Drug delivery.

Methods for the delivery of the products of biotechnology, namely peptides and proteins, are reviewed. More efficient methods of parenteral administration include the incorporation of drugs in liposomes, whereas the system favoured for respiratory delivery is the nasal route. The improved oral delivery of polypeptides remains an elusive goal.     

Application of <Emphasis Type="Italic">In Situ</Emphasis> Polymerization for Design and Development of Oral Drug Delivery Systems

Although preformed polymers are commercially available for use in the design and development of drug delivery systems, in situ polymerization has also been employed. In situ polymerization affords the platform to tailor and optimize the drug delivery properties of polymers. This review brings to light the benefits of in situ polymerization for oral drug delivery and the possibilities it provides to overcome the challenges of oral route of administration.     

Detection and Quantification of Flavobacterium psychrophilum-Specific Bacteriophages In Vivo in Rainbow Trout upon Oral Administration: Implications for Disease Control in Aquaculture

The use of bacteriophages in the treatment and prevention of infections by the fish pathogen Flavobacterium psychrophilum has attracted increased attention in recent years. It has been shown recently that phage delivery via the parenteral route resulted in immediate distribution of phages to the circulatory system and the different organs. However, little is known about phage dispersal and survival in vivo in rainbow trout after delivery via the oral route. Here we examined the dispersal and survival of F. psychrophilum phage FpV-9 in vivo in juvenile rainbow trout after administration by three different methods—bath, oral intubation into the stomach, and phage-coated feed—with special emphasis on the oral route of delivery. Phages could be detected in all the organs investigated (intestine, spleen, brain, and kidney) 0.5 h postadministration, reaching concentrations as high as ∼10⁵ PFU mg intestine⁻¹ and ∼10³ PFU mg spleen⁻¹ within the first 24 h following the bath and ∼10⁷ PFU mg intestine⁻¹ and ∼10⁴ PFU mg spleen⁻¹ within the first 24 h following oral intubation. The phages were most persistent in the organs for the first 24 h and then decreased exponentially; no phages were detected after 83 h in the organs investigated. Phage administration via feed resulted in the detection of phages in the intestine, spleen, and kidney 1 h after feeding. Average concentrations of ∼10⁴ PFU mg intestine⁻¹ and ∼10¹ PFU mg spleen⁻¹ were found throughout the experimental period (200 h) following continuous delivery of phages with feed. These experiments clearly demonstrate the ability of the phages to survive passage through the fish stomach and to penetrate the intestinal barrier and enter the circulatory system after oral delivery, although the quantity of phages found in the spleen was 100- to 1,000-fold lower than that in the intestine. It was also shown that phages could tolerate long periods of desiccation on the feed pellets, with 60% survival after storage at −80°C, and 10% survival after storage at 5°C, for ∼8 months. Continuous delivery of phages via coated feed pellets constitutes a promising method of treatment and especially prevention of rainbow trout fry syndrome.     

Lipospheres and pro-nano lipospheres for delivery of poorly water soluble compounds

Lipospheres are a drug encapsulation system composed of water dispersible solid microparticles of particle size between 0.01 and 100 μm in diameter with a solid hydrophobic lipid core stabilized by a layer of phospholipid molecules embedded in their surface. The bioactive compound is dissolved or dispersed in the solid lipid matrix of the internal core. Since lipospheres were introduced in the beginning of the 1990s, they have been used for the delivery of multiple types of drugs by various routes of administration. Later, a self-assembling pro-nano lipospheres (PNL) encapsulation system was developed for oral drug delivery. Lipospheres have several advantages over other delivery systems, such as better physical stability, low cost of ingredients, ease of preparation and scale-up, high dispersibility in an aqueous medium, high entrapment of hydrophobic drugs, controlled particle size, and extended release of entrapped drug after administration, from a few hours to several days. This review article focuses on updated information on several aspects of lipospheres and PNL, including preparation techniques, physicochemical properties and in vitro evaluation methods. Additionally, it covers lipospheres and PNL utilization for oral, ocular, and parenteral delivery, with special attention to unique considerations and aspects for each route of administration.     

BCG Moreau Rio de Janeiro: an oral vaccine against tuberculosis--review

The vaccine Bacillus of Calmette Guérin (BCG) was originally developed in France as an oral vaccine against tuberculosis. The oral use of this vaccine was replaced by the parenteral route in almost all countries after the Lubeck disaster. In contrast, Brazil retained the oral delivery of the vaccine until the mid-seventies when it was replaced by the intradermal route. This change in route of delivery was mainly secondary to pressure by medical practitioners based on the poor responses of oral immunized subjects to purified protein derivative (PPD) skin tests. Even after the change of route of delivery, Ataulpho de Paiva Foundation continued making the oral vaccine. Currently, BCG Moreau has been described as one of the most immunogenic and with fewer side effects than other BCGs. The genomics, proteomics and vaccine trials for oral BCG Moreau Rio de Janeiro are currently under investigation. In this review, we intend to describe the history of BCG Moreau Rio de Janeiro in Brazil.     

Design of a liquid nano-sized drug delivery system with enhanced solubility of rivaroxaban for venous thromboembolism management in paediatric patients and emergency cases

Abstract

The increasing incidence of venous thromboembolism (VTE) in paediatric population has stimulated the development of liquid anticoagulant formulations. Thus our goal is to formulate a liquid formulation of poorly-water soluble anticoagulant, rivaroxaban (RIVA), for paediatric use and to assess the possibility of its intravenous administration in emergencies. Self-nanoemulsifying drug delivery systems (SNEDDSs) were developed and characterized. SNEDDS constituents were estimated from the saturated solubility study followed by plotting the corresponding ternary phase diagrams to determine the best self-emulsified systems. Thermodynamic stability, emulsification, dispersibility, robustness to dilution tests, in vitro dissolution, particle size, and zeta potential were executed to optimize the formulations. The optimized formulation, that composed of Capryol 90:Tween 20:PEG 300 (5:45:50), increased RIVA solubility (285.7-fold than water), it formed nanoemulsion with a particle size of 16.15?nm, PDI of 0.25 and zeta potential of ?21.8. It released 100.83?±?2.78% of RIVA after 5?min. SNEDDS was robust to dilution with oral and parenteral fluids and showed safety to human RBCs. SNEDDS showed enhanced bioavailability after oral and intravenous administration than the oral drug suspension (by 1.25 and 1.26-fold, respectively). Moreover, it exhibited enhanced anticoagulant efficacy in the prevention and treatment of carrageenan-induced thrombosis rat model.     

Beyond liposomes: Recent advances on lipid based nanostructures for poorly soluble/poorly permeable drug delivery

Solid lipid nanoparticle (SLN), nanostructured lipid carriers (NLC) and hybrid nanoparticles, have gained increasing interest as drug delivery systems because of their potential to load and release drugs from the Biopharmaceutical classification system (BCS) of class II (low solubility and high permeability) and of class IV (low solubility and low permeability). Lipid properties (e.g. high solubilizing potential, biocompatibility, biotolerability, biodegradability and distinct route of absorption) contribute for the improvement of the bioavailability of these drugs for a set of administration routes. Their interest continues to grow, as translated by the number of patents being field worldwide. This paper discusses the recent advances on the use of SLN, NLC and lipid-polymer hybrid nanoparticles for the loading of lipophilic, poorly water-soluble and poorly permeable drugs, being developed for oral, topical, parenteral and ocular administration, also discussing the industrial applications of these systems. A review of the patents filled between 2014 and 2017, concerning the original inventions of lipid nanocarriers, is also provided.     

Lipid-based colloidal carriers for peptide and protein delivery--liposomes versus lipid nanoparticles

This paper highlights the importance of lipid-based colloidal carriers and their pharmaceutical implications in the delivery of peptides and proteins for oral and parenteral administration. There are several examples of biomacromolecules used nowadays in the therapeutics, which are promising candidates to be delivered by means of liposomes and lipid nanoparticles, such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC). Several production procedures can be applied to achieve a high association efficiency between the bioactives and the carrier, depending on the physicochemical properties of both, as well as on the production procedure applied. Generally, this can lead to improved bioavailability, or in case of oral administration a more consistent temporal profile of absorption from the gastrointestinal tract. Advantages and drawbacks of such colloidal carriers are also pointed out. This article describes strategies used for formulation of peptides and proteins, methods used for assessment of association efficiency and practical considerations regarding the toxicological concerns.     

Oral estrogen masculinizes female zebra finch song system

It is well established that parenteral treatment of female zebra finch chicks with estradiol masculinizes their song control nuclei and that as adults they are capable of song. Concern over the widespread use of putative environmental estrogens caused us to ask whether oral exposure to estrogens (a natural route of exposure) could produce similar effects. We dosed chicks orally with estradiol benzoate (EB; 1, 10, 100, and 1000 nmol/g of body mass per day, days 5-11 posthatch), the non-ionic surfactant octylphenol (100 and 1000 nmol/g), or the pesticides methoxychlor (100 and 1000 nmol/g) and dicofol (100 nmol/g) and measured their song control nuclei as adults. EB treatment produced increases in song nuclei comparable to that induced by parenteral administration of estrogens. This is the first study of which we are aware to use an oral route of administration, which simulates the natural process of parent birds feeding their nestlings. We conclude that oral exposure to estradiol alters song control nuclei and we report in a related paper (Millam et al., 2001) that such exposure severely disrupts reproductive performance. Although we detected no influence of xenobiotics on induction of song control nuclei the possibility remains that oral exposure to xenoestrogens in high enough doses could affect development.     

Investigating Transdermal Delivery of Vitamin D3

Transdermal delivery of therapeutic amounts of vitamin D₃ is proposed to overcome its variable oral bioavailability, especially for people who suffer from fat malabsorption. The main challenge for this delivery route is to overcome the barrier properties of skin, especially for very lipophilic compounds such as vitamin D₃. In this study, the effect of different penetration enhancers, such as oleic acid, dodecylamine, ethanol, oleic acid in propylene glycol, isopropyl myristate, octyldodecanol, and oleyl alcohol in propylene glycol were evaluated in vitro for their effectiveness in delivering vitamin D₃ through polyamide filter, polydimethylsiloxane membrane, and porcine skin. A diffusion cell was used to study the transdermal permeability of vitamin D₃. Ointment formulations of vitamin D₃ were prepared containing the most widely used penetration enhancers, oleic acid, and dodecylamine. The ointment containing oleic acid as chemical penetration enhancer did not improve delivery compared to control. On the other hand, the formulation containing dodecylamine as a penetration enhancer did improve the transdermal delivery of vitamin D₃. However, statistical significance and an amount high enough for nutritional supplementation purposes were reached only when the skin was pretreated with 50% ethanol. In these conditions, the ointment delivered an amount of 760-ng vitamin D₃ per cm² of skin. The research shows promise that transdermal delivery could be an effective administration route for vitamin D₃ when ethanol and dodecylamine are used as penetration enhancers.KEY WORDS: dodecylamine, ethanol, penetration enhancer, transdermal delivery, vitamin D₃     

Induction of spermiation in common carp after enhanced intestinal uptake of sGnRH-A and Pimozide

The inherent ability of the carp Cyprinus carpio gut to absorb intact salmon gonadotropin hormone-releasing hormone analogue (sGnRH-a)+Pimozide (Pim), without loss of their bioactivity is very limited. Artificial intestinal absorption enhancement boosted sGnRH-a and Pim induced GtH II release and milt production significantly. The intraperitoneal route of administration was more effective than the oral one. A potential application of the oral route for peptidergic drug delivery and the possibility of developing a dietary delivery system is discussed.     

Development of a size-dependent aerosol deposition model utilising human airway epithelial cells for evaluating aerosol drug delivery

Aerosol delivery to the airways of the human respiratory tract, followed by absorption, constitutes an alternative route of administration for compounds unsuitable for delivery by conventional oral and parenteral routes. The target for aerosol drug delivery is the airways epithelium, i.e. tracheal, bronchial, bronchiolar and alveolar cells, which become the site of drug deposition. These epithelial layers also serve as a barrier to the penetration of inhaled material. An in vitro model for aerosol deposition and transport across epithelia in the human airways may be a good predictor of in vivo disposition. The present preliminary studies begin an investigation that blends the dynamics of aerosol delivery and the basis of an in vitro simulated lung model to evaluate the transport properties of a series of molecular weight marker compounds across human-derived bronchiolar epithelial cell monolayers. An Andersen viable cascade impactor was used as a delivery apparatus for the deposition of size-segregated particles onto monolayers of small airway epithelial cells and Calu-3 cells. It was shown that these cell layers can withstand placement in the impactor, and that permeability can be tested subsequent to removal from the impactor.     

Uptake and biodistribution of free and liposomally incorporated lipopolysaccharide of aeromonas salmonicida administered via different routes to rainbow trout: (Oncorhynchus mykiss)

Abstract

The effects on uptake and biodistribution of radiolabelled lipopolysaccharide (LPS) due to changing routes of administration, encapsulation of LPS within liposomes and altering liposomal surface charge were examined in rainbow trout (Oncorhynchus mykiss). ³H-labelled LPS, positively- and negatively-charged (¹⁴C-labelled) liposomes or ¹⁴C-labelled liposomes containing ³H-LPS were administered to trout via intravenous, intraperitoneal, intramuscular, or oral routes. Twenty-four hours following administration, relative uptake of LPS and multilamellar vesicles (MLV) based on detection of ³H and ^1AC, respectively, was determined in samples taken from the kidney, spleen, liver, plasma, blood cells and skeletal muscle. In general, regardless of the route of administration, ³H-LPS, ^1AC-MLV and liposomally encapsulated LPS were recovered primarily in the kidney and spleen. Intravenous administration resulted in the greatest uptake of radiolabel by the kidney and spleen, followed by the intraperitoneal and intramuscular routes. Although oral administration yielded the lowest overall uptake of labelled material, detection of ³H and ¹⁴C in the liver was enhanced when compared with the other routes. Negatively-charged MLV were delivered more efficiently to the kidney and spleen than positively-charged MLV; but negatively- and positively-charged MLV containing LPS demonstrated the opposite relationship between charge and distribution among the kidney and spleen. These results suggest that liposomal encapsulation (particularly within positively-charged MLV) enhances delivery of LPS to the primary hemopoietic organs in rainbow trout.     

The Placement of DPP-4 Inhibitors in Clinical Practice Recommendations for the Treatment of Types 2 Diabetes

ObjectiveTo review the most recent clinical data on the safety and efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors and to evaluate their position in current treatment guidelines and algorithms.MethodsPubMed searches were performed to identify published data regarding both the safety and efficacy of DPP-4 inhibitors approved for use in the United States and clinical guidelines describing recommendations for their use.ResultsIn the past 2 years, more than 100 publications have added clinical trial data on DPP-4 inhibitors to the medical literature. Since becoming available in 2006, these agents have demonstrated an excellent safety/tolerability profile, and as add-on to metformin, DPP-4 inhibitors may have comparable glycemic efficacy as other oral agents. As a result, DPP-4 inhibitors have assumed roles in clinical practice guidelines and treatment algorithms that are comparable to the sulfonylurea class. Advantages of DPP-4 inhibitors include an oral route of administration, a mechanism of action based on glucose-stimulated insulin secretion, and a low risk of hypoglycemia. The main disadvantage associated with this class is a relatively high cost. There is also less clinical experience with DPP-4 agents than classes of agents that have been in use for decades; however, long-term data on the safety and efficacy of DPP-4 agents will be available in the near future to refine their place in therapy. From 2 large clinical trials recently reported, EXAMINE and SAVOR, this class of agents does not increase overall adverse cardiovascular outcomes nor the risk of pancreatitis or pancreatic cancer.ConclusionBased on comparisons of nonglycemic effects such as risk of hypoglycemia, weight gain, and durability, DPP-4 inhibitors may be considered as an alternative to sulfonylureas. However, direct cost may be a determining factor in the choice of therapy. (Endocr Pract. 2013;19:1050-1061)     

Effect of parenteral or oral vinpocetine on the hemorheological parameters of patients with chronic cerebrovascular diseases

IntroductionHemorheological factors play an important role in the pathomechanism of ischemic cerebrovascular disorders. Abnormal rheological conditions in patients with chronic cerebrovascular disease predispose for recurrent strokes. Vinpocetine (VP), a synthetic ethyl esther of apovincamine, has successfully been used in the treatment of cerebrovascular diseases, in part because of its favourable rheological effects.Patients and methodsThe study investigates the hemorheological changes in 40 patients in the chronic stage of ischemic cardiovascular disease after administration of vinpocetine. All patients received a high dose of intravenous VP in doses gradually increased to l mg/kg/day. In addition, 20 patients (mean age: 61±8 years) received 30 mg VP orally for 3 months. The other 20 patients (mean age: 59±6 years), who received placebo tablets, served as controls. Hemorheological parameters (hematocrit, plasma fibrinogen, whole blood viscosity, red blood cell aggregation and deformability) were evaluated at 1 and 3 months.ResultsThe high-dose parenteral VP significantly decreased red blood cell aggregation, plasma and whole blood viscosity (p<0.05) compared to the initial values. In patients with additional oral treatment, plasma and whole blood viscosities were significantly lower compared to the placebo patients at 3 months (p<0.05).ConclusionOur results confirmed the beneficial rheological effects of high-dose parenteral VP (partially caused by hemodilution) observed previously, and also warrant its long-term oral admission to maintain the beneficial rheological changes.     

Nanotechnology based drug delivery system(s) for the management of tuberculosis

The era of nanotechnology has allowed new research strategies to flourish in the field of drug delivery. Nanoparticle-based drug delivery systems are suitable for targeting chronic intracellular infections such as tuberculosis. Polymeric nanoparticles employing poly lactide-co-glycolide have shown promise as far as intermittent chemotherapy in experimental tuberculosis is concerned. It has distinct advantages over the more traditional drug carriers, i.e. liposomes and microparticles. Although the experience with natural carriers, e.g. solid lipid nanoparticles and alginate nanoparticles is in its infancy, future research may rely heavily on these carrier systems. Given the options for oral as well as parenteral therapy, the very nature of the disease and its complex treatment urges one to emphasize on the oral route for controlled drug delivery. Pending the discovery of more potent antitubercular drugs, nanotechnology-based intermittent chemotherapy provides a novel and sound platform for an onslaught against tuberculosis.     

Total Parenteral Nutrition in Management of Hyperlipidemic Pancreatitis During Pregnancy

ObjectiveTo describe a case of severe gestational hyperlipidemic pancreatitis successfully managed with minimal-lipid-containing parenteral nutrition (PN) followed by a minimal-fat diet, which resulted in delivery of a healthy full-term neonate.MethodsWe present the case of a young woman with gestational hyperlipidemic pancreatitis whose management included the use of PN during pregnancy. In addition, we review the literature pertaining to the management of hyperlipidemic pancreatitis during pregnancy and discuss the role for PN.ResultsA 32-year-old gravida 2, para 1 woman at 27 weeks 3 days of gestation presented with 1 day of nausea, bilious emesis, and severe abdominal pain caused by pancreatitis attributable to hypertriglyceridemia. Her initial serum triglyceride concentration was 9,450 mg/dL. She received fluids intravenously and minimal-lipid PN until resolution of her symptoms. The serum triglyceride level remained less than 850 mg/dL during administration of PN. She subsequently tolerated a minimal-fat diet, while the serum triglyceride level was maintained at less than 1,400 mg/dL, until delivery of a full-term, healthy neonate.ConclusionIn severe gestational hyperlipidemic pancreatitis, PN offers a safe and flexible treatment option by providing pancreatic rest and controlling serum triglyceride concentrations while maintaining fetal and maternal nutritional support. (Endocr Pract. 2005;11:325-330)     

Minimizing Venous Thromboembolism in Feminizing Hormone Therapy: Applying Lessons From Cisgender Women and Previous Data

ObjectiveTo review he impact of estrogen-containing feminizing hormone regimens on transgender individuals’ risk for VTE.MethodsWe evaluated VTE risk by screening 1170 relevant studies published from 1994 to 2020, focusing on meta-analysis data.ResultsThe type of oral estrogen, route of administration, patient demographics, and comorbidities may affect the risk of VTE. Venous thrombosis is the most common vascular complication associated with HT.ConclusionConjugated equine estrogens and 17-β estradiol appear to be safer than oral ethinyl estradiol. Transdermal estrogen formulations appear to be the least thrombogenic estrogens. Estrogens used concomitantly with progestins increase the risk of VTE compared to estrogens alone.To date, there are no data to demonstrate the benefit of holding HT prior to vaginoplasty or other gender affirming surgeries. For most young, healthy transgender women, there is little risk of VTE with HT, while older patients with risk factors should be discussed case by case.     

Developing inexpensive malaria vaccines from plants and algae

Malaria is a parasitic, mosquito-borne, infectious disease that threatens nearly half of the global population. The last decade has seen a dramatic drop in the number of malaria-related deaths because of vector control methods and anti-malarial drugs. Unfortunately, this strategy is not sustainable because of the emergence of insecticide-resistant mosquitoes and drug-resistant Plasmodium parasites. Eradication of malaria will ultimately require low-cost easily administered vaccines that work in concert with current control methods. Low cost and ease of administration will be essential components of any vaccine, because malaria endemic regions are poor and often lack an adequate healthcare infrastructure. Recently, several groups have begun addressing these issues using inexpensive photosynthetic organisms for producing vaccine antigens and exploring oral delivery strategies. Immune responses from plant-based injectable malaria vaccines are promising, but attempts to adapt these for oral delivery suggest we are far from a feasible strategy. Here, we review examples of these technologies and discuss the progress and potential of this research, as well as the obstacles ahead.     

An orally delivered small-molecule formulation with antiangiogenic and anticancer activity

Targeting angiogenesis, the formation of blood vessels, is an important modality for cancer therapy. TNP-470, a fumagillin analog, is among the most potent and broad-spectrum angiogenesis inhibitors. However, a major clinical limitation is its poor oral availability and short half-life, necessitating frequent, continuous parenteral administration. We have addressed these issues and report an oral formulation of TNP-470, named Lodamin. TNP-470 was conjugated to monomethoxy-polyethylene glycol-polylactic acid to form nanopolymeric micelles. This conjugate can be absorbed by the intestine and selectively accumulates in tumors. Lodamin significantly inhibits tumor growth, without causing neurological impairment in tumor-bearing mice. Using the oral route of administration, it first reaches the liver, making it especially efficient in preventing the development of liver metastasis in mice. We show that Lodamin is an oral nontoxic antiangiogenic drug that can be chronically administered for cancer therapy or metastasis prevention.