CN113939276A

CN113939276A - Pharmaceutical compositions and methods for treating psychiatric disorders, behavioral disorders, cognitive disorders

Info

Publication number: CN113939276A
Application number: CN201980095322.XA
Authority: CN
Inventors: ***; 崔歌平
Original assignee: La Pharmaceutical Research Technology Co ltd
Current assignee: La Pharmaceutical Research Technology Co ltd
Priority date: 2019-04-12
Filing date: 2019-04-12
Publication date: 2022-01-14
Also published as: EP3952840A1; CA3136633A1; WO2020209872A1; AU2019445048A1; JP2022535644A; JP7365426B2; EP3952840A4

Abstract

Pharmaceutical compositions comprising azelastine or a pharmaceutically acceptable salt of azelastine and memantine or a pharmaceutically acceptable salt of memantine as therapeutically active ingredients are disclosed. Also disclosed are methods of using the pharmaceutical compositions to treat patients suffering from psychiatric disorders, behavioral disorders, cognitive disorders.

Description

Pharmaceutical compositions and methods for treating psychiatric disorders, behavioral disorders, cognitive disorders

Technical Field

The present invention relates to the field of practical medicine, namely, to the combined use of pharmaceutical compositions that exhibit a neurotropic effect (neurotropic action), and that reduce clinical manifestations of psychiatric, behavioral, and cognitive disorders in the event of organic damage to various sources 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, alzheimer's disease 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 NMDA receptors. 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. Hair-like deviceThe AB plaque (pathological feature of AD) now induces 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 over-activates 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. membranes which depolarize chronically, 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.

Memantine is a rapid binding antagonist that binds to a channel in a pseudo-primary manner. However, it also dissociates rapidly from the receptor in a concentration independent manner. This allows the dose to affect memantine binding without affecting its elimination from the site of action and allows for increased efficacy with minimal side effects. Memantine has a faster course of action and therefore less influence on physiological mechanisms than other antagonists. For this reason, memantine offers many promise in the treatment of neurodegenerative diseases, as it will retain physiological function. In addition, the noncompetitive nature of the mechanism of action of memantine makes its antagonistic activity more effective in areas of massive NMDA receptor activation. The mechanism of action of memantine is also voltage dependent, which results in the elimination of memantine blockade by depolarization of the membrane. All of these properties make memantine a promising candidate for the treatment of conditions induced by excitotoxicity. In several studies, memantine was found to prevent neuronal death induced via an excitotoxicity mechanism.

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 pharmaceutical compositions comprising two active ingredients and one or more pharmaceutically acceptable excipients. The pharmaceutical composition comprises a first active ingredient which is azelastine or a pharmaceutically acceptable salt of azelastine and a second active ingredient which is memantine or a pharmaceutically acceptable salt of memantine.

In some embodiments of the invention, the pharmaceutically acceptable salt of azelastine in the pharmaceutical composition is azelastine hydrochloride and the pharmaceutically acceptable salt of memantine in the pharmaceutical composition is memantine hydrochloride.

In some embodiments of the invention, azelastine hydrochloride (and/or other salts) in the pharmaceutical composition is provided in an amount from about 1mg to about 20mg and/or memantine hydrochloride (and/or other salts) in the pharmaceutical composition is in an amount from about 1mg to about 30 mg.

The invention also includes oral pharmaceutical dosage forms that are pharmaceutical compositions in solid or liquid form.

The invention further includes medical uses of the oral pharmaceutical dosage form by administering the oral pharmaceutical dosage form to a pharmaceutical composition of a patient suffering from a neurodegenerative disorder such as alzheimer's disease, vascular dementia, or parkinson's disease.

In some embodiments of the invention, an oral pharmaceutical dosage form of a pharmaceutical composition comprising azelastine hydrochloride (and/or other salts) in an amount from about 6mg to about 12mg and/or memantine hydrochloride (and/or other salts) in an amount from about 2mg to about 6mg is administered to a patient with advanced alzheimer's disease.

Detailed Description

The inventors of the present invention have surprisingly found that a pharmaceutical composition comprising an active agent, a salt form of azelastine and a salt form of memantine in an oral dosage form is suitable for treating patients suffering from mental disorders, behavioural 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.

Mental disorders, behavioral disorders, cognitive disorders may include, but are not limited to, alzheimer's disease, dementia, parkinson's disease, huntington's disease, and combinations of any of these with other neurodegenerative disorders.

As used herein, the term "memantine" refers to memantine free base, 1-amino-3, 5-dimethyladamantane, 1, 3-dimethyl-5-amantadine, 3, 5-dimethyl-1-amantadine, or 3, 5-dimethyl tricyclic (3.3.1.1(3,7)) decan-1-amine. In certain embodiments, memantine further comprises any pharmaceutically acceptable salt, such as the hydrochloride or HCl salt. Preferably, in any embodiment of the invention as described herein, memantine is in the form of its hydrochloride salt, such as memantine hydrochloride or memantine HCl. More preferably, in any embodiment of the invention as described herein, reference to the amount and dosage range of memantine in an oral dosage form refers to the amount and dosage range of memantine hydrochloride.

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 the solid oral dosage form refers to the amount and dosage range of azelastine hydrochloride.

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, sufficient to effect 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 pharmaceutical composition may be administered by oral administration in a single dose or in multiple doses. Can be administered via capsule or tablet.

The term "about" as used herein 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.

Pharmaceutical compositions may be formulated for Pharmaceutical use using methods known in the art, for example, 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 compound 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.

The solid oral preparation of the present disclosure means a form of a tablet, a caplet, a bilayer tablet, a film-coated tablet, a pill, a capsule or 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.

Pharmaceutical compositions provided according to the present disclosure are typically administered orally. Accordingly, the present disclosure provides pharmaceutical compositions comprising a solid dispersion comprising azelastine and memantine 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, penetration 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 pharmaceutical composition may further comprise pharmaceutically acceptable excipients such as diluents, binders, fillers, glidants, disintegrants, lubricants, solubilizers, and combinations thereof. Some examples of suitable excipients are described herein. When the pharmaceutical composition is formulated as 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 embodiments, the pharmaceutical composition may comprise a) about 1mg to 50mg azelastine HCl (and/or other salts) and/or b) about 1mg to 70mg memantine HCl (and/or other salts), or a) about 2mg to 20mg azelastine HCl (and/or other salts) and/or b) about 2mg to 30mg memantine HCl (and/or other salts), or a) about 8mg to 16mg azelastine HCl (and/or other salts) and/or b) about 2mg to 5mg memantine HCl (and/or other salts). For example, the composition can comprise a) about 12mg azelastine HCl (and/or other salts) and/or b) about 3mg memantine HCl (and/or other salts). Further, for example, the compositions of the invention can comprise azelastine or a pharmaceutically acceptable salt of azelastine present in an amount ranging from about 1mg to about 50mg and/or memantine or a pharmaceutically acceptable salt of memantine present in an amount ranging from about 1mg to about 70 mg. In embodiments, the amount of azelastine HCl (and/or other salts) present in the composition can be equal to, greater than, or less than the amount of memantine HCl (and/or other salts) present in the composition. In embodiments, the amount of azelastine HCl (and/or other salts) present in the composition can be 2 times, or 3 times, or 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 75 times, 100 times, or 1,000 times the amount of memantine HCl (and/or other salts) present in the composition, or vice versa. Any one or more of the compositions of the present invention may be used with any one or more of the methods of the present invention disclosed herein or other methods of using the compositions.

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

Pharmaceutical compositions, pharmaceutical dosage forms, and tablets comprising azelastine HCl and memantine HCl as described herein are administered to a patient suffering from a neurodegenerative disorder such as alzheimer's disease by oral administration once daily, twice daily, once every other day, twice weekly, three times weekly, four times weekly, or five times weekly.

In embodiments, pharmaceutical dosage forms and tablets of the pharmaceutical compositions comprising azelastine HCl and memantine HCl as described herein are effective in reversing symptoms in patients with advanced alzheimer's disease within about 6-24 weeks.

The following examples are illustrative and should not be construed as limiting the scope of the inventive subject matter.

Example 1

A 79 year old female weighing 51 kg was diagnosed with advanced alzheimer's disease and treated with memantine (10mg) for 5 years. Her memory and cognitive skills continue to deteriorate. She can hardly remember anything and can only say a few words. She eventually needs all-weather help to assist her daily activities and personal care. She cannot go more than 10 steps even with assistance. At this stage she began once daily treatment with a liquid oral form of the pharmaceutical composition of the present invention containing 12mg azelastine HCl and 5mg memantine HCl. After only one and a half month she can walk with assistance. After 3 months, she had facial and eye expressions and could speak for a few minutes and walk with only slight help. After 6 months of treatment she was free to speak and sing and could walk independently. Her weight increased 5 kg during the 6 month treatment period.

Example 2

An 81 year old female weighing 55 kg was diagnosed with advanced alzheimer's disease. She needs all-weather help to assist her daily activities including personal care, eating, walking. She can only say less than 5 words and has irregular sleep habits. She was treated with a liquid oral form of the pharmaceutical composition of the present invention containing 12mg azelastine HCl and 5mg memantine HCl. After only one and a half month, her all-weather help was reduced by about 50%. After 3 months, she may perform basic personal care activities on her own and may speak more than 10 words.

Example 3

A77 year old male weighing 66 kg was diagnosed with advanced Alzheimer's disease. He can only say a few words. He had difficulty falling asleep. His personality is described as illogical or irrational, anxious or irritable, and aggressive or hostile. He is mostly out of compliance. He needs little help to walk. He is monitored by an assistant all the time. He was treated with a tablet containing a pharmaceutical composition of 14mg azelastine HCl and 5mg memantine HCl. After one and a half month, his personality is described as more rational, less aggressive and not hostile. After 3 months he can sleep regularly and he no longer needs all-weather help. He can speak for more than 1 minute.

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Loyd Allen,Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems,Tenth(2013)

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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 pharmaceutical composition comprising:

azelastine or a pharmaceutically acceptable salt of azelastine;

memantine or a pharmaceutically acceptable salt of memantine; and

one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition according to claim 1, wherein the azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount ranging from about 1mg to about 50 mg.

3. The pharmaceutical composition of claim 1, wherein the memantine or a pharmaceutically acceptable salt of memantine is present in the pharmaceutical composition in an amount ranging from about 1mg to about 70 mg.

4. The pharmaceutical composition of claim 1, wherein:

the azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount ranging from about 1mg to about 50 mg; and is

The memantine or a pharmaceutically acceptable salt of memantine is present in the pharmaceutical composition in an amount ranging from about 1mg to about 70 mg.

5. The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.

6. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable salt of memantine is memantine hydrochloride.

7. A pharmaceutical composition according to claim 5, wherein the azelastine hydrochloride is present in an amount ranging from about 2mg to about 20 mg.

8. A pharmaceutical composition according to claim 5, wherein the azelastine hydrochloride is present in an amount ranging from about 8mg to about 16 mg.

9. The pharmaceutical composition of claim 6, wherein the memantine hydrochloride is present in an amount ranging from about 2mg to about 20 mg.

10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated as an oral pharmaceutical dosage form.

11. The pharmaceutical composition of claim 10, wherein the oral pharmaceutical dosage form is in a solid form or a liquid form.

12. 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;

memantine or a pharmaceutically acceptable salt of memantine; and

one or more pharmaceutically acceptable excipients.

13. The method of claim 12, wherein the psychiatric, behavioral or cognitive disorder is alzheimer's disease, vascular dementia, parkinson's disease, huntington's disease, or any combination thereof.

14. The method of claim 12, wherein the psychiatric, behavioral or cognitive disorder is alzheimer's disease.

15. The method of claim 14, wherein the pharmaceutical composition is administered to the patient daily in oral solid or liquid form.

16. A method according to claim 15, wherein the azelastine or pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 1mg to about 50 mg.

17. The method of claim 15, wherein the memantine or a pharmaceutically acceptable salt of memantine is present in the pharmaceutical composition in an amount ranging from about 1mg to about 70 mg.

18. The method of claim 12, wherein: