Oral Administration Of Drug Research Articles

Intragastric amorphous calcium carbonate consumption triggered generation of in situ hydrogel piece for sustained drug release.

Sustained-release systems in solid forms are widely accepted except for those patients with dysphagia such as the elderly and infants. Herein, we have developed a sustained-release oral drug solution by dispersing polyaspartic acid stabilized amorphous calcium carbonate (ACC) nanoparticles (NPs) (<100nm) in drug-containing sodium alginate (SA) solution (2%). It can be supposed that ACC NPs would consume in the gastrointestinal tract acid environment and provide calcium ions as the crosslinker for SA polymer solution to gain in situ hydrogels. The pre-gel solution system appeared a distinct reversible shear-thin characteristic with high viscosity and stability during storage. Whereas, it can regain fine flowability for convenient oral administration after slightly shaking. In this study, ACC NPs consumption triggered solution-gel transition of this drug-containing pre-gel solution system was demonstrated in simulated gastric solution and in vivo, with the distinct sustained drug release profiles lasting for 10h. In addition, pharmacokinetics studies in SD rats showed that the Tmax (up to 1.79±0.24h) and AUC0-12 (46.37±2.71μg/mL·h) of ACC/SA in situ hydrogels treated group were significantly higher (p<0.05) than that of free drug solution. Overall, these results highlighted a novel promising platform for oral administration of drugs, reduced dosing frequency, and high potential compliance for patients with dysphagia.

An alternative method for oral drug administration by voluntary intake in male and female mice.

Drug administration to experimental rodents is often invasive and stressful, thus reducing animal welfare and potentially confounding experimental results. Methods of oral drug delivery in which rodents cooperate voluntarily minimize stress, pain and morbidity. We herein describe a method for oral administration through voluntary intake of strawberry jam, developed for C57BL/6J mice. During a 3-day habituation period, animals were placed in individual cages once daily and presented with a drop of jam. Five days later, the jam was again offered with admixed drug. Mice ingested it in less than 5 min, with latency times below 1 min, confirming the suitability of the administration method.

Molecular Design of Layer-by-Layer Functionalized Liposomes for Oral Drug Delivery.

Liposomes are small spherical vesicles composed mainly of phospholipids and cholesterol. Over the years, a number of liposomal formulations have shown clinical promise, but the use of liposomes in oral drug delivery is limited. This is partly due to the vulnerability of conventional liposomes to the detrimental effect of gastrointestinal destabilizing factors and also to the poor efficiency in intestinal absorption of liposomes. Some of these issues can be ameliorated using the layer-by-layer (LbL) assembly technology, which has been widely applied to modify the surface of various nanoparticulate systems. Discussions about LbL functionalization of liposomes as oral drug carriers, however, are scant in the literature. To fill this gap, this review presents an overview of the roles of LbL functionalization in the development of liposomes, followed by a discussion about major principles of molecular design and engineering of LbL-functionalized liposomes for oral drug delivery. Regarding the versatility offered by LbL assembly, it is anticipated that LbL-functionalized liposomes may emerge as one of the important carriers for oral drug administration in the future.

A case of epileptic seizure induced by oral administration of sparfloxacin and various anti-cold drugs

A case of epileptic seizure induced by oral administration of sparfloxacin and various anti-cold drugs

A simple artificial diet available for research of silkworm disease models.

This study was performed with the aim of making a very simple recipe of silkworm diet for research purposes, especially screening of drug candidates. We prepared a diet containing mulberry leaves powder and soybean flour at different ratios, fed them to fifth instar silkworm larvae, and observed their growth. We selected the diet with 1:1 ratio of mulberry powder and soybean flour, named MS-11, and used for further experiments. MS-11 diet was available for oral administration of drugs in silkworm hyperglycemic model and infection model. The availability of a simple artificial diet for experiments that require feeding silkworms will enhance the use of silkworms for biological, biotechnological, and pharmacological researches.

Fluorescein Isothiocyanate Chitosan Nanoparticles in Oral Drug Delivery Studies

Oral administration of drugs is one of the most patient-friendly drug delivery routes. However, drug bioavailability via the oral route remains poor due to the harsh gastrointestinal environment. In recent years, many nanocarriers have been designed to overcome this limitation. Among those, chitosan nanoparticles (ChNPs) have proved to be a quite popular choice. Here, we highlight the use of fluorescein isothiocyanate-tagged ChNPs as an invaluable tool to monitor the fate of ChNPs encapsulating oral drugs, leading to an in-depth understanding of drug biodistribution and, in turn, shedding light on ways to improve bioavailability.

(Carbonyl)oxyalkyl linker-based amino acid prodrugs of the HIV-1 protease inhibitor atazanavir that enhance oral bioavailability and plasma trough concentration

We describe the design, synthesis and pharmacokinetic (PK) evaluation of a series of amino acid-based prodrugs of the HIV-1 protease inhibitor atazanavir (1) derivatized on the pharmacophoric secondary alcohol using a (carbonyl)oxyalkyl linker. Prodrugs of 1 incorporating simple (carbonyl)oxyalkyl-based linkers and a primary amine in the promoiety were found to exhibit low chemical stability. However, chemical stability was improved by modifying the primary amine moiety to a tertiary amine, resulting in a 2-fold enhancement of exposure in rats following oral dosing compared to dosing of the parent drug 1. Further refinement of the linker resulted in the discovery of 22 as a prodrug that delivered the parent 1 to rat plasma with a 5-fold higher AUC and 67-fold higher C24 when compared to oral administration of the parent drug. The PK profile of 22 indicated that plasma levels of this prodrug were higher than that of the parent, providing a more sustained release of 1 invivo.

Assessment of Chemoprotective Potential of Curcumin against DMBA-Croton Oil Induced Skin Cancer in Mice

Background: Skin cancer is the most aggressive form of cancer with a high mortality rate. Different medications of skin cancer are accessible, yet because of improvement of multi-drug resistance, flow and rising chemotherapies have a generally low achievement rate. This emphasize the importance of discovering new compounds that are both safe and effective against skin cancer. This study used and compared different routes of administration of a natural compound curcumin to investigate the anti-cancer effect.&#x0D; In this investigation it has been resolved that the curcumin expands CAT and SOD levels alongside decline in the TBARS levels.&#x0D; Methods: The hindrance of tumour rate Curcumin was assessed in mice on two phase procedure of skin carcinogenesis incited by single utilization of DMBA/7,12-Dimethylbenz[a]-anthracene (100 µg/100 µl of CH3)2CO), and after 2 weeks advanced by rehashed use of croton oil (1% CH3)2CO/thrice in seven days) till the finish of the trial (i.e. 16 weeks). Oral administration of drug at a dose of 500 mg/kg body weight/day at the pre-initiation stage (i.e. 7 days prior and 7 days after DMBA application), promotional stage (for example from the time of croton oil application) and at both the stages (i.e. 7 days before DMBA application and proceeded till the finish of investigation) to the mice Treatment were started 1 week before the exposure to the carcinogen and continued till 25 weeks daily. At the end of experimental period all the animals were sacrificed and observed for various parameters.&#x0D; Results: The following parameters (body weight, biochemical studies, haematological studies) were observed and data was collected time to time and calculated statistically to evaluate the anticancer effect of curcumin was found to effective against the skin cancer.

Sterculia striata gum as a potential oral delivery system for protein drugs

Natural polysaccharides have been investigated as vehicles for oral insulin administration. Because of their non-toxic, renewable, low cost and readily available properties, gums find multiple applications in the pharmaceutical industry. This work aimed to develop a Sterculia striata gum-based formulation associated with additional biopolymers (dextran sulfate, chitosan, and albumin), a crosslinking agent (calcium chloride) and stabilizing agents (polyethylene glycol and poloxamer 188), to increase the oral bioavailability of proteins. Insulin was used as a model drug and the methods used to prepare the formulation were based on ionotropic pregelation followed by electrolytic complexation of oppositely charged biopolymers under controlled pH conditions. The developed formulation was characterized to validate its efficacy, by the determination of its average particle size (622 nm), the insulin encapsulation efficiency (70%), stability in storage for 30 days, and the in vitro mucoadhesion strength (92.46 mN). Additionally, the developed formulation preserved about 64% of initial insulin dose in a simulated gastric medium. This study proposed, for the first time, a Sterculia striata gum-based insulin delivery system with potential for the oral administration of protein drugs, being considered a valid alternative for efficient delivery of those drugs.

АЛЛЕРГИЗИРУЮЩИЕ И РАЗДРАЖАЮЩИЕ СВОЙСТВА НОВЫХ СЕЛЕКТИВНЫХ ПРЕПАРАТОВ НА ОСНОВЕ ЭКЗОСОМАЛЬНЫХ И ХИТОЗАНОВЫХ ЧАСТИЦ

Each drug, before being introduced to the pharmaceutical market, undergoes a mandatory set of preclinical and clinical studies, including those for allergenicity. As a result of the work carried out from 2015 to 2020 at the Department of Therapy and Pharmacology, selective preparations based on exosomal (Exazit) and chitosan (Chitasit) nanoparticles have been developed, and their physicochemical and pharmacological and therapeutic properties have been analyzed. This article presents the results of studying the allergenic and irritating properties of these drugs. To study the allergic effect after oral administration of drugs, 6 experimental and 6 control groups of guinea pigs weighing 250–300 g were formed. Testing of the sensitizing properties of drugs was carried out on days 10, 15 and 30 from the start of administration. The results of the conducted studies have established that the conjunctival test of sensitized guinea pigs, throughout the experiment, did not differ from the reaction in control animals. During a visual assessment of the state of the conjunctiva, cornea and eyelids of the eyes of experimental animals, it was found that the studied drugs did not cause irritation of the conjunctiva both immediately after instillation and throughout the entire experiment. The setting of the provocative nasal test did not cause hyperemia of the mucous membrane, sneezing and increased mucus secretion in animals. The percentage of degranulated mast cells in the experimental groups is less than 10%. Thus, as a result of the study of the allergenic properties of Exazit and Chitasit in guinea pigs, it was found that there is no allergenic effect that irritates the conjunctiva of the eyes and mucous membranes, the drugs do not cause degranulation of mast cells in rats beyond the permissible limits.

Volatile molecules for COVID-19: A possible pharmacological strategy?

COVID‐19 is a novel coronavirus disease with a higher incidence of bilateral pneumonia and pleural effusion. The high pulmonary tropism and contagiousness of the virus, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), have stimulated new approaches to combat its widespread diffusion. In developing new pharmacological strategies, the chemical characteristic of volatility can add therapeutic value to the hypothetical drug candidate. Volatile molecules are characterized by a high vapor pressure and are consequently easily exhaled by the lungs after ingestion. This feature could be exploited from a pharmacological point of view, reaching the site of action in an uncommon way but allowing for drug delivery. In this way, a hypothetical molecule for COVID‐19 should have a balance between its lung exhalation characteristics and both antiviral and anti‐inflammatory pharmacological action. Here, the feasibility, advantages, and disadvantages of a therapy based on oral administration of possible volatile drugs for COVID‐19 will be discussed. Both aerosolized antiviral therapy and oral intake of volatile molecules are briefly reviewed, and an evaluation of 1,8‐cineole is provided in view of a possible clinical use and also for asymptomatic COVID‐19.

PiDose: an open-source system for accurate and automated oral drug administration to group-housed mice

Drug treatment studies in laboratory mice typically employ manual administration methods such as injection or gavage, which can be time-consuming to perform over long periods and cause substantial stress in animals. These stress responses may mask or enhance treatment effects, increasing the risk of false positive or negative results and decreasing reliability. To address the lack of an automated method for drug treatment in group-housed mice, we have developed PiDose, a home-cage attached device that weighs individual animals and administers a daily dosage of drug solution based on each animal’s bodyweight through their drinking water. Group housed mice are identified through the use of RFID tagging and receive both regular water and drug solution drops by licking at a spout within the PiDose module. This system allows animals to be treated over long periods (weeks to months) in a fully automated fashion, with high accuracy and minimal experimenter interaction. PiDose is low-cost and fully open-source and should prove useful for researchers in both translational and basic research.

Adsorption of a poorly water-soluble drug onto porous calcium silicate by the sealed heating method

To improve the bioavailability of orally-administered drug, solubilization of poorly water-soluble drug is important. The solubility of a drug in its amorphous form is known to be higher than in its crystalline form. In this study, we attempted to adsorb a sublimable drug onto porous calcium silicate (Florite®, FLR) or non-porous calcium silicate (NPCS) by the sealed heating (SH) method and evaporated (EV) method. Ibuprofen (IBU) was used as the poorly water-soluble, sublimable drug. The physicochemical properties of samples were investigated using powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), and dissolution test. From the PXRD and DSC results, IBU crystals were adsorbed and amorphized by the SH and EV methods with FLR. From the results of FTIR, the shift to a higher frequency by the carbonyl stretching vibration band of IBU suggests an intermolecular interaction between IBU and FLR. In SH with FLR, improved solubilization was observed. IBU adsorbed onto FLR showed a greater dissolution rate than the IBU crystals or NPCS. Thus, the petal-like structure of FLR may be an effective method to adsorb IBU onto FLR using the SH method.

Antibiotic Administration Routes and Oral Exposure to Antibiotic Resistant Bacteria as Key Drivers for Gut Microbiota Disruption and Resistome in Poultry.

Previous studies have identified oral administration of antibiotics and gut-impacting drugs as critical drivers for fecal antibiotic resistance (AR) and microbiome disruption in lab mice, but the practical implications of these findings have yet to be validated in hosts nurtured in conventional environment. Using ampicillin (Amp) as a way to extrapolate the general effect of antibiotics, this project examined the impact of drug administration routes on fecal microbiota and resistome using poultry raised in a teaching farm. AR genes were found to be abundant in the feces of young Leghorn chicks without previous antibiotic treatment. In chickens seeded with blaCMY–2+ Escherichia coli, 300 mg/kg body weight of Amp was orally administered for 5 days. This led to the fecal microbiota switching from Firmicutes occupied (95.60 ± 2.62%) and Lactobacillus rich, to being dominated by Proteobacteria (70.91 ± 28.93%), especially Escherichia/Shigella. However, when Amp was given via muscle injection, Firmicutes was mostly retained (i.e., from 83.6 ± 24.4% pre- to 90.4 ± 15.2% post-treatment). In control chickens without seeding with blaCMY–2+ E. coli, oral Amp also led to the increase of Proteobacteria, dominated by Klebsiella and Escherichia/Shigella, and a reduction of Firmicutes. Specifically within Firmicutes, Enterococcus, Clostridium, etc. were enriched but Lactobacillus was diminished. The fecal resistome including Ampr genes was more abundant in chickens receiving oral Amp than those treated with muscle injection, but the difference was primarily within 1 log. The data illustrated that both drug administration routes and pre-existing gut microbiota have profound impacts on gut microbiome disruption when antibiotic treatment is given. In hosts nurtured in a conventional environment, drug administration route has the most evident impact on gut microbiota rather than the size of the targeted blaCMY–2+ gene pool, likely due to the pre-existing bacteria that are (i) less susceptible to Amp, and/or (ii) with Ampr- or multidrug resistance-encoding genes other than blaCMY–2+. These results demonstrated the critical interplay among drug administration routes, microbiota seeded through the gastrointestinal tract, AR, gut microbiota disruption, and the rise of common opportunistic pathogens in hosts. The potential implications in human and animal health are discussed.

In vivo cultivation of tuna blood fluke Cardicola orientalis in terebellid intermediate hosts

Some fish blood flukes of the genus Cardicola (Aporocotylidae) are considered important pathogens of farmed/ranched tuna, Thunnus spp. Infections with Cardicola spp. might obstruct the blood flow in the gills via massive accumulations of eggs and often lead to mass mortalities in captive tuna. At present, oral administration of an anthelminthic drug, praziquantel is the most effective treatment, but the tuna farming industries are seeking non-drug control measures. Development of prophylactic and holistic measures have been difficult, owing to a lack of basic knowledge about these parasites. Unlike other trematodes which use molluscs, blood flukes of marine actinopterygian fish use terebellid polychaetes as intermediate hosts. However, information about the development of Cardicola spp. within intermediate hosts is very limited. Recent success in Cardicola opisthorchis sporocyst transplantation into the host polychaete has opened possibilities for the cultivation of Cardicola in the laboratory. Here, we conducted several transplantation trials with another tuna blood fluke, Cardicol orientalis, into its natural and surrogate polychaete hosts. Cardicola orientalis sporocysts were injected into a total of 195 Nicolea gracilibranchis, the natural host, and clear sporocyst development and reproduction was observed in 32 recipients (overall success rate 16.4%). The production of daughter sporocysts in the transplanted polychaete occurred within 14 days post injection, and one sporocystogenous cycle took approximately 4 weeks. Serial passage culture via transplantation of in vivo-cultured sporocysts was also achieved, but with limited sporocyst reproduction. In addition, sporocysts were successfully retrieved from six and one individuals of the surrogate hosts, Thelepus setosus (n = 10) and Thelepus japonicus (n = 5), respectively. These results indicate that the in vivo cultivation of C. orientalis sporocysts is possible, not only in its natural host but also in other terebellids, although the problems of high mortality and inconsistency in successful transplantation need to be resolved.

Manipulation of Medicinal Products for Oral Administration to Paediatric Patients at a German University Hospital: An Observational Study.

Pharmacotherapy in children requires medicinal products in age-appropriate dosage forms and flexible dose strengths. Healthcare professionals often encounter a lack of licensed and commercially available formulations, which results in the need for manipulation. This study aimed to investigate the nature, frequency and preventability of the manipulation of medicinal products before oral drug administration to paediatric inpatients in Germany. A prospective, direct observational approach was used. Two thousand and three medication preparation processes (MPP) in 193 patients were included in the analysis. Medicines were manipulated in 37% of oral administrations, affecting 57% of the patients. The percentage of manipulations was highest in infants/toddlers (42%) and lowest in adolescents (31%). Antiepileptics were most frequently manipulated (27%), followed by vitamins (20%) and drugs for acid-related disorders (13%). Fifty-six per cent of all manipulations were off-label. In 71% of these, no alternative appropriate medicinal product was commercially available. These results demonstrate that the manipulation of medicinal products before oral administration is common in paediatric wards in Germany. About half of the manipulations were off-label, indicating that no suitable formulation was available. Evidence-based guidelines for manipulations are required, with the overall aim of improving the safety of paediatric drug therapy.

Analgesic impact of buprenorphine transdermal patch in total hip arthroplasty: A randomized controlled trial protocol.

Background:The efficacy and safety of buprenorphine transdermal patch (BTP) has been well established in chronic pain, but data regarding acute postoperative pain relief is still very limited. Therefore, we design a prospective, randomized, controlled study to evaluate the effectiveness and safety of the BTP for postoperative analgesia in total hip arthroplasty.Methods:This study is designed as a single-center, prospective, double-blind, randomized controlled trial. Group A receives a 10 mg patch of buprenorphine at the conclusion of surgery which is continued for 14 days. Group B receives a conventional analgesic regimen, that is, IV paracetamol 1 mg every 8 hours alternating with parenteral tramadol 50 mg every 8 hours for the first 2 postoperative days followed by oral administration of the same drug still the end of 2 weeks. A total of 160 patients are needed with an allowance for 10% drop-out. The primary outcome of this noninferiority study is opioid consumption within the first 24 hours following surgery. The secondary outcomes included numerical rating scale scores at rest, postoperative complications, length of hospital stay, and patient satisfaction.Results:This trial is expected to be the largest randomized trial assessing the efficacy of BTP after primary total hip arthroplasty and powered to detect a potential difference in the primary outcome.Trial registration number:This study protocol was registered in Research Registry (researchregistry5524).

In vitro and toxicological assessment of dexamethasone sodium phosphate loaded pH sensitive Pectin-g-poly(AA)/PVP semi interpenetrating network

Herein, we developed and characterized pH responsive semi interpenetrating network (semi-IPN) of Pectin-g-poly(AA)/PVP by free radical polymerization. These hydrogels were developed to overcome hurdles associated with; i) mechanical strength of formed system which was dealt by the use of combination of natural (pectin) and synthetic (PVP) polymers and ii) oral administration of drugs requiring action in distal part of gastrointestinal tract which was addressed by employing pectin and acrylic acid which conferred pH sensitivity due to carboxylic group in their structure.Structurally and morphologically, developed semi-IPN hydrogels were characterized by Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Scanning electron microscopy (SEM) and X-ray diffraction (XRD). Chemically, they were evaluated for swelling and release kinetics. Semi-IPN hydrogels restricted the swelling of system and therefore the release of dexamethasone sodium phosphate (DSP) at pH 1.2 but released it in controlled manner at pH 7.4 by non-Fickian diffusion.. Biologically, acute toxicity testing of developed semi-IPN hydrogels, revealed biocompatibility and safety of hydrogels after oral administration. Conclusively, prepared semi-IPN hydrogels showed good mechanical properties, swelling, biocompatibility, pH dependent DSP release for possible treatment of inflammatory bowel diseases.

Mesoporous silica nanospheres as nanocarriers for poorly soluble drug itraconazole with high loading capacity and enhanced bioavailability

Abstract The emerging trends in the combinatorial chemistry and drug design have led to the development of drug candidates with greater lipophilicity, high molecular weight and poor water solubility. The poor water solubility often leads to low bioavailability and therapy efficacy of oral administration. Herein, take itraconazole (ITZ), a poorly soluble antifungal agent, as a model drug, we demonstrate a general strategy that nano-amorphous formulation of ITZ with mesoporous silica nanospheres (MSNs) as nanocarriers can result in great enhancement of both the ITZ loading and releasing performance. We find that the sphere diameters and specific surface areas of MSNs have the potential in influencing the amorphous condition of ITZ, further affecting the ITZ loading and releasing behavior. The results indicate that the MSNs with diameter of around 50 nm can load high content (≥37.5 wt%) of ITZ with pure amorphous state, which results in almost 100% in vitro releasing (in simulated gastric fluid) and great enhancement of in vivo bioavailability (1.5 fold greater than that of commercial product Sporanox). Our nano-amorphous strategy for poorly soluble drugs with MSNs as nanocarriers would show great promising in the enhancement of bioavailability and therapy efficacy for oral administration of drugs with poor water solubility.

Enhanced absorption, and efficacy of oral self-assembled paclitaxel nanocochleates in multi-drug resistant colon cancer.

Chemotherapy in drug-resistant cancers remains a challenge. Owing to associated poor bioavailability, oral administration of hydrophobic anticancer drugs like paclitaxel has been quite challenging, with the scenario being further complicated by Pgp efflux in drug-resistant tumours. We developed a novel nanocochleates (CPT) system encapsulating paclitaxel (PTX) to treat resistant colon cancer by oral administration. PTX encapsulated nanocochleates (PTX-CPT), made up of phosphatidylserine in size range of 350-600nm with -20±5.2mV zeta potential were protected from degradation at acidic gastric pH and showed sustained PTX release over 48h under intestinal pH condition. In vitro cytotoxicity studies on HCT-116 & HCT-15 cells (multi-drug resistant) established IC50 value of <10 and 69nM, respectively, which was significantly lower when compared to commercial Taxol formulation. Further, the in vivo efficacy with five oral doses of 30mg/kg PTX-CPT in an HCT-15 drug-resistant colon cancer xenograft mouse model showed more than 25 fold reduction in the tumour growth inhibition as compared to intravenous Taxol which showed just 1.94% inhibition. Interestingly, PTX-CPT treated mice also showed significantly lower proliferation index and microvessel density when compared to Taxol treated mice. Nanocochleates showed lower toxicity with at LD-50 value greater than 300mg/kg as described in OECD 423 guideline. The enhanced efficacy of PTX-CPT speculated due to its internalization by active endocytosis, ability to escape Pgp efflux, and due to a combined effect of the pro-apoptotic and antiangiogenic role. Taken together, the results suggested the PTX-CPT a promising strategy for efficiently treating drug-resistant colon cancer orally.