KR20130117017A - A composition with d-amino-acid-oxidase for improving and delaying symptoms such as muscule weakness, amyotrophy, articulation disorder, dysphagia - Google Patents

Abstract

PURPOSE: A composition for treating or delaying muscular weakness, amyotrophy, dysarthria, and dysphagia is provided to effectively prevent or treat amyotrophic lateral sclerosis, myasthenia gravis, stroke, senile dementia, cerebellar atrophy, and other motor neuron diseases. CONSTITUTION: A composition contains 0.1 ng/ml-40 mg/ml of D-amino acid oxidase, 100 ppm(0.31 mg/l)-1000 ppm(3.1mg/l) of catalase, and 10 mg/ml-40 mg/ml of megestrol acetate as active ingredients. The composition prevents or treats amyotrophic lateral sclerosis, myasthenia gravis, stroke, senile dementia, Parkinson's disease, and other motor neuron diseases. The composition is formed in a tablet for oral administration by mixing the active ingredients and making the mixture with a wheat gluten coating agent.

Description

A COMPOSITION WITH D-AMINO-ACID-OXIDASE FOR IMPROVING AND DELAYING SYMPTOMS SUCH AS MUSCULE WEAKNESS, AMYOTROPHY, ARTICULATION DISORDER, DYSPHAGIA}

The present invention relates to a composition for delaying the improvement of symptoms of muscle weakness, muscular atrophy, dysfunction, dysphagia, dysphagia, specifically, muscular dystrophy by improving or delaying the symptoms of muscle weakness, muscular atrophy, dysfunction, dysphagia. A composition for treating sclerosis, myasthenia gravis, paralysis, senile dementia, Parkinson's disease, and other motor neuron diseases.

Muscle weakness, muscular dystrophy, dysphagia, and dysphagia are typical signs of Amyotrophic Lateral Sclerosis (ALS), severe work force, stroke, senile dementia, Parkinson's disease, and other motor neuron disease. .

In particular, amyotrophic lateral sclerosis (ALS) with all of these symptoms is a degenerative disease in which motor neuron cells of the central nervous system are destroyed. ALS is a family member due to genetic defects of Cu / Zn superoxide dismutase in about 10% of patients. Although cases have been reported, the most accurate pathophysiological mechanisms have not yet been identified in most disseminated cases.

One of the important mechanisms in the onset of ALS is the autoimmune hypothesis that ALS occurs due to cytotoxicity caused by autoimmune mechanism of ALS plasma component. To elucidate the autoimmune mechanism of ALS, In a series of experiments using immunoglobulin to identify neuronal degeneration, intracellular calcium inflow has been reported to play an important role in the mechanism of cell degeneration.

On the other hand, among the drugs prescribed in the ALS treatment in the clinic, there is a 'rirusol' that has the effect of delaying the progression of the disease. Riluzol is a drug that inhibits excessive glutamic acid, which is considered one of the causes of motor neuron destruction, and is the only treatment to extend ALS life to this day. However, several reports have shown that it is effective for delaying progression for about 4 months and does not improve symptoms. In terms of safety, it is still a controversial issue in many papers.

Specifically, several long-term clinical trials in Lou Gehrig's patients show conflicting results on the efficacy of rilusol. A study of Lou Gehrig's patients in Europe reported that rilusol had a life extension effect of at least four months. Another study found that after 12 months, there was an increase in survival of 4 months in the rerusol-treated group and 24% higher in the 4-year survival than the control group.

Contrary to the report, however, despite the introduction of rirusol, percutaneous endoscopic gastroscopy (PEG), and non-invasive ventilation (NIV), survival rates have not been shortened or changed over the past decade. Pointing to the trends, the effects of rilusol, PEG, and NIV are questioned.

Two studies on the appropriate duration and time of treatment for relusol suggest that it is desirable to take relusol as early as possible and to avoid the need for medication at the end of the illness, as the regression is ineffective in advanced ALS. have.

In addition, in the recently reported report of relusol, the relusol-treated group had an effect of prolonging life for 6 months compared to the control group until 12 months after diagnosis, but in the late stage of illness (18 months or more in this experiment), Announced no difference.

However, this is in stark contrast to the claim that relusol should only be prescribed for patients with ALS confirmed probable and definite in accordance with the El escorial criteria set forth in the AAL guidelines. It's still unclear which group of patients might be more effective than that.

On the other hand, there are many reports that the efficacy of relusol is better than the quadrilateral type in soft type, because the progression of disease is faster in case of soft type, because the time between the first symptoms and the diagnosis is short, It was estimated.

Yet another study found no significant difference in treatment effect between the soft and quadrilateral patients.

On the other hand, the efficacy of relusol by age is also being discussed. In one clinical study, the survival time was extended by 8 months compared to the non-administration group after taking relusol in elderly patients over 70 years, and the mortality rate decreased by 27% after 12 months. Reported, but other studies do not demonstrate this effect in older people.

On the other hand, side effects that occur after taking rirusol have been reported, including nausea, lethargy, dizziness, gastrointestinal disorders and elevated liver numbers. Among them, the increase in liver level is reported to be up to 3 times higher in the group treated with leurusol than the control group.

On the other hand, excessive secretion of D-Serine in motor neurons destroys N-methyl-D-aspartate receptors and plays a crucial role in the death of motor neurons in ALS patients with spontaneous or family history. The role of oxidase (D-Amono acid oxidase, DAO, DAAO) is becoming more important.

On the other hand, when reviewing the patent documents related to the present invention, the Republic of Korea Patent Publication No. 10-1034596 filed by the present inventors include Choo, Daegye, Confectionery, ephedra, Gilgyeong, Sansa, Licorice, dried radish skin, dried lacquer, sulfur and perforated It is disclosed that the extract of the composition is used to improve and delay the symptoms of muscle weakness, muscular atrophy, dysfunction, dysphagia, and swallowing disorder.

In addition, the Republic of Korea Patent Publication No. 2003-0066813 relates to the treatment of CNS diseases using diamino oxidase and diaspartate oxidase antagonist, and the Republic of Korea Patent Publication No. 10-0859991 transformed plants using diamino oxidase Each of the selection methods is described.

Therefore, the present inventors consider the situation that the efficacy and safety of the representative prescription drug, Riruzol, emerged in the clinic, and the drug using the di-Amono acid oxidase (DAO, DAAO) Since it has not been developed, a new therapeutic agent has been devised to improve and delay the symptoms of muscle weakness, muscle atrophy, dyspnea, and swallowing disorder using diamino oxidase.

1. Korean Registered Patent No. 10-1034596 (Published on May 12, 2011) 2. KOKAI Publication No. 2003-0066813 (published on August, 2003) 3. Korean Patent Registration No. 10-0859991 (published on September 25, 2008)

1. Traynor BJ, Alexander M, Corr B, et al. An outcome study of riluzole in amyotrophic lateral sclerosis. A population based study in Ireland, 1996-2000. Journal of Neurology. 2003; 250: 473-9. 2. Lacomblez L, Bensimon G, Leigh PN, et al. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis / Riluzole Study Group Ⅱ. Lancet. 1996; 347 (9013): 1425-31. 3. Forbes RB, Colville S, Cran GW, Swingler RJ. Unexpected decline in survival from amyotrophic lateral sclerosis / motor neuron disease. Journal of Neurology, Neurosurgery, and Psychiatry. 2004; 75: 1753-5. 4. Chio A, Mora G, Leone H, et al. Early symptom progression rate is related to ALS outcome. A prospective population-based study. Neurology. 2002; 59: 99-103. 5. Turner MR, Bakker M, Sham P, Shaw CE et al. Prognostic modeling of therapeutic interventions in amyotrophic lateral sclerosis. ALS and other motor neuron disorders. 2002; 3: 1521. 6. Zoccolella S, Beghi E, Palagano G, Fraddosio A, et al. Riluzole and amyotrophic lateral sclerosis survival: a population-based study in southern Italy. European Journal of Neurology. 2007; 14 (3): 262-8. 7. Quality Standards Subcommittee of the American Academy of Neurology. Practice advisory on the treatment of amyotrophic lateral sclerosis with riluzole. Neurology. 1997; 49: 657-9. 8. Jumpei Sasabe, Yurika Miyoshi, Masataka Suzuki, Masashi Mita, Ryuichi Konno, Masaaki Matsuoka, Kenji Hamase, and Sadakazu Aiso, D-Amino acid oxidase controls motoneuron degeneration through D-Serine. PNAS. 109 (2): 627-632

Accordingly, an object of the present invention is to relieve symptoms and delay symptoms such as muscle weakness, muscular atrophy, oral dysfunction, dysphagia, muscle atrophic lateral sclerosis, other motor neuron disease, myasthenia gravis, stroke, senile dementia, Parkinson's disease, cerebellar atrophy It is to provide a composition for treating a disease.

The present invention is a di-amino-acid-oxidase (D-Amino-acid-oxidase), catalase (Catalase) and megestrol acetate (Megestrol Acetate) as an active ingredient, muscle weakness, muscle atrophy, dysfunction, dysphagia symptoms The present invention aims to solve the technical problem by providing a composition for preventing or treating atrophic lateral sclerosis, myasthenia gravis, stroke, senile dementia, Parkinson's disease, and motor neuron disease.

According to the composition for improving or delaying symptoms of muscle weakness, muscular atrophy, dysfunction, dysphagia, dystrophic lateral atrophy, myasthenia gravis, stroke, senile dementia, Parkinson's disease, other motor neuron disease Can be.

The terms and words used in the present specification and claims should not be construed as limited to ordinary or dictionary terms and the inventor may properly define the concept of the term in order to best describe its invention It should be construed as meaning and concept consistent with the technical idea of the present invention.

Therefore, the examples, reference examples, experimental examples, formulation examples, and drawings described in the present specification are merely the most preferred examples of the present invention and do not represent all the technical ideas of the present invention. Therefore, It should be understood that various equivalents and modifications may be substituted for those embodiments.

Example  1. muscle weakness, Muscular dystrophy For improving and delaying symptoms of dysphagia, dysphagia and dysphagia

The composition of the present invention is for improving and delaying the symptoms of muscle weakness, muscular atrophy, dysfunction and dysphagia, and as an active ingredient, di-amino-acid-oxidase (DAO, DAAO) and catalase (Catalase). ).

Preferably, diamino oxidase (DAO, DAAO) is 0.1ng ~ 40 mg / ml, catalase (Catalase) is to be included in a concentration of 100 ppm (0.31 mg / l) to 1000 ppm (3.1 mg / l).

Here, diamino oxidase is a protein powder extracted from pig kidney, human placenta, horse placenta, horse kidney or horse, the color is yellow, the amount of protein in Biuret reaction is more than 50% and the solid content per unit / mg is more than 1.5 To be

Catalase is also included to help the reaction to decompose hydrogen peroxide that diamino oxidase can generate.

Diamino oxidase and catalase are made of wheat protein coating agent to prevent gastrointestinal rupture caused by ingredients and absorbed in the small intestine, making it easy to carry and ingest tablet type.

In other words, the pH range is 6.5 ~ 8.3, the temperature is 25 ~ 45 ℃, and the pH is 8.3 and it is manufactured to reach the optimum effect when the temperature is 40 ℃.

Example  2. muscle weakness, Muscular dystrophy For improving and delaying symptoms of dysphagia, dysphagia and dysphagia

As in Example 1, as an active ingredient to include a di-amino-acid-oxidase (D-Amino-acid-oxidase, DAO, DAAO) and catalase (Catalase).

Preferably, diamino oxidase (DAO, DAAO) is 0.1ng ~ 40 mg / ml, catalase (Catalase) is to be included in a concentration of 100 ppm (0.31 mg / l) to 1000 ppm (3.1 mg / l).

Here, diamino oxidase is a protein powder extracted from pig kidney, human placenta, horse placenta, horse kidney or horse, the color is yellow, the amount of protein in Biuret reaction is more than 50% and the solid content per unit / mg is more than 1.5 To be

Catalase is also included to help the reaction to decompose hydrogen peroxide that diamino oxidase can generate.

Diamino acid oxidase and catalase are prepared in the form of injections capable of endotoxin removal, pH 7.4, and sterilization followed by subcutaneous, intramuscular and vascular injections.

Example  3. muscle weakness, Muscular dystrophy For improving and delaying symptoms of dysphagia, dysphagia and dysphagia

The composition of the present invention is to improve and delay the symptoms of muscle weakness, muscular atrophy, dysfunction and dysphagia, as an active ingredient di-amino-acid-oxidase (DAO, DAAO), catalase (Catalase) ) And megestrol acetate.

Preferably, diamino oxidase (DAO, DAAO) is 0.1ng to 40 mg / ml, catalase is 100 ppm (0.31 mg / l) to 1000 ppm (3.1 mg / l), megestrol acetate (Megestrol) Acetate) should be included at a concentration of 10 mg / ml to 40 mg / ml.

Here, diamino oxidase is a protein powder extracted from pig kidney, human placenta, horse placenta, horse kidney or horse, the color is yellow, the amount of protein in Biuret reaction is more than 50% and the solid content per unit / mg is more than 1.5 To be

Catalase is also included to help the reaction to decompose hydrogen peroxide that diamino oxidase can generate.

Megestrol acetate is also included to perform the appetizer function in anorexia patients.

Diaminoacid oxidase, catalase and megestrol acetate are made from wheat protein coatings to prevent gastrointestinal rupture caused by ingredients and are absorbed in the small intestine, making it a tablet type that is easy to carry and consume.

In other words, the pH range is 6.5 ~ 8.3, the temperature is 25 ~ 45 ℃, and the pH is 8.3 and it is manufactured to reach the optimum effect when the temperature is 40 ℃.

Example  4. muscle weakness, Muscular dystrophy For improving and delaying symptoms of dysphagia, dysphagia and dysphagia

The composition of the present invention is intended to improve and delay the symptoms of muscle weakness, muscular atrophy, dysfunction and dysphagia, and as an active ingredient, di-amino-acid-oxidase (DAO, DAAO), catalase (Catalase). ), Choo, Jogu etc., Ginseng, Ogapi, Galge, Astronomical dong, Jahager (Intestinal Placenta or Horse Placenta), Low bone marrow, Daegye, Gilkyung, Licorice, Confectionery, Sansa, Chinese quince, Ephedra, Goku.

Preferably, diamino oxidase (DAO, DAAO) is 0.1ng ~ 40 mg / ml, catalase (Catalase) is to be included in a concentration of 100 ppm (0.31 mg / l) to 1000 ppm (3.1 mg / l).

In addition, 6g of choo, 12g of light bulbs, 12g of ginseng, 4g of ogapi, 12g of root, 12g of astronomical dong, 8g of cheonmundong, 30ml of bone marrow, 30ml of raw bone, 20g of gyekyung, 10g of licorice, 15g of licorice, 15g of hawthorn, 10g of quince, 10g of quince, It should contain 4g ephedra and 4g perforation.

Preferably, the components in a single daily dose of hot water extract and then highly concentrated freeze-drying so that the dosage is about 30 minutes after eating three times a day.

One dose is converted to 2mg per 1kg of body weight to make a protein coating agent orally administered to prevent gastrointestinal destruction caused by ingredients and absorbed in the small intestine, consisting of a tablet type that can be easily carried and consumed.

Meanwhile, in Examples 1 to 4, it was found that the composition of the present invention may be prepared in a tablet type or an injection, but in addition, powder, granule, capsule, suspension, emulsion, Oral formulations such as syrups, aerosols, external preparations, suppositories and the like can be used in the form of a formulation.

Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxy, hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.

Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included .

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsion lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used.

As a suppository base, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Preferred dosages of the compositions of the present invention vary depending on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art. The administration may be carried out once a day or divided into several doses. Accordingly, the dosage is not limited in any way to the scope of the present invention.

In addition, the composition of the present invention can be administered to various mammals such as rats, mice, livestock, humans. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.

Claims (4)

D-Amino-acid-oxidase, Catalase and Megestrol Acetate as active ingredients,
A composition for preventing or treating muscle atrophy, lateral sclerosis, myasthenia gravis, stroke, senile dementia, Parkinson's disease, and motor neuron disease by improving and delaying symptoms of muscle weakness, muscular dystrophy, dysfunction, dysphagia, dysphagia.
The method of claim 1,
The diamino oxidase is 0.1ng ~ 40 mg / ml, catalase is 100 ppm (0.31mg / l) ~ 1000 ppm (3.1mg / l), megestrol acetate in a concentration of 10 mg / ml to 40 mg / ml A composition, characterized in that it is included.
The method of claim 1,
Mixing each of the active ingredients in a powder type, and then made of a wheat protein coating agent to form a tablet (Tablet) type orally administered.
The method of claim 1,
The respective active ingredients are mixed in a powder type and then endotoxin is removed by sterilization and adjusted to PH 7.4 to form a subcutaneous, intramuscular, vascular injectable injection type.