A formulation for treatment of neurodegenerative and demyelinating and neuropathic disorders and a method for preparation thereof

Technical field of the invention

[0001] The present invention relates to a pharmaceutical formulation of medication for the treatment and prevention of neurodegenerative and demyelinating disorders. More specifically, the invention relates to the formulation for treatment of neurodegenerative and demyelinating disorders in which the central nervous system and peripheral nervous system and the related organs are affected by these disorders and the invention also discloses a method for preparation of said formulation. Background of the invention

[0002] Neurodegenerative disorders are the heterogenous range of conditions that primarily affect the neurons in the human brain. Neurodegenerative disorders generally occur when the nerve cells in the brain or peripheral nervous system lose function over time and gradually die.

[0003] Myelin is an insulating layer that forms around nerves, including those in the brain and spinal cord. It is generally made up of protein and fatty substances. Myelin encases the axons of neurons forming a layer known as the myelin sheath, which allows electrical impulses to transmit quickly and efficiently along the nerve cells. The primary purpose of myelin is to increase the speed at which nerve impulses propagate down the neural axon. Myelin also prevents the electrical current from leaving the axon by increasing the electrical resistance across the cell membrane. [0004] The alteration in the myelin sheath results in condition called as demyelination. Neural demyelination is a condition, which is characterized by reduction of the myelin sheath in the nervous system and is the basis for the onset of many neurodegenerative disorders or injuries.

[0005] Neurons are the building blocks of the nervous system including brain and the spinal cord. Normally, neurons shall not reproduce or replace themselves, so in case of damage or cell death, it is not possible to be replaced by the body. [0006] The main categories of neurodegenerative disorders include Parkinson's disease, Alzheimer's disease, Prion disease, Motor Neuron Disease (MND), Spinoerebellar Ataxia (SCA), Spinal Muscular Atrophy (SMA) and Huntington's disease.

[0007] Similarly, the demyelinating disorders includes multiple sclerosis, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), Progressive Muscular Atrophy (PMA), Primary Lateral Sclerosis (PLS), Spinal Muscular Atrophy (SMA).

[0008] The neurodegenerative disorders are incurable and debilitating conditions due to progressive degeneration of nerve cells resulting in difficulties in movement termed as called ataxias or mental functioning termed as dementias.

[0009] Alzheimer's disease is associated with progressive formation of senile plaques and neurofibrillary tangles in the cerebral cortex as well as neuron and synapse loss. The disease is associated with the development of multiple cognitive deficits resulting in memory deterioration and impairment in language, praxis, gnosis or executive functions.

[0010] Parkinson's disease is caused as a result of progressive death of neurons in substantia nigra, more specifically, in pars compacta. As a result, the synthesis of dopamine is decreased causing a dysfunction in the regulation of major brain structures involved in the control of movement. The main symptoms are slowness of movement, lack of spontaneous motility, resting tremor and rigidity. In addition, it is also associated with emotional symptoms such as anxiety, depression and apathy and impairment of memory, attention and information processing speed

[0011] Multiple sclerosis is a demyelinating disease that damages the white matter covering the axons. The clinical manifestations of multiple sclerosis include motor weakness, visual impairment, diplopia, dysarthria, ataxia, etc. However, it is also associated with cognitive deficits that mainly affect attention, concentration, information processing speed, memory and executive functions.

[0012] Neurodegenerative or demyelinating disorders affect millions of people worldwide. Alzheimer's disease and Parkinson's disease are the most common neurodegenerative disorders and in 2016, an estimated 5.4 million Americans were suffering from Alzheimer's disease. An estimated 930,000 people in the United States could be affected by Parkinson's disease by 2020.

[0013] The risk of the neurodegenerative disease increases dramatically with age. This leads to a critical need to improve our understanding of what causes neurodegenerative disorders and develop new approaches for treatment and prevention. It has been recognized that the combination of a person's genes and environment contributes to their risk of developing a neurodegenerative disease. That is, a person might have a gene that makes them more susceptible to a certain neurodegenerative disease. But whether, when, and how severely the person is affected depends on environmental exposures throughout life.

[0014] The US Application "US20120322727A1" entitled " Pharmaceutical Compositions for Intranasal Administration for the Treatment of Neurodegenerative Disorders" discloses a pharmaceutical composition for intranasal administration comprising insulin, dimethyl sulfoxide and at least one pharmaceutically acceptable excipient. In another embodiment of the invention, a pharmaceutical composition for intranasal administration comprises clioquinol, dimethyl sulfoxide and at least one pharmaceutically acceptable excipient. In yet another embodiment of the invention, a pharmaceutical composition for intranasal administration comprises insulin, clioquinol, dimethyl sulfoxide and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions of the invention may be used to treat or prevent a neurodegenerative disorder such as Alzheimer's disease, stroke, Parkinson's disease, multiple sclerosis, spinal cord injuries, and/or traumatic brain injuries and the like, in addition to other systemic and local disorders. The pharmaceutically acceptable excipient is polyethylene glycol, propylene glycol, glycerin, boric acid, and sodium bicarbonate.

[0015] The Japanese Application "JP6092843B2" entitled "Composition for the treatment of neurological disorders" discloses a formulation for the treatment of neurological disorders such as neurodegenerative disorders, autoimmune disorders and multiple sclerosis. The invention discloses the use of certain polyunsaturated fatty acids namely omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and omega-6 fatty acids such as linoleic acid (LA) and gamma linolenic acid. It relates to the use of high doses of GLA at a specific rate resulting in normalization of the essential fatty acid content in the cell membrane. More specifically, the invention relates to a combination of EPA, DHA, LA and GLA.

[0016] The Canadian Application No "CA3017367A1" entitled "Methods and compositions for the treatment of demyelinating disorders" provides methods and compositions for repairing and maintaining the myelin sheath of neuronal axons in a subject. In particular, the invention provides compositions comprising one or more TRPV1 agonists exhibiting promyelinating activity for treatment of demyelinating disorders.

[0017] It is observed that apoptosis of the neurons is the main reason for the onset of the neurodegenerative disorders and demyelinating disorders. In addition, several researches proved the influential mechanism of apoptosis process and the analysis of probable effects of neuroprotective combinations in decreasing neuron apoptosis and preventing neuron apoptosis by neuroprotective combinations on human beings with neurodegenerative disorders.

[0018] It is required to regenerate neurons to treat neurodegenerative disorders and is challenging to regenerate the neurons in adults. Further, the absence of effective treatments is a challenge in the medical society.

[0019] There are different approaches to address the effective treatment of neurodegenerative disorders. Embryonic stem cells have been used in the treatment of certain types of neurodegenerative disorders but are associated with preservation limitations and the method by which the stem cells are extracted. Hence, there is no success in the treatment of these disorders.

[0020] In addition, different pharmaceutical drugs are analyzed for the treatment of neurodegenerative and demyelinating disorders. However, the neuroprotective agents are not completely effective in the treatment of these disorders and they remained incurable. The only medication available is Rilosol which does not exhibit considerable effect in the treatment of neurodegenerative disorders and other medications such as Tizanidin, Dantrolen, Benzodiazepines, Baclofens and other antidepressant and antipsychotic drugs are used to only control the symptoms but does not result in cure of the disorders.

[0021] As neurons are incapable of regenerating automatically or are associated with limited rate of cell growth in response to neuroprotectants, it is required to retain the health of neurons and drugs that control the apoptosis of the neurons plays an important role in the development of specific treatment for neurodegenerative disorders.

[0022] Boric acid is a compound containing oxyanions. The simplest borate anion is B033-. In the nature, boron exists commonly as mineral boron. Boric acid is known for its biological activities such as antiseptic, antifungal, and antiviral properties. [0023] Although few treatments may help in relieving some of the physical or mental symptoms associated with neurodegenerative disorders, there is currently no available treatment or treatments to delay the disease progression and cure.

[0024] Hence, there is a need for neuroprotectants to prevent the apoptosis of neurons thus preventing the progression of the neurodegenerative and demyelinating disorders. Summary of the invention

[0025] The invention discloses a pharmaceutical formulation for the treatment and prevention of neurodegenerative and demyelinating disorders, in which the central nervous system and peripheral nervous system and other related organs are affected by these disorders and the invention also discloses a method for preparation of said formulation.

[0026] The formulation of the invention comprises a combination of elements in which boric acid is used as main ingredient. The formulation comprises boric acid at a concentration in the range between 0.5% to 4% by weight, potassium aluminum sulfate at a concentration in the range between 0.01% to 0.1%, sodium chloride at a concentration in the range between 0.1% to 0.9% and water is used as solvent to dissolve the elements of the formulation. The combination of the specific elements of the formulation exhibits neuroprotective activity.

[0027] The invention further discloses a method for preparation of the formulation. The method of preparation of the formulation comprises of heating a suitable solvent at a temperature in the range between 500 to 600 C to dissolve the elements of the formulation. According to the embodiment of the invention, the suitable solvents used are distilled water, normal saline, half saline, different type of Hydrophilic solvents. After heating, boric acid at a concentration in the range between 0.5% to 4% by weight, potassium aluminum sulfate at a concentration in the range between 0.01% to 0.1% and sodium chloride at a concentration in the range between 0.1% to 0.9% are sequentially added to the solvent to form a mixture. The mixture is allowed to be heated to maximum 600 C with continuous stirring to form a clear liquid. Finally, the liquid formulation is sterilized and prepared in different formulations accordingly.

[0028] The formulation of the invention is useful and can be used in various modes of administration such as Intra tissue injection or infiltration, intrathecal injection, intra epidural injection, intra ventriculat ( brain) injection, oral or enteral usage, topical application, intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, intravitreal and topical applications. The formulation is preferably used in the form of solution or gel for effective treatment.

[0029] The formulation of the invention in different concentrations is useful against various neurodegenerative disorders and demyelinating disorders, neuropathic pain, ophthalmic neuropathy and retinopathy. [0030] The formulation exerts neuroprotection by retaining and preserving the rate of apoptosis of neurons thus delaying the death of neurons ultimately delaying the onset of progression of the neurodegenerative disorders.

Brief description of the drawings [0031] The foregoing and other features of embodiments will become more apparent from the following detailed description of embodiments, when read in conjunction with the accompanying drawings. In the drawings, like reference numerals refer to like elements.

[0032] FIG 1 tabulates the composition of the formulation of medication of the invention according to an embodiment of the invention. [0033] FIG 2 illustrates a method of preparation of the formulation of the medication according to another embodiment of the invention.

Detailed description of the invention

[0034] Reference will now be made in detail to the description of the present subject matter. Each embodiment is provided to explain the subject matter and not a limitation. These embodiments are described in sufficient detail to enable a person skilled in the art to practice the invention, and it is to be understood that other embodiments may be utilized, and that logical, physical, and other changes may be made within the scope of the embodiments. The following detailed description is, therefore, not be taken as limiting the scope of the invention, but instead the invention is to be defined by the appended claims. [0035] In order to more clearly and concisely describe and point out the subject matter of the claimed invention, the following definitions are provided for specific terms, which are used in the following written description.

[0036] The term "Neurodegenerative Disease", refers to the range of conditions that primarily affect the neurons in the human brain and peripheral nerves. [0037] The term "Demyelinating Disease", refers to conditions that results in damage to the protective covering myelin sheath that surrounds nerve fibers in brain, optic nerves, spinal cord and peripheral nerve. [0038] The invention discloses a formulation of medication for the treatment of neurodegenerative and demyelinating disorders of brain, central nervous system and peripheral nervous system of human. The invention further discloses a method for preparation of the formulation of the medication.

[0039] The formulation generally results in more efficacy in combination than used alone. The combination of specific ingredients of the formulation results in the additive effect and synergism in contrast of using alone. The combination of the components in the formulation exerts improved efficacy against the neurodegenerative and demyelinating disorders.

[0040] According to an embodiment of an invention, the invention discloses a formulation of medication for treatment of neurodegenerative and demyelinating disorders. The formulation is a combination of components that provides a new medication which is useful as a curative medication for the mentioned disorders. The formulation of medication of the invention is in the category of New Drug Application (NDA).

[0041] The formulation of the invention is combination of specific elements for the treatment of neurodegenerative and demyelinating disorders. The formulation comprises boric acid, potassium aluminum sulfate (KAI(S0 ) ₂ , sodium chloride (NaCI) and water in a specific weight to exert improved efficacy.

[0042] FIG 1 tabulates the composition of the formulation of medication of the invention. The formulation comprises boric acid at a concentration in the range between 0.5% to 4% by weight, potassium aluminum sulfate at a concentration in the range between 0.01% to 0.1%, sodium chloride at a concentration in the range between 0.1% to 0.9% and water is used as solvent to dissolve the elements of the formulation. The elements of the formulation of the invention exert neuroprotective activity.

[0043] Boric acid also called as hydrogen borate, boracic acid, orthoboric acid and when occurring as a mineral, boric acid is called as Sassolite. It is a weak monobasic Lewis acid of boron, which is the basic component in the formulation of the medication. Preferably, boric acid is used as an antiseptic for minor burns or cuts. It exists in the form of colorless crystal or a white powder that is soluble in water and incorporates into biochemical processes.

[0044] Boric acid rapidly crosses the bloodstream through the gastrointestinal tract and hence is an effective element in the preparation of the formulation. In addition to water, boric acid is soluble in other ionic solvents. Boric acid is soluble in normal saline, half saline, distilled water, boiled water, different type of alcohols, hydrocortisone solution and etc.

[0045] Potassium aluminum sulfate called as potash alum is the double sulfate of potassium and aluminum. It is generally used as adjuvant to enhance the efficacy of boric acid in the formulation. The concentration of potassium aluminum sulfate used in the formulation is at a concentration of 0.01% to 0.1%. Potassium aluminum sulfate improves the aspect of learning, memory and other behavioral aspects in human.

[0046] Sodium chloride is one of the most abundant minerals on earth and an essential nutrient for many of the biological processes to absorb and transport nutrients. Sodium chloride representing 1:1 ratio of sodium and chloride ions helps in maintaining the balance of the fluids in the body. Alzheimer's disease is associated with impaired glutamate clearance and depressed Na+/K+ ATPase levels in brain that might lead to a cellular ion imbalance. This ion imbalance contributes to the pathophysiology of Alzheimer's disease. The presence of sodium chloride in the formulation restores the ion imbalance in the brain thus reducing the alleviation of the disease.

[0047] The elements of the formulation are mixed in mentioned concentration and dissolved in water to obtain a formulation which is effective in treatment and prevention of neurodegenerative disorders.

[0048] According to another embodiment, the invention discloses a method for preparation of the formulation of the medication. The method of preparation of the formulation comprises the steps of dissolving mentioned elements in a suitable solvent to obtain a homogenous mixture that is effective in treatment and prevention of neurodegenerative disorders.

[0049] FIG 2 illustrates a method of preparation of the formulation of the medication. The method (200) of preparation of the formulation starts at step (201) of heating a suitable solvent at a temperature in the range between 500 to 600 C to dissolve the elements of the formulation. According to the embodiment of the invention, the suitable solvents used are distilled water, normal saline, half saline and different types of Ionic and hydrophilic solvents. Preferably, the solvent used is water. At step (202), boric acid at a concentration in the range between 0.5% to 4% by weight, potassium aluminum sulfate at a concentration in the range between 0.01% to 0.1% and sodium chloride at a concentration in the range between 0.1% to 0.9% are added to the boiling water one by one to form a mixture. The elements boric acid is added followed by potassium aluminum sulfate and sodium chloride. At step (203), the mixture is heated at 60° C with continuous stirring to form a clear liquid. At step (203), the liquid formulation is sterilized and prepared in different formulations accordingly.

[0050] The method of the formulation of the invention results in the formulation which is effective against neurodegenerative disorders and demyelinating disorders. The method further results in simple, cost-effective approach for the preparation of formulation without the need of complex steps of scaling.

[0051] The formulation of the invention with boric acid as an active ingredient is effective in reducing the rate of apoptosis of neurons in brain thus reducing the death of normal cells.

[0052] The formulation of the invention is effective in restoring the myelin sheath thus preserving the integrity of the myelin layer and is effective against demyelinating disorders.

[0053] In certain embodiments, the formulation of the invention is used in various formulations. The formulation of the invention is available in different formulations such as Intra tissue injectable solution, intrathecal, intra ventricular, intra epidural space, oral, enteral, intravenous, topical, enteral, parental and etc. [0054] In certain embodiments, the formulation of the invention is prepared in the form of a solution or a gel. The solution or gel formulation of the invention is useful for different modes of delivery such as Intra tissue injection or infiltration, intrathecal, intra ventricular, intra epidural space, oral or enteral usage, intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, intravitreal and topical applications. [0055] The main advantage of the formulation of the invention results is curative than conservative in nature. The combination of formulation exhibits treatment as well as preventive measures due to the presence of boric acid and its activity is enhanced by the presence of adjuvant alum sulfate with the effect of improving the aspect of learning, memory and other behavioral aspects in human. [0056] The effectiveness of the formulation of the invention is shown by utilizing known models for neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and other nervous system and systemic disorders. The formulation is also effective in reducing the neuropathic pain and ophthalmic neuropathy and retinopathy. [0057] While the invention has been described with reference to certain embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from its scope. Therefore, it is intended that the invention not be limited to any particular embodiment disclosed.