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The potential of ODFs as carriers for drugs/vaccines against COVID-19
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M. S. Gupta and T. P. Kumar
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Abstract
COVID-19 has spread out its wings across the globe and is taking away many lives. Millions of people are (self) quarantined to prevent the spread of this viral disease. World Health Organization (WHO) has affirmed that there is not any medicine for COVID-19. Besides, there is also no single drug that is approved by any regulatory agency for usage against this dangerous disease. Researchers across the globe are working tirelessly to fix an end to this virus and to save precious lives. While the research is in full swing, one is not sure whether they would come up with a chemical/herbal drug or a vaccine. Irrespective of the type of active ingredient for COVID-19, one needs to have a proper system to deliver the identified active ingredient to subjects/patients across the globe. Orodispersible films (ODFs) are excellent and attractive drug delivery carriers that have the potential to deliver drugs, herbal extracts, and vaccines. They are apt for patients who have a problem consuming traditional drug products such as tablets or capsules. The beauty of this dosage form is that it does not need water to consume by the subjects and can be readily administered to the tongue. The present review highlights the true potential of ODFs to act as a carrier for the delivery of various antiviral drugs/herbs/vaccines.
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Abstract
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COVID-19 has spread out its wings across the globe and is taking away many lives. Millions of people are (self) quarantined to prevent the spread of this viral disease. World Health Organization (WHO) has affirmed that there is not any medicine for COVID-19. Besides, there is also no single drug that is approved by any regulatory agency for usage against this dangerous disease. Researchers across the globe are working tirelessly to fix an end to this virus and to save precious lives. While the research is in full swing, one is not sure whether they would come up with a chemical/herbal drug or a vaccine. Irrespective of the type of active ingredient for COVID-19, one needs to have a proper system to deliver the identified active ingredient to subjects/patients across the globe. Orodispersible films (ODFs) are excellent and attractive drug delivery carriers that have the potential to deliver drugs, herbal extracts, and vaccines. They are apt for patients who have a problem consuming traditional drug products such as tablets or capsules. The beauty of this dosage form is that it does not need water to consume by the subjects and can be readily administered to the tongue. The present review highlights the true potential of ODFs to act as a carrier for the delivery of various antiviral drugs/herbs/vaccines.
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Introduction
During the fag end of 2019, Wuhan – the most densely populated city and capital of Hubei Province – China was witnessing pneumonia whose etiology was unknown. At the beginning of 2020, the pathogen was successfully identified and was named as the 2019 novel corona virus (2019-nCoV) [1,2]. Later, on 20 February 2020, the International Committee on Taxonomy of Viruses (ICTV) named it as Severe Acute Respiratory Syndrome Corona virus 2 (SARS-CoV-2), a new variant of SARS-CoV, and the disease caused was corona virus disease 2019 (COVID-19) [3]. Since then the whole world is on ‘High Alert’ due to this new viral threat. Millions of people have been (self) quarantined to prevent it from further spreading [4]. Nonetheless, the individuals infected by corona virus are augmenting everyday [5]. There are absolutely no drugs that are approved by regulatory agencies across the globe. In India, the Indian Council of Medical Research (ICMR) strongly recommended the usage of hydroxychloroquine for asymptomatic purposes [6]. Followed by this development, emergency use authorization was granted by United States Food and Drug Administration (USFDA) to promote the usage of chloroquine phosphate or hydroxychloroquine sulfate for treating COVID-19 [7]. World Health Organization (WHO) identified and recommended usage of remdesivir, lopinavir–ritonavir with or without interferon, immunotherapy, and recuperative sera. WHO also launched SOLIDARITY trials for the above-prescribed drugs to support that they are effective in treating COVID-19 [8]. In addition, novel chemical entities against the corona virus protease were also proposed by some researchers [9] and some have proposed various integrated Chinese and Western medicines for treating this pandemic [10].
While the research is going on to identify an active agent for COVID-19. Identifying the mode of delivering the active moieties to patients and healthy subjects cannot be ignored. At present, there are several drug delivery systems, whereas the most novel and transformative drug delivery/carrier system is orodispersible films (ODFs). European Pharmacopoeia (Ph. Eur.) defines ODFs as ‘single or multilayered sheets of suitable materials, to be placed in the mouth where they disperse rapidly’ [11]. They are a type of oromucosal preparations which are ultra-thin, elegant, stamp sized, portable, patient friendly, and attractive dosage forms across all the age groups [12]. Clinical Data Interchange Standards Consortium (CDISC) defines ODFs as ‘A thin layer or coating which is susceptible to being dissolved when in contact with a liquid’ [13]. On the contrary, United States Pharmacopoeia (USP) employs a different terminology and called them as ‘Oral Films’ and defined as ‘Thin sheets that are placed in the oral cavity. They contain one or more layers. A layer might or might not contain API’ [14]. ODFs undergo rapid disintegration/dissolution and are usually swallowed along with saliva and a small amount of the drug gets absorbed via the oral mucosa due to its high vasculature [15,16].
ODFs are excellent and attractive carriers for delivery of various over the counter (OTC) or prescription drugs [17], herbal extracts [18–21], vaccines [22], probiotics [23], and vitamins [24]. Drugs are either directly introduced [25–28] in the formulation of ODFs or size reduced and converted to solid dispersions [29] or nanoparticles [30,31] or solid lipid microparticles [32] or micronized and surface modified using silica [33] which not only help in enhancing the amount of drug that could be loaded on to ODFs but also help in enhancing the release rate and, bioavailability of the drug. At present, ODFs are used as an excellent carrier system for delivering various therapeutically active agents. The composition of ODFs includes a drug substance (natural or synthetic), a film-forming agent and plasticizer. Additionally, it also includes saliva stimulating agent, organoleptic agents, and stabilizers [12]. The critical quality characteristics of ODFs are its appearance, stability, water content, uniformity of the active agent, color, taste, aftertaste, and mouthfeel. Most importantly, it shall not cause irritation of mucosa when administered [34]. The authors provided an overview on characterization of ODFs to determine various quality parameters of ODFs and also introduced a 3D printed disintegration test apparatus for testing the disintegration time of ODFs using sensor technology [35]. ODFs are capable for drug delivery in patients with swallowing problems, mentally retarded patients, subjects with Parkinson’s disease, bed-ridden patients, oral cancer patients, and uncooperative patients [36–38]. The present review is focused on critically analyzing the potential of ODFs as carriers for delivering antiviral drugs/herbs/vaccines with a potential for treatment of COVID-19, the global pandemic.
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.
ODFs as carriers for antiviral and immunity boosting herbs
WHO said ‘To date there is no specific medicine recommended to prevent or treat the novel coronavirus’ [68]. In view of the fact that there are no drugs and vaccines, that are approved, for treating COVID-19, many are turning toward herbal medicines that are either of the Indian or Chinese origin. There are many herbs in Indian Ayurveda that have the potential for prophylaxis and treatment of corona virus infection. For instance, Rastogi et al. reported a ‘pragmatic and plausible plan of action for Ayurvedic intervention’ of various Ayurvedic drugs that have the potential to be used in mild to severe COVID-19 symptoms [69]. Subjects who are not yet exposed and asymptomatic group can use Ayurvedic ‘Swarna Prashana’ and ‘Rasayana’ as potential immunity boosting agents [70–73]. This in combination with social distancing helps in preventing the spread of disease [74].
Ministry of Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homeopathy (AYUSH), Government of India recommends three immunity boosting measures. First and foremost is taking 10 g of Chyavanprash every day (not suitable to formulate as ODFs due to its heavy dose), second: drinking golden milk (milk with turmeric) twice a day, and lastly drinking herbal tea or a drink prepared by boiling tulsi, cinnamon, black pepper, dry ginger and raisin taken either by adding jiggery (natural sweet) or lemon juice for taste, if required – to be taken once a day or twice in a day [75]. The Ministry of AYUSH has also confirmed that clinical trials are initiated on AYUSH-64, a polyherbal anti-malarial Ayurvedic formulation [76]. Indian Institute of Delhi in collaboration with National Institute of Advanced Industrial Science and Technology, Japan has reported the potential of Ashwagandha against COVID-19 [77]. CSIR (Council of Scientific and Industrial Research) in collaboration with Sun Pharma are working on a phytopharmaceutical composition that is found to be effective in treatment of COVID-19 [78]. Very recently, Sun Pharma received approval for clinical trials of AQCH from Drugs Controller General of India (DCGI) [79].
Chinese National Health Commission announced, dated 14 April 2020, three patented Chinese herbal drugs for treatment of COVID-19 which include namely: ‘Lianhuaqingwen capsules and Jinhuaqinggan granules for mild conditions, and Xuebijing (injectable) for severe conditions’ [80]. Luo et al. carried out an excellent review on Chinese herbal medicines that have the strong potential for usage in prevention of COVID-19. They have also reported the highly used herbs for preventing COVID-19 infections [81]. A Korean company by name, Biostandard Inc, reported usage of fermented Isatidis Radix Extract and claim to be effective against corona virus infections and they have protected the same by a Korean patent application [82]. Few other companies/academic institutions that have patent protected herbal extracts effective in preventing COVID-19 are provided in Table 3.
Table 3. Patent protected herbs for preventing/treating COVID-19.
Name of the player Drug name and details Ref.
Biostandard Inc Fermented Isatidis Radix Extract [82]
Bioniche Life Sciences Inc Pyranocoumarin enriched composition (free from furanocoumarins) obtained from Zanthoxylum americanum (Prickly Ash) [83]
The University of Hong Kong Baicalin – compound extracted from Scutellaria baicalensis [84]
Seoul National University Industry-Academic Cooperation Foundation Extract of Angelica dahurica [85]
Amazon Biotech Inc. Herbal composition comprising ‘Boswellia carterii stem resin, Styrax benzoin stem resin, Cinnamomum zeylanicum bark, Curcuma zedoaria root, Syzygium aromaticum fruit, Nardostachys chinensis root, Betula alba bark, Impatiens balsamina bark, Costus spicatus root, Allium sativum bulb Cyperus rotundus root and Hyssopus officinalis’ [86]
Biopharmacopae Inc. Extracts of ginger and/or goldenrod (Solidago) [87] A decoction of various Ayurvedic herbs namely: ‘Tinospora cordifolia, Zingiber officinale, Curcuma longa, Ocimum sanctum, Glycyrrhiza glabra, Adhatoda vasica, Andrographis paniculata, Swertia chirayita, Moringa oleifera, Triphala and Trikatu’ have broad antiviral activity and protease inhibitor activity [88–90]. This decoction could be very useful in COVID-19 patients who are quarantined.
Turning now to ODFs of herbal extracts, Cure pharmaceuticals published US patent on herbs ((agrimony, andrographis paniculata, bistort, fenugreek, ginger, myrrh, solanum, etc.) tree and plant extracts ((licorice, shitake, sarsaparilla, slippery elm, etc.), and essential oils (clove, camphor, cinnamon, lemon, spearmint, etc.) that are formulated as multilayered edible oral thin films for management of cough/Pharyngitis [91]. Table 4 provides a list of ODFs formulated using herbal extracts. From the table, it is evident that solvent casting method is the most preferred method to fabricate herbal ODFs. Zim laboratories limited, a leading Indian company in the domain of oral thin films has published a research article on oral dissolving films of ginger [21]. Visser et al. reported ODFs of five Indonesian medicinal plants extracts namely: Lagerstroemia speciosa, Phyllanthus niruri, Cinnamomum burmannii, Zingiber officinale, and Phaleria macrocarpa [92] were prepared by solvent casting method [95]. Of these plant extracts, Phaleria macrocarpa and Zingiber officinale are associated with antiviral activity [96,97]. Song et al. evaluated antiviral activity of quercetin-7-glucoside isolated from Lagerstroemia speciosa [98]. Sri Wahyuni et al. reported antiviral activity of Phyllanthus niruri, particularly they reported its activity against hepatitis C virus [99]. Verma et al. reported ODFs of Piper betel and Foeniculum officinalis [93]. Foeniculum officinalis is reported to possess antiviral and antioxidant activity [100]. Similarly, Pawar and Butle reported ODFs of Allium sativum [94], a potent antiviral agent [101].
Table 4. Antiviral herbs formulated as ODFs.
Name of the herb and technique employed, if any, to load to ODFs Reason for choosing/selecting the herb to formulate as an ODFs Polymer Plasticizer Method Key highlight(s) Ref.
Ginger extract Existing formulations (capsules and liquids) of ginger suffer with problems of wettability of contents and inaccuracy in dosing. Hydroxypropyl methylcellulose (HPMC) or maltodextrin or pullulan Polyethylene glycol (PEG) Solvent casting method (SCM) HPMC based ODFs were found to be ideal with low disintegration time and stable at high temperature [21]
Indonesian herbal extracts of Phaleria macrocarpa and Zingiber officinale Selected based on the herbal extracts popularity, reproducibility and well established scientific support (clinical evidence) HPMC with carbomer 947p (or) hydroxypropyl cellulose (HPC) Glycerol SCM Stable ODFs were obtained and benzalkonium chloride was employed as a stabilizer and also for spreadability [92]
Foeniculum officinalis extract –a HPMC Glycerol SCM Employed super disintegrating agent (sodium starch glycollate) to achieve low disintegration time of ODF [93]
Garlic extract –a Hypromellose Glycerol SCM Menthol was used as a flavoring agent [94]
a Nothing found. Generally speaking, ODFs are well known to act as carriers for various herbal extracts [18–21]. But, from the above explanation, it is particularly evident that they have the potential to act as carriers to aid in the delivery of various antiviral herbs.
ODFs as carriers for antiviral vaccines
The Center for Disease Control and Prevention defines vaccines as ‘A product that stimulates a person’s immune system to produce immunity to a specific disease, protecting the person from that disease. Vaccines are usually administered through needle injections, but can also be administered by mouth or sprayed into the nose’ [102]. Vaccination is considered as one of the most effective ways of preventing cause of a disease [103]. At present, there are several companies, academic institutes that are actively working to develop a vaccine against COVID-19. Vaccines that are currently under development are provided in Table 5.
Table 5. Antiviral vaccines in pipeline for treating COVID-19.
Name of the player Details of antiviral vaccines under development Ref.
Migal Galilee Research Institute, Israel Developing an oral (mucosal) vaccine, wherein the viral antigen is delivered via mucosa tissues by self-activated endocytosis [104]
Entos Pharmaceuticals Fusogenix – DNA vaccine is being developed based on its patent protected platform, proteo-lipid vehicle (PLV). It uses a new mechanism for delivering genetic material into the cells [105,106]
Vaxart Inc Oral recombinant vaccine in tablet formulation using its VAAST platform. It has protected its vaccine tablet formulation by US patent applications [107–109]
University of Oxford – Jenner Institute ChAD0X1 nCoV-19 – prepared from cold virus (weakened) – initiated Phase III trials [110]
Altimmune AdCOVID – vaccine delivered via intranasal route platform technologies NasoVAX and NasoShield [111,112]
Medicago Developing a vaccine and also an antibody. It was successful in producing virus like particles of coronavirus. It is developing antibodies in collaboration with Laval University [113]
Inovio Pharmaceuticals INO-4800 – vaccine that is developed in collaboration with Beijing Advaccinee Biotechnology Company. It is proposing to deliver the vaccine using the device called as CELLECTRA® which works by creating a pulse for transferring the plasmids across the cell. It is also developing INO 4700 in collaboration with GeneOne Life Sciences company [114]
Moderna mRN 1273 – recently received fast track designation from USFDA. It vaccine basically targets spike protein of corona virus [115]
Tonix Pharmaceuticals TNX-1800 – developed based on its horsepox virus vaccine platform. It has filed a provisional patent application with USPTO [116]
Clover Biopharmaceuticals Subunit vaccine developed using trimeric spike protein developed using its patented technology [117]
Novavax, Inc Middle East Respiratory Syndrome (MERS) vaccine was developed using recombinant nanoparticle based vaccine technology. The vaccine showed positive results in inhibiting the virus when administered along with its patented adjuvant formulations [118–121]
Predictive oncology (PO) Introduced artificial intelligence for development of a vaccine using Inventa Biotech’s HSCTM technology which deals with chromatographic system of high throughput screening. In addition, PO is also developing a new vaccine based on nanoparticle (NSP-10: non specific protein) platform technology developed by Dr. Daniel Carter [122] Primarily, vaccines pose extreme challenges vis-a-vis its handling, (cold) storage and shipping, all expensive propositions. For instance, one of the studies reported that 38 billion USD would be spent on transportation and administration of 18 vaccines in 94 countries [123,124]. Therefore, there is a need for alternate dosage forms that can help reducing the cost. For instance, Vaxart Inc is developing recombinant vaccine for COVID-19 in tablet formulation using its patent protected technology called VAAST [107–109]. RP Scherer Technologies LLC is also developing a tablet formulation (fast dissolving) for influenza vaccine with starch as immune stimulating agent [125]. Tablets are highly traditional and conventional dosage forms that are difficult to administer to patients who have dysphagia or Parkinson’s disease and are extremely difficult to administer to pediatrics and geriatrics. Therefore, ODFs remain as an alternate choice of administration as they do not need water to consume. Most importantly, they are easy to transport from one place to another. Israel’s Migal Galilee Research Institute is actively developing a vaccine that is administered via oromucosal route [104]. Some of the vaccine preparations that are successfully formulated as ODFs are provided in Table 6.
Table 6. Antiviral vaccines that are formulated as ODFs.
Name of the player Name of vaccine formulated as ODFs Polymer Plasticizer Method employed Key highlight(s) Ref.
The Johns Hopkins University Several live-attenuated viruses were proposed, including the corona virus. Provided methodology to prepare rotavirus vaccine Eudragit Polyethylene glycol (PEG) and polyvinyl alcohol (PVA) Double emulsion solvent evaporation Prepared as monolayered or bi layered ODFs [126]
Brian Pulliam (single applicant and inventor) Rotavirus vaccine along with an antacid namely magnesium hydroxide or aluminum hydroxide nanoparticles for digestion purpose Polyvinyl pyrrolidone + hydroxypropyl cellulose (HPC) PEG Solvent casting method (SCM) Antacid successfully combined with a vaccine in layered fashion [22]
Nitto Denko Corporation Cancer vaccine comprising WT1 peptide or Db126 along with a promoter namely lipopolysaccharide or quercetin or ioxoprofen Mannitol, PEG, and HPC PEG, mannitol SCM Composition successfully induces cellular immunity in cancer patients [127]
Nasir Uddin from Larkin University Gonorrhoea microparticulate vaccine a a SCM Microparticulate vaccine particles were obtained by spray dryingBilayered ODFs can be prepared, outer layer acts as protection layer [128]
Aridis Pharmaceuticals Rotavirus vaccine a a a Patent protected vaccine stabilization technology and plasticized glass stabilization technology were employed in preparing the vaccine film [129–131]
a Nothing found. Administration of vaccines using fast dissolving buccal films is the most optimized form of administration as it has plethora of advantages when compared with parenteral route of administration [132]. Research suggests that vaccines administered via oral route are as good as or even better than those that are administered via parenteral route. For instance, Bajrovic et al. demonstrated that oral administration (sublingual and buccal routes) of influenza virus vaccine as a thin film formulation has shown good or better results than the vaccine that is administered via intramuscular route [133]. From Table 6, it is evident that ODFs comprising vaccines can be prepared as mono or bilayered using the most popular solvent casting method. Tian et al. prepared influenza virus vaccine by using trehalose and pullulan to maintain the stability and antigenicity of the vaccine. They also employed hypromellose that further helped in enhancing the stability of the film [134]. ODFs remain an excellent option for delivery of vaccines to subjects across all the age groups. They are easily portable and maintain stability of the vaccine during transportation till it reaches to the subject for consumption. All these strongly suggest that ODFs are cost-effective carriers and easy to consume dosage forms.
Conclusion
In light of the above, ODFs are a novel oromucosal carriers that could be used to deliver a new active agent (drug/vaccine) against COVID-19. ODFs have already proven its potential to act as a carrier for delivery of drug/herb/vaccine. But, more research is still needed vis-a-vis loading vaccines onto ODFs. Research in the domain of corona virus infections has taken the front seat across the globe and companies are heavily investing in R&D. Hopefully, soon the world will witness a new active entity for treating COVID-19 and the life of all the human beings will come to normalcy – from unusual to life as usual.
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Introduction
During the fag end of 2019, Wuhan – the most densely populated city and capital of Hubei Province – China was witnessing pneumonia whose etiology was unknown. At the beginning of 2020, the pathogen was successfully identified and was named as the 2019 novel corona virus (2019-nCoV) [1,2]. Later, on 20 February 2020, the International Committee on Taxonomy of Viruses (ICTV) named it as Severe Acute Respiratory Syndrome Corona virus 2 (SARS-CoV-2), a new variant of SARS-CoV, and the disease caused was corona virus disease 2019 (COVID-19) [3]. Since then the whole world is on ‘High Alert’ due to this new viral threat. Millions of people have been (self) quarantined to prevent it from further spreading [4]. Nonetheless, the individuals infected by corona virus are augmenting everyday [5]. There are absolutely no drugs that are approved by regulatory agencies across the globe. In India, the Indian Council of Medical Research (ICMR) strongly recommended the usage of hydroxychloroquine for asymptomatic purposes [6]. Followed by this development, emergency use authorization was granted by United States Food and Drug Administration (USFDA) to promote the usage of chloroquine phosphate or hydroxychloroquine sulfate for treating COVID-19 [7]. World Health Organization (WHO) identified and recommended usage of remdesivir, lopinavir–ritonavir with or without interferon, immunotherapy, and recuperative sera. WHO also launched SOLIDARITY trials for the above-prescribed drugs to support that they are effective in treating COVID-19 [8]. In addition, novel chemical entities against the corona virus protease were also proposed by some researchers [9] and some have proposed various integrated Chinese and Western medicines for treating this pandemic [10].
While the research is going on to identify an active agent for COVID-19. Identifying the mode of delivering the active moieties to patients and healthy subjects cannot be ignored. At present, there are several drug delivery systems, whereas the most novel and transformative drug delivery/carrier system is orodispersible films (ODFs). European Pharmacopoeia (Ph. Eur.) defines ODFs as ‘single or multilayered sheets of suitable materials, to be placed in the mouth where they disperse rapidly’ [11]. They are a type of oromucosal preparations which are ultra-thin, elegant, stamp sized, portable, patient friendly, and attractive dosage forms across all the age groups [12]. Clinical Data Interchange Standards Consortium (CDISC) defines ODFs as ‘A thin layer or coating which is susceptible to being dissolved when in contact with a liquid’ [13]. On the contrary, United States Pharmacopoeia (USP) employs a different terminology and called them as ‘Oral Films’ and defined as ‘Thin sheets that are placed in the oral cavity. They contain one or more layers. A layer might or might not contain API’ [14]. ODFs undergo rapid disintegration/dissolution and are usually swallowed along with saliva and a small amount of the drug gets absorbed via the oral mucosa due to its high vasculature [15,16].
ODFs are excellent and attractive carriers for delivery of various over the counter (OTC) or prescription drugs [17], herbal extracts [18–21], vaccines [22], probiotics [23], and vitamins [24]. Drugs are either directly introduced [25–28] in the formulation of ODFs or size reduced and converted to solid dispersions [29] or nanoparticles [30,31] or solid lipid microparticles [32] or micronized and surface modified using silica [33] which not only help in enhancing the amount of drug that could be loaded on to ODFs but also help in enhancing the release rate and, bioavailability of the drug. At present, ODFs are used as an excellent carrier system for delivering various therapeutically active agents. The composition of ODFs includes a drug substance (natural or synthetic), a film-forming agent and plasticizer. Additionally, it also includes saliva stimulating agent, organoleptic agents, and stabilizers [12]. The critical quality characteristics of ODFs are its appearance, stability, water content, uniformity of the active agent, color, taste, aftertaste, and mouthfeel. Most importantly, it shall not cause irritation of mucosa when administered [34]. The authors provided an overview on characterization of ODFs to determine various quality parameters of ODFs and also introduced a 3D printed disintegration test apparatus for testing the disintegration time of ODFs using sensor technology [35]. ODFs are capable for drug delivery in patients with swallowing problems, mentally retarded patients, subjects with Parkinson’s disease, bed-ridden patients, oral cancer patients, and uncooperative patients [36–38]. The present review is focused on critically analyzing the potential of ODFs as carriers for delivering antiviral drugs/herbs/vaccines with a potential for treatment of COVID-19, the global pandemic.
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Introduction
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During the fag end of 2019, Wuhan – the most densely populated city and capital of Hubei Province – China was witnessing pneumonia whose etiology was unknown. At the beginning of 2020, the pathogen was successfully identified and was named as the 2019 novel corona virus (2019-nCoV) [1,2]. Later, on 20 February 2020, the International Committee on Taxonomy of Viruses (ICTV) named it as Severe Acute Respiratory Syndrome Corona virus 2 (SARS-CoV-2), a new variant of SARS-CoV, and the disease caused was corona virus disease 2019 (COVID-19) [3]. Since then the whole world is on ‘High Alert’ due to this new viral threat. Millions of people have been (self) quarantined to prevent it from further spreading [4]. Nonetheless, the individuals infected by corona virus are augmenting everyday [5]. There are absolutely no drugs that are approved by regulatory agencies across the globe. In India, the Indian Council of Medical Research (ICMR) strongly recommended the usage of hydroxychloroquine for asymptomatic purposes [6]. Followed by this development, emergency use authorization was granted by United States Food and Drug Administration (USFDA) to promote the usage of chloroquine phosphate or hydroxychloroquine sulfate for treating COVID-19 [7]. World Health Organization (WHO) identified and recommended usage of remdesivir, lopinavir–ritonavir with or without interferon, immunotherapy, and recuperative sera. WHO also launched SOLIDARITY trials for the above-prescribed drugs to support that they are effective in treating COVID-19 [8]. In addition, novel chemical entities against the corona virus protease were also proposed by some researchers [9] and some have proposed various integrated Chinese and Western medicines for treating this pandemic [10].
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While the research is going on to identify an active agent for COVID-19. Identifying the mode of delivering the active moieties to patients and healthy subjects cannot be ignored. At present, there are several drug delivery systems, whereas the most novel and transformative drug delivery/carrier system is orodispersible films (ODFs). European Pharmacopoeia (Ph. Eur.) defines ODFs as ‘single or multilayered sheets of suitable materials, to be placed in the mouth where they disperse rapidly’ [11]. They are a type of oromucosal preparations which are ultra-thin, elegant, stamp sized, portable, patient friendly, and attractive dosage forms across all the age groups [12]. Clinical Data Interchange Standards Consortium (CDISC) defines ODFs as ‘A thin layer or coating which is susceptible to being dissolved when in contact with a liquid’ [13]. On the contrary, United States Pharmacopoeia (USP) employs a different terminology and called them as ‘Oral Films’ and defined as ‘Thin sheets that are placed in the oral cavity. They contain one or more layers. A layer might or might not contain API’ [14]. ODFs undergo rapid disintegration/dissolution and are usually swallowed along with saliva and a small amount of the drug gets absorbed via the oral mucosa due to its high vasculature [15,16].
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ODFs are excellent and attractive carriers for delivery of various over the counter (OTC) or prescription drugs [17], herbal extracts [18–21], vaccines [22], probiotics [23], and vitamins [24]. Drugs are either directly introduced [25–28] in the formulation of ODFs or size reduced and converted to solid dispersions [29] or nanoparticles [30,31] or solid lipid microparticles [32] or micronized and surface modified using silica [33] which not only help in enhancing the amount of drug that could be loaded on to ODFs but also help in enhancing the release rate and, bioavailability of the drug. At present, ODFs are used as an excellent carrier system for delivering various therapeutically active agents. The composition of ODFs includes a drug substance (natural or synthetic), a film-forming agent and plasticizer. Additionally, it also includes saliva stimulating agent, organoleptic agents, and stabilizers [12]. The critical quality characteristics of ODFs are its appearance, stability, water content, uniformity of the active agent, color, taste, aftertaste, and mouthfeel. Most importantly, it shall not cause irritation of mucosa when administered [34]. The authors provided an overview on characterization of ODFs to determine various quality parameters of ODFs and also introduced a 3D printed disintegration test apparatus for testing the disintegration time of ODFs using sensor technology [35]. ODFs are capable for drug delivery in patients with swallowing problems, mentally retarded patients, subjects with Parkinson’s disease, bed-ridden patients, oral cancer patients, and uncooperative patients [36–38]. The present review is focused on critically analyzing the potential of ODFs as carriers for delivering antiviral drugs/herbs/vaccines with a potential for treatment of COVID-19, the global pandemic.
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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.
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ODFs as carriers for antiviral drugs
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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.
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table-wrap
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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]
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Table 1.
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Antiviral drugs in pipeline for treating COVID-19.
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Antiviral drugs in pipeline for treating COVID-19.
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table
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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]
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Name of the company Details of antiviral drugs under development Ref.
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th
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Name of the company
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th
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Details of antiviral drugs under development
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th
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Ref.
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tr
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Innovation Pharmaceuticals Brilacidin – a defensin (protein) mimetic drug candidate [44]
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td
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Innovation Pharmaceuticals
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td
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Brilacidin – a defensin (protein) mimetic drug candidate
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td
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[44]
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tr
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CytoDyn Leronlimab – CCR5 antagonist [45]
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td
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CytoDyn
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td
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Leronlimab – CCR5 antagonist
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td
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[45]
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tr
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Roche Tocilizumab – Roche initiated phase III clinical trials [46]
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td
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Roche
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td
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Tocilizumab – Roche initiated phase III clinical trials
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td
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[46]
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tr
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Biocryst Pharma Galidesivir – adenosine nucleoside analogue acts by blocking viral RNA polymerase [47]
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td
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Biocryst Pharma
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td
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Galidesivir – adenosine nucleoside analogue acts by blocking viral RNA polymerase
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td
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[47]
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tr
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Roivant Sciences Gimsilumab – monoclonal antibody targets pro-inflammatory cytokine ‘granulocyte macrophage-colony stimulating factor (GM-CSF)’ which is high in corona virus patients. [48]
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td
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Roivant Sciences
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td
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Gimsilumab – monoclonal antibody targets pro-inflammatory cytokine ‘granulocyte macrophage-colony stimulating factor (GM-CSF)’ which is high in corona virus patients.
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td
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[48]
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tr
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I-Mab Biopharma TJM2 – acts by neutralizing high GM-CSF in corona virus infected patients [49]
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td
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I-Mab Biopharma
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td
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TJM2 – acts by neutralizing high GM-CSF in corona virus infected patients
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td
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[49]
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tr
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Airway Therapeutics AT-100 – developing human recombinant protein. It has collaborated with Celonic Group for producing AT-100 [50]
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td
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Airway Therapeutics
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td
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AT-100 – developing human recombinant protein. It has collaborated with Celonic Group for producing AT-100
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td
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[50]
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tr
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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]
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td
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Tiziana Life Sciences
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td
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TZLS-501 – a monoclonal antibody and are planning to deliver it using its proprietary formulation technology, which are patent protected
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td
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[51–53]
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tr
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OyaGen OYA1 – is a broad spectrum antiviral compound which is more effective than chlorpromazine HCl in inhibiting corona virus [54]
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td
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OyaGen
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td
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OYA1 – is a broad spectrum antiviral compound which is more effective than chlorpromazine HCl in inhibiting corona virus
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td
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[54]
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tr
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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]
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td
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Beyond Spring
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td
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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)
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td
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[55]
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tr
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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]
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td
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Algernon Pharmaceuticals
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td
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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
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td
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[56]
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tr
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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]
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td
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APEIRON Biologics
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td
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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
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td
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[57]
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tr
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Lattice Biologics Limited AmnioBoost – is an amniotic fluid concentrate obtained from subjects during cesarean delivery [57]
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td
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Lattice Biologics Limited
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td
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AmnioBoost – is an amniotic fluid concentrate obtained from subjects during cesarean delivery
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td
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[57]
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tr
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Synairgen Research SNG001 – is nothing but interferon β – 1a administered as an inhalation to COVID patients [58]
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td
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Synairgen Research
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td
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SNG001 – is nothing but interferon β – 1a administered as an inhalation to COVID patients
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td
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[58]
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tr
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Emanta Pharmaceuticals It is testing various known and new small molecule drug candidates that have the potential to act against COVID 19. [59]
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td
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Emanta Pharmaceuticals
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td
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It is testing various known and new small molecule drug candidates that have the potential to act against COVID 19.
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td
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[59]
|
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tr
|
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]
|
|
td
|
Vir Biotechnology
|
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td
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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
|
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td
|
[60]
|
|
tr
|
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]
|
|
td
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Columbia University
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td
|
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
|
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td
|
[61]
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p
|
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.
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table-wrap
|
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.
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label
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Table 2.
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caption
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Antiviral drugs formulated as ODFs.
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p
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Antiviral drugs formulated as ODFs.
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table
|
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]
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tr
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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.
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th
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Drug name – technique employed to load to ODFs
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th
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Reason for choosing the drug or API to formulate as an ODFs
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th
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Polymer
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th
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Plasticizer
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th
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Method
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th
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Key highlight(s)
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th
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Ref.
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tr
|
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]
|
|
td
|
Herpetrione (HPE) – extracted from Herpetospermum caudigerum.HPE nanoparticles were prepared using sodium dodecyl sulfate and PVP K-30
|
|
td
|
Poor water solubility and low bioavailability
|
|
td
|
Hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC), and l-hydroxypropyl cellulose (HPC)
|
|
td
|
PEG-400
|
|
td
|
Solvent casting method (SCM)
|
|
td
|
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
|
|
td
|
[62]
|
|
tr
|
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]
|
|
td
|
Herpetrione (HPE)Nanoparticles were prepared and optimized using the Box–Behnken design response surface methodology
|
|
td
|
Poor water solubility and low bioavailability
|
|
td
|
HPMC, MCC, L-HPC
|
|
td
|
PEG-400
|
|
td
|
SCM
|
|
td
|
ODFs formulation of HPE nanoparticles was successfully optimized using the Box–Behnken design response surface methodology
|
|
td
|
[63]
|
|
tr
|
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]
|
|
td
|
CidofovirNanoparticles were prepared using poly(ethylene glycol)–polycaprolactone (PEG-PCL)
|
|
td
|
To achieve its controlled release and also due to its wide spectrum anti-viral activity
|
|
td
|
HPC
|
|
td
|
a
|
|
td
|
Printed using inkjet printer
|
|
td
|
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
|
|
td
|
[64,65]
|
|
tr
|
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]
|
|
td
|
Acyclovir – solid dispersion was prepared
|
|
td
|
Poor water solubility and low bioavailability
|
|
td
|
HPMC
|
|
td
|
Glycerol
|
|
td
|
SCM
|
|
td
|
Oral administration of ODFs of acyclovir instead of intravenous route of administration
|
|
td
|
[66]
|
|
tr
|
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]
|
|
td
|
Entecavir (single or multi-layered ODFs)
|
|
td
|
Low dose − 0.5–1 mg per day
|
|
td
|
Starch, carrageenan, pullulan and many others
|
|
td
|
Acetyl triethyl citrate or propylene glycol or citrate ester or triacetin
|
|
td
|
SCM
|
|
td
|
Multi-layered ODFs were disclosed
|
|
td
|
[67]
|
|
table-wrap-foot
|
a Nothing found.
|
|
footnote
|
a Nothing found.
|
|
label
|
a
|
|
p
|
Nothing found.
|
|
sec
|
ODFs as carriers for antiviral and immunity boosting herbs
WHO said ‘To date there is no specific medicine recommended to prevent or treat the novel coronavirus’ [68]. In view of the fact that there are no drugs and vaccines, that are approved, for treating COVID-19, many are turning toward herbal medicines that are either of the Indian or Chinese origin. There are many herbs in Indian Ayurveda that have the potential for prophylaxis and treatment of corona virus infection. For instance, Rastogi et al. reported a ‘pragmatic and plausible plan of action for Ayurvedic intervention’ of various Ayurvedic drugs that have the potential to be used in mild to severe COVID-19 symptoms [69]. Subjects who are not yet exposed and asymptomatic group can use Ayurvedic ‘Swarna Prashana’ and ‘Rasayana’ as potential immunity boosting agents [70–73]. This in combination with social distancing helps in preventing the spread of disease [74].
Ministry of Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homeopathy (AYUSH), Government of India recommends three immunity boosting measures. First and foremost is taking 10 g of Chyavanprash every day (not suitable to formulate as ODFs due to its heavy dose), second: drinking golden milk (milk with turmeric) twice a day, and lastly drinking herbal tea or a drink prepared by boiling tulsi, cinnamon, black pepper, dry ginger and raisin taken either by adding jiggery (natural sweet) or lemon juice for taste, if required – to be taken once a day or twice in a day [75]. The Ministry of AYUSH has also confirmed that clinical trials are initiated on AYUSH-64, a polyherbal anti-malarial Ayurvedic formulation [76]. Indian Institute of Delhi in collaboration with National Institute of Advanced Industrial Science and Technology, Japan has reported the potential of Ashwagandha against COVID-19 [77]. CSIR (Council of Scientific and Industrial Research) in collaboration with Sun Pharma are working on a phytopharmaceutical composition that is found to be effective in treatment of COVID-19 [78]. Very recently, Sun Pharma received approval for clinical trials of AQCH from Drugs Controller General of India (DCGI) [79].
Chinese National Health Commission announced, dated 14 April 2020, three patented Chinese herbal drugs for treatment of COVID-19 which include namely: ‘Lianhuaqingwen capsules and Jinhuaqinggan granules for mild conditions, and Xuebijing (injectable) for severe conditions’ [80]. Luo et al. carried out an excellent review on Chinese herbal medicines that have the strong potential for usage in prevention of COVID-19. They have also reported the highly used herbs for preventing COVID-19 infections [81]. A Korean company by name, Biostandard Inc, reported usage of fermented Isatidis Radix Extract and claim to be effective against corona virus infections and they have protected the same by a Korean patent application [82]. Few other companies/academic institutions that have patent protected herbal extracts effective in preventing COVID-19 are provided in Table 3.
Table 3. Patent protected herbs for preventing/treating COVID-19.
Name of the player Drug name and details Ref.
Biostandard Inc Fermented Isatidis Radix Extract [82]
Bioniche Life Sciences Inc Pyranocoumarin enriched composition (free from furanocoumarins) obtained from Zanthoxylum americanum (Prickly Ash) [83]
The University of Hong Kong Baicalin – compound extracted from Scutellaria baicalensis [84]
Seoul National University Industry-Academic Cooperation Foundation Extract of Angelica dahurica [85]
Amazon Biotech Inc. Herbal composition comprising ‘Boswellia carterii stem resin, Styrax benzoin stem resin, Cinnamomum zeylanicum bark, Curcuma zedoaria root, Syzygium aromaticum fruit, Nardostachys chinensis root, Betula alba bark, Impatiens balsamina bark, Costus spicatus root, Allium sativum bulb Cyperus rotundus root and Hyssopus officinalis’ [86]
Biopharmacopae Inc. Extracts of ginger and/or goldenrod (Solidago) [87] A decoction of various Ayurvedic herbs namely: ‘Tinospora cordifolia, Zingiber officinale, Curcuma longa, Ocimum sanctum, Glycyrrhiza glabra, Adhatoda vasica, Andrographis paniculata, Swertia chirayita, Moringa oleifera, Triphala and Trikatu’ have broad antiviral activity and protease inhibitor activity [88–90]. This decoction could be very useful in COVID-19 patients who are quarantined.
Turning now to ODFs of herbal extracts, Cure pharmaceuticals published US patent on herbs ((agrimony, andrographis paniculata, bistort, fenugreek, ginger, myrrh, solanum, etc.) tree and plant extracts ((licorice, shitake, sarsaparilla, slippery elm, etc.), and essential oils (clove, camphor, cinnamon, lemon, spearmint, etc.) that are formulated as multilayered edible oral thin films for management of cough/Pharyngitis [91]. Table 4 provides a list of ODFs formulated using herbal extracts. From the table, it is evident that solvent casting method is the most preferred method to fabricate herbal ODFs. Zim laboratories limited, a leading Indian company in the domain of oral thin films has published a research article on oral dissolving films of ginger [21]. Visser et al. reported ODFs of five Indonesian medicinal plants extracts namely: Lagerstroemia speciosa, Phyllanthus niruri, Cinnamomum burmannii, Zingiber officinale, and Phaleria macrocarpa [92] were prepared by solvent casting method [95]. Of these plant extracts, Phaleria macrocarpa and Zingiber officinale are associated with antiviral activity [96,97]. Song et al. evaluated antiviral activity of quercetin-7-glucoside isolated from Lagerstroemia speciosa [98]. Sri Wahyuni et al. reported antiviral activity of Phyllanthus niruri, particularly they reported its activity against hepatitis C virus [99]. Verma et al. reported ODFs of Piper betel and Foeniculum officinalis [93]. Foeniculum officinalis is reported to possess antiviral and antioxidant activity [100]. Similarly, Pawar and Butle reported ODFs of Allium sativum [94], a potent antiviral agent [101].
Table 4. Antiviral herbs formulated as ODFs.
Name of the herb and technique employed, if any, to load to ODFs Reason for choosing/selecting the herb to formulate as an ODFs Polymer Plasticizer Method Key highlight(s) Ref.
Ginger extract Existing formulations (capsules and liquids) of ginger suffer with problems of wettability of contents and inaccuracy in dosing. Hydroxypropyl methylcellulose (HPMC) or maltodextrin or pullulan Polyethylene glycol (PEG) Solvent casting method (SCM) HPMC based ODFs were found to be ideal with low disintegration time and stable at high temperature [21]
Indonesian herbal extracts of Phaleria macrocarpa and Zingiber officinale Selected based on the herbal extracts popularity, reproducibility and well established scientific support (clinical evidence) HPMC with carbomer 947p (or) hydroxypropyl cellulose (HPC) Glycerol SCM Stable ODFs were obtained and benzalkonium chloride was employed as a stabilizer and also for spreadability [92]
Foeniculum officinalis extract –a HPMC Glycerol SCM Employed super disintegrating agent (sodium starch glycollate) to achieve low disintegration time of ODF [93]
Garlic extract –a Hypromellose Glycerol SCM Menthol was used as a flavoring agent [94]
a Nothing found. Generally speaking, ODFs are well known to act as carriers for various herbal extracts [18–21]. But, from the above explanation, it is particularly evident that they have the potential to act as carriers to aid in the delivery of various antiviral herbs.
|
|
title
|
ODFs as carriers for antiviral and immunity boosting herbs
|
|
p
|
WHO said ‘To date there is no specific medicine recommended to prevent or treat the novel coronavirus’ [68]. In view of the fact that there are no drugs and vaccines, that are approved, for treating COVID-19, many are turning toward herbal medicines that are either of the Indian or Chinese origin. There are many herbs in Indian Ayurveda that have the potential for prophylaxis and treatment of corona virus infection. For instance, Rastogi et al. reported a ‘pragmatic and plausible plan of action for Ayurvedic intervention’ of various Ayurvedic drugs that have the potential to be used in mild to severe COVID-19 symptoms [69]. Subjects who are not yet exposed and asymptomatic group can use Ayurvedic ‘Swarna Prashana’ and ‘Rasayana’ as potential immunity boosting agents [70–73]. This in combination with social distancing helps in preventing the spread of disease [74].
|
|
p
|
Ministry of Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homeopathy (AYUSH), Government of India recommends three immunity boosting measures. First and foremost is taking 10 g of Chyavanprash every day (not suitable to formulate as ODFs due to its heavy dose), second: drinking golden milk (milk with turmeric) twice a day, and lastly drinking herbal tea or a drink prepared by boiling tulsi, cinnamon, black pepper, dry ginger and raisin taken either by adding jiggery (natural sweet) or lemon juice for taste, if required – to be taken once a day or twice in a day [75]. The Ministry of AYUSH has also confirmed that clinical trials are initiated on AYUSH-64, a polyherbal anti-malarial Ayurvedic formulation [76]. Indian Institute of Delhi in collaboration with National Institute of Advanced Industrial Science and Technology, Japan has reported the potential of Ashwagandha against COVID-19 [77]. CSIR (Council of Scientific and Industrial Research) in collaboration with Sun Pharma are working on a phytopharmaceutical composition that is found to be effective in treatment of COVID-19 [78]. Very recently, Sun Pharma received approval for clinical trials of AQCH from Drugs Controller General of India (DCGI) [79].
|
|
p
|
Chinese National Health Commission announced, dated 14 April 2020, three patented Chinese herbal drugs for treatment of COVID-19 which include namely: ‘Lianhuaqingwen capsules and Jinhuaqinggan granules for mild conditions, and Xuebijing (injectable) for severe conditions’ [80]. Luo et al. carried out an excellent review on Chinese herbal medicines that have the strong potential for usage in prevention of COVID-19. They have also reported the highly used herbs for preventing COVID-19 infections [81]. A Korean company by name, Biostandard Inc, reported usage of fermented Isatidis Radix Extract and claim to be effective against corona virus infections and they have protected the same by a Korean patent application [82]. Few other companies/academic institutions that have patent protected herbal extracts effective in preventing COVID-19 are provided in Table 3.
|
|
table-wrap
|
Table 3. Patent protected herbs for preventing/treating COVID-19.
Name of the player Drug name and details Ref.
Biostandard Inc Fermented Isatidis Radix Extract [82]
Bioniche Life Sciences Inc Pyranocoumarin enriched composition (free from furanocoumarins) obtained from Zanthoxylum americanum (Prickly Ash) [83]
The University of Hong Kong Baicalin – compound extracted from Scutellaria baicalensis [84]
Seoul National University Industry-Academic Cooperation Foundation Extract of Angelica dahurica [85]
Amazon Biotech Inc. Herbal composition comprising ‘Boswellia carterii stem resin, Styrax benzoin stem resin, Cinnamomum zeylanicum bark, Curcuma zedoaria root, Syzygium aromaticum fruit, Nardostachys chinensis root, Betula alba bark, Impatiens balsamina bark, Costus spicatus root, Allium sativum bulb Cyperus rotundus root and Hyssopus officinalis’ [86]
Biopharmacopae Inc. Extracts of ginger and/or goldenrod (Solidago) [87]
|
|
label
|
Table 3.
|
|
caption
|
Patent protected herbs for preventing/treating COVID-19.
|
|
p
|
Patent protected herbs for preventing/treating COVID-19.
|
|
table
|
Name of the player Drug name and details Ref.
Biostandard Inc Fermented Isatidis Radix Extract [82]
Bioniche Life Sciences Inc Pyranocoumarin enriched composition (free from furanocoumarins) obtained from Zanthoxylum americanum (Prickly Ash) [83]
The University of Hong Kong Baicalin – compound extracted from Scutellaria baicalensis [84]
Seoul National University Industry-Academic Cooperation Foundation Extract of Angelica dahurica [85]
Amazon Biotech Inc. Herbal composition comprising ‘Boswellia carterii stem resin, Styrax benzoin stem resin, Cinnamomum zeylanicum bark, Curcuma zedoaria root, Syzygium aromaticum fruit, Nardostachys chinensis root, Betula alba bark, Impatiens balsamina bark, Costus spicatus root, Allium sativum bulb Cyperus rotundus root and Hyssopus officinalis’ [86]
Biopharmacopae Inc. Extracts of ginger and/or goldenrod (Solidago) [87]
|
|
tr
|
Name of the player Drug name and details Ref.
|
|
th
|
Name of the player
|
|
th
|
Drug name and details
|
|
th
|
Ref.
|
|
tr
|
Biostandard Inc Fermented Isatidis Radix Extract [82]
|
|
td
|
Biostandard Inc
|
|
td
|
Fermented Isatidis Radix Extract
|
|
td
|
[82]
|
|
tr
|
Bioniche Life Sciences Inc Pyranocoumarin enriched composition (free from furanocoumarins) obtained from Zanthoxylum americanum (Prickly Ash) [83]
|
|
td
|
Bioniche Life Sciences Inc
|
|
td
|
Pyranocoumarin enriched composition (free from furanocoumarins) obtained from Zanthoxylum americanum (Prickly Ash)
|
|
td
|
[83]
|
|
tr
|
The University of Hong Kong Baicalin – compound extracted from Scutellaria baicalensis [84]
|
|
td
|
The University of Hong Kong
|
|
td
|
Baicalin – compound extracted from Scutellaria baicalensis
|
|
td
|
[84]
|
|
tr
|
Seoul National University Industry-Academic Cooperation Foundation Extract of Angelica dahurica [85]
|
|
td
|
Seoul National University Industry-Academic Cooperation Foundation
|
|
td
|
Extract of Angelica dahurica
|
|
td
|
[85]
|
|
tr
|
Amazon Biotech Inc. Herbal composition comprising ‘Boswellia carterii stem resin, Styrax benzoin stem resin, Cinnamomum zeylanicum bark, Curcuma zedoaria root, Syzygium aromaticum fruit, Nardostachys chinensis root, Betula alba bark, Impatiens balsamina bark, Costus spicatus root, Allium sativum bulb Cyperus rotundus root and Hyssopus officinalis’ [86]
|
|
td
|
Amazon Biotech Inc.
|
|
td
|
Herbal composition comprising ‘Boswellia carterii stem resin, Styrax benzoin stem resin, Cinnamomum zeylanicum bark, Curcuma zedoaria root, Syzygium aromaticum fruit, Nardostachys chinensis root, Betula alba bark, Impatiens balsamina bark, Costus spicatus root, Allium sativum bulb Cyperus rotundus root and Hyssopus officinalis’
|
|
td
|
[86]
|
|
tr
|
Biopharmacopae Inc. Extracts of ginger and/or goldenrod (Solidago) [87]
|
|
td
|
Biopharmacopae Inc.
|
|
td
|
Extracts of ginger and/or goldenrod (Solidago)
|
|
td
|
[87]
|
|
p
|
A decoction of various Ayurvedic herbs namely: ‘Tinospora cordifolia, Zingiber officinale, Curcuma longa, Ocimum sanctum, Glycyrrhiza glabra, Adhatoda vasica, Andrographis paniculata, Swertia chirayita, Moringa oleifera, Triphala and Trikatu’ have broad antiviral activity and protease inhibitor activity [88–90]. This decoction could be very useful in COVID-19 patients who are quarantined.
|
|
p
|
Turning now to ODFs of herbal extracts, Cure pharmaceuticals published US patent on herbs ((agrimony, andrographis paniculata, bistort, fenugreek, ginger, myrrh, solanum, etc.) tree and plant extracts ((licorice, shitake, sarsaparilla, slippery elm, etc.), and essential oils (clove, camphor, cinnamon, lemon, spearmint, etc.) that are formulated as multilayered edible oral thin films for management of cough/Pharyngitis [91]. Table 4 provides a list of ODFs formulated using herbal extracts. From the table, it is evident that solvent casting method is the most preferred method to fabricate herbal ODFs. Zim laboratories limited, a leading Indian company in the domain of oral thin films has published a research article on oral dissolving films of ginger [21]. Visser et al. reported ODFs of five Indonesian medicinal plants extracts namely: Lagerstroemia speciosa, Phyllanthus niruri, Cinnamomum burmannii, Zingiber officinale, and Phaleria macrocarpa [92] were prepared by solvent casting method [95]. Of these plant extracts, Phaleria macrocarpa and Zingiber officinale are associated with antiviral activity [96,97]. Song et al. evaluated antiviral activity of quercetin-7-glucoside isolated from Lagerstroemia speciosa [98]. Sri Wahyuni et al. reported antiviral activity of Phyllanthus niruri, particularly they reported its activity against hepatitis C virus [99]. Verma et al. reported ODFs of Piper betel and Foeniculum officinalis [93]. Foeniculum officinalis is reported to possess antiviral and antioxidant activity [100]. Similarly, Pawar and Butle reported ODFs of Allium sativum [94], a potent antiviral agent [101].
|
|
table-wrap
|
Table 4. Antiviral herbs formulated as ODFs.
Name of the herb and technique employed, if any, to load to ODFs Reason for choosing/selecting the herb to formulate as an ODFs Polymer Plasticizer Method Key highlight(s) Ref.
Ginger extract Existing formulations (capsules and liquids) of ginger suffer with problems of wettability of contents and inaccuracy in dosing. Hydroxypropyl methylcellulose (HPMC) or maltodextrin or pullulan Polyethylene glycol (PEG) Solvent casting method (SCM) HPMC based ODFs were found to be ideal with low disintegration time and stable at high temperature [21]
Indonesian herbal extracts of Phaleria macrocarpa and Zingiber officinale Selected based on the herbal extracts popularity, reproducibility and well established scientific support (clinical evidence) HPMC with carbomer 947p (or) hydroxypropyl cellulose (HPC) Glycerol SCM Stable ODFs were obtained and benzalkonium chloride was employed as a stabilizer and also for spreadability [92]
Foeniculum officinalis extract –a HPMC Glycerol SCM Employed super disintegrating agent (sodium starch glycollate) to achieve low disintegration time of ODF [93]
Garlic extract –a Hypromellose Glycerol SCM Menthol was used as a flavoring agent [94]
a Nothing found.
|
|
label
|
Table 4.
|
|
caption
|
Antiviral herbs formulated as ODFs.
|
|
p
|
Antiviral herbs formulated as ODFs.
|
|
table
|
Name of the herb and technique employed, if any, to load to ODFs Reason for choosing/selecting the herb to formulate as an ODFs Polymer Plasticizer Method Key highlight(s) Ref.
Ginger extract Existing formulations (capsules and liquids) of ginger suffer with problems of wettability of contents and inaccuracy in dosing. Hydroxypropyl methylcellulose (HPMC) or maltodextrin or pullulan Polyethylene glycol (PEG) Solvent casting method (SCM) HPMC based ODFs were found to be ideal with low disintegration time and stable at high temperature [21]
Indonesian herbal extracts of Phaleria macrocarpa and Zingiber officinale Selected based on the herbal extracts popularity, reproducibility and well established scientific support (clinical evidence) HPMC with carbomer 947p (or) hydroxypropyl cellulose (HPC) Glycerol SCM Stable ODFs were obtained and benzalkonium chloride was employed as a stabilizer and also for spreadability [92]
Foeniculum officinalis extract –a HPMC Glycerol SCM Employed super disintegrating agent (sodium starch glycollate) to achieve low disintegration time of ODF [93]
Garlic extract –a Hypromellose Glycerol SCM Menthol was used as a flavoring agent [94]
|
|
tr
|
Name of the herb and technique employed, if any, to load to ODFs Reason for choosing/selecting the herb to formulate as an ODFs Polymer Plasticizer Method Key highlight(s) Ref.
|
|
th
|
Name of the herb and technique employed, if any, to load to ODFs
|
|
th
|
Reason for choosing/selecting the herb to formulate as an ODFs
|
|
th
|
Polymer
|
|
th
|
Plasticizer
|
|
th
|
Method
|
|
th
|
Key highlight(s)
|
|
th
|
Ref.
|
|
tr
|
Ginger extract Existing formulations (capsules and liquids) of ginger suffer with problems of wettability of contents and inaccuracy in dosing. Hydroxypropyl methylcellulose (HPMC) or maltodextrin or pullulan Polyethylene glycol (PEG) Solvent casting method (SCM) HPMC based ODFs were found to be ideal with low disintegration time and stable at high temperature [21]
|
|
td
|
Ginger extract
|
|
td
|
Existing formulations (capsules and liquids) of ginger suffer with problems of wettability of contents and inaccuracy in dosing.
|
|
td
|
Hydroxypropyl methylcellulose (HPMC) or maltodextrin or pullulan
|
|
td
|
Polyethylene glycol (PEG)
|
|
td
|
Solvent casting method (SCM)
|
|
td
|
HPMC based ODFs were found to be ideal with low disintegration time and stable at high temperature
|
|
td
|
[21]
|
|
tr
|
Indonesian herbal extracts of Phaleria macrocarpa and Zingiber officinale Selected based on the herbal extracts popularity, reproducibility and well established scientific support (clinical evidence) HPMC with carbomer 947p (or) hydroxypropyl cellulose (HPC) Glycerol SCM Stable ODFs were obtained and benzalkonium chloride was employed as a stabilizer and also for spreadability [92]
|
|
td
|
Indonesian herbal extracts of Phaleria macrocarpa and Zingiber officinale
|
|
td
|
Selected based on the herbal extracts popularity, reproducibility and well established scientific support (clinical evidence)
|
|
td
|
HPMC with carbomer 947p (or) hydroxypropyl cellulose (HPC)
|
|
td
|
Glycerol
|
|
td
|
SCM
|
|
td
|
Stable ODFs were obtained and benzalkonium chloride was employed as a stabilizer and also for spreadability
|
|
td
|
[92]
|
|
tr
|
Foeniculum officinalis extract –a HPMC Glycerol SCM Employed super disintegrating agent (sodium starch glycollate) to achieve low disintegration time of ODF [93]
|
|
td
|
Foeniculum officinalis extract
|
|
td
|
–a
|
|
td
|
HPMC
|
|
td
|
Glycerol
|
|
td
|
SCM
|
|
td
|
Employed super disintegrating agent (sodium starch glycollate) to achieve low disintegration time of ODF
|
|
td
|
[93]
|
|
tr
|
Garlic extract –a Hypromellose Glycerol SCM Menthol was used as a flavoring agent [94]
|
|
td
|
Garlic extract
|
|
td
|
–a
|
|
td
|
Hypromellose
|
|
td
|
Glycerol
|
|
td
|
SCM
|
|
td
|
Menthol was used as a flavoring agent
|
|
td
|
[94]
|
|
table-wrap-foot
|
a Nothing found.
|
|
footnote
|
a Nothing found.
|
|
label
|
a
|
|
p
|
Nothing found.
|
|
p
|
Generally speaking, ODFs are well known to act as carriers for various herbal extracts [18–21]. But, from the above explanation, it is particularly evident that they have the potential to act as carriers to aid in the delivery of various antiviral herbs.
|
|
sec
|
ODFs as carriers for antiviral vaccines
The Center for Disease Control and Prevention defines vaccines as ‘A product that stimulates a person’s immune system to produce immunity to a specific disease, protecting the person from that disease. Vaccines are usually administered through needle injections, but can also be administered by mouth or sprayed into the nose’ [102]. Vaccination is considered as one of the most effective ways of preventing cause of a disease [103]. At present, there are several companies, academic institutes that are actively working to develop a vaccine against COVID-19. Vaccines that are currently under development are provided in Table 5.
Table 5. Antiviral vaccines in pipeline for treating COVID-19.
Name of the player Details of antiviral vaccines under development Ref.
Migal Galilee Research Institute, Israel Developing an oral (mucosal) vaccine, wherein the viral antigen is delivered via mucosa tissues by self-activated endocytosis [104]
Entos Pharmaceuticals Fusogenix – DNA vaccine is being developed based on its patent protected platform, proteo-lipid vehicle (PLV). It uses a new mechanism for delivering genetic material into the cells [105,106]
Vaxart Inc Oral recombinant vaccine in tablet formulation using its VAAST platform. It has protected its vaccine tablet formulation by US patent applications [107–109]
University of Oxford – Jenner Institute ChAD0X1 nCoV-19 – prepared from cold virus (weakened) – initiated Phase III trials [110]
Altimmune AdCOVID – vaccine delivered via intranasal route platform technologies NasoVAX and NasoShield [111,112]
Medicago Developing a vaccine and also an antibody. It was successful in producing virus like particles of coronavirus. It is developing antibodies in collaboration with Laval University [113]
Inovio Pharmaceuticals INO-4800 – vaccine that is developed in collaboration with Beijing Advaccinee Biotechnology Company. It is proposing to deliver the vaccine using the device called as CELLECTRA® which works by creating a pulse for transferring the plasmids across the cell. It is also developing INO 4700 in collaboration with GeneOne Life Sciences company [114]
Moderna mRN 1273 – recently received fast track designation from USFDA. It vaccine basically targets spike protein of corona virus [115]
Tonix Pharmaceuticals TNX-1800 – developed based on its horsepox virus vaccine platform. It has filed a provisional patent application with USPTO [116]
Clover Biopharmaceuticals Subunit vaccine developed using trimeric spike protein developed using its patented technology [117]
Novavax, Inc Middle East Respiratory Syndrome (MERS) vaccine was developed using recombinant nanoparticle based vaccine technology. The vaccine showed positive results in inhibiting the virus when administered along with its patented adjuvant formulations [118–121]
Predictive oncology (PO) Introduced artificial intelligence for development of a vaccine using Inventa Biotech’s HSCTM technology which deals with chromatographic system of high throughput screening. In addition, PO is also developing a new vaccine based on nanoparticle (NSP-10: non specific protein) platform technology developed by Dr. Daniel Carter [122] Primarily, vaccines pose extreme challenges vis-a-vis its handling, (cold) storage and shipping, all expensive propositions. For instance, one of the studies reported that 38 billion USD would be spent on transportation and administration of 18 vaccines in 94 countries [123,124]. Therefore, there is a need for alternate dosage forms that can help reducing the cost. For instance, Vaxart Inc is developing recombinant vaccine for COVID-19 in tablet formulation using its patent protected technology called VAAST [107–109]. RP Scherer Technologies LLC is also developing a tablet formulation (fast dissolving) for influenza vaccine with starch as immune stimulating agent [125]. Tablets are highly traditional and conventional dosage forms that are difficult to administer to patients who have dysphagia or Parkinson’s disease and are extremely difficult to administer to pediatrics and geriatrics. Therefore, ODFs remain as an alternate choice of administration as they do not need water to consume. Most importantly, they are easy to transport from one place to another. Israel’s Migal Galilee Research Institute is actively developing a vaccine that is administered via oromucosal route [104]. Some of the vaccine preparations that are successfully formulated as ODFs are provided in Table 6.
Table 6. Antiviral vaccines that are formulated as ODFs.
Name of the player Name of vaccine formulated as ODFs Polymer Plasticizer Method employed Key highlight(s) Ref.
The Johns Hopkins University Several live-attenuated viruses were proposed, including the corona virus. Provided methodology to prepare rotavirus vaccine Eudragit Polyethylene glycol (PEG) and polyvinyl alcohol (PVA) Double emulsion solvent evaporation Prepared as monolayered or bi layered ODFs [126]
Brian Pulliam (single applicant and inventor) Rotavirus vaccine along with an antacid namely magnesium hydroxide or aluminum hydroxide nanoparticles for digestion purpose Polyvinyl pyrrolidone + hydroxypropyl cellulose (HPC) PEG Solvent casting method (SCM) Antacid successfully combined with a vaccine in layered fashion [22]
Nitto Denko Corporation Cancer vaccine comprising WT1 peptide or Db126 along with a promoter namely lipopolysaccharide or quercetin or ioxoprofen Mannitol, PEG, and HPC PEG, mannitol SCM Composition successfully induces cellular immunity in cancer patients [127]
Nasir Uddin from Larkin University Gonorrhoea microparticulate vaccine a a SCM Microparticulate vaccine particles were obtained by spray dryingBilayered ODFs can be prepared, outer layer acts as protection layer [128]
Aridis Pharmaceuticals Rotavirus vaccine a a a Patent protected vaccine stabilization technology and plasticized glass stabilization technology were employed in preparing the vaccine film [129–131]
a Nothing found. Administration of vaccines using fast dissolving buccal films is the most optimized form of administration as it has plethora of advantages when compared with parenteral route of administration [132]. Research suggests that vaccines administered via oral route are as good as or even better than those that are administered via parenteral route. For instance, Bajrovic et al. demonstrated that oral administration (sublingual and buccal routes) of influenza virus vaccine as a thin film formulation has shown good or better results than the vaccine that is administered via intramuscular route [133]. From Table 6, it is evident that ODFs comprising vaccines can be prepared as mono or bilayered using the most popular solvent casting method. Tian et al. prepared influenza virus vaccine by using trehalose and pullulan to maintain the stability and antigenicity of the vaccine. They also employed hypromellose that further helped in enhancing the stability of the film [134]. ODFs remain an excellent option for delivery of vaccines to subjects across all the age groups. They are easily portable and maintain stability of the vaccine during transportation till it reaches to the subject for consumption. All these strongly suggest that ODFs are cost-effective carriers and easy to consume dosage forms.
|
|
title
|
ODFs as carriers for antiviral vaccines
|
|
p
|
The Center for Disease Control and Prevention defines vaccines as ‘A product that stimulates a person’s immune system to produce immunity to a specific disease, protecting the person from that disease. Vaccines are usually administered through needle injections, but can also be administered by mouth or sprayed into the nose’ [102]. Vaccination is considered as one of the most effective ways of preventing cause of a disease [103]. At present, there are several companies, academic institutes that are actively working to develop a vaccine against COVID-19. Vaccines that are currently under development are provided in Table 5.
|
|
table-wrap
|
Table 5. Antiviral vaccines in pipeline for treating COVID-19.
Name of the player Details of antiviral vaccines under development Ref.
Migal Galilee Research Institute, Israel Developing an oral (mucosal) vaccine, wherein the viral antigen is delivered via mucosa tissues by self-activated endocytosis [104]
Entos Pharmaceuticals Fusogenix – DNA vaccine is being developed based on its patent protected platform, proteo-lipid vehicle (PLV). It uses a new mechanism for delivering genetic material into the cells [105,106]
Vaxart Inc Oral recombinant vaccine in tablet formulation using its VAAST platform. It has protected its vaccine tablet formulation by US patent applications [107–109]
University of Oxford – Jenner Institute ChAD0X1 nCoV-19 – prepared from cold virus (weakened) – initiated Phase III trials [110]
Altimmune AdCOVID – vaccine delivered via intranasal route platform technologies NasoVAX and NasoShield [111,112]
Medicago Developing a vaccine and also an antibody. It was successful in producing virus like particles of coronavirus. It is developing antibodies in collaboration with Laval University [113]
Inovio Pharmaceuticals INO-4800 – vaccine that is developed in collaboration with Beijing Advaccinee Biotechnology Company. It is proposing to deliver the vaccine using the device called as CELLECTRA® which works by creating a pulse for transferring the plasmids across the cell. It is also developing INO 4700 in collaboration with GeneOne Life Sciences company [114]
Moderna mRN 1273 – recently received fast track designation from USFDA. It vaccine basically targets spike protein of corona virus [115]
Tonix Pharmaceuticals TNX-1800 – developed based on its horsepox virus vaccine platform. It has filed a provisional patent application with USPTO [116]
Clover Biopharmaceuticals Subunit vaccine developed using trimeric spike protein developed using its patented technology [117]
Novavax, Inc Middle East Respiratory Syndrome (MERS) vaccine was developed using recombinant nanoparticle based vaccine technology. The vaccine showed positive results in inhibiting the virus when administered along with its patented adjuvant formulations [118–121]
Predictive oncology (PO) Introduced artificial intelligence for development of a vaccine using Inventa Biotech’s HSCTM technology which deals with chromatographic system of high throughput screening. In addition, PO is also developing a new vaccine based on nanoparticle (NSP-10: non specific protein) platform technology developed by Dr. Daniel Carter [122]
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label
|
Table 5.
|
|
caption
|
Antiviral vaccines in pipeline for treating COVID-19.
|
|
p
|
Antiviral vaccines in pipeline for treating COVID-19.
|
|
table
|
Name of the player Details of antiviral vaccines under development Ref.
Migal Galilee Research Institute, Israel Developing an oral (mucosal) vaccine, wherein the viral antigen is delivered via mucosa tissues by self-activated endocytosis [104]
Entos Pharmaceuticals Fusogenix – DNA vaccine is being developed based on its patent protected platform, proteo-lipid vehicle (PLV). It uses a new mechanism for delivering genetic material into the cells [105,106]
Vaxart Inc Oral recombinant vaccine in tablet formulation using its VAAST platform. It has protected its vaccine tablet formulation by US patent applications [107–109]
University of Oxford – Jenner Institute ChAD0X1 nCoV-19 – prepared from cold virus (weakened) – initiated Phase III trials [110]
Altimmune AdCOVID – vaccine delivered via intranasal route platform technologies NasoVAX and NasoShield [111,112]
Medicago Developing a vaccine and also an antibody. It was successful in producing virus like particles of coronavirus. It is developing antibodies in collaboration with Laval University [113]
Inovio Pharmaceuticals INO-4800 – vaccine that is developed in collaboration with Beijing Advaccinee Biotechnology Company. It is proposing to deliver the vaccine using the device called as CELLECTRA® which works by creating a pulse for transferring the plasmids across the cell. It is also developing INO 4700 in collaboration with GeneOne Life Sciences company [114]
Moderna mRN 1273 – recently received fast track designation from USFDA. It vaccine basically targets spike protein of corona virus [115]
Tonix Pharmaceuticals TNX-1800 – developed based on its horsepox virus vaccine platform. It has filed a provisional patent application with USPTO [116]
Clover Biopharmaceuticals Subunit vaccine developed using trimeric spike protein developed using its patented technology [117]
Novavax, Inc Middle East Respiratory Syndrome (MERS) vaccine was developed using recombinant nanoparticle based vaccine technology. The vaccine showed positive results in inhibiting the virus when administered along with its patented adjuvant formulations [118–121]
Predictive oncology (PO) Introduced artificial intelligence for development of a vaccine using Inventa Biotech’s HSCTM technology which deals with chromatographic system of high throughput screening. In addition, PO is also developing a new vaccine based on nanoparticle (NSP-10: non specific protein) platform technology developed by Dr. Daniel Carter [122]
|
|
tr
|
Name of the player Details of antiviral vaccines under development Ref.
|
|
th
|
Name of the player
|
|
th
|
Details of antiviral vaccines under development
|
|
th
|
Ref.
|
|
tr
|
Migal Galilee Research Institute, Israel Developing an oral (mucosal) vaccine, wherein the viral antigen is delivered via mucosa tissues by self-activated endocytosis [104]
|
|
td
|
Migal Galilee Research Institute, Israel
|
|
td
|
Developing an oral (mucosal) vaccine, wherein the viral antigen is delivered via mucosa tissues by self-activated endocytosis
|
|
td
|
[104]
|
|
tr
|
Entos Pharmaceuticals Fusogenix – DNA vaccine is being developed based on its patent protected platform, proteo-lipid vehicle (PLV). It uses a new mechanism for delivering genetic material into the cells [105,106]
|
|
td
|
Entos Pharmaceuticals
|
|
td
|
Fusogenix – DNA vaccine is being developed based on its patent protected platform, proteo-lipid vehicle (PLV). It uses a new mechanism for delivering genetic material into the cells
|
|
td
|
[105,106]
|
|
tr
|
Vaxart Inc Oral recombinant vaccine in tablet formulation using its VAAST platform. It has protected its vaccine tablet formulation by US patent applications [107–109]
|
|
td
|
Vaxart Inc
|
|
td
|
Oral recombinant vaccine in tablet formulation using its VAAST platform. It has protected its vaccine tablet formulation by US patent applications
|
|
td
|
[107–109]
|
|
tr
|
University of Oxford – Jenner Institute ChAD0X1 nCoV-19 – prepared from cold virus (weakened) – initiated Phase III trials [110]
|
|
td
|
University of Oxford – Jenner Institute
|
|
td
|
ChAD0X1 nCoV-19 – prepared from cold virus (weakened) – initiated Phase III trials
|
|
td
|
[110]
|
|
tr
|
Altimmune AdCOVID – vaccine delivered via intranasal route platform technologies NasoVAX and NasoShield [111,112]
|
|
td
|
Altimmune
|
|
td
|
AdCOVID – vaccine delivered via intranasal route platform technologies NasoVAX and NasoShield
|
|
td
|
[111,112]
|
|
tr
|
Medicago Developing a vaccine and also an antibody. It was successful in producing virus like particles of coronavirus. It is developing antibodies in collaboration with Laval University [113]
|
|
td
|
Medicago
|
|
td
|
Developing a vaccine and also an antibody. It was successful in producing virus like particles of coronavirus. It is developing antibodies in collaboration with Laval University
|
|
td
|
[113]
|
|
tr
|
Inovio Pharmaceuticals INO-4800 – vaccine that is developed in collaboration with Beijing Advaccinee Biotechnology Company. It is proposing to deliver the vaccine using the device called as CELLECTRA® which works by creating a pulse for transferring the plasmids across the cell. It is also developing INO 4700 in collaboration with GeneOne Life Sciences company [114]
|
|
td
|
Inovio Pharmaceuticals
|
|
td
|
INO-4800 – vaccine that is developed in collaboration with Beijing Advaccinee Biotechnology Company. It is proposing to deliver the vaccine using the device called as CELLECTRA® which works by creating a pulse for transferring the plasmids across the cell. It is also developing INO 4700 in collaboration with GeneOne Life Sciences company
|
|
td
|
[114]
|
|
tr
|
Moderna mRN 1273 – recently received fast track designation from USFDA. It vaccine basically targets spike protein of corona virus [115]
|
|
td
|
Moderna
|
|
td
|
mRN 1273 – recently received fast track designation from USFDA. It vaccine basically targets spike protein of corona virus
|
|
td
|
[115]
|
|
tr
|
Tonix Pharmaceuticals TNX-1800 – developed based on its horsepox virus vaccine platform. It has filed a provisional patent application with USPTO [116]
|
|
td
|
Tonix Pharmaceuticals
|
|
td
|
TNX-1800 – developed based on its horsepox virus vaccine platform. It has filed a provisional patent application with USPTO
|
|
td
|
[116]
|
|
tr
|
Clover Biopharmaceuticals Subunit vaccine developed using trimeric spike protein developed using its patented technology [117]
|
|
td
|
Clover Biopharmaceuticals
|
|
td
|
Subunit vaccine developed using trimeric spike protein developed using its patented technology
|
|
td
|
[117]
|
|
tr
|
Novavax, Inc Middle East Respiratory Syndrome (MERS) vaccine was developed using recombinant nanoparticle based vaccine technology. The vaccine showed positive results in inhibiting the virus when administered along with its patented adjuvant formulations [118–121]
|
|
td
|
Novavax, Inc
|
|
td
|
Middle East Respiratory Syndrome (MERS) vaccine was developed using recombinant nanoparticle based vaccine technology. The vaccine showed positive results in inhibiting the virus when administered along with its patented adjuvant formulations
|
|
td
|
[118–121]
|
|
tr
|
Predictive oncology (PO) Introduced artificial intelligence for development of a vaccine using Inventa Biotech’s HSCTM technology which deals with chromatographic system of high throughput screening. In addition, PO is also developing a new vaccine based on nanoparticle (NSP-10: non specific protein) platform technology developed by Dr. Daniel Carter [122]
|
|
td
|
Predictive oncology (PO)
|
|
td
|
Introduced artificial intelligence for development of a vaccine using Inventa Biotech’s HSCTM technology which deals with chromatographic system of high throughput screening. In addition, PO is also developing a new vaccine based on nanoparticle (NSP-10: non specific protein) platform technology developed by Dr. Daniel Carter
|
|
td
|
[122]
|
|
p
|
Primarily, vaccines pose extreme challenges vis-a-vis its handling, (cold) storage and shipping, all expensive propositions. For instance, one of the studies reported that 38 billion USD would be spent on transportation and administration of 18 vaccines in 94 countries [123,124]. Therefore, there is a need for alternate dosage forms that can help reducing the cost. For instance, Vaxart Inc is developing recombinant vaccine for COVID-19 in tablet formulation using its patent protected technology called VAAST [107–109]. RP Scherer Technologies LLC is also developing a tablet formulation (fast dissolving) for influenza vaccine with starch as immune stimulating agent [125]. Tablets are highly traditional and conventional dosage forms that are difficult to administer to patients who have dysphagia or Parkinson’s disease and are extremely difficult to administer to pediatrics and geriatrics. Therefore, ODFs remain as an alternate choice of administration as they do not need water to consume. Most importantly, they are easy to transport from one place to another. Israel’s Migal Galilee Research Institute is actively developing a vaccine that is administered via oromucosal route [104]. Some of the vaccine preparations that are successfully formulated as ODFs are provided in Table 6.
|
|
table-wrap
|
Table 6. Antiviral vaccines that are formulated as ODFs.
Name of the player Name of vaccine formulated as ODFs Polymer Plasticizer Method employed Key highlight(s) Ref.
The Johns Hopkins University Several live-attenuated viruses were proposed, including the corona virus. Provided methodology to prepare rotavirus vaccine Eudragit Polyethylene glycol (PEG) and polyvinyl alcohol (PVA) Double emulsion solvent evaporation Prepared as monolayered or bi layered ODFs [126]
Brian Pulliam (single applicant and inventor) Rotavirus vaccine along with an antacid namely magnesium hydroxide or aluminum hydroxide nanoparticles for digestion purpose Polyvinyl pyrrolidone + hydroxypropyl cellulose (HPC) PEG Solvent casting method (SCM) Antacid successfully combined with a vaccine in layered fashion [22]
Nitto Denko Corporation Cancer vaccine comprising WT1 peptide or Db126 along with a promoter namely lipopolysaccharide or quercetin or ioxoprofen Mannitol, PEG, and HPC PEG, mannitol SCM Composition successfully induces cellular immunity in cancer patients [127]
Nasir Uddin from Larkin University Gonorrhoea microparticulate vaccine a a SCM Microparticulate vaccine particles were obtained by spray dryingBilayered ODFs can be prepared, outer layer acts as protection layer [128]
Aridis Pharmaceuticals Rotavirus vaccine a a a Patent protected vaccine stabilization technology and plasticized glass stabilization technology were employed in preparing the vaccine film [129–131]
a Nothing found.
|
|
label
|
Table 6.
|
|
caption
|
Antiviral vaccines that are formulated as ODFs.
|
|
p
|
Antiviral vaccines that are formulated as ODFs.
|
|
table
|
Name of the player Name of vaccine formulated as ODFs Polymer Plasticizer Method employed Key highlight(s) Ref.
The Johns Hopkins University Several live-attenuated viruses were proposed, including the corona virus. Provided methodology to prepare rotavirus vaccine Eudragit Polyethylene glycol (PEG) and polyvinyl alcohol (PVA) Double emulsion solvent evaporation Prepared as monolayered or bi layered ODFs [126]
Brian Pulliam (single applicant and inventor) Rotavirus vaccine along with an antacid namely magnesium hydroxide or aluminum hydroxide nanoparticles for digestion purpose Polyvinyl pyrrolidone + hydroxypropyl cellulose (HPC) PEG Solvent casting method (SCM) Antacid successfully combined with a vaccine in layered fashion [22]
Nitto Denko Corporation Cancer vaccine comprising WT1 peptide or Db126 along with a promoter namely lipopolysaccharide or quercetin or ioxoprofen Mannitol, PEG, and HPC PEG, mannitol SCM Composition successfully induces cellular immunity in cancer patients [127]
Nasir Uddin from Larkin University Gonorrhoea microparticulate vaccine a a SCM Microparticulate vaccine particles were obtained by spray dryingBilayered ODFs can be prepared, outer layer acts as protection layer [128]
Aridis Pharmaceuticals Rotavirus vaccine a a a Patent protected vaccine stabilization technology and plasticized glass stabilization technology were employed in preparing the vaccine film [129–131]
|
|
tr
|
Name of the player Name of vaccine formulated as ODFs Polymer Plasticizer Method employed Key highlight(s) Ref.
|
|
th
|
Name of the player
|
|
th
|
Name of vaccine formulated as ODFs
|
|
th
|
Polymer
|
|
th
|
Plasticizer
|
|
th
|
Method employed
|
|
th
|
Key highlight(s)
|
|
th
|
Ref.
|
|
tr
|
The Johns Hopkins University Several live-attenuated viruses were proposed, including the corona virus. Provided methodology to prepare rotavirus vaccine Eudragit Polyethylene glycol (PEG) and polyvinyl alcohol (PVA) Double emulsion solvent evaporation Prepared as monolayered or bi layered ODFs [126]
|
|
td
|
The Johns Hopkins University
|
|
td
|
Several live-attenuated viruses were proposed, including the corona virus. Provided methodology to prepare rotavirus vaccine
|
|
td
|
Eudragit
|
|
td
|
Polyethylene glycol (PEG) and polyvinyl alcohol (PVA)
|
|
td
|
Double emulsion solvent evaporation
|
|
td
|
Prepared as monolayered or bi layered ODFs
|
|
td
|
[126]
|
|
tr
|
Brian Pulliam (single applicant and inventor) Rotavirus vaccine along with an antacid namely magnesium hydroxide or aluminum hydroxide nanoparticles for digestion purpose Polyvinyl pyrrolidone + hydroxypropyl cellulose (HPC) PEG Solvent casting method (SCM) Antacid successfully combined with a vaccine in layered fashion [22]
|
|
td
|
Brian Pulliam (single applicant and inventor)
|
|
td
|
Rotavirus vaccine along with an antacid namely magnesium hydroxide or aluminum hydroxide nanoparticles for digestion purpose
|
|
td
|
Polyvinyl pyrrolidone + hydroxypropyl cellulose (HPC)
|
|
td
|
PEG
|
|
td
|
Solvent casting method (SCM)
|
|
td
|
Antacid successfully combined with a vaccine in layered fashion
|
|
td
|
[22]
|
|
tr
|
Nitto Denko Corporation Cancer vaccine comprising WT1 peptide or Db126 along with a promoter namely lipopolysaccharide or quercetin or ioxoprofen Mannitol, PEG, and HPC PEG, mannitol SCM Composition successfully induces cellular immunity in cancer patients [127]
|
|
td
|
Nitto Denko Corporation
|
|
td
|
Cancer vaccine comprising WT1 peptide or Db126 along with a promoter namely lipopolysaccharide or quercetin or ioxoprofen
|
|
td
|
Mannitol, PEG, and HPC
|
|
td
|
PEG, mannitol
|
|
td
|
SCM
|
|
td
|
Composition successfully induces cellular immunity in cancer patients
|
|
td
|
[127]
|
|
tr
|
Nasir Uddin from Larkin University Gonorrhoea microparticulate vaccine a a SCM Microparticulate vaccine particles were obtained by spray dryingBilayered ODFs can be prepared, outer layer acts as protection layer [128]
|
|
td
|
Nasir Uddin from Larkin University
|
|
td
|
Gonorrhoea microparticulate vaccine
|
|
td
|
a
|
|
td
|
a
|
|
td
|
SCM
|
|
td
|
Microparticulate vaccine particles were obtained by spray dryingBilayered ODFs can be prepared, outer layer acts as protection layer
|
|
td
|
[128]
|
|
tr
|
Aridis Pharmaceuticals Rotavirus vaccine a a a Patent protected vaccine stabilization technology and plasticized glass stabilization technology were employed in preparing the vaccine film [129–131]
|
|
td
|
Aridis Pharmaceuticals
|
|
td
|
Rotavirus vaccine
|
|
td
|
a
|
|
td
|
a
|
|
td
|
a
|
|
td
|
Patent protected vaccine stabilization technology and plasticized glass stabilization technology were employed in preparing the vaccine film
|
|
td
|
[129–131]
|
|
table-wrap-foot
|
a Nothing found.
|
|
footnote
|
a Nothing found.
|
|
label
|
a
|
|
p
|
Nothing found.
|
|
p
|
Administration of vaccines using fast dissolving buccal films is the most optimized form of administration as it has plethora of advantages when compared with parenteral route of administration [132]. Research suggests that vaccines administered via oral route are as good as or even better than those that are administered via parenteral route. For instance, Bajrovic et al. demonstrated that oral administration (sublingual and buccal routes) of influenza virus vaccine as a thin film formulation has shown good or better results than the vaccine that is administered via intramuscular route [133]. From Table 6, it is evident that ODFs comprising vaccines can be prepared as mono or bilayered using the most popular solvent casting method. Tian et al. prepared influenza virus vaccine by using trehalose and pullulan to maintain the stability and antigenicity of the vaccine. They also employed hypromellose that further helped in enhancing the stability of the film [134]. ODFs remain an excellent option for delivery of vaccines to subjects across all the age groups. They are easily portable and maintain stability of the vaccine during transportation till it reaches to the subject for consumption. All these strongly suggest that ODFs are cost-effective carriers and easy to consume dosage forms.
|
|
sec
|
Conclusion
In light of the above, ODFs are a novel oromucosal carriers that could be used to deliver a new active agent (drug/vaccine) against COVID-19. ODFs have already proven its potential to act as a carrier for delivery of drug/herb/vaccine. But, more research is still needed vis-a-vis loading vaccines onto ODFs. Research in the domain of corona virus infections has taken the front seat across the globe and companies are heavily investing in R&D. Hopefully, soon the world will witness a new active entity for treating COVID-19 and the life of all the human beings will come to normalcy – from unusual to life as usual.
|
|
title
|
Conclusion
|
|
p
|
In light of the above, ODFs are a novel oromucosal carriers that could be used to deliver a new active agent (drug/vaccine) against COVID-19. ODFs have already proven its potential to act as a carrier for delivery of drug/herb/vaccine. But, more research is still needed vis-a-vis loading vaccines onto ODFs. Research in the domain of corona virus infections has taken the front seat across the globe and companies are heavily investing in R&D. Hopefully, soon the world will witness a new active entity for treating COVID-19 and the life of all the human beings will come to normalcy – from unusual to life as usual.
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back
|
Disclosure statement
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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sec
|
Disclosure statement
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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title
|
Disclosure statement
|
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p
|
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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