WO2024120452A1 - Compositions and methods for prophylaxis and treatment of covid-19 - Google Patents
Compositions and methods for prophylaxis and treatment of covid-19 Download PDFInfo
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Abstract
It provides compositions and methods for modulating ACE2 expression and for treating, reducing or preventing COVID-19 or post-COVID conditions, or a related disease or disorder.
Description
Priority Claims and Related Patent Applications
This application claims the benefit of priority to U.S. Provisional Application Serial Nos. 63/430,932, filed December 7, 2022, and 63/432,044, filed December 12, 2022, the entire content of each of which is incorporated herein by reference.
The invention generally relates to pharmaceutical compositions and methods for therapeutic uses thereof. In particular, the invention relates to pharmaceutical compositions and methods of use of berberine ursodeoxycholate (BUDC) for modulating angiotensin converting enzyme 2 (ACE2) and for the treatment, reduction and/or prevention of associated diseases and disorders (e.g., SARS-CoV-2 or COVID-19, post-COVID conditions or long COVID) , as monotherapy or in combination therapy with other agents or an adjuvant. The invention further relates to pharmaceutical compositions and methods of use of berberine (BBR) and ursodeoxycholic acid (UDCA) for modulating ACE2 and for the treatment, reduction and/or prevention of associated diseases and disorders (e.g., SARS-CoV-2 or COVID-19, post-COVID conditions or long COVID) , as monotherapy or in combination therapy with other agents or an adjuvant.
COVID-19 is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . SARS-CoV-2 virus can spread from an infected person’s mouth or nose in small liquid particles when the person coughs, sneezes, speaks or breathes. These particles range from larger respiratory droplets to smaller aerosols. Spike proteins on the surface of a virus mediate SARS-CoV-2’s entry into human cells. To fulfill its function, SARS-CoV-2 spike binds to its receptor human ACE2 through its receptor-binding domain (RBD) and is proteolytically activated by human proteases.
Symptoms of COVID-19 are variable, but often include fever, cough, fatigue, breathing difficulties, and loss of smell and taste. While most people have mild symptoms, a significant percentage of people develop acute respiratory distress syndrome (ARDS) . ARDS can be precipitated by cytokine storms, multi-organ failure, septic shock, and blood clots. Longer-term damage to organs, in particular the lungs and heart, has been frequently observed. (See, e.g., Ye, et al. 2020 The Journal of Infection 80 (6) : 607–613; Brevini, T., Maes, M., Webb, G.J. et al. Nature 2022. )
Increasing clinical evidence has shown that some people who have been infected with SARS-CoV-2 can experience long-term effects from their infection, known as post-COVID conditions (a.k.a., post-acute COVID-19, long COVID or chronic COVID, etc. ) . These patients experience returning or ongoing health problems long (e.g., weeks, months or years) after infection of COVID-19. For instance, it has been reported that between one month and one year after having COVID-19, 1 in 5 people ages 18 to 64 has at least one medical condition that might be attributable to COVID-19. (See, e.g., Perlis, et al. 2022 JAMA Netw Open. 5 (10) ; Household Pulse Survey, National Center for Health Statistics, 2022 https: //www. cdc. gov/nchs/covid19/pulse/long-covid. htm; Institute Report “Assessing the Global Burden of Post-COVID-19 Conditions” 2022, https: //www. iqvia. com/insights/the-iqvia-
institute/reports/assessing-the-global-burden-of-post-covid-19-conditions; Levine, et al. “Long COVID Research, Services, And Supports: A Call To Action” August 2, 2022 Health Affairs Forefront 10.1377/forefront. 20220801.50344. )
Symptoms of post-COVID conditions can be wide ranging, including fatigue, fever, respiratory and heart symptoms (e.g., difficulty breathing or shortness of breath, cough, chest pain, heart palpitations) , neurological symptoms (e.g., difficulty thinking or concentrating, sometimes referred to as "brain fog" ) , headache, sleep problems, lightheadedness, depression or anxiety, digestive symptoms (e.g., diarrhea, stomach pain) , joint or muscle pain, rash, etc. (See, e.g., Cassar, et al. 2021 EClinicalMedicine 41, 101159; Singh, et al. 2020 Am J Physiol Cell Physiol 319: C258–C267; Ajaz, et al. 2020 Am J Physiol Cell Physiol 320: C57–C65, 2021; Gibellini, et al. 2020 EMBO Molecular Medicine 12: e13001; Raman, et al. 2022 Euro. Heart J. 43, 1157–1172; Evans, et al. 2022 Lancet Respir. Med. 10: 761-75; Singh, et al. 2022 Chest 161 (1) : 54-63; Shields, et al. 2022 Clin. and Exper. Immun. 209, 3: 247–258; Pretorius, et al. 2021 Cardio Diabetology 20, No. 172. )
Currently, available prevention and/or treatment options include COVID-19 vaccination, supportive therapy, symptomatic treatment, and antiviral agents. Various antiviral medications have been investigated for COVID-19 with some showing efficacy and reduction of mortality. In November 2020, the U.S. FDA issued an EUA for the investigational monoclonal antibody therapy bamlanivimab for the treatment of mild-to-moderate COVID-19 and also granted EUA for casirivimab and imdevimab to be administered together for the treatment of mild to moderate COVID-19. In December 2021, emergency use authorizations (EUA) were granted in the U.S. for antiviral medications PAXLOVIDTM (nirmatrelvir; ritonavir) , developed by Pfizer, and LAGEVRIOTM (molnupiravir) , developed by Merck.
Despite these encouraging developments, vaccine-resistant and/or treatment-resistant viral variants have continued to emerge as the pandemic spreads to more vulnerable demographic populations including immunocompromised patients and high-risk groups such as seniors and others who do not response well to vaccines or currently available treatments.
BUDC is an ionic salt of BBR and UDCA, represented by
The compound was disclosed in WO 2016/015634 A1 (PCT/CN2015/085350) and WO 2018/205987 A1 (PCT/CN2018/086461) , the content of each of which is incorporated herein by reference in its entirety.
BUDC is currently under investigation for the treatment of primary sclerosing cholangitis (PSC) , primary biliary cirrhosis (PBC) and non-alcoholic steatohepatitis (NASH) . BUDC is an ionic salt formed between BBR and UDCA with 1: 1 stoichiometry and unique physico-chemical properties including enhanced bioavailability of BBR within the gut.
Efficacy demonstrated previously in non-clinical and clinical studies of BUDC include: improving glucose homeostasis, positively regulating lipoprotein metabolism, attenuating cholestatic liver and bile duct injury, anti-inflammatory, anti-fibrotic actions, and beneficial effects on gut microbiome.
UDCA, a.k.a ursodiol, is a secondary bile acid, produced in humans and most other species from metabolism by intestinal bacteria. UDCA has no measurable toxicity. It has been studied in connection with animal models of neurodegenerative diseases, including Huntington’s, amyotrophic lateral sclerosis, Parkinson’s, and Alzheimer’s disease. There have been various ongoing or proposed clinical studies of UDCA regarding diverse human clinical disorders. A Veterans Outcomes and Costs Associated with Liver disease (VOCAL) cohort (who received at least two doses of a COVID-19 mRNA vaccine) analysis demonstrated that patients on UDCA were less likely to develop moderate, severe or critical COVID-19 (p=0.026) according to the National Institute of Health COVID-19 severity score. (See, e.g., Subramanian, et al. 2020 Vaccines 8, 320. Ko, et al. 2017 PLoS ONE, 12, e0180673; Vang, et al. 2014 Glob. Adv. Health Med. 3, 58–69; Daruich, et al. 2019 Mol. Vis. 25, 610–624; Fobar, R. “China Promotes Bear Bile As Coronavirus Treatment: https: //www. nationalgeog raphic. com/animals/2020/03/chinese-government-promotes-bear-bile-as-coronavirus-covid19-treatment/; Brevini, T., Maes, M., Webb, G.J. et al. Nature 2022. )
BBR is an isoquinoline alkaloid and has been used for digestive ailments including travelers diarrhea. BBR has broad-spectrum activities with multiple modes of action. Previous studies on berberine reported that it exhibited antiviral, anti-inflammatory, hepatoprotective benefits, as well as in reduction of oxidative stress. For example, berberine has shown antiviral activities such as anti-influenza, anti-hepatitis C, anticytomegalovirus, and anti-alphavirus. It was considered an orally available therapeutic candidate against SARS-CoV-2 in guidelines issued by the China National Health Commission for COVID-19 to be combined with other therapies. (See, e.g., Wang, et al. 2021 The FASEB Journal 35: e21360; Berberine. Altern Med Rev. 2000, 5 (2) : 175-177; Xu, et al. 2018 Eur J Pharmacol. 819: 161-168; Wen, et al. 2020 Neurotox Res. 38 (1) : 59-73; Chen, et al. 2018 Mol Med Rep. 18 (5) : 4468-4476; Hao, et al. 2015 Xenobiotica 45 (11) : 1024-1029. )
A recent study showed that BBR may prevent SARS-CoV-2 entry to host cells via attaching to spike protein and/or ACE2 receptor and may halt SARS-COV-2 replication via attaching to M protease. It was additionally reported that BBR acts on TNF-α, STAT3, IL-6, CCL2 and other targets to inhibit inflammation and activate fibrocytes to achieve therapeutic effect on COVID-19 caused pneumonia pulmonary fibrosis. Other studies used SARS-CoV-2 infected human lung epithelial cells, where BBR significantly reduced viral replication, suppressed viral entry host receptor ACE2 and TMPSS2, and significantly decreased inflammatory markers including IL-6, IL-8, IL-1α, and CCL2 versus infected but not treated cells. A clinical study of 18 patients with severe COVID-19 indicated that for severe COVID-19 patients with diarrhea, BBR significantly improved IL-6, TNF-α and CRP levels (p<0.050) . (See, e.g., Majdalawieh, et al. 2022 Front Biosci (Landmark Ed) 2022 May 20; 27 (5) : 166; Cao, et al. 2022 Phytomed Plus. 2022 May; 2 (2) : 100252; Wang, et al. 2021 The FASEB Journal 35: e21360; Zhang, et al. 2021 British Journal of Surgery, Volume 108, Issue 1, January 2021, Pages e9–e11. )
Currently available therapeutics and methods for preventing or treating COVID-19 remain inadequate. In particular, there is an ongoing need for safe and effective prophylaxis and treatment for COVID-19 infections, in particular for the immunocompromised and other high-risk populations.
In one aspect, the invention generally relates to a method for modulating ACE2 expression in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising BUDC.
In another aspect, the invention generally relates to a method for reducing ACE2 expression, comprising administering to a subject in need thereof a pharmaceutical composition comprising BUDC.
In yet another aspect, the invention generally relates to a method for suppressing FXR signaling in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
In yet another aspect, the invention generally relates to a method for preventing or delaying infection of SARS-CoV-2 or a variant thereof, or a related disease or disorder, comprising administering to a subject in need there of a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
In yet another aspect, the invention generally relates to a method for treating infection of SARS-CoV-2 or a variant thereof, or a related disease or disorder, comprising administering to a subject in need there of a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
In yet another aspect, the invention generally relates to a method for preventing or treating post-COVID conditions, or a related disease or disorder, comprising administering to a subject in need there of a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
In yet another aspect, the invention generally relates to use of BUDC for the manufacture of a medicament for prevention or treatment of SARS-CoV-2 infection.
In yet another aspect, the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for prevention or treatment of SARS-CoV-2 infection.
In yet another aspect, the invention generally relates to use of BUDC for modulating ACE2 expression.
In yet another aspect, the invention generally relates to use of BUDC for suppressing FXR signaling.
In yet another aspect, the invention generally relates to use of BUDC for preventing or treating SARS-CoV-2 infection.
In yet another aspect, the invention generally relates to use of BUDC for preventing or treating post-COVID conditions, or a related disease or disorder.
In yet another aspect, the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for modulating ACE2 expression.
In yet another aspect, the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for suppressing FXR signaling.
In yet another aspect, the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for preventing or treating SARS-CoV-2 infection.
In yet another aspect, the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for preventing or treating post-COVID conditions, or a related disease or disorder.
In yet another aspect, the invention generally relates to a unit dosage form for use in preventing and/or treating SARS-CoV-2 infection or post-COVID conditions, or a related disease or disorder, comprising a therapeutically effective amount of BUDC.
In yet another aspect, the invention generally relates to a unit dosage form for use in preventing and/or treating SARS-CoV-2 infection or post-COVID conditions, or a related disease or disorder, comprising therapeutically effective amounts of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
FIG. 1. Exemplary data: After 5 days of administration, HTD1801 at 800 mg/kg p.o. q.d. reduced the animals’ body weight. The symbols represent the group mean, and the error bars signify the standard deviation.
FIG. 2. Exemplary data: Neither HTD1801 nor UDCA mitigates the body weight loss induced by intranasal infection with SARS-CoV-2. The symbols represent the group mean, and the error bars signify the standard deviation.
FIG. 3. Exemplary data: HTD1801 showed a tendency to mitigates the lung inflammation induced by intranasal infection with SARS-CoV-2. The symbols represent the group mean, and the error bars signify the standard deviation.
FIG. 4. Exemplary data: HTD1801 and UDCA suppresses the replication of SARS-CoV-2 in the lung of intranasally infected Syrian hamsters. The symbols represent the group mean, and the error bars signify the standard deviation. *: p<0.05 (one-tailed Mann-Whitney test) .
The invention is based in part on compositions and methods of use of BUDC, as well as combinations of BBR and UDCA, for prophylaxis and treatment for COVID-19 infections.
Not wishing to be bound by the theories, it is believed that BUDC, as well as combinations of BBR and UDCA, can effectively modulate expression of ACE2 and reduce, delay or prevent viral entry and infection in various organs (e.g., the respiratory, cardiovascular, digestive tract, and the biliary tree systems of the human body) . BUDC, as well as combinations of BBR and UDCA, can also effectively reduce, delay or prevent various post-COVID conditions.
In particular, the present invention relates to a novel strategy for prevention of SARS-CoV-2 infection through the modulation of viral host receptors, such as ACE2, and represents a unique chemoprophylactic approach that complements COVID-19 vaccination. Furthermore, BUDC can be used for both prevention and treatment thus offering an ideal approach for the management of COVID-19.
It is further believed that these agents present prophylaxis and/or treatment benefits through modulating mitochondrial dysfunction, endothelial dysfunction, autoimmune response, and/or chronic inflammation. For instance, the agents and methods disclosed herein can improve mitochondrial metabolism and vascular environment as well as reduce inflammation, thus helping prevent or alleviate post-COVID conditions.
More particularly, the present invention relates BUDC that synergistically combine the beneficial effects of UDCA and BBR: by modulation of viral host receptors, such as ACE2, to reduce ACE2 expression and suppress entry of SARS-CoV-2 into host cells, and by targeting inflammatory signaling pathways (including NF-κB, p38MAPK, autophagy etc. ) to suppress infectivity of SARS-CoV-2. The present invention thus provides a unique approach for both prophylaxis and treatment for COVID-19 infections, which is particularly important to the immunocompromised and high-risk populations.
In one aspect, the invention generally relates to a method for modulating ACE2 expression in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising BUDC.
In another aspect, the invention generally relates to a method for reducing ACE2 expression, comprising administering to a subject in need thereof a pharmaceutical composition comprising BUDC.
In yet another aspect, the invention generally relates to a method for suppressing farnesoid X receptor (FXR) signaling in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising BUDC.
In yet another aspect, the invention generally relates to a method for preventing or delaying infection of SARS-CoV-2 or a variant thereof, or a related disease or disorder, comprising administering to a subject in need there of a pharmaceutical composition comprising BUDC.
In yet another aspect, the invention generally relates to a method for treating infection of SARS-CoV-2 or a variant thereof, or a related disease or disorder, comprising administering to a subject in need there of a pharmaceutical composition comprising BUDC.
In yet another aspect, the invention generally relates to a method for preventing or treating post-COVID conditions, or a related disease or disorder, comprising administering to a subject in need there of a pharmaceutical composition comprising BUDC.
In yet another aspect, the invention generally relates to a method for modulating ACE2 expression in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
In yet another aspect, the invention generally relates to a method for reducing ACE2 expression, comprising administering to a subject in need thereof a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
In yet another aspect, the invention generally relates to a method for suppressing FXR signaling in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
In yet another aspect, the invention generally relates to a method for preventing or delaying infection of SARS-CoV-2 or a variant thereof, or a related disease or disorder, comprising administering to a subject in need there of a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
In yet another aspect, the invention generally relates to a method for treating infection of SARS-CoV-2 or a variant thereof, or a related disease or disorder, comprising administering to a subject in need there of a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
In yet another aspect, the invention generally relates to a method for preventing or treating post-COVID conditions, or a related disease or disorder, comprising administering to a subject in need there of a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
In yet another aspect, the invention generally relates to use of BUDC for the manufacture of a medicament for prevention or treatment of SARS-CoV-2 infection.
In yet another aspect, the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for prevention or treatment of SARS-CoV-2 infection.
In yet another aspect, the invention generally relates to use of BUDC for modulating ACE2 expression.
In yet another aspect, the invention generally relates to use of BUDC for suppressing FXR signaling.
In yet another aspect, the invention generally relates to use of BUDC for preventing or treating SARS-CoV-2 infection.
In yet another aspect, the invention generally relates to use of BUDC for preventing or treating post-COVID conditions, or a related disease or disorder.
In yet another aspect, the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for modulating ACE2 expression.
In yet another aspect, the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for suppressing FXR signaling.
In yet another aspect, the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for preventing or treating SARS-CoV-2 infection.
In yet another aspect, the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for preventing or treating post-COVID conditions, or a related disease or disorder.
In yet another aspect, the invention generally relates to a unit dosage form for use in preventing and/or treating SARS-CoV-2 infection or post-COVID conditions, or a related disease or disorder, comprising a therapeutically effective amount of BUDC.
In yet another aspect, the invention generally relates to a unit dosage form for use in preventing and/or treating SARS-CoV-2 infection or post-COVID conditions, or a related disease or disorder, comprising therapeutically effective amounts of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
In certain embodiments, methods of treatment and/or prevention disclosed herein further comprise administering to a subject in need thereof a second therapeutic agent, e.g., an antiviral agent, a nucleos (t) ide inhibitor or a protease inhibitor, a steroid, an antibody therapy.
In certain embodiments of the methods disclosed herein, BUDC is administered at a daily dosage in the range of about 0.1 mg to about 3,000 mg (e.g., about 1 mg to about 3,000 mg, about 10 mg to about 3,000 mg, about 50 mg to about 3,000 mg, about 100 mg to about 3,000 mg, about 0.1 mg to about 2,000 mg, about 0.1 mg to about 1,000 mg, about 0.1 mg to about 500 mg, about 1 mg to about 500 mg) for a time period of about 1 to about 30 days (e.g., about 1 to about 3 days, about 3 to about 5 days, about 5 to about 7 days, about 7 to about 14 days, about 14 to about 30 days) .
In certain embodiments, BUDC is administered at a daily dosage in the range of about 1 mg to about 500 mg (e.g., about 5 mg to about 500 mg, about 10 mg to about 500 mg, about 25 mg to about 500 mg, about 50 mg to about 500 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 5 mg to about 250 mg, about 10 mg to about 200 mg) for a time period of about 1 to about 30 days (e.g., about 1 to about 3 days, about 3 to about 5 days, about 5 to about 7 days, about 7 to about 14 days, about 14 to about 30 days) .
In certain embodiments, the pharmaceutical composition of BUDC disclosed herein comprises a pharmaceutically acceptable excipient, carrier, or diluent.
In certain embodiments of the methods disclosed herein, the total amount of BBR and UDCA are administered at a daily dosage in the range of about 0.1 mg to about 3,000 mg (e.g., about 1 mg to about 3,000 mg, about 10 mg to about 3,000 mg, about 50 mg to about 3,000 mg, about 100 mg to about 3,000 mg, about 0.1 mg to about 2,000 mg, about 0.1 mg to about 1,000 mg, about 0.1 mg to about 500 mg, about 1 mg to about 500 mg) for a time period of about 1 to about 30 days (e.g., about 1 to about 3 days, about 3 to about 5 days, about 5 to about 7 days, about 7 to about 14 days, about 14 to about 30 days) .
In certain embodiments, the total amount of BBR and UDCA is administered at a daily dosage in the range of about 1 mg to about 500 mg (e.g., about 5 mg to about 500 mg, about 10 mg to about 500 mg, about 25 mg to about 500 mg, about 50 mg to about 500 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 5 mg to about 250 mg, about 10 mg to about 200 mg) for a time period of about 1 to about 30 days (e.g., about 1 to about 3 days, about 3 to about 5 days, about 5 to about 7 days, about 7 to about 14 days, about 14 to about 30 days) .
In certain embodiments, the weight ratio of BBR to UDCA is in the range of about 3: 1 to about 1: 3 (e.g., 2: 1 to 1: 3, 1: 1 to 1: 3, 3: 1 to 1: 2, 3: 1 to 1: 1, about 1: 1) .
In certain embodiments, the pharmaceutical composition of BBR and UDCA disclosed herein comprises a pharmaceutically acceptable excipient, carrier, or diluent.
Various solid and crystalline forms of BUDC may be employed in the invention disclosed herein.
In certain embodiments, Form A of BUDC, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values selected from the group consisting of: 3.98, 7.06, 7.34, 7.93, 8.79, 9.47, 11.70, 11.94, 12.34, 12.55, 13.90, 14.17, 15.14, 15.50, 16.16, 16.54, 16.78, 17.53, 17.67, 18.23, 19.03, 19.98, 20.87, 21.13, 21.96, 23.49, 24.24, 24.97, 25.50, 26.63, 27.60, 28.06, 28.63, 29.40 and 30.49° (± 0.2°) obtained using Cu Kα radiation (
intensity ratio λ2/λ1 = 0.50) , is employed.
In certain embodiments, Form B of BUDC, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values selected from the group consisting of: 7.39, 9.31, 12.41, 13.14, 14.37, 14.76, 15.53, 18.65, 21.79, 22.87, 25.27, 25.53 and 28.12° (± 0.2°) obtained using Cu Kα radiation (intensity ratio λ2/λ1 = 0.50) , is employed.
In certain embodiments, Form C of BUDC, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values selected from the group consisting of: 7.23, 10.42, 12.10, 13.37, 14.24, 14.48, 15.28, 15.95, 17.00, 18.17, 20.12, 21.77 and 25.47° (± 0.2°) obtained using Cu Kα radiation (intensity ratio λ2/λ1 = 0.50) , is employed.
In certain embodiments, Form D of BUDC, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values selected from the group consisting of: 4.24, 6.79, 8.50, 10.25, 11.50, 13.62, 14.74, 15.20, 17.92, 18.39, 22.91 and 25.73° (± 0.2°) obtained using Cu Kα radiation (intensity ratio λ2/λ1 = 0.50) , is employed.
In certain embodiments, Form E of BUDC, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values selected from the group consisting of: 8.59, 10.55, 11.36, 11.86, 12.46, 13.08, 13.38, 14.34, 15.57, 17.24, 17.72, 18.43, 19.66, 19.84, 20.35, 20.91, 21.36, 21.95, 23.21, 24.67, 25.04, 25.82, 26.12, 27.01, 27.84, 28.97, 30.35, 33.33, 34.54 and 36.06° (± 0.2°) obtained using Cu Kα radiation (
intensity ratio λ2/λ1 = 0.50) , is employed.
In certain embodiments, Form H of BUDC, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values selected from the group consisting of: 13.05, 14.63 and 25.46° (± 0.2°) obtained using Cu Kα radiation (
intensity ratio λ2/λ1 = 0.50) , is employed.
In certain embodiments, Form I of BUDC, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values selected from the group consisting of: 4.19, 7.64, 10.03, 13.32, 13.84, 14.83, 16.73, 22.73, 25.61 and 28.57° (± 0.2°) obtained using Cu Kα radiation (intensity ratio λ2/λ1 = 0.50) , is employed.
In certain embodiments, Form J of BUDC, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values selected from the group consisting of: 4.61, 6.32, 7.38, 8.22, 9.21, 10.57, 11.73, 12.13, 12.62, 12.96, 13.87, 14.55, 14.78, 15.81, 16.48, 17.69, 18.39, 19.01, 20.06, 21.25, 22.13, 23.20, 24.47, 24.89, 26.31, 27.98, 30.25 and 33.35° (± 0.2°) obtained using Cu Kα radiation (intensity ratio λ2/λ1 = 0.50) , is employed.
In certain embodiments, Form P of BUDC, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values selected from the group consisting of: 3.11, 5.01, 5.78, 7.26, 9.20, 10.10, 10.79, 11.65, 13.70, 14.59, 15.22, 16.19, 16.54, 17.05, 18.06, 18.68, 20.52, 21.09, 21.73, 22.49, 24.73, 25.42, 25.94 and 30.11° (± 0.2°) obtained using Cu Kα radiation (intensity ratio λ2/λ1 = 0.50) , is employed.
In certain embodiments, Form W of BUDC, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values selected from the group consisting of: 6.49, 7.16, 8.51, 10.21, 12.01, 13.13, 13.90, 14.42, 15.18, 15.57, 16.03, 16.45, 16.74, 17.08, 17.85, 18.39, 19.61, 20.43, 21.39, 21.70, 23.51 and 25.21° (± 0.2°) obtained using Cu Kα radiation (intensity ratio λ2/λ1 = 0.50) , is employed.
In certain embodiments, Form X of BUDC, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values selected from the group consisting of: 3.63, 6.61, 7.24, 10.49, 11.95, 13.51, 14.26, 14.54, 15.14, 16.01, 16.82, 18.28, 20.26, 21.08, 21.49, 21.90, 25.60, 26.40, 27.31, 29.34, 30.59, 31.01, 34.04, 34.68 and 36.91° (± 0.2°) obtained using Cu Kα radiation (intensity ratio λ2/λ1 = 0.50) , is employed.
In certain embodiments, the solid or crystalline form (e.g., Form A of BUDC) is a hydrate of BUDC. In certain embodiments, the solid or crystalline form (e.g., Form A of BUDC) is a hemi-nonahydrate of BUDC.
In certain embodiments, the solid or crystalline form (e.g., Form A of BUDC) is crystalline. In certain embodiments, the crystalline form is characterized in a monoclinic crystal system and P21 space group. In certain embodiments of the crystalline form, each unit cell contains two asymmetric units and there are two BBR cations, two UDCA anions and nine H2O molecules per asymmetric unit, and four BBR cations, four UDCA anions and eighteen H2O molecules per unit cell.
Possible formulations include those suitable for oral, sublingual, buccal, parenteral (for example subcutaneous, intramuscular, or intravenous) , rectal, topical including transdermal, intranasal and inhalation administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. General principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry” , Thomas Sorrell, University Science Books, Sausalito: 2006.
As used herein, the term “effective amount” of an active agent refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the patient.
As used herein, the term “treating” , “reducing” , or “preventing” a disease or disorder” refers to ameliorating such a condition before or after it has occurred. As compared with an equivalent untreated control, such reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100%as measured by any standard technique.
As used herein, the term “pharmaceutically acceptable excipient, carrier, or diluent” refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
As used herein, the term “subject” refers to any animal (e.g., a mammal) , including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms “subject” and “patient” are used interchangeably herein in reference to a human subject.
Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% ( “substantially pure” ) , which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99%pure.
The following examples are meant to be illustrative of the practice of the invention, and not limiting in any way.
Examples
Efficacy of Compound Berberine Ursodeoxycholate (BUDC, a.k.a. HTD1801) Against SARS-CoV-2 Infection of Syrian Hamsters
The experiment was carried out to study the in vivo efficacy of HTD1801 in SARS-CoV-2 infected hamster model. Ursodeoxycholate, a compound with known efficacy against SARS-CoV-2, was used as positive control at a dose approximately equimolar to the HTD1801 dose. Both compounds were administered orally (p.o. ) , starting 7 days before challenge and continued for the duration of the study.
Experimental Design
The experiment was performed on Syrian hamsters. These animals express the wild-type hamster ACE2 receptor for SARS-CoV-2, which is homologous to human ACE2 and makes the hamsters susceptible for SARS-CoV-2 infection.
Approximately 100 g male Syrian hamsters were purchased from Envigo. The hamsters were group-housed in OptiMice cages (3 hamsters per cage) in the ABSL-3 suite. The animals were fed standard rodent chow and water ad libitum. All experiments were performed in accordance with federal regulations and following SLU AUP#2913.
Virus Challenge and Drug Treatment
The hamsters were randomly assigned to 4 groups with 9 hamsters in each: Normal control, Model control, HTD1801 treatment group and UDCA treatment group. Starting on Day 7, the appropriate doses of HTD1801, UDCA or 0.5%CMC were administered to the hamsters. Treatment continued daily for the duration of the experiment. At Day 0, hamsters in Group 1 received virus vehicle, while all other animals received 5x103 focus forming unit (FFU) of SARS-CoV-2 by intranasally inoculated (Table 1) . The hamsters infected with SARS-CoV-2 began to appear hunch-backed, ruffled, and showed progressive weight loss over the days that followed. Measurable outcomes included body weight loss, survival, virus burden in select organs, histopathology, etc.
Table 1. Groupings
Drug Formulation
HTD1801 and UDCA compounds were prepared in single batches. Both compounds were suspended in 0.5%carboxymethylcellulose (CMC) , sonicated to visual homogeneity, and stored at 4℃ with continuous stirring.
Monitoring and Endpoints
Body weights were recorded during the study period. Cage side observations were recorded daily.
Hamsters were sacrificed at Day 4 for virological analyses. The left lung was snap-frozen in dry-ice, while the right lung was preserved in 10%neutral buffered formalin (NBF) . The NBF-fixed right lung samples were saved. The left lung samples were used to determine the infectious virus titers using a focus-formation assay. Briefly, the frozen lung samples were weighed and homogenized, and the clarified supernatant was used to infect Vero E6 cells. After 24 h, the infected cells were fixed and immunostained for the presence of SARS-CoV-2. The stained foci were counted using an Elispot reader.
Data Analysis
All data were analyzed using the appropriate statistical analysis methods with GraphPad Prism software. The data were expressed as the mean ± SD. The difference was considered to be significant when P < 0.05.
Results
Formulation
Test compounds were formulated as described in Experimental Design. Particulate matters settled out from the suspensions of both HTD1801 and UDCA. The resulting suspensions were stored with continuous stirring on a magnetic stirrer. The aliquots of suspensions were vortexed before being drawn into a syringe for dosing.
In-life Observations
At the beginning of the study, the dose of HTD1801 in G3 group was set at 800 mg/kg, while the dose of UDCA in G4 group was 800mg/kg. Daily administration of HTD1801 p.o. at 800 mg/kg for 5 consecutive days (Day -7 to Day -3) caused a delay in weight gain compared to vehicle or UDCA treatment (FIG. 1) . This was possibly due to the weight reduction efficacy of HTD1801, which has been proven in non-clinical and clinical studies. Considering animal tolerance, staring from Day -2, the dose of HTD1801 was changed to 400 mg/kg p.o. q.d, while the dose of UDCA was adjusted to 400 mg/kg correspondingly. However, the HTD1801-treated hamsters continued to lose weight (FIG. 1) .
From 2 days after virus challenge, hamsters in all three virus-infected groups (G2, G3 and G4) continued to lose weight until they were sacrificed. (FIG. 2A) . There were no significant difference in the rate of weight change (compared to their body weight at Day 0) between the three virus-infected groups (FIG. 2B) . Neither HTD1081 nor UDCA mitigated the body weight loss induced by intranasal infection with SARS-CoV-2.
Necropsy
Four days post challenge, the hamsters in all three virus-infected groups (G2, G3 and G4) had dark-red mottled, rubbery lungs that did not deflate after opening of the thoracic cavity. No other significant findings were noted.
Compared to the G1, the virus-infected hamsters (G2) had increased lung weight, indicating inflammation (FIG. 3) . The lung weights of the HTD1801-treated hamsters (G3) were marginally lower, compared to the G2 group, although the differences did not reach statistical significance.
Virus Titers in the Lung
Four days post challenge, live, infectious virus was recovered from the lung of the hamsters in all three virus-infected groups. Both HTD1801 (G3) and UDCA (G4) showed decreased virus titer in lung compared to the vehicle group (G2) ; however, the decrease was statistically significant only for HTD1801 (p﹤0.05) (FIG. 4)
Based on measurements of lung weight and lung viral burden, administration of 400 mg/kg HTD1801 was shown to have inhibit viral replication in the lung of hamsters and reduced inflammation.
Applicant’s disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to “one embodiment, ” “an embodiment, ” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment, ” “in an embodiment, ” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.
The described features, structures, or characteristics of Applicant’s disclosure may be combined in any suitable manner in one or more embodiments. In the description, herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant’s composition and/or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.
In this specification and the appended claims, the singular forms "a, " "an, " and "the" include plural reference, unless the context clearly dictates otherwise.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.
Incorporation by Reference
References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.
Equivalents
The representative examples disclosed herein are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. The above examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.
Claims (26)
- A method for modulating ACE2 expression in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising BUDC.
- A method for reducing ACE2 expression, comprising administering to a subject in need thereof a pharmaceutical composition comprising BUDC.
- A method for suppressing farnesoid X receptor (FXR) signaling in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising BUDC.
- A method for preventing or delaying infection of SARS-CoV-2 or a variant thereof, or a related disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising BUDC.
- A method for treating infection of SARS-CoV-2 or a variant thereof, or a related disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising BUDC.
- A method for preventing or treating post-COVID conditions, or a related disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising BUDC.
- A method for modulating ACE2 expression in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
- A method for reducing ACE2 expression, comprising administering to a subject in need thereof a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
- A method for suppressing farnesoid X receptor (FXR) signaling in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
- A method for preventing or delaying infection of SARS-CoV-2 or a variant thereof, or a related disease or disorder, comprising administering to a subject in need there of a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
- A method for treating infection of SARS-CoV-2 or a variant thereof, or a related disease or disorder, comprising administering to a subject in need there of a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
- A method for preventing or treating post-COVID conditions, or a related disease or disorder, comprising administering to a subject in need there of a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
- Use of BUDC for the manufacture of a medicament for prevention or treatment of SARS-CoV-2 infection, or a related disease or disorder.
- Use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for prevention or treatment of SARS-CoV-2 infection, or a related disease or disorder.
- Use of BUDC for modulating ACE2 expression.
- Use of BUDC for reducing ACE2 expression.
- Use of BUDC for suppressing farnesoid X receptor (FXR) signaling.
- Use of BUDC for preventing or treating SARS-CoV-2 infection, or a related disease or disorder.
- Use of BUDC for preventing or treating post-COVID conditions, or a related disease or disorder.
- Use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for modulating ACE2 expression.
- Use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for reducing ACE2 expression.
- Use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for suppressing farnesoid X receptor (FXR) signaling.
- Use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for preventing or treating SARS-CoV-2 infection, or a related disease or disorder.
- Use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for preventing or treating post-COVID conditions, or a related disease or disorder.
- A unit dosage form for use in preventing and/or treating SARS-CoV-2 infection or post-COVID conditions, or a related disease or disorder, comprising a therapeutically effective amount of BUDC.
- A unit dosage form for use in preventing and/or treating SARS-CoV-2 infection or post-COVID conditions, or a related disease or disorder, comprising therapeutically effective amounts of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US63/430,932 | 2022-12-07 | ||
| US63/432,044 | 2022-12-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2024120452A1 true WO2024120452A1 (en) | 2024-06-13 |
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