ODFs as carriers for antiviral drugs
At present, there are no regulatory approved drugs for treatment of COVID-19. Current recommendations include supportive care, ventilator based assistance for respiration, usage of anti-infectives, antivirals, and glucocorticoid therapy [39]. National Health Commission of the People’s Republic of China has provided some preferred drugs for treatment of COVID-19 that include interferon alpha, lopinavir/ritonavir, chloroquine phosphate, ribavirin, and arbidol. Some of the drugs that are presently at clinical trials stage are chloroquine, arbidol, remdesivir, and favipiravir [40,41]. Of all these drugs lopinavir/ritonavir, chloroquine phosphate, and arbidol are administered via oral route. However, favipiravir appears to be the most potent and promising drug when compared to lopinavir/ritonavir. In India, Glenmark Pharmaceuticals has initiated phase III clinical trials for favipiravir and is expected to complete the trials by end of August 2020 [42]. The solubility of this drug is very poor in water and is necessary to convert it into its salt version (sodium or meglumine) and formulate it as an injection. A Chinese company by name Chengdu Xinhengchuang Pharmaceutical Co., Ltd. developed a tablet formulation that helps in overcoming the dissolution problem and achieved desired clinical results [43]. Table 1 provides a list of antiviral agents that are currently being developed by various investigators in the world for treating COVID-19. From the table, it is evident that researchers focus is on both small molecules [55] and biologics [45,46, 48]. Further, proteins such as brilacidin [44] and recombinant protein AT-100 [50] are being developed by Innovation Pharmaceuticals and Airway Therapeutics, respectively.
Table 1.  Antiviral drugs in pipeline for treating COVID-19.
Name of the company  Details of antiviral drugs under development  Ref.
Innovation Pharmaceuticals  Brilacidin – a defensin (protein) mimetic drug candidate  [44]
CytoDyn  Leronlimab – CCR5 antagonist  [45]
Roche  Tocilizumab – Roche initiated phase III clinical trials  [46]
Biocryst Pharma  Galidesivir – adenosine nucleoside analogue acts by blocking viral RNA polymerase  [47]
Roivant Sciences  Gimsilumab – monoclonal antibody targets pro-inflammatory cytokine ‘granulocyte macrophage-colony stimulating factor (GM-CSF)’ which is high in corona virus patients.  [48]
I-Mab Biopharma  TJM2 – acts by neutralizing high GM-CSF in corona virus infected patients  [49]
Airway Therapeutics  AT-100 – developing human recombinant protein. It has collaborated with Celonic Group for producing AT-100  [50]
Tiziana Life Sciences  TZLS-501 – a monoclonal antibody and are planning to deliver it using its proprietary formulation technology, which are patent protected  [51–53]
OyaGen  OYA1 – is a broad spectrum antiviral compound which is more effective than chlorpromazine HCl in inhibiting corona virus  [54]
Beyond Spring  BPI-002 – a small molecule, acts as an adjuvant when combined with a vaccine. This small molecule is protected by a provisional US patent application (yet to be published)  [55]
Algernon Pharmaceuticals  Ifenprodil – small molecule that can be delivered via oral route. Filed a pre-IND application with USFDA. Ifenprodil is a generic drug originally developed by Sanofi  [56]
APEIRON Biologics  APN01 – Recombinant form of human angiotensin convertase enzyme 2. Dr. Josef Penninger, University of British Columbia, has carried out extensive research on APN01 in collaboration with various companies and academic institutes  [57]
Lattice Biologics Limited  AmnioBoost – is an amniotic fluid concentrate obtained from subjects during cesarean delivery  [57]
Synairgen Research  SNG001 – is nothing but interferon β – 1a administered as an inhalation to COVID patients  [58]
Emanta Pharmaceuticals  It is testing various known and new small molecule drug candidates that have the potential to act against COVID 19.  [59]
Vir Biotechnology  VIR-7831 and VIR-7832 are two monoclonal antibodies that target the spike protein of the corona virus and enter via ACE2 cell receptor. Vir has collaborations for development of these antibodies  [60]
Columbia University  Received a research grant of 2.1 million USD from Jack Ma foundation to develop various drugs for treatment of corona virus. They are developing antiviral drugs and an antibody that has the potential to neutralize the virus  [61] The drugs that are being developed, mentioned in Table 1, could face many challenges when it comes to delivering to the subject. For instance, favipiravir is associated with poor water solubility and demands an injection formulation. A potential alternative to such a disadvantage of favipiravir and other similar drugs is to formulate them as ODFs. Table 2 provides a list of antiviral drugs that were successfully formulated as ODFs. It is evident from Table 2 that drugs with low solubility, bioavailability, and dose are excellent candidates for formulating as films. The most conventional method used to prepare ODFs is solvent casting method and the modern methods include printing technologies using inkjet printing, wherein antiviral drugs are printed either alone or in combination with other drugs, for instance, anticancer drugs printed alongside antiviral drugs [64,65]. In addition, antiviral ODFs can be prepared as a single layered or multi-layered dosage forms, example: entecavir [67]. Drugs could either be directly loaded onto ODFs or converted into nanoparticles before loading onto ODFs. The key ingredients include a film-forming material (polymer) and plasticizer.
Table 2.  Antiviral drugs formulated as ODFs.
Drug name – technique employed to load to ODFs  Reason for choosing the drug or API to formulate as an ODFs  Polymer  Plasticizer  Method  Key highlight(s)  Ref.
Herpetrione (HPE) – extracted from Herpetospermum caudigerum.HPE nanoparticles were prepared using sodium dodecyl sulfate and PVP K-30  Poor water solubility and low bioavailability  Hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC), and l-hydroxypropyl cellulose (HPC)  PEG-400  Solvent casting method (SCM)  Studies established that ODFs are suitable for delivery of poorly water-soluble drugsSCM is modified to prepare drug nanosuspensionOral bioavailability of HPE nanoparticles was higher when compared HPE coarse suspension  [62]
Herpetrione (HPE)Nanoparticles were prepared and optimized using the Box–Behnken design response surface methodology  Poor water solubility and low bioavailability  HPMC, MCC, L-HPC  PEG-400  SCM  ODFs formulation of HPE nanoparticles was successfully optimized using the Box–Behnken design response surface methodology  [63]
CidofovirNanoparticles were prepared using poly(ethylene glycol)–polycaprolactone (PEG-PCL)  To achieve its controlled release and also due to its wide spectrum anti-viral activity  HPC   a  Printed using inkjet printer  Combination of complexed anti cancer drug (Paclitaxel) and complexed anti viral drug (Cidofovir) were printed onto ODFsMechanical properties of film were enhanced due to drug printing  [64,65]
Acyclovir – solid dispersion was prepared  Poor water solubility and low bioavailability  HPMC  Glycerol  SCM  Oral administration of ODFs of acyclovir instead of intravenous route of administration  [66]
Entecavir (single or multi-layered ODFs)  Low dose − 0.5–1 mg per day  Starch, carrageenan, pullulan and many others  Acetyl triethyl citrate or propylene glycol or citrate ester or triacetin  SCM  Multi-layered ODFs were disclosed  [67]
a  Nothing found.