WO2020128928A1 - Formulation pour le traitement de troubles neurodégénératifs ainsi que de démyélinisation et neuropathiques et sa méthode de préparation - Google Patents

Formulation pour le traitement de troubles neurodégénératifs ainsi que de démyélinisation et neuropathiques et sa méthode de préparation Download PDF

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Publication number
WO2020128928A1
WO2020128928A1 PCT/IB2019/061061 IB2019061061W WO2020128928A1 WO 2020128928 A1 WO2020128928 A1 WO 2020128928A1 IB 2019061061 W IB2019061061 W IB 2019061061W WO 2020128928 A1 WO2020128928 A1 WO 2020128928A1
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Prior art keywords
formulation
solution
gel
administered
injection
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PCT/IB2019/061061
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English (en)
Inventor
Mihan JAFARI JAVID
Amir DADGARI
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Jafari Javid Mihan
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Publication of WO2020128928A1 publication Critical patent/WO2020128928A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/22—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • ALS amyotrophic lateral sclerosis
  • PBP progressive bulbar palsy
  • PMA Progressive Muscular Atrophy
  • PLS Primary Lateral Sclerosis
  • SMA Spinal Muscular Atrophy
  • 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.
  • 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.
  • Parkinson's disease is caused as a result of progressive death of neurons in substantia nigra, more specifically, in pars compacta.
  • 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.
  • emotional symptoms such as anxiety, depression and apathy and impairment of memory, attention and information processing speed
  • 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.
  • cognitive deficits that mainly affect attention, concentration, information processing speed, memory and executive functions.
  • 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.
  • 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.
  • a pharmaceutical composition for intranasal administration comprises clioquinol, dimethyl sulfoxide and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition for intranasal administration comprises insulin, clioquinol, dimethyl sulfoxide and at least one pharmaceutically acceptable excipient.
  • 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.
  • 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.
  • 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.
  • omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)
  • omega-6 fatty acids such as linoleic acid (LA) and
  • 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.
  • the invention provides compositions comprising one or more TRPV1 agonists exhibiting promyelinating activity for treatment of demyelinating 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.
  • Boric acid is a compound containing oxyanions.
  • the simplest borate anion is B033-.
  • boron exists commonly as mineral boron.
  • Boric acid is known for its biological activities such as antiseptic, antifungal, and antiviral properties.
  • 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.
  • 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.
  • 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.
  • the suitable solvents used are distilled water, normal saline, half saline, different type of Hydrophilic solvents.
  • 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% 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.
  • the liquid formulation is sterilized and prepared in different formulations accordingly.
  • 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.
  • the formulation of the invention in different concentrations is useful against various neurodegenerative disorders and demyelinating disorders, neuropathic pain, ophthalmic neuropathy and retinopathy.
  • 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.
  • FIG 1 tabulates the composition of the formulation of medication of the invention according to an embodiment of the invention.
  • FIG 2 illustrates a method of preparation of the formulation of the medication according to another embodiment of the invention.
  • Neurodegenerative Disease refers to the range of conditions that primarily affect the neurons in the human brain and peripheral nerves.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • Boric acid rapidly crosses the bloodstream through the gastrointestinal tract and hence is an effective element in the preparation of the formulation.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the suitable solvents used are distilled water, normal saline, half saline and different types of Ionic and hydrophilic solvents.
  • the solvent used is water.
  • 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.
  • step (203) The elements boric acid is added followed by potassium aluminum sulfate and sodium chloride.
  • step (203) the mixture is heated at 60° C with continuous stirring to form a clear liquid.
  • step (203) the liquid formulation is sterilized and prepared in different formulations accordingly.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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  • Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une formulation pour le traitement et la prévention de troubles neurodégénératifs et de démyélinisation. La formulation comprend de l'acide borique à une concentration de 0,5 % à 4 %, du sulfate de potassium et d'aluminium à une concentration de 0,01 % à 0,1 %, du chlorure de sodium à une concentration de 0,1 % à 0,9 % et de l'eau. L'invention concerne en outre une méthode de préparation de la formulation consistant à chauffer un solvant à une température s'inscrivant dans la plage de 500 à 600 °C pour dissoudre les éléments de la formulation. L'acide borique, le sulfate de potassium et d'aluminium et le chlorure de sodium sont ajoutés successivement au solvant chauffé pour former un mélange, que l'on chauffe à 600 °C pour former un liquide clair. La formulation est utile pour une injection ou une infiltration intratissulaire, une injection intrathécale, une injection intraépidurale, une utilisation orale ou entérale, une application topique, une injection intraveineuse, une injection intramusculaire contre divers troubles neurodégénératifs et troubles de démyélinisation et neuropathiques.
PCT/IB2019/061061 2018-12-19 2019-12-19 Formulation pour le traitement de troubles neurodégénératifs ainsi que de démyélinisation et neuropathiques et sa méthode de préparation WO2020128928A1 (fr)

Applications Claiming Priority (2)

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US201862781918P 2018-12-19 2018-12-19
US62/781,918 2018-12-19

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WO2020128928A1 true WO2020128928A1 (fr) 2020-06-25

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070105956A1 (en) * 2003-10-03 2007-05-10 Masao Sudoh Drug containing (2r)-2-propyloctanoic acid as the active ingredient
US20120322727A1 (en) * 2011-06-15 2012-12-20 Abdel Maksoud Yaser A Pharmaceutical Compositions for Intranasal Administration for the Treatment of Neurodegenerative Disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070105956A1 (en) * 2003-10-03 2007-05-10 Masao Sudoh Drug containing (2r)-2-propyloctanoic acid as the active ingredient
US20120322727A1 (en) * 2011-06-15 2012-12-20 Abdel Maksoud Yaser A Pharmaceutical Compositions for Intranasal Administration for the Treatment of Neurodegenerative Disorders

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