Category: Science and technology

Self-nanoemulsifying drug delivery systems as novel approach for pDNA drug delivery

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It was the aim of this study to investigate a novel strategy for oral gene delivery utilizing a self-nanoemulsifying drug delivery system (SNEDDS). After hydrophobic ion pairing a plasmid was incorporated into SNEDDS. The mean droplet size of resulting nanoemulsions was determined to be between 45.8 and 47.5 nm. A concentration dependent cytotoxicity of the formulations was found on HEK-293 cells via MTT assay. Degradation studies via DNase I showed that incorporation into SNEDDS led to significantly, up to 8-fold prolonged resistant time against enzymatic digestion compared to naked pDNA and pDNA–lipid complexes. Transfection studies carried out revealed a significantly improved transfection compared to naked pDNA. Further, no decrease in transfection efficiency compared to transfection using Lipofectin® transfection reagent was observed. (International Journal of Pharmaceutics. Volume 487, Issues 1–2, 20 June 2015, Pages 25-31.)

Impact of different hydrophobic ion pairs of octreotide on its oral bioavailability in pigs

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The objective of this study was to investigate the impact of different hydrophobic ion pairs (HIP) on the oral bioavailability of the model drug octreotide in pigs.

Octreotide was ion paired with the anionic surfactants deoxycholatedecanoate and docusate differing in lipophilicity. These hydrophobic ion pairs were incorporated in self-emulsifying drug delivery systems (SEDDS) based on BrijO10, octyldodecanol, propylene glycol and ethanol in a concentration of 5 mg/ml. SEDDS were characterized regarding size distribution, zeta potential, stability towards lipase, log DSEDDS/release medium and mucus diffusion behavior. The oral bioavailability of octreotide was evaluated in pigs via LC-MS/MS analyses.

Most efficient ion pairing was achieved at a molar ratio of 1:3 (peptide: surfactant). SEDDS containing the octreotide-deoxycholate, -decanoate and -docusate ion pair exhibited a mean droplet size of 152 nm, 112 nm and 191 nm and a zeta potential of − 3.7, − 4.6 and − 5.7 mV, respectively. They were completely stable towards degradation by lipase and showed a log DSEDDS/release medium of 1.7, 1.8 and 2.7, respectively. The diffusion coefficient of these SEDDS was in the range of 0.03, 0.11 and 0.17 × 10− 9 cm2/s, respectively. In vivo studies with these HIPs showed no improvement in the oral bioavailability in case of octreotide-decanoate. In contrast, octreotide-deoxycholate and octreotide-docusate SEDDS resulted in a 17.9-fold and 4.2-fold higher bioavailability vs. control.

According to these results, hydrophobic ion pairing could be identified as a key parameter for SEDDS to achieve high oral bioavailability. (Journal of Controlled Release. Volume 273, 10 March 2018, Pages 21-29.)

Polymer–drug conjugates: recent advances and future perspectives

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Polymer–drug conjugates (PDC) have exhibited clinical and commercial success in the field of drug delivery. A polymeric backbone, linker, targeting moiety, and drug constitute the building blocks of PDCs. Current attention is focusing on natural polymeric carriers, in particular the concept of graft copolymers, such as a combination of polymers and polysaccharides, to explore dual benefits such as combined vehicles and targeting moieties. Polymer heterogeneity, synthesis of PDCs, broad molecular weight distribution, conjugate variability, immunogenicity of polymers, safety, stability, and stringent regulatory approval are the major obstacles to the successful transition of PDCs to the clinic. In this review, we discuss natural and synthetic PDCs combined with computational modeling for diverse pharmaceutical and biomedical applications. (Drug Discovery Today. Volume 25, Issue 9, September 2020, Pages 1718-1726.)

Novel cosmeceuticals from plants—An industry guided review

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Novel cosmeceutical ingredients from plant sources are in huge demand by the personal care products manufacturing industry due to the growing consumer awareness about healthy products with natural ingredients. The advancements in the understanding of the skin physiology and ageing resulted in the identification of novel biochemical targets of skin health, chemical manipulation of which has the potential to regain and/or remain in a healthy state. Plants are the chief source of such phytochemicals which can alter or bring back the original healthy skin and external appearance. A number of plants have been used by the industry to create novel cosmeceutical formulations with specific objectives such as sun protection, anti-ageing, anti-wrinkling, anti-oxidant, anti-allergy. Plants growing in adverse environmental climates are being explored, evaluated and converted into novel products by the cosmeceutical industry. The current review aims at the novel plant sources which are utilized by the various industry leaders in the business and their scientific rationale for their cosmeceutical applications. Around 68 plant sources used by the industry belonging to the six major plant families, Asteraceae, Lamiaceae, Fabaceae, Poaceae, Malvaceae and Rosaceae are reviewed scientifically for their cosmeceutical claims. (Journal of Applied Research on Medicinal and Aromatic Plants. Volume 7, December 2017, Pages 1-26.)

Microneedle Mediated Transdermal Delivery of Protein, Peptide and Antibody Based Therapeutics: Current Status and Future Considerations

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The success of protein, peptide and antibody based therapies is evident – the biopharmaceuticals market is predicted to reach $388 billion by 2024, and more than half of the current top 20 blockbuster drugs are biopharmaceuticals. However, the intrinsic properties of biopharmaceuticals has restricted the routes available for successful drug delivery. While providing 100% bioavailability, the intravenous route is often associated with pain and needle phobia from a patient perspective, which may translate as a reluctance to receive necessary treatment. Several non-invasive strategies have since emerged to overcome these limitations. One such strategy involves the use of microneedles (MNs), which are able to painlessly penetrate the stratum corneum barrier to dramatically increase transdermal drug delivery of numerous drugs. This review reports the wealth of studies that aim to enhance transdermal delivery of biopharmaceutics using MNs. The true potential of MNs as a drug delivery device for biopharmaceuticals will not only rely on acceptance from prescribers, patients and the regulatory authorities, but the ability to upscale MN manufacture in a cost-effective manner and the long term safety of MN application. Thus, the current barriers to clinical translation of MNs, and how these barriers may be overcome are also discussed.

Microneedle (MN) arrays consist of multiple micro-projections assembled on one side of a supporting base, ranging in height from 25 to 900 μm. MN arrays effectively bypass the stratum corneum barrier by creating temporary microscopic aqueous channels within the epidermis, through which drug molecules can diffuse into the dense microcirculation, present in the dermis. MNs were first conceptualised by Gerstel and Place in 1971, but were not practically realised until 1998, when manufacturing capabilities and microfabrication techniques became more advanced. Today, MN technology has developed further and they are traditionally placed in five different categories: solid, coated, hollow, dissolving and hydrogel-forming. (Pharm Res. 2020; 37(6): 117.)

Centrally Acting Drugs for Obesity: Past, Present, and Future

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For many years obesity was believed to be a condition of overeating that could be resolved through counseling and short term drug treatment. Obesity was not recognized as a chronic disease until 1985 by the scientific community and 2013 by the medical community. Pharmacotherapy for obesity has advanced remarkably since the first class of drugs, amphetamines, were approved for short-term use. Most amphetamines were removed from the obesity market due to adverse events and potential for addiction, and it became apparent that obesity pharmacotherapies were needed that could safely be administered over the long-term. This review of central nervous system (CNS) acting anti-obesity drugs evaluates current therapies such as phentermine/topiramate which act through multiple neurotransmitter pathways to reduce appetite. In the synergistic mechanism of bupropion/ naltrexone, naltrexone blocks the feed-back inhibitory circuit of bupropion to give greater weight loss. Lorcaserin, a selective agonist of a serotonin receptor that regulates food intake, and the glucagon-like-peptide-1 (GLP- 1) receptor agonist liraglutide are reviewed. Future drugs include tesofensine, a potent triple reuptake inhibitor in phase III trials for obesity and semaglutide, an oral GLP-1 analog approved for diabetes and currently in trials for obesity. Another potential new pharmacotherapy, setmelanotide (Ac-Arg-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys-NH2, disulfide Cys2-Cys8), is a melanocortin-4 receptor agonist which is still in an early stage of development. As our understanding of the communication between the CNS, gut, adipose tissue, and other organs evolves, it is anticipated that obesity drug development will move toward new centrally acting combinations and then to drugs acting on peripheral target tissues. (Drugs. 2018 Jul; 78(11): 1113–1132.)

Esters of terpene alcohols as highly potent, reversible, and low toxic skin penetration enhancers

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Skin penetration/permeation enhancers are compounds that improve (trans)dermal drug delivery. We designed hybrid terpene-amino acid enhancers by conjugating natural terpenes (citronellol, geraniol, nerol, farnesol, linalool, perillyl alcohol, menthol, borneol, carveol) or cinnamyl alcohol with 6-(dimethylamino)hexanoic acid through a biodegradable ester linker. The compounds were screened for their ability to increase the delivery of theophylline and hydrocortisone through and into human skin ex vivo. The citronellyl, bornyl and cinnamyl esters showed exceptional permeation-enhancing properties (enhancement ratios up to 82) while having low cellular toxicities. The barrier function of enhancer-treated skin (assessed by transepidermal water loss and electrical impedance) recovered within 24 h. Infrared spectroscopy suggested that these esters fluidized the stratum corneum lipids. Furthermore, the citronellyl ester increased the epidermal concentration of topically applied cidofovir, which is a potent antiviral and anticancer drug, by 15-fold. In conclusion, citronellyl 6-(dimethylamino)hexanoate is an outstanding enhancer with an advantageous combination of properties, which may improve the delivery of drugs that have a limited ability to cross biological barriers.

Terpenes are a class of natural compounds with strong permeation-enhancing potential and have been generally recognized as safe (GRAS) adjuvants with relatively low and transient irritation. For example, the acyclic monoterpene alcohols citronellol, geraniol, and linalool, enhanced the permeation of ondansetron, caffeine and haloperidol, respectively. The cyclic monoterpenes borneol, carveol, menthol, and limonene were reported as enhancers for ibuprofen, curcumin, indomethacin, and valsartan, respectively. In addition, sesquiterpene farnesol increased the permeation of haloperidol. (Sci Rep. 2019; 9: 14617.)

The role of lipid metabolism in aging, lifespan regulation, and age‐related disease

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An emerging body of data suggests that lipid metabolism has an important role to play in the aging process. Indeed, a plethora of dietary, pharmacological, genetic, and surgical lipid‐related interventions extend lifespan in nematodes, fruit flies, mice, and rats. For example, the impairment of genes involved in ceramide and sphingolipid synthesis extends lifespan in both worms and flies. The overexpression of fatty acid amide hydrolase or lysosomal lipase prolongs life in Caenorhabditis elegans, while the overexpression of diacylglycerol lipase enhances longevity in both C. elegans and Drosophila melanogaster. The surgical removal of adipose tissue extends lifespan in rats, and increased expression of apolipoprotein D enhances survival in both flies and mice. Mouse lifespan can be additionally extended by the genetic deletion of diacylglycerol acyltransferase 1, treatment with the steroid 17‐α‐estradiol, or a ketogenic diet. Moreover, deletion of the phospholipase A2 receptor improves various healthspan parameters in a progeria mouse model. Genome‐wide association studies have found several lipid‐related variants to be associated with human aging. For example, the epsilon 2 and epsilon 4 alleles of apolipoprotein E are associated with extreme longevity and late‐onset neurodegenerative disease, respectively. In humans, blood triglyceride levels tend to increase, while blood lysophosphatidylcholine levels tend to decrease with age. Specific sphingolipid and phospholipid blood profiles have also been shown to change with age and are associated with exceptional human longevity. These data suggest that lipid‐related interventions may improve human healthspan and that blood lipids likely represent a rich source of human aging biomarkers.(Aging Cell. 2019 Dec; 18(6): e13048.)