Pharmaceutical compositions and methods of treatment using serratiopeptidase, mannose or a derivative thereof and optionally an anti-infective agent

Abstract

The present invention relates to methods of treating infectious diseases, wherein the treatment comprises administering to a human or animal, in the same or different compositions, serratiopeptidase, mannose or an isomer, salt or other derivative thereof, and one or more anti-infective agents. The present invention relates to pharmaceutical compositions comprising serratiopeptidase and mannose or an isomer, salt or other derivative thereof. The present invention relates to pharmaceutical compositions comprising serratiopeptidase, mannose or an isomer, salt or other derivative thereof, and one or more anti-infective agents.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 62 / 984,135, filed March 2, 2020, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present invention relates to methods of treating infectious diseases, wherein the treatment comprises administering to a human or animal, in the same or different compositions, serratiopeptidase, mannose or an isomer, salt or other derivative thereof, and one or more anti-infective agents. The present invention relates to pharmaceutical compositions comprising serratiopeptidase and mannose or an isomer, salt or other derivative thereof. The present invention relates to pharmaceutical compositions comprising serratiopeptidase, mannose or an isomer, salt or other derivative thereof, and one or more anti-infective agents. [Background technology]

[0003] Background of the Invention Today, the world is facing multiple health challenges. According to the WHO's top 10 challenges to human health in 2019, 5 out of the 10 challenges are infectious diseases. Microbial infections in various forms are the greatest threat to human health. Infectious diseases are caused by pathogenic microorganisms such as bacteria, viruses, parasites, fungi, etc. These infectious diseases spread from one person to another directly or indirectly through human or non-human sources. Infectious diseases can be acute or chronic.

[0004] In an infection, pathogens first invade the host's organs, and over a period of time, these free-floating pathogens attach to tissue surfaces with the aid of pili. These pathogens then grow as colonies and secrete extracellular polymers that provide a structural and protective matrix called a "biofilm." This biofilm provides the pathogen with protection from anti-infective agents.

[0005] Current treatment for recurrent infections involves anti-infective therapy alone. Anti-infective agents eradicate only free-floating pathogens, but pathogens within biofilms are protected from anti-infective agents. These protected pathogens sometimes later regrow and are the source of recurrent infections.

[0006] Therefore, there is an urgent need for improved therapies in the treatment of infectious diseases. Current solutions to treating recurrent infections involve dissolving biofilms and blocking the pathogen's pili so that it cannot attach to the cell surface. This helps prevent pathogen colonization and prevents new biofilm formation.

[0007] The present invention provides a solution to methods of treating infectious diseases, wherein the treatment comprises administering to humans or animals, in the same or different compositions, serratiopeptidase, mannose or a derivative thereof, and one or more anti-infective agents. This combination keeps pathogens free-floating, without biofilm or pathogen attachment, and provides improved anti-infective efficacy against free-floating pathogens, which aids in eradicating infection. Summary of the Invention

[0008] SUMMARY OF THE INVENTION The present invention relates to a pharmaceutical composition comprising serratiopeptidase and mannose or an isomer, salt or other derivative thereof. The pharmaceutical composition may optionally further comprise one or more anti-infective agents. The present invention relates to a method of treating infectious diseases, wherein the treatment comprises administering to a human or animal serratiopeptidase, mannose or an isomer, salt or other derivative thereof, and one or more anti-infective agents, in the same or different compositions. [Brief explanation of the drawings]

[0009] [Figure 1]FIG. 1 depicts comparative bacterial growth inhibition with the combination according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0010] Detailed Description of the Invention The present invention relates to pharmaceutical compositions and methods of treatment using serratiopeptidase, mannose or its isomers, salts, or other derivatives, and optionally one or more anti-infective agents. The active ingredients according to the present invention are used in therapeutically effective amounts.

[0011] The terms "anti-infective agent" or "anti-infective drug" are used interchangeably.

[0012] A "therapeutically effective amount" or "effective amount" refers to the amount of a pharmaceutically active agent that, when administered to a patient, is sufficient to affect such treatment for a disease. The therapeutically effective amount will vary depending on the disease and its severity, as well as the age, weight, and other conditions of the patient being treated.

[0013] As used herein, the term "pharmaceutical composition" refers to any composition for administration to a human or animal, including, but not limited to, immediate release, delayed release, sustained release, and pulsed release.

[0014] In one aspect, the present invention provides a method for producing a pharmaceutical composition comprising: a. a therapeutically effective amount of serratiopeptidase, and b. A therapeutically effective amount of mannose or its isomers, salts, or other derivatives The present invention relates to a pharmaceutical composition comprising:

[0015] In a preferred embodiment, the present invention provides a. a therapeutically effective amount of serratiopeptidase, and b. a therapeutically effective amount of D-mannose The present invention relates to a pharmaceutical composition comprising:

[0016] In a preferred embodiment, the present invention provides a. serratiopeptidase in an amount between 0.1 mg and 200 mg; and b. D-mannose in amounts between 0.1 mg and 1000 mg The present invention relates to an oral pharmaceutical composition comprising:

[0017] In one aspect, the present invention provides a method for producing a pharmaceutical composition comprising: a. a therapeutically effective amount of serratiopeptidase; b. a therapeutically effective amount of mannose or an isomer, salt, or other derivative thereof, and c. a therapeutically effective amount of one or more anti-infective agents The present invention relates to a pharmaceutical composition comprising:

[0018] In a preferred embodiment, the present invention provides a. a therapeutically effective amount of serratiopeptidase; b. a therapeutically effective amount of D-mannose, and c. a therapeutically effective amount of an antibiotic The present invention relates to a pharmaceutical composition comprising:

[0019] In a preferred embodiment, the present invention provides a. Serratiopeptidase in an amount between 0.1 mg and 200 mg; b. D-mannose in an amount between 0.1 mg and 1000 mg; and c. a therapeutically effective amount of an antibiotic The present invention relates to an oral pharmaceutical composition comprising:

[0020] In one aspect, the present invention relates to a method of treating an infectious disease, wherein the treatment comprises a. a therapeutically effective amount of serratiopeptidase; b. a therapeutically effective amount of mannose or an isomer, salt, or other derivative thereof, and c. a therapeutically effective amount of one or more anti-infective agents; comprising administering wherein the administration is in the same or different compositions and the treatment is administered to a human or animal.

[0021] In a preferred embodiment, the present invention relates to a method of treating an infectious disease, wherein said treatment comprises a. a therapeutically effective amount of serratiopeptidase; b. a therapeutically effective amount of D-mannose, and c. a therapeutically effective amount of an antibiotic; comprising administering wherein the administration is in the same or different compositions and the treatment is administered to a human or animal.

[0022] In a preferred embodiment, the present invention relates to a method of treating an infectious disease, wherein said treatment comprises a. Serratiopeptidase in an amount between 0.1 mg and 200 mg; b. D-mannose in an amount between 0.1 mg and 1000 mg; and c. a therapeutically effective amount of an antibiotic; comprising administering wherein the administration is in the same or different compositions and the treatment is administered to a human or animal.

[0023] In one or more embodiments, the pharmaceutical compositions as per the present invention include immediate release, delayed release, sustained release, or a combination thereof.

[0024] In one or more embodiments, pharmaceutical compositions according to the present invention include those for oral, intravenous, topical, inhalation, or other routes of administration.

[0025] In one or more embodiments, pharmaceutical compositions according to the present invention encompass solid, liquid, semi-solid, aerosol, or other dosage forms.

[0026] In one or more embodiments, the pharmaceutical composition or treatment is for a urinary tract infection or a respiratory infection or a soft tissue infection or a bone infection or a skin infection or a blood / plasma infection or a GI track infection.

[0027] In one or more embodiments, the pharmaceutical composition according to the present invention comprises one or more antibiotics selected from aminoglycosides, carbapenems, glycopeptides, quinolones, penicillins, fluoroquinolones, cephalosporins, sulfonamides, macrolides, nitrofurantoin, metronidazole, rifamycins, tetracyclines, lincomycins, telithromycin, and / or other antibiotics.

[0028] In a preferred embodiment, the invention comprises: a. Nitrofurantoin in amounts between 25 mg and 100 mg; b. serratiopeptidase in an amount between 0.1 mg and 200 mg; and c. D-mannose in amounts between 0.1 mg and 1000 mg The present invention relates to the treatment of recurrent urinary tract infections by administration of

[0029] In a preferred embodiment, the invention comprises: a. Ciprofloxacin / levofloxacin in amounts between 250 mg and 1000 mg; b. serratiopeptidase in an amount between 0.1 mg and 200 mg; and c. D-mannose in amounts between 0.1 mg and 1000 mg The present invention relates to the treatment of recurrent urinary tract infections by administration of

[0030] In a preferred embodiment, the invention comprises: Azithromycin / levofloxacin in amounts between 0.1 mg and 1000 mg; b. serratiopeptidase in an amount between 0.1 mg and 200 mg; and c. D-mannose in amounts between 0.1 mg and 1000 mg The present invention relates to the treatment of respiratory tract infections by administration of

[0031] In a preferred embodiment, the invention comprises: a. Nitrofurantoin in amounts between 25 mg and 100 mg; b. serratiopeptidase in an amount between 0.1 mg and 200 mg; and c. D-mannose in amounts between 0.1 mg and 1000 mg The present invention relates to a pharmaceutical composition comprising:

[0032] In a preferred embodiment, the invention comprises: a. Ciprofloxacin / levofloxacin in amounts between 250 mg and 1000 mg; b. serratiopeptidase in an amount between 0.1 mg and 200 mg; and c. D-mannose in amounts between 0.1 mg and 1000 mg The present invention relates to a pharmaceutical composition comprising:

[0033] In a preferred embodiment, the invention comprises: Azithromycin / levofloxacin in amounts between 0.1 mg and 1000 mg; b. serratiopeptidase in an amount between 0.1 mg and 200 mg; and c. D-mannose in amounts between 0.1 mg and 1000 mg The present invention relates to a pharmaceutical composition comprising:

[0034] Serratiopeptidase Serratiopeptidase is a proteolytic enzyme prescribed in surgery, orthopedics, dentistry, otolaryngology, and gynecology for its anti-inflammatory, anti-edema, and analgesic effects. It is produced by the nonpathogenic intestinal bacterium Serratia. This microorganism was originally isolated from silkworms in the late 1960s. Serratiopeptidase can be purified from cultures of Serratia E-15 bacteria.

[0035] The serratiopeptidase is administered in a therapeutically effective amount of between 0.1 mg and 200 mg, preferably between 10 mg and 120 mg. In preferred embodiments, the serratiopeptidase may be used in amounts of 0.1 mg or greater for pulmonary delivery or aerosol. In one or more embodiments of the present invention, the serratiopeptidase may be administered in an enteric-coated dosage form. The enteric coating consists of a pH-sensitive polymer that remains intact in the acidic pH of the stomach (1.5-3.5) and dissolves in the alkaline pH of the small intestine (6.5-7.6).

[0036] Mannose and its derivatives Mannose occurs in microorganisms, plants, and animals. Free mannose is found in small amounts in many fruits and in mammalian plasma. Mannose commonly exists as two different sized rings: the pyranose (6-membered) form and the furanose (5-membered) form. Each closed ring can have either an alpha or beta configuration at the anomeric position. The chemical undergoes rapid isomerization between these four forms. D-mannose can be aD-mannofuranose / aD-mannopyranose / bD-mannopyranose. [ka]

[0037] In one or more embodiments, the present invention preferably involves the use of D-mannose. D-mannose is an epimer of glucose at the C-2 position and occurs naturally as a component of mannans. It is a sugar monomer in the aldohexose series of carbohydrates. D-mannose may be used in amounts between 0.1 mg and 1000 mg. In preferred embodiments, D-mannose can be used in amounts greater than 0.1 mg for pulmonary delivery or aerosol. In preferred embodiments, D-mannose can be used in amounts between 10 mg and 1000 mg. [ka]

[0038] anti-infective drugs Infectious diseases are disorders caused by organisms such as bacteria, viruses, fungi, or parasites. Disease-causing microorganisms are called pathogens. Pathogens cause disease by disrupting the body's normal processes and / or stimulating the immune system to produce a defensive response, resulting in high fever, inflammation, and other symptoms. Infectious diseases are transmitted by one or more of the following: 1. From person to person, 2. by insects or other animals, 3. By consuming contaminated food or water.

[0039] Anti-infective agents are chemicals used to treat infections. The use of anti-infective agents depends on the type of organism being targeted. These anti-infective agents include antibacterial (antibiotic), antiviral, antifungal, and antiparasitic agents, and are administered orally, intravenously, or by other suitable routes, depending on the severity, location, and type of infection.

[0040] antibiotics Bacteria are single-celled microorganisms and come in many shapes, including spherical, rod-shaped, and spiral. Infectious bacteria can grow, divide, and spread within the body, leading to infectious diseases. Many infectious bacteria secrete toxins that increase the severity of some diseases.

[0041] Antibiotics are drugs that kill or inhibit the growth of bacteria and are widely used in the treatment and prevention of such infections. The various types of antibiotics are aminoglycosides, penicillins, cephalosporins, carbapenems, glycopeptides, quinolones, fluoroquinolones, sulfonamides, macrolides, nitrofurantoin, metronidazole, rifamycin, tetracyclines, lincomycin, telithromycin, and / or other antibiotics.

[0042] Antiviral drugs Viruses are small capsules that contain genetic material and replicate only in the living cells of other organisms. They invade, multiply, and damage cells. They can infect humans, animals, plants, bacteria, and other forms of living organisms.

[0043] Antiviral drugs are a class of drugs specifically used to treat viral infections. Most antiviral drugs are used for specific viral infections, but broad-spectrum antivirals are effective against a wide range of viruses. Various types of antiviral drugs include protease inhibitors, integrase inhibitors, reverse transcriptase inhibitors, neuroamidase inhibitors, guanosine analogs, and / or other antiviral drugs.

[0044] Pharmaceutical Composition Pharmaceutical compositions are various types of pharmaceutical preparations designed for targeted administration of one or more drugs. Pharmaceutical compositions according to the present invention include immediate release, delayed release, sustained release, and pulsed release. Pharmaceutical compositions can be prepared using a homogeneous mixture of two or more drugs. In one or more embodiments, pharmaceutical compositions can be prepared with one or more drugs in separate compartments within a single dosage form. Pharmaceutical compositions according to the present invention can be administered orally, topically, by inhalation, intravenously, or by other drug administration routes. Pharmaceutical compositions according to the present invention can be in solid, liquid, semisolid, aerosol, or any other dosage form. Pharmaceutical compositions according to the present invention can be prepared in a single dosage form with one or more drugs in a modified release and other drugs in an immediate release.

[0045] Oral pharmaceutical compositions include tablets, capsules, solutions, emulsions, suspensions, syrups, elixirs, aerosols, powders and granules for reconstitution, lozenges, dispersible powders and granules, medicated gums, chewable tablets, effervescent tablets, multiparticulate dosage forms, and the like. Multicompartment dosage forms include bilayer tablets, capsules in capsules, tablets in capsules, and any other dosage forms. Pharmaceutical compositions can be formulated by any technique known or recognized by those skilled in the art.

[0046] In one embodiment, the oral pharmaceutical composition optionally further comprises any one or combination of one or more pharmaceutically acceptable excipients, such as, but not limited to, carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and dissolution enhancers.

[0047] While the invention has been described with reference to various embodiments thereof, other embodiments will become apparent to those skilled in the art from consideration of the specification.

[0048] The innovation is further defined by reference to the following examples: It will be apparent to those skilled in the art that many variations, both to the composition and the treatment, may be practiced without departing from the scope of the invention.

[0049] example The following was performed: "In Vitro studies demonstrating superior inhibition of bacterial growth using serratiopeptidase, D-mannose and an antibiotic compared to serratiopeptidase and an antibiotic, D-mannose and an antibiotic, and an antibiotic alone."

[0050] Nutrient medium was prepared with a plastic thread suspended in it. The nutrient medium was inoculated with bacteria and allowed to stand overnight to allow biofilm formation. The following day, the plastic thread was transferred to new nutrient medium containing either D-mannose or serrapeptidase, or both D-mannose and serrapeptidase, or blank (no additives), and the bacteria were allowed to grow for 6-7 hours. After 6-7 hours, the plastic thread was added to the new nutrient medium, and then antibiotics were added.

[0051] Material preparation: 1) E. Coli culture 10 x 10 6 Preparation of CFU / ml: Stock E. coli ATCC 8739 (culture count 10 x 10 8 1 ml of the resulting culture (10 × 10 CFU / ml) was diluted to 10 ml with buffered peptone water with NaCl. 7 E. coli cultures (10 × 10 CFU / ml) were diluted to 10 ml with buffered peptone water with NaCl. 6 CFU / ml). 2) Preparation of buffered peptone water with NaCl: 16 g of peptone was suspended in 1000 ml of distilled water. Heat the medium, if necessary, to dissolve it. To this solution, 5 g of NaCl and 3.5 g of disodium phosphate were added. The solution was sterilized by autoclaving at 121°C and 15 lbs pressure for 15 minutes. 3) Preparation of nutrient liquid broth (soybean casein digest medium): 30 gm of medium was suspended in 1000 ml of distilled water, heating it if necessary to dissolve it. The broth was sterilized by autoclaving at 121°C and 15 lbs pressure for 15 minutes. 4) Preparation of nutrient liquid broth with glucose (Soyabean Casein Digest Medium with Glucose): 30 gm of medium and 10 gm of glucose were suspended in 1000 ml of distilled water, heated if necessary to dissolve. The broth was sterilized by autoclaving at 121°C and 15 lbs pressure for 15 minutes. 5) Preparation of D-mannose solution: Solution F. 500 mg of D-mannose was dissolved in 10 ml of distilled water. 6) Preparation of serratiopeptidase solution: Solution P. 500 mg of serratiopeptidase was dissolved in 10 ml of distilled water. 7) Preparation of antibiotic (nitrofurantoin): Solution A. 100 mg of anhydrous nitrofurantoin was dissolved in 100 ml of dimethyl sulfoxide. 8) Preparation of diluted antibiotic (nitrofurantoin): Solution A di1 . 100 mg of anhydrous nitrofurantoin was dissolved in 100 ml of dimethyl sulfoxide, and 3 ml of the resulting solution was diluted to 10 ml with dimethyl sulfoxide.

[0052] Step 1: 1. At 6:00 PM on Day 1, 50 ml of sterile soybean casein digest medium was added to five (5) sterile test tubes. To these tubes, 1 ml of E. coli culture (10 x 10 6 CFU / ml) were inoculated at 6 pm. Thin plastic threads (0.1 mm OD) of equal length were suspended from the center of all five test tubes and kept at 30-35°C overnight (17 hours). 2. At 11:00 AM on the second day, 50 ml of sterile soybean casein digest medium and 500 mg of glucose were added to another five (5) sterile test tubes. a. 1 ml of Solution F (D-mannose solution) was added to Test Tube 1. b. 1 ml of Solution P (serrapeptidase solution) was added to test tube 2. c. 1 ml of Solution F (D-mannose solution) and 1 ml of Solution P (serrapeptidase solution) were added to test tube 3. The thin plastic thread was transferred from the old test tube to the new one at 11:00 AM on Day 2. All five test tubes were kept at 30°C to 35°C for 7 hours. 3. At 6:00 PM on Day 2, add 50 ml of sterile soybean casein digest medium to five (5) additional sterile test tubes. Transfer the thin plastic thread from the old test tube to the new one at 6:00 AM on Day 2. Keep all five test tubes at 30°C to 35°C overnight (17 hours). 4. On the third day, at 11:00 AM, 1 ml of Solution A was administered. di1 (Diluted antibiotic (nitrofurantoin) solution) was added to test tube 1, test tube 2, test tube 3 and test tube 4. All five test tubes were kept at 30°C to 35°C for 7 hours. 5. At 6 pm on the third day, the plastic threads were removed from all five test tubes. The transmittance of the medium in all five test tubes was checked at 590 nm. a. Test tube 1: Solution F (D-mannose) and A di1 (with diluted antibiotics): 8.6 b. Test tube 2: Solutions P (serrapeptidase) and A di1 (with diluted antibiotics): 8.3 c. Test tube 3: Solutions F (D-mannose), P (serrapeptidase), and A di1 (with diluted antibiotics): 9.0 d. Test tube 4: A di1 (with diluted antibiotics): 8.4 e. Test tube 5: Blank: 8.3

[0053] Step 2: 1. At 6:00 PM on the fourth day, 50 ml of sterile soybean casein digest medium was added to five (5) sterile test tubes. To these test tubes, 1 ml of E. coli culture (10 x 10 6The tubes were inoculated with 10 ... 2. On the fifth day, at 11:00 AM, 50 ml of sterile soybean casein digest medium was added to another five (5) sterile test tubes along with 500 mg of glucose. a. 1 ml of Solution F (D-mannose solution) was added to Test Tube 1. b. 1 ml of Solution P (serrapeptidase solution) was added to test tube 2. c. 1 ml of Solution F (D-mannose solution) and 1 ml of Solution P (serrapeptidase solution) were added to test tube 3. The thick plastic thread was transferred from the old test tube to the new one at 11:00 AM on day 5. All five test tubes were kept at 30°C to 35°C for 7 hours. 3. At 6:00 PM on the fifth day, 50 ml of sterilized soybean casein digest medium was added to another five (5) sterile test tubes. 1 ml of Solution A (antibiotic (nitrofurantoin) solution) was then added to test tubes 1, 2, 3, and 4. The thick plastic thread was transferred from the old test tube to the new test tube at 6:00 PM on the fifth day. All five (5) test tubes were kept at 30°C to 35°C overnight (17 hours). 4. At 6 pm on the sixth day, the threads were removed from all five test tubes. The transmittance of the medium in all five test tubes was checked at 590 nm. a. Test tube 1: with solution F (D-mannose) and A (antibiotics): 5.7 b. Test tube 2: Solution P (serrapeptidase) and A (antibiotic): 6.0 c. Test tube 3: with solutions F (D-mannose), P (serrapeptidase), and A (antibiotics): 10.7 d. Tube 4: With A (antibiotic): 6.9 e. Test tube 5: Blank: 8.8

[0054] Results - In both tests, the tubes with D-mannose, serratiopeptidase and antibiotics show higher penetration rates (less bacterial growth) than the tubes with D-mannose, or the tubes with serratiopeptidase, or the blank tube (antibiotics only).

Claims

1. a. a therapeutically effective amount of serratiopeptidase; b. a therapeutically effective amount of D-mannose or a salt thereof; and c. a therapeutically effective amount of one or more antibiotics 10. A pharmaceutical composition for inhibiting bacterial growth, comprising:

2. 2. The pharmaceutical composition of claim 1, wherein the serratiopeptidase is in an amount of 0.1 mg to 200 mg.

3. 3. The pharmaceutical composition according to claim 1, wherein the D-mannose is present in an amount between 0.1 mg and 1000 mg.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the antibiotic is selected from the group consisting of nitrofurantoin, ciprofloxacin, levofloxacin and azithromycin.

5. A pharmaceutical composition according to any one of claims 1 to 4 for use in a method for treating an infectious disease caused by a bacterium, comprising: said treating comprising administering a pharmaceutical composition; The administration may be in the same or different compositions, and the treatment may be administered to a human or an animal. The pharmaceutical composition.

6. The pharmaceutical composition according to claim 5, wherein the infectious disease is a urinary tract infection.

7. The pharmaceutical composition according to claim 5, wherein the infectious disease is a respiratory tract infection.

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