CN113924098A

CN113924098A - Methods for treating mental disorders, behavioral disorders, cognitive disorders

Info

Publication number: CN113924098A
Application number: CN201980095741.3A
Authority: CN
Inventors: ***; 崔歌平
Original assignee: La Pharmaceutical Research Technology Co ltd
Current assignee: La Pharmaceutical Research Technology Co ltd
Priority date: 2019-04-30
Filing date: 2019-04-30
Publication date: 2022-01-11
Also published as: AU2019443520A1; WO2020222799A1; CA3137393A1; EP3962488A4; JP2022536017A; EP3962488A1

Abstract

Methods of treating a patient suffering from or exhibiting symptoms of a psychiatric, behavioral, and/or cognitive disorder with azelastine or a pharmaceutically acceptable salt of azelastine are disclosed.

Description

Methods for treating mental disorders, behavioral disorders, cognitive disorders

Technical Field

The present invention relates to the field of practical medicine, namely to the use of pharmaceutical compositions that show a neurotropic effect (neurotropic action), that reduce the clinical manifestations of psychotic disorders, behavioral disorders or cognitive disorders in the context of organic lesions of various origin of the central nervous system.

Background

Alzheimer's Disease (AD) is a progressive, chronic neurodegenerative disease that generally begins slowly and gradually worsens over time. In the elderly, AD is the most common cause of dementia. Dementia is a loss of cognitive function (thinking, memory and reasoning) and behavioral abilities to the extent of interfering with a person's daily life and activities. In its early stages, memory loss is mild, but in the case of late-stage AD, individuals lose the ability to engage in conversations and react to the environment in which they are located. AD eventually leads to death if left untreated. Typical life expectancy after diagnosis is 3 to 9 years, although the rate of progression may vary.

The core mechanism of learning and memory is long-term potentiation (LTP). LTP is mediated by the neurotransmitter glutamate via the N-methyl-D-aspartate (NMDA) receptor. NMDA receptors can be found widely throughout the brain. However, they are densely distributed in the dendrites of pyramidal cells in the hippocampus and cortex (areas known to be associated with cognition, learning, and memory). In addition to the relationship between LTP and learning, elevated glutamate levels are associated with excitotoxicity. Long-term low dose administration of NMDA receptor agonists has been shown to induce apoptosis, while high doses induce necrosis. Activation of glutamate receptors has also been found to induce glutamate release. Therefore, a large accumulation of glutamic acid occurs and Ca is induced²⁺Is accumulated in large amounts, resulting in apoptosis. Amyloid- β (AB) plaques have also been noted to increase the vulnerability of neurons to excitotoxicity. It was found that AB plaques (pathological feature of AD) induce depolarization of astrocytes, extracellular accumulation of glutamate and Ca²⁺Is deposited intracellularly. Therefore, glutamate-induced excitotoxicity pathways are excellent targets for the treatment of AD.

Under physiological conditions, glutamate released by neurons is metabolized or absorbed by neighboring cells. When these pathways are interrupted, the accumulated glutamate overactivates the NMDA receptor and induces the pathological features of neurodegenerative diseases. NMDA receptor agonizing calcium [ II ]]Ion (Ca)²⁺) The action of channels which are activated upon binding by glycine, glutamate and/or NMDA. However, only when the channel is covered by magnesium [ II ]]Ion (Mg)²⁺) Channels function when they block, leading to depolarization of the cell membrane. This prevents Ca when neurons are resting²⁺The internal flow of (2). In pathological conditions, e.g. chronic curePolarized film, Mg²⁺Leave the channel and neuronal metabolism is inhibited, leading to cell death. When this happens, Ca²⁺The time during which the internal flow is not restricted is longer than normal. Such Ca²⁺The influx of (a) contributes to the alteration of cellular function, leading to cell death by free radical or by mitochondrial overload, resulting in free radical formation, caspase activation and release of apoptosis-inducing factors. Antagonists of NMDA differ in affinity and in site of action, resulting in different changes to the channel. Regardless of the mechanism of action, antagonists decrease the permeability of the channel and prevent Ca²⁺The internal flow of (2). Therefore, NMDA receptor antagonists are considered as potential neuroprotective agents and potential therapies for neurodegenerative diseases.

Most NMDA antagonists are competitive antagonists and are not well tolerated by patients due to side effects that can include hallucinations and schizophrenic symptoms. Side effects are likely due to the competitive antagonist blocking the physiological function of the NMDA receptor. Its role in cognition, memory and learning makes any drug that uses the NMDA receptor as a target of action must retain physiological function to be therapeutically useful. Memantine acts on activated NMDA receptors by binding to sites located in the receptor's channels. However, memantine will not cure AD or prevent loss of these abilities at some point in the future. Therefore, there is currently no cure for AD, and the inventors' efforts are to find better ways to reverse the disease, delay and prevent its development.

On the other hand, genetic, cellular and molecular changes associated with AD support evidence that activated immune and inflammatory processes are part of the disease. In addition, epidemiological studies have shown that there is great benefit to the long-term use of NSAIDs. Thus, AD is generally considered to be in part an inflammatory disease and inhibition of inflammation is one option for treating AD.

Inflammation apparently occurs in the pathologically vulnerable areas of the AD brain and it occurs with the full complexity of local peripheral inflammatory responses. Peripherally, degenerated tissue and the deposition of highly insoluble foreign bodies are typical stimulators of inflammation. Similarly, in AD brain, damaged neurons and neurites, as well as highly insoluble amyloid beta peptide deposits and neuronal fiber entanglement provide a significant stimulus for inflammation. Since these stimuli are discrete, micro-localized and present from the early preclinical stage to the end of AD, local upregulation of complement, cytokines, acute phase reactants and other inflammatory mediators is also discrete, micro-localized and long-term. Over the years, direct and indirect damage from the inflammatory mechanisms of AD is likely to dramatically exacerbate the pathogenic processes that lead to AD. Thus, animal models and clinical studies to date strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding the inflammatory and immunoregulatory processes of AD, it should be possible to develop anti-inflammatory methods that can reverse or delay or prevent the development of this destructive disorder.

Azelastine is pharmacologically classified as a second generation antihistamine and is a relatively selective, non-sedating, competitive antagonist of the H1 receptor. More particularly, in addition to its antihistaminic and mast cell stabilizing effects, its inhibition of inflammatory mediators makes it a new generation of dual-effect anti-inflammatory agents. In addition to the high affinity of azelastine for the H1 receptor, its ability to modify several other inflammatory and allergic mediators contributes to its mechanism of action. In vitro and in vivo studies as well as clinical trials support the dual role of directly inhibiting and stabilizing inflammatory cells. In vitro data indicate that the affinity of azelastine for the H1 receptor is estimated to be several-fold higher than that of chlorpheniramine (first generation H1 antagonist). Azelastine has only a weak affinity for the H2 receptor. Histamine release from mast cells may also be inhibited by reversible inhibition of voltage-dependent L-type calcium channels. Among other things, inhibiting mast cell degranulation can also reduce the release of other inflammatory mediators, including leukotrienes and interleukin-1 β. Azelastine also directly antagonizes other inflammatory mediators, such as tumor necrosis factor- α, leukotrienes, endothelin-1, and platelet activating factor.

Disclosure of Invention

The present invention includes methods for finding administration of azelastine or a pharmaceutically acceptable salt of azelastine to a patient for the treatment of psychiatric, behavioral, cognitive disorders.

In some embodiments of the invention, the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.

In some embodiments of the invention, azelastine hydrochloride is provided in a daily effective amount of about 4mg to about 40 mg.

The invention also includes oral pharmaceutical dosage forms in the form of a pharmaceutically acceptable salt of azelastine as a solid or liquid form.

The invention further includes medical use of an oral pharmaceutical dosage form of azelastine or a pharmaceutically acceptable salt of azelastine, comprising administering the dosage form to a patient suffering from a psychiatric disorder, a behavioral disorder, a cognitive disorder such as alzheimer's disease, vascular dementia, huntington's disease, frontotemporal dementia, traumatic brain injury, corticobasal degeneration and/or parkinson's disease.

In some embodiments of the invention, an oral pharmaceutical dosage form of azelastine hydrochloride is administered once daily or twice daily to a patient with alzheimer's disease in a daily effective amount of about 8mg to about 16 mg.

Detailed Description

The inventors of the present invention have surprisingly found that a higher oral dose of azelastine or a pharmaceutically acceptable salt of azelastine is suitable for treating patients suffering from mental disorders, behavioral disorders, cognitive disorders.

The detailed description provided below is intended as a description of the present examples and is not intended to represent the only forms in which the present examples may be constructed or utilized. The description sets forth the functions of the example and the sequence of steps for constructing and operating the example. However, the same or equivalent functions and sequences may be accomplished by different examples.

Definition of

As used in this specification, the following words and phrases are generally intended to have the meanings as set forth below, unless the context in which they are used indicates otherwise.

Psychotic disorders, behavioral disorders, cognitive disorders including alzheimer's disease, vascular dementia, huntington's disease, frontotemporal dementia, traumatic brain injury, corticobasal degeneration, or parkinson's disease, and combinations of any of these with other neurodegenerative disorders.

As used herein, the term "azelastine" refers to azelastine free base or 4- (p-chlorobenzyl) -2- (hexahydro-1-methyl-1H-aza-1H-as

-4-yl) -1- (2H) -phthalazinone. In certain embodiments, azelastine also includes any pharmaceutically acceptable salt, such as the hydrochloride or HCl salt. Preferably, in any embodiment of the invention as described herein, the azelastine is in the form of its hydrochloride salt, such as azelastine hydrochloride or azelastine HCl. More preferably, in any embodiment of the invention as described herein, reference to the amount and dosage range of azelastine in an oral dosage form refers to the amount and dosage range of azelastine hydrochloride.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt of azelastine formed with an acid selected from the group consisting of: 1-hydroxy-2-naphthoic acid, 2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), decanoic acid (capric acid) (decanoic acid)), hexanoic acid (caproic acid) (hexanoic acid), octanoic acid (caprylic acid) (octanoic acid)), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid (galactaric acid), gentisic acid, glucoheptonic acid (D), gluconic acid (D), Glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid (pamoic acid), phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+ L), thiocyanic acid, toluenesulfonic acid (p), undecylenic acid.

As used herein, "treating" or "treatment" means either a complete cure or an incomplete cure, or it means that the symptoms of the underlying disease or related condition are at least reduced and/or delayed, and/or one or more of the underlying cellular, physiological, or biochemical causes or mechanisms causing the symptoms are reduced, delayed, and/or eliminated. It is to be understood that alleviating or delaying as used in this context means a state relative to the untreated disease, including the molecular state of the untreated disease, and not just the physiological state of the untreated disease.

The term "effective amount" refers to an amount, as defined below, that is sufficient therapeutically to affect treatment when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending on the patient being treated, the weight and age of the patient, the severity of the disease condition and the mode of administration, and the like, which can be readily determined by one of ordinary skill in the art. The pharmaceutically acceptable salt of azelastine can be administered by oral administration in a single dose or in multiple doses. Can be administered via capsule or tablet.

As used herein, the term "about" as used in the context of quantitative measurements means the specified amount ± 10%. For example, "about 5 mg" in the case of a range of ± 10% may mean 4.5-5.5 mg.

Oral Dosage Forms of azelastine or a pharmaceutically acceptable salt of azelastine in amounts of about 4mg to about 40mg can be formulated for Pharmaceutical use using methods known in the art, e.g., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 10 th edition (Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Vol.1-6, Sarfaraz K.Niazi). Thus, the incorporation of the active compound and a controlled or sustained release matrix can be carried out.

Fluid or solid unit dosage forms can be readily prepared for oral administration. For example, with conventional ingredients such as dicalcium phosphate, magnesium aluminum silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, acacia, methylcellulose and functionally similar materials as pharmaceutical excipients or carriers. Sustained release formulations may optionally be used. In older or allopathic subjects, sustained release formulations may even be preferred. Capsules may be formulated by mixing the compound with an inert pharmaceutical diluent and filling the mixture into hard gelatin capsules of suitable size. If a soft capsule is desired, a slurry of the pharmaceutically acceptable salt of azelastine with an acceptable vegetable oil, light petroleum oil, or other inert oil can be encapsulated by forming into a gelatin capsule.

Suspensions, syrups and elixirs may be employed for oral administration or in the form of fluid units. Fluid formulations containing oil may be used in the oil soluble form. Vegetable oils such as corn, peanut or flower oil (flower oil), for example, together with flavoring agents, sweetening agents and any preservatives, produce acceptable fluid formulations. Surfactants may be added to water to form a syrup for a fluid unit dose. Aqueous-alcoholic pharmaceutical preparations in the form of elixirs with acceptable sweetening agents, such as sugar, saccharin or the biological sweeteners, and flavoring agents may be used.

By solid oral formulation of a pharmaceutically acceptable salt of azelastine in the present disclosure is meant the form of a tablet, caplet, bilayer tablet, film-coated tablet, pill or capsule, and the like. Tablets according to the present disclosure may be prepared by any mixing and tableting technique well known in the pharmaceutical formulation industry. In some examples, the formulation is manufactured by directly compressing the separately prepared sustained-release part and immediate-release part by means of a punch and a die mounted to a rotary tablet press, ejecting or compression molding, or granulating after compression.

The pharmaceutically acceptable salts of azelastine provided according to the present disclosure are typically administered orally. Accordingly, the present disclosure provides a pharmaceutically acceptable salt of azelastine comprising a solid dispersion comprising a pharmaceutically acceptable salt of azelastine in an amount from about 4mg to about 40mg as described herein and one or more pharmaceutically acceptable excipients or carriers including, but not limited to, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, disintegrants, lubricants, binders, glidants, adjuvants, and combinations thereof. Such compositions are prepared in a manner well known in the Pharmaceutical art (see, e.g., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 10 th edition (Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Vol.1-6, Sarfaraz K. Niazi)).

The pharmaceutically acceptable salt of azelastine in an amount of about 4mg to about 40mg can further comprise a pharmaceutically acceptable excipient such as a diluent, a binder, a filler, a glidant, a disintegrant, a lubricant, a solubilizer, and combinations thereof. Some examples of suitable excipients are described herein. When the pharmaceutically acceptable salt of azelastine in an amount of about 4mg to about 40mg is formulated into a tablet, the tablet may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a longer lasting effect. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed alone or with a wax.

In certain embodiments, the pharmaceutically acceptable salt of azelastine is administered in a daily effective amount of about 4mg to about 40mg azelastine HCl, or about 4mg to about 20mg azelastine HCl, or about 8mg to about 16mg azelastine HCl.

It will be appreciated that the amount of azelastine HCl actually administered will generally be determined by a physician in light of the relevant circumstances (including the condition to be treated, the chosen route of administration, the age, weight and response of the individual patient, and the severity of the patient's symptoms, etc.).

The pharmaceutically acceptable salt of azelastine as described herein is administered to a patient suffering from psychiatric disorders, behavioral disorders, cognitive disorders, and other neurodegenerative disorders such as alzheimer's disease by oral administration once daily, twice daily, once every other day, once weekly, twice weekly, three times weekly, four times weekly, or five times weekly, in a daily effective amount of from about 4mg to about 40 mg.

In some embodiments, pharmaceutical dosage forms and tablets of a pharmaceutically acceptable salt of azelastine in a daily effective amount of about 4mg to about 40mg as described in the specification are effective to reverse symptoms in patients with early, intermediate or late stage alzheimer's disease for about 6-24 weeks.

The following examples are illustrative and should not be construed as limiting the scope of the inventive subject matter. The examples show that both patients significantly improved in memory, language, reasoning and timing after 6 months of treatment with 12mg azelastine HCl. Simple Mental State Examination (MMES) evaluation was not performed, but it is reasonably predictable that MMES would improve significantly if measured.

Example 1

An 80 year old female patient weighing 51 kg was diagnosed with advanced alzheimer's disease for 6 years, requiring all-weather assistance to assist her daily activities such as walking and finding items and personal care, and she speaks only in a few words. She had little knowledge of the surrounding environment before being treated with 12mg azelastine HCl once daily before bedtime. She was able to walk with mild help in her home after 6 weeks of treatment with 12mg azelastine HCl once daily before bedtime. After 12 weeks of treatment, she was able to speak for more than 1 minute, know the activities in her home and ask questions about the daily activities in her home. After 6 months of treatment, she is a completely different person as to what she can do than she could do before treatment, and she can actively talk to a person and does not need help for her daily activities and personal care. Therefore, her MMSE score is expected to improve as well. After 6 months of treatment, her weight increased 3 kg.

Example 2

An 83 year old female weighing 49 kg was diagnosed with mid to late stage alzheimer's disease. Her daily activities are limited because she cannot recall what has just happened and cannot determine the location of what she wants to retrieve by herself. She needed help for most of her daily activities (including personal care) before she began treatment with 12mg of azelastine HCl once daily before going to sleep. After 6 weeks of treatment she began showing signs that she was able to find something she wanted to retrieve. After 3 months of treatment she only needs help in a few daily activities or personal care and most can do so by herself. Her MMSE score is also expected to improve. After 6 months of treatment, she gained 2.5 kg in body weight.

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The invention has been described with reference to specific embodiments having various features. It will be apparent to those skilled in the art from the disclosure provided above that various modifications and variations can be made in the practice of the invention without departing from the scope or spirit thereof. Those skilled in the art will recognize that the disclosed features may be used alone, in any combination, or omitted based on the requirements and specifications of a given application or design. When an embodiment refers to "comprising" certain features, it is to be understood that the embodiment may alternatively consist of or consist essentially of any one or more of the features. Any of the methods disclosed herein can be used with any of the compositions disclosed herein or with any other composition. Likewise, any of the disclosed compositions can be used with any of the methods disclosed herein or with any other method. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention.

It is specifically noted that where a range of numerical values is provided in this specification, each value between the upper and lower limit of the range is also specifically disclosed. The upper and lower limits of these smaller ranges may also be independently included or excluded in the range. The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. It is intended that the specification and examples be considered as exemplary in nature, and that all changes that come within the spirit of the invention are desired to be protected. Furthermore, all references cited in this disclosure are each independently incorporated by reference herein in their entirety and are likewise intended to provide an effective means of supplementing the disclosure of the present invention and to provide a background that details the state of the art.

Claims

1. A method of treating a patient suffering from a psychiatric, behavioral or cognitive disorder comprising administering an effective amount of a pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt of azelastine.

2. The method of claim 1, wherein the pharmaceutical composition is an oral formulation.

3. A method according to claim 1, wherein the pharmaceutical composition comprises about 4mg to about 40mg of the azelastine or a pharmaceutically acceptable salt of azelastine.

4. A method according to claim 1, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.

5. A method according to claim 1, wherein the pharmaceutical composition comprises about 4mg to about 20mg of the azelastine or a pharmaceutically acceptable salt of azelastine.

6. A method according to claim 1, wherein the pharmaceutical composition comprises about 8mg to about 16mg of the azelastine or a pharmaceutically acceptable salt of azelastine.

7. The method of claim 2, wherein the oral formulation is in a solid form or a liquid form.

8. The method of claim 1, wherein the psychiatric, behavioral or cognitive disorder is alzheimer's disease, vascular dementia, parkinson's disease, huntington's disease, frontotemporal dementia, traumatic brain injury, corticobasal degeneration, or parkinson's disease, or any combination thereof.

9. The method of claim 1, wherein the psychiatric, behavioral or cognitive disorder is alzheimer's disease.

10. A method of treating a patient having alzheimer's disease comprising orally administering to a patient in need thereof a daily effective amount of azelastine hydrochloride of about 8mg to about 16 mg.

11. A method of treating a patient suffering from alzheimer's disease, comprising administering an effective amount of a pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt of azelastine, thereby improving the memory, language, reasoning and/or timing of the patient.

12. The method of claim 11, wherein the effective amount of the pharmaceutical composition comprises about 8mg to about 16mg of the azelastine or a pharmaceutically acceptable salt of azelastine.