WO2019039836A2 - Complex formulation composition for treatment of neurodegenerative disease - Google Patents

Complex formulation composition for treatment of neurodegenerative disease Download PDF

Info

Publication number
WO2019039836A2
WO2019039836A2 PCT/KR2018/009601 KR2018009601W WO2019039836A2 WO 2019039836 A2 WO2019039836 A2 WO 2019039836A2 KR 2018009601 W KR2018009601 W KR 2018009601W WO 2019039836 A2 WO2019039836 A2 WO 2019039836A2
Authority
WO
WIPO (PCT)
Prior art keywords
disease
treatment
sustained
inhibitor
present
Prior art date
Application number
PCT/KR2018/009601
Other languages
French (fr)
Korean (ko)
Other versions
WO2019039836A3 (en
Inventor
홍지만
임태성
최문희
Original Assignee
아주대학교산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 아주대학교산학협력단 filed Critical 아주대학교산학협력단
Publication of WO2019039836A2 publication Critical patent/WO2019039836A2/en
Publication of WO2019039836A3 publication Critical patent/WO2019039836A3/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • the present invention relates to a combination formulation for the treatment of neurodegenerative disorders, and more particularly to a composition for the treatment of neurodegenerative disorders of the degenerative nature comprising cholinesterase inhibitor, scopolamine butyl bromide and a pharmaceutically acceptable salt thereof. Compositions and sustained release formulations thereof.
  • Dementia is a type of degenerative brain disease that is characterized by a complex cognitive disorder characterized by memory loss, degenerative changes in intelligence, changes in personality, and behavioral disorders. This symptom is a gradual depletion of neurons in the central nervous system that cause degenerative diseases, resulting in irreversible dysfunctions in the neural network and ultimately leading to permanent loss of the human function.
  • choline acetyltransferase which synthesizes acetylcholine (ACh), a neurotransmitter
  • ChAT choline acetyltransferase
  • ACh acetylcholine
  • a drug using an inhibitor that inhibits choline esterase (ChE), an enzyme that hydrolyzes acetylcholine has been developed as an indirect treatment method.
  • Choline esterase has two forms: acetylcholinesterase (AChE) and butylcholinesterase (BuChE).
  • the above-mentioned acetylcholine esterase is an enzyme that hydrolyzes acetylcholine, which is one of neurotransmitters that mediate the activity of parasympathetic nerves in the body, into choline and acetate, and is formed in the endoplasmic reticulum membrane and moves to the cell membrane to perform its function .
  • These enzymes are most widely distributed in the cholinergic nerve and its surroundings, especially in the muscle nerve junction, and are important enzymes found in plasma, liver and other tissues.
  • acetylcholinesterase inhibitors are the most commonly used drugs for the treatment of dementia, and some drugs simultaneously inhibit acetylcholinesterase and butylcholinesterase inhibitors. Examples include Donepezil, Rivastigmine, Galantamine, Tacrine and the like. These drugs have the ability to reversibly inhibit acetylcholine esterase and / or butylcholinesterase, thereby increasing acetylcholine in the brain of a patient suffering from Alzheimer ' s Dementia, Activates the nervous system and, as a result, alleviates or slows down the symptoms of dementia.
  • a cholinesterase inhibitor drug is not only effective in preventing or treating Alzheimer's dementia, but also has a serious side effect as an oral agent.
  • oral administration of acetylcholinesterase inhibitors has been reported to cause side effects such as liver dysfunction, sneezing, digestive tract disorders such as nausea, vomiting, diarrhea and abdominal pain.
  • the cause of such side effects is that it is generally impossible to avoid the primary transit effect to the liver, and as a result, it is easy to affect the liver function, and it is present in high concentration in the digestive tract, and side effects are likely to appear in the digestive tract .
  • Scopolamine butylbromide also known as Buscopan, is a drug that has an anticholinergic action and has an antimicrobial effect. Although it is not a mechanism to eliminate pain itself, it can calm the overactive active smooth muscle to calm the cause of pain, and it can be used for various diseases such as spastic cramps, menstrual cramps, and digestive system abnormalities. In addition, since quaternary ammonium of scopolamine butylbromide is charged, it does not pass through the blood-brain barrier (BBB), so that it has an advantage that there is almost no side effect of the central nervous system (CNS). However, there have been no reports of co-administration with dementia drugs.
  • BBB blood-brain barrier
  • the present inventors have made intensive efforts to develop a method for sustaining the effect of the drug for a long time while reducing the side effects of the choline esterase inhibitor, and have completed the present invention.
  • the present invention provides a pharmaceutical composition for treating a degenerative neurological disease comprising a cholinesterase inhibitor, scopolamine butyl bromide and a pharmaceutically acceptable salt thereof, for solving the above-mentioned problems.
  • the present invention also provides a sustained release formulation for treating a degenerative neurological disease comprising a cholinesterase inhibitor and scopolamine butyl bromide.
  • the sustained-release formulation of the present invention is characterized in that it has a double-layer structure including a slow release layer and a slow release layer in the body including a immediate release layer and a hydrophilic matrix.
  • the immediate-release layer is characterized by releasing all active ingredients immediately or at least within one hour after the administration of the drug.
  • a pharmaceutically acceptable salt, carrier or excipient . ≪ / RTI >
  • the sustained-release layer gradually releases the active ingredient from the body for 12 hours to 36 hours after administration of the drug, and includes a hydrophilic matrix for the drug release effect.
  • the hydrophilic matrix may include a sustained-release polymer.
  • the sustained-release polymer may be selected from HPMC (Hydroxypropyl methylcellulose), but is not limited to a carrier or an excipient capable of slowly releasing a drug in the body for 12 to 36 hours .
  • the inventors of the present invention found that the combined use of acetylcholinesterase inhibitors donepezil and scopolamine butyl bromide increased the level of acetylcholine in the brain, and at the same time, the symptoms such as sore throat and abdominal pain, which are side effects of the digestive system, Thereby completing the present invention.
  • Another embodiment of the present invention relates to a method for treating a neurodegenerative disease, comprising administering to a patient having the disease a combined administration of a cholinesterase inhibitor and scopolaminebutyl bromide.
  • the cholinesterase inhibitor of the present invention may be an acetylcholine esterase inhibitor or a butylcholinesterase inhibitor and specifically includes donepezil, rivastigmin, galantamine, but are not limited to, at least one selected from the group consisting of mimopezil, ladostigil, huperzine, and tacrine.
  • the pharmaceutically acceptable salts of the present invention are acid addition salts of non-toxic acids.
  • the salts may be formed with organic acids such as, for example, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, Salts formed from malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p- aminobenzoic acid, glutamic acid, benzenesulfonic acid, theophylline acetic acid, , E. G. 8-bromo theophylline.
  • the salts may also be made from inorganic salts such as hydrochloric acid, hydrobromic acid, sulfuric acid,
  • the combined administration of the cholinesterase inhibitor and scopolaminebutyl bromide may take the form of a co-administration.
  • the cholinesterase inhibitor and scopolaminebutyl bromide are administered to the patient in the form of one dosage form containing both active ingredients at essentially the same time, or in separate dosage forms,
  • the combined administration of the cholinesterase inhibitor and scopolaminebutyl bromide involves the disparity between the administration of the two active ingredients.
  • either the choline esterase inhibitor or scopolamine butyl bromide may be administered initially.
  • the synergistic effect depends on whether a pharmacologically effective amount of both the cholinesterase inhibitor and scopolaminebutyl bromide is present in the body at the same time. This gives the upper limit of the time difference between administration of the cholinesterase inhibitor and scopolaminebutyl bromide.
  • &quot half-life " herein is the time required for the plasma level of the pharmaceutically active ingredient to reach 50% of the initial value of the ingredient.
  • the combined administration of donepezil and scopolaminebutyl bromide as cholinesterase inhibitors increases the level of acetylcholine in the brain and produces a synergistic effect.
  • similar characteristics were observed by the combination of donepezil and other cholinesterase inhibitors and scopolaminebutyl bromide.
  • the approved maintenance dosage (FDA) for the choline esterase inhibitor is 10 mg or 23 mg per day at an initial dose of 5 mg.
  • the present invention provides a method of treating a donepezil, comprising scophoramine butyl bromide administered at 1 mg, 5 mg, 15 mg or 20 mg per day, wherein the donepezil is at least 1 mg per day, for example, 2 mg Or more, for example, 5 mg or more, for example, 10 mg or more.
  • Specific examples include 5 mg to 10 mg of donepezil, together with 5 mg to 20 mg of scopolamine butyl bromide, for example 10 mg or 15 mg per day.
  • Specific examples include 10 mg to 25 mg of donepezil, for example 23 mg of donepezil, together with 5 mg to 20 mg of scopolamine butyl bromide per day, for example 10 mg or 15 mg.
  • the active pharmaceutical ingredients used in the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, either as single compounds or as multiple doses, as pure compounds .
  • the pharmaceutical compositions according to the present invention may be formulated with pharmaceutically acceptable carriers or diluents as well as conventional techniques such as those described in Remington: The Science and Practice of Pharmacy, 21 Edition, Hauber, Ed., Lippincott Williams & , ≪ / RTI > and other excipients and excipients.
  • compositions of the present invention may be used in the manufacture of a medicament for the treatment and / or prophylaxis of the diseases or disorders mediated by any particular route, for example, oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, , Intra-vertebral, intravenous and intradermal) routes, and oral routes are preferred. It will be appreciated that the preferred route may vary depending upon the overall condition and age of the subject to be treated, the nature of the condition to be treated, and the active ingredient selected.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders, and granules. Where appropriate, the solid dosage forms may be prepared with the coatings thereon.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and non-aqueous injection solutions, dispersions, suspensions or emulsions, as well as sterile injectable solutions or sterile powders to be reconstituted in a dispersion prior to use.
  • Suitable dosage forms include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants, and the like.
  • solutions of the compounds of the present invention in a sterile aqueous solution aqueous propylene glycol, aqueous vitamin E or sesame oil or peanut oil may be used.
  • aqueous solutions should be suitably buffered if necessary, and the liquid diluent should initially be isotonic with sufficient saline or glucose.
  • Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed can all be readily obtained by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers are lower alkyl ethers of lactose, clay, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • Formulations of the present invention suitable for oral administration may each be presented as discrete units, such as capsules or tablets, containing a predetermined amount of the active ingredient and containing suitable excipients.
  • the orally administrable formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
  • the preparation When the solid carrier is used for oral administration, the preparation may be in the form of tablets, for example, in hard gelatine capsules, in the form of powders or pellets, or in the form of trochinose lozenges.
  • the amount of solid carrier may vary, but will generally be from about 25 mg to about 1 g.
  • the preparation When a liquid carrier is used, the preparation may be in the form of a syrup, an emulsion, a soft gelatin capsule or a sterile injectable solution, for example an aqueous or nonaqueous liquid suspension or solution.
  • Tablets may be prepared by mixing the active ingredient with conventional excipients and / or diluents and then compressing the mixture in a conventional tablet machine.
  • adjuvants or diluents include corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gum and the like. Any other adjuvants or additives generally used for purposes such as coloring, flavoring and preserving may be used, but these are those which are miscible with the active ingredients.
  • the compounds of the present invention are administered as unit dosage forms containing cholinesterase inhibitor and scopolamine butyl bromide in an amount of about 1 mg to 100 mg, each.
  • the unit dose of scopolamine butyl bromide is 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg
  • the unit dose of the cholinesterase inhibitor is 1 mg, 2 mg, 5 mg, 10 mg, 20 mg or 25 mg.
  • the degenerative neurodegenerative diseases of the present invention are useful for the treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, immune system abnormal brain dysfunction, progressive neurodegenerative disease, metabolic brain disease, Dementia due to cerebral hemorrhage, but not limited to, diseases caused by degeneration of the central nervous system.
  • neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, immune system abnormal brain dysfunction, progressive neurodegenerative disease, metabolic brain disease, Dementia due to cerebral hemorrhage, but not limited to, diseases caused by degeneration of the central nervous system.
  • a " therapeutically effective amount " of a compound in the present invention means an amount sufficient to cure, alleviate or partially delay the clinical manifestations of a given disease and complications thereof in therapeutic intervention involving administration of the compound.
  • An amount sufficient to achieve this is defined as a " therapeutically effective amount ".
  • the quantities effective for each purpose will vary depending on the severity of the disease or injury, as well as the body weight and overall condition of the subject.
  • the terms " treating " and " treating &quot refer to the management and care of a patient for the purpose of preventing a condition, e.g., a disease or disorder.
  • the term encompasses the full range of treatment for any condition for which the patient is suffering, e. G., Relieving the symptoms or complications, delaying / delaying the progression of the condition, or administering the active compound to heal or eliminate the condition .
  • the patient to be treated is preferably a mammal, particularly a human.
  • sustained release formulations for the treatment of neurodegenerative disorders of the present invention not only significantly reduce the adverse effects of the central nervous system due to digestive system adverse effects or sudden increase in blood concentration inevitably caused by oral administration of choline esterase inhibitors, It is possible to maintain an effective blood concentration and thus to provide an agent effective for the treatment of highly degenerative neurological diseases or cognitive diseases.
  • scopolamine butylbromide used in the present invention has an advantage that it acts only in the small intestine mucosa and is not absorbed into the body, thereby minimizing the burden on the stomach.
  • combination formulation or sustained-release preparation of the present invention can be applied as a composition for relieving hangover, since it has the effect of eliminating digestive-related abnormalities such as swelling and vomiting without causing side effects of the central nervous system.
  • FIG. 1 is a schematic view showing the structure of a sustained-release preparation according to an embodiment of the present invention.
  • FIG. 1 shows the structure of a sustained release formulation according to one embodiment of the present invention.
  • the sustained-release preparation according to one embodiment of the present invention may be formulated so as to reduce the adverse side effects of acetylcholinesterase inhibitor, and to prevent side effects of scopolamine butyl bromide, Of double - layer structure. More specifically, the immediate-release layer can be rapidly eluted within 30 minutes by using the immediate-release tablets, and the slow-release layer can be slowly eluted for 24 hours using the hydrophilic matrix-type tablets. According to one embodiment of the present invention, the sustained-release preparation can be optimized to be administered once a day by the double-stranded structure as described above.
  • the cholinesterase inhibitor drug acts by increasing the active concentration of the central and peripheral cholines. Therefore, the side effects that are generally observed when the cholines increase may appear.
  • the combination therapy significantly reduced side effects of digestive system such as vomiting and sore throat as compared with the conventional administration of choline esterase inhibitor alone.
  • adverse side effects of the digestive system which occurred more than 50% initially in the conventional single administration method, occurred only in 7% of the examples of the present invention. There were no side effects at all.
  • all 33 patients in the experimental group showed rapid cognitive dysfunction and no other central and peripheral anticholinergic side effects.
  • choline esterase inhibitors such as donepezil alone at a high dose (23 mg / day) is more effective in improving behavioral and cognitive impairment than low doses (10 mg / day), but it is also effective in reducing digestive disorders such as nausea, vomiting, diarrhea, There are serious side effects.
  • Table 1 when the combination administration method of the present invention is applied, even when a low-dose choline esterase inhibitor is used, no adverse effects such as deterioration of cognitive function are produced at all, The use of inhibitors can also significantly reduce adverse gastrointestinal side effects such as vomiting and tingling, which can be effective in treating highly degenerative neurological or cognitive diseases.

Abstract

The present invention relates to a complex formulation composition for treatment of a neurodegenerative disease. More specifically, the present invention relates to a pharmaceutical composition for treatment of a neurodegenerative disease, the pharmaceutical composition containing a cholinesterase inhibitor, scopolamine butyl bromide, and a pharmaceutically acceptable salt thereof, and to a sustained-release preparation thereof. A sustained-release formation for treatment of a neurodegenerative disease of the present invention does not only remarkably reduce digestive system adverse effects inevitably caused by oral administration of a choline esterase inhibitor or central nervous system adverse effects due to a rapid increase in blood level, but can also maintain the effective blood level of a drug over a long period of time, and thus can provide a preparation, which is effective in the treatment of a high degree of neurodegenerative disease or cognitive disease. Furthermore, the complex formulation composition or sustained-release preparation of the present invention has an effect of solving digestive system abnormal symptoms, such as nausea and vomiting, while causing no central nervous system adverse effects, and thus can be applied as a composition for hangover relief.

Description

퇴행성 신경질환 치료용 복합 제형 조성물Composition formulation composition for the treatment of neurodegenerative diseases
본 발명은 퇴행성 신경질환 치료용 복합 제형 조성물에 관한 것으로서, 보다 상세하게 본 발명은 콜린에스터라제 저해제, 스코폴라민 부틸브로마이드 및 이의 약학적으로 허용 가능한 염을 포함하는 퇴행성 신경질환 치료용 약학적 조성물 및 이의 서방형 제제에 관한 것이다.The present invention relates to a combination formulation for the treatment of neurodegenerative disorders, and more particularly to a composition for the treatment of neurodegenerative disorders of the degenerative nature comprising cholinesterase inhibitor, scopolamine butyl bromide and a pharmaceutically acceptable salt thereof. Compositions and sustained release formulations thereof.
치매(dementia)는 퇴행성 뇌질환의 일종으로서 기억상실, 지능의 퇴보, 성격의 변화, 행동이상 등의 복합 인지장애가 특징인 증후군을 의미한다. 이 증상은 퇴행성 질환을 유발시키는 중추신경계의 신경세포가 서서히 사멸하여 신경회로망에 비가역적인 기능장애를 초래하게 되고, 결국에는 해당 인체 기능의 영구적인 손실을 초래하게 된다. Dementia is a type of degenerative brain disease that is characterized by a complex cognitive disorder characterized by memory loss, degenerative changes in intelligence, changes in personality, and behavioral disorders. This symptom is a gradual depletion of neurons in the central nervous system that cause degenerative diseases, resulting in irreversible dysfunctions in the neural network and ultimately leading to permanent loss of the human function.
치매의 원인에 대해서는 완전하게 규명하지 못한 상태이며, 다양한 병인학적, 병태생리학적 요소를 가지고 있기 때문에 단독으로 투여하는 치매 치료제는 없는 실정이다. 그러나 치매 환자들의 뇌에서 정상적인 사람보다 신경전달 물질인 아세틸콜린(acetylcholine, ACh)을 합성하는 콜린아세틸트랜스퍼라제(choline acetyltransferase, ChAT)가 20 ~ 30%로 감소된 것으로 알려졌으며, 이로 인해 아세틸콜린 농도가 16 ~ 30% 정도 감소하는 것으로 알려져 있다. 이러한 사실로부터 간접적인 치료방법으로서 아세틸콜린을 가수분해하는 효소인 콜린에스터라제(choline esterase, ChE)를 억제하는 저해제를 이용한 약물이 개발되었다.The cause of dementia has not been completely elucidated, and there are no treatments for dementia that are administered alone because of various pathologic and pathophysiological factors. However, choline acetyltransferase (ChAT), which synthesizes acetylcholine (ACh), a neurotransmitter, has been reported to be reduced to 20-30% in the brains of patients with dementia, Is reduced by 16 ~ 30%. From this fact, a drug using an inhibitor that inhibits choline esterase (ChE), an enzyme that hydrolyzes acetylcholine, has been developed as an indirect treatment method.
콜린에스터라제는 아세틸콜린에스터라제(acetylcholinesterase, AChE)와 부틸콜린에스터라제(butylcholinesterase, BuChE)의 두 가지 형태를 갖는다. 상기의 아세틸콜린에스터라제는 체내 부교감 신경의 활성을 매개하는 신경전달물질들 중의 하나인 아세틸콜린을 콜린과 아세테이트로 가수분해하는 효소로서, 소포체 막에서 형성되어 세포막으로 이동하여 그 기능을 수행한다. 상기의 효소는 콜린 신경과 그 주위, 특히 근신경 접합부에 가장 많이 분포되어 있고, 혈장, 간 및 다른 조직에서도 발견되는 중요한 효소이다.Choline esterase has two forms: acetylcholinesterase (AChE) and butylcholinesterase (BuChE). The above-mentioned acetylcholine esterase is an enzyme that hydrolyzes acetylcholine, which is one of neurotransmitters that mediate the activity of parasympathetic nerves in the body, into choline and acetate, and is formed in the endoplasmic reticulum membrane and moves to the cell membrane to perform its function . These enzymes are most widely distributed in the cholinergic nerve and its surroundings, especially in the muscle nerve junction, and are important enzymes found in plasma, liver and other tissues.
현재 치매 치료제로 사용되고 있는 물질은 아세틸콜린에스터라제 저해제가 대부분이며, 아세틸콜린에스터라제 및 부틸콜린에스터라제 저해 작용을 동시에 하는 약물도 있다. 그 예로 도네페질(Donepezil), 리바스티그민(Rivastigmine), 갈란타민(Galantamine), 타크린(Tacrine) 등이 이에 속한다. 상기 약물들은 아세틸콜린에스터라제 및/또는 부틸콜린에스터라제를 가역적으로 억제하는 효능을 지닌 것으로서, 이를 통해 아세틸콜린이 정상인에 비해 저하되어 있는 알츠하이머성 치매 환자의 뇌 속에 아세틸콜린을 증가시켜 콜린 작동성 신경을 활성화시키고, 결과적으로 치매 증상을 완화 또는 지연시키는 작용을 한다. Currently, acetylcholinesterase inhibitors are the most commonly used drugs for the treatment of dementia, and some drugs simultaneously inhibit acetylcholinesterase and butylcholinesterase inhibitors. Examples include Donepezil, Rivastigmine, Galantamine, Tacrine and the like. These drugs have the ability to reversibly inhibit acetylcholine esterase and / or butylcholinesterase, thereby increasing acetylcholine in the brain of a patient suffering from Alzheimer ' s Dementia, Activates the nervous system and, as a result, alleviates or slows down the symptoms of dementia.
그러나 이러한 콜린에스터라제 저해제 약물은 알츠하이머성 치매를 예방 또는 치료하는 효과가 있는 것은 아닐 뿐만 아니라, 경구제로서의 부작용이 심하다는 문제점이 있다. 특히 아세틸콜린에스터라제 저해제의 경구 투여 시 간 기능 장애, 울렁거림, 구역, 구토, 설사, 복통과 같은 소화기계 장애 등 부작용에 대한 보고가 있다. 상기 부작용이 일어나는 원인은 일반적으로 경구제는 간장으로의 일차 통과 효과를 회피하는 것이 불가능하고, 그 결과 간 기능에 영향을 주기 쉬우며, 소화관 내에서 고농도로 존재하여 소화관에서 부작용이 나타나기 쉽기 때문이다. 또한, 상기 약물의 경구 투여 후 도달하는 최대 혈중농도와 24시간 경과 후 혈중농도의 비가 크기 때문에 부작용이 나타나는 농도까지 혈중농도를 도달시키지 않으면서 장기간에 걸쳐 치료효과를 유지하기 어렵다는 문제가 있다. 현재까지 이와 같은 문제점을 해결하기 위해서 일반적으로 약물을 저용량으로 오랫동안 투여하는 방법이 사용되었으며, 리바스티그민의 경우 경피 투여용 제형이 개발되었다. 그러나 패치 제형의 특성 상 피부에 자극을 주거나 손상을 일으킬 수 있고, 치매 환자가 혼자 붙이는 데 어려움이 있으며, 외형상으로 패치가 노출되는 단점이 있어 여전히 치매 약물의 부작용을 줄이기 위한 새로운 제형의 개발이 필요한 실정이다.However, such a cholinesterase inhibitor drug is not only effective in preventing or treating Alzheimer's dementia, but also has a serious side effect as an oral agent. In particular, oral administration of acetylcholinesterase inhibitors has been reported to cause side effects such as liver dysfunction, sneezing, digestive tract disorders such as nausea, vomiting, diarrhea and abdominal pain. The cause of such side effects is that it is generally impossible to avoid the primary transit effect to the liver, and as a result, it is easy to affect the liver function, and it is present in high concentration in the digestive tract, and side effects are likely to appear in the digestive tract . In addition, there is a problem that it is difficult to maintain the therapeutic effect over a long period of time without reaching the concentration at which the side effects occur, because the ratio of the maximum blood concentration reached after oral administration of the drug to the blood concentration after 24 hours is large. In order to solve such problems, a method of administering a drug at a low dose for a long time has been generally used, and a formulation for transdermal administration has been developed in the case of rivastigmine. However, due to the nature of the patch formulation, it may cause irritation or damage to the skin, it is difficult for the dementia patient to attach alone, and there is a drawback that the patch is exposed to the external shape, so that the development of a new formulation to reduce the side effects of the dementia drug It is necessary.
부스코판(Buscopan)으로 잘 알려진 스코폴라민 부틸브로마이드(scopolamine butylbromide)는 항콜린성 작용으로 진경 효과를 가지는 약물이다. 통증 자체를 없애주는 기전은 아니지만 과잉활성된 평활근을 진정시켜 통증 유발 원인을 가라앉히는 역할을 하여, 경련성 복통, 생리통, 소화기계 활동 이상 등 여러 질환에 쓰일 수 있다. 또한, 스코폴라민 부틸부로마이드의 4가 암모늄이 전하를 띄기 때문에 뇌혈관장벽(Blood Brain Barrier, BBB)를 통과하지 않으므로 중추신경계(CNS) 부작용이 거의 없다는 장점이 있다. 그러나 아직까지 치매용 약물과 병용 투여된 사례는 보고된 바 없다.Scopolamine butylbromide, also known as Buscopan, is a drug that has an anticholinergic action and has an antimicrobial effect. Although it is not a mechanism to eliminate pain itself, it can calm the overactive active smooth muscle to calm the cause of pain, and it can be used for various diseases such as spastic cramps, menstrual cramps, and digestive system abnormalities. In addition, since quaternary ammonium of scopolamine butylbromide is charged, it does not pass through the blood-brain barrier (BBB), so that it has an advantage that there is almost no side effect of the central nervous system (CNS). However, there have been no reports of co-administration with dementia drugs.
이에 본 발명자들은, 콜린에스터라제 저해제의 부작용을 줄이면서 오랫동안 약물의 효과를 지속시킬 수 있는 방법을 개발하기 위해 예의 노력한 결과, 본 발명을 완성하였다.Accordingly, the present inventors have made intensive efforts to develop a method for sustaining the effect of the drug for a long time while reducing the side effects of the choline esterase inhibitor, and have completed the present invention.
본 발명의 목적은 퇴행선 신경질환 치료에 사용되는 콜린에스터라제 저해제의 부작용을 해소하면서 동시에 지속적인 약물 방출 농도를 달성할 수 있는 약학적 조성물을 제공하고자 하는 것이다.It is an object of the present invention to provide a pharmaceutical composition which can solve the side effect of the choline esterase inhibitor used in the treatment of the regression line neurological disease and achieve the continuous drug release concentration at the same time.
본 발명의 또 다른 목적은 콜린에스터라제 저해제 및 스코폴라민 부틸브로마이드를 포함하는 퇴행성 신경질환 치료용 서방형 제제를 제공하고자 하는 것이다.It is still another object of the present invention to provide a sustained-release preparation for the treatment of neurodegenerative disorders including cholinesterase inhibitor and scopolamine butyl bromide.
본 발명은 상술한 문제점을 해결하기 위한 것으로, 콜린에스터라제 저해제, 스코폴라민 부틸브로마이드 및 이의 약학적으로 허용 가능한 염을 포함하는 퇴행성 신경질환 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for treating a degenerative neurological disease comprising a cholinesterase inhibitor, scopolamine butyl bromide and a pharmaceutically acceptable salt thereof, for solving the above-mentioned problems.
또한 본 발명은 콜린에스터라제 저해제 및 스코폴라민 부틸브로마이드를 포함하는 퇴행성 신경질환 치료용 서방형 제제를 제공한다.The present invention also provides a sustained release formulation for treating a degenerative neurological disease comprising a cholinesterase inhibitor and scopolamine butyl bromide.
본 발명의 서방형 제제는 체내에서 즉시 방출되는 속방층 및 친수성 매트릭스를 포함하여 체내에서 천천히 방출되는 서방층을 포함하는 이중층 구조를 갖는 것을 특징으로 한다.The sustained-release formulation of the present invention is characterized in that it has a double-layer structure including a slow release layer and a slow release layer in the body including a immediate release layer and a hydrophilic matrix.
본 발명에 있어서 상기 속방층은 약물 투여 후 즉시 또는 적어도 1시간 이내에 유효성분을 모두 방출시키는 것을 특징으로 하며, 이러한 목적을 달성하기 위해 당업계에서 확인할 수 있는 약학적으로 허용된 염, 담체 또는 부형제를 포함할 수 있다.In accordance with the present invention, the immediate-release layer is characterized by releasing all active ingredients immediately or at least within one hour after the administration of the drug. In order to achieve this object, a pharmaceutically acceptable salt, carrier or excipient . ≪ / RTI >
본 발명에 있어서 상기 서방층은 약물 투여 후 체내에서 12시간 ~ 36시간에 걸쳐 유효 성분을 서서히 방출시키는 것을 특징으로 하며, 이와 같은 약물 방출 효과를 위해 친수성 매트릭스를 포함한다.In the present invention, the sustained-release layer gradually releases the active ingredient from the body for 12 hours to 36 hours after administration of the drug, and includes a hydrophilic matrix for the drug release effect.
상기 친수성 매트릭스는 서방형 폴리머를 포함할 수 있으며, 상기 서방형폴리머로 HPMC(Hydroxypropyl methylcellulose)를 선택할 수 있으나, 체내에서 12 ~ 36시간 동안 약물을 천천히 방출시킬 수 있는 담체 또는 부형제라면 이에 한정되지 않는다. The hydrophilic matrix may include a sustained-release polymer. The sustained-release polymer may be selected from HPMC (Hydroxypropyl methylcellulose), but is not limited to a carrier or an excipient capable of slowly releasing a drug in the body for 12 to 36 hours .
본 발명자는 아세틸콜린에스터라제 저해제인　도네페질과 스코폴라민 부틸브로마이드의 병합 사용이 뇌 내 아세틸콜린 수준을 증가시킴과 동시에 소화계통의 부작용인 울렁거림, 복통과 같은 증상이 현저히 감소하는 것을 확인하여 본 발명을 완성하였다. The inventors of the present invention found that the combined use of acetylcholinesterase inhibitors donepezil and scopolamine butyl bromide increased the level of acetylcholine in the brain, and at the same time, the symptoms such as sore throat and abdominal pain, which are side effects of the digestive system, Thereby completing the present invention.
본 발명의 또 다른 구현예는 퇴행성 신경 질환 치료 방법에 관한 것으로서, 상기 질환을 가진 환자에게 콜린에스터라제 저해제와 스코폴라민 부틸브로마이드를 복합 투여하는 것을 포함한다. Another embodiment of the present invention relates to a method for treating a neurodegenerative disease, comprising administering to a patient having the disease a combined administration of a cholinesterase inhibitor and scopolaminebutyl bromide.
본 발명의 상기 콜린에스터라제 저해제는 아세틸콜린에스터라제 저해제 또는 부틸콜린에스터라제 저해제일 수 있으며, 구체적으로 도네페질(donepezil), 리바스티그민(rivastigmin), 갈란타민(galantamine), 미모페질(mimopezil), 라도스티길(ladostigil), 후페르진(huperzine) 및 타크린(tacrine)으로 이루어진 군에서 하나 이상이 선택될 수 있으나, 이에 한정되지 않는다.The cholinesterase inhibitor of the present invention may be an acetylcholine esterase inhibitor or a butylcholinesterase inhibitor and specifically includes donepezil, rivastigmin, galantamine, but are not limited to, at least one selected from the group consisting of mimopezil, ladostigil, huperzine, and tacrine.
본 발명의 상기 약학적으로 허용 가능한 염들은 무독성인 산들의 산 부가염이다. 상기 염들은 유기산, 예를 들어 말레산, 푸마르산, 벤조산, 아스코르브산, 숙신산, 옥살산, 비스-메틸렌살리실산, 메탄설폰산, 에탄디설폰산, 아세트산, 프로피온산, 타르타르산, 살리실산, 시트르산, 글루콘산, 젖산, 말산, 만델산, 신남산, 시트라콘산, 아스파르트산, 스테아르산, 팔미트산, 이타콘산, 글리콜산, p-아미노벤조산, 글루탐산, 벤젠설폰산, 테오필린 아세트산으로부터 만들어진 염들, 그리고 8-할로테오필린, 예를 들어 8-브로모테오필린을 포함한다. 상기 염들은 또한 무기염, 예를 들어 염산, 브롬화수소산, 황산, 설팜산, 인산 및 질산으로부터 만들어질 수 있다.The pharmaceutically acceptable salts of the present invention are acid addition salts of non-toxic acids. The salts may be formed with organic acids such as, for example, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, Salts formed from malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p- aminobenzoic acid, glutamic acid, benzenesulfonic acid, theophylline acetic acid, , E. G. 8-bromo theophylline. The salts may also be made from inorganic salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid.
콜린에스터라제 저해제와 스코폴라민 부틸브로마이드의 병합 투여는 동시 투여의 형태를 취할 수 있다. 이러한 구현예에서, 콜린에스터라제 저해제와 스코폴라민 부틸브로마이드는 환자에게 본질적으로 동시에 두 유효성분을 모두 포함하는 하나의 투여형의 형태로 투여되거나, 또는 별도의 투여형들, 즉 콜린에스터라제 저해제를 포함하는 제1 투여형과　스코폴라민 부틸브로마이드를 포함하는 제2 투여형의 형태로 투여된다.The combined administration of the cholinesterase inhibitor and scopolaminebutyl bromide may take the form of a co-administration. In this embodiment, the cholinesterase inhibitor and scopolaminebutyl bromide are administered to the patient in the form of one dosage form containing both active ingredients at essentially the same time, or in separate dosage forms, A second dosage form comprising scopolamine butyl bromide, and a first dosage form comprising an inhibitor of < RTI ID = 0.0 >
대안적으로, 콜린에스터라제 저해제와 스코폴라민 부틸브로마이드의 병합 투여는 두 유효성분의 투여 간 시차를 포함한다. 이러한 구현예에서, 콜린에스터라제 저해제 또는 스코폴라민 부틸브로마이드 중 어느 하나가 처음에 투여될 수 있다. 실시예에 나타낸 데이터에 의해 증명되는 바와 같이, 콜린에스터라제 저해제와 스코폴라민 부틸브로마이드　간 상승 효과가 존재한다. 상기 상승 효과는 콜린에스터라제 저해제와 스코폴라민 부틸브로마이드　모두 약리학적 유효량이 체내에 동시에 존재하는지에 따라서 달라진다. 이로부터 콜린에스터라제 저해제와 스코폴라민 부틸브로마이드의 투여 사이에 나타나는 시차의 상한치를 부여한다. 실제로 투여될 2 개의 화합물들 중 첫 번째 화합물의 반감기에 대해 약 2 구간을 초과하는 간격을 두고 두 번째 약물을 투여한다면 상승 효과는 떨어질 가능성이 있다. 본원의 내용 중 “반감기”는 약학적으로 활성인 성분의 혈장 수준이 해당 성분의 처음 값의 50%에 도달하는데 필요한 시간이다.Alternatively, the combined administration of the cholinesterase inhibitor and scopolaminebutyl bromide involves the disparity between the administration of the two active ingredients. In this embodiment, either the choline esterase inhibitor or scopolamine butyl bromide may be administered initially. As demonstrated by the data presented in the examples, there is a synergistic effect between the cholinesterase inhibitor and scopolamine butyl bromide. The synergistic effect depends on whether a pharmacologically effective amount of both the cholinesterase inhibitor and scopolaminebutyl bromide is present in the body at the same time. This gives the upper limit of the time difference between administration of the cholinesterase inhibitor and scopolaminebutyl bromide. If the second drug is administered at intervals exceeding about 2 intervals for the half-life of the first of the two compounds to be actually administered, the synergistic effect is likely to decline. The term " half-life " herein is the time required for the plasma level of the pharmaceutically active ingredient to reach 50% of the initial value of the ingredient.
본원 명세서의 실시예에서 입증된 바와 같이, 콜린에스터라제 저해제로서도네페질과 스코폴라민 부틸브로마이드의 병합 투여는 뇌 내 아세틸콜린 수준을 증가시키고, 상승 효과를 일으킨다. 또한, 도네페질 뿐만 아니라 다른 콜린에스터라제 저해제들거과 스코폴라민 부틸브로마이드의 병용에 의해서도 유사하게 나타나는 특성을 확인할 수 있었다.As demonstrated in the examples herein, the combined administration of donepezil and scopolaminebutyl bromide as cholinesterase inhibitors increases the level of acetylcholine in the brain and produces a synergistic effect. In addition, similar characteristics were observed by the combination of donepezil and other cholinesterase inhibitors and scopolaminebutyl bromide.
콜린에스터라제 저해제에 대하여 승인된 유지 투여량(maintenance dosage)(FDA)은, 초기 용량 5 ㎎일 때 1 일 10 ㎎ 또는 23 ㎎이다. 따라서 하나의 구현예에서, 본 발명은 통상적으로 1 일 1 ㎎, 5 ㎎, 15 ㎎ 또는 20 ㎎으로 투여되는 스코폴라민 부틸브로마이드와 함께,　도네페질이 1 일 1 ㎎ 이상, 예를 들어 2 ㎎ 이상, 예를 들어 5 ㎎ 이상, 예를 들어 10 ㎎ 이상 투여되는 것에 관한 것이다. 구체적인 예들로서는 1 일 5 ㎎ 내지 20 ㎎, 예를 들어 10 ㎎ 또는 15 ㎎의 스코폴라민 부틸브로마이드와 함께, 5 ㎎ 내지 10 ㎎의　도네페질을 포함한다. 구체적인 예들로서는 1 일 5 ㎎ 내지 20 ㎎, 예를 들어 10 ㎎ 또는 15 ㎎의 스코폴라민 부틸브로마이드와 함께, 10 ㎎ 내지 25 ㎎의　도네페질, 예를 들어 23 ㎎의　도네페질을 포함한다.The approved maintenance dosage (FDA) for the choline esterase inhibitor is 10 mg or 23 mg per day at an initial dose of 5 mg. Thus, in one embodiment, the present invention provides a method of treating a donepezil, comprising scophoramine butyl bromide administered at 1 mg, 5 mg, 15 mg or 20 mg per day, wherein the donepezil is at least 1 mg per day, for example, 2 mg Or more, for example, 5 mg or more, for example, 10 mg or more. Specific examples include 5 mg to 10 mg of donepezil, together with 5 mg to 20 mg of scopolamine butyl bromide, for example 10 mg or 15 mg per day. Specific examples include 10 mg to 25 mg of donepezil, for example 23 mg of donepezil, together with 5 mg to 20 mg of scopolamine butyl bromide per day, for example 10 mg or 15 mg.
본 발명에 사용되는 활성 약학 성분들, 즉 스코폴라민 부틸브로마이드와 콜린에스터라제 저해제는 단일 용량 또는 복수 용량으로, 순수한 화합물들로서 단독 투여되거나 약학적으로 허용 가능한 담체들 또는 부형제들과 함께 투여될 수 있다. 본 발명에 따른 약학 조성물은 약학적으로 허용 가능한 담체 또는 희석제 뿐만 아니라 통상의 기법들, 예를 들어 문헌[Remington: The Science and Practice of Pharmacy, 21 Edition, Hauber, Ed., Lippincott Williams & Wilkins, 2006]에 개시된 것에 따른 임의의 기타 다른 공지된 보조제들 및 부형제들과 함께 제형화될 수 있다.The active pharmaceutical ingredients used in the present invention, namely scopolamine butylbromide and choline esterase inhibitor, may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, either as single compounds or as multiple doses, as pure compounds . The pharmaceutical compositions according to the present invention may be formulated with pharmaceutically acceptable carriers or diluents as well as conventional techniques such as those described in Remington: The Science and Practice of Pharmacy, 21 Edition, Hauber, Ed., Lippincott Williams & , ≪ / RTI > and other excipients and excipients.
본 발명의 약학적 조성물은 특히 임의의 적당한 경로, 예를 들어 경구, 직장, 비강, 폐, 국소(협측 및 설하를 포함함), 경피, 낭내, 복강내, 질내 및 비경구(피하, 근육내, 척추강내, 정맥내 및 진피내) 경로에 의한 투여용으로서 제형화될 수 있으며, 경구 경로가 바람직하다. 바람직한 경로는 치료될 피험체의 전체적인 상태와 연령, 치료될 병태의 본질, 그리고 선택된 활성 성분에 따라 달라질 수 있음이 이해될 것이다.The pharmaceutical compositions of the present invention may be used in the manufacture of a medicament for the treatment and / or prophylaxis of the diseases or disorders mediated by any particular route, for example, oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, , Intra-vertebral, intravenous and intradermal) routes, and oral routes are preferred. It will be appreciated that the preferred route may vary depending upon the overall condition and age of the subject to be treated, the nature of the condition to be treated, and the active ingredient selected.
경구 투여용 약학 조성물은 고체 투여형, 예를 들어 캡슐, 정제, 드라제, 알약, 로젠지, 분말 및 과립을 포함한다. 적절한 경우, 상기 고체 투여형은 코팅이 있는 상태로 제조될 수 있다. 경구 투여용 액체 투여형들은 용액, 에멀젼, 현탁액, 시럽 및 엘릭시르를 포함한다.Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders, and granules. Where appropriate, the solid dosage forms may be prepared with the coatings thereon. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
비경구 투여용 약학 조성물은 멸균 수성 및 비수성 주사 용액, 분산액, 현탁액 또는 에멀젼뿐만 아니라, 사용전 멸균 주사 용액 또는 분산액 중에 재구성될 멸균 분말을 포함한다.Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injection solutions, dispersions, suspensions or emulsions, as well as sterile injectable solutions or sterile powders to be reconstituted in a dispersion prior to use.
기타 다른 적당한 투여형들로서는 좌제, 스프레이, 연고, 크림, 겔, 흡입제, 진피 패치제, 임플란트 등을 포함한다.Other suitable dosage forms include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants, and the like.
비경구 투여에 있어서, 멸균 수용액, 수성 프로필렌 글리콜, 수성 비타민 E 또는 참기름이나 피넛 오일 중 본 발명의 화합물의 용액이 이용될 수 있다. 이와 같은 수용액들은 필요하다면 적당히 완충되어야 하고, 액체 희석제는 처음에 충분한 염수나 글루코스로 등장성이 되어야 한다. 수용액은 특히 정맥내, 근육내, 피하 및 복강내 투여용으로 적당하다. 이용된 멸균 수성 매질은 모두 당업자들에게 알려진 표준 기법들에 의해 용이하게 얻어질 수 있다.For parenteral administration, solutions of the compounds of the present invention in a sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame oil or peanut oil may be used. Such aqueous solutions should be suitably buffered if necessary, and the liquid diluent should initially be isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed can all be readily obtained by standard techniques known to those skilled in the art.
적당한 약학 담체들로서는 비활성 고체 희석제 또는 충전제, 멸균 수용액 및 다양한 유기 용매를 포함한다. 고체 담체의 예들로서는 락토스, 백토, 수크로스, 사이클로덱스트린, 활석, 젤라틴, 아가, 펙틴, 아카시아, 스테아르산마그네슘, 스테아르산 및 셀룰로스의 저급 알킬 에테르가 있다. 액체 담체의 예들로서는 시럽, 피넛 오일, 올리브 오일, 인지질, 지방산, 지방산 아민, 폴리옥시에틸렌 및 물이 있다. 본 발명에 사용된 화합물과 약학적으로 허용 가능한 담체들의 혼합에 의해 형성된 약학 조성물은 이후 개시된 투여 경로들에 적당한 여러 가지 투여형으로서 용이하게 투여된다.Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers are lower alkyl ethers of lactose, clay, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. The pharmaceutical composition formed by mixing the compound used in the present invention with pharmaceutically acceptable carriers is easily administered as various dosage forms suitable for the administration routes described hereinafter.
경구 투여에 적당한 본 발명의 제형들은 각각 소정량의 활성 성분을 함유하고, 적당한 부형제를 포함할 수 있는 개별 단위들, 예를 들어 캡슐이나 정제로서 제시될 수 있다. 뿐만 아니라, 경구 섭취 가능한 제형들은 분말이나 과립, 수성 또는 비수성 액체 중 용액이나 현탁액, 또는 수중유 또는 유중수 액체 에멀젼의 형태일 수 있다.Formulations of the present invention suitable for oral administration may each be presented as discrete units, such as capsules or tablets, containing a predetermined amount of the active ingredient and containing suitable excipients. In addition, the orally administrable formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
고체 담체가 경구 투여용으로서 사용되는 경우, 제조물은 정제, 예를 들어 경질 젤라틴 캡슐에 담긴 것, 분말이나 펠릿 형태 또는 트로키나 로젠지의 형태일 수 있다. 고체 담체의 양은 다양할 수 있으나, 일반적으로는 약 25 ㎎ 내지 약 1 g일 것이다. 액체 담체가 사용되는 경우, 제조물은 시럽, 에멀젼, 연질 젤라틴 캡슐 또는 멸균 주사액, 예를 들어 수성 또는 비수성 액체 현탁액 또는 용액의 형태일 수 있다.When the solid carrier is used for oral administration, the preparation may be in the form of tablets, for example, in hard gelatine capsules, in the form of powders or pellets, or in the form of trochinose lozenges. The amount of solid carrier may vary, but will generally be from about 25 mg to about 1 g. When a liquid carrier is used, the preparation may be in the form of a syrup, an emulsion, a soft gelatin capsule or a sterile injectable solution, for example an aqueous or nonaqueous liquid suspension or solution.
정제는 활성 성분과 통상의 보조제들 및/또는 희석제들이 혼합된 후 이 혼합물이 통상의 타정기 내에서 압착됨으로써 제조될 수 있다. 보조제 또는 희석제의 예들로서는 옥수수 전분, 감자 전분, 활석, 스테아르산마그네슘, 젤라틴, 락토스, 검 등을 포함한다. 일반적으로 착색, 착향 및 보존 등과 같은 목적으로 사용되는 기타 다른 임의의 보조제들 또는 첨가제들이 사용될 수 있되, 다만 이것들은 활성 성분들과 혼화 가능한 것들이다.Tablets may be prepared by mixing the active ingredient with conventional excipients and / or diluents and then compressing the mixture in a conventional tablet machine. Examples of adjuvants or diluents include corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gum and the like. Any other adjuvants or additives generally used for purposes such as coloring, flavoring and preserving may be used, but these are those which are miscible with the active ingredients.
편리하게, 본 발명의 화합물은 콜린에스터라제 저해제와 스코폴라민 부틸브로마이드를 각각 약 1 ㎎ 내지 100 ㎎의 양으로 함유하는 단위 투여형으로서 투여된다. 특히 콜린에스터라제 저해제의 단위 용량은 1 ㎎, 2 ㎎, 5 ㎎, 10 ㎎, 15 ㎎, 20 ㎎ 또는 25 ㎎이고, 스코폴라민 부틸브로마이드의 단위 용량은 5 ㎎, 10 ㎎, 15 ㎎, 20 ㎎ 또는 25 ㎎일 수 있다. Conveniently, the compounds of the present invention are administered as unit dosage forms containing cholinesterase inhibitor and scopolamine butyl bromide in an amount of about 1 mg to 100 mg, each. In particular, the unit dose of scopolamine butyl bromide is 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg, and the unit dose of the cholinesterase inhibitor is 1 mg, 2 mg, 5 mg, 10 mg, 20 mg or 25 mg.
본 발명의 퇴행성 신경질환은 알츠하이머 질환, 파킨슨 질환, 루게릭 질환, 헌팅톤 질환, 근위축성 측석 경화증, 다발성 경화증, 면역계이상 뇌기능 부전, 진행성　신경퇴행질환, 대사성 뇌질환, 니만-픽병, 뇌 허혈 및 뇌출혈로 인한 치매로 이루어진 군으로부터 선택될 수 있으나, 중추신경계의 퇴행으로 인하여 발생하는 질환이라면 이에 한정되지 않는다. The degenerative neurodegenerative diseases of the present invention are useful for the treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, immune system abnormal brain dysfunction, progressive neurodegenerative disease, metabolic brain disease, Dementia due to cerebral hemorrhage, but not limited to, diseases caused by degeneration of the central nervous system.
본 발명에 있어서 화합물의 “치료학적 유효량”이란, 상기 화합물의 투여를 포함하는 치료적 개입에 있어서 소정의 질병과 이의 합병증들의 임상 징후들을 치유, 경감 또는 부분 지연시키는데 충분한 양을 의미한다. 이를 달성하는데 충분한 양은 “치료학적 유효량”이라 정의된다. 각각의 목적에 효과적인 양들은 질병이나 손상의 중증도, 뿐만 아니라 피험체의 체중 및 전체적인 상태에 따라서 달라질 것이다.A " therapeutically effective amount " of a compound in the present invention means an amount sufficient to cure, alleviate or partially delay the clinical manifestations of a given disease and complications thereof in therapeutic intervention involving administration of the compound. An amount sufficient to achieve this is defined as a " therapeutically effective amount ". The quantities effective for each purpose will vary depending on the severity of the disease or injury, as well as the body weight and overall condition of the subject.
본원에 사용된 용어 “치료” 및 “치료하는 것”이란, 병태, 예를 들어 질병이나 장애가 발생하는 것을 막기 위한 목적으로 환자를 관리하고 돌보는 것을 의미한다. 상기 용어는 환자가 앓고 있는 소정의 병태에 대한 치료의 전 범위, 예를 들어 증상들이나 합병증들을 완화하거나, 병태의 진행을 지연시키고/지연시키거나 병태를 치유 또는 없애기 위한 활성 화합물의 투여를 포함하는 것으로 의도된다. 치료될 환자는 바람직하게 포유동물, 특히 사람이다.As used herein, the terms " treating " and " treating " refer to the management and care of a patient for the purpose of preventing a condition, e.g., a disease or disorder. The term encompasses the full range of treatment for any condition for which the patient is suffering, e. G., Relieving the symptoms or complications, delaying / delaying the progression of the condition, or administering the active compound to heal or eliminate the condition . The patient to be treated is preferably a mammal, particularly a human.
본 발명의 퇴행성 신경질환 치료용 서방형 제형은 콜린에스터라제 저해제의 경구 투여로 인해 불가피하게 나타나는 소화기계 부작용이나 급격한 혈중농도 상승에 따른 중추신경계 부작용을 현저히 감소시킬 뿐만 아니라, 장기간에 걸쳐 약물의 유효 혈중 농도를 유지할 수 있게 되어, 고도의 퇴행성 신경질환 또는 인지증 질환의 치료에 효과적인 제제를 제공할 수 있다. The sustained release formulations for the treatment of neurodegenerative disorders of the present invention not only significantly reduce the adverse effects of the central nervous system due to digestive system adverse effects or sudden increase in blood concentration inevitably caused by oral administration of choline esterase inhibitors, It is possible to maintain an effective blood concentration and thus to provide an agent effective for the treatment of highly degenerative neurological diseases or cognitive diseases.
또한 본 발명에서 사용되는 스코폴라민 부틸브로마이드(scopolamine butylbromide)는 소장 점막에서만 작용하고 몸 안으로 흡수되지 않는 특성이 있어 위장에 주는 부담을 최소화할 수 있는 장점이 있다.In addition, scopolamine butylbromide used in the present invention has an advantage that it acts only in the small intestine mucosa and is not absorbed into the body, thereby minimizing the burden on the stomach.
나아가 본 발명의 복합 제형 조성물 또는 서방형 제제는 중추신경계 부작용을 유발하지 않으면서 울렁거림, 구토와 같은 소화관계 이상 증상을 해소할 수 있는 효과가 있기 때문에 숙취 해소용 조성물로 적용될 수 있다.Furthermore, the combination formulation or sustained-release preparation of the present invention can be applied as a composition for relieving hangover, since it has the effect of eliminating digestive-related abnormalities such as swelling and vomiting without causing side effects of the central nervous system.
도 1은 본 발명의 일실시예에 따른 서방형 제제의 구조를 나타낸 모식도이다.1 is a schematic view showing the structure of a sustained-release preparation according to an embodiment of the present invention.
이하, 실시예를 통하여 본 발명을 더욱 상세하게 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다. Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are merely illustrative of the present invention and that the scope of the present invention is not construed as being limited by these embodiments.
도 1은 본 발명의 일실시예에 따른 서방형 제제의 구조이다. 본 발명의 일실시예에 따른 서방형 제제는 아세틸콜린에스터라제 저해제의 경구 투여 부작용을 줄이기 위해 스코폴라민 부틸브로마이드가 빠르게 흡수되면서 그 효과가 지속되도록 속방층(속효성) 및 서방층(지효성)의 이중충 구조로 구현하였다. 더욱 구체적으로, 상기 속방층은 즉시 방출형 정제를 이용하여 30분 이내로 빠르게 용출되는 형태로, 서방층은 친수성인 매트릭스형 정제를 이용하여 24시간 동안 천천히 용출되는 형태로 구현할 수 있다. 본 발명의 일실시예에 따르면, 상기와 같은 이중충 구조에 의해 1일 1회 투여가 가능하도록 서방형 제제를 최적화할 수 있다. Figure 1 shows the structure of a sustained release formulation according to one embodiment of the present invention. The sustained-release preparation according to one embodiment of the present invention may be formulated so as to reduce the adverse side effects of acetylcholinesterase inhibitor, and to prevent side effects of scopolamine butyl bromide, Of double - layer structure. More specifically, the immediate-release layer can be rapidly eluted within 30 minutes by using the immediate-release tablets, and the slow-release layer can be slowly eluted for 24 hours using the hydrophilic matrix-type tablets. According to one embodiment of the present invention, the sustained-release preparation can be optimized to be administered once a day by the double-stranded structure as described above.
실시예. 콜린에스터라제 저해제와 스코폴라민 부틸브로마이드의 병용 투여 효과 확인Examples. Confirming the concurrent administration of choline esterase inhibitor and scopolaminebutyl bromide
일반적으로, 콜린에스터라제 저해제 약물은 중추 및 말초 콜린의 활성 농도를 증가시켜 작용하게 되기 때문에 일반적으로 콜린이 증가했을 때 나타나는 부작용이 나타날 수 있는 바, 이러한 말초 콜린성 부작용을 줄이기 위하여 본 발명의 조성물을 투여하였다. In general, the cholinesterase inhibitor drug acts by increasing the active concentration of the central and peripheral cholines. Therefore, the side effects that are generally observed when the cholines increase may appear. To reduce such peripheral cholinergic side effects, the composition of the present invention ≪ / RTI >
알츠하이머병 혹은 혈관성 치매로 신경과 의사에게 진단받은 33명의 환자(남자 12명, 여자 21명)에게 콜린에스터라제 저해제(도네페질 또는 갈란타민)와 함께 스코폴라민 부틸브로마이드를 병용 투여하였다. 콜린에스터라제 저해제 용량에 따라 저용량군(n = 18)과 고용량군(n = 15)으로 나누었다. 스코폴라민 부틸브로마이드는 하루에 20 mg씩 1회 복용하거나 10 mg씩 2회 복용하였으며, 3개월 경과 후에 전문의의 관찰 소견으로 결과를 확인하였다. Thirty-three patients (12 males and 21 females) who were diagnosed with Alzheimer's disease or vascular dementia were treated with scopolaminebutyl bromide in combination with a cholinesterase inhibitor (donepezil or galantamine). (N = 18) and high dose (n = 15) groups according to the cholinesterase inhibitor dose. Scopolamine butyl bromide was administered once every 20 mg or twice daily at 10 mg, and after 3 months, the results were confirmed by a specialist observation.
본 실시예의 결과를 하기 [표 1]에 요약하여 나타내었다.The results of this embodiment are summarized in Table 1 below.
[표 1][Table 1]
Figure PCTKR2018009601-appb-I000001
Figure PCTKR2018009601-appb-I000001
그 결과 복합 요법으로 인해 종래 콜린에스터라제 저해제 단독 투여 시에 비해 구토나 울렁거림과 같은 소화기계 부작용이 현저히 감소하였다. 한 번에 높은 농도가 투여되는 고용량군의 경우, 종래 일반적인 단독 투여 방법에서는 초기에 50% 이상에서 발생하던 소화기계 부작용이 본 발명의 실시예에서는 7%에서만 발생하였고, 저용량군에서는 통상적인 소화기계 부작용이 전혀 나타나지 않았다. 아울러 실험군 33명에서 모두 급격한 인지기능 저하나 다른 중추 및 말초형의 항콜린성 부작용이 발견되지 않았다.As a result, the combination therapy significantly reduced side effects of digestive system such as vomiting and sore throat as compared with the conventional administration of choline esterase inhibitor alone. In the case of the high-dose group in which the high concentration is administered at once, adverse side effects of the digestive system, which occurred more than 50% initially in the conventional single administration method, occurred only in 7% of the examples of the present invention. There were no side effects at all. In addition, all 33 patients in the experimental group showed rapid cognitive dysfunction and no other central and peripheral anticholinergic side effects.
이를 통해 본 발명의 병용투여 방법을 통해 콜린에스터라제 저해제의 인지기능 저하와 같은 부작용은 전혀 발생시키지 않으면서, 구토나 울렁거림과 같은 소화기계 부작용을 현저히 감소시킬 수 있다는 점을 확인하였다.Thus, it was confirmed through the combined administration of the present invention that side effects such as depression of cognitive function of choline esterase inhibitor were not generated at all, and digestive system adverse effects such as vomiting and slackening could be significantly reduced.
도네페질과 같은 콜린에스터라제 저해제를 고용량(23mg/day)으로 단독으로복용하는 경우 저용량(10mg/day)보다 행동 및 인지력 장애 개선에 효과적이이지만, 구역, 구토, 설사, 복통 등과 같은 소화기계 부작용이 심한 문제가 있다. 그러나, 표 1에서 나타내는 바와 같이, 본 발명의 병용투여 방법을 적용하는 경우, 저용량의 콜린에스터라제 저해제를 사용하는 경우에도 인지기능 저하와 같은 부작용은 전혀 발생시키지 않으며, 고용량의 콜린에스터라제 저해제를 사용하는 경우에도 구토나 울렁거림과 같은 소화기계 부작용을 현저히 감소시킬 수 있는 바, 고도의 퇴행성 신경질환 또는 인지증 질환 치료에 효과적일 수 있다.Taking choline esterase inhibitors such as donepezil alone at a high dose (23 mg / day) is more effective in improving behavioral and cognitive impairment than low doses (10 mg / day), but it is also effective in reducing digestive disorders such as nausea, vomiting, diarrhea, There are serious side effects. However, as shown in Table 1, when the combination administration method of the present invention is applied, even when a low-dose choline esterase inhibitor is used, no adverse effects such as deterioration of cognitive function are produced at all, The use of inhibitors can also significantly reduce adverse gastrointestinal side effects such as vomiting and tingling, which can be effective in treating highly degenerative neurological or cognitive diseases.

Claims (11)

  1. 콜린에스터라제 저해제, 스코폴라민 부틸브로마이드 및 이의 약학적으로 허용 가능한 염을 포함하는 퇴행성 신경질환 치료용 약학적 조성물.A pharmaceutical composition for the treatment of degenerative neurological diseases comprising a cholinesterase inhibitor, scopolamine butyl bromide, and a pharmaceutically acceptable salt thereof.
  2. 제1항에 있어서,The method according to claim 1,
    상기 콜린에스터라제 저해제는 아세틸콜린에스터라제 저해제 또는 부틸콜린에스터라제 저해제인 것을 특징으로 하는 퇴행성 신경질환 치료용 약학적 조성물.Wherein the choline esterase inhibitor is an acetylcholine esterase inhibitor or a butylcholine esterase inhibitor.
  3. 제1항에 있어서,The method according to claim 1,
    상기 콜린에스터라제 저해제는 도네페질(donepezil), 리바스티그민(rivastigmin), 갈란타민(galantamine), 미모페질(mimopezil), 라도스티길(ladostigil), 후페르진(huperzine) 및 타크린(tacrine)으로 이루어진 군에서 선택되는 하나 이상인 것을 특징으로 하는 퇴행성 신경질환 치료용 약학적 조성물.The cholinesterase inhibitor may be selected from the group consisting of donepezil, rivastigmin, galantamine, mimopezil, ladostigil, huperzine and tacrine ). ≪ / RTI > A pharmaceutical composition for the treatment of neurodegenerative diseases, wherein the compound is at least one selected from the group consisting of
  4. 제1항에 있어서,The method according to claim 1,
    상기 퇴행성 신경질환은 알츠하이머 질환, 파킨슨 질환, 루게릭 질환, 헌팅톤 질환, 근위축성 측석 경화증, 다발성 경화증, 면역계이상 뇌기능 부전, 진행성　신경퇴행질환, 대사성 뇌질환, 니만-픽병, 뇌 허혈 및 뇌출혈로 인한 치매로 이루어진 군으로부터 선택되는 것을 특징으로 하는　퇴행성 신경질환 치료용 약학적 조성물.The degenerative neurological diseases are selected from the group consisting of Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, immune system dysfunction, progressive neurodegenerative disease, metabolic brain disease, And dementia caused by dementia caused by dementia.
  5. 콜린에스터라제 저해제 및 스코폴라민 부틸브로마이드를 포함하는 퇴행성 신경질환 치료용 서방형 제제.A cholinesterase inhibitor and scopolamine butyl bromide, for the treatment of degenerative neurological disorders.
  6. 제5항에 있어서,6. The method of claim 5,
    상기 콜린에스터라제 저해제는 아세틸콜린에스터라제 저해제 또는 부틸콜린에스터라제 저해제인 것을 특징으로 하는 퇴행성 신경질환 치료용 서방형 제제.Wherein the cholinesterase inhibitor is an acetylcholine esterase inhibitor or a butylcholinesterase inhibitor.
  7. 제5항에 있어서,6. The method of claim 5,
    상기 콜린에스터라제 저해제는 도네페질(donepezil), 리바스티그민(rivastigmin), 갈란타민(galantamine), 미모페질(mimopezil), 라도스티길(ladostigil), 후페르진(huperzine) 및 타크린(tacrine)으로 이루어진 군에서 선택되는 하나 이상인 것을 특징으로 하는 퇴행성 신경질환 치료용 서방형 제제.The cholinesterase inhibitor may be selected from the group consisting of donepezil, rivastigmin, galantamine, mimopezil, ladostigil, huperzine and tacrine ). ≪ / RTI > A sustained release formulation for the treatment of neurodegenerative disorders.
  8. 제5항에 있어서,6. The method of claim 5,
    상기 퇴행성 신경질환은 알츠하이머 질환, 파킨슨 질환, 루게릭 질환, 헌팅톤 질환, 근위축성 측석 경화증, 다발성 경화증, 면역계이상 뇌기능 부전, 진행성신경퇴행질환, 대사성 뇌질환, 니만-픽병, 뇌 허혈 및 뇌출혈로 인한 치매로 이루어진 군으로부터 선택되는 것을 특징으로 하는　퇴행성 신경질환 치료용 서방형 제제.The degenerative neurological diseases are selected from the group consisting of Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, immune system dysfunction, progressive neurodegenerative disease, metabolic brain disease, Dementia caused by dementia caused by dementia.
  9. 제5항에 있어서,6. The method of claim 5,
    상기 서방형 제제는 체내에서 즉시 방출되는 속방층; 및 Wherein the sustained release formulation comprises a immediate-release layer immediately released in the body; And
    친수성 매트릭스를 포함하여 체내에서 천천히 방출되는 서방층을 포함하는 이중층 구조를 갖는 것을 특징으로 하는 퇴행성 신경질환 치료용 서방형 제제.Wherein the sustained-release formulation has a bilayer structure including a sustained-release layer slowly released in the body including a hydrophilic matrix.
  10. 제9항에 있어서,10. The method of claim 9,
    상기 친수성 매트릭스는 서방형 폴리머를 포함하는 것을 특징으로 하는 퇴행성 신경질환 치료용 서방형 제제.Wherein the hydrophilic matrix comprises a sustained-release polymer.
  11. 제10항에 있어서,11. The method of claim 10,
    상기 서방형 폴리머는 HPMC(Hydroxypropyl methylcellulose)인 것을 특징으로 하는 퇴행성 신경질환 치료용 서방형 제제.Wherein the sustained-release polymer is HPMC (Hydroxypropyl methylcellulose).
PCT/KR2018/009601 2017-08-22 2018-08-21 Complex formulation composition for treatment of neurodegenerative disease WO2019039836A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2017-0105978 2017-08-22
KR20170105978 2017-08-22

Publications (2)

Publication Number Publication Date
WO2019039836A2 true WO2019039836A2 (en) 2019-02-28
WO2019039836A3 WO2019039836A3 (en) 2019-04-18

Family

ID=65439032

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2018/009601 WO2019039836A2 (en) 2017-08-22 2018-08-21 Complex formulation composition for treatment of neurodegenerative disease

Country Status (2)

Country Link
KR (1) KR20190021180A (en)
WO (1) WO2019039836A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113880899A (en) * 2020-10-30 2022-01-04 杭州拉林智能科技有限公司 Flavonoid glycoside-organic amine nerve agonist double salt compound and preparation method and application thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1121104B1 (en) * 1998-10-01 2005-01-12 Novartis AG New controlled release oral formulations for rivastigmine
CN1520818A (en) * 2003-02-09 2004-08-18 山东绿叶天然药物研究开发有限公司 Cholinesterase inhibitor pharmaceutical composition for senile dementia
TW201422254A (en) * 2012-11-21 2014-06-16 Ferring Bv Composition for immediate and extended release
US8999393B1 (en) * 2013-01-09 2015-04-07 Edgemont Pharmaceuticals Llc Sustained release formulations of lorazepam
KR101811700B1 (en) * 2016-10-13 2017-12-22 한국유나이티드제약 주식회사 Sustained Release Tablets Containing Levodropropizine and Manufacturing Method for the same

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113880899A (en) * 2020-10-30 2022-01-04 杭州拉林智能科技有限公司 Flavonoid glycoside-organic amine nerve agonist double salt compound and preparation method and application thereof
CN113880899B (en) * 2020-10-30 2023-06-23 杭州拉林智能科技有限公司 Flavonoid glycoside-organic amine nerve agonist double salt compound as well as preparation method and application thereof

Also Published As

Publication number Publication date
KR20190021180A (en) 2019-03-05
WO2019039836A3 (en) 2019-04-18

Similar Documents

Publication Publication Date Title
US9044472B2 (en) Use and composition for treating dementia
JP6226916B2 (en) Pharmaceutical composition
US11419850B2 (en) Combined acetylcholinesterase inhibitor and quaternary ammonium antimuscarinic therapy to alter progression of cognitive diseases
US9084753B2 (en) Uses for quaternary ammonium anticholinergic muscarinic receptor antagonists in patients being treated for cognitive impairment or acute delirium
KR101054248B1 (en) Disease Therapies
US20130172398A1 (en) Combined Acetylcholinesterase Inhibitor and Quaternary Ammonium Antimuscarinic Therapy to Alter Progression of Cognitive Diseases
EP1112067A2 (en) Use of acetylcholinesterase inhibitors for the preparation of pharmaceutical compositions for the treatment of functional and/or organic pain syndromes
WO2019039836A2 (en) Complex formulation composition for treatment of neurodegenerative disease
US20120122919A1 (en) Pharmaceutical composition combining tenatoprazole and a histamine h2-receptor antagonist
WO2020080866A1 (en) Use of carbamate compound for preventing, alleviating or treating diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy
CA2411553A1 (en) New use of angiotensin ii antagonists
AU2001274765A1 (en) New use of angiotensin II antagonists
CA2432945C (en) Use of doxylamime succinate and pyridoxine hydrochloride for prophylaxis and treatment of post-surgical vomiting
CA3192987A1 (en) Pharmaceutical combination for the treatment of human hypocholinergic disorders
US20220362202A1 (en) Drug For Treating And Preventing Dementia
EP0868915A1 (en) An anti-spasmodic and antiinflammatory composition containing a NSAID, pentifenone and fenpiverinium
US20050004181A1 (en) Use of anti-emetic for pre and post operative care
KR20230047412A (en) Pain relief itch relief pharmaceutical composition and its application method
JP2024505246A (en) Fixed-dose combination of a cholinesterase inhibitor and a quaternary ammonium antimuscarinic agent for the treatment of neurodegenerative cognitive disorders
CN116635034A (en) Pharmaceutical combination for the treatment of human hypocholinergic disorders
WO2020055739A1 (en) Fumaric acid compositions with increased bioavailability and reduced side effects
EP0934040A1 (en) Method for treating dementia due to aids
MX2008002907A (en) Therapy for the treatment of disease

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18847989

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18847989

Country of ref document: EP

Kind code of ref document: A2