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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/12—Ketones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system

Definitions

• the present invention relates to composition for the management of Chronic obstructive pulmonary disease. More specifically, the invention pertains to compositions comprising bisdemethoxycurcumin for regeneration of alveoli and for the management of Chronic obstructive pulmonary disease and Acute respiratory distress syndrome.
• COPD chronic obstructive pulmonary disease
• Emphysema is a condition in which the alveoli at the end of the smallest air passages (bronchioles) of the lungs are destroyed.
• Emphysema is defined by the American Thoracic Society as follows: “Emphysema is a condition of the lung characterized by abnormal, permanent enlargement of the air spaces distal to the terminal bronchiole, accompanied by destruction of their walls.” It is a major component of COPD and is characterized by alveolar extracellular matrix destruction, reduction in the alveolar capillary exchange area, which leads to partially reversible airflow obstruction. This causes destruction of the fragile walls and elastic fibers of the alveoli causing collapse in the small airways collapse impairing airflow out of lungs.
• the signs and symptoms include Shortness of breath, especially during physical activities. Wheezing, Chest tightness, A chronic cough that may produce mucus, Frequent respiratory infections, Lack of energy, Unintended weight loss (in later stages), Swelling in ankles, feet or legs (Thullbeck et al., Emphysema: Definition, Imaging, and Quantification, Benjamin Felson lecture, AJR 1994;163:1017-1025),
• ARDS acute respiratory distress syndrome
• COPD chronic respiratory distress syndrome
• ARDS acute respiratory distress syndrome
• Type I alveolar cells are irreversibly damaged and there is deposition of proteins, fibrin, and cellular debris, producing hyaline membranes in the denuded space.
• Injury to the surfactant-producing type II cells also contributes to alveolar collapse.
• the type II cells proliferate with some epithelial cell regeneration, fibroblastic reaction, and remodelling in the proliferative phase (Udobi et al., Acute Respiratory Distress
• COPD may be a risk factor for more severe COVID-19 disease (Alqahtani et al. Prevalence, severity and mortality associated with COPD and smoking in patients with COVID-19: a rapid systematic review and meta-analysis. PLoS One 2020; 15: e0233147).
• the pathogenesis ofCOVID-19 can be divided into three phases: First phase of the disease is in the nose, second phase in conducting airways, the bronchi and bronchioles and the third phase of the disease is the lethal phase, as the infection spreads into the gas exchange portion of the lung and infects alveolar type II cells.
• Alveolar regeneration therapies are now being considered as an effective treatment for the management of COPD and ARDS.
• the ability of adult mammals to regenerate organs seems to be limited to only the liver.
• mammals can continually replace cells composing epidermis, gut endoderm, blood, neurons etc.
• retinoic acid can induce the regeneration of lung alveoli in the experimentally damaged adult rat lung.
• the present invention discloses natural and novel compositions for the regeneration of alveoli and for managing COPD and ARDS.
• Turmeric has different compounds of which curcumin, dimethoxy curcumin and bisdemethoxycurcmnin are the major players.
• the biological properties of curcumin, bisdemethoxycurcumin and demethoxycurcumin vary in different diseases and the effect of bidemethoxycurucmin in managing COPD and related functions is not evaluated.
• the present invention discloses the biological potential of a composition comprising bisdemethoxycurcumin in alveolar regeneration and in managing symptoms of COPD and ARDS.
• composition comprising not less than 20% w/w bisdemethoxycurcumin for use in preventing the progression of chronic obstructive pulmonary disease to acute respiratory distress syndrome.
• the invention discloses a method for regeneration of alveolar cells in mammals with emphysema, said method comprising step of administering a composition comprising not less than 20% w/w bisdemethoxycurcumin to said mammals to bring about a reduction in features of emphysema
• the invention discloses a method of therapeutic management of chronic obstructive pulmonary disease in mammals, said method comprising step of administering a composition comprising not less than 20% w/w bisdemethoxycurcumin to said mammals to bring about a reduction in features and symptoms of chronic obstructive pulmonary disease.
• the invention discloses a method of preventing the progression of chronic obstructive pulmonary disease to acute respiratory distress syndrome in mammals, said method comprising step of administering a composition comprising not less than 20% w/w bisdemethoxycurcumin to said mammals to bring about a reduction in features and symptoms of chronic obstructive pulmonary disease.
• FIG 1 A is the graphical representation showing the dose dependant decrease in HIF-l ⁇ levels in COPD mice treated with varying doses (mg/kg bodyweight) of bisdemethoxycurcumin (BDMC) compared to normal and COPD control groups.
• BDMC bisdemethoxycurcumin
• FIG IB is the graphical representation showing decrease in HIF- ⁇ levels in COPD mice treated with varying doses (mg/kg bodyweight) of bisdemethoxycurcumin (BDMC) compared to curcumin and demethoxycurcumin (DMC).
• BDMC bisdemethoxycurcumin
• DMC demethoxycurcumin
• FIG 1C is the graphical representation showing the dose dependant decrease in HIF- ⁇ levels in COPD mice treated with varying doses (mg/kg bodyweight) of a composition comprising bisdemethoxycurcumin (BD3 complex) compared to curcumin C3 complex.
• FIG 2A is the graphical representation showing the dose dependant increase in surfactant protein D levels in COPD mice treated with varying doses (mg/kg bodyweight) of bisdemethoxycurcumin (BDMC) compared to normal and COPD control groups.
• BDMC bisdemethoxycurcumin
• FIG 2B is the graphical representation showing the dose dependant increase in surfactant protein D levels in COPD mice treated with varying doses (mg/kg bodyweight) of bisdemethoxycurcumin (BDMC) compared to curcumin and demethoxycurcumin (DMC).
• FIG 2C is the graphical representation showing the dose dependant increase in surfactant protein D levels in COPD mice treated with varying doses (mg/kg bodyweight) of a composition comprising bisdemethoxycurcumin (BD3 complex) compared to curcumin C3 complex.
• BDMC bisdemethoxycurcumin
• DMC demethoxycurcumin
• FIG 3A is the graphical representation showing the dose dependant increase in periostin levels in COPD mice treated with varying doses (mg/kg bodyweight) of bisdemethoxycurcumin (BDMC) compared to normal and COPD control groups.
• FIG 3B is the graphical representation showing the dose dependant increase in periostin levels in COPD mice treated with varying doses (mg/kg body weight) of a composition comprising bisdemethoxycurcumin (BD3 complex) compared to curcumin C3 complex.
• BDMC bisdemethoxycurcumin
• FIG 4 A is the graphical representation showing the dose dependant decrease in 12/15-LOX levels in COPD mice treated with varying doses (mg/kg bodyweight) of bisdemethoxycurcumin (BDMC) compared to normal and COPD control groups.
• the values in the bar represent 12 LOX and the line represent 15 LOX
• FIG 4B is the graphical representation showing the dose dependant decrease in 12/15-LOX levels in COPD mice treated with varying doses (mg/kg bodyweight) of a composition comprising bisdemethoxycurcumin (BD3 complex) compared to curcumin C3 complex.
• the values in the bar represent 12 LOX and the line represent 15 LOX
• FIG 5 A is the graphical representation showing the dose dependant decrease in bradykinin levels in COPD mice treated with varying doses (mg/kg bodyweight) of bisdemethoxycurcumin (BDMC) compared to normal and COPD control groups.
• BDMC bisdemethoxycurcumin
• FIG 5B is the graphical representation showing decrease in bradykinin levels in COPD mice treated with varying doses (mg/kg bodyweight) of bisdemethoxycurcumin (BDMC) compared to curcumin and demethoxycurcumin (DMC).
• BDMC bisdemethoxycurcumin
• FIG 5C is the graphical representation showing the dose dependant decrease in bradykinin levels in COPD mice treated with varying doses (mg/kg bodyweight) of a composition comprising bisdemethoxycurcumin (BD3 complex) compared to curcumin C3 complex
• FIG 6 A is the graphical representation showing the dose dependant decrease in IL-17 and IL-23 levels in COPD mice treated with varying doses (mg/kg bodyweight) of bisdemethoxycurcumin (BDMC) compared to normal and COPD control groups.
• BDMC bisdemethoxycurcumin
• FIG 6 B is the graphical representation showing the dose dependant decrease in IL-17 and IL-23 levels in COPD mice treated with varying doses (mg/kg bodyweight) of a composition comprising bisdemethoxycurcumin (BD3 complex) compared to curcumin C3 complex.
• BD3 complex bisdemethoxycurcumin
• FIG 7 A is the graphical representation showing the dose dependant decrease in IL-6 levels in COPD mice treated with varying doses (mg/kg bodyweight) of bisdemethoxycurcumin (BDMC) compared to normal and COPD control groups.
• BDMC bisdemethoxycurcumin
• FIG 7 B is the graphical representation showing the dose dependant decrease in IL-6 levels in COPD mice treated with varying doses (mg/kg bodyweight) of a composition comprising bisdemethoxycurcumin (BD3 complex) compared to curcumin C3 complex.
• FIG 8 A is the graphical representation showing the dose dependant decrease in CXCL8 levels in COPD mice treated with varying doses (mg/kg bodyweight) of bisdemethoxycurcumin (BDMC) compared to normal and COPD control groups.
• BDMC bisdemethoxycurcumin
• FIG 8 B is the graphical representation showing the dose dependant decrease in CXCL8 levels in COPD mice treated with varying doses (mg/kg bodyweight) of a composition comprising bisdemethoxycurcumin (BD3 complex) compared to curcumin C3 complex.
• FIG 9 A is the graphical representation showing the dose dependant decrease in LDH levels in COPD mice treated with varying doses (mg/kg bodyweight) of bisdemethoxycurcumin (BDMC) compared to normal and COPD control groups.
• BDMC bisdemethoxycurcumin
• FIG 9 B is the graphical representation showing the dose dependant decrease in LDH levels in COPD mice treated with varying doses (mg/kg bodyweight) of a composition comprising bisdemethoxycurcumin (BD3 complex) compared to curcumin C3 complex.
• FIG 10 is the immunohistochemical staining image of lung tissue sections of normal mice, COPD mice and mice treated with 25 mg/kg and 100 mg/kg BDMC, showing regeneration of alveolar type II cells.
• the invention discloses a method for regeneration of alveolar cells in mammals with emphysema, said method comprising step of administering a composition comprising not less than 20% w/w bisdemethoxycurcumin to said mammals to bring about a reduction in features of emphysema.
• the composition further comprises 10-35% w/w demethoxycurcumin and 10-45% w/w curcumin.
• the features of emphysema are selected from the group consisting of hypoxia, decreased levels of lung surfactant proteins, increased permeability of the alveolar-capillary barrier, inflammation, increased accumulation and recruitment of neutrophils, elevated alveolar pressure, increased oxidative stress, elevated inflammatory cytokines and chemokines, increased numbers of activated T lymphocytes and muscle damage.
• emphysema is induced by enzymes, viruses, bacteria, smoke and particulate irritants.
• the mammal is human.
• the invention discloses a method of therapeutic management of chronic obstructive pulmonary disease in mammals, said method comprising step of administering a composition comprising not less than 20% w/w bisdemethoxycurcumin to said mammals to bring about a reduction in features and symptoms of chronic obstructive pulmonary disease.
• the composition further comprises 10-35% w/w demethoxycurcumin and 10-45% w/w curcumin.
• the chronic obstructive pulmonary disease is emphysematous and non- emphysematous.
• the features of chronic obstructive pulmonary disease are selected from the group consisting of hypoxia, decreased levels of lung surfactant proteins, increased permeability of the alveolar-capillary barrier, inflammation, increased accumulation and recruitment of neutrophils, elevated alveolar pressure, increased oxidative stress, elevated inflammatory cytokines and chemokines, increased numbers of activated T lymphocytes and muscle damage.
• symptoms of chronic obstructive pulmonary disease are selected from the group consisting of shortness of breath, especially during physical activities, wheezing, chest tightness, chronic cough that may produce mucus, respiratory infections, lack of energy, unintended weight loss, and swelling in ankles, feet or legs.
• chronic obstructive pulmonary disease is induced by enzymes, viruses, bacteria, smoke and particulate irritants.
• the mammal is human.
• the invention discloses a method of preventing the progression of chronic obstructive pulmonary disease to acute respiratory distress syndrome in mammals, said method comprising step of administering a composition comprising not less than 20% w/w bisdemethoxycurcumin to said mammals to prevent onset acute respiratory syndrome by bringing about a reduction in features and symptoms of chronic obstructive pulmonary disease.
• the composition further comprises 10-35% w/w demethoxycurcumin and 10-45% w/w curcumin.
• the chronic obstructive pulmonary disease is emphysematous and non-emphysematous.
• the features of chronic obstructive pulmonary disease are selected from the group consisting of hypoxia, decreased levels of lung surfactant proteins, increased permeability of the alveolar-capillary barrier, inflammation, increased accumulation and recruitment of neutrophils, elevated alveolar pressure, increased oxidative stress, elevated inflammatory cytokines and chemokines, increased numbers of activated T lymphocytes and muscle damage.
• symptoms of chronic obstructive pulmonary disease are selected from the group consisting of shortness of breath, especially during physical activities, wheezing, chest tightness, chronic cough that may produce mucus, respiratory infections, lack of energy, unintended weight loss, and swelling in ankles, feet or legs.
• chronic obstructive pulmonary disease is induced by enzymes, viruses, bacteria, smoke and particulate irritants.
• the mammal is human.
• Example 1 Elastase-Induced Pulmonary Emphysema
• Wistar rats were divided into experimental groups and received an intratracheal administration of porcine pancreatic ELT (48.0 U/mg protein; at 0, 20, or 160 U dissolved in 100 ⁇ of Dulbecco’s calcium and magnesium-free phosphate-buffered saline under anesthesia.
• porcine pancreatic ELT 48.0 U/mg protein; at 0, 20, or 160 U dissolved in 100 ⁇ of Dulbecco’s calcium and magnesium-free phosphate-buffered saline under anesthesia.
• Curcumin C3 complex / C3 complex - a composition comprising 75-81% curcumin, 15-19% demethoxy curcumin, and 2.2-6.5% bisdemethoxy curcumin.
• BD3 complex - a composition comprising not less than 20% w/w bisdemethoxycurcumin, 10- 35% w/w demethoxycurcumin and 10-45% w/w curcumin (as disclosed in US provisional application no. 63126920, which is incorporated herein by reference)
• the concentration of BD3 complex used for the experiments is 32% w/w BDMC, 30% w/w DMC and 38% curcumin.
• BD3 complex used for the experiments is 32% w/w BDMC, 30% w/w DMC and 38% curcumin.
• a person skilled in the art would realise that the effects as shown in the following examples are applicable to the concentration of 20% w/w bisdemethoxycurcumin, 10-35% w/w demethoxycurcumin and 10-45% w/w curcumin.
• TTF-1 Mouse Anti-Human Thyroid Transcription Factor 1 (clone SPT24) M/s Master diagnostics, (Cat #MAD-000486QD-12) Granada.
• TTF-1 Mouse Anti-Human Thyroid Transcription Factor 1 (TTF-1) (clone SPT24) M/s Master diagnostica, (Cat #MAD-000486QD- 12) Granada of 1:50 dilution.
• H 2 O 2 Hydrogen peroxide (H 2 O 2 ) in methanol (3 %), Three per cent H 2 O 2 in methanol was prepared by adding one ml of 30 per cent H 2 O 2 to 9 ml of methanol.
• Antigen retrieval solution a. 1mM EDTA BUFFER (pH-8.4): b. 1 mM EDTA, pH 8.0 c. EDTA 0.37 g d. Distilled water 1 L
• DAB plus substrate 3,3-diamine benzidine tetrahydrochloride substrate was prepared freshly at the time of use by addition of 1 mg of 3,3-diamine benzidine tetrahydrochloride (Santacruz, USA) to 1 ml of 0.01 M PBS to which 12 ⁇ l of 3 per cent H 2 O 2 was added.
• Harris haematoxylin for nuclear staining Harris haematoxylin was used for nuclear staining. Counter staining was carried out for 45 seconds.
• a 2% solution of 3-aminopropyltriethoxy-silane (APES) in acetone in a dry staining dish was prepared. The slides were immersed in the APES solution for 5-15 minutes.
• APES 3-aminopropyltriethoxy-silane
• Tissue sections were mounted on 3-aminopropyltriethoxy-silane (APES) coated slides and dried at 37 °C for three hours. Later stored at 4 °C for further processing later. 2.
• the paraffin tissue sections were deparaffinized using xylene and rehydrated using descending grades of ethanol.
• HIER Heat induced epitope retrieval
• TTF-1 Mouse Anti-Human Thyroid Transcription Factor 1 (clone SPT24) was added to cover the sections. Subsequently the sections were incubated at room temperature in humidified chamber for one hour and washed with wash buffer as mentioned earlier.
• DAB plus substrate Freshly prepared 3, 3-diamine benzidine tetrahydrochloride (DAB) with 3 per cent H 2 O 2 was poured to cover the sections. This was incubated for 15-20 minutes or until the desired stain intensity was achieved. Later the sections were washed again with three changes of distilled water.
• DAB 3-diamine benzidine tetrahydrochloride
• hypoxia is a condition where not enough oxygen makes it to the cells and tissues in the body. This can happen even though blood flow is normal. It can lead to many serious, sometimes life-threatening complications.
• lung cells experience hypoxia in acute and chronic lung diseases, during travel to high altitude, and during fetal development. Chronic hypoxia leads to increase in inflammation, alveolar degeneration leading to emphysema which is one of the causative factors for the development of COPD and ARDS.
• Hypoxia Inducible factor (HIF-1) signalling pathway is activated in COPD, and the over- expression of related proteins such as HIF- ⁇ and VEGF is associated with a decrease of lung function, reduced quality of life and progression of COPD.
• hypoxia is a primary pathophysiologic feature and main cause of mortality in patients with severe COVID-19 and it accompanies all the stages of the disease.
• the protein targets of HIF-l ⁇ are involved in the severe hypoxia-induced activation of proinflammatory cytokine expression and the subsequent inflammation process and cytokine storm phase of COVID-19.
• Pulmonary surfactant is essential for life as it lines the alveoli to lower surface tension.
• the main functions of surfactant include 1) lowering surface tension at the air-liquid interface and thus preventing alveolar collapse at end-expiration, 2) interacting with and subsequent killing of pathogens and 3) modulating immune responses.
• Surfactant components are synthesized primarily by the alveolar type II cell, which synthesizes surfactant proteins SP- A, SP-B, and SP-D, collectively called Collectins. They bind to viruses, bacteria to facilitate pathogen removal. Host defense in the alveolar interface is extremely demanding since even moderate degrees of inflammation and exudation compromise gas exchange.
• SP-A and SP- D are present in the mucus layer and alveolar surface, they are well positioned to prevent infection of epithelial cells through viral neutralization, agglutination, and enhanced phagocytosis.
• SP-A and/or SP-D bind to hemagglutinin and neuraminidase of influenza A virus to inhibit their activity.
• Pulmonary collectins also bind to glycoproteins of viruses, including HIV, Respiratory syncytial virus (RSV) and severe acute respiratory syndrome (SARS) coronavirus.
• RSV Respiratory syncytial virus
• SARS severe acute respiratory syndrome
• SARS coronavirus spike glycoprotein is selectively recognized by lung surfactant protein D and activates macrophages.
• Pulmonary capillary leakage followed by influx of blood fluid into the air space of lung alveoli is a crucial step in the progression of lung injury. This influx is due to increased permeability of the alveolar-capillary barrier.
• the extracellular matrix (ECM) between the capillary and the epithelium is involved in prevention of the influx and the ECM architecture is organized by periostin, a matricellular protein localized in the alveolar walls.
• the binding sites on periostin contributes to the mechanical strength of connective tissues. It enhances intermolecular interactions in close proximity and their assembly into extracellular matrix architectures.
• BDMC increase the levels of periostin in a dose dependant manner (Fig. 3A).
• the composition comprising BDMC, curcumin and DMC (BD3 complex) was also effective in increasing the levels of periostin compared to Curcumin C3 complex (Fig. 3B).
• BDMC decreased the levels of 12/15-LOX in a dose dependant manner (Fig.4A).
• the composition comprising BDMC, curcumin and DMC (BD3 complex) was also effective in decreasing the levels of 12/15-LOX (Fig. 4B).
• Bradykinin is a physiologically and pharmacologically active peptide of the kinin group of proteins, consisting of nine amino acids. It is a potent endothelium-dependent vasodilator and mild diuretic, which causes lowering of the blood pressure. It also causes contraction of non-vascular smooth muscle in the bronchus and gut, increases vascular permeability and is also involved in the mechanism of pain.
• BDMC decreased the levels of Bradykinin in a dose dependant manner (Fig. 5A).
• BDMC was also very effective compared to curcumin and DMC in reducing the elevated levels of bradykinin (Fig. 5B).
• the composition comprising BDMC, curcumin and DMC (BD3 complex) was also effective in decreasing bradykinin levels (Fig. 5C), thereby decreasing pain, inflammation and vascular permeability.
• T helper type 17 (Thl7) cells are reported to release interleukin (IL)-17 as their effector cytokine under the control of IL-22 and IL-23. This, in turn, plays a role in inducing neutrophils and tissue re-modelling in the bronchi of the patients.
• IL-17 interleukin-17 in murine lung epithelium induces lung inflammation with a COPD- like phenotype involving recruitment of CD4 cells, mucus hypersecretion and small airways fibrosis. It also causes induction of the expression of many chemokines (including CXCL1 and CXCL 8) and matrix metalloproteinase-9.
• ILrl7 and IL-23 were significantly elevated in COPD, indicating increased neutrophilic inflammation.
• BDMC decreased the levels of these inflammatory markers in a dose dependant manner (Fig. 6A).
• the composition comprising BDMC, curcumin and DMC (BD3 complex) was also effective in decreasing IL-17 and IL-23 levels (Fig. 6B), thereby reducing inflammation and influx cytokines and chemokines.
• the levels of IL-6 was significantly elevated in COPD.
• BDMC and BD3 complex decreased the levels of IL6 in a dose dependant manner (Fig. 7A and 7B).
• Chemokines released from epithelial cells and macrophages in the lung recruit inflammatory cells from the circulation leading to the development of COPD.
• the inflammatory-cell trafficking orchestrated by multiple chemokines, blocked with selective antagonists is an effective anti-inflammatory strategy in this disease.
• the levels of CXCL8 were significantly elevated in COPD, indicating increased inflammation and chemokine influx.
• BDMC decreased the levels of these CXCL8 in a dose dependant manner (Fig. 8A).
• the composition comprising BDMC, curcumin and DMC was also effective in decreasing CXCL8 levels (Fig. 8B), thereby reducing inflammation.
• Lactate dehydrogenase is the enzyme that catalyses the final step in the glycolytic metabolism, regenerating NAD+ from reduced NADH, by conversion of pyruvate to lactate. If cell lysis occurs, or cell membranes are damaged, cytoplasmic enzymes, such as LDH are released into the extracellular space. Increased muscle LDH activity has been found in elderly male patients with COPD who were susceptible to contractile fatigue.
• the bronchial epithelium also showed occasional positive type II cells, indicating increased degeneration of alveoli.
• the lesion tissue in groups treated with 25 mg/kg bodyweight showed diffuse thickening of alveolar septa with infiltration of mononuclear cells.
• the alveoli remained distorted throughout the tissue section, the alveolar type II positive cells were seen in a diffuse manner throughout the parenchyma. There was a significant increase in number of type II positive cells when compared to disease control Group.
• the lesion tissue showed diffuse thickening of alveolar septa with infiltration of mononuclear cells.
• the alveoli remained distorted throughout the tissue section.
• the type II positive cells were mild to moderately high when compared with disease control.
• Occasionally bronchial epithelium showed type II positive cells, indicated regeneration of alveoli, damaged due to emphysema and COPD (FIG. 10)
• BDMC per se and the composition comprising BDMC decreased the activation of tissue macrophage, reduced hypoxia, decreased proinflammatory cytokines, chemokines and bradykinin thereby regenerating alveolar type II cells by restoring alveolar capillary barrier.
• the composition is very suitable for treating COPD and ARDS due to viral infections, specifically COVID 19 and for improving lung function during prognosis.

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