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Central nervous system (CNS) disorders, such as psychiatric disorders, neurodegeneration, chronic pain, stroke, brain tumor, spinal cord injury, and many other CNS diseases, would hugely benefit from specific and potent peptide pharmaceuticals and their low inherent toxicity. The delivery of peptides to the brain is challenging due to their low metabolic stability, which decreases their duration of action, poor penetration of the blood-brain barrier (BBB), and their incompatibility with oral administration, typically resulting in the need for parenteral administration. These challenges limit peptides’ clinical application and explain the interest in alternative routes of peptide administration, particularly nose-to-brain (N-to-B) delivery, which allows protein and peptide drugs to reach the brain noninvasively. N-to-B delivery can be a convenient method for rapidly targeting the CNS, bypassing the BBB, and minimizing systemic exposure; the olfactory and trigeminal nerves provide a unique pathway to the brain and the external environment. This review highlights the intranasal delivery of drugs, focusing on peptide delivery, illustrating various clinical applications, nasal delivery devices, and the scope and limitations of this approach.

Respiratory diseases are among the leading causes of morbidity and mortality worldwide. Innovations in biochemical engineering and understanding of the pathophysiology of respiratory diseases resulted in the development of many therapeutic proteins and peptide drugs with high specificity and potency. Currently, protein and peptide drugs are mostly administered by injections due to their large molecular size, poor oral absorption, and labile physicochemical properties. However, parenteral administration has several limitations such as frequent dosing due to the short half-life of protein and peptide in blood, pain on administration, sterility requirement, and poor patient compliance. Among various noninvasive routes of administrations, the pulmonary route has received a great deal of attention and is a better alternative to deliver protein and peptide drugs for treating respiratory diseases and systemic diseases. Among the various aerosol dosage forms, dry powder inhaler (DPI) systems appear to be promising for inhalation delivery of proteins and peptides due to their improved stability in solid state. This review focuses on the development of DPI formulations of protein and peptide drugs using advanced spray drying. An overview of the challenges in maintaining protein stability during the drying process and stabilizing excipients used in spray drying of proteins and peptide drugs is discussed. Finally, a summary of spray-dried DPI formulations of protein and peptide drugs, their characterization, various DPI devices used to deliver protein and peptide drugs, and current clinical status are discussed.

Coronavirus disease-2019 (COVID-19) is caused by coronavirus-2 (SARS-CoV-2) and has produced a global pandemic. As of 22 June 2021, 178 million people have been affected worldwide, and 3.87 million people have died from COVID-19. According to the Centers for Disease Control and Prevention (CDC) of the United States, COVID-19 virus is primarily transmitted between people through respiratory droplets and contact routes. Since the location of initial infection and disease progression is primarily through the lungs, the inhalation delivery of drugs directly to the lungs may be the most appropriate route of administration for treating COVID-19. This review article aims to present possible inhalation therapeutics and vaccines for the treatment of COVID-19 symptoms. This review covers the comparison between SARS-CoV-2 and other coronaviruses such as SARS-CoV/MERS, inhalation therapeutics for the treatment of COVID-19 symptoms, and vaccines for preventing infection, as well as the current clinical status of inhaled therapeutics and vaccines.

Obstructive sleep apnea (OSA) is a common sleep disorder characterized by the upper airway collapse, leading to interrupted breathing and reduced oxygen levels during sleep. This condition often results in chronic inflammation and is associated with various long-term health problems. To address OSA-related inflammation, an FDA-approved drug, Doxycycline, was formulated in this study as a dry powder inhaler due to its favorable anti-inflammatory properties that was tested in subsequent cellular and animal studies of OSA. This comprehensive and systematic study aimed to develop inhalable excipient-free spray-dried (SD) one-component drug powders of Doxycycline . Advanced organic solution spray-drying in closed mode, with three different feed pump rates (10%, 50%, and 100%), was used to design and produce Doxycycline microparticles in the solid state successfully. The SD Doxycycline formulations comprised hollow, spherical, dimpled particles (<2 μm). The solid-state characterization of SD formulations confirmed the amorphous nature of Doxycycline after spray drying with a glass transition temperature between 82.73 °C and 89.29 °C. However, compared to the raw drug, residual water content was higher in the SD formulation, ranging from 6.4 ± 0.02% w/w in SD Doxycycline at the low feed pump rate to 6.79 ± 0.06% w/w in SD Doxycycline at the high feed pump rate. SD formulations showed good aerosolization behavior with a Respirable Fraction (RF) of >60% with NeoHaler inhaler device (63.19 ± 7.59 to 68.53 ± 3.73%) while HandiHaler showed lower RF (39.61± 0.57 to 53.90 ± 8.03%). The fine particle fraction (FPF) was higher in the NeoHaler group (24.91 ± 1.17 to 36.72 ± 2.01%) compared to HandiHaler (19.61 ± 5.41 to 33.76 ± 5.21%). This could be explained by the difference in median aerodynamic diameter (8.21 ± 2.68 to 4.69± 1.27 μm) in the NeoHaler group compared to (3.07 ± 0.36 to 3.67 ± 0.59 μm) HandiHaler group. Furthermore, in vitro cell viability as a function of lung cell type and drug dose showed 10 µM of Doxycycline as a safe concentration for the A549, H358, H441, and Calu-3 epithelial-like immortal human cell lines. Inhalable dry powder formulation of Doxycycline could offer new treatment options for patients suffering from sleep apnea.

There are health concerns associated with increased folic acid intake from fortified food and supplements. Existing analytical methods, however, which can be employed to carry out epidemiological and bioavailability studies for folic acid involve laborious sample preparation and/or lengthy chromatographic analysis. In this paper we describe a simple, rapid, and sensitive high-performance liquid chromatography–electrospray ionisation-tandem mass spectrometry (HPLC–ESI-MS/MS) method for determination of unmetabolised folic acid in human plasma using folic acid-d4 as an internal standard. The method required only a simple sample preparation step of protein precipitation and had a total run time of 3.5 min, which is the shortest run time reported to date for HPLC–MS/MS method employed for quantifying folic acid in plasma. The analytes were separated on a C18 column (3 µm; 50 × 3.00 mm) using an isocratic mobile phase consisting of ammonium acetate (1 mM)-acetic acid-acetonitrile (9.9:0.1:90, v/v/v). The method was fully validated in terms of accuracy, precision, linearity, selectivity, recovery, matrix effect, and stability. The short run time and the minimal sample preparation makes the method a valuable tool for performing high-throughput analyses. To demonstrate the applicability of the method in real conditions, it was applied successfully in a bioavailability study for the determination of unmetabolised folic acid levels in vivo in human plasma after oral administration of folic acid.

The purpose of this study was to formulate Lactomorphin (MMP2200) in its pure state as spray-dried(SD) powders, and with the excipient Trehalose as co-spray-dried(co-SD) powders; for intranasal and deep lung administration with Dry Powder Inhalers (DPI). Lactomorphin is a glycopeptide which was developed for the control of moderate to severe pain. Particles were rationally designed and produced by advanced spray drying particle engineering in a closed mode from a dilute organic solution. Comprehensive physicochemical characterization using different analytical techniques was carried out to analyze the particle size, particle morphology, particle surface morphology, solid-state transitions, crystallinity/non-crystallinity, and residual water content. The particle chemical composition was confirmed using attenuated total reflectance-Fourier-transform infrared (ATR-FTIR), and Confocal Raman Microscopy (CRM) confirmed the particles’ chemical homogeneity. The solubility and Partition coefficient (LogP) of Lactomorphin were determined by the analytical and computational methodology and revealed the hydrophilicity of Lactomorphin. A thermal degradation study was performed by exposing samples of solid-state Lactomorphin to a high temperature (62 °C) combined with zero relative humidity (RH) and to a high temperature (62 °C) combined with a high RH (75%) to evaluate the stability of Lactomorphin under these two different conditions. The solid-state processed particles exhibited excellent aerosol dispersion performance with an FDA-approved human DPI device to reach lower airways. The cell viability resazurin assay showed that Lactomorphin is safe up to 1000 μg/mL on nasal epithelium cells, lung cells, endothelial, and astrocyte brain cells.

Two series of putatively brain-penetrant alamandine glycosides have been prepared for screening against the MrgD receptor. The first series retains the initial six residues of the alamandine sequence (ARVYIHP) as the “peptide message,” replacing the C-terminal proline (P) with several serine (S) glycosides at the C-terminus to produce “glycoside addresses”. In the second series, steric bulk was altered to modify the “peptide message”– the N-terminal alanine (A) residue was substituted with glycine (G); D-alanine (a); nor-valine (norV); D-nor-valine (D-norV); valine (V); and D-nor-valine (v), keeping the C-terminal serine-beta-D-glucoside (S-Glc) “glycoside address” constant. All the peptides and glycopeptides were synthesized as their C-terminal amides. The purity of native alamandine and its eleven selected derivatives were each confirmed using analytical HPLC. Also, the molecular weight and chemical composition were confirmed using mass spectroscopy. The MrgD receptor expression was evaluated in rationally chosen human cell lines, A549 and HEK 293. Both cell lines showed the presence of the MrgD receptor around 35 kDa, as confirmed by western blot analysis. The effect of varying concentrations of some alamandine derivatives on cell viability was evaluated on HEK 293 and A549 cell lines. Graphical abstract

The peptide hormone Angiotensin (1—7), Ang (1—7) or (Asp-Arg-Val-Tyr-Ile-His-Pro), is an essential component of the renin–angiotensin system (RAS) peripherally and is an agonist of the Mas receptor centrally. Activation of this receptor in the CNS stimulates various biological activities that make the Ang (1—7)/MAS axis a novel therapeutic approach for the treatment of many diseases. The related O-linked glycopeptide, Asp-Arg-Val-Tyr-Ile-His-Ser-(O-β-D-Glc)-amide (PNA5), is a biousian revision of the native peptide hormone Ang (1—7) and shows enhanced stability in vivo and greater levels of brain penetration. We have synthesized the native Ang (1—7) peptide and the glycopeptide, PNA5, and have formulated them for targeted respiratory delivery as inhalable dry powders. Solid phase peptide synthesis (SPPS) successfully produced Ang (1—7) and PNA5. Measurements of solubility and lipophilicity of raw Ang (1—7) and raw PNA5 using experimental and computational approaches confirmed that both the peptide and glycopeptide have high-water solubility and are amphipathic. Advanced organic solution spray drying was used to engineer the particles and produce spray-dried powders (SD) of both the peptide and the glycopeptide, as well as co-spray-dried powders (co-SD) with the non-reducing sugar and pharmaceutical excipient, trehalose. The native peptide, glycopeptide, SD, and co-SD powders were comprehensively characterized, and exhibited distinct glass transitions (Tg) consistent with the amorphous glassy state formation with Tgs that are compatible with use in vivo. The homogeneous particles displayed small sizes in the nanometer size range and low residual water content in the solid-state. Excellent aerosol dispersion performance with a human DPI device was demonstrated. In vitro human cell viability assays showed that Ang (1—7) and PNA5 are biocompatible and safe for different human respiratory and brain cells.

Pain is the most significant impairment and debilitating challenge for patients with bone metastasis. Therefore, the primary objective of current therapy is to mitigate and prevent the persistence of pain. Thus, cancer-induced bone pain is described as a multifaceted form of discomfort encompassing both inflammatory and neuropathic elements. We have developed a novel non-addictive pain therapeutic, PNA6, that is a derivative of the peptide Angiotensin-(1-7) and binds the Mas receptor to decrease inflammation-related cancer pain. In the present study, we provide evidence that PNA6 attenuates inflammatory, chemotherapy-induced peripheral neuropathy (CIPN) and cancer pain confined to the long bones, exhibiting longer-lasting efficacious therapeutic effects. PNA6, Asp-Arg-Val-Tyr-Ile-His-Ser-(O-β-Lact)-amide, was successfully synthesized using solid phase peptide synthesis (SPPS). PNA6 significantly reversed inflammatory pain induced by 2% carrageenan in mice. A second murine model of platinum drug-induced painful peripheral neuropathy was established using oxaliplatin. Mice in the oxaliplatin-vehicle treatment groups demonstrated significant mechanical allodynia compared to the oxaliplatin-PNA6 treatment group mice. In a third study modeling a complex pain state, E0771 breast adenocarcinoma cells were implanted into the femur of female C57BL/6J wild-type mice to induce cancer-induced bone pain (CIBP). Both acute and chronic dosing of PNA6 significantly reduced the spontaneous pain behaviors associated with CIBP. These data suggest that PNA6 is a viable lead candidate for treating chronic inflammatory and complex neuropathic pain.

Central nervous system (CNS) disorders, including neurodegeneration and chronic pain, and many respiratory diseases would greatly benefit from the specific and potent peptide pharmaceuticals and their low inherent toxicity. The delivery of peptides to target the brain is challenging, principally due to peptides' low metabolic stability, which decreases their duration of action, poor penetration of the blood-brain barrier (BBB), and their incompatibility with oral administration, typically resulting in the need for parenteral administration. These challenges limit the clinical application of peptides and explain the interest for alternative routes of peptide administration, particularly: delivery to the respiratory tract (upper and lower). Upper to target the brain through the olfactory route bypassing the blood-brain barrier (BBB), i.e., needle-free nose-to-brain delivery (N-to-B), which offers protein and peptide drugs the possibility to reach the brain noninvasively. N-to-B delivery can be a convenient method for rapidly targeting the CNS, bypassing the BBB, and minimizing systemic exposure. In addition, delivery to the lower respiratory tract as inhalation aerosol offers attractive advantages in delivering the drug locally to treat lung diseases; and to the CNS to treat its disorders at a low dose while minimizing systemic adverse effects. The lung is a low metabolic organ compared to the gastrointestinal (GI) tract. It allows rapid and high drug absorption due to the large surface area, the high blood flow, and the absence of the first-pass metabolism. In this study, several peptides and glycopeptides with different pharmacological mechanisms were developed. Some of these compounds were synthesized using the SPPS strategy and formulated as dry powders with characteristics tailored to target the respiratory tract (upper and/or lower) to treat various CNS and lung diseases. Advanced organic closed mode spray drying technique was used to produce microparticulate/ nanoparticulate formulations utilizing sugar-based excipients. The solubility and lipophilicity of all included compounds were determined computationally using molecular operating environment (MOE) software and experimentally using the shake-flask method (SFM). The raw and formulated compounds were comprehensively characterized in the solid-state. The safety of all peptides and glycopeptides covered in this dissertation was evaluated in vitro using the human nasal, brain, and pulmonary cell lines. The in vitro aerosol dispersion of the raw and spray-dried compounds was tested using an FDA-approved human inhaler device, and the influence of spray drying process conditions on the aerosol dispersion was evaluated.