key: cord-0950191-8cfmh0iv authors: Imran, Mohd; Alshrari, Ahmed Subeh; Asdaq, Syed Mohammed Basheeruddin; Abida, title: Trends in the development of remdesivir based inventions against COVID-19 and other disorders: A patent review date: 2021-06-27 journal: J Infect Public Health DOI: 10.1016/j.jiph.2021.06.013 sha: 00987fddfd6f4cc56f46342170db7b01bc059716 doc_id: 950191 cord_uid: 8cfmh0iv The development of remdesivir has been a breakthrough for COVID-19 treatment. It has been approved in about 50 countries, including Saudi Arabia, since 2020. The generic structure of remdesivir was first disclosed in 2009. This patent review summarizes the remdesivir based inventions to treat/prevent COVID-19 and other disorders from 2009 to May 16, 2021, emphasizing the patents related to medical and pharmaceutical sciences. The primary patents/patent applications of remdesivir are related to its compositions, new combinations with other therapeutic agents, delivery systems, and new indications. The inventive combinations have displayed synergistic effects against COVID-19, whereas the delivery systems/compositions have improved patient compliance. The inventions related to new indications of remdesivir to treat Ebola, hepatitis, idiopathic pulmonary fibrosis, diabetic nephropathy, and cardiovascular complications enhance its therapeutic area. Many new innovative combinations and delivery systems of remdesivir are anticipated to provide better treatment for COVID-19. alternative of remdesivir [11] . As of , remdesivir has been approved in about 50 countries since 2020 to treat COVID-19. These countries include Australia, India, United Arab Emirates, Argentina, Japan, Canada, Lebanon, Russia, Great Britain, European Union (about 30 countries), United States of America, Brazil, Israel, Guatemala, Qatar, Iraq, Saudi Arabia, South Korea, Kuwait, Hong Kong, Turkey, Switzerland, Singapore, Bahrain, Mexico, Jordan, and Taiwan [12] . J o u r n a l P r e -p r o o f lenzilumab, plitidepsin, and hydroxychloroquine, are in a clinical trial to treat COVID-19 [19] . However, it is also in a clinical trial for other conditions [20] , which is provided in Table 2 . Some critical patent reviews on coronavirus have been published [21] [22] [23] [24] [25] . These articles mention the name of remdesivir but are silent about its patent literature. The authors believe no review discusses remdesivir based patent inventions/innovations to treat COVID-19. This review updates the scientific fraternity about the existing inventions/innovations of remdesivir. It will help them generate innovative ideas to provide better remdesivir based treatments for COVID-19. The updated patent searching (June 14, 2021) was performed through Espacenet, WIPO, USPTO, and Scifinder databases. The exact structure search of remdesivir and its CAS number search was done by the Scifinder database. The keywords remdesivir and GS-5734 were used for patent search in the Espacenet, WIPO, and USPTO databases (Scheme 3). The compound patents of remdesivir were identified using the exact structure search of remdesivir in the Scifinder database. J o u r n a l P r e -p r o o f The patents/patent applications that do not use the terms "remdesivir or GS-5734" or the chemical structure of remdesivir specifically or generically in the claim section of the patent/patent application were excluded from the final list. The patents/patent applications related to the novel synthetic compounds as antiinfective/antiviral agents have not been included in this review because these compounds have never been tested in humans. The translation of the non-English patents/patent applications was obtained from Espacenet and WIPO databases. US10065958B2 provides ribosides, riboside phosphates, and prodrugs for treating infections caused by the Paramyxoviridae virus family, particularly for respiratory infections of syncytial parainfluenza virus. This patent covers remdesivir and its salts. The patent exemplifies the J o u r n a l P r e -p r o o f respiratory syncytial virus antiviral activity of the disclosed compounds and their cytotoxicity assays [26] . US8008264B2 claims the general structure of remdesivir. It also claims a method of treating a viral infection (dengue, yellow fever, etc.) using the disclosed compounds alone or in a combination of other therapeutic agents [27] . US8318682B2 [28] and USRE46762E [29] also claim the general structure of remdesivir to treat viral diseases. These three patents exemplify the antiviral activity of the disclosed compounds, including the IC50 and EC50 values of the Hepatitis C virus. US9724360B2 [30] and US9949994B2 [31] unveil ribosides, riboside phosphates, prodrugs thereof, and their pharmaceuticals compositions to treat Ebola, Cueva, and Marburg viral infections. These patents specifically cover the specific isomer of remdesivir ( Figure 1 ) to prepare its marketed dosage forms. They also exemplify the anti-Ebola virus activity and the cytotoxicity assays of the stated compounds. US10836787B2 claims the crystalline form of remdesivir. The disclosed crystalline form is claimed to have a bioavailability advantage, physical stability and is suitable to manufacture the solid dosage forms for the intended therapeutic use. The patent also mentions the method of preparation of the claimed polymorph [32] . 3 formulations of cannabinoid, which is also a hydrophobic drug [35] . WO2020210376A1 claims a composition comprising highly porous activated carbon (microporous carbon) and an antiviral agent (remdesivir). It states that charcoal has antiviral effects. The antiviral agents may be adsorbed and encapsulated within microporous carbon, causing a persistent release of the drug that generates a more considerable therapeutic effect. Due to the kidney function-related benefits, this charcoal-based drug delivery system avoids the renal toxicity issues associated with some antiviral agents, e,g. acyclovir. This patent application does not exemplify any formulation of remdesivir [36] . xylitol and fructose) and auxiliary materials (.e.g. antioxidants and preservatives). The claimed film is fast-acting, easy-to-carry and use, simple to prepare, and patient compliant. The patent application exemplifies the preparation of the fast-dissolving oral film of remdesivir [37] . CN112675143A claims a film-coated tablet of remdesivir comprising a pH regulator (Eudragit CN111467362A claims a pharmaceutical composition comprising azithromycin and remdesivir to treat an infectious disease (COVID-19), wherein the particle size of the azithromycin is 40-400 μm, and the D90 particle size is 200-400 μm. The particle size of azithromycin is responsible for its improved absorption. This patent application exemplifies the preparation of azithromycin compositions with different particle sizes and the effect of azithromycin particle size on blood concentration. There is no example wherein azithromycin has been combined with remdesivir [45] . CN112891327A provides a liquid preparation for remdesivir atomized inhalation and its preparation. The content of remdesivir in the liquid preparation ranges from 0.1% to 0.5% (w/v), and the pH ranges from 5 to 7. This delivery system increases the exposure of remdesivir in the lungs much higher than that of intravenous injection, which reduces the dosage, cost, and systemic side effects [52] . CN112274520A claims the application of remdesivir and its salts to prepare a medicine for treating idiopathic pulmonary fibrosis. It has been demonstrated that remdesivir can improve forced vital capacity, inhalation, and exhalation airway resistance; reduce lung collagen content and the area of pulmonary fibrosis. The patent application exemplifies the claimed effect of remdesivir on bleomycin's idiopathic pulmonary fibrosis model [58] . (BPIV3). The invention states and exemplifies that remdesivir inhibits/inactivates the BPIV3 virus by blocking its replication without any toxic effect [60] . (COVID-19) patient. These EVs can be used in combination with antiviral agents (remdesivir) to attenuate/treat the severity of the infection. No example of remdesivir and EVs combination has been provided in this patent application [61] . The CD-154 is involved in cell-mediated immunity, and its activation boosts immunity. This patent application claims an isolated antibody that binds to CD 154. It also claims a pharmaceutical composition comprising an anti-CD154 antibody and an antiviral agent (.e.g. remdesivir) to treat immune-related disease (.e.g. . However, no data of the composition of remdesivir and the claimed antibody has been disclosed in this patent application [65] . CN112135625A claims the use of lysozyme or a combination comprising lysozyme to prepare medicine or food for preventing or treating COVID-19. The lysozyme may be combined with an antiviral agent (remdesivir) and glycyrrhizic acid. The composition can be administered in an oral dosage form, injection dosage form, and inhalation dosage form. The patent application exemplifies the application of lysozyme in patients with new coronary pneumonia and high-risk infections, but without remdesivir [66] . [104] . The development of remdesivir, a broad-spectrum antiviral agent, has been a breakthrough for COVID-19 treatment. It is the first approved treatment for COVID-19 that is clinically used in about 50 countries [12] . The generic structure of remdesivir was first disclosed in WO2009132123A1 [105] to treat hepatitis C, dengue, and Flaviviridae virus infections. WO2009132123A1 [105] is a family member of US8318682B2 [28] and USRE46762E [29] that have already been discussed. Later, it was reported to possess activity against corona infections [33] . Gilead Sciences has developed remdesivir as a freeze-dried preparation for injection. The drug has to be prepared fresh and injected under the supervision of professionals [11] , which leads to poor patient compliance. Further, the freshly prepared injection is not stable for an extended period [40] . Therefore, novel compositions of remdesivir with improved patient compliance, safety, stability, and bioavailability have been invented. These include soft gel capsules [35] , charcoal-based drug delivery systems [36] , fast-dissolving oral film of remdesivir [37] , and film-coated tablets [38] . The marketed freeze-dried powder for injection contains SBECD to enhance the aqueous solubility of remdesivir. However, the solubilization process is optimal at a pH < 4. On the other hand, remdesivir is unstable in an acidic aqueous solution. Accordingly, the marketed freeze-dried powder for injection also contains pH regulators (hydrochloric acid and sodium hydroxide) [39] . Therefore, the preparation of the freeze-dried powder for injection is a complex process. Further, at the time of injection, remdesivir injection is acidic, which causes poor patient compliance. Accordingly, a new stable, safe, and patient compliant injection of remdesivir in non-aqueous solvent (absolute ethanol and polysorbate) having a short production process has been invented [39] . The non-aqueous injection is also safe for the kidney, unlike SBECD based injection, which causes renal dysfunction [8] . The development of new delivery systems is directed to improve the biological effect and bioavailability of a drug; improve patient compliance; reduce the side effects of the drug, and solve solubility and biodistribution [106] . Accordingly, new spray [48] and nebulizer preparations [49] of remdesivir have been invented to address its side effects and improve its J o u r n a l P r e -p r o o f biological action. A stable and effective sublingual tablet of remdesivir having quality pharmaceutical properties has also been invented [41] . Such tablets increase patient compliance in comparison to the marketed injectable formulation of remdesivir. Remdesivir based masks [50] and cosmetics [53] have also been developed that help to prevent the spread of COVID-19. Some patents related to the combinations of remdesivir and other drugs, for example, cell pathway inhibitors (.i.e. anti-inflammatory agents) [42] , pyrimidine compound [43] , isoxazoline parasiticides [44] , azithromycin [45, 47] , and viral protease inhibitory polypeptide [46] have been identified. Such combinations have revealed the synergistic effects against COVID-19 compared to the monotherapy of remdesivir. Many combinations of remdesivir are in a clinical trial also [19] . The development of further inventive composition (monotherapy, combinations, and delivery systems) is anticipated to tackle this disaster of the century. Remdesivir was first developed to treat Ebola infection. A patent has been granted for the use of remdesivir to treat Ebola infection [54] . Some patents/applications have been located that claim the use of remdesivir to treat different diseases that include cardiovascular complications of diabetes [56] , cardiotoxicity caused by the anti-tumor drugs [57] , idiopathic pulmonary fibrosis [58] , and hepatitis B virus (HBV) [59] . The clinical trial information of remdesivir for its new conditions has been provided in Table 2 . The compound patents of remdesivir are supposed to expire in October 2035. Gilead Sciences has also applied for the legal PTE (that may be up to five years) for its compound patents [31, 32] . The extension grant will extend the patent protection of remdesivir till October 2040 in many countries. The generic version of remdesivir may not be available to the patient by 2035-2040 in many countries. Accordingly, it is compulsory to look for alternative therapies also .e.g. drug repurposing of the existing therapeutic agents. The patent literature has revealed inventive compositions, combinations, delivery systems, and new indications of remdesivir. The primary inventions of remdesivir (compositions, combinations, and delivery systems) have been developed to provide synergistic treatment for J o u r n a l P r e -p r o o f COVID-19 and patient compliance. Some exciting innovations have also been disclosed to prevent COVID-19, for example, remdesivir based lipstick, masks, sprays, and nebulizers. The inventions related to new indications of remdesivir increase its therapeutic scope. It is expected that the scientific fraternity will create new ideas based on this review to combat COVID-19. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. It is not required. Wuhan to World: The COVID-19 Pandemic World Health Organization. WHO Coronavirus (COVID-19) Dashboard World Health Organization. Coronavirus disease (COVID-19) pandemic Pharmacogenetics Approach for the Improvement of COVID-19 Treatment COVID-2019 fundamentals Innovative diagnostic approach and investigation trends in COVID19-A systematic review Facing coronavirus disease 2019: What do we know so far? (Review) The journey of remdesivir: from Ebola to COVID-19 Challenges in reported COVID-19 data: best practices and recommendations for future epidemics Pharmacodynamic, and Drug-Interaction Profile of Remdesivir, a SARS-CoV-2 Replication Inhibitor United States Food and Drug Administration Gilead Sciences. Veklury® Global Marketing Authorization Status Other Viral Diseases Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency Recent knowledge in favor of remdesivir (GS-5734) as a therapeutic option for the COVID-19 A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19 The efficacy of remdesivir in coronavirus disease 2019 (COVID-19): a systematic review From Ebola to COVID-19 COVID-19: Characteristics and Therapeutics Coronavirus helicases: attractive and unique targets of antiviral drug-development and therapeutic patents Inhibitors of type II transmembrane serine proteases in the treatment of diseases of the respiratory tract -A review of patent literature Protease inhibitors targeting the main protease and papain-like protease of coronaviruses SARS-CoV-2 RNA-dependent RNA polymerase as a therapeutic target for COVID-19 COVID-19) treatment: a patent review Methods and compounds for treating Paramyxoviridae virus infections. United States patent number US10065958B2 1'-substituted carba-nucleoside analogs for antiviral treatment. United States patent number US8008264B2 1'-substituted carbanucleoside analogs for antiviral treatment. United States patent number US8318682B2 1'-substituted carbanucleoside analogs for antiviral treatment. United States patent number USRE46762E Methods for treating Filoviridae virus infections. United States patent number US9724360B2 Methods for treating Filoviridae virus infections. United States patent number US9949994B2 -yl)-5-cyano-3,4-dihydroxytetrahydro furan-2-yl)methoxy)(p-henoxy)phosphoryl)amino)propanoate. United States patent number US10836787B2 Methods for treating arenaviridae and coronaviridae virus infections. United States patent number US10695361B2 Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections. United States patent number US10675296B2 Oil-soluble drug containing compositions and methods of use thereof. United States patent application publication number US20200360292A1 Drug adsorbed highly porous activated carbon for enhanced drug delivery. PCT patent application publication number WO2020210376A1 Remdesivir oral fast dissolving film and preparation method thereof. Chinese patent application publication number CN111494349A Remdesivir tablet and preparation method thereof Chinese patent application publication number CN112675143A Remdesivir injection and preparation method thereof. Chinese patent application publication number CN112402371A Remdesivir eye drops and preparation method and application thereof. Chinese patent application publication number CN112656759A Transmucosal dosage forms of remdesivir. United States patent number US11020349B1 Method of treating, reducing, or alleviating a medical condition in a patient United States patent number US10925889B2 Potentiators of antimicrobial and/or antiviral agents. PCT patent application publication number WO2020227530A1 Systemic isoxazoline parasiticides for vector-borne and viral disease treatment or prophylaxis. PCT patent application publication number WO2020202111A1 Azithromycin pharmaceutical composition, and preparation method and application of azithromycin pharmaceutical composition. Chinese patent application publication number CN111467362A Preparation method of active peptide sterilization antiviral spray. Chinese patent application publication number CN112168956A Inhalation spray of antivirus medicines. Chinese patent application publication number CN111297838A Chinese patent application publication number CN111149804A Remdesivir liquid preparation for atomizer, and preparation method and application of remdesivir liquid preparation. Chinese patent application publication number CN111956630A Kind of pocket-plug-in mask. Chinese patent application publication number CN112515258A Methods of treatment of viral diseases. United States patent number US11013688B1 Liquid preparation for atomization inhalation of remdesivir and preparation method thereof. Chinese patent application publication number CN112891327A Lipstick with antiviral effect. Chinese patent application publication number CN111603408A Methods for treating Filoviridae virus infections. United States patent number US10251898B2 Methods for treating filoviridae virus infections. United States patent number US10695357B2 Application of remdesivir in the preparation of medicines for treating diabetic complications. Chinese patent application publication number CN112618557A Application of remdesivir in the preparation of anti-tumor drugs and cardiotoxic drugs Application of retegravir in preparation of medicine for treating idiopathic pulmonary fibrosis. Chinese patent application publication number CN112274520A Compositions and methods for treatment of hepatitis B virus infection. PCT patent application publication number WO2021067480A1 Application of remdesivir to preparation of medicine for resisting bovine parainfluenza virus 3. Chinese patent application publication number CN112843073A Methods for attenuating viral infection and for treating lung injury. United States patent application publication number US20200384034A1 Cell vesicle expressing chimeric antigen receptor and preparation method and application thereof. Chinese patent application publication number CN112522203A Anti-novel coronavirus monoclonal antibody and application thereof Chinese patent application publication number CN111592594A Modified TFF2 polypeptides. PCT patent application publication number WO2021038296A2 Anti-CD154 antibodies and uses thereof. PCT patent application publication number WO2021001458A1 Medicine and food for preventing or treating COVID-19 and application thereof. Chinese patent application publication number CN112135625A Synthesis method of drug for novel coronavirus COVID-19 infected pneumonia drug. Chinese patent application publication number CN111393478A Remdesivir related substance as well as preparation method and application thereof. Chinese patent application publication number CN112358504A Synthesis method of antiviral drug ridexivir and intermediate thereof. Chinese patent application publication number CN112321589A Retegravir related substance and preparation method and application thereof. Chinese patent application publication number CN112321642A Method for continuously preparing retegravir intermediate by using micro-channel reactor. Chinese patent application publication number CN112279855A Remdesivir related substance and preparation method and application thereof. Chinese patent application publication number CN111961079A Method for synthesizing retegravir by using micro-channel reaction technology. Chinese patent application publication number CN111848679A Preparation method of remdesivir derivative, remdesivir derivative and application of the remdesivir derivative. Chinese patent application publication number CN111875638A Synthetic method of C-nucleoside compound. Chinese patent application publication number CN111793101A Synthesis method of a remdesivir key fragment. Chinese patent application publication number CN111732618A Chinese patent application publication number CN111484537A Synthesis method of remdesivir. Chinese patent application publication number CN111471070A Preparation method of remdesivir intermediate 2-ethyl-1-butanol. Chinese patent application publication number CN111470946A Method for preparing retegravir by using micro-channel reaction device. Chinese patent application publication number CN111440215A Synthesis method of phosphorus chiral nucleoside drug and drug obtained by method. Chinese patent application publication number CN111393243A Synthesis of remdesivir key intermediate 2,3,5-tribenzyloxy-D-ribotide-1,4-lactone. Chinese patent application publication number CN111393392A Retegravir side chain intermediate and preparation method thereof. Chinese patent application publication number CN111269263A Synthesis method of retegravir Chinese patent application publication number CN111233931A Preparation method of retegravir. Chinese patent application publication number CN111233930A Method for rapidly preparing remdesivir intermediate. Chinese patent application publication number CN111233870A Novel compound for preparing key intermediate of remdesivir and preparation method thereof. Chinese patent application publication number CN111233869A Preparation method of Remdesivir. Chinese patent application publication number CN111205327A Synthesis method of remdesivir intermediate. Chinese patent application publication number CN111187269A Synthesis method of retegravir. Chinese patent application publication number CN111171078A Preparation method of remdesivir. Chinese patent application publication number CN111116656A Method for preparing remdesivir using microchannel reactor. Chinese patent application publication number CN112679542A Method for preparing and purifying remdesivir key intermediate 2-ethylbutyl Chinese patent application publication number CN112645982A A double-pump gradient liquid chromatograph for producing Radixivir. Chinese patent application publication number CN212904707U Preparation of 4-amino-pyrrolo A kind of reid intermediate raw material processing device Preparation method of remdesivir intermediate 4-nitrophenyl phenyl phosphoramidate or perfluorophenyl phenyl ((2S,3S)-3-(2-ethylbutoxy)butan-2-yl) phosphoramidate based on dynamic kinetic resolution. Chinese patent application publication number CN112500429A Synthetic process of remdesivir intermediate using phosphorus oxychloride. Chinese patent application publication number CN112457318A Method for preparing retegravir intermediate by using continuous flow reactor. Chinese patent application publication number CN112358513A Remdesivir related substance and preparation method thereof. Chinese patent application publication number CN112920203A Isomorphs of remdesivir and methods for synthesis of same. United States patent application publication number US2021161927A1 Potential Treatment Options for COVID-19: A Comprehensive Review of Global Pharmacological Development Efforts COVID-19 vaccine challenges: What have we learned so far and what remains to be done? Carba-nucleoside analogs for antiviral treatment. PCT patent application publication number WO2009132123A1