ORALLY ADMINISTERED COMPOSITION FOR TREATING CYSTIC FIBROSIS, COPD, ASTHMA AND OTHER INFLAMMATORY CONDITIONS

Abstract

The invention relates to a new orally administered composition, which in present embodiments is a standardized phytochemical formulation but other embodiments may contain designed molecules. This formulation is capable of suppressing inflammation in a variety of disease conditions having an underlying inflammatory component, including but not limited to cystic fibrosis, COPD, asthma, and pancreatitis. It is an objective of the invention to provide a non-toxic therapy, which exhibits anti-oxidant anti-inflammatory properties without deleterious side effects.

Claims

1. A composition for oral administration that is suitable for the treatment of an inflammatory condition in animals or humans, consisting of combinations of five or more natural and/or synthetic molecules that have anti-inflammatory and/or CFTR modulating functions wherein one or more compounds within the composition is capable of the following functions: (1) Molecule(s) demonstrated to reduce inflammation in experimental models and/or in vivo. (2) Molecule(s) demonstrated in experimental systems and/or in vivo to act as corrector(s) of CFTR. (3) Molecule(s) demonstrated in experimental systems and/or in vivo to act as potentiator(s) of CFTR. (4) Molecule(s) demonstrated in experimental systems and/or in vivo to increase levels of cyclic AMP. (5) Molecule(s) demonstrated in experimental systems and/or in vivo to act as phosphodiesterase inhibitors.

2. A composition according to claim 1, wherein the compounds are selected from the classes of molecules consisting of: proanthocyanidins, anthocyanins, procyanidins, catechins, flavones, flavone glycosides, flavonoids, isoflavones, curcuminoids, lipoic acids, stilbenes and stilbenoids, terpenes and terpenoids, diterpenes, triterpenes, pentacyclic tri-terpenes, carotenoids, rutosides, bithiazoles, pyrazolylthiazoles, benzoquinoliziums, xanthines, benzimidazoles, thiocyanates, isothiocyanates, boswellic acids, saponins, omega-3 fatty acids and phenolic acids.

3. The composition of claim 1 where the disease in need of treatment is selected among: smoker's cough, inflammatory lung disease, pulmonary fibrosis, pulmonary vasculitis, pulmonary sarcoidosis, inflammation and/or infection associated with lung transplantation, acute lung rejection, burn wounds, chemical injury, military wound, pulmonary artery hypertension, bronchitis, sinusitis, asthma, pancreatitis, ocular inflammation, ocular infection, dry eye, cystic fibrosis, bacterial infection, fungal infection, parasite infection, viral infection, chronic obstructive pulmonary disease (COPD), vasculitis, sinus infection, irritable bowel syndrome (IBS), Crohn's disease, bronchiolitis obliterans syndrome (BOS), primary ciliary dyskinesia (PCD), alveolar proteinosis, idiopathic pulmonary fibrosis, familial pulmonary fibrosis, military wounds, burn wounds, eosinophilic pneumonia, eosinophilic bronchitis, acute lung injury, acute respiratory distress syndrome (ARDS), inflammation and/or infection associated with mechanical ventilation, ventilator-associated pneumonia, asbestos-related airway disorder or disease, dust-related airway disorder or disease, silicosis, chemical agent-related airway disease or disorder and any combination thereof.

Description

DETAILED DESCRIPTION

[0039] (ABC) means ATP Binding Cassette, as in ABC transporter.

[0040] ABC transporter means a molecule that uses the energy of ATP to transport substrates across a cell membrane.

[0041] (ALI) means acute lung injury.

[0042] (ARDS) means acute respiratory disorder syndrome.

[0043] (CF)means cystic fibrosis.

[0044] (CFTR) means the Cystic Fibrosis Transmembrane Regulator or CF gene

[0045] (COPD) means chronic obstructive pulmonary disease.

[0046] (FEV.sub.1) means forced expiratory volume defined as the maximum amount of air expired in one second.

[0047] (FPF) means familial pulmonary fibrosis.

[0048] (IPF) means idiopathic pulmonary fibrosis.

[0049] (PAH) means pulmonary arterial hypertension.

[0050] (PCD) means primary ciliary dyskinesia.

[0051] (PPHN) means persistent pulmonary hypertension of the newborn.

[0052] Airway surface as used refers to airway surfaces below the larynx and in the lungs, as well as air passages in the head, including the sinuses, in the region above the larynx.

[0053] Corrector or CFTR corrector means a modulator of CFTR function that is a modulator of cellular processing and/or the localization the CFTR molecule within the cell.

[0054] Disease means any condition that damages or interferes with normal function of a cell, tissue, or organ.

[0055] Inflammation means a part of the complex biological response to harmful stimuli such as pathogens, cell damage, or irritants, and involves immune cells, blood vessels and molecular mediators.

[0056] Potentiator or CFTR potentiator means a modulator of CFTR function that increases CFTR function that is already properly localized within the cell.

[0057] Subject is defined to refer to any mammal requiring treatment. In the preferred embodiment, the subject is a human. The terms human, patient, and subject are used interchangeably hereafter.

[0058] Modulate CFTR function means to increase CFTR activity and/or stability and/or messenger RNA level.

[0059] Mucosal surfaces or mucosa are membranes that lines various cavities in the body and surround internal organs.

[0060] Natural extract as used herein denotes any extract that is obtained from a natural source, such as a plant, fruit, root, tree, and the like.

[0061] Natural compound as used herein denotes any individual molecule isolated from a plant or natural extract.

[0062] Treat, treating, and treatment refer to reducing a disease symptom and/or slowing progression of a disease.

[0063] Reducing inflammation means the ability to inhibit known biological pathways of inflammation under experimental conditions and/or to inhibit markers of inflammation and/or symptoms of inflammation in vivo, which include but are not limited to: pain, swelling, redness, and warmth, fatigue, headaches, muscle stiffness, inflammatory cell recruitment, tissue damage and vascular dysfunction.

[0064] Active component means formulation ingredient with a beneficial drug action and their salts or analogs.

[0065] Effective amount as used herein, means an amount of active ingredient sufficient to produce a selected effect.

[0066] Anti-inflammatory activity herein means activity as determined by any generally accepted in vitro or in vivo assay or test, for example an assay or test for any marker of inflammation, such as production of cytokines, prostaglandins or 8-isoprostane. Antioxidant activity herein means activity as determined by any generally accepted in vitro or in vivo antioxidant assay or test.

[0067] In some embodiments, the combination drug based on this invention is administered via oral administration. Suitable dosages of the present invention can be determined depending on such factors as the nature and/or severity of the illness, frequency of administration, the duration of treatment, condition of the patient, the size and age of the patient, and any other relevant factors. One skilled in the art would also know how to monitor the treatment progress in order to determine an effective dose and treatment plan. For example, one skilled in the art could monitor patient spirometry, chest X-rays and CT's, sputum cultures and blood tests. The treatment may be administered as frequently as 3-5 times daily in order to obtain the desired therapeutic effect of treating the inflammatory disease.

[0068] Frequency of administration will depend, for example, upon the nature of the dosage form used and upon the severity of the condition being treated. The present invention may be administered in combination with other therapeutic agents that are administered orally or by other routes of administration. Such therapeutic agents can be administered before, after or concurrently with administration of the invention. Particular doses of any of these and other additional co-administered therapeutic agents can be determined by a physician or other qualified medical professional depending on factors such as the type of therapeutic agent, the nature and severity of the illness, route and frequency of administration, the duration of treatment, condition of the patient, size and age of the patient, and any other relevant factors.

[0069] Additional therapeutic agents can also be delivered by a vaporizer, humidifier or fogger. The foregoing descriptions have been supplied merely to illustrate the invention and are not intended to be limiting. Each disclosed aspect and embodiment of the present invention may be considered individually or in combination with any other aspects, embodiments and variations of the invention. Modifications of the disclosed embodiments incorporating the spirit and substance of the present invention may occur to persons skilled in the art and such modifications are within the scope of the present invention. Furthermore, all references cited herein are incorporated by reference in their entirety.

[0070] Ingredients described herein can serve a plurality of functions, thus disclosure of an ingredient herein as exemplifying one function or functional class does not exclude the possibility that it can also exemplify another function or functional class.

[0071] Formulations and Administration

[0072] The active compounds disclosed herein may be orally administered to the subject by any suitable means. The oral composition is administered as capsules, chewables, tablets, powders, granules or liquid.

[0073] The formulations described herein may be co-administered with therapeutically active drugs, with other natural extract compounds and supplements, with vitamins or other compounds that may be advantageously utilized in a combination treatment according to the invention. The disclosed compositions maybe administered prior to administration of the known therapeutic, for example at least four hours prior to administration of the known therapeutic. Alternatively, the disclosed compositions may be administered concurrently with the known therapeutic provided there is no adverse interaction with the known therapeutic agent.

[0074] The following examples of the present invention in combination described in further detail, but the scope of the invention in any of these examples is not subject to restrictions.

[0075] Specific examples of active compounds that may be used to carry out the present invention are set forth below.

[0076] Dosing Regimen

[0077] The dosage of the formulation will vary depending on the condition being treated and the state of the subject. Those of a skill in the art will appreciate that the preferred dosing regimen can be varied depending on symptoms, body weight, health and condition of the patient, and the like, and that the preferred dosing regimen can be readily determined using known techniques.

[0078] The dosing regimen requires either multiple daily administrations for a time limited to duration of the disease or conditions in need of treatment, such as in acute lung injury or acute pulmonary hypertension, or multiple daily and/or chronic administrations, particularly among chronic diseases, such as cystic fibrosis, COPD and primary ciliary dyskinesia.

[0079] Efficacy Determination

[0080] The effect of the treatment may be clinically determined by measurements as described herein. Efficacy may be measured by the reduction of symptoms of inflammation and/or by other endpoints specific to the condition of the diseased subject. For lung diseases, efficacy of a therapy is measured by improvements in pulmonary function tests, improved oxygen saturation, improved quality of life and reduced frequency of exacerbations, however other endpoints may be desirable to include.

[0081] Patients with chronic lung diseases are closely monitored by regular clinic visits. Forced expiratory volume per one second (FEV1) will be measured regularly via spirometry, and also exacerbation rate, and blood 02 saturation. CF quality of life measures (CFQ-R), and exercise capacity are also useful clinical endpoints for lung diseases.

[0082] Specifically, treating and/or managing cystic fibrosis can include any one or more of the following: improved lung function, improved quality of life, reduced pulmonary exacerbation, reduced the microbial load, reversion of antibiotic susceptibilities of colonizing pathogens, improvement of the gastrointestinal tract and pancreatic function, and treatment of other mucus membranes of the body such as the sinuses.

[0083] Lung function may be improved by increasing the patient's forced expiratory volume in one second (FEV1), the forced vital capacity (FVC), and/or whole-lung mucus clearance. Lung function can be measured by spirometry or plethysmography. Lung function can also be assessed by measuring lung volume according to American Thoracic Society standards as described by the American Thoracic Society.

[0084] Pulmonary exacerbation is determined by clinical need for IV antibiotics and/or through presence of the following symptoms: change in sputum volume or color, new or increased hemoptysis, increased cough, increased dyspnea, malaise, fatigue or lethargy, a fever, anorexia or weight loss, sinus pain or tenderness, change in sinus discharge, change in findings on physical examination of the chest, decrease in pulmonary function from a previously recorded value, or radiographic change indicative of pulmonary infection.

[0085] Combination of the Formulation with Other Therapies

[0086] The formulations described herein provide a method to improve the pulmonary condition in cystic fibrosis and may, therefore, be effectively combined with other currently existing and known therapies. Individual therapeutic combinations, doses and specific formulations will depend on interaction with the other drug(s), which are expected to be minimal. The optimization of these combinations is based on the knowledge available in the art.

[0087] In particular, the formulation may be advantageously utilized in combination with a beta-agonist, steroid, anti-inflammatory agent, antibiotic, bronchodilator, mucolytic or another suitable drug. Safety endpoints for evaluation of this invention are: FEV1, systemic (blood) and urine levels of formulation active ingredients, liver enzymes, GI symptoms and other adverse events such as dyspnea, and chest tightness.

[0088] Efficacy endpoints for the determination of efficacy of the present invention are: pulmonary function (FEV1), and exhaled nitric oxide (NO). Chest X-rays and CT scans may also be taken. Exploratory endpoints for determination of efficacy include sputum expectoration culture.

EXAMPLES

[0089] Products based on this invention were prepared in an FDA-licensed facility under GMP (Good Manufacturing Practices) and their formulations are supplied below. Because all ingredients used in these formulations are on the FDA GRAS list (Generally Recognized as Safe) for use in dietary supplements, the products were made available immediately for distribution to patients for voluntary personal use through funding by the Sharktank Research Foundation, a 501(c)3 nonprofit lung disease research organization. Products released to date, based on this invention, are known by the name Indrepta.

[0090] The A and B versions of Indrepta (see Supplement Facts tables) were released first. Most patients with some residual CFTR function were able to discern an added benefit of the forskolin/amentoflavone cyclic AMP component of the B version in their ability to breathe.

[0091] The following formulations resulting from the invention disclosed herein are effective to increase FEV1 by double digits in patients with cystic fibrosis, as evidenced by voluntarily shared clinical data from doctor visits. Patients also report reduction of inflammation as determined by reduced need for steroid use and ibuprofen, and reduction in other CF symptoms. Formulations based on this invention to date are safe and well-tolerated when orally administered in vivo.

[0092] Formulation A is composed solely of compounds which are anti-inflammatory and/or CFTR corrector/potentiators, and lacks a cyclic AMP activator strategy (eg. Forskolin) and augmentation by phosphodiesterase inhibitors (eg. Amentoflavone) that is utilized in the B and C formulations that are derived from this invention.

Example 1

[0093] Formulation A

Example 2

Formulation B

Example 3

Formulation C

[0094] Formulation C is preferred with regard to reduction in symptoms by CF patients from most mutation classes who suffer from allergies, asthma or lung bleeds. These symptoms are reported by users to be improved significantly more by C vs B formulation. We do not observe that patients carrying dF508 mutations with a nonsense mutation show improved results with formulation C over patients carrying dF508 with a frameshift (a mutation that is unlikely to respond to CFTR modulation).

[0095] Examples of FEV1 Improvements in Patients with Cystic Fibrosis using Indrepta

[0096] Patient 1:

[0097] 21% FEV1 increase, 1 month on Indrepta

[0098] Adult female patient with cystic fibrosis, ddF508.

[0099] Lung function last clinic fev1 was 1.14. Today they are 1.39 sooooo happy. Percentage before I started was 30. It's 51 now.

[0100] Patient 2:

[0101] 15% FEV1 increase, approximately 1 month on Indrepta.

[0102] Female child with cystic fibrosis, age 6.

[0103] Her last CF clinic 7/11: PFTs were 79%, Wt to ht percentile was 47%. Today at her CF clinic: PFTs are 94% and wt to ht percentile is 60%.

[0104] Patient 3:

[0105] 14% FEV1 increase, 2 months on Indrepta

[0106] Adult female patient dF508 and 1209+1 G>A

[0107] I'm hooked and so happy to report my lung function improvement

[0108] Patient 4:

[0109] 7% FEV1 increase, approximately 2 weeks on Indrepta.

[0110] Adult male with cystic fibrosis, genotype unknown.

[0111] Well, my vest has been broken and is being repaired. And I still blew 82%. Been getting up a ton of junk during treatments even without the vest (using the VibraLung, but nothing beats a good shakedown) Around 2 weeks (give or take) on Indrepta.

[0112] Patient 5:

[0113] 21% increase in FEV1 after 7 weeks on Indrepta

[0114] Adult female dF508 and R758X

[0115] Yes, I had a PFT jump from Indrepta. Yes, I'm clearing out a ton of mucus. But can we get a hallelujah for waking up, not having a coughing fit, and not needing a breathing treatment?!

[0116] Patient 6:

[0117] 12% increase in FEV1 after 3 months on Indrepta

[0118] Adult female ddF508

[0119] This was amazing news for us. In addition to that, probably 5 out of the last 6 years, she would get pulmonary infection flareup in the spring time around March or April, that would require antibiotic IVs. This year she hasn't had any issues with that.

[0120] Patient 7:

[0121] 8.5% FEV1 increase after 5 weeks on Indrepta

[0122] Female child age 12 dF508 and 1717-1G>A

[0123] Back at clinic with my daughter, and she gained 1 lb, 4 ozs in 2 weeks. That has never happened before! ETA: Her pft's went from FEV1-58% to 66.5%

[0124] Patient 8:

[0125] 12% FEV1 increase in 5 weeks, gained 16 pounds

[0126] Adult female dF508 1304delA

[0127] Mine (PFT'S) have gone up 12%! I feel so clear, my husband has realized I hardly ever cough, and my pleurisy is almost GONE! I had pleurisy for 6 months from a bad case of pneumonia and a chest tube placed. I became very discouraged but I totally feel like this drug is a God send. My mucus is so clear (my doctor couldn't believe it) and I am able to run miles at a time now. I got weighed again today and gained 4 more pounds. I am up 16 pounds since March. I couldn't believe the scale when I saw it. This is insane! I truly believe I am absorbing Fats now from Indrepta. I'm so excited. I am a few pounds away from my GOAL weight!

[0128] Patient 9:

[0129] 15% FEV1 increase in 3 weeks

[0130] Adult female dF508 and g551s

[0131] Pft's done. I'm up to 45%. Amazing! If you haven't tried Indrepta, you should! 6 weeks on indrepta c and it's went up 15%. Also I have a cold right now. Transplant talk has been pushed up due to improvement in lung function!!!!

[0132] I had been without indrepta for well over a week and started taking B yesterday thanks to a friend sending me a full bottle. I can tell a huge difference within the first couple of hours of the first three caps. I had been up all night with a terrible junk that was just stuck. My indrepta arrived around 1 pm. By 3 pm my mucus had started getting thinner and coming up. I'm a a critic of everything. I believe in science, I just can't say it enough, you need to try Indrepta.

[0133] Quality of Life Improvements

[0134] Patient 5:

[0135] I was diagnosed with folliculitis and dermatitis by the dermatologist earlier this year. My skin (back and shoulders) were completely broken out, and it was from bacteria and yeast. They tried antibiotics which didn't work. Bleach baths and SeneSerum-C helped a good bit. I've dealt with these issues for almost 2 years now although progressively worse at the end of 2016.

[0136] I took a back photo today and it is sooooo ridiculously clear since being on Indrepta

[0137] Patient 10:

[0138] I'm proud to say that on August 14th I realized my nose was clear and no more yellow infection, my mucus is back to it's normal yellow and it's regular production!! My fevers have completely disappeared and I conquered a cold for the first time without IV antibiotics in over 10+ years!!! I'm completely amazed and thrilled!!

[0139] Patient 11:

[0140] Adult female age 42 dF508 and N1303K

[0141] The first time I beat a respiratory infection was my first few weeks on Indrepta. It was about 3 weeks last time but I was likely going through the normal mucus purge as well, In summary, in 3 months, I have beat 2 viruses, gained 2 pounds, have minimal mucus, am sleeping flat (not on pillow mtn) and have a lot more energy than I used to by end of day.

[0142] This makes me feel like I can be CF Ninja Warrior one day on American Ninja warrior. . .

[0143] The present invention is not to be limited in scope by specific embodiments described herein as examples, which are intended as single illustrations of individual aspects of the invention. Functionally equivalent methods and components not provided as examples are within the scope of the invention. Indeed, various modifications of the invention, in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[0144] The invention is a composition suitable for treatment of a subject with an inflammatory condition in need of such treatment, wherein said composition is composed of combinations of entirely natural plant-derived molecules, or which may also include synthetic molecules in combination with natural plant-derived molecules, or be composed entirely of synthetic molecules, such that these molecules included in the formulation serve to reduce inflammation at the disease site in the subject and/or to modulate CFTR function in a manner specified in the claims.

[0145] Examples of suitable classes of molecules for this invention include, but are not limited to: proanthocyanidins, anthocyanins, procyanidins, catechins, flavones, flavone glycosides, lipoic acids, flavonoids, isoflavones, curcuminoids, stilbenoids, terpenes, carotenoids, rutosides, bithiazoles, pyrazolylthiazoles, benzoquinoliziums, xanthines, benzimidazoles, thiocyanates, isothiocyanates, omega-3 fatty acids and phenolic acids, with examples from this list such as astaxanthin or pycnogenol, alpha lipoic acid, resveratrol, pterostilbene, luteolin, quercetin, eicosapentaenoic acid, evodiamine and evodol and also included are molecules that correct and/or potentiate and/or increase (modulate) CFTR function such as certain plant polyphenols (e.g., flavones, flavonoids, isoflavones, curcuminoids, stilbenoids, terpenes, carotenoids, rutosides, bithiazoles, pyrazolylthiazoles, benzoquinoliziums, xanthines, benzimidazoles, thiocyanates, isothiocyanates and the like), and molecules such as forskolin that increase cyclic AMP, thereby activating CFTR, and molecules that are natural phosphodiesterase inhibitors that maintain CFTR function by maintaining cyclic AMP levels such as amentoflavone.

[0146] The goal of formulations derived from this invention is to maximize the potential to reduce inflammation in the body and to successfully modulate a wide range of CFTR mutations. Further laboratory research and feedback from patients will allow further refinement of formulations derived from this invention.

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