CN111166868A - A composition for treating neurological diseases and disorders - Google Patents

Abstract

The present invention provides a composition comprising, in combination, a monoethanolamine salt of casein, whey protein and (soy or egg) phospholipid and at least one medium chain mono-, di-or triglyceride or mixtures thereof, preferably a diethanolamine salt of casein, whey protein, a (soy or egg) phospholipid and at least one Medium Chain Triglyceride (MCT). The compositions facilitate effective treatment for patients suffering from, susceptible to, or suspected of suffering from a neurological disorder.

Description

A composition for treating neurological diseases and disorders

[ technical field ] A method for producing a semiconductor device

The present invention relates to novel combinations and methods for treating neurological diseases and disorders. More specifically, the present invention relates to a novel combination therapy for neurological disorders based on a combination of caseinates, salts of diethanolamine, whey proteins, phospholipids (soy or egg) and medium chain mono-, di-or triglycerides.

[ background of the invention ]

Alzheimer's Disease (AD), a chronic progressive neurodegenerative disease, which is clinically manifested by a decline in cognitive function accompanied by various behavioral abnormalities, eventually leading to death, is also called senile dementia, is a neuropsychiatric symptom such as progressive memory disorder, cognitive dysfunction, personality change and language disorder, which seriously affects social, occupational and life functions, and the cause and pathogenesis of AD have not been elucidated, and characteristic pathological changes such as extracellular senile plaque formed by deposition of β amyloid and neuronal neurofibrillary tangle formed by hyperphosphorylation of tau protein, and neuronal loss accompanied by glial cell proliferation are not yet elucidated.

The classical description of alzheimer's disease has sufficient properties to allow identification of about 80% of cases. However, there does exist clinical heterogeneity, which is important for clinical management, and provides further implications for specific drug therapy of different forms of function.

impaired brain metabolism is generally considered to be the main cause of cognitive decline in age-related dementia, and in the case of AD, it may precede, accompany or even stimulate Α β plaque deposition, which may further inhibit glucose uptake in the mechanism of the vicious circle.

WO2009/133128, WO2009/133141, WO2009/133142, WO2011/054759 and WO2012/117076 disclose pharmaceutical combinations suitable for treating AD WO2012/117076 specifically discloses the therapeutic efficacy of certain drugs in AD, including preventing glutamate toxicity and/or a β toxicity.

despite active research in this area, there remains a need for alternative or improved effective therapies for neurological disorders and, in particular, neurological disorders associated with impaired glutamate and/or a β toxicity and/or glucose metabolism in neuronal cells.

At present, a plurality of medicines for preventing and treating senile dementia exist, but various problems exist, such as various side effects brought to the body of a patient, and the like. Therefore, the development of new products for preventing and treating senile dementia is significant.

Therefore, there is an urgent need in the art to develop a drug for treating neurodegenerative diseases with less side effects and low cost.

[ summary of the invention ]

The present invention provides novel therapeutic methods and compositions suitable for treating neurological disorders, particularly those associated with neuronal cell death and cognitive decline.

The present invention stems inter alia from the surprising discovery by the inventors that a combination of casein dimethylethanolamine salt, whey protein, (soy or egg) phospholipid and at least one medium chain mono-, di-or triglyceride provides significant and unexpected benefits to patients suffering from Alzheimer's Disease (AD). In particular, the inventors have surprisingly found that this combination provides a significant and unexpected improvement in cognitive function in an in vivo AD model, due to a strong protective effect on neuronal cells.

Thus, the combination of casein diethanolamine salt, whey protein, (soy or lecithin) phospholipid and at least one medium chain mono-, di-, or triglyceride contributes to an effective treatment for patients suffering from, susceptible to, or suspected of suffering from neurological disorders.

One object of the present invention therefore relates to a composition comprising, in combination, caseinates dimethylethanolamine, whey proteins and (soy or egg) phospholipids and at least one medium chain mono-, di-or triglyceride or a mixture thereof, preferably caseinates dimethylethanolamine, whey proteins, (soy or egg) phospholipids and at least one Medium Chain Triglyceride (MCT).

In a particular embodiment, the medium chain mono-, di-, or tri-glyceride has the formula:

wherein R1, R2 and R3 are each independently a medium chain fatty acid (C6-C12) or a hydroxyl group, and at least one of R1, R2 and R3 is a medium chain fatty acid (C6-C12).

In a more particular embodiment, R1, R2 and R3 are medium chain fatty acids (triglycerides), even more preferably R1, R2 and R3 are the same medium chain fatty acids.

The medium chain fatty acid may be selected from any fatty acid having 6 to 12 carbon atoms, for example, more preferably, caproic acid (C6), caprylic acid (C8), capric acid (C10) and/or lauric acid (C12). In this regard, preferred MCTs for use in the present invention are caproic acid triglyceride, caprylic acid triglyceride, capric acid triglyceride and lauric acid triglyceride.

As further disclosed herein, the compounds in the compositions or combinations of the present invention may be formulated separately or together. Moreover, they can be administered to a subject simultaneously, separately, sequentially and/or repeatedly.

The compositions of the present invention will generally further comprise one or more pharmaceutically acceptable excipients or carriers. They may also be in the form of sustained release formulations. Prodrugs or derivatives of the compounds may also be used.

In another preferred embodiment, a prodrug or derivative is used.

Another object of the invention is a process for preparing a pharmaceutical composition comprising admixing a casein dimethylethanolamine salt, whey protein, (soy or lecithin) phospholipid and at least one medium chain mono-, di-or triglyceride in a pharmaceutically acceptable excipient or carrier.

Preferably, the method comprises admixing, in a pharmaceutically acceptable excipient or carrier, casein dimethylethanolamine salt, whey protein, (soy or lecithin) phospholipid and at least one MCT.

A further object of the present invention relates to a composition or a combination as defined above for use in the treatment of neurological disorders, in particular Alzheimer's Disease (AD), AD related diseases, frontotemporal dementia (FTD), Parkinson's Disease (PD), dementia with lewy bodies, Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), peripheral neuropathy, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or withdrawal from drug abuse, Spinal Cord Injury (SCI), epilepsy, traumatic brain injury or cerebral ischemic events.

Another object of the present invention relates to a method for treating a neurological disorder in a mammalian subject in need thereof, preferably a human subject in need thereof, said method comprising administering to said subject an effective amount of a composition or combination of the present invention.

Another object of the present invention relates to a method of treating AD or an AD related disease in a mammalian subject in need thereof, preferably a human subject in need thereof, the method comprising administering to said subject an effective amount of a composition or combination as defined above.

A preferred object of the present invention relates to a method of treating neurological disorders in a mammalian subject in need thereof, preferably a human subject in need thereof, which method comprises administering to said subject an effective amount of a caseinate dimethylethanolamine salt, a whey protein, a (soy or lecithin) phospholipid and at least one medium chain mono-, di-or triglyceride simultaneously, separately or sequentially.

More preferably, the method comprises administering to said subject an effective amount of casein dimethylethanolamine salt, whey protein, (soy or lecithin) phospholipid and at least one MCT simultaneously, separately or sequentially.

A more preferred object of the present invention relates to a method of treating AD or an AD-associated disease in a mammalian subject in need thereof, preferably a human subject in need thereof, which method comprises administering to said subject an effective amount of a caseinate, a whey protein, a (soy or lecithin) phospholipid and at least one medium chain mono-, di-or triglyceride simultaneously, separately or sequentially.

Preferably, the method comprises simultaneously, separately or sequentially administering to said subject an effective amount of a caseinate dimethylethanolamine salt, a whey protein, a (soy or lecithin) phospholipid and at least one MCT.

More preferably, the method comprises simultaneously, separately or sequentially administering to said subject an effective amount of a caseinate dimethylethanolamine salt, a whey protein, a (soy or lecithin) phospholipid and at least one MCT compound selected from caprylic triglyceride, caproic triglyceride, capric triglyceride and lauric triglyceride, or a mixture thereof.

The invention can be used in a method of treating neurological disorders in a mammalian subject, preferably any human subject, at any stage of the disease. As will be disclosed in the examples, the composition of the invention is capable of alleviating a pathological condition in said subject.

Detailed Description

The present invention provides novel methods and compositions for treating neurological disorders. The present invention discloses novel active compound combinations which effectively correct these diseases and which can be used in any mammalian subject.

more specifically, the present invention provides novel compositions comprising a caseinate dimethylethanolamine salt, a whey protein, a (soy or lecithin) phospholipid and at least one medium chain glyceride as illustrated in the examples the presence of medium chain glycerides unexpectedly improves the in vivo performance of the caseinate dimethylethanolamine salt, whey protein- (soy or lecithin) phospholipid combination the invention is therefore useful for the treatment of any neurological disorder, in particular diseases involving nerve and/or neuronal damage, β amyloid, glutamate excitotoxicity and/or impaired glucose metabolism, such as neurodegenerative diseases.

One subject of the present invention is therefore a composition comprising:

-casein diethanolamine salt;

-whey protein;

- (soy or lecithin); and

-medium chain mono-, di-or triglycerides.

The term "medium chain mono-, di-, or triglycerides" is intended to include any compound of formula I:

wherein R1, R2 and R3 are each independently a medium chain fatty acid (C6 to C12) or a hydroxyl group, and at least one of R1, R2 and R3 is a medium chain fatty acid (C6-C12).

In a particular embodiment, two of R1, R2 and R3 are medium chain fatty acids, which may be the same or different (diglycerides).

In a preferred embodiment, R1, R2 and R3 all represent medium chain fatty acids (triglycerides), which may be the same or different, more preferably the same medium chain fatty acids.

The medium chain fatty acid may be any fatty acid having a carbon chain length including from 6 to 12 carbon atoms. Preferred examples of the fatty acid include caproic acid (C6), caprylic acid (C8), capric acid (C10) and lauric acid (C12).

In a preferred embodiment, R1, R2 and R3 corresponding to the same medium chain fatty acid are selected from caproic acid (C6), caprylic acid (C8), capric acid (C10) and lauric acid (C12).

In a more preferred embodiment, R1, R2 and R3 are octanoic acid (C8).

The medium chain mono-, di-, or triglycerides may comprise one molecular species or a mixture of more of the above medium chain mono-, di-, or triglycerides. In particular, the compositions of the invention may comprise one or a mixture of MCTs as described above.

The medium chain glycerides may be synthetic, semi-synthetic and/or comprised in or purified from natural sources.

MCTs can be prepared by methods known per se in the art (e.g., in the field of chemical synthesis). Moreover, medium chain mono-, di-, or triglycerides are naturally present in coconut and palm kernel oils. These oils can be hydrolyzed using conventional methods to liberate their fatty acids from glycerol, and the fatty acids are then purified by fractional distillation. Pure MCT preparations can then be prepared by re-esterification of purified Medium Chain Fatty Acids (MCFA) on glycerol. Different MCFAs can also be mixed in various ratios prior to esterification.

MCTs are also present in a variety of other plants, although they are less developed than coconut oil and palm kernel oil. For example, it has been shown that seeds of the cuphea genus produce oil composed of a variety of MCFAs. Moreover, the oils prepared by some species are almost entirely composed of one MCT. In c.pulcherrima, 94% of the total seed oil composition was caprylic triglyceride, while in c.schumannii, 94% was capric acid.

Thus, in a preferred embodiment, the compositions and methods of the invention employ purified or semi-synthetic MCTs. Alternatively, the invention also encompasses the use of impure triglyceride compositions, especially plant products such as coconut, palm kernel, or cuphea extracted oils, or extracts thereof, or mixtures thereof.

Preferred compositions of the invention comprise one of the following pharmaceutical combinations, administered in combination, separately or sequentially:

-caseinates, salts of diethanolamine, whey proteins and (soy or egg) phospholipids and caprylic triglyceride (C8),

-casein dimethylethanolamine salt, whey protein and (soya or lecithin) phospholipids and caproic acid triglyceride (C6),

-caseinates, whey proteins and (soy or egg) phospholipids and capric acid triglycerides (C10),

-caseinodimethylammonium salt, whey protein and (soy or egg) phospholipids and lauric triglycerides (C12).

The content of the medium-chain fatty glyceride in the composition provided by the invention is as follows: 5% to 90%, preferably 20% to 80%, preferably 30% to 70%, based on the total volume (or weight) of the entire composition.

The content of the casein dimethylethanolamine salt or the whey protein in the composition related to the invention is as follows: 1% to 40%, preferably 2% to 30%, preferably 3% to 25%, based on the total volume (or weight) of the total composition.

The content of (soy or lecithin) phospholipid in the composition related to the invention is as follows: 1% to 25%, preferably 2% to 15%, most preferably 3% to 10%, based on the total volume (or weight) of the total composition.

In the present invention, the components act in agreement, and their effects are as follows.

1) The medium-chain fatty glyceride can be degraded into ketone body, and can provide energy for brain.

2) The casein Dimethylethanolamine (DMAE) salt can stimulate the brain, can easily enter the brain tissue from blood and accelerate the brain to synthesize acetylcholine, and has the following effects:

the method improves senile dementia, attention deficit disorder and the work efficiency of cerebral neuron cells;

the memory and attention can be improved, the anxiety is relieved, the learning ability is improved, and the recovery of the stroke patient is promoted;

the casein can improve the metabolism rate, continuously release amino acid to blood, help human body to keep nitrogen, be used as a nutrition enhancer, also be used as a thickening and emulsifying stabilizer, and also be used as an adhesive, a filling agent and a carrier.

3) the whey protein is easy to digest, has high biological value, high digestibility, high protein efficiency ratio and high utilization rate, is a top-quality protein supplement of a human body, contains 8 amino acids necessary for the human body, is reasonable in proportion, is an essential substance indispensable to life activities such as growth, development and aging resistance of the human body, contains low content of fat and lactose, contains β -lactoglobulin, α -lactalbumin and immunoglobulin and also contains other active ingredients, and has a fatigue relieving function.

4) Phospholipids, which are lipid compounds containing phospholipid root, are the basic substances of life. The cell membrane is composed of approximately 40% protein and approximately 50% lipid (mainly phospholipid). It is composed of lecithin, inositol phosphatide, cephalin, etc. These phospholipids have corresponding functions to various parts and organs of the human body. Phospholipid plays an important role in activating cells, maintaining metabolism, basic metabolism and balanced secretion of hormones, and enhancing immunity and regenerative power of human bodies. In particular the following functions:

1) and proliferation action

The nerve cells and brain cells of human body are covered by cell membrane made of phospholipid, and the deficiency of phospholipid can cause damage of membrane, thus causing mental retardation and mental stress. And acetyl groups contained in phospholipids enter intercellular spaces to combine with choline to form acetylcholine. Acetylcholine is a signal molecule for transmitting information between various nerve cells and brain cells, and can accelerate the information transmission between nerve cells and brain cells, enhance memory, and prevent senile dementia.

2) Activating cells

Phospholipids are important components of cell membranes and shoulder the burden of exchange of intracellular and extracellular substances. If the daily phospholipid consumption of a human is not supplemented, the cells are in a state of nutritional deficiency and lose viability.

In addition, phospholipids also serve as emulsion stabilizers according to the invention.

The preparation method of the casein dimethylethanolamine salt comprises the following steps:

degreasing fresh milk, adding acid (lactic acid, acetic acid, hydrochloric acid or sulfuric acid), adjusting pH to 4.8 to remove charges of casein micelles and obtain acid casein, wherein the acid casein obtained by adding different types of acid is almost indistinguishable. The acid casein is white to yellowish powder or granule, and has slight milk odor and sour taste. Swelling acid casein in water, adding dimethylethanolamine to disperse and dissolve in water, and spray-freeze drying.

in particular, the present inventors have surprisingly found that in animals suffering from beta-amyloid intoxication, a combination of caseindimethylethanolamine salt, whey protein, (soy or lecithin) phospholipid and MCT has a strong and unexpected effect on improving cognitive impairment, and that this combination represents a new treatment for AD.

These drug combinations thus represent novel methods for the treatment of neurological disorders, such as AD and AD related diseases, frontotemporal dementia, MS, ALS, PD, dementia with lewy bodies, HD, peripheral neuropathy, alcohol abuse or alcohol withdrawal, neurological manifestations of drug abuse or withdrawal from drug abuse, SCI, epilepsy, traumatic brain injury or cerebral ischemic events.

The present invention therefore proposes a new treatment for neurological disorders based on a composition of caseinates dimethylethanolamine, whey proteins, (soy or lecithin) phospholipids and at least one medium chain mono-, di-or triglyceride. More specifically, the present invention proposes novel treatments for AD and AD related diseases, frontotemporal dementia, MS, ALS, PD, lewy body dementia, HD, peripheral neuropathy, alcohol abuse or withdrawal, neurological manifestations of drug abuse or withdrawal from drug abuse, SCI, epilepsy, traumatic brain injury or cerebral ischemic events based on a combination of caseindimethylethanolamine salt, whey protein, (soy or egg) phospholipid and medium chain mono-, di-or triglycerides.

In this regard, in a particular embodiment, the present invention relates to a combination comprising casein dimethylethanolamine salt, whey protein and (soy or egg) phospholipid and at least one medium chain mono-, di-or triglyceride for use in the treatment of AD, AD related diseases, frontotemporal dementia, MS, PD, dementia with lewy bodies, ALS, HD, peripheral neuropathy, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or withdrawal from drug abuse, SCI, epilepsy, traumatic brain injury or cerebral ischemic events.

In another embodiment, the invention relates to the use of casein dimethylethanolamine salt, whey protein, phospholipids (soy or lecithin) and at least one MCT for the preparation of a medicament for the treatment of AD, AD-related diseases, frontotemporal dementia, MS, PD, dementia with lewy bodies, ALS, HD, peripheral neuropathy, alcohol abuse or withdrawal, neurological manifestations of drug abuse or withdrawal from drug abuse, SCI, epilepsy, traumatic brain injury or an event of cerebral ischemia.

In a specific embodiment, the invention relates to the use of these combinations for the treatment of AD or AD-associated diseases in a subject in need thereof.

In a particular embodiment, the present invention relates to the use of these combinations for the treatment of frontotemporal dementia, MS, PD, ALS, HD, peripheral neuropathy, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or withdrawal from drug abuse, SCI, epilepsy, traumatic brain injury or cerebral ischemic events in a subject in need thereof.

An object of the present invention is therefore also a composition as defined above for use in the treatment of neurological disorders such as AD, AD related diseases, frontotemporal dementia, MS, PD, dementia with lewy bodies, ALS, HD, peripheral neuropathy, alcohol abuse or withdrawal from alcohol, neurological manifestations of drug abuse or withdrawal from drug abuse, SCI, epilepsy, traumatic brain injury or cerebral ischemic events.

More specifically, the examples show that the compositions of the present invention are particularly effective for protecting short-term as well as long-term memory in vivo.

Accordingly, one object of the present invention is the use of a caseinate, a diethanolamine salt, a whey protein, a (soy or egg) phospholipid and at least one medium chain mono-, di-or triglyceride for improving short-term and/or long-term memory in a subject suffering from AD, an AD related disease, frontotemporal dementia, PD, dementia with lewy bodies, HD, ALS, MS, peripheral neuropathy, alcohol abuse or alcohol withdrawal, neurological manifestations of drug abuse or withdrawal from drug abuse, SCI, epilepsy, traumatic brain injury or an ischemic event in the brain.

As previously mentioned, in the combination therapy of the present invention, the compounds or drugs may be formulated together or separately and administered together, separately or sequentially.

Another object of the present invention is the use of a composition as defined above for the manufacture of a medicament for the treatment of neurological disorders such as AD, AD related diseases, frontotemporal dementia, MS, PD, dementia with lewy bodies, ALS, HD, peripheral neuropathy, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or withdrawal from drug abuse, SCI, epilepsy, traumatic brain injury or cerebral ischemic events.

The present invention further provides a method of treating a neurological disorder such as AD, AD-related diseases, frontotemporal dementia, MS, PD, dementia with lewy bodies, ALS, HD, peripheral neuropathy, alcohol abuse or alcohol withdrawal, neurological manifestations of drug abuse or withdrawal from drug abuse, SCI, epilepsy, traumatic brain injury or cerebral ischemic events comprising administering to a subject in need thereof an effective amount of a composition as disclosed above.

Another object of the present invention is a method for the treatment of neurological disorders such as AD, AD related diseases, frontotemporal dementia, MS, PD, dementia with lewy bodies, ALS, HD, peripheral neuropathy, alcohol abuse or alcohol withdrawal, neurological manifestations of drug abuse or withdrawal from drug abuse, SCI, epilepsy, traumatic brain injury or cerebral ischemic events comprising administering to a subject in need thereof an effective amount of a composition as disclosed above simultaneously, separately or sequentially.

In a preferred embodiment, the present invention relates to a method of treating a neurological disorder such as AD, an AD related disease, frontotemporal dementia, MS, PD, dementia with lewy bodies, ALS, HD, peripheral neuropathy, alcohol abuse or withdrawal, neurological manifestations of drug abuse or withdrawal from drug abuse, SCI, epilepsy, traumatic brain injury or an ischemic event in a subject in need thereof, comprising administering to the subject simultaneously, separately or sequentially an effective amount of a dimethylethanolamine salt of casein, a whey protein, a (soy or egg) phospholipid and at least one medium chain mono-, di-or triglyceride.

In a more preferred embodiment, the present invention relates to a method of treating a neurological disorder such as AD, AD related diseases, frontotemporal dementia, MS, PD, lewy body dementia, ALS, HD, peripheral neuropathy, alcohol abuse or alcohol withdrawal, neurological manifestations of drug abuse or withdrawal from drug abuse, SCI, epilepsy, traumatic brain injury or an ischemic event in a subject in need thereof comprising administering to the subject simultaneously, separately or sequentially an effective amount of a caseindimethylethanolamine salt, a whey protein, a (soy or egg) phospholipid and at least one MCT.

Neurodegenerative diseases refer to diseases such as Alzheimer's Disease (AD) and AD related diseases, frontotemporal dementia (FTD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Parkinson's Disease (PD), lewy body dementia, Huntington's Disease (HD), Spinal Cord Injury (SCI), cerebral ischemic events, or epilepsy, including gradual loss of function and neuronal death.

The invention is particularly suitable for the treatment of AD and AD-related diseases. In the context of the present invention, the term "AD-associated diseases" includes senile dementia of the AD type (SDAT), vascular dementia, Mild Cognitive Impairment (MCI) and age-associated memory impairment (AAMI).

As used herein, "treating" includes treating, preventing, delaying, or reducing the symptoms caused by or causative of the above-mentioned disease or disorder.

The term "combination or combination therapy" refers to a treatment wherein at least a caseinate, a whey protein, a (soy or egg) phospholipid and at least one medium chain mono-, di-or triglyceride are co-administered to a subject to elicit a biological effect. In the combination therapy according to the invention, the at least three compounds may be administered together or separately, simultaneously or sequentially. Furthermore, the at least casein dimethylethanolamine salt, whey protein, phospholipid (soy or lecithin) and the at least one medium chain mono-, di-or triglyceride may be administered by different routes and schedules.

The compositions of the present invention generally comprise one or more pharmaceutically acceptable carriers or excipients. Furthermore, for use in the present invention, the drug or compound is typically admixed with a pharmaceutically acceptable excipient or carrier.

In this regard, another object of the present invention is a process for the preparation of a pharmaceutical composition, which process comprises mixing the above-mentioned compounds in a suitable excipient or carrier.

In a particular embodiment, the method comprises mixing the caseinates dimethylethanolamine, whey proteins, (soy or lecithin) phospholipids and at least one medium chain mono-, di-or triglyceride in a suitable excipient or carrier. Preferably, the at least one medium chain mono-, di-, or triglyceride is at least one MCT.

According to a preferred embodiment of the invention, as indicated above, the compounds are used as such or in the form of their pharmaceutically acceptable salts, prodrugs, derivatives or sustained/controlled release formulations.

Although highly effective in vivo, depending on the subject or particular condition, the combination therapies of the invention may be further combined or associated or combined with other drugs or treatments that are beneficial in treating a neurological disease in a subject.

other therapies used in combination with a drug or drug combination according to the invention may include one or more drugs that ameliorate AD, AD-related diseases, frontotemporal dementia, MS, PD, Lewy body dementia, ALS, HD, peripheral neuropathy, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or withdrawal from drug abuse, SCI, epilepsy, traumatic brain injury or cerebral ischemic events, or drugs that may be used in palliative treatment of these diseases, thus exemplary therapies that may be used with the combination of the invention are tacrine (CAS: 321-64-2), donepezil (CAS: 120014-06-4), galantamine (CAS: 357-70-0; 1953-04-4), rivastigmine (CAS: -03-2) or memantin (CAS: -26), domethazine (CAS: -26), or domethacridine) (CAS 10: -26), bullatadine (CAS 10: -26), or domethacrysoporidinine-26), or levocetirizine-7-44, or levocetirizine-4-7 (CAS-7-14-44), or levonorgestrel-7-14-7, or 4-7, or 4-7 for AD or 4-7 (CAS-7-14-7, or 5-7, or 4-7-or 4-7-14-7-or 4-or a (CAS-or a prodrug (CAS-or a prodrug, or a-7-or a prodrug, or a prodrug (CAS-7-or a-4-or a-7-4-or a prodrug (CAS-or a prodrug, or a-7-or a-4-7-or a prodrug (CAS-7-or a-7-or a-7-or a-7-or a combination of a-or a combination of a-or a-4 or a-7, or a-or a combination of the invention, or a combination of the invention, or a-or a combination of the invention, or a-or a combination of the invention, or a-or a combination of the invention, or a-4 or a combination of the invention, or a-4-or a combination of the invention, or a-or a combination of the invention, or a-or.

The therapy of the invention may be provided at home, in a doctor's office, clinic, hospital clinic or hospital so that the doctor can closely observe the effect of the therapy and make any needed adjustments.

The duration of treatment depends on the stage of the disease being treated, the age and condition of the patient, and how the patient responds to the treatment. The dosage, frequency and mode of administration of each component of the combination can be independently controlled. For example, one compound may be administered orally, while a second compound may be administered intramuscularly. Combination therapy may be provided by an intermittent cyclic regime including a recovery period so that the patient's body has an opportunity to recover from any side effects that have not yet been anticipated. The compounds may also be formulated together so that all of the drugs are delivered in a single administration.

Administration of each compound in the combination may be by any suitable means resulting in a concentration of the compound that, when combined with the other components, is capable of improving the condition of the patient and/or is effective in treating a disease or disorder.

Although the compounds of the combination may be administered as pure chemical substances, it is preferred to provide them as pharmaceutical compositions, also referred to herein as pharmaceutical formulations. Possible compositions include those suitable for oral, rectal, topical (including transdermal, buccal and sublingual) or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.

More generally, these pharmaceutical preparations are prescribed to the patient in the form of "patient packs" containing a plurality of metered dose units or other means for administering metered unit doses for use during different treatments in a single package, usually a blister pack. An advantage of patient packs over traditional prescriptions (pharmacists separating a patient's supply of medication from a bulk supply) is that the patient is always provided with the package insert contained in the patient pack, which is typically missing from traditional prescriptions. It has been shown that the inclusion of package inserts increases patient compliance with physician guidance. Accordingly, the present invention also includes the pharmaceutical compositions as described herein before in combination with packaging materials suitable for the formulation. In such patient packs, the intended method of use of the formulation for combination therapy can be inferred from the instructions, instruments, literature, indications, and/or other means for helping the formulation be most suitable for treatment. Such measures make the patient pack particularly suitable and suitable for treatment with the combination of the invention.

The compounds may be contained in any suitable carrier material in any suitable amount. The compound may be present in an amount up to 99% by weight of the total weight of the composition. The compositions may be provided in a dosage form suitable for oral, parenteral (e.g., intravenous, intramuscular), rectal, dermal, nasal, vaginal, inhalation, dermal (patch) or ocular routes of administration. Thus, the composition may take the form of, for example, a tablet, capsule, pill, powder, granule, suspension, emulsion, solution, gel including hydrogel, paste, ointment, cream, plaster, infusion, osmotic delivery device, suppository, enema, injection, implant, spray or aerosol.

Pharmaceutical compositions may be formulated in accordance with conventional pharmaceutical Practice (see, e.g., Remington: the science and Practice of Pharmacy [52] and the Encyclopedia of pharmaceutical technology [53 ]).

The pharmaceutical compositions of the present invention may be formulated to release the active compound substantially immediately after administration or within any predetermined time or period after administration.

Sustained/controlled release formulations include (i) formulations that produce a substantially constant concentration of the compound in vivo over an extended period of time; (ii) producing a formulation of substantially constant compound concentration in vivo over a longer period of time after a predetermined delay period; (iii) a formulation that maintains the effect of the compound for a predetermined period of time by maintaining a relatively constant, effective level of the drug in vivo, while minimizing undesirable side effects associated with fluctuations in plasma levels of the active drug; (iv) formulations that localize the action of the compound, for example, by spatially placing the controlled release composition near or in the diseased tissue or organ; and (v) formulations that target the action of the compounds through the use of carriers or chemical derivatives that deliver the drug to specific target cell types.

Administration of a drug in a sustained/controlled release formulation is particularly preferred where the drug has the following characteristics: (i) a narrow therapeutic index (i.e., the difference between the plasma concentrations that produce an adverse side effect or toxic response and those that produce a therapeutic effect is small; generally, the therapeutic index TI is defined as the ratio of the median lethal dose (LD50) to the median effective dose (ED 50)); (ii) a narrow absorption window in the gastrointestinal tract; or (iii) a very short biological half-life, such that frequent dosing is required in one day in order to maintain plasma levels at therapeutic levels.

Any of a number of strategies may be undertaken in order to obtain sustained/controlled release, wherein the release rate of the compound under study exceeds its metabolic rate. Controlled release can be achieved by appropriate selection of various formulation parameters and ingredients, including, for example, various types of controlled release compositions and coatings. Thus, the compounds are formulated into pharmaceutical compositions using suitable excipients that release the drug in a controlled manner upon administration (single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes).

Solid dosage form for oral use

Dosage forms for oral use include tablets comprising the compositions of the present invention in admixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, calcium phosphate, calcium sulfate or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starch including potato starch, croscarmellose sodium, alginates, or alginic acid); a binder (e.g., gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, glidants, and antiadherents (e.g., stearic acid, silicon dioxide, or talc). Other pharmaceutically acceptable excipients may be colorants, flavoring agents, plasticizers, wetting agents, buffers, and the like.

Tablets may be uncoated or they may be coated by known techniques to optionally delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. The coating may be adapted to release the active compound substance in a predetermined manner (e.g. in order to obtain a controlled release formulation), or it may be adapted not to release the active compound substance until after passage through the stomach (enteric coating). The coating may be a sugar coating, a film coating (e.g. based on hydroxypropyl methylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycol and/or polyvinylpyrrolidone) or an enteric coating (e.g. based on methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac and/or ethylcellulose). A time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Solid tablet compositions may include a coating suitable for protecting the composition from unwanted chemical changes (e.g., chemical degradation prior to release of the active drug). The coating may be applied to the solid dosage form in a similar manner to that described in Encyclopedia of pharmaceutical technology [53 ].

In tablets, the drugs/compounds may be mixed together or may be partitioned. For example, a first compound is contained within the tablet interior and a second compound is located on the exterior such that a substantial portion of the second compound is released prior to the release of the first compound.

Formulations for oral use may also be presented as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example potato starch, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example liquid paraffin or olive oil. Powders and granules may be prepared in conventional manner using the ingredients mentioned above in relation to tablets and capsules.

Controlled release compositions for oral use can be configured to release the active agent, for example, by controlling dissolution and/or diffusion of the active agent.

Controlled release by dissolution or diffusion can be achieved by suitable coating of tablets, capsules, pills or granular formulations of the drug, or by incorporating the drug into a suitable matrix. The controlled release coating may comprise one or more of the above-mentioned coating substances and/or, for example, shellac, beeswax, glycomax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylates, methyl methacrylate, 2-hydroxymethyl acrylate, methacrylate hydrogels, 1, 3-butanediol, ethylene glycol methacrylate and/or polyethylene glycol. In controlled release matrix formulations, the matrix material may also include, for example, hydrated methyl cellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halofluorocarbons.

Controlled release compositions containing one or more of the claimed drug combinations may also take the form of floating tablets or capsules (i.e., tablets or capsules that float on top of the gastric contents for a period of time after oral administration). A floating tablet formulation of the drug may be prepared by granulating a mixture of the drug with excipients and 20-75% w/w of a hydrogel agent such as hydroxyethyl cellulose, hydroxypropyl cellulose or hydroxypropylmethyl cellulose. The resulting granules can then be compressed into tablets. Upon contact with gastric fluid, the tablet forms a substantially water-impermeable barrier to gelling agents around its surface. This gel barrier layer participates in maintaining the density at less than 1, allowing the tablet to remain floating in the gastric fluid.

Liquid for oral administration

Powders, dispersible powders or granules suitable for preparation of an aqueous suspension by the addition of water are convenient dosage forms for oral administration. Formulations as suspensions provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable suspending agents are, for example, sodium carboxymethylcellulose, methylcellulose, sodium alginate and the like.

Parenteral composition

The pharmaceutical compositions may also be administered parenterally by injection, infusion or implantation (intravenous, intramuscular, subcutaneous, etc.), in dosage forms, formulations or by means of suitable delivery devices or implants containing conventional non-toxic pharmaceutically acceptable carriers and adjuvants. The formulation and preparation of such compositions is well known to those skilled in the art of pharmaceutical formulation.

Compositions for parenteral use may be provided in unit dosage form (e.g. in single dose ampoules) or in vials containing several doses, and wherein a suitable preservative may be added (see below). The composition may take the form of a solution, suspension, emulsion, infusion device or delivery device for implantation, or it may be presented as a dry powder for reconstitution with water or other suitable vehicle prior to use. In addition to the active compound, the compositions may contain suitable parenterally acceptable carriers and/or excipients. The active compounds may be incorporated into microspheres, microcapsules, nanoparticles, liposomes, and the like, for controlled release. The compositions may comprise suspending, solubilizing, stabilizing, pH adjusting and/or dispersing agents.

The pharmaceutical compositions of the present invention may take a form suitable for sterile injection. To prepare such compositions, a suitable active compound is dissolved or suspended in a parenterally acceptable liquid medium. Among the acceptable media and solvents that may be employed are water, water adjusted to a suitable pH by the addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1, 3-butanediol, ringer's solution and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl, or n-propyl parabens). In case one of the compounds is only sparingly soluble or slightly soluble in water, a solubility enhancing or solubilizing agent may be added, or the solvent may comprise 10-60% w/w propylene glycol or the like.

The controlled release parenteral composition may take the form of an aqueous suspension, microspheres, microcapsules, magnetic microspheres, an oil solution, an oil suspension or an emulsion. Alternatively, the active compound may be incorporated into a biocompatible carrier, liposome, nanoparticle, implant or infusion device. The materials used for the preparation of the microspheres and/or microcapsules are, for example, biodegradable/bioerodible polymers, such as polyglycolic acid (polylactan), poly (isobutyl cyanoacrylate), poly (2-hydroxyethyl-L-glutamine). Biocompatible carriers that may be used in formulating controlled release parenteral formulations are carbohydrates (e.g., dextran), proteins (e.g., albumin), lipoproteins or antibodies. The material used for the implant may be non-biodegradable (e.g. polydimethylsiloxane) or biodegradable (e.g. polycaprolactone, polyglycolic acid or polyorthoester).

Alternative approaches

Although less preferred and less convenient, other routes of administration are also contemplated, and thus other formulations are contemplated. In this regard, for rectal use, suitable dosage forms for the compositions include suppositories (of the emulsion or suspension type) and rectal gelatin capsules (solutions or suspensions). In typical suppository formulations, the active compound is combined with a suitable pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, glycerinated gelatin, and various water-soluble or water-dispersible bases such as polyethylene glycols. Various additives, enhancers or surfactants may be incorporated.

The pharmaceutical compositions may also be administered topically to the skin for transdermal absorption in dosage forms or formulations containing conventional non-toxic pharmaceutically acceptable carriers and excipients, including microspheres and liposomes. Formulations include creams, ointments, lotions, liniments, gels, hydrogels, solutions, suspensions, sticks, sprays, pastes, plasters and other types of transdermal drug delivery systems. Pharmaceutically acceptable carriers or excipients may include emulsifiers, antioxidants, buffers, preservatives, humectants, penetration enhancers, chelating agents, gel-forming agents, ointment bases, fragrances, and skin protectants.

Preservatives, moisturizers, penetration enhancers can be parabens such as methyl or propyl parabens, as well as benzalkonium chloride, glycerol, propylene glycol, urea, and the like.

The pharmaceutical compositions described above for topical administration to the skin may also be used in cases where the topical administration is to or near the part of the body to be treated. The composition may be suitable for direct application or for application using a tailor-made drug delivery device, such as a dressing or alternatively in the form of a plaster, pad, sponge, strip or other suitable flexible material.

Sustained release preparation

Any of the compounds of the combination therapies of the present invention may be used in sustained release formulations and/or formulated with agents that modify tissue distribution or bioavailability. More specifically, where applicable, one or more compounds of the present therapy are formulated with drug eluting polymers or biomolecules or micelles or liposome forming lipids or oil-in-water emulsions, or pegylated or solid nanoparticles or microparticles for oral or parenteral or intrathecal administration to modify tissue distribution or bioavailability. Specific examples of such formulation agents include PGA, PLGA, cyclodextrins, albumin or protein carriers, nano-and microparticles, liposomes, emulsions and PEG.

Conjugate (Conjugates)

In the combination therapy of the present invention, the compounds may be combined in different ways in the pharmaceutical composition. They may be mixed together as separate entities. They may be formulated separately. They may also be covalently or non-covalently linked with or without a linker. In a particular embodiment, at least two compounds are linked, preferably by a cleavable or non-cleavable linker.

Dosage and duration of treatment

It will be appreciated that the combined drugs/compounds may be administered simultaneously in the same or different pharmaceutical formulations or sequentially. If administered sequentially, the delay in administering the second (or additional) active ingredient should not result in a loss of benefit from the effective effect of the active ingredient combination. The minimum requirement for the combination of the present invention is that the combination should be intended for use in combination with the benefits of effective effect of the combination of active ingredients. The intended use of the combination can be inferred by the instruments, the appendix, the indications and/or other means for aiding the use of the combination of the invention.

A therapeutically effective amount of a compound in a combination of the invention includes, for example, an amount effective to reduce the symptoms of AD, to halt or slow disease progression (once it has clinical dominance), or to prevent or reduce the risk of disease progression.

Although the active agents of the invention may be administered in divided doses, for example 2 to 3 times daily, a single daily dose of each compound in the combination is preferred, with a single daily dose (unit dosage form) of all agents in a single pharmaceutical composition being most preferred.

Administration may be once to many times daily for several days to several years, and may even last for the lifetime of the patient. Chronic or at least cyclically repeated chronic administration is required in most cases.

The term "unit dosage form" refers to physically discrete units (e.g., capsules, tablets, filled syringe barrels, shakes, ampoules) suitable as unitary dosages for human subjects, each unit containing a predetermined quantity of active material or materials calculated to produce the desired therapeutic effect, in association with a required pharmaceutical carrier.

The preferred amount of each drug in a unit dosage composition depends on a variety of factors including the method of administration, the weight and age of the patient, the stage of the disease, the risk of potential side effects (given the general health of the individual to be treated). In addition, pharmacogenomic (the effect of genotype on pharmacokinetic, pharmacodynamic or therapeutic efficacy profiles) information about a particular patient can affect the dosage used.

In addition to the higher doses that may be required when corresponding to particularly compromised cases, the preferred dose of each drug in the combination will generally be within a range of doses not higher than those typically prescribed for long-term maintenance therapy or that prove safe in phase 3 clinical studies.

A significant advantage of the present invention is that the individual compounds can be used in low doses in combination therapy, but that the combination results in significant clinical benefit to the patient. This combination therapy may actually be effective at doses where the compounds alone have low or no effect. Thus, a particular advantage of the present invention resides in the ability to use less than optimal dosages of each compound, i.e., dosages lower than the usual prescribed therapeutic dosages, preferably 1/2 of the therapeutic dosage, more preferably 1/3, 1/4, 1/5, 1/6, 1/7, 1/8, 1/9 or even more preferably 1/10 of the therapeutic dosage. In particular examples, dosages as low as 1/20, 1/30, 1/50, 1/100, or even lower, of the therapeutic dose may be used.

At these sub-therapeutic doses, the compounds will show no side effects, whereas the combination according to the invention is fully effective in the treatment of AD.

The preferred dose corresponds to 1% up to 50% of the prescribed amount typically prescribed for long-term maintenance therapy.

The most preferred dose may correspond to an amount of 1% up to 10% of the prescribed dose for long-term maintenance therapy.

Specific examples of dosages of compounds for use in the present invention are provided below:

- (soy or lecithin) phospholipids at a dose of between 0.1 and 50 g/day, preferably between 1 and 30 g/day, more preferably between 5 and 15 g/day, these doses being particularly suitable for oral administration.

-caseinates dimethylethanolamine, whey proteins, respectively, from 0.1 to 16 g/day, preferably from 1 to 8 g/day, respectively, more preferably from 3 to 5 g/day, these doses being particularly suitable for oral administration.

-medium-chain fatty glycerides, between 0.1 and 100 g/day, preferably between 1 and 50 g/day, more preferably between 10 and 30 g/day, administered orally.

In the composition of the invention, the caseinates, whey proteins and (soy or egg) phospholipids may be used in different ratios, e.g. the weight ratio of (soy or egg) phospholipids/caseinates or whey proteins or medium chain fatty acid glycerides comprises 0.05 to 1000(w/w), preferably 0.05 to 100(w/w), more preferably 0.05 to 50 (w/w).

It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition or conditions to be treated, the particular composition being administered, the age, weight and response of the patient, the severity of the patient's symptoms, and the chosen route of administration. Accordingly, the above dosage ranges are intended only to provide general guidance and support for the teachings herein, and are not intended to limit the methods of the invention.

The following examples are given for illustrative purposes and are not intended to be limiting.

[ detailed description ] embodiments

Example 1

Formulation (1 single dose):

20g of medium-chain fatty acid (caprylic acid) glycerol (caprylic acid) triglyceride, 7g of casein diethanolamine salt, 5g of whey protein and 8g of soybean lecithin, and the components are mixed uniformly to obtain the feed.

Comparative example 1-1

Formulation (1 single dose):

the casein diethanolamine salt in the formulation of example 1 was replaced with an equal amount of casein ethanolamine salt, all other things being unchanged.

Comparative examples 1 to 2

Formulation (1 single dose):

the casein dimethylethanolamine salt in the formulation of example 1 was replaced by an equal amount of dimethylethanolamine tromethamine salt, all else unchanged.

Example 2

Formulation (1 single dose):

5g of medium-chain fatty acid (caproic acid) glyceride, 2g of casein diethanolamine salt, 1g of whey protein and 1g of soybean lecithin, and the components are mixed uniformly to obtain the soybean lecithin.

Example 3

Formulation (1 single dose):

80g of medium-chain fatty acid (capric acid) glyceride, 25g of casein diethanolamine salt, 25g of whey protein and 20g of soybean lecithin, and the components are mixed uniformly to obtain the feed.

Example 4

Formulation (1 single dose):

30g of medium-chain fatty acid (lauric acid) glyceride, 2g of casein diethanolamine salt, 25g of whey protein and 5g of lecithin, and the components are mixed uniformly to obtain the milk powder.

Example 5

Formulation (1 single dose):

20g of caprylic triglyceride, 20g of casein dimethylethanolamine salt, 5g of whey protein and 8g of soybean phospholipid, and the components are mixed uniformly to obtain the feed.

Example 6

Formulation (1 single dose):

20g of caprylic triglyceride, 7g of casein dimethylethanolamine salt, 5g of whey protein and 8g of soybean phospholipid, and the components are mixed uniformly to obtain the feed.

Example 7

Formulation (1 single dose):

20g of caprylic triglyceride, 3g of casein dimethylethanolamine salt, 5g of whey protein and 8g of soybean phospholipid, and the components are mixed uniformly to obtain the feed.

Test example

Data and method

1 general data

315 patients with AD (Alzheimer's disease) psychomotor symptoms were selected as study subjects. Inclusion criteria were: (1) all accord with AD diagnosis standard and are accompanied with psychobehavior symptoms; (2) no other medicine is taken for treatment within 1 month; (3) the patient and his family signed an informed consent. Exclusion criteria: (1) with severe disturbance of consciousness; (2) those with other brain diseases; (3) those with severe liver and kidney dysfunction; (4) contraindications exist for the study drug. 315 patients were randomized into study group 1 and control group 2, 105 patients each. 52 male patients, 53 female patients, age 53-78 years, mean age (75.65 +/-5.78) years, disease course 1-8 years and mean disease course (4.51 +/-1.02) years in the study group; in the control group, 53 male patients, 52 female patients, 55-79 years old, mean age (76.97 + -6.12) years old, course of disease 1-7 years old, and mean course of disease (4.12 + -0.97) years old.

2 method

The study group patients were treated with the samples of example 1, the control group 1 patients were treated with the samples of control examples 1-1, and the control group 2 patients were treated with the samples of control examples 1-2, both at an initial dose of 0.5 single dose/time, increasing to 1 single dose/time after 1 week, twice a day, and both for 12 consecutive weeks.

Description of the drawings: examples 2, 3 and 4 and examples 5, 6 and 7 were carried out as described above, i.e.the samples of examples (3, 4 or 6 and 7) were used for the control group.

3 standard of therapeutic effect

Clinical efficacy was evaluated according to the reduction rate of the pathological behavioral scale: the effect is shown: the reduction rate is more than 60 percent; the method has the following advantages: the reduction rate is more than 30 percent and less than or equal to 60 percent; and (4) invalidation: the reduction rate is less than or equal to 30 percent. Total effective rate (effective + effective)/total number of cases x 100%.

4 observation index

(1) After the treatment is finished, the clinical efficacy of 3 groups of patients is evaluated;

(2) recording AD pathological behavior score (BEHAVE AD), simple intellectual state examination (MMSE) score, Brief Psychiatric Rating Scale (BPRS) score for 3 groups of patients before and after treatment;

(3) before and after treatment, 10 mL of fasting venous blood of a patient in the early morning is extracted, an enzyme-linked immunosorbent assay is used for detecting the levels of Nitric Oxide (NO) and Vascular Endothelial Growth Factor (VEGF), and a double-antibody sandwich ABC ELISA is used for detecting the levels of interleukin 1 (IL-1) and tumor necrosis factor α (TNF- α);

(4) statistics were made on the incidence of adverse reactions during treatment in 3 groups of patients.

5 statistical treatment

SPSS 19.0 statistical software is applied, the comparison of counting data adopts a chi 2 test, the result of measuring data is expressed by (x +/-s), wherein x represents mean, s represents standard deviation, 2 groups adopt independent sample t test, the comparison before and after treatment in the group adopts pairing t test, and P < 0.05 represents that the difference has statistical significance.

Results

The total effective rate of the study group patients is obviously improved (P is less than 0.05) compared with the curative effect of the 2 control groups, and the treatment effect is shown in table 1.

TABLE 1-13 comparison of efficacy in groups of patients

Group of cases shows the effective and ineffective total effective rates

Example 110552341981.9%

Control group 110537214755.2%

Control group 210528265151.4%

χ2 6.70

P ＜0.05

TABLE 1-23 comparison of the efficacy of the patients

Group of cases shows the effective and ineffective total effective rates

Example 210513246835.2%

Example 310556351486.7%

Example 410537333566.7%

χ2 6.80

P ＜0.05

TABLE 1-33 comparison of efficacy in groups of patients

Group of adverse reaction incidence rate of digital display effect, effectiveness, invalidation and no efficiency

Example 510554361514.3% 25.6%

Example 610552371615.2% 9.2%

Example 710542323129.5% 4.7%

χ2 6.60

P ＜0.05

2 BEHAVE-AD, MMSE, BPRS score comparison

Before treatment, the difference of BEHAVE-AD, MMSE and BPRS scores of 3 groups of patients is not statistically significant (P is more than 0.05); after treatment, patients in group 3 had a lower BEHAVE-AD, lower BPRS score than before treatment and a higher MMSE score than before treatment (P < 0.05); the patients in the study group had better BEHAVE-AD, BPRS and MMSE scores than the control group (P < 0.05), and the results are shown in Table 2.

TABLE 2 comparison of BEHAVE-AD, MMSE, BPRS scores before and after treatment

Group BEHAVE-AD Scoring MMSE Scoring BPRS Scoring

Study group/example 1

Before treatment, 20.32 +/-5.6310.53 +/-3.4258.58 +/-10.25

6.73 +/-1.5226.67 +/-7.6420.56 +/-6.46 after treatment

Control group 1

21.34 + -5.8710.67 + -3.6258.26 + -10.84 before treatment

13.56 + -4.6615.65 + -6.4740.53 + -8.46 after treatment

Control group 2

Before treatment, 20.65 +/-6.4310.37 +/-3.3558.83 +/-11.23

14.53 +/-5.0316.74 +/-6.5342.38 +/-8.95 after treatment

Comparison of inflammatory factor and vascular endothelial marker levels before and after treatment in 33 groups of patients

before treatment, the differences of inflammatory factors and vascular endothelial index levels of 3 groups of patients have NO statistical significance (P is more than 0.05), after treatment, the water average of NO and VEGF of the 3 groups of patients is higher than that before treatment, the IL-1 and TNF- α levels are lower than that before treatment, and the improvement conditions of the NO, VEGF, IL-1 and TNF- α levels of the study group of patients are better than that of the 2 control group (P is less than 0.05), which is shown in Table 3.

TABLE 33 comparison of inflammatory factor and vascular endothelial marker levels before and after treatment in patients of group

group NO (μmol/l) VEGF (pg/ml) IL-1 (μ g/l) TNF- α (pg/ml)

Study group/example 1

Before treatment, 32.52 +/-3.43411.6 +/-42.60.72 +/-0.1475.6 +/-8.68

51.67 +/-6.21787 after treatment, +/-65.70.32 +/-0.1140.7 +/-5.73

Control group 1

Before treatment, 32.78 +/-3.75408.7 +/-39.90.73 +/-0.1876.6 +/-8.13

39.63 + -4.02513.7 + -53.60.51 + -0.1259. + -6.24 after treatment

Control group 2

Before treatment, 32.25 +/-3.13413.7 +/-43.80.71 +/-0.2176.2 +/-8.94

42.34 + -4.53523.7 + -56.80.56 + -0.1562.5 + -7.86 after treatment

43 groups comparison of incidence of adverse reactions

Study group/example 1 had 8 patients (7.62%) with adverse reactions, control group 1 had 17 patients (16.2%) with adverse reactions, control group 2 had 15 patients (14.3%) with adverse reactions, and the study group was superior to the control group.

Claims (24)

1. A composition, comprising: casein diethanolamine salt, whey protein and (soy or lecithin) phospholipid;

and at least one medium chain glyceride of the formula:

wherein R1, R2 and R3 are each independently a medium chain fatty acid (C6-C12) or a hydroxyl group, and at least one of R1, R2 and R3 is a medium chain fatty acid (C6-C12).

2. The composition of claim 1, wherein R1, R2, and R3 are the same medium chain fatty acids.

3. The composition according to claim 1, wherein the medium chain fatty acid is selected from caproic acid (C6), caprylic acid (C8), capric acid (C10) and/or lauric acid (C12).

4. The composition according to claim 1, wherein the at least one medium chain glyceride is selected from the group consisting of caproic acid triglyceride (C6), caprylic acid triglyceride (C8), capric acid triglyceride (C10), and lauric acid triglyceride (C12).

5. The composition according to claim 1, wherein the at least one medium chain glyceride is derived from coconut oil, palm kernel oil, and/or cuphea seed oil, or an extract thereof.

6. The composition of claim 1, wherein the at least one medium chain glyceride is derived from Cuphea pulcherrima seed oil, or an extract thereof.

7. The composition of claim 1, wherein the composition comprises at least one of a combination of-caseindimethylethanolamine salt, whey protein and soy or lecithin and caprylic acid triglyceride, -caseinylethanolamine salt, whey protein and soy or lecithin and caproic acid triglyceride, -caseinylethanolamine salt, whey protein and soy or lecithin and capric acid triglyceride, or-caseinylethanolamine salt, whey protein and soy or lecithin and lauric acid triglyceride.

8. The composition of claim 1, comprising as the only active agents: casein diethanolamine salt, whey protein, soy or lecithin and caprylic triglyceride.

9. The composition of claim 1, wherein the medium chain fatty acid glycerides are present in the composition in an amount of 5% to 90%, the caseinyldimethylammonium salt or the whey protein is present in the composition in an amount of 1% to 40%, and the (soy or lecithin) phospholipids are present in the composition in an amount of 1% to 25%, said amounts being based on the total volume (or weight) of the total composition.

10. The composition of any one of the preceding claims, further comprising a pharmaceutically acceptable carrier or excipient.

11. The composition of any one of the preceding claims for use in the preparation of a nutritional agent for treating a neurological disorder in a subject in need thereof.

12. The composition for use according to claim 11, wherein the neurological disorder is selected from alzheimer's disease, alzheimer's disease related diseases, frontotemporal dementia, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, spinal cord injury, peripheral neuropathy, cerebral ischemic events, parkinson's disease, dementia with lewy bodies, huntington's disease, neurological manifestations of drug abuse and withdrawal from drug abuse.

13. The composition for use according to claim 11, wherein the neurological disorder is an alzheimer's disease related disorder selected from the group consisting of senile dementia of the AD type, vascular dementia, mild cognitive impairment and age-related memory impairment.

14. The composition for use according to claim 11, wherein the neurological disorder is alzheimer's disease.

15. The composition of any one of the preceding claims, wherein the compounds in the composition are formulated together in a mixture.

16. The composition of any one of claims 1 to 14, wherein the compounds in the composition are formulated separately.

17. The composition for use according to any one of claims 11 to 14, wherein the compounds in the composition are administered together, separately or sequentially.

18. The composition for use according to any one of claims 11 to 14, wherein the composition is repeatedly administered to a subject.

19. The composition of any one of the preceding claims wherein the ratio (w/w) of soy or lecithin/casein dimethylethanolamine salt or whey protein is from 0.05 to 1000.

20. The composition of any one of the preceding claims, wherein the dose of the caseinates dimethylethanolamine salt, whey protein is less than 100 g/day.

21. The composition of any one of the preceding claims, wherein the dose of (soy or lecithin) phospholipid is less than 100 g/day.

22. A method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition according to any one of claims 1 to 10, 15, 16 or 19 to 22.

23. The method of claim 22, wherein the neurological disorder is selected from alzheimer's disease, alzheimer's disease related diseases, frontotemporal dementia, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, spinal cord injury, peripheral neuropathy, alcoholism or alcohol withdrawal, traumatic brain injury or cerebral ischemic event, parkinson's disease, lewy body dementia, huntington's disease, neurological manifestations of drug abuse, and withdrawal from drug abuse.

24. Use of a composition according to any one of claims 1 to 10, 15, 16 or 19 to 22 for the manufacture of a medicament for the treatment of a neurological disorder selected from alzheimer's disease, alzheimer's disease related diseases, frontotemporal dementia, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, spinal cord injury, peripheral neuropathy, alcoholism or alcohol withdrawal, traumatic brain injury or ischemic event, parkinson's disease, lewy body dementia, huntington's disease, neurological manifestations of drug abuse and drug abuse withdrawal.