WO2021165859A1

WO2021165859A1 - A composition comprising vitamin k2-7 in combination with vitamin k-1 in purest form

Info

Publication number: WO2021165859A1
Application number: PCT/IB2021/051357
Authority: WO
Inventors: Yogesh Dound
Original assignee: Yogesh Dound
Priority date: 2020-02-19
Filing date: 2021-02-18
Publication date: 2021-08-26

Abstract

The present invention relates to a composition comprising vitamin K2-7 in combination with vitamin K1 in purest form and a process for preparing the same. The vitamins are present in purest form without any impurity in the same. The compositions according to the present invention are fixed dose combination and oral solid dosage form.

Description

A COMPOSITION COMPRISING VITAMIN K2-7 IN COMBINATION WITH

VITAMIN K1 IN PUREST FORM.

PRIORITY:

This application claims the benefit of Indian complete application number 202021007016 dated 19^th Feb 2020 entitled, ‘A composition comprising Vitamin K2-7 in combination with vitamin K1 in purest form’, the contents of which are incorporated herein by reference.

Technical field of the invention:

The present invention relates to a composition comprising vitamin K2-7 in combination with vitamin K1 in purest form and a process for preparing the same.

Background of the invention:

Vitamin K2-7, also known as menaquinone supports healthy bone mineralization by acting as a cofactor in the carboxylation of osteocalcin, allowing calcium to bind to this protein in the extracellular matrix of bone.

Phytomenadione, also known as vitamin K1 or phylloquinone, is a vitamin found in food and used as a dietary supplement. As a supplement it is used to treat certain bleeding disorders. This includes in warfarin overdose, vitamin K deficiency, and obstructive jaundice. It is also recommended to prevent and treat hemorrhagic disease of the newborn. Use is typically recommended by mouth or injection under the skin. Use by injection into a vein or muscle is recommended only when other routes are not possible. When given by injection benefits are seen within two hours.

US20130045179 discloses therapy and methods for the treatment and prevention of diseases of cell proliferation such as cancer, benign tumors, and viral diseases such as HIV-AIDS, hepatitis B, hepatitis C and cirrhosis. The methods of this invention consist of the administration to a patient of a combination of effective amounts of agents capable of eradicating the neoplastic cells, while sparing the non-neoplastic cells from cytotoxic side- effects. The agents coadministered in therapeutically effective amounts are: chemotherapeutic agents, apoptotic agents, anti-angiogenic agents, cell differentiation agents, immunomodulating agents, antioxidants, vitamins, microelements, enzymes and natural extracts.

Hepatitis B is an infection of your liver. It can cause scarring of the organ, liver failure, and cancer. It can be fatal if it isn’t treated. It spreads when people come in contact with the blood, open sores, or body fluids of someone who has the hepatitis B virus.

The "WHO guidelines for the prevention, care and treatment of persons living with chronic hepatitis B infection" lay out a simplified approach to the care of people living with chronic hepatitis B, particularly in settings with limited resources. The preferred drugs that are recommended in the guidelines are tenofovir and entecavir. They have a very low risk of developing drug resistance, are easy to take as one pill once a day, and have few side effects.

Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV). Following initial infection a person may not notice any symptoms, or may experience a brief period of influenza-like illness. Typically, this is followed by a prolonged period with no symptoms. If the infection progresses, it interferes more with the immune system, increasing the risk of developing common infections such as tuberculosis, as well as other opportunistic infections, and tumors which are otherwise rare in people who have normal immune function. These late symptoms of infection are referred to as acquired immunodeficiency syndrome (AIDS). This stage is often also associated with unintended weight loss.

Treatment consists of highly active antiretroviral therapy (HAART) which slows progression of the disease. Current HAART options are combinations (or "cocktails") consisting of at least three medications belonging to at least two types, or "classes", of antiretroviral agents. Initially, treatment is typically a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside analog reverse transcriptase inhibitors. Typical NRTIs include: zidovudine (AZT) or tenofovir (TDF) and lamivudine (3TC) or emtricitabine (FTC). As of 2019, dolutegravir/lamivudine/tenofovir is listed by the World Health Organization as the first-line treatment for adults, with tenofovir/lamivudine/efavirenz as an alternative. Combinations of agents that include protease inhibitors (PI) are used if the above regimen loses effectiveness.

Hepatitis B virus (FIBV) and human immunodeficiency virus (HIV) are bloodborne viruses transmitted primarily through sexual contact and injection drug use. Because of these shared modes of transmission, people at risk for FI IV infection are also at risk for FIBV infection. Hepatitis C virus (FICV) is a bloodborne virus transmitted through direct contact with the blood of an infected person. It is estimated that FICV affects 2-15% of people living with H IV worldwide (and up to 90% of those are people who inject drugs (PWID)) and that chronic FIBV infection affects an estimated 5-20% of people living with FI IV. The global estimate of burden of FIIV-FICV co-infection is 2.75 million of whom 1.3 million are PWID, and for HBV-HCV coinfection of 2.6 million. The burdens of these co-infections are greatest in the African and South East Asia Regions.

The inventors of the present invention have developed a composition comprising vitamin K-2 in combination with vitamin K-1 in purest form for the treatment of hepatitis B and FI IV infection.

Objects of the invention:

An object of the present invention is to provide a composition comprising vitamin K-2 in combination with vitamin K-1 in purest form.

Yet another object of the present invention is to provide a synergistic composition comprising vitamin K-2 in combination with vitamin K-1 in purest form and a process for preparing the same. Other objects and benefits of the present invention will be more apparent from the following description, which is not intended to bind the scope of the present invention.

Summary of the invention:

The present invention relates to a synergistic pharmaceutical composition comprising vitamin K2-7 and vitamin K1.

In an aspect of the embodiment, vitamin K2-7 and vitamin K1 are used in purest form.

In another aspect of the embodiment, vitamin K2-7 and vitamin K1 are present in a fixed dose combination.

In yet another aspect of the embodiment, the composition is a solid oral dosage form.

In a further aspect of the embodiment, vitamin K2-7 is present in a dose range of 5 microgram to 1200 microgram.

In one more aspect of the embodiment, vitamin K1 is present in a dose range of 1 microgram to 1100 microgram.

In a further aspect of the embodiment, the ratio of vitamin K2-7 and vitamin K1 is between 1 : 1000 to 1000: 1.

In an aspect of the embodiment, the composition is administered orally.

In another aspect of the embodiment, the composition is used for the treatment of hepatitis B.

In one of the aspects of the embodiment, the composition is used for the management of HIV infection. Detailed description of the invention:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The terms used in the specification are defined as follows.

As used herein, the terms "comprising" (and any form of comprising, such as "comprise", "comprises", and "comprised"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include"), or "containing" (and any form of containing, such as "contains" and "contain"), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

A "subject," "individual," or "patient," is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Tissues, cells and their progeny of a biological entity obtained in vitro or cultured in vitro are also encompassed.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e. , meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non- claimed element as essential to the practice of the invention.

As used herein, the terms "treat," "treated," or "treating" mean both therapeutic treatment or prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or obtain beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i.e. , not worsening) state of condition, disorder or disease; delay in onset or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder or disease.

In an aspect of the embodiment, vitamin K2-7 and vitamin K1 are used in purest form. The purest form as used herein includes without any impurity present in it.

The compositions comprise one or more inert excipients. The term "inert excipients", denotes any of the components of a composition other than the active and which are approved by regulatory authorities or are generally ‘regarded as safe’ for human or animal use. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function. In a further aspect, the composition further comprises pharmaceutically acceptable inert excipients. The pharmaceutically acceptable inert excipients comprise binders; diluents; lubricants; disintegrating agents; glidants; stabilizers; dissolution enhancing agents; pH modifiers or surface active agents.

Examples of binders include, potato starch; pregelatinized starch; modified starch; gelatin; wheat starch; corn starch; celluloses such as methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose and sodium carboxy methyl cellulose; hydroxypropyl Starch, polymethacrylates; carbomers; natural gums such as acacia, alginic acid and guar gum; lactose (anhydrous, monohydrate, spray dried); liquid glucose; dextrin; sodium alginate; kaolin; povidone; syrup; polyethylene oxide; polyvinyl pyrrolidone; poly vinyl alcohol; poly-N-vinyl amide; polyethylene glycol; sucrose; polydextrose; gelatin; poly propylene glycol; tragacanth; ceratonia; glycerylbehenate; hydrogenated vegetable oil; zein; castor oil; paraffin; higher aliphatic alcohols; higher aliphatic acids; long chain fatty acids; fatty acid esters; agar; chitosan; maltodextrin; magnesium aluminum silicate; inulin and wax-like materials such as fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, stearic acid; Copovidone; dextrates, sunflower oil and stearyl alcohol.

Examples of diluents include microcrystalline cellulose; lactose, cellulose powdered, cellulose silicified, cellulose acetate, methyl cellulose, microcrystalline lactose; dibasic or tribasic calcium phosphate; saccharides; confectioner's sugar; compressible sugar; confectioner's sugar; sugar spheres; dextrates; dextrin; dextrose; fructose; maltose; sodium chloride; lactitol; maltodextrin; mannitol; sucrose; fructose; glycerylpalmitostearate; semithicone; Magnesium aluminum silicate; starch; pregelatinized starch; maltitol; xylitol; erythritol; isomalt; sorbitol; sulfobutylether b-cyclodextrin, polymethacrylates; talc; trehalose; ammonium alginate; calcium carbonate; ethyl cellulose; magnesium carbonate; magnesium oxide and calcium sulphate. The disintegrating agents include povidone, low-substituted hydroxypropyl cellulose; cross-linked polyvinyl pyrrolidone; cross-linked sodium carboxymethylcellulose; hydroxypropyl starch; sodium starch glycolate; sodium starch glycolate; sodium carboxymethylcellulose; carboxymethyl cellulose calcium; sodium carboxymethyl starch; ion-exchange resins such as polacrillin potassium; microcrystalline cellulose; starches and pregelatinized starch; formalin-casein; clays such as bentonite or veegum; guar gum; celluloses or cellulose derivatives; sodium alginate; calcium alginate; alginic acid; chitosan; magnesium aluminum silicate; colloidal silicon dioxide.

The lubricants may be selected from Mg, Al, Ca or Zn stearate; polyethylene glycol; polyvinyl alcohol; glycerylbehenate; glyceryl monostearate; Glycerylpalmitostearate; potassium benzoate; sodium benzoate; mineral oil; sodium stearylfumarate; palmitic acid, myristic acid; stearic acid; hydrogenated vegetable oil; hydrogenated castor oil; talc; hydrogenated soybean oil; stearyl alcohol; leucine; sodium lauryl sulfate; ethylene oxide polymers; poloxamer; octyldodecanol; Sodium stearylfumarate and colloidal silica.

The stabilizers may be selected from naturally occurring as well as synthetic phospholipids, their hydrogenated derivatives and mixtures thereof; organic acids like acetic acid, tartaric acid, citric acid, fumaric acid, lactic acid, and mixtures thereof sphingolipids and glycosphingolipids; physiological bile salts such as sodium cholate, sodium dehydrocholate, sodium deoxycholate, sodium glycocholate and sodium taurocholate; saturated and unsaturated fatty acids or fatty alcohols; ethoxylated fatty acids or fatty alcohols and their esters and ethers; alkylaryl-polyether alcohols such as tyloxapol; esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols; acetylated or ethoxylated mono- and diglycerides; synthetic biodegradable polymers like block co-polymers of polyoxyethylene and polyoxypropyleneoxide; ethoxylatedsorbitanesters or sorbitanethers; amino acids, polypeptides and proteins such as gelatine and albumin; or combination thereof. The glidants may be selected from magnesium trisilicate; powdered cellulose; starch; talc; tribasic calcium phosphate; calcium silicate; magnesium silicate; magnesium trisilicate; colloidal silicon dioxide; and silicon hydrogels.

Dissolution enhancing agents may be selected from, but are not limited to, organic acids, inorganic acids or combination thereof. The organic acids include, but not limited to citric acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic acid, oxalic acid, aspartic acid, mandelic acid, glutaric acid, and glutamic acid. The inorganic acids include but not limited to hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid.

Other agents like pH modifiers such as acetic acid/alkali metal acetate, fumaric acid/alkali metal fumarate, succinic acid/alkali metal succinate, citric acid/alkali metal citrate, tartaric acid/alkali metal tartrate, lactic acid/alkali metal lactate, maleic acid/alkali metal maleate, methanesulphonic acid/alkali metal methanesulphonate, monoalkali metal phosphate, the alkali metal in each of the above salts being, for example, sodium or potassium, etc may also be added in the pharmaceutical composition.

The surface active agents used may be hydrophilic, hydrophobic or combination thereof. Hydrophilic surfactants may be either ionic or non-ionic.

Suitable hydrophilic ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di glycerides; ammonium lauryl sulfate, sodium lauryl sulfate, sodium myreth sulfate, dioctyl sodium sulfosuccinate, perfluorooctanesulfonate, perfluorobutanesulfonate, alkyl benzene sulfonates, alkyl aryl ether phosphate, alkyl ether phosphate, alkyl carboxylates like, fatty acid salts, sodium stearate, sodium lauroylsarcosinate, octenidinedihydrochloride, cetyltrimethylammonium bromide (CTAB) or hexadecyltrimethyl ammonium bromide, cetyltrimethylammonium chloride (CTAC), cetylpyridinium chloride (CPC), polyethoxylated tallow amine (POEA), benzalkonium chloride (BAC), benzethonium chloride (BZT), 5-Bromo-5-nitro-1 ,3-dioxane, dimethyldioctadecylammonium chloride, dioctadecyldimethylammonium bromide (DODAB), cocam idopropylbetaine, cocam idopropylhydroxysultaine and mixtures thereof.

Suitable hydrophilic non-ionic surfactants include alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylenealkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylenesorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof.

Suitable lipophilic surfactants include, but are not limited to fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

In a further aspect of the embodiment, vitamin K2-7 is present in a dose range of 5 microgram to 1200 microgram. In one more aspect of the embodiment, vitamin K1 is present in a dose range of 1 microgram to 1100 microgram. In a further aspect of the embodiment, the ratio of vitamin K2-7 and vitamin K1 is between 1 : 1000 to 1000: 1.

In an aspect of the embodiment, the composition is administered orally.

In another aspect of the embodiment, the composition is used for the treatment of hepatitis B. It may be chronic or acute. In one of the aspects of the embodiment, the composition is used for the management of HIV infection. The combination provides its effect for the treatment of hepatitis B and management of HIV infection by

• preventing viral replication by inhibiting viral DNA polymerase;

• binding to specific cell-surface receptors and inhibiting viral penetration or uncoating;

• inhibiting viral protein synthesis; or blocking late stages of virus assembly.

In an aspect of the embodiment, vitamin K2-7 and vitamin K1 is used for the treatment of hepatitis B and/or management of HIV infection individually, concurrently or in a fixed dose combination. The pharmaceutical compositions of the invention can be prepared combining an active pharmaceutical ingredient of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid forms, such as tablets, capsules, powders, granules and microspheres.

The pharmaceutical compositions according to the present invention are prepared according to the conventional methods of preparation which are known to ordinary skilled in the art and may include the methods like dry granulation, wet granulation or direct compression.

Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient may take the form of one or more dosage units.

The foregoing examples are illustrative embodiments and are merely exemplary. A person skilled in the art may make variations and modifications without deviating from the spirit and scope of the invention. All such modifications and variations are intended to be included within the scope of the claims.

Example 1: Composition according to the invention:

The ingredients were mixed to obtain a mixture, which is compressed to obtain tablets.

Claims

aim:

1. A synergistic pharmaceutical composition comprising vitamin K2-7 and vitamin K1.

2. The pharmaceutical composition as claimed in claim 1, wherein vitamin K2-7 and vitamin K1 are used in purest form.

3. The pharmaceutical composition as claimed in claim 1, wherein vitamin K2-7 and vitamin K1 are present in a fixed dose combination.

4. The pharmaceutical composition as claimed in claim 1, wherein the composition is a solid oral dosage form.

5. The pharmaceutical composition as claimed in claim 1, wherein vitamin K2-7 is present in a dose range of 5 microgram to 1200 microgram.

6. The pharmaceutical composition as claimed in claim 1, wherein vitamin K1 is present in a dose range of 1 microgram to 1100 microgram.

7. The pharmaceutical composition as claimed in claim 1, wherein the ratio of vitamin K2-7 and vitamin K1 is between 1:1000 to 1000:1.

8. The pharmaceutical composition as claimed in claim 1, wherein the composition is administered orally.

9. The pharmaceutical composition as claimed in claim 1, wherein the composition is used for the treatment of hepatitis B.

10. The pharmaceutical composition as claimed in claim 1, wherein the composition is used for the management of HIV infection.