify (P0.05) the rate of drug release when compared to the effect of the more effective single agent. Due to their effects in improving the drug release profiles coupled with their intrinsic absorption-promoting properties, it is suggested that incorporation of 4% (w/w) Tween 20 and/or 25% (w/w) sodium salicylate in the composite polyethylene glycol chloroquine suppository formulations, may result in enhancement of rectal absorption of the drug. This necessitates an in vivo validation.     

Design of controlled-release morphine suppositories containing polyglycerol ester of fatty acid

Controlled-release morphine suppositories were prepared by utilizing polyglycerol ester of fatty acid (PGEF). The addition of PGEF to fatty suppository base Witepsol H15 resulted in a decrease of morphine release rate from suppositories. Among PGEFs examined, decaglycerol heptabehenate (HB750) was the most effective additive for the controlled-release of morphine from fatty suppositories. The apparent viscosity of suppository bases increased with the increase in HB750 content, and good correlation was observed between the apparent viscosity of suppository bases at 37 degrees C and the amount of HB750 added in the mixed base. The in vitro release rate of morphine was decreased by the addition of HB750 and the release rate constant (Higuchi's rate constant) for morphine release was significantly correlated with the HB750 content in the mixed bases as well as the apparent viscosity of mixed bases, indicating that the release of morphine from the mixed bases could be regulated by the HB750 content in the mixed bases. After rectal administration of Witepsol H-15-HB750 mixed suppositories to dogs, plasma concentrations of morphine did not increase rapidly at early time periods, but relatively high levels of morphine in plasma were sustained for longer time periods. Mean residence time of morphine was considerably prolonged without changing relative bioavailability in the case of the mixed base suppositories containing 15-17% HB750, compared with the Witepsol H15 suppository, clearly indicating that the mixed bases containing HB750 are expected to be useful for the design of controlled-release morphine suppositories.     

Layered excipient suppositories: The possibility of modulating drug availability

The release rate of a drug dose from suppositories is affected by characteristics of the excipient (melting temperature and rate, viscosity at rectal temperature, hydro-lipophilic characteristics). Release kinetics from excipients commonly available do not always respond to clinical requirements, even after the introduction of auxiliary agents. Release curves which were differentiated and adaptable to therapeutic conditions were obtained by vehicling a drug in suppositories of two superimposed layers of lipophilic excipients with different characteristics and hence with a difference in drug availability. The two distinct excipient layers release the drug from these suppositories contemporaneously but independently. The amount of drug released in the time course is the sum of the single amounts individually released by the two suppository layers. By previously mixing the two excipients, release rate becomes uniform in the suppository body overall and is conditioned only by the assumed characteristics of the mixture. The release mechanism for superimposed layer suppositories is confirmed by the good agreement between experimental and calculated curves. By using a pair of excipients with different characteristics in superimposed layers between which the drug is distributed, it is possible to modulate drug release kinetics by regulating the reciprocal ratio between the two suppository fractions.     

Thermally Reversible In Situ Gelling Carbamazepine Liquid Suppository

Carbamazepine (CBZ), indicated for the control of epilepsy, undergoes extensive hepatic first-pass elimination after oral administration. A rectal dosage form of CBZ is not commercially available, although it is of particular interest when oral administration is impossible. Conventional suppositories can cause patient discomfort and may reach the end of the colon; consequently, the drug can undergo the first-pass effect. Mucoadhesive liquid suppositories of CBZ were prepared by adding carbopol to formulation of thermally gelling suppositories that contain 20% poloxamer 407 and either 15% poloxamer 188 or 1% methylcellulose. Gellan gum was also tried instead of 20% poloxamer. All formulations contained 10% CBZ. The characteristics of the suppositories differed depending on the formulation. The formula containing 20% poloxamer 407, 1% methylcellulose, and 0.5% carbopol showed reasonable gelation temperature, gel strength and bioadhesive force. The analysis of release mechanism showed that CBZ released from the suppositories by Fickian diffusion. In vivo evaluation of the same formulation showed higher peak plasma concentration of CBZ compared with the orally administered suspension containing the equivalent amount of drug. However, there was no statistical significant difference (p > 0.05) in extent of bioavailability between the liquid suppository and oral suspension as indicated by the values of AUC_{0 - ∝}, 17.9 and 18.8 μ g.h/ml, respectively. These results suggested that mucoadhesive in situ gelling liquid suppository could be an effective and convenient delivery system of carbamazepine.     

Lacidipine encapsulated gastroretentive microspheres prepared by chemical denaturation for pylorospasm

The purpose of this research work was to formulate and systematically evaluate in vitro performance of mucoadhesive microspheres of lacidipine for treatment of pylorospasm. Lacidipine microspheres containing chitosan were prepared by chemical denaturation using glutaraldehyde as a cross-linking agent. The microspheres were evaluated for physical characteristics such as particle size, particle shape and surface morphology by scanning electron microscopy, drug entrapment efficiency and in vitro mucoadhesion. Results of preliminary trials indicated that the polymer concentration, cross-linking agent and stirring speed had a noticeable effect on size and surface morphology. A central composite design was employed to study the effect of independent variables, polymer concentration (X(1)), volume of glutaraldehyde (X(2)), stirring speed (X(3)) and cross-linking time (X(4)) on dependent variables, drug entrapment efficiency and percentage mucoadhesion. The entrapment efficiency varied from 14-40.82% depending upon the polymer concentration, volume of cross-linker and stirring speed. All batches of microspheres exhibited good mucoadhesive property (73-83%) in the in vitro wash-off test. It was observed that polymer concentration and glutaraldehyde volume had a more significant effect on the dependent variables. Maximum entrapment (36.53%) and mucoadhesion (81.33%) was predicted at 3.5% chitosan, 3 ml glutaraldehyde, 3000 rpm stirring speed and 75 min cross-linking time under optimized process condition. The selected formulation showed controlled release for more than 6 h. The release followed Higuchi kinetics via a Fickian diffusion.     

利福平丝素蛋白载药微球的制备及性能研究

目的通过测定利福平丝素蛋白微球的载药量、包封率及释放度,考察乳化转速、有机溶剂与丝素蛋白溶液比例,对微球的制备方法进行优化,筛选微球的最佳制备方法。方法采用乳化法制备利福平丝素蛋白微球,以不同转速、有机溶剂与丝素蛋白溶液不同比例分别制备利福平丝素蛋白微球,采用扫描电镜观察微球的形态,用紫外分光光度法测定微球的载药量、包封率及释放度,以形态、载药量、包封率及释放度为指标,筛选微球的最佳制备方法。在此基础上,采用最佳处方制备3批利福平丝素蛋白微球,对微球的形态、粒径、包封率、载药量和释放度进行考察。结果有机溶剂与丝素蛋白溶液体积比为4∶1、转速为200 r·min^-1时所得利福平丝素微球形态均匀,近似球形,载药量和包封率较高,所得载药微球有较好的缓释作用。以最佳处方制得微球载药量为66.1%±0.87%,包封率为87.80%±2.23%。结论有机溶剂与丝素蛋白溶液体积比为4∶1、转速为200 r·min^-1时载药量、包封率和释放度较好,故选择此处方为利福平丝素蛋白微球的最佳制备处方。     

Investigation of the relationship between melting-related parameters and in vitro drug release from vaginal suppositories

The effect of temperature on drug release from meteneprost potassium vaginal suppositories was investigated using a dissolution test based on the USP I apparatus. Comparison of the dissolution results with the DSC melting behaviour revealed that drug release was extremely slow until melting of the suppository was essentially complete. The melting behaviour of the meteneprost potassium suppositories was also varied by preparing suppositories from bases with higher and broader melting ranges. The observed dissolution behaviour (at 37 degrees C) confirmed that drug release increased as the melting temperature of a particular suppository decreased. Differential scanning calorimetry, viscosity and dilatometry methods were used to characterize the suppository melting process. The effects of suppository melting range, melt temperature and composition were investigated with respect to in vitro drug release. Methodology for the HPLC determination of meteneprost in suppositories and in dissolution media are also reported.     

Influence of viscosity and uronic acid composition of alginates on the properties of alginate films and microspheres produced by emulsification

This study investigated the influence of viscosity and uronic acid composition of alginates on the properties of alginate films and microspheres produced by emulsification. Tensile properties of films were determined while the yield, size, drug contents and release characteristics of the microspheres were examined. Tensile properties of calcium alginate matrix were significantly affected by the orientation and arrangement of the polymer chains. High viscosity alginates gave rise to higher yields and bigger microspheres. Generally, microspheres with high drug content and slower rate of drug release had high Ca²⁺ contents and were produced from alginates of higher viscosity. Within an alginate microsphere batch, small sized microsphere fractions had higher drug contents but showed faster drug release rates. Microspheres having a defined size range revealed great dependence of encapsulation efficiency and drug release rates on viscosity and extent of Ca²⁺-alginate interaction. Viscosity appeared to exert a predominant influence on the microsphere properties.     

Effect of Drug (Core) Particle Size on the Dissolution of Theophylline from Microspheres Made from Low Molecular Weight Cellulose Acetate Propionate

Three particle sizes (450, 120, and 5 µm) of theophylline were encapsulated in low molecular weight cellulose acetate propionate (intrinsic viscosity, 1.08 dl/g) by the solvent evaporation method. The theoretical drug content for all the batches of microspheres was 50% (w/w). Particle size analysis revealed that about 50% of the microspheres containing the large theophylline crystals (average length of 450 µm) were greater than 500 µm in diameter, whereas only about 35% of the microspheres containing the medium drug crystals (average length of 120 µm) were greater than 500 µm in diameter. The drug content of the larger microspheres prepared from the large drug crystals and the medium drug crystals was much greater than the theoretical drug content (50%, w/w); however, the drug content of all the batches of microspheres containing micronized drug was close to 50% (w/w). Release of the drug in simulated intestinal fluid was very rapid from microspheres containing large and medium drug crystals, while release was slower and more predictable from microspheres made from micronized drug.     

Improvement of solubility and dissolution properties of clotrimazole by solid dispersions and inclusion complexes

Solid dispersions of a slightly water-soluble drug, clotrimazole, were prepared in different weight ratios using polyethyleneglycol 4000 and different molecular weight polyvinyl pyrrolidones as carriers. Moreover, binary and ternary β-cyclodextrin complexes were prepared in different molar ratios. Both solid dispersions and β-cyclodextrin complexes were prepared by solvent evaporation technique. A phase solubility method was used to evaluate the effect of the tested carriers on the aqueous solubility of clotrimazole. The dissolution of all the preparations was tested using the USP paddle method. The selected solid dispersions and inclusion complexes were characterized by differential scanning calorimetry and X-ray powder diffractometry studies, and results clarified the role of the tested carriers in decreasing the crystallinity of clotrimazole and complexing abilities. Based on physical characters and in vitro drug release pattern, polyvinylpyrrolidone solid dispersions (1:1 weight ratio) and ternary cyclodextrin complexes (clotrimazole-β-cyclodextrin complexes with either polymer, 1:1 molar ratio) were selected as ideal batches for suppositories. Suppocire AM/50 mg carbopol 940, was chosen as a suppository base and the suppositories were prepared by molding technique. The prepared suppositories were characterized for weight variation, softening time and drug content. All these properties were found to be ideal. The in vitro drug release pattern was determined in citrate buffer (pH 4.5) containing 1% sodium lauryl sulfate. The in vitro release of clotrimazole from its solid dispersions and inclusion complexes incorporated suppositories was markedly improved when compared to the intact drug incorporated suppositories. Polyvinyl pyrrolidone solid dispersions incorporated suppositories were found to possess excellent antifungal activity.     

Development,optimization and in vitro evaluation of alginate mucoadhesive microspheres of carvedilol for nasal delivery

Abstract

The present research work was aimed at development and optimization of alginate mucoadhesive microspheres of carvedilol for nasal delivery to avoid first pass metabolism and to improve the therapeutic efficacy in the treatment of hypertension and angina pectoris. The microspheres were prepared by a water-in-oil (w/o) emulsification technique. A 2³ factorial design was employed with drug : polymer ratio, calcium chloride concentration and cross-linking time as independent variables while particle size of the microspheres and in vitro mucoadhesion were the dependent variables. Regression analysis was performed to identify the best formulation conditions. Particle size was analysed by dynamic laser light diffraction technique and found to be in the range of 26.36–54.32 µm, which is favourable for intranasal absorption. The shape and surface characteristics were determined by scanning electron microscopy (SEM) which depicted the spherical nature and nearly smooth surfaces of the microspheres. The percentage encapsulation efficiency was found to be in the range between 36.62–56.18. In vitro mucoadhesion was performed by adhesion number using sheep nasal mucosa and was observed in a range from 69.25–85.28. Differential scanning calorimetry and X-ray diffraction results indicated a molecular level dispersion of carvedilol in the microspheres. In vitro release studies in pH 6.2 phosphate buffer indicated non-Fickian or anomalous type of transport for the release of carvedilol from the microspheres.     

阿奇霉素缓释阴道栓的处方优化

目的:优化阿奇霉素缓释阴道栓的处方。方法:采用硬脂酸聚烃氧酯(S-40)为基质,以羟丙基甲基纤维素(HPMC)为缓释材料、甘油为保湿剂等制备阿奇霉素缓释阴道栓。以累积释药百分率和栓剂硬度为考察指标、8%HPMC和甘油在处方中的用量为考察因素,采用正交设计法进行处方优化,并进行验证试验及体外释药模型拟合。结果:优化后处方组成为阿奇霉素6g,8%HPMC23.52g,甘油29.40g,无水乙醇3g,尼泊金乙酯0.59g,S-40294g。由优化后处方制备的3批栓剂平均含量99.5%,硬度符合要求,体外释放重复性和均一性良好,180min时累积释药百分率均大于98%,体外释药动力学符合Higuchi方程。结论:优化后的阿奇霉素缓释阴道栓处方可行,制备工艺稳定,重复性好,符合缓释制剂要求。     

Development and characterization of mucoadhesive microspheres for nasal delivery of ketorolac

The objective of the present investigation was to prepare mucoadhesive microspheres of ketorolac for nasal administration by means of a solvent evaporation technique using carbopol (CP), polycarbophil (PL) and chitosan (CS) as mucoadhesive polymers. The prepared microspheres were characterized for morphology, swelling behavior, mucoadhesion, interaction studies, drug encapsulation efficiency, in vitro drug release, release kinetics, and ex vivo nasal cilio toxicity studies. The effects of various process variables on the particle size of the microspheres were investigated. Drug encapsulation efficiency and particle size of the microspheres ranged from 52-78% w/w and 14-46 microm respectively. Interaction studies revealed that there were no drug-polymer interactions. The in vitro release profiles showed prolonged-release of the drug. In vitro release data showed a good fit with the Higuchi model, and indicated Fickian diffusion. No severe damage was found to the integrity of nasal mucosa after ex vivo experiments.