Method of treatment for reducing pulmonary inflammation in a patient with pathogen infection using oral prostacyclin analog drugs

Abstract

A method of reducing mortality in a human patient with pulmonary inflammation due to coronavirus or other pathogen, the method including administering an oral dose of a prostacyclin analog drug to the patient within a therapeutic window. The prostacyclin analog drug includes oral iloprost or iloprost betadex clathrate.

Claims

1. A method of treating a human patient having a corona virus strain infection in order to reduce progression of the corona virus strain infection in the human patient, the method comprising: determining whether the corona virus strain consists essentially of Covid-19, 229E (alpha), NL63 (alpha), OC43 (beta), HKU1 (beta), MERS-CoV or SARS-CoV; then determining a stage of severity of the corona virus infection in the human patient; if the stage of severity is moderate to severe then administering an oral dose of iloprost or iloprost betadex clathrate to the human patient within a therapeutic window; wherein the oral dose of iloprost or iloprost betadex clathrate is substantially in a range of 50-150 micrograms administered twice daily; and maintaining the human patient within a defined therapeutic range.

2. The method of claim 1 further comprising subjecting the human patient to therapeutic drug monitoring.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) The following disclosure describes a method of treating pulmonary inflammation and related diseases such as pneumonia using a prostacyclin analog drug. Several features of methods and systems in accordance with example embodiments are set forth and described herein. It will be appreciated that methods in accordance with other example embodiments can include additional procedures or features different than those specifically described. Example embodiments are described herein with respect to treatment of a Covid-19 virus infection with orally administered iloprost (a prostacyclin analog). However, it will be understood that these examples are for the purpose of illustrating the principles, and that the invention is not so limited.

Definitions

(2) Generally, as used herein, the following terms have the following meanings, unless the use in context dictates otherwise:

(3) The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims or the specification means one or more than one, unless the context dictates otherwise. The term “about” means the stated value plus or minus the margin of error of measurement or plus or minus 10% if no method of measurement is indicated. The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or if the alternatives are mutually exclusive. The terms “comprise”, “have”, “include” and “contain” (and their variants) are open-ended linking verbs and allow the addition of other elements when used in a claim.

(4) Reference throughout this specification, the use of “one example” or “an example embodiment,” “one embodiment,” “an embodiment” or combinations and/or variations of these terms means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

(5) “Iloprost” as used herein is an anti-inflammation agent which comprises a synthetic analogue of prostacyclin PGI). Its formulation may include iloprost betadex clathrate.

(6) “Object” means an individual cell, human cell, mammal cell, item, thing or other entity.

(7) “Subject” as used herein means a human patient.

(8) “Therapeutic window” (or “pharmaceutical window”) of a drug as used herein is the range of drug dosages over time which can treat disease effectively without having toxic effects.

(9) “Therapeutic range” of a drug as used herein is the dosage range or blood plasma or serum concentration usually expected to achieve the desired therapeutic effect. In order to maintain a patient within a defined therapeutic range, they may be subject to therapeutic drug monitoring during the therapeutic window.

(10) In accordance with the invention herein, a prostacyclin analog drug may comprise iloprost in a form suitable for oral administration including tablets, troches, pills, capsules and the like. The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin can be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, including a liquid carrier. Various other materials can be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules can be coated with shellac, sugar or both. A syrup or elixir can contain the prostacyclin analog, sucrose as a sweetening agent, methyl and propylparabens a preservative, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the prostacyclin analog can be incorporated into sustained-release preparations and formulation.

(11) Iloprost, Inflammation, and COVID-19 Treatment

(12) Iloprost, a synthetic analogue of prostacyclin PGI2, is an excellent candidate for the treatment of COVID-19. Iloprost has been in use for decades as an effective therapeutic agent for the treatment of moderate to severe pulmonary arterial hypertension (PAH), usually in inhaled form. Perhaps the best evidence that iloprost will be an effective treatment of COVID-19 is a recently proposed Phase II clinical trial for the treatment of ARDS (Haeberle et al., 2020). In addition to its anti-inflammatory properties described below, through target-based virtual ligand screening, iloprost has been identified as a molecule with the potential to block the binding of the virus to its cellular receptor (Wu et al., 2020).

(13) Iloprost has been shown to reduce pulmonary inflammation in several animal studies. These studies include a pressure-induced model of lung injury (Birukova et al., 2010), ischemia-reperfusion (IR) injury (Kawashima et al., 2003; Yasa et al., 2008; Erer et al., 2014 and 2016); and porcine models of ARDS (Dembinski et al., 2005; Witter et al., 2005a and 2005b). One study with human patients demonstrated that iloprost improved gas exchange in patients with pulmonary hypertension and ARDS (Sawheny et al., 2013).

(14) There are several mechanisms by which iloprost has been shown to reduce pulmonary inflammation, including the cyclooxygenase-2 (COX-2) system with involvement of lipoxin A4 (Scully et al., 2012), Ras-related protein 1 (RAP-1) (Burkova, 2009), and IL-1β (Crutchley et al., 1994; Della Bella et al., 1997; Zor et al., 2010; Lammi et al., 2016), a critical component of lung inflammation during viral infection (Kim et al., 2015). Iloprost/prostacyclin suppresses inflammation through other pathways. Iloprost has been shown to possess anti-inflammatory and immunomodulating actions in vitro (Jores et al., 1997; Medsger et al., 1999; Czeslick et al., 2003; Zhou et al., 2007) and in vivo (Jaffar et al.; 2002; Di Renzo et al.; 2005; Zhou et al., 2007; Leibbrandt et al., 2008). Mechanisms by which iloprost reduces inflammation include its activity in reducing TNF-α production by T cells and the number of T regulatory cells, as well as in increasing IL-2 and RANKL (D'Amelio et al., 2010). In addition, iloprost has been shown to inhibit production of intracellular TNF-α and interleukin IL-6 in human monocytes (Czeslick et al., 2003).

(15) As mentioned above, iloprost is currently used to treat pulmonary arterial hypertension (PAH), scleroderma, Raynaud's syndroma. The synthesis of iloprost was developed by the pharmaceutical company Schering AG and is marketed by Bayer Schering Pharma AG in Europe. One advantageous formulation of iloprost is iloprost betadex clathrate; an oral formulation of the drug substance iloprost currently being used in clinical trials in the field of lung cancer and lung cancer prevention, but is not commercially available. However, this particular formulation would become commercially available upon FDA approval for clinical indications such as reduction of pulmonary dysplasia and conditions precedent to that, including pulmonary inflammation.

(16) In conclusion, an oral formulation of iloprost has been shown to have the properties required to be effective at treating COVID-19 infection, because it has been shown to be effective at inhibiting many of the pro-inflammatory molecules that result in the cytokine storm. In addition, at least theoretically, an oral formulation iloprost has the potential to block infection.

(17) Advantages of Iloprost Over Other Drugs for Treatment of COVID-19

(18) Unlike the other agents listed above, iloprost works through multiple pathways to inhibit pulmonary inflammation. In addition, Iloprost causes dilation of narrowed blood vessels in the lungs, decreasing pulmonary blood pressure and improving lung function. Iloprost has been used successfully for many years to treat pulmonary arterial hypertension (PAH) and Reynaud's syndrome and has no contraindications and minimal side effects.

(19) Advantage of Oral Iloprost Over Inhaled Iloprost

(20) The advantages of oral iloprost over the inhaled formulation (e.g., Ventavis) are based on dosing and serum levels, and on patient comfort and convenience. The half-life of inhaled iloprost is only 20 to 30 minutes. Following inhalation of iloprost (5 mcg) patients with pulmonary hypertension have iloprost peak serum levels of approximately 150 pg/mL, with Iloprost generally not detectable in the plasma 30 minutes to 1 hour after inhalation (accessdata.fda.gov). In contrast, oral iloprost is similar to infused iloprost with steady-state serum levels of 260 pg/mL (Hildebrand, 1997).

(21) The recommended dose of inhaled iloprost is as follows: “Ventavis should be taken 6 to 9 times per day (no more than once every 2 hours) during waking hours, according to individual need and tolerability. The maximum daily dose evaluated in clinical studies was 45 mcg (5 mcg 9 times per day).” As a result of this dosing, lung and serum levels of inhaled iloprost drops to zero as the patient sleeps. Therefore, for severe PAH, the dosing is around the clock.

(22) There are other dosing problems with inhaled medications that do not occur with oral delivery. These problems include shallow breathing in patients with respiratory disease (Kallet et al., 2007), sub-optimal use of inhalers (Price et al., 2013; Lavorini, 2013), and uneven distribution in the lungs with reduced deposition in distal regions (Berridge et al., 2000).

(23) In general, dosing with inhaled medications can cause undesirable spiking of the drug in a patient, making it difficult to maintain a therapeutic dosage between drug dosing. Dosing orally avoids such spiking effects.

(24) Oral Iloprost Dosage

(25) U.S. Pat. No. 8,623,917, entitled “Uses of Prostacyclin Analogs,” issued Jan. 7, 2014 to Keith et al. discloses a method for reducing a risk of developing lung cancer in a human former smoker. U.S. Pat. No. 8,623,917 (the Keith patent) is incorporated herein by reference. Although directed to treat dysplasia in subjects with high-risk for lung cancer, the Keith patent is informative with respect to dosages of iloprost that are within the therapeutic window (or pharmaceutical window) for oral iloprost. The method taught in the Keith patent comprises administering a therapeutically effective amount of prostacyclin analog comprising iloprost to the former smoker such that the risk of developing lung cancer in the former smoker is decreased by at least 10% relative to a control group with similar risk factors.

(26) According to the Keith patent, the therapeutic dosage can generally be from about 0.1 to about 1,000 nicrograms/day, and preferably from about 10 to about 100 micrograms/day, or from about 0.1 to about. 50 micrograms/Kg of body weight per day and preferably from about 0.1 to about 20 micrograms/Kg of body weight per day and can be administered in several different dosage units. Higher dosages, on the order of about 2× to about 4×, may be required for oral administration.

(27) In a later paper, Keith et al. found that “Following randomization, subjects were started on either iloprost or placebo at an initial dose of 1 sustained-release capsule twice daily (BID) (50 micrograms of iloprost clathrate, per capsule). The subjects had a monthly clinical evaluation and if well tolerated, iloprost or placebo was dose escalated by 1 capsule BID to a maximum dose of 3 capsules BID.” (Keith et al., 2020).

(28) In another study using oral iloprost for treatment of Raynaud's syndrome it was found that there were no serious adverse reactions or events following a protocol administering iloprost in a dosing range of 50-150 micrograms BID (Belch et al. 1995). The protocol implemented was to treat the subjects with one capsule twice on the first day. On the second day two capsules were administered BID and on the third day three capsules BID. The maximum tolerated dose was used for the remaining seven days of this study.

(29) In another study of asymptomatic volunteers, therapeutic efficacy was shown after i.v. infusion treatment in several states of peripheral vascular disease. It was recommended that for out-patient therapy an oral dosage form should be developed. Based upon dissolution profiles and in vivo data of a pig model, three different film-coated pellet formulations were selected for pharmacokinetic characterization in nine healthy volunteers. In the first part of the study groups of three test subjects were treated with increasing dosages (150-300 micrograms) of iloprost. At 300 micrograms flushing and headache led to the discontinuation of those escallations. All formulations exhibited dose-dependent serum level profiles. The cross-over characterization in all test subjects showed that one formulation, which exhibited a modified in vitro dissolution of 60% of the dose within 1 hour in pH 7.4 phosphate buffer, was optimal from the pharmacokinetic profile. After oral administration of this formulation the bioavailable dose fraction was highest and half-maximal serum levels lasted for 2.4 hours (mean); therapeutic serum levels were maintained for 2.1-5.0 hours. This formulation was chosen for further investigation to imitate therapeutic serum level profiles as obtained after i.v. infusion for 4-6 hours with a once-a-day dosage form (Hildebrand M, et al., 1991). In one example, extrapolating from these studies, dosages for treating pulmonary inflammation due to a coronavirus strain including, for example, Covid-19, 229E (alpha), NL63 (alpha), OC43 (beta), HKU1 (beta), MERS-CoV and/or SARS-CoV may be substantially in the range of 50-150 microgram administered to a patient twice per day (BID) to remain within a therapeutic dosage. Higher dosages may be used if indicated and tolerated by the patient.

(30) In one example, a method of reducing mortality in a human patient with pulmonary inflammation due to coronavirus or other pathogens, where the method comprises administering an oral dose of a prostacyclin analog drug to the patient within a therapeutic window.

(31) In another example of a method of reducing mortality in a human patient with pulmonary inflammation due to coronavirus or other pathogens, the prostacyclin analog drug consists essentially of iloprost or iloprost betadex clathrate.

(32) In another example of a method of reducing mortality in a human patient with pulmonary inflammation due to coronavirus or other pathogens, the oral dose is substantially in the range of 50-150 micrograms of iloprost or iloprost betadex clathrate administered twice daily (BID).

(33) In another example the human patient is maintained within a defined therapeutic range while subjecting the human patient to therapeutic drug monitoring.

(34) In another example, method of treating a human patient having a coronavirus infection in order to reduce progression of the corona virus infection in the human patient comprises determining a stage of severity of the infection in the human patient; and if the stage of severity is moderate to severe then administering an oral dose of a prostacyclin analog drug to the human patient within a therapeutic window.

(35) In another example of a method of treating a human patient having a coronavirus infection in order to reduce progression of the corona virus infection, the prostacyclin analog drug consists essentially of oral iloprost or iloprost betadex clathrate.

(36) In another example of a method of treating a human patient having a coronavirus infection in order to reduce progression of the corona virus infection, the oral dose is substantially in the range of 50-150 micrograms of iloprost administered twice daily (BID).

(37) In another example of a method of treating a human patient having a coronavirus infection in order to reduce progression of the corona virus infection, the method further comprises maintaining the human patient within a defined therapeutic range and the human patient is subjected to therapeutic drug monitoring.

(38) In another example, a method of treating a human patient having a Covid-19 virus infection in order to reduce progression of the Covid-19 virus infection in the human patient, comprises determining a stage of severity of the Covid-19 virus infection in the human patient; if the stage of severity is moderate to severe then administering an oral dose of iloprost or iloprost betadex clathrate to the human patient within a therapeutic window; wherein the oral dose of iloprost or iloprost betadex clathrate is substantially in the range of 50-150 micrograms administered twice daily (BID); and maintaining the human patient within a defined therapeutic range.

(39) In another example, a method of treating a human patient having a Covid-19 virus infection in order to reduce progression of the Covid-19 virus disease in the human patient, the method further comprises subjecting the human patient to therapeutic drug monitoring.

(40) In another example, a method of treating a human patient having a corona virus strain infection in order to reduce progression of a coronavirus virus strain infection in the human patient comprises determining whether the corona virus strain consists essentially of Covid-19, 229E (alpha), NL63 (alpha), OC43 (beta), HKU1 (beta), MERS-CoV or SARS-CoV; then determining a stage of severity of the corona virus infection in the human patient; if the stage of severity is moderate to severe then administering an oral dose of iloprost or iloprost betadex clathrate to the human patient within a therapeutic window; wherein the oral dose of iloprost or iloprost betadex clathrate is substantially in the range of 50-150 micrograms administered twice daily (BID); and maintaining the human patient within a defined therapeutic range.

(41) In another example, a method of treating a human patient having a corona virus infection in order to reduce progression of a coronavirus strain virus disease in the human patient further comprises subjecting the human patient to therapeutic drug monitoring.

(42) The invention has been described herein in considerable detail in order to comply with the Patent Statutes and to provide those skilled in the art with the information needed to apply the novel principles of the present invention, and to construct and use such exemplary and specialized components as are required. However, it is to be understood that the invention may be carried out by different equipment, and devices, and that various modifications, both as to the equipment details and operating procedures, may be accomplished without departing from the true spirit and scope of the present invention.

REFERENCES

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