Film coated tablets (ColoPulse technology) for targeted delivery in the lower intestinal tract: Influence of the core composition on release characteristics

The design of a film coating technology which allows a tablet to deliver the drug in the ileocolonic segment would offer new treatment possibilities. The objective is to develop a platform technology that is suitable for a broad range of drug compounds. We developed a coated tablet with a delayed, pulsatile release profile based on a pH-sensitive coating technology (ColoPulse). The production process was validated, and the effect of core composition on the in vitro release and water uptake investigated. The release profile of the standard tablet core composition, based on the use of cellulose as a filler, was independent of the coat thickness in a range of 9.0–13.2?mg/cm². The release profile of a coated tablet was strongly influenced when cellulose was partly replaced by the model substance glucose (loss of sigmoidal release), citric acid (stabilization), sodium bicarbonate (destabilization) or sodium benzoate (destabilization). The film coating takes up water when below the pH-threshold. However, this did not cause early disintegration of the coating. The ColoPulse technology is successfully applied on tablets. The in vitro release characteristics of the coated tablets are influenced by the composition of the core.     

Film coated tablets (ColoPulse technology) for targeted delivery in the lower intestinal tract: influence of the core composition on release characteristics

The design of a film coating technology which allows a tablet to deliver the drug in the ileocolonic segment would offer new treatment possibilities. The objective is to develop a platform technology that is suitable for a broad range of drug compounds. We developed a coated tablet with a delayed, pulsatile release profile based on a pH-sensitive coating technology (ColoPulse). The production process was validated, and the effect of core composition on the in vitro release and water uptake investigated. The release profile of the standard tablet core composition, based on the use of cellulose as a filler, was independent of the coat thickness in a range of 9.0-13.2?mg/cm(2). The release profile of a coated tablet was strongly influenced when cellulose was partly replaced by the model substance glucose (loss of sigmoidal release), citric acid (stabilization), sodium bicarbonate (destabilization) or sodium benzoate (destabilization). The film coating takes up water when below the pH-threshold. However, this did not cause early disintegration of the coating. The ColoPulse technology is successfully applied on tablets. The in vitro release characteristics of the coated tablets are influenced by the composition of the core.     

TARGIT technology: coated starch capsules for site-specific drug delivery into the lower gastrointestinal tract

TARGIT technology (West Pharmaceutical Services) is designed for site-specific delivery of drugs in the gastrointestinal (GI) tract and, in particular, targeted release into the colonic region. A key area of application is the delivery of therapeutic agents for local treatment of lower GI diseases. The technology is based on the application of pH-sensitive coatings onto injection-moulded starch capsules. An extensive body of clinical data has been generated showing reliable in vivo performance of the capsules. In gamma-scintigraphy studies around 90% of TARGIT capsules (n = 84) delivered their contents to the target site of the terminal ileum and colon. TARGIT-based products are in active clinical development for the treatment of conditions including inflammatory bowel diseases.     

Cell culture models of the respiratory tract relevant to pulmonary drug delivery.

The respiratory tract holds promise as an alternative site of drug delivery due to fast absorption and rapid onset of drug action, with avoidance of hepatic and intestinal first-pass metabolism as an additional benefit compared to oral drug delivery. At present, the pharmaceutical industry increasingly relies on appropriate in vitro models for the faster evaluation of drug absorption and metabolism as an alternative to animal testing. This article reviews the various existing cell culture systems that may be applied as in vitro models of the human air-blood barrier, for instance, in order to enable the screening of large numbers of new drug candidates at low cost with high reliability and within a short time span. Apart from such screening, cell culture-based in vitro systems may also contribute to improve our understanding of the mechanisms of drug transport across such epithelial tissues, and the mechanisms of action how advanced drug carriers, such as nanoparticles or liposomes, can help to overcome these barriers. After all, the increasing use and acceptance of such in vitro models may lead to a significant acceleration of the drug development process by facilitating the progress into clinical studies and product registration.     

Potential use of microencapsulation for sustained drug delivery to the respiratory tract.

Microencapsulation has long been regarded as a means of achieving sustained drug delivery. In these studies, a spray drying technique was used to produce salbutamol-loaded albumin microparticles with a view to formulating a controlled release system to be used in respiratory drug delivery. Encapsulation efficiencies (40-60 % w/w) obtained using this technique compared very favourably with those obtained using emulsification procedures (1-2 % w/w).     

Feasibility of a low dosage dynamic powder dispenser for drug delivery to the lungs.

Inhalation of drugs offers the opportunity to treat diseases of the respiratory tract. A manually operated prototype, called Dynamic Powder Dispenser (DPD), for dispensing a predetermined amount of powdered drug has been developed. This device actively disperses powder from a chamber through a mouthpiece ready for inhalation. The DPD is a multi-single dose device which delivers drugs actively and does not require breath actuation. This DPD which insufflates dry powder into the respiratory tract can be considered as a counterpart to an MDI. The respirable fraction was found in-vitro in the range of 10% and 25% for salbutamol and terbutaline, respectively.     

Bioadhesive polymer/lipid hybrid nanoparticles as oral delivery system of raloxifene with enhancive intestinal retention and bioavailability

Raloxifene (RLX) is a second-generation selective estrogen receptor modulator used to treat osteoporosis in postmenopausal women. RLX fails to be developed into injectable dosage forms due to poor solubility. Although oral formulations are clinically available, the lower bioavailability (<2%) embarrasses the pharmaceutists. This work reported a bioadhesive nanosystem intended for oral delivery of RLX to enhance its oral bioavailability and address the formulation challenge. The bioadhesive nanosystem refers to polymer–lipid hybrid nanoparticles made up of Carbopol 940, glyceryl distearate, and TGPS. RLX was solidly encapsulated into bioadhesive nanoparticles (bNPs) through a nanoprecipitation technique along with synchronous desalting of RLX·HCl. The resultant RLX-loaded bNPs (RLX-bNPs) were characterized by particle size, ζ potential, morphology, and entrapment efficiency. The in vitro release and in vivo oral bioavailability of RLX-bNPs in rats were comparatively investigated with RLX-loaded common lipid nanoparticles (RLX-cNPs). The preferred formulation possesses a particle size of 150 nm around with a polydispersity index (PDI) of 0.282. RLX-bNPs exhibited slower drug release than RLX-cNPs owing to the presence of an adhesive layer. After oral administration, RLX-bNPs resulted in significant enhancement in the bioavailability of RLX, up to 556.9% relative to RLX suspensions, while it was merely 244.7% for RLX-cNPs. Cellular testing and ex vivo transport imaging demonstrated that bNPs were endowed with excellent intestinal epithelial affinity and absorbability. Our study affords an alternative option for designing a suitable oral delivery system specific to amphiphobic drugs like RLX·HCl.     

Selective drug delivery to the colon using pectin:chitosan:hydroxypropyl methylcellulose film coated tablets.

A study has been carried out to assess the potential of pectin:chitosan:hydroxypropyl methylcellulose (HPMC) (P:C:H) films for colonic drug delivery. Radiolabelled (99mTc) tablets were coated with a 3:1:1, P:C:H film and administered to human volunteers. The gastro-intestinal transit of the tablets was assessed by gamma scintigraphy. The results showed that in all cases (n=4), the tablets were able to pass through the stomach and small intestine intact. Break up of the tablets commenced once they were in the colon, due to degradation of the coat by colonic bacteria. The study has highlighted the potential of this coating system for colonic drug delivery.     

Feasibility of drug delivery to the respiratory tract by a mechanical micro spray pump.

A hand actuated, propellant free spray device is being developed which may be suitable for medical inhalation therapy. The purpose was to evaluate the feasibility of the mechanical micro spray pump to produce a fine spray whose droplets were suitable for inhalation. The physical and technical requirements have been achieved using an air blast nozzle which has been improved by changing the geometry and therefore the dynamic properties within the spray nozzle. The generation of particles above 50 mum in diameter was suppressed and the injection time of the spray increased. These features resulted in a finer and more uniform spray. In-vivo experiments were conducted, where 15 mul per stroke of a 99mTc labeled saline solution was delivered to test persons. The activity was measured by gamma-scintigraphy. It was observed that without and with a spacer, a respective thoracic deposition of 8 %vol and 13 %vol was achieved on average.     

Site-specific drug delivery to the middle region of the small intestine by application of enteric coating with hypromellose acetate succinate (HPMCAS)

Enteric coatings that deliver drugs to specific regions of the small intestine were examined. Hypromellose acetate succinate (HPMCAS) with different values of succinoyl group contents was used. Decreasing the succinoyl group content resulted in an increase in the pH at which HPMCAS started to dissolve. Drug-containing granules with or without enteric coating were prepared and their in vitro dissolution in a simulated intestinal fluid of pH 6.8 was examined. Granules coated with HPMCAS having the succinoyl group content of 6.2% showed a lag time of about 30 min, although drug release from granules without coating was completed within 20 min. The time lag and dissolution rate were extended and reduced, respectively, as the succinoyl group content was decreased. Rat experiments indicated that enteric-coated granules disintegrated and the bulk of the drugs was immediately released when the granules reached a specific site of the small intestine where the pH corresponded to the pH at which the enteric coating agent started to dissolve. Similar results were observed in monkey experiments. It was suggested that HPMCAS with the succinoyl group content of about 5% was suitable as an enteric coating agent for delivering drugs to the middle-to-lower region of the small intestine.     

Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of intestinal absorption

For almost a half century scientists have striven to develop a theoretical model capable of predicting oral drug absorption in humans. From the pH-partition hypothesis to the compartmental absorption and transit (CAT) model, various qualitative/quantitative approaches have been proposed, revised and extended. In this review, these models are classified into three categories; quasi-equilibrium models, steady-state models and dynamic models. The quasi-equilibrium models include the pH-partition hypothesis and the absorption potential concept, the steady-state models include the film model and the mass balance approaches, and the dynamic models include the dispersion, mixing tank and CAT models. The quasi-equilibrium models generally provide a basic guideline for understanding drug absorption trends. The steady-state models can be used to estimate the fraction of dose absorbed. The dynamic models predict both the fraction of dose absorbed and the rate of drug absorption and can be related to pharmacokinetic models to evaluate plasma concentration profiles.     

下呼吸道感染主要病原菌及耐药性分析

目的了解某院内科患者下呼吸道感染病原菌的构成及耐药性情况,指导临床合理用药。方法收集内科住院下呼吸道感染患者的痰液标本进行分离培养和鉴定,并进行耐药性试验,记录、统计实验结果。结果321例痰液标本共分离病原菌194株,其中革兰阴性杆菌126株,占64．95％,革兰阳性球菌31株,占15．98％,真菌37株,占19．08％。革兰阴性菌对氨苄西林、复方磺胺甲基异口恶唑的耐药性较高,分别达到87．45％-97．74％和75．37％～91．75％。铜绿假单胞菌和鲍曼不动杆菌对所选抗生素耐药性较高,并呈现多重耐药性。结论下呼吸道感染患者的病原菌种类较多,革兰阴性菌感染占大多数,铜绿假单胞菌和鲍曼不动杆菌的耐药率较高。     

Effect of polymer architecture on curcumin encapsulation and release from PEGylated polymer nanoparticles: Toward a drug delivery nano-platform to the CNS

We developed a nanoparticles (NPs) library from poly(ethylene glycol)–poly lactic acid comb-like polymers with variable amount of PEG. Curcumin was encapsulated in the NPs with a view to develop a delivery platform to treat diseases involving oxidative stress affecting the CNS. We observed a sharp decrease in size between 15 and 20% w/w of PEG which corresponds to a transition from a large solid particle structure to a “micelle-like” or “polymer nano-aggregate” structure. Drug loading, loading efficacy and release kinetics were determined. The diffusion coefficients of curcumin in NPs were determined using a mathematical modeling. The higher diffusion was observed for solid particles compared to “polymer nano-aggregate” particles. NPs did not present any significant toxicity when tested in vitro on a neuronal cell line. Moreover, the ability of NPs carrying curcumin to prevent oxidative stress was evidenced and linked to polymer architecture and NPs organization. Our study showed the intimate relationship between the polymer architecture and the biophysical properties of the resulting NPs and sheds light on new approaches to design efficient NP-based drug carriers.     

pH-independent release of a basic drug from pellets coated with the extended release polymer dispersion Kollicoat SR 30 D and the enteric polymer dispersion Kollicoat MAE 30 DP.

The objective of this study was to obtain pH-independent release profiles from coated pellets containing drugs with pH-dependent solubility. pH-independent release of the basic model drug verapamil HCl was achieved by coating with a combination of the neutral polymer dispersions Kollicoat SR 30 D (aqueous dispersion of polyvinyl acetate) and the enteric polymer dispersion Kollicoat MAE 30 DP (aqueous dispersion of methacrylic acid and ethyl acrylate copolymer; methacrylic acid copolymer type C). The two polymers where applied either as separate layers (enteric polymer + extended release polymer or vice versa) or as a polymer blend. A careful balance of the ratios of the polymers allowed the achievement of a pH-independent release. Higher amounts of the enteric polymer in the polymer blend resulted in a reversal of the pH-dependency, e.g. a faster release at pH 6.8 than in 0.1 N HCl.     

Guide to drug therapy for lower urinary tract symptoms in patients with benign prostatic obstruction : implications for sexual dysfunction

The relationship between erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) caused by benign prostatic obstruction (BPO) has recently gained increasing attention. Both BPO and ED are highly prevalent in older men and both conditions frequently contribute to a reduction in overall quality of life. Current medical treatment of LUTS/BPO consists of monotherapy with alpha(1)-adrenoceptor antagonists or 5alpha-reductase inhibitors, a combination of these two agents or, in some cases, various phytotherapeutic approaches. When choosing a drug therapy, it is important to recognize that while 5alpha-reductase inhibitors increase the risk of ED and ejaculatory disorders, and combined therapy carries the cumulative risk of causing sexual dysfunction, some alpha(1)-adrenergic receptor antagonists have been reported to improve overall sexual function. Therefore, the successful evaluation and management of older men with LUTS associated with BPO should include an assessment of baseline sexual function and subsequent monitoring of medication-induced sexual adverse effects. In this review, we detail the pathophysiological mechanisms involved in LUTS/BPO-associated ED, including reduced nitric oxide/cyclic guanosine monophosphate system activity, enhanced endothelin-1/rhoA/rho kinase pathway activity, sympathetic overactivity, pelvic organ atherosclerosis and potential preventive approaches.     

Potential applications of gene therapy/transfer to the treatment of lower urinary tract diseases/disorders

Identification of molecular targets for novel therapeutics is a natural consequence of the age of molecular and personalized medicine. How this information is leveraged and applied to the treatment of functional diseases/disorders of the lower urinary tract will determine if this field of medicine can keep pace with technological developments and patient expectations for improved therapies. In this regard, therapeutic improvements for the treatment of lower urinary tract diseases and disorders have been largely incremental over the past 30 years. The goal of this report is to review the evidence pointing toward the enormous potential of gene therapy/transfer to provide a paradigm shift from palliative to curative therapeutic solutions for lower urinary tract diseases/disorders. In fact, it seems clear that gene therapy represents a biotechnology approach particularly suitable to applications in the lower urinary tract. Although much more research is required, ample preclinical evidence already indicates that, for example, gene therapy can favorably impact/alter virtually every aspect of bladder physiology/function. In short, further investigations and continued applications of gene therapy to the treatment of lower urinary tract diseases/disorders seems a prudent step toward potentially marked and more durable therapeutic improvements.     

儿科重症监护室下呼吸道感染常见病原菌分布及耐药分析

目的 探讨儿科重症监护室重症下呼吸道感染患儿痰液标本培养和药敏监测的意义.方法 回顾性分析1107例儿童重症监护室下呼吸道感染患儿痰液标本培养和药敏监测结果.结果 1107例标本共培养病原菌948株（85.64%）.其中G-菌616株（64.98%）中铜绿假单胞菌145株（15.30%）、肺炎克雷伯菌135株（14.24%）、鲍曼不动杆菌131株（13.82%）、大肠埃希菌89株（9.40%）;G＋菌129株（13.61%,主要以金黄色葡萄球菌为主）;真菌203株（21.41%,主要为白假丝酵母菌）.细菌主要敏感药物监测结果：G‘类为碳青霉烯类抗生素,G＋类为万古霉素.结论 重症患儿下呼吸道感染病原菌主要为G-菌,其次为G＋菌和真菌,感染菌对敏感抗生素具有高选择性,应根据药物敏感监测结果使用抗生素.     

Immunological control of drug absorption from the gastrointestinal tract: the mechanism whereby intestinal anaphylaxis interferes with the intestinal absorption of bromthymol blue in the rat

Rats were immunized intraperitoneally with ovalbumin and the disappearance of bromthymol blue (BTB) from the intestinal lumen, its accumulation in the tissue, and its net absorption were examined by means of an in-situ recirculation technique during local anaphylaxis. The disappearance of BTB from the intestinal lumen and its net absorption were significantly reduced, but there was no significant effect on its accumulation in the tissue. The pH value of the luminal solution and the perfusate volume were not influenced by intraluminal challenge with the antigen in ovalbumin-immunized rats. In addition, no significant effect was observed on intestinal permeability to BTB in the in-vitro everted sac technique. The intestinal blood flow, measured by a hydrogen clearance method, was not reduced significantly by the intraluminal exposure to antigen. There was enhanced Evans Blue leakage and mucus release in the perfusate after intraluminal challenge with ovalbumin in ovalbumin-immunized rats, but not in non-immunized rats. A significant increase of BTB binding with macromolecular substances in the perfusate was observed during the local anaphylaxis. These findings suggest that the decreased absorption of BTB is due to the interaction with the macromolecular substances in the perfusate during local anaphylaxis.     

Improved brain delivery of a nonsteroidal anti-inflammatory drug with a synthetic glyceride ester: a preliminary attempt at a CNS drug delivery system for the therapy of Alzheimer's disease

1,3-Diacetyl-2-ketoprofen glyceride (DAKG), a prodrug of ketoprofen, was synthesized as a model compound in our attempt to develop a central nervous system (CNS) drug delivery system to treat Alzheimer's disease. The primary purpose of the present study is to test whether DAKG improves the delivery of ketoprofen to the brain and to quantitatively evaluate several factors that influence the brain distribution of this prodrug. ddY mice were injected with either ketoprofen or DAKG at a dose of 40 micromol/kg and then the plasma and brain pharmacokinetics of these agents were assessed. The brain uptake clearance of ketoprofen and DAKG across the BBB was measured by in situ mouse brain perfusion. In addition, the efflux permeability of ketoprofen through the BBB was evaluated using the in vivo mouse brain microdialysis technique. The in vivo metabolism of DAKG in the brain was assessed by a short infusion into the internal carotid artery coupled with the brain metabolism index (BMI) method. Administration of DAKG produced an approximately 3-fold increase in the area under the brain concentration - time curve of ketoprofen, compared with administration of ketoprofen itself. The brain uptake clearance (CL(in) ) of ketoprofen across the BBB was 0.0308 +/- 0.0046 mL/min/g whereas the CL(in) of DAKG was 1.60 +/- 0.16 mL/min/g, suggesting a marked increase in BBB permeability following lipidization of ketoprofen. The BMI method confirmed that DAKG is taken up by the brain to rapidly release ketoprofen in a dose-dependent manner. The in vitro metabolism studies revealed that isolated bovine brain capillaries as well as whole brain homogenate have the hydrolysis activity to DAKG. In addition, the brain concentration of ketoprofen after DAKG administration was maintained for a significant period following co-administration of probenecid. These results suggest that DAKG improves the delivery of ketoprofen to the brain, and this improved delivery is due to avid uptake of DAKG across the BBB followed by rapid hydrolysis to ketoprofen within the brain. The ketoprofen produced in the brain was probably cleared by the active efflux system operating in the BBB. Significant inhibition of this efflux system by co-administration of probenecid could result in a sustained concentration of ketoprofen in the brain following DAKG administration.