NEW DOSAGE REGIMEN FOR INHALED VASOACTIVE INTESTINAL POLYPEPTIDE

Abstract

The present invention relates to new improved and effective administration regimen of aviptadil in order to reduce and eliminate the risks of nebulization treatment and to protect both patient relatives and healthcare workers especially in pandemic conditions such as Covid-19. Here, said dosage regimen of aviptadil for use in the treatment of lung diseases in a subject in need by thereof aims to reduce the dosing frequency. Accordingly, aviptadil is administered at least 2 times in a day and wherein the period between the administrations does not exceed 200 minutes.

Claims

1. A method of treating a lung disease in a patient in need thereof comprising administering to the patient aviptadil at least 2 times in a day wherein the period between administrations is between 5 to 200 minutes.

2. The method according to claim 1, wherein aviptadil is administered 2 times in a day.

3. The method according to claim 1, wherein the first dose of aviptadil is between 1 to 150 μg.

4. The method according to claim 1, wherein the first dose of aviptadil is between 40 to 120 μg.

5. The method according to claim 1, wherein the first dose of aviptadil is 100 μg.

6. The method according to claim 1, wherein the second dose of aviptadil is between 1 to 150 μg.

7. The method according to claim 1, wherein the second dose of aviptadil is between 40 to 120 μg.

8. The method according to claim 1, wherein the second dose of aviptadil is 100 μg.

9. The method according to claim 1, wherein the period between administrations is between 15 to 120 minutes.

10. The method according to claim 1, a wherein the period between administrations is 30 minutes.

11. The method according to claim 1, wherein the treatment is continued for 5 to 21 days.

12. The method according to claim 1, wherein the administration is applied with a nebulizer.

13. The method according to claim 1, wherein the lung disease is selected from the group consisting of Covid-19 disease caused by SARS-CoV-2 virus, asthma, pulmonary hypertension, chronic obstructive pulmonary disease, sarcoidosis and berylliosis.

14. The method according to claim 1, wherein the lung disease is Covid-19 disease caused by SARS-CoV-2 virus.

15. The method according to claim 1, wherein the patients hospitalized are at the age of 60 or older with Covid-19 pulmonary involvement.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention provides a method of treating a lung disease in a subject in need thereof by administering of an effective dose of aviptadil to the subject.

[0019] In one embodiment, the present invention provides aviptadil for use in the treatment of a lung disease in a subject in need thereof wherein said composition is administered at least 2 times in a day, preferably 2 times in a day compared to the prior art administration regimes. Thus, the virus transmission is decreased by reducing the dosing frequency instead of giving aviptadil by nebulization 3 times a day. The inventors aim to protect both patient relatives and healthcare workers especially in pandemic conditions such as Covid-19.

[0020] According to the present invention, aviptadil for use in the treatment of a lung disease in a subject in need thereof is administered at least 2 times in a day, preferably 2 times in a day, wherein the period between the administrations does not exceed 200 minutes or preferably the period between the administrations is from 5 to 120 minutes; more preferably from 15 to 110 minutes, from 20 to 100 minutes, from 25 to 90 minutes or from 15 to 90 minutes and most preferably 30 minutes. It has been surprisingly found that by significantly reducing the period between the administrations of aviptadil it is possible to provide a treatment while reducing the spread of virus and to increase the patient compliance without any side effects.

[0021] In another embodiment of the present invention, aviptadil is administered three times in a day wherein the period between the administrations does not exceed 200 minutes or preferably the period between the administrations is from 5 to 120 minutes; more preferably from 15 to 90 minutes and most preferably 30 minutes.

[0022] In all embodiment of the present invention, the treatment is continued for between 3 to 30 days, preferably between 5 to 21 days and more preferably between 7 to 14 days.

[0023] Herein, the term “dose” is the amount of aviptadil that is to be administered at one time. The dose of aviptadil is between 1 to 150 μg, preferably between 40 to 120 μg and more preferably 100 μg.

[0024] According to the present invention, aviptadil is administered at least 2 times in a day. Thus, the administration comprises a first and second doses. The first dose of aviptadil is between 1 to 150 μg, preferably between 40 to 120 μg and more preferably 100 μg. The second dose of aviptadil is between 1 to 150 μg, preferably between 40 to 120 μg and more preferably 100 μg.

[0025] According to the present invention, aviptadil is used for the treatment of a lung disease; preferably Covid-19 disease caused by SARS-CoV-2 virus, asthma, pulmonary hypertension, chronic obstructive pulmonary disease, sarcoidosis or berylliosis; and more preferably Covid-19 disease caused by SARS-CoV-2 virus.

[0026] According to the present invention, the administration of aviptadil is applied with a nebulizer, preferably M-neb mobile mesh nebulizer MN-300/9.

[0027] In all embodiments, the present invention provides a pharmaceutical composition of aviptadil for pulmonary administration for use in the treatment of lung disease. The composition is suitable for being delivered by a nebulizer.

[0028] According to the present invention, the composition comprises aviptadil in the range of 0.001-1% w/v.

[0029] In one embodiment of the present invention, the composition of aviptadil comprises at least one additional excipient which may be preservatives, antioxidants, chelating agents, buffering agents, acidifying agents, emulsifiers, alkalizing agents, coloring agents, solubilizers, stabilizers, plasticizers, viscosity modifiers or other excipients which are known in the prior art.

[0030] The composition of the present invention may comprise at least one emulsifier which may be selected from the group consisting of polysorbates, lecithins, alginic acid, alginates, gums, salts of fatty acids, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylmethylcellulose, carboxymethylcellulose or combinations thereof.

[0031] The composition of the present invention may also comprise at least one chelating agent which may be selected from the group consisting of EDTA or one of the known salts thereof (tetrasodium EDTA, disodium EDTA or sodium EDTA), sodium metasilicate, DTPA, NT or combinations thereof.

[0032] The composition of the present invention may also comprise at least one buffering agent which may be selected from the group consisting of sodium citrate, citric acid, trisodium citrate, a carbonate buffer, a hydroxide buffer, a phosphate buffer and an acetate buffer or combinations thereof.

[0033] According to the present invention, the composition is a dispersion of particles of aviptadil having a mass median aerodynamic diameter (MMAD) between 1 and 5 μm.

[0034] In a preferred embodiment of the present invention, aviptadil for use in the treatment of the lung disease is in a salt form, preferably acetate salt.

[0035] The composition according to the present invention may be obtained by a process comprising the steps of mixing aviptadil with the excipients and of adjusting the pH of composition. The process also comprises the steps of filtration and filling. In the process, the excipients are solved in water and then aviptadil is added to the composition of excipients and solved. The pH is adjusted to 5.7. Sterile filtration and filling steps are executed.

EXAMPLES

Example 1

[0036] In the study, placebo and treatment groups were compared. In placebo group, standard medical treatment, as deemed appropriate by physicians, is going to be according to the Turkish Republic COVID-19 (SARS-CoV-2 INFECTION) ADULT PATIENT TREATMENT GUIDELINES published by the Ministry of Health, General Directorate of Public Health and placebo will be used.

[0037] Current formulation of Investigational Medicinal Product and Placebo were listed below (Table 1). Both of Investigational Medicinal Product and Placebo were manufactured as sterile and compatible with good manufacturing requirements.

TABLE-US-00001 TABLE 1 Contents of Investigational Medicinal Product and Placebo Investigational Medicinal Product (mg/vial) Placebo(mg/vial) Aviptadil* 0.100 — Sodium chloride 8.50 8.50 Trisodium citrate 0.50 0.50 Polysorbate 80 0.20 0.20 Disodium EDTA 0.46 0.46 Citric acid q.s. q.s. Water 1 ml 1 ml *added as acetate salt

[0038] In the treatment group, in addition to the standard medical treatment mentioned above, patients randomized to this arm will be given inhaled Aviptadil 2 times in a day wherein the period of administration between both doses is 30 minutes. M-neb mobile mesh nebulizer MN-300/9 was used for nebulization. Mass Median Aerodynamic Diameter is 4±0.16 μm. Aviptadil treatment is aimed to be a minimum of 7 days and a maximum of 14 days. The study population will consist of patients 18 years of age and older with COVID-19 pulmonary involvement and hospitalized patients. The Efficacy, Safety and Tolerability of Inhaled Aviptadil with New Posology were evaluated. The rate of patients entering intensive care was evaluated as efficacy parameter.

[0039] Results:

[0040] Our main target is developing a new dosage regimen for Aviptadil for use in Covid-19 patients with reduced risk of transmission of COVID-19 infection without side effects. 16 patients were enrolled in treatment group and 13 patients enrolled in placebo group. In this method, new dosage of inhaled Aviptadil is well tolerated by patients. 47 adverse events are observed in 27 patient and 40.43% percent of these adverse events observed in Treatment Group. None of adverse events was found related with Investigational Medicinal Product (Table 2).

TABLE-US-00002 TABLE 2 Adverse Event Distribution Adverse Events (AEs) Related with Investigational Medicinal Product No 47 Yes 0 Distribution of AEs (%) Treatment 40.43 Placebo 59.57

[0041] When the rate of patients entering intensive care was evaluated in treatment group in 60 years and older patients, it was observed that percent of entering intensive care was found 25% in treatment group and 66.7% in placebo group (Table 3).

TABLE-US-00003 TABLE 3 Age Related Distribution of Entering Intensive Care Entering Intensive Care (%) Age > = 60 Treatment 25.0% Placebo 66.7%

CONCLUSION

[0042] The present invention provides a new dosage regimen for Aviptadil for use in Covid-19 patients with reduced risk of transmission of COVID-19 infection without side effects. By this aim, performed study demonstrated that Investigational Medicinal Product was well tolerated by all patients and effective in the high-risk age group. No drug and posology related adverse event were observed in this dose regimen.