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.)

N-terminus FITC labeling of peptides on solid support: the truth behind the spacer

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Fluorescein isothiocyanate (FITC) is an amine reactive derivative of fluorescein dye that has wide ranging application in biochemistry. It has been extensively used to label peptides and proteins. However, its use in solid phase peptide synthesis is restricted. Indeed, in acidic conditions required for linker cleavage, N-ter FITC-labeled peptides undergo a cyclization leading to the formation of a fluorescein with subsequent removal of the last amino acid. This can be avoided when a spacer such as amino hexanoic acid is used or if non-acidic cleavage is operated to release targeted peptide from the resin. (Tetrahedron Letters. Volume 50, Issue 3, 21 January 2009, Pages 260-263.)

GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics

Short-interfering RNA (siRNA)-induced RNAi responses have great potential to treat a wide variety of human diseases from cancer to pandemic viral outbreaks to Parkinson’s Disease. However, before siRNAs can become drugs, they must overcome a billion years of evolutionary defenses designed to keep invading RNAs on the outside cells from getting to the inside of cells. Not surprisingly, significant effort has been placed in developing a wide array of delivery technologies. Foremost of these has been the development of N-acetylgalactosamine (GalNAc) siRNA conjugates for delivery to liver. Tris-GalNAc binds to the Asialoglycoprotein receptor that is highly expressed on hepatocytes resulting in rapid endocytosis. While the exact mechanism of escape across the endosomal lipid bilayer membrane remains unknown, sufficient amounts of siRNAs enter the cytoplasm to induce robust, target selective RNAi responses in vivo. Multiple GalNAc-siRNA conjugate clinical trials, including two phase III trials, are currently underway by three biotech companies to treat a wide variety of diseases. GalNAc-siRNA conjugates are a simple solution to the siRNA delivery problem for liver hepatocytes and have shown the RNAi (and antisense oligonucleotide) field the path forward for targeting other tissue types.

Despite RNAi’s promising therapeutic features, due to its size (∼14,000 Da) and 40 negatively charged phosphates, siRNA RNAi therapeutics cannot enter cells on their own and require a delivery agent. Moreover, naked siRNAs are rapidly degraded in blood by RNAses, cleared by the kidneys, absorbed by liver scavenger receptors, and can activate the innate immune TLR3/7/8, RIG-I, and MDA-5 systems. All these factors contribute to a poor drug profile for siRNA, which must be addressed before the therapeutic potential of siRNAs can be realized. (https://www.liebertpub.com/doi/10.1089/nat.2018.0736)